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Drug Insight: insulin-sensitizing drugs in the treatment of polycystic ovary syndrome—a reappraisal

Abstract

The recognition that insulin resistance has a pivotal role in the pathogenesis of polycystic ovary syndrome (PCOS) revolutionized our understanding of this complex disorder. PCOS causes major metabolic and reproductive morbidities, including substantially increased risk for type 2 diabetes mellitus and the metabolic syndrome. Insulin-sensitizing drugs (ISDs) ameliorate reproductive abnormalities, restore ovulation and regular menses, increase pregnancy rates and reduce androgenic symptoms in affected women with PCOS. Accordingly, ISDs, specifically metformin, have been widely adopted as therapy for this condition. A recent, large, randomized, multicenter, clinical trial that assessed live-birth rates rather than surrogate end points suggested that metformin alone is inferior to clomiphene citrate in treating infertility associated with PCOS. There is, furthermore, no evidence to support the use of metformin during pregnancy to prevent spontaneous abortions or gestational diabetes mellitus in women with PCOS. Renewed safety concerns about thiazolidinediones followed recent studies that reported increased cardiovascular morbidity with these agents. These concerns might preclude thiazolidinedione use in otherwise healthy women with PCOS. Finally, although ISDs improve insulin action and cardiovascular disease risk, there is no evidence that they provide long-term health benefits in PCOS. This article discusses the role of ISDs in PCOS in light of these new data.

Key Points

  • Metformin is the only insulin-sensitizing drug recommended for use in women with polycystic ovary syndrome (PCOS) who do not have type 2 diabetes because of concerns about the cardiovascular safety of thiazolidinediones

  • Metformin is effective at ameliorating glucose intolerance and other features of the metabolic syndrome in women with PCOS

  • For the treatment of infertility in women with PCOS, recent data indicate that the live-birth rate with clomiphene citrate monotherapy is superior to that with metformin monotherapy; there is no evidence that combination therapy is superior to clomiphene citrate alone

  • There is no evidence to support the use of metformin during pregnancy to prevent spontaneous abortions or gestational diabetes mellitus

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References

  1. Franks S (1995) Polycystic ovary syndrome. N Engl J Med 333: 853–861

    Google Scholar 

  2. Knochenhauer ES et al. (1998) Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab 83: 3078–3082

    Google Scholar 

  3. Diamanti-Kandarakis E et al. (1999) A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile. J Clin Endocrinol Metab 84: 4006–4011

    Google Scholar 

  4. Stein I and Leventhal M (1935) Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 29: 181–191

    Google Scholar 

  5. Goldzieher JW and Green JA (1962) The polycystic ovary. I. Clinical and histologic features. J Clin Endocrinol Metab 22: 325–338

    Google Scholar 

  6. Burghen GA et al. (1980) Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease. J Clin Endocrinol Metab 50: 113–116

    Google Scholar 

  7. Sam S and Dunaif A (2003) Polycystic ovary syndrome: syndrome XX? Trends Endocrinol Metab 14: 365–370

    Google Scholar 

  8. Apridonidze T et al. (2005) Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab 90: 1929–1935

    Google Scholar 

  9. Grundy SM (2002) Obesity, metabolic syndrome, and coronary atherosclerosis. Circulation 105: 2696–2698

    Google Scholar 

  10. Solomon CG (1999) The epidemiology of polycystic ovary syndrome. Prevalence and associated disease risks. Endocrinol Metab Clin North Am 28: 247–263

    Google Scholar 

  11. Boomsma CM et al. (2006) A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome. Hum Reprod Update 12: 673–683

    Google Scholar 

  12. Legro RS (2003) Polycystic ovary syndrome and cardiovascular disease: a premature association? Endocr Rev 24: 302–312

    Google Scholar 

  13. Dunaif A (1997) Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 18: 774–800

    Google Scholar 

  14. Corbould A et al. (2005) Insulin resistance in the skeletal muscle of women with PCOS involves intrinsic and acquired defects in insulin signaling. Am J Physiol Endocrinol Metab 288: E1047–E1054

    Google Scholar 

  15. Polson DW et al. (1988) Polycystic ovaries—a common finding in normal women. Lancet 1: 870–872

    Google Scholar 

  16. Legro RS et al. (2005) Polycystic ovaries are common in women with hyperandrogenic chronic anovulation but do not predict metabolic or reproductive phenotype. J Clin Endocrinol Metab 90: 2571–2579

    Google Scholar 

  17. The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group (2004) Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 19: 41–47

  18. Robinson S et al. (1993) The relationship of insulin insensitivity to menstrual pattern in women with hyperandrogenism and polycystic ovaries. Clin Endocrinol (Oxf) 39: 351–355

    Google Scholar 

  19. Adams JM et al. (2004) Polycystic ovarian morphology with regular ovulatory cycles: insights into the pathophysiology of polycystic ovarian syndrome. J Clin Endocrinol Metab 89: 4343–4350

    Google Scholar 

  20. Chang PL et al. (2000) Normal ovulatory women with polycystic ovaries have hyperandrogenic pituitary–ovarian responses to gonadotropin-releasing hormone-agonist testing. J Clin Endocrinol Metab 85: 995–1000

    Google Scholar 

  21. Barber TM et al. (2007) Metabolic characteristics of women with polycystic ovaries and oligo-amenorrhoea but normal androgen levels: implications for the management of polycystic ovary syndrome. Clin Endocrinol (Oxf) 66: 513–517

    Google Scholar 

  22. Azziz R et al. (2006) Position statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 91: 4237–4245

    Google Scholar 

  23. Yki-Jarvinen H (2004) Thiazolidinediones. N Engl J Med 351: 1106–1118

    Google Scholar 

  24. Kirpichnikov D et al. (2002) Metformin: an update. Ann Intern Med 137: 25–33

    Google Scholar 

  25. Zhou G et al. (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108: 1167–1174

    Google Scholar 

  26. Shaw RJ et al. (2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310: 1642–1646

    Google Scholar 

  27. Inzucchi SE et al. (1998) Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med 338: 867–872

    Google Scholar 

  28. Maggs DG et al. (1998) Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 128: 176–185

    Google Scholar 

  29. Unger RH (1995) Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications. Diabetes 44: 863–870

    Google Scholar 

  30. Romero G and Larner J (1993) Insulin mediators and the mechanism of insulin action. Adv Pharmacol 24: 21–50

    Google Scholar 

  31. Nestler JE et al. (1999) Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome. N Engl J Med 340: 1314–1320

    Google Scholar 

  32. Velazquez EM et al. (1994) Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy? Metabolism 43: 647–654

    Google Scholar 

  33. Dunaif A et al. (1996) The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metab 81: 3299–3306

    Google Scholar 

  34. Lord JM et al. Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome. Cochrane Database of Systematic Reviews 2003, Issue 2. Art. No.: CD003053. 10.1002/14651858.CD003053

    Google Scholar 

  35. Diamanti-Kandarakis E et al. (1998) Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome. Eur J Endocrinol 138: 269–274

    Google Scholar 

  36. Azziz R et al. (2001) Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial. J Clin Endocrinol Metab 86: 1626–1632

    Google Scholar 

  37. Brettenthaler N et al. (2004) Effect of the insulin sensitizer pioglitazone on insulin resistance, hyperandrogenism, and ovulatory dysfunction in women with polycystic ovary syndrome. J Clin Endocrinol Metab 89: 3835–3840

    Google Scholar 

  38. Paradisi G et al. (2003) Troglitazone therapy improves endothelial function to near normal levels in women with polycystic ovary syndrome. J Clin Endocrinol Metab 88: 576–580

    Google Scholar 

  39. Ehrmann DA (2005) Polycystic ovary syndrome. N Engl J Med 352: 1223–1236

    Google Scholar 

  40. De Leo V et al. (2003) Insulin-lowering agents in the management of polycystic ovary syndrome. Endocr Rev 24: 633–667

    Google Scholar 

  41. Arlt W et al. (2001) Thiazolidinediones but not metformin directly inhibit the steroidogenic enzymes P450c17 and 3β-hydroxysteroid dehydrogenase. J Biol Chem 276: 16767–16771

    Google Scholar 

  42. Schoppee PD et al. (2002) Putative activation of the peroxisome proliferator-activated receptor γ impairs androgen and enhances progesterone biosynthesis in primary cultures of porcine theca cells. Biol Reprod 66: 190–198

    Google Scholar 

  43. Mansfield R et al. (2003) Metformin has direct effects on human ovarian steroidogenesis. Fertil Steril 79: 956–962

    Google Scholar 

  44. Nestler JE et al. (1991) A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab 72: 83–89

    Google Scholar 

  45. Fleming R et al. (2002) Ovarian function and metabolic factors in women with oligomenorrhea treated with metformin in a randomized double blind placebo-controlled trial. J Clin Endocrinol Metab 87: 569–574

    Google Scholar 

  46. Maciel GAR et al. (2004) Nonobese women with polycystic ovary syndrome respond better than obese women to treatment with metformin. Fertil Steril 81: 355–360

    Google Scholar 

  47. Harborne LR et al. (2005) Metformin and weight loss in obese women with polycystic ovary syndrome: comparison of doses. J Clin Endocrinol Metab 90: 4593–4598

    Google Scholar 

  48. Ortega-Gonzalez C et al. (2005) Responses of serum androgen and insulin resistance to metformin and pioglitazone in obese, insulin-resistant women with polycystic ovary syndrome. J Clin Endocrinol Metab 90: 1360–1365

    Google Scholar 

  49. Baillargeon J-P et al. (2004) Effects of metformin and rosiglitazone, alone and in combination, in nonobese women with polycystic ovary syndrome and normal indices of insulin sensitivity. Fertil Steril 82: 893–902

    Google Scholar 

  50. Sepilian V and Nagamani M (2005) Effects of rosiglitazone in obese women with polycystic ovary syndrome and severe insulin resistance. J Clin Endocrinol Metab 90: 60–65

    Google Scholar 

  51. van Santbrink EJ et al. (2005) Does metformin modify ovarian responsiveness during exogenous FSH ovulation induction in normogonadotrophic anovulation? A placebo-controlled double-blind assessment. Eur J Endocrinol 152: 611–617

    Google Scholar 

  52. Palomba S et al. (2005) A randomized controlled trial evaluating metformin pre-treatment and co-administration in non-obese insulin-resistant women with polycystic ovary syndrome treated with controlled ovarian stimulation plus timed intercourse or intrauterine insemination. Hum Reprod 20: 2879–2886

    Google Scholar 

  53. Tang T et al. (2006) The use of metformin for women with PCOS undergoing IVF treatment. Hum Reprod 21: 1416–1425

    Google Scholar 

  54. Palomba S et al. (2005) Prospective parallel randomized, double-blind, double-dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in nonobese anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab 90: 4068–4074

    Google Scholar 

  55. Moll E et al. (2006) Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial. BMJ 332: 1485

    Google Scholar 

  56. Legro RS et al. (2007) Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 356: 551–566

    Google Scholar 

  57. Palomba S et al. (2007) Clomiphene citrate versus metformin as first-line approach for the treatment of anovulation in infertile patients with polycystic ovary syndrome. J Clin Endocrinol Metab 92: 3498–3503

    Google Scholar 

  58. Balen AH and Rutherford AJ (2007) Management of infertility. BMJ 335: 608–611

    Google Scholar 

  59. Fujioka K et al. (2003) Glycemic control in patients with type 2 diabetes mellitus switched from twice-daily immediate-release metformin to a once-daily extended-release formulation. Clin Ther 25: 515–529

    Google Scholar 

  60. Glueck CJ et al. (2002) Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin. Hum Reprod 17: 2858–2864

    Google Scholar 

  61. Jakubowicz DJ et al. (2002) Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab 87: 524–529

    Google Scholar 

  62. Norman RJ and Clark AM (1998) Obesity and reproductive disorders: a review. Reprod Fertil Dev 10: 55–63

    Google Scholar 

  63. Wang JX et al. (2000) Body mass and probability of pregnancy during assisted reproduction treatment: retrospective study. BMJ 321: 1320–1321

    Google Scholar 

  64. Thatcher SS and Jackson EM (2006) Pregnancy outcome in infertile patients with polycystic ovary syndrome who were treated with metformin. Fertil Steril 85: 1002–1009

    Google Scholar 

  65. Palomba S et al. (2004) Metformin administration versus laparoscopic ovarian diathermy in clomiphene citrate-resistant women with polycystic ovary syndrome: a prospective parallel randomized double-blind placebo-controlled trial. J Clin Endocrinol Metab 89: 4801–4809

    Google Scholar 

  66. Norman RJ et al. (2004) Should we continue or stop insulin sensitizing drugs during pregnancy. Curr Opin Obstet Gynecol 16: 245–250

    Google Scholar 

  67. Vanky E et al. (2004) Metformin reduces pregnancy complications without affecting androgen levels in pregnant polycystic ovary syndrome women: results of a randomized study. Hum Reprod 19: 1734–1740

    Google Scholar 

  68. Legro RS et al. (1999) 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 84: 165–169

    Google Scholar 

  69. Glueck CJ et al. (2004) Height, weight, and motor-social development during the first 18 months of life in 126 infants born to 109 mothers with polycystic ovary syndrome who conceived on and continued metformin through pregnancy. Hum Reprod 19: 1323–1330

    Google Scholar 

  70. Glueck CJ et al. (2004) Metformin, pre-eclampsia, and pregnancy outcomes in women with polycystic ovary syndrome. Diabet Med 21: 829–836

    Google Scholar 

  71. Glueck CJ et al. (2004) Metformin during pregnancy reduces insulin, insulin resistance, insulin secretion, weight, testosterone and development of gestational diabetes: prospective longitudinal assessment of women with polycystic ovary syndrome from preconception throughout pregnancy. Hum Reprod 19: 510–521

    Google Scholar 

  72. Koren G et al. (2006) Metformin use during the first trimester of pregnancy. Is it safe? Can Fam Physician 52: 171–172

    Google Scholar 

  73. Hellmuth E et al. (2000) Oral hypoglycaemic agents in 118 diabetic pregnancies. Diabet Med 17: 507–511

    Google Scholar 

  74. Rowan JA (2007) A trial in progress: gestational diabetes: treatment with metformin compared with insulin (the Metformin in Gestational Diabetes [MiG] trial) [abstract]. Diabetes Care 30: S214–S219

    Google Scholar 

  75. Tang T et al. (2006) Combined lifestyle modification and metformin in obese patients with polycystic ovary syndrome. A randomized, placebo-controlled, double-blind multicentre study. Hum Reprod 21: 80–89

    Google Scholar 

  76. Pasquali R et al. (2000) 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 85: 2767–2774

    Google Scholar 

  77. Gambineri A et al. (2004) Effect of flutamide and metformin administered alone or in combination in dieting obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 60: 241–249

    Google Scholar 

  78. Gambineri A et al. (2006) Treatment with flutamide, metformin, and their combination added to a hypocaloric diet in overweight-obese women with polycystic ovary syndrome: a randomized, 12-month, placebo-controlled study. J Clin Endocrinol Metab 91: 3970–3980

    Google Scholar 

  79. Lord J et al. (2006) The effect of metformin on fat distribution and the metabolic syndrome in women with polycystic ovary syndrome—a randomised, double-blind, placebo-controlled trial. Br J Obstet Gynaecol 113: 817–824

    Google Scholar 

  80. Legro RS et al. (2003) Minimal response of circulating lipids in women with polycystic ovary syndrome to improvement in insulin sensitivity with troglitazone. J Clin Endocrinol Metab 88: 5137–5144

    Google Scholar 

  81. Diamanti-Kandarakis E et al. (2005) Metformin administration improves endothelial function in women with polycystic ovary syndrome. Eur J Endocrinol 152: 749–756

    Google Scholar 

  82. Kilicdag EB et al. (2005) Homocysteine levels in women with polycystic ovary syndrome treated with metformin versus rosiglitazone: a randomized study. Hum Reprod 20: 894–899

    Google Scholar 

  83. Legro RS et al. (2007) The effects of metformin and rosiglitazone, alone and in combination, on the ovary and endometrium in polycystic ovary syndrome. Am J Obstet Gynecol 196: 402e1–402e11

    Google Scholar 

  84. Rouzi AA and Ardawi MSM (2006) A randomized controlled trial of the efficacy of rosiglitazone and clomiphene citrate versus metformin and clomiphene citrate in women with clomiphene citrate-resistant polycystic ovary syndrome. Fertil Steril 85: 428–435

    Google Scholar 

  85. Korytkowski MT et al. (1995) Metabolic effects of oral contraceptives in women with polycystic ovary syndrome. J Clin Endocrinol Metab 80: 3327–3334

    Google Scholar 

  86. Dahlgren E et al. (1998) Effects of two antiandrogen treatments on hirsutism and insulin sensitivity in women with polycystic ovary syndrome. Hum Reprod 13: 2706–2711

    Google Scholar 

  87. Diamanti-Kandarakis E et al. (2003) A modern medical quandary: polycystic ovary syndrome, insulin resistance, and oral contraceptive pills. J Clin Endocrinol Metab 88: 1927–1932

    Google Scholar 

  88. Pasquali R et al. (1999) The natural history of the metabolic syndrome in young women with the polycystic ovary syndrome and the effect of long-term oestrogen–progestagen treatment. Clin Endocrinol (Oxf) 50: 517–527

    Google Scholar 

  89. Costello M et al. Insulin-sensitising drugs versus the combined oral contraceptive pill for hirsutism, acne and risk of diabetes, cardiovascular disease, and endometrial cancer in polycystic ovary syndrome. Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD005552. 10.1002/14651858.CD005552.pub2

    Google Scholar 

  90. Meyer C et al. (2007) Effects of medical therapy on insulin resistance and the cardiovascular system in polycystic ovary syndrome. Diabetes Care 30: 471–478

    Google Scholar 

  91. Luque-Ramirez M et al. (2007) Comparison of ethinyl-estradiol plus cyproterone acetate versus metformin effects on classic metabolic cardiovascular risk factors in women with the polycystic ovary syndrome. J Clin Endocrinol Metab 92: 2453–2461

    Google Scholar 

  92. Lopez LM et al. Steroidal contraceptives: effect on carbohydrate metabolism in women without diabetes mellitus. Cochrane Database of Systematic Reviews 2007, Issue 2. Art. No.: CD006133. 10.1002/14651858.CD006133.pub2

    Google Scholar 

  93. Salpeter SR et al. (2003) Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus: systematic review and meta-analysis. Arch Intern Med 163: 2594–2602

    Google Scholar 

  94. Gerstein HC et al. (2006) Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 368: 1096–1105

    Google Scholar 

  95. Dormandy JA et al. (2005) Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 366: 1279–1289

    Google Scholar 

  96. Nissen SE and Wolski K (2007) Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356: 2457–2471

    Google Scholar 

  97. Home PD et al. (2007) Rosiglitazone evaluated for cardiovascular outcomes—an interim analysis. N Engl J Med 357: 28–38

    Google Scholar 

  98. Nathan DM (2007) Rosiglitazone and cardiotoxicity—weighing the evidence. N Engl J Med 357: 64–66

    Google Scholar 

  99. Norman RJ et al. (2002) The role of lifestyle modification in polycystic ovary syndrome. Trends Endocrinol Metab 13: 251–257

    Google Scholar 

  100. Knowler WC et al. (2002) Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346: 393–403

    Google Scholar 

  101. Moghetti P et al. (2000) 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 85: 139–146

    Google Scholar 

  102. Hardiman P et al. (2003) Polycystic ovary syndrome and endometrial carcinoma. Lancet 361: 1810–1812

    Google Scholar 

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Charles P Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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Dunaif, A. Drug Insight: insulin-sensitizing drugs in the treatment of polycystic ovary syndrome—a reappraisal. Nat Rev Endocrinol 4, 272–283 (2008). https://doi.org/10.1038/ncpendmet0787

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