Best Practice & Research Clinical Endocrinology & Metabolism
Volume 20, Issue 2 , Pages 245-260 , June 2006

Prevention of diabetes and cardiovascular disease in women with PCOS: Treatment with insulin sensitizers

  • Susmeeta T. Sharma, MBBS (Research Intern, Division of Endocrinology and Metabolism)
  • ,
  • John E. Nestler, MD (William G. Blackard Professor of Medicine; Chair, Division of Endocrinology and Metabolism, and Vice Chair, Department of Internal Medicine)

      Affiliations

    • Corresponding Author InformationCorresponding author. Tel.: +1 804 828 9695; Fax: +1 804 828 8389.

References 

  1. Knochenhauer ES, Key TJ, Kahsar-Miller M, et al. Prevalence of the polycystic ovary syndrome in unselected black and white women of the Southeastern United States: a prospective study. Journal of Clinical Endocrinology and Metabolism. 1998;83(9):3078–3082
  2. Asuncion M, Calvo RM, San Millan JL, et al. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. Journal of Clinical Endocrinology and Metabolism. 2000;85(7):2434–2438
  3. Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. American Journal of Obstetrics and Gynecology. 1935;29:181–191
  4. Stein IF. Bilateral polycystic ovaries: significance in fertility. American Journal of Obstetrics and Gynecology. 1945;385–398
  5. Chang RJ, Nakamura RM, Judd HL, et al. Insulin resistance in nonobese patients with polycystic ovarian disease. Journal of Clinical Endocrinology and Metabolism. 1983;57:356–359
  6. Dunaif A, Graf M, Mandeli J, et al. Characterization of groups of hyperandrogenemic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. Journal of Clinical Endocrinology and Metabolism. 1987;65:499–507
  7. Dunaif A, Segal KR, Futterweit W, et al. Profound peripheral resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989;38:1165–1174
  8. Dunaif A, Segal KR, Shelley DR, et al. Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes. 1992;41:1257–1266
  9. Ciaraldi TP, el Roeiy A, Madar Z, et al. Cellular mechanisms of insulin resistance in polycystic ovarian syndrome. Journal of Clinical Endocrinology and Metabolism. 1992;75:577–583
  10. 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. Journal of Clinical Investigation. 1995;96:801–810
  11. Jahanfar S, Eden JA, Warren P, et al. A twin study of polycystic ovary syndrome. Fertility and Sterility. 1995;63:478–486
  12. Campbell PJ, Gerich JE. Impact of obesity on insulin action in volunteers with normal glucose tolerance: demonstration of a threshold for the adverse effect of obesity. Journal of Clinical Endocrinology and Metabolism. 1990;70:1114–1118
  13. Reaven GM. Banting lecture. Role of insulin resistance in human disease. Diabetes. 1988;37:1595–1607
  14. Reaven GM. Insulin resistance, hyperinsulinemia, hypertriglyceridemia, and hypertension. Parallels between human disease and rodent models. Diabetes Care. 1991;14:195–202
  15. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). Journal of the American Medical Association 2001; 285(19): 2486–2497.
  16. Ehrmann DA, Barnes RB, Rosenfield RL, et al. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care. 1999;22(1):141–146
  17. 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. Journal of Clinical Endocrinology and Metabolism. 1999;84(1):165–169
  18. Norman RJ, Masters L, Milner CR, et al. Relative risk of conversion from normoglycemia to impaired glucose tolerance or non-insulin dependent diabetes mellitus in polycystic ovarian syndrome. Human Reproduction. 2001;16(9):1995–1998
  19. Legro RS, Gnatuk CL, Kunselman AR, Dunaif A. Changes in glucose tolerance over time in women with polycystic ovary syndrome: a controlled study. Journal of Clinical Endocrinology and Metabolism. 2005;90(6):3236–3242
  20. Solomon CG, Hu FB, Dunaif A, et al. Long or highly irregular menstrual cycles as a marker for risk of type 2 diabetes mellitus. Journal of the American Medical Association. 2001;286(19):2421–2426
  21. Peppard HR, Marfori J, Iuorno MJ, Nestler JE. Prevalence of polycystic ovary syndrome among premenopausal women with type 2 diabetes. Diabetes Care. 2001;24(6):1050–1052
  22. Conn JJ, Jacobs HS, Conway GS. The prevalence of polycystic ovaries in women with type 2 diabetes mellitus. Clinical Endocrinology (Oxford). 2000;52(1):81–86
  23. Knowler WC, Barrett-Conner E, Fowler SE, et al. (Diabetes Prevention Program Research Group). Reduction in incidence of type 2 diabetes with lifestyle intervention or metformin. New England Journal of Medicine. 2002;346:393–403
  24. American association of clinical endocrinologists position statement on metabolic and cardiovascular consequences of polycystic ovary syndrome. Endocrine Practice 2005; 11(2): 125–134.
  25. Bjorntorp P. The android woman—a risky condition. Journal of Internal Medicine. 1996;239:105–110
  26. Holte J, Gennarelli G, Wide L, et al. High prevalence of polycystic ovaries and associated clinical, endocrine, and metabolic features in women with previous gestational diabetes mellitus. Journal of Clinical Endocrinology and Metabolism. 1998;83:1143–1150
  27. Rebuffe-Scrive M, Cullberg G, Lundberg P-A, et al. Anthropometric variables and metabolism in polycystic ovarian disease. Hormone and Metabolic Research. 1989;15:821–826
  28. Talbott E, Guzick D, Clerici A, et al. Coronary heart disease risk factors in women with polycystic ovary syndrome. Arteriosclerosis Thrombosis and Vascular Biology. 1995;15:821–826
  29. Talbott E, Clerici A, Berga SL, et al. Adverse lipid and coronary heart disease risk profiles in young women with polycystic ovary syndrome: results of a case–control study. Journal of Clinical Epidemiology. 1998;51:415–422
  30. Wild RA, Alaupovic P, Parker IJ. Lipid and apolipoprotein abnormalities in hirsutewomen. The association with insulin resistance. American Journal of Obstetrics and Gynecology. 1992;166:1191–1196
  31. Wild RA. Obesity, lipids, cardiovascular risk, and androgen excess. American Journal of Medicine. 1995;98:27S–32S
  32. 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. Journal of Clinical Endocrinology and Metabolism. 1997;82(7):2108–2116
  33. Velaquez 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(4):454–457
  34. Diamanti-Kandarakis E, Spina G, Kouli C, Migdalis I. Increased endothelin-1 levels in women with polycystic ovary syndrome and the beneficial effect of metformin therapy. Journal of Clinical Endocrinology and Metabolism. 2001;86(10):4666–4673
  35. Kelly CC, Lyall H, Petrie JR, et al. Low grade chronic inflammation in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism. 2001;86(6):2453–2455
  36. Paradisi G, Steinberg HO, Hempfling A, et al. Polycystic ovary syndrome is associated with endothelial dysfunction. Circulation. 2001;103(10):1410–1415
  37. Lakhani K, Constantinovici N, Purcell WM, et al. Internal carotid-artery response to 5% carbon dioxide in women with polycystic ovaries. Lancet. 2000;356(9236):1166–1167
  38. Kelly CJ, Speirs A, Gould GW, et al. Altered vascular function in young women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism. 2002;87(2):742–746
  39. Legro RS, Kunselman AR, Dunaif A. Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome. American Journal of Medicine. 2001;111:607–613
  40. Wild RA, Painter PC, Coulson PB, et al. Lipoprotein lipid concentration and cardiovascular risk in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism. 1985;61:946–951
  41. Mather KJ, Kwan F, Corenblum B. Hyperinsulinemia in polycystic ovary syndrome correlates with increased cardiovascular risk independent of obesity. Fertility and Sterility. 2000;73:150–156
  42. Apridonidze T, Essah PA, Iuorno MJ, Nestler JE. Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism. 2005;90(4):1929–1935
  43. Gardner CD, Fortmann SP, Krauss RM. Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women. Journal of the American Medical Association. 1996;276:875–881
  44. Austin MA, Breslow JL, Hennekens CH, et al. Low-density lipoprotein subclass patterns and risk of myocardial infarction. Journal of the American Medical Association. 1988;260:1917–1921
  45. Dejager S, Pichard C, Giral P, et al. particle size in women with polycystic ovary syndrome compared to controls. Clinical Endocrinology (Oxford). 2001;54:455–462
  46. 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. Clinical Endocrinology (Oxford). 2000;52:595–600
  47. Dahlgren E, Johansson S, Lindstedt G, et al. Women with polycystic ovary syndrome wedge resected in 1956–1965: a long-term follow-up focusing on natural history and circulating hormones. Fertility and Sterility. 1992;57:505–513
  48. Zimmermann S, Phillips RA, Dunaif A, et al. Polycystic ovary syndrome: lack of hypertension despite profound insulin resistance. Journal of Clinical Endocrinology and Metabolism. 1992;75:508–513
  49. Holte J, Gennarelli G, Berne C, et al. Elevated ambulatory day-time blood pressure in women with polycystic ovary syndrome: a sign of a pre-hypertensive state?. Human Reproduction. 1996;11:23–28
  50. Christian RC, Dumesic DA, Behrenbeck T, et al. Prevalence and predictors of coronary artery calcification in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism. 2003;88:2562–2568
  51. Talbott E, Zborowski JV, McHugh-Pemu K, et al. Metabolic cardiovascular syndromeand its relationship to coronary calcification in women with polycystic ovarian syndrome. Presented at Third International Workshop on Insulin Resistance, New Orleans, LA; 2003.
  52. Talbott EO, Zborowski JV, Rager JR, et al. Evidence for an association between metabolic cardiovascular syndrome and coronary and aortic calcification among women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism. 2004;89:5454–5461
  53. Talbott EO, Guzick DS, Sutton-Tyrrell K, et al. Evidence for association between polycystic ovary syndrome and premature carotid atherosclerosis in middle-aged women. Arteriosclerosis Thrombosis and Vascular Biology. 2000;20(11):2414–2421
  54. Glueck CJ, Papanna R, Wang P, et al. Incidence and treatment of metabolic syndrome in newly referred women with confirmed polycystic ovarian syndrome. Metabolism. 2003;52:908–915
  55. US Department of Health and Human Services (DHHS). National Center for Health Statistics. Third National Health and Nutrition Examination Survey (NHANES III), 1988–1994. Hyattsville, MD: Center for Disease Control and Prevention; 1996.
  56. Birdsall MA, Farquhar CM, White HD. Association between polycystic ovaries and extent of coronary artery disease in women having cardiac catheterization. Annals of Internal Medicine. 1997;126:32–35
  57. Elting MW, Korsen TJ, Bezemer PD, Schoemaker J. Prevalence of diabetes mellitus, hypertension and cardiac complaints in a follow-up study of a Dutch PCOS population. Human Reproduction. 2001;16:556–560
  58. Dahlgren E, Janson PO, Johansson S, et al. Polycystic ovary syndrome and risk for myocardial infarction: evaluated from a risk factor model based on a prospective population study of women. Acta Obstetricia et Gynecologica Scandinavica. 1992;71:599–604
  59. Pierpoint T, McKeigue PM, Isaacs AJ, et al. Mortality of women with polycystic ovary syndrome at long-term follow-up. Journal of Clinical Epidemiology. 1998;51(7):581–586
  60. Solomon CG, Hu FB, Dunaif A, et al. Menstrual cycle irregularity and risk for future cardiovascular disease. Journal of Clinical Endocrinology and Metabolism. 2002;87(5):2013–2017
  61. Legro RS. Polycystic ovary syndrome and cardiovascular disease: a premature association?. Endocrine Review. 2003;24(3):302–312
  62. Nestler JE. Polycystic ovarian syndrome: metabolic and cardiovascular complications. In:  Kreisberg RA editors. Clinical Endocrinology Update 2003 Syllabus. Chevy Chase, MD: The Endocrine Society Press; 2003;p. 299–303
  63. Palmert MR, Gordon CM, Kartashov AI, et al. Screening for abnormal glucose tolerance in adolescents with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism. 2002;87(3):1017–1023
  64. Gomez-Perez FJ, Aguilar-Salinas CA, Lopez-Alvarenga JC, et al. Lack of agreement between the World Health Organization Category of impaired glucose tolerance and the American Diabetes Association category of impaired fasting glucose. Diabetes Care. 1998;21(11):1886–1888
  65. de Vegt F, Dekker JM, Stehouwer CDA, et al. The 1997 American diabetes association criteria versus the 1985 World Health Organization criteria for the diagnosis of abnormal glucose tolerance: poor agreement in the hoorn study. Diabetes Care. 1998;21(10):1686–1690
  66. Korytkowski MT, Mokan M, Horwitz MJ, Berga SL. Metabolic effects of oral contraceptives in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism. 1995;80:3327–3334
  67. Dahlgren E, Landin K, Krotkiewski M, et al. Effects of two anti-androgen treatments on hirsutism and insulin sensitivity in women with polycystic ovary syndrome. Human Reproduction. 1998;13:2706–2711
  68. Morin-Papunen LC, Vauhkonen I, Koivunen RM, et al. Endocrine and metabolic effects of metformin versus ethinyl estradiol-cyproterone acetate in obese women with polycystic ovary syndrome: a randomized study. Journal of Clinical Endocrinology and Metabolism. 2000;85:3161–3168
  69. Elter K, Imir G, Durmusoglu F. 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. Human Reproduction. 2002;17:1729–1737
  70. Morin-Papunen L, Vauhkonen I, Koivunen R, et al. Metformin versus ethinyl estradiol-cyproterone acetate in the treatment of nonobese women with polycystic ovary syndrome: a randomized study. Journal of Clinical Endocrinology and Metabolism. 2003;88(1):148–156
  71. Diamanti-Kandarakis E, Baillargeon JP, Iuorno MJ, et al. A modern medical quandary: polycystic ovary syndrome, insulin resistance, and oral contraceptive pills. Journal of Clinical Endocrinology and Metabolism. 2003;88(5):1927–1932
  72. Baillargeon JP, McClish DK, Essah PA, Nestler JE. Association between the current use of low-dose oral contraceptives and cardiovascular arterial disease: a meta-analysis. Journal of Clinical Endocrinology and Metabolism. 2005;90(7):3863–3870
  73. Diamanti-Kandarakis E, Kouli C, Tsianateli T, Bergiele A. Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome. European Journal of Endocrinology. 1998;138:269–274
  74. Moghetti P, Castello R, Negri C, et al. 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. Journal of Clinical Endocrinology and Metabolism. 2000;85(1):139–146
  75. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352(9131):854–865
  76. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Finnish diabetes prevention study group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. New England Journal of Medicine. 2001;344(18):1343–1350
  77. Haechel R, Haechel H. Inhibition of gluconeogenesis from lactate by phenethylbiguanide in the perfused guinea pig liver. Diabetologia. 1982;7:117–124
  78. Gin H, Messerchnitt C, Brottier E. Metformin improves insulin resistance in type 1, insulin dependent, diabetic patients. Metabolism. 1985;34:923–925
  79. Pagano G, Tagliaferro V, Carta Q. Metformin reduces insulin requirement in type 1 diabetics. Diabetologia. 1998;24:351–354
  80. 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(5):647–654
  81. Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17α activity and serum free testosterone after reduction in insulin secretion in women with polycystic ovary syndrome. New England Journal of Medicine. 1996;335:617–623
  82. De Leo V, la Marca A, Ditto A, et al. Effects of metformin on gonadotropin-induced ovulation in women with polycystic ovary syndrome. Fertility and Sterility. 1999;72(2):282–285
  83. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. New England Journal of Medicine. 1998;338(26):1876–1880
  84. Chou KH, von Eye Corleta H, Capp E, Spritzer PM. Clinical, metabolic and endocrine parameters in response to metformin in obese women with polycystic ovary syndrome: a randomized, double-blind and placebo-controlled trial. Hormone and Metabolic Research. 2003;35(2):86–91
  85. Glueck CJ, Wang P, Fontaine R, et al. Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with the polycystic ovary syndrome. Metabolism. 1999;48(4):511–519
  86. Morin-Papunen L, Vauhkonen I, Koivunen R, et al. Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome. Fertility and Sterility. 1998;69(4):691–696
  87. Nestler JE, Jakubowicz DJ. Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17α activity and serum androgens. Journal of Clinical Endocrinology and Metabolism. 1997;82:4075–4079
  88. Morin-Papunen L, Rautio K, Ruokonen A, et al. Metformin reduces C-reactive protein levels in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism. 2003;88(10):4649–4654
  89. Crave JC, Fimbel S, Lejeune H, et al. Effects of diet and metformin administration on sex hormone binding globulin, androgens, and insulin in hirsute and obese women. Journal of Clinical Endocrinology and Metabolism. 1995;80:2057–2062
  90. Ehrmann DA, Cavaghan MK, Imperial J, et al. Effects of metformin on insulin secretion, insulin action, and ovarian steroidogenesis in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism. 1997;82:524–530
  91. Unluhizarci K, Kelestimur F, Bayram F, et al. The effects of metformin on insulin resistance and ovarian steroidogenesis in women with polycystic ovary syndrome. Clinical Endocrinology (Oxford). 1999;51:231–236
  92. Misbin RI. Troglitazone-associated hepatic failure. Annals of Internal Medicine. 1999;130(7 Pt 1):130
  93. Dunaif A, Scott D, Finegood D, et al. The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism. 1996;81(9):3299–3306
  94. 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. Fertility and Sterility. 1999;71(2):323–327
  95. Azziz R, Ehrmann D, Legro RS, et al. Troglitazone Study Group. Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial. Journal of Clinical Endocrinology and Metabolism. 2001;86(4):1626–1632
  96. Paradisi G, Steinberg HO, Shepard MK, et al. Troglitazone therapy improves endothelial function to near normal levels in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism. 2003;88(2):576–580
  97. Legro RS, Azziz R, Ehrmann D, et al. Minimal response of circulating lipids in women with polycystic ovary syndrome to improvement in insulin sensitivity with troglitazone. Journal of Clinical Endocrinology and Metabolism. 2003;88(11):5137–5144
  98. 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(5):271–273[Chinese]
  99. Ghazeeri G, Kutten WH, Bryer-Ash M, et al. Effect of rosiglitazone on spontaneous and clomiphene citrate-induced ovulation in women with polycystic ovary syndrome. Fertility and Sterility. 2003;79(3):562–566
  100. Baillargeon JP, Jakubowicz DJ, Iuorno MJ, et al. Effects of metformin and rosiglitazone, alone and in combination, in nonobese women with polycystic ovary syndrome and normal indices of insulin sensitivity. Fertility and Sterility. 2004;82(4):893–902
  101. Tarkun I, Cetinarslan B, Tureman E, et al. Effect of rosiglitazone on insulin resistance, C-reactive protein and endothelial function in non-obese young women with polycystic ovary syndrome. European Journal of Endocrinology. 2005;153(1):115–121
  102. Romualdi D, Guido M, Ciampelli M, et al. Selective effects of pioglitazone on insulin and androgen abnormalities in normo- and hyperinsulinaemic obese patients with polycystic ovary syndrome. Human Reproduction. 2003;18(6):1210–1218
  103. Brettenthaler N, De Gaytor C, Huber PR, Keller U. Effect of the insulin sensitizer pioglitazone on insulin resistance, hyperandrogenism, and ovulatory dysfunction in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism. 2004;89(8):3835–3840
  104. 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. Journal of Clinical Endocrinology and Metabolism. 2005;90(3):1360–1365
  105. Coetzee EJ, Jackson WPU. Metformin in management of pregnant insulin-dependent diabetics. Diabetologia. 1979;16:241–245

PII: S1521-690X(06)00020-0

doi: 10.1016/j.beem.2006.02.003

Best Practice & Research Clinical Endocrinology & Metabolism
Volume 20, Issue 2 , Pages 245-260 , June 2006