Hyperadrenocorticism (Cushing’s Syndrome) in Dogs

Overview of Canine Hyperadrenocorticism

Hyperadrenocorticism, commonly referred to as Cushing’s disease or Cushing’s syndrome, refers to a disease state in which an overactive adrenal tissue produces excessive amounts of cortisone. Cortisone and related substances are essential hormones of the body, but when produced in excessive amounts these substances may cause systemic illness.

A small tumor in the pituitary gland (located at the base of the brain) is the cause of Cushing’s syndrome in 80 to 85 percent of dogs with hyperadrenocorticism. The tumor produces a hormone called adrenocorticotropic hormone or ACTH that stimulates the adrenal glands to grow larger (become hyperplastic) and produce excessive amounts of cortisone. This type of Cushing’s syndrome is called pituitary-dependent hyperadrenocorticism because it originates from the pituitary gland.

In the remaining 15 to 20 percent of dogs with Cushing’s syndrome, the cause is a tumor of the adrenal gland. This form is called adrenal-dependent hyperadrenocorticism because it originates from the adrenal gland itself.

Occasionally, a dog might have a diagnosis of iatrogenic Cushing’s disease. This is not an adrenal disorder, but rather it is caused by the administration of steroids (given to treat other diseases) to a dog. Long-term administration of steroids can cause a dog to exhibit all the classic signs of Cushing’s disease. In this case, the excessive steroids are not being produced in the body, they are being provided as a form of medication to your pet.

Canine Cushing’s syndrome usually occurs in middle-aged to older dogs with most affected dogs being over 9 years of age at presentation. The syndrome does not have a strong gender bias, but it may occur slightly more often in female dogs than in males. Dogs of any breed can develop Cushing’s syndrome, but it is most common in poodles, dachshunds, miniature schnauzers, and German shepherds. Boxers and Boston terriers are prone to development of Cushing’s syndrome caused by pituitary tumors.

Hyperadrenocorticism can be difficult to recognize due to its variable clinical symptoms and very gradual onset. For example, many owners mistakenly assume that the changes they see in their dog are simply a result of the aging process.

What to Watch For with Cushing’s Syndrome in Dogs

Abnormal high blood concentration of cortisone results in the clinical symptoms of Cushing’s syndrome. These include:

• Increased water consumption (polydipsia)
• Increased urinations (polyuria)
• Increased appetite (polyphagia)
• Abdominal distension (pot-bellied appearance)
• Loss of hair on the trunk (alopecia)
• Chronic skin or urinary tract infections, excessive panting, lethargy, muscle weakness, and calcium deposits in the skin (calcinosis cutis) are other symptoms of Cushing’s syndrome.

Diagnosis of Hyperadrenocorticism in Dogs

No single laboratory test definitively identifies Cushing’s syndrome, and the disorder should not be diagnosed solely on the basis of laboratory tests. Your veterinarian should also consider the medical history and physical examination findings when establishing a diagnosis and determining the appropriate laboratory tests to perform. Several of the following diagnostic tests may be required for the diagnosis of Cushing’s syndrome:

• Complete blood count (CBC)
• Biochemical profile
• Urinalysis and bacterial culture of the urine
• Blood pressure measurement
• Radiographs (X-rays) of the chest and abdomen
• Urine cortisol-to-creatinine ratio
• Abdominal ultrasound examination
• ACTH stimulation test
• Low dose dexamethasone suppression test
• Measurement of blood ACTH concentration
• High dose dexamethasone suppression test
• CT (computed tomography) or MRI (magnetic resonance imaging) scans of the brain or abdomen\

Treatment of Hyperadrenocorticism (Cushing’s Syndrome) in Dogs

• Several approaches may be used to treat dogs with Cushing’s syndrome. Treatment options depend primarily on whether the Cushing’s syndrome is pituitary-dependent or adrenal-dependent.

Pituitary-dependent Hyperadrenocorticism in Dogs

• Medical therapy with o,p’-DDD (mitotane or Lysodren®) causes selective destruction of the cortisone-producing portions of the adrenal gland and limits the ability of the gland to produce cortisone.
• Therapy with Trilostane (Vetoryl) is also a very good option. It inhibits cortisol synthesis. It is a registered treatment in Europe but has had limited availability in the United States until recently.
• Ketoconazole (Nizoral®) is an anti-fungal drug that also blocks the synthesis of cortisone in the adrenal gland. It is sometimes used to treat hyperadrenocorticism.
• L-Deprenyl increases dopamine concentration in the brain. Increased dopamine concentration may decrease cortisone production in the adrenal glands. The use of L-deprenyl to treat Cushing’s syndrome in the dog is very controversial. Some veterinarians believe it has a beneficial clinical effect whereas others have found no evidence of an effect despite extensive laboratory testing of treated dogs.\

Adrenal-dependent Hyperadrenocorticism in Dogs

• Surgical removal of an adrenal tumor is a difficult, but potentially curative surgery. Surgery is not indicated if the adrenal tumor has invaded adjacent vessels and organs or spread distantly (metastasized).
• Adrenal tumors also can be treated medically with mitotane or ketoconazole. Medical therapy may be the only choice if the tumor has invaded locally or spread distantly.

Home Care

Follow your veterinarian’s instructions very closely when administrating medications, especially in the induction phase when using mitotane. Observe your dog for weakness, vomiting, diarrhea, loss of appetite or change in attitude. You should also observe your dog for improvement or worsening of clinical signs.

Follow-up with your veterinarian for routine re-evaluation of blood tests so as to maximize the chance for successful treatment.

Preventative Care

There is no known way to prevent Cushing’s syndrome. However, some preventative measures may lead to earlier diagnosis and potentially more effective treatment:

• As your dog gets older, more frequent routine visits to the veterinarian may identify early symptoms of the disease.
• Routine performance of blood tests (complete blood count, biochemical profile, urinalysis) in older dogs may identify laboratory abnormalities associated with hyperadrenocorticism.
• Monitor your dog for any changes in behavior or attitude, especially increased water consumption, increased urinations, and increased appetite.

In-Depth Information on Canine Hyperadrenocorticism

The adrenal glands are small endocrine organs located near the kidneys. They are comprised of two major parts:

• The adrenal cortex (outer layer)
• The adrenal medulla (inner layer)
• The adrenal cortex is further divided into three regions, each of which makes a different type of steroid hormone.
• The outermost region of the adrenal cortex produces a hormone called aldosterone that is important in regulation of salt and water balance.
• The mid-region produces cortisone, which has many important biological functions. Excessive cortisone production results in many of the clinical symptoms of Cushing’s syndrome.
• The inner region of the adrenal cortex produces sex hormones.
• The adrenal medulla produces catecholamine hormones such as epinephrine that help the body respond to sudden emergencies.
• Normally, control centers in the brain regulate the production of cortisone by the adrenal cortex. The hypothalamic region of the brain secretes a hormone called corticotrophin-releasing hormone (CRH), which in turn stimulates the pituitary gland to produce adrenocorticotropic hormone (ACTH). ACTH stimulates the production of cortisone by the adrenal cortex. High circulating concentrations of cortisone normally suppress ACTH production by the pituitary gland thus maintaining normal blood concentrations of cortisone by means of a “feed-back” mechanism. In dogs with Cushing’s syndrome, abnormally high blood concentrations of cortisone occur as a result of a pituitary tumor that produces abnormally high concentrations of ACTH or by an adrenal tumor that produces abnormally high concentrations of cortisone. An understanding of the body’s normal “feed-back” mechanism helps your veterinarian diagnose Cushing’s syndrome and identify the underlying cause (pituitary tumor vs. adrenal tumor).

Diseases that Can Produce Similar Signs of Cushing’s Disease

Several other diseases may produce symptoms similar to those of Cushing’s syndrome. Such disorders include:

• Iatrogenic Cushing’s disease. Animals that are receiving chronic (long term) oral, injectable, or even topical steroid preparations like ear drops or eye drops may have the same clinical signs as a true cushingoid dog. A slow withdrawal of the steroids will lead to a resolution of the clinical signs.
• Diabetes mellitus is caused by inadequate production of insulin by the pancreas. As a result, abnormally high blood glucose concentration (hyperglycemia) and spillage of glucose into the urine (glucosuria) occur. Increased water consumption (polydipsia), increased appetite (polyphagia), and increased urination (polyuria) are common signs of diabetes mellitus.
• Diabetes insipidus results from deficient production of anti-diuretic hormone (ADH) or failure of the kidney to respond to anti-diuretic hormone. This hormone is responsible for facilitating production of concentrated urine by the kidneys. Failure of this mechanism leads to increased urinations (polyuria) and increased water consumption (polydipsia).
• Hypothyroidism results in decreased production of thyroid hormone and may lead to obesity, lethargy, muscle weakness and high blood cholesterol concentration. These clinical findings may be confused with hyperadrenocorticism.
• Kidney disease may lead to increased urinations and increased water consumption.
• Liver disease may result in abnormally high blood concentrations of liver enzymes such as alkaline phosphatase, liver enlargement and increased thirst. These findings may be confused with Cushing’s syndrome.
• Dogs with disorders of growth hormone may develop clinical symptoms that may be confused with Cushing’s syndrome.
• Dogs treated with phenobarbital for control of epilepsy may develop increased water consumption, increased urinations, increased appetite, and abnormally high blood concentrations of liver enzymes. These findings may be confused with Cushing’s syndrome.
• Iatrogenic Cushing’s syndrome can result from long-term oral or topical administration of cortisone-like drugs (prednisolone, dexamethasone) may result in clinical and laboratory features similar to those observed in dogs with naturally-occurring hyperadrenocorticism.

In-depth Diagnosis of Hyperadrenocorticism in Dogs

The diagnosis of Cushing’s syndrome involves two steps.

• To determine whether or not Cushing’s syndrome is present
• To determine whether the Cushing’s syndrome is pituitary-dependent or adrenal-dependent
• A good medical history and complete physical examination are crucial to establishing a diagnosis. No single laboratory test conclusively establishes a diagnosis of Cushing’s syndrome. The diagnosis must be made on the basis of the medical history, physical findings and results of carefully selected laboratory tests and diagnostic imaging procedures. Often, Cushing’s syndrome is suspected on the basis of clinical findings, but the diagnosis remains elusive even after completion of appropriate diagnostic tests.

Diagnostic Tests may include:

• A complete blood count (CBC) evaluates the red and white blood cells. Some dogs with Cushing’s syndrome have what is called a “stress leukogram” due to the effects of high blood cortisone concentration. The term stress leukogram refers to a specific white blood cell distribution in the blood. This distribution includes a high total white blood cell count with increased numbers of neutrophils and monocytes and decreased numbers of lymphocytes and eosinophils. Each of these cells is a different type of white blood cell.
• The biochemical profile is a useful diagnostic test, because the majority of dogs with Cushing’s syndrome have an abnormally high concentration of alkaline phosphatase. The enzyme alkaline phosphatase is produced in the liver in response to stimulation by cortisone or as a consequence of primary liver disease. An abnormally high concentration of alkaline phosphatase is one of the most consistent abnormalities found in dogs with Cushing’s syndrome. Other biochemical abnormalities may include mild increases in other liver enzymes (e.g. alanine aminotransferase), mildly increased blood glucose concentration, and high blood cholesterol concentration.
• The urinalysis also may provide clues to the presence of Cushing’s syndrome. Due to the presence of increased water consumption and increased urination, dilute urine often is observed in dogs with Cushing’s syndrome. Urine concentration is assessed by a test that measures urine specific gravity that compares the concentration of urine to pure water. Dilute urine is found in approximately 85 percent of dogs with hyperadrenocorticism. Unfortunately, many other diseases also result in dilute urine. Occasionally, protein is present in the urine. Urinary tract infections are common in dogs with Cushing’s syndrome, and urine culture should be performed as part of the clinical assessment.
• Radiographs (X-rays) of the chest are taken to evaluate the dog for evidence of pulmonary infection (pneumonia) or metastatic disease (nodules in the lungs caused by distant spread of an adrenal tumor).
• Abdominal radiographs (X-rays) are taken to evaluate the adrenal glands for evidence of enlargement or calcification, which may indicate the presence of an adrenal tumor. Malignant adrenal tumors are more likely to be calcified than are benign tumors. Bladder stones also may be observed in dogs with Cushing’s syndrome. Hepatomegaly (increased liver size) also is a common finding on abdominal radiographs in dogs with Cushing’s syndrome.
• The urine cortisol-to-creatinine ratio can be used as a screening tool in the evaluation of dogs suspected to have Cushing’s syndrome. A negative result strongly suggests that a dog does not have Cushing’s syndrome, but a positive test result does not necessarily mean that a dog does have Cushing’s disease. False-positive results occur because the stress of non-adrenal illnesses can lead to an abnormal cortisol-to-creatinine ratio. Regardless, the urine cortisol-to-creatinine ratio is a useful and easy screening test because it only requires a single morning urine sample.
• Abdominal ultrasound examination is much more sensitive than abdominal radiographs in evaluating the animal for adrenal gland enlargement due to hyperplasia or a tumor. Presence of a single enlarged adrenal gland is suggestive of an adrenal tumor. Enlargement of both adrenal glands is suggestive of adrenal gland enlargement (hyperplasia) due to a pituitary tumor. If indicated, a liver biopsy can be obtained by ultrasound guidance and the tissue evaluated by a pathologist for microscopic changes associated with high blood cortisone concentration. The kidneys and bladder also can be evaluated during abdominal ultrasound examination to evaluate for the presence of stones or infection.
• A conclusive diagnosis of hyperadrenocorticism is based on measurement of blood cortisol concentration before and after stimulation with adrenocorticotropic hormone (ACTH stimulation test) or before and after suppression by intravenous administration of a potent cortisone-like drug called dexamethasone (dexamethasone suppression test). An exaggerated response to stimulation with ACTH and lack of suppression after dexamethasone administration are expected when blood cortisol concentrations are measured in dogs with Cushing’s syndrome. Measuring a single blood cortisol concentration at rest is of little or no value because blood cortisol concentrations in normal dogs and those with Cushing’s syndrome can vary greatly.
• The ACTH stimulation test works on the principle that the adrenal glands of the dog with Cushing’s syndrome are hypersensitive to ACTH. Blood cortisol concentration is measured before injection of the pituitary adrenocorticotropic hormone (ACTH). Depending on the type of ACTH used, a second blood cortisol concentration is determined 1 or 2 hours later. Blood cortisol concentration is expected in increase after ACTH stimulation both in normal dogs and in those with Cushing’s syndrome, but the response should be exaggerated in dogs with Cushing’s syndrome. The ACTH stimulation test is useful, but it is not definitive. Only approximately 80 percent of dogs with Cushing’s syndrome are identified by this test and some dogs with Cushing’s syndrome have normal test results (false-negative results). Furthermore, dogs that do not have Cushing’s syndrome but have some other stressful non-adrenal illness may have abnormal test results (false-positive results).
• The ACTH stimulation test is also the best method of diagnosing Iatrogenic Cushing’s disease. Dogs with the iatrogenic disease will actually have a decreased response to ACTH due to suppression of the production of endogenous (produced within the body) cortisol. This suppression of adrenal cortisol production is caused by the chronic administration of medications containing glucocorticoids.
• Low dose dexamethasone suppression test. Dexamethasone is a potent steroid hormone similar to cortisone. Even a low dose of dexamethasone should markedly decrease cortisol secretion by the normal adrenal gland as a result of the normal “feed-back” loop to the pituitary gland. Blood cortisol concentration is measured before dexamethasone injection, 4 hours after injection, and 8 hours after injection. In normal dogs, blood cortisol concentrations should be suppressed at both 4 and 8 hours after injection of dexamethasone. Lack of suppression suggests the presence of hyperadrenocorticism. The low dose dexamethasone test identifies most (95 percent) dogs with Cushing’s syndrome, but some (5 percent) affected dogs demonstrate suppression (false-negative results) and some dogs with non-adrenal illness will not demonstrate suppression (false-positive results).

Tests used to differentiate pituitary- and adrenal-dependent hyperadrenocorticism include:

• High dose dexamethasone suppression test. This works on the same principle as the low dose dexamethasone suppression test, but a higher dose of dexamethasone is used. The higher dose usually causes suppression of blood cortisol concentration in dogs with pituitary-dependent hyperadrenocorticism but not in those with adrenal-dependent disease.
• Blood ACTH concentration. This test reliably differentiates pituitary- and adrenal-dependent disease, but it is technically difficult to perform. The blood sample must be handled very carefully and sent to a special laboratory to insure accurate results. A low blood concentration of ACTH indicates the presence of an adrenal tumor whereas a normal or high blood concentration of ACTH suggests a pituitary tumor.
• Occasionally, the low dose dexamethasone suppression test can differentiate pituitary- and adrenal-dependent causes of Cushing’s syndrome. When adequate suppression is observed in the 4-hour sample, but not in the 8-hour sample (“escape”), pituitary-dependent disease should be suspected. Patients with adrenal-dependent disease (adrenal tumors) do not “escape” after suppression.
• Presence of one large and one small or normal-sized adrenal gland on abdominal ultrasonography suggests adrenal-dependent disease whereas presence of two large adrenal glands suggests pituitary-dependent disease.
• If the tests described above do not allow clear differentiation of pituitary- and adrenal-dependent disease, CT (computerized tomography) or MRI (magnetic resonance imaging) scanning of the brain to look for a pituitary tumor or abdomen to look for an adrenal tumor may be required. These specialized tests require referral to a specialty center.

Treatment of Pituitary-dependent Hyperadrenocorticism in Dogs

• Medical therapy with mitotane (Lysodren®). Medical therapy with mitotane proceeds in two stages. During the first stage, or induction, mitotane is given daily until blood cortisol concentrations become normal. Mitotane is tolerated best when divided into two daily doses, and it is best absorbed when given with food. Animals must be carefully monitored during this phase, because rapidly falling blood cortisol concentrations may cause illness.
• Therapy with Trilostane (Vetoryl) inhibits cortisol synthesis. It is a registered treatment in Europe but has had limited availability in the United States until recently. ACTH stimulation testing is recommended after 10 and 30 days of treatment effectiveness. Therapy consists of an oral medication once daily, although some dogs require twice a day dosing.
• Usually, the first sign that blood cortisol concentration is normalizing is a decrease in appetite or decrease in water consumption. If these signs are noted, you should contact your veterinarian to schedule re-evaluation. The ACTH stimulation test is used to monitor blood cortisol concentrations after mitotane treatment. The time required to normalize blood cortisol concentration and complete the induction phase of treatment is five to nine days. The time required, however, varies considerably from dog to dog depending on many factors, including the severity of their hyperadrenocorticism. Some dogs require only two or three days for induction whereas others may require three weeks or more.
• At any time during induction, if you feel that your dog is ill you should contact your veterinarian. If the induction phase continues too long, the dog’s blood cortisol concentration and the responsiveness of its adrenal glands may fall below the minimal level required for health, and a condition called hypoadrenocorticism (Addison’s disease) may develop, requiring immediate veterinary care. Prednisone (a synthetic cortisone-like drug) sometimes is prescribed for use in an emergency situation. The response to prednisone in a dog that has received too much mitotane during induction usually is dramatic. Some veterinarians advise giving small doses of prednisone routinely during the loading phase to minimize potential adverse effects. Other adverse effects of mitotane include vomiting, diarrhea, loss of appetite and lethargy. If the veterinarian and pet owner maintain close communication during the induction period, the induction phase usually proceeds smoothly and hyperadrenocorticism is controlled with few or no adverse effects.
• The second phase of treatment is the maintenance phase. The maintenance phase is designed to keep your dog in remission by maintaining low normal blood concentrations of cortisol and keeping the adrenal glands under-responsive to ACTH.
• Medical treatment with mitotane. During the maintenance phase, the daily loading dose of mitotane is given once weekly or divided in half and given twice per week in an effort to maintain normal blood cortisol concentrations. ACTH stimulation tests should be monitored at one month, three months and every six months thereafter because relapses are common and induction may need to be repeated.
• Medical treatment with Ketoconazole. Ketoconazole is an anti-fungal drug that also inhibits the production of steroid hormones by the adrenal glands. Whereas mitotane actually destroys adrenal tissue, ketoconazole reversibly interferes with steroid hormone synthesis but does not destroy adrenal tissue. Ketoconazole is not as effective as mitotane, but approximately 80 percent of dogs improve on this therapy. It is a fairly safe drug, but can cause gastrointestinal upset and is quite expensive. It must be given daily on an indefinite basis. Ketoconazole will not cause acute hypoadrenocorticism (Addisonian crisis) as can occasionally occur with mitotane. Ketoconazole is used most commonly as an alternative to mitotane, in the pre-operative management of a dog with an adrenal tumor removal, as a diagnostic to assess clinical response in a dog suspected to have Cushing’s syndrome, and to control clinical signs in dogs that are not surgical candidates due to the large size of their adrenal tumors.
• Medical treatment with L-deprenyl (Anipryl®). L-deprenyl is a monoamine oxidase inhibitor that increases concentrations of dopamine in the brain which in turn is thought to decreases ACTH concentration. A decrease in ACTH concentration is thought to decrease blood cortisol concentration and result in improvement of clinical signs. The use of L-deprenyl is very controversial. Some veterinarians believe they see clinical improvement in treated dogs, whereas research studies have shown little or no effect of L-deprenyl on laboratory tests used to assess hyperadrenocorticism. A four to six week trial of L-deprenyl is recommended to assess clinical response. The main advantage of this drug is its safety.
• Treatment of a large pituitary tumor (macroadenoma). Occasionally, a macroadenoma is suspected on the basis of clinical signs and diagnostic tests (CT and MRI scans). Treatment is difficult when these large tumors cause neurologic signs. Medical therapy usually is ineffective and may even make the clinical signs progress more rapidly. Some referral institutions offer radiation therapy for treatment of pituitary macroadenomas. Treatment success depends on the tumor size and the neurologic status of the affected dog.
• Removal of the pituitary gland or pituitary tumor is technically difficult due to the anatomy of the dog. Treatment methods are aimed at decreasing cortisol production by the adrenal gland via medical means.

Treatment of Adrenal-dependent Hyperadrenocorticism in Dogs

• Treatment of adrenocortical tumors. Approximately 50 percent of adrenocortical tumors are malignant. Before surgery, a conscientious effort should be made to determine whether or not the tumor has invaded adjacent structures, like large blood vessels such as the kidney vein or vena cava, or spread distantly to the lungs and to evaluate surgical accessibility of the tumor. Chest radiographs (X-rays), abdominal ultrasound, computerized tomography and magnetic resonance imaging most often are used for this purpose. If there is evidence of metastatic disease, a medical approach is warranted instead of surgery.
• Medical treatment of adrenocortical tumors. Patients with adrenocortical tumors may respond to mitotane or ketoconazole. Higher doses and longer induction periods generally are needed when using mitotane to treat a patient with an adrenocortical tumor.
• Surgical treatment of adrenocortical tumors. The surgical treatment for adrenocortical tumors involves removing the entire affected adrenal gland. It is a technically difficult surgery associated with a high frequency of postoperative complications. Surgery to remove an adrenocortical tumor ideally should be performed at a referral center by an experienced surgeon and the animal should be closely monitored during and after surgery. If the tumor has not spread, and surgery is successful, an affected animal potentially could be “cured” by surgery.

Optimal treatment for your dog requires a combination of home and professional veterinary care. Follow up can be crucial, especially if your dog does not improve. Administer as directed all medications prescribed by your veterinarian. Alert your veterinarian promptly if you are experiencing problems treating your dog.

Monitor for any recurrence of clinical signs, especially increased thirst, increased urination and increased appetite. If your dog suddenly deteriorates, especially during treatment with mitotane, contact your veterinarian immediately. He or she may prescribe prednisone to be given in the event of an emergency.

Routine blood testing (especially ACTH stimulation tests) will be needed at least twice a year.

Dogs on mitotane therapy generally require progressively higher maintenance dosages of the drug over time due to increasing blood cortisol concentrations.

Follow-up after surgical removal of an adrenal tumor includes monitoring the dog for recurrence by means of abdominal ultrasound examination.

Follow-up Care of Dogs with Cushing’s Disease

Optimal care for the dog with Cushing’s syndrome requires a good understanding of the disease and its symptoms, a significant financial and time commitment by the owner, and excellent communication between the veterinarian and the owner.