Biosynthesis

The two thyroid hormones, thyroxine (3,5,3′,5′-tetraiodothyronine) and 3,5,3′-triiodothyronine, are formed by the addition of iodine to an amino acid (tyrosine) component of a glycoprotein called thyroglobulin. Thyroglobulin is stored within the gland in follicles as the main component of a substance called the thyroid colloid. This arrangement, which provides a reserve of thyroid hormones, perhaps reflects the frequent scarcity of environmental iodine, particularly on land and in fresh water. Iodine is most abundant in the sea, where thyroidal biosynthesis probably first evolved. Although the possibility that the thyroid hormones originated as metabolic by-products is suggested by the widespread occurrence in animals of the binding of iodine to tyrosine, the binding commonly results only in the formation of iodotyrosines, not the thyroid hormones. Evidence suggests that only the vertebrates and the closely related protochordates have a mechanism to synthesize significant amounts of biologically active thyroid hormones.

The synthesis of thyroid hormones in vertebrates begins with the active uptake by thyroid-gland cells of inorganic iodide circulating in the bloodstream; the inorganic iodide is oxidized (combined with oxygen) during a reaction catalyzed by an enzyme (iodide peroxidase). The product of this reaction (active iodine) combines with tyrosine components of the thyroglobulin molecule to form two compounds (3-monoiodotyrosine and 3,5-diiodotyrosine), which then join to form the active hormones. The synthesis of the thyroid hormones is inhibited by certain chemical agents called goitrogens, which reduce the output of thyroid hormones, thereby causing, through negative feedback, an increased output of thyrotropin and hence an enlargement of the thyroid gland. Some goitrogens (e.g., thiocyanates) reduce or inhibit the uptake of iodide; others (e.g., thiourea, thiouracil) inhibit the peroxidase system and thus prevent the binding of iodine to thyroglobulin.

Release of the thyroid hormones into the bloodstream begins when the thyroid cells take up droplets of the stored thyroid colloid. The thyroglobulin in these droplets is then hydrolyzed (broken down in a reaction involving the elements of water) by an enzyme to form both iodotyrosines and the hormones. Normally, only the latter pass out of the cells in significant quantities. The iodine is removed from the iodotyrosines, which are not hormonally active, by an enzyme (deiodinase), and the iodine thus is conserved and used again. The hormones, usually bound to proteins (globulin and albumin) in the bloodstream, where they constitute the protein-bound iodine of the plasma, must be unbound from the proteins before they can function. The iodine is removed from the hormones largely in the liver and in the kidneys, and most of it returns to the thyroid gland, an economy that again emphasizes the need for conservation; some iodine, however, is lost in the alimentary tract.

Synthesis of the thyroid hormones is regulated by the level of circulating hormones (i.e., a negative feedback mechanism) operating, as indicated earlier, partly by direct action on the thyrotropin-secreting cells of the pituitary gland and partly by indirect action on the hypothalamus and its thyrotropin-releasing hormone. Thyrotropin attaches to the cells of the thyroid gland and may exert its effect by stimulating CAMP synthesis. It causes resorption of thyroid colloid and increases the rates of both glucose metabolism and protein synthesis as secretion of thyroid hormones increases in response to it. After the thyroid gland of the rat has been under thyrotropin stimulation for two or three hours, an increase in the size of the cells of the gland occurs, along with an increase in iodide uptake into them; prolonged thyrotropin action causes a marked enlargement of the gland (goitre), which in humans may become externally apparent as a swelling. Goitres, which are of various types, result from a negative feedback reaction that attempts to maintain output from the thyroid gland.

Effects

One established effect of the thyroid hormones in mammals is an increase in metabolic rate and in oxygen consumption, but the effects of the hormones undoubtedly are more wide-ranging than this. On the one hand, impairment of the thyroid function in mammals results in disturbances in the processes of growth and maturation. Both growth and maturation disturbances occur in the cretinous dwarfism resulting from thyroid deficiency in newborn infants; on the other hand, the metabolic effect is not apparent in lower vertebrates (e.g., fish), even though treatment of these animals with thyroid hormones promotes an increase in the growth rate, provided pituitary growth hormone is also secreted. In addition, evidence suggests that, in lower vertebrates, the thyroid hormones are active during moments of stress in the life cycle (e.g., migration and reproduction) and affect the activity of the central nervous system. Disturbance of thyroid output also affects reproduction in mammals, impairing the functioning of the ovary, for example, and causing irregularities of the ovarian cycle.

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therapeutics: Hormones

The complex effects of thyroid hormones are well documented in the metamorphosis, or change in body form, of the amphibian tadpole into a frog. Metamorphosis, which involves a diversity of integrated morphological and biochemical changes, requires the presence of the thyroid gland and depends upon a delicate balance between the changing output of its hormones and changing sensitivities of the target tissues. Studies involving the tail of the frog tadpole show that the thyroid hormones directly promote the formation of the enzymes needed for reduction of the tail and suggest that the diverse effects produced in vertebrates by the thyroid hormones might depend upon their capacity to regulate protein metabolism, in which case the target cells would have to be adapted to respond by appropriate patterns of enzyme synthesis.

Ultimobranchial tissue and calcitonin

The discovery of calcitonin (thyrocalcitonin) in 1961 demonstrated the importance of comparative studies in endocrinology. It originally had been thought that this hormone, which is present in preparations made from mammalian thyroid glands, was secreted by the parathyroid glands, which in some species are combined with the thyroid gland. Later, the hormone was concluded to be a secretion of the thyroid gland itself. In fact, calcitonin is not a product of either of them. Its actual source is the ultimobranchial tissue, represented in vertebrates from fishes upward by the ultimobranchial gland, which develops from the hinder part of the pharynx. Ultimobranchial tissue is the source of distinctive cells (called light, C, or parafollicular cells), which are found in the thyroid gland of mammals; in birds, however, the ultimobranchial gland is separate, thus making it possible to remove the gland and to show that it is the source of the hormone. The molecular structure of hog calcitonin is that of a polypeptide, containing 32 amino acids and having a molecular weight of about 3,400. The calcitonin of the salmon, which is more potent than that of the pig, has the same number (but some different types) of amino acids, and the molecular weight is about 3,430.

Calcitonin lowers the level of calcium in the blood (hypocalcemic action) when it rises above the normal level. Its secretion probably is regulated by a negative feedback relationship between the gland and the blood plasma. The hormone affects bone, which is an active tissue. It undergoes not only growth but also remodeling as it adapts to the changing patterns of stress to which it is subjected; its calcium exchanges continuously with that of the plasma. The effect of calcitonin is to decrease the mobilization (resorption) of calcium from the skeleton into the blood plasma. In this respect, it is opposite in direction to the effect of parathormone of the parathyroid glands. Little is known of the action of calcitonin in the lower vertebrates, but its presence in fish raises interesting functional problems. Elasmobranch fishes (e.g., sharks) lack bone, and many bony fishes have a type of bone that cannot be remodeled; the hormone, therefore, cannot act in these vertebrates as it does in higher ones. It is possible that in these fishes the hormone may control the level of plasma calcium by regulating its movement across cell membranes.