20 Oct 2015
Nicola Menzies-Gow
Job Title
Figure 1. A 15-year-old pony mare with generalised hypertrichosis suggestive of pituitary pars intermedia dysfunction.
Not all owners will elect to treat pituitary pars intermedia dysfunction specifically – depending on which clinical signs are present and how severe they are in an individual animal. The clinical signs can be managed individually – for example, clip excess hair, treat secondary infections, alter the diet to gain or lose weight and treat laminitis. Where medical therapy is employed, the treatment of choice is the dopamine agonist pergolide, which is licensed. It is reportedly effective in 65% to 80% of cases. The serotonin antagonist cyproheptadine does not appear to be any more effective than non-pharmacological management, but can be used in addition to pergolide in refractory cases.
The final drug that can be employed is the cortisol synthesis inhibitor trilostane. It will only reduce the clinical signs associated with excess cortisol and its effectiveness is questionable. Normalisation or improvement of endocrine tests can be used to monitor the response to therapy starting 30 days after initiation of pergolide treatment. Alternatively, improvement in the clinical signs can be used. Lifelong drug therapy and/or management of the clinical signs is required as all the available drugs will only help control the clinical signs, but not result in a cure. Despite this, many horses continue to have a good quality of life for a number of years.
Equine pituitary pars intermedia dysfunction (PPID) is a slowly progressive neurodegenerative disease with loss of dopaminergic (inhibitory) input to the melanotropes of the pituitary pars intermedia, which appears to be associated with localised oxidative stress and abnormal protein (α-synuclein) accumulation. However, the exact cause remains unknown.
The consequent dysfunction of this region results in hyperplasia of this area of the gland and overproduction of pars intermedia derived hormones – eventually, the area undergoes adenomatous change.
The condition is seen in older animals – the average age in retrospective case series ranges from 18 years to 23 years1-4. There is no breed or sex predilection, but ponies are more frequently affected than horses in some studies2-4. In one survey, 21% of horses aged more than 15 years had endocrine changes consistent with PPID5 and in a second, clinical signs consistent with PPID were documented in nearly 40% of horses more than 30 years of age6. However, it should be noted the disease is often recognised in animals younger than this, with the youngest reported case being in a seven-year-old animal7.
The clinical signs associated with PPID can be roughly divided into those seen early in the disease and those associated with advanced disease (Table 1; Figure 1). Diagnosis is based on signalment, clinical signs and further diagnostic test results. There is no ideal further diagnostic test; however, plasma basal adrenocorticotropic hormone (ACTH) concentrations and the ACTH response to thyrotropin releasing hormone are thought to be the most appropriate tests, as well as measurement of fasting insulin concentrations or performing an oral glucose or sugar test to assess for insulin dysregulation, which occurs in a subset of animals with PPID.
PPID is a slowly progressive, lifelong condition. The aim of treatment is not to cure the patient, but to increase the quality of life by reducing the clinical signs, including those that have the potential to be life-threatening. While the benefits of treating a laminitic case with a definitive diagnosis of PPID are clear, in cases with clinical signs that are not life-threatening, the decision to specifically treat the PPID is less clear-cut as there is no evidence to date demonstrating pergolide prevents laminitis or the progression of PPID.
Some argue pharmacological management in such cases is appropriate as it should be considered to be prophylactic treatment of a condition that may threaten health in the future. However, the decision should be made following discussion with the owner, taking into account the financial implications and potential adverse effects of lifelong treatment.
If an owner elects not to treat PPID specifically, the clinical signs can be managed individually:
Supporting the foot is an essential part of managing acute laminitis. The horse naturally adopts a stance that bears most of the weight over the caudal part of the foot rather than the painful toe region. Additional support should be supplied to this region of the foot to provide pain relief and minimise the mechanical forces on the laminae and, hence, laminar tearing and pedal bone movement. The simplest method is to increase the depth of the bedding – ensuring the bedding extends to the door where the horse will spend a significant proportion of its day standing.
Shavings, sand, peat or hemp-based products are best as they pack beneath the feet better than straw or paper. Extra support can be applied directly to the caudal two thirds of the foot itself. This can be done in a variety of ways that can be broadly divided into frog-only supports and combined frog and sole supports. Frog-only support can be achieved using rolled-up bandaging material of the same length as the frog, placed along the length of the frog and secured in place with adhesive tape.
Alternatively, a commercially available product such as a frog support can be used. Combined frog and sole support can be provided using, for example, dental impression material moulded to the contours of the caudal two thirds of the foot or polystyrene foam pads that are crushed by the weight of the horse. There is no evidence to suggest any one foot support method is superior11.
The use of vasodilator or vasoconstrictor therapy in the treatment of laminitis remains controversial due to lack of knowledge of the pathophysiology of the disease. Vasodilator therapy is frequently used once the clinical signs have become apparent based on laminitis being a consequence of digital hypoperfusion. Acepromazine is the most effective digital vasodilator available; however, it should be acknowledged that even if the pathophysiology of laminitis involves vasoconstriction, this has resolved once the clinical signs become apparent. Nevertheless, the sedative effect of acepromazine may have the additional beneficial effect of reducing movement or even resulting in increased periods of time spent recumbent with the weight taken off the feet.
More recently, digital hypothermia or cryotherapy has been advocated. It provided a protective effect clinically and histologically when employed prior to the onset of the disease process12,13 and after the onset of lameness14 in experimental models of laminitis and decreased the incidence of laminitis in horses with colitis15.
The efficacy of a variety of cooling methods used in clinical practice has been critically evaluated and immersion of the foot, or at least the pastern, in ice and water is required to achieve adequate cooling16. However, the effectiveness of digital cryotherapy in endocrinopathic laminitis has not yet been evaluated.
Laminitis is the most common clinical sign, which will enforce the use of pharmacological agents to help control the disease. Where specific medical therapy is used, three types of drugs are available.
Dopamine agonists replace the lost dopaminergic inhibition to the pars intermedia and so reduce hormone production. Interaction with D2 receptors inhibits the excessive hormone secretion and is, therefore, associated with improvement in clinical signs. It has not been determined whether pergolide treatment also inhibits the development of pituitary hyperplasia or reduces the size of pituitary adenomas, but these beneficial effects are plausible.
Pergolide is available as a product licensed in the UK for the treatment of PPID in horses and is reported to be effective in 65% to 80% of cases4,17. The initial dose is 2µg/kg po SID for four to six weeks18. The dose is increased in increments of 1µg/kg/day with reassessment every four to six weeks to a maximum of 6µg/kg/day if there is not adequate clinical or laboratory response or decreased slowly at four to six-week intervals to the lowest apparently effective dose19.
Side effects include anorexia, diarrhoea, depression and colic20; however, only anorexia and depression are reported with any frequency21-23. If signs of dose intolerance develop, treatment should be stopped for two to three days and then reinstituted at half of the previous dose18. The total daily dose may then be gradually increased until the desired clinical effect is achieved, increasing in 0.5mg increments every two to four weeks. Contraindications to using pergolide include animals with a known hypersensitivity to the drug or other ergot derivatives, animals less than two years of age and pregnant or lactating animals.
PPID is a slowly progressive disease and the amount of pergolide required to control the symptoms is likely to increase as the horse ages. In addition, there is a normal physiologic increase in hormone production by the pituitary gland in the autumn. Some horses only seem to need pergolide during this seasonal rise in the early stages of the disease. Alternatively, some horses appear to need an increased dose of pergolide during this seasonal rise.
These drugs decrease the serotonin-induced stimulation to the pars intermedia. Cyproheptadine (0.25mg/kg to 0.5mg/kg po SID or BID) was used for the treatment of PPID and reported to be effective in 28% to 60% of cases4,17,24. However, similar improvements were achieved with improved nutrition, preventive care and management alone21. In addition, pergolide has been shown to be more effective than cyproheptadine for the medical treatment of PPID4. Thus, cyproheptadine monotherapy is no longer advocated for the treatment of equine PPID, though it can be used in addition to pergolide in refractory cases.
Trilostane is a 3-β hydroxysteroid dehydrogenase inhibitor, thus, it inhibits cortisol production by the adrenal gland and so will only reduce the clinical signs associated with excess cortisol concentrations. In a single study, a dose of 0.5mg/kg to 1mg/kg SID was reported to be effective in 80% of cases25; however, the improvements in the endocrinological results in this study were not convincing.
Alternatives that have been investigated include an aqueous extract of the herb Vitex agnus-castus (chasteberry), which is reported to contain compounds (diterpenoids) that stimulate dopamine D2 receptor activity and inhibit different opioid receptors. However, in the only published study, it failed to resolve clinical signs or improve diagnostic test results in 14 horses with PPID26.
It has been shown that of the horses receiving 1.5mg pergolide SID, which showed an improvement in their ACTH concentrations, 52% to 72% showed an improvement within seven days, 62% to 82% within 14 days and 74% to 96% within four weeks. Thus it is proposed the best practice for monitoring PPID includes measurement of plasma ACTH concentrations 30 days after pergolide treatment is started27. If it has not returned to within the seasonally adjusted reference range at this time then the dose should be incrementally increased by 1μg/kg/day to 2μg/kg/day at four-week intervals until it does.
Once a suitable dose has been found, plasma ACTH concentrations should subsequently be measured annually – or some suggest biannually – in the autumn and spring, and the pergolide dose adjusted to maintain plasma ACTH concentrations within the reference range.
Some horses have very high plasma ACTH concentrations and so it may not be possible to return concentrations to normal in these cases18. Other approaches, therefore, must be considered. Ideally, the dose should be incrementally increased to try to return plasma ACTH concentrations to within the reference range up to a maximum dose of 5mg SID. If finances preclude this approach then an affordable dose that elicits a significant decrease in plasma ACTH concentration – even if concentrations remain above the reference range – should be used27.
Alternatively, the clinical responses to treatment can be monitored. The clinical signs should be evaluated at 60 days following initiation of treatment. Outcomes of pergolide treatment include:
Increased alertness and activity and decreased drinking and urination are reported to improve first within 30 days of starting treatment – other signs may take up to 12 months to improve. The dose of pergolide can be altered according to how well the clinical signs improve. Once the disease is controlled, clinical assessment should be performed every six months to monitor treatment success and the pergolide dose adjusted to maintain a clinical response.
The disease requires lifelong management and lifelong drug therapy as all the available drugs will only help to control the clinical signs, but not result in a cure. Two studies have evaluated short-term survival in horses with PPID. In one study, low serum insulin concentration before treatment was significantly associated with improved short-term survival up to one to two years28. In a second study, comparison of plasma ACTH concentrations at baseline, with those a median of two months after treatment, were found to be helpful when monitoring treatment of PPID in 42 horses, but improvement in clinical signs was considered the most important indicator of prognosis17.
Long-term survival has been evaluated once and the clinical signs and clinicopathologic data were not associated with survival; however, 50% of horses were alive 4.6 years after diagnosis8. Thus, many horses can continue to have a good quality of life for a number of years.
