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Metformin for treatment of the polycystic ovary syndrome

Authors
Robert L Barbieri, MD
David A Ehrmann, MD
Section Editors
Peter J Snyder, MD
William F Crowley, Jr, MD
Deputy Editor
Kathryn A Martin, MD

INTRODUCTION

The polycystic ovary syndrome (PCOS) is an important cause of both menstrual irregularity and androgen excess in women. When fully expressed, the manifestations include irregular menstrual cycles, hirsutism, obesity, and a constellation of cardiometabolic disturbances. It is a common endocrinopathy, occurring in 5 to 7 percent of reproductive age women [1-3].

The use of metformin in the management of PCOS will be reviewed here. The clinical manifestations, diagnosis, and other treatment options for PCOS are reviewed separately. (See "Clinical manifestations of polycystic ovary syndrome in adults" and "Diagnosis of polycystic ovary syndrome in adults" and "Treatment of polycystic ovary syndrome in adults".)

OVERVIEW

Interest in the use of metformin, an insulin-lowering drug, in PCOS increased when it was appreciated that insulin resistance played an important role in the pathophysiology of the disorder.

Early trials in women with PCOS subsequently demonstrated a small benefit for weight reduction, a decrease in serum androgens (without improvement in hirsutism), and restored menstrual cycles in approximately 50 percent of women with oligomenorrhea (although not always ovulatory). Early data also suggested that metformin was effective for ovulation induction in anovulatory women with PCOS. As a result, metformin was used "off-label" for a number of these indications [4].

Although there was widespread enthusiasm for metformin therapy in women with PCOS for a number of years, clinical data do not support the use of metformin for treatment of hirsutism or as first-line treatment for ovulation induction in this population. However, whether metformin has a beneficial long-term effect upon reducing the risk of conversion to diabetes from prediabetes has not been addressed.

                       

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Literature review current through: Nov 2016. | This topic last updated: Tue Sep 06 00:00:00 GMT+00:00 2016.
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References
Top
  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. J Clin Endocrinol Metab 1998; 83:3078.
  2. Diamanti-Kandarakis E, Kouli CR, Bergiele AT, et al. A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile. J Clin Endocrinol Metab 1999; 84:4006.
  3. Asunción M, Calvo RM, San Millán JL, et al. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab 2000; 85:2434.
  4. Nestler JE. Metformin for the treatment of the polycystic ovary syndrome. N Engl J Med 2008; 358:47.
  5. Bailey CJ, Turner RC. Metformin. N Engl J Med 1996; 334:574.
  6. Patanè G, Piro S, Rabuazzo AM, et al. Metformin restores insulin secretion altered by chronic exposure to free fatty acids or high glucose: a direct metformin effect on pancreatic beta-cells. Diabetes 2000; 49:735.
  7. Niafar M, Hai F, Porhomayon J, Nader ND. The role of metformin on vitamin B12 deficiency: a meta-analysis review. Intern Emerg Med 2015; 10:93.
  8. Glueck CJ, Wang P. Metformin before and during pregnancy and lactation in polycystic ovary syndrome. Expert Opin Drug Saf 2007; 6:191.
  9. 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. J Clin Endocrinol Metab 2000; 85:139.
  10. Unlühizarci K, Keleştimur F, Bayram F, et al. The effects of metformin on insulin resistance and ovarian steroidogenesis in women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 1999; 51:231.
  11. Fleming R, Hopkinson ZE, Wallace AM, et al. Ovarian function and metabolic factors in women with oligomenorrhea treated with metformin in a randomized double blind placebo-controlled trial. J Clin Endocrinol Metab 2002; 87:569.
  12. Velázquez E, Acosta A, Mendoza SG. Menstrual cyclicity after metformin therapy in polycystic ovary syndrome. Obstet Gynecol 1997; 90:392.
  13. 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; 48:511.
  14. Genazzani AD, Battaglia C, Malavasi B, et al. Metformin administration modulates and restores luteinizing hormone spontaneous episodic secretion and ovarian function in nonobese patients with polycystic ovary syndrome. Fertil Steril 2004; 81:114.
  15. Eisenhardt S, Schwarzmann N, Henschel V, et al. Early effects of metformin in women with polycystic ovary syndrome: a prospective randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab 2006; 91:946.
  16. Essah PA, Apridonidze T, Iuorno MJ, Nestler JE. Effects of short-term and long-term metformin treatment on menstrual cyclicity in women with polycystic ovary syndrome. Fertil Steril 2006; 86:230.
  17. Ibáñez L, Valls C, Ferrer A, et al. Sensitization to insulin induces ovulation in nonobese adolescents with anovulatory hyperandrogenism. J Clin Endocrinol Metab 2001; 86:3595.
  18. Carmina E, Lobo RA. Does metformin induce ovulation in normoandrogenic anovulatory women? Am J Obstet Gynecol 2004; 191:1580.
  19. Lord JM, Flight IH, Norman RJ. Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome. Cochrane Database Syst Rev 2003; :CD003053.
  20. 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. J Clin Endocrinol Metab 2000; 85:3161.
  21. Costello MF, Shrestha B, Eden J, et al. Metformin versus oral contraceptive pill in polycystic ovary syndrome: a Cochrane review. Hum Reprod 2007; 22:1200.
  22. Nestler JE, Stovall D, Akhter N, et al. Strategies for the use of insulin-sensitizing drugs to treat infertility in women with polycystic ovary syndrome. Fertil Steril 2002; 77:209.
  23. Tso LO, Costello MF, Albuquerque LE, et al. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. Cochrane Database Syst Rev 2009; :CD006105.
  24. Palomba S, Falbo A, La Sala GB. Effects of metformin in women with polycystic ovary syndrome treated with gonadotrophins for in vitro fertilisation and intracytoplasmic sperm injection cycles: a systematic review and meta-analysis of randomised controlled trials. BJOG 2013; 120:267.
  25. Palomba S, Falbo A, Carrillo L, et al. Metformin reduces risk of ovarian hyperstimulation syndrome in patients with polycystic ovary syndrome during gonadotropin-stimulated in vitro fertilization cycles: a randomized, controlled trial. Fertil Steril 2011; 96:1384.
  26. Al-Inany HG, Youssef MA, Ayeleke RO, et al. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database Syst Rev 2016; 4:CD001750.
  27. Ehrmann DA, Barnes RB, Rosenfield RL, et al. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 1999; 22:141.
  28. Sharma ST, Wickham EP 3rd, Nestler JE. Changes in glucose tolerance with metformin treatment in polycystic ovary syndrome: a retrospective analysis. Endocr Pract 2007; 13:373.
  29. Gokcel A, Gumurdulu Y, Karakose H, et al. Evaluation of the safety and efficacy of sibutramine, orlistat and metformin in the treatment of obesity. Diabetes Obes Metab 2002; 4:49.
  30. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm228830.htm (Accessed on October 11, 2010).
  31. Pasquali R, Gambineri A, Biscotti D, et al. 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 2000; 85:2767.
  32. Kay JP, Alemzadeh R, Langley G, et al. Beneficial effects of metformin in normoglycemic morbidly obese adolescents. Metabolism 2001; 50:1457.
  33. Freemark M, Bursey D. The effects of metformin on body mass index and glucose tolerance in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes. Pediatrics 2001; 107:E55.
  34. Harborne LR, Sattar N, Norman JE, Fleming R. Metformin and weight loss in obese women with polycystic ovary syndrome: comparison of doses. J Clin Endocrinol Metab 2005; 90:4593.
  35. Moran LJ, Pasquali R, Teede HJ, et al. Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society. Fertil Steril 2009; 92:1966.
  36. Yki-Järvinen H, Nikkilä K, Mäkimattila S. Metformin prevents weight gain by reducing dietary intake during insulin therapy in patients with type 2 diabetes mellitus. Drugs 1999; 58 Suppl 1:53.
  37. Haupt E, Knick B, Koschinsky T, et al. Oral antidiabetic combination therapy with sulphonylureas and metformin. Diabete Metab 1991; 17:224.
  38. Stumvoll M, Nurjhan N, Perriello G, et al. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med 1995; 333:550.
  39. Ladson G, Dodson WC, Sweet SD, et al. The effects of metformin with lifestyle therapy in polycystic ovary syndrome: a randomized double-blind study. Fertil Steril 2011; 95:1059.
  40. Tang T, Glanville J, Hayden CJ, et al. Combined lifestyle modification and metformin in obese patients with polycystic ovary syndrome. A randomized, placebo-controlled, double-blind multicentre study. Hum Reprod 2006; 21:80.
  41. 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. J Clin Endocrinol Metab 1997; 82:524.
  42. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med 1998; 338:1876.
  43. 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.
  44. 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 Med 1996; 335:617.
  45. 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 Metab 1996; 81:3299.
  46. 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.
  47. Nestler JE, Jakubowicz DJ, Reamer P, et al. Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome. N Engl J Med 1999; 340:1314.
  48. Ibáñez L, Valls C, Ferrer A, et al. Additive effects of insulin-sensitizing and anti-androgen treatment in young, nonobese women with hyperinsulinism, hyperandrogenism, dyslipidemia, and anovulation. J Clin Endocrinol Metab 2002; 87:2870.
  49. Ibáñez L, Valls C, Potau N, et al. Sensitization to insulin in adolescent girls to normalize hirsutism, hyperandrogenism, oligomenorrhea, dyslipidemia, and hyperinsulinism after precocious pubarche. J Clin Endocrinol Metab 2000; 85:3526.
  50. Pasquali R, Antenucci D, Casimirri F, et al. Clinical and hormonal characteristics of obese amenorrheic hyperandrogenic women before and after weight loss. J Clin Endocrinol Metab 1989; 68:173.
  51. Kolodziejczyk B, Duleba AJ, Spaczynski RZ, Pawelczyk L. Metformin therapy decreases hyperandrogenism and hyperinsulinemia in women with polycystic ovary syndrome. Fertil Steril 2000; 73:1149.
  52. Kelly CJ, Gordon D. The effect of metformin on hirsutism in polycystic ovary syndrome. Eur J Endocrinol 2002; 147:217.
  53. Harborne L, Fleming R, Lyall H, et al. Metformin or antiandrogen in the treatment of hirsutism in polycystic ovary syndrome. J Clin Endocrinol Metab 2003; 88:4116.
  54. Cosma M, Swiglo BA, Flynn DN, et al. Clinical review: Insulin sensitizers for the treatment of hirsutism: a systematic review and metaanalyses of randomized controlled trials. J Clin Endocrinol Metab 2008; 93:1135.
  55. Martin KA, Chang RJ, Ehrmann DA, et al. Evaluation and treatment of hirsutism in premenopausal women: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008; 93:1105.
  56. George SS, George K, Irwin C, et al. Sequential treatment of metformin and clomiphene citrate in clomiphene-resistant women with polycystic ovary syndrome: a randomized, controlled trial. Hum Reprod 2003; 18:299.
  57. Kocak M, Caliskan E, Simsir C, Haberal A. Metformin therapy improves ovulatory rates, cervical scores, and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome. Fertil Steril 2002; 77:101.
  58. Vandermolen DT, Ratts VS, Evans WS, et al. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil Steril 2001; 75:310.
  59. Morin-Papunen L, Rantala AS, Unkila-Kallio L, et al. Metformin improves pregnancy and live-birth rates in women with polycystic ovary syndrome (PCOS): a multicenter, double-blind, placebo-controlled randomized trial. J Clin Endocrinol Metab 2012; 97:1492.
  60. Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007; 356:551.
  61. Moll E, Bossuyt PM, Korevaar JC, et al. 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 2006; 332:1485.
  62. Palomba S, Orio F Jr, Falbo A, et al. 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 2005; 90:4068.
  63. Zain MM, Jamaluddin R, Ibrahim A, Norman RJ. Comparison of clomiphene citrate, metformin, or the combination of both for first-line ovulation induction, achievement of pregnancy, and live birth in Asian women with polycystic ovary syndrome: a randomized controlled trial. Fertil Steril 2009; 91:514.
  64. Johnson NP, Stewart AW, Falkiner J, et al. PCOSMIC: a multi-centre randomized trial in women with PolyCystic Ovary Syndrome evaluating Metformin for Infertility with Clomiphene. Hum Reprod 2010; 25:1675.
  65. Siebert TI, Viola MI, Steyn DW, Kruger TF. Is metformin indicated as primary ovulation induction agent in women with PCOS? A systematic review and meta-analysis. Gynecol Obstet Invest 2012; 73:304.
  66. Misso ML, Costello MF, Garrubba M, et al. Metformin versus clomiphene citrate for infertility in non-obese women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update 2013; 19:2.
  67. Tang T, Lord JM, Norman RJ, et al. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev 2012; :CD003053.
  68. Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Fertil Steril 2008; 89:505.
  69. Palomba S, Falbo A, Orio F Jr, et al. 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 2005; 20:2879.
  70. Yarali H, Yildiz BO, Demirol A, et al. Co-administration of metformin during rFSH treatment in patients with clomiphene citrate-resistant polycystic ovarian syndrome: a prospective randomized trial. Hum Reprod 2002; 17:289.
  71. Glueck CJ, Wang P, Goldenberg N, Sieve-Smith L. Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin. Hum Reprod 2002; 17:2858.
  72. Jakubowicz DJ, Iuorno MJ, Jakubowicz S, et al. Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab 2002; 87:524.
  73. Glueck CJ, Phillips H, Cameron D, et al. Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study. Fertil Steril 2001; 75:46.
  74. Thatcher SS, Jackson EM. Pregnancy outcome in infertile patients with polycystic ovary syndrome who were treated with metformin. Fertil Steril 2006; 85:1002.
  75. Palomba S, Falbo A, Orio F Jr, Zullo F. Effect of preconceptional metformin on abortion risk in polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials. Fertil Steril 2009; 92:1646.
  76. Mikola M, Hiilesmaa V, Halttunen M, et al. Obstetric outcome in women with polycystic ovarian syndrome. Hum Reprod 2001; 16:226.
  77. Vanky E, Stridsklev S, Heimstad R, et al. Metformin versus placebo from first trimester to delivery in polycystic ovary syndrome: a randomized, controlled multicenter study. J Clin Endocrinol Metab 2010; 95:E448.
  78. Gilbert C, Valois M, Koren G. Pregnancy outcome after first-trimester exposure to metformin: a meta-analysis. Fertil Steril 2006; 86:658.
  79. 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. Hum Reprod 2002; 17:1729.
  80. Cibula D, Fanta M, Vrbikova J, et al. The effect of combination therapy with metformin and combined oral contraceptives (COC) versus COC alone on insulin sensitivity, hyperandrogenaemia, SHBG and lipids in PCOS patients. Hum Reprod 2005; 20:180.