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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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J. Clin. Endocrinol. Metab.Home page
R. Azziz, D. Ehrmann, R. S. Legro, R. W. Whitcomb, R. Hanley, A. G. Fereshetian, M. O’Keefe, and M. N. Ghazzi
Troglitazone Improves Ovulation and Hirsutism in the Polycystic Ovary Syndrome: A Multicenter, Double Blind, Placebo-Controlled Trial
J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1626 - 1632.
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J. Clin. Endocrinol. Metab.Home page
R. B. Fogel, A. Malhotra, G. Pillar, S. D. Pittman, A. Dunaif, and D. P. White
Increased Prevalence of Obstructive Sleep Apnea Syndrome in Obese Women with Polycystic Ovary Syndrome
J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1175 - 1180.
[Abstract] [Full Text]


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J. Clin. Endocrinol. Metab.Home page
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.
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J. Clin. Endocrinol. Metab.Home page
A. N. Vgontzas, R. S. Legro, E. O. Bixler, A. Grayev, A. Kales, and G. P. Chrousos
Polycystic Ovary Syndrome Is Associated with Obstructive Sleep Apnea and Daytime Sleepiness: Role of Insulin Resistance
J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 517 - 520.
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J. Clin. Endocrinol. Metab.Home page
J. D. Veldhuis, S. M. Pincus, M. C. Garcia-Rudaz, M. G. Ropelato, M. E. Escobar, and M. Barontini
Disruption of the Joint Synchrony of Luteinizing Hormone, Testosterone, and Androstenedione Secretion in Adolescents with Polycystic Ovarian Syndrome
J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 72 - 79.
[Abstract] [Full Text]


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J. Clin. Endocrinol. Metab.Home page
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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Clin. DiabetesHome page
D. M. Karl
Case Study: A 36-Year-Old Woman With Type 2 Diabetes and Pregnancy
Clin. Diabetes, January 1, 2001; 19(1): 24 - 25.
[Full Text]


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Endocr. Rev.Home page
S. Matthaei, M. Stumvoll, M. Kellerer, and H.-U. Häring
Pathophysiology and Pharmacological Treatment of Insulin Resistance
Endocr. Rev., December 1, 2000; 21(6): 585 - 618.
[Abstract] [Full Text]


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Endocr. Rev.Home page
L. Ibáñez, J. DiMartino-Nardi, N. Potau, and P. Saenger
Premature Adrenarche--Normal Variant or Forerunner of Adult Disease?
Endocr. Rev., December 1, 2000; 21(6): 671 - 696.
[Abstract] [Full Text]


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J. Clin. Endocrinol. Metab.Home page
H. F. Escobar-Morreale, B. Roldán, R. Barrio, M. Alonso, J. Sancho, H. de la Calle, and R. GarcÍa-Robles
High Prevalence of the Polycystic Ovary Syndrome and Hirsutism in Women with Type 1 Diabetes Mellitus
J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4182 - 4187.
[Abstract] [Full Text]


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J. Clin. Endocrinol. Metab.Home page
L. Ibáñez, C. Valls, N. Potau, M. V. Marcos, and F. de Zegher
Sensitization to Insulin in Adolescent Girls to Normalize Hirsutism, Hyperandrogenism, Oligomenorrhea, Dyslipidemia, and Hyperinsulinism after Precocious Pubarche
J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3526 - 3530.
[Abstract] [Full Text]


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J. Clin. Endocrinol. Metab.Home page
A. Mifsud, S. Ramirez, and E. L. Yong
Androgen Receptor Gene CAG Trinucleotide Repeats in Anovulatory Infertility and Polycystic Ovaries
J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3484 - 3488.
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Endocr. Rev.Home page
D. Deplewski and R. L. Rosenfield
Role of Hormones in Pilosebaceous Unit Development
Endocr. Rev., August 1, 2000; 21(4): 363 - 392.
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J. Clin. Endocrinol. Metab.Home page
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]


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ANN INTERN MEDHome page
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]


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J. Clin. Endocrinol. Metab.Home page
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]


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J. Clin. Endocrinol. Metab.Home page
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]


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Hum ReprodHome page
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]


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


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Hum ReprodHome page
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]


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Hum ReprodHome page
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]


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J. Clin. Endocrinol. Metab.Home page
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]


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Hum ReprodHome page
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]


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J. Clin. Endocrinol. Metab.Home page
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.
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Endocr. Rev.Home page
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]


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Proc. Natl. Acad. Sci. USAHome page
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]


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


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NEJMHome page
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]


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Hum ReprodHome page
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.
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J. Clin. Endocrinol. Metab.Home page
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.
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Proc. Natl. Acad. Sci. USAHome page
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.
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J. Clin. Endocrinol. Metab.Home page
G. Forti and C. Krausz
Evaluation and Treatment of the Infertile Couple
J. Clin. Endocrinol. Metab., December 1, 1998; 83(12): 4177 - 4188.
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EndocrinologyHome page
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]


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J. Clin. Endocrinol. Metab.Home page
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]


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J. Clin. Endocrinol. Metab.Home page
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]


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J. Clin. Endocrinol. Metab.Home page
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]


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BMJHome page
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.
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