Co-treatment of gonadotropin and letrozole in infertile women with endometriosis: A double-blind randomized clinical trial


Background: The common causes of infertility in women with endometriosis are folliculogenesis alternation, steroidogenesis and fertilization impairment, oocyte and embryo quality reduction, and implantation defect.

Objective: To compare in vitro fertilization (IVF) cycle success rates of women with endometriosis who were treated with letrozole + gonadotropin (LA) vs. placebo + gonadotropin (PA).

Materials and Methods: This double-blind, randomized clinical trial study was conducted with 94 infertile women with endometriosis (47 in the LA group and 47 in the PA group) who were candidates for IVF, from April-June 2021. For all participants, the long agonist protocol was applied. In both groups, gonadotropin-releasing hormone agonist was prescribed in the mid-luteal stage and from the third day of the cycle, and gonadotropin was started and its doses were regulated based on the patient’s age, serum anti-Mullerian hormone and follicle-stimulating hormone. From the third day of the menstrual cycle, 5 mg of letrozole daily for 5 days was prescribed for the LA group, while the placebo was prescribed for the PA group on the identical days and duration. After embryo transfer, biochemical and clinical pregnancy were measured in the 2 groups.

Results: The gonadotropin dosage (p < 0.01) and estradiol level (p = 0.02) on the human chorionic gonadotropin administration day were significantly lower in the LA group compared with in the PA group. Fetus transfer was done for 32 women. No significant differences were detected between the study groups regarding biochemical or clinical pregnancy (p = 0.72 for both).

Conclusion: Letrozole as a co-treatment drug in the IVF cycle of women with endometriosis can significantly reduce the gonadotropin dosage and estradiol level with the same pregnancy rates.

Key words: Gonadotropin-releasing hormone, Fertilization in vitro, Letrozole, Endometriosis.

[1] Ozkan S, Murk W, Arici A. Endometriosis and infertility: Epidemiology and evidence-based treatments. Ann N Y Acad Sci 2008; 1127: 92–100.

[2] Abd Rabbo MS, Elmaghraby HA, Mashali NA, Moneim MEA. Effect of aromatase inhibitor (letrozole) with long agonist protocol on the results of ICSI/ET in females with minimal and mild endometriosis. Alexandria J Med 2012; 48: 303–307.

[3] Abu Hashim H. Aromatase inhibitors for endometriosisassociated infertility; Do we have sufficient evidence? Int J Fertil Steril 2016; 10: 270–277.

[4] Pavone ME, Bulun SE. Aromatase inhibitors for the treatment of endometriosis. Fertil Steril 2012; 98: 1370– 1379.

[5] Akbari Asbagh F, Davari Tanha F, Rezaei Z, Ebrahimi M, Hemmati T, Talebbidokhti M, et al. Evaluation of the in vitro fertilization success rate in transfer of top-quality embryo versus poor-quality embryos: A cohort study. Int J Women’s Health Reprod Sci 2021; 9: 1–5.

[6] Suzuki T, Izumi ShI, Matsubayashi H, Awaji H, Yoshikata K, Makino T. Impact of ovarian endometrioma on oocytes and pregnancy outcome in in vitro fertilization. Fertil Steril 2005; 83: 908–913.

[7] Tavmergen E, Ulukus M, Goker EN. Long-term use of gonadotropin-releasing hormone analogues before IVF in women with endometriosis. Curr Opin Obstet Gynecol 2007; 19: 284–288.

[8] Lee KH, Kim ChH, 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.

[9] 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.

[10] 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.

[11] Mitwally MFM, Casper RF. Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders. Fertil Steril 2002; 77: 776–780.

[12] Schwartz K, Llarena NC, Rehmer JM, Richards EG, Falcone T. The role of pharmacotherapy in the treatment of endometriosis across the lifespan. Expert Opin Pharmacother 2020; 21: 893–903.

[13] Inoue T, Ono Y, Yonezawa Y, Kishi J, Emi N. Improvement of live birth rate following frozen-thawed blastocyst transfer by combination of prednisolone administration and stimulation of endometrium embryo transfer. Open Journal of Obstetrics and Gynecology 2014; 4: 745–750.

[14] Chen TJ, Zheng WL, Liu CH, Huang I, Lai HH, Liu M. Using deep learning with large dataset of microscope images to develop an automated embryo grading system. Fertil Reprod 2019; 1: 51–56.

[15] Harb HM, Gallos ID, Chu J, Harb M, Coomarasamy A. The effect of endometriosis on in vitro fertilisation outcome: A systematic review and meta-analysis. BJOG 2013; 120: 1308–1320.

[16] Opøien HK, Fedorcsak P, Omland AK, Abyholm Th, Bjercke S, Ertzeid G, et al. In vitro fertilization is a successful treatment in endometriosis-associated infertility. Fertil Steril 2012; 97: 912–918.

[17] Brosens J, Verhoeven H, Campo R, Gianaroli L, Gordts S, Hazekamp J, et al. High endometrial aromatase P450 mRNA expression is associated with poor IVF outcome. Hum Reprod 2004; 19: 352–356.

[18] Dunselman GAJ, Vermeulen N, Becker C, Calhaz-Jorge C, D’Hooghe T, De Bie B, et al. ESHRE guideline: Management of women with endometriosis. Hum Reprod 2014; 29: 400–412.

[19] Yap C, Furness S, Farquhar C. Pre and post operative medical therapy for endometriosis surgery. Cochrane Database Syst Rev 2004; 2004: Cd003678.

[20] Sallam HN, Garcia-Velasco JA, Dias S, Arici A. Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosis. Cochrane Database Syst Rev 2006; 2006: Cd004635.

[21] Eftekhar M, Saeed L. Effect of adding letrozole to gonadotropin on in vitro fertilization outcomes: An RCT. Int J Reprod Biomed 2020; 18: 287–294.

[22] Oktay K, Hourvitz A, Sahin G, Oktem O, Safro B, Cil A, et al. Letrozole reduces estrogen and gonadotropin exposure in women with breast cancer undergoing ovarian stimulation before chemotherapy. J Clin Endocrinol Metab 2006; 91: 3885–3890.

[23] ElSharkawy SS, Abd Raboo MSAD, Al Abd MM, Khamis Mohamed SM. Study of the effect of adding letrozole to gonadotropin-releasing hormone antagonist protocol in poor responders undergoing intracytoplasmic sperm injection. Evidence Based Women’s Health Journal 2021; 11: 211–218.

[24] Moini A, Lavasani Z, Kashani L, Mojtahedi MF, Yamini N. Letrozole as co-treatment agent in ovarian stimulation antagonist protocol in poor responders: A double-blind randomized clinical trial. I Int J Reprod Biomed 2019; 17: 653–660.

[25] Piedimonte S, Volodarsky-Perel A, Tannus S, Tan SL, Dahan MH. Pretreatment with a gonadotropin-releasing hormone agonist and an aromatase inhibitor may improve outcomes in in vitro fertilization cycles of women with stage I-II endometriosis. F&S Science 2020; 1: 98–103.