Hirsuitism and obesity: Equine endocrine disease and metabolic syndromes (Proceedings)

Equine endocrine disease most often occurs in older horses as a result of dysfunction of the pituitary pars intermedia. Equine metabolic syndrome is the name applied to the association of obesity in older horses and the risk of development of laminitis. Horses are living longer lives and their owners are becoming more interested in preserving health, athletic function and quality of life through the later years. There are two endocrine disorders of mature horses: equine Cushing's disease and the metabolic syndrome. These two disorders feature some clinical similarities such as insulin resistance and chronic laminitis. However, the pathogenesis of each disease is quite different in each case.

Equine Cushing's disease is a disorder of the pituitary gland that causes a variety of clinical signs: a long, wavy hair coat; excessive sweating; lethargy; chronic recurrent laminitis; infertility; weight loss with muscle wasting; abnormal distribution of fat, with accumulations in the crest of the neck, tail head, sheath and above the eyes; polyuria and polydipsia; and increased susceptibility to infections. The disease tends to occur in middle-aged and geriatric horses.

In affected horses, the pituitary pars intermedia produces excessive amounts of pro-opiomelanocortin (POMC) from which is cleaved adrenocorticotropic hormone (ACTH). In healthy horses, the majority of circulating ACTH comes from the pars distalis which produces less ACTH when plasma cortisol concentrations increase (negative feedback). In contrast, function of the pars intermedia is not influenced by cortisol concentration. Instead, production of POMC by the pars intermedia is controlled by nerves arising from the hypothalamus. Dopamine and serotonin serve as the neurotransmitters. Horses with equine Cushing's disease have increased concentrations of dopamine in the pars intermedia causing increased production of POMC and in turn ACTH. The ACTH increases the amount of cortisol produced by the adrenal gland; this cortisol does not reduce the amount of ACTH produced by the pars intermedia. In contrast, serotonin released by hypothalamic nerves does reduce pars intermedia production of POMC. Therefore, treatment of equine Cushing's disease involves inhibiting the excess dopamine or increasing the concentrations of inhibitory serotonin (or both).

Identification of compatible clinical signs is an important aspect of diagnosis of Cushing's disease. The long, wavy hair coat (hirsuitism) is characteristic and fairly specific for this disease. However, diagnosis of earlier requires endocrinology tests. The dexamethasone suppression test is the most accurate method of diagnosis. A basal plasma sample (usually in heparin) is collected for cortisol measurement after which dexamethasone is administered by intramuscular injection (0.04 mg/kg). The post treatment samples can be collected at various intervals after dexamethasone treatment; however, the most important samples are collected at 16-18 hours (to confirm that suppression occurred) and at 24 hours (to confirm that suppression was sustained). The most sensitive use of dexamethasone suppression testing uses these two samples. Because horses with Cushing's disease are under pars intermedia control, they do not adequately suppress during dexamethasone suppression testing. Less sensitive tests for Cushing's disease includes ACTH sampling and Thyrotropin releasing hormone (TRH) testing. Measurement of plasma ACTH involves collection and analysis of a single blood sample; the pituitary gland in affected horses often secretes excessive amounts of ACTH into the bloodstream as compared to normal horses. Blood samples must be handled very carefully to avoid degradation of ACTH and falsely low measured values. Stress and pain due to other conditions may also result in falsely elevated values. Most importantly, horses with Cushing's disease do not keep elevated ACTH concentration 24 hours a day every day so false negative results often occur. TRH testing involves administering TRH and collecting blood samples to test for cortisol measurement. TRH increases cortisol production in Cushing's horses but not in healthy horses. This test only requires a few hours to complete but some horses with Cushing's disease will have normal test results. Supplemental tests that may be useful in suspect cases include measurements of blood glucose and insulin. Some affected horses are insulin resistant and this may impact development of laminitis.

Optimal management of Cushing's disease involves a combination of both specific medication to normalize the function of the pituitary gland and supportive care to address and prevent complications associated with the disease. Specific endocrine therapy manages the disease but is not curative necessitating life-long management. In the early stages, specific medication may not be required and conservative measures such as body clipping to remove the long hair coat, strict attention to diet, and scrupulous attention to teeth, hooves and preventive care may be sufficient to provide good quality of life. Diagnosis and aggressive treatment of bacterial infections is important. Since affected horses are often insulin resistant, sweet feed and other feedstuffs high in soluble carbohydrates should be avoided while fiber and fat are emphasized. Pelleted or extruded feeds designed specifically for older horses are strongly recommended.

Medications used to treat this condition focus on (1) reducing the amount of ACTH and other POMC derivatives secreted by the pituitary and/or (2) suppression of cortisol synthesis and release by the adrenal glands (e.g. trilostane). Because ACTH is not the only POMC derivative that causes clinical signs, drugs that act on the adrenal thereby reducing all POMCs are preferred over those acting at the adrenal. Reduction of pars intermedia POMC production is achieved by either inhibition of dopamine receptors or stimulation of serotonergic receptors. Drugs that do the later seem to be most effective and include cyproheptadine and pergolide. The drug of choice is currently pergolide mesylate (Permax®), which is administered daily by the oral route. An initial dose of 0.002 mg/kg (approximately 1 mg for a 1000-lb horse) once daily is recommended; this dose may be gradually increased if clinical improvement fails to occur after one to two months of therapy. Side effects include anorexia which improves when the dose is again reduced.

A favorable clinical response to therapy will be associated with improvement or normalization of results in the dexamethasone suppression and plasma ACTH tests. Occasional severe cases benefit from treatment with a combination of both pergolide and cyproheptadine (Periactin®). Trilostane, an inhibitor of adrenal cortisol synthesis, has shown some promise in clinical trials conducted in the United Kingdom; however this medication acts at the adrenal gland and does not inhibit other POMCs.

The syndrome associate with obesity and chronic laminitis in the absence of hirsuitism, weight loss, muscle wasting, polyuria and polydipsia, and propensity for infection has been coined the equine metabolic syndrome (EMS) also sometimes called the pre-laminitis metabolic syndrome (PLMS). Affected horses are characteristically obese, and tend to be aged between 8–18 years. However, it should be noted that not all affected horses are grossly obese, and use of the term ''obesity'' is often scorned by horse owners. Pony breeds and Morgan horses appear to be overrepresented. In addition to being generally overweight, excess fat distribution in the neck (''cresty neck'') and the rump are common. Horse owners generally report that it is very difficult to reduce the weight of these horses by dietary restriction (''easy keepers''). Affected geldings often develop a ''swollen sheath'' associated with fat deposition subcutaneously in the sheath. Chronic laminitis plagues these animals with usually mild recurring bouts; however, over time significant hoof remodeling can result in substantial lameness and performance limitations.

Our current understanding of the pathophysiology of EMS, in particular with regard to the mechanism of increased susceptibility to laminitis is very limited. Much more is known about the human metabolic syndrome resulting in extrapolation of pathogenesis to the equine disease. This must be done with care as there may be differences between the syndromes. Indeed, humans with metabolic syndrome exhibit differences in the dyslipidemia and more consistent changes in blood pressure than observed in horses. Further, an exact human correlate for laminitis has not been found. Nonetheless, hyperinsulinemia has been documented in many horses with EMS or PLMS and this demonstrates many similarities to the insulin resistance documented in humans with metabolic syndrome. Induction of hyperinsulinemia via insulin and glucose infusion for 50 to 72 hours induced laminitis in healthy ponies. There are several potential mechanisms by which hyperinsulinemia could lead to laminar failure. Altered glucose metabolism has been suggested; however, laminar glucose uptake is not necessarily insulin dependent. Glucotoxicity caused by insulin resistant hyperglycemia has been suggested; however, hyperinsulinemia induced laminitis in the presence of normal blood glucose concentrations. Alternatively, the hyperinsulin state may to disturbances in vascular function and inflammation that subsequently lead to laminar failure. Increased endothelin concentration, platelet adhesion, and neutrophil infiltration occur during laminitis supporting this hypothesis. Concurrent with the vascular dysfunction, insulin and neutrophil products induce matrix metalloproteinase production which is capable of degrading laminar support proteins.

Diagnosis of EMS and PLMS is largely based on identification of the obese phenotype with abnormal fat distribution. Plasma insulin concentrations can be measured and are elevated in many cases. Glucose tolerance testing can be performed with measurement of blood glucose and insulin concentrations to assess insulin sensitivity.

Diet is paramount in the management of horses for treatment or prevention of EMS or PLMS. Feeding diets high in starch (glycemic diets; high grain diets) and intensive grazing on pastures with high nonstructural carbohydrate contents (young spring grass; high in starch, sugar, and fructan) should be avoided in horses with this phenotype. Increased exercise has been demonstrated to decrease insulin concentrations in horses and ponies. Laminitis can restrict the ability to achieve increased exercise; but strategies to reduce the pain and structural deformation associated with chronic laminitis can often be very successful. Reduction of body condition scoring is pivotal as hormones released by adipose stores are likely to be the cause of insulin resistance.

Dietary and exercise strategies are pivotal to the treatment of this condition and medications are have limited benefit. Pergolide is one medication that is sometimes but efficacy has not been critically examined. Although some of the horses with EMS may concurrently have pituitary dysfunction, serotonin receptor activity is not likely to be the mechanism by which pergolide helps most horses with EMS. Research in laboratory animals suggests that pergolide has an affect outside the pituitary gland to reduce the inflammatory state induced by hyperinsulinemia leading to a potential direct affect on horses with EMS. Trilostane is an inhibitor of adrenal steroidogenesis that has been used in Europe to treat horses with EMS. Cortisol has been associated with insulin resistance so reduction of steroidogenesis may be partially beneficial; however, further study of efficacy of this medication is warranted. Endothelial dysfunction and neutrophil activation can lead to oxidant induced tissue injury that may play a role in laminar failure. Studies in black walnut induced laminitis failed to document evidence of oxidant damage; however, further investigation would be warranted. Antioxidant therapy with vitamin E may be beneficial. Chromium supplementation has been demonstrated to reduce insulin sensitivity in other species but one study in horses failed to document an effect.

Equine Cushing's syndrome and EMS are endocrine diseases that can lead to chronic laminitis. Although each can be associated with insulin resistance, distinct differences in the two diseases can be enumerated. Horses with EMS test negative for Equine Cushing's syndrome on ACTH and dexamethasone suppression testing. Horses with EMS are not hirsuit, are often younger, and do not exhibit muscle wasting.