Navigating through the volumes of information on equine Cushing’s disease and equine metabolic syndrome (EMS) can be time-consuming, frustrating, and extremely confusing for horse owners. Seeking clarity might not necessarily induce dizzy spells, but one might begin to feel much like Alice in Wonderland when she remarked: “It would be so nice if something made sense for a change.”

If equine Cushing’s and EMS are both endocrine disorders that share some of the same clinical signs, does it really matter which one is the underlying culprit?

“Absolutely,” says Nicholas Frank, DVM, PhD, Dipl. ACVIM, large animal medicine section chief at the University of Tennessee. “Equine metabolic syndrome is a disorder relating to increased metabolic efficiency and obesity that develops in young and middle-aged horses and ponies, whereas Cushing’s is more common in older horses and ponies and is caused by a small tumor developing in the pituitary gland. “Management of EMS primarily focuses upon weight control and dietary changes. In contrast, the drug pergolide is prescribed to manage Cushing’s disease by suppressing the activity of the tumor.

This article aims to make sense of the world of Cushing’s and EMS. We’ll describe the diseases’ primary features, compare clinical signs and available diagnostics, and highlight key treatment differences.

Equine Cushing’s

Equine Cushing’s is one of the most commonly diagnosed equine endocrine (hormonal) disorders. It is estimated to affect approximately 0.1% to 0.5% of all horses. Cushing’s is usually diagnosed in older horses (the average age of affected horses is 19 years), but it also can occur in young horses. Ponies appear to be more frequently affected than other breeds.

Equine Cushing’s is caused most often by enlargement of the region of the pituitary gland referred to as the pars intermedia, which is located near the base of the brain. Normally, the primary hormone the pars intermedia produces is alpha-melanocyte-stimulating hormone (aMSH). To produce aMSH it synthesizes a large protein called pro-opiomelanocortin (POMC), which is then broken down into other hormones. In the healthy horse POMC becomes aMSH within the pars intermedia.

Dopaminergic neurons in the hypothalamus generally keep the pars intermedia in a suppressed state using an inhibitory neurotransmitter they produce, called dopamine. As the horse ages, these neurons sustain oxidative damage, which causes them to degenerate. This loss of neurons allows cells of the pars intermedia to increase in size and number (hyperplasia), and this, in turn, increases hormone production and release; adrenocorticotropin hormone (ACTH), a derivative of POMC, is one of these hormones released.

At some point cells move from hyperplasia to neoplasia (a tumor), indicative of Cushing’s, but it’s unclear what the exact trigger is for this conversion. The neuron degeneration process explains why Cushing’s is more common in older horses.

Affected horses might be genetically predisposed, have pre-existing conditions such as EMS, or simply undergo more wear and tear over time. In addition, environmental factors such as diet likely play a role; low antioxidant levels in the diet predispose horses to Cushing’s disease.

A pars intermedia tumor’s increased ACTH production causes Cushing’s for two reasons: 1) a region that doesn’t normally secrete much ACTH is secreting it in larger quantities; and 2) this region of the gland doesn’t respond to negative feedback (the body’s natural response to stabilize and stop secretion). Higher ACTH concentrations stimulate increased secretion of the stress hormone cortisol–which at normal levels maintains many body processes–from the adrenal glands and lead to the clinical disorder recognized as Cushing’s.

Thus, equine Cushing’s is quite different than Cushing’s in people and dogs. In the latter two species, a tumor in a different part of the pituitary, the pars distalis, results in increased ACTH secretion, which subsequently increases cortisol secretion.

Clinical Signs

“Equine Cushing’s tends to have a long, slow onset, and a wide variety of clinical signs of disease can be observed,” says Frank. “This disorder is easy to recognize in its advanced stages, but very challenging to diagnose when it is first developing.”

Classic signs of advanced Cushing’s are:

• Abnormal (long/wavy) coat (hirsutism);
• Excessive sweating;
• Increased appetite:
• Increased drinking and urination;
• Lethargy and poor performance;
• A potbellied appearance;
• Muscle loss, especially along the topline;
• Abnormal fat distribution (primarily in the crest of the neck, tailhead, sheath, and above the eyes);
• Chronic or relapsing laminitis;
• Delayed wound healing and skin infections; and
• An increased susceptibility to internal parasites, among others.

Clinical signs of early Cushing’s disease, which can develop in middle-aged horses, include delayed shedding of the winter hair coat for a few additional weeks, retention of winter hairs in certain regions of the body, and a shift in body composition. This shift is often characterized by a loss of muscle mass, and retention of fat deposits in the neck or tailhead. Cushing’s disease occurs in horses with EMS, so animals diagnosed with EMS should be closely monitored for early signs of this endocrine disorder.

Diagnosing Equine Cushing’s

A veterinarian can diagnose Cushing’s in a horse with a long-standing presence of classic clinical signs (i.e., long, wavy hair coat, chronic laminitis, etc.). He or she should treat suspected cases presumptively; veterinarians often use response to treatment for future treatment guidelines.

Frank goes on to state that, “One limitation of the currently available diagnostic tests is that they may not detect early Cushing’s disease. An experienced veterinarian may, therefore, recommend a six-month trial period on pergolide on the basis of clinical judgment alone.”

The vet can perform laboratory testing to support the diagnosis of equine Cushing’s disease and assess response to treatment. The tests most commonly used for diagnosing equine Cushing’s disease are those quantifying resting (basal) ACTH and insulin levels (insulin is a hormone produced in the pancreas that binds to specific cellular receptors, such as those in the liver, causing the uptake of glucose into the cell for fuel), the low-dose dexamethasone suppression test (DST), and the thyrotropin-releasing hormone (TRH) response test. Other tests include an ACTH stimulation test, a urine cortisol to creatinine ratio test, a test that measures resting glucose levels, or any combination of the above tests.

“In my opinion, the most practical test is the resting plasma ACTH concentration test, because it is easily performed and can be included in annual spring wellness examinations for older horses,” says Frank.

Horses with advanced Cushing’s disease tested using a single blood sample show high ACTH levels, so veterinarians use this test to confirm diagnosis when classic clinical signs are present. The clinician should also measure glucose and insulin concentrations in the same blood samples, because some horses with Cushing’s were previously affected by EMS and remain insulin resistant (have a reduced sensitivity to insulin that decreases the ability of glucose to be transported to body cells from the bloodstream). Abnormal or false positive results are not uncommon, as other factors can cause increased levels of ACTH (improper sample handling, stress and pain of the horse, and time of year, for example). The veterinarian should be aware of these confounding factors and perform testing appropriately.

The vet performs a DST by taking one blood sample and injecting the horse with a small amount of dexamethasone (a steroid hormone like cortisol) intramuscularly. In normal horses administering the DST will result in a serum cortisol decrease. In contrast, horses with Cushing’s are unable to respond appropriately to the dexamethasone and suppress cortisol levels. The DST is widely considered the better test that can be used largely without complications, but the vet must make two separate trips to the farm in a 24-hour period, and there are concerns about occasional dexamethasone-induced laminitis.

Time of year can affect the DST, with false positive results occurring more often when testing is performed in the late summer and in autumn. Vets should avoid performing the test during these seasons.

Development of a diagnostic test for early Cushing’s disease remains a challenge for researchers.

Treatment

While there is no cure for equine Cushing’s, owners can manage affected animals via medication and supportive care. The treatment of choice for equine Cushing’s is oral administration of pergolide.

“Pergolide works by mimicking the action of dopamine and inhibiting hormone production within the pars intermedia and, thereby, lowering circulating ACTH and other hormone levels,” explains Frank.

Some horses develop transient anorexia and depression at the start of pergolide treatment; veterinarians address this by reducing the dose and slowly raising it over seven days. At high doses, however, in addition to anorexia and depression, some concerns exist regarding the stability and efficacy of compounded pergolide. This is the only pergolide product currently available, since production of the human drug that veterinarians used in horses was discontinued when adverse effects on human heart muscle were reported. Alternatively, veterinarians can prescribe the serotonin blocker cyproheptadine or trilostane, a drug used to suppress cortisol release by the adrenal glands.

Cushing’s researchers recommend supportive care and routine vet examinations. These management measures include clipping excessive hair, examining the horse for wounds or infections, ensuring prompt and thorough treatment of all infections (this can require prolonged use of antibiotic drugs), scheduling routine farrier and dental appointments, routine vaccination, and an appropriate deworming schedule.

Vets encourage owners of Cushing’s horses to decrease the amount of carbohydrates they feed (e.g., grains or other concentrates), maintain the horse at a healthy body condition score, and ensure his diet is properly balanced. Well-managed horses should live about five to seven years or more past diagnosis. In severely affected horses, however, laminitis and recurrent infections are time-consuming and expensive to manage and can shorten the horse’s anticipated life expectancy dramatically.

Equine Metabolic Syndrome

In contrast to Cushing’s, EMS is both a metabolic and a hormonal disorder that describes horses with:

• Obesity;
• Regional adiposity: a “cresty neck,” fat pads near the tailhead, fat accumulation in the sheath/near the mammary gland;
• Insulin resistance; and
• Laminitis.

“First, EMS is a metabolic disorder because affected horses are metabolically efficient,” says Frank. “They are commonly referred to as ‘easy keepers’ because they can thrive, or even become obese, on a diet that would barely maintain the other horses in the same herd. These horses can become overweight on pasture alone.”

Second, EMS is a hormonal disorder because insulin aberrations are present.

As described before, “Insulin resistance is a state in which insulin is not effective or as effective as it should be and glucose is not being taken up by the target cells,” he adds.

Over time, the pancreas secretes more and more insulin to control rising blood sugar. “Blood insulin concentrations rise above normal range in horses with EMS,” says Frank. “Insulin resistance is like an early form of diabetes. Horses remain in this state for years, with only a few animals developing true diabetes mellitus, which is characterized by persistent hyperglycemia (abnormally high blood glucose levels) and glucose in the urine.”

Laminitis is also an important feature of EMS in horses. In fact, it is the recognition of chronic laminitis that often spurs an owner or vet to consider EMS as the underlying cause. Laminitis often occurs right after a dietary change (e.g., in the spring when the horse is turned out on lush pastures).

Unlike horses with Cushing’s, horses are at risk for developing EMS as soon as they reach maturity, and the disorder is often observed in horses that are 5 to 15 years old. While any breed can be affected, EMS is more commonly observed in ponies and breeds that tend to be metabolically efficient, such as Morgans, Spanish Mustangs, Peruvian Pasos, and Paso Finos.

“Horses prone to EMS likely have some sort of genetic predisposition for the disease,” suggests Frank. “For example, these horses have likely evolved in harsh climates and their metabolic systems have been programmed to be highly efficient. As a result, they easily gain weight when fed good quality hay or pasture.”

Diagnosing EMS

EMS, like Cushing’s, typically has an insidious onset, meaning it develops so gradually that it’s well-established before becoming apparent. Clinical signs, most notably obesity and/or regional adiposity and laminitis (which is often recurrent or chronic), are usually the tip-off that there might be a problem. In contrast, delayed shedding of the winter hair coat or a long, curly hair coat are the most common clinical signs in Cushingoid horses.

“Diagnosis should be pursued when the horse is not in the midst of a laminitic episode, because pain and stress affect results,” advises Frank. “When the pain of laminitis has subsided, horses can be screened for insulin resistance by collecting a blood sample after fasting the horse for approximately six hours and measuring the glucose and insulin concentrations. If the horse or pony has an abnormally high insulin concentration with a glucose concentration that is still within reference range, we have diagnosed insulin resistance, and no further testing is required.

“Occasionally we detect … hyperglycemia,” notes Frank. “No matter what the insulin concentration is, we consider this to be a more serious situation. Unless hyperglycemia can be explained by pain or stress, we consider it to be an indication of diabetes mellitus, which demands more intensive management. The last scenario encountered is the horse or pony with obvious clinical signs of EMS, such as generalized obesity, a thick, cresty neck, and laminitis, that does not have an elevated glucose or insulin concentration. In this case, we remain suspicious of insulin resistance, but the screening test has failed to confirm the diagnosis. We must then perform a dynamic test.”

The “euglycemic insulin clamp” is considered the gold standard for diagnosing insulin resistance. In this test the vet provides a slow, constant intravenous infusion of insulin and glucose. He or she subsequently monitors and analyzes a series of blood tests to calculate the amount of insulin necessary to reduce the artificially elevated blood glucose levels. Clearly, this is not a simple or inexpensive test to perform or interpret and, therefore, it is not widely employed for diagnosing EMS. The combined glucose-insulin tolerance test (CGIT) is another option. The vet administers glucose and insulin (intravenously), then he or she measures the horse’s blood glucose and insulin levels over the next several hours. Like the euglycemic insulin clamp, the CGIT is typically performed at a referral center and not on the farm.

Treating EMS

Like the diabetes solution for obese people, there’s a three-pronged “Biggest Loser”-type approach to EMS management:

1. Weight loss;
2. Dietary changes; and
3. Regular exercise.

Believe it or not, most horses can be maintained on a forage-only diet. In fact, EMS horses (typically easy keepers) can become obese even on poor-quality forage. It is important to first recognize what a healthy body weight for your horse is, then feed him appropriately to achieve and maintain this healthy weight.

“Limit or even eliminate concentrates and limit or eliminate access to pasture,” advises Frank. “Work with an equine nutritionist. Have your hay analyzed and feed hays with a low sugar and starch content.”

Frank also recommends instituting an exercise program to properly manage EMS horses. Specifically, daily or near-daily exercise is advised: hand walking, longeing, long-lining, driving, riding, ponying, or any combination of the above. But don’t jump the gun. Keep your newfound enthusiasm for your horse’s fitness in check, and ensure he’s not currently suffering from a laminitic episode. Institute dietary changes, wait for the episode to resolve (if he is, in fact, battling one), then slowly increase your horse’s exercise level.

“For extreme cases that simply cannot be managed by instituting these three changes alone, there is some evidence that levothyroxine (drug to treat low thyroid activity) and metformin (an anti-diabetic drug) are beneficial,” relays Frank.

Point of Confusion

One confusing aspect of this topic is that veterinarians sometimes detect insulin resistance in horses with Cushing’s disease. According to Frank, “We suspect that horses and ponies with EMS are predisposed to Cushing’s disease, and insulin resistance appears to get worse when horses with EMS develop Cushing’s later in life.”

It is therefore important to check horses with Cushing’s for insulin resistance. This problem often improves with Cushing’s disease treatment, but the veterinarian should make appropriate dietary recommendations to manage insulin resistance. The owner should consider the carb content of feed, but vets do not recommend calorie restriction for thinner horses. Low-starch/low-sugar pelleted feeds are available.

Take-Home Message

When it comes to equine metabolic and hormonal disorders, it is not appropriate to shrug our shoulders and think, “Six of one and half a dozen of the other.”

“Cushing’s and EMS feature striking clinical similarities, most notably chronic laminitis, but the underlying disease biology is quite different,” says Frank.

“Successful management mandates that we distinguish between the two using all available tools and tests,” he concludes.

Comparison of Equine Cushing’s and Equine Metabolic Syndrome
	CUSHING’S DISEASE	EQUINE METABOLIC SYNDROME
Predisposition	More common in:	Most commonly detected:
	â–  Horses older than 15 years of age	â–  From maturity onward. Usually first detected when the horse is 5-15 years of age.
	â–  Ponies and Morgans of any age	â–  In “easy keeper” horse and pony breeds
Cause	â–  Enlargement of the pars intermedia (part of the pituitary gland) resulting in abnormal hormone production	â–  Genetics
		â–  Metabolic efficiency
		â–  Insulin resistance
Clinical signs	â–  Delayed shedding (early)	â–  Obesity or regional fat deposits (“cresty neck”)
	â–  Long, wavy hair coat (advanced)	â–  Laminitis (active case or history)
	â–  Chronic laminitis
	â–  Muscle loss and fat accumulation
Diagnosis	BASED ON:	BASED ON:
	â–  Clinical signs	â–  Clinical signs
	â–  Increased adrenocorticotropin hormone  (ACTH) levels	â–  Screening test: Showing an increased blood insulin level with normal glucose level (most cases). Detection of hyperglycemia (abnormally high glycogen levels in the blood) is of greater concern (diabetes mellitus).
	â–  Abnormal dexamethasone suppression test (DST) results (no cortisol suppression)	â–  Advanced test: Glucose tolerance test results are abnormal
Treatment	â–  Pergolide mesylate	â–  Management
	â–  Cyproheptadine	â–  Levothyroxine or metformin, only in extreme cases