Menopausal Hormone Therapy and Risk of Neuropsychiatric Disease: A Drug Target Mendelian Randomisation Study

Menopausal Hormone Therapy and Risk of Neuropsychiatric Disease: A Drug Target Mendelian Randomisation Study | 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 Article Menopausal Hormone Therapy and Risk of Neuropsychiatric Disease: A Drug Target Mendelian Randomisation Study Louise Schindler, Dipender Gill, Hannah Oppenheimer, Claudia Barth, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5252067/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract The effects of menopausal hormone therapy (MHT) on neurological and psychiatric disease risk have shown conflicting results across epidemiological and clinical studies. Given the widespread propagation of MHT among females experiencing menopausal symptoms, clarifying causality and impact is critical for informed decision-making. Although randomised controlled trials can establish causal effects, they are associated with significant costs and often of limited duration. Here, we present the first study using Mendelian randomisation (MR) to estimate causal effects of MHT on key neuropsychiatric and brain structural outcomes. To mimic the effects of MHT on oestrogen receptors (ER) α and β, we leveraged genetic variations located in the ESR1 and ESR2 genes that were significantly associated with positive controls as instrumental variables. In two-sample MR analyses, we used GWAS data on late-onset Alzheimer's disease (AD), key brain structural endophenotypes (cortical grey matter volume, hippocampal volume, and white matter hyperintensity volume), as well as depression and anxiety as outcomes, adjusting the p-values for multiple comparisons using false discovery rate correction with an α level of 0.05. There was no evidence for an impact of genetically proxied perturbation of ERα (β = -0.08, 95% CI [-0.34, 0.20], p=0.69 and β = -0.005, 95% CI [-1.45, 1.44], p=1.00) and ERβ (β = 0.35, 95% CI [-0.77, 1.47], p=0.69) on AD risk. Similarly, we found no significant impact of genetically proxied perturbation of ERα and ERβ on associated brain structural outcomes. Genetically proxied perturbation of ERβ was significantly related to higher depression risk (β = -0.66, 95% CI [-0.99, -0.32], p=0.002), but not anxiety risk. Our study provides support for a causal impact of genetically predicted oestrogen receptor perturbation on increased risk of depression, highlighting the importance of considering the implications of targeting these proteins with MHT, for psychiatric outcomes in clinical contexts. However, there was no support for either a harmful or protective causal effect of MHT on AD risk. Health sciences/Health care/Therapeutics/Hormonal therapies Biological sciences/Physiology/Reproductive biology hormones Menopausal hormone therapy Female Health Mental Health Alzheimer’s disease Mendelian Randomisation Drug targets Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 16 Sep, 2025 Reviews received at journal 14 Aug, 2025 Reviewers agreed at journal 03 Aug, 2025 Reviews received at journal 22 May, 2025 Reviewers agreed at journal 13 Apr, 2025 Reviewers agreed at journal 06 Jan, 2025 Reviewers invited by journal 12 Nov, 2024 Editor assigned by journal 17 Oct, 2024 Submission checks completed at journal 15 Oct, 2024 First submitted to journal 12 Oct, 2024 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. 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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-5252067","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":366281511,"identity":"270d5e05-c3ca-493c-81b2-60990193f172","order_by":0,"name":"Louise Schindler","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+klEQVRIie3NsWrCQBzH8X+Wulx76198iZ8ECoIkr5IjUJfUCl0yOASEuPgAAX2IQqFzQsApD5Chg1OnDHazS9tLdalwsWOH+8Ifjj/3uSOy2f5hN3rynxM7CYkZkWw3O6LARK5+ExD1E70JLpBjrKclaF/oJL3VsDjE5Mv1It01GD+49X2hf/GmRiIqlKIilb0Wy+EGd6OXehpoEj4aCUconZQCsEoHAiVu6wia5CrpIMXHJ/kn8gU3+wPJrxNyno4kB/gSEdtZKbasslql/Q1CcNVogtBIZG/x/H6Yj32ZTd64iT3IZeTu97FnJKf4fIHu+zabzWbr7hsXN1YuXWnPrQAAAABJRU5ErkJggg==","orcid":"","institution":"Lausanne University Hospital (CHUV) and University of Lausanne","correspondingAuthor":true,"prefix":"","firstName":"Louise","middleName":"","lastName":"Schindler","suffix":""},{"id":366281512,"identity":"e2634ad3-fe20-4ac7-a90d-b2c477f088c7","order_by":1,"name":"Dipender Gill","email":"","orcid":"","institution":"Imperial College London","correspondingAuthor":false,"prefix":"","firstName":"Dipender","middleName":"","lastName":"Gill","suffix":""},{"id":366281513,"identity":"b24ee651-3586-4c5b-a327-150403e912a9","order_by":2,"name":"Hannah Oppenheimer","email":"","orcid":"","institution":"Diakonhjemmet Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hannah","middleName":"","lastName":"Oppenheimer","suffix":""},{"id":366281514,"identity":"d4760816-7a24-4aa3-9707-7282b9e6cba7","order_by":3,"name":"Claudia Barth","email":"","orcid":"","institution":"Diakonhjemmet Hospital","correspondingAuthor":false,"prefix":"","firstName":"Claudia","middleName":"","lastName":"Barth","suffix":""},{"id":366281515,"identity":"d04a7c89-275e-4e3c-9cb8-1098015131dd","order_by":4,"name":"Ole Andreassen","email":"","orcid":"","institution":"Oslo University Hospital \u0026 Institute of Clinical Medicine, University of Oslo","correspondingAuthor":false,"prefix":"","firstName":"Ole","middleName":"","lastName":"Andreassen","suffix":""},{"id":366281516,"identity":"fe19fd45-f627-43d3-ac62-9c72a76a8171","order_by":5,"name":"Bogdan Draganski","email":"","orcid":"","institution":"University Hospital of Bern","correspondingAuthor":false,"prefix":"","firstName":"Bogdan","middleName":"","lastName":"Draganski","suffix":""},{"id":366281517,"identity":"ae47b0f7-44ed-4f4c-9669-22d831778ed0","order_by":6,"name":"Lars T. 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