Serum antimüllerian hormone predicts ovarian reserve in a monkey model

Abstract

Objective: A monkey model of the menopausal transition (perimenopause) would facilitate efforts to understand better the effect of hormonal fluctuations during this life phase on the initiation of chronic diseases associated with the postmenopausal years. Antimüllerian hormone (AMH) is a promising marker of ovarian reserve (primordial follicle number) in women. Here, we describe the relationship between AMH and ovarian reserve in cynomolgus monkeys (Macaca fascicularis) estimated to be 12 to 15 years of age (approximately 36-45 y in women).

Methods and results: The results of daily vaginal swabbing (to detect menses) and thrice weekly blood sampling for 12 weeks indicate that AMH is relatively stable across the menstrual cycle (intraclass correlation, approximately 0.80), with a slight although significant (P < 0.02) reduction (approximately 1.4-fold) on days 2 to 5 postovulation. Substantial interindividual variation in AMH concentrations were observed between monkeys, with values ranging from 4.46 +/- 0.17 to 18.80 +/- 0.71 ng/mL (mean +/- SE). Antimüllerian hormone concentrations were reduced by approximately 63% after the removal of one ovary (7.6 +/- 0.77 vs 2.75 +/- 0.37 ng/mL; P < 0.001; n = 19) and were below the level of detection after the removal of both ovaries (5.8 +/- 0.42 to <0.05 ng/mL; P < 0.001; n = 84), suggesting that the ovary is likely to be either the major or the sole source of AMH in the monkey. Finally, we examined the association between AMH and primordial, primary, and secondary follicles in 29 monkeys and found significant associations with all follicle types (r = 0.78, r = 0.66, and r = 0.80, respectively; P < 0.01).

Conclusions: The relationship between AMH and ovarian reserve in the monkey is similar to that in women, suggesting that monkeys may be a useful model for studying hormonal fluctuations across the menopausal transition.

Figure1

Panel A. Representative graph of serum estradiol (E2, Left axis), antimüllerian hormone (AMH), progesterone (P4) and follicle stimulating hormone (FSH) concentrations (Right axis) across an ovulatory menstrual cycle of a cynomolgus monkey. Monkeys were swabbed daily to detect menses (dashed box) and blood was collected 3 times/wk (M,W,F) for 12 weeks for AMH measurement. Panel B. Concentration of AMH prior to and following ovulation (ov) in twelve cynomolgus monkeys of estimated age 12-15 years. A total of 18 ovulatory cycles were included in the analysis and data are shown as mean ± SE for each cycle day relative to the day of ovulation (determined by FSH peak).

Figure 2

Panel A. Antimüllerian hormone (AMH) concentrations in cynomolgus monkeys ∼7 years of age while premenopausal (PrMP, n=19) and after removal of one ovary (Uni-Ovx, n=19); and cynomolgus monkeys ∼12-15 years of age while premenopausal (PrMP, n=84) and after complete ovariectomy (OVX, n=84). AMH was below the level of detection of the assay in OVX monkeys. Data are expressed as mean±SE. Panels B-D. Association between serum antimüllerian hormone (AMH) concentrations and primordial (B), primary (C) and secondary (D) follicles in cynomolgus monkeys age 12-15 years (n=29). Pearson correlation coefficients (r) are reported for each association.