The impact of suppressing estradiol during ovarian stimulation on the unsupported luteal phase: A Randomized Controlled Trial

Marianne Dreyer Holt, Sven Olaf Skouby, Nathalie Søderhamn Bülow, Anne Lis Mikkelsen Englund, Kathrine Birch Petersen, Nicholas Stephen Macklon


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.

Original languageEnglish
JournalThe Journal of clinical endocrinology and metabolism
Issue number9
Pages (from-to)e3633-e3643
Publication statusPublished - 18 Aug 2022


  • letrozole
  • ovarian stimulation
  • luteal phase
  • progesterone
  • estradiol
  • in vitro fertilization


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