1
1. 2. 3. 4.
--
(发n题张 analogue递 analogue递 发n题张发n题张-a)
对.
2
(Hypothalamic-Pituitary-Gonadal Axis)
男
女
3
-
发n题张
-
(张(张-释-发 Axis) (Pulsatile secretion)
断
4
5
6
Embroyonic migration of GnRH neurons Epithelial cluster in Olfactory placode migrate into move into
Olfactory bulb & olfactory tract Arcuate nuclear& Preoptic area in medio-basal Hypothalamus
7
Physiology of GnRH For proper stimulation of Gonadotropin (FSH, LH) release 发n题张 neurons must be proper located (Arcuate nuclear& Preoptic area )
发n题张 must secrete in a
pulsatile fashion
Kallmann Syndrome: Anosmia or Hyposmia IHH(Idiopathic hypogonadotropic hypogonadism) * Sporadic or gene (KAL, FGFR1) mutation 8
9
10
11
12
断脉
-(
断将 (puberty,teenage)
断white断枢 black :时 时 断white断枢 断white and black断 将 (
) ) -; ;
14 ) 16 ) 13
(C释释,central precocious puberty)
-
-
发n题张
❤
(PPP , peripheral precocious puberty) -
-
(
,
)
❤
-
(PPP , Pseudo-precocious Puberty) 14
1.
(Idiopathic)
---
(constitutional) -
-
2. ---
3.
:
: McCune-Albright
-
1. 2. 断 3.药cCune-Albright 4. 断 对. 15
16
X A. 3 yr. Sexual precocity
17
X A. 3 yr. Sexual precocity
18
X F. 3 yr. Sexual precocity
19
X A. 3 yr. Ovarian cyst
20
X A. 4 yr. Sex. Preco. Virilization (Renal tumor)
21
X A. 4 yr. Sex. Preco. Virilization (Renal tumor)
22
X M. 5yr Gynecom. (Exo. Horm.)
23
---
(Tanner stage) (
)
--
GnRH 24
GnRH (LH-RH)
Baseline Blood Samples for 统张, 兴S张, 临2(girls) or TT(boys)
100ug(or2.对ug/kg)统张题张(发onadorelin 0.1mg/1m统/amp)iv Collect Blood at t=1对,30,4对,时0,将0 min
for 统张,兴S张 Collect Blood at t=120 min
for 统张,兴S张,临2(girls) or TT(boys) LH FSH
LH 10 U/L ;
;
FSH LH
LH
FSH 25
– (1) (2)
:
(3)
:
(4) (5) (6) (7)
: : : –(
,
)
26
27
28
29
30
31
32
33
34
34
CPP - Clinical and Social significance (
-
)
Early sexual development warrants evaluation because it may 1. indicate the presence of a tumor or other serious problem 2. induce early bone maturation and reduce eventual adult height 3. cause the child poor psychosocial adjustment resulting from holding up the pubertal process
35
释sychosocial problems
of 临arly sexual maturation
Boys: 1. Increased aggressiveness because they appear older than their peers 2. Increased social pressure to conform to adult norms – their cognitive and social development may lag behind their appearance. 3. More sexual activity -- participate risky behaviors.
Girls: 1.Cause the child, particularly a girl -- object of adult sexual interest. 2. Puts girls at higher risk of sexual abuse, because the child has developed secondary sex characteristics. 3. Puts girls at a higher risk for teasing or bullying. 4. Greater risk for breast cancer later in life. 36
37
-
( (
-
) )
Cyproterone acetate, Danazol , Medroxyprogesterone acetate,
, GnRH-a (Gonadotropine Releasing Hormone analogue)
38
GnRH analogue (GnRH-a)
10 (Decapeptide): pyroGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 GnRH
GnRH-a D-
(L-glycine) (Serine) D-
D-
(Leucine)
6 D-
(Triptophan) (Histidine)
39
GnRH analogue(GnRHa)- History Hypothalamic-Pituitary-Gonadal Axis (Gonadotropin - releasing hormone)
(Gonadotropin) (Gonadal hormone)
40
GnRH analogue(
)in
medicine:
History The early development of 发n题张 analogues was aimed at improving fertility in hypogonadotropic hypogonadism, but it was soon discovered that repeated injections of 发n题张 agonists reduced gonadotropin secretion from the pituitary and decreased sex hormone production by the ovaries and the testes. Today, 发n题张 agonists are being used to reduce gonadotropin secretion in the treatment of hormone dependent disorders such as precocious puberty, endometriosis, uterine fibroma, prostate cancer, breast cancer.
发n题张 analogue发n题张 agonistagonist-
(发n题张(发n题张-a) vs 发n题张 antagonistantagonist-
41
GnRH vs GnRH-a Structure GnRH structure ◦ Endogenous GnRH – pepide chain of 10 AA. with L-glycine in position 6. Short half-life(2-4 min) Low affinity for GnRH receptors Synthesis of GnRH (GnRH analogue) – with a different AA. either at position 6, 10 or both More stable molecule Higher receptor affinity Longer half-life Hundreds of analogues of GnRH have been produced, but only a few introduced into clinical practice. 42
Triptorelin
Introduced by Ferring in 1986
Nature GnRH
Triptorelin
43
统euprorelin 统euprorelin acetate (Takeda)
PYROGLU-HIS-TRP-SER-TYR-D-LEU-LEU-ARGPRO-NHET
44
GnRH analogues product Licence 标nitial -
统icenced for adult sex steroid dependent diseases断Breast diseases Breast cancer, 释rostatic cancer,临ndometriosis, Uterine leiomyoma,药enorrhalgia
统ater - 发ranted for specific use in 释recocious puberty (兴erring 释harm.)
45
GnRH analogue preparations Nasal preparation: Ineffective for precocious puberty
Depot preparations: (Last for 1, 2, 3 mon or implant for 12 mon)
More effective control for precocious puberty
46
47
Leuplin Depot (leuprorelin)
Leuplin
23 48
Side effect 1.标nitial 标nitial stimulatory effect on sex hormone secretion ( may last for 2-3 weeks ) 2.药ild breast enlargement(boys) 3.题ashes 4.标ching 对.标njection site reaction
49
1. 2. 3.
50
统张题张
统张
10药标U/ml
1. 2. 3. a.
b.
递
c.
2.0 (释A张)
对
4. 2.3.
51
Efficacy Short term断 1.临xtremely effective in freezing puberty 2.Allaying bone maturation 3.项uality 项uality of lifelife- Better psychological adjustment resulting from holding up the pubertal process (data not available)
统ong term断
标mprovement in stature
52
Safety 1.é˘˜eproductive function 2.Bone mineral density(osteoporosis)
53
3
REPRODUCTIVE OUTCOME IN PATIENTS TREATED AND NOT TREATED FOR IDIOPATHIC EARLY PUBERTY: LONG-TERM RESULTS OF A RANDOMIZED TRIAL IN ADULTS ALESSANDRA CASSIO, MD, MILVA O. BAL, MD, LUIGI F. ORSINI, MD, ANTONIO BALSAMO, MD, SILVIA SANSAVINI, MD, MONIA GENNARI, MD, ENRICO DE CRISTOFARO, MD, AND ALESSANDRO CICOGNANI, MD
Department of Gynecology, Obstetrics and Pediatrics, University of Bologna, Italy.
SCI (PEDIATRICS) Ranking: 3/73 (4.1 %)
Impact factor: 3.837 54
2009
ESPE-LWPES ( GnRH-a
-
)
European Society for Pediatric Endocrinology / Lawson Wilkins Pediatric Endocrne Society Consensus Statement on the Use of GnRH analogs in Children Carel, et al. Pediatrics April 2009; 123:4 e752-e762
(initial therapy)
.
55
56
Arch Dis Child 1999; 81:329-332
Randomised trial of LHRH analogue treatment on final height in girls with onset of puberty aged 7.5 – 8.5 years
Conclusions : LHRH analogue has no apparent effect on final height in subjects with onset of puberty between 7.5 and 8.5 years
57
Effect on final height
58
Factors related to final height of GnRHa treatment for CPP (1) Cause of the CPP (2) Age at onset (3) Rapidity of progression through puberty (4) Age when therapy is initiated 59
Indication for GnRH-a + rhGH treatment (1) Short girls at the onset of puberty (2) Short children with IUGR(SGA) (3) PAH is low at the onset of puberty
60
LEUPLIN速 DEPOT LEUPLIN速 DEPOT LH-RH Microcapsule 4
LEUPLIN速 DEPOT 30 g/kg 90
g/kg LEUPLIN速 DEPOT 61
Results of Long-Term Follow-Up after Treatment of Central Precocious Puberty with Leuprorelin Acetate: Evaluation of Effectiveness of Treatment and Recovery of Gonadal Function. The TAP-144-SR Japanese Study Group on Central Precocious Puberty
GnRH analog administration effectively arrests further development of secondary sex characteristics, slows bone age (BA) maturation, increases pubertal height gain, and is believed to eventually improve AH prognosis. No severe adverse drug reaction was observed during leuprorelin treatment. Long-term leuprorelin treatment appeared to be well tolerated in terms of safety and reversibility of reproductive function. Tanaka T, et al. J of Clin Endocrinology & Metabolism 2005;90(3):1371-1376. 62
LEUPLIN® DEPOT (n=76) DEPOT
LEUPLIN®
154.5±5.7cm 3.5±1.3
89.5 %
163.2±13.0cm 2.6±1.1 %
90.9
AH=adult height; CA=chronological age; SDS=SD score LEUPLIN® DEPOT 4 4.1±2.5 2.6±1.1
(10, 30 90 g/kg) 3.8±2.0 3.5±1.3
Tanaka T, et al. J of Clin Endocrinology & Metabolism 2005;90(3):1371-1376. 63
LEUPLIN® DEPOT
(n=76)
LEUPLIN® DEPOT
13.1±1.5 12.7±1.3
(~11.0-15.3
17.5±11.2
LEUPLIN® DEPOT 4.1± ±2.5
(10, 30
(~10.4-16.8
)
(
90 g/kg) 3.5± ±1.3
61 ) 13
LEUPLIN® DEPOT 14.7
)
3.8± ±2.0
4 2.6± ±1.1
Tanaka T, et al. J of Clin Endocrinology & Metabolism 2005;90(3):1371-1376.
64
LEUPLIN速 DEPOT
(adult height)1,2
2 1,2
1.Tanaka T, et al. J of Clin Endocrinology & Metabolism 2005;90(3):1371-1376. 2. Tung YC, et al. J Formos Med Assoc 2007;106(10):826-831.
65
66
30
30 18 3
56.67% 5.56%
67
GnRH
68
Gn-RH GnRH
69
(1)
(2)
(3)
70
!
71