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CME / CE

Do Biomarkers Predict Fertility?

  • Authors: News Author: Troy Brown, RN; CME Author: Laurie Barclay, MD
  • CME / CE Released: 11/10/2017
  • THIS ACTIVITY HAS EXPIRED
  • Valid for credit through: 11/10/2018
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Target Audience and Goal Statement

This article is intended for primary care clinicians, obstetricians/gynecologists, women's health practitioners, diabetologists/endocrinologists, family medicine practitioners, nurses, and other members of the healthcare team for women with fertility issues.

The goal of this activity is to provide medical news to primary care clinicians and other healthcare professionals in order to enhance patient care.

Upon completion of this activity, participants will be able to:

  1. Examine the associations between biomarkers of ovarian reserve and reproductive potential among women of late reproductive age, based on a prospective cohort study
  2. Assess the clinical implications of the associations between biomarkers of ovarian reserve and reproductive potential among women of late reproductive age, based on a prospective cohort study


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Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.


Author(s)

  • Troy Brown, RN

    Freelance writer, Medscape

    Disclosures

    Disclosure: Troy Brown, RN, has disclosed no relevant financial relationships.

CME Author

  • Laurie Barclay, MD

    Freelance writer and reviewer, Medscape, LLC

    Disclosures

    Disclosure: Laurie Barclay, MD, has disclosed the following relevant financial relationships:
    Owns stock, stock options, or bonds from: Alnylam; Biogen; Pfizer Inc.

Editor/CME Reviewer/Nurse Planner

  • Amy Bernard, MS, BSN, RN-BC

    Lead Nurse Planner, Medscape, LLC

    Disclosures

    Disclosure: Amy Bernard, MS, BSN, RN-BC, has disclosed no relevant financial relationships.


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CME / CE

Do Biomarkers Predict Fertility?

Authors: News Author: Troy Brown, RN; CME Author: Laurie Barclay, MDFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED

CME / CE Released: 11/10/2017

Valid for credit through: 11/10/2018

processing....

Clinical Context

Many women are postponing attempts to conceive until older ages, but the oocyte and follicular pools decrease with aging, as does secretion of inhibin B and antimüllerian hormone (AMH) by granulosa cells. Several cohorts have shown an association of AMH with time to menopause, and AMH is an excellent predictor of oocyte yield among women with infertility undergoing controlled ovarian hyperstimulation for in vitro fertilization.

Biomarkers of reduced ovarian reserve, including low AMH, low inhibin B, and increased follicle-stimulating hormone (FSH) during the follicular phase, are being considered as potential markers of infertility among older women, despite lack of evidence of their predictive ability. The goal of this prospective cohort study was to examine the associations between biomarkers of ovarian reserve and reproductive potential among women of late reproductive age.

Study Synopsis and Perspective

Biomarkers used to estimate ovarian reserve were not associated with fertility among women aged 30 to 44 years with no history of infertility who had tried to conceive for 3 months or less, a prospective study has found.

"These findings do not support the use of urinary or blood FSH tests or AMH levels to assess natural fertility for women with these characteristics," the researchers conclude.

Anne Z. Steiner, MD, from the Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, and colleagues report their findings in an article published online October 10 in JAMA.[1]

"Despite lack of evidence of their utility, biomarkers of ovarian reserve are being used as markers of reproductive potential or fertility tests," the authors write. "Home fertility tests based on day 3 urinary FSH levels are commercially available. Additionally, clinicians use these tests when counseling about elective oocyte cryopreservation."

Therefore, the researchers conducted a prospective time-to-pregnancy study between 2008 and 2016. They enrolled 750 women who gave a blood and urine sample. The researchers adjusted for age, body mass index, race, current smoking status, and hormonal contraceptive use during the preceding year. They also conducted subgroup analyses by age and parity.

"The objective of this study was to determine the extent to which biomarkers of ovarian reserve (early-follicular-phase serum AMH, serum FSH, serum inhibin B, and urinary FSH) were associated with reproductive potential, as measured by the probability of conceiving naturally, in a cohort of women of older reproductive age recruited from the community," the researchers explain. "It was hypothesized that women with biomarker values suggesting diminished ovarian reserve would have a lower probability of conceiving in a given cycle (fecundability) by 6 cycles and by 12 cycles of trying to conceive."

However, the researchers found no association between low AMH (<0.7 ng/mL) or high FSH (>10 mIU/mL) and reduced fecundability or a decreased cumulative probability of conceiving by 6 or 12 cycles of attempting pregnancy, after adjusting for age, body mass index, race, current smoking status, and hormonal contraceptive use during the preceding year.

Among women with low AMH values, the probability of conceiving by 6 cycles of attempt was 65% (95% confidence interval [CI], 50%-75%) vs 62% among women with normal values (95% CI, 57%-66%). Similarly, there was no difference between the 2 groups after 12 attempting cycles (84%; [95% CI, 70%-91%] vs 75% [95% CI, 70%-79%], respectively).

Among those with high serum FSH values, the probability of conceiving by 6 attempting cycles (63%; 95% CI, 50%-73%) was also not significantly different compared with women with normal FSH values (62%; 95% CI, 57%-66%), nor was it different after 12 cycles of attempt (82% [95z% CI, 70%-89%] vs 75% [95% CI, 70%-78%]).

"Early-follicular-phase inhibin B levels were also not associated with fertility outcomes," the researchers write. The hazard ratio of conceiving during a given cycle was 0.999 per 1 pg/mL increase (95% CI, 0.997-1.001).

"Although both ovarian reserve and fertility decline with chronological age when looking at cross-sectional data, there may be little association between a given woman's ovarian reserve and factors that affect her fertility, such as egg quality. [AMH] and FSH levels may, however, affect follicular recruitment in those with diminished ovarian reserve," the authors explain. "It is possible that low AMH allows for a greater proportion of the remaining primordial follicle pool to activate and become growing follicles. Additionally, high FSH seen in women with low reserve could lead to 'superovulation' with multifollicular ovulation, increasing the odds of pregnancy."

"Several Caveats"

The study findings "should be considered in the context of several caveats," Nanette Santoro, MD, from the University of Colorado School of Medicine, Aurora, writes in an accompanying editorial.[2]

Importantly, the study excluded those with known fertility problems or with fertility problems affecting their partners. In addition, as the only pregnancy outcome available was a positive pregnancy test, it is possible that more pregnancy loss and lower live birth rates occurred among women with low ovarian reserve. As well, "although subsequent use of fertility medications may have affected outcomes for the group of women with low AMH, data from women who initiated fertility treatments were censored," Dr Santoro explains.

Dr Santoro points out, "[T]he findings differ from the authors' prior pilot study of 100 women, in which low AMH was associated with reduced odds of conception.... [E]ven though the overall sample size was relatively large, the number of women in the 38- to 44-year-old age group with low AMH was small (n = 28), and the loss to follow-up of women in this group to fertility treatment over the 12-month observation period may have influenced the results," she adds.

Finally, "the within-woman rate of decline in AMH over time is likely to be a useful factor to incorporate into prognostic models; however, serial measurements were not obtained in this study. Most work to date has involved cross-sectional studies with single determinations of AMH. It is possible that a subset of women who have a more rapid rate of decline in AMH levels have a more adverse fertility profile," Dr Santoro explains.

Different Approaches Needed for Women With and Without Infertility

"For clinical researchers who study menopause, AMH has appeared to represent the long-sought-after blood test to help a woman prospectively determine when her final menses will occur," Dr Santoro writes. "It seems critical to distinguish the infertile population, who have already tried unsuccessfully to become pregnant and are therefore encountered in clinical practice, from the noninfertile population, which consists of a group of women (most of whom will not ever come to medical attention for infertility) who may have a number of reproductive advantages that mitigate a low AMH when interpreting these biomarkers. Circulating AMH may mean different things in each of these circumstances."

Clinicians should not evaluate women who have never tried to conceive in a similar manner to how they evaluate women with infertility, Dr Santoro concludes. "Doing so can not only provide potentially misleading and anxiety-producing results but may also lead to costly fertility preservation treatments that have no value."

One coauthor reports receipt of personal fees from Merck, TherapeuticsMD, Agile Therapeutics, AbbVie, Noven, Pantarhei Bioscience, and Mithra. Dr Steiner and the remaining coauthors have disclosed no relevant financial relationships. Dr Santoro reports membership on the board of directors of the North American Menopause Society, stock options in Menogenix Inc, and consultancy for Astellix/Ogeda Pharmaceuticals.

JAMA. Published online October 10, 2017.

Study Highlights

  • The prospective cohort for this study included 981 women aged 30 to 44 years without a history of infertility who had been attempting conception for 3 or fewer months, recruited from the Raleigh-Durham, North Carolina, area.
  • Study duration was from 2008 through last follow-up in March 2016.
  • Measurements included early-follicular-phase serum levels of AMH, FSH, and inhibin B and urinary FSH.
  • Main study endpoints were cumulative probability of conception, defined as a positive pregnancy test, by 6 and 12 cycles of attempt, and relative fecundability, defined as probability of conception in a given menstrual cycle.
  • The analysis included 750 women who provided a blood and urine sample.
  • Mean age was 33.3±3.2 years, 77% were white, and 36% were overweight or obese.
  • Compared with women with normal AMH (n=579), women with low AMH (<0.7 ng/mL; n=84) did not differ significantly in predicted probability of conceiving by 6 cycles of attempt, after adjustment for age, body mass index, race, current smoking, and recent hormonal contraceptive use (62% [95% CI, 57%-66%] vs 65% [95% CI, 50%-75%]).
  • Conception by 12 cycles of attempt also did not differ significantly (75% [95% CI, 70%-79%] vs 84% [95% CI, 70%-91%]).
  • Findings were similar for women with high serum FSH (>10 mIU/mL; n=83) vs normal serum FSH (n=654) for probability of conceiving after 6 cycles (63% [95% CI, 50%-73%] vs 62% [95% CI, 57%-66%]) or 12 cycles (82% [95% CI, 70%-89%] vs 75% [95% CI, 70%-78%]).
  • Findings were also similar for women with high urinary FSH (>11.5 mIU/mg creatinine; n=69) vs normal urinary FSH (n=660) for probability of conceiving after 6 cycles (61% [95% CI, 46%-74%]) vs 62% [95% CI, 58%-66%]) or 12 cycles (70% [95% CI, 54%-80%] vs 76% [95% CI, 72%-80%]).
  • Among 737 women with inhibin B measurements, these were not associated with probability of conceiving in a given cycle (hazard ratio per 1 pg/mL increase, 0.999; 95% CI, 0.997-1.001).
  • Biomarkers of diminished ovarian reserve were also not associated with reduced fecundability.
  • Reduced ovarian reserve measured by AMH was not associated with reduced fecundability either in younger (age 30-35 years) or in older women, but high AMH was nonsignificantly associated with reduced fecundability in the younger women and increased fecundability in the older women.
  • On the basis of their findings, the investigators concluded that biomarkers indicating decreased vs normal ovarian reserve were not associated with reduced fertility among women aged 30 to 44 years without a history of infertility who had been attempting conception for 3 or fewer months.
  • Women with low AMH had an 84% predicted cumulative probability of conception by 12 cycles vs 75% in women with normal AMH, which is a nonsignificant difference.
  • The results do not support the use of urinary or blood FSH or AMH levels to evaluate natural fertility among women with these characteristics who attempt to conceive naturally, and these women should be warned not to use AMH levels as a marker of current fertility.
  • The current findings were contrary to the hypothesis being tested and conflicted with those of earlier studies, which were small or based on secondary analyses.
  • There may be little association between a given woman's ovarian reserve and factors affecting her fertility, such as egg quality, although AMH and FSH levels may affect follicular recruitment in those with reduced ovarian reserve.
  • AMH is also a potential marker for polycystic ovarian syndrome.
  • Diminished ovarian reserve could affect fecundity, which encompasses the ability to conceive, as well as to carry a fetus to viability, by increasing risk for miscarriage, perhaps via an effect on egg quality.
  • Study limitations include use of conception rather than live birth as the primary outcome, dropout of some women before 12 cycles of attempt, lack of assessment of ovulation or of semen quality, and insufficient power to study very low (≤0.1 ng/mL) AMH values, which are more consistent with the late perimenopausal transition.
  • An accompanying editorial also notes exclusion of couples with known fertility problems in either partner, censored data from women who began fertility treatments, a small number of women aged 38 to 44 years, and lack of serial measurements.
  • The editorial suggests that a subset of women with faster AMH decline may possibly have worse fertility, and that clinicians need to differentiate infertile women who have already tried unsuccessfully to become pregnant from noninfertile women who have never tried to conceive and who may have various reproductive advantages mitigating low AMH levels.
  • These groups of women should be evaluated differently to avoid potentially misleading test results causing anxiety, as well as costly fertility preservation treatments of no benefit.

Clinical Implications

  • Biomarkers indicating decreased vs normal ovarian reserve were not associated with reduced fertility among women aged 30 to 44 years without a history of infertility who had been attempting conception for 3 or fewer months, based on a prospective cohort study.
  • The results do not support the use of urinary or blood FSH or AMH levels to evaluate natural fertility among women with these characteristics who attempt to conceive naturally.
  • Implications for the Healthcare Team: To avoid potentially misleading test results causing anxiety, as well as costly fertility preservation treatments of no benefit, noninfertile women who have never tried to conceive should be evaluated differently from infertile women who have already tried unsuccessfully to become pregnant.

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