Blood steroid hormone profile and clinical outcomes following switching from metyrapone to osilodrostat in patients with Cushing disease

Steroidogenesis inhibitors such as metyrapone and osilodrostat, target 11β-hydroxylase to inhibit cortisol synthesis, are used in inoperable or recurrent Cushing disease. While osilodrostat has been reported to be more effective at lower doses than metyrapone, there are only a few reports describing the difference between osilodrostat and metyrapone in clinical practice. In this study, we evaluated the changes in steroid hormone profiles and clinical outcomes in seven Cushing disease patients switched from metyrapone to osilodrostat after incomplete remission post-transsphenoidal sinus surgery. Three of the seven patients were using trilostane, which was discontinued at the same time as metyrapone. Steroid hormone concentrations, including cortisol, progesterone (Prog), pregnenolone (Preg), deoxycorticosterone, corticosterone, 17-hydroxyprogesterone (17Prog), 17-hydroxypregnenolone (17Preg), and 11-deoxycortisol, were measured using high-performance liquid chromatography-mass spectrometry. No adverse events occurred after switching to osilodrostat. Potassium and ACTH levels increased significantly, and dehydroepiandrosterone sulfate and testosterone levels decreased significantly. Cortisol levels did not change significantly, whereas 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 disease receiving metyrapone, switching to osilodrostat may benefit cases with inadequate disease control and complications including hypertension, manifestation of masculinization, and gastric discomfort.