Adrenalectomy versus conservative management in mild autonomous cortisol secretion: a systematic review and meta-analysis

Abstract Background Mild autonomous cortisol secretion (MACS) is common in adrenal incidentaloma care, but treatment evidence remains fragmented across modern MACS trials, older subclinical Cushing syndrome terminology, nonrandomized cohorts, and database studies. Methods We conducted a systematic review and meta-analysis comparing adrenalectomy with conservative or nonoperative management in adults with MACS or closely related mild cortisol-autonomy phenotypes without overt Cushing syndrome. Randomized, nonrandomized, and database evidence were analyzed separately. Linked reports were grouped by study cohort before synthesis. Risk of bias was assessed using RoB 2 and ROBINS-I, and certainty was evaluated using GRADE. Results After deduplication, 1089 records were screened; 21 full-text reports were assessed, and 17 reports were retained for main or supporting synthesis. The retained evidence comprised 18 study-level or study-component rows, including seven randomized reports or trial-family components, ten nonrandomized comparative cohort components, and one propensity-matched database study. Individual comparative sample sizes ranged from 33 to 582 participants or matched patients. In randomized evidence, adrenalectomy was associated with improved blood-pressure control (RR 2.41, 95% CI 1.60 to 3.63; I-squared 0.0%; moderate certainty) and glycometabolic control (RR 3.40, 95% CI 1.68 to 6.87; I-squared 0.0%; low certainty). Objective ambulatory or 24-hour blood-pressure endpoints were less precise (RR 1.57, 95% CI 0.70 to 3.54; low certainty). One database study reported lower mortality and new-onset diabetes after adrenalectomy, but these associations were considered very low-certainty observational evidence. Postoperative adrenal insufficiency and surgical safety were clinically important and were summarized narratively because definitions and reporting windows differed. Conclusions Adrenalectomy probably improves blood-pressure control and may improve glycometabolic outcomes in selected patients with unilateral MACS or related mild cortisol-autonomy phenotypes. Evidence for fracture prevention, mortality, and other hard outcomes remains insufficient for firm clinical conclusions. Potential benefit should be weighed against operative risk, postoperative adrenal insufficiency, and the need for glucocorticoid replacement and monitoring. Clinical trial number Not applicable.