Challenges in treating hyperadrenocorticism in dogs (Proceedings)

Pituitary-Dependent Hyperadrenocorticism

Trilostane, currently the most used treatment for PDH, is a synthetic steroid analogue. It competitively inhibits the 3-beta hydroxysteroid dehydrogenase enzyme blocking cortisol, aldosterone and sex hormone production. Trilostane (Vetoryl, Dechra Veterinary Products) was recently granted FDA approval for treating canine hyperadrenocorticism. Trilostane should not be used in animals with renal failure, primary liver disease, lactating animals or those intended for breeding. The initial dose is 2–5 mg/kg/day PO with food. We recommend starting at the low end of this range to potentially reduce the risk of adrenal necrosis. This dosage can be given once daily or divided twice daily (the manufacturer currently recommends once daily administration. Recent studies, however, have shown that a significant number of patients can require twice daily trilostane to adequately control their hyperadrenocorticism. We generally start all patients on once daily therapy to increase client compliance and change to twice daily if necessary. Evaluate the response to treatment based on resolution of clinical signs of hyperadrenocorticism and results of ACTH stimulation tests. Examine patient and perform an ACTH stimulation test at 10 days, 1 month, 3 months and every 3 to 6 months thereafter. Complete blood counts and serum chemistry profiles should be regularly evaluated. Perform ACTH stimulation testing 4 hours after trilostane if it is being administered once daily and 8-10 hours after trilostane in dogs receiving it twice daily. Appropriate pre and post ACTH cortisol concentrations are between 2 and 6 ug/dl approximately 4 hours after trilostane in dogs on once daily therapy, and 5-10 ug/dl 8-12 hours after trilostane in dogs on twice daily therapy. In these situations trilostane is continued at the current dose. If the post ACTH serum cortisol concentration is >7 ug/dl (once daily dosing) or >10 ug/dl (twice daily dosing) increase the trilostane dose by 25-50%. If the post ACTH serum cortisol concentration is <2 ug/dl (once daily dosing) or <5 ug/dl (twice daily dosing), discontinue the trilostane for 7 days, decrease the dose by 25-50% and repeat an ACTH stimulation test in 10 days. If signs of hypoadrenocorticism occur, discontinue trilostane immediately, consider administering prednisone, and evaluate the dog with an ACTH stimulation test and a chemistry profile (including electrolytes) as soon as possible. During the first 6 months of therapy, at least 50% of dogs can be expected to require a change of dosage (usually an increase).

Trilostane is usually well tolerated. Adverse effects including lethargy, vomiting and diarrhea have been reported. Side effects required withdrawal of trilostane in approximately 3–4% of dogs in one study. Acute death and adrenal necrosis have been reported in rare cases usually within several days of starting trilostane therapy. The exact pathophysiology of these deaths is not completely clear at this time. One report describes bilateral adrenal necrosis seen on histopathology in 2 dogs on trilostane. Acute hypoadrenocorticism has been reported in 2 dogs. One of these cases died despite discontinuation of trilostane and appropriate medical intervention. Occasional instances of prolonged (up to several months) adrenocortical suppression can be seen in dogs receiving trilostane. It is not clear how an enzyme inhibitor can cause prolonged adrenocortical suppression or acute hypoadrenocorticism. Hyperkalemia and/or hyponatremia can be seen in a significant number of dogs at variable times after starting trilostane. These changes are not typically associated with clinical signs of hypoadrenocorticism or altered aldosterone levels. Trilostane is effective in controlling the clinical signs in most dogs with PDH. Reported efficacy is comparable to that of mitotane.

Mitotane (o,p'DDD; Lysodren) is frequently used in the treatment of PDH in dogs. Mitotane causes selective necrosis of the zona fasciculata and zone reticularis of the adrenal cortex. The administration protocol for mitotane involves an initial induction phase that uses a daily dosage for induction of remission generally over 10 days (loading dose), followed by a maintenance phase that uses a dosage given in divided doses weekly (maintenance dose). An ACTH stimulation test is performed at the end of the 10-day induction phase, or sooner if adverse effects develop. The goal of therapy is to achieve subclinical hypoadrenocorticism, whereby both basal and post-ACTH cortisol concentrations are within the normal basal cortisol range (1–5 ug/dl for most laboratories). The maintenance phase is started when desired cortisol concentrations are documented by ACTH stimulation testing. Continue mitotane at an initial maintenance dosage of 40 to 50 mg/kg weekly in 2–3 divided doses. Lifelong maintenance therapy is generally needed to maintain remission of the disease. About 20–25% of dogs experience side effects, usually mild, at some point during induction or maintenance mitotane therapy. Occasionally dogs develop iatrogenic hypoadrenocorticism with associated hyponatremia and hyperkalemia. These dogs generally require lifelong supplementation with glucocorticoids and mineralocorticoids. Nearly 50% of dogs with PDH have a relapse of disease within the first 12 months of maintenance therapy. These cases require an increase in the weekly maintenance dosage or reinduction with daily doses of mitotane for 7–10 days, followed by a higher maintenance dosage (weekly dosage usually increased by 50%). To ensure continued control and prevent serious relapse during mitotane treatment, repeat ACTH stimulation testing after 3 and 6 months of maintenance treatment and every 6 months thereafter. Relapse of PDH can thereby usually be detected before recurrence of clinical signs is evident.

l-Deprenyl (selegiline HCl; Anipryl, Pfizer) is a selective, monoamine oxidase type B inhibitor that decreases pituitary ACTH secretion by increasing dopaminergic tone to the hypothalamic-pituitary axis, with a resultant fall in serum cortisol concentrations. Initiate l-deprenyl therapy at a dosage of 1 mg/kg PO daily. If an inadequate response is seen after 2 months of therapy, increase the dose to 2 mg/kg/day. Should this dose also prove ineffective, use alternative therapy. If effective, continue daily therapy for the remainder of the dog's life. The drug is indicated for the treatment of uncomplicated cases of pituitary-dependent hyperadrenocorticism. l-Deprenyl is not recommended for treatment in dogs with concurrent diabetes mellitus, pancreatitis, heart failure, renal disease, or other severe illness, and it is not effective for the treatment of cortisol-secreting adrenocortical neoplasia. Independent studies have reported efficacy rates of 20% or less. Adverse effects such as anorexia, lethargy, vomiting, and diarrhea are uncommon (<5% of dogs) and usually mild. Other drawbacks of l-deprenyl therapy include the need for lifelong daily administration and the expense of the medication.

The prognosis for PDH is always guarded because of the many complications associated with the disease. Dogs that succumb to such complications usually do so within the first 3–6 months after diagnosis. Dogs that survive this period typically die of other geriatric disorders unrelated to hyperadrenocorticism.

Adrenal Tumors

Surgery is generally considered the treatment of choice in dogs with adrenal adenomas or small carcinomas. However, the surgery can be challenging and several peri- and postoperative complications can occur.

Mitotane is a relatively effective and safe treatment alternative for most dogs with adrenal tumors and has been successful for over 24 months in some cases. In general, higher dosages of mitotane are required than for treatment of dogs with pituitary-dependent hyperadrenocorticism. Only 15–20% of dogs with adrenal tumors respond to the standard treatment protocol used in dogs with PDH. Dogs with adrenal tumors often require a cumulative mitotane induction dose up to 10 times higher than dogs with pituitary-dependent hyperadrenocorticism (due to a longer period of daily mitotane administration). In dogs with adrenal tumors, mitotane is used as a true chemotherapeutic agent with the goal of destroying all functional, neoplastic adrenocortical tissue. Therefore, both the serum basal and post-ACTH cortisol concentrations should be low to undetectable (<1 ug/dl). The induction of overt hypoadrenocorticism may improve the long-term prognosis, but direct mitotane toxicity (from the high doses of mitotane needed) prevents achieving this in many dogs. Indications for mitotane therapy of adrenal tumors are gross metastatic disease evident prior to surgery, unresectable or incompletely resectable tumor, residual disease after adrenalectomy as detected by ACTH stimulation testing, unacceptable anesthetic or surgical risks to the patient, refusal of surgery by the client.

Trilostane has been used to treat a small number of dogs with adrenal-dependent hyperadrenocorticism with good response in some cases. Being an enzyme inhibitor, trilostane provides control of serum cortisol levels but should not effect the underlying neoplastic process. However, there are a few reports of acute hypoadrenocorticism as well as bilateral adrenal necrosis in dogs with pituitary-dependent hyperadrenocorticism receiving trilostane. Trilostane is not considered cytotoxic. Therefore mitotane may be preferable for treatment of malignant adrenocortical tumors. Trilostane may be useful for the preoperative control of serum cortisol concentrations and clinical signs in dogs undergoing adrenalectomy.