P-659 Letrozole versus hormone replacement therapy for endometrial preparation in frozen-thawed embryo transfer cycles: a systematic review and meta-analysis
Authors: Bosdou J , Venetis C , Zepiridis L , Lainas G , Lainas T , Chatzimeletiou K , Grimbizis G , Kolibianakis E 
Published: July 2024

Study question

Is the probability of pregnancy different when letrozole as compared with hormone replacement therapy (HRT) is used for endometrial preparation in frozen-thawed embryo transfer(FRET) cycles?

Summary answer

Α significantly higher probability of pregnancy is present when letrozole as compared with HRT is used for endometrial preparation in FRET cycles.

What is known already

Endometrial preparation with HRT has been a popular treatment during FRET cycles, mainly due to its convenience in cycle programming and its efficacy regarding pregnancy rates. However, recent data, focusing on obstetric outcomes after FRET, have highlighted the importance of corpus luteum (CL), favouring the adoption of strategies that lead to CL development. This is feasible either using a natural cycle or ovarian stimulation with gonadotrophins, clomiphene citrate or letrozole. Although a CL is present in letrozole stimulated cycles, whether the probability of pregnancy is maintained as compared to endometrial preparation with HRT has not yet been sufficiently elucidated.

Study design, size, duration

A systematic review and meta-analysis was performed aiming to identify randomized clinical trials (RCTs) comparing letrozole versus HRT in women undergoing endometrial preparation for FRET, irrespective of the type of infertility. For this purpose, a literature search was carried out until January 2024 in PubMed, Scopus, EmBase and CENTRAL. The primary outcome measure was live birth rate, while clinical pregnancy rate, ongoing pregnancy rate, endometrial thickness and miscarriage rate were evaluated as secondary outcomes.

Participants/materials, setting, methods

Citation, demographic, methodological and clinical data were extracted independently by two reviewers. Quality was assessed using the RoB2 Tool by Cochrane. Statistical heterogeneity was assessed by I2. Meta-analysis was performed using the random and fixed effects model depending on the presence or not of significant statistical or clinical heterogeneity. All results were combined using the intention-to-treat principle. Results are reported as relative risk (RR) or weighted mean difference (WMD) with 95% confidence interval (CI).

Main results and the role of chance

Four RCTs (n = 1242) were identified, published between 2014 and 2023. All of them were deemed as of high risk of bias. The number of patients included in these studies ranged from 163 to 713 patients. Letrozole was administered at doses of 2.5-5mg/day from day 2-3 of the menstrual cycle for 5 days, whereas in HRT cycles, estradiol valerate was administered at doses of 4-8mg/day from day 2-3 of the menstrual cycle. A significantly higher live birth rate was observed using letrozole for endometrial preparation as compared to HRT in women undergoing FRET (RR: 1.34, 95% CI:1.12 to 1.59; fixed effects model; heterogeneity: I2:0%; two studies, 883 patients). Similar differences between letrozole and HRT were also present regarding clinical pregnancy rate (RR: 1.23, 95% CI:1.08 to 1.39; fixed effects model; heterogeneity: I2:0%; four studies, 1240 patients) or ongoing pregnancy rate (RR:1.48, 95% CI:1.04 to 2.12; single study, 190 patients). No significant differences were observed using letrozole for endometrial preparation as compared to HRT regarding either miscarriage rate (RR:0.70, 95% CI:0.46 to 1.07; fixed effects model; heterogeneity: I2:0%; four studies, 1240 patients) or endometrial thickness (WMD:+0.09 mm, 95% CI: -0.86 to + 1.03; random effects model; heterogeneity: I2: 98.1%; three studies, 1070 patients).

Limitations, reasons for caution

This meta-analysis included a limited number of RCTs, which were generally of high risk of bias due to methodological limitations. Moreover, a considerable heterogeneity was present regarding the dosage of the medications administered and duration of treatment, warranting a cautious interpretation of the results obtained.

Wider implications of the findings

Endometrial preparation with letrozole seems to be preferable compared to HRT for FRET. In addition to an increased probability of pregnancy observed in the present meta-analysis, letrozole ensures the presence of CL which has been associated with a lower probability of hypertensive disorders of pregnancy.

Trial registration number

PROSPERO: CRD42024501838