The ACTH × DHEAS product as an ancillary biomarker of mild autonomous cortisol secretion in adrenal incidentalomas

Abstract

Introduction: Mild autonomous cortisol secretion (MACS) is usually classified by the 1-mg overnight dexamethasone suppression test (DST). However, a single post-DST cortisol value may not fully capture the chronicity or biological relevance of cortisol autonomy. Although adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS) reflect different but biologically linked components of hypothalamic–pituitary–adrenal (HPA) axis suppression, their combined assessment has not been sufficiently evaluated in adrenal incidentalomas. Objective: To evaluate the association between the ACTH × DHEAS product and DST-defined cortisol autonomy and to explore its potential role as an ancillary biochemical marker in adrenal incidentalomas. Methods: This retrospective study included 157 patients classified as having MACS or a nonfunctioning adrenal adenoma based on post-DST cortisol levels. Patients with overt endocrine syndromes, malignant or rare adrenal lesions, and ARMC5-positive disease were excluded. Correlation analyses, sex-adjusted multivariable logistic regression, exploratory receiver operating characteristic analyses, and a DeLong test were performed. Results: MACS was present in 79 patients (50.3%). Patients with MACS had larger tumors, higher basal and post-DST cortisol, and lower ACTH, DHEAS, and ln(ACTH × DHEAS). ln(ACTH × DHEAS) was inversely correlated with post-DST cortisol and larger tumor size. After adjustment for age, sex, basal cortisol, and larger tumor size, lower ln(ACTH × DHEAS) remained independently associated with MACS (odds ratio = 0.473, 95% CI: 0.304–0.737, p = 0.001). The corrected ln(ACTH × DHEAS) showed moderate discrimination (area under the curve = 0.693) but did not significantly outperform −DHEAS alone. Conclusion: ln(ACTH × DHEAS) may serve as a practical ancillary marker of chronic HPA-axis suppression, particularly in borderline or discordant cases. It should not replace DST or DHEAS alone, and prospective outcome-based validation is required before clinical implementation.