Despite its commonly used name of equine Cushing’s disease, the most interesting aspects of equine pituitary pars intermedia dysfunction (PPID) are, in fact, its dissimilarities from Cushing’s syndrome, in either humans or dogs. As the recommended name PPID would suggest, this is a disease affecting the pars intermedia of the pituitary gland, not the pars distalis or the adrenal gland. This has repercussions for the best ways of diagnosing and treating the disease.

 

UNDERLYING PATHOPHYSIOLOGY

Many aspects of the pathophysiology of this disorder are still unknown. However, the basics are relatively undisputed. It is a neurodegenerative disease affecting the periventricular dopaminergic neurones of the hypothalamus.^1,2 Loss of dopamine in the intermediate lobe of the pituitary gland prevents the inhibitory effects of D2 dopaminergic receptor stimulation in the cell membranes of the melanotrophs.

In health, this inhibition results in a decrease in synthesis and release of pars intermedia pro-opiomelanocortin (POMC)-derived peptides and a decrease in melanotroph proliferation. Loss of dopamine-mediated inhibition initially results in hypertrophy and hyperplasia of the intermediate lobe, with an increase in circulating α-melanocyte-stimulating hormone (α-MSH), adrenocorticotrophin (ACTH), β-endorphin and corticotrophin-like intermediate peptide (CLIP).³ With progression of the disease, the pars intermedia enlarges further, forming an adenoma which can compress adjacent pituitary, hypothalamic and cerebral structures.⁴

The cause of the degeneration of the dopamine-containing nerves is still unknown. There is evidence of accumulation of markers of oxidative stress,² misfolded nerve terminal proteins² and possibly altered protein clearance,⁵ but whether these are causes or consequences of the disease is as yet unproven.

 

DIFFICULTIES OF DIAGNOSIS

Diagnosis of PPID can be challenging and controversial. As with many progressive diseases, identification of advanced cases is straightforward, but that of early cases is more difficult.

An additional complication specific to equids is related to their adaptation to survival in temperate climates. Horses, and particularly ponies, have an ability to regulate their metabolism to store energy when nutrients are readily available in the spring and summer, in preparation for autumn and winter when nutrients are scarce. Seasonal temperature changes result in the growth of a long hair coat in winter which is shed in the spring. The pars intermedia is involved in these seasonal changes, as is evidenced by the seasonal variation in ACTH and MSH concentrations,⁶ cortisol response to dexamethasone suppression⁷ and ACTH response to thyrotrophin-releasing hormone (TRH) stimulation.^8,9

Studies investigating diagnostic methods are often hampered by the lack of a ‘gold standard’ ante-mortem test, and those studies using post-mortem diagnosis can also be flawed due to seasonal variation in the histological appearance of the pars intermedia¹⁰ and inconsistencies in histological diagnoses between pathologists.¹¹ Recent advances in post-mortem diagnosis have been made;¹² using these methods may allow further investigation of ante-mortem tests. The only test which results in no false positives is the presence of hypertrichosis, a pathognomonic clinical sign present in the more advanced stages of the disease.

The current recommendations for diagnosis are based on an algorithm designed by the Equine Endocrinology Group.¹³ In animals showing obvious clinical signs of PPID, resting ACTH is the first-line test. If this is high, compared with the seasonally adjusted reference range,^14,15 then treatment should be instigated. If resting ACTH is normal, and in animals with subtle signs of PPID, the TRH stimulation test should be performed and ACTH measured.¹⁶ An exaggerated response is seen in individuals affected by PPID.

Laminitis has long been linked to PPID. The current theory is that hyperinsulinaemia is the main risk factor for laminitis, and PPID may be a risk factor for hyperinsulinaemia. The current recommended test for the risk of clinically significant hyperinsulinaemia is measurement of the insulin response to oral sugar. If an exaggerated response is seen, management to reduce access to pasture and high levels of non-structural carbohydrate feed is required.

 

APPROACHES TO TREATMENT

Treatment has varied over the years but, since the authorisation of pergolide mesylate for use in PPID in horses in 2011 (Prascend®; Boehringer Ingelheim Vetmedica), the alternatives of cyproheptadine (a serotonin antagonist) and trilostane (an inhibitor of adrenal steroidogenesis) are rarely used.

Pergolide is a dopamine receptor agonist, acting to restore dopamine receptor-mediated inhibition of the melanotrophs of the pars intermedia. Treatment with pergolide reduces basal ACTH concentrations17 and improves clinical signs in the majority of cases, with the most common side effect being inappetence.^18,19 If pergolide does not result in sufficient improvement, cyproheptadine treatment can be trialled.

 

IMPROVING THE PROGNOSIS

Whilst treatment can improve the clinical signs and quality of life of horses with PPID, the condition can only be managed and not cured. The disease affects middle-aged to older animals, with varying degrees of the following clinical signs: hypertrichosis, abnormal sweating, predisposition to laminitis and/or infections, loss of muscle mass, lethargy, polyuria and polydipsia.²⁰ The combination of effective pharmacological and supportive management can anecdotally lead to improved quality of life for several years, although randomised controlled studies are lacking in this area.

Equine PPID has few similarities to human or canine Cushing’s syndrome; recognising the differences between the conditions has facilitated progress in the challenging areas of understanding the pathophysiology of equine PPID and how best to diagnose it.

 

Elizabeth Finding

Anatomy Demonstrator, Royal Veterinary College, London

 

REFERENCES

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