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Activity and Serum Androgens1
Departments of Internal Medicine, Obstetrics and Gynecology, and Pharmacology and Toxicology (J.E.N.), Division of Endocrinology and Metabolism, Medical College of Virginia/Virginia Commonwealth University, Richmond, Virginia 23298; and Department of Internal Medicine, Hospital de Clinicas Caracas (D.J.J.), Caracas, Venezuela
Address all correspondence and requests for reprints to: John E. Nestler, M.D., Medical College of Virginia, P.O. Box 980111, Richmond, Virginia 23298-0111. E-mail: nestler{at}gems.vcu.edu
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
activity
in nonobese women with PCOS, thereby increasing serum androgen
concentrations.
We assessed ovarian P450c17 activity (by measuring the response of
17-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-hydroxyprogesterone decreased from 3.4
± 0.3 to 2.5 ± 0.4 nmol/L (P = 0.05), and
GnRH-stimulated peak serum 17-hydroxyprogesterone decreased from
12.2 ± 1.6 to 7.5 ± 0.7 nmol/L (P =
0.005). Serum 17-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 activity in nonobese women with PCOS. They also indicate
that decreasing serum insulin with metformin reduces ovarian cytochrome
P450c17 activity and ameliorates the hyperandrogenism of these
women.
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L. A. Stadtmauer, B. C. Wong, and S. Oehninger Should patients with polycystic ovary syndrome be treated with metformin?: Benefits of insulin sensitizing drugs in polycystic ovary syndrome--beyond ovulation induction Hum. Reprod., December 1, 2002; 17(12): 3016 - 3026. [Abstract] [Full Text] [PDF]
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R. Homburg Should patients with polycystic ovarian syndrome be treated with metformin?: A note of cautious optimism Hum. Reprod., April 1, 2002; 17(4): 853 - 856. [Abstract] [Full Text] [PDF]
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D. J. Jakubowicz, M. J. Iuorno, S. Jakubowicz, K. A. Roberts, and J. E. Nestler Effects of Metformin on Early Pregnancy Loss in the Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 524 - 529. [Abstract] [Full Text] [PDF]
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R. M. Koivunen, L. C. Morin-Papunen, A. Ruokonen, J. S. Tapanainen, and H. K. Martikainen Ovarian steroidogenic response to human chorionic gonadotrophin in obese women with polycystic ovary syndrome: effect of metformin Hum. Reprod., December 1, 2001; 16(12): 2546 - 2551. [Abstract] [Full Text] [PDF]
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E. H. Y. Ng, N. M. S. Wat, and P. C. Ho Effects of metformin on ovulation rate, hormonal and metabolic profiles in women with clomiphene-resistant polycystic ovaries: a randomized, double-blinded placebo-controlled trial Hum. Reprod., August 1, 2001; 16(8): 1625 - 1631. [Abstract] [Full Text] [PDF]
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D. J. Jakubowicz, M. Seppälä, S. Jakubowicz, O. Rodriguez-Armas, A. Rivas-Santiago, H. Koistinen, R. Koistinen, and J. E. Nestler Insulin Reduction with Metformin Increases Luteal Phase Serum Glycodelin and Insulin-Like Growth Factor-Binding Protein 1 Concentrations and Enhances Uterine Vascularity and Blood Flow in the Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1126 - 1133. [Abstract] [Full Text]
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A. J. Jakimiuk, S. R. Weitsman, A. Navab, and D. A. Magoffin Luteinizing Hormone Receptor, Steroidogenesis Acute Regulatory Protein, and Steroidogenic Enzyme Messenger Ribonucleic Acids Are Overexpressed in Thecal and Granulosa Cells from Polycystic Ovaries J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1318 - 1323. [Abstract] [Full Text]
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J. E. Nestler Metformin and the Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1430 - 1430. [Full Text]
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H. E. Lebovitz, J. F. Dole, R. Patwardhan, E. B. Rappaport, and M. I. Freed Rosiglitazone Monotherapy Is Effective in Patients with Type 2 Diabetes J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 280 - 288. [Abstract] [Full Text]
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