The central nervous system regulates gonadotropin secretion and maintains reproductive cycles through the intermittent release of gonadotropin-releasing hormone (GnRH). The direct study of this critical process has been limited by the lack of an effective method for measuring GnRH release in unanesthetized animals. Such a method - a push-pull perfusion technique - is now available and will be used to address two fundamental questions regarding the physiology of GnRH neurosecretion: What is the role of GnRH release in the regulation of gonadotropin secretion? What neural and endocrine factors are important in the physiological regulation of GnRH release? In the proposed studies, the release of GnRH will be monitored with the push-pull perfusion system, and gonadotropin levels will be measured in blood samples obtained concurrently from an indwelling jugular catheter. The role of GnRH in the stimulation of pulsatile LH release, pulsatile FSH release, the primary gonadotropin surge, and the secondary FSH surge will first be clarified. An analysis of the physiological regulation of GnRH by ovarian, pituitary, and hypothalamic factors will then be undertaken. Barbiturates will be used to determine if a 24 h neural clock regulates GnRH release, and if estrogen or progesterone can either amplify or block the expression of this daily neuronal signal. The effects of ovariectomy and acute estrogen treatment will also be assessed. In a second series of experiments, the """"""""short-loop"""""""" feedback inhibition of GnRH release will be investigated through immunoneutralization of LH or the selective inhibition of FSH secretion by porcine follicular fluid. The hypothalamic regulation of GnRH by endogenous opioid peptide systems will then be characterized through systemic and local applications of opiate agonists and antagonists. The possible modulation of any opiate-GnRH interaction by estrogen, and the mediation of progesterone feedback effects by endogenous opiates will be examined. Finally, the existence of a GnRH-independent neural regulation of gonadotropin release will be investigated by means of push-pull trans-perfusion system. These studies will provide a substantial amount of new information pertinent to several long-standing questions regarding hypothalamic-pituitary-gonadal relationships. A greater knowledge of the neuroendocrine regulation of GnRH release should enhance the prospects of devising contraceptive methods based upon perturbations of hypothalamic/hypophysial function, and aid in treatment of reproductive endocrinopathies, such as hypothalamic amenorrhea.
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