Higher SHBG levels were inversely associated with the risk of ischemic stroke and its small-artery occlusion subtype, while no causal effects of estradiol or testosterone on ischemic stroke were identified.
SHBG was inversely associated with the risk of ischemic stroke overall.
SHBG was inversely associated with the small-artery occlusion subtype of ischemic stroke.
No causal association was found between SHBG and the large-artery atherosclerosis or cardioembolism subtypes of ischemic stroke.
No causal effects of estradiol on ischemic stroke risk were identified.
No causal effects of testosterone on ischemic stroke risk were identified.
The study employed a 2-sample Mendelian randomization design to assess causal relationships between sex hormones and ischemic stroke.
This research suggests that sex hormone-binding globulin (SHBG), a protein that binds and regulates the activity of sex hormones in the blood, may play a protective role against ischemic stroke (the most common type of stroke, caused by a blood clot blocking blood flow to the brain). Using a genetic analysis technique called Mendelian randomization — which uses inherited genetic variants as a natural experiment to test cause-and-effect relationships — the study found that genetically higher levels of SHBG were associated with approximately 8% lower odds of ischemic stroke overall, and about 16% lower odds of a specific subtype called small-artery occlusion stroke. This protective association did not extend to strokes caused by large-artery disease or by blood clots originating in the heart. Importantly, the study found no evidence that estradiol (a form of estrogen) or testosterone directly cause or prevent ischemic stroke, despite the well-known fact that stroke risk differs between men and women. This suggests that if sex hormones play a role in stroke risk, it may be through SHBG's regulatory effects rather than through estradiol or testosterone themselves. This research suggests that SHBG could represent a potential therapeutic target for stroke prevention, though the biological mechanisms by which SHBG might protect against stroke are not yet understood and require further investigation. Because Mendelian randomization relies on genetic proxies rather than directly measuring hormone levels over time, these findings provide strong evidence for a causal direction but should be followed up with studies examining the underlying biological pathways.
Huang Q, Li Q, Guo J. (2026). Causal relationship between sex hormones and ischemic stroke risk: A Mendelian randomization study.. Medicine. https://doi.org/10.1097/MD.0000000000050336