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Previous Volume 335:617-623 August 29, 1996 Number 9 Next

Decreases in Ovarian Cytochrome P450c17 Activity and Serum Free Testosterone after Reduction of Insulin Secretion in Polycystic Ovary Syndrome

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ABSTRACT

Background Insulin resistance and increased ovarian cytochrome P450c17 activity are both features of the polycystic ovary syndrome. P450c17, which is involved in androgen biosynthesis, has both 17-hydroxylase and 17,20-lyase activities. Increased activity of this enzyme results in exaggerated conversion of progesterone to 17-hydroxyprogesterone in response to stimulation by gonadotropin. We hypothesized that hyperinsulinemia stimulates ovarian P450c17 activity.

Methods We measured serum steroid concentrations during fasting and the response of serum 17-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 17-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 17-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-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<0.001). None of these values changed significantly in the placebo group.

Conclusions In obese women with the polycystic ovary syndrome, decreasing serum insulin concentrations with metformin reduces ovarian cytochrome P450c17 activity and ameliorates hyperandrogenism.

Source Information

From the Departments of Internal Medicine, Obstetrics and Gynecology, and Pharmacology and Toxicology, Division of Endocrinology and Metabolism, Medical College of Virginia, Virginia Commonwealth University, Richmond (J.E.N.); and the Department of Internal Medicine, Hospital de Clinicas Caracas, Caracas, Venezuela (D.J.J.).

Address reprint requests to Dr. Nestler at the Medical College of Virginia, P.O. Box 980111, Richmond, VA 23298-0111.

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