An early sign of reproductive aging in normal cycling women is the monotropic rise in FSH in the fact of preserved estradiol (E2) secretion. The mechanisms for this phenomenon are not know, but unlike the case in rodents, it is presumed to result from the incipient loss of negative feedback from ovarian inhibin, due to an accelerated decline in the pool of FSH-responsive follicles. Recently, this hypothesis has been challenged based on mounting evidence of altered pulsatile LH secretion well before the menopause, thus pointing to a contributory role for a decline in hypothalamic GnRH pacemakers in the onset of human ovarian failure. Through a detailed study of the ovarian negative feedback tone and sleep-induced changes in gonadotropin secretion (as a marker of the centrally-mediated GnRH signal generator), the goal is to determine the relative contribution of central aging effects to the onset of menopause in humans. Such information could assist in the development of improved strategies for menopause-related morbidity. Further, it perhaps could suggest therapies for the maintenance of follicular function and fertility in the 1 in every 100 women who will undergo premature ovarian failure and menopause before age 40. This proposal builds on a recent discovery using highly specific two-site assays that both inhibin B and Activin A (but no total and free follistatin or E2) are altered in aging, ovulatory women with magnified gonadotropin secretion. Whether such changes in ovarian function are a consequence or a cause of the menopausal transition remains to the determined. To separate the central and ovarian aspects of reproductive aging, plans are to assess pulsatile LH and FSH secretion for 1) follicular phase-dependent changes in the 24-hour dynamic secretory pattern (hypothalamic level) and 2) responsiveness to GnRH (pituitary level) in premenopausal, ovulatory women compared to younger controls and age-matched postmenopausal women; and 3) examine the individual effects of age and ovarian peptide feedback on gonadotropin dynamics by studying a comparative group of castrate women of different ages replaced with E2.
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