Is the Co-Administration of Metformin and Clomiphene Superior to Induce Ovulation in Infertile Patients With Poly Cystic Ovary Syndrome and Confirmed Insulin-Resistance: A Double Blind Randomized Clinical Trial
,
Abstract
Objective: This study aimed to compare the effects of clomiphene citrate (CC) combined with metformin or placebo on infertile patients with poly cystic ovary syndrome (PCOS) and insulin resistance (IR).
Materials and methods: We included 151 infertile women with PCOS and IR in a university hospital from November 2015 to April 2022 in this prospective, double-blind, randomized, placebo-controlled trial. Patients were randomized into two groups; group A: received CC plus metformin (n = 76) and group
B: received CC plus placebo (n = 75). The ovulation rate was the main outcome measure. Clinical pregnancy, ongoing pregnancy, live birth and abortion rates were secondary outcome measures.
Results: There was no remarkable difference in ovulation rate in two groups. Moreover, no significant changes were observed in clinical pregnancy, ongoing pregnancy, live birth and abortion rates between two groups. A larger proportion of women in group A suffered from side effects of metformin
(9.3% versus 1.4%; p=0.064), although this was not significant.
Conclusion: In IR infertile women with PCOS, metformin pre-treatment did not increase the ovulation, clinical pregnancy and live birth rates in patients on clomiphene citrate.
1. March WA, Moore VM, Willson KJ, Phillips DIW, Norman RJ, Davies MJ. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod 2010;25(2):544–51.
2. Franks S. Polycystic Ovary Syndrome. N Engl J Med 1995;333(13):853–61.
3. Horowitz E, Weissman A. The stair-step approach in treatment of anovulatory PCOS patients. Ther Adv Reprod Health 2020;14: 2633494120908818.
4. Shepard MK, Balmaceda JP, Leija CG. Relationship of Weight to Successful Induction of Ovulation with Clomiphene Citrate. Fertil Steril 1979;32(6):641–5.
5. Nestler JE, Jakubowicz DJ. Lean Women with Polycystic Ovary Syndrome Respond to Insulin Reduction with Decreases in Ovarian P450c17α Activity and Serum Androgens 1. J Clin Endocrinol Metab 1997;82(12):4075–9.
6. 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(26):1876–80.
7. Moll E, Bossuyt PMM, 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;332(7556):1485.
8. Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, et al. Clomiphene, Metformin, or Both for Infertility in the Polycystic Ovary Syndrome. N Engl J Med 2007;356(6):551–66.
9. Şahin Y, Yirmibeş Ü, Keleştimur 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;113(2):214–20.
10. Jungheim ES, Odibo AO. Fertility treatment in women with polycystic ovary syndrome: a decision analysis of different oral ovulation induction agents. Fertil Steril 2010;94(7):2659–64.
11. Leanza V, Coco L, Grasso F, Leanza G, Zarbo G PM. Ovulation induction with clomiphene citrate and metformin in women with polycystic ovary syndrome. Minerva Ginecol 2014;66(3):299–301.
12. Penzias A, Bendikson K, Butts S, Coutifaris C, Falcone T, Fossum G, et al. Role of metformin for ovulation induction in infertile patients with polycystic ovary syndrome (PCOS): a guideline. Fertil Steril 2017;108(3):426–41.
13. Sharpe A, Morley LC, Tang T, Norman RJ, Balen AH. Metformin for ovulation induction (excluding gonadotrophins) in women with polycystic ovary syndrome. Cochrane Database Syst Rev 2019;12(12): CD013505.
14. Nawrocka-Rutkowska J, Ciećwież S, Marciniak A, Brodowska A, Wiśniewska B, Kotlega D, et al. 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.
15. Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HWG, Behre HM, et al. World Health Organization reference values for human semen characteristics. Hum Reprod Update 2010;16(3):231–45.
16. Speroff L FM. Induction ovulation In :Cilinical gynecologic endocrinology and infertility. Philadelphi: Lippincott,Williams and Wilkins 2005;7th Ed:499-1180.
17. Bart CJM FM. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004;81(1):19–25.
18. Legro RS, Schlaff WD, Diamond MP, Coutifaris C, Casson PR, Brzyski RG, et al. Total Testosterone Assays in Women with Polycystic Ovary Syndrome: Precision and Correlation with Hirsutism. J Clin Endocrinol Metab 2010;95(12):5305–13.
19. Moll E, van der Veen F, van Wely M. The role of metformin in polycystic ovary syndrome: a systematic review. Hum Reprod Update 2007 ;13(6):527–37.
20. 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;75(5):692–7.
21. 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;51(2):125–9.
22. Morin-Papunen L, Rantala AS, Unkila-Kallio L, Tiitinen A, Hippeläinen M, Perheentupa A, 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(5):1492–500.
23. 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(1):101–6.
24. Ng EHY. Effects of metformin on ovulation rate, hormonal and metabolic profiles in women with clomiphene-resistant polycystic ovaries: a randomized, double-blinded placebo-controlled trial. Hum Reprod 2001 ;16(8):1625–31.
25. Lebovitz H. Insulin resistance: definition and consequences. Exp Clin Endocrinol Diabetes2001 ;109(Suppl 2):S135–48.
26. 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 Steril1999;71(2):323–7.
27. Liu KE, Tataryn IV, Sagle M. Use of Metformin for Ovulation Induction in Women Who Have Polycystic Ovary Syndrome With or Without Evidence of Insulin Resistance. J Obstet Gynaecol Can 2006;28(7):595-9.
28. Morgante G, Massaro MG, Scolaro V, Cappelli V, Luddi A, Troìa L, et al. Metformin doses and body mass index: clinical outcomes in insulin resistant polycystic ovary syndrome women. Eur Rev Med Pharmacol Sci 2020;24(15):8136–42.
29. Açbay O, Gündoğdu S. Can metformin reduce insulin resistance in polycystic ovary syndrome. Fertil Steril 1996;65(5):946–9.
2. Franks S. Polycystic Ovary Syndrome. N Engl J Med 1995;333(13):853–61.
3. Horowitz E, Weissman A. The stair-step approach in treatment of anovulatory PCOS patients. Ther Adv Reprod Health 2020;14: 2633494120908818.
4. Shepard MK, Balmaceda JP, Leija CG. Relationship of Weight to Successful Induction of Ovulation with Clomiphene Citrate. Fertil Steril 1979;32(6):641–5.
5. Nestler JE, Jakubowicz DJ. Lean Women with Polycystic Ovary Syndrome Respond to Insulin Reduction with Decreases in Ovarian P450c17α Activity and Serum Androgens 1. J Clin Endocrinol Metab 1997;82(12):4075–9.
6. 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(26):1876–80.
7. Moll E, Bossuyt PMM, 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;332(7556):1485.
8. Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, et al. Clomiphene, Metformin, or Both for Infertility in the Polycystic Ovary Syndrome. N Engl J Med 2007;356(6):551–66.
9. Şahin Y, Yirmibeş Ü, Keleştimur 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;113(2):214–20.
10. Jungheim ES, Odibo AO. Fertility treatment in women with polycystic ovary syndrome: a decision analysis of different oral ovulation induction agents. Fertil Steril 2010;94(7):2659–64.
11. Leanza V, Coco L, Grasso F, Leanza G, Zarbo G PM. Ovulation induction with clomiphene citrate and metformin in women with polycystic ovary syndrome. Minerva Ginecol 2014;66(3):299–301.
12. Penzias A, Bendikson K, Butts S, Coutifaris C, Falcone T, Fossum G, et al. Role of metformin for ovulation induction in infertile patients with polycystic ovary syndrome (PCOS): a guideline. Fertil Steril 2017;108(3):426–41.
13. Sharpe A, Morley LC, Tang T, Norman RJ, Balen AH. Metformin for ovulation induction (excluding gonadotrophins) in women with polycystic ovary syndrome. Cochrane Database Syst Rev 2019;12(12): CD013505.
14. Nawrocka-Rutkowska J, Ciećwież S, Marciniak A, Brodowska A, Wiśniewska B, Kotlega D, et al. 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.
15. Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HWG, Behre HM, et al. World Health Organization reference values for human semen characteristics. Hum Reprod Update 2010;16(3):231–45.
16. Speroff L FM. Induction ovulation In :Cilinical gynecologic endocrinology and infertility. Philadelphi: Lippincott,Williams and Wilkins 2005;7th Ed:499-1180.
17. Bart CJM FM. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004;81(1):19–25.
18. Legro RS, Schlaff WD, Diamond MP, Coutifaris C, Casson PR, Brzyski RG, et al. Total Testosterone Assays in Women with Polycystic Ovary Syndrome: Precision and Correlation with Hirsutism. J Clin Endocrinol Metab 2010;95(12):5305–13.
19. Moll E, van der Veen F, van Wely M. The role of metformin in polycystic ovary syndrome: a systematic review. Hum Reprod Update 2007 ;13(6):527–37.
20. 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;75(5):692–7.
21. 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;51(2):125–9.
22. Morin-Papunen L, Rantala AS, Unkila-Kallio L, Tiitinen A, Hippeläinen M, Perheentupa A, 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(5):1492–500.
23. 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(1):101–6.
24. Ng EHY. Effects of metformin on ovulation rate, hormonal and metabolic profiles in women with clomiphene-resistant polycystic ovaries: a randomized, double-blinded placebo-controlled trial. Hum Reprod 2001 ;16(8):1625–31.
25. Lebovitz H. Insulin resistance: definition and consequences. Exp Clin Endocrinol Diabetes2001 ;109(Suppl 2):S135–48.
26. 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 Steril1999;71(2):323–7.
27. Liu KE, Tataryn IV, Sagle M. Use of Metformin for Ovulation Induction in Women Who Have Polycystic Ovary Syndrome With or Without Evidence of Insulin Resistance. J Obstet Gynaecol Can 2006;28(7):595-9.
28. Morgante G, Massaro MG, Scolaro V, Cappelli V, Luddi A, Troìa L, et al. Metformin doses and body mass index: clinical outcomes in insulin resistant polycystic ovary syndrome women. Eur Rev Med Pharmacol Sci 2020;24(15):8136–42.
29. Açbay O, Gündoğdu S. Can metformin reduce insulin resistance in polycystic ovary syndrome. Fertil Steril 1996;65(5):946–9.
| Files | ||
| Issue | Vol 17, No 1 (March 2023) | |
| Section | Original Articles | |
| DOI | https://doi.org/10.18502/jfrh.v17i1.11973 | |
| Keywords | ||
| Clomiphene Citrate Infertility Insulin Resistance Metformin Poly Cystic Ovary Syndrome | ||
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How to Cite
1.
Azargoon A, Fatemi H, Mirmohammadkhani M, Darzi S. Is the Co-Administration of Metformin and Clomiphene Superior to Induce Ovulation in Infertile Patients With Poly Cystic Ovary Syndrome and Confirmed Insulin-Resistance: A Double Blind Randomized Clinical Trial. J Family Reprod Health. 2023;17(1):21-28.
