A totally surprising rebound effect in complete non- responders in search of an explanation

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 ( A dj ), Department Of Obstetrics & Gynecology, Vienna University School Of Medicine, Vienna, Austria

Translational Reproductive Biology & Clinical Reproductive Endocrinology 2019| New York, NY, USA| November 21-24, 2019 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. Our center serves, likely, the most unfavorable patient population of >500 U.S. ART centers

▪ Median age > 43 ▪ Universally high FSH ▪ Universally low AMH ▪ > 90% with prior IVF failures ▪ We, therefore, quite frequently encounter complete stimulation failures (CSF) Anecdotal observation ▪ Some patients with CSF experience “rebound” if gonadotropins were withdrawn for a few days ▪ Estimated rebound rate: ca. 15% 2017 formal study ▪ Rebound rate: 50% 2019 expanded study Surprising rate of rebound in follicle growth after cessation of ovarian stimulation in initial non-responders Norbert Gleicher, MDa,b,c,d, Andrea Weghofer, MD, PhD, MBA, MS a,d, Sarah K Darmon, PhD, MSa, David H Barad, MD, Msa,b aCenter for Human Reproduction, New York, NY 10021 USA bFoundation for Reproductive Medicine, New York, NY 10021 USA cStem Cell Biology and Molecular Embryology Laboratory, The Rockefeller University, New York, NY 10016 USA dDepartment of Obstetrics & Gynecology, Medical University Vienna, Vienna 1090 Austria Materials and methods ▪ 49 women ▪ Mean age 40.5 ± 5.1 years ▪ Range 23-52 years Results Rebound No Rebound P Median Age 40.0 ± 6.0 41.0 ± 7.0 N.S. N (%) 24 (49%) 25 (51%) 21/24 (87.5%) retrieval of 1-3 oocytes 15/24 (30.6%) embryo transfers Conclusions ▪ ~50% rebound ▪ 1-3 oocytes ▪ 30.6% reaching embryo transfer ▪ Must have an underlying cause! ▪ Endogenous rebounding gonadotropins? ▪ Differences in glycosylation? CHR Staff Affiliates (* Visiting Scientists) Rockefeller University: David F Albertini, PhD* Ali Brivanlou, PhD, MD David H Barad, MS, MD Ali Brivanlou, PhD, MD* Salk Institute for Biological Studies: Sarah Darmon, PhD, MS* Pradeep Reddy, PhD Dieter Egli, PhD* Norbert Gleicher, MD Jianjun Hu, MD, MS Pasquale Patrizio, MD, MBE* Aya Shohat-Tal, PhD* Andrea Vidali, MD* Andrea Weghofer, PhD, MS, MBA, MD* Mia Yang, PhD* Yao Yu, PhD*