Long COVID and menstruation: bidirectional associations and potential mechanisms.

Long COVID and menstruation: bidirectional associations and potential mechanisms. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Article Long COVID and menstruation: bidirectional associations and potential mechanisms. Jacqueline Maybin, Catherine Walker, Marianne Watters, Natalie Homer, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5725816/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Sep, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Women have reported both menstrual disruption following SARS-CoV-2 infection and that long COVID symptoms change across the menstrual cycle. Yet there is a lack of female-specific research on COVID and menstruation. We aimed to determine if (i) acute/long COVID is associated with abnormal uterine bleeding (AUB), (ii) long COVID symptoms vary across the menstrual cycle and (iii) the mechanisms underpinning any such associations. We reveal that long COVID was significantly associated with AUB in a UK population, with menstrual flow volume, duration, and intermenstrual bleeding reported as significantly increased (n=1048) compared to those who had never had COVID (n=9433). With acute COVID (n=2017), only menstrual volume was increased. Examination of long COVID symptoms in 54 women across the menstrual cycle revealed that symptom severity was increased during the peri-menstrual and proliferative phases. To determine the impact of long COVID on ovarian and endometrial function, we analysed blood serum and endometrial tissue from ten women with long COVID at three points of their menstrual cycle and age-matched samples collected pre-pandemic. Higher secretory phase serum 5α-dihydrotestosterone and lower menstrual and proliferative phase endometrial androgen receptor levels were found in those with long COVID versus controls. No other significant differences in ovarian sex steroid hormone levels were detected. Serum Anti-Mullerian Hormone levels were also comparable, consistent with no significant impact of long COVID on ovarian reserve. Serum cytokine profiling indicated more menstrual phase inflammation in those with long COVID versus controls and less inflammation during the proliferative phase. We detected menstrual endometrial immune cell aggregates in those with long COVID that may contribute to altered tissue inflammation and AUB. In conclusion, whilst long COVID was associated with menstrual disturbance, it reassuringly does not appear to significantly impact ovarian function. Differences in peripheral and endometrial inflammation may contribute to AUB and increase long COVID symptom severity at menstruation. We anticipate that these data from across the menstrual cycle will decrease the gender health gap in long COVID biomarker development and instigate further exploration of new therapeutic strategies for long COVID symptoms in women. Health sciences/Medical research/Translational research Biological sciences/Physiology/Reproductive biology Health sciences/Diseases/Reproductive disorders/Endocrine reproductive disorders Health sciences/Signs and symptoms/Reproductive signs and symptoms Full Text Additional Declarations Yes there is potential Competing Interest. The authors declare the following non-financial competing interests: HODC has received clinical research support for laboratory consumables and staff from Bayer AG and provides consultancy advice (all paid to institution; no personal remuneration) to Bayer AG, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc. and Myovant Sciences GmbH. H.O.D.C. has received royalties from UpToDate for an article on abnormal uterine bleeding. JAM has provided consultancy advice (with no personal remuneration) to Gedeon Richter. Supplementary Files TableS1.pdf Supplementary Table 1 TableS2.pdf Supplementary Table 2 TableS3.pdf Supplementary Table 3 TableS4.pdf Supplementary Table 4 TableS5.pdf Supplementary Table 5 TableS6.pdf Supplementary Table 6 TableS7.pdf Supplementary Table 7 TableS8.pdf Supplementary Table 8 TableS9Severityacrosscycle.pdf Supplementary Table 9 TableS10.pdf Supplementary Table 10 TableS11.pdf Supplementary Table 11 SupplFig1.pdf Supplementary Figure 1 SupplFig2.pdf Supplementary Figure 2 Cite Share Download PDF Status: Published Journal Publication published 16 Sep, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5725816","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":399502958,"identity":"09a5d341-d108-4569-b9d2-99918bc0ac58","order_by":0,"name":"Jacqueline Maybin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/0lEQVRIiWNgGAWjYBACxgYGZoYEMJOH4QBDBUgABA4QreUMEVqAgBlK8wANaCNCC3P74ccGDyoYovln5B48XDjPRraB/fADZp4zeBzWk2ackHCGIXfGjbyEwzO3pRk38KQZMPPcwOeXHOYDiW0MuQ03cgwO8247nNjAkMPAzPMBj5b+N0At/xhy54O1zPmf2MD/hoCWGTnMCUCTczeAtTQcSGyQANmCz2EznhkbJByTyN145l3CYZ5jycZtEs8MDs7B433D/uTHkj9qbHLnHc89/Jmnxk62nz/54YM3x/BoaQBTEgwMAgkQETYGAhEpD2fx41U3CkbBKBgFIxkAALkVWLZLxns+AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-1560-2840","institution":"University of Edinburgh","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Jacqueline","middleName":"","lastName":"Maybin","suffix":""},{"id":399502959,"identity":"fe458dfb-bb68-4a2f-aaf7-4e505f58590e","order_by":1,"name":"Catherine Walker","email":"","orcid":"","institution":"University of Edinburgh","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Catherine","middleName":"","lastName":"Walker","suffix":""},{"id":399502960,"identity":"9e80f49f-70b1-478e-ade4-a412923760e8","order_by":2,"name":"Marianne Watters","email":"","orcid":"","institution":"University of Edinburgh","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Marianne","middleName":"","lastName":"Watters","suffix":""},{"id":399502961,"identity":"1116ab5b-469d-44d2-b260-2a73cdf1ed74","order_by":3,"name":"Natalie Homer","email":"","orcid":"https://orcid.org/0000-0002-9262-2098","institution":"University of Edinburgh","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Natalie","middleName":"","lastName":"Homer","suffix":""},{"id":399502962,"identity":"5125dd58-c4f6-4b58-b581-8eb76b94877c","order_by":4,"name":"Joanna Simpson","email":"","orcid":"https://orcid.org/0000-0002-0939-8487","institution":"University of Edinburgh","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Joanna","middleName":"","lastName":"Simpson","suffix":""},{"id":399502963,"identity":"2e6438d3-7e0e-49a9-80de-a03e5c7e12e4","order_by":5,"name":"Cara Robb","email":"","orcid":"","institution":"University of Edinburgh","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Cara","middleName":"","lastName":"Robb","suffix":""},{"id":399502964,"identity":"d2dbbe33-a738-49a0-bb53-a5a576f16b78","order_by":6,"name":"Hilary O.D. 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Sciences GmbH. H.O.D.C. has received royalties from UpToDate for an article on abnormal uterine bleeding. JAM has provided consultancy advice (with no personal remuneration) to Gedeon Richter.","formattedTitle":"Long COVID and menstruation: bidirectional associations and potential mechanisms.","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5725816/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5725816/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Women have reported both menstrual disruption following SARS-CoV-2 infection and that long COVID symptoms change across the menstrual cycle. Yet there is a lack of female-specific research on COVID and menstruation. We aimed to determine if (i) acute/long COVID is associated with abnormal uterine bleeding (AUB), (ii) long COVID symptoms vary across the menstrual cycle and (iii) the mechanisms underpinning any such associations. \r\n \r\nWe reveal that long COVID was significantly associated with AUB in a UK population, with menstrual flow volume, duration, and intermenstrual bleeding reported as significantly increased (n=1048) compared to those who had never had COVID (n=9433). With acute COVID (n=2017), only menstrual volume was increased. Examination of long COVID symptoms in 54 women across the menstrual cycle revealed that symptom severity was increased during the peri-menstrual and proliferative phases. To determine the impact of long COVID on ovarian and endometrial function, we analysed blood serum and endometrial tissue from ten women with long COVID at three points of their menstrual cycle and age-matched samples collected pre-pandemic. Higher secretory phase serum 5α-dihydrotestosterone and lower menstrual and proliferative phase endometrial androgen receptor levels were found in those with long COVID versus controls. No other significant differences in ovarian sex steroid hormone levels were detected. Serum Anti-Mullerian Hormone levels were also comparable, consistent with no significant impact of long COVID on ovarian reserve. Serum cytokine profiling indicated more menstrual phase inflammation in those with long COVID versus controls and less inflammation during the proliferative phase. We detected menstrual endometrial immune cell aggregates in those with long COVID that may contribute to altered tissue inflammation and AUB. \r\n \r\nIn conclusion, whilst long COVID was associated with menstrual disturbance, it reassuringly does not appear to significantly impact ovarian function. Differences in peripheral and endometrial inflammation may contribute to AUB and increase long COVID symptom severity at menstruation. We anticipate that these data from across the menstrual cycle will decrease the gender health gap in long COVID biomarker development and instigate further exploration of new therapeutic strategies for long COVID symptoms in women.","manuscriptTitle":"Long COVID and menstruation: bidirectional associations and potential mechanisms.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-09 02:15:52","doi":"10.21203/rs.3.rs-5725816/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"4fd836d6-67f6-4296-b093-199e636a0d92","owner":[],"postedDate":"January 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":42568446,"name":"Health sciences/Medical research/Translational research"},{"id":42568447,"name":"Biological sciences/Physiology/Reproductive biology"},{"id":42568448,"name":"Health sciences/Diseases/Reproductive disorders/Endocrine reproductive disorders"},{"id":42568449,"name":"Health sciences/Signs and symptoms/Reproductive signs and symptoms"}],"tags":[],"updatedAt":"2025-09-17T07:06:14+00:00","versionOfRecord":{"articleIdentity":"rs-5725816","link":"https://doi.org/10.1038/s41467-025-62965-7","journal":{"identity":"nature-communications","isVorOnly":false,"title":"Nature Communications"},"publishedOn":"2025-09-16 04:00:00","publishedOnDateReadable":"September 16th, 2025"},"versionCreatedAt":"2025-01-09 02:15:52","video":"","vorDoi":"10.1038/s41467-025-62965-7","vorDoiUrl":"https://doi.org/10.1038/s41467-025-62965-7","workflowStages":[]},"version":"v1","identity":"rs-5725816","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5725816","identity":"rs-5725816","version":["v1"]},"buildId":"veTbxFhMMB0_faC6-Wkog","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}