So your pet has been diagnosed with Cushing’s syndrome (also known as
The normal pituitary-adrenal axis
Definitive diagnostic tests
What is Cushing’s syndrome?
Cushing’s syndrome is a condition in which there is an excess of cortisol
(cortisone). This can be caused by drugs (e.g. prednisone, depo-medrol,
dexamethasone, betamethasone) often prescribed for the treatment of many
diseases; this syndrome is known as iatrogenic Cushing’s syndrome.
It can also be caused by an excess of the body’s own cortisol, caused by
a pituitary tumor or adrenal tumor.
Iatrogenic Cushing’s syndrome
is caused by administration of drugs that suppress the body’s own cortisol
production. Clinical signs and complications are similar to the naturally
occuring disease. The dog can become dependent upon the drugs with
chronic use, and abrupt withdrawal can lead to signs related to lack of
cortisol, such as lethargy, depression, vomiting, and diarrhea. For
these reasons, chronic steroid use is not recommended except in cases of
life-threatening immune-mediated disease or chemotherapy protocols.
The lowest possible dose of steroids should be used for therapy.
Pituitary dependent Cushing’s
disease is caused by a functional pituitary tumor that stimulates the
adrenal glands to produce excess cortisol. The tumor is usually microscopic
and benign (a microadenoma). Sometimes the tumor can be large enough
to cause pressure on the nerves to the eyes and the part of the brain called
the hypothalamus, causing behavior changes, lack of appetite, and blindness,
in addition to the other signs of Cushing’s syndrome. These tumors
are known as macroadenomas. Pituitary-dependent Cushing’s disease
makes up about 85% of spontaneous Cushing’s disease cases.
Adrenal tumors can be benign, known
as adenomas, or malignant, known as carcinomas. They produce cortisol
independent of the normal regulatory mechanisms of the body.
Adrenal-dependent Cushing’s syndrome makes up about 15% of spontaneous
Cushing’s syndrome cases.
Clinical signs of Cushing’s
(excessive drinking & urination)
Polyphagia (increased appetite)
Abdominal enlargement ("potbelly")
Weight gain (may look like loss due to decreased muscle mass)
Decreased exercise tolerance/weakness
Symmetrical alopecia (hair loss) on the body
Slowed hair regrowth
Hyperpigmentation (darkening) of skin
Thin skin, bruising
Sterility/lack of cycling
Infections, skin and urinary tract
Also, rarely, stupor, blindness, inappetance, and behavior changes with
Medical complications associated with
Hypertension (high blood pressure) is associated with about half of the
cases of Cushing’s disease. It can cause blindness due to detachment
of the sight receptors in the eyes (retina) and bleeding. Kidney problems
are related to protein loss due to damage of the filtering system by the
high blood pressure. Loss of the protein antithrombin III, which
prevents clots, can cause thromboembolism (clots). Heart problems
are associated with hypertrophy (thickening of the heart muscle) and failure
due to the pumping of the heart against the increased pressure.
Glomerulopathy is damage to the filtering system of the kidney, causing
protein loss. Up to 75% of dogs with Cushing’s have some protein
loss, although most do not have severe complications. Proteins, especially
albumin, are important in holding fluid within the blood vessels, and excessive
loss can cause fluid accumulation in body cavities, underneath the skin,
and the lungs. There are other proteins, such as antithrombin III,
which are important in helping the body to prevent clotting within the
blood vessels. Loss of this protein can predispose the animal to
the development of thromboembolism (clots). A clot within an important
organ, such as the lungs, can lead to the animal’s death. Ultimately,
progressive glomerulopathy can lead to kidney failure, and predisposes
the animal to hypertension, further damaging the kidneys. This vicious
cycle can be the cause of the animal’s death.
Congestive heart failure is damage to the heart resulting in a decreased
ability to pump blood forward through the blood vessels. Eventually,
fluid accumulates in the lungs, chest & abdominal cavities, and can
lead to the animal’s death. Excess fluid in the blood vessels due
to too much fluid ingestion can lead to hypertension. Hypertension
causes the heart to pump too hard, resulting in failure. Also, since
many of these dogs are older animals, chronic valve disease may also be
present, predisposing them to heart problems. This is a rare complication.
Pancreatitis is inflammation of the pancreas, the organ that produces
enzymes to help digest food. With inflammation, the enzymes are excreted
into the bloodstream and abdominal cavity instead of the gastrointestinal
tract, resulting in a severe illness associated with vomiting, abdominal
pain, peritonitis (inflammation of the abdominal cavity), and loss of protein
into the abdominal cavity. If the disease is severe enough, the animal
can have fatal complications. Controversy exists as to whether excess
cortisol causes pancreatitis, since this complication is rare in dogs.
Thromboembolism is the formation of a clot within a blood vessel.
If the clot forms within an important organ, the animal requires intensive
care, and can have fatal complications. Cushing’s animals have thromboembolic
disease due to glomerulopathy and antithrombin III loss, vascular stasis
(blood pooling) due to an increase in blood cell numbers, damage to blood
vessels due to hypertension, and an increase in clotting factors in the
Infections are common in Cushing’s patients, since excess cortisol
suppresses the immune system. Urinary tract infections, skin infections,
and rarely systemic infections (sepsis) can occur. Since cortisol
also decreases inflammation, often there are no clinical signs or elevations
in white blood cells in the area of infection.
Decreased wound healing and slowed hair regrowth also occur in Cushing’s
patients, since the excess cortisol inhibits the normal healing and growth
processes. For this reason, surgery in adrenal tumors is often postponed
until the cortisol levels can be controlled, usually with ketoconazole.
Diagnosis of Cushing’s disease
Routine bloodwork and urinalysis:
-markedly increased serum alkaline phosphatase (SAP), which is induced
Increases in specific liver enzymes
-mildly increased ALT, GGT due to liver "swelling"
-elevated neutrophil count (the cells that fight infection)
"stress" leukogram (white blood cell count)
-decreased lymphocyte count (the cells that make antibodies)
-decreased eosinophil count (the cells that cause allergies)
nucleated (immature) red blood cells
low urine specific gravity (dilute urine)
Urine cortisol: creatinine ratio
This is a test on a single urine sample that measures the amount of cortisol
and creatinine (an enzyme filtered by the kidneys) and compares them.
The advantage is that a sample can be brought in by the owner and sent
to the lab. Unfortunately, many things can cause an elevation in
cortisol, so an increased urine cortisol:creatinine ratio can be due to
Cushing’s syndrome, stress, and other diseases. An elevation should prompt
the performance of more definitive tests. A normal urine cortisol: creatinine
ratio can be used to rule out Cushing’s syndrome.
ACTH stimulation test:
This is a 1-2 hour test in which a pre-ACTH blood sample is drawn, ACTH
is given, and a post-ACTH sample is drawn. This measures the adrenal’s
response to ACTH, and determines if it responds appropriately. A
decreased response is indicative of Addison’s disease or iatrogenic Cushing’s
syndrome, An increased response is indicative of Cushing’s syndrome.
This test diagnoses Cushing’s disease 80-85% of the time. If the
test is normal, but Cushing’s syndrome is still suspected, a low-dose dexamethasone
suppression test (LDDST) may be necessary, since about half of adrenal
tumors will not respond to this test.
dexamethasone suppression test (LDDST):
This is an 8 hour test in which a pre-dexamethasone blood sample is drawn,
a low dose of dexamethasone is given, and 4-hour and 8-hour post-dexamethasone
samples are drawn. This test measures the adrenal gland’s responsiveness
to the increased levels of steroid (dexamethasone) in the blood.
A normal dog’s adrenal gland will stop producing cortisol in response to
increased amounts of steroid in the bloodstream. A dog with Cushing’s
syndrome will not suppress or will eventually "escape" suppression, since
the adrenal gland is producing too much cortisol either due to an adrenal
tumor or pituitary tumor, which don’t respond to normal physiologic processes.
This test diagnoses Cushing’s disease 90-95% of the time. The adrenal’s
response can also be indicative of pituitary-dependent vs. adrenal-dependent
Cushing’s disease, since pituitary tumors are usually more responsive to
physiologic stimuli than adrenal tumors are.
Once Cushing’s syndrome has been diagnosed, treatment depends on the type
of disease: pituitary vs. adrenal. If the LDDST
is not definitive, or if only an ACTH stimulation
test was performed, further testing is necessary to decide which disease
dexamethasone suppression test (HDDST):
This is an 8-hour test in which a pre-dexamethasone sample is drawn, a
high dose of dexamethasone is given, and 4-hour and 8-hour post-dexamethasone
samples are drawn. Pituitary tumors are generally more responsive
to normal physiologic stimuli, so if the Cushing’s syndrome is pituitary-dependent,
the excess steroid (dexamethasone) will usually (about 80% of the time)
cause the adrenals to stop producing cortisol, resulting in suppression.
Adrenal tumors usually are not controlled by normal physiologic stimuli,
and will not suppress.
This is a one-time blood sample which must be processed in a special manner
in order to measure the body’s own production of ACTH. In a pituitary
tumor, the problem is excess production of ACTH, so the levels will be
high in the bloodstream. In an adrenal tumor, normal pituitary production
of ACTH is suppressed by the excess cortisol excreted by the adrenal gland,
and levels should be low.
In the hands of an experienced ultrasonogropher, the adrenal glands can
be found in the dog and measured. In pituitary tumors, the excess
ACTH stimulates both glands, so they will both be enlarged. In an
adrenal tumor, the abnormal gland will be enlarged, and sometimes mineralized.
The normal gland is often suppressed through normal physiologic processes,
and will be smaller.
Abdominal radiographs (x rays)
The normal adrenal glands are not seen on routine abdominal radiographs.
In adrenal tumors, a mineralized (bright white) area can sometimes be seen
cranial to (in front of) the kidneys. Usually the adrenal glands
are not seen in pituitary-dependent hyperadrenocorticism.
A CT scan is a "3-D" radiograph (x-ray). This procedure is currently only
performed at referral centers, such as here at Auburn. A CT scan of the
head to look at the pituitary gland is not usually performed, unless a
macroadenoma is suspected. The animal is anesthetized for this procedure,
because they must remain very still.
Iatrogenic Cushing’s disease
Since iatrogenic Cushing’s disease is caused by giving steroids, often
long-term, especially common in allergic dogs as "itch shots," withdrawal
of the steroids is important in resolving the clinical signs. Sometimes,
the body’s own production of cortisol is suppressed by the drugs, and slow
withdrawal of the drugs over weeks to months must be performed in order
to allow the body time to recover its own production mechanisms.
An ACTH stimulation test helps to measure
the body’s reserves for cortisol production.
Surgery to remove the abnormal pituitary has not been well-established
in veterinary patients, although it is a commonly used modality in humans,
because of the anatomy of the canine head. Removal of the entire
pituitary gland can result in permanent hypothyroidism and diabetes insipidus
(lack of urine concentrating ability). Currently, researchers at Auburn
are investigating techniques to make surgery more successful in dogs.
Medical therapy is currently the treatment of choice in dogs. The most
commonly used drug is Lysodren (mitotane, o,p’-DDD). This
drug causes death of the adrenal cells that produce cortisol, eliminating
the excessive production. Since it does not actually treat the underlying
pituitary gland problem, the therapy is lifelong. The initial phase is
induction, in which a daily dose is given, usually for 5-14 days to bring
the cortisol levels down into the normal range quickly, eliminating the
clinical signs of disease. The next phase is maintenance, in which
the drug is given usually 1-2 times weekly to help keep the cortisol levels
in the normal range. Signs that the dog’s disease is being controlled
include a decrease in water consumption, urination, and appetite.
Signs that an overdose has occurred include weakness, lethargy, lack of
appetite, vomiting, diarrhea, and occasionally even death if left untreated
(see Addison’s). Fortunately, these complications are rare; prompt
attention and supportive care with steroids will eliminate the danger of
these problems. Constant communication with your veterinarian is a MUST
in using this therapy, and frequent ACTH stimulation testing is necessary
to establish the proper dose. We usually recommend ACTH stimulation
testing at the end of induction and every 1-2 months until the proper dose
is established. Periodic retesting every 4-6 months thereafter monitors
the therapy safely.
Ketoconazole has also been used to treat Cushing’s disease.
This antifungal agent blocks the formation of the steroid hormones.
Daily therapy must be used, since cessation of therapy results in the continued
production of cortisol. This can become quite expensive. Up
to 25% of dogs will not respond to the drug. Oftentimes, this drug
is used to stabilize patients prior to surgery for an adrenal tumor.
L-Deprenyl is the newest drug to be licensed to treat pituitary-dependent
Cushing’s disease. It works to block the monoamine oxidase type B
enzyme, and enhances dopamine levels. In theory, a decrease in ACTH
levels will occur and control the pituitary-dependent Cushing’s disease.
It has no effect on cortisol levels, however. Many owners did report
an increase in their pet’s activity levels and a decrease in excessive
water consumption. There are no serious side effects reported.
This is also a daily, lifelong therapy, and is relatively expensive.
At Auburn, we still recommend Lysodren therapy in the majority of cases.
Large pituitary tumors causing signs such as blindness, behavior change,
and other neurologic signs are best treated with radiation therapy in order
to shrink the tumor. Fortunately, there are few side effects associated
with this treatment. Dogs do not experience nausea, vomiting, and
malaise while undergoing therapy. There may be some hair loss in
the radiated site, and some skin irritation that resolves within a few
weeks after treatment. The dog usually receives 10-11 treatments
over 3-4 weeks, and must be sedated for each treatment. While the
neurologic signs resolve, usually the Cushing’s disease persists, still
requiring medical therapy.
MRI image showing contrast-enhanced
Surgery is the best recommended treatment for adrenal tumors. Removal
of a benign tumor, or even a small malignant tumor, often results in a
cure. However, some tumors can be invasive into surrounding tissues,
and carcinomas (malignant tumors) can metastasize (spread) to other organs,
especially the liver and lungs. Prior to surgery, abdominal ultrasound
and chest radiographs (x-rays) must be performed to determine the chance
of tumor removal. Since Cushing’s disease can also cause decreased
wound healing, control of the excess cortisol levels prior to surgery is
also recommended. We routinely use ketoconazole to treat the effects
of excess cortisol prior to surgery. There can be serious complications
associated with surgery, including cortisol insufficiency, renal failure,
thromboembolism (clots), pneumonia, pancreatitis, and cardiac arrest.
This necessitates intensive monitoring during and after surgery to prevent,
recognize, and treat these potentially fatal problems. ACTH stimulation
tests before and after surgery determine the need for cortisol supplementation,
and monitor for the presence of continued cortisol production, indicating
incomplete removal of the tumor or metastasis.
Medical therapy for adrenal tumors can also be used, especially in animals
with metastatic disease, or animals who are not good surgical candidates.
Increased dosages and length of treatment are often necessary to control
an adrenal tumor with Lysodren, and not all tumors will respond.
There is also an increased risk of overdose and side effects with high-dose
Lysodren therapy. Ketoconazole has been used with some success to
manage these tumors.
Dogs usually respond very well to therapy and are able to lead normal lives.
Relapses are quite common with pituitary-dependent Cushing’s syndrome,
and occur in about 50% of dogs, requiring a change in the maintenance dose
or reinduction therapy. Overdose is also common, occuring in about
1/3 of treated dogs at some time during therapy. Fortunately, the
side effects are usually mild, and fatal complications from overdose occur
in < 1% of dogs. Good owner observation and communication with the veterinarian
are the most important factors that influence the success of treament.
Surgery will cure many benign adrenal tumors and small carcinomas.
If there are no post-operative complications, there can be prolonged survival
even with invasive tumors or with metastatic disease. Metastatic
disease can be treated with medical therapy, often for greater than a year.
© 1999 - Department of Small Animal Surgery and Medicine
Auburn University College of Veterinary Medicine