Mapping the Sex-Dimorphic Hormonal Ecosystem in Osteoarthritis: Non-Linear Interactions Between Androgen Activity and Estrogen

Mapping the Sex-Dimorphic Hormonal Ecosystem in Osteoarthritis: Non-Linear Interactions Between Androgen Activity and Estrogen | 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 Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Mapping the Sex-Dimorphic Hormonal Ecosystem in Osteoarthritis: Non-Linear Interactions Between Androgen Activity and Estrogen bin deng, Zugui Huang, Shuai Zhong, Ting Chen, Qiao Chen, Liangzhi Huang, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8470190/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Methods We performed a cross-sectional analysis of 13,848 adults from the U.S. National Health and Nutrition Examination Survey (NHANES), stratified by sex and menopausal status. Beyond complex-sampling logistic regression, we employed an advanced analytical framework integrating two-way restricted cubic splines, generalized additive models (GAMs), and interpretable machine learning (SHAP) to model non-linear interactions and identify risk thresholds. Results The FAI-OA association was markedly heterogeneous. After adjustment, higher FAI was protective in post-menopausal women (OR = 0.85, 95% CI: 0.74–0.97, P = 0.021), showed a non-significant protective trend in pre-menopausal women, and was not associated in men. Crucially, non-linear interaction analyses revealed distinct, sex-specific modification by estradiol : a “cross-over” pattern in men (protective at low estradiol, adverse at high estradiol) and a “buffering” pattern in post-menopausal women (higher estradiol mitigated risk at low FAI). Machine-learning models confirmed that the highest OA risk emerged from specific estradiol-FAI combinations (e.g., high E₂ + low FAI in men; low E₂ + low FAI in post-menopausal women), not from either hormone alone. Conclusions The influence of sex hormones on OA is governed by a context-dependent, non-linear interaction network . Our findings move beyond single-hormone paradigms, providing a dynamic “hormonal ecosystem” framework that explains sex disparities in OA through fundamentally distinct modes of steroid interaction. This approach offers novel mechanistic insights and a foundation for sex-specific, precision prevention strategies . Sex hormones Hormone interaction Osteoarthritis Precision prevention Sex disparities Non-linear modelling Machine learning Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 05 Feb, 2026 Reviewers agreed at journal 16 Jan, 2026 Reviewers invited by journal 13 Jan, 2026 Editor assigned by journal 30 Dec, 2025 Submission checks completed at journal 30 Dec, 2025 First submitted to journal 29 Dec, 2025 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board 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-8470190","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":575746116,"identity":"430e918f-969e-4449-9049-78938d449ca1","order_by":0,"name":"bin deng","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBklEQVRIie3RMUvEMBTA8XcE4hKqY4rF+wqRwC0K+lFeF2+5g44dbrklXc69Ln4M51cC1yU4FxQUBBcdCi43iBh1lOZuFMx/CCHkR0gCEIv9xQiAgQKxv1cRYbk44n6yE8nSlcupd2udCIc7EIBT1aFurgzLr+W5CoqkvbQvRXEvlCO0gvOpkYCwKW8GSepuL05q9SzSdklWiGxuDpc0Wrm7QaK62UQLZUXyfYrkc5MRspEJkIfXHwId+lGxKZeowqQT+umLHHjS1MhwK0ndbMJqT/wjI/W0Pjb+kZvQXZLW6bfi3Z75r7R9/rEYj6uqedyUw8TH5a8lCu33sX7LhlgsFvvvfQKA6mKMhnRRIwAAAABJRU5ErkJggg==","orcid":"","institution":"Nanping First Affiliated Hospital of Fujian Medical University","correspondingAuthor":true,"prefix":"","firstName":"bin","middleName":"","lastName":"deng","suffix":""},{"id":575746118,"identity":"5751a5d2-c71c-41af-b0df-23cc66e2e307","order_by":1,"name":"Zugui Huang","email":"","orcid":"","institution":"Nanping First Affiliated Hospital of Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zugui","middleName":"","lastName":"Huang","suffix":""},{"id":575746122,"identity":"02d1edc5-6e9c-4231-a5c5-315f60d5532d","order_by":2,"name":"Shuai Zhong","email":"","orcid":"","institution":"Nanping First Affiliated Hospital of Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shuai","middleName":"","lastName":"Zhong","suffix":""},{"id":575746126,"identity":"46e3ebe7-868f-4215-bc0a-4ac9e3f11190","order_by":3,"name":"Ting Chen","email":"","orcid":"","institution":"Nanping First Affiliated Hospital of Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ting","middleName":"","lastName":"Chen","suffix":""},{"id":575746129,"identity":"9da7d834-328e-42df-b9fc-29b4ec74bc1b","order_by":4,"name":"Qiao Chen","email":"","orcid":"","institution":"Nanping First Affiliated Hospital of Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Qiao","middleName":"","lastName":"Chen","suffix":""},{"id":575746131,"identity":"426bd064-2811-4ef2-978c-6a686fb85bce","order_by":5,"name":"Liangzhi Huang","email":"","orcid":"","institution":"Nanping First Affiliated Hospital of Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Liangzhi","middleName":"","lastName":"Huang","suffix":""},{"id":575746132,"identity":"afa72fa7-a68e-4338-95d4-2d68db4bd264","order_by":6,"name":"Zhanlin Liao","email":"","orcid":"","institution":"Nanping First Affiliated Hospital of Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zhanlin","middleName":"","lastName":"Liao","suffix":""}],"badges":[],"createdAt":"2025-12-29 07:23:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8470190/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8470190/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":100578363,"identity":"9c71ad0e-46fb-4baf-8e08-e1c2446c2ce0","added_by":"auto","created_at":"2026-01-19 10:45:46","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2645405,"visible":true,"origin":"","legend":"","description":"","filename":"MainTextv2.docx","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/8f9fb0cc47bd506fe4d1bf41.docx"},{"id":100578360,"identity":"60026eed-108d-4d17-8c1c-abbd02752a6d","added_by":"auto","created_at":"2026-01-19 10:45:46","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":9249,"visible":true,"origin":"","legend":"","description":"","filename":"9ee949bcd302412cb783edf52194ff7f.json","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/ede9ff7651dc40c48e4b8dd5.json"},{"id":100596019,"identity":"f17fc5d5-db20-4277-8683-728cf15a941d","added_by":"auto","created_at":"2026-01-19 13:50:18","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":121523,"visible":true,"origin":"","legend":"","description":"","filename":"9ee949bcd302412cb783edf52194ff7f1enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/6b8ad8704b1d4d8ed986d749.xml"},{"id":100578365,"identity":"3fe755a3-71f8-423d-9d0d-d18a42bf1227","added_by":"auto","created_at":"2026-01-19 10:45:46","extension":"png","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":37678,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/7a794973fa3720c586fdb1de.png"},{"id":100578377,"identity":"8fbdb450-80c7-4761-aadc-b107edcd52d3","added_by":"auto","created_at":"2026-01-19 10:45:46","extension":"jpeg","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":229919,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage10.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/1a30040731a1e76880a23778.jpeg"},{"id":100595943,"identity":"77b5b639-1184-41ad-ac26-89ca5cb4d462","added_by":"auto","created_at":"2026-01-19 13:49:47","extension":"jpeg","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":356384,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage11.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/c86221b88550f6f93cd80fdd.jpeg"},{"id":100596050,"identity":"9649e6f4-e8f5-465a-9499-8cd3bddd6efe","added_by":"auto","created_at":"2026-01-19 13:50:27","extension":"jpeg","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":739104,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage12.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/80bd1a7e854eed0e4d8b5a4b.jpeg"},{"id":100578362,"identity":"92a0a4c2-6468-4f04-a9e0-f8d0fbaa81ee","added_by":"auto","created_at":"2026-01-19 10:45:46","extension":"jpeg","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":810139,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage13.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/a59c16ff012f32c60a0c5230.jpeg"},{"id":100578361,"identity":"401d708a-c07f-4b07-b8d9-348544e7e6fd","added_by":"auto","created_at":"2026-01-19 10:45:46","extension":"jpeg","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":414186,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage14.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/2667b452dfba39338bdd40a3.jpeg"},{"id":100578367,"identity":"318842b7-063e-4ae8-afeb-1c4c57503026","added_by":"auto","created_at":"2026-01-19 10:45:46","extension":"jpeg","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":776965,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/9f4e5adcb4a4214e2bf3d60e.jpeg"},{"id":100595676,"identity":"8bbd3908-1954-4507-b0ab-b793523abee1","added_by":"auto","created_at":"2026-01-19 13:49:06","extension":"jpeg","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":355825,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/d54383926414c33598b826da.jpeg"},{"id":100578368,"identity":"7c7cbe25-a490-478c-b23f-c5b1b073b538","added_by":"auto","created_at":"2026-01-19 10:45:46","extension":"jpeg","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":634829,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/09c0ee1371c2e0f79ab665f2.jpeg"},{"id":100596088,"identity":"669efe93-895b-462a-8b49-4e172981d664","added_by":"auto","created_at":"2026-01-19 13:51:10","extension":"jpeg","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":323930,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/b289f645df28445835fb8aec.jpeg"},{"id":100578378,"identity":"ae4a5524-3cb7-414e-a378-e60f8e460f80","added_by":"auto","created_at":"2026-01-19 10:45:46","extension":"jpeg","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":417946,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage6.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/1fcbc39ad498291155ec77ae.jpeg"},{"id":100578375,"identity":"464b8f31-e4b5-449b-932a-84442d283a8a","added_by":"auto","created_at":"2026-01-19 10:45:46","extension":"jpeg","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":416127,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage7.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/dc537d38ca70acd6e5cfeaed.jpeg"},{"id":100595963,"identity":"a94d6b4f-94a1-498c-91a4-49ee2e16fe75","added_by":"auto","created_at":"2026-01-19 13:49:55","extension":"jpeg","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":379020,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage8.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/acd6d086dec927254a56d6f9.jpeg"},{"id":100596107,"identity":"326b99cd-1a36-46e4-a8b2-c6e7140379d8","added_by":"auto","created_at":"2026-01-19 13:52:01","extension":"jpeg","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":358764,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage9.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/49109aa0e08f97224ae783cf.jpeg"},{"id":100578370,"identity":"d3faf0f1-9667-4600-ab0f-c17408e6fc0c","added_by":"auto","created_at":"2026-01-19 10:45:46","extension":"png","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":9546,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/c5e0efa718c6b6b82f5417ec.png"},{"id":100578373,"identity":"d579e874-5ee3-4972-96d0-e01af6d6e73e","added_by":"auto","created_at":"2026-01-19 10:45:46","extension":"png","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":37047,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage10.png","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/dd657bf8f06cd3d0d52f96d0.png"},{"id":100578380,"identity":"69801a6e-572e-4e31-8d83-e0694dbfa851","added_by":"auto","created_at":"2026-01-19 10:45:46","extension":"png","order_by":19,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":66550,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage11.png","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/1f2bce5e79fa256b77a7bba7.png"},{"id":100578384,"identity":"d46c8377-bf56-4e72-8249-e5292d7f8c84","added_by":"auto","created_at":"2026-01-19 10:45:46","extension":"png","order_by":20,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":141186,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage12.png","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/9086aeb01be5054b83e7b66c.png"},{"id":100578382,"identity":"4e9ba746-2b77-4e83-94d8-9a98bb17e24c","added_by":"auto","created_at":"2026-01-19 10:45:46","extension":"png","order_by":21,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":158979,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage13.png","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/7e468aa78ba656086c107882.png"},{"id":100578381,"identity":"f755137a-fdcb-460f-8d10-08c3e2cd8126","added_by":"auto","created_at":"2026-01-19 10:45:46","extension":"png","order_by":22,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":84947,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage14.png","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/37aaaca5b915a576b5aea613.png"},{"id":100595731,"identity":"576c9ecf-1b2b-479e-a31a-b8cec6d1e9ba","added_by":"auto","created_at":"2026-01-19 13:49:17","extension":"png","order_by":23,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":167097,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/9af6c22412eb22f6a9d9f3b9.png"},{"id":100595909,"identity":"3bd73c0e-3399-486d-9cfe-a7d969fe2f35","added_by":"auto","created_at":"2026-01-19 13:49:39","extension":"png","order_by":24,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":73132,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/da499e47a49c8feb2f1c2381.png"},{"id":100578389,"identity":"e1fff9b4-3b00-45bf-a2b4-288b9b060ab9","added_by":"auto","created_at":"2026-01-19 10:45:47","extension":"png","order_by":25,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":134651,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/b65397fa1ff390f05de8283b.png"},{"id":100578387,"identity":"e575e177-4420-4d55-b0bd-c5cf1e59f7da","added_by":"auto","created_at":"2026-01-19 10:45:46","extension":"png","order_by":26,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":72188,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/c0b33e9fb6b258a2df93abfd.png"},{"id":100595639,"identity":"24af97a5-9ae1-4ec4-a1f7-110f7f35f29d","added_by":"auto","created_at":"2026-01-19 13:48:59","extension":"png","order_by":27,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":74921,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/c15c6d4a3d0fde9d7b1f6e9a.png"},{"id":100578383,"identity":"ab85dab5-38f6-4170-890f-59320781bbb8","added_by":"auto","created_at":"2026-01-19 10:45:46","extension":"png","order_by":28,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":59979,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/07ef8ca28c112d02abeb78fb.png"},{"id":100595829,"identity":"ebc7a3d8-f70c-4e2e-9b5d-603c0a4ed674","added_by":"auto","created_at":"2026-01-19 13:49:29","extension":"png","order_by":29,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":68144,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage8.png","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/223d34544b1c2eef9ddb7d8f.png"},{"id":100578386,"identity":"479d542b-a2ba-4575-8c0a-89bd72b9f0b0","added_by":"auto","created_at":"2026-01-19 10:45:46","extension":"png","order_by":30,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":62073,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage9.png","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/692ad21386d5082042992583.png"},{"id":100578385,"identity":"262252c1-625c-4cfa-9159-53734fb91fb4","added_by":"auto","created_at":"2026-01-19 10:45:46","extension":"xml","order_by":31,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":119584,"visible":true,"origin":"","legend":"","description":"","filename":"9ee949bcd302412cb783edf52194ff7f1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/973acf0b1bc0e4dbc3222d46.xml"},{"id":100578393,"identity":"fd420a31-b26b-48e2-82cb-6f6b1c2d3997","added_by":"auto","created_at":"2026-01-19 10:45:47","extension":"html","order_by":32,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":131884,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1/a253fceaeed3695b13abce59.html"},{"id":100597784,"identity":"ff5d0cc3-d60b-48b8-a2d4-90122321c1ec","added_by":"auto","created_at":"2026-01-19 14:20:45","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1860664,"visible":true,"origin":"","legend":"","description":"","filename":"MainTextv2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8470190/v1_covered_3866110e-0f14-4b0f-a8e8-f250ee0f1afc.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Mapping the Sex-Dimorphic Hormonal Ecosystem in Osteoarthritis: Non-Linear Interactions Between Androgen Activity and Estrogen","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"biology-of-sex-differences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bosd","sideBox":"Learn more about [Biology of Sex Differences](http://bsd.biomedcentral.com)","snPcode":"13293","submissionUrl":"https://submission.nature.com/new-submission/13293/3","title":"Biology of Sex Differences","twitterHandle":"@BiologySexDiff","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Sex hormones, Hormone interaction, Osteoarthritis, Precision prevention, Sex disparities, Non-linear modelling, Machine learning","lastPublishedDoi":"10.21203/rs.3.rs-8470190/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8470190/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eWe performed a cross-sectional analysis of 13,848 adults from the U.S. National Health and Nutrition Examination Survey (NHANES), stratified by sex and menopausal status. Beyond complex-sampling logistic regression, we employed an \u003cb\u003eadvanced analytical framework\u003c/b\u003e integrating \u003cb\u003etwo-way restricted cubic splines, generalized additive models (GAMs), and interpretable machine learning (SHAP)\u003c/b\u003e to model non-linear interactions and identify risk thresholds.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe FAI-OA association was markedly heterogeneous. After adjustment, higher FAI was protective in post-menopausal women (OR\u0026thinsp;=\u0026thinsp;0.85, 95% CI: 0.74\u0026ndash;0.97, P\u0026thinsp;=\u0026thinsp;0.021), showed a non-significant protective trend in pre-menopausal women, and was not associated in men. Crucially, \u003cb\u003enon-linear interaction analyses revealed distinct, sex-specific modification by estradiol\u003c/b\u003e: a \u003cb\u003e\u0026ldquo;cross-over\u0026rdquo; pattern in men\u003c/b\u003e (protective at low estradiol, adverse at high estradiol) and a \u003cb\u003e\u0026ldquo;buffering\u0026rdquo; pattern in post-menopausal women\u003c/b\u003e (higher estradiol mitigated risk at low FAI). Machine-learning models confirmed that the highest OA risk emerged from specific \u003cb\u003eestradiol-FAI combinations\u003c/b\u003e (e.g., high E₂ + low FAI in men; low E₂ + low FAI in post-menopausal women), not from either hormone alone.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe influence of sex hormones on OA is governed by a \u003cb\u003econtext-dependent, non-linear interaction network\u003c/b\u003e. Our findings move beyond single-hormone paradigms, providing a \u003cb\u003edynamic \u0026ldquo;hormonal ecosystem\u0026rdquo; framework\u003c/b\u003e that explains sex disparities in OA through fundamentally distinct modes of steroid interaction. This approach offers novel mechanistic insights and a foundation for \u003cb\u003esex-specific, precision prevention strategies\u003c/b\u003e.\u003c/p\u003e","manuscriptTitle":"Mapping the Sex-Dimorphic Hormonal Ecosystem in Osteoarthritis: Non-Linear Interactions Between Androgen Activity and Estrogen","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-19 10:45:41","doi":"10.21203/rs.3.rs-8470190/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-02-05T17:59:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"96822537303690255106277748529884777799","date":"2026-01-16T16:27:04+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-14T01:51:46+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-30T10:25:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-30T10:21:23+00:00","index":"","fulltext":""},{"type":"submitted","content":"Biology of Sex Differences","date":"2025-12-29T07:01:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"biology-of-sex-differences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bosd","sideBox":"Learn more about [Biology of Sex Differences](http://bsd.biomedcentral.com)","snPcode":"13293","submissionUrl":"https://submission.nature.com/new-submission/13293/3","title":"Biology of Sex Differences","twitterHandle":"@BiologySexDiff","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"96ca223a-8865-4c6c-a53f-7e7b03528d52","owner":[],"postedDate":"January 19th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-01-19T10:45:41+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-19 10:45:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8470190","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8470190","identity":"rs-8470190","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}