Amiodarone and the thyroid gland. Synthesis and action of thyroid hormones on the body. What effects are characteristic of thyroid hormones?

Lecture 8.

Thyroid. Physiological effects of thyroid hormones.

1. Structure. Embryogenesis.

5. The mechanism of action of thyroid hormones.

1. Structure. Embryogenesis.

All vertebrates have a thyroid gland. In humans, it is located in the anterior region of the neck, slightly below the cricoid cartilage of the larynx. It is horseshoe-shaped and consists of three main parts: two lateral lobes and a middle unpaired part - the isthmus.

During the process of human embryogenesis, the thyroid gland is formed in the 3rd week of intrauterine development. Already between the 12th and 14th weeks of intrauterine life, the thyroid gland is able to absorb and accumulate iodine. Between the 15th and 19th weeks, the organic binding of iodine and the synthesis of the hormone thyroxine begin. Thus, the thyroid gland begins to function in the fetus long before its birth, its hormonal activity is necessary for the full development of the fetus.

The thyroid tissue is divided by connective tissue layers into separate lobules. The main element of its parenchyma are follicles. the wall of each follicle consists of thyrocytes - single-layer epithelial cells that produce two iodine-containing thyroid hormones. During periods of low functional activity of the gland, the epithelium is flat; when it increases, it becomes cubic and even cylindrical. Inside the follicle contains a colloid - a homogeneous mass secreted by the epithelium of the follicle, containing iodine. Between the follicles there is loose connective tissue, in which there are accumulations of epithelial cells - interfollicular islands, which serve as a source of formation of new follicles.

In the wall of the follicles and in the interfollicular islands there are special round or oval cells, distinguished by light-colored cytoplasm (“light” cells). An increase in the activity of these cells occurs after perfusion of the thyroid gland with solutions with a high calcium content. “light” cells participate in the secretion of calcitonin, and therefore are called C-cells or K-cells (English - calcitonin or Russian calcitonin). During the process of evolution, a certain number of “light” cells migrated to other endocrine glands - the parathyroid and thymus glands.

The thyroid gland ranks first in the body in terms of blood supply (5.6 ml of blood flows through a gram of tissue in 1 minute, only 1.5 ml through the kidneys), which indicates the active endocrine function of the gland. The gland is innervated by sympathetic, parasympathetic and somatic nerves. Many sympathetic nerve endings are directly connected to the follicles, which creates conditions for their direct effect on the secretion of thyroid hormones.

2. Thyroid hormones and their formation.

Thyroid hormones include two iodinated hormones (thyroxine and triiodothyronine) and three peptide hormones that are members of the calcitonin family.

Thyroxine and triiodothyronine are formed in follicular epithelial cells. For the synthesis of these hormones, a constant supply of inorganic iodine to the body is necessary, which a person receives from food in the form of iodides - potassium iodide and sodium iodide (in the daily diet - 100-200 mcg). The human body contains 30-50 mg of iodine, of which about 15 mg is in the thyroid gland.

Hormone formation in the thyroid gland goes through the following phases:

1. Inorganic iodine that enters the body with food is absorbed into the blood and enters the follicles of the thyroid gland, where it is concentrated. Their iodides are then released through enzymatic oxidation to release elemental iodine.

2. Iodine combines with a tyrosine molecule to form monoiodotyrosine and diiodotyrosine. The iodinated tyrosines then oxidize, condense, and form thyroxine and triiodotyrosine. The ratio of synthesized thyroxine and triiodothyronine is approximately 4:1. The central role in the described processes belongs to the large molecular glycoprotein thyroglobulin , which includes amino acid residues tyrosine and iodine. Thyroglobulin is synthesized by the epithelial cells of the follicles and then accumulates in the colloid of the follicular cavity. It is inside its molecule that the processes of organic binding of iodine, the formation of iodinated tyrosines and their condensation occur. Thus, the biosynthesis of thyroxine and triiodothyronine is based on the continuous formation of thyroglobulin. This process can partially occur directly in thyrocytes.

3. Thyroid hormones are released from the thyroglobulin molecule and released into the blood. This stage begins with the entry of colloidal droplets into epithelial cells by pinocytosis, after which proteolytic cleavage of the thyroglobulin molecule occurs by cathepsins in the lysosomes of epithelial cells. As a result, thyroxine, triiodotyrosine, as well as mono- and diiodotyrosines are released. Hormones penetrate into the blood, and iotyrosines undergo deiodination.

The main thyroid hormone circulating in the blood is thyroxine. Thyroxine is in a protein-bound state. In humans, approximately 75% of circulating thyroxine is associated withα -globulin, 10-15% - with prealbumin, small amounts - with albumin. This connection is reversible. Triioditonin also binds to plasma proteins, but less firmly, so its physiological effect manifests itself more quickly than thyroxine. Protein binding prevents the loss of thyroid hormones through the kidneys.

Only free thyroxine and triiodothyronine penetrate into the cell, which are fixed by specific proteins. Metabolism of thyroid hormones occurs in peripheral tissues, including their deiodination. In this case, thyroxine partially transforms into the biologically more active triiodothyronine. with complete deiodination, as well as destruction of the peptide chain, the hormones are completely inactivated.

The body of an adult requires 100-300 mcg of thyroxine or 50-150 mcg of triiodothyronine per day. Thyroid hormones are destroyed quite slowly: the half-life of thyroxine is about 4 days, and triiodironine is 45 hours. Excess hormones are destroyed or eliminated from the body. Metabolic degradation of hormones occurs mainly in the liver. Moreover, it is believed that the resulting metabolites have physiological activity. It is known that the product of thyroxine deamination strongly stimulates metamorphosis in amphibians (the effect in mammals has not been studied).

The removal of thyroxine and triiodothyronine from the body is preceded by their conjugation with glucuronic and sulfuric acids in the liver. The resulting glucuronides and sulfoglucuronides of thyroid hormones pass into the bile and with it into the intestines. A small portion of these conjugates is hydrolyzed by intestinal enzymes and reabsorbed into the blood. Some thyroid hormones are excreted by the kidneys.

3. Regulation of biosynthesis and secretion of thyroid hormones.

The main regulator of thyroid follicle function is thyrotropin ( hormone secreted by the anterior pituitary gland). Under the influence of thyrotropin, the following changes occur:

1. Thyrocytes grow (after removal of the pituitary gland they become flat, and after the administration of thyrotropin they become cubic or cylindrical);

2. Activates the biosynthesis of threoid hormones at different stages:

Enhances the active transfer of iodides from the blood to the follicles of the gland, due to depolarization of cell membranes and increased ATPase activity;

Increases the oxidation of iodides, the formation of iodothyronines, the synthesis of thyroglobulin;

pinocytosis of thyroglobulin and its migration to lysosomes, its breakdown by proteolytic enzymes and the release of free thyroxine and triiodothyronine into the blood are enhanced.

All this explains why destruction of the anterior lobe of the pituitary gland leads to atrophy of the thyroid parenchyma and hypothyroidism, and why excessive production of thyrotropin leads to the development of hyperthyroidism.

The relationship between the pituitary gland and the thyroid gland occurs on the principle of direct and feedback.

The secretion of thyrotropin is activated by thyrotropin-releasing factor (thyrotropin-releasing factor), produced by the neurosecretory elements of the hypothalamus. Thus, a single system functions in the body: thyrotropin-releasing hormone-thyrotropin-thyroid hormones or the hypothalamus-pituitary-thyroid system. Through the hypothalamic region of the brain and the pituitary gland, signals from the central nervous system, including its higher parts, are transmitted to the thyroid gland. This mechanism underlies the acute (sometimes within 1-2 days) increase in the functional activity of the thyroid gland after mental trauma in humans.

There is also an inverse relationship between thyroid hormones and thyrotropin, on the one hand, and hypothalamic cells that produce thyrotropin-releasing hormone, on the other hand: increased production of thyroid hormones and thyrotropin inhibits the formation of thyrotropin-releasing hormone.

It is believed that the sympathetic nerves stimulate the secretory activity of the thyroid gland, and the parasympathetic nerves inhibit it. However, there is little direct evidence. There is evidence of contacts between sympathetic nerve endings and follicular epithelium. It is believed that the autonomic nervous system only innervates blood vessels (denervation of the thyroid gland does not interfere with its response to thyroid-stimulating hormone).

4. Methods for assessing the functional activity of the thyroid gland.

1. Assessment of the functional state of the thyroid gland based on the basal metabolic rate. The method is based on data that iodine-containing hormones can increase basal metabolism. However, this method is inaccurate, since the amount of basal metabolism can be influenced by other factors (tone of the autonomic nervous system, hormonal activity of other endocrine glands, etc.).

2. Applications of radioactive iodine. A small dose of radioactive iodine (1 to 5 μCi) is administered, and iodine uptake by the thyroid gland is determined after 2 and 24 hours (eg, using a Geiger-Muller counter). With normal functioning of the thyroid gland, the accumulation of iodine in it is: in 2 hours - 7-12%, and in 24 hours - 20-29% of the administered amount. When its function decreases, the corresponding values are 1-2 and 2-4%, respectively, and when its function is increased - 20-40 and 40-80%.

3. Determination of the amount of protein-bound plasma iodine (PBI). In healthy people, the BBI is 3.4-8 μg%, with thyrotoxicosis - over 8.5, and with hypothyroidism - less than 3 μg%.

4. Determination of the reactivity of the thyroid gland to thyrotropin: First, the basal concentration of thyroid hormones in the blood plasma (serum) is determined, and then their content after administration of thyrotropin.

5. Physiological significance and mechanisms of action of thyroid hormones.

Thyroxine and triiodothyronine have a very wide spectrum of effects on body functions.

Growth and development. Removal or weakening of the thyroid gland in adults helps to reduce the secretion of thyroid hormones, which leads to a decrease in basal metabolism by 40-50%. The skin loses its elasticity, the hairline thins, and the heart slows down. Children also experience delays in skeletal growth, development, and puberty. Thyroxine and triiodothyronine interact with growth hormone (somatotropic hormone). Congenital underdevelopment or even complete absence of the thyroid gland in humans contributes to the development cretinism . Cretinism is manifested by a violation of body proportions, growth retardation, a decrease in basal metabolism, changes in the condition of the integumentary tissues, underdevelopment of muscles, suppression of rational activity, infertility, cardiac weakness, etc. The nature of disturbances in the process of gland differentiation in embryogenesis has not yet been sufficiently elucidated. The cause of the development of spontaneous cretinism in humans can also be a chronic deficiency of iodide in the diet. Hyperfunction of the thyroid gland has the opposite changes in the human body.

Effect on the nervous system. When the function of the thyroid gland is suppressed or switched off at the initial stages of ontogenesis, profound dysfunctions of the higher parts of the brain occur: a decrease in conditioned reflex activity, a decrease in indicative reactions. Hypothyroidism leads to changes in other parts of the brain and the peripheral nervous system: the excitability of nerve centers, peripheral ganglia and nerve-organ synapses decreases. It is believed that these disorders are based on a sharply reduced degree of differentiation of nervous tissue: a decrease in the size of neurons, inhibition of the development of nerve terminals, inhibition of sypapsogenesis, decreased myelination of nerves and protein synthesis in brain tissue. According to some scientists, thyroxine is necessary to trigger the differentiation of nerve cells. Deficiency or excess of thyroid hormones during the critical period of central nervous system development causes profound changes in various parts of the brain. They can be compensated by normalizing the balance of thyroid hormones only within the same period, but not later (in humans in the first 3-6 months). After the completion of the critical period of development, the resulting changes in nerve cells become irreversible.

Table of contents of the topic "Adrenal hormones. Thyroid hormones.":
1. Adrenal hormones. Regulatory functions of adrenal hormones. Blood supply to the adrenal glands.
2. Hormones of the adrenal cortex and their effects in the body. Mineralcorticoids: Aldosterone. Renin - angiotensin - aldosterone system.
3. Glucocorticoids: cortisol and corticosterone. Transcortin. Lipocortin. Regulation of secretion and physiological effects of glucocorticoids.
4. Itsenko-Cushing syndrome. Symptoms of Itsenko-Cushing syndrome. Causes of Itsenko-Cushing syndrome.
5. Androgens. Regulation of secretion and physiological effects of sex steroids from the adrenal cortex. Virilization.
6. Adrenaline. Norepinephrine. APUD system. Catecholamines. Contrinsular hormone. Adrenomedullin. Adrenal medulla hormones and their effects in the body.
7. Regulatory functions of thyroid hormones. Blood supply to the thyroid gland.
8. Thyroglobulin. Triiodothyronine (T3). Tetraiodothyronine (thyroxine, T4). Thyrotropin. Regulation of secretion and physiological effects of iodine-containing thyroid hormones.
9. Excessive production of thyroid hormones. Hyperthyroidism. Cretinism. Hypothyroidism. Myxedema. Thyroid insufficiency.
10. Calcitonin. Catacalcin. Hypocalcemic hormone. Regulation of secretion and physiological effects of calcitonin.

Thyroglobulin. Triiodothyronine (T3). Tetraiodothyronine (thyroxine, T4). Thyrotropin. Regulation of secretion and physiological effects of iodine-containing thyroid hormones.

Thyrocytes form follicles filled with colloidal mass of thyroglobulin. The basement membrane of thyrocytes is closely adjacent to the blood capillaries, and from the blood these cells receive not only the substrates necessary for energy and protein synthesis, but also actively capture iodine compounds - iodides. In thyrocytes, thyroglobulin is synthesized and iodides are oxidized to form atomic iodine. Thyroglobulin contains a significant amount of amino acid residues on the surface of the molecule tyrosine(thyronines), which undergo iodization. Through the apical membrane of the thyrocyte thyroglobulin secreted into the lumen of the follicle.

During the secretion of hormones into the blood, the villi of the apical membrane surround and absorb by endocytosis droplets of colloid, which in the cytoplasm are hydrolyzed by lysosomal enzymes, and two products of hydrolysis - triiodothyronine (T3) And tetraiodothyronine (thyroxine, T4) secreted through the basement membrane into the blood and lymph. All described processes are regulated by thyrotropin of the adenohypophysis. The presence of so many processes regulated by one thyrotropin is ensured by the inclusion of many intracellular second messengers. There is also direct nervous regulation of the thyroid gland by autonomic nerves, although it plays a lesser role in activating hormone secretion than the effects of thyrotropin. The negative feedback mechanism in the regulation of thyroid function is realized by the level of thyroid hormones in the blood, which suppresses the secretion of thyrotropin-releasing hormone by the hypothalamus and thyrotropin by the pituitary gland. The intensity of secretion of thyroid hormones affects the volume of their synthesis in the gland (local positive feedback mechanism).

Rice. 6.16. Genomic and extragenomic mechanisms of action of thyroid hormones on the cell.

The effects of hormones are realized both after the penetration of hormones into the cell (influence on transcription in the nucleus and protein synthesis, influence on redox reactions and release of energy in mitochondria), and after binding of the hormone to the membrane receptor (formation of second messengers, increased transport of substrates into the cell , in particular amino acids necessary for protein synthesis).

Transport of T3 and T4 in the blood carried out with the help of special proteins, however, in such a protein-bound form, hormones are not able to penetrate into effector cells. Substantial part thyroxine deposited and transported by erythrocytes. Destabilization of their membranes, for example under the influence of ultraviolet irradiation, leads to the release of thyroxine into the blood plasma. When a hormone interacts with a receptor on the surface of the cell membrane, the hormone-protein complex dissociates, after which the hormone penetrates into the cell. Intracellular targets of thyroid hormones are the nucleus and organelles (mitochondria). The mechanism of action of thyroid hormones is shown in Fig. 6.16.

T3 is several times more active than T4, and T4 is converted to T3 in tissues. In this regard, the main part of the effects thyroid hormones provided by T3.

The main metabolic effects of thyroid hormones are:

1) increased oxygen absorption by cells and mitochondria with activation of oxidative processes and an increase in basal metabolism,
2) stimulation of protein synthesis by increasing the permeability of cell membranes for amino acids and activation of the cell’s genetic apparatus,
3) lipolytic effect and oxidation of fatty acids with a decrease in their level in the blood,
4) activation of cholesterol synthesis in the liver and its excretion with bile,
5) hyperglycemia due to activation of glycogen breakdown in the liver and increased glucose absorption in the intestine,
6) increased consumption and oxidation of glucose by cells,
7) activation of liver insulinase and acceleration of insulin inactivation,
8) stimulation of insulin secretion due to hyperglycemia.

Thus, redundant amount of thyroid hormones, by stimulating insulin secretion and simultaneously causing counter-insular effects, may also contribute to the development of diabetes mellitus.

Rice. 6.17. Iodine balance in the body.

500 mcg of iodine enters the body with food and water per day. Absorbed into the blood, iodides are delivered to the thyroid gland, where the main thyroid pool of iodine is deposited. Its consumption during the secretion of thyroid hormones is replenished from the reserve pool of blood. The main amount of iodine is excreted through the kidneys with urine (485 mcg), some is lost in feces (15 mcg), therefore, iodine excretion is equal to its intake into the body, which constitutes the external balance.

The main physiological effects of thyroid hormones, caused by the above metabolic changes, are manifested in the following:

1) ensuring normal processes of growth, development and differentiation of tissues and organs, especially the central nervous system, as well as processes of physiological tissue regeneration,
2) activation of sympathetic effects (tachycardia, sweating, vasoconstriction, etc.), both due to increased sensitivity adrenergic receptors, and as a result of suppression of enzymes (monoamine oxidase) that destroy norepinephrine,
3) increasing energy production in mitochondria and myocardial contractility,
4) increased heat generation and body temperature,
5) increasing the excitability of the central nervous system and activation of mental processes,
6) prevention of stress damage to the myocardium and ulcer formation in the stomach,
7) an increase in renal blood flow, glomerular filtration and diuresis with inhibition of tubular reabsorption in the kidneys,
8) maintaining reproductive function.

Video lesson thyroid hormones in health and disease

The thyroid gland (TG) and the hormones it produces play an extremely important role in the human body. The thyroid gland is part of the human endocrine system, which, together with the nervous system, regulates all organs and systems. Thyroid hormones regulate not only a person’s physical development, but also significantly influence his intelligence. Proof of this is mental retardation in children with congenital hypothyroidism (reduced production of thyroid hormones). The question arises, what hormones are produced here, what is the mechanism of action of thyroid hormones and the biological effects of these substances?

Structure and hormones of the thyroid gland

The thyroid gland is an unpaired endocrine organ (releases hormones into the blood), which is located on the front surface of the neck. The gland is enclosed in a capsule and consists of two lobes (right and left) and an isthmus that connects them. In some people, an additional pyramidal lobe is observed that extends from the isthmus. Iron weighs about 20-30 grams. Despite its small size and weight, the thyroid gland occupies a leading place among all organs of the body in terms of blood flow intensity (even the brain is inferior to it), which indicates the importance of the gland for the body.

All thyroid tissue consists of follicles (structural and functional unit). Follicles are round formations, which at the periphery consist of cells (thyrocytes), and in the middle are filled with colloid. Colloid is a very important substance. It is produced by thyrocytes and consists mainly of thyroglobulin. Thyroglobulin is a protein that is synthesized in thyrocytes from the amino acid tyrosine and iodine atoms, and is a ready supply of iodine-containing thyroid hormones. Both components of thyroglobulin are not produced in the body and must be regularly supplied with food, otherwise hormone deficiency and its clinical consequences may occur.

If the body needs thyroid hormones, then thyrocytes recapture synthesized thyroglobulin from the colloid (a depot of ready-made thyroid hormones) and break it down into two thyroid hormones:

T3 (triiodothyronine), its molecule has 3 iodine atoms;
T4 (thyroxine), its molecule has 4 iodine atoms.

After the release of T3 and T4 into the blood, they combine with special transport proteins in the blood and in this form (inactive) are transported to their destination (tissues and cells sensitive to thyroid hormones). Not all of the hormones in the blood are bound to proteins (they exhibit hormonal activity). This is a special protective mechanism that nature came up with against an excess of thyroid hormones. As needed in peripheral tissues, T3 and T4 are detached from transport proteins and perform their functions.

It should be noted that the hormonal activity of thyroxine and triiodothyronine is significantly different. T3 is 4-5 times more active, in addition, it binds poorly to transport proteins, which enhances its effect, unlike T4. Thyroxine, when it reaches sensitive cells, is disconnected from the protein complex and one iodine atom is split off from it, then it turns into active T3. Thus, the influence of thyroid hormones is 96-97% due to triiodothyronine.

The hypothalamic-pituitary system regulates the functioning of the thyroid gland and the production of T3 and T4 according to the principle of negative feedback. If there is an insufficient amount of thyroid hormones in the blood, this is detected by the hypothalamus (the part of the brain where the nervous and endocrine regulation of body functions smoothly transition into each other). It synthesizes thyrotropin-releasing hormone (TRH), which causes the pituitary gland (an appendage of the brain) to produce thyroid-stimulating hormone, which reaches the thyroid gland through the bloodstream and causes it to produce T3 and T4. And vice versa, if there is an excess of thyroid hormones in the blood, then less TRH, TSH and, accordingly, T3 and T4 are produced.

Mechanism of action of thyroid hormones

How exactly do thyroid hormones tell cells to do what they need to do? This is a very complex biochemical process; it requires the involvement of many substances and enzymes.

Thyroid hormones are those hormonal substances that exert their biological effects by binding to receptors inside cells (just like steroid hormones). There is a second group of hormones that act by connecting to receptors on the surface of cells (protein hormones, pituitary gland, pancreas, etc.).

The difference between them is the speed of the body's response to stimulation. Since protein hormones do not need to penetrate inside the nucleus, they act faster. In addition, they activate enzymes that are already synthesized. And thyroid and steroid hormones affect target cells by penetrating into the nucleus and activating the synthesis of the necessary enzymes. The first effects of such hormones appear after 8 hours, in contrast to the peptide group, which exert their effects within a fraction of seconds.

The entire complex process of how thyroid hormones regulate body functions can be depicted in a simplified version:

penetration of the hormone into the cell through the cell membrane;
connection of the hormone with receptors in the cytoplasm of the cell;
activation of the hormone-receptor complex and its migration into the cell nucleus;
interaction of this complex with a specific section of DNA;
activation of necessary genes;
synthesis of enzyme proteins that carry out the biological actions of the hormone.

Biological effects of thyroid hormones

The role of thyroid hormones can hardly be overestimated. The most important function of these substances is their effect on human metabolism (affects energy, protein, carbohydrate, and fat metabolism).

Main metabolic effects of T3 and T4:

increases the absorption of oxygen by cells, which leads to the production of energy necessary for cells for vital processes (increased temperature and basal metabolism);
activate protein synthesis by cells (processes of tissue growth and development);
lipolytic effect (break down fats), stimulate the oxidation of fatty acids, which leads to their reduction in the blood;
activate the formation of endogenous cholesterol, which is necessary for the construction of sex, steroid hormones and bile acids;
activation of glycogen breakdown in the liver, which leads to increased blood glucose;
stimulate insulin secretion.

All biological effects of thyroid hormones are based on metabolic capabilities.

The main physiological effects of T3 and T4:

ensuring normal processes of growth, differentiation and development of organs and tissues (especially the central nervous system). This is especially important during the period of intrauterine development. If at this time there is a lack of hormones, then the child will be born with cretinism (physical and mental retardation);
rapid healing of wounds and injuries;
activation of the sympathetic nervous system (increased heart rate, sweating, vasoconstriction);
increased cardiac contractility;
stimulation of heat generation;
affect water metabolism;
increase blood pressure;
inhibit the processes of formation and deposition of fat cells, which leads to weight loss;
activation of human mental processes;
maintaining reproductive function;
stimulate the formation of blood cells in the bone marrow.

Norms of thyroid hormones in the blood

To ensure normal functioning of the body, the concentration of thyroid hormones must be within normal values, otherwise disturbances in the functioning of organs and systems appear that are associated with a deficiency (hypothyroidism) or excess (thyrotoxicosis) of thyroid hormones in the blood.

Reference values for thyroid hormones:

TSH (thyroid-stimulating hormone of the pituitary gland) - 0.4-4.0 mU/l;
Free T3 - 2.6-5.7 pmol/l;
Free T4 - 9.0-22.0 pmol/l;
Total T3 - 1.2-2.8 mIU/l;
T4 total - 60.0-160.0 nmol/l;
thyroglobulin – up to 50 ng/ml.

A healthy thyroid gland and an optimal balance of thyroid hormones are very important for the normal functioning of the body. In order to maintain normal levels of hormones in the blood, it is necessary to prevent a deficiency in food of the necessary components for the construction of thyroid hormones (tyrosine and iodine).

Thyroid hormones have a wide spectrum of action, but most of all their influence affects the cell nucleus. They can directly affect processes occurring in 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.

The stimulating effect of these hormones on the rate of oxygen consumption (calorigenic effect) by the entire body, as well as individual tissues and subcellular fractions, has long been known. A significant role in the mechanism of the physiological calorigenic effect of T 4 and T 3 can be played by the stimulation of the synthesis of such enzymatic proteins that, in the process of their functioning, use the energy of adenosine triphosphate (ATP), for example, membrane sodium-potassium ATPase, which is sensitive to oubaine, and prevents the intracellular accumulation of sodium ions. Thyroid hormones, in combination with adrenaline and insulin, can directly increase the uptake of calcium into cells and increase the concentration of cyclic adenosine monophosphoric acid (cAMP) in them, as well as the transport of amino acids and sugars across the cell membrane.

Thyroid hormones play a special role in regulating the function of the cardiovascular system. Tachycardia in thyrotoxicosis and bradycardia in hypothyroidism are characteristic signs of a violation of thyroid status. These (as well as many other) manifestations of thyroid diseases have long been attributed to an increase in sympathetic tone under the influence of thyroid hormones. However, it has now been proven that excessive levels of the latter in the body lead to a decrease in the synthesis of adrenaline and norepinephrine in the adrenal glands and a decrease in the concentration of catecholamines in the blood. In hypothyroidism, the concentration of catecholamines increases. Data on slowing down the degradation of catecholamines in 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 in a number of tissues (including the heart) has been described.

The mechanisms of penetration of thyroid hormones into cells are not well understood. Regardless of whether passive diffusion or active transport takes place, these hormones penetrate into target cells quite quickly. Binding sites for T 3 and T 4 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 areas that best satisfy the criteria for hormonal receptors. The affinity of the corresponding proteins for various T 4 analogues is usually proportional to the biological activity of the latter. The degree of occupancy of such areas in some cases is proportional to the magnitude of the cellular response to the hormone. The binding of thyroid hormones (mainly T3) in the nucleus is carried out by non-histone chromatin proteins, the molecular weight of which after solubilization is approximately 50,000 daltons. The nuclear action of thyroid hormones does not appear to 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 the interaction of thyroid hormones with chromatin receptors, the activity of RNA polymerase increases quite quickly and the formation of high molecular weight RNA increases. It has been shown that, in addition to a 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 pituicytes and, possibly, the mitochondrial enzyme alpha-glycerophosphate dehydrogenase and cytoplasmic malic enzyme . At physiological hormone concentrations, nuclear receptors are more than 90% bound to T3, while T4 is present in complex with the receptors in very small quantities. This justifies the view of T4 as a prohormone and T3 as a true thyroid hormone.

Regulation of secretion. T 4 and T 3 may depend not only on pituitary TSH, but also on other factors, in particular iodide concentration. However, the main regulator of thyroid activity is still TSH, the secretion of which is under dual control: from the hypothalamic TRH and peripheral thyroid hormones. If the concentration of the latter increases, the TSH response to TRH is suppressed. TSH secretion 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 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 does not differ from that in other polypeptide hormones (LH, FSH, human chorionic gonadotropin). The biological activity and specificity of TSH is determined by its beta subunit, which is separately synthesized by the thyrotrophs of the pituitary gland and subsequently attached to the alpha subunit. This interaction occurs quite 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 influence of TRH in an unbalanced ratio.

Pituitary secretion of TSH is very sensitive to changes in the concentration of T4 and T3 in the blood serum. A decrease or increase in this concentration even by 15-20% leads to reciprocal shifts in the secretion of TSH and its response to exogenous TRH. The activity of T 4 -5 deiodinase in the pituitary gland is especially high, so serum T 4 is converted into T 3 more actively in it than in other organs. This is probably why a decrease in T 3 levels (while maintaining a normal T 4 concentration in the serum), recorded in severe non-thyroid 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 concentrations of T4 and T3 in the serum. Conversely, a sharp drop in thyroid hormone levels after removal of the thyroid gland leads to the restoration of basal TSH secretion and its response to TRH only after several months or even later. This must be taken into account when assessing the state of the pituitary-thyroid axis in patients undergoing treatment for thyroid diseases.

The hypothalamic stimulator of TSH secretion - thyrotropin-releasing hormone (tripeptide pyroglutamylhistidylprolinamide) - 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 is poorly understood. Like other peptide hormones, TRH interacts with pituicyte membrane receptors. Their number decreases not only under the influence of thyroid hormones, but also with an increase in the level of TRH itself (“down regulation”). Exogenous TRH stimulates the secretion of not only TSH, but also prolactin, and in some patients with acromegaly and chronic dysfunction of the liver and kidneys, 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 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 TSH secretion, it is modulated by a number of steroid hormones. Thus, estrogens and oral contraceptives increase the TSH response to TRH (possibly due to an increase in the number of TRH receptors on the membrane of the cells of the anterior pituitary gland) and limit the inhibitory effect of dopaminergic drugs and thyroid hormones. Pharmacological doses of glucocorticoids reduce the basal secretion of TSH, its response to TRH and the rise 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 of the metabolic processes in the thyroid parenchyma. Its main acute effect is to stimulate the production and secretion of thyroid hormones, and its chronic effect is 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 guanyl nucleotide binding protein most likely plays a conjugating role in the interaction of the hormone receptor complex and the enzyme. The factor determining the stimulating effect of the receptor on cyclase may be the (3-subunit of the hormone. Many effects of TSH are apparently mediated by the formation of cAMP from ATP under the action of adenylate cyclase. Although reintroduced TSH continues to bind to the receptors of thyrocytes, the thyroid gland for certain period appears to be refractory to repeated administration of the hormone.The mechanism of this autoregulation of the cAMP response to TSH is unknown.

The cAMP formed under the influence 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, which restore the state of the corresponding proteins. The chronic action of TSH leads to an increase in the volume and height of the thyroid epithelium; then the number of follicular cells increases, which causes their protrusion into the colloidal space. In cultured thyrocytes, TSH promotes the formation of microfollicular structures.

TSH initially reduces the iodide-concentrating capacity of the thyroid gland, probably due to a cAMP-mediated increase in membrane permeability that accompanies membrane depolarization. However, the chronic action of TSH sharply increases iodide uptake, which is apparently indirectly affected by increased synthesis of transporter molecules. Large doses of iodide not only themselves 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.

TSH directly stimulates the synthesis and iodination of thyroglobulin. Under the influence of TSH, oxygen consumption by the thyroid gland quickly and sharply increases, 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 turnover and synthesis of phospholipids in it, increases the activity of phospholipase Ag, which affects the amount of prostaglandin precursor - arachidonic acid.

The thyroid hormones thyroxine (T4) and triiodothyroxine (T3) affect the intensity of metabolism and energy, they increase the absorption of oxygen by cells and tissues, stimulate the breakdown of glycogen, inhibit its synthesis, and affect fat metabolism. The effect of thyroid hormones on the cardiovascular system is especially important. By increasing the sensitivity of cardiovascular system receptors to catecholamines, thyroid hormones increase heart rate and increase blood pressure. Thyroid hormones are necessary for the normal development and functioning of the central nervous system; their deficiency leads to the development of cretinism.
Thyrotoxin stimulates metabolism, accelerates biochemical reactions, affects all organs, and maintains normal tone of the nervous system. The hormone thyroxine affects the activity of adrenaline and cholinesterase, water metabolism, regulating the reabsorption of fluid in the renal tubules, affects cellular permeability, protein, fat and carbohydrate metabolism, the level of oxidative processes in the body, basal metabolism, and hematopoiesis.
Thyroid hormones have a great influence on the hormonal development of the child.
If they are deficient, congenital thyrotoxicosis results in short stature and delayed bone maturation. As a rule, bone age is slower than body growth.
The main effect of thyroid hormones occurs at the level of cartilage; in addition, thyroxine also plays a role in bone mineralization.

Fetal thyroid hormones are produced from the thyroid gland. Maternal thyroid hormones do not pass through the placenta. In this regard, brain development and bone formation in children with congenital athyroidism or hypothyroidism are slowed down at birth. However, children with athyroidism are born with normal weight and height, which gives reason to believe that during intrauterine growth, thyroid hormones do not affect the increase in body weight and height.
Thyroid hormones determine postnatal growth and especially bone maturation. Physiological doses cause a growth effect only in athyroidism and hypothyroidism, but not in healthy children. Normal levels of growth hormone are also required for this effect. In growth hormone deficiency, thyroid hormones can correct only delayed bone maturation, but not delayed growth.
Regulates the secretion of thyroid hormones by thyroid-stimulating hormone, which is synthesized in the anterior lobe of the pituitary gland; its synthesis is controlled by thyrotropin-releasing hormone (a hormone of the hypothalamus). Loss of function of the hypothalamus and pituitary gland leads to hypothyroidism and, conversely, excessive activity of thyroid-stimulating pituitary cells or the presence of thyrotropin-secreting formations of the pituitary gland leads to hyperfunction of the thyroid gland and the development of thyrotoxicosis.

The thyroid-stimulating hormone of the pituitary gland enters the thyroid gland through the bloodstream, binds to special receptors located on the surface of follicular cells, and stimulates their biosynthetic and secretory activity. Most of the thyroxine entering the blood forms a complex with certain serum proteins, but only the free hormone has biological activity.
Triiodothyronine is bound to serum proteins to a lesser extent than thyroxine. The functional activity of the thyroid gland is constant, it decreases only in old age. In the prepubertal and pubertal periods, the activity of the thyroid gland in girls is higher than in boys.
With excess production of thyroid hormones, autoimmune processes can occur, in which the biosynthesis of thyroid hormones and their excess production is controlled not by thyrotropin hormone, but by thyroid-stimulating antibodies. The latter are components of serum immunoglobulins. This leads to a disruption of the immunological balance in the body, a deficiency of T-lymphocytes, T-suppressors, which perform the function of “immunological surveillance” in the body. As a result, “forbidden” clones of T-lymphocytes survive, resulting from mutations of lymphoid cells or their precursors T-chimeras, the latter, sensitized to antigens, interact with B-lymphocytes, which turn into plasma cells capable of synthesizing thyroid-stimulating antibodies.

The most studied are the long-acting thyroid stimulator LATS and LATS-protector, which compete with thyrotropin for binding to its receptors and have an effect similar to that of thyrotropin. Antibodies that exert an isolated trophic effect on the thyroid gland are also determined. Excessive secretion of thyroid hormones enhances catabolic processes in the body: protein breakdown, glycogenolysis, lipolysis, breakdown and conversion of cholesterol.
As a result of dissimilation of processes activated by the thyroid gland, the release of potassium and water from tissues and their elimination from the body increases, vitamin deficiency appears, and body weight decreases. An excess of thyroid hormones initially has an exciting effect on the central nervous system, and subsequently leads to a weakening of both inhibitory and excitatory processes and the emergence of mental instability. It contributes to a disruption of energy utilization, a decrease in the plastic and energy supply of the myocardium, and an increase in sensitivity to the sympathetic influences of catecholamines.
Insufficient production of the pituitary and hypothalamic hormones thyrotropin and thyrotropin-releasing hormone leads to a decrease in the level of thyroid hormones in the body.

Hormone deficiency causes disruption of all types of metabolism:
1) protein - the synthesis and breakdown of protein is disrupted;
2) glycosaminoglycan metabolism (myxidema);
3) carbohydrate - slowing down the absorption of glucose;
4) lipid - increased cholesterol levels;
5) water-salt - water retention in tissues.
Inhibition of oxidative processes is manifested by a decrease in basal metabolism.