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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 Women¹

School of Nursing (N.E.R.)., Department of Pediatrics (V.P.), and Reproductive Sciences Program (N.E.R., T.L.W., V.P.), University of Michigan, Ann Arbor, Michigan 48109; and the Institute of Reproduction and Development, Monash University (D.J.P., D.M.d.K.), Clayton, Victoria 3168, Australia

Address all correspondence and requests for reprints to: Vasantha Padmanabhan, Ph.D., Reproductive Sciences Program, University of Michigan, 300 North Ingalls Building, Ann Arbor, Michigan 48109-0404. E-mail: vasantha{at}umich.edu

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, 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.

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