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August 17, 2017

Equine Endocrinology: Cushing’s Disease and Metabolic Syndrome


Introduction

With each passing year, horses are living longer lives and their owners are becoming more interested in preserving health, athletic function and quality of life throughout middle age and the geriatric years. This article reviews two related endocrine disorders of mature and geriatric horses: equine Cushing’s disease and a recently recognized condition that is currently known as “metabolic syndrome.”

Old horse in a meadow with dandelions

Although the two disorders feature some striking clinical similarities— most notably a predisposition to development of chronic laminitis— the underlying disease biology is quite different in each case and successful management requires that the equine veterinarian distinguish between them. Our understanding of both conditions, especially metabolic syndrome, is incomplete and subject to continuous evolution, but sufficient information is currently available to highlight some important similarities and differences for the interested horse owner.

What is Equine Cushing’s Disease?

Equine Cushing’s disease is a disorder of the pituitary gland that results in hormonal imbalances, causing a variety of clinical signs: a long, wavy haircoat that fails to shed according to normal seasonal patterns; excessive sweating; lethargy and poor athletic performance; chronic recurrent laminitis; infertility; weight loss; muscle wasting, especially along the topline; abnormal distribution of fat, with accumulations in the crest of the neck, tail head, sheath and above the eyes; consumption of large volumes of water and passage of large amounts of urine; delayed wound healing; and increased susceptibility to infections.

The disease tends to occur in middle-aged and geriatric horses, with an average age of approximately 20 years at the time of diagnosis. Without treatment, symptoms tend to worsen over time and many horses are euthanized as a consequence of laminitis, recurrent foot abscesses or complications related to bacterial infections.

What Causes Equine Cushing’s Disease?

In dogs and humans, Cushing’s disease is caused by a hormone-secreting tumor of the anterior part (pars distalis) of the pituitary gland at the base of the brain. In horses, by contrast, the disease involves the intermediate part (pars intermedia) of the pituitary. This portion of the gland is comprised of different hormone-secreting cells than are present in the anterior pituitary, accounting for a different hormone profile observed in equine Cushing’s disease as compared to humans and dogs.

In affected horses, the pars intermedia produces excessive amounts of pro-opiomelanocortin (POMC) and several hormonally-active derivatives, including adrenocorticotropic hormone (ACTH). Function of the pars intermedia is normally kept in check by dopamine-secreting nerve cells arising from the hypothalamus, a nearby part of the brain that regulates a variety of body functions such as thirst, hunger, body temperature, water balance and blood pressure. In most cases of equine Cushing’s disease, the pituitary gland is not truly neoplastic, but rather enlarged and overactive as a result of faulty regulation by the hypothalamus. In fact, the most effective available medication for the disease, pergolide, works by mimicking the inhibitory effect of hypothalamic nerve cells on the pituitary. In dogs and humans, the major hormone produced by the abnormal pituitary gland is ACTH, which stimulates the adrenal glands to produce large amounts of cortisol, a hormone usually released transiently and at low levels to help the body respond to short periods of physical, emotional or environmental stress.

Sustained secretion of excessive cortisol is responsible for many of the clinical signs of Cushing’s disease in those two species. In equine Cushing’s disease, by contrast, levels of cortisol are usually normal or even low, indicating that POMC derivatives other than ACTH play a more important role in disease development. In view of the significant biological differences between human and canine Cushing’s disease and the equine version, the name pituitary pars intermedia dysfunction (PPID) is now favored among many veterinary scientists to describe the disease in horses.

Diagnosis of Equine Cushing’s Disease

In advanced cases characterized by a long, wavy haircoat and other classical signs of Cushing’s disease, diagnosis is relatively straightforward and may not require any specialized testing. Diagnosis of early cases or those characterized by few obvious clinical signs, however, is considerably more difficult. A variety of endocrinologic tests have been promoted for this purpose, but few have been scientifically validated in horses for which the diagnosis has been subsequently confirmed by necropsy examination. In my opinion, the two most practical and accurate tests currently available are: (1) the dexamethasone suppression test, and (2) measurement of plasma ACTH concentration. The dexamethasone suppression test is an overnight protocol in which a pretreatment blood sample is collected in the late afternoon, after which a low dose of dexamethasone is administered by intramuscular injection. A second sample of blood is collected the following day at around noon and both samples are submitted for measurement of plasma cortisol. In normal horses, administration of dexamethasone stimulates a negative-feedback response that suppresses secretion of cortisol from the adrenal glands, yielding a much lower concentration in the second blood sample. In horses suffering from Cushing’s disease, however, the negative-feedback response is blunted and a lesser degree of suppression, if any, is observed.

Although it is widely considered the most accurate test currently available, the dexamethasone suppression test has two significant drawbacks that limit its use in some cases: (1) it requires two visits to the farm by the veterinarian, which increases its cost to the owner, and (2) many owners and veterinarians fear that administration of dexamethasone might increase the risk of laminitis in a horse that is already predisposed to its development. For these reasons, many veterinarians prefer an alternative test, measurement of plasma ACTH. This test 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. While useful, this test is generally considered to be somewhat less accurate than the dexamethasone suppression test, and 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.

Supplemental tests that may be useful in suspect cases include measurements of blood glucose and insulin. Many affected horses are insulin resistant and some are significantly hyperglycemic; early recognition and tracking of these abnormalities will aid in rational nutritional management of the disease and provide additional criteria by which to evaluate the horse’s response to treatment.

Treatment of Equine Cushing’s Disease

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. In both cases, management will be life-long as there is no way to reverse the disease process. 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.

Since affected horses are often insulin resistant, sweet feed and other feedstuffs high in soluble carbohydrates should be avoided in favor of diets emphasizing fiber and fat. Pelleted or extruded feeds designed specifically for older horses are strongly recommended, but those with high levels of sugar or molasses should be avoided unless needed to encourage the horse to eat.

In both mildly and severely affected horses, the importance of early diagnosis and aggressive treatment of bacterial infections cannot be overstated. Medications used to treat this condition focus on (1) reducing the amount of ACTH and other POMC derivatives secreted by the pituitary (e.g. cyproheptadine, pergolide), and/or (2) suppression of cortisol synthesis and release by the adrenal glands (e.g. trilostane). 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.

A favorable clinical response to therapy will be associated with improvement or normalization of results in the dexamethasone suppression and plasma ACTH tests. Early cases or those characterized by seasonal exacerbation of clinical signs may benefit from intermittent courses of therapy, while more advanced cases generally require continuous treatment for the life of the horse. 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, but this drug is not currently available in the United States.

In addition to these medications, a variety of nutritional supplements and alternative therapies have been advocated for the management of equine Cushing’s disease. A comprehensive review of these strategies is beyond the scope of this article, but two that may be helpful and are unlikely to pose significant risks include dietary supplementation of magnesium (to achieve a target calcium:magnesium ratio of 2:1) and chromium picolinate. These nutrients are helpful in the management of type 2 diabetes and insulin resistance in humans, and may be beneficial in equine cases complicated by insulin resistance and hyperglycemia. An herbal product prepared from chasteberry extract (Vitus agnus castus) has also been recommended for the management of equine Cushing’s disease, but a recent scientific study performed at the University of Pennsylvania’s New Bolton Center found it ineffective.

What is Equine Metabolic Syndrome?

Equine veterinarians have long recognized a related syndrome of obesity, insulin resistance and chronic laminitis affecting a somewhat younger group of adult horses. Although these horses were initially suspected to comprise a subset of equine Cushing’s disease cases, a long haircoat is not a feature of the condition and tests of pituitary function (e.g. the dexamethasone suppression test and plasma ACTH concentrations) usually yield normal results. Furthermore, affected horses do not respond to medications such as cyproheptadine and pergolide, which are frequently of benefit in Cushing’s disease.

In the past few years, veterinary scientists have begun to examine this condition more closely and researchers at the University of Missouri have advanced a new name, “metabolic syndrome.” Selection of this name was based on several apparent similarities between affected horses and the human condition known as metabolic syndrome, which is characterized by (1) obesity, especially involving accumulation of fat within the abdomen; (2) elevated blood lipids and reduced concentrations of high-density lipoprotein (so-called “good”) cholesterol; (3) insulin resistance and hyperglycemia; and (4) high blood pressure. Since affected horses are frequently obese, insulin resistant and hyperglycemic, there are clearly some legitimate points of comparison with the human disease. Significant differences are also evident, however, as affected horses usually exhibit normal blood pressure and do not consistently exhibit elevated levels of blood lipids.

The extent to which the equine and human syndromes are biologically analogous remains to be seen and will only be determined through years of careful research. Until further information is available to guide the rational selection of management strategies, it will be important to keep an open mind and focus on therapeutic measures that are truly effective in the horse and not simply assumed to be effective based on extrapolation from the human metabolic syndrome.

What Causes Equine Metabolic Syndrome?

Obesity appears to be the central problem in both humans and horses suffering from metabolic syndrome. Although body fat is commonly viewed as an inert substance that functions solely as a storage form for energy, nothing could be farther from the truth. Body fat (especially that stored within the abdomen, liver and skeletal muscle) contains cells that are very active metabolically and hormonally, and when present in excessive amounts their effects can trigger a cascade of metabolic disturbances leading to insulin resistance and persistent hyperglycemia. These abnormalities, in turn, exert a variety of deleterious effects on the cardiovascular system, cartilage and bone. One of these effects is increased synthesis and release of cortisol within the peripheral tissues of the body, which may account for the predisposition to laminitis in affected horses.

Diagnosis of Metabolic Syndrome

Metabolic syndrome is usually first recognized when chronic recurrent laminitis becomes evident in fat horses lacking other founder triggers. Affected horses are often grossly obese, with excessive accumulations of fat in the crest of the neck, over the rump and around the tail head and in the sheath of male horses. There is no single test that can offer a definitive diagnosis of metabolic syndrome at present, but diagnostic tests that are helpful in arriving at a clinical diagnosis include measurements of insulin and glucose in the blood following a period of fasting, the intravenous glucose tolerance test and tests for equine Cushing’s disease (e.g. the dexamethasone suppression test and plasma ACTH concentration).

It is particularly important to distinguish cases of metabolic syndrome from early cases of Cushing’s disease, because the latter horses can be expected to respond to therapy with pergolide while the former group probably will not. In obese horses with advanced metabolic syndrome, fasting concentrations of insulin are almost always elevated, and blood glucose concentrations are frequently elevated. In less severely affected cases, the intravenous glucose tolerance test may be needed to demonstrate insulin resistance. This test involves serial measurement of blood glucose and insulin following intravenous administration of a standard dose of glucose. In normal horses, concentrations of both insulin and glucose rise initially, but return to normal within one to two hours. Insulin resistant horses, by contrast, show greater elevations in both insulin and glucose, and these higher levels are sustained for a longer period of time before returning to baseline values.

Treatment of Metabolic Syndrome

At present, treatment strategies for equine metabolic syndrome focus almost exclusively on reversal of obesity and insulin resistance through strict dietary modification and implementation of an exercise program, if possible. Of course, horses suffering active bouts of laminitis cannot be exercised until founder has been brought under satisfactory control. The most important principle of feeding affected horses is strict limitation of soluble carbohydrate in the diet.

Nutritional requirements should be met with exclusively fiber-based feedstuffs such as good quality grass hay; 1.0 – 1.5% of bodyweight per day is a useful guideline for the amount to feed, but particularly thrifty horses may require further restriction before significant weight loss is achieved. Sources of soluble carbohydrate such grain, sweet feed, carrots, apples and fresh pasture must be eliminated completely, as even very small amounts are likely to sustain insulin resistance. If horses must be turned out onto pasture, they should be fitted with grazing muzzles that have been partially or completely taped to prevent grass intake. If greater dietary energy is required once obesity has been brought under control and an exercise program has been initiated, grass hay should be supplemented with soaked beet pulp and/or fat (vegetable oil or rice bran) rather than grain. It is likely that a variety of commercial complete feeds targeting metabolic syndrome will become available in the near future, which will greatly simplify nutritional management of affected horses and eliminate the need for feed analysis.

If horses fail to respond to dietary management despite what appears to be an appropriate diet, analysis of the forage by a nutritional laboratory such as DairyOne (http://www.dairyone.com) is strongly recommended, as the nutritional composition and soluble carbohydrate content of grass hay varies significantly, depending on species, geography and environmental conditions during growth, drying and storage. Forage analysis also permits quantification of minerals such as calcium and magnesium, which can be used to guide their rational supplementation.

A variety of supplements have been advocated in the management of equine metabolic syndrome, but there is currently little scientific evidence to support or refute their effectiveness. As with Cushing’s disease, supplementation with chromium picolinate and magnesium to achieve a dietary calcium:magnesium ratio of 2:1 is widely recommended, and equine nutritionists also recommend that dietary levels of calcium, magnesium, phosphorus, copper, zinc, manganese and selenium should be at least 150% of the levels recommended by the National Research Council. Analysis of the forage is required to balance minerals accurately in this manner. Cinnamon has recently been advocated as an adjunctive therapy; it exerts some beneficial effects humans with type 2 diabetes and is unlikely to be harmful in any way. One nutritionist has recommended administration at a rate of 4 tsp per 1000-lb horse per day. Owners of affected horses are often tempted to deliver supplements such as minerals, cinnamon, and other medications in a small amount of grain, but this practice is strongly discouraged as it may be sufficient to prevent resolution of insulin resistance. Small amounts of soaked beet pulp that have not been treated with molasses are a much better choice. In humans, exercise and dietary control are frequently supplemented with medications that interfere with cortisol synthesis and increase insulin sensitivity, but these have not yet been evaluated in equine disease. Nevertheless, such medications represent additional options for valuable horses that fail to respond to conservative management.

 

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