The thyroid gland consists of two parts located on both sides of the trachea. Due to the free combination with the larynx, it rises and falls when swallowing, shifts to the side when turning the head. The thyroid gland is well supplied with blood (it holds the first place among organs in terms of the amount of blood flowing per unit of time per unit mass). The gland is innervated by sympathetic, parasympathetic and somatic nerve branches.
There are many interoreceptors in the gland. The gland tissue of each particle consists of numerous follicles, the cavities of which are filled with a thick, viscous yellowish mass - a colloid formed mainly by thyroglobulin - the main protein that contains iodine. The colloid also contains mucopolysaccharides and nucleoproteins - proteolytic enzymes that belong to cathepsin, and other substances. The colloid is produced by the epithelial cells of the follicles and continuously enters their cavity, where it is concentrated. The amount of colloid and its consistency depend on the phase of secretory activity and may be different in different follicles of the same gland.
Thyroid hormones divided into two groups: iodinated (thyroxine and triiodothyronine) and thyrocalcitonin (calcitonin). The content of thyroxine in the blood is greater than triiodothyronine, but the activity of the latter is several times higher than that of thyroxine.
thyroxine and triiodothyronine are formed in the bowels of a specific protein of the thyroid gland - thyroglobulin, which contains a large amount of organically bound iodine. The biosynthesis of thyroglobulin, which is part of the colloid, is carried out in the epithelial cells of the follicles. In the colloid, thyroglobulin is subject to iodination. This is a very complex process. Iodization begins with the intake of iodine in the body with food in the form of organic compounds or in a reduced state. During digestion, organic and chemically pure iodine is converted into iodide, which is easily absorbed from the intestines into the blood. The main mass of iodide is concentrated in the thyroid gland. The part that remains is excreted in urine, saliva, gastric juice and bile. Iodide immersed in iron is oxidized to elemental iodine, then it is bound in the form of iodotyrosin and their oxidative condensation into thyroxine and triiodothyronine molecules in the depths of thyroglobulin. The ratio of thyroxine and triiodothyronine in the thyroglobulin molecule is 4: 1. Thyroglobulin iodine is stimulated by a special enzyme, thyroiodine peroxidase. The withdrawal of hormones from the follicle into the blood occurs after the hydrolysis of thyroglobulin, which occurs under the influence of proteolytic enzymes - atepsin. Hydrolysis of thyroglobulin releases the active hormones thyroxine and triiodothyronine, which enter the bloodstream.
Both hormones in the blood are in combination with proteins of the globulin fraction (thyroxine-binding globulin), as well as with plasma albumins. Thyroxine binds better to blood proteins than triiodothyronine, as a result of which the latter penetrates tissues more easily than thyroxine. In the liver, thyroxine forms paired compounds with glucuronic acid, which have no hormonal activity and are excreted in the bile into the digestive organs. Thanks to the process of detoxification, there is no unprofitable blood saturation with thyroid hormones,
Physiological effects of iodinated thyroid hormones. Named hormones affect the morphology and functions of organs and tissues: the growth and development of the body, on all types of metabolism, the activity of enzyme systems, on the functions of the central nervous system, higher nervous activity, vegetative functions of the body.
Influence on growth and differentiation of tissues. With the removal of the thyroid gland in experimental animals and with hypothyroidism in young people, growth retardation (dwarfism) and the development of almost all organs, including the gonads, retardation of puberty (cretinism) are observed. The lack of thyroid hormones in the mother adversely affects the processes of differentiation of the embryo, in particular its thyroid gland. The insufficiency of the processes of differentiation of all tissues, and especially the central nervous system, causes a number of severe mental disorders.
Influence on metabolism. Thyroid hormones stimulate the metabolism of proteins, fats, carbohydrates, water and electrolyte metabolism, vitamin metabolism, heat production, and basal metabolism. They enhance oxidative processes, processes of oxygen uptake, nutrient consumption, glucose uptake by tissues. Under the influence of these hormones, glycogen stores in the liver decrease, and fat oxidation accelerates. Strengthening of energy and oxidative processes is the cause of weight loss, observed with hyperfunction of the thyroid gland.
Influence on the central nervous system. Thyroid hormones are essential for brain development. The effect of hormones on the central nervous system is manifested by a change in conditioned reflex activity and behavior. Their increased secretion is accompanied by increased excitability, emotionality, and rapid exhaustion. In hypothyroid states, reverse phenomena are observed - weakness, apathy, weakening of excitation processes.
Thyroid hormones significantly affect the state of nervous regulation of organs and tissues. Due to the increased activity of the autonomic, predominantly sympathetic, nervous system under the influence of thyroid hormones, heart contractions are accelerated, breathing rate increases, sweating increases, secretion and motility of the gastrointestinal tract are disturbed. In addition, thyroxine reduces the ability of blood to coagulate by reducing the synthesis in the liver and other organs of the factors involved in the process of blood coagulation. This hormone enhances the functional properties of platelets, their ability to adhere (glue) and aggregate.
Thyroid hormones affect the endocrine and other endocrine glands. This is evidenced by the fact that the removal of the thyroid gland leads to dysfunction of the entire endocrine system, the development of the gonads is delayed, the pid-sternal gland atrophies, the anterior lobe of the pituitary gland and the adrenal cortex grow.
Mechanism of action of thyroid hormones. The very fact that thyroid hormones affect the state of almost all types of metabolism indicates the effect of these hormones on fundamental cellular functions. It has been established that their action at the cellular and subcellular levels is associated with a diverse effect: 1) on membrane processes (the transport of amino acids into the cell is intensified, the activity of Na + / K + -ATPase, which ensures the transport of ions due to the energy of ATP, increases markedly); 2) on mitochondria (the number of mitochondria increases, ATP transport in them accelerates, the intensity of oxidative phosphorylation increases), 3) on the nucleus (stimulates the transcription of specific genes and induction of the synthesis of a certain set of proteins) 4) on protein metabolism (increases protein metabolism, oxidative deamination) 5) on the process of lipid metabolism (both lipogenesis and lipolysis increase, which leads to other overuse of ATP, an increase in heat production) 6) on the nervous system (the activity of the sympathetic nervous system increases; dysfunction of the autonomic nervous system is accompanied by general arousal, anxiety, tremor and muscle fatigue , diarrhea).
Regulation of thyroid function. Control over the activity of the thyroid gland has a cascade character. Previously, peptidergic neurons in the preoptic region of the hypothalamus synthesize and secrete thyrotropin-releasing hormone (TRH) into the pituitary portal vein. Under its influence, thyroid stimulating hormone (TSH) is secreted in the adenohypophysis (in the presence of Ca2 +), which is carried into the thyroid gland by blood and stimulates the synthesis and release of thyroxine (T4) and triiodothyronine (T3) in it. The influence of TRH is modeled by a number of factors and hormones, primarily the level of thyroid hormones in the blood, by the feedback principle inhibit or stimulate the formation of TSH in the pituitary gland. TSH inhibitors are also glucocorticoids, growth hormone, somatostatin, dopamine. Estrogens, on the contrary, increase the sensitivity of the pituitary gland to TRH.
The synthesis of TRH in the hypothalamus is influenced by the adrenergic system, its mediator norepinephrine, which, acting on a-adrenergic receptors, promotes the production and release of TSH in the pituitary gland. Its concentration also increases with decreasing body temperature.
Dysfunction of the thyroid gland can be accompanied by both an increase and a decrease in its hormone-creating function. If hypothyroidism develops in childhood, then there is cretinism. With this disease, growth retardation, a violation of the proportions of the body, sexual and mental development are observed. Hypothyroidism can cause another pathological condition - myxedema (mucous edema). Patients have an increase in body weight due to an excess amount of interstitial fluid, puffiness of the face, mental retardation, drowsiness, decreased intelligence, impaired sexual function and all types of metabolism. The disease develops mainly in childhood and in menopause.
At hyperfunction of the thyroid gland(hyperthyroidism) develops thyrotoxicosis (Graves' disease). Typical signs of this disease are intolerance to elevated air temperature, diffuse sweating, increased heart rate (tachycardia), increased basal metabolism and body temperature. Despite a good appetite, a person loses weight. The thyroid gland increases, bulging eyes (exophthalmos) appear. Increased excitability and irritability, up to psychosis, are observed. This disease is characterized by excitation of the sympathetic nervous system, muscle weakness and fatigue.
In some geographical regions (Carpathians, Volyn, etc.), where there is a deficiency of iodine in water, the population suffers from endemic goiter. This disease is characterized by an increase in the thyroid gland due to a significant growth of its tissue. The number of follicles in it increases (a compensatory reaction in response to a decrease in the content of thyroid hormones in the blood). Salt iodization in these areas is an effective measure to prevent the disease.
To assess the function of the thyroid gland in the clinic, a number of tests are used: the introduction of radionuclides - iodine-131, technetium, the determination of basal metabolism, the determination of the concentrations of TSH, triiodothyronine and thyroxine in the blood, and ultrasound examination.
Physiological effects of thyrocalcitonin. Thyrocalcitonin is produced by parafollicular cells (C-cells) of the thyroid gland located behind its glandular follicles. Thyrocalcitonin is involved in the regulation of calcium metabolism. The secondary mediator of thyrocalcitonin action is cAMP. Under the influence of the hormone, the level of Ca2 + in the blood decreases. This is due to the fact that thyrocalcitonin activates the function of osteoblasts involved in the formation of new bone tissue and inhibits the function of osteoclasts that destroy it. At the same time, the hormone inhibits the excretion of Ca2 + from the bone tissue, contributing to its deposition in it. In addition, thyrocalcitonin inhibits the absorption of Ca 2 + and phosphates from the renal tubules into the blood, thus facilitating their excretion from the body in the urine. Under the influence of thyrocalcitonin, the concentration of Ca2 + in the cytoplasm of cells decreases. This is due to the fact that the hormone activates the activity of the Ca2 + pump on the plasma membrane and stimulates the uptake of Ca2 + by the mitochondria of the cell.
The content of thyrocalcitonin in the blood increases during pregnancy and lactation, as well as during the period of restoration of the integrity of the bone after a fracture.
Regulation of the synthesis and content of calcitonin depends on the level of calcium in the blood serum. At a high concentration, the amount of calcitonin decreases, at a low one, on the contrary, it increases. In addition, the formation of calcitonin stimulates the gastrointestinal hormone-gastrin. Its release into the blood indicates the intake of calcium into the body with food.
The biological effects of thyroid hormones extend to many physiological functions of the body.
Functions of triiodothyronine and thyroxine:
1. Stimulation of metabolic processes: increased breakdown of proteins, fats, carbohydrates; strengthening of oxidative processes; thermogenesis; activation of digestive processes, increased productivity.
2. Regulation of growth, development, tissue differentiation. Metamorphosis. Bone formation. Hairline growth. Development of nervous tissue and stimulation of nervous processes.
3. Strengthening of cardiac activity, increasing the sensitivity of the heart to the influence of the sympathetic nervous system.
The sympathetic nervous system increases the activity of the thyroid gland, the parasympathetic depresses. Physiological hypofunction of the thyroid gland: during sleep. Physiological hyperfunction of the gland: during pregnancy and lactation. In particular, hormones regulate the rate of basal metabolism, growth and differentiation of tissues, metabolism of proteins, carbohydrates and lipids, water and electrolyte metabolism, the activity of the central nervous system, the digestive tract, hematopoiesis, the function of the cardiovascular system, the need for vitamins, and the body's resistance to infections.
In the embryonic period, thyroid hormones have an exceptional effect on the formation of the main brain structures responsible for motor functions and intellectual capabilities of a person, and also contribute to the maturation of the “cochlea” of the auditory analyzer.
Although there is some evidence to support cell surface and mitochondrial action of thyroid hormones, most of the biological effects characteristic of thyroid hormones are believed to be mediated by interaction of T 3 with specific receptors. The mechanism of action of thyroid hormones is very similar to that of steroid hormones in that the hormone binds to a nuclear receptor, resulting in changes in the transcription of specific messenger RNAs.
Thyroid hormones, like steroid hormones, easily diffuse through the lipid cell membrane and are bound by intracellular proteins. According to other data, thyroid hormones first interact with the receptor on the plasma membrane and only then enter the cytoplasm, where they are complexed with proteins, forming an intracellular pool of thyroid hormones. The biological action is mainly carried out by T3, which binds to the cytoplasmic receptor. The mechanism of action of thyroid hormones is illustrated by the diagram shown in the figure below.
Rice. Mechanism of action of thyroid hormones
MB - cell membrane; P, membrane receptor; NM, nuclear membrane; RC, cytoplasmic receptor; NR, nuclear receptor; ER, endoplasmic reticulum; M - mitochondrion.
The thyroid cytoplasmic complex first dissociates, and then T 3 directly binds to nuclear receptors, which have a high affinity for it. In addition, high-affinity T3 receptors are also found in mitochondria. It is believed that the calorigenic action of thyroid-stimulating hormones is carried out in mitochondria through the generation of new ATP, for the formation of which adenosine diphosphate (ADP) is used.
Thyroid-stimulating hormones regulate protein synthesis at the level of transcription, and this action of them is detected after 12-24 hours; the introduction of inhibitors of RNA synthesis can be blocked. In addition to their intracellular action, thyroid hormones stimulate the transport of glucose and amino acids across the cell membrane, directly affecting the activity of certain enzymes localized in it.
Thus, the specific action of hormones is manifested only after it is compensated with the corresponding receptor. The receptor, after recognition and binding of the hormone, generates physical or chemical signals that cause a sequential chain of post-receptor interactions, ending in the manifestation of a specific biological effect of the hormone. It follows that the biological effect of the hormone depends not only on its content in the blood, but also on the number and functional state of receptors, as well as on the level of functioning of the post-receptor mechanism.
Unlike steroid hormone receptors, which cannot anchor firmly in the nucleus prior to hormone binding (and thus are found in cytosolic fractions after cell destruction), thyroid hormone receptors are tightly bound to acidic, non-histone nuclear proteins. The high hydrophobicity of T 3 and T 4 is the basis for their action by the cytosolic mechanism. It turned out that thyroid hormone receptors are mainly located in the nucleus and the formed hormone-receptor complexes, interacting with DNA, change the functional activity of some parts of the genome. The result of the action of T 3 is the induction of transcription processes and, as a result, protein biosynthesis. These molecular mechanisms underlie the influence of thyroid hormones on many metabolic processes in the body. In response to thyroid hormones, the number of receptors increases, not their affinity. This nuclear thyroid hormone receptor has a low capacity (approximately 1 pmol/mg DNA) and a high affinity for T 3 around (10 -10 M). The affinity of the receptor for T 4 is about 15 times less.
The main metabolic function of thyroid hormones is to increase oxygen uptake. The effect is observed in all organs except the brain, reticuloendothelial system and gonads. Mitochondria, in which T4 causes morphological changes and uncouples oxidative phosphorylation, attract special attention. These effects require large amounts of the hormone and almost certainly do not occur under physiological conditions. Thyroid hormones induce mitochondrial α-glycerophosphate dehydrogenase, possibly due to their effect on O2 uptake.
According to the Edelman hypothesis, most of the energy utilized by the cell is used to operate the Na + / K + - ATPase pump. Thyroid hormones increase the efficiency of this pump by increasing the number of units that make it up. Since all cells possess such a pump and virtually every one of them responds to thyroid hormones, the increased utilization of ATP and the associated increase in oxygen consumption during oxidative phosphorylation may represent the main mechanism of action of these hormones.
Thyroid hormones, like steroids, induce protein synthesis by activating the mechanism of gene transcription. This appears to be the mechanism by which T3 enhances overall protein synthesis and maintains a positive nitrogen balance. There is a connection between two groups of hormones that affect growth: thyroid hormones and growth hormones. T 3 and glucocorticoids increase the level of transcription of the growth hormone gene, thereby increasing the formation of the latter. This explains the classic observation that growth hormone is absent in the pituitary gland of T3-deficient animals. Very high concentrations of T 3 inhibit protein synthesis and cause a negative nitrogen balance.
Thyroid hormones also interact with low-affinity binding sites in the cytoplasm, which are obviously not identical to the nuclear receptor protein. Cytoplasmic binding may serve to keep hormones close to the true receptors. Thyroid hormones are known to be important modulators of developmental processes.
Since it is T3 that performs the main metabolic action at the level of the nucleus and mitochondria, and the effectiveness of T3 interaction with the intracellular receptor apparatus depends on a number of factors, a change in the hormone-binding activity of the cell in relation to T3 can affect the efficiency of transformation of the hormonal signal into the biochemical response of the cell. It is possible that the impairment of the cell's ability to bind thyroid hormones may play a role in the pathogenesis of thyroid cancer and thyroiditis.
Hdeficiency of thyroid hormones
Severe thyroid hormone deficiency in children is called cretinism and is characterized by growth and mental retardation. Child development milestones such as sitting and walking are set aside. Disruption of linear growth can lead to dwarfism, characterized by disproportionately short limbs compared to the trunk. When thyroid hormone insufficiency occurs in later childhood, mental retardation is less pronounced and linear growth disorder is the main characteristic. As a result, the child looks younger than his chronological age. The development of the epiphyses is delayed, so that the bone age becomes less than chronological. age.
The onset of thyroid hormone deficiency in adults is usually subtle; signs and symptoms occur gradually over months or years. Early symptoms are nonspecific. Over time, mental processes and motor activity in general slow down. Although there is some weight gain, appetite is usually reduced, so severe obesity is rare. Cold intolerance may be the first manifestation of thyroid hormone deficiency, with individual complaints of feeling cold in a room in which others feel comfortable. Women may experience menstrual irregularities, with heavier periods occurring more frequently than menstruation cessation. Decreased clearance of adrenal androgens may facilitate the formation of estrogens outside the glands, leading to anovulatory cycles and infertility. When thyroid hormone deficiency is prolonged and severe, there is an accumulation of mucopolysaccharides in the subcutaneous tissues and other organs, referred to as myxedema. Infiltration of the dermis leads to coarsening of the features, periorbital edema, and edema of the arms and legs not related to pressure. Hardening and soreness of the muscles may be due to swelling of the muscles as an early manifestation of the disease. Delayed muscle contractions and relaxations lead to slow movements and delayed tendon reflexes. Both the volume of emissions and the heart rate are reduced, so that the performance of the heart is reduced. The heart may enlarge and an exudative pericardium may develop. Pleural fluid, rich in protein and mucopolysaccharides, accumulates. Mental retardation is characterized by impaired memory, slow speech, reduced initiative, and ultimately drowsiness. When exposed to the environment, mild hypothermia sometimes becomes more severe. Ultimately, coma may develop in combination with hypoventilation.
Excess thyroid hormones
The earliest manifestations of excess thyroid hormones are nervousness, excitability or emotional instability, palpitations, fatigue, and heat intolerance. As with thyroid insufficiency, the latter can manifest itself as discomfort in a room in which others feel comfortable. There is usually increased sweating.
Weight loss despite normal or increased food intake is one of the most common manifestations. The increased food intake can sometimes be so great that it overcomes the hypermetabolic status and leads to weight gain. Most patients report that their increased caloric intake occurs predominantly in the form of carbohydrates. In women, menstrual bleeding is reduced or absent. The frequency of peristalsis per day often increases, but true watery diarrhea rarely occurs. External signs may include warm, moist skin with a velvety texture, often compared to newborn skin; changes to the fingernails, called onycholysis, which include detachment of the nail from the nail bed; weakness of the proximal muscles, often making it difficult for the patient to rise from a sitting or squatting position. The hair is of good texture, but hair loss may occur. Characterized by tachycardia that persists during sleep, atrial arrhythmia and congestive heart failure may develop.
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Thyroid hormones have a wide spectrum of action, but most of all their influence affects the cell nucleus.
They can directly affect the processes occurring in mitochondria, as well as in the cell membrane.
In mammals and humans, thyroid hormones are especially important for the development of the central nervous system and for the growth of the organism as a whole.
The stimulating effect of these hormones on the rate of oxygen consumption (calorigenic effect) of the whole organism, as well as individual tissues and subcellular fractions, has long been known. A significant role in the mechanism of the physiological calorigenic effect of T4 and Tz can be played by the stimulation of the synthesis of such enzymatic proteins that use the energy of adenosine triphosphate (ATP) in the course of their functioning, for example, membrane sodium-potassium-ATPase that is sensitive to oubain and prevents the intracellular accumulation of sodium ions. Thyroid hormones in combination with adrenaline and insulin are able to directly increase calcium uptake by cells and increase the concentration of cyclic adenosine monophosphoric acid (cAMP) in them, as well as the transport of amino acids and sugars through the cell membrane.
Thyroid hormones play a special role in the regulation of the function of the cardiovascular system. Tachycardia in thyrotoxicosis and bradycardia in hypothyroidism are characteristic signs of thyroid status disorder. These (as well as many other) manifestations of thyroid diseases have long been attributed to an increase in sympathetic tone under the action of thyroid hormones. However, it has now been proven that the excess content of the latter in the body leads to a decrease in the synthesis of adrenaline and norepinephrine in the adrenal glands and a decrease in the concentration of catecholamines in the blood.
In hypothyroidism, the concentration of catecholamines increases. The data on slowing down the degradation of catecholamines under conditions of excessive levels of thyroid hormones in the body have not been confirmed either. Most likely, due to the direct (without the participation of adrenergic mechanisms) action of thyroid hormones on tissues, the sensitivity of the latter to catecholamines and mediators of parasympathetic influences changes. Indeed, an increase in the number of (3-adrenergic receptors) in a number of tissues (including the heart) has been described in hypothyroidism.
The mechanisms of penetration of thyroid hormones into cells are not well understood. Regardless of whether passive diffusion or active transport takes place here, these hormones penetrate into the “target” cells fairly quickly. Binding sites for T3 and T4 were found not only in the cytoplasm, mitochondria, and nucleus, but also on the cell membrane; however, it is in the nuclear chromatin of cells that the sites that best meet the criteria for hormone receptors are found.
The affinity of the corresponding proteins for various T4 analogs is usually proportional to the biological activity of the latter. The degree of occupation of such areas in some cases is proportional to the magnitude of the cellular response to the hormone.
Binding of thyroid hormones (mainly T3) in the nucleus is carried out by non-histone chromatin proteins, the molecular weight of which after solubilization is approximately 50,000 daltons. For the nuclear action of thyroid hormones, in all likelihood, no prior interaction with cytosolic proteins is required, as is described for steroid hormones. The concentration of nuclear receptors is usually particularly high in tissues known to be sensitive to thyroid hormones (anterior pituitary, liver) and very low in the spleen and testes, which are reported to be unresponsive to T4 and T3.
After the interaction of thyroid hormones with chromatin receptors, the activity of RNA polymerase increases quite rapidly and the formation of high-molecular RNA increases. It has been shown that, in addition to a generalized effect on the genome, Ts can selectively stimulate the synthesis of RNA encoding the formation of specific proteins, for example, α2-macroglobulin in the liver, growth hormone in pituicites, and, possibly, the mitochondrial enzyme α-glycerophosphate dehydrogenase and the cytoplasmic malic enzyme. At physiological concentrations of hormones, nuclear receptors are more than 90% associated with T3, while T4 is present in a complex with receptors in a very small amount. This justifies the notion of T4 as a prohormone and T3 as the true thyroid hormone.
Secretion regulation
T4 and T3 may depend not only on the pituitary TSH, but also on other factors, in particular the concentration of iodide. However, the main regulator of thyroid activity is still TSH, the secretion of which is under double control: from the hypothalamic TRH and peripheral thyroid hormones. In the case of an increase in the concentration of the latter, the reaction of TSH to TRH is suppressed. The secretion of TSH is inhibited not only by T3 and T4, but also by hypothalamic factors - somatostatin and dopamine. The interaction of all these factors determines the very fine physiological regulation of thyroid function in accordance with the changing needs of the body.TSH is a glycopeptide with a molecular weight of 28,000 daltons.
It consists of 2 peptide chains (subunits) linked by non-covalent forces and contains 15% carbohydrates; a-subunit of TSH does not differ from that in other polypeptide hormones (LH, FSH, human chorionic gonadotropin).
The biological activity and specificity of TSH is determined by its (3-subunit), which is separately synthesized by the pituitary thyrotrophs and subsequently attached to the cc-subunit. This interaction occurs quite quickly after synthesis, since the secretory granules in thyrotrophs contain mainly the finished hormone. However, a small number of individual subunits can be released under the action of TRH in a non-equilibrium ratio.
The pituitary secretion of TSH is very sensitive to changes in the concentration of T4 and Tz in the blood serum. A decrease or increase in this concentration even by 15-20% leads to reciprocal shifts in the secretion of TSH and its response to exogenous TRH. The activity of T4-5-deiodinase in the pituitary gland is especially high; therefore, serum T4 in it is converted into T3 more actively than in other organs. This is probably why a decrease in the level of T3 (while maintaining a normal concentration of T4 in the serum), recorded in severe non-thyroidal diseases, rarely leads to an increase in TSH secretion.
Thyroid hormones reduce the number of TRH receptors in the pituitary gland, and their inhibitory effect on TSH secretion is only partially blocked by inhibitors of protein synthesis. The maximum inhibition of TSH secretion occurs after a long time after reaching the maximum concentration of T4 and T3 in serum. Conversely, a sharp drop in thyroid hormone levels after removal of the thyroid gland leads to the restoration of basal secretion of TSH and its response to TRH only after a few months or even later. This should be taken into account when assessing the status of the pituitary-thyroid axis in patients undergoing treatment for thyroid disease.
The hypothalamic stimulator of TSH secretion - thyreoliberin (tripeptide pyroglutamylhistidylprolinamide) - is present in the highest concentration in the median eminence and arcuate nucleus. However, it is also found in other areas of the brain, as well as in the gastrointestinal tract and pancreatic islets, where its function is poorly understood. Like other peptide hormones, TRH interacts with membrane receptors in pituitocytes. Their number decreases not only under the influence of thyroid hormones, but also with an increase in the level of TRH itself (“down regulation”).
Exogenous TRH stimulates the secretion of not only TSH, but also prolactin, and in some patients with acromegaly and chronic disorders of the liver and kidneys - and the formation of growth hormone. However, the role of TRH in the physiological regulation of the secretion of these hormones has not been established. The half-life of exogenous TRH in human serum is very short - 4-5 minutes. Thyroid hormones probably do not affect its secretion, but the problem of regulation of the latter remains practically unexplored.
In addition to the mentioned inhibitory effect of somatostatin and dopamine on TSH secretion, it is modulated by a number of steroid hormones. Thus, estrogens and oral contraceptives increase the response of TSH to TRH (possibly due to an increase in the number of TRH receptors on the cell membrane of the anterior pituitary), limit the inhibitory effect of dopaminergic drugs and thyroid hormones. Pharmacological doses of glucocorticoids reduce the basal secretion of TSH, its response to TRH and the rise in its level in the evening. However, the physiological significance of all these modulators of TSH secretion is unknown.
Thus, in the system of regulation of thyroid function, thyrotrophs of the anterior pituitary gland, secreting TSH, occupy a central place. The latter controls most of the metabolic processes in the thyroid parenchyma.
Its main acute effect is to stimulate the production and secretion of thyroid hormones, and chronic - to hypertrophy and hyperplasia of the thyroid gland.
On the surface of the thyrocyte membrane there are receptors specific for the a-subunit of TSH. After the interaction of the hormone with them, a more or less standard sequence of reactions for polypeptide hormones unfolds. The hormone-receptor complex activates adenylate cyclase located on the inner surface of the cell membrane. The protein that binds guanyl nucleotides most likely plays a conjugating role in the interaction of the hormone receptor complex and the enzyme.
The factor determining the stimulating effect of the receptor on cyclase may be the β-subunit of the hormone. Many of the effects of TSH appear to be mediated by the formation of cAMP from ATP by adenylate cyclase. Although the re-introduced TSH continues to bind to thyroid receptors, the thyroid gland is refractory to repeated injections of the hormone for a certain period. The mechanism of this autoregulation of the cAMP response to TSH is unknown.
The cAMP formed under the action of TSH interacts in the cytosol with the cAMP-binding subunits of protein kinases, leading to their separation from the catalytic subunits and activation of the latter, i.e., to the phosphorylation of a number of protein substrates, which changes their activity and thereby the metabolism of the entire cell. Phosphoprotein phosphatases are also present in the thyroid gland, restoring the state of the corresponding proteins. Chronic action of TSH leads to an increase in the volume and height of the thyroid epithelium; then the number of follicular cells also increases, which causes their protrusion into the colloidal space. In the culture of thyrocytes, TSH promotes the formation of microfollicular structures.
TSH initially reduces the iodide-concentrating capacity of the thyroid gland, probably due to a cAMP-mediated increase in membrane permeability that accompanies membrane depolarization. However, the chronic effect of TSH sharply increases iodide uptake, which, apparently, is indirectly affected by an increase in the synthesis of carrier molecules. Large doses of iodide not only by themselves inhibit the transport and organization of the latter, but also reduce the response of cAMP to TSH, although they do not change its effect on protein synthesis in the thyroid gland.
TSH directly stimulates the synthesis and iodination of thyroglobulin. Under the influence of TSH, oxygen consumption by the thyroid gland increases rapidly and sharply, which is probably due not so much to an increase in the activity of oxidative enzymes, but to an increase in the availability of adenine diphosphoric acid - ADP. TSH increases the overall level of pyridine nucleotides in the thyroid tissue, accelerates the circulation and synthesis of phospholipids in it, increases the activity of phospholipase A2, which affects the amount of prostaglandin precursor arachidonic acid.
Catecholamines stimulate the activity of thyroid adenylate cyclase and protein kinases, but their specific effects (stimulation of the formation of colloidal droplets and the secretion of T4 and T3) are clearly manifested only against the background of a reduced content of TSH. In addition to the effect on thyrocytes, catecholamines affect the blood flow in the thyroid gland and change the exchange of thyroid hormones in the periphery, which in turn can affect its secretory function.
N.T. Starkov
1. Adrenal hormones. Regulatory functions of adrenal hormones. Blood supply to the adrenal glands.
2. Hormones of the adrenal cortex and their effects in the body. Mineralcorticoids: Aldosterone. Renin - angiotensin - aldosterone system.
3. Glucocorticoids: cortisol and corticosterone. Transcortin. Lipocortin. Regulation of secretion and physiological effects of glucocorticoids.
4. Syndrome Itsenko - Cushing. Symptoms of Itsenko-Cushing's syndrome. Causes of Itsenko-Cushing's syndrome.
5. Androgens. Regulation of secretion and physiological effects of sex steroids of the adrenal cortex. Virilization.
6. Adrenaline. Norepinephrine. APUD system. Catecholamines. Control hormone. Adrenomedullin. Adrenal medulla hormones and their effects in the body.
7. Regulatory functions of thyroid hormones. Blood supply to the thyroid gland.
8. Thyroglobulin. Triiodothyronine (T3). Tetraiodothyronine (thyroxine, T4). Thyrotropin. Regulation of secretion and physiological effects of iodine-containing thyroid hormones.
9. Excess production of thyroid hormones. Hyperthyroidism. Cretinism. Hypothyroidism. Myxedema. Thyroid insufficiency.
10. Calcitonin. Catacalcin. hypocalcemic hormone. Regulation of secretion and physiological effects of calcitonin.
Thyroglobulin. Triiodothyronine (T3). Tetraiodothyronine (thyroxine, T4). Thyrotropin. Regulation of secretion and physiological effects of iodine-containing thyroid hormones.
thyrocytes form follicles filled with a colloidal mass of thyroglobulin. The basement membrane of thyrocytes is closely adjacent to the blood capillaries, and from the blood these cells receive not only the substrates necessary for energy and protein synthesis, but also actively capture iodine compounds - iodides. Thyroglobulin is synthesized in thyrocytes, iodides are oxidized to form atomic iodine. thyroglobulin contains a significant amount of amino acid residues on the surface of the molecule tyrosine(thyronins), which are iodinated. Through the apical membrane of the thyrocyte thyroglobulin released into the lumen of the follicle.
When hormones are secreted into the blood, the villi of the apical membrane surround and absorb colloid droplets by endocytosis, which are hydrolyzed by lysosomal enzymes in the cytoplasm, and two hydrolysis products - triiodothyronine (T3) and tetraiodothyronine (thyroxine, T4) secreted through the basement membrane into the blood and lymph. All the described processes are regulated by adenohypophysis thyrotropin. The presence of such numerous processes regulated by one thyrotropin is ensured by the inclusion of many intracellular second messengers. There is also a direct nervous regulation of the thyroid gland by autonomic nerves, although for the activation of hormone secretion it plays a lesser role than the effects of thyrotropin. The mechanism of negative feedback in the regulation of thyroid function is realized by the level of thyroid hormones in the blood, which suppresses the secretion of thyroliberin by the hypothalamus and thyrotropin by the pituitary gland. The intensity of secretion of thyroid hormones affects the volume of their synthesis in the gland (local positive feedback mechanism).
Rice. 6.16. Genomic and extragenomic mechanisms of action of thyroid hormones on the cell.The effects of hormones are realized both after the penetration of hormones into the cell (influence on transcription in the nucleus and protein synthesis, influence on redox reactions and energy release in mitochondria), and after the binding of the hormone to the membrane receptor (formation of secondary messengers, increased transport of substrates into the cell). , in particular the amino acids needed for protein synthesis).
Transport of T3 and T4 in the blood It is carried out with the help of special proteins, however, in such a protein-bound form, hormones are not able to penetrate into effector cells. significant portion thyroxine deposited and transported by erythrocytes. Destabilization of their membranes, for example, under the influence of ultraviolet radiation, leads to the release of thyroxine into the blood plasma. When a hormone interacts with a receptor on the surface of the cell membrane, the hormone-protein complex dissociates, after which the hormone penetrates into the cell. Intracellular targets of thyroid hormones are the nucleus and organelles (mitochondria). The mechanism of action of thyroid hormones is shown in Fig. 6.16.
T3 is several times more active than T4, and T4 is converted to T3 in tissues. As a result, most of the effects thyroid hormones provided by T3.
Major metabolic effects of thyroid hormones are:
1) increased oxygen uptake by cells and mitochondria with activation of oxidative processes and an increase in basal metabolism,
2) stimulation of protein synthesis by increasing the permeability of cell membranes for amino acids and activating the genetic apparatus of the cell,
3) lipolytic effect and oxidation of fatty acids with a decrease in their level in the blood,
4) activation of cholesterol synthesis in the liver and its excretion with bile,
5) hyperglycemia due to activation of the breakdown of glycogen in the liver and increased absorption of glucose in the intestine,
6) increased consumption and oxidation of glucose by cells,
7) activation of liver insulinase and acceleration of insulin inactivation,
8) stimulation of insulin secretion due to hyperglycemia.
Thus, excess amount of thyroid hormones, stimulating the secretion of insulin and at the same time causing contrainsular effects, can also contribute to the development of diabetes mellitus.
Rice. 6.17. The balance of iodine in the body.
500 mcg of iodine enters the body with food and water per day. Being absorbed into the blood, iodides are delivered to the thyroid gland, where the main thyroid iodine pool is deposited. Its consumption during the secretion of thyroid hormones is replenished from the reserve blood pool. The main amount of iodine is excreted through the kidneys with urine (485 mcg), a part is lost with feces (15 mcg), therefore, the excretion of iodine is equal to its intake into the body, which is the external balance.
Main physiological effects of thyroid hormones, due to the above metabolic shifts, are manifested in the following:
1) ensuring the normal processes of growth, development and differentiation of tissues and organs, especially the central nervous system, as well as the processes of physiological tissue regeneration,
2) activation of sympathetic effects (tachycardia, sweating, vasoconstriction, etc.), as due to increased sensitivity adrenoreceptors, and as a result of suppression of enzymes (monoamine oxidase) that destroy norepinephrine,
3) increased energy production in mitochondria and myocardial contractility,
4) increase in heat generation and body temperature,
5) increased excitability of the central nervous system and activation of mental processes,
6) prevention of stress damage to the myocardium and ulceration in the stomach,
7) an increase in renal blood flow, glomerular filtration and diuresis with inhibition of tubular reabsorption in the kidneys,
8) maintaining reproductive function.
Video lesson thyroid hormones in normal and disease
Hypothalamic thyrotropin-releasing hormone (TRH) stimulates anterior pituitary thyroid cells to secrete TSH, which in turn stimulates thyroid growth and secretion of thyroid hormones. In addition, the action of thyroid hormones in the pituitary and peripheral tissues is modulated by local deiodinases, which convert T 4 into the more active T 3 . Finally, the molecular effects of T 3 in individual tissues depend on T 3 receptor subtypes, activation or repression of specific genes, and the interaction of T 3 receptors with other ligands, other receptors (eg, retinoid X receptor, RXR), as well as coactivators and corepressors.
thyrotropin-releasing hormone
TRH (tripeptide pyroglutamyl-histidyl-prolinamide) is synthesized by neurons of the supraoptic and paraventricular nuclei of the hypothalamus. It accumulates in the median eminence of the hypothalamus, and then is transported through the hypothalamic-pituitary portal vein system, passing through the pituitary stalk, to its anterior lobe, where it controls the synthesis and secretion of TSH. In other parts of the hypothalamus and brain, as well as in the spinal cord, TRH can play the role of a neurotransmitter. The TRH gene, located on chromosome 3, encodes a large pre-pro-TRH molecule containing five hormone precursor sequences. Expression of the TRH gene is suppressed by both plasma T3 and T3 formed as a result of T4 deiodination in the peptidergic neurons themselves.
In the anterior pituitary gland, TRH interacts with its receptors localized on the membranes of TSH- and PRL-secreting cells, stimulating the synthesis and secretion of these hormones. The TRH receptor belongs to the family of G-protein coupled receptors with seven transmembrane domains. TRH binds to the third transmembrane helix of the receptor and activates both the formation of cGMP and the inositol-1,4,5-triphosphate (IF3) cascade, which leads to the release of intracellular Ca 2+ and the formation of diacylglycerol and, consequently, to the activation of protein kinase C. These reactions are responsible for stimulation of TSH synthesis, coordinated transcription of genes encoding TSH subunits, and post-translational glycosylation of TSH, conferring its biological activity.
TRH-stimulated TSH secretion is impulsive; the average amplitude of impulses recorded every 2 hours is 0.6 mU/l. In a healthy person, TSH secretion follows a circadian rhythm. The maximum plasma TSH level is determined between midnight and 4 am. This rhythm is set, apparently, by the impulse generator of TRH synthesis in the neurons of the hypothalamus.
Thyroid hormones reduce the number of TRH receptors on pituitary thyrotrophs, which forms an additional negative feedback mechanism. As a result, in hyperthyroidism, the amplitude of TSH impulses and its nocturnal release decrease, and in hypothyroidism, both increase. In experimental animals and newborns, exposure to cold enhances the secretion of TRH and TSH. The synthesis and secretion of TRH is also stimulated by certain hormones and drugs (for example, vasopressin and a-adrenergic agonists).
When administered intravenously to humans, TRH in doses of 200–500 μg serum TSH concentration rapidly increases 3–5 times; the reaction reaches a peak in the first 30 minutes after administration and lasts 2-3 hours. In primary hypothyroidism, against the background of an elevated basal level of TSH, the response of TSH to exogenous TRH increases. In patients with hyperthyroidism, autonomously functioning thyroid nodules, and central hypothyroidism, as well as those receiving high doses of exogenous thyroid hormones, the TSH response to TRH is weakened.
TRH is also present in islet cells of the pancreas, gastrointestinal tract, placenta, heart, prostate, testicles, and ovaries. Its production in these tissues is not inhibited by T3, and its physiological role remains unknown.
Thyrotropin (thyroid stimulating hormone, TSH)
TSH is a glycoprotein (28 kDa) consisting of α- and β-subunits non-covalently linked to each other. The same α-subunit is part of two more pituitary glycoprotein hormones - follicle-stimulating (FSH) and luteinizing (LH), as well as the placental hormone - human chorionic gonadotropin (hCG); The β-subunits of all these hormones differ, and it is they that determine the binding of hormones to their specific receptors and the biological activity of each of the hormones. The genes for the α- and β-subunits of TSH are localized on chromosomes 6 and 1, respectively. In humans, the α-subunit contains a polypeptide core of 92 amino acid residues and two oligosaccharide chains, and the β-subunit contains a polypeptide core of 112 amino acid residues and one oligosaccharide chain. Each of the polypeptide chains of the α- and β-subunits of TSH forms three loops folded into a cystine knot. In the SER and the Golgi apparatus, glycosylation of polypeptide nuclei occurs, i.e., the addition of glucose, mannose and fucose residues and terminal residues of sulfate or sialic acid to them. These carbohydrate residues increase the duration of the hormone's presence in plasma and its ability to activate the TSH receptor (TSH-R).
TSH regulates cell growth and thyroid hormone production by binding to its specific receptor. There are approximately 1000 such receptors on the basolateral membrane of each thyrocyte. TSH binding activates intracellular signaling pathways mediated by both cyclic adenosine monophosphate (cAMP) and phosphoinositol. The TSH-R gene, located on chromosome 14, encodes a single-chain glycoprotein of 764 amino acid residues. TSH-R belongs to the family of G-protein-coupled receptors with seven transmembrane domains; the extracellular part of TSH-R binds the ligand (TSH), while the intramembrane and intracellular parts are responsible for activating signaling pathways, stimulating thyrocyte growth, and synthesis and secretion of thyroid hormones.
Known hereditary defects in TSH synthesis or action include mutations in transcription factor genes that determine differentiation of pituitary thyrotrophs (POU1F1, PROP1, LHX3, HESX1), mutations in TRH genes, TSH β-subunit, TSH-P, and GSa protein, which transmits a signal from binding TSH to TSH -R for adenylate cyclase. Serum thyroid-blocking antibodies can also lead to hypothyroidism.
The most common form of hyperthyroidism is Graves' disease, in which TSH-R is bound and activated by autoantibodies. However, TSH-R is involved in the pathogenesis of other forms of hyperthyroidism. Activating mutations of the TSH-R gene in germ cells underlie familial hyperthyroidism, and somatic mutations of this gene underlie toxic thyroid adenoma. Other mutations may cause the production of abnormal TSH-R, which is activated by a structurally similar ligand, hCG, as seen in familial hyperthyroidism in pregnancy.
The effect of TSH on thyroid cells
TSH has a diverse effect on thyrocytes. Most of them are mediated by the G-protein-adenylate cyclase-cAMP system, but activation of the phosphatidylinositol (FIF 2) system also plays a role, accompanied by an increase in intracellular calcium levels. The main effects of TSH are listed below.
Change in the morphology of thyrocytes
TSH quickly induces the appearance of pseudopodia at the border of thyrocytes with colloid, which accelerates the resorption of thyroglobulin. The content of colloid in the lumen of the follicles decreases. Drops of colloid appear in the cells, the formation of lysosomes and the hydrolysis of thyroglobulin are stimulated.
Growth of thyrocytes
Individual thyrocytes increase in size. The vascularization of the thyroid gland increases and eventually a goiter develops.
iodine metabolism
TSH stimulates all stages of iodide metabolism - from its absorption and transport in the thyroid gland to thyroglobulin iodination and secretion of thyroid hormones. The effect on iodide transport is mediated by cAMP, and thyroglobulin iodination is mediated by the hydrolysis of phosphatidylinositol-4,5-diphosphate (FIF 2) and an increase in the intracellular Ca 2+ level. TSH acts on the transport of iodide into thyrocytes in two phases: iodide absorption is initially inhibited (iodide outflow), and after a few hours it increases. The outflow of iodide may be a consequence of the acceleration of hydrolysis of thyroglobulin with the release of hormones and the expiration of iodide from the gland.
Other effects of TSH
Other effects of TSH include stimulation of transcription of thyroglobulin and TPO mRNA, acceleration of the formation of MIT, DIT, T 3 and T 4 and increased activity of lysosomes with increased secretion of T 4 and T 3 . Under the influence of TSH, the activity of 5 "-deiodinase type 1 also increases, which contributes to the preservation of iodide in the thyroid gland.
In addition, TSH stimulates glucose uptake and oxidation, as well as oxygen uptake by the thyroid gland. The circulation of phospholipids is also accelerated and the synthesis of purine and pyrimidine precursors of DNA and RNA is activated.
Serum TSH concentration
Both whole TSH molecules and its separate a-subunits are present in the blood, the concentrations of which, when determined by immunological methods, are normally 0.5-4.0 mU / l and 0.5-2 μg / l, respectively. Serum TSH levels rise in primary hypothyroidism and fall in thyrotoxicosis, whether endogenous or associated with excessive thyroid hormone intake. T 1/2 TSH in plasma is approximately 30 minutes, and its daily production is about 40-150 honey.
Patients with TSH-secreting pituitary tumors in serum often have a disproportionately high content of the a-subunit. Its increased concentration is also characteristic of healthy women in the postmenopausal period, since during this period the secretion of gonadotropins increases.
Regulation of pituitary secretion of TSH
Synthesis and secretion of TSH are mainly regulated by two factors:
- the level of T 3 in thyrotrophic cells, which determines the expression of TSH mRNA, its translation and secretion of the hormone;
- TRH, which regulates post-translational glycosylation of TSH subunits and again its secretion.
High levels of T 4 and T 3 in serum (thyrotoxicosis) inhibit the synthesis and secretion of TSH, and low levels of thyroid hormones (hypothyroidism) stimulate these processes. A number of hormones and drugs (somatostatin, dopamine, bromocriptine, and glucocorticoids) also have an inhibitory effect on TSH secretion. A decrease in TSH secretion is observed in acute and chronic diseases, and after recovery, a “recoil effect” is possible, i.e., an increase in the secretion of this hormone. The substances listed above usually only slightly reduce the serum TSH concentration, which remains detectable, while in overt hyperthyroidism, the TSH concentration may fall below the sensitivity limits of the most modern immunological methods.
Disturbances in the secretion of TRH and TSH can occur with tumors and other diseases of the hypothalamus or pituitary gland. Hypothyroidism due to dysfunction of the pituitary gland is called "secondary", and due to the pathology of the hypothalamus - "tertiary".
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Other stimulants and inhibitors of thyroid function
Thyroid follicles are surrounded by a dense network of capillaries, which terminate noradrenergic fibers of the superior cervical ganglion, as well as fibers of the vagus nerve and thyroid ganglia containing acetylcholinesterase. Parafollicular C cells secrete calcitonin and a calcitonin-related gene-related peptide (PRGC). In experimental animals, these and other neuropeptides affect thyroid blood flow and secretion of thyroid hormones. In addition, growth factors such as insulin, IGF-1, and epidermal growth factor, as well as autocrine factors, prostaglandins and cytokines, influence the growth of thyrocytes and the production of thyroid hormones. However, the clinical significance of all these influences remains unclear.
The role of pituitary and peripheral deiodinases
The main amount of T 3 in the thyrotrophs of the pituitary gland and the brain is formed as a result of deiodination of T 4 under the action of type 2 5 "-deiodinase. In hypothyroidism, the activity of this enzyme increases, which makes it possible to maintain a normal concentration of T 3 in the brain structures for some time, despite to a decrease in the level of T 4 in plasma. In hyperthyroidism, the activity of 5 "-deiodinase type 2 decreases, which protects the pituitary gland and nerve cells from excessive action of T 3. In contrast, the activity of type 1 5'-deiodinase decreases in hypothyroidism, maintaining T 4 , and increases in hyperthyroidism, accelerating T 4 metabolism.
Autoregulation in the thyroid gland
Autoregulation can be defined as the ability of the thyroid gland to adapt its function to changes in iodine availability, independent of pituitary TSH. Normal secretion of thyroid hormones is maintained with fluctuations in iodide intake from 50 micrograms to several milligrams per day. Some of the effects of iodide deficiency or excess have been discussed above. The main mechanism of adaptation to a low intake of iodide in the body is to increase the proportion of synthesized T3, which increases the metabolic efficiency of thyroid hormones. On the other hand, excess iodide inhibits many thyroid functions, including iodide transport, cAMP formation, hydrogen peroxide production, thyroid hormone synthesis and secretion, and binding of TSH and autoantibodies to TSH-R. Some of these effects may be mediated by the formation of iodinated fatty acids in the thyroid gland. The ability of a normal gland to "escape" from the inhibitory influences of excess iodide (the Wolff-Chaikoff effect) allows the secretion of thyroid hormones to be maintained when iodide intake is high. It is important to note that the mechanism of the Wolf-Chaikoff effect differs from that of the therapeutic action of iodide in Graves' disease. In the latter case, high doses of iodide chronically inhibit thyroglobulin endocytosis and the activity of lysosomal enzymes, inhibiting the secretion of thyroid hormones and reducing their concentration in the blood. In addition, pharmacological doses of iodide reduce the blood supply to the thyroid gland, which facilitates surgical interventions on it. However, this effect persists for a short time - from 10 days to 2 weeks.
Action of thyroid hormones
1. Thyroid hormone receptors and their mechanisms of action
Thyroid hormones realize their effects by two main mechanisms:
- genomic effects suggest the interaction of T 3 with its nuclear receptors, which regulate gene activity;
- non-genomic effects are mediated by the interaction of T 3 and T 4 with certain enzymes (eg, calcium ATPase, adenylate cyclase, monomeric pyruvate kinase), glucose transporters, and mitochondrial proteins.
Free thyroid hormones, either by specific carriers or by passive diffusion, pass through the cell membrane into the cytoplasm and then into the nucleus, where T3 binds to its receptors. Nuclear T3 receptors belong to the superfamily of nuclear proteins, which also includes receptors for glucocorticoids, mineralocorticoids, estrogens, progestins, vitamin D, and retinoids.
In humans, thyroid hormone receptors (TP) are encoded by two genes: TPa, located on chromosome 17, and TPβ, localized on chromosome 3. As a result of alternative splicing of mRNA transcribed from each of these genes, two different protein products are formed:
TPα1 and TPα2 and TPβ1 and TPβ2, although TPα2 is believed to be devoid of biological activity. TPs of all types contain a C-terminal ligand-binding and central DNA-binding domain with two zinc fingers, which facilitate the interaction of receptors with DNA elements sensitive to thyroid hormones (TSE). HSE are located in the promoter regions of target genes and regulate the transcription of the latter. In different tissues and at different stages of development, different amounts of certain TRs are synthesized. For example, the brain contains predominantly TPα, the liver contains TPβ, and the heart muscle contains both types of receptors. Point mutations in the TPβ gene that disrupt the structure of the ligand-binding domain of this receptor underlie generalized thyroid hormone resistance (GenRTH). The HSEs that TPs interact with are usually unique paired oligonucleotide sequences (eg, AGGTCA). TPs can also bind to HSEs as heterodimers with receptors for other transcription factors, such as RChR and the retinoid acid receptor. In the operon, HSEs are usually located before the transcription start site of the coding region of the target genes. In the case of thyroid hormone-activated genes, TPs, in the absence of a ligand, form bonds with corepressors [e.g., nuclear receptor corepressor (NCoR) and retinoic acid and thyroid hormone receptor quencher (SMRT)]. This leads to the activation of histone deacetylases, which change the local structure of chromatin, which is accompanied by repression of basal transcription. When TP binds to T3, the corepressor complexes break down, and TPs form complexes with coactivators that promote histone acetylation. T 3 bound TPs also attach other proteins (in particular, a protein that interacts with the vitamin D receptor); the resulting protein complexes mobilize RNA polymerase II and activate transcription. The expression of some genes (for example, the pre-pro-TRH gene and the TSH α- and β-subunit genes) is reduced by T3-bound TP, but the molecular mechanisms of these effects are less well understood. Changes in the synthesis of individual RNAs and proteins determine the nature of the reactions of different tissues to the action of thyroid hormones.
A number of cellular responses to thyroid hormones occur before the processes of transcription in the nucleus could change; in addition, binding of T 4 and T 3 with extranuclear cell structures was found. All this suggests the existence of non-genomic effects of thyroid hormones. Recently it has been shown, for example, that they bind to the αVβ3 membrane integrin protein, which mediates the stimulatory effect of thyroid hormones on the MAP kinase cascade and angiogenesis.
2. Physiological effects of thyroid hormones
The effect of T3 on gene transcription reaches its maximum after several hours or days. These genomic influences alter a number of vital functions, including tissue growth, brain maturation, heat production and oxygen consumption, as well as the health of the heart, liver, kidneys, skeletal muscle, and skin. The non-genomic effects of thyroid hormones include a decrease in the activity of type 2 5'-deiodinase in the pituitary gland and the activation of glucose and amino acid transport in some tissues.
Impact on fetal development
The ability of the thyroid gland to concentrate iodide and the appearance of TSH in the pituitary gland are observed in the human fetus at about the 11th week of pregnancy. Due to the high content of 5-deiodinase type 3 in the placenta (which inactivates most of the maternal T 3 and T 4), very little free maternal thyroid hormone enters the blood of the fetus. However, they are extremely important for the early stages of fetal brain development. After the 11th week of pregnancy, the development of the fetus depends mainly on its own thyroid hormones. Some ability of the fetus to grow is preserved even in the absence of a thyroid gland, but the development of the brain and the maturation of the skeleton under such conditions are sharply disturbed, which is manifested by cretinism (mental retardation and dwarfism).
Influence on oxygen consumption, heat production and formation of free radicals
The increase in O 2 consumption under the influence of T 3 is partly due to the stimulation of Na + , K + -ATPase in all tissues, with the exception of the brain, spleen and testicles. This contributes to an increase in basal metabolic rate (total 02 consumption at rest) and heat sensitivity in hyperthyroidism and to the opposite in hypothyroidism.
Effect on the cardiovascular system
T3 stimulates the synthesis of Ca 2+ -ATPase of the sarcoplasmic reticulum, which increases the rate of diastolic relaxation of the myocardium. Under the influence of T 3, the synthesis of the α-isoforms of myosin heavy chains, which have a greater contractility, also increases, which determines the strengthening of the systolic function of the myocardium. In addition, T 3 affects the expression of various isoforms of Na + , K + -ATPase, enhances the synthesis of β-adrenergic receptors and reduces the concentration of inhibitory G-protein (Gi) in the myocardium. The increase in heart rate is due to the acceleration of both depolarization and repolarization of the cells of the sinus node under the action of T 3 . Thus, thyroid hormones have a positive inotropic and chronotropic effect on the heart, which, together with an increase in its sensitivity to adrenergic stimulation, determines tachycardia and an increase in myocardial contractility in hyperthyroidism and opposite shifts in hypothyroidism. Finally, thyroid hormones reduce peripheral vascular resistance, and this contributes to a further increase in cardiac output in hyperthyroidism.
Effects on the sympathetic nervous system
Thyroid hormones increase the number of β-adrenergic receptors in the heart, skeletal muscle, adipose tissue, and lymphocytes, and possibly enhance the effect of catecholamines at the post-receptor level. Many clinical manifestations of thyrotoxicosis reflect hypersensitivity to catecholamines, and β-blockers often eliminate such manifestations.
Pulmonary effects
Thyroid hormones contribute to the preservation of the reactions of the respiratory center of the brain stem to hypoxia and hypercapnia. Therefore, hypoventilation may occur in severe hypothyroidism. The function of the respiratory muscles is also regulated by thyroid hormones.
Effect on hematopoiesis
An increase in the need of cells for O 2 in hyperthyroidism causes increased production of erythropoietin and acceleration of erythropoiesis. However, due to faster RBC destruction and hemodilution, hematocrit usually does not increase. Under the influence of thyroid hormones in erythrocytes, the content of 2,3-diphosphoglycerate increases, which accelerates the dissociation of oxyhemoglobin and increases the availability of O 2 for tissues. Hypothyroidism is characterized by opposite shifts.
Effect on the gastrointestinal tract
Thyroid hormones increase intestinal motility, which leads to increased bowel movements in hyperthyroidism. In hypothyroidism, on the contrary, the passage of food through the intestines slows down and constipation occurs.
Effect on bones
Thyroid hormones stimulate the circulation of bone tissue, accelerating bone resorption and (to a lesser extent) osteogenesis. Therefore, hyperthyroidism develops hypercalciuria and (rarely) hypercalcemia. In addition, chronic hyperthyroidism may be accompanied by clinically significant bone mineral loss.
Neuromuscular effects
In hyperthyroidism, protein turnover is accelerated, and its content in skeletal muscles decreases. This leads to the proximal myopathy characteristic of this disease. Thyroid hormones also increase the rate of contraction and relaxation of skeletal muscles, which is clinically manifested in hyperthyroidism by hyperreflexia, and in hypothyroidism by slowing down the relaxation phase of deep tendon reflexes. Hyperthyroidism is also characterized by a subtle tremor of the fingers. It has already been noted above that thyroid hormones are necessary for the normal development and functioning of the central nervous system, and thyroid insufficiency in the fetus leads to severe mental retardation (Timely detection of congenital hypothyroidism (newborn screening) helps prevent the development of such disorders). In adults with hyperthyroidism, hyperactivity and fussiness are observed, while in patients with hypothyroidism, slowness and apathy are observed.
Influence on lipid and carbohydrate metabolism
Hyperthyroidism accelerates both glycogenolysis and gluconeogenesis in the liver, as well as glucose absorption in the gastrointestinal tract. Therefore, hyperthyroidism makes it difficult to control glycemia in patients who simultaneously suffer from diabetes mellitus. Thyroid hormones accelerate both the synthesis and breakdown of cholesterol. The latter effect is associated mainly with an increase in hepatic low-density lipoprotein (LDL) receptors and an acceleration of LDL clearance. In hypothyroidism, total cholesterol and LDL cholesterol levels are usually elevated. Lipolysis is also accelerated, resulting in an increase in the content of free fatty acids and glycerol in the plasma.
Endocrine effects
Thyroid hormones alter the production, regulation of secretion, and metabolic clearance of many other hormones. In children with hypothyroidism, the secretion of growth hormone is disrupted, which slows down the growth of the body in length. Hypothyroidism can also delay sexual development by disrupting the secretion of GnRH and gonadotropins. However, in primary hypothyroidism, precocious puberty is sometimes observed, probably due to the interaction of very large amounts of TSH with gonadotropin receptors. Some women with hypothyroidism develop hyperprolactinemia. Characterized by menorrhagia (prolonged and severe uterine bleeding), anovulation and infertility. In hypothyroidism, the response of the hypothalamic-pituitary-adrenal system to stress is weakened, which is somewhat offset by a slowdown in the metabolic clearance of cortisol. Restoration of euthyroidism in such cases can lead to adrenal insufficiency, as cortisol clearance is accelerated and cortisol reserves remain reduced.
With hyperthyroidism in men, the development of gynecomastia is possible, due to the accelerated aromatization of androgens with the formation of estrogens and an increased level of globulin that binds sex hormones. The gonadotropic regulation of ovulation and the menstrual cycle can also be disturbed, which leads to infertility and amenorrhea. The restoration of euthyroidism, as a rule, eliminates all these endocrine disorders.
