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. 2023;113(7):770-784.
doi: 10.1159/000529146. Epub 2023 Jan 16.

A Prospective Analysis of the Metyrapone Short Test Using Targeted and Untargeted Metabolomics

Anna Katharina Seoudy  1   2 , Kristina Schlicht  2 , Alexandra Kulle  3 , Tobias Demetrowitsch  4 , Alexia Beckmann  1   2 , Corinna Geisler  2 , Kathrin Türk  2 , Nathalie Rohmann  2 , Katharina Hartmann  2 , Juliane Brandes  2 , Dominik M Schulte  1   2 , Stefan Schreiber  1 , Karin Schwarz  4 , Paul-Martin Holterhus  3 , Matthias Laudes  1   2
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A Prospective Analysis of the Metyrapone Short Test Using Targeted and Untargeted Metabolomics

Anna Katharina Seoudy et al. Neuroendocrinology. 2023.

Abstract

Introduction: The present study aimed to prove the metyrapone short test in a day clinic to be suitable for examining the integrity of the hypothalamic-pituitary-adrenal (HPA) axis in patients with suspected secondary and tertiary adrenal insufficiency and to identify novel effector molecules in acute stress response.

Methods: 44 patients were prospectively enrolled. Based on stimulated 11-deoxycortisol levels, patients were divided into a physiological (11-deoxycortisol ≥70 μg/L) and a pathological (11-deoxycortisol <70 μg/L) response group. Clinical follow-up examination was performed for validation. Ultraperformance liquid chromatography tandem mass spectrometry and a Fourier-transform-ion-cyclotron-resonance-mass-spectrometry were used for targeted and untargeted steroid metabolomics.

Results: At baseline, lower levels of cortisone (42 vs. 50 nmol/L, p = 0.048) and 17-OH-progesterone (0.6 vs. 1.2 nmol/L, p = 0.041) were noted in the pathological response group. After metyrapone administration, the pathological response group exhibited significantly lower 11-deoxycortisol (39.0 vs. 94.2 μg/L, p < 0.001) and ACTH (49 vs. 113 pg/mL, p < 0.001) concentrations as well as altered upstream metabolites. Untargeted metabolomics identified a total of 76 metabolites to be significantly up- or downregulated by metyrapone. A significant increase of the bile acid glycochenodeoxycholic acid (GCDC, p < 0.01) was detected in both groups with an even stronger increase in the physiological response group. After a mean follow-up of 17.2 months, an 11-deoxycortisol cut-off of 70 µg/L showed a high diagnostic performance (sensitivity 100%, specificity 96%).

Conclusion: The metyrapone short test is safe and feasible in a day clinic setting. The alterations of the bile acid GCDC indicate that the liver might be involved in the acute stress response of the HPA axis.

Keywords: Adrenal gland; Hypothalamus; Hypothalamus-pituitary-adrenal axis.

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