Improved Urinary Cortisol Metabolome in Addison Disease: A Prospective Trial of Dual-Release Hydrocortisone.

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.

• Authors: Stéphanie Espiard, Johanna McQueen, Mark Sherlock, Oskar Ragnarsson, Ragnhildur Bergthorsdottir, Pia Burman, Per Dahlqvist, Bertil Ekman, Britt Edén Engström, Stanko Skrtic, Jeanette Wahlberg, Paul M Stewart, Gudmundur Johannsson
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 106 Issue 3 Pg. 814-825 (03 08 2021) ISSN: 1945-7197 [Electronic] United States
• PMID: 33236103 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.

Chemical References

• Delayed-Action Preparations
• Pregnanes
• Steroids
• cortolone
• cortol
• Tetrahydrocortisone
• Tetrahydrocortisol
• Cortisone
• Hydrocortisone

Topics

• Addison Disease (drug therapy, metabolism, urine)
• Adult
• Aged
• Cortisone (metabolism, urine)
• Cross-Over Studies
• Delayed-Action Preparations (pharmacokinetics, therapeutic use)
• Europe
• Female
• Humans
• Hydrocortisone (pharmacokinetics, therapeutic use, urine)
• Male
• Metabolome (drug effects)
• Middle Aged
• Pregnanes (metabolism, urine)
• Steroids (metabolism, urine)
• Tetrahydrocortisol (metabolism, urine)
• Tetrahydrocortisone (metabolism, urine)
• Urinalysis