DECREASES IN OVARIAN CYTOCHROME P450C17-ALPHA ACTIVITY AND SERUM-FREETESTOSTERONE AFTER REDUCTION OF INSULIN-SECRETION IN POLYCYSTIC-OVARY-SYNDROME

Background Insulin resistance and increased ovarian cytochrome P450c17 alpha activity are both features of the polycystic ovary syndrome. P4 50c17 alpha, which is involved in androgen biosynthesis, has both 17 a lpha-hydroxylase and 17,20-lyase activities. Increased activity of thi s enzyme results in exaggerated conversion of progesterone to 17 alpha -hydroxyprogesterone in response to stimulation by gonadotropin. We hy pothesized that hyperinsulinemia stimulates ovarian P450c17 alpha acti vity. Methods We measured serum steroid concentrations during fasting and the response of serum 17 alpha-hydroxyprogesterone to leuprolide, a gonadotropin-releasing hormone agonist, and performed oral glucose-t olerance tests before and after oral administration of either metformi n (500 mg three times daily) or placebo for four to eight weeks in 24 obese women with the polycystic ovary syndrome. Results In the 11 wome n given metformin, the mean (+/-SE) area under the serum insulin curve after oral glucose administration decreased from 9303+/-1603 to 4982/-911 mu U per milliliter per minute (56+/-10 to 30+/-6 nmol per liter per minute) (P = 0.004). This decrease was associated with a reductio n in the basal serum 17 alpha-hydroxyprogesterone concentration from 1 35+/-21 to 66+/-7 ng per deciliter (4.1+/-0.6 to 2.0+/-0.2 nmol per li ter) (P = 0.01) and a reduction in the leuprolide-stimulated peak seru m 17 alpha-hydroxyprogesterone concentration from 455+/-54 to 281+/-52 ng per deciliter (13.7+/-1.6 to 8.5+/-1.6 nmol per liter) (P = 0.01), The serum 17 alpha-hydroxyprogesterone va rues increased slightly in the placebo group. In the metformin group, the basal serum luteinizing hormone concentration decreased from 8.5+/-2.2 to 2.8+/-0.5 mlU per m illiliter (P = 0.01), the serum free testosterone concentration decrea sed from 0.34+/-0.07 to 0.19+/-0.05 ng per deciliter (12+/-3 to 7+/-2 pmol per liter) (P = 0.009), and the serum sex hormone-binding globuli n concentration increased from 0.8+/-0.2 to 2.3+/-0.6 mu g per decilit er (29+/-7 to 80+/-21 nmol per liter) (P < 0.001). None of these value s changed significantly in the placebo group. Conclusions In obese wom en with the polycystic ovary syndrome, decreasing serum insulin concen trations with metformin reduces ovarian cytochrome P450c17 alpha activ ity and ameliorates hyperandrogenism. (C) 1996, Massachusetts Medical Society.