Thyroid hormone physiologic actions

Most of the physiologic activity of thyroid hormones is from the actions of T3. T4 can be thought of primarily as a prohormone. Eighty percent of needed T3 is derived from the conversion of T4 to T3 in peripheral tissue under the influence of tissue deiodinases. These deiodinases allow end organs to produce the amount of T3 needed to control local metabolic functions. These enzymes also catabolize T3 and T4 to biologically inactive metabolites. Thyroid hormones bind to intracellular receptors and regulate the transcription of various genes. 

Retinoids are a family of naturally occurring and synthetic analogues of vitamin A. The skin of subjects deficient in vitamin A becomes hyperplastic and keratotic (phrynoderma, or toad skin). While natural vitamin A is occasionally employed therapeutically, synthetic retinoids are more effective and represent a major advance in dermatological pharmacotherapy. Retinoids have myriad effects on cellular differentiation and proliferation it is likely that nuclear retinoic acid receptors mediate these effects by activating gene expression in a manner analogous to receptors for steroid hormones and thyroid hormones. Despite a common mechanism of action, however, retinoids vary widely in their physiological effects. 

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. 

Failure of the thyroid to produce sufficient thyroid hormone is the most common cause of hypothyroidism and is known as primary hypothyroidism. Secondary hypothyroidism occurs much less often and results from diminished release of TSH from the pituitary. Treatment of hypothyroidism is achieved by the replacement of thyroid hormone, primarily T4. A synthetic preparation of T4 is available, levothyroxine (Synthroid ), which has been a popular choice for hypothyroidism because of its consistent potency and prolonged duration of action. No toxicity occurs when given in physiological replacement doses. Desiccated animal thyroid is also available at a lesser cost. Overdoses cause symptoms of hyperthyroidism and can be used as a guide in clinical management. Hypothyroidism is not cured by the daily intake of thyroid hormone it is a life-long regimen. 

Several important features of thyroid hormone action have been obtained by using pituitary cell lines (GH3, GH , GC) derived from the somatotrophs, i.e., the cells which synthesize and secrete growth hormone [43,46], When cultured in thyroid hormone depleted media such cells are responsive to thyroid hormone. Tsai and Samuels [47] first demonstrated that GH cells synthesize 3-10-times more GH when cultured in the presence of physiological concentration of T3 (0.1-1 nM). A detectable increase in GH synthesis occurs 45-60 min after significant binding to nuclear sites. Such an increase is paralleled by changes in total cytoplasmic GH mRNA... 

Polymorphism of the resistin gene is associated with obesity. Resistin has an anti-insulin action, and is itself suppressed by insulin and the pro-inflammatory cytokines. Output is increased by thyroid hormone T4 but the physiological function is not yet understood. 

Only those physiologic actions of thyroid hormone that influence fuel metabolism are considered here. It is important to stress the term physiologic, because the effects of supraphysiologic concentrations of thyroid hormone on fuel metabolism may not be simple extensions of their physiologic effects. In general, the following... 

In physiologic concentrations, thyroid hormone sensitizes the muscle cell to the glycogenolytic actions of epinephrine. Glycolysis in muscle is increased by this action of T3. 

Physiological Actions of Thyroid Hormones—Oxygen Consumption and Calorigenesis... 

Because of the role of mitochondria in cellular respiration and energy production, efforts to elucidate the mechanism of thyroid hormone action in metabolism and calorigenesis have focused on mitochondrial studies. Thyroid hormones in vitro are known to uncouple oxidative phosphorylation in isolated mitochondria, but these effects occur at unphysiological doses of T4. In physiological concentrations, T4 increases adenosine triphosphate (ATP) formation and the number and inner membrane surface area of mitochondria (21), but T4 does not reduce the efficiency of oxidative phosphorylation. Furthermore, 2,4-dinitrophenol, a classic uncoupler of oxidative phosphorylation, can neither relieve hypothyroidism nor duplicate other physiological effects of thyroid hormones. 

Sohwartz HL, Oppenheimer JH. Physiologic and biochemical actions of thyroid hormone. Pharmaool Ther 1978 B3 349-376. 

In mammals the physiological actions of the thyroid hormones are multiple, and it is still not clear wheth< r or not they are manifestations of but a single action at the cellular level. Calorigcnesis is the effect of the hormones which has been most exten.sively investigated. It will be discussexl in detail below. 

In the evaluation of in vitro studies on the potency of various thyroxine analogs, differences in the physiological disposition of these compounds must clearly be taken into account. An analog active by an in vitro assay will not be potent in vivo if it does not reach its site of action. Moreover, since the thyroid hormones alter the metabolic function of many tissues, an analog which is selectively concentrated in a particular tissue might be expected to affect that tissue more profoundly than others. I hese points will be illustrated in the following consideration of the relative function and physiological disposition of the D- and L-isomers of thyroxine. 

The proposition that the mechanism of action of thyroid hormones is the same as that of DNP is untenable on physiological grounds, for while DNP can raise the BMR of a myxedematous patient to normal, the other symptoms of myxedema are unrelieved (cf. Pitt-Rivers and Tata, 1959). An uncoupling of oxidative phosphorylation secondary to some other and more general action of thyroxine is, however, possible such a decreased phos-phorylating ability has, in fact, been demonstrated with mitochondria from thyrotoxic rats (Niemeyer et al., 1951 Lardy and Feldott, 1951 ... 

The role of transferrin has been investigated by measuring iron absorption by isolated intestinal loops. Although it appears that transferrin accelerates iron absorption, the rate of intestinal absorption of iron is not limited by transferrin levels in blood. A number of hormones influence iron absorption by the intestine. The molecular mechanism of these hormonal effects is not known, and only the ultimate response to the hormonal stimulus can be described. In many if not all cases, the hormonal effect on iron absorption is probably secondary to the action of the hormone on other physiological or biochemical functions. Pituitary and thyroid hormones stimulate iron absorption thyroid hormones probably act by increasing erythropoiesis and oxygen consumption. 

The overall effect of these cellular and systemic actions is to stimulate respiratory and other enzyme synthesis, which results in increased oxygen consumption and resultant increased basal metabolic rate. This affects heart rate, respiratory rate, mobilization of carbohydrates, cholesterol metabolism, and a wide variety of other physiological activities. In addition, thyroid hormones stimulate growth and development and, as noted earlier, are critical for the normal proliferation, growth, and development of brain cells. Table 2 shows the estimated iodine concentration in selected organs. 

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