Indication of metformin in the management of hormonal dysfunctionsecondary to polycystic ovarian syndrome : prospective comparative dtudy about 63 cases.

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Published May 5, 2010
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Vol. 88 No. 5 (2010): Issue May 2010

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Khaled Boudhraa
Mohamed Amine Jellouli
Mouna Amri
Monia Farhat
Fatma Torkhani
Mohamed Faouzi Gara

Abstract

Background : Polycystic ovarian syndrome (PCOS) is the most common hormonal dysfunction in women. It’s a cause of female infertility by oligoanovulation, clinical and biochemical hyperandrogenism and polycystic ovaries. Weight loss, firstly proposed in overweight or obese patient suffering from PCOS, aims to reduce hyperinsulinism and hyperandrogenism. Recently, Metformin, an insulin sensitizer, has been proposed as an alternative first line treatment for polycystic ovarian syndrome by improving hyperinsulinemia and hyperandrogenism in these women.
Aim :The aim of our study, and through a literature review, is to demonstrate if Metformin should be used as a first-line drug for infertile women with this syndrome or as an adjunction to Clomifene Citrate, the longest established treatment already used in this syndrome.
Methods: A prospective comparative study including 63 patients with PCOS has been done during 2 years. Women were randomly allocated to clomifene + Metformin (Metformin group, Metformin took during 8 weeks, 850 mg twice a day, plus Clomifene 100 mg per day during five days) or Clomifene only (100 mg per day during five days). All patients underwent a two- month’s diet.
Results:The middle age was about 30.63 years and the body mass index (BMI) was about 29.88 kg/ m2. We noticed a 6.2% weight loss in both groups (a non significant difference in p=0.04). The median of infertility period was about 2.49 years. The ovulation rate in the Metformin group was 53.12% (significant difference for inducing ovulation p=0.02) and 32.25% in Clomifene group (non-significant difference 0.07). There was also a significant difference for ongoing pregnancies (p=0.04). In fact, 11 on 32 patients (34%) achieved a full-term pregnancy in Metformin group versus only 4 ones on 31 patients (12.9%) in Clomifene group.
Conclusion:Our conclusion is that Metformin is an effective addition to Clomifene Citrate in term of reestablishment of ovulation and full-term pregnancies achievement, excluding ART cycles.

Keywords:

PCOS, Metformin, ovulation induction, Clomifene

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References

  1. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome .The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Fertil Steril 2004;81:19-25.
  2. Costello MF, Chapman M,Conway U. A systematic review and metaanalysis of randomized controlled trials on metformin coadministration during gonadotrophin ovulation induction or IVF in women with polycystic ovary syndrome. Hum Reprod 2006;21:1387- 99.
  3. Legro RS, Barnhart HX, Schaff WD et al. Clomiphene,metformin,or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007;356:551-66.
  4. Wickenheisser JK. Quin PG. Differential activity of the cytochrome P450 17·-hydroxylase and steroidogenic acute regulatory protein gene promoters in normal in normal and polycystic ovary syndrome theca cells. J Clin Endocrinol Metab 2000;85:2304-11
  5. Coviello AD, Legro RS, Dunaif A. Adolescent girls with polycystic ovary syndrome have an increased risk of the metabolic syndrome associated with increasing androgen levels independent of obesity and insulin resistance. J Clin Endocrinol Metab 2005;91:492-497
  6. Ibanez L, de Zegher P, Potati N. Anovulation after precocious pubarche: early markers and time course in adolescence. J Clin Endocrinol Metab 1997;1:599-604
  7. Jedel E, Kowalski J, Stener-Victorin E. Assessment of health-related quality of life: Swedish version of polycystic ovary syndrome questionnaire. Acta Obstet Gynecol Scand. 2008;87:1329-35.
  8. Jones GL, Hall JM, Balen AH, Ledger WL. Health-related quality of life measurement in women with polycystic ovary syndrome: a systematic review. Hum Reprod. 2008;14:15-25.
  9. Sam S, Legro RS, Bentley-Lewis R, Dunaif A 2005 Dyslipidemia and metabolic syndrome in the sisters of women with polycystic ovary syndrome. J Clin Endocrinol Metab 90:4797-4802.
  10. Norman RJ. Masters S. Hague W. Hyperinsulinemia is common in family members of women with polycystic ovary syndrome. Proc Natl Acad USA 1998;95:14956-60.
  11. Amato P, Simpson J-L. Génétique du syndrome des ovaries polykystiques. EMC (Elsevier SAS, Paris). Gynécologie, 140-A-20, 2006.
  12. Stein I, Leventhal M. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 1935;29:181-91
  13. Yildiz BO, Knochenhauer ES, Azziz R. Impact of obesity on the risk for polycystic ovary syndrome. J Clin Endocrinol Metab 2008;93:162-8.
  14. 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;43:647-54.
  15. Lord JM, Flight IHK, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 2003;327:951-3.
  16. Christin-Maître S. La Metformine : une alternative pour traiter l'infertilité. Gynéco Obstét et fertilité 2009;37:12-13
  17. 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, doubleblind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab 2000;85:139-46.
  18. Eisenhardt S, Schwarzmann N, Henschel V, Germeyer A, von Wolff M, Hamann A, 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;91:946-52.
  19. 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;87:569-74
  20. Creanga AA, Bradley HM, McCormick C, Witkop CT. Use of metformin in polycystic ovary syndrome: a meta-analysis. Obstet Gynecol 2008;111:959-68.
  21. Sinawat S, Buppasiri P, Lumbiganon P, Pattanittum P. Long versus short course treatment with metformin and clomiphene citrate for ovulation induction in women with PCOS (Review). Cochrane Database Syst Rev 2008;(1):CD006226.
  22. Moll E, Korevaar JC, Bossuyt PM, van der Veen F. Does adding metformin to clomifene citrate lead to higher pregnancy rates in a subset of women with polycystic ovary syndrome? Hum Reprod 2008;23:1830-4.
  23. Kashyap S, WellsGA, Rosenwaks Z. lnsulm-sensitizing agents as primary therapy for patients with polycystic ovarian syndrome. Hum Reprod 2004;19:2474-83.
  24. Kumari AS, Haq A, Jayasundaram R, Abdel-Waretk 10, Al Haïja SA,Alva-res M. Metformin monotherapy in lean women with polycystic ovary syndrome Reprod Biomed Online 2005;10:100-4.
  25. Kjotrod SB, Von During V, Carlsen SM. Metformin treatment before IVF/ICSI in women with polycystic ovary syndrome: a prospective, randomized, double blind study. Hum Reprod 2004;19:1315-22.
  26. Tang T, Glanville ], Hayden CJ, White D, Barth JH, Balen AH. Combined lifestyle modification and metformin in obese patients with polycystic ovary syn¬drome. A randomized, placebo-controlled, double-blind multicentre study. Hum Reprod 2006;21:80-9.
  27. Ehrmann DA, Cavaghan MK, Imperial J, Sturis J, Rosenfield RL, Polonsky KS. Effects of metformin on insulin secretion, insulin action, and ovarian steroi-dogenesis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1997;82:524-30.
  28. Palomba S, Orio FJr, Falbo A et al. Prospective parallel randomized, double-blind, double dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-time treatment for ovulation induction in non obese anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005;90:4068-74.
  29. 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;87:113-20.
  30. Legro RS, Barnhart HX, Schlaff WD et al Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007;356:551-66.
  31. Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, Van der Veen F. Effect of clomiphene citrate plus metformin and clomiphene citrate plus placebo on in¬duction of ovulation in women with newly diagnosed polycystic ovary syndrome; randomized double blind clinical trial. BMJ 2006;332:1485.
  32. Siebert Tl, Kruger IF, Steyn DW, Nosarka S. Is the addition of metformin efficacious in the treatment of clomiphene citrate-resistant patients with polycys¬tic ovary syndrome? A structured literature review. Fertil Steril 2006;86:1432-7.
  33. Dunaif A. Medscape. Drug insight: insulin-sensitizing drugs in the treatment of polycystic ovary syndrome-a reappraisal. Nat Clin Pract Endocrinol Metab 2008;4:272-83.
  34. Palomba S, Orio F, Falbo A, Russo T, Tolino A, Zullo F. Clomiphene citrate versus metformin as first-line approach for the treatment of anovulation in infertile patients with polycystic ovary syndrome. J Clin Endocrinol Metab 2007;92:3498-503.
  35. Palomba S, Orio F ]r, Nardo LG et al. 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 2004;89:4801-9.
  36. Doldi N, Perciso P, Di Sebastiano F, Marsiglio E, Ferrari A. Gonadotrophin-releasing hormone antagonist and metformin for treatment of polycystic ovary syndrome patients undergoing in vitro feriilization-embryo transfer. Gynecol Endocrinol 2006;22:235-8.
  37. Glueck CJ, Wang P, GoldenbergN, Sieve-Smith L. Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin. Hum Reprod 2002;17:2858-64.
  38. Boomsma CM, Fauser BC, Macklon NS. Pregnancy complications in wo¬men with polycystic ovary syndrome. Semin Reprod Med 2008;26:72-84.
  39. Gilbert C, Valois M, Koren G. Pregnancy outcome afterfirst-trimester expo-sure to metformin: a meta-analysis. Fertil Steril 2006;86:658-63.
  40. Thatcher SS, Jackson EM Pregnancy outcome in infertile patients with polycystic ovary syndrome who were treated with metformin. Fertil Steril 2006;85:1002-9.
  41. Costello M, Shrestha B, Eden J, Sjoblom P, Johnson N. insulinsensitising 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 Syst Rev 2007(1): CD005552.