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

Espiard, Stéphanie ; McQueen, Johanna ; Sherlock, Mark ; Ragnarsson, Oskar ; Bergthorsdottir, Ragnhildur ; Burman, Pia LU ; Dahlqvist, Per ; Ekman, Bertil ; Engström, Britt Edén and Skrtic, Stanko , et al. (2021) In The Journal of clinical endocrinology and metabolism 106(3). p.814-825
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
11β-hydroxysteroid dehydrogenase, Addison disease, cortisol metabolism, dual-release hydrocortisone, hydrocortisone, primary adrenal insufficiency
in
The Journal of clinical endocrinology and metabolism
volume
106
issue
3
pages
12 pages
publisher
Oxford University Press
external identifiers
  • pmid:33236103
  • scopus:85102910999
ISSN
1945-7197
DOI
10.1210/clinem/dgaa862
language
English
LU publication?
yes
id
7986bfcc-d77f-4607-b68e-2dd0c397a50d
date added to LUP
2021-03-31 09:13:54
date last changed
2025-04-06 13:57:04
@article{7986bfcc-d77f-4607-b68e-2dd0c397a50d,
  abstract     = {{<p>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 &lt; .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 &lt; .05), but remained increased vs controls (P &lt; .001). 11β-HSD2 activity measured by urinary free cortisone/free cortisol ratio was decreased with TID-HC vs controls (P &lt; .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.</p>}},
  author       = {{Espiard, Stéphanie and McQueen, Johanna and Sherlock, Mark and Ragnarsson, Oskar and Bergthorsdottir, Ragnhildur and Burman, Pia and Dahlqvist, Per and Ekman, Bertil and Engström, Britt Edén and Skrtic, Stanko and Wahlberg, Jeanette and Stewart, Paul M. and Johannsson, Gudmundur}},
  issn         = {{1945-7197}},
  keywords     = {{11β-hydroxysteroid dehydrogenase; Addison disease; cortisol metabolism; dual-release hydrocortisone; hydrocortisone; primary adrenal insufficiency}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{814--825}},
  publisher    = {{Oxford University Press}},
  series       = {{The Journal of clinical endocrinology and metabolism}},
  title        = {{Improved Urinary Cortisol Metabolome in Addison Disease : A Prospective Trial of Dual-Release Hydrocortisone}},
  url          = {{http://dx.doi.org/10.1210/clinem/dgaa862}},
  doi          = {{10.1210/clinem/dgaa862}},
  volume       = {{106}},
  year         = {{2021}},
}