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Three hormones, thyroxine (3,5,3',5'-tetraiodothy-ronine, or T4), triiodothyronine (3,5,3'-triiodothyronine, or T3), and calcitonin (see Chapter 66) are secreted by the thyroid gland. The hormones T4 and T3 are iodine-containing amino acid derivatives and are unique in that they have no discrete target tissue. Every tissue in the body is affected in some way by thyroid hormones, and almost all cells appear to require constant optimal amounts for normal operation.

Thyroid hormones exert a wide variety of physiological actions through genomic and nongenomic mechanisms and influence the metabolism of proteins, carbohydrates, and lipids; cell morphology; membrane transport; ion homeostasis; oxygen consumption; heat production; and so on. Relatively constant circulating concentrations of T4 and T3 are required for normal growth and development and the proper functioning of the neural, reproductive, cardiovascular, gastrointestinal, and hematopoietic systems. Unlike most other hormones, whose circulating concentrations vary widely in response to external and internal stimuli, the circulating concentrations of thyroid hormones are usually held relatively constant over time.

In health, two negative feedback control systems operate to maintain circulating thyroid hormone levels. The first, the hypothalamic-pituitary-thyroid axis (HPTA), acts to regulate the concentration of thyroid hormones in the blood by controlling their synthesis and secretion by the thyroid gland. The second negative feedback control system is the thyroid autoregulatory system. It is intrinsic to the thyroid gland and acts to ensure that an adequate supply of iodide is extracted from the blood and made available for thyroid hormone synthesis despite variations in dietary iodine intake.

Worldwide, the most common thyroid disorder is hypothyroidism resulting from dietary iodine deficiency. In iodine-replete areas of the world, most thyroid disorders are the result of autoimmune disease. The symptoms manifested in hypothyroid and hyperthyroid states are largely independent of any underlying disorder of the thyroid gland itself; they are a function of the degree of hormone deficiency or excess.

A second dietary trace element, selenium, is also essential for normal thyroid hormone metabolism. Selenium in the form of selenocysteine is a required component for three enzymes that remove iodide from thyroid hormones. Deiodination is the major metabolic pathway by which T4 and T3 are cleared from the system. After secretion by the thyroid gland, T4 may be deiodinated to yield either T3 or the physiologically inactive reverse T3 (3,3',5'-triiodothyronine, or rT3). T3 and rT3 are further deiodinated to form less active metabolites. Selenium, like iodine, is deficient in many areas of the world.

BIOSYNTHESIS, STORAGE, SECRETION, AND METABOLISM OF THYROID HORMONES

Thyroid epithelial cells synthesize and secrete T4 and T3 and make up the functional units of thyroid glandular tissue, the thyroid follicles. Thyroid follicles are hollow vesicles formed by a single layer of epithelial cells that are filled with colloid. T4,T3, and iodine are stored in the follicular colloid. T4 and T3 are derived from tyrosyl residues of the protein thyroglobulin (Tg). Thyroid fol-licular cells synthesize and secrete Tg into the follicular lumen. Thyroid follicular cells also remove iodide (I") from the blood and concentrate it within the follicular lumen. Within the follicles, some of the tyrosyl residues of Tg are iodinated, and a few specific pairs of iodoty-rosyl residues may be coupled to form T4 and T3. Thus, T4, T3, and iodine (in the form of iodinated tyrosyl residues) are found within the peptide structure of the Tg that is stored in the follicular lumen.

The secretion of T4 and T3 requires the uptake of fol-licular contents across the follicular cell apical membrane, the enzymatic release of T4 and T3 from peptide linkage within Tg, and the transport of T4 and T3 across the follicular cell basal membrane to the blood. Several of the steps in synthesis and secretion of T4 and T3 may be compromised by iodine deficiency or disease and can be blocked selectively by a variety of chemicals and drugs.

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