Current best practice in clinical management of equine endocrine patients
Endocrine disorders are commonly diagnosed in horses and our knowledge of equine endocrinology has expanded in recent years. Original research reports, case series and review articles included in this virtual issue of Equine Veterinary Education and Equine Veterinary Journal are examples of the work being conducted in this developing area of equine medicine. Pituitary pars intermedia dysfunction (PPID) and insulin dysregulation (ID) are the most common endocrine disorders encountered in horses and have high prevalence rates. McGowan et al. (2013a) report a prevalence rate of 21.2% for PPID in horses aged ≥15 years from a cross-sectional survey of horse owners in Queensland, Australia and this is consistent with the previously reported 22% prevalence rate for haircoat changes associated with PPID in aged horses in the United Kingdom (Ireland et al. 2012). Insulin dysregulation also appears to be common in horses, as a component of equine metabolic syndrome (EMS) or accompanying PPID (Frank and Tadros 2013). Hyperinsulinaemia (fed plasma insulin concentration ≥30 mu/l) occurred with a prevalence of 10% in a cross-sectional study of mixed light-breed horses in Virginia, USA (Pleasant et al. 2013) and basal hyperinsulinaemia (>20 mu/l) was detected in 32% of aged (≥15 years) horses with PPID in Queensland (McGowan et al. 2013b). There appears to be a genetic basis to ID, with certain breeds of horse, including ponies, Morgan horses and Arabians being overrepresented. Other endocrine disorders of horses include hyperparathyroidism, as discussed by Axiak and Johnson (2012) in their article focused on paraneoplastic syndromes, and diabetes mellitus (Durham et al. 2009; Dunkel et al. 2013). In contrast, some of the common endocrinopathies of human patients, dogs and cats such as Addison's disease, hyperthyroidism and hypothyroidism, are rarely seen in horses. This discussion of best practices in clinical management of equine endocrine patients focuses on PPID and ID because of their high prevalence rates.
Before making management decisions, the clinician should first consider the stage of the endocrinopathy and appreciate the dynamic nature of endocrine disorders. Pituitary pars intermedia dysfunction is a neurodegenerative condition that progresses over time and occurs in its advanced form in old horses. It is important to recognise, however, that this disorder first develops at a younger age and advances in diagnostic testing have allowed us to detect PPID in its earlier stages. Pituitary pars intermedia dysfunction should be considered in horses aged >10 years that exhibit poor performance, loss of muscle mass and subtle haircoat changes such as retained hairs in small areas (regional hypertrichosis). Detection of early PPID is important because the disorder is easily managed with pergolide treatment and it is advisable to prevent laminitis, rather than wait for this condition to develop. Both PPID and ID are associated with laminitis, and relationships among these conditions were reviewed by Tadros and Frank (2013) and discussed extensively in the Equine Veterinary Journal virtual issue on laminitis (http://onlinelibrary.wiley.com/journal/10.1001/(ISSN)2042-3306/homepage/laminitis__recent_advances_and_future_directions.htm).
Insulin dysregulation can also change over time. If we consider certain horses to be genetically predisposed to this problem, the degree of ID is determined by the management of the horse and development of concurrent medical conditions. A genetically predisposed horse that is well managed can remain free of health problems whereas obesity, hyperinsulinaemia and laminitis may develop if the same animal is overfed or exposed to feeds and forages that elicit a marked insulinaemic response. Obesity, regional adiposity, ID, hypertriglyceridaemia and hyperleptinaemia are all components of EMS, a collection of endocrine and metabolic abnormalities associated with the development of laminitis in equids. Insulin dysregulation can also be exacerbated by PPID and anecdotal evidence suggests that horses with EMS are predisposed to PPID. This concern has led to the recommendation that all horses with EMS that are aged >10 years be closely monitored for signs of pituitary dysfunction.
Management and monitoring of PPID
Pergolide is recommended for the treatment of PPID in horses at a dosage of 0.002 mg/kg bwt and is available as Prascend®1 in 1 mg tablets. Anorexia can be encountered as pergolide treatment is initiated, so it is advisable to start horses on half the dose every other day for 2 doses and then half the dose daily for 3 days to avoid this complication. Cyproheptadine is also used for the management of PPID, but is reserved for horses with advanced PPID on higher dosages of pergolide. In these situations cyproheptadine is administered at a dosage of 0.25 mg/kg bwt orally every 12 h and given to animals concurrently receiving pergolide.
Best practices for managing PPID include measurement of plasma adrenocorticotropin hormone (ACTH) concentrations 30 days after pergolide treatment is initiated at the full dose. Plasma ACTH concentrations are also measured to diagnose PPID and this is an easy test to perform because only a single blood sample is required. The other recommended diagnostic test for PPID is the thyrotropin-releasing hormone (TRH) stimulation test and this is performed by collecting a blood sample, injecting 1.0 mg TRH i.v. and collecting a second blood sample 10 min later. Horses with PPID have a marked increase in plasma ACTH concentrations in response to TRH. The TRH stimulation test appears to have greater sensitivity than resting ACTH measurements and is therefore recommended when clinical signs are subtle and early PPID is suspected.
Reference intervals are required when plasma ACTH concentrations are used to diagnose and monitor PPID, and these intervals must be appropriate for the time of year when the horse is tested and assay used. Copas and Durham (2012) established seasonal reference intervals for plasma ACTH concentrations in horses and reported upper limits of 29 pg/ml between November and July and 47 pg/ml between August and October for horses in the UK. Seasonally adjusted reference intervals allow horses to be evaluated in the late summer and autumn when ACTH concentrations are higher and melanotrophs within the pars intermedia are more active. Alpha melanocyte-stimulating hormone concentrations are also increased with PPID and are affected by season (McGowan et al. 2013aa), but this measure is not offered by laboratories. The August to October period was avoided in the past, but this time of year is now recommended as an appropriate time to assess horses on pergolide treatment. Plasma ACTH concentrations should be measured biannually, in the autumn and spring, and the pergolide dosage should be adjusted to maintain plasma ACTH concentrations within reference intervals at both times of the year.
Only the laboratory response to pergolide treatment has been discussed so far and this is the recommended approach when managing horses with early PPID that respond well to treatment. However, horses with advanced PPID at the time of first diagnosis often have very high plasma ACTH concentrations, sometimes in excess of 1000 pg/ml. It may not be possible to return plasma ACTH concentrations to normal in these cases, so other approaches must be considered. The first approach is to adjust the pergolide dosage until a significant downward shift in ACTH concentrations is detected. For example, a downward shift to 250 pg/ml represents a significant improvement in a horse with a plasma ACTH concentration of 1000 pg/ml. If the owner can afford to administer pergolide at higher doses, the dosage should be incrementally increased to try and return plasma ACTH concentrations to within the reference interval. In the authors' experience, pergolide can be administered to a maximum dosage of 0.01 mg/kg bwt (5 mg for a 500 kg horse) without adverse health effects. Although this is the preferred approach, it is also practical to consider the finances of the owner and select a dosage that elicits a significant downward shift in plasma ACTH concentration, even if concentrations remain above reference interval. When discussing prognosis, clinicians can point out that only some of the ACTH produced in horses with advanced PPID is likely to be biologically active, so the laboratory values might be only loosely correlated with clinical signs. In the same example, lowering the ACTH concentration to 250 pg/ml could therefore be associated with a significant improvement in clinical signs. Our second recommendation is therefore to monitor clinical responses to treatment. Outcomes of pergolide treatment include increased alertness and activity, resolution of polyuria and polydipsia, lower incidence of laminitis, improved immune function and fewer bacterial infections, mitigation of hyperglycaemia and hyperinsulinaemia, increased muscle mass, and improvements in haircoat quality, hair length and shedding. If a downward shift in ACTH concentrations is detected and clinical signs improve, owners should be encouraged to continue long-term treatment. Some horses show gradual improvement in clinical signs over time, even when receiving pergolide at a dosage suboptimal from a laboratory standpoint. Pituitary pars intermedia dysfunction is a manageable endocrine disorder, even in its advanced stages, and geriatric medicine is a growing field in equine practice.
There are a number of secondary problems encountered in horses with advanced PPID that should be kept in mind. As mentioned above, polyuria and polydipsia are encountered in horses with advanced PPID and result from the reduced action of antidiuretic hormone on the kidney, as described in a recent report by Moses et al. (2013). Hypertriglyceridaemia is also a concern when horses enter negative energy balance, as occurs with colic, dental disease or systemic illness. Dunkel et al. (2013) describe this problem in their recent retrospective study of hospitalised horses and ponies. Of the 7 animals identified with endocrine disorders and hypertriglyceridaemia (serum triglyceride concentration >5.65 mmol/l), 3 horses and 3 ponies were diagnosed with PPID and 5 had concurrent type 2 diabetes mellitus. This report and the 3 horses with type 2 diabetes mellitus described by Durham et al. (2009), have raised our awareness of these problems in horses with PPID. Glucose concentrations must be closely monitored in horses with PPID that encounter stress associated with medical conditions or hospitalisation, and insulin therapy should be considered if hyperglycaemia and hypertriglycerideaemia are encountered.
Management and monitoring of insulin dysregulation
Insulin dysregulation collectively refers to increased insulin responses to oral sugars, hyperinsulinaemia and insulin resistance, and these problems manifest to different degrees in genetically susceptible horses and ponies. The degree of ID depends upon modifying factors, including obesity, diet and PPID. Adiposity and tissue insulin sensitivity are negatively correlated in horses (Carter et al. 2009), so the first goal of managing ID in an obese horse or pony is to induce weight loss. Exercise should be increased and energy intake restricted by removing energy-dense feeds such as grain from the diet and limiting pasture access. Obese equids should be maintained on a diet of hay plus a ration balancer to provide essential nutrients. Amounts of hay can be calculated using digestible energy requirements or a simple approach can be followed in which hay is fed in amounts equivalent to 1.5% of current bodyweight. If body fat mass does not decrease after 4 weeks, the daily amount of hay should be lowered to 1.25% of bodyweight. A further reduction in hay ration to 1.0% of bodyweight is needed in some cases. Some horses and ponies remain obese on low-energy diets even after exercise is increased to consume energy; and this is referred to as weight loss resistance (Argo et al. 2012). Levothyroxine sodium can be administered to accelerate weight loss in these animals, but this approach is only practical in the USA where the drug is inexpensive.
Our understanding of the relationships between insulin and laminitis is improving as more research is performed, including the 3 studies described in this virtual issue (Venugopal et al. 2011; Burns et al. 2013; Gauff et al. 2013), and these findings emphasise the need for ID to be diagnosed and managed in horses to prevent laminitis. Two tests are recommended for diagnosing and monitoring ID: 1) an oral sugar/glucose test and 2) measurement of fasting insulin concentrations. The first test evaluates insulinaemic responses to ingested sugars and the oral sugar test (OST) or in-feed oral glucose test (OGT) can be performed. The OST is more commonly used in the USA where corn syrup is readily available for purchase in supermarkets. When this test is performed, the horse is fasted from midnight onwards and corn syrup (0.15 ml/kg bwt) is administered orally using dose syringes the next morning. Blood samples are collected at 60 and 90 min and a high insulin response is currently defined by an insulin concentration >60 mu/l at either time point. The OGT is also performed after fasting and the horse is fed 0.5 kg chaff-based feed that contains added dextrose powder (1 g/kg bwt) mixed with water. A blood sample is collected 2 h later and an insulin concentration ≥87 mu/l is a high insulin response. Fasting insulin concentrations can also be measured to test horses for ID. A single blood sample is collected after a short fast and fasting hyperinsulinaemia is defined by an insulin concentration >20 mu/l. This test is easy to perform and can be used when owners have concerns about the OST or OGT. However, breed-specific reference intervals are required to improve the performance of this test and its sensitivity is low, which raises concern about false negative results in mildly affected horses.
If it is established from OST or OGT results that insulin responses to ingested sugars are high, a diet should be selected to minimise post prandial hyperinsulinaemia by limiting the intake of simple sugars and starches, which are rapidly hydrolysed to glucose. Grain and sweet feeds should be fed with caution and the amount of grass consumed on pasture should be limited by restricting the area for grazing or placing a grazing muzzle on the horse to decrease feed intake. If insulin concentrations markedly increase during the OST, hay with low nonstructural carbohydrate content should be selected and forage analysis is recommended. Hay can be soaked in cold water for 30 min to lower the sugar content although this method does not yield a predictable decrease in sugars.
Metformin hydrochloride is administered to horses with ID despite its low oral bioavailability (Hustace et al. 2009) and a study performed by Rendle et al. (2013) examines the mechanism of action of this drug in equids. Results indicate that metformin acts locally at the intestinal level to lower post prandial glucose and insulin concentrations. Only healthy horses were evaluated in the study, but results support the use of metformin to limit post prandial hyperinsulinaemia in horses with ID, and current recommendations are to administer metformin at a dosage of 30 mg/kg bwt orally every 8–12 h, with the drug administered 30–60 min before the horse is fed, if possible. The authors reserve metformin treatment for horses and ponies with markedly increased OST insulin concentrations, even after loss of body fat mass and dietary management.
Insulin dysregulation should be monitored by measuring fasting insulin concentrations (if initially elevated) or repeating the OST or OGT. High plasma triglyceride and leptin concentrations can also accompany ID and obesity, and should decrease with appropriate management. Adiposity is monitored through body condition scoring, measuring abdominal circumference at the umbilicus, or neck crest scoring. Pituitary pars intermedia dysfunction exacerbates ID and horses aged >10 years should be closely monitored for the development of this condition.
Equine endocrine disorders are increasingly recognised and have become an integral part of wellness evaluations in horses. Establishing best practices in the diagnosis and management of the 2 common endocrine disorders, PPID and ID, will lower the risk of laminitis and improve the health of horses. Increased awareness of endocrine disorders, including rarer conditions such as diabetes mellitus and hyperparathyroidism, is expanding our knowledge in this area of veterinary medicine.
Authors' declaration of interests
Dr Frank is a consultant on study design for Boehringer Ingelheim Vetmedica, manufacturer of Prascend®.
Boehringer Ingelheim Vetmedica, Ingelheim, Germany.