Gene, Intrauterine Environment and PCOS

Northwestern University, Evanston IL

Investigators

Linked publications & trials

Abstract

Polycystic ovary syndrome (PCOS) is among the most common endocrine disorders in premenopausal women. Women with PCOS have profound insulin resistance as well as pancreatic beta-cell dysfunction, independent of obesity and glucose intolerance. However, skeletal muscle insulin resistance reverse in cultured myotubes suggesting that insulin resistance in this tissue is induced by factors in the in vivo environment. We have recently shown that hyperandrogenemia is the reproductive phenotype in males as well as female relatives of PCOS women. Moreover, Urbanek and colleagues have shown (Project 2) that this phenotype appears to have a genetic basis in PCOS families and shows significant linkage and association with a marker locus on chromosome 19P in the region of the insulin receptor (allele 8 of D19S884). We now have extremely existing evidence that this allele is also associated with a metabolic phenotype in PCOS probands and their brothers: increased post-challenge glucose levels, apparent defects in insulin secretion, especially in response to sulfonylurea, and accelerated weight gain with age. Abbott (Project 3) has shown that in utero testosterone excess can reproduce many features of the PCOS reproductive and metabolic phenotype in female rhesus monkeys, including decreased insulin secretion and increased LH levels. Levine (Project 4) has shown that one mechanism for these changes is androgen-mediated sulfonylurea-stimulated insulin secretion by the pancreatic beta cells. Taken together, these observations have led to a new hypothesis for the etiology of PCOS: genetic variation resulting in hyperandrogenemia results in many of the reproductive and metabolic features of PCOS by fetal androgen programming. In this Project, we will test two components of the hypothesis. First, is the metabolic phenotype that is associated with the marker locus decreased insulin secretion, consistent with androgen-mediated suppression of K+/ATP channels? Second, is there in utero androgen excess, decreased fetal insulin secretion and/or intrauterine growth retardation (IUGR) in the female offspring of PCOS women, and does the marker allele identify a subpopulation of offspring with these findings?