Thyroid hormone: old hormone, new insights

ABSTRACT

Thyroid hormone mediates its many actions by binding to thyroid receptors which are ligand-dependent nuclear transcription factors bound to specific DNA sequences known as thyroid hormones response elements. There are three isoforms of the thyroid hormone receptor, namely TR, TRB 1 and TRB 2, which differ in their tissue distribution and transcriptional activity. Resistance to thyroid hormone (RTH) is a dominantly inherited condition which occurs when an affected individual harbours a mutation in one allele of the thyroid hormone receptor beta gene (TRB 1 and B2). Most affected patients exhibit elevated thyroid hormone concentrations associated with inappropriate secretion of thyrotropin (TSH). The clinical presentation of these patients is variable. Patients with generalised RTH exhibit varying degrees of peripheral insensitivity to thyroid hormone which manifests itself in some families as growth retardation and learning disabilities. In contrast, individuals with pituitary resistance present with signs and symptoms of thyrotoxicosis. To further elucidate the roles of these mutant receptors on the pituitary-hypothalamic thyroid axis, we have developed a transgenic mouse model of RTH by expressing a mutual thyroid hormone receptor (TRB 1) selectively in the pituitary. The mice developed profound pituitary resistance to thyroid hormone as demonstrated by markedly elevated baseline non T3 suppressible, serum TSH and pituitary TSHB and rnRNA. Paradoxically serum T4 levels were normal suggesting bioinactive TSH. The reduced biologic activity of the TSH in transgenic mice was reversed by throtropin releasing hormone (TRH) administration which resulted in markedly elevated T4 concentrations intransgenic but not in wild type mice.(AU)