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.