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TREATMENT OF PITUITARY CUSHINGS
We will begin this section by noting that pituitary-dependent Cushing's syndrome does not always require treatment. The ultimate goal of therapy is to improve the patient's life quality and to fortify the patient's bond with his or her owner so if the Cushing's patient is not having problems with his or her symptoms, treatment may not be indicated. In deciding whether or not to treat Cushing's syndrome, consider symptoms that this particular individual patient is dealing with. For example, if the patient is drinking excessively but is not urinating in the house, this may not be a problem. If the patient has recurrent bladder or skin infections, high blood pressure, urinary protein loss, or is so hungry as to be raiding the kitchen regularly then he or she needs treatment.
There are two medications commonly used in the management of pituitary dependent Cushing’s disease: Lysodren® (also called Mitotane or o,p’-DDD), Trilostane (brand name Vetoryl®). 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-dependent Cushing's syndrome. Two other medications: Ketoconazole and Selegiline re also sometimes used but with less reliable results but they may be applicable in special circumstances. We will review all four choices.
HOW THIS MEDICATION WORKS
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.
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 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 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.
You should call your veterinarian if any of the following signs observed:
These signs indicate not only that endpoint has been reached but that a Lysodren® or Addisonian reaction is probably occurring (see below) and your dog may need to receive the antidote. When endpoint is reached, the dog should have an ACTH stimulation test within 24 hours if possible.
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 may be continued or the maintenance dose may simply need to be higher than originally planned. Most dogs are ready for maintenance within the first week of induction but others require more time, especially if they are taking concurrent drugs that alter the metabolism of Lysodren®. (Phenobarbital would be the obvious such medication.)
After achieving maintenance, another ACTH stimulation test is recommended after about 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 or a change in maintenance dose.
Trilostane is given once or twice a day with food (as opposed to Lysodren® which is given twice a week). Common side effects are mild lethargy and appetite reduction especially when medication is started and the body adapts to its hormonal changes. Addisonian reactions (see below) have been reported where the adrenal cortex actually dies off. Most trilostane reactions are minor and can be reversed with discontinuation of the trilostane; however, permanent Addisonian reactions, where cortisol suppression is too strong (see below), are possible just as with Lysodren® with an important difference. With Lysodren® reactions depend on the amount being given (higher dose = more chance of reaction) but with trilostane reactions are random and unpredictable ("idiosyncratic").
Both Lysodren® and trilostane have their doses adjusted based on results of periodic blood tests (ACTH stimulation tests) typically done at 14 days, 30 days, 90 days and then every 4-6 months depending on results. 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®
Disadvantages of Trilostane Compared to Lysodren®
WHAT IS ADDISON’S DISEASE / ADDISONIAN REACTION?
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 or if there is an idiosyncratic trilostane response, an Addisonian reaction occurs which 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 occurring, a dose of prednisone (which has hopefully been provided to keep on hand in case of emergency) should reverse the reaction within 30 minutes (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 drug 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 very expensive, especially for larger dogs, and it is generally felt that the creation of Addison’s disease is undesirable. That said, in Europe it is common to treat Cushing's disease by purposely creating an Addisonian state as it is much simpler to treat Addison's disease than it is to treat Cushing's disease. The technique for purposely creating Addison's disease is called "medical adrenalectomy." It involves very high doses of Lysodren® and is done in a very controlled manner. It is not a common procedure in the U.S.
See more information on Addison's disease, which can also occur in animals (and people) as a natural occurrence with no help from Lysodren®.
KETOCONAZOLE AND SELEGILINE: RARELY USED ALTERNATIVES NOWADAYS
A NOTE ON SURGERY
Since pituitary-dependent Cushing's syndrome is caused by a pituitary tumor, the question arises about removing the tumor surgically. This treatment has received more attention recently but the location of the pituitary (at the base of the brain) makes surgery problematic. Surgery is not at this time a common treatment in the U.S. and very special facilities are required for this type of surgery. Unless you live in a unique community where there is a surgeon with extensive experience in this as yet esoteric procedure, we recommend sticking with the medical therapies.
Choosing a therapy for pituitary Cushing's syndrome should take into account efficacy, cost, monitoring schedule, dosing schedule, and side effects potential. In the future, surgical options are likely to come forward as they have in the treatment of human Cushing's syndrome. Please direct further concerns and questions to your regular veterinarian as you pick an option.
Page last updated: 9/16/2020