Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Thyroid Metabolic Hormones
The thyroid gland, located immediately below the larynx on each side of and anterior to the trachea, is one of the largest of the endocrine glands, normally weighing 15 to 20 grams in adults. The thyroid secretes two major metabolic hormones, thyroxine and triiodothyronine, commonly called T 4 and T 3 , respectively. Both of these hormones profoundly increase the metabolic rate of the body. Complete lack of thyroid secretion usually causes the basal metabolic rate to fall 40% to 50% below normal, and extreme excesses of thyroid secretion can increase the basal metabolic rate to 60% to 100% above normal. Thyroid secretion is controlled primarily by thyroid-stimulating hormone (TSH) secreted by the anterior pituitary gland.
The thyroid gland also secretes calcitonin, a hormone involved in calcium metabolism that is discussed in Chapter 80 .
The purpose of this chapter is to discuss the formation and secretion of the thyroid hormones, their metabolic functions, and regulation of their secretion.
Synthesis and Secretion of the Thyroid Metabolic Hormones
About 93% of the metabolically active hormones secreted by the thyroid gland is thyroxine and 7% is triiodothyronine . However, almost all the thyroxine is eventually converted to triiodothyronine in the tissues, so both are functionally important. The functions of these two hormones are qualitatively the same, but they differ in rapidity and intensity of action. Triiodothyronine is about four times as potent as thyroxine, but it is present in the blood in much smaller quantities and persists for a much shorter time compared with thyroxine.
Physiologic Anatomy of the Thyroid Gland
As shown in Figure 77-1 , the thyroid gland is composed of large numbers of closed follicles (100–300 micrometers in diameter) that are filled with a secretory substance called colloid and lined with cuboidal epithelial cells that secrete into the interior of the follicles. The major constituent of colloid is the large glycoprotein thyroglobulin, which contains the thyroid hormones. Once the secretion has entered the follicles, it must be absorbed back through the follicular epithelium into the blood before it can function in the body. The thyroid gland has a blood flow about five times the weight of the gland each minute, which is a blood supply as great as that of any other area of the body, with the possible exception of the adrenal cortex.
The thyroid gland also contains C cells that secrete calcitonin , a hormone that contributes to regulation of plasma calcium ion concentration, as discussed in Chapter 80 .
Iodine is Required for Thyroxine Formation
To form normal quantities of thyroxine, about 50 milligrams of ingested iodine in the form of iodides are required each year, or about 1 mg/week . To prevent iodine deficiency, common table salt is iodized with about 1 part sodium iodide to every 100,000 parts sodium chloride.
Fate of Ingested Iodides
Iodides ingested orally are absorbed from the gastrointestinal tract into the blood in about the same manner as chlorides. Normally, most of the iodides are rapidly excreted by the kidneys, but only after about one fifth are selectively removed from the circulating blood by the cells of the thyroid gland and used for synthesis of the thyroid hormones.
Iodide Pump—the Sodium-Iodide Symporter (Iodide Trapping)
The first stage in formation of thyroid hormones, shown in Figure 77-2 , is transport of iodides from the blood into the thyroid glandular cells and follicles. The basal membrane of the thyroid cell has the specific ability to pump the iodide actively to the interior of the cell. This pumping is achieved by the action of a sodium-iodide symporter , which co-transports one iodide ion along with two sodium ions across the basolateral (plasma) membrane into the cell. The energy for transporting iodide against a concentration gradient comes from the sodium-potassium adenosine triphosphatase (Na + -K + ATPase) pump, which pumps sodium out of the cell, thereby establishing a low intracellular sodium concentration and a gradient for facilitated diffusion of sodium into the cell.
This process of concentrating the iodide in the cell is called iodide trapping. In a normal gland, the iodide pump concentrates the iodide to about 30 times its concentration in the blood. When the thyroid gland becomes maximally active, this concentration ratio can rise to as high as 250 times. The rate of iodide trapping by the thyroid is influenced by several factors, the most important being the concentration of TSH; TSH stimulates and hypophysectomy greatly diminishes the activity of the iodide pump in thyroid cells.
Iodide is transported out of the thyroid cells across the apical membrane into the follicle by a chloride-iodide ion counter-transporter molecule called pendrin . The thyroid epithelial cells also secrete into the follicle thyroglobulin that contains tyrosine amino acids to which the iodine will bind, as discussed in the next section.
Thyroglobulin and Formation of Thyroxine and Triiodothyronine
Formation and Secretion of Thyroglobulin by the Thyroid Cells
The thyroid cells are typical protein-secreting glandular cells, as shown in Figure 77-2 . The endoplasmic reticulum and Golgi apparatus synthesize and secrete into the follicles a large glycoprotein molecule called thyroglobulin, with a molecular weight of about 335,000.
Each molecule of thyroglobulin contains about 70 tyrosine amino acids, and they are the major substrates that combine with iodine to form the thyroid hormones. Thus, the thyroid hormones form within the thyroglobulin molecule. That is, the thyroxine and triiodothyronine hormones formed from the tyrosine amino acids remain part of the thyroglobulin molecule during synthesis of the thyroid hormones and even afterward as stored hormones in the follicular colloid.
Oxidation of the Iodide Ion
The first essential step in thyroid hormone formation is conversion of iodide ions to an oxidized form of iodine, either nascent iodine (I 0 ) or I 3 − , which is then capable of combining directly with the amino acid tyrosine. This oxidation of iodine is promoted by the enzyme peroxidase and its accompanying hydrogen peroxide, which provide a potent system capable of oxidizing iodides. The peroxidase is either located in the apical membrane of the cell or attached to it, thus providing the oxidized iodine at exactly the point in the cell where the thyroglobulin molecule issues forth from the Golgi apparatus and through the cell membrane into the stored thyroid gland colloid. When the peroxidase system is blocked or when it is hereditarily absent from the cells, the rate of formation of thyroid hormones falls to zero.
Iodination of Tyrosine and Thyroid Hormone Formation—“Organification” of Thyroglobulin
The binding of iodine with the thyroglobulin molecule is called organification of the thyroglobulin. Oxidized iodine even in the molecular form will bind directly but slowly with the amino acid tyrosine. In thyroid cells, however, the oxidized iodine is associated with thyroid peroxidase enzyme (see Figure 77-2 ) that causes the process to occur within seconds or minutes. Therefore, almost as rapidly as thyroglobulin is released from the Golgi apparatus or as it is secreted through the apical cell membrane into the follicle, iodine binds with about one sixth of the tyrosine amino acids within the thyroglobulin molecule.
Figure 77-3 shows the successive stages of iodination of tyrosine and final formation of thyroxine and triiodothyronine. Tyrosine is first iodized to monoiodotyrosine and then to diiodotyrosine. Then, during the next few minutes, hours, and even days, more and more of the iodotyrosine residues become coupled with one another.
The major hormonal product of the coupling reaction is the molecule thyroxine (T 4 ), which is formed when two molecules of diiodotyrosine are joined together; the thyroxine then remains part of the thyroglobulin molecule. Or one molecule of monoiodotyrosine couples with one molecule of diiodotyrosine to form triiodothyronine (T 3 ), which represents about one-fifteenth of the final hormones. Small amounts of reverse T 3 (RT 3 ) are formed by coupling of diiodotyrosine with monoiodotyrosine, but RT 3 does not appear to be of functional significance in humans.
Storage of Thyroglobulin
The thyroid gland is unusual among the endocrine glands in its ability to store large amounts of hormone. After synthesis of the thyroid hormones has run its course, each thyroglobulin molecule contains up to 30 thyroxine molecules and a few triiodothyronine molecules. In this form, the thyroid hormones are stored in the follicles in an amount sufficient to supply the body with its normal requirements of thyroid hormones for 2 to 3 months. Therefore, when synthesis of thyroid hormone ceases, the physiological effects of deficiency are not observed for several months.
Release of Thyroxine and Triiodothyronine from the Thyroid Gland
Most of the thyroglobulin is not released into the circulating blood; instead, thyroxine and triiodothyronine are cleaved from the thyroglobulin molecule, and then these free hormones are released. This process occurs as follows: The apical surface of thyroid cells sends out pseudopod extensions that close around small portions of the colloid to form pinocytic vesicles that enter the apex of the thyroid cell. Then lysosomes in the cell cytoplasm immediately fuse with these vesicles to form digestive vesicles containing digestive enzymes from the lysosomes mixed with the colloid. Multiple proteases among the enzymes digest the thyroglobulin molecules and release thyroxine and triiodothyronine in free form, which then diffuse through the base of the thyroid cell into the surrounding capillaries. Thus, the thyroid hormones are released into the blood.
Some of the thyroglobulin in the colloid enters the thyroid cell by endocytosis after binding to megalin , a protein located on the lumen membrane of the cells. The megalin-thyroglobulin complex is then carried across the cell by transcytosis to the basolateral membrane, where a portion of the megalin remains bound to thyroglobulin and is released into the capillary blood.
About three-quarters of the iodinated tyrosine in the thyroglobulin never become thyroid hormones but remain monoiodotyrosine and diiodotyrosine. During the digestion of the thyroglobulin molecule to cause release of thyroxine and triiodothyronine, these iodinated tyrosines also are freed from the thyroglobulin molecules. However, they are not secreted into the blood. Instead, their iodine is cleaved from them by a deiodinase enzyme that makes virtually all this iodine available again for recycling within the gland for forming additional thyroid hormones. Congenital absence of this deiodinase enzyme may cause iodine deficiency because of failure of this recycling process.
Daily Rate of Secretion of Thyroxine and Triiodothyronine
About 93% of the thyroid hormone released from the thyroid gland is normally thyroxine and only 7% is triiodothyronine. However, during the ensuing few days, about one-half of the thyroxine is slowly deiodinated to form additional triiodothyronine. Therefore, the hormone finally delivered to and used by the tissues is mainly triiodothyronine—a total of about 35 μg of triiodothyronine per day.
Transport of Thyroxine and Triiodothyronine to Tissues
Thyroxine and Triiodothyronine Are Bound to Plasma Proteins
Upon entering the blood, more than 99% of the thyroxine and triiodothyronine combines immediately with several of the plasma proteins, all of which are synthesized by the liver. They combine mainly with thyroxine-binding globulin and much less so with thyroxine-binding prealbumin and albumin .
Thyroxine and Triiodothyronine Are Released Slowly to Tissue Cells
Because of high affinity of the plasma-binding proteins for the thyroid hormones, these substances—in particular, thyroxine—are released to the tissue cells slowly. Half the thyroxine in the blood is released to the tissue cells about every 6 days, whereas half the triiodothyronine—because of its lower affinity—is released to the cells in about 1 day.
Upon entering the tissue cells, both thyroxine and triiodothyronine again bind with intracellular proteins, with the thyroxine binding more strongly than the triiodothyronine. Therefore, they are again stored, but this time in the target cells, and they are used slowly over a period of days or weeks.
Thyroid Hormones Have Slow Onset and Long Duration of Action
After injection of a large quantity of thyroxine into a human being, essentially no effect on the metabolic rate can be discerned for 2 to 3 days, thereby demonstrating that there is a long latent period before thyroxine activity begins. Once activity does begin, it increases progressively and reaches a maximum in 10 to 12 days, as shown in Figure 77-4 . Thereafter, it decreases with a half-life of about 15 days. Some of the activity persists for as long as 6 weeks to 2 months.
The actions of triiodothyronine occur about four times as rapidly as those of thyroxine, with a latent period as short as 6 to 12 hours and maximal cellular activity occurring within 2 to 3 days.
Most of the latency and the prolonged period of action of these hormones are probably caused by their binding with proteins both in the plasma and in the tissue cells, followed by their slow release. However, we shall see in subsequent discussions that part of the latent period also results from the manner in which these hormones perform their functions in the cells.
Physiological Functions of the Thyroid Hormones
Thyroid Hormones Increase Transcription of Many Genes
The general effect of thyroid hormone is to activate nuclear transcription of many genes ( Figure 77-5 ). Therefore, in virtually all cells of the body, great numbers of protein enzymes, structural proteins, transport proteins, and other substances are synthesized. The net result is a generalized increase in functional activity throughout the body.
Most of the Thyroxine Secreted by the Thyroid Is Converted to Triiodothyronine
Before acting on the genes to increase genetic transcription, one iodide is removed from almost all the thyroxine, thus forming triiodothyronine. Intracellular thyroid hormone receptors have a high affinity for triiodothyronine. Consequently, more than 90% of the thyroid hormone that binds with the receptors is triiodothyronine.
Thyroid Hormones Activate Nuclear Receptors
Thyroid hormone receptors are either attached to the DNA genetic strands or located in proximity to them. The thyroid hormone receptor usually forms a heterodimer with retinoid X receptor (RXR) at specific thyroid hormone response elements on the DNA. After binding with thyroid hormone, the receptors become activated and initiate the transcription process. Large numbers of different types of messenger RNA are then formed, followed within another few minutes or hours by RNA translation on the cytoplasmic ribosomes to form hundreds of new intracellular proteins. However, not all the proteins are increased by similar percentages—some are increased only slightly, and others at least as much as sixfold. Most of the actions of thyroid hormone result from the subsequent enzymatic and other functions of these new proteins.
Thyroid hormones also appear to have nongenomic cellular effects that are independent of their effects on gene transcription. For example, some effects of thyroid hormones occur within minutes, too rapidly to be explained by changes in protein synthesis, and are not affected by inhibitors of gene transcription and translation. Such actions have been described in several tissues, including the heart and pituitary, as well as adipose tissue. The site of nongenomic thyroid hormone action appears to be the plasma membrane, cytoplasm, and perhaps some cell organelles such as mitochondria. Nongenomic actions of thyroid hormone include regulation of ion channels and oxidative phosphorylation and appear to involve activation of intracellular secondary messengers such as cyclic adenosine monophosphate (cAMP) or protein kinase signaling cascades.
Thyroid Hormones Increase Cellular Metabolic Activity
Thyroid hormones increase the metabolic activities of almost all the tissues of the body. The basal metabolic rate can increase to 60% to 100% above normal when large quantities of thyroid hormones are secreted. The rate of utilization of foods for energy is greatly accelerated. Although the rate of protein synthesis is increased, at the same time the rate of protein catabolism is also increased. The growth rate of young people is greatly accelerated. The mental processes are excited, and the activities of most of the other endocrine glands are increased.
Thyroid Hormones Increase the Number and Activity of Mitochondria
When thyroxine or triiodothyronine is given to an animal, the mitochondria in most cells of the animal’s body increase in size and number. Furthermore, the total membrane surface area of the mitochondria increases almost directly in proportion to the increased metabolic rate of the whole animal. Therefore, one of the principal functions of thyroxine might be simply to increase the number and activity of mitochondria, which in turn increases the rate of formation of adenosine triphosphate to energize cellular function. However, increases in the number and activity of mitochondria could be the result of increased activity of the cells, as well as the cause of the increase.
Thyroid Hormones Increase Active Transport of Ions Through Cell Membranes
One of the enzymes that increases its activity in response to thyroid hormone is Na + -K + ATPase . This increased activity in turn increases the rate of transport of sodium and potassium ions through the cell membranes of some tissues. Because this process uses energy and increases the amount of heat produced in the body, it has been suggested that this might be one of the mechanisms by which thyroid hormone increases the body’s metabolic rate. In fact, thyroid hormone also causes the cell membranes of most cells to become leaky to sodium ions, which further activates the sodium pump and further increases heat production.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here