Electron micrograph of a parafollicular cell. Cytoplasmic processes of follicular cells (arrows) partially surround the parafollicular cell (PC), which contains numerous electron-dense granules and a prominent Golgi apparatus (G). A basal lamina (BL) is associated with the follicu lar cells (FC). A portion of the central mass of colloidal material (C) in two adjacent follicles can be seen in the left corners of the micrograph. xl2,000. (Courtesy of Dr. Emmanuel-Adrien Nunez.)
table 20.7. Hormones of the Thyroid Gland
(tetraiodothyronine, T„ and triiodothyronine
Composition lodinated tyrosine derivatives
Polypeptide containing 32 amino acids
Follicular cells (principal cells)
Parafollicular cells (C cells)
Regulates tissue basal metabolism (increases rate of carbohydrate use, protein synthesis and degradation, and fat synthesis and degradation); regulates heat production; influences body and tissue growth and development of the nervous system in the fetus and young child"; increases absorption of carbohydrates from the intestine
Decreases blood calcium levels by inhibiting bone resorption and stimulating absorption of calcium by the bones
"Thyroid gland secretes substantially more T„ than T3; however about 40% of T4 is peripherally converted to T3) which acts more rapidly and is a more potent hormone.
"Deficiency of T3 and T„ during development results in fewer and smaller neurons, defective myelination, and mental retardation.
cells. Both hormones regulate cell and tissue basal metabolism and heat production and influence body growth and development. Secretion of these hormones is regulated by TSH released from the anterior lobe of the pituitary gland. • Calcitonin (thyrocalcitonin) is synthesized by the parafollicular cells (C cells) and is a physiologic antagonist to parathyroid hormone (PTH). Calcitonin lowers blood calcium levels by suppressing the resorptive action of osteoclasts and promotes calcium deposition in bones by increasing the rate of osteoid calcification. Secretion of calcitonin is regulated directly by blood calcium levels. High levels of calcium stimulate secretion; low levels inhibit it. Secretion of calcitonin is unaffected by the hypothalamus and pituitary gland. Although calcitonin is used to treat patients with hypercalcemia, no clinical disease has been associated with its deficiency or even its absence after total thyroidectomy.
The principal component of colloid is thyroglobulin, an inactive storage form of thyroid hormones
The principal component of colloid is a large (660 kDa) iodinated glycoprotein called thyroglobulin containing about 120 tyrosine residues. Colloid also contains several enzymes and other glycoproteins. It stains with both basic and acidic dyes and is strongly PAS positive. Thyroglobulin is not a hormone. It is an inactive storage form of the thyroid hormones. Active thyroid hormones are liberated from thyroglobulin and released into the fenestrated blood capillaries that surround the follicles only after further cellular processing. The thyroid is unique among endocrine glands because it stores large amounts of its secretory product extracellularly.
The synthesis of the two major thyroid hormones, thyroxine (T4) and T, takes place in the thyroid follicle in a series of discrete steps (see Fig. 20.13):
1. Synthesis of thyroglobulin. The precursor of thyroglobulin is synthesized in the rER of the follicular epithelial cells; it is glycosylated there and in the Golgi apparatus before it is packaged into vesicles and secreted by exocytosis into the lumen of the follicle.
2. Resorption, diffusion, and oxidation of iodide. Follicular epithelial cells actively transport iodide from the blood into their cytoplasm using ATP-dependent iodide transporters. These cells can establish an intracellular concentration of iodide that is 30 to 40 times greater than that of the serum. Iodide ions then diffuse rapidly toward the apical cell membrane where they are oxidized to iodine, the active form of iodide. This process occurs in the apical cytoplasm and is catalyzed by membrane-bound thyroid peroxidase. After oxidation the iodine is then released into the colloid.
3. Iodination of thyroglobulin. One or two iodine atoms are then added to the specific tyrosine residues of thyroglobulin. This process occurs in the colloid at the microvillar surface of the follicular cells and is also catalyzed by thyroid peroxidase. Addition of one iodine atom to a single tyrosine residue forms monoiodotyrosine (MIT). Addition of a second iodine atom to the MIT residue forms a diiodotyrosine (DIT) residue.
4. Formation ofT3 and T4 by oxidative coupling reactions. The thyroid hormones are formed by oxidative coupling reactions of two iodinated tyrosine residues in close proximity. For example, when neighboring DIT and MIT residues undergo a coupling reaction, T3 is formed; when two DIT residues react with each other, T4 is formed. After iodination, T4 and T3 as well as the DIT and MIT residues that are still linked to a thyroglobulin molecule are stored as the colloid within the lumen of the follicle.
5. Resorption of colloid. In response to TSFI, follicular cells take up thyroglobulin from the colloid by a process of receptor-mediated endocytosis. Large endo-cytotic vesicles called colloidal resorption droplets are present at this stage in the apical region of the follicular cells. They gradually migrate to the basal surface of the cells, where they fuse with lysosomes. Thyroglobulin is then degraded by lysosomal proteases into constituent amino acids and carbohydrates, leaving free T4, T3, DIT, and MIT molecules. If the levels of TSH remain high, the amount of colloid in the follicle is reduced because it is synthesized, secreted, iodinated, and resorbed too rapidly to accumulate.
6. Release of T4 and T3 into the circulation and recycling processes. T., and T, are liberated from thyroglobulin by lysosomal action in a T4-to-T3 ratio of 20:1. They cross the basal membrane and enter the blood and lymphatic capillaries. Most of the released hormones are immediately bound to either a specific plasma protein (54 kDa), thyroxin-binding protein (70%), or a nonspecific prealbumin fraction of serum protein (25%), leaving only small amounts (-5%) of free circulating hormones that are metabolically active. Only the follicular cells are capable of producing T4, whereas most T,, which is five times more active than T4, is produced through conversion from T4 by organs such as the kidney, liver, and heart. The free circulating hormones also function in the feedback system that regulates the secretory activity of the thyroid. Once uncoupled from thyroglobulin, DIT and MIT molecules are further deiodinated within the cytoplasm of the follicular cells to release the amino acid tyrosine and iodide, which are then available for recycling.
Functional Considerations: Feedback Control of Thyroid Hormone Synthesis
Synthesis of T3 and T4 is regulated by a simple feedback system. The secretion of thyroid hormones is controlled by the release of TSH from the anterior lobe of the pituitary gland into the bloodstream. Under the influence of TSH, thyroid follicular epithelial cells increase in size and activity. The cells become more columnar, and the iodide transporters and extracellular iodination of thyroglobuiin are stimulated. In addition, thy-roglobulin synthesis, endocytosis, and lysosomal breakdown increase, resulting in the release of large amounts of thyroid hormones. Low levels of free T3 and T„ initiate the release of TRH from the hypothalamus. In turn, TRH stimulates thy-rotropes in the anterior lobe of the pituitary gland to secrete TSH. High serum levels of free T3 and T, inhibit the synthesis and release of TSH.
Thyroid hormones play an essential role in normal fetal development
In humans, thyroid hormones are essential to normal growth and development. In normal pregnancy both T3 and T4 cross the placental barrier and are critical in the early stages of brain development. In addition, the fetal thyroid gland begins to function during the fourteenth week of gestation and also contributes additional thyroid
Hypothyroidism can be caused by insufficient dietary iodine (iodine-deficiency goiter, endemic goiter) or by one of several inherited autoimmune diseases, such as Hashimoto's thyroiditis. The low levels of circulating thyroid hormone stimulate release of excessive amounts of TSH, which cause hypertrophy of the thyroid through synthesis of more thyroglobuiin. Adult hypothyroidism is called myxedema and is characterized by mental and physical sluggishness and edema of the connective tissue.
In hyperthyroidism (toxic goiter, Graves' disease), thyroid cells are stimulated and increase in number and size. However, there is little colloid. Thyroid hormones secreted at abnormally high rates cause an increase in metabolism. Often, toxic amounts of hormones are produced (thyrotoxicosis). Levels of TSH are usually normal in hyperthyroidism. In some cases, an abnormal immunoglobulin called long-acting thyroid stimulator (LATS) appears to bind to the TSH receptors on the follicular cells, which leads to continuous stimulation of the cells.
hormones. Thyroid hormone deficiency during fetal development results in irreversible damage to the CNS, including reduced numbers of neurons, defective myelination, and mental retardation. If maternal thyroid deficiency is present prior to the development of the fetal thyroid gland, the mental retardation is severe. Recent studies reveal that thyroid hormones also stimulate gene expression for GH in the somatotropes. Therefore, in addition to neural abnormalities, a generalized stunted body growth is typical. The combination of these two abnormalities is called congenital hypothyroidism (cretinism).
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