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Today's VeTerinary PracTice | november/december 2015 | tvpjournal.com canine PiTuiTary dePendenT HyPeradrenocorTicism series Peer reviewed 40 PREVALENCE The study of pituitary tumors in both humans and animals is important because new discoveries regarding pathogenesis and treatment options in one species may cross over to the other, resulting in an example of One Medicine. Humans In humans, PAs are common tumors, with an overall prevalence in the general U.S. population estimated at 16.7%. 2 • Corticotroph adenomas, comprising functional ACTH-PAs and silent corticotroph adenomas, represent approximately 10% to 15% of all PAs. • Functional ACTH-PAs are the most common cause of Cushing's syndrome (hypercortisolemia from any source), accounting for an estimated 70% of all cases. • Prevalence of Cushing's syndrome is estimated to be 1.2 to 2.4 per 1 million people, and it affects approximately 12,000 people in the U.S. This number, however, may be much higher, given that Cushing's syndrome is frequently misdiagnosed and diagnosis is often delayed. 2 Dogs Functional ACTH-PAs have a reported incidence of 0.2% in all dogs (1–2 cases/1000 dogs/year), with approximately 100,000 dogs affected yearly in the United States. 3,4 PDH accounts for approximately 85% to 90% of cases of hyperadrenocorticism, with the remainder of cases resulting from functional adrenal tumors, meal/ food-induced cases, occult, or atypical disease. 4 • Meal or food-induced Cushing's syndrome is thought to occur as the result of a congenital defect resulting in aberrant expression of the gastric inhibitory polypeptide (GIP) receptor in the adrenal cortex. Stimulation of this receptor by GIP, normally released by the stomach in response to a meal, leads to clinical signs of hyperadrenocorticism in younger dogs. 5 • Occult hyperadrenocorticism refers to presence of elevated adrenal steroid concentrations in the absence of clinical signs, and has been best described in Scottish terriers with elevated serum alkaline phosphatase and vacuolar hepatopathy. 6 • Atypical hyperadrenocorticism refers to animals with clinical signs of classic hyperadrenocorticism secondary to excess sex steroid production rather than excessive cortisol secretion. 7 PATHOGENESIS The pathogenesis of pituitary tumors that produce ACTH is becoming more evident based on ongoing studies evaluating gene and protein expression in both humans and dogs. This information will aid our understanding of tumorigenesis and point us toward targeted specifc therapies. Two theories have been put forward to explain the development of an ACTH producing pituitary tumor (ACTH-PA, corticotrophinoma): 8 1. Hypothalamic theory 2. Monoclonal theory. Hypothalamic Theory In this theory, the hypothalamus stimulates corticotrophs through enhanced secretion of corticotropin releasing hormone (CRH) and vasopressin. 9 In addition, concurrent defects in the pituitary glucocorticoid receptors (GRs) on the corticotroph cells lead to decreased negative feedback by cortisol on CRH and ACTH synthesis. 10 Gene Mutation. Karl and colleagues 11,12 and Lamberts 10 described a mutation in the gene in humans that encodes the GR, with a reduction in the sites of DNA binding, while maintaining affnity for cortisol. This de novo mutation promotes GR resistance that precedes the formation of the corticotrophinoma. Recent studies by Teshima and colleagues, 13,14 using trilostane to decrease cortisol, demonstrated pituitary tumor growth as a consequence of a reduction in negative feedback. Their studies on canine ACTH tumor cells suggest that reduced negative feedback might frst lead to corticotroph hyperplasia followed by a subsequent somatic mutation that could lead to tumor development. 9 Dopaminergic Actions. Other possibilities for a hypothalamic theory of PDH include: • Dopaminergic neurodegeneration in aged individuals 15-17 • Decreased expression of the D 2 dopaminergic receptor on the corticotroph cells, resulting in decreased dopaminergic inhibition and subsequent hyperplasia. 18-20 With this possibility, adenomas would evolve secondary to somatic mutations in hyperplastic cells. The hypothalamic theory is reinforced by the recurrence of ACTH producing tumors following surgery or in patients in which no tumor was found on MRI or when exploring the sella. Both scenarios suggest stimulation or lack of inhibition of ACTH producing cells from higher centers (hypothalamus or hippocampus). This hypothesis is also supported by the fact that individuals with chronic stress and greater activation of the hypothalamic–pituitary– adrenal axis show corticotroph hyperplasia. 21