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					          Diagnosis and Management of Equine Cushing’s Disease
                                Harold C. Schott II, DVM, PhD, DACVIM
                                   Professor, Equine Internal Medicine
                              Department of Large Animal Clinical Sciences
                                    D-202 Veterinary Medical Center
                         Michigan State University, East Lansing, MI 48824-1314
                                 (517)-353-9710 schott@cvm.msu.edu


Prevalence: Although the frequency of diagnosis and treatment of pituitary pars intermedia dysfunction
(PPID) in horses has clearly increased over the past decade, there is no evidence that the prevalence of
PPID is actually increasing. Increased recognition of the disease is likely a consequence of clients
maintaining their horses to more advanced ages as well as improved health care (e.g., diet and dentistry)
being provided to older horses. A recent survey of horse owners in Queensland, Australia revealed a
prevalence of 15-20% of PPID in horses and ponies 15 years of age and older. There is no gender
predilection and average age of affected horses is around 20 years. All breeds and types of equids can
be affected with PPID but Morgan horses and ponies appear to be at greater risk.

Pathophysiology: In humans and dogs, Cushing’s disease is most commonly attributed to a corticotroph
adenoma in the pars distalis of the pituitary gland. These adenomas are thought to arise spontaneously.
In contrast, Cushing’s disease in horses is almost exclusively attributed to hyperplasia or adenoma
formation in the pars intermedia that appears to be due to loss of hypothalamic innervation. Abnormal
pars intermedia tissue in horses contains markedly reduced amounts of dopamine, about 10% that of
normal pars intermedia tissue, consistent with a specific loss of hypothalamic dopaminergic innervation.
Recent evidence suggests that this loss of dopaminergic innervation is due to oxidant-induced injury to
hypothalamic tissue. Thus, a risk factor for affected horses may be reduced anti-oxidant defense
mechanisms in neural tissue. Further, insoluble aggregates of the neural protein α-synuclein have been
found in dopaminergic nerve terminals of PPID-affected horses. These protein aggregates are also found
in humans with Parkinson’s disease suggesting that the two neurodegenerative disorders may share a
similar pathogenesis. However, the population of neurons affected in horses, as compared to humans,
appears to be different leading to the difference in clinical signs observed in each species.

Abnormal pars intermedia cells, exclusively melanotropes, produce excessive amounts of pro-
opiomelanocortin (POMC) and a number of POMC-derived peptides including adrenocoticotropin (ACTH).
Also unlike Cushing’s disease in humans and dogs, adrenocortical hyperplasia accompanying equine
Cushing’s disease is relatively uncommon, occurring in ~20% of affected horses. These differences in
location and pathophysiology between human, canine, and equine pituitary adenomas have lead several
authors to suggest that the disease in horses should not be called equine Cushing’s disease; rather,
pituitary pars intermedia dysfunction (PPID) has been advanced as a more appropriate descriptor.

Clinical signs: The classic clinical sign of PPID in horses is hirsutism, a long and curly hair coat that fails
to shed. In some affected horses, coat color changes have also been observed. The pathogenesis of
hirsutism, which is characterized by arrest of hair follicles in telogen, remains unknown. Hyperhidrosis is
also observed in up to two-thirds of horses with PIPD, most commonly over the neck and shoulders, and
has been attributed to a thermoregulatory response to the long hair coat. Weight loss and lethargy, or
poor performance, are also commonly observed in horses with PPID. In addition to true weight loss,
protein catabolism due to increased cortisol activity leads to loss of muscle mass. This is most notable in
advanced cases as a loss of epaxial and rump musculature. Despite weight loss, appetite in affected
horses is normal or even increased (polyphagia). However, dental abnormalities, leading to painful
mastication and quidding, may compromise feed intake and contribute to weight loss in some horses.
Combined with, or often preceding, loss of muscle mass is deposition of fat along the crest of the neck,
over the tail head, and in the sheath of male horses. Another area where abnormal fat deposition may
occur is above and behind the eyes. Horses with PPID have also been described as overly docile and
more tolerant of pain than normal horses. The latter signs have been attributed to increased plasma and
cerebrospinal fluid concentrations of -endorphin that are 60- and more than 100-fold greater,
respectively, in horses with PPID than in normal horses.

Chronic, insidious-onset laminitis is perhaps the major clinical complication of PPID with more than 50%
of horses affected in most reports. Although the condition is more amenable to management in ponies
due to their lower body weight, chronic or recurrent pain with exacerbation of laminitis or associated foot
abscesses is often the reason for euthanasia. Polydipsia and polyuria (PU/PD) develops in about one-
third of horses with PPID. Equids with PPID tend to have delayed wound healing and are frequently
affected with secondary infections. Commonly recognized infections include skin infections (e.g.,
refractory “scratches” and fistulous tracts), recurrent subsolar abscesses, conjunctivitis, sinusitis,
gingivitis, alveolar periostitis, and bronchopneumonia.

Other signs that have been reported in horses with PPID include persistent lactation and infertility. Central
nervous system (CNS) dysfunction, including ataxia, blindness, dementia, and seizure-like activity, are
occasionally observed in equids with PPID. A major complication of hypercortisolism in affected human
patients is osteoporosis. Although occurrence of this complication has not been investigated in horses, it
is interesting to note that euthanasia of horses with PPID has been reported due to development of
pelvic, pedal bone, mandibular, and multiple rib fractures.

Clinicopathologic findings: Abnormal laboratory data in horses with PPID may include mild anemia, an
absolute or relative neutrophilia, and an absolute or relative lymphopenia. Although one or more of these
abnormalities is usually found in a third or more of equids afflicted with PPID, the true prevalence is not
well documented. As well as being increased in number, neutrophils in affected animals may appear
hypersegmented. This finding reflects maturity of neutrophils and can be attributed to a longer half-life of
circulating neutrophils because cortisol excess limits diapedesis from the vasculature. Eosinopenia is also
recognized in human and canine patients with hyperadrenocorticism but is difficult to document in horses
because equids typically have a low numbers of circulating eosinophils. The most common abnormality
detected on serum biochemical evaluation is mild to moderate hyperglycemia, reported in 25-75% of
cases, depending on the upper end of the reference range used. Additional abnormal biochemical
findings may include elevations in liver enzyme activities, hypercholesterolemia, and hypertriglyceridemia.

Diagnosis: Practically, the diagnosis of PPID is most commonly made by observation of hirsutism and
other clinical signs in older equids. However, establishing a diagnosis of PPID in less severely affected
horses can be challenging. As a result, a number of endocrinologic tests have been used to evaluate
horses with suspected PPID.

Plasma cortisol concentration and loss of diurnal cortisol rhythm. Although hyperadrenocorticism can be
accompanied by an elevated plasma cortisol concentration, resting cortisol concentration does not
routinely exceed the upper end of the reference range in horses with PPID. Thus, measurement of
plasma cortisol concentration alone is not a valid diagnostic test. Because plasma cortisol concentration
has a diurnal rhythm of secretion, with an increase in the morning hours, loss of the diurnal rhythm has
been advanced as an accurate screening tool for evaluation of horses with suspected PPID. However,
the effects of external stressors and disease on plasma cortisol concentration make loss of cortisol
rhythmicity a poor screening tool for PPID.

Dexamethasone suppression test: The overnight dexamethasone suppression test (DST) is considered
by many equine clinicians to be the “gold standard” endocrinologic test to support of a diagnosis of PPID.
However, this statement is not without controversy and there is concern, although poorly documented,
that administration of dexamethasone may induce or exacerbate laminitis in PPID-affected equids. In its
most simple form, the overnight DST consists of measuring cortisol in the late afternoon (typically 5 pm)
followed by administration of dexamethasone (40 g/kg, IM = 20 mg to a 500 kg horse) and subsequently
measuring plasma cortisol concentration 17 to 19 hours later (between 10 am and noon the following
day). The major limitation of the overnight DST for ambulatory practitioners is that it requires two visits to
the horse. However, considering the fact that the most important value is the cortisol concentration
following dexamethasone administration, the overnight DST can be simplified by dispensing
dexamethasone to the client for administration and limiting the test to one visit the following morning.
When using this test, it is probably wise to consider dexamethasone as a “sledgehammer” in terms of
feedback to the hypothalamic-pituitary axis. In other words, failure of dexamethasone to induce
suppression of circulating endogenous cortisol concentration is strongly supportive of PPID. However, the
overnight DST may be less effective in diagnosis of PPID in the earlier stages of the disease process. In
this clinician’s opinion, this is not an important limitation of the test because in the earlier stages of PPID,
when DST results may be normal (not supportive of PPID), it may be difficult to justify treatments other
than body clipping to limit hirsutism.

An important limitation of using the DST is that seasonal variation can affect results. In a recent study of
horses and ponies without clinical signs of PPID, abnormal DST results were found in 10 of 39 equids in
September. To further examine the effect of season on DST results, the author performed the overnight
DST monthly for a year in a group of 18 aged horses (>19 years) without clinical signs of PPID. Seven of
18 horses had normal overnight DST results throughout the year while 11 horses had overnight DST
results supportive of PPID from 1 to 9 months of the year. Test results from late July through late October
(in the northern hemisphere) were most commonly affected by seasonal variation. Thus, the overnight
DST is best performed from December through June and overnight DST results from July through
November, if abnormal, should be interpreted with caution. Although the author prefers not to perform the
test during these months, it warrants emphasis that normal overnight DST results during late summer to
fall can be useful. A further observation in the author’s study that warrants mention is that no signs of
laminitis were induced in this group of older horses during performance of 216 overnight DSTs.

Thyrotropin stimulation test and combined dexamethasone suppression/thyrotropin stimulation test.
Thyrotropin (TRH) is a releasing hormone for several pituitary hormones that has been shown to increase
plasma cortisol concentration when administered to horses and ponies with PPID. In theory, the TRH
stimulation test should be a more specific test for PPID because TRH receptors are found on
melanotropes in the pars intermedia but not on corticotrophs in the pars distalis. Although the TRH
stimulation test has not been as well validated as the overnight DST, it has also been advocated for use
in horses with laminitis because of concerns about exacerbating foot pain following dexamethasone
administration. When used, a 50% increase in cortisol concentration between 15 and 90 minutes after
administration of TRH can be supportive of a diagnosis of PPID. Unfortunately, interpretation of the
response is complicated by considerable variability of the initial cortisol concentration as well as the
problem that up to 50% of normal horses may have a false-positive result with this test. Thus, although
theoretically better, the TRH stimulation test has not been demonstrated to be either highly sensitive or
specific and is no longer recommended as an endocrine test for diagnosis of PPID.
In an attempt to overcome these problems with the TRH stimulation test, a combined DST/TRH
stimulation test has been developed. Three hours prior to TRH administration, dexamethasone (40 g/kg,
IM) is administered to suppress cortisol concentration to similar values in both PPID-affected and normal
horses. Cortisol concentration is subsequently measured before and 30 minutes after TRH (1 mg, IV)
administration and equids with PPID show an increase in comparison to a lack of change in normal
animals. After 24 hours, plasma cortisol concentration remains suppressed in normal horses while it
returns to the basal (pre-dexamethasone) concentration in PPID affected horses. Although this combined
test appears to improve the accuracy of the TRH stimulation test, it is both more expensive for the client
as well as less practical for the ambulatory clinician than the overnight DST. As a consequence, this
combined test has not been widely used.
Plasma ACTH concentration. Horses with PPID typically have excessive amounts of ACTH in abnormal
pars intermedia tissue and increased amounts of ACTH are released into plasma. Thus, plasma ACTH
concentration would seem a likely choice for a single sample test to support a diagnosis of PPID. In fact,
increased plasma ACTH concentrations, with a maximum reported value exceeding 12,000 pg/ml, have
been documented in several reports of PPID in equids. Further, ACTH concentrations exceeding 27 or 50
pg/ml (6 and 11 pmol/l) in ponies and horses, respectively, have been reported to have a high
sensitivity for diagnosis of PIPD. Limitations of using plasma ACTH concentration as the only
endocrinologic test to support a diagnosis of PPID are that sample handling can be problematic and that
different laboratories may use different assays for measuring ACTH. Because ACTH can be adsorbed
onto glass and can be degraded by proteolytic enzymes in both whole blood and plasma, collection of
blood into plastic tubes, rapid separation from red cells, and freezing of plasma prior to shipment for
analysis has been recommended. Practitioners interested in using ACTH concentration as a diagnostic
aid should contact the testing laboratory prior to sample collection for sample handling recommendations
and should only send samples to a laboratory using an assay that has been validated as specific for
ACTH in equine plasma. As with the overnight DST, another limitation of using plasma ACTH
concentration is seasonal variation in test results. In normal ponies and horses without signs of PPID,
plasma ACTH concentrations measured in September were above the threshold for diagnosis of PPID.
This finding complicates use of plasma ACTH concentration as the sole endocrinologic test for both
diagnosis and monitoring response to treatment of PPID.

Domperidone stimulation test. The most recent endocrinologic test developed for diagnosis of PPID is a
provocative test utilizing administration of domperidone, a dopamine receptor antagonist. In theory, this
drug should exacerbate the loss of dopaminergic inhibition in horses with PPID and thereby increase
release of endogenous ACTH by pars intermedia melanotropes. To test this hypothesis, plasma ACTH
concentration was determined in 33 horses with or without clinical signs of PPID prior to and 4 and 8
hours after oral administration of domperidone (3.3 mg/kg). After testing, horses were euthanized for
histopathological examination of the pituitary glands. In this study, plasma ACTH concentration increased
modestly (by about 50%) in horses without clinical signs of PPID or significant pars intermedia pathology
while plasma ACTH concentration more than doubled in horses with clinical signs of PPID and more
advanced pars intermedia histolopathologic abnormalities. Unfortunately, the domperidone challenge test
was performed in the late summer and fall in some horses leading to seasonal variation as a possible
confounding factor. Nevertheless, this novel test may offer promise of detection of PPID in the earlier
stages of the disease and further investigation is warranted.

Serum insulin concentration. Many equids with PPID, especially ponies, may have insulin insensitivity and
the frequency of hyperinsulinemia appears to be greater than that of hyperglycemia. As a consequence,
an elevated fasting serum insulin concentration could support a diagnosis of PPID. However,
hyperinsulinemia can accompany other metabolic disorders including type II diabetes mellitus and the
“equine metabolic syndrome”. Thus, use of serum insulin concentration alone as a supportive test for
diagnosis of PIPD can be misleading because hyperinsulinemia is not specific to PPID. However,
measurement of fasting insulin concentration may be of benefit in the initial evaluation of equids with
suspected PPID because one case series found poorer survival in PPID-affected equids with
hyperinsulinemia as compared to PPID equids with a normal insulin concentration.

Management: Management of pituitary pars intermedia dysfunction (PPID) in equids consists of
improved husbandry, including adequate nutrition and limiting competition for feed, body-clipping,
dentistry, and appropriate treatment of concurrent medical problems. In addition, specific treatment with
the dopamine agonist pergolide can improve quality of life and reverse many clinical signs of the disease
in PPID-affected equids. Treatment with both pergolide and cyproheptadine, in the author’s experience,
may also prove beneficial in more advanced cases. For patients with chronic laminitis, appropriate
trimming or shoeing and judicious use of analgesic medications is also necessary. Although many
nutritional supplements and nutraceuticals have been advocated for use in equids with PPID, none have
established data to support their claimed benefits. Finally, due to the expense of lifelong medication, a
decision of whether or not to treat affected horses with pergolide should be made on a case-by-case
basis in consideration of the client’s goals for the patient.

Husbandry and nutritional considerations. Management of equids with PPID initially involves attention to
general health care along with a variety of management changes to improve the condition of older
animals. In the earlier stages of PPID, when hirsutism may be the primary complaint, body-clipping to
remove the long hair may be the only treatment required. Next, since many affected animals are aged,
routine oral care and correction of dental abnormalities cannot be overemphasized. In addition,
assessment of diet and incorporation of pelleted feeds designed specifically for older equids (e.g., senior
diets) should be pursued. In the author’s experience, aged horses both with and without clinical signs of
PPID can easily gain 50 or more pounds within 3-4 weeks of placing them on a Senior feed.
Sweet feed and other concentrates high in soluble carbohydrate are best avoided (unless that is all that
horse will eat), especially when patients are hyperinsulinemic, hyperglycemic, or both. Also, affected
equids may need to be separated from the herd if they are not getting adequate access to feed.
Unfortunately, because the abdomen may become somewhat pendulous, weight loss and muscle wasting
in more severely affected animals may not be well recognized by owners. In these instances,
measurement of body weight, or estimation with a weight tape or body condition score, are important
parameters to monitor during treatment.

Whether or not it is “safe” to allow PPID-affected equids to graze pasture as a forage source remains
controversial. Pasture, especially lush spring and early summer pasture, should be considered similar to
feeding concentrates high in soluble carbohydrates and many veterinarians recommend that PPID-
affected equids NOT be turned out on pasture. In my opinion, it is important to assess the overall
condition of the patient. If the horse or pony is considered overweight and has abnormal fat deposits,
supportive of insulin resistance, pasture turn out would not be recommended. Instead, feeding grass hay
at 1.5% of the body weight daily would be the preferred forage diet and animals that are overweight
clearly do not need an additional “low starch” concentrate feed. However, if body condition is somewhat
poor, strategic grazing for several hours per day can be a useful way to increase caloric intake and
produce weight gain. Again, caution is advised and access to lush spring or early summer pasture should
be avoided or at least limited to one or more shorter periods per day, especially if there is a history of
laminitis.

Hoof care and secondary infections. Since the major musculoskeletal complication of PPID is chronic
laminitis, regular hoof care is essential to lessen the risk of flare-ups. It is important to emphasize to
clients that starting medical treatment for PPID (i.e., pergolide) may not lead to complete resolution of the
pain and intermittent hoof abscessation that accompanies chronic laminitis, due to the damage to the
laminar bed that has previously been sustained. Further, intermittent use of non-steroidal anti-
inflammatory drugs, primarily phenylbutazone, may be necessary. Although flare-ups of chronic laminitis
remain a leading cause for a decision for euthanasia in PPID-affected equids, it also warrants emphasis
that a combination of medical treatment for PPID along with regular hoof care can lead to substantial
clinical improvement. Finally, because many PPID affected patients may have secondary infections (e.g.,
sinusitis, dermatitis, and bronchopneumonia), intermittent or long-term administration of antibiotics,
typically a potentiated sulfonamide, may be necessary.

Medications for treatment of PPID: Medications that have been used to treat equids with PPID include
serotonin antagonists (cyproheptadine), dopamine agonists (pergolide mesylate), and, more recently, an
inhibitor of adrenal steroidogenesis (trilostane). Cyproheptadine was one of the initial drugs used because
serotonin had been shown to be a secretagogue of ACTH in isolated rat pars intermedia tissue. Early
indications that cyproheptadine (0.25 mg/kg, q 12-24 h) results in clinical improvement and normalization
of laboratory data within 1-2 months have been disputed as a similar response has been obtained with
improved nutrition and management alone. The margin of safety of cyproheptadine appears to be high as
several horses have received twice the recommended dose twice daily without untoward effects. Mild
ataxia has been described in some horses treated with cyproheptadine but this author has not observed
this.
Because loss of dopaminergic innervation appears to be an important pathophysiologic mechanism for
PPID, treatment with dopaminergic agonists represents a logical approach to therapy. Pergolide
administered in both “high dose” (0.006-0.01 mg/kg, PO, q 24 hours [3-5 mg to a 500 kg horse]) and “low
dose” (0.002 mg/kg, PO, q 24 hours [1 mg/day for a 500 kg. horse]) protocols have been reported to be
an effective treatment. Adverse effects of pergolide include anorexia, diarrhea, and colic; however, the
latter problems are more often associated with higher doses of the drug. Usually, only transient anorexia
is recognized during the initial week of “low dose” pergolide treatment and can be overcome in time or by
cutting the dose in half for 2-4 days.

Trilostane (0.4-1.0 mg/kg q 24 hours in feed), a competitive inhibitor of 3-β-hydroxysteroid
dehydrogenase, has been reported to be effective in reversing both clinical signs (primarily laminitis) and
abnormal endocrinologic test results in a series of equine PIPD cases. However, horses and ponies in
that study received additional management for laminitis and the “improvement” in endocrinologic test
results was not overly convincing. In contrast, early attempts at treatment with the adrenocorticolytic
agent o,p’-DDD were largely unsuccessful. Because adrenocortical hyperplasia has been recognized in,
at most, 20% of horses with PPID, drugs targeting adrenal steroidogenesis would intuitively seem less
likely to be successful. However, it is possible that concurrent use of pergolide and trilostane (currently
not available in the United States) could produce a greater clinical response than use of pergolide alone.

At present, it is the author’s opinion that the initial medical treatment for equids with PPID should be
pergolide mesylate at a dose of 0.002 mg/kg, PO, q 24 hours. If no improvement is noted within 8-12
weeks (depending on season as hair coat changes will vary with the time of year that treatment is
initiated), the daily dose can be increased by 0.002 mg/kg monthly up to a total dose of 0.006 mg/kg (3
mg/day for a 500 kg horse). If only a limited response is observed with 0.006 mg/kg of pergolide and
endocrinologic test results remain abnormal, the author typically recommends addition of cyproheptadine
(0.5 mg/kg, PO, q 12 hours) to pergolide therapy. It is important to recognize that the rate of clinical
improvement is higher than that for normalization of hyperglycemia and endocrinologic test results. For
example, in a treatment study performed by the author, 13 of 20 pergolide treated horses were reported
to have improved clinically while only 7 of 20 had normalization of endocrinologic test results. Thus, it is
prudent to measure blood glucose concentration and regularly perform follow-up endocrinologic testing
when managing an equid with PPID. The author currently recommends performing an overnight DST (or
measurement of plasma ACTH concentration) at least yearly in horses that appear to be stable and 6-8
weeks after a change in medication dose or addition of cyproheptadine). Finally, it is important to
remember that, at present, treatment with either pergolide or cyproheptadine remains both empirical and
off-label, as pharmacological studies of the drugs have not been performed in equids. Further, although
pregnant mares have been treated with the drugs, safety of use during pregnancy has not been studied in
equids. Pergolide mesylate is currently only available from a number of compounding pharmacies as the
pharmaceutical grade tablets (Permax) were recently removed from the human market due to
development of heart valve problems in a limited number of patients. A major advantage of the
compounded products is lower cost; however, pergolide may not remain stable in an aqueous solution
(suspension) for longer than 7 days. Thus, it is important to determine how the drug is prepared and
dispensed by the compounding pharmacy before specific formulations can be recommended for use.

As with many chronic diseases in the horse, specific nutrient supplementation and complementary or
alternative therapies, including acupuncture, homeopathy, and herbal remedies, have been
recommended and used in equids with PPID. Both magnesium and chromium supplementation have
been advocated for supportive treatment of this condition. Magnesium supplementation (to achieve a
dietary calcium:magnesium ratio of 2:1) has been recommended because magnesium deficiency appears
to be a risk factor for insulin insensitivity and type 2 diabetes in humans and anecdotal reports suggest
that supplementation may help horses with obesity-associated laminitis. Similarly, chromium
supplementation is recommended to improve carbohydrate metabolism (specifically glucose uptake) and
improve insulin sensitivity in type 2 diabetes. An herbal product made from chasteberry has also been
advocated for treatment of PPID. However, the claim was supported with a series of case testimonials in
which the diagnosis of PPID was poorly documented and a recent field study demonstrated that this
herbal product was ineffective for treatment of PPID.
Prognosis: Once present, PPID is a lifelong condition. Thus, the prognosis for correction of the disorder
is poor. However, PPID can be effectively treated with a combination of management changes and
medications. Thus, the prognosis for life is guarded to fair. There has been little longitudinal study of
equids with PPID but in one report survival time from initial diagnosis to development of complications
necessitating euthanasia ranged from 120 to 368 days in four untreated horses. Further, there are
numerous anecdotal reports of horses being maintained for several years as long as response to medical
treatment was good and close patient monitoring and follow-up was performed. The author has followed a
handful of horses treated for PPID with pergolide for nearly a decade and has gained a clinical impression
that the drug improves the quality of life but that does not necessarily equate to prolonging life. A recent
case series also found that concurrent presence of hyperinsulinemia with PPID was a negative prognostic
factor. This finding supports measurement of fasting insulin concentration in the initial evaluation and
ongoing management of horses with PPID.

				
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