Endocrine Abstracts

JOINT3047

Osilodrostat is an oral steroidogenesis inhibitor used to treat hypercortisolism by inhibiting 11-beta-hydroxylase. It can cause adrenal insufficiency (AI) in about 40% of patients, which is typically considered a natural consequence of therapy. However, along with a few early reports, suggest that AI can persist even after discontinuation of osilodrostat.[1, 3, 5] We present the case of a 74-year-old female patient with ectopic ACTH-dependent Cushing’s syndrome who developed prolonged AI despite the withdrawal of osilodrostat. The patient underwent radiotherapy for a primary lesion located in the anterior mediastinum. During treatment, osilodrostat was introduced (2-4 mg/d), and adrenal insufficiency developed within four weeks. She required hydrocortisone replacement therapy, and over time, undetectable morning cortisol levels were observed. After reducing morning serum cortisol levels, osilodrostat dose was decreased and withdrawn 15 months into therapy. Despite 31 weeks off the drug, morning cortisol remained undetectable, with no response to a high-dose ACTH test, and the patient required ongoing hydrocortisone substitution. Discussion of prolonged AI after osilodrostat discontinuation should mention a study presenting reduced adrenal size (despite stable ACTH levels), suggesting a potential adrenolytic effect of the drug.[4] Another case report decscirbe decrease in 11-deoxycortisol in prolonged AI after osilodrostat treatment.[1] Given the drug’s mechanism, 11-deoxycortisol levels should increase due to inhibited conversion to cortisol. However, also in the LINC 3 study, after an initial rise, despite remaining above reference ranges, the levels declined during follow-up.[2] Another aspect is the observed increase in AI from week 48 to week 72 during osilodrostat treatment in a clinical trial which may suggest the link to the mechanism seen in our and previous cases.[2] The mechanism of prolonged AI after osilodrostat discontinuation is not yet understood. Case reports are needed to raise awareness, potentially prompting further research to clarify these effects and explore broader therapeutic applications.

References: [1] Ferriere, A. et al. 2024. Prolonged adrenal insufficiency following discontinuation of osilodrostat treatment for intense hypercortisolism. EJE 190,1 (Jan. 2024), L1–L3. [2] Fleseriu, M. et al. 2022. Long-term outcomes of osilodrostat in Cushing’s disease: LINC 3 study extension. EJE187,4 (Oct. 2022),531. [3] Poirier, J. et al. 2023. Prolonged adrenocortical blockade following discontinuation of Osilodrostat. EJE188,6(Jun. 2023), K29–K32. [4] Sawabe, F. et al. 2024. A Case of an Ectopic ACTH-Producing Tumor With Adrenal Shrinkage During Osilodrostat Administration. JCEM2, (Jan. 2024). [5] Tejani, S. et al. 2024. Prolonged Adrenal Insufficiency After Osilodrostat Exposure With Eventual Recovery of Adrenal Function. JCEM2,6(May 2024).