Cushing's Disease in Horses

It's spring, yet your aging equine has failed to shed his long, shaggy, winter coat. Furthermore, he's developed a saggy belly coupled with loss of muscle over his croup and rump. He's gulping down far more water than he used to, and his stall is always wet. All these are the classic signs of pituitary pars intermedia dysfunction (PPID), more commonly known as equine Cushing's disease or Cushing's syndrome.

Cushing's is a disorder that likely affects more than half the population of horses aged 14 years and older, according to studies performed by Frank M. Andrews, DVM, MS, Dipl. ACVIM, professor and section chief of large animal medicine, and his research team (Nicholas Frank, DVM, PhD, Dip. ACVIM, assistant professor of large animal internal medicine; Carla Som-mardahl, DVM, PhD, BS, Dipl. ACVIM, assistant professor of equine medicine and pathology; and Hugo Eiler, DVM, PhD, MS, professor in the department of comparative medicine with a specialty in physiology) at the University of Tennessee (UT) College of Veterinary Medicine. If unmanaged, affected horses are at risk for laminitis, disordered glucose homeostasis (a "pre-diabetic" condition), and hoof soreness, and they are immune-suppressed, increasing their risk of numerous infections.

Clearly, this is a disease to be taken seriously.

The term "Cushing's" is broadly used to represent any clinical situation attributed to the action of excess glucocorticoids (any group of steroid hormones involved in metabolism), such as administration of glucocorticoid drugs and adrenal gland tumors, explains Philip J. Johnson, BVSc (Hons), Dipl. ACVIM, Dipl. ECEIM, MRCVS, professor of equine internal medicine at the University of Missouri at Columbia (UMC) and spokesperson on behalf of the UMC equine endocrinology team (including Nat T. Messer IV, DVM, Dipl. ABVP, associate professor of equine medicine and surgery, and Venkataseshu Ganjam, DVM, PhD, professor of veterinary biomedical sciences). PPID speaks specifically to the common pituitary disease in horses--it is one form of Cushing's in this species, and it is by far the most common.

Although equine Cushing's resembles human Cushing's disease (hence its popular moniker) the equine form differs somewhat.

Generally, the human form is caused by a tumor in the anterior lobe of the pituitary gland; most equine cases are attributed to abnormal pituitary function in the pars intermedia, the intermediate lobe, Johnson explains.

"Equine Cushing's used to be thought to be a pituitary adenoma (a benign tumor), but more up-to-date thinking refers to it as a dysfunction," Johnson states. "The pars intermedia is especially important for herbivores: Its functions include getting ready for winter (lengthening the haircoat, adding weight before winter, increase of appetite, etc.)."

With pre-winter preparation, pituitary gland activities normally increase, but for unknown reasons in many older horses, this normal increased activity is not properly suppressed and becomes perpetual.

"The normally heightened activity coincides with the end of summer and beginning of fall; with age and onset of PPID, this normal phase fails to shut down," says Johnson.

"Aspects of Cushing's can also occur in horses that have been treated with synthetic corticosteroids such as betamethasone, dexamethasone, prednisone, triamcinolone, etc.," Johnson adds. "In rare instances, Cushing's has been attributed to cancer of the adrenal glands (as is the most common form of Cushing's in dogs)."

Haywired Hormones & Crazy Corticosteroids

Cushing's is caused by an excess of particular hormones and glucocorticoids. The term "pituitary pars intermedia dysfunction" refers to the overproduction of hormones by the pars intermedia, an anatomic region of the pituitary gland. "In a normal horse, the cells in this particular portion of the pituitary gland have very little activity," says Andrews, "That's because they are inhibited by dopamine, a neurotransmitter. But when a horse with PPID ages, the dopamine levels decrease. The inhibition is released, allowing the cells there to start secreting high levels of hormones, including adrenocorticotrophic hormone (ACTH), alpha-melanocyte stimulating hormone (MSH), corticotropin-like-intermediate peptide, and beta-endorphin."

Unregulated, these hormones cause excess production of glucocorticoids by the adrenal glands; these glucocorticoids are involved in carbohydrate, protein, and fat metabolism and are anti-inflammatory and immunosuppressive. When these hormones and corticosteroids run amuck, they cause all kinds of adverse changes.

Notes Andrews, "MSH is important for stimulating the skin cells to be the proper pigment (color), but in excess can cause dark-colored skin or the haircoat to grow at inappropriate times. ACTH stimulates production of cortisol, which is important for proper body metabolism, resisting stress, and fighting off minor illness. Too much cortisol results in a decreased immune response, leaving horses prone to pneumonia and infections of the teeth, sinuses, and hooves. Also, the horse is prone to chronic bacterial, fungal, or parasitic infections, and according to a recent article (Equine Veterinary Education 2005, vol 7 no. 4 pp 232-240), equine protozoal myeloencephalitis (EPM)."

Excess hormones also cause weakened muscles, reduction of skeletal muscle, new fat tissue arising on the neck, head, rump, and abdomen, and increased fat pads--a combination of which leads to saggy abdominal muscles, a pot-bellied appearance, and bulgy eyes. Increased thirst, resulting in increased water consumption and urinary output, is another common side effect, as is laminitis.

Risk Factors

The primary predisposing factor for a horse developing Cushing's is age. "Dopamine levels seem to decrease as horses get older," Andrews states.

A study conducted by Andrews and the research team at UT found that 56% of horses 13 years or older were affected, while Johnson reports that the disorder is "quite common" in horses older than 18 years. Although rare in horses younger than 10, Cushing's has been diagnosed in horses as young as seven, says Johnson.

There could be other predisposing or contributing factors involved, notes Johnson, including:

  • Appears to be more common in pony and Morgan breeds; 
  •  Feeding a lot of grain to inactive, obese horses and especially ponies in their younger years;
  • Tolerating an obese phenotype in inactive horses (i.e., not reducing diet or increasing activity); and
  • A potential role of oxidative stress (mediated damage) in dopamine nerves in the brains of Cushing's-affected horses.

"Recently published information suggests that although oxidative loss of some dopamine nerves is probably normal with age, it is significantly more severe in PPID-affected horses and ponies," says Johnson. "These nerves are important to suppress the pars intermedia. With both age and PPID they are lost. Dianne MacFarlane, DVM, PhD, assistant professor in the department of physiological sciences at Oklahoma State University, showed that loss of dopaminergic nerves to the pars intermedia is likely attributable to oxidative stress and may contribute to the explanation for why the pars intermedia is producing too much of the hormone products in this disease."

With respect to equine Cushing's, the cause of oxidative loss is unknown. "In a study at Cornell, a good example of a known cause of oxidative stress that was found in horses is the equine motor neuron disease that has been attributed to insufficiency of vitamin E, an important dietary antioxidant," says Johnson.

Making the Diagnosis

In absence of a definitive, universally accepted test, diagnosis is based on history, clinical signs, and/or tests that rule out some diseases and suggest Cushing's.

History--The development of infectious diseases that might not typically be seen in older horses--such as EPM--as well as those more common in aged horses (including tooth root infections and sole abscesses) are potential consequences of Cushing's, Johnson says. Also noteworthy is laminitis or founder in the absence of an initiating event (i.e., chowing down on lush pastures, feasting on large amounts of grain, or spending a lot of time on pavement), says Andrews.

A 1993 study found that 24% of Cushing's-affected horses were laminitic. That same study found a strong association with pre-diabetic state in Cushing's-affected horses (38% of affected horses had signs consistent with diabetes). Increased water intake and urinary output are also typically reported.

Clinical signs--The tell-tale shaggy haircoat is one of the most obvious signs of Cushing's. As a result of this heavy coat, many horses sweat excessively, making them more prone to skin infections and rain rot, says Andrews.

The pot-bellied appearance with or without a loss of muscle mass over the croup and rump is another sign. "Owners often report their horses have been losing weight," Andrews says, "but it's not always a true weight loss, just a redistribution of muscle mass that makes them look skinnier on the topline."

Some horses also have an enlargement of the fat pads above their eyes, giving them a bulgy-eyed look.

Tests--Routine bloodwork can reveal a stress response related to the cortisol stimulation, hyperglycemia (an increase in blood sugar), and increased liver enzymes. Although nonspecific for Cushing's, these results suggest this disease if the horse also has signs such as the wooly haircoat and laminitis with no probable cause.

"It's a bit of gray area," Andrews says, "but in horses with a long, shaggy haircoat, I usually prefer to go ahead and put the horse on a treatment as opposed to recommending further testing. But testing every horse may be an alternative to putting the horse on treatment. The problem is some tests, especially the dexamethasone suppression test, where dexamethasone is
administered, can cause some horses to founder. But in horses that have very subtle clinical signs, that don't have the classic changes in their haircoat or laminitis, weight loss or increased water intake/urine output, we recommend doing further testing."

When further testing is desired, Johnson recommends the low-dose dexamethasone suppression test (DST), whereby the veterinarian obtains a blood sample, gives an injection of dexamethasone, then measures the cortisol level in blood several hours later. In normal horses, the cortisol levels are suppressed and very low; in affected horses, the post-dexamethasone treatment cortisol levels are not suppressed. Unfortunately, the test can sometimes produce false negatives and false positives. However, Johnson says that, "False results are not common--most any test will have risks of false results. It's a good test, and has produced a small number of inaccurate diagnoses."

"In my opinion, the extent to which this test yields false results has been overstated and has led to confusion," says Johnson. "Several of the commonly used PPID tests tend to yield false positive results in normal horses and ponies during the period (late summer and early fall) when the pituitary gland is normally more active."

Andrews advocates a combined dexamethasone suppression test/thyrotropin-releasing hormone stimulation (DST/TRH) test, developed by the team at the University of Tennessee. "This test is more accurate in the diagnosis of PPID," he says,
"because it combines two independent measures--a rise in plasma cortisol concentration after TRH administration and the lack of suppression of plasma cortisol concentration after dexamethasone is administered. (This paper was presented at the 2004 AAEP Meeting in Denver, Colo., and it is currently being reviewed for publication in the Journal of Veterinary Internal Medicine.)

Other ways of testing include measuring the ACTH levels and insulin levels, neither of which, Andrews says, provide a reliable diagnosis. "ACTH is produced in two regions of the pituitary gland," he explains. "ACTH levels can be high because the horse is in a stressful environment or because the horse has PPID, so there is variable concentration, in general. Insulin levels are also variable and can be high in chubby horses."

A more accurate test, not yet available for veterinary diagnostics, could be an alpha-MSH test, says Johnson. "It simply involves taking a blood sample. Preliminary results have been very encouraging."

Dealing With It

Cushing's has no cure, but medication and management can relieve the clinical signs and side effects related to this disease.

"The most commonly prescribed drug approach is low-dose pergolide treatment, a pharmaceutical given orally every day for the remaining life of the PPID-affected animal," says Johnson. "Pergolide is a dopamine replacement agent used to treat Parkinsonism in people."

Studies show overall improvement in most areas for the majority of treated horses, although long-term efficacy is unknown.

"Another drug sometimes recommended for PPID-affected equids, but which seems to be less effective, is cyproheptadine," says Johnson. "Cyproheptadine is an antihistamine used to inhibit the serotonin hormone that stimulates the (pituitary) gland. It is often used to supplement pergolide in relatively refractory (chronic) cases of PPID."

Studies found that clinical signs were reduced in only 25% of treated horses, although cyproheptadine was more likely to show an improvement in horses with laminitis than pergolide.

A third drug that has shown promise is trilostane, which is used in Europe and Canada but is not yet available in the United States. "Trilostane inhibits the release of cortisol from the adrenal gland," says Andrews. "It works further down the line (blocking the cortisol that is a result of pituitary over-stimulation) after the hormones have already been released (as opposed to pergolide, which inhibits the release of the hormones from the pituitary). It's been used in dogs quite effectively and found to be fairly effective in horses. The data looks pretty good."

A study following horses for one or two years of trilostane treatment found that 81% of treated horses showed improvement in laminitis, and all horses had reductions in lethargy, excess thirst, and excess urination.

Besides drug therapy, management changes and supportive treatments that address side effects of Cushing's are important for helping keep the horse healthy. Due to the horse's reduced immune response, owners should maintain vaccination and deworming programs and treat infections quickly and aggressively.

Because sugar and starch can exacerbate diabetes and increase laminitis risk, limit sugar and starch intake. "Avoid treats, apples, and especially sweet feeds--anything that is high in soluble sugars," Andrews recommends. "If you have to feed a grain, choose whole oats or crimped oats, something that is relatively high in fiber and low in soluble sugars."

Avoid alfalfa hay, which is high in sugar, opting instead for grass hay. "We really recommend testing the hay for the presence of sugars; sugar content of less than 10% is ideal," says Andrews. "If the sugar content is greater than 10%, then the hay should be soaked in water prior to feeding to reduce the amount of sugars."

Limit pasture grazing, especially early in the year when the pastures have a high sugar content and in the fall on mornings after a hard, overnight freeze. That's when cool season grasses such as orchard grass, timothy, and fescue have the highest concentration of soluble sugar (up to 35%). Because some dead or dormant grass and weeds have increased amounts of carbohydrates, which can trigger laminitis in susceptible horses, they should be avoided.

Some owners and veterinarians also recommend supplementing with chromium to improve insulin effectiveness, and vitamin E, vitamin C, and zinc to improve immune function. "These supplements have not been proven to be helpful for PPID, but probably are not harmful," Andrews states.

Expectations

Johnson reports that some experts believe the prevalence of Cushing's is increasing. "This could be a function of the tendency to keep older horses longer (better nutrition and better veterinary care) or perhaps a function of increased awareness of the problem," he says.

Johnson also notes that there appears to be a rise in Cushing's in younger horses prior to the development of the classic clinical signs (poor-looking, shaggy-coated horse/pony). "Newer work points to the concept of a latent form of the disease affecting teenage horses that might be affected by some aspects of PPID (immune compromise, risk of laminitis) before they become thin and hairy," he says.

Regardless, with a significant segment of the aged equine population affected by Cushing's, odds are good that owners of older horses will encounter this disorder.

If left untreated, Cushing's horses generally experience chronic bouts of disease, a decline in health and comfort, and reduced quality of life. Attempting to handle these related, secondary problems without addressing the primary problem will not yield successful, long-term results, and ultimately will be expensive.

Horses that are correctly managed have a much brighter, healthier future. "Treated individuals will require critical monitoring throughout their lives," notes Johnson. "But most of these horses will improve and their quality of life will get better."

About the Author

Marcia King

Marcia King is an award-winning freelance writer based in Ohio who specializes in equine, canine, and feline veterinary topics. She's schooled in hunt seat, dressage, and Western pleasure.

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