A comprehensive meta-analysis of exogenous estrogen, progesterone, and testosterone in animal models of ischemic and hemorrhagic stroke

TL;DR

This study reviews how exogenous sex hormones like estrogen and progesterone affect stroke outcomes in animal models, finding potential benefits for ischemic stroke but unclear effects for hemorrhagic stroke.

Contribution

This is the first synthesis of pre-clinical evidence on sex hormones in hemorrhagic stroke and updates findings on ischemic stroke.

Findings

Estrogen and progesterone improved outcomes in ischemic stroke models, but evidence certainty is low to moderate.

Testosterone showed mostly null effects in ischemic stroke and inconclusive results in hemorrhagic stroke.

Sex and gonadal status are significant moderators of hormone effects on stroke outcomes.

Abstract

Exogenous sex hormones have been extensively studied for their influence on stroke risk and outcome. This meta-analysis served to update the pre-clinical acute ischemic stroke (AIS) literature and provide the first synthesis of the intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) literature on how estrogen, progesterone, and testosterone affect post-stroke outcomes.

This study was pre-registered with PROSPERO (CRD42024544794). Medline, EMBASE, Scopus, and Web of Science were searched; studies using animal models of stroke investigating exogenous estrogen, progesterone, or testosterone, alone or in combination, compared to non-treated controls were included. Assessments of injury volume, edema, and behaviour (neurological deficits, sensorimotor and cognitive outcomes) were analyzed via hierarchical meta-analyses. Risk of bias was assessed via SYRCLE and CAMARADES, and evidence certainty via an adaptation of the GRADE tool.

In total, 211 studies were included. Estrogen and progesterone improved all post-AIS outcomes (SMDs = 0.32–1.30, 95% CIs [0.02, 2.07], very low to moderate certainty of evidence), whereas testosterone had mostly null effects (very low to moderate certainty). Fewer studies investigated hemorrhagic stroke, with null effects of estrogen (very low to low certainty) and conflicting results of progesterone (SMDs = 0.15–1.16 [-2.20, 2.58], very low to moderate certainty) in ICH, as well as benefit of progesterone in SAH (SMD = 2.63 [0.98, 4.30], very low certainty). Uncertainty in our evidence arose from low scientific and translational rigor. Sex and gonadal status were consistent moderators of these effects, and gonadal depletion length (i.e., the ‘timing hypothesis’) was a significant moderator of estrogen’s effect on post-AIS injury volume.

Estrogen and progesterone are promising cerebroprotectants for AIS. Further focussed and rigorous pre-clinical research on remaining research gaps (e.g., dosage parameters) are needed to guide clinical investigations and maximize the likelihood of translational success. The impact of testosterone and sex hormones in hemorrhagic stroke remain inconclusive due to lack of research.

The online version contains supplementary material available at 10.1186/s13293-026-00828-6.

Exogenous sex hormones (estrogen, progesterone, testosterone) have been linked to increased stroke risk in humans and improved post-stroke outcomes (e.g., motor and cognitive functions) in animals.

This pre-clinical meta-analysis included experimental studies investigating exogenous estrogen, progesterone, and/or testosterone in animal models of ischemic stroke, intracerebral hemorrhage (ICH), or subarachnoid hemorrhage (SAH).

Estrogen and progesterone are cytoprotective following ischemic stroke, though further rigorous research on key issues (e.g., dosage parameters) are needed prior to clinical trials.

Sex, gonadal status, and related factors (e.g., length of gonadal depletion, or the ‘timing hypothesis’) are moderators of sex hormone effects.

The effect of testosterone in AIS and all sex hormones in hemorrhagic stroke are unclear due to lack of research.

The online version contains supplementary material available at 10.1186/s13293-026-00828-6.

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