Sexual development of the mammalian species is a complex process involving the dynamic interaction of multiple control mechanisms. For example, while much is understood about the resultant action of gonadal gonadotropin secretion, little is known about the role of additional controlling factors (such as the endogenous opioid peptide [EOP] system). Utilizing several recently developed techniques, we plan to study the interrelationships of mammalian sexual development and the hypothalamic EOP system. To this end, we will: I. Undertake a series of clinical studies employing a moderately rigorous sample collection paradigm, together with analytic techniques including computer-assisted pulse detection algorithms and deconvolution mechanics (to identify and characterize secretory events), to: (a) evaluate the opiate receptor blockade on gonadotropin secretion during both the day and night in normal boys at different stages of puberty; (b) assess the effects of androgen administration to prepubertal boys on the development of a hypothalamic opioid peptide control system as reflected by alterations gonadotropin secretion following opiate antagonism; and (c) evaluate the effects of opiate receptor blockade on gonadotropin release in normal pubertal boys during the administration of an anti-androgen (flutamide). II. Undertake a series of basic science studies using the technique of in situ hybridization histochemistry to document gonadal steroid- and androgen receptor-dependent variations in hypothalamic proopiomelanocortin gene expression of: (a) normal male and androgen receptor-deficient rats at different stages of pubertal development; and (b) normal male rats prior to and after castration, and also following specific sex hormone replacement. These studies will greatly enhance the understanding of the dynamic interplay in sexual development of gonadal steroid hormones and hypothalamic opioid peptides, and the resultant effect of their combined actions on the GnRH generator.
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