Thyroxine is produced and secreted by the thyroid gland. This gland wraps around the front of the windpipe (trachea) and expands into a lobe on either side (see Figures 40.5 and 40.12). There are two cell types in the thyroid gland, each of which produces a specific hormone. Thyroxine is produced by epithelial cells that make up round, colloid-containing structures called follicles (Figure 40.11A). Calcitonin is produced by cells in the spaces between the follicles and is involved in blood calcium regulation (which we will describe shortly).

Thyroxine, a crucial signal in the regulation of cellular energy metabolism, begins as the glycoprotein thyroglobulin, which is synthesized by the follicle cells and packaged in secretory vesicles. The follicle cells actively take up iodide from the blood and move it into the lumen of the follicle (Figure 40.11B). Each thyroglobulin molecule contains about 100 tyrosine units. When the secretory vesicles release thyroglobulin into the lumen of the follicle, they also release an enzyme that catalyzes the iodination of the tyrosine units in the thyroglobulin. When the thyroid gland is stimulated to release thyroxine, the follicle cells take up thyroglobulin from the follicle by endocytosis. These bits of thyroglobulin are then cleaved to form smaller molecules consisting of only two tyrosine units, and these molecules leave the follicle cells and enter the blood. If these molecules are iodinated at the maximum of four sites on the tyrosine units, the hormone is tetraiodothyronine, or T₄:

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and if they are iodinated at only three sites, they are triiodothyronine, or T₃:

The thyroid usually releases about ten times as much T₄ as T₃. However, T₃ is a more active hormone than T₄, so when you read about the effects of thyroxine, keep in mind that the actions discussed are primarily those of T₃. The difference in the activities of T₃ and T₄ makes it possible to control the effects of thyroxine in different tissues. Within target cells, T₄ can be converted to T₃ by an enzyme called deiodinase. A different deiodinase can convert T₄ into an inactive hormone called reverse T₃. Deiodinase can also inactivate T₃ by converting it into T₂ or T₁. Thus each target cell can set a unique sensitivity to thyroid hormones using these enzymes to control the conversion of T₄ to T₃ or to reverse T₃.

TSH AND TRH REGULATE THYROXINE PRODUCTION The tropic hormone thyroid-stimulating hormone (TSH), also known as thyrotropin), produced by the anterior pituitary, activates the thyroxine-producing follicle cells in the thyroid. Thyrotropin-releasing hormone (TRH), produced in the hypothalamus and transported to the anterior pituitary through the portal blood vessels, activates the TSH-producing pituitary cells. The hypothalamus uses environmental information, such as temperature or day length, to determine whether to increase or decrease its secretion of TRH. This sequence of steps is regulated by a negative feedback loop (see Figure 40.7B). Circulating thyroxine inhibits the response of pituitary cells to TRH, so less TSH is released when thyroxine levels are high, and more TSH is released when thyroxine levels are low. Circulating thyroxine also exerts negative feedback on the production and release of TRH by the hypothalamus.

Because thyroxine is lipid-soluble, it enters cells readily and binds to receptors in the nucleus. When combined with thyroxine, these receptors (which are found in most cells of the body) stimulate the transcription of numerous genes whose products are transport proteins, structural proteins, and enzymes involved in metabolic pathways; thus thyroxine elevates the metabolic rates of most cells and tissues. Exposure to cold for several days leads to an increased release of thyroxine, an increased conversion of T₄ to T₃, and therefore an increased basal metabolic rate (see Key Concept 39.5).

During development and growth, thyroxine promotes amino acid uptake and protein synthesis. Insufficient thyroxine in a human fetus or growing child greatly retards physical and mental development, resulting in a condition known as cretinism.

GOITER A goiter is an enlarged thyroid gland (Figure 40.12) that can be associated with either hyperthyroidism (excess production of thyroxine) or hypothyroidism (thyroxine deficiency). The negative feedback loop whereby thyroxine controls TSH release helps explain how two seemingly opposite conditions can result in the same symptom.

Goiter affects about 5 percent of the world’s population. The addition of iodide to table salt has greatly reduced the incidence of hypothyroid goiter in industrialized nations, but the condition is still common in other parts of the world and is a leading cause of intellectual impairment.