Stroke Risk Increase in Women With Elevated Lifetime Estrogen Exposure

Peige Song, PhD

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Results from a recent analysis based on the China Kadoorie Biobank cohort study suggest that women with a lower level of estrogen exposure have a decreased risk of ischemic stroke and intracerebral hemorrhage than their counterparts with the highest levels of estrogen exposure.^1,2 This study provided evidence of the cumulative effects of reproductive factors during a reproductive life course on stroke and stroke subtypes.

Comparison of risk among different quartiles of estrogen exposure indicated those in the lowest quartile of reproductive lifespan had a lower risk of total stroke (adjusted HR, 0.95; 95% CI, 0.92-0.98), ischemic stroke (aHR, 0.95; 95% CI, 0.92-0.98), and intracerebral hemorrhage (aHR, 0.87; 95% CI, 0.81-0.94) compared to those in the highest quartile.

“Our study suggests that higher estrogen levels due to a number of reproductive factors, including a longer reproductive life span and using hormone therapy or contraceptives, are linked to a lower risk of ischemic stroke and intracerebral hemorrhage,” study investigator Peige Song, PhD, of the Zhejiang University School of Medicine in Hangzhou, China, noted.³ “These findings might help with new ideas for stroke prevention, such as considering screenings for people who have a short lifetime exposure to estrogen.”

The study, which enrolled individuals from 2004-2008, identified 122,939 postmenopausal women without prior stroke at baseline. This cohort had a median age at menarche of 16.0 (IQR, 14.0-17.0) years, a median age at menopause of 49 (IQR, 47.0-51.0) years, and median age at baseline of 58.3 (IQR, 54.0-65.1).

For the purpose of analysis, lifetime cumulative estrogen exposure due to reproductive factors was assessed using reproductive lifespan, endogenous estrogen exposure, and total estrogen exposure. The primary outcome of interest for the study was incidence of stroke, with stroke subtypes serving as secondary outcomes of interest. Investigators pointed out multivariable-adjusted Cox proportional hazards regression models were applied to estimate the adjusted HR for risk of stroke by quartiles of reproductive lifespan, endogenous estrogen exposure, and total estrogen exposure.

Results of the investigators’ analyses, which included a median follow-up period of 8.9 years, indicated a total of 15,139 new-onset stroke cases occurred within the follow-up, with 12,853 cases of ischemic stroke, 2,580 cases of intracerebral hemorrhage, and 269 cases of subarachnoid hemorrhage.

Further analysis indicated graded associations were observed for both endogenous estrogen exposure (EEE) and total estrogen exposure (TEE) with total stroke (EEE: aHR 0.85 [95% CI, 0.82-0.89]; TEE: aHR, 0.87 [95% CI, 0.84-0.90]), ischemic stroke (EEE: aHR, 0.86 [95% CI, 0.83-0.90]; TEE: aHR, 0.86 [95% CI, 0.83-0.89]), and intracerebral hemorrhage (EEE: aHR, 0.73 [95% CI, 0.65-0.81]; TEE: aHR, 0.83 [95% CI, 0.76-0.91]) (P for all <.001).

“Estrogen exposure throughout life could potentially be a useful indicator of a person’s risk of different types of stroke following menopause,” Song noted.¹ “However, more research is needed on the biological, behavioral, and social factors that may contribute to the link between estrogen exposure and stroke risk across a woman’s lifespan.”

References
1. Hou L, Li S, Zhu S, et al. Lifetime cumulative effect of reproductive factors on stroke and its subtypes in postmenopausal Chinese: A prospective cohort study. Neurology. https://n.neurology.org/content/early/2023/02/01/WNL.0000000000206863. Published February 1, 2023. Accessed February 6, 2023.
2. Study design. China Kadoorie Biobank (CKB). https://www.ckbiobank.org/study-resources/study-design. Accessed February 6, 2023.
3. Does Lifetime Exposure to Estrogen Affect Risk of Stroke? Does lifetime exposure to estrogen affect risk of stroke? https://www.aan.com/PressRoom/Home/PressRelease/5044. Published February 1, 2023. Accessed February 6, 2023.