Mild Autonomous Cortisol Secretion and Metabolic Syndrome: An Emerging Clinical Link

Adrenal incidentalomas are increasingly encountered in routine clinical practice, driven by widespread imaging use and rising cardiometabolic disease burden. Mild autonomous cortisol secretion (MACS), characterized by low-grade, adrenocorticotropic hormone-independent cortisol excess in the absence of overt Cushingoid features, is the most common functional phenotype. Across observational cohorts, MACS is associated with a higher burden of hypertension, dysglycemia, dyslipidemia, obesity, and fractures; importantly, risk increases continuously with rising post-dexamethasone suppression test (DST) cortisol levels, including values traditionally categorized as nonfunctioning. Diagnosis centers on the 1-mg overnight DST, interpreted in clinical context and with careful attention to common interferents. The limitations of cortisol thresholds alone have prompted interest in adjunctive hormonal markers and composite clinical-biochemical risk stratification. Management is individualized, ranging from optimized cardiometabolic therapy to adrenalectomy in selected patients with clinically relevant comorbidities, while medical cortisol-modulating therapies remain investigational. This review synthesizes current evidence on the diagnosis, cardiometabolic implications, and management of MACS; highlights key uncertainties; and outlines future directions aimed at improving risk stratification and informing clinical decision-making for this increasingly prevalent condition.