title: Adrenocorticotropic hormone, but not trilostane, causes severe adrenal hemorrhage, vacuolization, and apoptosis in rats.
abstract: Adrenal necrosis has been reported as a complication of trilostane application in dogs with hyperadrenocorticism. One suspicion was that necrosis results from the increase of adrenocorticotropic hormone (ACTH) during trilostane therapy. The aim of the current study was to assess the effects of ACTH and trilostane on adrenal glands of rats. For experiment 1, 36 rats were divided into 6 groups. Groups 1.1 to 1.4 received ACTH in different doses (60, 40, 20, and 10 μg/d) infused subcutaneously with osmotic minipumps for 16 wk. Group 1.5 received saline, and group 1.6 received no therapy. For experiment 2, 24 rats were divided into 3 groups. Group 2.1 and 2.2 received 5 and 50 mg/kg trilostane/d orally mixed into chocolate pudding for 16 wk. Eight control rats received pudding alone. At the end of the experiments, adrenal glands were assessed for necrosis by histology and immunohistochemistry; levels of endogenous ACTH and nucleosomes were assessed in the blood. Rats treated with 60 μg ACTH/d showed more hemorrhage and vacuolization and increased numbers of apoptotic cells in the adrenal glands than rats treated with 20 or 10 μg ACTH/d, trilostane, or control rats. Rats treated with 60 μg ACTH/d had a higher amount of nucleosomes in the blood compared with rats treated with 10 μg ACTH/d, trilostane, or saline. We conclude that in healthy rats ACTH, but not trilostane, causes adrenal degeneration in a dose-dependent manner. Results of this study support the hypothesis that adrenal gland lesions seen in trilostane-treated dogs are caused by ACTH and not by trilostane.
authors.affiliation: Clinic for Small Animal Internal Medicine, Vetsuisse Faculty University of Zurich, Zurich, Switzerland.
authors.forename: W A
authors.initials: WA
authors.lastname: Burkhardt
authors.forename: F
authors.initials: F
authors.lastname: Guscetti
authors.forename: F S
authors.initials: FS
authors.lastname: Boretti
authors.forename: A
authors.initials: A
authors.lastname: Ivos Todesco
authors.forename: N
authors.initials: N
authors.lastname: Aldajarov
authors.forename: T A
authors.initials: TA
authors.lastname: Lutz
authors.forename: C E
authors.initials: CE
authors.lastname: Reusch
authors.forename: N S
authors.initials: NS
authors.lastname: Sieber-Ruckstuhl
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects* / Q000473:pathology*; D000308:Adrenocortical Hyperfunction / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology / Q000662:veterinary*; D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001835:Body Weight / Q000502:physiology; D013196:Dihydrotestosterone / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D004283:Dog Diseases / Q000188:drug therapy / Q000473:pathology*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D009336:Necrosis; D009707:Nucleosomes / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric
chemical_list: D004791:Enzyme Inhibitors; D009707:Nucleosomes; D013196:Dihydrotestosterone; D000324:Adrenocorticotropic Hormone; C009954:trilostane