BACKGROUND
Insulin resistance and increased ovarian cytochrome P450c17α activity are both features of the polycystic ovary syndrome. P450c17α, which is involved in androgen biosynthesis, has both 17α-hydroxylase and 17,20-lyase activities. Increased activity of this enzyme results in exaggerated conversion of progesterone to 17α-hydroxyprogesterone in response to stimulation by gonadotropin. We hypothesized that hyperinsulinemia stimulates ovarian P450c17α activity. METHODS
We measured serum steroid concentrations during fasting and the response of serum 17α-hydroxyprogesterone to leuprolide, a gonadotropin-releasing hormone agonist, and performed oral glucose-tolerance tests before and after oral administration of either metformin (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 women given metformin, the mean (±SE) area under the serum insulin curve after oral glucose administration decreased from 9303±1603 to 4982±911 μU per milliliter per minute (56±10 to 30±6 nmol per liter per minute) (P = 0.004). This decrease was associated with a reduction in the basal serum 17α-hydroxyprogesterone concentration from 135±21 to 66±7 ng per deciliter (4.1±0.6 to 2.0±0.2 nmol per liter) (P = 0.01) and a reduction in the leuprolide-stimulated peak serum 17α-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 17α-hydroxyprogesterone values 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 milliliter (P = 0.01), the serum free testosterone concentration decreased 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 globulin concentration increased from 0.8±0.2 to 2.3±0.6 μg per deciliter (29±7 to 80±21 nmol per liter) (P CONCLUSIONS
In obese women with the polycystic ovary syndrome, decreasing serum insulin concentrations with metformin reduces ovarian cytochrome P450c17α activity and ameliorates hyperandrogenism
