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11β-hydroxysteroid dehydrogenase activity in the brain does not contribute to systemic interconversion of cortisol and cortisone in healthy men

Lookup NU author(s): Professor Brian Walker

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Abstract

Copyright © 2015 by the Endocrine Society. Context and Objective: 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyses regeneration of cortisol in liver, adipose tissue, and skeletal muscle, making a substantial contribution to circulating cortisol as demonstrated in humans by combining stable isotope tracer infusion with arteriovenous sampling. In the brain, 11βHSD1 is a potential therapeutic target implicated in age-associated cognitive dysfunction. We aimed to quantify brain 11βHSD1 activity, both to assess its contribution to systemic cortisol/cortisone turnover and to develop a tool for measuring 11βHSD1 in dementia and following administration of 11βHSD1 inhibitors. Design, Setting, and Participants: With ethical approval and informed consent, 8 healthy men aged 38.1 years (sd 16.5) underwent an ECG-gated phase-contrast magnetic resonance scan to quantify internal jugular vein blood flow and were infused with 1,2 [2H]2-cortisone and 9,11,12,12 [2H]4-cortisol for 3 h before samples were obtained from the internal jugular vein and an arterialized hand vein. Steroids were quantified by liquid chromatography-tandem mass spectrometry. Main Outcome Measures and Results: Steady state tracer enrichments were achieved and systemic indices of cortisol/cortisone interconversion were consistent with previous studies in healthy men. However, there was no measurable release or production of cortisol, 9,12,12 [2H]3-cortisol or cortisone into the internal jugular vein. Conclusions: Although cerebral 11βHSD1 reductase activity may be greater in cognitively impaired patients, in healthy men any contribution of 11βHSD1 in the brain to systemic cortisol/cortisone turnover is negligible. The influence of 11βHSD1 in the brain is likely confined to subregions, notably the hippocampus. Alternative approaches are required to quantify pharmacodynamics effects of 11βHSD1 inhibitors in the human brain.


Publication metadata

Author(s): Kilgour AHM, Semple S, Marshall I, Andrews P, Andrew R, Walker BR

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Endocrinology and Metabolism

Year: 2015

Volume: 100

Issue: 2

Pages: 483-489

Print publication date: 01/02/2015

Online publication date: 01/02/2015

Acceptance date: 10/11/2014

ISSN (print): 0021-972X

ISSN (electronic): 1945-7197

Publisher: Endocrine Society

URL: https://doi.org/10.1210/jc.2014-3277

DOI: 10.1210/jc.2014-3277

PubMed id: 25393644


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