Regulation Of Thyroid Function

Effects of Thyroid-Stimulating Hormone

Although the thyroid gland can carry out all of the steps of hormone biosynthesis, storage, and secretion in the absence of any external signals, autonomous function is far too sluggish to meet bodily needs for thyroid hormone. The principal regulator of thyroid function is the thyroid-stimulating hormone (TSH), which is secreted by thyrotropes in the pituitary gland (see Chapter 38). It may be recalled that TSH consists of two glycosylated peptide subunits including the same ^-subunit that is also found in FSH, and LH (Chap. 38). The ^-subunit is the part of the hormone that confers thyroid-specific stimulating activity, but free ^-subunits are inactive, and stimulate the thyroid only when linked to a-subunits in a complex three dimensional configuration.

Thyroid-stimulating hormone binds to a single class of heptihelical G protein-coupled receptors (see Chapter 2) in the basolateral surface membranes of thyroid follicular cells. The TSH receptor is the product of a single gene, but it is comprised of two subunits held together by a disulfide bond. It appears that after the molecule has been properly folded and its disulfide bonds formed, a loop of about 50 amino acids is excised proteolytically from the extracellular portion of the receptor. The a-subunit includes about 300 residues at the amino terminus and contains most of the TSH binding surfaces. The ^-subunit contains the seven-membrane-spanning a-helices and the short carboxyl-terminal tail in the cytoplasm. Reduction of the disulfide bond may lead to release of the a-subunit into the extracellular fluid, and may have important implications for the development of antibodies to the TSH receptor and thyroid disease (see below). Binding of TSH to the receptor results in activation of both adenylyl cyclase through Gas and phospholipase C through Gaq and leads to increases in both the cyclic AMP and diacyl-glycerol/IP3 second messenger pathways (see Chapter 2). Activation of the cyclic AMP pathway appears to be the more important transduction mechanism because all of the known effects of TSH can be duplicated by cyclic AMP. Because TSH increases cyclic AMP production at much lower concentrations than are needed to increase phospholipid turnover, it is likely that IP3 and DAG are redundant mediators that reinforce the effects of cyclic AMP at times of intense stimulation, but it is also possible that these second messengers signal some unique responses. Increased turnover of phospholipid is associated with release of arachidonic acid and the consequent increased production of prostaglandins that also follows TSH stimulation of the thyroid.

In addition to regulating all aspects of hormone biosynthesis and secretion, TSH increases blood flow to the thyroid, and with prolonged stimulation TSH also increases the height of the follicular epithelium (hypertrophy) and can stimulate division of follicular cells (hyperplasia). Stimulation of thyroid follicular cells by TSH is a good example of a pleiotropic effect of a hormone in which multiple separate but complementary actions sum to produce an overall response. Each step of hormone biosynthesis, storage, and secretion appears to be directly stimulated by a cyclic AMP-dependent process that is accelerated independently of the preceding or following steps in the pathway. Thus, even when increased iodide transport is blocked with a drug that specifically affects the iodide pump, TSH nevertheless accelerates the remaining steps in the synthetic and secretory process. Similarly, when iodination of tyrosine is blocked by a drug specific for the organification process, TSH still stimulates iodide transport and thyroglobulin synthesis.

Most of the responses to TSH depend on activation of protein kinase A and the resultant phosphorylation of proteins including transcription factors such as CREB (cyclic AMP response element-binding protein; see Chapter 2). TSH increases expression of the genes for the sodium iodide symporter, thyroglobulin, thyroid oxidase, and thyroid peroxidase. These effects are exerted through cooperative interactions of TSH-activated nuclear proteins with thyroid-specific transcription factors whose expression is also enhanced by TSH. TSH appears to increase blood flow by activating the gene for nitric oxide synthase, which increases production of the potent vasodilator, nitric oxide, and by inducing expression of paracrine factors that promote capillary growth (angiogenesis). Precisely how TSH increases thyroid growth is not understood, but it is apparent that synthesis and secretion of a variety of local growth factors is induced.

Autoregulation of Thyroid Hormone Synthesis

Although production of thyroid hormones is severely impaired when too little iodide is available, iodide uptake and hormone biosynthesis are temporarily blocked when the concentration of iodide in blood plasma becomes too high. This effect of iodide has been exploited clinically to produce short-term suppression of thyroid hormone secretion. This inhibitory effect of iodide apparently depends on its being incorporated into some organic molecule and is thought to represent an autoregulatory phenomenon that protects against overproduction of thyroxine. Blockade of thyroid hormone production is short lived, and the gland eventually "escapes" from the inhibitory effects of iodide by mechanisms that include down-regulation of the sodium iodide symporter.

Biosynthetic activity of the thyroid gland may also be regulated by the thyroglobulin that accumulates in the follicular lumen. Evidence has been presented that thyroglobulin, acting through a receptor on the apical

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