P-109 Letrozole versus hormone replacement therapy for frozen embryo transfer: A randomized clinical trial
Authors: Haikin Herzberger E , Shavit T , Hershko-Klement A , Miller N , Atzmon Y , Lahav G , Mashiach J , Berkovitz A , Shalom Paz E , Wiser A 
Published: June 2023

Study question

Do the outcomes of frozen embryo transfer cycles differ according to endometrial preparation (EP) with letrozole versus hormone replacement therapy (HRT)?

Summary answer

Letrozole seems to be as effective as HRT preparation in frozen cycles in terms of treatment outcomes.

What is known already

Vitrification improved the survival of vitrified-warmed embryos and increased the number of FET cycles. A common EP strategy for FET includes augmentation of the endometrium using estrogen followed by progesterone supplements. Retrospective studies have shown that using aromatase inhibitors (letrozole) in FET cycles was associated with higher clinical pregnancy and live birth rates, with a lower miscarriage rate, as compared to HRT cycles.

Letrozole maintains regular feedback mechanisms, facilitating normal follicular growth, and promotes single follicle development and ovulation. Moreover, it does not have any negative effects on the endometrium and can improve endometrial receptivity.

Study design, size, duration

This randomized controlled trial was performed in two university-affiliated medical centers.

A total of 170 patients undergoing frozen embryo transfer cycles from June 2018 to June 2021 were eligible.

Participants/materials, setting, methods

Patients were randomized to either letrozole (n = 69) or HRT protocol (n = 101) for EP, using a blocked randomization method. Inclusion criteria were single blastocyst transfer with normal uterine cavity. Exclusion criteria were patients older than 40 years, oocyte donation cycles, or more than 3 previous transfers without a pregnancy. The primary study outcome was percentage of clinical pregnancies, defined as clinical pregnancies/embryo transfers, excluding canceled treatments.

Main results and the role of chance

The characteristics of the study groups were comparable in age, BMI, gravidity, parity, previous treatment history and characteristics of the relevant fresh cycle in which the embryo was frozen. After excluding 5 cancelled treatments in the letrozole group and 2 in the HRT group, the percentage of clinical pregnancies between the letrozole and HRT arms were similar (24 (38.0%) versus 34 (34.6%), respectively, p = 0.67). There was no difference in the percentages of live births (22 (34.9%) versus 28 (28.6%), respectively, p = 0.4) or missed abortions (1 (4.1%) versus 5 (14.7%), p = 0.19). For patients who did not achieve pregnancy in the randomized treatment cycle, we retrospectively examined the outcome of the next treatment cycle with the other EP protocol, when possible. Achievement of a clinical pregnancy was the same for change in treatment for both study groups (7(50%) in the letrozole group and 9(50%) in the HRT group).

Limitations, reasons for caution

Limitations of this study included the heterogeneous study groups. Even though class II ovulation disorders were similar in prevalence in both groups, they included different indications for ART. Pregnancy complications were not evaluated and should be further investigated in a study with a larger sample size.

Wider implications of the findings

Letrozole seems to be as effective as HRT for EP in frozen cycles, with possible advantages of fewer missed abortions and pregnancy complications. Letrozole could be a suitable option for EP, as it is effective and, enables more convenient timing, versus natural FET.

Trial registration number

NCT03540979