Interactions between serum FSH, inhibin B and antral follicle count in the decline of serum AMH during the menstrual cycle in late reproductive age

Abstract

Objective: To investigate the hormonal interrelationships during the menstrual cycle in women of late reproductive age with suppressed serum AMH and antral follicle count (AFC).

Methods: Serum hormones (AMH, FSH, LH, estradiol, progesterone, inhibin A, inhibin B), AFC (2-10 mm) and AMH/AFC ratio (an estimate of AMH/follicle) were assessed every 2-3 days across the menstrual cycle in 26 healthy ovulatory women aged 18-50 years.

Results: An 11-fold fall in AMH/AFC was observed in women aged ≥45 years compared to those 18-45 years (P < .001). Although women ≥45 years exhibited normal menstrual cycle patterns of serum estradiol, progesterone, LH and inhibin A, FSH was elevated (P < .001) and inhibin B suppressed (P < .001) compared to the younger group. Overall FSH was inversely correlated (r = .55, P < .05) and AMH directly correlated (r = .88, P < .01) with AFC; however, these relationships were curvilinear and more pronounced when AFC was low. Inhibin B was directly linearly correlated (r = .70, P < .01) with AFC across both high and low AMH/follicle groups.

Conclusions: It is hypothesized that the marked fall in AMH/follicle in late reproductive age is attributed to the change in the hormonal interplay between the pituitary and ovary. The fall in AFC leads to a decrease in inhibin B and a concomitant increase in FSH by a recognized feedback mechanism. It is postulated the elevated FSH suppresses AMH either directly or indirectly through oocyte-specific growth factors leading to a marked fall in AMH/follicle. We propose that pituitary-ovarian and intra-ovarian regulatory systems underpin the accelerated fall in AMH/follicle during the transition to menopause.

Keywords: BMP15; GDF9; cumulin; estradiol; inhibin A; menopause; oocytes.

Figure 1

Relationship between serum AMH, inhibin B and AFC calculated as an average value across the interovulatory interval for each subject with age. Note the dramatic fall in AMH/AFC ratios (an estimate of AMH/follicle) after the age of 45 y. Panel A: AMH and AFC with age. Panel B: AMH/AFC and inhibin B/AFC ratios with age. HRG, high AMH/AFC ratio group; LRG, low AMH/AFC ratio group

Figure 2

Profiles of mean serum hormones across the menstrual cycle in women that were divided into two groups based on average AMH levels/follicle (open columns, high AMH/AFC ratio (HRG); closed columns, low AMH/AFC ratio (LRG)). Serum estradiol, progesterone, AMH, antral follicle count (AFC, 2‐10 mm) and ratios of AMH/AFC and inhibin B/AFC are presented. Serum sample values have been averaged in 3‐d groups across the intra‐ovulatory interval between ovulations (OV1 and OV2) as follows: LFP1, late follicular phase, ELP, MLP, LLP, VLLP (early, mid‐late, very late luteal phase); M, menses EFP, MFP, LFP2, early, mid‐late follicular phases

Figure 3

Relationship of serum AMH, inhibin B, FSH and antral follicle count (AFC) in women in two groups separated according to high or low AMH/AFC ratios (HRG (open circles) and LRG (closed circles). The data are presented as average values across the interovulatory interval for each subject. The LRG compared to HRG is characterized by significant associations between decreasing FSH (A), and increasing AMH (B) and inhibin B (C) with increasing follicle number. This is mirrored by inverse relationships between FSH and both AMH (D) and inhibin B (E). It is postulated that the increase in inhibin B with increasing AFC leads to a decrease in serum FSH by a reciprocal feedback mechanism and, in turn, an increase in AMH due to a decrease in inhibition by FSH. In panel (F), the distance in days between the rise in serum inhibin B and inhibin A across the follicular phase is plotted against antral follicle count

Figure 4

Schematic diagram of the interactions of antral follicle count (AFC), inhibin B and FSH in the regulation of AMH. In the low AMH/AFC group, the low AFC is associated with low inhibin B which in turn leads to an increase in FSH by a reciprocal feedback mechanism. The elevated FSH inhibits AMH by either a direct and/or indirect mechanism through oocyte‐specific growth factors (GDF9/BMP15). These relationships are reversed in the high AMH/AFC group. The numbered steps refer to the corresponding regression analyses and correlation coefficients presented in Figure 3 and Table 3