FIGURE 12 Feedback regulation of thyroid hormone secretion. ( + ), stimulation; (—), inhibition.

and T4 accompanied by high concentrations of TSH reflect a defect in the pituitary or hypothalamus. As already noted, the high concentrations of T4 and T3 seen in Graves' disease are accompanied by very low concentrations of TSH in blood as a result of negative feedback inhibition of TSH secretion.

Negative feedback inhibition of TSH secretion results from actions of thyroid hormones exerted both on TRH neurons in the paraventricular nuclei of the hypothalamus and on thyrotropes in the pituitary. Results of animal studies indicate that T3 and T4 inhibit TRH synthesis and secretion. Events thought to occur within the thyrotropes are illustrated in Fig. 13. TRH binds its G-protein-coupled heptihelical receptors (Chapter 2) on the surface of thyrotropes. The resulting activation of phospholipase C generates the second messengers inosi-tol trisphosphate (IP3) and diacylglycerol (DAG). IP3 promotes calcium mobilization, and DAG activates protein kinase C, both of which rapidly stimulate release of stored hormone. This effect is augmented by influx of extracellular calcium following activation of membrane calcium channels. In addition, transcription of genes for both subunits of TSH is increased. TRH also promotes processing of the carbohydrate components of TSH necessary for maximum biological activity. Meanwhile, both T4 and T3 enter the cell at a rate determined by their free concentrations in blood plasma, and T4 is deiodinated to T3 in the cytoplasm. T3 enters the nucleus, binds to its receptors, and down-regulates transcription of the genes for both the a- and ^-subunits of TSH and for TRH receptors. In addition, T3 inhibits release of stored hormone and accelerates TRH receptor degradation. The net consequence of these actions of T3 is a reduction in the sensitivity of the thyrotropes to TRH (Fig. 14).

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Get Rid of Gallstones Naturally

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