The broad goal of this competing renewal application is to examine the physiology and pathophysiology of the reproductive system in the human male by combining the in vivo clinical models of normal men, GnRH deficient men undergoing longterm GnrH replacement, and men with reproductive disorders with the latest in vitro techniques such as monoclonal antibody technology, radioreceptor assays, and molecular biology. Monoclonal antibodies quite specific for the measurement of the free alpha subunit (FAS) of the gonadotropins will be used to define the physiologic regulation of FAS secretion and excretion. Since this surrogate marker of endogenous GnRH secretion can be monitored via its urinary excretion, its role as a non-invasive marker of the neuroendocrine integrity of GnRH secretion across normal sexual development and disorders of sexual maturation in males merits definition. Using newly developed radioreceptor assays (RRAs) for measurement of LH and FSH, the ratio between these receptor-based determinations and the dimer- specific sandwich assays for the gonadotropins is usually near unity (i.e. the RRA/RIA ration = 1) in normal men. However, in discrete subsets of men with hypogonadism in the face of elevated gonadotropins by RIAs, we have now been identified 2 separate types of abnormalities, high and low RRA/RIA ratios. Using PCR amplification, a family with low RRA/RIA ratios have been documented to have a point mutation in the LH beta gene. Using immunoprecipitation, the subjects with elevated RRA/RIA have been discovered to have circulating gonadotropin receptor binding competitors. The realization that hypergonadotropic hypogonadism is not always indicative of primary gonadal pathology may well have important therapeutic implications. the scope and import of both of these groups of abnormalities will be defined further. Finally, methodologic stumbling blocks still remain to the accurate measurement of inhibin in the circulation of the human. Using a newly- designed, beta/alpha sandwich assay and techniques to block inhibin binding to proteins, specific measurements of inhibin will now be possible and the physiology of dimeric inhibin as well as that of its alpha subunit can now be ...