Biomarkers of Reproductive Potential Anne Z. Steiner, MD, MPH Professor and Chief Division of Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology Duke University
Disclosure • Dr. Steiner serves as a consultant for Prima-Temp.
Objectives • Understand the impact of female aging on oocyte quality and quantity • Be able to counsel women about the meaning (clinical implications) of an ovarian reserve test such as AMH • Explore the potential use of AMH as a marker of PCOS
Oocytes ARE LIKE A BOX OF CHOCOLATES
Over Time…. • There are fewer and fewer chocolates (Quantity) • Those chocolates remaining become stale….. (Quality)
Cumulative Pregnancy Rate by 12 Cycles of Attempt by Age 100 90 80 70 60 Percent 50 40 30 Nulligravid 20 Gravid 10 0 30-31 32-33 38-39 40-41 42-43 34-35 36-37 Age (years) Steiner & Jukic; Fertil Steril 2016
Percentage of aneuploid embryos Percentage of women with no euploid embryos Franasiak et al., Fertility and Sterility, Volume 101, Issue 3, 2014, 656–663.e1
Miscarriage and Age Andersen A-M Nybo West J Med 2000;173:331
only • Age is the best marker of egg quality. • We do not have a way to stop the decline in egg quality.
Oocyte Quantity Steiner AZ. Semin Reprod Med 2013;31:437-42.
Primordial follicle number Karl R. Hansen, George M. Hodnett, Nicholas Knowlton, LaTasha B. Craig Correlation of ovarian reserve tests with histologically determined primordial follicle number Fertility and Sterility, Volume 95, Issue 1, 2011, 170–175
Reproductive Aging Hormonal Changes Hypothalmus GnRH FSH Inhibin + AMH Aging Ovary Ovary
Ovulation Luteal Follicular 2 6 8 10 12 16 20 22 4 14 18 24 26 28 CYCLE DAY MENSTRUAL CYCLE LENGTH
Percentage of ART cycles resulting in pregnancy* by historical menstrual cycle length 45 40 35 30 Percent 25 20 15 10 5 0 <26 26-27 28-29 30-31 32-34 >34 Menstrual Cycle Length (Days) * Per cycle start Brodin et al. Fertil Steril 2008
Fecundability by historical menstrual cycle length 30.00 25.00 20.00 Percent 15.00 10.00 5.00 0.00 <25 25-26 27-29 30-31 32-33 >34 Menstrual Cycle Length (days) Snart Gravid TTC Wise et al AJE 2011; 174: 701-9/
Reproductive Aging Hormonal Changes Hypothalmus GnRH FSH Inhibin + AMH Ovary
AMH physiology • Glycoprotein • Produced by the granulosa cells in pre- antral and early antral follicles • Inhibits recruitment of primary follicles from AMH AMH primordial pool • Progressively reduces responsiveness of developing follicles to FSH
Primordial follicle number Karl R. Hansen, George M. Hodnett, Nicholas Knowlton, LaTasha B. Craig Correlation of ovarian reserve tests with histologically determined primordial follicle number Fertility and Sterility, Volume 95, Issue 1, 2011, 170–175
AMH by Age Figure from Dolleman et al. JCEM 2013.
EVIDENCE THAT BIOMARKERS OF OVARIAN RESERVE ARE MARKERS OF REPRODUCTIVE POTENTIAL
Oocyte Quantity Steiner AZ. Semin Reprod Med 2013;31:437-42.
Hansen, KR. Menopause. 2012 Feb; 19(2): 164–171.
Age at Menopause • AMH levels are associated with age at menopause 1,2 • But are poor predictors of age at menopause – Women with AMH <0.2ng/ml- 45-48 yo --6 years, 35- 39---10 years 1 – Only 60% of women with undetectable AMH aged 45- 49 entered menopause within 5 years 5 – Prediction intervals broad, median predicted age 48- 55 3 , 42-55 4 1. Penn Ovarian Aging Study 2. Sowers et al. JCEM 2008 3. Broer et al JCEM 2011 4. Dolleman JCEM 2013 5. Cardia Study
Rate of Different Increase decline shape before slower decrease De Kat et al. BMC Med 2016
AMH and Oocyte Yield in IVF Cooke and Nelson, TOG 2011
AMH and Natural Fertility Number (%) Fecundability ratio of affected (95% confidence interval) subjects Unadjusted Age-adjusted TTC Pilot (N=100) AMH≤0.7ng/ml 18 (18%) 0.36* 0.38* (0.01, 0.84) (0.08, 0.91) Danish Study (N=186) AMH≤10pmol/L 11% 0.88 £ (0.48 - 1.61) EAGER Trial AMH<1.0ng/ml 10% 1.13 (0.85 - 1.49) Steiner et al. Obstet Gynecol 2011;117:798-804 *Day-specific probabilities Hagen et al, Fertil Steril 2012, In Press £ Cycle-specific
Methods • Prospective, time-to-pregnancy study • Inclusion: – Women 30-44 years of age – Trying to conceive for 3 or fewer months – Heterosexual and cohabitating with partner • Exclusion: – History of Infertility – Diagnosis of endometriosis, PCOS, or pelvic inflammatory disease – Partner with a history of infertility – Plans to use therapeutic donor insemination to conceive • Followed from enrollment until early pregnancy or 12 months of pregnancy attempt
Study Flow Enrolled in Time to Conceive (N=981) Conceived prior to study visit (N=142) Failed to show for study visit (N=69) Study visit (N=770) Duration of attempt unable to be determined (N=7) No follow up (N=13) Women included in analysis (N=750)
Low AMH Normal AMH High AMH Survival Analysis Biomarker 6 cycles 12 cycles AMH < 0.7 ng/ml (N=82) 65% (50-75) 84% (70-91) 0.7-8.4 ng/ml (N=581) 62% (57-66) 75% (70-79) ≥ 8.5 ng/ml (N=74) 59% (45-69) 66% (57-77)
Clinical Value of AMH • Measure of ovarian reserve • Compare ovarian reserve within age groups • Predicts response to stimulation • Associated with age at menopause; but poor predictor for an individual. • Not a predictor of reproductive potential
AMH testing • Induce Anxiety – Young woman with a low AMH – Does not predict her reproductive potential • False reassurance – Older woman with high AMH – Does not escape the age-related decline in fertility • Should not be used as a decision aid for egg freezing
AMH AND PCOS
Polycystic Ovarian Syndrome • 2003 Rotterdam Criteria • 2 out of 3 of the following – Oligo or anovulation – Clinical and/or biochemical signs of hyperandrogenism – Polycystic ovaries (PCO) (12 or more follicles measuring 2-9 mm in diameter) • Exclusion of Other Causes
AMH and PCOS • AMH levels are highly correlated with antral follicle count (2-10mm follicles). – Cut-off for PCO? • PCOS patients have more growing follicles (that secrete AMH). – AMH more “sensitive” for PCOS? • Granulosa cells from women with PCOS produce more AMH.
AMH to Predict PCOS • AMH as a marker of PCO – ROC: 0.67-0.92 – Cut-off values range from 3-4 ng/ml – Considerable overlap between cases and controls • AMH as a marker of PCOS – ROC: 0.5 to 0.88 – Cut-off values range from 4-7 ng/ml Teede et al. Trends in Endocrinology & Metabolism 2019
Verdict • Associations • Biologic plausibility • No definitive cut-off value • Overlap between cases and controls • No guidelines or change in the diagnostic criteria at this timepoint.
THANK YOU!
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