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Evidence indicates that loss of dopamine inhibition is critical to the
pathology of Cushing’s Syndrome. Dopamine and dopamine-metabolite
concentrations in the pituitary pars intermedia of Cushing’s Syndrome
horses is decreased eight fold compared to age matched controls.
Supplementation of dopamine or a dopamine agonist to horses with
Cushing’s Syndrome results in a decrease in plasma concentration of
excess hormones (McFarlane, 2006). Please see the section on Pergolide
below for further information on dopamine agonists.
Diagnosis of ECS
Determining the sensitivity and specificity of diagnostic tests for ECS
is difficult due to the small numbers of cases confirmed by histological
examination of the pituitary gland. Hirsutism has been considered the
gold standard for ECS because it is pathognomonic. There are basically
two types of endocrine tests, basal and dynamic. Basal tests can be
obtained by a single sample but are limited due to a reduction in
sensitivity and specificity of diagnosis. Dynamic endocrine testing can
provide much greater diagnostic sensitivity and specificity.
Basal tests
Basal plasma ACTH concentration
Basal ACTH has been shown to be quite sensitive (>90%) and is the best
option for a basal diagnostic test, however it is recommended that serum
insulin be monitored during the course of treatment (McGowan, 2005).
Horses with plasma ACTH values greater than 50 pg/ml are very likely to
have ECS.
Further reference material on ACTH: A high plasma ACTH level should be a
good indicator of ECS because the hyperplastic pars intermedia produces
excessive amounts of pro-opiomelanocorticotropes (POMCs) that are
cleaved into ACTH and other corticotrope-like hormones and released into
the circulation (Orth et al., 1982, Wilson et al., 1982). However,
pulses of ACTH are released from the pituitary causing peaks in plasma
ACTH approximately every 11-17 minutes, but are not equal in all horses
and can significantly affect a single plasma ACTH measurement (Cudd et
al., 1995). Horses with advanced ECS had plasma ACTH concentrations
above the reference range (Dybdal et al., 1994, Perkins et al., 2002,
van der Kolk et al., 1995). In one article (Couetil et al., 1996) plasma
ACTH concentrations were evaluated in a group of healthy equids composed
of 18 horses and 9 ponies, and in 22 equids with a clinical diagnosis of
hyperadrenocorticism (11 horses and 11 ponies). The mean plasma ACTH
concentration in horses and ponies with ECD, (199.18 +/- 182.82 pg/mL
and 206.21 +/- 319.56 pg/mL, respectively), were significantly higher
than the mean ACTH concentration in the control animals (18.68 +/- 6.79
pg/mL (mean +/- SD) and 8.35 +/- 2.92 pg/mL, respectively; P < .001). In
The Michigan Cushing’s Project (Schott et al., 2001), of 77 horses
enrolled in the study, plasma ACTH concentration was elevated in 64% of
horses that had DST or TRH results supportive of Cushing’s Syndrome.
Measurement of plasma ACTH concentration was found to produce both false
positive and false negative results when compared with DSH or TRH
results for diagnosis of a pituitary adenoma. The sensitivity and
specificity a chemiluminescent immunoassay for ACTH in the diagnosis of
ECS was reported to be 84% and 78% respectively (Donaldson et al.,
2004). In another study (Donaldson et al., 2002), stated that baseline
endogenous ACTH concentration is a valuable diagnostic test for ECS,
however not all horses with ECS will have high plasma concentrations of
ACTH and that evaluation of a single sample may lead to a false-negative
diagnosis. False positives were attributed to stress (e.g. associated
with laminitis) and subsequent ACTH release.
Blood glucose concentration
Elevations in blood glucose as a diagnostic test was developed on the
premise that horses with ECS have a high risk of developing secondary
insulin resistance and hyperglycaemia. However this does not occur in
all cases of ECS, reducing the sensitivity of the test (McGowan, 2005).
Urinary corticoid:creatine ratio
This is generally higher in horses with ECS but has a low sensitivity
and specificity so is not recommended for diagnosis (McGowan, 2005).
Insulin
Basal serum insulin concentration has been shown to be sensitive (>90%)
test for the diagnosis of Cushing’s disease, but has been shown to have
a low specificity so is not recommended as a diagnostic test. False
positives can occur in overweight ponies with insulin resistance.
Further reference material on insulin and ECS: Horses with ECS are
frequently insulin resistant and have increased serum glucose and
insulin concentrations (Garcia & Beech, 1986). Hyperglycaemia, while
only having a reported sensitivity of 64% may be a useful guide for
evaluating response to treatment. In The Michigan Cushing’s Project
(Schott et al., 2001), of 77 horses enrolled in the study, serum insulin
concentrations were elevated in 71% of horses that had DST or TRH
results supportive of Cushing’s Syndrome. A group of horses were
identified who had clinical signs of abnormal fat deposition and
laminitis, without hirsutism but had elevated serum insulin
concentrations and normal DST or TRH results. Differential diagnosis of
these horses is important as they would not be expected to improve with
treatment with pergolide. A lack of decline in serum insulin
concentrations in pergolide treated horses has been observed (Donaldson
et al., 2002). This may be due to incomplete factors that result in
dysregulation of insulin secretion. Because of normal daily fluctuations
in insulin level, the evaluation of single samples may be misleading
(McGowan et al., 2004). It is also possible that hyperinsulinaemia might
persist in spite of effective control of ECS in obese horses.
Cortisol
Basal serum cortisol concentration has no value as a diagnostic test for
ECS as it can be low, normal or elevated in horses with ECS (McGowan,
2005).
Dynamic endocrine tests
The overnight low-dose dexamethasone suppression test (DST) is
considered to be the most sensitive and specific diagnostic method and
is regarded as the diagnostic test of choice, however because of the
purported infrequent association between corticosteroid administration
and laminitis and the frequent existence of laminitis in affected
horses, some clinicians prefer to use other tests (Donaldson et al.,
2004, Dybdal et al., 1994).
Low dose dexamethasone suppression test (DST)
The aim of the DST is to detect a failure in the suppression of cortisol
following the administration of dexamethasone in horses with ECS. The
rationale is that the ACTH and resultant adrenal cortisol production
from affected horses are not affected by negative feedback. The pars
intermedia is not affected by negative feedback, so affected horses fail
to show a suppression of cortisol following administration of the
exogenous glucocorticoid dexamathasone. The DST is not affected by the
time of day, but it is generally more convenient to perform an overnight
test starting the afternoon before (McGowan, 2005).
ACTH stimulation test
The ACTH stimulation test assesses abnormal adrenal function so is
therefore not relevant for the investigation of ECS (McGowan, 2005).
Thyrotropin releasing hormone (TRH) stimulation test
The TRH stimulation test has been used extensively in the UK due to
popular opinion that the test was “safer” than the DST. However
according to McGowen, 2005, the test has a low sensitivity and
specificity with false positives especially in horses with initially
elevated plasma cortisol concentrations. Pharmacological grade TRH is
also expensive to obtain in Australia.
Combined Dexamethasone Suppression/TRH stimulation test
This combination does appear to be able to clearly distinguish between
normal horses and those with ECS (McGowan, 2005). The test is easier to
interpret with two points of difference between normal and ECS horses
rather than one with the DST alone, although the increase in sensitivity
and specificity is regarded as being small. The disadvantage is the
added cost and time in performing the test.
Pergolide mesylate
Cushing’s Syndrome is the most common endocrinopathy of horses, which,
to date has no therapeutic product registered specifically for animal
application. Pergolide mesylate is an ergot dopamine receptor agonist at
both D1 and D2 receptor sites. It has been sold in Australia for human
use as an anti-Parkinson’s Disease therapy as the TGA registered drug
PERMAX (Eli Lilly). Off label use of pergolide mesylate by veterinarians
has been frequent in recent years, where the drug has been described as
the “treatment of choice” for ECS. Pergolide works by binding with drug
receptors in the brain that control the production of dopamine in the
hypothalamus. Therapy of horses has consisted of either human pergolide
mesylate tablets crushed for oral use, or compound pharmacy products
produced from human product raw material. There is currently no
pergolide product registered for veterinary application.
Pergolide efficacy studies
At the 1995 Annual Meeting of the American Association of Equine
Practitioners, “low dose” pergolide therapy was advocated as the “best”
treatment for ECS (Peters et al., 1995). Since then researchers have
continued to investigate the efficacy of pergolide compared to other
treatments for Equine Cushing’s Syndrome. The Michigan Cushing’s Project
(Schott et al., 2001) was initiated in 1997 as a collaborative effort
between Michigan veterinarians and Michigan State University in an
attempt to determine if there were differences in clinical and/or
endocrine responses in horses with Cushing’s disease that are treated
with cyproheptadine (a serotonin antagonist), pergolide or those that
are untreated. After 6 months of treatment with 1mg pergolide (2 µg/kg)
or cyproheptadine (1.2mg/kg), clinical improvement was most apparent
with pergolide, although a few horses were also reported to improve with
cyproheptadine. None of the non-treated horses were reported to have any
clinical improvement. Low-dose dexamethasone suppressions test (DST) and
thyrotropin-releasing hormone (TRH) results had returned to normal (nonsupportive
of ECS) for 7/20, 1/7 and 1/5 of pergolide, cyproheptadine, and non
treated horses respectively. Mean plasma ACTH and serum insulin
concentrations decreased significantly after 6-12 months of treatment
with pergolide in contrast to a lack of significant changes in other
groups. Several pergolide treated horses were reported to have a
decrease in appetite during the first week of treatment. Reduction of
the dose for a few days seemed helpful in resolving the partial anorexia
in these horses. The results demonstrated that treatment with pergolide
produced clinical and laboratory responses superior to treatment with
cyproheptadine.
In another study (Donaldson et al., 2002) evaluated the response of
horses with ECS to treatment with pergolide or cyproheptadine by
evaluating clinical signs and plasma ACTH, insulin, and glucose
concentrations before and after treatment. Twenty horses were treated
with pergolide, while 7 were treated with cyproheptadine. The mean
pergolide dose was 3 µg/kg (range 1.7 – 5.5 µg/kg) PO q 24h. Horses were
treated for an average of 2 and 2.5 months respectively with pergolide
and cyproheptadine. ACTH concentrations were significantly lower in
pergolide treated horses and there was a correlation between ACTH
concentration after treatment and the duration of treatment and
pergolide dose. Significantly more owners of horses treated with
pergolide (85%) reported an improvement in clinical signs compared to
owners of horses treated with cyproheptadine. There were no significant
differences in insulin or glucose concentrations after treatment with
pergolide and no significant difference in ACTH, insulin or glucose
concentrations after treatment with cyproheptadine. The authors
concluded that pergolide is more effective than cyproheptadine in the
treatment of ECS.
A group of American researchers (Beech et al., 2002) investigated the
use of Vitex agnus castus (Chaste Berry) Extract compared to pergolide
in horses believed to have Equine Cushing’s Syndrome based on clinical
signs of pituitary dysfunction and elevated plasma ACTH concentrations
or dexamethasone suppression testing. The results indicated that the
Vitex agnus castus Extract used in this experiment did not have a
beneficial effect in horses with Equine Cushing’s Syndrome; clinical
signs sometimes worsened, plasma ACTH concentrations decreased in only 1
of 12 horses and the dexamethasone suppression test remained abnormal in
the horses tested. In contrast, with the exception of one horse (out of
nine), pergolide had a beneficial effect, although individual horses
often required dosages above what many practitioners customarily use
(dosages tested ranged from 1 – 3mg per day). While the authors did
acknowledge that it was unknown if higher doses of Vitex agnus castus
would have a more beneficial effect, they did not advise using Vitex
agnus castus for treatment of Cushing’s Disease.
Dose rate of pergolide
A large dose range has been reported for treatment of ECS with
pergolide, from 0.0017mg/kg to 0.0125 mg/kg PO q24h (Beech, 1999, Peters
et al., 1995). The dose rate that is most cost effective is the low
dose: 0.002mg/kg/day which works out to be 1mg per 500kg horse. It is
recommended that initial medical treatment for ECS should be at a
pergolide dose of 0.002mg/kg, q 24 h, PO. If no improvement in noted
within 4 – 8 wk, the daily dose can be increased by 0.002mg/kg monthly
up to a total daily dose of 0.006mg/kg (Schott, 2006). Dose rates of up
to 0.01mg/kg have been used, however at the higher dose rates adverse
effects of anorexia and depression may be frequently seen. If these side
effects are seen the dose should be reduced gradually until an optimum
dose is found. It should be noted that the dose rate of 0.002 mg/kg/day
is the low-dose and attempts to reduce the dose further can result in
treatment failure. Long-term, some horses have been managed on less than
this dose but reduction should be monitored carefully (McGowan, 2005).
Toxicity
Acute toxicity tests of pergolide mesylate using oral, intravenous and
intraperitoneal routes were conducted in mice, rats, rabbits and dogs.
The oral acute median lethal doses ranged from 8.4 to 33.6mg/kg in rats
and from 54 to 87.2mg/kg in mice. Oral doses of 20 and 25mg/kg produced
no mortality in rabbits or dogs, respectively. The predominant signs of
toxicity in acute studies included hyperactivity, poor grooming, ptosis,
aggressive behaviour, tremors, convulsions and emesis.
In subchronic and chronic studies, rats, mice and Beagle dogs were
administered pergolide either by gavage or in the diet for up to 1 year.
Daily doses in these studies ranged up to 20mg/kg for rats, 45mg/kg for
mice, and 5mg/kg for dogs. The predominant treatment-related effects
seen in these studies were CNS mediated signs in rats and dogs, weight
loss or decreased weight gain, and emesis (vomiting) in dogs (Francis et
al., 1994). No work has been done on high doses of pergolide in horses
specifically.
The most common adverse effect of pergolide, recognized in 5-10% of
horses, is a mild decrease in appetite during the first few days after
treatment has been initiated (Schott et al., 2001). When this problem
develops, treatment is stopped for a couple of days and reinstituted at
one-half the previous dose; most horses seem to tolerate this approach
(Schott, 2006). There are no references to other deleterious side
effects, as are found in humans, but it should be added that pergolide
therapy in equines is designed to improve health and quality of life for
aged horses, thus extending quality of life for several years only. The
relevance of side effects as seen in human therapy is questionable in
equine use.
Ranvet wish to point out that the treatment of Equine Cushing’s Disease
with pergolide mesylate is not intended to result in a clinical cure:
daily treatment of old horses diagnosed with the condition is simply to
alleviate clinical signs and improve quality of the remaining life for
both the horse and owner. If therapy with pergolide mesylate is stopped
for any reason, clinical signs rapidly redevelop in affected horses.
Known precautions and drug Interactions:
Phenothiazine tranquilizers such as acepromazine may interfere with the
action of pergolide and dopamine antagonists should not be administered
together with pergolide because they reduce its efficacy.
Suspect cases
A huge challenge is how to approach treatment of mature, non-hirsuit
horses with insidious-onset laminitis or horses suffering from chronic
laminitis for which an inciting cause cannot be identified and
endocrinologic test results are non-supportive of ECS. In these
instances, pergolide is sometimes tried for 3 – 6 months as a “trial and
error” treatment, as adverse effects seem to be minimal. Unfortunately,
in these cases efficacy of medication is often impossible to establish
as clinical improvement is the only endpoint (Schott, 2006).
Ranvet’s Pergolide
Ranvet’s Pergolide is a prescription only product manufactured under an
APVMA Permit to strict GMP standards. It provides 1mg pergolide mesylate
in a 5ml once daily oral liquid dose, for use in horses with a confirmed
diagnosis of Equine Cushing’s Syndrome. Ranvet always recommends
consultation with your veterinarian for proper diagnosis and treatment.
Monitoring therapy and prognosis
Basal tests are probably the most useful for monitoring therapy. There
is no treatment for ECS that will actually reverse the pathology that is
occurring. Monitoring clinical signs is crucial. Pergolide at the
low-dose may not restore normal coat shedding but may improve coat
quality. Insulin can be useful as a prognostic indictor and for
monitoring treatment but levels can vary considerably over 24 hours
(McGowan, 2005) and is affected by diet and exercise. Insulin collected
at midday has been shown to have at least 90% sensitivity and
specificity for production of survival to two years with horses with
serum insulin < 62µU/ml more likely to survive than those with insulin >
188µU/ml (McGowan et al., 2004). Medical therapy does not completely
stop the progression of the disease, but can alleviate clinical signs
and improve the quality of life of animals on treatment. Not all horses
will respond to therapy, but many horses can continue in comfort for
many years (McGowan, 2005).
Management of horses with ECS
Good husbandry and awareness of potential complications of ECS are
essential in the management of this disease. Affected horses should
receive regular dental and foot care, deworming and good nutrition.
Horses with hirsutism should be clipped to prevent heat stress and
dermatologic problems associated with sweating.
As with many chronic diseases in the horse, specific dietary formulation
is recommended. Meals high in non-structural carbohydrates (NSC) such as
grains and molasses should be avoided. Pastures can also contain high
levels of starch and fructan and access should be limited. Carrots and
apples also have relatively high levels of NSC. In general, feeds low in
NSC include soyhulls, sunflower seeds, cottonseed meal, lucerne hay, and
beet pulp, however some of these feeds can be unpalatable and require
processing. For more severe cases, hay may be soaked in double its
volume in lukewarm water for 1 hour then drained before feeding to
remove soluble sugars and NSCs. Many people put affected horses carrying
extra weight on a “starvation diet” and severely limit the horses’ diet
of all nutrients. This will only make matters worse as the horse still
needs maintenance energy to function as well as essential amino acids,
vitamins and minerals, particularly if laminitis is present. Both
magnesium and chromium supplementation have been advocated for
supportive treatment of this condition (Schott, 2006).
Ranvet 500 PLUS is a superior protein supplement containing high levels
of minerals and is low in NSC. This supplement is ideal for ECS ponies
and horses in combination with chaffs and hay. Balanced oils, such as
Ranvet’s Racing Oil may also be added as a source of energy if required.
For further assistance in a custom diet formulation for ECS cases,
please feel free to contact Ranvet on 1800 727 217.
References
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