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Serum AMH Levels: An Early Reproductive Marker for Bone Loss?

Menopause hallmarks the cessation of reproductive function and is associated with various health issues, including cardiovascular disease (CVD), type 2 diabetes, and osteoporosis. It iswell establishedby several epidemiological studies that an earlier age at menopause increases the risk for these diseases compared with women with a later age at menopause. The age of menopause can only retrospectively be determined after 12 consecutive months of amenorrhea in the absence of pathological conditions. Among women of European descent, the mean age of natural menopause is around the age of 51 years but with a broad range of 10 years at each side. Although menopause marks the final stage of reproductive aging, it is preceded by several stages with changes in menstrual cycle characteristics and hormone profile levels (Fig. 1). Centered on the final menstrual period (FMP), the reproductive stage is divided into an early, peak, and late stage, followed by the early and late menopausal transition (MT). The menopausal transition plus the first 12 months after the FMP is considered the perimenopause stage. After the FMP, an early and late postmenopausal stage is defined according to Stages of Reproductive Aging Workshop (STRAW) criteria. Although initially the hypothalamic-pituitary-gonadal axis can compensate to maintain follicle growth and hormone production, this is not the case during the MT, resulting in decreased inhibin B and estrogen levels, increased follicle-stimulating hormone (FSH) levels, and irregular menstrual cycles. The late MT stage is estimated to last 1 to 3 years. During the early postmenopausal stage, which lasts up to 2 years, FSH levels continue to increase and estradiol levels to decrease. Thereafter, levels of both hormones become stable. Regarding postmenopausal diseases, particularly the MT stage has been identified as a critical period. At this stage of a women’s life, the rate of bone loss considerably increases. The decline in bone mineral density (BMD) and deterioration in bone microarchitecture as a consequence of postmenopausal estrogen deficiency results in osteoporosis and an increased fracture risk. Thus, the MT stage may be an important window to implement preventive strategies to reduce the risk for postmenopausal fractures. Therefore, markers to predict the start of MT, rather than determining this retrospectively based on the FMP, are key. Unfortunately, changes in menstrual cycle regularity and FSH and estrogen levels occur relatively late during reproductive aging. Over the years, serum anti-Müllerian hormone (AMH) levels have proven to be a marker for reproductive aging, whose levels decline early in the process (Fig. 1). AMH is an ovaryspecific growth factor, produced by the small growing follicles, which are independent of gonadotropins. Hence, in contrast to FSH, inhibin B, and estrogen levels, serumAMH levels are relatively stable during the menstrual cycle. Serum AMH levels correlate strongly with antral follicle count, and subsequently, after plateauing at 20 to 25 years of age, serum AMH levels decline with increasing age to undetectable levels at menopause. Hence, several studies have analyzed whether serum AMH can predict age of menopause or FMP. Based on a meta-analysis, serum AMH levels indeed predict the time to menopause, although the added value compared with age was limited. In this issue of JBMR, Karlamangla and colleagues have analyzed whether serum AMH levels could predict the rate of future BMD decline. Analyzing more than 3000 participants of the SWAN study, a prospective cohort study of menopause transition, repeated AMH measurements were performed from each woman before becoming postmenopausal. Annualized BMD decline rate was calculated as the percentage BMD lost over the 3 to 4 years after AMH measurement to determine whether AMH could predict future BMD loss. The authors observed that women with more than a 50% decrease in serum AMH had a 0.14% per year faster decline in lumbar spine BMD and a 0.11% per year decline in femoral neck BMD. This decline was only significant when women were premenopausal or early perimenopausal but not late perimenopausal. The authors also determined whether AMH could predict the magnitude of ongoing BMD loss. Womenwith a 50% decrease in serum AMH had an additional 0.37% loss in lumbar spine BMD and a 0.27% loss in femoral neck BMD relative to baseline BMD. Larger effects were observed in the late perimenopausal stage compared with the early perimenopausal stage. Finally, the authors tested whether an AMH level at a selected threshold could predict bone loss. An AMH value less than 100 pg/mL detected significant bone loss with a sensitivity of 50% in premenopausal, 80% in early perimenopausal, and 98% in late perimenopausal women. The sensitivity declined with lower AMH threshold values. The study furthermore showed that AMH levels may predict future rate of BMD decline in the preand early perimenopausal stage but not in late perimenopausal stage because the positive predictive value was nearly similar to the prevalence of bone loss. These results are in line with other recent studies assessing AMH during the preand perimenopausal stage to predict fracture risk or osteoarthritis. In a cohort of 300 Indian perimenopausal women, AMH serum levels were significantly lower in women with vertebral fractures compared with those without.