Exploring Sex Differences in Stroke Outcomes: A Comprehensive Analysis From the SPAN 1 Trial

Stroke is a sexually dimorphic disease, with different risk factors, incidence, outcomes, and treatment responses in men and women. While sex differences have been documented in preclinical studies, these findings often come from single-site studies with small sample sizes and require validation across diverse research settings.

We used data from the SPAN (Stroke Preclinical Assessment Network), a randomized, placebo-controlled, blinded, multilaboratory trial, to determine if sex differences in neurological outcomes are present in preclinical stroke models. We analyzed data from 665 stroke animals treated with saline, including young mice, diet-induced obese mice, aging mice, young rats, and spontaneously hypertensive rats. We compared the corner test index and brain morphology between the sexes using linear random effect models and assessed the mortality rate using Cox proportional hazard regression models.

No significant sex differences were found in neurological outcome measured with the corner test on either day 7 or day 30 after stroke, regardless of the mouse or rat stroke model used. Additionally, female and male mice exhibited similar infarct sizes on day 2 magnetic resonance imaging and on brain atrophy measures on day 30 after stroke, indicating a lack of sex differences in brain injury. Similarly, no sex differences were observed in acute or chronic sensorimotor or tissue outcomes in young rats. In 1 subanalysis, sex differences were seen in the spontaneously hypertensive rats cohort. Female rats exhibited a higher corner test index on day 30 than males, indicating more severe sensorimotor injury.

In this multicenter preclinical study, we did not detect sex differences in stroke outcomes in mice, although sex differences in behavioral outcomes were observed in spontaneously hypertensive rats. These findings highlight that sex differences may be model-specific and subtle, emphasizing the need for methodological consistency and thoughtful inclusion of diverse animal models in translational stroke research to better understand if sex-specific responses contribute to stroke outcomes.