V. De Marco1; E.M. Pinto2; B.B. Mendonça2
In dogs with Cushing disease, the therapy with mitotane is highly effective, normalizing circulating cortisol levels resulting in prompt improvement of clinical signs. However in some cases, adrenal cortex is completely destroyed causing permanent iatrogenic hypoadrenocorticism resulting in intense stimulation of ACTH release, enhancing the growth rate of pituitary corticotrophs. In this situation, the development of progressively enlarging pituitary tumor may be a potential problem. Retinoic acid has been shown to be useful in decreasing corticotroph secretion and proliferation in rodent models and in dogs with Cushing's disease because it inhibits the transcriptional activity of POMC reducing ACTH levels in tumor corticotroph cells. There are no reports of Nelson's syndrome treatment in dogs. Our aim was to evaluate retinoic acid effect in a dog with Nelson's syndrome. A 14-year old male Poodle dog developed Cushing's syndrome characterized by polyphagia, polyuria, polydipsia, abdomen enlargement, hypertension and bilateral adrenal hyperplasia on ultrasound. Initial tests were consistent with ACTH-dependent hyperadrenocorticism: no suppression of cortisol levels after IV dexamethasone, elevated alkaline phosphatase, hypercholesterolemia, hyposthenuria. One month after mitotane therapy, this dog developed iatrogenic hypoadrenocorticism. Since then, he has been supplemented with prednisone and fludrocortisone and Cushing signs disappeared. After five years, he started showing progressive weight lost, hyporexia, behavior disturbances and compulsive running. Biochemical exams were normal but ACTH levels were extremely elevated (25,000 pg/ml; normal values = 15-35 pg/ml;) and the pituitary computed tomography disclosed a macrotumor. Retinoic acid (2 mg/kg/d) was prescribed and hepatic enzymatic activity was measured every 30 days with no alterations. We observed resolution of clinical signs and ACTH levels showed a significant reduction to 5,000 pg/ml 3 months after the beginning of the therapy and to 95 pg/ml after 10 months, in addition to decrease in tumor size at tomography. This is the first report of Nelson's syndrome in a dog with iatrogenic hypoadrenocorticism induced by mitotane. We reported a significant reduction in plasma ACTH and in the pituitary macroadenoma size after retinoic acid therapy. Retinoic acid has an anti-proliferative action, inhibits ACTH and cortisol production highlighting the possibility of its use in dogs with Cushing's disease and Nelson's syndrome.