Tissue Glucocorticoid Metabolism in Adrenal Insufficiency: A Prospective Study of Dual-release Hydrocortisone Therapy.

Autor:	Dineen RA; Academic Department of Endocrinology, Beaumont Hospital/Royal College of Surgeons in Ireland, Dublin, D09 YD60, Ireland., Martin-Grace J; Academic Department of Endocrinology, Beaumont Hospital/Royal College of Surgeons in Ireland, Dublin, D09 YD60, Ireland., Ahmed KMS; Robert Graves Institute of Endocrinology, Tallaght University Hospital, Dublin, D24 TP66, Ireland., Taylor AE; Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, UK., Shaheen F; Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, UK., Schiffer L; Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, UK., Gilligan LC; Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, UK., Lavery GG; Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, UK., Frizelle I; Robert Graves Institute of Endocrinology, Tallaght University Hospital, Dublin, D24 TP66, Ireland., Gunness A; Robert Graves Institute of Endocrinology, Tallaght University Hospital, Dublin, D24 TP66, Ireland., Garrahy A; Academic Department of Endocrinology, Beaumont Hospital/Royal College of Surgeons in Ireland, Dublin, D09 YD60, Ireland., Hannon AM; Academic Department of Endocrinology, Beaumont Hospital/Royal College of Surgeons in Ireland, Dublin, D09 YD60, Ireland., Methlie P; Department of Clinical Science, University of Bergen, 5021 Bergen, Norway., Eystein SH; Department of Clinical Science, University of Bergen, 5021 Bergen, Norway., Stewart PM; Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UK., Tomlinson JW; Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UK., Hawley JM; Department of Clinical Biochemistry, University Hospital of South Manchester, Manchester Academic Health Science Centre, The University of Manchester, Manchester M23 9LT, UK., Keevil BG; Department of Clinical Biochemistry, University Hospital of South Manchester, Manchester Academic Health Science Centre, The University of Manchester, Manchester M23 9LT, UK., O'Reilly MW; Academic Department of Endocrinology, Beaumont Hospital/Royal College of Surgeons in Ireland, Dublin, D09 YD60, Ireland., Smith D; Academic Department of Endocrinology, Beaumont Hospital/Royal College of Surgeons in Ireland, Dublin, D09 YD60, Ireland., McDermott J; Department of Endocrinology, Connolly Hospital, Dublin, D15 X40D, Ireland., Healy ML; Department of Endocrinology, St James Hospital, Dublin, D08 K0Y5, Ireland., Agha A; Academic Department of Endocrinology, Beaumont Hospital/Royal College of Surgeons in Ireland, Dublin, D09 YD60, Ireland., Pazderska A; Department of Endocrinology, St James Hospital, Dublin, D08 K0Y5, Ireland., Gibney J; Robert Graves Institute of Endocrinology, Tallaght University Hospital, Dublin, D24 TP66, Ireland., Behan LA; Robert Graves Institute of Endocrinology, Tallaght University Hospital, Dublin, D24 TP66, Ireland., Thompson CJ; Academic Department of Endocrinology, Beaumont Hospital/Royal College of Surgeons in Ireland, Dublin, D09 YD60, Ireland., Arlt W; Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, UK.; Medical Research Council London, Institute of Medical Sciences, London W12 0NN, UK., Sherlock M; Academic Department of Endocrinology, Beaumont Hospital/Royal College of Surgeons in Ireland, Dublin, D09 YD60, Ireland.
Jazyk:	angličtina
Zdroj:	The Journal of clinical endocrinology and metabolism [J Clin Endocrinol Metab] 2023 Nov 17; Vol. 108 (12), pp. 3178-3189.
DOI:	10.1210/clinem/dgad370
Abstrakt:	Background: Patients with adrenal insufficiency (AI) require life-long glucocorticoid (GC) replacement therapy. Within tissues, cortisol (F) availability is under the control of the isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD). We hypothesize that corticosteroid metabolism is altered in patients with AI because of the nonphysiological pattern of current immediate release hydrocortisone (IR-HC) replacement therapy. The use of a once-daily dual-release hydrocortisone (DR-HC) preparation, (Plenadren®), offers a more physiological cortisol profile and may alter corticosteroid metabolism in vivo. Study Design and Methods: Prospective crossover study assessing the impact of 12 weeks of DR-HC on systemic GC metabolism (urinary steroid metabolome profiling), cortisol activation in the liver (cortisone acetate challenge test), and subcutaneous adipose tissue (microdialysis, biopsy for gene expression analysis) in 51 patients with AI (primary and secondary) in comparison to IR-HC treatment and age- and BMI-matched controls. Results: Patients with AI receiving IR-HC had a higher median 24-hour urinary excretion of cortisol compared with healthy controls (72.1 µg/24 hours [IQR 43.6-124.2] vs 51.9 µg/24 hours [35.5-72.3], P = .02), with lower global activity of 11β-HSD2 and higher 5-alpha reductase activity. Following the switch from IR-HC to DR-HC therapy, there was a significant reduction in urinary cortisol and total GC metabolite excretion, which was most significant in the evening. There was an increase in 11β-HSD2 activity. Hepatic 11β-HSD1 activity was not significantly altered after switching to DR-HC, but there was a significant reduction in the expression and activity of 11β-HSD1 in subcutaneous adipose tissue. Conclusion: Using comprehensive in vivo techniques, we have demonstrated abnormalities in corticosteroid metabolism in patients with primary and secondary AI receiving IR-HC. This dysregulation of pre-receptor glucocorticoid metabolism results in enhanced glucocorticoid activation in adipose tissue, which was ameliorated by treatment with DR-HC. (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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