The Horse Interactive -- Features, Feb. 1997: Cushings DiseaseHello everyone - Here's a great article on Cushing's that explains some of our recent comments - how cypro and pergolide works and about why pergolide used to be a problem with laminitis. I have read it many times and still learn something new each time. Karen is updating this article for Equus and hopefully it will be out soon. (I'm sure some of you have found and read this before - sorry for the repeat.)
Take care, Makyla & 4-legged friends
February 1997
Cushing's Syndrome
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© 1997, Karen Briggs
Nan Rawlins
If Cushingoid symptoms are caught early, treatment can be extremely successful.
To many horse owners, it's just "old horse disease," and it's an affliction with a number of names--pituitary pars intermedia dysfunction (PPID), hyperadrenocorticism, ECD (equine Cushing's disease), and, most commonly, Cushing's syndrome. It can appear in horses as young as seven, but is most frequently found in horses which are geriatric. Whatever the name, it's becoming more common in equine populations, due in part to advances in veterinary care and nutrition that help horses lead longer lives.
Equine victims of Cushing's syndrome (named for turn-of-the-century American surgeon Harvey Cushing, who researched the human brain and pituitary gland) are easily recognized by a heavy, coarse, wavy hair coat that fails to shed in the summer (occurring in more than 85% of cases). Even before that characteristic hair coat appears, a horse with Cushing's syndrome might demonstrate a host of other symptoms that are sometimes overlooked or chalked up to old age.
The first symptom to appear generally is polydipsia (excessive thirst) coupled with polyuria (excessive urination)--which might go unnoticed if the animal is kept outside rather than stabled. Horses might go through as much as 80 liters of water a day instead of the normal 20 to 30 liters. Other symptoms can include a swaybacked or potbellied appearance, increased appetite (generally with no corresponding weight gain), loss of muscle over the topline, and chronic laminitis. Horses with Cushing's syndrome become more susceptible to diseases and infections due to a compromised immune system. They frequently suffer bouts of respiratory disease, skin infections, foot abscesses, buccal (mouth) ulcers and periodontal disease, and even infections of the tendon sheath or joints. Wound healing is also noticeably slowed.
Less commonly, a mare's estrous cycle might be suppressed or abnormal, and she might even produce milk without being pregnant. Some horses become lethargic or depressed, and they frequently acquire an unhealthy gutload of internal parasites, including ascarids (pinworms), which are comparatively rare in adult horses.
At the cellular level, there's even more going on. Blood tests often will detect high blood sugar and high blood fats, anemia, reduced lymphocyte counts, and electrolyte derangements.
When Hormones Run Wild
What's at the heart of a case of Cushing's syndrome? Well, in horses, it's a benign tumor of the pituitary gland, called a pars intermedia pituitary adenoma. The pituitary, a marble-sized gland at the base of the brain, is responsible for the regulation of almost all of the body's endocrine systems--in fact, it's sometimes referred to as the "master gland."
Frank Andrews, DVM, an associate professor of equine medicine at the University of Tennessee's College of Veterinary Medicine, notes, "This particular disease is a little different in horses than Cushing's in dogs or humans. In horses, Cushing's is associated exclusively with tumors of the pars intermedia (or intermediate lobe) section of the pituitary--an area that is well-developed in horses, but not in dogs and cats. In dogs and humans, Cushing's is usually associated either with tumors of the pars dystalis area of the pituitary, or with a tumor of the adrenal glands. In horses, adrenal tumors aren't seen."
Though no one has established just why horses don't seem to get adrenal tumors (or why they do get pituitary adenomas), it does at least simplify the issues somewhat. Diagnosis of Cushing's syndrome in dogs, for example, begins with a battery of tests to determine whether it's the adrenal gland (sometimes operable) or the pituitary gland that's the culprit--and the results are not always conclusive.
Pituitary adenomas are classified as benign tumors, though Andrews points out that any tumor located in or near the brain is an "active" tumor. The typical tumor that causes Cushing's is slow growing, and on necropsy might be large and easily identified, or very small; the size seems to have very little to do with its effect, as some small tumors have been noted to have "profound effects," while larger masses might be non-functional.
Over the course of months or years, the tumor can grow to the point where it puts pressure on the adjacent hypothalamus, which controls thermoregulation (among other things); some researchers feel this might be the reason behind the growth of the characteristic heavy hair coat. The tumor also, eventually, might press on the optic nerve, which lies close by the pituitary, causing blindness. Other symptoms of very advanced Cushing's include head-tilting and dementia.
Pituitary adenomas are "functional" tumors, a description indicating that they secrete hormones. The secretion of these hormones is key to all of the problems that arise in a Cushing's horse's system. It interferes with normal pituitary function and sets the whole endocrine system out of whack. Here's what happens.
A Wrench In The Works
The process begins when melantrope cells in the pars intermedia area of the pituitary become overgrown and overactive. They produce excess quantities of a peptide called pro-opiolipomelanocortin (POLMC, mercifully, for short). Peptides are simple compounds that act on specific target tissues. POLMC influences the adrenal glands, perched on top of the kidneys, to produce an important hormone called cortisol, which:
a.. maintains blood pressure and cardiac function;
b.. reduces the immune system's inflammatory response;
c.. regulates nerve tissue function, muscle tone, and connective tissue repair;
d.. balances the effects of insulin in breaking down sugar for energy;
e.. regulates the metabolism of carbohydrates, proteins, and fats;
f.. helps the body respond to stress.
Under normal circumstances, cortisol production is balanced by the hormone CRH (corticotropin releasing hormone) from the hypothalamus, which stimulates ACTH (adrenocorticotropic hormone) from the pituitary. ACTH in turn normally stimulates the release of cortisol. When there is enough cortisol in the bloodstream, ACTH and CRH secretion "backs off." Pituitary adenomas, however, essentially put a wrench in the works and allow rampant secretion of POLMC. As a result, the levels of cortisol in the horse's system can rise dramatically, causing the symptoms of Cushing's.
In humans, Cushing's syndrome is sometimes correctable by surgery or radiation treatments. In dogs, it might be operable if the symptoms arise from a tumor in the adrenal glands rather than the pituitary. But in horses, surgery, unfortunately, is not an option. Not only is the pituitary gland just about as inaccessible as it could get, but the typical horse with a pituitary adenoma is more than 20 years old, already has a compromised immune system, and is a very poor bet for surviving a general anaesthetic. Therefore, drug therapies are the treatment of choice for equine Cushing's.
Diagnosing Cushing's
"The clinical signs of (pituitary adenomas) are pretty obvious in horses," says Andrews. "Some practitioners may just start horses on drug treatment (without any diagnostic tests) if the signs are definitive."
Diagnostic tests do, however, exist for Cushing's syndrome; in fact, an entire battery of tests has been used over the past three decades. Jill Beech, VMD, of the University of Pennsylvania's New Bolton Center, has described these tests in a series of papers on pituitary adenomas in horses, and suggests that practitioners begin with a CBC (complete blood count) and a blood test to identify hyperglycemia--affected horses show blood sugar levels over 120 mg per dl, and sometimes even greater than 300 mg per dl. Urinalysis also can be performed to detect glucosuria and ketonuria (abnormally high levels of glucose and ketones in the urine). A repeat blood test to establish the consistency of high blood sugar might prompt a veterinarian to perform more specific, hormone-related tests to confirm the diagnosis of Cushing's syndrome.
One of the two most commonly used diagnostics is the dexamethasone suppression test (DST). Dexamethasone, a glucocorticoid anti-inflammatory similar to natural cortisol, is injected intramuscularly into the horse after a baseline blood sample has been drawn. Nineteen to 24 hours later, another blood sample is drawn and tested for cortisol levels. A drop in cortisol level is the normal response (indicating that ACTH-producing cells in the pituitary have responded to normal feedback mechanisms). In a Cushing's horse, however, the ACTH production will throttle back, but the diseased melantrope cells will continue to produce peptides, creating a response of elevated cortisol.
The other test, ACTH stimulation, involves administering 1 unit per kg of ACTH gel, intramuscularly or intravenously, and measuring cortisol levels in the blood four to eight hours later. A normal response is a two- to three-fold increase in cortisol, but a Cushingoid horse might show a four-fold rise.
Insulin tolerance tests (where crystalline insulin is injected intravenously and the glucose level response in the blood is measured at intervals after administration) can also help in diagnosing Cushing's syndrome; however, most practitioners are cautious about using this diagnostic because pony breeds are known to be less sensitive to insulin, and even less so if they are obese or have chronic laminitis.
The problem with all of these tests, says Andrews, is that "the values of normal horses may overlap considerably with the values of horses with pituitary tumors. There's a wide range of variation--in my experience, up to a 30% overlap."
To address this problem, Andrews and a team of researchers at the University of Tennessee recently developed a new, combined diagnostic test to identify more definitively Cushing's syndrome in horses. Presented at the 1996 International Society of Endocrinology Congress in San Francisco, the test combines a dexamethasone suppression test with a TRH (thyroid stimulating hormone release) test.
Andrews explains: "The veterinarian administers the dexamethasone first and measures blood cortisol levels three hours later. Just after drawing blood, he administers the TRH, which stimulates the tumor, if present, to produce cortisol.
"Then blood is drawn at 30-minute intervals, up to two hours later, and the cortisol levels are graphed. If there's a tumor present, you'll see a 'spike' in the cortisol levels 30 to 45 minutes after the TRH.
"The advantage of this test is there's no overlap in the numbers. The peak value shows in all horses with pituitary adenomas, and we've found it's pretty definitive."
Even the cost of this test is reasonable--Andrews estimates the average owner would pay between $60 and $80.
Turning Back The Clock
Once a definitive diagnosis of Cushing's syndrome has been made, it's time to consider treatment. The good news is that if the symptoms are caught early, treatment can be extremely successful, essentially returning the horse to normal health for several years.
"As diseases go," says Andrews, "Cushing's is fairly easy to manage. Horses with advanced symptoms like immunosuppression or recurrent founder may be more difficult to bring back, but that's more because of those secondary symptoms."
There are three drugs that have been used with success to reverse some or all of the symptoms of Cushing's. All three operate on similar principles--they are either dopamine agonists, or serotonin antagonists. Dopamine and serotonin are two naturally occurring neurotransmitters in the brain, which help regulate the secretion of peptides like POLMC. One of dopamine's functions is to inhibit melantrope cells in the pituitary; when dopamine levels are low, the melantrope cells become overactive. Serotonin performs the opposing function, stimulating the melantrope cells. Drugs that mimic the action of these neurotransmitters can, in essence, achieve the same aim from two different angles.
Bromocriptine mesylate (trade name Parlodel), a dopamine agonist, is the "original" drug used to treat Cushing's syndrome. It mimics dopamine to inhibit overproduction of activating peptides, and it has been shown to mildly decrease plasma ACTH and cortisol levels. There is a problem with the drug, however, which limits its use--in an oral form, its absorption is poor, and the IM injectible form, which has to be administered twice a day, is impractical for long-term use. It is also reported to have a number of side effects.
A more successful choice is the serotonin blocker cyproheptadine. Available in an easily absorbed tablet form, cyproheptadine has been used to treat Cushingoid horses for a number of years. Andrews says, "In my practice, it's the drug of choice. It's fairly inexpensive, at $30 to $40 for 1,000 tablets, and I find 60-70% of Cushing's horses respond favorably to it.
"It's an interesting drug," he continues, "because you start on a dose level (usually about 0.13 mg/kg, or about 58 mg for an average 440 kg horse) and increase it until you see the clinical signs of Cushing's begin to improve."
The simplest way to do this is by monitoring the horse's water intake over a 24-hour period, easily done as long as the horse is kept stabled and is watered by bucket, rather than an automatic waterer. The drug dosage is slowly increased until the horse's drinking returns to normal levels (about six to eight weeks). During this time, owners commonly report that other symptoms, such as the heavy hair coat and pot belly, disappear as well, and their horses regain their vigor and muscle tone.
"Once the horse has maintained a level of improvement for a month, we slowly decrease the dosage of cyproheptadine until we've got it down to a maintenance level," says Andrews. "Sometimes, we can get the horse down to a dose every other day, or even only once or twice a week. Frequently the horse is on medication for life, but he can function normally for a number of years."
Andrews does report that a few horses respond unfavorably to cyproheptadine. Its action as a serotonin antagonist can have an effect on other systems in the brain, and the development of an aggressive temperament is a rare, but documented, side effect.
"Fortunately," he notes, "if one drug doesn't work, there are other drugs that are sufficiently different that you can try
another."
The "another" he refers to is pergolide mesylate (trade name Permax), a dopamine agonist that recently has become a very viable treatment alternative. Originally a drug used to treat human Parkinson's disease, pergolide had been considered as a treatment for equine Cushing's in the past, but at dosages comparable to those used for cyproheptadine, it had an intense vasoconstricting effect that practitioners felt could worsen the chronic laminitis some of their patients already were suffering.
In 1993, Montana equine veterinarian Duncan Peters, DVM, tried pergolide on a 28-year-old Cushingoid horse at a "somewhat arbitrary dosage" that was a fraction of the usual human dose (about 0.75 mg a day for a 440 kg horse, about one-sixth of what a human would receive) and found he could get a good response without the risk of exacerbating founder. He followed this result with a study of nine horses and ponies and saw significant improvement with the drug in eight of the nine cases, with no remarkable side effects. The average response time was about 22 days, and improvement continued until the horses stabilized at an average time period of 21 weeks. Since then, pergolide has become well accepted by veterinarians as a treatment option.
Like cyproheptadine, pergolide can be administered orally, as a tasteless tablet that can be crushed and mixed with a little molasses. The cost is a little higher than cyproheptadine (an estimated $75-90 a month), but Andrews notes that once you establish a maintenance dose, you might be able to use less of the drug, and reduce your costs to about $1 a day.
When deciding whether to medicate a Cushing's horse, owners must take into account the cost and the condition of the horse in question. Horses whose symptoms are fairly mild definitely respond best to the medication, and might have their useful lives extended by a number of years; but a horse which is already suffering from chronic founder and recurrent infections might derive limited benefit. It is worth remembering that none of these drug therapies addresses the root of the problem, the pituitary tumor itself. They merely treat the symptoms, and the tumor will continue to grow until at last it compromises the horse's quality of life enough that euthanasia is the kindest answer. Methods of removing or stopping the growth of pituitary adenomas are still, unfortunately, in the future of veterinary medicine.
Maintaining a horse with Cushing's syndrome also requires an owner to focus on careful health management and preventative care. Particular care should be paid to diet, vaccinations, deworming, and teeth maintenance, as well as prompt response to infections. Some Cushingoid horses might require body-clipping in the summer months, and because they have trouble with thermoregulation, they should be provided with shelter and/or blankets in winter. Horses with laminitis will require ongoing and expert farrier care, as well. All of these considerations, however, might be worth it to owners who feel strongly about maintaining the health of a treasured old friend.
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RED HERRINGS
Reliable diagnostics can be particularly valuable when there is some doubt as to a Cushing's diagnosis (for example, when the symptoms are somehow atypical). There are two conditions that produce some similar symptoms, and which can lead to misdiagnoses--hypothyroidism, and diabetes mellitus.
A hypothyroid horse often exhibits some of the same signs as a Cushing's victim--delayed shedding of the winter coat, lethargy, retarded growth, and healing. Unlike a Cushingoid horse, however, he will usually suffer a decrease in appetite, but gain weight nonetheless, and he often develops a characteristically thick, cresty neck. (Cushing's horses will often look potbellied, but rarely gain much weight.) And while Cushing's horses usually remain quite bright in attitude, a hypothyroid horse will strike one as "depressed."
Most practitioners feel that, in general, hypothryoidism is overdiagnosed, and that it is actually quite rare. Differentiating the two conditions must be done carefully, however, as a horse which has abnormally high cortisol levels as a result of a pituitary tumor will also show low thyroid hormone levels in his bloodstream--without anything being wrong with his thyroid gland.
Based on symptoms that include losing weight, polydipsia (excessive thirst), and high glucose levels in the blood, Cushing's syndrome also occasionally has been mistaken for diabetes mellitus. Diabetes, though it does occur in the horse, is exceptionally rare. Andrews says: "Let me put it this way. I've been in practice 13 years, and I have yet to see a case." He notes that the curly hair coat typical of Cushing's should be an important differentiating symptom, as it is not typical of a diabetic horse.
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About The Author
Karen Briggs writes for more than 20 equine magazines in Canada, the United States, and Great Britain. Based in Ontario, she also is a Canadian certified riding coach, an equine nutritionist, and an active competitor at the preliminary level of three-day eventing with her Thoroughbred gelding Sweeney Todd.
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