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

  • J Clin Endocrinol Metab. 2021 Mar 8;106(3):814-825. doi: 10.1210/clinem/dgaa862.
Stéphanie Espiard  1 ,  Johanna McQueen  1 ,  Mark Sherlock  2 ,  Oskar Ragnarsson  1 ,  Ragnhildur Bergthorsdottir  1 ,  Pia Burman  3 ,  Per Dahlqvist  4 ,  Bertil Ekman  5 ,  Britt Edén Engström  6 ,  Stanko Skrtic  1  7 ,  Jeanette Wahlberg  5 ,  Paul M Stewart  8 ,  Gudmundur Johannsson  1
Affiliations
  • 1. Department of Endocrinology, Sahlgrenska University Hospital and Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
  • 2. Department of Endocrinology, Beaumont Hospital and Royal College of Surgeons in Ireland, Co. Dublin 9, Ireland.
  • 3. Department of Endocrinology, Skåne University Hospital Malmö, Malmö and University of Lund, Lund, Sweden.
  • 4. Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
  • 5. Department of Endocrinology, Department of Medical and Health Sciences, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
  • 6. Department of Medical Sciences, Endocrinology and Metabolism, Uppsala University Hospital, Uppsala, Sweden.
  • 7. AstraZeneca R&D, Mölndal, Sweden.
  • 8. Faculty of Medicine and Health, University of Leeds, Leeds, UK.
PMID: 33236103 DOI: 10.1210/clinem/dgaa862
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.

Keywords
11β-hydroxysteroid dehydrogenase; Addison disease; cortisol metabolism; dual-release hydrocortisone; hydrocortisone; primary adrenal insufficiency.
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