Hypercortisolism: Causes, Consequences and Clinical Significance – A Review of Pathophysiology

ABSTRACT

Hypercortisolism or Cushing syndrome is a heterogeneous clinical spectrum caused by chronic glucocorticoid excess, ranging from exogenous Cushing syndrome to rare endogenous aetiologies and the increasingly recognised entity of mild autonomous cortisol secretion (MACS). Physiological cortisol production is tightly regulated by the hypothalamic–pituitary–adrenal axis, and disruption at any level may lead to clinically significant cortisol excess. Endogenous hypercortisolism is broadly classified into corticotropin‐dependent and corticotropin‐independent forms. The clinical phenotype varies according to the source, severity, and duration of cortisol excess. Overt Cushing syndrome is classically associated with centripetal adiposity, proximal myopathy, skin fragility, hypertension, and glucose intolerance, whereas MACS lacks overt cushingoid features despite conferring substantial cardiometabolic and skeletal risk. Cortisol excess affects multiple organ systems, including endocrine, cardiovascular, hepatic, musculoskeletal, neuropsychiatric, immune, dermatologic, and reproductive pathways. Importantly, many complications persist despite biochemical remission, underscoring the long‐term burden of disease. This review summarises the aetiologies, pathophysiology, clinical manifestations, and systemic consequences of hypercortisolism.