Fertility and Sterility
Volume 91, Issue 2 , Pages 514-521 , February 2009

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

  • Murizah Mohd Zain, M.D., M.Med. (O&G)

      Affiliations

    • Department of Obstetric and Gynaecology, Alor Setar Hospital, Kedah, Malaysia
    • Research Centre of Reproductive Health, School of Paediatrics and Reproductive Health, University of Adelaide, South Australia, Australia
    • Corresponding Author InformationReprint requests: Murizah Mohd Zain, M.D., University of Adelaide, School of Pediatric and Reproductive Health, 6th floor, Medical School North, Adelaide, South Australia 5005 Australia (FAX: 618-83036100).
  • ,
  • Ridzuan Jamaluddin, M.D.

      Affiliations

    • Department of Obstetric and Gynaecology, Science University Hospital, Kelantan, Malaysia
  • ,
  • Adibah Ibrahim, M.D., M.Med. (O&G)

      Affiliations

    • Department of Obstetric and Gynaecology, Science University Hospital, Kelantan, Malaysia
  • ,
  • Robert J. Norman, M.D., F.R.A.N.Z.C.O.G., F.R.C.O.G., F.R.C.P.A.

      Affiliations

    • Research Centre of Reproductive Health, School of Paediatrics and Reproductive Health, University of Adelaide, South Australia, Australia

Received 5 October 2007 ,Revised 7 December 2007 ,Accepted 7 December 2007.

References 

  1. Frank S. Polycystic ovary syndrome. N Engl J Med. 1995;333:833–861
  2. Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol. 1934;29:181–191
  3. Wild RA. Long-term health consequences of PCOS. Hum Reprod Update. 2002;8:231–241
  4. The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Hum Reprod. 2004;19:41–47
  5. Hull MG. Epidemiology of infertility and polycystic ovarian disease: endocrinological and demographic studies. Gynecol Endocrinol. 1987;1:235–245
  6. Homburg R, Armar NA, Eshel A, Adams J, Jacobs HS. Influence of serum luteinising hormone concentrations on ovulation, conception and early pregnancy loss in polycystic ovary syndrome. BMJ. 1988;297:1024–1026
  7. Boomsma CM, Eijkemans MJ, Hughes EG, Visser GH, Fauser BC, Macklon NS. A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome. Hum Reprod Update. 2006;12:673–683
  8. Kim H, Taylor AE, Barbieri RL. Insulin sensitizers and polycystic ovary syndrome: can a diabetes medication treat infertility?. Fertil Steril. 2000;73:1097–1098
  9. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. 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
  10. Bailey CS, Turner RC. Metformin drug therapy. N Engl J Med. 1996;334:574–579
  11. Lord JM, Flight IHK, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ. 2003;327:951–953
  12. Lord JM, Flight IHK, Norman RJ. Insulin sensitizing drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovarian syndrome. [Review] Cochrane Database Syst Rev. 2003;3:CD003053
  13. Norman RJ. Metformin—comparison with other therapies in ovulation induction in polycystic ovary syndrome. [Editorial] J Clin Endocrinol Metab. 2004;89:4797–4800
  14. Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, van der Veen F. Effect of clomiphene citrate plus metformin and clomiphene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomized double blind clinical trial. BMJ. 2006;332:1485–1489
  15. Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Sandra AC, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356:551–566
  16. Ng EHY, Wat WMS, Ho PC. Effects of metformin on ovulation rate, hormonal and metabolic profiles in women with clomide resistant polycystic ovaries, a randomized, double blinded placebo-controlled trial. Hum Reprod. 2001;16:1625–1631
  17. Hugues E, Collins J, Vandekerckhove P, Lilford R. Clomiphene citrate for ovulation induction in women with oligo-amenorrhea. Cochrane Database Syst Rev. 2000;(2):CD000056
  18. Gonen Y, Casper RF. Sonographic determination of a possible adverse effect of clomiphene citrate on endometrial growth. Hum Reprod. 1990;5:670–674
  19. Asch RH, Greenblatt RB. Update on the safety and efficacy of clomiphene citrate as a therapeutic agent. J Reprod Med. 1976;17:175–180
  20. DeFronzo RA, Barzilai N, Simonson DC. Mechanism of metformin action in obese and lean noninsulin-dependent diabetic subjects. J Clin Endocrinol Metab. 1991;73:1294–1301
  21. Attia GR, Rainey WE, Carr BR. Metformin directly inhibits androgen production in human theca cells. Fertil Steril. 2001;76:517–524
  22. 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;338:1876–1880
  23. Velazquez EM, Acosta A, Mendoza SG. Menstrual cyclicity after metformin therapy in polycystic ovary syndrome. Obstet Gynecol. 1997;90:392–395
  24. Moghetti P, Castello R, Negri C, Tosi F, Perrone F, Caputo M, 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;85:139–146
  25. Ehrmann DA, Cavaghan MK, Imperial J, Sturis J, Rosenfield RL, Polonsky KS. Effects of metformin on insulin secretion, insulin action, and ovarian steroidogenesis in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1997;82:524–530
  26. Yilmaz S, Unal Y, Fahrettin K, Ercan A. The effects of metformin on insulin resistance, clomiphene-induced ovulation and pregnancy rates in women with polycystic ovary syndrome. J Obstet Gynecol Reprod Biol. 2004;113:214–220
  27. Palomba S, Orio F, Falbo A, Manguso F, Russo T, Cascella T, 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;90:4068–4074
  28. Neveu N, Granger L, St-Michel P, Lavoie HB. Comparison of clomiphene citrate, metformin, or the combination of both for first line ovulation induction and achievement of pregnancy in 154 women with polycystic ovary syndrome. Fertil Steril. 2007;87:113–120
  29. Legro RS, Myers ER, Barnhart HX, Carr BR, Diamond MP, Sandra AC, et al. The pregnancy in polycystic ovary syndrome: baseline characteristics of the randomized cohort including racial effects. Fertil Steril. 2006;86:914–932
  30. Ming-I Hsu, Tsan-Hon Liou, Szu-Yuan Chou, Chuan-Yaw Chang, Chun-Sen Hsu. Diagnostic criteria for polycystic ovary syndrome in Taiwanese Chinese women: comparison between Rotterdam 2003 and NIH 1990. Fertil Steril. 2007;88:727–729
  31. Takashi I, Toshiya M, Masahiro M, Naoko T, Fumi S, Yahko H, et al. Diagnostic performance of serum total testosterone for Japanese patients with polycystic ovary syndrome. Endocrine J. 2007;54:233–238
  32. Aruna J, Mittal S, Kumar S, Misra R, Dadhwal V, Vimala N, et al. Metformin therapy in women with polycystic ovary syndrome. Inter J Obst Gynaecol. 2004;87:237–241
  33. Sugimoto O, Aono . The Committee for Reproductive and Endocrine in Japan Society of Obstetrics and Gynaecology. Annual Report (1991–1992) for the determination of diagnostic criteria for PCOS. Acta Obstet Gynaecol Jpn. 1993;45:1359–1367
  34. 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;335:617–623
  35. Fleming R, Hopkinson ZE, Wallace AM, Greer IA, Sattar N. 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;87:569–574

PII: S0015-0282(07)04184-2

doi: 10.1016/j.fertnstert.2007.12.002

Fertility and Sterility
Volume 91, Issue 2 , Pages 514-521 , February 2009