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 AI could be associated with adrenal gland shrinkage. DESIGN: Noninterventional, retrospective, longitudinal, institutional review board-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 computed tomography (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: Ten 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 < .001 over a median of 19 months. AV reduction positively correlated with maximum osilodrostat dose, r = 0.626, P = .027. CONCLUSION: 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.