Biomarkers of Reproductive Potential Anne Z. Steiner, MD, MPH - - PowerPoint PPT Presentation

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Biomarkers of Reproductive Potential Anne Z. Steiner, MD, MPH - - PowerPoint PPT Presentation

Aug 29, 2023 17 likes •401 views

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

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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

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Disclosure

  • Dr. Steiner serves as a consultant for

Prima-Temp.

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Objectives

  • Understand the impact of female aging on
  • ocyte quality and quantity
  • Be able to counsel women about the

meaning (clinical implications) of an

  • varian reserve test such as AMH
  • Explore the potential use of AMH as a

marker of PCOS

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Oocytes

ARE LIKE A BOX OF CHOCOLATES

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Over Time….

  • There are fewer and fewer chocolates

(Quantity)

  • Those chocolates remaining become

stale….. (Quality)

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30-31 32-33 34-35 36-37 38-39 40-41 42-43 10 20 30 40 50 60 70 80 90 100 Percent Age (years)

Cumulative Pregnancy Rate by 12 Cycles of Attempt by Age

Nulligravid Gravid Steiner & Jukic; Fertil Steril 2016

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Franasiak et al., Fertility and Sterility, Volume 101, Issue 3, 2014, 656–663.e1

Percentage

  • f aneuploid

embryos Percentage of women with no euploid embryos

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Andersen A-M Nybo West J Med 2000;173:331

Miscarriage and Age

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  • Age is the best marker of egg quality.
  • We do not have a way to stop the decline

in egg quality.

  • nly
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Oocyte Quantity

Steiner AZ. Semin Reprod Med 2013;31:437-42.

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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

Primordial follicle number

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FSH Ovary Hypothalmus

Inhibin

+

GnRH

Aging Ovary

Reproductive Aging

Hormonal Changes AMH

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MENSTRUAL CYCLE LENGTH

Ovulation

Follicular Luteal CYCLE DAY

2 10 12 14 4 6 8 16 28 18 24 20 22 26

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5 10 15 20 25 30 35 40 45 <26 26-27 28-29 30-31 32-34 >34 Percent Menstrual Cycle Length (Days)

Percentage of ART cycles resulting in pregnancy* by historical menstrual cycle length

* Per cycle start Brodin et al. Fertil Steril 2008

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0.00 5.00 10.00 15.00 20.00 25.00 30.00 <25 25-26 27-29 30-31 32-33 >34 Percent Menstrual Cycle Length (days)

Fecundability by historical menstrual cycle length

Snart Gravid TTC Wise et al AJE 2011; 174: 701-9/

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FSH Ovary Hypothalmus

Inhibin

+

GnRH

Reproductive Aging

Hormonal Changes AMH

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AMH physiology

  • Glycoprotein
  • Produced by the

granulosa cells in pre- antral and early antral follicles

  • Inhibits recruitment of

primary follicles from primordial pool

  • Progressively

reduces responsiveness of developing follicles to FSH

AMH AMH

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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

Primordial follicle number

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AMH by Age

Figure from Dolleman et al. JCEM 2013.

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EVIDENCE THAT BIOMARKERS OF OVARIAN RESERVE ARE MARKERS OF REPRODUCTIVE POTENTIAL

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Oocyte Quantity

Steiner AZ. Semin Reprod Med 2013;31:437-42.

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Hansen, KR. Menopause. 2012 Feb; 19(2): 164–171.

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Age at Menopause

  • AMH levels are associated with age at

menopause1,2

  • But are poor predictors of age at menopause

– Women with AMH <0.2ng/ml- 45-48 yo --6 years, 35- 39---10 years1 – Only 60% of women with undetectable AMH aged 45- 49 entered menopause within 5 years5 – Prediction intervals broad, median predicted age 48- 553, 42-554

1. Penn Ovarian Aging Study 2. Sowers et al. JCEM 2008 3. Broer et al JCEM 2011 4. Dolleman JCEM 2013 5. Cardia Study

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De Kat et al. BMC Med 2016 Different shape Increase before decrease Rate of decline slower

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AMH and Oocyte Yield in IVF

Cooke and Nelson, TOG 2011

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AMH and Natural Fertility

Number (%)

  • f affected

subjects Fecundability ratio (95% confidence interval) Unadjusted Age-adjusted TTC Pilot (N=100) AMH≤0.7ng/ml 18 (18%) 0.36* (0.01, 0.84) 0.38* (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 Hagen et al, Fertil Steril 2012, In Press

*Day-specific probabilities £ Cycle-specific

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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

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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)

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Biomarker Survival Analysis 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) Low AMH Normal AMH High AMH

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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
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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

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AMH AND PCOS

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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
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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.

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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

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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.

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THANK YOU!