Persistent isolated hypocortisolism following brief treatment with trilostane

Abstract

A 12‐year‐old male neutered Miniature Poodle with confirmed pituitary‐dependent hyperadrenocorticism was treated with trilostane. After three doses, it developed clinical and laboratory changes suggestive of isolated hypocortisolism (‘atypical hypoadrenocorticism’), which persisted and progressed for more than 3 months despite immediate withdrawal of the trilostane. The clinical signs of hyperadrenocorticism resolved without further trilostane. After 3 months, prednisolone treatment was started and the clinical signs of hypocortisolism resolved. Prednisolone therapy was required for more than 1 year. Ultrasonography initially demonstrated large hypoechoic adrenal cortices, typical of dogs with hyperadrenocorticism, which then became small and heteroechoic, consistent with the development of adrenal necrosis. Persistent isolated hypocortisolism has not been reported previously as a complication of trilostane therapy. The case is also remarkable for the very short duration of trilostane therapy that elicited this complication. Clinicians should be aware that trilostane therapy may result in adrenal necrosis, even in the very earliest stages of therapy, but prompt action can prevent a life‐threatening situation.

Adrenocorticotropic hormone, but not trilostane, causes severe adrenal hemorrhage, vacuolization, and apoptosis in rats

“…Other researchers, however, used doses up to 300 mg/kg trilostane/d in rats and reported a dose-dependent increase in adrenal weight, but no adrenal necrosis [1,28,29]. Notably, our study is the first study to report long-term therapy with trilostane (4 months), as in all other studies trilostane was administered for only [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] days.…”

“…When dosed optimally, side effects during trilostane therapy are rare. However, recently, adrenal necrosis has been described in trilostane-treated dogs with PDH [9][10][11]. Necrosis of the adrenal cortex cannot be explained by the known enzyme-inhibiting mechanism of trilostane [1]; the cell death was therefore attributed most probably to either the hypersecretion of ACTH or to a direct action of trilostane or one of its metabolites [9][10][11].…”

“…Furthermore, long-term studies in animals using high doses of trilostane and evaluating adrenal changes are lacking. As ACTH concentrations during trilostane therapy can increase impressively in dogs, it has been hypothesized by several researchers that adrenal necrosis seen in trilostane-treated dogs with PDH could be attributed to the increased ACTH concentration [9][10][11]19]. To gain further insight into the effects of ACTH and trilostane on adrenal cells, the authors intended to evaluate their effects in an experimental animal model.…”

Trilostane in Dogs

“…Most affected cases have typical electrolyte changes (hyponatremia, hyperkalemia) typical of hypoadrenocorticism. However one case has been described which developed isolated hypocortisolism [33] There is also a theoretical risk that trilostane-induced adrenal hyperplasia could develop into adrenal tumours [34]. However no evidence for this has been published.…”

“…This has been documented in 2 case reports, one fatal and the other requiring permanent glucocorticoid therapy [32,33]. It may also have been the cause of sudden death and sudden decreases in trilostane requirement in a few other cases [16].…”