The overall aim of this proposal is to increase our understanding of the changes in the regulation of gonadotropin secretion and the presumed changes in GnRH secretion, during human sexual maturation and throughout the menstrual cycle. The hypothesis that GnRH pulse frequency may play a regulatory role in human sexual maturation and throughout the menstrual cycle will be examined in several ways. Specifically, we plan 1) to characterize in detail changes in the regulation of gonodotropin secretion which occur between mid-late childhood and early puberty; 2) to determine the effects of changing GnRH pulse frequency on gonadotropin secretion in normal and hypogonadal adults; and 3) to determine the mechanisms responsible for the increased FSH/LH ratio during the follicular phase of the menstrual cycle. Our major approaches to these objectives will include a) the pulsatile i.v. administration of synthetic GnRH at varying frequencies but at dosages which mimic pituitary portal concentrations; b) opiate receptor blockade to investigate the mechanisms of gonadotropin inhibition during childhood; c) assessment of whether the feedback effects of mid-pubertal concentrations of estradiol or testosterone are dependent on the sleep-wake cycle in early pubertal children; and d) assessment of whether administration of estradiol and progesterone to mimic the luteal phase of the cycle can effect a reversal in the serum FSH/LH ratio. In addition to a better understanding of reproductive physiology, these studies should provide the basis for rational therapeutic regimens in the future.
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