This competing renewal application proposes to continue our investigations into the neuroendocrine-gonadal control of puberty in the human employing 2 clinical models. The first model, children with centrally-mediated precocious puberty, represent a population of 120 subjects whom we have been following for the past 6 years prior to and following suppression of their gonadal steroid secretion by administration of a long-acting LHRH agonist. During prolonged LHRHa administration, these subjects sustain a prepubertal gonadal steroid milieu for several years during an otherwise normal childhood and thus permit examination of several previously unaddressable hypotheses relating to a basic understanding of the determinants of growth and maturation during puberty in the human. The second model, men with idiopathic hypogonadotropic hypogonadism (IHH), have a selective deficiency of LHRH secretion and thus remain prepubertal into adult life. During the long-term administration of pulsatile LHRH, these subjects permit their hypothalamic replacement therapy to be controlled experimentally and thus represent a valuable complement to the CPP patients. Utilizing these 2 models, we plan to investigate: a) the impact of activation of the reproductive axis upon the growth axis by examining the effect of LHRH upon GH secretion and the effect of sex steroids upon GH and SmC secretion; b) alpha subunit secretion as a corroborating and perhaps more sensitive marker of LHRH secretion; c) the ontogeny of free alpha subunit and inhibin secretion across sexual development; and d) the time course and metabolic consequences of adrenarche during suppression of gonadarche. Using a combination of these models, it should be possible to provide further insights into the neuroendocrine and gonadal control of sexual development in the human.
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