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

in European Journal of Endocrinology
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  • 1 Assistance Publique – Hôpitaux de Paris, UF d’Hormonologie – Hôpitaux Universitaires Paris-Centre, Paris, France
  • | 2 Institut Cochin, Inserm U1016-CNRS UMR8104-Université de Paris, Paris, France
  • | 3 Assistance Publique – Hôpitaux de Paris, Service d’Endocrinologie et Maladies Métaboliques – Hôpitaux Universitaires Paris-Centre, Paris, France
  • | 4 Faculté de Pharmacie Paris Centre, Université de Paris, Paris, France
  • | 5 Assistance Publique – Hôpitaux de Paris, Department of Pharmacokinetics and Pharmacochemistry, Cochin Hospital, Paris, France
  • | 6 UMR8038 CNRS, U1268 INSERM, Faculty of Pharmacy, PRES Sorbonne Paris Cité, University of Paris, Paris, France
  • | 7 Hopital Europeen Georges Pompidou, Physiology, Paris, France

Correspondence should be addressed to F Bonnet-Serrano; Email: fideline.bonnet@aphp.fr
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Introduction

Osilodrostat is a new 11β-hydroxylase inhibitor with a mode of action analogous to Metyrapone. The objective of this study was to compare steroidogenic profiles in patients treated with either Osilodrostat or Metyrapone for adrenocorticotrophic hormone (ACTH)-dependent Cushing’s syndrome (CS).

Methods

Patients followed up at 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 five steroids (cortisol, 11-deoxycortisol, 17-hydroxyprogesterone, androstenedione and testosterone) was determined using UPLC- tandem mass spectrometry (UPLC-MS/MS).

Results

Nineteen patients treated with Osilodrostat, eight patients treated with Metyrapone and six patients treated with consecutive Metyrapone then Osilodrostat were included. Hypocortisolism (basal cortisol <100 nmol/L) was found in 48% of patients treated with Osilodrostat and 7% of patients treated with Metyrapone. 11-deoxycortisol and androstenedione levels were higher in patients treated with Metyrapone (80.9 (2.2–688.4) and 14.9 (2.5–54.3) nmol/L, respectively) than in patients treated with 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 significantly 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 androgen levels in patients treated with Osilodrostat.

Supplementary Materials

 

     European Society of Endocrinology

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