title: Trilostane-induced inhibition of cortisol secretion results in reduced negative feedback at the hypothalamic-pituitary axis.
abstract: Cushing's disease caused by pituitary corticotroph adenoma in dogs is usually treated by medical treatment, and the efficacy of this treatment has been reported. However, controversy remains as to whether reduced negative feedback through the inhibition of cortisol secretion, similar to Nelson's syndrome, may appear as an adverse effect. The purpose of this study was to investigate the effect of reduced negative feedback through the inhibition of cortisol secretion by daily trilostane administration on the pituitary-adrenal axis in clinically normal dogs. Dogs were administered 5mg/kg trilostane twice a day every day for 8 weeks (n=8) or 16 weeks (n=3). After the initiation of trilostane administration, plasma adrenocorticotropic hormone (ACTH) concentrations were increased remarkably. As assessed by magnetic resonance imaging (MRI) during administration, the pituitary became enlarged. After trilostane administration, the cytoplasmic areas of the pituitary corticotrophs were increased and the ratio of pituitary corticotrophs to all cells in the anterior lobe was greater in the trilostane-treated dogs than that in untreated animals. In addition, histological examinations revealed bilateral adrenal cortical hyperplasia. Using real-time PCR quantification, the expression of proopiomelanocortin (POMC) mRNA in the pituitary and ACTH receptor (ACTH-R) mRNA in the adrenal gland was greater in the dogs treated with trilostane than in untreated dogs. These results indicate that reduced negative feedback induced hyperfunction of the pituitary corticotrophs and pituitary enlargement in healthy dogs. These changes suggest that the inhibition of cortisol secretion by trilostane may increase the risk for accelerating the growth of corticotroph adenomas in dogs with Cushing's disease.
authors.affiliation: Division of Veterinary Surgery, Department of Veterinary Science, Faculty of Veterinary Medicine, Nippon Veterinary and Life Science University, 1-7-1 Kyonan-cho, Musashino-shi, Tokyo 180-8602, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Teshima
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Hara
authors.forename: Susumu
authors.initials: S
authors.lastname: Takekoshi
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nezu
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Harada
authors.forename: Takuya
authors.initials: T
authors.lastname: Yogo
authors.forename: Akira
authors.initials: A
authors.lastname: Teramoto
authors.forename: Robert Y
authors.initials: RY
authors.lastname: Osamura
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tagawa
mesh_terms: D000311:Adrenal Glands / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D052680:Corticotrophs / Q000187:drug effects / Q000648:ultrastructure; D013196:Dihydrotestosterone / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004285:Dogs; D025461:Feedback, Physiological / Q000187:drug effects; D005260:Female; D006854:Hydrocortisone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006965:Hyperplasia; D007031:Hypothalamus / Q000187:drug effects*; D008279:Magnetic Resonance Imaging; D008297:Male; D010902:Pituitary Gland / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D011333:Pro-Opiomelanocortin / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D018043:Receptors, Corticotropin / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D012333:RNA, Messenger; D018043:Receptors, Corticotropin; D013196:Dihydrotestosterone; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; C009954:trilostane; D006854:Hydrocortisone