The proposed U54 Center at the University of Virginia will have a major goal of promoting translational research leading to application of new basic findings to clinical application. The Center theme is Clinical and Basic Studies in Polycystic Ovarian Syndrome (PCOS). This topic is appropriate to the goals of the Cooperative Centers Program, in that present therapeutic approaches to the anovulation and metabolic abnormalities in the disorder are of limited efficacy, and importantly, the basic mechanisms underlying PCOS remain uncertain. Current hypotheses as to of the etiology of PCOS center on regulation of GnRH secretion and action, and/or disordered ovarian function, either primary in nature or consequent to abnormal stimulation by gonadotropins or co-gonadotropins such as insulin and IGF-1. The U54 Center proposes 1 clinical project, 1 clinical pilot project, and 2 related basic projects to investigate these areas. Project I addresses abnormalities (testosterone induced resistance to progesterone action) in the regulation of the GnRH pulse generator in normal and obese adolescent girls and is directly related to basic studies in Projects II, modulation of GnRH-Gonadotrope responses - steroid-metabolic interactions, and Project III on steroid-metabolic interactions in the control of GnRH neurons. The pilot project is a clinical project addressing factors determining obesity-associated hyperandrogenemia in peripubertal girls. The Center subprojects are supported by two Cores proposed to operate under an open access formula. Overall integration of the research will be performed by the Administration Core, and specific laboratory services will be available to U54 projects and to eligible funded RSB program relevant projects through the Ligand Assay and Analysis Core, the latter having been designated a national resource by the RSB. The proposed U54 Center will build on the productive collegial atmosphere of the existing U54 Center at the University of Virginia and allow clinical and basic investigation of factors in the etiology of a common disorder of women during the reproductive years. The linking of basic and clinical projects will allow rapid transfer of basic information to clinical application, with the overall goal of enhancing our abilities to predict the disorder in adolescents and to enhance therapeutic approaches to PCOS with a resultant improvement in health for some 6-8% of women in the U.S.