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Dysregulation of cortisol metabolism in equine pituitary pars intermedia dysfunction

Lookup NU author(s): Professor Brian Walker

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Equine Cushing's Disease (Pituitary pars intermedia dysfunction (PPID)) is a common condition of older horses but its pathophysiology is complex and poorly understood. In contrast to pituitary-dependent hyperadrenocorticism in other species, PPID is characterised by elevated plasma ACTH but not elevated plasma cortisol. In this study, we address this paradox and the hypothesis that PPID is a syndrome of ACTH excess in which there is dysregulation of peripheral glucocorticoid metabolism and binding. In 14 PPID horses compared with 15 healthy controls, we show that: in plasma, cortisol levels and cortisol binding to CBG were not different; in urine, glucocorticoid and androgen metabolites were increased up to four-fold; in liver, 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) expression was reduced; in peri-renal adipose tissue 11ß-HSD1 and carbonyl reductase 1 expression was increased; and tissue cortisol levels were not measurably different. The combination of normal plasma cortisol with markedly enhanced urinary cortisol metabolite excretion and dysregulated tissue-specific steroid-metabolising enzymes suggests that cortisol clearance is increased in PPID horses. We infer that the ACTH excess may be compensatory and pituitary pathology and autonomous secretion may be a secondary rather than primary pathology. It is possible, that successful therapy in PPID may be targeted either at lowering ACTH or, paradoxically, at reducing cortisol clearance.


Publication metadata

Author(s): Morgan RA, Keen JA, Homer N, Nixon M, McKinnon-Garvin A, Moses-Williams J, Davis D, Hadoke PWF, Walker BR

Publication type: Article

Publication status: Published

Journal: Endocrinology

Year: 2018

Volume: 159

Issue: 11

Pages: 3791-3800

Print publication date: 01/11/2018

Online publication date: 04/10/2018

Acceptance date: 28/09/2018

Date deposited: 25/10/2018

ISSN (print): 0013-7227

ISSN (electronic): 1945-7170

Publisher: Oxford University Press

URL: https://doi.org/10.1210/en.2018-00726

DOI: 10.1210/en.2018-00726


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Funding

Funder referenceFunder name
206587/Z/17/Z
BBSRC
British Heart Foundation
ISSF2
R42126/82976
Wellcome Trust

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