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May 11, 2007

Be On The Lookout For Cushing's Disease

Early detection can make a big difference in treatment as our horses’ lifespans continue to increase.

With horses living longer and longer lives, more challenges arise in caring for the older horse, and Cushing’s disease is one of those potential problems for the senior equine.

Also called hyperpituitarism, Equine Cushing’s disease is the most common endocrine disorder in horses. It is now often called Pituitary Pars Intermedia Dysfunction in equine veterinary literature, however, since it is not the same disease as Cushing’s in humans and dogs.

This problem is most commonly seen in horses 15 years or older, due to metabolic changes in the body caused by improper pituitary function and resultant overproduction of various hormones. The pituitary gland is located at the base of the brain, where it stores and/or secretes many of the hormones that are crucial to body functions.

Amy Gill, PhD, an equine nutritionist in Kentucky, said the first change a horse owner might notice is that the horse is a little overweight. “These horses have excess fat deposited in various parts of the body, such as development of a cresty neck, fat over the tailhead, behind the elbow, and in the sheath of geldings,” said Gill. “These horses are not very metabolically active and tend to store fat. They are also slow to shed in the spring, and as the disease progresses they may not shed at all.”

In horses, the interme-diate lobe of the pituitary is controlled (inhibited in its growth and production of hormones) by dopamine.

Dopamine is a chemical in the brain produced by the hypothalamus—the part of the brain concerned with operating the autonomic nervous system, regulating body temperature, appetite and thirst, and producing various hormones that are stored in the pituitary gland.

Dopamine travels directly from the hypothalmus to the intermediate lobe of the pituitary via nerves extending from the hypothalmus. If dopamine is missing because of degeneration of these nerves, there is nothing to control (inhibit) the hormone production of the intermediate lobe of the pituitary, and it over-produces certain hormones, which leads to serious metabolic imbalances.

“Certain cells in the pituitary gland respond to dopamine, and when insufficient amounts are released from the hypothalmus, the pituitary gland becomes enlarged in response,” said Gill. “This is a very progressive disease, occurring in older horses, so there are all the elements of aging on top of it.”

The sooner it is recognized and treated, the better off the horse will be—because some of the debilitating changes can be slowed, said Gill.

We are still learning about these meta-bolic changes and the resultant problems in horses, and our understanding keeps changing. The overactive intermediate lobe of the pituitary produces too much of its hormones, including ACTH (adrenocorticotropic hormone), which stimulates the adrenal glands to enlarge and overproduce cortisol—and the excess cortisol in the body is part of what creates the various problems that we’ve termed Cushing’s disease.

There are many clinical signs of this disease, including weight loss and loss of muscle mass, pot belly, being slow to shed the winter coat, and eventually a long, curly coat that doesn’t shed at all. Horses with Cushing’s are prone to laminitis and have trouble fighting off infection, due to the high levels of cortisol in the body.

Understanding The Causes

Dianne McFarlane, DVM, PhD, assistant professor, department of Physiological Sciences, Oklahoma State University, has been studying this disease for years, and it was the focus of her doctoral study. Much of her research has been aimed at understanding the cause.

“I have been looking at this in a number of different ways. One thing that was already known about Cushing’s is that it appeared to be most likely the result of loss of dopamine in the pituitary gland,” she said.

If dopamine isn’t there, the pituitary enlarges and creates an excess of other hormones. It was shown in the late 1980s that dopamine is decreased in horses with Cushing’s.

“Dopamine is also the neuro-transmitter [chemical] that is missing in Parkinson’s disease, a neurodegenerative disease in aged humans. So we looked to see if the neurons that control the part of the pituitary that becomes abnormal in Equine Cush-ing’s disease showed similar changes to those that become abnormal in Parkinson’s disease. All our evidence suggests that Equine Cushing’s is also a neurodegenerative disease, and similar toxic events are occurring,” said McFarlane.

The neurons in Parkinson’s disease that degenerate get damaged by oxidative stress (chemical changes due to oxidation). “This is thought to be part of the reason these neurons become dysfunctional,” added McFarlane. “Cushing’s horses also show oxidative stress of the neurons; a similar kind of age-related damage is occurring.” This may be one reason we see Cushing’s in older horses.

In Parkinson’s disease, a second event that causes the neurons to degenerate is accumulation of abnormal proteins, making the neurons unhealthy and leading ultimately to their degeneration.

“I looked for this particular protein [known as synuclien] in horses with Cushing’s,” said McFarlane. “That protein is indeed increased in horses with Cushing’s. So it looks like the same type of neurons—dopamine producing neurons—are being targeted, and maybe for some of the same  reasons; some of the same age-related events are occurring.”

Although both of these diseases affect dopamine producing neurons, they are anatomically different neurons. “In horses, these neurons control the pituitary, and when those neurons are gone, the pituitary gland is able to enlarge and over-produce hormones. In the human, by contrast, those neurons are in the brain and they control movement, so when they are lost you have movement disorder," McFarlane said.

There are three lobes in the pituitary. The pars intermedia (the intermediate lobe) is typically controlled by dopamine. “When those neurons aren’t there, the dopamine decreases,” McFarlane said. “Since dopamine  is what turns off that lobe (controlling the production of certain hormones), the pars intermedia grows and makes lots of hormones.”

This enlargement of the intermediate lobe of the pituitary is often called a tumor, but people tend to think of a “tumor” as cancer, which this is not. That portion of the pituitary gland merely grows because the factor that is supposed to turn it off (dopamine) isn’t there anymore.

“The cells still function normally; they are simply functioning too much and making extra hormones,” said McFarlane.

The intermediate lobe produces ACTH (adrenocorticotropic hormone), which stimulates the adrenal glands to enlarge and overproduce cortisol.

“But that lobe of the pituitary also produces other hormones that may be more important, such as MSH (melanocyte-stimulating hormone). Not all Cushing’s horses have large adrenal glands,” she said. “The pars intermedia makes several hormones, the primary ones being MSH and beta endorphin, along with the ACTH, which goes to the adrenal glands to increase cortisol production. Through some combination of these hormones, this overproduction leads to signs of disease.”

Once the horse is affected, the adrenal glands may start to enlarge, from all the ACTH. “Cushing’s disease, per se, involves an increase in cortisol. But the ACTH [that stimulates the cortisol production] is not the primary product of the intermediate lobe of the pituitary,” explained McFarlane.

Diagnosing The Problem

Horse owners should be aware of early signs of the disease, such as weight loss. “Old horses in general tend to lose muscle mass, but these horses tend to lose it more markedly; they start to lose the shape of the topline and get a pot belly appearance. They may also be slow to shed in the spring, and retain some of the longer guard hairs,” McFarlane said.

If the horse can be tested and diagnosed then, then early treatment and management can prevent some of the more adverse effects. “It is important to recognize early on that a horse is developing the disease, rather than waiting until he has the typical long, curly hair coat,” said McFarlane.

Laminitis may also be a sign. If a horse 15 years or older develops laminitis for no apparent reason, it is important to test the horse, to see whether or not he has PPID. “Studies have shown that about half the adult horses that founder for no apparent reason have evidence of Cushing’s disease. Sometimes this is the only sign. The hair coat and body condition are fine, but the horse founders. This could be the first sign that the pituitary has a problem,” said McFarlane.

“As we try to identify the disease earlier, it is important to remember that some of the Cushing’s change will not have taken place yet, in these early stages. Only one third of the horses in one of the studies that was done actually had enlarged adrenal glands. While this can occur, it does not always occur. What always occurs in PPID is that there is an increase in size in the intermediate lobe of the pituitary, and if horses have this disease they have an increase in production of intermediate lobe hormones,” said McFarlane.

As horses get older, it’s wise to check the ACTH levels or do a dexamethasone sup-pression test. ACTH is measured on a blood sample, and there is no risk. This test should be part of a routine check-up.

“Often the pattern in an individual animal is more revealing than a single sample. You can look for trends. Part of a healthy aged-horse check is checking ACTH concentration, which is an indicator of pituitary function,” said McFarlane.

There are a number of tests that are more specific for Cushings, but the one that is done routinely is the dexamethasone suppression test. “This is a two-day test and a bit more expensive because it involves two visits from your vet (to see if plasma cortisol concentration suppresses in response to the administration of dexamethasone). This test might be a little more specific, but for just routine screening of an older horse, I think the ACTH test is appropriate. Whether you do it once or twice a year would be up to your veterinarian, based on your specific situation,” said McFarlane.

The main thing she suggests is not to do it in the fall, because the horse’s hormones are changing then, preparing the body for winter. “We’ve measured their pituitary hormones, and in the horses we’ve measured, those hormones all go up in the fall. The body changes metabolically and you can get some false results if you test in the fall,” she said.

Managing The Disease

Pergolide, a dopamine agonist, is most often used in treatment, to replace the missing dopamine. “The reason it works is that the cells in the pituitary are still normal; they are just missing their dopamine—at least early on in the disease,” said McFarlane.

There are some other treatments, but pergolide is recommended most, because it’s the most effective. “Cost of treatment will vary, depending on where you buy the drug, but it’s much more reasonable than it was earlier,” she added.

Cyproheptadine was the first drug used for this disease. “It was quite cheap in comparison,” McFarlane said. “Pergolide was better, but it was so expensive that a lot of people didn’t use it. But now pergolide is less expensive than cyproheptadine, so there is really no reason not to use it as a first choice.”

Not enough research has been done yet to know the long-term effects of early treatment—whether the overgrowth of the pituitary can be turned back. “We also don’t know if we can prevent any further progression of abnormal growth, but in theory it should, if the treatment dose is optimal. We just haven’t been able to document that, yet. No one has actually looked at this to see if the size does not increase, over time, with treatment,” she said.

A horse being treated with pergolide may not have as many complications (laminitis, infection) as an untreated horse.

“I know of old horses that have been on the drug for four years or more and died from something else rather than this disease. It does seem possible that they can do quite well with treatment,” said McFarlane.

If you can avoid the effects of the disease by getting the hormones back under control, it appears that you can add quite a bit of time and quality of life for the older horse.

McFarlane emphasized the importance of good health care to go along with the drug treatment: “It is really important to be sure you keep up good parasite control, because these horses are much more susceptible to parasites. They should be dewormed frequently and have a fecal egg count done to make sure the program is working for them. They need good nutritional care, as most older horses do, and need their feet well cared for,” she said.

Since these horses have problems regulating metabolism, keeping the horse on a low grain ration is also advisable. “The senior [feed] products are good, because they tend to be higher in fat and protein, giving calories in other ways than sugar and soluble starch. I suggest that when giving treats, owners not give anything with a lot of molasses. Proper diet should help improve use of glucose and avoid the insulin resistance that can lead to other problems such as drinking and urinating excessively,” she said.

Gill said you want to initially reduce the calorie content of the diet, if the horse is overweight and storing fat, but make sure the diet is still balanced—with enough good quality protein, amino acids, vitamins and minerals. “For the Cushing’s horse, choose a forage that’s low in fructans, sugar and starch, and use some type of protein/vitamin/mineral supplement to make sure the horse has a balanced diet that’s low in calories,” said Gill.

“Over time, however, the horse will lose weight because Cushing’s is a catabolic disease [metabolizing tissue], and these horses lose muscle mass,” she said. “They start to metabolize protein in the body and use up their muscle tissue. This is why it becomes crucial that the diet be well fortified with quality protein sources such a soybean meal which supplies the proper amino acids in correct amount—so the horse can re-build new proteins such as muscle tissue.”

Since these horses tend to suffer from laminitis when allowed free choice pasture (because of the fructans and high calories) they should be limited in grazing time or wear a grazing muzzle.

“The best option would be a grazing muzzle so they can still be out at pasture leading a normal life,” said Gill. Confinement leads to stress, and stress is bad for horses with Cushings because it increases the amount of cortisol produced from the adrenal glands.

Even when the horse is losing weight, you must make sure the diet is low in sugar and soluble starch, with extra calories coming from fat and fiber, said Gill. “You still have to monitor pasture intake because of the possibility of ingesting fructans in grass. These horses are always predisposed to laminitis; they all end up with laminitis if they go untreated.”

McFarlane pointed out that 10 years ago, the disease wasn’t considered common. “But at that time people were only looking for horses that had the long, curly hair coat and other signs of advanced problems,” she said.

More recent studies that have examined older horses’ pituitary glands at necropsy show that this problem may be as common as affecting one fourth of all horses that reach their 20s; they have this disease to some degree, though it may not be as advanced as some cases.

Many horses today are living longer, and people are taking good care of them, so this disease is coming more to our attention.

“It’s very common in older horses, so I think it’s important to be on the lookout for it, aware of early signs. The horses in my studies tend to be in their late 20s and early 30s.

Ten years ago, the studies of older horses were using horses that were closer to 20,” said McFarlane.

Horse owners are more able to manage and treat an older horse now, to help assure many more years of usefulness or comfortable retirement.

Similar Metabolic Problems

There are several metabolic conditions (Cushing’s, equine metabolic syndrome and insulin resistance) that people tend to lump together, said Amy Gill, an equine nutritionist in Kentucky. But they are very different disorders, all caused by different things but very similar in their management (proper diet).

“Controlling caloric intake and making sure the ration is balanced without excessive calories, starch and sugar, is most important,” Gill said.

Cushing’s generally doesn’t affect horses until they reach the age of 15 or older.  “If a younger horse shows these symptoms—overweight, cresty neck, sluggishness, etc.—you would suspect equine metabolic syndrome instead.  This disease also creates too much cortisol, but it’s actually coming from the fat cells in the abdomen and the bowel, rather than from the adrenal glands.

“There’s an enzyme coming from those fat cells, changing inactive cortisone into cortisol.  That’s why these particular horses have elevated cortisol; it’s not from an enlargement in the pituitary,” added Gill.  The cortisol in this instance is coming from too much fat deposited in the body.

 
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