The Impact of Suppressing Estradiol During Ovarian Stimulation on the Unsupported Luteal Phase: A Randomized Controlled Trial

Abstract

Context: Supraphysiological sex steroid levels at the follicular-luteal phase transition are implicated as the primary cause of luteal insufficiency after ovarian stimulation (OS) for in vitro fertilization.

Objective: We aimed to determine the impact of suppressing estradiol levels during OS of multiple dominant follicles on the unsupported luteal phase and markers of endometrial maturation.

Methods: At 2 university hospitals, 25 eligible egg donors were randomized to undergo OS using exogenous gonadotropins with or without adjuvant letrozole 5 mg/day. Final oocyte maturation was triggered with a GnRH agonist. No luteal support was provided. The primary outcome was the duration of the luteal phase. Secondary outcomes were luteal phase hormone profiles and the endometrial transcriptomic signature 5 days after oocyte pick up (OPU + 5).

Results: The median (interquartile range [IQR]) luteal phase duration was 8.0 (6.8-11.5) days compared with 5.0 (5.0-6.8) days in the intervention and control group, respectively (P < 0.001). Estradiol levels were effectively suppressed in the letrozole group with a median of 0.86 (0.23-1.24) nmol/L at OPU compared to 2.82 (1.34-3.44) nmol/L in the control group. Median (IQR) progesterone levels at OPU + 5 were 67.05 (15.67-101.75) nmol/L in the letrozole group vs 2.27 (1.05-10.70) nmol/L in the control group (P < 0.001). In the letrozole group, 75% of participants revealed endometrial transcriptomic signatures interpreted as post-receptive. In the control group, 40% were post-receptive and 50% noninformative.

Conclusion: Suppressing estradiol levels in the follicular phase with adjuvant letrozole significantly reduces the disruption of the unsupported luteal phase after OS.

Trial registration: ClinicalTrials.gov NCT04524026.

Keywords: estradiol; in vitro fertilization; letrozole; luteal phase; ovarian stimulation; progesterone.