Multi-steroid interactions in ischemic stroke neuroprotection: a conceptual and mechanistic framework

Stroke remains a leading cause of mortality and long-term disability worldwide, and potential neuroprotective strategies remain elusive. While estrogen has been extensively investigated, emerging evidence indicates that progesterone, androgens, and neurosteroids may also contribute to neuroprotection through interconnected and context-dependent mechanisms. This narrative, systematized review critically synthesizes current experimental and clinical evidence on sex steroids and neurosteroids in ischemic stroke and proposes a mechanistically grounded “multi-steroid landscape” framework for neuroprotection. PubMed, Scopus, and Google Scholar were searched through December 28, 2025, using search terms including “cerebral ischemia”, “estrogen”, “progesterone”, “androgen”, and “neurosteroid”, along with relevant Medical Subject Headings (MeSH) terms. Peer-reviewed English-language studies with mechanistic, preclinical, or clinical relevance were qualitatively synthesized. Evidence was interpreted in relation to biological context, including sex, age, dose, and therapeutic timing. Steroid hormones and neurosteroids are reported to modulate key determinants of ischemic injury, including apoptosis, neuroinflammation, mitochondrial function, oxidative stress, and blood-brain barrier integrity. These systems appear to converge on shared signaling pathways, notably PI3K/Akt and MAPK/ERK, while maintaining distinct receptor-specific actions that shape context-dependent outcomes. This evidence was integrated into a hypothesis-generating multi-steroid framework that highlights potential interactions among steroid systems and identifies priorities for future investigation. Although preclinical data consistently suggest neuroprotective effects, clinical translation has remained limited, largely due to variability in therapeutic window, dosing paradigms, and patient heterogeneity. This review is limited by its narrative design, potential selection bias, and heterogeneity of the included studies, and does not include formal quality grading or meta-analysis. Overall, the proposed multi-steroid framework provides a conceptual basis for integrating current evidence and generating testable hypotheses regarding hormone-mediated neuroprotection in ischemic stroke. Future experimental and translational studies are needed to determine whether these interactions have clinical relevance.