Sex differences in delirium: Neuroendocrine-immune mechanisms and implications for precision Neurocritical care

Delirium is an acute and multifactorial syndrome that remains highly prevalent in critical illness and is associated with avoidable morbidity, persistent cognitive decline, and increased mortality. Its mechanisms appear to involve a close interaction between neuroendocrine and immune pathways, including gonadal hormones, neuroactive steroids produced within the brain, and hypothalamic-pituitary-adrenal axis activity. Because these systems differ between sexes, biological sex may influence delirium risk, clinical presentation, and recovery, although this has rarely been examined in a systematic way. Here, we discuss how estradiol, progesterone, allopregnanolone, and androgens may affect microglial responses, blood-brain barrier integrity, stress reactivity, neurotransmission, inflammation, mitochondrial function, oxidative balance, and epigenetic regulation. Clinical evidence suggests possible sex-related differences in hypoactive and hyperactive presentations, antipsychotic exposure, and ICU length of stay. Future studies should integrate sex, hormonal status, neurosteroids, and cortisol dynamics to refine delirium prevention and treatment.