The effects of thyroid hormones. Physiological effects of thyroid hormones and their mechanism of action

CHAPTER II
AMIODARON AND THYROID

1. PHYSIOLOGICAL EFFECT OF THYROID HORMONES ON THE CARDIOVASCULAR SYSTEM

1.1. THYROID HORMONES

The thyroid gland synthesizes two hormones that directly control the activity of the cardiovascular system and provide a change in hemodynamics in response to the changing metabolic needs of the body, thyroxine and triiodothyronine. Thyroid hormones play an essential role in the regulation of various physiological functions, including growth, reproduction, and tissue differentiation. Thyroid hormones are able not only to activate metabolism in the body, but also to change the hemodynamic, respiratory, drainage function cardiovascular system and blood, adapting them to a variety of physiological and pathological conditions. Every day, the thyroid gland, with a sufficient intake of iodine, secretes 90-110 μg T 4 and 5-10 μg T 3.

The main substrate for the synthesis of thyroid hormones is iodine. The daily requirement for it is 100-200 mcg. After entering the body, iodine selectively accumulates in the thyroid gland, where it goes through a complex path of transformations and becomes an integral part of T 4 and T 3 (the numbers indicate the number of iodine atoms in the molecule) (Fig. 1). In organism healthy person contains about 15-20 mg of iodine, of which 70-80% is in the thyroid gland. Usually iodine enters the body with food, but under certain conditions, for example, when performing diagnostic procedures or treatment measures, the dose of iodine administered can significantly exceed the physiological requirement. In such cases, an excessive amount of iodine can lead to a change in the synthesis of thyroid hormones and dysfunction of the thyroid gland with the development of hypothyroidism or thyrotoxicosis.

Fig. 1. The main ways of thyroxine metabolism

A large amount of thyroid hormones is stored in the thyroid gland itself, as part of the protein - thyroglobulin, and, as necessary, T 4 and T 3 are secreted into the blood, while the concentration of T 4 is 10-20 times higher than the concentration of T 3. The physiological meaning of this difference lies in the different functional purpose of hormones. Although thyroxine is the main product of the thyroid gland and it is able to exert a number of effects through its own receptors in target cells, in the blood and peripheral tissues under the action of enzymes that split off iodine (deiodinases), T 4 is formed from T 4 and reverse (inactive) pT 3 ( fig. 2). At the level of the cell nucleus, T 3 acts mainly, the biological activity of which is 5 times higher than T 4. Thus, the cells themselves regulate the amount of a more active hormone - T 3 or its reverse form, in order to redistribute energy consumption and conservation in certain situations.

Fig. 2. Regulation of the synthesis and secretion of thyroid hormones

In the blood, T 4 and T 3 circulate in two states: in a free form and in a form associated with transport proteins. A dynamic balance is established between the bound and free fractions of hormones. A drop in free hormone concentration leads to a decrease in binding and vice versa. This buffering system maintains a constant concentration of free hormones in the blood. This is very important for the body, since only free fractions of hormones penetrate into the cell. T 3 has a lower affinity for plasma proteins than T 4, and, therefore, T 4 remains in the blood longer than T 3 (the half-life of T 4 from the body is approximately 7-9 days, T 3 is 1-2 days).

In clinical practice, we are able to determine both free and protein-bound hormone fractions. The value of the total T 4 and T 3 depends to a greater extent on the concentration of binding proteins than on the degree of thyroid dysfunction. With an increase in the content of transport proteins (contraceptives, pregnancy) or with a decrease (androgens, liver cirrhosis, nephrotic syndrome, genetic disorders), the total concentration of hormones changes, while the content of free fractions does not change.

Changes in the concentration of binding proteins can complicate the interpretation of the results of the study of total T 4 and T 3. In this regard, the determination of free fractions T 4 and T 3 is of great diagnostic value.

The main stimulator of the synthesis and secretion of thyroid hormones is the thyroid stimulating hormone of the pituitary gland, which, in turn, is under the control of the hypothalamus, which produces thyroliberin (TRH). The regulation of the secretion of TRH and TSH is carried out using the mechanism of negative feedback and is closely related to the level of T 4 and T 3 in the blood (Fig. 3). If the level of thyroid hormones in the blood decreases, the secretion of TRH and TSH rapidly increases and the concentration of thyroid hormones in the blood is restored. This rigid system helps maintain the optimal concentration of hormones in the blood.

Fig. 3. Regulation of genes that determine the synthesis of proteins in cardiac myocytes by means of triiodothyronine

(Klein I., Ojamaa K. Thyroid hormone and the cardiovascular system, N Engl J Med. 2001; 344: 501-509) as amended.

Laboratory diagnostics of thyroid pathology includes TSH testing, St. T 4 and St. T 3. Testing priority is given primarily to the definition of TSH. Currently, the study of the level of TSH is performed by a highly sensitive third-generation method, which characterizes the function of the thyroid gland with a high degree of reliability. Serum TSH testing is the only reliable method for diagnosing primary hypothyroidism and thyrotoxicosis. In cases where the TSH level does not fit into the normal range, the definition of St. T 4. In some cases (for example, low TSH, St. T 4 is normal), as part of a diagnostic search, St. T 3 (Fig. 4).

In thyroidology, there are three states of the functional activity of the thyroid gland:

• Euthyroidism - TSH, T 4, T 3 are normal.
• Thyrotoxicosis - TSH is decreased, T 4 is increased, T 3 is increased or normal (the exception is TSH - producing pituitary adenoma and syndrome of "inadequate" TSH secretion, caused by pituitary resistance to thyroid hormones).
• Hypothyroidism - TSH increased, T 4 decreased, T 3 decreased or normal.

Subclinical variants of thyroid dysfunction are characterized by normal T 3 and T 4 values \u200b\u200bwith an altered TSH level:

• Subclinical hypothyroidism - TSH is increased, T 4 and T 3 are normal.
• Subclinical thyrotoxicosis - TSH is reduced, T 4 and T 3 are normal.

1.2. MECHANISM OF ACTION OF THYROID HORMONES ON CARDIOMYOCYTES

The action of thyroid hormones on cardiomyocytes is carried out in two ways: through the direct effect of thyroid hormones on gene transcription in the heart muscle and indirectly, through a change in the permeability of plasma membranes, the functioning of mitochondria and sarcoplasmic reticulum. Currently, a number of genes sensitive to the action of thyroid hormones have been isolated. They are presented in Table 3. Thyroid hormones can have both positive and negative regulation. Positive regulation leads to an increase in gene transcriptional activity and an increase in mRNA production. The result of negative regulation is inhibition of the transcriptional activity of the gene and a decrease in the formation of mRNA.

Table 3. Regulation of genes that determine the synthesis of proteins in cardiac myocytes by means of triiodinine

The mechanism of penetration of thyroid hormones through the cell membrane is not well understood. It has been established that the cell membranes of cardiomyocytes contain specific transport proteins for T 3. Although type 2 deiodinase was found in cardiac myocytes, the presence of which may indirectly indicate the conversion of T 4 to T 3, there is no clear evidence in favor of such a conversion. It is T 3 that has the greatest affinity for nuclear receptors. Penetrating into the cell, T 3 enters the nucleus and binds to nuclear receptors, forming a nuclear receptor complex, which, in turn, recognizes a specific DNA region - T 3 sensitive element of the gene promoter, initiating gene transcription and mRNA synthesis (Fig. 3) ...

The coordinated movement of the heart muscle is possible due to the cyclical process of formation and dissociation of the myosin and actin complex. The physiological regulator of muscle contraction is Ca2 +, the action of which is mediated by tropomyosin and the troponin complex. The sequence of information transfer is as follows: Ca2 + - troponin - tropomyosin - actin - myosin. Three isoforms of cardiac muscle myosin molecules are known: α / α, α / β, β / β. They differ in the level of ATPase activity, the a-isoform of the myosin heavy chain has more high level ATPase activity and a higher rate of muscle fiber shortening than the b-isoform. The synthesis of each myosin isoform is encoded by different genes, the expression of which is controlled by thyroid hormones.

In the human heart muscle, b-isoforms of myosin heavy chains, which have a lower contractile activity, prevail. T 3 stimulates the synthesis of the a-isoform of the myosin heavy chain, which has a higher ATPase activity and contractility, which is accompanied by an improvement in the pumping function of the myocardium. Another mechanism of regulation of contraction and relaxation of myocardial fibers is the rate of Ca2 + release into the sarcoplasm and its return to the sarcoplasmic reticulum. T 3 regulates the transcription of genes responsible for the production of proteins of the sarcoplasmic reticulum, Ca-activated ATPase (Ca2 + -ATPase). Ca2 + -ATPase ensures the return of Ca2 + from the sarcoplasm to the sarcoplasmic reticulum. The rate of Ca exchange between the sarcoplasm and the sarcoplasmic reticulum determines the systolic contractile function and diastolic relaxation. Thus, T 3 regulates calcium transport in cardiomyocytes, altering the systolic and diastolic functions of the myocardium.

In addition to a direct effect on the myocardium, T 3 also has an indirect effect through the activation of the synthesis of b-adrenergic receptors in the heart muscle. Under the action of thyroid hormones, there is an increase in the number of β-adrenergic receptors, an increase in the affinity of these receptors for catecholamines, and an increase in the rate of norepinephrine turnover in synapses. Thyroid hormones can exert their influence independently of catecholamines, using common intracellular signaling pathways. By increasing the density of b-adrenergic receptors, T 3 increases the sensitivity of the heart to b-adrenergic stimulation, leading to an increase in heart rate, pulse pressure and cardiac output.

In addition, thyroid hormones have an additional effect on hemodynamics due to extra-nuclear effects. By changing the permeability of plasma membranes for glucose, sodium and calcium, thyroid hormones increase the activity of the 1st order pacemaker.

Thyroid hormones stimulate cellular and tissue respiration. They accelerate the absorption of ADP by mitochondria, activate the tricarboxylic acid cycle, enhance the absorption of phosphate, stimulate ATP synthetase, mitochondrial cytochrome c oxidase, and stimulate electron transport chains.

An increase in respiration, an increase in the formation of ATP and an increase in heat production by mitochondria is the result of a simultaneous increase in the size of mitochondria, synthesis of the structural components of the respiratory chain, the number of enzymes and an increase in the level of free Ca2 + in mitochondria, changes in the structure and properties of mitochondrial membranes.

Under the influence of thyroid hormones, metabolism is accelerated in both directions - both anabolism and catabolism, which is accompanied by increased glycolysis and beta-oxidation of fatty acids, energy expenditure, and increased heat generation. Thus, thyroid hormones, having transcriptional and non-transcriptional effects, can modulate the function of the myocardium and the cardiovascular system under physiological and pathological conditions.

1.3. EFFECT OF THYROID HORMONES ON HEMODYNAMICS

Thyroid hormones have multiple effects on the cardiovascular system and hemodynamics. Indicators of cardiac activity, such as heart rate, cardiac output, blood flow velocity, blood pressure, total peripheral resistance, cardiac contractile function, are directly related to thyroid status.

Thyroid hormones affect the level of energy production, protein synthesis and cell functioning, that is, they provide the vital activity of the body. In addition to the well-studied ability of thyroid hormones to increase tissue oxygen consumption and basal metabolism, causing a secondary change in hemodynamics to meet the increased metabolic needs of the body, thyroid hormones have a direct positive inotropic effect on the heart, regulating the expression of myosin isoforms in cardiomyocytes (Fig. 4).

Fig. 4. The effect of triiodothyronine on the cardiovascular system

Thyroid hormones decrease the total peripheral vascular resistance, causing relaxation of arterioles. Vasodilation is carried out due to the direct effect of T 3 on vascular smooth muscle. As a result of a decrease in vascular resistance, blood pressure decreases, which leads to the release of renin and activation of the angiotensin-aldosterone system. The latter, in turn, stimulates sodium reabsorption, leading to an increase in plasma volume. Thyroid hormones also stimulate the secretion of erythropoietin. The combined effect of these two actions leads to an increase in circulating blood mass, heart rate, blood flow rate and an increase in cardiac output fraction, which helps to meet the increased metabolic needs of the body. Thyroid hormones also affect diastolic function, increasing the rate of isometric relaxation of cardiac myofibrils and reducing the concentration of calcium in the cytosol. By changing the heart rate (positive chronotropic effect), thyroid hormones accelerate the diastolic depolarization of the sinus node and improve the conduction of excitation through the atrioventricular node, providing positive dromotropic and batmotropic effects (Table 4).

Essential thyroid hormones of the thyroid gland play an important role in the functioning of the whole organism.

They are a kind of fuel that ensures the full functioning of all systems and tissues of the body.

During normal functioning of the thyroid gland, their work is invisible, but one has only to disturb the balance active substances endocrine system, then immediately the lack of thyrohormone production becomes noticeable.

The physiological effect of thyroid hormones in the thyroid gland is very broad.
It affects following systems organism:

• cardiac activity;
• respiratory system;
• synthesis of glucose, control of glycogen production in the liver;
• the work of the kidneys and the production of hormones of the adrenal cortex;
• temperature balance in the human body;
• formation nerve fibers, adequate transmission of nerve impulses;
• breakdown of fat.

Without thyroid hormones, oxygen exchange between the cells of the body is not possible, as well as the delivery of vitamins and minerals to the cells of the body.

The mechanism of action of the endocrine system

The work of the thyroid gland is directly affected by the work of the hypothalamus and pituitary gland.

The mechanism for regulating the production of thyrohormones in the thyroid gland directly depends on - TSH, and, on the pituitary gland, it occurs bilaterally due to nerve impulses that transmit information in two directions.

The system works as follows:

1. As soon as there is a need for reinforcement in the thyroid gland, a neural impulse from the gland enters the hypothalamus.
2. The release factor required for the production of TSH is sent from the hypothalamus to the pituitary gland.
3. In the cells of the anterior, the required amount of TSH is synthesized.
4. Thyrotropin entering the thyroid gland stimulates the production of T3 and T4.

It is known that in different time days and under different circumstances, this system works in different ways.

So, the maximum concentration of TSH is found from the evening hours, and the hypothalamus releasing factor is active precisely in the early morning hours after a person wakes up.

It is possible that medicines will have to be taken all your life to maintain the normal functioning of the gland, but it is advisable to know about others.

The thyroid gland (thyroid gland) and the hormones that 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 the physical development of a person, but also significantly affect his intellect. Proof of this is mental retardation in children with congenital hypothyroidism (decreased 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?

The structure and hormones of the thyroid gland

The thyroid gland is an unpaired organ of internal secretion (secreting hormones into the blood), which is located on the front 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 the intensity of blood flow (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 rounded formations that consist of cells (thyrocytes) along the periphery, and are filled with colloid in the middle. 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 consumed with food, otherwise hormone deficiency and its clinical consequences may occur.

If the body needs thyroid hormones, then thyrocytes take back synthesized thyroglobulin from the colloid (a depot of ready thyroid hormones) and split it 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 portion of hormones in the blood is associated with proteins (they also exhibit hormonal activity). This is a special protective mechanism that nature has invented against an excess of thyroid hormones. As needed, T3 and T4 are detached from transport proteins in peripheral tissues 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, in contrast to T4. When thyroxine reaches sensitive cells, it detaches from the protein complex and one atom of iodine is split off from it, then it turns into active T3. Thus, the influence of thyroid hormones is carried out by 96-97% due to triiodothyronine.

The hypothalamic-pituitary system regulates the work 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, then this is captured by the hypothalamus (the part of the brain where the nervous and endocrine regulation of body functions smoothly merge 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 with blood flow and causes it to produce T3 and T4. Conversely, if there is an excess of thyroid hormones in the blood, then less TRH, TSH and, accordingly, T3 and T4 are produced.

The mechanism of action of thyroid hormones

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

Thyroid hormones are hormonal substances that exert their biological effects by connecting with receptors inside cells (just like steroid hormones). There is also a second group of hormones that act by connecting with receptors on the surface of cells (hormones of a protein nature, 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 into the nucleus, they act faster. In addition, they activate enzymes that have already been synthesized. And thyroid and steroid hormones act on target cells by penetrating 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 a second.

The whole difficult process how thyroid hormones regulate body functions can be shown in a simplified way:

• penetration of the hormone into the cell through the cell membrane;
• the 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 the desired genes;
• synthesis of protein-enzymes, which 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 to influence human metabolism (it affects energy, protein, carbohydrate, fat metabolism).

The 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 (increase in temperature and basal metabolism);
• activate the synthesis of proteins by cells (processes of growth and development of tissues);
• lipolytic effect (break down fats), stimulate the oxidation of fatty acids, which leads to their decrease in the blood;
• activate the formation of endogenous cholesterol, which is necessary for the construction of sex, steroid hormones and bile acids;
• activation of the breakdown of glycogen in the liver, which leads to an increase in 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 intrauterine development. If at this time there is a lack of hormones, then the child will be born with cretinism (physical and mental retardation);
• fast healing of wounds and injuries;
• activation of the sympathetic nervous system (increased heart rate, sweating, vasoconstriction);
• increased contractility of the heart;
• stimulation of heat production;
• affect water exchange;
• increase blood pressure;
• inhibit the formation and deposition of fat cells, which leads to weight loss;
• activation mental processes a person;
• maintaining reproductive function;
• stimulate the formation of blood cells in the bone marrow.

Norms of thyroid hormones in the blood

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

Thyroid hormone reference values:

• 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;
• T3 total - 1.2-2.8 mMe / 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).

Hypothalamic thyrotropin-releasing hormone (TRH) stimulates the thyrotrophic cells of the anterior pituitary gland, secreting TSH, which in turn stimulates the growth of the thyroid gland and the secretion of thyroid hormones. In addition, the action of thyroid hormones in the pituitary gland and peripheral tissues is modulated by local deiodinases, which convert T 4 into more active T 3. Finally, the molecular effects of T 3 in individual tissues depend on T 3 receptor subtypes, activation or repression of specific genes, and the interaction of T 3 receptors with other ligands, other receptors (eg, retinoid X receptor, PXR), as well as coactivators and corepressors.

Thyrotropin-releasing hormone
TRH (pyroglutamyl-histidyl-prolineamide tripeptide) is synthesized by neurons of the supraoptic and paraventricular nuclei of the hypothalamus. It accumulates in the median eminence of the hypothalamus, and then is transported along the hypothalamic-pituitary portal vein system, passing through the pituitary pedicle, to its anterior lobe, where it controls the synthesis and secretion of TSH. In other parts of the hypothalamus and brain, as well as in the spinal cord, TRH can play the role of a neurotransmitter. The TRH gene, located on chromosome 3, encodes a large pre-pro-TRH molecule containing five hormone precursor sequences. Expression of the TRH gene is inhibited by both plasma T 3 and T 3 formed as a result of T 4 deiodination in peptidergic neurons themselves.
In the anterior lobe of the pituitary gland, TRH interacts with its receptors localized on the membranes of TSH- and PRL-secreting cells, stimulating the synthesis and secretion of these hormones. The TRH receptor belongs to the family of G-protein coupled receptors with seven transmembrane domains. TRH binds to the third transmembrane helix of the receptor and activates both the formation of cGMP and the inositol-1,4,5-triphosphate (IF 3) cascade, which leads to the release of intracellular Ca 2+ and the formation of diacylglycerol and, therefore, to the activation of protein kinase C. These reactions are responsible for the stimulation of TSH synthesis, coordinated transcription of genes encoding TSH subunits, and post-translational glycosylation of TSH, which imparts biological activity to it.
TRH-stimulated TSH secretion is impulsive; the average amplitude of impulses recorded every 2 hours is 0.6 mU / L. In a healthy person, TSH secretion follows a circadian rhythm. The maximum plasma TSH level is determined between midnight and 4 a.m. This rhythm is set, apparently, by an impulse generator of TRH synthesis in hypothalamic neurons.
Thyroid hormones decrease the number of TRH receptors on pituitary thyrotrophs, which forms an additional negative feedback mechanism. As a result, in hyperthyroidism, the amplitude of TSH impulses and its nocturnal output decrease, and in hypothyroidism, both increase. In experimental animals and newborns, exposure to cold increases the secretion of TRH and TSH. The synthesis and secretion of TRH is also stimulated by some hormones and drugs (for example, vasopressin and a-adrenergic agonists).
When intravenous administration human TRH in doses of 200-500 μg, the serum TSH concentration rapidly increases 3-5 times; the reaction reaches its peak in the first 30 minutes after administration and lasts 2-3 hours. In primary hypothyroidism, against the background of an increased basal TSH level, the TSH response to exogenous TRH increases. In patients with hyperthyroidism, autonomously functioning thyroid nodules and central hypothyroidism, as well as in patients receiving high doses of exogenous thyroid hormones, the TSH response to TRH is weakened.
TRH is also present in the islet cells of the pancreas, gastrointestinal tract, placenta, heart, prostate, testes and ovaries. Its production in these tissues is not inhibited by T 3, and its physiological role remains unknown.

Thyrotropin (thyroid-stimulating hormone, TSH)
TSH is a 28 kDa glycoprotein composed of α- and β-subunits non-covalently linked to each other. The same α-subunit is part of two more pituitary glycoprotein hormones - follicle stimulating hormone (FSH) and luteinizing hormone (LH), as well as the placental hormone - human chorionic gonadotropin (hCG); The β-subunits of all these hormones are different, and it is they that determine the binding of hormones to their specific receptors and the biological activity of each of the hormones. The genes for the α- and β-subunits of TSH are located on chromosome 6 and 1, respectively. In humans, the α-subunit contains a polypeptide nucleus of 92 amino acid residues and two oligosaccharide chains, while the β-subunit contains a polypeptide nucleus of 112 amino acid residues and one oligosaccharide chain. Each of the polypeptide chains of the α- and β-subunits of TSH forms three loops folded into a cystine knot. In the SHER and the Golgi apparatus, glycosylation of polypeptide nuclei occurs, that is, the addition of glucose, mannose and fucose residues and terminal residues of sulfate or sialic acid to them. These carbohydrate residues increase the duration of the hormone's presence in plasma and its ability to activate the TSH receptor (TSH-R).
TSH regulates cell growth and the production of thyroid hormones by binding to its specific receptor. There are about 1000 such receptors on the basolateral membrane of each thyrocyte. TSH binding activates intracellular signaling pathways mediated by both cyclic adenosine monophosphate (cAMP) and phosphoinositol. The gene TSH-P, located on chromosome 14, encodes a single-stranded glycoprotein of 764 amino acid residues. TSH-R belongs to the family of G-protein coupled receptors with seven transmembrane domains; the extracellular part of TSH-R binds the ligand (TSH), and the intramembrane and intracellular parts are responsible for the activation of signaling pathways, stimulation of thyrocyte growth and the synthesis and secretion of thyroid hormones.
Known hereditary defects in the synthesis or action of TSH include mutations in the genes of transcription factors that determine the differentiation of pituitary thyrotrophs (POU1F1, PROP1, LHX3, HESX1), mutations in the genes of TRH, the β-subunit of TSH, TSH-R, and the GSa protein, which transmits the signal from TSH binding to TSH -P for adenylate cyclase. The appearance of thyroid-blocking antibodies in the serum can also lead to hypothyroidism.
Most frequent form hyperthyroidism is Graves' disease in which TSH-R is bound and activated by autoantibodies. However, TSH-R is involved in the pathogenesis of other forms of hyperthyroidism. Activating mutations of the TSH-P gene in germ cells underlie familial hyperthyroidism, and somatic mutations of this gene underlie toxic thyroid adenoma. Other mutations can lead to the synthesis of abnormal TSH-R, which is activated by a structurally similar ligand, hCG, as is observed in familial hyperthyroidism of pregnancy.

Effect of TSH on thyroid cells
TSH has a variety of effects on thyrocytes. Most of them are mediated by the G-protein-adenylate cyclase-cAMP system, but the activation of the phosphatidylinositol (FIF 2) system, accompanied by an increase in the intracellular calcium level, also plays a role. The main effects of TSH are listed below.

Changes in thyrocyte morphology

TSH quickly induces the appearance of pseudopodia at the border of thyrocytes with the colloid, which accelerates the resorption of thyroglobulin. The colloid content in the lumen of the follicles decreases. Colloid drops appear in the cells, the formation of lysosomes and the hydrolysis of thyroglobulin are stimulated.

Growth of thyroid cells
Individual thyrocytes increase in size. The vascularization of the thyroid gland increases and goiter develops over time.

Iodine metabolism
TSH stimulates all stages of iodide metabolism - from its absorption and transport in the thyroid gland to iodination of thyroglobulin and the secretion of thyroid hormones. The effect on the transport of iodide is mediated by cAMP, and on the iodination of thyroglobulin - by the hydrolysis of phosphatidylinositol-4,5-diphosphate (FIF 2) and an increase in the intracellular level of Ca 2+. TSH acts on the transport of iodide to thyrocytes in two phases: the absorption of iodide is initially inhibited (outflow of iodide), and after a few hours it increases. The outflow of iodide can be a consequence of the acceleration of thyroglobulin hydrolysis with the release of hormones and the outflow of iodide from the gland.

Other effects of TSH
Other effects of TSH include stimulation of thyroglobulin and TPO mRNA transcription, acceleration of the formation of MIT, DIT, T 3 and T 4, and increased lysosome activity with increased secretion of T 4 and T 3. Under the influence of TSH, the activity of type 1 5'-deiodinase also increases, which contributes to the preservation of iodide in the thyroid gland.
In addition, TSH stimulates the absorption and oxidation of glucose as well as oxygen consumption by the thyroid gland. The cycle of phospholipids is also accelerated and the synthesis of purine and pyrimidine precursors of DNA and RNA is activated.

Serum TSH concentration
The blood contains both whole TSH molecules and its individual α-subunits, the concentrations of which, when determined by immunological methods, are normally 0.5-4.0 mU / l and 0.5-2 μg / l, respectively. The serum TSH content increases in primary hypothyroidism and decreases in thyrotoxicosis, whether endogenous or associated with the intake of excessive amounts of thyroid hormones. T 1/2 TSH in plasma is approximately 30 minutes, and its daily production is about 40-150 mU.
In patients with TSH-secreting pituitary tumors, a disproportionately high content of the α-subunit is often found in the serum. Its increased concentration is also characteristic of healthy women in the postmenopausal period, since the secretion of gonadotropins increases during this period.

Regulation of pituitary TSH secretion

The synthesis and secretion of TSH is mainly regulated by two factors:

1. the level of T 3 in thyroid-trophic cells, which determines the expression of TSH mRNA, its translation and secretion of the hormone;
2. TRH, which regulates post-translational glycosylation of TSH subunits and, again, its secretion.

High levels of T 4 and T 3 in serum (thyrotoxicosis) inhibit the synthesis and secretion of TSH, and low levels of thyroid hormones (hypothyroidism) stimulate these processes. A number of hormones also have an inhibitory effect on TSH secretion. medicines (somatostatin, dopamine, bromocriptine and glucocorticoids). A decrease in TSH secretion is observed in acute and chronic diseases, and after recovery, a "recoil effect" is possible, that is, an increase in the secretion of this hormone. The substances listed above usually only slightly reduce the concentration of TSH in serum, which remains detectable, whereas with overt hyperthyroidism, the concentration of TSH may fall below the detection limits of the most modern immunological methods.

Disorders of TRH and TSH secretion can occur in tumors and other diseases of the hypothalamus or pituitary gland. Hypothyroidism caused by dysfunction of the pituitary gland is called "secondary", and caused by the pathology of the hypothalamus - "tertiary".

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Other stimulants and inhibitors of thyroid function
The follicles of the thyroid gland are surrounded by a dense network of capillaries, on which noradrenergic fibers of the superior cervical ganglion end, as well as fibers vagus nerve and thyroid ganglia containing acetylcholinesterase. Parafollicular C cells secrete calcitonin and a calcitonin gene-related peptide (PRGC). In experimental animals, these and other neuropeptides affect the blood flow in the thyroid gland and the secretion of thyroid hormones. In addition, growth factors such as insulin, IGF-1 and epidermal growth factor, as well as autocrine factors such as prostaglandins and cytokines, affect the growth of thyrocytes and the production of thyroid hormones. However, the clinical significance of all of these influences remains unclear.

Role of pituitary and peripheral deiodinases
The main amount of T 3 in the thyrotrophs of the pituitary gland and the brain is formed as a result of deiodination of T 4 under the action of type 2 5'-deiodinase. In hypothyroidism, the activity of this enzyme increases, which allows for some time to maintain a normal concentration of T 3 in the brain structures, despite to decrease the level of T 4 in plasma.In hyperthyroidism, the activity of type 2 5'-deiodinase decreases, which protects the pituitary gland and nerve cells from excessive action of T 3. In contrast, the activity of type 1 5'-deiodinase in hypothyroidism decreases, ensuring the maintenance of T 4, while in hyperthyroidism it increases, accelerating the metabolism of T 4.

Autoregulation in the thyroid gland
Autoregulation can be defined as the ability of the thyroid gland to adapt its function to changes in iodine availability independently of the pituitary TSH. The normal secretion of thyroid hormones is maintained when iodide consumption fluctuates from 50 μg to several milligrams per day. Some of the effects of iodide deficiency or excess have been discussed above. The main mechanism of adaptation to a low intake of iodide in the body is to increase the proportion of synthesized T3, which increases the metabolic efficiency of thyroid hormones. On the other hand, excess iodide inhibits many thyroid functions, including iodide transport, cAMP production, hydrogen peroxide production, thyroid hormone synthesis and secretion, and TSH and autoantibody binding to TSH-R. Some of these effects may be mediated by the formation of iodinated fatty acids in the thyroid gland. The ability of the normal gland to "escape" from the inhibitory influences of excess iodide (the Wolf-Chaikoff effect) allows the secretion of thyroid hormones to be maintained at high iodide consumption. It is important to note that the mechanism of the Wolff-Chaikoff effect differs from the mechanism of the therapeutic action of iodide in Graves' disease. In the latter case, high doses of iodide chronically inhibit thyroglobulin endocytosis and the activity of lysosomal enzymes, inhibiting the secretion of thyroid hormones and reducing their concentration in the blood. Besides, pharmacological doses iodide reduce the blood supply to the thyroid gland, which makes it easier surgical interventions on it. However, this effect also lasts for a short time - from 10 days to 2 weeks.

Action of thyroid hormones

1. Receptors of thyroid hormones and mechanisms of their action

Thyroid hormones realize their effects by two main mechanisms:

1. genomic effects involve the interaction of T 3 with its nuclear receptors, which regulate gene activity;
2. non-genomic effects are mediated by the interaction of T 3 and T 4 with certain enzymes (for example, calcium ATPase, adenylate cyclase, monomeric pyruvate kinase), glucose transporters and mitochondrial proteins.

Free thyroid hormones, using specific carriers or by passive diffusion, pass through the cell membrane into the cytoplasm, and then into the nucleus, where T 3 binds to its receptors. Nuclear T 3 receptors belong to the superfamily of nuclear proteins, which also includes receptors for gluco- and mineral-corticoids, estrogens, progestins, vitamin D, and retinoids.
In humans, thyroid hormone (TP) receptors are encoded by two genes: TPa, located on chromosome 17, and TPβ, localized on chromosome 3. As a result of alternative splicing of mRNAs transcribed from each of these genes, two different protein products are formed:
TPα1 and TPα2 and TPβ1 and TPβ2, although TPα2 is believed to be devoid of biological activity. TPs of all types contain a C-terminal ligand-binding and a central DNA-binding domain with two zinc fingers, which facilitate the interaction of receptors with DNA elements sensitive to thyroid hormones (TSHE). TSEs are located in the promoter regions of target genes and regulate the transcription of the latter. In different tissues and at different stages of development, different amounts of certain TRs are synthesized. For example, the brain contains mainly TPα, the liver contains TPβ, and the heart muscle contains both types of receptors. Point mutations of the TPβ gene, disrupting the structure of the ligand-binding domain of this receptor, underlie generalized resistance to thyroid hormones (HRTHH). The TPEs with which TP interact are usually peculiar paired oligonucleotide sequences (for example, AGGTCA). TP can bind to TSE and in the form of heterodimers with receptors for other transcription factors, such as PXP and the retinoic acid receptor. In the operon, TChEs are located, as a rule, in front of the start site of transcription of the coding region of target genes. In the case of genes activated by thyroid hormones, TPs, in the absence of a ligand, form bonds with corepressors [for example, the corepressor of nuclear receptors (NCoR) and the “quencher” of the effects of retinoic acid and thyroid hormone receptors (SMRT)]. This leads to the activation of histone deacetylases, which change the local structure of chromatin, which is accompanied by repression of basal transcription. When TP binds to T 3, corepressor complexes break down, and TP form complexes with coactivators that promote histone acetylation. Associated with T 3 TP also bind other proteins (in particular, a protein that interacts with the vitamin D receptor); the resulting protein complexes mobilize RNA polymerase II and activate transcription. The expression of some genes (for example, the pre-pro-TRH gene and the genes of the α- and β-subunits of TSH) under the influence of TP associated with T 3 is reduced, but the molecular mechanisms of such effects are less well understood. The change in the synthesis of individual RNA and proteins determines the nature of the reactions of different tissues to the action of thyroid hormones.
A number of cellular reactions to thyroid hormones arise earlier than the processes of transcription in the nucleus could change; in addition, the binding of T 4 and T 3 with the extra-nuclear structures of cells was found. All this suggests the existence of non-genomic effects of thyroid hormones. Recently, it has been shown, for example, that they bind to the membrane protein integrin αVβ3, which mediates the stimulating effect of thyroid hormones on the MAP kinase cascade and angiogenesis.

2. Physiological effects of thyroid hormones
The effect of T 3 on gene transcription reaches its maximum after a few hours or days. These genomic influences alter a number of vital functions, including tissue growth, brain maturation, heat production and oxygen consumption, as well as heart, liver, kidney, skeletal muscle, and skin health. The non-genomic effects of thyroid hormones include a decrease in the activity of type 2 5'-deiodinase in the pituitary gland and the activation of glucose and amino acid transport in some tissues.

Influence on fetal development
The ability of the thyroid gland to concentrate iodide and the appearance of TSH in the pituitary gland are observed in the human fetus around the 11th week of pregnancy. Due to the high content of type 3 5-deiodinase in the placenta (which inactivates most maternal T 3 and T 4) a very small amount of free maternal thyroid hormones enters the fetal bloodstream. However, they are extremely important for early stages development of the fetal brain. After the 11th week of pregnancy, the development of the fetus depends mainly on its own thyroid hormones. Some ability of the fetus to grow is preserved even in the absence of a thyroid gland, but the development of the brain and the maturation of the skeleton under such conditions are sharply impaired, which is manifested by cretinism (mental retardation and dwarfism).

Effects on oxygen consumption, heat production and free radical formation
The increase in O 2 consumption under the influence of T 3 is partly due to the stimulation of Na +, K + -ATPase in all tissues, with the exception of the brain, spleen and testes. This contributes to an increase in basal metabolism (total consumption of 02 at rest) and sensitivity to heat in hyperthyroidism and in opposite shifts in hypothyroidism.

Effects on the cardiovascular system
T3 stimulates the synthesis of Ca 2+ -ATPase of the sarcoplasmic reticulum, which increases the rate of diastolic relaxation of the myocardium. Under the influence of T 3, the synthesis of α-isoforms of myosin heavy chains with greater contractility also increases, which determines the enhancement of the systolic function of the myocardium. In addition, T 3 affects the expression of various isoforms of Na +, K + -ATPase, enhances the synthesis of β-adrenergic receptors and reduces the concentration of inhibitory G-protein (Gi) in the myocardium. The increase in heart rate is due to the acceleration of both depolarization and repolarization of the cells of the sinus node under the influence of T 3. Thus, thyroid hormones have a positive inotropic and chronotropic effect on the heart, which, together with an increase in its sensitivity to adrenergic stimulation, determines tachycardia and an increase in myocardial contractility in hyperthyroidism and opposite shifts in hypothyroidism. Finally, thyroid hormones reduce peripheral vascular resistance, and this contributes to a further increase in cardiac output in hyperthyroidism.

Effects on the sympathetic nervous system
Thyroid hormones increase the number of β-adrenergic receptors in the heart, skeletal muscle, adipose tissue and lymphocytes, and, possibly, enhance the effect of catecholamines at the postreceptor level. Many clinical manifestations thyrotoxicosis reflect increased sensitivity to catecholamines, and β-blockers often eliminate such manifestations.

Pulmonary Effects
Thyroid hormones contribute to the preservation of the reactions of the respiratory center of the brain stem to hypoxia and hypercapnia. Therefore, in severe hypothyroidism, hypoventilation may occur. Respiratory muscle function is also regulated by thyroid hormones.

Influence on hematopoiesis
An increase in the need for cells in O 2 in hyperthyroidism causes increased production of erythropoietin and acceleration of erythropoiesis. However, due to the more rapid destruction of red blood cells and hemodilution, the hematocrit does not usually increase. Under the influence of thyroid hormones in erythrocytes, the content of 2,3-diphosphoglycerate increases, which accelerates the dissociation of oxyhemoglobin and increases the availability of O 2 for tissues. Hypothyroidism is characterized by opposite shifts.

Effect on the gastrointestinal tract
Thyroid hormones increase intestinal peristalsis, which leads to increased frequency of bowel movements in hyperthyroidism. In hypothyroidism, on the other hand, the passage of food through the intestines slows down and constipation occurs.

Effect on bones
Thyroid hormones stimulate the circulation bone tissue, accelerating bone resorption and (to a lesser extent) osteogenesis. Therefore, hyperthyroidism develops hypercalciuria and (less often) hypercalcemia. In addition, chronic hyperthyroidism may be accompanied by a clinically significant loss of bone mineral matter.

Neuromuscular effects
In hyperthyroidism, protein circulation is accelerated, and its content in skeletal muscles decreases. This leads to the proximal myopathy characteristic of this disease. Thyroid hormones also increase the rate of contraction and relaxation of skeletal muscles, which is clinically manifested in hyperthyroidism by hyperreflexia, and in hypothyroidism - by slowing down the relaxation phase of deep tendon reflexes. Subtle tremors of the fingers are also typical of hyperthyroidism. It has already been noted above that thyroid hormones are necessary for the normal development and functioning of the central nervous system, and a failure of the thyroid gland in the fetus leads to severe mental retardation (Early detection of congenital hypothyroidism (newborn screening) helps prevent the development of such disorders). In adults with hyperthyroidism, hyperactivity and fussiness are observed, while in patients with hypothyroidism, slowness and apathy are observed.

Effect on lipid and carbohydrate metabolism
With hyperthyroidism, both glycogenolysis and gluconeogenesis in the liver are accelerated, as well as the absorption of glucose in the gastrointestinal tract. Therefore, hyperthyroidism makes it difficult to control glycemia in patients who simultaneously suffer diabetes mellitus... Thyroid hormones accelerate both the synthesis and breakdown of cholesterol. The latter effect is mainly associated with an increase in hepatic low-density lipoprotein (LDL) receptors and an acceleration of LDL clearance. In hypothyroidism, total and LDL cholesterol levels are generally elevated. Lipolysis is also accelerated, as a result of which the content of free fatty acids and glycerol in the plasma increases.

Endocrine effects
Thyroid hormones alter the production, regulation of secretion, and metabolic clearance of many other hormones. In children with hypothyroidism, the secretion of growth hormone is disrupted, which slows down the growth of the body in length. Hypothyroidism can delay and sexual development, disrupting the secretion of GnRH and gonadotropins. However, in primary hypothyroidism, premature sexual development is sometimes observed, probably due to the interaction of very large amounts of TSH with gonadotropin receptors. Some women with hypothyroidism develop hyperprolactinemia. Menorrhagia (prolonged and severe uterine bleeding), anovulation and infertility. In hypothyroidism, the reaction of the hypothalamic-pituitary-adrenal system to stress is weakened, which is somewhat offset by a slowdown in the metabolic clearance of cortisol. The restoration of euthyroidism in such cases can lead to adrenal insufficiency, since the clearance of cortisol is accelerated, and its reserves remain reduced.
With hyperthyroidism in men, gynecomastia may develop, due to the accelerated aromatization of androgens with the formation of estrogens and an increased level of globulin that binds sex hormones. The gonadotropic regulation of ovulation may also be impaired and menstrual cycleleading to infertility and amenorrhea. Restoration of euthyroidism usually eliminates all of these endocrine disorders.