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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

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Prof.Duru Shah MD FRCOG FCPS, FICS FICOG, FICMCH DGO DFP

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  1. 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. Prof.Duru Shah MD FRCOG FCPS, FICS FICOG, FICMCH DGO DFP

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

  3. PCOS • 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

  4. 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) Oligoand / 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. 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. Pathophysiology • 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

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

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

  10. PCOS- Major Challenges in infertility management • 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 & 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/ m2 • - 2.7 times with BMI > 31 kg/ m2 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 → ↑ androgens Premature follicular atresia ↓ follicular maturation Infertility anovulation Contd… Ref. Franks S, et.al. Hum Reprod Update 2008;14:367-78

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

  16. Obesity PCOS & Infertility 3586 obese women, 25% with PCOS 27% (95 % CI 0.57, 0.96) P <.001 ↓ 50% 95% CI 0.32,0.77) 0 10 20 30 40 50 60 70 80 90 100 BMI / Kg/m2 Normal < 25 >35 25 - 29 30 - 34 Ref. Wang JX et. al. BMJ 2000;321:1320-1

  17. Weight loss in infertile obese PCOS • 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. 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. Ref. Practice Committee of ASRM – Obesity & Reproduction Fertil Steril 2008, 90:S21-9 Contd…

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

  20. Hyperinsulinaemia & Hyperandrogenemia

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

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

  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. PPCOS trial (Pregnancy in PCOS Trial) Study : 626 infertile women randomly assigned to CC+Placebo Metformin + placebo x 6 months Metformin + Clomiphene CONCLUSION Clomiphene is superior to Metformin in achieving live birth in infertile women with PCOS though multiple birth is a complication 26.8% 22.5% 6% 7.2% 3.1% 0% 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

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

  30. Gynaecworld Fertility Unit Mean pregnancy rate = 86/269 = 32.71% Metformin added to all cycles. PCOS COH + IUI cycles = 269

  31. ART Results- PCOS v/s Non PCOS Meta-analysis of 9 observational studies • 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. Ref. Heijnen EM, et.al. Hu. Reprod. Update 12(1), 13-21 (2006)

  32. Gynaecworld Fertility Unit -ART Data

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

  34. Predictive Markers for Ovarian response • 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. Ref. Nardo LG, Gelbaya TA et.al. Fertil Steril. 2009 Nov;92 (5): 1586- 93 Epub 2008 Oct 18

  35. 132.8 Gynaecworld Data • Total no.of PCOS pts. = 151 AMH < 6 85.5 AMH < 6 - 10 AMH < 10 - 15 0 15 30 45 60 90 120 49.3 29.4 18.6 15.4 11.5 11.4 7.9 8.2 5.7 4.9 LH FAI SIF SIPG

  36. Levels prior to Rx. Gynaecworld Experience -PCOS & Predictive Markers

  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.

  39. International Faculties

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