1. Improved Urinary Cortisol Metabolome in Addison Disease: A Prospective Trial of Dual-Release Hydrocortisone.
- Author
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Espiard S, McQueen J, Sherlock M, Ragnarsson O, Bergthorsdottir R, Burman P, Dahlqvist P, Ekman B, Engström BE, Skrtic S, Wahlberg J, Stewart PM, and Johannsson G
- Subjects
- Adult, Aged, Cortisone metabolism, Cortisone urine, Cross-Over Studies, Delayed-Action Preparations pharmacokinetics, Delayed-Action Preparations therapeutic use, Europe, Female, Humans, Hydrocortisone therapeutic use, Hydrocortisone urine, Male, Metabolome drug effects, Middle Aged, Pregnanes metabolism, Pregnanes urine, Steroids metabolism, Tetrahydrocortisol metabolism, Tetrahydrocortisol urine, Tetrahydrocortisone metabolism, Tetrahydrocortisone urine, Urinalysis, Addison Disease drug therapy, Addison Disease metabolism, Addison Disease urine, Hydrocortisone pharmacokinetics, Steroids urine
- Abstract
Context: Oral once-daily dual-release hydrocortisone (DR-HC) replacement therapy has demonstrated an improved metabolic profile compared to conventional 3-times-daily (TID-HC) therapy among patients with primary adrenal insufficiency. This effect might be related to a more physiological cortisol profile, but also to a modified pattern of cortisol metabolism., Objective: This work aimed to study cortisol metabolism during DR-HC and TID-HC., Design: A randomized, 12-week, crossover study was conducted., Intervention and Participants: DC-HC and same daily dose of TID-HC were administered to patients with primary adrenal insufficiency (n = 50) vs healthy individuals (n = 124) as controls., Main Outcome Measures: Urinary corticosteroid metabolites were measured by gas chromatography/mass spectrometry at 24-hour urinary collections., Results: Total cortisol metabolites decreased during DR-HC compared to TID-HC (P < .001) and reached control values (P = .089). During DR-HC, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity measured by tetrahydrocortisol + 5α-tetrahydrocortisol/tetrahydrocortisone ratio was reduced compared to TID-HC (P < .05), but remained increased vs controls (P < .001). 11β-HSD2 activity measured by urinary free cortisone/free cortisol ratio was decreased with TID-HC vs controls (P < .01) but normalized with DR-HC (P = .358). 5α- and 5β-reduced metabolites were decreased with DR-HC compared to TID-HC. Tetrahydrocortisol/5α-tetrahydrocortisol ratio was increased during both treatments, suggesting increased 5β-reductase activity., Conclusions: The urinary cortisol metabolome shows striking abnormalities in patients receiving conventional TID-HC replacement therapy, with increased 11β-HSD1 activity that may account for the unfavorable metabolic phenotype in primary adrenal insufficiency. Its change toward normalization with DR-HC may mediate beneficial metabolic effects. The urinary cortisol metabolome may serve as a tool to assess optimal cortisol replacement therapy., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.)
- Published
- 2021
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