Evidence-based treatment of POR and POF. Ovarian Club X and CoGEN in Asia December 16-17, 2017 Hong Kong

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1 Evidence-based treatment of POR and POF Norbert Gleicher, MD Medical Director and Chief Scientist, Center For Human Reproduction, New York, NY Presi d ent, Foundation For Reproductive Medicine, New York, NY G u est Investigato r, Rockefeller Universi ty, New York, NY Professor ( Adj), Department Of Obstetri c s & Gynecology, Vienna Universi ty School Of Medicine, Vienna, Austri a Ovarian Club X and CoGEN in Asia December 16-17, 2017 Hong Kong

2 Conflict Statement Dr. Gleicher is listed as co-inventor on a number of pending patent applications claiming diagnostic and therapeutic benefits from determination of CGG repeat numbers and ovarian FMR1 genotypes and sub-genotypes. Dr. Gleicher is co-inventor of awarded U.S. patents, claiming therapeutic benefits for supplementation of DHEA in women with diminished ovarian reserve, a topic discussed in this talk. Other patent applications in regards to DHEA and other fertility-related claims, with no relationship to this talk, are pending. Dr. Gleicher receives royalties from, and owns shares in Fertility Neutraceuticals, LLC, a distributor of a DHEA product.

3 Index Defining functional ovarian reserve Preparing the ovaries Androgens HGH Stimulating the ovaries Embryology What can be achieved

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6 FSH and Androgen Receptors Reproductive Biology and Endocrinology 2011, 9:116 doi: /

7 Activity of HGH (via IGF-I) FSH and IGF-I synergistically stimulate steroid production Silencing the IGF-gene leads to infertility and/or hypogonadism Well-known effects of FSH on Cyp19 and AKT in GCs depend on IGF- I and on expression and activation of IGF-IR Zhou et al. Mol Endocrinol 2013;27: IGF-I knockout stops follicle development at preantral stage

8 Follicle Development from Primordial and Preovulatory Status NEW OLD Broekmans FJ et al, Endocrine Reviews 2009

9 Index Defining ovarian reserve Preparing the ovaries Stimulating the ovaries Embryology What can be achieved

10 The DHEA Story

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12 Count Egg and Embryo Yields Eggs Embryos D H E A Treatment Cycle Gleicher and Barad, Fertil Steril 2005;84(3):756.

13 Previously Reported Reproductive Benefits of DHEA Improves egg/embryo numbers Improves egg/embryo quality Improves spontaneous pregnancy rates Improves IVF pregnancy rates Improves time to conception Improves cumulative pregnancy rates Casson et al. Hum Reprod 2000 Barad and Gleicher, Hum Reprod 2006 Barad and Gleicher, Fertil Steril 2005 Barad et al, J Assist Reprod Genet 2007

14 AMH response to DHEA Reprod Biomed Online 2010:

15 Comparison of Miscarriage Rates between DHEA Supplemented Infertility Patients and 2004 National US IVF Outcome Data National DHEA < >42 Gleicher et al, Reprod Biol Endocrinol 2009;7:108

16 Gleicher et al., Reprod Biol Endocrinol 2010;8:140. Comparison of Absolute and Percentages of Aneuploidy in DHEA and Control Patients

17 Wiser et al. Hum Reprod 2010;25: First Prospectively Randomized Study DOR: 17 DHEA 16 Controls DHEA: Live Births (23.1% vs. 4.0%; p=0.05)

18 Percent of Follicles DHEA Mimics DHT Effects on Follicular Development Antral Follicle Count FSH (10ng/ml) DHEA (100nM) Flutamide (100nM) 0 FSH FSH + DHEA FSH + DHEA + Flutamide Sen et al; Personal Communication

19 17bHSD 17bHSD 17bHSD DHEA in DOR Patients - IVF DHEA 3bHSD Androstenedione CYP19 Estrone Androstenediol 3bHSD Testosterone CYP19 Estradiol AR Follicular survival AMH expression FSH sensitivity DHEA AFC Sen et al; Personal Communication # of oocytes retrieved during IVF

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21 Androgens, Cortisol and Ratios DOR is an androgen deficiency state Box and whisker plots of serum androgen levels, serum cortisol levels and the ratio of total testosterone concentration over serum cortisol levels for controls, POA/OPOI, and physicologic DOR. The mean is depicted with a dashed line, the median with a solid line, and the normal range for serum androgens with a grey background. (a) Comparison of serum androgen levels: an asterisk denotes significant differences in mean between groups. (b) Shows distribution of serum cortisol levels. (c) Shows the ratio of TT over cortisol levels. Gleicher et al, Hum. Reprod. 2013: 28 (4):

22 Testosterone Response

23 Index Defining ovarian reserve Preparing the ovaries Stimulating the ovaries Embryology What can be achieved

24 No Suppressive Treatments No long agonists No antagonists No OCPs

25 Age-Specific Model of Pregnancies and Live Births based on Good-Quality Embryos Produced per Cycle

26 Index Defining ovarian reserve Preparing the ovaries Stimulating the ovaries Embryology What can be achieved

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28 Index Defining ovarian reserve Preparing the ovaries Stimulating the ovaries Embryology What can be achieved

29 2015 CHR IVF Outcomes Age Distribution of Fresh IVF Cycles 60 Pregnancy Rates by Age (%) % 4% 14% % % 15% <

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31 Case 1 43 y/o G0 FSH 14.3 miu/ml AMH 0.4 ng/ml FT 0.8 pg/ml TT 18.4 ng/ml SHBG nmol/l Good prognosis

32 Case 2 41 y/o G1 FSH 18.7 miu/ml AMH undetectable FT 2.8 pg/ml TT 36.2 ng/ml SHBG 42.6 nmol/l Poorer prognosis

33 Case 3 26 y/o G0 FSH 23.6 miu/ml AMH undetectable FT 0.4 pg/ml TT 12.1 ng/ml SHBG nmol/l Very good prognosis

34 Case 4 39 y/o G0, BMI 23.0 FSH 9.2 miu/ml AMH 6.8 ng/ml FT 0.8 pg/ml TT 18.9 ng/ml DHEAS 85.0 μg/dl Autoimmunity especially thyroid Low cortisol H-PCOS Good prognosis

35 CHR Staff (* Visiting Scientists) David F Albertini, PhD David H Barad, MS, MD Ali Brivanlou, PhD, MD* Sarah Darmon, PhD, MS Dieter Egli, PhD* Norbert Gleicher, MD Vitaly A Kushnir, MD Emanuela Lazzaroni-Tealdi, MS Kenneth Seier, MS* Aya Shohat-Tal, PhD* Andrea Vidali, MD* Andrea Weghofer, PhD, MS, MBA, MD* Ping Zhou, PhD Yan-Guang Wu, PhD* Yao Yu, PhD* Affiliates Rockefeller University: Ali Brivanlou, PhD, MD Gist Croft, PhD Salk Institute for Biological Studies: Pradeep Reddy, PhD

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