oxidized iodine to the amino acid tyrosine to generate mono- and diiodotyrosine (MIT and DIT, respectively), and the coupling of a MIT and a DIT to generate T3, and two DITs to generate T4. T4 and T3 are then secreted into the peripheral circulation where they are tightly bound to plasma proteins, primarily the thyroid-hormone binding globulin (TBG), an inter alpha globulin. Very small fractions of the circulating hormones are not bound to TBG, and these free or unbound hormones are available to enter all peripheral cells. It is generally recognized that T3, not T4, is the bioactive hormone and that the major source of T3 is not the thyroid but, in the peripheral tissues, the removal of an iodine from the outer or phenolic ring of T4 by a selenoenzyme, 5'-deiodinase. T3 binds to T3 nuclear receptors in the cells of the peripheral tissues and stimulates a wide variety of genomic events that result in enhanced protein synthesis and increased metabolism.
Central nervous system control of thyroid function resides in the anterior hypothalamus, which synthesizes and secretes a tripeptide, thyrotropin-releasing hormone (TRH), into the hypothalamic-pituitary portal circulation. TRH binds to the TRH receptor on the beta cells of the anterior pituitary to stimulate and release into the peripheral circulation the glycoprotein, thyroid-stimulating hormone (thyrotropin or TSH), which consists of an alpha (α) subunit and a beta (β) subunit. The β subunit binds to the TSH receptor on the basal cell surface of the thyroid cell, stimulates the synthesis of the iodine-rich thyroid hormones, T4 and T3, and releases them into the peripheral circulation.
It is evident that to maintain normal thyroid function (euthyroidism), the synthesis of the thyroid hormones and their release from the thyroid must be under tight control. That is accomplished by the classical negative-feedback system so typical of endocrine systems. Thus, a small rise in the circulating free thyroid hormones results in a decrease in the release of TSH from the anterior pituitary and, less so, TRH from the hypothalamus, thereby decreasing T4 and T3 synthesis and their release from the thyroid and maintaining euthyroidism. In contrast, a small decrease in circulating T4 and T3 concentrations enhances the release of TSH from the anterior pituitary and, less so, TRH from the anterior hypothalamus