The Latest on Cushing's Disease

Recent research and treatment options available make it easier than ever to keep horses with Cushing's Syndrome, now callled PPID, healthy and comfortable in their senior years. By Joanne Meszoly for EQUUS magazine.
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More horses than ever are developing conditions that used to be considered rare complications of old age. And, in part, that's a good thing.

Whereas once the equine lifespan topped off in the late teens, advances in medical care, parasite control, pharmaceuticals and nutrition now make unprecedented longevity possible. The price, of course, is an upswing in the incidence of aging-related problems. And Cushing's disease leads that list.

The basic facts about Cushing's have been known practically since the disorder was first identified some 70 years ago: Amalfunction of the pituitarygland, the marble-size organ at the base of the brain, causes the release of excessive levels of the hormone adrenocorticotropin (ACTH). This, in turn, triggers the adrenal gland to increase the production of cortisol, and the resulting hormonal imbalances lead to the hallmarks of Cushing's: a long, shaggy hair coat, loss of muscle mass, laminitis and
susceptibility to infection.

No one knows for sure how many aged horses are affected by pituitary dysfunction, but itwas the most common specific diagnosis in a 2003 study of 467 horses aged 20 or older admittedto the Tufts University clinic. In related research, a survey of 218 horse owners revealed that 30 percent of their horses had signs associated with Cushing's even though only 8 percent of the cases had been diagnosed.

But research has focused on far more than the incidence of Cushing's.

Over the past decade or so, studies have illuminated the complex processes underlying the disorder, and along the way several false assumptions have fallen by the wayside. As a result, Cushing's horses today have a better prognosis than ever before, and with proper treatment and management they can enjoy long and productive lives.

Why the New Name?
Originally, equine Cushing's shared the name of similar pituitary disorders in people and dogs,which are both known as Cushing's syndrome. Nowadays, however, experts prefer to call the equine condition "pituitary pars intermedia dysfunction" (PPID),which more accurately reflects its nature. In horses, the intermediate lobe of the pituitary gland is affected; in human and canine Cushing's, the anterior lobe malfunctions.

Dianne McFarlane, DVM, PhD, assistant professor at Oklahoma State University, has done pioneering research on PPID. In a recent study, McFarlane's team investigated the role of the hypothalamus, the portion of the brain connected to the pituitary by neurons.

Although the pituitary is often referred to as the "master gland" because it controls the endocrine system, the hypothalamus actually regulates the pituitary's release of hormones. In recent studies, McFarlane has found that PPID begins when hypothalamic neurons degenerate and produce less dopamine, the substance that restrains pituitary secretion.

"This has been suggested in literature since the 1980s; recently we were able to confirm this finding," she says. Without a steady supply of dopamine, the pituitary cells secrete uncontrolled levels of hormones, including ACTH, and the adrenal gland responds by releasing high levels of cortisol.

ACTH plays an important role in PPID, says McFarlane, but it's likely that a combination of hormones are responsible for the variable signs of illness. "We don't know precisely how each hormone is involved," she says. "It's possible, for example, that another hormone known as a-MSH is responsible for a decreased immune response and a susceptibility to infection, butwe don't know for sure. The clinical signs probably result from a combination of these different hormones."

A Similar Disorder
Although research findings show that PPID is different from Cushing's in people, they also suggest a similarity to another human illness: Parkinson's, a neurologic disease believed to be caused by deterioration of the brain cells that produce dopamine. "PPID and Parkinson's are both associated with the degeneration of dopamine neurons," says McFarlane, but they are not identicall--different neurons are affected with Parkinson's. What causes the degeneration is unclear. A leading theory holds that the neurons are damaged by free radicals, byproducts of the oxidative processes of metabolism that are known to damage cells, proteins and DNA by altering their chemical structure.

"It's possible that horses who get this disease are more susceptible to oxidative stress in this part of the brain," says Harold Schott, DVM, PhD, an associate professor at Michigan State Universitywho published a study called "The Michigan Cushing's Project" in 2001. McFarlane agrees: "We haven't proven oxidative stress causes PPID, but there's been a strong association of oxidative stress to the neurons in these horses compared to normal aged horses."

Also under investigation are the physical changes within the pituitary gland. What was once thought to be a tumor of the pituitary is now better described as an enlargement, although a collection of benign tumors called adenomas may also contribute to PPID. "In severe cases, part of the pituitary can become enlarged and compress the other lobes--even the hypothalamus--and you can lose function of those
structures,which also can contribute to clinical signs," says McFarlane.

Diagnostic Options
Many horses with PPID have a distinctive appearance. "You can look at a horse who has an unnaturally shaggy hair coat and figure its probably PPID, but we encourage owners to get a good veterinary examination and evaluation, including bloodwork," says Schott. Three tests are used to investigate whether a horse has PPID:

Most diagnoses are made based on the dexamethasone suppression test. On the first day, blood is drawn and the horse is given an injection of dexamethasone, a synthetic form of cortisol. The next day, a second blood sample is drawn and both are tested to measure levels of natural cortisol. In a healthy horse, the dexamethasone injection suppresses the release of cortisol, and the second blood sample
shows lower levels of the hormone. In a horse with PPID, cortisol levels are unaffected by the dexamethasone.

One major concern with the test is the possibility that dexamethasone may trigger laminitis in some animals. Schott says this risk is probably smaller than most people perceive; in a study with 18 horses at Michigan State University, no clinical signs of laminitis were induced by the dexamethasone suppression test.

Another common test looks for elevated levels of ACTH in the horse's plasma. This plasma ACTH test has no association with laminitis and requires just one blood sample, but it is considered less accurate because a healthy horse's ACTH levels fluctuate with the time of day or seasonal changes.

"You can measure levels at 10 a.m. and come back an hour later and get a completely different reading," explains Schott. "This is because ACTH is released in a pulse fashion when sending signals to other glands." Seasonal influences such as shorter days signal the pituitary gland to secrete more hormones to store fat, halt the release of reproductive hormones and otherwise prepare for wintermonths.

"Because ACTH is elevated in normal horses, we try not to test between August and November," says Schott.

The newest option for diagnosing PPID combines the dexamethasone suppression test with a similar analysis using thyrotropin-releasing hormone (TRH). In addition to analyzing cortisol levels after a dexamethasone injection, this test measures levels of the hormone after TRH is introduced--in a normal horse cortisol levels will drop in response. The test is less frequently used because it requires additional sampling and is more costly, but researchers at the University of Tennessee found that it is very accurate.

The Right Medicine
PPID cannot be cured, but its effects can be controlled with medication and management.

The drug most commonly used to treat horses with PPID is pergolide mesylate, a dopamine agonist that helps to regulate the pituitary gland. Originally developed to treat Parkinson's disease, pergolide is considered an off-label medication for horses, meaning it is prescribed to treat conditions for which it was not approved by the Food and Drug Administration (FDA).

In the past, the biggest drawback to pergolide treatment was the expense; on average it costs about $3 to $4 a day for brand name (Permax) pills or $1 to $2 a day for the generic compounded product.

However, for a brief period this spring, the future availability of pergolide in any form was uncertain. In March 2007, the FDA ordered a recall of pergolide after studies showed that 22 percent of Parkinson's patients taking the drug developed heart valve damage. The recall not only meant that Permax would be unavailable, but it also called into question the legality of obtaining the drug through compounding pharmacies,which can legally produce only formulations of products approved by the FDA.

In response to a petition from concerned horse owners as well as pressure from equine veterinary groups, the FDA in May 2007 announced that, in essence, it would allow the continued compounding of pergolide so long as certain criteria were met: For example, the drug can be provided only with a valid prescription for an individual animal, and bulk ingredients must be clearly labeled "for veterinary
use only."

Horses treated with pergolide generally remain on the drug for life. According to McFarlane, veterinarians have discussed whether horses could be treated with pergolide in the summer and fall, then weaned off in the winter and spring when hormone levels are naturally lower. "But," she says, "there hasn't been enough testing done to know how effective this protocol is."

The serotonin blocker cyproheptadine is an alternative treatment for PPID, but studies suggest that it is not as effective as pergolide in controlling clinical signs.

Management Measures
In addition to drug treatment, simple adjustments to your management routine can help keep a PPID horse healthy and comfortable:

Diet. A low-carbohydrate/high-fat diet can help counter the effects of muscle loss while reducing the risk of insulin resistance, a related syndrome that can occur in some PPID horses. Consult with your veterinarian or equine nutritionist about the benefits of eliminating grain and replacing it with pellets, a low-carb senior feed or molasses-free beet pulp. Also, limit the horse's access to lush pasture grasses; grass hays are a safer option than legumes (clover, alfalfa) because they contain fewer carbohydrates.

Supplements. Although the effectiveness of antioxidant supplements in preventing the neural degeneration underlying PPID is still under study, McFarlane says supplementation is necessary for horses with diets deficient in selenium, a trace mineral that prevents cellular damage from free radicals. "Horses get selenium from forage, so if there's a deficiency in the soil, you'll want to supplement with it," she says. "But it's not something to just add arbitrarily. It can be toxic in high levels." McFarlane recommends testing selenium levels in forage as well as in affected horses through bloodwork.

Parasite control. Because their immune systems are compromised, PPID horses are extremely susceptible to internal parasites, says McFarlane. Discuss an optimum deworming program with your veterinarian and test its effectiveness by taking periodic fecal-egg counts.

Dental care. PPID increases a horse's risk for periodontal disease and sinus infections, so frequent dental checkups are recommended.

Farriery. Hoof abscesses and laminitis occurmore frequently in PPID horses,which makes regular farriery care vital. Also keep a close eye on your horse's hooves and gait, looking for flares at the toes or shortened strides at the walk and trot.

Grooming. A body clip will help keep shaggy-coated PPID horses cool in warm and/or humid weather.

To gauge your horse's response to therapy and monitor his overall condition, ask your veterinarian to check his ACTH level at least once a year, preferably in the spring. In fact, says McFarlane, even if your aging horse doesn't have PPID it's wise to have a full panel of routine bloodwork done annually to screen for abnormal findings. "It's nice to have reference values that we know are specific to that individual animal," she says. "It's then easier to find out if levels are changing and the horse requires further care or medication."

But even if your horse has PPID, she says, there are reasons for optimism. "We're fortunate that we have a very good treatment for PPID that targets the source of the problem. We don't know which hormones or which combinations affect the horse, but we're able to regulate the pituitary so that all of the hormones are close to where they should be. That's our therapeutic goal."

This article originally appeared in the August 2007 issue of EQUUS magazine.

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