Physiology 5th Ed.


Thyroid hormones are synthesized and secreted by epithelial cells of the thyroid gland. They have effects on virtually every organ system in the body including those involved in normal growth and development. The thyroid gland was the first of the endocrine organs to be described by a deficiency disorder. In 1850, patients without thyroid glands were described as having a form of mental and growth retardation called cretinism. In 1891, such patients were treated by administering crude thyroid extracts (i.e., hormone replacement therapy). Disorders of thyroid deficiency and excess are among the most common of the endocrinopathies (disorders of the endocrine glands), affecting 4% to 5% of the population in the United States and an even greater percentage of people in regions of the world where there is iodine deficiency.

Synthesis and Transport of Thyroid Hormones

The two active thyroid hormones are triiodothyronine (T3) and tetraiodothyronine, or thyroxine (T4). The structures of T3 and T4 differ only by a single atom of iodine, as shown in Figure 9-16. Although T3 is more active than T4, almost all hormonal output of the thyroid gland is T4. This “problem” of secreting the less active form is solved by the target tissues, which convert T4 to T3. A third compound, reverse T3(not shown in Fig. 9-16), has no biologic activity.


Figure 9–16 Structures of the thyroid hormones thyroxine (T4) and triiodothyronine (T3).

Synthesis of Thyroid Hormones

Thyroid hormones are synthesized by the follicular epithelial cells of the thyroid gland. The follicular epithelial cells are arranged in circular follicles 200 to 300 µm in diameter, as shown in Figure 9-17. The cells have a basal membrane facing the blood and an apical membrane facing the follicular lumen. The material in the lumen of the follicles is colloid, which is composed of newly synthesized thyroid hormones attached to thyroglobulin. When the thyroid gland is stimulated, this colloidal thyroid hormone is absorbed into the follicular cells by endocytosis.


Figure 9–17 Schematic drawing of a thyroid follicle. Colloid is present in the follicular lumen.

The synthesis of thyroid hormones is more complex than that of most hormones. There are three unusual features of the synthetic process: (1) Thyroid hormones contain large amounts of iodine, which must be adequately supplied in the diet. (2) Synthesis of thyroid hormones is partially intracellular and partially extracellular, with the completed hormones stored extracellularly in the follicular lumen until the thyroid gland is stimulated to secrete. (3) As noted, although T4 is the major secretory product of the thyroid gland, it is not the most active form of the hormone.

The steps in thyroid hormone biosynthesis in follicular epithelial cells are illustrated in Figure 9-18. The circled numbers in the figure correlate with the following steps:


Figure 9–18 Steps involved in the synthesis of thyroid hormones in thyroid follicular cells. Also see the text for an explanation of the circled numbers. DIT, Diiodotyrosine; ER, endoplasmic reticulum; MIT, monoiodotyrosine; PTU, propylthiouracil; TG, thyroglobulin; T3, triiodothyronine; T4, thyroxine.

1.          Thyroglobulin (TG), a glycoprotein containing large quantities of tyrosine, is synthesized on the rough endoplasmic reticulum and the Golgi apparatus of the thyroid follicular cells. Thyroglobulin is then incorporated into secretory vesicles and extruded across the apical membrane into the follicular lumen. Later, the tyrosine residues of thyroglobulin will be iodinated to form the precursors of thyroid hormones.

2.          Na+-I cotransport, or “I-trap.” I is actively transported from blood into the follicular epithelial cells against both chemical and electrical gradients. The activity of this pump is regulated by I levels in the body. For example, low levels of I stimulate the pump. When there is a dietary deficiency of I, the Na+-I cotransport increases its activity, attempting to compensate for the deficiency. If the dietary deficiency is severe, however, even the Na+-I cotransport cannot compensate and the synthesis of thyroid hormones will be decreased.

  There are several competitive inhibitors of Na+-I cotransport including the anions thiocyanate and perchlorate, which block I uptake into follicular cells and interfere with the synthesis of thyroid hormones.

3.          Oxidation of I to I2. Once I is pumped into the cell, it traverses the cell to the apical membrane, where it is oxidized to I2 by the enzyme thyroid peroxidase. Thyroid peroxidase catalyzes this oxidation step and the next two steps (i.e., organification of I2 into thyroglobulin and the coupling reactions).

  Thyroid peroxidase is inhibited by propylthiouracil (PTU), which blocks the synthesis of thyroid hormones by blocking all of the steps catalyzed by thyroid peroxidase. Thus, administration of PTU is an effective treatment for hyperthyroidism.

4.          Organification of I2. At the apical membrane, just inside the lumen of the follicle, I2 combines with the tyrosine moieties of thyroglobulin, catalyzed by thyroid peroxidase, to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). MIT and DIT remain attached to thyroglobulin in the follicular lumen until the thyroid gland is stimulated to secrete its hormones. High levels of I inhibit organification and synthesis of thyroid hormones, which is known as the Wolff-Chaikoff effect.

5.          Coupling reaction. While still part of thyroglobulin, two separate coupling reactions occur between MIT and DIT, again catalyzed by thyroid peroxidase. In one reaction, two molecules of DIT combine to form T4. In the other reaction, one molecule of DIT combines with one molecule of MIT to form T3. The first reaction is faster, and as a result, approximately 10 times more T4 is produced than T3. A portion of MIT and DIT does not couple (is “left over”) and simply remains attached to thyroglobulin. After the coupling reactions occur, thyroglobulin contains T4, T3, and leftover MIT and DIT. This iodinated thyroglobulin is stored in the follicular lumen as colloiduntil the thyroid gland is stimulated to secrete its hormones (e.g., by TSH).

6.          Endocytosis of thyroglobulin. When the thyroid gland is stimulated, iodinated thyroglobulin (with its attached T4, T3, MIT, and DIT) is endocytosed into the follicular epithelial cells. Pseudopods are pinched off the apical cell membrane, engulf a portion of colloid, and absorb it into the cell. Once inside the cell, thyroglobulin is transported in the direction of the basal membrane by microtubular action.

7.          Hydrolysis of T4 and T3 from thyroglobulin by lysosomal enzymes. Thyroglobulin droplets fuse with lysosomal membranes. Lysosomal proteases then hydrolyze peptide bonds to release T4, T3, MIT, and DIT from thyroglobulin. T4 and T3 are transported across the basal membrane into nearby capillaries to be delivered to the systemic circulation. MIT and DIT remain in the follicular cell and are recycled into the synthesis of new thyroglobulin.

8.          Deiodination of MIT and DIT. MIT and DIT are deiodinated inside the follicular cell by the enzyme thyroid deiodinase. The I generated by this step is recycled into the intracellular pool and added to the I transported by the pump. The tyrosine molecules are incorporated into the synthesis of new thyroglobulin to begin another cycle. Thus, both I and tyrosine are “salvaged” by the deiodinase enzyme. A deficiency of thyroid deiodinase therefore mimics dietary I

Binding of Thyroid Hormones in the Circulation

Thyroid hormones (T4 and T3) circulate in the bloodstream either bound to plasma proteins or free (unbound). Most T4 and T3 circulates bound to thyroxine-binding globulin (TBG). Smaller amounts circulate bound to T4-binding prealbumin and albumin. Still smaller amounts circulate in the free, unbound form. Because only free thyroid hormones are physiologically active, the role of TBG is to provide a large reservoir of circulating thyroid hormones, which can be released and added to the pool of free hormone.

Changes in the blood levels of TBG alter the fraction of free (physiologically active) thyroid hormones. For example, in hepatic failure, blood levels of TBG decrease because there is decreased hepatic protein synthesis. The decrease in TBG levels results in a transient increase in the level of free thyroid hormones; a consequence of increased free thyroid hormone is inhibition of synthesis of thyroid hormones (by negative feedback). In contrast, during pregnancy, the high level of estrogen inhibits hepatic breakdown of TBG and increases TBG levels. With a higher level of TBG, more thyroid hormone is bound to TBG and less thyroid hormone is free and unbound. The transiently decreased level of free hormone causes, by negative feedback, increased synthesis and secretion of thyroid hormones by the thyroid gland. In pregnancy, as a consequence of all these changes, levels of total T4 and T3 are increased (due to the increased level of TBG), but levels of free, physiologically active, thyroid hormones are normal and the person is said to be “clinically euthyroid.”

Circulating levels of TBG can be indirectly assessed with the T3 resin uptake test, which measures the binding of radioactive T3 to a synthetic resin. In the test, a standard amount of radioactive T3 is added to an assay system that contains a sample of the patient’s serum and the T3-binding resin. The rationale is that radioactive T3 will first bind to unoccupied sites on the patient’s TBG and any “leftover” radioactive T3 will bind to the resin. Thus, T3 resin uptake is increased when circulating levels of TBG are decreased (e.g., hepatic failure) or when endogenous T3 levels are increased (i.e., endogenous hormone occupies more sites than usual on TBG). Conversely, T3 resin uptake is decreased when circulating levels of TBG are increased (e.g., during pregnancy) or when endogenous T3 levels are decreased (i.e., endogenous hormone occupies fewer sites than usual on TBG).

Activation of T4 in Target Tissues

As noted, the major secretory product of the thyroid gland is T4, which is not the most active form of thyroid hormone. This “problem” is solved in the target tissues by the enzyme 5′ iodinase, which converts T4 to T3 by removing one atom of I2. The target tissues also convert a portion of the T4 to reverse T3 (rT3), which is inactive. Essentially, T4 serves as a precursor for T3, and the relative amounts of T4converted to T3 and rT3 determine how much activehormone is produced in the target tissue.

In starvation (fasting), target tissue 5′ iodinase plays an interesting role. Starvation inhibits 5′ iodinase in tissues such as skeletal muscle, thus lowering O2 consumption and basal metabolic rate during periods of caloric deprivation. However, brain 5′ iodinase differs from the 5′ iodinase in other tissues and is, therefore, not inhibited in starvation; in this way, brain levels of T3 are protected even during caloric deprivation.

Regulation of Thyroid Hormone Secretion

The factors that increase or decrease the secretion of thyroid hormones are summarized in Table 9-8. Major control of the synthesis and secretion of thyroid hormones is via the hypothalamic-pituitary axis (Fig. 9-19). Thyrotropin-releasing hormone (TRH) is secreted by the hypothalamus and acts on the thyrotrophs of the anterior pituitary to cause secretion of thyroid-stimulating hormone (TSH). TSH then acts on the thyroid gland to stimulate the synthesis and secretion of thyroid hormones.

Table 9–8 Factors Affecting Thyroid Hormone Secretion

Stimulatory Factors

Inhibitory Factors


Thyroid-stimulating immunoglobulins

Increased TBG levels (e.g., pregnancy)

I deficiency

Deiodinase deficiency

Excessive I intake (Wolff-Chaikoff effect)

Perchlorate; thiocyanate (inhibit Na+-I cotransport)

Propylthiouracil (inhibits peroxidase enzyme)

Decreased TBG levels (e.g., liver disease)

TBG, Thyroxine-binding globulin; TSH, thyroid-stimulating hormone.


Figure 9–19 Regulation of thyroid hormone secretion. TRH, Thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone; T3, triiodothyronine; T4, thyroxine.

image TRH, a tripeptide, is secreted by the paraventricular nuclei of the hypothalamus. TRH then acts on the thyrotrophs of the anterior pituitary to stimulate both transcription of the TSH gene and secretion of TSH. (Recall that the other action of TRH is to stimulate the secretion of prolactin by the anterior pituitary.)

image TSH, a glycoprotein, is secreted by the anterior lobe of the pituitary in response to stimulation by TRH. The role of TSH is to regulate the growth of the thyroid gland (i.e., a trophic effect) and the secretion of thyroid hormones by influencing several steps in the biosynthetic pathway. The thyrotrophs of the anterior pituitary develop and begin secreting TSH at approximately gestational week 13, the same time that the fetal thyroid gland begins secreting thyroid hormones.

TSH secretion is regulated by two reciprocal factors: (1) TRH from the hypothalamus stimulates the secretion of TSH, and (2) Thyroid hormones inhibit the secretion of TSH by down-regulating the TRH receptor on the thyrotrophs, thus decreasing their sensitivity to stimulation by TRH. This negative feedback effect of thyroid hormones is mediated by free T3, which is possible because the anterior lobe contains thyroid deiodinase (converting T4 to T3). The reciprocal regulation of TSH secretion by TRH and negative feedback by free T3 results in a relatively steady rate of TSH secretion, which, in turn, produces a steady rate of secretion of thyroid hormones (in contrast to growth hormone secretion, whose secretion is pulsatile).

image The actions of TSH on the thyroid gland are initiated when TSH binds to a membrane receptor, which is coupled to adenylyl cyclase via a Gs protein. Activation of adenylyl cyclase generates cAMP,which serves as the second messenger for TSH. TSH has two types of actions on the thyroid gland. (1) It increases the synthesis and secretion of thyroid hormones by stimulating each step in the biosynthetic pathway: I uptake and oxidation, organification of I2 into MIT and DIT, coupling of MIT and DIT to form T4 and T3, endocytosis, and proteolysis of thyroglobulin to release T4 and T3 for secretion. (2) TSH has a trophic effect on the thyroid gland. This trophic effect is exhibited when TSH levels are elevated for a sustained period of time and leads to hypertrophy and hyperplasia of thyroid follicular cells and increased thyroidal blood flow.

image The TSH receptor on the thyroid cells also is activated by thyroid-stimulating immunoglobulins, which are antibodies to the TSH receptor. Thyroid-stimulating immunoglobulins are components of the immunoglobulin G (IgG) fraction of plasma proteins. When these immunoglobulins bind to the TSH receptor, they produce the same response in thyroid cells as TSH: stimulation of thyroid hormone synthesis and secretion and hypertrophy and hyperplasia of the gland (i.e., hyperthyroidism). Graves disease, a common form of hyperthyroidism, is caused by increased circulating levels of thyroid-stimulating immunoglobulins. In this disorder, the thyroid gland is intensely stimulated by the antibodies, causing circulating levels of thyroid hormones to be increased. In Graves disease, TSH levels are actually lower than normal because the high circulating levels of thyroid hormones inhibit TSH secretion by negative feedback.

Actions of Thyroid Hormones

Thyroid hormones act on virtually every organ system in the human body (Fig. 9-20): Thyroid hormones act synergistically with growth hormone and somatomedins to promote bone formation; they increase basal metabolic rate (BMR), heat production, and oxygen consumption; and they alter the cardiovascular and respiratory systems to increase blood flow and oxygen delivery to the tissues.


Figure 9–20 Mechanism of action of thyroid hormones. Thyroxine (T4) is converted to triiodothyronine (T3) in target tissues. The actions of T3 on several organ systems are shown. BMR, Basal metabolic rate; CNS, central nervous system; DNA, deoxyribonucleic acid; mRNA, messenger ribonucleic acid.

The first step in the action of thyroid hormones in target tissues is conversion of T4 to T3 by 5′-iodinase. (Recall that T4 is secreted in far greater amounts than T3, but it also is much less active.) In an alternate pathway, T4 can be converted to rT3, which is physiologically inactive. Normally, the tissues produce T3 and rT3 in approximately equal amounts (T3, 45% and rT3, 55%). However, under certain conditions, the relative amounts may change. For example, pregnancy, fasting, stress, hepatic and renal failure, and β-adrenergic blocking agents all decrease the conversion of T4 to T3 (and increase conversion to rT3), thus decreasing the amount of the active hormone. Obesity increases the conversion of T4 to T3, increasing the amount of the active hormone.

Once T3 is produced inside the target cells, it enters the nucleus and binds to a nuclear receptor. The T3-receptor complex then binds to a thyroid-regulatory element on DNA, where it stimulates DNA transcription. The newly transcribed mRNAs are translated, and new proteins are synthesized. These new proteins are responsible for the multiple actions of thyroid hormones. Other T3 receptors located in ribosomes and mitochondria mediate posttranscriptional and posttranslational events.

A vast array of new proteins are synthesized under the direction of thyroid hormones, including Na+-K+ ATPase, transport proteins, β1-adrenergic receptors, lysosomal enzymes, proteolytic proteins, and structural proteins. The nature of the protein induced is specific to the target tissue. In most tissues, Na+-K+ ATPase synthesis is induced, which leads to increased oxygen consumption, BMR, and heat production. In myocardial cells, myosin, β1-adrenergic receptors, and Ca2+ ATPase are induced, accounting for thyroid hormone–induced increases in heart rate and contractility. In liver and adipose tissue, key metabolic enzymes are induced, leading to alterations in carbohydrate, fat, and protein metabolism.

The effects of thyroid hormone (T3) on various organ systems are as follows:

image Basal metabolic rate (BMR). One of the most significant and pronounced effects of thyroid hormone is increased oxygen consumption and a resulting increase in BMR and body temperature. Thyroid hormones increase oxygen consumption in all tissues except brain, gonads, and spleen by inducing the synthesis and increasing the activity of the Na+-K+ ATPase. The Na+-K+ ATPase is responsible for primary active transport of Na+ and K+ in all cells; this activity is highly correlated with and accounts for a large percentage of the total oxygen consumption and heat production in the body. Thus, when thyroid hormones increase Na+-K+ ATPase activity, they also increase oxygen consumption, BMR, and heat production.

image Metabolism. Ultimately, increased oxygen consumption depends on increased availability of substrates for oxidative metabolism. Thyroid hormones increase glucose absorption from the gastrointestinal tract and potentiate the effects of other hormones (e.g., catecholamines, glucagon, growth hormone) on gluconeogenesis, lipolysis, and proteolysis. Thyroid hormones increase both protein synthesis and degradation, but, overall, their effect is catabolic(i.e., net degradation), which results in decreased muscle mass. These metabolic effects occur because thyroid hormones induce the synthesis of key metabolic enzymes including cytochrome oxidase, NADPH cytochrome C reductase, α-glycerophosphate dehydrogenase, malic enzyme, and several proteolytic enzymes.

image Cardiovascular and respiratory. Because thyroid hormones increase O2 consumption, they create a higher demand for O2 in the tissues. Increased O2 delivery to the tissues is possible because thyroid hormones produce an increase in cardiac output and ventilation. The increase in cardiac output is the result of a combination of increased heart rate and increased stroke volume (increased contractility). These cardiac effects are explained by the fact that thyroid hormones induce the synthesis of (i.e., up-regulate) cardiac β1-adrenergic receptors. Recall that these β1 receptors mediate the effects of the sympathetic nervous system to increase heart rate and contractility. Thus, when thyroid hormone levels are high, the myocardium has an increased number of β1 receptors and is more sensitive to stimulation by the sympathetic nervous system. (In complementary actions, thyroid hormones also induce the synthesis of cardiac myosin and sarcoplasmic reticulum Ca2+ ATPase.)

image Growth. Thyroid hormone is required for growth to adult stature. Thyroid hormones act synergistically with growth hormone and somatomedins to promote bone formation. Thyroid hormones promote ossification and fusion of bone plates and bone maturation. In hypothyroidism, bone age is less than chronologic age.

image Central nervous system (CNS). Thyroid hormones have multiple effects on the CNS, and the impact of these effects is age dependent. In the perinatal period, thyroid hormone is essential for normal maturation of the CNS.Hypothyroidism in the perinatal period causes irreversible mental retardation. For this reason, screening of newborns for hypothyroidism is mandated; if it is detected in the newborn, thyroid hormone replacement can reverse the CNS effects. In adults, hypothyroidism causes listlessness, slowed movement, somnolence, impaired memory, and decreased mental capacity. Hyperthyroidism causes hyperexcitability, hyperreflexia, and irritability.

image Autonomic nervous system. Thyroid hormones interact with the sympathetic nervous system in ways that are not fully understood. Many of the effects of thyroid hormones on BMR, heat production, heart rate, and stroke volume are similar to those produced by catecholamines via β-adrenergic receptors. The effects of thyroid hormones and catecholamines on heat production, cardiac output, lipolysis, and gluconeogenesis appear to be synergistic. The significance of this synergism is illustrated by the effectiveness of β-adrenergic blocking agents (e.g., propranolol) in treating many of the symptoms of hyperthyroidism.

Pathophysiology of Thyroid Hormone

The most common endocrine abnormalities are disturbances of thyroid hormones. The constellation of signs and symptoms produced by an excess or a deficiency of thyroid hormones are predictable on the basis of the hormones’ physiologic actions. Thus, disturbances of thyroid hormones will affect growth, CNS function, BMR and heat production, nutrient metabolism, and the cardiovascular system. The symptoms of hyperthyroidism and hypothyroidism, common etiologies, TSH levels, and treatments are summarized in Table 9-9.

Table 9–9 Pathophysiology of Thyroid Hormones





Increased basal metabolic rate

Weight loss

Negative nitrogen balance

Increased heat production


Increased cardiac output

Dyspnea (shortness of breath)

Tremor, muscle weakness



Decreased basal metabolic rate

Weight gain

Positive nitrogen balance

Decreased heat production

Cold sensitivity

Decreased cardiac output


Lethargy, mental slowness

Drooping eyelids


Growth retardation

Mental retardation (perinatal)



Graves disease (increased thyroid-stimulating immunoglobulins)

Thyroid neoplasm

Excess TSH secretion

Exogenous T3 or T4 (factitious)

Thyroiditis (autoimmune or Hashimoto thyroiditis)

Surgery for hyperthyroidism

I deficiency

Congenital (cretinism)

Decreased TRH or TSH

TSH Levels

Decreased (feedback inhibition of T3 on the anterior lobe)

Increased (if defect is in anterior pituitary)

Increased (by negative feedback if primary defect is in thyroid gland)

Decreased (if defect is in hypothalamus or anterior pituitary)


Propylthiouracil (inhibits peroxidase enzyme and thyroid hormone synthesis)


131I (destroys thyroid)

β-Adrenergic blocking agents (adjunct therapy)

Thyroid hormone replacement therapy


The most common form of hyperthyroidism is Graves disease, an autoimmune disorder characterized by increased circulating levels of thyroid-stimulating immunoglobulins. These immunoglobulins are antibodies to TSH receptors on thyroid follicular cells. When present, the antibodies intensely stimulate the thyroid gland, resulting in increased secretion of thyroid hormones and hypertrophy of the gland. Other causes of hyperthyroidism are thyroid neoplasm, excessive secretion of TRH or TSH, and administration of excessive amounts of exogenous thyroid hormones.

The diagnosis of hyperthyroidism is based on symptoms and measurement of increased levels of T3 and T4. TSH levels may be decreased or increased, depending on the cause of the hyperthyroidism. If thecause of hyperthyroidism is Graves disease, thyroid neoplasm (i.e., the disorder is in the thyroid gland), or exogenous administration of thyroid hormones (factitious hyperthyroidism), then TSH levels will be decreased by negative feedback of the high levels of T3 on the anterior pituitary. However, if the cause of hyperthyroidism is increased secretion of TRH or TSH (i.e., the disorder is in the hypothalamus or anterior pituitary), then TSH levels will be increased.

The symptoms of hyperthyroidism are dramatic and include weight loss accompanied by increased food intake due to the increased metabolic rate; excessive heat production and sweating secondary to increased oxygen consumption; rapid heart rate due to up-regulation of β1 receptors in the heart; breathlessness on exertion; and tremor, nervousness, and weakness due to the CNS effects of thyroid hormones. The increased activity of the thyroid gland causes it to enlarge, called goiter. The goiter may compress the esophagus and cause difficulty in swallowing.

Treatment of hyperthyroidism includes administration of drugs such as propylthiouracil, which inhibit the synthesis of thyroid hormones; surgical removal of the gland; or radioactive ablation of the thyroid gland with 131I-.


The most common cause of hypothyroidism is autoimmune destruction of the thyroid gland (thyroiditis) in which antibodies may either frankly destroy the gland or block thyroid hormone synthesis. Other causes of hypothyroidism are surgical removal of the thyroid as treatment for hyperthyroidism, hypothalamic or pituitary failure, and I deficiency. Rarely, hypothyroidism is the result of target tissue resistance caused by down-regulation of thyroid-hormone receptors.

The diagnosis of hypothyroidism is based on symptoms and a finding of decreased levels of T3 and T4. Depending on the cause of the hypothyroidism, TSH levels may be increased or decreased. If the defect is in the thyroid gland (e.g., thyroiditis), TSH levels will be increased by negative feedback; the low circulating levels of T3 stimulate TSH secretion. If the defect is in the hypothalamus or pituitary, then TSH levels will be decreased.

The symptoms of hypothyroidism are opposite those seen in hyperthyroidism and include decreased metabolic rate and weight gain without increased food intake; decreased heat production and cold intolerance; decreased heart rate; slowing of movement, slurred speech, slowed mental activity, lethargy, and somnolence; periorbital puffiness; constipation; hair loss; and menstrual dysfunction. In some cases, myxedema develops, in which there is increased filtration of fluid out of the capillaries and edema due to accumulation of osmotically active mucopolysaccharides in interstitial fluid. When the cause of hypothyroidism is a defect in the thyroid, a goiter develops from the unrelenting stimulation of the thyroid gland by the high circulating levels of TSH. Finally, and of critical importance, if hypothyroidism occurs in the perinatal period and is untreated, it results in an irreversible form of growth and mental retardation called cretinism.

Treatment of hypothyroidism involves thyroid hormone replacement therapy, usually T4. Like endogenous hormone, exogenous T4 is converted to its active form, T3, in the target tissues.


Goiter (i.e., enlarged thyroid) can be associated with certain causes of hyperthyroidism and also, perhaps surprisingly, with certain causes of hypothyroidism and euthyroidism. The terms hyperthyroid, hypothyroid, and euthyroid describe, respectively, the clinical states of excess thyroid hormone, deficiency of thyroid hormone, and normal levels of thyroid hormone. Thus, they describe blood levels of thyroid hormone, not the size of the thyroid gland. The presence or absence of goiter can be understood only by analyzing the etiology of the various thyroid disorders. The central principle in understanding goiter is that high levels of TSH and substances that act like TSH (e.g., thyroid-stimulating immunoglobulins) have a trophic (growth) effect on the thyroid and cause it to enlarge.

image Graves disease. In Graves disease, the most common cause of hyperthyroidism, the high levels of thyroid-stimulating immunoglobulins drive excess secretion of T4 and T3 and also have a trophic effect on the thyroid gland to produce goiter. Although TSH levels are decreased (by negative feedback) in Graves disease, the trophic effect is due to the TSH-like effect of the immunoglobulins.

image TSH-secreting tumor. TSH-secreting tumors are an uncommon cause of hyperthyroidism. Increased levels of TSH drive the thyroid to secrete excess T4 and T3 and have a trophic effect on the thyroid gland to produce goiter.

image Ingestion of T4. Ingestion of exogenous thyroid hormones, or factitious hyperthyroidism, is associated with increased levels of thyroid hormone (from the ingestion), which causes decreased levels of TSH (by negative feedback). Because TSH levels are low there is no goiter; in fact, with time, the thyroid gland shrinks, or involutes.

image Autoimmune thyroiditis. Autoimmune thyroiditis is a common cause of hypothyroidism, in which thyroid hormone synthesis is impaired by antibodies to peroxidase, leading to decreased T4 and T3 secretion. TSH levels are increased (by negative feedback), and the resulting high levels of TSH have a trophic effect on the thyroid gland to produce goiter. That’s right! The gland enlarges even though it is not effectively synthesizing thyroid hormones.

image TSH deficiency (anterior pituitary failure). TSH deficiency is an uncommon cause of hypothyroidism, where the decreased levels of TSH cause decreased thyroid hormone secretion and no goiter.

image Ideficiency. Deficiency of I leads to transiently decreased synthesis of T4 and T3, which increases TSH secretion by negative feedback. Increased TSH levels then have a trophic effect on the gland, causing goiter. The enlarged gland (which is otherwise normal) can often maintain normal blood levels of thyroid hormone (due to the high TSH levels); in that case, the person will be clinically euthyroid and asymptomatic. If the gland cannot maintain normal blood levels of thyroid hormone, then the person will be clinically hypothyroid.