Anti-Müllerian hormone for the diagnosis and prediction of menopause: a systematic review

Abstract

Background: The early onset of menopause is associated with increased risks of cardiovascular disease and osteoporosis. As a woman's circulating anti-Müllerian hormone (AMH) concentration reflects the number of follicles remaining in the ovary and declines towards the menopause, serum AMH may be of value in the early diagnosis and prediction of age at menopause.

Objective and rationale: This systematic review was undertaken to determine whether there is evidence to support the use of AMH alone, or in conjunction with other markers, to diagnose menopause, to predict menopause, or to predict and/or diagnose premature ovarian insufficiency (POI).

Search methods: A systematic literature search for publications reporting on AMH in relation to menopause or POI was conducted in PubMed®, Embase®, and the Cochrane Central Register of Controlled Trials up to 31 May 2022. Data were extracted and synthesized using the Synthesis Without Meta-analysis for diagnosis of menopause, prediction of menopause, prediction of menopause with a single/repeat measurement of AMH, validation of prediction models, short-term prediction in perimenopausal women, and diagnosis and prediction of POI. Risk-of-bias was evaluated using the Tool to Assess Risk of Bias in Cohort Studies protocol and studies at high risk of bias were excluded.

Outcomes: A total of 3207 studies were identified, and 41, including 28 858 women, were deemed relevant and included. Of the three studies that assessed AMH for the diagnosis of menopause, one showed that undetectable AMH had equivalent diagnostic accuracy to elevated FSH (>22.3 mIU/ml). No study assessed whether AMH could be used to shorten the 12 months of amenorrhoea required for a formal diagnosis of menopause. Studies assessing AMH with the onset of menopause (27 publications [n = 23 835 women]) generally indicated that lower age-specific AMH concentrations are associated with an earlier age at menopause. However, AMH alone could not be used to predict age at menopause with precision (with estimates and CIs ranging from 2 to 12 years for women aged <40 years). The predictive value of AMH increased with age, as the interval of prediction (time to menopause) shortened. There was evidence that undetectable, or extremely low AMH, may aid early diagnosis of POI in young women with a family history of POI, and women presenting with primary or secondary amenorrhoea (11 studies [n = 4537]).

Wider implications: The findings of this systematic review support the use of serum AMH to study the age of menopause in population studies. The increased sensitivity of current AMH assays provides improved accuracy for the prediction of imminent menopause, but diagnostic use for individual patients has not been rigorously examined. Prediction of age at menopause remains imprecise when it is not imminent, although the finding of very low AMH values in young women is both of clinical value in indicating an increased risk of developing POI and may facilitate timely diagnosis.

Keywords: AMH; anti-Müllerian hormone; fertility; menopause; ovarian reserve; premature ovarian insufficiency.

Prediction of age at menopause remains imprecise when not imminent, but very low AMH in young women can indicate increased risk of developing POI. AMH, anti-Müllerian hormone; POI, premature ovarian insufficiency.

Figure 1.

There is a steep decline in AMH prior to the final menstrual period. Solid lines represent the average predicted population means whilst 95% confidence intervals are indicated by dashed lines. Data are from the Avon Longitudinal Study of Parents and Children (ALSPAC) and reproduced from Soares et al. (2020), CC-BY. AMH, anti-Müllerian hormone.

Figure 2.

PRISMA flow chart.

Figure 3.

Age-specific AMH values can indicate the predicted age of menopause. Lines reflect indicative distribution of age at menopause for women with age-specific AMH concentrations that are low (green line), mid-range (blue), or in the higher (purple) normal range. From Nelson and Anderson (2021) (modified from Broer et al., 2011). Prediction of premature ovarian insufficiency: foolish fallacy or feasible foresight? SM Nelson and RA Anderson, Climacteric, 2021 Taylor & Francis, reprinted by permission of the publisher (Taylor & Francis Ltd, http://www.tandfonline.com). AMH, anti-Müllerian hormone.

Figure 4.

Positive predictive value of AMH <10 pg/ml for final menstrual period occurring within 12, 24, and 36 months for women aged 45 (green squares) and 49–51 (purple squares) years of age. Data are from the Study of Women’s Health Across the Nation (SWAN), a multicentre, multiethnic, community-based longitudinal study of the menopause transition (Finkelstein et al., 2020). 95% CIs are represented by vertical bars. AMH, anti-Müllerian hormone; PPV, positive predictive value.