What is high acth in horses?

In this condition, a gland that sits at the base of the brain called the Pituitary gland becomes enlarged and produces too much of the hormone called the adrenocorticotropic hormone (ACTH), as well as a few other hormones. High levels of ACTH cause an over production of cortisol from the adrenal glands.

Cushings Syndrome has many “names” –pituitary pars intermedia dysfunction (PPID), hyperadrenocorticism, ECD (equine Cushing’s disease), and, most commonly, Cushing’s syndrome. Classically, this ailment occurs in geriatric horses however Cushings can be diagnosed in horses less than ten years old. Why is this medical condition becoming prevalent? The answer is straightforward, horses are living longer lives!

How does Cushings Syndrome develop and what is the function of cortisol?

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). POLMC influences the adrenal glands, which reside on top of the kidneys, to produce an important hormone called cortisol. Cortisol has many functions;

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 result in excessive secretion of POLMC. Therefore, cortisol levels system can rise dramatically, producing the symptoms of Cushing’s.

Anatomic diagram showing the location of the equine hypothalamus and Pituitary retrieved from http://d1uhp0uy75me04.cloudfront.net/mmah/d8/63a1783bd2449f831bc5f76848d087/fileVT0610_hembroff_CE.pdf

Clinical Signs

1. Increased water consumption and urination, 2. Development of a long and curly hair coat, Subtle hair coat changes, such as development of patchy areas of long hairs and a tendency for the winter hair coat to come in earlier and shed out later than normal, may precede more profound changes by many years. 3. Excessive sweating 4. Milk production in mares 5. Chronic infections such as sinusitis 6. Dental disease 7. Hoof abscesses 8. Laminitis and founder 9. Mares with Cushing’s disease often have reproductive problems such as complete failure to cycle, irregular estrous cycles, estrus suppression, decreased follicle development, ovulation failure, and reduced fertility 10. Presumably affected stallions would exhibit decreased sperm production and decreased conception rates in mares bred.

Diagnosis

Diagnosis of Cushing’s disease is usually based on the combination of clinical signs and blood tests. Affected horses may have elevated levels of glucose, insulin, cortisol and ACTH in their blood. A CBC (complete blood count) blood test is utilized to identify hyperglycemia–affected horses may have 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). The veterinarians at Arizona Equine frequently repeat these blood tests and urinalysis to establish the consistency of high blood sugar. This may prompt our veterinarians to perform more specific, hormone-related tests to confirm the diagnosis of Cushing’s syndrome.

The next test for Cushings is the dexamethasone suppression test and is the ‘gold standard’ for diagnosis of Cushing’s disease. Administration of dexamethasone (synthetic cortisol) to normal horses causes suppression of blood cortisol, whereas horses with Cushing’s disease have little to no change in cortisol levels in response to dexamethasone. The dexamethasone suppression test (DST) is one of the most commonly utilized tests. The “Dex-suppression test” is as follows; dexamethasone 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 decrease in response to the dexamethasone injection, but the diseased melantrope cells will continue to produce peptides, creating a response of elevated cortisol.

Additional diagnostic tests include evaluation of cortisol levels in blood samples collected 8 to 10 hours apart or measurement of cortisol levels before and after administration of dexamethasone or other hormones. Evaluation of cortisol rhythm is a can be utilized as screening test for the presence of Cushing’s disease and is often performed as an alternative to the dexamethasone suppression test in horses with a history of laminitis. However, the cortisol rhythm test may yield false positive or false negative results, and one needs to be cautious basing a diagnosis on this test alone.

The hypothalamic–pituitary–adrenal axis creates a negative feedback loop that regulates homeostasis within the body. (a) In a healthy horse, the hypothalamus releases hormones that stimulate the pituitary to produce and release ACTH, which stimulates the production of glucocorticoids (cortisol) in the adrenal cortex. Exposure to an increased level of cortisol signals the hypothalamus to reduce its stimulation of the pituitary, reducing the release of ACTH and, in turn, lowering cortisol productionand maintaining homeostasis. (b) When dexamethasone (a synthetic form of cortisol) is given to a horse with a normally functioning pituitary, ACTH excretion is notably suppressed, as it would be if the horse were exposed to excessive endogenous cortisol, rapidly lowering the plasma cortisol level. (c) When dexamethasone is administered to a horse with PPID, the hyperplastic pars intermedia, which is poorly sensitive to the suppressive effect associated with hypothalamic exposure to cortisol, may continue to secrete a high level of ACTH. This stimulates the adrenal glands to continue releasing a high level of cortisol; therefore, the serum cortisol level is not suppressed.

Retrieved from http://d1uhp0uy75me04.cloudfront.net/mmah/d8/63a1783bd2449f831bc5f76848d087/fileVT0610_hembroff_CE.pdf

Treatment

Medical management of affected horses is usually a long-term or life-long commitment. Horses with Cushing’s disease require excellent management practices, including routine foot care, deworming, vaccinations, dentistry, and nutrition. Medical treatment regimens usually include administration of the dopamine agonist pergolide mesylate or the antiserotonin compound cyproheptadine. Clinical improvement, if any, is noted within 6 to 8 weeks after the onset of treatment. When an effective dose is established, the horse is maintained on that dose for life.

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 injectable form, which has to be administered twice a day, is impractical for long-term use.

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

A third medication is pergolide mesylate (Prescend), a dopamine agonist that recently has become a very viable treatment alternative.

Conclusion

Horses whose symptoms are fairly mild definitely may 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. Caring for a horse with Cushing’s syndrome requires meticulous health management and preventative care. Key points are diet, vaccinations, deworming, hoof care and dentistry. Frequently these horses require body-clipping in the summer months to remove excessive coat. Treasured equine friends with Cushings can live a happy life if when their condition is well managed.

Contact Arizona Equine today if you have any further questions or are seeking treatment for your horse.

References

1. Schott II HC. Pituitary pars intermedia dysfunction: challenges of diagnosis and treatment. Proc AAEP 2006.

2. McFarlane D. Role of the equine hypothalamic-pituitary pars intermedia axis in health and disease. Proc AAEP 2006.

3. Lloyd DH, Littlewood JD, Craig JM, Thomsett LR. Practical Equine Dermatology. Hoboken: Blackwell Publishing; 2008:106. 4. Donaldson MT, Jorgensen AJ, Beech J. Evaluation of suspected pituitary pars intermedia dysfunction in horses with laminitis. JAVMA 2004;224(7):1123-1127.

5. McFarlane D. Clinical forum: diagnosing pituitary pars intermedia dysfunction. Compend Equine 2007;2(4):208-213.

6. McFarlane D. Diagnosing equine pituitary pars intermedia dysfunction in ambulatory practice. Proc AAEP 2008.

7. Beech J, Boston RC, McFarlane D, Lindborg S. Evaluation of plasma ACTH, α-melanocyte–stimulating hormone, and insulin concentrations during various photoperiods in clinically normal horses and ponies and those with pituitary pars intermedia dysfunction. JAVMA 2009;235:715-722.

PPID is a common condition in older horses and ponies.  30% of 15 year old horses and 80% of 30 year old horses will be affected.  There will be a wide range of (clinical) signs.

Often the clinical signs of Cushing's disease will be quite obvious but usually further tests will be needed to confirm the diagnosis. Unfortunately simply measuring the levels of Cortisol in the blood is not very reliable as there is quite a large variation in levels in normal horses, and levels fluctuate throughout the day. However there are other blood tests we can carry out :–

Ideally, we would test blood levels of ACTH, glucose, and insulin to give us the best picture of what is going on in each case. ACTH levels are used for monitoring response to treatment.

In laminitics, we will also test for Equine Metabolic Syndrome

NB It is also important to run routine blood tests (haematology and biochemistry) to check other body systems e.g. the liver which may be compromised in older horses or to identify underlying infection. Underlying disease may affect the choice and dose of drugs to be used for treatment.

Siskin after treatment

Unfortunately, due to the nature of the condition, we can not cure horses with PPID, but we can manage them very successfully improving their quality of life (massively in some cases). Management is usually based around administration of drugs that eliminate clinical signs, combined with a healthy diet and regular preventative medicine e.g. worming and dentistry.

The drug of choice is called Pergolide (Prascend), which is a dopamine agonist.  This drug is very effective,with a wide dose range and is licensed for use in horses.  It will need to be given daily for the rest of the horse’s life.  The rate of improvement after starting treatment is variable, depression and lethargy are usually lost first and the horse is brighter and more energetic after a few weeks. Most importantly, there is a reduction in the painful bouts of laminitis. The hairy coat may take a little longer to improve. Treatment can be very successful and returns many horses to normal health for several years. (Our longest patient under treatment currently has been under control for >7 years.) Regular blood testing for ACTH levels are required to monitor the response to treatment and to see if adjustments to drug dosage are required.

Horses suffering with ECD are immunosuppressed so preventative health care is very important and seemingly mild ailments such as a touch of dermatitis or snotty nose should be treated as a matter of urgency. It is important that ECD horses are vaccinated and wormed appropriately.

Successful management of ECD sufferers requires the following;

Pituitary Pars Intermedia Dysfunction (PPID) remains the most commonly diagnosed endocrinopathy in the horse. Degeneration of the dopaminergic neurons in the hypothalamus causes a loss of the normal tonic inhibition of the pars intermedia.

This leads to overproduction of many peptides including proopiomelanocortin, α-melanocytestimulating hormone, corticotrophin-like intermediate peptide and ACTH. Clinical signs of PPID include hirsutism, sweating, abnormal fat deposition, muscle wastage, laminitis, lethargy and polydipsia.

Diagnosis in advanced cases is often easy based on the presence of clinical signs. However, laboratory diagnosis is important for less advanced cases and to aid in monitoring the response to treatment.

The recommended diagnostic tests for PPID have not changed in the last few years and diagnosis relies mainly on measurement of basal Adrenocorticotropic hormone (ACTH) concentration or the response to the administration of Thyrotropinreleasing hormone (TRH).

Recent research has focused on learning more about the interpretation of these tests under different circumstances. The result of this is that many more ‘grey-areas’ have become apparent and having a clear cut-off value to reach a diagnosis is more difficult. It is likely that over the next few years, we will be able to reach a better understanding of how to most effectively use and interpret these tests.

This document summarises some of the currently available information, which should help in reaching a diagnosis in clinical practice. An excellent resource is the Equine Endocrinology Group website.

Basal plasma ACTH concentration

This is the recommended first line test Sampling protocol:

Interpreting the result

When using this test in horses with advanced clinical disease the test has both a high sensitivity and specificity. However, when this test is used as a screening test in horses with a lower incidence of disease (for example younger horses with vague clinical signs) then the positive predictive power of the test falls significantly and many false positives occur.

Season (and specifically day-length) has a major impact on ACTH concentration in normal horses. Healthy horses have a significant increase in ACTH concentration in the Autumn. Recently, much higher cut-off values for the diagnosis of PPID in the Autumn months have been proposed than those that have traditionally been used. There is also much less certainty that testing in the Autumn leads to an increased sensitivity of diagnosis rather than a greater rate of false positive test results.

The following table summarises the suggested cut-offs agreed at the recent ACVIM endocrinology special interest group meeting. Results are listed in pg/ml.

During the Autumn months there may be greater variation in ACTH concentrations than previously thought. Durham (2020) has recently published reference ranges by week. These are shown in the following figure (Reference Durham et al 2020). This graph shows the weekly variation in ACTH concentrations of a large mixed population of horses.

This data also demonstrates the importance of considering the signalment of the horse being tested. In a young horse without clinical signs the positive predictive value of ACTH is low and so a threshold with a higher specificity is required (this is shown with the open circles). In an aged horse with hirsutism or more obvious clinical signs then a test with a higher sensitivity is required (black triangles).

The breed of horse being tested should also be considered. Pony breeds, Arabians and donkeys have all been shown to have higher plasma ACTH concentrations, especially in the Autumn months. Concurrent disease, stress and travel can also have an impact on ACTH concentration and the presence or absence of these factors should be considered when interpreting any result. It is also important that the assay used is considered when interpreting a result as reference ranges vary according to the test used. In summary, ACTH concentration remains the initial screening test for diagnosis of PPID. When interpreting a result, consideration should be given to the factors discussed above and a clinical judgement made as to the likelihood of a diagnosis of PPID. The diagnostic threshold used will vary depending on the case being tested and repeat testing or a TRH stimulation test may be needed for further evaluation.

Thyrotropin releasing hormone stimulation test (TRHST)

This is currently considered the most accurate test for the diagnosis of PPID. The test relies on an excessive pituitary response to the administration of Thyrotropin-releasing hormone (TRH) in horses with PPID when compared to normal horses.

However, the test still has limitations and ongoing research is needed to help us fully understand how to interpret the results. This test is appropriate when the results of a basal ACTH test have been equivocal, or in a case in which PPID is still suspected despite a negative ACTH test result.

Sampling protocol

Availability of TRH

Pharmaceutical grade TRH is not available on the veterinary or human markets in the UK.

Chemical grade TRH can be cheaply purchased from here https://phoenixpeptide.com - the specific product is listed here.  We believe this to be legal via the cascade but full VMD guidance can be found here.

Preparation of TRH

The TRH comes in a vial of 25mg which should be stored in the refrigerator. This should be diluted with 5mls of sterile water to make a 5mg/ml solution. 0.2mls (1mg) of this solution should be drawn up from the vial and diluted with a further 0.8mls of sterile water to give a total volume of 1ml. This should be injected intravenously.

TRH is stable at room temperature once reconstituted for 18 days, or after freezing and thawing. This means that multiple syringes of 1mg of TRH can be made up at one time and stored in the freezer for future use.

Interpreting the result

Seasonal differences in the response to TRH occur in healthy horses. Currently there is not enough data available to establish accurate cut off values to support a diagnosis of PPID during the Autumn months.This has led to the recommendation that this test is best avoided in the autumn months (mid-July to mid- November). However, an ACTH of <110 pg/ml 10 min after TRH administration in the autumn months can be useful to exclude a diagnosis of PPID.The following table summarises the current diagnostic thresholds recommended by the Equine Endocrinology Group.

In horses with equivocal results that have clinical signs highly suggestive of PPID or active laminitis, it may be prudent to treat the horse with pergolide. In other situations, it will be more appropriate to wait and retest the horse in 2-3 months.

Side effects of TRH administration

Side effects are rare but include trembling, lip-smacking and flehmen type behaviour.

Dexamethasone suppression test

This test was previously considered the gold standard for the diagnosis of PPID. However, this test is much less reliable than the other tests previously discussed. The test is also unreliable in the Autumn months and requires the administration of corticosteroids which is often contra-indicated in horses judged to be at high risk for the development of laminitis. Consequently, this test is not currently recommended.

Other tests in horses with PPID