This research proposal plans to investigate the physiology of GnRH in the normal human menstrual cycle; to explore the range of pathophysiologic defects of GnRH in anovulatory infertility; to attempt to induce ovulation in ovulatory disorders with pulsatile GnRH; and to explore a GnRH antagonist across the human menstrual cycle. In continuation of our previous studies on the human menstrual cycle we plan to complete the study of the normal range of frequency and amplitude changes of GnRH-induced gonadotropin pulsations which occur in 60 normal females throughout the course of an ovulatory menstrual cycle. In addition, we will document the spectrum and nature of the abnormalities of GnRH which exist in specific subsets of anovulatory infertility including, a) hypothalamic amenorrhea, b) hyperprolactinemia in the absence of a pituitary tumor, c) polycystic ovarian disease, and d) inadequate luteal phase. Following a comprehensive baseline assessment of their GnRH program we plan to induce ovulation in them using intravenous administration of GnRH at hourly intervals throughout the follicular phase at a dose of 25 ng/kg. When ovulation has been documented by ultrasound, estradiols, and basal body temperature charts, the frequency of GnRH administration will be progressively slowed at a schedule compatible with that observed in the normal human menstrual cycle. Finally, a GnRH antagonist will be explored in three phases of the menstrual cycle in a log order of doses and the optimized dose used at six separate phases of the menstrual cycle to induce a temporary blockade of GnRH function and employ this physiologic probe to examine intra- and inter-cycle relationships mediated by GnRH's induction of pulsatile gonadotropin release.
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