The thyroid gland is a bilateral organ that bridges the lower larynx and upper trachea with a narrow isthmus. A third pyramidal lobe, remnant of the thyroglossal duct, is not unusual. As one of the most vascularized endocrines, it receives blood from the superior thyroid arteries, branches of the external carotid artery, and is drained by corresponding veins into the internal jugular vein. In normal individuals, vascularity, size and microscopic structures vary with the levels of the pituitary tropic hormone, thyroid-stimulating hormone (TSH) or thyrotropin, nutrition, temperature, sex and age.

The functional units of the thyroid gland are multiple, variable-sized follicles, formed by a single layer of epithelial cells, filled with colloid (a proteinaceous material containing thyroglobulin, a glycoprotein necessary for the synthesis of T3 and T4). At high magnification the cell surface lining the follicle is rich in microvilli that project into the follicular lumen where the colloid is secreted; hormones are secreted into the blood at the opposite basal cell pole adjoining the rich capillary net.

The control of the thyroid gland cannot be viewed in isolation but must be considered in the context of:
1. regulation at the hypothalamo-pituitary axis,
2 thyroid hormone metabolism and
3. interactions with receptors at target cells.

These connected levels of integration can be briefly outlined as follows:
1. At the level of the hypothalamus, thyrotropin-releasing hormone or TRH, a tripeptide, is secreted into the portal capillaries relaying secreted TRH to the anterior pituitary. There, TRH stimulates the anterior lobe thyrotropes to synthesize and release thyroid-stimulating hormone or thyrotropin or TSH. Secretion of TSH is, in turn, inhibited by the negative feedback of thyroid hormones and stimulated or inhibited by stimuli from higher brain centers in response to environmental changes.

2. At the pituitary level, TSH is a glycoprotein secreted by the basophilic thyrotropes. TSH secretion is regulated by negative feedback of thyroid hormones, i.e. the higher the serum levels of these hormones, the lower TSH release and vice versa, and stimulation from TRH. In the absence of TSH (e.g. by hypophysectomy in experimental animals) thyroid function is depressed and the thyroid gland atrophies; administration of TSH stimulates the thyroid gland and increases circulating levels of thyroid hormones.

3. At the thyroid level, thyroid hormones, thyroxine, T4, triiodothyronine, T3, and to a much lesser extent, reverse T3, rT3, are iodothyronines, iodine-containing derivatives of the amino acid tyrosine. They are synthesized by iodination and condensation of the tyrosyl residues of thyroglobulin molecules stored in the colloid of the thyroid follicle. Iodinated thyroglobulin enters the thyroid cells by endocytosis and is hydrolyzed there to liberate T4 and T3 which are released into the circulation. Cells of the thyroid gland contain TSH receptors. Binding of TSH to its receptors activates the enzyme adenylate cyclase with increase in intracellular cAMP. Most of TSH actions are mediated through this cAMP increase but some depend on stimulation of cell membrane phospholipids.

The major secreted product of the thyroid gland is T4 while T3 is secreted only in small amounts and derives mainly from the peripheral deiodination of T4. One third of circulating T4 is converted to T3 in peripheral tissues. Both hormones are present in serum either bound to proteins or in the free state. T3 is less tightly bound to plasma proteins than is T4 and is therefore more readily available for cellular uptake. The free hormone is biologically active and interacts with specific receptors localized in the membrane, mitochondria, cytoplasm and nucleus of responsive cells. T3 binds to nuclear receptors to a much greater extent than T4, hence T3 is more rapidly and biologically active than T4. T3 and T4 are deiodinated and deaminated in the tissues. In the liver, they are conjugated, pass into the bile and are excreted into the intestine. Conjugated and free hormones are also excreted by the kidney.

This aspect of thyroid function may be summarized by pointing out that:
1. the major source of circulating T3 is not from thyroid secretion, but from peripheral deiodination of T4;
2. the negative feedback at the pituitary anterior lobe is principally through T4 taken from the circulation and converted in the thyrotrope to T3 by thyrotrope deiodinase;
3. the peripheral deiodination depends on the physiological state of the organism. It allows an autonomy of response of the tissues to the hormones. Deiodination can convert T4 (a less active hormone) to T3 (a more active hormone) or not. The conversion depends on activities of the various deiodinating enzymes.