Thyroid-stimulating hormone actions

Figure 25-8. Control of adipose tissue lipolysis. (TSH, thyroid-stimulating hormone FFA, free fatty acids.) Note the cascade sequence of reactions affording amplification at each step. The lipolytic stimulus is "switched off" by removal of the stimulating hormone the action of lipase phosphatase the inhibition of the lipase and adenylyl cyclase by high concentrations of FFA the inhibition of adenylyl cyclase by adenosine and the removal of cAMP by the action of phosphodiesterase. ACTFI,TSFI, and glucagon may not activate adenylyl cyclase in vivo, since the concentration of each hormone required in vitro is much higher than is found in the circulation. Positive ( ) and negative ( ) regulatory effects are represented by broken lines and substrate flow by solid lines.

Li+ has been reported to affect virtually every component of the endocrine system to some extent however any resulting clinical manifestations are very rare [169]. Although these influences do not appear to be related to its mechanism of action in manic-depression, some are involved in the side effects experienced by Li+-treated patients. Apart from elevated levels of thyroid stimulating hormone (TSH), Li+ does not appear to affect the basal levels of hormones significantly however some hormone responses are reported to be altered by Li+ treatment of bipolar patients [170]. Neuronal activity stimulates the adrenal medulla to release norepinephrine and epinephrine into the blood and, consequently, the plasma from people with mania and depression shows increased levels of both neurotransmitters [171]. 

Many of the adverse effects of lithium can be ascribed to the action of lithium on adenylate cyclase, the key enz)nne that links many hormones and neurotransmitters with their intracellular actions. Thus antidiuretic hormone and thyroid-stimulating-hormone-sensitive adenylate cyclases are inhibited by therapeutic concentrations of the drug, which frequently leads to enhanced diuresis, h)rpoth)n oidism and even goitre. Aldosterone synthesis is increased following chronic lithium treatment and is probably a secondary consequence of the enhanced diuresis caused by the inhibition of antidiuretic-hormone-sensitive adenylate cyclase in the kidney. There is also evidence that chronic lithium treatment causes an increase in serum parathyroid hormone levels and, with this, a rise in calcium and magnesium concentrations. A decrease in plasma phosphate and in bone mineralization can also be attributed to the effects of the drug on parathyroid activity. Whether these changes are of any clinical consequence is unclear. 

There is no final consensus on whether normal use of lithium, without any episode of toxicity (the vast majority of patients), may result in permanent renal impairment. Polyuria occurs in 20-40% and is due to inhibition of antidiuretic hormone (ADH) by lithium. It usually resolves on cessation of lithium as do any effects on glomerular function. Interference with thyroid function is due to inhibition of the action of thyroid stimulating hormone (TSH) and is easily managed by administration of thyroxine. Lithium is contraindicated during pregnancy (major vessel anomalies in fetus) and breastfeeding. 

The many effects of lithium on thyroid physiology and on the hypothalamic-pituitary axis and their clinical impact (goiter, hypothyroidism, and hyperthyroidism) have been reviewed (620). Lithium has a variety of effects on the hypothalamic-pituitary-thyroid axis, but it predominantly inhibits the release of thyroid hormone. It can also block the action of thyroid stimulating hormone (TSH) and enhance the peripheral degradation of thyroxine (620). Most patients have enough thyroid reserve to remain euthyroid during treatment, although some initially have modest rises in serum TSH that normalize over time. 

Control of thyroid function via thyroid-pituitary feedback is also discussed in Chapter 37 Hypothalamic Pituitary Hormones. Briefly, hypothalamic cells secrete thyrotropin-releasing hormone (TRH) (Figure 38-3). TRH is secreted into capillaries of the pituitary portal venous system, and in the pituitary gland, TRH stimulates the synthesis and release of thyroid-stimulating hormone (TSH). TSH in turn stimulates an adenylyl cyclase-mediated mechanism in the thyroid cell to increase the synthesis and release of T4 and T3. These thyroid hormones act in a negative feedback fashion in the pituitary to block the action of TRH and in the hypothalamus to inhibit the synthesis and secretion of TRH. Other hormones or drugs may also affect the release of TRH or TSH. 

The thyroid-pituitary-hypothalamus axis controls thyroid hormone homeostasis. Thyrotropin-releasing hormone (TRH), released from the hypothalamus, stimulates the synthesis and release of thyroid-stimulating hormone (thyrotropin, TSH) from the anterior pituitary. TSH increases the release of thyroid hormones by several mechanisms, including stimulation of the I pump. While lower than normal levels of T3 and T4 cause an exaggerated response of the pituitary to TRH, released thyroid hormones, in feedback control, blunt the stimulating action of TRH on the pituitary. For further discussion of TSH and TRH biochemistry, see, for example, the review by Kannan48. 

In thyroid cells in culture, ceilcitriol reduces production of cAMP in response to thyr oid stimulating hormone by a nuclear- action on the synthesis of G-protein subunits. However, it also reduces the responsiveness to cAMP, emd attenuates cell growth and iodide uptake in response to thyroid stimulating hormone, with a rapid time course from direct action on protein kinase A (Berg andHaug, 1999). 

Thyrotropin, thyroliberin, or thyroid-stimulating hormone (TSH) is a peptide released by the anterior pituitary gland that stimulates the thyroid gland to release thyroxine (Ladram et al., 1994). The release of TSH is triggered by the action of thyrotropin-releasing faetor (TRF), a peptidic substance found in the hypothalamus of the brain and influencing the secretion of glandula thyroidea. 

However, it is now known to exist in various nerve tracts and neuroendocrine tissues and it has general inhibitor actions. It can also inhibit release of other pituitary hormones (including thyroid-stimulating hormone (TSH) and prolactin). other endocrine hormones including pancreatic hormones (insulin and glucagon), peptide hormones from a variety of neuroendocrine tumours (e.g. VIPomas and glucagonomas) and also the release of most intestinal hormones. It is produced in the gut, the pancreas and in some peripheral nerves (see hypothalamic hormones PITUITARY hormones). Somatostatin is a cyclic peptide of 14 residues (SRIF-14) but is formed from a precursor of 28 residues (SRIF-28). 

Ml. Macchia, V., and Pastan, I., Action of phospholipase C on the thyroid. Abolition of the response to thyroid-stimulating hormone. J. Biol. Chem. 242, 1864-1869... 

FIGURE 56-5 Regulation of thyroid hormone secretion. Myriad neural inputs influence hypothalamic secretion of thyrotropin-releasing hormone (TRH). TRH stimulates release of thyrotropin (TSH, thyroid-stimulating hormone) from the anterior pituitary TSH stimulates the synthesis and release of the thyroid hormones and T,. and T, feed back to inhibit the synthesis and release of TRH and TSH. Somatostatin (SST) can inhibit TRH action, as can dopamine and high concentrations of glucocorticoids. Low levels of L are required for thyroxine synthesis, but high levels inhibit thyroxine synthesis and release. 

Figure 21.4 Regulation of the symporter ooours through a variety of hormones and moleoules. This finding is consistent with its expression in diverse tissue types. NIS expression can be changed through the actions of thyroid-stimulating hormone (TSH), oxytocin, prolactin, estrogen, inflammatory cytokines, iodide, or cAMP levels.

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