Early follicular phase serum FSH as a function of age: the roles of inhibin B, inhibin A and estradiol.

OBJECTIVE: Reproductive aging in regularly cycling normal women is characterized by a gradual decline in ovarian follicle number and a progressive increase in serum follicle stimulating hormone (FSH), particularly over the age of 40 years. The lack of any consistent decrease in circulating estradiol and progesterone has led to the hypothesis that the FSH increase results from decreasing ovarian inhibin production. The aim of this study was to investigate the relationship between serum inhibins A and B, FSH and estradiol in normal women between the ages of 20 and 50 years. DESIGN AND PATIENTS: Serum from 66 regularly cycling subjects, aged 20-50 years, was collected on days 3-5 of the menstrual cycle for this cross-sectional study. MEASUREMENTS: Serum inhibin A and inhibin B levels were measured by specific enzyme-linked immunosorbent assays (ELISAs). Alpha subunit forms were determined by an immunofluorometric assay which detects all known monomeric and dimeric forms of inhibin A and inhibin B and free alpha subunit. FSH and estradiol levels were measured by immunoassay. Data were log transformed before analysis.
RESULTS: Serum FSH, inhibin A and estradiol, but not inhibin B, were positively correlated (p < 0.05-p < 0.001) with age between years 20 and 50. Between 40 and 50 years, serum FSH was negatively correlated with inhibin B (r = -0.61, p < 0.001) and alpha subunit forms (r = -0.47, p < 0.05) and with estradiol (r = -0.39, p < 0.05), but not with inhibin A (r = -0.21, not significant). When log(FSH) was modelled as a function of log(inhibin B) and log(estradiol) with age fitted as a covariate, inhibin B only was a significant independent predictor of FSH (beta = -0.30, p < 0.01). Using purified inhibin A and B standards for the three assays, which were calibrated in terms of their alpha subunit content, serum inhibin A levels were 10-15% of those of inhibin B, with inhibin A + B levels being 22% of total alpha subunit levels. No significant correlation was observed between total inhibin alpha subunit and its dimers. The free alpha subunit, as determined from the difference in levels of total alpha subunit and inhibin A + B, remained relatively unchanged with age, suggesting that it is not differentially regulated.
CONCLUSIONS: This study shows that, during the early follicular phase, FSH, inhibin A and estradiol but not inhibin B increase with age. Some of the increase in inhibin A and estradiol may be the result of accelerated follicular development with increasing age. Serum inhibin B and estradiol but not inhibin A are inversely correlated with FSH between ages 40 and 50, but only inhibin B is a significant independent predictor of FSH. This supports the postulate that inhibin B is the main form of inhibin regulating FSH at this stage of the menstrual cycle. During the early follicular phase, serum levels of inhibin A are presumably too low to play a significant physiological role or are less active.