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. Director Gynaecworld….. The Center for Womens Health & Fertility Prof.Duru Shah Prof.and : Breach Candy Hosp. Cons. Obs. Jaslok Hospital & Gyn Global Hospital

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

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

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 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

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

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

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

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

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.

Ovarian Surgery Extensive Ovarian Drilling for PCOS 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…

Other Factors Single Ovary Chronic Smoking New Factors proposed 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,no7, pp825-831 Uterine Artery Embolization W.J.J. Hehenkamp, et. al. Human Reproduction vol. 22, no.7, pp1996-2007

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.

Ultrasound –Antral Follicle count Parameter Normal responders (n=81) Poor Responders (n=29) P Endpoints Total no. of follicles 17.7±9.7 4.6±2.6 <.001 Total no. of oocytes 14.9±8.1 3.0±1.6 Ongoing pregnancy n(%) 22(24) 2(10) HOW DOES IT DEVELOP? Endometriosis remains an enigma despite having been extensively studied. Its aetiology remains unclear, although there is a positive correlation with retrograde menstruation, probably with a background genetic predisposition. Additional factors that may be important in pathogenesis OF ENDOMETRIOSIS include - Immunologic abnormalities, - Endometrial disorders, and - Peritoneal dysfunction The cause of endometriosis is not clear, although the predominant theory is that retrograde menstruation is the cause. Additional factors in pathogenesis include immunologic abnormalities, endometrial disorders, and peritoneal dysfunction, hematologic spread, lymphatic spread, genetic factors and combination of the above. Ref : Kwee J et al Reprod Biology & Endocrinology 2007 5:9

Hormonal investigations Parameter Normal responders (n=81) Poor Responders (n=29) P Value Age at baseline (y) CD3 33.5+4.0 35.3+3.0 .029 FSH(IU/L) 6.6+1.8 12.0+1.5 <.001 E2(pmol/L) 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 HOW DOES IT DEVELOP? Endometriosis remains an enigma despite having been extensively studied. Its aetiology remains unclear, although there is a positive correlation with retrograde menstruation, probably with a background genetic predisposition. Additional factors that may be important in pathogenesis OF ENDOMETRIOSIS include - Immunologic abnormalities, - Endometrial disorders, and - Peritoneal dysfunction The cause of endometriosis is not clear, although the predominant theory is that retrograde menstruation is the cause. Additional factors in pathogenesis include immunologic abnormalities, endometrial disorders, and peritoneal dysfunction, hematologic spread, lymphatic spread, genetic factors and combination of the above. Contd.. Ref : Kwee J et al Reprod Biology & Endocrinology 2007 5:9

Value of AMH as a prognostic indicator of IVF outcome Study To evaluate AMH values to predict oocyte yield, cycle cancellation and pregnancy outcomes. Retrospective study of IVF patients in an academic center. 2760 pts. – 4072 cycles of IVF with both Agonist and Antagonist cycles. Contd…. Ref. David Reichman et.al. Fertil Steril Vol. 101, No.4 April 2014

AMH levels at various ages Patient Age in years. < 35 35-37 38-40 41-42 >42 Total <0.17 7 24 40 21 42 134 0.17-0.30 27 74 59 60 260 0.31-0.70 101 139 189 152 95 676 0.17-1.00 94 87 115 56 37 389 1.01-2.00 213 147 165 89 33 647 2.01-4.00 181 91 90 31 414 >4.00 133 65 29 9 4 240 756 593 702 417 292 2760 Ref. David Reichman et.al. Fertil Steril Vol. 101, No.4 April 2014

Oocytes retrieved according to age & AMH Patient Age Mean oocytes <0.17 <35 4.8 35-37 4.9 38-40 4.1 41-42 4.2 >42 3.6 1.01-2.00 13.4 11.5 11.9 11.2 12.1 AMH Patient Age Mean oocytes 2.01-4.00 <35 15.3 35-37 14.3 38-40 13.5 41-42 12.8 >42 15.6 >4.00 15.1 15.9 14.5 15.8 12.7 Contd…. Ref. David Reichman et.al. Fertil Steril Vol. 101, No.4 April 2014

Clinical Pregnancy correlated with AMH & age (ng/mL) <35 yrs. 35-37 38-40 41-42 >42 >4.00 60.5(114) 63.0(54) 57.7(26) 80.0(5) 0(2) 2.01-4.00 56.2(169) 48.2(81) 59.2(76) 30.0(30) 15.8(19) 1.01-2.00 51.6(184) 52.9(136) 42.5(146) 35.8(81) 28.6(28) 0.71-1.00 46.8(79) 51.3(76) 39.8(103) 36.7(49) 3.0(33) 0.31-0.70 42.7(82) 42.0(112) 41.2(153) 29.2(113) 5.6(71) 0.17-0.30 26.3(19) 32.1(28) 34.0(50) 22.5(40) 8.6(35) <0.17 40.0(5) 33.3(12) 24.0(25) 25.0(12) 3.9(26) Adj-P for trenda .002 .016 .003 .268 .095 Ref. David Reichman et.al. Fertil Steril Vol. 101, No.4 April 2014

Folliculogenesis Ref. A La. Marca et.al. Human Reproduction Update, Vol.16, 2010 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

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

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

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

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

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

Early Ovarian Aging- are women with PCOS protected? 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.. 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

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

Clinical Pregnancy correlated with AMH & age – Our data ART : 369 pts. Age No. of pts. Mean AMH Oocytes Retrieved at OPU Preg. rate 26- 30 93 3.86 13 41.93% 31-35 151 2.98 10 34.43% 36 – 40 78 1.59 6 25.64% >40 47 0.5 3 10.64% Ref. Gynaecworld data 2015-16

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

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

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

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

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 AMH(pmol/I 39.9 ± 6.1*** 15.7 ± 2.1 * p<0.025 ** p<0.01 ***p<0.001 Contd.. Ref. M. Hudecova et.al. Hum. Repro. Vol.24, No 5 pp1176-1183,2009

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

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

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

Reproductive outcome did not differ between 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

Mean ovarian volume and number of antral 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

FMRI Gene her-norm / low sub- genotype PCO like ovarian phenotype at young ages large number of eggs recruited in the maturation process. Leading to DOR in older age Contd.. Ref. D. Nilolaou et.al. Hum. Reprod. Vol. 19, No.10, pp.2175-2179, 2004

FMRI Gene her-norm / high FMRI genotype Slow recruitment of immature eggs at young ages. Good ovarian reserve at advanced ages (above 42 years) Contd.. Ref. D. Nilolaou et.al. Hum. Reprod. Vol. 19, No.10, pp.2175-2179, 2004

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

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