The Thyroid Gland PDF

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,...

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 metabolic rate of the body. Complete lack of thyroid secretion usually causes the basal metabolic rate to fall 40 to 50 per cent below normal, and extreme excesses of thyroid secretion can increase the basal metabolic rate to 60 to 100 per cent above normal. Thyroid secretion is controlled primarily by *thyroid-stimulating hormone (TSH)* secreted by the anterior pituitary gland. The thyroid gland also secretes *calcitonin*, an important hormone for calcium metabolism that is considered in detail in Chapter 79. 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 per cent of the metabolically active hormones secreted by the thyroid gland is *thyroxine*, and 7 per cent *triiodothyronine*. However, almost all the thyroxine is eventually converted to triiodothyronine in the tissues, so that 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 than does thyroxine. **Physiologic Anatomy of the Thyroid Gland.** The thyroid gland is composed, as shown in Figure 76--1, of large numbers of closed *follicles* (100 to 300 micrometers in diameter) 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 within its molecule. 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. **Iodine Is Required for Formation of Thyroxine** 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, *932* **Unit XIV** *Endocrinology and Reproduction* 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 (Iodide Trapping)** The first stage in the formation of thyroid hormones, shown in Figure 76--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 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. **Thyroglobulin, and Chemistry** **of Thyroxine and** **Triiodothyronine Formation** **Formation and Secretion of Thyroglobulin by the Thyroid Cells.** The thyroid cells are typical protein-secreting glandular cells, as shown in Figure 76--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 the formation of the thyroid hormones is conversion of the iodide ions to an *oxidized form of iodine*, either nascent iodine (I0) or I3 \_, that 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. Follicle Cuboidal epithelial cells Colloid Red blood cells **Figure 76--1** Microscopic appearance of the thyroid gland, showing secretion of thyroglobulin into the follicles. Iodination and coupling \+ I2 I- I- H2O2 Peroxidase Peroxidase Pinocytosis Secretion MIT DIT MIT, DIT ER Golgi Proteases Colloid droplet Deiodination Tyrosine Thyroglobulin precursor (TG) TG TG T3 T4 T3 T4 T3 T4 **Figure 76--2** Thyroid cellular mechanisms for iodine transport, thyroxine and triiodothyronine formation, and thyroxine and triiodothyronine release into the blood. MIT, monoiodotyrosine; DIT, diiodotyrosine; T3, triiodothyronine; T4, thyroxine; TG, thyroglobulin. **Chapter 76** *Thyroid Metabolic Hormones 933* **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 very slowly with the amino acid tyrosine. In the thyroid cells, however, the oxidized iodine is associated with an *iodinase* enzyme (Figure 76--2) that causes the process to occur within seconds or minutes.Therefore, almost as rapidly as the thyroglobulin molecule 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 76--3 shows the successive stages of iodination of tyrosine and final formation of the two important thyroid hormones, 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* that remains part of the thyroglobulin molecule. Or one molecule of monoiodotyrosine couples with one molecule of diiodotyrosine to form *triiodothyronine,* which represents about one fifteenth of the final hormones. **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 physiologic effects of deficiency are not observed for several months. **Release of Thyroxine and** **Triiodothyronine from the** **Thyroid Gland** Thyroglobulin itself is not released into the circulating blood in measurable amounts; instead, thyroxine and triiodothyronine must first be cleaved from the thyroglobulin molecule, and then these free hormones are released. This process occurs as follows: The apical surface of the 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. These then diffuse through the base of the thyroid cell into the surrounding capillaries. Thus, the thyroid hormones are released into the blood. About three quarters of the iodinated tyrosine in the thyroglobulin never becomes thyroid hormones but remains 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. In the congenital absence of this deiodinase enzyme, many persons become iodine-deficient because of failure of this recycling process. **Daily Rate of Secretion of Thyroxine and Triiodothyronine.** About 93 per cent of the thyroid hormone released from the thyroid gland is normally thyroxine and only 7 per cent 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 HO CH2 CHNH2 COOH O Diiodotyrosine + Diiodotyrosine Monoiodotyrosine + Diiodotyrosine HO CH2 CHNH2 COOH HO O CH2 CHNH2 COOH HO CH2 CHNH2 COOH + I2 + HO CH2 CHNH2 COOH Iodinase **Tyrosine** **Monoiodotyrosine** **Diiodotyrosine** **3,5,3\'-Triiodothyronine** **Thyroxine** **Figure 76--3** Chemistry of thyroxine and triiodothyronine formation. *934* **Unit XIV** *Endocrinology and Reproduction* used by the tissues is mainly triiodothyronine, a total of about 35 micrograms of triiodothyronine per day. **Transport of Thyroxine and** **Triiodothyronine to Tissues** **Thyroxine and Triiodothyronine Are Bound to Plasma Proteins.** On entering the blood, over 99 per cent 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. On entering the tissue cells, both thyroxine and triiodothyronine again bind with intracellular proteins, 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, as shown in Figure 76--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 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 themselves. **Physiologic Functions of the** **Thyroid Hormones** **Thyroid Hormones Increase the** **Transcription of Large Numbers** **of Genes** The general effect of thyroid hormone is to activate nuclear transcription of large numbers of genes (Figure 76--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 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 very high affinity for triiodothyronine. Consequently, more than 90 per cent of the thyroid hormone molecules that bind with the receptors is triiodothyronine. **Thyroid Hormones Activate 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. On binding with thyroid hormone, the receptors become activated and initiate the transcription process. Then large numbers of different types of messenger RNA are 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 only slightly, and others at least as much as sixfold. It is believed that most, if not all, of the actions of thyroid hormone result from the subsequent enzymatic and other functions of these new proteins. **Thyroid Hormones Increase Cellular** **Metabolic Activity** The thyroid hormones increase the metabolic activities of almost all the tissues of the body. The basal +10 +5 0 0 10 20 30 40 **Basal metabolic rate** **Days** **Thyroxine injected** **Figure 76--4** Approximate prolonged effect on the basal metabolic rate caused by administering a single large dose of thyroxine. **Chapter 76** *Thyroid Metabolic Hormones 935* metabolic rate can increase to 60 to 100 per cent above normal when large quantities of the 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 as well as 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 (ATP) to energize cellular function. However, the increase 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 in turn increases the rate of transport of both 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. Iodinase Cell membrane Cytoplasm Nuclear membrane Nucleus Thyroid hormone receptor Thyroid hormone response Gene transcription mRNA Synthesis of new proteins Metabolism Cardiac output Tissue blood flow Heart rate Heart strength Respiration Mitochondria Na+-K+-ATPase O2 consumption Glucose absorption Gluconeogenesis Glycogenolysis Lipolysis Protein synthesis BMR Many other systems Gene Retinoid X receptor T4 T3 T3 T3 Cardiovascular CNS development Growth **Figure 76--5** Thyroid hormone activation of target cells. Thyroxine (T4) and triiodothyronine (T3) readily diffuse through the cell membrane. Much of the T4 is deiodinated to form T3, which interacts with the thyroid hormone receptor, bound as a heterodimer with a retinoid X receptor, of the thyroid hormone response element of the gene. This causes either increases or decreases in transcription of genes that lead to formation of proteins, thus producing the thyroid hormone response of the cell. The actions of thyroid hormone on cells of several different systems are shown. mRNA, messenger ribonucleic acid. *936* **Unit XIV** *Endocrinology and Reproduction* **Effect of Thyroid Hormone on Growth** Thyroid hormone has both general and specific effects on growth. For instance, it has long been known that thyroid hormone is essential for the metamorphic change of the tadpole into the frog. In humans, the effect of thyroid hormone on growth is manifest mainly in growing children. In those who are hypothyroid, the rate of growth is greatly retarded. In those who are hyperthyroid, excessive skeletal growth often occurs, causing the child to become considerably taller at an earlier age. However, the bones also mature more rapidly and the epiphyses close at an early age, so that the duration of growth and the eventual height of the adult may actually be shortened. An important effect of thyroid hormone is to promote growth and development of the brain during fetal life and for the first few years of postnatal life. If the fetus does not secrete sufficient quantities of thyroid hormone, growth and maturation of the brain both before birth and afterward are greatly retarded, and the brain remains smaller than normal. Without specific thyroid therapy within days or weeks after birth, the child without a thyroid gland will remain mentally deficient throughout life. This is discussed more fully later in the chapter. **Effects of Thyroid Hormone** **on Specific Bodily Mechanisms** **Stimulation of Carbohydrate Metabolism.** Thyroid hormone stimulates almost all aspects of carbohydrate metabolism, including rapid uptake of glucose by the 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. **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. This also increases the free fatty acid concentration in the plasma and greatly accelerates the oxidation of free fatty acids by the cells. **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. Conversely, *decreased* thyroid secretion greatly *increases* the plasma concentrations of cholesterol, phospholipids, and triglycerides and almost always causes excessive deposition of fat in the liver as well.The large increase in circulating plasma cholesterol in prolonged hypothyroidism is often associated with severe atherosclerosis, discussed in Chapter 68. One of the mechanisms by which thyroid hormone decreases the plasma cholesterol concentration is to increase significantly the rate of cholesterol secretion in the bile and consequent loss in the feces.A possible mechanism for the increased cholesterol secretion is that thyroid hormone induces increased numbers of low-density lipoprotein receptors on the liver cells, leading to rapid removal of low-density lipoproteins from the plasma by the liver and subsequent secretion of cholesterol in these lipoproteins by the liver cells. **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 causes increased 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. **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 per cent above normal. Conversely, when no thyroid hormone is produced, the basal metabolic rate falls almost to one-half normal. Figure 76--6 shows the approximate relation between the daily supply of thyroid hormones and the basal metabolic rate. Extreme amounts of the hormones are required to cause very high basal metabolic rates. **Decreased Body Weight.** Greatly increased thyroid hormone almost always decreases the body weight, +30 +20 +10 0 -40 -30 -20 -10 -45 0 100 200 300 **Basal metabolic rate** **Thyroid hormones (**m**g/day)** **Figure 76--6** Approximate relation of daily rate of thyroid hormone (T4 and T3) secretion to the basal metabolic rate. **Chapter 76** *Thyroid Metabolic Hormones 937* and greatly decreased hormone almost always increases the body weight; these effects do not always occur, because thyroid hormone also increases the appetite, and this may counterbalance the change in the metabolic rate. **Effect of Thyroid Hormones on the Cardiovascular System** **Increased Blood Flow and Cardiac Output.** Increased metabolism in the tissues causes more rapid utilization of oxygen than normal and release of greater than normal quantities of metabolic end products from the tissues. These 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 per cent or more above normal when excessive thyroid hormone is present and falling to only 50 per cent of normal in very severe hypothyroidism. **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. Therefore, thyroid hormone seems to have a direct effect on the excitability of the heart, which in turn increases the heart rate. This effect is of particular importance 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. **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 is analogous to the increase in heart strength that occurs in mild fevers and during exercise. However, when thyroid hormone is increased markedly, the 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 to increased cardiac load imposed by the increase in cardiac output. **Normal Arterial Pressure.** The *mean* arterial pressure usually remains about normal after administration of thyroid hormone. Because of increased blood flow through the tissues between heartbeats, the pulse pressure is often increased, with the systolic pressure elevated in hyperthyroidism 10 to 15 mm Hg and the diastolic pressure reduced a corresponding amount. **Increased Respiration.** The increased rate of metabolism increases the utilization of oxygen and formation of carbon dioxide; these effects activate all the mechanisms that increase the rate and depth of respiration. **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 often results in diarrhea. Lack of thyroid hormone can cause constipation. **Excitatory Effects on the Central Nervous System.** In general, thyroid hormone increases the rapidity of cerebration but also often dissociates this; conversely, lack of thyroid hormone decreases this function. The hyperthyroid individual is likely to have extreme nervousness and many psychoneurotic tendencies, such as anxiety complexes, extreme worry, and paranoia. **Effect on the Function of the Muscles.** 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. **Muscle Tremor.** One of the most characteristic signs of hyperthyroidism is a fine muscle tremor.This is not the coarse tremor that occurs in Parkinson's disease or in shivering, 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. **Effect on Sleep.** Because of the exhausting effect of thyroid hormone on the musculature and on the central nervous system, the hyperthyroid subject often has 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. **Effect on Other Endocrine Glands.** Increased thyroid hormone increases the rates of secretion of most 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 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. Thyroid hormone also increases the rate at which adrenal glucocorticoids are inactivated by the liver. This leads to feedback increase in adrenocorticotropic hormone production by the anterior pituitary and, therefore, increased rate of glucocorticoid secretion by the adrenal glands. **Effect of Thyroid Hormone on Sexual Function.** For normal sexual function, thyroid secretion needs to be *938* **Unit XIV** *Endocrinology and Reproduction* approximately normal. In men, lack of thyroid hormone is likely to cause loss of libido; great excesses of the hormone, however, sometimes cause impotence. In women, lack of thyroid hormone often causes *menorrhagia* and *polymenorrhea---* that is, respectively, excessive and frequent menstrual bleeding. Yet, strangely enough, in other women thyroid lack may cause irregular periods and occasionally even *amenorrhea*. A hypothyroid woman, like a man, is likely to have greatly decreased libido.To make the picture still more confusing, in the hyperthyroid woman, *oligomenorrhea*, which means greatly reduced bleeding, is common, and occasionally amenorrhea results. The action of thyroid hormone on the gonads cannot be pinpointed to a specific function but probably results from a combination of direct metabolic effects on the gonads as well as excitatory and inhibitory feedback effects operating through the anterior pituitary hormones that control the sexual functions. **Regulation of Thyroid** **Hormone Secretion** To maintain normal levels of metabolic activity in the body, precisely the right amount of thyroid hormone must be secreted at all times; to achieve this, specific feedback mechanisms operate through the hypothalamus and anterior pituitary gland to control the rate of thyroid secretion. These mechanisms are as follows. **TSH (from the Anterior Pituitary Gland) Increases Thyroid Secretion.** TSH, also known as *thyrotropin*, is an anterior pituitary hormone, a glycoprotein with a molecular weight of about 28,000. This hormone, also discussed in Chapter 74, increases the secretion of thyroxine and triiodothyronine by the thyroid gland. Its specific effects on the thyroid gland are as follows: 1\. *Increased proteolysis of the thyroglobulin* that has already been stored in the follicles, with resultant release of the thyroid hormones into the circulating blood and diminishment of the follicular substance itself 2\. *Increased activity of the iodide pump*, which increases the rate of "iodide trapping" in the glandular cells, sometimes increasing the ratio of intracellular to extracellular iodide concentration in the glandular substance to as much as eight times normal 3\. *Increased iodination of tyrosine* to form the thyroid hormones 4\. *Increased size and increased secretory activity of* *the thyroid cells* 5\. *Increased number of thyroid cells* plus a change from cuboidal to columnar cells and much infolding of the thyroid epithelium into the follicles In summary, TSH increases all the known secretory activities of the thyroid glandular cells. The most important early effect after administration of TSH is to initiate proteolysis of the thyroglobulin, which causes release of thyroxine and triiodothyronine into the blood within 30 minutes. The other effects require hours or even days and weeks to develop fully. **Cyclic Adenosine Monophosphate Mediates the Stimulatory** **Effect of TSH.** In the past, it was difficult to explain the many and varied effects of TSH on the thyroid cell. It is now clear that most, if not all, of these effects result from activation of the "second messenger" *cyclic* *adenosine monophosphate (cAMP)* system of the cell. The first event in this activation is binding of TSH with specific TSH receptors on the basal membrane surfaces of the thyroid cell. This then activates *adenylyl* *cyclase* in the membrane, which increases the formation of cAMP inside the cell. Finally, the cAMP acts as a *second messenger* to activate protein kinase,which causes multiple phosphorylations throughout the cell. The result is both an immediate increase in secretion of thyroid hormones and prolonged growth of the thyroid glandular tissue itself. This method for control of thyroid cell activity is similar to the function of cAMP as a "second messenger" in many other target tissues of the body, as discussed in Chapter 74. **Anterior Pituitary Secretion of TSH Is** **Regulated by Thyrotropin-Releasing** **Hormone from the Hypothalamus** Anterior pituitary secretion of TSH is controlled by a hypothalamic hormone, *thyrotropin-releasing* *hormone (TRH)*, which is secreted by nerve endings in the median eminence of the hypothalamus. From the median eminence, the TRH is then transported to the anterior pituitary by way of the hypothalamichypophysial portal blood, as explained in Chapter 74. TRH has been obtained in pure form. It is a simple substance, a tripeptide amide---*pyroglutamyl-histidylproline-* *amide*. TRH directly affects the anterior pituitary gland cells to increase their output of TSH.When the blood portal system from the hypothalamus to the anterior pituitary gland becomes blocked, the rate of secretion of TSH by the anterior pituitary decreases greatly but is not reduced to zero. The molecular mechanism by which TRH causes the TSH-secreting cells of the anterior pituitary to produce TSH is first to bind with TRH receptors in the pituitary cell membrane.This in turn *activates the phospholipase* *second messenger system* inside the pituitary cells to produce large amounts of phospholipase C, followed by a cascade of other second messengers, including calcium ions and diacyl glycerol, which eventually leads to TSH release. **Effects of Cold and Other Neurogenic Stimuli on TRH and TSH** **Secretion.** One of the best-known stimuli for increasing the rate of TRH secretion by the hypothalamus, **Chapter 76** *Thyroid Metabolic Hormones 939* and therefore TSH secretion by the anterior pituitary gland, is exposure of an animal to cold. This effect almost certainly results from excitation of the hypothalamic centers for body temperature control. Exposure of rats for several weeks to severe cold increases the output of thyroid hormones sometimes to more than 100 per cent of normal and can increase the basal metabolic rate as much as 50 per cent. Indeed, persons moving to arctic regions have been known to develop basal metabolic rates 15 to 20 per cent above normal. Various emotional reactions can also affect the output of TRH and TSH and therefore indirectly affect the secretion of thyroid hormones. Excitement and anxiety---conditions that greatly stimulate the sympathetic nervous system---cause an acute decrease in secretion of TSH, perhaps because these states increase the metabolic rate and body heat and therefore exert an inverse effect on the heat control center. Neither these emotional effects nor the effect of cold is observed after the hypophysial stalk has been cut, demonstrating that both of these effects are mediated by way of the hypothalamus. **Feedback Effect of Thyroid Hormone** **to Decrease Anterior Pituitary** **Secretion of TSH** Increased thyroid hormone in the body fluids decreases secretion of TSH by the anterior pituitary. When the rate of thyroid hormone secretion rises to about 1.75 times normal, the rate of TSH secretion falls essentially to zero. Almost all this feedback depressant effect occurs even when the anterior pituitary has been separated from the hypothalamus. Therefore, as shown in Figure 76--7, it is probable that increased thyroid hormone inhibits anterior pituitary secretion of TSH mainly by a direct effect on the anterior pituitary gland itself. Regardless of the mechanism of the feedback, its effect is to maintain an almost constant concentration of free thyroid hormones in the circulating body fluids. **Antithyroid Substances** Drugs that suppress thyroid secretion are called antithyroid substances.The best known of these substances are *thiocyanate*, *propylthiouracil*, and high concentrations of *inorganic iodides.* The mechanism by which each of these blocks thyroid secretion is different from the others, and they can be explained as follows. **Thiocyanate Ions Decrease Iodide Trapping.** The same active pump that transports iodide ions into the thyroid cells can also pump thiocyanate ions, perchlorate ions, and nitrate ions. Therefore, the administration of thiocyanate (or one of the other ions as well) in high enough concentration can cause competitive inhibition of iodide transport into the cell--- that is, inhibition of the iodide-trapping mechanism. The decreased availability of iodide in the glandular cells does not stop the formation of thyroglobulin; it merely prevents the thyroglobulin that is formed from becoming iodinated and therefore from forming the thyroid hormones. This deficiency of the thyroid hormones in turn leads to increased secretion of TSH by the anterior pituitary gland, which causes overgrowth of the thyroid gland even though the gland still does not form adequate quantities of thyroid hormones. Therefore, the use of thiocyanates and some other ions to block thyroid secretion can lead to development of a greatly enlarged thyroid gland, which is called a *goiter.* **Propylthiouracil Decreases Thyroid Hormone Formation.** Propylthiouracil (and other, similar compounds, such as methimazole and carbimazole) prevents formation of thyroid hormone from iodides and tyrosine. The mechanism of this is partly to block the peroxidase enzyme that is required for iodination of tyrosine and partly to block the coupling of two iodinated tyrosines to form thyroxine or triiodothyronine. Propylthiouracil, like thiocyanate, does not prevent formation of thyroglobulin. The absence of thyroxine and triiodothyronine in the thyroglobulin can lead to tremendous feedback enhancement of TSH secretion by the anterior pituitary gland, thus promoting growth of the glandular tissue and forming a goiter. **Iodides in High Concentrations Decrease Thyroid Activity and** **Thyroid Gland Size.** When iodides are present in the blood in *high concentration* (100 times the normal plasma level), most activities of the thyroid gland are decreased, but often they remain decreased for only a few weeks. The effect is to reduce the rate of iodide trapping, so that the rate of iodination of tyrosine to form thyroid hormones is also decreased. Even more important, the normal endocytosis of colloid from the follicles by the thyroid glandular cells is paralyzed by the high iodide concentrations. Because this is the first step in release of the thyroid hormones from the storage colloid, there is almost immediate shutdown of thyroid hormone secretion into the blood. Because iodides in high concentrations decrease all phases of thyroid activity, they slightly decrease the size of the thyroid gland and especially decrease its blood Hypothalamus (? increased temperature) (Thyrotropin-releasing hormone) Anterior pituitary Hypertrophy Iodine Thyroxine Thyroid Increased secretion Thyroidstimulating hormone Cells Increased metabolism **Inhibits** **?** **?** **Figure 76--7** Regulation of thyroid secretion. *940* **Unit XIV** *Endocrinology and Reproduction* supply, in contradistinction to the opposite effects caused by most of the other antithyroid agents. For this reason, iodides are frequently administered to patients for 2 to 3 weeks before surgical removal of the thyroid gland to decrease the necessary amount of surgery, especially to decrease the amount of bleeding. **Diseases of the Thyroid** **Hyperthyroidism** Most effects of hyperthyroidism are obvious from the preceding discussion of the various physiologic effects of thyroid hormone. However, some specific effects should be mentioned in connection especially with the development, diagnosis, and treatment of hyperthyroidism. **Causes of Hyperthyroidism (Toxic Goiter, Thyrotoxicosis, Graves'** **Disease).** In most patients with hyperthyroidism, the thyroid gland is increased to two to three times normal size, with tremendous hyperplasia and infolding of the follicular cell lining into the follicles, so that the number of cells is increased greatly. Also, each cell increases its rate of secretion severalfold; radioactive iodine uptake studies indicate that some of these hyperplastic glands secrete thyroid hormone at rates 5 to 15 times normal. The changes in the thyroid gland in most instances are similar to those caused by excessive TSH. However, plasma TSH concentrations are less than normal rather than enhanced in almost all patients and often are essentially zero. However, other substances that have actions similar to those of TSH are found in the blood of almost all these patients. These substances are immunoglobulin antibodies that bind with the same membrane receptors that bind TSH. They induce continual activation of the cAMP system of the cells, with resultant development of hyperthyroidism. These antibodies are called *thyroid-stimulating immunoglobulin* and are designated TSI. They have a prolonged stimulating effect on the thyroid gland, lasting for as long as 12 hours, in contrast to a little over 1 hour for TSH. The high level of thyroid hormone secretion caused by TSI in turn suppresses anterior pituitary formation of TSH. The antibodies that cause hyperthyroidism almost certainly occur as the result of autoimmunity that has developed against thyroid tissue. Presumably, at some time in the history of the person, an excess of thyroid cell antigens was released from the thyroid cells, and this has resulted in the formation of antibodies against the thyroid gland itself. **Thyroid Adenoma.** Hyperthyroidism occasionally results from a localized adenoma (a tumor) that develops in the thyroid tissue and secretes large quantities of thyroid hormone. This is different from the more usual type of hyperthyroidism, in that it usually is not associated with evidence of any autoimmune disease. An interesting effect of the adenoma is that as long as it continues to secrete large quantities of thyroid hormone, secretory function in the remainder of the thyroid gland is almost totally inhibited because the thyroid hormone from the adenoma depresses the production of TSH by the pituitary gland. **Symptoms of Hyperthyroidism** The symptoms of hyperthyroidism are obvious from the preceding discussion of the physiology of the thyroid hormones: (1) a high state of excitability, (2) intolerance to heat, (3) increased sweating, (4) mild to extreme weight loss (sometimes as much as 100 pounds), (5) varying degrees of diarrhea, (6) muscle weakness, (7) nervousness or other psychic disorders, (8) extreme fatigue but inability to sleep, and (9) tremor of the hands. **Exophthalmos.** Most people with hyperthyroidism develop some degree of protrusion of the eyeballs, as shown in Figure 76--8. This condition is called *exophthalmos.* A major degree of exophthalmos occurs in about one third of hyperthyroid patients, and the condition sometimes becomes so severe that the eyeball protrusion stretches the optic nerve enough to damage vision. Much more often, the eyes are damaged because the eyelids do not close completely when the person blinks or is asleep. As a result, the epithelial surfaces of the eyes become dry and irritated and often infected, resulting in ulceration of the cornea. The cause of the protruding eyes is edematous swelling of the retro-orbital tissues and degenerative changes in the extraocular muscles. In most patients, immunoglobulins can be found in the blood that react with the eye muscles. Furthermore, the concentration of these immunoglobulins is usually highest in patients who have high concentrations of TSIs. Therefore, there is much reason to believe that exophthalmos, like hyperthyroidism itself, is an autoimmune process.The exophthalmos usually is greatly ameliorated with treatment of the hyperthyroidism. **Figure 76--8** Patient with exophthalmic hyperthyroidism. Note protrusion of the eyes and retraction of the superior eyelids. The basal metabolic rate was +40. (Courtesy Dr. Leonard Posey.) **Chapter 76** *Thyroid Metabolic Hormones 941* **Diagnostic Tests for Hyperthyroidism.** For the usual case of hyperthyroidism, the most accurate diagnostic test is direct measurement of the concentration of "free" thyroxine (and sometimes triiodothyronine) in the plasma, using appropriate radioimmunoassay procedures. Other tests that are sometimes used are as follows: 1\. The basal metabolic rate is usually increased to +30 to +60 in severe hyperthyroidism. 2\. The concentration of TSH in the plasma is measured by radioimmunoassay. In the usual type of thyrotoxicosis, anterior pituitary secretion of TSH is so completely suppressed by the large amounts of circulating thyroxine and triiodothyronine that there is almost no plasma TSH. 3\. The concentration of TSI is measured by radioimmunoassay. This is usually high in thyrotoxicosis but low in thyroid adenoma. **Physiology of Treatment in Hyperthyroidism.** The most direct treatment for hyperthyroidism is surgical removal of most of the thyroid gland. In general, it is desirable to prepare the patient for surgical removal of the gland before the operation. This is done by administering propylthiouracil, usually for several weeks, until the basal metabolic rate of the patient has returned to normal. Then, administration of high concentrations of iodides for 1 to 2 weeks immediately before operation causes the gland itself to recede in size and its blood supply to diminish. By using these preoperative procedures, the operative mortality is less than 1 in 1000 in the better hospitals, whereas before development of modern procedures, operative mortality was 1 in 25. **Treatment of the Hyperplastic Thyroid Gland with** **Radioactive Iodine** Eighty to 90 per cent of an injected dose of iodide is absorbed by the hyperplastic, toxic thyroid gland within 1 day after injection. If this injected iodine is radioactive, it can destroy most of the secretory cells of the thyroid gland. Usually 5 millicuries of radioactive iodine is given to the patient, whose condition is reassessed several weeks later. If the patient is still hyperthyroid, additional doses are administered until normal thyroid status is reached. **Hypothyroidism** The effects of hypothyroidism, in general, are opposite to those of hyperthyroidism, but there are a few physiologic mechanisms peculiar to hypothyroidism. Hypothyroidism, like hyperthyroidism, probably is initiated by autoimmunity against the thyroid gland, but immunity that destroys the gland rather than stimulates it.The thyroid glands of most of these patients first have autoimmune "thyroiditis," which means thyroid inflammation. This causes progressive deterioration and finally fibrosis of the gland, with resultant diminished or absent secretion of thyroid hormone. Several other types of hypothyroidism also occur, often associated with development of enlarged thyroid glands, called *thyroid goiter*, as follows. **Endemic Colloid Goiter Caused by Dietary Iodide Deficiency.** The term "goiter" means a greatly enlarged thyroid gland. As pointed out in the discussion of iodine metabolism, about 50 milligrams of iodine are required *each year* for the formation of adequate quantities of thyroid hormone. In certain areas of the world, notably in the Swiss Alps, the Andes, and the Great Lakes region of the United States, insufficient iodine is present in the soil for the foodstuffs to contain even this minute quantity. Therefore, in the days before iodized table salt, many people who lived in these areas developed extremely large thyroid glands, called *endemic goiters.* The mechanism for development of large endemic goiters is the following: Lack of iodine prevents production of both thyroxine and triiodothyronine. As a result, no hormone is available to inhibit production of TSH by the anterior pituitary; this causes the pituitary to secrete excessively large quantities of TSH.The TSH then stimulates the thyroid cells to secrete tremendous amounts of thyroglobulin colloid into the follicles, and the gland grows larger and larger. But because of lack of iodine, thyroxine and triiodothyronine production does not occur in the thyroglobulin molecule and therefore does not cause the normal suppression of TSH production by the anterior pituitary. The follicles become tremendous in size, and the thyroid gland may increase to 10 to 20 times normal size. **Idiopathic Nontoxic Colloid Goiter.** Enlarged thyroid glands similar to those of endemic colloid goiter can also occur in people who do not have iodine deficiency. These goitrous glands may secrete normal quantities of thyroid hormones, but more frequently, the secretion of hormone is depressed, as in endemic colloid goiter. The exact cause of the enlarged thyroid gland in patients with idiopathic colloid goiter is not known, but most of these patients show signs of mild thyroiditis; therefore, it has been suggested that the thyroiditis causes slight hypothyroidism, which then leads to increased TSH secretion and progressive growth of the noninflamed portions of the gland. This could explain why these glands usually are nodular, with some portions of the gland growing while other portions are being destroyed by thyroiditis. In some persons with colloid goiter, the thyroid gland has an abnormality of the enzyme system required for formation of the thyroid hormones. Among the abnormalities often encountered are the following: 1\. *Deficient iodide-trapping mechanism*, in which iodine is not pumped adequately into the thyroid cells 2\. *Deficient peroxidase system*, in which the iodides are not oxidized to the iodine state 3\. *Deficient coupling of iodinated tyrosines in the* *thyroglobulin molecule*, so that the final thyroid hormones cannot be formed 4\. *Deficiency of the deiodinase enzyme*, which prevents recovery of iodine from the iodinated tyrosines that are not coupled to form the thyroid hormones (this is about two thirds of the iodine), thus leading to iodine deficiency Finally, some foods contain *goitrogenic substances* that have a propylthiouracil-type of antithyroid activity, thus also leading to TSH-stimulated enlargement of the thyroid gland. Such goitrogenic substances are found especially in some varieties of turnips and cabbages. **Physiologic Characteristics of Hypothyroidism.** Whether hypothyroidism is due to thyroiditis, endemic colloid goiter, idiopathic colloid goiter, destruction of the thyroid gland by irradiation, or surgical removal of the thyroid gland, the physiologic effects are the same.They *942* **Unit XIV** *Endocrinology and Reproduction* include fatigue and extreme somnolence with sleeping up to 12 to 14 hours a day, extreme muscular sluggishness, slowed heart rate, decreased cardiac output, decreased blood volume, sometimes increased body weight, constipation, mental sluggishness, failure of many trophic functions in the body evidenced by depressed growth of hair and scaliness of the skin, development of a froglike husky voice, and, in severe cases, development of an edematous appearance throughout the body called myxedema. **Myxedema.** *Myxedema* develops in the patient with almost total lack of thyroid hormone function. Figure 76--9 shows such a patient, demonstrating bagginess under the eyes and swelling of the face. In this condition, for reasons not explained, greatly increased quantities of hyaluronic acid and chondroitin sulfate bound with protein form excessive tissue gel in the interstitial spaces, and this causes the total quantity of interstitial fluid to increase. Because of the gel nature of the excess fluid, it is mainly immobile, and the edema is the nonpitting type. **Atherosclerosis in Hypothyroidism.** As pointed out earlier, lack of thyroid hormone increases the quantity of blood cholesterol because of altered fat and cholesterol metabolism and diminished liver excretion of cholesterol in the bile.The increase in blood cholesterol is usually associated with increased atherosclerosis. Therefore, many hypothyroid patients, particularly those with myxedema, develop atherosclerosis, which in turn results in peripheral vascular disease, deafness, and coronary artery disease with consequent early death. **Diagnostic Tests in Hypothyroidism.** The tests already described for diagnosis of hyperthyroidism give opposite results in hypothyroidism. The free thyroxine in the blood is low.The basal metabolic rate in myxedema ranges between -30 and -50. And the secretion of TSH by the anterior pituitary when a test dose of TRH is administered is usually greatly increased (except in those rare instances of hypothyroidism caused by depressed response of the pituitary gland to TRH). **Treatment of Hypothyroidism.** Figure 76--4 shows the effect of thyroxine on the basal metabolic rate, demonstrating that the hormone normally has a duration of action of more than 1 month. Consequently, it is easy to maintain a steady level of thyroid hormone activity in the body by daily oral ingestion of a tablet or more containing thyroxine. Furthermore, proper treatment of the hypothyroid patient results in such complete normality that formerly myxedematous patients have lived into their 90s after treatment for more than 50 years. **Cretinism** Cretinism is caused by extreme hypothyroidism during fetal life, infancy, or childhood. This condition is characterized especially by failure of body growth and by mental retardation. It results from congenital lack of a thyroid gland (*congenital cretinism*), from failure of the thyroid gland to produce thyroid hormone because of a genetic defect of the gland, or from iodine lack in the diet (*endemic cretinism*). The severity of endemic cretinism varies greatly, depending on the amount of iodine in the diet, and whole populaces of an endemic geographic iodine-deficient soil area have been known to have cretinoid tendencies. A neonate without a thyroid gland may have normal appearance and function because it was supplied with some (but usually not enough) thyroid hormone by the mother while in utero, but a few weeks after birth, the neonate's movements become sluggish and both physical and mental growth begin to be greatly retarded. Treatment of the neonate with cretinism at any time with adequate iodine or thyroxine usually causes normal return of physical growth, but unless the cretinism is treated within a few weeks after birth, mental growth remains permanently retarded.This results from retardation of the growth, branching, and myelination of the neuronal cells of the central nervous system at this critical time in the normal development of the mental powers. Skeletal growth in the child with cretinism is characteristically more inhibited than is soft tissue growth. As a result of this disproportionate rate of growth, the soft tissues are likely to enlarge excessively, giving the child with cretinism an obese, stocky, and short appearance. Occasionally the tongue becomes so large in relation to the skeletal growth that it obstructs swallowing and breathing, inducing a characteristic