Endocrine Abstracts

PCOS is a complex genetic disease resulting from the interplay between susceptibility genes and environmental factors. The syndrome is characterized by hyperandrogenism, disordered gonadotropin secretion, profound insulin resistance and, frequently, obesity. It is a leading risk factor for type 2 diabetes mellitus and MBS in adolescent and young adult women. In PCOS, MBS risk increases with increasing androgen levels, independent of insulin resistance and obesity, and antagonizing androgen action ameliorates features of MBS. Obese premenarchal girls have elevated androgen levels. Hyperandrogenemia is the major reproductive phenotype in families of women with PCOS, including mothers and brothers. First-degree relatives also have metabolic phenotypes, including MBS. We have now mapped a genetic variant conferring PCOS susceptibility to an allele of a dinucleotide repeat in an intron of the fibrillin-3 gene on chromosome 19p13.2 that is both linked and associated with the reproductive phenotype. Further, the PCOS susceptibility allele is associated with metabolic phenotypes in women with PCOS and their first-degree relatives. These observations suggest that the cardinal reproductive defect in PCOS, hyperandrogenemia, itself contributes to metabolic risk. In utero testosterone excess can reproduce features of the PCOS reproductive and metabolic phenotypes in rodents, sheep and non-human primates. We propose that hyperandrogenemia resulting from variation in a gene(s) regulating steroidogenesis causes many of reproductive and metabolic features of PCOS by programming actions at critical periods of development as well as by ongoing actions in the adult. Additional environmental factors, such as obesity, modify these phenotypes.