Cardiometabolic comorbidities in overt Cushing's syndrome

Endogenous Cushing's syndrome (CS) is characterized by chronic glucocorticoid excess that drives a severe cardiometabolic phenotype responsible for most morbidity and mortality associated with the disorder. Cortisol excess induces a constellation of metabolic derangements-including visceral adiposity, insulin resistance, hypertension, dyslipidemia, and ectopic fat deposition-that closely mirror and amplify the components of metabolic syndrome. These abnormalities result from widespread glucocorticoid actions on adipose tissue, liver, skeletal muscle, pancreas, vasculature, and the heart, mediated through genomic, nongenomic, and local tissue-specific mechanisms such as altered AMPK signaling and dysregulated 11β-HSD activity. Cardiovascular disease represents the leading cause of death in CS, with increased risks of myocardial infarction, stroke, heart failure, and venous thromboembolism. Structural and functional cardiovascular changes-including arterial stiffness, endothelial dysfunction, concentric left ventricular hypertrophy, myocardial fibrosis, and coronary microvascular impairment-are frequently observed and often only partially reversible. Although biochemical remission leads to improvement in many metabolic and cardiovascular parameters, substantial residual cardiometabolic risk persists, with high rates of persistent hypertension, dyslipidemia, glucose abnormalities, central adiposity, and prothrombotic imbalance. Long-term mortality remains elevated even decades after cure, particularly in patients with prolonged hypercortisolism or coexisting cardiometabolic disease. The recognition that overt CS constitutes an accelerated model of metabolic syndrome underscores the need for early diagnosis, prompt cortisol normalization, and aggressive long-term management of cardiovascular and metabolic comorbidities.