Expanding the Clinical Profile of Mild Autonomous Cortisol Secretion: New Diagnostic Markers and Emerging Complications

Objective: Mild autonomous cortisol secretion (MACS) is a frequent finding in adrenal incidentalomas (AI), yet its diagnosis remains challenging. We aimed to compare clinical and biochemical profiles between MACS and non-functioning AIs and to identify reliable biomarkers, alternative to the 1 mg dexamethasone suppression test (DST), that can support the diagnosis of MACS. Methods: We retrospectively analyzed 171 patients with AIs (70 MACS,101 non-functioning AI) evaluated between 2005 and 2025. MACS was defined by DSTcortisol >1.8 μg/dL without overt Cushing’s syndrome. Results: Patients with MACS showed a higher prevalence of dyslipidemia (68.1% vs 52.0%; P = .037) and anxiety-depressive disorders (25.0% vs 11.0%; P = .018). Biochemically, they showed lower adrenocorticotropic hormone (11.1 pg/mL vs 16.8 pg/mL; P = .014), dehydroepiandrosterone-sulfate (0.3 μg/mL vs 0.9 μg/mL; P < .001), and testosterone levels in male (3.56 ng/ml vs 5.41 ng/ml, P = .04), with higher post-DST cortisol (2.8 μg/dL vs 1.2 μg/dL; P < .001), 24-hour urinary-free cortisol (67.2 μg/24h vs 44.8 μg/24h; P < .001), and late-night serum cortisol (8.2 μg/dL vs 3.6 μg/dL, P < .001). Adrenocorticotropic hormone <15 pg/mL (P = .029) and dehydroepiandrosterone-sulfate <0.5 μg/mL (P = .009) independently predicted MACS (area under the curve: 0.78) and were combined into a 2-point diagnostic score with 89.5% sensitivity and 97.5% negative predictive value. Late-night cortisol ≥5.1 μg/dL showed good accuracy (area under the curve: 0.83) for identifying patients with MACS and correlated with the number of MACS-related comorbidities (P = .0178). Conclusions: MACS is associated with neuropsychiatric and gonadal dysfunction. A simple and easily applicable biochemical score, together with late-night cortisol, may support diagnosis, particularly when the DST is inconclusive or in hospitalized patients.