Journal of Clinical Endocrinology & Metabolism, Vol 81, 3299-3306, Copyright © 1996 by Endocrine Society

ARTICLES

The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome

A Dunaif, D Scott, D Finegood, B Quintana and R Whitcomb
Department of Medicine, Pennsylvania State University College of Medicine, Hershey 17033, USA. adunaif@med.hmc.psu.edu

We performed this study to investigate the hypothesis that insulin resistance plays a role in the pathogenesis of reproductive abnormalities in women with the polycystic ovary syndrome (PCOS). Twenty-five women with PCOS were enrolled in a double-blind randomized 3-month trial of two doses of the insulin-sensitizing agent, troglitazone, 21 of whom completed the study: 200 mg, n = 10; 400 mg, n = 11. Baseline hormonal parameters and glucose tolerance were compared with 12 age- and weight-matched ovulatory control women. There were no significant changes in body mass index during the study. Fasting (P < 0.01) and 2-h post-75-g glucose load insulin levels (P < 0.05), as well as integrated insulin responses to the glucose load, decreased (P < 0.05), and insulin sensitivity assessed by a frequently sampled iv glucose tolerance test increased significantly (P < 0.001) during troglitazone treatment. This was accompanied by significant decreases in the levels of nonsex hormone-binding globulin-bound testosterone (P < 0.01), dehydroepiandrosterone sulfate (P < 0.001), estradiol (P < 0.01), and estrone (P < 0.001). Stepwise regression analysis indicated that decreases in nonsex hormone-binding globulin testosterone levels were significantly correlated with decreases in integrated insulin responses to the glucose load (r2 0.44, P < 0.01). The only significant changes at the 200-mg troglitazone dose were an increase in insulin sensitivity (P < 0.05) and decreases in dehydro-epiandrosterone sulfate (P < 0.01) and estrone (P < 0.05) levels. At the 400-mg dose, in addition to the changes noted in the entire troglitazone treatment group, increases in the disposition index (the product of insulin sensitivity and secretion) achieved significance, as did decreases in androstenedione (P < 0.01) and LH (P < 0.05) levels and increases in sex hormone-binding globulin levels (P < 0.01). Two PCOS women had ovulatory menses. We conclude that 1) troglitazone improves total body insulin action in PCOS, resulting in lower circulating insulin levels; 2) insulin resistance, probably via hyperinsulinemia, results in a general augmentation of steroidogenesis and LH release in PCOS; and 3) insulin-sensitizing agents, such as troglitazone, may provide a novel therapy for PCOS.

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				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]

				R. A. Lobo and E. Carmina The Importance of Diagnosing the Polycystic Ovary Syndrome Ann Intern Med, June 20, 2000; 132(12): 989 - 993. [Abstract] [Full Text] [PDF]

				B. Imani, M. J. C. Eijkemans, F. H. de Jong, N. N. Payne, P. Bouchard, L. C. Giudice, and B. C. J. M. Fauser Free Androgen Index and Leptin Are the Most Prominent Endocrine Predictors of Ovarian Response during Clomiphene Citrate Induction of Ovulation in Normogonadotropic Oligoamenorrheic Infertility J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 676 - 682. [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]

				A. la Marca, T. O. Egbe, G. Morgante, T. Paglia, A. Ciani, and V. De Leo Metformin treatment reduces ovarian cytochrome P-450c17{alpha} response to human chorionic gonadotrophin in women with insulin resistance-related polycystic ovary syndrome Hum. Reprod., January 1, 2000; 15(1): 21 - 23. [Abstract] [Full Text] [PDF]

				R.D. Murray, R.M. Davison, R.C. Russell, and G.S. Conway Clinical presentation of PCOS following development of an insulinoma: Case Report Hum. Reprod., January 1, 2000; 15(1): 86 - 88. [Abstract] [Full Text] [PDF]

				Taylor Genetically Defined Forms of Diabetes in Children J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4390 - 4396. [Full Text]

				L. Ciotta, V. De Leo, F. Galvani, A. La Marca, and A. Cianci Endocrine and metabolic effects of octreotide, a somatostatin analogue, in lean PCOS patients with either hyperinsulinaemia or lean normoinsulinaemia Hum. Reprod., December 1, 1999; 14(12): 2951 - 2958. [Abstract] [Full Text] [PDF]

				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]

				S. Lemieux, G. F. Lewis, A. Ben-Chetrit, G. Steiner, and E. M. Greenblatt Correction of Hyperandrogenemia by Laparoscopic Ovarian Cautery in Women with Polycystic Ovarian Syndrome Is Not Accompanied by Improved Insulin Sensitivity or Lipid-Lipoprotein Levels J. Clin. Endocrinol. Metab., November 1, 1999; 84(11): 4278 - 4282. [Abstract] [Full Text]

				M.F.M. Mitwally, N.K. Kuscu, and T.M. Yalcinkaya High ovulatory rates with use of troglitazone in clomiphene-resistant women with polycystic ovary syndrome Hum. Reprod., November 1, 1999; 14(11): 2700 - 2703. [Abstract] [Full Text] [PDF]

				C.-B. Book and A. Dunaif Selective Insulin Resistance in the Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., September 1, 1999; 84(9): 3110 - 3116. [Abstract] [Full Text]

				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]

				M. Urbanek, R. S. Legro, D. A. Driscoll, R. Azziz, D. A. Ehrmann, R. J. Norman, J. F. Strauss III, R. S. Spielman, and A. Dunaif Thirty-seven candidate genes for polycystic ovary syndrome: Strongest evidence for linkage is with follistatin PNAS, July 20, 1999; 96(15): 8573 - 8578. [Abstract] [Full Text] [PDF]

				J. F. Strauss III and A. Dunaif Molecular Mysteries of Polycystic Ovary Syndrome Mol. Endocrinol., June 1, 1999; 13(6): 800 - 805. [Full Text]

				M. Nagamani, C. Osuampke, and M. E. Kelver Increased Bioactive Luteinizing Hormone Levels and Bio/Immuno Ratio in Women with Hyperthecosis of the Ovaries: Possible Role of Hyperinsulinemia J. Clin. Endocrinol. Metab., May 1, 1999; 84(5): 1685 - 1689. [Abstract] [Full Text]

				J. E. Nestler, D. J. Jakubowicz, P. Reamer, R. D. Gunn, and G. Allan Ovulatory and Metabolic Effects of d-Chiro-Inositol in the Polycystic Ovary Syndrome N. Engl. J. Med., April 29, 1999; 340(17): 1314 - 1320. [Abstract] [Full Text] [PDF]

				E. Carmina, F. Gonzalez, A. Vidali, F.Z. Stanczyk, M. Ferin, and R.A. Lobo The contributions of oestrogen and growth factors to increased adrenal androgen secretion in polycystic ovary syndrome Hum. Reprod., February 1, 1999; 14(2): 307 - 311. [Abstract] [Full Text] [PDF]

				R. S. Legro, A. R. Kunselman, W. C. Dodson, and A. Dunaif Prevalence and Predictors of Risk for Type 2 Diabetes Mellitus and Impaired Glucose Tolerance in Polycystic Ovary Syndrome: A Prospective, Controlled Study in 254 Affected Women J. Clin. Endocrinol. Metab., January 1, 1999; 84(1): 165 - 169. [Abstract] [Full Text]

				R. S. Legro, D. Driscoll, J. F. Strauss III, J. Fox, and A. Dunaif Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome PNAS, December 8, 1998; 95(25): 14956 - 14960. [Abstract] [Full Text] [PDF]

				G. Forti and C. Krausz Evaluation and Treatment of the Infertile Couple J. Clin. Endocrinol. Metab., December 1, 1998; 83(12): 4177 - 4188. [Full Text]

				S. Gasic, Y. Bodenburg, M. Nagamani, A. Green, and R. J. Urban Troglitazone Inhibits Progesterone Production in Porcine Granulosa Cells Endocrinology, December 1, 1998; 139(12): 4962 - 4966. [Abstract] [Full Text] [PDF]

				D. S. Willis, H. Watson, H. D. Mason, R. Galea, M. Brincat, and S. Franks Premature Response to Luteinizing Hormone of Granulosa Cells from Anovulatory Women with Polycystic Ovary Syndrome: Relevance to Mechanism of Anovulation J. Clin. Endocrinol. Metab., November 1, 1998; 83(11): 3984 - 3991. [Abstract] [Full Text]

				R. S. Legro, D. Finegood, and A. Dunaif A Fasting Glucose to Insulin Ratio Is a Useful Measure of Insulin Sensitivity in Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., August 1, 1998; 83(8): 2694 - 2698. [Abstract] [Full Text]

				N. Moghrabi, I. A. Hughes, A. Dunaif, and S. Andersson Deleterious Missense Mutations and Silent Polymorphism in the Human 17{beta}-Hydroxysteroid Dehydrogenase 3 Gene (HSD17B3) J. Clin. Endocrinol. Metab., August 1, 1998; 83(8): 2855 - 2860. [Abstract] [Full Text]

				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]