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Today's VeTerinary PracTice | november/december 2015 | tvpjournal.com canine PiTuiTary dePendenT HyPeradrenocorTicism series Peer reviewed 42 Corticotroph & Melanotroph Cell Marker: Tpit In the pituitary glands of humans and mice, corticotrophs and melanotrophs have a specifc marker in common, the T-box transcription factor (Tpit, or Tbx19), which regulates the late differentiation of corticotrophs and melanotrophs and, therefore, may contribute to the pathogenesis of corticotroph adenomas. A recent study in 14 dogs with PDH examined the expression and mutation analysis of Tpit in normal canine pituitary and corticotroph adenomas: 27 • Tpit was expressed in corticotroph and melanotroph cells of normal and adenomatous canine pituitaries, and remained present in nonadenomatous corticotrophs of pituitaries from PDH dogs. • No tumor-specific mutation in Tpit cDNA from corticotroph adenomas was found; however, a missense polymorphism (see Polymorphism Versus Mutation, page 41) in the highly conserved DNA- binding domain, the T-box, was discovered in one dog. The study concluded that Tpit can be used as a reliable marker for corticotroph and melanotroph cells in canine pituitary tissue, but that mutations in the Tpit gene are unlikely to play a major role in pathogenesis of canine corticotroph adenomas. Corticotroph Differentiation Markers: LIF & LIFR Leukemia inhibitory factor (LIF) is a cytokine of the IL-6 family that activates the hypothalamic–pituitary– adrenal axis and promotes corticotroph differentiation during development. LIF and leukemia inhibitory factor receptor (LIFR) expression were studied in pituitary glands of control dogs and specimens of corticotroph adenoma tissue collected from dogs with PDH. 28 Their results demonstrated that: 1. LIFR was highly co-expressed with ACTH and alpha-melanocyte-stimulating hormone in the control canine pituitary gland and corticotroph adenomas. 2. There was a strong co-expression of LIFR and ACTH 1-24 in the cytoplasm of cells in the pars distalis and pars intermedia of control pituitary tissue. In pituitary glands harboring an adenoma, cytoplasmic expression of LIFR followed that of ACTH 1-24. 3. Nontumorous cells of the pars distalis showed no cytoplasmic staining but did demonstrate nuclear to perinuclear immunoreactivity for LIFR in 10 of 12 tissue specimens from PDH dogs. 4. This nuclear immunoreactivity was not observed in the control pituitary tissues or in the pituitary cells with corticotrope hyperplasia. Role of ACTH Production & Glucocorticoids As mentioned earlier, a characteristic biochemical feature of corticotroph adenomas is their relative resistance to negative feedback by glucocorticoids. In a recent study, gene expression related to ACTH production and secretion, and the negative feedback by glucocorticoids in canine corticotroph adenoma, was evaluated in pituitary tumors in 10 dogs with Cushing's disease. The results demonstrated increased ACTH production and resistance to negative feedback by glucocorticoids in canine corticotroph adenomas. 14 Therapeutic Role of EGFR Since tumors in dogs and humans express epidermal growth factor receptor (EGFR), in another study we examined whether EGFR might provide a therapeutic target for Cushing's disease. 29 • In cell cultures from surgically resected human and canine corticotroph tumors, blocking EGFR also suppressed expression of proopiomelanocortin (POMC), the ACTH precursor. • In mouse corticotroph EGFR transfectants, ACTH secretion was enhanced and POMC promoter activity was increased. In mice, blocking EGFR activity with geftinib, an EGFR tyrosine kinase inhibitor: • Attenuated POMC expression • Inhibited corticotroph tumor cell proliferation and induced apoptosis • Decreased both tumor size and corticosterone levels • Reversed signs of hypercortisolemia, including elevated glucose levels and excess omental fat. These study results indicate that inhibiting EGFR signaling may be a novel strategy for treating Cushing's disease. DIAGNOSIS Diagnosis of PDH requires incorporating information from the history, physical examination, and routine laboratory tests. Clinical Signs Clinical signs, as well as laboratory abnormalities, seen in patients with PDH are secondary to the effects of steroid excess, well recognized and similar in scope to those seen with exogenous glucocorticoid supplementation (Tables 3 and 4). • Polyuria and polydipsia occur as the result of