Cushing’s Disease

Cushing’s Disease, or to give its proper title, Pituitary Pars Intermedia Dysfunction (PPID), is probably the most common hormonal disorder affecting horses, especially older animals.  The primary significance of Cushing’s disease is in its potential to induce and perpetuate laminitis, and it is in the laminitic animal that we most frequently make this diagnosis.  A recent study showed that more than 80% of horses and ponies with laminitis have an underlying hormonal disorder, and we consider testing for these problems imperative in all but the simplest cases.

What Causes Cushings Disease?

In the normal horse, production of steroid hormone is tightly regulated by the Hypothalamic-Pituitary-Adrenal axis (HPA axis).  The pituitary gland is a small gland at the base of the brain, which is controlled by a special part of the brain itself, the hypothalamus.  In times of stress or disease, extra steroid hormone is required by the body, so the hypothalamus stimulates the pituitary gland to secrete AdrenoCorticoTrophic Hormone (ACTH).  ACTH enters the bloodstream and passes to the adrenal glands (situated above each kidney), where it stimulates the adrenals to produce steroid hormone (principally cortisol).  This steroid hormone prepares the body for stressful events, and is a vital part of normal metabolism.

In horses with PPID, this same sequence of events occurs, but tight regulation of the pathway is lost.  The pituitary gland produces uncontrolled, often extremely large amounts of ACTH.  Following the same pathway as above, the ACTH stimulates the adrenal glands to produce large amounts of steroid hormone.  It is the large, uncontrolled amounts of steroid hormone produced by the adrenal glands that causes the signs associated with Cushings Disease, although the root cause lies in the pituitary gland.

In the majority of cases there is no structural change to the pituitary gland – researchers typically find a “normal” pituitary gland that is simply overproducing ACTH.  In a minority (1-5%) of cases, there is a benign growth of the pituitary gland causing ACTH overproduction.

What Are The Signs Of Cushings Disease?

There are many clinical signs that may show themselves to us in horses with Cushings Disease, some of which have more significance than others.  We will list them and discuss why they occur:

• Altered coat
  • The classic sign of Cushings Disease is a long and curly hair coat, but this does not always occur.  In many cases there is simply a long coat or an unshed winter coat when entering summer.  Having a normal hair coat does not mean your horse cannot have Cushings.
  • Hair coat changes occur due to the effect of steroid hormone on hair follicles.  Hair production uses energy and protein that a stressed horse cannot afford to waste! (Remember steroid hormones “natural” role is in times of stress.)
• Laminitis
  • This is almost certainly the most commonly seen sign of Cushings Disease, as well as the sign with the biggest potential for harm.  See our article on laminitis for more information.
  • How Cushings Disease causes laminitis is still something of a mystery, with much research ongoing.  Unfortunately as fast as a new theory seems promising, there is a new study proving it wrong!  Although the details are unclear, it probably relates to disruption of glucose metabolism.
• Abnormal Fat Deposits
  • Fat is laid down in unusual locations, such as above the eyes and behind the shoulder.
  • Steroid hormone acts to relocate fat from extremities to the centre of the body, and this is a side effect of that process.

• Weight Loss
  • Loss of condition is often visible to some degree, and is usually most visible on the horse’s topline.
  • Normal glucose metabolism is affected by steroid hormone, and the body starts to use muscle and fat as an energy source, leading to weight loss.
• Increased Drinking and Urination
  • Known as PU/PD (Polyuria/Polydipsia), this is another common sign, although one that can easily go unnoticed.
  • Steroid hormone prevents the horse’s kidneys from reabsorbing water in the kidneys, so water is lost in very dilute urine, causing increased urine volume.  Increased drinking occurs to compensate for this water loss.
• Increased susceptibility to infection
  • This can occur in many different forms.  For example, you may find your horse’s mud rash becomes much more difficult to manage.
  • White Blood Cells that normally fight infection are impaired from performing their proper functions by steroid hormone.
• Reproductive Problems
  • Stallions and mares with Cushings Disease can have reduced fertility, or even become infertile.
  • Steroid hormone prevents the reproductive system from gaining the necessary energy to produce healthy sperm and eggs.  In the mare there may also be an issue with uterine infections, similar to the last point.
  • Mares with Cushings Disease may lactate inappropriately.  This can be lactation without a foal, or prolonged lactation after weaning of the foal.
  • Cortisol affects the production of many similar hormones, including Prolactin, which stimulated milk production.

Diagnosing Cushings Disease

As stated above, the most common situation in which we diagnose Cushings Disease is in horse with laminitis that is either unresponsive to treatment, or recurs frequently.  There are several approaches to diagnosis, each with advantages and disadvantages.  Often a diagnosis can be reached based on the above clinical signs alone, however, even in these extremely obvious cases then testing is worthwhile as it gives an idea of disease severity, what treatment to use, and allows monitoring of the efficacy of treatment.  We have several blood tests available to us

• Endogenous ACTH Level
  • Looking back at the causes of the disease above, we can see that the root cause is overproduction of ACTH by the pituitary gland.  We can directly measure this level and see if it is elevated.
  • The traditional disadvantage of this test was the high number of “false-positive” (normal horses with positive test results) that were found, especially in autumn.  Fortunately this problem has been solved by the development of different normal values for different times of the year, and this test is now considered extremely accurate.
  • ACTH levels also vary throughout the day, so sampling is normally recommended first thing in the morning.
  • The other issue is one of sample handling.  ACTH degenerates quickly at room temperature, so samples must be stored cold.  We take blood samples and immediately place them on ice, and then send them to the lab in special freezer packs to ensure we get accurate results.
• Endogenous Insulin Level
  • Steroid hormone has a powerful effect in preventing insulin from working properly (Insulin Resistance).  This results in high blood sugar, and a resulting increased production of insulin.  We can directly measure the level of insulin, and an elevated level is strongly supportive of a diagnosis of Cushings Disease.
  • A condition known as Equine Metabolic Syndrome can also cause raised insulin levels, so a raised insulin level is not enough to make a diagnosis of Cushings Disease.
  • Insulin levels vary greatly depending on when the horse last ate, so we usually test first thing in the morning after approximately 8 hours starvation.  This allows us to interpret the results with far greater accuracy.
  • Testing is important as the presence of insulin resistance has important implications on treatment.
• Dexamethasone Suppression Test
  • This test involves taking a baseline blood sample, injecting a small amount of artificial steroid hormone, then collecting another blood sample.  In a normal horse, injecting steroid hormone will lower ACTH levels; in a horse with Cushings Disease there will be little or no effect.
  • This test used to be the “gold standard”, however, with the advent of seasonally adjusted ACTH ranges (see above) has fallen out of favour.
  • There are two major disadvantages – firstly, the injection of more steroid hormone into a horse that is already overproducing it could be harmful.  In practice, this does not prove to be a major problem.  Secondly, taking two samples is very time consuming and not cost-effective.

In our practice we commonly combine the first two tests (ACTH/Insulin).  In some cases we may also take a sample for glucose level measurement.  Testing is normally performed first thing in the morning, and we would advise feeding a small haynet the night before so that your horse is starved for approximately 8 hours before sampling.  This allows accurate interpretation of results.

Treating Cushings Disease

The treatment of Cushings Disease has advanced considerably in recent years, and the vast majority of horses will respond well to medication.  Treatment is based on managing the disease, with a cure unfortunately not available, and medication is likely to be needed for the rest of the horse’s life.

Medical treatment is usually based upon reducing the amount of ACTH produced by pituitary gland, which will in turn reduce the amount of steroid hormone produced by the adrenal glands.  It was previously thought that ACTH secretion by the pituitary gland was controlled by two factors – serotonin would increase ACTH secretion, and dopamine would decrease ACTH secretion.  We could therefore use treatments that would either act against serotonin, or mimic the effect of dopamine.  Unfortunately, this was based on research performed in rats, and perhaps somewhat predictably it has recently been found that horses are different to rats!  In the horse, serotonin has no effect on ACTH production by the pituitary, so treatments aimed at reducing serotonin levels will be ineffective.  Instead, our therapeutic focus must be on either increasing dopamine levels, or mimicking the effect of dopamine.  In practice, we use a drug that mimics the effect of dopamine – Pergolide mesylate, often just referred to as pergolide.

Pergolide comes in the form of a small tablet that is given orally, usually on a once daily basis.  The dosage needed to control a horse’s disease can be quite variable, and is initially chosen based on the blood test results.  Fine tuning of the dose will then be achieved by assessing the response to treatment, and follow-up blood tests.  Adequate dosing should result in the resolution of all clinical signs.

Pergolide is usually a superbly effective drug, with more than 90% of horses responding well.  Side effects are few and far between, although drowsiness is sometimes reported.  In humans treated with pergolide heart conditions are known to occur, but this has never been observed in horses.  Indeed, the only drawback of pergolide seems to be its foul taste, and some horses will refuse to eat feed with the tablet in.  This can usually be overcome by feeding the tablet with treats, but if this still doesn’t work then there are alternatives.

After commencing treatment with pergolide, it often takes up to 6 weeks to see any changes in your horse, and indeed, recent research has shown that it can take up to 13 weeks before it reaches its full effect.

A veterinary formulation of pergolide has recently been licensed, and is called Prascend, produced by Boehringer-Ingelheim.  Unfortunately this has resulted in an increase in the cost of the drug, but due to prescribing laws we are no longer legally allowed to either sell or prescribe the commonly, safely and effectively used human form of the drug.

In horses that simply refuse to eat pergolide, or in the small percentage of cases that do not respond well to treatment, then there is an alternative.  Instead of using a drug that aims to reduce ACTH secretion by the pituitary gland, we instead use a drug called Trilostane (marketed as Vetoryl).  This drug stops the adrenal glands from producing steroid hormone, despite the high ACTH levels.  The major drawback is the much higher cost of this drug.

If we identify insulin resistance (see testing section above), then we may also use a drug called Metformin to make your horse more sensitive to its own insulin.  This drug has essentially the same effect as exercise, so we use it in actively laminitic horses that need to be strictly rested.  In horses that are not being rested, then exercise is usually as effective a treatment as drug therapy.

Management changes can also aid horses with Cushings Disease.  A diet low in soluble carbohydrates is ideal for horses with insulin resistance (a diet low in soluble carbohydrates is ideal for all horses!).  Horses with long hair coats are prone to overheating, and clipping out can provide valuable relief.

Prognosis

A horse with Cushings Disease will require treatment for its entire life.  Although the treatment we can give is effective, many horses will still suffer from recurrent laminitis.  However, early and effective treatment can give your horse a new lease of life, which can remain for many years.