Physiological effects of thyroid hormones and the mechanism of their action

Thyroid hormones have a wide spectrum of action, but most of all their effect affects the cell nucleus. They can directly affect the 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 body as a whole.

It has long been known that the stimulating effect of these hormones on the rate of oxygen consumption (caloric effect) by the whole organism, as well as by individual tissues and subcellular fractions. An essential role in the mechanism of the physiological caloric effect of T ₄ and T ₃ can be the stimulation of the synthesis of such enzyme proteins, which in the course of their functioning use the energy of adenosine triphosphate (ATP), for example, membrane-sensitive sodium potassium-ATPase, which is sensitive to oubain, which prevents intracellular accumulation of sodium ions. Thyroid hormones in combination with epinephrine and insulin are able to directly increase the uptake of calcium by cells and increase the concentration of cyclic adenosine monophosphoric acid (cAMP) in them, as well as transport of amino acids and sugars through the cell membrane.

A special role is played by thyroid hormones in regulating the function of the cardiovascular system. Tachycardia with thyrotoxicosis and bradycardia with hypothyroidism are characteristic signs of a thyroid status disorder. These (as well as many other) manifestations of thyroid diseases for a long time attributed to an increase in sympathetic tone under the influence of thyroid hormones. However, it has now been proven that an excessive amount of the latter in the body leads to a decrease in the synthesis of epinephrine and norepinephrine in the adrenal glands and a decrease in the concentration of catecholamines in the blood. With hypothyroidism, the concentration of catecholamines increases. Data on the slowing down of catecholamine degradation in conditions of excess thyroid hormone levels in the body were not confirmed. Most likely, due to direct (without participation of adrenergic mechanisms) action of thyroid hormones on the tissue, the sensitivity of the latter to catecholamines and mediators of parasympathetic influences changes. Indeed, with hypothyroidism, an increase in the number of beta-adrenoreceptors in a number of tissues (including the heart) is described.

The mechanisms of penetration of thyroid hormones into cells have not been studied enough. Regardless of whether passive diffusion or active transport takes place here, these hormones penetrate target cells quickly enough. The binding sites for T ₃ and T _{4 are} found not only in the cytoplasm, mitochondria and nucleus, but also on the cell membrane, but it is in the nuclear chromatin of the cells that the areas most satisfying the criteria of the hormonal receptors are contained. The affinity of the corresponding proteins for various T ₄ analogues is usually proportional to the biological activity of the latter. The degree of employment of such sites in some cases is proportional to the magnitude of the cellular reaction to the hormone. The binding of thyroid hormones (predominantly T3) in the nucleus is mediated by nonhistone chromatin proteins, whose molecular mass after solubilization is approximately 50,000 daltons. For the nuclear action of thyroid hormones, in all likelihood, no preliminary interaction with the proteins of the cytosol is required, as described for steroid hormones. The concentration of nuclear receptors is usually particularly high in tissues known for their sensitivity to thyroid hormones (anterior pituitary gland, liver) and very low in the spleen and testes, which, according to available data, do not react to T ₄ and T ₃.

After the interaction of thyroid hormones with chromatin receptors, the activity of RNA polymerase rapidly increases and the formation of high-molecular RNA increases. It is shown that, in addition to the generalized effect on the genome, T3 can selectively stimulate the synthesis of RNA encoding the formation of specific proteins, for example, alpha2-macroglobulin in the liver, growth hormone in pituitary cells and, possibly, the mitochondrial enzyme alpha-glycerophosphate dehydrogenase and cytoplasmic malic enzyme . With a physiological concentration of hormones, the nuclear receptors are more than 90% bound to T ₃, whereas T4 is present in complex with the receptors in a very small amount. This justifies the view as the prohormone T4 and T ₃ as a true thyroid hormone.

Regulation of secretion. T ₄ and T ₃ can depend not only on the TTG of the pituitary gland, 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 double control: from the side of hypothalamic TGH and peripheral thyroid hormones. If the concentration of the latter increases, the reaction of TSH to TRH is suppressed. Secretion of TSH is inhibited not only by T ₃ and T ₄, but also by hypothalamic factors - somatostatin and dopamine. The interaction of all these factors determines the very fine physiological regulation of the thyroid function in accordance with the changing needs of the organism.

TSH is a glycopeptide with a molecular weight of 28,000 daltons. It consists of 2 peptide chains (subunits), connected by non-covalent forces, and contains 15% carbohydrates; alpha-subunit of TSH does not differ from that in other polypeptide hormones (LH, FSH, chorionic gonadotropin). The biological activity and specificity of TSH is due to its beta subunit, which is separately synthesized by the thyroid pituitary and subsequently attached to the alpha subunit. This interaction occurs quite quickly after synthesis, since the secretory granules in thyrotrophs contain basically a ready-made hormone. However, a small number of individual subunits can be released under the influence of TRH in a nonequilibrium ratio.

Pituitary TSH secretion is very sensitive to changes in the concentration of T ₄ and T ₃ in serum. Decrease or increase of this concentration even by 15-20% leads to reciprocal shifts in the secretion of TSH and its reaction to exogenous TRH. The activity of T ₄ -5-deiodinase in the pituitary gland is particularly high, so serum T ₄ in it is converted to T ₃ more actively than in other organs. This is probably why reduction of T ₃ (while maintaining normal concentration of T ₄ in serum), the registrant in severe netireoidnyh diseases rarely leads to increased secretion of TSH. Thyroid hormones reduce the number of TGH receptors in the pituitary gland, and their inhibitory effect on TSH secretion is only partially blocked by protein synthesis inhibitors. The maximum inhibition of TSH secretion occurs after a long time after reaching the maximum concentration of T ₄ and T ₃ in the serum. Conversely, a sharp drop in the level of thyroid hormones after removal of the thyroid gland results in the restoration of the basal secretion of TSH and its reaction to TRH only a few months or even later. This need to be taken into account when assessing the pituitary-thyroid axis in patients undergoing treatment for thyroid disorders.

The hypothalamic stimulator of TSH secretion - thyreoliberin (tripeptide pyroglutamylgystidilprolinamide) - is present at the highest concentration in the middle elevation and arcuate nucleus. However, it is found in other parts of the brain, as well as in the gastrointestinal tract and pancreatic islets, where its function is poorly understood. Like other peptide hormones, TRH interacts with the membrane receptors of pituitary cells. Their number decreases not only under the influence of thyroid hormones, but also with an increase in the level of the TRH itself ("decreasing regulation"). Exogenous TGH stimulates the secretion of not only TSH, but prolactin, and in some patients with acromegaly and chronic impairment of liver and kidney function - and the formation of growth hormone. However, the role of TRH in the physiological regulation of the secretion of these hormones is not established. The half-life of exogenous TRH in human serum is very small - 4-5 minutes. Thyroid hormones probably do not affect its secretion, but the problem of regulation of the latter remains practically unexplored.

In addition to the mentioned inhibitory effect of somatostatin and dopamine on the secretion of TSH, it is modulated by a number of steroid hormones. So, 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 anterior pituitary cells), limit the inhibitory effect of dopaminergic agents and thyroid hormones. Pharmacological doses of glucocorticoids reduce the basal secretion of TSH, its reaction to TGH and its rise in the evening hours. However, the physiological significance of all these modulators of TSH secretion is unknown.

Thus, in the system of thyroid function regulation, the thyrotrophs of the anterior lobe of the pituitary gland occupy the central place, 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 chronic - to hypertrophy and hyperplasia of the thyroid gland.

On the surface of the thyrotoxic membrane there are specific for the alpha-subunit of TSH receptors. After the interaction of the hormone, a more or less standard sequence of reactions for the polypeptide hormones unfolds with them. The hormone-receptor complex activates adenylate cyclase located on the inner surface of the cell membrane. The protein binding the guanyl nucleotides, in all likelihood, plays an interfacing role in the interaction of the hormone receptor complex and the enzyme. The factor that determines the stimulating effect of the receptor on the cyclase may be the (3-subunit of the hormone, many effects of TSH appear to be mediated by the formation of cAMP from ATP by adenylate cyclase, although the re-introduced TSH continues to bind to thyroid receptors, the thyroid gland for of a certain period is refractory to repeated administration of the hormone.The mechanism of this autoregulation of the reaction of cAMP on TSH is unknown.

The cAMP produced by the 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 phosphorylation of a number of protein substrates, which changes their activity and thereby the metabolism of the whole cell. In the thyroid gland, there are also phosphatases of phosphoproteins, which 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 colloidal space. In the culture of thyreocytes, TSH promotes the formation of microfunctional structures.

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

TTG directly stimulates the synthesis and iodination of thyroglobulin. Under the influence of TTG, the consumption of oxygen by the thyroid gland rapidly and sharply increases, which is probably due not so much to the increase in the activity of oxidative enzymes, but rather to the increase in the availability of adenine diphosphate acid-ADP. TSH increases the total level of pyridine nucleotides in thyroid tissue, accelerates the circulation and synthesis of phospholipids in it, increases the activity of the phospholipase Ar, 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 T ₄ and T ₃ ) are clearly manifested only against a background of reduced TSH. In addition to the action on thyreocytes, catecholamines affect the blood flow in the thyroid gland and alter the exchange of thyroid hormones on the periphery, which in turn can affect its secretory function.

[1], [2], [3], [4], [5], [6], [7]