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Prof.Duru Shah

Founder President “The PCOS Society” (India) President Elect of the Indian Society for Assisted Reproduction (ISAR) Honorary Fellow of the Royal College of Obs. & Gyn. First Indian to receive FIGO’s “Distinguished Merit Award” for Services towards women’s health.

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Prof.Duru Shah

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  1. Founder President “The PCOS Society” (India) • President Elect of the Indian Society • for Assisted Reproduction (ISAR) • Honorary Fellow of the Royal College • of Obs. & Gyn. • First Indian to receive FIGO’s • “Distinguished Merit Award” for • Services towards women’s health. • Director Gynaecworld….. The Center • for Womens Health & Fertility Prof.Duru Shah Prof.and :Breach Candy Hosp. Cons. Obs. Jaslok Hospital & Gyn Global Hospital

  2. Poor Responders in PCOS Prof. Duru Shah MD FRCOG FCPS FICS FICOG FICMCH DGO DFP SMART OBGYN 16th April, 2016 Mumbai Org.by MOGS in asso. with SAFOG,FOGSI & AICRCOG

  3. Definition • Failure to respond adequately to standard protocols and to recruit adequate follicles is called “poor ovarian response”. • This results in decreased oocyte production, cycle cancellation and, overall it is associated with a significantly diminished probability of pregnancy. Ref: Shanbhag S. et.al. Cochrane Database Syst Rev. 2007;(1): CD004379

  4. 3 main groups Responses to Gonadotropins • Normal Responders When stimulated aggressively with Gn will develop 5-8 mature follicles as well as several smaller ones. • Poor Responders (older age, poor ovarian reserve) Failure to produce an adequate no. of mature follicles(<4) & or a peak E2 levels < 500 pg/ml. • High Responders (PCOS) Defined as those women with peak E2 levels > 4000 pg/ml on the day of hCG administration or > 15 retrieved oocytes

  5. Poor Responders • Concept of Poor Ovarian • Response introduced 30 yrs. • ago. • Results in ↑ cancellation rates • ↓ nos. of oocytes retrieved • ↓ preg. rates • Universal definition of Poor • Responders in 2011- • Bologna Criteria – ESHRE • WORKING group. Re. ASRM Fertil Steril, 2011, 96: 1058-61

  6. Bologna Criteria- 2011 • At least two of the following three features must • be present: • Advanced maternal age (≥ 40 yrs.) or any • other risk factor for POR. • A previous POR (≤ 3 oocytes with a • conventional stimulation protocol): • An abnormal ovarian reserve test (ie. AFC • <5-7 follicles or AMH <0.5-1.1 ng/ml) Ref. A.P. Ferraretti et. al. Human Reproduction Vol.26, No.7, pp.1616- 1624,2011

  7. Risk factors for Poor Ovarian Reserve • Age > 37 yrs., varies with • ethnicity. • Ovarian surgery • Endometriosis • Genetic Defects • Chemo / Radiotherapy • Autoimmune Disorders Contd… Ref. A.P Ferraretti et.al. Human Reproduction vol. 26, no. 7 pp 1616-1624,2011

  8. Declining follicle/oocyte numbers with advancing age. Ref : Gleicher et.al. Reproductive Biology & Endocrinology (2015) 13:34

  9. Genetic Defects • Under hormonal control • Genetic control which may either slow or hasten the process of recruitment • Genes identified currently are : - AMH type II – Receptor gene (AMHR2) - FMRI Gene ( Fragile X Mental Retardation Gene) - BRCA1 Gene Above Genes when mutated, blocked or knocked out, lead to rapid depletion of primordial follicles.

  10. Contd… Ovarian Surgery • Extensive Ovarian Drilling for PCOS • Prophylactic oophorectomy→ POF • Salpingectomy for ectopic pregnancy → ↓ AFC→↓ oocytes obtained during ART and for hydrosalpinx. • Ovarian Cystectomy for endometriomas. • Ovarian Neoplasms in Adolescents Contd…

  11. Contd… • Single Ovary • Chronic Smoking • New Factors proposed • Diabetes Mellitus Type I • N. Soto, G et.al. Human Rep. Vol. 24, no. 11 pp 2838-2844, 2009 • Transfusion dependant β Thalassemia • H.H. Chang, M-J et.al. British Journal of Obs. & Gyn. vol. 118,no7, • pp825-831 • Uterine Artery Embolization • W.J.J. Hehenkamp, et. al. Human Reproduction vol. 22, no.7, • pp1996-2007 Other Factors

  12. Identifying Poor Responders High Risk Group • Day 3 - FSH > 10 m IU /ml - Inhibin B < 45 pg/ml - AMH < 3 ng/mL - Total Antral Follicle Count < 10 • Age > 37 years of age - younger pts. may also have a poor response.

  13. Ultrasound –Antral Follicle count Ref : Kwee J et al Reprod Biology & Endocrinology 2007 5:9

  14. Hormonal investigations Contd.. Ref : Kwee J et al Reprod Biology & Endocrinology 2007 5:9

  15. Folliculogenesis Ref. A La. Marca et.al. Human Reproduction Update, Vol.16, 2010 No.2 pp 113-130

  16. Folliculogenesis • AMH corelates well with AFC, IVF out come. • AMH expression starts after growth initiation • of primordial follicles and disappears after the • small Antral follicles stage in the ovaries. Ref. Fanchin R. et. al. Hum. Reprod. 18, 323-327

  17. Folliculogenesis in PCOS • AMH significantly ↑ in PCOS reflecting ↑ • Primordial count. • Median density of primary follicles seen in • ovarian biopsies is 6 times ↑ in anovulatory • PCO v/s normal ovaries, suggesting • a larger ovarian reserve. Ref. Laven J. et.al. (2004) J. Clin Endocrinol Metab 89, 318-323

  18. Folliculogenesis in PCOS • Women with PCO are born • with a larger pool of resting foll. • - genetically determined process • which occurs in fetal life. • Larger the pool of Primordial • follicles → ↑ chance of PCOS in a certain environment. Contd.. Ref. D. Nilolaou et.al. Hum. Reprod. Vol. 19, No.10 pp. 2175-2179,2004

  19. Folliculogenesis in PCOS • Women with PCO are unlikely to undergo a rapid depletion of their ovarian reserve too early. • Hence Poor responders to ovarian stimulation in PCO women are rarely seen. Ref. D. Nilolaou et.al. Hum. Reprod. Vol. 19, No.10 pp. 2175-2179,2004

  20. Ovarian Aging • Normal Ovarian Ageing • → ↓oocyte quality and quantity rapidly in late • thirties. • Early Ovarian Ageing seen in 10% of women • → ↓ oocyte quantity which is faster than • qualitative decline before age 32 yrs. Contd.. Ref. D. Nilolaou et.al. Hum. Reprod. Vol. 19, No.10, pp.2175-2179, 2004

  21. Early Ovarian Aging- are women with PCOS protected? • AFC- good predictor of ovarian response and • corelates well with chronological age. • PCO women have a higher no. of AFC • PCO ovaries tend to be larger and have ↑ peak • stromal blood flow velocityon Doppler studies. • PCOS women have ↑ Day 2 Inhibin B levels and • ↑ early follicular VEGF levels. Contd.. Ref. Nikolaou & Templeton A (2003) Hum Repro. 18, 1137-1139 Nikolaou D & Templeton A (2004) Eur J. ObstetGynaecol 113, 126-133

  22. Contd.. Early Ovarian Aging- are women with PCOS protected? • Using AMH + AFC • Women with PCOS perform better with ovarian • reserve tests as compared to women with normal • ovaries. • Poor response to ovarian stimulation is a • predictor of early ovarian ageing v/slarger • number of oocytes recruited during ovarian • stimulation, increasing the risk for developing • OHSS Contd.. Ref. Nikolaou & Templeton A (2003) Hum Repro. 18, 1137-1139 Nikolaou D & Templeton A (2004) Eur J. ObstetGynaecol 113,126-133

  23. Early Ovarian Aging- are women with PCOS protected? • PCO(older data) • → Large no. of follicles with compromised • quality due to ↓ fertilization rates • ↑ miscarriage rates • ↑ recurrent miscarriage rates • PCO (recent data) • Above true only if PCOS exists ie. Polycystic • ovaries (PCO) associated with • →menstrual irreg. • → Hyperandrogenism (PCOS) • → Associated Insulin Resistance (IR) Contd.. Ref. D. Nilolaou et.al. Hum. Reprod. Vol. 19, No.10, pp.2175-2179, 2004

  24. Early Ovarian Aging- are women with PCOS protected? • More oocytes • More embryos • ↑ cumulative preg. rates • Similar miscarriages rates as • normal women. • Comparable oocyte quality • Time to pregnancy similar • Hence women with PCOS, but no clinical PCOS, • have a larger no. of good quality oocytes Ref. Rai et.al. 2000 Hum. Reprod. 15,612-615

  25. Clinical Pregnancy correlated with AMH & age – Our data ART : 369 pts. Ref. Gynaecworld data 2015-16

  26. Pregnancy rates correlated with Age + AMH (PCOS pts) Total no. of pts. 189 . Ref. Gynaecworld data 2015-16

  27. Pregnancy rates correlated with Age + AMH (Non PCOS pts) Total no. of pts. 180 . Ref. Gynaecworld data 2015-16

  28. Long-term follow-up of patients with PCOS syndrome: reproductive outcome and ovarian reserve • Study • 91 pts. with confirmed PCOS and 87 healthy controls included in the study. • Diagnosed bet 1987 and 1995, at the time of the follow-up subjects were 35 yrs. of age or older. Contd.. Ref. M. Hudecova et.al. Hum. Repro. Vol.24, No 5 pp1176-1183,2009

  29. Contd.. Long-term follow-up of patients with PCOS syndrome: reproductive outcome and ovarian reserve Contd.. Ref. M. Hudecova et.al. Hum. Repro. Vol.24, No 5 pp1176-1183,2009

  30. Long-term follow-up of patients with PCOS syndrome: reproductive outcome and ovarian reserve * p<0.025 ** p<0.01 ***p<0.001 Contd.. Ref. M. Hudecova et.al. Hum. Repro. Vol.24, No 5 pp1176-1183,2009

  31. Contd.. Ovarian Volume Contd.. Ref. M. Hudecova et.al. Hum. Repro. Vol.24, No 5 pp1176-1183,2009

  32. Contd.. Antral Follicles Contd.. Ref. M. Hudecova et.al. Hum. Repro. Vol.24, No 5 pp1176-1183,2009

  33. AMH Ref. M. Hudecova et.al. Hum. Repro. Vol.24, No 5 pp1176-1183,2009

  34. Contd.. • Results: • Reproductive outcome did not differ between • women with a previous diagnosis of PCOS and • healthy control subjects. • Ovarian reserve better preserved in women • with PCOS • Live birth rate and rate of miscarriages similar in • PCOS patients and control women. Contd.. Ref. M. Hudecova et.al. Hum. Repro. Vol.24, No 5 pp1176-1183,2009

  35. Contd.. • Results: • Mean ovarian volume and number of antral • follicles, significantly higher in PCOS patients. • PCOS patients have markedly higher serum • concentration of AMH. • More than two-thirds of the PCOS patients in the • present study reported at least one • spontaneous pregnancy. • PCOS patients have a good fecundity. Ref. M. Hudecova et.al. Hum. Repro. Vol.24, No 5 pp1176-1183,2009

  36. Conclusions • Recent findings support that, women with PCOS are born with a larger pool of resting follicles, almost certainly genetically determined. • The rate of decline of the ovarian reserve • depends on the number of remaining • primordial and small pre-antral follicles. Contd.. Ref. D. Nilolaou et.al. Hum. Reprod. Vol. 19, No.10, pp.2175-2179, 2004

  37. Conclusions • Hence women with PCO are unlikely to • undergo a rapid depletion of their ovarian • reserve too early. • PCO most likely forms a low-risk group for • early ovarian aging and poor ovarian • response Contd.. Ref. D. Nilolaou et.al. Hum. Reprod. Vol. 19, No.10, pp.2175-2179, 2004

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