Sex-Based Differences in Severe Trauma and Hemorrhagic Shock: A Systematic Review of Pre-Clinical and Veterinary Animal Studies.

PURPOSE: To systematically review preclinical studies to determine whether biological sex alters outcomes after severe trauma with hemorrhagic shock (T/HS), identify the mechanistic drivers of any sex dimorphism, and define key gaps that limit translation to critical care.

METHODS

Following PRISMA guidance, we searched PubMed and Google Scholar through December 2025 for original animal or veterinary T/HS studies, comparing biological sexes or manipulating sex hormones. Exclusions included non-hemorrhagic shock, traumatic brain injury, and reviews. Two reviewers independently screened 1,450 records and assessed risk of bias via SYRCLE. Data were extracted on species, hormonal status, survival, organ function, and mechanisms. A structured narrative synthesis was performed as study heterogeneity precluded quantitative meta-analysis.

RESULTS

Of the 1,450 records, 66 met the inclusion criteria. In rodents, females, particularly during proestrus, exhibited superior survival, preserved organ function, and reduced inflammation. These advantages were typically reversed by ovariectomy and mimicked by estrogen or ER-β agonists. Conversely, male vulnerability was linked to androgen-driven immune dysfunction and mitigated by castration or flutamide. Age and sepsis often reverse female benefits. Emerging research highlighted non-classical pathways, such as autophagy and pyroptosis. High model heterogeneity and reporting gaps precluded meta-analysis.

CONCLUSION

Preclinical evidence confirms sex-dependent resilience in T/HS, primarily driven by sex steroids and immune-vascular modulation. To bridge the translational gap, clinical studies should adopt sex-stratified analyses and prospectively record hormonal status. Future preclinical research must prioritize standardized reporting and the use of large-animal or uncontrolled hemorrhage models to validate these findings for critical care.