Age at menopause and the risk of stroke: observational and mendelian randomisation analysis in 204,244 postmenopausal women

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Abstract Background Observational 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. Purpose We conducted a large-scale analysis to investigate the observational association between age at menopause and different types of stroke accompanied by a Mendelian Randomisation analysis to evaluate causality. Methods We analysed 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., ischaemic stroke, haemorrhagic stroke, intracerebral haemorrhage, and subarachnoid haemorrhage). 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 haemoglobin, total cholesterol, and hypertension, and (3) ever use of hormone replacement therapy and age at menarche. We used two-sample Mendelian Randomisation analysis to study whether there is a causal relationship between genetically proxied age at menopause and risk of stroke. Results A 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 ischaemic stroke, 1.10 (1.04, 1.16) for haemorrhagic stroke, 1.14 (1.08, 1.20) for intracerebral haemorrhage, and 1.00 (0.84, 1.20) for subarachnoid haemorrhage. The Mendelian Randomization analysis found no evidence for a causal relationship between genetically proxied age at menopause and risk of any type of stroke. Conclusion Earlier age at menopause is associated with, but no causally related to the risk of stroke.

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