Effectiveness of inositol, metformin and their combination in women with PCOS undergoing assisted reproduction: systematic review and meta-analysis

References

• Rotterdam ESHRE/ASRM‐Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long‐term health risks related to polycystic ovary syndrome (PCOS). Human Reproduction. 2004;19(1):41–47.
   PubMed Web of Science ®Google Scholar
• Teede HJ, Misso ML, Deeks AA, Moran L, Stuckey BG, Wong JL, Norman R, Costello MF, Guideline Development Groups, Assessment and management of polycystic ovary syndrome: summary of an evidence-based guideline. Med J Aust. 2011;195(6):S65–S112.
   PubMed Web of Science ®Google Scholar
• Teede H, Misso M, Costello M, Dokras A, Laven J, Moran L, Piltonen T, Norman R. International evidence-based guideline for the assessment and management of polycystic ovary syndrome 2018. National Health and Medical Research Council (NHMRC). 2018:1–198.
   Google Scholar
• Jauhari R, Mathur P, Gupta V. Infertility riding on polycystic ovarian syndrome (PCOS): a review of treatment modalities. JPRI. 2021;:1–14.
   Google Scholar
• Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.
   PubMed Web of Science ®Google Scholar
• Zawadzski JK. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. Polycystic Ovary Syndrome. 1992:39–50.
   Google Scholar
• Zain MM, Jamaluddin R, Ibrahim A, Norman, RJ. 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. Fertil Steril. 2009;91(2):514–521.
   PubMed Web of Science ®Google Scholar
• Maged AM, Elsawah H, Abdelhafez A, Bakry A, Mostafa WA. The adjuvant effect of metformin and N-acetylcysteine to clomiphene citrate in induction of ovulation in patients with polycystic ovary syndrome. Gynecol Endocrinol. 2015;31(8):635–638.
   PubMed Web of Science ®Google Scholar
• Hwu YM, Lin SY, Huang WY, Lin MH, Lee RKK. Ultra-short metformin pretreatment for clomiphene citrate-resistant polycystic ovary syndrome. Int J Gynaecol Obstet. 2005;90(1):39–43.
   PubMedGoogle Scholar
• Vandermolen DT, Ratts VS, Evans WS, Stovall DW, Kauma SW, Nestler JE. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil Steril. 2001;75(2):310–315.
   PubMed Web of Science ®Google Scholar
• Basirat Z, Kashifard M, Amiri MG. Enhanced ovarian follicular development by metformin does not correlate with pregnancy rate: a randomized trial. Int J Fertil Steril. 2012;6(1):31.
   PubMedGoogle Scholar
• Johnson NP, Stewart AW, Falkiner J, REACT-NZ (REproduction And Collaborative Trials in New Zealand), a multi-centre fertility trials group, et al. PCOSMIC: a multi-Centre randomized trial in women with PolyCystic Ovary Syndrome evaluating metformin for infertility with clomiphene. Hum Reprod. 2010;25(7):1675–1683.
   PubMed Web of Science ®Google Scholar
• Cheng J, Lv J, Li CY, Xue Y, Huang Z, Zheng W. Clinical outcomes of ovulation induction with metformin, clomiphene citrate and human menopausal gonadotrophin in polycystic ovary syndrome. J Int Med Res. 2010;38(4):1250–1258.
   PubMedGoogle Scholar
• Kar S, Sanchita S. Clomiphene citrate, metformin or a combination of both as the first-line ovulation induction drug for Asian Indian women with polycystic ovarian syndrome: a randomized controlled trial. J Hum Reprod Sci. 2015;8(4):197–201.
   PubMedGoogle Scholar
• 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 Obstetr Gynecol Reproduct Biol. 2004;113(2):214–220.
   PubMedGoogle Scholar
• 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):101–106.
   PubMedGoogle Scholar
• Legro RS, Barnhart HX, Schlaff WD, Cooperative Multicenter Reproductive Medicine Network, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356(6):551–566.
   PubMed Web of Science ®Google Scholar
• Doldi N, Persico P, Di Sebastiano F, Marsiglio E, Ferrari A. Gonadotropin-releasing hormone antagonist and metformin for treatment of polycystic ovary syndrome patients undergoing in vitro fertilization-embryo transfer. Gynecol Endocrinol. 2006;22(5):235–238.
   PubMed Web of Science ®Google Scholar
• MalkawiHasan Y, HS, Qublan. The effect of metformin plus clomiphene citrate on ovulation and pregnancy rates in clomiphene-resistant women with polycystic ovary syndrome. Saudi Med J. 2002;23(6):663–666.
   PubMedGoogle Scholar
• Hosseini MA, Alleyassin A, Sarvi F, Safdarian L, Kokab A, Fanisalek M. Metformin treatment in different phenotypes of polycystic ovary syndrome. Arch Gynecol Obstet. 2013;288(5):1131–1136.
   PubMedGoogle Scholar
• Begum MR, Akhter S, Ehsan M, Begum MS, Khan F. Pretreatment and co‐administration of oral anti‐diabetic agent with clomiphene citrate or rFSH for ovulation induction in clomiphene‐citrate‐resistant polycystic ovary syndrome. J Obstet Gynaecol Res. 2013;39(5):966–973.
   PubMedGoogle Scholar
• Tasdemir S, Ficicioglu C, Yalti S, Gurbuz B, Basaran T, Yildirim G. The effect of metformin treatment to ovarian response in cases with PCOS. Arch Gynecol Obstet. 2004;269(2):121–124.
   PubMedGoogle Scholar
• Palomba S, Falbo A, Orio F, 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;20(10):2879–2886.
   PubMedGoogle Scholar
• Morin-Papunen L, Rantala AS, Unkila-Kallio L, Tiitinen A, Hippeläinen M, Perheentupa A, Tinkanen H, Bloigu R, Puukka K, Ruokonen A. 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):1492–1500.
   PubMed Web of Science ®Google Scholar
• Abdalmageed OS, Farghaly TA, Abdelaleem AA, Abdelmagied AE, Ali MK, Abbas AM. Impact of metformin on IVF outcomes in overweight and obese women with polycystic ovary syndrome: a randomized double-blind controlled trial. Reprod Sci. 2019;26(10):1336–1342.
   PubMedGoogle Scholar
• Kjøtrød SB, von Düring V, Carlsen SM. Metformin treatment before IVF/ICSI in women with polycystic ovary syndrome; a prospective, randomized, double-blind study. Human Reproduc. 2004;19(6):1315–1322.
   PubMed Web of Science ®Google Scholar
• Wei Z, Cao Y, Cong L, Zhou P, Zhang Z, Li J. RETRACTED: Effect of metformin pretreatment on pregnancy outcome of in vitro matured oocytes retrieved from women with polycystic ovary syndrome. Fertil Steril. 2008;90(4):1149–1154.
   PubMedGoogle Scholar
• Palomba S, Falbo A, Carrillo L, Villani MT, Orio F, Russo T, Cello AD, Cappiello F, Capasso S, Tolino A. Metformin reduces risk of ovarian hyperstimulation syndrome in patients with polycystic ovary syndrome during gonadotropin-stimulated in vitro fertilization cycles: a randomized, controlled trial. Fertil Steril. 2011;96(6):1384–1390.e4.
   PubMed Web of Science ®Google Scholar
• Palomba S, Falbo A, Di Cello A, Cappiello F, Tolino A, Zullo F. Does metformin affect the ovarian response to gonadotropins for in vitro fertilization treatment in patients with polycystic ovary syndrome and reduced ovarian reserve? A randomized controlled trial. Fertil Steril. 2011;96(5):1128–1133.
   PubMedGoogle Scholar
• Qublan HS, Al-Khaderei S, Abu-Salem AN, Al-Zpoon A, Al-Khateeb M, Al-Ibrahim N, Al-Ahmad N. Metformin in the treatment of clomiphene citrate-resistant women with polycystic ovary syndrome undergoing in vitro fertilization treatment: a randomized controlled trial. J Obstet Gynaecol. 2009;29(7):651–655.
   PubMedGoogle Scholar
• Tang T, Glanville J, Orsi N, Barth JH, Balen AH. The use of metformin for women with PCOS undergoing IVF treatment. Hum Reprod. 2006;21(6):1416–1425.
   PubMed Web of Science ®Google Scholar
• Jacob SL, Brewer C, Tang T, Picton HM, Barth JH, Balen AH. A short course of metformin does not reduce OHSS in a GnRH antagonist cycle for women with PCOS undergoing IVF: a randomized placebo-controlled trial. Hum Reprod. 2016;31(12):2756–2764.
   PubMedGoogle Scholar
• Kjøtrød SB, Carlsen SM, Rasmussen PE, et al. Use of metformin before and during assisted reproductive technology in non-obese young infertile women with polycystic ovary syndrome: a prospective, randomized, double-blind, multi-Centre study. Hum Reprod. 2011;26(8):2045–2053.[21606131].
   PubMed Web of Science ®Google Scholar
• Önalan G, Pabuçcu R, Goktolga U, Ceyhan T, Bagis T, Cıncık M. Metformin treatment in patients with polycystic ovary syndrome undergoing in vitro fertilization: a prospective randomized trial. Fertil Steril. 2005;84(3):798–801.
   PubMedGoogle Scholar
• Emekçi Özay Ö, Özay AC, Çağlıyan E, Okyay RE, Gülekli B. Myo-inositol administration positively effects ovulation induction and intrauterine insemination in patients with polycystic ovary syndrome: a prospective, controlled, randomized trial. Gynecol Endocrinol. 2017;33(7):524–528.
   PubMed Web of Science ®Google Scholar
• Papaleo E, Unfer V, Baillargeon J-P, Fusi F, Occhi F, De Santis L. Myo-inositol may improve oocyte quality in intracytoplasmic sperm injection cycles. A prospective, controlled, randomized trial. Fertil Steril. 2009;91(5):1750–1754.
   PubMed Web of Science ®Google Scholar
• Raffone E, Rizzo P, Benedetto V. Insulin sensitizer agents alone and in co-treatment with r-FSH for ovulation induction in PCOS women. Gynecol Endocrinol. 2010;26(4):275–280.
   PubMed Web of Science ®Google Scholar
• Rajasekaran K, Malhotra N, Mahey R, Khadgawat R, Kalaivani M. Myoinositol versus metformin pretreatment in GnRH-antagonist cycle for women with PCOS undergoing IVF: a double-blinded randomized controlled study. Gynecol Endocrinol. 2022;38(2):140–147.
   PubMedGoogle Scholar
• Prabhakar P, Mahey R, Gupta M, Khadgawat R, Kachhawa G, Sharma JB, Vanamail P, Kumari R, Bhatla N. Impact of myoinositol with metformin and myoinositol alone in infertile PCOS women undergoing ovulation induction cycles-randomized controlled trial. Gynecol Endocrinol. 2021;37(4):332–336.
   PubMed Web of Science ®Google Scholar
• Agrawal A, Mahey R, Kachhawa G, Khadgawat R, Vanamail P, Kriplani A. Comparison of metformin plus myoinositol vs metformin alone in PCOS women undergoing ovulation induction cycles: randomized controlled trial. Gynecol Endocrinol. 2019;35(6):511–514.
   PubMed Web of Science ®Google Scholar
• 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: randomized double-blind clinical trial. BMJ. 2006;332(7556):1485.
   PubMedGoogle Scholar
• McGuinness LA, Higgins JPT. Risk-of-bias VISualization (robvis): an R package and shiny web app for visualizing risk of-bias assessments. Res Syn Meth. 2021;12(1):55–61.
   PubMed Web of Science ®Google Scholar
• Saltiel AR. Second messengers of insulin action. Diabetes Care. 1990;13(3):244–256.
   PubMed Web of Science ®Google Scholar
• Defronzo RA, Barzilai NIR, Simonson DC. Mechanism of metformin action in obese and lean noninsulin-dependent diabetic subjects. J Clin Endocrinol Metab. 1991;73(6):1294–1301.
   PubMed Web of Science ®Google Scholar
• Papaleo E, Unfer V, Baillargeon JP, Chiu TT. Contribution of myo-inositol to reproduction. Eur J Obstet Gynecol Reprod Biol. 2009;147(2):120–123.
   PubMed Web of Science ®Google Scholar
• Carlomagno G, Unfer V. Inositol safety: clinical evidences. Eur Rev Med Pharmacol Sci. 2011;15(8):931–936.
   PubMed Web of Science ®Google Scholar
• Fruzzetti F, Perini D, Russo M, Bucci F, Gadducci A. Comparison of two insulin sensitizers, metformin and myo-inositol, in women with polycystic ovary syndrome (PCOS). Gynecol Endocrinol. 2017;33(1):39–42.
   PubMed Web of Science ®Google Scholar
• Showell MG, Mackenzie-Proctor R, Jordan V, Hodgson R, Farquhar C. Inositol for subfertile women with polycystic ovary syndrome. Cochrane Database Syst Rev. 2018;12:CD012378.
   PubMedGoogle Scholar