Human reproduction is regulated by a single gonadotropin-releasing hormone (GnRH) secreted by the hypothalamus. This proposal will explore the concept that the ability to change the frequency of GnRH secretion is critical for the maintenance of regular cyclic ovulation in women. Different pattern (frequency and amplitude) of GnRH stimuli differentially regulate synthesis and secretion of pituitary LH and FSH in rats. Thus GnRH secretory patterns may exert similar actions in women, in part effecting the cycles of predominant FSH followed by LH secretion leading to ovulation. Studies will examine regulation of GnRH secretion normal women and in polycystic ovarian syndrome (PCOS)-proposed to be a disorder of GnRH secretion. In normal women studies aim to define if E2 plays a specific role in slowing the frequency of GnRH secretion. We hypothesize that: --a GnRH pulse frequency of approx 1/h is the basal frequency in postpubertal women in the absence of ovarian regulation; the regulatory event needed to maintain ovulatory cycles may be suppression of this rapid frequency by the combined effects of luteal E2 and P, P playing the predominant role. This will be tested by assessing if rapid GnRH frequency (1/h) is regained in the presence of maintained luteal conc'n of E2 alone, after slowing is initially attained by E2 and P administration. PCOS may reflect the effects of unremitting rapid (1/h) GnRH secretion, due to an abnormal high hypothalamic threshold for feedback slowing of GnRH by E2 and P. Comparison of the timecourse of feedback and dose responses (varying P conc'n) will be performed in PCOS and normal controls. Preliminary data suggest that slowing the frequency of GnRH secretion requires a higher P conc'n in PCOS compared to normals. LH and FSH pulsatile release, responses to GnRH and follicular maturation are followed in all protocols. The possibility of applying these principles to induce follicular maturation and ovulation in PCOS will be explored after long term (6 weeks) suppression of GnRH secretion by luteal conc'n of E2 and P. Studies will assess if the preferential FSH secretion which follows E2 and P withdrawal is adequate to induce ovulation. These studies aim to elucidate the importance of ovarian feedback modulation of the frequency of GnRH secretion in maintaining normal cycles, and in the pathogenesis of PCOS, a disorder associated with abnormalities of GnRH pulse frequency. The results will be applied in an effort to induce ovulation in PCOS, based on a physiological approach of initial suppression of the rapid (1/h) GnRH pulse frequency.
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