Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome

Our preliminary family studies have suggested that some female first-degree relatives of women with polycystic ovary syndrome (PCOS) have hyperandroge nemia per se. It was our hypothesis that this may be a genetic trait and th us could represent a phenotype suitable for linkage analysis. To investigat e this hypothesis, we examined 115 sisters of 80 probands with PCOS from un related families. PCOS was diagnosed by the combination of elevated serum a ndrogen levels and less than or equal to 6 menses per year with the exclusi on of secondary causes. The sisters were compared with 70 healthy age- and weight-comparable control women with regular menses, no clinical evidence o f hyperandrogenemia, and normal glucose tolerance. Twenty-two percent of th e sisters fulfilled diagnostic criteria for PCOS. In addition, 24% of the s isters had hyperandrogenemia and regular menstrual cycles. Circulating test osterone (T) and nonsex hormone-binding globulin-bound testosterone (uT) le vels in both of these groups of sisters were significantly increased compar ed with unaffected sisters and control women (P < 0.0001 for both T and uT) . Probands, sisters with PCOS, and hyperandrogenemic sisters had elevated s erum luteinizing hormone levels compared with control women. We conclude th at there is familial aggregation of hyperandrogenemia (with or without olig omenorrhea) in PCOS kindreds. In affected sisters, only one-half have oligo menorrhea and hyperandrogenemia characteristic of PCOS, whereas the remaini ng one-half have hyperandrogenemia per se. This familial aggregation of hyp erandrogenemia in PCOS kindreds suggests that it is a genetic trait. We pro pose that hyperandrogenemia be used to assign affected status in Linkage st udies designed to identify PCOS genes.