Letrozole as co-treatment agent in ovarian stimulation antagonist protocol in poor responders: A double-blind randomized clinical trial
Background: Ovarian stimulation (OS) for poor ovarian response (POR) patients is still a major challenge in assisted reproductive techniques. Aromatase inhibitors as co-treatment in antagonist protocol are suggested to these patients, but there are controversial reports.
Objective: To evaluate the effectiveness Letrozole (LZ) as adjuvant treatment in gonadotropin-releasing hormone (GnRH)-antagonist protocol in POR patients undergoing in vitro fertilization/intracytoplasmic sperm injection cycles.
Materials and Methods: This double-blind randomized clinical trial was conducted in Arash women’s hospital. One hundred sixty infertile women with POR based on Bologna criteria were allocated into two groups randomly: LZ + GnRH-antagonist (LA) and placebo + GnRH-antagonist (PA) groups. In the experimental group, the patients received 5 mg LZ on the first five days of OS with 150 IU of recombinant human follicle-stimulating hormone (rFSH) and 150 IU of human menopausal gonadotropin (HMG). The cycle outcomes were compared between groups.
Results: The total number of retrieved oocytes and the metaphase II oocytes in LA-treated group were significantly higher than those in the control group (p = 0.008, p = 0.002). The dosage of hMG used and the duration of OS and antagonist administration in LZ-treated group were significantly lower than those of the control group. The number of patients with no oocyte, in the control group, was higher than the LZ-treated group, and the clinical pregnancy rate in LA-treated group (25%) was higher than the control group (18%); however, the differences were not significant statistically.
Conclusion: Adding 5 mg of LZ to rFSH/hMG antagonist protocol may improve the in vitro fertilization/intracytoplasmic sperm injection cycle outcome in POR patients.
Key words: Letrozole, Ovarian reserve, Primary ovarian insufficiency, Ovulation induction, Fertilization in vitro, Aromatase inhibitors.
 Schoolcraft WB, Surrey ES, Minjarez DA, Stevens JM, Gardner DK. Management of poor responders: can outcomes be improved with a novel gonadotropin-releasing hormone antagonist/letrozole protocol? Fertil Steril 2008; 89: 151–156.
 Ubaldi F, Vaiarelli A, D’Anna R, Rienzi L. Management of poor responders in IVF: is there anything new? Biomed Res Int 2014; 2014: 352098.
 Patrizio P,Vaiarelli A, Levi Setti PE, Tobler KJ, Shoham G, Leong M, et al. How to define, diagnose and treat poor responders? Responses from a worldwide survey of IVF clinics. Reprod Biomed Online 2015; 30: 581–592.
 Yang R, Li H, Li R, Liu P, Qiao J. A comparison among different methods of letrozole combined with gonadotropin in an antagonist protocol and high-dose gonadotropin ovarian stimulation antagonist protocol in poor ovarian responders undergoing in vitro fertilization. Arch Gynecol Obstet 2016; 294: 1091–1097.
 Lee KH, Kim CH, Suk HJ, Lee YJ, Kwon SK, Kim SH, et al. The effect of aromatase inhibitor letrozole incorporated in gonadotrophin-releasing hormone antagonist multiple dose protocol in poor responders undergoing in vitro fertilization. Obstet Gynecol Sci 2014; 57: 216–222.
 Winer EP, Hudis C, Burstein HJ, Chlebowski RT, Ingle JN, Edge SB, et al. American society of clinical oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for women with hormone receptor-positive breast cancer: status report 2002. J Clin Oncol 2002; 20: 3317–3327.
 Elnashar A, Fouad H, Eldosoky M, Saeid N. Letrozole induction of ovulation in women with clomiphene citrate-resistant polycystic ovary syndrome may not depend on the period of infertility, the body mass index, or the luteinizing hormone/follicle-stimulating hormone ratio. Fertil Steril 2006; 85: 511–513.
 Goswami SK, Das T, Chattopadhyay R, Sawhney V, Kumar J, Chaudhury K, et al. A randomized single-blind controlled trial of letrozole as a low-cost IVF protocol in women with poor ovarian response: a preliminary report. Hum Reprod 2004; 19: 2031–2035.
 Garcia-Velasco JA, Moreno L, Pacheco A, Guillen A, Duque L, Requena A, et al. The aromatase inhibitor letrozole increases the concentration of intraovarian androgens and improves in vitro fertilization outcome in low responder patients: a pilot study. Fertil Steril 2005; 84: 82–87.
 Mitwally MF, Casper RF, Diamond MP. The role of aromatase inhibitors in ameliorating deleterious effects of ovarian stimulation on outcome of infertility treatment. Reprod Biol Endocrinol 2005; 3: 54.
 Pritts EA, Yuen AK, Sharma S, Genisot R, Olive DL. The use of high dose letrozole in ovulation induction and controlled ovarian hyperstimulation. ISRN Obstet Gynecol 2011; 2011: 242864.
 Fouda UM, Sayed AM. Extended high dose letrozole regimen versus short low dose letrozole regimen as an adjuvant to gonadotropin releasing hormone antagonist protocol in poor responders undergoing IVF-ET. Gynecol Endocrinol 2011; 27: 1018–1022.
 Song Y, Li Z, Wu X, Wang X, Xiao J, Wang B. Effectiveness of the antagonist/letrozole protocol for treating poor responders undergoing in vitro fertilization/ intracytoplasmic sperm injection: a systematic review and meta-analysis. Gynecol Endocrinol 2014; 30: 330–334.
 Ebrahimi M, Akbari-Asbagh F, Ghalandar-Attar M. Letrozole+ GnRH antagonist stimulation protocol in poor ovarian responders undergoing intracytoplasmic sperm injection cycles: An RCT. Int J Reprod Biomed 2017; 15: 101–108.
 Ozmen B, So¨ nmezer M, Atabekoglu CS, Olmus¸ H. Use of aromatase inhibitors in poor-responder patients receiving GnRH antagonist protocols. Reprod Biomed Online 2009; 19: 478–485.
 Davar R, Oskouian H, Ahmadi S, Firouzabadi RD. GnRH antagonist/letrozole versus microdose GnRH agonist flare protocol in poor responders undergoing in vitro fertilization. Taiwan J Obstet Gynecol 2010; 49: 297–301.
 Lee VC, Chan CC, Ng EH, Yeung WS, Ho PC. Sequential use of letrozole and gonadotrophin in women with poor ovarian reserve: a randomized controlled trial. Reprod Biomed Online 2011; 23: 380–388.
 Mohsen IA, El Din RE. Minimal stimulation protocol using letrozole versus microdose flare up GnRH agonist protocol in women with poor ovarian response undergoing ICSI. Gynecol Endocrinol 2013; 29: 105–108.
 Cakiroglu Y, Kopuk SY, Basarir O, Filiz S, Vural B. Comparison of microdose GnRH agonist protocol with GnRH antagonist/letrozole protocol in patients with poor ovarian response. J Turk Soc Obstet Gynecol 2013; 10: 132–137.
 Eftekhar M, Mohammadian F, Davar R, Pourmasumi S. Comparison of pregnancy outcome after letrozole versus clomiphene treatment for mild ovarian stimulation protocol in poor responders. Iran J Reprod Med 2014; 12: 725–730.
 Bastu E, Buyru F, Ozsurmeli M, Demiral I, Dogan M, Yeh J. A randomized, single-blind, prospective trial comparing three different gonadotropin doses with or without addition of letrozole during ovulation stimulation in patients with poor ovarian response. Eur J Obstet Gynecol Reprod Biol 2016; 203: 30–34.
 Nabati A, Peivandi S, Khalilian A, Mirzaeirad S, Hashemi SA. Comparison of GnRh Agonist Microdose Flare Up and GnRh Antagonist/Letrozole in Treatment of Poor Responder Patients in Intra Cytoplaspic Sperm Injection: Randomized Clinical Trial. Glob J Health Sci 2015; 8: 166–171.
 Soligo AG, Rodrigues RS, Setti AS, Braga DPAF, Iaconelli Jr A, Borges Jr E. Letrozole in poor responders: association of practical, saving and good results. Fertil Steril 2012; 98: S78.
 Yarali H, Esinler I, Polat M, Bozdag G, Tiras B. Antagonist/letrozole protocol in poor ovarian responders for intracytoplasmic sperm injection: a comparative study with the microdose flare-up protocol. Fertil Steril 2009; 92: 231–235.
 Sekhon L, Lee JA, Whitehouse M, Copperman AB, Grunfeld L. Letrozole as an adjunct in GnRH antagonist cycles improves IVF outcome in poor responders. Fertil Steril 2014; 102: e221.