Protracted osilodrostat-induced pan-adrenal steroidogenic suppression and adrenal size reduction in Cushing disease.

Osilodrostat, a potent 11β-hydroxylase inhibitor, is used for Cushing syndrome. Transient adrenal insufficiency during dose titration is common and usually reversible, whereas prolonged adrenal insufficiency after treatment discontinuation appears uncommon. A man with treatment-resistant Cushing disease was treated with osilodrostat after prior transsphenoidal surgeries and stereotactic radiosurgery. He initially demonstrated the expected biochemical profile of 11β-hydroxylase inhibition, with elevated adrenocorticotropic hormone (ACTH) and 11-deoxycortisol concentrations. After 18 months of therapy, he developed adrenal insufficiency with morning cortisol 1.27 μg/dL (SI: 35 nmol/L) [reference 5-22.6 μg/dL; 145-619 nmol/L], ACTH 989 pg/mL (SI: 217.6 pmol/L) [reference 4-46 pg/mL; 1.0-10.1 pmol/L], suppressed aldosterone 1.2 ng/dL (SI: 33.2 pmol/L) [reference 2-35 ng/dL; 55.4-970 pmol/L], markedly elevated direct renin 288.5 mIU/mL [reference 4.4-46.1 mIU/mL], and suppression of adrenal androgen production. Osilodrostat was discontinued and glucocorticoid replacement initiated, with later introduction of mineralocorticoid replacement. At 2.5 years, glucocorticoid and androgen suppression persist, together with prolonged mineralocorticoid dysfunction and adrenal size reduction. Review of 10 previous reports suggests prolonged adrenal insufficiency is uncommon and mineralocorticoid deficiency rarely documented, while persistent androgen suppression has not previously been reported. This case highlights prolonged pan-adrenal steroidogenic suppression with adrenal shrinkage and suggests recovery of adrenal function may take years.