Thyroid hormones are synthesized in the thyroid gland by the iodination and coupling of two molecules of the amino acid tyrosine, a process that is dependent on an adequate supply of iodide. Iodide in the diet is absorbed rapidly from the small intestine. In areas where the iodide content of the soil is very low, there used to be a high incidence of enlargement of the thyroid gland (goitre), but the general use of artificially iodized salt has made this a less common occurrence. Seafoods generally have a high iodide content. Therefore fish and iodized salt are the main dietary sources of the element. Normally about a third of dietary iodide is taken up by the thyroid gland and the rest is renally excreted.
Synthesis of thyroid hormones
Iodide is actively taken up by the thyroid gland under the control of thyroid-stimulating hormone (TSH
) via a sodium/iodide symporter. Uptake is blocked by thiocyanate and perchlorate. The concentration of iodide in the gland is at least 20 times that in plasma and may exceed it by 100 times or more.
Iodide is rapidly converted to iodine within the thyroid gland, catalysed by thyroid peroxidase (TPO
). Iodination of tyrosine residues in a large 660-kDa glycoprotein, thyroglobulin, takes place to form mono-iodotyrosine (MIT
) and di-iodotyrosine (DIT
) mediated by the enzyme TPO
. This step is inhibited by carbimazole and propylthiouracil.
Iodotyrosines are coupled to form T4
) and T3
) (Fig. 11.1
), which are stored in the lumen of the thyroid follicular cells. Normally much more T4
is synthesized, but, if there is an inadequate supply of iodide, the ratio of T3
in the gland increases. The thyroid hormones, still incorporated in thyroglobulin, are stored in the colloid of the thyroid follicle.
Prior to the secretion of thyroid hormones, thyroglobulin is taken up by the follicular cells, by a process involving endocytosis and then phagocytosis, and T4
are released by proteolytic enzymes into the bloodstream. This process is stimulated by TSH
and inhibited by iodide. The thyroid hormones are immediately bound to plasma proteins. Monoiodotyrosine and DIT
, released at the same time, are de-iodinated and the iodine is reused.
Each step is controlled by specific enzymes, and congenital deficiency of any of these enzymes can lead to goitre and, if severe, hypothyroidism. The uptake of iodide, as well as the synthesis and secretion of thyroid hormones, is regulated by TSH
, secreted from the anterior pituitary gland. About 10 times more T4
is formed, with most of the latter being formed by de-iodination in the liver, kidneys and muscle.
Figure 11.1 Chemical structure of the thyroid hormones.
Protein binding of thyroid hormones in plasma
Most of the plasma T4
is protein bound, mainly (70 per cent) to an α-globulin, thyroxine-binding globulin (TBG
), and, to a lesser extent (15 per cent), transthyretin (previously called pre-albumin), with about 10-15 per cent bound to albumin. In keeping with many other hormones, the free unbound fraction is the physiologically active form, which also regulates TSH
secretion from the anterior pituitary. Modern laboratory assays tend to measure the free hormones. Changes in the plasma concentrations of the binding proteins, particularly TBG
, alter plasma total T4
concentrations, but not the concentrations of free hormones.
Peripheral conversion of thyroid hormone
Some of the circulating T4
is de-iodinated by enzymes in peripheral tissues, especially in the liver and kidneys. About 80 per cent of the plasma T3
is produced by the removal of an iodine atom from the outer (β) ring; the remaining 20 per cent is secreted by the thyroid gland. De-iodination of the inner (a) ring produces reverse T3
, which is probably inactive. The T3
binds more avidly to thyroid receptors than T4
and is the main active form. The conversion of T4
reduced by many factors, of which the most important are:
increased by drugs that induce hepatic enzyme activity, such as phenytoin.
The plasma T3
concentration is therefore a poor indicator of thyroid hormone secretion because it is influenced by many non-thyroidal factors and its measurement is rarely indicated, except if thyrotoxicosis is suspected.
Action of thyroid hormones
Thyroid hormones affect many metabolic processes, increasing oxygen consumption. They bind to specific receptors in cell nuclei and change the expression of certain genes. Thyroid hormones are essential for normal growth, mental development and sexual maturation and also increase the sensitivity of the cardiovascular and central nervous systems to catecholamines, thereby influencing cardiac output and heart rate.
Control of thyroid-stimulating hormone secretion
Thyroid-stimulating hormone stimulates the synthesis and release of thyroid hormones from the thyroid gland. Its secretion from the anterior pituitary gland is controlled by thyrotrophin-releasing hormone (TRH
) and circulating concentrations of thyroid hormones.
Effect of thyrotrophin-releasing hormone
synthesis and release are stimulated by TRH
, a tripeptide produced in the hypothalamus and released into the portal capillary plexus. The action of TRH
can be over-ridden by high circulating free T4
) concentrations, and therefore exogenous TRH
has little effect on TSH
secretion in hyperthyroidism (see later for TRH
test). Once TRH
reaches the pituitary, it binds to TRH
receptors, members of the seven-transmembrane-spanning receptor family, which are coupled to G proteins.
Effects of thyroid hormones in the control of thyroidstimulating hormone secretion
Thyroid hormones reduce TSH
secretion by negative feedback. Tri-iodothyronine binds to anterior pituitary nuclear receptors. In the anterior pituitary gland, most of the intracellular T3
is derived from circulating fT4
. Therefore this gland is more sensitive to changes in plasma T4
than to T3
The secretion and control of thyroid hormones is summarized in Figure 11.2