Effect of supraphysiological estradiol levels during controlled ovarian stimulation on endometrial receptivity: A literature review
DOI:
https://doi.org/10.37800/RM.1.2026.672Keywords:
Controlled ovarian stimulation (COS), estradiol, endometrial receptivity, Assisted Reproductive Technologies (ART), window of implantation, freeze-all strategy, hyperestrogenismAbstract
Relevance: Supraphysiological levels of estradiol (E2) induced by controlled ovarian stimulation (COS) create a suboptimal preimplantation microenvironment and reduce endometrial receptivity.
The study aimed to investigate the association between supraphysiological estradiol concentrations in COS cycles and changes in the endometrial morphological, transcriptomic, and immune profiles, and to determine threshold E2 levels that are significant for selecting an embryo transfer strategy.
Materials and Methods: A literature search was performed in the international databases PubMed, Scopus, Web of Science, and Google Scholar (2014–2025). Clinical and experimental studies, systematic reviews, and meta-analyses assessing the effect of supraphysiological E2 levels on the endometrium in COS cycles were included. Studies with low levels of evidence, small sample sizes, insufficient quantitative E2 assessment, and conference abstracts were excluded. The final analysis included 30 publications out of more than 120 selected. The relationship between peak E2 levels and clinical outcomes of assisted reproductive technologies was analyzed.
Results: Upregulation of endometrial estradiol levels ≥3,000-4,000 pg/mL (11,010-14,680 pmol/L) is associated with glandular-stromal dyssynchrony and ultrastructural changes in the endometrium, including premature pinopodia formation, leading to a shift in the implantation window. At the molecular level, dysregulation of key receptor genes (HOXA11, LIF, CDH1) was detected, with only 46% of the transcriptome matching that of a spontaneous cycle. Immunological changes include an eightfold increase in the B-cell population and a modified uterine NK cell phenotype. Clinically, E2 levels > 2,500-3,000 pg/mL (9,175-11,010 pmol/L) are associated with an increased risk of placental abnormalities and low birth weight, while E2 levels > 6,000 pg/mL (22,020 pmol/L) are associated with a decreased cumulative live birth rate.
Conclusion: A unified approach to embryo transfer in controlled ovarian stimulation (COS) settings is suboptimal. Personalizing the strategy based on the E2 level on the trigger day is crucial: with E2 concentrations >2,000 pg/mL (7340 pmol/L) for blastocysts and >3,900 pg/mL (14,313 pmol/L) for Day 3 embryos, the “freeze-all” strategy increases implantation efficiency and reduces obstetric risks.
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