The overall goal of this project is to examine the regulation and roles of pulsatile GnRH secretion in human beings: a) throughout sexual maturation, and b) in the maintenance of normal cyclical ovulation. All of the proposed studies are directed toward the unifying hypothesis that the ability to secrete GnRH at a """"""""fast"""""""" approximately circhoral, or """"""""faster"""""""" frequency throughout the day develops during puberty, and that the ability to change the frequency and amplitude of pulsatile GnRH secretion is critical for cyclical ovarian follicular maturation and ovulation. This hypothesis will be approached in several ways. Specifically we plan 1) detailed evaluation of the sleep-entrained patterns of GnRH and sex steroid (T and E2) secretion in normal and hypogonadal children; 2) examination of the acute effects of sex steroids, either via stimulation by pulsatile GnRH, intravenous infusion, or transcutaneous absorption, on the sleep- entrained patterns of GnRH secretion in pubertal boys and men; 3) examination of the role of endogenous opioids, via opioid receptor blockade in the sex steroid regulation of GnRH secretion in pubertal boys and normal men; 4) examination of the role of E2 in regulating GnRH pulse frequency throughout the transition from luteal to follicular stages of the menstrual cycle; 5) examination of the hypothesis that polycystic ovarian disease (PCO) results from fast frequency GnRH secretion, and evaluation of the effects of E2 and P in slowing GnRH secretion and inducing ovulation; and 6) examination of the role of excess hypothalamic opioid activity in the slow frequency GnRH secretion in hypothalamic amenorrhea, and evaluation of naltrexone in inducing ovulation. The principal approaches to these objectives will include: a) indirect assessment of GnRH secretion via detailed assessment of the secretory patterns of immunoreactive LH; b) assessment of the acute effects of sex steroid infusion on the sleep- entrained increase in gonadotropin secretion in pubertal boys; c) opioid receptor blockade via nalaxone or naltrexone to investigate the role(s) of endogenous opioids in gonadotropin regulation; d) administration of physiological amounts of E2 and P to normal women and women with PCO to test the hypothesis that PCO syndrome is the result of excess hypothalamic pulsatile secretion of GnRH, and e) evaluation of the effects of dexamethasone on LH secretion in patients who have hypothalamic amenorrhea but who are unresponsive to opioid blockade. Normal adult men and women, and adults and children with suspected or proven hypothalamic/pituitary dysfunction will participate in detailed protocols performed in the Clinical Research Center. Well established radioimmunoassays will be used for serial hormone determinations, and objective computer analyses will be used for determination of pulsatile secretory patterns. These studies should provide a more thorough understanding of the physiology of human reproduction and should lead to more rational therapies for patients with precocious or delayed maturation. Moreover, the possibilities that anovulation can also result from fast frequency GnRH secretion (or an inability to slow GnRH secretion) will be examined and the results may lead to novel, physiological approaches to ovulation induction in these patients.
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