Dysregulation of Cortisol Metabolism in Equine Pituitary Pars Intermedia Dysfunction

Abstract

Equine Cushing 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 characterized 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 horses with PPID compared with 15 healthy controls, we show that in plasma, cortisol levels and cortisol binding to corticosteroid binding globulin were not different; in urine, glucocorticoid and androgen metabolites were increased up to fourfold; in liver, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) expression was reduced; in perirenal 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-metabolizing enzymes suggests that cortisol clearance is increased in horses with PPID. 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.

Restoring pars intermedia dopamine concentrations and tyrosine hydroxylase expression levels with pergolide: evidence from horses with pituitary pars intermedia dysfunction

“…[46][47][48] Previous work has shown that PPID horses treated with DA agonists have decreased levels of POMC peptides and ACTH in the PI, and cortisol concentrations in plasma. 14,46,49 Our data demonstrate that pergolide treatment also re-establishes levels of DA and TH in PI tissue of PPID horses.…”

“…50 There is mounting evidence that PPID is a neurodegenerative disorder characterized by loss of DA neurons and, subsequently, dopaminergic input to PI melanotropes. The lack of endogenous DA-mediated inhibition of PI POMC production in PPID-affected equids, may also result in multiclonal expansion which could explain (in addition to the uctuation of cortisol release in the blood stream) 14 PI hyperplasia and formation of multifocal adenomas. Dorsal expansion of the PG and compression of surrounding structures including the hypothalamus and infundibular stalk might explain, in part, loss off PVN dopaminergic axon terminals which decreases the concentration of DA and DA-metabolites.…”

“…13 Thus, a small increase in ACTH coupled with larger increases in potentiating peptides, α-MSH and β-endorphin, may be su cient to stimulate adrenocortical steroidogenesis, resulting in increased plasma cortisol levels and loss of circadian rhythmicity of cortisol secretion. 10,14 Hence, horses with PPID are commonly referred to as having equine Cushing's disease.…”

Restoring pars intermedia dopamine concentrations and tyrosine hydroxylase expression levels with pergolide: evidence from horses with pituitary pars intermedia dysfunction

“…Administration of DA agonists is a logical therapeutic strategy for horses with PPID [ 46 – 48 ], which our data further reinforce. Previous work has shown that PPID horses treated with DA agonists have decreased levels of POMC peptides and adrenocorticotropic hormone (ACTH) in the PI, and cortisol concentrations in plasma [ 14 , 46 , 49 ].…”

“…For example, α-MSH and β-endorphin are capable of inducing a six-fold increase in the steroidogenic properties of ACTH [ 13 ]. Thus, a small increase in ACTH coupled with larger increases in potentiating peptides, α-MSH and β-endorphin, may be sufficient to stimulate adrenocortical steroidogenesis, resulting in increased plasma cortisol levels and loss of circadian rhythmicity of cortisol secretion [ 10 , 14 ]. Hence, horses with PPID are commonly referred to as having equine Cushing’s disease.…”