Thyroid disease mediated by molecular defects in cell surface and nuclear receptors1

  • Donald L. Bodenner
    Requests for reprints should be addressed to Dr. Donald L. Bodenner, Department of Internal Medicine, Division of Endocrinology and Metabolism, 4301 West Markham, Little Rock, Arkansas 72205
    Department of Internal Medicine (DLB), Division of Endocrinology and Metabolism, Little Rock, Arkansas, USA
    Search for articles by this author
  • Robert W. Lash
    Department of Internal Medicine (RWL), Division of Endocrinology and Metabolism, University of Michigan Health System, Ann Arbor, Michigan, USA
    Search for articles by this author
      Thyroid hormone homeostasis is regulated primarily by the action of thyroid-stimulating hormone (TSH) secreted by the pituitary. TSH, by binding to specific TSH receptors (TSH-R) on the surface of the thyroid follicular epithelium, stimulates glandular growth, thyroid hormone synthesis, and thyroid hormone release. In the euthyroid state, there is tightly regulated feedback between circulating concentrations of the thyroid hormones thyroxine (T4) and triiodothyronine (T3) and TSH. TSH secretion is also controlled by the hypothalamic factor thyrotropin-releasing hormone (TRH). As shown in Figure 1, small decreases in circulating thyroid hormone levels are detected by the pituitary and hypothalamus, with compensatory increases in TSH (and TRH) synthesis and secretion. Higher levels of TSH, in turn, stimulate thyroid hormone synthesis, with a subsequent decrease in TSH concentration. In the euthyroid state, these changes in thyroid hormone and TSH concentrations are minimal, and occur within the normal range for each hormone. Given the central role of the TSH-R in maintaining thyroid hormone homeostasis, it is not surprising that abnormalities of TSH-R function are associated with both hypothyroidism and hyperthyroidism (
      • Russo D.
      • Arturi F.
      • Chiefari E.
      • Filetti S.
      Molecular insights into TSH receptor abnormality and thyroid disease.
      • Tonacchera M.
      • Van Sande J.
      • Parma J.
      • et al.
      TSH receptor and disease.
      • Paschke R.
      • Ludgate M.
      The thyrotropin receptor in thyroid diseases.
      Figure thumbnail GR1
      Figure 1The hypothalamic-pituitary-thyroid axis. Thyroid hormone homeostasis is controlled by feedback loops involving the hypothalamus, pituitary gland, and thyroid gland. Thyrotropin-releasing hormone (TRH) is released by the hypothalamus, stimulating the synthesis and secretion of thyroid-stimulating hormone (TSH). TSH, in turn, activates thyroid hormone synthesis, as well as the release of the thyroid hormones thyroxine (T4) and triiodothyronine (T3). These thyroid hormones (primarily T3) provide negative feedback on both TRH and TSH secretion. In addition, hypothalamic somatostatin has an inhibitory effect on TSH secretion.
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