An early sign of reproductive aging in normal cycling women is the monotropic rise in FSH in the face of preserved estradiol (E2) secretion. The mechanisms for this phenomenon are not known, 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), our goal is to determine the relative contribution of central aging effects to the onset of menopause in humans. This proposal builds on our recent discovery using highly specific two-site assays that both inhibin B and Activin A (but not 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 be determined. To this end, we will assess pulsatile LH and FSH secretion for 1) follicular phase-dependent changes in the 24 hr 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. In this way, we will be able to determine the importance of central aging mechanisms in the explanatory model for spontaneous reproductive senescence in women.
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