{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T21:50:00Z","timestamp":1789595400345,"version":"build-2803163510"},"reference-count":67,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T00:00:00Z","timestamp":1751932800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Nitric oxide (NO) predominantly regulates endometrial receptivity, angiogenesis, immunological tolerance, and trophoblast invasion throughout the implantation period. Both insufficient and excessive nitric oxide production have been linked to\u00a0suboptimal embryo implantation and infertility. The primary enzymatic source of uterine nitric oxide, along with hormonal, metabolic, and immunological variables and genetic variations in the endothelial nitric oxide synthase gene (NOS3), affects endothelial nitric oxide synthase (eNOS). Despite its considerable importance, there is limited knowledge regarding the practical implementation of nitric oxide-related diagnoses and therapies in reproductive medicine. A comprehensive assessment was performed in accordance with the PRISMA principles. Electronic searches were carried out in PubMed, Scopus, and Embase, and we analyzed the literature published from 2000 to 2024 regarding the association between NO, its metabolites (NO2\u2212 and NO3\u2212), eNOS expression, NOS3 gene variants, and reproductive outcomes. Relevant studies encompassed clinical trials, observational studies, and experimental research using either human or animal subjects. We collected data about therapeutic interventions, hormonal and immunological associations, nitric oxide measurement techniques, and in vitro fertilization success rates. A total of thirty-four studies were included. Dysregulated nitric oxide signaling, characterized by modified eNOS expression, oxidative stress, or NOS3 polymorphisms (e.g., Glu298Asp and intron 4 VNTR), was linked to diminished endometrial receptivity and an elevated risk of implantation failure and miscarriage. The dynamics of local uterine NO are essential as elevated and diminished systemic levels of NO2\u2212\/NO3\u2212 corresponded with enhanced and decreased implantation rates, respectively. Among many therapeutic approaches, targeted hormone treatments, antioxidant therapy, and dietary nitrate supplements have demonstrated potential in restoring nitric oxide balance and enhancing reproductive outcomes. In animal models, the modification of nitric oxide significantly impacted decidualization, angiogenesis, and embryo viability. Nitric oxide is a multifaceted molecular mediator with considerable ramifications for successful implantation. Its therapeutic and diagnostic efficacy increases with its sensitivity to environmental, hormonal, and genetic alterations. Integrating targeted nitric oxide modulation, oxidative stress assessment, and NOS3 genotyping with personalized reproductive therapy will enhance endometrial receptivity and improve IVF outcomes. Future translational research should incorporate nitric oxide signaling into personalized treatment protocols for patients with unexplained infertility or recurrent implantation failure.<\/jats:p>","DOI":"10.3390\/ijms26146569","type":"journal-article","created":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T11:58:07Z","timestamp":1751975887000},"page":"6569","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Unlocking Implantation: The Role of Nitric Oxide, NO2-NO3, and eNOS in Endometrial Receptivity and IVF Success\u2014A Systematic Review"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9477-7619","authenticated-orcid":false,"given":"Charalampos","family":"Voros","sequence":"first","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 VasilissisSofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iwakeim","family":"Sapantzoglou","sequence":"additional","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 VasilissisSofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1220-6594","authenticated-orcid":false,"given":"Despoina","family":"Mavrogianni","sequence":"additional","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 VasilissisSofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diamantis","family":"Athanasiou","sequence":"additional","affiliation":[{"name":"IVF Athens Reproduction Center V. Athanasiou, 15123 Maroussi, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8725-7103","authenticated-orcid":false,"given":"Antonia","family":"Varthaliti","sequence":"additional","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 VasilissisSofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7563-4305","authenticated-orcid":false,"given":"Kyriakos","family":"Bananis","sequence":"additional","affiliation":[{"name":"King\u2019s College Hospitals NHS Foundation Trust, London SE5 9RS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia","family":"Athanasiou","sequence":"additional","affiliation":[{"name":"IVF Athens Reproduction Center V. Athanasiou, 15123 Maroussi, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aikaterini","family":"Athanasiou","sequence":"additional","affiliation":[{"name":"IVF Athens Reproduction Center V. Athanasiou, 15123 Maroussi, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthi-Maria","family":"Papahliou","sequence":"additional","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 VasilissisSofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8203-6407","authenticated-orcid":false,"given":"Constantinos G.","family":"Zografos","sequence":"additional","affiliation":[{"name":"2nd Surgical Department, General Hospital of Athens \u201cLAIKO\u201d, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1376-7895","authenticated-orcid":false,"given":"Athanasios","family":"Gkirgkinoudis","sequence":"additional","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 VasilissisSofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9723-5054","authenticated-orcid":false,"given":"Ioannis","family":"Papapanagiotou","sequence":"additional","affiliation":[{"name":"Athens Medical School, National and Kapodistrian University of Athens, 15772 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyriaki","family":"Migklis","sequence":"additional","affiliation":[{"name":"Athens Medical School, National and Kapodistrian University of Athens, 15772 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitris","family":"Mazis Kourakos","sequence":"additional","affiliation":[{"name":"Athens Medical School, National and Kapodistrian University of Athens, 15772 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgios","family":"Papadimas","sequence":"additional","affiliation":[{"name":"Athens Medical School, National and Kapodistrian University of Athens, 15772 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Anastasia","family":"Daskalaki","sequence":"additional","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 VasilissisSofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2106-5922","authenticated-orcid":false,"given":"Panagiotis","family":"Antsaklis","sequence":"additional","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 VasilissisSofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8686-594X","authenticated-orcid":false,"given":"Dimitrios","family":"Loutradis","sequence":"additional","affiliation":[{"name":"Athens Medical School, National and Kapodistrian University of Athens, 15772 Athens, Greece"},{"name":"Fertility Institute-Assisted Reproduction Unit, Paster 15, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7108-211X","authenticated-orcid":false,"given":"Georgios","family":"Daskalakis","sequence":"additional","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 VasilissisSofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.semcdb.2007.10.008","article-title":"Uterine receptivity to human embryonic implantation: Histology, biomarkers, and transcriptomics","volume":"19","author":"Aghajanova","year":"2008","journal-title":"Semin. 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