Differences in the spectrum of steroidogenic enzyme inhibition between Osilodrostat and Metyrapone in ACTH-dependent Cushing syndrome patients

Abstract

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.

11-Oxygenated C19 steroids are the predominant androgens responsible for hyperandrogenemia in Cushing's disease

“…This might be due to a stronger 17α‑hydroxylase (CYP17A1) and potentially cholesterol side chain cleavage enzyme and/or StaR protein inhibition, which has been proposed for osilodrostat ( 31 ) and verified in a recent publication. Bonnet-Serrano et al showed that in patients on osilodrostat but not on metyrapone, 21-hydroxylase and CYP17A1 activity were significantly decreased ( 32 ). In our small subgroup of patients on metyrapone, but not on osilodrostat medication, treatment also led to a significant elevation of classical androgens, in particular of A4, thus, confirming the in vitro and in vivo results.…”

Cushing’s Disease: Long-Term Effectiveness and Safety of Osilodrostat in a Polish Group of Patients with Persistent Hypercortisolemia in the Experience of a Single Center

“…Adrenal androgens and mineralocorticoid precursor increase-related AEs are the main limitations of metyrapone use; however, they may occur in 42.3-58.4% of patients on osilodrostat, as previously mentioned [14,21]. Nevertheless, Bonnet-Serrano et al showed a smaller increase in 11-deoxycortisol and androgen concentrations in patients with osilodrostat compared with metyrapone therapy [36]. Additionally, mean levels of adrenal hormone precursors and androgens decreased during long-term osilodrostat treatment [23].…”

Severe Cushing’s syndrome from an ectopic adrenocorticotropic hormone-secreting neuroendocrine tumour treated by osilodrostat

“…Isolated 11β-hydroxylase block leads to accumulation of precursors such as 11-deoxycortisol and androgens (androstenedione, testosterone and DHEA/DHEAS). Treatment by osilodrostat showed only mild androgen elevations when compared to metyrapone ( 12 ). In this patient DHEA, DHEAS decreased, while androstenedione and testosterone were slightly elevated during the osilodrostat treatment ( Table 2 ).…”

“…While osilodrostat was initially developed as an aldosterone synthase (CYP11B2) inhibitor, it was found to have strong 11β-hydroxylase (CYP11B1) inhibition and further clinical studies suggest that the drug also inhibits 17α-hydroxylase and 21-hydroxylase based on measured ratios of precursors/metabolites ( 12 ). Interestingly, when expressed alone, negligible inhibition of these enzymes occurred in vitro ( 13 ).…”