Sexual Dimorphism in Spinal Cord Injury: From Molecular Mechanisms to Clinical Translation.

Traumatic spinal cord injury (SCI) shows pronounced biological sex differences in incidence and short-term outcomes, yet mechanistic studies and therapeutic development are not consistently sex-informed. Here we summarize evidence that sex hormones, sex-chromosome effects and immune-glial interactions shape key components of the secondary injury cascade, including blood-spinal cord barrier (BSCB) disruption, neuroinflammation, oxidative stress, cell death and remyelination. Estrogens and progesterone generally support barrier stabilization, temper leukocyte infiltration, bias microglia/macrophages toward reparative programs, and promote neurotrophin signaling and myelin repair. In males, post-injury androgen deficiency together with stronger early innate immune activation may exacerbate oxidative damage, demyelination and scar formation, potentially limiting plasticity. Clinical evidence remains limited and confounded, but available data support the need for adequately powered, sex-stratified trials, particularly for time-sensitive hormonal and immunomodulatory interventions. Incorporating sex as a biological variable in experimental design and translation may improve target selection, dosing and therapeutic windows for SCI.