Cushing's disease caused by pituitary
corticotroph adenoma is a common
endocrine disease in dogs. A characteristic biochemical feature of
corticotroph adenomas is their relative resistance to suppressive negative feedback by
glucocorticoids. The abnormal expression of
11beta-hydroxysteroid dehydrogenase (11HSD), which is a
cortisol metabolic
enzyme, is found in human and murine
corticotroph adenomas. Our recent studies demonstrated that canine
corticotroph adenomas also have abnormal expression of 11HSD. 11HSD has two
isoforms in dogs, 11HSD type1 (HSD11B1), which converts
cortisone into active
cortisol, and 11HSD type2 (HSD11B2), which converts
cortisol into inactive
cortisone. It has been suggested that
glucocorticoid resistance in corticotroph
tumors is related to the overexpression of HSD11B2. Therefore it was our aim to investigate the effects of
carbenoxolone (CBX), an 11HSD inhibitor, on the healthy dog's pituitary-adrenal axis. Dogs were administered 50 mg/kg of CBX twice each day for 15 days. During CBX administration, no adverse effects were observed in any dogs. The plasma
adrenocorticotropic hormone (
ACTH), and serum
cortisol and
cortisone concentrations were significantly lower at day 7 and 15 following
corticotropin releasing hormone stimulation. After completion of CBX administration, the HSD11B1
mRNA expression was higher, and HSD11B2
mRNA expression was significantly lower in the pituitaries. Moreover,
proopiomelanocortin mRNA expression was lower, and the ratio of
ACTH-positive cells in the anterior pituitary was also significantly lower after CBX treatment. In adrenal glands treated with CBX, HSD11B1 and HSD11B2
mRNA expression were both lower compared to normal canine adrenal glands. The results of this study suggested that CBX inhibits
ACTH secretion from pituitary due to altered 11HSD expressions, and is potentially useful for the treatment of canine
Cushing's disease.