1. Duru Shah Prof.Duru Shah MD FRCOG FCPS, FICS FICOG, FICMCH DGO DFP Founder President of the PCOS Society, India President Elect of the Indian Society for Assisted Reproduction (ISAR). Director, Gynaecworld – the Center for Women’s Health and Fertility. Founder- Chairperson Women’s Empowerment (WE) Foundation First & only Indian to receive the “Distinguished Merit Award” from FIGO for services toward womens’ health.

2. Duru Shah Prof. Duru Shah MD FRCOG FCPS FICS FICOG FICMCH DGO DFP Prof. Duru Shah MD FRCOG FCPS FICS FICOG FICMCH DGO DFP PCOS & Infertility- Overview Fertility Forum 15.05.2016 Organized by The PCOS Society, India Supported by USV

3. Duru Shah Polycystic Ovary Syndrome (PCOS) is one of the most common endocrinopethies. Affects 6% - 7% of reproductive age women. Polycystic Ovary Syndrome (PCOS) is one of the most common endocrinopethies. Affects 6% - 7% of reproductive age women. Ref: Azziz R. et.al. : J Clin Endocrin. Metab 2004: 39 PCOS

4. Duru Shah 1999 Criteria (both 1+2) Chronic Anovulation Clinical and / or biochemical signs of hyperandrogenism and exclusion of other etiologies. 1999 Criteria (both 1+2) Chronic Anovulation Clinical and / or biochemical signs of hyperandrogenism and exclusion of other etiologies. 2003 Rotterdam Criteria (2 out of 3) Oligo and / or anovulation Clinical and / or biochemical signs of hyperandrogenism. Polycystic ovaries and exclusion of other etiologies PCOS – Definition Revised 2003 Consensus on diagnostic criteria

5. Duru Shah PCOS - Infertility Areas for Discussion Pathophysiology Challenges in infertility management in PCOS - Obesity - Hyperinsulinaemia & Hyperandrogenaemia - ↑ LH Ovulation Induction - Best practices Useful markers for management Conclusions

6. Pathophysiology Etiology of PCOS unknown. Increasing evidence to support the view Complex Endocrine Trait Contribution of several genes (CYP 17, CYP 11a VNTR etc) Act jointly with Environmental + Nutritional factors PCOS Abnormal Ovarian Steroidogenesis Contd..

7. Hypersecretion of LH 40% of pts. ↑ LH →menstrual disorders infertility → ↑ ovarian androgen production → direct interference with oocyte maturation ↓ ovulation rates & ↑ abortion rates → ↓ implantation & pregnancy rates in ART cycles Pathophysiology

8. Hyperinsulinemia Liver Hyperandrogenaemia Obesity Insulin resistance Polycystic Ovarian Syndrome Pathophysiology of PCOS ↓ sex hormone Binding globulin ↑ Insulin –like growth Factor 1 ↓ Insulin-like Growth factor 1 Binding protein ↑ Luteinizing hormone Ovary Thecal Cell hyperplasia Anovulation Courtesy : www blackwell-synergy.com Obesity

9. Ovulation Fertilization Implantation Fetal Viability Healthy Live born Poor Oocyte Quality Affects gestational diabetes and hypertension Endometrial receptivity Hyperinsulinemia Why does PCOS lead to infertility?

10. PCOS- Major Challenges in infertility management Hyperandrogenaemia Hyperinsulinemia Obesity Premature LH Surge Hyperandrogenaemia Hyperinsulinemia Obesity Premature LH Surge

11. Strategies to optimize fertility in PCOS women Weight loss Insulin Sensitizers Ovulation Induction Laparoscopic Ovarian drilling Assisted Reproduction Contd …..

12. Obesity Obesity&PCOS

13. Obesity & Infertility Facts: Obese women 3 times more likely to have infertility v/s normal women. 80% PCOS have ↑ BMI Infertility rate ↑ x 4 times / BMI unit Central obesity ↓ conception by 30% per cycle for each 0.1 ↑ in W.H. Ratio RR of anovulation v/s normal wt. women - 1.3 times with BMI 24-31 kg/ m 2 - 2.7 times with BMI > 31 kg/ m 2 Ref. Lisa J. Moran, et.al. Endocrinol Metab Clin N Am 40 (2011) 895-906

14. Obesity & Infertility Follicular fluid insulin and androgen levels corelate with BMI in obese infertile women even in absence of PCOS. ↑ BMI → Ref. Franks S, et.al. Hum Reprod Update 2008;14:367-78 Contd… ↑ androgens Premature follicular atresia ↓ follicular maturation anovulation Infertility

15. Obesity & Infertility O besity ↑ Adipokines (leptin, TNF- ά, IL – 6) → antagonise effect of Insulin → Insulin Resistance → Negative effects on oocyte development, embryo development, endometrial receptivity. Ref. Lisa J. Moran, et.al. Endocrinol Metab Clin N Am 40 (2011) 895-906 Contd…

16. Obesity PCOS & Infertility 3586 obese women, 25% with PCOS Ref. Wang JX et. al. BMJ 2000;321:1320-1 0 10 20 30 40 50 60 70 80 90 100 ↓ 50% 95% CI 0.32,0.77) 27% (95 % CI 0.57, 0.96) P <.001 BMI / Kg/m 2 Normal < 25 25 - 2930 - 34 >35

17. 5 % - 10% wt. loss can improve I.R, ovulation rate, pregnancy rate even if BMI > normal range No consensus on commencement of fertility Rx based on optimal BMI. Ref. Practice Committee of ASRM – Obesity & Reproduction Fertil Steril 2008, 90:S21-9 Contd… Weight loss in infertile obese PCOS Ref. Clark AM, et. al. Hum Reprod 1998;13:1502-5 ASRM recommends that though BMI of < 35 should be achieved before conception, “the benefits of postponing pregnancy to achieve wt. loss must be balanced against risk of declining fertility with advancing age.

18. Obesity in PCOS- Treatment Diet Exercise Bariatric surgery may be considered for obese PCOS pts. Pharmacological Rx Bariatric Surgery Not recommended for Ovulation Induction Wt. loss is the first line therapy in obese women with PCOS Ref. Palomba et.al. Hum. Reprod. 2010, Nov. 25 :11

19. Obesity in PCOS Ref. Palomba et.al. Hum. Reprod. 2010, Nov. 25 :11 96 overweight and obese CC Resistant PCOS pts. SET + Hypo- calorie diet 2 wks. obser. Followed by one cycle of CC therapy SET plus hypocalorie diet for 6 wks. + 1 cycle of CC after 2 weeks Ovulation rate 12.5 % + P=.05 RR = 3.9 9.4 % Ovulation rate 37.5% + P=.008 RR= 4 SET= Structural Exercise Training A BC Significant improvement in clinical & biochem. androgen & insulin sensitivity index.

20. Hyperinsulinaemia Hyperinsulinaemia&Hyperandrogenemia

21. Hyperinsulinemia Insulin Resistance (IR) is present in approx. 50% of women with PCOS. Insulin Resistance (IR) is present in approx. 50% of women with PCOS. 90% of obese women with PCOS have IR 90% of obese women with PCOS have IR IR exacerbates ovulation dysfunction. IR exacerbates ovulation dysfunction. Ref. William Hurd et.al. Fertil Steril, Vol96, Oct 2011

22. Hyperinsulinaemia & PCOS 10 9 8 7 6 5 4 3 2 1 0 0 30 60 90 120 150 100 50 0 Glucose Tolerance Curves ( mmols / L ) Glucose Stimulated Insulin Concs. ( mu / L ) Time ( Mins ) Normal PCOS Normal PCOS

23. Insulin Sensitizers Mainstay of managing insulin resistant PCOS is with insulin sensitizers. Commonest drug used is Metformin. Dose of 1500 –1700mg/day in divided doses. Causes G.I. side effects

24. Study : 626 infertile women randomly assigned to CC+Placebo Metformin + placebo x 6 months Metformin + Clomiphene 22.5% 7.2% 26.8% 6% 0% 3.1% CONCLUSION Clomiphene is superior to Metformin in achieving live birth in infertile women with PCOS though multiple birth is a complication PPCOS trial (Pregnancy in PCOS Trial) PPCOS trial (Pregnancy in PCOS Trial) Ref : Lagro RS et al N. Engl J Med 2007 Feb

25. PPCOS trial (Pregnancy in PCOS Trial) Ref : Lagro RS et al N. Engl J Med 2007 Feb

26. Insulin Sensitizers in PCOS Conclusion : - Metformin is an effective treatment for anovulation in women with PCOS - Ovulation rates higher when combined with CC - Reduces risk of OHSS by approximately 75% - ↓ serum E2 levels Contd….. Ref : Lord J M, Flight HK et al. Cocherane syst Rev 2005:3

27. Other Insulin Sensitizers Rosiglitazone; Piolitazone have been used but associated weight gain, less favorable pregnancy profile and possible cardiovascular risk limit their use for this purpose. Inositols Ref. Cochrane Database Syst. Rev 2010

28. Anovulation Anovulation

29. BMI Specific programs For lifestyle Modifications (at least 6 months) in Obese women Clomiphene Citrate Metformin Metformin+CC Metformin+ Gonadotropins (?) LOD (in infertile PCOS pts when co- factors of sub fertility are suspected and/or diagnosed) Gonadotropins COS+TI / IUI ARTs PREGNANCY Palomba. Ovulation induction in PCOS. Fertil Steril 2006 Ovulation Induction in PCOS- Best Practices Practices Gh + Gn Antagon + IUI

30. Gynaecworld Fertility Unit PCOS COH + IUI cycles = 269 PCOS COH + IUI cycles = 269 Pregnancy rate based on different stimulation protocols No. of cyclesPositive preg.Success % CC461532.6% CC + Gonadotropins591322.03% Only Gonadotropins611727.87% CC/ Gn+ Antagon1034341.74% Mean pregnancy rate = 86/269 = 32.71% Metformin added to all cycles.

31. ART Results- PCOS v/s Non PCOS Meta-analysis of 9 observational studies Ref. Heijnen EM, et.al. Hu. Reprod. Update 12(1), 13-21 (2006) 458 women with PCOS - 793 cycles 694 matched controls - 1116 cycles In PCOS women- - ↑ cycle cancellation rate - ↑ risk of OHSS - ↑ no. of eggs collected - Lower fertilization rate - Similar pregnancy rate - Similar miscarriage rate as non PCOS pts.

32. Gynaecworld Fertility Unit -ART Data No. of PCOSNo. of Non PCOS Total follicles910423 Oocytes recovered800360 Mature oocytes695 (86.87%)314(87.22%) Grade 1 Embryos recovered from Mature oocytes 605 (87.05%)277 (88.21%) Total pts.6939 Pregnancies3318 Pregnancy rates47.83%46.15% Ongoing pregnancy9.09%11.11% Live Birth Rates75.76%72.22% Abortion Rates6.06%5.55% Biochemical pregnancy6.06%5.55% Ectopic pregnancy3.03%5.55%

33. Predictive Markers for Ovarian Response Ref. Nardo LG, Gelbaya TA et.al. Fertil Steril. 2009 Nov;92 (5): 1586- 93 Epub 2008 Oct 18 FSH, AMH, AFC Prospective cohort study 165 women - 134 normal responders 15 poor responders 16 high responders Contd..

34. Ref. Nardo LG, Gelbaya TA et.al. Fertil Steril. 2009 Nov;92 (5): 1586- 93 Epub 2008 Oct 18 AMH levels & AFC levels ↑ in high responders ↓ in poor responders AMH – performed better in the prediction of excessive response to ovarian stimulation compared to FSH & AFC AMH to be in corporated into work up protocols to predict pts. ovarian response to treatment. Predictive Markers for Ovarian response

35. Gynaecworld Data Total no.of PCOS pts. = 151 LH FAI SIF SIPG 5.7 11.511.4 4.9 8.2 15.4 7.9 18.6 29.4 49.3 85.5 132.8 AMH < 6 AMH < 6 - 10 AMH < 10 - 15 0 15 30 45 60 90 120

36. Gynaecworld Experience -PCOS & Predictive Markers Mean - values PregnantNon Pregnant P. Value AMH 4.093.17< 0.0001 LH 12.075.18< 0.0001 BMI 28.1022.12< 0.0001 FI 11.467.2< 0.001 PGI 53.6522.39< 0.001 Levels prior to Rx.

37. Conclusions If obese, weight loss, should be recommended prior to initiation of therapy. Hyperandrogenism, Hyperinsulinemia should be looked for in every PCOS woman Ovulation inducing agents and adjuvants should be customized. Use of Metformin improves pregnancy rates when added to the ovulation induction protocol Contd..

38. Conclusions Use of Metformin and Antagonist help to reduce the risk of OHSS following ovulation induction. ART results in PCOS are comparable to non PCOS pts. AMH levels and AFC can serve as predictive markers for response to COH.

40. International Faculties International Faculties