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Cushing’s Disease in the Horse (PPID)

Cushing’s disease in the horse is becoming a more popular diagnosis, creating confusion with many horse owners.  Cushing’s disease or Pituitary Pars Intermedia Dysfunction (PPID) is most commonly diagnosed in the aged horse, but is increasingly become more common in perceived younger horses with concurrent usage of medications to control the condition.  The impact of Cushing’s disease in the equine community is large, with more cases being diagnosed as the lifespan of the horse increases, and can create many management frustrations for the horse owner.  The syndrome is very complex, leaving many unanswered questions but many roads for possible exploration to enhance quality of life for these patients.

Cushing’s disease is actually a disorder of the pituitary gland located at the base of the brain, just below the hypothalmus.  The pituitary gland is divided into 4 lobes but only the par intermedia lobe appears to be clinically active in this disorder.  The pituitary gland is regulated by the hypothalmus in most respects, but overall is responsible for the production of many “pro” hormones, which then regulate the production of other hormones throughout the body.  In cases of Cushing’s disease, there is an over-production of a hormone called ACTH, which directly stimulates the adrenal glands causing an enhanced production of cortisol.  Increased levels of cortisol actually contribute to muscle loss, weakness, decreased immune response, increased water consumption and other clinical signs.

One interesting fact to note is that the pars intermedia actually demonstrates a higher level of activity in the normal horse during late summer and fall, resulting in increased hormone production.  This is perceived to occur as a manner of preparing the animal for demands of winter and reduced food intake.  Some of the hormones, including α-MSH, help to regulate appetite and even impact the inflammatory process. 

The exact cause of Cushing’s disease or PPID in horses is not known, but if we can look at basic physiology and anatomy, we can begin to understand some key concepts that go astray.  In horses, the pars intermedia is controlled by nerve input from the hypothalmus through dopamine secretion.  With increasing dopamine input, the par intermedia section of the pituitary is regulated and the output of associated hormones from that region are decreased.  In cases of PPID, there appears to be nerve degeneration on the input side from the hypothalmus, which then leads to less dopamine regulation and an increase in hormone output from the pars intermedia.  In fact, with decreased regulation, the pars intermedia portion of the pituitary begins to enlarge in size or hypertrophy, often forming masses termed adenomas.  If the enlargement of this region is significant, there can be compression to other adjacent areas of the pituitary and brain structures, which can regulate other body functions.

Clinical signs

Most clinical signs seen in cases of Cushing’s disease or PPID are generally a result of increased hormone production by the pars intermedia, which include but are not restricted to:

  • Weight Loss (muscle loss)
  • Increased water consumption
  • Increased urine output or production
  • Changes in personality
  • Changes in hair coat
  • Increased incidence of infection
  • Possible episodes of laminitis

One of the most common clinical signs with many older horses is what is termed ‘hirsuitism’, which is abnormal regulation of the hair coat resulting in an excessively thick and long coat.  Typically, this coat is resistant to shedding or may have a delayed release, often resulting in the need to clip the horses in the spring in summer to maintain thermoregulation.  Although the presence of hirsuitism is almost always diagnostic for PPID, it is not always a reliable indicator and not all horses with PPID or Cushing’s disease will demonstrate this finding.  There does appear to be a somewhat seasonality to the syndrome as well, with a worsening of clinical signs in the fall due, suspected to be due to a natural increase in pars intermedia function at this time of year.

Causes and Connections

Cushing’s disease is horses is essentially a result of an unregulated pars intermedia portion of the pituitary gland, as a result of loss of connectivity from the hypothalmus due to decreased dopamine input.  The exact reason for the decreased dopamine presence in the pars intermedia is not known, but there is evidence that there is nerve degeneration occurring between the pituitary and the hypothalmus.  The cause of the nerve degeneration is uncertain again, but there is evidence of ongoing damage due to oxidative stress, which is correlated to chronic inflammation.  There is also growing evidence of what is termed protein mis-folding within the pars intermedia, which can then cause protein accumulation and eventual deterioration of organ function.  This type of protein mis-folding has been noted to be a primary factor in Parkinson’s disease in humans.  Again, the cause of the protein mis-folding is unknown, but may be connected with oxidative stress, gene mutation or a decrease in protein clearance, which then leads to accumulation.1

Due to ongoing research on inflammation and oxidative stress, one has to raise the question as to the primary cause and if there is a connection with other clinical conditions. The nerve degeneration present in Cushing’s horses is considered somewhat typically a result of the aging process, which then correlates with a higher prevalence of this condition in our older patients.  Aging is strongly correlated with an increased production of pro-inflammatory proteins which contribute to outward appearance changes typical with advanced aging, but also contribute to many other health conditions due to decreased cellular function.

It is in my observation as a practitioner that many of our patients are originally diagnosed as being overweight or easy keepers, which then soon progresses to metabolic syndrome and insulin resistance. Laminitis is common clinical finding in insulin resistant horses, but was originally thought to be a frequent finding in PPID horses as well. Actually the prevalence of laminitis in cases of PPID is much lower than originally thought and those horses with PPID that do have laminitis, there is strong suggestion that those horses also have concurrent insulin resistance, which is more likely to be contributing to the condition.  

So, when looking at all this and taking things into consideration, we tend to see a trend or at least I do.  That trend is the potential impact of ongoing inflammation and oxidative stress on health and cellular function.  Metabolic syndrome and insulin resistance in horses and people are strongly connected to chronic inflammation, which impacts cellular function and insulin receptivity.  Many of those horses are also considered overweight or obese, which by itself carries a heightened level of inflammation, compounding the problem.  Many horses that are diagnosed with PPID have also in the past been diagnosed with metabolic syndrome or insulin resistance, which raises the question if one clinical syndrome is a progression of another.  Meaning, is it possible that uncontrolled metabolic syndrome or insulin resistant horses continue to deteriorate due to inflammation and oxidative stress, opening the door for Cushing’s disease development? This is an area of research and one in which I am not the only one raising this possibility.  

Diagnosis

Diagnosis of Cushing’s disease can be a challenge as there are many gray zones.  If we had the ability to perform a standing MRI study of the braiin, we might be more definitive, but until then we have to rely on detecting hormone levels.  In most cases, we attempt to evaluate levels of ACTH or cortisol, which can be a challenge towards the fall as we naturally see a increase in pars intermedia function as originally discussed.  There are a few tests available to try to determine the presence of PPID and include the dexamethasone suppression test, ACTH levels and the TRH stimulation test. Each test has its own merits and limitations, however the TRH (thryotropin-releasing hormone) test is becoming more reliable.2 In some cases, the veterinarian will often bypass testing and rule out the presence of the disease by response to medication administration.

The other thing to consider, as mentioned, is the concurrent presence of insulin resistance in these patients and thus, testing is generally recommended.  Generally insulin resistance is detected by measuring glucose and insulin values after a fasting period or through an oral sugar challenge.

Medical Management:

Typical management of the PPID patient includes the use of a medication called Pergolide, which acts as a dopamine agonist to increase levels within the pituitary.  The dose of the medication is graduated, meaning that a lower dose is originally utilized with increases implemented as needed.  Another medication called Cyproheptadine has been used, which blocks the stimulatory actions of serotonin on the pars intermedia, but results are less reliable.  In some cases, both Pergolide and Cyproheptadine have been used together in resistant patients. Overall response to these types of medications can be extremely variable, with some showing benefits while others desire more.

If there is concurrent insulin resistance, this generally must be managed additionally which is usually through dietary modifications and reduced pasture access, especially if there is concurrent laminitis. 

Final Thoughts and Better Management

As a practitioner and consultant, I have noted a strong correlation between the progressive development of PPID in prior metabolic syndrome horses. The typical presentation of a PPID horse is one with advanced age, but recently, we appear to be having younger horses diagnosed with the condition that appear outwardly in good physical condition.  Many of these horses are high level athletes and are also being diagnosed with insulin resistance and other health conditions such as muscle wasting, joint disease and tendon disease.  Do I feel these younger horses truly have Cushing’s disease which justifies the use of the medication Pergolide?  I don’t have the answer to this as many of the appear to respond positively to the medication, which supports the idea that the disease may be present, but why in such young animals?  Could it be a serial progression of ongoing inflammation and oxidative stress, which may be compounded by excessive stress due to competition and training? Again, I don’t know, but it is a plausible theory in my eyes.

Considering this, we have to wonder what if any impact there could be through the use of natural anti-inflammatories and antioxidants.  One researcher had noted that there was evidence of oxidative stress leading to nerve degeneration but that levels of antioxidants within the animals appears to be normal and not depleted.  If we look at human research data on Parskinson’s and Alzheimer’s disease, we see a positive influence with the use of antioxidants such as CoQ10, Lipoic Acid and Curcumin, not to mention many others.  Could it be that if we supply a higher level of the right antioxidants and anti-inflammatories that maybe we could slow the progression of Cushing’s disease and possibly impact insulin resistance?  There is plenty of interesting research there to support this idea, including our own data and observations, but yet there is not enough support to make it an accepted treatment method at this time unfortunately

The other possible option is the use of natural occurring adaptogen herbs, including Ashwaghanda, which have demonstrated the ability to reduce plasma levels of cortisol, which impacts Cushing’s patients.  Again, there is plenty of clinical observations noting improvement in these patients when these herbs are utilized, helping to make their conditions more manageable.  Unfortunately, the research data is not there and thus general support is not achieved, despite some good results and no side effects.

In our Cushing’s or PPID equine patients, we tend to approach them in a similar fashion as we would a metabolic patient, seeking to modify the inflammatory response, provide antioxidant support, balance cortisol levels and address underlying GI issues.  This last point regarding gastrointestinal issues is important, as we have found that problems exist on many levels in most metabolic patients, to which many PPID patients fall into this category.  The main approach we have used with great success has been through the combination of the Cur-OST® EQ Total Support and the Cur-OST® EQ Adapt formulas.  Most of these patients have improved in overall health, secondary problems including feet also improved and often, there was a noted reduction in demand for pharmaceutical medications.  Many of those patients also demontrated an improved back towards normal, of the ACTH levels.  

There is still much to be discovered regarding Cushing’s disease in horses, but we have to realize that we don’t have to be limited in our thinking when attempting to manage them.  They can be difficult at times, but often their quality of life can be improved benefiting the welfare of the patient.

 

All our best,

Tom Schell, D.V.M.

Nouvelle Research, Inc.

www.nouvelleresearch.com

 

References:

1. McFarlane, D. Review of Current Understanding of Pituitary Pars Intermedia Dysfunction, AAEP Proceedings, vol. 59, 2013, 294-296

2. Frank, N., Diagnosis and Medical Management of Endrocrine Disorders in the Aged Horse, AAEP Proceedings, vol 59, 2013, 305-309

(image acquired from Google Images)

 

 

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