Retinoic Acid as a Novel Medical Therapy for Cushing’s Disease in Dogs

Cushing’s disease is almost always caused by an ACTH-secreting pituitary tumor, but effective medical therapy is currently limited. Because retinoic acid has been shown to be potentially useful in decreasing corticotroph secretion and proliferation in rodent models, we have studied its action in dog...

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Published in:Endocrinology (Philadelphia) 2006-09, Vol.147 (9), p.4438-4444
Main Authors: Castillo, Victor, Giacomini, Damiana, Páez-Pereda, Marcelo, Stalla, Johanna, Labeur, Marta, Theodoropoulou, Marily, Holsboer, Florian, Grossman, Ashley B, Stalla, Günter K, Arzt, Eduardo
Format: Article
Language:English
Subjects:
Adenoma - pathology
Adrenals. Adrenal axis. Renin-angiotensin system (diseases)
Adrenocorticotropic Hormone - blood
alpha-MSH - blood
Animals
Biological and medical sciences
Body Weight
Creatinine - urine
Dog Diseases - drug therapy
Dogs
Endocrinopathies
Female
Fundamental and applied biological sciences. Psychology
Hydrocortisone - urine
Ketoconazole - therapeutic use
Magnetic Resonance Imaging - veterinary
Male
Medical sciences
Non tumoral diseases. Target tissue resistance. Benign neoplasms
Pituitary ACTH Hypersecretion - drug therapy
Pituitary ACTH Hypersecretion - pathology
Pituitary ACTH Hypersecretion - veterinary
Pituitary Gland - pathology
Pituitary Neoplasms - pathology
Survival Rate
Tretinoin - therapeutic use
Vertebrates: endocrinology
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Summary:Cushing’s disease is almost always caused by an ACTH-secreting pituitary tumor, but effective medical therapy is currently limited. Because retinoic acid has been shown to be potentially useful in decreasing corticotroph secretion and proliferation in rodent models, we have studied its action in dogs with Cushing’s disease. A randomized treatment with retinoic acid (n = 22) vs. ketoconazole (n = 20) in dogs with Cushing’s disease was assigned for a period of 180 d. Clinical signs, plasma ACTH and α-MSH, the cortisol/creatinine urine ratio, and pituitary magnetic resonance imaging were assessed and compared at different time points. We recorded a significant reduction in plasma ACTH and α-MSH, and also in the cortisol/creatinine urine ratio, of the dogs treated with retinoic acid. Pituitary adenoma size was also significantly reduced at the end of retinoic acid treatment. Survival time and all the clinical signs evaluated showed an improvement in the retinoic-acid-treated dogs. No adverse events or signs of hepatotoxicity were observed, suggesting that the drug is not only effective but also safe. Retinoic acid treatment controls ACTH and cortisol hyperactivity and tumor size in dogs with ACTH-secreting tumors, leading to resolution of the clinical phenotype. This study highlights the possibility of using retinoic acid as a novel therapy in the treatment of ACTH-secreting tumors in humans with Cushing’s disease.
ISSN:0013-7227
1945-7170
DOI:10.1210/en.2006-0414