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

Abstract

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 alpha-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 alpha-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.

Potential of retinoic acid derivatives for the treatment of corticotroph pituitary adenomas

“…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 [58]. It is important to note that according to the "U.S. Food and Drug Administration guidelines" for extrapolating animal doses to human equivalent doses considering weight and skin surface, the retinoic acid doses used in the above described mice [46] and dogs [58] studies are within the range of doses that could be used in humans.…”

“…A randomised study using retinoic acid in dogs with Cushing's disease was performed [58]. Dogs were treated with retinoic acid (n=22 dogs) or ketoconazole (n=20 dogs) for a period of 180 days.…”

“…Dogs were treated with retinoic acid (n=22 dogs) or ketoconazole (n=20 dogs) for a period of 180 days. Clinical signs, plasma ACTH and α-MSH, the cortisol/creatinine (RC/C) urine ratio and pituitary MRI were assessed and compared at different time points [58]. In dogs, two convertase enzymes are involved in processing the POMC gene products, one active in anterior pituitary cells secreting ACTH, whereas the other is located in the intermediate-lobe cells secreting α-MSH [59].…”

“…Moreover, in the ketoconazole group, more than 50% of the animals died before completing the treatment, usually from complications of the glucocorticoid excess [58].…”

Pharmacological management of Cushing's syndrome: an update

“…The dose was 10 mg/kg which is within the dose range in human cancer therapy (108). Studies in rodents and dogs models of Cushing's disease have been successful but there is now a need for studies in human (108,109).…”