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 IVF. Objective To determine the impact of suppressing estradiol levels during OS of multiple dominant follicles on the unsupported luteal phase and markers of endometrial maturation. Design and setting Randomized controlled trial in two University Hospitals. Methods Twenty-five 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 five days after oocyte pick up (OPU+5). Results The median (interquartile range) luteal phase duration was 8.0 (6.8-11.5) days compared to 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 (inter-quartile range) 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). 75% of participants in the letrozole group revealed endometrial transcriptomic signatures interpreted as post receptive. In the control group, 40% were post receptive and 50% non-informative. Conclusion Suppressing estradiol levels in the follicular phase with adjuvant letrozole significantly reduces the disruption of the unsupported luteal phase after OS.

High estrogen during ovarian stimulation induced loss of maternal imprinted methylation that is essential for placental development via overexpression of TET2 in mouse oocytes

“…Mild stimulation has been hailed as a safer, patient-friendly approach, with the additional benefit of reducing the cost of gonadotropins [ 62 ]. It was also found that adjuvant letrozole in OS could suppress estradiol levels throughout the follicular phase of IVF [ 63 ]. Mild stimulation or the use of letrozole in OS may reduce the loss of DNA methylation in oocytes caused by estradiol during ovarian stimulation, increase safety, and reduce epigenetic abnormalities from ART procedures.…”