Rhythmic bursts of gonadotropin-releasing hormone (GnRH) from hypothalamic neurons are essential for initiation and maintenance of secretion of the gonadotropins. The frequency and amplitude of these neural and pituitary events are regulated, in turn, by circulating levels of estradiol-17 beta (E2) and progesterone (P). One of these ovarian steroids, E2, inhibits luteinizing hormone (LH) release, whereas it enhances GnRH release; the second steroid (P) slows pulsatile LH release, in part, by increasing central opioid inhibition of GnRH secretion. The identify of other neuropeptides and catecholamines and their mode of actions and interactions of GnRH secretion in the ovulatory process and the normal menstrual cycle remain unclear. We propose to measure the patterns of GnRH in push-pull perfusion (PPP) samples from the hypothalamus and to compare these GnRH patterns with those of peripheral gonadotropins, E2, and P during the menstrual cycle in rhesus macaques and in the periovulatory period in rabbits. We will examine the roles of selected neuropeptides (neuropeptide Y, endorphins, corticotropin-releasing factor, and substance P) and that of norepinephrine in control of GnRH release by one or more of three methods: ( 1) measure their endogenous release rates in PPP samples, (2) infuse the test compound intrahypothalamically and measure changes in GnRH release, and (3) give specific antagonists or antibodies to a peptide and record these effects on endocrine and post-coital behavioral parameters. We will then study the influence of E2, P, and cortisol on the release of selected peptides and catecholamines in PPP samples and relate these findings to those on GnRH release. We propose also to measure GnRH release after intrahypothalamic infusion of pituitary hormones and inhibin and after unilateral ovariectomy for direct evidence on shortloop feedback and on hypothalamic laterality in feedback signaling. To explore these hypothalamo- hypophyseal interactions, we will use specific radioimmunoassays for peptides and steroids and a radioenzymatic assay for the catecholamines. Blood and/or PPP samples will be collected during superfusion of hypothalamic tissues (in vitro) and hypothalamic PPP in freely-moving females (in vivo). These findings will provide insight into how the hypothalamus influences the normal reproductive process, and hence may be useful in treating certain causes of infertility, anorexia nervosa, and obesity.
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