Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17α activity and serum androgens

It is unknown whether hyperinsulinemia plays a role in the pathogenesis of polycystic ovary syndrome (PCOS) in normal weight or thin women. Evidence indicates that these women are insulin resistant and hyperinsulinemic, and this study was conducted to test the hypothesis that hyperinsulinemia stimulates ovarian cytochrome P450c17 alpha activity in nonobese women with PCOS, thereby increasing serum androgen concentrations. We assessed ovarian P450c17 alpha activity (by measuring the response of 17 alpha-hydroxyprogesterone to a GnRH agonist), fasting serum steroids, and oral glucose tolerance before and after oral administration of either metformin (500 mg) or placebo three times daily for 4-6 weeks in 31 nonobese women with PCOS. In the 19 women given metformin, the mean (+/-SE) area under the serum insulin curve after oral glucose administration decreased from 44 +/- 5 to 24 +/- 3 nmol/L.min (P = 0.003). Basal serum 17 alpha-hydroxyprogesterone decreased from 3.4 +/- 0.3 to 2.5 +/- 0.4 nmol/L (P = 0.05), and GnRH-stimulated peak serum 17 alpha-hydroxyprogesterone decreased from 12.2 +/- 1.6 to 7.5 +/- 0.7 nmol/L (P = 0.005). Serum 17 alpha-hydroxyprogesterone values did not change in the placebo group. In the metformin group, serum free testosterone decreased by 70% from 18.2 +/- 3.1 to 5.5 +/- 0.7 pmol/L (P < 0.001), and serum sex hormone-binding globulin increased from 84 +/- 6 to 134 +/- 15 nmol/L (P = 0.002). None of these values changed in the placebo group. These findings suggest that hyperinsulinemia stimulates ovarian P450c17 alpha activity in nonobese women with PCOS. They also indicate that decreasing serum insulin with metformin reduces ovarian cytochrome P450c17 alpha activity and ameliorates the hyperandrogenism of these women.