The overall goal of this continuing renewal application for Years 9-13 is to extend our understanding of (a) the physiology of GnRH secretion in the normal menstrual cycle; (b) the pathophysiology of reproductive failure; and (c) the development of new techniques to evaluate the reproductive axis in the human female. It is now proposed to examine the neuroendocrine control of the midcycle gonadotropin surge during its spontaneous appearance in normal women with intact hypothalamic-pituitary axes, during estradiol and progesterone evocation of gonadotropin surges in normal subjects, and in GnRH deficient women whose regimen of exogenous GnRH administration can be experimentally varied to actively test hypotheses derived from the monitoring studies. The neuroendocrine control of the luteal-follicular transition will be examined in GnRH deficient women. The contribution of the abrupt increase in endogenous GnRH frequency previously described during this transition to the relatively isolated rise in FSH secretion occurring during this stage of the cycle will be explored. Finally, development will be continued of new techniques with which to examine reproductive physiology in the human, including: (a) the monitoring of pulsatile secretion of the free alpha subunit of gonadotropins as an alternative marker for endogenous GnRH secretion; (b) the use of a novel FSH radioreceptor assay for categorization of various pathophysiologic subsets of patients with premature ovarian failure; and (c) specific assays for measurement and determination of the normal physiology of the large molecular weight precursor forms of the alpha-subunit of inhibin and their role in premature ovarian failure.
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