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 patterns (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 cycle of predominant FSH followed by LH secretion leading to ovulation. Studies will examine regulation of GnRH secretion in normal women and polycystic ovarian syndrome (PCOS)-proposed to be a disorder of GnRH secretion. We hypothesize that: -a GnRH pulse frequency of approximately 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 E/2 and P, P playing the predominant role. In normal women we will assess if follicular E2 is required to regain a GnRH frequency of 1/h after slowing is initially attained by E/2 and P administration. PCOS may in part reflect the effects of unremitting rapid (1/h) GnRH secretion, due to an abnormal high hypothalamic threshold for slowing of GnRH by E/2 and P. Initial studies have shown that E/2 and P suppress GnRH pulses to a greater degree in normal women than in PCOS. In dose response studies slowing the frequency of GnRH secretion required a higher P conc/n in PCOS compared to normals.
We aim to determine if this reflects an inherent hypothalamic abnormality in PCOS, or is secondary to the effects of elevated androgens or to insulin resistance. Dose response studies of P suppression of GnRH will be performed before and after 4 weeks of blockade of androgen action by flutamide, and after reduction of plasma insulin by metformin. 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 E/2 and P, we will assess if the preferential FSH secretion which follows E/2 and P withdrawal is adequate to induce ovulation.
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