HUMAN REPRODUCTION Glance
Contents 1
Human reproduction
1
1.1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1.1.1
The human male . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1.1.2
The human female . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
1.2.1
Sexual intercourse
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
1.2.2
Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
1.2.3
Birth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
1.2.4
Parental care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
1.3
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
1.4
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
1.2
2
Anatomy
Puberty
4
2.1
Differences between male and female puberty . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4
2.2
Puberty onset . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5
2.2.1
Effects of early and late puberty onset . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5
Physical changes in boys . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6
2.3.1
Testicular size, penis size, fertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6
2.3.2
Morning wood and random or unwanted erections . . . . . . . . . . . . . . . . . . . . . .
6
2.3.3
Foreskin retraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6
2.3.4
Pubic hair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
2.3.5
Body and facial hair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
2.3.6
Voice change and Adam’s apple . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
2.3.7
Male musculature and body shape . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
2.3.8
Body odor and acne . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
Physical changes in girls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
2.4.1
Breast development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
2.4.2
Pubic hair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
2.4.3
Vagina, uterus, ovaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
2.4.4
Menstruation and fertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
2.4.5
Body shape, fat distribution, and body composition . . . . . . . . . . . . . . . . . . . . . .
8
2.4.6
Body odor and acne . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
2.4.7
Other effects of hormonal changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
2.3
2.4
i
ii
CONTENTS 2.5
Variations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
2.5.1
Timing of the onset of puberty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
2.5.2
Genetic inuence and environmental factors . . . . . . . . . . . . . . . . . . . . . . . . .
10
2.5.3
Variations of sequence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
2.5.4
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
Neurohormonal process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
2.6.1
Components of the endocrine reproductive system . . . . . . . . . . . . . . . . . . . . . .
12
2.6.2
Major hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
2.6.3
Endocrine perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
2.6.4
Hormonal changes in boys . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
2.6.5
Hormonal changes in girls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
2.7
Stages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
2.8
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
2.9
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
2.10 Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17
2.11 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17
Male reproductive system
19
3.1
External genital organs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19
3.1.1
Penis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19
3.1.2
Scrotum
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19
Internal genital organs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20
3.2.1
Epididymis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20
3.2.2
Vas deferens
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20
3.2.3
Accessory glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20
3.3
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20
3.4
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21
2.6
3
3.2
4
Scrotum 4.1
22 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22
4.1.1
Innervation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22
4.1.2
Blood supply . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22
4.1.3
Integument . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22
4.1.4
Lymphatic system
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22
4.2.1
Genital homology between sexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22
4.2.2
Scrotal growth and puberty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
23
4.3
Internal structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
23
4.4
Function
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
23
4.5
Clinical signiďŹ cance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24
4.6
Diseases and conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24
4.7
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24
4.2
Structure
Development
CONTENTS
5
4.8
Bibliography
4.9
References
8
25
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
25 26
5.1
Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26
5.1.1
External appearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26
5.1.2
Internal structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27
5.1.3
Temperature regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28
5.1.4
Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28
Evolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29
5.2.1
External testes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29
5.2.2
Testicular size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29
Clinical significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
30
5.3.1
Protection and injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
30
5.3.2
Diseases and conditions that affect the testes . . . . . . . . . . . . . . . . . . . . . . . . .
30
5.3.3
Effects of exogenous hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
30
5.4
Society and culture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
31
5.5
History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
31
5.5.1
Etymology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
31
5.6
Gallery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
31
5.7
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
31
5.8
Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
31
5.3
7
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Testicle
5.2
6
iii
Vas deferens
33
6.1
Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33
6.1.1
Blood supply . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33
6.2
Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33
6.3
Clinical significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33
6.3.1
Contraception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33
6.3.2
Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33
6.3.3
Uses in pharmacology and physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33
6.4
Other animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
34
6.5
Additional images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
34
6.6
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
34
6.7
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
34
6.8
External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
34
Male accessory gland
36
7.1
Accessory Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
36
7.2
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
36
7.3
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
36
Seminal vesicle
38
iv
CONTENTS 8.1
9
Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
38
8.1.1
Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
38
8.1.2
Histology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
38
8.2
Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
38
8.3
Additional images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
39
8.4
Clinical significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
39
8.4.1
39
Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.5
References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
39
8.6
External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
40
Epididymis
41
9.1
Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
41
9.1.1
Histology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
41
9.1.2
Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
9.2.1
Role in storage of sperm and ejaculant . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
Clinical significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
9.3.1
Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
9.3.2
Surgical removal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
9.4
Gallery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
9.5
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
9.6
Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
9.7
External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
43
9.2 9.3
10 Prostate
44
10.1 Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
44
10.1.1 Zones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
44
10.1.2 Lobes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
44
10.1.3 Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
45
10.1.4 Histology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
45
10.2 Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
45
10.2.1 Male sexual response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
45
10.2.2 Secretions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
45
10.2.3 Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
45
10.3 Clinical significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
45
10.3.1 Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
45
10.3.2 Benign prostatic hyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
46
10.3.3 Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
46
10.4 Female prostate gland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
10.5 Additional images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
10.6 In other mammals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
10.7 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
CONTENTS
v
10.8 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
10.9 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
49
11 Bulbourethral gland
50
11.1 Location . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
50
11.2 Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
50
11.3 Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
50
11.4 Gallery
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
50
11.5 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
50
11.6 Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
51
12 Human penis
52
12.1 Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
52
12.1.1 Parts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
52
12.1.2 Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
52
12.2 Development
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
53
12.2.1 Genital homology between sexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
53
12.2.2 Penile growth and puberty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
53
12.3 Physiological functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
53
12.3.1 Urination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
53
12.3.2 Voiding position . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
54
12.3.3 Erection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
54
12.3.4 Ejaculation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
54
12.3.5 Normal variations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
55
12.3.6 Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
55
12.3.7 Altering the genitalia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
56
12.3.8 Surgical replacement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
57
12.3.9 Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
57
12.4 Cultural aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
58
12.5 Additional images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
58
12.6 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
58
12.7 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
60
12.8 Related information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
60
13 Female reproductive system
61
13.1 Internal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
61
13.1.1 Vagina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
62
13.1.2 Cervix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
62
13.1.3 Uterus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
62
13.1.4 Fallopian tube . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
62
13.1.5 Ovaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
62
13.2 External . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
62
vi
CONTENTS 13.3 Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
62
13.4 Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
63
13.5 Female genital modiďŹ cation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
63
13.6 Diseases of the vagina
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
64
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
64
13.6.2 Bacterial vaginosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
64
13.6.3 Yeast infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
64
13.7 History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
64
13.8 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
64
13.9 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
64
13.10External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
64
13.6.1 Vaginitis
14 Ovary
65
14.1 Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
65
14.1.1 Ligaments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
65
14.1.2 Extremities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
65
14.1.3 Histology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
65
14.2 Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
65
14.2.1 Gamete production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
66
14.2.2 Endocrine function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
66
14.2.3 Ovarian aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
66
14.3 Clinical signiďŹ cance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
66
14.4 Society and culture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
66
14.4.1 Cryopreservation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
66
14.5 Other animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
67
14.6 Additional images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
67
14.7 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
67
14.8 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
67
14.9 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
68
15 Uterus
69
15.1 Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
69
15.1.1 Regions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
69
15.1.2 Layers
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
69
15.1.3 Support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
70
15.1.4 Axes
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
70
15.1.5 Position . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
70
15.1.6 Shape . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
70
15.1.7 Blood supply . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
71
15.1.8 Nerve supply . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
71
15.1.9 Histology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
71
15.1.10 Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
71
CONTENTS 15.2 Function
vii . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
71
15.3 Diseases of the uterus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
72
15.4 Uterus transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
72
15.5 Additional images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
72
15.6 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
73
15.7 References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
73
15.8 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
73
16 Fallopian tube
74
16.1 History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
74
16.2 Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
74
16.2.1 Histology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
74
16.2.2 Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
74
16.3 Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
74
16.3.1 Fertilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
74
16.4 Clinical significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
75
16.4.1 Patency testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
75
16.4.2 Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
75
16.4.3 Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
75
16.4.4 Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
75
16.5 Additional images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
75
16.6 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
75
16.7 References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
76
16.8 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
76
17 Spermatogenesis
77
17.1 Purpose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
77
17.2 Location . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
77
17.3 Duration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
77
17.4 Stages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
77
17.4.1 Spermatocytogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
78
17.4.2 Spermatidogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
78
17.4.3 Spermiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
78
17.5 Role of Sertoli cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
79
17.6 Influencing factors
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
79
17.7 Hormonal control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
80
17.8 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
80
17.9 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
80
17.10Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
81
17.11External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
81
18 Spermatozoon
82
viii
CONTENTS 18.1 Mammalian spermatozoan structure, function, and size . . . . . . . . . . . . . . . . . . . . . . . .
82
18.1.1 Humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
82
18.1.2 Avoidance of immune system response . . . . . . . . . . . . . . . . . . . . . . . . . . . .
82
18.2 Spermatozoa in other organisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
83
18.2.1 Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
83
18.2.2 Plants, algae and fungi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
83
18.3 Spermatozoa production in mammals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
83
18.4 Spermatozoa activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
83
18.5 Artificial storage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
84
18.6 History
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
84
18.7 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
84
18.8 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85
19 Spermatogonium
86
19.1 Additional images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
86
19.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
86
20 Spermatocyte
87
20.1 Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
87
20.2 Endocrine initiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
87
20.3 Cell type summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
88
20.4 History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
88
20.5 Damage, repair, and failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
89
20.6 Specific mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
89
20.7 Unique properties in different species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
89
20.8 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
90
20.9 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
90
20.10External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
90
21 Spermatid
91
21.1 Additional images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
91
21.2 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
91
22 Seminiferous tubule
92
22.1 Additional images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
92
22.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
92
22.3 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
92
23 Leydig cell
93
23.1 Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
93
23.1.1 Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
93
23.2 Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
93
23.3 Clinical significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
93
CONTENTS
ix
23.4 History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
93
23.4.1 Etimology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
93
23.5 Additional images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
94
23.6 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
94
23.7 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
94
23.8 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
94
24 Sperm
95
24.1 Sperm in animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
95
24.1.1 Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
95
24.1.2 Origin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
96
24.1.3 Sperm quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
96
24.1.4 Market for human sperm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
96
24.1.5 History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
96
24.1.6 Forensic analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
96
24.2 Sperm in plants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
96
24.3 Motile sperm cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
96
24.4 Non-motile sperm cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
97
24.5 Sperm nuclei . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
97
24.6 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
97
24.7 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
98
24.8 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
98
25 Axoneme
99
25.1 Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 25.1.1 Motile cilia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 25.1.2 Non-motile/primary cilia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 25.2 Clinical signiďŹ cance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 25.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 25.4 Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 26 Acrosome
101
26.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 27 Spermiogenesis
102
27.1 Phases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 27.1.1 Golgi phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 27.1.2 Cap/Acrosome phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 27.1.3 Formation of Tail . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 27.1.4 Maturation phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 27.2 Spermiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 27.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 27.4 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
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28 Androgen-binding protein
104
28.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 28.2 References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
28.3 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 29 Egg cell
105
29.1 Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 29.1.1 Human and mammal ova . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 29.1.2 Ooplasm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 29.1.3 Ova development in oviparous animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 29.1.4 Ovoviviparity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 29.2 Plants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 29.3 Other organisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 29.4 History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 29.5 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 29.6 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 29.7 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 30 Corona radiata (embryology)
108
30.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 30.2 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 31 Oogonium
109
31.1 In the mammalian fetus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 31.1.1 Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 31.1.2 Development and dierentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 31.1.3 Regulation of oogonia dierentiation and entry into oogenesis . . . . . . . . . . . . . . . . 110 31.1.4 Oogonial stem cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 31.2 In certain thallophytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 31.2.1 Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 31.2.2 Fertilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 31.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 31.4 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 32 Zona pellucida
112
32.1 Immunocontraception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 32.2 Zona pellucida glycoproteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 32.3 Additional images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 32.4 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 32.5 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 32.6 Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 32.7 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
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xi
33 Oocyte
114
33.1 Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 33.2 Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 33.2.1 Cytoplasm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 33.2.2 Nucleus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 33.2.3 Nest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 33.3 Maternal Contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 33.3.1 Avoidance of damage to germ-line DNA . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 33.3.2 mRNAs and Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 33.3.3 Mitochondria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 33.3.4 Nucleolus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 33.3.5 Ribosomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 33.4 Paternal contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 33.5 Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 33.6 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 33.7 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 33.8 Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 33.9 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 34 Ovulation
118
34.1 Ovulation in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 34.1.1 Follicular phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 34.1.2 Ovulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 34.1.3 Luteal phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 34.2 Clinical presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 34.3 Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 34.4 Induction and suppression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 34.4.1 Induced ovulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 34.4.2 Suppressed ovulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 34.5 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 34.6 Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 34.7 Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 34.8 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 35 Ovarian follicle atresia
122
35.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122 35.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122 36 Ovarian follicle
123
36.1 Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 36.1.1 Oocyte . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 36.1.2 Granulosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
xii
CONTENTS 36.1.3 Thecal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 36.1.4 Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 36.1.5 Development of oocytes in ovarian follicles . . . . . . . . . . . . . . . . . . . . . . . . . . 123 36.2 Clinical signiďŹ cance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 36.2.1 Cryopreservation and culture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 36.3 Additional images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 36.4 References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
36.5 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 37 Corpus luteum
126
37.1 Development and structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 37.2 Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 37.2.1 When egg is not fertilized . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 37.2.2 When egg is fertilized . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 37.2.3 Content of carotenoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 37.3 Additional images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 37.4 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 37.5 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 38 In vitro maturation
129
38.1 Techniques available . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 38.2 Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 38.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 39 Human fertilization 39.1 Anatomy
130
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
39.1.1 Corona radiata . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 39.1.2 Cone of attraction and perivitelline membrane . . . . . . . . . . . . . . . . . . . . . . . . 130 39.1.3 Sperm preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 39.1.4 Zona pellucida . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 39.2 Fusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 39.2.1 Cell membranes
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
39.2.2 Transformations
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
39.2.3 Replication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 39.2.4 Mitosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 39.3 Fertilization age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 39.4 Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 39.5 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 39.6 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 39.7 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 40 Acrosome reaction
133
40.1 Variations among species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
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40.1.1 Echinoderms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 40.1.2 Mammals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 40.2 The process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 40.3 In in vitro fertilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 40.3.1 Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 40.4 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 40.5 References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
40.6 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 41 Capacitation
136
41.1 Capacitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 41.2 Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 41.3 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 41.4 Footnotes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 41.5 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 41.6 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 42 Human embryogenesis 42.1 Germinal stage
138
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
42.1.1 Fertilization
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
42.1.2 Cleavage stage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 42.1.3 Blastulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 42.1.4 Implantation
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
42.1.5 Embryonic disc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140 42.2 Gastrulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140 42.3 Neurulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 42.3.1 Development of the nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142 42.4 Development of the heart and circulatory system . . . . . . . . . . . . . . . . . . . . . . . . . . . 143 42.5 Clinical signiďŹ cance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143 42.6 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144 42.7 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144 42.8 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145 43 Cleavage (embryo)
146
43.1 Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 43.2 Types of cleavage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 43.2.1 Determinate
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
43.2.2 Indeterminate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 43.2.3 Holoblastic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 43.2.4 Meroblastic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 43.3 Mammals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 43.4 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
43.6 Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 43.7 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 44 Polarity in embryogenesis 44.1 References
150
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150
44.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 45 Morula
151
45.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 45.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 45.3 Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 46 Blastomere
152
46.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152 46.2 References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
47 Yolk
153
47.1 Chicken egg yolk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 47.1.1 Uses
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
47.1.2 Composition of chicken egg yolk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 47.1.3 Yolk proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 47.1.4 Yolk vitamins and minerals
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
47.1.5 Double-yolk eggs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 47.1.6 Yolkless eggs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 47.1.7 Yolk color
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
47.2 In ďŹ sh . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 47.3 References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
47.4 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 48 Blastula
157
48.1 Development
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
48.1.1 Mid-blastula transition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 48.2 Structure
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
48.2.1 Cellular adhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 48.3 Clinical implications
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
48.3.1 Fertilization technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 48.3.2 Stem cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 48.4 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 48.5 Notes and references . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 48.6 Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 49 Blastocoele
160
49.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
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49.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 50 Germ layer
161
50.1 Germ layers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 50.1.1 Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 50.1.2 Endoderm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 50.1.3 Mesoderm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 50.1.4 Ectoderm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 50.1.5 Neural crest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 50.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 50.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 51 Trophoblast
164
51.1 Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 51.2 Differentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 51.3 Note . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 51.4 Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 51.5 Additional images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 51.6 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 51.7 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 51.8 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 52 Gastrulation
166
52.1 In amniotes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166 52.1.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166 52.1.2 Loss of symmetry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166 52.1.3 Formation of the primitive streak . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167 52.1.4 Epithelial to mesenchymal transition and ingression . . . . . . . . . . . . . . . . . . . . . 167 52.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167 52.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167 52.3.1 Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167 52.3.2 Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168 52.4 Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168 52.5 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 53 Ectoderm 53.1 History
170 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
53.2 Differentiation
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
53.2.1 Initial appearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 53.2.2 Early development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 53.2.3 Later development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 53.3 Clinical significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 53.3.1 Ectodermal dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
54 Mesoderm
173
54.1 DeďŹ nition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 54.2 Development of the mesodermal germ layer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 54.3 Paraxial mesoderm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 54.4 Molecular Regulation of Somite Dierentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 54.5 Intermediate mesoderm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 54.6 Lateral plate mesoderm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 54.7 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 54.8 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 54.9 Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 54.10External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 55 Endoderm
176
55.1 Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176 55.2 Additional images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176 55.3 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176 55.4 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176 56 Implantation (human embryo)
177
56.1 Implantation window . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177 56.2 Adaptation of uterus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177 56.2.1 Predecidualization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177 56.2.2 Decidualization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 56.2.3 Decidua throughout pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 56.2.4 Pinopodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 56.3 Adaptation of secretions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 56.3.1 Nourishment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 56.3.2 Growth and implantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 56.4 Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 56.4.1 Zona hatching . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 56.4.2 Apposition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 56.4.3 Adhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 56.4.4 Invasion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 56.5 Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180 56.6 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 56.7 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 56.8 Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 57 Birth
182
57.1 Birth in mammals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
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57.1.1 Human birth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 57.1.2 Cattle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183 57.1.3 Dogs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 57.1.4 Marsupials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 57.2 Birth in other animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 57.3 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 57.4 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 57.5 Cited texts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186 58 Mammary gland
187
58.1 Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 58.1.1 Histology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 58.1.2 Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 58.2 Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 58.2.1 Hormonal control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 58.2.2 Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 58.2.3 Weaning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 58.3 Clinical signiďŹ cance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 58.4 Other mammals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 58.4.1 General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 58.4.2 Evolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 58.5 Additional images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 58.6 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 58.7 References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
58.8 Bibliography
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
58.9 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 59 Menstrual cycle
192
59.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 59.2 Cycles and phases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 59.2.1 Ovarian cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 59.2.2 Uterine cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 59.3 Length . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 59.4 Fertile window
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
59.5 Eect on other systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 59.6 Mood and behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 59.7 Cycle abnormalities and disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197 59.8 Ovulation suppression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197 59.8.1 Hormonal contraception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197 59.8.2 Lactational amenorrhea
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
59.9 Etymological and biological associations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198 59.9.1 Nightlighting and the moon
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
xviii
CONTENTS
59.10References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
59.11External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202 60 Reproductive health
203
60.1 Sexual health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 60.2 Childbearing and health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 60.3 Availability of modern contraception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204 60.4 Female genital mutilation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204 60.5 Sexually transmitted diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204 60.6 Adolescent health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204 60.7 International Conference on Population and Development (ICPD), 1994
. . . . . . . . . . . . . . 205
60.8 Millennium Development Goals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206 60.9 Reproductive health and abortion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206 60.10See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 60.11References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
60.12External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 60.13Text and image sources, contributors, and licenses . . . . . . . . . . . . . . . . . . . . . . . . . . 209 60.13.1 Text . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 60.13.2 Images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 60.13.3 Content license . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
Chapter 1
Human reproduction For other uses, see Human Reproduction (journal). Human reproduction is any form of sexual reproduction resulting in human fertilization, typically involving sexual intercourse between a man and a woman. During sexual intercourse, the interaction between the male and female reproductive systems results in fertilization of the woman’s ovum by the man’s sperm, which after a gestation period, typically for nine months, is followed by childbirth. The fertilization of the ovum may nowadays be achieved by artificial insemination methods, which do not involve sexual intercourse. Lao students study a display about the human reproductive system. Exhibits such as this are rare in many less-developed countries, such as Laos. This event was held by Big Brother Mouse, a literacy and education project, which added Lao explanations to a commercially-available set of panels that were printed with English.
1.1 Anatomy Further information: Human reproductive system
1.1.2 The human female 1.1.1
For more details on this topic, see Human female reproductive system.
The human male
For more details on this topic, see Human male reproductive system. The male reproductive system contains two main divisions: the testes where sperm are produced, and the penis. In humans, both of these organs are outside the abdominal cavity. Having the testes outside the abdomen facilitates temperature regulation of the sperm, which require specific temperatures to survive about 2-3 °C less than the normal body temperature i.e. 37°C. In particular, the extraperitoneal location of the testes may result in a 2-fold reduction in the heat-induced contribution to the spontaneous mutation rate in male germinal tissues compared to tissues at 37°C.[1] If the testicles remain too close to the body, it is likely that the increase in temperature will harm the spermatozoa formation, making conception more difficult. This is why the testes are carried in an external pouch viz. scrotum rather than within the abdomen; they normally remain slightly cooler than body temperature, facilitating sperm production.
The female reproductive system likewise contains two main divisions: the vagina and uterus, which will receive the semen, and the ovaries, which produces the ova. The vagina is attached to the uterus through the cervix, while the uterus is attached to the ovaries via the Fallopian tubes. At certain intervals, the ovaries release an ovum, which passes through the fallopian tube into the uterus. The fertilization of the ovum with the sperm occurs at the ampullary-isthimic junction only. That is why not all intercourse results in pregnancy. The ovum meets with Spermatozoon, a sperm may penetrate and merge with the egg, fertilizing it with the help of certain hydrolytic enzymes present in the acrosome. The fertilization usually occurs in the oviducts, but can happen in the uterus itself. The zygote then becomes implanted in the lining of the uterus, where it begins the processes of embryogenesis and morphogenesis. When the fetus is developed enough to survive outside the womb, the cervix 1
2
CHAPTER 1. HUMAN REPRODUCTION
dilates and contractions of the uterus propel it through the umbilical cord. This drain of nutrients can be quite taxbirth canal, which is the vagina. ing on the female, who is required to ingest slightly higher The ova, which are the female sex cells, are much larger levels of calories. In addition, certain vitamins and other than the spermatozoon and are normally formed within nutrients are required in greater quantities than normal, the ovaries of the female fetus before its birth. They are often creating abnormal eating habits. Gestation period is mostly fixed in location within the ovary until their tran- about 266 days in humans. While in the uterus, the baby sit to the uterus, and contain nutrients for the later zygote first endures a very brief zygote stage, then the embryand embryo. Over a regular interval, in response to hor- onic stage, which is marked by the development of major organs and lasts for approximately eight weeks, then monal signals, a process of oogenesis matures one ovum of which is released and sent down the Fallopian tube. If the fetal stage, which revolves around the development bone cells while the fetus continues to grow in size.[2] not fertilized, this egg is flushed out of the system through menstruation.
1.2.3 Birth
1.2 Process
Main article: Childbirth
Human reproduction normally begins with sexual intercourse, followed by nine months of pregnancy before childbirth, though it may be achieved through artificial insemination. Many years of parental care are required before a human child becomes independent, typically between twelve and eighteen or more. Pregnancy can be avoided with the use of contraceptives such as condoms and Intrauterine devices.
Once the fetus is sufficiently developed, chemical signals begin the process of birth, which begins with the fetus being pushed out of the birthing canal. The newborn, which is called an Infant in humans, should typically begin respiration on its own shortly after birth. Not long after, the placenta eventually falls off on its own. The person assisting the birth may also sever the umbilical cord.
1.2.4 Parental care 1.2.1
Sexual intercourse
Main article: Parenting
Main article: Sexual intercourse A human baby is nearly helpless and the growing child requires high levels of parental care for many years. One Human reproduction takes place as internal fertilisation important type of early parental care is lactation, feeding by sexual intercourse. During this process, the male inthe baby milk from the mother’s mammary glands in her serts his penis, which needs to be erect, into the female’s breasts.[3] vagina, and then either partner initiates rhythmic pelvic thrusts until the male ejaculates semen, which contains sperm, into the vaginal canal. This process is also known as “coitus”, “mating”, “having sex”, or, euphemistically, 1.3 See also “making love”. The sperm and the ovum are known as gametes (each containing half the genetic information of • Evolution of sexual reproduction the parent, created through meiosis). The sperm (being • Female infertility one of approximately 250 million sperm in a typical male ejaculation, travels through the vagina and cervix into the • Human Reproduction (journal) uterus or Fallopian tubes where it fertilizes the ovum, creating a zygote. Upon fertilization and implantation, ges• Journal of Human Reproductive Sciences tation of the fetus then occurs within the female’s uterus. • Male infertility
1.2.2
Pregnancy
Main article: Pregnancy Pregnancy is the period of time during which the fetus develops, dividing via mitosis inside the female. During this time, the fetus receives all of its nutrition and oxygenated blood from the female, filtered through the placenta, which is attached to the fetus’ abdomen via an
• Reproduction • Reproductive system
1.4 References [1] Baltz RH, Bingham PM, Drake JW (1976). Heat mutagenesis in bacteriophage T4: The transition pathway. Proc. Nat. Acad. Sci. USA 73(4): 1269-1273. PMID 4797
1.4. REFERENCES
[2] Feist, Gregory J.; Rosenberg, Erika L. Psychology: Perspectives and Connections (Second ed.). McGraw Hill. pp. (171–172). ISBN 978-0-07-803520-3. [3] Sexual Reproduction in Humans. 2006. John W. Kimball. Kimball’s Biology Pages, and online textbook.
3
Chapter 2
Puberty “Pubescent” redirects here. For the botanical term, see in Western culture, wherein adolescence is the period Leaf § Surface. of mental transition from childhood to adulthood, which “Sexual development” redirects here. For sexual de- overlaps much of the body’s period of puberty.[15] velopment of non-human organisms, see Sexual maturity.
2.1 Differences between male and female puberty
Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction to enable fertilization. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a boy. In response to the signals, the gonads produce hormones that stimulate libido and the growth, function, and transformation of the brain, bones, muscle, blood, skin, hair, breasts, and sex organs. Physical growth—height and weight—accelerates in the first half of puberty and is completed when the child has developed an adult body. Until the maturation of their reproductive capabilities, the pre-pubertal physical differences between boys and girls are the external sex organs.
Two of the most significant differences between puberty in girls and puberty in boys are the age at which it begins, and the major sex steroids involved, the testosterones and the estrogens. Birth
Child development periods
Age
Weeks Months Years
= Change in time scale
= Definitions differ in faded interval
Infancy
Primary school age
Neonate/newborn
0
1
2 0
Play age
1
2 3 0
4
5
6
7
8
9 10 11
1
Preteen
Preschooler
12 - 23 2
3
4
5
Adulthood
Secondary school age Puberty (boys) Puberty (girls)
Toddlerhood
3
Adolescence
Preadolescence
Childhood
Periods
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Approximate outline of development periods in child and teenager development. Puberty is marked in green at right.
On average, girls begin puberty at ages 10–11; boys at ages 11–12.[1][2] Girls usually complete puberty by ages 15–17,[2][3][4] while boys usually complete puberty by ages 16–17.[2][3][5] The major landmark of puberty for females is menarche, the onset of menstruation, which occurs on average between ages 12–13;[6][7][8][9] for males, it is the first ejaculation, which occurs on average at age 13.[10] In the 21st century, the average age at which children, especially girls, reach puberty is lower compared to the 19th century, when it was 15 for girls and 16 for boys.[11] This can be due to any number of factors, including improved nutrition resulting in rapid body growth, increased weight and fat deposition,[12] or exposure to endocrine disruptors such as xenoestrogens, which can at times be due to food consumption or other environmental factors.[13][14] Puberty which starts earlier than usual is known as precocious puberty. Puberty which starts later than usual is known as delayed puberty.
Although there is a wide range of normal ages, girls typically begin the process of puberty at age 10 or 11; boys at ages 11–12.[1][2] Girls usually complete puberty by ages 15–17,[2][3][4] while boys usually complete puberty by ages 16–17.[2][3][5] Girls attain reproductive maturity about four years after the first physical changes of puberty appear.[4] In contrast, boys accelerate more slowly but continue to grow for about six years after the first visible pubertal changes.[16] Any increase in height beyond the post-pubertal age is uncommon. For boys, an androgen called testosterone is the principal sex hormone. While testosterone is produced, all boys’ changes are characterized as virilization, a substantial product of testosterone metabolism in males is estradiol. The conversion of testosterone to estradiol depends on the amount of body fat and estradiol levels in boys are typically much lower than in girls. The male “growth spurt” also begins later, accelerates more slowly, and lasts longer before the epiphyses fuse. Although boys are on average 2 cm shorter than girls before puberty begins, adult men are on average about 13 cm (5.2 inches) taller than women. Most of this sex difference in adult heights is attributable to a later onset of the growth spurt and a slower progression to completion, a direct result of the later rise and lower adult male levels of estradiol.[17]
Notable among the morphologic changes in size, shape, composition, and functioning of the pubertal body, is the development of secondary sex characteristics, the “filling in” of the child’s body; from girl to woman, from boy to man. Derived from the Latin puberatum (age of maturity), the word puberty describes the physical changes to sexual maturation, not the psychosocial and cultural maturation denoted by the term adolescent development 4
2.2. PUBERTY ONSET
5 pearance of axillary and pubic hair. The first androgenic hair resulting from adrenarche can be also transient and disappear before the onset of true puberty. The onset of puberty is associated with high GnRH pulsing, which precedes the rise in sex hormones, LH and FSH.[19] Exogenous GnRH pulses cause the onset of puberty.[20] Brain tumors which increase GnRH output may also lead to premature puberty.[21]
1 Follicle-stimulating hormone - FSH 2 Luteinizing hormone - LH 3 Progesterone 4 Estrogen 5 Hypothalamus 6 Pituitary gland 7 Ovary 8 Pregnancy - hCG (Human chorionic gonadotropin) 9 Testosterone 10 Testicle 11 Incentives 12 Prolactin - PRL
The hormone that dominates female development is an estrogen called estradiol. While estradiol promotes growth of the breasts and uterus, it is also the principal hormone driving the pubertal growth spurt and epiphyseal maturation and closure.[18] Estradiol levels rise earlier and reach higher levels in women than in men. The hormonal maturation of females is considerably more complicated than in boys. The main steroid hormones, testosterone, estradiol, and progesterone as well as prolactin play important physiological functions in puberty. Gonadal steroidgenesis in girls starts with production of testosterone which is typically quickly converted to estradiol inside the ovaries. However the rate of conversion from testosterone to estradiol (driven by FSH/LH balance) during early puberty is highly individual, resulting in very diverse development patterns of secondary sexual characteristics. Production of progesterone in the ovaries begins with the development of ovulatory cycles in girls (during the lutheal phase of the cycle), before puberty low levels of progesterone are produced in the adrenal glands of both boys and girls.
The cause of the GnRH rise is unknown. Leptin might be the cause of the GnRH rise. Leptin has receptors in the hypothalamus which synthesizes GnRH.[22] Individuals who are deficient in leptin fail to initiate puberty.[23] The levels of leptin increase with the onset of puberty, and then decline to adult levels when puberty is completed. The rise in GnRH might also be caused by genetics. A study[24] discovered that a mutation in genes encoding both Neurokinin B as well as the Neurokinin B receptor can alter the timing of puberty. The researchers hypothesized that Neurokinin B might play a role in regulating the secretion of Kisspeptin, a compound responsible for triggering direct release of GnRH as well as indirect release of LH and FSH.
2.2.1 Effects of early and late puberty onset Several studies about puberty have examined the effects of an early or a late onset of puberty in males and females. In general, girls who enter puberty late experience positive outcomes in adolescence and adulthood while girls who enter puberty early experience negative outcomes. Boys who have earlier pubertal timing generally have more positive outcomes in adulthood but more negative outcomes in adolescence, while the reverse is true for later pubertal timing.[25]
Girls
For girls who have an earlier onset of puberty, outcomes have generally pointed towards the general conclusion that the early onset can be psychologically damaging. The main reason for this detrimental effect is the issue of body image. As they physically develop, gaining weight in several areas of the body, early-maturing girls usually look larger than girls who have not yet entered puberty. A result of the social pressure to be thin, the earlymaturing girls develop a negative view of their body image. In addition, boys may tease the girls about their visible breasts, forcing the early-maturing girl to hide her breasts by dressing differently. The embarrassment of a more developed body may also result in the refusal to 2.2 Puberty onset undress for gym. These experiences lead to lower selfand poorer body image in these Puberty is preceded by adrenarche, marking an increase esteem, more depression [25] early-maturing girls. of adrenal androgen production between ages 6–10. Adrenarche is sometimes accompanied by the early ap- Furthermore, as physical and emotional differences set
6
CHAPTER 2. PUBERTY
them apart from people in their same age group, earlymaturing girls develop relationships with older people. For instance, some early-maturing girls have older boyfriends, “attracted to the girls’ womanly figure and girlish innocence.”[25] While having an older boyfriends might improve popularity among peers, it also increases the risk of alcohol and drug use, increased sexual relations (often unprotected), eating disorders and bullying.[25]
set of puberty. After the boy’s testicles have enlarged and developed for about one year, the length and then the breadth of the shaft of the penis will increase and the glans penis and corpora cavernosa will also start to enlarge to adult proportions.[28] While 18–20 cm3 is an average adult size, there is wide variation in testicular size in the normal population.[29]
The testes have two primary functions: to produce Generally, later onset of puberty in girls produce positive hormones and to produce sperm. The Leydig cells prooutcomes. They exhibit positive behaviors in adolescence duce testosterone, which in turn produces most of the that continue to adulthood.[25] male pubertal changes. Most of the increasing bulk of testicular tissue is spermatogenic tissue (primarily Sertoli and Leydig cells). Sperm can be detected in the morning Boys urine of most boys after the first year of pubertal changes, and occasionally earlier. On average, potential fertility in In the past, early onset of puberty in boys have been as- boys is reached at 13 years old, but full fertility will not sociated with positive outcomes, such as leadership in be gained until 14–16 years of age. high school and success in adulthood.[26] However, recent studies have revealed that the risks and problems of early During puberty, a male’s scrotum will become larger and begin to dangle or hang below the body as opposed to bematuration in males might outweigh the benefits.[25] ing up tight. This is to accommodate the testicles to hang Early-maturing boys develop “more aggressive, law- lower whereby the testicles need a certain temperature to breaking, and alcohol abusing” behaviors, which result be fertile and produce sperm. This is colloquially referred in anger towards parents, trouble in school and with the to as “balls dropping”. police. Early puberty also correlates with increased sexual activity and a higher instance of teenage pregnancy, both of which can lead to depression and other psychoso- 2.3.2 Morning wood and random or uncial issues.[25] However, early puberty might also result wanted erections in positive outcomes, such as popularity among peers, higher self-esteem and confidence, as a result of physical Erections during sleep or when waking up are medically developments, such as taller height, developed muscles, known as nocturnal penile tumescence and colloquially and better athletic ability. referred to as morning wood.[30] The penis can regularly On the other hand, late-maturing boys develop lower self- get erect during sleep and men or boys often wake-up esteems and confidence and generally have lower popular- with an erection.[31] Once a boy reaches his teenage years, ity among peers, due to their less-developed physiques. erections occur much more frequently due to puberty.[32] Also, they experience problems with anxiety and depres- Erections can occur spontaneously at any time of day, and sion and are more likely to be afraid of sex than other if clothed may cause a bulge or “hump”. This can be boys.[25] disguised or hidden by wearing close-fitting underwear, a long shirt and baggier clothes.[33] Erections are common for male children and infants, and can even occur before birth.[34] Spontaneous erections are also known as 2.3 Physical changes in boys involuntary or unwanted erections and are normal. Such erections can be embarrassing if they happen in public, See also: Tanner scale such as a classroom or living room.[35][36]
2.3.1
Testicular size, penis size, fertility
In boys, testicular enlargement is the first physical manifestation of puberty (and is termed gonadarche).[27] Testes in prepubertal boys change little in size from about 1 year of age to the onset of puberty, averaging about 2–3 cm in length and about 1.5–2 cm in width. The size of the testicles is among the parameters of the tanner scale for male genitals, from stage I which represents a volume of less than 1.5 ml, to stage V which represents a testicular volume of greater than 20 ml. Testicular size reaches maximal adult size about 6 years after the on-
2.3.3 Foreskin retraction During puberty, if not before, the tip and opening of a boy’s foreskin becomes wider, progressively allowing for retraction down the shaft of the penis and behind the glans, which ultimately should be possible without pain or difficulty. The membrane that bonds the inner surface of the foreskin with the glans disintegrates and releases the foreskin to separate from the glans. The foreskin then gradually becomes retractable. Research by Øster (1968) found that with the onset and continuation of puberty, the proportion of boys able to
2.3. PHYSICAL CHANGES IN BOYS pull back their foreskins increased. At ages 12–13, Øster found that only 60% of boys were able to retract their foreskins; this increased to 85% by ages 14–15, and 95% by 16–17. He also found that 1% of those unable to fully retract experienced phimosis at ages 14–17, the remainder were partially able to.[37] The findings were supported by further research by Kayaba et al (1996) on a sample of over 600 boys,[38] and Ishikawa and Kawakita (2004) found that by age 15, 77% of their sample of boys could retract their foreskins.[39] Beaugé (1997) reports that boys may assist the development of retractile foreskin by manual stretching.[40] Once a boy is able to retract his foreskin, penile hygiene should become an important feature of his routine body care. Although the American Academy of Pediatrics states there is “little evidence to affirm the association between circumcision status and optimal penile hygiene”,[41] various studies suggest that boys be educated about the role of hygiene, including retracting the foreskin while urinating and rinsing under it and around the glans at each bathing opportunity. Regular washing under the foreskin was found by Krueger and Osborn (1986) to reduce the risk of numerous penile disorders.[42]
2.3.4
Pubic hair
Pubic hair often appears on a boy shortly after the genitalia begin to grow. The pubic hairs are usually first visible at the dorsal (abdominal) base of the penis. The first few hairs are described as stage 2. Stage 3 is usually reached within another 6–12 months, when the hairs are too many to count. By stage 4, the pubic hairs densely fill the “pubic triangle.” Stage 5 refers to the spread of pubic hair to the thighs and upward towards the navel as part of the developing abdominal hair.
2.3.5
Body and facial hair
7 may develop androgenic hair. The usual sequence is: underarm (axillary) hair, perianal hair, upper lip hair, sideburn (preauricular) hair, periareolar hair, and the beard area.[43] As with most human biological processes, this specific order may vary among some individuals. Arm, leg, chest, abdominal, and back hair become heavier more gradually. There is a large range in amount of body hair among adult men, and significant differences in timing and quantity of hair growth among different racial groups. Facial hair is often present in late adolescence, but may not appear until significantly later.[44][45] Facial hair will continue to get coarser, darker and thicker for another 2–4 years after puberty.[44] Some men do not develop full facial hair for up to 10 years after the completion of puberty.[44] Chest hair may appear during puberty or years after. Not all men have chest hair.
2.3.6 Voice change and Adam’s apple “Squeaky-voiced teen” redirects here. For the fictional character, see Squeaky-Voiced Teen (The Simpsons). Main article: Voice change Under the influence of androgens, the voice box, or larynx, grows in both sexes. This growth is far more prominent in boys, causing the male voice to drop and deepen, sometimes abruptly but rarely “overnight,” about one octave, because the longer and thicker vocal folds have a lower fundamental frequency. Before puberty, the larynx of boys and girls is about equally small.[46] Occasionally, voice change is accompanied by unsteadiness of vocalization in the early stages of untrained voices. Most of the voice change happens during stage 3-4 of male puberty around the time of peak growth. Adult pitch is attained at an average age of 15 years, although the voice may not fully settle until early twenties. It usually precedes the development of significant facial hair by several months to years.
2.3.7 Male musculature and body shape By the end of puberty, adult men have heavier bones and nearly twice as much skeletal muscle. Some of the bone growth (e.g. shoulder width and jaw) is disproportionately greater, resulting in noticeably different male and female skeletal shapes. The average adult male has about 150% of the lean body mass of an average female, and about 50% of the body fat.
Facial hair of a male.
This muscle develops mainly during the later stages of puberty, and muscle growth can continue even after boys are biologically adult. The peak of the so-called “strength spurt”, the rate of muscle growth, is attained about one year after a male experiences his peak growth rate.
In the months and years following the appearance of pu- Often, the fat pads of the male breast tissue and the male bic hair, other areas of skin that respond to androgens nipples will develop during puberty; sometimes, espe-
8
CHAPTER 2. PUBERTY
cially in one breast, this becomes more apparent and is 2.4.3 Vagina, uterus, ovaries termed gynecomastia. It is usually not a permanent phenomenon. Perineal skin keratinizes due to effect of estrogen increasing its resistance to infection. The mucosal surface of the vagina also changes in response to increasing levels 2.3.8 Body odor and acne of estrogen, becoming thicker and duller pink in color (in contrast to the brighter red of the prepubertal vaginal Rising levels of androgens can change the fatty acid com- mucosa).[50] Mucosa changes into a multilayered strucposition of perspiration, resulting in a more “adult” body ture with superficial layer of squamous cells. Estrogen odor. As in girls, another androgen effect is increased increase glycogen content in vaginal epithelium, which secretion of oil (sebum) from the skin and the resultant in future plays important part in maintaining vaginal pH. variable amounts of acne. Acne can not be prevented or Whitish secretions (physiologic leukorrhea) are a normal diminished easily, but it typically fully diminishes at the effect of estrogen as well.[47] In the two years followend of puberty. However, it is not unusual for a fully ing thelarche, the uterus, ovaries, and the follicles in the grown adult to suffer the occasional bout of acne, though ovaries increase in size.[51] The ovaries usually contain it is normally less severe than in adolescents. Some may small follicular cysts visible by ultrasound.[52][53] Before desire using prescription topical creams or ointments to puberty, uterine body to cervix ratio is 1:1; which inkeep acne from getting worse, or even oral medication, creases to 2:1 or 3:1 after completion of pubertal period. due to the fact that acne is emotionally difficult and can cause scarring.
2.4.4 Menstruation and fertility
2.4 Physical changes in girls 2.4.1
Breast development
The first physical sign of puberty in girls is usually a firm, tender lump under the center of the areola of one or both breasts, occurring on average at about 10.5 years of age.[47] This is referred to as thelarche. By the widely used Tanner staging of puberty, this is stage 2 of breast development (stage 1 is a flat, prepubertal breast). Within six to 12 months, the swelling has clearly begun in both sides, softened, and can be felt and seen extending beyond the edges of the areolae. This is stage 3 of breast development. By another 12 months (stage 4), the breasts are approaching mature size and shape, with areolae and nipples forming a secondary mound. In most young women, this mound disappears into the contour of the mature breast (stage 5), although there is so much variation in sizes and shapes of adult breasts that stages 4 and 5 are not always separately identifiable.[48]
2.4.2
The first menstrual bleeding is referred to as menarche, and typically occurs about two years after thelarche.[49] The average age of menarche is 12.5 in the United States.[7] Most American girls experience their first period at 11, 12 or 13, but some experience it earlier than their 11th birthday and others after their 14th birthday. In fact, anytime between 8 and 16 is normal. In Canada, the average age of menarche is 12.72,[8] and in the United Kingdom it is 12.9.[9] The time between menstrual periods (menses) is not always regular in the first two years after menarche.[54] Ovulation is necessary for fertility, but may or may not accompany the earliest menses.[55] In postmenarchal girls, about 80% of the cycles were anovulatory in the first year after menarche, 50% in the third year and 10% in the sixth year.[54] Initiation of ovulation after menarche is not inevitable. A high proportion of girls with continued irregularity in the menstrual cycle several years from menarche will continue to have prolonged irregularity and anovulation, and are at higher risk for reduced fertility.[56]
Pubic hair
2.4.5 Body shape, fat distribution, and body composition Pubic hair is often the second noticeable change in puberty, usually within a few months of thelarche.[49] It is referred to as pubarche. The pubic hairs are usually visible first along the labia. The first few hairs are described as Tanner stage 2.[48] Stage 3 is usually reached within another 6–12 months, when the hairs are too numerous to count and appear on the pubic mound as well. By stage 4, the pubic hairs densely fill the “pubic triangle.” Stage 5 refers to spread of pubic hair to the thighs and sometimes as abdominal hair upward towards the navel. In about 15% of girls, the earliest pubic hair appears before breast development begins.[49]
During this period, also in response to rising levels of estrogen, the lower half of the pelvis and thus hips widen (providing a larger birth canal).[48][57] Fat tissue increases to a greater percentage of the body composition than in males, especially in the typical female distribution of breasts, hips, buttocks, thighs, upper arms, and pubis. Progressive differences in fat distribution as well as sex differences in local skeletal growth contribute to the typical female body shape by the end of puberty. On average, at 10 years, girls have 6% more body fat than boys.[58]
2.5. VARIATIONS
2.4.6
Body odor and acne
Rising levels of androgens can change the fatty acid composition of perspiration, resulting in a more “adult” body odor. This often precedes thelarche and pubarche by one or more years. Another androgen effect is increased secretion of oil (sebum) from the skin. This change increases the susceptibility to acne, a skin condition that is characteristic of puberty.[59] Acne varies greatly in its severity.[59]
2.4.7
Other effects of hormonal changes
9 The average age at which puberty begins may be affected by race as well. For example, the average age of menarche in various populations surveyed has ranged from 12[7][8][9] to 18 years. The earliest average onset of puberty is for African-American girls and the latest average onset for high altitude subsistence populations in Asia. However, much of the higher age averages reflect nutritional limitations more than genetic differences and can change within a few generations with a substantial change in diet. The median age of menarche for a population may be an index of the proportion of undernourished girls in the population, and the width of the spread may reflect unevenness of wealth and food distribution in a population.
Estradiol in girls causes thickening of lips and oral mucosa as well as further development of the vulva. In the vulva and vagina estradiol causes thickening (stratification) of the skin, growth of the myopethelial layer and smooth muscle of the vagina. Typically estradiol will also cause pronounced growth of the labia minora and to a lesser degree of the labia majora.
Researchers have identified an earlier age of the onset of puberty. However, they have based their conclusions on a comparison of data from 1999 with data from 1969. In the earlier example, the sample population was based on a small sample of white girls (200, from Britain). The later study identified as puberty as occurring in 48% of African-American girls by age nine, and 12% of white Estradiol is also responsible for the increased production girls by that age.[65] of pheomelanin, resulting in the characteristic red color One possible cause of a delay in the onset of puberty past of the lips, labia minora and sometimes labia majora. the age 14 in girls and 15 in boys is Kallmann syndrome, Estradiol together with other ovarian steroids also cause a form of hypogonadotropic hypogonadism (HH). Kallthe darker coloration of the areola. mann syndrome is also associated with a lack of sense of Testosterone will cause an enlargement of the clitoris and smell (anosmia). Kallmann syndrome and other forms of possibly has important effects on the growth and matu- HH affect both men and women. It is caused by a failration of the vestibular bulbs, corpus cavernosum of the ure in HPG axis at puberty which results in low or zero clitoris and urethral sponge.[60] gonadotropin (LH and FSH) levels with the subsequent result of a failure to commence or complete puberty, secChanges of the vulva initiated by estradiol as well as its ondary hypogonadism and infertility.[66][67] direct effects also appear to influence the functioning of the lower urinary tract.[61][62]
2.5 Variations 2.5.1
Historical shift
Timing of the onset of puberty
The average age at which the onset of puberty occurs has dropped significantly since the 1840s.[68][69][70] This was dubbed 'the secular trend' by J. M. Tanner. In every decade from 1840 to 1950 there was a drop of four months in the average age of menarche among Western European females. In Norway, girls born in 1840 had their menarche at an average age of 17 years. In France, the average in 1840 was 15.3 years. In England, the average in 1840 was 16.5 years. In Japan the decline hapThe age at which puberty begins varies between individ- pened later and was then more rapid: from 1945 to 1975 uals; usually, puberty begins between 10 and 13 years of in Japan there was a drop of 11 months per decade. age. The age at which puberty begins is affected by both A 2006 study in Denmark found that puberty, as evigenetic factors and by environmental factors such as nu- denced by breast development, started at an average age tritional state and social circumstances.[63] An example of of 9 years and 10 months, a year earlier than when a simsocial circumstances is the Vandenbergh effect; a juvenile ilar study was done in 1991. Scientists believe the phefemale who has significant interaction with adult males nomenon could be linked to obesity or exposure to chemwill enter puberty earlier than juvenile females who are icals in the food chain, and is putting girls at greater longnot socially overexposed to adult males.[64] term risk of breast cancer.[71] The definition of the onset of puberty may depend on perspective (e.g., hormonal versus physical) and purpose (establishing population normal standards, clinical care of early or late pubescent individuals, etc.). A common definition for the onset of puberty is physical changes to a person’s body.[4] These physical changes are the first visible signs of neural, hormonal, and gonadal function changes.
10
2.5.2
CHAPTER 2. PUBERTY
Genetic influence and environmental about BPA’s behavioral effects on fetuses, infants, and children at current exposure levels because it can affect factors
Various studies have found direct genetic effects to account for at least 46% of the variation of timing of puberty in well-nourished populations.[72][73][74][75] The genetic association of timing is strongest between mothers and daughters. The specific genes affecting timing are not yet known.[72] Among the candidates is an androgen receptor gene.[76] Researchers[77] have hypothesized that early puberty onset may be caused by certain hair care products containing estrogen or placenta, and by certain chemicals, namely phthalates, which are used in many cosmetics, toys, and plastic food containers. If genetic factors account for half of the variation of pubertal timing, environment factors are clearly important as well. One of the first observed environmental effects is that puberty occurs later in children raised at higher altitudes. The most important of the environmental influences is clearly nutrition, but a number of others have been identified, all which affect timing of female puberty and menarche more clearly than male puberty.
Hormones and steroids There is theoretical concern, and animal evidence, that environmental hormones and chemicals may affect aspects of prenatal or postnatal sexual development in humans.[78] Large amounts of incompletely metabolized estrogens and progestagens from pharmaceutical products are excreted into the sewage systems of large cities, and are sometimes detectable in the environment. Sex steroids are sometimes used in cattle farming but have been banned in chicken meat production for 40 years. Although agricultural laws regulate use to minimize accidental human consumption, the rules are largely selfenforced in the United States. Significant exposure of a child to hormones or other substances that activate estrogen or androgen receptors could produce some or all of the changes of puberty.
the prostate gland, mammary gland, and lead to early puberty in girls. BPA mimics and interferes with the action of estrogen—an important reproduction and development regulator. It leaches out of plastic into liquids and foods, and the Centers for Disease Control and Prevention (CDC) found measurable amounts of BPA in the bodies of more than 90 percent of the U.S. population studied. The highest estimated daily intakes of BPA occur in infants and children. Many plastic baby bottles contain BPA, and BPA is more likely to leach out of plastic when its temperature is increased, as when one warms a baby bottle or warms up food in the microwave.[79] Nutritional influence
Nutritional factors are the strongest and most obvious environmental factors affecting timing of puberty.[72] Girls are especially sensitive to nutritional regulation because they must contribute all of the nutritional support to a growing fetus. Surplus calories (beyond growth and activity requirements) are reflected in the amount of body fat, which signals to the brain the availability of resources for initiation of puberty and fertility. Much evidence suggests that for most of the last few centuries, nutritional differences accounted for majority of variation of pubertal timing in different populations, and even among social classes in the same population. Recent worldwide increased consumption of animal protein, other changes in nutrition, and increases in childhood obesity have resulted in falling ages of puberty, mainly in those populations with the higher previous ages. In many populations the amount of variation attributable to nutrition is shrinking. Although available dietary energy (simple calories) is the most important dietary influence on timing of puberty, quality of the diet plays a role as well. Lower protein intakes and higher dietary fiber intakes, as occur with typical vegetarian diets, are associated with later onset and slower progression of female puberty.
Harder to detect as an influence on puberty are the more Obesity influence and exercise diffusely distributed environmental chemicals like PCBs (polychlorinated biphenyl), which can bind and trigger es- Scientific researchers have linked early obesity with an trogen receptors. earlier onset of puberty in girls. They have cited obesity More obvious degrees of partial puberty from direct ex- as a cause of breast development before nine years and posure of young children to small but significant amounts menarche before twelve years.[80] Early puberty in girls of pharmaceutical sex steroids from exposure at home can be a harbinger of later health problems.[81] may be detected during medical evaluation for precocious The average level of daily physical activity has also been puberty, but mild effects and the other potential expo- shown to affect timing of puberty, especially in females. sures outlined above would not. A high level of exercise, whether for athletic or body imBisphenol A (BPA) is a chemical used to make plastics, and is frequently used to make baby bottles, water bottles, sports equipment, medical devices, and as a coating in food and beverage cans. Scientists are concerned
age purposes, or for daily subsistence, reduces energy calories available for reproduction and slows puberty. The exercise effect is often amplified by a lower body fat mass and cholesterol.
2.6. NEUROHORMONAL PROCESS Physical and mental illness
11 Another limitation of the social research is that nearly all of it has concerned girls, partly because female puberty requires greater physiologic resources and partly because it involves a unique event (menarche) that makes survey research into female puberty much simpler than male. More detail is provided in the menarche article.
Chronic diseases can delay puberty in both boys and girls. Those that involve chronic inflammation or interfere with nutrition have the strongest effect. In the western world, inflammatory bowel disease and tuberculosis have been notorious for such an effect in the last century, while in areas of the underdeveloped world, chronic parasite 2.5.3 infections are widespread.
Variations of sequence
Mental illnesses occur in puberty. The brain undergoes significant development by hormones which can contribute to mood disorders such as Major depressive disorder, bipolar disorder, dysthymia and schizophrenia. Girls aged between 15 and 19 make up 40% of anorexia nervosa cases.[82]
The sequence of events of pubertal development can occasionally vary. For example, in about 15% of boys and girls, pubarche (the first pubic hairs) can precede, respectively, gonadarche and thelarche by a few months. Rarely, menarche can occur before other signs of puberty in a few girls. These variations deserve medical evaluation because they can occasionally signal a disease.
Stress and social factors
2.5.4 Conclusion
Some of the least understood environmental influences on timing of puberty are social and psychological. In comparison with the effects of genetics, nutrition, and general health, social influences are small, shifting timing by a few months rather than years. Mechanisms of these social effects are unknown, though a variety of physiological processes, including pheromones, have been suggested based on animal research.
In a general sense, the conclusion of puberty is reproductive maturity. Criteria for defining the conclusion may differ for different purposes: attainment of the ability to reproduce, achievement of maximal adult height, maximal gonadal size, or adult sex hormone levels. Maximal adult height is achieved at an average age of 15 years for an average girl and 18 years for an average boy. Potential fertility (sometimes termed nubility) usually precedes The most important part of a child’s psychosocial envi- completion of growth by 1–2 years in girls and 3–4 years ronment is the family, and most of the social influence in boys. Stage 5 typically represents maximal gonadal research has investigated features of family structure and growth and adult hormone levels. function in relation to earlier or later female puberty. Most of the studies have reported that menarche may occur a few months earlier in girls in high-stress households, 2.6 Neurohormonal process whose fathers are absent during their early childhood, who have a stepfather in the home, who are subjected to The endocrine reproductive system consists of the prolonged sexual abuse in childhood, or who are adopted hypothalamus, the pituitary, the gonads, and the adrenal from a developing country at a young age. Conversely, glands, with input and regulation from many other body menarche may be slightly later when a girl grows up in a systems. True puberty is often termed “central puberty” large family with a biological father present. because it begins as a process of the central nervous sysMore extreme degrees of environmental stress, such as tem. A simple description of hormonal puberty is as folwartime refugee status with threat to physical survival, lows: have been found to be associated with delay of maturation, an effect that may be compounded by dietary inad1. The brain’s hypothalamus begins to release pulses of equacy. GnRH. Most of these reported social effects are small and our 2. Cells in the anterior pituitary respond by secreting understanding is incomplete. Most of these “effects” are LH and FSH into the circulation. statistical associations revealed by epidemiologic surveys. Statistical associations are not necessarily causal, and a 3. The ovaries or testes respond to the rising amounts variety of covariables and alternative explanations can be of LH and FSH by growing and beginning to proimagined. Effects of such small size can never be conduce estradiol and testosterone. firmed or refuted for any individual child. Furthermore, 4. Rising levels of estradiol and testosterone produce interpretations of the data are politically controversial bethe body changes of female and male puberty. cause of the ease with which this type of research can be used for political advocacy. Accusations of bias based on political agenda sometimes accompany scientific crit- The onset of this neurohormonal process may precede the first visible body changes by 1–2 years. icism.
12
2.6.1
CHAPTER 2. PUBERTY
Components of the endocrine reproductive system
The arcuate nucleus of the hypothalamus is the driver of the reproductive system. It has neurons which generate and release pulses of GnRH into the portal venous system of the pituitary gland. The arcuate nucleus is affected and controlled by neuronal input from other areas of the brain and hormonal input from the gonads, adipose tissue and a variety of other systems. The pituitary gland responds to the pulsed GnRH signals by releasing LH and FSH into the blood of the general circulation, also in a pulsatile pattern. The gonads (testes and ovaries) respond to rising levels of LH and FSH by producing the steroid sex hormones, testosterone and estrogen. The adrenal glands are a second source for steroid hormones. Adrenal maturation, termed adrenarche, typically precedes gonadarche in mid-childhood.
2.6.2
Major hormones
• Neurokinin B (a tachykinin peptide) and kisspeptin (a neuropeptide), both present in the same hypothalamic neurons, are critical parts of the control system that switches on the release of GnRH at the start of puberty.[83]
• Estradiol is a steroid hormone produced by aromatization of testosterone. Estradiol is the principal human estrogen and acts on estrogen receptors throughout the body. The largest amounts of estradiol are produced by the granulosa cells of the ovaries, but lesser amounts are derived from testicular and adrenal testosterone. • Adrenal androgens are steroids produced by the zona reticulosa of the adrenal cortex in both sexes. The major adrenal androgens are dehydroepiandrosterone, androstenedione (which are precursors of testosterone), and dehydroepiandrosterone sulfate which is present in large amounts in the blood. Adrenal androgens contribute to the androgenic events of early puberty in girls. • IGF1 (insulin-like growth factor 1) rises substantially during puberty in response to rising levels of growth hormone and may be the principal mediator of the pubertal growth spurt. • Leptin is a protein hormone produced by adipose tissue. Its primary target organ is the hypothalamus. The leptin level seems to provide the brain a rough indicator of adipose mass for purposes of regulation of appetite and energy metabolism. It also plays a permissive role in female puberty, which usually will not proceed until an adequate body mass has been achieved.
• GnRH (gonadotropin-releasing hormone) is a peptide hormone released from the hypothalamus 2.6.3 Endocrine perspective which stimulates gonadotrope cells of the anterior pituitary. The endocrine reproductive system becomes functional • LH (luteinizing hormone) is a larger protein hor- by the end of the first trimester of fetal life. The testes and mone secreted into the general circulation by go- ovaries become briefly inactive around the time of birth nadotrope cells of the anterior pituitary gland. The but resume hormonal activity until several months after main target cells of LH are the Leydig cells of testes birth, when incompletely understood mechanisms in the and the theca cells of the ovaries. LH secretion brain begin to suppress the activity of the arcuate nucleus. changes more dramatically with the initiation of pu- This has been referred to as maturation of the prepubertal berty than FSH, as LH levels increase about 25-fold “gonadostat,” which becomes sensitive to negative feedwith the onset of puberty, compared with the 2.5- back by sex steroids. The period of hormonal activity until several months after birth, followed by suppression fold increase of FSH. of activity, may correspond to the period of infant sexu• FSH (follicle stimulating hormone) is another pro- ality, followed by a latency stage, which Sigmund Freud tein hormone secreted into the general circulation described.[84] by the gonadotrope cells of the anterior pituitary. Gonadotropin and sex steroid levels fall to low levels The main target cells of FSH are the ovarian fol- (nearly undetectable by current clinical assays) for aplicles and the Sertoli cells and spermatogenic tissue proximately another 8 to 10 years of childhood. Evidence of the testes. is accumulating that the reproductive system is not to• Testosterone is a steroid hormone produced primarily by the Leydig cells of the testes, and in lesser amounts by the theca cells of the ovaries and the adrenal cortex. Testosterone is the primary mammalian androgen and the “original” anabolic steroid. It acts on androgen receptors in responsive tissue throughout the body.
tally inactive during the childhood years. Subtle increases in gonadotropin pulses occur, and ovarian follicles surrounding germ cells (future eggs) double in number. Normal puberty is initiated in the hypothalamus, with deinhibition of the pulse generator in the arcuate nucleus. This inhibition of the arcuate nucleus is an ongoing active suppression by other areas of the brain. The signal
2.6. NEUROHORMONAL PROCESS and mechanism releasing the arcuate nucleus from inhibition have been the subject of investigation for decades and remain incompletely understood. Leptin levels rise throughout childhood and play a part in allowing the arcuate nucleus to resume operation. If the childhood inhibition of the arcuate nucleus is interrupted prematurely by injury to the brain, it may resume pulsatile gonadotropin release and puberty will begin at an early age.
13 nadotropin pulses seems to be less necessary for progression of male than female puberty.
However, a significant portion of testosterone in adolescent boys is converted to estradiol. Estradiol mediates the growth spurt, bone maturation, and epiphyseal closure in boys just as in girls. Estradiol also induces at least modest development of breast tissue (gynecomastia) in a large proportion of boys. Boys who develop mild Neurons of the arcuate nucleus secrete gonadotropin re- gynecomastia or even developing swellings under nipples leasing hormone (GnRH) into the blood of the pituitary during puberty are told the effects are temporary in some portal system. An American physiologist, Ernst Kno- male teenagers due to high levels of estradiol. bil, found that the GnRH signals from the hypothalamus Another hormonal change in males takes place during the induce pulsed secretion of LH (and to a lesser degree, teenage years for most young men. At this point in a FSH) at roughly 1-2 hour intervals. The LH pulses are male’s life the testosterone levels slowly rise, and most of the consequence of pulsatile GnRH secretion by the ar- the effects are mediated through the androgen receptors cuate nucleus that, in turn, is the result of an oscillator by way of conversion dihydrotestosterone in target organs or signal generator in the central nervous system (“GnRH (especially that of the bowels). pulse generator”).[85] In the years preceding physical puberty, Robert M. Boyar discovered that the gonadotropin pulses occur only during sleep, but as puberty progresses they can be detected during the day.[86] By the end of puberty, there is little day-night difference in the amplitude and frequency of gonadotropin pulses. 2.6.5 Hormonal changes in girls Some investigators have attributed the onset of puberty to a resonance of oscillators in the brain.[87][88][89][90] By this As the amplitude of LH pulses increases, the theca cells mechanism, the gonadotropin pulses that occur primarily of the ovaries begin to produce testosterone and smaller [91][92][93] at night just before puberty represent beats. amounts of progesterone. Much of the testosterone An array of “autoamplification processes” increases the moves into nearby cells called granulosa cells. Smaller production of all of the pubertal hormones of the hy- increases of FSH induce an increase in the aromatase acpothalamus, pituitary, and gonads. tivity of these granulosa cells, which converts most of the Regulation of adrenarche and its relationship to mat- testosterone to estradiol for secretion into the circulation. uration of the hypothalamic-gonadal axis is not fully The remaining testosterone, together with adrenal androunderstood, and some evidence suggests it is a paral- gens is responsible for the typical androgenic changes of lel but largely independent process coincident with or female puberty: pubic hair, other androgenic hair as outeven preceding central puberty. Rising levels of adrenal lined above, body odor, acne. The bioactivity of testosandrogens (termed adrenarche) can usually be detected terone is to a large degree limited by SHBG which in between 6 and 11 years of age, even before the in- turn is mainly controlled by estradiol and prolactin levels creasing gonadotropin pulses of hypothalamic puberty. (estradiol stimulates, prolactin decreases SHBG syntheAdrenal androgens contribute to the development of pu- sis). bic hair (pubarche), adult body odor, and other androgenic changes in both sexes. The primary clinical significance of the distinction between adrenarche and gonadarche is that pubic hair and body odor changes by themselves do not prove that central puberty is underway for an individual child.
Rising levels of estradiol produce the characteristic estrogenic body changes of female puberty: growth spurt, acceleration of bone maturation and closure, breast growth, increased fat composition, growth of the uterus, increased thickness of the endometrium and the vaginal mucosa, and widening of the lower pelvis.
As the estradiol levels gradually rise and the other autoamplification processes occur, a point of maturation is 2.6.4 Hormonal changes in boys reached when the feedback sensitivity of the hypothalamic “gonadostat” becomes positive. This attainment of Early stages of male hypothalamic maturation seem to be positive feedback is the hallmark of female sexual mavery similar to the early stages of female puberty, though turity, as it allows the mid cycle LH surge necessary for ovulation. occurring about 1–2 years later. LH stimulates the Leydig cells of the testes to make testosterone and blood levels begin to rise. For much of puberty, nighttime levels of testosterone are higher than daytime. Regularity of frequency and amplitude of go-
Growth hormone levels rise steadily throughout puberty. IGF1 levels rise and then decline as puberty ends. Growth finishes and adult height is attained as the estradiol levels complete closure of the epiphyses.
14
2.7 Stages • adrenarche (approximately age 7) • gonadarche (approximately age 8) • thelarche (approximately age 11 in females) • pubarche (approximately age 12) • menarche (approximately age 12.5 in females) • spermarche (in males)
2.8 See also • Adolescent sexuality • Child sexuality • Delayed puberty • Eunuch • Hebephilia • Precocious puberty • Secondary sex characteristic • Puberphonia • Kallmann syndrome
2.9 References [1] Kail, RV; Cavanaugh JC (2010). Human Development: A Lifespan View (5th ed.). Cengage Learning. p. 296. ISBN 0495600377. Retrieved September 11, 2014. [2] “For girls, puberty begins around 10 or 11 years of age and ends around age 16. Boys enter puberty later than girlsusually around 12 years of age-and it lasts until around age 16 or 17.” “Teenage Growth & Development: 11 to 14 Years”. Palo Alto Medical Foundation/pamf.org. Retrieved 2013-11-09. [3] “Teenage Growth & Development: 15 to 17 Years”. Palo Alto Medical Foundation/pamf.org. Retrieved 2013-1109. [4] “Puberty and adolescence”. University of Maryland. Retrieved July 5, 2009. [5] Marshall (1986), p. 176–7 [6] (Tanner, 1990). [7] Anderson SE, Dallal GE, Must A; Dallal; Must (April 2003). “Relative weight and race influence average age at menarche: results from two nationally representative surveys of US girls studied 25 years apart”. Pediatrics 111 (4 Pt 1): 844–50. doi:10.1542/peds.111.4.844. PMID 12671122.
CHAPTER 2. PUBERTY
[8] Al-Sahab B, Ardern CI, Hamadeh MJ, Tamim H; Ardern; Hamadeh; Tamim (2010). “Age at menarche in Canada: results from the National Longitudinal Survey of Children & Youth”. BMC Public Health (BMC Public Health) 10: 736. doi:10.1186/1471-2458-10-736. PMC 3001737. PMID 21110899. [9] Hamilton-Fairley, Diana. “Obstetrics and Gynaecology” (Second ed.). Blackwell Publishing. Retrieved 2013-1109. [10] (Jorgensen & Keiding 1991). [11] Alleyne, Richard (2010-06-13). “Girls now reaching puberty before 10 - a year sooner than 20 years ago”. The Daily Telegraph (London). [12] Guillette EA, Conard C, Lares F, Aguilar MG, McLachlan J, Guillette LJ; Conard; Lares; Aguilar; McLachlan; Guillette Jr (March 2006). “Altered breast development in young girls from an agricultural environment”. Environ. Health Perspect. 114 (3): 471–5. doi:10.1289/ehp.8280. PMC 1392245. PMID 16507474. [13] Buck Louis GM, Gray LE, Marcus M, Ojeda SR, Pescovitz OH, Witchel SF, Sippell W, Abbott DH, Soto A, Tyl RW, Bourguignon JP, Skakkebaek NE, Swan SH, Golub MS, Wabitsch M, Toppari J, Euling SY; Gray Jr; Marcus; Ojeda; Pescovitz; Witchel; Sippell; Abbott; Soto; Tyl; Bourguignon; Skakkebaek; Swan; Golub; Wabitsch; Toppari; Euling (February 2008). “Environmental factors and puberty timing: expert panel research needs”. Pediatrics. 121 Suppl 3: S192–207. doi:10.1542/peds.1813E. PMID 18245512. [14] Mouritsen A, Aksglaede L, Sørensen K, Mogensen SS, Leffers H, Main KM, Frederiksen H, Andersson AM, Skakkebaek NE, Juul A; Aksglaede; Sørensen; Mogensen; Leffers; Main; Frederiksen; Andersson; Skakkebaek; Juul (April 2010). “Hypothesis: exposure to endocrine-disrupting chemicals may interfere with timing of puberty”. Int. J. Androl. 33 (2): 346– 59. doi:10.1111/j.1365-2605.2010.01051.x. PMID 20487042. [15] The Oxford Dictionary of English Etymology, C.T. Onions ed. Oxford University Press 1996 p. 720. [16] Garn, SM. Physical growth and development. In: Friedman SB, Fisher M, Schonberg SK., editors. Comprehensive Adolescent Health Care. St Louis: Quality Medical Publishing; 1992. Retrieved on 2009-02-20 [17] Abbassi V (1998). “Growth and normal puberty.”. Pediatrics 102 (2 Pt 3): 507–513. PMID 9685454. [18] MacGillivray MH, Morishima A, Conte F, Grumbach M, Smith EP; Morishima; Conte; Grumbach; Smith (1998). “Pediatric endocrinology update: an overview. The essential roles of estrogens in pubertal growth, epiphyseal fusion and bone turnover: lessons from mutations in the genes for aromatase and the estrogen receptor”. Hormone research. 49 Suppl 1: 2–8. PMID 9554463. [19] Plant TM (2001). “Leptin, growth hormone, and the onset of primate puberty.”. The Journal of Clinical Endocrinology and Metabolism 86 (1): 458–460. doi:10.1210/jc.86.1.459. PMID 11232044.
2.9. REFERENCES
[20] Essential Reproduction, M Johnson, Blackwell Publishers, 6th Rev Ed edition (29 Jun 2007) [21] “Precocious Puberty”. MERCK. May 16, 2008. [22] Meister B, Håkansson ML; Håkansson (2001). “Leptin receptors in hypothalamus and circumventricular organs”. Clinical and experimental pharmacology & physiology 28 (7): 610–617. doi:10.1046/j.1440-1681.2001.03493.x. PMID 11458889. [23] Clayton PE, Trueman JA; Trueman (2000). “Leptin and puberty”. Archives of Disease in Childhood 83 (1): 1–4. doi:10.1136/adc.83.1.1. PMC 1718397. PMID 10868988. [24] Topaloglu AK, Reimann F, Guclu M, Yalin AS, Kotan LD, Porter KM, Serin A, Mungan NO, Cook JR, Ozbek MN, Imamoglu S, Akalin NS, Yuksel B, O'Rahilly S, Semple RK; Reimann; Guclu; Yalin; Kotan; Porter; Serin; Mungan et al. (2009). “TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction”. Nature Genetics 41 (3): 354–358. doi:10.1038/ng.306. PMID 19079066. [25] Berger, Kathleen Stassen (2014). Invitation to the Life Span. New York: Worth Publishers. [26] Taga, Keiko A. (3 May 2006). “A Longitudinal Investigation of Associations Between Boys’ Pubertal Timing and Adult Behavioral Health and Well-Being”. Journal of Youth and Adolescence.
15
[38] Kayaba H, Tamura H, Kitajima S, Fujiwara Y, Kato T, Kato T (November 1996). Hiromi Tamura, Seiichi Kitajima, Yoshiyuki Fujiwara, Tetsuo Kato and Tetsuro Kato. “Analysis of Shape and Retractability of the Prepuce in 603 Japanese Boys”. Journal of Urology (American Urological Association, Inc.) 156 (5): 1813–1815. doi:10.1016/S0022-5347(01)65544-7. PMID 8863623. [39] Ishikawa, E.; Kawakita, M. (2004). “Preputial development in Japanese boys”. Hinyokika Kiyo 50 (5): 305–8. [40] Beaugé M. The causes of adolescent phimosis. Br J Sex Med. 1997;(Sept/Oct):26. [41] “Circumcision Policy Statement”. Pediatrics 103 (3): 686–93. 1999. doi:10.1542/peds.103.3.686. PMID 10049981. [42] Krueger H, Osborn L (1986). “Effects of hygiene among the uncircumcised.”. The Journal of family practice 22 (4): 353–5. PMID 3958682. [43] “Puberty -- Changes for Males”. pamf.org. Retrieved 2009-02-20. [44] “Getting The Facts: Puberty”. ppwr. Archived from the original on 2008-01-04. Retrieved 2009-02-20. [45] “The No-Hair Scare”. PBS. Retrieved 2009-02-20. [46] “The structure of the larynx”. Encyclopædia Britannica. Retrieved 2009-02-20. [47] Marshall (1986), p. 187
[27] Styne (2002), p. 598
[48] Marshall (1986), p. 188
[28] Jones, Kenneth W. (2006). Smith’s Recognizable Patterns of Human Malformation. St. Louis, Mo: Elsevier Saunders. ISBN 0-7216-0615-6.
[49] Tanner JM, Davies PS (1985). “Clinical longitudinal standards for height and height velocity for North American children.”. The Journal of pediatrics 107 (3): 317–329. doi:10.1016/S0022-3476(85)80501-1. PMID 3875704.
[29] Marshall (1986), p. 180. [30] h2g2 - The Morning Glory (or Nocturnal Penile Tumescence)
[50] Gordon (2005), p. 151 [51] Marshall (1986), p. 186–7
[31] Sexuality Now: Embracing Diversity: Embracing Diversity - Janell L. Carroll - Google Books
[52] Rosenfield (2002), p. 462
[32] What’s Happening to My Body? Book for Boys: Revised Edition - Lynda Madaras - Google Books
[53] Siegel MJ, Surratt JT (1992). “Pediatric gynecologic imaging.”. Obstetrics and gynecology clinics of North America 19 (1): 103–127. PMID 1584537.
[33] Making Sense of Sex: A Forthright Guide to Puberty, Sex and Relationships ... - Sarah Attwood - Google Books [34] Erections in Babies | LIVESTRONG.COM [35] What’s Happening to My Body? Book for Boys: Revised Edition - Lynda Madaras - Google Books [36] What’s Happening to My Body? Book for Girls: Revised Edition - Lynda Madaras - Google Books [37] Oster J (April 1968). “Further Fate of the Foreskin Incidence of Preputial Adhesions, Phimosis, and Archives of Smegma among Danish Schoolboys”. Disease in Childhood (Department of Paediatrics, Central Hospital, Randers, Denmark) 43: 200–202. doi:10.1136/adc.43.228.200. PMC 2019851. PMID 5689532. Retrieved November 14, 2011.
[54] Apter D (1980). “Serum steroids and pituitary hormones in female puberty: a partly longitudinal study.”. Clinical endocrinology 12 (2): 107–120. doi:10.1111/j.13652265.1980.tb02125.x. PMID 6249519. [55] Marshall (1986), p. 196-7 [56] Southam AL, Richart RM (1966). “The prognosis for adolescents with menstrual abnormalities.”. American journal of obstetrics and gynecology 94 (5): 637–645. PMID 5906589. [57] “Hips widen during female puberty”. Columbia. Retrieved 2013-11-09. [58] Gungor (2002), pages 699-700 [59] Rosenfield (2002)
16
[60] Kalloo NB, Gearhart JP, Barrack ER (1993). “Sexually dimorphic expression of estrogen receptors, but not of androgen receptors in human fetal external genitalia”. The Journal of Clinical Endocrinology and Metabolism 77 (3): 692–698. doi:10.1210/jcem.77.3.8370691. PMID 8370691. [61] Andersson KE, Wein AJ (2004). “Pharmacology of the Lower Urinary Tract: Basis for Current and Future Treatments of Urinary Incontinence”. Pharmacological Reviews 56 (4): 581–631. doi:10.1124/pr.56.4.4. PMID 15602011. [62] Robinson D, Cardozo L (2011). “Estrogens and the lower urinary tract”. Neurourology and Urodynamics 30 (5): 754–757. doi:10.1002/nau.21106. PMID 21661025. [63] Kaplowitz PB, Slora EJ, Wasserman RC, Pedlow SE, Herman-Giddens ME (2001). “Earlier onset of puberty in girls: relation to increased body mass index and race.”. Pediatrics 108 (2): 347–53. doi:10.1542/peds.108.2.347. PMID 11483799. [64] Nelson RJ. 2005. Introduction to Behavioral Endocrinology. Sinauer Associates: Massachusetts. p357. [65] Zuckerman, Diana (May 2009). “Early Puberty in Girls”. National Research Center for Women and Families. Retrieved 2010-07-13. [66] Mitchell AL, Dwyer A, Pitteloud N, Quinton R (2011). “Genetic basis and variable phenotypic expression of Kallmann syndrome: towards a unifying theory.”. Trends Endocrinol Metab. 22 (7): 249–58. doi:10.1016/j.tem.2011.03.002. PMID 21511493. [67] Oxford Endocrinology Library. Testosterone Deficiency in Men. 2008. ISBN 978-0199545131 Editor: Hugh Jones. Chapter 9. Puberty & Fertility. [68] Finley, Harry. “Average age at menarche in various cultures”. Museum of Menstruation and Women s Health. Retrieved 2007-08-02. [69] Whincup PH, Gilg JA, Odoki K, Taylor SJ, Cook DG (2001). “Age of menarche in contemporary British teenagers: survey of girls born between 1982 and 1986”. BMJ 322 (7294): 1095–6. doi:10.1136/bmj.322.7294.1095. PMC 31261. PMID 11337438. [70] “Girls maturing slightly earlier”. BBC News. 2001-0503. Retrieved 2007-08-02. [71] Rogers, Lois (2010-06-13). “Girls now begin puberty aged 9”. The Times (London). [72] Ge, Xiaojia; Natsuaki, Misaki N.; Neiderhiser, Jenae M.; Reiss, David (2007). “Genetic and Environmental Influences on Pubertal Timing: Results From Two National Sibling Studies”. Journal of Research on Adolescence 17: 767. doi:10.1111/j.1532-7795.2007.00546.x. [73] Mustanski BS, Viken RJ, Kaprio J, Pulkkinen L, Rose RJ (2004). “Genetic and environmental influences on pubertal development: longitudinal data from Finnish twins at ages 11 and 14.”. Developmental psychology 40 (6): 1188–1198. doi:10.1037/0012-1649.40.6.1188. PMID 15535766.
CHAPTER 2. PUBERTY
[74] Treloar SA, Martin NG (1990). “Age at menarche as a fitness trait: nonadditive genetic variance detected in a large twin sample.”. American Journal of Human Genetics 47 (1): 137–148. PMC 1683767. PMID 2349942. [75] Kaprio J, Rimpelä A, Winter T, Viken RJ, Rimpelä M, Rose RJ (1995). “Common genetic influences on BMI and age at menarche.”. Human biology; an international record of research 67 (5): 739–753. PMID 8543288. [76] Comings DE, Muhleman D, Johnson JP, MacMurray JP (2002). “Parent-daughter transmission of the androgen receptor gene as an explanation of the effect of father absence on age of menarche.”. Child Development 73 (4): 1046–1051. doi:10.1111/1467-8624.00456. PMID 12146732. [77] Diana Zuckerman, “When Little Girls Become Women: Early Onset of Puberty in Girls” (This article appeared in The Ribbon, a newsletter of the Cornell University Program on Breast Cancer and Environmental Risk Factors in New York States (BCERF), Vol 6, No. 1, Winter 2001.) Early Puberty in Girls [78] , T., Dumanoski, D. and Myers, J.P. Our Stolen Future, 1996, Plume: New York. [79] “Are Bisphenol A (BPA) Plastic Products Safe for Infants and Children?". [80] McKenna, Phil (2007-03-05). “Childhood obesity brings early puberty for girls”. New Scientist. Archived from the original on 2008-04-19. Retrieved 2010-05-22. [81] Molly, M. Ginty, “US Girls’ Early Puberty Attracts Research Flurry”, Women’s eNews [82] Bulik CM, Reba L, Siega-Riz AM, Reichborn-Kjennerud T (2005). “Anorexia nervosa: definition, epidemiology, and cycle of risk.”. The International Journal of Eating Disorders. 37 Suppl: S2–9; discussion S20–1. doi:10.1002/eat.20107. PMID 15852310. [83] Topaloglu AK, Reimann F, Guclu M, Yalin AS, Kotan LD, Porter KM, Serin A, Mungan NO, Cook JR, Ozbek MN, Imamoglu S, Akalin NS, Yuksel B, O'Rahilly S, Semple RK (2008). “TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction”. Nature Genetics 41 (3): 354–8. doi:10.1038/ng.306. PMID 19079066. Lay summary – e! Science News (200812-11). [84] Lehrer S (1984). “Modern correlates of Freudian psychology. Infant sexuality and the unconscious.”. The American Journal of Medicine 77 (6): 977–80. doi:10.1016/0002-9343(84)90172-4. PMID 6507468. [85] Neill JD (2001). “In Memoriam: Ernst Knobil Endocrine Reviews 22 (6): 721–3. (1926-2000)". doi:10.1210/er.22.6.721. PMID 11739328. [86] Boyar R, Finkelstein J, Roffwarg H, Kapen S, Weitzman E, Hellman L (1972). “Synchronization of augmented luteinizing hormone secretion with sleep during puberty.”. The New England Journal of Medicine 287 (12): 582–586. doi:10.1056/NEJM197209212871203. PMID 4341276.
2.11. EXTERNAL LINKS
[87] Sizonenko PC, Aubert ML (1986). “Neuroendocrine changes characteristic of sexual maturation.”. Journal of neural transmission. Supplementum 21: 159–181. PMID 3462329. [88] Rivest RW (1991). “Sexual maturation in female rats: hereditary, developmental and environmental aspects.”. Experientia 47 (10): 1027–1038. doi:10.1007/bf01923338. PMID 1936201. [89] Yellon SM, Newman SW (1991). “A developmental study of the gonadotropin-releasing hormone neuronal system during sexual maturation in the male Djungarian hamster.”. Biology of Reproduction 45 (3): 440–446. doi:10.1095/biolreprod45.3.440. PMID 1782292. [90] Armstrong SM, Redman JR (1991). “Melatonin: a chronobiotic with anti-aging properties?". Medical Hypotheses 34 (4): 300–309. doi:10.1016/03069877(91)90046-2. PMID 1865836. [91] Lehrer S (1983). “Puberty and resonance: a hypothesis.”. The Mount Sinai journal of medicine, New York 50 (1): 39–43. PMID 6601758. [92] Lehrer S (1986). “Rats on 22.5-hr light:dark cycles have vaginal opening earlier than rats on 26-hr light: dark cycles.”. Journal of Pineal Research 3 (4): 375– 378. doi:10.1111/j.1600-079X.1986.tb00759.x. PMID 3783418. [93] Vilaplana J, Madrid JA, Sánchez-Vázquez J, Campuzano A, Cambras T, Díez-Noguera A (1995). “Influence of period length of light/dark cycles on the body weight and food intake of young rats.”. Physiology & Behavior 58 (1): 9–13. doi:10.1016/0031-9384(95)00021-A. PMID 7667433.
2.10 Further reading • Gordon, Catharine M.; Laufer, MR (2005). “Chapter 4: Physiology of puberty”. In Emans SJH, Goldstein DP, Laufer, MR, eds. Pediatric and Adolescent Gynecology (5th ed.). Philadelphia: Lippincott, Williams & Wilkins. pp. 120–155. ISBN 0-78174493-8. • Gungor, Neslihan; Arslanian SA (2002). “Chapter 21: Nutritional disorders: integration of energy metabolism and its disorders in childhood”. In Sperling, MA ed. Pediatric Endocrinology (2nd ed.). Philadelphia: Saunders. pp. 689–724. ISBN 07216-9539-6.
17 ed. Pediatric Endocrinology (2nd ed.). Philadelphia: Saunders. pp. 455–518. ISBN 0-7216-9539-6. • Styne, Dennis M. (2002). “Chapter 18: The testes: disorders of sexual differentiation and puberty in the male”. In Sperling, MA ed. Pediatric Endocrinology (2nd ed.). Philadelphia: Saunders. pp. 565–628. ISBN 0-7216-9539-6. • Colburn, T., Dumanoski, D. and Myers, J.P. Our Stolen Future, 1996, Plume: New York. • Ducros, A. and Pasquet, P. “Evolution de l'âge d'apparition des premières règles (ménarche) en France”. Biométrie Humaine (1978), 13, 35–43. • Herman-Giddens ME, Slora EJ, Wasserman RC, Bourdony CJ, Bhapkar MV, Koch GG, Hasemeier CM (1997). “Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network.”. Pediatrics 99 (4): 505– 12. doi:10.1542/peds.99.4.505. PMID 9093289. Newer data suggesting that lower age thresholds for evaluation should be used. • Plant TM, Lee PA, eds. The Neurobiology of Puberty. Bristol: Society for Endocrinology, 1995. Proceedings of the latest (4th) International Conference on the Control of the Onset of Puberty, containing summaries of current theories of physiological control, as well as GnRH analog treatment. • Tanner JM, Davies PS (1985). “Clinical longitudinal standards for height and height velocity for North American children.”. The Journal of pediatrics 107 (3): 317–29. doi:10.1016/S0022-3476(85)805011. PMID 3875704. Highly useful growth charts with integrated standards for stages of puberty. • Sizonenko, PC. Role of sex steroids during development—integration. in Bourguignon, Jean Pierre & Tony M. Plant. The Onset of Puberty in Perspective: Proceedings of the 5th International Conference on the Control of the Onset of Puberty, Held in Liège, Belgium, 26–28 September 1999. Elsevier. Amsterdam & New York 2000. ISBN 0444-50296-3. pp 299–306.
2.11 External links
• Marshall, William A.; Tanner, JM (1986). “Chapter 8: Puberty”. In Falkner F, Tanner JM, eds. Human Growth: A Comprehensive Treatise (2nd ed.). New York: Plenum Press. pp. 171–209. ISBN 0-30641952-1.
• Support for teens
• Rosenfield, Robert L. (2002). “Chapter 16: Female puberty and its disorders”. In Sperling, MA
• Pictures and detailed information about breast development during puberty
• University of Maryland guide to puberty and adolescence • Growing Up Sexually: A World Atlas
18 • Research shows how evolution explains age of puberty, ScienceDaily, December 1, 2005. • Gluckman PD, Hanson MA; Hanson (2006). “Evolution, development and timing of puberty”. Trends in endocrinology and metabolism: TEM 17 (1): 7–12. doi:10.1016/j.tem.2005.11.006. PMID 16311040. • Terasawa E, Fernandez DL; Fernandez (2001). “Neurobiological mechanisms of the onset of puberty in primates”. Endocrine Reviews 22 (1): 111– 51. doi:10.1210/er.22.1.111. PMID 11159818. • Puberty in girls: interactive animation of Tanner stages • Puberty in boys: interactive animation of Tanner stages
CHAPTER 2. PUBERTY
Chapter 3
Male reproductive system This article is about the human male reproductive system. For the male reproductive systems of other placental mammals, see Mammalian reproduction#Male placental mammals. For the marsupial male reproductive system, see Marsupial#Male reproductive system. The male reproductive system consists of a number of sex organs that form a part of the human reproductive process. In this type of reproductive system, these sex organs are located outside the body, around the pelvic region. The main male sex organs are the penis and the testicles which produce semen and sperm, which, as part of sexual intercourse, fertilize an ovum in the female’s body; the fertilized ovum (zygote) develops into a fetus, which is later born as a child. Corresponding equivalent among females is the female reproductive system. External male genital organs
3.1 External genital organs 3.1.1
Penis
Main article: Human penis The penis is the male copulatory organ. It has a long shaft and an enlarged bulbous-shaped tip called the glans penis, which supports and is protected by the foreskin in uncircumcised males. When the male becomes sexually aroused, the penis becomes erect and ready for sexual activity. Erection occurs because sinuses within the erectile tissue of the penis become ďŹ lled with blood. The arteries of the penis are dilated while the veins are passively compressed so that blood ows into the erectile cartilage under pressure.
3.1.2
Scrotum
Main article: Scrotum
The scrotum is a pouch-like structure that hangs behind the penis. It holds and protects the testes. It also contains numerous nerves and blood vessels. During times of lower temperatures, the Cremaster muscle contracts and pulls the scrotum closer to the body, while the Dartos muscle gives it a wrinkled appearance; when the temperature increases, the Cremaster and Dartos muscles relax to bring down the scrotum away from the body and remove the wrinkles respectively. The scrotum remains connected with the abdomen or pelvic cavity by the inguinal canal. (The spermatic cord, formed from spermatic artery, vein and nerve bound together with connective tissue passes into the testis through inguinal canal.)
19
20
CHAPTER 3. MALE REPRODUCTIVE SYSTEM Seminal vesicles Main article: Seminal vesicle Seminal vesicles are sac-like structures attached to the vas deferens at one side of the bladder. They produce a sticky, yellowish fluid that contain fructose. This fluid provides sperm cells energy and aids in their motility. 70% of the semen is its secretion. Prostate gland Main article: Prostate gland
Image showing innervation and blood-supply of the human external male genitalia.
The prostate gland surrounds the ejaculatory ducts at the base of the male urethra, just below the bladder. The prostate gland is responsible for the proof semen, a liquid mixture of sperm cells, prostate fluid and seminal fluid. This gland is also responsible for making the semen milky in appearance by mixing calcium to the semen coming from seminal vesicle (semen coming from the seminal vesicle is yellowish in color); the semen remains cloudy and clumpy until the prostatic profibrinolysin is formed into fibrinolysin and lysis of the fibrinogen from the seminal vesicle fluids occurs.
3.2 Internal genital organs
Bulbourethral glands
3.2.1
Main article: Bulbourethral gland
Epididymis
The bulbourethral glands, or Cowper’s glands, are peasized structures located on the sides of the urethra just below the prostate gland. These glands produce a clear, The epididymis, a whitish mass of tightly coiled tubes slippery fluid that empties directly into the urethra. This cupped against the testicles, acts as a maturation and storfluid serves to lubricate the urethra and to neutralize any age for sperm before they pass into the vas deferens, that acidity that may be present due to residual drops of urine carry sperm to the ampullary gland and prostatic ducts. in the urethra. Main article: Epididymis
3.2.2
Vas deferens
Main article: Vas deferens The vas deferens, also known as the sperm duct, is a thin tube approximately 30 centimetres (0.98 ft) long that starts from the epididymis to the pelvic cavity.
3.3 See also • Human sexuality#Male anatomy and reproductive system • Orgasm#In males • Evolution of sexual reproduction
3.2.3
Accessory glands
Three accessory glands provide fluids that lubricate the duct system and nourish the sperm cells. They are the seminal vesicles, the prostate gland, and the bulbourethral glands (Cowper glands).
• Male infertility • Oncofertility • Reproductive system • Spermatogenesis
3.4. REFERENCES
3.4 References
21
Chapter 4
Scrotum For the obsolete dinosaur fossil name, see Megalosaurus#"Scrotum humanum�. The scrotum is an anatomical male reproductive structure that consists of a suspended sack of skin and smooth muscle that is dual-chambered, present in most terrestrial male mammals and is located under the penis. The left testis is lower than the right to avoid compression in the event of impact. The perineal raph is a small, vertical, slightly raised ridge of scrotal skin under which scrotal septum exists. It appears as a thin longitudinal line that runs front to back over the entire scrotum. The scrotum contains the external spermatic fascia, testes, epididymis, ductus deferens. Stream-lined, aquatic mammals such as whales and seals typically lack an external scrotum.[1] It is an distention of the perineum and carries abdominal tissues some into its cavity including the testicular artery, testicular vein and pampinform plexus. In humans and some other mammals, the scrotum becomes covered with pubic hair at puberty. The scrotum is biologically homologous to the labia majora in females.
4.1 Structure 4.1.1
Innervation
4.1.2
Blood supply
4.1.3
Integument
Stages in the development of the male external genitalia.
4.2.1 Genital homology between sexes
The skin on the scrotum is more highly pigmented compared to the rest of the body. The septum is a connective tissue membrane dividing the scrotum into two cavities. Main article: Sexual homology [4]
4.1.4
Lymphatic system
4.2 Development Main article: Development of the reproductive system
Male sex hormones are secreted by the testes later in embryonic life to cause the development of secondary sex organs. The scrotum is developmentally homologous to the labia minora and labia majora. The raphe does not exist in females. Reproductive organs and tissues develop in females and males begin during the ďŹ fth week after fertilization. The gonadal ridge grows behind the peritoneal membrane. 22
4.4. FUNCTION By the sixth week, string-like tissues called primary sex cords form within the enlarging gonadal ridge. Externally, a swelling called the genital tubercule appears over the cloacal membrane. Up until the eighth week after fertilization, the reproductive ogans do not appear to be different between the male and female and are called in-differentiated. Testosterone secretion starts during week eight, reaches peak levels during week 13 and eventually declines to very low levels by the end of the second trimester. The testosterone causes the masculinization of the labioscrotal folds into the scrotum. The scrotal raphe is formed when the embryonic, urethral groove closes by week 12.[6]
4.2.2
23 • Tunica vasculosa testis • Appendix of epididymidis • Septa • Leydig cell • Sertoli cell
4.4 Function
Scrotal growth and puberty
Though the testes and scrotum form early in embryonic life, sexual maturation begins upon entering puberty. The increased secretion of testosterone causes the darkening of the skin and development of pubic hair on the scrotum.[7] Image showing musculature and inner workings of the scrotum.
4.3 Internal structure
The function of the scrotum is to keep the temperature of the testes at about 35-36 degrees Celsius (95-96.8 degrees Fahrenheit), i.e. one to two degrees below the Additional tissues and organs reside inside the scrotum body temperature of 37 degrees Celsius (98.6 degrees and are described in more detail in the following articles: Fahrenheit).[8] High scrotum temperature is damaging to sperm production. Temperature control is accomplished • Testes by the smooth muscles of the scrotum moving the testicles either closer to or further away from the abdomen • Epididymis dependent upon the ambient temperature. This is accomplished by the cremaster muscle in the abdomen and the • Ductus Deferens dartos fascia (muscular tissue under the skin). • Spermatic cord Having the scrotum and testicles situated outside the abdominal cavity may provide additional advantages. The • Vas deferens external scrotum is not affected by abdominal pressure. • Cremaster muscle This may prevent the emptying of the testes before the sperm were matured sufficiently for fertilization.[9] Some • Dartos mammals — elephants and marine mammals, for example – do keep their testes within the abdomen and there • Paradidymis may be mechanisms to prevent this inadvertent emptying. • Tunica albuginea Abdominal muscles, and changes in intra-abdominal • Scrotal septum • Lobule of testes • Rete testes • Efferent ductules • Cavity of tunical albuginea • Tunica vaginalis parietal layer • Tunica vaginalis visceral layer • Median septum
pressure, can often lift and lower the testicles within the scrotum. Contraction of the muscle fibers of the dartos tunic (or fascia) is completely involuntary and results in the appearance of increased wrinkling and thickening of the scrotal skin. The testicles are not directly attached to the skin of the scrotum, so this dartos contraction results in their sliding toward the abdomen. They also, in some men, can be lifted the same way by tightening the anus and pelvic muscles, doing Kegel exercises. Although the ideal temperature for sperm growth varies between species, it usually appears, in warm-blooded species, to be a bit cooler than internal body temperature, making the scrotum necessary. Since this leaves
24
CHAPTER 4. SCROTUM • varicocele • inguinal hernia • epiditymo-orchitis • testicular torsion • genital warts • testicular cancer • dermatitis • undescended testes • Chyloderma
Diagram of the scrotum. On the left side the cavity of the tunica vaginalis has been opened; on the right side only the layers superficial to the Cremaster muscle have been removed.
• mumps
the testicles vulnerable in many species, there is some debate on the evolutionary advantage of such a system. One theory is that the impregnation of females who are ill is less likely when sperm is highly sensitive to elevated body temperatures. An alternative explanation is to protect the testes from jolts and compressions associated with an active lifestyle. Animals that have stately movements – such as elephants, whales, and marsupial moles – have internal testes and no scrotum.[10]
• herpes
• scabies
• pubic lice • Chancroid (Haemophilus ducreyi) • Chlamydia (Chlamydia trachomatis) • Gonorrhea (Neisseria gonorrhoeae) • Granuloma inguinale or (Klebsiella granulomatis)
4.5 Clinical significance A study has indicated that use of a laptop computer positioned on the lap can negatively affect sperm production.[11][12]
4.6 Diseases and conditions The scrotum and its contents can develop diseases or incur injuries. These include:
• Syphilis (Treponema pallidum) • scrotum eczema[14] • scrotal psoriasis disease[15] • Riboflavin deficiency[15] • Red Scrotum disease[16]
4.7 See also
• Candidiasis (yeast infection) • sebaceous cyst
This article uses anatomical terminology; for an overview, see anatomical terminology.
• epidermal cyst • hydrocele • hematocele • Molluscum contagiosum
• Scrotal infusion, a temporary form of body modification • Sex organ
• spermatocele
• Retroperitoneal lymph node dissection
• Paget’s disease of the scrotum[13]
• Testicular self-examination
4.9. REFERENCES
4.8 Bibliography Books • This article incorporates text from a public domain edition of Gray’s Anatomy. • Van De Graaff, Kent M.; Fox, Stuart Ira (1989). Concepts of Human Anatomy and Physiology. Dubuque, Iowa: William C. Brown Publishers. ISBN 0697056759. • Elson, Lawrence; Kapit, Wynn (1977). The Anatomy Coloring. New York, New York: Harper & Row. ISBN 0064539148. • “Gross Anatomy Image”. Medical Gross Anatomy Atlas Images. University of Michigan Medical School. 1997. Retrieved 2015-02-23. • Berkow, MD, editor, Robert (1977). The Merck Manual of Medical Information; Home Edition. Whitehouse Station, New Jersey: Merck Research Laboratories. ISBN 0911910875.
4.9 References [1] “Scrotum”. National Institutes of Health. Retrieved 6 January 2011. [2] Moore, Keith; Anne Agur (2007). Essential Clinical Anatomy, Third Edition. Lippincott Williams & Wilkins. p. 132. ISBN 0-7817-6274-X. [3] Elson 1977. [4] “Scrotum”. Encyclopedia Britannica. Retrieved 2015-0224. [5] “VIII. The Lymphatic System. 5. The Lymphatics of the Lower Extremity. Gray, Henry. 1918. Anatomy of the Human Body.”. Retrieved 2015-02-24. [6] vandegraaff 1989, p. 927-931. [7] vandegraaff 1989, p. 935. [8] “About the Male Reproductive System”. KidsHealth. Retrieved 6 January 2011. [9] “Science : Bumpy lifestyle led to external testes - 17 August 1996 - New Scientist”. Retrieved 2007-11-06. [10] “Science : Bumpy lifestyle led to external testes - 17 August 1996 - New Scientist”. Retrieved 2007-11-06. [11] “Laptops may damage male fertility”. BBC News. 200412-09. Retrieved 2012-01-30. [12] Sheynkin, Yefim; et al. (February 2005). “Increase in scrotal temperature in laptop computer users”. Hum. Reprod. 20 (2): 452–455. doi:10.1093/humrep/deh616. PMID 15591087.
25
[13] “Paget’s disease of the scrotum Symptoms, Diagnosis, Treatments and Causes”. RightDiagnosis.com. Retrieved 2015-02-24. [14] “Common scrotal skin diseases”. TCMWell. Retrieved 2015-02-24. [15] TCMwell. [16] Uwe, Wollina (Sep 21, 2011). “Red scrotum syndrome”. J Dermatol Case Rep 5 (3): 38–41. doi:10.3315/jdcr.2011.1072.
Chapter 5
Testicle 5.1 Structure 5.1.1 External appearance Almost all healthy male vertebrates have two testicles. They are typically of similar size, although in sharks, that on the right side is usually larger, and in many bird and mammal species, the left may be the larger. The primitive jawless fish have only a single testis, located in the midline of the body, although even this forms from the fusion of paired structures in the embryo.[3] The testicles of a dromedary camel are 7–10 cm (2.8–3.9 in) long, 4.5 cm (1.8 in) deep and 5 cm (2.0 in) in width. The right testicle is often smaller than the left.[4] The testicles of a male red fox attain their greatest weight in December–February.[5] Spermatogenesis in male golden jackals occurs 10–12 days before the females enter estrus and, during this time, males’ testicles triple in weight.[6] In mammals, the testes are often contained within an extension of the abdomen called the scrotum. In mammals with external testes it is most common for one testicle to hang lower than the other. While the size of the testicle varies, it is estimated that 21.9% of men have their higher testicle being their left, while 27.3% of men have reported to have equally positioned testicles.[7] This is due to differences in the vascular anatomical structure on the right and left sides.
Diagram of an adult human testicle: A.) Blood vessels; B.) Head of epididymis; C.) Efferent ductules; D.) Seminiferous tubules; E.) Parietal lamina of tunica vaginalis; F.) Visceral lamina of tunica vaginalis; G.) Cavity of tunica vaginalis; H.) Tunica albuginea; I.) Lobule of testis; J.) Tail of epididymis; K.) Body of epididymis; L.) Mediastinum; M.) Vas deferens.
The testicle (from Latin testiculus, diminutive of testis, meaning “witness” of virility,[1] plural testes) is the male gonad in animals. Like the ovaries to which they are homologous, testes are components of both the reproductive system and the endocrine system. The primary functions of the testes are to produce sperm (spermatogenesis) and to produce androgens, primarily testosterone.
In healthy European adult humans, average testicular volume is 18 cm³ per testis, with normal size ranging from 12 cm³ to 30 cm³.[8] The average testicle size after puberty measures up to around 2 inches long, 0.8 inches in breadth, and 1.2 inches in height (5 x 2 x 3 cm). Measurement in the living adult is done in two basic ways:
• comparing the testicle with ellipsoids of known sizes Both functions of the testicle are influenced by go(orchidometer). nadotropic hormones produced by the anterior pituitary. Luteinizing hormone (LH) results in testosterone release. • measuring the length, depth and width with a ruler, The presence of both testosterone and follicle-stimulating a pair of calipers or ultrasound imaging. hormone (FSH) is needed to support spermatogenesis. It has also been shown in animal studies that if testes are exposed to either too high or too low levels of estrogens The volume is then calculated using the formula for the (such as estradiol; E2) spermatogenesis can be disrupted volume of an ellipsoid: 4/3 π × (length/2) × (width/2) × to such an extent that the animals become infertile.[2] (depth/2). 26
5.1. STRUCTURE
27
Human testicles are smaller than chimpanzee testicles but puberty into old age, develop into sperm cells (also known larger than gorilla testicles.[9] as spermatozoa or male gametes). The developing sperm The size of the testicles is among the parameters of the travel through the seminiferous tubules to the rete testis Tanner scale for the maturity of male genitals, from stage located in the mediastinum testis, to the efferent ducts, I which represents a volume of less than 1.5 ml, to stage and then to the epididymis where newly created sperm V which represents a testicular volume of greater than 20 cells mature (see spermatogenesis). The sperm move into the vas deferens, and are eventually expelled through the ml. urethra and out of the urethral orifice through muscular contractions.
5.1.2
Internal structure
Amphibians and most fish do not possess seminiferous tubules. Instead, the sperm are produced in spherical structures called sperm ampullae. These are seasonal structures, releasing their contents during the breeding season, and then being reabsorbed by the body. Before the next breeding season, new sperm ampullae begin to form and ripen. The ampullae are otherwise essentially identical to the seminiferous tubules in higher vertebrates, including the same range of cell types.[3] Primary cell types Within the seminiferous tubules
Transverse section through the left side of the scrotum and the left testis.
• Here, germ cells develop into spermatogonia, spermatocytes, spermatids and spermatozoon through the process of spermatogenesis. The gametes contain DNA for fertilization of an ovum[10] • Sertoli cells – the true epithelium of the seminiferous epithelium, critical for the support of germ cell development into spermatozoa. Sertoli cells secrete inhibin.[11] • Peritubular myoid cells surround the seminiferous tubules.[12] Between tubules (interstitial cells) • Leydig cells – cells localized between seminiferous tubules that produce and secrete testosterone and other androgens important for sexual development and puberty, secondary sexual characteristics like facial hair, sexual behavior and libido, supporting spermatogenesis and erectile function. Testosterone also controls testicular volume.
Cross section of rabbit testis, photographed in bright field microscopy at 40× magnification.
• Also present are: • Immature Leydig cells
Duct system
• Interstitial macrophages and epithelial cells.
Under a tough membranous shell, the tunica albuginea, Blood supply and lymphatic drainage the testis of amniotes and some teleost fish, contains very fine coiled tubes called seminiferous tubules. The tubules Blood supply and lymphatic drainage of the testes and are lined with a layer of cells (germ cells) that from scrotum are distinct:
28 • The paired testicular arteries arise directly from the abdominal aorta and descend through the inguinal canal, while the scrotum and the rest of the external genitalia is supplied by the internal pudendal artery (itself a branch of the internal iliac artery). • The testis has collateral blood supply from 1. the cremasteric artery (a branch of the inferior epigastric artery, which is a branch of the external iliac artery), and 2. the artery to the ductus deferens (a branch of the inferior vesical artery, which is a branch of the internal iliac artery). Therefore, if the testicular artery is ligated, e.g., during a FowlerStevens orchiopexy for a high undescended testis, the testis will usually survive on these other blood supplies.
CHAPTER 5. TESTICLE ficient at lower and higher temperatures. This is presumably why the testes are located outside the body. There are a number of mechanisms to maintain the testes at the optimum temperature.
Cremasteric muscle
The cremasteric muscle is part of the spermatic cord. When this muscle contracts, the cord is shortened and the testicle is moved closer up toward the body, which provides slightly more warmth to maintain optimal testicular temperature. When cooling is required, the cremasteric muscle relaxes and the testicle is lowered away from the warm body and is able to cool. It also occurs in response to stress (the testicles rise up toward the body in an effort • Lymphatic drainage of the testes follows the tes- to protect them in a fight). There are persistent reports ticular arteries back to the paraaortic lymph nodes, that relaxation indicates approach of orgasm. There is a while lymph from the scrotum drains to the inguinal noticeable tendency to also retract during orgasm. lymph nodes. The cremaster muscle can reflexively raise each testicle individually if properly triggered. This phenomenon is known as the cremasteric reflex. The testicles can also be Layers lifted voluntarily using the pubococcygeus muscle, which Many anatomical features of the adult testis reflect its de- partially activates related muscles. velopmental origin in the abdomen. The layers of tissue enclosing each testicle are derived from the layers of the anterior abdominal wall. Notably, the cremasteric muscle 5.1.4 Development arises from the internal oblique muscle. The blood–testis barrier Large molecules cannot pass from the blood into the lumen of a seminiferous tubule due to the presence of tight junctions between adjacent Sertoli cells. The spermatogonia are in the basal compartment (deep to the level of the tight junctions) and the more mature forms such as primary and secondary spermatocytes and spermatids are in the adluminal compartment. The function of the blood–testis barrier (red highlight in diagram above) may be to prevent an auto-immune reaction. Mature sperm (and their antigens) arise long after immune tolerance is established in infancy. Therefore, since sperm are antigenically different from self tissue, a male animal can react immunologically to his own sperm. In fact, he is capable of making antibodies against them.
There are two phases in which the testes grow substantially; namely in embryonic and pubertal age.
Embryonic During mammalian development, the gonads are at first capable of becoming either ovaries or testes.[13] In humans, starting at about week 4 the gonadal rudiments are present within the intermediate mesoderm adjacent to the developing kidneys. At about week 6, sex cords develop within the forming testes. These are made up of early Sertoli cells that surround and nurture the germ cells that migrate into the gonads shortly before sex determination begins. In males, the sex-specific gene SRY that is found on the Y-chromosome initiates sex determination by downstream regulation of sex-determining factors, (such as GATA4, SOX9 and AMH), which leads to development of the male phenotype, including directing development of the early bipotential gonad down the male path of development.
Injection of sperm antigens causes inflammation of the testis (auto-immune orchitis) and reduced fertility. Thus, the blood–testis barrier may reduce the likelihood that sperm proteins will induce an immune response, reducTestes follow the “path of descent” from high in the posteing fertility and so progeny. rior fetal abdomen to the inguinal ring and beyond to the inguinal canal and into the scrotum. In most cases (97% full-term, 70% preterm), both testes have descended by 5.1.3 Temperature regulation birth. In most other cases, only one testis fails to deThe testes work best at temperatures slightly less than scend (cryptorchidism) and that will probably express itcore body temperature. The spermatogenesis is less ef- self within a year.
5.2. EVOLUTION
29
Pubertal
very high core body temperatures have internal testes and did not evolve external testes.[15] It was once theorized The testes grow in response to the start of that birds used their air sacs to cool the testes internally, spermatogenesis. Size depends on lytic function, but later studies revealed that birds’ testes are able to funcsperm production (amount of spermatogenesis present in tion at core body temperature.[15] testis), interstitial fluid, and Sertoli cell fluid production. Some mammals which have seasonal breeding cycles After puberty, the volume of the testes can be increased keep their testes internal until the breeding season at by over 500% as compared to the pre-pubertal size. which point their testes descend and increase in size and Testicles are fully descended before one reaches puberty. become external.[16]
5.2 Evolution 5.2.1
External testes
The basal condition for mammals is to have internal testes. Boreoeutherian land mammals however, the large group of mammals that includes humans, have externalized testes. Their testes function best at temperatures lower than their core body temperature. Their testes are located outside of the body, suspended by the spermatic cord within the scrotum. The testes of the non-boreotherian mammals such as the monotremes, armadillos, sloths, elephants remain within the abdomen.[14] There are also some Boreoeutherian mammals with internal testes, such as the rhinoceros.
2) Irreversible adaptation to sperm competition. It has been suggested that the ancestor of the boreoeutherian mammals was a small mammal that required very large testes (perhaps rather like those of a hamster) for sperm competition and thus had to place its testes outside the body.[17] This led to enzymes involved in spermatogenesis, spermatogenic DNA polymerase beta and recombinase activities evolving a unique temperature optimum, slightly less than core body temperature. When the boreoeutherian mammals then diversified into forms that were larger and/or did not require intense sperm competition they still produced enzymes that operated best at cooler temperatures and had to keep their testes outside the body. This position is made less parsimonious by the fact that the kangaroo, a non-boreoeutherian mammal, has external testicles. The ancestors of kangaroos might, separately from boreotherian mammals, have also been subject to heavy sperm competition and thus developed external testes, however, kangaroo external testes are suggestive of a possible adaptive function for external testes in large animals.
Marine boreotherian mammals, such as whales and dolphins, also have internal testes. As external testes would increase drag in the water they have internal testes which are kept cool by special circulatory systems that cool the 3) Protection from abdominal cavity pressure arterial blood going to the testes by placing the arteries changes. One argument for the evolution of external near veins bringing cooled venous blood from the skin. testes is that it protects the testes from abdominal cavity There are several hypotheses why most boreotherian pressure changes caused by jumping and galloping.[18] mammals have external testes which operate best at a temperature that is slightly less than the core body temperature, e.g. that it is stuck with enzymes evolved in 5.2.2 Testicular size a colder temperature due to external testes evolving for different reasons, that the lower temperature of the testes simply is more efficient for sperm production. 1) More efficient. The classic hypothesis is that cooler temperature of the testes allows for more efficient fertile spermatogenesis. In other words, there are no possible enzymes operating at normal core body temperature that are as efficient as the ones evolved, at least none appearing in our evolution so far. The early mammals had lower body temperatures and thus their testes worked efficiently within their body. However it is argued that boreotherian mammals have higher body temperatures than the other mammals and had to develop external testes to keep them cool. It is argued that those mammals with internal testes, such A human testicle is being measured with an orchidometer and is as the monotremes, armadillos, sloths, elephants, and typically 15 to 25 ml in volume. rhinoceroses, have a lower core body temperatures than those mammals with external testes. Testicular size as a proportion of body weight varies However, the question remains why birds despite having widely. In the mammalian kingdom, there is a tendency
30
CHAPTER 5. TESTICLE
for testicular size to correspond with multiple mates • Some jockstraps are designed to provide support to (e.g., harems, polygamy). Production of testicular output the testicles.[23] sperm and spermatic fluid is also larger in polygamous animals, possibly a spermatogenic competition for survival. The testes of the right whale are likely to be the largest of 5.3.2 Diseases and conditions that affect the testes any animal, each weighing around 500 kg (1,100 lb).[19] Among the Hominidae, gorillas have little female promisSome prominent conditions and differential diagnoses incuity and sperm competition and the testes are small comclude: pared to body weight (0.03%). Chimpanzees have high promiscuity and large testes compared to body weight • Testicular cancer and other neoplasms To improve (0.3%). Human testicular size falls between these exthe chances of catching possible cases of testicular tremes (0.08%).[20] cancer or other health issues early, regular testicular self-examination is recommended. There is some evidence to suggest that average human testicle size and weight has been progressively shrinking in • Varicocele, swollen vein(s) from the testes, usually recent years among younger cohorts in Western industriaffecting the left side,[24] the testis usually being noralized nations. This has been suggested to be associated mal with a possible decline in sperm counts in some world regions. The recent changes suggest involvement of en• Hydrocele testis, swelling around testes caused by vironmental or lifestyle factor(s) such as increasing expoaccumulation of clear liquid within a membranous sure to endocrine disruptors.[21] sac, the testis usually being normal Testis weight also varies in seasonal breeders like deer and horses. The change is related to changes in testosterone production.
5.3 Clinical significance Main article: Testicular disease
5.3.1
Protection and injury
Further information: Testicular pain
• Endocrine disorders can also affect the size and function of the testis. • Certain inherited conditions involving mutations in key developmental genes also impair testicular descent, resulting in abdominal or inguinal testes which remain nonfunctional and may become cancerous. Other genetic conditions can result in the loss of the Wolffian ducts and allow for the persistence of Müllerian ducts. • Bell Clapper Deformity is a deformity in which the testicle is not attached to the scrotal walls, and can rotate freely on the spermatic cord within the tunica vaginalis. This deformity has been linked to Testicular torsion.
• Epididymitis, a painful inflammation of the epididymis or epididymides frequently caused by bac• The testicles are well-known to be very sensitive to terial infection but sometimes of unknown origin. impact and injury. The pain involved travels up from each testicle into the abdominal cavity, via the spermatic plexus, which is the primary nerve of each testicle. This will cause pain in the hip and the back. 5.3.3 Effects of exogenous hormones The pain usually goes away in a few minutes. To some extent, it is possible to change testicular size. • Testicular torsion is a medical emergency. Treat- Short of direct injury or subjecting them to adverse conment within 4–6 hours of onset can prevent necrosis ditions, e.g., higher temperature than they are normally accustomed to, they can be shrunk by competing against of the testis.[22] their intrinsic hormonal function through the use of exter• Testicular rupture is a medical emergency caused by nally administered steroidal hormones. Steroids taken for blunt force impact, sharp edge, or piercing impact to muscle enhancement (especially anabolic steroids) often one or both testicles, which can lead to necrosis of have the undesired side effect of testicular shrinkage. the testis in as little as 30 minutes. Similarly, stimulation of testicular functions via • Penetrating injuries to the scrotum may cause castration, or physical separation or destruction of the testes, possibly along with part or all of the penis, which results in total sterility if the testicles are not reattached quickly.
gonadotropic-like hormones may enlarge their size. Testes may shrink or atrophy during hormone replacement therapy or through chemical castration. In all cases, the loss in testes volume corresponds with a loss of spermatogenesis.
5.7. SEE ALSO
5.4 Society and culture Main article: Animelles Testicles of a male calf or other livestock are used to comprise a dish, sometimes called Rocky Mountain oysters.[25]
5.5 History Main article: Sex selection
31 • Testis surface • Testis cross section • The right testis, exposed by laying open the tunica vaginalis. • Microscopic view of Rabbit testis 100× • Testicle
5.7 See also • Anorchia
In the Middle Ages, men who wanted a boy sometimes had their left testicle removed. This was because people believed that the right testicle made “boy” sperm and the left made “girl” sperm.[26] As early as 330 BC, Aristotle prescribed the ligation (tying off) of the left testicle in men wishing to have boys.[27]
• Cryptorchidism (cryptorchismus)
5.5.1
• Orchidometer
Etymology
The etymology of the word is based on Roman law. The Latin word "testis", witness, was used in the firmly established legal principle "Testis unus, testis nullus" (one witness [equals] no witness), meaning that testimony by any one person in court was to be disregarded unless corroborated by the testimony of at least another. This led to the common practice of producing two witnesses, bribed to testify the same way in cases of lawsuits with ulterior motives. Since such “witnesses” always came in pairs, the meaning was accordingly extended, often in the diminutive (testiculus, testiculi). Another theory says that testis is influenced by a loan translation, from Greek parastatēs “defender (in law), supporter” that is “two glands side by side”.[28]
5.6 Gallery • Testicle • Testicle • Testicle hanging on cremaster muscle. These are two healthy testicles. Heat causes them to descend, allowing cooling. • A healthy scrotum containing normal size testes. The scrotum is in tight condition. The image also shows the texture. • Testicle of a cat: 1: Extremitas capitata, 2: Extremitas caudata, 3: Margo epididymalis, 4: Margo liber, 5: Mesorchium, 6: Epididymis, 7: testicular artery and vene, 8: Ductus deferens
• Polyorchidism • Infertility • List of homologues of the human reproductive system
• Spermatogenesis • Sterilization (surgical procedure), vasectomy • Testicondy • Epididymis • Spermatic cord • Penis • Perineum • Bollocks • WikiSaurus:testicles — the WikiSaurus list of synonyms and slang words for testicles in many languages • Ejaculation
5.8 Notes • Heptner, V. G.; Naumov, N. P. (1998). Mammals of the Soviet Union Vol.II Part 1a, SIRENIA AND CARNIVORA (Sea cows; Wolves and Bears). Science Publishers, Inc. USA. ISBN 1-886106-81-9. Retrieved 2013-11-09. [1] “Blackwell Synergy”. 2010-10-25.
Blackwell Synergy.
Retrieved
[2] Sierens, J. E.; Sneddon, S. F.; Collins, F.; Millar, M. R.; Saunders, P. T. (2005). “Estrogens in Testis Biology”. Annals of the New York Academy of Sciences 1061: 65– 76. doi:10.1196/annals.1336.008. PMID 16467258.
32
CHAPTER 5. TESTICLE
[3] Romer, Alfred Sherwood; Parsons, Thomas S. (1977). The Vertebrate Body. Philadelphia, PA: Holt-Saunders International. pp. 385–386. ISBN 0-03-910284-X. [4] Mukasa-Mugerwa, E. The Camel (Camelus dromedarius): A Bibliographical Review. pp. 11–3.
[22] S. Khan, J. Rehman, B. Chughtai, D. Sciullo, E. Mohan & H. Rehman: “Anatomical Approach to Scrotal Emergencies: A New Paradigm for the Diagnosis and Treatment of the Acute Scrotum”. The Internet Journal of Urology. (2010) Volume 6: Number 2. ISSN 1528-8390.
[5] Heptner & Naumov 1998, p. 537
[23] Amazon.com: Suspensory Jockstrap for Scrotal/Testicle Support: Health & Personal Care
[6] Heptner & Naumov 1998, pp. 154–155
[24] “Varicocele”. Kidshealth.org. Retrieved 2010-10-25.
[7] Scrotal Asymmetry: Right-Left and the scrotum in male sculpture”" By I. C. Manus
[25] Reviving a very delicate delicacy
[8] Andrology: Male Reproductive Health and Dysfunction”" By E. Nieschlag, Hermann M. Behre, H. van. Ahlen [9] Human Origins 101 – Page 138, Holly M. Dunsworth – 2007 [10] Histology, A Text and Atlas by Michael H. Ross and Wojciech Pawlina, Lippincott Williams & Wilkins, 5th ed, 2006 [11] Skinner M, McLachlan R, Bremner W (1989). “Stimulation of Sertoli cell inhibin secretion by the testicular paracrine factor PModS”. Mol Cell Endocrinol 66 (2): 239–49. doi:10.1016/0303-7207(89)90036-1. PMID 2515083. [12] Arch Histol Cytol. 1996 Mar;59(1):1–13 [13] Online textbook: "Developmental Biology" 6th ed. By Scott F. Gilbert (2000) published by Sinauer Associates, Inc. of Sunderland (MA). [14] Spermatogenesis [15] BIOLOGY OF REPRODUCTION 56, 1570–1575 (1997)- Determination of Testis Temperature Rhythms and Effects of Constant Light on Testicular Function in the Domestic Fowl (Gallus domesticus) [16] “Ask a Biologist Q&A / Human sexual physiology – good design?". Askabiologist.org.uk. 2007-09-04. Retrieved 2010-10-25. [17] "'The Human Body as an Evolutionary Patchwork' by Alan Walker, Princeton.edu”. RichardDawkins.net. 2007-04-10. Retrieved 2010-10-25. [18] Newscientist.com testes
–
bumpy-lifestyle-led-to-external-
[19] Crane, J.; Scott, R. (2002). “Eubalaena glacialis”. Animal Diversity Web. Retrieved 2009-05-01. [20] Shackelford, T. K.; Goetz, A. T. (2007). “Adaptation to Sperm Competition in Humans”. Current Directions in Psychological Science 16: 47. doi:10.1111/j.14678721.2007.00473.x. [21] Dindyal, S. (2007). “The sperm count has been decreasing steadily for many years in Western industrialised countries: Is there an endocrine basis for this decrease?". The Internet Journal of Urology 2 (1): 1–21.
[26] Understanding genetics; Human health and genome Stanford school of medicine, Dr. Barry Starr [27] Hoag, Hannah. I'll take a girl, please... Cherry-picking from the dish of life. Drexel University Publication. [28] The American Heritage Dictionary of the English Language, Fourth Edition
Chapter 6
Vas deferens The vas deferens (Latin: “carrying-away vessel"; plural: vasa deferentia), also called ductus deferens (Latin: “carrying-away duct"; plural: durukljctuli deferentes), is part of the male anatomy of many vertebrates; these vasa transport sperm from the epididymis to the ejaculatory ducts in anticipation of ejaculation.
6.1 Structure There are two ducts, connecting the left and right epididymis to the ejaculatory ducts in order to move sperm. Each tube is about 30 centimeters (0.98 ft) long (in humans), 3 to 5 mm in diameter and is muscular (surrounded by smooth muscle). Its epithelium is lined by stereocilia. They are part of the spermatic cords.
6.1.1
[1]
Blood supply
deferentia are permanently cut, though in some cases it can be reversed. A modern variation, which is also known as a vasectomy even though it does not include cutting the vas, involves injecting an obstructive material into the ductus to block the flow of sperm. Investigational attempts for male contraception have focused on the vas with the use of the intra vas device and reversible inhibition of sperm under guidance.
6.3.2 Disease The vas deferens may be obstructed, or may be completely absent in a condition called as Congenital Absence of Vas Deferens ( CABD ), (the latter a potential feature of cystic fibrosis), causing male infertility. Acquired obstructions can occur due to infections. It can be overcome by testicular sperm extraction (TESE), Micro Epididymis Sperm Extraction ( MESA ), collecting sperm cells directly from the testicle or Epididymis .
The vas deferens is supplied by an accompanying artery (artery of vas deferens). This artery normally arises from 6.3.3 the superior (sometimes inferior) vesical artery, a branch of the internal iliac artery.
Uses in pharmacology and physiology
The vas deferens has a dense sympathetic innervation (Sjöstrand, NO (1965). The adrenergic innervation of 6.2 Function the vas deferens and the accessory male genital organs. Acta Physiologica Scandinavica 257:S1–82), making it During ejaculation, the smooth muscle in the walls of a useful system for studying sympathetic nerve function [2] the vas deferens contracts reflexively, thus propelling the and for studying drugs that modify neurotransmission. sperm forward. This is also known as peristalsis. The It has been used: sperm is transferred from the vas deferens into the urethra, collecting secretions from the male accessory sex • as a bioassay for the discovery of enkephalins, the glands such as the seminal vesicles, prostate gland and endogenous opiates.[3] the bulbourethral glands, which form the bulk of semen. • to demonstrate quantal transmission from sympathetic nerve termianals.[4]
6.3 Clinical significance 6.3.1
• as the first direct measure of free Ca2+ concentration in a postganglionic nerve terminal.[5]
Contraception
The procedure of deferentectomy, also known as a vasectomy, is a method of contraception in which the vasa 33
• to develop an optical method for monitoring quantal transmission.[6]
34
CHAPTER 6. VAS DEFERENS
6.4 Other animals Most vertebrates have some form of duct to transfer the sperm from the testes to the urethra. In cartilaginous fish and amphibians, sperm is carried through the archinephric duct, which also partially helps to transport urine from the kidneys. In teleosts, there is a distinct sperm duct, separate from the ureters, and often called the vas deferens, although probably not truly homologous with that in humans.[7] In cartilaginous fishes, the part of the archinephric duct closest to the testis is coiled up to form an epididymis. Below this are a number of small glands secreting components of the seminal fluid. The final portion of the duct also receives ducts from the kidneys in most species.[7] In amniotes, however, the archinephric duct has become a true vas deferens, and is used only for conducting sperm, never urine. As in cartilaginous fish, the upper part of the duct forms the epididymis. In many species, the vas deferens ends in a small sac for storing sperm.[7] The only vertebrates to lack any structure resembling a vas deferens are the primitive jawless fishes, which release sperm directly into the body cavity, and then into the surrounding water through a simple opening in the body wall.[7]
6.5 Additional images • Male reproductive system. • Coronal section of pelvis, showing arrangement of fasciæ. Viewed from behind. • The relations of the femoral and abdominal inguinal rings, seen from within the abdomen. Right side. • The spermatic cord in the inguinal canal. • Fundus of the bladder with the vesiculæ seminales. • Vertical section of bladder, penis, and urethra. • Prostate with seminal vesicles and seminal ducts, viewed from in front and above. • Prostate • Microscopic cross section. • Testis, spermatic vessels and vas deferens
6.6 See also This article uses anatomical terminology; for an overview, see anatomical terminology. • Vasectomy
• Intra vas device • Excretory duct of seminal gland • vas deferens in the reproductive system of gastropods
6.7 References [1] Dr C Sharath Kumar, Ph D Thesis, University of Mysore, 2013 [2] Burnstock, G; Verkhratsky, A (2010). “Vas deferens-a model used to establish sympathetic cotransmission”. Trends in Pharmacological Sciences 31 (3): 131–9. doi:10.1016/j.tips.2009.12.002. PMID 20074819. [3] Hughes, J; Smith, T. W.; Kosterlitz, H. W.; Fothergill, L. A.; Morgan, B. A.; Morris, H. R. (1975). “Identification of two related pentapeptides from the brain with potent opiate agonist activity”. Nature 258 (5536): 577–80. doi:10.1038/258577a0. PMID 1207728. [4] Brock, J. A.; Cunnane, T. C. (1987). “Relationship between the nerve action potential and transmitter release from sympathetic postganglionic nerve terminals”. Nature 326 (6113): 605–7. doi:10.1038/326605a0. PMID 2882426. [5] Brain, K. L.; Bennett, M. R. (1997). “Calcium in sympathetic varicosities of mouse vas deferens during facilitation, augmentation and autoinhibition”. The Journal of physiology 502 (3): 521–36. PMC 1159525. PMID 9279805. [6] Brain, K. L.; Jackson, V. M.; Trout, S. J.; Cunnane, T. C. (2002). “Intermittent ATP release from nerve terminals elicits focal smooth muscle Ca2+ transients in mouse vas deferens”. The Journal of physiology 541 (Pt 3): 849– 62. doi:10.1113/jphysiol.2002.019612. PMC 2290369. PMID 12068045. [7] Romer, Alfred Sherwood; Parsons, Thomas S. (1977). The Vertebrate Body. Philadelphia, PA: Holt-Saunders International. pp. 393–395. ISBN 0-03-910284-X.
6.8 External links • Anatomy photo:36:07-0301 at the SUNY Downstate Medical Center - “Inguinal Region, Scrotum and Testes: Layers of the Spermatic Cord” • Anatomy photo:44:02-0301 at the SUNY Downstate Medical Center - “The Male Pelvis: Distribution of the Peritoneum in the Male Pelvis” • MedicalMnemonics.com: 2424 319 • Cross section image: pelvis/pelvis-e12-15 - Plastination Laboratory at the Medical University of Vienna
6.8. EXTERNAL LINKS • inguinalregion at The Anatomy Lesson by Wesley Norman (Georgetown University) (testes)
35
Chapter 7
Male accessory gland Male accessory glands in humans are the seminal vesicles, prostate gland, and the bulbourethral glands.[1] In insects, male accessory glands produce products that mix with the sperm to protect and preserve them.[2] Some insecticides can induce an increase in the protein content of the male accessory glands of certain types of insects. This has the unintended effect of increasing the number of offspring they produce.[3] These glands secrete fluid for nourishment of sperms.
the body and the disseminate part. Low cuboidal to low columnar epithelium provides the lining for this compound, tubuloalveolar gland which consists primarily of serous secretory end pieces. The secretion of this gland is more serous in dogs and more mucous in bulls. It serves to promote the movement of spermatozoa and to form a vaginal plug. Additionally, in bulls, the secretion contains high amounts of fructose and citric acid. Concretions may be present in the secretory end pieces as well as parts of the duct system. Bulbourethral Glands
7.1 Accessory Glands The male accessory glands are the ampullary, vesicular, prostate, bulbourethral, and urethral glands. The products of these glands serve to nourish and activate the spermatozoa, to clear the urethral tract prior to ejaculation, serve as the vehicle of transport of the spermatozoa in the female tract, and to plug the female tract after placement of spermatozoa to help ensure fertilization. Although the glands are usually described as being branched tubular or branched tubuloalveolar, they vary in their organization and in their distribution in different species.
The lining of these paired, compound, tubuloalveloar glands is simple columnar epithelium. A capsule of dense connective tissue contains some smooth muscle as well as skeletal muscle of the bulbocavernous and urethral muscles. All domestic species have these glands except the dog, and their mucous secretion serves to clear the urethra of urine and to lubricate it and the vagina. The product may also serve as an energy source for the spermatozoa. Urethral Glands In some species, branched tubular mucous glands are found along the length of the urethra, especially dorsal to the lumen of the urethra. The exact function of their product is not clear.
Ampullary Glands Each of these branched tubular glands lined by simple columnar epithelium is an enlargement of the ductus deferens in its terminal portion. These are typical tubular glands in ruminants, horses and dogs; absent in the cat and poorly developed in boars. The function of the white serous secretion is not known.
7.2 See also • Pesticide resistance
7.3 References
Vesicular Glands The secretory endpieces of these glands are lined with simple columnar epithelium; the main ducts are lined with stratified columnar epithelium. These glands do not occur in carnivores, but are present in some form in horses, ruminants and swine. Seminal fluid, the product of this gland, serves as a vehicle for the transport of spermatozoa. Prostate Gland Grossly the prostate gland can be divided into two parts:
36
[1] Darling, David. “male reproductive accessory glands”. male reproductive accessory glands. [2] Keeley, Larry. “INSECT ORGANIZATION: STRUCTURE AND FUNCTION”. Texas A&M University. [3] Li-Ping Wang, Jun Shen, Lin-Quan Ge, Jin-Cai Wu, GuoQin Yang and Gary C. Jahn. Insecticide-induced increase in the protein content of male accessory glands and its effect on the fecundity of females in the brown planthopper
7.3. REFERENCES
Nilaparvata lugens St책l (Hemiptera: Delphacidae). Crop Protection 29:1280-1285.
37
Chapter 8
Seminal vesicle The seminal vesicles (Latin: glandulae vesiculosae), system. vesicular glands,[1] or seminal glands, are a pair of simple tubular glands posteroinferior to the urinary bladder The height of these columnar cells, and therefore activity, of some male mammals. Carnivores do not have seminal is dependent upon testosterone levels in the blood. vesicles.[2] Seminal vesicles are located within the pelvis.
8.1 Structure
• The lamina propria, containing underlying small blood vessels and lymphatics. Together with the epithelia, this is called the mucosa, and is arranged into convoluted folds, increasing the overall surface area
The seminal vesicles are a pair of glands that are positioned below the urinary bladder and lateral to the vas deferens. Each vesicle consists of a single tube folded and coiled on itself, with occasional diverticula in its wall.[3]
• A muscular layer, consisting of an inner circular and outer longitudinal layer of smooth muscle, can also be found.
The excretory duct of each seminal gland unites with the corresponding vas deferens to form the two ejaculatory ducts, which immediately pass through the substance of the prostate gland before opening separately into the verumontanum of the prostatic urethra.[3][4] Each seminal vesicle spans approximately 5 cm, though its full unfolded length is approximately 10 cm, but it is curled up inside the gland’s structure.
8.1.1
Spermatozoa may occasionally be found within the lumen of the glands, even though the vesicles are blindended in nature. This is thought to be because of slight reflux due to muscular contractions of the urethera during ejaculation.[6] • Low magnification micrograph of seminal vesicle. H&E stain. • High magnification micrograph of seminal vesicle. H&E stain.
Development
Each vesicle forms as an outpocketing of the wall of the • Seminal vesicles ampulla of one vas deferens. The seminal vesicles develop as one of three structures of the male reproductive system that develops at the junction between the urethra 8.2 Function and vas deferens. Both the urethra and vas deferens are derived from the mesonephric ducts, structures that deThe seminal vesicles secrete a significant proportion of velop from mesoderm.[5] the fluid that ultimately becomes semen. Lipofuscin granules from dead epithelial cells give the secretion its yellowish color. About 50-70%[7] of the seminal fluid in 8.1.2 Histology humans originates from the seminal vesicles, but is not Under microscopy, the seminal vesicles can be seen to expelled in the first ejaculate fractions which are domihave a mucosa, consisting of a lining of interspersed nated by spermatozoa and zinc-rich prostatic fluid. The columnar cells and a laminar propria; and a thick mus- excretory duct of each seminal gland opens into the corcular wall. The lumen of the glands is highly irregular responding vas deferens as it enters the prostate gland. and stores secretions from the glands of the vesicles. In Seminal vesicle fluid is alkaline, resulting in human semen having a mildly alkaline pH.[8] The alkalinity of sedetail:[6] men helps neutralize the acidity of the vaginal tract, pro• The epithelia is pseudostratified columnar in charac- longing the lifespan of sperm. Acidic ejaculate (pH <7.2) ter, similar to other tissues in the male reproductive may be associated with Ejaculatory duct obstruction. The 38
8.5. REFERENCES
39
vesicle produces a substance that causes the semen to be- hematospermia; irritative and obstructive voiding sympcome sticky/jelly-like after ejaculation. toms; and impotence.[11] The thick secretions from the seminal vesicles contain proteins, enzymes, fructose, mucus, vitamin C, flavins, phosphorylcholine and prostaglandins. The high fructose concentrations provide nutrient energy for the spermatozoa when stored in semen in the laboratory. In vitro studies have shown that sperm expelled together with seminal vesicular fluid show poor motility and survival, and the sperm chromatin is less protected. Therefore the exact physiological importance of seminal vesicular fluid is not clear.
8.3 Additional images • Human male reproductive system. • Seminal vesicles • Coronal section of pelvis, showing arrangement of fasciae. Viewed from behind. • Male pelvic organs seen from right side. • Fundus of the bladder with the vesiculae seminales. • Vesiculae seminales and ampullae of ductus deferentes, seen from the front. • Vertical section of bladder, penis, and urethra. • Cross section of seminal vesicle through a microscope.
8.4 Clinical significance Physical examination of the seminal vesicles is difficult. Laboratory examination of seminal vesicle fluid requires a semen sample, e.g. for semen culture or semen analysis. Fructose levels provide a measure of seminal vesicle function and, if absent, bilateral agenesis or obstruction is suspected.[9]
It is usually treated by administration of antibiotics. In intractable cases, in case of patient discomfort, transurethral seminal vesiculoscopy may be considered.[12][13]
8.5 References [1] Wilke; W. Lee Wilke; Rowen D. Frandson; Anna Dee Fails (2009). Anatomy and Physiology of Farm Animals. John Wiley and Sons. ISBN 0-8138-1394-8. Retrieved 2013-11-03. [2] http://urology.jhu.edu/newsletter/prostate_cancer511. php [3] Michael H. Ross; Wojciech Pawlina (2010). “22”. Histology: A Text and Atlas, 6th Edition. ISBN 9780781772006. [4] Drake, Richard L.; Vogl, Wayne; Tibbitts, Adam W.M. Mitchell; illustrations by Richard; Richardson, Paul (2005). Gray’s anatomy for students. Philadelphia: Elsevier/Churchill Livingstone. pp. 407–409. ISBN 978-08089-2306-0. [5] Larsen’s human embryology (4th ed., Thoroughly rev. and updated. ed.). Philadelphia: Churchill Livingstone/Elsevier. 2009. pp. “Development of the urogenital system”. ISBN 9780443068119. |first1= missing |last1= in Authors list (help) [6] Deakin, Barbara Young ... [et al.] ; drawings by Philip J. (2006). Wheater’s functional histology : a text and colour atlas (5th ed. ed.). [Edinburgh?]: Churchill Livingstone/Elsevier. p. 355. ISBN 978-0-443-06850-8. [7] Kierszenbaum, Abraham L. (2002). Histology and cell biology : an introduction to pathology. St. Louis [u.a.]: Mosby. p. 558. ISBN 0-323-01639-1. [8] “CHEMICAL COMPOSITION OF HUMAN SEMEN AND OF THE SECRETIONS OF THE PROSTATE AND SEMINAL VESICLES”. http://ajplegacy.physiology.org. Retrieved 2010-08-10. [9] El-Hakim, Assaad (November 13, 2006). “Diagnosis and Treatment of Disorders of the Ejaculatory Ducts and Seminal Vesicles”. In Smith, Arthur D. Smith’s Textbook of Endourology, 2nd Edition. Wiley-Blackwell. pp. 759– 766. ISBN 978-1550093650.
Disorders of the seminal vesicles include seminal vesiculitis, acquired cysts, abscess, congenital anomalies (such as agenesis, hypoplasia and cysts), amyloidosis, tuberculosis, schistosomiasis, hydatid cyst, calculi and [10] “Seminal vesicle diseases”. Geneva Foundation for Meditumours.[9][10] cal Education and Research.
8.4.1
Inflammation
[11] Zeitlin, S. I.; Bennett, C. J. (November 1, 1999). “Chapter 25: Seminal vesiculitis”. In Curtis Nickel, J. Textbook of Prostatitis. CRC Press. pp. 219–225. ISBN 9781901865042.
Seminal vesiculitis (also known as spermatocystitis) is an inflammation of seminal vesicles, most often caused [12] La Vignera S (Oct 2011). “Male accessory gland infecby bacterial infection. Symptoms of seminal vesiculition and sperm parameters.”. Int J Androl 42 (34): e330– tis can include vague back or lower abdominal pain; 47. doi:10.1111/j.1365-2605.2011.01200.x. PMID 21696400. penile, scrotal, or perineal pain; painful ejaculation;
40
[13] Liu B (Feb 2014). “Transurethral seminal vesiculoscopy in the diagnosis and treatment of intractable seminal vesiculitis.”. J Int Med Res 42 (1): 236–42. doi:10.1177/0300060513509472. PMID 24391141.
8.6 External links • Histology image: 17501loa — Histology Learning System at Boston University - “Male Reproductive System: prostate, seminal vesicle” • Anatomy photo:44:04-0202 at the SUNY Downstate Medical Center - “The Male Pelvis: The Urinary Bladder” • Anatomy photo:44:08-0103 at the SUNY Downstate Medical Center - “The Male Pelvis: Structures Located Posterior to the Urinary Bladder”
CHAPTER 8. SEMINAL VESICLE
Chapter 9
Epididymis The epididymis (/ɛpɨˈdɪdɨmɪs/; plural: epididymides /ɛpɨdɨˈdɪmədiːz/ or /ɛpɨˈdɪdəmɪdiːz/) is part of the male reproductive system and is present in all male reptiles, birds, and mammals. It is a single, narrow, tightly-coiled tube (in adult humans, six to seven meters in length[1] ) connecting the efferent ducts from the rear of each testicle to its vas deferens.
acid, glycoproteins, and glycerylphosphorylcholine into the lumen. • Basal cells: shorter, pyramid-shaped cells which contact the basal lamina but taper off before their apical surfaces reach the lumen.[3] These are thought to be undifferentiated precursors of principal cells.[3]
9.1 Structure
• Apical cells: predominantly found in the head region[3]
The epididymis can be divided into three main regions: • Clear cells: predominant in the tail region[3] • The head (Latin: Caput). The head of the epididymis receives spermatozoa via the efferent ducts of the mediastinium of the testis. It is characterized histologically by a thin myoepithelium. The concentration of the sperm here is dilute.
• Intraepithelial lymphocytes: distributed throughout the tissue.[3] • Intraepithelial macrophages[4][5]
• The body (Latin: Corpus) • The tail (Latin: Cauda). This has a thicker myoep- Stereocilia ithelium than the head region, as it is involved in absorbing fluid to make the sperm more concentrated. The stereocilia of the epididymis are structures which aid in absorption. They are long cytoplasmic projections that In reptiles, there is an additional canal between the testis have no motility. and the head of the epididymis and which receives the Unlike the stereocilia of the inner ear, which play a role various efferent ducts. This is, however, absent in all birds in hearing, stereocilia in the epididymis are more like [2] and mammals. the long, absorptive microvilli of other epithelia. These membrane extensions increase the surface area of the cell, allowing for greater absorption and secretion.[6] 9.1.1 Histology The epididymis is covered by a two layered pseudostratified epithelium. The epithelium is separated by a basement membrane from the connective tissue wall which has smooth muscle cells. The major cell types in the epithelium are: • Main cells: columnar cells that, with the basal cells, form the majority of the epithelium. These cells extend from the lumen to the basal lamina,[3] They also have non-motile stereocilia, which are long and branching in the head region and shorter in the tail region.[3] They also secrete carnitine, sialic
The stereocilia in the epididymis are shaped by an internal actin network with no microtubule structure, and unlike true cilia are non-motile.[7] Because sperm are initially nonmotile as they leave the seminiferous tubules, large volumes of fluid are secreted to propel them, aided by the cilia of the pathway, to the epididymis. The core function of the stereocilia is to resorb 90% of this fluid as the spermatozoa start to become motile. This absorption creates a fluid current that moves the immobile sperm from the seminiferous tubules to the epididymis. Spermatozoa do not reach full motility until they reach the vagina, where the alkaline pH is neutralized by acidic vaginal fluids.
41
42
9.1.2
CHAPTER 9. EPIDIDYMIS
Development
is the surgical removal of the epididymis sometimes performed for post-vasectomy pain syndrome and for refracIn the embryo, the epididymis develops from tissue that tory cases of epididymitis. once formed the mesonephros, a primitive kidney found in many aquatic vertebrates. Persistence of the cranial end of the mesonephric duct will leave behind a rem- 9.4 Gallery nant called the appendix of the epididymis. In addition, some mesonephric tubules can persist as the paradidymis, • Human Male reproductive system. a small body caudal to the efferent ductules. A Gartner’s duct is a homologous remnant in the female.
• Testis
9.2 Function
• Schematic drawing of a cross-section through a testicle.
9.2.1
Role in storage of sperm and ejaculant
Spermatozoa formed in the testis enter the caput epididymis, progress to the corpus, and finally reach the cauda region, where they are stored. Sperm entering the caput epididymis are incomplete—they lack the ability to swim forward (motility) and to fertilize an egg. It stores the sperm for 2–3 months. During their transit in the epididymis, sperm undergo maturation processes necessary for them to acquire these functions.[8] Final maturation is completed in the female reproductive tract (capacitation). During ejaculation, sperm flow from the lower portion of the epididymis (which functions as a storage reservoir). They have not been activated by products from the prostate gland, and they are unable to swim, but are transported via the peristaltic action of muscle layers within the vas deferens, and are mixed with the diluting fluids of the seminal vesicles and other accessory glands prior to ejaculation (forming semen). The epithelial cells of the epididymis possess numerous apical modifications that are often referred to as stereocilia, as under the light microscope they look like cilia. However, as electron microscopy has revealed them to be structurally and functionally more similar to microvilli, some now refer to them as stereovilli.[9]
9.3 Clinical significance 9.3.1
Inflammation
An inflammation of the epididymis is called epididymitis. It is much more common than testicular inflammation, termed orchitis.
9.3.2
Surgical removal
Epididymotomy is the placing of an incision into the epididymis and is sometimes considered as a treatment option for acute suppurating epididymitis. Epididymectomy
• Micrograph of an epididymis. H&E stain. • Microscopic shot.
9.5 See also This article uses anatomical terminology; for an overview, see anatomical terminology. • Epididymal hypertension
9.6 Notes [1] Kim, Howard H.; Goldstein, Marc (2010). “Chapter 53: Anatomy of the epididymis, vas deferens, and seminal vesicle”. In Graham, Sam D.; Keane, Thomas E.; Glenn, James F. Glenn’s urological surgery (7th ed.). Philadelphia: Lippincott Williams & Wilkins. p. 356. ISBN 9780-7817-9141-0. [2] Romer, Alfred Sherwood; Parsons, Thomas S. (1977). The Vertebrate Body. Philadelphia, PA: Holt-Saunders International. pp. 394–395. ISBN 0-03-910284-X. [3] Kierszenbaum, Abraham L. (2002). Histology and cell biology : an introduction to pathology. St. Louis: Mosby. p. 556. ISBN 0-323-01639-1. [4] Da Silva N, Cortez-Retamozo V, Reinecker HC, et al. (May 2011). “A dense network of dendritic cells populates the murine epididymis”. Reproduction 141 (5): 653– 63. doi:10.1530/REP-10-0493. PMC 3657760. PMID 21310816. [5] Shum WW, Smith TB, Cortez-Retamozo V, et al. (May 2014). “Epithelial basal cells are distinct from dendritic cells and macrophages in the mouse epididymis”. Biology of Reproduction 90 (5): 90. doi:10.1095/biolreprod.113.116681. PMID 24648397. [6] How sperm are re-absorbed into the body. vasectomyinformation.com [7] Efferent Ducts and Epididymis. umdnj.edu
9.7. EXTERNAL LINKS
[8] Jones RC (April 1999). “To store or mature spermatozoa? The primary role of the epididymis”. International Journal of Andrology 22 (2): 57–67. doi:10.1046/j.13652605.1999.00151.x. PMID 10194636. [9] Ross, Michael H.; Pawlina, Wojciech (2011). Histology: A Text and Atlas. Lippincott Williams & Wilkins. pp. 110–112. ISBN 978-0-7817-7200-6.
9.7 External links • Histology image: 16903loa — Histology Learning System at Boston University • inguinalregion at The Anatomy Lesson by Wesley Norman (Georgetown University) (testes)
43
Chapter 10
Prostate For the female prostate gland, see Skene’s gland. For the “prostrate” body position, see Prostration. The prostate (from Greek προστάτης, prostates, literally “one who stands before”, “protector”, “guardian”[1] ) is a compound tubuloalveolar exocrine gland of the male reproductive system in most mammals.[2][3] It differs considerably among species anatomically, chemically, and physiologically. The function of the prostate is to secrete a slightly alkaline fluid, milky or white in appearance, that in humans usually constitutes roughly 30% of the volume of the semen along with spermatozoa and seminal vesicle fluid.[4] Semen is made alkaline overall with the secretions from the other contributing glands, including, at least, the seminal vesicle fluid.[5] The alkalinity of semen helps neutralize the acidity of the vaginal tract, prolonging the lifespan of sperm. The prostatic fluid is expelled in the first ejaculate fractions, together with most of the spermatozoa. In comparison with the few spermatozoa expelled together with mainly seminal vesicular fluid, those expelled in prostatic fluid have better motility, longer survival and better protection of the genetic material.
Micrograph of benign prostatic glands with corpora amylacea. H&E stain.
from the bladder is called the prostatic urethra and merges with the two ejaculatory ducts.[8] The prostate can be divided in two ways: by zone, or by lobe.[9] It does not have a capsule; rather an integral fibromuscular band surrounds it.[10] It is sheathed in the muscles of the pelvic floor, which contract during the ejaculatory process.
The prostate also contains some smooth muscles that help expel semen during ejaculation.
10.1.1 Zones
10.1 Structure A healthy human male prostate is classically said to be slightly larger than a walnut. The mean weight of the normal prostate in adult males is about 11 grams, usually ranging between 7 and 16 grams.[6] It surrounds the urethra just below the urinary bladder and can be felt during a rectal exam.
The “zone” classification is more often used in pathology. The idea of “zones” was first proposed by McNeal in 1968. McNeal found that the relatively homogeneous cut surface of an adult prostate in no way resembled “lobes” and thus led to the description of “zones”.[11]
The prostate gland has four distinct glandular regions, two of which arise from different segments of the prostatic The secretory epithelium is mainly pseudostratified, com- urethra: prising tall columnar cells and basal cells which are supported by a fibroelastic stroma containing randomly oriented smooth muscle bundles that’s continuous with the bladder. The epithelium is highly variable and areas of low cuboidal or squamous epithelium are also present, 10.1.2 Lobes with transitional epithelium in the distal regions of the longer ducts.[7] Within the prostate, the urethra coming The “lobe” classification is more often used in anatomy. 44
10.2. FUNCTION
45
10.2 Function 10.2.1 Male sexual response Main article: Prostate massage During male ejaculation, sperm is transmitted from the ductus deferens into the male urethra via the ejaculatory ducts, which lie within the prostate gland. It is possible for men to achieve orgasm solely through stimulation of the prostate gland, such as prostate massage or receptive anal intercourse.[17][18][19]
10.2.2 Secretions Prostatic secretions vary among species. They are generally composed of simple sugars and are often slightly acidic. In human prostatic secretions, the protein content is less than 1% and includes proteolytic enzymes, prostatic acid phosphatase, beta-microseminoprotein, and prostate-specific antigen. The secretions also contain zinc with a concentration 500–1,000 times the concentration in blood.
10.2.3 Regulation Urinary bladder (black butterfly-like shape) and hyperplastic prostate (BPH) visualized by Medical ultrasonography technique
10.1.3
Development
To function properly, the prostate needs male hormones (testosterones), which are responsible for male sex characteristics. The main male hormone is testosterone, which is produced mainly by the testicles. Some male hormones are produced in small amounts by the adrenal glands. However, it is dihydrotestosterone that regulates the prostate.
The prostatic part of the urethra develops from the pelvic (middle) part of the urogenital sinus (endodermal origin). Endodermal outgrowths arise from the prostatic part of the urethra and grow into the surrounding mesenchyme. 10.3 Clinical significance The glandular epithelium of the prostate differentiates from these endodermal cells, and the associated mes- 10.3.1 Inflammation enchyme differentiates into the dense stroma and the smooth muscle of the prostate.[15] The prostate glands Main article: Prostatitis represent the modified wall of the proximal portion of the male urethra and arises by the 9th week of embryonic life in the development of the reproductive system. Condensation of mesenchyme, urethra and Wolffian ducts gives rise to the adult prostate gland, a composite organ made up of several glandular and non-glandular components tightly fused.
10.1.4
Histology
• Glandular cells • Myoepithelial cells • Subepithelial interstitial cells[16]
Digital rectal examinations can establish how inflamed a
46
CHAPTER 10. PROSTATE egory III prostatitis as well.[22] Category IV prostatitis, relatively uncommon in the general population, is a type of leukocytosis.
prostate is
Bladder
10.3.2 Benign prostatic hyperplasia
Prostate
Main article: Benign prostatic hyperplasia
Urethra Prostate cancer pressing on urethra
Benign prostatic hyperplasia (BPH) occurs in older men;[23] the prostate often enlarges to the point where urination becomes difficult. Symptoms include needing to urinate often (frequency) or taking a while to get started (hesitancy). If the prostate grows too large, it may constrict the urethra and impede the flow of urine, making A diagram of prostate cancer pressing on the urethra, urination difficult and painful and, in extreme cases, comwhich can cause symptoms pletely impossible. BPH can be treated with medication, a minimally invasive procedure or, in extreme cases, surgery that removes the prostate. Minimally invasive procedures include transurethral needle ablation of the prostate (TUNA) and transurethral microwave thermotherapy (TUMT).[24] These outpatient procedures may be followed by the insertion of a temporary prostatic stent, to allow normal voluntary urination, without exacerbating irritative symptoms.[25] Micrograph showing an inflamed prostate gland, the histologic correlate of prostatitis. A normal noninflamed prostatic gland is seen on the left of the image. H&E stain.
The surgery most often used in such cases is called transurethral resection of the prostate (TURP or TUR). In TURP, an instrument is inserted through the urethra to remove prostate tissue that is pressing against the upper part of the urethra and restricting the flow of urine. TURP results in the removal of mostly transitional zone tissue in a patient with BPH. Older men often have corpora amylacea[26] (amyloid), dense accumulations of calcified proteinaceous material, in the ducts of their prostates. The corpora amylacea may obstruct the lumens of the prostatic ducts, and may underlie some cases of BPH.
Urinary frequency due to bladder spasm, common in Micrograph showing normal prostatic glands and glands older men, may be confused with prostatic hyperplaof prostate cancer (prostate adenocarcinoma) – right sia. Statistical observations suggest that a diet low in upper aspect of image. HPS stain. Prostate biopsy. fat and red meat and high in protein and vegetables, as well as regular alcohol consumption, could protect against [27] Prostatitis is inflammation of the prostate gland. There BPH. are primarily four different forms of prostatitis, each Life-style changes to improve the quality of urination inwith different causes and outcomes. Two relatively un- clude urinating in the sitting position.[28] This reduces the common forms, acute prostatitis and chronic bacterial amount of residual volume in the bladder, increases the prostatitis, are treated with antibiotics (category I and urinary flow rate and decreases the voiding time. II, respectively). Chronic non-bacterial prostatitis or male chronic pelvic pain syndrome (category III), which comprises about 95% of prostatitis diagnoses, is treated 10.3.3 Cancer by a large variety of modalities including alpha blockers, phytotherapy,[20] physical therapy,[21] psychotherapy, Main article: Prostate cancer antihistamines, anxiolytics, nerve modulators, surgery, and more. More recently, a combination of trigger point and psychological therapy has proved effective for cat- Prostate cancer is one of the most common cancers affecting older men in developed countries and a significant
10.5. ADDITIONAL IMAGES cause of death for elderly men[29][30] (estimated by some specialists at 3%). Despite this, the American Cancer Society's position regarding early detection is “Research has not yet proven that the potential benefits of testing outweigh the harms of testing and treatment”. They believe “that men should not be tested without learning about... the risks and possible benefits of testing and treatment” which should be discussed with a doctor at age 50 or at age 45 if the patient is black or has a father or brother who acquired prostate cancer before age 65. [31] If checks are performed, they can be in the form of a physical rectal exam, measurement of prostate specific antigen (PSA) level in the blood, or checking for the presence of the protein Engrailed-2 (EN2) in the urine. Co-researchers Hardev Pandha and Richard Morgan published their findings regarding checking for EN2 in urine in the 1 March 2011 issue of the journal Clinical Cancer Research.[32] A laboratory test currently identifies EN2 in urine, and a home test kit is envisioned similar to a home pregnancy test strip. According to Morgan, “We are preparing several large studies in the UK and in the US and although the EN2 test is not yet available, several companies have expressed interest in taking it forward.”[33]
Vasectomy and risk of prostate cancer
47 officially renamed to female prostate by the Federative International Committee on Anatomical Terminology.[35] The female prostate, like the male prostate, secretes PSA and levels of this antigen rise in the presence of carcinoma of the gland. The gland also expels fluid, like the male prostate, during orgasm.[36]
10.5 Additional images 10.6 In other mammals The prostate is found as a male accessory gland in all placental mammals excepting edentates, martens, badgers and otters.[37] The structure of the prostate varies, ranging from tubuloalveolar (as in humans) to branched tubular. The gland is particularly well developed in dogs, foxes and boars, though in other mammals, such as bulls, it can be small and inconspicuous.[38][39] Dogs can produce in one hour as much prostatic fluid as a human can in a day. They excrete this fluid along with their urine to mark territory.[40] In many rodents and bats, the prostatic fluid contains a coagulant. This mixes with and coagulates semen during copulation to form a mating plug that temporarily prevents further copulation.[41][42] The prostate gland originates with tissues in the urethral wall. This means the urethra, a compressible tube used for urination, runs through the middle of the prostate. This leads to an evolutionary design fault for some mammals, including human males. The prostate is prone to infection and enlargement later in life, constricting the urethra so urinating becomes slow and painful.[43]
In 1983, the Journal of the American Medical Association reported a connection between vasectomy and an increased risk of prostate cancer. Reported studies of 48,000 and 29,000 men who had vasectomies showed 66 percent and 56 percent higher rates of prostate cancer, respectively. The risk increased with age and the number of years since the vasectomy was performed. Skene’s gland is found in both female humans and roHowever, in March of the same year, the National In- dents. Historically it was thought to be a vestigial orstitute of Child Health and Human Development held a gan, but recently it has been discovered that it produces protein markers, PSA and PAB, as the male conference cosponsored by the National Cancer Institute the same [44] prostrate. This means Skene’s gland functions as a feand others to review the available data and information on male prostate, a histologic homolog to the male prostate the link between prostate cancer and vasectomies. It was [45][46] gland. determined that an association between the two was very weak at best, and even if having a vasectomy increased one’s risk, the risk was relatively small.
10.7 See also
In 1997, the NCI held a conference with the prostate cancer Progressive Review Group (a committee of scientists, • Corpora amylacea medical personnel, and others). Their final report, published in 1998 stated that evidence that vasectomies help to develop prostate cancer was weak at best.[34] Glossary Further information: Index of oncology articles
10.4 Female prostate gland Skene’s gland, also known as the paraurethral gland, found in females, is homologous to the prostate gland in 10.8 males. However, anatomically, the uterus is in the same position as the prostate gland. In 2002, Skene’s gland was Notes
References
48
CHAPTER 10. PROSTATE
[1] Harper, Douglas. “Prostate”. Online Etymology Dictionary. Retrieved 2013-11-03. [2] Romer, Alfred Sherwood; Parsons, Thomas S. (1977). The Vertebrate Body. Philadelphia, PA: Holt-Saunders International. p. 395. ISBN 0-03-910284-X. [3] Tsukise, A.; Yamada, K. (1984). “Complex carbohydrates in the secretory epithelium of the goat prostate”. The Histochemical Journal 16 (3): 311–9. doi:10.1007/BF01003614. PMID 6698810.
[17] “The male hot spot — Massaging the prostate”. Go Ask Alice!. 2002-09-27 [Last Updated/Reviewed on 200803-28]. Retrieved 2010-04-21. [18] Rosenthal, Martha (2012). Human Sexuality: From Cells to Society. Cengage Learning. pp. 133–135. ISBN 0618755713. Retrieved September 17, 2012. [19] Komisaruk, Barry R.; Whipple, Beverly; Nasserzadeh, Sara and Beyer-Flores, Carlos (2009). The Orgasm Answer Guide. JHU Press. pp. 108–109. ISBN 0-80189396-8. Retrieved 6 November 2011.
[4] “Chemical composition of human semen and of the secretions of the prostate and seminal vehicles”. Am J Physiol 136 (3): 467–473. 1942.
[20] “Quercetin Treatment for Prostatitis/chronic pelvic pain syndrome”. 2014. Retrieved 2014-10-22.
[5] “Semen analysis”. 2009-04-28.
Retrieved
[21] “Physical Therapy Treatment for Prostatitis/chronic pelvic pain syndrome”. 2014. Retrieved 2014-10-22.
[6] Leissner KH, Tisell LE (1979). “The weight of the human prostate”. Scand. J. Urol. Nephrol. 13 (2): 137–42. doi:10.3109/00365597909181168. PMID 90380.
[22] Anderson RU, Wise D, Sawyer T, Chan CA (2006). “Sexual dysfunction in men with chronic prostatitis/chronic pelvic pain syndrome: improvement after trigger point release and paradoxical relaxation training”. J. Urol. 176 (4 Pt 1): 1534–8; discussion 1538–9. doi:10.1016/j.juro.2006.06.010. PMID 16952676.
www.umc.sunysb.edu.
[7] “Prostate Gland Development”. ana.ed.ac.uk. Archived from the original on 2003-04-30. Retrieved 2011-08-03. [8] “The Prostate”. Gray’s Anatomy. Retrieved 2014-09-12. [9] “Instant Anatomy – Abdomen – Vessels – Veins – Prostatic plexus”. Retrieved 2007-11-23. [10] Raychaudhuri, B.; Cahill, D. (2008). “Pelvic fasciae in urology”. Annals of the Royal College of Surgeons of England 90 (8): 633–637. doi:10.1308/003588408X321611. PMC 2727803. PMID 18828961. [11] Myers, Robert P (2000). “Structure of the adult prostate from a clinician’s standpoint”. Clinical Anatomy 13 (3): 214–5. doi:10.1002/(SICI)10982353(2000)13:3<214::AID-CA10>3.0.CO;2-N. PMID 10797630. [12] “Basic Principles: Prostate Anatomy”. Urology Match. Www.urologymatch.com. Web. 14 June 2010. [13] “Prostate Cancer Information from the Foundation of the Prostate Gland.” Prostate Cancer Treatment Guide. Web. 14 June 2010. [14] Cohen RJ, Shannon BA, Phillips M, Moorin RE, Wheeler TM, Garrett KL (2008). “Central zone carcinoma of the prostate gland: a distinct tumor type with poor prognostic features”. The Journal of Urology 179 (5): 1762–7; discussion 1767. doi:10.1016/j.juro.2008.01.017. PMID 18343454. [15] Moore, Keith L.; Persaud, T. V. N. and Torchia, Mark G. (2008) Before We Are Born, Essentials of Embryology and Birth Defects, 7th edition, Saunders Elsevier, ISBN 978-1-4160-3705-7 [16] (English)Gevaert, T; Lerut, E; Joniau, S; Franken, J; Roskams, T; De Ridder, D (2014). “Characterization of subepithelial interstitial cells in normal and pathologic human prostate”. Histopathology: n/a. doi:10.1111/his.12402. PMID 24571575.
[23] Verhamme KM; Dieleman JP; Bleumink GS et al. (2002). “Incidence and prevalence of lower urinary tract symptoms suggestive of benign prostatic hyperplasia in primary care—the Triumph project”. Eur. Urol. 42 (4): 323–8. doi:10.1016/S0302-2838(02)00354-8. PMID 12361895. [24] Christensen, TL; Andriole, GL (February 2009). “Benign Prostatic Hyperplasia: Current Treatment Strategies”. Consultant 49 (2). [25] Dineen MK, Shore ND, Lumerman JH, Saslawsky MJ, Corica AP (2008). “Use of a Temporary Prostatic Stent After Transurethral Microwave Thermotherapy Reduced Voiding Symptoms and Bother Without Exacerbating Irritative Symptoms”. J. Urol. 71 (5): 873–877. doi:10.1016/j.urology.2007.12.015. PMID 18374395. [26] “Slide 33: Prostate, at ouhsc.edu”. [27] Kristal AR; Arnold KB; Schenk JM et al. (2008). “Dietary patterns, supplement use, and the risk of symptomatic benign prostatic hyperplasia: results from the prostate cancer prevention trial”. Am. J. Epidemiol. 167 (8): 925–34. doi:10.1093/aje/kwm389. PMID 18263602. [28] de Jong, Y; Pinckaers, JH; Ten Brinck, RM; Lycklama À Nijeholt, AA; Dekkers, OM (2014). “Urinating Standing versus Sitting: Position Is of Influence in Men with Prostate Enlargement. A Systematic Review and Meta-Analysis.”. PLOS ONE 9 (7): e101320. doi:10.1371/journal.pone.0101320. PMC 4106761. PMID 25051345. [29] “Watchful Waiting Advised .Some Prostate Patients Benefit”. The Daily Courier. Aug 23, 1995. p. 4. Retrieved 10 February 2014. [30] Michael Wiener. “Vital Facts About Male Reproductive Health”. Retrieved 10 February 2014.
10.9. EXTERNAL LINKS
[31] American Cancer Society American Cancer Society Guidelines for the early detection of cancer Cited: September 2011. Cancer.org. Retrieved on 2013-01-21. [32] Morgan, R.; Boxall, A.; Bhatt, A.; Bailey, M.; Hindley, R.; Langley, S.; Whitaker, H. C.; Neal, D. E.; Ismail, M. (2011). “Engrailed-2 (EN2): A Tumor Specific Urinary Biomarker for the Early Diagnosis of Prostate Cancer”. Clinical Cancer Research 17 (5): 1090–8. doi:10.1158/1078-0432.CCR-10-2410. PMID 21364037. [33] New prostate cancer twice as effective as a PSA test could be available by next year. medicinechest.co.uk (2 March 2011) [34] “Defeating Prostate Cancer: Crucial Directions for Research”. National Cancer Institute. August 1998. Retrieved 2012-08-19. [35] Flam, Faye (2006-03-15). “The Seattle Times: Health: Gee, women have ... a prostate?". seattletimes.nwsource.com. Retrieved 2013-11-03. [36] Kratochvíl S (1994). “Orgasmic expulsions in women”. Česk Psychiatr (in Czech) 90 (2): 71–7. PMID 8004685. [37] Olsen, Bruce D (2009) Understanding Human Anatomy Through Evolution Second edition, page 112, Lulu Press. ISBN 9780578021645. [38] Sherwood L, Klandorf H and Yancey P (2012) Animal Physiology: From Genes to Organisms Cengage Learning, page 779. ISBN 9781133709510. [39] Nelsen, O. E. (1953) Comparative embryology of the vertebrates Blakiston, page 31. [40] Glover, Tim (2012) Mating Males: An Evolutionary Perspective on Mammalian Reproduction Cambridge University Press, page 31. ISBN 9781107000018. [41] Animal reproductive system Encyclopædia Britannica. Retrieved 18 January 2015. [42] Asdell S A (1965) “Reproduction and Development” In: William Mayer (Ed) Physiological Mammalogy, Volume 2, page 9. Elsevier. ISBN 9780323155250. [43] Coyne, Jerry A (2009) Why Evolution Is True page 90, Oxford University Press. ISBN 9780199230846. [44] Zaviačič M and Ablin R J (1999) The Human Female Prostate: From Vestigial Skene’s Paraurethral Glands and Ducts to Woman’s Functional Prostate Slovak Academic Press. ISBN 9788088908500. [45] Santos F C A and Taboga S R (2006) “Female prostate: a review about the biological repercussions of this gland in humans and rodents” Animal Reproduction, 3 (1): 3–18. [46] Risbridger G and Taylor R (2006) “Physiology of the male accessory sex structures: the prostate gland, seminal vesicles, and bulbourethral glands” In: J D Neill (Ed) (2005) Knobil and Neill’s Physiology of Reproduction, page 1165, Academic Press. ISBN 9780080535272.
Sources
49 • Portions of the text of this article were taken from NIH Publication No. 02-4806, a public domain resource. “What I need to know about Prostate Problems”. 2002-06-01. Archived from the original on 2002-06-01. Retrieved 2011-01-24.
10.9 External links • Media related to Prostate at Wikimedia Commons
Chapter 11
Bulbourethral gland Not to be confused with Bulbus glandis.
are composed of several lobules held together by a fibrous covering. Each lobule consists of a number of acini, lined by columnar epithelial cells, opening into a duct that joins with the ducts of other lobules to form a single excretory duct. This duct is approximately 2.5 cm long and opens into the urethra at the base of the penis. The glands gradually diminish in size with advancing age.[3]
A bulbourethral gland, also called a Cowper gland for English anatomist William Cowper, is one of two small exocrine glands in the reproductive system of many male mammals (of all domesticated animals, they are only absent in the dog).[1] They are homologous to Bartholin’s A study published in Human Fertility in March of 2011 glands in females. suggests that some human males often or always excrete sperm carried out of the body by Cowper’s gland secretions prior to ejaculation, at concentrations similar to 11.1 Location those found in their semen.[4] This could result in the possibility of conception from the introduction of preBulbourethral glands are located posterior and lateral to ejaculate alone to the vagina, though the direct probability the membranous portion of the urethra at the base of of pregnancy has not been assessed. the penis, between the two layers of the fascia of the urogenital diaphragm, in the deep perineal pouch. They The Cowper’s gland also produces some amount of are enclosed by transverse fibers of the sphincter urethrae prostate-specific antigen (PSA), and Cowper’s tumors may increase PSA to a level that makes prostate cancer membranaceae muscle. suspected.
11.2 Structure
11.3 Function The bulbourethral gland contributes about 0.1 to 0.2 ml or 5% of the ejaculate. The secretion is a clear fluid that is rich in mucoproteins. The secretion also helps to lubricate the distal urethra.
Internal Urethral Opening Urethral Crest Prostatic Utricle Ejaculatory Duct opening
11.4 Gallery
Seminal Colliculus Prostatic Duct opening Bulbourethral Gland
• Structure of the penis
Sphincter Urethrae Muscle
• Male pelvic organs seen from right side. • Vertical section of bladder, penis, and urethra.
Dissection of prostate showing the bulbourethral glands within the fibers of the external urethral sphincter just underneath the prostate.
• Bulbourethral gland labeled at center left.
The bulbourethral glands are compound tubulo-alveolar glands, each approximately the size of a pea in humans. In chimpanzees, they are not visible during dissection, but can be found on microscopic examination.[2] In boars, they are up to 18 cm long and 5 cm in diameter.[1] They
11.5 See also
50
• List of homologues of the human reproductive system
11.6. NOTES
11.6 Notes [1] Mark McEntee (December 2, 2012). Reproductive Pathology of Domestic Mammals. Elsevier Science. p. 333. ISBN 978-0-323-13804-8. Retrieved August 20, 2013. [2] Jeffrey H. Schwartz (1988). Orang-utan Biology. Oxford University Press. p. 92. ISBN 978-0-19-504371-6. Retrieved August 20, 2013. [3] Gray’s Anatomy, 38th ed., p 1861. [4] Stephen R. Killick; Christine Leary; James Trussell; Katherine A. Guthrie (March 2011). “Sperm content of pre-ejaculatory fluid”. Human Fertility (Informa) 14 (1): 48–52. doi:10.3109/14647273.2010.520798. ISSN 1464-7273. PMC 3564677. PMID 21155689.
51
Chapter 12
Human penis The human penis is an external male sexual organ. It 12.1.1 Parts is a reproductive, intromittent organ that additionally serves as the urinal duct. The main parts are the root • Root of the penis (radix): It is the attached part, con(radix); the body (corpus); and the epithelium of the pesisting of the bulb of penis in the middle and the crus nis including the shaft skin and the foreskin covering the of penis, one on either side of the bulb. It lies within glans penis. The body of the penis is made up of three the superficial perineal pouch. columns of tissue: two corpora cavernosa on the dorsal side and corpus spongiosum between them on the ventral • Body of the penis (corpus): It has two surfaces: dorside. The human male urethra passes through the prostate sal (posterosuperior in the erect penis), and ventral gland, where it is joined by the ejaculatory duct, and then or urethral (facing downwards and backwards in the through the penis. The urethra traverses the corpus sponflaccid penis). The ventral surface is marked by a giosum, and its opening, the meatus /miːˈeɪtəs/, lies on groove in a lateral direction. the tip of the glans penis. It is a passage both for urine and for the ejaculation of semen. • Epithelium of the penis consists of the shaft skin, the foreskin, and the preputial mucosa on the inside The penis is homologous to the clitoris. An erection is the of the foreskin and covering the glans penis. The stiffening and rising of the penis, which occurs during epithelium is not attached to the underlying shaft so sexual arousal, though it can also happen in non-sexual it is free to glide to and fro.[1] situations. The most common form of genital alteration is circumcision, removal of part or all of the foreskin for various cultural, religious, and more rarely, medical rea12.1.2 sons. There is controversy surrounding circumcision. While results vary across studies, the consensus is that the average erect human penis is approximately 12.9–15 cm (5.1–5.9 in) in length with 95% of adult males falling within the interval 10.7–19.1 cm (4.2–7.5 in). Neither age nor size of the flaccid penis accurately predicts erectile length.
12.1 Anatomy
Lateral cross section of the penis.
Structure
The human penis is made up of three columns of tissue: two corpora cavernosa lie next to each other on the dorsal side and one corpus spongiosum lies between them on the ventral side. The enlarged and bulbous-shaped end of the corpus spongiosum forms the glans penis, which supports the foreskin, or prepuce, a loose fold of skin that in adults can retract to expose the glans. The area on the underside of the penis, where the foreskin is attached, is called the frenum, or frenulum. The rounded base of the glans is called the corona. The perineal raphe is the noticeable line along the underside of the penis.
Anatomical diagram of a human penis
52
12.3. PHYSIOLOGICAL FUNCTIONS
53
The urethra, which is the last part of the urinary tract, traverses the corpus spongiosum, and its opening, known as the meatus /miːˈeɪtəs/, lies on the tip of the glans penis. It is a passage both for urine and for the ejaculation of semen. Sperm are produced in the testes and stored in the attached epididymis. During ejaculation, sperm are propelled up the vas deferens, two ducts that pass over and behind the bladder. Fluids are added by the seminal vesicles and the vas deferens turns into the ejaculatory ducts, which join the urethra inside the prostate gland. The prostate as well as the bulbourethral glands add further secretions, and the semen is expelled through the penis. The raphe is the visible ridge between the lateral halves of the penis, found on the ventral or underside of the penis, running from the meatus (opening of the urethra) across the scrotum to the perineum (area between scrotum and anus). The human penis differs from those of most other mammals, as it has no baculum, or erectile bone, and instead relies entirely on engorgement with blood to reach its erect state. It cannot be withdrawn into the groin, and it is larger than average in the animal kingdom in proportion to body mass.
12.2 Development Main article: Development of the reproductive system
12.2.1
Genital homology between sexes
Main article: Sexual homology
Stages in the development of the male external genitalia.
growth is typically complete not later than age 17, and possibly earlier.[2]
12.3 Physiological functions
In short, this is a known list of sex organs that evolve from 12.3.1 the same tissue in females and males. The glans of the penis is homologous to the clitoral glans; the corpora cavernosa are homologous to the body of the clitoris; the corpus spongiosum is homologous to the vestibular bulbs beneath the labia minora; the scrotum, homologous to the labia minora and labia majora; and the foreskin, homologous to the clitoral hood. The raphe does not exist in females, because there, the two halves are not connected.
Urination
Main article: Urination
In males, the expulsion of urine from the body is done through the penis. The urethra drains the bladder through the prostate gland where it is joined by the ejaculatory duct, and then onward to the penis. At the root of the penis (the proximal end of the corpus spongiosum) lies the external sphincter muscle. This is a small sphincter of striated muscle tissue and is in healthy males under voluntary control. Relaxing the urethra sphincter allows 12.2.2 Penile growth and puberty the urine in the upper urethra to enter the penis properly On entering puberty, the penis, scrotum and testicles will and thus empty the urinary bladder. begin to develop. During the process, pubic hair grows Physiologically, urination involves coordination between above and around the penis. A large-scale study assessing the central, autonomic, and somatic nervous systems. In penis size in thousands of 17–19 year old males found no infants, some elderly individuals, and those with neudifference in average penis size between 17 year olds and rological injury, urination may occur as an involuntary 19 year olds. From this, it can be concluded that penile reflex. Brain centers that regulate urination include the
54
CHAPTER 12. HUMAN PENIS
pontine micturition center, periaqueductal gray, and the cerebral cortex.[3] During erection, these centers block the relaxation of the sphincter muscles, so as to act as a physiological separation of the excretory and reproductive function of the penis, and preventing sperm from entering the upper portion of the urethra during ejaculation.[4]
12.3.2
Voiding position
The distal section of the urethra allows a human male to direct the stream of urine by holding the penis. This flexibility allows the male to choose the posture in which to urinate. In cultures where more than a minimum of clothing is worn, the penis allows the male to urinate while standing without removing much of the clothing. Some men are used to urinating in sitting or crouching positions. The preferred position may be influenced by cultural or religious beliefs.[5] Research on the medical superiority of either position exists, but the data are heterogenic. A meta-analysis[6] summarizing the evidence found no superior position for young, healthy males. For elderly males with LUTS however, in the sitting position compared to the standing:
A ventral view of a penis flaccid (left) and erect (middle); a dorsal view of a penis erect (right).
An erection is the stiffening and rising of the penis, which occurs during sexual arousal, though it can also happen in non-sexual situations. The primary physiological mechanism that brings about erection is the autonomic dilation of arteries supplying blood to the penis, which allows more blood to fill the three spongy erectile tissue chambers in the penis, causing it to lengthen and stiffen. The now-engorged erectile tissue presses against and constricts the veins that carry blood away from the penis. More blood enters than leaves the penis until an equilibrium is reached where an equal volume of blood flows into the dilated arteries and out of the constricted veins; • the post void residual volume (PVR, ml) was signif- a constant erectile size is achieved at this equilibrium. icantly decreased Erection facilitates sexual intercourse though it is not es• the maximum urinary flow (Qmax, ml/s) was in- sential for various other sexual activities. creased • the voiding time (VT, s) was decreased
Erection angle
Although many erect penises point upwards (see illustraThis urodynamic profile is related to a lower risk of uro- tion), it is common and normal for the erect penis to point logic complications, such as cystitis and bladder stones. nearly vertically upwards or nearly vertically downwards or even horizontally straight forward, all depending on the tension of the suspensory ligament that holds it in posi12.3.3 Erection tion. The following table shows how common various erection angles are for a standing male, out of a sample of 1,564 males aged 20 through 69. In the table, zero degrees is pointing straight up against the abdomen, 90 degrees is horizontal and pointing straight forward, while 180 degrees would be pointing straight down to the feet. An upward pointing angle is most common.[7]
12.3.4 Ejaculation Main article: Ejaculation The development of a penile erection, also showing the foreskin gradually retracting over the glans. See also: Commons image gallery
Main article: Erection
Ejaculation is the ejecting of semen from the penis, and is usually accompanied by orgasm. A series of muscular contractions delivers semen, containing male gametes known as sperm cells or spermatozoa, from the penis. It is usually the result of sexual stimulation, which may
12.3. PHYSIOLOGICAL FUNCTIONS include prostate stimulation. Rarely, it is due to prostatic disease. Ejaculation may occur spontaneously during sleep (known as a nocturnal emission or wet dream). Anejaculation is the condition of being unable to ejaculate. Ejaculation has two phases: emission and ejaculation proper. The emission phase of the ejaculatory reflex is under control of the sympathetic nervous system, while the ejaculatory phase is under control of a spinal reflex at the level of the spinal nerves S2–4 via the pudendal nerve. A refractory period succeeds the ejaculation, and sexual stimulation precedes it.
12.3.5
Normal variations
55 the British Medical Association, treatment (topical steroid cream and/or manual stretching) does not need to be considered until age 19. • Curvature: few penises are completely straight, with curves commonly seen in all directions (up, down, left, right). Sometimes the curve is very prominent but it rarely inhibits sexual intercourse. Curvature as great as 30° is considered normal and medical treatment is rarely considered unless the angle exceeds 45°. Changes to the curvature of a penis may be caused by Peyronie’s disease.
12.3.6 Disorders • Paraphimosis is an inability to move the foreskin forward, over the glans. It can result from fluid trapped in a foreskin left retracted, perhaps following a medical procedure, or accumulation of fluid in the foreskin because of friction during vigorous sexual activity. • In Peyronie’s disease, anomalous scar tissue grows in the soft tissue of the penis, causing curvature. Severe cases can benefit from surgical correction. • A thrombosis can occur during periods of frequent and prolonged sexual activity, especially fellatio. It is usually harmless and self-corrects within a few weeks. • Infection with the herpes virus can occur after sexual contact with an infected carrier; this may lead to the development of herpes sores.
Pearly penile papules, a common anatomical variation, may be the vestigial remnants of penis spines.
• Pearly penile papules are raised bumps of somewhat paler color around the base (sulcus) of the glans which typically develop in men aged 20 to 40. As of 1999, different studies had produced estimates of incidence ranging from 8 to 48 percent of all men.[8] They may be mistaken for warts, but are not harmful or infectious and do not require treatment.[9] • Fordyce’s spots are small, raised, yellowish-white spots 1–2 mm in diameter that may appear on the penis, which again are common and not infectious. • Sebaceous prominences are raised bumps similar to Fordyce’s spots on the shaft of the penis, located at the sebaceous glands and are normal. • Phimosis is an inability to retract the foreskin fully, is harmless in infancy and pre-pubescence, occurring in about 8% of boys at age 10. According to
• Pudendal nerve entrapment is a condition characterized by pain on sitting and loss of penile (or clitoral) sensation and orgasm. Occasionally there is a total loss of sensation and orgasm. The pudendal nerve can be damaged by narrow, hard bicycle seats and accidents. • Penile fracture can occur if the erect penis is bent excessively. A popping or cracking sound and pain is normally associated with this event. Emergency medical assistance should be obtained. Prompt medical attention lowers likelihood of permanent penile curvature. • In diabetes, peripheral neuropathy can cause tingling in the penile skin and possibly reduced or completely absent sensation. The reduced sensations can lead to injuries for either partner and their absence can make it impossible to have sexual pleasure through stimulation of the penis. Since the problems are caused by permanent nerve damage, preventive treatment through good control of the diabetes is the primary treatment. Some limited recovery may be possible through improved diabetes control.
56 • Erectile dysfunction is the inability to develop and maintain an erection sufficiently firm for satisfactory sexual performance. Diabetes is a leading cause, as is natural aging. A variety of treatments exist, most notably including the phosphodiesterase type 5 inhibitor drugs (such as sildenafil citrate, marketed as Viagra), which work by vasodilation.
CHAPTER 12. HUMAN PENIS • Hypospadias is a developmental disorder where the meatus is positioned wrongly at birth. Hypospadias can also occur iatrogenically by the downward pressure of an indwelling urethral catheter.[12] It is usually corrected by surgery. • A micropenis is a very small penis caused by developmental or congenital problems.
• Priapism is a painful and potentially harmful med• Diphallia, or penile duplication (PD), is the condiical condition in which the erect penis does not retion of having two penises. However, this disorder turn to its flaccid state. The causative mechanisms is extremely rare. are poorly understood but involve complex neurological and vascular factors. Potential complications include ischaemia, thrombosis, and impotence. In Alleged and observed psychological disorders serious cases the condition may result in gangrene, which may needs amputation only if the organ is • Penis panic (koro in Malaysian/Indonesian)— broke out and injured because of it lost of functions delusion of shrinkage of the penis and retraction permanently or disabled completely. The condition into the body. This appears to be culturally condihas been associated with a variety of drugs including tioned and largely limited to Ghana, Sudan, China, prostaglandin but not sildenafil (Viagra).[10] Japan, Southeast Asia, and West Africa. • Lymphangiosclerosis is a hardened lymph vessel, although it can feel like a hardened, almost calcified or fibrous, vein. It tends not to share the common blue tint with a vein however. It can be felt as a hardened lump or “vein” even when the penis is flaccid, and is even more prominent during an erection. It is considered a benign physical condition. It is fairly common and can follow a particularly vigorous sexual activity for men, and tends to go away if given rest and more gentle care, for example by use of lubricants.
• In April 2008, Kinshasa, Democratic Republic of Congo, West Africa’s 'Police arrested 14 suspected victims (of penis snatching) and sorcerers accused of using black magic or witchcraft to steal (make disappear) or shrink men’s penises to extort cash for cure, amid a wave of panic. Arrests were made in an effort to avoid bloodshed seen in Ghana a decade before, when 12 penis snatchers were beaten to death by mobs.[13] • Penis envy – the contested Freudian belief of all women inherently envying men for having penises.
• Carcinoma of the penis is rare with a reported rate of 1 person in 100,000 in developed countries. Cir- 12.3.7 Altering the genitalia cumcision is said to protect against this disease but this notion remains controversial.[11] Main article: Genital modification and mutilation Developmental disorders
The penis is sometimes pierced or decorated by other body art. Other than circumcision, genital alterations are almost universally elective and usually for the purpose of aesthetics or increased sensitivity. Piercings of the penis include the Prince Albert, the apadravya, the ampallang, the dydoe, and the frenum piercing. Foreskin restoration or stretching is a further form of body modification, as well as implants under the shaft of the penis. Male to female transsexuals who undergo sex reassignment surgery, have their penis surgically modified into a neovagina. Female to male transsexuals may have a phalloplasty.
Hypospadias
Other practices that alter the penis are also performed, although they are rare in Western societies without a diagnosed medical condition. Apart from a penectomy, perhaps the most radical of these is subincision, in which the urethra is split along the underside of the penis. Subincision originated among Australian Aborigines, although it is now done by some in the U.S. and Europe.
12.3. PHYSIOLOGICAL FUNCTIONS
57
Penis removal is another form of alteration done to the neonatal period.[25] Opponents of circumcision argue, for penis. example, that the practice has been and is still defended through the use of various myths; that it interferes with normal sexual function; that it is extremely painful; and Circumcision that when performed on infants and children, it violates the individual’s human rights.[26] Main article: Circumcision The most common form of genital alteration is The American Medical Association stated in 1999: “Virtually all current policy statements from specialty societies and medical organizations do not recommend routine neonatal circumcision, and support the provision of accurate and unbiased information to parents to inform their choice.”[27]
A labelled dorsal view of a circumcised penis: (1)Shaft, (2)Circumcision scar, (3)Corona, (4)Glans, (5)Meatus.
The World Health Organization (WHO; 2007), the Joint United Nations Programme on HIV/AIDS (UNAIDS; 2007), and the Centers for Disease Control and Prevention (CDC; 2008) state that evidence indicates male circumcision significantly reduces the risk of HIV acquisition by men during penile-vaginal sex, but also state that circumcision only provides partial protection and should not replace other interventions to prevent transmission of HIV.[28][29] In addition, some doctors have expressed concern over the policy and the data that supports it.[30][31]
circumcision: removal of part or all of the foreskin for various cultural, religious, and more rarely medical rea12.3.8 Surgical replacement sons. For infant circumcision, modern devices such as the Gomco clamp, Plastibell, and Mogen clamp are The first successful penis allotransplant surgery was done available.[14] in September 2005 in a military hospital in Guangzhou, With all modern devices the same basic procedure is fol- China.[32] A man at 44 sustained an injury after an accilowed. First, the amount of foreskin to be removed is dent and his penis was severed; urination became diffiestimated. The foreskin is then opened via the preputial cult as his urethra was partly blocked. A recently brainorifice to reveal the glans underneath and ensured that it is dead man, aged 23, was selected for the transplant. Denormal. The inner lining of the foreskin (preputial epithe- spite atrophy of blood vessels and nerves, the arteries, lium) is then separated from its attachment to the glans. veins, nerves and the corpora spongiosa were successfully The device is then placed (this sometimes requires a dor- matched. But, on 19 September (after two weeks), the sal slit) and remains there until blood flow has stopped. surgery was reversed because of a severe psychological Finally, part, or all, of the foreskin is then removed. problem (rejection) by the recipient and his wife.[33] Adult circumcisions are often performed without clamps and require 4 to 6 weeks of abstinence from masturbation or intercourse after the operation to allow the wound to heal.[15] In some African countries, male circumcision is often performed by non-medical personnel under unsterile conditions.[16] After hospital circumcision, the foreskin may be used in biomedical research,[17] consumer skin-care products,[18] skin grafts,[19][20][21] or βinterferon-based drugs.[22] In parts of Africa, the foreskin may be dipped in brandy and eaten by the patient, eaten by the circumciser, or fed to animals.[23] According to Jewish law, after a Brit milah, the foreskin should be buried.[24]
In 2009, researchers Chen, Eberli, Yoo and Atala have produced bioengineered penises and implanted them on rabbits.[34] The animals were able to obtain erection and copulate, with 10 of 12 rabbits achieving ejaculation. This study shows that in the future it could be possible to produce artificial penises for replacement surgeries or phalloplasties.
There is controversy surrounding circumcision. Advocates of circumcision argue, for example, that it provides important health advantages that outweigh the risks, has no substantial effects on sexual function, has a low complication rate when carried out by an experienced physician, and is best performed during the
While results vary across studies, the consensus is that the average erect human penis is approximately 12.9–15 cm (5.1–5.9 in) in length with 95% of adult males falling within the interval 10.7–19.1 cm (4.2–7.5 in). Neither age nor size of the flaccid penis accurately predicted erectile length. Stretched length most closely correlated with
12.3.9 Size Main article: Human penis size
58 erect length.[35][36][37] The average penis size is slightly larger than the median size (i.e., most penises are below average in size). Length of the flaccid penis does not necessarily correspond to length of the erect penis; some smaller flaccid penises grow much longer, while some larger flaccid penises grow comparatively less.[38] Among all primates, the human penis is the largest, both in length and girth.[39] A research project, summarizing dozens of published studies conducted by physicians of different nationalities, shows that, worldwide, erect-penis size averages vary between 9.6 and 16 cm (3.8 and 6.3 in). It has been suggested that this difference is caused not only by genetics but also by environmental factors such as fertility medications,[40] culture, diet, and chemical/pollution exposure.[41][42][43] Endocrine disruption resulting from chemical exposure has been linked to genital deformation in both sexes (among many other problems). The longest officially documented human penis was found by Doctor Robert Latou Dickinson. It was 34.3 cm (13.5 in) long and 15.9 cm (6.26 in) around.[44]
12.4 Cultural aspects In many cultures, referring to the penis is taboo or vulgar, and a variety of slang words and euphemisms are used to talk about it. In English, these include 'dick', 'cock', 'prick', 'dork', 'peter', 'pecker', 'putz', and 'schmuck'. Many of these (especially 'dick', 'prick', 'dork', 'putz', and 'schmuck') are used as insults -- though sometimes playfully--, meaning an unpleasant or unworthy person.[45][46] • Aesthetic, e.g., Body modification • In humor, considered indecent or completely taboo in various cultures • Religious veneration, see St. Priapus Church[47] • In symbology, e.g., Phallus • In architecture and sculpture, Phallic architecture
12.5 Additional images • Dissection showing the fascia of the penis as well as several surrounding structures. • Image showing innervation and blood-supply of the human male external genitalia.
12.6 References [1] Video of gliding action
CHAPTER 12. HUMAN PENIS
[2] Ponchietti R, Mondaini N, Bonafè M, Di Loro F, Biscioni S, Masieri L (February 2001). “Penile length and circumference: a study on 3,300 young Italian males”. European Urology 39 (2): 183–6. doi:10.1159/000052434. PMID 11223678. [3] Sie JA, Blok BF, de Weerd H, Holstege G (2001). “Ultrastructural evidence for direct projections from the pontine micturition center to glycine-immunoreactive neurons in the sacral dorsal gray commissure in the cat”. J. Comp. Neurol. 429 (4): 631– 7. doi:10.1002/1096-9861(20010122)429:4<631::AIDCNE9>3.0.CO;2-M. PMID 11135240. [4] Schirren, C.; Rehacek, M.; Cooman, S. de; Widmann, H.-U. (24 April 2009). “Die retrograde Ejakulation”. Andrologia 5 (1): 7–14. doi:10.1111/j.14390272.1973.tb00878.x. [5] Y. de Jong, R.M. ten Brinck, J.H.F.M. Pinckaers, A.A.B. Lycklama à Nijeholt. “Influence of voiding posture on urodynamic parameters in men: a literature review”. Nederlands Tijdschrift voor urologie). Retrieved 201407-02. [6] de Jong, Y; Pinckaers, JH; Ten Brinck, RM; Lycklama À Nijeholt, AA; Dekkers, OM (2014). “Urinating Standing versus Sitting: Position Is of Influence in Men with Prostate Enlargement. A Systematic Review and Meta-Analysis.”. PLOS ONE 9 (7): e101320. doi:10.1371/journal.pone.0101320. PMC 4106761. PMID 25051345. [7] Sparling J (1997). “Penile erections: shape, angle, and length”. Journal of Sex & Marital Therapy 23 (3): 195–207. doi:10.1080/00926239708403924. PMID 9292834. [8] Brown, Clarence William (February 13, 2014). “Pearly Penile Papules: Epidemiology”. Medscape. Retrieved 2014-03-08. [9] Spots on the penis [10] Goldenberg MM (1998). “Safety and efficacy of sildenafil citrate in the treatment of male erectile dysfunction”. Clinical Therapeutics 20 (6): 1033–48. doi:10.1016/S0149-2918(98)80103-3. PMID 9916601. [11] Boczko S, Freed S (November 1979). “Penile carcinoma in circumcised males”. New York State Journal of Medicine 79 (12): 1903–4. PMID 292845. [12] Andrews HO, Nauth-Misir R, Shah PJ (March 1998). “Iatrogenic hypospadias—a preventable injury?". Spinal Cord 36 (3): 177–80. doi:10.1038/sj.sc.3100508. PMID 9554017. [13] Reuters, Lynchings in Congo as penis theft panic hits capital [14] Holman JR, Lewis EL, Ringler RL (August 1995). “Neonatal circumcision techniques”. American Family Physician 52 (2): 511–8, 519–20. PMID 7625325. [15] Holman JR, Stuessi KA (March 1999). “Adult circumcision”. American Family Physician 59 (6): 1514–8. PMID 10193593.
12.6. REFERENCES
[16] Rosenthal, Elisabeth (2007-02-27). “In Africa, a problem with circumcision and AIDS”. The New York Times. [17] Hovatta O, Mikkola M, Gertow K, et al. (July 2003). “A culture system using human foreskin fibroblasts as feeder cells allows production of human embryonic stem cells”. Human Reproduction 18 (7): 1404–9. doi:10.1093/humrep/deg290. PMID 12832363. [18] "'Miracle' Wrinkle Cream’s Key Ingredient”. Banderasnews.com. Banderas News, Inc. April 2008. Retrieved 2010-10-22. [19] “High-Tech Skinny on Skin Grafts”. www.wired.com: science:discoveries (CondéNet, Inc). 1999-02-16. Retrieved 2008-08-20. [20] “Skin Grafting”. www.emedicine.com. WebMD. Retrieved 2008-08-20. [21] Amst, Catherine; Carey, John (July 27, 1998). “Biotech Bodies”. www.businessweek.com. The McGraw-Hill Companies Inc. Retrieved 2008-08-20. [22] Cowan, Alison Leigh (April 19, 1992). “Wall Street; A Swiss Firm Makes Babies Its Bet”. New York Times: Business (New York Times). Retrieved 2008-08-20. [23] Anonymous (editorial) (1949-12-24). “A ritual operation”. British Medical Journal 2 (4642): 1458–1459. doi:10.1136/bmj.2.4642.1458. PMC 2051965. PMID 20787713. ...in parts of West Africa, where the operation is performed at about 8 years of age, the prepuce is dipped in brandy and eaten by the patient; in other districts the operator is enjoined to consume the fruits of his handiwork, and yet a further practice, in Madagascar, is to wrap the operation specifically in a banana leaf and feed it to a calf. [24] Shulchan Aruch, Yoreh Deah, 265:10 [25] Schoen EJ (December 2007). “Should newborns be circumcised? Yes”. Canadian Family Physician 53 (12): 2096–8, 2100–2. PMC 2231533. PMID 18077736. [26] Milos MF, Macris D (1992). “Circumcision. A medical or a human rights issue?". Journal of Nurse-midwifery 37 (2 Suppl): 87S–96S. doi:10.1016/0091-2182(92)90012R. PMID 1573462. [27] “Report 10 of the Council on Scientific Affairs (I99):Neonatal Circumcision”. 1999 AMA Interim Meeting: Summaries and Recommendations of Council on Scientific Affairs Reports. American Medical Association. December 1999. p. 17. Retrieved 2006-06-13.
59
[30] G. Dowsett, M. Couch. “Male Circumcision and HIV Prevention: Is There Really Enough of the Right Kind of Evidence?". Reproductive Health Matters. Retrieved 201311-07. [31] Vardi Y, Sadeghi-Nejad H, Pollack S, AisuodionoeShadrach OI, Sharlip ID (July 2007). “Male circumcision and HIV prevention”. J Sex Med 4 (4 Pt 1): 838–43. doi:10.1111/j.1743-6109.2007.00511.x. PMID 17627731. [32] Guangzhou Daily [33] Sample, Ian (2006-09-18). “Man rejects first penis transplant”. The Guardian (London). Retrieved 2010-05-22. [34] Chen KL, Eberli D, Yoo JJ, Atala A (November 2009). “Regenerative Medicine Special Feature: Bioengineered corporal tissue for structural and functional restoration of the penis”. Proceedings of the National Academy of Sciences of the United States of America 107 (8): 3346–50. doi:10.1073/pnas.0909367106. PMC 2840474. PMID 19915140. [35] Wessells H, Lue TF, McAninch JW (September 1996). “Penile length in the flaccid and erect states: guidelines for penile augmentation”. The Journal of Urology 156 (3): 995–7. doi:10.1016/S0022-5347(01)65682-9. PMID 8709382. [36] Chen J, Gefen A, Greenstein A, Matzkin H, Elad D (December 2000). “Predicting penile size during erection”. International Journal of Impotence Research 12 (6): 328– 33. doi:10.1038/sj.ijir.3900627. PMID 11416836. [37] “ANSELL RESEARCH – The Penis Size Survey”. March 2001. Retrieved 2006-07-13. [38] “Penis Size FAQ & Bibliography”. 2009. Retrieved 2013-11-07.
Kinsey Institute.
[39] Penis size: An evolutionary perspective retrieved 10 February 2012 [40] Center of Disease Control. “DES Update: Consumers”. Retrieved 2013-11-07. [41] Swan SH, Main KM, Liu F, et al. (August 2005). “Decrease in anogenital distance among male infants with prenatal phthalate exposure”. Environmental Health Perspectives 113 (8): 1056–61. doi:10.1289/ehp.8100. PMC 1280349. PMID 16079079. [42] Montague, Peter. “PCBs Diminish Penis Size”. Rachel’s Hazardous Waste News 372. Archived from the original on 2012-03-03.
[28] “New Data on Male Circumcision and HIV Prevention: Policy and Programme Implications” (PDF). World Health Organization. March 28, 2007. Retrieved 200708-13.
[43] “Hormone Hell”. DISCOVER. Retrieved 2008-04-05.
[29] “Male Circumcision and Risk for HIV Transmission and Other Health Conditions: Implications for the United States”. Centers for Disease Control and Prevention. 2008. Retrieved 2013-11-07.
[45] Marv Rubinstein, American English Compendium: A Portable Guide to the Idiosyncrasies, Subtleties, Technical Lingo, and Nooks and Crannies of American English, ISBN 1442232838, p. 147
[44] Dickinson, R.L. (1940). The Sex Life of the Unmarried Adult. New York: Vanguard Press.
60
[46] Ruth Bell, Changing Bodies, Changing Lives: Expanded Third Edition: A Book for Teens on Sex and Relationships, ISBN 0307794067, p. 15 [47] Fritscher, Jack; Anton Szandor La Vey (2004). Popular witchcraft: straight from the witch’s mouth. Popular Press. p. 161. ISBN 978-0-299-20304-7. Retrieved 2013-1107.
12.7 External links • Kinsey Institute on the penis
12.8 Related information
CHAPTER 12. HUMAN PENIS
Chapter 13
Female reproductive system This article is about the human female reproductive system. For female reproductive systems of other mammals, see Mammalian reproduction#Female placental mammals. For the reproductive systems of other organisms, see Reproductive system. The female reproductive system (or female genital system) contains two main parts: the uterus, which hosts the developing fetus, produces vaginal and uterine secretions, and passes the male’s sperm through to the fallopian tubes; and the ovaries, which produce the female’s egg cells. These parts are internal; the vagina meets the external organs at the vulva, which includes the labia, clitoris and urethra. The vagina is attached to the uterus through the cervix, while the uterus is attached to the ovaries via the Fallopian tubes. At certain intervals, the ovaries release an ovum, which passes through the Fallopian tube into the uterus. If, in this transit, it meets with sperm, the sperm penetrate and merge with the egg, fertilizing it. Corresponding equivalent among males is the male re- Sagittal MRI showing the location of the vagina, cervix and uterus productive system. During the reproductive process, the egg releases certain molecules that are essential to guiding the sperm and these allow the surface of the egg to attach to the sperm’s surface then the egg can absorb the sperm and fertilization begins.[1] The fertilization usually occurs in the oviducts, but can happen in the uterus itself. The zygote then implants itself in the wall of the uterus, where it begins the processes of embryogenesis and morphogenesis. When developed enough to survive outside the womb, the cervix dilates and contractions of the uterus propel the fetus through the birth canal, which is the vagina. The ova are larger than sperm and have formed by the time a female is born. Approximately every month, a process of oogenesis matures one ovum to be sent down the Fallopian tube attached to its ovary in anticipation of fertilization. If not fertilized, this egg is flushed out of the Illustration depicting female reproductive system (sagittal view). system through menstruation.
13.1 Internal The female internal reproductive organs are the vagina, uterus, uterine tubes (Fallopian tubes, oviducts) and ovaries. 61
62
13.1.1
CHAPTER 13. FEMALE REPRODUCTIVE SYSTEM
Vagina
13.1.4 Fallopian tube
Main article: Vagina
Main article: Fallopian tube
The vagina is a fibro-muscular tubular tract leading from the uterus to the exterior of the body in female mammals, or to the cloaca in female birds and some reptiles. Female insects and other invertebrates also have a vagina, which is the terminal part of the oviduct. The vagina is the place where semen from the male penis is deposited into the female’s body at the climax of sexual intercourse, a phenomenon commonly known as ejaculation. The vagina is a canal that joins the cervix (the lower part of uterus) to the outside of the body. It also is known as the birth canal.
The Fallopian tubes or oviducts are two tubes leading from the ovaries of female mammals into the uterus. On maturity of an ovum, the follicle and the ovary’s wall rupture, allowing the ovum to escape and enter the Fallopian tube. There it travels toward the uterus, pushed along by movements of cilia on the inner lining of the tubes. This trip takes hours or days. If the ovum is fertilized while in the Fallopian tube, then it normally implants in the endometrium when it reaches the uterus, which signals the beginning of pregnancy.
13.1.2
Cervix
Main article: Cervix The cervix is the lower, narrow portion of the uterus where it joins with the top end of the vagina. It is cylindrical or conical in shape and protrudes through the upper anterior vaginal wall. Approximately half its length is visible to the naked eye, the remainder lies above the vagina beyond view. The vagina has a thick layer outside and it is the opening where the fetus emerges during delivery. The cervix is also named the neck of the uterus.
13.1.3
Uterus
Main article: Uterus
13.1.5 Ovaries Main article: Ovary The ovaries are small, paired organs that are located near the lateral walls of the pelvic cavity. These organs are responsible for the production of the ova and the secretion of hormones. Ovaries are the place inside the female body where ova or eggs are produced. The process by which the ovum is released is called ovulation. The speed of ovulation is periodic and impacts directly to the length of a menstrual cycle. After ovulation, the ovum is captured by the oviduct, after traveling down the oviduct to the uterus, occasionally being fertilized on its way by an incoming sperm, leading to pregnancy and the eventual birth of a new human being. The Fallopian tubes are often called the oviducts and they have small hairs (cilia) to help the egg cell travel.
The uterus or womb is the major female reproductive organ of humans. The uterus provides mechanical protection, nutritional support, and waste removal for the de- 13.2 External veloping embryo (weeks 1 to 8) and fetus (from week 9 until the delivery). In addition, contractions in the muscular wall of the uterus are important in pushing out the See also: Sex organ fetus at the time of birth. The uterus contains three suspensory ligaments that help The external components include the mons pubis, stabilize the position of the uterus and limits its range of pudendal cleft, labia majora, labia minora, Bartholin’s movement. The uterosacral ligaments keep the body from glands, and clitoris. moving inferiorly and anteriorly. The round ligaments restrict posterior movement of the uterus. The cardinal ligaments also prevent the inferior movement of the uterus.
13.3 Development
The uterus is a pear-shaped muscular organ. Its major function is to accept a fertilized ovum which becomes implanted into the endometrium, and derives nourishment from blood vessels which develop exclusively for this purpose. The fertilized ovum becomes an embryo, develops into a fetus and gestates until childbirth. If the egg does not embed in the wall of the uterus, a female begins menstruation.
Chromosome characteristics determine the genetic sex of a fetus at conception. This is specifically based on the 23rd pair of chromosomes that is inherited. Since the mother’s egg contains an X chromosome and the father’s sperm contains either an X or Y chromosome, it is the male who determines the fetus’s sex. If the fetus inherits the X chromosome from the father, the fetus will be
13.5. FEMALE GENITAL MODIFICATION a female. In this case, testosterone is not made and the Wolffian duct will degrade thus, the Müllerian duct will develop into female sex organs. The clitoris is the remnants of the Wolffian duct. On the other hand, if the fetus inherits the Y chromosome from the father, the fetus will be a male. The presence of testosterone will stimulate the Wolffian duct which will bring about the development of the male sex organs and the Müllerian duct will degrade.[2]
13.4 Physiology The reproductive tract (or genital tract) is the lumen that starts as a single pathway through the vagina, splitting up into two lumens in the uterus, both of which continue through the Fallopian tubes, and ending at the distal ostia that open into the abdominal cavity. In the absence of fertilization, the ovum will eventually traverse the entire reproductive tract from the fallopian tube until exiting the vagina through menstruation. The reproductive tract can be used for various transluminal procedures such as fertiloscopy, intrauterine insemination and transluminal sterilization.
13.5 Female genital modification Main articles: Female genital modification and Female genital mutilation There are surgical procedures which change the appearance of external female genitalia. Clitoral hood reduction, also known as clitoridotomy, is a procedure intended to reposition the protruding clitoris and reduce the length and projection of the clitoral hood. The procedure is indicated in women with mild clitoral enlargement who are unwilling to undergo a formal clitoris reduction.[3] Clitoral hood removal, also known as hoodectomy, is a cosmetic surgery intended to enhance a female’s sexual experience. This surgery involves the trimming back of the clitoral hood or a complete clitoris hood removal.[4] Removal of the protective hood allows for more clitoral exposure which increases sensitivity in the clitoris. This procedure, sometimes called female circumcision, is different from a clitoral excision and is not intended to prevent a woman from experiencing sexual pleasure.[5] Clitoral reduction is indicated to reduce the size of the clitoris which may be enlarged due to hormonal abnormalities, ingestion of steroids, or birth. Surgery can reduce the glans or shaft of the clitoris through an outpatient procedure.[6] Female genital mutilation (FGM) is defined by the United Nations (UN) and World Health Organization (WHO) as the complete or partial removal of the female genital or-
63 gans or any other harmful injury inflicted on them for cultural, religious, or recreational reasons. FGM has deep roots in historical, religious, and cultural traditions. It has become a topic of debate in the 21st century because most people argue that it is inhumane and unsafe. Feminists argue that it is a form of subjugation of women and genderbased discrimination.[7] Contrary to surgical procedures intended to enhance a woman’s sexual experience or her physical appearance, female genital mutilation does not have cosmetic or health benefits and can be harmful to the emotional and physical well-being of those it is inflicted upon.[8] This kind of procedure may have complications including, but not limited to, severe bleeding, tetanus, sepsis, urine retention, open sores in the genital area, irreparable tissue damage, potential childbirth complications, infertility, and death.[8] The practice of female genital mutilation is common in the western, eastern and north-eastern regions of Africa. It also takes place in some countries in Asia and the Middle East. The mutilation is practiced by some immigrant communities in North America and Europe.[8] There are four types of genital mutilation. Type 1, also known as circumcision or Sunna (Arab word meaning tradition), is the excision of the precipice, which is the fold of skin surrounding the clitoris. Type 2, also known as clitoridectomy, is the excision of the clitoris with partial or total removal of the labia minora, which are the smaller inner folds of the vulva. Type 3, also known as infibulation or pharaonic circumcision, is the excision of part or all of the external genitalia and stitching or narrowing of the vaginal opening. Type 4, which can include a range of procedures such as piercing, pricking, burning, scraping, cutting, or introduction of corrosive substances into the vagina.[7] Type 1 (circumcision) and Type 2 (clitoridectomy) are the most common forms of FGM making up about 80% of cases and Type 3 is the most extreme form and makes up about 15%. Type 3 is commonly a practice of choice in several African countries. The risks of FGM include physical, sexual, psychological, and pregnancy consequences. The procedure is done in a secluded area in the home and the child may be blindfolded or allowed to see where it will take place. Once they arrive the girl is often immobilized on her back with her legs spread apart so that the procedure may be performed. After the procedure is finished the girl’s legs are bounded together and left in a secluded area to recover for 40 days. The people who perform the “surgical” procedure are usually untrained midwives or elderly women and they more than often use unsterilized razor blades, scissors, knives, broken glass, sharp rocks, or even their teeth. This and the binding of their legs cause infection in the uterus, fallopian tubes, and ovaries. Research has shown that circumcised women have significantly lower levels of selfesteem as opposed to uncircumcised women. [7]
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CHAPTER 13. FEMALE REPRODUCTIVE SYSTEM
13.6 Diseases of the vagina
13.7 History
It is claimed in the Hippocratic writings that both males and females contribute their seed to conception; otherwise, children would not resemble either or both of their Vaginitis is one of the most common infections in the parents. Four-hundred years later, Galen “identifies” the female reproductive system and accounts for more than source of female semen as the ovaries in female reproten million office visits per year. It is difficult to deductive organs.[10] termine the organism most responsible for vaginitis because it varies from range of age, sexual activity, and method of microbial identification. Vaginitis is not necessarily a sexually transmitted disease due to many infec- 13.8 See also tious agents that make use of the close proximity to mu• Conception cous membranes and secretions. Vaginitis is usually diagnosed based on the presence of vaginal discharge, which • Development of the reproductive system can have a certain color, odor, or quality.[9] • Evolution of sexual reproduction
13.6.1
Vaginitis
• Female infertility
13.6.2
Bacterial vaginosis
Bacterial Vaginosis is another common infection in women but it differs from vaginitis in that there is no inflammation. Organisms known to cause bacterial vaginosis are Trichomonas and Candida, which is the most common active pathogen in the female genital tract. Bacterial vaginosis is not an infection by a single organism but an overgrowth of multiple colonizing bacteria. The diagnosis for bacterial vaginosis is made if three of the following four criteria are present: (1) Homogenous, thin discharge, (2) a pH of 4.5 in the vagina, (3) epithelial cells in the vagina with bacteria attached to them, or (4) a fishy odor. Bacterial vaginosis is treated with acetic acid, estrogen, or fermented milk. It has been associated with an increased risk of other genital tract infections such as endometritis. [9]
• Oogenesis • Human sexuality#Female anatomy and reproductive system • Reproductive system
13.9 References [1] Freedman, David H. (1992). “The Aggressive Egg”in DISCOVER. Biology & Medicine. [2] “Details of genital development”. Retrieved August 6, 2010. [3] “Clitoropexy / Clitoral Hood Reduction”. Retrieved August 6, 2010. [4] “Clitoris Hood Removal Surgery and More”. Retrieved August 6, 2010. [5] “Clitoral Hood Removal”. Retrieved August 6, 2010.
13.6.3
Yeast infection
[6] “Clitoral Reduction and Clitoral Hood Removal”. Retrieved August 6, 2010.
Yeast infection is a common cause of vaginal irritation and according to the Centers for Disease Control and Pre- [7] Baron & Denmark, Erika & Florence. “An Exploration of Female Genital Mutilation”. vention (CDC) at least 75% of adult women have experienced one at least once in their lifetime. Yeast infec- [8] “Female Genital Mutilation”. World Health Organization. Retrieved August 6, 2010. tions are caused by an overgrowth of fungus in the vagina known as Candida. Yeast infections are usually caused [9] Zaino, Nucci, & Kurman, Richard, Marisa, & Robert. by an imbalance of the pH in the vagina, which is usually “Diseas of the Vagina”. acidic. Other factors such as pregnancy, diabetes, weakened immune systems, tight fitting clothing, or douching [10] Anwar, Etin. “The Transmission of Generative Self and Women’s Contribution to Conception.” Gender and Self can also be a cause. Symptoms of yeast infections include in Islam. London: Routledge, 2006. 75. Print. itching, burning, irritation, and a white cottage-cheeselike discharge from the vagina. Women have also reported that they experience painful intercourse and urination as well. Taking a sample of the vaginal secre- 13.10 External links tions and placing them under a microscope for evidence • Female reproductive system of yeast can diagnose a yeast infection. Treatment varies from creams that can be applied in or around the vaginal • Interactive diagram of female reproductive system area to oral tablets that stop the growth of fungus. [9]
Chapter 14
Ovary 14.1.2 Extremities
For ovary as part of plants, see Ovary (botany).
There are two extremities to the ovary: “Ovaria” redirects here. This is also a proposed section and a synonym of Solanum.
• The end to which the fallopian tube attaches is called the tubal extremity and ovary is connected to it by infundibulopelvic ligament.[1]
As a component of names, see Overy.
• The other extremity is called the uterine extremity. The ovary (From Latin: ovarium, literally “egg” or “nut”) It points downward, and it is attached to the uterus is an ovum-producing reproductive organ, often found in via the ovarian ligament. pairs as part of the vertebrate female reproductive system. Ovaries in female individuals are analogous to testes in male individuals, in that they are both gonads and 14.1.3 Histology endocrine glands. Although ovaries occur in a wide variety of animals, both vertebrate and invertebrate, this ar• Follicular cells flat epithelial cells that originate from ticle is primarily about ovaries in humans. surface epithelium covering the ovary • Granulosa cells - surrounding follicular cells have changed from flat to cuboidal and proliferated to produce a stratified epithelium
14.1 Structure In the case of human ovaries, each one is whitish in color and located alongside the lateral wall of the uterus in a region called the ovarian fossa. The fossa usually lies beneath the external iliac artery and in front of the ureter and the internal iliac artery. It is about 4 cm x 3 cm x 2 cm in size.[1] Usually each ovary takes turns releasing an egg each month; however, if there was a case where one ovary was absent or dysfunctional then the other ovary would continue providing eggs to be released.
14.1.1
Ligaments
• Gametes[2] • The outermost layer is called the germinal epithelium. • The ovarian cortex consists of ovarian follicles and stroma in between them. Included in the follicles are the cumulus oophorus, membrana granulosa (and the granulosa cells inside it), corona radiata, zona pellucida, and primary oocyte. The zona pellucida, theca of follicle, antrum and liquor folliculi are also contained in the follicle. Also in the cortex is the corpus luteum derived from the follicles. • The innermost layer is the ovarian medulla. It can be hard to distinguish between the cortex and medulla, but follicles are usually not found in the medulla.
In the human the paired ovaries lie within the pelvic cavity, on either side of the uterus, to which they are attached via a fibrous cord called the ovarian ligament. The ovaries [3] are uncovered in the peritoneal cavity but are tethered to The ovary also contains blood vessels and lymphatics. the body wall via the suspensory ligament of the ovary. The part of the broad ligament of the uterus that covers the ovary is known as the mesovarium. The ovary is thus 14.2 Function considered an intraperitoneal organ. 65
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14.2.1
CHAPTER 14. OVARY
Gamete production
Main article: Oogenesis The ovaries are the site of production and periodical release of egg cells, the female gametes. In the ovaries, the developing egg cell (or oocyte) grows within the environmet provided by follicles. Follicles are composed of different types and number of cells according to the stage of their maturation, and their size is indicative of the stage of oocyte development.[4]:833 When the oocyte finishes its maturation in the ovary, a surge of luteinizing hormone secreted by the pituitary gland stimulates the release of the oocyte through the rupture of the follicle, a process called ovulation.[5] The follicle remains functional and reorganizes into a corpus luteum, which secretes progesterone in order to prepare the uterus for an eventual implantation of the embryo.[4]:839
14.2.2
Endocrine function
Ovaries secrete estrogen, testosterone[6][7] and progesterone. In women, fifty percent of testosterone is produced by the ovaries and adrenal glands and released directly into the blood stream.[8] Estrogen is responsible for the appearance of secondary sex characteristics for females at puberty and for the maturation and maintenance of the reproductive organs in their mature functional state. Progesterone prepares the uterus for pregnancy, and the mammary glands for lactation. Progesterone functions with estrogen by promoting menstrual cycle changes in the endometrium.
14.2.3
Ovarian aging
pair DNA double-strand breaks. Titus et al.[11] showed that DNA double-strand breaks accumulate with age in humans and mice in primordial follicles. Primodial follicles contain oocytes that are at an intermediate (prophase I) stage of meiosis. Meiosis is the general process in eukaryotic organisms by which germ cells are formed, and it is likely an adaptation for removing DNA damages, especially double-strand breaks, from germ line DNA.[12] (see Meiosis and Origin and function of meiosis). Homologous recombinational repair is especially promoted during meiosis. Titus et al.[11] also found that expression of 4 key genes necessary for homologous recombinational repair of DNA double-strand breaks (BRCA1, MRE11, RAD51 and ATM) decline with age in the oocytes of humans and mice. They hypothesized that DNA doublestrand break repair is vital for the maintenance of oocyte reserve and that a decline in efficiency of repair with age plays a key role in ovarian aging.
14.3 Clinical significance Ovarian diseases can be classified as endocrine disorders or as a disorders of the reproductive system. If the egg fails to release from the follicle in the ovary an ovarian cyst may form. Small ovarian cysts are common in healthy women. Some women have more follicles than usual (polycystic ovary syndrome), which inhibits the follicles to grow normally and this will cause cycle irregularities. Other conditions include: • Ovarian neoplasms, including Ovarian cancer • Luteoma
• Hypogonadism As women age, they experience a decline in reproductive performance leading to menopause. This decline is tied • Hyperthecosis to a decline in the number of ovarian follicles. Although • Ovarian torsion about 1 million oocytes are present at birth in the human ovary, only about 500 (about 0.05%) of these ovulate, and • Ovarian apoplexy (rupture) the rest are wasted. The decline in ovarian reserve ap[9] pears to occur at a constantly increasing rate with age, and leads to nearly complete exhaustion of the reserve by about age 52. As ovarian reserve and fertility decline with 14.4 Society and culture age, there is also a parallel increase in pregnancy failure and meiotic errors resulting in chromosomally abnormal 14.4.1 Cryopreservation conceptions. Women with an inherited mutation in the DNA repair gene BRCA1 undergo menopause prematurely,[10] suggesting that naturally occurring DNA damages in oocytes are repaired less efficiently in these women, and this inefficiency leads to early reproductive failure. The BRCA1 protein plays a key role in a type of DNA repair termed homologous recombinational repair that is the only known cellular process that can accurately re-
Cryopreservation of ovarian tissue, often called ovarian tissue cryopreservation, is of interest to women who want to preserve their reproductive function beyond the natural limit, or whose reproductive potential is threatened by cancer therapy,[13] for example in hematologic malignancies or breast cancer.[14] The procedure is to take a part of the ovary and carry out slow freezing before storing it in liquid nitrogen whilst therapy is undertaken. Tissue
14.6. ADDITIONAL IMAGES can then be thawed and implanted near the fallopian, either orthotopic (on the natural location) or heterotopic (on the abdominal wall),[14] where it starts to produce new eggs, allowing normal conception to take place.[15] A study of 60 procedures concluded that ovarian tissue harvesting appears to be safe.[14] The ovarian tissue may also be transplanted into mice that are immunocompromised (SCID mice) to avoid graft rejection, and tissue can be harvested later when mature follicles have developed.[16]
14.5 Other animals
67 The ovary of teleosts is also often hollow, but in this case, the eggs are shed into the cavity, which opens into the oviduct.[17] Certain nematodes of the genus Philometra are parasitic in the ovary of marine fishes and can be spectacular, with females as long as 40 cm, coiled in the ovary of a fish half this length.[18] These nematodes never parasitize humans. Although most normal female vertebrates have two ovaries, this is not the case in all species. In most birds and in platypuses, the right ovary never matures, so that only the left is functional. (Exceptions include the Kiwi and some, but not all raptors, in which both ovaries persist.[19][20] ) In some elasmobranchs, only the right ovary develops fully. In the primitive jawless fish, and some teleosts, there is only one ovary, formed by the fusion of the paired organs in the embryo.[17]
14.6 Additional images • Left Ovary • Ovaries • Uterus
14.7 See also • Ovarian reserve • Folliculogenesis Ovary of a marine fish and its parasite, the nematode Philometra fasciati
Ovaries of some kind are found in the female reproductive system of many animals that employ sexual reproduction, including invertebrates. However, they develop in a very different way in most invertebrates than they do in vertebrates, and are not truly homologous.[17] Many of the features found in human ovaries are common to all vertebrates, including the presence of follicular cells, tunica albuginea, and so on. However, many species produce a far greater number of eggs during their lifetime than do humans, so that, in fish and amphibians, there may be hundreds, or even millions of fertile eggs present in the ovary at any given time. In these species, fresh eggs may be developing from the germinal epithelium throughout life. Corpora lutea are found only in mammals, and in some elasmobranch fish; in other species, the remnants of the follicle are quickly resorbed by the ovary. In birds, reptiles, and monotremes, the egg is relatively large, filling the follicle, and distorting the shape of the ovary at maturity.[17] Amphibians and reptiles have no ovarian medulla; the central part of the ovary is a hollow, lymph-filled space.
• Oophorectomy
14.8 References [1] Daftary, Shirish; Chakravarti, Sudip (2011). Manual of Obstetrics, 3rd Edition. Elsevier. pp. 1-16. ISBN 9788131225561. [2] Langman’s Medical Embryology, Lippincott Williams & Wilkins, 10th ed, 2006 [3] Brown, H. M.; Russell, D. L. (2013). “Blood and lymphatic vasculature in the ovary: Development, function and disease”. Human Reproduction Update 20: 29. doi:10.1093/humupd/dmt049. [4] Ross M, Pawlina W (2011). Histology: A Text and Atlas (6th ed.). Lippincott Williams & Wilkins. ISBN 978-07817-7200-6. [5] Melmed, S; Polonsky, KS; Larsen, PR; Kronenberg, HM (2011). Williams Textbook of Endocrinology (12th ed.). Saunders. p. 595. ISBN 978-1437703245. [6] Normal Testosterone and Estrogen Levels in Women [7] Testosterone: MedlinePlus Medical Encyclopedia
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[8] Androgens in women [9] Hansen KR, Knowlton NS, Thyer AC, Charleston JS, Soules MR, Klein NA. (2008). A new model of reproductive aging: the decline in ovarian non-growing follicle number from birth to menopause. Hum Reprod 23(3):699-708. doi: 10.1093/humrep/dem408. PMID 18192670 [10] Rzepka-Górska I, Tarnowski B, Chudecka-Głaz A, Górski B, Zielińska D, Tołoczko-Grabarek A. (2006). Premature menopause in patients with BRCA1 gene mutation. Breast Cancer Res Treat 100(1):59-63. PMID 16773440 [11] Titus S, Li F, Stobezki R, Akula K, Unsal E, Jeong K, Dickler M, Robson M, Moy F, Goswami S, Oktay K. (2013). Impairment of BRCA1-related DNA doublestrand break repair leads to ovarian aging in mice and humans. Sci Transl Med 5(172):172ra21. doi: 10.1126/scitranslmed.3004925. PMID 23408054 [12] Harris Bernstein, Carol Bernstein and Richard E. Michod (2011). Meiosis as an Evolutionary Adaptation for DNA Repair. Chapter 19 in DNA Repair. Inna Kruman editor. InTech Open Publisher. DOI: 10.5772/25117 http://www.intechopen.com/books/dna-repair/ meiosis-as-an-evolutionary-adaptation-for-dna-repair [13] Isachenko V, Lapidus I, Isachenko E, et al. (2009). “Human ovarian tissue vitrification versus conventional freezing: morphological, endocrinological, and molecular biological evaluation.”. Reproduction 138 (2): 319–27. doi:10.1530/REP-09-0039. PMID 19439559. [14] Oktay K, Oktem O (November 2008). “Ovarian cryopreservation and transplantation for fertility preservation for medical indications: report of an ongoing experience”. Fertil. Steril. 93 (3): 762–8. doi:10.1016/j.fertnstert.2008.10.006. PMID 19013568. [15] Livebirth after orthotopic transplantation of cryopreserved ovarian tissue The Lancet, Sep 24, 2004 [16] Lan C, Xiao W, Xiao-Hui D, Chun-Yan H, Hong-Ling Y (December 2008). “Tissue culture before transplantation of frozen-thawed human fetal ovarian tissue into immunodeficient mice”. Fertil. Steril. 93 (3): 913–9. doi:10.1016/j.fertnstert.2008.10.020. PMID 19108826. [17] Romer, Alfred Sherwood; Parsons, Thomas S. (1977). The Vertebrate Body. Philadelphia, PA: Holt-Saunders International. pp. 383–385. ISBN 0-03-910284-X. [18] Moravec, František; Justine, Jean-Lou (2014). “Philometrids (Nematoda: Philometridae) in carangid and serranid fishes off New Caledonia, Parasite 21: 21. including three new species”. doi:10.1051/parasite/2014022. ISSN 1776-1042. PMC 4023622. PMID 24836940. [19] Fitzpatrick, F. L. 1934. Unilateral and bilateral ovaries in raptorial birds. The Wilson Bulletin 46 (1): 19-22. [20] Kinsky, F. C. 1971. The consistent presence of paired ovaries in the Kiwi(Apteryx) with some discussion of this condition in other birds. Journal of Ornithology 112 (3): 334–357.
CHAPTER 14. OVARY
14.9 External links • From the American Medical Association • Merck Online Medical Library: Female Reproductive System
Chapter 15
Uterus “Womb” redirects here. For other uses, see Womb (disambiguation). “Hystera” and “Uterine” redirect here. For the state of mind, see hysteria. For siblings with the same mother but different fathers, see Uterine siblings.
of as something between a monotreme egg and a “true” placenta), in which the egg’s yolk sac supplies a large part of the embryo’s nutrition but also attaches to the uterine wall and takes nutrients from the mother’s bloodstream.
The uterus (from Latin “uterus”, plural uteri) or womb is a major female hormone-responsive reproductive sex organ of most mammals, including humans. One end, the cervix, opens into the vagina, while the other is connected to one or both fallopian tubes, depending on the species. It is within the uterus that the fetus develops during gestation, usually developing completely in placental mammals such as humans and partially in marsupials such as kangaroos and opossums. Two uteri usually form initially in a female and usually male fetus, and in placental mammals they may partially or completely fuse into a single uterus depending on the species. In many species with two uteri, only one is functional. Humans and other higher primates such as chimpanzees, usually have a single completely fused uterus, although in some individuals the uteri may not have completely fused. Horses, on the other hand, have bipartite uteri. In English, the term uterus is used consistently within the medical and related professions, while the Germanic-derived term womb is more common in everyday usage.
15.1 Structure The uterus is located inside the pelvis immediately dorsal (and usually somewhat rostral) to the urinary bladder and ventral to the rectum. The human uterus is pear-shaped and about 3 in. (7.6 cm) long, 4.5 cm broad (side to side) and 3.0 cm thick (anteroposterior).[2] A nonpregnant adult uterus weighs about 60 grams. The uterus can be divided anatomically into four segments: The fundus, corpus, cervix and the internal os.
15.1.1 Regions From outside to inside, the path to the uterus is as follows:
Most animals that lay eggs, such as birds and reptiles, including most ovoviviparous species, have an oviduct instead of a uterus. Note however, that recent research into the biology of the viviparous (not merely ovoviviparous) skink Trachylepis ivensi has revealed development of a very close analogue to eutherian mammalian placental development.[1]
• Cervix uteri - “neck of uterus” • External orifice of the uterus • Canal of the cervix • Internal orifice of the uterus • corpus uteri - “Body of uterus” • Cavity of the body of the uterus • Fundus (uterus)
In monotremes, mammals which lay eggs, namely the platypus and the echidnas, either the term uterus or 15.1.2 Layers oviduct is used to describe the same organ, but the egg does not develop a placenta within the mother and thus The three layers, from innermost to outermost, are as foldoes not receive further nourishment after formation and lows: fertilization. Marsupials have two uteri, each of which connect to a Endometrium The lining of the uterine cavity is called the “endometrium”. It consists of the functional lateral vagina and which both use a third, middle “vagina” endometrium and the basal endometrium from which functions as the birth canal. Marsupial embryos which the former arises. Damage to the basal form a choriovitelline “placenta” (which can be thought endometrium results in adhesion formation and/or 69
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CHAPTER 15. UTERUS fibrosis (Asherman’s syndrome). In all placental mammals, including humans, the endometrium builds a lining periodically which is shed or reabsorbed if no pregnancy occurs. Shedding of the functional endometrial lining is responsible for menstrual bleeding (known colloquially as a “period” in humans, with a cycle of approximately 28 days, +/−7 days of flow and +/−21 days of progression) throughout the fertile years of a female and for some time beyond. Depending on the species and attributes of physical and psychological health, weight, environmental factors of circadian rhythm, photoperiodism (the physiological reaction of organisms to the length of day or night), the effect of menstrual cycles to the reproductive function of the uterus is subject to hormone production, cell regeneration and other biological activities. The menstrual cycles may vary from a few days to six months, but can vary widely even in the same individual, often stopping for several cycles before resuming. Marsupials and monotremes do not have menstruation.
Myometrium The uterus mostly consists of smooth muscle, known as “myometrium.” The innermost layer of myometrium is known as the junctional zone, which becomes thickened in adenomyosis. Perimetrium The loose connective tissue around the uterus.
15.1.3
Support
15.1.5 Position The uterus is in the middle of the pelvic cavity in frontal plane (due to ligamentum latum uteri). The fundus does not surpass the linea terminalis, while the vaginal part of the cervix does not extend below interspinal line. The uterus is mobile and moves posteriorly under the pressure of a full bladder, or anteriorly under the pressure of a full rectum. If both are full, it moves upwards. Increased intraabdominal pressure pushes it downwards. The mobility is conferred to it by musculo-fibrous apparatus that consists of suspensory and sustentacular part. Under normal circumstances the suspensory part keeps the uterus in anteflexion and anteversion (in 90% of women) and keeps it “floating” in the pelvis. The meaning of these terms are described below: Sustentacular part supports the pelvic organs and comprises the larger pelvic diaphragm in the back and the smaller urogenital diaphragm in the front. The pathological changes of the position of the uterus are: • retroversion/retroflexion, if it is fixed • hyperanteflexion - tipped too forward; most commonly congenital, but may be caused by tumors • anteposition, retroposition, lateroposition - the whole uterus is moved; caused by parametritis or tumors • elevation, descensus, prolapse • rotation (the whole uterus rotates around its longitudinal axis), torsion (only the body of the uterus rotates around)
The uterus is primarily supported by the pelvic di• inversion aphragm, perineal body and the urogenital diaphragm. Secondarily, it is supported by ligaments and the periIn cases where the uterus is “tipped”, also known as toneum (broad ligament of uterus)[3] retroverted uterus, women may have symptoms of pain during sexual intercourse, pelvic pain during menstruation, minor incontinence, urinary tract infections, fertil15.1.4 Axes ity difficulties,[5] and difficulty using tampons. A pelvic by a doctor can determine if a uterus is Normally the uterus lies in anteversion & anteflexion. In examination [6] tipped. most women, the long axis of the uterus is bent forward on the long axis of the vagina. This position is referred to as anteversion of the uterus. Furthermore, the long axis 15.1.6 Shape of the body of the uterus is bent forward at the level of the internal os with the long axis of the cervix. This position In mammals, the four main forms in which it is found are: is termed anteflexion of the uterus.[4] Uterus assumes anteverted position in 50% women, retroverted position in Duplex There are two wholly separate uteri, with one 25% women and rest have midposed uterus.[2] fallopian tube each. Found in marsupials (such as kangaroos, Tasmanian devils, opossums, etc.), rodents (such as mice, rats, and guinea pigs), and Major ligaments lagomorpha (rabbits and hares). It is held in place by several peritoneal ligaments, of which Bipartite The two uteri are separate for most of their the following are the most important (there are two of length, but share a single cervix. Found in ruminants (deer, moose, elk etc.), hyraxes, cats, and horses. each):
15.2. FUNCTION Bicornuate The upper parts of the uterus remain separate, but the lower parts are fused into a single structure. Found in dogs, pigs, elephants, whales, dolphins, and tarsiers, and strepsirrhine primates among others.
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Ovarian artery Arcuate artery Radial artery
Simplex The entire uterus is fused into a single organ. Found in higher primates (including humans and chimpanzees) . Occasionally, some individual females (including humans) may have a bicornuate uterus, a uterine malformation where the two parts of the uterus fail to fuse completely during fetal development. In monotremes such as the platypus, the uterus is duplex and rather than nurturing the embryo, secretes the shell around the egg. It is essentially identical with the shell gland of birds and reptiles, with which the uterus is homologous.[7]
Basal artery Spiral artery
Endometrium Myometrium Uterine artery Schematic diagram of uterine arterial vasculature seen as a crosssection through the myometrium and endometrium.
15.1.7
Blood supply 15.1.10 Development Bilateral Müllerian ducts form during early fetal life. In males, MIF secreted from the testes leads to their regression. In females, these ducts give rise to the Fallopian tubes and the uterus. In humans the lower segments of the two ducts fuse to form a single uterus, however, in cases of uterine malformations this development may be disturbed. The different uterine forms in various mammals are due to various degrees of fusion of the two Müllerian ducts.
Vessels of the uterus and its appendages, rear view.
15.2 Function
The uterus is supplied by arterial blood both from the uterine artery and the ovarian artery. Another anasto- The uterus consists of a body and a cervix. The cervix motic branch may also supply the uterus from anastomo- protrudes into the vagina. The uterus is held in position within the pelvis by condensations of endopelvic fascia, sis of these two arteries. which are called ligaments. These ligaments include the pubocervical, transverse cervical ligaments or Mackenrodt’s ligaments or cardinal ligaments, and the uterosacral 15.1.8 Nerve supply ligaments. It is covered by a sheet-like fold of peritoneum, the broad ligament.[8] Afferent nerves supplying uterus are T11 and T12. Sym- The uterus is essential in sexual response by directing pathetic supply is from hypogastric plexus and ovarian blood flow to the pelvis and to the external genitalia, inplexus. Parasympathetic supply is from second, third and cluding the ovaries, vagina, labia, and clitoris. fourth sacral nerves. The reproductive function of the uterus is to accept a fertilized ovum which passes through the utero-tubal junction from the fallopian tube. It implants into the 15.1.9 Histology endometrium, and derives nourishment from blood vessels which develop exclusively for this purpose. The fer• Vertical section of mucous membrane of human tilized ovum becomes an embryo, attaches to a wall of the uterus. uterus, creates a placenta, and develops into a fetus (ges-
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CHAPTER 15. UTERUS
tates) until childbirth. Due to anatomical barriers such as the pelvis, the uterus is pushed partially into the abdomen due to its expansion during pregnancy. Even during pregnancy the mass of a human uterus amounts to only about a kilogram (2.2 pounds).
15.3 Diseases of the uterus Some pathological states include: • Prolapse of the uterus • Carcinoma of the cervix – malignant neoplasm
• Accumulation of fluids other than blood or of unknown constitution. One study came to the conclusion that postmenopausal women with endometrial fluid collection on gynecologic ultrasonography should undergo endometrial biopsy if the endometrial lining is thicker than 3 mm or the endometrial fluid is echogenic. In cases of a lining 3 mm or less and clear endometrial fluid, endometrial bipsy was not regarded to be necessary, but endocervical sampling to rule out endocervical cancer was recommended.[9]
15.4 Uterus transplantation
In 2012, the world’s first womb transplant from a dead donor was performed on a Turkish woman who was born without a womb, but has her own ovaries. She is in good Fibroids – benign neoplasms condition and the womb is functional. In the year 2000 Adenomyosis – ectopic growth of endometrial tissue in Saudi Arabia a similar transplant was performed, but from a live donor. Although womb transplants have been within the myometrium successful in animals such as mice, rats and sheep, the prevailing opinion in the field is that the risks are too Endometritis, infection at the uterine cavity. great. Apart from risks of rejection of the new womb, Pyometra – infection of the uterus, most commonly there is concern that the drugs necessary for prevention of seen in dogs rejection of the donated womb might harm the fetus.[10]
• Carcinoma of the uterus – malignant neoplasm • • • •
• Uterine malformations mainly congenital malformations including Uterine Didelphys, bicornuate uterus and septate uterus. It also includes congenital absence of the uterus Rokitansky syndrome • Asherman’s syndrome, also known as intrauterine adhesions occurs when the basal layer of the endometrium is damaged by instrumentation (e.g. D&C) or infection (e.g. endometrial tuberculosis) resulting in endometrial scarring followed by adhesion formation which partially or completely obliterates the uterine cavity. • Hematometra, which is accumulation of blood within the uterus.
15.5 Additional images • Schematic frontal view of female and male anatomy • Uterus and uterine tubes. • • Sectional plan of the gravid uterus in the third and fourth month. • Fetus in utero, between fifth and sixth months. • Uterus and right broad ligament, seen from behind. • Female and male pelvis and its contents, seen from above and in front. • Sagittal section of the lower part of a female and male trunk, right segment. • Posterior half of uterus and upper part of vagina. • The arteries of the internal organs of generation of the female and male, seen from behind. • Median sagittal section of female and male pelvis.
Transvaginal ultrasonography showing a uterine fluid accumulation in a postmenopausal woman.
• (Description located on image page) • Uterus
15.8. EXTERNAL LINKS
15.6 See also • Ovule • Hysterectomy • Menopause • Uterine glands • Artificial uterus • Retroverted uterus • Social uterus
15.7 References [1] Blackburn, D. G.; Flemming, A. F. (2011). “Invasive implantation and intimate placental associations in a placentotrophic African lizard, Trachylepis ivensi (scincidae)". Journal of Morphology. doi:10.1002/jmor.11011. [2] Manual of Obstetrics. (3rd ed.). Elsevier 2011. pp. 1-16. ISBN 9788131225561. [3] The Pelvis University College Cork Archived from the original on 2008-02-27 [4] Snell, Clinical Anatomy by regions, 8th edition [5] http://www.womens-health.co.uk/retrover.asp [6] Tipped Uterus:Tilted Uterus AmericanPregnancy.org. Accessed 25 March 2011 [7] Romer, Alfred Sherwood; Parsons, Thomas S. (1977). The Vertebrate Body. Philadelphia, Pennsylvania: HoltSaunders International. pp. 390–392. ISBN 0-03910284-X. [8] Gray’s Anatomy for Students, 2nd edition [9] Takacs P, De Santis T, Nicholas MC, Verma U, Strassberg R, Duthely L (November 2005). “Echogenic endometrial fluid collection in postmenopausal women is a significant risk factor for disease”. J Ultrasound Med 24 (11): 1477– 81. PMID 16239648. [10] “The world’s first womb transplant: Landmark surgery brings hope to millions of childless women - and it could be in Britain soon”. May 25, 2012.
15.8 External links • Gray’s s268 • Anatomy photo:43:01-0102 at the SUNY Downstate Medical Center - “The Female Pelvis: Organs in the Female and male Pelvis in situ” • Encyclopedia.com • Uterus Anatomy • Uterus Pregnancy
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Chapter 16
Fallopian tube ina propria is a vascular connective tissue.[1] There are two types of cells within the simple columnar epithelium of the Fallopian tube (oviduct). Ciliated cells predominate throughout the tube, but are most numerous in the infundibulum and ampulla. Estrogen increases the production of cilia on these cells. Interspersed between the ciliated cells are peg cells, which contain apical granules and produce the tubular fluid. This fluid contains nutrients for spermatozoa, oocytes, and zygotes. The secre16.1 History tions also promote capacitation of the sperm by removing glycoproteins and other molecules from the plasma memThey are named after their discoverer, the 16th century brane of the sperm. Progesterone increases the number Italian anatomist, Gabriele Falloppio. of peg cells, while estrogen increases their height and seThough the name 'Fallopian tube' is eponymous, some cretory activity. Tubal fluid flows against the action of the texts spell it with a lower case 'f' from the assumption ciliae, that is toward the fimbrial end. that the adjective 'fallopian' has been absorbed into mod- In view of longitudinal variation in histological features ern English as the de facto name for the structure. of tube, the isthmus has thick muscular coat and simThe Fallopian tubes, also known as oviducts, uterine tubes, and salpinges (singular salpinx), are two very fine tubes lined with ciliated epithelia, leading from the ovaries of female mammals into the uterus, via the uterotubal junction. In non-mammalian vertebrates, the equivalent structures are the oviducts.
ple mucosal folds; whereas ampulla has complex mucosal folds.[1]
The Greek word salpinx (σαλπιγξ) means "trumpet".
16.2 Structure
16.2.2 Development
In a woman’s body the tube allows passage of the egg from the ovary to the uterus. Its different segments are (lateral to medial): the infundibulum with its associated fimbriae near the ovary, the ampullary region that represents the major portion of the lateral tube, the isthmus which is the narrower part of the tube that links to the uterus, and the interstitial (also known as intramural) part that transverses the uterine musculature. The tubal ostium is the point where the tubal canal meets the peritoneal cavity, while the uterine opening of the Fallopian tube is the entrance into the uterine cavity, the utero-tubal junction.
16.2.1
Embryos have two pairs of ducts to let gametes out of the body; one pair (the Müllerian ducts) develops in females into the Fallopian tubes, uterus and vagina, while the other pair (the Wolffian ducts) develops in males into the epididymis and vas deferens. Normally, only one of the pairs of tubes will develop while the other regresses and disappears in utero. The homologous organ in the male is the rudimentary appendix testis.
16.3 Function
Histology
A cross section of Fallopian tube shows four distinct layers: Serosa, subserosa, lamina propria and innermost mucosal layer. The serosa is derived from visceral peritoneum. Subserosa is composed of loose adventitious tissue, blood vessels, lymphatics, an outer longitudinal and inner circular smooth muscle coats. This layer is responsible for peristaltic action of fallopian tube. Lam-
16.3.1 Fertilization When an oocyte is developing in an ovary, it is encapsulated in a spherical collection of cells known as an ovarian follicle. Just prior to ovulation the primary oocyte completes meiosis I to form the first polar body and a secondary oocyte which is arrested in metaphase of meio-
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16.5. ADDITIONAL IMAGES sis II. This secondary oocyte is then ovulated. The follicle and the ovary’s wall rupture, allowing the secondary oocyte to escape. The secondary oocyte is caught by the fimbriated end and travels to the ampulla of the uterine tube where typically the sperm are met and fertilization occurs; meiosis II is promptly completed. The fertilized ovum, now a zygote, travels towards the uterus aided by activity of tubal cilia and activity of the tubal muscle. After about five days the new embryo enters the uterine cavity and on about the sixth day implants on the wall of the uterus.
75 Salpingitis is inflammation of the Fallopian tubes and may be found alone, or be a component of pelvic inflammatory disease (PID). Saccular dilation of the fallopian tube at its narrow portion, due to inflammation, is known as salpingitis isthmica nodosa. Like PID and endometriosis, it may lead to Fallopian tube obstruction. Fallopian tube obstruction is associated with infertility and ectopic pregnancy.
16.4.3 Cancer
The release of an oocyte does not alternate between the Main article: Fallopian tube cancer two ovaries and seems to be random. After removal of an ovary, the remaining one produces an egg every month.[2] Fallopian tube cancer, which typically arises from the Occasionally the embryo implants into the Fallopian tube epithelial lining of the Fallopian tube, has historically instead of the uterus, creating an ectopic pregnancy, com- been considered to be a very rare malignancy. Recent monly known as a “tubal pregnancy”. evidence suggests it probably represents a significant portion of what has been classified as ovarian cancer in the past.[4] While tubal cancers may be misdiagnosed as ovar16.4 Clinical significance ian cancer, it is of little consequence as the treatment of both ovarian and Fallopian tube cancer is similar.
16.4.1
Patency testing
While a full testing of tubal functions in patients with infertility is not possible, testing of tubal patency is important as tubal obstruction is a major cause of infertility. A hysterosalpingogram, laparoscopy and dye, or HyCoSy will demonstrate that tubes are open. Tubal insufflation is a standard procedure for testing patency. During surgery the condition of the tubes may be inspected and a dye such as methylene blue can be injected into the uterus and shown to pass through the tubes when the cervix is occluded. As tubal disease is often related to Chlamydia infection, testing for Chlamydia antibodies has become a cost-effective screening device for tubal pathology.[3]
16.4.4 Surgery The surgical removal of a Fallopian tube is called a salpingectomy. To remove both sides is a bilateral salpingectomy. An operation that combines the removal of a Fallopian tube with removal of at least one ovary is a salpingo-oophorectomy. An operation to remove a fallopian tube obstruction is called a tuboplasty.
16.5 Additional images • Sectional plan of the gravid uterus in the third and fourth month. • Broad ligament of adult, showing epoöphoron. • Uterus and right broad ligament, seen from behind. • pelvis and its contents, seen from above and in front. • Posterior half of uterus and upper part of vagina. • The arteries of the internal organs of generation of the female, seen from behind. • Uterus and uterine tubes. • Histology
Fallopian tube
16.4.2
Inflammation
Main article: Salpingitis
• Uterine tubes
16.6 See also This article uses anatomical terminology; for an overview, see anatomical terminology.
76 • Menstrual cycle
16.7 References [1] Daftary, Shirish; Chakravarti, Sudip (2011). Manual of Obstetrics, 3rd Edition. Elsevier. pp. 1-16. ISBN 9788131225561. [2] “Menstrual Cycle: Biology of the Female Reproductive System: Merck Manual Home Health Handbook”. Merck.com. Retrieved 2011-03-06. [3] Kodaman PH, Arici A, Seli E. (June 2004). “Evidencebased diagnosis and management of tubal factor infertility.”. Current Opinion in Obstetrics and Gynecology 2004 Jun;16(3):221-9. 16 (3): 221–9. doi:10.1097/00001703200406000-00004. PMID 15129051. [4] Hirst, JE.; Gard, GB.; McIllroy, K.; Nevell, D.; Field, M. (Jul 2009). “High rates of occult fallopian tube cancer diagnosed at prophylactic bilateral salpingooophorectomy.”. Int J Gynecol Cancer 19 (5): 826–9. doi:10.1111/IGC.0b013e3181a1b5dc. PMID 19574767.
16.8 External links • uterine+tube at eMedicine Dictionary • Histology image: 18501loa — Histology Learning System at Boston University • Menstrual Cycle - Merck
CHAPTER 16. FALLOPIAN TUBE
Chapter 17
Spermatogenesis Spermatogenesis is the process in which spermatozoa are produced from male primordial germ cells by way of mitosis and meiosis. The initial cells in this pathway are called spermatogonia, which yield primary spermatocytes by mitosis. The primary spermatocyte divides meiotically (Meiosis I) into two secondary spermatocytes; each secondary spermatocyte divides into two spermatids by Meiosis II. These develop into mature spermatozoa, also known as sperm cells. Thus, the primary spermatocyte gives rise to two cells, the secondary spermatocytes, and the two secondary spermatocytes by their subdivision produce four spermatozoa.[1]
arising from incorrect spermatogenesis results in congenital defects and abnormal birth defects (Down Syndrome, Klinefelter’s Syndrome) and in most cases, spontaneous abortion of the developing fetus.
17.2 Location
Spermatozoa are the mature male gametes in many sexually reproducing organisms. Thus, spermatogenesis is the male version of gametogenesis. In mammals it occurs in the seminiferous tubules of the male testes in a stepwise fashion. Spermatogenesis is highly dependent upon optimal conditions for the process to occur correctly, and is essential for sexual reproduction. DNA methylation and histone modification have been implicated in the regulation of this process.[2] It starts at puberty and usually continues uninterrupted until death, although a slight decrease can be discerned in the quantity of produced sperm with increase in age (see Male infertility).
Spermatogenesis takes place within several structures of the male reproductive system. The initial stages occur within the testes and progress to the epididymis where the developing gametes mature and are stored until ejaculation. The seminiferous tubules of the testes are the starting point for the process, where stem cells adjacent to the inner tubule wall divide in a centripetal direction— beginning at the walls and proceeding into the innermost part, or lumen—to produce immature sperm. Maturation occurs in the epididymis. The location [Testes/Scrotum] is specifically important as the process of spermatogenesis requires a lower temperature to produce viable sperm, specifically 1°−8°C lower then normal body temperature of 37°C (98.6°F).[3] Clinically, small fluctuations in temperature such as from a athletic support strap, causes no impairment in sperm viability or count.[4]
17.1 Purpose
17.3 Duration
Spermatogenesis produces mature male gametes, commonly called sperm but specifically known as spermatozoa, which are able to fertilize the counterpart female gamete, the oocyte, during conception to produce a singlecelled individual known as a zygote. This is the cornerstone of sexual reproduction and involves the two gametes both contributing half the normal set of chromosomes (haploid) to result in a chromosomally normal (diploid) zygote.
For humans, the entire process of spermatogenesis takes 74 days. Including the transport on ductal system, it takes 3 months. Testes produce 200 to 300 million spermatozoa daily.[5] However, only about half or 100 million of these become viable sperm. [6]
To preserve the number of chromosomes in the offspring – which differs between species – each gamete must have half the usual number of chromosomes present in other body cells. Otherwise, the offspring will have twice the normal number of chromosomes, and serious abnormalities may result. In humans, chromosomal abnormalities
The entire process of spermatogenesis can be broken up into several distinct stages, each corresponding to a particular type of cell in human. In the following table, ploidy, copy number and chromosome/chromatid counts are for one cell, generally prior to DNA synthesis and division (in G1 if applicable). The primary spermatocyte is
17.4 Stages
77
78
CHAPTER 17. SPERMATOGENESIS
arrested after DNA synthesis and prior to division.
17.4.1
Spermatocytogenesis
producing two diploid intermediate cells called primary spermatocytes. Each primary spermatocyte then moves into the adluminal compartment of the seminiferous tubules and duplicates its DNA and subsequently undergoes meiosis I to produce two haploid secondary spermatocytes, which will later divide once more into haploid spermatids. This division implicates sources of genetic variation, such as random inclusion of either parental chromosomes, and chromosomal crossover, to increase the genetic variability of the gamete. Each cell division from a spermatogonium to a spermatid is incomplete; the cells remain connected to one another by bridges of cytoplasm to allow synchronous development. It should also be noted that not all spermatogonia divide to produce spermatocytes; otherwise, the supply of spermatogonia would run out. Instead, certain types of spermatogonia divide mitotically to produce copies of themselves, ensuring a constant supply of spermatogonia to fuel spermatogenesis.[7]
The process of spermatogenesis as the cells progress from primary spermatocytes, to secondary spermatocytes, to spermatids, to Sperm
17.4.2 Spermatidogenesis Main article: Spermatidogenesis Spermatidogenesis is the creation of spermatids from secondary spermatocytes. Secondary spermatocytes produced earlier rapidly enter meiosis II and divide to produce haploid spermatids. The brevity of this stage means that secondary spermatocytes are rarely seen in histological studies.
17.4.3 Spermiogenesis Main article: Spermiogenesis
Schematic diagram of Spermatocytogenesis
Main article: Spermatocytogenesis Spermatocytogenesis is the male form of gametocytogenesis and results in the formation of spermatocytes possessing half the normal complement of genetic material. In spermatocytogenesis, a diploid spermatogonium, which resides in the basal compartment of the seminiferous tubules, divides mitotically,
During spermiogenesis, the spermatids begin to form a tail by growing microtubules on one of the centrioles, which turns into basal body. These microtubules form an axoneme. The anterior part of the tail (called midpiece) thickens because mitochondria are arranged around the axoneme to ensure energy supply. Spermatid DNA also undergoes packaging, becoming highly condensed. The DNA is packaged ďŹ rstly with speciďŹ c nuclear basic proteins, which are subsequently replaced with protamines during spermatid elongation. The resultant tightly packed chromatin is transcriptionally inactive. The Golgi apparatus surrounds the now condensed nucleus, becoming the acrosome. One of the centrioles of the cell elongates to become the tail of the sperm. Maturation then takes place under the inďŹ&#x201A;uence of testosterone, which removes the remaining unnecessary cytoplasm and organelles. The excess cytoplasm, known as residual bodies, is phagocytosed by surrounding Sertoli cells in the testes. The resulting spermatozoa are now mature but lack motility, rendering them sterile. The ma-
17.6. INFLUENCING FACTORS
79
ture spermatozoa are released from the protective Sertoli cells into the lumen of the seminiferous tubule in a process called spermiation.
• Secrete androgen-binding protein (ABP), which concentrates testosterone in close proximity to the developing gametes
The non-motile spermatozoa are transported to the epididymis in testicular fluid secreted by the Sertoli cells with the aid of peristaltic contraction. While in the epididymis the spermatozoa gain motility and become capable of fertilization. However, transport of the mature spermatozoa through the remainder of the male reproductive system is achieved via muscle contraction rather than the spermatozoon’s recently acquired motility.
• Testosterone is needed in very high quantities for maintenance of the reproductive tract, and ABP allows a much higher level of fertility • Secrete hormones affecting pituitary gland control of spermatogenesis, particularly the polypeptide hormone, inhibin • Phagocytose residual cytoplasm left over from spermiogenesis • Secretion of antiMullerian hormone causes deterioration of the Müllerian duct[8]
17.5 Role of Sertoli cells
• Protect spermatids from the immune system of the male, via the blood-testis barrier
6
8 7
5 7
4 3 2 1
Labelled diagram of the organisation of Sertoli cells (red) and spermatocytes (blue) in the testis. Spermatids which have not yet undergone spermination are attached to the lumenal apex of the cell
The intercellular adhesion molecules ICAM-1 and soluble ICAM-1 have antagonistic effects on the tight junctions forming the blood-testis barrier.[9] ICAM-2 molecules regulate spermatid adhesion on the apical side of the barrier (towards the lumen).[9] during spermatogenesis, the cells are closely associated with sertoli cells which lies at regular interval alone the seminiferous tubules. sertoli cells perform the following tasks: • are target cells for follicular stimulating hormones (FSH) • synthesize an androgen binding protein that maintain a high levels of testosterone inside the seminiferous tubules • maintain the blood-testes barrier which protect the body’s immune system from destroying the developing sperm cells
Main article: Sertoli cell
• create an environment that is necessary in the differentiation of sperm cell
At all stages of differentiation, the spermatogenic cells are in close contact with Sertoli cells which are thought to provide structural and metabolic support to the developing sperm cells. A single Sertoli cell extends from the basement membrane to the lumen of the seminiferous tubule, although the cytoplasmic processes are difficult to distinguish at the light microscopic level.
• degrade the residual cytoplasm that is shed during spermatogenesis.
17.6 Influencing factors
The process of spermatogenesis is highly sensitive to flucSertoli cells serve a number of functions during spermato- tuations in the environment, particularly hormones and genesis, they support the developing gametes in the fol- temperature. Testosterone is required in large local conlowing ways: centrations to maintain the process, which is achieved via the binding of testosterone by androgen binding protein • Maintain the environment necessary for develop- present in the seminiferous tubules. Testosterone is produced by interstitial cells, also known as Leydig cells, ment and maturation, via the blood-testis barrier which reside adjacent to the seminiferous tubules. • Secrete substances initiating meiosis • Secrete supporting testicular fluid
Seminiferous epithelium is sensitive to elevated temperature in humans and some other species, and will be adversely affected by temperatures as high as normal body
80 temperature. Consequently, the testes are located outside the body in a sack of skin called the scrotum. The optimal temperature is maintained at 2 °C (man)–8 °C (mouse) below body temperature. This is achieved by regulation of blood flow[10] and positioning towards and away from the heat of the body by the cremasteric muscle and the dartos smooth muscle in the scrotum. Dietary deficiencies (such as vitamins B, E and A), anabolic steroids, metals (cadmium and lead), x-ray exposure, dioxin, alcohol, and infectious diseases will also adversely affect the rate of spermatogenesis. In addition, the male germ line is susceptible to DNA damage caused by oxidative stress, and this damage likely has a significant impact on fertilization and pregnancy.[11] Exposure to pesticides also affects spermatogenesis.[12]
CHAPTER 17. SPERMATOGENESIS • Folliculogenesis • Germ cells • Male infertility • Meiosis • Oncofertility • Oogenesis • Origin and function of meiosis • Sertoli cells • Sexual reproduction • Semen analysis
17.7 Hormonal control Hormonal control of spermatogenesis varies among species. In humans the mechanism is not completely understood, however it is known that initiation of spermatogenesis occurs at puberty due to the interaction of the hypothalamus, pituitary gland and Leydig cells. If the pituitary gland is removed, spermatogenesis can still be initiated by follicle stimulating hormone and testosterone. Follicle stimulating hormone stimulates both the production of androgen binding protein by Sertoli cells, and the formation of the blood-testis barrier. Androgen binding protein is essential to concentrating testosterone in levels high enough to initiate and maintain spermatogenesis, which can be 20–50 times higher than the concentration found in blood. Follicle stimulating hormone may initiate the sequestering of testosterone in the testes, but once developed only testosterone is required to maintain spermatogenesis. However, increasing the levels of follicle stimulating hormone will increase the production of spermatozoa by preventing the apoptosis of type A spermatogonia. The hormone inhibin acts to decrease the levels of follicle stimulating hormone. Studies from rodent models suggest that gonadotropin hormones (both LH and FSH) support the process of spermatogenesis by suppressing the proapoptotic signals and therefore promote spermatogenic cell survival.[13] The Sertoli cells themselves mediate parts of spermatogenesis through hormone production. They are capable of producing the hormones estradiol and inhibin. The Leydig cells are also capable of producing estradiol in addition to their main product testosterone.
17.8 See also • Anisogamy • Evolution of sexual reproduction
17.9 References [1] “The Spermatozoön, in Gray’s Anatomy”. 2010-10-07.
Retrieved
[2] Song, Ning; Liu, Jie; An, Shucai; Nishino, Tomoya; Hishikawa, Yoshitaka; Koji, Takehiko (2011). “Immunohistochemical Analysis of Histone H3 Modifications in Germ Cells during Mouse Spermatogenesis”. Acta Histochemica et Cytochemica 44 (4): 183– 90. doi:10.1267/ahc.11027. PMC 3168764. PMID 21927517. [3] “scrotum”. Encyclopædia Britannica. Encyclopædia Britannica Online. Encyclopædia Britannica Inc., 2015. Web. 14 Jan. 2015 <http://www.britannica.com/ EBchecked/topic/530078/scrotum>. [4] Wang C, McDonald V, Leung A, Superlano L, Berman N, Hull L et al. (1997). “Effect of increased scrotal temperature on sperm production in normal men”. Fertil. Steril. 68 (2): 334–9. PMID 9240266. [5] Padubidri, VG; Daftary, SN, eds. (2011). Shaw’s Textbook of Gynaecology (15th ed.). p. 201. ISBN 978-81312-2548-6. [6] Johnson L, Petty C, Neaves W (1983). “Further quantification of human spermatogenesis: germ cell loss during postprophase of meiosis and its relationship to daily sperm production”. Biol. Reprod. 29 (1): 207–15. PMID 6615966. [7] Fishelson, Lev; Gon, Ofer; Holdengreber, Vered; Delarea, Yakob (2007). “Comparative spermatogenesis, spermatocytogenesis, and spermatozeugmata formation in males of viviparous species of clinid fishes (Teleostei: Clinidae, Blennioidei)". The Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology 290 (3): 311– 23. doi:10.1002/ar.20412. PMID 17525946. [8] Hadley, Mac E.; Levine, Jon E. (2007). Endocrinology (6th ed. ed.). Upper Saddle River, NJ: Prentice Hall. p. 369. ISBN 0-13-187606-6.
17.11. EXTERNAL LINKS
[9] Xiao, X.; Mruk, D. D.; Cheng, C. Y. (2013). “Intercellular adhesion molecules (ICAMs) and spermatogenesis”. Human Reproduction Update 19 (2): 167–86. doi:10.1093/humupd/dms049. PMC 3576004. PMID 23287428. [10] Harrison, RG; Weiner, JS (1949). “Vascular patterns of the mammalian testis and their functional significance”. The Journal of experimental biology 26 (3): 304–16, 2 pl. PMID 15407652. [11] Lewis, SE; Aitken, RJ (2005). “DNA damage to spermatozoa has impacts on fertilization and pregnancy”. Cell and tissue research 322 (1): 33–41. doi:10.1007/s00441005-1097-5. PMID 15912407. [12] Mehrpour, O; Karrari P (2014). “Occupational exposure to pesticides and consequences on male semen and fertility: A review.”. Toxicol Lett. doi:10.1016/j.toxlet.2014.01.029. PMID 24487096. [13] Pareek, Tej K.; Joshi, Ayesha R.; Sanyal, Amartya; Dighe, Rajan R. (2007). “Insights into male germ cell apoptosis due to depletion of gonadotropins caused by GnRH antagonists”. Apoptosis 12 (6): 1085–100. doi:10.1007/s10495-006-0039-3. PMID 17268770.
17.10 Further reading • “The testes and spermatogenesis”. University of Wisconsin. 1998. Retrieved 2006-11-27. • Johnson, L.; Blanchard, T.L.; Varner, D.D.; Scrutchfield, W.L. (1997). “Factors affecting spermatogenesis in the stallion”. Theriogenology 48 (7): 1199–216. doi:10.1016/S0093-691X(97)00353-1. PMID 16728209. • Bardin, C.W. (1991). “Pituitary-testicular axis”. In Yen, S.S.C.; Jaffee, R.B. Reproductive Endocrinology (3rd ed.). Philadelphia: WB Saunders. ISBN 0721632068. • Chambers, CV; Shafer, MA; Adger, H; Ohm-Smith, M; Millstein, SG; Irwin Jr, CE; Schachter, J; Sweet, R (1987). “Microflora of the urethra in adolescent boys: Relationships to sexual activity and nongonococcal urethritis”. The Journal of pediatrics 110 (2): 314–21. doi:10.1016/S0022-3476(87)801804. PMID 3100755. • Czyba, J.C.; Girod, C. (1980). “Development of normal testis”. In Hafez, E.S.E. Descended and Cryptorchid Testis. The Hague: Martinus Nijhoff. ISBN 9024723337. • Whitmore Wf, 3rd; Karsh, L; Gittes, RF (1985). “The role of germinal epithelium and spermatogenesis in the privileged survival of intratesticular grafts”. The Journal of Urology 134 (4): 782–6. PMID 2863395.
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17.11 External links • Spermatogenesis — male reproductive physiology • Spermatogenesis animation
Chapter 18
Spermatozoon A spermatozoon (pronounced /ˌspɜrmætəˈzoʊən/, alternate spelling spermatozoön; plural spermatozoa; from Ancient Greek: σπέρμα “seed” and Ancient Greek: ζῷον “living being”) is a motile sperm cell, or moving form of the haploid cell that is the male gamete. A spermatozoon joins an ovum to form a zygote. (A zygote is a single cell, with a complete set of chromosomes, that normally develops into an embryo.)
the sperm to progress optimally. The spermatozoon is characterized by a minimum of cytoplasm and the most densely packed DNA known in eukaryotes. Compared to mitotic chromosomes in somatic cells, sperm DNA is at least sixfold more highly condensed.[4]
The specimen contributes with DNA/chromatin, a centriole and perhaps also an oocyte-activating facSperm cells contribute approximately half of the nuclear tor (OAF).[5] It may also contribute with paternal genetic information to the diploid offspring (excluding, in messenger RNA (mRNA), also contributing to embrymost cases, mitochondrial DNA). In mammals, the sex of onic development.[5] the offspring is determined by the sperm cell: a spermatozoon bearing a Y chromosome will lead to a male (XY) • Electron micrograph of human spermatozoa magnioffspring, while one bearing an X chromosome will lead fied 3140 times. to a female (XX) offspring. Sperm cells were first ob[1] served by Anton van Leeuwenhoek in 1677. • Sperm cells in the urine sample of a 45 year old male patient who is being followed with the diagnosis of benign prostate hyperplasia.
18.1 Mammalian spermatozoan structure, function, and size 18.1.1
• Another image from the same urine sample as with the image on the left.
Humans
The human spermatozoon contains over 6000 different proteins.[6]
The human sperm cell is the reproductive cell in males and will only survive in warm environments; once it leaves the male body the sperm’s survival likelihood is reduced and it may die, thereby decreasing the total sperm quality. Sperm cells come in two types, “female” and “male”. Sperm cells that give rise to female (XX) offspring after fertilization differ in that they carry an X-chromosome, while sperm cells that give rise to male (XY) offspring carry a Y-chromosome. Human sperm cells consist of a flat, disc shaped head 5.1 µm by 3.1 µm and a tail 50 µm long.[2] The tail flagellates, which propels the sperm cell (at about 1–3 mm/minute in humans) by whipping in an elliptical cone.[3] Semen has an alkaline nature, and they do not reach full motility (hypermotility) until they reach the vagina where the alkaline pH is neutralized by acidic vaginal fluids. This gradual process takes 20–30 minutes. In this time, fibrinogen from the seminal vesicles forms a clot, securing and protecting the sperm. Just as they become hypermotile, fibrinolysin from the prostate dissolves the clot, allowing
18.1.2 Avoidance of immune system response Glycoprotein molecules on the surface of ejaculated sperm cells are recognized by all human female immune systems, and interpreted as a signal that the cell should not be rejected. The female immune system might otherwise attack sperm in the reproductive tract. The specific glycoproteins coating sperm cells are also utilized by some cancerous and bacterial cells, some parasitic worms, and HIV-infected white blood cells, thereby avoiding an immune response from the host organism.[7] The blood-testis barrier, maintained by the tight junctions between the Sertoli cells of the seminiferous tubules, prevents communication between the forming spermatozoa in the testis and the blood vessels (and immune cells circulating within them) within the interstitial space. This prevents them from eliciting an immune response. The
82
18.3. SPERMATOZOA PRODUCTION IN MAMMALS
83
blood-testis barrier is also important in preventing toxic spermatozoon, measuring over 58 mm in size. In D. substances from disrupting spermatogenesis. melanogaster the entire sperm, tail included, gets incorporated into the oocyte cytoplasm, however, for D. bifurca only a small portion of the tail enters the oocyte.[9]
18.2 Spermatozoa in other organisms
The wood mouse Apodemus sylvaticus possesses spermatozoa with falciform morphology. What makes these gametocytes even more unique is the presence of an apical hook on the sperm head. This hook is used to attach to the hooks or to the flagella of other spermatozoa. Aggregation is caused by these attachments and mobile trains result. These trains provide improved motility in the female reproductive tract and are a means by which fertilization is promoted.[10] Sea urchins such as Arbacia punctulata—are ideal organisms to use in sperm research, they spawn large numbers of sperm into the sea, making them well-suited as model organisms for experiments.
18.2.2 Plants, algae and fungi The gametophytes of bryophytes, ferns and some gymnosperms produce motile sperm cells, contrary to pollen grains employed in most gymnosperms and all angiosperms. This renders sexual reproduction in the absence of water impossible, since water is a necessary medium for sperm and egg to meet. Algae and lower plant sperm cells are often multi-flagellated (see image) and thus morphologically different from animal spermatozoa. Some algae and fungi produce non-motile sperm cells, called spermatia. In higher plants and some algae and fungi, fertilization involves the migration of the sperm nucleus through a fertilization tube (e.g. pollen tube in higher plants) to reach the egg cell.
18.3 Spermatozoa production in mammals Main article: Spermatogenesis Motile sperm cells of algae and seedless plants.
See also: Sperm and Female sperm storage
18.2.1
Animals
Fertilization relies on spermatozoa for most sexually reproductive animals.
Spermatozoa are produced in the seminiferous tubules of the testes in a process called spermatogenesis. Round cells called spermatogonia divide and differentiate eventually to become spermatozoa. During copulation the cloaca or vagina gets inseminated, and then the spermatozoa move through chemotaxis to the ovum inside a Fallopian tube or the uterus.
Some species of fruit fly produce the largest known sper- 18.4 Spermatozoa activation matozoon found in nature.[8] Drosophila melanogaster produces sperm that can be up to 1.8 mm, while its Main article: Acrosome reaction relative Drosophila bifurca produce the largest known Approaching the egg cell is a rather complex, multistep
84
CHAPTER 18. SPERMATOZOON
Vitelline layer
Egg Plasma Membrane
Protein receptors
EGG CYTOPLASM Sperm head Mitochondrial material Nucleus
Perivitelline space
Jelly coat
Actin
Cortical granule content.
Cortical granule
Acrosomal granule
Acrosome reaction
Fused plasma membrane
Acrosome reaction on a sea urchin cell
process of chemotaxis guided by different chemical substances/stimuli on individual levels of phylogeny. One of the most significant, common signaling characters of the event is that a prototype of professional chemotaxis receptors, formyl peptide receptor (60.000 receptor/cell) as well as the activator ability of its ligand formyl Met-LeuPhe have been demonstrated in the surface membrane even in the case of human sperms.[11] Mammalian sperm cells become even more active when they approach an egg cell in a process called sperm activation. Sperm activation has been shown to be caused by calcium ionophores in vitro, progesterone released by nearby cumulus cells and binding to ZP3 of the zona pellucida. The cumulus cells are embedded in a gel-like substance made primarily of hyaluronic acid, and developed in the ovary with the egg and support it as it grows. The initial change is called “hyperactivation”, which causes a change in spermatozoa motility. They swim faster and their tail movements become more forceful and erratic. A recent discovery links hyperactivation to a sudden influx of calcium ion into the tails. The whip-like tail (flagellum) of the sperm is studded with ion channels formed by proteins called CatSper. These channels are selective, allowing only calcium ions to pass. The opening of CatSper channels is responsible for the influx of calcium. The sudden rise in calcium levels causes the flagellum to form deeper bends, propelling the sperm more forcefully through the viscous environment. Sperm hyperactivity is necessary for breaking through two physical barriers that protect the egg from fertilization. The second process in sperm activation is the acrosome reaction. This involves releasing the contents of the acrosome, which disperse, and the exposure of enzymes attached to the inner acrosomal membrane of the sperm. This occurs after the sperm first meets the egg. This lock-and-key type mechanism is species-specific and prevents the sperm and egg of different species from fusing. There is some evidence that this binding is what triggers the acrosome to release the enzymes that allow the sperm to fuse with the egg.
ZP3, one of the proteins that make up the zona pellucida, then binds to a partner molecule on the sperm. Enzymes on the inner acrosomal membrane digest the zona pellucida. After the sperm penetrates the zona pellucida, part of the sperm’s cell membrane then fuses with the egg cell’s membrane, and the contents of the head diffuse into the egg. Upon penetration, the oocyte is said to have become activated. It undergoes its secondary meiotic division, and the two haploid nuclei (paternal and maternal) fuse to form a zygote. In order to prevent polyspermy and minimise the possibility of producing a triploid zygote, several changes to the egg’s zona pellucida renders them impenetrable shortly after the first sperm enters the egg.
18.5 Artificial storage Spermatozoa can be stored in diluents such has the Illini Variable Temperature (IVT) diluent, which have been reported to be able to preserve high fertility of spermatozoa for over seven days.[12] The IVT diluent is composed of several salts, sugars and antibacterial agents and gassed with CO2 .[12] Semen cryopreservation can be used for far longer storage durations. For human spermatozoa, the longest reported successful storage with this method is 21 years.[13]
18.6 History • In 1677 microbiologist Antonie van Leeuwenhoek discovers spermatozoa. • In 1841 the Swiss anatomist Albert von Kölliker wrote about spermatozoon in his work Untersuchungen uber die Bedeutung der Samenfäden.
18.7 References [1] “Timeline: Assisted reproduction and birth control”. CBC News. Retrieved 2006-04-06. [2] Smith, D.J. (2009). “Human sperm accumulation near surfaces: a simulation study”. Journal of Fluid Mechanics 621: 295. doi:10.1017/S0022112008004953. Retrieved 20 May 2012. [3] Sumio Ishijima, Shigeru Oshio, Hideo Mohri, "Flagellar movement of human spermatozoa", Gamete research, 1986, vol. 13, no3, pp. 185–197 (27 ref.) [4] Ward WS, Coffey DS (1991). “DNA packaging and organization in mammalian spermatozoa: comparison with somatic cells”. Biol. Reprod. 44 (4): 569–74. doi:10.1095/biolreprod44.4.569. PMID 2043729.
18.8. EXTERNAL LINKS
[5] Developmental sperm contributions: fertilization and beyond Gerardo Barroso, M.D., M.Sc.a, Carlos Valdespin, M.D.a, Eva Vega, M.Sc.a, Ruben Kershenovich, M.D.a, Rosaura Avila, B.Sc.a, Conrado Avendaño, M.D.b, Sergio Oehninger, M.D., Ph.D.b. FertStert, Volume 92, Issue 3, Pages 835-848 (September 2009) [6] Amaral, A.; Castillo, J.; Ramalho-Santos, J.; Oliva, R. (2013). “The combined human sperm proteome: Cellular pathways and implications for basic and clinical science”. Human Reproduction Update 20: 40. doi:10.1093/humupd/dmt046. [7] “Sperm clue to 'disease immunity'". BBC News. 200712-17. [8] Than, Ker. “Longest Known Sperm Create Paradox of Nature”. www.livescience.com. Retrieved 20 May 2012. [9] Pitnick, S., Spicer, G. S., & Markow, T. A. (1995). How long is a giant sperm Nature, 375(6527), 109. doi:10.1038/375109a0 [10] Moore, Harry et al., Exceptional sperm cooperation in Wood Mouse. Nature 418, 174–177 (2002) [11] Gnessi L, Fabbri A, Silvestroni L, Moretti C, Fraioli F, Pert CB, Isidori A. (1986). “Evidence for the presence of specific receptors for N-formyl chemotactic peptides on human spermatozoa.”. J Clin Endocrinol Metab 63 (4): 841–6. doi:10.1210/jcem-63-4-841. PMID 3018025. [12] Watson, P. F. (1993). “The potential impact of sperm encapsulation technology on the importance of timing of artificial insemination: A perspective in the light of published work”. Reproduction, Fertility and Development 5 (6): 691–9. doi:10.1071/RD9930691. PMID 9627729. [13] Planer NEWS and Press Releases > Child born after 21 year semen storage using Planer controlled rate freezer 14/10/2004
18.8 External links • Slower conception 'leads to boys’ • Human Sperm Under a Microscope
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Chapter 19
Spermatogonium A spermatogonium (plural: spermatogonia) is an undifferentiated male germ cell, originating in a seminiferous tubule and dividing into two primary spermatocytes (a kind of germ cell) in the production of spermatozoa. There are three subtypes: • Type A(d) cells, with dark nuclei. These cells replicate to ensure a constant supply of spermatogonia to fuel spermatogenesis. • Type A(p) cells, with pale nuclei. These cells divide by mitosis to produce Type B cells. • Type B cells, which divide to give rise to primary spermatocytes. Each primary spermatocyte duplicates its DNA and subsequently undergoes meiosis I to produce two haploid secondary spermatocytes. Each of the two secondary spermatocytes further undergo meiosis II to produce two spermatids (haploid). (1 primary spermatocyte => 4 spermatids) The spermatids then undergo spermiogenesis to produce spermatozoa.
19.1 Additional images • Transverse section of a tubule of the testis of a rat. X 250. • Schematic diagram of Spermatocytogenesis
19.2 References
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Chapter 20
Spermatocyte
Figure 2. Spermatogonia going through mitosis to form primary spermatocytes in Grasshopper testes.
Figure 1. The process of spermatogenesis as the cells progress from spermatogium, to primary spermatocytes, to secondary spermatocytes, to spermatids and to Sperm.
Spermatocytes are a type of male gametocyte in animals. They derive from immature germ cells called spermatogonia. They are found in the testis, in a structure known as the seminiferous tubules.[1] There are two types of spermatocytes, primary and secondary spermatocytes (Figure 1). Primary and secondary spermatocytes are formed through the process of spermatocytogenesis (Figure 3).[2]
tached to the nuclear envelope; one is dark (Ad) and the other is pale (Ap), which can be seen in Figure 3. The Ad cells are spermatogonia that will stay in the basal compartment (outer region of the tubule); these cells are created to replenish the spermatogonia stores. Type Ap cells will mature and become type B cells, which have round nuclei and heterochromatin attached to the nuclear envelope and the center of nucleolus.[4] Type B cells will move on to the adluminal compartment (towards the inner region of tubule) and become primary spermatocytes; this process takes about 16 days to complete.[2][5]
Primary spermatocytes are diploid (2N) cells containing 46 chromosomes. After Meiosis I, two secondary The primary spermatocytes within the adluminal comspermatocytes are formed. Secondary spermatocytes are partment will continue on to Meiosis I and divide into haploid (N) cells that contain 23 chromosomes.[1] two daughters cells, known as secondary spermatocytes, a All male animals produce spermatocytes, even process which takes 24 days to complete. Each secondary [1] hermaphrodites such as C. elegans, which exist as a spermatocyte will form two spermatids after Meiosis II. male or hermaphrodite. In hermaphrodite C. elegans, sperm production occurs ďŹ rst and is then stored in the spermatheca. Once the eggs are formed, they are able to self-fertilize and produce up to 350 progenies.[3]
Although spermatocytes that divide miotically and meiotically are sensitive to radiation and cancer, spermatogonia stem cells are not. Therefore, after termination of radiation therapy or chemotherapy, the spermatognia stems cells may re-initiate the formation of spermatogenesis.[4]
20.1 Formation At puberty, spermatogonia located along the walls of the 20.2 Endocrine initiation seminiferous tubules within the testis will be initiated and start to divide mitotically, forming two types of A cells The formation of primary spermatocytes (a process that contain an oval shaped nucleus with a nucleolus at- known as spermatocytogenesis) begins in humans when 87
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CHAPTER 20. SPERMATOCYTE cells, which act as nursing cells where spermatids will go to mature after Meiosis II. LH promotes leydig cell secretion of testosterone into the testes and blood, which induce spermatogenesis and aid the formation of secondary sex characteristics. From this point on, the secretion of FSH and LH (inducing production of testosterone) will stimulate spermatogenesis until the male dies.[7] Increasing the hormones FSH and LH in males will not increase the rate of spermatogenesis. However, with age, the rate of production will decrease, even when the amount of hormone that is secreted is constant; this is due to higher rates of degeneration of germ cells during meiotic prophase.[1]
20.3 Cell type summary In the following table, ploidy, copy number and chromosome/chromatid counts listed are for a single cell, generally prior to DNA synthesis and division (in G1 if applicable). Primary spermatocytes are arrested after DNA synthesis and prior to division.[1][2] Figure 3. Schematic diagram of Spermatocytogenesis
20.4 History The spermatogenesis process has been elucidated throughout the years by researchers who divided the process into multiple stages or phases, depending on intrinsic (germ and Sertoli cells) and extrinsic (FSH and LH) factors.[8] The spermatogenesis process in mammals as a whole, involving cellular transformation, mitosis, and meiosis, has been well studied and documented from the 1950s to 1980s. However, during the 1990s and 2000s researchers have focused around increasing understanding of the regulation of spermatogenesis via genes, proteins, and signaling pathways, and the biochemical and molecular mechanisms involved in these processes. Most recently, the environmental eďŹ&#x20AC;ects on spermatogenesis have become a focus as male infertility in men has become more prevalent.[9]
Figure 4. Hormones produced by the Pituitary gland. GnRH is secreted by the hypothalamus, which induces anterior pituitary to produce FSH and LH upon puberty.
a male is sexually matured at puberty, around the age of 10 through 14.[6] Formation is initiated upon the pulsated surges of gonadotropin-releasing hormone (GnRH) from the hypothalamus, which leads to the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) produced by the anterior pituitary gland (Figure 4). The release of FSH into the testes will enhance Meiosis in Grasshopper testes (primary spermatocytes in zyspermatogenesis and lead to the development of sertoli gotene, pachytene, prophase I).
20.7. UNIQUE PROPERTIES IN DIFFERENT SPECIES An important discovery in the spermatogenesis process was the identification of the seminiferous epithelial cycle in mammals—work by C.P. Leblound and Y. Clermont in 1952 that studied the spermatogonia, spermatocyte layers and spermatids in rat seminiferous tubules. Another critical discovery was that of the hypothalamic-pituitarytesticular hormone chain, which plays a role in spermatogenesis regulation; this was studied by R. M. Sharpe in 1994.[9]
89 Mutations in Mtap2, a microtubule-associated protein, as observed in repro4 mutant spermatocytes, have been shown to arrest spermatogenesis progress during the prophase of Meiosis I. This is observed by a reduction in spermatid presence in repro4 mutants.[13] Recombinant-defective mutations can occur in Spo11, DMC1, ATM and MSH5 genes of spermatocytes. These mutations involve double strand break repair impairment, which can result in arrest of spermatogenesis at stage IV of the seminiferous epithelium cycle.[14]
20.5 Damage, repair, and failure Spermatocytes regularly overcome meiotically induced double strand breaks in the prophase stage; these are likely caused by Spo11, an enzyme required in meiotic recombination. These double strand breaks are repaired by homologous recombination pathways and utilize RAD1 and γH2AX, which recognize double strand breaks and modify chromatin, respectively. As a result, double strand breaks in meiotic cells, unlike mitotic cells, do not typically lead to apoptosis, or cell death.[10]
20.7 Unique properties in different species
Primary cilia are common organelles found in eukaryotic cells; they play an important role in development of animals. Drosophila have unique properties in their spermatocyte primary cilia—they are assembled by four centrioles independently in the G2 phase and are sensitive to microtubule-targeting drugs. Normally, primary cilia It is known that heterozygous chromosomal rearrangewill develop from one centriole in the G0/G1 phase and ments lead to spermatogenic disturbance or failure; howare not affected by microtubule targeting drugs.[15] ever the molecular mechanisms that cause this are not as well known. It is suggested that a passive mechanism involving asynaptic region clustering in spermatocytes is a possible cause. Asynaptic regions are associated with BRCA1, kinase ATR and γH2AX presence in pachytene spermatocytes.[11]
20.6 Specific mutations
Figure 6. Mesostoma ehrenbergii Figure 5. Wild-type spermatocyte progression compared to repro4 mutated spermatocytes.
Stimulated By Retinoic Acid 8 (STRA8) is a gene required for retinoic-acid signaling pathway in humans, which leads to meiosis initiation. STRA8 expression is more present in preleptotene spermatocytes (at the earliest stage of Prophase I in meiosis) than spermatogonia. STRA8-mutant spermatocytes have been shown to be capable of meiosis initiation; however they cannot complete the process. Mutations in leptotene spermatocytes can result in premature chromosome condensation.[12]
Mesostoma ehrenbergii is a rhabdocoel flatworm with a distinctive male meiosis stage within the formation of spermatocytes. During the pre-anaphase stage, cleavage furrows are formed in the spermatocyte cells containing four univalent chromosomes. By the end of the anaphase stage, there is one at each pole moving between the spindle poles without actually having physical interactions with one another (also known as distance segregation). These unique traits allow researchers to study the force created by the spindle poles to allow the chromosomes to move, cleavage furrow management and distance segregration.[16][17]
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20.8 See also • Germ cells • Gametes • Gametocytogenesis • Leydig • Mitosis • Meiosis • Sertoli cells • Spermatogenesis • Spermatogonia • Spermatid • Spermatocytogenesis • Spermatidogenesis • Sperm
20.9 References [1] Boron, Walter F., MD, Ph.D., Editor; Boulpaep, Emile L. (2012). “54”. Medical physiology a cellular and molecular approach (Print) (Updated second ed.). Philadelphia: Saunders Elsevier. ISBN 978-1-4377-1753-2. [2] Schöni-Affolter, Dubuis-Grieder, Strauch, Franzisk, Christine, Erik Strauch. “Spermatogenesis”. Retrieved 22 March 2014. [3] Riddle, DL; Blumenthal, T; Riddle, B.J., editors. (1997). “I, The Biological Model”. C. elegans II (2nd ed.). Cold Spring Harbor. NY: Cold Spring Harbor Laboratory Press. Retrieved April 13, 2014. [4] Tres, Abraham L. Kierszenbaum, Laura L. (2012). Histology and cell biology : an introduction to pathology (3rd ed. ed.). Philadelphia, PA: Saunders. pp. Chapter 20. ISBN 9780323078429. [5] Y, Clermont (1966). Renewal of spermatogonia in man. American Journal of Anatomy. pp. 509–524. [6] Starr, Taggart, Evers, Starr, Cecie, Ralph, Christine, Lisa (January 1, 2012). Animal Structure & Function. Cengage Learning. p. 736. ISBN 9781133714071. [7] Sherwood, Lauralee (2010). Human physiology : from cells to systems (7th ed. ed.). Australia: Brooks/Cole, Cengage Learning. p. 751. ISBN 0495391840. [8] Cheng, edited by C. Yan (2008). Molecular mechanisms in spermatogenesis. New York: Springer Science+Business Media. pp. Chapter 1, page 1. ISBN 9780-387-79990-2.
CHAPTER 20. SPERMATOCYTE
[9] Cheng, C. Yan; Dolores D. Mruk (19 April 2010). “The biology of spermatogenesis: the past, present and future”. Phil. Trans. R. Soc. B. 1546 365 (1546): 1459–1463. doi:10.1098/rstb.2010.0024. Retrieved 23 April 2014. [10] Matulis S, Handel MA (August 2006). “Spermatocyte responses in vitro to induced DNA damage”. Molecular Reproduction and Development 73 (8): 1061–72. doi:10.1002/mrd.20508. PMID 16700071. [11] Sciurano RB, Rahn MI, Rey-Valzacchi G, Coco R, Solari AJ (August 2012). “The role of asynapsis in human spermatocyte failure”. International Journal of Andrology 35 (4): 541–9. doi:10.1111/j.1365-2605.2011.01221.x. PMID 21977946. [12] Mark, Manuel; Hugues Jacobs, Mustapha OuladAbdelghani, Chriistine Dennefeld, Betty Feret, Nadege Vernet, Carmen-Alina Codreanu, Pierre Chambon, Norbert Ghyselinck (7 July 2008). “STRA8-deficient spermatocytes initiate, but fail to complete, meiosis and undergo premature chromosome condensation”. Journal of Cell Science 121 (19): 3233–3242. doi:10.1242/jcs.035071. [13] Sun, Fengyun; Mary Ann Handel (10 January 2011). “A Mutation in Mtap2 is Associated with Arrest of Mammalian Spermatocytes before the First Meiotic Division”. Genes 2 (1): 21–35. doi:10.3390/genes2010021. [14] Barchi, Marco; S. Mahadevaiah; M. Di Giacomo; F. Baudat; D. de Rooij; P. Burgoyne; M. Jasin; S. Keeney (August 2005). “Surveillance of Different Recombination Defects in Mouse Spermatocytes Yields Distinct Responses despite Elimination at an Identical Developmental Stage”. Molecular and Cellular Biology 25 (16): 7203– 7215. doi:10.1128/MCB.25.16.7203-7215.2005. PMC 1190256. PMID 16055729. [15] Riparbelli MG, Cabrera OA, Callaini G, Megraw TL (2013). “Unique properties of Drosophila spermatocyte primary cilia”. Biology Open 2 (11): 1137–47. doi:10.1242/bio.20135355. PMC 3828760. PMID 24244850. [16] Ferraro-Gideon J, Hoang C, Forer A (January 2014). “Meiosis-I in Mesostoma ehrenbergii spermatocytes includes distance segregation and inter-polar movements of univalents, and vigorous oscillations of bivalents”. Protoplasma 251 (1): 127–43. doi:10.1007/s00709-013-05329. PMID 23921676. [17] Ferraro-Gideon J, Hoang C, Forer A (September 2013). “Mesostoma ehrenbergii spermatocytes--a unique and advantageous cell for studying meiosis”. Cell Biology International 37 (9): 892–8. doi:10.1002/cbin.10130. PMID 23686688.
20.10 External links • Spermatogenesis • The Male Reproductive System • The Reproductive System
Chapter 21
Spermatid The spermatid is the haploid male gametid that results from division of secondary spermatocytes. As a result of meiosis, each spermatid contains only half of the genetic material present in the original primary spermatocyte. Spermatids are connected by cytoplasmic material and have superfluous cytoplasmic material around their nuclei. When formed, early round spermatids must undergo further maturational events to develop into spermatozoa, a process termed spermiogenesis (also termed spermeteliosis). The spermatids begin to grow a living thread, develop a thickened mid-piece where the mitochondria become localised, and form an acrosome. Spermatid DNA also undergoes packaging, becoming highly condensed. The DNA is packaged firstly with specific nuclear basic proteins, which are subsequently replaced with protamines during spermatid elongation. The resultant tightly packed chromatin is transcriptionally inactive.
21.1 Additional images • Scheme showing analogies in the process of maturation of the ovum and the development of the Genyo spermatids (young spermatozoa).
21.2 External links • Histology image: 17804loa — Histology Learning System at Boston University - “Male Reproductive System: testis, early spermatids” • Histology image: 17805loa — Histology Learning System at Boston University - “Male Reproductive System: testis, late spermatids” • Histology at okstate.edu
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Seminiferous tubule Seminiferous tubules are located within the testes, and are the specific location of meiosis, and the subsequent creation of gametes, namely spermatozoa.
22.3 External links
The epithelium of the tubule consists of sustentacular or Sertoli cells, which are tall, columnar type cells that line the tubule. In between the Sertoli cells are spermatogenic cells, which differentiate through meiosis to sperm cells. Sertoli cells function to nourish the developing sperm cells. They secrete testosterone binding protein, which increases the concentration of testosterone inside the seminiferous tubules. Embryologically, they also secrete the Anti-Mulleran Factor necessary for the female mulleran ducts to regress. There are two types: convoluted and straight, convoluted toward the lateral side, and straight as the tubule comes medially to form ducts that will exit the testis. The seminiferous tubules are formed from primitive sex cords. It is the medullary cords which develop into the seminiferous tubules and the cortical cords regress. The cords were formed from the gonadal ridge.
22.1 Additional images • Seminiferous tubule (right) with sperm (black, tiny, ovoid). H&E stain. • Transverse section through the left side of the scrotum and the left testis (Semeniferous tubules visible in center, but not labeled). • Microscopic shot of seminiferous tubule (cross section). • Photomicrograph of rat testis.
22.2 See also • Leydig cells 92
• Histology image: 17802loa — Histology Learning System at Boston University • Image • Diagram
Chapter 23
Leydig cell Leydig cells, also known as interstitial cells of Leydig, are found adjacent to the seminiferous tubules in the testicle. They produce testosterone in the presence of luteinizing hormone (LH). Leydig cells are polyhedral in shape, display a large prominent nucleus, an eosinophilic cytoplasm and numerous lipid-filled vesicles.
23.1 Structure
when stimulated by the pituitary hormone luteinizing hormone (LH). LH increases cholesterol desmolase activity (an enzyme associated with the conversion of cholesterol to pregnenolone), leading to testosterone synthesis and secretion by Leydig cells. Prolactin (PRL) increases the response of Leydig cells to LH by increasing the number of LH receptors expressed on Leydig cells.
The mammalian Leydig cell is a polyhedral epithelioid 23.3 Clinical significance cell with a single eccentrically located ovoid nucleus. The nucleus contains one to three prominent nucleoli and large amounts of dark-staining peripheral heterochromatin. The acidophilic cytoplasm usually contains numerous membrane-bound lipid droplets and large amounts of smooth endoplasmic reticulum (SER). Besides the obvious abundance of SER with scattered patches of rough endoplasmic reticulum, several mitochondria are also prominent within the cytoplasm. Frequently, lipofuscin pigment and rod-shaped crystal-like structures 3 to 20 micrometres in diameter (Reinke crystals) are found. These inclusions have no known function, are found in less than half of all Leydig cell tumors, but serve to clinch the diagnosis of a Leydig cell tumor.[1][2] No other interstitial cell within the testes has a nucleus or cytoplasm with these Micrograph of a Leydig cell tumour. H&E stain. characteristics, making identification relatively easy. Leydig cells may grow uncontrollably and form a Leydig cell tumour. These tumours are usually benign. They may 23.1.1 Development be hormonally active, i.e. secrete testosterone. 'Adult'-type Leydig cells differentiate in the post-natal testis and are quiescent until puberty. They are preceded in the testis by a population of 'fetal'-type Leydig cells from the 8th to the 20th week of gestation, which produce enough testosterone for masculinisation of a male fetus.[3]
23.2 Function
Adrenomyeloneuropathy is another example of a disease affecting the Leydig cell: the patient’s testosterone may fall despite higher-than-normal levels of LH and FSH. Electrostimulation therapy has been found to induce destruction of Leydig cells.[4]
23.4 History 23.4.1 Etimology
Leydig cells release a class of hormones called androgens (19-carbon steroids). They secrete testosterone, Leydig cells are named after the German anatomist Franz androstenedione and dehydroepiandrosterone (DHEA), Leydig, who discovered them in 1850.[5] 93
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23.5 Additional images • Section of a genital cord of the testis of a human embryo 3.5 cm. long. • Intermediate magnification micrograph of a Leydig cell tumour. H&E stain. • High magnification micrograph of a Leydig cell tumour. H&E stain. • Cross-section of seminiferous tubules. Arrows indicate location of Leydig cells.
23.6 See also • Sertoli cell • Sertoli-Leydig cell tumour
23.7 References [1] Al-Agha O, Axiotis C (2007). “An in-depth look at Leydig cell tumor of the testis”. Arch Pathol Lab Med 131 (2): 311–7. doi:10.1043/15432165(2007)131[311:AILALC]2.0.CO;2. PMID 17284120. [2] Ramnani, Dharam M (2010-06-11). “Leydig Cell Tumor : Reinke’s Crystalloids”. Retrieved 2011-11-06. [3] Svechnikov K, Landreh L, Weisser J, Izzo G, Colón E, Svechnikova I, Söder O (2010). “Origin, development and regulation of human Leydig cells”. Horm Res Paediatr. 73 (2): 93–101. doi:10.1159/000277141. PMID 20190545. [4] Bomba G, Kowalski IM, Szarek J, Zarzycki D, Pawlicki R. (2001). “The effect of spinal electrostimulation on the testicular structure in rabbit.”. Med Sci Monit. 7 (3): 363– 8. PMID 11386010. [5] synd/625 at Who Named It?
23.8 External links • Histology image: 16907loa — Histology Learning System at Boston University • Reproductive Physiology • Diagram at umassmed.edu
CHAPTER 23. LEYDIG CELL
Chapter 24
Sperm For other uses, see Sperm (disambiguation). Sperm is the male reproductive cell and is derived from Acrosome
Plasma membrane
Mitochondria Nucleus Terminal disc Centriole
Axial filament
Tail
Mid (connecting) piece
Head
End piece
Sub-acrosomal space
Peri-acrosomal space Cell membrane
Nuclear envelope
Acrosome Nuclear vacuoles
outer acrosome membrane
Nucleus
Equatorial segment
Post-acrosomal region
Centriole
Post-acrosomal sheath
Redundant nuclear envelope
Posterior ring Centriole
Connecting Piece
Video of human sperm cells recorded by an affordable home microscope.
Mitochondrial sheath Outer dense fibers Axoneme FRONT VIEW
Central Pair
24.1.1 Anatomy
Axoneme SIDE VIEW
Diagram of a human sperm cell
the Greek word (σπέρμα) sperma (meaning “seed”). In the types of sexual reproduction known as anisogamy and oogamy, there is a marked difference in the size of the gametes with the smaller one being termed the “male” or sperm cell. A uniflagellar sperm cell that is motile is referred to as a spermatozoon, whereas a non-motile sperm cell is referred to as a spermatium. Sperm cells cannot divide and have a limited life span, but after fusion with egg cells during fertilization, a new organism begins developing, starting as a totipotent zygote. The human sperm cell is haploid, so that its 23 chromosomes can join the 23 chromosomes of the female egg to form a diploid cell. In mammals, sperm develops in the testicles and is released from the penis. It is also possible to extract sperm through TESE. Some sperm banks hold up to 170 litres (37 imp gal; 45 US gal) of sperm.[1]
24.1 Sperm in animals Further information: Spermatozoon
Sperm and egg fusing
The mammalian sperm cell consists of a head, a midpiece and a tail. The head contains the nucleus with densely coiled chromatin fibres, surrounded anteriorly by an acrosome, which contains enzymes used for penetrating the female egg. The midpiece has a central filamentous core with many mitochondria spiralled around it, used for ATP production for the journey through the female cervix, uterus and uterine tubes. The tail or "flagellum" executes the lashing movements that propel the spermatocyte.
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CHAPTER 24. SPERM
During fertilization, the sperm provides three essential parts to the oocyte: (1) a signalling or activating factor, which causes the metabolically dormant oocyte to activate; (2) the haploid paternal genome; (3) the centrosome, which is responsible for maintaining the microtubule system.[2] Although semen contains millions of sperm, the egg will admit only one. The other ones will soon die and be absorbed.
24.1.2
Origin
The spermatozoa of animals are produced through spermatogenesis inside the male gonads (testicles) via meiotic division. The initial spermatozoon process takes around 70 days to complete. The spermatid stage is where the sperm develops the familiar tail. The next stage where it becomes fully mature takes around 60 days when it is called a spermatozoan.[3] Sperm cells are carried out of the male body in a fluid known as semen. Human sperm cells can survive within the female reproductive tract for more than 5 days post coitus.[4] Semen is produced in the seminal vesicles, prostate gland and urethral glands.
24.1.3
Sperm quality
On the global market, Denmark has a well-developed system of human sperm export. This success mainly comes from the reputation of Danish sperm donors for being of high quality[6] and, in contrast with the law in the other Nordic countries, gives donors the choice of being either anonymous or non-anonymous to the receiving couple.[6] Furthermore, Nordic sperm donors tend to be tall and highly educated[7] and have altruistic motives for their donations,[7] partly due to the relatively low monetary compensation in Nordic countries. More than 50 countries worldwide are importers of Danish sperm, including Paraguay, Canada, Kenya, and Hong Kong.[6] However, the Food and Drug Administration (FDA) of the US has banned import of any sperm, motivated by a risk of transmission of Creutzfeldt-Jakob disease, although such a risk is insignificant, since artificial insemination is very different from the route of transmission of Creutzfeldt-Jakob disease.[8] The prevalence of Creutzfeldt-Jakob disease is one in a million, probably less for donors. If prevalence was the case, the infectious proteins would then have to cross the blood-testis barrier to make transmission possible.[8]
24.1.5 History See also: Homunculus § Homunculus of spermists Sperm were first observed in 1677 by Antonie van Leeuwenhoek[9] using a microscope, he described them as being animalcules (little animals), probably due to his belief in preformationism, which thought that each sperm contained a fully formed but small human.
24.1.6 Forensic analysis
Human sperm stained for semen quality testing.
Ejaculated fluids are detected by ultraviolet light, irrespective of the structure or colour of the surface.[10] Sperm heads, e.g. from vaginal swabs, are still detected by microscopy using the “Christmas Tree Stain” method, i.e., Kernechtrot-Picroindigocarmine (KPIC) staining.[11][12]
Main article: Semen quality
24.2 Sperm in plants Sperm quantity and quality are the main parameters in semen quality, which is a measure of the ability of semen to accomplish fertilization. Thus, in humans, it is a measure of fertility in a man. The genetic quality of sperm, as well as its volume and motility, all typically decrease with age.[5] (See paternal age effect.)
Sperm cells in algal and many plant gametophytes are produced in male gametangia (antheridia) via mitotic division. In flowering plants, sperm nuclei are produced inside pollen.
24.1.4
24.3 Motile sperm cells
Market for human sperm
Further information: Sperm donation
Motile sperm cells typically move via flagella and require a water medium in order to swim toward the egg for fertil-
24.4. NON-MOTILE SPERM CELLS
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24.4 Non-motile sperm cells Non-motile sperm cells called spermatia lack flagella and therefore cannot swim. Spermatia are produced in a spermatangium.[13] Because spermatia cannot swim, they depend on their environment to carry them to the egg cell. Some red algae, such as Polysiphonia, produce non-motile spermatia that are spread by water currents after their release.[13] The spermatia of rust fungi are covered with a sticky substance. They are produced in flask-shaped structures containing nectar, which attract flies that transfer the spermatia to nearby hyphae for fertilization in a mechanism similar to insect pollination in flowering plants.[15] Fungal spermatia (also called pycniospores, especially in the Uredinales) may be confused with conidia. Conidia are spores that germinate independently of fertilization, whereas spermatia are gametes that are required for fertilization. In some fungi, such as Neurospora crassa, spermatia are identical to microconidia as they can perform both functions of fertilization as well as giving rise to new organisms without fertilization.[16]
24.5 Sperm nuclei
Motile sperm cells of algae and seedless plants.[13]
ization. In animals most of the energy for sperm motility is derived from the metabolism of fructose carried in the seminal fluid. This takes place in the mitochondria located in the sperm’s midpiece (at the base of the sperm head). These cells cannot swim backwards due to the nature of their propulsion. The uniflagellated sperm cells (with one flagellum) of animals are referred to as spermatozoa, and are known to vary in size. Motile sperm are also produced by many protists and the gametophytes of bryophytes, ferns and some gymnosperms such as cycads and ginkgo. The sperm cells are the only flagellated cells in the life cycle of these plants. In many ferns and lycophytes, they are multiflagellated (carrying more than one flagellum).[13] In nematodes, the sperm cells are amoeboid and crawl, rather than swim, towards the egg cell.[14]
In many land plants, including most gymnosperms and all angiosperms, the male gametophytes (pollen grains) are the primary mode of dispersal, for example via wind or insect pollination, eliminating the need for water to bridge the gap between male and female. Each pollen grain contains a spermatogenous (generative) cell. Once the pollen lands on the stigma of a receptive flower, it germinates and starts growing a pollen tube through the carpel. Before the tube reaches the ovule, the nucleus of the generative cell in the pollen grain divides and gives rise to two sperm nuclei which are then discharged through the tube into the ovule for fertilization.[13] In some protists, fertilization also involves sperm nuclei, rather than cells, migrating toward the egg cell through a fertilization tube. Oomycetes form sperm nuclei in a syncytical antheridium surrounding the egg cells. The sperm nuclei reach the eggs through fertilization tubes, similar to the pollen tube mechanism in plants.[13]
24.6 See also • Ejaculation • Female sperm • Female sperm storage • Polyspermy • Semen
98 • Sperm competition • Sperm donation • Sperm granuloma • Spermatogenesis • Spermatozoon
24.7 References [1] Come inside: the world’s biggest sperm bank retrieved 4 August 2013 [2] Hewitson, Laura & Schatten, Gerald P. (2003). “The biology of fertilization in humans”. In Patrizio, Pasquale et al. A color atlas for human assisted reproduction: laboratory and clinical insights. Lippincott Williams & Wilkins. p. 3. ISBN 978-0-7817-3769-2. Retrieved 2013-11-09. [3] Semen and sperm quality [4] Gould JE, Overstreet JW and Hanson FW (1984) Assessment of human sperm function after recovery from the female reproductive tract. Biol Reprod 31,888–894. [5] Gurevich, Rachel (06-10-2008). “Does Age Affect Male Fertility?". About.com:Fertility. About.com. Retrieved 14 February 2010. Check date values in: |date= (help) [6] Assisted Reproduction in the Nordic Countries ncbio.org [7] FDA Rules Block Import of Prized Danish Sperm Posted Aug 13, 08 7:37 AM CDT in World, Science & Health [8] The God of Sperm By Steven Kotler [9] “Timeline: Assisted reproduction and birth control”. CBC News. Retrieved 2006-04-06. [10] Anja Fiedler, Mark Benecke et al. “Detection of Semen (Human and Boar) and Saliva on Fabrics by a Very High Powered UV-/VIS-Light Source”. Retrieved 2009-12-10. [11] Allery, J. P.; Telmon, N.; Mieusset, R.; Blanc, A.; Rougé, D. (2001). “Cytological detection of spermatozoa: Comparison of three staining methods”. Journal of forensic sciences 46 (2): 349–351. PMID 11305439. [12] Illinois State Police/President’s DNA Initiative. “The Presidents’s DNA Initiative: Semen Stain Identification: Kernechtrot”. Retrieved 2009-12-10. [13] Raven, Peter H.; Ray F. Evert; Susan E. Eichhorn (2005). Biology of Plants, 7th Edition. New York: W.H. Freeman and Company Publishers. ISBN 0-7167-1007-2. [14] Bottino D, Mogilner A, Roberts T, Stewart M, Oster G (2002). “How nematode sperm crawl”. J. Cell. Sci. 115 (Pt 2): 367–84. PMID 11839788. [15] Sumbali, Geeta (2005). The Fungi. Alpha Science Int'l Ltd. ISBN 1-84265-153-6. [16] Maheshwari R (1999). “Microconidia of Neurospora crassa”. Fungal Genet. Biol. 26 (1): 1–18. doi:10.1006/fgbi.1998.1103. PMID 10072316.
CHAPTER 24. SPERM
24.8 External links • The Great Sperm Race pdf • Human Sperm Under a Microscope
Chapter 25
Axoneme 1 2 3
4
5
Micrograph of thin x-section cut through Chlamydomonas axoneme
6
Eukaryotic flagella. 1-axoneme, 2-cell membrane, 3-IFT (intraflagellar transport), 4-basal body, 5-cross section of flagella, 6-triplets of microtubules of basal body.
Radial Central Plasma microtubules spokes membrane
Inner sheath Nexin
A simplified model of intraflagellar transport.
B tubule Dynein arms
(cilia or eukaryotic flagella) whose inner core consists of a cytoskeletal structure called the axoneme.[1] The axDoublet microtubule oneme serves as the “skeleton” of these organelles, both giving support to the structure and, in some cases, causing Cross section of an axoneme it to bend. Though distinctions of function and/or length may be made between cilia and flagella, the internal strucNumerous eukaryotic cells carry whip-like appendages ture of the axoneme is common to both. A tubule
99
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CHAPTER 25. AXONEME
25.1 Structure
25.2 Clinical significance
Inside cilia and flagella is a microtubule-based cytoskeleton called the axoneme. The axoneme of primary cilia typically has a ring of nine outer microtubule triplets (called a 9+0 axoneme), and the axoneme of a motile cilium has two central microtubules in addition to the nine outer doublets (called a 9+2 axoneme). The axonemal cytoskeleton acts as a scaffolding for various protein complexes and provides binding sites for molecular motor proteins such as kinesin II, that help carry proteins up and down the microtubules.[2]
Mutations or defects in primary cilia have been found to play a role in human diseases. These “ciliopathies” include polycystic kidney disease (PKD), retinitis pigmentosa, Bardet-Biedl syndrome, and other developmental defects.
25.1.1
Motile cilia
The building-block of the axoneme is the microtubule; each axoneme is composed of several microtubules aligned in parallel. To be specific, the microtubules are arranged in a characteristic pattern known as the “9x2 + 2,” as shown in the image at right. Nine sets of “doublet” microtubules (a specialized structure consisting of two linked microtubules) form a ring around a “central pair” of single microtubules. Besides the microtubules, the axoneme contains many proteins and protein complexes necessary for its function. The dynein arms, for example, are motor complexes that produce the force needed for bending. Each dynein arm is anchored to a doublet microtubule; by “walking” along an adjacent microtubule, the dynein motors can cause the microtubules to slide against each other. When this is carried out in a synchronized fashion, with the microtubules on one side of the axoneme being pulled 'down' and those on the other side pulled 'up,' the axoneme as a whole can bend back and forth. This process is responsible for ciliary/flagellar beating, as in the well-known example of the human sperm. The radial spoke is another protein complex of the axoneme. Thought to be important in regulating the motion of the axoneme, this “T"-shape complex projects from each set of outer doublets toward the central microtubules. The inter-doublet connections between adjacent microtubule pairs are termed nexin linkages.
25.1.2
Non-motile/primary cilia
The axoneme structure in non-motile (“primary”) cilia shows some variation from the canonical “9x2 + 2” anatomy. No dynein arms are found on the outer doublet microtubules, and there is no pair of central microtubule singlets. This organization of axoneme is referred as “9x2 + 0”. In addition, “9x2 + 1” axonemes, with only a single central microtubule, have been found to exist. Primary cilia appear to serve sensory functions.
25.3 References [1] Porter, M.; Sale, W. (2000). “The 9 + 2 axoneme anchors multiple inner arm dyneins and a network of kinases and phosphatases that control motility”. The Journal of Cell Biology 151 (5): F37–F42. doi:10.1083/jcb.151.5.F37. PMC 2174360. PMID 11086017. [2] Gardiner, Mary Beth (September 2005). “The Importance of Being Cilia” (PDF). HHMI Bulletin (Howard Hughes Medical Institute) 18 (2). Retrieved 2010-03-18.
25.4 Further reading • Wilson, C.W. et al. (2009). “Fused has evolved divergent roles in vertebrate Hedgehog signalling and motile ciliogenesis”. Nature 459 (7243): 98–102. doi:10.1038/nature07883. PMC 3204898. PMID 19305393. • Vogel, G. (2005). “Betting on cilia”. Science 310 (5746): 216–8. doi:10.1126/science.310.5746.216. PMID 16223997. • Porter, M.E. and Sale, W.S. (2000). “The 9 + 2 Axoneme Anchors Multiple Inner Arm Dyneins and a Network of Kinases and Phosphatases that Control Motility”. The Journal of Cell Biology 151 (5): F37– 42. doi:10.1083/jcb.151.5.F37. PMC 2174360. PMID 11086017. • Dillon, R.H. and Fauci, L.J. (2000). “An Integrative Model of Internal Axoneme Mechanics and External Fluid Dynamics in Ciliary Beating”. Journal Theoretical Biology 207 (3): 415–30. doi:10.1006/jtbi.2000.2182. PMID 11082310. • Omoto, C.K., Gibbons, I.R., Kamiya, R., Shingyoji, C., Takahashi, K., and Witman, G.B. (1999). “Rotation of the Central Pair Microtubules in Eukaryotic Flagella”. Molecular Biology Cell 10 (1): 1–4. PMC 25148. PMID 9880321. • Rosenbaum, J.L., Cole, D.G., and Diener D.R. (1999). “Intraflagellar transport: the eyes have it”. Journal of Cell Biology 1999 (3): 385–8. doi:10.1083/jcb.144.3.385. PMC 2132910. PMID 9971734.
Chapter 26
Acrosome The acrosome is an organelle that develops over the anterior half of the head in the spermatozoa (sperm cells) of many animals. It is a cap-like structure derived from the Golgi apparatus. Acrosome formation is completed during testicular maturation. In Eutherian mammals the acrosome contains digestive enzymes (including hyaluronidase and acrosin).[1] These enzymes break down the outer membrane of the ovum, called the zona pellucida, allowing the haploid nucleus in the sperm cell to join with the haploid nucleus in the ovum. This shedding of the acrosome, or acrosome reaction, can be stimulated in vitro by substances a sperm cell may encounter naturally such as progesterone or follicular fluid, as well as the more commonly used calcium ionophore A23187. This can be done to serve as a positive control when assessing the acrosome reaction of a sperm sample by flow cytometry[2] or fluorescence microscopy. This is usually done after staining with a fluoresceinated lectin such as FITC-PNA, FITC-PSA, FITC-ConA, or fluoresceinated antibody such as FITC-CD46.[3]
Human spermatozoön
In the case of globozoospermia (sperm with round heads), the Golgi apparatus is not transformed into the acrosome, causing male infertility.[4]
26.1 References [1] “acrosome definition - Dictionary - MSN Encarta”. Archived from the original on 2009-10-31. Retrieved 2007-08-15. [2] Miyazaki R, Fukuda M, Takeuchi H, Itoh S, Takada M (1990). “Flow cytometry to evaluate acrosomereacted sperm”. Arch. Androl. 25 (3): 243–51. doi:10.3109/01485019008987613. PMID 2285347. [3] Carver-Ward JA, Moran-Verbeek IM, Hollanders JM
101
(February 1997). “Comparative flow cytometric analysis of the human sperm acrosome reaction using CD46 antibody and lectins”. J. Assist. Reprod. Genet. 14 (2): 111–9. doi:10.1007/bf02765780. PMC 3454831. PMID 9048242. [4] Hermann Behre; Eberhard Nieschlag (2000). Andrology : Male Reproductive Health and Dysfunction. Berlin: Springer. p. 155. ISBN 3-540-67224-9.
Chapter 27
Spermiogenesis Acrosome
Plasma membrane
Mitochondria Nucleus Terminal disc Centriole
Axial filament
Tail
Mid (connecting) piece
Head
End piece
Sub-acrosomal space
Peri-acrosomal space Cell membrane
Nuclear envelope
Acrosome Nuclear vacuoles
outer acrosome membrane
Nucleus
Equatorial segment
Post-acrosomal region
Centriole
Post-acrosomal sheath
Redundant nuclear envelope
Posterior ring Centriole
Connecting Piece Mitochondrial sheath Outer dense fibers
Central Pair Axoneme
Axoneme FRONT VIEW
SIDE VIEW
Complete diagram of a human spermatozoon The process of spermatogenesis. 1. Primary spermatocyte 2. Secondary spermatocytes 3. Spermatids 4. Sperm
Spermiogenesis is the final stage of spermatogenesis, which sees the maturation of spermatids into mature, motile spermatozoa. The spermatid is more or less circular cell containing a nucleus, Golgi apparatus, centriole and mitochondria. All these components take part in forming the spermatozoon.
where the mitochondria gather and the distal centriole begins to form an axoneme. Spermatid DNA also undergoes packaging, becoming highly condensed. The DNA is packaged first, with specific nuclear basic proteins, which are subsequently replaced with protamines during spermatid elongation. The resultant tightly packed chromatin is transcriptionally inactive.
27.1 Phases 27.1.2 Cap/Acrosome phase
The process of spermiogenesis is traditionally divided into four stages: the Golgi phase, the cap phase,formation The Golgi apparatus surrounds the condensed nucleus, of tail, and the maturation stage.[1] becoming the acrosomal cap.
27.1.1
Golgi phase
27.1.3 Formation of Tail
The spermatids, which up until now have been mostly One of the centrioles of the cell elongates to become radially symmetrical, begin to develop polarity. the tail of the sperm. A temporary structure called the “manchette” assists in this elongation. • The head forms at one end, and the Golgi apparatus During this phase, the developing spermatozoa orient creates enzymes that will become the acrosome. themselves so that their tails point towards the center of • At the other end, it develops a thickened mid-piece, the lumen, away from the epithelium. 102
27.4. EXTERNAL LINKS
103 • Overview at yale.edu
Note how the tails of the sperm point inward. This orientation occurs during the acrosomal phase.
27.1.4
Maturation phase
The excess cytoplasm, known as residual bodies, is phagocytosed by surrounding Sertoli cells in the testes.
27.2 Spermiation The mature spermatozoa are released from the protective Sertoli cells into the lumen of the seminiferous tubule and a process called spermiation then takes place, which removes the remaining unnecessary cytoplasm and organelles. The resulting spermatozoa are now mature but lack motility, rendering them sterile. The non-motile spermatozoa are transported to the epididymis in testicular fluid secreted by the Sertoli cells with the aid of peristaltic contraction. Whilst in the epididymis, they acquire motility. However, transport of the mature spermatozoa through the remainder of the male reproductive system is achieved via muscle contraction rather than the spermatozoon’s motility. A glycoprotein coat over the acrosome prevents the sperm from fertilizing the egg prior to traveling through the male and female reproductive tracts. Capacitation of the sperm by the enzymes FPP (fertilization promoting peptide, produced by the male) and heparin (in the female reproductive tract) remove this coat and allow sperm to bind to the egg.
27.3 References [1] ANAT D502 – Basic Histology
27.4 External links • Swiss embryology (from UL, UB, and UF) cgametogen/spermato05 • Images and video of spermiogenesis - University of Arizona
Chapter 28
Androgen-binding protein Androgen-binding protein (ABP) is a glycoprotein (beta-globulin) produced by the Sertoli cells in the seminiferous tubules of the testis that binds specifically to testosterone (T), dihydrotestosterone (DHT), and 17beta-estradiol. Because ABP binds to T and DHT, these hormones are made less lipophilic and become concentrated within the luminal fluid of the seminiferous tubules. The higher levels of these hormones enable spermatogenesis in the seminiferous tubules and sperm maturation in the epididymis. ABP has the same amino acid sequence as sex hormonebinding globulin (SHBG); the difference is the site of production and the addition of different sugar moieties. ABP contains 403 amino acids, resulting in a molecular weight of 44,533. Its gene is located on chromosome 17. ABP’s production is regulated under influence of FSH on Sertoli cell, enhanced by insulin, retinol, and testosterone. ABP may also be secreted in other organs; for instance, mice produce a salivary ABP.
28.1 See also • Sex hormone-binding globulin (SHBG)
28.2 References • Androgen-Binding Protein at the US National Library of Medicine Medical Subject Headings (MeSH)
28.3 External links • Ensembl Gene ref Protein ref
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Chapter 29
Egg cell â&#x20AC;&#x153;Ovumâ&#x20AC;? redirects here. It is not to be confused with Ovule. The egg cell is the female reproductive cell (gamete) in oogamous organisms. The egg cell is typically not capable of active movement, and it is much larger (visible to the naked eye) than the motile sperm cells. When egg and sperm fuse, a diploid cell (the zygote) is formed, which gradually grows into a new organism.
29.1 Animals Ovum and sperm fusing together
In animals, egg cells are also known as ova (singular ovum, from the Latin word ovum meaning egg or egg cell). The term ovule is used for the young ovum of an animal. In higher animals, ova are produced by female gonads (sexual glands) called ovaries and all of them are present at birth in mammals and mature via oogenesis.
Vitelline layer
Egg Plasma Membrane
Protein receptors
EGG CYTOPLASM Sperm head Mitochondrial material Nucleus
Perivitelline space
Jelly coat
Actin
29.1.1
Cortical granule content.
Cortical granule
Acrosomal granule
Human and mammal ova
Acrosome reaction
Fused plasma membrane
The process of fertilizing an ovum (Top to bottom)
In viviparous animals (which include humans and all other placental mammals), the ovum is fertilized inside the female body. The human ova grow from primitive germ cells that are embedded in the substance of the ovaries. Each of them divides repeatedly to give secretions of the uterine glands, ultimately forming a blastocyst.[1]
Diagram of a human egg cell
The ovum is one of the largest cells in the human body, typically visible to the naked eye without the aid of a microscope or other magniďŹ cation device. The human ovum measures approximately 0.12 mm in diameter.[2] 105
106
CHAPTER 29. EGG CELL
29.1.2
Ooplasm
29.1.3
Ova development in oviparous animals
(sporophyte). In seed plants, the archegonia are formed inside a structure called ovule, which contains the feOoplasm (also: oöplasm) is the yolk of the ovum, a male gametophyte. The gametophyte produces an egg cell substance at its center, which contains its nucleus, cell. After fertilization, the ovule develops into a seed named the germinal vesicle, and the nucleolus, called the containing the embryo. germinal spot.[3] In flowering plants, the female gametophyte has been reThe ooplasm consists of the cytoplasm of the ordinary duced to just eight cells referred to as the embryo sac animal cell with its spongioplasm and hyaloplasm, often inside the ovule. The gametophyte cell closest to the called the formative yolk; and the nutritive yolk or deuto- micropyle opening of the embryo sac develops into the plasm, made of rounded granules of fatty and albuminoid egg cell. Upon pollination, a pollen tube delivers sperm substances imbedded in the cytoplasm.[3] into the embryo sac and one sperm nucleus fuses with Mammalian ova contain only a tiny amount of the nutri- the egg nucleus. The resulting zygote develops into an tive yolk, for nourishing the embryo in the early stages embryo inside the ovule. The ovule in turn develops of its development only. In contrast, bird eggs contain into a seed and in many cases the plant ovary develops enough to supply the chick with nutriment throughout the into a fruit to facilitate the dispersal of the seeds. Upon germination, the embryo grows into a seedling. whole period of incubation.[3]
In the oviparous animals (all birds, most fish, amphibians and reptiles) the ova develop protective layers and pass through the oviduct to the outside of the body. They are fertilized by male sperm either inside the female body (as in birds), or outside (as in many fish). After fertilization, an embryo develops, nourished by nutrients contained in the egg. It then hatches from the egg, outside the mother’s body. See egg for a discussion of eggs of oviparous animals. The egg cell’s cytoplasm and mitochondria are the sole means the egg is able to reproduce by mitosis and eventually form a blastocyst after fertilization.
29.1.4
Ovoviviparity
There is an intermediate form, the ovoviviparous animals: the embryo develops within and is nourished by an egg as in the oviparous case, but then it hatches inside the mother’s body shortly before birth, or just after the egg leaves the mother’s body. Some fish, reptiles and many invertebrates use this technique.
29.2 Plants
Gene expression pattern determined by histochemical GUS assays in Physcomitrella patens. The Polycomb gene FIE is expressed (blue) in unfertilised egg cells of the moss Physcomitrella patens (right) and expression ceases after fertilisation in the developing diploid sporophyte (left). In situ GUS staining of two female sex organs (archegonia) of a transgenic plant expressing a translational fusion of FIE-uidA under control of the native FIE promoter
In the moss Physcomitrella patens, the Polycomb protein FIE is expressed in the unfertilised egg cell (Figure, right) All land plants have alternating diploid and haploid gener- as the blue colour after GUS staining reveals. Soon after ations. Gametes are produced by the gametophyte, which fertilisation the FIE gene is inactivated (the blue colour is is the haploid generation. The female gametophyte pro- no longer visible, left) in the young embryo. [4] duces structures called archegonia, and the egg cells form within them via mitosis. The typical bryophyte archegonium consists of a long neck with a wider base containing the egg cell. Upon maturation, the neck opens to al- 29.3 Other organisms low sperm cells to swim into the archegonium and fertilize the egg. The resulting zygote then gives rise to an In algae, the egg cell is often called oosphere. Drosophila embryo, which will grow into a new diploid individual oocytes develop in individual egg chambers that are sup-
29.7. EXTERNAL LINKS
107
ported by nurse cells and surrounded by somatic follicle cells. The nurse cells are large polyploid cells that synthesize and transfer RNA, proteins and organelles to the oocytes. This transfer is followed by the programmed cell death (apoptosis) of the nurse cells. During the course of oogenesis, 15 nurse cells die for every oocyte that is produced.[5] In addition to this developmentally regulated cell death, egg cells may also undergo apoptosis in response to starvation and other insults.[5]
[4] Mosquna, Assaf; Katz, Aviva; Decker, Eva L.; Rensing, Stefan A.; Reski, Ralf; Ohad, Nir (2009). “Regulation of stem cell maintenance by the Polycomb protein FIE has been conserved during land plant evolution”. Development 136: 2433–2444. doi:10.1242/10.1242/dev.035048.
29.4 History
[7] Lopata, Alex (April 2009). “History of the Egg in Embryology”. Journal of Mammalian Ova Research 26 (1): 2–9. doi:10.1274/jmor.26.2.
While the non-mammalian animal egg was obvious, the doctrine ex ova omne vivum (“every living [animal comes from] an egg”), associated with William Harvey (15781657), was a rejection of spontaneous generation and preformationism as well as a bold assumption that mammals also reproduced via eggs. Karl Ernst von Baer discovered the mammalian ovum in 1827, and Edgar Allen discovered the human ovum in 1928. The fusion of spermatozoa with ova (of a starfish) was observed by Oskar Hertwig in 1876.[6][7]
29.5 See also • Egg • Fertilization • Insemination • Menstrual cycle • Ova bank • Ovulation • Polar body • Pollination • Pregnancy • Spawn (biology)
29.6 References [1] Regan, Carmen L. (2001). “Pregnancy”. In Worell, Judith. Encyclopedia of Women and Gender: Sex Similarities and Differences and the Impact of Society on Gender, Volume 1. Academic Press. p. 859. ISBN 9780122272455. Retrieved 2013-11-03. [2] Search result of “120 micrometers” in Level O Biology Google books [3] “The Ovum”. Gray’s Anatomy. Retrieved 2010-10-18.
[5] McCall K (October 2004). “Eggs over easy: cell death in the Drosophila ovary”. Dev. Biol. 274 (1): 3–14. doi:10.1016/j.ydbio.2004.07.017. PMID 15355784. [6] Needham, Joseph (1959). A History of Embryology (2d revised ed.). Cambridge: Cambridge University Press.
29.7 External links • The Ovarian Kaleidoscope Database description of 1800 genes involved in ovarian functions
Chapter 30
Corona radiata (embryology) For the structure in neuroanatomy, see Corona radiata. The corona radiata is the innermost layer of the cumulus oophorus and is directly adjacent to the zona pellucida, the outer protective layer of the ovum.[1] Its main purpose in many animals is to supply vital proteins to the cell. It is formed by follicle cells adhering to the oocyte before it leaves the ovarian follicle, and originates from the squamous granulosa cells present at the primordial stage of follicular development. The corona radiata is formed when the granulosa cells enlarge and become cuboidal, which occurs during the transition from the primordial to primary stage. These cuboidal granulosa cells, also known as the granulosa radiata, form more layers throughout the maturation process, and remain attached to the zona pellucida after the ovulation of the Graafian follicle. For fertilization to occur, sperm cells rely on hyaluronidase (an enzyme found in the acrosome of spermatozoa) to disperse the corona radiata from the zona pellucida of the secondary (ovulated) oocyte, thus permitting entry into the perivitelline space and allowing contact between the sperm cell and the nucleus of the oocyte. It takes the secretions of dozens of sperm to weaken the layer enough for one sperm to penetrate.
30.1 References [1] Gilbert, Scott F. Developmental Biology (Ninth ed.). Sinauer Associates, Inc. p. 126. ISBN 0878933840.
30.2 External links • Image at Berkeley • Histology image: 18404loa — Histology Learning System at Boston University • Animation: Maturation of the Follicle and Oocyte
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Chapter 31
Oogonium Not to be confused with Oedogonium.
granular material whereas the somatic cells have a more condensed nucleus that creates a darker outline under the microscope. Oogonial nuclei also contain dense promiAn oogonium (plural oogonia) is either a primordial oocyte in a female fetus or the female gametangium of nent nucleoli. The chromosomal material in the nucleus of mitotically dividing oogonia shows as a dense mass surcertain thallophytes. rounded by vesicles or double membranes.[1] The cytoplasm of oogonia appears similar to that of the surrounding somatic cells and similarly contains large round mitochondria with lateral cristae. The Endoplasmic Reticulum (E.R.) of oogonia, however, is Main article: Oogenesis very underdeveloped and is made up of several small vesicles. Some of these small vesicles contain cisternae with Oogonia are formed in large numbers by mitosis early ribosomes and are found located near the golgi apparain fetal development from primordial germ cells. In hu- tus.[1] mans they start to develop between weeks 4 and 8 and are Oogonia that are undergoing degeneration appear slightly present in the fetus between weeks 5 and 30. different under the electron microscope. In these oogonia, the chromosomes clump together into an indistinguishable mass within the nucleus and the mitochondria 31.1.1 Structure and E.R. appear to be swollen and disrupted. Degenerating oogonia are usually found partially or wholly engulfed in neighboring somatic cells, identifying phagocytosis as the mode of elimination.[1]
31.1 In the mammalian fetus
31.1.2 Development and differentiation
Haematoxylin & Eosin staining of sections of human gonads at E16.5. GO/G1 quiescent oogonia are indicated by arrowheads.
Normal oogonia in human ovaries are spherical or ovoid in shape and are found amongst neighboring somatic cells and oocytes at different phases of development. Oogonia can be distinguished from neighboring somatic cells, under an electron microscope, by observing their nuclei. Oogonial nuclei contain randomly dispersed fibrillar and
In the blastocyst of the mammalian embryo, primordial germ cells arise from proximal epiblasts under the influence of extra-embryonic signals. These germ cells then travel, via amoeboid movement, to the genital ridge and eventually into the undifferentiated gonads of the fetus.[2] During the 4th or 5th week of development, the gonads begin to differentiate. In the absence of the Y chromosome, the gonads will differentiate into ovaries. As the ovaries differentiate, ingrowths called cortical cords develop. This is where the primordial germ cells collect.[3][4] During the 6th to 8th week of female (XX) embryonic development, the primordial germ cells grow and begin to differentiate into oogonia. Oogonia proliferate via mitosis during the 9th to 22nd week of embryonic development. There can be up to 600,000 oogonia by the 8th week of development and up to 7,000,000 by the 5th month.[3]
109
110
CHAPTER 31. OOGONIUM
Eventually, the oogonia will either degenerate or further differentiate into primary oocytes through asymmetric division. Asymmetric division is a process of mitosis in which one oogonium divides unequally to produce one daughter cell that will eventually become an oocyte through the process of oogenesis, and one daughter cell that is an identical oogonium to the parent cell. This occurs during the 15th week to the 7th month of embryonic development.[2] Most oogonia have either degenerated or differentiated into primary oocytes by birth.[3][5]
menstrual cycle. Because there is an absence of regenerating germ cells and oogonia in the human, the number of primary oocytes dwindles after each menstrual cycle until menopause, when the female no longer has a population of primary oocytes.[2] Recent research, however, has identified that renewable oogonia may be present in the lining of the female ovaries of humans, primates and mice.[2][7][8] It is thought that these germ cell might be necessary for the upkeep of the reproductive follicles and oocyte development, well into adulthood. It has also been discovered, that some stem cells may migrate from the bone marrow to the ovaries as a source of extra-genial germ cells. These mitotically active germ cells found in mammalian adults were identified by tracking several makers that were common in oocytes. These potential renewable germs cells were identified as positive for these essential oocyte markers.[2]
Primary oocytes will undergo oogenesis in which they enter meiosis. However, primary oocytes are arrested in prophase 1 of the first meiosis and remain in that arrested stage until puberty begins in the female adult.[6] This is in contrast to male primordial germ cells which are arrested in the spermatogonial stage at birth and do not enter into spermatogenesis and meiosis to produce primary spermatocytes until puberty in the adult male.[3] The discovery of these active germ cells and oogonia in the adult female could be very useful in the advancement [2][8] Germ 31.1.3 Regulation of oogonia differentia- of fertility research and treatment of infertility. cells have been extracted, isolated and grown successfully tion and entry into oogenesis in vitro.[8] These germ cells have been used to restore fertility in mice by promoting follicle generation and upkeep The regulation and differentiation of germ cells into priin previously infertile mice. There is also research being mary gametocytes ultimately depends on the sex of the done on possible germ line regeneration in primates. Miembryo and the differentiation of the gonads. In female totically active human female germ cells could be very mice, the protein RPSO1 is responsible for the differenbeneficial to a new method of embryonic stem cell detiation of female (XX) gonads into ovaries. RSPO1 acvelopment that involves a nuclear transfer into a zygote. tivates the β-catenin signaling pathway by up-regulating Using these functional oogonia may help to create patientWnt4 which is an essential step in ovary differentiation. specific stem cells lines using this method.[2] Research has shown that ovaries lacking Rspo1 or Wnt4 will exhibit sex reversal of the gonads, the formation of ovotestes and the differentiation of somatic sertoli cells, 31.2 In certain thallophytes which aid in the development of sperm.[4] After female (XX) germ cells collect in the undifferentiated gonads, the up-regulation of Stra8 is required for the germ cell to differentiation into an oogonium and eventually enter meiosis. One major factor that contributes to the up-regulation of Stra8, is the initiation of the βCatenin signaling pathway via RSPO1, which is also responsible for ovary differentiation. Since RSPO1 is produced in somatic cells, this protein acts on germ cells in a paracrine mode. Rspo1, however, is not the only factor in Stra8 regulation. Many other factors are under scrutiny and this process is still being evaluated.[4]
31.1.4
Oogonial stem cells
Because it is hypothesized that oogonia either degenerate or differentiate into primary oocytes which enter oogenesis and are halted in prophase I of the first meiosis post partum, it is concluded that adult mammalian females lack a population of germ cells that are able to renew or regenerate. But instead, have a large population of primary oocytes that are arrested in the first meiosis until puberty.[2] At puberty, one primary oocyte will complete meiosis to eventually form an ovum during each
In phycology and mycology, oogonium refers to a female gametangium if the union of the male (motile or non-motile) and the female gamete takes place within this structure.[9][10] In Oomycota and some other organisms, the female oogonia, and the male equivalent antheridia, are a result of sexual sporulation, i.e. the development of structures within which meiosis will occur. The haploid nuclei (gametes) are formed by meiosis within the antheridia and oogonia, and when fertilization occurs, a diploid oospore is produced which will eventually germinate into the diploid somatic stage of the thallophyte life cycle.[11]
31.2.1 Structure The oogonia of certain Thallophyte species are usually round or ovoid, with contents are divided into several uninucleate oospheres. This is in contrast to the male antheridia which are elongate and contain several nuclei.[11] In heterothallic species, the oogonia and antheridia are located on hyphal branches of different thallophyte
31.4. EXTERNAL LINKS
111
colonies. Oogonia of this species can only be fertil- [10] Smyth, G.M. 1955. Cryptogamic Botany. vol. 1. McGraw-Hill Book Company ized by antheridia from another colony and ensures that self-fertilization is impossible. In contrast, homothallic [11] “Sexual Sporulation in Oomycota”. Retrieved 6 April species display the oogonia and antheridia on either the 2012. same hyphal branch or on separate hyphal branches but within the same colony.[11]
31.4 External links 31.2.2
Fertilization
In a common mode of fertilization found in certain species of Thallophytes, the antheridia will bind with the oogonia. The antheridia will then form fertilization tubes connecting the antheridial cytoplasm with each oosphere within the oogonia. A haploid nucleus (gamete) from the antheridium will then be transferred through the fertilization tube into the oosphere, and fuse with the oosphere’s haploid nucleus forming a diploid oospore. The oospore is then ready to germinate and develop into an adult diploid somatic stage.[11]
31.3 References [1] Baker, T.G.; L. L. Franchi (1967). “The Fine Structures of Oogonia Oocytes in Human Ovaries”. Journal of Cell Science 2 (2): 213–224. PMID 4933750. Retrieved 6 April 2012. [2] “Germ Stem Cells, A Scientific Summary”. New Jersey Medical School. Retrieved 6 April 2012. [3] Jones, Richard E. (1997). Human Reproductive Biology, 2nd Ed. San Diego: Academic Press, Elsevier. pp. 26– 40, 90–107, 117–125,. ISBN 0-12-389775-0. [4] Chassot, A. A.; E.P. Gregory, R. Lavery, M.M. Taketo, D.G. de Rooij, et al. (2011). “RSPO1/β-Catenin Signaling Pathway Regulates Oogonia Differentiation and Entry into Meiosis in the Mouse Fetal Ovary”. PLoS ONE 6 (10). doi:10.1371/journal.pone.0025641. Retrieved 6 April 2012. [5] “Human Emryology, Embryogenesis”. Module 3, Gametogenesis. Retrieved 6 April 2012. [6] “Genetics, Meiosis and Gaetogenesis”. www.emich.edu. Retrieved 6 April 2012. [7] Telfer, Evelyn E.; David F. Albertini (2012). “The Quest for Human Ovarian Stem Cells”. Nature Medicine 18 (3): 353–354. doi:10.1038/nm.2699. [8] White, Yvonne A. R.; Dori C Woods; Yashushi Takai; OSamu Ishihara; Hiroyuki Seki; Jonathan L. Tilly (2012). “Oocyte Formation by Mitotically Active Germ Cells Purified From Ovaries of Reprodutive-Age Women”. Nature Medicine 18 (3): 413–421. doi:10.1038/nm.2669. PMC 3296965. PMID 22366948. Retrieved 6 April 2012. [9] Stegenga, H. Bolton, J.J. and Anderson, R.J. 1997. Seaweeds of the South African West Coast. Bolus Herbarium, University of Cape Tow. ISBN 0-7992-1793-X
• Diagram at University of Toronto
Chapter 32
Zona pellucida The zona pellucida (plural zonae pellucidae, also egg coat or pellucid zone) is a glycoprotein layer surrounding the plasma membrane of mammalian oocytes. It is a vital constitutive part of the oocyte, external but of essential importance to it. The zona pellucida first appears in unilaminar primary oocytes. It is secreted by both the oocyte and the follicular cells. The zona pellucida is surrounded by the cumulus oophorus. The cumulus is composed of cells that care for the egg when it is emitted from the ovary.[1]
the bloodstream of another, it results in sterility of the second species due to immune response. This effect can be temporary or permanent, depending on the method used. In New Jersey, porcine zona pellucida is used to keep deer populations low, and this process is commonly referred to as “spay-vac”.
This structure binds spermatozoa, and is required to initiate the acrosome reaction. In the mouse (the best characterised mammalian system), the zona glycoprotein, ZP3, is responsible for sperm binding, adhering to proteins on the sperm plasma membrane (GalT). ZP3 is then involved in the induction of the acrosome reaction, whereby a spermatozoon releases the contents of the acrosomal vesicle. The exact characterisation of what occurs in other species has become more complicated as further zona proteins have been identified.[2][3]
There are four major zona pellucida glycoproteins, termed ZP1-4. ZP1, ZP3 and ZP4 bind to capacitated spermatozoa and induce the acrosome reaction. Successful fertilization depends on the ability of sperm to penetrate the extracellular matrix that surrounds the egg. In the mouse:
32.2 Zona pellucida glycoproteins
• ZP3 allows species-specific sperm binding • ZP2 mediates subsequent sperm binding
In humans, five days after the fertilization, the blastocyst • ZP1 cross-links ZP2 and ZP3. performs zona hatching; the zona pellucida degenerates and decomposes, to be replaced by the underlying layer Data with native human protein are not currently availof trophoblastic cells. able. The zona pellucida is essential for oocyte death and fertilization. In some older texts, it has also been called zona striata and stratum lucidum[4] (not to be confused with the stratum lucidum of the skin).
32.3 Additional images
• First stages of segmentation of a mammalian ovum • Section of vesicular ovarian follicle of cat, x 50 • The initial stages of human embryogenesis
32.1 Immunocontraception Glycoproteins in ZP1, 2, 3 and 4 are targets for immunocontraception in mammals. In non-mammalian animals, the zona pellucida (called vitelline layer) plays an important role in preventing cross-breeding of different species, especially in species that fertilize outside of the body (e.g. fish).
32.4 See also • Maternal influence on sex determination
32.5 References
The zona pellucida is commonly used to control wildlife population problems by immunocontraception. When the zona pellucida of one animal species is injected into 112
[1] Gilbert, Scott (2013). Developmental Biology. Sinauer Associates Inc. p. 123. ISBN 9781605351926.
32.7. EXTERNAL LINKS
[2] Conner, SJ; Hughes, DC (2003). “Analysis of fish ZP1/ZPB homologous genes--evidence for both genome duplication and species-specific amplification models of evolution”. Reproduction 126 (3): 347–52. doi:10.1530/rep.0.1260347. PMID 12968942. [3] Conner, S.J.; Lefièvre, L; Hughes, DC; Barratt, CL (2005). “Cracking the egg: Increased complexity in the zona pellucida”. Human Reproduction 20 (5): 1148–52. doi:10.1093/humrep/deh835. PMID 15760956. [4] Wigham, J. T. (1936). “Endometrioma and other similar abnormalities”. Irish Journal of Medical Science 11 (6): 279–80. doi:10.1007/BF02956856.
32.6 Further reading • Bork, Peer; Sander, Chris (1992). “A large domain common to sperm receptors (Zp2 and Zp3) and TGF-β type III receptor”. FEBS Letters 300 (3): 237–40. doi:10.1016/0014-5793(92)80853-9. PMID 1313375. • Oehninger, Sergio (2003). “Biochemical and functional characterization of the human zona pellucida”. Reproductive BioMedicine Online 7 (6): 641– 8. doi:10.1016/S1472-6483(10)62086-X. PMID 14748962. • Boja, E. S.; Hoodbhoy, T; Fales, HM; Dean, J (2003). “Structural Characterization of Native Mouse Zona Pellucida Proteins Using Mass Spectrometry”. Journal of Biological Chemistry 278 (36): 34189–202. doi:10.1074/jbc.M304026200. PMID 12799386. • Bagnell C (2005). “Animal Reproduction”. Rutgers University Department of Animal Sciences. • Jovine, Luca; Darie, Costel C.; Litscher, Eveline S.; Wassarman, Paul M. (2005). “Zona Pellucida Domain Proteins”. Annual Review of Biochemistry 74: 83–114. doi:10.1146/annurev.biochem.74.082803.133039. PMID 15952882. • Monné, Magnus; Han, Ling; Jovine, Luca (2006). “Tracking Down the ZP Domain: From the Mammalian Zona Pellucida to the Molluscan Vitelline Envelope”. Seminars in Reproductive Medicine 24 (4): 204–16. doi:10.1055/s-2006-948550. PMID 16944418. • Wassarman, P. M. (2008). “Zona Pellucida Glycoproteins”. Journal of Biological Chemistry 283 (36): 24285–9. doi:10.1074/jbc.R800027200. PMC 2528931. PMID 18539589. • Wassarman, Paul M.; Litscher, Eveline S. (2008). “Mammalian fertilization:the eggs multifunctional zona pellucida”. The International Journal
113 of Developmental Biology 52 (5–6): 665–76. doi:10.1387/ijdb.072524pw. PMID 18649280. • Monné, Magnus; Han, Ling; Schwend, Thomas; Burendahl, Sofia; Jovine, Luca (2008). “Crystal structure of the ZP-N domain of ZP3 reveals the core fold of animal egg coats”. Nature 456 (7222): 653– 7. doi:10.1038/nature07599. PMID 19052627. • Han, Ling; Monné, Magnus; Okumura, Hiroki; Schwend, Thomas; Cherry, Amy L.; Flot, David; Matsuda, Tsukasa; Jovine, Luca (2010). “Insights into Egg Coat Assembly and Egg-Sperm Interaction from the X-Ray Structure of Full-Length ZP3”. Cell 143 (3): 404–15. doi:10.1016/j.cell.2010.09.041. PMID 20970175.
32.7 External links • Histology image: 18404loa — Histology Learning System at Boston University - “Female Reproductive System: ovary, cumulus oophorus " • Histology image: 14805loa — Histology Learning System at Boston University - “Female Reproductive System: ovary, multilaminar primary follicle” • Anatomy photo: Reproductive/mammal/ovary2/ovary7 Comparative Organology at University of California, Davis “Mammal, canine ovary (LM, High)" • Image at um.edu.mt • Image at um.edu.mt
Chapter 33
Oocyte An oocyte (UK /ˈoʊəsʌɪt/, US /ˈoʊ.oʊ.saɪt/), oöcyte, ovo- 33.2 Characteristics cyte, or rarely ocyte, is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in 33.2.1 Cytoplasm the ovary during female gametogenesis. The female germ cells produce a primordial germ cell (PGC), which then Oocytes are rich in cytoplasm, which contains yolk granundergoes mitosis, forming oogonia. During oogenesis, ules to nourish the cell early in development. the oogonia become primary oocytes.
33.1 Formation
33.2.2 Nucleus During the primary oocyte stage of oogenesis, the nucleus is called a germinal vesicle.[2] The only normal human type of secondary oocyte has the 23rd (sex) chromosome as 23,X (female-determining), whereas sperm can have 23,X (female-determining) or 23,Y (male-determining).
33.2.3 Nest The space whithin an ovum or immature ovum is located is the cell-nest.[3]
33.3 Maternal Contributions
Diagram showing the reduction in number of the chromosomes in the process of maturation of the ovum; the process is known as meiosis.
Main article: Oogenesis The formation of an oocyte is called oocytogenesis, which is a part of oogenesis.[1] Oogenesis results in the formation of both primary oocytes before birth, and of secondary oocytes after it as part of ovulation.
Because the fate of an oocyte is to become fertilized and ultimately grow into a fully functioning organism, it must be ready to regulate multiple cellular and developmental processes. The oocyte, a large and complex cell, must be supplied with numerous molecules that will direct the growth of the embryo and control cellular activities. As the oocyte is a product of female gametogenesis, the maternal contribution to the oocyte and consequently the newly fertilized egg is enormous. There are many types of molecules that are maternally supplied to the oocyte, which will direct various activities within the growing zygote.
114
33.3. MATERNAL CONTRIBUTIONS
115
33.3.2 mRNAs and Proteins During the growth of the oocyte, a variety of maternally transcribed messenger RNAs, or mRNAs, are supplied by maternal cells. These mRNAs can be stored in mRNP (message ribonucleoprotein) complexes and be translated at specific time points, they can be localized within a specific region of the cytoplasm, or they can be homogeneously dispersed within the cytoplasm of the entire oocyte.[6] Maternally loaded proteins can also be localized or ubiquitous throughout the cytoplasm. The translated products of the mRNAs and the loaded proteins have multiple functions; from regulation of cellular “house-keeping” such as cell cycle progression and cellular metabolism, to regulation of developmental processes such as fertilization, activation of zygotic transcription, and formation of body axes.[6] Below are some examples of maternally inherited mRNAs and proteins found in Xenopus laevis oocytes.
Oocyte Poles
33.3.1
Avoidance of damage to germ-line DNA
The DNA of a cell is vulnerable to the damaging effect of oxidative free radicals produced as byproducts of cellular metabolism. DNA damage occurring in oocytes, if not repaired, can be lethal and result in reduced fecundity and loss of potential progeny. Oocytes are substantially larger than the average somatic cell, and thus considerable metabolic activity is necessary for their provisioning. If this metabolic activity were carried out by the oocyte’s own metabolic machinery, the oocyte genome would be exposed to the reactive oxidative by-products generated. Thus it appears that a process evolved to avoid this vulnerability of germ line DNA. It was proposed that, in order to avoid damage to the DNA genome of the oocytes, the metabolism contributing to the synthesis of much of the oocyte’s constituents was shifted to other maternal cells that then transferred these constituents to oocytes.[4][5] Thus, oocytes of many organisms are protected from oxidative DNA damage while storing up a large mass of substances to nurture the zygote in its initial embryonic growth.
Maternal Determinants in Xenopus laevis Oocyte
33.3.3 Mitochondria The oocyte receives mitochondria from maternal cells, which will go on to control embryonic metabolism and apoptotic events.[6] The partitioning of mitochondria is carried out by a system of microtubules that will localize mitochondria throughout the oocyte. In certain organ-
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CHAPTER 33. OOCYTE
isms, such as mammals, paternal mitochondria brought to the oocyte by the spermatozoon are degraded through the attachment of ubiquitinated proteins. The destruction of paternal mitochondria ensures the strictly maternal inheritance of mitochondria and mitochondrial DNA or mtDNA.[6]
33.3.4
Nucleolus
In mammals, the nucleolus of the oocyte is derived solely from maternal cells.[19] The nucleolus, a structure found within the nucleus, is the location where rRNA is transcribed and assembled into ribosomes. While the nucleolus is dense and inactive in a mature oocyte, it is required for proper development of the embryo.[19]
33.3.5
Ribosomes
Maternal cells also synthesize and contribute a store of ribosomes that are required for the translation of proteins before the zygotic genome is activated. In mammalian oocytes, maternally derived ribosomes and some mRNAs are stored in a structure called cytoplasmic lattices. These cytoplasmic lattices, a network of fibrils, protein, and RNAs, have been observed to increase in density as the number of ribosomes decrease within a growing oocyte.[20]
33.4 Paternal contributions
example 22,X or 24,X. This is the cause of conditions like Down syndrome and Edwards syndrome in humans. It is more likely with advanced maternal age. • Some oocytes have multiple nuclei, although it is thought they never mature.
33.6 See also • Oocyte maturation inhibitor • Folliculogenesis • Polar body
33.7 References [1] answers.com [2] Biology-online [3] Grier HJ, Uribe MC, Parenti LR (April 2007). “Germinal epithelium, folliculogenesis, and postovulatory follicles in ovaries of rainbow trout, Oncorhynchus mykiss (Walbaum, 1792) (Teleostei, protacanthopterygii, salmoniformes)". J. Morphol. 268 (4): 293–310. doi:10.1002/jmor.10518. PMID 17309079. [4] Bernstein C. (1993). Sex as a response to oxidative DNA damage. Chapter 10 (see pages 204-205) in “DNA and Free Radicals” (editors: Barry Halliwell, Okezie I Aruoma). Ellis Horwood Limited (publisher), Great Gritain ISBN 0-13-222035-0
The spermatozoon that fertilizes an oocyte will contribute its pronucleus, the other half of the zygotic genome. In some species, the spermatozoon will also contribute a centriole, which will help make up the zygotic centrosome required for the first division. However, in some species, such as in the mouse, the entire centrosome is acquired maternally.[21] Currently under investigation is the possibility of other cytoplasmic contributions made to the embryo by the spermatozoon.
[5] Bernstein, C. (1998). Sex as a response to oxidative DNA damage. Chapter 4, see pages 112-113. In “DNA and Free Radicals: Techniques, Mecchanisms & Applications” (editors: Okezie I Aruoma, Barry Halliwell). OICA International (publisher), Saint Lucia and London ISBN 976-8056169
During fertilization, the sperm provides three essential parts to the oocyte: (1) a signalling or activating factor, which causes the metabolically dormant oocyte to activate; (2) the haploid paternal genome; (3) the centrosome, which is responsible for maintaining the microtubule system. See anatomy of sperm
[7] Zhang J., King M.L. (1996). Xenopus VegT RNA is localized to the vegetal cortex during oogenesis and encodes a novel T-box transcription factor involved in mesodermal patterning. Development. 12, 4119–29.
33.5 Abnormalities • nondisjunction—a failure of proper homolog separation in meiosis I, or sister chromatid separation in meiosis II can lead to aneuploidy, in which the oocyte has the wrong number of chromosomes, for
[6] Mtango N.R., Potireddy S., Latham K.E. (2008). Oocyte quality and maternal control of development. Int. Rev. Cell Mol. Biol. 268, 223-290.
[8] Heasman J., Wessely O., Langland R., Craig E.J., Kessler D.S. (2001). Vegetal localization of maternal mRNAs is disrupted by VegT depletion. Dev Biol. 240, 377–386. [9] Zhao H., Cao Y., Grunz H. (2003). Xenopus X-box binding protein 1, a leucine zipper transcription factor, is involved in the BMP signaling pathway. Dev Biol. 257, 278–291. [10] Sundaram N., Tao Q., Wylie C., Heasman J. (2003). The role of maternal CREB in early embryogenesis of Xenopus laevis. Dev Biol. 261, 337–352.
33.9. EXTERNAL LINKS
[11] Kofron M., Puck H., Standley H., Wylie C., Old R., Whitman M., et al. (2004). New roles for FoxH1 in patterning the early embryo. Development. 131, 5065–5078. [12] Takebayashi-Suzuki K., Funami J., Tokumori D., Saito A., Watabe T., Miyazono K., et al. (2003). Interplay between the tumor suppressor p53 and TGF beta signaling shapes embryonic body axes in Xenopus. Development. 130, 3929–3939. [13] Heasman, J. (2006). Maternal determinants of embryonic cell fate. Semin. Cell Dev. Biol. 17, 93-98. [14] Song J., Slack J.M. (1994). Spatial and temporal expression of basic fibroblast growth factor (FGF-2) mRNA and protein in early Xenopus development. Mech Dev. 48, 141–151. [15] Dupont S., Zacchigna L., Cordenonsi M., Soligo S., Adorno M., Rugge M., et al. (2005). Germ-layer specification and control of cell growth by Ectodermin, a Smad4 ubiquitin ligase. Cell. 121, 87–99. [16] Birsoy B., Berg L., Williams P.H., Smith J.C., Wylie C.C., Christian J.L., et al. (2005). XPACE4 is a localized pro-protein convertase required for mesoderm induction and the cleavage of specific TGFbeta proteins in Xenopus development. Development. 132, 591–602. [17] Bell E., Munoz-Sanjuan I., Altmann C.R., Vonica A., Brivanlou A.H. (2003). Cell fate specification and competence by Coco, a maternal BMP, TGFbeta and Wnt inhibitor. Development. 130, 1381–1389. [18] Chan A. P., Kloc M., Larabell C. A., LeGros M., Etkin L.D. (2007). The maternally localized RNA fatvg is required for cortical rotation and germ cell formation. Mech Dev. 124, 350-363. [19] Ogushi S., et al. (2008). The maternal nucleolus is essential for early embryonic development in mammals. Science. 319, 613-616 [20] Vitale A.M., Yurttas P., Fitzhenry R.J., Cohen-Gould, L., Wu W., Gossen J.A., Coonrod S.A. (2009). Role for PADI6 and the CPLs in ribosomal storage in oocytes and translation in the early embryo. Development. 135, 26272636. [21] Sutovsky P., Schatten G. (2000). Paternal contributions to the mammalian zygote: fertilization after sperm-egg fusion. Int. Rev. Cytol. 195, 1-65.
33.8 Sources • William K. Purves, Gordon H. Orians, David Sadava, H. Craig Heller, Craig Heller (2003). Life: The Science of Biology (7th ed.), pp. 823–824.
33.9 External links • Micrograph of a primary oocyte and follicle of a monkey
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Chapter 34
Ovulation Ovulation is the event of de Graafâ&#x20AC;&#x2122;s follicles rupturing and releasing secondary oocyte ovarian cells. It is the phase of a femaleâ&#x20AC;&#x2122;s menstrual cycle when an egg(ovule) is released from the ovaries.[1] After ovulation, during the luteal phase, the egg will be available to be fertilized by sperm. Concomitantly, the uterine lining (endometrium) is thickened to be able to receive a fertilized egg. If no conception occurs, the uterine lining as well as blood will be shed during menstruation.[2]
34.1 Ovulation in humans
Ovulation occurs about midway through the menstrual cycle, after the follicular phase, and is followed by the luteal phase. Note that ovulation is characterized by a sharp spike in levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), resulting from the peak of estrogen levels during the follicular phase.
In humans, ovulation occurs about midway through the menstrual cycle, after the follicular phase. The few days surrounding ovulation (from approximately days 10 to 18 of a 28 day cycle), constitute the most fertile phase.[3][4][5][6] The time from the beginning of the last menstrual period (LMP) until ovulation is, on average, 14.6[7] days, but with substantial variation between
This diagram shows the hormonal changes around the time of ovulation, as well as the inter-cycle and inter-woman variabilities in its timing.
women and between cycles in any single woman, with an overall 95% prediction interval of 8.2 to 20.5[7] days. The process of ovulation is controlled by the hypothalamus of the brain and through the release of hormones secreted in the anterior lobe of the pituitary
118
34.2. CLINICAL PRESENTATION gland, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In the pre-ovulatory phase of the menstrual cycle, the ovarian follicle will undergo a series of transformations called cumulus expansion, which is stimulated by FSH. After this is done, a hole called the stigma will form in the follicle, and the secondary oocyte will leave the follicle through this hole. Ovulation is triggered by a spike in the amount of FSH and LH released from the pituitary gland. During the luteal (post-ovulatory) phase, the secondary oocyte will travel through the fallopian tubes toward the uterus. If fertilized by a sperm, the fertilized secondary oocyte or ovum may implant there 6–12 days later.[8]
119 two cells: the larger secondary oocyte that contains all of the cytoplasmic material and a smaller, inactive first polar body. Meiosis II follows at once but will be arrested in the metaphase and will so remain until fertilization. The spindle apparatus of the second meiotic division appears at the time of ovulation. If no fertilization occurs, the oocyte will degenerate between 12 and 24 hours after ovulation.[12] The mucous membrane of the uterus, termed the functionalis, has reached its maximum size, and so have the endometrial glands, although they are still non-secretory.
34.1.3 Luteal phase 34.1.1
Follicular phase Main article: Luteal phase
See also: Folliculogenesis The follicular phase (or proliferative phase) is the phase of the menstrual cycle during which the ovarian follicles mature. The follicular phase lasts from the beginning of menstruation to the start of ovulation.[9][10] For ovulation to be successful, the ovum must be supported by the corona radiata and cumulus oophorous granulosa cells. The latter undergo a period of proliferation and mucification known as cumulus expansion. Mucification is the secretion of a hyaluronic acid-rich cocktail that disperses and gathers the cumulus cell network in a sticky matrix around the ovum. This network stays with the ovum after ovulation and has been shown to be necessary for fertilization. An increase in cumulus cell number causes a concomitant increase in antrum fluid volume that can swell the follicle to over 20 mm in diameter. It forms a pronounced bulge at the surface of the ovary called the blister.
34.1.2
Ovulation
The follicle proper has met the end of its lifespan. Without the oocyte, the follicle folds inward on itself, transforming into the corpus luteum (pl. corpora lutea), a steroidogenic cluster of cells that produces estrogen and progesterone. These hormones induce the endometrial glands to begin production of the proliferative endometrium and later into secretory endometrium, the site of embryonic growth if implantation occurs. The action of progesterone increases basal body temperature by onequarter to one-half degree Celsius (one-half to one degree Fahrenheit). The corpus luteum continues this paracrine action for the remainder of the menstrual cycle, maintaining the endometrium, before disintegrating into scar tissue during menses.
34.2 Clinical presentation Further information: Concealed ovulation, Fertility awareness and Mittelschmerz
Estrogen levels peak towards the end of the follicular phase, which causes a surge in levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This lasts from 24 to 36 hours, and results in the rupture of the ovarian follicles, causing the oocyte to be released from the ovary via the oviduct.[11]
The start of ovulation can be detected by signs. Because the signs are not readily discernible by people other than the woman herself, humans are said to have a concealed ovulation. In many animal species there are distinctive signals indicating the period when the female is fertile. Several explanations have been proposed to explain conThrough a signal transduction cascade initiated by LH, cealed ovulation in humans. proteolytic enzymes are secreted by the follicle that de- Women near ovulation experience changes in the cervix, grade the follicular tissue at the site of the blister, form- in mucus produced by the cervix, and in their basal body ing a hole called the stigma. The cumulus-oocyte com- temperature. Furthermore, many women experience secplex (COC) leaves the ruptured follicle and moves out ondary fertility signs including Mittelschmerz (pain assointo the peritoneal cavity through the stigma, where it is ciated with ovulation) and a heightened sense of smell, caught by the fimbriae at the end of the fallopian tube and can sense the precise moment of ovulation.[13][14] (also called the oviduct). After entering the oviduct, the Many women experience heightened sexual desire in the ovum-cumulus complex is pushed along by cilia, begin- several days immediately before ovulation.[15] One study ning its journey toward the uterus. concluded that women subtly improve their facial attracBy this time, the oocyte has completed meiosis I, yielding tiveness during ovulation.[16]
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CHAPTER 34. OVULATION
Symptoms related to the onset of ovulation, the moment of ovulation and the body’s process of beginning and ending the menstrual cycle vary in intensity with each woman but are fundamentally the same. The charting of such symptoms — primarily basal body temperature, Mittelschmerz and cervical position — is referred to as the sympto-thermal method of fertility awareness, which allow auto-diagnosis by a woman of her state of ovulation. Once training has been given by a suitable authority, fertility charts can be completed on a cycle-by-cycle basis to show ovulation. This gives the possibility of using the data to predict fertility for natural contraception and pregnancy planning.
Ovulation induction is a promising assisted reproductive technology for patients with conditions such as polycystic ovary syndrome (PCOS) and oligomenorrhea. It is also used in in vitro fertilization to make the follicles mature before egg retrieval. Usually, ovarian stimulation is used in conjunction with ovulation induction to stimulate the formation of multiple oocytes.[20] Some sources[20] include ovulation induction in the definition of ovarian stimulation. A low dose of human chorionic gonadotropin (HCG) may be injected after completed ovarian stimulation. Ovulation will occur between 24–36 hours after the HCG injection.[20]
The moment of ovulation has been photographed.[17]
34.4.2 Suppressed ovulation
34.3 Disorders
Contraception can be achieved by suppressing the ovulation.
Disorders of ovulation are classified as menstrual disorThe majority of hormonal contraceptives and conception ders and include oligoovulation and anovulation: boosters focus on the ovulatory phase of the menstrual cycle because it is the most important determinant of fer• Oligoovulation is infrequent or irregular ovulation tility. Hormone therapy can positively or negatively inter(usually defined as cycles of greater than 36 days or fere with ovulation and can give a sense of cycle control fewer than 8 cycles a year) to the woman. • Anovulation is absence of ovulation when it would Estradiol and progesterone, taken in various forms includbe normally expected (in a post-menarchal, pre- ing combined oral contraceptive pills, mimics the hormenopausal woman). Anovulation usually manifests monal levels of the menstrual cycle and engage in negitself as irregularity of menstrual periods, that is, ative feedback of folliculogenesis and ovulation. unpredictable variability of intervals, duration, or bleeding. Anovulation can also cause cessation of periods (secondary amenorrhea) or excessive bleed34.5 See also ing (dysfunctional uterine bleeding). The World Health Organization (WHO) has developed the following classification of ovulatory disorders:[18] • WHO group I: Hypothalamic–pituitary-gonadal axis failure • WHO group II: Hypothalamic–pituitary-gonadal axis dysfunction. WHO group II is the most common cause of ovulatory disorders, and the most common causative member is polycystic ovary syndrome (PCOS).[19] • WHO group III: Ovarian failure • WHO group IV: Hyperprolactinemia
34.4 Induction and suppression 34.4.1
Induced ovulation
Main article: Ovulation induction
• Anovulatory cycle • Corpus luteum • Folliculogenesis • Menstrual cycle • Oogenesis
34.6 Notes [1] Ovulation Test at Duke Fertility Center. Retrieved July 2, 2011 [2] Young, Barbara (2006). Wheater’s Functional Histology: A Text and Colour Atlas (5th ed.). Elsevier Health Sciences. p. 359. ISBN 9780443068508. Retrieved 201311-09. [3] Chaudhuri, S.K. (2007). “Natural Methods of Contraception”. Practice of Fertility Control: A Comprehensive Manual, 7/e. Elsevier India. p. 49. ISBN 9788131211502. Retrieved 2013-11-09.
34.7. FURTHER READING
[4] Allen, Denise (2004). Managing Motherhood, Managing Risk: Fertility and Danger in West Central Tanzania. University of Michigan Press. pp. 132–133. ISBN 9780472030279. Retrieved 2013-11-09. [5] Rosenthal, Martha (2012). Human Sexuality: From Cells to Society. Cengage Learning. p. 322. ISBN 9780618755714. Retrieved 2013-11-09. [6] Nichter, Mark; Nichter, Mimi (1996). “Cultural Notions of Fertility in South Asia and Their Influence on Sri Lankan Family Planning Practices”. In Nichter, Mark; Nichter, Mimi. Anthropology & International Health: South Asian Case Studies. Psychology Press. pp. 8–11. ISBN 9782884491716. Retrieved 2013-11-09. [7] Geirsson RT (1991). “Ultrasound instead of last menstrual period as the basis of gestational age assignment”. Ultrasound in Obstetrics and Gynecology 1 (3): 212– 9. doi:10.1046/j.1469-0705.1991.01030212.x. PMID 12797075. [8] Wilcox AJ, Baird DD, Weinberg CR (1999). “Time of implantation of the Conceptus and loss of pregnancy”. New England Journal of Medicine 340 (23): 1796– 1799. doi:10.1056/NEJM199906103402304. PMID 10362823. [9] Littleton, Lynna A. & Engebretson, Joan C. Maternity Nursing Care. Cengage Learning. p. 195. ISBN 9781401811921. Retrieved 2013-11-09. [10] Gupta, Ramesh C. (2011). Reproductive and Developmental Toxicology. Academic Press. p. 22. ISBN 9780123820334. Retrieved 2013-11-09. [11] Watson, Stephanie & Stacy, Kelli Miller (2010). “The Endocrine System”. In McDowell, Julie. Encyclopedia of Human Body Systems. Greenwood. pp. 201–202. ISBN 9780313391750. Retrieved 2013-11-09. [12] Ovarian ultrasonography highlights precision of symptoms of ovulation as markers of ovulation [13] Navarrete-Palacios E, Hudson R, Reyes-Guerrero G, Guevara-Guzmán R (July 2003). “Lower olfactory threshold during the ovulatory phase of the menstrual cycle”. Biol Psychol 63 (3): 269–79. doi:10.1016/S03010511(03)00076-0. PMID 12853171. [14] Beckmann, Charles R.B., ed. (2010). Obstetrics and Gynecology. Lippincott Williams & Wilkins. pp. 306–307. ISBN 9780781788076. Retrieved 2013-11-09. [15] Susan B. Bullivant, Sarah A. Sellergren, Kathleen Stern, et al. (February 2004). “Women’s sexual experience during the menstrual cycle: identification of the sexual phase by noninvasive measurement of luteinizing hormone”. Journal of Sex Research 41 (1): 82–93 (in online article, see pp.14–15, 18–22). doi:10.1080/00224490409552216. PMID 15216427. [16] Roberts S, Havlicek J, Flegr J, Hruskova M, Little A, Jones B, Perrett D, Petrie M (August 2004). “Female facial attractiveness increases during the fertile phase of the menstrual cycle”. Proc Biol Sci 271 (Suppl 5:S): 270– 2. doi:10.1098/rsbl.2004.0174. PMC 1810066. PMID 15503991.
121
[17] “article in BBC News”. BBC. 2008-06-12. [18] Page 54 in: Guillebaud, John; Enda McVeigh; Roy Homburg (2008). Oxford handbook of reproductive medicine and family planning. Oxford [Oxfordshire]: Oxford University Press. ISBN 0-19-920380-6. [19] “Health and fertility in World Health Organization group 2 anovulatory women”. Human Reproduction Update 18 (5): 586–599. 2012. doi:10.1093/humupd/dms019. PMID 22611175. [20] IVF.com > Ovulation Induction Retrieved on Mars 7, 2010
34.7 Further reading • Baerwald AR, Adams GP, Pierson RA (July 2003). “A new model for ovarian follicular development during the human menstrual cycle”. Fertil. Steril. 80 (1): 116–22. doi:10.1016/S0015-0282(03)005442. PMID 12849812. • Chabbert Buffet N, Djakoure C, Maitre SC, Bouchard P (July 1998). “Regulation of the human menstrual cycle”. Front Neuroendocrinol 19 (3): 151–86. doi:10.1006/frne.1998.0167. PMID 9665835. • Fortune JE (February 1994). “Ovarian follicular growth and development in mammals”. Biol. Reprod. 50 (2): 225–32. doi:10.1095/biolreprod50.2.225. PMID 8142540. • Guraya SS, Dhanju CK (November 1992). “Mechanism of ovulation—an overview”. Indian J. Exp. Biol. 30 (11): 958–67. PMID 1293040. • Klowden, Marc J. (2009). “Oviposition Behavior”. In Resh, Vincent H. & Carde, Ring T. Encyclopedia of Insects. Academic Press. ISBN 9780080920900. Retrieved 2013-11-09.
34.8 External links • Human egg makes accidental debut on camera • Ovulation moment caught on camera
Chapter 35
Ovarian follicle atresia Ovarian follicle atresia is the periodic process in which immature ovarian follicles degenerate and are subsequently re-absorbed during the follicular phase of the menstrual cycle. Typically around 20 follicles mature each month and only a single follicle is ovulated. The rest undergo atresia. That single dominant follicle becomes a corpus luteum following ovulation.[1][2][3][4]
35.2 References
Atresia is a hormonally controlled apoptotic process[5] that depends dominantly on granulosa cell apoptosis. To date, at least five cell-death ligand-receptor systems have been reported in granulosa cells to play a role in atresia regulation.[6][7][3] They are: • tumor necrosis factor alpha (TNF alpha) and receptors • Fas ligand and receptors[2] • TNF-related apoptosis-inducing ligand (TRAIL; also called APO-2) and receptors • APO-3 ligand and receptors
[1] Rolaki A, Drakakis P, Millingos S, Loutradis D, Makrigiannakis A (July 2005). “Novel trends in follicular development, atresia and corpus luteum regression: a role for apoptosis”. Reprod. Biomed. Online 11 (1): 93–103. doi:10.1016/S1472-6483(10)61304-1. PMID 16102296. [2] Manabe N, Matsuda-Minehata F, Goto Y, et al (July 2008). “Role of cell death ligand and receptor system on regulation of follicular atresia in pig ovaries”. Reprod. Domest. Anim. 43. Suppl 2: 268– 72. doi:10.1111/j.1439-0531.2008.01172.x. PMID 18638134. [3] Manabe N, Goto Y, Matsuda-Minehata F, et al (October 2004). “Regulation mechanism of selective atresia in porcine follicles: regulation of granulosa cell apoptosis during atresia” (– Scholar search ). J. Reprod. Dev. 50 (5): 493–514. doi:10.1262/jrd.50.493. PMID 15514456. [4] Hsueh AJ, Billig H, Tsafriri A (December 1994). “Ovarian follicle atresia: a hormonally controlled apoptotic process”. Endocr. Rev. 15 (6): 707–24. PMID 7705278. [5] Kaipia A, Hsueh AJ (1997). “Regulation of ovarian follicle atresia”. Annu. Rev. Physiol. 59 (1): 349–63. doi:10.1146/annurev.physiol.59.1.349. PMID 9074768.
• PFG-5 ligand and receptors In addition, two intracellular inhibitor proteins, cellular FLICE-like inhibitory protein short form (cFLIPS) and long form (cFLIPL), which were strongly expressed in granulosa cells, may act as anti-apoptotic factors. It has been proposed that enhanced levels of Nitrogen oxide in rats can prevent atresia of the ovarian follicle, and depressed levels have the opposite effect.[8]
[6] Matsuda-Minehata F, Goto Y, Inoue N, Manabe N (October 2005). “Changes in expression of anti-apoptotic protein, cFLIP, in granulosa cells during follicular atresia in porcine ovaries”. Mol. Reprod. Dev. 72 (2): 145–51. doi:10.1002/mrd.20349. PMID 16010689. [7] Matsuda F, Inoue N, Goto Y, et al (October 2008). “cFLIP regulates death receptor-mediated apoptosis in an ovarian granulosa cell line by inhibiting procaspase-8 cleavage” (– Scholar search ). J. Reprod. Dev. 54 (5): 314–20. doi:10.1262/jrd.20051. PMID 18603835. [8] Najati V, Ilkhanipour M, Salehi S, Sadeghi-Hashjin G (January 2008). “Role of nitric oxide on the generation of atretic follicles in the rat ovaries”. Pak. J. Biol. Sci. 11 (2): 250–4. doi:10.3923/pjbs.2008.250.254. PMID 18817198.
35.1 See also • Folliculogenesis • Ovary • Ovarian reserve 122
Chapter 36
Ovarian follicle Ovarian follicles are the basic units of female reproductive biology, each of which is composed of roughly spherical aggregations of cells found in the ovary. They contain a single oocyte (immature ovum or egg). These structures are periodically initiated to grow and develop, culminating in ovulation of usually a single competent oocyte in humans. These eggs/ova are developed only once every menstrual cycle (e.g. once a month in humans), a woman begins puberty with about 400,000 follicles.[1]
36.1 Structure
36.1.2 Granulosa Granulosa cells within the follicle surround the oocyte; their numbers increase directly in response to heightened levels of circulating gonadotropins or decrease in response to testosterone. They also produce peptides involved in ovarian hormone synthesis regulation. Folliclestimulating hormone (FSH) induces granulosa cells to express luteinizing hormone (LH) receptors on their surfaces; when circulating LH binds to these receptors, proliferation stops.[3]
36.1.3 Thecal The granulosa cells, in turn, are enclosed in a thin layer of extracellular matrix – the follicular basement membrane or basal lamina (fibro-vascular coat in picture). Outside the basal lamina, the layers theca interna and theca externa are found.
36.1.4 Development Main article: Folliculogenesis
Section of vesicular ovarian follicle of cat. X 50.
Primordial follicles are indiscernible to the naked eye. However, these eventually develop into primary, secondary and tertiary vesicular follicles. Tertiary vesicular follicles (also called “mature vesicular follicles” or “ripe vesicular follicles”) are sometimes called Graafian follicles (after Regnier de Graaf).
In humans, oocytes are established in the ovary before birth and may lie dormant awaiting initiation for up to 50 The cells of the ovarian follicle are the oocyte, granulosa years.[4] cells and the cells of the internal and external theca layers. After rupturing, the follicle is turned into a corpus luteum.
36.1.1
Oocyte
36.1.5 Development of oocytes in ovarian follicles Once a month, one of the ovaries releases a mature egg, known as an oocyte. A follicle is an anatomical structure in which the primary oocyte develops. The nucleus of Main article: Oogenesis such an oocyte is called a germinal vesicle [2] (see picture). 123
124
CHAPTER 36. OVARIAN FOLLICLE
In a larger perspective, the whole folliculogenesis from cancer.[10] primordial to preovulatory follicle is located in the stage For in vitro culture of follicles, there are various techof meiosis I of ootidogenesis in oogenesis. niques to optimize the growth of follicles, including The embryonic development doesn't differ from the male the use of defined media, growth factors and threeone, but follows the common path before gametogenesis. dimensional extracellular matrix support.[11] Molecular Once gametogonia enter the gonadal ridge, however, they methods and immunoassay can evaluate stage of matattempt to associate with these somatic cells. Develop- uration and guide adequate differentiation.[11] Animal ment proceeds and the gametogonia turn into oogonia, studies have generally showed correct imprinted DNA which become fully surrounded by a layer of cells (pre- methylation establishment in oocytes resulting from folgranulosa cells). licle culture.[12] The Oogonia multiply by dividing mitotically; this proliferation ends when the oogonia enter meiosis. The amount of time that oogonia multiply by mitosis is not species specific. In the human fetus, cells undergoing mitosis are seen until the second and third trimester of pregnancy.[5][6] After beginning the meiotic process, the oogonia (now called primary oocytes) can no longer replicate. Therefore the total number of gametes is established at this time. Once the primary oocytes stop dividing the cells enter a prolonged ‘resting phase’. This ‘resting phase’ or dictyate stage can last anywhere up to fifty years in the human. For several primary oocytes that undergo meiosis, only one functional oocyte is produced. The other two or three cells produced are called polar bodies. Polar bodies have no function and eventually deteriorate. The primary oocyte turns into a secondary oocyte in mature ovarian follicles. Unlike the sperm, the egg is arrested in the secondary stage of meiosis until fertilization. Upon fertilization by sperm, the secondary oocyte continues the second part of meiosis and becomes a zygote.
36.2 Clinical significance Any ovarian follicle that is larger than about two centimeters is termed an ovarian cyst. Ovarian function may be measured by gynecologic ultrasonography of follicular volume. Presently, ovarian follicle volumes can be measured rapidly and automatically from three-dimensionally reconstructed ultrasound images.[7] Rupture of the follicle can result in abdominal pain (mittelschmerz) and is to be considered in the differential diagnosis in women of childbearing age.[8]
36.2.1
Cryopreservation and culture
Follicles can develop from ovarian tissue after cryopreservation. Cryopreservation of ovarian tissue is of interest to women who want to preserve their reproductive function beyond the natural limit, or whose reproductive potential is threatened by cancer therapy,[9] for example in hematologic malignancies or breast
36.3 Additional images • Pre-antral follicle • Graafian follicles • Primordial ovarian follicle. The oocyte is surrounded by a single layer of flat granulosa cells.
36.4 References [1] David Krogh (2010), Biology: A Guide to the Natural World, Benjamin-Cummings Publishing Company, p. 638, ISBN 978-0-321-61655-5 [2] Biology-online [3] Katz: Comprehensive Gynecology, 5th ed. [4] McGee E. A., Hsueh A. J. (2000). “Initial and cyclic recruitment of ovarian follicles”. Endocrine Reviews 21 (2): 200–14. doi:10.1210/er.21.2.200. PMID 10782364. [5] Baker, T. G. (1982). Oogenesis and ovulation. In “Book 1: Germ cells and fertilization” (C. R. Austin and R. V. Short, Eds.), pp. 17-45. Cambridge University Press, Cambridge. [6] Byskov, A. G., and Hoyer, P. E. (1988). Embryology of mammalian gonads and ducts. In “The physiology of reproduction” (E. Knobil and J. Neill, Eds.), pp. 265-302. Raven Press, Ltd, New York. [7] Salama S, Arbo E, Lamazou F, Levailllant JM, Frydman R, Fanchin R (April 2010). “Reproducibility and reliability of automated volumetric measurement of single preovulatory follicles using SonoAVC”. Fertil. Steril. 93 (6): 2069–73. doi:10.1016/j.fertnstert.2008.12.115. PMID 19342038. [8] http://www.merck.com/mmpe/sec02/ch011/ch011b. html [9] Isachenko V, Lapidus I, Isachenko E, et al. (2009). “Human ovarian tissue vitrification versus conventional freezing: morphological, endocrinological, and molecular biological evaluation.”. Reproduction 138 (2): 319–27. doi:10.1530/REP-09-0039. PMID 19439559.
36.5. EXTERNAL LINKS
[10] Oktay K, Oktem O (November 2008). “Ovarian cryopreservation and transplantation for fertility preservation for medical indications: report of an ongoing experience”. Fertil. Steril. 93 (3): 762–8. doi:10.1016/j.fertnstert.2008.10.006. PMID 19013568. [11] Smitz J, Dolmans MM, Donnez J, et al. (February 2010). “Current achievements and future research directions in ovarian tissue culture, in vitro follicle development and transplantation: implications for fertility preservation”. Hum Reprod Update 16 (4): 395–414. doi:10.1093/humupd/dmp056. PMC 2880913. PMID 20124287. [12] Anckaert, E.; De Rycke, M.; Smitz, J. (2012). “Culture of oocytes and risk of imprinting defects”. Human Reproduction Update 19 (1): 52–66. doi:10.1093/humupd/dms042. PMID 23054129.
36.5 External links • Anatomy photo:43:05-0105 at the SUNY Downstate Medical Center - “The Female Pelvis: The Ovary” • Histology image: 14803loa — Histology Learning System at Boston University • Slide at fda.gov • Images at okstate.edu • Life cycle at gfmer.ch
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Chapter 37
Corpus luteum The corpus luteum (Latin for “yellow body"; plural corpora lutea) is a temporary endocrine structure in female mammals that is involved in the production of relatively high levels of progesterone and moderate levels of estradiol and inhibin A. It is colored as a result of concentrating carotenoids (including lutein) from the diet and secretes a moderate amount of estrogen to inhibit further release of gonadotropin-releasing hormone (GnRH) and thus secretion of luteinising hormone (LH) and folliclestimulating hormone (FSH). A new corpus luteum develops with each menstrual cycle.
37.1 Development and structure The corpus luteum develops from an ovarian follicle during the luteal phase of the menstrual cycle or oestrous cycle, following the release of a secondary oocyte from the follicle during ovulation. The follicle first forms a corpus hemorrhagicum before it becomes a corpus luteum, but the term refers to the visible collection of blood left after rupture of the follicle that secretes progesterone. While the oocyte (later the zygote if fertilization occurs) traverses the Fallopian tube into the uterus, the corpus luteum remains in the ovary.
phorylates steroidogenic acute regulatory protein (StAR) and translocator protein to transport cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane.[4] The development of the corpus luteum is accompanied by an increase in the level of the steroidogenic enzyme P450scc that converts cholesterol to pregnenolone in the mitochondria.[5] Pregnenolone is then converted to progesterone that is secreted out of the cell and into the blood stream. During the bovine estrous cycle, plasma levels of progesterone increase in parallel to the levels of P450scc and its electron donor adrenodoxin, indicating that progesterone secretion is a result of enhanced expression of P450scc in the corpus luteum.[5] The mitochondrial P450 system electron transport chain including adrenodoxin reductase and adrenodoxin has been shown to leak electrons leading to the formation of superoxide radical.[6][7] Apparently to cope with the radicals produced by this system and by enhanced mitochondrial metabolism, the levels of antioxidant enzymes catalase and superoxide dismutase also increase in parallel with the enhanced steroidogenesis in the corpus luteum.[5] 21 12 19 2 3
4
5
H
6
7
H
H
15
26
Mineralocorticoids
25
23
16
O OH
HO
17,20 lyase
HO
OH
OH
O
OH
11-deoxycortisol
O OH
Corticosterone
O
OH O OH
HO
Cortisol O
O
O
O
Androstenedione
O
17β-HSD OH
O
Estrone HO
OH
s) on
arb
8c s (1 en
OH
og
tr Es
Dihydrotestosterone H
(21 carbons) OH
OH
Estriol HO
Estradiol HO
5α-reductase
O
Glucocorticoids
O
Testosterone
Androstenediol HO
O
OH O
HO
(liver and placenta)
Dehydroepiandrosterone
17α-hydroxy progesterone
Aromatase
Androgens (19 carbons)
O
O
Aldosterone synthase
OH
DeoxyO corticosterone 21-hydroxylase
17α-hydroxy pregnenolone
3-beta-hydroxysteroid dehydrogenase (3β-HSD)
Pregnenolone 17α-hydroxylase
Aldosterone
O
Progesterone O
OH
HO
Cholesterol
O
HO
O O
(21 carbons)
27
Cholesterol side-chain cleavage enzyme Progestagens (21 carbons)
Its cells develop from the follicular cells surrounding the ovarian follicle.[3] The follicular theca cells luteinize into small luteal cells (thecal-lutein cells) and follicular granulosa cells luteinize into large luteal cells (granulosallutein cells) forming the corpus luteum. Progesterone is synthesized from cholesterol by both the large and small luteal cells upon luteal maturation. CholesterolLDL complexes bind to receptors on the plasma membrane of luteal cells and are internalized. Cholesterol is released and stored within the cell as cholesterol ester. LDL is recycled for further cholesterol transport. Large luteal cells produce more progesterone due to uninhibited/basal levels of protein kinase A (PKA) activity within the cell. Small luteal cells have LH receptors that regulate PKA activity within the cell. PKA actively phos-
HO
8
24
22
17
14
9
10
20
18
13
11β-hydroxylase
The corpus luteum is typically very large relative to the size of the ovary; in humans, the size of the structure ranges from under 2 cm to 5 cm in diameter.[1][2]
1
11
Cellular location of enzymes Mitochondria Smooth endoplasmic reticulum
Steroidogenesis, with progesterone in yellow field at upper center. The androgens are shown in blue field, and aromatase at lower center - the enzyme present in granulosa lutein cells that convert androgens into estrogens (shown in pink triangle).
126
37.3. ADDITIONAL IMAGES Like the previous theca cells, the theca lutein cells lack the aromatase enzyme that is necessary to produce estrogen, so they can only perform steroidogenesis until formation of androgens.[9] The granulosa lutein cells do have aromatase, and use it to produce estrogens, using the androgens previously synthesized by the theca lutein cells, as the granulosa lutein cells in themselves do not have the 17α-hydroxylase or 17,20 lyase to produce androgens.[9]
127 the blastocyst secrete the hormone human chorionic gonadotropin (hCG, or a similar hormone in other species) by day 9 post-fertilization.
Human chorionic gonadotropin signals the corpus luteum to continue progesterone secretion, thereby maintaining the thick lining (endometrium) of the uterus and providing an area rich in blood vessels in which the zygote(s) can develop. From this point on, the corpus luteum is called Once the corpus luteum regresses the remnant is known the corpus luteum graviditatis. as corpus albicans.[10] The introduction of prostaglandins at this point causes the
37.2 Function The corpus luteum is essential for establishing and maintaining pregnancy in females. The corpus luteum secretes progesterone, which is a steroid hormone responsible for the decidualization of the endometrium (its development) and maintenance, respectively.
37.2.1
When egg is not fertilized
degeneration of the corpus luteum and the abortion of the fetus. However, in placental animals such as humans, the placenta eventually takes over progesterone production and the corpus luteum degrades into a corpus albicans without embryo/fetus loss. Luteal support refers to the administration of medication (generally progestins) for the purpose of increasing the success of implantation and early embryogenesis, thereby complementing the function of the corpus luteum.
37.2.3 Content of carotenoids
The yellow color and name of the corpus luteum, like that of the macula lutea of the retina, is due to its concentration of certain carotenoids, especially lutein. In 1968, a report indicated that beta-carotene was synthesized in laboratory conditions in slices of corpus luteum The uterine lining sloughs off without progesterone and is from cows. However, attempts have been made to repliexpelled through the vagina (in mammals that go through cate these findings, but have not succeeded. The idea a menstrual cycle). In an estrous cycle, the lining degen- is not presently accepted by the scientific community.[11] erates back to normal size. Rather, the corpus luteum concentrates carotenoids from the diet of the mammal. If the egg is not fertilized, the corpus luteum stops secreting progesterone and decays (after approximately 10 days in humans). It then degenerates into a corpus albicans, which is a mass of fibrous scar tissue.
37.2.2
When egg is fertilized
37.3 Additional images • Order of changes in ovary • Human ovary with fully developed corpus luteum • Luteinized follicular cyst. H&E stain.
37.4 References [1] “Corpus Luteum Cyst of Pregnancy”. DrSpock.com. Retrieved 2009-05-26. [2] Vegetti W, Alagna F (2006). “FSH and follucogenesis: from physiology to ovarian stimulation”. Reproductive biomedicine Online. Retrieved 2009-05-26.
Vaginal ultrasound showing a corpus luteum in a pregnant woman, with a fluid-filled cavity in its center.
[3] Page 1159 in: Boron WF, Boulpaep EL (2004). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 1300. ISBN 1-4160-2328-3.
If the egg is fertilized and implantation occurs, the syncytiotrophoblast (derived from trophoblast) cells of
[4] Niswender GD (March 2002). “Molecular control of luteal secretion of progesterone”. Reproduction 123 (3): 333–9. doi:10.1530/rep.0.1230333. PMID 11882010.
128
[5] Rapoport R, Sklan D, Wolfenson D, Shaham-Albalancy A, Hanukoglu I (March 1998). “Antioxidant capacity is correlated with steroidogenic status of the corpus luteum during the bovine estrous cycle”. Biochim. Biophys. Acta 1380 (1): 133–40. doi:10.1016/S0304-4165(97)001360. PMID 9545562. [6] Hanukoglu I, Rapoport R, Weiner L, Sklan D (September 1993). “Electron leakage from the mitochondrial NADPH-adrenodoxin reductase-adrenodoxin-P450scc (cholesterol side chain cleavage) system”. Arch. Biochem. Biophys. 305 (2): 489–98. doi:10.1006/abbi.1993.1452. PMID 8396893. [7] Rapoport R, Sklan D, Hanukoglu I (March 1995). “Electron leakage from the adrenal cortex mitochondrial P450scc and P450c11 systems: NADPH and steroid dependence”. Arch. Biochem. Biophys. 317 (2): 412–6. doi:10.1006/abbi.1995.1182. PMID 7893157. [8] The IUPS Physiome Project --> Female Reproductive System – Cells Retrieved on Nov 9, 2009 [9] Chapter 54, The Female Reproductive System > THE OVARIAN STEROIDS, in: Boron WF, Boulpaep EL (2004). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 1300. ISBN 1-41602328-3. [10] [11] Brian Davis. Carotenoid metabolism as a preparation for function. Pure & Applied Chemistry, Vol. 63, No. 1, pp. 131–140, 1991. available online. Accessed April 30, 2010.
37.5 External links • Histology image: 18201loa — Histology Learning System at Boston University • Anatomy photo:43:05-0106 at the SUNY Downstate Medical Center – “The Female Pelvis: The Ovary” • CT of the abdomen showing a ruptured hemorrhagic copus luteal cyst
CHAPTER 37. CORPUS LUTEUM
Chapter 38
In vitro maturation In vitro maturation (IVM) is the technique of letting ovarian follicles mature in vitro.
oocytes can mature outside the body, such as prior to IVF.[4] However, there still isn't enough evidence to prove the effectiveness and security of the technique.[4]
38.1 Techniques available The ability of in IVM depends on how mature the follicle already is. There are several stages in folliculogenesis, starting with a primordial follicle, which then becomes a primary, secondary, early tertiary (antral), late tertiary and eventually a preovulatory follicle. If a follicle has reached the early tertiary or antral stage, IVM can be carried out. A few live births have already been made[1] by taking small early tertiary follicles, letting them mature in vitro and subsequently fertilizing them. However, for follicles that haven't reached the early tertiary stage, IVM is still under development. There are a lot of cellular changes in the oocyte and the rest of the cells in the follicle, which makes it very susceptible. Nevertheless, it is possible to let a primordial follicle mature to a secondary follicle outside the body by growing it in a slice of ovarian tissue.[1] The subsequent maturity from secondary to early tertiary stage can then be supported in test-tubes.[1]
• For research. There are a million of oocytes in the ovary at birth, but only about 400 of these will be ovulated. The rest will die by Ovarian follicle atresia. When oocytes destined to die are extracted, IVM enables the maturation of these follicles. Thus, they can be studied to gather more information on folliculogenesis and oocyte maturation.[1]
38.3 References
IVM can be expanded with hCG-priming, which is exposing the ovarian tissue to human chorionic gonadotropin (hCG). This results in an expanding or dispersed pattern of the cumulus oophorus around the egg cell, facilitating its identification within follicular fluid.[2] However, the evidence of a clinical effect of hCG priming is still lacking.[2] IVM can also be expanded with intracytoplasmic sperm injection (ICSI), which should be performed at least one hour (and optimally two to four hours) after the first polar body extrusion.[3]
38.2 Applications • Facilitate IVF, and provide an alternative to ovulation induction. Before an IVF, an ovarian hyperstimulation is usually performed. By injecting gonadotropins, multiple oocytes will mature. Similar methods are applied in ovulation induction for other purposes. However, with IVM, injection of gonadotropins into the body isn't essential. Rather, 129
[1] NCBI:In vitro maturation of oocytes. Hardy K, Wright CS, Franks S, Winston RM [2] Son, W. -Y.; Tan, S. L. (2010). “Laboratory and embryological aspects of hCG-primed in vitro maturation cycles for patients with polycystic ovaries”. Human Reproduction Update 16 (6): 675–689. doi:10.1093/humupd/dmq014. PMID 20504873. [3] Chang-Seop Hyun; Jung-Ho Cha, Weon-Young Son, San-Hyun Yoon, Kyung-Ae Kim, and Jin-Ho Lim (2007-07-07). “Optimal ICSI timing after the first polar body extrusion in in vitro matured human oocytes”. Human Reproduction 22 (7): 1991–1995. doi:10.1093/humrep/dem124. PMID 17513319. Retrieved 2012-07-14. [4] Vejledning om kunstig befrugtning 2006 (Danish)
Chapter 39
Human fertilization Vitelline layer
vitro fertilization, external ejaculation without copulation, or copulation shortly after ovulation.[2][3][4] Upon encountering the secondary oocyte, the acrosome of the sperm produces enzymes which allow it to burrow through the outer jelly coat of the egg. The sperm plasma then fuses with the egg’s plasma membrane, the sperm head disconnects from its flagellum and the egg travels down the Fallopian tube to reach the uterus.
Egg Plasma Membrane
Protein receptors
EGG CYTOPLASM Sperm head Mitochondrial material Nucleus
Perivitelline space
Jelly coat
Actin
Cortical granule content.
Cortical granule
Acrosomal granule
Acrosome reaction
In vitro fertilization (IVF) is a process by which egg cells are fertilized by sperm outside the womb, in vitro.
Fused plasma membrane
The acrosome reaction for a sea urchin, a similar process. Note that the picture shows several stages of one and the same spermatozoon - only one penetrates the ovum
39.1 Anatomy 39.1.1 Corona radiata The sperm bind through the corona radiata, a layer of follicle cells on the outside of the secondary oocyte. Fertilization occurs when the nucleus of both a sperm and an egg fuse to form a diploid cell, known as zygote. The successful fusion of gametes forms a new organism.
39.1.2 Cone of attraction and perivitelline membrane
Illustration depicting ovulation and fertilization.
Where the spermatozoon is about to pierce, the yolk (ooplasm) is drawn out into a conical elevation, termed the cone of attraction or reception cone. Once the spermatozoon has entered, the peripheral portion of the yolk changes into a membrane, the perivitelline membrane, which prevents the passage of additional spermatozoa.[5]
Human fertilization is the union of a human egg and sperm, usually occurring in the ampulla of the uterine 39.1.3 Sperm preparation tube. The result of this union is the production of a zygote, or fertilized egg, initiating prenatal development. Further information: Acrosome reaction Scientists discovered the dynamics of human fertilization in the nineteenth century.[1] At the beginning of the process, the sperm undergoes a The process of fertilization involves a sperm fusing with series of changes, as freshly ejaculated sperm is unable an ovum. The most common sequence begins with or poorly able to fertilize.[6] The sperm must undergo ejaculation during copulation, follows with ovulation, and capacitation in the female’s reproductive tract over sevfinishes with fertilization. Various exceptions to this se- eral hours, which increases its motility and destabilizes quence are possible, including artificial insemination, In its membrane, preparing it for the acrosome reaction, the 130
39.2. FUSION
131
enzymatic penetration of the egg’s tough membrane, the After the sperm enters the cytoplasm of the oocyte (also zona pellucida, which surrounds the oocyte. called ovocyte), the cortical reaction takes place, preventing other sperm from fertilizing the same egg. The oocyte now undergoes its second meiotic division producing the 39.1.4 Zona pellucida haploid ovum and releasing a polar body. The sperm nucleus then fuses with the ovum, enabling fusion of their After binding to the corona radiata the sperm reaches the genetic material. zona pellucida, which is an extra-cellular matrix of glycoproteins. A special complementary molecule on the surface of the sperm head binds to a ZP3 glycoprotein in the zona pellucida. This binding triggers the acrosome to 39.2.1 Cell membranes burst, releasing enzymes that help the sperm get through The cell membranes of the secondary oocyte and sperm the zona pellucida. fuse. Some sperm cells consume their acrosome prematurely on the surface of the egg cell, facilitating the penetration by other sperm cells. As a population, sperm cells have on average 50% genome similarity so the premature acro- 39.2.2 Transformations somal reactions aid fertilization by a member of the same cohort.[7] It may be regarded as a mechanism of kin se- In preparation for the fusion of their genetic material both the oocyte and the sperm undergo transformations as a lection. reaction to the fusion of cell membranes. Recent studies have shown that the egg is not passive durThe oocyte completes its second meiotic division. This ing this process.[8][9] results in a mature ovum. The nucleus of the oocyte is called a pronucleus in this process, to distinguish it from Cortical reaction the nuclei that are the result of fertilization. Once the sperm cells find their way past the zona pellucida, the cortical reaction occurs. Cortical granules inside the secondary oocyte fuse with the plasma membrane of the cell, causing enzymes inside these granules to be expelled by exocytosis to the zona pellucida. This in turn causes the glyco-proteins in the zona pellucida to crosslink with each other — i.e. the enzymes cause the ZP2 to hydrolyse into ZP2f — making the whole matrix hard and impermeable to sperm. This prevents fertilization of an egg by more than one sperm. The cortical reaction and acrosome reaction are both essential to ensure that only one sperm will fertilize an egg.[10]
The sperm’s tail and mitochondria degenerate with the formation of the male pronucleus. This is why all mitochondria in humans are of maternal origin. Still, a considerable amount of RNA from the sperm is delivered to the resulting embryo and likely influences embryo development and the phenotype of the offspring.[11]
39.2.3 Replication The pronuclei migrate toward the center of the oocyte, rapidly replicating their DNA as they do so to prepare the zygote for its first mitotic division.[12]
39.2 Fusion 39.2.4 Mitosis The male and female pronuclei don't fuse, although their genetic material do. Instead, their membranes dissolve, leaving no barriers between the male and female chromosomes. During this dissolution, a mitotic spindle forms between them. The spindle captures the chromosomes before they disperse in the egg cytoplasm. Upon subsequently undergoing mitosis (which includes pulling of chromatids towards centrioles in anaphase) the cell gathers genetic material from the male and female together. Thus, the first mitosis of the union of sperm and oocyte is the actual fusion of their chromosomes.[12]
Fertilization and implantation in humans.
Each of the two daughter cells resulting from that mitosis has one replica of each chromatid that was replicated in the previous stage. Thus, they are genetically identical.
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CHAPTER 39. HUMAN FERTILIZATION
39.3 Fertilization age
[3] http://www.americanpregnancy.org/ preventingpregnancy/pregnancyfaqmyths.html
The fertilization is the most commonly event marking the zero point in descriptions of prenatal development of the embryo or fetus. The resultant age is known as fertilization age, fertilizational age, embryonic age, fetal age or (intrauterine) developmental (IUD)[13] age.
[4] Lawyers Guide to Forensic Medicine ISBN 978-1-85941159-9 By Bernard Knight - Page 188 “Pregnancy is well known to occur from such external ejaculation ...” [5] “Fertilization of the Ovum”. Gray’s Anatomy. Retrieved 2010-10-16.
Gestational age, in contrast, takes the beginning of the [6] “Fertilization”. Retrieved 28 July 2010. last menstrual period (LMP) as the zero point. By convention, gestational age is calculated by adding 14 days to [7] Angier, Natalie (2007-06-12). “Sleek, Fast and Focused: The Cells That Make Dad Dad”. The New York Times. fertilization age and vice versa.[14] In fact, however, fertilization usually occurs within a day of ovulation, which, in [8] Suzanne Wymelenberg, Science and Babies, National turn, occurs on average 14.6 days after the beginning of Academy Press, page 17 the preceding menstruation (LMP).[15] There is also con[9] Richard E. Jones and Kristin H. Lopez, Human Reprosiderable variability in this interval, with a 95% prediction ductive Biology, Third Edition, Elsevier, 2006, page 238 interval of the ovulation of 9 to 20 days after menstruation even for an average woman who has a mean LMP- [10] “Fertilization: The Cortical Reaction”. Boundless. Boundless. Retrieved 14 March 2013. to-ovulation time of 14.6.[16] In a reference group representing all women, the 95% prediction interval of the [11] Jodar, M.; Selvaraju, S.; Sendler, E.; Diamond, M. P.; LMP-to-ovulation is 8.2 to 20.5 days.[15] Krawetz, S. A.; for the Reproductive Medicine Network (2013). “The presence, role and clinical use of sperFertilization age is sometimes used postnatally (after matozoal RNAs”. Human Reproduction Update 19 (6): birth) as well to estimate various risk factors. For exam604–624. doi:10.1093/humupd/dmt031. PMC 3796946. ple, it is a better predictor than postnatal age for risk of PMID 23856356. intraventricular hemorrhage in premature babies treated [12] Marieb, Elaine M. Human Anatomy and Physiology, 5th with extracorporeal membrane oxygenation.[17] ed. pp. 1119-1122 (2001). ISBN 0-8053-4989-8
39.4 Diseases Various disorders can arise from defects in the fertilization process. • Polyspermy results from multiple sperm fertilizing an egg.
[13] Wagner F, Erdösová B, Kylarová D (December 2004). “Degradation phase of apoptosis during the early stages of human metanephros development”. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 148 (2): 255–6. PMID 15744391. [14] Robinson, H. P.; Fleming, J. E. E. (1975). “A Critical Evaluation of Sonar “crown-Rump Length” Measurements”. BJOG: an International Journal of Obstetrics and Gynaecology 82 (9): 702. doi:10.1111/j.14710528.1975.tb00710.x.
However, some researchers have found that in rare pairs [15] Geirsson RT (May 1991). “Ultrasound instead of last of fraternal twins, their origin might have been from the menstrual period as the basis of gestational age asfertilization of one egg cell from the mother and eight signment”. Ultrasound Obstet Gynecol 1 (3): 212– sperm cells from the father. This possibility has been 9. doi:10.1046/j.1469-0705.1991.01030212.x. PMID investigated by computer simulations of the fertilization 12797075. process.
39.5 See also
[16] Derived from a standard deviation in this interval of 2.6, as given in: Fehring RJ, Schneider M, Raviele K (2006). “Variability in the phases of the menstrual cycle”. J Obstet Gynecol Neonatal Nurs 35 (3): 376– 84. doi:10.1111/j.1552-6909.2006.00051.x. PMID 16700687.
• Spontaneous conception, the unassisted conception of a subsequent child after prior use of assisted re- [17] Alan H. Jobe, MD, PhD. Post-fertilizational age and IVH productive technology in ECMO patients. RadiologySource Volume 145, Issue 2, Page A2 (August 2004). PII: S0022-3476(04)00583-9. doi:10.1016/j.jpeds.2004.07.010.
39.6 References [1] Garrison, Fielding. An Introduction to the History of Medicine, pages 566-567 (Saunders 1921). [2] http://www.goaskalice.columbia.edu/0116.html
39.7 External links • Fertilization (Conception)
Chapter 40
Acrosome reaction 40.1.1 Echinoderms Vitelline layer
Egg Plasma Membrane
Protein receptors
EGG CYTOPLASM Sperm head Mitochondrial material Nucleus
Perivitelline space
Jelly coat
Actin
In some lower animal species a protuberance (the acrosomal process) forms at the apex of the sperm head, supported by a core of actin microfilaments. The membrane at the tip of the acrosomal process fuses with the egg’s plasma membrane.
Cortical granule content.
Cortical granule
Acrosomal granule
In some echinoderms, including starfish and sea urchins, a major portion of the exposed acrosomal content contains a protein that temporarily holds the sperm on the egg’s surface.
Acrosome reaction
Fused plasma membrane
Acrosome reaction on a Sea Urchin cell
During fertilization, a sperm must first fuse with the plasma membrane and then penetrate the female egg in order to fertilize it. Fusing to the egg usually causes little problem, whereas penetrating through the egg’s hard shell can present more of a problem to the sperm. Therefore sperm cells go through a process known as the acrosome reaction which is the reaction that occurs in the acrosome of the sperm as it approaches the egg. The acrosome is a cap-like structure over the anterior half of the sperm’s head.
40.1.2 Mammals In mammals the acrosome reaction releases hyaluronidase and acrosin; their role in fertilization is not yet clear. The acrosomal reaction does not begin until the sperm comes into contact with the oocyte’s zona pellucida. Upon coming into contact with the zona pellucida, the acrosomal enzymes begin to dissolve and the actin filament comes into contact with the zona pellucida. Once the two meet, a calcium influx occurs, causing a signaling cascade. The cortical granules inside the oocyte then fuse to the outer membrane and a transient fast block reaction occurs.
As the sperm approaches the zona pellucida of the egg, which is necessary for initiating the acrosome reaction, the membrane surrounding the acrosome fuses with the plasma membrane of the spermatozoa, exposing the contents of the acrosome. The contents include surface anti- It also alters a patch of pre-existing sperm plasma memgens and numerous enzymes which are responsible for brane so that it can fuse with the egg plasma membrane. breaking through the egg’s tough coating and allowing ferA sperm penetration assay includes an acrosome reaction tilization to occur. test that assesses how well a sperm is able to perform during the fertilization process. Sperm that are unable to properly go through the acrosome reaction will not be able to fertilize an egg. However, this problem only occurs in about 5% of men that have the test done. This test 40.1 Variations among species is rather expensive and provides limited information on a man’s fertility.[1] There are considerable species variations in the morphology and consequences of the acrosome reaction. In several species the trigger for the acrosome reaction has been identified in a layer that surrounds the egg.
In other cases, such as in the wood mouse Apodemus sylvaticus, premature acrosome reactions have been found to cause increased motility in aggregates of spermatozoa promoting fertilization [2]
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134
40.2 The process The acrosomal reaction normally takes place in the ampulla of the fallopian tube (site of fertilization) when the sperm penetrates the secondary oocyte. A few events precede the actual acrosome reaction. The sperm cell acquires a “hyperactive motility pattern” by which its flagellum produces vigorous whip-like movements that propel the sperm through the cervical canal and uterine cavity, until it reaches the isthmus of the fallopian tube. The sperm approaches the ovum in the ampulla of the fallopian tube with the help of various mechanisms, including chemotaxis. Glycoproteins on the outer surface of the sperm then bind with glycoproteins on the zona pellucida of the ovum. The first stage is the penetration of corona radiata, by releasing hyaluronidase from the acrosome to digest cumulus cells surrounding the oocyte and exposing acrosin attached to the inner membrane of the sperm. The cumulus cells are embedded in a gel-like substance made primarily of hyaluronic acid, and developed in the ovary with the egg and support it as it grows. After reaching the zona pellucida the actual acrosome reaction begins. Acrosin digests the zona pellucida and membrane of the oocyte. Part of the sperm’s cell membrane then fuses with the egg cell’s membrane, and the contents of the head sink into the egg. In the mouse it has been demonstrated that ZP3, one of the proteins that make up the zona pellucida, binds to a partner molecule (to the β1,4-galactosyl transferase receptors) on the sperm. This lock-and-key type mechanism is species-specific and prevents the sperm and egg of different species from fusing. There is some evidence that this binding is what triggers the acrosome to release the enzymes that allow the sperm to fuse with the egg. It is likely that a similar mechanism occurs in other mammals, but the diversity of zona proteins across species means that the relevant protein and receptor may differ.
CHAPTER 40. ACROSOME REACTION
40.3 In in vitro fertilization When using intracytoplasmic sperm injection (ICSI) for IVF, the implantation rate is higher in oocytes injected with spermatozoa that have undergone acrosome reaction (~40%) vs. those injected with nonreacted spermatozoa (~10%). The implantation rate is ~25% in when injected with both reacted and nonreacted spermatozoa. The delivery rate per cycle follows the same trend.[3] The acrosome reaction can be stimulated in vitro by substances a sperm cell may encounter naturally such as progesterone or follicular fluid, as well as the more commonly used calcium ionophore A23187.
40.3.1 Assessment Birefringence microscopy,[3] flow cytometry [4] or fluorescence microscopy can be used for assessing the shedding of the acrosome or “acrosome reaction” of a sperm sample. Flow cytometry and fluorescence microscopy are usually done after staining with a fluoresceinated lectin such as FITC-PNA, FITC-PSA, FITC-ConA, or fluoresceinated antibody such as FITCCD46.[5] The antibodies/lectins have a high specificity for different parts of the acrosomal region, and will only bind to a specific site (acrosomal content/ inner/outer membrane). If bound to a fluorescent molecule, regions where these probes have bound can be visualised. Sperm cells with artificially induced acrosome reactions may serve as positive controls.
For fluorescence microscopy a smear of washed sperm cells are made, airdried, permealized and then stained. Such a slide is then viewed under light of a wavelength that will cause the probe to fluoresce if it is bound to the acrosomal region. At least 200 cells are viewed in an arbitrary fashion and classified as either acrosome intact (fluorescing bright green) or acrosome reacted (no probe present, or only on the equatorial region). It is then Upon penetration, if all is occurring normally, the pro- expressed as a percentage of the counted cells. cess of egg-activation occurs and the oocyte is said to For assessment with flow cytometry the washed cells are have become activated. This is thought to be induced by incubated with the chosen probe, (possibly washed again) a specific protein phospholipase c zeta. It undergoes its and then sampled in a flow cytometer. After gating the secondary meiotic division, and the two haploid nuclei cell population according to forward- and side-scatter the (paternal and maternal) fuse to form a zygote. In order to resulting data can be analysed (E.g. mean fluorescences prevent polyspermy and minimise the possibility of pro- compared). With this technique a probe for viability, like ducing a triploid zygote, several changes to the egg’s cell propidium iodide (PI) could also be included in order to membranes renders them impenetrable shortly after the exclude dead cells from the acrosome assessment, since first sperm enters the egg. many sperm cells will spontaneously lose their acrosome The aforementioned process describes the physiologi- when they die. cally relevant events. One should however bear in mind that a certain percentage of sperm cells will undergo a spontaneous acrosome reaction without the presence of 40.4 See also the ovum. Those cells are not able to fertilise the egg, even if they do reach it later. Other cells will sponta• Cortical reaction neously shed their acrosome during the process of apop• Hamster zona-free ovum test tosis/necrosis.
40.6. EXTERNAL LINKS • ZP3
40.5 References [1] Your path to fertility: Acrosome Reaction. 2007. doi: http://www.sharedjourney.com/define/mcp.html [2] Moore, Harry et al., Exceptional sperm cooperation in Wood Mouse. Nature 418, 174-177 (2002). [3] Gianaroli L, Magli MC, Ferraretti AP, et al. (December 2008). "Birefringence characteristics in sperm heads allow for the selection of reacted spermatozoa for intracytoplasmic sperm injection”. Fertil. Steril. 93 (3): 807–813. doi:10.1016/j.fertnstert.2008.10.024. PMID 19064263. [4] Miyazaki et al. Archives of Andrology 25:243-251 (1990) [5] Carver-Ward et al. Journal of Assisted Reproduction and Genetics, Vol. 14, no. 2, 1997
40.6 External links • Acrosome reaction at the US National Library of Medicine Medical Subject Headings (MeSH) • Physiology at MCG 5/5ch8/s5ch8_21 • Animation at stanford.edu
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Chapter 41
Capacitation This article is about a biological process related to repro- stimulatory effect with adenosine that increases adenylyl duction. For the conceptual approach to development, cyclase activity in the sperm. FPP is found in the seminal see Capacity building. fluid (FPP produced in prostate gland), and comes into contact with the spermatozoa upon ejaculation. Capacitation is the penultimate[1] step in the maturation of mammalian spermatozoa and is required to render them competent to fertilize an oocyte. This step is a biochemical event; the sperm move normally and look mature prior to capacitation. In vivo this step typically occurs after ejaculation, in the female reproductive tract. In vitro, capacitation can occur by incubating sperms that have either undergone ejaculation or have been extracted from the epididymis in a defined medium for several hours. The uterus aids in the steps of capacitation by secreting sterol-binding albumin, lipoproteins, proteolytic and glycosidasic enzymes such as heparin.
41.2 Discovery The discovery of this process was independently reported in 1951 by both Min Chueh Chang[2] and Colin Russell Austin.[3][4] Historically, the term “capacitation” has evolved in meaning and this should be taken into account when consulting sources.
41.3 See also
Non-mammalian spermatozoa do not require this capacitation step and are ready to fertilize an oocyte immediately after release from the male. After this capacitation the sperm must undergo activation involving the acrosome reaction.
• Cortical reaction • Acrosome reaction
41.4 Footnotes 41.1 Capacitation
[1] Essential Reproduction, Johnson, 6th edition, Blackwell Publishing
Capacitation involves the destabilisation of the acrosomal sperm head membrane allowing greater binding between sperm and oocyte. This change is facilitated by the removal of steroids (e.g. cholesterol) and non-covalently bound epididymal/seminal glycoproteins. The result is a more fluid membrane with an increased permeability to Ca2+ . An influx of Ca2+ produces increased intracellular cAMP levels and thus, an increase in motility. Hyperactivation coincides with the onset of capacitation and is the result of the increased Ca2+ levels. The tripeptide FPP (fertilization promoting peptide) produced by the male is essential for capacitation (high levels of FPP prevent capacitation, the proper concentration occurs after ejaculation in the female reproductive tract where the concentration drops after mixing with vaginal secretions and/or becomes less active due to the pH of the vagina). It has a synergistic
[2] Chang, M. C. (1951) “Fertilizing capacity of spermatozoa deposited into the fallopian tubes,” Nature, vol. 168, pages 697-698. [3] Austin, C. R. (1951) “Observations of the penetration of sperm into the mammalian egg,” Australian Journal of Scientific Research, Series B, vol. 4, pages 581-596. [4] Austin, Colin Russell: obituary: “Colin Austin,” Australian Academy of Science Newsletter, No. 60, page 11 (August–November 2004). Available on-line at: http: //www.science.org.au/newsletters/aas60.pdf .
41.5 References
136
• Beaudin, Stacey; Kipta, Donna; and Orr, Annamarie. (October 9, 1996). Current research into
41.6. EXTERNAL LINKS sperm capacitation: An Essay on Visconti, et al. Development 121: 1129-1150 (1995). Verified availability 2005-04-06. • Visconti, Pablo E.; Bailey, Janice L.; Moore, Grace D.; Pan, Dieyun; Olds-Clarke, Patricia; and Kopf, Gregory S. (1995). Capacitation of mouse spermatozoa: I. Correlation between the capacitation state and protein tyrosine phosphorylation. Development 121, 1129-1137. PMID 7743926. full article text available on-line
41.6 External links • Sperm Capacitation at the US National Library of Medicine Medical Subject Headings (MeSH)
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Chapter 42
Human embryogenesis This article is about Human embryogenesis. For Embryo- form in a process called histogenesis, and the processes genesis in general, see Embryogenesis. of neurulation and organogenesis follow. The embryo is Human embryogenesis is the process of cell division referred to as a fetus in the later stages of prenatal development, usually taken to be at the beginning of the ninth week. In comparison to the embryo, the fetus has more recognizable external features, and a more complete set of developing organs. The entire process of embryogenesis involves coordinated spatial and temporal changes in gene expression, cell growth and cellular differentiation. A nearly identical process occurs in other species, especially among chordates. inner cell mass
polar body pronuclei
blastocoelic cavity trophoblast
inner cell
zona blastomere
Day 1: Fertilisation
tight cell junction
Day 2: Cleavage
Day 3: Compaction
Day 4: Differentiation
Day 5: Cavitation
epiblast
hypoblast
uterine epithelium
trophoblast
bilaminar disc
Day 12: Bilaminar disc formation
Day 9: cell mass differentiation amniotic sac
Day 7: Implantation trophoectoderm
exocoelom
mesoderm
Day 12: Mesoderm formation
42.1 Germinal stage
amnion
ectoderm endoderm
umbilical cord chorion
primitive streak
mesoderm
Day 6: Zona hatching
chorion
yolk sac
42.1.1 Fertilization
embryo digestive tract
Day 18: Mesoderm spreading
Day 23: Amniotic sac enlargment
The initial stages of human embryogenesis.
and cellular differentiation of the embryo that occurs during the early stages of development. In biological terms, human development entails growth from a one celled zygote to an adult human being. Fertilisation occurs when the sperm cell successfully enters and fuses with an egg cell (ovum). The genetic material of the sperm and egg then combine to form a single cell called a zygote and the germinal stage of prenatal development commences.[1] Embryogenesis covers the first eight weeks of development and at the beginning of the ninth week the embryo is termed a fetus. Human embryology is the study of this development during the first eight weeks after fertilisation. The normal period of gestation (pregnancy) is nine months or 38 weeks. The germinal stage, refers to the time from fertilization, through the development of the early embryo until implantation is completed in the uterus. The germinal stage takes around 10 days.[2] During this stage, the zygote, which is defined as an embryo because it contains a full complement of genetic material, begins to divide, in a process called cleavage. A blastocyst is then formed and implanted in the uterus. Embryogenesis continues with the next stage of gastrulation when the three germ layers of the embryo
Fertilization takes place when the spermatozoon has successfully entered the ovum and the two sets of genetic material carried by the gametes, fuse together, resulting in the zygote, (a single diploid cell). This usually takes place in the ampulla of one of the fallopian tubes. Successful fertilisation is enabled by three processes which also act as controls to ensure species-specificity. The first is that of chemotaxis which directs the movement of the sperm towards the ovum. Secondly there is an adhesive compatibility between the sperm and the egg. With the sperm adhered to the ovum, the third process of acrosomal reaction takes place; the front part of the spermatozoon head is capped by an acrosome which contains digestive enzymes to break down the zona pellucida and allow its entry.[3] The entry of the sperm causes calcium to be released which blocks entry to other sperm cells. A parallel reaction takes place in the ovum called the zona reaction. This sees the release of cortical granules that release enzymes which digest sperm receptor proteins, thus preventing polyspermy. The granules also fuse with the plasma membrane and modify the zona pellucida in such a way as to prevent further sperm entry. The zygote contains the combined genetic material carried by both the male and female gametes which consists of the 23 chromosomes from the nucleus of the ovum and the 23 chromosomes from the nucleus of the sperm. The 46 chromosomes undergo changes prior to the mitotic di-
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42.1. GERMINAL STAGE
139
vision which leads to the formation of the embryo having two cells.
42.1.2
Cleavage stage
Further information: Cleavage (embryo) This first division marks the beginning of the cleavage
endometrium inner cell mass (embryoblast) trophoblast blastocyst cavity (blastocoele)
Blastocyst with an inner cell mass and trophoblast.
8-cell embryo, at 3 days
process which continues with the division of the first two cells by mitosis to give four cells which then divide to give eight cells and so on. This is quite a slow process taking from 12 to 24 hours for each division. The dividing cells which are termed blastomeres (blastos Greek for sprout) are still enclosed within the strong membrane of glycoproteins (termed the zona pellucida) of the ovum, which the successful spermatozoon managed to penetrate. The zygote (which is large compared to any other cell) undergoes further cleavage, increasing the number of cells without any increase in the size of the initial zygote. This means that the proportion of nuclear genetic material is greater than that of the cytoplasm in each cell. When eight blastomeres have formed they are undifferentiated and aggregated into a sphere. The cells begin to form gap junctions by this time, enabling them to develop in an integrated way and co-ordinate their response to physiological signals and environmental cues.[4] When the cells number about sixteen or thirty-two the solid sphere of cells is termed a morula.[5] At this stage the cells start to bind firmly together in a process called compaction, and cleavage continues as cellular differentiation begins.
42.1.3
Blastulation
Cleavage itself is the first stage in blastulation, the process of forming the blastocyst. Cells differentiate into an outer layer of cells (collectively called the trophoblast) and an inner cell mass. With further compaction the individual outer blastomeres, the trophoblasts, become indistinguishable, and are still enclosed within the zona pellucida.
This compaction serves to make the structure watertight since the cells will later secrete fluid. The inner mass of cells differentiate to become embryoblasts and polarise at one end. They close together and form gap junctions in order to facilitate cellular communication. This polarisation leaves a cavity, the blastocoel in which is now termed the blastocyst. (In animals other than mammals, this is called the blastula). The trophoblasts secrete fluid into the blastocoel. By this time the size of the blastocyst has increased which makes it 'hatch' through the zona pellucida which then disintegrates.[6][7] The inner cell mass will give rise to the embryo proper, the amnion, yolk sac and allantois, while the fetal part of the placenta will form from the outer trophoblast layer. The embryo plus its membranes is called the conceptus and by this stage the conceptus is in the uterus. The zona pellucida ultimately disappears completely, and the now exposed cells of the trophoblast allow the blastocyst to attach itself to the endometrium, where it will implant. The formation of the hypoblast and epiblast occurs at the beginning of the second week, which are the two main layers of the bilaminar germ disc.[8] Either the inner cells embryoblast or the outer cells trophoblast will turn into two sub layers each other.[9] The inner cells will turn into the hypoblast layer that will surround the other layer called epiblast layer, and these layers will form the embryonic disc in which the embryo will develop.[8][9] The place where the embryo develops is called the amniotic cavity, which is the inside the disc.[8] Also the trophoblast will develop two sub-layers; the cytotrophoblast that is front of the syncytiotrophoblast that is inside of the endometrium.[8] Next, another layer called the exocoelomic membrane or Heuser’s membrane will appear and surround the cytotrophoblast, as well as the primitive yolk sac.[9] The syncytiotrophoblast will grow and will enter a phase called lacunar stage, in which some vacuoles will appear and be filled by blood in the following days.[8][9] The development of the yolk sac starts with the hypoblastic flat cells that form the exocoelomic membrane, which will coat the inner part of
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CHAPTER 42. HUMAN EMBRYOGENESIS
the cytotrophoblast to form the primitive yolk sac. An erosion of the endothelial lining of the maternal capillaries by the syncytiotrophoblastic cells of the sinusoids will form where the blood will begin to penetrate and flow through the trophoblast to give rise to the uteroplacental circulation.[10][11] Subsequently new cells derived from yolk sac will be established between trophoblast and exocelomic membrane and will give rise to extra-embryonic mesoderm, which will form cavities known as chorionic cavity.[9] At the end of the second week of development, some cells of the trophoblast penetrate and form rounded columns into the syncytiotrophoblast. These columns are known as primary villi. At the same time, other migrating cells form into the exocelomic cavity a new cavity named as secondary or definitive yolk, smaller in size than the primitive yolk sac.[9][10]
42.1.4
blastocyst and the myometrium and forms the maternal part of the placenta. The implantation is assisted by hydrolytic enzymes that erode the epithelium. The syncytiotrophoblast also produces human chorionic gonadotropin (hCG), a hormone that stimulates the release of progesterone from the corpus luteum. Progesterone enriches the uterus with a thick lining of blood vessels and capillaries so that it can sustain the developing embryo. The villi begin to branch and contain blood vessels of the embryo. Other villi, called terminal or free villi, have the role of nutrient exchange. The embryo is joined to the trophoblastic shell by a narrow connecting stalk that develops into the umbilical cord to attach the placenta to the embryo.[9][12] Arteries in the decidua are remodelled to increase the maternal blood flow into the intervillous spaces of the placenta, allowing gas exchange to take place as well as the transfer of nutrients to the embryo. Waste products from the embryo will diffuse across the placenta.
Implantation
As the syncytiotrophoblast starts to penetrate the uterine wall, the inner cell mass (embryoblast) also develops. The inner cell mass is the source of embryonic stem cells, Main article: Implantation (human embryo) After ovulation, the endometrial lining becomes trans- which are pluripotent and can develop into any one of the three germ layer cells.
42.1.5 Embryonic disc
Trophoblast differentiation
formed into a secretory lining in preparation of accepting the embryo. It becomes thickened with its secretory glands becoming elongated, and is increasingly vascular. This lining of the uterine cavity (or womb), is now known as the decidua and it produces a great number of large decidual cells in its increased interglandular tissue. The trophoblast then differentiates into an inner layer, the cytotrophoblast and an outer layer, the syncytiotrophoblast. The cytotrophoblast contains cuboidal epithelial cells having cell boundaries and are the source of dividing cells and the syncytiotrophoblast is a layer without cell boundaries.
The embryoblast forms an embryonic disc which is a bilaminar disc of two layers, an upper layer the epiblast (primitive ectoderm), and a lower layer the hypoblast (primitive endoderm). The disc is stretched between what will become the amniotic cavity and the yolk sac. The epiblast is adjacent to the trophoblast and made of columnar cells; the hypoblast is closest to the blastocyst cavity, and made of cuboidal cells. The epiblast migrates away from the trophoblast downwards, forming the amniotic cavity, the lining of which is formed from amnioblasts developed from the epiblast. The hypoblast is pushed down and forms the yolk sac (exocoelomic cavity) lining. Some hypoblast cells migrate along the inner cytotrophoblast lining of the blastocoel, secreting an extracellular matrix along the way. These hypoblast cells and extracellular matrix are called Heuser’s membrane (or exocoelomic membrane), and they cover the blastocoel to form the yolk sac (or exocoelomic cavity). Cells of the epiblast migrate along the outer edges of this reticulum and form the extraembryonic mesoderm, which makes it difficult to maintain the extraembryonic reticulum. Soon pockets form in the reticulum, which ultimately coalesce to form the chorionic cavity or extraembryonic coelom.
The syncytiotrophoblast implants the blastocyst in the decidual epithelium, by projections of chorionic villi forming the embryonic part of the placenta. The placenta 42.2 Gastrulation develops once the blastocyst is implanted, and forms to connect the embryo to the uterine wall. The decidua Main article: Gastrulation The primitive streak, a linear band of cells formed by here is termed the decidua basalis and lies between the
42.3. NEURULATION
Histogenesis of the three germ layers
Artificially colored - gestational sac, yolk sac and embryo (measuring 3 mm at 5 weeks)
141 come mesenchymal stem cells, multipotent stromal cells that can differentiate into various cell types. The hypoblast is pushed out of the way and goes on to form the amnion.The epiblast keeps moving and forms a second layer, the mesoderm. The epiblast has now differentiated into the three germ layers of the embryo, so that the bilaminar disc is now a trilaminar disc, the gastrula. The three germ layers are the ectoderm, mesoderm and endoderm, and are formed as three overlapping flat discs. It is from these three layers that all the structures and organs of the body will be derived through the processes of somitogenesis, histogenesis and organogenesis.[13] The embryonic endoderm is formed by invagination of epiblastic cells that migrate to the hypoblast, while the mesoderm is formed by the cells that develop between the epiblast and endoderm. In general, all germ layers will derive from the epiblast.[9][12] The upper layer of ectoderm will give rise to the outermost layer of skin, central and peripheral nervous systems, eyes, inner ear, and many connective tissues.[14] The middle layer of mesoderm will give rise to the heart and the beginning of the circulatory system as well as the bones, muscles and kidneys. The inner layer of endoderm will serve as the starting point for the development of the lungs, intestine and bladder. Following ingression, a blastopore develops where the cells have ingressed, in one side of the embryo and it deepens to become the archenteron, the first formative stage of the gut. The blastopore becomes the anus whist the gut tunnels through the embryo to the other side where the opening becomes the mouth. With a functioning digestive tube, gastrulation is now completed and the next stage of neurulation can begin.
Embryo attached to placenta in amniotic cavity
the migrating epiblast, appears, and this marks the beginning of gastrulation, which takes place around the sixteenth day (week 3) after fertilisation. The process of gastrulation reorganises the two-layer embryo into a three-layer embryo, and also gives the embryo its specific head-to-tail, and front-to-back orientation, by way of the primitive streak which establishes bilateral symmetry. A primitive node (or primitive knot) forms in front of the primitive streak which is the organiser of neurulation. A primitive pit forms as a depression in the centre of the primitive node which connects to the notochord which lies directly underneath. The node has arisen from epiblasts of the amniotic cavity floor, and it is this node that induces the formation of the neural plate which serves as the basis for the nervous system. The neural plate will form opposite the primitive streak from ectodermal tissue which thickens and flattens into the neural plate. The epiblast in that region moves down into the streak at the location of the primitive pit where the process called ingression, which leads to the formation of the mesoderm takes place. This ingression sees the cells from the epiblast move into the primitive streak in an epithelial-mesenchymal transition; epithelial cells be-
42.3 Neurulation Main article: Neurulation Following gastrulation, the ectoderm gives rise to epithe-
lial and neural tissue, and the gastrula is now referred to as the neurula. The neural plate that has formed as a thickened plate from the ectoderm, continues to broaden and its ends start to fold upwards as neural folds. Neurulation refers to this folding process whereby the neural plate is
142
CHAPTER 42. HUMAN EMBRYOGENESIS
Neural plate border
Neural plate
42.3.1 Development of the nervous system Main article: Neural development Late in the fourth week, the superior part of the neu-
Epidermis Ectoderm
Convergence
Thickens to become:
Neural plate
Neural fold
Neural folds rise and fuse to form:
Neural tube
Foramen magnum
Primary Brain Vesicles
Spinal Cord
Prosencephalon
Mesencephalon
Alar Plate
Secondary Brain Vesicles
Neural groove
Telencephalon
Diencephalon
Mesencephalon
Cerebral cortex basal nuclei
Retina of the eye Thalamus Hypotalamus
Midbrain superior colliculi inferior colliculi
Neural crest is tissue "left out" when neural tube forms
Rhombencephalon
Metencephalon
Myelencephalon
Pons Cerebellum
Medulla
Dorsal (Posterior) Horn [Sensory]
Basal Plate
Migrates to form
Ventral (Anterior) Horn [motor]
- Dorsal (posterior) root ganglia - Enteric plexi - Chromaffin cells of medulla - Melanocytes of skin
Epidermis
Neural crest Neural tube
Neural plate
ral tube flexes at the level of the future midbrain— the mesencephalon. Above the mesencephalon is the prosencephalon (future forebrain) and beneath it is the rhombencephalon (future hindbrain). The optical vesicle (which eventually becomes the optic nerve, retina and iris) forms at the basal plate of the prosencephalon. The alar plate of the prosencephalon expands to form the cerebral hemispheres (the telencephalon) whilst its basal plate becomes the diencephalon. Finally, the optic vesicle grows to form an optic outgrowth.
transformed into the neural tube, and this takes place during the fourth week. They fold, along a shallow neural groove which has formed as a dividing median line in the neural plate. This deepens as the folds continue to gain height when they will meet and close together. The cells that migrate through the most cranial part of the primitive line form the paraxial mesoderm, which will give rise to the somitomeres that in the process of somitogenesis will differentiate into somites that will form the sclerotome, the syndetome,[15] the myotome and the dermatome to form cartilage and bone, tendons, dermis (skin), and Spinal cord at 5 weeks muscle. The intermediate mesoderm gives rise to the urogenital tract and consists of cells that migrate from the middle region of the primitive line. Other cells migrate through the caudal part of the primitive line and form the lateral mesoderm, and those cells migrating by the most caudal part contribute to the extraembryonic mesoderm.[9][12] The embryonic disc begins flat and round, but eventually elongates to have a wider cephalic part and narrowshaped caudal end.[8] At the beginning, the primitive line extends in cephalic direction and 18 days after fertilization returns caudally until it disappears. In the cephalic portion, the germ layer shows specific differentiation at the beginning of the 4th week, while in the caudal portion it occurs at the end of the 4th week.[9] Cranial and caudal neuropores become progressively smaller until they close Head and neck at 32 days completely (by day 26) forming the neural tube.[16]
42.5. CLINICAL SIGNIFICANCE
42.4 Development of the heart and circulatory system
143 terior part of the right atrium, the sinoatrial node and the coronary sinus.[20]
Cardiac looping begins to shape the heart in a process called morphogenesis and this completes by the end of Main article: Heart development The heart is the first functional organ to develop the fourth week. Programmed cell death (apoptosis) is involved in this process, at the joining surfaces enabling fusion to take place.[21] In the middle of the fourth week, the sinus venosus receives blood from the three major veins: the vitelline, the umbilical and the common cardinal veins. During the first two months of development, the interatrial septum begins to form. This septum divides the primitive atrium into a right and a left atrium. Firstly it starts as a crescent-shaped piece of tissue which grows downwards as the septum primum. The crescent shape prevents the complete closure of the atria allowing blood to be shunted from the right to the left atrium through the opening known as the ostium primum. This closes with further development of the system but before it does, a second opening (the ostium secundum) begins to form in the upper atrium enabling the continued shunting of blood.[22] and starts to beat and pump blood at around 21 or 22 days.[17] Cardiac myoblasts and blood islands in the splanchnopleuric mesenchyme on each side of the neural plate, give rise to the cardiogenic region.[9] This is a horseshoe-shaped area near to the head of the embryo. By day 19, following cell signalling, two strands begin to form as tubes in this region, as a lumen develops within them. These two endocardial tubes grow and by day 21 have migrated towards each other and fused to form a single primitive heart tube, the tubular heart. This is enabled by the folding of the embryo which pushes the tubes into the thoracic cavity.[18] Also at the same time that the tubes are forming, vasculogenesis (the development of the circulatory system) has begun. This starts on day 18 with cells in the splanchnopleuric mesoderm differentiating into angioblasts that develop into flattened endothelial cells. These join to form small vesicles called angiocysts which join up to form long vessels called angioblastic cords. These cords develop into a pervasive network of plexuses in the formation of the vascular network. This network grows by the additional budding and sprouting of new vessels in the process of angiogenesis.[19]
A second septum (the septum secundum) begins to form to the right of the septum primum. This also leaves a small opening, the foramen ovale which is continuous with the previous opening of the ostium secundum. The septum primum is reduced to a small flap that acts as the valve of the foramen ovale and this remains until its closure at birth. Between the ventricles the septum inferius also forms which develops into the muscular intraventricular septum.[23]
42.5 Clinical significance Toxic exposures during the germinal stage may cause prenatal death resulting in a miscarriage, but do not cause developmental defects. However, toxic exposures in the embryonic period can be the cause of major congenital malformations, since the precursors of the major organ systems are now developing. Each cell of the preimplantation embryo has the potential to form all of the different cell types in the developing embryo. This cell potency means that some cells can be removed from the preimplantation embryo and the remaining cells will compensate for their absence. This has allowed the development of a technique known as preimplantation genetic diagnosis, whereby a small number of cells from the preimplantation embryo created by IVF, can be removed by biopsy and subjected to genetic diagnosis. This allows embryos that are not affected by defined genetic diseases to be selected and then transferred to the mother’s uterus.
The tubular heart quickly forms five distinct regions. From head to tail, these are the infundibulum, bulbus cordis, primitive ventricle, primitive atrium, and the sinus venosus. Initially, all venous blood flows into the sinus venosus, and is propelled from tail to head to the truncus arteriosus. This will divide to form the aorta and pulmonary artery; the bulbus cordis will develop into the right (primitive) ventricle; the primitive ventricle will form the left ventricle; the primitive atrium will become Sacrococcygeal teratomas, tumours formed from differthe front parts of the left and right atria and their ap- ent types of tissue, that can form, are thought to be pendages, and the sinus venosus will develop into the pos- related to primitive streak remnants, which ordinarily
144 disappear..[8][9][11] Spina bifida a congenital disorder is the result of the incomplete closure of the neural tube.
CHAPTER 42. HUMAN EMBRYOGENESIS
[9] Sadler, T.W.; Langman, Jan (2012) [1st. Pub. 2001]. “Chapter 3: Primera semana del desarrollo: de la ovulación a la implantación”. In Seigafuse, sonya. Langman, Embriología médica. Lippincott Williams & Wilkins, Wolters Kluwer. pp. 29–42. ISBN 978-84-15419-83-9.
Vertically transmitted infections can be passed from the mother to the unborn child at any stage of its [10] Moore, Keith L.; Persaud, V.N. (2003) [1t. Pub. 1996]. development. Hypoxia a condition of inadequate oxygen supply can be a serious consequence of a preterm or premature birth.
42.6 See also • CDX2 • Developmental biology • Embryogenesis • Potential person • Recapitulation theory
42.7 References [1] Sherk, Stephanie Dionne. "http://www.healthline.com/ galecontent/prenatal-development". Gale Encyclopedia of Children’s Health, 2006. Gale. Retrieved 6 October 2013. [2] “germinal stage”. Mosby’s Medical Dictionary, 8th edition. Elsevier. Retrieved 6 October 2013. [3] “acrosome definition - Dictionary - MSN Encarta”. Archived from the original on 2009-10-31. Retrieved 2007-08-15. [4] Brison, D. R.; Sturmey, R. G.; Leese, H. J. (2014). “Metabolic heterogeneity during preimplantation development: the missing link?". Human Reproduction Update 20 (5): 632–640. doi:10.1093/humupd/dmu018. ISSN 1355-4786. [5] Boklage, Charles E. (2009). How New Humans Are Made: Cells and Embryos, Twins and Chimeras, Left and Right, Mind/Self/Soul, Sex, and Schizophrenia. World Scientific. p. 217. ISBN 978-981-283-513-0. [6] http://www.vanat.cvm.umn.edu/TFFLectPDFs/ LectEarlyEmbryo [7] Forgács, G. & Newman, Stuart A. (2005). “Cleavage and blastula formation”. Biological physics of the developing embryo. Cambridge University Press. p. 27. ISBN 9780-521-78337-8. [8] Carlson, Bruce M. (1999) [1t. Pub. 1997]. “Chapter 4: Formation of germ layers and initial derivatives”. Human Embryology & Developmental Biology. Mosby, Inc. pp. 62–68. ISBN 0-8151-1458-3.
“Chapter 3: Formation of the bilaminar embryonic disc: second week”. The Developing Human, Clinically Oriented Embryology. W B Saunders Co. pp. 47–51. ISBN 0-7216-9412-8.
[11] Larsen, William J.; Sherman, Lawrence S.; Potter, S. Steven; Scott, William J. (2001) [1t. Pub. 1998]. “Chapter 2: Bilaminar embryonic disc development and establishment of the uteroplacental circulation”. Human Embryology. Churchill Livingstone. pp. 37–45. ISBN 0443-06583-7. [12] Smith Agreda, Víctor; Ferrés Torres, Elvira; Montesinos Castro-Girona, Manuel (1992). “Chapter 5: Organización del desarrollo: Fase de germinación”. Manual de embriología y anatomía general. Universitat de València. pp. 72–85. ISBN 84-370-1006-3. [13] Ross, Lawrence M. & Lamperti, Edward D., ed. (2006). “Human Ontogeny: Gastrulation, Neurulation, and Somite Formation”. Atlas of anatomy: general anatomy and musculoskeletal system. Thieme. ISBN 978-3-13-142081-7.|url=http://books.google.com/ books?id=NK9TgTaGt6UC&pg=PA6 [14] “Pregnancy week by week”. Retrieved 28 July 2010. [15] Brent AE, Schweitzer R, Tabin CJ (April 2003). “A somitic compartment of tendon progenitors”. Cell 113 (2): 235–48. doi:10.1016/S0092-8674(03)00268-X. PMID 12705871. Retrieved 2014-04-20. [16] Larsen, W J (2001). Human Embryology (3rd ed.). Elsevier. p. 87. ISBN 0-443-06583-7. [17] Betts, J. Gordon (2013). Anatomy & physiology. pp. 787– 846. ISBN 1938168135. [18] Larsen, W J (2001). Human Embryology (3rd ed.). Elsevier. pp. 170–190. ISBN 0-443-06583-7. [19] Larsen, W J (2001). Human Embryology (3rd ed.). Elsevier. pp. 170–190. ISBN 0-443-06583-7. [20] Betts, J. Gordon (2013). Anatomy & physiology. pp. 787– 846. ISBN 1938168135. [21] Larsen, W J (2001). Human Embryology (3rd ed.). Elsevier. pp. 170–190. ISBN 0-443-06583-7. [22] Larsen, W J (2001). Human Embryology (3rd ed.). Elsevier. pp. 170–190. ISBN 0-443-06583-7. [23] Larsen, W J (2001). Human Embryology (3rd ed.). Elsevier. pp. 170–190. ISBN 0-443-06583-7.
42.8. EXTERNAL LINKS
42.8 External links • Photo of blastocyst in utero • Slideshow: In the Womb • Online course in embryology for medicine students developed by the universities of Fribourg, Lausanne and Bern
145
Chapter 43
Cleavage (embryo) In embryology, cleavage is the division of cells in the 43.2 Types of cleavage early embryo. The zygotes of many species undergo rapid cell cycles with no significant growth, producing a cluster 43.2.1 Determinate of cells the same size as the original zygote. The different cells derived from cleavage are called blastomeres and Determinate cleavage (also called mosaic cleavage) is in form a compact mass called the morula. Cleavage ends most protostomes. It results in the developmental fate of with the formation of the blastula. the cells being set early in the embryo development. Each Depending mostly on the amount of yolk in the egg, the blastomere produced by early embryonic cleavage does cleavage can be holoblastic (total or entire cleavage) or not have the capacity to develop into a complete embryo. meroblastic (partial cleavage). The pole of the egg with the highest concentration of yolk is referred to as the vegetal pole while the opposite is referred to as the animal 43.2.2 Indeterminate pole. A cell can only be indeterminate if it has a complete set of Cleavage differs from other forms of cell division in that it undisturbed animal/vegetal cytoarchitectural features. It increases the number of cells without increasing the mass. is characteristic of deuterostomes - when the original cell This means that with each successive subdivision, the ra- in a deuterostome embryo divides, the two resulting cells tio of nuclear to cytoplasmic material increases.[1] can be separated, and each one can individually develop into a whole organism.
43.1 Mechanism
43.2.3 Holoblastic
The rapid cell cycles are facilitated by maintaining high levels of proteins that control cell cycle progression such as the cyclins and their associated cyclin-dependent kinases (cdk). The complex Cyclin B/cdc2 a.k.a. MPF (maturation promoting factor) promotes entry into mitosis. The processes of karyokinesis (mitosis) and cytokinesis work together to result in cleavage. The mitotic apparatus is made up of a central spindle and polar asters made up of polymers of tubulin protein called microtubules. The asters are nucleated by centrosomes and the centrosomes are organized by centrioles brought into the egg by the sperm as basal bodies. Cytokinesis is mediated by the contractile ring made up of polymers of actin protein called microfilaments. Karyokinesis and cytokinesis are independent but spatially and temporally coordinated processes. While mitosis can occur in the absence of cytokinesis, cytokinesis requires the mitotic apparatus.
In the absence of a large concentration of yolk, four major cleavage types can be observed in isolecithal cells (cells with a small even distribution of yolk) or in mesolecithal cells (moderate amount of yolk in a gradient) - bilateral holoblastic, radial holoblastic, rotational holoblastic, and spiral holoblastic, cleavage.[2] These holoblastic cleavage planes pass all the way through isolecithal zygotes during the process of cytokinesis. Coeloblastula is the next stage of development for eggs that undergo these radial cleavaging. In holoblastic eggs the first cleavage always occurs along the vegetal-animal axis of the egg, the second cleavage is perpendicular to the first. From here the spatial arrangement of blastomeres can follow various patterns, due to different planes of cleavage, in various organisms.
The end of cleavage coincides with the beginning of zygotic transcription. This point is referred to as the midblastula transition and appears to be controlled by the nuclear:cytoplasmic ratio (about 1/6). 146
• Bilateral The first cleavage results in bisection of the zygote into left and right halves. The following cleavage planes are centered on this axis and result in the two halves being mirror images of
43.2. TYPES OF CLEAVAGE one another. In bilateral holoblastic cleavage, the divisions of the blastomeres are complete and separate; compared with bilateral meroblastic cleavage, in which the blastomeres stay partially connected. • Radial Radial cleavage is characteristic of the deuterostomes, which include some vertebrates and echinoderms, in which the spindle axes are parallel or at right angles to the polar axis of the oocyte.
147 quartets, meaning that there is alternating symmetry between the odd and even quartets.[3] In other words, the orientation of divisions that produces each quartet alternates between being clockwise and counterclockwise with respect to the animal pole.[7] The alternating cleavage pattern that occurs as the quartets are generated produces quartets of micromeres that reside in the cleavage furrows of the four macromeres.[5] When viewed from the animal pole, this arrangement of cells displays a spiral pattern.
• Rotational Mammals display rotational cleavage, and an isolecithal distribution of yolk (sparsely and evenly distributed). Because the cells have only a small amount of yolk, they require immediate implantation onto the uterine wall in order to receive nutrients. Rotational cleavage involves a normal first division along the meridional axis, giving rise to two daughter cells. The way in which this cleavage differs is that one of the daughter cells divides meridionally, whilst the other divides equatorially. • Spiral Spiral cleavage is conserved between many members of the lophotrochozoan taxa, referred to as Spiralia.[3] Most spiralians undergo equal spiral cleavage, although some undergo unequal cleavage (see below).[4] This group includes annelids, molluscs, and sipuncula. Spiral cleavage can vary between species, but generally the first two cell divisions result in four macromeres, also called blastomeres, (A, B, C, D) each representing one quadrant of the embryo. These first two cleavages are oriented in planes that occur at right angles parallel to the animal-vegetal axis of the zygote.[3] At the 4-cell stage, the A and C macromeres meet at the animal pole, creating the animal crossfurrow, while the B and D macromeres meet at the vegetal pole, creating the vegetal crossfurrow.[5] With each successive cleavage cycle, the macromeres give rise to quartets of smaller micromeres at the animal pole.[6][7] The divisions that produce these quartets occur at an oblique angle, an angle that is not a multiple of 90o, to the animal-vegetal axis.[7] Each quartet of micromeres is rotated relative to their parent macromere, and the chirality of this rotation differs between odd and even numbered
D quadrant specification through equal and unequal cleavage mechanisms. At the 4-cell stage of equal cleavage, the D macromere has not been specified yet. It will be specified after the formation of the third quartet of micromeres. Unequal cleavage occurs in two ways: asymmetric positioning of the mitotic spindle, or through the formation of a polar lobe (PL).
Specification of the D macromere and is an important aspect of spiralian development. Although the primary axis, animal-vegetal, is determined during oogenesis, the secondary axis, dorsal-ventral, is determined by the specification of the D quadrant.[7] The D macromere facilitates cell divisions that differ from those produced by the other three macromeres. Cells of the D quadrant give rise to dorsal and posterior structures of the spiralian.[7] Two known mechanisms exist to specify the D quadrant. These mechanisms include equal cleavage and unequal cleavage. In equal cleavage, the first two cell divisions produce four macromeres that are indistinguishable from one another. Each macromere has the potential of becoming the D macromere.[6] After the formation of the third quartet, one of the macromeres initiates maximum contact with the overlying micromeres in the animal pole of the embryo.[6][7] This contact is required to distinguish one macromere as the official D quadrant blastomere. In equally cleaving spiral embryos, the
148
CHAPTER 43. CLEAVAGE (EMBRYO) D quadrant is not specified until after the formation of the third quartet, when contact with the micromeres dictates one cell to become the future D blastomere. Once specified, the D blastomere signals to surrounding micromeres to lay out their cell fates.[7] In unequal cleavage, the first two cell divisions are unequal producing four cells in which one cell is bigger than the other three. This larger cell is specified as the D macromere.[6][7] Unlike equally cleaving spiralians, the D macromere is specified at the four-cell stage during unequal cleavage. Unequal cleavage can occur in two ways. One method involves asymmetric positioning of the cleavage spindle.[7] This occurs when the aster at one pole attaches to the cell membrane, causing it to be much smaller than the aster at the other pole.[6] This results in an unequal cytokinesis, in which both macromeres inherit part of the animal region of the egg, but only the bigger macromere inherits the vegetal region.[6] The second mechanism of unequal cleavage involves the production of an enucleate, membrane bound, cytoplasmic protrusion, called a polar lobe.[6] This polar lobe forms at the vegetal pole during cleavage, and then gets shunted to the D blastomere.[5][6] The polar lobe contains vegetal cytoplasm, which becomes inherited by the future D macromere.[7]
• Superficial In superficial cleavage, mitosis occurs but not cytokinesis, resulting in a polynuclear cell. With the yolk positioned in the center of the egg cell, the nuclei migrate to the periphery of the egg, and the plasma membrane grows inward, partitioning the nuclei into individual cells. Superficial cleavage occurs in arthropods that have centrolecithal egg cells (egg cells with the yolk located in the center of the cell).
43.3 Mammals inner cell mass
polar body pronuclei
blastocoelic cavity trophoblast
inner cell zona blastomere
Day 1: Fertilisation
tight cell junction
Day 2: Cleavage
Day 3: Compaction
Day 4: Differentiation
Day 5: Cavitation
epiblast hypoblast
uterine epithelium
trophoblast
bilaminar disc
Day 12: Bilaminar disc formation
Day 9: cell mass differentiation amniotic sac
Day 7: Implantation trophoectoderm
exocoelom
mesoderm ectoderm endoderm
Day 12: Mesoderm formation
umbilical cord chorion amnion
primitive streak
mesoderm
Day 6: Zona hatching
chorion
yolk sac
embryo digestive tract
Day 18: Mesoderm spreading
Day 23: Amniotic sac enlargment
The initial stages of human embryogenesis.
Spiral cleavage in marine snail of the genus Trochus.
Differences exist between the cleavage in placental mammals and the cleavage in other animals. Mammals have a slow rate of division that is between 12 and 24 hours. These cellular divisions are asynchronous. Zygotic transcription starts at the two-, four-, or eight-cell stage. Cleavage is holoblastic and rotational.
At the eight-cell stage, the embryo goes through some changes. Most of the blastomeres in this stage become polarized and develop tight junctions with the other blasIn the presence of a large amount of yolk in the fertil- tomeres. This process leads to the development of two ized egg cell, the cell can undergo partial, or meroblastic, different populations of cells: Polar cells on the outcleavage. Two major types of meroblastic cleavage are side and apolar cells on the inside. The outer cells, discoidal and superficial.[8] called the trophoblast cells, pump sodium in from the outside, which automatically brings water in with it to • Discoidal the basal (inner) surface to form a blastocoel cavity in a process called compaction. The embryo is now called a In discoidal cleavage, the cleavage furrows do blastocyst. The trophoblast cells will eventually give rise not penetrate the yolk. The embryo forms a to the embryonic contribution to the placenta called the disc of cells, called a blastodisc, on top of the chorion. The inner cells are pushed to one side of the cavyolk. Discoidal cleavage is commonly found in ity (because the embryo isn't getting any bigger) to form monotremes, birds, reptiles, and fish that have the inner cell mass (ICM) and will give rise to the embryo telolecithal egg cells (egg cells with the yolk and some extraembryonic membranes. At this stage, the concentrated at one end). embryo is called a blastocyst.
43.2.4
Meroblastic
43.7. EXTERNAL LINKS
43.4 See also • Embryogenesis • Blastocyst
43.5 References [1] Forgács, G. & Newman, Stuart A. (2005). “Cleavage and blastula formation”. Biological physics of the developing embryo. Cambridge University Press. p. 27. ISBN 9780-521-78337-8. [2] “Early Development of the Nematode Caenorhabditis elegans”. Retrieved 2007-09-17. [3] Shankland, M.; Seaver, E. C. (2000). “Evolution of the bilaterian body plan: What have we learned from annelids?". Proceedings of the National Academy of Sciences 97 (9): 4434–7. Bibcode:2000PNAS...97.4434S. doi:10.1073/pnas.97.9.4434. JSTOR 122407. PMC 34316. PMID 10781038. [4] Henry, J. (2002). “Conserved Mechanism of Dorsoventral Axis Determination in Equal-Cleaving Spiralians”. Developmental Biology 248 (2): 343–355. doi:10.1006/dbio.2002.0741. PMID 12167409. [5] Boyer, Barbara C.; Jonathan, Q. Henry (1998). “Evolutionary Modifications of the Spiralian Developmental Program”. Integrative and Comparative Biology 38 (4): 621–33. doi:10.1093/icb/38.4.621. JSTOR 4620189. [6] Freeman, Gary; Lundelius, Judith W. (1992). “Evolutionary implications of the mode of D quadrant specification in coelomates with spiral cleavage”. Journal of Evolutionary Biology 5 (2): 205–47. doi:10.1046/j.14209101.1992.5020205.x. [7] Lambert, J.David; Nagy, Lisa M (2003). “The MAPK cascade in equally cleaving spiralian embryos”. Developmental Biology 263 (2): 231–41. doi:10.1016/j.ydbio.2003.07.006. PMID 14597198. [8] “Current Notes”. Retrieved 2007-09-17. [9] Gilbert SF (2003). Developmental biology (7th ed.). Sinauer. p. 214. ISBN 0-87893-258-5. [10] Kardong, Kenneth V. (2006). Vertebrates: Comparative Anatomy, Function, Evolution (4th ed.). McGraw-Hill. pp. 158–64.
43.6 Bibliography • Wilt, F. & Hake, S. (2004). Principles of Developmental Biology. • Scott F. Gilbert (2003). Developmental Biology.
149
43.7 External links • Valentine, James W. (1997). “Cleavage Patterns and the Topology of the Metazoan Tree of Life”. Proceedings of the National Academy of Sciences of the United States of America 94 (15): 8001–5. Bibcode:1997PNAS...94.8001V. doi:10.1073/pnas.94.15.8001. PMC 21545. PMID 9223303. • 'What are the 'advantages’ of developing a deuterostome pattern of embryonic' on MadSci Network • Lee, Seung-Cheol; Mietchen, Daniel; Cho, JeeHyun; Kim, Young-Sook; Kim, Cheolsu; Hong, Kwan Soo; Lee, Chulhyun; Kang, Dongmin; Lee, Wontae; Cheong, Chaejoon (200 7). “In vivo magnetic resonance microscopy of differentiation in Xenopus laevis embryos from the first cleavage onwards”. Differentiation 75. doi:10.1111/j.14320436.2006.00114.x. Check date values in: |date= (help)
Chapter 44
Polarity in embryogenesis is thought to differentiate into the extraembryonic membranes that protect and nourish the developing embryo, such as the placenta in mammals and the chorion in birds. In the frog Xenopus laevis, a pigment pattern provides the oocyte with features of a radially symmetrical body with a distinct polarity. The animal hemisphere is dark brown, and the vegetal hemisphere is only weakly pigmented. The axis of symmetry passes through on one side the animal pole, and on the other side the vegetal pole. The two hemispheres are separated by an unpigmented equatorial belt. Polarity has a major influence on the mergence of the embryonic structures. In fact, the axis polarity serves as one coordinate of geometrical system in which early embryogenesis is organised.[2]
44.1 References [1] Text-book of Embryology, Volume 1 [2] P. Hausen, M. Riebesell: The Early Embryonic Development of Xenopus Laevis - An Atlas of the Histology ISBN 3-921ö15-ö4-9
44.2 See also • gastrulation
An oocyte with poles depicted
• embryogenesis In developmental biology, an embryo is divided into two hemispheres: the animal pole and the vegetal pole within a blastula. The animal pole consists of small cells that divide rapidly, in contrast with the vegetal pole below it. The animal pole draws its name from its liveliness relative to the slowly developing vegetal pole. In some cases, the animal pole is thought to differentiate into the later embryo itself, forming the three primary germ layers and participating in gastrulation. Sperm enters the egg at the animal pole.[1] The vegetal pole contains large yolky cells that divide very slowly, in contrast with the animal pole above it. The vegetal pole draws its name from its inactivity relative to the lively animal pole. In some cases, the vegetal pole 150
Chapter 45
Morula For the South African football player, see Lebohang Morula.
[3] Sherman, Lawrence S. et al., ed. (2001). Human embryology (3rd ed.). Elsevier Health Sciences. p. 20. ISBN 978-0-443-06583-5.
A morula (Latin, morum: mulberry) is an early stage embryo consisting of cells (called blastomeres) in a solid ball contained within the zona pellucida.[1][2]
[4] Chard, Tim & Lilford, Richard (1995). Basic sciences for obstetrics and gynaecology. Springer. p. 18. ISBN 9783-540-19903-8.
The morula is produced by a series of cleavage divisions of the early embryo, starting with the single-celled zygote. Once the embryo has divided into 16 cells, it begins to resemble a mulberry, hence the name morula (Latin, morus: mulberry).[3] Within a few days after fertilization, cells on the outer part of the morula become bound tightly together with the formation of desmosomes and gap junctions, becoming nearly indistinguishable. This process is known as compaction.[4][5] A cavity forms inside the morula, by the active transport of sodium ions from trophoblast cells and osmosis of water. This results in a hollow ball of cells known as the blastocyst.[6][7] The blastocyst’s outer cells will become the first embryonic epithelium (the trophectoderm). Some cells, however, will remain trapped in the interior and will become the inner cell mass (ICM), and are pluripotent. In mammals (except monotremes), the ICM will ultimately form the “embryo proper”, while the trophectoderm will form the placenta and extra-embryonic tissues. However, reptiles have a different ICM. The stages are prolonged and divided in 4 parts.[8][9][10][11]
[5] Mercader, Amparo et al. (2008). “Human embryo culture”. In Lanza, Robert & Klimanskaya, Irina. Essential stem cell methods. Academic Press. p. 343. ISBN 978-012-374741-9. [6] Patestas, Maria Antoniou & Gartner, Leslie P. (2006). A textbook of neuroanatomy. Wiley-Blackwell. p. 11. ISBN 978-1-4051-0340-4. [7] Geisert, R.D. & Malayer, J.R. (2000). “Implantation: Blastocyst formation”. In Hafez, B. & Hafez, Elsayed S.E. Reproduction in farm animals. Wiley-Blackwell. p. 118. ISBN 978-0-683-30577-7. [8] Morali, Olivier G. et al. (2005). “EpitheliumMesenchyme Transitions are Crucial Morphogenetic Events Occurring During Early Development”. In Savagner, Pierre. Rise and fall of epithelial phenotype: concepts of epithelial-mesenchymal transition. Springer. p. 16. ISBN 978-0-306-48239-7. [9] Birchmeier, Carmen et al. (1997). “Morphogenesis of epithelial cells”. In Paul, Leendert C. & Issekutz, Thomas B. Adhesion molecules in health and disease. CRC Press. p. 208. ISBN 978-0-8247-9824-6. [10] Nagy, András (2003). Manipulating the mouse embryo: a laboratory manual. CSHL Press. pp. 60–61. ISBN 978-0-87969-591-0.
45.1 See also • Cleavage (embryo)
[11] Connell, R.J. & Cutner, A. (2001). “Basic Embryology”. In Cardozo, Linda & Staskin, David. Textbook of female urology and urogynaecology. Taylor & Francis. p. 92. ISBN 978-1-901865-05-9.
• Blastula
45.2 References [1] Boklage, Charles E. (2009). How New Humans Are Made: Cells and Embryos, Twins and Chimeras, Left and Right, Mind/Self/Soul, Sex, and Schizophrenia. World Scientific. p. 217. ISBN 9789812835130.
45.3 Further reading
[2] “The Early Embryology of the Chick”. UNSW Embryology. Retrieved 2015-03-03.
151
• “Regulative development in mammals”
Chapter 46
Blastomere In biology, a blastomere is a type of cell produced by cleavage (cell division) of the zygote after fertilization and is an essential part of blastula formation.[1]
46.1 See also • Blastocoel • Blastocyst • Oocyte
46.2 References [1] Blastomere Encyclopædia Britannica. Encyclopædia Britannica Online. Encyclopædia Britannica Inc., 2012. Web. 06 Feb. 2012.
• “Blastomere.” Stedman’s Medical Dictionary, 27th ed. (2000). ISBN 0-683-40007-X • Moore, Keith L. and T.V.N. Persaud. The Developing Human: Clinically Oriented Embryology, 7th ed. (2003). ISBN 0-7216-9412-8
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Chapter 47
Yolk Not to be confused with yoke. of the germinal disc. The yolk is a part of an egg (or just of the egg cell in non- As a food, chicken egg yolks are a major source of vitamins and minerals. They contain all of the egg’s fat and cholesterol, and about one-half of the protein. If left intact while cooking fried eggs, the yellow yolk surrounded by a flat blob of whites creates a distinctive sunny-side up form. Mixing the two components together before frying results in a pale yellow mass, as in omelettes and scrambled eggs.
47.1.1 Uses • It is at times separated from the egg white and used in cooking (for mayonnaise, custard, hollandaise sauce, crème brûlée, avgolemono, and ovos moles). The yolk of a chicken egg
• It is used in painting as a component of traditional egg-tempera.
egg-laying animals) that feeds the developing embryo in animals. In whole eggs, 43% of the protein comes from the yolk.
• It is used in the production of egg-yolk agar plate medium, useful in testing for the presence of Clostridium perfringens.
Also known as deutoplasm, this food material is accumulated during oogenesis, together with RNA molecules and other substances. These may be synthesized by the oocyte itself or by the cytoplasm of other non-germ cells.[1] The amount of yolk in an egg cell affects the developmental processes that follow fertilization.
• Egg yolk contains an antibody called antiglobulin (IgY). The antibody transfers from the laying hen to the egg yolk by passive immunity to protect both embryo and hatchling from microorganism invasion.
Apart from animals, other organisms, like algae, specially in the oogamous, can also accumulate resources in their female gametes. In gymnosperms, the remains of the female gametophyte serve also as food supply, and in flowering plants, the endosperm.
• Egg yolk can be used to make liqueurs such as Advocaat or eggnog. • Egg yolk is used to extract egg oil which has various cosmetic, nutritional and medicinal uses. • The developing embryo inside the egg uses the yolk as sustenance.
47.1 Chicken egg yolk In the avian egg, the yolk usually is some shade of yellow in colour. It is spherical and is suspended in the egg white (known alternatively as albumen or glair/glaire) by one or two spiral bands of tissue called the chalazae. Prior to fertilization, the yolk is a single cell, the ovum or egg cell, one of the few single cells that can be seen by the naked eye.[2] This fact was discovered by Hoyer in 1858.[3]
47.1.2 Composition of chicken egg yolk The yolk makes up about 33% of the liquid weight of the egg; it contains approximately 60 calories, three times the caloric content of the egg white.
The yolk of one large egg (50 g total, 17 g yolk) contains approximately: 2.7 g protein, 210 mg cholesterol, 0.61 g After the fertilization, the cleavage leads to the formation carbohydrates, and 4.51 g total fat.[4] 153
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All of the fat-soluble vitamins (A, D, E, and K) are found 47.1.5 Double-yolk eggs in the egg yolk. Egg yolk is one of the few foods naturally containing vitamin D. Double-yolk eggs occur when ovulation occurs too The composition (by weight) of the most prevalent fatty rapidly, or when one yolk becomes joined with another yolk. These eggs may be the result of a young hen’s reacids in egg yolk is typically as follows:[5] productive cycle not yet being synchronized.[12] • Unsaturated fatty acids: • Oleic acid, 47% • Linoleic acid, 16% • Palmitoleic acid, 5% • Linolenic acid, 2% • Saturated fatty acids: • Palmitic acid, 23% • Stearic acid, 4% • Myristic acid, 1%
Double-yolked eggs seldom lead to successful hatchlings without human intervention, as the chicks interfere with each other’s hatching process and do not survive.[13] Higher-order yolks are rare, although heavier poultry breeds such as the Buff Orpington have been known to lay triple-yolk eggs occasionally. • Comparison of an egg and a maxi egg with a double-yolk (closed) • Comparison of an egg and a maxi egg with a double-yolk (opened) • Double-yolk egg - Opened
Egg yolk is a source of lecithin as well as egg oil for cos- 47.1.6 Yolkless eggs metic and pharmaceutical applications. Based on weight, Main article: Cock egg egg yolk contains about 9% lecithin.[6] The yellow color is due to lutein and zeaxanthin, which without yolks are known as “dwarf” or “wind” are yellow or orange carotenoids known as xanthophylls. Eggs [14] eggs, or the archaic term “cock egg”.[15] Such an egg is most often a pullet’s first effort, produced before her laying mechanism is fully ready. Mature hens rarely lay a 47.1.3 Yolk proteins yolkless egg, but it sometimes happens that a piece of reproductive tissue breaks away and passes down the tube. The different yolk’s protein has distinct roles. Phosvitins Such a scrap of tissue may stimulate the egg-producing are important in sequestering calcium, iron and other glands to react as though it were a yolk and wrap it in alcations for the developing embryo. Phosvitins are one bumen, membranes and a shell as it travels through the of the most phosphorylated (10%) proteins in nature, the egg tube. This is usually what causes an egg to contain a high concentration of phosphate groups providing effi- small particle of grayish tissue instead of a yolk. cient metal-binding sites in clusters.[7][8] Lipovitellins are involved in lipid and metal storage, and contain a het- Since these eggs contain no yolk and therefore can not were traditionally believed to have been laid erogeneous mixture of about 16% (w/w) noncovalently hatch, they [16] by roosters. This type of egg occurs in many varieties bound lipid, most being phospholipid. Lipovitellin-1 conof fowl and has been found in chickens, both standard and [9][10] tains two chains, LV1N and LV1C. bantams, guineas and coturnix quail.
47.1.4
Yolk vitamins and minerals
Yolks hold more than 90% of the calcium, iron, phosphorus, zinc, thiamine, B6, folate, and B12, and pantothenic acid of the egg. In addition, yolks cover all of the fat soluble vitamins A, D, E, and K in the egg, as well as all of the essential fatty acids (EFAs). A single yolk from a large egg contains approximately 22 mg of calcium, 66 mg of phosphorus, 9.5 micrograms of selenium and 19 mg of potassium, according to the USDA. Refer to the chart at right for quantities of nutrients per 100 g of egg yolk. [11]
47.1.7 Yolk color The color of an egg yolk is directly influenced by the makeup of the chicken feed.[17] Egg yolk color is generally improved with a feed containing a large component of yellow, fat-soluble pigments, such as the carotenes in dark green plant material, for example alfalfa. Although much emphasis is put onto the color of the egg yolk, it does not reliably reflect the nutritional value of an egg. For example, some of the natural pigments that produce a rich yolk color are xanthophylls without much nutritional value, rather than the carotenoids that act as provitamin A
47.3. REFERENCES
155
[4] U.S. Department of Agriculture, Agricultural Research Service, 2010. USDA National Nutrient Database for Standard Reference, Release 23, Nutrient Data Laboratory Home Page: http://www.ars.usda.gov/nutrientdata [5] National Research Council, 1976, Fat Content and Composition of Animal Products, Printing and Publishing Office, National Academy of Science, Washington, D.C., ISBN 0-309-02440-4; p. 203, online edition [6] Chris Clarke (2004). The science of ice cream. Cambridge, Eng: Royal Society of Chemistry. p. 49. ISBN 0-85404-629-1. Retrieved 2013-03-20. Egg yolk has the approximate composition (by weight) of 50% water, 16% protein, 9% lecithin, 23% other fat, 0.3% carbohydrate and 1.7% minerals. A chicken egg frying with an extremely thick red yolk
in the body. Also, a diet rich in vitamin A itself, but without A-provitamins or xanthophylls, can produce practically colourless yolks that are just as nutritious as any richly colored yolks. Since unhealthy chickens produce fewer and smaller eggs, farmers ensure that whatever the source of their feed, the quality is adequate, so there is not likely to be much difference in the nutritional quality of the eggs.[18]
[7] Matsubara T, Sawaguchi S, Ohkubo N (2006). “Identification of two forms of vitellogenin-derived phosvitin and elucidation of their fate and roles during oocyte maturation in the barfin flounder, Verasper moseri”. Zool. Sci. 23 (11): 1021–9. doi:10.2108/zsj.23.1021. PMID 17189915. [8] Goulas A, Triplett EL, Taborsky G (1996). “Oligophosphopeptides of varied structural complexity derived from the egg phosphoprotein, phosvitin”. J. Protein Chem. 15 (1): 1–9. doi:10.1007/BF01886805. PMID 8838584. [9] Banaszak LJ, Thompson JR (2002). “Lipid-protein inter-
Yolks, particularly from free-range eggs, can be of a wide actions in lipovitellin”. Biochemistry 41 (30): 9398–9409. range of colors, ranging from nearly white, through yeldoi:10.1021/bi025674w. PMID 12135361. low and orange to practically red, but even olive green, depending on the pigments in their food. Feeding fowls [10] Banaszak LJ, Anderson TA, Levitt DG (1998). “The structural basis of lipid interactions in lipovitellin, large amounts of capsicum peppers for example, tends a soluble lipoprotein”. Structure 6 (7): 895–909. to result in red or deep orange yolks. This has nothdoi:10.1016/S0969-2126(98)00091-4. PMID 9687371. ing to do with adding colors such as cochineal to eggs [19] in cooking. [11] U.S. Department of Agriculture, Agricultural Research
47.2 In fish
Service, 2010. USDA National Nutrient Database for Standard Reference, Release 23, Nutrient Data Laboratory Home Page: http://www.ars.usda.gov/nutrientdata [12] “Odd Eggs, Double Yolks, No Yolks, etc.”. poultry-
help.com. 2005-03-04. Retrieved 2008-10-25. All bony fish, some sharks and rays have yolk sacs at some stage of development, with all oviparous fishes re- [13] Kruszelnicki, Karl S. (2003). “Double-yolked eggs and taining the sac after hatching. Lamniform sharks are chicken development”. Australian Broadcasting Corporaovoviviparous, in that their eggs hatch in utero, in addition. Retrieved 2007-12-09. tion to eating unfertilized eggs, unborn sharks participate in intrauterine-cannibalism: stronger pups consume their [14] “Dwarf Eggs and the Timing of Ovulation in the Domestic Fowl”. Nature Publishing Group. 1996-06-25. Retrieved weaker womb-mates.[20][21][22] 2008-10-25.
[15] “Cock’s egg”. Retrieved 2010-09-02.
47.3 References [1] Barnes, Richard Stephen Kent (2001). The Invertebrates: A Synthesis. Wiley-Blackwell, p. 347. ISBN 978-0-63204761-1. [2] Patten, B. M. (1951). Early Embryology of the Chick, 4th edition. McGraw-Hill, New York, p. 17. [3] Callebaut, M. Historical evolution of preformistic versus neoformistic (epigenetic) thinking in embryology.
[16] http://www.oedilf.com/db/Lim.php?Word=cock%27s% 20egg [17] Poultry Science by richard page 216 [18] Donald D. Bell; William Daniel Weaver (January 2002). Commercial Chicken Meat and Egg Production. Springer. ISBN 978-0-7923-7200-4. Retrieved 1 September 2013. [19] Mathew Attokaran, PhD (13 January 2011). Natural Food Flavors and Colorants. John Wiley & Sons. pp. 1–. ISBN 978-0-470-95911-4. Retrieved 1 September 2013.
156
[20] Meisner, A & Burns, J: Viviparity in the Halfbeak Genera Dermogenys and Nomorhamphus (Teleostei: Hemiramphidae). Journal of Morphology 234, pp. 295–317, 1997 [21] Peter Scott: Livebearing Fishes, p. 13. Tetra Press 1997. ISBN 1-56465-193-2 [22] Leonard J. V. Compagno (1984). Sharks of the World: An annotated and illustrated catalogue of shark species known to date. Food and Agriculture Organization of the United Nations. ISBN 92-5-104543-7. OCLC 156157504.
47.4 External links • Anatomy of an Egg from the Exploratorium • Making egg tempera from the Society of Tempera Painters
CHAPTER 47. YOLK
Chapter 48
Blastula as well as the continued improvement of fertility treatments.[5] Embryonic stem cells are a field which, though controversial, have tremendous potential for treating disease. In Xenopus, blastomeres behave as pluripotent stem cells which can migrate down several pathways, depending on cell signaling.[8] By manipulating the cell signals during the blastula stage of development, various tissues can be formed. This potential can be instrumental in regenerative medicine for disease and injury cases. In vitro fertilisation involves implantation of a blastula into a mother’s uterus.[9] Blastula cell implantation could potentially serve to eliminate infertility.
Blastocoel and blastoderm
The blastula (from Greek βλαστός (blastos), meaning “sprout”) is a hollow sphere of cells, referred to as blastomeres, surrounding an inner fluid-filled cavity called the blastocoele formed during an early stage of embryonic development in animals.[1] Embryo development begins with a sperm fertilizing an egg to become a zygote which undergoes many cleavages to develop into a ball of cells called a morula. Only when the blastocoele is formed does the early embryo become a blastula. The blastula precedes the formation of the gastrula in which the germ layers of the embryo form.[2]
48.1 Development The blastula stage of early embryo development begins with the appearance of the blastocoele. The origin of the blastocoele in Xenopus has been shown to be from the first cleavage furrow, which is widened and sealed with tight junctions to create a cavity.[10]
In many organisms the development of the embryo up to this point and for the early part of the blastula stage is A common feature of a vertebrate blastula is that it concontrolled by maternal mRNA, so called because it was sists of a layer of blastomeres, known as the blastoderm, produced in the egg prior to fertilization and is therefore which surrounds the blastocoele.[3][4] In mammals the exclusively from the mother.[11][12] blastula is referred to as a blastocyst. The blastocyst contains an embryoblast (or inner cell mass) that will eventually give rise to the definitive structures of the fetus, and the trophoblast, which goes on to form the extra- 48.1.1 Mid-blastula transition embryonic tissues.[2][5] In many organisms including Xenopus and Drosophila, During the blastula stage of development, a significant the mid-blastula transition usually occurs after a particuamount of activity occurs within the early embryo to es- lar number of cell divisions for a given species, and is detablish cell polarity, cell specification, axis formation, fined by the ending of the synchronous cell division cycles and regulate gene expression.[6] In many species such of the early blastula development, and the lengthening of as Drosophila and Xenopus, the mid blastula transition the cell cycles by the addition of the G1 and G2 phases. (MBT) is a crucial step in development during which the Prior to this transition, cleavage occurs with only the synmaternal mRNA is degraded and control over develop- thesis and mitosis phases of the cell cycle.[12] The addiment is passed to the embryo.[7] Many of the interac- tion of the two growth phases into the cell cycle allows for tions between blastomeres are dependent on cadherin ex- the cells to increase in size, as up to this point the blaspression, particularly E-cadherin in mammals and EP- tomeres undergo reductive divisions in which the overall cadherin in amphibians.[6] size of the embryo does not increase, but more cells are The study of the blastula and of cell specification has created. This transition begins the growth in size of the many implications on the field of stem cell research organism.[2] 157
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The mid-blastula transition is also characterised by a marked increase in transcription of new, non-maternal mRNA transcribed from the genome of the organism. Large amounts of the maternal mRNA are destroyed at this point, either by proteins such as SMAUG in Drosophila[13] or by microRNA.[14] These two processes shift the control of the embryo from the maternal mRNA to the nuclei.
48.2 Structure
bryonic cells which are capable of interacting, rather than a group of diffuse and undifferentiated cells. E-cadherin adhesion defines the apico-basal axis in the developing embryo and turns the embryo from an indistinct ball of cells to a more polarized phenotype which sets the stage for further development into a fully formed blastocyst.[15] Xenopus membrane polarity is established with the first cell cleavage. Amphibian EP-cadherin and XB/U cadherin perform a similar role as E-cadherin in mammals establishing blastomere polarity and solidifying cell-cell interactions which are crucial for further development.[15]
A blastula is a sphere of cells surrounding a blastocoele. The blastocoele is a fluid filled cavity which contains 48.3 Clinical implications amino acids, proteins, growth factors, sugars, ions and other components which are necessary for cellular dif- 48.3.1 Fertilization technologies ferentiation. The blastocoele also allows blastomeres to move during the process of gastrulation.[15] Experiments with implantation in mice show that In Xenopus embryos, the blastula is composed of three hormonal induction, superovulation and artificial insemidifferent regions. The animal cap forms the roof of the nation successfully produce preimplantion mice embryos. blastocoele and goes on primarily to form ectodermal In the mice, ninety percent of the females were induced derivatives. The equatorial or marginal zone, which com- by mechanical stimulation to undergo pregnancy and im[16] pose the walls of the blastocoel differentiate primar- plant at least one embryo. These results prove to be enily into mesodermal tissue. The vegetal mass is com- couraging because they provide a basis for potential imposed of the blastocoel floor and primarily develops into plantation in other mammalian species, such as humans. endodermal tissue.[6] In the mammalian blastocyst (term for mammalian blastula) there are three lineages that give rise to later tissue development. The epiblast gives rise to the fetus itself while the trophoblast develops into part of the placenta and the primitive endoderm becomes the yolk sac.[5] In mouse embryo, blastocoele formation begins at the 32-cell stage. During this process, water enters the embryo, aided by an osmotic gradient which is the result of Na+ /K+ ATPases that produce a high Na+ gradient on the basolateral side of the trophectoderm. This movement of water is facilitated by aquaporins. A seal is created by tight junctions of the epithelial cells that line the blastocoele.[5]
48.2.1
48.3.2 Stem cells Blastula-stage cells can behave as pluripotent stem cells in many species. Pluripotent stem cells are the starting point to produce organ specific cells that can potentially aid in repair and prevention of injury and degeneration. Combining the expression of transcription factors and locational positioning of the blastula cells can lead to the development of induced functional organs and tissues. Pluripotent Xenopus cells, when used in an in vivo strategy, were able to form into functional retinas. By transplanting them to the eye field on the neural plate, and by inducing several mis-expressions of transcription factors, the cells were committed to the retinal lineage and could guide vision based behavior in the Xenopus.[17]
Cellular adhesion
Tight junctions are very important in embryo development. In the blastula, these cadherin mediated cell interactions are essential to development of epithelium which are most important to paracellular transport, maintenance of cell polarity and the creation of a permeability seal to regulate blastocoel formation. These tight junctions arise after the polarity of epithelial cells is established which sets the foundation for further development and specification. Within the blastula, inner blastomeres are generally non-polar while epithelial cells demonstrate polarity.[15]
48.4 See also
Mammalian embryos undergo compaction around the 8cell stage where E-cadherins as well as alpha and beta catenins are expressed. This process makes a ball of em-
48.5 Notes and references
• Blastocyst • Cellular differentiation • Gastrulation • Polarity in embryogenesis
[1] “Blastula”. Encyclopedia Britannica. 2013.
48.6. BIBLIOGRAPHY
[2] Gilbert, Scott (2010). Developmental Biology 9th Ed + Devbio Labortatory Vade Mecum3. Sinauer Associates Inc. pp. 243–247, 161. ISBN 978-0-87893-558-1. [3] Lombardi, Julian (1998). “Embryogenesis”. Comparative vertebrate reproduction. Springer. p. 226. ISBN 978-07923-8336-9. [4] Forgács & Newman, 2005: p. 27 [5] Cockburn, Katie; Rossant, Janet (1 April 2010). “Making the blastocyst: lessons from the mouse”. Journal of Clinical Investigation 120 (4): 995–1003. doi:10.1172/JCI41229. [6] Heasman, J (November 1997). “Patterning the Xenopus blastula.”. Development (Cambridge, England) 124 (21): 4179–91. PMID 9334267. [7] Tadros, Wael; Lipshitz, Howard D. (1 March 2004). “Setting the stage for development: mRNA translation and stability during oocyte maturation and egg activation inDrosophila”. Developmental Dynamics 232 (3): 593– 608. doi:10.1002/dvdy.20297. PMID 15704150. [8] Gourdon, John B.; Standley, Henrietta J. (Dec 2002). “Uncommitted Xenopus blastula cells can be directed to uniform muscle gene expression by gradient interpretation and a community effect”. The International Journal of Developmental Biology (Cambridge, UK) 46 (8): 993– 8. PMID 12533022. [9] Toth, Attila. “Treatment: Addressing the Causes of Infertility in Men and Women”. Macleod Laboratory. Retrieved 22 March 2013. [10] Kalt, MR (August 1971). “The relationship between cleavage and blastocoel formation in Xenopus laevis. I. Light microscopic observations.”. Journal of embryology and experimental morphology 26 (1): 37–49. PMID 5565077. [11] Tadros, W; Lipshitz, HD (March 2005). “Setting the stage for development: mRNA translation and stability during oocyte maturation and egg activation in Drosophila.”. Developmental dynamics : an official publication of the American Association of Anatomists 232 (3): 593–608. doi:10.1002/dvdy.20297. PMID 15704150. [12] Etkin, LD (1988). “Regulation of the mid-blastula transition in amphibians.”. Developmental biology (New York, N.Y. : 1985) 5: 209–25. doi:10.1007/978-1-4615-68179_7. PMID 3077975. [13] Tadros, W; Westwood, JT; Lipshitz, HD (June 2007). “The mother-to-child transition.”. Developmental cell 12 (6): 847–9. doi:10.1016/j.devcel.2007.05.009. PMID 17543857. [14] Weigel, D; Izaurralde, E (24 March 2006). “A tiny helper lightens the maternal load.”. Cell 124 (6): 1117–8. doi:10.1016/j.cell.2006.03.005. PMID 16564001. [15] Fleming, Tom P.; Papenbrock, Tom; Fesenko, Irina; Hausen, Peter; Sheth, Bhavwanti (1 August 2000). “Assembly of tight junctions during early vertebrate development”. Seminars in Cell & Developmental Biology 11 (4): 291–299. doi:10.1006/scdb.2000.0179. PMID 10966863.
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[16] Watson, J.G. (Oct 1977). “Collection and Transfer of Preimplantation Mouse Embryos”. Biology of Reproduction 17 (3): 453–8. doi:10.1095/biolreprod17.3.453. PMID 901897. [17] Viczian, Andrea S.; Solessio, Eduardo C.; Lyou, Yung; Zuber, Michael E (Aug 2009). “Generation of Functional Eyes from Pluripotent Cells”. PloS Biology 7 (8): e1000174. doi:10.1371/journal.pbio.1000174. PMID 19688031.
48.6 Bibliography • Forgács, G. & Newman, Stuart A. (2005). “Cleavage and blastula formation”. Biological physics of the developing embryo. Cambridge University Press. ISBN 978-0-521-78337-8. • Cullen, K.E. (2009). “embryology and early animal development”. Encyclopedia of life science, Volume 2. Infobase. ISBN 978-0-8160-7008-4. • McGeady, Thomas A., ed. (2006). “Gastrulation”. Veterinary embryology. Wiley-Blackwell. ISBN 978-1-4051-1147-8.
Chapter 49
Blastocoele A blastocoel(e) or blastocele (also called blastocyst cavity,[1] cleavage cavity or segmentation cavity) is the fluid-filled central region of a blastula and mammalian blastocyst. A blastocoele forms during embryogenesis when a zygote (a fertilized ovum) divides into many cells through mitosis. The adjectival of “blastocoel(e)" is blastocoelic. A blastocoel can be described as the first cell cavity formed as the embryo enlarges. It is essential for later gastrulation.
49.1 References [1] “The Carnegie stages”. Retrieved 2007-10-13.
49.2 See also • Embryo • Blastula
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Chapter 50
Germ layer See also: Germ cell A germ layer is a primary layer of cells that form during embryogenesis.[1] The three germ layers in vertebrates are particularly pronounced; however, all eumetazoans, (animals more complex than the sponge) produce two or three primary germ layers. Animals with radial symmetry, like cnidarians, produce two germ layers (the ectoderm and endoderm) making them diploblastic. Animals with bilateral symmetry produce a third layer (the mesoderm), between these two layers. making them triploblastic. Germ layers eventually give rise to all of an animal’s tissues and organs through the process of Micrograph of a teratoma, a tumour that characteristically has organogenesis.
tissue from all three germ layers. The image shows tissue derived from the mesoderm (immature cartilage - left-upper corner of image), endoderm (gastrointestinal glands - center-bottom of image) and ectoderm (epidermis - right of image). H&E stain.
50.1 Germ layers
differentiated cells (e.g. collar cells), they lack true tissue coordination. Diploblastic animals, Cnidaria and Ctenophora, show an increase in complexity, having two germ layers, the endoderm and ectoderm. Diploblastic animals are organized into recognisable tissues. All higher animals (from flatworms to humans) are triploblastic, possessing a mesoderm in addition to the germ layers found in Diploblasts. Triploblastic animals develop recognisable organs.
Gastrulation of a diploblast: The formation of germ layers from a (1) blastula to a (2) gastrula. Some of the ectoderm cells (orange) move inward forming the endoderm (red).
50.1.1 Development Fertilization leads to the formation of a zygote. During the next stage, cleavage, mitotic cell divisions transform the zygote into a hollow ball of cells, a blastula. This early embryonic form undergoes gastrulation, forming a gastrula with either two or three layers (the germ layers). In all vertebrates, these progenitor cells differentiate into all adult tissues and organs.[2]
Caspar Friedrich Wolff observed organization of the early embryo in leaf-like layers. In 1817, Heinz Christian Pander discovered three primordial germ layers while studying chick embryos. Between 1850 and 1855, Robert Remak had further refined the germ cell layer concept, and introduced into English were the terms "mesoderm" In humans, after about three days, the zygote forms a by Huxley in 1871 and "ectoderm" and "endoderm" by solid mass of cells by mitotic division, called a morula. Lankester in 1873. This then changes to a blastocyst, consisting of an outer Among animals, sponges show the simplest organiza- layer called a trophoblast, and an inner cell mass called tion, having a single germ layer. Although they have the embryoblast. Filled with uterine fluid, the blas161
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CHAPTER 50. GERM LAYER
tocyst breaks out of the zona pellucida and undergoes implantation. The inner cell mass initially has two layers: the hypoblast and epiblast. At the end of the second week, a primitive streak appears. The epiblast in this region moves towards the primitive streak, dives down into it, and forms a new layer, called the endoderm, pushing the hypoblast out of the way (this goes on to form the amnion.) The epiblast keeps moving and forms a second layer, the mesoderm. The top layer is now called the ectoderm.[3] The mesoderm aids in the production of cardiac muscle, skeletal muscle, smooth muscle, tissues within the kidneys, and red blood cells.
50.1.2
Endoderm
50.1.3 Mesoderm Main article: Mesoderm The mesoderm germ layer forms in the embryos of triploblastic animals. During gastrulation, some of the cells migrating inward contribute to the mesoderm, an additional layer between the endoderm and the ectoderm. The formation of a mesoderm leads to the development of a coelom. Organs formed inside a coelom can freely move, grow, and develop independently of the body wall while fluid cushions and protects them from shocks.
The endoderm produces tissue within the lungs, thyroid, and pancreas.
Main article: Endoderm
The mesoderm has several components which develop into tissues: intermediate mesoderm, paraxial mesoderm, lateral plate mesoderm, and chorda-mesoderm. The chorda-mesoderm develops into the notochord. The intermediate mesoderm develops into kidneys and gonads. The paraxial mesoderm develops into cartilage, skeletal muscle, and dermis. The lateral plate mesoderm develops into the circulatory system (including the heart and spleen), the wall of the gut, and wall of the human body.[4]
Through cell signaling cascades and interactions with the ectodermal and endodermal cells, the mesodermal cells The endoderm is one of the germ layers formed during begin the process of differentiation.[5] animal embryogenesis. Cells migrating inward along the archenteron form the inner layer of the gastrula, which The mesoderm forms: muscle (smooth and striated), bone, cartilage, connective tissue, adipose tisdevelops into the endoderm. sue, circulatory system, lymphatic system, dermis, The endoderm consists at first of flattened cells, which genitourinary system, serous membranes, and notochord. subsequently become columnar. It forms the epithelial lining of the whole of the digestive tube except part of the mouth and pharynx and the terminal part of the rectum 50.1.4 Ectoderm (which are lined by involutions of the ectoderm). It also forms the lining cells of all the glands which open into the digestive tube, including those of the liver and pancreas; Main article: Ectoderm the epithelium of the auditory tube and tympanic cavity; the trachea, bronchi, and air cells of the lungs; the urinary The ectoderm generates the outer layer of the embryo, bladder and part of the urethra; and the follicle lining of and it forms from the embryo’s epiblast.[6] The ectoderm develops into the surface ectoderm, neural crest, and the the thyroid gland and thymus. [7] The endoderm forms: the stomach, the colon, the liver, neural tube. the pancreas, the urinary bladder, the epithelial parts of The surface ectoderm develops into: epidermis, hair, trachea, the lungs, the pharynx, the thyroid, the parathy- nails, lens of the eye, sebaceous glands, cornea, tooth roid, and the intestines. enamel, the epithelium of the mouth and nose.
50.3. REFERENCES
163
[6] Gilbert, Scott F (2003). “Early Mammalian Development”. Developmental Biology. Sinauer Associates. [7] Gilbert, Scott F (2003). “The Central Nervous System and The Epidermis”. Developmental Biology. Sinauer Associates. [8] Hall BK (2000). “The neural crest as a fourth germ layer and vertebrates as quadroblastic not triploblastic”. Evolution & Development 2, 3-5. PMID 11256415.
The ectoderm produces tissues within the epidermis, aids in the formation of neurons within the brain, and constructs melanocytes.
The neural crest of the ectoderm develops into: peripheral nervous system, adrenal medulla, melanocytes, facial cartilage, dentin of teeth. The neural tube of the ectoderm develops into: brain, spinal cord, posterior pituitary, motor neurons, retina. Note: The anterior pituitary develops from the ectodermal tissue of Rathke’s pouch.
50.1.5
Neural crest
Because of its great importance, the neural crest is sometimes considered a fourth germ layer.[8] It is, however, derived from the ectoderm.
50.2 See also • Histogenesis • Neurulation
50.3 References [1] Gilbert, Scott F (2003). “The Epidermis and the Origin of Cutaneous Structures”. Developmental Biology. Sinauer Associates. [2] Gilbert, Scott F (2000). “Comparative Embryology”. Developmental Biology. Sinauer Associates. [3] Gilbert, Scott F (2000). “Early Mammalian Development”. Developmental Biology. Sinauer Associates. [4] Gilbert, Scott F (2003). “Paraxial and Intermediate Mesoderm”. Developmental Biology. Sinauer Associates. [5] Brand, Thomas (1 June 2003). “Heart development: molecular insights into cardiac specification and early morphogenesis”. Developmental Biology 258 (1): 1–19. doi:10.1016/S0012-1606(03)00112-X.
Chapter 51
Trophoblast Trophoblasts (from Greek trephein: to feed, and blas- 51.2 Differentiation tos: germinator) are cells forming the outer layer of a blastocyst, which provide nutrients to the embryo and The trophoblast proliferates and differentiates into 2 cell develop into a large part of the placenta. They are layers at approximately 6 days after fertilization for huformed during the first stage of pregnancy and are the mans: first cells to differentiate from the fertilized egg. This layer of trophoblasts is also collectively referred to as “the trophoblast”,[1] or, after gastrulation,[2] the trophectoderm, as it is then contiguous with the ectoderm of the 51.3 Note embryo. 80% of trophoblasts are found in the sexual organs, while the remaining 20% are distributed throughout the body. There is a known link between the function of trophoblasts and cancer cells. 51.1 Function Trophoblasts are specialized cells of the placenta that play an important role in embryo implantation and interac- 51.4 Pathology tion with the decidualised maternal uterus. The core of placental villi contain mesenchymal cells and placental The invasion of a specific type of trophoblast (extravillous blood vessels that are directly connected to the fetal cir- trophoblast) into the maternal uterus is a vital stage in the culation via the umbilical cord. This core is surrounded establishment of pregnancy: by two layers of trophoblast; a single layer of mononuclear cytotrophoblast that fuse together to form the over• Failure of the trophoblast to invade sufficiently is lying multinucleated syncytiotrophoblast layer that covers important in the development of some cases of prethe entire surface of the placenta. It is this syncytiotroeclampsia. phoblast that is in direct contact with the maternal blood that reaches the placental surface, and thus facilitates the • Too firm an attachment may lead to placenta accreta. exchange of nutrients, wastes and gases between the maternal and fetal systems. Gestational trophoblastic disease represents a form of In addition, cytotrophoblast in the tips of villi can differ- proliferation. entiate into another type of trophoblast called the extravillous trophoblast. Extravillous trophoblast grow out from the placenta and penetrate into the decidualised uterus. 51.5 Additional images This process is essential not only for physically attaching the placenta to the mother, but also for altering the • Blastodermic vesicle of Vespertilio murinus. vasculature in the uterus to allow it to provide an adequate blood supply to the growing fetus as pregnancy • Section through embryonic disk of Vespertilio murprogresses. Some of these trophoblast even replace the inus. endothelial cells in the uterine spiral arteries as they remodel these vessels into wide bore conduits that are in• Transverse section of a chorionic villus. dependent of maternal vasoconstriction. This ensures the fetus receives a steady supply of blood, and the placenta • Scheme of placental circulation. is not subjected to fluctuations in oxygen that could cause • The initial stages of human embryogenesis it damage. 164
51.8. EXTERNAL LINKS
51.6 See also • Syncytiotrophoblast • Hydatidiform mole
51.7 References [1] http://www.britannica.com/EBchecked/topic/606502/ trophoblast [2] Merriam-Webster’s Medical Dictionary > trophectoderm Retrieved August 2010
51.8 External links • Swiss embryology (from UL, UB, and UF) iperiodembry/carnegie02 • Oklahoma State • University of Illinois
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Chapter 52
Gastrulation like); (2) the differentiation of cells into one of three types (endodermal, mesodermal, and ectodermal); and (3) the digestive function of a large number of endodermal cells.[6] Lewis Wolpert, pioneering developmental biologist in the field, has been credited for noting that “It is not birth, marriage, or death, but gastrulation, which is truly the most important time in your life.” Gastrulation occurs when a blastula, made up of one layer, folds inward and enlarges to create a gastrula. This diagram is colorcoded: ectoderm, blue; endoderm, green; blastocoel (the yolk sack), yellow; and archenteron (the gut), purple.
The terms "gastrula" and “gastrulation” were coined by Ernst Haeckel, in his 1872 work “Biology of Calcareous Sponges”.[7]
Although gastrulation patterns exhibit enormous variation throughout the animal kingdom, they are unified by the five basic types of cell movements that occur during gastrulation: 1) invagination 2) involution 3) ingression Gastrulation is a phase early in the embryonic de4) delamination 5) epiboly.[8] velopment of most animals, during which the singlelayered blastula is reorganized into a trilaminar (“threelayered”) structure known as the gastrula. These three germ layers are known as the ectoderm, mesoderm, and 52.1 In amniotes endoderm.[1][2] Gastrulation takes place after cleavage and the formation of the blastula. Gastrulation is followed by organogenesis, when individual organs develop within the newly formed germ layers.[3] Each layer gives rise to specific tissues and organs in the developing embryo. The ectoderm gives rise to epidermis, and to the neural crest and other tissues that will later form the nervous system. The mesoderm is found between the ectoderm and the endoderm and gives rise to somites, which form muscle; the cartilage of the ribs and vertebrae; the dermis, the notochord, blood and blood vessels, bone, and connective tissue. The endoderm gives rise to the epithelium of the digestive system and respiratory system, and organs associated with the digestive system, such as the liver and pancreas.[4] Following gastrulation, cells in the body are either organized into sheets of connected cells (as in epithelia), or as a mesh of isolated cells, such as mesenchyme.[2][5] The molecular mechanism and timing of gastrulation is different in different organisms. However, some common features of gastrulation across triploblastic organisms include: (1) A change in the topological structure of the embryo, from a simply connected surface (sphere-like), to a non-simply connected surface (torus-
52.1.1 Overview In amniotes, gastrulation occurs in the following sequence: (1) the embryo becomes asymmetric; (2) the primitive streak forms; (3) cells from the epiblast at the primitive streak undergo an epithelial to mesenchymal transition and ingress at the primitive streak to form the germ layers.[4]
52.1.2 Loss of symmetry In preparation for gastrulation, the embryo must become asymmetric along both the proximal-distal axis and the anterior-posterior axis. The proximal-distal axis is formed when the cells of the embryo form the “egg cylinder,” which consists of the extraembryonic tissues, which give rise to structures like the placenta, at the proximal end and the epiblast at the distal end. Many signaling pathways contribute to this reorganization, including BMP, FGF, nodal, and Wnt. Visceral endoderm surrounds the epiblast. The distal visceral endoderm (DVE) migrates to the anterior portion of the embryo, forming the “anterior visceral endoderm” (AVE). This breaks
166
52.2. SEE ALSO
167
anterior-posterior symmetry and is regulated by nodal layer, the cells must undergo an epithelial to mesenchymal signaling.[4] transition (EMT) to lose their epithelial characteristics, such as cell-cell adhesion. FGF signaling is necessary for proper EMT. FGFR1 is needed for the up regulation of Snail1, which down regulates E-cadherin, causing a loss of cell adhesion. Following the EMT, the cells ingress through the primitive streak and spread out to form a new layer of cells or join existing layers. FGF8 is implicated in the process of this dispersal from the primitive streak.[11]
52.2 See also Epithelial to Mesenchmyal Cell Transition – loss of cell adhesion leads to constriction and extrusion of newly mesenchymal cell.
• Blastocyst • Deuterostome • Fate mapping
52.1.3
Formation of the primitive streak
The primitive streak is formed at the beginning of gastrulation and is found at the junction between the extraembryonic tissue and the epiblast on the posterior side of the embryo and the site of ingression.[9] Formation of the primitive streak is reliant upon nodal signaling[4] in the Koller’s sickle within the cells contributing to the primitive streak and BMP4 signaling from the extraembryonic tissue.[9][10] Furthermore, Cer1 and Lefty1 restrict the primitive streak to the appropriate location by antagonizing nodal signaling.[11] The region defined as the primitive streak continues to grow towards the distal tip.[4]
• Henson’s Node[16] • Invagination • Neurulation • Protostome • Vegetal rotation
52.3 References 52.3.1 Notes
During the early stages of development, the primitive streak is the structure that will establish bilateral sym- [1] Mundlos 2009: p. 422 metry, determine the site of gastrulation and initiate germ layer formation. To form the streak, reptiles, [2] McGeady, 2004: p. 34 birds and mammals arrange mesenchymal cells along the [3] Hall, 1998: pp. 132-134 prospective midline, establishing the first embryonic axis, as well as the place where cells will ingress and mi- [4] Arnold & Robinson, 2009 grate during the process of gastrulation and germ layer formation.[12] The primitive streak, extends through this [5] Hall, 1998: p. 177 midline and creates the antero-posterior body axis,[13] be- [6] Harrison 2011: p. 206 coming the first symmetry-breaking event in the embryo, and marks the beginning of gastrulation.[14] This pro- [7] Ereskovsky 2010: p. 236 cess involves the ingression of mesoderm and endo[8] Gilbert 2010: p. 164. derm progenitors and their migration to their ultimate position,[13][15] where they will differentiate into the three [9] Tam & Behringer, 1997 germ layers.[12] The localization of the cell adhesion and signaling molecule beta-catenin is critical to the proper [10] Catala, 2005: p. 1535 formation of the organizer region that is responsible for [11] Tam, P.P. & Loebel, D.A (2007). “Gene function in initiating gastrulation. mouse embryogenesis: get set for gastrulation”. Nat Rev Genet 8 (5): 368–81. doi:10.1038/nrg2084. PMID 17387317.
52.1.4
Epithelial to mesenchymal transition and ingression
In order for the cells to move from the epithelium of the epiblast through the primitive streak to form a new
[12] Mikawa T, Poh AM, Kelly KA, Ishii Y, Reese DE. (2004). “Induction and patterning of the primitive streak, an organizing center of gastrulation in the amniote.”. Dev Dyn 229 (3): 422–32. doi:10.1002/dvdy.10458. PMID 14991697.
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[13] Downs KM. (2009). “The enigmatic primitive streak: prevailing notions and challenges concerning the body axis of mammals.”. Bioessays 31 (8): 892–902. doi:10.1002/bies.200900038. PMC 2949267. PMID 19609969. [14] Chuai M, Zeng W, Yang X, Boychenko V, Glazier JA, Weijer CJ. (2006). “Cell movement during chick primitive streak formation.”. Dev Biol. 296(1)) (1): 137– 49. doi:10.1016/j.ydbio.2006.04.451. PMC 2556955. PMID 16725136. [15] Chuai M, Weijer CJ. (2008). “The mechanisms underlying primitive streak formation in the chick embryo.”. Curr Top Dev Biol. 81: 135–56. doi:10.1016/S00702153(07)81004-0. PMID 18023726. [16] See
52.3.2
Bibliography
• Arnold, Sebastian J.; Robertson, Elizabeth J. (2009). “Making a commitment: cell lineage allocation and axis patterning in the early mouse embryo”. Nat. Rev. Mol. Cell Biol. 10 (2): 91–103. doi:10.1038/nrm2618. PMID 19129791. • Catala, Martin (2005). “Embryology of the Spine and Spinal Cord”. In Tortori-Donati, Paolo et al.. Pediatric Neuroradiology: Brain. Springer. ISBN 978-3-540-41077-5. • Ereskovsky, Alexander V. (2010). The Comparative Embryology of Sponges. Springer. ISBN 978-90481-8574-0. • Gilbert, Scott F. (2010). Developmental Biology (Ninth ed.). Sinauer Associates. ISBN 978-087893-558-1. • Hall, Brian Keith (1998). “8.3.3 The gastrula and gastrulation”. Evolutionary developmental biology (2nd ed.). The Netherlands: Kluwer Academic Publishers. ISBN 978-0-412-78580-1. • Harrison, Lionel G. (2011). The Shaping of Life: The Generation of Biological Pattern. Cambridge University Press. ISBN 978-0-521-55350-6. • McGeady, Thomas A., ed. (2006). “Gastrulation”. Veterinary embryology. Wiley-Blackwell. ISBN 978-1-4051-1147-8. • Mundlos, Stefan (2009). “Gene action: developmental genetics”. In Speicher, Michael et al.. Vogel and Motulsky’s Human Genetics: Problems and Approaches (4th ed.). Springer. doi:10.1007/978-3540-37654-5. ISBN 978-3-540-37653-8. • Tam, Patrick P.L. & Behringer, Richard R. (1997). “Mouse gastrulation: the formation of a mammalian body plan”. Mech. Dev. 68 (1-2): 3– 25. doi:10.1016/S0925-4773(97)00123-8. PMID 9431800.
52.4 Further reading • Baron, Margaret H. (2001). “Embryonic Induction of Mammalian Hematopoiesis and Vasculogenesis”. In Zon, Leonard I. Hematopoiesis: a developmental approach. Oxford University Press. ISBN 978-019-512450-7. • Cullen, K.E. (2009). “embryology and early animal development”. Encyclopedia of life science, Volume 2. Infobase. ISBN 978-0-8160-7008-4. • Forgács, G. & Newman, Stuart A. (2005). “Cleavage and blastula formation”. Biological physics of the developing embryo. Cambridge University Press. ISBN 978-0-521-78337-8. • Forgács, G. & Newman, Stuart A. (2005). “Epithelial morphogenesis: gastrulation and neurulation”. Biological physics of the developing embryo. Cambridge University Press. ISBN 978-0-521-78337-8. • Hart, Nathan H. & Fluck, Richard A. (1995). “Epiboly and Gastrulation”. In Capco, David. Cytoskeletal mechanisms during animal development. Academic Press. ISBN 978-0-12-153131-7. • Knust, Elizabeth (1999). “Gastrulation movements”. In Birchmeier, Walter & Birchmeier, Carmen. Epithelial Morphogenesis in Development and Disease. CRC Press. pp. 152–153. ISBN 978-905702-419-1. • Kunz, Yvette W. (2004). “Gastrulation”. Developmental biology of Teleost fishes. Springer. ISBN 978-1-4020-2996-7. • Nation, James L., ed. (2009). “Gastrulation”. Insect physiology and biochemistry. CRC Press. ISBN 978-0-8493-1181-9. • Ross, Lawrence M. & Lamperti, Edward D., ed. (2006). “Human Ontogeny: Gastrulation, Neurulation, and Somite Formation”. Atlas of anatomy: general anatomy and musculoskeletal system. Thieme. ISBN 978-3-13-142081-7. • Sanes, Dan H. et al. (2006). “Early embryology of metazoans”. Development of the nervous system (2nd ed.). Academic Press. pp. 1–2. ISBN 978-012-618621-5. • Stanger, Ben Z. & Melton, Douglas A. (2004). “Development of Endodermal Derivatives in the Lungs, Liver, Pancreas, and Gut”. In Epstein, Charles J. et al. Inborn errors of development: the molecular basis of clinical disorders of morphogenesis. Oxford University Press. ISBN 978-0-19-514502-1.
52.5. EXTERNAL LINKS
52.5 External links • Gastrulation Animations • Gastrulation illustrations and movies from Gastrulation: From Cells To Embryo edited by Claudio Stern
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Chapter 53
Ectoderm Ectoderm is one of the three primary germ layers in the very early embryo. The other two layers are the mesoderm (middle layer) and endoderm (most proximal layer), with the ectoderm as the most exterior (or distal) layer.[1] It emerges and originates from the outer layer of germ cells. The word ectoderm comes from the Greek ektos meaning “outside”, and derma, meaning “skin.”[2]
53.2.1 Initial appearance
The ectoderm can first be observed in amphibians and fish during the later stages of a process called gastrulation. At the start of this process, the developing embryo has divided into many cells separating the embryo, which is now a hollow sphere of cells called the blastula, into two Generally speaking, the ectoderm differentiates to parts, the animal hemisphere and vegetal hemisphere. It form the nervous system (spine, peripheral nerves and is the animal hemisphere of[2]the blastula that will eventubrain),[3][4] tooth enamel and the epidermis (the outer ally become the ectoderm. part of integument). It also forms the lining of mouth, anus, nostrils, sweat glands, hair and nails.[4]
53.2.2 Early development
In vertebrates, the ectoderm has three parts: external ectoderm (also known as surface ectoderm), the neural Like the other two germ layers, mesoderm and endocrest, and neural tube. The latter two are known as derm, the ectoderm forms shortly after the egg is fertilneuroectoderm. ized, and rapid cell division initiates. The epidermis of the skin originates from the less dorsal ectoderm which surrounds the neuroectoderm at the early gastrula stage of embryonic development. The position of the ectoderm relative to the other germ layers of the embryo is 53.1 History governed by “selective affinity”, meaning that the inner surface of the ectoderm has a strong (positive) affinity Heinz Christian Pander, a Russian biologist, has been for the mesoderm, and a weak (negative) affinity for the credited for the discovery of the three germ layers that endoderm layer. This selective affinity changes during form during embryogenesis. Pander received his doc- different stages of development. The strength of the attorate in zoology from the University of Wurzburg in traction between two surfaces of two germ layers is de1817. He began his studies in embryology using chicken termined by the amount and type of cadherin molecules eggs, which allowed for his discovery of the ectoderm, present on the cells’ surface. For example, the expression mesoderm and endoderm. Due to his findings, Pander of N-cadherin is crucial to maintaining separation of preis sometimes referred to as the “founder of embryol- cursor neural cells from precursor epithelial cells.[2] The ogy”. Pander’s work of the early embryo was contin- ectoderm is instructed to become the nervous system by ued by a Prussian-Estonian biologist named Karl Ernst the notochord, which is typically positioned above it.[2] von Baer. Baer took Pander’s concept of the germ layers and through extensive research of many different types of species, he was able to extend this principle to all verte- Gastrulation brates. Baer also received credit for the discovery of the blastula. Baer published his findings, including his germ During the process of gastrulation, a special type of cells layer theory, in a textbook which translates to On the De- called bottle cells invaginates a hole on the surface of the blastula which is called the dorsal lip of the blastopore. velopment of Animals which he released in 1828.[5] Once this lip has been established, the bottle cells will extend inward and migrate along the inner wall of the blastula known as the roof of the blastocoel. The once superficial cells of the animal pole are destined to be53.2 Differentiation come the cells of the middle germ layer called the mesoderm. Through the process of radial extension, cells of 170
53.3. CLINICAL SIGNIFICANCE
171
the animal pole that were once several layers thick di- cells together, which leaves neural crest cells between the vide to from a thin layer. At the same time, when this prospective epidermis and hollow, neural tube.[2] thin layer of dividing cells reaches the dorsal lip of the blastopore, another process occurs termed convergent extension. During convergent extension, cells that approach Organogenesis the lip intercalate mediolaterally, in such a way that cells are pulled over the lip and inside the embryo. These two processes allow for the prospective mesoderm cells to be placed between the ectoderm and the endoderm. Once convergent extension and radial intercalation are underway, the rest of the vegetal pole, which will become endoderm cells, is completely engulfed by the prospective ectoderm, as these top cells undergo epiboly, where the ectoderm cells divide in a way to form one layer. This creates a uniform embryo composed of the three germ layers in their respective positions.[2]
53.2.3
Later development
Once there is an embryo with three established germ layers, differentiation among these three layers proceeds. The next event that will take place within the ectoderm is the process of neurulation, which results in the formation of the neural tube, neural crest cells and the epidermis. It is these three components of the ectoderm that will each give rise to a particular set of cells. The neural tube cells will become the central nervous system, neural crest cells will become the central nervous system, along with melanocytes, facial cartilage and the dentin of teeth, and Ectodermal specification the epidermal cell region will give rise to epidermis, hair, nails, sebaceous glands, olfactory and mouth epithelium, All of the organs that rise from the ectoderm such as the nervous system, teeth, hair and many exocrine glands, as well as eyes.[2] originate from two adjacent tissue layers: the epithelium and the mesenchyme. [7] Several signals mediate Neurulation the organogenesis of the ectoderm such as: FGF, TGFβ, Wnt, and regulators from the hedgehog family. The speNeurulation proceeds by primary and secondary neuru- cific timing and manner that the ectodermal organs form lation, both positioning neural crest cells between a su- is dependent on the invagination of the epithelial cells.[8] perficial epidermal layer and a deep neural tube. During FGF-9 is an important factor during the initiation of tooth primary neurulation, the notochord cells of the mesoderm germ development. The rate of epithelial invagination in signal the adjacent, superficial ectoderm cells to reposi- significantly increased by action of FGF-9, which is only tion themselves in a columnar pattern to form cells of the expressed in the epithelium, and not in the mesenchyme. ectodermal neural plate.[6] As the cells continue to elon- FGF-10 helps to stimulate epithelial cell proliferation, in gate, a group of cells immediately above the notochord order make larger tooth germs. Mammalian teeth dechange their shape, forming a wedge in the ectodermal velop from ectoderm derived from the mesenchyme: oral region. These special cells are called medial hinge cells ectoderm and neural crest. The epithelial components (MHP). Now, as the ectoderm continues to elongate, the of the stem cells for continuously growing teeth form ectodermal cells of the neural plate fold inward. The in- from tissue layers called the stellate reticulum and the ward folding of the ectoderm by virtue of mainly cell di- suprabasal layer of the surface ectoderm.[8] vision continues until another group of cells form within the neural plate. These cells are termed dorsolateral hinge cells (DLHP), and once formed, the inward folding of the 53.3 Clinical significance ectoderm stops. The DLHP cells function in a similar fashion as MHP cells regarding their wedge like shape, however, the DLHP cells result in the ectoderm con- 53.3.1 Ectodermal dysplasia verging. This convergence is led by ectodermal cells above the DLHP cells known as the neural crest. The Ectodermal dysplasia is a rare but severe condition where neural crest cells eventually pull the adjacent ectodermal the tissue groups (specifically teeth, skin, hair, nails and
172 sweat glands) derived from the ectoderm undergo abnormal development. Ectodermal dysplasia is a vague term, as there are over 170 subtypes of ectodermal dysplasia. It has been accepted that the disease is caused by a mutation or a combination of mutations in a number of genes. Research of the disease is ongoing, as only a fraction of the mutations involved with an ectodermal dysplasia subtype have been identified.[9]
CHAPTER 53. ECTODERM
53.4 See also • Ectoderm specification • Coelom • Embryology • Endoderm • Gastrulation • Mesoderm • Neural plate
53.5 References [1] Langman’s Medical Embryology, 11th edition. 2010. [2] Gilbert, Scott F. Developmental Biology. 9th ed. Sunderland, MA: Sinauer Associates, 2010: 333-370. Print. [3] http://www.bioethics.gov/reports/stemcell/glossary.html [4] http://simple.wikipedia.7val.com/wiki/Mate [5] Baer KE von (1986) In: Oppenheimer J (ed.) and Schneider H (transl.), Autobiography of Dr. Karl Ernst von Baer. Canton, MA: Science History Publications.
Dental abnormalities in a 5-year-old girl from north Sweden family who suffered from various symptoms of autosomal dominant hypohidrotic ectodermal dysplasia (HED) a) Intraoral view. Note that the upper incisors have been restored with composite material to disguise their original conical shape. b) Orthopantomogram showing absence of ten primary and eleven permanent teeth in the jaws of the same individual.
[6] O'Rahilly R, Müller F. Neurulation in the normal human embryo. Ciba Found Symp. 1994;181:70-82; discussion 82-9. Review. PubMed PMID 8005032.forabettalorretta 21:18, 19 March 2013 [7] Pispa, J; Thesleff, I (Oct 15, 2003). “Mechanisms of ectodermal organogenesis.”. Developmental biology 262 (2): 195–205. doi:10.1016/S0012-1606(03)00325-7. PMID 14550785. [8] Tai, Y. Y.; Chen, R. S.; Lin, Y.; Ling, T. Y.; Chen, M. H. (2012). “FGF-9 accelerates epithelial invagination for ectodermal organogenesis in real time bioengineered organ manipulation”. Cell Communication and Signaling 10 (1): 34. doi:10.1186/1478-811X-10-34. PMC 3515343. PMID 23176204.
Hypohidrotic ectodermal dysplasia (HED) is the most common subtype of the disease. Clinical cases of patients with this condition displayed a range of symptoms. One of the common abnormalities of HED is hypohidrosis, or the inability to sweat, which can be attributed to dysfunc- [9] Priolo, M.; Laganà, C (September 2001). “Ectodertional sweat glands. This aspect can be especially danmal Dysplasias: A New Clinical-Genetic Classification”. Journal of Medical Genetics 38 (9): 579–585. gerous in warm climates where the patient could potendoi:10.1136/jmg.38.9.579. PMID 11546825. tially suffer from hyperthermia. Facial malformations are also related to HED such as disfigured or absent teeth, [10] Clarke, A., D. I. Phillips, R. Brown, and P. S. Harper. wrinkled skin around the eyes, misshaped nose along “Clinical Aspects of X-linked Hypohidrotic Ectoderwith scarce and thin hair. Skin problems, like eczema mal Dysplasia.” Archives of Disease in Childhood 62.10 have also been observed in cases.[10] It typically follows (1987): 989-96. Print. an X-linked recessive pattern of inheritance of the EDA genes.[11] This disease typically affects males because [11] Bayes, M.; Hartung, A. J.; Ezer, S.; Pispa, J.; Thesleff, I.; Srivastava, A. K.; Kere, J. (1998). “The Anhidrotic Ecthey have only one X chromosome, meaning only one todermal Dysplasia Gene (EDA) Undergoes Alternative copy of the mutated gene is enough to cause abnormal Splicing and Encodes Ectodysplasin-A with Deletion Mudevelopment. For females to be affected, both X chrotations in Collagenous Repeats”. Human Molecular Gemosomes would need to carry the gene mutation. If a netics 7 (11): 1661–1669. doi:10.1093/hmg/7.11.1661. female has a mutated version of the gene on one X chroPMID 9736768. mosome, they are considered carrier of the disease.
Chapter 54
Mesoderm In all bilaterian animals, the mesoderm is one of the three primary germ layers in the very early embryo. The other two layers are the ectoderm (outside layer) and endoderm (inside layer), with the mesoderm as the middle layer between them.[1][2] The mesoderm forms mesenchyme (connective tissue), mesothelium, non-epithelial blood cells and coelomocytes. Mesothelium lines coeloms; forms the muscles in a process known as myogenesis, septa (cross-wise partitions) and mesenteries (length-wise partitions); and forms part of the gonads (the rest being the gametes).[1] The mesoderm differentiates from the rest of the embryo through intercellular signaling, after which the mesoderm is polarized by an organizing center.[3] The position of the organizing center is in turn determined by the regions in which beta-catenin is protected from degradation by GSK-3. Beta-catenin acts as a co-factor that alters the activity of the transcription factor tcf-3 from repressing to activating, which initiates the synthesis of gene products critical for mesoderm differentiation and gastrulation. Furthermore, mesoderm has the capability to induce the growth of other structures, such as the neural plate, the precursor to the nervous system.
54.1 Definition The mesoderm is one of the three germinal layers that appears in the third week of embryonic development. It is formed through a process called gastrulation. There are three important components, the paraxial mesoderm, the intermediate mesoderm and the lateral plate mesoderm. The paraxial mesoderm forms the somitomeres, which give rise to mesenchyme of the head and organize into somites in occipital and caudal segments. Somites give rise to the myotome (muscle tissue), sclerotome (cartilage and bone), and dermatome (subcutaneous tissue of the skin).[1][2] Signals for somite differentiation are derived from surroundings structures, including the notochord, neural tube and epidermis. The intermediate mesoderm connects the paraxial mesoderm with the lateral plate, eventually it differentiates into urogenital structures consisting of the kidneys, gonads, their associated ducts, and
the adrenal glands. The lateral plate mesoderm give rise to the heart, blood vessels and blood cells of the circulatory system as well as to the mesodermal component of the limbs.[4] Some of the mesoderm derivatives include the muscle (smooth, cardiac and skeletal), the muscles of the tongue (occipital somites), the pharyngeal arches muscle (muscles of mastication, muscles of facial expressions), connective tissue, dermis and subcutaneous layer of the skin, bone and cartilage, dura mater, endothelium of blood vessels, red blood cells, white blood cells, microglia and Kupffer cells, the kidneys and the adrenal cortex.[5]
54.2 Development of the mesodermal germ layer During the third week a process called gastrulation creates a mesodermal layer between the endoderm and the ectoderm. This process begins with formation of a primitive streak on the surface of the epiblast.[6] The cells of the layers move between the epiblast and hypoblast and begin to spread laterally and cranially. The cells of the epiblast move toward the primitive streak and slip beneath it in a process called invagination. Some of the migrating cells displace the hypoblast and create the endoderm, and others migrate between the endoderm and the epiblast to create the mesoderm. The remaining cells form the ectoderm. After that, the epiblast and the hypoblast establish contact with the extraembryonic mesoderm until they cover the yolk sac and amnion. They move onto either side of the prechordal plate. The prechordal cells migrate to the midline to form the notochordal plate. The chordamesoderm is the central region of trunk mesoderm.[4] This forms the notochord which induces the formation of the neural tube and establishes the anterior-posterior body axis. The notochord extends beneath the neural tube from the head to the tail. The mesoderm moves to the midline until it covers the notochord, when the mesoderm cells proliferate they form the paraxial mesoderm. In each side, the mesoderm remains thin and is known as the lateral plate. The intermediate mesoderm lies between the paraxial mesoderm and the lateral plate. Between days 13 and 15, the proliferation of extraembry-
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onic mesoderm, primitive streak and embryonic mesoderm take place. The notochord process occurs between days 15 and 17. Eventually, the development of the notochord canal and the axial canal takes place between days 17 and 19 when the first three somites are formed.[7]
54.3 Paraxial mesoderm During the third week, the paraxial mesoderm is organized into segments. If they appear in the cephalic region and grow with cephalocaudal direction, they are called somitomeres. If they appear in the cephalic region but establish contact with the neural plate, they are known as neuromeres, which later will form the mesenchyme in the head. The somitomeres organize into somites which grow in pairs. In the fourth week the somites lose their organization and cover the notochord and spinal cord to form the backbone. In the fifth week, there are 4 occipital somites, 8 cervical, 12 thoracic, 5 lumbar, 5 sacral and 8 to 10 coccygeal that will form the axial skeleton. Somatic derivatives are determined by local signaling between adjacent embryonic tissues, in particular the neural tube, notochord, surface ectoderm and the somatic compartments themselves.[8] The correct specification of the deriving tissues, skeletal, cartilage, endothelia and connective tissue is achieved by a sequence of morphogenic changes of the paraxial mesoderm, leading to the three transitory somatic compartments: dermomyotome, myotome and sclerotome. These structures are specified from dorsal to ventral and from medial to lateral.[8] each somite will form its own sclerotome that will differentiate into the tendon cartilage and bone component. Its myotome will form the muscle component and the dermatome that will form the dermis of the back. The myotome and dermatome have a nerve component.[1][2]
54.4 Molecular Regulation Somite Differentiation
of
Surrounding structures such as the notochord, neural tube, epidermis and lateral plate mesoderm send signals for somite differentiation[1][2] Notochord protein accumulates in presomitic mesoderm destined to form the next somite and then decreases as that somite is established. The notochord and the neural tube activate the protein SHH which helps the somite to form its sclerotome. The cells of the sclerotome express the protein PAX1 that induces the cartilage and bone formation. The neural tube activates the protein WNT1 that expresses PAX 2 so the somite creates the myotome and dermatome. Finally, the neural tube also secretes neurotrophin 3 (NT-3), so that the somite creates the dermis. Boundaries for each somite are regulated by retinoic acid (RA) and a combination of FGF8and WNT3a.[1][2] So the retinoic acid is and endogenous signal that main-
tains the bilateral synchrony of mesoderm segmentation and controls bilateral symmetry in vertebrates. The bilaterally symmetric body plan of vertebrate embryos is obvious in somites and their derivates such as the vertebral column. Therefore asymmetric somite formation correlates with a left-right desynchronization of the segmentation oscillations.[9] Many studies with Xenopus and zebrafish have analyzed the factors of this development and how they interact in signaling and transcription. However, there are still some doubts in how the prospective mesodermal cells integrate the various signals they receive and how they regulate their morphogenic behaviours and cell-fate decisions.[8] Human embryonic stem cells for example have the potential to produce all of the cells in the body and they are able to self-renew indefinitely so they can be used for a large-scale production of therapeutic cell lines. They are also able to remodel and contract collagen and were induced to express muscle actin. This shows that these cells are multipotent cells.[10]
54.5 Intermediate mesoderm The intermediate mesoderm connects the paraxial mesoderm with the lateral plate and differentiates into urogenital structures.[11] In upper thoracic and cervical regions this forms the nephrotomes, and in caudally regions this forms the nephrogenic cord. It also helps to develop the excretory units of the urinary system and the gonads.[4]
54.6 Lateral plate mesoderm The lateral plate mesoderm splits into parietal (somatic) and visceral (splanchnic) layers. The formation of these layers starts with the appearance of intercellular cavities.[11] The somatic layer depends on a continuous layer with mesoderm that covers the amnion. The splanchnic depends on a continuous layer that covers the yolk sac. The two layers cover the intraembryonic cavity. The parietal layer together with overlying ectoderm forms the lateral body wall folds. The visceral layer forms the walls of the gut tube. Mesoderm cells of the parietal layer form the mesothelial membranes or serous membranes which line the peritoneal, pleural and pericardial cavities.[1][2]
54.7 See also • Chordamesoderm (also known as axial mesoderm) which later on gives rise to notochord in all chordates • Embryogenesis • Gastrulation
54.9. FURTHER READING • Histogenesis • Intermediate mesoderm • Lateral plate mesoderm • Mesenchyme • Mesothelium • Organogenesis • Paraxial mesoderm • Somites • Triploblastic
54.8 References [1] Ruppert, E.E., Fox, R.S., and Barnes, R.D. (2004). “Introduction to Bilateria”. Invertebrate Zoology (7th ed.). Brooks/Cole. pp. 217–218. ISBN 0-03-025982-7. [2] Langman’s Medical Embryology, 11th edition. 2010. [3] Kimelman, D. & Bjornson, C. (2004). “Vertebrate Mesoderm Induction: From Frogs to Mice”. In Stern, Claudio D. Gastrulation: from cells to embryo. CSHL Press. p. 363. ISBN 978-0-87969-707-5. [4] Scott, Gilbert (2010). Developmental biology (ninth ed.). USA: Sinauer Associates. [5] Dudek, Ronald W. (2009). High-yield. Embryology (4th ed.). Lippincott Williams & Wilkins. [6] “Paraxial Mesoderm: The somites and their derivatives”. NCBI. Retrieved April 15, 2013. [7] Drew, Ulrich (1993). Color atlas of embryology. German: Thieme. [8] Yusuf, Faisal (2006). “The eventful somite: Patterning, fate determination and cell division in the somite”. Anatomy and embryology: 21–30. [9] Vermot, J.; Gallego Llamas, J.; Fraulob, V.; Niederreither, K.; Chambon, P.; Dollé, P. (April 2005). “Retinoic acid controls the bilateral symmetry of somite formation in the mouse embryo”. Science 308 (5721): 563–566. doi:10.1126/science.1108363. PMID 15731404. [10] Boyd, N.L.; Robbins KR, K.R.; Dhara SK, S.K.; West FD,, F.D.; Stice SL., S.L. (August 2009). “Human embryonic stem cell-derived mesoderm-like epithelium transitions to mesenchymal progenitor cells”. Tissue Engineering. Part A. 15 (8): 1897–1907. doi:10.1089/ten.tea.2008.0351. PMID 19196144. [11] Kumar, Rani (2008). Textbook of human embryology. I.K. International.
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54.9 Further reading • Gurdon, J.B. (1995). “The formation of mesoderm and muscle in Xenopus". In Zagris, Nikolas et al. Organization of the early vertebrate embryo. Springer. ISBN 978-0-306-45132-4. • Kenderew, John Cowdery & Lawrence, Eleanor, ed. (1994). “Mesoderm Induction”. The encyclopedia of molecular biology. John Wiley & Sons. p. 541. ISBN 978-0-632-02182-6. • Liu, Shu Q. (2007). “Early Embryonic Organ Development”. Bioregenerative engineering: principles and applications. John Wiley & Sons. ISBN 978-0471-70907-7. • McGeady, Thomas A. et al (2006). “Establishment of the Basic Body Plan”. Veterinary embryology. Wiley-Blackwell. ISBN 978-1-4051-1147-8. • Pappaioannou, Virginia, E. (2004). “Early Embryonic Mesoderm Development”. In Lanza, Robert Paul. Handbook of stem cells, Volume 1. Gulf Professional Publishing. ISBN 978-0-12-436642-8. • Sherman, Lawrence S. et al., ed. (2001). Human embryology (3rd ed.). Elsevier Health Sciences. ISBN 978-0-443-06583-5.
54.10 External links • Embryology at UNSW Notes/skmus6 • Embryology at Temple EMBIII97/sld039
Chapter 55
Endoderm Endoderm is one of the three primary germ layers in the very early embryo. The other two layers are the ectoderm (outside layer) and mesoderm (middle layer), with the endoderm as the innermost layer.[1] Cells migrating inward along the archenteron form the inner layer of the gastrula, which develops into the endoderm.
• Endodermal sinus tumor • Gastrulation
55.4 References
The endoderm consists at first of flattened cells, which subsequently become columnar. It forms the epithelial lining of multiple systems.
[1] Langman’s Medical Embryology, 11th edition. 2010. [2] Gilbert, SF. “Edoderm”. Sinauer Associates. Retrieved 14 March 2013. [3] The General category denotes that all or most of the animals containing this layer produce the adjacent product.
55.1 Production The following chart shows the products produced by the endoderm. The embryonic endoderm develops into the interior linings of two tubes in the body, the digestive and respiratory tube.[2]
[4] Zaret KS (October 2001). “Hepatocyte differentiation: from the endoderm and beyond”. Curr. Opin. Genet. Dev. 11 (5): 568–74. doi:10.1016/S0959-437X(00)00234-3. PMID 11532400.
Liver and pancreas cells are believed to derive from a common precursor.[4] This article incorporates text from a public domain edition In humans,the endoderm can differentiate into distin- of Gray’s Anatomy. guishable organs after 5 weeks of embryonic development.
55.2 Additional images • Section through the embryo. • Section through ovum imbedded in the uterine decidua • Signaling pathway to inducing endoderm
55.3 See also • Ectoderm • Germ layer • Histogenesis • Mesoderm • Organogenesis 176
Chapter 56
Implantation (human embryo) the uterine fluid. These changes are collectively known as the plasma membrane transformation and bring the blastocyst nearer to the endometrium and immobilize it. During this stage the blastocyst can still be eliminated by being flushed out of the uterus. Scientists have hypothesized that the hormones cause a swelling that fills the flattened out uterine cavity just prior to this stage, which may also help press the blastocyst against the endometrium.[6] The implantation window may also be initiated by other preparations in the endometrium of the uterus, both structurally and in the composition of its secretions.
Fertilization in humans. The sperm and ovum unite through fertilization, creating a conceptus that (over the course of 8-9 days) will implant in the uterine wall, where it will reside over the course of 9 months.
56.2 Adaptation of uterus To enable implantation, the uterus goes through changes in order to be able to receive the conceptus.
In humans (as in all other mammals, except for monotremes), implantation is the very early stage of pregnancy at which the conceptus adheres to the wall of 56.2.1 Predecidualization the uterus.[1] At this stage of prenatal development, the conceptus is a blastocyst. It is by this adhesion that the The endometrium increases thickness, becomes foetus receives oxygen and nutrients from the mother to vascularized and its glands grow to be tortuous and be able to grow. boosted in their secretions. These changes reach their In humans, implantation of a fertilized ovum is most maximum about 7 days after ovulation. likely to occur about 9 days after ovulation, ranging beFurthermore, the surface of the endometrium produces a tween 6 and 12 days.[2] kind of rounded cells, which cover the whole area toward the uterine cavity. This happens about 9 to 10 days after ovulation.[7] These cells are called decidual cells, which 56.1 Implantation window emphasises that the whole layer of them is shed off in every menstruation if no pregnancy occurs, just as leaves The reception-ready phase of the endometrium of the of deciduous trees. The uterine glands, on the other hand, uterus is usually termed the “implantation window” and decrease in activity and degenerate already 8 to 9 days[7] lasts about 4 days. The implantation window follows after ovulation in absence of pregnancy. around 6 days after the peak in luteinizing hormone lev- The stromal cells originate from the stromal cells that are els. With some disparity between sources, it has been always present in the endometrium. However, the decidstated to occur from 7 days after ovulation until 9 days ual cells make up a new layer, the decidua. The rest of the after ovulation,[3] or days 6-10 postovulation.[4] On aver- endometrium, in addition, expresses differences between age, it occurs during the 20th to the 23rd day after the the luminal and the basal sides. The luminal cells form last menstrual period.[5] the zona compacta of the endometrium, in contrast to the The implantation window is characterized by changes to basalolateral zona spongiosa, which consists of the rather the endometrium cells, which aid in the absorption of spongy stromal cells.[7] 177
178
56.2.2
CHAPTER 56. IMPLANTATION (HUMAN EMBRYO)
Decidualization
Decidualization succeeds predecidualization if pregnancy occurs. This is an expansion of it, further developing the uterine glands, the zona compacta and the epithelium of decidual cells lining it. The decidual cells become filled with lipids and glycogen and take the polyhedral shape characteristic for decidual cells.
Trigger It is likely that the blastocyst itself makes the main contribution to this additional growing and sustaining of the decidua. An indication of this is that decidualization occurs at a higher degree in conception cycles than in nonconception cycles.[7] Furthermore, similar changes are observed when giving stimuli mimicking the natural invasion of the embryo.[7]
56.2.4 Pinopodes Main article: Pinopod Pinopodes are small, finger-like protrusions from the endometrium. They appear between day 19 and day 21[7] of gestational age. This corresponds to a fertilization age of approximately 5 to 7 days, which corresponds well with the time of implantation. They only persist for 2 to 3 days.[7] The development of them is enhanced by progesterone but inhibited by estrogens.
Function in implantation Pinopodes endocytose uterine fluid and macromolecules in it. By doing so, the volume of the uterus decreases, taking the walls closer to the embryoblast floating in it. Thus, the period of active pinocytes might also limit the implantation window.[7]
Parts of decidua The decidua can be organized into separate sections, al- Function during implantation though they have the same composition. Pinopodes continue to absorb fluid, and removes most of it during the early stages of implantation. • Decidua basalis - This is the part of the decidua which is located basalolateral to the embryo after implantation.
56.3 Adaptation of secretions • Decidua capsularis - Decidua capsularis grows over the embryo on the luminal side, enclosing it into Not only the lining of the uterus transforms, but in addithe endometrium. It surrounds the embryo together tion, the secretion from its epithelial glands changes. This with decidua basalis. change is induced by increased levels of progesterone from the corpus luteum. The target of the secretions is the embryoblast, and has several functions on it. • Decidua parietalis - All other decidua on the uterine surface belongs to decidua parietalis.
56.3.1 Nourishment 56.2.3
Decidua throughout pregnancy
After implantation the decidua remains, at least through the first trimester.[7] However, its most prominent time is during the early stages of pregnancy, during implantation. Its function as a surrounding tissue is replaced by the definitive placenta. However, some elements of the decidualization remain throughout pregnancy.[7] The compacta and spongiosa layers are still observable beneath the decidua in pregnancy. The glands of the spongiosa layer continue to secrete during the first trimester, when they degenerate. However, before that disappearance, some glands secrete unequally much. This phenomenon of hypersecretion is called the AriasStella phenomenon,[7] after the pathologist Javier AriasStella.
The embryoblast spends approximately 72 hours[7] in the uterine cavity before implanting. In that time, it cannot receive nourishment directly from the blood of the mother, and must rely on secreted nutrients into the uterine cavity, e.g. iron[7] and fat-soluble vitamins.[7]
56.3.2 Growth and implantation In addition to nourishment, the endometrium secretes several steroid-dependent proteins,[7] important for growth and implantation. Cholesterol[7] and steroids[7] are also secreted. Implantation is further facilitated by synthesis of matrix substances, adhesion molecules and surface receptors for the matrix substances.
56.4. MECHANISM
56.4 Mechanism
179 Molecular Mechanism
Implantation is initiated when the blastocyst comes into The identity of the molecules on the trophoblast and the endometrial epithelia that mediate the initial intercontact with the uterine wall. action between the two remain unidentified. However, a number of research groups have proposed that MUC1, a member of the Mucin family of glycosylated proteins, is involved.[8] MUC1 is a transmembrane glycoprotein 56.4.1 Zona hatching expressed at the apical surface of endometrial epithelial cells during the window of implantation in humans and Main article: Zona hatching has been shown to be differentially expressed between fertile and infertile subjects during this time.[8] MUC1 To be able to perform implantation, the blastocyst first displays carbohydrate moieties on its extracellular doneeds to get rid of its zona pellucida. This process can be main that are ligands of L-selectin, a protein expressed called “hatching”. on the surface of trophoblast cells.[9] An in vitro model of implantation developed by Genbacev et al., gave evidence to support the hypothesis that L-selectin mediates apposition of the blastocyst to the uterine epithelium by Factors interacting with its ligands.[10] Lytic factors in the uterine cavity, as well as factors from the blastocyst itself are essential for this process. Mechanisms in the latter are indicated by that the zona pellucida remains intact if an unfertilized egg is placed in the uterus under the same conditions.[7] A substance probably involved is plasmin. Plasminogen, the plasmin precursor, is found in the uterine cavity, and blastocyst factors contribute to its conversion to active plasmin. This hypothesis is supported by lytic effects in vitro by plasmin.[7] Furthermore, plasmin inhibitors also inhibit the entire zona hatching in rat experiments.[7]
56.4.3 Adhesion Adhesion is a much stronger attachment to the endometrium than the loose apposition. The trophoblasts adhere by penetrating the endometrium, with protrusions of trophoblast cells.
Communication
56.4.2
Apposition
There is massive communication between the blastocyst and the endometrium at this stage. The blastocyst signals The very first, albeit loose, connection between the blas- to the endometrium to adapt further to its presence, e.g. tocyst and the endometrium is called the apposition.[7] by changes in the cytoskeleton of decidual cells. This, in turn, dislodges the decidual cells from their connection to the underlying basal lamina, which enables the blastocyst to perform the succeeding invasion.[7] Location This communication is conveyed by receptor-ligandOn the endometrium, the apposition is usually made interactions, both integrin-matrix and proteoglycan ones. where there is a small crypt in it, perhaps because it increases the area of contact with the rather spherical blastocyst. proteoglycan receptors Another ligand-receptor sysOn the blastocyst, on the other hand, it occurs at a loca- tem involved in adhesion is proteoglycan receptors, found tion where there has been enough lysis of the zona pel- on the surface of the decidua of the uterus. Their counterlucida to have created a rupture to enable direct contact parts, the proteoglycans, are found around the trophoblast between the underlying trophoblast and the decidua of the cells of the blastocyst. This ligand-receptor system also endometrium.[7] However, ultimately, the inner cell mass, is present just at the implantation window.[7] inside the trophoblast layer, is aligned closest to the decidua. Nevertheless, the apposition on the blastocyst is not dependent on if it is on the same side of the blastocyst as the inner cell mass. Rather, the inner cell mass 56.4.4 Invasion rotates inside the trophoblast to align to the apposition.[7] In short, the entire surface of the blastocyst has a potential Invasion is an even further establishment of the blastocyst to form the apposition to the decidua. in the endometrium.
180 Syncytiotrophoblasts The protrusions of trophoblast cells that adhere into the endometrium continue to proliferate and penetrate into the endometrium. As these trophoblast cells penetrate, they differentiate to become a new type of cells, syncytiotrophoblast. The prefix syn- refers to the transformation that occurs as the boundaries between these cells disappear to form a single mass of many cell nuclei (a syncytium). The rest of the trophoblasts, surrounding the inner cell mass, are hereafter called cytotrophoblasts. Invasion continues with the syncytiotrophoblasts reaching the basal membrane beneath the decidual cells, penetrating it and further invading into the uterine stroma. Finally, the whole embryo is embedded in the endometrium. Eventually, the syncytiotrophoblasts come into contact with maternal blood and form chorionic villi. This is the initiation of forming the placenta. Secretions
CHAPTER 56. IMPLANTATION (HUMAN EMBRYO) Immunosuppressive The embryo differs from the cells of the mother, and would be rejected as a parasite by the immune system of the mother if it didn't secrete immunosuppressive agents. Such agents are Platelet-activating factor, human chorionic gonadotropin, early pregnancy factor, immunosuppressive factor, Prostaglandin E2, Interleukin 1-alpha, Interleukin 6, interferon-alpha, leukemia inhibitory factor and Colony-Stimulating Factor. Decidualization Factors from the blastocyst also trigger the final formation of decidual cells into their proper form. In contrast, some decidual cells in the proximity of the blastocyst degenerate, providing nutrients for it.[7] Prevention of menstruation Human chorionic gonadotropin (hCG) not only acts as an immunosuppressive,[7] but also “notifies” the mother’s body that she is pregnant, preventing menstruation by sustaining the function of the corpus luteum.
The blastocyst secretes factors for a multitude of purposes during invasion. It secretes several autocrine fac- Other factors Other factors secreted by the blastocyst tors, targeting itself and stimulating it to further invade are; the endometrium.[7] Furthermore, secretions loosen de• ovum factor cidual cells from each other, prevent the embryo from being rejected by the mother, trigger the final decidual• Embryo-derived histamine-releasing factor ization and prevent menstruation. • Tissue plasminogen activator as well as its inhibitors Autocrine Human chorionic gonadotropin is an autocrine growth factor for the blastocyst.[7] Insulin-like growth factor 2,[7] on the other hand, stimulates the invasiveness of it.
• Estradiol • β1-integrins • Fibroblast growth factor • Transforming growth factor alpha
Dislodging The syncytiotrophoblasts dislodges decidual cells in their way, both by degradation of cell adhesion molecules linking the decidual cells together as well as degradation of the extracellular matrix between them. Cell adhesion molecules are degraded by syncytiotrophoblast secretion of Tumor necrosis factor-alpha. This inhibits the expression of cadherins and beta-catenin.[7] Cadherins are cell adhesion molecules, and beta-catenin helps to anchor them to the cell membrane. Inhibited expression of these molecules thus loosens the connection between decidual cells, permitting the syncytotrophoblasts and the whole embryo with them to invade into the endometrium. The extracellular matrix is degraded by serine enExamples of dopeptidases and metalloproteinases. such metalloproteinases are collagenases, gelatinases and stromelysins.[7] These collagenases digest Type-I collagen, Type-II collagen, Type-III collagen, Type-VII collagen and Type-X collagen.[7] The gelatinases exist in two forms; one digesting Type-IV collagen and one digesting gelatin.[7]
• inhibin
56.5 Failure Implantation failure is considered to be caused by inadequate uterine receptivity in two-thirds of cases, and by problems with the embryo itself in the other third.[11] Inadequate uterine receptivity may be caused by abnormal cytokine and hormonal signaling as well as epigenetic alterations.[12] Recurrent implantation failure is a cause of female infertility. Therefore, pregnancy rates can be improved by optimizing endometrial receptivity for implantation.[12] Evaluation of implantation markers may help to predict pregnancy outcome and detect occult implantation deficiency.[12] Luteal support is the administration of medication, generally progestins, for the purpose of increasing the success rate of implantation and early embryogenesis, thereby complementing the function of the corpus luteum.
56.8. FURTHER READING
181
In women with more than 3 implantation failures [11] Melford, S. E.; Taylor, A. H.; Konje, J. C. (2013). “Of mice and (wo)men: factors influencing successful implanin assisted reproduction, a review of several small tation including endocannabinoids”. Human Reproduction randomized controlled studies estimated that the use Update 20 (3): 415–428. doi:10.1093/humupd/dmt060. of adjunct low molecular weight heparin (LMWH) imISSN 1355-4786. [13] proves live birth rate by approximately 80%.
56.6 See also • Embryonic diapause • Blastocyst
56.7 References [1] http://www.stfm.org/fmhub/fm2004/November/ Walter690.pdf [2] Wilcox AJ, Baird DD, Weinberg CR (1999). “Time of implantation of the Conceptus and loss of pregnancy”. New England Journal of Medicine 340 (23): 1796– 1799. doi:10.1056/NEJM199906103402304. PMID 10362823. [3] Xiao, Y.; Sun, X.; Yang, X.; Zhang, J.; Xue, Q.; Cai, B.; Zhou, Y. (2010). “Leukemia inhibitory factor is dysregulated in the endometrium and uterine flushing fluid of patients with adenomyosis during implantation window”. Fertility and Sterility 94 (1): 85–89. doi:10.1016/j.fertnstert.2009.03.012. PMID 19361790. [4] Aboubakr M. Elnashar, Gamal I. Aboul-Enein. Endometrial receptivity. Middle East Fertility Society Journal, Vol. 9, No. 1, 2004, pp. 10-24 [5] 6.2 Implantation stages from embryology.ch at by the universities of Fribourg, Lausanne and Bern (Switzerland). Retrieved May, 2012 [6] “Implantation stages”. Human Embryology. Online course in embryology for medicine students developed by the universities of Fribourg, Lausanne and Bern (Switzerland) with the support of the Swiss Virtual Campus. Retrieved 6 December 2011. [7] Boron, Walter; Emile Boulpaep (2004). Medical Physiology: A Cellular And Molecular Approaoch. Oxford: Elsevier. ISBN 1-4160-2328-3. OCLC 61527528. [8] Margarit, L.; et al., (2010). “MUC1 as a discriminator between endometrium from fertile and infertile patients with PCOS and endometriosis.”. J. Clin. Endocrinol. Metab. 95: 5320. [9] Carson, D. D.; et al., (2006). “MUC1 is a scaffold for selectin ligands in the human uterus.”. Front. Biosci. 1 (11): 2903. [10] Genbacev, O. D.; et al., (2003). “Trophoblast L-selectinmediated adhesion at the maternal-fetal interface.”. Science 299: 405.
[12] Cakmak, H.; Taylor, H. S. (2010). “Implantation failure: Molecular mechanisms and clinical treatment”. Human Reproduction Update 17 (2): 242–253. doi:10.1093/humupd/dmq037. PMC 3039220. PMID 20729534. [13] Potdar, N.; Gelbaya, T. A.; Konje, J. C.; Nardo, L. G. (2013). “Adjunct low-molecular-weight heparin to improve live birth rate after recurrent implantation failure: A systematic review and metaanalysis”. Human Reproduction Update 19 (6): 674–684. doi:10.1093/humupd/dmt032. PMID 23912476.
56.8 Further reading • “Implantation of the blastocyst...”
Chapter 57
Birth For other uses, see Birth (disambiguation) and these large animals, the birth process is similar to that of Childbirth. a human though in most, the offspring is precocial. This Birth, also known as parturition, is the act or process means that it is born in a more advanced state than a human baby and is able to stand, walk and run (or swim in the case of an aquatic mammal) shortly after birth.[2] In the case of whales, dolphins and porpoises, the single calf is normally born tail first which minimises the risk of drowning.[3] The mother encourages the newborn calf to rise to the surface of the water to breathe.[4] Most smaller mammals have multiple births, producing litters of young which may number twelve or more. In these animals, each fetus is surrounded by its own amniotic sac and has a separate placenta. This separates from the wall of the uterus during labor and the fetus works its way towards the birth canal. Lambing: the mother licks the first lamb while giving birth to the second
of bearing or bringing forth offspring.[1] In mammals, the process is initiated by hormones which cause the muscular walls of the uterus to contract, expelling the fetus at a developmental stage when it is ready to feed and breathe. In some species the offspring is precocial and can move around almost immediately after birth but in others it is altricial and completely dependent on parenting. In marsupials, the fetus is born at a very immature stage after a short gestational period and develops further in its mother’s pouch. It is not only mammals that give birth. Some reptiles, amphibians, fish and invertebrates carry their developing young inside them. Some of these are ovoviviparous, with the eggs being hatched inside the mother’s body, and others are viviparous, with the embryo developing inside her body, as in mammals.
57.1 Birth in mammals Large mammals, such as primates, cattle, horses, some antelopes, giraffes, hippopotamuses, rhinoceroses, elephants, seals, whales, dolphins, and porpoises, generally are pregnant with one offspring at a time; although, they may have twin or multiple births on occasion. In
57.1.1 Human birth Main article: Childbirth Humans usually produce a single offspring at a time. The mother’s body is prepared for birth by hormones produced by the pituitary gland, the ovary and the placenta.[2] The total gestation period from fertilization to birth is normally about 38 weeks (birth usually occurring 40 weeks after the last menstrual period). The normal process of childbirth takes several hours and has three stages. The first stage starts with a series of involuntary contractions of the muscular walls of the uterus and gradual dilation of the cervix. The active phase of the first stage starts when the cervix is dilated more than about 4 cm in diameter and is when the contractions become stronger and regular. The head (or the buttocks in a breech birth) of the baby is pushed against the cervix, which gradually dilates until is fully dilated at 10 cm diameter. At some time, the amniotic sac bursts and the amniotic fluid escapes (also known as rupture of membranes or breaking the water).[5] In stage two, starting when the cervix is fully dilated, strong contractions of the uterus and active pushing by the mother expels the baby out through the vagina, which during this stage of labour is called a birth canal as this passage contains a baby, and the baby is born with umbilical cord attached.[6] In stage three, which begins after the birth of the baby, further contractions expel the placenta, amniotic sac, and the remaining portion of the
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57.1.2 Cattle
Cow and newborn calf
An illustration of normal head-first presentation by the obstetrician William Smellie from about 1792. The membranes have ruptured and the cervix is fully dilated.
umbilical cord usually within a few minutes.[7] Enormous changes take place in the newborn’s circulation to enable breathing in air. In the uterus, the unborn baby is dependent on circulation of blood through the placenta for sustenance including gaseous exchange and the unborn baby’s blood bypasses the lungs by flowing though the foramen ovale, which is a hole in the septum dividing the right atrium and left atrium. After birth the umbilical cord is clamped and cut, the baby starts to breathe air, and blood from the right ventricle starts to flow to the lungs for gaseous exchange and oxygenated blood returns to the left atrium, which is pumped into the left ventricle, and then pumped into the main arterial system. As result of these changes, the blood pressure in the left atrium exceeds the pressure in the right atrium, and this pressure difference forces the foramen ovale to close separating the left and right sides of the heart. The umbilical vein, umbilical arteries, ductus venosus and ductus arteriosus are not needed for life in air and in time these vessels become ligaments (embryonic remnants).[8]
Birthing in cattle is typical of a larger mammal. A cow goes through three stages of labor during normal delivery of a calf. During stage one, the animal seeks a quiet place away from the rest of the herd. Hormone changes cause soft tissues of the birth canal to relax as the mother’s body prepares for birth. The contractions of the uterus are not obvious externally, but the cow may be restless. She may appear agitated, alternating between standing and lying down, with her tail slightly raised and her back arched. The fetus is pushed toward the birth canal by each contraction and the cow’s cervix gradually begins to dilate. Stage one may last several hours, and ends when the cervix is fully dilated. Stage two can be seen to be underway when there is external protrusion of the amniotic sac through the vulva, closely followed by the appearance of the calf’s front hooves and head in a front presentation (or occasionally the calf’s tail and rear end in a posterior presentation).[9] During the second stage, the cow will usually lie down on her side to push and the calf progresses through the birth canal. The complete delivery of the calf (or calves in a multiple birth) signifies the end of stage two. The cow scrambles to her feet (if lying down at this stage), turns round and starts vigorously licking the calf. The calf takes its first few breaths and within minutes is struggling to rise to its feet. The third and final stage of labor is the delivery of the placenta, which is usually expelled within a few hours and is often eaten by the normally herbivorous cow.[9][10]
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57.1.3
CHAPTER 57. BIRTH
Dogs
57.2 Birth in other animals
Further information: Canine reproduction § Gestation The vast majority of invertebrates, most fish, reptiles and and litters amphibians and all birds are oviparous, that is, they lay eggs with little or no embryonic development taking place In the dog, as birth approaches, contractions become within the mother. In aquatic organisms, fertilization is more frequent. The amniotic sac looking like a glisten- nearly always external with sperm and eggs being libering grey balloon, with a puppy inside, is propelled through ated into the water (an exception is sharks and rays, which the vulva. After further contractions, the sac is expelled have internal fertilization[13] ). Millions of eggs may be and the bitch breaks the membranes releasing clear fluid produced with no further parental involvement, in the exand exposing the puppy. The mother chews at the umbili- pectation that a small number may survive to become macal cord and licks the puppy vigorously, which stimulates ture individuals. Terrestrial invertebrates may also proit to breathe. If the puppy has not taken its first breath duce large numbers of eggs, a few of which may avoid within about six minutes, it is likely to die. Further pup- predation and carry on the species. Some fish, reptiles pies follow in a similar way one by one usually with less and amphibians have adopted a different strategy and instraining than the first. The mother will then usually eat vest their effort in producing a small number of young at a more advanced stage which are more likely to survive the afterbirth.[11] to adulthood. Birds care for their young in the nest and provide for their needs after hatching and it is perhaps unsurprising that internal development does not occur in birds, given their need to fly.[14] 57.1.4 Marsupials See also: Marsupial § Reproductive system and Marsupial § Early development An infant marsupial is born in a very immature state.
A kangaroo joey firmly attached to a nipple inside the pouch
The gestation period is usually shorter than the intervals between oestrus periods. During gestation there is no placenta but the fetus is contained in a little yellow sac and feeds on a yolk. The first sign that a birth is imminent is the mother cleaning out her pouch. When it is born, the infant is pink, blind, furless and a few centimetres long. It has nostrils in order to breathe and forelegs to cling onto its mother’s hairs but its hind legs are undeveloped. It crawls through its mother’s fur and makes its way into the pouch. Here it fixes onto a teat which swells inside its mouth. It stays attached to the teat for several months until it is sufficiently developed to emerge.[12]
Ovoviviparity is a mode of reproduction in which embryos develop inside eggs that are retained within the mother’s body until they are ready to hatch. Ovoviviparous animals are similar to viviparous species in that there is internal fertilization and the young are born in an advanced state, but differ in that there is no placental connection and the unborn young are nourished by egg yolk. The mother’s body provides gas exchange (respiration), but that is largely necessary for oviparous animals as well.[14] In many sharks the eggs hatch in the oviduct within the mother’s body and the embryos are nourished by the egg’s yolk and fluids secreted by glands in the walls of the oviduct. The Lamniforme sharks practice oophagy, where the first embryos to hatch consume the remaining eggs and sand tiger shark pups cannibalistically consume neighbouring embryos. The requiem sharks maintain a placental link to the developing young, this practice is known as viviparity. This is more analogous to mammalian gestation than to that of other fishes. In all these cases, the young are born alive and fully functional.[15] The majority of caecilians are oviviviparous and give birth to already developed offspring. When the young have finished their yolk sacs they feed on nutrients secreted by cells lining the oviduct and even the cells themselves which they eat with specialist scraping teeth.[16] The Alpine salamander (Salamandra atra) and several species of Tanzanian toad in the genus Nectophrynoides are oviviviparous, developing through the larval stage inside the mother’s oviduct and eventually emerging as fully formed juveniles.[17] A more developed form of vivipary called placental viviparity is adopted by some species of scorpions[18] and cockroaches,[19] certain genera of sharks, snakes and velvet worms. In these, the developing embryo is nourished by some form of placental structure. The earliest known placenta was found recently in a group of extinct
57.4. REFERENCES fishes called placoderms, which are ancestral to mammals. A fossil from Australia’s Gogo Formation, laid down in the Devonian period, 380 million years ago, was found with an embryo inside it connected by an umbilical cord to a yolk sac. The find confirmed the hypothesis that a sub-group of placoderms, called ptyctodontids, fertilized their eggs internally. Some fishes that fertilize their eggs internally also give birth to live young, as seen here. This discovery moved our knowledge of live birth back 200 million years.[20] The fossil of another genus was found with three embryos in the same position.[21] Placoderms are a sister group of the ancestor of all living jawed fishes (Gnathostomata), including both chondrichthyians, the sharks & rays, and Osteichthyes, the bony fishes. Among lizards, the viviparous lizard Zootoca vivipara, slow worms and many species of skink are viviparous, giving birth to live young. Some are ovoviviparous but others such as members of the genera Tiliqua and Corucia, give birth to live young that develop internally, deriving their nourishment from a mammal-like placenta attached to the inside of the mother’s uterus. In a recently described example, an African species, Trachylepis ivensi, has developed a purely reptilian placenta directly comparable in structure and function to a mammalian placenta.[22] Vivipary is rare in snakes, but boas and vipers are viviparous, giving birth to live young.
185 • Breeding season • Dystocia • Foaling (horses) • Gestation • Lambing (sheep) • Mating system • Reproduction • Reproductive system • Perineal massage • Episiotomy • Caesarean section • Forceps delivery • Ventouse • Odon device • Kegel exercises
57.4 References [1] “birth”. OED Online. June 2013. Oxford University Press. Entry 19395 (accessed 30 August 2013). [2] Dorit, R. L.; Walker, W. F.; Barnes, R. D. (1991). Zoology. Saunders College Publishing. pp. 526–527. ISBN 978-0-03-030504-7. [3] Mark Simmonds, Whales and Dolphins of the World, New Holland Publishers (2007), Ch. 1, p. 32 ISBN 1845378202. Female aphid giving birth
[4] Crockett, Gary (2011). “Humpback Whale Calves”. Humpback whales Australia. Retrieved 2013-08-28.
The majority of insects lay eggs but a very few give birth [5] to offspring that are miniature versions of the adult.[14] The aphid has a complex life cycle and during the sum- [6] mer months is able to multiply with great rapidity. Its [7] reproduction is typically parthenogenetic and viviparous and females produce unfertilized eggs which they retain [8] within their bodies.[23] The embryos develop within their mothers’ ovarioles and the offspring are clones of their mothers. Female nymphs are born which grow rapidly [9] and soon produce more female offspring themselves.[24] In some instances, the newborn nymphs already have developing embryos inside them.[14] [10]
57.3 See also • Animal sexual behaviour
NICE (2007). Section 1.6, Normal labour: first stage NICE (2007). Section 1.7, Normal labour: second stage NICE (2007). Section 1.8, Normal labour: third stage Houston, Rob (editor); Lea, Maxine (art editor) (2007). The Human Body Book. Dorling Kindersley. p. 215. ISBN 978-1-8561-3007-3. “Calving”. Alberta: Agriculture and Rural Development. 2000-02-01. Retrieved 2013-08-28. “Calving Management in Dairy Herds: Timing of Intervention and Stillbirth”. The Ohio State University College of Veterinary Medicine Extension. 2012. Retrieved 2013-12-17.
[11] Dunn, T.J. “Whelping: New Puppies On The Way!". Puppy Center. Pet MD. Retrieved 2013-08-28.
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[12] “Reproduction and development”. Thylacine Museum. Retrieved 2013-08-28. [13] Sea World, Sharks & Rays; accessed 2013.09.09. [14] Attenborough, David (1990). The Trials of Life. pp. 26– 30. ISBN 9780002199124. [15] “Birth and care of young”. Animals: Sharks and rays. Busch Entertainment Corporation. Retrieved 2013-0828. [16] Stebbins, Robert C.; Cohen, Nathan W. (1995). A Natural History of Amphibians. Princeton University Press. pp. 172–173. ISBN 978-0-691-03281-8. [17] Stebbins, Robert C.; Cohen, Nathan W. (1995). A Natural History of Amphibians. Princeton University Press. p. 204. ISBN 978-0-691-03281-8. [18] Capinera, John L., Encyclopedia of entomology. Springer Reference, 2008, p. 3311. [19] Costa, James T., The Other Insect Societies. Belknap Press, 2006, p. 151. [20] Dennis, Carina (2008-05-28). “Nature News: The oldest pregnant mum: Devonian fossilized fish contains an embryo”. Nature 453 (7195): 575. Bibcode:2008Natur.453..575D. doi:10.1038/453575a. [21] Long, John A.; Trinastic, Kate; Young, Gavin C.; Senden, Tim (2008-05-28). “Live birth in the Devonian period”. Nature 453 (7195): 650–652. Bibcode:2008Natur.453..650L. doi:10.1038/nature06966. PMID 18509443. [22] Blackburn, Daniel G.; Flemming, Alexander F.; Flemming (2012). “Invasive implantation and intimate placental associations in a placentotrophic African lizard, Trachylepis ivensi (Scincidae)". Journal of Morphology 273 (2): 137–159. doi:10.1002/jmor.11011. PMID 21956253. [23] Blackman, Roger L (1979). “Stability and variation in aphid clonal lineages”. Biological Journal of the Linnean Society 11 (3): 259–277. doi:10.1111/j.10958312.1979.tb00038.x. ISSN 1095-8312. [24] Conrad, Jim (2011-12-10). “The aphid life cycle”. The Backyard Nature Website. Retrieved 2013-08-31.
57.5 Cited texts • “Intrapartum care: Care of healthy women and their babies during childbirth”. NICE. September 2007.
CHAPTER 57. BIRTH
Chapter 58
Mammary gland “Mammary” redirects here. For the mountain in Alaska, Mammary epithelial ECM mainly contains myoepithelial basement membrane and the connective tissue. They not see Mammary Peak. only help to support mammary basic structure, but also A mammary gland is an organ in female mammals that serve as a communicating bridge between mammary epithelia and their local and global environment throughout produces milk to feed young offspring. Mammals get [5][6] their name from the word “mammary.” In humans, the this organ’s development. mammary glands are situated in the breasts. In ruminants such as cows, goats, and deer, the mammary glands are 58.1.1 Histology contained in the udders. The mammary glands of mammals other than primates, such as dogs and cats, are someA mammary gland is a specific type of apocrine gland times called dugs. specialized for manufacture of colostrum when giving birth. Mammary glands can be identified as apocrine because they exhibit striking “decapitation” secretion. 58.1 Structure Many sources assert that mammary glands are modified sweat glands.[7][8][9] Some authors dispute that and argue instead that they are sebaceous glands.[7] See also: Breast The basic components of a mature mammary gland are the alveoli (hollow cavities, a few millimeters large) lined with milk-secreting cuboidal cells and surrounded by myoepithelial cells. These alveoli join to form groups known as lobules. Each lobule has a lactiferous duct that drains into openings in the nipple. The myoepithelial cells contract under the stimulation of oxytocin, excreting the milk secreted by alveolar units into the lobule lumen toward the nipple. As the infant begins to suck, the oxytocin-mediated “let down reflex” ensues and the mother’s milk is secreted — not sucked from the gland — into the baby’s mouth. All the milk-secreting tissue leading to a single lactiferous duct is called a “simple mammary gland"; in a “complex mammary gland” all the simple mammary glands serve one nipple. Humans normally have two complex mammary glands, one in each breast, and each complex mammary gland consists of 10–20 simple glands. The presence of more than two nipples is known as polythelia and the presence of more than two complex mammary glands as polymastia. Maintaining the correct polarized morphology of the lactiferous duct tree requires another essential component – mammary epithelial cells extracellular matrix (ECM) which, together with adipocytes, fibroblast, inflammatory cells, and others, constitute mammary stroma.[4]
58.1.2 Development Further information: Mammary gland development Mammary glands develop during different growth cycles. They exist in both sexes during embryonic stage, forming only a rudimentary duct tree at birth. In this stage, mammary gland development depends on systemic (and maternal) hormones,[4] but is also under the (local) regulation of paracrine communication between neighboring epithelial and mesenchymal cells by parathyroid hormone-related protein(PTHrP).[10] This locally secreted factor gives rise to a series of outside-in and insideout positive feedback between these two types of cells, so that mammary bud epithelial cells can proliferate and sprout down into the mesenchymal layer until they reach the fat pad to begin the first round of branching.[4] At the same time, the embryonic mesenchymal cells around the epithelial bud receive secreting factors activated by PTHrP, such as BMP4. These mesenchymal cells can transform into a dense, mammary-specific mesenchyme, which later develop into connective tissue with fibrous threads, forming blood vessels and the lymph system.[11] A basement membrane, mainly containing laminin and collagen, formed afterward by differentiated myoepithelial cells, keeps the polarity of this primary duct tree.
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58.2 Physiology 58.2.1
Hormonal control
Lactiferous duct development occurs in females in response to circulating hormones. First development is frequently seen during pre- and postnatal stages, and later during puberty. Estrogen promotes branching differentiation,[12] whereas in males testosterone inhibits it. A mature duct tree reaching the limit of the fat pad of the mammary gland comes into being by bifurcation of duct terminal end buds (TEB), secondary branches sprouting from primary ducts[5][13] and proper duct lumen formation. These processes are tightly modulated by components of mammary epithelial ECM interacting with systemic hormones and local secreting factors. However, for each mechanism the epithelial cells’ "niche" can be delicately unique with different membrane receptor profiles and basement membrane thickness from specific branching area to area, so as to regulate cell growth or differentiation sub-locally.[14] Important players include beta-1 integrin, epidermal growth factor receptor (EGFR), laminin-1/5, collagen-IV, matrix metalloproteinase(MMPs), heparan sulfate proteoglycans, and others. Elevated circulating level of growth hormone and estrogen get to multipotent cap cells on TEB tips through a thin, leaky layer of basement membrane. These hormones promote specific gene expression. Hence cap cells can differentiate into myoepithelial and luminal (duct) epithelial cells, and the increased amount of activated MMPs can degrade surrounding ECM helping duct buds to reach further in the fat pads.[15][16] On the other hand, basement membrane along the mature mammary ducts is thicker, with strong adhesion to epithelial cells via binding to integrin and non-integrin receptors. When side branches develop, it is a much more “pushing-forward” working process including extending through myoepithelial cells, degrading basement membrane and then invading into a periductal layer of fibrous stromal tissue.[5] Degraded basement membrane fragments (laminin-5) roles to lead the way of mammary epithelial cells migration.[17] Whereas, laminin−1 interacts with non-integrin receptor dystroglycan negatively regulates this side branching process in case of cancer.[18] These complex “Yin-yang” balancing crosstalks between mammary ECM and epithelial cells “instruct” healthy mammary gland development until adult.
tissue and a richer blood flow. In gestation, serum progesterone remains at a stably high concentration so signaling through its receptor is continuously activated. As one of the transcribed genes, Wnts secreted from mammary epithelial cells act paracrinely to induce more neighboring cells’ branching.[20][21] When the lactiferous duct tree is almost ready, “leaves” alveoli are differentiated from luminal epithelial cells and added at the end of each branch. In late pregnancy and for the first few days after giving birth, colostrum is secreted. Milk secretion (lactation) begins a few days later due to reduction in circulating progesterone and the presence of another important hormone prolactin, which mediates further alveologenesis, milk protein production, and regulates osmotic balance and tight junction function. Laminin and collagen in myoepithelial basement membrane interacting with beta-1 integrin on epithelial surface again, is essential in this process.[22][23] Their binding ensures correct placement of prolactin receptors on the basal lateral side of alveoli cells and directional secretion of milk into lactiferous ducts.[22][23] Suckling of the baby causes release of the hormone oxytocin, which stimulates contraction of the myoepithelial cells. In this combined control from ECM and systemic hormones, milk secretion can be reciprocally amplified so as to provide enough nutrition for the baby.
58.2.3 Weaning
During weaning, decreased prolactin, missing mechanical stimulation (baby suckling), and changes in osmotic balance caused by milk stasis and leaking of tight junctions cause cessation of milk production. In some species there is complete or partial involution of alveolar structures after weaning, in humans there is only partial involution and the level of involution in humans appears to be highly individual. The glands in the breast do secrete fluid also in nonlactating women.[24] In some other species (such as cows), all alveoli and secretory duct structures collapse by programmed cell death (apoptosis) and autophagy for lack of growth promoting factors either from the ECM or circulating hormones.[25][26] At the same time, apoptosis of blood capillary endothelial cells speeds up the regression of lactation ductal beds. Shrinkage of the mammary duct tree and ECM remodeling by various proteinase is under the control of somatostatin and other growth inhibiting hormones and [27] There is preliminary evidence that soybean intake mildly local factors. This major structural change leads loose stimulates the breast glands in pre- and postmenopausal fat tissue to fill the empty space afterward. But a functional lactiferous duct tree can be formed again when a women.[19] female is pregnant again.
58.2.2
Pregnancy
58.3 Clinical significance
Secretory alveoli develop mainly in pregnancy, when rising levels of prolactin, estrogen, and progesterone cause Tumorigenesis in mammary glands can be induced biofurther branching, together with an increase in adipose chemically by abnormal expression level of circulating
58.5. ADDITIONAL IMAGES hormones or local ECM components,[28] or from a mechanical change in the tension of mammary stroma.[29] Under either of the two circumstances, mammary epithelial cells would grow out of control and eventually result in cancer. Almost all instances of breast cancer originate in the lobules or ducts of the mammary glands.
58.4 Other mammals 58.4.1
General
The constantly protruding breasts of the adult human female, unusually large relative to body size, are a unique evolutionary development whose purpose is not yet fully known (see breast); other mammals tend to have less conspicuous mammary glands that protrude only while actually filling with milk. The number and positioning of complex and simple mammary glands varies widely in different mammals. The nipples and glands can occur anywhere along the two milk lines, two nearly parallel lines along the ventral aspect of the body. In general most mammals develop mammary glands in pairs along these lines, with a number approximating the number of young typically birthed at a time. The number of nipples varies from 2 (in most primates) to 18 (in pigs). The Virginia Opossum has 13, one of the few mammals with an odd number.[30][31] The following table lists the number and position of glands normally found in a range of mammals:
189 well, supporting such theories with fossil evidence is difficult. Many of the current theories are based on comparisons between lines of living mammals – monotremes, marsupials and eutherians. One theory proposes that mammary glands evolved from glands that were used to keep the eggs of early mammals moist[38][39] and free from infection[40][41] (monotremes still lay eggs). Other theories suggest that early secretions were used directly by hatched young,[42] or that the secretions were used by young to help them orient to their mothers.[43] Lactation is assumed to have developed long before the evolution of the mammary gland and mammals; see evolution of lactation.
58.5 Additional images • Cross section of the breast of a human female • Cattle • Cat • Pig • Goat • Elephant • Human
58.6 See also Male mammals typically have rudimentary mammary glands and nipples, with a few exceptions: male mice do not have nipples,[34] and male horses lack nipples and mammary glands. The male Dayak fruit bat has lactating mammary glands.[35] Male lactation occurs infrequently in some species, including humans. Mammary glands are true protein factories, and several labs have constructed transgenic animals, mainly goats and cows, to produce proteins for pharmaceutical use.[36] Complex glycoproteins such as monoclonal antibodies or antithrombin cannot be produced by genetically engineered bacteria, and the production in live mammals is much cheaper than the use of mammalian cell cultures.
58.4.2
Evolution
The evolution of the mammary gland is difficult to explain; this is because mammary glands are typically required by mammals to feed their young. There are many theories on how mammary glands evolved, for example, it is believed that the mammary gland is a transformed sweat gland, more closely related to apocrine sweat glands.[37] Since mammary glands do not fossilize
This article uses anatomical terminology; for an overview, see anatomical terminology. • Breastfeeding • Mammary tumor • Mammaglobin • Gynecomastia • Udder • Witch’s milk • Milk line • List of glands of the human body#Skin
58.7 References [1] Gray, Henry (1918). Anatomy of the Human Body. [2] Macéa, José Rafael; Fregnani, José Humberto Tavares Guerreiro (1 December 2006). “Anatomy of the Thoracic Wall, Axilla and Breast”. International Journal of Morphology 24 (4). doi:10.4067/S071795022006000500030.
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[3] Lawrence, Ruth A.; Lawrence, Robert M. Breastfeeding: A Guide for the Medical Profession (7th ed.). Maryland Heights, Maryland: Mosby/Elsevier. p. 54. ISBN 9781437735901.
CHAPTER 58. MAMMARY GLAND
doi:10.1083/jcb.200302090. 12975354.
PMC 2172848.
PMID
[4] Watson, C. J.; Khaled, W. T. (2008). “Mammary development in the embryo and adult: A journey of morphogenesis and commitment”. Development 135 (6): 995– 1003. doi:10.1242/dev.005439. PMID 18296651.
[16] Koshikawa, N.; Giannelli, G.; Cirulli, V.; Miyazaki, K.; Quaranta, V. (2000). “Role of cell surface metalloprotease MT1-MMP in epithelial cell migration over laminin-5”. The Journal of cell biology 148 (3): 615– 624. doi:10.1083/jcb.148.3.615. PMC 2174802. PMID 10662785.
[5] Wiseman, B. S.; Werb, Z. (2002). “Stromal Effects on Mammary Gland Development and Breast Cancer”. Science 296 (5570): 1046–1049. doi:10.1126/science.1067431. PMC 2788989. PMID 12004111.
[17] Dogic, D.; Rousselle, P.; Aumailley, M. (1998). “Cell adhesion to laminin 1 or 5 induces isoform-specific clustering of integrins and other focal adhesion components”. Journal of cell science. 111 (Pt 6): 793–802. PMID 9472007.
[6] Pavlovich, A. L.; Manivannan, S.; Nelson, C. M. (2010). “Adipose Stroma Induces Branching Morphogenesis of Engineered Epithelial Tubules”. Tissue Engineering Part A 16 (12): 3719–3726. doi:10.1089/ten.TEA.2009.0836. PMC 2991209. PMID 20649458.
[18] Muschler, J.; Levy, D.; Boudreau, R.; Henry, M.; Campbell, K.; Bissell, M. J. (2002). “A role for dystroglycan in epithelial polarization: Loss of function in breast tumor cells”. Cancer research 62 (23): 7102–7109. PMID 12460932.
[7] Ackerman (2005) ch.1 Apocrine Units [8] Moore (2010) ch.1 Thorax, p. 99 [9] Krstic, Radivoj V. (18 March 2004). Human Microscopic Anatomy: An Atlas for Students of Medicine and Biology. Springer. p. 466. ISBN 9783540536666. [10] Wysolmerski, J. J.; Philbrick, W. M.; Dunbar, M. E.; Lanske, B.; Kronenberg, H.; Broadus, A. E. (1998). “Rescue of the parathyroid hormone-related protein knockout mouse demonstrates that parathyroid hormone-related protein is essential for mammary gland development”. Development (Cambridge, England) 125 (7): 1285–1294. PMID 9477327. [11] Hens, J. R.; Wysolmerski, J. J. (2005). “Key stages of mammary gland development: Molecular mechanisms involved in the formation of the embryonic mammary gland”. Breast Cancer Research 7 (5): 220–224. doi:10.1186/bcr1306. PMC 1242158. PMID 16168142. [12] Sternlicht, M. D. (2006). “Key stages in mammary gland development: The cues that regulate ductal branching morphogenesis”. Breast Cancer Research 8 (1): 201–203. doi:10.1186/bcr1368. PMC 1413974. PMID 16524451. [13] Sternlicht, M. D.; Kouros-Mehr, H.; Lu, P.; Werb, Z. (2006). “Hormonal and local control of mammary branching morphogenesis”. Differentiation 74 (7): 365– 381. doi:10.1111/j.1432-0436.2006.00105.x. PMC 2580831. PMID 16916375. [14] Fata, J. E.; Werb, Z.; Bissell, M. J. (2003). “Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes”. Breast Cancer Research 6 (1): 1–11. doi:10.1186/bcr634. PMC 314442. PMID 14680479. [15] Wiseman, B. S.; Sternlicht, M. D.; Lund, L. R.; Alexander, C. M.; Mott, J.; Bissell, M. J.; Soloway, P.; Itohara, S.; Werb, Z. (2003). “Site-specific inductive and inhibitory activities of MMP-2 and MMP3 orchestrate mammary gland branching morphogenesis”. The Journal of Cell Biology 162 (6): 1123–1133.
[19] Kurzer MS (March 2002). “Hormonal effects of soy in premenopausal women and men”. The Journal of Nutrition 132 (3): 570S–573S. PMID 11880595. Also cited by Petrakis NL, Barnes S, King EB, Lowenstein J, Wiencke J, Lee MM, Miike R, Kirk M, Coward L (October 1996). “Stimulatory influence of soy protein isolate on breast secretion in pre- and postmenopausal women”. Cancer Epidemiology, Biomarkers & Prevention: a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology (review) 5 (10): 785–94. PMID 8896889. [20] Robinson, G. W.; Hennighausen, L.; Johnson, P. F. (2000). “Side-branching in the mammary gland: The progesterone-Wnt connection”. Genes & development 14 (8): 889–894. PMID 10783160. [21] Brisken, C.; Heineman, A.; Chavarria, T.; Elenbaas, B.; Tan, J.; Dey, S. K.; McMahon, J. A.; McMahon, A. P.; Weinberg, R. A. (2000). “Essential function of Wnt-4 in mammary gland development downstream of progesterone signaling”. Genes & development 14 (6): 650–654. PMC 316462. PMID 10733525. [22] Streuli, C. H.; Bailey, N.; Bissell, M. J. (1991). “Control of mammary epithelial differentiation: Basement membrane induces tissue-specific gene expression in the absence of cell-cell interaction and morphological polarity”. The Journal of cell biology 115 (5): 1383–1395. doi:10.1083/jcb.115.5.1383. PMC 2289247. PMID 1955479. [23] Streuli, C. H.; Schmidhauser, C.; Bailey, N.; Yurchenco, P.; Skubitz, A. P.; Roskelley, C.; Bissell, M. J. (1995). “Laminin mediates tissue-specific gene expression in mammary epithelia”. The Journal of cell biology 129 (3): 591–603. doi:10.1083/jcb.129.3.591. PMC 2120432. PMID 7730398. [24] Nicholas L. Petrakis; Lynn Mason; Rose Lee; Barbara Sugimoto; Stella Pawson; Frank Catchpool (1975). “Association of Race, Age, Menopausal Status, and Cerumen Type With Breast Fluid Secretion in Nonlactating Women, as Determined by Nipple Aspiration”. Journal
58.8. BIBLIOGRAPHY
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of the National Cancer Institute (JNCI) 54 (4): 829–834. doi:10.1093/jnci/54.4.829.
[38] Lactating on Eggs. Smithsonian National Zoo, July 14, 2003.
[25] Zarzynska, J.; Motyl, T. (2008). “Apoptosis and autophagy in involuting bovine mammary gland”. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society. 59 Suppl 9: 275–288. PMID 19261986.
[39] Oftedal, OT (2002). “The mammary gland and its origin during synapsid evolution”. Journal of Mammary Gland Biology and Neoplasia 7 (3): 225–52. doi:10.1023/A:1022896515287. PMID 12751889.
[26] Fadok, V. A. (1999). “Clearance: The last and often forgotten stage of apoptosis”. Journal of mammary gland biology and neoplasia 4 (2): 203–211. doi:10.1023/A:1011384009787. PMID 10426399. [27] Motyl, T.; Gajkowska, B.; Zarzyńska, J.; Gajewska, M.; Lamparska-Przybysz, M. (2006). “Apoptosis and autophagy in mammary gland remodeling and breast cancer chemotherapy”. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society. 57 Suppl 7: 17–32. PMID 17228094. [28] Gudjonsson, T.; Rønnov-Jessen, L.; Villadsen, R.; Rank, F.; Bissell, M. J.; Petersen, O. W. (2002). “Normal and tumor-derived myoepithelial cells differ in their ability to interact with luminal breast epithelial cells for polarity and basement membrane deposition”. Journal of cell science 115 (Pt 1): 39–50. PMC 2933194. PMID 11801722. [29] Provenzano, P. P.; Inman, D. R.; Eliceiri, K. W.; Knittel, J. G.; Yan, L.; Rueden, C. T.; White, J. G.; Keely, P. J. (2008). “Collagen density promotes mammary tumor initiation and progression”. BMC Medicine 6: 11. doi:10.1186/1741-7015-6-11. PMC 2386807. PMID 18442412. [30] “With the Wild Things – Transcripts”. Digitalcollections.fiu.edu. Retrieved 2013-04-05. [31] Stockard, Mary (2005) Raising Orphaned Baby Opossums. Alabama Wildlife Center. [32] Cunningham, Merle; LaTour, Mickey A. and Acker, Duane (2005). Animal Science and Industry. Pearson Prentice Hall. ISBN 978-0-13-046256-5. [33] Dog breeds vary in the number of mammary glands: larger breeds tend to have 5 pairs, smaller breeds have 4 pairs. [34] Julie Ann Mayer; John Foley; Damon De La Cruz; ChengMing Chuong; Randall Widelitz (November 2008). “Conversion of the Nipple to Hair-Bearing Epithelia by Lowering Bone Morphogenetic Protein Pathway Activity at the Dermal-Epidermal Interface”. [35] Francis, C. M.; Anthony, E. L. P.; Brunton, J. A.; Kunz, T. H. (1994). “Lactation in male fruit bats”. Nature 367 (6465): 691. doi:10.1038/367691a0. [36] “BBC News – The goats with spider genes and silk in their milk”. bbc.co.uk. 17 January 2012. Retrieved 26 April 2012. [37] Oftedal, O. T. (2002). “The origin of lactation as a water source for parchment-shelled eggs”. Journal of mammary gland biology and neoplasia 7 (3): 253–266. doi:10.1023/A:1022848632125. PMID 12751890.
[40] Breast beginnings. scienceblogs.com [41] Vorbach, C.; Capecchi, M. R.; Penninger, J. M. (2006). “Evolution of the mammary gland from the innate immune system?". BioEssays 28 (6): 606–616. doi:10.1002/bies.20423. PMID 16700061. [42] Lefèvre, C. M.; Sharp, J. A.; Nicholas, K. R. (2010). “Evolution of Lactation: Ancient Origin and Extreme Adaptations of the Lactation System”. Annual Review of Genomics and Human Genetics 11: 219–238. doi:10.1146/annurev-genom-082509-141806. PMID 20565255. [43] Graves, B. M.; Duvall, D. (1983). “A Role for Aggregation Pheromones in the Evolution of Mammallike Reptile Lactation”. The American Naturalist 122 (6): 835. doi:10.1086/284177.
58.8 Bibliography • Ackerman, A. Bernard; Almut Böer; Bruce Bennin; Geoffrey J. Gottlieb (2005). Histologic Diagnosis of Inflammatory Skin Diseases An Algorithmic Method Based on Pattern Analysis. ISBN 978-1-893357-259. • Moore, Keith L. et al. (2010) Clinically Oriented Anatomy 6th Ed
58.9 External links • Comparative Mammary Gland Anatomy by W. L. Hurley • On the anatomy of the breast by Sir Astley Paston Cooper (1840). Numerous drawings, in the public domain. • mammary+gland at eMedicine Dictionary
Chapter 59
Menstrual cycle See also: Menstruation and Menstruation (mammal) ing sexual reproduction possible.[1][2] Its timing is govThe menstrual cycle is the cycle of natural changes that erned by endogenous (internal) biological cycles. The menstrual cycle is essential for the production of eggs, and for the preparation of the uterus for pregnancy.[1] The cycle occurs only in fertile female humans and other female primates. In human females, the menstrual cycle occurs repeatedly between the age of menarche, when cycling begins, until menopause, when it ends. In humans, the length of a menstrual cycle varies greatly among women (ranging from 21 to 35 days), with 28 days designated as the average length.[3] Each cycle can be divided into three phases based on events in the ovary (ovarian cycle) or in the uterus (uterine cycle).[1] The ovarian cycle consists of the follicular phase, ovulation, and luteal phase whereas the uterine cycle is divided into menstruation, proliferative phase, and secretory phase. Both cycles are controlled by the endocrine system and the normal hormonal changes that occur can be interfered with using hormonal contraception to prevent reproduction.[4]
Figure showing the progression of the menstrual cycle and the different hormones contributing to it.
occurs in the uterus and ovary as an essential part of mak-
By convention, the length of an individual menstrual cycle in days is counted starting with the first day of menstrual bleeding. Stimulated by gradually increasing amounts of estrogen in the follicular phase, discharges of blood (menses) flow then stop, and the lining of the uterus thickens. Follicles in the ovary begin developing under the influence of a complex interplay of hormones, and after several days one or occasionally two become dominant (non-dominant follicles atrophy and die). Approximately mid-cycle, 24–36 hours after the Luteinizing Hormone (LH) surges, the dominant follicle releases an ovum, or egg, in an event called ovulation. After ovulation, the egg only lives for 24 hours or less without fertilization while the remains of the dominant follicle in the ovary become a corpus luteum; this body has a primary function of producing large amounts of progesterone. Under the influence of progesterone, the endometrium (uterine lining) changes to prepare for potential implantation of an embryo to establish a pregnancy. If implantation does not occur within approximately two weeks, the corpus luteum will involute, causing sharp drops in levels of both progesterone and estrogen. The hormone drop causes the uterus to shed its lining and egg in a process termed menstruation.
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59.2. CYCLES AND PHASES
193
In the menstrual cycle, changes occur in the female reproductive system as well as in other bodily systems (which can lead to breast tenderness or mood changes, for example). A woman’s first menstruation is termed menarche, and occurs typically around age 12-13. The end of a woman’s reproductive phase of life is called the menopause, and this commonly occurs somewhere between the ages of 45 and 55. Menstrual cycle
59.1 Overview The average age of menarche in humans is 12–13 years, but it is considered normal for it to occur anywhere between ages 8 and 16. The average age of menarche is about 12.5 years in the United States,[5] 12.72 in Canada,[6] 12.9 in the UK[7] and 13.06 ± 0.10 years in Iceland.[8] Factors such as heredity, diet and overall health can accelerate or delay menarche.[9] The cessation of menstrual cycles at the end of a woman’s reproductive period is termed menopause. The average age of menopause in women is 52 years, with anywhere between 45 and 55 being common. Menopause before age 45 is considered premature in industrialised countries.[10] Like the age of menarche, the age of menopause is largely a result of cultural and biological factors;[11] however, illnesses, certain surgeries, or medical treatments may cause menopause to occur earlier than it might have otherwise.[12]
59.2.1 Ovarian cycle Follicular phase Main article: Follicular phase The follicular phase is the first part of the ovarian cycle. During this phase, the ovarian follicles mature and get ready to release an egg.[1] The latter part of this phase overlaps with the proliferative phase of the uterine cycle. Through the influence of a rise in follicle stimulating hormone (FSH) during the first days of the cycle, a few ovarian follicles are stimulated.[18] These follicles, which were present at birth[18] and have been developing for the better part of a year in a process known as folliculogenesis, compete with each other for dominance. Under the influence of several hormones, all but one of these follicles will stop growing, while one dominant follicle in the ovary will continue to maturity. The follicle that reaches maturity is called a tertiary, or Graafian, follicle, and it contains the ovum.[18]
The length of a woman’s menstrual cycle typically varies somewhat, with some shorter cycles and some longer cycles. A woman who experiences variations of less than eight days between her longest cycles and shortest cycles is considered to have regular menstrual cycles. It is unusual for a woman to experience cycle length variations of less than four days. Length variation between eight Ovulation and 20 days is considered as moderately irregular cycles. Variation of 21 days or more between a woman’s shortest Main article: Ovulation and longest cycle lengths is considered very irregular. [13] Ovulation is the second phase of the ovarian cycle in which a mature egg is released from the ovarian follicles In a number of countries, mainly in Asia, legislation into the oviduct.[19] During the follicular phase, estradiol or corporate practice has introduced formal menstrual suppresses production of luteinizing hormone (LH) from leave to provide women with either paid or unpaid the anterior pituitary gland. When the egg has nearly maleave of absence from their employment while they are tured, levels of estradiol reach a threshold above which menstruating.[14][15] The practice is controversial.[16][17] this effect is reversed and estrogen stimulates the production of a large amount of LH. This process, known as the LH surge, starts around day 12 of the average cycle and may last 48 hours.[20] 59.2 Cycles and phases The menstrual cycle can be described by the ovarian or uterine cycle. The ovarian cycle describes changes that occur in the follicles of the ovary whereas the uterine cycle describes changes in the endometrial lining of the uterus. Both cycles can be divided into three phases. The ovarian cycle consists of the follicular phase, ovulation, and the luteal phase whereas the uterine cycle consists of menstruation, proliferative phase, and secretory phase.[1]
The exact mechanism of these opposite responses of LH levels to estradiol is not well understood.[21]:86 In animals, a Gonadotropin-releasing hormone (GnRH) surge has been shown to precede the LH surge, suggesting that estrogen’s main effect is on the hypothalamus, which controls GnRH secretion.[21]:86 This may be enabled by the presence of two different estrogen receptors in the hypothalamus: estrogen receptor alpha, which is responsible for the negative feedback estradiol-LH loop, and
194
CHAPTER 59. MENSTRUAL CYCLE It has usually reached the blastocyst stage at the time of implantation. In some women, ovulation features a characteristic pain called mittelschmerz (German term meaning middle pain).[26] The sudden change in hormones at the time of ovulation sometimes also causes light mid-cycle blood flow.[27] Luteal phase Main article: Luteal phase
An ovary about to release an egg.
The luteal phase is the final phase of the ovarian cycle and it corresponds to the secretory phase of the uterine cycle. During the luteal phase, the pituitary hormones FSH and LH cause the remaining parts of the dominant follicle to transform into the corpus luteum, which produces progesterone. The increased progesterone in the adrenals starts to induce the production of estrogen. The hormones produced by the corpus luteum also suppress production of the FSH and LH that the corpus luteum needs to maintain itself. Consequently, the level of FSH and LH fall quickly over time, and the corpus luteum subsequently atrophies.[18] Falling levels of progesterone trigger menstruation and the beginning of the next cycle. From the time of ovulation until progesterone withdrawal has caused menstruation to begin, the process typically takes about two weeks, with 14 days considered normal. For an individual woman, the follicular phase often varies in length from cycle to cycle; by contrast, the length of her luteal phase will be fairly consistent from cycle to cycle.[28]
estrogen receptor beta, which is responsible for the positive estradiol-LH relationship.[22] However in humans it has been shown that high levels of estradiol can provoke abrupt increases in LH, even when GnRH levels and pulse frequencies are held constant,[21]:86 suggesting that estrogen acts directly on the pituitary to provoke the LH surge. The loss of the corpus luteum is prevented by fertilizaThe release of LH matures the egg and weakens the wall tion of the egg. The syncytiotrophoblast, which is the of the follicle in the ovary, causing the fully developed outer layer of the resulting embryo-containing structure follicle to release its secondary oocyte.[18] The secondary (the blastocyst) and later also becomes the outer layer oocyte promptly matures into an ootid and then becomes of the placenta, produces human chorionic gonadotropin a mature ovum. The mature ovum has a diameter of (hCG), which is very similar to LH and which preserves the corpus luteum. The corpus luteum can then continue about 0.2 mm.[23] to secrete progesterone to maintain the new pregnancy. Which of the two ovaries—left or right—ovulates ap- Most pregnancy tests look for the presence of hCG.[18] pears essentially random; no known left and right coordination exists.[24] Occasionally, both ovaries will release an egg;[24] if both eggs are fertilized, the result is 59.2.2 Uterine cycle fraternal twins.[25] After being released from the ovary, the egg is swept into Menstruation the fallopian tube by the fimbria, which is a fringe of tissue at the end of each fallopian tube. After about a day, Main article: Menstruation an unfertilized egg will disintegrate or dissolve in the fallopian tube.[18] Menstruation (also called menstrual bleeding, menses, Fertilization by a spermatozoon, when it occurs, usually catamenia or a period) is the first phase of the utertakes place in the ampulla, the widest section of the fal- ine cycle. The flow of menses normally serves as a sign lopian tubes. A fertilized egg immediately begins the pro- that a woman has not become pregnant. (However, this cess of embryogenesis, or development. The developing cannot be taken as certainty, as a number of factors embryo takes about three days to reach the uterus and can cause bleeding during pregnancy; some factors are another three days to implant into the endometrium.[18] specific to early pregnancy, and some can cause heavy
59.3. LENGTH flow.)[29][30][31]
195 products are marketed to women for use during their menstruation. Proliferative phase The proliferative phase is the second phase of the uterine cycle when estrogen causes the lining of the uterus to grow, or proliferate, during this time.[18] As they mature, the ovarian follicles secrete increasing amounts of estradiol, and estrogen. The estrogens initiate the formation of a new layer of endometrium in the uterus, histologically identified as the proliferative endometrium. The estrogen also stimulates crypts in the cervix to produce fertile cervical mucus, which may be noticed by women practicing fertility awareness.[37] Secretory phase The secretory phase is the final phase of the uterine cycle and it corresponds to the luteal phase of the ovarian cycle. During the secretory phase, the corpus luteum produces progesterone, which plays a vital role in making the endometrium receptive to implantation of the blastocyst and supportive of the early pregnancy, by increasing blood flow and uterine secretions and reducing the contractility of the smooth muscle in the uterus;[38] it also has the side effect of raising the woman’s basal body temperature.[39]
59.3 Length The average menstrual cycle lasts 28 days. The variability of menstrual cycle lengths is highest for women under 25 years of age and is lowest, that is, most regular, for Levels of estradiol (the main estrogen), progesterone, luteiniz- ages 35 to 39.[40] Subsequently, the variability increases ing hormone, and follicle-stimulating hormone during the men- slightly for women aged 40 to 44.[40] Usually, length varistrual cycle, taking inter-cycle and inter-woman variability into ation between eight and 20 days in a woman is considered account. as moderately irregular menstrual cycles.[13] Variation of [13] Eumenorrhea denotes normal, regular menstruation that 21 days or more is considered very irregular. lasts for a few days (usually 3 to 5 days, but anywhere As measured on women undergoing in vitro fertilizafrom 2 to 7 days is considered normal).[26][32] The aver- tion, a longer menstrual cycle length is associated with age blood loss during menstruation is 35 milliliters with higher pregnancy and delivery rates, even after age 10–80 ml considered normal.[33] Women who experience adjustment.[41] Delivery rates after IVF have been estiMenorrhagia are more susceptible to iron deficiency than mated to be almost doubled for women with a menstrual the average person.[34] An enzyme called plasmin inhibits cycle length of more than 34 days compared with women clotting in the menstrual fluid.[35] with a menstrual cycle length shorter than 26 days.[41] A Painful cramping in the abdomen, back, or upper thighs longer menstrual cycle length is also significantly associto gonadotropin stimuis common during the first few days of menstruation. ated with better ovarian response [41] embryo quality. lation and Severe uterine pain during menstruation is known as dysmenorrhea, and it is most common among adolescents and younger women (affecting about 67.2% of adolescent females).[36] When menstruation begins, symptoms of premenstrual syndrome (PMS) such as breast tenderness and irritability generally decrease.[26] Many sanitary
The luteal phase of the menstrual cycle is about the same length in most individuals (mean 14/13 days, SD 1.41 days)[42] whereas the follicular phase tends to show much more variability (log-normally distributed with 95% of individuals having follicular phases between 10.3 and
196 16.3 days).[43] The follicular phase also seems to get significantly shorter with age (geometric mean 14.2 days in women aged 18–24 vs. 10.4 days in women aged 40– 44).[43]
59.4 Fertile window Main article: Fertility testing The most fertile period (the time with the highest likelihood of pregnancy resulting from sexual intercourse) covers the time from some 5 days before until 1 to 2 days after ovulation.[44] In a 28‑day cycle with a 14‑day luteal phase, this corresponds to the second and the beginning of the third week. A variety of methods have been developed to help individual women estimate the relatively fertile and the relatively infertile days in the cycle; these systems are called fertility awareness. Fertility awareness methods that rely on cycle length records alone are called calendar-based methods.[45] Methods that require observation of one or more of the three primary fertility signs (basal body temperature, cervical mucus, and cervical position)[46] are known as symptoms-based methods.[45] Urine test kits are available that detect the LH surge that occurs 24 to 36 hours before ovulation; these are known as ovulation predictor kits (OPKs).[47] Computerized devices, such as Lady-Comp, that interpret basal body temperatures, urinary test results, or changes in saliva are called fertility monitors.
CHAPTER 59. MENSTRUAL CYCLE of women with intractable partial epilepsy have catamenial epilepsy.[51][52][53] An effect of hormones has been proposed, in which progesterone declines and estrogen increases would trigger seizures.[54] Recently, studies have shown that high doses of estrogen can cause or worsen seizures, whereas high doses of progestrone can act like an antiepileptic drug.[55] Studies by medical journals have found that women experiencing menses are 1.68 times more likely to commit suicide.[56] Mice have been used as an experimental system to investigate possible mechanisms by which levels of sex steroid hormones might regulate nervous system function. During the part of the mouse estrous cycle when progesterone is highest, the level of nerve-cell GABA receptor subtype delta was high. Since these GABA receptors are inhibitory, nerve cells with more delta receptors are less likely to fire than cells with lower numbers of delta receptors. During the part of the mouse estrous cycle when estrogen levels are higher than progesterone levels, the number of delta receptors decrease, increasing nerve cell activity, in turn increasing anxiety and seizure susceptibility.[57] Estrogen levels may affect thyroid behavior.[58] For example, during the luteal phase (when estrogen levels are lower), the velocity of blood flow in the thyroid is lower than during the follicular phase (when estrogen levels are higher).[59] Among women living closely together, it was once thought that the onsets of menstruation tend to synchronize. This effect was first described in 1971, and possibly explained by the action of pheromones in 1998.[60] Subsequent research has called this hypothesis into question.[61]
A woman’s fertility is also affected by her age.[48] As a woman’s total egg supply is formed in fetal life,[49] to be ovulated decades later, it has been suggested that this long lifetime may make the chromatin of eggs more vulner- Research indicates that women have a significantly higher able to division problems, breakage, and mutation than likelihood of anterior cruciate ligament injuries in the pre[62] the chromatin of sperm, which are produced continuously ovulatory stage, than post-ovulatory stage. during a man’s reproductive life. However, despite this hypothesis, a similar paternal age effect has also been observed. 59.6 Mood and behavior
59.5 Effect on other systems Some women with neurological conditions experience increased activity of their conditions at about the same time during each menstrual cycle. For example, drops in estrogen levels have been known to trigger migraines,[50] especially when the woman who suffers migraines is also taking the birth control pill. Many women with epilepsy have more seizures in a pattern linked to the menstrual cycle; this is called "catamenial epilepsy".[51] Different patterns seem to exist (such as seizures coinciding with the time of menstruation, or coinciding with the time of ovulation), and the frequency with which they occur has not been firmly established. Using one particular definition, one group of scientists found that around one-third
The different phases of the menstrual cycle correlate with women’s moods. In some cases, hormones released during the menstrual cycle can cause behavioral changes in females; mild to severe mood changes can occur.[63] The menstrual cycle phase and ovarian hormones may contribute to increased empathy in women. The natural shift of hormone levels during the different phases of the menstrual cycle has been studied in conjunction with test scores. When completing empathy exercises, women in the follicular stage of their menstrual cycle performed better than women in their midluteal phase. A significant correlation between progesterone levels and the ability to accurately recognize emotion was found. Performances on emotion recognition tasks were better when women had lower progesterone levels. Women in the follicular stage showed higher emotion recognition accuracy than
59.8. OVULATION SUPPRESSION their midluteal phase counterparts. Women were found to react more to negative stimuli when in midluteal stage over the women in the follicular stage, perhaps indicating more reactivity to social stress during that menstrual cycle phase.[64] Overall, it has been found that women in the follicular phase demonstrated better performance in tasks that contain empathetic traits.
197 tive years.
George Preti, an organic chemist at the Monell Chemical Senses Center in Philadelphia and Winnefred Cutler of the University of Pennsylvania's psychology department, discovered that women with irregular menstrual cycles became regular when exposed to male underarm extracts.[72] They hypothesized that the only explanation Fear response in women during two different points in the was that underarms contain pheromones, as there was no menstrual cycle has been examined. When oestrogen is other explanation for the effects, which mirrored how highest in the preovulatory stage, women are significantly pheromones affect other mammals.[72] better at identifying expressions of fear than women who were menstruating, which is when oestrogen levels are lowest. The women were equally able to identify happy 59.8 Ovulation suppression faces, demonstrating that the fear response was a more powerful response. To summarize, menstrual cycle phase and the oestrogen levels correlates with women’s fear 59.8.1 Hormonal contraception processing.[65] Main article: Hormonal contraception However, the examination of daily moods in women with While some forms of birth control do not affect the menmeasuring ovarian hormones may indicate a less powerful connection. In comparison to levels of stress or physical health, the ovarian hormones had less of an impact on overall mood.[66] This indicates that while changes of ovarian hormones may influence mood, on a day-to-day level it does not influence mood more than other stressors do.
59.7 Cycle abnormalities and disorders Main article: Menstrual disorder Infrequent or irregular ovulation is called oligoovulation.[67] The absence of ovulation is called anovulation. Normal menstrual flow can occur without ovulation preceding it: an anovulatory cycle. In some cycles, follicular development may start but not be completed; nevertheless, estrogens will be formed and stimulate the uterine lining. Anovulatory flow resulting from a very thick endometrium caused by prolonged, continued high estrogen levels is called estrogen breakthrough bleeding. Anovulatory bleeding triggered by a sudden drop in estrogen levels is called changes.[68] Anovulatory cycles commonly occur before menopause (perimenopause) and in women with polycystic ovary syndrome.[69]
Half-used blister pack of a combined oral contraceptive. The white pills are placebos, mainly for the purpose of reminding the woman to continue taking the pills.
strual cycle, hormonal contraceptives work by disrupting it. Progestogen negative feedback decreases the pulse frequency of gonadotropin-releasing hormone (GnRH) release by the hypothalamus, which decreases the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by the anterior pituitary. Decreased levels of FSH inhibit follicular development, preventing an increase in estradiol levels. Progestogen negative feedback and the lack of estrogen positive feedback on LH release prevent a mid-cycle LH surge. Inhibition of follicular development and the absence of a LH surge prevent [73][74][75] Very little flow (less than 10 ml) is called hypomenorrhea. ovulation. Regular cycles with intervals of 21 days or fewer are The degree of ovulation suppression in progestogenpolymenorrhea; frequent but irregular menstruation is only contraceptives depends on the progestogen activity known as metrorrhagia. Sudden heavy flows or amounts and dose. Low dose progestogen-only contraceptives— greater than 80 ml are termed menorrhagia.[70] Heavy traditional progestogen only pills, subdermal implants menstruation that occurs frequently and irregularly is Norplant and Jadelle, and intrauterine system Mirena— menometrorrhagia. The term for cycles with intervals ex- inhibit ovulation in about 50% of cycles and rely mainly ceeding 35 days is oligomenorrhea.[71] Amenorrhea refers on other effects, such as thickening of cervical mucus, for to more than three[70] to six[71] months without menses their contraceptive effectiveness.[76] Intermediate dose (while not being pregnant) during a woman’s reproduc- progestogen-only contraceptives—the progestogen-only
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pill Cerazette and the subdermal implant Nexplanon— allow some follicular development but more consistently inhibit ovulation in 97–99% of cycles. The same cervical mucus changes occur as with very low-dose progestogens. High-dose, progestogen-only contraceptives—the injectables Depo-Provera and Noristerat—completely inhibit follicular development and ovulation.[76]
59.9.1 Nightlighting and the moon
Breastfeeding causes negative feedback to occur on pulse secretion of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH). Depending on the strength of the negative feedback, breastfeeding women may experience complete suppression of follicular development, follicular development but no ovulation, or normal menstrual cycles may resume.[77] Suppression of ovulation is more likely when suckling occurs more frequently.[78] The production of prolactin in response to suckling is important to maintaining lactational amenorrhea.[79] On average, women who are fully breastfeeding whose infants suckle frequently experience a return of menstruation at fourteen and a half months postpartum. There is a wide range of response among individual breastfeeding women, however, with some experiencing return of menstruation at two months and others remaining amenorrheic for up to 42 months postpartum.[80]
59.10 References
See also: Culture and menstruation and Lunar effect
The word “menstruation” is etymologically related to “moon”. The terms “menstruation” and “menses” are derived from the Latin mensis (month), which in turn relates Combined hormonal contraceptives include both an es- to the Greek mene (moon) and to the roots of the English trogen and a progestogen. Estrogen negative feedback on words month and moon.[81] the anterior pituitary greatly decreases the release of LH, Some authors believe that, historically, women in tradiwhich makes combined hormonal contraceptives more tional societies without nightlighting ovulated with the effective at inhibiting follicular development and prevent- full moon and menstruated with the new moon,[82] and ing ovulation. Estrogen also reduces the incidence of one author documents the controversial attempts to use irregular breakthrough bleeding.[73][74][75] Several com- the association to improve the rhythm method of regulatbined hormonal contraceptives—the pill, NuvaRing, and ing conception.[81] the contraceptive patch—are usually used in a way that [83] and other animals[84] causes regular withdrawal bleeding. In a normal cy- Some studies in both humans cle, menstruation occurs when estrogen and progesterone have found that artificial light at night does influence the levels drop rapidly.[39] Temporarily discontinuing use of menstrual cycle in humans and the estrus cycle in mice combined hormonal contraceptives (a placebo week, not (cycles are more regular in the absence of artificial light using patch or ring for a week) has a similar effect of at night). It has also been suggested that bright light ex[85] causing the uterine lining to shed. If withdrawal bleeding posure in the morning promotes more regular cycles. One author has suggested that sensitivity of women’s cyis not desired, combined hormonal contraceptives may cles to nightlighting is caused by nutritional deficiencies be taken continuously, although this increases the risk of of certain vitamins and minerals.[86] breakthrough bleeding. A meta-analysis of studies from 1996 showed no correlation between the human menstrual cycle and the lunar cycle.[87][88][89][90][91][92] Dogon villagers did not have electric lighting and spent most nights outdoors, talking 59.8.2 Lactational amenorrhea and sleeping; so they were an ideal population for detecting a lunar influence; none, however, was found.[93] Main article: Lactational amenorrhea method
59.9 Etymological and biological associations
[1] Silverthorn, Dee Unglaub (2013). Human Physiology: An Integrated Approach (6th ed.). Glenview, IL: Pearson Education, Inc. pp. 850–890. ISBN 0-321-75007-1. [2] Sherwood, Laurelee (2013). Human Physiology: From Cells to Systems (8th ed.). Belmont, CA: Cengage. pp. 735–794. ISBN 1-111-57743-9. [3] Widmaier, Eric P.; Raff, Hershel; Strang, Kevin T. (2010). Vander’s Human Physiology: The Mechanism of Body Function (12th ed.). New York, NY: McGrawHill. pp. 555–631. ISBN 0-077-35001-4. [4] Klump KL, Keel PK, Racine SE, Burt SA, Burt AS, Neale M, Sisk CL, Boker S, Hu JY (February 2013). “The interactive effects of estrogen and progesterone on changes in emotional eating across the menstrual cycle”. J Abnorm Psychol 122 (1): 131–7. doi:10.1037/a0029524. PMID 22889242. [5] Anderson SE, Dallal GE, Must A (April 2003). “Relative weight and race influence average age at menarche: results from two nationally representative surveys of US girls studied 25 years apart”. Pediatrics 111 (4 Pt 1): 844–50. doi:10.1542/peds.111.4.844. PMID 12671122.
59.10. REFERENCES
[6] Al-Sahab B, Ardern CI, Hamadeh MJ, Tamim H (2010). “Age at menarche in Canada: results from the National Longitudinal Survey of Children & Youth”. BMC Public Health 10: 736. doi:10.1186/1471-2458-10-736. PMC 3001737. PMID 21110899. [7] Hamilton-Fairley, Diana (2004) [1999]. Lecture notes on obstetrics and gynaecology (pdf) (2nd ed.). Blackwell. p. 29. ISBN 1-4051-2066-5. [8] Macgússon TE (May 1978). “Age at menarche in Iceland”. Am. J. Phys. Anthropol. 48 (4): 511–4. doi:10.1002/ajpa.1330480410. PMID 655271. [9] “At what age does a girl get her first period?". National Women’s Health Information Center. Retrieved 20 November 2011. [10] “Clinical topic - Menopause”. NHS. Retrieved 2 November 2009. [11] Beyene, Yewoubdar (1989). From Menarche to Menopause: Reproductive Lives of Peasant Women in Two Cultures. Albany, NY: State University of New York Press. ISBN 0-88706-866-9. [12] Shuman, Tracy (February 2006). “Your Guide to Menopause”. WebMD. Retrieved 16 December 2006. [13] Kippley, John; Kippley, Sheila (1996). The Art of Natural Family Planning (4th ed.). Cincinnati: The Couple to Couple League. p. 92. ISBN 978-0-926412-13-2. [14] Maila Ager (18 August 2008). “Mandatory menstruation leave measure filed in House”. Inquirer.net. Retrieved 16 June 2011. [15] Owoseje, Toyin (31 July 2013). “Menstruation Leave: Russian Lawmaker Proposes Paid Days Off For Women Employees on Period”. International Business Times. Retrieved 3 January 2014. [16] Iuliano, Sarah. “Menstrual leave: delightful or discriminatory?". 5 August 2013. Lip Magazine. Retrieved 3 January 2014. [17] Price, Catherine (11 October 2006). “Should women get paid menstruation leave?". Salon. Retrieved 3 January 2014. [18] Losos, Jonathan B.; Raven, Peter H.; Johnson, George B.; Singer, Susan R. (2002). Biology. New York: McGrawHill. pp. 1207–09. ISBN 0-07-303120-8. [19] Ovulation Test at Duke Fertility Center. Retrieved 2 July 2011 [20] “Ovulation Calendar”. Pregnology. [21] Lentz, Gretchen M; Lobo, Rogerio A.; Gershenson, David M; Katz, Vern L. (2013). Comprehensive gynecology. St. Louis: Elsevier Mosby. ISBN 978-0-323-06986-1. Retrieved 5 April 2012. [22] Hu L, Gustofson RL, Feng H, Leung PK, Mores N, Krsmanovic LZ, Catt KJ (October 2008). “Converse regulatory functions of estrogen receptor-alpha and -beta subtypes expressed in hypothalamic gonadotropin-releasing
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[40] Chiazze L, Brayer FT, Macisco JJ, Parker MP, Duffy BJ (February 1968). “The length and variability of the human menstrual cycle”. JAMA 203 (6): 377– 80. doi:10.1001/jama.1968.03140060001001. PMID 5694118.
[54] Scharfman HE, MacLusky NJ (September 2006). “The influence of gonadal hormones on neuronal excitability, seizures, and epilepsy in the female”. Epilepsia 47 (9): 1423–40. doi:10.1111/j.1528-1167.2006.00672.x. PMC 1924802. PMID 16981857.
[41] Brodin T, Bergh T, Berglund L, Hadziosmanovic N, Holte J (2008). “Menstrual cycle length is an age-independent marker of female fertility: Results from 6271 treatment cycles of in vitro fertilization”. Fertility and Sterility 90 (5): 1656–1661. doi:10.1016/j.fertnstert.2007.09.036. PMID 18155201.
[55] “Menstrual cycle”. epilepsy.com. Retrieved 19 October 2012.
[42] Lenton EA, Landgren BM, Sexton L (July 1984). “Normal variation in the length of the luteal phase of the menstrual cycle: identification of the short luteal phase”. Br J Obstet Gynaecol 91 (7): 685–9. doi:10.1111/j.14710528.1984.tb04831.x. PMID 6743610. [43] Lenton EA, Landgren BM, Sexton L, Harper R (July 1984). “Normal variation in the length of the follicular phase of the menstrual cycle: effect of chronological age”. Br J Obstet Gynaecol 91 (7): 681–4. doi:10.1111/j.14710528.1984.tb04830.x. PMID 6743609. [44] Weschler (2002), pp.242,374 [45] “Medical Eligibility Criteria for Contraceptive Use: Fertility awareness-based methods”. Third edition. World Health Organization. 2004. Retrieved 29 April 2008. [46] Weschler (2002), p.52
[56] Baca-García E, Diaz-Sastre C, Ceverino A, SaizRuiz J, Diaz FJ, de Leon J (2003). “Association between the menses and suicide attempts: a replication study”. Psychosom Med 65 (2): 237– 44. doi:10.1097/01.PSY.0000058375.50240.F6. PMID 12651991. [57] Maguire JL, Stell BM, Rafizadeh M, Mody I (June 2005). “Ovarian cycle-linked changes in GABA(A) receptors mediating tonic inhibition alter seizure susceptibility and anxiety”. Nat. Neurosci. 8 (6): 797–804. doi:10.1038/nn1469. PMID 15895085. [58] Doufas AG, Mastorakos G (2000). “The hypothalamicpituitary-thyroid axis and the female reproductive system”. Annals of the New York Academy of Sciences 900: 65–76. doi:10.1111/j.1749-6632.2000.tb06217.x. PMID 10818393. [59] Krejza J, Nowacka A, Szylak A, Bilello M, Melhem LY (July 2004). “Variability of thyroid blood flow Doppler parameters in healthy women”. Ultrasound Med Biol 30 (7): 867–76. doi:10.1016/j.ultrasmedbio.2004.05.008. PMID 15313319.
[47] MedlinePlus Encyclopedia LH urine test (home test) [48] Leridon H (July 2004). “Can assisted reproduction technology compensate for the natural decline in fertility with age? A model assessment”. Hum. Reprod. 19 (7): 1548– 53. doi:10.1093/humrep/deh304. PMID 15205397. [49] Krock, Lexi (October 2001). “Fertility Throughout Life”. 18 Ways to Make a Baby. NOVA Online. Retrieved 24 December 2006. Haines, Cynthiac (January 2006). “Your Guide to the Female Reproductive System”. The Cleveland Clinic Women’s Health Center. WebMD. Retrieved 24 December 2006. [50] “Migraine and Estrogen Officially Linked”. The Daily Headache. Retrieved 19 October 2012. [51] Herzog AG (March 2008). “Catamenial epilepsy: definition, prevalence pathophysiology and treatment”. Seizure doi:10.1016/j.seizure.2007.11.014. 17 (2): 151–9. PMID 18164632. [52] Herzog AG, Harden CL, Liporace J, Pennell P, Schomer DL, Sperling M, Fowler K, Nikolov B, Shuman S, Newman M (September 2004). “Frequency of catamenial seizure exacerbation in women with localizationrelated epilepsy”. Annals of Neurology 56 (3): 431–4. doi:10.1002/ana.20214. PMID 15349872. [53] Herzog AG, Klein P, Ransil BJ (October 1997). “Three patterns of catamenial epilepsy”. Epilepsia 38 (10): doi:10.1111/j.1528-1157.1997.tb01197.x. 1082–8. PMID 9579954.
[60] Stern K, McClintock MK (March 1998). “Regulation of ovulation by human pheromones”. Nature 392 (6672): 177–9. doi:10.1038/32408. PMID 9515961. [61] Adams, Cecil (20 December 2002). “Does menstrual synchrony really exist?". The Straight Dope. The Chicago Reader. Retrieved 10 January 2007. [62] Renstrom P, Ljungqvist A, Arendt E, Beynnon B, Fukubayashi T, Garrett W, Georgoulis T, Hewett TE, Johnson R, Krosshaug T, Mandelbaum B, Micheli L, Myklebust G, Roos E, Roos H, Schamasch P, Shultz S, Werner S, Wojtys E, Engebretsen L (June 2008). “Non-contact ACL injuries in female athletes: an International Olympic Committee current concepts statement”. Br J Sports Med 42 (6): 394–412. doi:10.1136/bjsm.2008.048934. PMC 3920910. PMID 18539658. [63] Schmidt PJ, Nieman LK, Danaceau MA, Adams LF, Rubinow DR (January 1998). “Differential behavioral effects of gonadal steroids in women with and in those without premenstrual syndrome”. N. Engl. J. Med. 338 (4): 209–16. doi:10.1056/NEJM199801223380401. PMID 9435325. [64] Derntl B, Hack RL, Kryspin-Exner I, Habel U (January 2013). “Association of menstrual cycle phase with the core components of empathy”. Horm Behav 63 (1): 97– 104. doi:10.1016/j.yhbeh.2012.10.009. PMC 3549494. PMID 23098806.
59.10. REFERENCES
[65] Schwartz DH, Romans SE, Meiyappan S, De Souza MJ, Einstein G (September 2012). “The role of ovarian steroid hormones in mood”. Horm Behav 62 (4): 448– 54. doi:10.1016/j.yhbeh.2012.08.001. PMID 22902271. [66] Pearson R, Lewis MB (March 2005). “Fear recognition across the menstrual cycle”. Horm Behav 47 (3): 267–71. doi:10.1016/j.yhbeh.2004.11.003. PMID 15708754. [67] Galan, Nicole (16 April 2008). “Oligoovulation”. about.com. Retrieved 12 October 2008. [68] Weschler (2002), p.107 [69] Anovulation at eMedicine [70] Menstruation Disorders at eMedicine [71] Oriel KA, Schrager S (October 1999). “Abnormal uterine bleeding”. Am Fam Physician 60 (5): 1371–80; discussion 1381–2. PMID 10524483. [72] Delude, Cathryn M. (2 September 2003). “Looking for love potion number nine”. Boston Globe. [73] Trussell, James (2007). “Contraceptive Efficacy”. In Hatcher, Robert A., et al. Contraceptive Technology (19th rev. ed.). New York: Ardent Media. ISBN 0-96649020-7. [74] Speroff, Leon; Darney, Philip D. (2005). “Oral Contraception”. A Clinical Guide for Contraception (4th ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 21– 138. ISBN 0-7817-6488-2. [75] Loose, Davis S.; Stancel, George M. (2006). “Estrogens and Progestins”. In Brunton, Laurence L.; Lazo, John S.; Parker, Keith L. (eds.). Goodman & Gilman’s The Pharmacological Basis of Therapeutics (11th ed.). New York: McGraw-Hill. pp. 1541–71. ISBN 0-07-142280-3. [76] Glasier, Anna (2006). “Contraception”. In DeGroot, Leslie J.; Jameson, J. Larry (eds.). Endocrinology (5th ed.). Philadelphia: Elsevier Saunders. pp. 3000–1. ISBN 0-7216-0376-9. [77] McNeilly AS (2001). “Lactational control of reproduction”. Reprod. Fertil. Dev. 13 (7–8): 583–90. doi:10.1071/RD01056. PMID 11999309. [78] Kippley, John; Sheila Kippley (1996). The Art of Natural Family Planning (4th ed.). Cincinnati, OH: The Couple to Couple League. p. 347. ISBN 0-926412-13-2.
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[91] Zimecki M (2006). “The lunar cycle: effects on human and animal behavior and physiology”. Postepy Hig Med Dosw (Online) 60: 1–7. PMID 16407788. [92] Kelly, Ivan; Rotton, James; Culver, Roger (1986). “The Moon Was Full and Nothing Happened: A Review of Studies on the Moon and Human Behavior”. Skeptical Inquirer 10 (2): 129–43.. Reprinted in The Hundredth Monkey - and other paradigms of the paranormal, edited by Kendrick Frazier, Prometheus Books. Revised and updated in The Outer Edge: Classic Investigations of the Paranormal, edited by Joe Nickell, Barry Karr, and Tom Genoni, 1996, CSICOP. [93] Strassmann B. I. (1997). “The biology of menstruation in Homo sapiens: total lifetime menses, fecundity, and nonsynchrony in a natural fertility population”. Current Anthropology 38: 123–9. doi:10.1086/204592. JSTOR 2744446.
59.11 External links
CHAPTER 59. MENSTRUAL CYCLE
Chapter 60
Reproductive health “Sexual health” redirects here. For the journal, see free of coercion, discrimination and violence. For sexual International Journal of Sexual Health. health to be attained and maintained, the sexual rights of all persons must be respected, protected and fulfilled.”[4] However, while used by WHO as well as other organizaWithin the framework of the World Health Organizaand should not tion's (WHO) definition of health as a state of complete tions, this is not an official WHO position, be used or quoted as a WHO definition.[4] physical, mental and social well-being, and not merely the absence of disease or infirmity, reproductive health, or Emerging research in the field of sexual and reproductive sexual health/hygiene, addresses the reproductive pro- health (SRH) identifies a series of factors that enhance the cesses, functions and system at all stages of life.[1] Repro- translation of research into policy and practice.[5] These ductive health implies that people are able to have a re- include discursive changes (creating spaces for public desponsible, satisfying and safer sex life and that they have bate); content changes (to laws and practices); procedural the capability to reproduce and the freedom to decide if, changes (influencing how data on SRH are collected) and when and how often to do so. One interpretation of this behavioural changes (through partnerships with civil soimplies that men and women ought to be informed of and ciety, advocacy groups and policy makers).[5] to have access to safe, effective, affordable and acceptable methods of birth control; also access to appropriate health care services of sexual, reproductive medicine and implementation of health education programs to stress the importance of women to go safely through pregnancy and childbirth could provide couples with the best chance of having a healthy infant. Individuals do face inequalities in reproductive health ser- 60.2 Childbearing and health vices. Inequalities vary based on socioeconomic status, education level, age, ethnicity, religion, and resources available in their environment. It is possible for example, that low income individuals lack the resources for appro- See also: Maternal health and Family planning priate health services and the knowledge to know what is appropriate for maintaining reproductive health.[2] Early childbearing and other behaviours can have health According to the WHO, “Reproductive and sexual ill- risks for women and their infants. Waiting until a woman to have children health accounts for 20% of the global burden of ill-health is at least 18 years old before trying [6][7] If an additional improves maternal and child health. [3] for women, and 14% for men.” Reproductive health is child is to be conceived, it is considered healthier for the a part of sexual and reproductive health and rights. mother, as well as for the succeeding child, to wait at least 2 years after the previous birth before attempting to conception.[6] After a fetal fatality, it is healthier to wait at least 6 months.[6] 60.1 Sexual health An official working definition for sexual health is that “Sexual health is a state of physical, emotional, mental and social well-being in relation to sexuality; it is not merely the absence of disease, dysfunction or infirmity. Sexual health requires a positive and respectful approach to sexuality and sexual relationships, as well as the possibility of having pleasurable and safe sexual experiences,
The WHO estimates that each year, 358 000 women die due to complications related to pregnancy and childbirth; 99% of these deaths occur within the most disadvantaged population groups living in the poorest countries of the world.[8] Most of these deaths can be avoided with improving women’s access to quality care from a skilled birth attendant before, during and after pregnancy and childbirth.
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60.3 Availability of modern contraception
infertility, childbirth complications and newborn deaths. FGM procedures that seal or narrow a vaginal opening (known as type 3) lead to a need for future surgeries of cutting open in order to allow for sexual intercourse and Modern contraception is often unavailable in certain parts childbirth.[12] of the world. According to the WHO, about 222 million women worldwide have an unmet need for modern contraception, and the lack of access to modern contra60.5 Sexually transmitted diseases ception is highest among the most disadvantaged populations: the poor, those living in rural areas and urban slums, those living with HIV, and those who are internally displaced.[9] In developing parts of the world, the lack of access to contraception is a main cause of unintended pregnancy, which is associated with poorer reproductive outcomes.[9] According to UNFPA, access to contraceptive services for all women could prevent about one in three deaths related to pregnancy and childbirth.[10]
60.4 Female genital mutilation Estimated prevalence in % of HIV among young adults (15–49) per country as of 2011.[14] Iraq 8
Burkina Faso 76 Senegal 26
Egypt 91 Mauritania Mali 69
Niger 89 Chad 2 Gambia 44 76 Guinea Nigeria 96 Côte Guinea-Bissau 27 CAR d'Ivoire 50 38 24 Cameroon Sierra Leone 1 88 Benin Liberia Togo 13 66 Ghana 4 4
Eritrea 89
Main article: Sexually transmitted diseases
Sudan 88
Yemen 23 Djibouti 93
Ethiopia Somalia 98 74 Uganda 1 Kenya 27 Tanzania 15
Prevalence of FGM 0 – 9% 10 – 29% 30 – 49% 50 – 69% 70 – 89% 90 – 99%
Prevalence of FGM by country, according to a 2013 UNICEF report[11]
Main article: Female genital mutilation Female genital mutilation (FGM), also known as female genital cutting or female circumcision, “comprises all procedures that involve partial or total removal of the external female genitalia, or other injury to the female genital organs for non-medical reasons”.[12] The practice is concentrated in 29 countries in Africa and the Middle East; and more than 125 million girls and women today are estimated to have been subjected to FGM.[12] FGM also takes place in immigrant communities in Western countries, such as the UK.[13]
Sexually transmitted diseases (STD), also referred to as sexually transmitted infections (STI) or venereal diseases (VD), are illnesses that have a significant probability of transmission between humans by means of sexual activity. Common STDs include chlamydia, gonorrhea, herpes, HIV/AIDS, hepatitis B, human papillomavirus (HPV), syphilis, trichomoniasis.[15][16] Sexually transmitted infections (STIs) affect reproductive and sexual health, having a profound negative impact worldwide.[17] Programs aimed at preventing STIs include comprehensive sex education; STI and HIV preand post-test counseling; safer sex/risk-reduction counseling; condom promotion; and interventions targeted at key and vulnerable populations.[17] Having access to effective medical treatment for STIs is very important.
60.6 Adolescent health
FGM does not have any health benefits, and has negative effects on reproductive and sexual health, including severe pain, shock, hemorrhage, tetanus or sepsis (bacterial infection), urine retention, open sores in the genital region and injury to nearby genital tissue, recurrent blad- Teenage birth rate per 1,000 females aged 15–19, 2000– der and urinary tract infections, cysts, increased risk of 2009[18] <10 10-20 20-30 30-40 40-50 >50
60.7. INTERNATIONAL CONFERENCE ON POPULATION AND DEVELOPMENT (ICPD), 1994 Further information: Teenage pregnancy and Adolescent sexuality Issues affecting adolescent reproductive and sexual health are similar to those of adults, but may include additional concerns about teenage pregnancy and lack of adequate access to information and health services. Worldwide, around 16 million adolescent girls give birth every year, mostly in low- and middle-income countries.[19] The causes of teenage pregnancy are diverse. In developing countries girls are often under pressure to marry young and bear children early (see child marriage). Some adolescent girls do not know how to avoid becoming pregnant, are unable to obtain contraceptives, or are coerced into sexual activity.[19] Adolescent pregnancy, especially in developing countries, carries increased health risks, and contributes to maintaining the cycle of poverty.[20] The availability and type of sex education for teenagers varies in different parts of the world. LGBT teens may suffer additional problems if they live in places where homosexual activity is socially disapproved and/or illegal; in extreme cases there can be depression, social isolation and even suicide among LGBT youth.
60.7 International Conference on Population and Development (ICPD), 1994 The International Conference on Population and Development (ICPD) was held in Cairo, Egypt, from 5 to 13 September 1994. Delegations from 179 States took part in negotiations to finalize a Programme of Action on population and development for the next 20 years. Some 20,000 delegates from various governments, UN agencies, NGOs, and the media gathered for a discussion of a variety of population issues, including immigration, infant mortality, birth control, family planning, and the education of women. In the ICPD Program of Action, 'Reproductive health' is defined as: a state of complete physical, mental and social well-being and...not merely the absence of disease or infirmity, in all matters relating to the reproductive system and its functions and processes. Reproductive health therefore implies that people are able to have a satisfying and safe sex life and that they have the capability to reproduce and the freedom to decide if, when and how often to do so. Implicit in this last condition are the right of men and women to be informed [about] and to have access to safe, effective, affordable and acceptable methods of family planning of their choice, as well as other methods of birth control which
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are not against the law, and the right of access to appropriate health-care services that will enable women to go safely through pregnancy and childbirth and provide couples with the best chance of having a healthy infant.[21]
This definition of the term is also echoed in the United Nations Fourth World Conference on Women, or the so-called Beijing Declaration of 1995.[22] However, the ICPD Program of Action, even though it received the support of a large majority of UN Member States, does not enjoy the status of an international legal instrument; it is therefore not legally binding. The Program of Action endorses a new strategy which emphasizes the numerous linkages between population and development and focuses on meeting the needs of individual women and men rather than on achieving demographic targets.[23] The ICPD achieved consensus on four qualitative and quantitative goals for the international community, the final two of which have particular relevance for reproductive health:
• Reduction of maternal mortality: A reduction of maternal mortality rates and a narrowing of disparities in maternal mortality within countries and between geographical regions, socio-economic and ethnic groups. • Access to reproductive and sexual health services including family planning: Family planning counseling, pre-natal care, safe delivery and postnatal care, prevention and appropriate treatment of infertility, prevention of abortion and the management of the consequences of abortion, treatment of reproductive tract infections, sexually transmitted diseases and other reproductive health conditions; and education, counseling, as appropriate, on human sexuality, reproductive health and responsible parenthood. Services regarding HIV/AIDS, breast cancer, infertility, delivery, hormone therapy, sex reassignment therapy, and abortion should be made available. Active discouragement of female genital mutilation (FGM).
Key to this new approach is empowering women and providing them with more choices through expanded access to education and health services and promoting skill development and employment. The Programme advocates making family planning universally available by 2015, or sooner, as part of a broadened approach to reproductive health and rights, provides estimates of the levels of national resources and international assistance that will be required, and calls on Governments to make these resources available.
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60.8 Millennium Goals
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Development
• to collate, synthesize and generate scientifically sound evidence on unsafe abortion prevalence and practices;
Achieving universal access to reproductive health by 2015 is one of the two targets of Goal 5 - Improving Maternal Health - of the eight Millennium Development Goals.[24] To monitor global progress towards the achievement of this target, the United Nations has agreed on the following indicators:
• to develop improved technologies and implement interventions to make abortion safer;
• 5.3: contraceptive prevalence rate
• to translate evidence into norms, tools and guidelines; • and to assist in the development of programmes and policies that reduce unsafe abortion and improve access to safe abortion and high quality post-abortion care
• 5.4: adolescent birth rate • 5.5: antenatal care coverage • 5.6: unmet need for family planning According to the MDG Progress Report, regional statistics on all four indicators have either improved or remained stable between the years 2000 and 2005.[25] However, progress has been slow in most developing countries, particularly in Sub-saharan Africa, which remains the region with the poorest indicators for reproductive health.[26] According to the WHO in 2005 an estimated 55% of women do not have sufficient antenatal care and 24% have no access to family planning services.[26]
60.9 Reproductive abortion
health
and
An article from the World Health Organization calls safe, legal abortion a "fundamental right of women, irrespective of where they live” and unsafe abortion a “silent pandemic".[27] The article states “ending the silent pandemic of unsafe abortion is an urgent public-health and human-rights imperative.” It also states “access to safe abortion improves women’s health, and vice versa, as documented in Romania during the regime of President Nicolae Ceaușescu" and “legalisation of abortion on request is a necessary but insufficient step toward improving women’s health” citing that in some countries, such as India where abortion has been legal for decades, access to competent care remains restricted because of other barriers. WHO’s Global Strategy on Reproductive Health, adopted by the World Health Assembly in May 2004, noted: “As a preventable cause of maternal mortality and morbidity, unsafe abortion must be dealt with as part of the MDG on improving maternal health and other international development goals and targets.” [28] The WHO’s Development and Research Training in Human Reproduction (HRP), whose research concerns people’s sexual and reproductive health and lives,[29] has an overall strategy to combat unsafe abortion that comprises four interrelated activities:[28]
During and after the ICPD, some interested parties attempted to interpret the term ‘reproductive health’ in the sense that it implies abortion as a means of family planning or, indeed, a right to abortion. These interpretations, however, do not reflect the consensus reached at the Conference. For the European Union, where legislation on abortion is certainly less restrictive than elsewhere, the Council Presidency has clearly stated that the Council’s commitment to promote ‘reproductive health’ did not include the promotion of abortion.[30] Likewise, the European Commission, in response to a question from a Member of the European Parliament, clarified: The term ‘reproductive health’ was defined by the United Nations (UN) in 1994 at the Cairo International Conference on Population and Development. All Member States of the Union endorsed the Programme of Action adopted at Cairo. The Union has never adopted an alternative definition of ‘reproductive health’ to that given in the Programme of Action, which makes no reference to abortion.[31] With regard to the US, only a few days prior to the Cairo Conference, the head of the US delegation, Vice President Al Gore, had stated for the record: Let us get a false issue off the table: the US does not seek to establish a new international right to abortion, and we do not believe that abortion should be encouraged as a method of family planning.[32] Some years later, the position of the US Administration in this debate was reconfirmed by US Ambassador to the UN, Ellen Sauerbrey, when she stated at a meeting of the UN Commission on the Status of Women that: Nongovernmental organizations are attempting to assert that Beijing in some way creates or contributes to the creation of an internationally recognized fundamental right to
60.11. REFERENCES abortion[33] There is no fundamental right to abortion. And yet it keeps coming up largely driven by NGOs trying to hijack the term and trying to make it into a definition.[34]
60.10 See also • Sexual intercourse#Health effects • Abortion debate • Demography • ICPD: International Conference on Population and Development
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[5] Theobold, Sally; et al (2011). “Strengthening the research to policy and practice interface: exploring strategies used by research organisations working on sexual and reproductive health and HIV/AIDS”. Health Research Policy and Systems 9 (1): S2. doi:10.1186/1478-4505-9-s1-s2. Retrieved 24 May 2012. [6] “Healthy Timing and Spacing of Pregnancy: HTSP Messages”. USAID. Retrieved 2008-05-13. [7] Brown, H. L.; Fan, Y. D.; Gonsoulin, W. J. (1991). “Obstetric complications in young teenagers”. South Medical Journal 84: 46–48. doi:10.1097/00007611-19910100000012. PMID 1986428. [8] World Health Organization: Maternal and perinatal health accessed 3 March 2011 [9] http://apps.who.int/iris/bitstream/10665/102539/1/ 9789241506748_eng.pdf?ua=1
• POPLINE: World’s largest reproductive health [10] http://www.unfpa.org/public/home/mothers/pid/4382 database • The INFO Project • Reproductive justice • Obstetric transition • Organizations:
[11] “Prevalence of FGM/C”. UNICEF. Retrieved 18 August 2014. [12] http://www.who.int/mediacentre/factsheets/fs241/en/ [13] http://www.nhs.uk/conditions/ female-genital-mutilation/pages/introduction.aspx [14] “AIDSinfo”. UNAIDS. Retrieved 4 March 2013.
• Association of Reproductive Health Professionals
[15] http://www.cdc.gov/STD/
• Centre for Development and Population Activities
[16] http://www.nhs.uk/conditions/ Sexually-transmitted-infections/Pages/Introduction. aspx
• EngenderHealth • Guttmacher Institute • German Foundation for World Population • International Planned Parenthood Federation • Marie Stopes International
[17] http://www.who.int/mediacentre/factsheets/fs110/en/ [18] Live births by age of mother and sex of child, general and age-specific fertility rates: latest available year, 2000–2009 — United Nations Statistics Division – Demographic and Social Statistics
• Reproductive Health Supplies Coalition
[19] http://www.who.int/mediacentre/factsheets/fs364/en/
• United Nations Population Fund
[20] http://www.who.int/reproductivehealth/publications/ adolescence/9789241502214/en/
60.11 References
[21] ICPD Programme of Action, paragraph 7.2. [22] The United Nations Fourth World Conference on Women
[1] “WHO: Reproductive health”. Retrieved 2008-08-19. [2] Hall, Kelli Stidham, Caroline Moreau, and James Trussell. “Determinants Of And Disparities In Reproductive Health Service Use Among Adolescent And Young Adult Women In The United States, 2002-2008.” American Journal Of Public Health 102.2 (2012): 359-367. Academic Search Premier. Web. 7 Nov. 2012
[23] ICPD. “ICPD Program of Action”. Retrieved 2009-0204. [24] UN. “Tracking the Millennium Development Goals”. Retrieved 2008-08-26. [25] UN. “2008 MDG Progress Report”. pp. 28–29. Retrieved 2009-02-04.
[3] “Reproductive Health Strategy - World Health Organization”. Retrieved 2008-07-24.
[26] WHO. “What progress has been made on MDG 5?". Retrieved 2009-02-04.
[4] “WHO - Gender and human rights”. Retrieved 2010-0904.
[27] “WHO: Unsafe Abortion - The Preventable Pandemic”. Retrieved 2010-01-16.
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[28] http://www.who.int/reproductivehealth/topics/unsafe_ abortion/hrpwork/en/index.html [29] http://www.who.int/hrp/en/ [30] European Parliament, 4 December 2003: Oral Question (H-0794/03) for Question Time at the part-session in December 2003 pursuant to Rule 43 of the Rules of Procedure by Dana Scallon to the Council. In the written record of that session, one reads: Posselt (PPE-DE): “Does the term ‘reproductive health’ include the promotion of abortion, yes or no?” - Antonione, Council: “No.” [31] European Parliament, 24 October 2002: Question no 86 by Dana Scallon (H-0670/02) [32] Jyoti Shankar Singh, Creating a New Consensus on Population (London: Earthscan, 1998), 60 [33] Lederer, AP/San Francisco Chronicle, 1 March 2005 [34] Leopold, Reuters, 28 February 2005
60.12 External links • CDC Division of Reproductive Health • WHO Reproductive health and research
CHAPTER 60. REPRODUCTIVE HEALTH
60.13. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
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60.13 Text and image sources, contributors, and licenses 60.13.1
Text
• Human reproduction Source: http://en.wikipedia.org/wiki/Human%20reproduction?oldid=646243573 Contributors: Quoth, Alan Liefting, Bobo192, Zachlipton, Alansohn, Wouterstomp, Ahruman, Woohookitty, SqueakBox, BD2412, ScottJ, The wub, RobertG, Wavelength, Brad Eleven, Katieh5584, Yvwv, Gilliam, Jdfoote, Ohnoitsjamie, Persian Poet Gal, Darth Panda, Rrburke, Aldaron, Gobonobo, Waggers, Iridescent, Blehfu, Christian75, Epbr123, Headbomb, Klausness, Mentifisto, JAnDbot, Bongwarrior, DerHexer, WLU, Caramesc, R'n'B, CommonsDelinker, Nono64, Trusilver, Uncle Dick, Mikael Häggström, Cmichael, Ja 62, VolkovBot, Philip Trueman, Martin451, Jackfork, Earthdirt, Madhero88, Synthebot, Lova Falk, Dawn Bard, Yintan, Flyer22, Denisarona, Animeronin, ClueBot, Ewawer, Wysprgr2005, Drmies, Boing! said Zebedee, LizardJr8, Jusdafax, Promethean, Morel, Moberg, Stickee, Rror, Johnmackoh, Avoided, Skarebo, Addbot, Freakmighty, Ronhjones, Jncraton, Fluffernutter, Bernstein0275, Tide rolls, Anxietycello, Jarble, Narutolovehinata5, HARRYCROSSISSOCOOL, THEN WHO WAS PHONE?, AmeliorationBot, Jim1138, Piano non troppo, Materialscientist, JimVC3, 4twenty42o, TheWeakWilled, Jackdanmatt99, S08038, Lido, Javert, DrilBot, Pinethicket, 10metreh, Hamtechperson, A8UDI, Chrisdafish, Blue Plover, Zhernovoi, Sheogorath, Jonkerz, Mariachi12, Tbhotch, Sisterlulu, DARTH SIDIOUS 2, 1XUu6BGK, NerdyScienceDude, John of Reading, Salsero35, Tommy2010, Wikipelli, Ncknightgirl, A930913, L Kensington, Rocketrod1960, ClueBot NG, Smtchahal, Bjtplett, Satellizer, Vacation9, Pengortm, Kasirbot, Widr, Derf81, Names are hard to think of, Crazymonkey1123, North Atlanticist Usonian, Harsha malhotra, Qbgeekjtw, Messagefire, NotWith, CeraBot, Baseballsoup8, YFdyh-bot, Wywin, Drraynemanny, OKdudette, Funnyman3104, Shaikh Azher, Usernameandanotherusername12345, Kogmaw, Leoesb1032, TCMemoire, WikiJuggernaut, Hihihihibarfatron, English400ash and Anonymous: 204 • Puberty Source: http://en.wikipedia.org/wiki/Puberty?oldid=645828586 Contributors: Zundark, The Anome, Karen Johnson, Montrealais, Hephaestos, DennisDaniels, Patrick, MartinHarper, Gabbe, Wapcaplet, Ixfd64, Dcljr, Theresa knott, JWSchmidt, Александър, EdH, Timwi, Haukurth, Raul654, Pollinator, Lumos3, Northgrove, Rhys, Sjorford, Nufy8, Robbot, Jw6aa, Pigsonthewing, Romanm, Lowellian, Pingveno, Davodd, Hadal, Fuelbottle, HaeB, Diberri, David Gerard, Gobeirne, DocWatson42, Christopher Parham, Marnanel, Inter, Ferkelparade, Orangemike, Everyking, No Guru, Frencheigh, Dmmaus, Dumbo1, Decagon, Pne, Bobblewik, Btphelps, Arethusa, PeterC, Alteripse, Beland, OverlordQ, Ot, Kevin B12, Zfr, Thparkth, Asbestos, Joyous!, Ukexpat, Kevyn, Kate, Discospinster, Rich Farmbrough, Rhobite, Guanabot, Michael Zimmermann, ESkog, JJJJust, Brian0918, Wasteland, El C, Shanes, RoyBoy, Adambro, Bobo192, Longhair, Smalljim, BrokenSegue, Duk, Brim, Arcadian, SpeedyGonsales, Minghong, Unused000701, MPerel, Sam Korn, Nsaa, Zachlipton, Alansohn, Gary, Borisblue, Mykej, Wouterstomp, Lightdarkness, Mac Davis, Garfield226, Pedro Aguiar, InShaneee, Mysdaao, ClockworkSoul, Yuckfoo, Evil Monkey, Dan East, HGB, Tariqabjotu, Mhazard9, Revived, Zntrip, Isfisk, Thryduulf, Angr, OwenX, Woohookitty, WadeSimMiser, JeremyA, Kelisi, Jacottier, Dmol, Andrea.gf, JRHorse, Pictureuploader, Laurap414, Moleskiner, Zpb52, Patl, Graham87, Magister Mathematicae, FreplySpang, Jclemens, Mendaliv, Edison, Canderson7, Rjwilmsi, SMC, Kazrak, MapsMan, Yamamoto Ichiro, Dan Guan, Alhutch, Andy85719, RexNL, Gurch, Drumguy8800, Pete.Hurd, King of Hearts, Chobot, Lightsup55, WiccaIrish, Sharkface217, Bornhj, Bomb319, Flcelloguy, YurikBot, Chanlyn, Huw Powell, Sputnikcccp, Chris Capoccia, CanadianCaesar, Stephenb, Gaius Cornelius, CambridgeBayWeather, Kyorosuke, Kimchi.sg, NawlinWiki, Astral, Tetsuo, Dureo, Irishguy, Kingpomba, The Filmaker, E rulez, FatM1ke, Alex43223, Dbfirs, Andrewr47, Tachyon01, Elkman, Wknight94, Searchme, Silverchemist, Richardcavell, 21655, Lt-wiki-bot, Ageekgal, Closedmouth, SMcCandlish, Shyam, Emc2, Nippoo, Luk, Crystallina, SmackBot, MattieTK, Xkoalax, DCGeist, FloNight, Hydrogen Iodide, Bomac, Andrew.in.snow, Richard B, HalfShadow, Bengtang, Gilliam, Ohnoitsjamie, Jushi, Chris the speller, Jon513, MalafayaBot, Cfairhope, Dlohcierekim’s sock, J. Spencer, Whispering, Teamgoon, Konstable, Krallja, Oatmeal batman, Zebruh, Zachorious, OrphanBot, Rrburke, Addshore, Downtown dan seattle, Davr, BocoROTH, Belscb, Mattut, DMacks, Sigma 7, Kukini, Qmwne235, David.johnston-bell, SashatoBot, Robomaeyhem, Srikeit, Kuru, Heimstern, Ocee, Tktktk, Accurizer, Tlesher, Joshua Scott, Slakr, Ddkiller, Noah Salzman, Dbo789, Waggers, SandyGeorgia, Mets501, Brennan1993, Whomp, BranStark, HisSpaceResearch, IvanLanin, CapitalR, Courcelles, Angeldeb82, JayHenry, Tawkerbot2, Zlovestny13, Joshuagross, Lahiru k, Eastlaw, SkyWalker, Belginusanl, CmdrObot, KyraVixen, JohnCD, Phrack3r, Dgw, TipPt, Neelix, Tex, Mojo29, Nilfanion, Atomaton, Wikpedar, Mike65535, MC10, Steel, DrunkenSmurf, Anonymi, Adolphus79, Jamielovesgreenday, B, Tawkerbot4, Chrislk02, Ameliorate!, Jamrifis, Emmett5, Omicronpersei8, Jguard18, Daniel Olsen, UberScienceNerd, Wexcan, PamD, Richhoncho, EvocativeIntrigue, Rjm656s, Thijs!bot, Epbr123, LeeG, HappyInGeneral, Martin Hogbin, N5iln, Sopranosmob781, John254, SomeStranger, The Wednesday Island, JustAGal, Danaidh, Big Bird, FreshFruitsRule, Central2, Vaniac, Porqin, Ju66l3r, CerealBabyMilk, AntiVandalBot, Luna Santin, Jj137, TimVickers, Fmyers, Teilhardo, LibLord, Sirona, TheFid2, Richiez, Res2216firestar, Dogru144, ZZninepluralZalpha, Dybryd, Fetchcomms, Honette, DanB DanD, Roleplayer, Kipholbeck, Penubag, Pedro, Bongwarrior, VoABot II, Fallon Turner, JNW, Joe112, Bravedog, JCMasterpiece, GroovySandwich, Animum, Cgingold, EagleFan, Robotman1974, 28421u2232nfenfcenc, Allstarecho, Tins128, DerHexer, JaGa, Purslane, Patstuart, Oroso, Neilsmith38, S3000, Mmustafa, Hdt83, BossyBitch, CliffC, Gandydancer, Sagar55, Lilac Soul, J.delanoy, Pharaoh of the Wizards, Trusilver, Robbiehay1, Numbo3, Boghog, Uncle Dick, Danrz, Ohleetone, Binkyfinder, McSly, Maestrovoci, Mikael Häggström, Skier Dude, Angisson, Cadwaladr, Bobianite, Mufka, Acewolf359, Matt2307, Cometstyles, Carlo V. Sexron, Bonadea, Pdcook, Ja 62, Useight, Wikieditor06, X!, Deor, VolkovBot, CWii, MAJORdorMo, ABF, John Darrow, AlnoktaBOT, Bovineboy2008, Tameeria, Hqb, Pandacomics, Janahan, Transfat, Melsaran, Rbpolsen, Jackfork, LeaveSleaves, Kosherklassix, Justinfr, Madhero88, Brdnylund, Eyebeeuk, Lova Falk, O9h9c9e9, Smartie960, Harryfrank, Justincarpenter, Hazerd260, Twoageman, Nagy, IndulgentReader, Signsolid, LordofPens, OsamaK, Knanier, SieBot, StAnselm, Claire a bell, Frans Fowler, WereSpielChequers, BotMultichill, Dawn Bard, Muttonking, Shadow master66, RJaguar3, Triwbe, Calabraxthis, The Mingler, Andersmusician, Keilana, Flyer22, Undead Herle King, Freddie Coster, JSpung, Faradayplank, AngelOfSadness, Nikon307, Lara bran, Tombomp, Hobartimus, Realist2, Manway, Macy, Harry the Dirty Dog, IdreamofJeanie, OKBot, Svick, Anchor Link Bot, Georgette2, Alokprasad84, Patilsaurabhr, Pinkadelica, Escape Orbit, Explicit, Faithlessthewonderboy, ClueBot, SummerWithMorons, LAX, Rumping, Binksternet, Snigbrook, The Thing That Should Not Be, Rodhullandemu, SoundBlast, Ewawer, Ndenison, Blanchardb, Auntof6, Excirial, Ffsgoogle, Irisom, PixelBot, Pmronchi, Abrech, Gtstricky, Leonard^Bloom, Jacksinterweb, ParisianBlade, Tyler, Grey Matter, Piggggu, Dekisugi, Rol0012, Puppydog2896, Niceandcool, La Pianista, Waterloocook, Unmerklich, Wiped mean, Thingg, Aitias, Versus22, PCHS-NJROTC, TheProf07, CAC001, DumZiBoT, Koalabear3, Pompreet, XLinkBot, AnotherSolipsist, Dark Mage, BodhisattvaBot, Stickee, Dthomsen8, Feinoha, Pratryan, Oligopiste, Unlimitednk, PL290, Noctibus, Twalsh0, Rhio, Cabo GC, The Rationalist, Ejosse1, Gggh, Pokemaster1, HexaChord, Jtknowles, Sem boy, Andrewcapone, Addbot, Brumski, Mahasanti, AVand, DOI bot, Sherlock Boy, Next-Genn-Gamer, Friginator, CL, Sunandheir, Fieldday-sunday, D0762, Zaheer12a, CanadianLinuxUser, Jthan 299, Tricklife14, Chamal N, Dynamization, Lihaas, Schmausschmaus, Favonian, Whaawhaawhaa, Hacker94, Ransac838, Taopman, Justpassin, AguaitantPV, Jasonfitz, Qazkingtyuiop, Bfigura’s puppy, ForesticPig, Hatered, Gaaylike, Jarble, Halaster, LGF1992UK, Luckasbot, ZX81, Yobot, Senator Palpatine, Les boys, Legobot II, II MusLiM HyBRiD II, Wheelchair Epidemic, Sub5nattys, Mmxx, THEN WHO WAS PHONE?, Funeralworld, KamikazeBot, Licenine, Mrtummytums, Hazzagazza, Alexkin, I Don't Like CWii, Bility, Urall-
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homos, AnomieBOT, Marauder40, Twalsh000, Killiondude, Walrus heart, Piano non troppo, Ularevalo98, Templatehater, AdjustShift, Yachtsman1, Astanak, Ulric1313, Flewis, Mann jess, Typesships, Cocoisland098, 90 Auto, ArdWar, Citation bot, Pitke, Cheeseynips, LilHelpa, Xqbot, Zad68, S h i v a (Visnu), Capricorn42, Eggchick, Notorious404, Mặt trời đỏ, Ricanguyz, Inferno, Lord of Penguins, Jarad88868759, GrouchoBot, Smartkid1998, Ser24, Susanhurstcalderone, Amaury, Doulos Christos, PlayerapX, Shadowjams, StevenJ20, Astatine-210, Alfie Crowe, Samwb123, Perelta, Captain-n00dle, Starwars1791...continued, Skydeepblue, Meepmoo, Citation bot 1, Åkebråke, XxTimberlakexx, Edderso, Hunterdude64, RedBot, Wikitanvir, Scmd, Didactik, Buddy23Lee, Dinamik-bot, Theo10011, Rttam, Luv2read83197, Eirik1231, Tbhotch, Mramz88, Hmmwhatsthisdo, Dustinchan, Andrea105, RjwilmsiBot, Lkddflkj, HOSKINGJ, Totalbacon, AndrewAfresh, Heymid, Snowyguy10, Lednarb, Laxman20, Iscrewthingsupalot, SolidSnake48, Sepguilherme, Ilovebighairymen, Deemfingtee, Jack McCormack, Traxs7, Cybermud, Aquamareie, Govteeninc, Thisonechick, Ol3slice, H3llBot, Unreal7, Blosspara, Dennis Kwaria, Civilian knowledge, TBM10, Ajiwa, Sugarcube73, Movses-bot, Snotbot, Telpardec, North Atlanticist Usonian, Helpful Pixie Bot, Newyork1501, BG19bot, They, Ceradon, George Ponderevo, PhnomPencil, JacobTrue, Puggie4276, Mathurah, BattyBot, Paruk.z, Tandrum, Moscowsky, JasonMacker, ThinkSlam, Hilarybean, Pincrete, Melonkelon, Eric Corbett, DudeWithAFeud, Tn9005, Monkbot, Σούπερμαν, K. Bautista, Gervasija and Anonymous: 832 • Male reproductive system Source: http://en.wikipedia.org/wiki/Male%20reproductive%20system?oldid=648126931 Contributors: William Avery, Robbot, Jredmond, Queerwiki, Antandrus, Jayjg, Discospinster, Clawed, Kooo, ZeroOne, Kelvinc, Arcadian, Giraffedata, Deryck Chan, Jakew, Alansohn, Arthena, Sl, Lightdarkness, Snachodog, Snowolf, Bsadowski1, Alai, Jun-Dai, Kelly Martin, Schzmo, Lafeber, Graham87, Rjwilmsi, The wub, Jamesmusik, Musical Linguist, Jalapenodude, Chobot, DVdm, Bgwhite, YurikBot, Wavelength, Chanlyn, Sceptre, Daverocks, David R. Ingham, NawlinWiki, Aaron Schulz, Nopol10, Elkman, Closedmouth, Dspradau, Katieh5584, NetRolller 3D, KnightRider, SmackBot, Tarret, George Rodney Maruri Game, DHN-bot, Nmacpherson, Decltype, MMX, Panthro, Birdman1, The undertow, JzG, Llamadog903, Piepants, TwistOfCain, Nightrider083, Tawkerbot2, SkyWalker, JForget, ForeverJammin, Jaeger5432, WeggeBot, Travelbird, JFreeman, Eu.stefan, Tawkerbot4, Shirulashem, Argymeg, FrancoGG, John254, Pfranson, Seaphoto, QuiteUnusual, Prolog, Spencer, Kauczuk, Kaobear, PhilKnight, Magioladitis, Ima learning, QuizzicalBee, WhatamIdoing, WLU, MartinBot, STBot, Speck-Made, Trixt, CommonsDelinker, Marc919, LedgendGamer, 3dscience, Tgeairn, Erkan Yilmaz, J.delanoy, CFCF, Trusilver, Katalaveno, Gurchzilla, FEVB, Da.skitz, Bonadea, Dakota1234, Inas, VolkovBot, Thedjatclubrock, DSRH, Jeff G., Ryan032, Philip Trueman, TXiKiBoT, Zidonuke, Tameeria, Monkey Bounce, LeaveSleaves, Poopydoopy12321, , E2e3v6, Doc James, PlutoniumExperiment, RJaguar3, Happysailor, Flyer22, Oxymoron83, Poindexter Propellerhead, Mygerardromance, Daffycrooke12, Kanonkas, Animeronin, ClueBot, The Thing That Should Not Be, Ewawer, Drmies, Arunsingh16, DragonBot, Excirial, BOTarate, XLinkBot, Avoided, Ejosse1, Iranway, Addbot, Some jerk on the Internet, MartinezMD, Mentisock, Morning277, Bernstein0275, Minidude4eva, Favonian, SpBot, Tide rolls, WikiDreamer Bot, Jarble, Luckas-bot, Yobot, II MusLiM HyBRiD II, Nallimbot, KamikazeBot, Priya9690, Ningauble, AnakngAraw, IW.HG, AnomieBOT, Piano non troppo, Flewis, Bluerasberry, Materialscientist, Jmarchn, Obersachsebot, Zad68, Capricorn42, Tyrol5, Resident Mario, RibotBOT, Danifierce, Harryhoman, Supasaint, Pinethicket, Elockid, MastiBot, Wikitanvir, SpaceFlight89, BCbasketballstar, Fama Clamosa, Kiritampo, Jorge Sanders, Reaper Eternal, Bubbleswallower, Tinkba, TjBot, Bhawani Gautam, Sincere22k, DoRD, EmausBot, Efficacious, YEloi, Annardugan, K6ka, Davden90925, Trinidade, Tolly4bolly, Cyberdog958, Orange Suede Sofa, NTox, Justmarc, 28bot, TBM10, ClueBot NG, Bballman14, Vendysqa, Pddaniel92, Jteague2003, Patmc01, Gsvanenikka, Pengortm, Yearstypes, Signssaids, Frietjes, Rezabot, Widr, Antiqueight, Derf81, Formarcster, Titodutta, Calabe1992, Jamie.bryant, ISTB351, AwamerT, PokemonGuy2, NotWith, Rickc1969, Farfed, Gavin.hayes, JYBot, Interlude65, Raiankita06, 331dot, Lugia2453, Drraynemanny, Faizan, Forgot to put name, I am One of Many, D Eaketts, Peacebuddy420, Vbrb2013, St170e, Hasith lakshan muthukumara, MartinPolka, Asdklf; and Anonymous: 368 • Scrotum Source: http://en.wikipedia.org/wiki/Scrotum?oldid=649559199 Contributors: The Anome, Malcolm Farmer, Gianfranco, William Avery, Zoe, Steverapaport, Patrick, Infrogmation, Paul Barlow, Zanimum, Karada, Tregoweth, Ahoerstemeier, Julesd, Netsnipe, Rob Hooft, Arteitle, Adoarns, Rednblu, DJ Clayworth, Lypheklub, Fvw, Bloodshedder, Raul654, Pakaran, Northgrove, Gromlakh, Sander123, Altenmann, Academic Challenger, Caknuck, Hadal, Diberri, Dina, Sj, Robodoc.at, Michael Devore, Guanaco, Jessamyn, Kandar, Utcursch, Alexf, Sonjaaa, Antandrus, Beland, OverlordQ, Apathyjunkie, AlexanderWinston, DragonflySixtyseven, TiMike, Lockz, Sonett72, Bluemask, Shotwell, Alkivar, A-giau, Discospinster, Jon Backenstose, Orbital, Chowells, N, Kbh3rd, Syp, Mr. Billion, MBisanz, NickGorton, RoyBoy, Renice, Crocogator, Bobo192, Longhair, Arcadian, Guiltyspark, Escapeartist, Minghong, Notafish, Jumbuck, 578, Alansohn, Anthony Appleyard, Polarscribe, Andrew Gray, Wouterstomp, Ekko, InShaneee, Mysdaao, Snowolf, Marianocecowski, Wtmitchell, RainbowOfLight, Bsadowski1, Blaxthos, HenryLi, Dennis Bratland, Angr, Mindmatrix, Macronyx, Qaddosh, Kmg90, Pictureuploader, TheAlphaWolf, Phlebas, Mandarax, Kakashi-sensei, WBardwin, Anarchivist, FreplySpang, Sjö, Rjwilmsi, Koavf, PHenry, The wub, Nandesuka, Sango123, FlaBot, Margosbot, Usni, Mickfors, RexNL, Gurch, Brendan Moody, Consumed Crustacean, King of Hearts, Chobot, DVdm, Random user 39849958, Voodoom, Cactus.man, Antonio Di Dio, YurikBot, Chanlyn, Mhocker, RussBot, Kevs, RadioFan, Hydrargyrum, Akamad, Stephenb, Gaius Cornelius, Wimt, NawlinWiki, Ozzykhan, Cquan, Phoenix79, FFLaguna, Dureo, Anetode, Aaron Schulz, WolFox, DeadEyeArrow, Fpmax, Sickarroll, Wknight94, 21655, Theodolite, Zzuuzz, Lt-wiki-bot, Theda, Closedmouth, Dspradau, GraemeL, Mustafarox, Kevin, TLSuda, NeilN, Tom Morris, DT29, Locke Cole, SmackBot, Andreas Erick, KnowledgeOfSelf, Jfurr1981, PJM, EaZyZ99, Edgar181, Yamaguchi , Cool3, Asdre, Gilliam, Ohnoitsjamie, Indium, Angelbo, Lapsus Linguae, Vande, HartzR, Idiot 7, Billprins, Robth, Gruzd, Lmsilva, Nazgjunk, John Reaves, Dethme0w, Can't sleep, clown will eat me, Chlewbot, OrphanBot, Andrea Parton, Onorem, OSborn, Rrburke, Reaving edge, Thrane, Threeafterthree, Dharmabum420, BostonMA, Ianmacm, Khukri, Nakon, Dreadstar, Sbluen, Hammer1980, Kukini, SashatoBot, Esrever, Dbtfz, Kuru, Jidanni, Wickethewok, Joshua Scott, IronGargoyle, The Man in Question, BillFlis, Tasc, Booksworm, Childzy, Meco, Ryulong, Manifestation, Avant Guard, BranStark, Iridescent, Radiant chains, Tawkerbot2, Daniel5127, Altonbr, SkyWalker, Zotdragon, JForget, ATPhil, Mcstrother, KnightLago, Dragon-Girl, Karenjc, MrFish, Atomaton, Gogo Dodo, Palffy, JFreeman, A Softer Answer, Pascal.Tesson, Difluoroethene, Wildnox, Shmed, Dancter, Delta Spartan, Chris4682, EqualRights, Kozuch, Omicronpersei8, Gimmetrow, Satori Son, EnglishEfternamn, Thijs!bot, Epbr123, Pajz, Janviermichelle, Chitomcgee, N5iln, Mojo Hand, Tickletom, Marek69, A3RO, NorwegianBlue, Renamed user 1752, Ram4eva, Dgies, Natalie Erin, CerealBabyMilk, Gossamers, AntiVandalBot, Karlosofbego, Luna Santin, Seaphoto, SummerPhD, TimVickers, RJDJKTMMER, David Shankbone, LegitimateAndEvenCompelling, Amberroom, Yancyfry jr, JAnDbot, Kaobear, MER-C, Jacketeer, Xeno, PhilKnight, Cyningaenglisc, .anacondabot, Acroterion, Bencherlite, NaldoOfThePlains, Bongwarrior, VoABot II, Iriseyes, JNW, Jmac1811, Tutankamondelfuturo, Kiloalpha, Walchop825, Altake, Killer the Clown, Elcajonfarms, Cinnamon88, Allstarecho, Chivista, Glen, DerHexer, Booyah 007, IlliterateSage, Rainy Day Industries, Mmustafa, MartinBot, Poeloq, Jorjepot, KtWTupac, Manman3, Alro, Joie de Vivre, Dick Hyman, Tgeairn, Slash, MarkM, J.delanoy, Lord balron, CFCF, Elmer Homero, Extransit, WarthogDemon, DD2K, Ijustam, Icseaturtles, Dodoheaddy, CFlorida416, DarkFalls, Qwertyster, Thejollyrancher, Drengrave, Eskitorrr, MKoltnow, Penis007, Shshshsh, Cometstyles, WJBscribe, Butcherbaker, Treisijs, Dorftrottel, Martial75, RJASE1, Lights, Jeff G., Philip Trueman, TXiKiBoT, Biggiesteel23, KevinTR, Technopat, Sparkzy, Z.E.R.O., Sean D Martin, Shoopingdawooping, Qxz, Lradrama, Martin451, Freakpizzaboy18, Whatitis69, Takers biggest fan, Tiddie43, Saturn star, Chris9086, RandomXYZb, SutharsanJIsles, Suction Man, Enviroboy, Happycat01, PrinceMiroku16, Brianga, Monty845, Overdrive panta, Sue Rangell, DDDee92, Logan, Bfpage, SMC89, Club Penguin Advisor, SieBot, Tiddly Tom, AS, Work per-
60.13. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
211
mit, Euryalus, Vinnivince, Invisible Noise, Revent, Lamilli, Ipoundz, Gayhobos, Keilana, Miamiman323, Bentogoa, Toddst1, Flyer22, Wilson44691, Arknascar44, Kobcorn78, Aruton, Lehisport, Nikon307, Benea, Faxmonkey, Alex.muller, Thisnamestaken, Lighted1, OKBot, PrinceMiroku20, Dillard421, The Stickler, Pinkadelica, Jimqbob, Runnerboy4life09, Thevirusupayfor, Dahahaha, Mr. Granger, Pussy101, Atif.t2, Felipe Aira, Loren.wilton, ClueBot, The Thing That Should Not Be, Dean Wormer, Fountainsquad21, Mild Bill Hiccup, TheOldJacobite, Fairywings1980, Thebassplaya, Faruki12, Boing! said Zebedee, Gerbil8011, Alpineos, Blanchardb, Neverquick, Puchiko, Awickert, Ktr101, Excirial, Alexbot, Jusdafax, Halloween party, Estirabot, Deutschland1985, Maser Fletcher, Religion and supersition, ParisianBlade, Staymyth, Gabriel321, Promethean, Minicirc, Bouncyallz, Pab101390, Ranjithsutari, Alteclanisni, Qwfp, SoxBot III, Egmontaz, Darkicebot, EdChem, Nick in syd, XLinkBot, Fastily, Spitfire, Jedir0x, Dthomsen8, WikHead, ScrotalRaphe, Billybobjoebob123, Airplaneman, Ludwic51, Apocalypse2011, Rohondra, Tk18, Addbot, Xp54321, P0lit0o, Grayfell, Lmbd uk, Some jerk on the Internet, Landon1980, Peaceoverall, Theleftorium, Dkmaf, Ronhjones, B2xiao, Fieldday-sunday, Mnh, Martindo, Joeljsh11, Conorcxnt, Glane23, Ld100, Glass Sword, Chzz, Favonian, Ginosbot, 5 albert square, Yohomes2, Steunafisch, Batchfile, THEDEATHOFYOUALL, Tide rolls, BrianKnez, Fuzcotton, Gail, David0811, Jarble, Fielding IV, LuK3, Gympreace, AchillesLastStand, Slomkam, Luckas-bot, Vedran12, Ptbotgourou, Senator Palpatine, Hill-e, Ojay123, Yngvadottir, Drooblyballs69, Mmxx, Rkaseff, AnomieBOT, Juliaaz1, Howie121294, Jim1138, Dwayne, JackieBot, Chuckiesdad, Citation bot, Srinivas, Jacketsfourtyfour, GB fan, ArthurBot, Xqbot, CStrife, Renaissancee, Pontificalibus, Quintus314, AV3000, Wikignome0529, Prunesqualer, Amaury, Basharh, N419BH, Emptybone, Shadowjams, GT5162, Cake cake cake cake is nice, Remotelysensed, Fatalb, Lccpride33, IRONMAN48, Carr34, Stuffhappens1112, Blackhorseinn, Tetraedycal, Laaa200, DivineAlpha, Heyychrissyx, Pshent, Intelligentsium, Tintenfischlein, Pinethicket, I dream of horses, Edderso, Calmer Waters, Yofootball127, Picklepie00, A8UDI, Itjj91, RedBot, JamesFranelli, Sweatydonkeyshlong, EdoDodo, Vageface123, Slipoftheknot1, YoungMoneyJock, Jauhienij, Peaches-x, Mjs1991, TobeBot, Trappist the monk, Mrhappytruthteller, Duffmanusa007, Fandango87, Professor Fiendish, Vrenator, Jcool5, I am Blue 862, Ahd83, TheLongTone, Gavelaa, Jhenderson777, Stroppolo, Minimac, RichMchwest, DARTH SIDIOUS 2, SackSlappa, Expert19612005, Andrea105, Hornswaggle69, Mean as custard, RjwilmsiBot, Neifion, NiallGaf, Hajatvrc, NerdyScienceDude, JohnnyEvers, Jewbag420000, DASHBot, Juicyfruitskeet69, EmausBot, Orphan Wiki, Miguel2020, Sophie, Nuujinn, Nece3283, Me6888, Wikipelli, Tänzer, K6ka, TheLemon1234, Susfele, DavidMCEddy, Bobdole41, Azuris, THE GREAT AP, Mrseanington, Toygun1234, A930913, Vmconcernedad, Gz33, Nuts1234, Soccercd1998, Wikitürkçe, Eminem0145, Jay-Sebastos, L Kensington, Doctersmartman, Thepersone3224, Nzfauna, Justmarc, Jacqui x, TBM10, Clhobbs01, Lovetinkle, Atmışdokuz, ClueBot NG, Rixster69, Info456789, IEDITSHIZ, Cntras, Hdryfgghf, Daudei, Marechal Ney, Miltiamenfred, Fragay, Beastybrodie, NOOBKILLER xD, North Atlanticist Usonian, Hank1357, Wet Scrote, Iste Praetor, 2001:db8, Joannavelarde, Drbardi, Manwholikesclit, Theperson6969, Wiki13, Mark Arsten, Altaïr, Derpyherpyhur, Funnykid999, Slimjim55, 07amossam, DUFFFMANN, Su Madre22, Fred-93, Philippguertler, Jimsardine, Katehparkher, TheZendnb, BattyBot, Obsant, Jimw338, Carlitosbouchot, Swagadactyl, Gigibreakfast, Rfyu2, Aussie.rox, Khazar2, Zebart00, EuroCarGT, Supernatural Cow, Webclient101, Mogism, Morenzoninick, KANOA3Z, Jamiaz, Lugia2453, JakobSteenberg, NeatIndeed, Frosty, Csj597, Mouldyman, Big fatboo saclk, Chodelover69, Pansy Anon, Rykill892, Fagatron101, Acetotyce, Meyakas, Melonkelon, Metaphidippus manni, Tentinator, Faker1, EvergreenFir, STKoz98, LT910001, NorthBySouthBaranof, Zenibus, XxEpicTacosxX, Jpavey88, Jolza371, Liz, Noongahsa, Maximustheman.312, DudeWithAFeud, Tn9005, Henry Height, Thewrongtuber, Rm707042, Monkbot, Filedelinkerbot, BethNaught, 400 Lux, Alberteagle, Nzdilf, The.Fluffy.Poonmaster, Eddieford123, Holahola5121472, Piddle99 and Anonymous: 698 • Testicle Source: http://en.wikipedia.org/wiki/Testicle?oldid=642726570 Contributors: AxelBoldt, Kpjas, The Anome, Ed Poor, Danny, Fubar Obfusco, Sean, Daniel C. Boyer, Jaknouse, Montrealais, Patrick, Infrogmation, D, Lexor, Dominus, Ixfd64, Karada, Delirium, Rolken, Dori, Pcb21, Mdebets, Ahoerstemeier, Ronz, Bueller 007, Julesd, Netsnipe, JASpencer, Harris7, RickK, Selket, Clattuc, LMB, Jose Ramos, Mackensen, Raul654, Jerzy, Francs2000, Aliekens, Chuunen Baka, Gromlakh, Robbot, Sander123, Kizor, Chris 73, RedWolf, ZimZalaBim, Romanm, TimothyPilgrim, Mirv, Texture, Meelar, Yacht, Hadal, Huckfinne, Fuelbottle, Mushroom, SoLando, Diberri, Dina, Marc Venot, Gobeirne, Marnanel, Nmg20, ShaunMacPherson, Mintleaf, Tom harrison, Lupin, Leflyman, Obli, Robodoc.at, Bradeos Graphon, Everyking, Hans-Friedrich Tamke, Rpyle731, Alfa, Guanaco, Mboverload, Macrakis, Jackol, Bobblewik, Sonjaaa, Antandrus, Alteripse, OverlordQ, The Inedible Bulk, PDH, Kesac, DragonflySixtyseven, CBDroege, Sam Hocevar, Ezekiel Cheever, Joyous!, Trevor MacInnis, Grunt, Lacrimosus, PhotoBox, Mike Rosoft, AliveFreeHappy, Imroy, DanielCD, Diagonalfish, Discospinster, Brianhe, Solitude, Paul August, Bender235, Kbh3rd, Kaisershatner, Mr. Billion, Zscout370, Ascorbic, Szquirrel, Gilgamesh he, Kaveh, Bobo192, Circeus, Hurricane111, Shenme, Brim, Elipongo, Arcadian, ParticleMan, Giraffedata, Nk, Minghong, Helix84, Nsaa, Luckyluke, Timmywimmy, Ranveig, Storm Rider, Zachlipton, Abstraktn, Alansohn, Gary, Nereocystis, Keenan Pepper, Fat pig73, Kelnage, Cdc, Plange, Mysdaao, Spangineer, Bart133, Caesura, Snowolf, Wtmitchell, CaseInPoint, Gdavidp, KingTT, QuixoticKate, Stephan Leeds, Vcelloho, Mauvila, RainbowOfLight, Wadems, Bsadowski1, Kusma, Gene Nygaard, Djsasso, Antifamilymang, BerserkerBen, Natalya, Zntrip, Bobrayner, Nuno Tavares, OwenX, 2004-12-29T22:45Z, JarlaxleArtemis, Uncle G, Ekem, WadeSimMiser, MONGO, Grika, Bbatsell, GregorB, Hughcharlesparker, Pictureuploader, Palica, Mandarax, Wiggy!, Graham87, Demonuk, RxS, Mendaliv, Edison, Sjakkalle, Coemgenus, Vary, Strait, Tangotango, Uwe Gille, MZMcBride, SMC, Vegaswikian, Bhadani, Ch1902, DoubleBlue, Nandesuka, Dar-Ape, Yamamoto Ichiro, FlaBot, SchuminWeb, RobertG, Musical Linguist, Margosbot, Nihiltres, Harmil, Kerowyn, RexNL, Drumguy8800, Terrx, EronMain, Butros, CiaPan, Chobot, CAD6DEE2E8DAD95A, Igordebraga, Gwernol, Corington, Meireles, EamonnPKeane, YurikBot, Wavelength, Chanlyn, RobotE, Sceptre, Tznkai, Wolfmankurd, RussBot, Lexi Marie, Pigman, Epolk, Netscott, Hydrargyrum, Stephenb, C777, CambridgeBayWeather, Kyorosuke, Salsb, Wimt, MosheA, NawlinWiki, Wiki alf, Bachrach44, ExRat, ImGz, Shaun F, Irishguy, Tm8, Anetode, Brbigam, Brandon, Dppowell, Brian Crawford, Cholmes75, Xdenizen, Tony1, Epipelagic, Bucketsofg, Aaron Schulz, Gadget850, DeadEyeArrow, Nlu, Wknight94, MrShamrock, Crisco 1492, Silverchemist, Daremyth, Zzuuzz, Chase me ladies, I'm the Cavalry, Closedmouth, Jwissick, Ketsuekigata, E Wing, Dspradau, Livitup, JoanneB, Kevin, Ghetteaux, ArielGold, Garion96, Archer7, Kungfuadam, Junglecat, NeilN, Benandorsqueaks, Airconswitch, Elliskev, DVD R W, CIreland, A bit iffy, SmackBot, MattieTK, Evilgrug, Andreas Erick, Haymaker, Herostratus, KnowledgeOfSelf, Royalguard11, VigilancePrime, Joonhon, FloNight, Hydrogen Iodide, Gnangarra, Unyoyega, Pgk, Blue520, Jacek Kendysz, DTM, Delldot, Frymaster, Canthusus, BiT, HalfShadow, Gar34, Gaff, Yamaguchi , PeterSymonds, Inkstersco, Gilliam, Brianski, Ohnoitsjamie, Andy M. Wang, GoneAwayNowAndRetired, Master Jay, Bluebot, Kurykh, SynergyBlades, Persian Poet Gal, NCurse, Catchpole, Miquonranger03, SchfiftyThree, Sampi, Harrym, Baa, Konstable, Darth Panda, Yanksox, Deewhite, Royboycrashfan, Kotra, Can't sleep, clown will eat me, Jinxed, DéRahier, Onorem, Snowmanradio, Avb, Darthgriz98, Rrburke, TKD, Addshore, Amazins490, Threeafterthree, Jmlk17, Soosed, Flyguy649, Khukri, Nakon, Dreadstar, Mstngofire, Weregerbil, Xagent86, Sljaxon, Wisco, DMacks, Joeyjoejnr, Vina-iwbot, Kukini, Rockpocket, Nathanael Bar-Aur L., CheesusChrist, Akira Tomosuke, Soap, Kuru, John, Buchanan-Hermit, Rodsan18, Heimstern, Gobonobo, ZGames, Lazylaces, Mr.Clown, Masato Kobayashi, LestatdeLioncourt, Minna Sora no Shita, Goodnightmush, Mr. Lefty, 041744, TheAmelianator, Slakr, Checkemlads, LuYiSi, George The Dragon, Timothychavis, MarphyBlack, Ryulong, Outsider2810, Nicolharper, KJS77, BranStark, Iridescent, Rufusgriffin, Wysdom, Shoeofdeath, Dreamychance, NativeForeigner, StephenBuxton, Tony Fox, Amakuru, DavidOaks, Blehfu, Jbolden1517, Radiant chains, Yskyflyer, Tawkerbot2, Emote, Enamul h khan, SkyWalker, INkubusse, JForget, Sleeping123, Ale jrb, Irwangatot, Wafulz, Unionhawk, Jorcoga, Robotsintrouble, Scohoust, Picaroon, 0zymandias, Runningonbrains, R9tgokunks, Lmcelhiney, KnightLago,
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CHAPTER 60. REPRODUCTIVE HEALTH
Dgw, NickW557, MarsRover, Shandris, Nickben, Nauticashades, Badseed, Cydebot, Mike Christie, Gogo Dodo, JFreeman, Flowerpotman, Strom, Tawkerbot4, Codetiger, DumbBOT, Chrislk02, Phydend, FastLizard4, EqualRights, Kozuch, Thesisbinder, Omicronpersei8, Woland37, Satori Son, Bensnowden, EvocativeIntrigue, CieloEstrellado, Thijs!bot, Epbr123, Dbarnes99, Npatchett, Daniel, Ucanlookitup, HappyInGeneral, N5iln, PearlJam, Andyjsmith, Mojo Hand, Sopranosmob781, Muddleman592, Marek69, John254, Tapir Terrific, James086, Merbabu, Shot info, Philippe, Booshakla, CharlotteWebb, Lithpiperpilot, Natalie Erin, Escarbot, Mentifisto, Hmrox, Porqin, AntiVandalBot, Karlosofbego, Luna Santin, Turlo Lomon, Opelio, Paste, DarkAudit, Butthead45, Lyricmac, Jongrahamisalegend, Jj137, Lordmetroid, Danger, Gdo01, Spencer, Blair Bonnett, Trakesht, David Shankbone, Skad4life11, Myanw, Amberroom, Canadian-Bacon, JAnDbot, Dan D. Ric, Kaobear, MER-C, Instinct, Fetchcomms, Andonic, Hut 8.5, Ryan4314, Suduser85, .anacondabot, Acroterion, Bencherlite, Meeples, Magioladitis, Connormah, Bongwarrior, VoABot II, ChuckStone, Fusionmix, Carom, JNW, Bakken, Appraiser, Drcoop, Jéské Couriano, Trebloc, Sixevans, WODUP, Bubba hotep, Weathered26, Catgut, Animum, Captin Shmit, Mtd2006, Elcajonfarms, ArmadilloFromHell, Glen, DerHexer, Booyah 007, Esanchez7587, KenyaSong, TheRanger, Patstuart, Seba5618, The lojak, Oroso, Jedithebomber, Xandergr8, DancingPenguin, Cliff smith, Hdt83, MartinBot, Arjun01, Rettetast, Anaxial, Keith D, Nave787, Uriel8, CommonsDelinker, AlexiusHoratius, Flip22sorry, PrestonH, LedgendGamer, Watch37264, J.delanoy, Captain panda, Pharaoh of the Wizards, CFCF, TyrS, BillWSmithJr, Tommyjxxx, Uncle Dick, Eliz81, Extransit, Aerillion, Squeezeweasel, Scottreast, Wandering Ghost, DarkFalls, LordAnubisBOT, McSly, Nemo bis, BaseballDetective, Starnestommy, Naniwako, Mikael Häggström, AntiSpamBot, (jarbarf), BoredTerry, Belovedfreak, NewEnglandYankee, SmilesALot, SJP, Gregfitzy, Chrisnydeniscool, Froddy, Rumpelstiltskin223, Matt2307, Juliancolton, Kidlittle, Cometstyles, Lauraxx88xx, Jaystar8899, Tiggerjay, Rawr1, Monkey999, Ballsbadgerman2, Michman42, Guyzero, Mooblez, Karekare0, Acidskater, Homologeo, Delta212, CardinalDan, RJASE1, Lights, VolkovBot, Bayareadude, Davemallet, Thedjatclubrock, DSRH, Science4sail, Jeff G., Soliloquial, Davidwr, The All-Traq, Chienlit, BlazeTheMovieFan, Philip Trueman, TXiKiBoT, Yotyu, Kamelot75, Cosmic Latte, MIkeobrienisafag, GregisaacIV, MIkeobrienisgay, PizzaBox, Vipinhari, Anonymous Dissident, ElinorD, CoJaBo, Woodsstock, BlueLint, Qxz, Someguy1221, Una Smith, Seraphim, Brunton, Boggeroo, Chazisthebest, Harley gayry, John999doe, 1234hyhyhy, JhsBot, Lakenheath45, LeaveSleaves, Optigan13, Return Of Love Monkey, Vgranucci, BrendonLOL, Lafadaf, Cremepuff222, Hrundi Bakshi, Imperiex9873, Earthdirt, OvanIsTriEdgespoilers, Jacob1990, Xavcam, Dannwhite, Madhero88, Jeffistheshiznit, Greswik, Blurpeace, Cgkimpson, Kenmanic, Vaubin, Thestanky, Gillyweed, Carinemily, Lokaloola, Enviroboy, Zooweee, Full and utter disclosure, Burntsauce, Happycat01, Neothe, Insanity Incarnate, Drummerface, Everybody’s Got One, Why Not A Duck, Brianga, Ceranthor, Zarek, Nagy, Snakecrack76, Kehrbykid, Legend of ledbury, Rocko52003, Thierryhenry14legend, Runewiki777, EmxBot, Zemania, Theoneintraining, The Random Editor, Thw1309, Ejacson1969, SieBot, Bdentremont, Madman, Coicoiul, Ttony21, Tiddly Tom, Scarian, Skingski, Threelakesgirl, Boytoy9393, BotMultichill, Kappore, Winchelsea, Caltas, New England, Big bobby 2k7, Yintan, Revent, Aribocian, Crash Underride, Barliner, Ilhackyounoob, Keilana, Speedigecko, Dwane E Anderson, Xenophon777, Digwuren, I'mFeelingABitPressured, Aillema, Happysailor, Toddst1, The Evil Spartan, Oda Mari, Bahz, JSpung, Will Aaron 6, Oxymoron83, Antonio Lopez, Smilesfozwood, Nuttycoconut, Nikon307, Steven Zhang, Poindexter Propellerhead, Smiggle16, IdreamofJeanie, Dlh-stablelights, Hatmatbbat10, SolomonSimon, Nicklovesbigwang, Spartan-James, RJGatorman, StaticGull, Verethor, Gardam, Wuhwuzdat, Radonir, Ken123BOT, Joshschr, Funnykitty789, DRTllbrg, Drgarden, Escape Orbit, Yourmotherisacunt, TheCatalyst31, Gubernatoria, Atif.t2, Gleye182, AlternateHamburgerBeta, Felipe Aira, ClueBot, LAX, JonnybrotherJr, Fyyer, The Thing That Should Not Be, Fadesga, Notoriousdoa, Rjd0060, Latenightlance, Wysprgr2005, Boing! said Zebedee, Jackjackjackjackjackjack, Clerkcosts, Boggi89, Jhapeman, Ansh666, Blanchardb, Incin32, Freepieyeah, Wct 123, Baalsinyourmouth, Nick Kucharski, Lakewood Ranch High School, Jharrisonr, Muhherfuhher, LeoFrank, Excirial, Alexbot, Who ordered 137?, Eeekster, Abrech, Law & Disorder, SpikeToronto, Lartoven, Untilcited, Afftonz, Tyler, Drpspzep, NuclearWarfare, Teethmerit, Staymyth, Sbfw, Minicirc, Who3671, Lieslnel, Mikaey, Jasonpeace0620, La Pianista, Waterloocook, Rui Gabriel Correia, Thingg, Bugs32, Darren23, Aqwerty1, Aitias, Versus22, Burner0718, Apparition11, Lickdeeznuts11, Glacier Wolf, ACIDNATION, DumZiBoT, Finalnight, Crazy Boris with a red beard, The dumpster, XLinkBot, Fastily, Floridagator818, Gnowor, Rror, Badinfinity, Fishers Lackey, Hoops22, Pratryan, Wobclub, NellieBly, Firebat08, 1h4xor31337, Noctibus, HarlandQPitt, MystBot, Mrjphillip, Dnvrfantj, CPT Destroyer, Good Olfactory, Airplaneman, Qwertyuiop0978, RyanCross, Largetesticles, Thatguyflint, Mkaplan13, HexaChord, MasterTate2011, Addbot, Sexyskooter, Proofreader77, Goon111113, Willking1979, Iamawierdo9, Jojhutton, Tcncv, Otisjimmy1, Shibbydik, Lasalle-nee-72, Mthorstad, Fieldday-sunday, Adrian 1001, Coolross, Zaheer12a, CanadianLinuxUser, Hiolhi, Kenokeno13, NjardarBot, MIAUGMIAUG, LaaknorBot, Ccacsmss, PranksterTurtle, DFS454, Glane23, AndersBot, Debresser, FCSundae, Tim diperi, Wootness24, Jthrush, Djpismyhero, Nickstar514, Stimpysven, Numbo3-bot, Im.dead.95, Issyl0, Amazingrape, Tide rolls, Zerfro123, Hawelka, Blackbeltpussy, CHESSNUT1995CHESSNUT, Jan eissfeldt, Ecrone, Let me go z2, Jarble, Reedzupancic, Quantumobserver, Axlindgren, Azdel, Matt.T, Aaroncrick, Epic Bread, Legobot, आशीष भटनागर, Drpickem, Luckas-bot, Vedran12, Yobot, 2D, Tohd8BohaithuGh1, Jonas1234, Senator Palpatine, Newportm, Kline.brian, Salvador Barley, The Earwig, Mmxx, THEN WHO WAS PHONE?, Beeswaxcandle, Whtrbtobj, KamikazeBot, Mrtummytums, Erty1234, Sbsggshshjjjsnnsiicnncus, Magog the Ogre, Synchronism, Ashcrofter, N1RK4UDSK714, Backslash Forwardslash, AnomieBOT, KDS4444, Bolognacheese, Fantasticbob, Poo.bot.deluxe, The Parting Glass, ThaddeusB, Shaman57, Boobs66, Killiondude, IRP, Dougdoug2000, Sharpe966, Qdinar, AdjustShift, Dmercado15, Kingpin13, Discoveralaska, Ulric1313, Flewis, Garcha, Almosteverywhere, Giants27, Driv3r89, ImperatorExercitus, Coolrjwtf, OllieFury, Arctic Fox, Vito1219, TIMMAY2013, Atom AVA, Tahu9050, Gordoman000, Fluval, Xqbot, Echohanter, Joekelly101, Macphysto, Sionus, Capricorn42, Xxkiwixx5623, TechBot, Jeffrey Mall, Fauxphantom1, Hikula, Cronaldo21234567, Honeycombs22, MorganFreman, The Evil IP address, Johnnyp77, Almabot, Abce2, Jasonww, Wiki Ruler135, Losesome2winsome, Dabigking13, Jezhotwells, RibotBOT, Indexedyarn, Wikieditor1988, Buttchin1658, In the sack, Xzeronight, Basharh, MasterHam, Doulos Christos, Dmzo21, IShadowed, Lamperougue, YOVivo, Born Gay, Wiikkiiwriter, BrawlMasterROB, IamHHH, Emptybone, Logijenn, Shadowjams, Tabledhote, SchnitzelMannGreek, Heatragrampibb, Ruffruff24801, Andykeller51, Ryryrules100, Cyrus3195, Classicd123, StaticVision, Skaterj, RoyGoldsmith, Hb948, Biecnal, VI, Fortskin, Stuffhappens1112, Flanny11, Ptrickster, Twodollarbill, Online9, Exitiums, Miguelnone, AsA2345671, Silverbackk, Treeoutside, 1989moto, Intelligentsium, Nirmos, Jiljojasaurus, CoolnessX29, Worcester university1334, ASETC, Stan56, A3501000, Calmer Waters, Esmith3636, John Elson, Ak92394, Nagharim, Fui in terra aliena, Wespeakthetruth, Lolidcare, Roflmao3434, Steve2011, Gods left nippel, Jauhienij, Bball 7778678, Jackperrte, Jlcarter2, A Hostile Clown, FlameHorse, Neonleon123456789, Random3212, Qwertymam1234, Whitenleaf, Flanman223, Boxoflunch93, Acdcmetallica, Billops, Diannaa, Littleam, Jhenderson777, Magiczlol, Adi4094, Suffusion of Yellow, Ilovecatsanddogs, Reach Out to the Truth, Angelito7, DARTH SIDIOUS 2, Wiwr, Mrsmosher, MisterJayEm, Martinh0107, Meridith K, RjwilmsiBot, Mrapoza, Dlarge1125, Brikwall96, NerdyScienceDude, Pam0111, DASHBot, EmausBot, GiraffeOfPlains, Alexfrusher, Gfoley4, Furblesnuzz, Kovachz, Mufasashomeforabandonedchildren, Wehrmachtsniper, NotAnonymous0, Somebody500, HiW-Bot, Kinsu08, ZéroBot, Ganesh Paudel, Access Denied, SporkBot, Someone65, Inswoon, Samxdeshields, Ngarcia57, Peter Karlsen, Senator2029, DASHBotAV, Whoop whoop pull up, ManlyMcDude, Teaktl17, Kevouille, Faizanalivarya, KDS444, Pengortm, North Atlanticist Usonian, Helpful Pixie Bot, Mark Marathon, PhnomPencil, Mark Arsten, Whistler101, NotWith, Anatomist90, Tangled nest spider, Trefeuil, Acadēmica Orientālis, Tropic of Capricorn, EuroCarGT, Dexbot, Everything Is Numbers, RomanGrandpa, LT910001, Medmyco, Tn9005, Fafnir1, Monkbot, Sgaqua323, Filedelinkerbot, 400 Lux and Anonymous: 1229 • Vas deferens Source: http://en.wikipedia.org/wiki/Vas%20deferens?oldid=649502486 Contributors: AxelBoldt, The Anome, Michael
60.13. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
213
Hardy, Mac, Timwi, Dysprosia, Furrykef, Omegatron, Raul654, Robbot, Romanm, Diberri, Matt Gies, Obli, Sublium, Guanaco, Xwu, Sonjaaa, Arcadian, Larry V, Minghong, Sam Korn, Ekem, Hovea, Graham87, Pmj, Zcrayfish, FlaBot, RexNL, Chobot, Korg, Albrozdude, YurikBot, Tadanisakari, Chanlyn, RussBot, Hydrargyrum, Snek01, Dddstone, Nlu, Wknight94, Richardcavell, Closedmouth, Unschool, Eveningmist, AlexNordeen, Keegan, John Reaves, Daniel.o.jenkins, Jpogi, Credmond, דניאל צבי, Missionary, Saperea, CapitalR, Thijs!bot, NotALizard, RFerreira, Calaka, AntiVandalBot, Kauczuk, TuvicBot, JAnDbot, Txomin, .anacondabot, Magioladitis, Bongwarrior, Homework8589, Robotman1974, Anaxial, Mikael Häggström, Ahuskay, Hschiong, Natl1, Squids and Chips, VolkovBot, Tameeria, SieBot, Revent, Radonir, Indiemike79, Meenat, Solaman12, Timstheory, DragonBot, Negative Two Seventy Three, Doksum, Addbot, Quercus solaris, Akyoyo94, Jarble, Vedran12, Yobot, Beeswaxcandle, Tucoxn, Kingpin13, Materialscientist, Jmarchn, Prunesqualer, Tabledhote, GT5162, A trolls view, MastiBot, Thinking of England, MondalorBot, RjwilmsiBot, EmausBot, Nuujinn, Klbrain, EWikist, Caspertheghost, RaptureBot, DASHBotAV, Petrb, ClueBot NG, Wimpus, Byron Golding, Anatomist90, Dr Bilal Alshareef, JakobSteenberg, Dr MaOh, LT910001, DR C SHARATH KUMAR, Filedelinkerbot, WanderingLost, HoneyBadger4, Velikij19, Bobby ze giber and Anonymous: 100 • Male accessory gland Source: http://en.wikipedia.org/wiki/Male%20accessory%20gland?oldid=616032681 Contributors: Bearcat, RHaworth, Wavelength, SmackBot, Magioladitis, Wilhelmina Will, McLondon, Dthomsen8, Jarble, Yobot, AnomieBOT, Fingerz, Jesse V., Dawgkulap, ClueBot NG, BG19bot, Dough34 and Anonymous: 5 • Seminal vesicle Source: http://en.wikipedia.org/wiki/Seminal%20vesicle?oldid=638740793 Contributors: Bryan Derksen, Tristanb, Raul654, Diberri, Robodoc.at, Everyking, Guanaco, D3, Knutux, Iwilcox, Arcadian, Danski14, Abstraktn, Alansohn, Jeffrey O. Gustafson, Oliphaunt, Bluemoose, Flamingspinach, Palica, Hovea, Rjwilmsi, OneWeirdDude, FlaBot, Chanlyn, RussBot, Hede2000, Hydrargyrum, DragonHawk, Raven4x4x, Caroline Sanford, Richardcavell, SmackBot, Andreas Erick, MalafayaBot, Dlohcierekim’s sock, Can't sleep, clown will eat me, Ratel, AngelSL, Kurrupt3d, Oenus, Jpogi, Serephine, FSHero, Beve, Beno1000, AdriaDracis, PaddyM, Mcstrother, Basawala, Gogo Dodo, Clovis Sangrail, Thijs!bot, Nick Number, Kauczuk, TuvicBot, Kaobear, Magioladitis, Appraiser, Anaxial, Jeepday, TXiKiBoT, Vanished user ikijeirw34iuaeolaseriffic, Cmcnicoll, Nagy, Tsaitgaist, SieBot, Flyer22, Permacultura, Wmpearl, AaaghItsMrHell, Ken123BOT, Dlrohrer2003, Deviator13, DragonBot, Miley1006, McLondon, Addbot, Martindo, Udo.schroeter, Tide rolls, Jarble, Luckas-bot, Androlog, AnomieBOT, .غامدي.أحمد24, Xqbot, AV3000, Nuviapalomar, Locobot, Seminalvesicles, Per Flaatten, PigFlu Oink, Pinethicket, Naturehead, RedBot, Jhenderson777, John of Reading, WikitanvirBot, SporkBot, Lexusuns, Darwinoclv, Msfishi, ClueBot NG, North Atlanticist Usonian, Helpful Pixie Bot, Vagobot, NotWith, Anatomist90, Cglion, ChrisGualtieri, JYBot, Johnsmithwhatatool, JakobSteenberg, Theo’s Little Bot, LT910001, Tn9005, Monkbot, Lmodric, HoneyBadger4 and Anonymous: 78 • Epididymis Source: http://en.wikipedia.org/wiki/Epididymis?oldid=638742254 Contributors: The Anome, Whkoh, Raul654, Robbot, Romanm, Hadal, Diberri, Matt Gies, Robodoc.at, Guanaco, Jason Quinn, Mike Rosoft, Mani1, Bender235, Szquirrel, Kwamikagami, BarkingFish, Dungodung, Arcadian, Jag123, Nsaa, Abstraktn, Guaca, Ekem, Dysepsion, Porcher, Stevenfruitsmaak, LeCire, YurikBot, Chanlyn, RussBot, Chris Capoccia, SpuriousQ, Hydrargyrum, Nephron, Osnimf, Snalwibma, RupertMillard, Arc Orion, Chris the speller, Nbarth, Pwjb, Drphilharmonic, Jpogi, Fredwerner, Paul venter, JoeBot, Courcelles, PaddyM, Mcstrother, AdaronKentano, Luna Santin, Kauczuk, JAnDbot, Deflective, Magioladitis, Ramurf, Freedomlinux, VoABot II, WLU, Arjun01, Anaxial, Keith D, Biglovinb, STBotD, Remember the dot, Squids and Chips, VolkovBot, TXiKiBoT, Tameeria, Red Act, AlleborgoBot, EmxBot, SieBot, BotMultichill, Jauerback, Gerakibot, Flyer22, Georgette2, Hkarim19, DumZiBoT, Cmungall, HexaChord, Addbot, DOI bot, Luckas-bot, Vedran12, Yobot, Timeroot, AnomieBOT, KDS4444, Jim1138, Materialscientist, Citation bot, Jmarchn, LilHelpa, Yefi, Chinux, 78.26, Shadowjams, Rushbugled13, Naturehead, MondalorBot, Fui in terra aliena, Minimac, RjwilmsiBot, EmausBot, Perfect Introvert, Stemoc, Lexusuns, Giancoli, Donner60, LibertyOrDeath, Jabaway, DASHBotAV, ClueBot NG, Helpful Pixie Bot, AvocatoBot, Hyperborea13, Anatomist90, Zedshort, JakobSteenberg, Frosty, Tentinator, LT910001, Tn9005, Monkbot, Filedelinkerbot, Bibo2020, Matho120, Aidanbh and Anonymous: 91 • Prostate Source: http://en.wikipedia.org/wiki/Prostate?oldid=649921776 Contributors: AxelBoldt, Mav, Bryan Derksen, The Anome, Alex.tan, Montrealais, Xoder, Frecklefoot, AlexR, Mkweise, Mac, Darkwind, Julesd, Emperorbma, Janko, Bemoeial, Fuzheado, Tpbradbury, Raul654, Keldan, Chuunen Baka, Nufy8, Robbot, Romanm, Diberri, Centrx, Timpo, Zigger, Michael Devore, Jfdwolff, Guanaco, Daveb, Gugilymugily, Wmahan, OldakQuill, Mariushendrik, SarekOfVulcan, Lesouris, Drzaphod, Kevin Rector, Iwilcox, Revision17, DanielCD, Discospinster, Rich Farmbrough, FT2, Vsmith, Livajo, Szquirrel, Bobo192, Circeus, Davidruben, Arcadian, Giraffedata, Helix84, Googie man, Jumbuck, Abstraktn, Anthony Appleyard, Atlant, Keenan Pepper, Kocio, Tainter, Jun-Dai, Markaci, Roland2, Bushytails, BillC, Before My Ken, Eleassar777, KaurJmeb, KarlFarrell, SCEhardt, LanguageMan, Rjwilmsi, Nightscream, Vegaswikian, GregAsche, Yamamoto Ichiro, FlaBot, Crazycomputers, Gurch, DevastatorIIC, Stevenfruitsmaak, BMF81, King of Hearts, Chobot, Gwernol, Cuahl, YurikBot, Chanlyn, Todd Vierling, RussBot, Bleakcomb, RadioFan, Hydrargyrum, Ajp, Gaius Cornelius, Eleassar, Wimt, Anomalocaris, Grafen, Exir Kamalabadi, Wynler, Nick, Nephron, Diotti, Epipelagic, Dbfirs, DeadEyeArrow, Moreau36, Asarelah, Richardcavell, Abune, Livitup, Wsiegmund, Alasdair, Chriswaterguy, NeilN, RichF, Eog1916, AndrewWTaylor, SmackBot, Tomyumgoong, Slashme, C.Fred, InvictaHOG, CMD Beaker, Delldot, Gilliam, Ohnoitsjamie, Ctrlfreak13, MalafayaBot, Deli nk, Jerome Charles Potts, Paulfp, Jammie, Mike hayes, Can't sleep, clown will eat me, Frap, Ww2censor, Ratel, TheLimbicOne, Kntrabssi, Jklin, FallenAngelII, SashatoBot, Dono, Boradis, Kieron a m, JHunterJ, Beetstra, Serephine, Waggers, TastyPoutine, Odedee, MTSbot, Xionbox, Hu12, Iridescent, JumpingInSlowMotion, Tawkerbot2, BBuchbinder, Patho, CmdrObot, Patrick Berry, Mcstrother, Imnotoneofyou, Disposableman, Maxxicum, HalJor, Cydebot, Reywas92, Johnbtv, Ibanix, Roberta F., Mathew5000, Kozuch, Kw0, Thijs!bot, Enviromaxinfo, Spudst3r, Headbomb, John robinson, Scottandrewhutchins, Seaphoto, HJames, Academia salad, Spencer, Glennwells, Qwerty Binary, Kaobear, NapoliRoma, MER-C, Patxi lurra, Larryclapp, Openhands, Andonic, Alt f in, Rothorpe, .anacondabot, Acroterion, Pedro, Bongwarrior, VoABot II, CattleGirl, AMK1211, LafinJack, Michael Goodyear, CTF83!, ThoHug, Indon, REscano, Chris G, DGG, Gildindaimoth, Gwern, MartinBot, Dennisthe2, Kronnang Dunn, Reggy73, Anaxial, J.delanoy, Pharaoh of the Wizards, CFCF, Zorakoid, Bizflyer, Thedeadlypython, NightFlyer, Mikael Häggström, 97198, Velps, SJP, Hanacy, Mghabmw, KylieTastic, Juliancolton, Myrealana, MishaPan, Janice Vian, Unit 5, Nitroshockwave, VolkovBot, Johan1298, Macedonian, Philip Trueman, TXiKiBoT, WJSProwler1, Tameeria, Leafyplant, Jackfork, Joshuas88, Ilyushka88, Doug, Stepheng4, Fleela, Judgeking, Monty845, JJHeart, EmxBot, Munblog, CMBJ, Misslloid, SieBot, Mycoderma, Orange roughie, The very model of a minor general, Flyer22, Cairo123, Man It’s So Loud In Here, Whizistic, Oxymoron83, Prince Harry of England, Bgordski, Andrij Kursetsky, Fajar78, Biolog2, Sitush, Laburke, Ssetd, ClueBot, Jayelani, The Thing That Should Not Be, Psytrist, Daleee, Sarbruis, Michael.Urban, Westogent, Bopizzle, Miss Tanit, Blanchardb, Evo584, DragonBot, Excirial, LonghornDIT, ToNToNi, PixelBot, Zomno, Bald Zebra, Project icecap, Mczack26, Pcp111, Baazandar, Miami33139, XLinkBot, Doru001, Ihealthbuzz, Tbsdy lives, Vianello, Digitalh2o, Websi7, Thebestofall007, Addbot, ERK, DOI bot, Radinruslan, OttRider, Jmunroo, TutterMouse, Djb217, Isfppoet, Azmcs, Orlandoturner, Norman21, Cnjanis, Tide rolls, XfreddytanX, Hybernizer, Jarble, Legobot, Luckas-bot, Yobot, Navy10760, Hardcorelife, Jrsvc, Androlog, AnomieBOT, Fokklife, Etan J. Tal, Materialscientist, Citation bot, Johanname, Myseda, Jmarchn, Alanhay, Xqbot, Conductcode, Ruy Pugliesi, Omnipaedista, Nuviapalomar, CompliantDrone, Trafford09, Vanished user giiw8u4ikmfw823foinc2, Ole E. Sorensen, Paine Ellsworth, Hirpex, Contentmaven, Weetoddid, A little insignificant, Gareth.ellisthomas, Citation bot 1, Citation bot 4, Pinethicket, Lineslarge, Sultan11, FoxBot, Trappist the monk, Fama Clamosa, Vrenator,
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علی ویکی, David Hedlund, Reaper Eternal, Jhenderson777, RjwilmsiBot, Beyond My Ken, NerdyScienceDude, EmausBot, Gfoley4, Cmmuell, Djsignal, Luckygohappy115, ZéroBot, Traxs7, Dffgd, H3llBot, SporkBot, Gsarwa, Msfishi, Raxicoricofallapatorius, Ebehn, ClueBot NG, Ishfaq Khan8, Prostatainforma, Nongendered, ZainAliNawazish, Bigjhoninelcasa28, Pbmaise, Novusuna, Dragon12597, Roerbakmix, WoodsGnome, Floppy Tits, NotWith, BattyBot, GoShow, Codeh, John from Idegon, JYBot, Shellinbox, MLPainless, Melonkelon, Iztwoz, LT910001, Dontalibin, Itsalleasy, Tn9005, Corax rarus, Omideazadi, Tilifa Ocaufa, Mnzuhair and Anonymous: 431 • Bulbourethral gland Source: http://en.wikipedia.org/wiki/Bulbourethral%20gland?oldid=646887611 Contributors: Bryan Derksen, Montrealais, Ellywa, Den fjättrade ankan, Dpol, Fibonacci, Raul654, Romanm, KellyCoinGuy, Diberri, DocWatson42, Guanaco, KarlHenner, Bender235, Sfahey, Szquirrel, Arcadian, Giraffedata, Kjkolb, Obradovic Goran, Alansohn, Keenan Pepper, Tchaika, Japanese Searobin, Arent, Jugger90, Eras-mus, Hovea, Rjwilmsi, YurikBot, Chanlyn, RussBot, Hede2000, Caiyu, Nephron, Wknight94, SmackBot, Durova, Jeffro77, Ratel, Drphilharmonic, Serephine, Meco, Novangelis, Mcstrother, Kylu, TheJC, Omicronpersei8, Thijs!bot, James086, Macaddict10, Nick Number, AnemoneProjectors, Kauczuk, Qwerty Binary, Anonymousphrase, MartinBot, Jerry, Ahuskay, DorganBot, TXiKiBoT, Rei-bot, BotMultichill, Stupid6, Animeronin, Alexbot, Versus22, XLinkBot, Addbot, Brushdrawn, Orlandoturner, Ahmad.ghamdi.24, Jarble, Luckas-bot, Yobot, AnomieBOT, KDS4444, Myseda, GrouchoBot, Omnipaedista, Nuviapalomar, Citation bot 1, Dinamik-bot, EmausBot, Lexusuns, Wimpus, Frietjes, Monkbot, Zachfield and Anonymous: 73 • Human penis Source: http://en.wikipedia.org/wiki/Human%20penis?oldid=649459718 Contributors: Infrogmation, WhisperToMe, Bearcat, Timpo, Macrakis, Gadfium, Antandrus, Nigelj, Enric Naval, Arcadian, Trevj, Jakew, Mister Handy, Graham87, BD2412, Rjwilmsi, Banaticus, Hydrargyrum, CambridgeBayWeather, MosheA, CecilWard, NeilN, Master Deusoma, BirdValiant, Rmosler2100, HartzR, OSborn, Ianmacm, OnBeyondZebrax, Gogo Dodo, Anthonyhcole, Difluoroethene, Qwyrxian, Dr. Blofeld, JAnDbot, Deflective, Ocram, Burhan Ahmed, SHCarter, Mrmagoo2006, Petter Bøckman, CFCF, Peter Chastain, Abidagus, VolkovBot, BlazeTheMovieFan, Guillaume2303, Michaelsbll, Bfpage, Keilana, Flyer22, Yerpo, Csloomis, Sempre30, RobinHood70, Rodhullandemu, GR Scriptor, SoxBot, Wnt, 3193th, Nathan Johnson, Dthomsen8, Ost316, Addbot, Grayfell, Cst17, 5 albert square, Jarble, Hartz, Luckas-bot, Jim1138, Zad68, Dan6hell66, Sheffno1gunner, FrescoBot, Surv1v4l1st, Kweiss93, Der Elbenkoenig, David Hedlund, Jhenderson777, DARTH SIDIOUS 2, RjwilmsiBot, TjBot, Fitoschido, EmausBot, Britannic124, YEloi, SecretName101, Amkutzko, ZéroBot, Stemoc, Zloyvolsheb, Wikitürkçe, Anglais1, CHUCAO, Dr eng x, Nayyurc, TBM10, ClueBot NG, Wpici, Sugarcube73, Hon-3s-T, Ulasts, Manandwolf, Ninjasquirrel52, Wpgne, North Atlanticist Usonian, Helpful Pixie Bot, Barrodrajesh, Kevvy9, Roerbakmix, BG19bot, Wiriuss, PokemonGuy2, NotWith, Bunser, Metsfreak2121, Smileguy91, LlamaAl, Y26Z3, GoShow, SD5bot, JYBot, Hq-anatomy-photos, Pontmarcheur, Moscowsky, Lakeside75, Mogism, Makecat-bot, VampireProject23, Lugia2453, OBCPO1, StanEminemFan, Camyoung54, Melonkelon, Eyesnore, Surfer43, Count Awesome, Rybec, DesignDeath, Christianblueeyes, Trtehp35, FrozenIcicle96, Memegui, Tn9005, Japanese Rail Fan, Monkbot, Filedelinkerbot, BethNaught, ADHZ07111989, GoAnimaterules12333 and Anonymous: 14 • Female reproductive system Source: http://en.wikipedia.org/wiki/Female%20reproductive%20system?oldid=649684843 Contributors: Zanimum, Theresa knott, Pakaran, David Gerard, Jackol, Golbez, Utcursch, Alexf, CALR, Discospinster, Bobo192, Maurreen, Arcadian, Deryck Chan, Minghong, Pearle, Storm Rider, Alansohn, Anthony Appleyard, Free Bear, Wouterstomp, Snowolf, Mikeo, Bsadowski1, Tobyc75, TheCoffee, Brookie, Roboshed, Woohookitty, Camw, Meeso, Kmg90, Gimboid13, Graham87, BD2412, Mendaliv, Canderson7, Tabercil, Koavf, Jake Wartenberg, Jamesmusik, Musical Linguist, RobyWayne, King of Hearts, Chobot, Sharkface217, DVdm, YurikBot, Wavelength, Chanlyn, RussBot, Lexi Marie, Pigman, Zelmerszoetrop, Hydrargyrum, Vincej, Wimt, NawlinWiki, Bachrach44, Irishguy, Brandon, Dbfirs, BOT-Superzerocool, Mysid, Theda, Closedmouth, Josh3580, Katieh5584, NeilN, KNHaw, TravisTX, SmackBot, Unschool, Delldot, Buck O'Nollege, Commander Keane bot, Cool3, Ohnoitsjamie, Chris the speller, Bluebot, TimBentley, Persian Poet Gal, I7s, Bazonka, WeniWidiWiki, DHN-bot, Nmacpherson, Darth Panda, Gracenotes, Can't sleep, clown will eat me, DéRahier, Snowmanradio, Celarnor, Kalathalan, Kukini, Lambiam, Swatjester, ABurness, John, Heimstern, Mgiganteus1, Doobuzz, Stupid Corn, Avant Guard, KJS77, Iridescent, CzarB, Shoeofdeath, NativeForeigner, Mamaremere, Courcelles, Emote, Ale jrb, KnightLago, Dgw, WeggeBot, Clappingsimon, Clayoquot, Chasingsol, Alaibot, FastLizard4, Biblbroks, Didohotep, Zalgo, Richhoncho, Epbr123, Dasani, Ucanlookitup, Luigifan, Marek69, John254, Seaphoto, Dustin Kaiser M. Bompat, LibLord, Danger, Kauczuk, Wiki0709, Kaobear, MERC, Kerotan, SiobhanHansa, Acroterion, Magioladitis, Connormah, Bongwarrior, VoABot II, Fusionmix, JNW, SwiftBot, WhatamIdoing, Indon, Thernlund, Allstarecho, DerHexer, Edward321, Esanchez7587, Roswell Crash Survivor, MartinBot, STBot, Poeloq, CommonsDelinker, 3dscience, Erkan Yilmaz, Paranomia, J.delanoy, CFCF, EscapingLife, 2012Olympian, Uncle Dick, Vengeful juggalo, Shawn in Montreal, LEHarth, McSly, Mikael Häggström, Jamesofur, RJASE1, VolkovBot, Jeff G., Philip Trueman, TXiKiBoT, Oshwah, Willymakeit, Sean D Martin, Qxz, Imasleepviking, Leafyplant, Norq05, Jackfork, Optigan13, Andyo2000, Earthdirt, Dansypen, Nocturnal Wanderer, Hunnie69, Doc James, Sfmammamia, NHRHS2010, Jthomp7905, 4wajzkd02, Tiddly Tom, Matthew Brandon Yeager, Android Mouse, Flyer22, Radon210, Wilson44691, Doctorfluffy, Wsteven, Harry, Kaitaray, Ascidian, Pramod2007, Thiswontbethend123, Struway2, ImageRemovalBot, Atif.t2, Elassint, Animeronin, ClueBot, Marth33, The Thing That Should Not Be, Quinxorin, Drmies, Blanchardb, Puchiko, Rockfang, Manishearth, Squirrelsear, Luke4545, DragonBot, Excirial, Erebus Morgaine, Akane700, M0M3NTUM, SpikeToronto, Lartoven, Streetkil1, Zuzzerack, Thingg, Meatloaf04021105, Ih8freeencylopedias, Aitias, CKCortez, Subash.chandran007, Pzoxicuvybtnrm, Hockybumm, XLinkBot, Gwandoya, BodhisattvaBot, Little Mountain 5, Iranway, Addbot, Grayfell, Willking1979, Seattlefan12, Hda3ku, D757ec, CanadianLinuxUser, Coraily, Download, Ccacsmss, Whistling42, Bernstein0275, Ovaryslam, Roux, FCSundae, Lilmizer29, Favonian, SpBot, West.andrew.g, Jollymonsing, Tide rolls, SekciiLeanne x, David0811, Jarble, Runemaster 1 1, Noitaloiv, Bigfatphony, Qwerty61, ThinkingTwice, THEN WHO WAS PHONE?, Bob chang, Ayrton Prost, AnakngAraw, VinuVarughese, Tonyrex, AnomieBOT, Rubinbot, Jim1138, IRP, Ularevalo98, Zimbo15, Kingpin13, Ulric1313, Isablidine, Materialscientist, Grantbennett123, Usuck93, E2eamon, Jmarchn, Waagfour, Clark89, Pcdxox, Capricorn42, Termininja, Jmundo, Jeffydere, Dsm1998, Erik9bot, Dougofborg, Thehelpfulbot, BoomerAB, FrescoBot, Luther a. pringle, Lolgrl, KuroiShiroi, Yumcookies987, Tetraedycal, Adhere to the truth, Pnak444, Pinethicket, I dream of horses, CHUCKIE123454321, Lyndaek, Hiphophippie420, Wikitanvir, Lostlazy, Buuuuuh, Smilly77, Vrenator, Defender of torch, Diannaa, Joshi1067, Reach Out to the Truth, Hmmwhatsthisdo, DARTH SIDIOUS 2, J238417, Onel5969, Qwety0987654321, Sincere22k, The big guy666, Slon02, EmausBot, John of Reading, Murrrder5150, RA0808, YEloi, Spongy3733, Arcanepwner5, Slightsmile, K6ka, AsceticRose, Justincheng12345, Josve05a, Malfieris, Holoo, Redrams, Discoscabs, Clarkc200, Mr little irish, Wayne Slam, Augurar, L Kensington, Donner60, Adam4nt42z, Orange Suede Sofa, VictorianMutant, Justmarc, Whoop whoop pull up, ClueBot NG, This lousy T-shirt, General Hindsight, Jimmybobjoe12345678987654321, Mao.26, FiachraByrne, Vibhijain, Da bin ich wieder, DBigXray, Northamerica1000, Dzlinker, Rher525, NotWith, Anatomist90, Djgiorhjur, BattyBot, Tutelary, Cimorcus, Pratyya Ghosh, Mdann52, I Am Lying to You, Kanke8, YFdyh-bot, Zachariffic, Webclient101, Lorem Ipsum Generator, JakobSteenberg, Hair, Hwangrox99, Robinlemon, Cmonica4, LT910001, BruceBlaus, Whatamidoing (WMF), Formula1stunter, Vbrb2013, Hasith lakshan muthukumara, Falconswagyolo69, Snabbkaffe, Selenaaz, Tilifa Ocaufa, Mr.super17 and Anonymous: 508 • Ovary Source: http://en.wikipedia.org/wiki/Ovary?oldid=648165298 Contributors: AxelBoldt, Taw, Alex.tan, Andre Engels, Youssefsan, Vanderesch, PierreAbbat, Karen Johnson, Robert Foley, Someone else, Ixfd64, Karada, NuclearWinner, Ellywa, Habj, Emperorbma, Marshman, Saltine, Raul654, Pollinator, Robbot, RedWolf, Romanm, Nilmerg, Huckfinne, Isopropyl, Diberri, Marnanel, Barbara Shack,
60.13. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
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Mintleaf, Leflyman, Jrquinlisk, Michael Devore, Slowking Man, Antandrus, Alteripse, Jossi, Tsemii, Szquirrel, Shanes, Bobo192, Arcadian, Kjkolb, Tritium6, Minghong, Ranveig, Alansohn, Anthony Appleyard, Keenan Pepper, Mysdaao, Osmodiar, Mauvila, Adrian.benko, Nuno Tavares, Macronyx, MONGO, Isnow, Eras-mus, Wisq, Graham87, Paiste, FreplySpang, BorgHunter, Rjwilmsi, RiseAbove, Tangotango, Uwe Gille, FlaBot, Naraht, CiaPan, Chobot, YurikBot, Chanlyn, Huw Powell, RussBot, Pigman, Hydrargyrum, Ajp, Rsrikanth05, Wimt, Bug42, Dysmorodrepanis, Syrthiss, EEMIV, Mholland, Open2universe, Lt-wiki-bot, Kungfuadam, Lyrl, NeilN, Paul Erik, DVD R W, robot, SmackBot, Andreas Erick, Brya, Unyoyega, Rrius, KocjoBot, Delldot, Eskimbot, Canthusus, Ohnoitsjamie, Agateller, Berton, Akanemoto, Colonies Chris, SundarBot, Ratel, Jóna Þórunn, Clicketyclack, Cyberevil, Rory096, CenozoicEra, Soumyasch, 041744, Waggers, Novangelis, Igoldste, Tawkerbot2, Filelakeshoe, The Letter J, Patho, Di4gram, Dycedarg, Woudloper, Mcstrother, JohnCD, CWY2190, MarsRover, Treybien, Travelbird, Anthonyhcole, A Softer Answer, DumbBOT, Kozuch, Kobe91288, Didohotep, Thijs!bot, Epbr123, Massimo Macconi, Escarbot, Mentifisto, AntiVandalBot, Ozgod, Joehall45, JAnDbot, Carolyns, Bongwarrior, VoABot II, QuizzicalBee, Jon f, Rivertorch, Gr1st, Janette.quennell, Edward321, Mmustafa, Anaxial, Gidip, Keith D, R'n'B, CommonsDelinker, AlexiusHoratius, Erkan Yilmaz, Watch37264, J.delanoy, Pharaoh of the Wizards, Trusilver, EscapingLife, Wilsbadkarma, Ginsengbomb, Mrob27, LEHarth, Mikael Häggström, Jasonasosa, Glacious, Vanished user 39948282, RJASE1, Idioma-bot, Spellcast, Petergreen12, PissonDemand, Jeff G., AlnoktaBOT, Philip Trueman, TXiKiBoT, GDonato, Loserbackpacker, Guldenat, Monkeynoze, Grafic, Gillyweed, Arm86, Neothe, Why Not A Duck, Alcmaeonid, AlleborgoBot, Sleep is good, SieBot, Flyer22, Doctorfluffy, Oxymoron83, BenoniBot, Patilsaurabhr, Invertzoo, ClueBot, The Thing That Should Not Be, Jcpstud, DAStroh, Briankohl, Arunsingh16, Matticooper, Chrisbarnes20048, Walkingstick3, Thingg, Vanished User 1004, Rey101011, Avoided, WikHead, PL290, Addbot, Dryphi, DaughterofSun, Fieldday-sunday, Nilsonne, Download, CarsracBot, Bernstein0275, AndersBot, Christopher140691, 5 albert square, Numbo3-bot, Prim Ethics, Tide rolls, H3mcostlymilk, Maily812, David0811, Jarble, 2enable, Luckas-bot, Doctorruthshopeful, THEN WHO WAS PHONE?, IW.HG, XL2D, BLAKEWRAPP, Materialscientist, Driv3r89, Citation bot, Xqbot, Anders Torlind, Micemug, Datguydurr, Nuviapalomar, Pepemonbu, Amaury, Schekinov Alexey Victorovich, FrescoBot, VS6507, Recognizance, Pinethicket, I dream of horses, Adlerbot, BobJudy, Nicholascage69, Wikitanvir, SpaceFlight89, ScottMHoward, RandomStringOfCharacters, Ambenoxan, TobeBot, Fama Clamosa, MrX, Igotnolife, Rmcusc, A p3rson, Diannaa, Jhenderson777, DrBuzz2, Tbhotch, Fruitboot2009, DARTH SIDIOUS 2, RjwilmsiBot, Cornellalum, Agent Smith (The Matrix), Ibbn, YEloi, Tommy2010, Gailabby, K6ka, Kmoksy, Werieth, Imperial Monarch, Katherine.munn1, Zaher kadour, SporkBot, ChuispastonBot, ClueBot NG, Intoronto1125, Arne Saknussem, Skrawk, Brickmack, Jk2q3jrklse, Jorgenev, HMSSolent, BG19bot, JarritoFJ, John tickle, MusikAnimal, Goldster5, NotWith, Anatomist90, SaminTietokirja, Poongus, Jeanloujustine, Schafhirt, Turbo teabagger, MisterJS, Orangeflavoured99, Yogwi21, JakobSteenberg, Fox2k11, MyNipsGivMeTips, SANDQICH, Meena10, Zippedleader070, Ugog Nizdast, LT910001, Ginsuloft, Drstephen.kennedy, Tn9005, Quinnhelmig, Monkbot, TrollZayn, Karinpower, Royerlraph79, Tilifa Ocaufa, Mebutler443 and Anonymous: 276 • Uterus Source: http://en.wikipedia.org/wiki/Uterus?oldid=649247233 Contributors: The Anome, Taw, Malcolm Farmer, Alex.tan, Andre Engels, Camembert, Montrealais, Rickyrab, Ubiquity, Ellywa, William M. Connolley, Andres, Kaihsu, Rob Hooft, Timc, Raul654, Pollinator, JorgeGG, Robbot, Altenmann, Ppe42, Ojigiri, Diberri, Carnildo, Marnanel, Kandar, SarekOfVulcan, Knutux, Antandrus, Jossi, Maximaximax, Karl-Henner, Austin Hair, Rfl, Rich Farmbrough, Guanabot, Adambro, Causa sui, Circeus, Reinyday, Arcadian, Larry V, Haham hanuka, Red Winged Duck, Stephen G. Brown, Alansohn, Anthony Appleyard, Nik42, Free Bear, Atlant, Keenan Pepper, Osmodiar, Wtmitchell, Mauvila, Metju, Bsadowski1, Bookandcoffee, AirBa, Miaow Miaow, Uncle G, Ekem, Sengkang, Sweetfreek, Palica, Sin-man, Graham87, BD2412, Rjwilmsi, Jivecat, MZMcBride, Nneonneo, Fred Bradstadt, FlaBot, Brysonborg, Margosbot, Nivix, Travis.Thurston, King of Hearts, Sherool, YurikBot, Chanlyn, Quentin X, RobotE, RussBot, Icarus3, Pigman, SpuriousQ, Crism, Hydrargyrum, Ajp, Manop, Eleassar, Mysid, Newagelink, Theda, Modify, Sean Whitton, Barbatus, Jonathan.s.kt, Lyrl, Alextrevelian 006, A13ean, SmackBot, Unschool, Unyoyega, C.Fred, Bwilliams, Jfurr1981, Alex earlier account, Gilliam, Ohnoitsjamie, Choalbaton, Smeggysmeg, Chris the speller, Bluebot, Flagmantho, MalafayaBot, Akanemoto, Colonies Chris, Yanksox, John Reaves, MaxSem, Ian Burnet, Can't sleep, clown will eat me, Shalom Yechiel, Darthgriz98, Yidisheryid, Dreadstar, BullRangifer, Soap, Kuru, Joelmills, Goodnightmush, IronGargoyle, JHunterJ, Beetstra, Manifestation, Hu12, DDD DDD, Skapur, Tawkerbot2, JForget, Bizz42, Neelix, Flowerpotman, ST47, Kozuch, Didohotep, Nol888, Thijs!bot, Carpentc, JustAGal, RoboServien, CerealBabyMilk, AntiVandalBot, Nisselua, Seaphoto, JovianPerihelion, Johnian144, Sluzzelin, JAnDbot, Kaobear, Acroterion, Bongwarrior, VoABot II, Professor marginalia, Steven Walling, Catgut, Allstarecho, Donignacio, Just James, Glen, DerHexer, Patstuart, Gwern, MartinBot, Rettetast, Speck-Made, Anaxial, CommonsDelinker, Aimholtz12, Captain panda, CFCF, Trusilver, Alioud, Gzkn, LEHarth, Mikael Häggström, Jasonasosa, Olegwiki, TRL True, Remember the dot, DorganBot, Nsd12, JustAnMD, Rehmatullahbhatti, Berestede, Vinsfan368, Squids and Chips, Idioma-bot, ACSE, AlnoktaBOT, Bovineboy2008, Xenophrenic, Asarlaí, Goldfritter, Justinclarkdawg, Madhero88, BigDunc, Gillyweed, Falcon8765, !dea4u, Logan, EmxBot, EJF, SieBot, Tiddly Tom, BotMultichill, Lautensd, Caltas, Sims1256, Andrewjlockley, Flyer22, Mike2vil, Maralia, Mr. Stradivarius, Patilsaurabhr, Thanisha, Pinkadelica, Dlrohrer2003, ClueBot, Jriessman, The Thing That Should Not Be, DragonBot, Excirial, Alexbot, Estirabot, Jotterbot, Tnxman307, Kaiba, Razorflame, Walkingstick3, Versus22, Apparition11, Manmanda, XLinkBot, Maky, Floranerolia, Facts707, Marktgordon, CapnZapp, HarlandQPitt, Vianello, Sgpsaros, Fangusu, HexaChord, Addbot, Some jerk on the Internet, Crazysane, Disrhythm, CarsracBot, Nickylame3, Tassedethe, Tide rolls, Jarble, Zackvdh, Legobot, आशीष भटनागर, Luckasbot, Yobot, AnakngAraw, Magog the Ogre, AnomieBOT, Jim1138, Ipatrol, Iren2000, Giants27, Citation bot, Bernadette188, LovesMacs, Xqbot, , Lambent Ametrine, Capricorn42, Mar4ela, Jujment699, Jmundo, Almabot, Pmlineditor, GrouchoBot, Jasonww, Ireneabbasi, RibotBOT, Basharh, Bleekbeen, Philliesfan1992, SchnitzelMannGreek, Khmir2467, Captain-n00dle, Prari, FrescoBot, LucienBOT, Paine Ellsworth, Pepper, Ghost det, Americancheerleader27, Mihirdll, Pinethicket, I dream of horses, PrincessofLlyr, Rameshngbot, Naturehead, Ccocallas, Wikitanvir, Waldemahr, Adamsconnor1, Meaghan, Jauhienij, FoxBot, Fama Clamosa, Lb.at.wiki, Reaper Eternal, Jhenderson777, TjBot, NerdyScienceDude, EmausBot, WikitanvirBot, Sassafrass1111111111, The Mysterious El Willstro, Thecheesykid, Fæ, SporkBot, Cymru.lass, Gsarwa, Mentibot, ChuispastonBot, Fliuzzi, Ebehn, JonRichfield, H.K.Jermaine, ClueBot NG, Vacation9, Widr, North Atlanticist Usonian, Lindacoudray, Keyport6, Tucker.kunzel, Mirrorbones, BG19bot, Essayturk, NotWith, Anatomist90, Jaysn1, Lilwayne’sgames9, JYBot, Futurist110, JakobSteenberg, Epicgenius, Howicus, MiSky13, Anatha, LT910001, Tritario, Yesnoplease, Yesnoplease123, Frost7697, Monkbot, Conorpoundtown and Anonymous: 292 • Fallopian tube Source: http://en.wikipedia.org/wiki/Fallopian%20tube?oldid=638597208 Contributors: AxelBoldt, Mav, Alex.tan, Deb, Karen Johnson, Heron, Karada, Kosebamse, Ellywa, Julesd, Cratbro, Tpbradbury, Raul654, Rhys, Romanm, Diberri, Marnanel, Robodoc.at, Knutux, Eranb, Creidieki, Oknazevad, Rfl, Freakofnurture, ESkog, Kjoonlee, RoyBoy, Arcadian, Deryck Chan, Alansohn, Wouterstomp, Osmodiar, Ekem, Macronyx, Bbatsell, Pufferfish101, Scm83x, Macaddct1984, Graham87, Rjwilmsi, XLerate, Margosbot, DaGizza, YurikBot, Borgx, Chanlyn, NTBot, Chomo, Pigman, Hydrargyrum, Gaius Cornelius, Grafen, Nephron, Daniduc, Mysid, Jcvamp, Richardcavell, Zargulon, Zzuuzz, Lt-wiki-bot, Tvarnoe, Garion96, Jonathan.s.kt, Isangaft220, SmackBot, Bigbluefish, KocjoBot, Kurykh, Oli Filth, MaxSem, Billfranke, Can't sleep, clown will eat me, Chlewbot, Rrburke, Zrulli, SashatoBot, Kuru, Jpogi, Noah Salzman, Unclevinny, Daipenmon, WeggeBot, JVinocur, Cydebot, Treybien, Was a bee, Didohotep, The64, Thijs!bot, AntiVandalBot, JAnDbot, Badtuesday, LafinJack, STBot, Rettetast, Speck-Made, Anaxial, CommonsDelinker, J.delanoy, Thisischris, LEHarth, Mikael Häggström, Jasonasosa, Sedital, Glacious, Muchclag, RJASE1, VolkovBot, Itsfullofstars, Jeff G., TXiKiBoT, Mariah24o7, Gillyweed, FraekofNuture,
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CHAPTER 60. REPRODUCTIVE HEALTH
Cmcnicoll, Izzy259, SieBot, Stewardofgod, BotMultichill, Phe-bot, Gsberger, Andrewjlockley, Uboo99, Flyer22, Patilsaurabhr, ImageRemovalBot, The Thing That Should Not Be, Drmies, Mild Bill Hiccup, Karena 01, Alexbot, ToNToNi, BOTarate, DumZiBoT, Addbot, Moosehadley, NjardarBot, Download, Tide rolls, Lightbot, Maily812, Teles, Zorrobot, Jarble, आशीष भटनागर, Luckas-bot, Yobot, THEN WHO WAS PHONE?, AnakngAraw, Killiondude, Xqbot, Erud, RibotBOT, SassoBot, Chodid, CaboverPete, Atlantia, Wikitanvir, Paiamshadi, Reach Out to the Truth, DARTH SIDIOUS 2, MrArifnajafov, RjwilmsiBot, NerdyScienceDude, Androstachys, EmausBot, Slapshot579, Kmoksy, Anirudh Emani, Eponymous, ChuispastonBot, Uziel302, Petrb, ClueBot NG, Tone.itdown1901, Anatomist90, ChrisGualtieri, Dick9969, Cerabot, JakobSteenberg, LT910001, Princemaddiepants57, Anrnusna, Monkbot, Wolfielikeyumyum, Diptanu chakraborty and Anonymous: 123 • Spermatogenesis Source: http://en.wikipedia.org/wiki/Spermatogenesis?oldid=644725462 Contributors: Lexor, Julesd, Andres, Tristanb, Robbot, Yelyos, Caknuck, Diberri, GreatWhiteNortherner, Matt Gies, Kandar, Jutta, Roberdin, Rich Farmbrough, Arcadian, Obradovic Goran, Abstraktn, Alansohn, Riana, Caesura, RyanGerbil10, 2004-12-29T22:45Z, Magister Mathematicae, Rjwilmsi, Mirmillon, Klortho, FlavrSavr, Gsp, FlaBot, YurikBot, Wavelength, Chanlyn, RussBot, Chris Capoccia, Rsrikanth05, Voyevoda, D. Wu, Nephron, Alex43223, Mieciu K, User27091, Lt-wiki-bot, Jonathan.s.kt, KnightRider, Jrockley, Eskimbot, Bluebot, RDBrown, Octahedron80, Caue.cm.rego, Richard0612, Mitsuki152, SashatoBot, Deepankar s, AmiDaniel, Heimstern, LestatdeLioncourt, TheAmelianator, Serephine, Citicat, Novangelis, MTSbot, Grothmag, High Elf, Dgw, DanielRigal, Shanew2, Khatru2, Jsherwood0, Thijs!bot, Luke poa, Picus viridis, Mentifisto, Alphachimpbot, JAnDbot, Kaobear, CheckIt, Ishikawa Minoru, Med-Wiki, Temposs, MartinBot, Niel924, EyeSerene, Trixt, Worldedixor, J.delanoy, CFCF, Mikael Häggström, Brendan19, Ollie Dyas, Apostle1, SERSeanCrane, Philip Trueman, Intery, TXiKiBoT, LeaveSleaves, BotKung, Earthdirt, Sufergirl16, SieBot, Oldag07, Steveking 89, Sovbeos, Lightmouse, Trashbird1240, Ecthelion83, Patilsaurabhr, ClueBot, The Thing That Should Not Be, Pakaraki, Auntof6, Sun Creator, Arjayay, Jaygajera, Addbot, DOI bot, Jncraton, Diptanshu.D, Download, Hroychow, Bernstein0275, Favonian, Rhodospirillum, Luckas-bot, Yobot, Ptbotgourou, Materialscientist, Citation bot, RibotBOT, VS6507, Bowdren, Cannolis, Citation bot 1, Tjmoel, Amkilpatrick, LeavXC, John of Reading, Mintymiller, ZéroBot, Érico Júnior Wouters, H3llBot, Judygreenberg, Whoop whoop pull up, ClueBot NG, Frietjes, Mammaljuice504, They, Mark Arsten, Mmeinstein, Dr knowland, Abbybelasen, GoShow, Hosorio97, TwizteDope, Yogwi21, HUBS, Bobercool, FamAD123, Fmrfmr, Melonkelon, Mikebrooke101, Tn9005, Monkbot, Tatabox8, AntyJusteen, BethNaught, Stepneylawrence, AMMedStudent and Anonymous: 165 • Spermatozoon Source: http://en.wikipedia.org/wiki/Spermatozoon?oldid=649606571 Contributors: Magnus Manske, Brion VIBBER, Eloquence, Bryan Derksen, AstroNomer, Andre Engels, Youssefsan, Patrick, Michael Hardy, Lexor, Wapcaplet, Ixfd64, Delirium, 168..., Ahoerstemeier, Julesd, Habj, Tristanb, Rawr, Quizkajer, Feedmecereal, Dcoetzee, Harris7, RickK, Vincent Ramos, Fuzheado, Patrick0Moran, Saltine, Renato Caniatti, Jeffq, Northgrove, Robbot, Academic Challenger, Rhombus, Bkell, Diberri, Marc Venot, Jeremiah, DocWatson42, Jyril, Lupin, Everyking, No Guru, Duncharris, Pne, AdamJacobMuller, Delta G, Kandar, Ryanaxp, Etaonish, Utcursch, Andycjp, Slowking Man, Beland, AlexanderWinston, Snoogit, Maximaximax, Thincat, Kasreyn, Rich Farmbrough, Wikiacc, MarkS, Zaslav, Neko-chan, Violetriga, Aranel, NickGorton, Summer Song, RoyBoy, Sole Soul, Elipongo, Arcadian, La goutte de pluie, Pdb, Idleguy, Unused000701, Nsaa, Danski14, Abstraktn, Alansohn, Hu, Caesura, KJK::Hyperion, Vcelloho, Kazvorpal, Killing Vector, Gmaxwell, OwenX, 2004-12-29T22:45Z, Mindmatrix, JBellis, MONGO, RobJ, LadyofHats, Wayward, Stevey7788, Dysepsion, Graham87, FreplySpang, Canderson7, Sjakkalle, Rjwilmsi, Kinu, SeanMack, Bhadani, Hathawayc, Yamamoto Ichiro, Dionyseus, FayssalF, FlaBot, Twipley, Drumguy8800, BradBeattie, Silversmith, King of Hearts, Sbrools, Bornhj, Gwernol, Borgx, Chanlyn, Kafziel, KokoBot, Icarus3, Conscious, Hede2000, SpuriousQ, Hydrargyrum, Dotancohen, Chensiyuan, Stephenb, Wimt, Nick, Lukeholman, MSJapan, Aaron Schulz, Sahands, Wknight94, Encephalon, ChrisGriswold, Lyrl, Carlosguitar, Maxamegalon2000, Nippoo, JerryOrr, SmackBot, Hazaw, Reedy, FloNight, Hydrogen Iodide, Bomac, WilyD, Jrockley, Delldot, Drkarthi, Mak17f, Gilliam, Vercalos, Reza1615, KaragouniS, Raymondluxuryacht, Miquonranger03, Deli nk, Robinrocks, J. Spencer, Eclinchy, Can't sleep, clown will eat me, Atropos, Nixeagle, Rrburke, TKD, Adamantios, GVnayR, Bowlhover, Jiddisch, RaCha'ar, Nrcprm2026, Nonstopdrivel, DMacks, Lupine nickt, Pilotguy, Midkay, Kuru, Akendall, Epingchris, ZGames, Sir Nicholas de Mimsy-Porpington, LestatdeLioncourt, Saigon punkid, Accurizer, RandomCritic, TheAmelianator, Bendzh, VioLence, Ryulong, Condem, ShakingSpirit, Emx, Shoeofdeath, J Di, Hynca-Hooley, SweetNeo85, Courcelles, Tawkerbot2, Alegoo92, Cadmus72, Hibernophile, Xcentaur, Deon, Jaeger5432, KyraVixen, MarsRover, Leujohn, Dead Or Alive, Gogo Dodo, Tom.freeman, JFreeman, B, Christian75, Roberta F., Chrislk02, Dipics, Krm500, Omicronpersei8, Satori Son, Thijs!bot, John254, James086, Escarbot, AntiVandalBot, Willscrlt, Susan S Suarez, Smartse, Mack2, Gdo01, Salgueiro, Leevclarke, Myanw, Figma, Canadian-Bacon, JAnDbot, Husond, Johnson 124981, MER-C, Arch dude, SiobhanHansa, Bongwarrior, VoABot II, Nytewing07, RebekahThorn, Kohlasz, Glen, Nevit, SwedishPsycho, ChrisSerrano, Cocytus, ClubOranje, MartinBot, Julius011, Keith D, Jay Litman, Alro, CommonsDelinker, Ifimay94, John Duncan, TyrS, Uncle Dick, Thisischris, Wandering Ghost, McSly, Lilbuck10, Samtheboy, Qwertyster, Mikael Häggström, Jayden54, Poo4u, EMT1871, Cue the Strings, Zoe99, Michael Joseph Jackson fan, OsirisV, Davecrosby uk, CardinalDan, Coolguy999, Mastrchf91, Meiskam, Loserzluk14, VolkovBot, Wesrox, HansFotzeficker, BlakeCS, Chienlit, TXiKiBoT, Kimullen, Tameeria, Grunglerules, Xerxesnine, Qxz, WazzaMan, Bobyman, Songs, DoktorDec, כל יכול, Butterscotch, Jennyjany2009, Lizyo, Wikipedian3000, Monty845, AlleborgoBot, Iammrysh, Rocko52003, SieBot, Euryalus, Caltas, Yintan, Keilana, Tiptoety, Radon210, Sovbeos, Paradocks5, Electronz, PhilMacD, KoshVorlon, JohnnyMrNinja, De728631, ClueBot, Chazzek, Jusdafax, Nem1yan, Scalhotrod, Versus22, Vanished user uih38riiw4hjlsd, Nicolae Coman, Marklar2007, Gggh, Addbot, DOI bot, FlowRate, Tcncv, Tanhabot, Vishnava, Fluffernutter, Ostate20, NjardarBot, Ka Faraq Gatri, Morning277, Ahmad.ghamdi.24, 5 albert square, Erutuon, Tide rolls, Lightbot, Teles, Jarble, Lisa256B, Quantumobserver, LuK3, Legobot, Luckas-bot, TaBOT-zerem, XL2D, KDS4444, Robinbanerji, Jim1138, Human4321, Abercrombiegrl113, Swithrow2546, Misskhue, Citation bot, Question Guy, Neurolysis, Xqbot, Mnyakaba-GMU, Ph3nom24, Disendya, GrouchoBot, Omnipaedista, RibotBOT, Amaury, Absolutezero273, SD5, IanKDavis, Worky worky, Metalman94, , Jamesooders, Stephen Morley, Citation bot 1, Jb1100, A8UDI, Tomnewton101, Jessey2k, Kiritampo, MiraAroyo, Diannaa, Tbhotch, Lord of the Pit, RjwilmsiBot, TjBot, Alph Bot, Alexkiah, Aircorn, EmausBot, John of Reading, StallionWriter, Immunize, MarleyRoberts44, TheSperminator, Conmorris, Fæ, StereoTypo, Ebrambot, IGeMiNix, Donner60, Vanished 1850, ClashofAges, Ebehn, ClueBot NG, Louis595, CocuBot, Hazhk, Jake4356, I have HIV, Forskerunv, EdwardZhao, Fopnor, Sfnagle, Min.neel, Trollmaster57, Hairy paperclip, A114112836, Cait Tomlinson, Boogie314, Qwertyloverboi, Lugia2453, Boligoma, Haltopub, Tn9005, Gusbus69 and Anonymous: 443 • Spermatogonium Source: http://en.wikipedia.org/wiki/Spermatogonium?oldid=635441679 Contributors: PDH, Rich Farmbrough, Arcadian, Kappa, Lachaume, 2004-12-29T22:45Z, SCEhardt, Peter Grey, DoriSmith, Espresso Addict, Mat8989, Robotsintrouble, Cydebot, Thijs!bot, JAnDbot, Kaobear, Easixy5, Sovbeos, ClueBot, Squirrels2nuts, Lab-oratory, Addbot, SpBot, KamikazeBot, Xqbot, Bensisko95, LucienBOT, Craig Pemberton, DrilBot, EmausBot, ZéroBot, Stemoc, Frietjes, Transposagen, Melonkelon, Demax hemed, Aelamass, Filedelinkerbot and Anonymous: 15 • Spermatocyte Source: http://en.wikipedia.org/wiki/Spermatocyte?oldid=648508079 Contributors: Ianml, Brim, Arcadian, 2004-1229T22:45Z, Scottkeir, Rjwilmsi, RussBot, Chris Capoccia, SmackBot, Serephine, Vanisaac, Cydebot, JamesAM, Kaobear, Mikael Häggström, Wikiisawesome, Keilana, 7&6=thirteen, Addbot, Frederikfederspiel, AnomieBOT, AdmiralHood, GrouchoBot, Erik9bot,
60.13. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
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ZéroBot, ClueBot NG, Frietjes, Widr, Rdumbill, BattyBot, Melonkelon, Monkbot, Magladem96, Tatabox8, Amanaresi, Richarnj and Anonymous: 9 • Spermatid Source: http://en.wikipedia.org/wiki/Spermatid?oldid=635441698 Contributors: Chowbok, Arcadian, Abstraktn, 2004-1229T22:45Z, YurikBot, Diligent, Gilliam, Kaobear, Alexbot, Addbot, AdmiralHood, FrescoBot, Wikielwikingo, EmausBot, ZéroBot, Stemoc, Alsbluegoat, ClueBot NG, Frietjes, Filedelinkerbot and Anonymous: 11 • Seminiferous tubule Source: http://en.wikipedia.org/wiki/Seminiferous%20tubule?oldid=637597822 Contributors: Karada, Alison, Starbane, Dcfleck, Arcadian, Kjkolb, Pearle, Osmodiar, Moormand, RussBot, Nephron, Haemo, Brianyoumans, Jab843, Drphilharmonic, Illnab1024, Jpogi, Kylu, Cydebot, Thijs!bot, Epbr123, AntiVandalBot, Cyhborg, Philip Trueman, Tameeria, SieBot, Kanesue, ClueBot, Good Olfactory, Addbot, Tanhabot, Verazzano, Luckas-bot, Beeswaxcandle, FrescoBot, Naturehead, WikitanvirBot, Stemoc, ClueBot NG, Frietjes, Rezabot, Melonkelon, Filedelinkerbot, Dsprc, Ykher and Anonymous: 24 • Leydig cell Source: http://en.wikipedia.org/wiki/Leydig%20cell?oldid=647199665 Contributors: Magnus Manske, Hadal, Fuelbottle, Diberri, Vogon77, M1ss1ontomars2k4, Arcadian, Pearle, Abstraktn, TheParanoidOne, Adrian.benko, Rjwilmsi, FlaBot, Fct, YurikBot, Hydrargyrum, Nephron, KnightRider, SmackBot, Andreas Erick, InvictaHOG, Eskimbot, Greid, Drphilharmonic, Jpogi, Scohoust, MaxEnt, Coldbringer, Cydebot, Tim hole, Thijs!bot, CopperKettle, Liquid-aim-bot, Uriel8, Chopin-Ate-Liszt!, Mikael Häggström, ELLusKa 86, VolkovBot, Cezarika1, AlleborgoBot, Coolstoryhansel, Franamax, Estirabot, Addbot, DOI bot, Lightbot, Zorrobot, Jarble, Luckas-bot, Yobot, Citation bot, Xqbot, GrouchoBot, Craig Pemberton, A8UDI, RedBot, Amkilpatrick, RjwilmsiBot, GoingBatty, ZéroBot, Stemoc, H3llBot, Lji1942, ClueBot NG, One50ne, Pengortm, Filedelinkerbot, Tilifa Ocaufa, Musashi San17 and Anonymous: 28 • Sperm Source: http://en.wikipedia.org/wiki/Sperm?oldid=649917396 Contributors: Patrick, D, Julesd, Deisenbe, Vargenau, MichaK, Stone, Hyacinth, Francs2000, HaeB, Jackol, Beland, OverlordQ, Thincat, Ukexpat, Sam nead, Grstain, Discospinster, Vsmith, Bender235, Mairi, Bobo192, Wisdom89, Urthogie, Sam Korn, Andrewpmk, RainbowOfLight, Gjuny, Feezo, OwenX, 2004-12-29T22:45Z, LizardWizard, Commander Keane, WadeSimMiser, Mihalis, MarcoTolo, Jclemens, Edison, WCFrancis, Hiberniantears, Gadha, Yamamoto Ichiro, Rangek, Titoxd, PubLife, Nihiltres, Nivix, Gurch, Press Start, Wavelength, Sceptre, RussBot, Pigman, Stephenb, CambridgeBayWeather, Pseudomonas, Ospalh, DeadEyeArrow, Private Butcher, Wknight94, Kelovy, 21655, Zzuuzz, Lindentree, Ketsuekigata, Pb30, Ray Chason, Lec CRP1, Markbenecke, Sexworms, Cornchips, CIreland, Hiddekel, SmackBot, TheBilly, AaronM, InverseHypercube, KnowledgeOfSelf, Delldot, Gilliam, Ohnoitsjamie, Wlmg, Chris the speller, Agateller, Miquonranger03, Silly rabbit, Octahedron80, Nintendude, Zsinj, Rrburke, Nakon, Dreadstar, Richard001, Wirbelwind, Adrigon, Acdx, Kukini, Kuru, FrozenMan, Rodsan18, Linnell, AB, Accurizer, Ocatecir, Aleenf1, Werdan7, Manifestation, Hogyn Lleol, Hu12, MikesPlant, HisSpaceResearch, Iridescent, Nfutvol, CapitalR, Blehfu, LadyofShalott, Gekaap, Filelakeshoe, Benfranklinlover, FunPika, Dycedarg, Rglong, Dgw, MarsRover, Fl, Torc2, Gonzo fan2007, Epbr123, Pajz, Osborne, Dasani, James086, Dikteren, Escarbot, Shibby970, Sidasta, AntiVandalBot, Luna Santin, Womblejonny, TimVickers, Smartse, Mack2, Spencer, Kyleeberle, JAnDbot, Kaobear, Avaya1, Instinct, Lomis, GoodDamon, LittleOldMe, Acroterion, Bongwarrior, VoABot II, Drsocc, Transcendence, Indon, David Eppstein, DerHexer, Shadiac, Lenticel, TheNoise, MartinBot, Keith D, Mschel, AlexiusHoratius, J.delanoy, Svetovid, TyrS, MoogleEXE, Extransit, SU Linguist, Darth Mike, Ryan Postlethwaite, Jeepday, Mikael Häggström, Skier Dude, Gurchzilla, Jasonasosa, Nwbeeson, Gregfitzy, Pcarter7, Juliancolton, Cometstyles, Treisijs, Joost de Kleine, Useight, X!, CWii, Thedjatclubrock, Dreby14, Philip Trueman, Tameeria, ColinBoylett, Bass fishing physicist, Guldenat, Xavcam, Madhero88, RandomXYZb, Gspinoza, Insanity Incarnate, Dumbnuts, Dickneck99, HeirloomGardener, Twooars, IndulgentReader, Chuck Sirloin, NHRHS2010, Deconstructhis, Alexandre Bouthors, Beeftheboss, EJF, Ahmed32 UK, Coffee, Tiddly Tom, Bytenik, YKWSG, Addit, YourEyesOnly, Caltas, Xymmax, P-squad4251, Rafael MC, Andrewjlockley, GrooveDog, Keilana, Raquel PWNZ, RucasHost, Flyer22, Tiptoety, Oda Mari, Sohelpme, JSpung, Telcourbanio, Oxymoron83, Avnjay, Steven Zhang, Poindexter Propellerhead, Guntiur983, AMbot, Jumbawumba, Dust Filter, Florentyna, Baosheng, Greystoke35, Joannyluteman534, WikipedianMarlith, Twinsday, John Doe42, Martarius, ClueBot, Surfeited, Phil havercroft, Gurukkal, Foxj, The Thing That Should Not Be, Nnemo, Meekywiki, Storch6308, Chris Bainbridge, Smashingpumkin, Kiyi-chan, JammydodgerUK, Niceguyedc, Richerman, Neverquick, SeanBBSc, Excirial, INazi, Nosolution182, Kewsss, Lartoven, Mike-shearer92, Katdye123, Nattycan, Bob™, Razorflame, Ohyababy1, Richardedgerton, Dekisugi, Gtva1234, Polly, Waterloocook, 123456789101121cccccc, Aitias, Novjunulo, Rey101011, Rror, Wootwootlmaoftw, Bhojanimihir, Nicolae Coman, Camelface123, Revancher, Fess56, Al tally, Gggh, Wingschlong, Jtknowles, Blairbob, Addbot, Uravjjfaceandvjjarms, Supersixfour, Longhorngirl 5284, MartinezMD, Fieldday-sunday, Pimpboy, CanadianLinuxUser, Briefblowtothehead(dick), Chamal N, Rawfact, JayFS89, Horny t, Dikwad1, Ahmad.ghamdi.24, GuffasBorgz8, Jcaliguy, Wowcamj, Gail, Jarble, Newlyteeth, , Smithy998877665544332211, Frederikfederspiel, Luckas-bot, Yobot, Eaglesiegle, Xhellxringerx, This deserves inclusion, THEN WHO WAS PHONE?, Brougham96, Bility, AnomieBOT, Ftwklg, Piano non troppo, I.r.ande.t.a, HotHistoryBuff69, D1536, Andrei Anghelov, Shawtyrockmi, Theguy14, GB fan, .غامدي.أحمد24, LilHelpa, Bakerccm, Rsmn, Rohitrrrrr, Wervo, , Citation bot 1, HRoestBot, Notedgrant, FoxBot, RjwilmsiBot, Rami radwan, Dominus Vobisdu, Vikoula5, Dantheman216, Esc2003, TheiGuard, H3llBot, Thine Antique Pen, MikeNicho231, Mesoderm, North Atlanticist Usonian, Helpful Pixie Bot, Slushy9, Jonadin93, BattyBot, Y12J, JYBot, Tessmac9708, Hwangrox99, Tmshates, Predspread, StirlingJulian, Tn9005, Monkbot and Anonymous: 359 • Axoneme Source: http://en.wikipedia.org/wiki/Axoneme?oldid=632979877 Contributors: MichaK, Ianml, Iwilcox, Syp, Arcadian, Zachlipton, Howrealisreal, Cburnett, 2004-12-29T22:45Z, Teuteul, Rjwilmsi, Gurch, Roboto de Ajvol, YurikBot, Sentausa, Ezeu, SmackBot, AaronM, InvictaHOG, Stepa, Edgar181, OrphanBot, Nhahmad, Alexei Kouprianov, N2e, Cydebot, Kupirijo, Smartse, Benjamin.friedrich, Cjmclark, Leebo, WOSlinker, TXiKiBoT, AlleborgoBot, Brenont, SpectrumAnalyser, Exothermic, Elemandia, Lenrodman, Leontios, Addbot, DOI bot, Luckas-bot, Citation bot, FrescoBot, Enfermero, Citation bot 1, Emulawn, Ahmedsy6, Inferior Olive, Mentibot, EdoBot, Monkbot, NewEnglandDr and Anonymous: 25 • Acrosome Source: http://en.wikipedia.org/wiki/Acrosome?oldid=624739857 Contributors: Magnus Manske, Ahoerstemeier, Flockmeal, Robodoc.at, Andycjp, Onco p53, Usrnme h8er, Bluemask, Arcadian, Abstraktn, Arthena, ClockworkSoul, Cburnett, 2004-12-29T22:45Z, Isnow, LadyofHats, Rjwilmsi, Gurch, Chobot, YurikBot, Anetode, SMcCandlish, Chrishmt0423, SmackBot, InvictaHOG, RDBrown, Andy120290, Radagast83, Valenciano, Wikier.ko, Brazucs, Novangelis, Kaarel, R, Cydebot, Thijs!bot, RalphS, Alphachimpbot, Gökhan, JAnDbot, Ummagumma23, STBot, Gzkn, Mikael Häggström, TXiKiBoT, Anna Lincoln, Ktulu789, Ipodamos, ClueBot, Gits (Neo), El bot de la dieta, Vojtěch Dostál, MystBot, Addbot, Jarble, Legobot, THEN WHO WAS PHONE?, GrouchoBot, WebCiteBOT, Sahmejil, Simple Machine, Jbribeiro1, Kittenono, Miguelferig, Crrnorthwestern, AioftheStorm, Monkbot and Anonymous: 20 • Spermiogenesis Source: http://en.wikipedia.org/wiki/Spermiogenesis?oldid=641564524 Contributors: Julesd, Arcadian, Wtmitchell, 2004-12-29T22:45Z, GregorB, Ian Pitchford, RussBot, Dysmorodrepanis, Drphilharmonic, PhiJ, Serephine, Cydebot, Glen, CommonsDelinker, Ryancormack, DumZiBoT, Addbot, Zorrobot, Ptbotgourou, Totodu74, Trupti patil, Sxoa, Stemoc, Donner60, ClueBot NG, Mark Arsten, ChrisGualtieri, Anchor207, Filedelinkerbot and Anonymous: 18 • Androgen-binding protein Source: http://en.wikipedia.org/wiki/Androgen-binding%20protein?oldid=649008786 Contributors: Discospinster, Sfahey, Femto, Arcadian, Ekem, Mushin, Drphilharmonic, Joseph Solis in Australia, Planktonbot, Magioladitis, R'n'B,
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Dabomb87, TubularWorld, Addbot, AttoRenato, Ptbotgourou, AnomieBOT, EmausBot, WikitanvirBot, ZéroBot, Wuerzele and Anonymous: 9 • Egg cell Source: http://en.wikipedia.org/wiki/Egg%20cell?oldid=649515617 Contributors: Rjwilmsi, Hydrargyrum, LuisVilla, Gilliam, Seaphoto, CommonsDelinker, TomS TDotO, Nadiatalent, Sintaku, Avoided, KDS4444, Materialscientist, Dr. Esra, A.amitkumar, Jonesey95, Danmuz, ClueBot NG, Cricetus, Hwangrox99, InfinityMC1999, FamAD123, Tentinator, JaconaFrere, Tn9005, Chaya5260, Vieque, Ben89129, Qwertyxp2000, Raghav wahi, Calell13 and Anonymous: 17 • Corona radiata (embryology) Source: http://en.wikipedia.org/wiki/Corona%20radiata%20(embryology)?oldid=620168795 Contributors: Bearcat, Mu, Xezbeth, Arcadian, Cjthellama, Stemonitis, RussBot, BOT-Superzerocool, SmackBot, LittleT889, Cydebot, Karol007, Rei-bot, Andrewjlockley, ImageRemovalBot, Alexbot, Addbot, Diptanshu.D, Luckas-bot, Xqbot, Ketie G., Scarecr0w 4, Ripchip Bot, Frietjes, T mocz, Glacialfox, Joshua Born, APerson, Ranze and Anonymous: 7 • Oogonium Source: http://en.wikipedia.org/wiki/Oogonium?oldid=647625190 Contributors: Diberri, Nmg20, Gadfium, Kwamikagami, Remuel, Arcadian, 2004-12-29T22:45Z, BD2412, Rjwilmsi, Roboto de Ajvol, Borgx, Hydrargyrum, Bazonka, Shalom Yechiel, AThing, Epingchris, NickW557, Cydebot, Osborne, Marek69, Kaobear, R'n'B, Mikael Häggström, Red Act, MiloszD, Flyer22, Mild Bill Hiccup, Puchiko, Sun Creator, SchreiberBike, Vojtěch Dostál, Tiphaine800, Addbot, Luckas-bot, Yobot, Ptbotgourou, Xqbot, Nasnema, EmausBot, ClueBot NG, Rainbowwrasse, Snotbot, Helpful Pixie Bot, Cutiger08, Sminthopsis84, Sanador2.0, Monkbot, Buntypatel8852079739 and Anonymous: 21 • Zona pellucida Source: http://en.wikipedia.org/wiki/Zona%20pellucida?oldid=637267589 Contributors: AxelBoldt, The Anome, Diberri, Cyrius, Chowbok, CALR, Iamunknown, Arcadian, Abstraktn, Rjwilmsi, FlaBot, Gurch, Wavelength, Chris Capoccia, Garion96, SmackBot, Zephyris, Epingchris, Cajolingwilhelm, Gbozzato, GAThrawn22, Luna Santin, Karol007, CommonsDelinker, Mikael Häggström, Tameeria, Nickwilkie, Weisheng9, 456RTD, ImageRemovalBot, Mild Bill Hiccup, JCKB, Alexbot, Tiphaine800, Addbot, DOI bot, NjardarBot, Anxietycello, Ayacop, Luckas-bot, Citation bot, Gigemag76, Citation bot 1, MondalorBot, RjwilmsiBot, ChuispastonBot, ClueBot NG, Frietjes, Helpful Pixie Bot, Joshua Born, AioftheStorm, Elephantsofearth, Rraju2 and Anonymous: 27 • Oocyte Source: http://en.wikipedia.org/wiki/Oocyte?oldid=648644845 Contributors: Edward, Lexor, Gabbe, Snoyes, Glimz, Furrykef, Robbot, RedWolf, Arkuat, Fuelbottle, Nmg20, Rasbak, Remuel, Arcadian, Abstraktn, Riana, Cburnett, Ceyockey, 2004-12-29T22:45Z, MarcosR, Crazycomputers, EamonnPKeane, Stephenb, Snek01, Trovatore, Mysid, Modify, Leeannedy, Kerfern, Srnec, Skizzik, Chris the speller, Hgrosser, Cameron Nedland, Minna Sora no Shita, Mgiganteus1, Sugemax, Manifestation, Phuzion, Stylese, Cydebot, Shano85, Saintrain, Oliver202, JAnDbot, Deflective, Kaobear, Db099221, EagleFan, CommonsDelinker, CFCF, Mikael Häggström, Sdou, VolkovBot, Tameeria, AlleborgoBot, Addit, James.Denholm, Bobjgalindo, Haripandit, InverseSubstance, Arunsingh16, Kbusdriver, Megiddo1013, Vanished User 1004, ברוקולי, Vojtěch Dostál, Addbot, Basilicofresco, PlankBot, Luckas-bot, Ptbotgourou, Materialscientist, Tour86rocker, Omnipaedista, Amaury, PauAmma, FrescoBot, Citation bot 1, Microinjection, Catcasillas, Nkmosley, Erianna, Whoop whoop pull up, ClueBot NG, Cwmhiraeth, Frietjes, Thomas 564312, Curb Chain, ChrisGualtieri, Poissonbreaker, Tmshates, Lymanbellows, B14709, Brainiacal, Chaya5260, Somayeh.keshavarzi, Monkbot, Tilifa Ocaufa and Anonymous: 73 • Ovulation Source: http://en.wikipedia.org/wiki/Ovulation?oldid=645899494 Contributors: PierreAbbat, Camembert, Ellywa, Habj, DonPaolo, MiLo28, Dpbsmith, Jamesday, Sander123, Altenmann, COGDEN, Robodoc.at, Everyking, Kaldari, Sam Hocevar, Paulbee, DanielCD, Rich Farmbrough, MisterSheik, Laurascudder, Bobo192, Davidruben, Arcadian, Kjkolb, Abstraktn, AnnaP, Arthena, Wouterstomp, Adrian.benko, Woohookitty, BlaiseFEgan, Xiong Chiamiov, Alienus, Rjwilmsi, RobertG, KarlFrei, Ewlyahoocom, CiaPan, Bgwhite, YurikBot, Chanlyn, Icarus3, Carl T, Guslacerda, Pigman, DanMS, Gaius Cornelius, Eleassar, D. Wu, Supten, Deepakkamboj, Yonidebest, Lt-wiki-bot, Closedmouth, Jonathan.s.kt, Lyrl, SmackBot, Eperotao, Herostratus, AnOddName, Edgar181, Rune X2, Ohnoitsjamie, Anwar saadat, RDBrown, Deli nk, PureRED, Tlusťa, COMPFUNK2, Downtown dan seattle, Nakon, Copysan, Agradman, Kuru, Scientizzle, Epingchris, Slakr, Beetstra, Whomp, MTSbot, Ginkgo100, Majora4, MarAI, Jen1026, WeggeBot, NE Ent, Cydebot, Dream of Goats, Gogo Dodo, Jayen466, Mervin Chung, Dasani, Amerpre, Pregdoc, Esowteric, Mentifisto, Majorly, Seaphoto, Emeraldcityserendipity, Mack2, Flex Flint, Joehall45, Barek, MER-C, Hut 8.5, Magioladitis, VoABot II, JNW, DonVincenzo, Joie de Vivre, CommonsDelinker, Kmp5p, CFCF, Boghog, Hallandnash, Naniwako, Mikael Häggström, Hexane2000, RJASE1, Hchoe, Jeff G., Kwsn, ^demonBot2, Michaeldsuarez, Satteliterover, Lova Falk, Kbw079, Jobberone, SieBot, TCO, Editore99, Nuttycoconut, Ashar77, Susan118, Denisarona, ImageRemovalBot, ClueBot, Drmies, HenryPhillips, Auntof6, Excirial, ParisianBlade, Thingg, XLinkBot, RyanCross, Gggh, Addbot, DOI bot, Landon1980, AkhtaBot, Download, Whistling42, Tide rolls, Jarble, Laplacian54, Shakadooda, Legobot, Chaldor, Luckas-bot, Yobot, KamikazeBot, AnakngAraw, AnomieBOT, Adeliine, AdjustShift, 90 Auto, Citation bot, Jock Boy, Bihco, XZeroBot, Yanksfan17994, VS6507, Citation bot 1, Pinethicket, TobeBot, EmausBot, John of Reading, WikitanvirBot, Dewritech, Passionless, Wikipelli, Pandabear555, Luckygohappy115, ZéroBot, John Cline, Sn303002, Sheikshabootay, RaptureBot, RDO Medical, Peteb4, Anniblue, Miradre, ClueBot NG, Mother natural, Jedisum66, Frietjes, Schmoobert, Mesoderm, Widr, Helpful Pixie Bot, Curb Chain, Womenproblems, Kookookook, Tuff244, Vanished user lt94ma34le12, Drcourtneyclux, Nanagirl07, Guido81, SteenthIWbot, Sofiaporto, Tn9005, Monkbot, Partypants85, Mostlymicrobes, Ocelot12, ResoAU, Vipin.sharma2015 and Anonymous: 222 • Ovarian follicle atresia Source: http://en.wikipedia.org/wiki/Ovarian%20follicle%20atresia?oldid=626928996 Contributors: Lockley, SmackBot, Krychek, Nono64, Madhero88, Bernstein0275, Jarble, Spyderhydrant, AnomieBOT, Citation bot, Citation bot 1, Damskibeat, BG19bot, Monkbot and Anonymous: 4 • Ovarian follicle Source: http://en.wikipedia.org/wiki/Ovarian%20follicle?oldid=642885585 Contributors: Bueller 007, Habj, Robbot, Diberri, Robodoc.at, Jfdwolff, Neutrality, Jimj, Mwanner, Arcadian, AnnaP, Osmodiar, Eras-mus, MC MasterChef, Rjwilmsi, Koavf, Chanlyn, RussBot, Icarus3, Pigman, Hydrargyrum, E rulez, Hydrology, Jpogi, Epingchris, Lottamiata, JAnDbot, Epeefleche, Janette.quennell, Karol007, CommonsDelinker, Zygiskr, Pekaje, Mikael Häggström, VolkovBot, ImageRemovalBot, Addbot, TheNeutroniumAlchemist, Luckas-bot, Sarrus, AnakngAraw, Apollo1758, Citation bot, Stephanie85, Erud, Omnipaedista, Craig Pemberton, OgreBot, Mj455972007, EmausBot, TuHan-Bot, Wikipelli, Puldis, Dr Bilal Alshareef, Yogwi21, JakobSteenberg, FamAD123, Uzumaki1107, LT910001, JaconaFrere, Monkbot, Tilifa Ocaufa and Anonymous: 50 • Corpus luteum Source: http://en.wikipedia.org/wiki/Corpus%20luteum?oldid=646149286 Contributors: Bryan Derksen, Gdarin, Habj, Robbot, Diberri, DocWatson42, Robodoc.at, Esufer, Lylum, M1ss1ontomars2k4, CanisRufus, CDN99, Arcadian, Jag123, Wtmitchell, Kelly Martin, Woohookitty, Eras-mus, Prashanthns, Bgwhite, Bubbachuck, Klingoncowboy4, RussBot, Pigman, Eleassar, Miert, Nephron, Lt-wiki-bot, SmackBot, Bomac, Jfurr1981, Sbharris, Tsca.bot, Drphilharmonic, NcSchu, Psquared2, Siebrand, Stylese, Matt26, Seejyb, Jsherwood0, Hoffmeier, Epeefleche, Mark Lundquist, DerHexer, Dudewheresmywallet, CommonsDelinker, Boghog, Jmjanzen, Schaaftin, Mikael Häggström, Markjohndaley, Winderful1, KylieTastic, VolkovBot, Jackfork, Doc James, Kero584, Lyzzis, Gerakibot, Ivan.Lt, Chilian51, Drmies, Ricksakti, DragonBot, Excirial, Gnowor, NellieBly, Lab-oratory, Addbot, Fieldday-sunday, Quercus solaris, Jarble, Luckasbot, Yobot, Grenadine, Materialscientist, ArthurBot, Xqbot, Erud, Omnipaedista, Earlypsychosis, FrescoBot, Sky Attacker, Mgutierrezyach, Oreobrine, Omegawp, TobeBot, EmausBot, Imprint007, Donner60, Wafaashohdy, ClueBot NG, Vldscore, Frietjes, Widr, BG19bot,
60.13. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
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Vokesk, MusikAnimal, Rytyho usa, Yogwi21, Epicgenius, Gjbbms640, Frickson, Cattycat95, Ginsuloft, Manul, Monkbot, Welley93, Tilifa Ocaufa and Anonymous: 117 • In vitro maturation Source: http://en.wikipedia.org/wiki/In%20vitro%20maturation?oldid=607259563 Contributors: The Anome, Bearcat, Wouterstomp, Rjwilmsi, Gaius Cornelius, Modify, Canley, J. Spencer, Alaibot, CZmarlin, Steve98052, Adavidb, Boghog, Mikael Häggström, Addbot, Yobot, RjwilmsiBot, EmausBot, Qetuth and Anonymous: 7 • Human fertilization Source: http://en.wikipedia.org/wiki/Human%20fertilization?oldid=649726649 Contributors: Halfdan, Andycjp, R. fiend, Yik Lin Khoo, Anythingyouwant, Freakofnurture, ESkog, Arcadian, Alansohn, Evil Monkey, Kitch, Rjwilmsi, Tdowling, AySz88, RobyWayne, Sceptre, Rsrikanth05, Mark Kim, Brian Crawford, Allens, Lyrl, Crystallina, SmackBot, Ashill, Jfurr1981, Gilliam, Hmains, Amatulic, Can't sleep, clown will eat me, Flyguy649, AngelSL, Shinryuu, Spook`, Ginkgo100, Missionary, Fezz, Bazzargh, DumbBOT, Krm500, Northumbrian, Fr33ke, Seaphoto, Mack2, One Artiste, MikeLynch, Ctill, Bongwarrior, QuizzicalBee, Homunq, WhatamIdoing, Canyouhearmenow, DerHexer, Tyler path, Pruthvi.Vallabh, CommonsDelinker, JeremyWJ, Mikael Häggström, Kyle the bot, Philip Trueman, Tameeria, Anna Lincoln, Donarnold, Lova Falk, Temporaluser, Darthsion101, Bfpage, Maddiekate, RandomHumanoid, Plynch22, Loren.wilton, ClueBot, The Thing That Should Not Be, Arakunem, Auntof6, Excirial, KSUdvm2b, Helenginn, KeasbeyMornings, Daughter of Mímir, MystBot, Addbot, Ronhjones, Lonely goatherd, Abiyoyo, Gail, Jarble, Angrysockhop, Yobot, Fraggle81, AnakngAraw, Fatal!ty, Materialscientist, The High Fin Sperm Whale, ArthurBot, Glenk1973, Capricorn42, Papercutbiology, Shadowjams, FrescoBot, ThiagoRuiz, Pinethicket, I dream of horses, Rushbugled13, Pmokeefe, Ryt 007, Merlion444, Curiousranger, Aslmolin, John of Reading, Theonlymichael, RedChuck14, Openstrings, Brandmeister, Ready, LibertyOrDeath, Judygreenberg, Wafaashohdy, ClueBot NG, Joezak, Ctap, Widr, Helpful Pixie Bot, Slefuyhiluaenrflouhesf, Lowercase sigmabot, AdventurousSquirrel, MrBill3, Sungta, AioftheStorm, Ginsuloft, BruceBlaus, Keyboardthegreater, Monkbot, Shadowhunterxd and Anonymous: 180 • Acrosome reaction Source: http://en.wikipedia.org/wiki/Acrosome%20reaction?oldid=647204062 Contributors: Magnus Manske, Rich Farmbrough, Mike Schwartz, Arcadian, Irdepesca572, Ktaylor, Rjwilmsi, SmackBot, Rrburke, Novangelis, Thijs!bot, CommonsDelinker, Jojoflynmonky, Mikael Häggström, WJBscribe, VolkovBot, TXiKiBoT, Tameeria, Red Act, Anna Lincoln, Hadseys, Gits (Neo), JCKB, Josq, Jovianeye, Addbot, Diptanshu.D, Ala-mks, Jarble, Ettrig, Luckas-bot, Yobot, Rubinbot, Templatehater, Swithrow2546, Citation bot, Naj-GMU, Dkabban-GMU, LilHelpa, Imagine-GMU, Mnyakaba-GMU, Thehelpfulbot, Sahmejil, John of Reading, G.Dimmock, Tdsedits, Crrnorthwestern, Monkbot, Slashedone and Anonymous: 23 • Capacitation Source: http://en.wikipedia.org/wiki/Capacitation?oldid=540864386 Contributors: The Anome, Karada, Sam Hocevar, Arcadian, Unused000701, Abstraktn, JoaoRicardo, Ceyockey, GregorB, FlaBot, YurikBot, SmackBot, InvictaHOG, TedE, DMacks, Epingchris, HongQiGong, Cydebot, RalphS, Gamag, Troytsm98, AlleborgoBot, SieBot, Cwkmail, Ryancormack, Addbot, Jarble, Yobot, EmausBot, WikitanvirBot, ClueBot NG, Curb Chain, Theobp, Knowledgeforever2, Ranze and Anonymous: 19 • Human embryogenesis Source: http://en.wikipedia.org/wiki/Human%20embryogenesis?oldid=649434804 Contributors: AxelBoldt, Gracefool, Arcadian, Wouterstomp, Seans Potato Business, Woohookitty, Rjwilmsi, Kolbasz, Bgwhite, Wavelength, Hairy Dude, Mfero, Dhollm, JPMcGrath, SmackBot, Krychek, Lagringa, Zephyris, Andrew c, JHunterJ, Kudakups, Was a bee, Svna91, Casliber, James086, OckRaz, WhatamIdoing, NikNaks, CFCF, Zoara, Boghog, Mikael Häggström, MishaPan, Squids and Chips, Signalhead, TXiKiBoT, Lova Falk, Northfox, Doovie, Plynch22, Ascidian, Maxcip, Niceguyedc, WikHead, Tiphaine800, Addbot, Anxietycello, Yobot, AnomieBOT, Nishanthb, Z0OMD, Machn, Rayman60, Gongoozler123, Wafaashohdy, ClueBot NG, ManyueGPH, ChrisGualtieri, GoShow, Makecatbot, Zumwalte, Iztwoz, NJSfour, Monkbot, Abirnehal and Anonymous: 33 • Cleavage (embryo) Source: http://en.wikipedia.org/wiki/Cleavage%20(embryo)?oldid=649730783 Contributors: JWSchmidt, Arkuat, Arcadian, Arthena, RoySmith, Phi beta, Jackhynes, Polyparadigm, Joygerhardt, Rjwilmsi, Nihiltres, Flowerparty, YurikBot, Chris Capoccia, Snek01, Daniel Mietchen, 2over0, SmackBot, Zephyris, IlliniWikipedian, Shalom Yechiel, Drphilharmonic, Ligulembot, Shinryuu, Alexei Kouprianov, Neelix, Cydebot, Eubanks718, Odmrob, Lauranrg, CommonsDelinker, Boghog, Mikael Häggström, SuW, VolkovBot, Albval, Neparis, Bfpage, SieBot, Nursenjo, ClueBot, Excirial, Alexbot, SkyMaja, BOTarate, PotentialDanger, Koumz, Addbot, Metsavend, Tgm8, Favonian, Anxietycello, Yobot, KamikazeBot, AnomieBOT, Citation bot, Xqbot, Smallman12q, FrescoBot, C.orosco, ChuispastonBot, ClueBot NG, Mesoderm, Helpful Pixie Bot, X -robot- X, Mogism, Epicgenius, Zorahia, NJSfour and Anonymous: 48 • Polarity in embryogenesis Source: http://en.wikipedia.org/wiki/Polarity%20in%20embryogenesis?oldid=648705063 Contributors: Rich Farmbrough, Xezbeth, Daniel Mietchen, Sjdk13, Gilliam, Chris the speller, Epingchris, WahreJakob, CmdrObot, Benzenetoaster, Mr. Stradivarius, Gazdage, Glane23, Anxietycello, Yobot, LilHelpa, Xqbot, Erik9bot, BattyBot, Mannintg, Lauragaguilar and Anonymous: 6 • Morula Source: http://en.wikipedia.org/wiki/Morula?oldid=649732473 Contributors: Heron, Hephaestos, Lexor, Robbot, RoyBoy, Bobo192, Arcadian, SpeedyGonsales, Metju, Benbest, Eyu100, FlaBot, Margosbot, YurikBot, Mfero, Lepidoptera, Nolanus, Kubra, SmackBot, InvictaHOG, Jfurr1981, EncycloPetey, Audriusa, Ravi12346, Lottamiata, Robotsintrouble, Neelix, Peter morrell, Daniel, Escarbot, The prophet wizard of the crayon cake, W7347, JAnDbot, SilentWings, Ubiquita, CommonsDelinker, AlphaEta, Sollosonic, VolkovBot, Synthebot, Bfpage, Chhandama, Yerpo, ClueBot, Alexbot, Addbot, CarsracBot, SpBot, Anxietycello, Zorrobot, Fryed-peach, Luckas-bot, Yobot, AnomieBOT, Materialscientist, Maxis ftw, DynamoDegsy, Erud, GrouchoBot, Erik9bot, DrilBot, 3BBOOD, RjwilmsiBot, Amerias, ZéroBot, ClueBot NG, Frietjes, Mesoderm, Helpful Pixie Bot, Snow Blizzard, Iztwoz, Tilifa Ocaufa and Anonymous: 38 • Blastomere Source: http://en.wikipedia.org/wiki/Blastomere?oldid=608969592 Contributors: AxelBoldt, Lexor, Henrygb, Arcadian, Arthena, SemperBlotto, MarcoTolo, FlaBot, Roboto de Ajvol, EricCHill, Reedy, Jfurr1981, SashatoBot, Novangelis, Rosskey711, JAnDbot, A4bot, ClueBot, Vojtěch Dostál, Addbot, , Adeliine, Frietjes, Rbj2012, Mannintg, Vicktory7 and Anonymous: 16 • Yolk Source: http://en.wikipedia.org/wiki/Yolk?oldid=649081644 Contributors: Jedimike, Kils, Andres, Itai, Topbanana, RedWolf, Lupo, Barbara Shack, Zigger, Tsca, Ans, Pamri, Uranographer, Esperant, Thorwald, Mike Rosoft, Dr.frog, Rich Farmbrough, Bender235, Violetriga, Bobo192, Circeus, R. S. Shaw, Dungodung, Anthony Appleyard, LtNOWIS, Qwghlm, Arthena, Mysdaao, Fourthords, HenryLi, Woohookitty, Bluemoose, Cai, Mendaliv, Snafflekid, Rjwilmsi, XP1, Dvulture, MarnetteD, Harmil, Kerowyn, RexNL, Gurch, Igglevideo, McDogm, Taichi, Bgwhite, Roboto de Ajvol, YurikBot, Wavelength, Mushin, Hede2000, ScottMainwaring, CanadianCaesar, RadioFan, Stephenb, Gaius Cornelius, ENeville, Twin Bird, Peter Delmonte, Zwobot, DeadEyeArrow, Black Falcon, Sandstein, Colin, Vicarious, Curpsbot-unicodify, Kungfuadam, Rehevkor, AndrewWTaylor, Crystallina, SmackBot, Aim Here, McGeddon, Anastrophe, EncycloPetey, Gilliam, Skizzik, Rorybowman, Deli nk, Foogod, Memming, DMacks, Domentolen, DO11.10, Javit, 16@r, Ohyeahilovegirlz, BillFlis, PEiP, Boiert, Dodo bird, Hu12, Iridescent, Supertigerman, Lark ascending, Yaris678, Icek, AWilliamson., Gogo Dodo, JFreeman, Libro0, DumbBOT, Ameliorate!, Mojo Hand, NorwegianBlue, StephanieNYC, Mmortal03, Stephen Wilson, Stonemaccas, Tjmayerinsf, .alyn.post., JAnDbot, Ikanreed, MaxBrains, Philip.marshall, VoABot II, J.P.Lon, SwiftBot, Panser Born, Alash, Oroso, MartinBot, Anaxial, Rhinestone K, Hodja Nasreddin, DanielEng, Skier Dude, ABF, Kakoui, Philip Trueman, TXiKiBoT, Teddey, Mullyman, BotKung,
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Gibson Flying V, Insanity Incarnate, Twooars, SieBot, Work permit, Claudia23456, Cjw0808, Flyer22, Bob98133, Oxymoron83, SimonTrew, Missdlea, JohnnyMrNinja, Carl von Blixen, T.Neo, MorganaFiolett, Mild Bill Hiccup, Osm agha, Bob bobato, Pendant, Excirial, Yggdriedi, I Enjoy Commenting, 1ForTheMoney, XLinkBot, NellieBly, Addbot, DaughterofSun, Fluffernutter, LaaknorBot, Chzz, West.andrew.g, ArchibolCunningham, Legobot, Luckas-bot, Yobot, Williamdanes, Amirobot, Untrue Believer, AnomieBOT, Sanmania, Galoubet, Kingpin13, Csigabi, Materialscientist, Citation bot, E2eamon, NinetyNineFennelSeeds, ArthurBot, Xqbot, Capricorn42, Gigemag76, Guy Courtois, Anna Frodesiak, Gap9551, Badair, IcedNut, Finalius, Pinethicket, Minusia, RedBot, Yutsi, Σ, Ɱ, Paradiže, Kgrad, Archaic.avenger, Silenceisgod, Kommett, Skylarbblue, Lunaisbestbookevar, David Hedlund, Reaper Eternal, Suffusion of Yellow, Minimac, Caitlz, VegasEyes, EmausBot, WikitanvirBot, Rockin291, Super48paul, Nanabotman99999, Slightsmile, Tommy2010, Gzuufy, ZéroBot, Fæ, Taymonkey, Makecat, Wayne Slam, Erianna, Wikiloop, Orange Suede Sofa, ChuispastonBot, JonRichfield, ClueBot NG, Satellizer, Justlettersandnumbers, Akedia1, Egg Centric, O.Koslowski, TheFame123, Helpful Pixie Bot, OKFarmgirl, Lowercase sigmabot, AvocatoBot, Fylbecatulous, Preetham.raghu, Mrt3366, Sermadison, MadGuy7023, Dexbot, TwoTwoHello, 77tons of coal, Zorahia, Umairras, Redd Foxx 1991, Innisbrook, Umair6996, Mojojojo1234y, Heruilúvë, Atko1, ChamithN, Editor.mani, Hsin-Lin, Iapsd and Anonymous: 225 • Blastula Source: http://en.wikipedia.org/wiki/Blastula?oldid=649732763 Contributors: Bryan Derksen, Lexor, Angela, Bender235, Nectarflowed, Arcadian, Giraffedata, Jumbuck, Alansohn, Axl, Tycho, Metju, Drbreznjev, Woohookitty, Mindmatrix, Rjwilmsi, Uwe Gille, FlaBot, Margosbot, Dj Capricorn, YurikBot, Wavelength, Shawn81, Ugur Basak, Lepidoptera, Caroline Sanford, InvictaHOG, EncycloPetey, Audriusa, Dl2000, Lottamiata, Bobamnertiopsis, Woodshed, JForget, Thijs!bot, Beelaj., JAnDbot, Leuko, Struthious Bandersnatch, Adavidb, RTBoyce, Silkwilk5, Squids and Chips, TXiKiBoT, Bfpage, Stfg, ClueBot, Mild Bill Hiccup, Puchiko, Excirial, Vojtěch Dostál, Addbot, Ronhjones, Fryed-peach, Luckas-bot, Yobot, AnomieBOT, Xqbot, RibotBOT, Smallman12q, Saiarcot895, FoxBot, RjwilmsiBot, Bohemian89, RockMagnetist, ClueBot NG, Frietjes, Chingla, Mesoderm, Supadude54, Helpful Pixie Bot, Strike Eagle, BattyBot, JYBot, Makecat-bot, Mannintg, Bgumbardo, Dickhitch, Tadala.jumbe, Monkbot, Prakhar vashist, Musashi San17 and Anonymous: 62 • Blastocoele Source: http://en.wikipedia.org/wiki/Blastocoele?oldid=622587832 Contributors: Lexor, Merovingian, Onco p53, Arcadian, Seans Potato Business, FlaBot, Margosbot, Modify, Kubra, Jonathan.s.kt, SmackBot, BirdValiant, Cryptex, JLCA, Tawkerbot2, Dr. Blofeld, CommonsDelinker, NewEnglandYankee, VolkovBot, Vojtěch Dostál, Addbot, Tide rolls, Yobot, Gigemag76, ZéroBot, Frietjes, Gurt Posh, Makecat-bot, Mannintg and Anonymous: 20 • Germ layer Source: http://en.wikipedia.org/wiki/Germ%20layer?oldid=648588806 Contributors: Heron, Lexor, Jebba, Nikai, Zarius, RodC, Dave6, Curps, PDH, Fungus Guy, Nina Gerlach, Tinus, Bender235, CheekyMonkey, RoyBoy, Arcadian, Jag123, Alansohn, Wouterstomp, Tycho, Ceyockey, Woohookitty, Benbest, Shao, Dj Capricorn, Nephron, Zwobot, Wknight94, RupertMillard, KnowledgeOfSelf, Kipmaster, J.Steinbock, Bluebot, Tamfang, Radagast83, TheLimbicOne, Bansp, Clicketyclack, Werlop, Epingchris, Jon186, Lottamiata, Vsoulremix, Jamoche, A876, Thijs!bot, Kilva, GAThrawn22, AntiVandalBot, Alphachimpbot, JAnDbot, RuthieK, STBot, Wlodzimierz, CFCF, Ginsengbomb, Jotunn, JBarno, VolkovBot, LeilaniLad, TXiKiBoT, BotKung, AlleborgoBot, SieBot, Kochipoik, Anchor Link Bot, ClueBot, Eric Van Bogaert, Addbot, 2enable, Yobot, AnomieBOT, Lapabc, RibotBOT, FrescoBot, D'ohBot, Fama Clamosa, TjBot, JaysonSunshine, EmausBot, GoingBatty, Donner60, ClueBot NG, Harps21, Mesoderm, Newyorkadam, BG19bot, Biolprof, Kenneth.jh.han, Mannintg, Biologize, Iztwoz, Sonicnation, Comp.arch and Anonymous: 75 • Trophoblast Source: http://en.wikipedia.org/wiki/Trophoblast?oldid=640803087 Contributors: Glimz, Iosif, LastCaress, Violetriga, Brian0918, Arcadian, Seans Potato Business, SabineCretella, Tabletop, FlaBot, Jbarfield, NTBot, Wolfmankurd, Draeco, Grafen, Mccready, Nephron, FloNight, Stepa, Zephyris, Drphilharmonic, Lottamiata, Alfirin, Chasingsol, Thijs!bot, Boghog, Theespuja, Mikael Häggström, CardinalDan, Ronsword, Winchelsea, Xenobiologista, Bobjgalindo, Vojtěch Dostál, Addbot, Anxietycello, Yobot, Wlady 2009, AnomieBOT, Golgibody, Strawbaby, ZéroBot, Jackalackapot1, OrcLady, Wafaashohdy, ClueBot NG, Frietjes, Mesoderm, Iztwoz and Anonymous: 20 • Gastrulation Source: http://en.wikipedia.org/wiki/Gastrulation?oldid=647019712 Contributors: The Anome, Malcolm Farmer, Lexor, Angela, MichaK, Robbot, Dina, Robodoc.at, JeffreyN, Discospinster, Arcadian, SpeedyGonsales, MPerel, Snowolf, KingTT, Tycho, Metju, Alai, Ceyockey, Woohookitty, Hendrik Fuß, BD2412, Kissekatt, Rjwilmsi, Agrumer, FlaBot, Jrtayloriv, Banaticus, YurikBot, Wavelength, SLATE, GeeJo, Zwobot, BOT-Superzerocool, Drosboro, Mike Dillon, SmackBot, Saravask, Essent, Radagast83, TheLimbicOne, T-borg, James McNally, Clicketyclack, Mgiganteus1, Mike Doughney, Vanished user, Lottamiata, Zinzen, TheTito, Kupirijo, Eubanks718, Odmrob, GAThrawn22, Nipisiquit, JAnDbot, Rothorpe, Bissinger, R'n'B, Wlodzimierz, Mikael Häggström, Dexter prog, Nwbeeson, Squids and Chips, VolkovBot, Philip Trueman, Etruria, Earthdirt, Mwilso24, Ian Glenn, Happysailor, Flyer22, Hxhbot, The Thing That Should Not Be, Robomanx, Ndenison, Iandiver, Msgarrett, Excirial, Alexbot, Flatjosh, Alboyle, Frostus, Addbot, Tide rolls, Cesiumfrog, Fryed-peach, Yobot, Vini 17bot5, AnomieBOT, Kyng, TheChymera, FrescoBot, Sinekonata, RandomStringOfCharacters, FoxBot, Makki98, Agent Smith (The Matrix), John of Reading, MirekDve, GoingBatty, Hardrockcrossing, Palomitaviajera, White Trillium, Matthewrbowker, ClueBot NG, Mesoderm, Temperamental1, Widr, Helpful Pixie Bot, B2322858, Dean72, Trefeuil, CeraBot, Biolprof, Khazar2, Apynekeeper, Iztwoz, Haned6011, Depalmal, NJSfour, T1d7 and Anonymous: 76 • Ectoderm Source: http://en.wikipedia.org/wiki/Ectoderm?oldid=648273471 Contributors: Alex.tan, Ellywa, Docu, Altenmann, Fuelbottle, Thijs!, Woggly, Sayeth, Nina Gerlach, JemeL, Bender235, Smalljim, AllyUnion, Arcadian, Jag123, Wouterstomp, Wtmitchell, Tycho, Hsmith254, Julien Tuerlinckx, Ruziklan, BD2412, Margosbot, Shao, YurikBot, Nicke L, Chodges, Chazz88, J.Steinbock, Radagast83, TheLimbicOne, Clicketyclack, SashatoBot, Epingchris, Robotsintrouble, Hebrides, Thijs!bot, GAThrawn22, Bbman4ever, Smartse, Alphachimpbot, JAnDbot, Txomin, RebelRobot, Kelleyo2l, Nyq, Japo, The cattr, Rettetast, Verdatum, Boghog, Chiswick Chap, Squids and Chips, VolkovBot, AlnoktaBOT, Drgarden, PipepBot, Niceguyedc, Profipix, Wikalliz, Addbot, Kongr43gpen, Guffydrawers, Luckas-bot, Yobot, Lynntyler, JackieBot, Citation bot, Smallman12q, Erik9bot, FrescoBot, Pinethicket, Verrr55449988776655, FoxBot, RjwilmsiBot, EmausBot, WikitanvirBot, GoingBatty, Daonguyen95, Fæ, Ws04, Froggy980, ClueBot NG, Harps21, Qbobdole, Mesoderm, Hakeleh, Rytyho usa, BattyBot, Khazar2, Kenneth.jh.han, Tyler7810, Olefsky, Aadharm, Hegarty.michael.c, Monkbot and Anonymous: 41 • Mesoderm Source: http://en.wikipedia.org/wiki/Mesoderm?oldid=647843760 Contributors: Magnus Manske, Alex.tan, Lexor, Kimiko, Emperorbma, Fuelbottle, Diberri, Creidieki, T-Boy, HCA, CanisRufus, Arcadian, Jag123, Tycho, Georgia guy, Mandarax, Zxccxz, FlaBot, Shao, Bgwhite, YurikBot, NTBot, DRosenbach, Closedmouth, J.Steinbock, Khoikhoi, Radagast83, TheLimbicOne, Vina-iwbot, Clicketyclack, FrozenMan, Mgiganteus1, RelentlessRecusant, Thijs!bot, Peter morrell, GAThrawn22, Alphachimpbot, Gökhan, Txomin, Magioladitis, AlphaEta, Philcha, Numbo3, Nbauman, AlnoktaBOT, Broadbot, AlleborgoBot, SieBot, Loquetudigas, PixelBot, Dthomsen8, Addbot, Download, ماني, Luckas-bot, Yobot, Atgnclk, AnomieBOT, JackieBot, Citation bot, Xqbot, Macholl, Sviolante, Machn, DrilBot, Hamtechperson, Wdanbae, EmausBot, Werieth, ClueBot NG, Harps21, Mesoderm, Helpful Pixie Bot, Reza luke, Hakeleh, Smettems, Kenneth.jh.han, JakobSteenberg, N1424, DrLinguini, Depalmal, SachiPaulete, Alejandra Sotres, Arielrinon, Editor N and Anonymous: 49
60.13. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
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• Endoderm Source: http://en.wikipedia.org/wiki/Endoderm?oldid=646386016 Contributors: Alex.tan, Lexor, Docu, MichaK, Topbanana, Mike Rosoft, Nina Gerlach, Bobo192, Arcadian, HasharBot, Rjwilmsi, Ligulem, FlaBot, Shao, YurikBot, Postglock, Hede2000, Dysmorodrepanis, Zwobot, DRosenbach, KnightRider, SmackBot, J.Steinbock, Tsca.bot, TheLimbicOne, Clicketyclack, SashatoBot, Narayanese, Thijs!bot, Barticus88, GAThrawn22, Oreo Priest, KineticScientist, Exiledone, DrewBY, J.delanoy, Lionesschan, VolkovBot, TXiKiBoT, Una Smith, Drgarden, ClueBot, NuclearWarfare, Addbot, Luckas-bot, Yobot, Amirobot, Rubinbot, Xqbot, Smallman12q, TobeBot, EmausBot, AvicBot, Qbobdole, Frietjes, Mesoderm, Widr, Reza luke, Webclient101, Kenneth.jh.han, Daniilkaz, Richjoo, Monkbot and Anonymous: 35 • Implantation (human embryo) Source: http://en.wikipedia.org/wiki/Implantation%20(human%20embryo)?oldid=642446511 Contributors: Stevertigo, Ixfd64, Altenmann, Postdlf, GreatWhiteNortherner, Discospinster, Longhair, Arcadian, Anthony Appleyard, Alai, NCdave, Rjwilmsi, Eyu100, Gurch, Hariraja, RussBot, Chris Capoccia, IanManka, BOT-Superzerocool, Lyrl, SmackBot, Eveningmist, Gilliam, Bluebot, Aartie, Clicketyclack, Filippowiki, LethargicParasite, JForget, Alaibot, Wisebridge, Daniel, Marek69, Mack2, Kauczuk, JamesBWatson, EagleFan, Gandydancer, Anaxial, Boghog, Mikael Häggström, Idioma-bot, VolkovBot, Melsaran, Doc James, Yintan, Coolstoryhansel, Fyyer, Michał Sobkowski, Cfsenel, Leonard^Bloom, Queerbubbles, Zodon, Addbot, Jarble, Luckas-bot, AnomieBOT, Quebec99, Slotfi, Pinethicket, RedBot, Kapusman, Sxoa, Nimravid, Balupraveen123, ClueBot NG, Mesoderm, MsBatfish, Michele Chung, Saralee13, Megan983, Ttrue12, Zumwalte, Samdowland, Vicktory7, JaconaFrere, Monkbot, Jmorganmay and Anonymous: 66 • Birth Source: http://en.wikipedia.org/wiki/Birth?oldid=649079319 Contributors: The Anome, Tarquin, Montrealais, Stevertigo, Michael Hardy, Booyabazooka, Sannse, NuclearWinner, Ahoerstemeier, Mac, Rossami, Evercat, Samw, Jay, Andrewman327, Secretlondon, Owen, SD6-Agent, Ashley Y, Academic Challenger, Seth Ilys, BovineBeast, Alan Liefting, DocWatson42, Fennec, Barbara Shack, Geeoharee, Ding, Knutux, Beland, ShakataGaNai, Gscshoyru, Ta bu shi da yu, DanP, *drew, Lima, Bobo192, Wisdom89, Cardbottleenvelope, Thewayforward, Rje, Ranveig, Alansohn, Pinar, Monado, RainbowOfLight, BDD, 2004-12-29T22:45Z, Commander Keane, Essjay, Graham87, Magister Mathematicae, BD2412, Rjwilmsi, Nandesuka, Yamamoto Ichiro, Jameshfisher, Ewlyahoocom, Maustrauser, Chobot, Gdrbot, The Rambling Man, Wavelength, Tznkai, RussBot, Severa, Hede2000, Bcatt, NawlinWiki, Shawn fard, Yoninah, Mad Max, Bota47, Zzuuzz, ArielGold, Lyrl, Tom Morris, SmackBot, KnowledgeOfSelf, Speight, Fretwurst, Delldot, Müslimix, Gilliam, Chaojoker, Bidgee, Persian Poet Gal, Warbirdadmiral, Can't sleep, clown will eat me, Snowmanradio, OOODDD, Addshore, COMPFUNK2, Flyguy649, Quixada, Pilotguy, Kukini, SashatoBot, Xdamr, Harryboyles, NoLightofMyOwn, Soumyasch, Coredesat, SpyMagician, Ckatz, 16@r, MarkSutton, Robert Bond, Waggers, Nsusa, Ryulong, NinjaCharlie, Ginkgo100, Iridescent, Madaise, LadyofShalott, Courcelles, Dlohcierekim, Argon233, ShelfSkewed, Moreschi, Montanabw, HalJor, Cydebot, Gogo Dodo, Dougweller, Medicobaby, Casliber, Thijs!bot, Sagaciousuk, AgentPeppermint, Philippe, Escarbot, The Obento Musubi, Wayiran, Husond, Plantsurfer, Awien, Hut 8.5, Beaumont, LittleOldMe, Geniac, SOK, Bongwarrior, JamesBWatson, Chacha8, Faustnh, Allstarecho, DerHexer, Nevit, WLU, Drm310, Hdt83, MartinBot, Diciassettedimaggio, R'n'B, Joie de Vivre, RockMFR, CFCF, Nigholith, Mike.lifeguard, Crickeys, LEHarth, Qupqugiak, Cobi, Joost 99, Fwgoebel, Olegwiki, KellyPhD, Sly-eye, VolkovBot, Thedjatclubrock, AlnoktaBOT, Philip Trueman, Alicelight, Rrmadore, Ychastnik APL, Una Smith, Seraphim, Broadbot, Jackfork, Cuddlyable3, JennyMHatch, Madhero88, Billinghurst, Superjustinbros., Gillyweed, Synthebot, Tythepi, Juliepatt, Symane, IndulgentReader, Iloverickey, Iamaloser12, Cheezeman, Mungo Kitsch, Lucasbfrbot, Flyer22, Antonio Lopez, Tombomp, Taggard, Fratrep, HAL(Old), BillShurts, Akaohio, Artisol2345, Celique, SlackerMom, ClueBot, Pax6, Drmies, Piledhigheranddeeper, Jusdafax, Hammerdickulous, Nyttend backup, Thingg, 7, Tim Berkey, SoxBot III, XLinkBot, BodhisattvaBot, IngerAlHaosului, ZooFari, Surtsicna, HexaChord, Mojska, Addbot, ConCompS, Willking1979, Captain-tucker, Pattych, Bumdarts, Valkrie1496, Frally123, Heeheehahahohoho, Tassedethe, Tide rolls, Jarble, Quantumobserver, VP-bot, Luckas-bot, Yobot, Ptbotgourou, Fraggle81, IW.HG, AnomieBOT, Roxie09, Yachtsman1, Materialscientist, Citation bot, Xqbot, Animonster, DSisyphBot, Jambornik, Jkhbgcdijkhbnomkj, C+C, GrouchoBot, Geopersona, Multixfer, Shadowjams, Aaron Kauppi, Masrudin, Ohjung5000, LucienBOT, Mickihirsch, Djhills, RoyGoldsmith, Mateuse71, Thegonugget, DrilBot, Denkealsobin, V.narsikar, Max Duchess, Lotje, Callanecc, Vancouver Outlaw, Aldio Yudha Trisandy, Tbhotch, Ace Oliveira, EmausBot, John of Reading, Rajkiandris, Wikipelli, Solomonfromfinland, ZéroBot, Donniebravo, L Kensington, Subrata Roy, ChuispastonBot, DASHBotAV, Pizzatime, Sandy sakura, ClueBot NG, Cwmhiraeth, Blackshadow1998, Marechal Ney, Nadinemaina, North Atlanticist Usonian, Arnavchaudhary, Pablodiego15, Iamthecheese44, FieryTurdGymnast, ChrisGualtieri, Zanizaila, Zelenyj, Lugia2453, Xkonor, Thinkinbtu, AslanEntropy, Monkbot, 16yearoldb!tch, Cristainblawblaw, Me and the monkey, Zykeiyah, Horothewisewolf and Anonymous: 220 • Mammary gland Source: http://en.wikipedia.org/wiki/Mammary%20gland?oldid=644175284 Contributors: AxelBoldt, The Anome, Alex.tan, Rickyrab, Cointyro, Steverapaport, Karada, Timc, Itai, Robbot, Henrygb, Clngre, Diberri, Dina, Zigger, Oneiros, Rich Farmbrough, Clawed, Bender235, Arcadian, Jumbuck, Keenan Pepper, Carbon Caryatid, Dan100, Jackhynes, Star Trek Man, Woohookitty, Daniel Case, MONGO, Tabletop, Eras-mus, SDC, Graham87, Rjwilmsi, Flarn2006, Latka, Kerowyn, CiaPan, YurikBot, Chanlyn, RussBot, Chaser, Hydrargyrum, NawlinWiki, ENeville, Brian Crawford, Antoshi, Gadget850, Emijrp, Jwissick, Arthur Rubin, Paul Erik, Search255, SmackBot, Takagi, Jfurr1981, Rune X2, Septegram, Gilliam, Darth Panda, CTho, BullRangifer, Illnab1024, Rockpocket, Nishkid64, Rory096, Joelmills, EdC, LeyteWolfer, Matt26, Celllist, Van helsing, Dynzmoar, Neelix, Gogo Dodo, Anthonyhcole, Julian Mendez, Christian75, Westvoja, Louis Waweru, Luigifan, The Wednesday Island, Scottandrewhutchins, Mentifisto, Caulfieldholden, TimVickers, Richiez, Roleplayer, VoABot II, Lmbhull, Steven Walling, Cgingold, Torchiest, Adrian J. Hunter, Chris G, WLU, Scottalter, CommonsDelinker, CFCF, Sp3000, Ginsengbomb, JackAidley, HiEv, WinterSpw, My Core Competency is Competency, VolkovBot, CWii, I liek breasts, DoorsAjar, Batsnumbereleven, Nhsnoboarder17, Raymondwinn, Synthebot, Why Not A Duck, Toyalla, MrCheeseBasket, SieBot, ConfuciusOrnis, Keilana, Flyer22, Ursasapien, Techman224, Ealdgyth, Fratrep, Millw001, ClueBot, SummerWithMorons, The Thing That Should Not Be, Osm agha, Tinman11, SchreiberBike, Brow276, DumZiBoT, Dthomsen8, SilvonenBot, Chrisn0113, Addbot, Ackerman22, DOI bot, SpillingBot, AndersBot, Favonian, Orlandoturner, CarTick, Jarble, Kartano, Grakk, Amirobot, Mmxx, QueenCake, Rubinbot, Ulric1313, Flewis, Materialscientist, ArthurBot, Carturo222, Andrewmc123, TinucherianBot II, Erud, Khajidha, RibotBOT, WerewolfHunter65, Craig Pemberton, Citation bot 1, Pecolee, Naturehead, Gvw686, Jlcarter2, Beth 84, Notonegoro, Salvio giuliano, EmausBot, NotAnonymous0, HiMyNameIsDick, Trinanjon, ClamDip, ClueBot NG, Ccevo2010, 10k, Helpful Pixie Bot, Soerfm, Hamish59, Brest39, Prof. Squirrel, JYBot, Steinsplitter, Lucy346, RNLockwood, SophiePon, Hans.vmobile, AlrightEdits, LT910001, Axeman225, Monkbot, Thesuperpotato2000, Littleasskicker, Kath29 RD, Hassan ejaz khan and Anonymous: 143 • Menstrual cycle Source: http://en.wikipedia.org/wiki/Menstrual%20cycle?oldid=648626635 Contributors: AxelBoldt, Mav, The Anome, Tarquin, Alex.tan, XJaM, Anthere, Montrealais, Someone else, Ubiquity, Dcljr, Sannse, Wintran, Ihcoyc, Ronz, Theresa knott, Snoyes, JWSchmidt, Aarchiba, Julesd, Glenn, Kimiko, Kaihsu, Sethmahoney, Like a Virgin, EdH, Rob Hooft, Charles Matthews, Timwi, Dcoetzee, Viajero, Dysprosia, Teresag, Jay, Pedant17, Furrykef, Grendelkhan, Joy, Fvw, Raul654, Gakrivas, Flockmeal, David.Monniaux, Pollinator, Aron1, Rogper, Robbot, Ke4roh, Chris 73, Pingveno, YBeayf, SchmuckyTheCat, Jfire, Davodd, Lpetrazickis, David Gerard, Marc Venot, Ancheta Wis, Fabiform, Matt Gies, Andries, Barbara Shack, Mintleaf, Nunh-huh, Lupin, Robodoc.at, No Guru, Capitalistroadster, Rick Block, Sukh, Jfdwolff, Guanaco, Sundar, Chameleon, PlatinumX, Pne, RayTomes, Decoy, Chowbok, Jizz, Omiah, Gordon Axmann, Lcb, Zhuuu, Antandrus, Alteripse, Quarl, Kaldari, PDH, Noirum, Rdsmith4, Sam Hocevar, Joyous!, JavaTenor, Deeceevoice, Cyprus2k1,
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CHAPTER 60. REPRODUCTIVE HEALTH
Hadj, OntarioQuizzer, ChrisRuvolo, Heegoop, Venu62, Jrp, Discospinster, Rich Farmbrough, Vsmith, Smyth, Narsil, Cdyson37, Mani1, Paul August, ESkog, Wild Bill, Dpotter, MisterSheik, Livajo, NTiOzymandias, Miraceti, Cg41386, Susvolans, Sietse Snel, Triona, Wee Jimmy, Bobo192, Chenggn, Smalljim, Spoom, Davidruben, Cmdrjameson, GentooBox, Cardbottleenvelope, Cohesion, Dungodung, Maurreen, Arcadian, Matrona, Pschemp, Sam Korn, (aeropagitica), Haham hanuka, SPUI, Officiallyover, Licon, Conny, AnnaP, Avkrules, Carbon Caryatid, Wouterstomp, Riana, Viridian, YDZ, Bart133, Snowolf, Mbimmler, Melaen, Revbean, Stevegray, Sciurinæ, Red dwarf, Ron Ritzman, Lkinkade, MickWest, Simetrical, Rorschach, OwenX, Woohookitty, TigerShark, Justinlebar, Camw, Swamp Ig, PatGallacher, Oliphaunt, Jacobolus, Ekem, Canaen, JBellis, Ruud Koot, Al E., Terence, Shlomo K, Wayward, Btyner, Ashmoo, Graham87, JiMidnite, Sparkit, Kbdank71, DJ Silverfish, FreplySpang, Ryan Norton, Rjwilmsi, Chirags, Vary, Loudenvier, MarSch, Carbonite, Tangotango, Arisa, Mirmillon, Oblivious, Kazrak, Ligulem, CQJ, Reactor, Bubba73, Brighterorange, Yamamoto Ichiro, RobertG, Weihao.chiu, Latka, NeoChrono Ryu, Nihiltres, Corcov, Harmil, Gurch, Stevenfruitsmaak, Tedder, Emiao, Butros, King of Hearts, Ahpook, Gwernol, Hariraja, Wavelength, Chanlyn, Angus Lepper, Petiatil, Icarus3, Chris Capoccia, Epolk, Wikispork, CambridgeBayWeather, Wimt, Frybread, Royalbroil, NawlinWiki, Ethan, ImGz, Ino5hiro, D. Wu, Dementedd, RUL3R, Chrishota, Amakuha, Alex43223, Supten, Dbfirs, Samir, CDA, Asarelah, Kewp, MacMog, Elkman, Nicanor5, Galar71, Warfreak, Theda, Closedmouth, Pb30, Sean Whitton, BorgQueen, GraemeL, PaulJones, Whobot, JLaTondre, GinaDana, Skittle, Staxringold, RG2, NatsukiGirl, Lyrl, NeilN, Miniyazz, BiH, DVD R W, Blastwizard, Magn0lia, Ticamagalhaes, SmackBot, ThreeDee912, InverseHypercube, McGeddon, David.Mestel, PJM, Gilliam, Donama, Ohnoitsjamie, SteveO, Xjessxcore, Agateller, RDBrown, Ctrlfreak13, Tito4000, Oli Filth, Anchoress, Jax184, Redd Dragon, Mgifford, Roy Al Blue, Darth Panda, Mihai preda, Brideshead, Zsinj, Can't sleep, clown will eat me, Danielkueh, Ismail ngr, Sephiroth BCR, Talmage, Caue.cm.rego, OSborn, JDiPierro, ASwann, Fvox13, Artemisboy, Kinotgell, Stevenmitchell, Dohzer, Faithl17, Krich, Zrulli, Richard001, DMacks, Dacxjo, Petr Tomasovsky, Daniel.Cardenas, Ligulembot, Ceoil, Lambiam, Chrisk8800, Kuru, John, Epingchris, Daniel90, Mr. Lefty, IronGargoyle, AbuAmir, Ckatz, Andypandy.UK, Optimale, SandyGeorgia, Mets501, Interlingua, Funnybunny, Whomp, Rip-Saw, Big Smooth, Keitei, Fionah, Fredil Yupigo, WikiHaquinator, Lord Anubis, Fmitchell2, Valnelson, IvanLanin, Jaksmata, Fsotrain09, Wwallacee, Marysunshine, Ecco1983, CharlesM, Tawkerbot2, Liwymi, Ghaly, ChrisCork, Annie*, CalebNoble, Gdang, Alexander Iwaschkin, JForget, DangerousPanda, Geex, Aitsukai, Efkeathley, Vedanti, Makeemlighter, Mcstrother, GHe, Jokes Free4Me, Johner, Seejyb, Cydebot, Abeg92, Chhajjusandeep, Nam4anad, Mato, Gogo Dodo, Travelbird, Anthonyhcole, RobKeetlaer, Tawkerbot4, HK51, Christian75, Telex, Gnobal, Zer0faults, Brad101, Omicronpersei8, JodyB, Casliber, EvocativeIntrigue, Epbr123, Wikid77, Npatchett, Dasani, N5iln, Headbomb, Marek69, Tokataro, Haidentity, Escarbot, Persianhottie234, I already forgot, Mentifisto, Rakinva, Emeraldcityserendipity, Mariusvr, Lady Voldything, BINNO, Mack2, Spencer, Ramanoyo, Tapdancer2000, Richiez, Joehall45, Sluzzelin, JAnDbot, Husond, Eotc, Kaobear, Avaya1, Janejellyroll, Ikanreed, SiobhanHansa, Acroterion, VoABot II, QuizzicalBee, Sarahj2107, Tweety102193, Cadsuane Melaidhrin, Martinklopstock, WhatamIdoing, Indon, NoychoH, Chris G, DerHexer, JaGa, Esanchez7587, Jolenine, Lu33, DancingPenguin, MartinBot, Gandydancer, Speck-Made, TheEgyptian, Joie de Vivre, CommonsDelinker, Verdatum, Creol, Paranomia, J.delanoy, Lord balron, DrKiernan, CFCF, Boghog, Kex1, Cheabean, Shobhit102, Skinny McGee, McSly, Naniwako, Mikael Häggström, Hunstiger, NewEnglandYankee, Sunderland06, Juliancolton, Aiingel, Treisijs, Bonadea, Skeetypeety, Specter01010, Satheeshr, CardinalDan, Spellcast, VolkovBot, CWii, Jeff G., Soliloquial, Philip Trueman, Greatwalk, TXiKiBoT, EricSerge, Jssimpson, Tameeria, Captain Courageous, Anna Lincoln, Corvus cornix, Cheddy7, Modernvoid, Dlae, Cremepuff222, Grafic, Madhero88, Kurowoofwoof111, Aquaterra, Laurau, Falcon8765, HippieChick1776, Doc James, Logan, Ogarbuk, Gcarotsans, OsamaK, Hotmoma134, SieBot, Mikemoral, PanagosTheOther, Caltas, Yintan, Andrewjlockley, CoralieK, Keilana, Flyer22, Oxymoron83, Nuttycoconut, Steven Zhang, Lightmouse, JackSchmidt, Correogsk, Cyfal, Pinkadelica, Hordaland, Struway2, DRTllbrg, Denisarona, Escape Orbit, Into The Fray, Explicit, Eoajadi, Invertzoo, ClueBot, Mariasree, ICAPTCHA, Abee60, Jriessman, Snigbrook, TransporterMan, Astrarouge, The Thing That Should Not Be, All Hallow’s Wraith, Leviel, Drmies, Tizzle999, Jozsefs, Nymf, Mihaiam, Abluescarab, Vivio Testarossa, Smundy, Rab0503, Bxlatinaflirt, Jgreen19, PowerSam, Aitias, 7, Ozzyhendrix, Sotuman, DumZiBoT, Karppinen, PuppyAddict, XLinkBot, Tarheel95, Rror, Vanished 45kd09la13, Skarebo, Zodon, Robotpandazombie, Torchflame, Major dudette, ElFisico, HexaChord, Hywelford, Alpengruebler, Addbot, Cxz111, Grayfell, AVand, TheTwoRoads, DOI bot, Guoguo12, Fyrael, Thecocksak, Ronhjones, TutterMouse, Metsavend, Whistling42, Glane23, Bassbonerocks, Stringcheese13, Arabella x, LinkFA-Bot, Katharine908, Tide rolls, Iune, Teles, Gail, Slgcat, Jackelfive, Ben Ben, Legobot, Drpickem, Luckas-bot, Pesky911, Yobot, Mrsblain98, Dede2008, GateKeeper, RomanLady, Againme, AnomieBOT, Lemonsandgrapes, Jim1138, AdjustShift, RandomAct, Giants27, Materialscientist, Danno uk, Citation bot, Souch, LilHelpa, JimVC3, Mlpearc, Beg4mpg1, Inferno, Lord of Penguins, Horseduke, Tulrun, Metafax1, GrouchoBot, PatternSpider, Littlewing98, Jordiebebo, Dionisis1979, Illioplius, The Interior, Supercatz78, Amaury, Joxemai, Metalindustrien, Griffinofwales, Leontaurus, Jilkmarine, FrescoBot, Altg20April2nd, Vierko, Recognizance, Santonellis, Squire of the Infernal Knight-Lord of Penguins, Haeinous, Craig Pemberton, Citation bot 1, Aldy, Xxglennxx, Szucp, Pinethicket, Elockid, LinDrug, Naturehead, A8UDI, Wikitanvir, SpaceFlight89, Jujutacular, Tea with toast, Kathleenks, Reconsider the static, VMHman, ASVIN91, Ranmore, Vrenator, Myclam, JessieTech, Lt. Poop, Atozinco, Jcbmz, Minimac, DARTH SIDIOUS 2, Kjwalsh2, Pooppooppooppoop123123123123, Mean as custard, RjwilmsiBot, FlowersAndFilth, Becritical, Jlbvrs, DASHBot, Acttaccat, Esoglou, EmausBot, Orphan Wiki, Candicell, Tamara.tozija, Da500063, Boonshofter, RenamedUser01302013, Slightsmile, Tommy2010, ThoAppelsin, Wikipelli, Frostdaddy, Shearonink, Savh, Fæ, Yangjen16, Methadone1763, H3llBot, Yduocizm, Catalogist, GeorgeBarnick, Theonefoster, IGeMiNix, L Kensington, Shebeee, DASHBotAV, Davey2010, Faria geraldo, Gwen-chan, ClueBot NG, Jjp08146, This lousy T-shirt, FurukimiStationer, Mesoderm, O.Koslowski, Widr, WikiPuppies, North Atlanticist Usonian, Helpful Pixie Bot, Chkitoutkc, Hbomb0732, Dandygurl098, Ilikedupyourgran, 69rofll, Tomboz, Heading indexing, BG19bot, Missusa101, OttawaAC, Rorobear6, MrBill3, Weoluvgracie12, Wjdittmar, Geekchick77, Glacialfox, Dr Jacobo, Klilidiplomus, Rutebega, Biosthmors, Cult Handsome Seriously Silly, Lightning Island, Amameehuntasher, ChrisGualtieri, GoShow, Kenunderscore, Professor Havok, EagerToddler39, Dexbot, Jerusalempoo, Smittywerbenjagermanjensen, Webclient101, Suryoday38, Skiddadles, Lugia2453, Treeyoyo, ICTResearch301, RandomLittleHelper, I am One of Many, Jodosma, Tentinator, DavidLeighEllis, Lauren22222, Ugog Nizdast, Seppi333, Binko100, Ginsuloft, Sirpickleman, Depthdiver, Anrnusna, Haydencasali, Monkbot, Audreyvhall, Vuagunny2608, Bdt801, KekDoge, Vanished user 9j34rnfjemnrjnasj4, Cooldudepronoy, Nyes117, Joe1010101234, KatBerg52, Kittengender, StewdioMACK, Dinfedetissekone, Sikandermir, Neenaw581, Krking01 and Anonymous: 1109 • Reproductive health Source: http://en.wikipedia.org/wiki/Reproductive%20health?oldid=641377311 Contributors: SimonP, Angela, Robbot, Timrollpickering, Andycjp, Kaldari, Rfl, Bender235, JoeSmack, Neko-chan, Arcadian, Cavrdg, Versageek, Ceyockey, RyanGerbil10, Ekem, Rjwilmsi, Wavelength, Pigman, IanManka, Closedmouth, Sardanaphalus, SmackBot, Moeron, Ohnoitsjamie, David Ludwig, Roscelese, Nixeagle, COMPFUNK2, Beetstra, SQGibbon, CmdrObot, Lamiot, Argon233, Gogo Dodo, Khatru2, Thijs!bot, Headbomb, Dawnseeker2000, Fayenatic london, Mack2, Kauczuk, Kaobear, Globalhealth, VoABot II, Hullaballoo Wolfowitz, Cgingold, Simonxag, Yobol, R'n'B, Phyesalis, Mikael Häggström, Tkn20, Idioma-bot, Funandtrvl, Daimore, Station1, Stephen Goldstein, Jennifer2007, JJHeart, CBallard17, K. Annoyomous, Flyer22, Correogsk, Dgodot, Dmannsanco, Luvndance23, Ddickso1, Tomas e, SchreiberBike, Badmintonhist, Redblueball, XLinkBot, Trabelsiismail, Mitch Ames, IvanShim, Zodon, Kbdankbot, Addbot, Ave Caesar, Download, Jonspangler1, UKwebwonders, HFEA, Jarble, Luckas-bot, Fraggle81, Plasticbot, Jim1138, Suloshini, Gallowolf, LilHelpa, Vaneditor12345, Fijnlijn, A.amitkumar, FrescoBot, Nadaga, Pinethicket, Mathiaseu, JerseyGirlMedia, Guyforsports, NortyNort, Noergler, LilyKitty, Tbhotch,
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AXRL, RjwilmsiBot, Josh0122, EmausBot, John of Reading, WikitanvirBot, Xzenu, H3llBot, Samkange, DASHBotAV, Gingerwombat, ClueBot NG, Gareth Griffith-Jones, Souzaj, Everynameused, Satellizer, Guptan99, Jorgenev, Row03boat, Milmar89, Johnsa123, Drmadeye, Ongepotchket, Loriendrew, Eric1300, Ytic nam, Bethmills, SFK2, Mikivi, Laxmi Rose, Nsaunders, I am One of Many, Jianhui67, Monkbot, Prof. P. Arumugam and Anonymous: 83
60.13.2
Images
• File:1810_Major_Pituitary_Hormones.jpg Source: http://upload.wikimedia.org/wikipedia/commons/4/4a/1810_Major_Pituitary_ Hormones.jpg License: CC BY 3.0 Contributors: Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/, Jun 19, 2013. Original artist: OpenStax College • File:2037_Embryonic_Development_of_Heart.jpg Source: http://upload.wikimedia.org/wikipedia/commons/7/74/2037_Embryonic_ Development_of_Heart.jpg License: CC BY 3.0 Contributors: Anatomy & Physiology, Connexions Web site. http://cnx.org/content/ col11496/1.6/, Jun 19, 2013. Original artist: OpenStax College • File:2910_The_Placenta-02.jpg Source: http://upload.wikimedia.org/wikipedia/commons/2/2d/2910_The_Placenta-02.jpg License: CC BY 3.0 Contributors: Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/, Jun 19, 2013. Original artist: OpenStax College • File:4.B._Ovogonias._Quiescentes_en_G0-G1_(flechas).png Source: http://upload.wikimedia.org/wikipedia/commons/8/82/4.B. _Ovogonias._Quiescentes_en_G0-G1_%28flechas%29.png License: CC BY 3.0 Contributors: doi:10.1371/journal.pone.0025641.g004 Original artist: Chassot A-A, Gregoire EP, Lavery R, Taketo MM, de Rooij DG, et al. • File:AIDS_and_HIV_prevalence.svg Source: http://upload.wikimedia.org/wikipedia/commons/e/ee/AIDS_and_HIV_prevalence.svg License: Public domain Contributors: UNAIDS, Image:HIV Epidem.png, Image:BlankMap-World6.svg Original artist: Escondites Permission= PD-self • File:Acrosome_reaction_diagram_en.svg Source: http://upload.wikimedia.org/wikipedia/commons/8/83/Acrosome_reaction_ diagram_en.svg License: Public domain Contributors: I made this diagram myself using the diagrams on: [1] , [2],and [3]. I used Adobe Illustrator to do it, and I am freeing it into public domain. LadyofHats. Original artist: LadyofHats. • File:Ambox_important.svg Source: http://upload.wikimedia.org/wikipedia/commons/b/b4/Ambox_important.svg License: Public domain Contributors: Own work, based off of Image:Ambox scales.svg Original artist: Dsmurat (talk · contribs) • File:Anatomy_of_an_egg_unlabeled_horizontal.svg Source: http://upload.wikimedia.org/wikipedia/commons/b/b3/Anatomy_of_an_ egg_unlabeled_horizontal.svg License: CC-BY-SA-3.0 Contributors: graphic created by de:Benutzer:Horst Frank, SVG version by cs:User: -xfi- Original artist: de:Benutzer:Horst Frank, SVG code cs:User:-xfi-, rotation and text removal by User:Kjoonlee • File:Aphid-giving-birth.jpg Source: http://upload.wikimedia.org/wikipedia/commons/1/11/Aphid-giving-birth.jpg License: CC-BYSA-3.0 Contributors: English Wikipedia. The original description page is/was here Original artist: MedievalRich • File:Blastocyst_English.svg Source: http://upload.wikimedia.org/wikipedia/commons/7/72/Blastocyst_English.svg License: CC-BYSA-3.0 Contributors: Blastocyst.png Original artist: Seans Potato Business (derivative of the source cited above) • File:Blastula.png Source: http://upload.wikimedia.org/wikipedia/commons/d/d9/Blastula.png License: Public domain Contributors: Own work Original artist: Abigail Pyne • File:Blastula_(PSF).jpg Source: http://upload.wikimedia.org/wikipedia/commons/1/1e/Blastula_%28PSF%29.jpg License: Public domain Contributors: Pearson Scott Foresman, donated to the Wikimedia Foundation Original artist: Pearson Scott Foresman • File:Blausen_0400_FemaleReproSystem_02.png Source: http://upload.wikimedia.org/wikipedia/commons/8/8e/Blausen_0400_ FemaleReproSystem_02.png License: CC BY 3.0 Contributors: Own work Original artist: BruceBlaus. When using this image in external sources it can be cited as: • File:Blausen_0404_Fertilization.png Source: http://upload.wikimedia.org/wikipedia/commons/7/79/Blausen_0404_Fertilization.png License: CC BY 3.0 Contributors: Own work Original artist: BruceBlaus. When using this image in external sources it can be cited as: • File:Brown_chicken_egg.jpg Source: http://upload.wikimedia.org/wikipedia/commons/8/81/Brown_chicken_egg.jpg License: Public domain Contributors: Own work Original artist: Garitzko • File:Bulbourethral_gland_--_very_high_mag.jpg Source: http://upload.wikimedia.org/wikipedia/commons/a/ab/Bulbourethral_ gland_--_very_high_mag.jpg License: CC BY-SA 3.0 Contributors: Own work Original artist: Nephron • File:Cephalicpre.JPG Source: http://upload.wikimedia.org/wikipedia/commons/0/03/Cephalicpre.JPG License: Public domain Contributors: Plate 14, from A Set of Anatomical Tables with Explanations. archive.org Original artist: William Smellie • File:Child_development_stages.svg Source: http://upload.wikimedia.org/wikipedia/commons/9/9e/Child_development_stages.svg License: Public domain Contributors: Own work Original artist: Mikael Häggström • File:Chlamydomonas_TEM_17.jpg Source: http://upload.wikimedia.org/wikipedia/commons/d/de/Chlamydomonas_TEM_17.jpg License: Public domain Contributors: Source and public domain notice at http://remf.dartmouth.edu/imagesindex.html Original artist: Dartmouth Electron Microscope Facility, Dartmouth College • File:Circumcised_penis_labelled.jpg Source: http://upload.wikimedia.org/wikipedia/commons/a/a6/Circumcised_penis_labelled.jpg License: CC BY-SA 3.0 Contributors: • Penis_Stitch_Scar.jpg Original artist: Penis_Stitch_Scar.jpg: Adam • File:Commons-logo.svg Source: http://upload.wikimedia.org/wikipedia/en/4/4a/Commons-logo.svg License: ? Contributors: ? Original artist: ? • File:Complete_diagram_of_a_human_spermatozoa_en.svg Source: http://upload.wikimedia.org/wikipedia/commons/9/9f/ Complete_diagram_of_a_human_spermatozoa_en.svg License: Public domain Contributors: I did the diagram myself based on the one found on the book “Gray’s anatomy” 36th edition, Williams & Warwick, 1980; and a diagram found of the review “Formation and organization of the mammalian sperm head” from Kiyotaka Toshimori and Chizuro Ito. (Chiba, Japan). Original artist: Mariana Ruiz Villarreal
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• File:Corpora_amylacea_intermed_mag.jpg Source: http://upload.wikimedia.org/wikipedia/commons/e/ee/Corpora_amylacea_ intermed_mag.jpg License: CC BY-SA 3.0 Contributors: Own work Original artist: Nephron • File:Cow_and_calf_K9486-1.jpg Source: http://upload.wikimedia.org/wikipedia/commons/2/2d/Cow_and_calf_K9486-1.jpg License: Public domain Contributors: This image was released by the Agricultural Research Service, the research agency of the United States Department of Agriculture, with the ID k9486-1 <a class='external text' href='//commons.wikimedia.org/w/index.php?title=Category: Media_created_by_the_United_States_Agricultural_Research_Service_with_known_IDs,<span>,&,</span>,filefrom=k9486-1#mwcategory-media'>(next)</a>. Original artist: Scott Bauer • File:Cscr-featured.svg Source: http://upload.wikimedia.org/wikipedia/en/e/e7/Cscr-featured.svg License: ? Contributors: ? Original artist: ? • File:DEV035048A.jpg Source: http://upload.wikimedia.org/wikipedia/commons/8/86/DEV035048A.jpg License: CC BY 1.0 Contributors: Laboratory of Prof. Ralf Reski Original artist: Laboratory of Prof. Ralf Reski • File:Development_of_Male_External_Genitalia.png Source: http://upload.wikimedia.org/wikipedia/commons/5/58/Development_ of_Male_External_Genitalia.png License: Public domain Contributors: • Gray1119.png Original artist: Gray1119.png: Gray’s Anatomy • File:Development_of_the_neural_tube.png Source: http://upload.wikimedia.org/wikipedia/commons/4/4c/Development_of_the_ neural_tube.png License: Public domain Contributors: Figure 6 (p. 24) of “The anatomy of the nervous system” by Stephen Walter Ranson, published W.B. Saunders, 1920 Original artist: user:Looie496 created file, original artist unknown • File:Diagram_showing_prostate_cancer_pressing_on_the_urethra_CRUK_182.svg Source: http://upload.wikimedia.org/ wikipedia/commons/5/59/Diagram_showing_prostate_cancer_pressing_on_the_urethra_CRUK_182.svg License: CC BY-SA 4.0 Contributors: Original email from CRUK Original artist: Cancer Research UK • File:Digital_rectal_exam_nci-vol-7136-300.jpg Source: http://upload.wikimedia.org/wikipedia/commons/e/e0/Digital_rectal_exam_ nci-vol-7136-300.jpg License: Public domain Contributors: This image was released by the National Cancer Institute, an agency part of the National Institutes of Health, with the ID 7136 (image) <a class='external text' href='//commons.wikimedia.org/w/index.php?title= Category:Media_from_National_Cancer_Institute_Visuals_Online_with_known_IDs,<span>,&,</span>,filefrom=7136#mw-categorymedia'>(next)</a>. Original artist: Unknown • File:Ectoderm.png Source: http://upload.wikimedia.org/wikipedia/commons/1/1d/Ectoderm.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:EctodermalSpecification.png Source: http://upload.wikimedia.org/wikipedia/commons/4/47/EctodermalSpecification.png License: Public domain Contributors: Own work Original artist: Sofia mr007 • File:Edit-clear.svg Source: http://upload.wikimedia.org/wikipedia/en/f/f2/Edit-clear.svg License: Public domain Contributors: The Tango! Desktop Project. Original artist: The people from the Tango! project. And according to the meta-data in the file, specifically: “Andreas Nilsson, and Jakub Steiner (although minimally).” • File:Embryo,_8_cells.jpg Source: http://upload.wikimedia.org/wikipedia/commons/6/6b/Embryo%2C_8_cells.jpg License: Public domain Contributors: ? Original artist: ekem, Courtesy: RWJMS IVF Program • File:Endoderm2.png Source: http://upload.wikimedia.org/wikipedia/commons/c/c0/Endoderm2.png License: Public domain Contributors: http://en.wikipedia.org/wiki/Image:Endoderm2.png Original artist: en:User:J.Steinbock • File:Endometrial_fluid_accumulation,_postmenopausal.jpg Source: http://upload.wikimedia.org/wikipedia/commons/b/bd/ Endometrial_fluid_accumulation%2C_postmenopausal.jpg License: CC0 Contributors: Own work Original artist: Mikael Häggström. • File:Epididymis-KDS.jpg Source: http://upload.wikimedia.org/wikipedia/commons/c/c0/Epididymis-KDS.jpg License: CC BY-SA 3.0 Contributors: Own work Original artist: KDS444 • File:Equal_vs_unequal_cleavage.jpg Source: http://upload.wikimedia.org/wikipedia/commons/6/68/Equal_vs_unequal_cleavage.jpg License: Public domain Contributors: Transferred from en.wikipedia by SreeBot Original artist: C.orosco at en.wikipedia • File:Erection_Development_V2.jpg Source: http://upload.wikimedia.org/wikipedia/commons/e/e7/Erection_Development_V2.jpg License: CC0 Contributors: • File:Erection_Development.jpg Original artist: File:Erection_Development.jpg: OrlandoDL • File:Eukarya_Flagella.svg Source: http://upload.wikimedia.org/wikipedia/commons/2/27/Eukarya_Flagella.svg License: CC BY-SA 3.0 Contributors: Own work Original artist: Franciscosp2 • File:Eukaryotic_flagellum.svg Source: http://upload.wikimedia.org/wikipedia/commons/b/b9/Eukaryotic_flagellum.svg License: CC BY-SA 3.0 Contributors: File:Axoneme.JPG and Figure 19.28 on page 819 of “Molecular Cell Biology, 4th edition, Lodish and Berk” ISBN 0-7167-3706-X Original artist: en:User:Smartse • File:FGM_prevalence_UNICEF_2013.svg Source: http://upload.wikimedia.org/wikipedia/commons/5/51/FGM_prevalence_ UNICEF_2013.svg License: CC BY-SA 4.0 Contributors: Own work Original artist: Johnuniq • File:Figure_28_00_01.JPG Source: http://upload.wikimedia.org/wikipedia/commons/e/ea/Figure_28_00_01.JPG License: CC BY 3.0 Contributors: Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/, Jun 19, 2013. Original artist: OpenStax College • File:Figure_28_01_02.JPG Source: http://upload.wikimedia.org/wikipedia/commons/5/53/Figure_28_01_02.JPG License: CC BY 3.0 Contributors: Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/, Jun 19, 2013. Original artist: OpenStax College • File:Figure_28_01_03.JPG Source: http://upload.wikimedia.org/wikipedia/commons/5/55/Figure_28_01_03.JPG License: CC BY 3.0 Contributors: Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/, Jun 19, 2013. Original artist: OpenStax College
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• File:Figure_28_01_04.jpg Source: http://upload.wikimedia.org/wikipedia/commons/b/b1/Figure_28_01_04.jpg License: CC BY 3.0 Contributors: Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/, Jun 19, 2013. Original artist: OpenStax College • File:Figure_28_02_01.JPG Source: http://upload.wikimedia.org/wikipedia/commons/5/57/Figure_28_02_01.JPG License: CC BY 3.0 Contributors: Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/, Jun 19, 2013. Original artist: OpenStax College • File:Figure_28_02_07.jpg Source: http://upload.wikimedia.org/wikipedia/commons/f/f3/Figure_28_02_07.jpg License: CC BY 3.0 Contributors: Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/, Jun 19, 2013. Original artist: OpenStax College • File:Flaccid_penis_cropped.jpg Source: http://upload.wikimedia.org/wikipedia/commons/8/87/Flaccid_penis_cropped.jpg License: CC BY-SA 2.0 Contributors: • Flaccid_penis_shaved.jpg Original artist: Flaccid_penis_shaved.jpg: stnu • File:Folder_Hexagonal_Icon.svg Source: http://upload.wikimedia.org/wikipedia/en/4/48/Folder_Hexagonal_Icon.svg License: Cc-bysa-3.0 Contributors: ? 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Original artist: ? • File:Teenage_birth_rate_per_1000_women_15–19,_2000-09.svg Source: http://upload.wikimedia.org/wikipedia/commons/f/ff/ Teenage_birth_rate_per_1000_women_15%E2%80%9319%2C_2000-09.svg License: Public domain Contributors: • 2009_Freedom_House_world_map.svg Original artist: 2009_Freedom_House_world_map.svg: *derivative work: Voland77 (<a href='//commons.wikimedia.org/wiki/User_talk:Voland77' title='User talk:Voland77'>talk</a>) • File:Teratoma_2_low_mag.jpg Source: http://upload.wikimedia.org/wikipedia/commons/1/11/Teratoma_2_low_mag.jpg License: CC BY-SA 3.0 Contributors: Own work Original artist: Nephron • File:Testicle-histology-boar.jpg Source: http://upload.wikimedia.org/wikipedia/commons/8/8c/Testicle-histology-boar.jpg License: CC-BY-SA-3.0 Contributors: Own work Original artist: User:Uwe Gille • File:Testis.gif Source: http://upload.wikimedia.org/wikipedia/commons/e/ea/Testis.gif License: CC BY-SA 3.0 Contributors: Own work Original artist: KDS444 • File:Text_document_with_red_question_mark.svg Source: http://upload.wikimedia.org/wikipedia/commons/a/a4/Text_document_ with_red_question_mark.svg License: Public domain Contributors: Created by bdesham with Inkscape; based upon Text-x-generic.svg from the Tango project. Original artist: Benjamin D. Esham (bdesham) • File:Transversetestis.png Source: http://upload.wikimedia.org/wikipedia/commons/6/66/Transversetestis.png License: Public domain Contributors: Henry Gray (1918) Anatomy of the Human Body (See “Book” section below) Original artist: Henry Vandyke Carter • File:Ultrasonography_of_corpus_luteum.jpg Source: http://upload.wikimedia.org/wikipedia/commons/f/fb/Ultrasonography_of_ corpus_luteum.jpg License: CC0 Contributors: Own work Original artist: Mikael Häggström • File:UltrasoundBPH.jpg Source: http://upload.wikimedia.org/wikipedia/commons/e/ec/UltrasoundBPH.jpg License: CC BY 3.0 Contributors: Own work Original artist: Etan J. 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