CHAPTER II
AMIODARONE AND THE THYROID GLAND
1. PHYSIOLOGICAL EFFECT OF THYROID HORMONES ON THE CARDIOVASCULAR SYSTEM
1.1. THYROID HORMONES
IN thyroid gland two hormones are synthesized that directly control the activity of the cardiovascular system and ensure changes in hemodynamics in response to the changing metabolic needs of the body, thyroxine and triiodothyronine. Thyroid hormones play a significant role in the regulation of various physiological functions, including growth, reproduction, tissue differentiation. Hormones thyroid gland are able not only to activate metabolism in the body, but also to change the hemodynamic, respiratory, drainage functions of the cardiovascular system and blood, adapting them to a variety of physiological and pathological conditions. Every day, the thyroid gland, with sufficient iodine intake, secretes 90-110 μg of T 4 and 5-10 μg of T 3.
The main substrate for the synthesis of thyroid hormones is iodine. Daily requirement it contains 100-200 mcg. After entering the body, iodine selectively accumulates in the thyroid gland, where it passes difficult path 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 the body healthy person contains about 15-20 mg of iodine, of which 70-80% is found in the thyroid gland. Typically, iodine enters the body with food products, but under certain conditions, for example, when conducting diagnostic procedures or therapeutic measures, the dose of iodine administered can significantly exceed physiological need. In such cases, an excess amount of iodine can lead to changes in the synthesis of thyroid hormones and dysfunction of the thyroid gland with the development of hypothyroidism or thyrotoxicosis.
Rice. 1. Main pathways of thyroxine metabolism
A large amount of thyroid hormones are stored in the thyroid gland itself, as part of the protein thyroglobulin, and as needed, 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 purposes of hormones. Although thyroxine is the main product of the thyroid gland and it is capable of exerting a number of effects through its own receptors in target cells, in the blood and peripheral tissues under the action of enzymes that cleave iodine (deiodinases), T 4 is formed from T 3 and reverse (inactive) pT 3 ( Fig. 2). At the level of the cell nucleus, T3 acts predominantly, the biological activity of which is 5 times higher than T4. Thus, the cells themselves regulate the amount of more active hormone- T 3 or its reverse form, in order to redistribute energy consumption and conservation in certain situations.
Rice. 2. Regulation of 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 bound to transport proteins. A dynamic equilibrium is established between bound and free fractions of hormones. A decrease in the concentration of free hormone leads to a decrease in binding and vice versa. This buffer system allows you to maintain constant concentration 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 less 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 - 1-2 days).
IN clinical practice We are able to determine both free and protein-bound fractions of hormones. The magnitude of total T4 and T3 depends to a greater extent on the concentration of binding proteins than on the degree of dysfunction of the thyroid gland. When the content of transport proteins increases (contraceptives, pregnancy) or when they decrease (androgens, liver cirrhosis, nephrotic syndrome, genetic disorders) there is a change in the total concentration of hormones, while the content of free fractions does not change.
Changes in the concentration of binding proteins may complicate the interpretation of the results of studies of total T 4 and T 3 . In this regard, the determination of free fractions T 4 and T 3 has great diagnostic significance.
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 thyrotropin-releasing hormone (TRH). Regulation of the secretion of TRH and TSH is carried out using a negative feedback mechanism 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 quickly increases and the concentration of thyroid hormones in the blood is restored. This rigid system allows you to maintain optimal concentrations of hormones in the blood.
Rice. 3. Regulation of genes that determine protein synthesis in cardiac myocytes through triiodothyronine
(Klein I., Ojamaa K. Thyroid hormone and the cardiovascular system, N Engl J Med. 2001; 344: 501-509) with additions.
Laboratory diagnosis of thyroid pathology includes testing of TSH, st. T 4 and St. T 3. Testing priority is given primarily to TSH determination. Currently, the study of TSH levels is carried out using 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 diagnostic method primary hypothyroidism and thyrotoxicosis. In cases where the TSH level does not fall within the range of normal values, a determination of St. is carried out. T 4. In some cases (for example, low TSH, St. T 4 is normal), St. is determined as part of the diagnostic search. T 3 (Fig. 4).
In thyroidology, there are three states of functional activity of the thyroid gland:
Subclinical variants of thyroid dysfunction are characterized by normal T 3 and T 4 levels with an altered TSH level:
1.2. MECHANISM OF ACTION OF THYROID HORMONES ON CARDIOMYOCYTES
The effect of thyroid hormones on cardiomyocytes occurs in two ways: through the direct influence of thyroid hormones on gene transcription in the heart muscle and indirectly, through changes in the permeability of plasma membranes, the functioning of mitochondria and the sarcoplasmic reticulum. Currently, a number of genes sensitive to the action of thyroid hormones have been identified. They are presented in Table 3. Thyroid hormones can exert both positive and negative regulation. Positive regulation leads to increased transcriptional activity of the gene and increased mRNA production. The result of negative regulation is inhibition of gene transcriptional activity and decreased mRNA production.
Table 3. Regulation of genes that determine protein synthesis in cardiac myocytes by 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 T3. Although type 2 deiodinase has been found in cardiac myocytes, the presence of which may indirectly indicate the conversion of T4 to T3, clear evidence in favor of such a conversion has not been obtained. It is T3 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 section of DNA - the T 3 sensitive element of the gene promoter, initiating gene transcription and mRNA synthesis (Fig. 3) .
Coordinated movement of the cardiac muscle is possible due to the cyclic process of formation and dissociation of the myosin-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 a higher level of 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 human cardiac muscle, b-isoforms of myosin heavy chains predominate, which have lower contractile activity. T 3 stimulates the synthesis of the a-isoform of the myosin heavy chain, which has higher ATPase activity and contractility, which is accompanied by improvement pumping function myocardium. Another mechanism for regulating the contraction and relaxation of myocardial fibers is the rate of release of Ca2+ into the sarcoplasm and its return to the sarcoplasmic reticulum. T 3 regulates the transcription of genes responsible for the production of sarcoplasmic reticulum proteins, 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 systolic contractile function and diastolic relaxation. Thus, T 3 regulates calcium transport in cardiomyocytes, changing the systolic and diastolic function of the myocardium.
Besides direct action on the myocardium, T 3 also has an indirect effect through activation of the synthesis of b-adrenergic receptors in the heart muscle. Under the influence of thyroid hormones, there is an increase in the number of b-adrenergic receptors, an increase in the affinity of these receptors for catecholamines, and an increase in the rate of turnover of norepinephrine in synapses. Thyroid hormones can exert their influence independently of catecholamines, using common pathways of intracellular signaling. 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 additional effects on hemodynamics due to extranuclear effects. By changing the permeability of plasma membranes to glucose, sodium and calcium, thyroid hormones increase the activity of the 1st order pacemaker.
Thyroid hormones stimulate cellular and tissue respiration. They accelerate the uptake of ADP by mitochondria, activate the tricarboxylic acid cycle, enhance phosphate uptake, stimulate ATP synthetase, mitochondrial cytochrome c oxidase, and stimulate electron transport chains.
Increased respiration, increased ATP production and increased heat production by mitochondria are the result of a simultaneous increase in the size of mitochondria, the synthesis of 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 accelerates in both directions - both anabolism and catabolism, which is accompanied by increased glycolysis and beta-oxidation fatty acids, energy consumption, increased heat generation. Thus, thyroid hormones, exerting transcriptional and non-transcriptional effects, can modulate myocardial and cardiovascular function under physiological and pathological conditions.
1.3. INFLUENCE OF THYROID HORMONES ON HEMODYNAMICS
Thyroid hormones have multiple effects on cardiovascular system and hemodynamics. Indicators of cardiac activity, such as heart rate, cardiac output, blood flow velocity, blood pressure, total peripheral resistance, contractile function hearts are directly related to thyroid status.
Thyroid hormones affect the level of energy production, protein synthesis and cell functioning, i.e., they ensure the vital functions 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 by regulating the expression of myosin isoforms in cardiomyocytes (Fig. 4).
Rice. 4. Effect of triiodothyronine on the cardiovascular system
Thyroid hormones reduce total peripheral vascular resistance, causing arterioles to relax. Vasodilation occurs due to the direct effect of T 3 on smooth muscles vessels. 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 velocity and an increase in the fraction cardiac output, which helps 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 heart rate (a positive chronotropic effect), thyroid hormones accelerate diastolic depolarization sinus node and improve the conduction of excitation through the atrioventricular node, providing positive dromotropic and bathmotropic effects (Table 4).
Produced by the thyroid gland, responsible for regulating metabolism. Iodine is required for the production of T3 and T4. Iodine deficiency leads to decreased production of T3 and T4, resulting in enlargement of the thyroid tissue and the development of a condition known as goiter. The main form of thyroid hormones in the blood is thyroxine (T4), which has more long period half-life than T3. The ratio of T4 to T3 released into the bloodstream is approximately 20 to 1. T4 is converted to active T3 (three to four times more potent than T4) in cells by deiodinases (5"-iodinase). The substance then undergoes decarboxylation and deiodination , producing iodothyronamine (T1a) and thyronamine (T0a). All three isoforms of deiodinases are selenium-containing enzymes, so the body requires dietary intake to produce T3.
Thyronines act on almost all cells of the body. They speed up basal metabolism, affect protein synthesis, and help regulate growth long bones(acting in synergy with ), are responsible for the maturation of neurons and increase the body's sensitivity to catecholamines (for example, adrenaline) due to permissiveness. Thyroid hormones are necessary for normal development and differentiation of all cells of the human body. These hormones also regulate protein, fat and carbohydrate water exchange, influencing how human cells use energy compounds. In addition, these substances stimulate the metabolism of vitamins. The synthesis of thyroid hormones is influenced by numerous physiological and pathological factors.
Thyroid hormones influence the release of heat in the human body. However, the mechanism by which thyronamines inhibit neuronal activity, which plays an important role in the hibernation cycles of mammals and molting in birds, is still unknown. One of the effects of using thyronamines is a sharp decrease in body temperature.
Thyroid hormones (T3 and T4) are synthesized by the follicular cells of the thyroid gland and are regulated by thyroid-stimulating hormone (TSH)-produced thyrotropes from the anterior pituitary gland. T4's effects natural conditions mediated by T3 (T4 is converted to T3 in target tissues). The activity of T3 is 3-5 times higher than the activity of T4.
Thyroxine (3,5,3,5"-tetraiodothyronine) is produced by the follicular cells of the thyroid gland. It is produced as a precursor to thyroglobulin (this is not the same as thyroxine-binding globulin), which is broken down by enzymes to produce active T4.
During this process the following steps are carried out:
The Na+/I- symporter transports two sodium ions across the basement membrane of follicle cells along with an iodine ion. It is a secondary active transporter that uses the Na+ concentration gradient to move I- against the concentration gradient.
I- moves along the apical membrane into the follicle colloid.
Thyroid peroxidase oxidizes two I- to form I2. Iodide is not reactive and the more reactive iodine is required for the next step.
Thyroid peroxidase iodines thyroglobulin residues in the colloid. Thyroglobulin is synthesized on the ER (endoplasmic reticulum) of the follicular cell and secreted into the colloid.
Thyroid-stimulating hormone (TSH), released from the pituitary gland, binds to the TSH receptor (Gs protein-coupled receptor) on the basolateral membrane of the cell and stimulates endocytosis of the colloid.
Endocytosed vesicles fuse into the lysosomes of the follicular cell. Lysosomal enzymes cleave T4 from iodinated thyroglobulin.
These vesicles then undergo exocytosis, releasing thyroid hormones.
Thyroxine is produced by attaching iodine atoms to ring structures of molecules. Thyroxine (T4) contains four iodine atoms. Triiodothyronine (T3) is identical to T4, but its molecule contains one less iodine atom.
Iodide is actively absorbed from the blood through a process called iodide uptake. Sodium here is cotransported with iodide from the basolateral side of the membrane into the cell and then accumulates in the thyroid follicles in concentrations thirty times higher than its concentration in the blood. Through a reaction with the enzyme thyroid peroxidase, iodine binds to residues in thyroglobulin molecules, forming monoiodotyrosine (MIT) and diiodotyrosine (DIT). When two fragments of DIT bind, thyroxine is formed. The combination of one MIT particle and one DIT particle produces triiodothyronine.
DIT + MIT = R-T3 (biologically inactive)
MIT + DIT = triiodothyronine (T3)
DIT + DIT = thyroxine (T4)
Proteases process iodinated thyroglobulin, releasing the hormones T4 and T3, biologically active substances, playing a central role in the regulation of metabolism.
Thyroxine is a prohormone and reservoir for the most active and main thyroid hormone T3. T4 is converted in tissues by iodothyronine deiodinase. Deiodinase deficiency can mimic iodine deficiency. T3 is more active than T4 and is the final form of the hormone, although it is present in the body in smaller quantities than T4.
Thyrotropin-releasing hormone (TRH) is released from the hypothalamus for 6-8 weeks. Secretion thyroid-stimulating hormone(TSH) from the fetal pituitary gland becomes noticeable at 12 weeks of gestation, and at 18-20 weeks the production of (T4) in the fetus reaches clinical significant level. Fetal triiodothyronine (T3) still remains low (less than 15 ng/dL) until 30 weeks of gestation and then increases to 50 ng/dL. Adequate production of thyroid hormones in the fetus protects the fetus from possible abnormalities in brain development caused by maternal hypothyroidism.
If there is a lack of iodine in the diet, the thyroid gland will not be able to produce thyroid hormones. A lack of thyroid hormones leads to decreased negative feedback on the pituitary gland, which leads to increased production of thyroid-stimulating hormone, promoting enlargement of the thyroid gland (endemic colloid goiter). At the same time, the thyroid gland increases the accumulation of iodide, compensating for iodine deficiency, which allows it to produce a sufficient amount of thyroid hormones.
Most thyroid hormones circulating in the blood are associated with protein transport. Only a very small proportion of circulating hormones are free (unbound) and biologically active, therefore measuring the concentration of free thyroid hormones has important diagnostic value.
When thyroid hormone is bound, it is not active, so the amount of free T3/T4 is of particular importance. For this reason, measuring is not as effective total number in the blood.
Although T3 and T4 are lipophilic substances, they cross the cell membrane via ATP-dependent carrier-mediated transport. Thyroid hormones function through a well-studied set of nuclear receptors in the cell nucleus, the thyroid hormone receptors.
T1a and T0a are positively charged and do not cross the membrane. They function through the remnant amine-coupled receptor TAAR1 (TAR1, TA1), a G-protein coupled receptor located in the cell membrane.
Another important diagnostic tool is to measure the amount of thyroid-stimulating hormone (TSH) present.
Contrary to popular belief, thyroid hormones do not passively cross cell membranes like other lipophilic substances. Iodine in the ortho position makes the phenolic OH group more acidic, resulting in a negative charge at physiological pH. However, at least 10 different active, energy-dependent, and genetically regulated iodothyronine transporters have been identified in humans. Thanks to them, more high levels thyroid hormones than in blood plasma or interstitial fluid.
Little is known about the intracellular kinetics of thyroid hormones. Recently, however, it was demonstrated that CRYM crystallin binds 3,5,3"-triiodothyronine in vivo.
Levels can also be quantified by measuring either free or free triiodothyronine, which are measures of activity and triiodothyronine in the body. The total amount or triiodothyronine can also be measured, which also depends on the triiodothyronine bound to thyroxine-binding globulin. A related parameter is the free index, which is calculated by multiplying the total amount by the thyroid hormone absorption, which in turn is a measure of unbound thyroxine-binding globulin.
Increased cardiac output
Increased heart rate
Increasing ventilation intensity
Acceleration of basal metabolism
Potentiation of the effects of catecholamines (i.e. increased sympathetic activity)
Enhancing Brain Development
Endometrial saturation in women
Acceleration of protein and carbohydrate metabolism
Both T3 and T4 are used to treat thyroid hormone deficiency (hypothyroidism). Both substances are well absorbed in the intestines, so they can be taken orally. Levothyroxine is the pharmaceutical name for levothyroxine sodium (T4), which is metabolized more slowly than T3 and therefore usually requires only once daily dosing. Natural dried thyroid hormones are extracted from the thyroid gland of pigs. “Natural” treatment for hypothyroidism involves taking 20% T3 and small amounts of T2, T1 and calcitonin. There are also synthetic T3/T4 combinations in various ratios (for example, liotrix), as well as drugs containing pure T3 (liothyronine). Levothyroxine sodium is usually included in the first trial course of treatment. Some patients believe that it is better for them to use desiccated thyroid-stimulating hormone, however, this assumption is based on anecdotal evidence and clinical trials did not show the advantages of natural hormone over biosynthesized forms.
Thyronamines are still not used in medicine, however, they are supposed to be used to control the induction of hypothermia, which causes the brain to enter a protective cycle, which is useful in preventing damage from ischemic shock.
Synthetic thyroxine was first successfully produced by Charles Robert Harrington and George Barger in 1926.
Today, most patients take levothyroxine or similar synthetic forms of thyroid hormone. However, natural thyroid hormone supplements made from dried animal thyroid glands are still available. Natural thyroid hormone is becoming less popular due to evidence that the thyroid glands of animals contain different concentrations of hormones, causing different preparations to have different potencies and stability. Levothyroxine contains only T4 and is therefore largely ineffective for patients who cannot convert T4 to T3. These patients may be more suited to using natural hormone thyroid because it contains a mixture of T4 and T3, or synthetic T3 supplements. In such cases, synthetic liothyronine is preferable to natural one. It is illogical to take T4 alone if the patient is unable to convert T4 to T3. Some products containing natural thyroid hormone are approved by the F.D.A., while others are not. Thyroid hormones are generally well tolerated. Thyroid hormones, as a rule, do not pose a danger to pregnant women and nursing mothers, but the drug must be taken under medical supervision. Women with hypothyroidism without proper treatment have increased risk birth of a child with birth defects. During pregnancy, women with a poorly functioning thyroid gland also need to increase their dose of thyroid hormones. The only exception is that taking thyroid hormones may worsen the severity of heart disease, especially in older patients; therefore, doctors may give these patients lower doses initially and do their best to avoid the risk of a heart attack.
Both excess and deficiency can cause the development of various diseases.
Hyperthyroidism (an example is Graves' disease), clinical syndrome caused by excess circulating free triiodothyronine, free triiodothyronine, or both. It is a common condition, affecting approximately 2% of women and 0.2% of men. Hyperthyroidism is sometimes confused with thyrotoxicosis, but there are subtle differences between these diseases. Although thyrotoxicosis also increases circulating thyroid hormone levels, this can be caused by pill use or an overactive thyroid, while hyperthyroidism can only be caused by an overactive thyroid.
Hypothyroidism (for example, Hashimoto's thyroiditis) is a disease in which there is a deficiency of triidothyronine, or both substances.
Clinical depression can sometimes be caused by hypothyroidism. Research has shown that T3 is found at the junctions of synapses and regulates the amount and activity of serotonin, norepinephrine and () in the brain.
At premature birth developmental disorders of the nervous system may occur due to the lack of maternal thyroid hormones, when the child’s own thyroid gland is not yet able to satisfy the postpartum needs of the body.
The uptake of iodine against a concentration gradient is mediated by the sodium-iodine symporter and is associated with the sodium-potassium ATPase. Perchlorate and thiocyanate are drugs that can compete with iodine in this area. Compounds such as goitrin can reduce thyroid hormone production by interfering with iodine oxidation.
Table of contents of the topic "Adrenal hormones. Thyroid hormones.":Thyrocytes form follicles filled with colloidal mass of thyroglobulin. The basement membrane of thyrocytes is closely adjacent to 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 a direct neural regulation thyroid gland by the 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. A significant part thyroxine deposited and transported by erythrocytes. Destabilization of their membranes, for example under the influence 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 shifts, 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) increasing renal blood flow, glomerular filtration and diuresis with inhibition of tubular reabsorption in the kidneys,
8) maintaining reproductive function.
THYROID HORMONES (thyroid hormones)
Thyroid hormones are represented by two different classes of biologically active substances: iodothyronines And polypeptide hormone calcitonin. These classes of substances perform different physiological functions: iodothyronines regulate the state of basal metabolism, and calcitonin is one of the growth factors and affects the state of calcium metabolism, and also participates in the processes of growth and development of the bone apparatus (in close interaction with other hormones).
Microscopically, the thyroid tissue is represented mainly by spherical thyroid follicles that synthesize two so-called thyroid hormones - thyroxine (T4) And triiodothyronine (T3), which are iodinated derivatives of the amino acid tyrosine and differ only in the number of iodine atoms in the molecule, but have common physiological properties. Thyroid hormones directly inhibit the secretion of TSH by the adenohypophysis.
From 60 to 80 percent of the total amount of thyroid hormones produced by the thyroid gland enters the blood in the form of thyroxine, which is a relatively low-active thyroid hormone, in fact a prohormone, and weakly binds directly to thyroid hormone receptors in tissues. Before having an effect on the cells of target organs, most of the thyroxine is converted directly in the cells into a biologically active form - triiodothyronine. This process occurs with the participation of a metalloenzyme - selenium-dependent monodeiodinase.
The epithelial cells of the thyroid follicles contain the protein thyroglobulin. This is a glycoprotein containing many amino acid tyrosine residues (about 3% of the protein mass). The synthesis of thyroid hormones comes from tyrosine and iodine atoms precisely as part of the thyroglobulin molecule and includes 2 stages. On the apical membranes of follicle cells, tyrosine is first iodinated to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). The next step is the condensation of MIT and DIT to form T3 and T4.
This iodinated thyroglobulin molecule is secreted into the lumen of the follicle, into the colloid. When a signal in the form of TSH (thyroid-stimulating hormone) arrives in the thyroid gland, follicle cells capture colloid droplets along with thyroglobulin, lysosomal protease enzymes hydrolyze the protein to amino acids, and the finished T3 and T4 enter the blood.
In the blood, thyroid hormones bind to the carrier protein and in this form are transported to target tissues. The concentration of T4 in the blood is 10 times greater than T3, which is why T4 is called the main form of thyroid hormones in the blood. But T3 is 10 times more active than T4.
The target tissues for thyroid hormones are all tissues except the spleen and testes.
In target tissues, thyroid hormones are released from protein and enter the cell. In cells, 90% of T4 loses 1 atom of iodine and turns into T3. Thus, the main intracellular form of the hormone is T3.
The effect of thyroid hormones on the body depends on the concentration of these hormones in the blood: in physiological doses they have an anabolic effect, in large doses they have a catabolic effect.
Physiological action
Thyroid hormones stimulate the growth and development of the body, growth and differentiation of tissues. Increases tissue oxygen demand. Increases systemic blood pressure, heart rate and strength. Increases body temperature and basal metabolic rate.
Thyroid hormones increase blood glucose levels, enhance gluconeogenesis in the liver, and inhibit glycogen synthesis in the liver and skeletal muscles. They also increase the uptake and utilization of glucose by cells, increasing the activity of key glycolytic enzymes. Thyroid hormones increase lipolysis (fat breakdown) and inhibit the formation and deposition of fat.
The effect of thyroid hormones on protein metabolism depends on the concentration of the hormones. In low concentrations, they have an anabolic effect on protein metabolism, increase protein synthesis and inhibit their breakdown, causing a positive nitrogen balance. In high concentrations, thyroid hormones have a strong catabolic effect on protein metabolism, causing increased protein breakdown and inhibition of their synthesis, and as a result, a negative nitrogen balance.
Thyroid hormones increase the sensitivity of tissues to catecholamines. The effect of thyroid hormones on the growth and development of the body is synergistic with the action of somatotropic hormone, and the presence of a certain concentration of thyroid hormones is a necessary condition for the manifestation of a number of effects of somatotropic hormone.
Thyroid hormones enhance the processes of erythropoiesis in bone marrow. They also affect water metabolism, reduce tissue hydrophilicity and tubular reabsorption of water.
The essential thyroid hormones of the thyroid gland play an important role in the functioning of the entire body.
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 unnoticeable, but as soon as the balance of the active substances of the endocrine system is disturbed, the lack of production of thyroid hormones immediately becomes noticeable.
The physiological action of thyroid hormones of the thyroid gland is very wide.
It affects the following body systems:
Without thyroid hormones, oxygen exchange between the cells of the body, as well as the delivery of vitamins and minerals to the cells of the body, is not possible.
The functioning of the thyroid gland is directly affected by the work of the hypothalamus and pituitary gland.
The mechanism for regulating the production of thyroid hormones in the thyroid gland directly depends on the hormone of the anterior pituitary gland - TSH, and the influence of the thyroid gland on the pituitary gland occurs bilaterally due to nerve impulses, transmitting information in two directions.
The system works as follows:
It is known that at different times of the day and under different circumstances this system works differently.
So, maximum concentration TSH is detected in the evening hours, and the hypothalamic releasing factor is active in the early morning hours after a person wakes up.
This daily rhythm of the endocrine system is called the circadian rhythm.
The hormone triiodothyronine T3 is the main active substance of the thyroid gland.
It contains three molecules of iodine. It is produced in lower concentrations than T4.
In the blood, T3 moves with the help of a special protein - thyroid binding globulin.
As triiodothyronine approaches the target cells, it is released from the TSH binding to penetrate into the cell membrane.
Thus, T3 can be observed in the blood both in a free state and in a bound state.
The hormone thyroxine T4 is a kind of prohormone of triiodothyronine. It contains 4 iodine molecules.
Its concentration is always 3-4 times greater than the amount of T3, but the activity is much less.
T4 hormone is a kind of strategic reserve of thyroid hormones, since it is easily converted into triiodothyronine by releasing one molecule of iodine if needed.
The body always has a certain supply of this hormone for 10 days in advance.
Thyroid hormones of the thyroid gland are the only active substances in the body that contain pure iodine molecules in their structure.
Therefore, for their production, iodine is constantly captured.
The synthesis of thyroid hormones occurs in the A-cells of the thyroid gland according to the following principle:
Thyroid hormones affect not only the tissues and cells of the body, but also other endocrine glands.
They are of great importance for the synthesis of sex hormones, both male and female. Thanks to their action, the menstrual cycle in women is regulated, which affects the ability to conceive a child and carry it to full term.
Elevated levels of thyroid hormones negatively affect the functioning of all body systems.
The thyroid gland begins to synthesize increased amount T3 and T4 for many reasons.
This condition is called hyperthyroidism and depends on the following factors:
Hyperthyroidism may be accompanied by an enlarged thyroid gland.
But most frequent symptoms of this disease are:
With hyperthyroidism, the rhythm of all metabolic processes, while body temperature and sweating increase.
The effect of this condition is dangerous for humans, since all resources are consumed very quickly and the body is depleted. In addition, there is a risk of developing cardiovascular diseases, in particular, the occurrence of a heart attack.
Blood tests can determine hyperthyroidism if the TSH level is low, while the concentration of T3 and T4 is, on the contrary, high.
The opposite of hyperthyroidism, hypothyroidism is a condition characterized by decreased levels of thyroid hormones.
A significant reason for its development is the lack of iodine in human food. This pathology especially often affects middle-aged and older women.
Hypothyroidism can cause the following ailments:
A decrease in the amount of thyroid hormones can be determined by the following signs slow metabolism:
This condition is corrected by taking hormone replacement drugs.
Medicines may need to be taken for life to maintain normal operation glands, but it is advisable to know about other ways to restore the thyroid gland.
Hormones of both the cortical and adrenal medulla play in human body big role. The main hormones produced by the adrenal cortex are cortisol, androgens and aldosterone.
If we consider the adrenal glands from an anatomical point of view, they can be divided into three zones - glomerular, fascicular and reticular. The zona glomerulosa synthesizes mineralocorticoids, the zona fasciculata synthesizes glucocorticoids, and the zona reticularis produces androgens—sex hormones. The brain part has a simpler structure - it consists of nerve and glandular cells, which, when activated, synthesize adrenaline and norepinephrine. Hormones of the adrenal cortex, despite the fact that they perform different functions, are synthesized from the same compound - cholesterol.
That is why, before completely refusing to eat fat, you need to think about what hormones in the adrenal zone will be synthesized from.
If the hormones of the medulla are produced with the active participation of the nervous system, then the hormones of the cortex are regulated by the pituitary gland. In this case, ACTH is released, and the more of this substance is contained in the blood, the faster and more actively the hormones are synthesized. Feedback also occurs - if the level of hormones increases, the level of the so-called control substance decreases.
Hormones of the zona reticularis of the adrenal cortex are largely represented by androstenedione - this hormone is closely related to estrogen and testosterone. Physiologically, it is weaker than testosterone and is a male hormone. female body. How secondary sexual characteristics will be formed depends on how much it is present in the body. Insufficient or excessive amounts of androstenedione in a woman’s body can cause disruptions in the body, which can cause the development of certain endocrine diseases:
In addition to androstedione, the reticular layer of the adrenal glands synthesizes dehydroepiandrosterone. Its role is to produce protein molecules, and athletes are very familiar with it, since they use this hormone to build muscle mass.
In this zone they synthesize steroid hormones- cortisol and cortisone. Their action is as follows:
Aldesterone is produced in this part of the adrenal gland, its role in reducing the concentration of potassium in the kidneys and enhancing the absorption of fluid and sodium. This way, these two minerals are balanced in the body. Very often, people with persistently high blood pressure have increased level aldosterone.
The role of adrenal hormones for the human body is very great, and naturally, disruption of the adrenal glands and their hormones not only entails disruptions in the functioning of the entire body, but also directly depends on the processes that occur in it. In particular, hormonal disorders can develop with the following pathologies:
Regarding congenital pathologies, then we are talking about hyperplasia of the adrenal cortex. In this case, androgen synthesis increases, and girls with this pathology develop signs of pseudohermaphrodite, and boys mature sexually ahead of schedule. Children with these disorders are stunted because bone differentiation stops.
The very first signs of poor hormonal functioning are fatigue and increased fatigue; later, other symptoms appear, which can replace each other depending on the degree of disturbance.
Violation of functionality is accompanied by the following:
Of course, every person can detect at least one of these signs, and naturally running to the pharmacy for medicine in this case is unwise. Each symptom, taken individually, may be the body’s response to a stressful situation, therefore, to clarify the diagnosis, it is necessary to consult with a specialist, take a necessary tests and only then make a decision about drug therapy.
In women, malfunction of the adrenal glands leads to:
Men may experience the following:
Currently, it is not difficult to determine a malfunction of the adrenal glands. Laboratory testing can determine hormone levels using a routine urine or blood test. As a rule, this is quite enough to set correct diagnosis. In some cases, the doctor may prescribe an ultrasound, CT or MRI of the endocrine organ of interest.
As a rule, studies are most often prescribed to people who have delayed sexual development, recurrent miscarriage or infertility. In addition, the doctor can examine the activity of the adrenal glands in case of disruptions in the menstrual cycle, muscle atrophy, osteoporosis, persistent high blood pressure, obesity or increased pigmentation of the skin.
Fasting and stressful situations lead to dysfunction of the adrenal glands. Since the synthesis of corticosteroids occurs in a certain rhythm, it is necessary to eat in accordance with this rhythm. In the morning, the synthesis of hormones is highest, so breakfast should be hearty; in the evening, increased production of hormones is not required, so a light dinner can reduce their concentration in the blood.
Active ingredients help normalize the production of hormones. physical activity. It is best to engage in sports in the first half of the day, and if you prefer evening time for sports activities, then in this case only light loads will be useful.
Naturally proper nutrition also has a positive effect on the functioning of the adrenal glands - everything should be present in the diet essential vitamins and minerals. If the situation is advanced, the doctor may prescribe drug treatment, in some cases, such therapy may be prescribed for life, since otherwise severe disorders may develop.
The principle of drug therapy is based on restoration hormonal levels, so patients are discharged hormonal drugs– synthetic analogues of missing hormones. At excess quantity certain hormones, hormonal drugs are also prescribed that act on the hypothalamus and pituitary gland, they stop the excessive functionality of the gland, and it synthesizes less hormones.
Therapy includes the following:
The most famous and common medications used in treatment hormonal imbalance adrenal glands are as follows:
Self-administration medications is unacceptable, all medications should be prescribed only by a competent specialist.
Knowing what the adrenal cortex is, what hormones are synthesized in it and what diseases a hormone imbalance can cause, it is necessary to think about the prevention of diseases of these endocrine organs. The first step is to prevent diseases and disorders that can cause a malfunction of the adrenal glands. In most cases, dysfunction of these organs occurs due to prolonged stress and depression, so all doctors recommend avoiding negative situations that can lead to stress.
Proper nutrition and active image life is also a very important component of adrenal health.
