LAUSR

INTRODUCTION Osilodrostat is a new 11 ß-hydroxylase inhibitor with a mode of action analogue to Metyrapone. The objective of this study was to compare steroidogenic profiles in patients treated by either Osilodrostat or Metyrapone for ACTH-dependent Cushing's Syndrome (CS). METHODS Patients followed in Cochin hospital Endocrinology department between March 2019 and December 2021 for an ACTH-dependent CS, controlled by either Osilodrostat or Metyrapone were included. A serum profile of 5 steroids (cortisol, 11-deoxycortisol, 17-hydroxyprogesterone, androstenedione and testosterone) was determined using UPLC - tandem mass spectrometry (UPLC-MS/MS). RESULTS Nineteen patients treated by Osilodrostat, 8 patients treated by Metyrapone and 6 patients treated by consecutive Metyrapone then Osilodrostat were included. Hypocortisolism (basal cortisol < 100 nmol/L) was found in 48% of patients treated by Osilodrostat and 7% of patients treated by Metyrapone. 11-deoxycortisol and androstenedione levels were higher in patients treated by Metyrapone (respectively, 80.9 [2.2-688.4] and 14.9 [2.5-54.3] nmol/L) than in patients treated by Osilodrostat (10.3 [0.5-71.9] and 4.0 [0.3-13.3] nmol/L) (p=0.0009 and p=0.0005). Testosterone level in women was also higher in Metyrapone group (3.3 [0.93-4.82] nmol/L vs 1.31[0.13-5.09] nmol/L, p=0.0146). CYP11B1 activity (11-deoxycortisol/cortisol) was not significantly different between the two groups. CYP21A2 activity, (17OHprogesterone/11-deoxycortisol) and CYP17A1 activity (17OHprogesterone/androstenedione) were decreased in Osilodrostat group (p<0.0001). CONCLUSION In patients with ACTH-dependent CS, the use of CYP11B1 inhibitors in routine care suggests that Osilodrostat has a less specific effect on the inhibition of steroidogenic enzymes than Metyrapone. This might explain a smaller increase in 11-deoxycortisol and androgens levels in patients treated by Osilodrostat.