Hyperandrogenism and Insulin Resistance in the Ontogeny of PCOS

Polycystic Ovary Syndrome (PCOS), which is the most common endocrinopathy in women, presents clinically with anovulatory infertility. In girls, premature pubarche may be the earliest sign of PCOS. Many women with PCOS and girls with premature pubarche are also insulin resistant, a phenotypic characteristic common to both conditions. Familial clustering appears to be a feature of PCOS and our previous work has demonstrated that hyperandrogenism and insulin resistance are transmissible traits, We hypothesize that daughters of women with PCOS are likely to develop hyperandrogenism in mid puberty, exacerbated by hyperinsulinemia, and that transmission of a candidate allele on Chromosome 19 predicts risk. We propose a case/control longitudinal study of girls of women with PCOS compared to girls of women without PCOS, carefully matched for pubertal stage. We will phenotype these girls for abnormalities associated with PCOS and follow them through later pubertal stages. We present compelling preliminary data supporting our hypotheses and the feasibility of these studies. Further, the ontogeny of these abnormalities in the pubertal transition provides insight into the contributions of insulin resistance and hyperandrogenemia to the etiology of the syndrome, that will be further tested by a double blind randomized controlled trial of metformin in girls with premature pubarche. These studies are intended to provide a basis for identifying girls likely to develop PCOS and anovulatory infertility and to enable development of preventive strategies. Our specific aims are: to examine androgen status in daughters of women with PCOS and its temporal relation to hyperinsulinemia, to document the effects of insulin sensitization on improvement in hyperandrogenism and hyperinsulinemia in girls with premature pubarche, and to examine the predictive ability of genetic markers on the development of PCOS and response to metformin. These studies are important to several key goals of the U54 Reproductive Center mission including: 1) the etiology, pathophysiology, and prevention of female infertility due to PCOS, with particular emphasis on those conditions that are genetically based, and 2) the use of genomics to develop novel, non-invasive diagnostics for reproductive diseases and disorder