Live birth after letrozole as an adjunct to follicle-stimulating hormone versus follicle-stimulating hormone alone for ovarian stimulation in in vitro fertilisation cycles-study protocol for a randomised controlled trial

Wei Guo, Hang Wun Raymond Li, Zi Yang, Lin Zeng, Rui Yang, Jie Qiao, Rong Li, Ernest Hung Yu Ng, Wei Guo, Hang Wun Raymond Li, Zi Yang, Lin Zeng, Rui Yang, Jie Qiao, Rong Li, Ernest Hung Yu Ng

Abstract

Introduction: In vitro fertilisation (IVF) is an effective infertility treatment but the live birth rate remains unsatisfactory. Ovarian stimulation by follicle-stimulating hormone (FSH) is routinely used in IVF and the resulting high serum estradiol levels may impair oocyte/embryo quality and endometrial receptivity. Letrozole, an aromatase inhibitor, can reduce serum estradiol levels following ovarian stimulation. We aim to test the hypothesis that co-treatment with letrozole reduces supraphysiological serum estradiol levels and improves endometrial receptivity, leading to a higher live birth rate of IVF. We are conducting a randomised controlled trial (RCT) to evaluate whether letrozole as an adjunct to FSH in IVF is superior to FSH alone in the live birth rate of fresh embryo transfer.

Methods/design: This is an open-label randomised controlled superiority trial being performed in two assisted reproduction centres in China. Infertile women who have antral follicle count (AFC) before ovarian stimulation or on day 5 of ovarian stimulation ≥15 are randomly allocated in a 1:1 ratio to receive either letrozole and FSH or FSH alone in a GnRH antagonist protocol. Recruited women follow the standard operating procedures of the two centres. The primary outcome is the live birth rate of the fresh embryo transfer. Stimulation parameters, maternal side effects and obstetric and perinatal complications are secondary outcomes. The planned sample size is 900, i.e. 450 per group.

Discussion: The present study is the first multicentre randomised study to compare the live birth rate of the fresh embryo transfer following ovarian stimulation by letrozole and FSH versus FSH alone in women with anticipated high ovarian responses.

Trial registration: ClinicalTrials.gov NCT02912988 . Registered on September 23, 2016. This trial protocol is version 2.0.

Keywords: Estradiol; Fresh embryo transfer; In vitro fertilisation; Letrozole; Live birth rate; Randomised controlled trial.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Flowchart of clinical RCT study: letrozole + FSH vs FSH alone for ovarian stimulation in IVF

References

    1. Ferraretti AP, Goossens V, de Mouzon J, Bhattacharya S, Castilla JA, Korsak V, et al. Assisted reproductive technology in Europe, 2008: results generated from European registers by ESHRE. Hum Reprod. 2012;27(9):2571–2584. doi: 10.1093/humrep/des255.
    1. Ng EH. Adverse effects of excessive ovarian response on the pregnancy rate of in vitro fertilization treatment. Gynecol Endocrinol. 2009;25(1):2–7. doi: 10.1080/09513590802296237.
    1. Silva Martins R, Helio Oliani A, Vaz Oliani D, Martinez de Oliveira J. The predictive value of serial serum estradiol and serial endometrial volume on endometrial receptivity on assisted reproductive technology cycles. BMC Pregnancy Childbirth. 2021;21(1):184. doi: 10.1186/s12884-021i-03672-1.
    1. Macklon NS, Stouffer RL, Giudice LC, Fauser BC. The science behind 25 years of ovarian stimulation for in vitro fertilization. Endocr Rev. 2006;27(2):170–207. doi: 10.1210/er.2005-0015.
    1. Rubio C, Mercader A, Alama P, Lizan C, Rodrigo L, Labarta E, et al. Prospective cohort study in high responder oocyte donors using two hormonal stimulation protocols: impact on embryo aneuploidy and development. Hum Reprod. 2010;25(9):2290–2297. doi: 10.1093/humrep/deq174.
    1. Santos MA, Kuijk EW, Macklon NS. The impact of ovarian stimulation for IVF on the developing embryo. Reproduction. 2010;139(1):23–34. doi: 10.1530/REP-09-0187.
    1. Baart EB, Martini E, Eijkemans MJ, Van Opstal D, Beckers NG, Verhoeff A, et al. Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial. Hum Reprod. 2007;22(4):980–988. doi: 10.1093/humrep/del484.
    1. Horcajadas JA, Minguez P, Dopazo J, Esteban FJ, Dominguez F, Giudice LC, et al. Controlled ovarian stimulation induces a functional genomic delay of the endometrium with potential clinical implications. J Clin Endocrinol Metab. 2008;93(11):4500–4510. doi: 10.1210/jc.2008-0588.
    1. Boomsma CM, Kavelaars A, Eijkemans MJ, Fauser BC, Heijnen CJ, Macklon NS. Ovarian stimulation for in vitro fertilization alters the intrauterine cytokine, chemokine, and growth factor milieu encountered by the embryo. Fertil Steril. 2010;94(5):1764–1768. doi: 10.1016/j.fertnstert.2009.10.044.
    1. Devroey P, Bourgain C, Macklon NS, Fauser BC. Reproductive biology and IVF: ovarian stimulation and endometrial receptivity. Trends Endocrinol Metab. 2004;15(2):84–90. doi: 10.1016/j.tem.2004.01.009.
    1. Diedrich K, Fauser BC, Devroey P, Griesinger G. Evian Annual Reproduction Workshop G. The role of the endometrium and embryo in human implantation. Hum Reprod Update. 2007;13(4):365–377. doi: 10.1093/humupd/dmm011.
    1. Imudia AN, Awonuga AO, Doyle JO, Kaimal AJ, Wright DL, Toth TL, et al. Peak serum estradiol level during controlled ovarian hyperstimulation is associated with increased risk of small for gestational age and preeclampsia in singleton pregnancies after in vitro fertilization. Fertil Steril. 2012;97(6):1374–1379. doi: 10.1016/j.fertnstert.2012.03.028.
    1. Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril. 2018;110(3):364–379. doi: 10.1016/j.fertnstert.2018.05.004.
    1. Bonardi B, Massarotti C, Bruzzone M, Goldrat O, Mangili G, Anserini P, et al. Efficacy and safety of controlled ovarian stimulation with or without letrozole co-administration for fertility preservation: a systematic review and meta-analysis. Front Oncol. 2020;10:574669. doi: 10.3389/fonc.2020.574669.
    1. Haas J, Bassil R, Meriano J, Samara N, Barzilay E, Gonen N, et al. Does daily co-administration of letrozole and gonadotropins during ovarian stimulation improve IVF outcome? Reprod Biol Endocrinol. 2017;15(1):70. doi: 10.1186/s12958-017-0288-8.
    1. Goldrat O, Van Den Steen G, Gonzalez-Merino E, Dechene J, Gervy C, Delbaere A, et al. Letrozole-associated controlled ovarian hyperstimulation in breast cancer patients versus conventional controlled ovarian hyperstimulation in infertile patients: assessment of oocyte quality related biomarkers. Reprod Biol Endocrinol. 2019;17(1):3. doi: 10.1186/s12958-018-0443-x.
    1. Sonigo C, Sermondade N, Calvo J, Benard J, Sifer C, Grynberg M. Impact of letrozole supplementation during ovarian stimulation for fertility preservation in breast cancer patients. Eur J Obstet Gynecol Reprod Biol X. 2019;4:100049. doi: 10.1016/j.eurox.2019.100049.
    1. Hu YJ, Chen YZ, Zhu YM, Huang HF. Letrozole stimulation in endometrial preparation for cryopreserved-thawed embryo transfer in women with polycystic ovarian syndrome: a pilot study. Clin Endocrinol (Oxf). 2014;80(2):283–289. doi: 10.1111/cen.12280.
    1. Li SJ, Zhang YJ, Chai XS, Nie MF, Zhou YY, Chen JL, et al. Letrozole ovulation induction: an effective option in endometrial preparation for frozen-thawed embryo transfer. Arch Gynecol Obstet. 2014;289(3):687–693. doi: 10.1007/s00404-013-3044-0.
    1. Zhang J, Liu H, Wang Y, Mao X, Chen Q, Fan Y, et al. Letrozole use during frozen embryo transfer cycles in women with polycystic ovary syndrome. Fertil Steril. 2019;112(2):371–377. doi: 10.1016/j.fertnstert.2019.04.014.
    1. 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(6):1244–1248. doi: 10.1093/humrep/dex066.
    1. Zheng X, Guo W, Zeng L, Zheng D, Yang S, Wang L, et al. Live birth after in vitro maturation versus standard in vitro fertilisation for women with polycystic ovary syndrome: protocol for a non-inferiority randomised clinical trial. Bmj Open. 2020;10(4):e035334. doi: 10.1136/bmjopen-2019-035334.
    1. Zheng X, Guo W, Zeng L, Zheng D, Yang S, Xu Y, et al. In vitro maturation without gonadotropins versus in vitro fertilization with hyperstimulation in women with polycystic ovary syndrome: a non-inferiority randomized controlled trial. Hum Reprod. 2022;37(2):242–253. doi: 10.1093/humrep/deab243.
    1. Eftekhar M, Saeed L. Effect of adding letrozole to gonadotropin on in vitro fertilization outcomes: an RCT. Int J Reprod Biomed. 2020;18(4):287–294. doi: 10.18502/ijrm.v13i4.6891.
    1. Yang AM, Cui N, Sun YF, Hao GM. Letrozole for female infertility. Front Endocrinol (Lausanne). 2021;12:676133. doi: 10.3389/fendo.2021.676133.
    1. Shapira M, Orvieto R, Lebovitz O, Nahum R, Aizer A, Segev-Zahav A, et al. Does daily co administration of gonadotropins and letrozole during the ovarian stimulation improve IVF outcome for poor and sub optimal responders? J Ovarian Res. 2020;13(1):66. doi: 10.1186/s13048-020-00666-z.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe