Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone 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. P450c17 alpha, which is involved in androgen biosynthesis, has both 17 alpha-hydroxylase and 17,20-lyase activities. Increased activity of this enzyme results in exaggerated conversion of progesterone to 17 alpha-hydroxyprogesterone in response to stimulation by gonadotrophin. We hypothesized that hyperinsulinemia stimulates ovarian P450c17 alpha activity.


METHODS
We measured fasting serum steroid concentrations and the response of serum 17 alpha-hydroxyprogesterone to leuprolide, a gonadotrophin-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 microU 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 alpha-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 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 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 microgram 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 alpha activity and ameliorates hyperandrogenism.
Nestler
J E
JE
Department of Internal Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298-0111, USA.
Jakubowicz
D J
DJ
D019326:17-alpha-Hydroxyprogesterone; D000293:Adolescent; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D005260:Female; D006801:Humans; D006908:Hydroxyprogesterones / Q000097:blood; D017588:Hyperandrogenism / Q000150:complications / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000097:blood / Q000502:physiology*; D016729:Leuprolide / Q000494:pharmacology; D007986:Luteinizing Hormone / Q000097:blood; D008687:Metformin / Q000494:pharmacology; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D011085:Polycystic Ovary Syndrome / Q000150:complications / Q000201:enzymology* / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism*; D013739:Testosterone / Q000097:blood
D001786:Blood Glucose; D006908:Hydroxyprogesterones; D007004:Hypoglycemic Agents; D007328:Insulin; D013739:Testosterone; D019326:17-alpha-Hydroxyprogesterone; D007986:Luteinizing Hormone; D008687:Metformin; D013254:Steroid 17-alpha-Hydroxylase; D016729:Leuprolide