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 (McFarlane, 2014). It appears to be associated with localised oxidative stress and abnormal protein (⍺-synuclein) accumulation, but the exact cause remains unknown. The consequent dysfunction of the region results in hyperplasia of this area of the gland and overproduction of normal 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 to 23 years. There is no breed or sex predilection, but ponies appear to be more frequently affected than horses. The clinical signs can be roughly divided into those that are seen early in the dis-ease and those that are associated with advanced disease.
Early signs include decreased athletic performance, change in attitude/lethargy, delayed hair coat shedding, regional hypertrichosis, change in body conformation, regional adiposity and laminitis. Late signs include lethargy, generalised hypertrichosis (Figure 1), skeletal muscle atrophy (Figure 2), hyperhidrosis, polyuria/polydipsia, recurrent infections, infertility and laminitis. There is no ideal further diagnostic test for equine PPID, but plasma basal adrenocorticotrophic hormone (ACTH) concentrations and the ACTH response to TRH are currently thought to be the most appropriate tests available. In addition, since a subset of animals with PPID have insulin dysregulation (ID), tests to detect ID should be undertaken.
Equine metabolic syndrome (EMS) is a collection of risk factors for endocrinopathic laminitis (Durham et al., 2019). The central and consistent feature of EMS is insulin dysregulation which can manifest in three ways, namely: hyperinsulinaemia, an excessive insulin response to oral carbohydrate and peripheral (tissue) insulin resistance. Additional features of EMS include obesity (Figure 3), hypertriglyceridaemia and adipose dysregulation manifesting as abnormal plasma adipokine concentrations including hypoadiponectinaemia and hyperleptinaemia.
Laminitis is the primary clinical consequence of EMS (Figure 4). Horses with EMS might also be at risk of further problems including hyperlipaemia and critical care-associated metabolic derangements including hyperglycaemia and hypertriglyceridaemia. A diagnosis of EMS is based on demonstration of ID. Resting (basal) insulin concentrations can be measured to detect hyperinsulinaemia, but this is of low diagnostic sensitivity. Ideally, dynamic tests should be performed including an oral sugar test (OST) to detect an excessive insulin response to oral carbohydrate and an insulin tolerance test (ITT) to assess tissue insulin sensitivity.
Treatment of PPID
Seeing as PPID is a slowly progressive, lifelong condition, the aim of treatment is to improve the quality of life through reducing the clinical signs, rather than cure the condition. Whilst the benefits of treating an animal with PPID that has life-threatening clinical signs such as laminitis are clear, the decision to specifically treat the PPID in animals with clinical signs that are not life threatening is less clear-cut.
There is no published evidence demonstrating that pergolide prevents laminitis or the progression of PPID. It could be argued that 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. Thus, this decision should be made following discussion with the owner taking into account the financial implications and potential adverse effects of life-long treatment.
Pharmacological treatment
There are two types of drug available: dopamine agonists and serotonin (5-hydroxytryptamine; 5-HT) antagonists. The former replace the lost dopaminergic inhibition to the pars intermedia, whilst the latter decrease the serotonin-induced stimulation to the pars intermedia. Both result in a reduction in the excessive hormone secretion and so an improvement in the clinical signs. It has not been determined whether treatment with these drugs also inhibits the development/progression of the pituitary hyperplasia or reduces the size of pituitary adenomas once they have developed.
Pergolide
Pergolide is a dopamine agonist that is available as a product licensed in the UK for the treatment of PPID in horses (Prascend, Boehringer Ingleheim). It is reported to be effective in 65 to 80 percent of cases. The initial dose is 2 μg/kg PO SID for four to six weeks (0.5mg for a 250kg pony and 1.0mg for a 500kg horse). Side effects include anorexia, diarrhoea, depression and colic; however, only anorexia and depression are reported with any frequency. If signs of dose intolerance develop, treatment should be stopped for two to three days and then reinstituted at half of the previous dose for the first four days or by administering half the dose morning and evening. 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 pergolide 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 physiological 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.
Cyproheptadine
Cyproheptadine is a serotonin antagonist that was previously recommended for the treatment of PPID and was reported to be effective in 28 to 60 percent of cases. However, similar improvements can be achieved with improved nutrition, preventative care and management alone and pergolide has been shown to be more effective. Thus, cyproheptadine monotherapy is no longer advocated and instead it should only be used in addition to pergolide in refractory cases.
Non-pharmacological management
If an owner decides not to treat the PPID specifically, then the clinical signs can be managed individually. For example, excess hair can be clipped, the diet can be altered to promote weight gain or loss as appropriate and the laminitis can be treated with analgesia and foot support. The only complementary or alternative therapy that has been investigated is the use of an aqueous extract of the herb Vitex agnus-castus (chasteberry), which is reported to contain compounds (diterpenoids) that stimulate dopamine receptor activity and inhibit different opioid receptors. However, it did not resolve the clinical signs or improve diagnostic test results in 14 horses with PPID.
Monitoring of PPID
There are three monitoring strategies that can be used:
- Laboratory response
- Clinical response
- Combined laboratory and clinical response
If the laboratory response is monitored, the plasma ACTH concentration should be measured approximately 30 days after initiation of pergolide therapy. If it has not decreased to within the seasonally adjusted reference range, the dose of pergolide should be increased in increments of 1μg/kg/day with reassessment every four to six weeks to a maximum of 6μg/kg/day. Once a suitable pergolide dose has been found, plasma ACTH concentrations should 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 it may not be possible to return plasma ACTH concentrations to normal in these cases. Instead, an affordable pergolide dose that results in a significant decrease in plasma ACTH concentration, even if concentrations remain above the reference range, should be used.If the clinical response to treatment is being monitored, increased alertness and activity and decreased drinking and urination should be expected within 30 days of starting treatment.
Other signs such as hypertrichosis and skeletal muscle atrophy may take up to 12 months to improve. The dose of pergolide can then be altered according to how well the clinical signs improve. Once the disease is controlled, clinical assessment should be performed every six months and the pergolide dose adjusted to maintain a clinical response.
Finally and ideally, the laboratory response can be assessed in conjunction with the clinical response.
Treatment of equine metabolic syndrome
EMS can also be managed rather than cured. Management consists of dietary modification, exercise and the use of pharmacological agents.
Diet
Dietary modification recommendations will depend on whether the individual animal is obese or lean.
Obese animals require energy restriction through limiting intake and feeding a diet based on grass hay (or hay substitute) with low (less than 10 percent) non-structural carbohydrate (NSC) content. A daily allowance of 1.25 to 1.5 percent of actual body mass (BM) as dry matter intake (DMI), or 1.4 to 1.7 percent of actual BM as fed is widely recommended in order to achieve a target weight loss of 0.5 to 1.0 percent BM weekly. The forage should be divided into three to four feeds per day and strategies to prolong feed intake time should be considered, such as use of haynets with multiple small holes.
In horses with weight loss resistance, a further restriction to 1.0 percent BM as DMI or 1.15 percent BM as fed may be considered if appropriately monitored. The nutrient composition of the forage should be determined where possible and hays with low NSC content (less than 10 percent) are recommended to limit postprandial insulin responses. Soaking is advised to reduce the NSC content of the hay if necessary, and as forages can be low in protein and mineral and vitamin leaching occurs after soaking, these nutrients must be balanced by low calorie supplements to cover requirements.
During the initial 6 to 12 weeks of dietary restriction, pasture access should be prevented; even partial access is very difficult to quantify. Successful long-term management of EMS cases can include some grazing provided that ID, especially assessed by the insulin response to oral carbohydrates or grazing, is under control and grazing is carefully controlled. Grains or cereal-based feeds should be excluded due to their high NSC content and high-fat feeds should be avoided due to their high energy content. Finally, the use of dietary supplements such as cinnamon, magnesium and chromium to facilitate weight loss or to improve ID is popular, but their efficacy remains questionable or unproven. Lean animals should be fed a low glycaemic diet in order to minimise the postprandial insulin response. The diet should be based on forage with a low (ideally less than 10 percent) NSC content, and additional calories provided in the form of fat (eg vegetable oil) and high quality fibre such as beet pulp. A low calorie vitamin, mineral and protein ration balancer should be fed as required.
Exercise
Exercise has been shown to improve insulin sensitivity in horses; however, the exercise intensities required for this effect may be higher than are often undertaken. Animals should only be exercised if there is no current laminitis and all exercise should be increased gradually based on the baseline fitness level. In non-laminitic horses with ID, current minimum recommendations are low to moderate intensity exercise (canter to fast canter, ridden or unridden; or HR 150 to 170bpm) for more than 30 minutes, more than five times per week. In previously laminitic horses with recovered and stable hoof lamellae, minimum exercise recommendations are low intensity exercise on a soft surface (fast trot to canter unridden; or HR 130 to 150bpm) for more than 30 minutes, more than three times per week, whilst carefully monitoring for signs of lameness.
Pharmacological agents
If management changes are unsuccessful alone, then pharmacological interventions can be additionally used in the short term (three to six months). Metformin (15 to 30mg/kg two to three times daily PO) was initially advocated to improve insulin sensitivity; however, the bioavailability is very low and it does not have insulin sensitising effects in the horse. Instead metformin may reduce the glycaemic and insulinaemic responses to oral carbohydrate ingestion; thus it may be more useful in preventing post-prandial hyperinsulinaemia associated with pasture turn out or feed consumption.
Levothyroxine (0.1 to 0.15mg/kg PO SID) is advocated in animals with generalised or regional adiposity. Weight loss is promoted through an increase in the metabolic rate; however, the diet has to be strictly controlled because poly-phagia may be a consequence of medication.
Monitoring of EMS
Initial veterinary re-examinations should be performed monthly after starting dietary restriction and then less frequently (6 to 12 monthly intervals) once good progress is made. The minimum database for each visit includes an updated diet and exercise history, physical examination, body weight (using a weighbridge or weigh tape), body condition score, visual inspection of hooves for signs of laminitis and dynamic endocrine tests (eg OST, ITT). The dietary and exercise recommendations can then be altered according to the response of the ID and weight loss.
