There are several different medications available to treat pituitary dependent Cushing's syndrome in animals. Each medication has its own benefits and risks. Here we present some of those available options. This data is presented in a manner that can be used to explain therapeutic options to the client. Some of the descriptions may appear simplistic to the attending veterinarian.

#1 Lysodren
Lysodren (generically known as mitotane and chemically known as o,p’-DDD) used to be the only medical treatment option for pituitary dependent Cushing’s disease. It is still used today because of the convenience associated with its use and the fact that it is relatively inexpensive.  It does, however, have the potential for causing very serious side effects. Because this medication has been used for treating canine Cushing’s syndrome for decades, most veterinarians have extensive experience with its administration and in interpreting the monitoring laboratory tests, therefore minimizing the potential for problems with its use. One of the disadvantages of Lysodren therapy is the need for these regular monitoring blood tests.

Lysodren should be considered a "chemotherapy" drug. It actually erodes the layers of the adrenal gland that produce corticosteroid hormones. Although the pituitary tumor continues to secrete and excessively stimulate, the adrenal gland is no longer capable of excess hormone production in response to this stimulation. Problems result when too much of the adrenal cortex is eroded. This is sometimes referred to as an Addisonian crisis.

Short-term Lysodren reactions are common (approximately 30 percent of dogs will have a problem at some point), necessitating the use of prednisone as an "antidote" pill. In the event of a short-term reaction, Lysodren is discontinued until the adrenal gland can re-grow, at which time therapy is resumed, possibly at a lower dose. In some cases, permanent, excessive adrenal erosion can occur at which point the dog must be treated for cortisone deficiency. This is somewhat more serious, and this complication has been the driving force behind the search for better medications to treat pituitary dependent Cushing’s disease.  

How this medication is used

There are two phases to the Lysodren treatment protocol: 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 receives a prescription of Lysodren and a bottle of prednisone tablets to be used as an "antidote" should a Lysodren reaction occur. Lysodren is given daily, with meals. It is very important that Lysodren be given with food or it will not be absorbed into the dog’s body. The goal is to "shave down" the plump, excessively stimulated adrenal gland - to a desired size.  A test called an ACTH stimulation test (the same test which may have been used to diagnose Cushing’s disease) is used to confirm that the induction endpoint has been reached. An ACTH stimulation test is generally scheduled for the 8^th or 9^th day into induction however, it is important that pet owners recognize the signs of "endpoint" should it occur sooner.  You should call your veterinarian if any of the following are observed:

• Vomiting or diarrhea
• 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

It is a good idea to maintain close contact with your veterinarian during induction as it is at this point that a dog becomes at greatest risk for complications. If any of the signs of "endpoint" are observed, the veterinarian may recommend an earlier follow up to repeat the ACTH stimulation test or might suggest giving an "antidote" (prednisone) pill.  

When the follow up ACTH stimulation test indicates that sufficient adrenal erosion has taken place, then the Lysodren dose is reduced and given once or twice a week instead of daily, and the pet can enter the maintenance phase of therapy. If the test indicates that more adrenal erosion is needed, induction continues. Most dogs have reached maintenance by the 10 to 16^th day of induction, but others require more time, especially if they are concurrently taking drugs that alter the metabolism of Lysodren (such as Phenobarbital).

Maintenance
After achieving maintenance, another ACTH stimulation test is recommended after about a month and then at least twice a year. Approximately 50 percent 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 that water consumption will normalize. The last sign to show improvement 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 pet's veterinarian should be notified. Once again, it may be recommended to administer the prednisone "antidote" pill. A Lysodren reaction generally reverses within 30 minutes after an "antidote" (prednisone) pill.

#2 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 - it is considered as effective as Lysodren. Initially, it was considered to have very few side effects but it is now used with the same amount of care and caution 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. Most reactions are minor and can be reversed with the discontinuation of Trilostane; however, permanent Addisonian reactions are possible, just as with Lysodren. While the 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. The risk of a permanent or life-threatening Addisonian reaction has been reported to be 2 to 3 percent with Trilostane and 2 to 5 percent with Lysodren.

As with Lysodren, the dose is modified according the results of periodic ACTH stimulation tests (at 10 to 14 days, 30 days, 90 days, and then every 6 months). So, why consider Trilostane when its monitoring is similar to that of Lysodren and its dosing schedule is less convenient Because this is an effective alternative medication for pets that do not tolerate Lysodren or who have had difficulty achieving regulation with Lysodren. Additionally, Lysodren can be difficult to obtain.

Disadvantages of Trilostane Compared to Lysodren

Initial references to Trilostane suggested it was safer than Lysodren, however 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 must be identified for the individual pet
• 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
  

#3 L-Deprenyl

Instead of trying to interfere with the over-production of steroid hormones by the adrenal gland, L-Deprenyl directly addresses issues presented by the pituitary tumor.

Studies with L-Deprenyl began when it was discovered that this medication might be helpful in treating humans with Parkinson's disease. L-Deprenyl inhibits enzymes involved in the  degradation of dopamine (a neurotransmitter). This means that dopamine presence is prolonged. This drug also stimulates the production of other neurotransmitters that serve to stimulate dopamine production.  

It just so happens that the secretion of ACTH is impacted by the neurotransmitter dopamine. When dopamine levels are high, ACTH secretion shuts down. L-Deprenyl inhibits the enzymes involved in degradation of dopamine. More dopamine leads to less ACTH release, which means less steroid production by the adrenal glands. 

An Especially Low Incidence of Side Effects
Approximately 5% experience nausea, restlessness or reduction in hearing.

When dogs with Cushing's disease become more active and their appetites normalize, is it because their Cushing's disease is controlled or because of the stimulant by-products of L-Deprenyl?  

No one knows. The metabolic breakdown products of L-Deprenyl are amphetamine and methamphetamine (strong stimulants that also suppress hunger). 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 five seemed 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 action of this medication, an Addisonian reaction is not a concern with L-Deprenyl and, thus, these monitoring tests are not required with its use. In frail dogs with only minor Cushing's symptoms, L-Deprenyl may be an excellent choice.

Advantages of Lysodren Over L-Deprenyl
L-Deprenyl is more expensive than Lysodren and response to L-Deprenyl is not reliable and may only be partial or may take some time. The usual protocol, if no response is noted after two months of therapy, is to double the dose and continue for an additional month before determining the patient to be a non-responder and considering another medication. With Lysodren, response is rapid and and be documented with testing.

Addison's Disease / Addisonian Crisis
Addison’s disease, also called hypoadrenocorticism, is the opposite of Cushing’s disease; Addison's results from a deficiency of the body's natural cortisone. If Lysodren erodes too much of the adrenal gland, Addison’s disease can be a permanent result. If this occurs, hormone supplementation is needed indefinitely to prevent life threatening shock, as the body becomes unable to adapt to various forms 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.

Contributed by: Karen Helton-Rhodes, DVM, Diplomate ACVD