Net Increase in Stimulatory Input Resulting from a Decrease in Inhibin B and an Increase in Activin A May Contribute in Part to the Rise in Follicular Phase Follicle-Stimulating Hormone of Aging Cycling Women

Abstract

Recent studies suggest that an age-related decline in ovarian inhibin B may play a role in the increase in follicular phase FSH in menstrual cycles of older women. Considering that the peripheral feedback regulation of FSH is dictated by the overall tone of inhibins, activins, and follistatins as well as estradiol, it is essential to determine the relative inputs of all of these regulators in assessing whether the collective peripheral input to FSH is one of inhibition or stimulation. To test the hypothesis that changes in the overall tone of peripheral feedback may contribute to this hallmark sign of aging, we compared the concentrations of dimeric inhibin A, inhibin B, activin A, and total and free follistatin in 7 young (mean age, 27.9 +/- 2.6 yr) and 10 older (mean age, 43.6 +/- 0.9 yr) cycling women during the follicular (FOLL; cycle day 6) and midluteal (ML; 7 days post-LH surge) phases of the menstrual cycle. Subjects were preselected on the basis of FOLL phase FSH levels (older, > or = 8.0 mIU/mL; younger, < 8 mIU/mL). Circulating FSH regulatory peptide concentrations were determined from samples pooled from blood drawn every 10 min for 8 daytime h using specific 2-site assays. In the older group, cycle length was shorter (29.1 +/- 0.5 vs. 26.1 +/- 0.5, young vs. older; P < 0.001), mean LH levels during the follicular phase were higher (LH, 5.6 +/- 0.8 vs. 8.8 +/- 1.1 mIU/mL, young vs. older; P < 0.001). Mean FSH levels for the older and younger groups averaged 10.8 +/- 0.8 and 6.2 +/- 0.3 mIU/mL, respectively. Estradiol levels were higher, but not statistically different, than those in the younger group (99 +/- 13 vs. 169 +/- 25 pmol/L, young vs. older; P = 0.06). In both age groups, inhibin B levels were higher in the FOLL vs. ML phase, inhibin A levels were higher in the ML vs. FOLL phase, but total activin A and total and free follistatin did not differ across cycle days. FOLL phase inhibin A levels were higher in the older group (16.3 +/- 2.4 vs. 26.4 +/- 3.4 pg/mL, young vs. older; P = 0.024), but levels of inhibin B were lower (323 +/- 80 vs. 163 +/- 24 pg/mL, young vs. older; P = 0.03). Overall, the estimated total inhibin activity (inhibin A plus inhibin B) was lower in older cycling than in younger women (339 +/- 82 and 189 +/- 24 pg/mL, young vs. older). Total and free follistatin levels were not different among the 2 groups of women. In contrast, total activin A levels were higher in the older cycling group (0.51 +/- 0.05 and 0.68 +/- 0.05 ng/mL, young vs. older; P = 0.02). No differences in age groups were observed during the ML phase for any of the variables measured. These data suggest that a net increase in stimulatory input resulting from a decrease in inhibin B and an increase in activin A may contribute in part to the monotropic FSH increase in aging women.

Comparison of Basal and Clomiphene Citrate Induced FSH and Inhibin B, Ovarian Volume and Antral Follicle Counts as Ovarian Reserve Tests and Predictors of Poor Ovarian Response in IVF

“…Others, in a recent study, failed to find these correlations and concluded that although CCCT was useful as a test of ovarian reserve, there was no additional value for inhibin B testing (13). Aging women have increasing levels of FSH during early follicular phase, which in turn might be a consequence of declining secretion of inhibin by reduced number of ovarian follicles (8,25,26). Patients with high serum levels of FSH on day 3 had granulosa cells of diminished capacity for secreting dimeric inhibins (9).…”

Effect of FSH and cell localization on dimeric inhibin-A secretion from bovine granulosa cells in culture

“…In rats and in humans, it has become clear that both inhibin-A and inhibin-B are important for the regulation of FSH secretion (Woodruff et al 1996, Reame et al 1998, Smitz & Cortvrindt 1998; however, inhibin-B has never been isolated from ruminant follicular fluid and assays for inhibin-B do not detect this inhibin form in sheep follicular fluid (Knight et al 1998). It is at present likely that inhibin-B is not a major secretory product of the ruminant follicle.…”

Reproductive ageing in women

“…Several studies have shown a significant decrease in the serum levels of inhibin B during the follicular phase in women of advanced reproductive age with ovulatory cycles, concomitant with an increase in the FSH levels [76][77][78][79][80][81][82][83][84]. It has been shown that the main sources of inhibin B in the circulation are the pre-antral and small antral follicles [85][86][87].…”

“…It has been shown that the main sources of inhibin B in the circulation are the pre-antral and small antral follicles [85][86][87]. The decrease in the serum inhibin B levels has been attributed to the diminishing number of these follicles in the ovaries [76][77][78][79][80][81]. It has been suggested that the resulting reduced negative feedback from inhibins on pituitary FSH secretion could be responsible for the observed elevated serum FSH levels in women of advanced reproductive age [76][77][78][79][80][81].…”

“…The decrease in the serum inhibin B levels has been attributed to the diminishing number of these follicles in the ovaries [76][77][78][79][80][81]. It has been suggested that the resulting reduced negative feedback from inhibins on pituitary FSH secretion could be responsible for the observed elevated serum FSH levels in women of advanced reproductive age [76][77][78][79][80][81]. Longitudinal prospective studies have also shown age-related decline in serum inhibin B levels with advancing age during the menopausal transition [88,89].…”