Thyroid hormone regulation, feedback

Outline of the Feedback Loop in Thyroid Hormone Regulation. 388... 

If the feedback hypothesis of thyroid hormone regulation is correct, TSH levels in the blood of hypothyroid people should be increased. Several reports (Table 1) confirm this, including reports based on studies using radioimmunoassay techniques. TSH levels decline when patients are treated by thyroid hormone replacement (02). This does not apply when the hypothyroidism is secondary to pituitary dysfunction. 

Thyroid hormone production is regulated by TSH secreted by the anterior pituitary, which in turn is under negative feedback control by the circulating level of free thyroid hormone and the positive influence of hypothalamic thyrotropin-releasing hormone. Thyroid hormone production is also regulated by extrathyroidal deiodination of T4 to T3, which can be affected by nutrition, nonthyroidal hormones, drugs, and illness. 

Thyroid hormones accelerate metabolism. Their release (A) is regulated by the hypophyseal glycoprotein TSH, whose release, in turn, is controlled by the hypothalamic tripeptide TRH. Secretion of TSH declines as the blood level of thyroid hormones rises by means of this negative feedback mechanism, hormone production is automatically adjusted to demand. 

Regulation of secretion Secretion of TSH by the anterior pituitary is stimulated by the hypothalamic TRH. Feedback inhibition of both TRH and TSH secretion occurs with high levels of circulating thyroid hormone or iodide. Most of the hormone (T3 and T4) is bound to thyroxine-binding globulin in the plasma. 

Animals employ several mechanisms to prevent excessive hormone synthesis and release. The most prominent of these is feedback inhibition. The hypothalamus and anterior pituitary are controlled by the target cells they regulate. For example, TSH release by the anterior pituitary is inhibited when blood levels of T3 and T4 rise (Figure 16.10). The thyroid hormones inhibit the responsiveness of TSH-synthesizing cells to TRH. In addition, several tropic hormones inhibit the synthesis of their releasing factors. 

The components of the hypothalamie-pituitary-thyroid axis are outlined in Figure 2. TRH, a tripeptide, is secreted by the hypothalamus and in turn causes the synthesis of a large glycoprotein hormone. TSH. from the anterior pituitary. This drives the synthesis of thyroid hormones by the thyroid. Production of TSH is regulated by feedback from circulating unbound thyroid hormones. A knowledge of these basics is essential for the correct interpretation of results in the investigation of thyroid disease. Remember ... 

T.SH is the feedback of thyroid hormone activity on the pituitary, and to a lesser extent on the hypothalamus. Other factors also play a role. There is a diurnal rhythm with the serum TSH peaking around midday when the concentration is approximately 30% higher than at midnight, when it isaliLsnadir. Insy.stemic illness the normal regulation of TSH.Tj and T, secretion, and the subsequent metabolism of the thyroid hormones, is disturbed. Increased amounts of T are converted to the biologically inactive reverse Tj, rather than to T,. The resultant reduction in thyroid hormone activity does not result in an increased serum TSH concentration. TSH secretion is also suppressed, and the secretion of T and T, by the thyroid gland is therefore decreased. 

Thyroid hormones enter the extrathyroidal tissues by the action of specific transporters the organic anion transport protein (OATP) and the monocarboxylic transporter (MCT8) (Ekins et al. 1994 Friesema et al. 1999, 2005). Within some cells, deiodinating enzymes can remove an iodine atom from the T4 or T3 molecules and thereby modify the sensitivity of a cell to the actions of the thyroid hormones. The cellular actions of the thyroid hormones are mediated by nuclear receptor proteins, which bind to DNA and regulate transcription with at least two types of genes that encode these receptors (Barettino, Ruiz, and Stunnenberg 1994) these also provide a negative feedback action on the hypothalamic-pituitary axis. T4 is sometimes... 

Fig. 43.11. Feedback regulation of thyroid hormone levels. TRH from the hypxjthalamus stimulates the release of TSH from the anterior pituitary, which stimulates the release of T3 and T4 from the thyroid. T4 is converted to T3 in the liver and other cells. T3 and T4 inhibit the release of TSH from the anterior pituitary and of TRH from the hypothalamus.

Experiments comparing bile fistula rats with intact rats are difficult to interpret. In the bile fistula rat, the enterohepatic circulation of bile acids is interrupted, feedback inhibition by the circulating pool is abolished, and bile acid synthesis is presumably at a maximum. The effects of thyroid hormone are thus superimposed on a system that is operating already at or near maximal capacity. The stimulation of bile acid output by thyroid hormone can thus be seen more readily in the intact rat, where bile acid synthesis is under feedback regulation by the circulating bile acid pool. 

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