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The steroids estradiol (E2) and progesterone (P4) promote anti-inflammatory immune responses and their therapeutic use for COVID-19 has been under investigation. The aim of the study was to evaluate the efficacy of a short systemic E2 and P4 combination in mitigating COVID-19 severity in hospitalized men and women. In a phase 2, single center, double blind, randomized placebo-controlled trial, ten male and female participants hospitalized for COVID-19 with scores 3\u20135 on the 9-point WHO ordinal scale were randomized to receive either (1) E2 cypionate (5\u00a0mg, IM) and micronized P4 (200\u00a0mg, PO), or (2) placebo-equivalent, in addition to standard of care (SOC). The primary outcome was the proportion of patients whose WHO scores improved to 1\u20132 on the day of discharge. Secondary outcomes included length of hospital stay (LOS), days on oxygen therapy (DOT), readmission rates (RR), adverse events (AEs), and change in circulating biomarkers using untargeted proteomics and cytokine profiling. There were no significant changes between the groups in primary outcome, LOS, DOT, RR or AEs. The E2P4 group exhibited a decrease in biomarker pathways of respiratory and gastrointestinal disease inflammation, infection by coronavirus, and immune cell trafficking and inflammatory response. A short-term E2P4 treatment in patients hospitalized for COVID-19 decreases biomarkers of inflammation. Considering the availability, low cost, and safety of E2 and P4, our results warrant additional studies to explore their effects in mitigating other viral pandemics. <jats:italic>Clinical Trial Registration<\/jats:italic> NCT04865029, ClinicalTrials.gov; (First trial registration 29\/04\/2021).<\/jats:p>","DOI":"10.1038\/s41598-024-73263-5","type":"journal-article","created":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T17:02:50Z","timestamp":1727715770000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Acute estradiol and progesterone therapy in hospitalized adults to reduce COVID-19 severity: a randomized control trial"],"prefix":"10.1038","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2607-8768","authenticated-orcid":false,"given":"Dragana","family":"Lovre","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6764-6151","authenticated-orcid":false,"given":"M. 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Data from: E2P4 COVID19 2024 Manuscript. 2024. doi:https:\/\/zenodo.org\/doi\/10.5281\/zenodo.10570112"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-73263-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-73263-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-73263-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T17:05:57Z","timestamp":1727715957000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-73263-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,30]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["73263"],"URL":"https:\/\/doi.org\/10.1038\/s41598-024-73263-5","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,30]]},"assertion":[{"value":"7 June 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 September 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 September 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This study was supported by National Institutes of Health awards (DK074970) (FMJ), an American Diabetes Association COVID-19 Research Award (7-20-COVID-051) (FMJ), a US Department of Veterans Affairs Merit Review Award (BX003725) (FMJ), a US Department of Veterans Affairs Career Development Award (CX002225) (DL) and the Tulane Center of Excellence in Sex Based Biology & Medicine.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Sources of support"}},{"value":"Patients and\/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Patient and public involvement"}},{"value":"Not applicable.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Patient consent for publication"}},{"value":"The sponsor of this study is the Center of Excellence in Sex-Based Biology & Medicine at Tulane University, New Orleans, Louisiana, USA. Ethical approval for the study and the consent was obtained from the Tulane institutional review board (IRB) on May 14, 2021. The study was reviewed by the US Food and Drug Administration and granted Investigational New Drug (IND) #152499. In the conduct of this clinical trial, we affirm that all procedures and methodologies employed were rigorously designed and executed in full compliance with the prevailing ethical standards and regulatory guidelines. This encompasses adherence to the principles delineated in the Declaration of Helsinki. We have obtained all necessary informed consent from participants and have ensured the confidentiality and anonymity of their data.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics and dissemination"}}],"article-number":"22732"}}