Founder President The PCOS Society India President Elect

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

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

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): Duru Shah CD 004379

Responses to Gonadotropins 3 main groups • 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 E 2 levels < 500 pg/ml. • High Responders (PCOS) Defined as those women with peak E 2 levels > 4000 pg/ml on the day of h. CG administration or > 15 retrieved oocytes Duru Shah

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 Duru Shah

Bologna Criteria- 2011 • At least two of the following three features must be present: Ø Advanced maternal age (≥ 40 yrs. ) or any other risk factor for POR. Ø A previous POR (≤ 3 oocytes with a conventional stimulation protocol): Ø 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. 16161624, 2011 Duru Shah

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

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

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 (AMHR 2) - FMRI Gene ( Fragile X Mental Retardation Gene) - BRCA 1 Gene Above Genes when mutated, blocked or knocked out, lead to rapid depletion of primordial follicles. Duru Shah

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… Duru Shah

Contd… Other Factors • 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, no 7, pp 825 -831 • Uterine Artery Embolization W. J. J. Hehenkamp, et. al. Human Reproduction vol. 22, no. 7, pp 1996 -2007 Duru Shah

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

Ultrasound –Antral Follicle count Parameter Normal responders (n=81) Poor Responders (n=29) P 17. 7± 9. 7 4. 6± 2. 6 <. 001 14. 9± 8. 1 3. 0± 1. 6 <. 001 22(24) 2(10) <. 001 Endpoints Total no. of follicles Total no. of oocytes Ongoing pregnancy n(%) Ref : Kwee J et al Reprod Biology & Endocrinology 2007 5: 9 Duru Shah

Hormonal investigations Parameter Age at baseline (y) CD 3 FSH(IU/L) Normal Poor P responders Responders Value (n=81) (n=29) 33. 5+4. 0 35. 3+3. 0 . 029 6. 6+1. 8 12. 0+1. 5 <. 001 138. 4± 156. 5 124. 1± 54. 1 . 632 Inhibin B (ng/L) 93. 1± 43. 0 76. 0± 47. 4 . 077 AMH( g/L) 3. 53± 2. 46 1. 48± 2. 59 <. 001 E 2(pmol/L) Ref : Kwee J et al Reprod Biology & Endocrinology 2007 5: 9 Contd. . Duru Shah

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

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 Duru Shah

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 Duru Shah

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 Duru Shah

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 Duru Shah

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. Ref. D. Nilolaou et. al. Hum. Reprod. Vol. 19, No. 10, pp. 2175 -2179, 2004 Contd. . Duru Shah

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 velocity on 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. Obstet Gynaecol 113, 126 -133 Duru Shah

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/s larger number of oocytes recruited during ovarian stimulation, increasing the risk for developing OHSS Contd. . Duru Shah Ref. Nikolaou & Templeton A (2003) Hum Repro. 18, 1137 -1139 Nikolaou D & Templeton A (2004) Eur J. Obstet Gynaecol 113, 126 -133

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 Duru Shah

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 Duru Shah

Clinical Pregnancy correlated with AMH & age – Our data ART : 369 pts. Age No. of pts. Mean AMH 3. 86 2. 98 Oocytes Retrieved at OPU 13 10 26 - 30 31 -35 93 151 36 – 40 >40 41. 93% 34. 43% 78 1. 59 6 25. 64% 47 0. 5 3 10. 64% Ref. Gynaecworld data 2015 -16 Preg. rate Duru Shah

Pregnancy rates correlated with Age + AMH (PCOS pts) Total no. of pts. 189. Patients age in years No. of Pts. AMH Ng/ml <30 (n=26) 31 -35 (n=88) >36 (n=66) 29 ≤ 1 16. 70% 18. 20% 14. 60% 64 1. 1 – 3 33. 10% 32. 40% 22. 30% 47 3. 1 - 6 38. 46% 34. 50% 23. 30% 49 ≥ 6. 1 39. 90% 35. 40% 24. 60% Ref. Gynaecworld data 2015 -16 Duru Shah

Pregnancy rates correlated with Age + AMH (Non PCOS pts) Total no. of pts. 180. Patients age in years No. of Pts. AMH Ng/ml <30 (n=26) 31 -35 (n=88) >36 (n=66) 41 ≤ 1 20. 00% 15. 00% 10. 50% 83 1. 1 – 3 33. 30% 40. 00% 21. 10% 36 3. 1 - 6 35. 70% 34. 20% 22. 20% 20 ≥ 6. 1 36. 80% 35. 60% 22. 80% Ref. Gynaecworld data 2015 -16 Duru Shah

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. Ref. M. Hudecova et. al. Hum. Repro. Vol. 24, No 5 pp 1176 -1183, 2009 Contd. . Duru Shah

Contd. . Long-term follow-up of patients with PCOS syndrome: reproductive outcome and ovarian reserve Ref. M. Hudecova et. al. Hum. Repro. Vol. 24, No 5 pp 1176 -1183, 2009 Contd. . Duru Shah

Long-term follow-up of patients with PCOS syndrome: reproductive outcome and ovarian reserve Premenopausal women without hormone treatment PCOS (n=52) Controls (n=56) Age (yrs. ) 42. 4 ± 4. 5 41. 5 ± 4. 6 Ovarian volume (ml) 9. 5 ± 0. 9** 6. 6 ± 0. 5 Antral follicles (n) 11. 7 ± 1. 7*** 5. 0 ± 0. 3 Estradiol (pmol/1) 514 ± 79 * 710 ± 90 Testosterone (nmol/1) 1. 5 ± 0. 1** 1. 0 ± 0. 1 SHBG (nmol/1) 50. 4 ± 4. 5* 64. 0 ± 4. 8 FAI 5. 1 ± 0. 8** 2. 0 ± 0. 2 FSH (U/I) 6. 2 ± 1. 1* 9. 6 ± 1. 3 LH(IU/I) 7. 1 ± 0. 7 10. 4 ± 1. 7 39. 9 ± 6. 1*** 15. 7 ± 2. 1 AMH(pmol/I Ref. M. Hudecova et. al. Hum. Repro. Vol. 24, No 5 pp 1176 -1183, 2009 * p<0. 025 ** p<0. 01 ***p<0. 001 Contd. . Duru Shah

Contd. . Ovarian Volume Ref. M. Hudecova et. al. Hum. Repro. Vol. 24, No 5 pp 1176 -1183, 2009 Contd. . Duru Shah

Contd. . Antral Follicles Ref. M. Hudecova et. al. Hum. Repro. Vol. 24, No 5 pp 1176 -1183, 2009 Contd. . Duru Shah

AMH Ref. M. Hudecova et. al. Hum. Repro. Vol. 24, No 5 pp 1176 -1183, 2009 Duru Shah

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. Ref. M. Hudecova et. al. Hum. Repro. Vol. 24, No 5 pp 1176 -1183, 2009 Contd. . Duru Shah

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 pp 1176 -1183, 2009 Duru Shah

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. Ref. D. Nilolaou et. al. Hum. Reprod. Vol. 19, No. 10, pp. 2175 -2179, 2004 Contd. . Duru Shah

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 Ref. D. Nilolaou et. al. Hum. Reprod. Vol. 19, No. 10, pp. 2175 -2179, 2004 Contd. . Duru Shah

Duru Shah