{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T09:10:40Z","timestamp":1789117840077,"version":"build-2803163510"},"reference-count":187,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Clin. Med.","JCM"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/jcm15187039","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T08:17:42Z","timestamp":1789114662000},"page":"7039","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Optimizing the Endometrial Factor in Recurrent Implantation Failure: From Established Diagnostics to Mechanism-Informed Management"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-9553-6803","authenticated-orcid":false,"given":"Athanasios","family":"Zikopoulos","sequence":"first","affiliation":[{"name":"Department of Reproductive Medicine and Surgery, University College London Hospitals NHS Foundation Trust, 235 Euston Road, London NW1 2BU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3333-2620","authenticated-orcid":false,"given":"Efthalia","family":"Moustakli","sequence":"additional","affiliation":[{"name":"Department of Nursing, School of Health Sciences, University of Ioannina, 45500 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7716-1521","authenticated-orcid":false,"given":"Anastasios","family":"Potiris","sequence":"additional","affiliation":[{"name":"Third Department of Obstetrics and Gynecology, University General Hospital \u201cATTIKON\u201d, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasilios Sebastian","family":"Paraschos","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Corewell Health Hospital, 4700 Schaefer Road Suite 310, Dearborn, MI 48126, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariadni Theodora","family":"Katopodi","sequence":"additional","affiliation":[{"name":"Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0031-809X","authenticated-orcid":false,"given":"Nikolaos","family":"Kathopoulis","sequence":"additional","affiliation":[{"name":"Third Department of Obstetrics and Gynecology, University General Hospital \u201cATTIKON\u201d, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ismini","family":"Anagnostaki","sequence":"additional","affiliation":[{"name":"Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4337-7871","authenticated-orcid":false,"given":"Ioannis","family":"Tsakiridis","sequence":"additional","affiliation":[{"name":"Third Department of Obstetrics and Gynecology, General Hospital Ippokratio, Medical School, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2863-5839","authenticated-orcid":false,"given":"Themistoklis","family":"Dagklis","sequence":"additional","affiliation":[{"name":"Third Department of Obstetrics and Gynecology, General Hospital Ippokratio, Medical School, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5382-2170","authenticated-orcid":false,"given":"Eriketi","family":"Kokkosi","sequence":"additional","affiliation":[{"name":"Department of Midwifery, Faculty of Health and Caring Sciences, University of West Attica, 12243 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1100-4627","authenticated-orcid":false,"given":"Angeliki","family":"Sarella","sequence":"additional","affiliation":[{"name":"Department of Midwifery, Faculty of Health and Caring Sciences, University of West Attica, 12243 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1350-4182","authenticated-orcid":false,"given":"Konstantinos","family":"Zikopoulos","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University Hospital of Ioannina, 45500 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofoklis","family":"Stavros","sequence":"additional","affiliation":[{"name":"Third Department of Obstetrics and Gynecology, University General Hospital \u201cATTIKON\u201d, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Ma, J., Gao, W., and Li, D. 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