Age at menopause and the risk of stroke: Observational and Mendelian Randomization analysis in 204,244 postmenopausal women
Authors: Tschiderer Lena , Peters Sanne AE , van der Schouw Yvonne T , van Westing Anniek C , Tong Tammy YN , Willeit Peter , Seekircher Lisa , Moreno-Iribas Conchi , Huerta José María , Crous-Bou Marta , Söderholm Martin , Schulze Matthias B , Johansson Cecilia , Själander Sara , Heath Alicia K , Macciotta Alessandra , Dahm Christina C , Ibsen Daniel B , Pala Valeria , Mellemkjær Lene , Burgess Stephen , Wood Angela , Kaaks Rudolf , Katzke Verena , Amiano Pilar , Rodriguez-Barranco Miguel , Engström Gunnar , Weiderpass Elisabete , Tjønneland Anne , Halkjær Jytte , Panico Salvatore , Danesh John , Butterworth Adam , Onland-Moret N Charlotte 
Published: February 2023

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. 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.

Methods

We 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.

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 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.

Conclusions

Earlier age at menopause is associated with, but not causally related to the risk of stroke.

Clinical Perspective

What 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 menopauseper sedoes 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.