Thyroid hormones Thyroid hormones are obtained synthetically and are used when there is insufficiency of its function. Medicines based on them can be combined and contain mineral elements, for example potassium iodide.

This group of medicines includes:

A natural thyroid preparation is thyroidin, which is obtained from the dried fat-free thyroid glands of slaughtered cattle. It contains two hormones - thyroxine (tetraiodothyronine) and triiodine thyronine.

Synthetic thyroid drugs (triiodothyronine = liothyronine, thyroxine = levothyroxine = euthyrox). Moreover, some of them contain both triiodothyronine (T3) and thyroxine (T4): liotrix (T4/T3 ratio is 4:1), thyrotom (T4/T3 is 3:1), thyrocomb (T4/T3 is 7:1 In addition, this drug contains potassium iodide).

Pharmacodynamics. Iodine-containing hormone preparations penetrate into cells mainly by diffusion.

The interaction of hormonal drugs with nuclear receptors leads to the activation of RNA polymerase and DNA transcription, and this in turn leads to increased synthesis of mRNA and proteins (enzymes).

The interaction of hormonal drugs with mitochondrial receptors increases energy metabolism due to the activation of dehydrogenases involved in hydrogen transport in the respiratory chain.

In addition, it is known that thyroid hormone drugs can directly stimulate membrane Na", K" ATPase, an enzyme that regulates the transport of ions to cells and potassium into the cell.

In accordance with the biological activity of hormones, the affinity of receptors for triiodothyronine is almost 10 times higher than for thyroxine.

Pharmacological effects. Iodine-containing thyroid hormone preparations promote tissue differentiation, enchondral bone growth, skeletal formation and the development of nervous tissue. They also increase the tissue response to catecholamines, which is associated with an increase in the number of beta-adrenergic receptors and (or) increased reactivity; inhibit free radical reactions; promote the synthesis of lung surfactant.

The effect of these drugs is noted after 2-3 days of treatment, the final effect is observed later - after 3-4 weeks.

It must be emphasized that the effect of thyroid hormone drugs may vary depending on the dose. Thus, small doses of thyroxine have an anabolic effect, while large doses lead to increased protein breakdown. In large doses, thyroid hormones inhibit the thyroid-stimulating activity of the pituitary gland.

Pharmacokinetics. Synthetic drugs are administered parenterally (preferably intravenously) or administered orally. The natural drug thyroidin is used only internally in the first half of the day after meals. Their absorption occurs in the duodenum and jejunum. In this case, the absorption of thyroxine averages 80%, and triiodothyronine more than 95%. Absorption depends on the nature of the food and the simultaneous use of appropriate medications. Thus, drug absorption decreases with high protein content in foods or with simultaneous administration aluminum-containing antacids, iron supplements, etc. In addition, absorption processes are usually impaired in hypothyroidism.

Binding to thyroxine-binding globulin is more than 99%. Moreover, triiodothyronine binds slightly less (0.4%) to blood plasma proteins and therefore penetrates cell membranes faster than thyroxine.

The latent period of action of triiodothyronine is 4-8 hours, and that of thyroxine is 24-48 hours.

The main route of biotransformation of thyroxine in peripheral tissues is deiodination (85%). Moreover, the deiodination process can occur due to monodeiodination of the outer ring of the thyroxine molecule, then triiodothyronine (30-35%) is formed, which is 3-5 times more active than thyroxine itself, or due to monodeiodination of the inner ring; as a result, thyroxine is converted into metabolically inactive reverse triiodothyronine (45-50%). Further deiodination, which occurs mainly in the liver, is accompanied by a loss of thyroid hormone activity. The half-elimination period for thyroxine is 7 days, for triiodothyronine - 2 days, so the effect of the first after a single administration lasts 2-3 weeks, and the second - about 1 week.

Interaction. The biotransformation of iodine-containing hormonal drugs increases with the simultaneous administration of inducers of microsomal oxidation (for example, phenobarbital, diphenin, carbamazenin, zixorin, rifampicin, etc.). By the way, thyroid drugs themselves are autoinducers and accelerate the biotransformation of other drugs.

The level of the free fraction of thyroxine and triiodothyronine in the blood increases significantly when they are combined with non-steroidal anti-inflammatory drugs, sulfa drugs, as well as corticosteroids, androgens, etc. Conversely, the concentration of circulating iodine-containing hormonal drugs decreases when they are combined with estrogens, which increase production thyroxine binding globulin in the liver.

When thyroid hormone drugs are used in combination with diabetogenic drugs (glucocorticoids, thiazide and loop diuretics, somatotropin, etc.), the risk of provoking diabetes increases. As already mentioned, thyroid hormone medications cannot be administered orally at the same time as aluminum-containing antacids and iron supplements, as this reduces the absorption of the former.

Undesirable effects

Exacerbation of coronary heart disease, heart failure, the occurrence of atrial fibrillation. It is especially dangerous to prescribe thyroid hormone drugs to patients with coronary atherosclerosis and other heart diseases. Such patients need to start treatment with reduced doses.

Allergic reactions (more often when using thyroidin).

Worsening of diabetes mellitus, provocation of prediabetes.

In case of overdose, phenomena characteristic of hyperthyroidism occur: increased heart rate, systolic murmur at the apex, changes in the ECG (increased P and T waves, increased voltage of R waves, shift of the S-T interval below the isoelectric axis), arrhythmias, increased excitability of the central nervous system, sweating, weakness and muscle fatigue, increased deep tendon reflexes, moderate polyuria, increased appetite, weight loss, diarrhea, osteoporosis, etc., with the exception of exophthalmos.

Indications for use

Hypothyroidism, myxedema: cold and swollen skin, brittle hair and nails, weight gain, drooping eyelids, periorbital edema, enlarged tongue, decreased blood pressure, bradycardia, ECG changes (decreased voltage of all waves, decreased S-T interval below the isoelectric line and prolongation P-Q interval), dullness of heart sounds, neuropsychic retardation, drowsiness, decreased intelligence, impairment reproductive function etc. Children experience severe growth retardation and irreversible mental retardation (cretinism).

This pathology may result from chronic Hashimoto's thyroiditis (an immunological disorder in genetically predisposed individuals); congenital pathology of the thyroid gland (cretinism); death of thyroid tissue under the influence of radiation or its surgical removal; endemic, sporadic goiter or thyroid cancer (with hypofunction); the effects of drugs (for example, iodides, lithium, cobalt compounds, PAS, mercazolil, propylthiouracil, carbimazole, amiodarone, etc.); diseases of the pituitary gland or hypothalamus. In the last two cases, as a rule, treatment consists of discontinuing medications that suppress thyroid function or prescribing thyroid-stimulating hormone. In all other cases, thyroid hormone preparations are used for life.

Levothyroxine is considered the drug of choice, since it does not contain foreign allergenic proteins and has a long half-life (7 days), which allows it to be prescribed once a day. In addition, levothyroxine is converted into triiodothyronine in the body, so its administration allows you to obtain both hormones. It must be emphasized that the average dose of the drug for children up to six months should be 8-9 times higher than for adults. In order to avoid irreversible mental development defects in children with cretinism, treatment should begin as early as possible and continue throughout life. In some cases, complex drugs containing both hormones are used (for example, Lyothrix, Thyreotome, Thyreocomb). The use of thyroidin in economically prosperous countries has now been practically abandoned, since problems associated with the antigenicity of proteins, instability and variability in hormone concentrations, as well as the complexity of laboratory monitoring, outweigh the advantage of low price.

Hypothyroidism caused by panhypopituitarism requires replacement therapy not only with thyroid hormones, but also with corticosteroids.

Myxedema coma. In this case, preference should be given to more active drug- triiodothyronine (liothyronine). Intravenous levothyroxine can be used.

Untreated patients die from hypothyroidism, and if too intensive treatment coma death occurs from cardiovascular collapse caused by increased metabolism.

Excessive thyroid-stimulating function of the pituitary gland.

Pituitary-thyroid function is assessed by the concentration of triiodothyronine, thyroxine and thyrotropin (normally, the concentration of TSH in the blood is 0.3-5.0 µU/ml), as well as by the ability of the pituitary gland to respond to the introduction of releasing hormone, which stimulates the secretion of TSH (normally the TSH level in the blood serum 30-45 minutes after TRH injection increases by more than 6 μU/ml; in people over 40 years of age, the TSH response is smoothed - less than 2 μU/ml). The results of these determinations are considered more informative than measuring the absorption of radioactive iodine by the thyroid gland (normally, the uptake of iodine 123 in 24 hours is 5-35%), since the latter process is affected by drugs containing iodine, as well as salicylates and pyrazolones.

Diffuse toxic goiter. Thyroid hormone drugs are prescribed in combination with antithyroid drugs.

Respiratory distress syndrome in premature newborns.

Hypervitaminosis A.

The endocrine organ, the thyroid gland, provides the body with hormones. They are divided into two main groups: non-iodized and iodized, mainly violations occur in last group Therefore, the term thyroid hormones refers to iodine-containing hormones. These include thyroxine-T4 and triiodothyronine-T3; when they enter the human blood, they are distributed throughout the body and control it. We will look at what these hormones are, what their functions are, and what consequences disruptions in their production can lead to.

What functions do iodine-containing hormones perform?

Iodinated hormones perform the following important functions:

All these functions help organs function in the mode prescribed by nature and lead to enhanced human development.

Interesting! The human thyroid gland produces a teaspoon of hormones in one year.

What happens when there is an excess?

There are cases when iodine-containing thyroid hormones are produced in large quantities. This occurs due to a malfunction of the human immune system. The body's immunity causes damage to the receptors responsible for the production of the hormones T3 and T4. They continue to cope well with their function, but due to their excess, accelerated metabolism occurs and poor health, expressed in the following symptoms:

• rapid heartbeat;
• regularly elevated temperature;
• sharp weight loss with good appetite;
• tremor of the limbs;
• bad sleep;
• sudden change of mood.

What happens when there is a deficiency?

In addition to an excess of hormones produced by the thyroid gland, there is also a deficiency. It appears because the body's immune system seems to eat the cells of the thyroid gland, leading to a deterioration in its functioning. There is a decrease in iodine levels in the body, which manifests itself in a lack of hormones T3 and T4. A small amount of triiodothyronine and thyroxine causes disruptions in the performance of the entire body, which manifests itself in the following symptoms:

• general weakness, drowsiness;
• bowel dysfunction;
• sudden weight gain;
• memory impairment;
• disruptions of the female cycle;
• problem with conception;
• decreased sexual desire;
• depression.

Interesting! You can check for yourself whether your body is experiencing iodine deficiency. To do this, you need to draw an iodine grid on the body. If it disappears after 2 hours, then there is a lack of iodine, which leads to a deficiency of iodine-containing hormones.

Reasons that cause the thyroid gland to produce low or high levels of hormones

The human body regularly experiences negative external influences, which leads to the suppression of the functioning of the thyroid gland and, as a consequence, to a failure in the synthesis of iodine-containing hormones. Such reasons include:

• stress;
• hereditary factor;
• negative environmental conditions;
• increased radiation levels;
• infectious diseases;
• pancreatic disease;
• lack of vitamins and organic substances.

The production of iodine-containing hormones is important for the functioning of the body. If any symptoms are detected, you need to consult a specialist who, using simple tests, will determine the level of synthesis of iodine-containing hormones and, if necessary, prescribe treatment.

It consists of two lobes and an isthmus and is located in front of the larynx. The mass of the thyroid gland is 30 g.

The main structural and functional unit of the gland is follicles - rounded cavities, the wall of which is formed by one row of cuboidal epithelial cells. Follicles are filled with colloid and contain hormones thyroxine And triiodothyronine, which are bound to the protein thyroglobulin. In the interfollicular space there are C-cells that produce the hormone thyrocalcitonin. The gland is richly supplied with blood and lymphatic vessels. The amount of water flowing through the thyroid gland in 1 minute is 3-7 times higher than the mass of the gland itself.

Biosynthesis of thyroxine and triiodothyronine is carried out due to iodization of the amino acid tyrosine, therefore, active absorption of iodine occurs in the thyroid gland. The iodine content in the follicles is 30 times higher than its concentration in the blood, and with hyperfunction of the thyroid gland this ratio becomes even greater. Iodine absorption occurs through active transport. After combining tyrosine, which is part of thyroglobulin, with atomic iodine, monoiodotyrosine and diiodotyrosine are formed. By combining two molecules of diiodotyrosine, tetraiodothyronine, or thyroxine, is formed; condensation of mono- and diiodotyrosine leads to the formation of triiodothyronine. Subsequently, as a result of the action of proteases that break down thyroglobulin, active hormones are released into the blood.

The activity of thyroxine is several times less than that of triiodothyronine, but the content of thyroxine in the blood is approximately 20 times greater than triiodothyronine. Thyroxine, when deiodinated, can be converted into triiodothyronine. Based on these facts, it is assumed that the main thyroid hormone is triiodothyronine, and thyroxine functions as its precursor.

The synthesis of hormones is inextricably linked with the intake of iodine into the body. If there is a deficiency of iodine in the water and soil in the region of residence, there is also little iodine in food products of plant and animal origin. In this case, in order to ensure sufficient synthesis of the hormone, the thyroid gland of children and adults increases in size, sometimes very significantly, i.e. goiter occurs. The increase can be not only compensatory, but also pathological, it is called endemic goiter. The lack of iodine in the diet is best compensated for by seaweed and other seafood, iodized salt, table mineral water containing iodine, and baked goods with iodine additives. However, excessive intake of iodine into the body puts a strain on the thyroid gland and can lead to serious consequences.

Thyroid hormones

Effects of thyroxine and triiodothyronine

Basic:

• activate the genetic apparatus of the cell, stimulate metabolism, oxygen consumption and the intensity of oxidative processes

Metabolic:

• protein metabolism: stimulate protein synthesis, but when the level of hormones exceeds the norm, catabolism predominates;
• fat metabolism: stimulate lipolysis;
• carbohydrate metabolism: during overproduction, glycogenolysis is stimulated, blood glucose levels increase, its entry into cells is activated, liver insulinase is activated

Functional:

• ensure the development and differentiation of tissues, especially nervous;
• enhance the effects of the sympathetic nervous system by increasing the number of adrenergic receptors and inhibiting monoamine oxidase;
• prosympathetic effects are manifested in an increase in heart rate, systolic volume, blood pressure, respiratory rate, intestinal motility, central nervous system excitability, and increased body temperature

Manifestations of changes in the production of thyroxine and triiodothyronine

Comparative characteristics of insufficient production of somatotropin and thyroxine

The effect of thyroid hormones on body functions

The characteristic effect of thyroid hormones (thyroxine and triiodothyronine) is to increase energy metabolism. Introduction is always accompanied by an increase in oxygen consumption, and removal of the thyroid gland is always accompanied by a decrease. When the hormone is administered, metabolism increases, the amount of energy released increases, and body temperature rises.

Thyroxine increases consumption. Weight loss and intensive tissue consumption of glucose from the blood occur. The loss of glucose from the blood is compensated by its replenishment due to the increased breakdown of glycogen in the liver and muscles. Lipid reserves in the liver are reduced, and the amount of cholesterol in the blood decreases. The excretion of water, calcium and phosphorus from the body increases.

Thyroid hormones cause increased excitability, irritability, insomnia, and emotional imbalance.

Thyroxine increases minute blood volume and heart rate. Thyroid hormone is necessary for ovulation, it helps maintain pregnancy, and regulates the function of the mammary glands.

The growth and development of the body is also regulated by the thyroid gland: a decrease in its function causes growth to stop. Thyroid hormone stimulates hematopoiesis, increases gastric and intestinal secretions and milk secretion.

In addition to iodine-containing hormones, the thyroid gland produces thyrocalcitonin, reducing calcium levels in the blood. Thyrocalcitonin is an antagonist of parathyroid hormone of the parathyroid glands. Thyroid calcitonin acts on bone tissue, enhances the activity of osteoblasts and the mineralization process. In the kidneys and intestines, the hormone inhibits the reabsorption of calcium and stimulates the reabsorption of phosphates. The implementation of these effects leads to hypocalcemia.

Hyper- and hypofunction of the gland

Hyperfunction (hyperthyroidism) causes a disease called Graves' disease. The main symptoms of the disease: goiter, bulging eyes, increased metabolism, heart rate, increased sweating, physical activity (fussiness), irritability (moody, rapid mood swings, emotional instability), fast fatiguability. A goiter is formed due to diffuse enlargement of the thyroid gland. Treatments are now so effective that severe cases of the disease are quite rare.

Hypofunction (hypothyroidism) thyroid disease, which occurs at an early age, up to 3-4 years, causes the development of symptoms cretinism. Children suffering from cretinism lag behind in physical and mental development. Symptoms of the disease: dwarf stature and abnormal body proportions, a wide, deeply sunken bridge of the nose, widely spaced eyes, an open mouth and a constantly protruding tongue, as it does not fit in the mouth, short and curved limbs, a dull facial expression. The life expectancy of such people usually does not exceed 30-40 years. In the first 2-3 months of life, subsequent normal mental development can be achieved. If treatment begins at one year of age, then 40% of children exposed to this disease remain at a very low level of mental development.

Hypofunction of the thyroid gland in adults leads to a disease called myxedema, or mucous swelling. With this disease, the intensity of metabolic processes decreases (by 15-40%), body temperature, the pulse becomes less frequent, blood pressure decreases, swelling appears, hair falls out, nails break, the face becomes pale, lifeless, and mask-like. Patients are characterized by slowness, drowsiness, and poor memory. Myxedema is a slowly progressive disease that, if left untreated, leads to complete disability.

Regulation of thyroid function

A specific regulator of the thyroid gland is iodine, the thyroid hormone itself and TSH (Thyroid Stimulating Hormone). Iodine in small doses increases TSH secretion, and in large doses inhibits it. The thyroid gland is under the control of the central nervous system. Such food products, like cabbage, rutabaga, turnips, inhibit the function of the thyroid gland. The production of thyroxine and triiodothyronine increases sharply under conditions of prolonged emotional arousal. It is also noted that the secretion of these hormones accelerates with a decrease in body temperature.

Manifestations of endocrine thyroid function disorders

With an increase in the functional activity of the thyroid gland and excess production of thyroid hormones, a condition occurs hyperthyroidism (hyperthyroidism), characterized by an increase in the level of thyroid hormones in the blood. The manifestations of this condition are explained by the effects of thyrsoid hormones in elevated concentrations. Thus, due to an increase in basal metabolism (hypermetabolism), patients experience a slight increase in body temperature (hyperthermia). Body weight decreases despite preserved or increased appetite. This condition is manifested by an increase in oxygen demand, tachycardia, increased myocardial contractility, increased systolic blood pressure, and increased ventilation. The activity of the ATP increases, the number of β-adrenoreceptors increases, sweating and heat intolerance develop. Excitability and emotional lability increase, tremors of the limbs and other changes in the body may appear.

Increased formation and secretion of thyroid hormones can be caused by a number of factors, the correct identification of which determines the choice of method for correcting thyroid function. Among them are factors that cause hyperfunction of the follicular cells of the thyroid gland (tumors of the gland, mutation of G-proteins) and an increase in the formation and secretion of thyroid hormones. Hyperfunction of thyrocytes is observed with excessive stimulation of thyrotropin receptors by an increased content of TSH, for example, with pituitary tumors, or reduced sensitivity of thyrotropin hormone receptors in the thyrotrophs of the adenohypophysis. A common cause of hyperfunction of thyrocytes and an increase in the size of the gland is stimulation of TSH receptors by antibodies produced to them during autoimmune disease, called Graves-Bazedow disease (Fig. 1). A temporary increase in the level of thyroid hormones in the blood can develop due to the destruction of thyrocytes due to inflammatory processes in the gland (Hashimoto's toxic thyroiditis), taking an excess amount of thyroid hormones and iodine preparations.

Increased thyroid hormone levels may occur thyrotoxicosis; in this case they talk about hyperthyroidism with thyrotoxicosis. But thyrotoxicosis can develop when an excess amount of thyroid hormones is introduced into the body in the absence of hyperthyroidism. The development of thyrotoxicosis due to increased sensitivity of cell receptors to thyroid hormones has been described. There are also known opposite cases, when the sensitivity of cells to thyroid hormones is reduced and a state of resistance to thyroid hormones develops.

Reduced formation and secretion of thyroid hormones can be caused by many reasons, some of which are a consequence of disruption of the mechanisms regulating the function of the thyroid gland. So, hypothyroidism (hypothyroidism) can develop with a decrease in the formation of TRH in the hypothalamus (tumors, cysts, radiation, encephalitis in the hypothalamus, etc.). This hypothyroidism is called tertiary. Secondary hypothyroidism develops due to insufficient production of TSH by the pituitary gland (tumors, cysts, radiation, surgical removal of part of the pituitary gland, encephalitis, etc.). Primary hypothyroidism can develop as a result of autoimmune inflammation of the gland, with a deficiency of iodine, selenium, excessively excessive intake of goitrogens - goitrogens (some varieties of cabbage), after irradiation of the gland, long-term use of a number of medications (iodine, lithium, antithyroid drugs), etc.

Rice. 1. Diffuse enlargement of the thyroid gland in a 12-year-old girl with autoimmune thyroiditis (T. Foley, 2002)

Insufficient production of thyroid hormones leads to a decrease in metabolic rate, oxygen consumption, ventilation, myocardial contractility and minute blood volume. Severe hypothyroidism may develop a condition called myxedema- mucous swelling. It develops due to accumulation (possibly under the influence higher level TSH) mucopolysaccharides and water in the basal layers of the skin, which leads to facial puffiness and pasty skin consistency, as well as increased body weight, despite decreased appetite. Patients with myxedema may develop mental and motor retardation, drowsiness, chilliness, decreased intelligence, decreased tone of the sympathetic section of the ANS and other changes.

The complex processes of thyroid hormone formation involve ion pumps that provide iodine supply and a number of protein enzymes, among which thyroid peroxidase plays a key role. In some cases, a person may have a genetic defect leading to a disruption of their structure and function, which is accompanied by a disruption in the synthesis of thyroid hormones. Genetic defects in the structure of thyroglobulin may be observed. Autoantibodies are often produced against thyroid peroxidase and thyroglobulin, which is also accompanied by a disruption in the synthesis of thyroid hormones. The activity of the processes of iodine uptake and its inclusion in thyroglobulin can be influenced by a number of pharmacological agents, regulating the synthesis of hormones. Their synthesis can be influenced by taking iodine preparations.

The development of hypothyroidism in the fetus and newborns can lead to cretinism - physical (short stature, imbalance of body proportions), sexual and mental underdevelopment. These changes can be prevented by adequate thyroid hormone replacement therapy in the first months after birth.

Structure of the thyroid gland

It is the largest endocrine organ in terms of mass and size. It usually consists of two lobes connected by an isthmus and is located on the anterior surface of the neck, being fixed to the anterior and lateral surfaces of the trachea and larynx by connective tissue. The average weight of a normal thyroid gland in adults ranges from 15-30 g, but its size, shape and topography of location vary widely.

The functionally active thyroid gland is the first of the endocrine glands to appear during embryogenesis. The thyroid gland in the human fetus is formed on the 16-17th day of intrauterine development in the form of an accumulation of endodermal cells at the root of the tongue.

At the early stages of development (6-8 weeks), the gland primordium is a layer of intensively proliferating epithelial cells. During this period, the gland grows rapidly, but hormones are not yet formed in it. The first signs of their secretion are detected at 10-11 weeks (in fetuses about 7 cm in size), when the gland cells are already able to absorb iodine, form a colloid and synthesize thyroxine.

Single follicles appear under the capsule, in which follicular cells form.

Parafollicular (parafollicular) or C-cells grow into the thyroid rudiment from the 5th pair of gill pouches. By the 12-14th weeks of fetal development, the entire right lobe of the thyroid gland acquires a follicular structure, and the left one two weeks later. By 16-17 weeks, the fetal thyroid gland is already fully differentiated. The thyroid glands of fetuses 21-32 weeks of age are characterized by high functional activity, which continues to increase until 33-35 weeks.

In the parenchyma of the gland there are three types of cells: A, B and C. The bulk of parenchyma cells are thyrocytes (follicular, or A-cells). They line the wall of the follicles, in the cavities of which the colloid is located. Each follicle is surrounded by a dense network of capillaries, into the lumen of which thyroxine and triiodothyronine secreted by the thyroid gland are absorbed.

In the unchanged thyroid gland, the follicles are evenly distributed throughout the parenchyma. When the functional activity of the gland is low, thyrocytes are usually flat; when the functional activity is high, they are cylindrical (the height of the cells is proportional to the degree of activity of the processes occurring in them). The colloid that fills the lumens of the follicles is a homogeneous viscous liquid. The bulk of the colloid is thyroglobulin, secreted by thyrocytes into the lumen of the follicle.

B cells (Ashkenazi-Hurthle cells) are larger than thyrocytes, have eosinophilic cytoplasm and a round, centrally located nucleus. Biogenic amines, including serotonin, were found in the cytoplasm of these cells. B cells first appear at the age of 14-16 years. They are found in large numbers in people aged 50-60 years.

Parafollicular, or C-cells (in Russian transcription K-cells), differ from thyrocytes in the lack of the ability to absorb iodine. They provide the synthesis of calcitonin, a hormone involved in the regulation of calcium metabolism in the body. C-cells are larger than thyrocytes and are usually located singly within follicles. Their morphology is characteristic of cells that synthesize protein for export (a rough endoplasmic reticulum, Golgi complex, secretory granules, and mitochondria are present). On histological preparations, the cytoplasm of C-cells appears lighter than the cytoplasm of thyrocytes, hence their name - light cells.

If at the tissue level the main structural and functional unit of the thyroid gland is follicles surrounded by basement membranes, then one of the putative organ units of the thyroid gland may be microlobules, which include follicles, C-cells, hemocapillaries, and tissue basophils. The microlobule consists of 4-6 follicles surrounded by a membrane of fibroblasts.

By the time of birth, the thyroid gland is functionally active and structurally fully differentiated. In newborns, the follicles are small (60-70 microns in diameter); as the child’s body develops, their size increases and reaches 250 microns in adults. In the first two weeks after birth, the follicles develop intensively; by 6 months they are well developed throughout the gland, and by one year they reach a diameter of 100 microns. During puberty, there is an increase in the growth of the parenchyma and stroma of the gland, an increase in its functional activity, manifested by an increase in the height of thyrocytes and an increase in enzyme activity in them.

In an adult, the thyroid gland is adjacent to the larynx and the upper part of the trachea in such a way that the isthmus is located at the level of the II-IV tracheal semirings.

The weight and size of the thyroid gland changes throughout life. In a healthy newborn, the mass of the gland varies from 1.5 to 2 g. By the end of the first year of life, the mass doubles and slowly increases by puberty up to 10-14 g. The increase in mass is especially noticeable at the age of 5-7 years. The weight of the thyroid gland at the age of 20-60 years ranges from 17 to 40 g.

The thyroid gland has an exceptionally abundant blood supply compared to other organs. The volumetric flow rate of blood in the thyroid gland is about 5 ml/g per minute.

The thyroid gland is supplied with blood by paired superior and inferior thyroid arteries. Sometimes the unpaired, lowest artery (a. thyroideaima).

The outflow of venous blood from the thyroid gland is carried out through veins that form plexuses around the lateral lobes and the isthmus. The thyroid gland has an extensive network of lymphatic vessels, through which the lymph flows into the deep cervical lymph nodes, then into the supraclavicular and lateral cervical deep lymph nodes. Efferent lymphatic vessels of the lateral cervical deep lymph nodes They form a jugular trunk on each side of the neck, which flows into the thoracic duct on the left and into the right lymphatic duct on the right.

The thyroid gland is innervated by postganglionic fibers of the sympathetic nervous system from the superior, middle (mainly) and inferior cervical ganglia of the sympathetic trunk. The thyroid nerves form plexuses around the vessels approaching the gland. These nerves are believed to perform a vasomotor function. The vagus nerve, which carries parasympathetic fibers to the gland as part of the superior and inferior laryngeal nerves, also participates in the innervation of the thyroid gland. The synthesis of iodine-containing thyroid hormones T 3 and T 4 is carried out by follicular A-cells - thyrocytes. Hormones T 3 and T 4 are iodinated.

Hormones T 4 and T 3 are iodinated derivatives of the amino acid L-tyrosine. Iodine, which is part of their structure, makes up 59-65% of the mass of the hormone molecule. The iodine requirement for normal synthesis of thyroid hormones is presented in table. 1. The sequence of synthesis processes is simplified as follows. Iodine in the form of iodide is captured from the blood using an ion pump, accumulates in thyrocytes, is oxidized and incorporated into the phenolic ring of tyrosine in thyroglobulin (iodine organization). Iodination of thyroglobulin with the formation of mono- and diiodotyrosines occurs at the boundary between thyrocyte and colloid. Next, the connection (condensation) of two diiodotyrosine molecules is carried out to form T 4 or diiodotyrosine and monoiodotyrosine to form T 3 . Some of the thyroxine undergoes deiodination in the thyroid gland to form triiodothyronine.

Table 1. Iodine consumption standards (WHO, 2005. according to I. Dedov et al. 2007)

Iodinated thyroglobulin, together with T4 and T3 attached to it, accumulates and is stored in the follicles in the form of a colloid, acting as depot thyroid hormones. The release of hormones occurs as a result of pinocytosis of the follicular colloid and subsequent hydrolysis of thyroglobulin in phagolysosomes. The released T 4 and T 3 are secreted into the blood.

The basal daily secretion by the thyroid gland is about 80 μg of T4 and 4 μg of T3. In this case, thyrocytes of the thyroid follicles are the only source of the formation of endogenous T4. Unlike T4, T3 is formed in small quantities in thyrocytes, and the main formation of this active form of the hormone occurs in the cells of all tissues of the body through deiodination of about 80% of T4.

Thus, in addition to the glandular depot of thyroid hormones, the body has a second, extraglandular depot of thyroid hormones, represented by hormones associated with transport proteins in the blood. The role of these depots is to prevent rapid decline the level of thyroid hormones in the body, which could occur with a short-term decrease in their synthesis, for example, with a short-term decrease in iodine intake. The bound form of hormones in the blood prevents their rapid removal from the body through the kidneys and protects cells from the uncontrolled entry of hormones into them. Free hormones enter the cells in quantities commensurate with their functional needs.

Thyroxine entering the cells undergoes deiodination under the action of deiodinase enzymes, and when one iodine atom is removed, a more active hormone is formed - triiodothyronine. In this case, depending on the deiodination pathways, both active T3 and inactive reverse T3 (3,3",5"-triiodo-L-thyronine - pT3) can be formed from T4. These hormones, through sequential deiodination, are converted into metabolites T2, then T1 and T0, which are conjugated with glucuronic acid or sulfate in the liver and excreted in the bile and through the kidneys from the body. Not only T3, but also other metabolites of thyroxine can also exhibit biological activity.

The mechanism of action of thyrsoid hormones is primarily due to their interaction with nuclear receptors, which are non-histone proteins located directly in the cell nucleus. There are three main subtypes of thyroid hormone receptors: TPβ-2, TPβ-1, and TRA-1. As a result of interaction with T 3, the receptor is activated, the hormone-receptor complex interacts with the hormone-sensitive region of DNA and regulates the transcriptional activity of genes.

A number of non-genomic effects of thyrsoid hormones in mitochondria and the plasma membrane of cells have been identified. In particular, thyroid hormones can change the permeability of mitochondrial membranes for hydrogen protons and, by uncoupling the processes of respiration and phosphorylation, reduce ATP synthesis and increase heat production in the body. They change the permeability of plasma membranes to Ca 2+ ions and influence many intracellular processes carried out with the participation of calcium.

Main effects and role of thyroid hormones

The normal functioning of all organs and tissues of the body without exception is possible with normal levels of thyroid hormones, as they affect the growth and maturation of tissues, energy exchange and the exchange of proteins, lipids, carbohydrates, nucleic acids, vitamins and other substances. The metabolic and other physiological effects of thyroid hormones are distinguished.

Metabolic effects:

• activation of oxidative processes and an increase in basal metabolism, increased absorption of oxygen by tissues, increased heat generation and body temperature;
• stimulation of protein synthesis (anabolic effect) in physiological concentrations;
• increased oxidation of fatty acids and decreased levels in the blood;
• hyperglycemia due to activation of glycogenolysis in the liver.

Physiological effects:

• ensuring normal processes of growth, development, differentiation of cells, tissues and organs, including the central nervous system (myelination of nerve fibers, differentiation of neurons), as well as processes of physiological tissue regeneration;
• enhancing the effects of the SNS through increasing the sensitivity of adrenergic receptors to the action of Adr and NA;
• increased excitability of the central nervous system and activation of mental processes;
• participation in ensuring reproductive function (promote the synthesis of GH, FSH, LH and the implementation of the effects of insulin-like growth factor - IGF);
• participation in the formation of adaptive reactions of the body to adverse effects, in particular cold;
• participation in the development of the muscular system, increasing the strength and speed of muscle contractions.

Regulation of the formation, secretion and transformations of thyroid hormones is carried out by complex hormonal, nervous and other mechanisms. Their knowledge allows us to diagnose the causes of decreased or increased secretion of thyroid hormones.

A key role in the regulation of the secretion of thyroid hormones is played by hormones of the hypothalamic-pituitary-thyroid axis (Fig. 2). Basal secretion of thyroid hormones and its changes under various influences are regulated by the level of TRH of the hypothalamus and TSH of the pituitary gland. TRH stimulates the production of TSH, which has a stimulating effect on almost all processes in the thyroid gland and the secretion of T4 and T3. Under normal physiological conditions, the formation of TRH and TSH is controlled by the level of free T4 and T in the blood based on negative feedback mechanisms. In this case, the secretion of TRH and TSH is inhibited by a high level of thyroid hormones in the blood, and when their concentration is low, it increases.

Rice. 2. Schematic representation of the regulation of the formation and secretion of hormones in the hypothalamus-pituitary-thyroid axis

The state of sensitivity of receptors to the action of hormones at various levels of the axis is important in the mechanisms of regulation of hormones of the hypothalamic-pituitary-thyroid axis. Changes in the structure of these receptors or their stimulation by autoantibodies may cause disruption of the formation of thyroid hormones.

The formation of hormones in the gland itself depends on the receipt of a sufficient amount of iodide from the blood - 1-2 mcg per 1 kg of body weight (see Fig. 2).

When there is insufficient intake of iodine in the body, adaptation processes develop in it, which are aimed at the most careful and effective use of the iodine available in it. They consist of increased blood flow through the gland, more efficient uptake of iodine by the thyroid gland from the blood, changes in the processes of hormone synthesis and Tu secretion. Adaptive reactions are triggered and regulated by thyrotropin, the level of which increases with iodine deficiency. If the daily intake of iodine in the body is less than 20 mcg for a long time, then prolonged stimulation of thyroid cells leads to the proliferation of its tissue and the development of goiter.

The self-regulatory mechanisms of the gland under conditions of iodine deficiency ensure its greater uptake by thyrocytes at a lower level of iodine in the blood and more efficient reutilization. If about 50 mcg of iodine is delivered to the body per day, then due to an increase in the rate of its absorption by thyrocytes from the blood (iodine of food origin and reutilized iodine from metabolic products), about 100 mcg of iodine per day enters the thyroid gland.

Coming from gastrointestinal tract 50 mcg of iodine per day is the threshold at which the long-term ability of the thyroid gland to accumulate it (including reutilized iodine) in quantities when the content of inorganic iodine in the gland remains at the lower limit of normal (about 10 mg). Below this threshold intake of iodine into the body per day, the effectiveness of the increased rate of iodine uptake by the thyroid gland is insufficient, iodine absorption and its content in the gland decrease. In these cases, the development of thyroid dysfunction becomes more likely.

Simultaneously with the activation of the adaptive mechanisms of the thyroid gland in case of iodine deficiency, a decrease in its excretion from the body in the urine is observed. As a result, adaptive excretory mechanisms ensure the removal of iodine from the body per day in quantities equivalent to its lower daily intake from the gastrointestinal tract.

Intake of subthreshold iodine concentrations into the body (less than 50 mcg per day) leads to an increase in the secretion of TSH and its stimulating effect on the thyroid gland. This is accompanied by an acceleration of iodination of tyrosyl residues of thyroglobulin, an increase in the content of monoiodotyrosines (MIT) and a decrease in diiodotyrosines (DIT). The MIT/DIT ratio increases, and, as a result, T4 synthesis decreases and T3 synthesis increases. The T 3 /T 4 ratio increases in iron and blood.

With severe iodine deficiency, there is a decrease in serum T4 levels, an increase in TSH levels and normal or increased T3 levels. The mechanisms of these changes are not clearly understood, but most likely they are the result of an increase in the rate of formation and secretion of T3, an increase in the ratio of T3 to T4, and an increase in the conversion of T4 to T3 in peripheral tissues.

An increase in the formation of T3 under conditions of iodine deficiency is justified from the point of view of achieving the greatest final metabolic effects of TG with the lowest “iodine” capacity. It is known that the effect on metabolism of T 3 is approximately 3-8 times stronger than T 4, but since T 3 contains only 3 iodine atoms in its structure (and not 4 like T 4), then for the synthesis of one T 3 molecule only 75% of iodine costs are needed, compared to the synthesis of T4.

With a very significant iodine deficiency and decreased thyroid function against the background of high TSH levels, T 4 and T 3 levels decrease. More thyroglobulin appears in the blood serum, the level of which correlates with the level of TSH.

Iodine deficiency in children has a stronger effect on metabolic processes in the thyrocytes of the thyroid gland than in adults. In iodine-deficient areas of residence, thyroid dysfunction in newborns and children is much more common and more pronounced than in adults.

When a small excess of iodine enters the human body, the degree of iodide organization, TG synthesis and their secretion increase. There is an increase in the level of TSH, a slight decrease in the level of free T4 in the serum with a simultaneous increase in the content of thyroglobulin in it. Longer-term excess iodine intake may block TG synthesis by inhibiting the activity of enzymes involved in biosynthetic processes. By the end of the first month, there is an increase in the size of the thyroid gland. With chronic excessive intake of excess iodine into the body, hypothyroidism may develop, but if the intake of iodine into the body is normalized, then the size and function of the thyroid gland may return to its original values.

Sources of iodine that may cause excess iodine intake often include iodized salt, multivitamin supplements containing mineral supplements, foods, and some iodine-containing medications.

The thyroid gland has an internal regulatory mechanism that allows it to effectively cope with excess iodine intake. Although iodine intake may fluctuate, serum TG and TSH concentrations may remain constant.

It is believed that maximum amount iodine, which, when entering the body, does not yet cause changes in thyroid function, is about 500 mcg per day for adults, but at the same time there is an increase in the level of TSH secretion due to the action of thyrotropin-releasing hormone.

The intake of iodine in quantities of 1.5-4.5 mg per day leads to a significant decrease in the serum content of both total and free T4 and an increase in TSH levels (T3 levels remain unchanged).

The effect of excess iodine suppressing the function of the thyroid gland also occurs in thyrotoxicosis, when by taking an excess amount of iodine (in relation to natural daily requirement) eliminate the symptoms of thyrotoxicosis and lower serum TG levels. However, with prolonged intake of excess iodine into the body, the manifestations of thyrotoxicosis return again. It is believed that a temporary decrease in the level of TG in the blood with excess iodine intake is primarily due to inhibition of hormone secretion.

The intake of small excess amounts of iodine into the body leads to a proportional increase in its uptake by the thyroid gland, up to a certain saturating value of absorbed iodine. When this value is reached, iodine uptake by the gland may decrease despite its intake into the body in large quantities. Under these conditions, under the influence of pituitary TSH, the activity of the thyroid gland can vary widely.

Since when excess iodine enters the body, the TSH level increases, one would expect not an initial suppression, but an activation of thyroid function. However, it has been established that iodine inhibits an increase in the activity of adenylate cyclase, suppresses the synthesis of thyroid peroxidase, and inhibits the formation of hydrogen peroxide in response to the action of TSH, although the binding of TSH to the cell membrane receptor of thyrocytes is not impaired.

It has already been noted that the suppression of thyroid function by excess iodine is temporary and the function is soon restored despite the continued intake of excess amounts of iodine into the body. The thyroid gland adapts or escapes from the influence of iodine. One of the main mechanisms of this adaptation is a decrease in the efficiency of iodine uptake and transport into the thyrocyte. Since it is believed that the transport of iodine through the basement membrane of the thyrocyte is associated with the function of Na+/K+ ATPase, it can be expected that excess iodine may affect its properties.

Despite the existence of mechanisms for the thyroid gland to adapt to insufficient or excessive iodine intake in order to maintain its normal function The body must maintain iodine balance. With a normal level of iodine in soil and water, up to 500 mcg of iodine in the form of iodide or iodate can enter the human body per day with plant foods and, to a lesser extent, with water, which are converted into iodides in the stomach. Iodides are rapidly absorbed from the gastrointestinal tract and distributed into the extracellular fluid of the body. The concentration of iodide in the extracellular spaces remains low, since part of the iodide is quickly captured from the extracellular fluid by the thyroid gland, and the remaining is excreted from the body at night. The rate of iodine uptake by the thyroid gland is inversely proportional to the rate of its excretion by the kidneys. Iodine can be excreted by the salivary and other glands of the digestive tract, but is then reabsorbed from the intestines into the blood. About 1-2% of iodine is secreted by the sweat glands, and with increased sweating, the proportion of iodine secreted with iot can reach 10%.

Of the 500 mcg of iodine absorbed from the upper intestine into the blood, about 115 mcg is captured by the thyroid gland and about 75 mcg of iodine is used per day for the synthesis of TG, 40 mcg is returned back to the extracellular fluid. Synthesized T 4 and T 3 are subsequently destroyed in the liver and other tissues, the iodine released in the amount of 60 mcg enters the blood and extracellular fluid, and about 15 mcg of iodine, conjugated in the liver with glucuronides or sulfates, is excreted in bile.

In the total volume, blood is an extracellular fluid, constituting about 35% of body weight in an adult (or about 25 l), in which about 150 mcg of iodine is dissolved. Iodide is freely filtered in the glomeruli and approximately 70% is passively reabsorbed in the tubules. During the day, about 485 mcg of iodine is excreted from the body in urine and about 15 mcg in feces. The average iodine concentration in blood plasma is maintained at about 0.3 μg/L.

With a decrease in iodine intake into the body, its amount in body fluids decreases, excretion in urine decreases, and the thyroid gland can increase its absorption by 80-90%. The thyroid gland is capable of storing iodine in the form of iodothyronines and iodinated tyrosines in quantities close to the body's 100-day requirement. Due to these iodine-saving mechanisms and stored iodine, TG synthesis under conditions of iodine deficiency in the body can remain unimpaired for a period of up to two months. Longer iodine deficiency in the body leads to a decrease in TG synthesis despite its maximum uptake by the gland from the blood. Increasing the intake of iodine into the body can accelerate the synthesis of TG. However, if daily iodine intake exceeds 2000 mcg, iodine accumulation in the thyroid gland reaches a level where iodine uptake and hormone biosynthesis are inhibited. Chronic iodine intoxication occurs when the daily intake of iodine into the body is more than 20 times the daily requirement.

Iodide entering the body is excreted mainly through urine, therefore its total content in the volume of daily urine is the most accurate indicator of iodine intake and can be used to assess the iodine balance in the whole organism.

Thus, a sufficient supply of exogenous iodine is necessary for the synthesis of TG in quantities adequate to the needs of the body. Moreover, the normal implementation of the effects of TG depends on the effectiveness of their binding to nuclear receptors of cells, which contain zinc. Consequently, the intake of a sufficient amount of this trace element (15 mg/day) into the body is also important for the manifestation of the effects of TG at the level of the cell nucleus.

The formation of active forms of TH from thyroxine in peripheral tissues occurs under the action of deiodinases, the manifestation of which activity requires the presence of selenium. It has been established that the intake of selenium into the adult human body in quantities of 55-70 mcg per day is a necessary condition for the formation of a sufficient amount of T v in peripheral tissues

The nervous mechanisms of regulation of thyroid function are carried out through the influence of the neurotransmitters SPS and PSNS. The SNS innervates glandular vessels and glandular tissue with its postganglionic fibers. Norepinephrine increases the level of cAMP in thyrocytes, enhances their absorption of iodine, synthesis and secretion of thyroid hormones. PSNS fibers also approach the follicles and vessels of the thyroid gland. An increase in the tone of the PSNS (or the introduction of acetylcholine) is accompanied by an increase in the level of cGMP in thyrocytes and a decrease in the secretion of thyroid hormones.

Under the control of the central nervous system is the formation and secretion of TRH by small cell neurons of the hypothalamus, and, consequently, the secretion of TSH and thyroid hormones.

The level of thyroid hormones in tissue cells, their transformation into active forms and metabolites is regulated by the system of deiodinases - enzymes whose activity depends on the presence of selenocysteine ​​in the cells and the intake of selenium into the body. There are three types of deiodinases (D1, D2, D3), which are distributed differently in different tissues of the body and determine the pathways for the conversion of thyroxine into active T 3, or inactive pT 3 and other metabolites.

Endocrine function of parafollicular K cells of the thyroid gland

These cells synthesize and secrete the hormone calcitonin.

Calcitonip (thyreocalcitoin)- a peptide consisting of 32 amino acid residues, the content in the blood is 5-28 pmol/l, acts on target cells, stimulating T-TMS membrane receptors and increasing the level of cAMP and IFZ in them. Can be synthesized in the thymus, lungs, central nervous system and other organs. The role of extrathyroidal calcitonin is unknown.

The physiological role of calcitonin is the regulation of calcium (Ca 2+) and phosphate (PO 3 4 -) levels in the blood. The function is implemented through several mechanisms:

• inhibition of the functional activity of osteoclasts and suppression of bone resorption. This reduces the excretion of Ca 2+ and PO 3 4 - ions from bone tissue into the blood;
• reducing the reabsorption of Ca 2+ and PO 3 4 - ions from primary urine in the renal tubules.

Due to these effects, an increase in the level of calcitonin leads to a decrease in the content of Ca 2 and PO 3 4 - ions in the blood.

Regulation of calcitonin secretion is carried out with the direct participation of Ca 2 in the blood, the concentration of which is normally 2.25-2.75 mmol/l (9-11 mg%). An increase in calcium levels in the blood (hypsocalcismia) causes active secretion of calcitonin. A decrease in calcium levels leads to a decrease in hormone secretion. The secretion of calcitonin is stimulated by catecholamines, glucagon, gastrin and cholecystokinin.

An increase in calcitonin levels (50-5000 times higher than normal) is observed in one of the forms of thyroid cancer (medullary carcinoma), which develops from parafollicular cells. At the same time, the determination of high levels of calcitonin in the blood is one of the markers of this disease.

An increase in the level of calcitonin in the blood, as well as an almost complete absence of calcitonin after removal of the thyroid gland, may not be accompanied by disturbances in calcium metabolism and the condition of the skeletal system. These clinical observations indicate that the physiological role of calcitonin in the regulation of calcium levels remains incompletely understood.

For the endocrine system, the key concept is “hormone”. Hormones- intercellular humoral chemical regulators - secreted in internal environment body (mainly into the blood) from specialized (endocrine) cells and act on target cells containing receptor molecules for specific hormones. This distant (through the bloodstream) interaction between hormone-producing cells and target cells is known as endocrine regulation. Paracrine regulation implies the effects of hormones that influence neighboring target cells through diffusion, and autocrine regulation directly affects the cells secreting these hormones (see Fig. 4-7). There are also many other “non-classical” hormone-producing glands. This includes the central nervous system, kidneys, stomach, small intestine, skin, heart and placenta. New research in cellular and molecular biology is constantly expanding our understanding of the endocrine system, such as the discovery leptin- a hormone produced from fat cells.

Information intercellular interactions carried out by hormones fit into the following sequence of events: "signal (hormone) - receptor - (second messenger) - physiological response." Physiological concentrations of hormones that carry out humoral regulation of functions range from 10 -7 -10 -12 M, i.e. hormones are effective in extremely low concentrations.

A variety of hormones and hormonal systems regulate almost all body functions, including metabolism, reproduction, growth and development, fluid and electrolyte balance and behavior. The activity of many endocrine glands is regulated using feedback mechanisms by the pituitary gland and hypothalamus.

The synthesis of some hormones (adrenaline, norepinephrine, etc.) does not directly depend on the regulatory influence of the pituitary gland and is controlled by the sympathetic nervous system.

Chemistry of hormones

According to their chemical structure, hormones, as well as other biologically active substances of a regulatory nature (for example, growth factors, interleukins, interferons, chemokines, angiotensins, Pg and a number of others) are divided into peptide, steroid, derivatives of amino acids and arachidonic acid.

Peptide hormones belong to polar substances that cannot directly penetrate biological membranes. Therefore, the mechanism of exocytosis is used for their secretion. For the same reason, peptide hormone receptors are built into the plasma membrane of the target cell, and signal transmission to intracellular structures is carried out by second messengers.

Steroid hormones- mineralocorticoids, glucocorticoids, androgens, estrogens, progestins, calcitriol. These compounds - derivatives of cholesterol - are non-polar substances, so they freely penetrate biological membranes. For this reason, the secretion of steroid hormones occurs without the participation of secretory vesicles. For the same reason, receptors for non-polar molecules are located inside the target cell. Such receptors are generally called nuclear receptors.

Amino acid derivatives- tyrosine (iodine-containing thyroid hormones, norepinephrine, adrenaline and dopamine), histidine (histamine), tryptophan (melatonin and serotonin).

Arachidonic acid derivatives(eicosanoids, or prostanoids). Eicosanoids (from the Greek. eikosi- twenty) consist (like arachidonic acid) of 20 carbon atoms. These include prostaglandins (Pg), thromboxanes, prostacyclins, leukotrienes, hydroxyeicosotetraenoic (HETE, from the English hydroxyeicosatetraenoic) and epoxyeicosotrienoic acids, as well as derivatives of these acids. All eicosanoids have high and versatile physiological activity, many of them function only inside the cell.

Mechanisms of action of hormones on target cells

Information intercellular interactions implemented in the endocrine system provide for the following sequence of events:

hormone - target cell receptor - (second messenger) - answer

target cells

Each hormone has a regulatory effect on the target cell if and only if it, as a ligand, binds to a receptor protein specific to it in the target cell.

Circulation in the blood. Hormones circulate in the blood either freely or in combination with proteins that bind them (T 4, T 3, steroid hormones, insulin-like growth factors, growth hormone). Binding to such proteins significantly increases the half-life of hormones. Thus, T4 circulates as part of the complex for about 1 week, while the half-life of free T4 is several minutes.

Section summary

The endocrine system integrates the functions of organs and systems through hormones that are secreted both from classical endocrine glands and from organs and tissues whose primary function is not endocrine.

Hormones can send signals to the cells that produce them (autocrine regulation) or to neighboring cells (paracrine regulation); classical endocrine glands release chemical signals into the blood that reach distant tissue targets.

Target cells recognize hormones depending on specific highly related receptors, which can be located on the cell surface, inside the cytoplasm, or on the target cell nucleus.

Hormonal signals are organized into a hierarchical feedback system, cascades that enhance the effects millions of times and sometimes determine the nature of the secretion released.

Most hormones have a variety of effects and have the ability, along with other hormones, to control vital parameters.

Chemically, hormones can be metabolites of individual amino acids, peptides or cholesterol metabolites and, depending

Due to their solubility, they are transported into the blood in free form (amines and peptides) or bound to transport proteins (steroid and thyroid hormones).

HORMONES AND THEIR PHYSIOLOGICAL EFFECTS

This section gives physiological characteristic various hormones synthesized and secreted by cells of the endocrine system.

HYPOTHALAMIC-PITITUITARY SYSTEM

Part of the diencephalon - the hypothalamus - and the pituitary gland extending from its base anatomically and functionally form a single whole - the hypothalamic-pituitary endocrine system (see Fig. 16-2, C, D).

Hypothalamus

Neurosecretory neurons of the hypothalamus synthesize neuropeptides that enter the anterior (releasing hormones) and posterior (oxytocin and vasopressin) lobes of the pituitary gland.

Releasing hormones

Hypothalamic releasing hormones (from English. releasing hormone)- a group of neurohormones whose targets are endocrine cells of the anterior pituitary gland. From a functional point of view, releasing hormones are divided into liberins (releasing hormones that enhance the synthesis and secretion of the corresponding hormone in the endocrine cells of the anterior pituitary gland) and statins (releasing hormones that suppress the synthesis and secretion of hormones in target cells). Hypothalamic liberins include somatostatin, gonadoliberin, thyrotropin-releasing hormone and corticoliberin, and statins are represented by somatostatin and prolactinostatin.

Somatostatin- a powerful regulator of the functions of the endocrine and nervous system, inhibitory synthesis and secretion of many hormones and secretions.

Somatoliberin. Hypothalamic somatoliberin stimulates the secretion of growth hormone in the anterior pituitary gland.

Gonadotropin-releasing hormone (Luliberin) and prolactinostatin. Gene LHRH

encodes the amino acid sequences for GnRH and prolactinostatin. GnRH is the most important neuroregulator of reproductive function; He stimulates synthesis and secretion of FSH and LH in gonadotroph-producing cells, and prolactinostatin suppresses secretion of prolactin from lactotrophic cells of the anterior pituitary gland. Luliberin is a decapeptide.

Thyroid hormone- a tripeptide that is synthesized by many neurons of the central nervous system (including neurosecretory neurons of the paraventricular nucleus). Thyroid hormone stimulates secretion of prolactin from lactotrophs and thyrotropin from thyrotrophs of the anterior pituitary gland.

Corticoliberin synthesized in neurosecretory neurons of the paraventricular nucleus of the hypothalamus, placenta, T-lymphocytes. In the anterior lobe of the pituitary gland, corticoliberin stimulates the synthesis and secretion of ACTH and other products of proopiomelanocortin gene expression.

Melanostatin suppresses the formation of melanotropins. Liberins and statins along the axons of hypothalamic neurons

reach the median eminence, where they are secreted into the blood vessels of the portal blood flow system, then through the portal veins of the pituitary gland, these neurohormones enter the anterior lobe of the pituitary gland and regulate the activity of its endocrine cells (Table 18-1, see Fig. 16-2, C, D ).

Table 18-1.Effects of hypothalamic neurohormones on the secretion of hormones of the adenohypophysis

The role of dopamine. An intermediate product of tyrosine metabolism and a precursor of norepinephrine and adrenaline, the catechol amine dopamine (3-hydroxytyramine), which enters the cells of the anterior pituitary gland through the blood, inhibits the secretion of FSH, lutropin (LH), TSH and prolactin.

Posterior pituitary hormones

Nanopeptides vasopressin and oxytocin are synthesized in the perikarya of neurosecretory neurons of the paraventricular and supraoptic nuclei of the hypothalamus, transported along their axons as part of the hypothalamic-pituitary tract to the posterior lobe of the pituitary gland, where they are secreted into the blood (see Fig. 16-2, D). The signal for secretion is the impulse activity of these same neurosecretory neurons.

Vasopressin(arginine vasopressin, antidiuretic hormone - ADH) has antidiuretic(regulator of water reabsorption in the kidney tubules) and vasoconstrictor(vasoconstrictor) effects(these effects of the hormone cause an increase in systemic blood pressure). The main function of ADH is regulation of water exchange(maintaining constant osmotic pressure of body fluids), which occurs in close connection with sodium metabolism.

Secretion of ADH stimulate hypovolemia through baroreceptors of the carotid region, hyperosmolality through osmoreceptors of the hypothalamus, transition to a vertical position, stress, anxiety.

Secretion of ADH suppress alcohol, α-adrenergic agonists, glucocorticoids.

Oxytocinstimulates contraction of the myometrial SMC during childbirth, during orgasm, in the menstrual phase, secreted upon irritation of the nipple and isolamapillary area and stimulates contraction of myoepithelial cells that make up the alveoli of the lactating mammary gland (milk secretion reflex).

Anterior pituitary gland

In the anterior lobe, the so-called tropic hormones and prolactin are synthesized and secreted. Tropic hormones are hormones whose targets are other endocrine cells.

According to their chemical structure, adenohypophysis hormones are either peptide hormones or glycoproteins.

Glycoproteins- thyroid-stimulating hormone and gonadotropins (luteinizing hormone - LH and follicle-stimulating hormone - FSH).

Polypeptide hormones- growth hormone, adrenocorticotropic hormone (ACTH) and prolactin. When the proopiomelanocortin gene is expressed, in addition to ACTH, the synthesis and secretion of a number of other peptides occurs: β- and γ-lipotropins, melanocortins (α-, β- and γ-melanotropins), β-endorphin, ACTH-like peptide, and it has been established that melanotropins perform hormonal function; the functions of the remaining peptides have not been sufficiently studied.

Growth hormones

Growth hormone (somatotroph hormone - STH, somatotropin) is normally synthesized only in acidophilic cells (somatotrophs) of the anterior pituitary gland. Another growth hormone - human chorionic somatomammotrophin(placental lactogen). The effects of growth hormones are mediated by insulin-like growth factors - somatomedins. Growth hormones are anabolic, they stimulate the growth of all tissues.

Expression regulators(Table 18-2).

Table 18-2.Stimulating and suppressive effect on growth hormone secretion

Daily frequency of secretion. GH enters the blood cyclically - “explosions of secretion”, alternating with periods of cessation of secretion (the duration of such a cycle is

la is measured in minutes). The peak secretion of GH occurs in the third and fourth phases of sleep.

Age-related changes in GH secretion. The content of GH in the blood plasma is maximum in early childhood, it gradually decreases with age and is 6 ng/ml at 5-20 years (with a peak at puberty), at 20-40 years 3 ng/ml, after 40 years - 1 ng/ml.

Functions

STG- anabolic hormone, stimulating the growth of all cells due to increased supply of amino acids into cells and increased protein synthesis. The most obvious are the long-term effects of GH on bone growth. In this case, the targets of GH are the cells of the epiphyseal cartilaginous plate of long tubular bones and the osteoblasts of the periosteum and endosteum.

Metabolic effects HGH is biphasic and is aimed at maintaining blood glucose levels and providing the body with energy expenditure.

Initial phase(insulin-like effect). STG increases glucose uptake by muscle and adipose tissue, and amino acid uptake and protein synthesis by muscle and liver. At the same time, GH inhibits lipolysis in adipose tissue. After a few minutes, the delayed phase of the effects of GH develops.

Delayed phase (anti-insulin-like or diabetogenic effect). After a few tens of minutes it happens oppression absorption and utilization of glucose (blood glucose increases) and gain lipolysis (the content of free fatty acids in the blood increases).

Protein metabolism.HGH stimulates the supply of amino acids and protein synthesis in cells (anabolic effect).

Fat metabolism.HGH enhances lipolysis, and the fatty acids released are used to replenish the energy costs of cells.

As a result, under the influence of GH, the order of use of substances necessary to obtain energy changes: Fats are used rather than carbohydrates or proteins. Since GH has an anabolic effect, it leads to weight gain without fat accumulation.

Circulation in the blood. The half-life of GH in the blood is about 25 minutes. Approximately 40% of the released GH forms a complex with the GH-binding protein, and the half-life of GH increases significantly.

GH receptor belongs (together with the receptors for prolactin, a number of interleukins and erythropoietin) to the family of cytokine receptors (tyrosine kinase-related receptors). STH also binds to the prolactin receptor.

Somatomedins C and A(polypeptides of 70 and 67 amino acid residues, respectively) mediate the effects of GH, acting as autocrine growth factors. Both somatomedins have strong structural homology with proinsulin, which is why they are also called insulin-like growth factors. Somatomedin receptors, like the insulin receptor, belong to receptor tyrosine kinases. Somatomedin C, by binding to its receptors, stimulates synthesis of pituitary growth hormone and hypothalamic somatostatin and suppresses synthesis of hypothalamic somatoliberin.

Adrenocorticotropic hormone

Adrenocorticotropic hormone (ACTH, corticotropin). The structure of ACTH is encoded by the proopiomelanocortin gene.

Circadian rhythm. ACTH secretion begins to increase after falling asleep and reaches a peak upon awakening.

Functions. ACTH stimulates synthesis and secretion of adrenal hormones (mainly the glucocorticoid cortisol).

ACTH receptors(ACTH binds to the melanocortin receptor type 2) are membrane-bound, G-protein coupled (activates adenylate cyclase, which, with the help of cAMP, ultimately activates numerous enzymes for the synthesis of glucocorticoids).

Melanocortins

Melanocortins (melanotropins) control pigmentation of the skin and mucous membranes. The expression of ACTH and melanocortins is largely combined. Melanostatin suppresses secretion of melanotropins (probably also ACTH). Several types of melanocortin receptors are known; ACTH also acts through type 2 of these receptors.

Gonadotropic hormones

This group includes the pituitary follitropin(follicle stimulating hormone - FSH) and lutropin(LH, luteinizing hormone), as well as human chorionic gonadotropin(HCT) placenta.

Follicle stimulating hormone(FSH, follitropin) in women causes the growth of ovarian follicles, in men it regulates spermatogenesis (FSH targets are Sertoli cells).

Luteinizing hormone(LH, lutropin) stimulates the synthesis of testosterone in the Leidig cells of the testicles (in men, LH is sometimes called interstitial cell stimulating hormone), the synthesis of estrogen and progesterone in the ovaries, stimulates ovulation and the formation of the corpus luteum in the ovaries.

Human chorionic gonadotropin(HCT) is synthesized by trophoblast cells from the 10-12th day of development. During pregnancy, hCG interacts with the cells of the corpus luteum and stimulates synthesis and secretion of progesterone.

Thyroid-stimulating hormone

Thyroid-stimulating hormone of a glycoprotein nature (TSH, thyrotropin) stimulates the synthesis and secretion of iodine-containing thyroid hormones (T 3 and T 4). Thyrotropin stimulates the differentiation of epithelial cells of the thyroid gland (except for the so-called light cells that synthesize thyrocalcitonin) and their functional state (including the synthesis of thyroglobulin and the secretion of T 3 and T 4).

Prolactin

Prolactin accelerates the development of the mammary gland and stimulates milk secretion. Prolactin synthesis occurs in acidophilic adenocytes (lactotrophs) of the anterior pituitary gland. The number of lactotrophs makes up at least a third of all endocrine cells of the adenohypophysis. During pregnancy, the volume of the anterior lobe doubles due to an increase in the number of lactotrophs (hyperplasia) and an increase in their size (hypertrophy). The main function of prolactin is to stimulate the function of the mammary gland.

Section summary

The hypothalamic-pituitary axis is represented by the hypothalamus, anterior and posterior pituitary glands.

Arginine-vasopressin and oxytocin are synthesized in hypothalamic neurons, the axons of which end in the posterior lobe of the pituitary gland.

Arginine vasopressin increases renal water reabsorption in response to increased blood osmolarity or decreased blood volume.

Oxytocin stimulates the release of milk from the mammary gland in response to sucking and muscle contraction of the uterus in response to the dilation of the cervix during labor.

The hormones ACTH, STH, prolactin, LH, FSH, TSH are synthesized in the anterior lobe of the pituitary gland and are released in response to hypothalamic releasing hormones entering the blood of the portal circulation of the pituitary gland.

PINEAL BODY

Pineal body (corpus рineale)- a small (5-8 mm) outgrowth of the diencephalon, connected by a pedicle to the wall of the third ventricle (Fig. 18-1). From the parenchymal cells of this gland - pinealocytes - the production is secreted into the cerebrospinal fluid and blood.

Rice. 18-1. Topography and innervation of the pineal gland.

aqueous tryptophan - melatonin. The organ is supplied with numerous postganglionic nerve fibers from the superior cervical sympathetic ganglion. The gland takes part in the implementation of circadian (circadian) rhythms.

Circadian rhythm. The circadian rhythm is one of the biological rhythms (daily, monthly, seasonal and annual rhythms), coordinated with the daily cyclicity of the Earth’s rotation, somewhat inconsistent with 24 hours. Many physiological processes, including hypothalamic neurosecretion, are subject to a circadian rhythm.

Melatonin(I-acetyl-5-methoxytryptamine) is secreted into the cerebrospinal fluid and blood mainly at night. The plasma melatonin content at night is 250 pg/ml in children aged 1 to 3 years, 120 pg/ml in adolescents and 20 pg/ml in people aged 50-70 years. At the same time, during the day the melatonin content is only about 7 pg/ml in people of any age.

Regulation of melatonin expression occurs when norepinephrine interacts with α- and β-adrenergic receptors of pinealocytes: the G-protein associated with the receptors (activation of adenylate cyclase) ultimately causes an increase in the transcription of the arylalkylamine-L-acetyltransferase gene, the main enzyme in the synthesis of melatonin. The complete chain of events - from the retina to the pinealocytes - is as follows (see Fig. 18-1).

♦ Changes in retinal illumination through the optic tract and additional pathways affect the discharges of neurons in the supracrossus nucleus (rostroventral part of the hypothalamus).

■ Signals: from the retina to the hypothalamus do not arise in rods and cones, but in other cells (possibly amacrine) of the retina containing photopigments of the cryptochrome group.

■ The supracross nucleus contains the so-called endogenous clock- a generator of biological rhythms of unknown nature (including circadian rhythms), controlling the duration of sleep and wakefulness, eating behavior, hormone secretion, etc. Signal

generator - a humoral factor secreted from the supraciscus nucleus (including into the cerebrospinal fluid).

♦ Signals: from the supracrossus nucleus through neurons: paraventricular nucleus (n. paraventricularis) activate preganglionic sympathetic neurons of the lateral columns of the spinal cord (columna lateralis).

♦ Sympathetic preganglionic nerve fibers activate neurons of the superior cervical ganglion of the sympathetic trunk.

♦ Postganglionic sympathetic fibers from the superior cervical ganglion secrete norepinephrine, which interacts with adrenergic receptors in the plasmalemma of pinealocytes.

Effects of melatonin studied: poorly studied, but it is known that melatonin in the hypothalamus and pituitary gland initiates gene transcription Period-1(one of the genes related to the so-called endogenous clock).

Melatonin receptors- transmembrane glycoproteins associated with G-protein (activation of adenylate cyclase) - found: in the pituitary gland, supracrossus nucleus (n. suprachiasmaticus) hypothalamus, in the retina, some areas of the central nervous system and a number of other organs.

THYROID

In the cells of the thyroid gland, the synthesis of two chemically and functionally different classes of hormones occurs - iodine-containing hormones (synthesized in the epithelial follicles of the gland) and products of the expression of calcitonin genes (synthesized in the so-called light cells of the follicles - C-cells).

Iodine-containing hormones glands are tyrosine derivatives. Thyroxine (T 4) and triiodothyronine (T 3) enhance metabolic processes, accelerate the catabolism of proteins, fats and carbohydrates, increase heart rate and cardiac output; they are necessary: ​​for the normal development of the central nervous system.

Calcitonin(32-amino acid peptide) and katacalcin(21-amino acid peptide). Their functions are antagonistic to the effects of PTH - the hormone parathyroid gland: calcitonin reduces [Ca 2+] in the blood, stimulates mineralization

bones, increases renal excretion of Ca 2 +, phosphates and Na + (their reabsorption in the kidney tubules decreases).

Calcitonin gene-related peptidesα and β (37 amino acids) are expressed in a number of neurons in the central nervous system and in the periphery (especially in association with blood vessels). Their role is participation in nociception, eating behavior, as well as in the regulation of vascular tone. Receptors for these peptides are found in the central nervous system, heart, and placenta.

The synthesis and secretion of iodine-containing hormones occurs in the epithelial follicles of the thyroid gland. These follicles have different sizes and shapes (mostly round), consist of a wall (formed by one layer of follicular cells) and a follicular cavity containing the so-called colloid. Function of follicular cells stimulates thyrotropin. Follicular cells can have different heights (from low cubic to cylindrical), which depends on the intensity of their functioning: the height of the cells is proportional to the intensity of the processes carried out in them. The complete cycle of synthesis and secretion of iodine-containing hormones occurs between follicular cells and colloid

(Figure 18-2).

Synthesis of iodine-containing hormones

The synthesis and secretion of T 4 and T 3 is a multi-stage process under the activating influence of TSH.

Iodine absorption. Iodine in the form of organic and inorganic compounds enters the gastrointestinal tract with food and drinking water. Transport of iodine from the blood capillaries to the gland occurs due to the follicular cells built into the plasma membrane of the basal part, which make up the molecules of the transmembrane carrier of sodium and iodine ions (the so-called iodine trap). From the apical part of the follicular cells, I - enters the colloid using an anion transporter (pendrin).

The body's daily need for iodine is 150-200 mcg. Iodine deficiency develops when there is insufficient iodine intake from food and water. Reducing synthesis

Rice. 18-2. Stages of synthesis and secretion of iodine-containing hormones . On the left side of the figure, the direction of processes is shown from bottom to top (from the lumen of blood capillaries to follicular cells and then to the colloid), on the right side of the figure - from top to bottom (from colloid to follicular cells and then to the lumen of capillaries).

thyroid hormones occurs when iodine intake

decreases below 10 mcg/day. The ratio of concentrations of I - in iron and concentration

I - in blood serum is normally 25:1. Iodine oxidation(I - - I+) occurs with the help of iodide peroxidase (thyroid peroxidase) immediately after entering the colloid. The same enzyme catalyzes the addition of oxidized iodine to tyrosine residues in thyroglobulin molecules.

Thyroglobulin. This glycoprotein containing 115 tyrosine residues is synthesized in follicular cells and secreted into the colloid. This is the so-called immature thyroglobulin.

Iodization of thyroglobulin

The maturation of thyroglobulin occurs within approximately 2 days on the apical surface of follicular cells through its iodination using thyroid peroxidase.

Under the action of thyroid peroxidase, oxidized iodine reacts with tyrosine residues, resulting in the formation of monoiodotyrosines and diiodotyrosines. Mono- and diiodotyrosines do not have hormonal activity; both compounds are released from follicular cells but are quickly reuptaken and deiodinated. Two diiodotyrosine molecules condense to form iodothyronine (T 4), and monoiodotyrosine and diiodotyrosine condense to form iodothyronine (T 3).

Mature thyroglobulin (fully iodized) is a prohormone of iodine-containing hormones, a form of their storage in a colloid.

Endocytosis and breakdown of thyroglobulin

As needed, mature thyroglobulin enters (internalized) from the colloid into follicular cells via receptor-mediated L-acetylglucosamine endocytosis.

Secretion of T 3 and T 4

The amino acids formed during the breakdown of thyroglobulin are used for new synthesis processes, and T 3 and T 4 from the basal part of the follicular cells enter the blood.

Normally, the thyroid gland secretes 80-100 mcg T 4 and 5 mcg T 3 per day. Another 22-25 μg of T 3 is formed as a result of deiodination of T 4 in peripheral tissues, mainly in the liver.

Regulation of iodothyronine synthesis

The synthesis and secretion of iodothyronines is regulated by the hypothalamic-pituitary system via a feedback mechanism (Fig. 18-3).

Rice. 18-3. Regulatory relationships between the hypothalamus, adenohypophysis and thyroid gland. Activating influences - solid line, inhibitory influences - dotted line. TSH-RH - thyrotropin-releasing hormone. The stimulus for increasing the secretion of TSH-RG and TSH is a decrease in the concentration of iodothyronines in the blood.

Thyroxine

Thyroxine (β-[(3,5-diiodo-4-hydroxyphenoxy)-3,5-diiodophenyl] alanine, or 3,5,3",5"-tetraiodothyronine, C 15 H 11 I 4 NO 4, T 4, mol. mass 776.87) is formed from a pair of diiodotyrosines. Thyroxine is the main iodine-containing hormone, T 4 accounts for at least 90%

of all iodine contained in the blood.

Transport is in the blood. No more than 0.05% T 4 circulates in the blood

in free form, almost all thyroxine is in the form bound to plasma proteins. The main transport protein is thyroxine-binding globulin (binds 80% of T 4), the share of thyroxine-binding prealbumin, as well as albumin, accounts for 20% of T 4. Circulation time in the blood (half-life) T 4 is about 7 days, with hyperthyroidism 3-4 days, with hypothyroidism - up to 10 days.

L -form thyroxine is physiologically approximately twice as active as racemic (DZ-thyroxine), D-shape not hormonally active.

Deiodination of outer ring thyroxine, partly occurring in the thyroid gland, occurs mainly in the liver and causes the formation of T 3.

Reversible triiodothyronine. Deiodination of the inner ring of thyroxine occurs in the thyroid gland, mainly in the liver and partially in the kidney. As a result, reverse (reverse) T 3 is formed - 3,3",5"-triiodothyronine, rT 3 (from the English reverse), which has insignificant physiological activity after birth.

Triiodothyronine

Triiodothyronine is formed from monoiodothyronine and diiodothyronine (about 15% of T3 circulating in the blood is synthesized in the thyroid gland, the rest of triiodothyronine is formed during monodeiodination of the outer ring of thyroxine, which occurs mainly in the liver). T 3 accounts for only 5% of the iodine contained in the blood, but T 3 is essential for the body and for the implementation of the effects of iodine-containing hormones.

Transport is in the blood. No more than 0.5% of T 3 circulates in the blood in free form, almost all triiodothyronine is in bound form.

Circulation time in the blood (half-life) T 3 is about 1.5 days.

Physiological activity T 3 is approximately four times higher than that of thyroxine, but the half-life is much shorter. The biological activity of both T 3 and T 4 is due to the unbound fraction.

Catabolism of iodothyronines. T 3 and T 4 are conjugated in the liver with glucuronic or sulfuric acid and secreted into bile, absorbed in the intestine, deiodized in the kidneys and excreted in the urine.

Thyroid hormone receptors

Nuclear receptors of thyroid hormones are transcription factors. At least three subtypes of these receptors are known: α 1, α 2 and β. α 1 - and β-subtypes - transforming genes ERBA1 And ERBA2 respectively.

Functions of iodine-containing hormones

The functions of iodine-containing hormones are numerous. T 3 and T 4 increase the intensity of metabolic processes, accelerate the catabolism of proteins, fats and carbohydrates, increase heart rate and cardiac output; they are necessary for the normal development of the central nervous system. The extremely diverse effects of iodine-containing hormones on target cells (which are almost all cells of the body) are explained by an increase in protein synthesis and oxygen consumption.

Protein synthesis increases as a result of transcription activation in target cells, including the growth hormone gene. Iodothyronines are regarded as growth hormone synergists. With T 3 deficiency, pituitary cells lose the ability to synthesize GH.

Oxygen consumption increases as a result of increased activity of Na+-, K+-ATPase.

Liver. Iodothyronines accelerate glycolysis, cholesterol synthesis and bile acid synthesis. In the liver and adipose tissue, T 3 increases the sensitivity of cells to the effects of adrenaline (stimulation of lipolysis in adipose tissue and mobilization of glycogen in the liver).

Muscles. T 3 increases glucose consumption, stimulates protein synthesis and an increase in muscle mass, and increases sensitivity to the action of adrenaline.

Heat production. Iodothyronines are involved in shaping the body's response to cooling by increasing heat production, increasing the sensitivity of the sympathetic nervous system to norepinephrine and stimulating the secretion of norepinephrine.

Hyperiodothyroninemia. Very high concentrations of iodothyronines inhibit protein synthesis and stimulate catabolic processes, which leads to the development of a negative nitrogen balance.

The physiological effects of thyroid hormones are given in Table. 18-3.

Thyroid function assessment

F Radioimmunoassay allows you to directly measure the content of T 3, T 4, TSH.

F Absorption of hormones resins - an indirect method for determining hormone-binding proteins.

F Free thyroxine index- assessment of free T4.

F TSH stimulation test with thyrotropin-releasing hormone determines the secretion of thyrotropin into the blood in response to intravenous administration of thyrotropin-releasing hormone.

F Tests for detecting antibodies to TSH receptors identify a heterogeneous group of Igs that bind to TSH receptors of endocrine cells of the thyroid gland and change its functional activity.

F Scanning thyroid gland using technetium isotopes (99p1 Ts) allows you to identify areas of reduced radionuclide accumulation (cold nodes), detect ectopic foci of the thyroid gland or a defect in the parenchyma of the organ. 99t Tc accumulates only in the thyroid gland, the half-life is only 6 hours.

F Radioactive iodine absorption study using iodine-123 (123 I) and iodine-131 (131 I).

F Iodine content in drinking water. Iodization of water is carried out at waterworks.

F Table salt. In Russia it is prohibited to produce non-iodized table salt.

Thyroid status determines the endocrine function of the thyroid gland. Euthyroidism- no deviations. Thyroid disease can be suspected when symptoms of endocrine dysfunction appear (hypothyroidism), excessive effects of thyroid hormones (hyperthyroidism) or with focal or diffuse enlargement of the thyroid gland (goiter).

End of table. 18-3

Calcitonin and catalcin

C-cells (pronounced "see-cells", from English calcitonin - calcitonin) in the follicles are also called parafollicular. Gene CALC1 contains nucleotide sequences encoding the peptide hormones calcitonin, katacalcin and peptide α related to the calcitonin gene. Regulators of Ca 2+ metabolism - calcitonin and catalcin - are synthesized in the thyroid gland; peptide α is not expressed in the normal thyroid gland.

Calcitonin- a peptide containing 32 amino acid residues, mol. weight 3421.

F Expression regulator- [Ca 2 +] blood plasma. Intravenous administration of calcium chloride significantly increases the secretion of calcitonin. β-Adrenergic agonists, dopamine, estrogens, gastrin, cholecystokinin, glucagon and secretin also stimulate calcitonin secretion.

F Functions calcitonin are diverse. Calcitonin is one of the regulators of calcium metabolism; The functions of calcitonin are antagonistic to the functions of the parathyroid hormone.

♦ Decrease in Ca 2+ content in the blood(parathyrocrine increases Ca 2+ content).

♦ Stimulation of mineralization bones (PTH enhances bone resorption).

♦ Increased renal excretion of Ca 2 +, phosphates and Na +(their reabsorption in the kidney tubules decreases).

♦ Gastric and pancreatic secretion. Calcitonin reduces the acidity of gastric juice and the content of amylase and trypsin in pancreatic juice.

♦ Hormonal regulation bone tissue condition(see below).

F Calcitonin receptor belongs to the secretin receptor family, when calcitonin binds to the receptor in target cells (for example, osteoclasts), the content of cAMP increases. Katacalcin- a peptide consisting of 21 amino acids

residue - performs the same functions as calcitonin.

Section summary

The main thyroid hormones are thyroxine (T 4) and triiodothyronine (T 3), which contain iodine.

The breakdown of thyroglobulin within follicular cells releases thyroid hormones from the thyroid gland.

TSH regulates the synthesis and release of thyroid hormones by activating adenylate cyclase and generating cAMP.

The concentration of thyroid hormones in the blood regulates the release of TSH from the anterior pituitary gland.

In peripheral tissues, the enzyme 5"-deiodinase deiodinizes T4 into the physiologically active hormone T3.

Thyroid hormones are the most important regulators of the development of the central nervous system.

Thyroid hormones stimulate growth by regulating the release of growth hormone from the pituitary gland and have a direct effect on target tissues such as bone.

Thyroid hormones regulate basal and intermediate metabolism by influencing ATP synthesis in mitochondria and through the expression of genes that control metabolic enzymes.

Increased excitability and increased metabolic rate, leading to weight loss, indicate an excess of thyroid hormone (hyperthyroidism).

A decrease in the basal metabolic rate, leading to excess weight, characterizes a deficiency of thyroid hormone (hypothyroidism).

PARATHYROID GLANDS

Four small parathyroid glands are located on the posterior surface and under the capsule of the thyroid gland.

Since the parathyroid glands are topographically connected to the thyroid gland, during its surgical resection there is a danger of removing the parathyroid glands. In this case, hypocalcemia, tetany, and convulsions develop; death is possible.

The function of the parathyroid glands is the synthesis and secretion of Ca 2 + - the regulatory peptide hormone parathyroidocrine (PTH). PTH, together with calcitonin and catacalcin of the thyroid gland, as well as vitamin D, regulates the metabolism of calcium and phosphate.

Hormones

The parathyroid gland synthesizes and secretes parathyrocrine (PTH) and the PTH-related protein into the blood. These hormones encode different genes, but the physiological significance of the PTH-related protein is much broader.

Parathyrocrine

Parathyreocrine (parathyrin, parathyroid hormone, parathyroid hormone, parathyroid hormone, PTH) is a polypeptide of 84 amino acid residues.

Regulators of PTH expression

Serum F[Ca 2+] - main regulator PTH secretion. Ca 2 + ions interact with Ca 2 + receptors (Ca 2 + sensor) of the main cells of the parathyroid glands.

♦ Hypocalcemia(↓[Ca 2+ ] in the blood) enhances secretion

PTG.

♦ Hypercalcemia[Ca 2+ ] in the blood) reduces secretion

PTG.

■ Ca 2 + sensor is a transmembrane glycoprotein found in the chief cells of the parathyroid glands, as well as in the epithelium of the renal tubules. The binding of Ca 2+ to the receptor stimulates phospholipase C, which leads to the release of ITP and diacylglycerol, followed by the release of Ca 2+ from its intracellular stores. An increase in intracellular [Ca 2+] activates

protein kinase C. The end result is suppression PTH secretion.

Vitamin D - auxiliary regulator PTH gene expression. Vitamin D (calcitriol) receptors are nuclear transcription factors. Binding of the calcitriol-calcitriol receptor complex to DNA depresses transcription of the PTH gene.

Magnesium ions.Reduced Mg 2+ content stimulates secretion of PTH, excess Mg 2 + has an inhibitory effect on it.

PTH secretion increases under the influence of activation β -adrenergic receptors and cAMP.

PTH receptors- transmembrane glycoproteins associated with G-protein, are found in significant quantities in bone tissue (osteoblasts) and the renal cortex (epithelium of the convoluted tubules of the nephron). There are two types of PTH receptors: type I binds PTH and PTH-related protein, type II binds only PTH. When ligands bind to the receptor in target cells, not only does the intracellular content of cAMP increase, but phospholipase C is also activated (release of ITP and diacylglycerol, release of Ca 2 + from its intracellular stores, activation of Ca 2 +-dependent protein kinases).

Functions. PTH maintains calcium and phosphate homeostasis. F PTH increases calcium levels in the blood, enhancing bone resorption and leaching of calcium from bones, as well as enhancing tubular reabsorption of calcium in the kidneys.

F PTH stimulates the formation of calcitriol in the kidneys, calcitriol enhances the absorption of calcium and phosphates in the intestine.

F PTH reduces the reabsorption of phosphates in the kidney tubules and enhances their leaching from the bones.

Mineral metabolism and bone tissue

Bones form the skeleton of the body, protect and support vital organs, and serve as a calcium depot for the needs of the whole body. There are two lines of cells in bone - constructive (osteogenic cells - osteoblasts - osteocytes) and destructive (multinuclear osteoclasts). Bone cells

surrounded by bone matrix. There are immature (non-mineralized) bone matrix - osteoid and mature (calcified or calcified) bone matrix.

Bone matrix

Mature bone matrix makes up 50% of bone dry mass and consists of inorganic (50%) and organic (25%) parts and

water (25%).

Organic part. Organic substances of the bone matrix are synthesized by osteoblasts. Macromolecules of the organic matrix include collagens (type I collagen - 90-95% and type V collagen) and non-collagen proteins (osteonectin, osteocalcin, proteoglycans, sialoproteins, morphogenetic proteins, proteolipids, phosphoproteins), as well as glycosaminoglycans (chondroitin sulfate, keratan sulfate).

Inorganic part contains two in significant quantities chemical element- calcium (35%) and phosphorus (50%), forming hydroxyapatite crystals - . The inorganic part of the bone also includes bicarbonates, citrates, fluorides, Mg 2 +, K +, Na + salts.

F Hydroxyapatite crystals connect to collagen molecules through osteonectin. This ligament makes bones extremely resistant to tension and compression.

F The adult human body contains about 1000 g of calcium. 99% of all calcium is found in the bones. About 99% of bone calcium is contained in hydroxyapatite crystals. Only 1% of bone calcium is in the form of phosphate salts; they are easily exchanged between bone and blood and play the role of a buffer (“exchange calcium”) when the concentration of calcium in the blood plasma changes.

Mineralization of osteoid

Osteoid is a non-mineralized organic bone matrix around osteoblasts that synthesize and secrete its components. Subsequently, the osteoid is mineralized due to the activity of alkaline phosphatase. This enzyme hydrolyzes phosphoric acid esters to form orthophosphate, which interacts with Ca 2 +, which leads to the formation of a precipitate in the form of amorphous calcium phosphate Ca 3 (PO 4) 2 and the subsequent formation of hydroxyapatite crystals from it.

For normal mineralization of osteoid, 1α,25-dihydroxycholecalciferol (the active form of vitamin D 3 - calcitriol) is especially necessary. By promoting the absorption of calcium and phosphorus in the intestine, calcitriol provides their necessary concentration to initiate crystallization processes in the bone matrix. By directly affecting osteoblasts, calcitriol increases alkaline phosphatase activity in these cells, promoting bone matrix mineralization.

Bone cells

Osteoblasts actively synthesize and secrete bone matrix substances across almost the entire cell surface, which allows the osteoblast to surround itself with matrix on all sides. As synthetic and secretory activity decreases, osteoblasts become osteocytes embedded in the bone matrix. Both osteoblasts and osteocytes express PTH and calcitriol receptors.

Osteocytes- mature non-dividing cells located in bone cavities, or lacunae. Thin processes of osteocytes are located in tubules extending in different directions from the bone cavities (lacunar-tubular system). Osteocytes maintain the structural integrity of the mineralized matrix and participate in the regulation of Ca 2 + metabolism in the body. This function of osteocytes is controlled by Ca 2 + in the blood plasma and various hormones. Lacunar canalicular system filled with tissue fluid through which the exchange of substances between osteocytes and blood occurs. Fluid constantly circulates in the tubules, which supports the diffusion of metabolites and the exchange between the lacunae and the blood vessels of the periosteum. The concentration of Ca 2 + and PO 4 3- in the lacunar-tubular fluid exceeds critical level for spontaneous precipitation of Ca 2 + salts, which indicates the presence of precipitation inhibitors secreted by bone cells that control the mineralization process.

Osteoclasts- large multinucleated cells of the mononuclear phagocyte system. The precursors of osteoclasts are monocytes. Macrophage colony stimulating factor (M-CSF) and

calcitriol, and to activate them - IL-6 and osteoclast differentiation factor produced by osteoblasts (osteoprotegerin ligand). Osteoclasts are located in the area of ​​bone resorption (destruction) (Fig. 18-4, I). F Corrugated border of the osteoclast (Fig. 18-4, II) - numerous cytoplasmic projections directed towards the surface of the bone. A large amount of H+ and Cl - is released through the membrane of the osteoclast outgrowths, which creates and maintains an acidic environment (pH about 4) in the enclosed space of the lacuna, optimal for dissolving calcium salts of the bone matrix. The formation of H+ in the osteoclast cytoplasm is catalyzed by carbonic anhydrase II. Osteoclasts contain numerous lysosomes, the enzymes of which (acid hydrolases, collagenases, cathepsin K) destroy the organic part of the bone matrix.

Hormonal regulation

Growth regulation

The synthesis of bone matrix macromolecules is stimulated by calcitriol, PTH, somatomedins, transforming growth factor β, and polypeptide growth factors from bone.

Somatomedins stimulate anabolic processes in skeletal tissues (synthesis of DNA, RNA, protein, including proteoglycans), as well as sulfation of glycosaminoglycans. The activity of somatomedins is determined by growth hormone (somatotropin).

Vitamin C necessary for collagen formation. A deficiency of this vitamin slows bone growth and fracture healing.

Vitamin A supports bone formation and growth. Lack of vitamin inhibits osteogenesis and bone growth. Excess vitamin A causes overgrowth of the epiphyseal cartilaginous plates and slows down the growth of bone in length.

Regulation of mineralization

Calcitriol, necessary for the absorption of Ca 2 + in the small intestine, supports the mineralization process. Calcitriol stimulates mineralization at the transcriptional level, increasing the expression of osteocalcin. Vitamin D 3 deficiency leads to

Rice. 18-4. Bone. I - osteoclast. The cytoplasmic processes of the corrugated border are directed towards the surface of the bone matrix. The cytoplasm contains numerous lysosomes; II - osteoclast and bone resorption. When an osteoclast interacts with the surface of a mineralized bone matrix, carbonic anhydrase II (CA II) catalyzes the formation of H + and HC0 3 ". H + is actively pumped out of the cell with the help of proton H + -, K + -ATPase, which leads to acidification of the closed space of the lacuna. Hydrolytic Lysosome enzymes break down fragments of the bone matrix: A - osteoclast on the surface of the bone, B - part of the corrugated border, C - part of the osteoclast cell membrane in the area of ​​the corrugated border.

Rice. 18-4.Continuation.Ill - trabeculae of bone tissue. On the left - normal, on the right - osteoporosis; IV - age-related dynamics of bone mass. For hydroxyapatite, relative values ​​are given.

disruption of bone mineralization, which is observed with rickets in children and osteomalacia in adults. Regulation of resorption

Bone resorption strengthen PTH, interleukins-1, and -6, transforming growth factor α, Pg. Bone resorption support iodine-containing thyroid hormones.

Increased resorption under the influence of PTH is not associated with the direct effect of this hormone on osteoclasts, since these cells do not have PTH receptors. The activating effect of PTH and calcitriol on osteoclasts occurs indirectly through osteoblasts. PTH and calcitriol stimulate the formation of osteoclast differentiation factor, a ligand for osteoprotegerin.

Bone resorption and osteoclast activity suppress calcitonin (through receptors in the plasmalemma of osteoclasts) and γ-interferon.

Estrogens inhibit the production of macrophage colony-stimulating factor (M-CSF) by reticular cells of the bone marrow, which is necessary for the formation of osteoclasts, which inhibits bone resorption.

Section summary

A decrease in plasma calcium levels below normal levels causes the appearance of spontaneous action potentials in nerve endings, leading to convulsive contractions of skeletal muscles.

About half of circulating calcium is in free or ionized form, about 10% is bound to small anions and about 40% is bound to plasma proteins. Most of phosphorus circulates in the blood in the form of orthophosphates.

The bulk of calcium consumed with food is not absorbed into the gastrointestinal tract and is excreted in the feces. On the contrary, phosphates are almost completely absorbed in the gastrointestinal tract and excreted from the body in the urine.

A decrease in the content of ionized calcium in plasma stimulates the secretion of PTH, a polypeptide hormone secreted by the parathyroid glands. PTH plays a vital role in calcium and phosphorus homeostasis and acts on the bones, kidneys and intestines to increase calcium concentrations and decrease plasma phosphate concentrations.

In the liver and kidneys, as a result of a whole chain of reactions, vitamin D is converted into the active hormone 1,25-dihydroxyferol. This hormone stimulates the absorption of calcium in the intestine and, therefore, increases the concentration of calcium in the plasma.

Calcitonin is a polypeptide hormone that is secreted by the thyroid gland and acts by lowering the concentration of calcium in the plasma.

ADRENAL GLANDS

The adrenal glands are paired organs located retroperitoneally at the upper poles of the kidney at the level of Th 12 and L 1. Formally, these are two glands - bark And brain part,- having different origins (the adrenal cortex develops from the mesoderm, chromaffin cells of the medulla are derivatives of neural crest cells). The chemical structure of the synthesized hormones is also different: cells of the adrenal cortex synthesize steroid hormones (mineralocorticoids, glucocorticoids and androgen precursors), chromaffin cells of the medulla synthesize catechol amines. At the same time, from a functional point of view, each adrenal gland is part of a single system of rapid response to a stressful situation, ensuring the execution of the “flight or attack” behavioral response. In this context, the following circumstances are important, functionally ensuring the connection between the sympathetic part of the nervous system, chromaffin cells and glucocorticoids.

The humoral effector of the “flight or fight” response is adrenaline released into the bloodstream from the adrenal medulla.

Chromaffin cells form synapses with preganglionic sympathetic neurons and are regarded as postganglionic cells of efferent sympathetic innervation, releasing adrenaline into the blood in response to the synaptic secretion of acetylcholine and its binding to nicotinic cholinergic receptors.

The adrenal medulla receives blood containing glucocorticoids from the cortex of the organ. In other words, the synthesis and secretion of adrenaline from chromaffin cells is under the control of glucocorticoids.

Adrenal cortex

Epithelial steroidogenic cells of the adrenal cortex - depending on their function and morphology - look different. Directly under the organ capsule are the cells of the zona glomerulosa (occupying 15% of the total volume of the cortex), the cells of the zona fasciculata lie deeper (70% of the volume of the cortex), and at the border with the medulla are the cells of the zona reticularis. Different groups of steroid hormones are synthesized in different zones of the adrenal cortex: mineralocorticoids, glucocorticoids and androgen precursors.

Mineralocorticoids(zona glomerulosa). Aldosterone- main mineralocorticoid. Its job is to maintain the balance of electrolytes in body fluids; in the kidney, aldosterone increases the reabsorption of sodium ions (as a result of sodium retention, the water content in the body increases and blood pressure increases), increases the excretion of potassium ions (loss of potassium causes hypokalemia), as well as the reabsorption of chlorine, bicarbonate and excretion of hydrogen ions. Aldosterone synthesis stimulated angiotensin II.

Glucocorticoids(fascicular and reticular zones). Cortisol- the main glucocorticoid, accounting for 80% of all glucocorticoids. The remaining 20% ​​is cortisone, corticosterone, 11-deoxycortisol and 11-deoxycorticosterone. Glucocorticoids control the metabolism of proteins, carbohydrates and fats, suppress immune reactions, and also have an anti-inflammatory effect. Glucocorticoid synthesis stimulated tropic hormone of the adenohypophysis - ACTH.

Androgen precursors(fascicular and reticular zones). Dehydroepiandrosterone and androstenedione are precursors of androgens; their further transformations occur outside the adrenal gland and are discussed in Chapter 19. Gonadotropic hormones of the pituitary gland do not influence on the secretion of sex hormones in the reticular zone.

Glucocorticoids

The main natural glucocorticoid secreted by the adrenal glands is cortisol(the volume of secretion is from 15 to 20 mg/day, the concentration of cortisol in the blood is about 12 mcg/100 ml). For cortisol, as well as for regulating its synthesis and secretion of cortico-

Berin and ACTH are characterized by a pronounced daily periodicity. At normal rhythm during sleep, cortisol secretion increases after falling asleep and reaches a maximum upon awakening. As a drug in clinical practice Synthetic glucocorticoids (dexamethasone, prednisolone, methylprednisone, etc.) are usually used. Almost all glucocorticoids also have mineralocorticoid effects.

Regulation of glucocorticoid secretion(Figure 18-5).

Activating (descending) influences. The direct activator of the synthesis and secretion of cortisol is ACTH. ACTH is secreted by the cells of the anterior pituitary gland under the influence of corticoliberin, which enters the blood of the hypothalamic-pituitary portal system from the hypothalamus. Stressful stimuli activate the entire descending system of influences, causing a rapid release of cortisol. Cortisol has various metabolic effects aimed at eliminating the damaging nature of stress.

Ascending (inhibitory) influence cortisol acts on the principle of negative feedback, suppressing the secretion of ACTH in the anterior lobe of the pituitary gland and corticoliberin in the hypothalamus. As a result, the concentration of cortisol in the plasma decreases at a time when the body is not exposed to stress.

Metabolism

Bound and free forms. More than 90% of glucocorticoids circulate in the blood in connection with proteins - albumin and corticoid binding globulin (transcortin). About 4% of plasma cortisol is the free fraction.

Circulation time determined by the strength of binding to transcortin (the half-life of cortisol is up to 2 hours, corticosterone is less than 1 hour).

Water-soluble forms. Modification of lipophilic cortisol occurs primarily in the liver; conjugates with glucuronide and sulfate are formed. Modified glucocorticoids - water-soluble compounds capable of excretion.

Excretion.Conjugated forms of glucocorticoids are secreted with bile in the gastrointestinal tract, of which 20% is lost in the urine.

Rice. 18-5. Regulatory circuits in the GnRH-ACTH-cortisol system. The symbols “+” and “-” indicate stimulating and inhibitory influences.

scrap, 80% is absorbed in the intestines. From the blood 70% gluco-

corticoids are excreted in the urine. Functions glucocorticoids are diverse - from the regulation of metabolism to the modification of immunological and inflammatory responses.

Carbohydrate metabolism. The main events take place between skeletal muscles, body fat depots and the liver. The main metabolic pathways are stimulation of glucose

coneogenesis, glycogen synthesis and a decrease in glucose consumption by internal organs (except the brain). The main effect is an increase in blood glucose concentration.

♦ Gluconeogenesis- synthesis of glucose due to amino acids, lactate and fatty acids, i.e. non-carbohydrate substrates.

■ In skeletal muscles, glucocorticoids strengthen protein breakdown. The resulting amino acids enter the liver.

■ In the liver glucocorticoids stimulate synthesis of key enzymes of amino acid metabolism - substrates of gluconeogenesis.

♦ Glycogen synthesisintensifies due to activation of glycogen synthetase. Stored glycogen is easily converted into glucose by glycogenolysis.

Lipid metabolism.Cortisol increases mobilization of fatty acids - a source of substrates for gluconeogenesis.

♦ Lipolysisintensifies in the limbs.

♦ Lipogenesisintensifies in other parts of the body (torso and face).

Proteins and nucleic acids.

♦ Anabolic effect in the liver.

♦ Catabolic effect in other organs (especially skeletal muscles).

The immune system. In high doses, glucocorticoids act as immunosuppressants(used as a means of preventing the rejection of transplanted organs in severe pseudoparalytic myasthenia gravis - myasthenia gravis- the result of the appearance of autoantibodies to nicotinic acetylcholine receptors).

Inflammation.Glucocorticoids have a pronounced anti-inflammatory effect.

Collagen synthesis. Glucocorticoids with long-term use inhibit synthetic activity of fibroblasts and osteoblasts, resulting in skin thinning and osteoporosis.

Skeletal muscles. Long-term use of glucocorticoids maintains muscle catabolism, which leads to muscle atrophy and weakness.

Φ Airways. The administration of glucocorticoids can reduce swelling of the mucous membrane, which develops, for example, in bronchial asthma.

Φ The physiological reactions of organs and body systems caused by cortisol are given in table. 18-4.

Table 18-4.Physiological responses to cortisol

Aldosterone

Aldosterone is the main mineralocorticoid. The normal concentration of aldosterone in the blood is about 6 ng per 100 ml, the volume of secretion is from 150 to 250 mcg/day. Other adrenal steroids, regarded as glucocorticoids (cortisol, 11-deoxycortisol, 11-deoxycorticosterone, corticosterone), also have mineralocorticoid activity, although compared with aldosterone their total contribution to mineralocorticoid activity is not so great.

Regulators of synthesis and secretion (Fig. 18-6).

Φ Angiotensin II- a component of the renin-angiotensin system - the main regulator of the synthesis and secretion of aldosterone. This peptide stimulates release of aldosterone.

Φ Cardiac natriuretic factor(atriopeptin) inhibits aldosterone synthesis.

Φ Na+.The effects of hypo- and hypernatremia are realized through the renin-angiotensin system.

Rice. 18-6. Maintaining balance in body fluids. The symbols “+” and “-” indicate stimulating and inhibitory influences. ACE - angiotensin-converting enzyme.

Φ K+. The effects of potassium ions do not depend on the content of Na+ and angiotensin II in the blood.

♦ Hyperkalemiastimulates secretion of aldosterone.

♦ Hypokalemiaslows down secretion of aldosterone. Φ Prostaglandins.

♦ E 1 And E 2stimulate aldosterone synthesis.

♦ F 1a And F 2aslow down secretion of mineralocorticoids.

Φ Injuries and stress conditionsincrease secretion of aldosterone due to the activating effect of ACTH on the adrenal cortex.

Metabolism. Aldosterone practically does not bind to blood plasma proteins; for this reason, its circulation time in the blood (half-life) does not exceed 15 minutes. Aldosterone is removed from the blood by the liver, where it is transformed into tetrahydroaldosterone-3-glucuronide, excreted by the kidneys.

Aldosterone receptor- intracellular (nuclear) polypeptide - binds aldosterone and activates the transcription of genes, primarily the Na+-, K+-ATPase genes and the combined transmembrane transporter of Na+, K+ and Cl -. Aldosterone receptors are found in the epithelial cells of the renal tubules, salivary and sweat glands. High affinity receptor in systems in vitro also binds cortisol, but in vivo There is virtually no interaction between cortisol and the receptor, since intracellular 11β-hydroxysteroid dehydrogenase converts cortisol to cortisone, which binds poorly to the mineralocorticoid receptor. Consequently, the glucocorticoid cortisol does not exhibit a mineralocorticoid effect in target cells.

Function mineralocorticoids - maintaining the balance of electrolytes in body fluids - is carried out by influencing the reabsorption of ions in the renal tubules (distal convoluted tubules and the initial part of the collecting ducts). Φ Na+. Aldosterone enhances reabsorption of sodium ions.

As a result sodium retention The water content in the body increases and blood pressure rises.

Φ K + . Aldosterone increases excretion of potassium ions. Potassium loss causes hypokalemia.

Φ Cl - , HCO 3 - , H+. Aldosterone enhances reabsorption of chlorine, bicarbonate and renal excretion of hydrogen ions.

Chromaffin fabric

The endocrine function of the adrenal medulla is performed by chromaffin cells derived from the neural crest, which also form paraganglia. Small clusters and single chromaffin cells are also found in the heart, kidneys, and sympathetic ganglia. Chromaffin cells are characterized by granules with electron-dense content containing either adrenaline (the majority of them) or norepinephrine, which gives a chromaffin reaction with potassium dichromate. The granules also contain ATP and chromogranins.

Catechol amines

Synthesis. Catecholamines are synthesized from tyrosine along the chain: tyrosine (the conversion of tyrosine is catalyzed by tyrosine hydroxylase) - DOPA (DOPA decarboxylase) - dopamine (dopamine- β -hydroxylase) - norepinephrine (phenylethanolamine-N-methyltransferase) - adrenalin.

Φ DOPA(dioxyphenylalanine). This amino acid is isolated from beans Vicia faba Its L-form, levodopa, is used as an antiparkinsonian drug. (X-DOPA, levodopa, 3-hydroxy-L-tyrosine, L-dihydroxyphenylalanine).

Φ Dopamine- 4-(2-aminoethyl)pyrocatechol.

Φ Norepinephrine- demethylated precursor of adrenaline. The norepinephrine synthesis enzyme (dopamine β-hydroxylase) is secreted from chromaffin cells and noradrenergic terminals along with norepinephrine.

Φ Adrenalin- l-1-(3,4-dihydroxyphenyl)-2-(methylamino)ethanol - only a humoral factor, not involved in synaptic transmission.

Secretion. When the sympathetic nervous system is activated, chromaffin cells release catechol amines into the blood (mainly adrenalin). Together with catecholamines, ATP and proteins are released from the granules. Adrenaline-containing cells also contain opioid peptides (enkephalins) and secrete them along with adrenaline.

Metabolism adrenaline and other biogenic amines occurs under the influence of catechol-O-methyltransferase and monoamine oxidases. As a result, excreted in urine are formed.

metanephrines and vanillylmandelic acid, respectively. The half-life of catecholamines in plasma is about 2 minutes. In a healthy man in a lying position, the blood content of norepinephrine is about 1.8 nmol/l, adrenaline - 16 nmol/l and dopamine - 0.23 nmol/l. Effects. Catecholamines have a wide spectrum of action (effects on glycogenolysis, lipolysis, gluconeogenesis, significant effects on the cardiovascular system). Vasoconstriction, cardiac muscle contraction parameters and other effects of catechol amines are realized through α- and β-adrenergic receptors on the surface of target cells (SMCs, secretory cells, cardiomyocytes). Receptors catechol amines - adrenergic. Φ Adrenergic receptors target cells (including synaptic) are bound by norepinephrine, adrenaline and various adrenergic drugs (activating - agonists, adrenergic agonists, blocking - antagonists, adrenergic blockers). Adrenergic receptors are divided into α- and β-subtypes. Among α- and β-adrenergic receptors, they distinguish α 1 - (for example, postsynaptic in the sympathetic part of the autonomic nervous system), α 2 - (for example, presynaptic in the sympathetic part of the autonomic nervous system and postsynaptic in the brain), β 1 - (in particular, cardiomyocytes), β 2 - and β 3 -adrenergic receptors. Adrenergic receptors are coupled to G protein.

♦ All subtypes of β 2 -adrenergic receptors activate adenylate cyclase and increase

♦ α 2 -Adrenoreceptors inhibit adenylate cyclase and reduce intracellular cAMP content.

♦ α 1 -Adrenergic receptors activate phospholipase C, which increases (through ITP and diacylglycerol) the intracytoplasmic content of Ca 2+ ions.

Effects,mediated by different subtypes of adrenergic receptors - see also Chapter 15.

♦ α 1

■ Glycogenolysis.Gain.

■ SMC of blood vessels and the genitourinary system.Reduction.

♦ α 2

■ Gastrointestinal tract. Relaxation.

■ Lipolysis. Suppression.

■ Insulin, renin. Suppression of secretion.

■ Cardiomyocytes. Increased contraction force.

■ Lipolysis. Gain.

■ Insulin, glucagon, renin.Increased secretion.

■ SMC of the bronchi, gastrointestinal tract, blood vessels, genitourinary system. Relaxation.

■ Liver.Gainglycogenolysis and gluconeogenesis.

■ Muscles.Gain glycogenolysis.

■ Lipolysis. Gain.

Emergency function of the sympathoadrenal system

“Emergency function of the sympathoadrenal system” (“fight reaction”, “flight or attack” situation), as the various effects of a sudden increased release of adrenaline into the blood are often called, are presented in Table. 18-5.

Table 18-5.Physiological changes during the “fight” response

Section summary

The adrenal gland consists of an outer cortex surrounding an inner medulla. The cortex contains three histologically different zones(from outside to inside) - glomerular, fascicular and reticular.

Hormones secreted by the adrenal cortex include glucocorticoids, the mineralocorticoid aldosterone, and adrenal androgens.

The glucocorticoids cortisol and corticosterone are synthesized in the zona fasciculata and zona reticularis of the adrenal cortex.

The mineralocorticoid aldosterone is synthesized in the glomerular zone of the adrenal cortex.

ACTH increases the synthesis of glucocorticoids and androgens in the cells of the zona fasciculata and reticularis, increasing the intracellular content of cAMP.

Angiotensin II and angiotensin III stimulate the synthesis of aldosterone in cells of the zona glomerulosa, increasing the calcium content in the cytosol and activating protein kinase C.

Glucocorticoids bind to glucocorticoid receptors located in the cytosol of target cells. The glucocorticoid receptor travels to the nucleus and binds to glucocorticoid response elements in the DNA molecule to increase or decrease the transcription of specific genes.

Glucocorticoids are necessary for the body to adapt to loads, damage and stress.

Chromaffin cells of the adrenal medulla synthesize and secrete catecholamines: adrenaline and norepinephrine.

Catecholamines interact with adrenergic receptors: α ρ α 2, β 1, and β 2, which mediate the cellular effects of hormones.

Stimuli such as injury, anger, pain, cold, exhausting work and hypoglycemia cause impulses in the cholinergic preganglionic fibers innervating chromaffin cells, leading to the secretion of catecholamines.

By counteracting hypoglycemia, catecholamines stimulate the formation of glucose in the liver, the release of lactic acid from muscles and lipolysis in adipose tissue.

PANCREAS

The pancreas contains from half a million to two million small clusters of endocrine cells - the islets of Langerhans. Several types of endocrine cells have been identified in the islets that synthesize and secrete peptide hormones: insulin (β-cells, 70% of all islet cells), glucagon (α-cells, 15%), somatostatin (δ-cells), pancreatic polypeptide (PP-cells) , seu F cells) and in children younger age- gastrins (G-cells, seu D cells).

Insulin- main regulator of energy metabolism in the body- controls the metabolism of carbohydrates (stimulation of glycolysis and suppression of gluconeogenesis), lipids (stimulation of lipogenesis), proteins (stimulation of protein synthesis), and also stimulates cell proliferation (mitogen). The main target organs of insulin are the liver, skeletal muscle and adipose tissue.

Glucagon- insulin antagonist - stimulates glycogenolysis and lipolysis, which leads to rapid mobilization of energy sources (glucose and fatty acids). The glucagon gene also encodes the structure of the so-called enteroglucagons - glycentin and glucagon-like peptide-1 - stimulators of insulin secretion.

Somatostatin suppresses the secretion of insulin and glucagon in the pancreatic islets.

Pancreatic polypeptide consists of 36 amino acid residues. It is classified as a regulator of the nutritional regime (in particular, this hormone inhibits the secretion of the exocrine pancreas). The secretion of the hormone is stimulated by protein-rich foods, hypoglycemia, fasting, and physical exercise.

Gastrins I and II(identical 17-amino acid peptides differ in the presence of a sulfate group at tyrosyl at position 12) stimulate the secretion of hydrochloric acid in the stomach. The secretion stimulator is gastrin-releasing hormone, the secretion inhibitor is hydrochloric acid. The gastrin/cholecystokinin receptor is found in the central nervous system and gastric mucosa.

Insulin

Transcription of the insulin gene leads to the formation of preproinsulin mRNA containing sequences A, C and B, as well as

the untranslated 3" and 5" ends. After translation, a polypeptide chain of proinsulin is formed, consisting at the N-terminus of successive domains B, C and A. In the Golgi complex, proteases cleave proinsulin into three peptides: A (21 amino acids), B (30 amino acids) and C (31 amino acids). Peptides A and B, integrating through disulfide bonds, form a dimer - insulin. Secretory granules contain equimolar amounts of hormonally active insulin and non-hormonally active C-peptide, as well as traces of proinsulin.

Insulin secretion

The amount of insulin secreted during relative fasting (for example, in the morning before breakfast) is about 1 U/hour; it increases 5-10 times after eating. On average, a healthy adult male secretes 40 units (287 mmol) of insulin during the day.

Contents of secretory granulesβ -cells enter the blood as a result of exocytosis caused by an increase in the content of intracellular Ca 2 +. Exactly intracellular calcium(more preciselyT) is the direct and main signal for insulin secretion. Promote exocytosis also activatedT[cAMP] protein kinase A and activatedT[diacylglycerol] protein kinase C, which phosphorylate several proteins involved in exocytosis.Regulators of insulin secretion Stimulate insulin secretion, hyperglycemia (increased plasma glucose), hyperkalemia, some amino acids, acetylcholine, glucagon and some other hormones, food intake, as well as sulfonylurea derivatives.

♦ Glucose- master regulator of insulin secretion

■ With an increased glucose content in the blood plasma (more than 5 mM, see Table 18-8), molecules of this sugar, as well as molecules of galactose, mannose, β-keto acid included Vβ -cells by facilitated diffusion through the transmembrane glucose transporter (importer) GLUT2.

■ Sugar molecules entering the cell undergo glycolysis, resulting in increases ATP content.

■ Increased content of intracellular ATP closes sensitive to ATP and potassium channels of the plasma membrane, which inevitably leads to its depolarization.

■ Depolarization of the plasma membrane β -cells opens voltage-sensitive calcium channels of the plasma membrane, as a result, calcium ions enter the cell from the intercellular space.

■ Increase in cytosol stimulates exocytosis of secretory granules, insulin of these granules appears outside β -cells.

♦ Hyperkalemia

■ Increased K+ content in the internal environment of the body blocks sensitive to potassium channels of the plasma membrane, which leads to its depolarization.

■ Further events unfold as described above (see points 4 and 5).

♦ Amino acids(especially arginine, leucine, alanine and lysine) enter the β -cells with the help of a transmembrane amino acid transporter and metabolize tricarboxylic acids in the mitochondrial cycle, resulting in increases ATP content. Further events unfold as described above (see points 3-5).

♦ Sulfonylurea derivativesblock potassium channels in the plasmalemma β -cells, interacting with the sulfonylurea receptor as part of the K+- and ATP-sensitive potassium channels of the plasma membrane, which leads to its depolarization. Further events unfold as described above (see points 4 and 5).

♦ Acetylcholine, secreted from the nerve fiber endings of the right vagus nerve, interacts with G-protein coupled muscarinic cholinergic receptors of the plasma membrane. The G protein activates phospholipase C, which leads to the cleavage of two second messengers - cytosolic ITP and membrane diacylglycerol - from phosphoinositol biphosphate phospholipids of the cell membrane.

■ ITP, by binding to its receptors, stimulates release of Ca 2 + from the cisterns of the smooth endoplasmic reticulum, which leads to exocytosis of secretory granules with insulin.

■ Diacylglycerol activates protein kinase C, which leads to phosphorylation of some proteins involved in exocytosis, resulting in insulin secretion.

♦ Cholecystokinin interacts with its receptors (G-protein coupled receptors). The G protein activates phospholipase C. Further events occur as described above for acetylcholine.

♦ Gastrin binds to the cholecystokinin type B receptor. Further events occur as described above for cholecystokinin and acetylcholine.

♦ Gastrin releasing hormone Also stimulates insulin secretion.

♦ Glucagon-like peptide-1(see below) - the most powerful stimulant insulin secretion.

Insulin secretion inhibitors

♦ Adrenaline and norepinephrine (through α 2 -adrenergic receptors and a decrease in cAMP content) suppress insulin secretion. Through β-adrenergic receptors (cAMP content increases), these agonists stimulate insulin secretion, but α-adrenergic receptors predominate in the islets of Langerhans, resulting in oppression insulin secretion.

■ Stress. The role of adrenaline in suppressing insulin secretion is especially great during the development of stress, when sympathetic system excited. Adrenaline one-

temporarily increases the concentration of glucose and fatty acids in the blood plasma. The meaning of this double effect is as follows: adrenaline causes powerful glycogenolysis in the liver, causing the release of a significant amount of glucose into the blood within a few minutes, and at the same time has a direct lipolytic effect on adipose tissue cells, increasing the concentration of fatty acids in the blood. Consequently, adrenaline creates opportunities for the use of fatty acids under stress.

♦ Somatostatin and neuropeptide galanin, binding to their receptors, they cause a decrease in the intracellular content of cAMP and suppress insulin secretion. Φ Dietary regime is extremely important both for the secretion of insulin and the content of glucose in the blood plasma, and for the insulin-dependent metabolism of protein, fats and carbohydrates in the target organs of insulin (Table 18-6).

Table 18-6.The influence of fasting and food intake on the content and effects of insulin

Metabolism of insulin. Insulin and C-peptide circulate in the blood in free form for 3-5 minutes. More than half of the insulin is broken down in the liver immediately upon entering this organ through the portal veins. C-peptide is not destroyed in the liver, but is excreted through the kidneys. For these reasons, reliable laboratory data

the indicator of insulin secretion is not the hormone itself (insulin), but the C-peptide.

Physiological effects of insulin

Target organs of insulin. The main targets of insulin are the liver, skeletal muscles, and adipose tissue cells. Since insulin is the main regulator of the metabolism of molecules - sources of energy metabolism in the body - it is in these organs that the main physiological effects of insulin on the metabolism of proteins, fats and carbohydrates are manifested.

Functions insulin are varied (regulation of the metabolism of energy sources - carbohydrates, lipids and proteins). In target cells, insulin stimulates transmembrane transport of glucose and amino acids, synthesis of protein, glycogen and triglycerides, glycolysis, as well as cell growth and proliferation, but suppresses proteolysis, lipolysis and fat oxidation (see details below).

The rate of manifestation of insulin effects. The physiological effects of insulin, based on the speed of their onset after the interaction of the hormone with its receptors, are divided into fast (develop within seconds), slow (minutes) and delayed (Table 18-7).

Table 18-7.Long-term effects of insulin

The effect of insulin on carbohydrate metabolism

Liver. Insulin has the following effects on hepatocytes: Φ glucose constantly enters liver cells through a transmembrane transporter GLUT2; insulin mobilizes an additional transmembrane transporter GLUT4, promoting its integration into the plasma membrane of hepatocytes;

Φ from entering the hepato-

glucose cytes, increasing transcription of the glucokin-gene

zy and activating glycogen synthase; Φ prevents the breakdown of glycogen, inhibiting the activity of gly-

cogen phosphorylase and glucose-6-phosphatase; Φ activating glu-

cokinase, phosphofructokinase and pyruvate kinase; Φ activates glucose metabolism through hexose monophosphate

shunt;

Φ accelerates the oxidation of pyruvate, activating pyruvate dehydrogenase;

Φ suppresses gluconeogenesis, inhibiting the activity of phosphoenolpyruvate carboxykinase, fructose-1,6-biphosphatase and glucose-6-phosphatase.

Skeletal muscles. In skeletal muscle insulin:

Φ through

promotes glycogen synthesis from entering the hepato-

glucose cytes, increasing transcription of the hexokinase gene

and activating glycogen synthase; Φ stimulates glycolysis and carbohydrate oxidation, activating hec-

sokinase, phosphofructokinase and pyruvate kinase;

Adipose tissue. Insulin affects adipocyte metabolism in the following ways:

Φ activates the entry of glucose into the sarcoplasm through

transmembrane transporter GLUT4, facilitating its

integration into the plasma membrane; Φ stimulates glycolysis, what contributes to education

α-glycerophosphate, used to build triglycerides; Φ accelerates the oxidation of pyruvate, activating pyruvate dehydro-

genase and acetyl-CoA carboxylase, which favors

synthesis of free fatty acids.

CNS. Insulin has virtually no effect on either the transport of glucose into nerve cells or their metabolism. Neurons in the brain differ from cells in other organs in that they use glucose rather than fatty acids as their main source of energy. Moreover, nerve cells are not able to synthesize glucose. This is why an uninterrupted supply of glucose to the brain is so important for the functioning and survival of neurons.

Other organs. Like the central nervous system, many organs (such as the kidney and intestines) are not sensitive to insulin.

Glucose homeostasis

The glucose content in the internal environment of the body must be within strictly limited limits. Thus, on an empty stomach, the concentration of glucose in the blood plasma fluctuates between 60-90 mg% (normoglycemia), increases to 100-140 mg% (hyperglycemia) within one hour after eating and usually returns to normal values ​​within 2 hours. There are situations when the concentration of glucose in the blood plasma decreases to 60 mg% and below (hypoglycemia). The need to maintain a constant concentration of glucose in the blood is dictated by the fact that the brain, retina and some other organs and cells use predominantly glucose as an energy source. So, in the intervals between meals, the main part of the glucose found in the internal environment of the body is used for brain metabolism.

Glucose homeostasis is maintained by the following mechanisms. Φ The liver dampens fluctuations in glucose concentration. So,

When blood glucose rises to high concentrations after meals and the amount of insulin secreted increases, more than 60% of the glucose absorbed from the intestine is stored in the liver in the form of glycogen. In the following hours, when glucose concentrations and insulin secretion decrease, the liver releases glucose into the blood.

Φ Insulin and glucagon reciprocally regulate normal blood glucose levels. Increased glucose levels compared to normal levels act through a feedback mechanism on the β-cells of the islets of Langerhans and cause increased insulin secretion, which leads to

glucose concentration to normal. A lower than normal glucose level inhibits the formation of insulin, but stimulates the secretion of glucagon, which brings the glucose level back to normal.

Φ Hypoglycemia has a direct effect on the hypothalamus, which excites the sympathetic nervous system. As a result, adrenaline is secreted from the adrenal glands and increases the release of glucose by the liver.

Φ Prolonged hypoglycemia stimulates the release of growth hormone and cortisol, which reduce the rate at which most cells in the body consume glucose, allowing blood glucose concentrations to return to normal levels.

After meals monosaccharides absorbed in the intestine: triglycerides and amino acids enter the liver through the portal vein system, where various monosaccharides are converted into glucose. Glucose in the liver is stored in the form of glycogen (glycogen synthesis also occurs in the muscles); only a small part of the glucose is oxidized in the liver. Glucose that is not used by hepatocytes ends up in the general circulation system and enters various organs, where it is oxidized to water and CO 2 and provides the energy needs of these organs. Φ Incretins. When chyme enters the intestine from the endocrine cells of its wall, so-called incretins are released into the internal environment of the body: gastric inhibitory peptide, enteroglucagon (glycentin) and glucagon-like peptide 1, which potentiate glucose-induced insulin secretion. Φ Glucose absorption from the intestinal lumen are carried out by Na+-dependent cotransporters of sodium and glucose ions built into the apical plasma membrane of enterocytes, which require (unlike the GLUT glucose transporters) energy expenditure. On the contrary, the release of glucose from enterocytes into the internal environment of the body, occurring through the plasmalemma of their basal part, occurs through facilitated diffusion. Φ Excretion of glucose through the kidneys

♦ Filtration glucose molecules from the lumen of the blood capillaries of the renal corpuscles into the cavity of Bowman's capsule -

Shumlyansky is carried out in proportion to the concentration of glucose in the blood plasma.

♦ Reabsorption. Typically, all glucose is reabsorbed in the first half of the proximal convoluted tubule at a rate of 1.8 mmol/min (320 mg/min). Reabsorption of glucose occurs (as does its absorption in the intestine) through the combined transfer of sodium and glucose ions.

♦ Secretion. In healthy individuals, glucose is not secreted into the lumen of the nephron tubules.

♦ Glucosuria. Glucose appears in the urine when its content in the blood plasma exceeds 10 mM.

Between meals Glucose enters the blood from the liver, where it is formed due to glycogenolysis (the breakdown of glycogen to glucose) and gluconeogenesis (the formation of glucose from amino acids, lactate, glycerol and pyruvate). Due to the low activity of glucose-6-phosphatase, glucose does not enter the blood from the muscles.

Φ At rest The glucose content in the blood plasma is 4.5-5.6 mM, and the total glucose content (calculations for an adult healthy man) in 15 liters of intercellular fluid is 60 mmol (10.8 g), which approximately corresponds to the hourly consumption of this sugar. It should be remembered that glucose is not synthesized neither in the central nervous system nor in erythrocytes and is not stored in the form of glycogen and at the same time is an extremely important source of energy.

Φ Between meals, glycogenolysis, gluconeogenesis and lipolysis predominate. Even with a short fast (24-48 hours), a reversible condition close to diabetes mellitus develops - starvation diabetes. At the same time, neurons begin to use ketone bodies as an energy source.

During physical activity glucose consumption increases several times. At the same time, glycogenolysis, lipolysis and gluconeogenesis, regulated by insulin, as well as functional insulin antagonists (glucagon, catecholamines, growth hormone, cortisol), increase.

Φ Glucagon. See below for the effects of glucagon. Φ Catecholamines. Physical activity through the hypothalamic centers (hypothalamic glucostat) activates

sympathoadrenal system. As a result, the release of insulin from β-cells decreases, the secretion of glucagon from α-cells increases, the flow of glucose into the blood from the liver increases, and lipolysis increases. Catecholamines also potentiate the increase in mitochondrial oxygen consumption caused by T3 and T4. Φ Thanks growth hormone The glucose content in the blood plasma increases, as glycogenolysis in the liver increases, the sensitivity of muscles and fat cells to insulin decreases (as a result, their absorption of glucose decreases), and the release of glucagon from α-cells is stimulated.

Φ Glucocorticoidsstimulate glycogenolysis and gluconeogenesis, but suppress the transport of glucose from the blood to different cells.

Glucostat. Regulation of glucose contained in the internal environment of the body is aimed at maintaining the homeostasis of this sugar within normal values ​​(glucostat concept) and is carried out on different levels. The mechanisms that allow maintaining glucose homeostasis at the level of the pancreas and insulin target organs (peripheral glucostat) are discussed above. It is believed that the central regulation of glucose content (central glucostat) is carried out by insulin-sensitive nerve cells of the hypothalamus, which then send signals to activate the sympathoadrenal system, as well as to the neurons of the hypothalamus that synthesize corticoliberin and somatoliberin. Since the glucose content in the internal environment of the body deviates from normal values, as judged by the glucose content in the blood plasma, hyperglycemia or hypoglycemia develops.

Φ Hypoglycemia- decrease in blood glucose level less than 3.33 mmol/l. Hypoglycemia can occur in healthy individuals after several days of fasting. Clinically, hypoglycemia manifests itself when the glucose level decreases below 2.4-3.0 mmol/l. The key to diagnosing hypoglycemia is Whipple's triad: neuropsychiatric manifestations during fasting, blood glucose less than 2.78 mmol/l, relief of an attack by oral or intravenous administration of

dextrose solution (40-60 ml of 40% glucose solution). The extreme manifestation of hypoglycemia is hypoglycemic coma. Φ Hyperglycemia. The massive intake of glucose into the internal environment of the body causes an increase in its content in the blood - hyperglycemia (the glucose content in the blood plasma exceeds 6.7 mM). Hyperglycemia stimulates secretion of insulin from β-cells and suppresses secretion of glucagon from α-cells of the islets of Langerhans. Both hormones block the formation of glucose in the liver during glycogenolysis and gluconeogenesis. Hyperglycemia, due to the fact that glucose is an osmotically active substance, can cause cell dehydration and the development of osmotic diuresis with loss of electrolytes. Hyperglycemia can cause damage to many tissues, especially blood vessels. Hyperglycemia is a characteristic symptom of diabetes mellitus.

The effect of insulin on fat metabolism

Liver. Insulin in hepatocytes:

Φ promotes synthesis of fatty acids from glucose, activating acetyl-CoA carboxylase and fatty acid synthase. Fatty acids, adding α-glycerophosphate, are converted into triglycerides;

Φ suppresses oxidation of fatty acids due to increased conversion of acetyl-CoA to malonyl-CoA. Malonyl-CoA inhibits the activity of carnitine acyltransferase (transports fatty acids from the cytoplasm into the mitochondria for their β-oxidation and conversion into keto acids. In other words, insulin has an anti-ketogenic effect.

Adipose tissue. In lipocytes, insulin promotes the conversion of free fatty acids into triglycerides and their deposition as fat. This effect of insulin occurs in several ways. Insulin:

Φ increases pyruvate oxidation, activating pyruvate dehydrogenase and acetyl-CoA carboxylase, which favors the synthesis of free fatty acids;

Φ increases transport of glucose into lipocytes, the subsequent conversion of which contributes to the appearance of α-glycerophosphate;

Φ promotes triglyceride synthesis from α-glycerophosphate and free fatty acids;

Φ prevents the breakdown of triglycerides on glycerol and free fatty acids, inhibiting the activity of hormone-sensitive triglyceride lipase;

Φ activates the synthesis of lipoprotein lipase, transported to endothelial cells, where this enzyme breaks down chylomicron triglycerides and very low-density lipoproteins.

The effect of insulin on protein metabolism and body growth

Insulin in the liver, skeletal muscle, and other target organs and target cells stimulates protein synthesis and inhibits protein catabolism. In other words, insulin- strong anabolic hormone. The anabolic effect of insulin is realized in several ways. Insulin:

stimulates absorption of amino acids by cells;

enhances gene transcription and mRNA translation;

suppresses breakdown of proteins (especially muscle proteins) and inhibits their release into the blood;

reduces rate of gluconeogenesis from amino acids. The anabolic effects of insulin and growth hormone are synergistic

us. This is not least determined by the fact that the effects of growth hormone are carried out through the insulin-like growth factor - somatomedin C.

Glucagon and glucagon-like peptides

The glucagon gene contains sequences encoding the structure of several physiologically related hormones with glucagon effects. Transcription produces preproglucagon mRNA, but this mRNA is cleaved differently (differential splicing) in the α cells of the islets of Langerhans and endocrine L cells of the upper small intestinal mucosa, causing the formation of different proglucagon mRNAs.

Φ Glycentin consists of 69 amino acid residues, stimulates the secretion of insulin and gastric juice, and also takes part in the regulation of gastrointestinal motility. Glycentin is also found in nerve cells of the hypothalamus and brain stem.

Φ Glucagon-like peptide-1(amino acid sequences 7-37) is the most powerful stimulator of glucose-induced insulin secretion (which is why, in particular, the glucose tolerance test is performed orally and not intravenously). This peptide suppresses gastric secretion and is regarded as a physiological mediator of the feeling of satiety. The peptide is also synthesized in neurons of the paraventricular nucleus of the hypothalamus and neurons of the central nucleus amygdala. Both groups of nerve cells are directly involved in the regulation of eating behavior.

Φ Glucagon-like peptide-2 stimulates the proliferation of intestinal crypt cells and absorption in the small intestine.

Glucagon secretion

Intracellular events that ensure the secretion of glucagon from α-cells occur by the same mechanisms as the secretion of insulin from β-cells (see the section “Regulators of insulin secretion” above), but the same extracellular signals trigger the secretion of glucagon, often ( but not always!) lead to opposite results.

Stimulate glucagon secretion, amino acids (especially arginine and alanine), hypoglycemia, insulin, gastrin, cholecystokinin, cortisol, exercise, fasting,β -adrenergic stimulants, food intake (especially protein-rich).

Suppress glucagon secretion glucose, insulin, somatostatin, secretin, free fatty acids, ketone bodies,α - adrenergic stimulants.

The half-life of glucagon in the blood is about 5 minutes.

Physiological effects of glucagon

The main target of glucagon is the liver (hepatocytes), and to a lesser extent - adipocytes and striated muscle tissue (including cardiomyocytes). The glucagon receptor is located in the plasmalemma of target cells; it binds only glucagon and through the G protein activates adenylate cyclase. Mutations in the glucagon receptor gene cause non-insulin-dependent diabetes mellitus. Glucagon is regarded as an insulin antagonist; this hormone stimulates glycogenolysis and lipolysis, which

leads to rapid mobilization of energy sources (glucose and fatty acids). At the same time, glucagon has a ketogenic effect, i.e. stimulates the formation of ketone bodies.

Glucagon increases glucose levels(promotes hyperglycemia) in blood plasma. This effect is realized in several ways.

Φ Stimulation of glycogenolysis. Glucagon, by activating glycogen phosphorylase and inhibiting glycogen synthase in hepatocytes, causes rapid and pronounced breakdown of glycogen and the release of glucose into the blood.

Φ Suppression of glycolysis. Glucagon inhibits key enzymes of glycolysis (phosphofructokinase, pyruvate kinase) in the liver, which leads to an increase in the content of glucose-6-phosphate in hepatocytes, its dephosphorylation and the release of glucose into the blood.

Φ Stimulation of gluconeogenesis. Glucagon enhances the transport of amino acids from the blood to hepatocytes and simultaneously activates the main enzymes of gluconeogenesis (pyruvate carboxylase, fructose-1,6-biphosphatase), which increases the glucose content in the cytoplasm of cells and its entry into the blood.

Glucagon promotes the formation of ketone bodies, stimulating the oxidation of fatty acids: since the activity of acetyl-CoA carboxylase is inhibited, the content of the carnitine acyltransferase inhibitor - malonyl-CoA is reduced, which causes an increased flow of fatty acids from the cytoplasm into the mitochondria, where they occur β -oxidation and conversion to keto acids. In other words, unlike insulin, glucagon has a ketogenic effect.

Section summary

The distribution of alpha, beta, delta and F cells within each of the islets of Langerhans has a certain pattern, indicating that paracrine regulation of secretion is possible.

Plasma glucose levels are the primary physiological regulator of insulin and glucagon secretion. Amino acids, fatty acids and some gastrointestinal hormones also take part in this process.

Insulin has an anabolic effect on carbohydrate, fat and protein metabolism in the tissues that are the target of its action.

The effect of glucagon on carbohydrate, fat and protein metabolism primarily manifests itself in the liver and is catabolic in nature.

TESTLES

Steroid androgens and α-inhibin are synthesized in the testes. Their physiological significance is discussed in Chapter 19; brief characteristics of hormones are given here.

Steroid androgens produced by interstitial Leidig cells (testosterone and dihydrotestosterone) and cells of the zona reticularis of the adrenal cortex (dehydroepiandrosterone and androstenedione, which have weak androgenic activity).

Φ Testosterone- the main circulating androgen. During embryogenesis, androgens control the development of the fetus according to the male type. During puberty, they stimulate the development of male characteristics. With the onset of puberty, testosterone is necessary to maintain spermatogenesis, secondary sexual characteristics, secretory activity of the prostate gland and seminal vesicles.

Φ Dihydrotestosterone. 5α-Reductase catalyzes the conversion of testosterone to dihydrotestosterone in Leidig cells, prostate, and seminal vesicles.

α -Inhibin. This glycoprotein hormone is synthesized in the Sertoli cells of the convoluted seminiferous tubules and blocks the synthesis of pituitary FSH.

OVARIES

The ovaries synthesize female steroid hormones, glycoprotein hormones inhibins and peptide relaxins. Their physiological significance is discussed in Chapter 19; here are brief characteristics of hormones.

Female sex hormones Estrogens (estradiol, estrone, estriol) and progestins (progesterone) are steroids.

Φ Estrogens during puberty they stimulate the development of female gender characteristics. In women of childbearing age, estrogens activate the proliferation of follicular cells, and in the endometrium they control the proliferative phase of the menstrual cycle.

♦ Estradiol(17β-estradiol, E 2) - 17β-estra-1,3,5(10)-trien-3,17-diol - is formed from testosterone by aromatization, has pronounced estrogenic activity. The formation of aromatic C18-estrogens from C19-androgens is catalyzed by aromatase, also called estrogen synthase. The synthesis of this enzyme in the ovary is induced by FSH.

♦ Estrone(E 1) - 3-hydroxyestra-1,3,5(10)-trien-17-one - a metabolite of 17β-estradiol, formed by aromatization of androstenedione, has little estrogenic activity, and is excreted in the urine of pregnant women.

♦ Estriol- 16α,17β-estri-1,3,5(10)-triene-3,16,17-triol - is formed from estrone. This weak estrogen is excreted in the urine of pregnant women and is present in significant quantities in the placenta.

♦ Estrogen receptor belongs to nuclear receptors, a polypeptide of 595 amino acid residues, has pronounced homology with a proto-oncogene v-erbA.

Φ Progesterone refers to progestins, it is synthesized by the cells of the corpus luteum of the ovary in the luteal stage of the ovarian-menstrual cycle, as well as by chorion cells during pregnancy. Progesterone in the endometrium controls the secretory phase of the menstrual cycle and significantly increases the threshold of excitability of myometrial SMCs. Stimulate synthesis of progesterone LH and HGT. The progestin receptor is a nuclear transcription factor; due to gene defects of the receptor, changes in the endometrium characteristic of the secretory phase of the menstrual cycle do not occur. Relaxins- peptide hormones from the insulin family, synthesized by the cells of the corpus luteum and cytotrophoblast, during pregnancy have a relaxing effect on the myometrial SMC, and before childbirth they contribute to the softening of the symphysis pubis and cervix.

Inhibins, synthesized in the ovary, suppress the synthesis and secretion of hypothalamic gonadoliberin and pituitary

FSH.

PLACENTA

The placenta synthesizes many hormones and other biological active substances, which are important for the normal course of pregnancy and fetal development.

Peptide hormones (including neuropeptides and releasing hormones): human chorionic gonadotropin (CHT), placental variant of growth hormone, human chorionic somatomammotropins 1 and 2 (placental lactogens), thyrotropin (TSH), thyrotropin-releasing hormone (TSH-RH), corticoliberin (ACTH-RH), gonadoliberin , somatoliberin, somatostatin, substance P, neurotensin, neuropeptide Y, ACTH-related peptide, glycodelin A (insulin-like growth factor binding protein), inhibins.

Steroid hormones: progesterone, estrone, estradiol, estriol.

KIDNEYS

Different kidney cells synthesize a significant amount of substances that have hormonal effects.

Renin is not a hormone, this enzyme (a protease whose substrate is angiotensinogen) is the initial link in the renin-angiotensinogen-angiotensin system (reninangiotensin system), the most important regulator of systemic blood pressure. Renin is synthesized in modified (epithelioid) SMCs of the wall of the afferent arterioles of the renal corpuscles, which are part of the periglomerular complex, and is secreted into the blood. Regulators of renin synthesis and secretion: 1) β-adrenergic receptor-mediated sympathetic innervation (stimulation of renin secretion); 2) angiotensins (based on the principle of negative feedback); 3) macula densa receptors as part of the periglomerular complex (registration of NaCl content in the distal tubules of the nephron); 4) baroreceptors in the wall of the afferent arteriole of the renal corpuscles.

Calcitriol(1α, 25-dihydroxycholecalciferol) - the active form of vitamin D 3 - is synthesized in the mitochondria of the proximal convoluted tubules, promotes absorption

calcium and phosphates in the intestines, stimulates osteoblasts (accelerates bone mineralization). The formation of calcitriol is stimulated by PTH and hypophosphatemia (low phosphate levels in the blood) and suppressed by hyperphosphatemia (increased phosphate levels in the blood).

Erythropoietin- protein containing sialic acid - synthesized by interstitial cells, stimulates erythropoiesis at the stage of proerythroblast formation. The main stimulus for the production of erythropoietin is hypoxia (a decrease in pO 2 in tissues, including that depending on the number of circulating red blood cells).

Vasodilators- substances that relax the SMC walls of blood vessels, expanding their lumen and thereby reducing blood pressure. In particular, bradykinin and some prostaglandins (Pg) are synthesized in the interstitial cells of the renal medulla.

Φ Bradykinin- a nonapeptide formed from the decapeptide kallidin (lysyl-bradykinin, kininogen, bradykininogen), which in turn is cleaved from α 2 -globulin under the action of peptidases - kallikreins (kininogenins).

Φ Prostaglandin E 2 relaxes the SMC of the blood vessels of the kidney, thereby reducing the vasoconstrictor effects of sympathetic stimulation and angiotensin II.

HEART

Natriuretic factors (atrial factor - atriopeptin) is synthesized by cardiomyocytes of the right atrium and some neurons of the central nervous system. The targets of natriuretic peptides are cells of the renal corpuscles, collecting ducts of the kidney, zona glomerulosa of the adrenal cortex, and vascular SMCs. The functions of natriuretic factors are control of the volume of extracellular fluid and electrolyte homeostasis (inhibition of the synthesis and secretion of aldosterone, renin, vasopressin). These peptides have a strong vasodilatory effect and lower blood pressure.

STOMACH AND INTESTINES

The wall of the tubular organs of the gastrointestinal tract contains a huge number of various endocrine cells (enteroendocrine

cells) that secrete hormones. Together with the cells of the gastrointestinal tract's own nervous system (enteric nervous system), which produce various neuropeptides, the enteroendocrine system regulates many functions of the digestive system (discussed in Chapter 21). Here, as an example, we will name the peptide hormones gastrin, secretin and cholecystokinin.

Gastrin stimulates the secretion of HCl by parietal cells of the gastric mucosa.

Secretin stimulates the release of bicarbonate and water from the secretory cells of the glands of the duodenum and pancreas.

Cholecystokinin stimulates contractions of the gallbladder and the release of enzymes from the pancreas.

VARIOUS ORGANS

Cells various organs produce many regulatory chemicals that are not formally related to hormones and the endocrine system (for example, Pg, interferons, interleukins, growth factors, hematopoietins, chemokines, etc.).

Eicosanoids influence the contractility of SMCs of blood vessels and bronchi, change the threshold of pain sensitivity and participate in the regulation of many body functions (maintaining hemostasis, regulating SMC tone, secretion of gastric juice, maintaining immune status, etc.). For example, in the lungs, PgD 2 and leukotriene C 4 are powerful contractile agonists of the SMC of the airways, their effects are respectively 30 and 1000 times stronger than the effects of histamine. At the same time, PgE 2 is a vasodilator, and leukotrienes D 4 and E 4 are vasoconstrictors; they also increase the permeability of the blood vessel wall.

Φ Pg at physiological pH values ​​poorly penetrate biological membranes. Their transmembrane transport is carried out by special transporter proteins built into cell membranes.

Φ PG receptors are embedded in the plasma membrane of target cells and are associated with G proteins.

Histamine- a powerful stimulator of hydrochloric acid secretion in the stomach, the most important mediator of immediate allergic reactions

reactions and inflammation, causes contraction of airway SMCs and bronchoconstriction, but at the same time is a vasodilator for small vessels.

Interferons- glycoproteins with antiviral activity; There are at least four types of interferons (α, β, γ, ω).

Interleukins(at least 31) - cytokines that act as growth factors and differentiation of lymphocytes and other cells.

Growth factors stimulate growth and differentiation, and sometimes transformation (malignancy) of various cells. Several dozen growth factors are known: epidermal, fibroblasts, hepatocytes, nerves, etc.

Chemokines(several dozen) - small secretory proteins, primarily regulating the movements of leukocytes. Examples of chemokine names: fractalkine, lymphotactin, monocyte chemotaxis factor, IL-18, eutactin and many others.

Colony-stimulating factors- protein factors necessary for the survival, proliferation and differentiation of hematopoietic cells. They are named after the cells they stimulate: granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), and multi-cell colony-stimulating factor (IL-3). . These factors are produced by macrophages, T-lymphocytes, endothelium, and fibroblasts.

Leptin, a hormone produced in adipocytes, acts on the hypothalamus, reducing food intake and increasing energy expenditure.

Adiponectin is a hormone produced in the same way as leptin in adipocytes, but acts as a leptin antagonist.