Thyroid hormone physiology and biosynthesis

The thyroid gland is the largest endocrine gland in the body, residing in the neck, anterior to the trachea, between the cricoid cartilage and the suprasternal notch. The thyroid gland produces two biologically active hormones, thyroxine (T4) and triiodo-

thyronine (T4). Thyroid hormones are essential for proper fetal growth and development, particularly of the CNS. After delivery, the primary role of thyroid hormone is in the regulation of energy metabolism. These hormones can affect the function of virtually every organ in the body. The parafollicular C cells of the thyroid gland produce calcitonin. The function of calcitonin and its therapeutic use are discussed in other chapters in this book.

T4 and T3 are produced by the organification (binding of iodine to tyrosine residues of thyroglobulin) of iodine in the thyroid gland. Iodine is actively transported into the thyroid follicular cells. This inorganic iodine is oxidized by thyroid peroxidase and covalently bound to tyrosine residues of thyroglobulin. These iodinated tyrosine residues monoiodotyrosine and diiodotyrosine couple to form T4 and T3. Eighty percent of thyroid hormone is synthesized as T4 and is stored in the thyroid bound to thyroglobulin. Thyroid hormones are released from the gland when needed, primarily under the influence of TSH (thyroid stimulating hormone, thyrotropin) from the anterior pituitary. T4 and T3 are transported in the blood by three proteins, 70% to thyroid-binding globulin (TBG), 15% to transthyretin (thyroid-binding prealbumin), and 15% to albumin. T4 is 99.97% protein-bound, and T3 is 99.7% protein-bound, with only the unbound or free fractions physiologically active. The high degree of protein-binding results in a long half-life of these hormones: approximately 7 to 10 days for T4 and 24 hours for T4.

Most of the physiologic activity of thyroid hormones is from the actions of T3. T4 can be thought of primarily as a prohormone. Eighty percent of needed T3 is derived from the conversion of T4 to T3 in peripheral tissue under the influence of tissue dei-odinases. These deiodinases allow end organs to produce the amount of T3 needed to control local metabolic functions. These enzymes also catabolize T3 and T4 to biologically inactive metabolites.

The production and release of thyroid hormones are regulated by the hypothalamic-pituitary-thyroid axis (Fig. 44-1). Hypothalamic thyrotropin-releasing hormone (TRH) stimulates the release of TSH (thyrotropin) when there are physiologically inadequate levels of thyroid hormones. TSH promotes the production and release of thyroid hormones from the gland. As circulating thyroid hormone levels rise to needed levels, negative feedback results in decreased release of TSH and TRH. The release of TRH is inhibited by somatostatin and its analogs, and the release of TSH can be inhibited by dopamine, dopamine agonists, and high levels of glucocorticoids.

FIGURE 44-1. Hypothalamic-pituitary-thyroid axis. Thyrotropin-releasing hormone (TRH) is synthesized in the neurons within the paraventricular nucleus of the hypothalamus. TRH is released into the hypothalamic-pituitary portal circulation and carried to the pituitary, where it activates the pituitary to synthesize and release thyrotropin (TSH). TSH activates the thyroid to stimulate the synthesis and secretion of thyroxine (T4) and triiodothyronine (T3). T4 and T3 inhibit TRH and TSH secretion, closing the feedback loop.

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