SUN-074 Effects of Switching from Metyrapone to Osilodrostat on Steroid Hormone Profiles and Clinical Outcomes in Patients with persistent Cushing’s Disease

Abstract Disclosure: K. Yokozeki: None. H. Kameda: None. S. Jin: None. K. Matoba: None. A. Nakamura: None. T. Atsumi: None. Background: Cushing’s disease results from excessive ACTH secretion by pituitary adenomas, leading to hypercortisolemia and increased mortality if untreated. Surgical removal of the tumor is the primary treatment, but medical therapy is required in cases of persistent or recurrent disease or when surgery is infeasible.Drug therapies include agents targeting ACTH secreting tumor (e.g., pasireotide, cabergoline) and those inhibiting adrenal cortisol production (e.g., metyrapone, osilodrostat, ketoconazole). Metyrapone and osilodrostat inhibit 11β-hydroxylase (CYP11B1), the enzyme catalyzing the final step of cortisol synthesis. However, osilodrostat is reportedly more effective at lower doses, and its use is associated with milder side effects than metyrapone.While some studies compare metyrapone and osilodrostat, limited research exists on steroid hormone profiles and clinical outcomes after switching between the two drugs. This study aimed to evaluate these changes in patients who transitioned from metyrapone to osilodrostat.MethodsThis study included seven patients (five with Cushing’s disease and two with cyclic Cushing’s disease) who failed to achieve remission after transsphenoidal sinus surgery. Patients who switched steroid hormone inhibitors from metyrapone to osilodrostat were enrolled. Steroid hormone concentrations, including cortisol, progesterone, 17-hydroxyprogesterone (17Prog), and 17-hydroxypregnenolone (17Preg), were measured using high-performance liquid chromatography–mass spectrometry. ResultsNo adverse events occurred after switching to osilodrostat. Potassium and adrenocorticotropic hormone levels increased significantly, and dehydroepiandrosterone sulfate and testosterone levels decreased significantly. Cortisol levels did not change significantly; the ratios reflecting CYP17A1 activity (17Preg/Preg and 17Prog/Prog) decreased significantly, suggesting superior inhibition of CYP17A1 with osilodrostat. Clinical improvements included reduced antihypertensive medication requirements, decreased masculinization, and resolved gastric discomfort. Different inhibition patterns of the steroid synthetic enzymes may explain the observed clinical outcomes between these drugs. These data suggest that in patients with Cushing’s disease receiving metyrapone, switching to osilodrostat may benefit cases with inadequate disease control and complications including hypertension, manifestation of masculinization, and gastric discomfort.ConclusionSwitching from metyrapone to osilodrostat significantly altered steroid hormone profiles and improved clinical outcomes in patients with Cushing’s disease. Osilodrostat’s superior suppression of CYP17A1, as evidenced by reduced androgen precursors, contributed to improved management of hypertension and masculinization symptoms. Presentation: Sunday, July 13, 2025