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Response to ACOG Committee Opinion Summary Number 773: The Use of Antimüllerian Hormone in Women Not Seeking Fertility Care

Response to ACOG Committee Opinion Summary Number 773: The Use of Antimüllerian Hormone in Women Not Seeking Fertility Care

Original Abstract from ACOG: Anti-müllerian hormone (AMH) is produced by the granulosa cells surrounding each oocyte in the developing ovarian follicle. The production and serum levels of AMH at any given time are reflective of a woman’s ovarian reserve, and multiple studies have demonstrated that antimüllerian hormone levels decline across the reproductive lifespan. Data exist to support the use of antimüllerian hormone levels for the assessment of ovarian reserve in infertile women and to select ovarian stimulation protocols in this population; however, using serum antimüllerian hormone levels for fertility counseling in women without a diagnosis of infertility is not currently supported by data from high-quality sources. The obstetrician–gynecologist should exercise caution when considering the predictability of serum antimüllerian hormone levels in any population of women with a low prevalence of infertility, including reproductive-aged women who either have never tried to become pregnant or have become pregnant previously without assistance. Based on the current information, a single serum antimüllerian hormone level assessment obtained at any point in time in a population of women with presumed fertility does not appear to be useful in predicting time to pregnancy and should not be used for counseling patients in this regard. At this time, routine antimüllerian hormone testing for prediction of pregnancy loss is not recommended. More data are needed to determine the utility of antimüllerian hormone as a predictor of time to menopause, a biomarker for polycystic ovary syndrome, or a predictor of future menses in women who have received gonadotoxic therapy.

Serum antimüllerian hormone level assessment generally should not be ordered or used to counsel women who are not infertile about their reproductive status and future fertility potential.

  • We believe that the ACOG committee has omitted one very important reason for AMH testing in women without infertility: the ability to screen for the risk of primary ovarian insufficiency (POI). In other committee opinions, ACOG has proposed AMH testing as a method for diagnosing POI.
  • AMH is the best and most reliable marker of functional ovarian reserve, and has been shown to improve prediction of menopause as compared to maternal age of menopause alone.
  • POI affects 1 in 100 women, is associated with various comorbidities (including infertility) and an increase in all-cause mortality.
  • Because of the prevalence and severity of this disorder, we would like to highlight the important role of AMH in screening for risk of POI, especially for patients taking oral contraceptives (OC).
  • 62% of women ages 15-44 years use contraception, of whom 28% use OCs. The rate of OC use is even higher in younger women: 47.3% of women ages 15-24 years of who use contraception, use OCs.
  • Thus, assessing amenorrhea, gonadotropin or estradiol levels to screen for POI would not be appropriate in this population (which numbers 10.6 million American women).
  • However, even in women not taking OCs, declines in AMH will be seen before changes in FSH and E2, so there is utility in testing AMH regardless of contracepting status. (While OCs are known to suppress AMH levels, patients with low age-specific AMH could undergo further assessment to determine if they are at risk of POI.)
  • We forward AMH testing as a practical alternative method to screen for risk of POI in this population,,,.
  • Secondly, as more women of reproductive age chose to undergo fertility preservation, the utility of AMH testing in women with presumed fertility will only increase.
  • Last month, the ASRM Bulletin noted that “Fertility preservation cycles...increased to 10,936 in 2017 from 8825 in 2016.” This is a 24% increase year-over-year and as this trend continues, AMH testing in fertile women will become more widespread.

Although serum antimüllerian hormone levels are a known predictor of ovarian response to exogenous gonadotropin stimulation in infertile women undergoing assisted reproduction cycles, the use of antimüllerian hormone in women with presumed fertility is limited by a lack of international assay standards and differing assay methodologies.

  • We agree that the field has been hampered by the lack of an international standard for AMH.
  • The National Institute for Biological Standards and Control has completed an evaluation of a candidate reference material and a decision will be made in this year (2019) in conjunction with the WHO. Thus efforts are well underway and we hope more effective inter-assay comparison is on the horizon.
  • However, the lack of an international standard does not mean that the utility of AMH is too limited to preclude interpretation in terms of assay-specific, validated outcomes. For example, the newly FDA-approved AMH assay by Beckman-Coulter was validated for the prediction of antral follicle count and poor ovarian response and for discriminating PCOS patients from controls.
  • The introduction of automated assays by Roche and Beckman-Coulter that utilize the same antibody has dramatically decreased the intra- and inter-assay variation to less than 10%,11,,.

A single serum antimüllerian hormone level assessment obtained at any point in time in a population of women with presumed fertility does not appear to be useful in predicting time to pregnancy.

  • We agree that there is not enough evidence that a single AMH measurement can predict time to pregnancy (TTP), and for this reason we agree that physicians should exercise caution when interpreting AMH levels.
  • However, it should be noted that some studies (other than the much cited example) do show an association with TTP and AMH in natural conception. Thus, more evidence is needed to understand the role AMH plays in fecundity before its utility in women without infertility is dismissed.
  • Additionally, more studies on the longitudinal decline of AMH and fertility outcomes (such as time to pregnancy, miscarriage, and live birth) in a presumed fertile population are needed.
  • We encourage the development of research programs that measure pre-conception AMH levels and outcome variables, such as TTP, in a presumed fertility population, to further elucidate its the utility of AMH as a marker of both quantity and quality of the ovarian reserve.

Currently, serum antimüllerian hormone levels are not part of the accepted diagnostic criteria for polycystic ovary syndrome (PCOS).

  • As has been summarized cogently elsewhere, in PCOS women total AMH levels and production of AMH per follicle are elevated, granulosa cell AMH mRNA expression is increased and AMH levels are positively associated with the severity of the disease.
  • In contrast, the continued refinements in technology have required the diagnostic criteria for antral follicles to be recently adjusted upwards due to improved visualization of the ovary, further limiting the utility of ultrasound alone to diagnose polycystic ovarian morphology.
  • It is therefore reassuring that large meta-analyses have shown that serum AMH can predict PCOS with appropriate sensitivity and specificity, despite the limitations of the older assays.
  • With the widespread adoption of the automated assay platforms and international standardization of AMH values, we anticipate that an AMH threshold will soon be agreed upon for PCOS.
  • There has already been movement in that direction, as the joint recommendation of the International PCOS Network wrote just last year “There is emerging evidence that improved standardization of assays and established cut-off levels or thresholds based on large scale validation in populations of different ages and ethnicities, AMH assays will be more accurate in the detection of PCOM.” 20
  • At present, we believe there is still considerable value in measuring AMH in women presenting with PCOS symptoms. In particular for those women presenting initially to primary care physicians and endocrinologists who are unable to perform a transvaginal scan, the inclusion of AMH as part of the initial blood panel in the diagnostic work-up is a significant step forward and will ensure appropriate onward referral.

More data on the use of serum antimüllerian hormone levels to predict postchemotherapy fertility and to guide fertility counseling in these patients are needed.

  • We agree that a single AMH measurement in this patient population is inadequate to counsel women on their future fertility potential after chemotherapy.
  • However, AMH is a better marker of ovarian function in cancer survivors than traditional markers, such a regular menses, estradiol or FSH levels and AFCs, which do not consistently predict ovarian function in these patients.,
  • We advocate for studies that will follow cancer survivors longitudinally, including performing repeat AMH measurements to better understand the relationship between AMH, ovarian function, and age at menopause to improve prognosis for the oncofertlity patient.

Routine antimüllerian hormone testing for prediction of pregnancy loss is not recommended.

  • We agree that there is not yet enough data to employ AMH testing for the routine prediction of pregnancy loss.
  • We encourage the development of research programs that measure pre-conception AMH levels and outcome variables, such as chemical/early and clinical pregnancy loss, in a presumed fertile population.

The use of antimüllerian hormone levels as a predictor of the onset of menopause is unsuitable for clinical practice at this time.

  • We agree with the Committee that the ability of AMH to predict menopause onset is not ready for prime time.
  • However, AMH is still the best available measure of functional ovarian reserve, and performs better than maternal age at menopause which was previously the gold standard.
  • The ability to measure functional ovarian reserve has never been a more pressing public health concern. This is a direct result of the fact that, for the first time in recorded history, more American women are having children in their 30s than their 20s.
  • As childbearing years and the menopausal transition begin to overlap, more and more women and couples will experience primary and secondary infertility.
  • The Committee Opinion stresses that their recommendations are applicable for woman “not seeking treatment for infertility.” However, knowing more about ovarian reserve, in addition to the well known effects of age on fertility, could potentially save many people from experiencing age-related infertility.

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  10. J. Ferguson, personal communication, April 9, 2019
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