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Troglitazone Improves Defects in Insulin Action, Insulin Secretion, Ovarian Steroidogenesis, and Fibrinolysis in Women with Polycystic Ovary Syndrome¹

Departments of Medicine (D.A.E., M.K.C., J.I., R.L.R., K.S.P.) and Pediatrics (R.L.R.), University of Chicago, Chicago, Illinois 60637; and the Department of Medicine (D.J.S., B.E.S.), University of Vermont, Burlington, Vermont 00000

Address all correspondence and requests for reprints to: David A. Ehrmann, M.D., Department of Medicine, Section of Endocrinology, University of Chicago Pritzker School of Medicine, 5841 South Maryland Avenue, MC 1027, Chicago, Illinois 60637. E-mail: dehrmann{at}medicine.bsd.uchicago.edu

Abstract

Women with polycystic ovary syndrome (PCOS) are characterized by defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis. We administered the insulin-sensitizing agent troglitazone to 13 obese women with PCOS and impaired glucose tolerance to determine whether attenuation of hyperinsulinemia ameliorates these defects. All subjects had oligomenorrhea, hirsutism, polycystic ovaries, and hyperandrogenemia. Before and after treatment with troglitazone (400 mg daily for 12 weeks), all had 1) a GnRH agonist (leuprolide) test, 2) a 75-g oral glucose tolerance test, 3) a frequently sampled iv glucose tolerance test to determine the insulin sensitivity index and the acute insulin response to glucose, 4) an oscillatory glucose infusion to assess the ability of the ß-cell to entrain to glucose as quantitated by the normalized spectral power for the insulin secretion rate, and 5) measures of fibrinolytic capacity [plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator].

There was no change in body mass index (39.9 ± 1.4 vs. 40.2 ± 1.4 kg/m²) or body fat distribution after treatment. Both the fasting (91 ± 3 vs. 103 ± 3 mg/dL; P < 0.001) and 2 h (146 ± 8 vs. 171 ± 6 mg/dL; P < 0.02) plasma glucose concentrations during the oral glucose tolerance test declined significantly. There was a concordant reduction in glycosylated hemoglobin to 5.7 ± 0.1 from a pretreatment level of 6.1 ± 0.1% (P < 0.03). Insulin sensitivity increased from 0.58 ± 0.14 to 0.95 ± 0.26 10^-5 min^-1/pmol·L (P < 0.01) after treatment as did the disposition index (745 ± 135 vs. 381 ± 96; P < 0.05). The ability of the ß-cell to appropriately detect and respond to an oscillatory glucose infusion improved significantly after troglitazone treatment; the normalized spectral power for the insulin secretion rate increased to 5.9 ± 1.1 from 4.3 ± 0.8 (P < 0.05). Basal levels of total testosterone (109.3 ± 15.2 vs. 79.4 ± 9.8 ng/dL; P < 0.05) and free testosterone (33.3 ± 4.0 vs. 21.2 ± 2.6 pg/mL; P < 0.01) declined significantly after troglitazone treatment. Leuprolide-stimulated levels of 17-hydroxyprogesterone, androstenedione, and total testosterone were significantly lower posttreatment compared to pretreatment. The reduction in androgen levels occurred independently of any changes in gonadotropin levels. A decreased functional activity of PAI-1 in blood (from 12.7 ± 2.8 to 6.3 ± 1.4 AU/mL P < 0.05) was associated with a decreased concentration of PAI-1 protein (from 64.9 ± 9.1 to 44.8 ± 6.1 ng/mL; P < 0.05). No change in the functional activity of tissue plasminogen activator (from 5.3 ± 0.4 to 5.1 ± 0.5 IU/mL) was observed despite a decrease in its concentration (from 9.6 ± 0.9 to 8.2 ± 0.7 ng/mL; P < 0.05). The marked reduction in PAI-1 could be expected to improve the fibrinolytic response to thrombosis in these subjects.

We conclude that administration of troglitazone to women with PCOS and impaired glucose tolerance ameliorates the metabolic and hormonal derangements characteristic of the syndrome. Troglitazone holds potential as a useful primary or adjunctive treatment for women with PCOS.

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				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]

				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]

				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]

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

				S. B. Seminara, J. E. Hall, A. E. Taylor, W. F. Crowley Jr., and K. A. Martin The Reproductive Endocrine Associates of the Massachusetts General Hospital: Fifteen Years of Integrated Clinical Practice and Investigation J. Clin. Endocrinol. Metab., June 1, 1999; 84(6): 1912 - 1918. [Full Text]

				B. E. Sobel Increased Plasminogen Activator Inhibitor-1 and Vasculopathy : A Reconcilable Paradox Circulation, May 18, 1999; 99(19): 2496 - 2498. [Full Text] [PDF]

				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]

				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]

				L. S. Liu, H. Tanaka, S. Ishii, and J. Eckel The New Antidiabetic Drug MCC-555 Acutely Sensitizes Insulin Signaling in Isolated Cardiomyocytes Endocrinology, November 1, 1998; 139(11): 4531 - 4539. [Abstract] [Full Text] [PDF]

				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]

				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]

				J. E. Nestler, D. J. Jakubowicz, W. S. Evans, and R. Pasquali Effects of Metformin on Spontaneous and Clomiphene-Induced Ovulation in the Polycystic Ovary Syndrome N. Engl. J. Med., June 25, 1998; 338(26): 1876 - 1880. [Abstract] [Full Text] [PDF]

				B. E. Sobel, J. Woodcock-Mitchell, D. J. Schneider, R. E. Holt, K. Marutsuka, and H. Gold Increased Plasminogen Activator Inhibitor Type 1 in Coronary Artery Atherectomy Specimens From Type 2 Diabetic Compared With Nondiabetic Patients : A Potential Factor Predisposing to Thrombosis and Its Persistence Circulation, June 9, 1998; 97(22): 2213 - 2221. [Abstract] [Full Text] [PDF]

				M. Guido, V. Pavone, M. Ciampelli, F. Murgia, A. M. Fulghesu, R. Apa, A. Caruso, S. Mancuso, and A. Lanzone Involvement of Ovarian Steroids in the Opioid-Mediated Reduction of Insulin Secretion in Hyperinsulinemic Patients with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., May 1, 1998; 83(5): 1742 - 1745. [Abstract] [Full Text]

				D. J. Loskutoff and F. Samad The Adipocyte and Hemostatic Balance in Obesity : Studies of PAI-1 Arterioscler. Thromb. Vasc. Biol., January 1, 1998; 18(1): 1 - 6. [Full Text] [PDF]

				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]

				T. L. Daniels and S. L. Berga Resistance of Gonadotropin Releasing Hormone Drive to Sex Steroid-Induced Suppression in Hyperandrogenic Anovulation J. Clin. Endocrinol. Metab., December 1, 1997; 82(12): 4179 - 4183. [Abstract] [Full Text] [PDF]

				A. Arroyo, G. A. Laughlin, A. J. Morales, and S. S. C. Yen Inappropriate Gonadotropin Secretion in Polycystic Ovary Syndrome: Influence of Adiposity J. Clin. Endocrinol. Metab., November 1, 1997; 82(11): 3728 - 3733. [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]

				E. Mueller, M. Smith, P. Sarraf, T. Kroll, A. Aiyer, D. S. Kaufman, W. Oh, G. Demetri, W. D. Figg, X.-P. Zhou, et al. Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer PNAS, September 26, 2000; 97(20): 10990 - 10995. [Abstract] [Full Text] [PDF]