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Pia Burman


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


  • 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

Summary, in English

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.


  • Genomics, Diabetes and Endocrinology

Publishing year







The Journal of clinical endocrinology and metabolism





Document type

Journal article


Oxford University Press


  • Endocrinology and Diabetes


  • 11β-hydroxysteroid dehydrogenase
  • Addison disease
  • cortisol metabolism
  • dual-release hydrocortisone
  • hydrocortisone
  • primary adrenal insufficiency



Research group

  • Genomics, Diabetes and Endocrinology


  • ISSN: 1945-7197