Adolescence issue 11

Issue 11 | Pages 20

ADOLESCENCE

Adolescent Health Committee FOGSI

Address for correspondence : Olyai Hospital, Hospital Road, Gwalior- 474009 (MP) India. Phone : (91) -(751)- (2320616) http://www.youtube.com/watch?v=NsR0H0ril20

Adolescent Health Committee FOGSI

ADOLESCENCE Message from

President FOGSI 2014...

Message from

Secretary General's Desk...

From the Editor’s Desk Dr. Roza Olyai M.S. MICOG, FICOG, FICMCH Vice President FOGSI (2014) Member Board of Governing Council Indian College of Obst. & Gyn.(ICOG 2012-15) Member “Anti-Violence against Women Cell” of FOGSI (2013-15) National Chairperson Adolescent Health Committee FOGSI (2009-12) Director Olyai Hospital,Gwalior-MP India E-mail: rozaolyai@gmail.com http://www.youtube.com/watch?v=NsR0H0ril20

Dr. Nozer Sheriar Secretary General FOGSI

Prof. Dr. Suchitra N. Pandit President FOGSI 2014

Dear Friends, It is a great pleasure to write this for Adolescent Health Magazine.

Adolescence is a transitional period between childhood and adulthood, and it responsibility of the society, parents, healthcare workers to get the young adolescents ready for adult roles It involves education, training, as well as a gradual change of roles and responsibilities. So this magazine makes very good reading and gives food for thought. Hearty congratulations to Dr. Roza Olyai for the good information given through this magazine.

We all agree that the youth are the future of tomorrow. In keeping with our commitment towards empowering and educating the youth, we have initiated the concept of “Youth Mela” for young boys and girls (16-24 years) and I hope to reach out to various parts of India.

Some of the topics which we will be addressing in 2014 during the Youth Mela are: Communication skills, Know Your Body, Healthy Diet, Protecting yourself from an unwanted Pregnancy using Contraception, Prevention of HIV/Sexually Transmitted Infections/Cancer Cervix, Staying fit, Self-defense, Prevention and protection from sexual abuse and First Aid.

Dear Colleagues and Friends, 'Whether you think you can, or that you can't, you are usually right.'

- Henry Ford The adolescent health activities of FOGSI have of course been very effectively managed by the Adolescent Health Committee under the stewardship of a series of very dynamic chairpersons. The committee has striven for greater heights under Dr. Roza Olyai with regular publications, advocacy and national and international recognition. As the Website Coordinator, I have seen the great response of netizens to the eight issues of the Adolescence Newsletter in our publications section.

Am very happy to see that Dr. Jayyam Kannan the newly elected Chairperson is continuing with the publication of the Adolescence Magazine. I wish the committee my very best and thank them on behalf of FOGSI for doing this very important work so sincerely.

Keep up the good work!

Dr. Nozer Sheriar Secretary General FOGSI

Prof. Dr. Suchitra N. Pandit President FOGSI 2014

FOGSI's Adolescent Health Committee The adolescent health committee of FOGSI has been doing impressive work to improve the health and well being of adolescents through education and basic health screening initiatives under the sterling leadership of Dr Roza Olyai and her colleagues. They have undertaken activities to increase access to comprehensive sexual and reproductive health and overall health information and services through study days and the use of mobile technology among young people. This no doubt would result in safer sex practices and improved reproductive health outcomes as well as better nutritional practices.

On the long run we need to promote the positive roles that young men can play in improving their own sexual and reproductive health and those of women and children. I am sure the committee will seek to work with both young men and young women. Sexual and reproductive health topics are rarely covered in a comprehensive non-judgemental manner. In order to dispel the myths and misinformation surrounding these issues and to promote a positive approach to adolescent sexual and reproductive rights a range of issues from contraception to sexual violence has been discussed by the committee members via the FOGSI branches. This ensures a holistic approach to be adopted for improving adolescent health, issues around good nutrition and overall healthy behaviour.

Generations of adolescents may benefit if the current activities are shown to be successful, can be sustained and reproduced in more and more centres in the country. To this goal I wish the FOGSI's Adolescent health committee the very best to continue with their excellent and forward thinking activities.

With best wishes and kind regards,

Message from

Chairperson (2013-15) 2014 is a year Memorable for the Adolescent Health committee, as this year has the FOGSI President Prof Suchitra Pandit, who has keen interest in adolescent Health, has done many programmes, trainingsessions for many years. To add feathers to her crown is the Vice President in charge of the Adolescent committee, who is none other than DrRoza Olyai whose dedication to the budding youth is immeasurable. To be an executor of these two stalwarts command is my proud privilege as the chairperson of the adolescent health committee.

The concept of Youth Meladesigned, nurtured and promoted this Year 2014, speaks for the enormous enthusiasm intubated into this committee members. TOT programs have been done for Doctors with keen interest to work in this committee.85 doctors have been trained in these TOTs in Ahamadabad,Faridabad,Mysore,Lucknow,Pune .

Dr. Jayamkannan Chairperson Adolescent Health Committee FOGSI (2013-15) Emeritus professor, Tamil Nadu MGR medical university Member PMNCH WHO programme Web coordinator FOGSI Member antiviolence cell FOGSI

Dr. Suchitra Pandit President FOGSI,Dr.pritivyas,Dr.sankeit&Dr.jayamkannan are keenly involved in these TOTs. West Zone Yuva Fogsi, under theable leadership of Dr.Roza Olyai Vice President FOGSIis gettingconcentrated on Youth Mela and Adolescent health committee workshop. “The Modern Technology to save lives” Fogsi conference at Trichy Tamilnadu in October 2014 is gearing up with an educative programme for 17-24 years with oratorical and essay competitions, many youth Melas as preconference programmes which were inaugurated by the Vice Chancellor of the Bharathidasan University. Nearly 15 programmes are planned, 3 are already over by July 31st 2014.

Yuva clinics are actively functioning at many centres; many state governments are also supporting this inthe Primary health centres. We are continuing these activities in 2014 as the credit goes to the untiring efforts of the members of the committee, without whom this success cannot beachieved. Thanks to Dr.Sampathkumari , national coordinator ,Dr.pritivyas Youth Mela national coordinator.

Dear friends, I take this opportunity to address you all to join us in large numbers and educate our youths, who are the future leaders of the great country.

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Wish you all a prosperous year ahead!

Sir Sabaratnam Arulkumaran President, FIGO Professor Emeritus, St George's University of London

Dear Friends, It gives me great pleasure to share with you the 11th issue of the news magazine of the Adolescent Health Committee FOGSI. One of our main activity this year has been hosting the YUVA FOGSI West Zone in Nasik on 12-14 Sept. 2014 with the theme focused on Adolescence & youth. The unique feature this year in the Yuva FOGSI West Zone has been that the Conference begins with a youth mela with lots of fun activities & galaxy of good faculty.

Am thankful to Dr. Suchitra Pandit President FOGSI 2014 for giving me this opportunity as Vice President FOGSI in charge of this conference, I hope that it has been a good learning experience for all our delegates! The team Nasik has been working very hard &am very grateful to them.

Dr. Jayyam Kannan the dynamic Chairperson Adolescent Health Committee FOGSI has been actively involved in carrying the committee activities to greater heights, specially supporting the Adolescence magazine to be continued as an ongoing publication of the committee for which am thankful to her.

Young Women's club is a friendly club for girls in between age groups 19-30 yrs where in they meet once in three months to discuss other than health issues important social related issues, cooking, life skill development, premarital counseling etc. There is a format made for the same, I would request you all to have this club inaugurated in your cities & for the details you can contact me.

We have included interesting articles, in this Issue such as: Reproductive Health Protection in Adolescents: Start Young!, Primary Amenorrhoea, Metablic Syndrome in PCOS, Secondary Amenorrhoea, Poly Cystic Ovarian Syndrome in Adolescents, Ovulation Induction in PCOS, IUI Recommended Guidelines, Ovulation Induction with IUI. We are thankful to our esteemed authors for their contributions.

FOGSI Office Bearers 2014 Dr. Suchitra Pandit Dr. Roza Olyai Dr. Ritu Joshi Dr. Indrani Ganguli Dr. Gokul Chandra Das Dr. Sheela Mane Dr. Hema Divakar Dr. Prakash Trivedi Dr. Nozer Sheriar Dr. Hrishikesh D. Pai Dr. Jaydeep Tank Dr Gorakh Mandrupkar Dr. Madhuri Patel

President Vice President Vice President Vice President Vice President Vice President Immediate Past President President Elect (2015) Secretary General Deputy Secretary General Treasurer Jt. Secretary Jt. Treasurer

IUI & Ovulation induction workshops are our main team for CMEs this year with focused topics. CD & informative materials have been prepared with team of experts.

One of our major ongoing project is “Challenges for the youth today & tomorrow”. We were able to cover more girls in the coming months through various school/ college health talks, sharing with them the informative booklets which our committee has prepared. Am very grateful to Emcure Pharma, in supporting the activities of the Adolescent Health Committee FOGSI & helping to spread the message across the country through this magazine for the betterment of the youth.

Your suggestions & feedback will be of great help, kindly share your articles& achievements with us.

Wish you all a happy reading!

Dr. Roza Olyai 2

Adolescent Health Committee FOGSI

ADOLESCENCE

Grand Inauguration of the IUI & Ovulation Induction CME at New Delhi on July 19th 2014 IUI & OI CME is the National FOGSI project this year under Dr. Roza Olyai as Vice President in charge. The CME is being conducted under the Infertility Committee FOGSI Chaired by Dr. Sonia Malik & the National coordinator for this CME Dr. Madhuri Patil. The CME will be conducted this year in various B & C FOGSI societies.

During the event, the release of the IUI & OI CD was done by Dr. Deepa Singh who was the Guest of Honor in memory of Late Prof. Perin Olyai. The Adolescence Magazine was released by Dr. Shivani Sachdeva. HOPE is an educative documentary CD produced by Dr. Roza Olyai for patient awareness program for the Infertile couples. The CD can be used in the clinics by the gynecologists for their patient’s education towards various modalities of infertility treatment. We are thankful to Emcure pharma for sponsoring this program & helping spread the message.

Grand Inauguration of the IUI & Ovulation Induction CME at New Delhi on July 19th 2014

Reproductive Health Protection in Adolescents: Start Young!!

Dr. Reena J Wani (MD, MRCOG, FICOG, DNBE, DFP, DGO, FCPS) Professor (Addl) , I/C Family Welfare Program, TNMC & BYLNair Ch. Hospital, Mumbai 400 008.

Correspondence: reena.wani@rediffmail.com “Catch them young” is a mantra often quoted for many areas but should be highlighted when we speak of women's health. With a growing number of “young people” we need to focus on different areas of adolescent health to make an impact on the health of the nation. To protect the future reproductive health, we have to take steps today…as health care providers we can make a diiference!

Adolescence is viewed as a transitional period between childhood and adulthood, whose cultural purpose is the preparation of children for adult roles. About 30% of India's population is in the adolescent age group of 10-19 years. It is estimated that there are almost 331 million adolescents in India. They represent a resource for the future whose potential can either be wasted or nurtured in a positive manner.

Diet and Exercise : Simple measures like supplements of iron- folate ( as per WHO 2011 guidelines), counselling for healthy dietary habits and exercise will go a long way. Problems of “Mall Nutrition” with junk food are as important as malnutrition... an unhealthy life style leading to obesity, soon to become an epidemic. This is assuming serious proportions in cities and is particularly affecting young children and adults in the reproductive age group. Polycystic ovarian syndrome, especially the obese phenotype is often linked with metabolic syndrome. These present another health care opportunity where proper planning of diet, weight control and exercise will go a long way as a healthy investment for the future.

Along with cosmetic and body image issues, self esteem and mental health should also be tackled.

Sexual & Reproductive Health : At this age, young people need special attention along with sexual and reproductive health information and care that meet their needs. Sexual and reproductive ill health is one of the major causes of morbidity and mortality in young people[1]. There has been an increasing concern for adolescent sexual and reproductive health concerns due to the rise in case of HIV/AIDS especially in the age group of 15-45 yrs[1]. Additionally, early childbearing and its known complications and impact on the reproductive health have been also a cause for concern. Thus, there is an urgent need for sexual and reproductive health services targeting adolescents. This has now become a focus and a part of many countries national agenda.

Adolescent sexual and reproductive health concerns include substance abuse such as smoking , alcohol and drug abuse along with high risk sexual behavior[2] . Many a times these are seen together and they lead to unsafe abortions, high-risk behavior, reproductive tract infections (RTIs) and sexually transmitted infections (STIs) including HIV/AIDS and non-consensual sex. Smoking in young girls is often perceived as “cool” which leads to addiction. Additionally, lack of awareness of health risks and contraceptive use and peer pressure pose a distinct array of reproductive and sexual health challenges.

This creates an "unmet need" for reproductive and sexual healthcare.

Reproductive Tract infections represent another huge global burden which can adversely impact a woman's sexual and obstetric career.

Our national and state programs have seen the importance of investing in prevention strategies and linked screening and syndromic management with both public and private clinics.

Reproductive health services under the public sector are more oriented towards adult married women. Unmarried adolescents hesitate to seek health services due to the fear that these services are not confidential, inability to pay, requirement of parents' approval and negative or insensitive attitude of health providers. They also shy away from seeking healthcare due to embarrassment and the taboo

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Co-author : Dr. Namrata Rajput (M.S., DNB, DGO) associated with reproductive and sexual health problems. Also, at times the non availability of trained health personnel and fear of being ridiculed and being judged has made planning of any such programs unsuccessful.

It is important that Adolescent Friendly Health Services[3] be made an integral part of the health system. Apart from re-organizing the existing public health system, the public-private partnership and linkages are required. Additionally, non-governmental organizations (NGOs), schools and various voluntary agencies would be of utmost significance. Inter-sectoral linkage with various national programs will determine appropriate service delivery without any overlapping of services. Setting up an AFHC in school or college premises for easy accessibility should be considered. A comparative study on utilization of adolescent health services found that school based services were better utilized than health facility based services.

We have many examples of adolescent friendly health service created in other countries. For example the school health center approach in the United States. They provide a broad range of reproductive services either on site or by means of referrals. The other example is of Thailand where under the label of “Friendly Corners“, these centers being located at attractive sites which are visited frequently by adolescents such as shopping malls , discotheques and cinema theatres. Their experiences can guide us and it is now understood that a holistic approach encompassing a broad range of health issues including but not restricted to sexual and reproductive health should be taken. This would mean utilization of health services by providing intensive information, education and communication (IEC).

Additionally, reaching out to the youth through various outreach activities, press releases, public service advertisements, directional signs, newsletters and partnership with NGOs and government agencies.

However, the most promising intervention, highlighted in recent Cochrane reviews, is the Strengthening Families Program for Parents and Youth 1014, which has been shown to significantly reduce smoking, alcohol and illicit drug use after 4 years[4]. The program consists of weekly family sessions. This may encompass: clarifying expectations; appropriate discipline; managing strong emotions; effective communication and peer skills. Thus creating a strong positive influence in the lives of adolescents and giving a high degree of attention to their personal issues can definitely go a long way in preventing high risk behavior. This should be one of the lines in which programs should be designed.

Indian Scenario: Through the years, the Adolescent Health Committee of FOGSI has conducted numerous programs to reach out to the youth and share correct information and have personalinteraction. This year FOGSI President Dr Suchitra Pandit and her teamare doing Youth Melas across the country which were started in her MOGS Presidential year.

Hence, there are numerous challenges while planning programs on reproductive health of adolescents. Only knowledge and information without proper guidance from parents, guardians teachers, health workers may fail. One should always keep in mind the social and cultural norms, mass media influence and peer pressure while chalking out reforms. The “social network” which is extremely popular with the youth of today is a double edged sword and should be used to develop a positive influence in their lives. Facebook and WhatsApp are powerful influences which may be utilized advantageously by health care providers. Planning for the youth development needs dedication and role models and can be made 4

Adolescent Health Committee FOGSI

ADOLESCENCE acceptable only if the youth can identify with it.

There is current research on protective factors and a new study is ongoing in the same direction called Positive Youth Development(PYD)[5]. PYD seeks to strengthen the adolescent's ability to respond to developmental challenges in effective ways. PYD may provide the motivation needed for adolescents to apply the skills and knowledge learned in sex education programs. PYD programs help youth to strengthen relationships and skills, embed them in positive networks of supportive adults, and develop a more positive view of their future by providing academic, economic, and volunteer opportunities. Such development programs can help youth develop the motivation, skills, and confidence needed to make healthy decisions.

3. Foxcraft D, Ireland D et al “Long term primary prevention for alcohol misuse in young people “ A systematic review Addiction 2003;98-397-411

Dr. Vijaylaxmi Ganorkar Director Dr. Ganorkar Hospital & Maternity Home Organising Chairperson West Zone YUVA FOGSI ,NASHIK

4. Nath A, Garg S. Adolescent friendly health services in India: A need of the hour. Indian J Med Sci 2008;62:465-72 5. Lorrie E Gavin, Richard F Catalano 'Positive Youth Development as a Strategy to Promote Adolescent Sexual and Reproductive Health' Journal of Adolescent Health Volume 46, Issue 3, Supplement, Pages S1S6, March 2010

The differential diagnosis of primary amenorrhea has long been a challenging intellectual exercise, an exercise which has become more fascinating with the unfolding knowledge of genetics and hormonal influence on phenotypic development.

It is possible for all these patients to lead a normal life, although many will be infertile. The objective of this article is to simplify the understanding and evaluation of primary amenorrhea.

For a nation as populous as ours, it is quintessential to develop and sustain high degree of sexual and reproductive health amongst its youth. It can achieved with establishment of clinical reproductive health service as well as by complimenting youth development approaches with availability of accurate, age appropriate and evidence based sex education programs.

However we should bear in mind that sex education programs alone cannot bring about the herculean task of developing sexual and reproductive health in the youth. It has to be coupled with a social reform to reduce the negative influence of society on development and behavior of youth which should be borne in the minds of Government policy makers to make the step socially acceptable. Measures should also be taken to safeguard the youth of the nation from negative influences and expose them to opportunities to engage in activities that nurture positive development.

Primary Amenorrhea

2. Caroline Jackson, Marion Henderson 'An overview of prevention of multiple risk behavior in adolescents and young adulthood' J Public Health (2012) 34 (suppl 1): i31-i40

Definition: Primary amenorrhea can be diagnosed when the adolescent 1. Has not menstruated by age 14 and who lacks evidence of pubertal development 2. No menstruation by age 16 with presence of pubertal development Puberty isinitiated by release of pulsatile GnRH. With pulses of GnRH, peaks of oesradiol result and eventually menarche appears.

The HPO axis matures, and ovulation occurs by late puberty.

Youth Mela held at TNMC & BYL Nair Hospital with youngsters : 239 young medical and nursing students benefited

The timing of puberty is mainly determined by genetics. The other factors affecting puberty are general health, nutritional and psychological factors, and geographic location Critical body weight is also a major factor for menarche. A body weight around 45kgswith a shift in body composition to more fat is required.

Summary: By looking at adolescent sexuality and contraceptive options realistically and offering comprehensive services we can thus reduce problems like salpingitis, endometritis, pelvic inflammatory diseases, tubal block, ectopic pregnancy, unsafe abortion and infertility which are major sequelae affecting our women's reproductive health.

Causes of Primary Amenorrhea A clinically useful and simple classification is suggested by the American Society of Reproductive Medicine A. Primary amenorrhea with breast development

Diet, Exercise, Mental and Spiritual Health…These are some of the areas we need to cover to assure the health of adolescents and lay the foundation for future good health! Lets join hands and work together to achieve this goal!

C. Primary amenorrhea with no breast development And decreasedFSH

References :

Causes of primary amenorrhea

1. Blum Robert W. ' Risk and protective factors affecting adolescent reproductive health in developing coutries' WHO library Cataloging in publication data

B. Primary amenorrheawith no breast development And increased FSH

Keep in mind to rule out associated conditions like concurrent renal tract anomalies 30 %, and skeletal anomalies-12% Treatment: Mainly to create a neovagina either with the use to serial dilators (make take upto 18 months) or the surgical creation of a neovagina (McIndoe Surgery).

Transverse Vaginal Septum : Rare: Seen in 1:70,000 cases.

Commonly seen in upper and middle third of the vagina.

May present as hematometra, hematocolpos.

MRI helps in the diagnosis of this condition.

Treatment lies in surgical excision of the septum.

Imperforate Hymen : This is the most common obstructive lesion presenting as hematocolpos or urinary retention.

Seen in 1:2000 cases.

It differs from vaginal septum in that the hymen bulges with a valsalva maneuver Treatment is hymenotomy or hymenectomy Androgen Insensitivity : Incidence 1:60,000 but represents 9% of patients presenting with primary amenorrhea.

It is an X-linked recessive condition with an XY genotype in a phenotype female.

It occurs due to mutations in the androgen receptors.

On examination these adolescents are taller than average, have large breasts, with juvenile nipples and absent pubic and axillary hair.

Normal external genitalia with a blind vaginal pouch and absent middle line structure are seen.

Testosterone values are in the normal to high range.

Removal of gonads after complete pubertal development by 16-18 years is recommended since there is a 22% incidence of malignancy.

Figure 1 : Poster for YOUTH MELA

B. Primary amenorrhea no breast development and increased FSH

Glimpses of the GCPR committee meet in making guidelines headed by Dr.Sanjay Gupte & Dr. Suchitra Pandit at Amby Valley July 2014

45 XO

20%

46 XX

15%

46 XY

5%

Turners Syndrome 45 XO or Mosaic :There is an absence of the ovarian determinant genes resulting in premature loss of germ cells.

Many will lose all germ cells prior to birth, less than 15% have enough germ cells to start pubertal process by adolescence. Characteristic features show short stature, webbing of neck, low hair line poor breast development and streak gonads.

A. Primary amenorrhea with breast development

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Gonadal dysgenesis:

Mullerian agenesis -

46 XX :It is the commonest cause of primary amenorrhea

It occurs with a frequency of 1:5000 casesand is the second most common cause second only to gonadaldysgenesis (Rein dollar 1981 Aittomaki 2001). It occurs due to mutations in the Anti Mullerian Hormone (AMH) or AMH receptor.

Incidence 1:10,000, with a familial inheritance of 7-30%.

A normal complement of germ cells is present in the early fetal ovary.

However, oocytes undergo accelerated atresia and the ovaries are replaced by fibrous streaks.

Physical examination shows normal breast development, normal secondary sexualcharacters. Investigations reveal XX normal karyotype and normal FSH, LH values.

Premutation in the FMRI gene (fragile X syndrome) is seen. 15% of carries will have POF. This condition is associated with auto immune diseases.

On pelvic examination, normal external genitalia, withan absence of midline structures is seen.

Diagnosis is confirmed by demonstrating a high FSH level and streak ovaries on USG (60%) 6

Adolescent Health Committee FOGSI

ADOLESCENCE Treatment is mainly with hormone replacement with low dose estradiol and progesterone.

Physical Exam

Gonadal Dysgenesis Swyer Syndrome

Growth chart/BMI

46 XY:It occurs due to a mutation in the SRY gene.

Secondary sexual characteristics: Tanner staging, breast development, pubic hair

Metabolic Syndrome in PCOS

Review: Evaluation of Amenorrhea: Examination

Streak gonads with no testicular formation is seen. Therefore, antimullerian hormone and testestrone are not produced. This results in the development of normal uterus tube and female external genitalia.

Dysmorphic features: webbed neck, short stature, widely spaced nipples

There is no estrogen from gonads so no breast development is seen.

Hirsute features, Acne

Elevated FSH levels are obtained.

Thyroid exam

The streak gonads need removal since there is 25% risk of the development of germ cell tumors.

Pelvic exam: rudimentary or absent uterus, transverse vaginal septum, imperforate hymen, virilization, clitiromegaly

C. Primary amenorrheawith no breast development and decreased FSH

Algorithm for Primary amenorrhea:

Prof. Jayam Kannan Chairperson Adolescent Health committee FOGSI, TN MGR Medical university Tamilnadu

Diagnosis of the condition is confirmed by an MRI of the pituitary fossa.

Polycystic ovarian syndrome (PCOS) is a complex, multifaceted, heterogeneous disorder the prevalence of which is 18% according to the community based prevalence study on current Rotterdam diagnostic criteria. It affects 4-11% of reproductive age women in India. In the past, PCOS was considered only a hyperandrogenic disorder which can lead to infertility, current data shows that diagnosis of PCOS is related to an increased risk of metabolic disturbances called the metabolic syndrome (MS). The MS is however present in 30-40% of individuals with PCOS, and people with MS are twice as likely to die from and three times as likely to have a heart attack or stroke compared with people without the syndrome. They are at five fold greater risk of developing type II Diabetes (DM). With the MS driving the twin global epidemics of type II diabetes and cardio vascular disease (CVD) there is an overwhelming moral, medical and economic imperative to identify those individuals with MS early, and defining preventive methods in women with PCOS at early stage are definite goals of the treatment of PCOS.

Treatment is mainly with bromocriptine/cabergoline.

Diagnostic criteria for MS

Causes: Constitutional delay, Prolactinoma, Kallmans Syndrome, Other CNS abnormality, Chronic weight loss, anorexia, PCOS and others Prolactinoma : It is the most common cause of pituitary related amenorrhea Elevated PRL levels suppress hypothalamic GnRH secretion.

Remember to rule out hypothyroidism

80% of hyperprolactinemia will resolve and microadenomas will shrink.

Transsphenoidal surgery is recommended when medical therapy fails.

Hypothalamic Amenorrhea: Functional hypothalamic amenorrhea is seen with stress, chronic malnutrition and excessive exercise. Alteration in normal pulsatile release of GnRH occurs.

There is a complex interplay between neuropeptides.

Malnourishment causes a decrease in Leptin levels leading to amenorrhea.

Conclusion: Abnormalities in the normal progression of factors responsible for sexual differentiation in utero are the commonest causes of primary amenorrhea. The factors responsible for normal differentiation should be understood for a rational approach to the clinical problem of primary amenorrhea. With suitable investigation a precise diagnosis can usually be reached and it is possible to treat these patients on rational and physiological principles. All should be able to lead normal, sexually mature lives, but the prospect of fertility may be possible for a minority only.

A number of expert groups have developed clinical criteria for MS like WHO, The European group for the study of insulin resistance (EGIR), but widely used are the National cholesterol Education Program- third adult treatment panel (NCEP-ATPIII) and International Diabetes Federation (2005). According to NCEP-ATPIII the presence of any three criteria from central obesity (=88 cm in women), serum triglycerides (=150mg/dl), serum HDL (<50mg/dl), systemic hypertension >130/85mmHg and fasting plasma glucose (= 100 mg/dl) is diagnostic of MS.

Kallman Syndrome This is an X-linked recessive condition, due to mutation in KAL gene.

References:

These patients show the following peculiar characteristicsviz; Hypogonatrophic hypogonadism, anosmia, midline facial defects, occasional renal agenesis, absence of pubertal development and primary amenorrhea.

Abby Delaney, MD HO2, Advisor: Dr. Victoria Maclin, MD, February 2, 2011

Treatment: Hormone replacement therapy to promote sexual maturation.

Congetinal Adrenal Hyperplasia

Current Evaluation of Amenorrhea.Fertility and Sterility 2008 80(3): S219-S225.

Constitutional Delay:

Deligeoroglou et al. Evaluation and management of adolescent amenorrhea.Annals of the New York Academy of Sciences.2010; pg 23-32

This is defined when puberty occurs at a time greater than 2.5 standard deviations from the mean.

Lindenman et al. Mullerian Agenesis: An Update. Obstetrics and Gynecology.1997. 90(2): 307-312.

A family history of delayed puberty can be elicited.

Sultan et al. Disorders of Androgen Action.Seminars in Reproductive Medicine.2002: 20(3); 217-227

May present very rarely as primary amenorrhea.Presents more commonly with hirsutism, virilization and ovulation.

*The ethnic specific value for waist circumference in south Asian females is = 80 cm and it is the middle circumference between iliac crest and the lateral costal margin.

Diagnostic criteria for MS in children and adolescents

Social History: exercise, weight loss, illicit drug use

Nearly 35.3% of the adolescents with PCOS were found to be at risk of MS; where as only 15.5% had this risk without PCOS. The International Diabetes Federation put forward a new definition to identify children and adolescents with metabolic syndrome in 2007.

The definition is easily applicable in clinical practice and categorized according to the age group. The IDF suggests that the diagnosis of metabolic syndrome should not be used for children younger than 10 years of age. If the waist circumference is =90 percentile in the children younger than 10 years of age, weight reduction is recommended. For children aged between 10 and 16, the presence of abdominal obesity according to waist circumference percentiles with any two clinical features (elevated TG, low levels of HDL, elevated blood pressure, elevated fasting glucose) is sufficient for the diagnosis of metabolic syndrome. For children aged 16 years and older, it is recommended to use the adult criteria.

Family History: history of pubertal delay, infertility,

Pathophysiology of metabolic syndrome

Review of Systems: anosmia, galactorrhea, headaches, visual changes, hirsutism or acne, s/sx of thyroid disease, vasomotor symptoms

Insulin resistance (IR), Hyperinsulinemia, Hyperandrogenism and

Typical features show a significantly short stature, lagging bone age , low gonadotropin levels.

Diagnosis is by exclusion of other disorders.

Review: Evaluation of Amenorrhea : History OB/GYN: Pubertal development, premenstrual symptoms, dysmenorrhea/ cyclic abdominal pain Past Medical History: chronic illness, exposure to radiation, current medications

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Cameron et al. Non-Chromosomal, Non-Iatrogenic Premature Ovarian Failure in an Adolescent Population: A Case Series. Pediatric Adolescent Gynecology.2009: 21(3) pg 3-8.

Timmreck LS and Reindollar RH.Contemporary issues in primary amenorrhea.Obstetrics and Gynecology Cinics of North America.2003: (30); 287-302 Wu T, Mendola P, Buck GM. Ethnic differences in the presence of secondary sex characteristics and menarche among US girls: the Third National Health and Nutrition Examination Survey. 19881994. Pediatrics.110: 752, 2002.

obesity are the main predisposing factors for metabolic syndrome (MS). Hyperandrogenism in PCOS result from increased synthesis and release of ovarian androgens. Elevated luteinizing hormone and insulin synergistically increase androgen production. Insulin resistance leads to Hyperinsulinemia, reduces SHBG and raises free circulating testosterone and hyperandrogenism. Mechanisms involved in insulin resistance are likely to be complex with genetic and environmental contributors. Specific abnormalities of insulin metabolism identified in PCOS include reductions in secretion, reduced hepatic extraction, impaired suppression of hepatic gluconeogenesis and abnormalities in insulin receptor signaling.

Interestingly, there is a paradoxical expression of insulin resistance in PCOS whereby insulin-stimulated androgen production persists while its role in glucose metabolism is impaired. Therefore, insulin resistance in PCOS results in Hyperinsulinemia with its associated diverse and complex effects on regulating lipid metabolism, protein synthesis and modulation of androgen production. If woman with PCOS is overweight, she may also demonstrate extrinsic insulin resistance associated with adiposity. Alongside insulin resistance, metabolic syndrome, IGT and DM2, women with PCOS also have increased novel cardiovascular risk factors (inflammation, oxidative stress and impaired fibrinolysis). Also, increased early clinical and subclinical markers of atherosclerosis are seen in PCOS such as endothelial dysfunction, impaired pulse wave velocity, increased carotid intima media wall thickness, presence of carotid plaque and increased coronary artery calcification.

Characteristics and predictors of MS Using the NCEP-ATP III metabolic abnormalities diagnostic of the metabolic syndrome, low high-density lipoprotein cholesterol (HDL-C) occurred most frequently (68%), followed closely by elevated body mass index (BMI) and waist circumference (67%), high blood pressure (45%), hypertriglyceridemia (35%) ,elevated LDL-C, and elevated fasting glucose(4%). Compared to women with PCOS who did not meet the diagnostic criteria of the metabolic syndrome, women with PCOS and the metabolic syndrome more frequently demonstrated the phenotypic feature of acanthosis nigricans, a marker of insulin resistance. Fasting insulinalthough not used to diagnose metabolic syndrome or PCOShas been reported to be twice as high in women who meet the criteria for both PCOS and metabolic syndrome compared with women diagnosed with PCOS alone.

Predictive markers used are Adiponectin, Gherlin, and Leptin along with inflammatory markers like C - reactive protein.

Management of metabolic syndrome Reduction of insulin resistance is the primary goal for treatment of metabolic syndrome in women with PCOS. Lifestyle modification through diet, increased physical activity and reduction in body weight, especially waist circumference, represents the first-line therapy for metabolic syndrome in PCOS. Successful maintenance of exercise and weight loss can lower blood pressure, central adiposity, and very low density lipoprotein cholesterol while improving HDL-C and insulin sensitivity. Pharmacologic reduction in insulin levels should be considered for management for obese women who fail weight loss and for possible prevention of diabetes in PCOS, particularly among lean women. Metformin is widely used with fewer side effects. Specific additional treatment t for high blood pressure, dyslipidemia, obesity may be needed for these individuals. Additionally, Bariatric surgery may be another option for severe obesity with metabolic co morbidities.

8

Adolescent Health Committee FOGSI

ADOLESCENCE

Secondary Amenorrhoea

Dr. S. Sampathkumari MD, DGO, FICOG, FC Diab HoD, OG, Government Tiruvannamalai Medical College & Hospital, Tamilnadu

Dr. Prasheetha Fellow in reproductive medicine Gharbbha Rakshambigai Fertility Centre, chennai Secondary amenorrhoea is defined as the cessation of previously regular menses for three months or previously irregular menses for six months (1). Among the pathological causes the most common are PCOS, hypothalamic amenorrhoea, Hyperprolactinemia and premature ovarian failure.

antihypertensives, anti psychotics, illicit drugs, can increase the levels of a hormone that prevents ovulation and the menstrual cycle.

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Chemotherapy and radiation treatments for hematologic cancer (including blood, bone marrow, and lymph nodes) and breast or gynaecologic cancer can destroy estrogen-producing cells and Primordial follicles in the ovaries, leading to amenorrhea. The resulting amenorrhea may be short-term, especially in younger women.

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Ashermann syndrome, cervical stenosis produced by previous procedures in the uterus.

CAUSES OF SECONDARY AMENORRHOEA • Gynaecological conditions. Unbalanced hormone levels are common features of certain conditions that have secondary amenorrhea as a main symptom. These can include: -

Polycystic ovary syndrome (PCOS). Most women with PCOS either have amenorrhea or experience irregular periods.

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PREMATURE OVARIAN FAILURE. POF is an early ovarian malfunction, different from menopause which disrupts follicle production, resulting in amenorrhoea in women less than 40yrs of age. Incidence is about 1-3%. Most of the cases are idiopathic, genetic variations, aberrant interaction between genes, autoimmune causes, iatrogenic including radio and chemotherapy, viruses and toxins can be the causes.

Evaluation include elevated FSH, reduction in Anti Mullarian Hormone and Antral follicular count in USG.(2)

• Hypothalamic amenorrhea. This condition occurs when the hypothalamus, slows or stops releasing gonadotropin-releasing hormone (GnRH), the hormone that starts the menstrual cycle.

Common characteristics of women with hypothalamic amenorrhea include: -

Low body weight

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Traumatic brain injury, tumour in brain.

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Eating disorder, malabsorption

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Infection like meningitis, tuberculosis, syphilis.

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Emotional stress

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Strenuous exercise that burns more calories than are taken in through food

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Deficiency of leptin, a protein hormone that regulates appetite and metabolism.

• Hormonal disorders -

Hyperprolactinomas seen in 9% of women with secondary amenorrhea, Pathological hyperprolactinemia can be caused by both hypothalamic-pituitary disease (prolactinomas) as well as non-hypothalamic-pituitary disease.(3)

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Thyroid disorders

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Adult onset adrenal hyperplasia.

MANAGEMENT OF SECONDARY AMENORRHOEA Management of secondary amenorrhoea includes the treatment of underlying cause. Progesterone challenge test and if it fails, Estrogen and Progesterone challenge tests help in differentiating cause of secondary amenorrhoea. Once the causative factor is known treatment goals include preservation of fertility and, prevention of complications such as endometrial hyperplasia, osteoporosis, and heart disease through hormone replacement therapy. In cases of premature ovarian failure with infertility donor oocyte program is advised, with reasonable success rates.

Guidelines for Progestogen and Oestrogen/Progestogen Challenge Tests

• Medications and therapies.

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Certain birth control pills, injectable contraceptives, and intrauterine devices (IUDs) can cause amenorrhea. It can take a few months after stopping birth control for the menstrual cycle to restart and become regular.

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Medications, including certain antidepressants and

REFERENCES 1. Practice Committee of American Society for Reproductive Medicine. Current evaluation of amenorrhea. Fertil Steril 2008; 90(5) S219-S225.

2. Farkhondeh P, Zahra F. Premature Ovarian Failure: A critical condition in the reproductive potential with various genetic causes.

Int J Fertil Steril 2014; 8(1): 1-12.

3. Abha M, Nisha SM. Hyperprolactinemia. J Hum Reprod Sci 2013; 6(3): 168175.

4. David AK, Merrily AP. Amenorrhoea: An approach to diagnosis and management. Am Fam Physician 2013; 87(11): 781-788.

9

Poly Cystic Ovarian Syndrome in Adolescents

Polycystic ovarian syndrome, a heterogenous syndrome of unknown aetiology, is the leading cause of anovulation endocrinopathy.

Polycystic ovary syndrome (PCOS) is a hormone imbalance that can cause irregular periods, unwanted hair growth, and acne. PCOS emerges at puberty, with a long term side effect of cardiovascular disease, hypertension, endometrial cancer, type2 DM and hyperlipedemia through menopause. Hence, it should be managed in adolescence in view to prevent the long term sequelae.

Prevalence is reported to be 6.5% to 6.8% according to National Institute of Health Criteria, but prevalence in adolescence has not been specifically mentioned. Due to increased incidence of childhood obesity there are increases in the prevalence and severity of symptoms of PCOS in adolescent girls.

PCOS HISTROY 1721- Antonio Vallisneri -Young peasant woman, married, moderately plump, infertile, with ovaries larger than normal, like doves' eggs, lumpy, shiny and whitish.

1935-Stein & Leventhal described as Stein - Leventhal syndrome Women with amenorrhea, hirsutism, and obesity, found to have a polycystic appearance in ovaries.

1980 - Linked to hyperinsulinemia and impaired glucose tolerance.

1990- NIH consensus conference defined PCOS as Chronic anovulation /Oligo-ovulation with clinical and/ or biochemical hyperandrogenism, with exclusion of other mimicking etiologies, such as thyroid or Adrenal dysfunction.

2003 - Rotterdam consensus (ESHRE/ASRM) workshop proposed that 2 out of 3 criteria should be fulfilled - Oligo- and/or anovulation, Clinical and/ or biochemical hyperandrogenism, Polycystic ovaries on ultrasound (other etiologies must be excluded).

2006 - The Androgen Excess - PCOS Society recommended that PCOS be defined as clinical and/or biochemical, hyperandrogenism, with Oligo / anovulation and /or PCO excluding related disease.

PCOS is a disorder that is characterised principally by oligomenorrhea or amenorrhea with clinical or laboratory evidence of hyperandrogenemia and a significant proportion of overweight women with PCOS have hyperinsulinemia.

MECHANISM OF PCOS: 1. Growth hormone secretion during early puberty induces the release of IGF-1 by liver and most other tissues. This hormone also provokes Insulin Resistance which affect peripheral Glucose metabolism, this Hyperinsulinemia acting on IGF-1 causes ovarian hyperstimulation inducing Theca cell Hyperplasia and Hyperandrogenism. The increased androgen causes follicular atresia which causes increased LH secretion from pituitary which aggravates theca cell stimulation. After puberty the insulin and IGF-1 levels decline but in PCOS they remain as such. Therefore Hyperandrogenism is the primary abnormality in PCOS due to inherent defect in ovarian theca steroidogenesis. Insulin Resistance is superimposed upon ovarian dysfunction.

Hyperinsulinemia also aggravate androgen over production and contribute to various metabolic abnormalities.

2. Genetic factors - PCOS is an autosomal dominant condition through at least one group of patient with heritable X-linked forms of PCOS has been described and presence of Hyperinsulinemia, Hypertriglyceridemia, PCOS in other females, premature baldness in males & dyslipedimia among the members of the family suggest a genetic predisposition or susceptibility COMBINATION OF GENES are- CY 11 A /CYP 19 / CYP 17,VNTR LOCUS OF INSULIN GENE / INSULIN RECEPTOR / POST RECEPTOR and FOLLISTATIN GENE 3. Obesity - 40% - 60% of PCOS Adolescents are overweight and obese with greater visceral and abdominal adiposity. Adipose

tissue is the major site for direct formation of testosterone from circulating steroid precursor, Hence obesity is a major determinant of metabolic phenotype of PCOS 4. Gestational factors - SGA, LGA, IUGR leading to low birth weight, weight gain in postnatal life especially in SGA are precursors of PCOS 5. Premature menarche before 8 years has risk of 15 - 20% developing PCOS CLINICAL FEATURES HYPERANDROGENISM : 1. Hirsutism - affects 65-75% of pcos adolescence - presence of 5 alpha reductase in skin determines hirsutism. 2. Acne - about 25% cases is affected by this disorder. 3.

Androgenic alopecia - related to scalp hair loss, uncommon feature, incidence less than 5%. 4. Deepening of voice ANOVULATION: 60 - 85% of adolescence has oligomenorrhea, amenorrhea & rarely polymenorrhea. And DUB with endometrial hyperplasia INSULIN RESISTANCE - prevalence is 50 - 75% - acanthosis nigricans and obesity. Insulin resistance is the root cause of obesity with PCOS: 1. Lack of sensitivity of insulin receptor sites on cells – prevent the cell to utilize the glucose, the unmetabolised glucose leads to increase free glucose level in blood. This further leads to increase in insulin secretion finally causing imbalanced glucose & insulin levels.

2. Free glucose in blood is converted into fat by the liver – weight gain and obesity 3. Insulin resistance and obesity if unchecked is associated with increase in abnormal amount of male hormone testosterone – prevents ovulation, hence accumulation of unruptured eggs and infertility, facial/body hair.

Long term sequelae of PCOS are 1. Cardiovascular disease: Presence of obesity and metabolic disturbance in PCOS increases the cardiovascular risk in women with PCOS. 2. Diabetes mellitus type II: 20% of lean PCOS and 40% of obese PCOS show impaired glucose tolerance. This, combined with central obesity, accounts for higher incidence of Dm type 2 in later life.

3. Dyslipidemis: Women with PCOS show increased triglycerides and decreased HDL levels. It increases the cardiovascular risk in women.

4. Endometrial cancer: the risk of developing endometrial cancer is increased in PCOS due to unopposed estrogens, infertility and obesity.

5. Breast cancer: Presence of obesity, hyperandrogenism as well as infertility in PCOS favors breast cancer.

6. Ovarian cancer: Few studies have suggested an association between PCOS and ovarian cancer due to use of associated multiple ovulations for assisted reproductive technique Laboratory tests 1. TSH and Prolactin- To r/o Thyroid dysfunction and Hyperprolactinemia.

2. 17-OHP- To r/o NCAH by doing ACTH stimulation test.

3. DHEAS 4. Total and free testosterone - To assess for hyperandrogenemia if no clinical evidence of hyperandrogenism.

5. Luteal phase Progesterone - To assess ovulation in patients with hirsuitism who report “regular menses”.

6. 1 mg DST or 24 hr urinary free cortisol - To screen for Cushings Syndrome if clinical stigmata are present.

7. FSH, LH, Estradiol (In amenorrheic subjects) Once PCOS is confirmed, DO Fasting and 2 hour GTT, Lipid Panel and Fasting insulin USG findings in PCOS: TVS/MRI – 100% sensitive. TAS – 70%

10

Adolescent Health Committee FOGSI

ADOLESCENCE sensitive CRITERIA Enlarged ovaries, Hyperechogenic stroma, Peripheral array of microcysts 2 - 6mm >10 in number, Ovarian volume increased 5.5 – 10cm3, Increased spherocity index – width/length of ovary >0.7, Urterus width: ovarian length <1and Ovarian area >11cm3 Biochemical alterations in PCOS are • FSH normal • LH ↑ • FSH/LH >1.3 • Testosterone ↑ • SHBG ↓ • DHEA normal or ↑ • Androstenedione ↑ • Prolactin normal or ↑ • Sr. Insulin normal or ↑ • FBS/Sr. insulin <4.5 • E1 ↑ • E2 normal or ↓ • PAI 1 ↑ One-third of adolescents with PCOS meet criteria for metabolic syndrome. Paediatric ATP III Diagnostic Criteria for Metabolic Syndrome in Adolescents (3 of 5 criteria): 1. Blood glucose > 100 mg/dL 2. HDL-C < 40 mg/dL 3. Triglycerides ≥ 110 mg/dL 4. Waist circumference ≥ 90th percentile for age and sex 5. Blood pressure ≥ 90th percentile for age and sex.

ATP III, Adult Treatment Panel III; HDL-C, high-density lipoprotein cholesterol MANAGEMENT IN ADOLESCENCE Is mainly for menstrual regularization, to correct hyperandrogenism, obesity and to prevent long term sequalae Life style modification 1. DIET- carbohydrate should be reduced to only 40% of total calories(130gms/d). Snacks and meals should be taken three times a day and total calories per day should be 1500-1600 calories Breakfast should be taken within 2 hrs of waking up.

During sleep body is in fasting state where there is poor glucose / insulin metabolism – if prolonged there will be poor metabolism of glucose causing weight gain .so breakfast should never be skipped.

Avoid refined carbohydrates and sugars in processed foods which cause higher insulin spikes and fibre content in diet should be increased by increasing fruit and vegetables / oat bran / barley which will also prevent constipation and allows the body to eliminate toxins and decrease cholesterol (25-35 gms of fibre can reduce insulin peaks).Increased intake of omega 3/6 fatty acids – fish / nut / olive oil 2. EXERCISE - Moderate physical activity is essential to reduce weight and resume normal menses. 30-60 mts/day or 150 mts/wk of moderate exercise should be the goal of all adolescent girls. This will lower circulating free androgen and insulin level and increases SHBG there by lowers free testosterone.

3. Cigarette smoking should be abandoned. It lowers estrogen level and increases DHEA & Androgen level MEDICAL MANAGEMENT:A. 1. Oral contraceptives: Estrogen in OCP suppresses Androgen & adrenal hormones. 4th generation of combined OC pills is preferred which contain low dose E2 (30mcg), 2-3 mg Drospirenone (progestin with anti androgen] raises the secretion of SHBG in the liver which binds with testosterone, it also suppresses LH and it helps to reduce hirsutism and acne 2. GNRH - Selective suppression of ovarian androgenesis. Leuprolide acetate 3.75mg every 28 days decreases hirsutism .Osteoporosis is undesirable in young girls even with Add-back therapy with OC's / estrogen replacement. so not used B. Antiandrogens -: 1. Cyproterone acetate - it is antiandrogenic progestogen. This blocks the hormone action at receptor level. it decreases 5-alpha reductase activity. It induces hepatic enzyme & increases the metabolic clearance of plasma androgens. Also acts as a potent 11

progestogen having agonist effect on progesterone receptors. This is given in a dose of 50-100mg for 10dys from day5 of the cycle or given in combination with estrogen as OC pills. Recommended in case of hyperandrogenic state.

2. Flutamide-it is nonsteroidal antiandrogen. It blocks the androgen receptor site; dose is 250mg daily for 6mths not in use regularly due to hepatic toxicity 3. Spirinolactone- it is antialdosterone diuretics. It inhibits androgen biosynthesis from ovary & adrenal. Dose is 25-150mg/day.

4. Finasteride - it inhibits 5-alpha reductase activity. 5mg daily dose is effective to reduce hirsutism.

5. Ketoconazole -inhibits enzyme for androgen synthesis.

6. Cimetidine - H2 receptor antagonist having antiandrogenic effects.

C. Insulin sensitizer - Metformin- Biguanide - lowers blood glucose by inhibiting hepatic glucose production &enhancing peripheral glucose uptake. Hyperandrogenism is also relieved. Dose is 500mg tid .It reduces hirsutism by reducing insulin resistance .It is given to girls to improve ovulation.

D. Combination of OCPS, antiandrogen, or metformin are superior to mono therapy.

E. Anti obesity drugs 1. Orlistat-pancreatic lipase inhibitor prevents absorption of 30% dietay fat 2. Sibutramine-centrally acting serotonin and non adrenalline reuptake inhibitor enhances satiety.

Both improve insulin resistance, lipid profile and glycemic control.

F. Other methods 1. Bariatric surgery is indicated in cases of failed medical management 2. Mechanical methods to remove hair Temporary methods are shaving, waxing and depilatory creams.

Permanent methods are electrolysis and laser.

3. Laparoscopic ovarin drilling is not encouraged which is the last mode of treatment Recent study –AMH lowers sensitivity of follicles to FSH. AMH levels are significantly elevated in pcos The hormonal interactions between HPO axis and ACTH axis in adolescence

CONCLUSION 1. PCOS is common in adolescents and should be considered in an adolescent with irregular menses and excess weight.

2. Lifestyle changes are the first-line intervention in young women with PCOS, who are overweight 3. Management of the PCOS adolescent with metformin is beneficial and well tolerated, but the longer term effects are not yet established 4. Adolescent girls with androgenic features(acne, hirsutism,scalp bald) need to be evaluated for hormonal treatment.

5. The metabolic syndrome is a common feature of PCOS. Testing for glucose intolerance and dyslipidemia is required, particularly in the presence of obesity.

References 1. JSAFOG Jp journals 10006-1192 Adolescent polycystic ovary syndrome management dilemma. Richa singh, Poonam yadow, Roochi parveen.

2. PCOD in adolescence Susan k.Bask,John c.marshall Dept of int medicine, University of Virginia, USA. 3. AJOG,Vol 203, page 201-5 Diagnosis of PCOD in adolescence Emcocarnia, Rogen A.lab.

Ovulation Induction In PCOS Prof. Jaideep Malhotra M.D., F.I.C.O.G., Hon. Sec ICOG Director – Rainbow Hospitals, Agra INTRODUCTION Polycystic ovary syndrome is a heterogeneous endocrine condition that affects approximately 5% to 10% of women in the reproductive age group. Patients with PCOS are often plagued by infertility secondary to both ovulatory dysfunction and the effects of hyperandrogenism.

Several methods have been effective for ovulation induction and fertility treatment in women with PCOS: • Weight loss, exercise, and lifestyle modifications • Clomiphene citrate • Metformin • Gonadotropins • Ovarian drilling • IVF Weight Loss and Lifestyle Modifications Obesity is strongly associated with PCOS and may be present in up to 50% of cases. Obese women with PCOS are more likely than thin women with PCOS to suffer from anovulation. This effect on ovulation is secondary to insulin resistance. Weight loss through exercise and diet has been proven effective in restoring ovulatory cycles and achieving pregnancy. In obese, anovulatory women with PCOS, weight loss of even 5%to 10%of body weight often restores ovulatory cycles. Studies also show that overweight women are less likely to respond to pharmacologic ovulation induction methods. Routine exercise is also very important in the reproductive health of women with PCOS. Exercise increases insulin sensitivity and helps achieve and maintain weight loss. Other lifestyle factors such as excessive caffeine intake, alcohol consumption, and smoking should also be addressed.

Clomiphene Citrate Clomiphene citrate has been used as a first-line ovulation induction agent for over 40 years. It is a selective estrogenrecept or modulator that stimulates endogenous FSH production and secretion by interrupting estrogen feedback to the hypothalamus and pituitary.

PCOS patients can be sensitive to ovulation induction medications because of a large number of antral follicles. This places some women with PCOS at risk of over-response with multiple follicular development and ovarian hyper stimulation; however, other women have a poor response without development of a dominant follicle, despite using higher doses of CC. The starting dose of clomiphene citrate is 50 mg per day for5 days, commencing between day 2 and 5 of menses. The earlier start (day 2) improves follicular recruitment. Menses may be induced with a progestin if required. If this dose produces multiple follicular development, the dose can be lowered to 25mg. If ovulation is not achieved using 50mg per day, the dose can be increased in increments of 50 mg. The recommended maximum dose is 150 mg/day as there is no clear evidence of efficacy at higher doses. Cycle monitoring should be considered in at least the first cycle and when the treatment dose has to be increased because of failure to ovulate. Although 60% to 85% of patients will ovulate on CC, only about one half will conceive. Approximately 50% of conceptions will occur on 50mg, with another 20% and 10% occurring on 100mg and 150mg, respectively. Lack of conception despite evidence of ovulation may be due to anti-estrogenic effects of CC on the endometrium, which may manifest as a thin endometrium on ultrasound. Similarly, if pregnancy does not occur within 6 ovulatory cycles, another ovulation induction method should be considered. Drawbacks of CC include an increased rate of twin(7% to 9%) and triplet (0.3%) pregnancy, and side effects such as vasomotor hot flashes. Unusual visual symptoms(visual blurring or persistent after-images) are also noted in 1% to 2% of patients taking CC, which are likely due to anti-estrogenic effects of CC on the visual cortex. Although more studies are required, it is best to

Dr. Alka Saraswat M.S. Saraswat Nursing Home Agra limit a patient's lifetime exposure to CC to 12 treatment cycles, as additional cycles may place the patient at increased risk of border line ovarian tumours.

Insulin Sensitizing Agents The recognition of an association between PCOS and hyper insulinemia has led to the use of insulin-sensitizing agents in ovulation induction. Metformin, the most widely studied agent used in PCOS, is a big uanide insulin-sensitizing agent that acts by inhibiting hepatic glucose production and increasing peripheral glucose uptake. It does not stimulate secretion of insulin or cause hypoglycemia.

Meta-analysis comparing CC and metformin, both alone and in combination, found that metformin alone increased the odds of ovulation compared with placebo but did not result in a statistically significant difference in pregnancy rates. When CC and metformin were compared with CC alone, both ovulation and pregnancy rates were statistically increased to 4.39and 2.67 respectively. Live birth rates using CC alone or with metformin were significantly higher than rates with metformin alone (7.2%).The evidence supports the use of clomiphene citrate over metformin as first-line pharmacologic therapy following lifestyle modification in women with PCOS. However, there may be a role for the addition of metformin to CC in women who are clomiphene-resistant. Women with PCOS who are older and have increased visceral obesity benefit more from the additional use of metformin.

Patients on metformin often experience unpleasant side effects of nausea, bloating, cramps, and diarrhea, and they should be counselled to start with 250 mg to 500 mg PO daily and increase as tolerated to the optimal daily dose of 500 to750 mg 3 times daily with food. A long-acting formulation once daily can be used to improve compliance.

Although some studies have shown that continuing metformin in pregnancy may decrease the spontaneous abortion rate, randomized controlled trials are needed in this area before sustained metformin treatment throughout pregnancy can be recommended.

Gonadotropins Use of intramuscular gonadotropins began in the 1960s. These preparations, from the purified urine of postmenopausal women, contained both FSH and LH. Over the last decade, recombinant human FSH has been the main preparation, and it can be selfadministered subcutaneously. Gonadotropins are used when PCOS patients fail either to ovulate or to conceive with oral ovulation inducing medications. The chronic low dose regimen of FSH stimulation is used to avoid overstimulation of follicles, multiple follicle development and prevent OHSS and multiple pregnancy. A starting dose of 75IU- 150IU of recombinant FSH is given for an initial 14 day period with an incremental dose rise of 25IU-37.5IU for 7 days followed by a further increment of 25-37.5Iu for the next 7 days.

Daily injections of gonadotropins are combined with concurrent serum estradiol and ultrasound monitoring with the aim of monofollicular development. Once the dominant follicle has reached the appropriate size, hCG is administered to trigger ovulation. Because of the high number of antral follicles in women with PCOS, it is not uncommon that treatment is cancelled to minimize the occurrence of multiple pregnancy and also of ovarian hyperstimulation syndrome.Pregnancy rates with gonadotropins are 20% to 25% per cycle. Drawbacks to gonadotropin treatment, as mentioned earlier, are requirements for intensive monitoring, cost, multiple pregnancy, and ovarian hyperstimulation.

Ovarian Drilling Surgical ovarian wedge resection by open laparotomy was one of the first treatments for an ovulation due to PCOS. Because of the operative 12

Adolescent Health Committee FOGSI

ADOLESCENCE morbidity of the procedure and the risk of postoperative adhesions, ovarian wedge resection by laparotomy has largely been abandoned With the popularity of minimally invasive surgery, laparoscopic ovarian drilling (LOD) is thought to be less destructive to the ovary and has a lower risk of adhesion formation. Laparoscopic ovarian drilling uses either cautery or laser. The most commonly employed method is the introduction of a monopolar PCO drilling needle at right angle with 40 watts current making 4-5 holes each lasting 4 seconds at a depth of 4mm on both ovaries. Approximately 80% of PCOS patients will become ovulatory after LOD as the reduction in androgen after ovarian drilling lowers the peripheral aromatisation of estrogens and results in restoration of feedback to the hypothalamus and pituitary. There was no difference found in the rates of miscarriage, ongoing pregnancy, or live birth between patients who underwent LOD and patients treated with gonadotropins for ovulation induction. There were significantly fewer multiple pregnancies in the LOD than in the gonadotropin treatment groups. Adjuvant therapy with CC or gonadotropins may be required to achieve equivalent pregnancy and live birthrates in patients remaining an ovulatory 8 weeks after LOD or those who subsequently become an ovulatory.

In Vitro Fertilization IVF, with or without intra cytoplasmic sperm injection, is the next treatment option for women with PCOS who fail to conceive with gonadotropin treatment or in the presence of other indications for advanced reproductive technologies. In IVF, gonadotropins are administered to achieve multifollicular development for oocyte retrieval and generation of embryos for transfer into the uterus.

Pregnancy rates can approach 40% to 50% per cycle with IVF, but, as with fertility in general, success is significantly influenced by the women's age. PCOS patients achieve pregnancy and live birth rates similar to those of non-PCOS patients during conventional IVF cycles.

The risk of multiple pregnancy is more easily controlled with IVF than with ovulation induction with gonadotropins, because the number of embryos transferred into the patient's uterus can be limited and surplus good quality embryos cryo preserved for future transfer.

GnRh analogues have important clinical applications in PCOS. Use of antagonists for down regulation in non ART and ART cycles is growing in popularity due to shorter duration of treatment and patient friendly approach. Agonist trigger for oocyte maturation in antagonist cycles where ART is planned is a major step towards OHSS-free clinic.

Summary 1. Weight loss, exercise, and lifestyle modifications have beenproven effective in restoring ovulatory cycles and achieving pregnancy in overweight women with PCOS and should be the first-line option for these women. Morbidly obese women should seek expert advice about pregnancy risk.

2. Clomiphene citrate has been proven effective in ovulation induction for women with PCOS and should be considered the first-line therapy. Patients should be informed that there is an increased risk of multiple pregnancy with ovulation induction using clomiphene citrate.

3. Metformin combined with clomiphene citrate may increase ovulation rates and pregnancy rates but does not significantly improve the live birth rate over that of clomiphene citrate alone.

Metformin may be added to clomiphene citrate in women with clomiphene resistance who are older and who have visceral obesity.

4. Gonadotropin should be considered second-line therapy for fertility in an ovulatory women with PCOS. The treatment requires ultrasound and laboratory monitoring. High costs and the risk of multiple pregnancy and ovarian hyper stimulation syndrome are drawbacks of the treatment.

Chennai, Tamil Nadu Report of Adolescent health activity by : Prof. Dr. S. Sampathkumari, National Coordinator, FOGSI Adolescent Health Education Committee

Program on July 20th, 2014. Dr. ShaanthyGunasingh, Secretary, OGSSI was the Chief Guest. This program was conducted in celebration of the 'Adolescent Week' on July 20th, 2014.

At Kancheepuram on July 9th, 2014 a) Dhusi Polytechnic College – more than 200 students attended the event in the morning & in the afternoon programs at 2 schools– b) Dr. Jayam Kannan conducted the event at GovtHr Sec School c) Dr. Sampath kumari conducted the event at C S I High School 13

On 7th June, 2014 at Semmencheri an Adolescent Program was conducted at Community hall – Talks on Anaemia, Menstrual problems, Sexual Abuse & Vaccination. M/s.

Thozhamai NGO was the co organizer.

At Kolapakkam Panchayat Hr Sec School, Near Vandalur on July 23rd, 2014 In association with M/s. Tagore Medical College an Adolescent program was conducted at Kolapakkam Panchayat Hr Sec School. 100 students from 9th – 12thStd participated. Dr. Premalatha from Tagore Medical College was the other resource person to conduct the event along with Dr. S. Sampathkumari

IUI Recommended Guidelines Dr Jyoti Bali Consultant (Infertility Specialist) Bloom IVF Centre, Fortis La Femme Hospital GK-II, New Delhi.

IUI with or without COH (controlled ovarian hyperstimulation) is an indispensable part of infertility treatment because it is a non invasive and a successful procedure. IUI being available in low cost settings make it popular. IUI instimulated cycles may be considered where IVF is not an option because of cost (ESHRE Capri Workshop Group 2009).

First paper entitled IUI was published in 1962, since then IUI has evolved through innovations such as COH protocols, sperm preparation techniques, monitoring of preovulatory timing and induction of ovulation with hCG. Therefore, to have good practice guidelines for this indispensible procedure in the armentarium of the infertility management is the need of the hour.

Steps of IUI • Selection • Counseling • COH protocol • Follicular and endometrial monitoring • Semen preparation • Procedure i) Selection • Although IUI is less invasive and expensive than IVF, it should only be applied if the probability of conception is improved significantly as compared to natural cycle.

• IUI with partner's sperm can be used as a potentially effective treatment for infertility of all causes in women under 40 years of age, except for cases with tubal blockage, severe tubal damage, very poor egg quality, ovarian failure and severe male factor infertility.

• Evaluating before initiating therapy is essential. Three basic tests include semenogram, midluteal progesterone, HSG ± laproscopy to establish tubal patency.

• In anovulatory cycles weight loss, metformin, D-chiro-inostiol and life style modification is recommended. ii) Counselling • Counselling plays a key role for the couple undergoing the procedure in terms of completing the treatment with comfort and compliance.

• Couple should receive adequate counseling prior to starting the treatment, especially when donor sperm is to be used.

• Assurance regarding complete confidentiality, and information of the means by which donors are selected, screened and matched.

• Success rates of the procedure, cost involved, the time logistics etc. should be detailed before the commencement of IUI cycles.

• Psychological issues surrounding insemination should be addressed. iii) Ovulation induction in IUI • Principles of ovulation induction o Anovulatory patients – monofollicular o Ovulatory patients – 2-3 follicles only • The ovulation induction cycle could achieve a higher pregnancy rate than the natural cycle in IUI, whether with Chomiphene Citrate + Progesterone, CLOMIPHENE CITRATE + HMG, particularly for the infertile patients under 35 years. But the natural cycle is preferable for the > or = 35-year-olds (Chen L, Liu Q. Zhonghua Nan Ke Xue. 2009 Dec).

• There is evidence that IUI with Ovarian stimulation increases the live birth rate compared to IUI alone.

• The likelihood of pregnancy was also increased for treatment with IUI compared to Timed Intercourse in stimulated cycles.

• One adequately powered multicentre trial showed no evidence of effect of IUI in natural cycles compared with expectant management.

• There is insufficient data on multiple pregnancies and other adverse events for treatment with ovulation induction.

• Therefore couples should be fully informed about the risks of IUI

and ovulation induction as well as alternative treatment options (Veltman-Verhulst SM, Cochrane Database Syst Rev.2012 Sep 12).

• Clomiphene treatment outcome o Pregnancy rate of 36% o Failure - no pregnancy despite ovulation – 25% o Resistance - no ovulation – 27% o Antiestrogenic effect – 5% o (Homburg et al,2005 hum reprod) • CLOMIPHENE CITRATE 100mg Day 2 to Day 6 • HMG/FSH 75/150 units Day 6 to Day 9 • Serial USG & E2 levels • Ovulation trigger with IUI • Advantages o Comparable pregnancy rate o Cost effective o Less multiple pregnancy & OHSS • Problems encountered in OI o Premature LH surge- Seen in 20% of cycles and has deleterous effect on fertilisation and pregnancy rates (detection - urinary or serum LH estimations or use Gnrh antagonists/ Gnrh-a) o Poor responders o Ovarian Hyper Stimulation Syndrome o Poor endometrial development • GnRh Antagonist - Indications & Uses (Ragni et al Human Reprod, Jan 2004) o Standard Protocol for IUI – 34% PR o Elimination of LH surge o Convenience of converting IUI to IVF cycle, if more than 5 dominant follicles ≥ 16mm. o Programming of IUI cycles – can avoid weekends o Fixed or flexible protocol – in a fixed protocol antagonist injection is started on day 6 of stimulation and in a flexible protocol it is started once the leading follicle is of ≥ 14mm.

• The use of a GnRH antagonist in conjunction with controlled ovarian stimulation and IUI significantly increases pregnancy rates and reduces the incidence of premature luteinization (Bakas P. Fertil Steril.2011 May) • Identification of Patient at risk of hyperstimulation o PCO pattern on USG o High AMH o Previous history • Identification of risk during cycle o E2 > 1500 –2000 pg/ml o Dominant Follicles > 5 Follicular and endometrial monitoring • Serial USG (TVS) • Occasional serum E2 levels (optional) • Urinary LH surge (optional) • Baseline E2 if D1 < 150 pmol/l a woman was 3.2 times more likely to conceive than those with higher E2 levels (Costello et al, 2001) • CLOMIPHENE CITRATE - exerts antiestrogenic effects on the endometrium Treatment • Delay ovulation trigger till endometrium >7mm • Clomiphene Citrate + Gonadotrophins / Gonadotrophins only • Mock endometrial-preparatory cycle • Use of aspirin 50 to 75 mg daily, Viagra 25 mg 3 times daily (vaginally) • Hysteroscopy • Endometrial sampling significantly increases pregnancy rates in 14

Adolescent Health Committee FOGSI

ADOLESCENCE IUI procedures when it is done in the proliferative phase of the IUI cycle, or the cycle prior to IUI, than pregnancy rates with IUI alone (Abdelhamid AM, Arch Gynecol Obstet.2013 Mar 15) • Trigger o HCG at 18-20 mm (Clomiphene Citrate + Gonadotrophins cycles) o HCG at 20-22 mm (Clomiphene Citrate cycles) o Recombinant HCG o Occasionally GnRha – if risk of hyperstimulation • HCG administered when the largest follicle size reaches 16.016.9 mm leads to similar clinical and ongoing pregnancy rates as when it reaches 18.0-18.9 mm in IUI cycles (da Silva AL, Eur J Obstet Gynecol Reprod Biol.2012 Oct) Semen preparation • Sexual abstinence of atleast 2 days prior to IUI ® 88% pregnancy rate • No abstinence 46% pregnancy rate • The highest pregnancy rate was seen with abstinence inter val of ≤ 3 days (14%) and the lowest pregnancy rate with abstinence of ≥ 10 days (3 %) • Reason ? Sperm senescence and functional damage (Jurema MW. Fertil steril 2005) Collection of Semen • Split ejaculates – usually by masturbation and is collected into a non toxic, sterile container.

• Vol < 2ml • Presence of antisperm Ab – The addition of culture medium to the specimen pot before the semen collection results in improved motility, if there has been previous marked viscosity of the semen, likewise, addition of 50% albuminar 5 to the pot will reduce sperm agglutination, if there are antisperm antibodies in the ejaculate.

• Sample with low no. of motile sperms - 2nd sample is advised after 2 hrs.

• Higher no. of motile sperms • IUI pregnancy outcome is enhanced by shorter intervals from sperm collection to sperm wash, from sperm wash to IUI time and from semen collection to IUI time. Delaying semen processing from 30 min up to 1 hour and/or delaying IUI from 90 mins upto 2 hours after collection compromises the pregnancy outcome in hMG-IUI cycles (Y Yavas et al).

Selection of Semen Processing Technique (from slide) • Density gradient separation of sperm for artificial insemination • In addition to technical simplicity and robustness, a sperm preparation method needs to select not just the more motile and morphologically normal spermatozoa but also those spermatozoa with reduced DNA damage.

• Currently the most effective and efficient technique for this is density gradient centrifugation, which has been extensively validated through research and clinical application (Mortimer D , Methods Mol Biol. 2013).

• In low cost settings, swim up technique can be used, though density gradient is recommended in cases with low sperm count and or motility.

Procedure • Vagina and cervix to be cleant with normal saline • Cervical mucus to be aspirated gently with tuberculin syringe o Pregnancy rate was 15% in the cervical mucus aspiration group and 9.9% in the control group. o Mucus aspiration led to significantly increased pregnancy rates for women with unexplained infertility (Int J Gynaecol Obstet.

2008 Nov; Simsek EHaydardedeoglu ) • Avoid holding with cervix with tenaculum as it can elicit uterine contractions • IUI by passive straightening of the uterus by means of bladder filling, or IUI performed with an empty bladder • The pregnancy rate was higher in the full bladder group than in the empty bladder (control) group 13.5% vs 7.4.

• The risk of undergoing difficult IUI was higher in the empty bladder group than the full bladder group 10.0% vs 37.8%.

• The clinical pregnancy rate was also higher in the group of patients who had easy IUI than in the group of patients who had difficult IUI -12.7% vs 5.5% (Ayas S J Obstet Gynaecol Res. 2011 Nov 9) 15

• Ultrasound guidance in IUI improves pregnancy rates and reduces the frequency of difficult IUI (Oztekin D, Med Princ Pract. 2013) • Inseminated volume – similar pregnancy rate for 0.5 ml and 3 ml of inseminated semen, so volume of processed semen does not influence the success rate of IUI. • Soft versus firm catheters for intrauterine insemination o There was no evidence of a significant effect difference regarding the choice of catheter type for any of the outcomes (van der Poel N. Cochrane Database Syst Rev.2010).

• 10 min bed rest after IUI has positive effect on pregnancy rate (Saleh et al, 2000).

Luteal Support • Vaginal progestin pessaries • 100 mg twice daily - if Clomiphene Citrate/ FSH/ HMG cycle • 200 mg thrice daily - if GnRha+HMG/FSH • Vaginal Gel • Oral – dehydrogestone 10mg bid • HCG 2000-2500 U IM day 3 • Progesterone – IM 50-100mg Impact of luteal phase support on pregnancy rate in IUI • Pregnancy rates per cycle were significantly higher in the group using luteal support (21%) compared with the control group (12%). Live birth rate per cycle and per patient was also significantly higher in patients with luteal support • Luteal phase support with vaginal progesterone gel significantly affects the success of ovarian stimulation and IUI cycles in patients with unexplained infertility (Fertil Steril. 2009, Erdem A) Factors Influencing Success Rate • Cause of infertility • Age of both partners • Duration of infertility • Treatment cycle rank • Sperm parameters • Number of Cycles • In patients with unexplained or mild male subfertility and a poor prognosis for natural conception, one cycle of IVF-eSET might be as effective as three cycles of IUI-COS as primary treatment. Elective single embryo transfer does not seem an effective strategy in preventing multiple pregnancies in this particular population (Custers IM, Fertil Steril.2011 Nov) The couple with the best chance of pregnancy can be described as follows : An under 30 woman with cervical or anovulatory infertility and a man with a TMS >/=5 million spermatozoa. The "ideal" stimulation cycle enables the recruitment of two follicles measuring >16 mm with an E(2) concentration >500 pg/mL on the day of hCG administration.

The best results are obtained when IUI is performed using a soft catheter (Merviel P, Fertil Steril.2010 Jan).

REFERENCES 1. ESHRE Capri Workshop Group 2009 2. Chen L, Liu Q. Zhonghua Nan Ke Xue. 2009 Dec 3. Veltman-Verhulst SM, Cochrane Database Syst Rev.2012 Sep 12 4. Homburg et al,2005 hum reprod 5. Ragni et al Human Reprod, Jan 2004 6. Bakas P. Fertil Steril.2011 May 7. Costello et al, 2001 8. Abdelhamid AM, Arch Gynecol Obstet.2013 Mar 15 9. da Silva AL, Eur J Obstet Gynecol Reprod Biol.2012 Oct 10. Jurema MW. Fertil steril 2005 11. Y Yavas et al 12. Mortimer D , Methods Mol Biol. 2013 13. Int J Gynaecol Obstet. 2008 Nov; Simsek EHaydardedeoglu 14. Ayas S J Obstet Gynaecol Res. 2011 Nov 9 15. Oztekin D, Med Princ Pract. 2013 16. van der Poel N. Cochrane Database Syst Rev.2010 17. Saleh et al, 2000 18. Fertil Steril. 2009, Erdem A 19. Custers IM, Fertil Steril.2011 Nov 20. Merviel P, Fertil Steril.2010 Jan

Ovulation Induction with IUI

Dr. Madhuri Patil MD, DGO, FCPS, DFP, FICOG (Mum) Dr. Patil's Fertility & Endoscopy Clinic, Bangalore Infertility is a very common condition affecting approximately 13-14% of reproductive-aged couples. Despite a stable prevalence of infertility in this population, the demand for infertility services has increased substantially over the past decade.

IUI is a widely utilized technique for treatment of infertility, indications being extremely varied and has often being used empirically. Though there is serious disagreement about the results of the procedure, it has still become a popular method because of its simplicity, low operational cost and ambulatory character. Although widely used, its effectiveness remains a matter of debate. Although IUI is less invasive and less expensive than ART, it should only be applied if the probability of conception is improved significantly as compared to the natural chance of conceiving. To increase the number of available oocytes at the site of fertilization, ovulation induction (oral or gonadotropins) can be applied in conjunction with IUI. IUI with partner's sperm can be used as a potentially effective treatment for infertility of all causes in women under the age of 40 years except for cases with tubal blockage, severe tubal damage, very poor egg quality, ovarian failure (menopause), and severe male factor infertility.

If we compare timed intercourse with IUI the probability of conception is more with IUI. If we compare IUI in an natural cycle and stimulated cycle it is higher in an stimulated cycle.

Indications for IUI The most common indications for performing an IUI cycle are: • Anovulation/Oligoovulation • PCOD • Hypothalamic/pituitary dysfunction • Luteal phase defects • Unexplained infertility • Endometriosis • Cervical factor which cannot be overcome by medical treatment.

• Immune related infertility • Mild to moderate male factor in which the semen sample shows deficiencies in the number (oligospermia), motility (asthenospermia), or morphology (teratospermia) of spermatozoa.

A threshold of at least 1 million motile sperms seems a reasonable requirement • Immunological problem in the male • The impossibility of vaginal ejaculation (psychogenic or organic impotence, severe hypospadias, retrograde ejaculation and vaginal dysfunction) • The use of sperm cryopreserved prior to cancer treatment or vasectomy.

Advantages 1. Bypasses Vaginal acidity + cervical mucus hostility 2. Deposition of a well prepared sperms as close as possible to the oocytes (Short distance) 3. Non invasive & Inexpensive 4. Simple to perform and for this reason are easily repeatable 5. Eliminates PG, antimotility& anti-capacitation factors present in seminal plasma 6. Cumulative rate of pregnancy after three IUI cycles is usually greater than the natural expectancy of pregnancy which these couples have during the same period of time 7. Antenatal & perinatal complications similar to pregnancies from normal Spontaneous conceptions

Disadvantages 1. Multiple pregnancy (> than IVF) number of follicles that grow or rupture can not be precisely controlled 2. Infection resulting in iatrogenic infertility 3. Psychological 4. OHSS 5. Ovarian cyst 6. Need for cycle monitoring 7. Expense of treatment 8. Possible late health risk – Cancer 9. Great variability of its efficacy depending on the different indications 10 Risks from repeated cycles of ovulation stimulation that are required to achieve a satisfactory pregnancy rate.

Three semen parameters including total motile count, motility and normal morphology before and after sperm separation were identified as predictors of pregnancy by IUI. If the couple fails to conceive with 46 IUI cycles done for the correct indication and when no contraindications exist, it is not recommended to do IUI one cycle after another. It is best to counsel the patients for IVF/ICSI. Steps of IUI include 1. Selection + counseling 2. Protocol (spontaneous or stimulated cycle) 3. Ultrasound for follicular size and Endometrial thickness 4. Timing of insemination 5. Semen preparation 6. Procedure 7. ?LPS Evaluation before initiating therapy is essential A baseline ultrasound scan is very important to rule out any uterine, ovarian and adenexal pathology or other potential sub fertility factors.

After which three basic test include 1. Semenogram 2. Midlutealprogestrone 3. HSG + laparoscopy Other test may be done as indicated and include Endocrine evaluation on Day 2/3 • FSH • LH • Prolactin • TSH • DHEAS • Testosterone • Androstenidione • Alpha hydroxy progesterone Success rates are contingent upon the procedure being performed 1. for correct indication 2. avoiding performance of IUI when CI exist 3. whether women is ovulating normally on her own 4. the age of women The review of literature over the past 15 years has shown a wide range of variation in the pregnancy rates from 0 - 26% per cycle done for different indications. Take home baby is controversial as there is no evidence- based infertility data.Factors affecting success of IUI include couple factors like age, duration and cause of infertility, BMI. It also depends semen processing technique, protocol of COH and timing of insemination.

Timing of insemination is very important as viable sperms should be 16

Adolescent Health Committee FOGSI

ADOLESCENCE present at the time of ovulation, which makes it mandatory to detectthe exact time of ovulation. This can be done either by monitoring serum or urinary LH levels or administration of hCG (5000 IU of urinary hCG or recombinant hCG 250 mcg SC )when the leading follicle is more than 18 – 20 mm at transvaginal ultrasound.

Transvaginal scan (TVS) is repeated 24 and 36 hours later. A 24 hour scan is to be done as at times if there is a endogenous LH surge the follicle would rupture early. Otherwise the IUI needs to be done at 36 hours, when the TVS is done. If the follicles is ruptured IUI is done once or else IUI is again repeated after 12 hours after confirming ovulation. But the Cochrane review has published that that double IUI showed no significant benefit over single IUI. The IUI should be done only with processed sample. The sperm preparation helps in 1. Removal of • Non-motile spermatozoa, • Leucocytes and immature forms • Seminal plasma – PG & antigenic proteins responsible for contraction and cramps • Seminal plasma microorganisms might induce inflammatory process 2. Decreases • Release of lymphokines and/or cytokines • Formation of free oxygen radicals causing functional demise of spermatozoa and sperm oocyte interaction Selection of sperm for IUIrequires different sperm preparation procedures to obtain spermatozoa with highest potential to maximize chances of fertilization. With normal semen sample it is easy, where as if the sample is abnormal it requires refinement of technique. Final Result of semen processing is to obtain enriched fraction of motile and morphologically normal spermatozoa with better fertilizing ability. It is necessary to select the sperm preparation techniqueaccording to the individual semen sample. Whether one uses the swim up technique or density gradient will depend on the count, motility, morphology, source of sample and presence or absence of debris& other cellular contamination.

Procedure Semen samples were allowed to liquefy for 30 minutes at 37°C and a drop of undiluted semen is examined on Makler's chamber.

The choice of the methods is made as follows • Sperm concentration > 15 million/ml with good forward progressive motility, swim up performed • Borderline samples, & samples with large amount of debris, extreme oilgozoospermia, severely compromised motility best prepared by gradient separation • Samples collected by electroejaculation - low motile sperm concentration best suited for gradient separation Type of catheter used for the procedure is again an important determinant of success. Open ended/rounded tip teflon catheters least traumatic & most efficient. A 10 minutes bed rest after IUI has a positive effect on the PR. Pregnancies resulting from IUI occur during early treatment cycles,80 % occurring during the first four cycles.

Dramatic fall is seen in PR after 4 cycles and therefore continued IUI after 4 cycles not recommended.

The treatment needs ovulation induction with oral ovulogens or gonadotropins with careful monitoring in order to prevent the risk of ovarian hyperstimulation and/or multiple pregnancy.

Ovulation Induction for IUI IUI can be done in a spontaneous cycle (cervical factor infertility & sexual dysfunction) or stimulated cycle. When done in a stimulated cycle one needs to modulate the dose of the drugs to achieve monofollicular deveopment or at most two.

Ovarian Stimulation Protocol Our Aim is to use proper drugs after proper evaluation and investigations and at a proper time and the drugs used for ovulation Induction are enumarated below.

1. Clomiphene Citrate 17

2. Tamoxifen 3. Human Menopausal Gonadotrophins (hMG) 4. Purified & Ultrapurified FSH 5. Recombinant Gonadotrophins: FSH, LH 6. Gonadotrophin Releasing Hormone antagonist (GnRHa) 7. GnRH antagonist.

8. URinary or recombinant hCG As selection of dominant follicle occurs,in the early follicular phase, OI drugs should be initiated within 3 days of MC. The dose of CC/Tamoxifen/GT tailored to each individual.

Clomiphene Citrate Down regulates estrogen receptors on the hypothalamus resulting in the pituitary secreting more FSH. • CC is started from D2 - 6 of spontaneous or induced MC • Starting dose is 50 - 100 mg and the maximum dose that can be used is 150 mg • Treatment is discontinued if 2 consecutive cycles are anovulatory • Ovulation occurs in 70 – 85 % with a pregnancy rate of 40 – 50 % • Antiestrogenic effect on cervical mucosa and endometrium reduce the success rate • Abnormal endocrine response in the form of elevated LH levels from D9 may result in premature luteinization reducing the success rate • Cycles require close monitoring by USG, mid follicular LH levels and PCT Tamoxifen • Tamoxifen is started in the dose of 20 mg from D 2 or 3 of spontaneous or P4 induced bleeding for 5 days • Combination treatment of CC 50 mg &Tamoxifen 20 mg from D 2 or 3 of MC for 5 days can also be used in selected cases • If no response dose increased to maximum of 40 mg • Discontinued if patient anovulatory despite 40 mg in consecutive cycle It is not the first-line treatment for OI in patients with adequate endometrium but is a promising alternative to CC for ovarian stimulation in the subgroup of patients who failed to develop an adequate endometrial thickness in a previous OI cycle with CC. Follicular maturation can be induced by 1. Endogenous LH surge 2. Exogenous hCG – 5000 IU IM 3. GnRha 1mg subcutaneous Gonadotropins for ovulation induction Indications • Clomiphene resistance/failure • Persistent hyper secretion of LH • Negative post coital test • IUI and ART cycles OI Protocols using Gonadotrophinsare shown in the figures below 1. Combination protocols - CC/Tamoxifen + GT Protocol

CC 100 mg orTamoxifen 20 mg from day 2 – 6 of menstrual cycle + hMG or FSH 75 IU from day 7 till hCG We could also use gonadotrophins in the following protocols along with CC or Tamoxifen which are given from day 2 – 6.

Gonadotrophins can be used as follows • On day 3, 5, 7, 9, & 11 • Single dose hMG/FSH 150 IU on day 9 or • hMG / FSH 37.5 - 75 IU D 2 onwards and dose titrated depending on the response • hMG / FSH 75 IU given 5 onwards daily 2. hMG/FSH/Recombinant FSH Conventional Step-up protocol

Low dose protocol

Chronic low dose protocol

Step down protocol

The side effects of gonadotrophins are • multiple pregnancy (25%) • breast tenderness • swelling and rash at injection site • abdominal bloating • depression, mood swings • mild to severe OHSS • miscarriage and premature deliveries Contraindications to GT therapy include 1. Tumors of ovary, breast, pituitary or hypothalamus 2. Pregnancy or lactation 3. Undiagnosed vaginal bleeding

4. Primary ovarian failure 5. Ovarian cyst 6. Malformation of sexual organs / fibroid uterus incompatible to pregnancy Disadvantages of COH 1. Time consuming & stressful to the couple 2. Imposes heavy financial burden 3. Result in OHSS – May be life threatening 4. Detrimental effect on embryo implantation due to altered estrogen progesterone balance 5. Higher incidence of multiple pregnancy with its complications like pre-term delivery 6. 8-folds higher incidence of abortions even in singleton pregnancies 7. Women undergoing ovulation promoting medications and especially in those women who are complicated by OHSS are at increasing risk of thromboembolism Adjuvant drugs to prevent premature LH surge with gonadotropin therapy GnRH agonists/ GnRH antagonistscan be used in combination with GT. Though LH surge is an absolute requirement for luteinization, final maturation of the oocyte and follicle rupture but a premature LH surge can occur in natural cycleand in 25 – 30% of stimulated cycles resulting in premature lutenization of follicle, early rupture of follicle so that exact time of ovulation is missed resulting in treatment failures in an timed intercourse and IUI cycle.

Monitoring ovulation induction IUI cycles All OI cycles should be monitored to ensure effectiveness of ovulation induction drugs and the choice of monitoring should be tailored to the needs of the specific patient. The figure below shows follicular tracking in clomiphene and gonadotropin cycles.

Luteal Phase Support Given empirically in CC and COH cycles due to · Lack of clearly defined treatment goals either morphologic or hormonal that relate to appropriate endometrial preparation for implantation during luteal phase of COH cycles · Altered E2 /P4 ratio · Endometrium sensitive to decreased steroid levels Use of progesterone for luteal phase support may help in increasing success of IUI. Luteal phase support is essential in all IUI cycles, which use GnRHanalouges along with gonadotropins.

Conclusion Ovulatory dysfunction is one of the most common causes of reproductive failure in sub- fertile and infertile couples. In the absence of other significant infertility factors, successful ovulation induction often will restore normal fertility. Clomiphene citrate (CC) is the best initial treatment in majority of anovulatory infertile women.

Gonadotropin therapy is generally used in CC resistant patients and in those patients who do not conceive after repeated courses of clomiphene citrate and those who are for ART.GnRH antagonists may have a role in ovarian stimulation for IUI but use of GnRH agonist does not improve the outcome in IUI cycles.

Before treatment with gonadotrophins, evaluation should also exclude abnormalities of thyroid function and hyperprolactinemia, and tubal pathology by hysterosalpingography (HSG).

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