HOW IS CUSHING’S SYNDROME TREATED? I’M CONFUSED!

KAREN HELTON RHODES, DVM, DACVD

TERRI BONENBERGER, DVM, DACVD 

CUSHING’S SYNDROME:  YOUR DOG IS PRODUCING WAY TOO MUCH CORTISOL….A STEROID HORMONE.  THE ADRENAL GLAND MUST BE STOPPED FROM PRODUCING THIS HORMONE IN EXCESS AMOUNTS IN ORDER TO CONTROL THE PROBLEM.

THERAPY FOR CUSHING’S SYNDROME: UNDERSTAND YOUR OPTIONS

THERE IS NO PERFECT MEDICATION. THERE ARE PLUS AND MINUS POINTS FOR EACH CHOICE. YOUR VETERINARIAN WILL HELP YOU DECIDE IF TREATMENT IS NECESSARY & WHICH MEDICATION IS THE BEST OPTION. NOT ALL CASES OF CUSHING’S SYNDROME MUST BE TREATED.

 

LET’S EXPLORE SOME OF YOUR OPTIONS: THIS INFORMATION MAY SEEM DETAILED BUT YOU REALLY NEED TO UNDERSTAND ALL OF THE PARAMETERS!

 

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 as a chemotherapy drug. 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 (approximately 30% of dogs will have a problem at some point), necessitating the use of prednisone as an antidote pill. 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

1.    During induction, the pet owner receives a prescription for Lysodren plus a bottle of prednisone tablets to be used as antidotes should any lysodren reactions occur. Be sure you understand which pill is which. Lysodren is given daily with meals during this period so that the plump, excessively stimulated adrenal gland can be rapidly shaved down to the desired size. It is very 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 ACTH stimulation test is generally scheduled for the 8th or 9th day of induction however, it is important that you recognize the signs of endpoint should they occur sooner.

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

a.     Diarrhea or vomiting 

b.    Appetite loss (this may be as subtle as less enthusiasm towards eating when the food is served, not running for the bowl etc.) 

c.     Decrease in water consumption (it may be helpful for you to measure water consumption during the induction period) 

d.    Lethargy or listlessness

3.    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 close e-mail or telephone contact with your vet during induction as it is at this point that a dog becomes at risk for reaching an early induction endpoint.

4.    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 daily 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 10-16 th day of induction but others require more time, especially if they are taking concurrent drugs that alter the metabolism of lysodren (such as Phenobarbital).

 

Maintenance

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

a.     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.

b.    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 after an antidote pill.

 

TRILOSTANE

1.    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.

2.    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 Addisonianreaction was 2-3% with trilostane and 2-5% with Lysodren.

3.    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.

4.    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 Addisonianreaction. 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

1.    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.

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

3.    Lysodren costs substantially less since it is given less frequently.

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

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

 

 

 

 

L-DEPRENYL (BRAND NAME: ANIPRYL):  

1.    To the treatment of cushings disease, 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.

2.    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.

3.    Research using L-Deprenyl showed us that ACTH secretion in the “intermediate area” of the pituitary is governed by the neurotransmitter: dopamine. When dopamine levels are high, ACTH secretion shuts down.

4.    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.

5.    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 minor 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.

WHAT IS ADDISON'S DISEASE/ADDISONIAN CRISIS?

1.    Addison’s disease, also called hypoadrenocorticism, is the opposite of Cushing’s disease; Addison's results from a deficiency of cortisone. If lysodren erodes away too much of the adrenal gland, Addison’s disease can be a permanent result. 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. Medications to treat Addison's disease can be very expensive, especially for larger dogs, and it is generally felt that the induction of Addison’s disease is undesirable.