DESCRIPTION (provided by applicant): We have found evidence for familial aggregation of hyperandrogenemia in sisters and brothers of PCOS probands. There are two reproductive phenotypes in affected sisters: classic PCOS (anovulation and hyperandrogenemia) and hyperandrogenemia with regular menstrual cycles (designated the HA phenotype). We plan the following studies to investigate the genetic basis of PCOS. In Aim 1 we will test the hypothesis that there is familial aggregation of hyperandrogenemia and other potential intermediate phenotypes in PCOS families by more than doubling the number of families that we extensively phenotype (~ 400 families to date). We will also have the unique opportunity to perform biochemical reproductive phenotyping in Amish women with low parity and other features of PCOS. In Aim 2 we will test the hypothesis that insulin sensitivity determines the reproductive phenotype in HA and PCOS women by experimentally altering insulin sensitivity. In Aim 3 we will define the male phenotype in PCOS families. It is our hypothesis that hyperandrogenemia in the sisters of PCOS probands is due to a genetic defect in ovarian and adrenal steroidogenesis and that elevations of the adrenal androgen dehydroepiandrosterone sulfate (DHEAS) may reflect the same defect in affected male relatives. We will determine whether abnormalities in adrenal or testicular androgen biosynthesis can be unmasked with provocative testing in the brothers of PCOS probands. In Specific Aim 4 we will test for phenotypic differences corresponding to allelic variation at genes (including genetic markers) where we find linkage and/or association with PCOS. For example, our preliminary data suggest that PCOS women who are homozygous or heterozygous for allele 8 of the marker D19S884 are less glucose-tolerant, less fertile, and have higher DHEAS levels than PCOS women without this allele. We will also determine whether carriers of allele 8 have any differences in responses to interventions planned in Aim 2. These studies are a model for the type of phenotype-genotype studies that we plan to conduct for any new potential marker loci that we identify.
|Effective start/end date||1/10/01 → 30/09/02|
- National Institute of Child Health and Human Development
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