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The exponential growth in our knowledge on the pathophysiology of hypothalamic-pituitary-thyroid axis and, in particular, of thyroid hormone action, largely stems from the studies on the various syndromes of resistance to the hormones involved in the function of the axis. These syndromes essentially encompass two forms, i. e. the resistance to thyroid hormones and that to TSH action. The contribution of molecular biology has been fundamental in understanding the etiology of these different thyroid disorders and led to the discovery of new pathogenetic mechanisms, e. g. the dominant negative effects of a mutant protein on the normal one. In this book, I have assembled an internationally renewed group of experts devoted to the studies of both basic and clinical thyroidology. Taking the syndromes of resistance as a template, the novelties on the mechanisms of action of the various hormones, the etiopathogenesis of the syndromes, the instruments for the diagnosis, as well as the pitfalls in managing these diseases, are deeply revisited. The insights from different animal models are discussed, with particular focus on tissue specific action of thyroid hormones, as well as on the still enigmatic mechanism of negative feedback control of thyroid hormones on TSH secretion and the different etiologic mechanisms causing thyroid hormone resistance in patients without mutations in the thyroid hormone receptor ~. The role of the structure of thyroid hormone and TSH receptors in designing agonist or antagonist molecules is extensively debated. Moreover, new forms of congenital or acquired resistance to thyroid hormones are presented.
Preface. 1. Molecular basis of thyroid hormone action; P.M. Yen. 2. Tissues specific action of thyroid hormones: insights from knock out animal models; M. Plateroti, C. Angelin-Duclos, F. Flamant, J. Samarut. 3. Learning from nature's experiments on the thyroid hormone receptor; X-ray structures of RTH mutant ligand-binding domains; B.H. Sandler, J.D. Baxter, R.J. Fletterick. 4. Molecular pathogenesis of resistance to thyroid hormone; V.K.K. Chatterjee. 5. Syndromes of resistance to thyroid hormone: clinical aspects; D. Mannavola, P. Beck-Peccoz. 6. Resistance to thyroid hormone in the absence of mutations in the thyroid hormone receptor genes; S. Refetoff, P.M. Sadow, S. Reutrakul, K. Dennis, D. Mannavola, J. Pohlenz, R.E. Weiss. 7. Lessons learned from TR-beta mutant mice; F.E. Wondisford. 8. Towards the rational design of hormone analogs which complement receptor mutations; J.T. Koh, M.C. Putnam. 9. Multi-factorial regulation of in vivo action of TRbeta mutants. Lessons learned from RTH mice with a targeted mutation in the TRbeta gene; Sheue-yann Cheng. 10. The effect of vitamin A, retinoids and retinoid receptors on the hypothalamic-pituitary-thyroid axis; B.R. Haugen. 11. Pituitary resistance to thyroxine action due to a defect in the type 2 deiodinase; V.A. Galton. 12. Different forms of resistance to thyrotropin (TSH) action; L. Persani, D. Calebiro, T. de Filippis. Index.