Comparison of letrozole with gonadotropin-releasing hormone agonist in frozen embryo transfer after recurrent implantation failure: A randomized control trial


Background: The use of frozen embryo transfer (FET) is increasing worldwide in the treatment of infertility by in vitro fertilization. Different methods of endometrial preparation for FET have been suggested.

Objective: The aim of this study was to compare the pregnancy outcomes after treatment with letrozole and those after treatment with the combination of gonadotropin-releasing hormone (GnRH) agonist and estradiol in FET.

Materials and Methods: This randomized controlled trial study was conducted on 142 infertile women with a history of previous FET failure. Subjects were randomly assigned to one of two groups (n = 71 each). The GnRH group received 500 µg of buserelin plus 4mg estradiol (which increased to 8 mg if endometrial thickness was less than 5 mm), and the letrozole group received 5 mg of letrozole plus 75 IU of recombinant human follicle-stimulating hormone). At least two high-quality embryos were transferred to each subject in both groups. The outcome measures were clinical pregnancy rate and fetal heart rate detection

Results: Subjects in the study groups had similar demographic characteristics and baseline clinical condition. Mean endometrial thickness in the letrozole and GnRH agonist groups were 8.90 ± 0.88 mm and 8.99 ± 0.85 mm, respectively (p = 0.57). The number of positive results of the beta human chorionic gonadotropin test and detection of fetal heartbeat were not significantly different between the groups (p > 0.05).

Conclusions: The administration of letrozole and GnRH may produce similar pregnancy outcomes in FET.

Key words: Letrozole; Fertilization in vitro; Pregnancy outcome.

[1] Aflatoonian A, Asgharnia M. Factors affecting the successful embryo transfer. Iran J Reprod Med 2006; 4: 45–50.

[2] Nikzad H, Haddad Kashani H, Kabir-Salmani M, Akimoto Y, Iwashita M. Expression of galectin-8 on human endometrium: Molecular and cellular aspects. Iran J Reprod Med 2013; 11: 65–70.

[3] Wirleitner B, Schuff M, Stecher A, Murtinger M, Vanderzwalmen P. Pregnancy and birth outcomes following fresh or vitrified embryo transfer according to blastocyst morphology and expansion stage, and culturing strategy for delayed development. Hum Reprod 2016; 31: 1685–1695.

[4] Gomaa H, Casper RF, Esfandiari N, Bentov Y. Non-synchronized endometrium and its correction in non-ovulatory cryopreserved embryo transfer cycles. Reprod Biomed Online 2015; 30: 378–384.

[5] Aflatoonian A, Mansoori Moghaddam F, Mashayekhy M, Mohamadian F. Comparison of early pregnancy and neonatal outcomes after frozen and fresh embryo transfer in ART cycles. J Assist Reprod Genet 2010; 27: 695–700.

[6] Cerrillo M, Herrero L, Guillén A, Mayoral M, García-Velasco JA. Impact of endometrial preparation protocols for frozen embryo transfer on live birth rates. Rambam Maimonides Med J 2017; 8: doi: 10.5041/RMMJ.10297.

[7] Aleyasin A, Aghahosseini M, Safdarian L, Noorzadeh M, Fallahi P, Rezaeian Z, et al. Can letrozole plus HMG protocol improve pregnancy outcomes in frozen-thawed embryo transfer? An RCT. Int J Reprod Biomed 2017; 15: 83–86.

[8] Yarali H, Polat M, Mumusoglu S, Yarali I, Bozdag G. Preparation of endometrium for frozen embryo replacement cycles: a systematic review and meta-analysis. J Assist Reprod Genet 2016; 33: 1287–1304.

[9] Li H, Qiao J, Chi HB, Chen XN, Liu P, Ma CH. Comparison of the major malformation rate of children conceived from cryopreserved embryos and fresh embryos. Chin Med J 2010; 123: 1893–1897.

[10] Basirat Z, Adib Rad H, Esmailzadeh S, Jorsaraei SG, Hajian-Tilaki K, Pasha H, et al. Comparison of pregnancy rate between fresh embryo transfers and frozen-thawed embryo transfers following ICSI treatment. Int J Reprod Biomed 2016; 14: 39–46.

[11] Aflatoonian A, Karimzadeh Maybodi MA, Aflatoonian N, Tabibnejad N, Amir-Arjmand MH, Soleimani M, et al. Perinatal outcome in fresh versus frozen embryo transfer in ART cycles. Int J Reprod Biomed 2016; 14: 167–172.

[12] Tatsumi T, Jwa SC, Kuwahara A, Irahara M, Kubota T, Saito H. Pregnancy and neonatal outcomes following letrozole use in frozen-thawed single embryo transfer cycles. Hum Reprod 2017; 32: 1244–1248.

[13] Huang PX, Wei JH, Wei LH. Gonadotropin-releasing hormone agonist for oocyte triggering in endometrial preparation of letrozole stimulation protocols does not affect clinical outcome of frozen-thawed embryo transfer. Int J Clin Exp Med 2015; 8: 19072–19078.

[14] Dahan MH, Tannus S, Tan S. A comparison of pre-treatment with and without GnRH-agonist or letrozole in women with 2 failed embryo transfers undergoing a frozen cycle and no evidence of endometriosis. Fertil Steril 2018; 110 (Suppl.): e190–e191.

[15] Gardner DK, Lane M, Stevens J, Schlenker T, Schoolcraft WB. Blastocyst score affects implantation and pregnancy outcome: towards a single blastocyst transfer. Fertil Steril 2000; 73: 1155–1158.

[16] Gingold JA, Lee JA, Rodriguez-Purata J, Whitehouse MC, Sandler B, Grunfeld L, et al. Endometrial pattern, but not endometrial thickness, affects implantation rates in euploid embryo transfers. Fertil Steril 2015; 104: 620–628.e5.

[17] Seikkula J, Ahinko K, Polo-Kantola P, Anttila L, Hurme S, Tinkanen H, et al. Mid-luteal phase gonadotropin-releasing hormone agonist support in frozen-thawed embryo transfers during artificial cycles: A prospective interventional pilot study. J Gynecol Obstet Hum Reprod 2018; 47: 391–395.

[18] Khayat S, Elliott B, Dahan MH. Management of recurrent implantation failure by gonadotropin-releasing hormone agonist and aromatase inhibitor suppression, in women without evidence of endometriosis. Gynecol Endocrinol 2019; 350: 267–270.

[19] Konc J, Kanyo K, Varga E, Kriston R, Cseh S. The effect of cycle regimen used for endometrium preparation on the outcome of day 3 frozen embryo transfer cycle. Fertil Steril 2010; 94: 767–768.

[20] Sibai H, El Husseiny A, Elgindy E. Letrozole versus artificial hormonal endometrial preparation for vitrified-warmed embryos transfer cycles. Middle East Fertility Society Journal; 21: 96–100.

[21] Franik S, Kremer JA, Nelen WL, Farquhar C. Aromatase inhibitors for subfertile women with polycystic ovary syndrome. Cochrane Database Syst Rev 2014; 2: CD010287.