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Is There an Ideal Stimulation for Poor Ovarian Reserve?

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Is There an Ideal Stimulation for Poor Ovarian Reserve? Evidence-based treatment of POR and POF 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 Ovarian Club X and CoGEN in Asia | December 16-17, 2017 | Hong Kong 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 OLD NEW 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 20 18 Eggs 16 Embryos 14 12 D 10 H 8 E Count 6 A 4 2 0 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 National DHEA 0.2 0.1 0 <35 35-37 38-40 41-42 >42 Gleicher et al, Reprod Biol Endocrinol 2009;7:108 Comparison of Absolute and Percentages of Aneuploidy in DHEA and Control Patients Gleicher et al., Reprod Biol Endocrinol 2010;8:140. 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 20 FSH (10ng/ml) 10 DHEA (100nM) Flutamide (100nM) Percent of Follicles of Percent 0 FSH FSH + FSH + DHEA DHEA + Flutamide Sen et al; Personal Communication DHEA in DOR Patients - IVF 3bHSD CYP19 DHEA Androstenedione Estrone HSD HSD HSD b b b 17 17 17 3bHSD CYP19 Androstenediol Testosterone Estradiol AR Follicular AMH FSH survival expression sensitivity DHEA AFC # of oocytes retrieved during IVF Sen et al; Personal Communication 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 Pregnancy Rates by Age (%) Age Distribution of Fresh IVF Cycles 60 50 50 4% 39.1 14% 40 30% 35.3 30 11% 30 23.1 15% 20 18.4 17.4 26% 10 8.3 5.9 0 30-35 36-37 38-40 41-43 44+ <30 30-35 36-37 38-39 40 41 42 43 44+ 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 138.5 nmol/L Good prognosis 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 Case 3 • 26 y/o G0 • FSH 23.6 mIU/mL • AMH undetectable • FT 0.4 pg/mL • TT 12.1 ng/mL • SHBG 156.2 nmol/L Very good prognosis 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 CHR Staff Affiliates (* Visiting Scientists) Rockefeller University: David F Albertini, PhD Ali Brivanlou, PhD, MD David H Barad, MS, MD Gist Croft, PhD Ali Brivanlou, PhD, MD* Sarah Darmon, PhD, MS Salk Institute for Biological Studies: Dieter Egli, PhD* Pradeep Reddy, 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* .
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