Sex differences in clinical and metabolic outcomes of glucocorticoid replacement therapy in adrenal insufficiency.

Adrenal insufficiency (AI) requires lifelong glucocorticoid replacement therapy, yet patients continue to experience excess morbidity, impaired quality of life, and increased mortality. AI exhibits marked sex differences in epidemiology, particularly in primary adrenal insufficiency, where autoimmune disease predominates in women. Whether sex differences extend to clinical outcomes and responses to glucocorticoid replacement remains incompletely understood. In this review, we synthesize available evidence on sex differences in epidemiology, cardiometabolic health, bone outcomes, quality of life, cognition, and mortality across primary, secondary, and glucocorticoid-induced AI. Emerging data suggest greater impairment in quality of life, lipid metabolism, cardiovascular risk, and subjective cognition in women, while men may be more vulnerable to skeletal complications. However, most studies were not designed to evaluate sex-specific outcomes, limiting definitive conclusions. We further review biological mechanisms that may underlie sex-specific vulnerability, including differences in cortisol transport, tissue-specific metabolism, glucocorticoid receptor signaling, adipose tissue distribution, sex hormone interactions, and highlight priorities for future sex-informed research in AI.