Dysregulation of cortisol metabolism in equine pituitary pars intermedia dysfunction

Ruth A Morgan, John A Keen, Natalie Homer, Mark Nixon, Anna M McKinnon-Garvin, Jodie A Moses-Williams, Sarah R Davis, Patrick W F Hadoke, Brian R Walker

Research output: Contribution to journalArticlepeer-review

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, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) expression was reduced; in peri-renal adipose tissue 11β-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.

Original languageEnglish
Pages (from-to)3791–3800
Number of pages10
JournalEndocrinology
Volume159
Issue number11
Early online date4 Oct 2018
DOIs
Publication statusE-pub ahead of print - 4 Oct 2018

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