Optimizing the Endometrial Factor in Recurrent Implantation Failure: From Established Diagnostics to Mechanism-Informed Management

Background: Recurrent implantation failure (RIF) remains one of the most challenging presentations in assisted reproductive technology and is characterized by failure to achieve clinical pregnancy despite the transfer of multiple good-quality embryos. Advances in embryo selection and preimplantation genetic testing have highlighted the contribution of endometrial factors to a substantial proportion of otherwise unexplained implantation failures. Methods: This narrative review summarizes current evidence regarding endometrial receptivity, the principal endometrial mechanisms implicated in RIF, contemporary diagnostic approaches, and available therapeutic strategies. Electronic literature searches were conducted using PubMed/MEDLINE, Scopus, ScienceDirect, and the Cochrane Library for publications available up to June 2026. Results: Anatomical, inflammatory, temporal, hormonal, immunological, and vascular endometrial causes of RIF can all be broadly categorized. Progesterone resistance, impaired decidualization, chronic endometritis, microbiome dysbiosis, displacement of the window of implantation, and immune dysregulation represent proposed mechanisms contributing to implantation failure in selected patients. Diagnostic evaluation is most effective when performed using a stepwise approach that prioritizes clinically actionable findings and avoids indiscriminate testing. Management primarily focuses on optimizing hormonal support, whereas immunomodulatory and antithrombotic therapies should be reserved for carefully selected patients. Emerging approaches, including granulocyte colony-stimulating factor, platelet-rich plasma, and microbiome-directed therapies, have shown promising preliminary results in selected patient populations; however, further validation is required. Conclusions: RIF is best regarded as a heterogeneous clinical outcome rather than a single disease entity, reflecting multiple disturbances in endometrial receptivity. Overall, current evidence supports a mechanism-informed approach that integrates targeted diagnostics with individualized, evidence-based therapeutic strategies.