Cushing's disease in dogs and humans.
ABSTRACT BACKGROUND: Cushing's disease (CD) is a common endocrinological disorder in dogs with an estimated incidence of 1 to 2 cases/1,000 dogs/year. This is in contrast to humans in whom CD is rare. The clinical presentation of CD, however, is highly similar between dogs and humans, with characteristic signs, such as abdominal obesity, weight gain, fatigue, muscle atrophy and skin changes. Canine CD may therefore serve as an animal model for human CD, especially since therapeutic canine hypophysectomy can generate substantial amounts of primary corticotroph adenoma tissue for in vitro research purposes. In a recent study, we found that dopamine (DA) D(2) and somatostatin (SS) receptor subtypes are well expressed in canine corticotroph adenomas, but there are some distinct differences compared with the expression profile observed in human CD. These differences need to be considered when using canine CD as a model to evaluate the efficacy of novel DA/SS compounds for potential use in human CD. CASE REPORT: This case involves an 8-year-old female dog that developed signs of exercise intolerance, muscle weakness and polyuria/polydipsia due to an adrenocorticotropic hormone-secreting pituitary adenoma. The dog underwent curative transsphenoidal hypophysectomy and has remained in complete remission in the 3.5 years since surgery.
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ABSTRACT: Extrinsic factors such as hypothalamic hormones or intrapituitary growth factors may stimulate clonal expansion of a genomically altered cell and therefore play a role in pituitary tumorigenesis. Here we report on the effects of the hypophysiotrophic hormones corticotrophin-releasing hormone (CRH) and vasopressin (AVP) and the intrapituitary growth factor insulin-like growth factor-I (IGF-I) on the proliferation of, as measured by the bromodeoxyuridine labelling index, and ACTH secretion by normal canine pituitary cells and corticotrophic adenoma cells of dogs with pituitary-dependent hyperadrenocorticism. The sensitivity to inhibition by cortisol was analysed under various conditions. Under basal conditions, no significant differences were found in the bromodeoxyuridine labelling indices between control cells and tumour cells. CRH, AVP, IGF-I and cortisol had no effect on the proliferation of canine pituitary cells or canine corticotrophic adenoma cells. In contrast with normal pituitary cells, the proliferation of corticotrophic adenoma cells was stimulated by fetal calf serum (FCS). This FCS-induced proliferation was not inhibited by cortisol. The CRH-induced ACTH secretion by corticotrophic adenoma cells was significantly (P < 0.05) lower than that by normal pituitary cells after 4 h incubation with CRH. Incubation with cortisol for 24 h resulted in reduced ACTH secretion under basal and AVP- or IGF-I-stimulated conditions. The relative inhibition was, however, significantly (P < 0.05) lower in ACTH-producing tumour cells than in normal pituitary cells. Cortisol did not inhibit the CRH-induced ACTH secretion in normal pituitary cells after 24 h. In conclusion, canine corticotrophic adenomas are less sensitive to stimulation by CRH and less sensitive to inhibition by glucocorticoids. These tumours have an aberrant sensitivity to a growth-promoting factor present in FCS. This factor may have an important role in the growth promotion of canine corticotrophic tumours.European Journal of Endocrinology 03/1998; 138(3):309-15. · 3.14 Impact Factor
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ABSTRACT: Negative feedback regulation of the proopiomelanocortin (POMC) gene by the glucocorticoid (Gc) receptor (GR) is a critical feature of the hypothalamo-pituitary-adrenal axis, and it is in part exerted by trans-repression between GR and the orphan nuclear receptors related to NGFI-B. We now show that Brg1, the ATPase subunit of the Swi/Snf complex, is essential for this trans-repression and that Brg1 is required in vivo to stabilize interactions between GR and NGFI-B as well as between GR and HDAC2. Whereas Brg1 is constitutively present at the POMC promoter, recruitment of GR and HDAC2 is ligand-dependent and results in histone H4 deacetylation of the POMC locus. In addition, GR-dependent repression inhibits promoter clearance by RNA polymerase II. Thus, corecruitment of repressor and activator at the promoter and chromatin modification jointly contribute to trans-repression initiated by direct interactions between GR and NGFI-B. Loss of Brg1 or HDAC2 should therefore produce Gc resistance, and we show that approximately 50% of Gc-resistant human and dog corticotroph adenomas, which are the hallmark of Cushing disease, are deficient in nuclear expression of either protein. In addition to providing a molecular basis for Gc resistance, these deficiencies may also contribute to the tumorigenic process.Genes & Development 11/2006; 20(20):2871-86. · 12.44 Impact Factor
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ABSTRACT: The long-term survival, disease-free fractions, and the complications of hypophysectomy in 150 dogs with pituitary-dependent hyperadrenocorticism (PDH) were examined in a prospective study. Long-term survival and disease-free fractions in relation to pituitary size were analyzed by the Kaplan-Meijer estimate procedure. The 1-, 2-, 3-, and 4-year estimated survival rates were 84% (95% confidence interval [CI], 76-89%), 76% (67-83%), 72% (62-79%), and 68% (55-77%), respectively. Treatment failures included procedure-related mortalities (12 dogs) and incomplete hypophysectomies (9 dogs). The 1-, 2-, 3-, and 4-year estimated relapse-free fractions were 88% (CI: 80-93%), 75% (64-83%), 66% (54-76%), and 58% (45-70%), respectively. Postoperative reduction of tear production (58 eyes in 47 dogs) was often reversible but remained low until death in 11 eyes of 10 dogs. Central diabetes insipidus (CDI) occurred more frequently (62%) in dogs with enlarged pituitaries than in dogs with nonenlarged pituitaries (44%). Survival and disease-free fractions after hypophysectomy were markedly higher in dogs with nonenlarged pituitaries than in dogs with enlarged pituitaries. Transsphenoidal hypophysectomy is an effective treatment for PDH in dogs. The survival and disease-free fractions after hypophysectomy decrease and the incidence of CDI increases with increasing pituitary size. Therefore, early diagnosis of PDH is important and transsphenoidal hypophysectomy is expected to have the best outcome when used as primary treatment for dogs with nonenlarged or moderately enlarged pituitaries.Journal of Veterinary Internal Medicine 01/2005; 19(5):687-94. · 2.06 Impact Factor