Androgen supplementation in women with low functional ovarian reserve 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
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.
Index Defining functional ovarian reserve Preparing the ovaries Androgens HGH Stimulating the ovaries Embryology What can be achieved
FSH and Androgen Receptors Reproductive Biology and Endocrinology 2011, 9:116 doi:10.1186/1477-7827-9-116
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;27:511-23 IGF-I knockout stops follicle development at preantral stage
Follicle Development from Primordial and Preovulatory Status NEW OLD Broekmans FJ et al, Endocrine Reviews 2009
Index Defining ovarian reserve Preparing the ovaries Stimulating the ovaries Embryology What can be achieved
The DHEA Story
Egg and Embryo Yields Count 20 18 16 14 12 10 8 6 4 2 0 Eggs Embryos D H E A 1 2 3 4 5 6 7 8 9 Treatment Cycle Gleicher and Barad, Fertil Steril 2005;84(3):756.
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
AMH response to DHEA Reprod Biomed Online 2010: 360-365.
Comparison of Miscarriage Rates between DHEA Supplemented Infertility Patients and 2004 National US IVF Outcome Data. 0.6 0.5 0.4 0.3 0.2 National DHEA 0.1 0 <35 35-37 38-40 41-42 >42 Gleicher et al, Reprod Biol Endocrinol 2009;7:108
Gleicher et al., Reprod Biol Endocrinol 2010;8:140. Comparison of Absolute and Percentages of Aneuploidy in DHEA and Control Patients
Wiser et al. Hum Reprod 2010;25:2496-2500 First Prospectively Randomized Study DOR: 17 DHEA 16 Controls DHEA: Live Births (23.1% vs. 4.0%; p=0.05)
DHEA Mimics DHT Effects on Follicular Development Antral Follicle Count Percent of Follicles 20 10 0 FSH FSH + DHEA FSH + DHEA + Flutamide FSH (10ng/ml) DHEA (100nM) Flutamide (100nM) Sen et al; Personal Communication
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 Sen et al; Personal Communication # of oocytes retrieved during IVF
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):1084-1091.
Testosterone Response
Index Defining ovarian reserve Preparing the ovaries Stimulating the ovaries Embryology What can be achieved
No Suppressive Treatments No long agonists No antagonists No OCPs
Age-Specific Model of Pregnancies and Live Births based on Good-Quality Embryos Produced per Cycle
Index Defining ovarian reserve Preparing the ovaries Stimulating the ovaries Embryology What can be achieved
Index Defining ovarian reserve Preparing the ovaries Stimulating the ovaries Embryology What can be achieved
2015 CHR IVF Outcomes Age Distribution of Fresh IVF Cycles 60 Pregnancy Rates by Age (%) 50 50 30% 4% 14% 40 39.1 35.3 11% 30 30 23.1 26% 15% 20 18.4 17.4 10 8.3 5.9 30-35 36-37 38-40 41-43 44+ 0 <30 30-35 36-37 38-39 40 41 42 43 44+
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