Journal of Clinical Endocrinology & Metabolism, Vol 80, 2057-2062, Copyright © 1995 by Endocrine Society

ARTICLES

Effects of diet and metformin administration on sex hormone-binding globulin, androgens, and insulin in hirsute and obese women

JC Crave, S Fimbel, H Lejeune, N Cugnardey, H Dechaud and M Pugeat
Hospices Civils de Lyon, Laboratoire de la Clinique Endocrinologique, Hopital de l'Antiquaille, France.

Evidence suggests that hyperinsulinemic insulin resistance may increase serum levels of ovarian androgens and reduce sex hormone-binding globulin (SHBG) levels in humans. The present study was conducted to assess the effect of administration of the biguanide metformin, a drug commonly used in the treatment of diabetes mellitus, on androgen and insulin levels in 24 hirsute patients. The patients selected for the study were obese, with a body mass index higher than 25 kg/m2 and high fasting insulin (> 90 pmol/L) and low SHBG levels (< 30 nmol/L). All patients were given a low calorie diet (1500 Cal/day) and randomized for either metformin administration at a dose of 850 mg or a placebo, twice daily for 4 months, in a double blind study. In the placebo group, diet resulted in a significant decrease in body mass index (30.8 +/- 1.0 vs. 32.7 +/- 1.5 kg/m2; P < 0.0001), fasting insulin (127 +/- 11 vs. 156 +/- 14 pmol/L; P < 0.01), non-SHBG-bound testosterone (0.19 +/- 0.02 vs. 0.28 +/- 0.03 nmol/L; P < 0.02), androstenedione (5.8 +/- 0.5 vs. 9.0 +/- 1.1 nmol/L; P < 0.03), and 3 alpha-diolglucuronide (8.6 +/- 1.1 vs. 11.7 +/- 1.9; P < 0.005) plasma concentrations and a significant increase in the glucose/insulin ratio (0.047 +/- 0.005 vs. 0.035 +/- 0.003; P < 0.001) and plasma concentrations of SHBG (26.0 +/- 3.3 vs. 19.1 +/- 1.9 nmol/L; P < 0.001) and dehydroepiandrosterone sulfate (8.7 +/- 1.5 vs. 8.4 +/- 1.3; P < 0.05). Beneficial effects of diet were not significantly different in the patients who were given metformin instead of placebo. These results confirm that weight loss induced by a low calorie diet is effective in improving hyperinsulinemia and hyperandrogenism in obese and hirsute women. With our study design, metformin administration had no additional benefit over the effect of diet.

This article has been cited by other articles:

				K. Elkind-Hirsch, O. Marrioneaux, M. Bhushan, D. Vernor, and R. Bhushan Comparison of Single and Combined Treatment with Exenatide and Metformin on Menstrual Cyclicity in Overweight Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2670 - 2678. [Abstract] [Full Text] [PDF]

				A. Gambineri, L. Patton, A. Vaccina, M. Cacciari, A. M. Morselli-Labate, C. Cavazza, U. Pagotto, and R. Pasquali Treatment with Flutamide, Metformin, and Their Combination Added to a Hypocaloric Diet in Overweight-Obese Women with Polycystic Ovary Syndrome: A Randomized, 12-Month, Placebo-Controlled Study J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 3970 - 3980. [Abstract] [Full Text] [PDF]

				T. Tang, J. Glanville, C. J. Hayden, D. White, J. H. Barth, and A. H. Balen Combined lifestyle modification and metformin in obese patients with polycystic ovary syndrome. A randomized, placebo-controlled, double-blind multicentre study Hum. Reprod., January 1, 2006; 21(1): 80 - 89. [Abstract] [Full Text] [PDF]

				H. F. Escobar-Morreale, J. I. Botella-Carretero, F. Alvarez-Blasco, J. Sancho, and J. L. San Millan The Polycystic Ovary Syndrome Associated with Morbid Obesity May Resolve after Weight Loss Induced by Bariatric Surgery J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6364 - 6369. [Abstract] [Full Text] [PDF]

				G. Onalan, B. Selam, Y. Baran, M. Cincik, R. Onalan, U. Gunduz, A. U. Ural, and R. Pabuccu Serum and follicular fluid levels of soluble Fas, soluble Fas ligand and apoptosis of luteinized granulosa cells in PCOS patients undergoing IVF Hum. Reprod., September 1, 2005; 20(9): 2391 - 2395. [Abstract] [Full Text] [PDF]

				L. R. Harborne, N. Sattar, J. E. Norman, and R. Fleming Metformin and Weight Loss in Obese Women with Polycystic Ovary Syndrome: Comparison of Doses J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4593 - 4598. [Abstract] [Full Text] [PDF]

				M.A. Checa, A. Requena, C. Salvador, R. Tur, J. Callejo, J.J. Espinos, F. Fabregues, J. Herrero, and (Reproductive Endocrinology Interest Group of the Insulin-sensitizing agents: use in pregnancy and as therapy in polycystic ovary syndrome Hum. Reprod. Update, July 1, 2005; 11(4): 375 - 390. [Abstract] [Full Text] [PDF]

				D. Ertunc, E.C. Tok, A. Aktas, E.M. Erdal, and S. Dilek The importance of IRS-1 Gly972Arg polymorphism in evaluating the response to metformin treatment in polycystic ovary syndrome Hum. Reprod., May 1, 2005; 20(5): 1207 - 1212. [Abstract] [Full Text] [PDF]

				R. V. Mehta, K. S. Patel, M. S. Coffler, M. H. Dahan, R. Y. Yoo, J. S. Archer, P. J. Malcom, and R. J. Chang Luteinizing Hormone Secretion Is Not Influenced by Insulin Infusion in Women with Polycystic Ovary Syndrome Despite Improved Insulin Sensitivity during Pioglitazone Treatment J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2136 - 2141. [Abstract] [Full Text] [PDF]

				E. B. Kilicdag, T. Bagis, H. B. Zeyneloglu, E. Tarim, E. Aslan, B. Haydardedeoglu, and S. Erkanli Homocysteine levels in women with polycystic ovary syndrome treated with metformin versus rosiglitazone: a randomized study Hum. Reprod., April 1, 2005; 20(4): 894 - 899. [Abstract] [Full Text] [PDF]

				D. A. Ehrmann Polycystic Ovary Syndrome N. Engl. J. Med., March 24, 2005; 352(12): 1223 - 1236. [Full Text] [PDF]

				P. MUTI The Role of Endogenous Hormones in the Etiology and Prevention of Breast Cancer: The Epidemiological Evidence Ann. N.Y. Acad. Sci., December 1, 2004; 1028(1): 273 - 282. [Abstract] [Full Text] [PDF]

				J. E. Swain, R. L. Dunn, D. McConnell, J. Gonzalez-Martinez, and G. D. Smith Direct Effects of Leptin on Mouse Reproductive Function: Regulation of Follicular, Oocyte, and Embryo Development Biol Reprod, November 1, 2004; 71(5): 1446 - 1452. [Abstract] [Full Text] [PDF]

				E. DIAMANTI-KANDARAKIS and H. A. KANDARAKIS Conservative Management of Gynecologic Diseases: Insulin Sensitizing Agents in Polycystic Ovary Syndrome Ann. N.Y. Acad. Sci., November 1, 2003; 997(1): 322 - 329. [Abstract] [Full Text] [PDF]

				L. Harborne, R. Fleming, H. Lyall, N. Sattar, and J. Norman Metformin or Antiandrogen in the Treatment of Hirsutism in Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4116 - 4123. [Abstract] [Full Text] [PDF]

				D. Romualdi, M. Guido, M. Ciampelli, M. Giuliani, F. Leoni, C. Perri, and A. Lanzone Selective effects of pioglitazone on insulin and androgen abnormalities in normo- and hyperinsulinaemic obese patients with polycystic ovary syndrome Hum. Reprod., June 1, 2003; 18(6): 1210 - 1218. [Abstract] [Full Text] [PDF]

				L. Morin-Papunen, I. Vauhkonen, R. Koivunen, A. Ruokonen, H. Martikainen, and J. S. Tapanainen Metformin Versus Ethinyl Estradiol-Cyproterone Acetate in the Treatment of Nonobese Women with Polycystic Ovary Syndrome: A Randomized Study J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 148 - 156. [Abstract] [Full Text] [PDF]

				R. Kaaks, A. Lukanova, and M. S. Kurzer Obesity, Endogenous Hormones, and Endometrial Cancer Risk: A Synthetic Review Cancer Epidemiol. Biomarkers Prev., December 1, 2002; 11(12): 1531 - 1543. [Abstract] [Full Text] [PDF]

				U. Pagotto, A. Gambineri, V. Vicennati, M. L. Heiman, M. Tschop, and R. Pasquali Plasma Ghrelin, Obesity, and the Polycystic Ovary Syndrome: Correlation with Insulin Resistance and Androgen Levels J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5625 - 5629. [Abstract] [Full Text] [PDF]

				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]

				R. Murray Recognizing the Signs of Metabolic Syndrome and Polycystic Ovary Syndrome in a Caucasian Adolescent Girl: Differentiating Type 2 From Type 1 Diabetes Diabetes Spectr, October 1, 2002; 15(4): 227 - 231. [Full Text] [PDF]

				E. Seli and A. J. Duleba Should patients with polycystic ovarian syndrome be treated with metformin? Hum. Reprod., September 1, 2002; 17(9): 2230 - 2236. [Abstract] [Full Text] [PDF]

				K. Elter, G. Imir, and F. Durmusoglu Clinical, endocrine and metabolic effects of metformin added to ethinyl estradiol-cyproterone acetate in non-obese women with polycystic ovarian syndrome: a randomized controlled study Hum. Reprod., July 1, 2002; 17(7): 1729 - 1737. [Abstract] [Full Text] [PDF]

				R. KAAKS and A. LUKANOVA Effects of Weight Control and Physical Activity in Cancer Prevention: Role of Endogenous Hormone Metabolism Ann. N.Y. Acad. Sci., June 1, 2002; 963(1): 268 - 281. [Abstract] [Full Text] [PDF]

				M. Wolf, L. Sandler, K. Munoz, K. Hsu, J. L. Ecker, and R. Thadhani First Trimester Insulin Resistance and Subsequent Preeclampsia: A Prospective Study J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1563 - 1568. [Abstract] [Full Text] [PDF]

				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]

				R. T. Chlebowski, E. Aiello, and A. McTiernan Weight Loss in Breast Cancer Patient Management J. Clin. Oncol., February 15, 2002; 20(4): 1128 - 1143. [Abstract] [Full Text] [PDF]

				H. Yarali, B. O. Yildiz, A. Demirol, H. B. Zeyneloglu, N. Yigit, O. Bukulmez, and Z. Koray Co-administration of metformin during rFSH treatment in patients with clomiphene citrate-resistant polycystic ovarian syndrome: a prospective randomized trial Hum. Reprod., February 1, 2002; 17(2): 289 - 294. [Abstract] [Full Text] [PDF]

				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]

				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]

				F. Berrino, C. Bellati, G. Secreto, E. Camerini, V. Pala, S. Panico, G. Allegro, and R. Kaaks Reducing Bioavailable Sex Hormones through a Comprehensive Change in Diet: the Diet and Androgens (DIANA) Randomized Trial Cancer Epidemiol. Biomarkers Prev., January 1, 2001; 10(1): 25 - 33. [Abstract] [Full Text]

				L. C. Morin-Papunen, I. Vauhkonen, R. M. Koivunen, A. Ruokonen, H. K. Martikainen, and J. S. Tapanainen Endocrine and Metabolic Effects of Metformin Versus Ethinyl Estradiol-Cyproterone Acetate in Obese Women with Polycystic Ovary Syndrome: A Randomized Study J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3161 - 3168. [Abstract] [Full Text]

				R. Pasquali, A. Gambineri, D. Biscotti, V. Vicennati, L. Gagliardi, D. Colitta, S. Fiorini, G. E. Cognigni, M. Filicori, and A. M. Morselli-Labate Effect of Long-Term Treatment with Metformin Added to Hypocaloric Diet on Body Composition, Fat Distribution, and Androgen and Insulin Levels in Abdominally Obese Women with and without the Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., August 1, 2000; 85(8): 2767 - 2774. [Abstract] [Full Text]

				P. Moghetti, R. Castello, C. Negri, F. Tosi, F. Perrone, M. Caputo, E. Zanolin, and M. Muggeo Metformin Effects on Clinical Features, Endocrine and Metabolic Profiles, and Insulin Sensitivity in Polycystic Ovary Syndrome: A Randomized, Double-Blind, Placebo-Controlled 6-Month Trial, followed by Open, Long-Term Clinical Evaluation J. Clin. Endocrinol. Metab., January 1, 2000; 85(1): 139 - 146. [Abstract] [Full Text]

				I.R. Pirwany, R.W.S. Yates, I.T. Cameron, and R. Fleming Effects of the insulin sensitizing drug metformin on ovarian function, follicular growth and ovulation rate in obese women with oligomenorrhoea Hum. Reprod., December 1, 1999; 14(12): 2963 - 2968. [Abstract] [Full Text] [PDF]

				L. Poretsky, N. A. Cataldo, Z. Rosenwaks, and L. C. Giudice The Insulin-Related Ovarian Regulatory System in Health and Disease Endocr. Rev., August 1, 1999; 20(4): 535 - 582. [Abstract] [Full Text] [PDF]

				Z. E C Hopkinson, N. Sattar, R. Fleming, and I. A Greer Fortnightly Review: Polycystic ovarian syndrome: the metabolic syndrome comes to gynaecology BMJ, August 1, 1998; 317(7154): 329 - 332. [Full Text]

				L. C. Morin-Papunen, R. M. Koivunen, C. Tomás, A. Ruokonen, and H. K. Martikainen Decreased Serum Leptin Concentrations during Metformin Therapy in Obese Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., July 1, 1998; 83(7): 2566 - 2568. [Abstract] [Full Text]

				P. Cousin, H. Déchaud, C. Grenot, H. Lejeune, M. Pugeat with the technical assistance of, C. Baret, and C. Brébant Human Variant Sex Hormone-Binding Globulin (SHBG) with an Additional Carbohydrate Chain Has a Reduced Clearance Rate in Rabbit J. Clin. Endocrinol. Metab., January 1, 1998; 83(1): 235 - 240. [Abstract] [Full Text]

				A. Dunaif Insulin Resistance and the Polycystic Ovary Syndrome: Mechanism and Implications for Pathogenesis Endocr. Rev., December 1, 1997; 18(6): 774 - 800. [Abstract] [Full Text]

				D. A. Ehrmann, M. K. Cavaghan, J. Imperial, J. Sturis, R. L. Rosenfield, and K. S. Polonsky Effects of Metformin on Insulin Secretion, Insulin Action, and Ovarian Steroidogenesis in Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., February 1, 1997; 82(2): 524 - 530. [Abstract] [Full Text] [PDF]

				J. E. Nestler and D. J. Jakubowicz Decreases in Ovarian Cytochrome P450c17{alpha} Activity and Serum Free Testosterone after Reduction of Insulin Secretion in Polycystic Ovary Syndrome N. Engl. J. Med., August 29, 1996; 335(9): 617 - 623. [Abstract] [Full Text] [PDF]

				W. Arlt, R. J. Auchus, and W. L. Miller Thiazolidinediones but Not Metformin Directly Inhibit the Steroidogenic Enzymes P450c17 and 3beta -Hydroxysteroid Dehydrogenase J. Biol. Chem., May 11, 2001; 276(20): 16767 - 16771. [Abstract] [Full Text] [PDF]