Osilodrostat-associated Adrenal Gland Shrinkage: a Case Series of Patients with ACTH-Dependent Cushing’s Syndrome

Context Medical therapy for Cushing’s syndrome (CS) is increasingly used. A potent adrenal steroidogenesis inhibitor, osilodrostat, has been rarely linked to prolonged adrenal insufficiency (AI). Objective We hypothesized that osilodrostat-induced adrenal insufficiency could be associated with adrenal gland shrinkage. Design Non-interventional, retrospective, longitudinal, IRB-approved study of patients with CS treated at Oregon Health and Science University between January 1, 2000 and July 1, 2025. Setting Ambulatory and inpatient, academic, quaternary medical center. Patients or Other Participants Patients with ACTH-dependent CS, treated with osilodrostat for >3 months, and CT imaging before and after osilodrostat available for adrenal volume (AV) measurement. Intervention(s) Age, sex, osilodrostat doses and duration, laboratory data and AI were recorded. AV was calculated using manual segmentation on CT images by a board-certified radiologist. Main Outcome Measure(s) AV before and after initiation of osilodrostat was expressed as percent reduction. Results 10 patients (5 ectopic CS, 4 unknown ACTH source, 1 Cushing’s disease) were included. Osilodrostat mean starting, maximum and final doses: 7.7, 13.8 and 5.9 mg/day, respectively, over 23 months. Four patients received block-and-replace regimen, AI developed in 5. Adrenal gland volume decreased by 46.7±22.2% from 25.5±9.9 ml to 12.7±6.4 ml, p<0.001 over a median of 19 months. AV reduction positively correlated with maximum osilodrostat dose, r=0.626, p=0.027. Conclusions We found that in selected patients with ACTH-dependent CS, osilodrostat can induce significant adrenal shrinkage, with or without AI. Further confirmation by larger studies of different CS types and monitoring for AI is required for all patients.