Association of Testosterone-to-Estradiol Ratio and Coronary Heart Disease: A NHANES-Based Study with the Weight-Adjusted Waist Index as a Potential Mediator

Association of Testosterone-to-Estradiol Ratio and Coronary Heart Disease: A NHANES-Based Study with the Weight-Adjusted Waist Index as a Potential Mediator | 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 Association of Testosterone-to-Estradiol Ratio and Coronary Heart Disease: A NHANES-Based Study with the Weight-Adjusted Waist Index as a Potential Mediator Yifan Li, Weiwei Chen, Ningning Liu, Jicheng Xi This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9203321/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objectives Sex differences in coronary heart disease (CHD) are well known, but the impact of sex hormone balance on cardiovascular risk is still unclear. We studied how the testosterone-to-estradiol ratio (TT/E2) relates to CHD and investigated whether abdominal fatness mediates this relationship across different sexes and menopausal states. Methods We included 9,558 adults aged ≥ 30 years from the 2013–2016 National Health and Nutrition Examination Survey (NHANES). Serum total testosterone and estradiol levels were measured using isotope-dilution liquid chromatography–tandem mass spectrometry. The TT/E2 ratio was log-transformed and standardized. CHD was defined as a self-reported physician diagnosis. Survey-weighted logistic regression models with multiple imputation estimated odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for demographic and cardiometabolic variables. Interaction terms evaluated effect modification by sex and menopausal status. Restricted cubic splines assessed dose–response relationships. A counterfactual mediation analysis was used to examine the mediating effect of the weight-adjusted waist index (WWI). Results In fully adjusted models, a higher log(TT/E2) was associated with a lower odds of CHD in men (OR per 1-SD increase: 0.81; 95% CI 0.70–0.94), but this association was not observed in women overall. There were significant interactions with sex ( p _interaction = 0.017) and menopausal status ( p _interaction = 0.009). Stratified analysis revealed an inverse relationship in premenopausal women (OR 0.73; 95% CI 0.56–0.95), but not in postmenopausal women. Spline analyses showed a mainly linear inverse association in men. WWI partially mediated the link in men (indirect effect p = 0.019), but not in premenopausal women. Conclusions A higher TT/E2 ratio was inversely associated with CHD in men and premenopausal women, with partial mediation by abdominal adiposity in men. These findings underscore the context-dependent role of sex hormone balance in cardiovascular risk. Coronary heart disease Testosterone-to-estradiol ratio Sex differences Abdominal adiposity NHANES Full Text Additional Declarations No competing interests reported. Supplementary Files supplementarymaterials.docx Cite Share Download PDF Status: Posted 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. 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-9203321","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":611598097,"identity":"486d5a43-821f-4ee6-a042-0d94884afcb1","order_by":0,"name":"Yifan Li","email":"","orcid":"","institution":"Shanxi Cardiovascular Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yifan","middleName":"","lastName":"Li","suffix":""},{"id":611598098,"identity":"381ecf6e-2495-4dc3-93a3-7488cad17f7a","order_by":1,"name":"Weiwei Chen","email":"","orcid":"","institution":"Shanxi Cardiovascular Hospital","correspondingAuthor":false,"prefix":"","firstName":"Weiwei","middleName":"","lastName":"Chen","suffix":""},{"id":611598099,"identity":"1befa057-0809-4c84-89ff-a48265dc905a","order_by":2,"name":"Ningning Liu","email":"","orcid":"","institution":"Shanxi Cardiovascular Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ningning","middleName":"","lastName":"Liu","suffix":""},{"id":611598100,"identity":"0441f1f9-035f-4261-95b9-8bd78b214837","order_by":3,"name":"Jicheng Xi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4UlEQVRIiWNgGAWjYBACgwMHG5gZDGzsGOcfPnDgww+itRSkJTPPYEs8OLOHCC2SDQwMzAwfDjO2z+AxPszBRoQWfsbDjZ8LDJiZeWf3fDjMwMMgzy92AL8WNoaDzdIzDNj4JOec3XC4wILBcObsBIJa2ph5DHiYDRtyNxyewcOQYHCbgBZ+iBYJxv0Hch4c5mEjQotkA1iLAWPjjBwG4rQAA7lZmscgIZmx55gBMJAlCPvF4Mbxh595/vy3Y2xvfvzhww8beX5pAloYJA6gcgkoBwH+BiIUjYJRMApGwcgGAHJcStQt9xCaAAAAAElFTkSuQmCC","orcid":"","institution":"Shanxi Cardiovascular Hospital","correspondingAuthor":true,"prefix":"","firstName":"Jicheng","middleName":"","lastName":"Xi","suffix":""}],"badges":[],"createdAt":"2026-03-23 17:23:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9203321/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9203321/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106959112,"identity":"d5d9ee3e-4df9-417d-95a0-cfb8d7b6c299","added_by":"auto","created_at":"2026-04-15 08:46:36","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":643640,"visible":true,"origin":"","legend":"","description":"","filename":"AssociationofTestosteronetoEstradiolRatioandCoronaryHeartDisease.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9203321/v1_covered_1d256660-c4b2-413b-84e7-7b01959b509a.pdf"},{"id":105411811,"identity":"003a543b-2bc1-422e-a89e-4047bcd54cd2","added_by":"auto","created_at":"2026-03-25 17:26:25","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":168318,"visible":true,"origin":"","legend":"","description":"","filename":"supplementarymaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-9203321/v1/87a3fe48d2d5a45b361ce9f5.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Association of Testosterone-to-Estradiol Ratio and Coronary Heart Disease: A NHANES-Based Study with the Weight-Adjusted Waist Index as a Potential Mediator","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Coronary heart disease, Testosterone-to-estradiol ratio, Sex differences, Abdominal adiposity, NHANES","lastPublishedDoi":"10.21203/rs.3.rs-9203321/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9203321/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eSex differences in coronary heart disease (CHD) are well known, but the impact of sex hormone balance on cardiovascular risk is still unclear. We studied how the testosterone-to-estradiol ratio (TT/E2) relates to CHD and investigated whether abdominal fatness mediates this relationship across different sexes and menopausal states.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe included 9,558 adults aged\u0026thinsp;\u0026ge;\u0026thinsp;30 years from the 2013\u0026ndash;2016 National Health and Nutrition Examination Survey (NHANES). Serum total testosterone and estradiol levels were measured using isotope-dilution liquid chromatography\u0026ndash;tandem mass spectrometry. The TT/E2 ratio was log-transformed and standardized. CHD was defined as a self-reported physician diagnosis. Survey-weighted logistic regression models with multiple imputation estimated odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for demographic and cardiometabolic variables. Interaction terms evaluated effect modification by sex and menopausal status. Restricted cubic splines assessed dose\u0026ndash;response relationships. A counterfactual mediation analysis was used to examine the mediating effect of the weight-adjusted waist index (WWI).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn fully adjusted models, a higher log(TT/E2) was associated with a lower odds of CHD in men (OR per 1-SD increase: 0.81; 95% CI 0.70\u0026ndash;0.94), but this association was not observed in women overall. There were significant interactions with sex (\u003cem\u003ep\u003c/em\u003e_interaction\u0026thinsp;=\u0026thinsp;0.017) and menopausal status (\u003cem\u003ep\u003c/em\u003e_interaction\u0026thinsp;=\u0026thinsp;0.009). Stratified analysis revealed an inverse relationship in premenopausal women (OR 0.73; 95% CI 0.56\u0026ndash;0.95), but not in postmenopausal women. Spline analyses showed a mainly linear inverse association in men. WWI partially mediated the link in men (indirect effect \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.019), but not in premenopausal women.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eA higher TT/E2 ratio was inversely associated with CHD in men and premenopausal women, with partial mediation by abdominal adiposity in men. These findings underscore the context-dependent role of sex hormone balance in cardiovascular risk.\u003c/p\u003e","manuscriptTitle":"Association of Testosterone-to-Estradiol Ratio and Coronary Heart Disease: A NHANES-Based Study with the Weight-Adjusted Waist Index as a Potential Mediator","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-25 17:26:18","doi":"10.21203/rs.3.rs-9203321/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"afc7cf5e-065b-4455-8ec2-a39202d46cc8","owner":[],"postedDate":"March 25th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-12T10:54:54+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-25 17:26:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9203321","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9203321","identity":"rs-9203321","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}