Physiological effects of thyroid hormones and their mechanism of action

Thyroid hormones have a broad spectrum of action, but their influence is greatest on the cell nucleus. They can directly affect processes occurring in the mitochondria, as well as in the cell membrane.

In mammals and humans, thyroid hormones are especially important for the development of the central nervous system and for the growth of the organism as a whole.

The stimulating effect of these hormones on the rate of oxygen consumption (calorigenic effect) by the entire organism, as well as by individual tissues and subcellular fractions, has long been known. A significant role in the mechanism of the physiological calorigenic effect of T4 _and T3 _can be played by stimulation of the synthesis of such enzymatic proteins that use the energy of adenosine triphosphate (ATP) in the process of their functioning, for example, the membrane sodium-potassium-ATPase sensitive to oubain, which prevents the intracellular accumulation of sodium ions. Thyroid hormones in combination with adrenaline and insulin are capable of directly increasing the uptake of calcium by cells and increasing the concentration of cyclic adenosine monophosphoric acid (cAMP) in them, as well as the transport of amino acids and sugars through the cell membrane.

Thyroid hormones play a special role in regulating the cardiovascular system. Tachycardia in thyrotoxicosis and bradycardia in hypothyroidism are characteristic signs of thyroid status disorders. These (as well as many other) manifestations of thyroid diseases were long attributed to an increase in sympathetic tone under the influence of thyroid hormones. However, it has now been proven that excess levels of the latter in the body lead to a decrease in the synthesis of adrenaline and noradrenaline in the adrenal glands and a decrease in the concentration of catecholamines in the blood. In hypothyroidism, the concentration of catecholamines increases. Data on the slowing down of catecholamine degradation under conditions of excess levels of thyroid hormones in the body have not been confirmed either. Most likely, due to the direct (without the participation of adrenergic mechanisms) action of thyroid hormones on tissues, the sensitivity of the latter to catecholamines and mediators of parasympathetic influences changes. Indeed, in hypothyroidism, an increase in the number of beta-adrenergic receptors has been described in a number of tissues (including the heart).

The mechanisms of thyroid hormone penetration into cells have not been sufficiently studied. Regardless of whether passive diffusion or active transport takes place, these hormones penetrate into target cells fairly quickly. Binding sites for T3 _and T4 _are found not only in the cytoplasm, mitochondria, and nucleus, but also on the cell membrane; however, it is the nuclear chromatin of cells that contains sites that best meet the criteria of hormonal receptors. The affinity of the corresponding proteins to various T4 analogues _is usually proportional to the biological activity of the latter. The degree of occupancy of such sites is in some cases proportional to the magnitude of the cellular response to the hormone. Binding of thyroid hormones (primarily T3) in the nucleus is accomplished by non-histone chromatin proteins, the molecular weight of which after solubilization is approximately 50,000 daltons. The nuclear action of thyroid hormones probably does not require prior interaction with cytosolic proteins, as is described for steroid hormones. The concentration of nuclear receptors is usually particularly high in tissues known to be sensitive to thyroid hormones (anterior pituitary gland, liver) and very low in the spleen and testes, which are reported to be unresponsive to _T4 and _T3.

After interaction of thyroid hormones with chromatin receptors, RNA polymerase activity increases rather rapidly and formation of high-molecular RNA increases. It has been shown that, in addition to generalized influence on the genome, T3 can selectively stimulate synthesis of RNA encoding formation of specific proteins, for example, alpha2-macroglobulin in the liver, growth hormone in pituicytes and, possibly, mitochondrial enzyme alpha-glycerophosphate dehydrogenase and cytoplasmic malic enzyme. At physiological concentration of hormones, nuclear receptors are more than 90% bound with T3 _, while T4 is present in complex with receptors in very small quantities. This justifies the opinion about T4 as a prohormone and T3 _as a true thyroid hormone.

Regulation of secretion. T4 _and T3 _may depend not only on the pituitary TSH, but also on other factors, in particular the concentration of iodide. However, the main regulator of thyroid activity is still TSH, the secretion of which is under dual control: by the hypothalamic TRH and peripheral thyroid hormones. In the case of an increase in the concentration of the latter, the reaction of TSH to TRH is suppressed. TSH secretion is inhibited not only by T3 _and T4 _, but also by hypothalamic factors - somatostatin and dopamine. The interaction of all these factors determines the very fine physiological regulation of thyroid function in accordance with the changing needs of the body.

TSH is a glycopeptide with a molecular weight of 28,000 daltons. It consists of 2 peptide chains (subunits) linked by non-covalent forces and contains 15% carbohydrates; the alpha subunit of TSH is no different from that of other polypeptide hormones (LH, FSH, human chorionic gonadotropin). The biological activity and specificity of TSH are determined by its beta subunit, which is synthesized separately by pituitary thyrotrophs and subsequently joins the alpha subunit. This interaction occurs fairly quickly after synthesis, since the secretory granules in thyrotrophs contain mainly the finished hormone. However, a small number of individual subunits can be released under the action of TRH in a nonequilibrium ratio.

Pituitary TSH secretion is very sensitive to changes in serum T4 and T3 concentrations. A decrease or increase in this concentration by even 15-20% leads to reciprocal shifts in TSH secretion and its response to exogenous TRH. The activity of T4-5 _- deiodinase _inthe pituitary gland is especially high, so serum T4 _is converted into T3 more actively there _than in other organs. This is probably why a decrease in the T3 level ₍ while maintaining a normal T4 concentration _in the serum), recorded in severe non-thyroidal diseases, rarely leads to an increase in TSH secretion. Thyroid hormones reduce the number of TRH receptors in the pituitary gland, and their inhibitory effect on TSH secretion is only partially blocked by protein synthesis inhibitors. Maximum inhibition of TSH secretion occurs a long time after reaching the maximum concentration of T4 _and T3 _in the serum. Conversely, a sharp drop in thyroid hormone levels after thyroidectomy results in restoration of basal TSH secretion and its response to TRH only after several months or even later. This should be taken into account when assessing the state of the pituitary-thyroid axis in patients undergoing treatment for thyroid disease.

The hypothalamic stimulator of TSH secretion, thyroliberin (tripeptide pyroglutamyl histidyl prolinamide), is present in the highest concentration in the median eminence and arcuate nucleus. However, it is also found in other areas of the brain, as well as in the gastrointestinal tract and pancreatic islets, where its function has been little studied. Like other peptide hormones, TRH interacts with membrane receptors of pituicytes. Their number decreases not only under the influence of thyroid hormones, but also with an increase in the level of TRH itself ("downregulation"). Exogenous TRH stimulates the secretion of not only TSH, but also prolactin, and in some patients with acromegaly and chronic liver and kidney dysfunction, the formation of growth hormone. However, the role of TRH in the physiological regulation of the secretion of these hormones has not been established. The half-life of exogenous TRH in human serum is very short - 4-5 min. Thyroid hormones probably do not affect its secretion, but the problem of its regulation remains virtually unstudied.

In addition to the above-mentioned inhibitory effect of somatostatin and dopamine on TSH secretion, it is modulated by a number of steroid hormones. Thus, estrogens and oral contraceptives increase the reaction of TSH to TRH (possibly due to an increase in the number of TRH receptors on the membrane of the cells of the anterior pituitary gland), limit the inhibitory effect of dopaminergic agents and thyroid hormones. Pharmacological doses of glucocorticoids reduce the basal secretion of TSH, its reaction to TRH and the increase in its level in the evening hours. However, the physiological significance of all these modulators of TSH secretion is unknown.

Thus, in the system of regulation of thyroid function, the central place is occupied by thyrotrophs of the anterior pituitary gland, secreting TSH. The latter controls most metabolic processes in the thyroid parenchyma. Its main acute effect is reduced to stimulation of production and secretion of thyroid hormones, and the chronic effect is reduced to hypertrophy and hyperplasia of the thyroid gland.

On the surface of the thyrocyte membrane there are receptors specific for the alpha-subunit of TSH. After the hormone interacts with them, a more or less standard sequence of reactions for polypeptide hormones unfolds. The hormone-receptor complex activates adenylate cyclase, located on the inner surface of the cell membrane. The protein that binds guanine nucleotides most likely plays a coupling role in the interaction of the hormone-receptor complex and the enzyme. The factor determining the stimulating effect of the receptor on the cyclase may be the β-subunit of the hormone. Many of the effects of TSH are apparently mediated by the formation of cAMP from ATP under the action of adenylate cyclase. Although re-administered TSH continues to bind to thyrocyte receptors, the thyroid gland is refractory to repeated administrations of the hormone for a certain period. The mechanism of this autoregulation of the cAMP response to TSH is unknown.

The cAMP formed under the action of TSH interacts in the cytosol with the cAMP-binding subunits of protein kinases, leading to their separation from the catalytic subunits and activation of the latter, i.e. to the phosphorylation of a number of protein substrates, which changes their activity and thereby the metabolism of the entire cell. The thyroid gland also contains phosphoprotein phosphatases that restore the state of the corresponding proteins. Chronic action of TSH leads to an increase in the volume and height of the thyroid epithelium; then the number of follicular cells also increases, which causes their protrusion into the colloid space. In the culture of thyrocytes, TSH promotes the formation of microfollicular structures.

TSH initially reduces the iodide-concentrating capacity of the thyroid gland, probably due to the cAMP-mediated increase in membrane permeability accompanying membrane depolarization. However, chronic action of TSH sharply increases iodide uptake, which is apparently indirectly affected by increased synthesis of carrier molecules. Large doses of iodide not only inhibit transport and organization of the latter, but also reduce the cAMP response to TSH, although they do not change its effect on protein synthesis in the thyroid gland.

TSH directly stimulates the synthesis and iodination of thyroglobulin. Under the influence of TSH, the consumption of oxygen by the thyroid gland increases rapidly and sharply, which is probably associated not so much with an increase in the activity of oxidative enzymes, but with an increase in the availability of adenine diphosphoric acid - ADP. TSH increases the total level of pyridine nucleotides in the thyroid tissue, accelerates the circulation and synthesis of phospholipids in it, increases the activity of phospholipase A1, which affects the amount of the precursor of prostaglandins - arachidonic acid.

Catecholamines stimulate the activity of thyroid adenylate cyclase and protein kinases, but their specific effects (stimulation of the formation of colloidal droplets and secretion of T4 _and T3 ₎ are clearly manifested only against the background of reduced TSH levels. In addition to their effect on thyrocytes, catecholamines affect blood flow in the thyroid gland and change the metabolism of thyroid hormones in the periphery, which in turn can affect its secretory function.

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