Cushing's syndrome

Shortly after she purchased Silver to be her 5-year-old daughter's special pony, Chris Knudsen noticed that something about the gentle mare was amiss. "Silver was about 15 1/2 years old when we bought her for Lily," she said. "We noticed soon after she came to live with us that her appearance was changing; she was skinny, but her stomach became bloated. Her coat continued to be very, very heavy, even during the summer; she didn't shed. Her hooves required frequent trims, and her feet periodically seemed painful with a lameness that moved from foot to foot. When the farrier came to trim her hooves, he saw blood between the laminae, and that can be a symptom of founder.

"As soon as we realized there was a problem with Silver's feet, we consulted our vet, and the results of a dexamethasone suppression test showed that Silver had a severe case of equine Cushing's syndrome. We were not too surprised; we had watched her symptoms develop, and we'd seen that disease before. Cushing's syndrome is more common in ponies than it is in horses, and Silver had it with a vengeance!"

An Overview of Equine Cushing's Syndrome

Equine Cushing's syndrome is hyperadrenocorticism that affects all breeds of ponies, horses, and donkeys (in this article, the term "horses" refers to those types of equines). It most often afflicts older horses1 and is usually caused by a pituitary adenoma that secretes increased concentrations of adrenocorticotropic hormone (ACTH), beta-endorphin, and alpha-melanocytestimulating hormone.2 A high concentration of ACTH causes the increased production of cortisol, which can result in immunosuppression as well as other signs of the disorder.1 Although not all horses exhibit the same signs of equine Cushing's syndrome, its most common manifestations are failure to shed the hair coat, drinking and urinating in an increased volume, hyperhidrosis, laminitis and the subsequent development of overgrown hooves ("pixie feet"), muscle wasting and fat redistribution (a pot-bellied appearance), infertility, and recurrent infections (especially dermatologic diseases).2 Laminitis causes very painful feet, and horses afflicted with that disorder tend to rock back on their heels to avoid placing weight on the toe of an affected hoof. Equine Cushing's syndrome may also produce periorbital bulges and a fat pad above the tail head. Many affected horses exhibit behavioral changes, such as depression or lethargy, that may be caused by an increased concentration of endorphin in the cerebrospinal fluid. 1,2

Treatment

Horses with Cushing's syndrome are treated with either cyproheptadine hydrochloride 0.25 mg/kg/day once daily in crushed-pill form or with the more effective pergolide mesylate 1 mg orally once daily, which can be compounded for administration as a powder that is mixed with feed, as a liquid, or as a chewy tablet that most horses find palatable.

Cyproheptadine: Once the Drug of Choice

In Silver's case, Cushing's syndrome was treated with cyproheptadine hydrochloride. "Our vet prescribed it in little white pills," said Knudsen. "We'd crush them and mix them with molasses and sweet feed to form a little nugget that was the most attractive part of Silver's meal. She had a great appetite, so we felt that she had a good chance of receiving the required dose. Treatment with pergolide mesylate was also available, but it was too expensive.

"About 3 weeks after Silver had received the first dose of cyproheptadine, we noticed that she began to have a few better days and was periodically less lame, but she never really shed her coat. We worked closely with our farrier because her hooves continued to grow at a tremendous rate, and we fed her a recommended low-protein diet: no grain and no grazing. We maintained Silver that way for between 3 and 4 years, and during most of that time she was never ridden. Eventually, her bad days began to outnumber her good days because she was growing older and we couldn't easily find the grass hay that she needed. Then Silver had some good luck: She went to live with my cousin, a farrier who lives in Nevada, where low-protein grass hay is plentiful. There Silver had a donkey companion with similar dietary requirements. Her medication was stopped, and she seemed to do just about as well as she had while she was treated with cyproheptadine because she was fed a very strict diet. Silver lived to the age of 22."

The Benefits of Pergolide

Since Silver was treated for equine Cushing's syndrome, the dopamine agonist pergolide has become more affordable. Cushing's syndrome has developed in two other horses at the Knudsen's ranch, and their prognoses are good. "Skip and Moondance, who are now in their 30s, also began to have that cushingoid look," said Knudsen, "and their test results were positive for Cushing's syndrome. We're treating them with pergolide, which is less expensive than it was when we had Silver; it now costs about $65 to $100 (instead of $300 to $400) per month per horse. Pergolide is much more effective than cyproheptadine; it has a different mechanism of action, and no dietary restrictions are required for horses that are treated with it. We buy it in chews that we mash with molasses to form a sweet little once-daily treat. A week or two after we started that therapy, we noticed an improvement: Both horses finally began to shed, and they eventually gained weight and filled out. They now look great, and they have a high energy level. Skip, the quarter horse, has been taking pergolide for a year or two, and Moondance has been treated for a couple of months. Both of them have improved remarkably. Pergolide is definitely the drug of choice for treating Cushing's syndrome in horses!"

Cushing's Disease or Cushing's Syndrome?

Philip J.Johnson, BVSc(Hons), DVM, MS, Diplomate ACVIM, MRCVS, a professor of internal medicine in the College of Veterinary Medicine at the University of Missouri-Columbia, is a specialist in the treatment of disorders such as equine Cushing's syndrome. He differentiates the human form of the disease from the type that occurs in horses. "`Cushing's disease' refers to the clinical manifestations of excess glucocorticoids (adrenal gland steroids) resulting from a pituitary tumor in humans. In horses, that condition is called `equine Cushing's syndrome.' The type of pituitary tumor and the resultant hormone abnormalities that occur in horses differ from those in humans. The cause of the tumor that produces equine Cushing's syndrome is unknown. Horses of all breeds and both genders are affected, and the disease is not endemic to a particular geographic area. No known environmental conditions trigger it, and it is not transmitted by any known vectors. Until we know the cause of classic pituitary-dependent equine Cushing's syndrome, we can suggest no precautionary action. It can be attributed to other nonpituitary causes such as the administration of steroids, primary adrenal gland disease, diseases of the hypothalamus, and cancers that produce hormonally active substances, but those occurrences are very rare."

Supportive Management and Drug Therapy Produce Optimal Results

Dr. Johnson noted that a combination of appropriate management (hoof care, hair-coat management, dental care) and the use of an effective drug (cyproheptadine or pergolide) produces the best response. "Pergolide acts like dopamine (a neurotransmitter in the pituitary gland), and cyproheptadine inhibits serotonin (another neurotransmitter in the pituitary gland)," he explained. "However, many cushingoid horses do not respond to cyproheptadine. Pergolide is more effective in inhibiting the hormonal activity of the pituitary tumor. Usually, low-dose orally administered pergolide therapy is prescribed; most horses respond to 0.5 to 1.0 mg/day. Adverse effects from treatment with pergolide have not been reported to a meaningful extent, although the bioavailability of the orally administered drug varies among horses. Pergolide has not been specifically approved for use in horses, so the drug prescribed in pill form for humans is often crushed and mixed with the horse's feed. However, the dose of pergolide for horses is quite low when compared with that prescribed for humans.

"Improvement from pergolide therapy, which is usually noted in 3 to 4 weeks, is manifested in the reduction of water consumption to a more normal level, improved diagnostic test results, appropriate shedding of the hair coat, less laminitic pain, and fewer infections. Without treatment, some affected horses succumb to secondary effects of equine Cushing's syndrome; for example, disease-related neurologic impairment or laminitis. Treated horses, however, are less likely to be affected by complications caused by the disorder. They are also more comfortable and have a better quality of life."

Angel DePuy, DVM, a veterinarian in the equine division of the veterinary hospital that managed Silver's treatment, has also identified Cushing's syndrome in many horses and ponies. "If we suspect that a horse has Cushing's syndrome, we measure the amount of ACTH in its blood. The ACTH test involves a one-time blood draw and, unlike the dexamethasone suppression test, it does not require the administration of steroids that can induce laminitis in a cushingoid horse. The sensitivity of the plasma ACTH concentration as an indicator of equine Cushing's syndrome is 90.9% in horses and 81.8% in ponies, and the specificity of the test is 100% in both groups. Hyperglycemia and sometimes an elevation in alkaline phosphatase or an increase in triglyceride or cholesterol levels can also occur. Surgery is not an option for the type of tumor that causes the problem, and the tumor will never go away. It might enlarge and impinge on other areas of the brain, but usually it simply persists and causes no problems other than Cushing's syndrome."

Dr. DePuy also relies on pergolide as a first-line treatment. "Pergolide, a type 2 dopaminergic agonist, is now the most commonly used therapy for equine Cushing's syndrome," she said. "Pergolide replaces dopamine, which many cushingoid horses lack. It's more effective than cyproheptadine, which is an antiserotonergic and antihistamine, and it provides better control of the disease. Horses just don't seem to respond as fully to cyproheptadine; some symptoms may improve with treatment but others do not. For example, skin infections may resolve, but the hair coat may not shed well. I prescribe 1 mg of pergolide administered orally once daily for life. Treated horses eventually shed their hair coat and they heal better, so the incidence of recurrent laminitis and skin infections decreases." Dr. DePuy noted that few side effects are produced by either drug. "Pergolide can produce anorexia or dizziness and cyproheptadine can cause dizziness or drowsiness, but those effects are dose-dependent," she said. "We now believe that diet does not play a role in the development or management of the syndrome, and horses that take either medicine are no longer required to adhere to a special diet."

Follow-up remains an important part of treatment. "I monitor the horse's progress by observing the resolution of clinical signs," said DePuy. "With the owner's consent, we reevaluate the ACTH and insulin levels 1 to 2 months after the initiation of therapy. An improvement in the hair coat is usually noticed during the season after the initiation of treatment. If the hooves are properly trimmed and shod, laminitis (and other symptoms) can resolve within 1 or 2 months after the start of therapy."

Dr. DePuy agrees with client Chris Knudsen about the cost of treatment. "Pergolide used to be much more expensive than cyproheptadine, but now those drugs are similar in cost. We use compounded formulations of pergolide, which are more affordable for our patients. We can have the drug compounded in any of several dosage forms: as a powder, a tiny scoop of which is applied daily to feed; as a chewy tab that can be eaten as a treat; and as a liquid administered with a syringe. If horses with Cushing's syndrome are treated with pergolide, symptoms can resolve to a manageable level, the horse's quality of life can be greatly improved, and the consequences of founder can be avoided. Many can even be ridden again (although not competitively), but those that have had laminitis may always require special hoof care."

No longer a sentence of death or certain misery, equine Cushing's syndrome can be managed with proper medication and supportive care. Chris Knudsen agrees; her cushingoid horses, treated with pergolide, have a good quality of life. "Skip and Moondance have been retired," she said. "Now they spend their days running around on our lawn and enjoying their twilight years, thanks to their much-improved health."

For additional information about the treatment of equine Cushing's syndrome, contact Philip J. Johnson, DVM, University of Missouri-- Columbia Veterinary Medical Teaching Hospital, East Campus Drive, Columbia, MO 65211, e-mail: johnsonpj@missouri. edu; or Angel DePuy, DVW, Adobe Animal Hospital, 1600 Soquel Drive, Santa Cruz, CA 95065, e-mail: angeldepuy@hotmail.com

References

1. Mair T, Love S, Schumacher J, et al. Equine Medicine, Surgery and Reproduction. London:WB Saunders Company Ltd;1998:183-184.

2. Kobluk CN, Ames TR, Geor RJ. The Horse. Clinical Diseases and Management. Philadelphia:WB Saunders Company; 1995:1145-1146.

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