Expired CME Article

Insulin Resistance in Polycystic Ovarian Disease

Authors: Vishal Bhatia, MBBS, MD

Abstract

The classic polycystic ovarian syndrome (PCOS) was originally described by Stein and Leventhal as the association of amenorrhea with polycystic ovaries and, variably, hirsutism and/or obesity. It is estimated that 5 to 10% of women of reproductive age have PCOS. Although insulin resistance is not part of the diagnostic criteria for PCOS, its importance in the pathogenesis of PCOS cannot be denied. PCOS is associated with insulin resistance, independent of total or fat-free body mass. Postreceptor defects in the action of insulin have been described in PCOS that are similar to those found in obesity and type 2 diabetes. Treatment with insulin sensitizers, metformin, and thiazolidinediones (TZDs) improve both metabolic and hormonal patterns and also improve ovulation in PCOS. Recent studies have shown that women who have PCOS have higher circulating levels of inflammatory mediators such as C-reactive protein, tumor necrosis factor, tissue plasminogen activator, and plasminogen activator inhibitor-1 (PAI-1). It is possible that the beneficial effect of insulin sensitizers in PCOS may be partly due to a decrease in inflammation.


Key Points


* Polycystic ovarian syndrome involves anovulation and hyperandrogenism.


* Polycystic ovarian syndrome is associated with insulin resistance.


* Insulin sensitizers are promising agents for polycystic ovarian syndrome.


* Insulin sensitizers have not been approved by the Food and Drug Administration for polycystic ovarian syndrome.

This content is limited to qualifying members.

Existing members, please login first

If you have an existing account please login now to access this article or view purchase options.

Purchase only this article ($25)

Create a free account, then purchase this article to download or access it online for 24 hours.

Purchase an SMJ online subscription ($75)

Create a free account, then purchase a subscription to get complete access to all articles for a full year.

Purchase a membership plan (fees vary)

Premium members can access all articles plus recieve many more benefits. View all membership plans and benefit packages.

References

1. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensuson diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2003;81:19–25.
 
2. Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 1997;18:774–800.
 
3. Franks S. Polycystic ovary syndrome. N Engl J Med 1995;333:853–861.
 
4. Franks S, White DM. Prevalence of and etiological factors in polycystic ovarian syndrome. Ann N Y Acad Sci 1993;687:112–114.
 
5. Venturoli S, Porcu E, Fabbri R, et al. Episodic pulsatile secretion of FSH, LH, prolactin, oestradiol, oestrone, and LH circadian variations in polycystic ovary syndrome. Clin Endocrinol (Oxf) 1988;28:93–107.
 
6. Kletzky OA, Davajan V, Nakamura RM, et al. Clinical categorization of patients with secondary amenorrhea using progesterone-induced uterine bleeding and measurement of serum gonadotropin levels. Am J Obstet Gynecol 1975;121:695–703.
 
7. Rebar R, Judd HL, Yen SS, et al. Characterization of the inappropriate gonadotropin secretion in polycystic ovary syndrome. J Clin Invest 1976;57:1320–1329.
 
8. Waldstreicher J, Santoro NF, Hall JE, et al. Hyperfunction of the hypothalamic-pituitary axis in women with polycystic ovarian disease: indirect evidence for partial gonadotroph desensitization. J Clin Endocrinol Metab 1988;66:165–172.
 
9. Chang RJ, Mandel FP, Lu JK, Judd HL. Enhanced disparity of gonadotropin secretion by estrone in women with polycystic ovarian disease. J Clin Endocrinol Metab 1982;54:490–494.
 
10. Eagleson CA, Gingrich MB, Pastor CL, et al. Polycystic ovarian syndrome: evidence that flutamide restores sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone. J Clin Endocrinol Metab 2000;85:4047–4052.
 
11. Adashi EY, Hsueh AJ, Yen SS. Insulin enhancement of luteinizing hormone and follicle-stimulating hormone release by cultured pituitary cells. Endocrinology 1981;108:1441–1449.
 
12. Soldani R, Cagnacci A, Yen SS. Insulin, insulin-like growth factor I (IGF-I) and IGF-II enhance basal and gonadotrophin-releasing hormone-stimulated luteinizing hormone release from rat anterior pituitary cells in vitro. Eur J Endocrinol 1994;131:641–645.
 
13. Soldani R, Cagnacci A, Paoletti AM, et al. Modulation of anterior pituitary luteinizing hormone response to gonadotropin-releasing hormone by insulin-like growth factor I in vitro. Fertil Steril1995;64:634–637.
 
14. Dunaif A, Graf M. Insulin administration alters gonadal steroid metabolism independent of changes in gonadotropin secretion in insulin-resistant women with the polycystic ovary syndrome. J Clin Invest1989;83:23–29.
 
15. Nestler JE, Clore JN, Strauss 3rd JF, Blackard WG. The effects of hyperinsulinemia on serum testosterone, progesterone, dehydroepiandrosterone sulfate, and cortisol levels in normal women and in a woman with hyperandrogenism, insulin resistance, and acanthosis nigricans. J Clin Endocrinol Metab1987;64:180–184.
 
16. Dunaif A, Scott D, Finegood D, et al. The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metab1996;81:3299–3306.
 
17. Hasegawa I, Murakawa H, Suzuki M, et al. Effect of troglitazone on endocrine and ovulatory performance in women with insulin resistance-related polycystic ovary syndrome. Fertil Steril1999;71:323–327.
 
18. Velazquez E, Acosta A, Mendoza SG. Menstrual cyclicity after metformin therapy in polycystic ovary syndrome. Obstet Gynecol 1997;90:392–395.
 
19. Patel K, Coffler MS, Dahan MH, et al. Increased luteinizing hormone secretion in women with polycystic ovary syndrome is unaltered by prolonged insulin infusion. J Clin Endocrinol Metab2003;88:5456–5461.
 
20. Pasquali R, Casimirri F, Venturoli S, et al. Insulin resistance in patients with polycystic ovaries: its relationship to body weight and androgen levels. Acta Endocrinol (Copenh) 1983;104:110–116.
 
21. Dunaif A, Graf M, Mandeli J, et al. Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. J Clin Endocrinol Metab1987;65:499–507.
 
22. Mehta RV, Patel KS, Coffler MS, et al. 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 2005;90:2136–2141.
 
23. Arroyo A, Laughlin GA, Morales AJ, Yen SS. Inappropriate gonadotropin secretion in polycystic ovary syndrome: influence of adiposity. J Clin Endocrinol Metab 1997;82:3728–3733.
 
24. Mason HD, Margara R, Winston RM, et al. Insulin-like growth factor-I (IGF-I) inhibits production of IGF-binding protein-1 while stimulating estradiol secretion in granulosa cells from normal and polycystic human ovaries. J Clin Endocrinol Metab 1993;76:1275–1279.
 
25. Homburg R, Eshel A, Kilborn J, et al. Combined luteinizing hormone releasing hormone analogue and exogenous gonadotrophins for the treatment of infertility associated with polycystic ovaries. Hum Reprod 1990;5:32–35.
 
26. Scheele F, Hompes PG, van der Meer M, et al. The effects of a gonadotrophin-releasing hormone agonist on treatment with low dose follicle stimulating hormone in polycystic ovary syndrome. Hum Reprod 1993;8:699–704.
 
27. Yki-Jarvinen H, Makimattila S, Utriainen T, Rutanen EM. Portal insulin concentrations rather than insulin sensitivity regulate serum sex hormone-binding globulin and insulin-like growth factor binding protein 1 in vivo. J Clin Endocrinol Metab 1995;80:3227–3232.
 
28. Haffner SM, Karhapaa P, Mykkanen L, Laakso M. Insulin resistance, body fat distribution, and sex hormones in men. Diabetes 1994;43:212–219.
 
29. Laaksonen DE, Niskanen L, Punnonen K, et al. Sex hormones, inflammation and the metabolic syndrome: a population-based study. Eur J Endocrinol 2003;149:601–608.
 
30. l’Allemand D, Penhoat A, Lebrethon MC, et al. Insulin-like growth factors enhance steroidogenic enzyme and corticotropin receptor messenger ribonucleic acid levels and corticotropin steroidogenic responsiveness in cultured human adrenocortical cells. J Clin Endocrinol Metab 1996;81:3892–3897.
 
31. Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med 1999;340:115–126.
 
32. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002;105:1135–143.
 
33. Festa A, D’Agostino R Jr, Howard G, et al. Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation 2000;102:42–47.
 
34. Haffner SM, Mykkanen L, Festa A, et al. Insulin-resistant prediabetic subjects have more atherogenic risk factors than insulin-sensitive prediabetic subjects: implications for preventing coronary heart disease during the prediabetic state. Circulation 2000;101:975–980.
 
35. Gonzalez F, Thusu K, Abdel-Rahman E, et al. Elevated serum levels of tumor necrosis factor alpha in normal-weight women with polycystic ovary syndrome. Metabolism 1999;48:437–441.
 
36. Kelly CC, Lyall H, Petrie JR, et al. Low grade chronic inflammation in women with polycystic ovarian syndrome. J Clin Endocrinol Metab 2001;86:2453–2455.
 
37. Kelly CJ, Lyall H, Petrie JR, et al. A specific elevation in tissue plasminogen activator antigen in women with polycystic ovarian syndrome. J Clin Endocrinol Metab 2002;87:3287–3290.
 
38. Atiomo WU, Bates SA, Condon JE, et al. The plasminogen activator system in women with polycystic ovary syndrome. Fertil Steril 1998;69:236–241.
 
39. Atiomo WU, Fox R, Condon JE, et al. Raised plasminogen activator inhibitor-1 (PAI-1) is not an independent risk factor in the polycystic ovary syndrome (PCOS). Clin Endocrinol (Oxf) 2000;52:487–492.
 
40. Glueck CJ, Wang P, Fontaine RN, et al. Plasminogen activator inhibitor activity: an independent risk factor for the high miscarriage rate during pregnancy in women with polycystic ovary syndrome.Metabolism 1999;48:1589–1595.
 
41. Wild S, Pierpoint T, McKeigue P, Jacobs H. Cardiovascular disease in women with polycystic ovary syndrome at long-term follow-up: a retrospective cohort study. Clin Endocrinol (Oxf) 2000;52:595–600.
 
42. Aljada A, Garg R, Ghanim H, et al. Nuclear factor-kappaB suppressive and inhibitor-kappaB stimulatory effects of troglitazone in obese patients with type 2 diabetes: evidence of an antiinflammatory action? J Clin Endocrinol Metab 2001;86:3250–3256.
 
43. Ghanim H, Garg R, Aljada A, et al. Suppression of nuclear factor-kappaB and stimulation of inhibitor kappaB by troglitazone: evidence for an anti-inflammatory effect and a potential antiatherosclerotic effect in the obese. J Clin Endocrinol Metab 2001;86:1306–1312.
 
44. Garg R, Kumbkarni Y, Aljada A, et al. Troglitazone reduces reactive oxygen species generation by leukocytes and lipid peroxidation and improves flow-mediated vasodilatation in obese subjects.Hypertension 2000;36:430–435.
 
45. Parulkar AA, Pendergrass ML, Granda-Ayala R, et al. Nonhypoglycemic effects of thiazolidinediones. Ann Intern Med 2001;134:61–71.
 
46. Haffner SM, Greenberg AS, Weston WM, et al. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 2002;106:679–684.
 
47. Ehrmann DA, Schneider DJ, Sobel BE, et al. Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1997;82:2108–2116.
 
48. Paradisi G, Steinberg HO, Shepard MK, et al. Troglitazone therapy improves endothelial function to near normal levels in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003;88:576–580.
 
49. Morin-Papunen L, Rautio K, Ruokonen A, et al. Metformin reduces serum C-reactive protein levels in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003;88:4649–4654.
 
50. Velazquez EM, Mendoza SG, Wang P, Glueck CJ. Metformin therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoprotein(a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome. Metabolism 1997;46:454–457.
 
51. Burghen GA, Givens JR, Kitabchi AE. Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease. J Clin Endocrinol Metab 1980;50:113–116.
 
52. Legro RS, Kunselman AR, Dodson WC, Dunaif A. 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 1999;84:165–169.
 
53. Dahlgren E, Johansson S, Lindstedt G, et al. Women with polycystic ovary syndrome wedge resected in 1956 to 1965: a long-term follow-up focusing on natural history and circulating hormones.Fertil Steril 1992;57:505–513.
 
54. Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 1989;38:1165–1174.
 
55. Ehrmann DA, Sturis J, Byrne MM, et al. Insulin secretory defects in polycystic ovary syndrome: Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus. J Clin Invest 1995;96:520–527.
 
56. Dunaif A, Finegood DT. Beta-cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome. J Clin Endocrinol Metab 1996;81:942–947.
 
57. Peppard HR, Marfori J, Iuorno MJ, Nestler JE. Prevalence of polycystic ovary syndrome among premenopausal women with type 2 diabetes. Diabetes Care 2001;24:1050–1052.
 
58. White MF, Kahn CR. The insulin signaling system. J Biol Chem 1994;269:1–4.
 
59. Caro JF, Ittoop O, Pories WJ, et al. Studies on the mechanism of insulin resistance in the liver from humans with noninsulin-dependent diabetes: Insulin action and binding in isolated hepatocytes, insulin receptor structure, and kinase activity. J Clin Invest 1986;78:249–258.
 
60. Considine RV, Caro JF. Protein kinase C: mediator or inhibitor of insulin action? J Cell Biochem1993;52:8–13.
 
61. Kruszynska YT, Olefsky JM. Cellular and molecular mechanisms of non-insulin dependent diabetes mellitus. J Investig Med 1996;44:413–428.
 
62. Ek I, Arner P, Bergqvist A, et al. Impaired adipocyte lipolysis in nonobese women with the polycystic ovary syndrome: a possible link to insulin resistance? J Clin Endocrinol Metab1997;82:1147–1153.
 
63. Rosenbaum D, Haber RS, Dunaif A. Insulin resistance in polycystic ovary syndrome: decreased expression of GLUT-4 glucose transporters in adipocytes. Am J Physiol 1993;264:E197–E202.
 
64. Dunaif A, Xia J, Book CB, et al. Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome. J Clin Invest 1995;96:801–810.
 
65. Hotamisligil GS. Mechanisms of TNF-alpha-induced insulin resistance. Exp Clin Endocrinol Diabetes 1999;107:119–125.
 
66. Zhang LH, Rodriguez H, Ohno S, Miller WL. Serine phosphorylation of human P450c17 increases 17,20-lyase activity: implications for adrenarche and the polycystic ovary syndrome. Proc Natl Acad Sci U S A 1995;92:10619–10623.
 
67. Tsilchorozidou T, Overton C, Conway GS. The pathophysiology of polycystic ovary syndrome. Clin Endocrinol (Oxf) 2004;60:1–17.
 
68. Lin Y, Fridstrom M, Hillensjo T. Insulin stimulation of lactate accumulation in isolated human granulosa-luteal cells: a comparison between normal and polycystic ovaries. Hum Reprod1997;12:2469–2472.
 
69. Nestler JE, Jakubowicz DJ, de Vargas AF, et al. Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J Clin Endocrinol Metab 1998;83:2001–2005.
 
70. Willis D, Mason H, Gilling-Smith C, Franks S. Modulation by insulin of follicle-stimulating hormone and luteinizing hormone actions in human granulosa cells of normal and polycystic ovaries. J Clin Endocrinol Metab 1996;81:302–309.
 
71. Barbieri RL, Makris A, Randall RW, et al. Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism. J Clin Endocrinol Metab 1986;62:904–910.
 
72. Franks S, Robinson S, Willis DS. Nutrition, insulin and polycystic ovary syndrome. Rev Reprod1996;1:47–53.
 
73. Gilling-Smith C, Willis DS, Beard RW, Franks S. Hypersecretion of androstenedione by isolated thecal cells from polycystic ovaries. J Clin Endocrinol Metab 1994;79:1158–1165.
 
74. Hillier SG, Tetsuka M. Role of androgens in follicle maturation and atresia. Baillieres Clin Obstet Gynaecol 1997;11:249–260.
 
75. Stripp B, Taylor AA, Bartter FC, et al. Effect of spironolactone on sex hormones in man. J Clin Endocrinol Metab 1975;41:777–781.
 
76. Lee O, Farquhar C, Toomath R, Jepson R. Spironolactone versus placebo or in combination with steroids for hirsutism and/or acne. Cochrane Database Syst Rev 2000;CD000194.
 
77. Milewicz A, Silber D, Kirschner MA. Therapeutic effects of spironolactone in polycystic ovary syndrome. Obstet Gynecol 1983;61:429–432.
 
78. Shaw JC, White LE. Long-term safety of spironolactone in acne: results of an 8-year followup study.J Cutan Med Surg 2002;6:541–545.
 
79. Spritzer PM, Lisboa KO, Mattiello S, Lhullier F. Spironolactone as a single agent for long-term therapy of hirsute patients. Clin Endocrinol (Oxf) 2000;52:587–594.
 
80. Ganie MA, Khurana ML, Eunice M, et al. Comparison of efficacy of spironolactone with metformin in the management of polycystic ovary syndrome: an open-labeled study. J Clin Endocrinol Metab2004;89:2756–2762.
 
81. Wu MS, Johnston P, Sheu WH, et al. Effect of metformin on carbohydrate and lipoprotein metabolism in NIDDM patients. Diabetes Care 1990;13:1–8.
 
82. Perriello G, Misericordia P, Volpi E, et al. Acute antihyperglycemic mechanisms of metformin in NIDDM. Evidence for suppression of lipid oxidation and hepatic glucose production. Diabetes1994;43:920–928.
 
83. Fantus IG, Brosseau R. Mechanism of action of metformin: insulin receptor and postreceptor effects in vitro and in vivo. J Clin Endocrinol Metab 1986;63:898–905.
 
84. Inzucchi SE, Maggs DG, Spollett GR, et al. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med 1998;338:867–872.
 
85. Velazquez EM, Mendoza S, Hamer T, et al. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 1994;43:647–654.
 
86. Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med1996;335:617–623.
 
87. Nestler JE, Jakubowicz DJ. Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17 alpha activity and serum androgens. J Clin Endocrinol Metab 1997;82:4075–4079.
 
88. Haas DA, Carr BR, Attia GR. Effects of metformin on body mass index, menstrual cyclicity, and ovulation induction in women with polycystic ovary syndrome. Fertil Steril 2003;79:469–481.
 
89. Glueck CJ, Wang P, Kobayashi S, et al. Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome. Fertil Steril2002;77:520–525.
 
90. Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ. Nuclear receptors and lipid physiology: opening the X-files. Science 2001;294:1866–1870.
 
91. Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med 2002;53:409–435.
 
92. Barbier O, Torra IP, Duguay Y, et al. Pleiotropic actions of peroxisome proliferator-activated receptors in lipid metabolism and atherosclerosis. Arterioscler Thromb Vasc Biol 2002;22:717–726.
 
93. Duez H, Chao YS, Hernandez M, et al. Reduction of atherosclerosis by the peroxisome proliferator-activated receptor alpha agonist fenofibrate in mice. J Biol Chem 2002;277:48051–48057.
 
94. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol: Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999;341:410–418.
 
95. Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study: a randomised study. Lancet 2001;357:905–910.
 
96. Willson TM, Lambert MH, Kliewer SA. Peroxisome proliferator-activated receptor gamma and metabolic disease. Annu Rev Biochem 2001;70:341–367.
 
97. Dubois M, Pattou F, Kerr-Conte J, et al. Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in normal human pancreatic islet cells. Diabetologia 2000;43:1165–1169.
 
98. Nolan JJ, Ludvik B, Beerdsen P, et al. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med 1994;331:1188–1193.
 
99. Suter SL, Nolan JJ, Wallace P, et al. Metabolic effects of new oral hypoglycemic agent CS-045 in NIDDM subjects. Diabetes Care 1992;15:193–203.
 
100. Miyazaki Y, Glass L, Triplitt C, et al. Effect of rosiglitazone on glucose and non-esterified fatty acid metabolism in Type II diabetic patients. Diabetologia 2001;44:2210–2219.
 
101. Miyazaki Y, Mahankali A, Matsuda M, et al. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 2002;87:2784–2791.
 
102. Miyazaki Y, Mahankali A, Matsuda M, et al. Improved glycemic control and enhanced insulin sensitivity in type 2 diabetic subjects treated with pioglitazone. Diabetes Care 2001;24:710–719.
 
103. Tack CJ, Ong MK, Lutterman JA, Smits P. Insulin-induced vasodilatation and endothelial function in obesity/insulin resistance: Effects of troglitazone. Diabetologia 1998;41:569–576.
 
104. Ghazeeri G, Kutteh WH, Bryer-Ash M, et al. Effect of rosiglitazone on spontaneous and clomiphene citrate-induced ovulation in women with polycystic ovary syndrome. Fertil Steril2003;79:562–566.
 
105. Zheng Z, Li M, Lin Y, Ma Y. [Effect of rosiglitazone on insulin resistance and hyperandrogenism in polycystic ovary syndrome]. Zhonghua Fu Chan Ke Za Zhi 2002;37:271–273.
 
106. Mitwally MF, Witchel SF, Casper RF. Troglitazone: a possible modulator of ovarian steroidogenesis. J Soc Gynecol Investig 2002;9:163–167.
 
107. Ortega-Gonzalez C, Luna S, Hernandez L, et al. Responses of serum androgen and insulin resistance to metformin and pioglitazone in obese, insulin-resistant women with polycystic ovary syndrome. J Clin Endocrinol Metab 2004;90:1360–1365.
 
108. Kelly IE, Han TS, Walsh K, Lean ME. Effects of a thiazolidinedione compound on body fat and fat distribution of patients with type 2 diabetes. Diabetes Care 1999;22:288–293.
 
109. Akazawa S, Sun F, Ito M, et al. Efficacy of troglitazone on body fat distribution in type 2 diabetes.Diabetes Care 2000;23:1067–1071.
 
110. Fonseca V, Grunberger G, Gupta S, et al. Addition of nateglinide to rosiglitazone monotherapy suppresses mealtime hyperglycemia and improves overall glycemic control. Diabetes Care2003;26:1685–1690.
 
111. Ortega-Gonzalez C, Cardoza L, Coutino B, et al. Insulin sensitizing drugs increase the endogenous dopaminergic tone in obese insulin-resistant women with polycystic ovary syndrome. J Endocrinol 2005;184:233–239.
 
112. Lv L, Liu Y. Effect of rosiglitazone on endocrine, metabolism and ovulatory performance in patients with polycystic ovary syndrome and insulin resistance. J Huazhong Univ Sci Technolog Med Sci2004;24:480–482.
 
113. Schoppee PD, Garmey JC, Veldhuis JD. Putative activation of the peroxisome proliferator-activated receptor gamma impairs androgen and enhances progesterone biosynthesis in primary cultures of porcine theca cells. Biol Reprod 2002;66:190–198.
 
114. Veldhuis JD, Zhang G, Garmey JC. Troglitazone, an insulin-sensitizing thiazolidinedione, represses combined stimulation by LH and insulin of de novo androgen biosynthesis by thecal cells in vitro. J Clin Endocrinol Metab 2002;87:1129–1133.