Endocrine Abstracts

Osilodrostat is an oral inhibitor of steroidogenesis that blocks 11β-hydroxylase, a key enzyme in cortisol synthesis. Adrenal insufficiency (AI) is reported in around 40% of treated patients, usually considered an expected pharmacological effect. Recently, however, cases of prolonged AI persisting after drug withdrawal have been described. We report a 74-year-old woman with ectopic ACTH-dependent Cushing’s syndrome who developed long-lasting AI after osilodrostat discontinuation. She presented with typical clinical features of hypercortisolism, including moon face, supraclavicular fat accumulation, buffalo hump, muscle wasting, easy bruising, arterial hypertension, and type 2 diabetes. Laboratory evaluation confirmed ACTH-dependent hypercortisolism, and Ga-68-DOTA-TATE PET-CT revealed a large neuroendocrine tumour in the anterior mediastinum. Histopathology showed a neuroendocrine tumour negative for ACTH staining. Because of technical difficulties with biopsy and resection, the patient underwent mediastinal radiotherapy (60 Gy/30 fr). Osilodrostat was started concurrently (titrated up to 4 mg/day). Four weeks later, prior to radiotherapy, AI developed and steroid replacement was required. Hydrocortisone and subsequently dexamethasone were administered, during which both morning cortisol and urinary free cortisol remained undetectable. After 10 months, dexamethasone was stopped and hydrocortisone resumed, but endogenous cortisol remained suppressed. Osilodrostat was tapered and discontinued after 15 months of treatment. Despite drug withdrawal, adrenal recovery was absent. A high-dose ACTH stimulation test four months later showed only minimal cortisol response (35.7 nmol/l). Even 11 months after stopping osilodrostat, the patient remained biochemically adrenally insufficient (morning cortisol 37.2 nmol/l; ACTH 108 pg/mL) and required hydrocortisone substitution. Retrospective CT analysis demonstrated a marked reduction in adrenal volume after therapy. This case demonstrates that osilodrostat-induced AI may persist long after treatment cessation. The mechanism is unclear but may involve persistent enzyme inhibition, interference with steroidogenesis, or even adrenolytic effects. Awareness of this potential complication is essential as more patients are treated with osilodrostat.