Lowering the dexamethasone suppression test cut-off: is it time yet?

Purpose: Cushing’s syndrome (CS) is a rare condition marked by overt hypercortisolism, while mild autonomous cortisol secretion (MACS) refers to asymptomatic or subclinical cortisol excess, often associated with adrenal incidentalomas (AI). MACS is significantly more prevalent than CS, particularly in older populations. The 1 mg overnight dexamethasone suppression test (F-1mgDST) is the main diagnostic tool, but the appropriateness of its current cut-off value of 1.8 µg/dL is under debate. Methods: This review briefly analyses existing literature to assess whether this threshold accurately identifies patients with cortisol-related comorbidities, especially in those with non-functioning AI (NFAI). We searched PubMed, Web of Science and Scopus between January 1990 and March 2025 using the following keywords: “adrenal incidentalomas, non-functioning adrenal incidentalomas, adrenal adenomas, non-functioning adrenal adenomas, subclinical hypercortisolism, mild hypercortisolism, less severe hypercortisolism, hidden hypercortisolism, mild autonomous cortisol secretion”. Results: Evidence suggests that NFAI patients often present with metabolic, cardiovascular, bone and muscle alterations typical of cortisol excess, even with F-1mgDST values below 1.8 µg/dL. Several studies propose that a lower threshold (around 1.2 µg/dL) may better capture at-risk individuals, although this could reduce specificity and increase false positives. Conclusions: The review highlights the need for more sensitive diagnostic criteria, possibly including biomarkers and pharmacological challenge tests. It also introduces the concept of a cortisol “milieu” in eucortisolemic individuals, suggesting that even normal-range cortisol activity and/or altered cortisol circadian rhythm may contribute to chronic conditions. In light of current evidence, closer monitoring of AI patients with F-1mgDST above 1.2 µg/dL is recommended, pending validation from longitudinal and interventional studies.