The long-term goal of this research is to understand the neuroendocrine regulation of the ovarian cycle, more specifically to understand regulation of the secretion and the physiological actions of gonadotropin- releasing hormone (GnRH) leading up to ovulation. It has recently been determined that, during the follicular phase of the estrous cycle of sheep, there is a profound change in the pulsatile pattern of GnRH secretion followed by a large and prolonged preovulatory GnRH surge that far outlasts the LH surge. This proposal is developed on the premise that changes in the pattern of GnRH secretion during the follicular phase are caused, in large measure, by changes in the secretion of estradiol from the developing preovulatory follicle, and that the resulting GnRH surge is a crucial signal for expression of the preovulatory sequence of events. There are four specific aims, each to address one of the following questions: Does estradiol induce the GnRH surge by causing a progressive change in output of the GnRH neurosecretory system, leading to a switch from strictly pulsatile to continuous release? What is the nature of the estradiol signal that causes the progressive changes in GnRH release? How much of the massive and prolonged GnRH surge is needed to induce the preovulatory LH surge and what, if any, is the function of all the GnRH secreted beyond the time of the LH peak? Does estradiol enhance GnRH-gene expression and stimulate synthesis and neuronal transport of GnRH from cell bodies to terminals during the surge? These questions will be addressed using a variety of experimental designs and approaches including: direct monitoring of GnRH secretion into pituitary portal blood; patterned delivery of specific estradiol signals; administration of a GnRH antagonist to block the biological actions of endogenous GnRH; in situ hybridization for GnRH mRNA; measurement of GnRH and its precursor in hypothalamic tissue to monitor GnRH gene expression; and radioimmunoassays to monitor circulating patterns of various hormones. The significance of this project to health-related issues is that it pertains directly to the control of ovulation and, thus, to fertility regulation. The proposed research will provide a description of the secretory dynamics of GnRH leading to ovulation, and the regulation of those patterns, at a level never before achieved. The information gained will enhance basic knowledge of the normal physiology of the ovarian cycle; this should lead to new approaches to manipulating fertility.
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