Potential mechanisms of the glucocorticoid withdrawal syndrome

Glucocorticoid withdrawal syndrome (GWS) is a frequent and clinically significant consequence of reducing chronic endogenous or exogenous glucocorticoid exposure. The syndrome presents with a range of symptoms involving musculoskeletal, gastrointestinal, neuropsychiatric, cardiovascular, and metabolic domains, which can closely resemble adrenal insufficiency or recurrence of an underlying autoimmune/inflammatory disease. As a result, the true prevalence, history, and clinical burden of GWS remain poorly defined, and recognition varies widely across clinical settings. The lack of treatment options for GWS contributes to detrimental exogenous glucocorticoid exposure in patients with rheumatologic, oncologic, and endocrine diseases. The underlying biological mechanisms of GWS remain incompletely understood, which represents a major barrier to the recognition and treatment of this syndrome. This review synthesizes current evidence on the epidemiology, clinical manifestations, and management challenges of GWS. We integrate mechanistic insights from studies of chronic glucocorticoid excess, postoperative recovery of Cushing syndrome, and experimental models of glucocorticoid excess and deficiency. Glucocorticoid excess leads to central and peripheral adaptations involving the hypothalamic-pituitary-adrenal axis, glucocorticoid receptor signaling, circadian rhythms, immune and inflammatory pathways, metabolic and autonomic regulation, and glucocorticoid-sensitive neural circuits. We propose that GWS arises due to the confluence of these persisting adaptations with relative glucocorticoid deficiency and tissue- or cell-specific adaptations and recovery timelines. Thus, we provide a mechanistic framework for understanding the diverse manifestations of GWS and highlight key gaps that need to be addressed to improve mechanistic understanding, diagnosis, and clinical management.