Ericka Teleg, MD

Welten SJGC, Onland-Moret NC, Boer JMA, Verschuren WMM, van der Schouw YT. Age at Menopause and Risk of Ischemic and Hemorrhagic Stroke. Stroke. 2021.

Stroke risk in women and increasing its knowledge globally will help contribute to understanding specific risk factors to improve stroke prevention and treatment in women. Studies in women are not straightforward due to the presence of heterogeneity among variables and outcome measures, which the article emphasizes in its introduction. This remains a challenge in epidemiological studies in women.

The objective of this prospective cohort study investigates whether the age at menopause is a risk factor for total, ischemic and hemorrhagic stroke. The authors explore if this association is present in natural and surgical menopause.

In their methodology, their study population involved Dutch women and comprises 17357 ages 49 to 70 years old, living in Utrecht in the Netherlands, and recruited between 1993 and 1997 through a breast screening program. This gives a light that women and their health are of value in the community as community programs are established to provide ways to improve women’s health in a continuum, since the year 1993.

The definition of age at menopause is widely variable among women. The Dutch cohort provides and gives a premise that despite variability in age group, cultural and genetic confounders may not largely affect the significance of the results. It will be interesting to compare women of different heritage, who have other varied environmental and genetic combintations with follow-up studies. This study provides a platform for future studies based on their methodology and findings. This study categorized age at menopause into five groups, wherein the 50 to 54 years old age group was used as a reference category. The characteristics of menopause among women included their reproductive history and use of hormone replacement therapy. This information was taken through a self-reported questionnaire. Stroke ascertainment was also established. The strength of the statistical analysis was the awareness that the association between age at menopause and stroke may vary according to the type of menopause. Hence, they repeated analyses for women who obtained a natural and surgical menopause separately. The authors have taken on into their analyses the following challenges: heterogeneity of the data, presence of possible uncontrollable confounders, and bias.

The results answer the study’s objective. In summary, earlier age at menopause was significantly associated with a higher risk of total and ischemic stroke but not with hemorrhagic stroke. Their discussion delved into the physiology of menopause, indicating  endogenous hormones such as estradiol may be the explanation for the association between earlier age at menopause and stroke risk. The early decline in estradiol has a negative adverse effect on blood vessels. However, the role of hormone replacement therapy does not give a protective role in the occurrence of stroke.

The study mentions strengths and limitations of their analyses. The 15-year follow-up and the large sample size provide a robust sample. However, overestimation may be present in terms of time events, as women with older age menopause can have a stroke before their menopause.

Limitations include the likelihood of recall bias, from a self-reported questionnaire. They emphasized that women aged 49 to 70 years old were involved, and on acquisition, not all women were postmenopausal at inclusion. This is versus those women included have already went through menopause, are early menopause subjects as deemed by their definition. The question of estimation of true effect comes to play as stroke and menopause are ascertained. Also, the ascertainment of stroke among women who had a natural versus surgical menopause may have led to misclassification bias., Follow-up on stroke events was obtained through registries upon discharge, and incomplete follow-data specifically on the diagnostic work-up was evident. Also, in terms of hemorrhagic stroke, there was a small number of identified strokes that were hemorrhagic, and using the menopausal age categories, there was only a limited number of the cases that could be analyzed. Hence, this could explain why similar hazard ratios were not statistically significant. Overall, this study holds merit considering the heterogeneity and complexity of women’s physiology and stroke occurrence. It is quite remarkable that despite variability and the overarching timeline of women and events that they hold in their lifetime, stroke ascertainment remains valuable to develop potential novel biomarkers to enhance stroke prevention in women.