Age at menopause and the risk of stroke: Observational and Mendelian Randomization analysis in 204,244 postmenopausal women
Age at menopause and the risk of stroke: Observational and Mendelian Randomization analysis in 204,244 postmenopausal women
Abstract BackgroundObservational studies have shown that women with an early menopause are at higher risk of stroke compared to women with a later menopause. However, associations with stroke subtypes are inconsistent and the causality is unclear. Therefore, we conducted a large-scale analysis to investigate the observational association between age at menopause and different types of stroke accompanied by a Mendelian Randomization analysis to evaluate causality. MethodsWe analyzed data of the UK Biobank and EPIC-CVD study. Postmenopausal women without a history of stroke at baseline were eligible for inclusion. The study endpoints were total stroke and stroke subtypes (i.e., ischemic stroke, hemorrhagic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage). We investigated the observational association between age at menopause and risk of stroke using Cox-regression analysis in each study separately before combining effect sizes using random-effects meta-analysis. Cox-regression analyses were progressively adjusted for (1) age, (2) smoking status, body mass index, glycated hemoglobin, total cholesterol, and hypertension, and (3) ever use of hormone replacement therapy and age at menarche. We used two-sample Mendelian Randomization analysis to study whether there is a causal relationship between genetically proxied age at menopause and risk of stroke. ResultsA total of 204,244 women were included (7,883 from EPIC-CVD [5,292 from the sub-cohort]; 196,361 from the UK Biobank). Pooled mean baseline age was 58.9 years (SD 5.8) and pooled mean age at menopause was 47.8 years (SD 6.2). Natural menopause occurred in 77.6% of all women. Over a median follow-up of 12.6 years (IQR 11.8, 13.3), 6,770 women experienced a stroke. In multivariable adjusted observational analyses, the pooled hazard ratios per five years younger age at menopause were 1.09 (95% CI: 1.07, 1.12) for stroke, 1.09 (1.06, 1.13) for ischemic stroke, 1.10 (1.04, 1.16) for hemorrhagic stroke, 1.14 (1.08, 1.20) for intracerebral hemorrhage, and 1.00 (0.84, 1.20) for subarachnoid hemorrhage. The Mendelian Randomization analysis found no evidence for a causal relationship between genetically proxied age at menopause and risk of any type of stroke. ConclusionsEarlier age at menopause is associated with, but not causally related to the risk of stroke. Clinical PerspectiveWhat is new?This analysis involves over 200,000 postmenopausal women and more than 6,000 incident stroke cases and investigates the observational association between age at menopause and various subtypes of stroke. Furthermore, a Mendelian Randomization analysis was conducted to study whether associations are causal or not.Earlier age at menopause was statistically significantly associated with a higher risk of stroke and its subtypes ischemic stroke, hemorrhagic stroke, and intracerebral hemorrhage. We found no statistically significant relationship between earlier or later age at menopause and risk of subarachnoid hemorrhage.The Mendelian Randomization analysis suggested no causal effect of genetically proxied age at menopause and risk of any type of stroke.What are the clinical implications?Women with earlier age at menopause are at higher risk of stroke. The underlying reasons need to be further investigated.Our analysis suggested that earlier menopause per se does not cause stroke. For prevention and adequate treatment of stroke in women, a better understanding of the specific role of menopause and the mechanistic background that leads to higher risk of stroke is needed.
Amiano Pilar、Panico Salvatore、Peters Sanne AE、van Westing Anniek C、Seekircher Lisa、Huerta Jos¨| Mar¨aa、Butterworth Adam、S?derholm Martin、Johansson Cecilia、Macciotta Alessandra、Mellemkj?r Lene、Kaaks Rudolf、Katzke Verena、Crous-Bou Marta、Onland-Moret N Charlotte、Heath Alicia K、Wood Angela、Burgess Stephen、Dahm Christina C、van der Schouw Yvonne T、Moreno-Iribas Conchi、Willeit Peter、Rodriguez-Barranco Miguel、Schulze Matthias B、Danesh John、Weiderpass Elisabete、Pala Valeria、Engstr?m Gunnar、Tong Tammy YN、Tj?nneland Anne、Sj?lander Sara、Ibsen Daniel B、Halkj?r Jytte、Tschiderer Lena
Ministry of Health of the Basque Government, Sub Directorate for Public Health and Addictions of Gipuzkoa||Biodonostia Health Research Institute, Epidemiology of Chronic and Communicable Diseases Group||Centro de Investigaci¨?n Biom¨|dica en Red de Epidemiolog¨aa y Salud P¨2blica (CIBERESP)School of Medicine, Federico II UniversityJulius Center for Health Sciences and Primary Care, University Medical Center Utrecht||The George Institute for Global Health, School of Public Health, Imperial College London||The George Institute for Global Health, University of New South WalesJulius Center for Health Sciences and Primary Care, University Medical Center Utrecht||Division of Human Nutrition and Health, Wageningen UniversityInstitute of Health Economics, Medical University of InnsbruckDepartment of Epidemiology, Murcia Regional Health Council-IMIB||Centro de Investigaci¨?n Biom¨|dica en Red de Epidemiolog¨aa y Salud P¨2blica (CIBERESP)Department of Public Health and Primary Care, University of Cambridge||Heart and Lung Research Institute, University of Cambridge||NIHR Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge||BHF Centre of Research Excellence, School of Clinical Medicine, Addenbrooke?ˉs Hospital||Health Data Research UK Cambridge, Wellcome Genome Campus and University of CambridgeDepartment of Neurology, Sk?ne University Hospital||Department of Clinical Sciences, Malm?, Lund UniversitySkellefte? Research Unit, Department of Public Health and Clinical Medicine, Ume? UniversityCentre for Biostatistics, Epidemiology, and Public Health (C-BEPH), Department of Clinical and Biological Sciences, University of TurinDanish Cancer Society Research CenterDivision of Cancer Epidemiology, German Cancer Research CenterDivision of Cancer Epidemiology, German Cancer Research CenterUnit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO) - Bellvitge Biomedical Research Institute (IDIBELL), L?ˉHospitalet de Llobregat||Department of Epidemiology, Harvard T.H. Chan School of Public HealthJulius Center for Health Sciences and Primary Care, University Medical Center UtrechtDepartment of Epidemiology and Biostatistics, School of Public Health, Imperial College LondonDepartment of Public Health and Primary Care, University of CambridgeDepartment of Public Health and Primary Care, University of Cambridge||Heart and Lung Research Institute, University of Cambridge||MRC Biostatistics Unit, School of Clinical Medicine, University of CambridgeDepartment of Public Health, Aarhus UniversityJulius Center for Health Sciences and Primary Care, University Medical Center UtrechtInstituto de Salud P¨2blica y Laboral de Navarra||Centro de Investigaci¨?n Biom¨|dica en Red de Epidemiolog¨aa y Salud P¨2blica (CIBERESP)||Navarra Institute for Health Research (IdiSNA)Institute of Health Economics, Medical University of Innsbruck||Department of Public Health and Primary Care, University of CambridgeEscuela Andaluza de Salud P¨2blica (EASP)||Instituto de Investigaci¨?n Biosanitaria ibs.GRANADA||Centro de Investigaci¨?n Biom¨|dica en Red de Epidemiolog¨aa y Salud P¨2blica (CIBERESP)Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke||Institute of Nutritional Science, University of PotsdamBHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge||National Institute for Health and Care Research Cambridge Biomedical Research Centre, Cambridge University Hospitals||The National Institute for Health and Care Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics, University of Cambridge||Human Genetics, Wellcome Sanger Institute||Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge||British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, Addenbrooke?ˉs HospitalInternational Agency for Research on Cancer, World Health OrganizationEpidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei TumoriDepartment of Clinical Sciences, Malm?, Lund UniversityCancer Epidemiology Unit, Nuffield Department of Population Health, University of OxfordDanish Cancer Society Research Center||Department of Public Health, Section of Environmental Health, Faculty o f Health and Medical Sciences, University of CopenhagenDepartment of Public Health and Clinical Medicine, Ume? UniversityDepartment of Public Health, Aarhus University||Steno Diabetes Center Aarhus||MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine||Department of Nutrition, Exercise and Sports, University of CopenhagenDanish Cancer Society Research CenterJulius Center for Health Sciences and Primary Care, University Medical Center Utrecht||Institute of Health Economics, Medical University of Innsbruck
医药卫生理论医学研究方法内科学
Amiano Pilar,Panico Salvatore,Peters Sanne AE,van Westing Anniek C,Seekircher Lisa,Huerta Jos¨| Mar¨aa,Butterworth Adam,S?derholm Martin,Johansson Cecilia,Macciotta Alessandra,Mellemkj?r Lene,Kaaks Rudolf,Katzke Verena,Crous-Bou Marta,Onland-Moret N Charlotte,Heath Alicia K,Wood Angela,Burgess Stephen,Dahm Christina C,van der Schouw Yvonne T,Moreno-Iribas Conchi,Willeit Peter,Rodriguez-Barranco Miguel,Schulze Matthias B,Danesh John,Weiderpass Elisabete,Pala Valeria,Engstr?m Gunnar,Tong Tammy YN,Tj?nneland Anne,Sj?lander Sara,Ibsen Daniel B,Halkj?r Jytte,Tschiderer Lena.Age at menopause and the risk of stroke: Observational and Mendelian Randomization analysis in 204,244 postmenopausal women[EB/OL].(2025-03-28)[2025-05-24].https://www.medrxiv.org/content/10.1101/2023.02.08.23285676.点此复制
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