Metformine and CC Compared With Placebo and CC for Induction Ovulation in PCOS Patients With Insulin Resistant

Summary

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility which affects 12-21% of the population.Several studies performed evaluate the possible benefit of metformin alone or in combination with clomiphene (CC)as first-line treatment for infertility in women with PCOS have reported conflicting results. These conflicting results may be due to the presence or absence of insulin resistance(IR).Metformin decreases IR .However there is not a single randomized clinical trial with metformin in IR PCOS patients. Therefore, the aim of current study is to compare CC with coadministration of metformin and with CC with coadministration of placebo in IR PCOS patients to induce ovulation.

Timeline

Start

2015-11

Primary completion

2022-04

Completion

2022-04

Publications

• Background Franks S. Polycystic ovary syndrome. N Engl J Med. 1995 Sep 28;333(13):853-61. doi: 10.1056/NEJM199509283331307. No abstract available.
• Background Moll E, van Wely M, Lambalk CB, Bossuyt PM, van der Veen F. Health-related quality of life in women with newly diagnosed polycystic ovary syndrome randomized between clomifene citrate plus metformin or clomifene citrate plus placebo. Hum Reprod. 2012 Nov;27(11):3273-8. doi: 10.1093/humrep/des310. Epub 2012 Aug 27.
• Background Hammond MG. Monitoring techniques for improved pregnancy rates during clomiphene ovulation induction. Fertil Steril. 1984 Oct;42(4):499-509. doi: 10.1016/s0015-0282(16)48129-x.
• Background Shepard MK, Balmaceda JP, Leija CG. Relationship of weight to successful induction of ovulation with clomiphene citrate. Fertil Steril. 1979 Dec;32(6):641-5. doi: 10.1016/s0015-0282(16)44411-0.
• Background Homburg R. Polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol. 2008 Apr;22(2):261-74. doi: 10.1016/j.bpobgyn.2007.07.009. Epub 2007 Sep 5.
• Background Chang RJ, Nakamura RM, Judd HL, Kaplan SA. Insulin resistance in nonobese patients with polycystic ovarian disease. J Clin Endocrinol Metab. 1983 Aug;57(2):356-9. doi: 10.1210/jcem-57-2-356.
• Background Dunaif A, Graf M, Mandeli J, Laumas V, Dobrjansky A. Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. J Clin Endocrinol Metab. 1987 Sep;65(3):499-507. doi: 10.1210/jcem-65-3-499.
• Background Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989 Sep;38(9):1165-74. doi: 10.2337/diab.38.9.1165.
• Background Dunaif A, Segal KR, Shelley DR, Green G, Dobrjansky A, Licholai T. Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes. 1992 Oct;41(10):1257-66. doi: 10.2337/diab.41.10.1257.
• Background 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 Jun 25;338(26):1876-80. doi: 10.1056/NEJM199806253382603.
• Background Nestler JE, Jakubowicz DJ. Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17 alpha activity and serum androgens. J Clin Endocrinol Metab. 1997 Dec;82(12):4075-9. doi: 10.1210/jcem.82.12.4431.
• Background Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, van der Veen F. 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 Jun 24;332(7556):1485. doi: 10.1136/bmj.38867.631551.55. Epub 2006 Jun 12.
• Background Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, Steinkampf MP, Coutifaris C, McGovern PG, Cataldo NA, Gosman GG, Nestler JE, Giudice LC, Leppert PC, Myers ER; Cooperative Multicenter Reproductive Medicine Network. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007 Feb 8;356(6):551-66. doi: 10.1056/NEJMoa063971.
• Background Sahin Y, Yirmibes U, Kelestimur F, Aygen E. The effects of metformin on insulin resistance, clomiphene-induced ovulation and pregnancy rates in women with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2004 Apr 15;113(2):214-20. doi: 10.1016/j.ejogrb.2003.09.036.
• Background Baran S, Api M, Goksedef BP, Cetin A. Comparison of metformin and clomiphene citrate therapy for induction of ovulation in the polycystic ovary syndrome. Arch Gynecol Obstet. 2010 Oct;282(4):439-43. doi: 10.1007/s00404-010-1497-y. Epub 2010 May 16.
• Background 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(4):304-13. doi: 10.1159/000335253. Epub 2012 Apr 17.
• Background Jungheim ES, Odibo AO. Fertility treatment in women with polycystic ovary syndrome: a decision analysis of different oral ovulation induction agents. Fertil Steril. 2010 Dec;94(7):2659-64. doi: 10.1016/j.fertnstert.2010.03.077. Epub 2010 May 7.
• Background Leanza V, Coco L, Grasso F, Leanza G, Zarbo G, Palumbo M. Ovulation induction with clomiphene citrate and metformin in women with polycystic ovary syndrome. Minerva Ginecol. 2014 Jun;66(3):299-301.
• Background Xiao J, Chen S, Zhang C, Chang S. The effectiveness of metformin ovulation induction treatment in patients with PCOS: a systematic review and meta-analysis. Gynecol Endocrinol. 2012 Dec;28(12):956-60. doi: 10.3109/09513590.2012.705368. Epub 2012 Jul 19.
• Background Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD003053. doi: 10.1002/14651858.CD003053.pub4.
• Background Misso ML, Costello MF, Garrubba M, Wong J, Hart R, Rombauts L, Melder AM, Norman RJ, Teede HJ. Metformin versus clomiphene citrate for infertility in non-obese women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2013 Jan-Feb;19(1):2-11. doi: 10.1093/humupd/dms036. Epub 2012 Sep 6.
• Background Nawrocka-Rutkowska J, Ciecwiez S, Marciniak A, Brodowska A, Wisniewska B, Kotlega D, Starczewski A. Insulin resistance assessment in patients with polycystic ovary syndrome using different diagnostic criteria--impact of metformin treatment. Ann Agric Environ Med. 2013;20(3):528-32.
• Background Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HW, Behre HM, Haugen TB, Kruger T, Wang C, Mbizvo MT, Vogelsong KM. World Health Organization reference values for human semen characteristics. Hum Reprod Update. 2010 May-Jun;16(3):231-45. doi: 10.1093/humupd/dmp048. Epub 2009 Nov 24.
• Background Speroff L, Fritz MA. Induction ovulation In :Cilinical gynecologic endocrinology and infertility. 7th Ed. Philadelphi: Lippincott,Williams and Wilkins; 2005: 499-1180.
• Background Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004 Jan;81(1):19-25. doi: 10.1016/j.fertnstert.2003.10.004.
• Background Legro RS, Schlaff WD, Diamond MP, Coutifaris C, Casson PR, Brzyski RG, Christman GM, Trussell JC, Krawetz SA, Snyder PJ, Ohl D, Carson SA, Steinkampf MP, Carr BR, McGovern PG, Cataldo NA, Gosman GG, Nestler JE, Myers ER, Santoro N, Eisenberg E, Zhang M, Zhang H; Reproductive Medicine Network. Total testosterone assays in women with polycystic ovary syndrome: precision and correlation with hirsutism. J Clin Endocrinol Metab. 2010 Dec;95(12):5305-13. doi: 10.1210/jc.2010-1123. Epub 2010 Sep 8.
• Background Moll E, van der Veen F, van Wely M. The role of metformin in polycystic ovary syndrome: a systematic review. Hum Reprod Update. 2007 Nov-Dec;13(6):527-37. doi: 10.1093/humupd/dmm026. Epub 2007 Sep 1.
• Background Karimzadeh MA, Javedani M. An assessment of lifestyle modification versus medical treatment with clomiphene citrate, metformin, and clomiphene citrate-metformin in patients with polycystic ovary syndrome. Fertil Steril. 2010 Jun;94(1):216-20. doi: 10.1016/j.fertnstert.2009.02.078. Epub 2009 May 21.
• Background Parsanezhad ME, Alborzi S, Zarei A, Dehbashi S, Omrani G. Insulin resistance in clomiphene responders and non-responders with polycystic ovarian disease and therapeutic effects of metformin. Int J Gynaecol Obstet. 2001 Oct;75(1):43-50. doi: 10.1016/s0020-7292(01)00470-2.
• Background Khorram O, Helliwell JP, Katz S, Bonpane CM, Jaramillo L. Two weeks of metformin improves clomiphene citrate-induced ovulation and metabolic profiles in women with polycystic ovary syndrome. Fertil Steril. 2006 May;85(5):1448-51. doi: 10.1016/j.fertnstert.2005.10.042. Epub 2006 Mar 31.
• Background Legro RS, Brzyski RG, Diamond MP, Coutifaris C, Schlaff WD, Casson P, Christman GM, Huang H, Yan Q, Alvero R, Haisenleder DJ, Barnhart KT, Bates GW, Usadi R, Lucidi S, Baker V, Trussell JC, Krawetz SA, Snyder P, Ohl D, Santoro N, Eisenberg E, Zhang H; NICHD Reproductive Medicine Network. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med. 2014 Jul 10;371(2):119-29. doi: 10.1056/NEJMoa1313517.
• Background Hosseinpanah F, Barzin M, Tehrani FR, Azizi F. The lack of association between polycystic ovary syndrome and metabolic syndrome: Iranian PCOS prevalence study. Clin Endocrinol (Oxf). 2011 Nov;75(5):692-7. doi: 10.1111/j.1365-2265.2011.04113.x.
• Background Hasegawa I, Murakawa H, Suzuki M, Yamamoto Y, Kurabayashi T, Tanaka K. Effect of troglitazone on endocrine and ovulatory performance in women with insulin resistance-related polycystic ovary syndrome. Fertil Steril. 1999 Feb;71(2):323-7. doi: 10.1016/s0015-0282(98)00454-3.
• Background Johnson N. Metformin is a reasonable first-line treatment option for non-obese women with infertility related to anovulatory polycystic ovary syndrome--a meta-analysis of randomised trials. Aust N Z J Obstet Gynaecol. 2011 Apr;51(2):125-9. doi: 10.1111/j.1479-828X.2010.01274.x. Epub 2011 Jan 28.
• Background Morin-Papunen L, Rantala AS, Unkila-Kallio L, Tiitinen A, Hippelainen M, Perheentupa A, Tinkanen H, Bloigu R, Puukka K, Ruokonen A, Tapanainen JS. 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 May;97(5):1492-500. doi: 10.1210/jc.2011-3061. Epub 2012 Mar 14.
• Background Lebovitz HE. Insulin resistance: definition and consequences. Exp Clin Endocrinol Diabetes. 2001;109 Suppl 2:S135-48. doi: 10.1055/s-2001-18576.
• Background Palomba S, Falbo A, Orio F Jr, Manguso F, Russo T, Tolino A, Annamaria C, Dale B, Zullo F. 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 Oct;20(10):2879-86. doi: 10.1093/humrep/dei130. Epub 2005 Jun 15.
• Background DeUgarte CM, Bartolucci AA, Azziz R. Prevalence of insulin resistance in the polycystic ovary syndrome using the homeostasis model assessment. Fertil Steril. 2005 May;83(5):1454-60. doi: 10.1016/j.fertnstert.2004.11.070.
• Background Goverde AJ, van Koert AJ, Eijkemans MJ, Knauff EA, Westerveld HE, Fauser BC, Broekmans FJ. Indicators for metabolic disturbances in anovulatory women with polycystic ovary syndrome diagnosed according to the Rotterdam consensus criteria. Hum Reprod. 2009 Mar;24(3):710-7. doi: 10.1093/humrep/den433. Epub 2008 Dec 17.
• Background Mather K. Surrogate measures of insulin resistance: of rats, mice, and men. Am J Physiol Endocrinol Metab. 2009 Feb;296(2):E398-9. doi: 10.1152/ajpendo.90889.2008. No abstract available.
• Background Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care. 2004 Jun;27(6):1487-95. doi: 10.2337/diacare.27.6.1487.
• Background Legro RS, Castracane VD, Kauffman RP. Detecting insulin resistance in polycystic ovary syndrome: purposes and pitfalls. Obstet Gynecol Surv. 2004 Feb;59(2):141-54. doi: 10.1097/01.OGX.0000109523.25076.E2.
• Background Zheng J, Shan PF, Gu W. The efficacy of metformin in pregnant women with polycystic ovary syndrome: a meta-analysis of clinical trials. J Endocrinol Invest. 2013 Nov;36(10):797-802. doi: 10.3275/8932. Epub 2013 Apr 12.
• Background Mueller A, Schofl C, Dittrich R, Cupisti S, Oppelt PG, Schild RL, Beckmann MW, Haberle L. Thyroid-stimulating hormone is associated with insulin resistance independently of body mass index and age in women with polycystic ovary syndrome. Hum Reprod. 2009 Nov;24(11):2924-30. doi: 10.1093/humrep/dep285. Epub 2009 Aug 3.
• Results March WA, Moore VM, Willson KJ, Phillips DI, Norman RJ, Davies MJ. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod. 2010 Feb;25(2):544-51. doi: 10.1093/humrep/dep399. Epub 2009 Nov 12.

Drugs

Indications