The Effect of metformin on outcome of Intrauterine insemination (IUI) in insulin non-resistant infertile women with polycystic ovarian syndrome

Document Type : Original Article

Authors

1 Associate Professor, Department of Obstetrics and Gynecology, School of Medicine, Lorestan University of Medical Sciences, Lorestan, Iran.

2 Assistant Professor, Department of Obstetrics and Gynecology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Abstract

Introduction: polycystic ovary syndrome is the common cause of infertility due to anovulation, and insulin resistance, increasing high body mass Index and waist: hip ratio (WHR) are known risk factors in poor outcome of infertility treatment and also clinical response to metformin. This study was performed with aim to assess the effect of metformin on prediction of treatment outcomes of IUI in insulin – resistant and non-resistant infertile women with polycystic ovarian syndrome (PCOS) and the effect of resistant to insulin, BMI and WHR on them.
Methods: This non randomized clinical trial study was performed on 74 infertile women with PCOS who were candidate for IUI referred to infertility clinic of Mirza Koochackan Hospital of Tehran between 2011 and 2012. The patients were divided in two groups of Insulin Resistance and nonresistance according to the results of GTT(Glucose Tolerance Test) and Insulin level hormone test and were divided to four groups according to BMI. All patients received metformin 500mg, three times daily, six weeks before the IUI cycle and both groups subsequently underwent treatment with drugs of ovulation induction for IUI. Data were analyzed with T-test and ANOVA test. PResults: from 74 studied women, 34 cases were insulin resistance and 37 nonresistance. Treatment with metformin caused more ovulation rate, mean follicular size, positive result of pregnancy test, clinical pregnancy and adverse effects in Insulin resistance group, but these differences were not significant (P>0.05). But, two groups showed a significant difference in BMI and WHR ratio (P=0.02). 11 cases (29.7%) in resistance group and 9 (24.3%) in nonresistance group become pregnant, but this difference was not significant (P>0.05). In four indexes, two groups were not statistically significant in terms of IUI results and pregnancy incidence (P=0.05). But, in over weigh patients (BMI=25-30) in both groups, more pregnancy rate was observed.
Conclusion: Metformin can be administered for all PCOS patient regardless of Insulin resistant and nonresistance. Also BMI is a better predictor for the rate of response to treatment with metformin.

Keywords


  1. Adams J, Polson DW,  Franks S. Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. Br Med J (Clin Res Ed) 1986; 293(6543): 355.
  2. Hull MGR. Epidemiology of infertility and polycystic ovarian disease: endocrinological and demographic studies. Gynecol Endocrinol 1987; 1(3):235-45.  
  3. Edwards RG, Beard HK. Is thesuccess of human IVF more amatter of genetics and evolution than growing blastocysts?. HumReprod 1999;14(1):1
  4. Shoham Z, Weissman A. Polycystic ovarian disease: obesity andinsulin resistance In: Kempers RD, Cohen J, Haney AF,Younger JB, editors. Fertility and Reproductive Medicine.Amsterdam: Elsevier; 1998. p. 363-72.
  5. Kousta E, White DM, Frank S. Modern USC of Clomiphen citrate in induction of ovulation. Hum Reported Roduction 1997; 3(4): 359-65.
  6. Tan SL, Farhi J, Hombury R, Jacobs HS. Induction of ovulation in Clomiphen resistant PCOS with GnRH. Obstet Gynecol 1996, 88(2):221-6.
  7. Speroff L, Fritz MA. Clinical Gynecologic Endocrinology and Infertility. 7th ed. Philadephia: Lippincott Williams & Wilkins; 2005. p. 1175-205.
  8. Conway GS, Jacobs HS. Clinical implications of hyperinsulinemia in women. Clin Endocrinol. 1993; 39(6):623-32.
  9. Barbieri RL, Makris A, Randall RW, Daniels G, Kistner RW, Ryan KJ. Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism. J Clin Endocrinol Metab 1986;62(5):904-10.
  10. Tiitinen AE, Laatikainen TJ, Seppälä MT. Serum levels of insulin-like growth factor binding protein-1 and ovulatory responses to clomiphene citrate in women with polycystic ovarian disease. Fertil Steril 1993;60(1):58-62.
  11. Soule S.G. Neuroendocrinology of PCOS. Baillieres Clin Endocrinol Metab 1996; 10(2): 205-19.
  12. Kiddy DS, Hamilton FD, Seppala M, SEPPÄLÄ M, KOISTINEN R, JAMES VHD,  et al. Diet-induced changes in sex hormone binding globulin and free testosterone in women with normal or PCO correlation with serum insulin and ILGF-1. Clin Endocrinol 1994; 31(6): 771.
  13. Nestler JE, Clore JN, Blackard WG. The central role of obesity (hyperinsulinemia) in the pathogenesis of the polycystic ovary syndrome. Am J Obstet Gynecol 1989;161(5):1095-7.
  14. Dale PO, Tanbo T, Ertzeid G, Bjercke S, Oldereid N, Fedorcsák P, et al. The impact of insulin resistance on the outcome of laparoscopic ovarian electrocautery in infertile women with the polycystic ovary syndrome. Gynecol Endocrinol 2004;19(4):182-9
  15. Seibel M.M. A comprehensive text of infertility. 2th ed. Boston:Appelton & Lange; 1999.p.121- 32
  16. Kjøtrød SB, von Düring V, Carlsen SM. Metformin treatment before IVF/ICSI in women with polycystic ovary syndrome; a prospective, randomized, double blind study. Hum Reprod 2004;19(6):1315-22.
  17. Ronsini S ,Filippo Di ,Grieco N ,Cappiello F. D̒Anielo G. Ovulation induction in insulin- resistant infertility. ESHRE annual meeting of the 2006; i24
  18. Glueck CJ, Wang P, Goldenberg N, Sieve-Smith L. Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin. Hum Reprod 2002;17(11):2858-64
  19. Rossing M.A., Daling J.R., Weiss N.S. Ovarian tumors in a cohort of infertile women. N Engl J Med 1994; 331(12):771-6.
  20. Zeyneloglu  HB., Arici A, Olive DL, Duleba AJ. Comparison of intra uterine insemination with timed intercourse in superovulated cycles with gonadotropins a, metaanalysis. Fertil Steril 1998; 69(3):486-91.
  21. Zhathin LM, Nulsen A. Comparative analysis of cycle fecundity rate associated with HMG and IUI versus either HMG or IUI alone. Fertil Steril 1991; 55(2):252-7
  22. Legro RS,Finegood D and Dunaif A.A fasting glucose to insulin ration is a useful measure of insulin sensitivity in women with polycystic ovary syndrome.Jclin Endocrinol Metab 1998.83:2694-2698
  23. Moll E., Korenaar J.C. , Bossuyt P.M.M., et al. Does adding metformin to clomifene citrate lead to higher pregnancy rates in a subset of women with polycysticovary syndrome ?. Human Reproduction 2008;23;8 : 1830-1834.
  24. Palomba S, Pasquali R, Orio F Jr, Nestler JE. Clomiphene citrate, metforminor both as first-step approach in treating anovulatory infertility in patientswith polycystic ovary syndrome (PCOS) : a systematic review andmeta-analysis. Clin Endocrinol 2008; 70(2): 311-21
  25. Kashyap S, Wells GA, Rosenwaks Z. Insulin-sensitizing agents as primary therapy for patients with polycystic ovarian syndrome. Hum Reprod 2004; 19(11):2474–2483.
  26. Glueck, CJ,  Phlips H Cameron D, Sieve-Smith L, Wang P. Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce firsttrimester spontaneous abortion : a pilot study. Fertil.Steril 2001;75(1):46-52.
  27. Kocak I, Üstün C. Effect of metformin on insulin resistance, androgen concentration, ovulation and pregnancy rates in women with polycystic ovary ayndrome following laparoscopic ovarian drilling. J Obstet Gynaecol 2006, 32(3):292-8.
  28. Santbrink E ,Hohmann F ,Eijkemans M ,Laven J ,Fauser B.Dose metformin modify ovarian responsiveness during exogenous FSH ovulation induction in normogonadotrophic anovulation ? A placebo-controlled double-blind assessment. European Journal of Endocrinology 2005 ;152(4) :611-7
  29. 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. Human Reproduction 2005; 20(10): 2879-86.
  30. Nestler JE, Stovall D, Akhter N, Iuorno MJ, Jakubowicz DJ.Strategies for the use of insulinsensitizing drugs to treat infertility in women with polycystic ovary syndrome. Fertill Steril.2002; 77(2):209- 15.
  31. Onalan G1, Goktolga U, Ceyhan T, Bagis T, Onalan R, Pabuçcu R..Predictive value of glucose-insulin ratio in PCOS and profile of women who will benefit from metformin therapy : Obese, lean, hyper or normoinsulinemic?.  European journal of Obstetrics & Gynecology and Reproductive Biology 2005; 123(2):204-211.
  32. Knowler WC, Pettitt DJ, Saad MF, Charles MA, Nelson RG, Howard BV, et al. Obesity in the Pima Indians: its magnitude and relationship with diabetes. Amer J Clin Nutri 1991;53(6):1543S.
  33. Koh-Banerjee P, Chu NF, Spiegelman D, Rosner B, Colditz G, Willett W, et al. Prospective study of the association of changes in dietary intake, physical activity, alcohol consumption, and smoking with 9-y gain in waist circumference among 16 587 US men. Amer J Clin Nutri 2003;78(4):719-27.