Two canine cases of pituitary-dependent hyperadrenocorticism are described below to highlight some valuable treatment considerations for this condition.
Idiosyncratic, Trilostane-induced Adrenocortical Necrosis
An eight year old castrated male French bulldog was evaluated at Portland Veterinary Emergency and Specialty Care for polyuria, polydipsia, polyphagia, and panting. An abdominal ultrasound showed bilateral adrenal gland enlargement. A low dose dexamethasone suppression test supported a diagnosis of hyperadrenocorticism. The author of this article always initiates trilostane therapy at the low end of the recommended dosing range. Trilostane therapy was initiated at a 1 mg/kg PO BID dose.
Just days after starting therapy, the patient’s appetite declined, he became lethargic, and he began vomiting. He was re-evaluated emergently. Clinical abnormalities at the time included moderate dehydration and hypothermia. Biochemical abnormalities included hyperkalemia, hyponatremia, hypercalcemia, and mild azotemia. An ACTH stimulation test showed pre- and post-ACTH cortisol values that were too low to read, consistent with iatrogenic hypoadrenocorticism.
Trilostane was discontinued immediately. Intravenous fluids were administered. Oral, physiologic prednisone therapy was initiated. The patient received 1.5 mg/kg of desoxycorticosterone pivalate subcutaneously. Within 24 hours there was both clinical and biochemical improvement. Adrenal gland function never recovered in this patient, who is now being managed long-term for hypoadrenocorticism.
Conclusion: Clinicians should be aware that trilostane therapy, even at conservative, very appropriate doses, may result in adrenocortical necrosis within days of starting therapy. However, prompt recognition and appropriate treatment can correct a life-threatening situation. Adrenocortical necrosis induced by trilostane can be permanent.
Mitotane: When to use It
A ten year old spayed female mixed breed dog was evaluated at Portland Veterinary Emergency and Specialty Care for poorly controlled diabetes mellitus. Clinical findings at the time of the initial evaluation included moderate overconditioning, a pot-bellied appearance, panting, and diffuse mild muscle atrophy. Biochemical findings included marked hyperglycemia and a severely elevated ALP. An ultrasound showed a hyperechoic, enlarged liver with rounded margins and bilateral adrenomegaly. A low dose dexamethasone suppression test supported a diagnosis of hyperadrenocorticism. Trilostane therapy was initiated at the low end of the recommended dosing range, 1 mg/kg PO BID.
This patient’s clinical and biochemical changes continued to progress, despite the upward titration of the trilostane dose. The author of this article chooses to monito Cushinoid patients’ treatment efficacy using a combination of clinical signs, reassessment of the ALP, and pre-trilostane cortisol values. With treatment success, clinical signs should abate, the ALP elevation should improve, and the pre-trilostane cortisol concentration is typically between 1-5 ug/dl. Even with 4 mg/kg of twice daily trilostane, this patient’s ALP continued to climb. Her pre-trilostane cortisol values were consistently > 10.0 ug/dl. Her clinical signs progressed to the point where she developed Cushing’s myopathy, a development that severely limited her mobility.
Rather than continuing to escalate her trilostane dose, we made the decision to transition this patient to mitotane. Mitotane is a cytotoxic agent that selectively kills adrenocortical cells. Its use typically involves an induction phase where the drug is administered daily (with extremely close monitoring) and a maintenance phase where it is administered less frequently long-term. The induction phase for this patient involved administration of 40 mg/kg/day of oral mitotane. After one week, an ACTH stimulation test was performed. With both her pre- and post-ACTH cortisol values falling between 1-5 ug/dl, and with clinical improvement being noted over just the first week of therapy, we were able to transition to the maintenance phase for mitotane administration.
Conclusion: Mitotane therapy should be considered in cases where trilostane is either not well tolerated or ineffective. The response to mitotane therapy in dogs with pituitary-dependent hyperadrenocorticism is typically very predictable. However, careful monitoring is required during the initiation phase of mitotane therapy. Mitotane also effectively lowers the adrenal sex steroids progesterone, androstenedione, and 17-hydroxyprogesterone concentrations. Its use should also be prioritized in cases of atypical Cushing’s disease characterized by elevations in these adrenal sex hormones. Trilostane, which is now more commonly used, will commonly increase adrenal sex hormone concentrations, thus rendering it potentially ineffective in atypical cases characterized by high sex hormone concentrations.
Authored by: Adam Shoelson, DVM, DACVIM (Small Animal Internal Medicine)