The overall goal of this project is to test the hypothesis that gonadotropin-releasing hormone (GnRH) pulse frequency plays a regulatory role(s) in human sexual maturation and in particular, in the maintenance of normal menstrual cyclicity. We propose that the ability to secrete GnRH at a """"""""fast"""""""" (approximately circhoral or faster) frequency is acquired during puberty and that the ability to maintain a """"""""fast"""""""" frequency is necessary for normal functioning of the adult reproductive system. This hypothesis will be approached in several ways. Specifically, we plan 1) to perform a detailed assessment of the neuroendocrine regulation of GnRH secretion during human puberty; 2) to assess whether altered (decreased) frequency of GnRH secretion plays a role in the pathogenesis of idiopathic oligospermia; and 3) to assess the role of altered GnRH pulse frequency in the maintenance of normal menstrual cycles and in the anovulation associated with hypothalamic amenorrhea and hyperprolactinemia. The principal approaches to these objectives will include: a) indirect assessment of GnRH secretion via detailed assessment of the secretory patterns of immunoreactive and bioactive LH and the Alpha-subunit; b) assessment of the acute effects of sex steroid infusion on the sleep-entrained increase in gonadotropin secretion in pubertal children; c) opiate receptor blockade via naloxone or naltrexone to investigate the role(s) of endogenous opiates in gonadotropin regulation throughout human puberty and in amenorrheic women and oligospermic men; d) longitudinal assessment of sex steroid feedback during human puberty; e) assessment of the effects of clonidine, a putative Alpha 2 agonist, on gonadotropin secretion in women with hypothalamic amenorrhea; f) examining the role of prolactin in the regulation of GnRH pulse frequency in hyperprolactinemic women and in normal women (via metoclopramide administration); g) pulsatile i.v. administration of synthetic GnRH at several frequencies but at dosages which mimic pituitary portal concentrations; and h) determining the specific feedback roles of estradiol and progesterone throughput the menstrual cycle. 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 and in vitro bioassays will be used for serial hormone determinations. These studies should provide a more thorough understanding of the physiology of human reproduction and should lead to more rational therapies for children with precocious or delayed maturation and for adults with hypogonadotropic hypogonadism and infertility.
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