ECE2018 Guided Posters Adrenal clinical (10 abstracts)
The urinary cortisol metabolome in patients with adrenal insufficiency: dual-release hydrocortisone is less deleterious than conventional hydrocortisone therapy
Stéphanie Espiard 1, , Johanna McQueen 1, , Mark Sherlock 3 , Oskar Ragnarsson 1, , Ragnhildur Bergthorsdottir 1, , Pia Burman 4 , Per Dahlqvist 5 , Bertil Ekman 6 , Britt Edén Engström 7 , Anna G Nilsson 1, , Stanko Skrtic 2, , Jeanette Wahlberg 6 , Paul M Stewart 9 & Gudmundur Johannsson 1,
1Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden; 2Institute of Medicine, University of Gothenburg, Gothenburg, Sweden; 3Department of Endocrinology and Diabetes, Beaumont Hospital, Dublin, Ireland; 4Department of Endocrinology, Skåne University Hospital, Malmö, Sweden; 5Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden; 6Department of Endocrinology, Department of Medical and Health Sciences, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; 7Department of Medical Sciences, Endocrinology and Metabolism, Uppsala University Hospital, Uppsala, Sweden; 8AstraZeneca R&D, Mölndal, Sweden; 9Faculty of Medicine and Health, University of Leeds, Leeds, UK.
Introduction: Oral once-daily dual-release hydrocortisone (DR-HC) therapy provides a more physiological cortisol profile than conventional thrice-daily (TID) replacement therapy and has demonstrated improved metabolic profile among patients with adrenal insufficiency (AI). The mechanisms by which this metabolic improvement occurs may be due to less total exposure, changed cortisol time exposure profile, but also modified metabolism of cortisol.
Objective: The aim was to study steroid enzyme activities related to corticosteroids during DR-HC and TID.
Methods: Patients with primary AI received DR-HC or an equal total daily dose of TID hydrocortisone in a 12-week crossover multi-center study. 24 h urinary collection was performed during both treatment and in 124 healthy controls. Urinary cortisol metabolites were measured using gas chromatography/mass spectrometry providing an index of total cortisol exposure and metabolism.
Results: Fifty patients (22 female, mean age 47 years (range 19–71)) and 124 healthy controls [73 females, mean age 48 years (range 20–81)] were included in the study. Total cortisol metabolites (F, E, THF, 5αTHF, THE, cortols, cortolones) were significantly decreased during DR-HC treatment [median: 6380 μg/24h] compared to TID (8825 μg/24 h); P<0.001] and returned to similar value compared to controls (6850 μg/24 h; P=0.089). Compared to controls, the urinary THF+5αTHF/THE ratio reflecting 11βHSD1 activity was increased during both DR-HC (P<0.001) and TID treatments (P<0.001), being more marked in TID compared to DR-HC (P<0.05) compatible with cortisol induced 11βHSD1 activity. Urinary F/E reflecting 11βHSD2 activity was slightly higher in TID versus controls (P<0.01), but normalized during DR-HC (P=0.358). The 5α-reduced metabolite, 5αTHF, was similar in patients compared to control but decreased significantly with DR-HC compared to TID (P<0.001). The 5β-reduced metabolite, THF, was higher in patients compared to control (P<0.001) but decreased significantly with DR-HC compared to TID (P<0.001). The urinary 5αTHF/THF ratio increased significantly in patients (controls: 1.3; TID: 2.3, P<0.001; DR-HC: 2, P<0.001) indicating that the main driver for this was an increase in 5β-reductase activity during TID and to a lesser extent during DR-HC.
Conclusion: The urinary cortisol metabolome shows more striking abnormalities in patients receiving TID compared to DR-HC replacement therapy and maybe a more sensitive marker of “optimal cortisol replacement”. The increased 11βHSD1 activity in patients on TID may account for the deleterious metabolic phenotype reported in patients with AI and its reduced activity during DR-HC may also mediate some of the beneficial effects previously seen with this treatment.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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