Treatment of Pituitary-dependent Hyperadrenocorticism
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. 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.
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.