Thyroid Gland— Synthesis and Physiological Effects of Thyroid Hormones

Thyroid Gland

Introduction

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 hormones, thyroxine and triiodothyronine, commonly called T4 and T3, respectively. Both of these hormones profoundly increase the basal metabolic rate (BMR) of the body. Complete lack of thyroid secretion usually causes the basal metabolic rate to fall 40 to 50 percent below normal, and extreme excesses of thyroid secretion can increase the basal metabolic rate to 60 to 100 percent above normal.

Also read, Cardiac Cycle and Interpretation of ECG.

Physiological Anatomy of Thyroid Gland

The thyroid gland is composed of large numbers of closed follicles called thyroid follicles (100 to 300 micrometers in diameter) that are filled with a secretory substance called colloid and lined with cuboidal epithelial cells, or G cells, that secrete into the interior of the follicles. The major constituent of colloid is the large glycoprotein thyroglobulin, which contains the thyroid hormones – triiodothyronine (T3) and tetraiodothyronine (thyroxine or T4).

Interestingly, 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.

Thyroid gland is richly supplied with blood. 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.

Iodine Requirement for Synthesis of Thyroid Hormones

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.

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.

Sodium-Iodide Symporters

The first stage in the formation of thyroid hormones, 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 (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.

Biochemistry of Iodothyronine formation

The thyroid cells are typical protein secreting glandular cells. 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.

Oxidation of Iodide Ions

The first essential step in the formation of thyroid hormones is conversion of iodide ions to an oxidized form of iodine, either nascent iodine (I⁰) or I3⁻, 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 Formation of the Thyroid Hormones—“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 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.

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 (T₄), 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 (T3), which represents about one fifteenth of the final hormones.

Small amounts of reverse T3 (RT3) are formed by coupling of diiodotyrosine with monoiodotyrosine, but RT3 does not appear to be of functional significance in humans.

Storage of Thyroglobulins

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.

Daily Rate of Secretion of Iodothyronines

About 93 percent of the thyroid hormone released from the thyroid gland is normally thyroxine and only 7 percent 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 micrograms of triiodothyronine per day.

Thyroxine and Triiodothyronine are bound to plasma proteins. Upon entering the blood, more than 99 percent 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 themselves, 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. 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.

Physiological Effects of Thyroid Gland

The general effect of thyroid hormone is to activate nuclear transcription of large numbers of genes. 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 percent of the thyroid hormone molecules that bind with the receptors is triiodothyronine.

Thyroid Hormones have Nuclear Receptors

The 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. It is believed that most of the actions of thyroid hormone result from the subsequent enzymatic and other functions of these new proteins.

Non-Genomic Effects of Thyroid Gland

Thyroid hormones also appear to have non-genomic 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 non-genomic thyroid hormone action appears to be the plasma membrane, cytoplasm, and perhaps some cell organelles such as mitochondria.

Non-genomic actions of thyroid hormone include the regulation of ion channels and oxidative phosphorylation and appear to involve the activation of intracellular secondary messengers such as cyclic adenosine monophosphate (cAMP) or protein kinase signaling cascades.

Secretion and Physiological Effects

Effects of thyroid hormone on body functions include:

  1. Stimulation of Carbohydrate Metabolism. Thyroid hormone stimulates almost all aspects of carbohydrate metabolism, including rapid glucose uptake by cells, enhanced glycolysis, enhanced gluconeogenesis, increased rate of absorption from the gastrointestinal tract, and even increased insulin secretion with its resultant secondary effects on carbohydrate metabolism. All these effects probably result from the overall increase in cellular metabolic enzymes caused by thyroid hormone.
  2. Stimulation of Fat Metabolism. Essentially all aspects of fat metabolism are also enhanced under the influence of thyroid hormone. In particular, lipids are mobilized rapidly from the fat tissue, which decreases the fat stores of the body to a greater extent than almost any other tissue element. Mobilization of lipids from fat tissue also increases the free fatty acid concentration in the plasma and greatly accelerates the oxidation of free fatty acids by the cells.
  3. Effect on Plasma and Liver Fats. Increased thyroid hormone decreases the concentrations of cholesterol, phospholipids, and triglycerides in the plasma, even though it increases the free fatty acids. One of the mechanisms by which thyroid hormone decreases plasma cholesterol concentration is to increase significantly cholesterol secretion in the bile and consequent loss in the feces.
  4. Increased Requirement for Vitamins. Because thyroid hormone increases the quantities of many bodily enzymes and because vitamins are essential parts of some of the enzymes or coenzymes, thyroid hormone increases the need for vitamins. Therefore, a relative vitamin deficiency can occur when excess thyroid hormone is secreted, unless at the same time increased quantities of vitamins are made available.
  5. Increased Basal Metabolic Rate. Because thyroid hormone increases metabolism in almost all cells of the body, excessive quantities of the hormone can occasionally increase the basal metabolic rate 60 to 100 percent above normal. Conversely, when no thyroid hormone is produced, the basal metabolic rate falls to almost one-half normal.
  6. Decreased Body Weight. A greatly increased amount of thyroid hormone almost always decreases body weight, and a greatly decreased amount of thyroid hormone almost always increases body weight; however, these effects do not always occur because thyroid hormone also increases the appetite, which may counterbalance the change in the metabolic rate.
  7. Increased Blood Flow and Cardiac Output. Increased metabolism in the tissues causes more rapid utilization of oxygen than normal and the release of greater than normal quantities of metabolic end products from the tissues. T hese effects cause vasodilation in most body tissues, thus increasing blood flow. The rate of blood flow in the skin especially increases because of the increased need for heat elimination from the body. As a consequence of the increased blood flow, cardiac output also increases, sometimes rising to 60 percent or more above normal when excessive thyroid hormone is present and falling to only 50 percent of normal in severe hypothyroidism.
  8. Increased Heart Rate. The heart rate increases considerably more under the influence of thyroid hormone than would be expected from the increase in cardiac output. T herefore, thyroid hormone seems to have a direct effect on the excitability of the heart, which in turn increases the heart rate. This effect is especially important because the heart rate is one of the sensitive physical signs that the clinician uses in determining whether a patient has excessive or diminished thyroid hormone production.
  9. Increased Heart Strength. The increased enzymatic activity caused by increased thyroid hormone production apparently increases the strength of the heart when only a slight excess of thyroid hormone is secreted. This effect is analogous to the increase in heart strength that occurs in mild fevers and during exercise. However, when thyroid hormone is increased markedly, heart muscle strength becomes depressed because of long-term excessive protein catabolism. Indeed, some severely thyrotoxic patients die of cardiac decompensation secondary to myocardial failure and increased cardiac load imposed by the increase in cardiac output.
  10. Increased Respiration. The increased rate of metabolism increases the utilization of oxygen and the formation of carbon dioxide; these effects activate all the mechanisms that increase the rate and depth of respiration.
  11. Increased Gastrointestinal Motility. In addition to increased appetite and food intake, which has been discussed, thyroid hormone increases both the rates of secretion of the digestive juices and the motility of the gastrointestinal tract. Hyperthyroidism therefore often results in diarrhea, whereas lack of thyroid hormone can cause constipation.
  12. Excitatory Effects on the Central Nervous System. In general, thyroid hormone increases the rapidity of cerebration, although thought processes may be dissociated; conversely, lack of thyroid hormone decreases rapidity of cerebration. A person with hyperthyroidism is likely to be extremely nervous and have many psychoneurotic tendencies, such as anxiety complexes, extreme worry, and paranoia.
  13. Effect on the Function of the Muscles. A slight increase in thyroid hormone usually makes the muscles react with vigor, but when the quantity of hormone becomes excessive, the muscles become weakened because of excess protein catabolism. Conversely, lack of thyroid hormone causes the muscles to become sluggish, and they relax slowly after a contraction.
  14. Muscle Tremor. One of the most characteristic signs of hyperthyroidism is a fine muscle tremor. This symptom is not the coarse tremor that occurs in Parkinson’s disease or when a person shivers because it occurs at the rapid frequency of 10 to 15 times per second. The tremor can be observed easily by placing a sheet of paper on the extended fingers and noting the degree of vibration of the paper. This tremor is believed to be caused by increased reactivity of the neuronal synapses in the areas of the spinal cord that control muscle tone. The tremor is an important means for assessing the degree of thyroid hormone effect on the central nervous system.
  15. Effect on Sleep. Because of the exhausting effect of thyroid hormone on the musculature and on the central nervous system, persons with hyperthyroidism often have a feeling of constant tiredness, but because of the excitable effects of thyroid hormone on the synapses, it is difficult to sleep. Conversely, extreme somnolence is characteristic of hypothyroidism, with sleep sometimes lasting 12 to 14 hours a day.
  16. Effect on Other Endocrine Glands. Increased thyroid hormone increases the rates of secretion of several other endocrine glands, but it also increases the need of the tissues for the hormones. For instance, increased thyroxine secretion increases the rate of glucose metabolism almost everywhere in the body and therefore causes a corresponding need for increased insulin secretion by the pancreas. Also, thyroid hormone increases many metabolic activities related to bone formation and, as a consequence, increases the need for parathyroid hormone. T hyroid hormone also increases the rate at which adrenal glucocorticoids are inactivated by the liver. This increased rate of inactivation leads to feedback increase in adrenocorticotropic hormone production by the anterior pituitary and, therefore, an increased rate of glucocorticoid secretion by the adrenal glands.
  17. Effect of Thyroid Hormone on Sexual Function. For normal sexual function, thyroid secretion needs to be approximately normal. In men, lack of thyroid hormone is likely to cause loss of libido; a great excess of the hormone, however, sometimes causes impotence.

In women, lack of thyroid hormone often causes menorrhagia and polymenorrhea—that is, excessive and frequent menstrual bleeding, respectively. Yet, strangely enough, in other women a lack of thyroid hormone may cause irregular periods and occasionally even amenorrhea (absence of menstrual bleeding).

Hypothyroidism in women, as in men, is likely to result in a greatly decreased libido. To make the picture still more confusing, in women with hyperthyroidism, oligomenorrhea (greatly reduced bleeding) is common, and occasionally amenorrhea occurs.