The proposed U54 Center at the University of Virginia has a major goal of promoting translational research leading to clinical application of novel basic findings. The Center theme is Clinical and Basic Studies in Polycystic Ovarian Syndrome (PCOS), with a focus on the etiology of the hypothalamic abnormalities in pre- adult models. The etiology of PCOS remains uncertain, but involves abnormal regulation of GnRH secretion and disordered ovarian function, either primary or consequent upon continuous stimulation by gonadotropins and/or cogonadotropins. Our focus is specifically to elucidate the mechanisms by which excess androgens, prior to maturation, modify estradiol and progesterone regulation of the firing frequency of the hypothalamic GnRH pulse generator. Hyperandrogenemia (HA) is common in obese girls, with some 65-70% having an elevated free testosterone (T) in plasma. Adolescent HA is a recognized precursor of PCOS in adults. Thus we propose to assess the sources and effects of elevated T on sex steroid feedback in girls, on suppression of hypothalamic steroid receptor feedback mechanisms in primates, and on the evolution of the GnRH neuronal network in young rodents. The Outreach Core aims to enhance physical activity in overweight girls, through educational programs for adolescents in the community, enhancing their understanding of how exercise reduces obesity and decreases the risks of long-term metabolic complications. The three Projects are supported by two Cores proposed to operate in an open access format. The Administrative Core oversees overall integration of the research and provides fiscal and billing support to the Ligand Assay Core. Ligand Assay Core services will be available to all approved Fertility & Infertility Branch (FIB) projects and will continue t function as a national resource to the FIB. The proposed U54 Center will build on prior productive, collegial interactions with Dr. S. Moenter (U Michigan) and Dr. J. Levine (U Wisconsin). The clinical and basic projects are closely linked and use optimum models to investigate the mechanisms of steroid regulation of GnRH secretion and development of the GnRH neuronal network in maturing animals. This linking 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 enhance therapeutic approaches to PCOS at an earlier age, with resultant improvement in health for some 6-8% of women in the U.S.
PCOS affects 6-8% of women of reproductive age and is of uncertain etiology. PCOS first manifests during puberty with hyperandrogenemia, later infertility and is associated with obesity, the metabolic syndrome and increased risk of diabetes mellitus. We aim to identify the mechanisms underlying abnormal regulation of GnRH secretion, with a goal of early identification and application of effective therapies. The Outreach Core aims to enhance understanding and modify behavior to reverse the negative effects of obesity in young girls.
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