Download Canine Hyperadrenocorticism - VCA Specialty Animal Hospitals

Diagnosis and Treatment of
Hyperadrenocorticism in Dogs
David Bruyette, DVM, DACVIM
VCA West Los Angeles Animal Hospital
1818 South Sepulveda Blvd
Los Angeles, CA 90025
[email protected]
1. Introduction
A. Cushing's syndrome refers to all causes of hyperadrenocorticism
with overproduction of cortisol.
1. ACTH-dependent
A. Cushing's disease: Pituitary hypersecretion of ACTH which
results in bilateral adrenal hyperplasia (90% of cases)
B. Ectopic ACTH production: Non-pituitary tumors secreting
ACTH resulting in bilateral adrenal hyperplasia. Has not been
completely documented in dogs or cats.
2. ACTH independent
A. Adrenocortical adenoma or carcinoma: Hypersecretion of
cortisol with atrophy of normal adrenal and suppressed ACTH
concentrations (10% of cases).
3. Iatrogenic
A. Excessive or prolonged administration of glucocorticoids.
Clinically indistinguishable from natural disease. Results in
adrenal atrophy and suppressed ACTH levels.
2. Signalment
A. Poodles, Dachshunds, Schnauzers, Boston Terriers, Boxers.
B. Middle to old age. Average 12 years; range 6 months to 17 years.
C. No sex predilection.
D. Rare in cats. Usually seen with insulin resistant diabetes mellitus
and/or cats with severe dermal atrophy/ulceration.
3. Clinical Signs
A. PU / PD
B. Pendulous, "pot-bellied abdomen": Due to muscle catabolism by
glucocorticoids and hepatomegaly.
C. Bilaterally symmetric alopecia: Head and extremities spared.
D. Thin skin
E. Muscle weakness and muscle atrophy; cruciate ruptures
F. Mineralization of skin (calcinosis cutis)
G. Hyperpigmentation: ACTH similar to MSH, co-existing
hypothyroidism, chronic skin irritation.
H. Reproductive abnormalities
1. Anestrus
2. Clitoral hypertrophy
3. Testicular atrophy
4. Perianal adenomas in females and neutered males.
I. Respiratory signs
1. Panting: Pulmonary hypertension and decreased compliance,
primary CNS disturbance, pulmonary mineralization.
2. Dyspnea: Rare; seen with pulmonary thromboembolism and
concurrent congestive heart failure.
J. Central nervous system
1. Seen with large pituitary tumors (macroadenomas). Present at
time of diagnosis or following therapy for Cushing's disease as
microscopic pituitary tumors enlarge into macroadenomas.
2. Signs due to compression/invasion of pituitary and/or
hypothalamus:
A. Seizures
B. Pacing
C. Lethargy
D. Inappetence
E. Behavior change
F. Head pressing
G. Circling
4. Diagnosis of Hyperadrenocorticism
A. History and clinical signs
B. R/O iatrogenic disease with questions concerning current or past
medications. These medications can include oral, ophthalmic, otic, and
topical medications. Make sure the owner tells you about everything
and anything that went on or in their pet.
C. Laboratory data
1. Hemogram
A. Polycythemia (PCV 45-55%)
B. Stress leukogram
1. Lymphopenia
2. Eosinopenia
3. Neutrophilia (mature)
2. Biochemistry profile
A. Elevations in:
1. Serum alkaline phosphatase (SAP)
2. Cholesterol
3. Serum alanine aminotransferase (ALT)
4. Fasting blood glucose: Diabetes in 5-10%.
3. Thyroid function tests
A. T3 and T4 basal levels are generally decreased.
B. Response to TSH parallels normal.
C. Secondary to negative feedback of cortisol on
pituitary.
D. 80% have a normal fT4ED
D. Does not require thyroid supplementation.
4. Blood pressure: 50 – 80% are hypertensive, cause unknown.
A. Recent study demonstrated normal or decreased levels
of atrial natriuretic factor (ANF) in dogs with
hyperadrenocorticism. Argues against hypervolemia as
the etiology of the hypertension.
5. Urinalysis
A. Decreased urine specific gravity.
B. Proteinuria
D. Radiographic abnormalities
1. Thoracic films
A. Bronchial calcification
B. Metastases from adrenal adenocarcinoma
2. Abdominal films
A. Hepatomegaly
B. Osteopenia
C. 50% of adrenal tumors are visualized as soft tissue or
calcified masses.
D. Subcutaneous calcification
E. Adrenal function tests
1. Three tests used to diagnose hyperadrenocorticism. They do
not differentiate between PDH or AT.
A. ACTH stimulation test
1. Look for exaggerated cortisol response in
response to ACTH.
2. See protocols at the end of this discussion.
3. Diagnostic in 85% of pituitary-dependent cases
(PDH)
4. Diagnostic in 70% of adrenal tumors (AT)
5. Overall accuracy 80-85 %
6. A suppressed response to ACTH in animals with
clinical signs of hyperadrenocorticism suggests
iatrogenic disease.
B. Low-dose dexamethasone suppression test
1. Low doses of dexamethasone inhibit ACTH
release from the pituitary via negative feedback
and decrease plasma cortisol concentrations in
normal dogs.
2. Dogs with Cushing's are more resistant to
steroid suppression. Therefore, lack of suppression
following dexamethasone = hyperadrenocorticism.
3. Diagnostic in 95% of PDH
4. Diagnostic in 100% of AT
5. Overall 90-95%
6. May also be used to distinguish PDH from AT
(see below)
7. See protocols
C. Urine cortisol/creatinine ratio
1. Assessment of cortisol production and
excretion rate.
2. Sensitivity of this test is greater than that of
the LDDS (some animals with clinical signs of
hyperadrenocorticism may have normal LDDS
response tests but elevated urine cortisol to
creatinine ratios). Used as a screening test.
3. Test is easy to perform.
4. As with all adrenal function tests, elevated
results may occur in animals with non-adrenal
disease.
5. Positive tests confirmed with a LDDS.
6. Must be performed on urine obtained at home,
preferably in the AM
2. Tests to differentiate PDH from AT (performed after
confirming diagnosis of hyperadrenocorticism).
A. High-dose dexamethasone suppression test
1. With PDH, a high dose of dexamethasone results
in a decrease in ACTH release from the pituitary
and a decrease in plasma cortisol.
2. With AT, the tumor secretes cortisol
autonomously thereby suppressing ACTH
production. With low ACTH concentrations already
present, dexamethasone has no effect on plasma
cortisol.
3. 70% of patients with PDH suppress plasma
cortisol to less than 50% of the pre-treatment
value.
4. 100% of patients with AT do not suppress.
5. Therefore: Suppression = PDH; Lack of
suppression = Inconclusive
6. See protocol
B. Endogenous ACTH concentration
1. PDH: Levels normal or high
2. AT: Levels low to undetectable
3. Contact lab regarding sample handling and
collection. Use of the preservative (Aprotinin)
allows for greater utilization of this test.
4. Excellent method to differentiate PDH from
AT.
Testing Protocols
These are suggested protocols that are used in the evaluation of
patients with hyperadrenocorticism. You must use the protocol and
normal values from the laboratory to whom you are submitting samples
to properly evaluate endocrine tests.
1. ACTH Stimulation Test
A. Synthetic ACTH (Cortrosyn) 5 ug/kg IV or IM; collect
serum at 0 and 1 hour, or
B. ACTH gel (Acthar) 2.2 U/kg IM; collect serum at 0 and
2 hours.
C. Hyperadrenocorticism if post-cortisol > 20 ug/dl (530
nmol/L)
2. Low-Dose Dexamethasone Suppression Test
A. 8 A.m: Baseline serum cortisol. Administer 0.01 mg/kg
dexamethasone sodium phosphate (0.015 mg/kg
dexamethasone) IV.
B. 12 p.m: Collect 4 hour post-dexamethasone cortisol.
C. 4 p.m: Collect 8 hour post-dexamethasone cortisol.
D. In normal animals cortisol suppresses to less than 1.0
ug/dl (27.5 mmol/L) at 8 hours.
E. 50% or greater suppression at either 4 or 8 hours
together with lack of suppresion at 8 hours is diagnostic
for PDH and additional tests are not necessary.
3. Urine Cortisol/Creatinine Ratio
A. First morning urine sample is preferred. Sample should
be obtained at home. Requires 1 – 2 mls.
B. Stable at room temperature or refrigerated for 3
days.
C. Normal range 2.8 - 4.8. A normal result effectively
rules-out hyperadrenocorticism, an abnormal result
should be confirmed with a LDDS or ACTH stimulation
test.
Differentiating PDH From AT
1. Low-Dose Dexamethasone Suppression Test
A. See above.
2. High-Dose Dexamethasone Suppression Test
A. 8 a.m: Obtain serum cortisol. Administer 0.1
mg/kg dexamethasone sodium phosphate (0.15
mg/kg dexamethasone) IV.
B. 4 p.m: Collect post-dexamethasone cortisol.
C. Suppression defined as greater than a 50%
reduction of cortisol.
D. Suppression = PDH, non-suppression =
Inconclusive
3. Endogenous ACTH Concentration
A. Check with lab on sample collection and handling.
B. Normal: 20-100 pg/ml (4.4-22.0 pmol/L)
C. PDH: 40-500 pg /ml (8.8-110 pmol/L)
D. AT: < 20 pg/ml (<4.4 pmol/L)
Treatment Options
A. Pituitary-dependent hyperadrenocorticism
1. Surgical management
A. Bilateral adrenalectomy
1. Technically difficult
2. Poor surgical/anesthetic risk
3. Permanently hypoadrenal and require lifelong
replacement therapy
B. Hypophysectomy
1. See discussion at the end of this section
2. Lifelong therapy with thyroid hormone and
prednisone necessary.
2. Medical therapy
A. Lysodren (o,p'-DDD)
1. Selective necrosis of adrenal cortical cells
producing cortisol (zona fasiculata and reticularis).
2. Zona glomerulosa usually spared maintaining
aldosterone secretion.
3. Side-effects (35 – 40%)
A. Vomiting
B. Anorexia
C. Lethargy
D. Diarrhea
E. Neurologic signs
F. Addison’s disease (< 5 %)
4. Most commonly used therapy for PDH.
Treatment Protocol For Initiating Lysodren Therapy
Goals of therapy:
A. Eliminate clinical signs
B. Avoid toxicity
C. Pre and post-ACTH plasma cortisols within the normal
resting range (<4.0 ug/dl; <100 nmol/L)
1. Owners assess water consumption and appetite at home for
3-5 days.
2. Begin Lysodren at 25 mg/kg PO BID.
3. When water consumption or appetite starts to decrease or
following seven consecutive days of therapy (which ever occurs
first) the medication is discontinued and an ACTH response
test is performed.
4. If an adequate response to therapy is seen (pre and post
cortisols within the resting range) maintenance therapy is
begun. If an adequate response has not been seen, daily therapy
is continued until clinical signs improve or for an additional 7
days and another ACTH stimulation test is performed.
5. If adverse reactions are noted at any time during therapy
(reduction in appetite, anorexia, vomiting, diarrhea) therapy
should be discontinued and the animal brought in as soon as
possible for evaluation. Electrolytes, BUN, and an ACTH
stimulation test should be performed. If the animal can not be
brought in within the next 12-24 hours, replacement doses of
steroids (0.25 mg/kg/day of prednisone) are started and the
animal is seen at the earliest possible time. Owners should have
5 mg prednisone tablets at home for emergency use.
Maintenance Therapy
1. Lysodren is given at 50 mg/kg once a week or divided twice a
week.
2. Watch for clinical signs of returning hyperadrenocorticism.
3. ACTH stimulation test in 4 weeks then every 3-4 months.
4. Electrolytes every 3-4 months. Even though the zona
glomerulosa is fairly resistant to the effects of o,p'-DDD,
mineralocorticoid deficiency can occur (see treatment for
hypoadrenocorticism).
5. Therapy is life-long.
Another protocol that has been used with o,p'-DDD in the
management of Cushing's disease is total adrenal ablation. In this
protocol, Lysodren is administered at 100 mg/kg/day divided BID for
30 days. Supplemental cortisone acetate (2 mg/kg divided BID) and
fludrocorticone tablets (0.1 mg/10 # once a day) are begun beginning
on day 1 of Lysodren therapy. The diet is supplemented with 1-5 grams
of NaCl per day. One week after the induction phase with o,p'-DDD,
the dose of cortisone is reduced to 1 mg/kg/day. Electrolytes and an
ACTH stimulation test are performed at the end of the induction
period, every six months, and at any time the animal demonstrates
signs compatible with either hyperadrenocorticism or
hypoadrenocorticism. While this form of therapy may be effective in
the management of canine hyperadrenocorticism, is does require close
patient monitoring and life-long daily therapy. Close attention must be
paid to these animals during times of stress and episodes of nonadrenal illness.
2. Medical therapy (con't)
B. Ketoconazole (Nizoral)
1. Inhibits adrenal enzymes responsible for the
synthesis of cortisol. Enzymatic inhibition is
reversible.
2. No affect on aldosterone.
3. Does not destroy adrenal tissue.
4. Can be used for both PDH and AT.
5. Side-effects:
A. Anorexia
B. Vomiting
C. Increased liver enzymes.
D. Lightening of hair coat.
6. Dosage:
A. 10-15 mg/kg BID
B. Assess response to therapy with ACTH
stimulation tests just as with Lysodren.
C. Daily therapy must be maintained.
7. Indications:
A. Animals not able to tolerate Lysodren.
B. Animals non-responsive to therapy with
Lysodren or Anipryl.
C. Pre-operative stabilization prior to
adrenalectomy (4-6 weeks).
D. Palliative therapy in animals with
metastatic adrenal tumors.
E. Effective in approximately 50% of
patients.
C. l-Deprenyl (Anipryl)
l-Deprenyl (Anipryl) is a selective monoamine oxidase-B
inhibitor (MAO-B) that is currently approved for the
treatment of Parkinson's disease in man and PDH and
cognitive dysfunction in the dog. There are several
reasons why dopamine depletion and monoamine oxidase
inhibitors may play a role in the pathogenesis and
treatment of canine PDH. First dopamine concentrations
are decreased in canine patients with PDH. Secondly,
PDH is a geriatric disease and it is known that the
concentration of MAO-B increases with age. Together
these events lead to further functional dopamine
depletion. Thirdly, treatment with dopamine agonists
(man, dog, horses) has been beneficial in some patients
with PDH. Dopamine affects the HPA axis primarily
through tonic inhibition of ACTH release from the pars
intermedia (PI). Based on previous studies, approximately
30% of cases of PDH in the dog arise from adenomas or
adenomatous hyperplasia in the PI. In addition, it appears
that dopamine depletion also play a role in enhancing
corticotropin releasing hormone (CRH) mediated ACTH
release. In the dog, treatment with the dopamine
antagonist domperidone results in enhanced CRH
mediated ACTH release. This suggests that dopamine
depletion can impact ACTH release from both the PI and
pars distalis (PD) and that dopamine depletion may play a
role in the pathogenesis of canine PDH. MAO-B can be
effectively and irreversibly inhibited in the dog with
chronic, daily oral administration of l-deprenyl with few
adverse side effects. Therapy with l-deprenyl has
recently been shown to be effective in 4 studies involving
125 dogs with PDH. The drug was administered once a
day. Efficacy of therapy was evaluated on the basis of
reversal of clinical signs and normalization or a return
toward normal in the low dose dexamethasone
suppression test. Seventy-five percent of the dogs
treated with 1.0 or 2.0 mg/kg, were considered
treatment successes based on clinical and biochemical
criteria.
3. Radiation therapy
A. Used to treat pituitary macroadenomas
B. Good results in reducing tumor size and decreasing
neurologic signs, but frequently poor results on
controlling excess tumor secretion of ACTH so medical
therapy is still needed.
B. Adrenal tumors
1. Adrenalectomy
A. Treatment of choice according to the literature.
Unfortunately, adrenal tumors, even benign ones, can be
very large, highly vascular, and locally invasive (vena cava,
aorta, kidney). If you are considering surgical therapy
consider referral to someone who does these often and
who has the ability to determine extent of disease prior
to surgery (CT, ultrasound, angiography). Always
remember the goal of therapy is to alleviate clinical signs.
B. Submit all tissue for histopathology and prognosis.
50% of adrenal tumors are malignant and carry a very
poor prognosis.
C. Intra and post-operative care is critical to survival.
D. Begin supraphysiologic doses of glucocorticoids during
surgery and for the first few days after recovery. The
dose is gradually tapered over 4-6 weeks.
2. Lysodren
A. Responses can be achieved albeit at higher dosages
than normally considered for PDH.
B. Induction protocol is the same as for PDH.
C. May require 100-200 mg/kg/day to obtain remission.
Maintenance therapy is then started using the effective
daily induction dosage given once or twice a week.
D. When used in this fashion you are using Lysodren as a
chemotherapeutic drug and the goal is to wipe out all
adrenal tissue thereby inducing both glucocorticoid and
mineralocorticoid insufficiency.
3. Ketoconazole
A. Will decrease cortisol production by the tumor, no
good evidence for any effect on destroying tumor tissue.
B. Good medication for palliative therapy.
C. Do not use Lysodren and ketoconazole together.
D. Use dosage and protocol as described for PDH.
6. Management of Diabetes and Hyperadrenocorticism
As the clinical signs of diabetes mellitus and hyperadrenocorticism
are similar, clinical suspicion of hyperadrenocorticism is usually made
based on physical examination findings and the occurrence of insulin
resistance. The diagnosis of hyperadrenocorticism in a diabetic
patient can be difficult. Unregulated or poorly regulated diabetic dogs
can have exaggerated cortisol responses to ACTH, an elevated urine
cortisol/creatinine ratio, and an abnormal LDDS test, without having
hyperadrenocorticism. While well regulated diabetics have normal
ACTH response tests, most ACTH response tests on diabetic dogs are
being performed because of difficulties with glucose regulation. If
you have a diabetic animal in which you suspect hyperadrenocorticism
it is probably best to institute insulin therapy (even if it requires high
doses) in order to regulate the diabetes. Once an adequate response
to insulin therapy has been observed (based on clinical signs and serial
blood sugars) adrenal function tests can then be performed. Prior to
initiating Lysodren, insulin therapy is reduced to 0.5 to 1.0 U/kg BID.
This will help avoid the occurrence of ketoacidosis while helping to
prevent severe hypoglycemic reactions that may occur as insulin
requirements decrease. Owners are asked to monitor urine sugars 2-3
times a day and if negative readings are obtained the dose of insulin is
reduced by 25%. One-third of treated dogs may be able to
discontinue insulin therapy entirely following successful management
of the hyperadrenocorticism.
A. Start daily Lysodren at 25 mg/kg/day.
B. Insulin requirements may change rapidly. Owner should
monitor urine samples 2-3 times a day for glucose. With
negative results, insulin dose is lowered 25% at next injection.
C. Cortisol causes insulin antagonism so with resolution of
hyperadrenocorticism:
1. Insulin requirements will decrease.
2. Some dogs may be able to stop insulin.
3. These patients may be prone to more severe
hypoglycemic reactions due to loss of one of the
counterregulatory hormones, cortisol.
D. Aside from starting with a decreased dose, the protocol is
the same as that used for treating PDH without diabetes.
7. Prognosis
A. Most dogs with PDH live normal lives (average 2.2 years, but
remember most are geriatric to begin with.)
1. Complications
A. Recurrence of disease.
B. CNS signs.
C. Pulmonary thromboembolism.
D. Infections.
E. Hypertension.
F. Congestive heart failure.
2. Adrenal tumors:
1. Adenomas: Good if no evidence of local invasion.
2. Carcinomas: Guarded to grave with metastases.
Trilostane Therapy Of Canine Hyperadrenocorticism
INTRODUCTION
Canine hyperadrenocorticism (HAC) has been most commonly treated with
the adrenolytic drug o, p'-DDD (mitotane). However, it is well recognised
that mitotane has several side effects, is associated with a high frequency
of relapses and is not without risk to owners. Other drugs such as
ketoconazole and l-deprenyl (selegeline) have also been investigated for the
treatment of HAC. Recently it has been suggested that trilostane was an
effective treatment for canine hyperadrenocorticism. Several workers in
the field have subsequently used trilostane in canine pituitary dependent and
adrenal dependent hyperadrenocorticism, in feline hyperadrenocorticism and
in equine Cushing's syndrome. Trilostane is a synthetic, orally active steroid
analogue. It can act as a competitive inhibitor of the 3ß hydroxysteroid
dehydrogenase enzyme system and thereby inhibit the synthesis of several
steroids, including cortisol and aldosterone. This blockade is reversible and
seems to be dose-related.
Use in humans
In humans, trilostane has been mainly used for Cushing's syndrome. However
the clinical response was rather disappointing with only few patients showing
clinical improvement. Decreases in cortisol levels and in blood pressure were
even less common. Other conditions in humans treated with trilostane are
Conn's disease (primary aldosteronism) and advanced breast cancer. In
humans, trilostane is given orally at a dose of 60 mg four times daily for
three days with adjustment according to the patient's response. Usually a
final dose of 120-480 mg daily in divided doses is required with a maximal
dose of 960 mg recommended. Uncommon dose-related side effects of
trilostane in humans include flushing, nausea and vomiting, diarrhoea,
rhinorhoea and palatal oedema. Acute addisonian episodes have also been
reported.
CLINICAL STUDIES
Canine pituitary dependent hyperadrenocorticism (PDH)
The efficacy and safety of trilostane in the treatment of canine PDH were
evaluated in a multicentre study at the Royal Veterinary College in London,
the Veterinary Teaching Hospital in Dublin and Small Animal Hospital in
Glasgow. Seventy-eight dogs with confirmed PDH were treated with
trilostane for up to 3 years. The starting dose varied from 1.8 to 20 mg/kg
(mean = 5.9 mg/kg).
Trilostane appeared to be well tolerated by almost all dogs with only 2 dogs
developing signs and biochemical evidence of hypoadrenocorticism. One of
these dogs recovered with appropriate therapy. The other died despite
withdrawal of trilostane and administration of appropriate therapy. A
further two dogs died within one week of starting trilostane but in neither
case could a direct link with the trilostane therapy be established. The low
prevalence of side effects compared favourably to those reported with
mitotane.
Trilostane was found to be nearly as effective as mitotane in resolving the
signs of hyperadrenocorticsm. Polyuria, polydipsia and polyphagia had
dissipated in 40 dogs within 3 weeks after starting trilostane. Within 2
months, a further 20 dogs showed decreases in their water and food
consumption. These improvements were maintained as long as the dogs
remained on adequate doses of trilostane. Skin changes resolved in 24 out of
39 (62%) of dogs that initially presented with dermatological signs. All of
these improvements were maintained as long as the dogs remained on
adequate doses of trilostane. Only 8 dogs that were treated with trilostane
for more than 2 months showed poor control of clinical signs. In contrast,
mitotane is effective in about 80% of cases of pituitary dependent
hyperadrenocorticism (PDH).
Trilostane caused a significant (p<0.001) reduction in both the mean basal
and post-ACTH stimulation cortisol concentrations after 10 days of
treatment. The post ACTH cortisol concentration decreased to less than
250 nmol/l (9 µg/dl) in 81% of dogs within one month and in another 15% at
some time whilst on treatment. These improvements were also maintained in
the study population for the duration of the trial.
Thirty-five dogs had at least one dose adjustment over the treatment
period. The dose was increased in 23 dogs up to four times the starting
dose. In one dog the dose was increased nine fold over a period of six
months. The dose was decreased in nine dogs to as low as a quarter of the
starting dose.
The mean survival of all trilostane treated dogs was 661 days. Direct
comparison with mitotane was difficult as 65% of the dogs were still alive at
the time of censor and therefore the mean survival may still increase.By
comparison, the mean survival of mitotane treated dogs has been reported
to be 810 to 900 days.
Subsequently it has been demonstrated that the effects of trilostane on
basal cortisol concentrations are short lived (less than 20 hours) in most
dogs with hyperadrenocorticism. Furthermore there are significant
differences between the cortisol responses in ACTH stimulation tests
performed at 4 and 24 hours post dosing 12. It has also been suggested that
adrenal glands increase in size in response to therapy. This may be as a
result of an increase in endogenous ACTH during therapy.
Canine adrenal dependent hyperadrenocorticism
Only a few cases of adrenal dependent hyperadrenocorticism (ADH) have
been treated with trilostane. A reduction in post-ACTH cortisol
concentrations has been demonstrated and extended survival times (more
than 2 years) have been achieved in some cases. Insufficient cases have
been collected to compare the long-term efficacy of trilostane with that of
mitotane. Trilostane is not cytotoxic and it is likely to be inferior to
mitotane for the prevention and control of metastatic disease. The value of
trilostane for pre-operative therapy before adrenalectomy has not been
examined in a systematic fashion. However, given the data presented above,
it would suggest that trilostane might be an effective and safer alternative
to ketoconazole in this respect.
Clinical studies in other species
Trilostane has been used in 20 cases of equine HAC at a dose of 120-240 mg
once daily 14. The drug was effective as assessed by reduction in lethargy,
laminitis and polyuria/polydipsia and a corresponding decrease in cortisol
response to TRH administration. Some of these horses have been treated
for up to one year so far with no side effects noticed. The use of trilostane
in feline HAC has not been reported.
CURRENT RECOMMENDATIONS FOR THE USE OF TRILOSTANE IN
DOGS
Dosage and administration
As pharmacokinetic data for trilostane are not yet available, the optimal
dose rate and frequency interval for the treatment of canine HAC are not
yet known. The current suggested starting dose rate for dogs with PDH is 510 mg/kg once daily. This needs to be adjusted according to clinical signs and
serum cortisol values (see below). Doses up to 40-50 mg/kg (divided twice
daily) have been given with no unwanted side effects. In some dogs twice
daily dosing may be necessary. The drug is given with food.
Cautions and drug interactions
In dogs only minor side effects are commonly seen such as mild lethargy and
decreased appetite 2-4 days from start of therapy (potentially due to
steroid withdrawal syndrome) and mild electrolyte abnormalities. Overt
hypoadrenocorticism seems to be a rare event despite the marked decrease
in serum cortisol values found shortly after trilostane dosing. It has been
shown that trilostane terminates pregnancy in rhesus monkeys at a dose of
50mg/monkey at various time points through pregnancy. The drug should
therefore not be used in pregnant animals.
As trilostane can cause hyperkalemia through its aldosterone inhibiting
effect it is advised to use caution if given together with a potassium-sparing
diuretic. No unwanted drug interactions have been seen in dogs on trilostane
together with several non-steroidal anti-inflammatory drugs, various
antibiotics, insulin and levothyroxine. The effect of angiotensin converting
enzyme inhibitors might be potentiated (again due to it's aldosterone
inhibiting effect) but no studies have looked into this.
Monitoring
It is important to monitor the clinical and biochemical effects of therapy
and to adjust the trilostane dose to achieve optimal control. Dogs are reexamined and an ACTH stimulation test is performed at 10 to 14 days, 30
days and 90 days after starting therapy. It is important that all ACTH
stimulation tests are performed 4 to 6 hours after trilostane administration
and interpreted in the light of the history and the findings of a thorough
physical examination. If the post ACTH cortisol concentration is less than
20 nmol/l (0.7 µg/dl) the trilostane is stopped for 48 hours and then reintroduced at a lower dose. If the post ACTH cortisol concentration is more
than 120 nmol/l (4.3 µg/dl) then the dose of trilostane is increased. If the
post ACTH cortisol concentration is between these two values and the
patient appears to be clinically well controlled then the dose is unaltered. If
however the post ACTH cortisol concentration is between these two values
and the patient appears not to be clinically well controlled then the
trilostane may need to be given twice daily. If an ACTH stimulation test is
performed at times other than 4 to 6 hours after trilostane then the post
ACTH cortisol concentration should be more than 20 nmol/l (0.7 µg/dl) and
less than 250 nmol/l (9 µg/dl).
Once the clinical condition of the animal and the dose rate has been
stabilized then dogs should be examined and an ACTH stimulation test
performed every 3 to 4 months. Serum biochemistry (especially
electrolytes) should be performed periodically to check for hyperkalemia.
CONCLUSIONS
It is concluded that trilostane is an acceptable alternative to mitotane for
the treatment of canine PDH. However, the optimal dose rate and frequency
of administration need to be determined from pharmacokinetic studies.
Trilostane may also be useful in canine ADH and equine Cushing's disease but
more studies are needed. Its use in any of these diseases does not remove
the need for regular veterinary monitoring. As the post-ACTH cortisol
concentration is variable depending on the time at which the test is
performed it may not be the optimal test for assessing the efficacy of
trilostane therapy. However no comparison has yet been made with other
tests of adrenal gland function.
TRANSSPEHOIDAL HYPOPHYSECTOMY
A variety of treatments are available for PDH. Medical treatment options
include drugs that chemically destroy the adrenals (lysodren or op-DDD)
inhibit enzymes in the adrenal leading to the synthesis of cortisol
(ketoconazole, trilostane) or inhibit the release of ACTH from the pituitary
gland (Anipryl or selegiline). While these treatments can improve the clinical
signs in 40-80% of patients they need to be chronically administered,
necessitate frequent monitoring and do not cure or address the primary
cause of the disease (the pituitary tumor). In humans, surgery to remove the
tumor is the most successful long-term therapy. The most common approach
used is the transsphenoidal method, in which a passage way is made in the
sphenoid sinus, an air space behind the back of the nose, which is just below
the pituitary gland. Surgical cure rates for PDH are reported to be in the
range of 65-85%, although more recent long-term follow up data suggest
that the recurrence rate is as high as 25 % within 5 years. When no
discrete adenoma can be identified, remission of hypercortisolism is
observed in only about 40%. Surgery has also been used to treat PDH in
dogs. Several groups, most notably in the Netherlands have performed these
surgeries with success rates paralleling those reported for humans.
However, these surgeries have generally not been performed in the US.
Veterinarians at VCAWLAAH, in collaboration with human neurosurgeons
that regularly perform transsphenoidal surgery in humans have developed
the methods to perform these surgeries in the US and are conducting a
research study to determine how effectively these surgeries can be
performed.
Given the survival times and the ability to cure the disease by removing the
pituitary tumor we are conducting ongoing studies to evaluate the role of
transsphenoidal hypophysectomy in the treatment of canine PDH. We will
also be looking at the tumor tissue to investigate the pathogenesis of
Cushing’s disease and evaluate novel medical therapies.
The enclosed CD contains a movie with additional information on canine
Cushing’s disease.