Cushing’s syndrome (hyperadrenocorticism) is a chronically debilitating hormone imbalance that can affect many species, humans included. We will limit our discussion to dogs and cats, however. Cushing’s syndrome, also called Cushing’s disease, results from excessive cortisol in the bloodstream and the symptoms all stem from long-term over-exposure to this hormone.

There are many clinical signs associated with Cushing’s syndrome (also called hyperadrenocorticism) in dogs. These signs usually come on gradually and, because of this slow onset, these changes are often written off as part of the normal aging process.

 

The following list of common symptoms that an owner might observe in their pet at home is:

• Drinking excessively
• Urinating excessively
• Panting
• Pot belly appearance
• VERY hungry!!

 

Owners often notice that lately the water bowl must be filled more frequently than in the past. Some dogs are unable to hold their bladder all night and begin crying to go outside during the night when previously this was unnecessary.

Also, urinary tract infections may also be detected and true urine leaking may be observed.

 

How Much Water Consumption is Normal?

Each day a dog should drink about one cup of water for each ten pounds of body weight, though this can vary somewhat with environmental temperature and activity level. Dogs that truly have excessive water consumption will consume vastly more than this regularly.

 

Increased or even Ravenous Appetite

This symptom often leads dogs to beg incessantly or steal food from the garbage. It is important for an owner not to be fooled by the pet’s “good appetite”: eating well is not necessarily a sign of normal health.

 

Pot-bellied Appearance

This symptom, seen in over 90% of Cushing’s syndrome dogs, results from hormonal redistribution of body fat plus a breakdown of abdominal musculature.

 

Muscle Weakness

Muscle protein is broken down in Cushing’s syndrome. The result may be seen as exercise intolerance, lethargy, reluctance to jump up on furniture or climb stairs.

 

Skin Disease

The classical signs of endocrine (hormonal) skin diseases are:

•  Hair loss on the main body sparing the head and legs
• Thin, wrinkled skin with poor wound healing
• Hair that does not grow back after clipping.
• Blackheads and darkening of the skin, especially on the abdomen.
• Persistent or recurring skin infections (especially if the dog is not itchy during times when the skin infection is cleared)

Another condition of the skin that may be observed is called calcinosis cutis, in which calcium deposits occur within the skin. These are raised, hard, almost rock-like areas that can occur almost anywhere on the body.

Some other notable findings might include: excessive panting and shortness of breath, infertility, extreme muscle stiffness (called pseudomyotonia – a very, very rare symptom in Cushing’s disease), and high blood pressure.

Aside from the symptoms described above, advanced untreated Cushing’s disease puts a dog at risk for the following serious problems:

Calcium oxalate bladder stones

Diabetes mellitus

Pulmonary thromboembolism

 

Cats

In cats, the clinical features of Cushing’s disease are similar to those in the dog: excess water consumption, muscle wasting, pot-bellied appearance, thin coat, and skin abnormalities. Some cats develop a peculiar curling-in of their ear tips. An important difference to note is that while only 10% of dogs with Cushing’s disease develop diabetes mellitus, 80% of cats with Cushing’s disease develop diabetes mellitus. Diabetes in an animal with Cushing’s disease is difficult to control until the Cushing’s disease is controlled.

 

What Exactly is Cushing’s Disease

Cushing’s syndrome is the resulting set of symptoms observed when the body is exposed to excess cortisone (or related hormones) over a long period of time. Cortisone, or more correctly cortisol, is a hormone produced by the adrenal glands, which are located atop the kidneys. Cortisol is stored in the adrenal gland and is released in times of stress where it helps our bodies prepare for a fight or flight situation. It adjusts the metabolism to expect physical exertion by mobilizing fat and sugar stores and retaining sodium and water. It puts us in a state of break down so that our stored resources can be used quickly. However, if the body is exposed to this hormone most of the time instead of during short stressful periods only, the state of break down becomes debilitating.

There are several mechanisms that can lead to Cushing’s syndrome and, as they are treated differently, it is important to determine which one is at work in a given animal.

In the normal body, the pituitary gland, located at the base of the brain, can detect when cortisol levels in the blood are declining. In response, the pituitary secretes a stimulating substance, called ACTH, which causes the adrenal gland to release more cortisol. When the pituitary gland detects that cortisol levels are again appropriate, it stops its stimulatory message.

You can think of the pituitary gland as a sort of a thermostat for cortisol. This raising and lowering of cortisol blood level is regulated throughout the day via ACTH secretion and occurs rapidly.

 

Pituitary-Dependent Cushing’s Syndrome

This form of Cushing’s disease accounts for 85% of dogs with Cushing’s syndrome. Basically, the pituitary gland grows a small tumor. The tumor is generally too small to cause any trouble due to its size and it is generally a benign tumor. This tumor, however, over-produces ACTH, thus leading to over-stimulation and enlargement of both adrenal glands and an over-production of cortisone. Occasionally (10% of pituitary-dependent Cushing’s dogs), these benign pituitary tumors are large enough to compress the brain. In these cases, neurological signs may be observed; these cases are unusual but very hard to treat (see section on macrotumors.)

 

Adrenal-Dependent Cushing’s Syndrome

In 15% of dogs with Cushing’s syndrome, an adrenal tumor is directly over-producing cortisone. The tumor is often large enough to see with radiographs or ultrasound and may be malignant. There is very little or no production of ACTH from the pituitary gland and as a result the opposite adrenal gland is usually atrophied/small.

 

Overuse of Cortisone-Type Hormones

Cortisone derivatives may well be the most over-used drugs in veterinary medicine. Their anti-inflammatory actions soothes such common maladies as allergic skin disease (especially flea allergic dermatitis) and degenerative arthritis. Relief is usually rapid and many owners find themselves requesting cortisone shots or pills over and over again. In time, Cushing’s syndrome can result, not from any inherent disease in the pet’s system but from the effects of the hormones given over the long term.

The pituitary gland perceives the high steroid levels yielded by the medication and does not send stimulation to the adrenal glands. In time, the adrenal glands atrophy and are not able to release cortisone on their own should they be required to do so. This effect lasts as long as a period of three months after the cortisone medication has been discontinued. To allow the adrenal to gradually recover, cortisone pills are usually prescribed in a decreasing dose, rather than a sudden stoppage; an owner should never discontinue the pills suddenly.

Commonly prescribed cortisone derivatives include: Vetalog, Azium, prednisone, prednisolone , dexamethasone, Depo-Medrol, triamcinolone and others. These medications have important parts to play in medicine but they must be respected and not used indiscriminately, nor discontinued suddenly after prolonged use.

 

Treatment: Pituitary Cushing’s Syndrome

There are four treatments commonly used in the management of pituitary dependent Cushing’s disease: mitotane or o,p’-DDD (Lysodren®), trilostane (Vetoryl®), ketoconazole (Nizoral®), and L-Deprenyl hydrochloride (Anipryl®, Eldepryl® Carbex®, or selegiline). These medications are associated with different side effects potential and expense and any of them can be expected to produce good results in a confirmed case of pituitary Cushing’s disease.

 

Lysodren: The Traditional Therapy

Lysodren (generically known as mitotane and chemically known as o,p’-DDD) has been the only treatment for pituitary dependent Cushing’s disease until relatively recently. It is convenient to use and relatively inexpensive, though it does have the potential for very serious side effects. Because this medication has been in use for canine Cushing’s disease for decades, most veterinarians have extensive experience with its use and with the monitoring tests needed to prevent side effect difficulties. One of the disadvantages of lysodren therapy is the need for regular monitoring blood tests.

 

How This Medication Works

Lysodren should be considered to be a drug of chemotherapy. It actually erodes the layers of the adrenal gland that produce corticosteroid hormones. The pituitary tumor continues to secrete excess stimulation but the adrenal gland is no longer capable of excess hormone production in response. Problems result when too much of the adrenal cortex is eroded. Short-term lysodren reactions are common (something like 30% of dogs will have one at some point), necessitating the use of a prednisone antidote pill that the veterinarian supplies. In event of such short term reactions, lysodren is discontinued until the adrenal gland can re-grow and therapy is resumed, possibly at a lower dose. Sometimes excess adrenal erosion is permanent and the dog must be treated for cortisone deficiency. This is more serious and the potential for this kind of reaction has been the driving force behind the search for better medications for the treatment of pituitary dependent Cushing’s disease.

 

How This Medication is Used

There are two phases to the treatment of Cushing’s disease with Lysodren: an induction phase to gain control of the disease and a lower dose maintenance phase which ideally lasts for the animal’s entire life.

 

Induction

During induction, the pet owner receives a prescription for lysodren (usually obtained through a local human pharmacy) plus a bottle of prednisone tablets to be used as an antidote should any lysodren reactions erupt. Be sure you understand which pill is which. Lysodren is given twice a day with meals during this period so that the plump, excessively stimulated adrenal gland can be rapidly shaved down to the desired size. It is important that lysodren be given with food or it will not be absorbed into your dog’s body. A test called an ACTH stimulation test (the same test which may have been used to diagnose Cushing’s disease originally) is used to confirm that the induction endpoint has been reached.

An approach gaining popularity involves reducing the dog’s food intake by 30% the day before induction begins to ensure the dog is very hungry for induction. The food is restricted in this way throughout the induction period. The endpoint of induction is determined by a subtle reduction in the patient’s appetite (looking up half way through eating the bowl of food, not running to the bowl as quickly as usual, not finishing the meal etc.) Should any of these signs be observed, this would indicate that the endpoint of induction has been reached and it is time for the ACTH stimulation test. Induction proceeds until endpoint has been reached but if 8-9 days have passed and a clear endpoint has not been observed, the dog should have the ACTH stimulation test at that time anyway

Note: Lysodren therapy should never be used in a dog that does not have a good appetite.

A Cushing’s dog that does not have a good appetite has an additional problem

which must be diagnosed before pursuing therapy for Cushing’s syndrome.

 

You should call your veterinarian if any of the following signs of induction endpoint are observed:

•  Diarrhea or vomiting
• Appetite loss (this may be as subtle as less enthusiasm towards eating when the food is served, not running for the bowl etc.)
• Decrease in water consumption (it may be helpful for you to measure water consumption during the induction period)
• Lethargy or listlessness

If any of these signs occur, let your veterinarian know. It may be time for an early ACTH stimulation test or possibly even for an antidote pill. It is a good idea to maintain daily telephone contact with your vet after the third day or so of induction as it is at this point that a dog becomes at risk for reaching an early induction endpoint.

If none of the above signs are noted, then the ACTH Stimulation test proceeds as scheduled on the 8th or 9th day of induction. If this test indicates that sufficient adrenal erosion has taken place, then the Lysodren dose is given once or twice a week instead of twice a day and the dog has successfully entered maintenance. If the test indicates that more adrenal erosion is needed, induction continues. Most dogs have reached maintenance by the 16 th day of induction but others require more time, especially if they are taking concurrent drugs that alter the metabolisim of lysodren. (Phenobarbital would be the obvious such medication.)

 

Maintenance

After achieving maintenance, another ACTH stimulation test is recommended afterabout a month and then twice a year or so thereafter. Approximately 50% of dogs will experience a relapse at some point and require a second round of induction.

Full reversal of clinical signs associated with Cushing’s disease can be expected after 4 to 6 months of Lysodren therapy. Usually the first, sign to show improvement is the excess water consumption. The last sign to show change will be hair re-growth.

If appetite loss, vomiting, diarrhea or listlessness occur at any time during maintenance, a lysodren reaction should be suspected. The veterinarian should be notified; it may be time for one of the prednisone antidote pills. A Lysodren reaction generally reverses within 30 minutes on an antidote pill.

 

What is Addison’s Disease/Addisonian Crisis?Addison’s disease, also called hypoadrenocorticism, is the opposite of Cushing’s disease; Addison’s disease results from a deficiency of cortisone. If lysodren erodes away too much of the adrenal gland, an Addisonian reaction occurs that can be temporary or permanent. The symptoms mentioned above (vomiting, diarrhea, listlessness, appetite loss) may be seen and if untreated, the patient can go into shock and die. If one suspects an Addisonian reaction is occuring, a dose of prednisone – which has hopefully been provided to keep on hand in case of emergency – should reverse the reaction within 30 minutes, and within a couple of hours at most. If no response to prednisone is seen, the dog has some other illness. If the dog is back to normal after the prednisone dose, then the veterinarian should be contacted for further instructions. The prednisone will likely have to be continued for a couple of weeks.

Addison’s disease can be permanent after a lysodren reaction. If this occurs, hormone supplementation becomes needed indefinitely to prevent life-threatening shock as the body becomes unable to adapt to any sort of stress on its own. Medications to treat Addison’s disease can be expensive, especially for larger dogs, and it is generally felt that the induction of Addison’s disease is undesirable.

It should be noted that there are some specialists who feel that the treatment of Addison’s disease is much simpler than the treatment of Cushing’s disease. They use lysodren at high doses on purpose with the goal of inducing Addison’s disease and administering long-term treatment accordingly. This is not a common method of treating Cushing’s disease in the U.S. and if “medical adrenalectomy” is performed, it is done in a controlled way.

 

Trilostane

Trilostane is an inhibitor of an enzyme called 3-beta-hydroxysteroid dehydrogenase. This enzyme is involved in the production of several steroids, including cortisol. Inhibiting this enzyme inhibits the production of cortisol. Several studies have determined this medication to be effective in the treatment of pituitary-dependent Cushing’s disease, probably as effective as Lysodren.

Trilostane is given once or twice a day with food. Common side effects are mild lethargy and appetite reduction especially when medication is started and the body adapts to its hormonal changes. Addisonian reactions have been reported in which the adrenal cortex dies off. Most reactions are minor and can be reversed with discontinuation of trilostane; however, permanent Addisonian reactions are possible, just as with Lysodren. While these permanent reactions are generally dose-dependent with Lysodren, they are idiosyncratic with trilostane, meaning that they can occur unpredictably and at any dose. For this reason, monitoring blood tests are just as important with trilostane as they are with Lysodren. In two studies, the risk of a permanent or life-threatening Addisonian reaction was 2-3% with trilostane and 2-5% with Lysodren.

For many years trilostane was not available in the U.S. and had to be obtained from another country (usually the U.K.) with permission from the FDA. As of 2009, trilostane (brand name Vetoryl®) has become licensed as a veterinary product in the U.S. and is readily available to most veterinarians through their regular distributors.

As with Lysodren, the dose is modified according the results of periodic ACTH stimulation tests (at 10-14 days, 30 days, 90 days, and then every 6 months). One might ask why one might consider trilostane given that its monitoring is similar to that of Lysodren while its dosing schedule is less convenient. Initially it was believed that because trilostane uses an enzyme inhibitor with reversible effects, trilostane would not have the potential to cause a life-threatening Addisonian reaction. This is no longer felt to be true but at least there is an alternative effective medication for pets that do not tolerate Lysodren or who have had difficulty achieving regulation with Lysodren.

 

Advantages of Trilostane over Lysodren

Trilostane does not erode the adrenal cortex. It acts as an enzyme inhibitor and the inhibition it causes is fully reversible. It is unclear why Addisonian reaction is still possible with this medication. In theory it should be safer.

 

Disadvantages of Trilostane Compared to Lysodren

Because initial references to trilostane suggested it was safer than Lysodren, it is possible for a pet owner to have a false sense of security and ignore important signs of drug reaction.

A precise dosing regimen for trilostane has not yet been worked out.

Lysodren costs substantially less since it is given less frequently.

Trilostane is given once or twice daily while Lysodren is given only once or twice a week.

There is currently little experience with trilostane in the U.S. veterinary community. Your veterinarian may require periodic consultation with other experts.

Trilostane may be a reliable alternative for dogs that do not tolerate Lysodren. If this is a treatment you are interested in, discuss trilostane with your veterinarian.

 

Ketoconazole: Another Approach

The potential for the induction of Addison’s disease as well as the need for periodic expensive monitoring tests have provided impetus for the development of a Lysodren alternative. Ketoconazole was actually developed for a totally different purpose.

Prior to the introduction of Ketoconazole in the 1980s, systemic fungal infections could only be treated with a medication called Amphotericin B. Amphotericin B could only be given by intravenous infusion and was associated with an unacceptably high rate of kidney failure. Ketoconazole was developed as an alternative to Amphotericin B. Ketoconazole can be given orally and is not associated with severe side effects either in the kidneys or other body systems. Hospitalization and monitoring expenses could be eliminated. This was an amazing breakthrough  in the treatment of patients with fungal infections but soon a problem was noted: some of the male patients on this medication developed breast tissue and a more feminized physical appearance. Ketoconazole was interfering with the metabolism of sex steroid hormones. Soon newer generations of anti-fungal products were developed (such as itraconazole and fluconazole) and this problem was eliminated from males being treated for fungal disease.

But this steroid interference did not go unnoticed by the veterinary profession. Since most pets have been spayed or neutered, the sex steroids were generally not of concern but adrenal steroids most certainly were and are of definite relevance. Ketoconazole was investigated as an adrenal suppressor and by 1990, ketoconazole was becoming widely used in the treatment of Cushing’s disease in dogs. Typically, a low dose is used for a week and if no adverse symptoms result in that time, the higher maintaining dose is used.

 

Advantages of Ketoconazole over Lysodren

Because of the nature of the adrenal interference produced by Ketoconazole, it is not possible to induce Addison’s disease.  Because Addison’s disease is not of concern, monitoring tests are not necessary when Ketoconazole is used to treat Cushing’s disease. An ACTH stimulation test is often recommended after the first month or so of ketoconazole therapy simply to determine if the medication is working.

Ketoconazole lists vomiting and diarrhea as potential side effects as does Lysodren but with ketoconazole, no “antidote” pills are needed. Ketoconazole is simply discontinued until the side effects resolve. The dose is modified and re-started.

 

Advantages of Lysodren over Ketoconazole

Ketoconazole is given twice a day indefinitely whereas Lysodren is given once or twice a week, a much more convenient scheduling.

Ketoconazole is enormously expensive even when compared to the cost of all the monitoring tests associated with Lysodren.

Because few people can afford to treat with Ketoconazole, most veterinarians do not have a lot of experience using this drug.  Most veterinarians have extensive experience with Lysodren.

Approximately one dog in five will not respond to Ketoconazole. This is thought to be a problem with absorption of the drug from the intestinal tract.

 

L-Deprenyl (Brand name:Anipryl):

So the search for a better Lysodren alternative continued. L-Deprenyl represents a completely different approach. Rather than trying to interfere with the adrenal gland’s over-production of steroid hormones, L-Deprenyl addresses the pituitary tumor directly.

Studies with L-Deprenyl began when it was found that this medication might be helpful in treating humans with Parkinson’s disease. Research in dogs, however, uncovered some surprising results involving ACTH release from the pituitary gland.

Previously in this web site, we reviewed the feed back loop involving the regulation of adrenal secretion by the pituitary gland. In fact, only part of the pituitary gland (the anterior pituitary) is involved in the feedback loop presented. There are two other parts to the pituitary gland: the intermediate part and the posterior part. The posterior part is involved in the regulation of unrelated hormones and does not concern us but the intermediate part is definitely able to secrete ACTH and is not subject to the same feedback loop as the anterior pituitary is.

So how might we influence ACTH secretion of the intermediate pituitary gland? Research using L-Deprenyl showed us that ACTH secretion in this area of the pituitary is governed by the neurotransmitter: dopamine. When dopamine levels are high, ACTH secretion shuts down.

Pituitary tumors are not very responsive to normal regulatory mechanisms in the body, but most pituitary tumors in dogs with Cushing’s disease are not located in the intermediate pituitary area. This means the intermediate area is still able to respond normally to dopamine regulation.

So how do we raise dopamine levels in the pituitary gland? L-Deprenyl inhibits the enzymes involved in degradation of dopamine. This means that the dopamine present lasts much longer. It also stimulates the production of other neurotransmitters that serve to stimulate dopamine production. It is also able to synergize with dopamine as dopamine binds to the intermediate pituitary gland. More dopamine, means less ACTH release overall, which means less steroid production by the adrenal glands.

 

SIDE EFFECTS HAVE AN ESPECIALLY LOW INCIDENCE WITH L-DEPRENYL USE

(APPROXIMATELY 5% EXPERIENCED MINOR NAUSEA, RESTLESSNESS, OR REDUCED HEARING CAPACITY)

 

Does it really work? The metabolic breakdown products of L-Deprenyl are amphetamine and methamphetamine (strong stimulants that also suppress hunger). When dogs with Cushing’s disease become more active and their excessive appetites become more normal, is it because their Cushing’s disease is controlled or because of the stimulant by-products of L-Deprenyl? No one knows and because of the way L-Deprenyl works in the pituitary, the usual monitoring tests to evaluate Cushing’s treatment progress are not helpful. In independent studies, about one dog in 5 was felt to improve on L-Deprenyl. In studies funded by the manufacturer, about one dog in five did not improve on L-Deprenyl.

 

Advantages of L-Deprenyl Over Lysodren

Because of the unique mechanism of this medication, Addison’s disease is not a concern and thus no monitoring tests are required with the use of L-Deprenyl. L-Deprenyl is the only medication approved by the FDA for the treatment of Cushing’s disease in the dog.For frail dogs with only light Cushing’s symptoms, L-Deprenyl may be an excellent choice.

 

Advantages of Lysodren Over L-Deprenyl

L-Deprenyl is substantially more expensive than Lysodren. Response to L-Deprenyl is not reliable or may be partial or may take some time. The usual protocol if no response has been seen after two months of therapy is to double the dose and continue for one more month before determining the patient to be a non-responder and selecting another medication. With Lysodren, response is rapid and documentable with testing.

 

Date Published: 1/1/2001

Date Reviewed/Revised: 11/18/2012

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