Ontogeny of the new hypo-androgenic PCOS phenotype

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1 Ontogeny of the new hypo-androgenic PCOS phenotype Norbert Gleicher, MD Medical Director and Chief Scientist, Center For Human Reproduction, New York, NY President, Foundation For Reproductive Medicine, New York, NY Guest Investigator, Rockefeller University, New York, NY Professor (Adj), Department Of Obstetrics & Gynecology, Vienna University School Of Medicine, Vienna, Austria Translational Reproductive Biology and Clinical Reproductive Endocrinology November 16-19, 2017

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. Dr. Gleicher is co-inventor of three pending patent applications claiming potential therapeutic benefit for anti-müllerian hormone (AMH) in infertile women. Dr. Gleicher owns shares in OvaNova Laboratories, LLC.

3 Outline Definition of PCOS PCOS phenotypes PCOS phenotypes change with age Sources of androgens How androgens control ovaries The hypo-androgenic PCOS

4 Definition of PCOS Amalgam of clinical conditions Various classifications proposed None universally accepted 2003 Rotterdam Criteria Oligo-/Amenorrhea Hyperandrogenism Chemial and clinical Ovarian PCO phenotype

5 Varying PCOS Definitions NIH 1990 Hyperandrogenism andor hyperandrogenemia Oligoovulation Exclusion of other causes Rotterdam 2003 Exclusion of other causes 2/3 Oligoovulation Hyperandrogenism Polycystic ovaries

6 Rotterdam 2003 Expanded NIH 1990 by 2 New Phenotypes Ovulatory women with PCO and hyperandrogenism Oligoanovulatory with PCO but without hyperandrogenism Phenotype-D!

7 Other Phenotypical Descriptions of PCOS Classical: Obese/high AMH Hirsute/anovuulatory/hyperandrogenic Metabolic syndrome Lean: Skinny /high AMH Often regular menses Hyper-through hypo-androgenic, depending on age Treatment resistant Hypo-androgenic PCOS

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

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

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

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

13 Testosterone Response

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16 Hypoandrogenic PCOS Clinical diagnosis High AMH for age in reference to FSH Low T Low DHEAS High SHBG Autoimmunity Low cortisol Good response to DHEA mostly to thyroid

17 Endocrinol 2017; In press

18 Once recognized, hypoandrogenic PCOS is surprisingly common at all ages in tertiary fertility centers

19 If diagnosed and properly androgen-supplemented, patients have excellent pregnancy and live birth chances

20 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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