Genetics of ovarian disorders: Polycystic ovary syndrome

Polycystic ovary syndrome is a common and complex endocrine disorder of uncertain aetiology but there is clear evidence for a major genetic component. Studies to date have employed a candidate gene approach but few have been sufficiently powered to provide conclusive evidence for inclusion or exclusion of any one gene. There is evidence, from both clinical and in vitro studies of human ovarian theca cells, of dysregulation of the rate-limiting enzyme in androgen biosynthesis, cytochrome P450c17alpha, which catalyzes both 17-hydroxylase and 17-20 lyase activities. Initial data suggested that alleles of CYP17, the gene encoding P450c17alpha, were associated with PCOS but these findings have not been supported by results of subsequent studies. CYP11a, encoding cholesterol side chain cleavage appears to be a more likely locus for aetiology of hyperandrogenism in women with PCO but the finding that the expression of other enzymes in the androgen biosynthetic pathway is also upregulated suggests that this may not be the only focus for genetic abnormalities of steroidogenesis. A number of candidate genes have been proposed to explain the metabolic abnormalities of PCOS. Thus far, the most robust evidence favours the insulin gene VNTR as a significant susceptibility locus but even these findings have applied to relatively small data sets. Other proposed candidates, for which there is at least preliminary supporting evidence, include a locus near to the insulin receptor gene on chromosome 19 and the genes coding for insulin receptor substrates 1 and 2. A unifying hypothesis is suggested to account for the heterogeneity of polycystic ovary syndrome. It is suggested that the primary abnormality is a genetically determined ovarian abnormality which results in hypersecretion of androgens and this in turn predisposes to abnormal LH secretion, insulin resistance and anovulation. Other genes and environmental factors, especially nutrition, interact with this primary process and influence the clinical and biochemical phenotype.