Volume 2 Issue1 Feb.-May 2017 Pages 12

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1 PANDORA Volume 2 Issue1 Feb.-May 2017 Pages 12 New patrons, life members & Committees Page 02 Editorial Page 03 Events & Update Page 04 Announcing 2 nd International Conference Page 05 Scientific Article Insulin Sensitizing Properties of Inositol: Experimental Studies Dr. Fabio Facchinetti & Daniela Menichini Page 06 Scientific Article Is Letrozole Better for Ovulation Induction? Dr. B. N. Chakravarty, Dr. Shikha Bathwal & Dr. Elavarasan Subramani Page 07 PCOS Quiz Page 09 PCOS and Obesity Dr. Jayasshree Todkar Page 11 Registered Address Kwality House, 1 st Floor, August Kranti Marg, Kemps Corner, Mumbai Phone: , , Fax: thepcossociety@gmail.com

2 Executive Committee Dr. Duru Shah, Founder President Dr. Shashank Joshi, Vice President Dr. Rekha Sheth, Vice President Dr. Piya Thakkar, Honorary Secretary Dr. Sangeeta Agarwal, Joint Honorary Secretary Dr. Uday Thanawala, Honorary Treasuer Dr. Madhuri Patil, Scientific Coordinator Constitution Committee Krishnendu Gupta, Chair Shashank Joshi, Chair Newsletter Committee Anita Soni, Chair Toral Shinde, Co-Chair Research Committee Padma Rekha Jirge, Chair Ganpat Sawant, Co-Chair CME Committee Sujata Kar, Chair Kanthi Bansal, Co-Chair Website Committee Nandini Rambabu, Chair Public Awareness Committee Nalini Mahajan, Chair Sanjeev Khurd, Co-Chair Sudha Tandon, Co-Chair Sharda Maroju, Co-Chair Gautam Khastgir, Co-Chair Membership Committee Ritu Joshi, Chair International Committee Shanti Shrinivasan, Member Social Media Committee Bina Vasan, Chair Altamash Shaikh, Co-Chair Welcoming... Our New Patrons Dr. Anagha Pramod Walavalkar Dr. Indu Kaul Dr. Manjula Anagani Dr. Nilesh Ramakant Shinde Dr. Rajalaxmi Walavalkar Dr. Sasmita Swair Dr. Siddhartha Chatterjee Dr. Sripriya Pragasam Dr. Sudhaa Sharma Our New Life Members Dr. Akansha Mishra Dr. Akhil Saxena Dr. Anupama Sethi Arora Dr. Asha Anil Baxi Dr. B. D. Parsewar Dr. B. Sandhya Rani Dr. Bela Jayesh Zaveri Dr. Chaitra S. Dr. Deepak Goenka Dr. Dhaval Baxi Dr. Fehmida Shaikh Dr. Jignesh Maheshbhai Pandya Dr. Kalu Tulshiram Bagul Dr. Karuna Hemant Murkey Dr. Kavitha Senthil Dr. Mary Anne Raja Dr. Mohan T. Shenoy Dr. Mrs. Noorunnisa Bashir Ahmed Kotwal Dr. Partha Bhattacharya Dr. Pinky Shah Dr. Pooja Chetan Ghorpade Dr. R. Nirupama Dr. Rakesh Pratap Khuteta Dr. Ranjana Gupta Dr. Reitu Patel Dr. Ruchika Garg Dr. S. M. Sredevi Dr. Sabahat Rasool Dr. Sarla Nihlani Dr. Satishkumar Manmohan Sajanwala Dr. Seeru Garg Dr. Sheela Prakash Paknikar Dr. Sudhir Naik Dr. Susan William Dr. Sushila Khuteta Dr. T. Hema Dr. V. Sita Rama Raju Congratulations Dr. Duru Shah for taking over as the President of Indian Society of Assisted Reproduction (ISAR) on 21 st April, We wish you a year full of academic excellence! 2

3 Editorial Editorial Team Dear Friends, When I decided to name the PCOS Newsletter "PANDORA" it originated from "Pandora's Box" which is a well-known phrase for an action which may be very simple, but as you get deeper and deeper into it, it gets more and more detrimental it's a never ending situation with far reaching negative consequences! In Greek mythology, Pandora was the first woman created by the Gods, on the instructions of the Greek God Zeus. Pandora was created as "the beautiful evil" woman after humans stole the gift of fire from Prometheus. She was created to give humanity a punishing gift to Dr. Duru Shah MD, FRCOG, FCPS, FICS, FICOG, FICMCH, DGO, DFP Director, Gynaecworld, The Center for Women s Fertility & Health, Mumbai compensate for the boon (fire) they had stolen. God Zeus commanded Hephaestus to mould her from earth as, a "beautiful evil" whose descendants would torment the human race. President, The PCOS Society (India) Chief Editor, Pandora According to the myth, Pandora opened a jar (not a box) out of curiosity releasing all the evils of humanity and she could retain only "Hope" inside the jar once she had closed the lid quickly. So when you open this Newsletter, all the mysteries of PCOS should disappear and our hope remains, that one day we will be able to decipher the enigma called PCOS. Our last issue for the year 2016 was published in late December 2016 which you must have received in early January Since then we have had many academic activities, which you will find in this Newsletter and even on the PCOS Website We also have many exciting forthcoming events, in which I request you to participate wholeheartedly, Dr. Sabahat Rasool though we may have smaller numbers of delegates, but believe me, the interactions are just brilliant! MD, DNB, MNAMS, FMAS, MRCOG (UK) Ian Donald Diplomate in OBGY Ultrasound, Croatia Fertility Consultant, Gynaecworld, Mumbai Our "Whatapp groups" which are open to only our members, have some amazing discussions and many Associate Editor, Pandora queries are sorted out by many of our senior members who contribute their expertise. I thank them for their time, expertise and love to teach. We have created beautiful Certificates for our members, which you would love to display on your walls. All members have been sent their Membership Numbers and will soon receive their Certificates, if their paperwork is complete. So, please watch out for this precious package which you will soon receive. And if you don't get it by the middle of May please send us a mail and we will track the package for you. I welcome you all to the beautiful city of Bengaluru, between 16, 17, 18 June 2017 where we are hosting our Second Annual International Conference of the PCOS Society of India in collaboration with the Dr. Anita Soni Androgen Excess and PCOS Society. You will find the details of the conference on our Website and in this MD, DNB, FCPS, DGO Consultant OBGYN, Hiranandani Hospital, Powai Newsletter. Please register at your earliest! Chair, The Newsletter Committee Please also check out our Website for all the archived educational events which are hosted therehttp:// These include Power Point Slides, Webinars and Lectures, you will enjoy them. I must thank all our academic contributors especially Prof. B. N. Chakravarty and team who have written a brilliant article on "Is Letrozole Better for Ovulation Induction" and Prof. Fabio Facchinetti who has written an excellent review on "Insulin Sensitizing Properties of Inositol: Experimental Studies"and abeautiful article by Dr. JayshreeTodkar on "PCOS & Obesity". I thank my Editorial team for all their help and inputs and Mr. Manoj Purandare from Sun Pharma for offering us an unrestricted educational grant to make this issue possible. Ms. Rochelle Lobo Administrative Assistant thepcossociety@gmail.com Dr. Duru Shah Founder President, PCOS Society Disclaimer Published by the The PCOS SOCIETY (INDIA). Contributions to the editor are assumed intended for this publication and are subject to editorial review and acceptance. PANDORA is not responsible for articles submitted by any contributor. These contributions are presented for review and comment and not as a statement on the standard of care. All advertising material is expected to conform to ethical medical standards, acceptance does not imply endorsement by PANDORA. 3

4 Events & Updates PCOS Symposia An Update on Surgical Solutions for PCOS An Update on Surgical Solutions for PCOS" was organized by The PCOS Society, India, in collaboration with Meril Endosurgery Pvt Ltd on 18th19 th March, 2017 at Meril Academy, Daman. Dr. Duru Shah was the chief convenor. The conference was structured as 4 sessions over 2 days followed by 3 debates & panel dicussion on Bariatric surgery vs. Cosmetic surgery, Laparoscopic vs. Open surgery and OCPs vs. LNG in DUB. The panel discussion was moderated by Dr. Duru Shah and Dr. Madhuri Patil. Solutions for PCOS women". The symposia focused on understanding and optimizing the use of various surgical disciplines and imbibing the latest research towards a better quality of life for young girls and women with PCOS. This exclusive two-day program was meticulously designed to upgrade and discuss various "Surgical The topics were focused on the very complicated and vast topic of PCOS and surgical treatment of PCOS. The impact of PCOS on fertility, and the effects of fertility enhancing surgeries in PCOS was extensively discussed. The 1st day sessions included 'Fertility Surgeries in PCOS' & 'Obesity & Laparoscopic Surgery'. The 2 nd day sessions included 'Difficulties at Hysteroscopic Surgeries' and 'PCOS and Obesity'. International Webinar PCOS Beyond Boundaries Focusing on Hyperandrogenism in PCOS The PCOS Society (India) conducted an International Webinar titled PCOS Beyond Boundaries Focusing on Hyperandrogenism in PCOS, on 4th March, at Taj Santacruz Mumbai with support from Bayer Zydus Pharma which connected with 6 webcast centres Salem, Vizag, Dehradun, Bhubaneshwar, Gurgaon, Patna. Prof. Roy Homburg connected live from Malta and made an extraordinary presentation on PCOS The Global Conundrum, & was joined by a multispecialty panel of distinguished experts from India Dr. Duru Shah (Gynaecologist), Dr. Shashank Joshi (Endocrinologist), Dr. Ashwini Bhalerao (Gynaecologist), Dr. Gulrez Tyebkhan (Dermatologist) 290 doctors participated in the Webinar at the 7 centers, with 254 online viewers, and the webinar was rated as very educative and informative. 4 Continued on page 11

5 S C I E N T I F I C P R O G R A M M E 16 th June 2017 PRE-CONGRESS WORKSHOPS am pm Workshop am Session I : Ultrasound in PCOS Diagnosis of PCOS by USG What are the new criteria? Is ultrasound a good diagnostic method in adolescent PCOS? Should Serum AMH replace ultrasound PCO morphology as a diagnostic marker? Assessment of ovarian blood flow in PCOS, Does 3D power doppler have any role? am pm Session II : Monitoring a Fertility cycle Should follicle monitoring be done by the Fertility expert/ Radiologist / USG Nurse? How should we monitor the follicles and endometrium during a COS cycle by ultrasound? How should we assess OHSS by ultrasound, what are the high risk markers? pm Live Demonstration of Ultrasound in PCOS women pm Workshop 2 Practical Management of Ovulation Induction in PCOS Case-based discussion Lean / Obese PCOS High AMH, Insulin resistance Role of Letrozole for OI in PCOS Role of Adjuvants in PCOS Which Gonadotropin? / Step up or Step down regimen? GnRH agonist or antagonist Monitoring the Ovulation Induction cycle USG or USG+ Hormones Avoiding Premature LH surge and lutenization during COH Role of laparoscopic drilling, ultrasound only protocols for monitoring COS cycle pm Inaugural Lectures International guidelines in PCOS Interaction Adipose tissue dysfunction in PCOS Interaction Abhiyan PCOS A consortium for Research, Advocacy and Action Interaction pm Inauguration pm onwards Fun filled Tambola pm DINNER 17 th June 2017 Conference Day 1 Scientific Session I am Session I : Free Papers am Session II : Basics we need to Know Diagnosis of PCOS What are the different Phenotypes of PCOS? Its importance in management The role of environmental factors from fetal life to adulthood in PCOS "The thrifty gene" hypothesis--- how has the PCOS phenotype survived evolution? am pm Session III : Obesity and PCOS Metabolic risk of the "lean" PCOS women Weight loss drugs How do we select the right formulation? When should we suggest Bariatric surgery in PCOS? Is snoring in obese women a health concern? pm Session IV : Keynote Address Are we telling patients all they need to know about PCOS? Role of GWAS in identifying the PCOS genes pm Session V : Hirsutism and hyperandrogenism Does Insulin Resistance (IR) cause hyperandrogenemia (HA) or HA causes IR? Medical options for women with Acne and Hirsutism Cosmetic options pm Session VI: Current update on Inositols Pharmacology and Mode of action Inositol and Reproductive Function Current evidence for its use in Infertility and Pregnancy pm Session VII: The Great Controversies Controversy 1 Should Metformin be continued in pregnancy? Yes No Controversy 2 Is PCOS is associated with a higher pregnancy loss? Yes No pm Session VIII : Stump the Experts Interesting cases Menstrual dysfunction in PCOS women Insulin resistance and hyperandrogenemia Gestational Diabetes Mellitus Obstetric complications other than GDM pm General Body Meeting of The PCOS Society (India) pm COCKTAILS & DINNER with Entertainment 18 th June 2017 Conference Day 2 Scientific Session II am Round Tables with development of Algorithms 1. Vitamin D deficiency and PCOS 2. Management of acne, pigmentation 3. Increased lipids 4. GDM am Session IX : Lifestyle Modification Does it impact Fertility? How do lifestyle changes help in PCOS? Do Metformin and Inositols help? Exercise in PCOS Nutrition in PCOS and role of anti-inflammatory diet am Session X : PCOS and Assisted Reproduction Does PCOS compromise the oocyte and embryo quality or the endometrium? Should"Freeze all" be a strategy in all PCOS women undergoing IVF? Does pre implantation genetic screening (PGS) followed by elective single embryo transfer (eset) have a role in women with PCOS? noon pm Session XI : Surgical options in PCOS Ovarian Drilling Current Status Endometrial Polyps Other ovarian pathologies associated with PCOS pm Session XII: Long-term effect of PCOS COS and Cancer Risk Dysfunctional Uterine Bleeding Liver and PCOS: what we really know? pm Valedictory pm LUNCH International Faculty Anuja Dokras,USA Enrico Carmina, Italy Helena Teede, Australia Joop Laven, Netherlands Richard Legro,USA National Faculty Abha Majumdar Ameet Patki Anita Soni Arti Prasad Arulmozhi Ramarajan Bina Vasan Chander Lulla Chitra Ganesh Devika Gunasheela Duru Shah Ganapathi B. Gita Arjun Gulrez Tyebkhan Jyotika Desai Kamini Rao Kanthi Bansal Kedar Ganla Korula George M. G. Bhat Madhuri Patil Mirudhubashini Govindarajan Nalini Mahajan Padmarekha Jirge Paul PG Piya Ballani Pratap Kumar Priti Venkatesh Ragini Agrawal Rama Vaidya Reeta Billiangady Rekha Sheth S. Suresh Sachin Kulkarni Sadhana Desai Sadhana Patwardhan Sangeeta Agrawal Shashank Joshi Sheela Mane Shilpa Joshi Shobha Gudi Shobhana Patted Smita Mahale Sonia Malik Sujata Kar Sujata Misra Suma Kumar Susheela Rani Uday Thanawala Usha Sriram...many more 5

6 Insulin Sensitizing Properties of Inositol: Experimental Studies Dr. Fabio Facchinetti Chairman, Unit of Obstetrics and Gynecology, Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Italy Introduction 'Inositol' refers to a group of molecules called 'stereoisomers' of inositol. They exist in nine possible forms, all composed of the same basic structure, named myo-, scyllo-, epi-, D-chiro-, L-chiro, neo-, allo-, cis-, and muco-isomers 1. Inositol sugars comprise of a cyclic six-carbon structure with one hydroxyl group at each carbon. Among the isomers, Myo-Inositol (MI) is the most abundant, naturally present in animal and plant cells, either in its free form or as a bound-component of phospholipids or inositol phosphate derivatives. It is a precursor for phosphorylated compounds known as phosphoinositides, which are involved in signal transduction, including diacylglycerol and inositol triphosphate (IP3), a second messenger, responsible for the regulation of many hormones such as insulin, thyroid-stimulating hormone (TSH), and folliclestimulating hormone (FSH) 2. For this reason, MI is essential for the smooth running of a wide range of cell functions, including cell growth and survival 3, development and function of peripheral nerves 4, osteogenesis 5 and reproduction 6. It is absorbed by the tissues via a sodium-dependent inositol cotransporter that also mediates glucose uptake (competitively inhibits inositol uptake) 7. In addition, the minor isomer, D-chiro-inositol (DCI) is involved in insulin signaling and has been speculated to be associated with glucose homeostasis since abnormalities in their metabolism are associated to insulin-resistance and long-term diabetic microvascular complications in diabetic subjects 8. Indeed, in primary sites for the development of diabetic microvascular complications such as kidneys, sciatic nerve, retina and lens, a concomitant depletion of intracellular MI and accumulation of intracellular sorbitol is commonly observed in diabetic animal models and human subjects Experimental studies: animal models Several experimental studies have shown that MI depletion in experimental models of rhesus monkeys 10 and GotoKakizaki (GK) rat 11 resulted in an excessive excretion of MI and decreased amounts of DCI in urine (a phenomenon called inosituria). The same inositol abnormal pattern is observed in insulin sensitive tissues (liver, muscle, fat and kidney) of human 12 and animal 11 diabetic subjects. Excessive urinary MI excretion reduces its plasma level and consequently emphasizes MI intracellular depletion, which results in a decreased production of DCI from MI, reducing the availability of intracellular DCI for its incorporation into IPGs, second messengers of insulin. Therefore, the decreased DCI content in insulin target tissues reduces insulin signal transduction involving IPGs and further enhances or contributes to insulin resistance in those tissues. Depleted plasma levels of DCI are, 6 Daniela Menichini Researcher, Department of Maternal Fetal Medicine, University of Texas Health Science Centre at Houston, USA. in fact, observed in Polycystic Ovary Syndrome (PCOS) patients, emphasizing the correlation between impaired plasma DCI and insulin resistance 8. A recent study evaluated the therapeutic efficacy of MI in models of hyperlipidemic and insulin-resistant rats. Hyperlipidemia was induced by single intraperitoneal injection of Triton WR-1339 (200 mg/ kg) suspended in phosphate-buffered-saline in rats fed with high-fat diet (HFD) for 5 weeks, while insulin resistance was created by feeding the rats with highfat diet (HFD) and with streptozotocin. They found that in hyperlipidemic rats, MI exhibited significant reductions in total cholesterol and triglycerides while insulin-resistant diabetic rats receiving MI showed significant reductions in fasting blood glucose & plasma insulin level when compared with controls. The inositol treatment significantly normalized the hyperglycemia-induced biochemical abnormalities in insulin-resistant diabetic rats suggesting that MI could play an effective role in glucose disposal into adipose tissue by insulin-dependent signaling cascade mechanism; hence it could be used in the treatment of obesity-associated T2DM Experimental studies conducted in pregnancy A mixture of MI and DCI has recently been tested in pregnant obese mouse model and in pregnant metabolic-like syndrome mouse model obtained from the offspring born to hypertensive dams lacking endothelial nitric oxide synthase, fed with HFD. The treatment with combined inositol during pregnancy improved blood pressure, glucose levels at the glucose tolerance test, and leptin levels in pregnant dams with metabolic-like syndrome phenotype but not in obese pregnant dams. In addition, inositol treatment resulted in lower gestational weight gain in the obese but not in the metabolic-like syndrome pregnant dams 2. MI has also been clinically experimented on pregnant overweight women with the aim of reducing gestational diabetes mellitus (GDM) rate. An openlabel randomized trial evaluated the effectiveness of the supplementation of MI or placebo from the first trimester to delivery in pregnant overweight nonobese women. The incidence of GDM was significantly reduced in the MI group compared to the placebo group, driving to the conclusion that MI supplementation, since early pregnancy, reduces GDM incidence in overweight non-obese women Experimental studies: Polycystic ovary syndrome (PCOS) PCOS is an endocrine disorder affecting up to 10-15% of women in reproductive age, mainly causing infertility. Insulin resistance (IR) plays a key role in such syndrome. Recently, MI and DCI have shown to be an efficient and safe alternative in PCOS management, as both inositol isoforms can counteract downstream consequences of insulin resistance. Yet, whereas DCI contributes in mediating insulin activity mainly on non-ovarian tissues, MI displays specific effects on ovary, chiefly by modulating glucose metabolism and FSH-signaling. Moreover, MI may also improve ovarian functions by modulating steroid metabolism through noninsulin-dependent pathways. As DCI and MI activity likely involves different biological mechanisms, both inositol isoforms can be synergistically integrated according to a multitargeted design, by combining MI and DCI in a ratio corresponding to their physiological plasma relative amount (40:1). New experimental and clinical evidence with MI plus DCI evidenced the suitability of such integrated approach, and provided promising results. Further studies need to investigate thoroughly the molecular mechanism and confirm such preliminary data 15. MI administration increases clinical pregnancy rates and reduces the total FSH dose and the duration of ovulation induction. This had been demonstrated by a study conducted in Turkey which investigated the effect of MI on pregnancy rates of patients diagnosed with PCOS who underwent controlled ovulation induction and intrauterine insemination (IUI). Infertile patients diagnosed with PCOS were given 4g MI and 400mg folic acid before and during ovulation induction. The patients underwent controlled ovarian hyper stimulation (COH) with recombinant FSH and IUI. The patients in the control group were given recombinant FSH directly and 400mg folic acid. The primary outcome measure of this study was the clinical pregnancy rate. The treatment group women needed significantly lower doses of FSH and lower cycle duration, and had higher clinical pregnancy rates than the control group 16. Conclusion Dietary supplement of inositol isomers was found to be efficient in lowering post-prandial plasma glucose in several animal models of diabetes or insulin resistance 8. The insulin-mimetic properties of dietary inositol supplements are believed to be related to the production of inositol glycan secondary messengers containing either MI or DCI. Randomized control trials on inositol dietary supplements gave positive results in the improvement of insulin resistance and reduced cardiovascular risk in women with PCOS, gestational diabetes mellitus or metabolic syndrome and obesity (also in pregnancy). Inositol has a role in restoring maternal cardiovascular and metabolic compliance in pregnancies affected by obesity and metabolic syndrome. Continued on page 11

7 Is Letrozole Better for Ovulation Induction? Dr. B. N. Chakravarty Dr. Elavarasan Subramani Institute of Reproductive Medicine, Kolkata Institute of Reproductive Medicine, Kolkata Introduction Over the past five decades, clomiphene citrate (CC) continues to be the first line treatment primarily for ovulation induction and also for ovulation augmentation in unexplained infertility and in intrauterine insemination (IUI) cycles1. However, it is reported that 20-25% of women fail to ovulate due to CC-resistance2. In view of this, administration of gonadotropins is considered to be the conventional option in such cases. Though use of gonadotropins is highly effective, it is associated with inevitable risk of multiple pregnancies and ovarian hyperstimulation in a significant proportion of women 3. As an alternative management to gonadotropins, use of laparoscopic ovarian drilling (LOD) in CC-resistant women has also been advocated4. Addition of CC with Gonadotropins (FSH/hMG) helps in decreasing the dose of total amount of gonadotropins required for optimum stimulation and makes it more costeffective in women who fail to respond to only CC treatment5. Acceptable pregnancy rates with CC and sequential hmg ovulation induction protocol in IUI following previous CC and IUI treatment failure have also been reported6. However, supra-physiological level of estradiol (E2) is an undesirable consequence of both CC and gonadotropin stimulation. Apart from risk of hyperstimulation and multiple pregnancies, adverse effects of supra-physiological level of E2 have been observed at several levels. These are Dyssynchrony between endometrium and embryo maturation during 'implantation window' period, abnormal expression of endometrial pinopodes, defective endometrial estrogen progesterone receptors, abnormal endometrial blood flow and abnormal integrin expression. These are some of the reasons for low pregnancy rate in spite of having good ovulatory response following CC induction in anovulatory infertility. These limitations motivated researchers to find out an alternative drug which would be less expensive than gonadotropins and at the same time safe, simple and equally if not more effective than clomiphene. Letrozole was considered to be an alternative acceptable molecule. How and Why Letrozole? In women with intact hypothalamic-pituitary-ovarian axis, the commonest cause of anovulation is Polycystic Ovarian Syndrome (PCOS). One of the significant causes of anovulation in PCOS women is 'static' (not pulsatile) elevated or normal level of oestrogen. Static level of estrogen through 'negative feed-back' mechanism on 'hypothalamic-pituitary (HP) axis' inhibits adequate release of pituitary FSH. Low (not absent) level of FSH results in inadequate growth and development of follicles, not allowing them to reach maturity and ovulation. At the same time, tonic elevated level of oestrogen through 'positive feed-back' effect on HP axis results in release of static elevated 'tonic' level of LH. There is no LH surge and therefore anovulation. Aromatase inhibitors (letrozole) by inhibiting oestrogen synthesis temporarily release hypothalamic-pituitary block by tonic elevated oestrogen thereby normalizing fluctuating (and not tonic) release of pituitary FSH which helps in restoration of normal ovulatory cycle. Therefore, letrozole was considered to be an effective drug for induction of ovulation. Literature review: Several research groups have studied the new group of drugs (aromatase inhibitors) for ovulation induction in the past few years7-9. Letrozole, a potent and highly specific nonsteroidal aromatase inhibitor, has been observed to be effective in inducing ovulation in anovulatory and ovulatory infertile women with inadequate response to CC. Initially, letrozole was primarily used as a potent reversible oral aromatase inhibitor which acts a chemotherapeutic agent in postmenopausal women with metastatic breast cancer 10. Being a chemotherapeutic agent, when the drug was used for ovulation induction, concerns were raised about teratogenic effect on oocyte and embryo. Moreover, the resulting hypo-estrogenic may have adverse impact on bone mineral metabolism leading to osteoporosis. The other controversy relating to the use of letrozole as a first-line agent, before CC has been used, is based on the fact that in normogonadotropic women, aromatase inhibition is likely to be effective only when baseline estradiol is elevated. The cut-off level of the elevated baseline estrogen is not yet demarcated. Hence use of letrozole as a primary ovulation-inducing drug replacing clomiphene warrants further investigation. An abstract presented at American Society for Reproductive Medicine (ASRM) meeting 2005 regarding increased teratogenic risk of cardiac malformations with letrozole11 and other safety concerns eventually led to the ban on this drug in India in Nevertheless, there is an increased concern on the factuality of the observation due to the shortcomings and biases of this study. In the later years, various studies indicated that letrozole is not associated with increased teratogenic risk12,13. Our earlier study showed that the overall Dr. Shikha Bathwal Institute of Reproductive Medicine, Kolkata rate of congenital malformations among children born to mothers who conceived naturally or after letrozole or CC treatment was observed to be comparable12. Our group has conducted one of the largest-ever randomized clinical trials to explore the efficacy of letrozole in ovulation induction on 1387 infertile PCOS women who failed to conceive with CC treatment14. This study showed that letrozole appears to be a suitable ovulation inducing agent in polycystic ovary syndrome (PCOS) women with CC failure and is found to be most effective when baseline E2 level >60 pg/ml. It is well known that infertility itself is a risk factor and is associated with increased malformation risk as compared to the general population. Several published studies, both controlled and non controlled, comparing letrozole with CC alone or in combination with gonadotropins confirm the effectiveness of letrozole as an ovulation inducing agent Based on these various reports, Government of India, Ministry of Health and Family Welfare removed the ban on use of letrozole as ovulation induction agent. Evolution of aromatase inhibitors for clinical use Aromatase inhibitors suppress estrogen production by inhibiting the conversion of androgens to estrogens. Letrozole, the drug commonly used in clinical practice, has been developed following extensive trial through three generations of aromatase inhibitors. Third generation aromatase inhibitors like letrozole and anastrozole have been a great leap forward in the treatment of breast cancer. Their clinical efficacy, excellent tolerability and safety profile compare favourably with that of tamoxifen, which has been the cornerstone of endocrine therapy for years. Concept leading to the use of letrozole for induction of ovulation The goal of ovulation induction is to induce monofollicular development and subsequent ovulation in anovulatory infertile women. As discussed in previous paragraphs, anovulation in PCOS or any normogonadotropic anovulatory cycle is due to the block of hypothalamic receptors by static elevated supraphysiological level of oestradiol, which is preventing the release of pulsatile luteinizing hormone-releasing hormone (LHRH). Decline in static elevated oestrogen level can help in restoration of 7

8 synchronized and pulsatile LHRH release. Antiestrogenic effect of letrozole was the concept behind using it for ovulation induction. This was first reported in literature by Mitwally et al. 19, in anovulatory women resistant to ovulation induction by CC. Need of an alternative drug for ovulation induction other than clomiphene citrate Several drawbacks with CC had been the reason for lookout for an alternative ovulation inducing agent in certain cases. CC remains bound with oestrogen receptors for 60 days because of its long half life. In case CC fails to induce ovulation or establish pregnancy, other ovulation inducing drugs cannot be initiated before 60 days. It is thought that dose of 150 mg or more will confer no benefit. CC induces ovulation in 70-85% of patients while only 20-40% will conceive. The pregnancy rate per cycle is around 10-20%. About 20-25% anovulatory women are clomiphene resistant. CC has unfavourable effects on endometrial thickness and cervical mucus due to its antiestrogenic effect. The incidence of miscarriage after CC therapy has been reported to be about 23.6%. It has been shown that with prolonged CC use, along with low endometrial thickness, there is also decreased uterine blood flow during early luteal and peri-implantation phase. There have been evidences suggesting that supra-physiological serum luteinizing hormone (LH) level from day 9 until the LH surge, together with premature luteinisation and higher serum oestrogen levels throughout the cycle can lead to higher chances of either non-conception or miscarriage. Difference in mechanism of action of CC and letrozole In CC, hypothalamic receptors are bound to oestrogenic component of CC and therefore these receptors become unaware of presence of supraphysiological levels of circulating estrogens, allowing hypothalamus to release effective synchronized pulsatile LHRH, thereby leading to LH surge and ovulation. Fig-1: mechanism of action (ovulation induction) with CC 8 Letrozole causes direct inhibition of oestrogen synthesis thereby allowing follicle-stimulating hormone (FSH) to induce active folliculogenesis. This hypo-estrogenic state is quickly reversible due to the short half-life of letrozole (45 hours). There is no antioestrogenic effect on endometrium. Also there is temporary elevation of testosterone to an optimum level which is beneficial as it increases the follicular sensitivity to gonadotropin. Excess levels of androgen cause detrimental effects whereas a very low level of testosterone impairs follicular development. Common features in mechanism of action of CC and letrozole Though the drugs act in different ways, there are some common features in their mechanism of actions. These are: (a) Release of hypothalamus from negative tonic feedback effect of static normal or elevated level of oestrogen (b) Allowing release of pulsatile gonadotropin-releasing hormone (GnRH) (c) FSH & LH ratio is synchronized (d) LH surge effective for ovulation. These have been illustrated in Fig- 1&Fig-2. Ovulation induction in anovulatory women with PCOS Letrozole versus CC in PCOS women has been tested in several randomized trials 14, However, the efficacy of letrozole in ovulation induction remains unclear. One of the largest randomized controlled trials conducted in our institute comparing efficacy of letrozole with continuous gonadotropins and CCgonadotropin combination for ovulation induction in 1387 PCOS women after clomiphene citrate failure concluded that the ovulation and pregnancy rate with letrozole was significantly higher with letrozole compared to CC-rFSH combination (79.30% vs 56.95%, p value < and 23.39% vs 14.35%, p value < respectively) (14). Also there was a significantly lower cycle cancellation rate with letrozole compared to CC-rFSH (20.70% vs 43.05%, p value <0.0001). Another group had reported comparable pregnancy rate with letrozole and CChMG therapy in a pilot study 24. An analysis of four early randomized studies observed a significantly higher pregnancy and delivery rate in women treated with aromatase inhibitor compared with CC 25. Nonetheless, the trials involved were heterogeneous with a limited number of patients. A recent well-designed double blind multicentre randomized control trial comparing letrozole versus clomiphene for infertile PCOS women has concluded that letrozole was associated with higher live birth and ovulation rates. Therefore, letrozole is considered to be superior than CC as a treatment for anovulatory infertility in women with PCOS 26. Similar findings were observed by other studies 27, 28. A meta-analysis published in 2015 analysed 4999 ovulation cycles (2455 with letrozole, 2544 with CC) indicated that live birth and pregnancy rates were higher in patients with PCOS following treatment with letrozole as compared to CC. However, there was no difference in ovulation rate/cycle, miscarriage rate or multiple pregnancy rate between the two drugs 29. A study by Liu et al. on 141 CC-resistant PCOS women showed comparison between letrozole and LOD. They found letrozole had superior reproductive outcomes compared with LOD in women with CC resistant PCOS and that letrozole could be used as 1 st line treatment for women with CC-resistant PCOS. The number of cycles with synchronised follicular and endometrial growth was also significantly higher in letrozole group 30. A study comparing efficacy of letrozole with tamoxifen observed that tamoxifen was inferior to letrozole in terms of ovulation and pregnancy rate 31. Ovulation induction/stimulation in unexplained infertility Aromatase inhibitors are recommended as an alternative drug to CC in women with unexplained infertility, either alone or with gonadotrophins. Nonetheless, it is likely to be less efficacious compared with treatment in PCOS women. Letrozole results in lesser number of mature follicles (monoovulation) in comparison to CC because it has less anti-estrogenic effects in the later part of follicular phase. Thus, it may not be the first choice in patients with unexplained infertility. A meta-analysis of seven randomized control trials showed comparable clinical pregnancy rates between aromatase inhibitor and CC in women with unexplained infertility 32. These findings are in good agreement with another large trial where no statistically significant difference was observed between 100 mg of CC versus 5 mg of letrozole in terms of clinical pregnancy rate in unexplained infertility 33. A recent large multicentre trial on 900 women with unexplained infertility concluded that letrozole resulted in lower frequency of multiple pregnancies but also lower live birth rates as compared to gonadotropins. However, when letrozole was compared to clomiphene alone, pregnancy rates were similar 34. Safety concerns with letrozole Concerns had been raised regarding the use of letrozole for ovulation induction, as it might interrupt the normal aromatase function in tissues during early fetal development and can be potentially teratogenic 35. This issue was discussed in the Annual Meeting of the American Society for Reproductive Fig-2: mechanism of action (ovulation induction) with letrozole Medicine in An abstract presentation by the authors discussing the use of letrozole for

9 infertility treatment may be associated with a higher risk of congenital cardiac and bone malformations in the newborns 11. Following this, Novartis Pharmaceuticals, the company that developed letrozole for breast cancer treatment, issued a warning to infertility clinics asserting that it does not advocate letrozole use for infertility treatment. In October 2011 the Ministry of Health and Family Welfare, India issued a directive to suspend the use of letrozole in infertile women with immediate effect citing concerns regarding its safety. A study analysing 911 newborns born after infertility treatment with either CC or letrozole found no difference in overall rates of major and minor congenital malformations between the two groups 36. In a recent retrospective trial from Asian sub-continent analysing 646 women, congenital malformations were found to be comparable following natural conception, letrozole and CC 12. Most recent trial by Tatsumi et al. (2017) reported that no increase in the risk of major congenital anomalies or adverse pregnancy or neonatal outcomes was observed in letrozole treated women compared with natural cycles in women undergoing ART 37. Considering these reports, Indian Health Ministry has recently removed the ban on letrozole for use in infertility. Therefore, letrozole may PCOS Quiz 1. Metformin is the drug of choice for a. Glucose intolerance b. CC resistant PCOS c. High risk of hyperstimulation d. All the above 2. To avoid the risk of OHSS in PCOS patients, the best protocol for ovulation induction is a. low dose step up protocol b. step down protocol c. Long protocol d. All three 3. What percentage of PCOS patients have hyperandrogenaemia? a. 50% b % c % d. <10% 4. Which of these statements is not true about Asian PCOS women? a. Have lower BMI b. Higher prevalence of Metabolic Syndrome c. More severe hyperandrogenism d. All of the above 5. Which is the the most common determinant of ovulation outcome in PCOS women? a. Obesity b. Insulin Resistance c. Antral follicle count & AMH d. Both a & b 6. PCOS patients needing Bariatric surgeries have a BMI of a. 30 & above b. 26 & above c. 35 & above d. 45 & above be considered as a safe option for ovulation induction. References 1. Dankert T, Kremer JAM, Cohlen BJ, Hamilton CJCM, Pasker-de Jong PCM, Straatman H, van Dop PA. A randomized clinical trial of clomiphene citrate versus low dose recombinant FSH for ovarian hyperstimulation in intrauterine insemination cycles for unexplained and male subfertility. Hum Reprod. 2007;22: Elnashar A, Fouad H, Eldosoky M, Saeid N. Letrozole induction of ovulation in women with clomiphene citrate-resistant polycystic ovary syndrome may not depend on the period of infertility, the body mass index, or the luteinizing hormone/follicle-stimulating hormone ratio. Fertil Steril. 2006;85: Eijkemans MJ, Polinder S, Mulders AG, Laven JS. Habbema JDF, Fauser BC: Individualized cost-effective conventional ovulation induction treatment in normogonadotrophic anovulatoryinfertility (WHO group 2). Hum Reprod. 2005;20: Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Fertil Steril. 2008;89: Mitwally MFM, Casper RF. Aromatase inhibition reduces gonadotrophin dose required for controlled ovarian stimulation in women with unexplained infertility. Hum Reprod. 2003;8: Brzechffa P, Daneshmand S, Buyalos R. Sequential clomiphene citrate and human menopausal gonadotrophin with intrauterine insemination: the effect of patient age on clinical outcome. Hum Reprod. 1998;13: Goswami SK, Das T, Chattopadhyay R, Sawhney V, Kumar J, Chaudhury K, Chakravarty BN, Kabir SN. A randomized singleblind controlled trial of letrozole as a low-cost IVF protocol in women with poor ovarian response: a preliminary report. Hum Reprod. 2004;19: Casper RF, Mitwally MFM. Review: Aromatase Inhibitors for Ovulation Induction. J Clin Endocrinol Metab. 2006;91: Barroso G, Menocal G, Felix H, Rojas-Ruiz JC, Arslan M, Oehninger S. Comparison of the efficacy of the aromatase inhibitor letrozole and clomiphene citrate as adjuvants to recombinant follicle-stimulating hormone in controlled ovarian hyperstimulation: a prospective, randomized, blinded clinical trial. Fertil Steril. 2006;86: The ability of an oocyte to resume meiosis, get fertilized and become a blastocyst is known as a. oocyte quality b. oocyte competence c. both a & b d. none of the above 8. What contributes to adverse pregnancy and Perinatal outcomes in PCOS patients? a. Oocyte competence b. Oocyte quality c. Phenotypic severity d. Both a & c e. Both a, b & c 9. Which of the following are true about ovulation induction in PCOS? a. Women with PCOS are about 50% more likely to have a live birth with letrozole compared to clomiphene citrate (CC) b. With letrozole ovulation induction, estradiol levels are lowered and luteal progesterone levels are increased c. Letrozole has lower multiple pregnancy rates compared to CC d. a+b+c e. b+c 10. The following statements about Metformin use in PCOS are correct: a. Prolonged treatment is required before it becomes efficacious b. Immediate release is better than extended release for ovulation c. Is more useful when used alone rather than with CC d. none of the above Answers for PCOS QUIZ 1. D 2. A 3. B 4. C 5. D 6. C 7. B 8. D 9. D 10. D 10. Harriet M. Lamb, Julie C. Adkins. Letrozole-A Review of its Use in Postmenopausal Women with Advanced Breast Cancer. Drugs, 1998;56: Al-Fadhli R, Sylvestre C, Buckett W, Tan SL, Tulandi T. A randomized trial of superovulation with two different doses of letrozole. Fertil Steril. 2006;85: (Presented at the American Society for Reproductive Medicine 61st Annual Meeting; October 14-19, 2005; Montreal, Quebec. Abstract O-91). 12. Sharma S, Ghosh S, Singh S, Chakravarty A, Ganesh A, Rajani S, Chakravarty BN. Congenital malformations among babies born following letrozole or clomiphene for infertility treatment. PLoS One. 2014;9:e Tatsumi T, Jwa SC, Kuwahara A, Irahara M, Kubota T, Saito H. No increased risk of major congenital anomalies or adverse pregnancy or neonatal outcomes following letrozole use in assisted reproductive technology. Hum Reprod. 2017;32: Ganesh A, Goswami SK, Chattopadhyay R, Chaudhury K, Chakravarty B. Comparison of letrozole with continuous gonadotropins and clomiphene-gonadotropin combination for ovulation induction in 1387 PCOS women after clomiphene citrate failure: a randomized prospective clinical trial. J Assist Reprod Genet. 2009;26: Mattenberg C, Fondop JJ, Romoscanu I, Luyet C, Bianchi-Demicheli F, de Ziegler D. Use of aromatase inhibitors in infertile women. Gynecol Obstet Fertil. 2005;33: Bedaiwy MA, Forman R, Mousa NA, Al Inany HG, Casper RF. Costeffectiveness of aromatase inhibitor co-treatment for controlled ovarian stimulation. Hum Reprod. 2006;21: Jee BC, Ku SY, Suh CS, Kim KC, Lee WD, Kim SH. Use of letrozole versus clomiphene citrate combined with gonadotropins in intrauterine insemination cycles: a pilot study. Fertil Steril. 2006;85: Homburg R. Oral agents for ovulation-induction-clomiphene citrate versus aromatase inhibitors. Hum Fertil (Camb). 2008;11: Mitwally MFM, Casper RF. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertil Steril. 2001;75: Casper RF. Letrozole versus clomiphene citrate: which is better for ovulation induction? Fertil Steril. 2009;92: Quintero RB, Urban R, Lathi RB, Westphal LM, Dahan MH. A comparison of letrozole to gonadotropins for ovulation induction, in subjects who failed to conceive with clomiphene citrate. Fertil Steril. 2007;88: Barroso G, Menocal G, Felix H, Rojas-Ruiz JC, Arslan M, Oehninger S.Comparison of the efficacy of the aromatase inhibitor letrozole and clomiphene citrate as adjuvants to recombinant follicle-stimulating hormone in controlled ovarian hyperstimulation: a prospective, randomized, blinded clinical trial. Fertil Steril. 2006;86: Bayar U, Tanriverdi HA, Barut A, Ayo?lu F, Ozcan O, Kaya E. Letrozole vs. clomiphene citrate in patients with ovulatory infertility. Fertil Steril. 2006;85: Jee BC, Ku SY, Suh CS, Kim KC, Lee WD, Kim SH. Use of letrozole versus clomiphene citrate combined with gonadotropins in intrauterine insemination cycles: a pilot study. Fertil Steril. 2006;85: Polyzos NP, Tsappi M, Mauri D, Atay V, Cortinovis I, Casazza G. Aromatase inhibitors for infertility in polycystic ovary syndrome. The beginning or the end of a new era? Fertil Steril. 2008;89: Legro RS, Brzyski RG, Diamond MP, Coutifaris C, Schlaff WD, Casson P, Christman GM, Huang H, Yan Q, Alvero R, Haisenleder DJ, Barnhart KT, Bates GW, Usadi R, Lucidi S, Baker V, Trussell JC, Krawetz SA, Snyder P, Ohl D, Santoro N, Eisenberg E, Zhang H; NICHD Reproductive Medicine Network. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med. 2014;371: Banerjee Ray P, Ray A, Chakraborti PS. Comparison of efficacy of letrozole and clomiphene citrate in ovulation induction in Indian women with polycystic ovarian syndrome. Arch Gynecol Obstet. 2012;285: Roy KK, Baruah J, Singla S, Sharma JB, Singh N, Jain SK, Goyal M. A prospective randomized trial comparing the efficacy of Letrozole and Clomiphene citrate in induction of ovulation in polycystic ovarian syndrome. J Hum Reprod Sci. 2012;5: Roque M, Tostes AC, Valle M, Sampaio M, Geber S. Letrozole versus clomiphene citrate in polycystic ovary syndrome: systematic review and meta-analysis. Gynecol Endocrinol. 2015;31: Liu W, Dong S, Li Y, Shi L, Zhou W, Liu Y, Liu J, Ji Y. Randomized controlled trial comparing letrozole with laparoscopic ovarian drilling in women with clomiphene citrate-resistant polycystic ovary syndrome. Exp Ther Med. 2015;10: El-Gharib MN, Mahfouz AE, Farahat MA. Comparison of letrozole versus tamoxifen effects in clomiphen citrate resistant women with polycystic ovarian syndrome. J Reprod Infertil. 2015;16: Polyzos NP, Tzioras S, Mauri D, Tsappi M, Cortinovis I, Tsali L, Casazza G. Treatment of unexplained infertility with aromatase inhibitors or clomiphene citrate: a systematic review and meta-analysis. Obstet Gynecol Surv. 2008;63: Badawy A, Elnashar A, Totongy M. Clomiphene citrate or aromatase inhibitors for superovulation in women with unexplained infertility undergoing intrauterine insemination: a prospective randomized trial. Fertil Steril. 2009;92(4): Diamond MP, Legro RS, Coutifaris C, Alvero R, Robinson RD, Casson P, Christman GM, Ager J, Huang H, Hansen KR, Baker V, Usadi R, Seungdamrong A, Bates GW, Rosen RM, Haisenleder D, Krawetz SA, Barnhart K, Trussell JC, Ohl D, Jin Y, Santoro N, Eisenberg E, Zhang H; NICHD Reproductive Medicine Network. Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility. N Engl J Med. 2015;373: Biljan MM, Hemmings R, Brassard N. The outcome of 150 babies following the treatment with letrozole or letrozole and gonadotropins. Fertil Steril. 200;)84: O Tulandi T, Martin J, Al-Fadhli R, Kabli N, Forman R, Hitkari J, Librach C, Greenblatt E, Casper RF. Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate. Fertil Steril. 2006;85: Tatsumi T, Jwa SC, Kuwahara A, Irahara M, Kubota T, Saito H. No increased risk of major congenital anomalies or adverse pregnancy or neonatal outcomes following letrozole use in assisted reproductive technology. Hum Reprod. 2017;32:

10 PCOS and Obesity 10 Dr. Jayasshree Todkar Laparoscopic and Bariatric Surgeon, Fellow Gastro Obeso Centre, Brazil, Cleveland Clinic, Ohio, USA Introduction Since its original description in 1935, obesity has been recognized as a common feature of the Polycystic Ovary Syndrome (PCOS). Moreover, obesity exacerbates many of the reproductive and metabolic abnormalities associated with PCOS. This review explores the available data on the mechanisms of this association. Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have a negative effect on health. People are generally considered obese when their body mass index (BMI), a measurement obtained by dividing a person's weight in kgs by the square of the person's height in metres, is over 30 kg/m2, with the range kg/m2 defined as overweight. Pathophysiology PCOS has metabolic characteristics that include prominent defects in insulin and b-cell function that confer a substantially increased risk for glucose intolerance and type 2 diabetes. Furthermore, the metabolic abnormalities associated with PCOS, such as b-cell dysfunction and type 2 diabetes, have heritable components in families of women with PCOS. To date, the genes responsible for PCOS have not been clearly identified. Considering the close association between PCOS and obesity, it is likely that similar or interrelated genes may also predispose to obesity in affected women. No doubt environmental factors (high-caloric diets and reduced exercise) also play a major role in the high prevalence of obesity in women with PCOS 1,2. Insulin resistance is a predominant finding in PCOS. Insulin-mediated glucose disposal, reflecting mainly insulin action on skeletal muscle, is decreased by 35-40% in women with PCOS compared to weight comparable reproductively normal women. This defect is significantly correlated to obesity. Hepatic insulin resistance, characterized by both increased post absorptive glucose production and reduced sensitivity to insulin, is present in obese women with PCOS 3. Fasting insulin levels are increased in PCOS & are more pronounced in women with PCOS who have a first-degree relative with type 2 diabetes. Under normal circumstances, the relation between insulin secretion and sensitivity is constant so that changes in insulin sensitivity are accompanied by reciprocal changes in insulin secretion that maintain normal glucose tolerance; this relationship is known as the "disposition index." Women with PCOS have a lower disposition index compared to weight-matched normal women 4. PCOS is associated with high rates of glucose intolerance resulting from defects in insulin action and b-cell function. Detection of glucose abnormalities in women with PCOS is best performed by means of glucose tolerance testing, since fasting glucose levels may be normal despite presence of glucose intolerance 5,6. Treatment for PCOS PCOS treatment starts with a proper diagnosis. Treatments are then chosen based on a woman's symptoms, age and future pregnancy plans. Treatment for PCOS is not effective unless the baseline metabolic disorders-obesity and Insulin Resistance are dealt with scientifically. As per the scientific and clinical evidence, these are the treatments options for Obesity/Adiposity and the Insulin Resistance: 1. Supervised Diet and Exercise Modifications are a must in this treatment. But may not be effective enough alone Pharmacotherapy Apart from Metformin, inositols and Orlistat, no pharmacotherapy in really available to treat adiposity/obesity/ metabolic syndrome. 3. Bariatric Surgery in PCOS 10% of women world wide are suffering from PCOS, and will seek help for gynaecological disorders or body image. Many such women are at a risk of Metabolic Syndrome, predisposed to glucose abnormalities ie. DM, Dyslipidemia, Cardiovascular diseases. Metabolic Syndrome (MS) and obesity co-exist. Bariatric surgery can be an effective and safe means of treatment for obese women with PCOS. Bariatric surgery can prevent or reverse Metabolic Syndrome associated with PCOS, leading to reproductive benefits PCOS treatment requires combination of medical therapy, psychological support, lifestyle modifications and should include bariatric surgery as a firm treatment modality, wherever indicated. Bariatric surgeries help obese women in terms of improved fertility index, improved interpersonal relationships & sexual behavior, prevention of Gestational Diabetes & Pregnancy Induced Hypertension. Women with morbid obesity, who are infertile secondary to PCOS, may have a new surgical option in the form of bariatric surgery. Studies report that 100 % of the morbidly obese women who were diagnosed with PCOS-related infertility became pregnant within three years following Bariatric Surgery. Methods of Bariatric Surgery Bariatric surgery has been available for decades. Most procedures are now performed laparoscopically. Three most common procedures performed are: 1. Laparoscopic adjustable gastric banding (LAGB) 2. Laparoscopic roux-en-y gastric bypass (LRYGB) 3. Laparoscopic sleeve gastrectomy (LSG) Weight loss for each procedure increases subsequently in each of the first 3 years postoperatively. Decreased surgical time, shorter hospital stay and quicker recovery are the advantages of latest advances in techniques of laparoscopic surgery. Metabolic improvements after bariatric surgery: BMI and excess body weight decrease substantially after surgery. Improvement is noted in glucose abnormalities, dyslipidemia and hypertension. Insulin abnormalities may improve very early postoperatively in pre-menopausal women with MS. Bariatric procedures showed improved insulin values proportional to changes in BMI. The effects on hypertension have been shown to be independent of the magnitude of weight loss. Reproductive age women fitting the profile of PCOS are included in many of the studies. Most women regained normal menstrual function and most had documented spontaneous ovulation. Patients had significant improvement in hirsutism & androgen profiles post Bariatric Surgery. Follow up for more than 2 years showed that all women resumed normal menstrual cycles, half had resolution of hirsutism and HbA1C decreased from 8.2% to 5.1%. Dyslipidemia, hypertension and diabetes mellitus almost completely resolved. Interestingly, women became pregnant spontaneously after surgery. 78% of women saw improvement in MS and 48% showed improvement in PCOS specifically with regards to menstrual cycles, fertility and/or hirsutism. PCOS presents a unique challenge since many obese PCOS women are adolescents. Although patients and physicians may at first be wary of a young patient considering surgical weight loss, these patients have an important opportunity. Bariatric surgery may actually provide primary prevention of coronary artery disease, eliminate MS and cause meaningful, long term reduction in morbidity and mortality. Young women with PCOS show evidence of atherosclerosis by abnormal carotid intima media thickness measurement and the prevalence of diabetes mellitus before the age of 50 is exceptionally high and estimated at 3-4 times the general population prevalence 8. Reproductive concerns may also lead PCOS women with MS to consider bariatric surgery. The relationship between PCOS, obesity and infertility has been documented for many years. Known effects include anovulation, miscarriage, impairment in folliculogenesis and altered endometrial receptivity. Risks in pregnant woman with PCOS & MS are high, namely diabetes, pre-eclampsia, growth disorders, higher rates of cesarean delivery, higher maternal mortality and increase risks of metabolic disease in their children. Bariatric surgery in reproductive age women has been shown to decrease menstrual irregularities. PCOS women have less hyperandrogenism post. LH and FSH levels have been reported to increase after surgery. On a more functional level, ovulatory function measured by luteal LH and progesterone secretion improved postoperatively, although levels were still below normal values. Additionally, leptin levels decrease after bariatric surgery, reflecting improved reproductive metabolic status. These changes certainly would suggest improved reproductive function. Women already take pregnancy into consideration when electing for bariatric surgery. Although women tend to seek medical care for menstrual irregularities and hirsutism, this encounter offers a chance for evaluation, education and risk prevention of MS. Lifestyle modification and treatment of risk factors are appropriate and even necessary for long term control. Bariatric surgery is a powerful tool that should not be overlooked simply because a woman is young or presents with PCOS and MS rather than diabetes mellitus, myocardial

11 infarction and severe chronic hypertension. In our experience of Bariatric surgery since 2003, we have treated more than 60% women patients for overweight/ Obesity and related co morbidities. Out of this population, around 70% belonged to the reproductive age. The BMI range was between 28 to 70 kg/m2. 42% of these women had PCOS and infertility as the primary concern. All of them showed improved ovulatory function and fertility index after Bariatric surgery. References 1. Legro RS, Driscoll D, Strauss JF 3rd, et al. Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. ProcNatlAcadSci U S A 1998;95: Tsilchorozidou, T., Overton, C., Conway, G.S. The pathophysiology of polycystic ovary syndrome. ClinEndocrinol (Oxf). 2004;60: Alvarez-Blasco F, Botella-Carretero JI, San Millan JL, et al. Prevalence and characteristics of the polycystic ovary syndrome in overweight and obese women. Arch Intern Med 2006;166: Conway, G.S., Dewailly, D., Diamanti-Kandarakis, E. et al, The polycystic ovary syndrome: an endocrinological perspective from the European Society of Endocrinology. Eur J Endocrinol. 2014;171: Plascencia Gomez, A., Vega Memije, M.E., Torres Tamayo, M. et al, Skin disorders in overweight and obese patients and their relationship with insulin. ActasDermosifiliogr. 2014;105: Vgontzas, A.N., Legro, R.S., Bixler, E.O. et al, Polycystic ovary syndrome is associated with obstructive sleep apnea and daytime sleepiness: role of insulin resistance. J ClinEndocrinolMetab. 2001;86: Domecq JP, Prutsky G, Mullan RJ, et al. Lifestyle modification programs in polycystic ovary syndrome: systematic review and meta-analysis. J ClinEndocrinolMetab 2013;98: McCartney, C.R., Eagleson, C.A., Marshall, J.C. Regulation of gonadotropin secretion: implications for polycystic ovary syndrome. SeminReprod Med. 2002;20: Continued from page 6 Insulin Sensitizing Properties of Inositol: Experimental Studies Such effects are mediated by specific changes in placenta pathways that improve intrauterine environment in humans and mouse, resulting finally in the interruption of the epigenetic vicious cycle which transfer maternal metabolic and cardiovascular diseases to the offspring. Moreover, inositol counteracts the downstream consequences of insulin resistance in women affected by PCOS, ameliorating the fertility by decreasing the need of ovarian hyper stimulation and increasing the pregnancy rate. Lastly, inositol supplementation from the first trimester of pregnancy demonstrated to have a role in reducing the incidence of GDM in overweight and obese women. However, larger studies, in double-blind trials, including a more heterogeneous population would be necessary, to confirm the previous results for women with GDM, PCOS or post-menopausal and to test a possible application for a more generalized population of subjects already presenting an insulin resistance or at risk of developing one because of genetic predisposition. References 1. Micheal J B, Robin F I. Inositol triphosphate, a novelsecond messenger in cellular signal transduction. Nature. 1984;308(22): Ferrari F, Facchinetti F, Ontiveros AE, Roberts RP, Saade MM, Blackwell SC, et al. The effect of combined inositol supplementation on maternal metabolic profile in pregnancies complicated by metabolic syndrome and obesity. Am J Obstet Gynecol. 2016;215(4):503.e1-503.e8. 3. Harry E, Vance I O, Mina L, Aaron F. Myo-Inositol as an Essential Growth Factor for Normal and Malignant Human Cells in Tissue Culture. Sci New Ser. 1956;123(3202): Jenny F L C, M K L, Janice W S L, Sookja K C, Stephen S M C. Sodium/myoinositol cotransporter-1 is essential for the development and function of the peripheral nerves. FASEB J. 2005;19(5). 5. Dai Z, Chung SK, Miao D, Lau KS, Chan AWH, Kung AWC. Sodium/myoinositol cotransporter 1 and myo-inositol are essential for osteogenesis and bone formation. J Bone Miner Res. 2011;26(3): Carlomagno G, Nordio M, Chiu TT, Unfer V. Contribution of myo-inositol and melatonin to human reproduction. Eur J Obstet Gynecol Reprod Biol. 2011;159(2): Coady M, Wallendorff B, Gagnon D, Lapointe J. Identification of a novel Na+/myo-inositol cotransporter. J Biol Chem. 2002;277(38): Croze ML, Soulage CO. Potential role and therapeutic interests of myoinositol in metabolic diseases. Biochimie. 2013;95(10): Winegrad A. Does a common mechanism induce the diverse complications of diabetes? Diabetes. 1987;36: Allison S K, Cynthia R H, James C, Clifton B, Itmar R, Heidi K O, et al. Low urinary chiro-inositol excretion in non-insulin-dependent diabetes mellitus. N Engl J Med. 1990;323: Sun TH, Heimark DB, Nguygen T, Nadler JL, Larner J. Both myo-inositol to chiro-inositol epimerase activities and chiro-inositol to myo-inositol ratios are decreased in tissues of GK type 2 diabetic rats compared to Wistar controls. Biochem Biophys Res Commun. 2002;293(3): Asplin I, Galasko G, Larner J. chiro-inositol deficiency and insulin resistance: a comparison of the chiro-inositol and the myo-inositol containing insulin mediators isolated from urine, hemodialysate, and muscle of control and type II diabetic subjects. Proc Natl Acad Sci U S A. 1993;90(13): Antony PJ, Gandhi GR, Stalin A, Balakrishna K, Toppo E, Sivasankaran K, et al. Myoinositol ameliorates high-fat diet and streptozotocin-induced diabetes in rats through promoting insulin receptor signaling. Biomed Pharmacother. 2017;88: Santamaria A, Di Benedetto A, Petrella E, Pintaudi B, Corrado F, D'Anna R, et al. Myo-inositol may prevent gestational diabetes onset in overweight women: a randomized, controlled trial. J Matern Fetal Neonatal Med [Internet]. 2015;7058(March 2017):1-4. Available from: Monastra G, Unfer V, Harrath A, Bizzarri M. Combining treatment with myo-inositol and D-chiro-inositol (40:1) is effective in restoring ovary function and metabolic balance in PCOS patients. Gynecol Endocrinol. 2017;33(1): Emekçi Özay Ö, Özay A, Ça?l?yan E, Okyay R, Gülekli B. Myo-inositol administration positively effects ovulation induction and intrauterine insemination in patients with polycystic ovary syndrome: a prospective, controlled, randomized trial. Gynecol Endocrinol. 2017;3:1-5. Events & Updates Symposium on PCOS Science to Practice One day Symposium on "PCOS Science to Practice" was organized by the Guwahati Obstetrics & Gynaecological Society under the aegis of PCOS Society of India on the 11th December 2016 at Hotel Landmark, Guwahati. Dr. R. K. Talukdar was the chief conevenor, & Dr. Gitanjali Deka was the organizing secretary. Experts in the fields of gnaecology, infertility, dermatology and endocrinology spoke on the various aspect of the multifaceted condition of PCOS. Drs. Rekha Sheth, Saswati S. Chaudhary, Uma Kaima Saikia & Ashok Bhuyan were the keynote speakers. The symposium was attended by 140 gynaecologists and was spread over 6 sessions, which focused on Basics in PCOS, Infertility & PCOS, Evidence Based treatment, PCOS & Pregnancy, Health risks of PCOS and Drugs in PCOS. The attendees expressed their interest to seek more information through CMEs in the diagnosis & phenotypes of PCOS, IVF in PCOS and etiopathogenesis of PCOS. 11

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