Disturbance of the mechanism of action of hormones

The change in the response of tissues to a particular hormone can be due to the production of an abnormal hormone molecule, a deficiency in receptors or enzymes that react to hormonal stimulation. Clinical forms of endocrine diseases have been identified in which shifts in hormone receptor interaction are the cause of pathology (lipoatrophic diabetes, some forms of insulin resistance, testicular feminization, neurogenic form of diabetes insipidus).

Common features of the action of any hormones are cascade enhancement of the effect in the target cell; regulation of the rate of pre-existing reactions, and not the initiation of new ones; relatively long (from minute to day) preservation of the effect of nervous regulation (fast - from milliseconds to a second).

For all hormones, the initial stage of action is to bind to a specific cellular receptor that triggers a cascade of reactions that lead to a change in the amount or activity of a number of enzymes, which forms the physiological response of the cell. All hormonal receptors are proteins that non-covalently bind hormones. Since any attempt of a more or less detailed exposition of this problem presupposes the need for a deep coverage of the fundamental questions of biochemistry and molecular biology, only a brief summary of the relevant questions will be given here.

First of all, it should be noted that hormones are able to influence the function of individual groups of cells (tissues and organs), not only through a special effect on cellular activity, but also in a more general way, stimulating an increase in the number of cells (often called a trophic effect), and changing blood flow through the body (adrenocorticotropic hormone - ACTH, for example, not only stimulates the biosynthetic and secretory activity of cells of the adrenal cortex, but also increases blood flow in the steroid-producing glands).

At the level of a single cell, hormones tend to control one or more of the speed-limiting stages of cellular metabolism reactions. Almost always, such control implies the enhancement of the synthesis or activation of specific enzyme proteins. The specific mechanism of this influence depends on the chemical nature of the hormone.

It is believed that hydrophilic hormones (peptides or amines) do not penetrate into the cell. Their contact is confined to receptors located on the outer surface of the cell membrane. Although convincing evidence of "internalization" of peptide hormones (in particular, insulin) has been obtained in recent years, the connection of this process with the induction of the hormonal effect remains unclear. The binding of the hormone by the receptor triggers a series of intramembrane processes that lead to the cleavage of the active catalytic unit located on the inner surface of the cell membrane of the adenylate cyclase enzyme. In the presence of magnesium ions, the active enzyme converts adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP). The latter activates one or more cells of cAMP-dependent protein kinases present in the cytosol, which promote the phosphorylation of a number of enzymes, which causes their activation or (sometimes) inactivation, and can alter the configuration and properties of other specific proteins (for example, structural and membrane), resulting in protein synthesis increases at the level of the ribosomes, the processes of transmembrane transfer, etc., etc., ie, the cellular effects of the hormone appear. The key role in this cascade of reactions is played by cAMP, the level of which in the cell determines the intensity of the developing effect. An enzyme that destroys intracellular cAMP, i.e., converting it into an inactive compound (5'-AMP), is phosphodiesterase. The above scheme is the essence of the so-called concept of the second mediator, first proposed in 1961. E. V. Sutherland et al. On the basis of the analysis of the action of hormones on the decomposition of glycogen in the cells of the liver. The first mediator is the hormone itself, suitable to the cell outside. The effects of some compounds may also be related to a decrease in the level of cAMP in the cell (via inhibition of adenylate cyclase activity or an increase in phosphodiesterase activity). It should be emphasized that cAMP is not the only second mediator known to date. Other cyclic nucleotides, such as cyclic guanosine monophosphate (cGMP), calcium ions, phosphatidylinositol metabolites, and possibly prostaglandins that result from the action of the hormone on the phospholipids of the cell membrane, can play a role. In any case, the most important mechanism of action of the second intermediaries is the phosphorylation of intracellular proteins.

Another mechanism is postulated in relation to the action of lipophilic hormones (steroid and thyroid), the receptors of which are localized not on the cell surface but inside the cells. Although the question of how these hormones enter the cell at present remains controversial, the classical scheme is based on their free penetration as lipophilic compounds. However, after getting into the cell, steroid and thyroid hormones come to the object of their action - the cell nucleus - in different ways. The former interact with cytosolic proteins (receptors), and the resulting complex, the steroid receptor, is translocated to the nucleus, where it reversibly binds to DNA, acting as a gene activator and changing the transcription processes. As a result, a specific mRNA emerges, which leaves the nucleus and causes the synthesis of specific proteins and enzymes on the ribosomes (translation). The thyroid hormones that directly enter the chromatin of the cell nucleus behave in a different way, whereas cytosolic binding not only does not promote, but even hinders the nuclear interaction of these hormones. In recent years, there have been reports of a fundamental similarity in the mechanisms of the cellular action of steroid and thyroid hormones and that these discrepancies between them can be related to the errors in the method of investigation.

Particular attention is also paid to the possible role of a specific calcium-binding protein (calmodulin) in the modulation of cellular metabolism after exposure to hormones. The concentration of calcium ions in the cell regulates a variety of cellular functions, including the metabolism of the cyclic nucleotides themselves, the mobility of the cell and its individual organelles, endo- and exocytosis, axonal current and the release of neurotransmitters. The presence in the cytoplasm of almost all cells of calmodulin allows to assume its essential role in the regulation of many cellular activities. The available data indicate that calmodulin can play the role of a calcium ion receptor, ie, the latter acquire physiological activity only after binding them with calmodulin (or similar proteins).

Resistance to the hormone depends on the state of the complex hormone-receptor complex or on the pathways of its post-receptor action. Cellular resistance to hormones can be due to changes in the receptors of cell membranes or a violation of the connection with intracellular proteins. These disorders are caused by the formation of abnormal receptors and enzymes (more often - congenital pathology). Acquired resistance is associated with the occurrence of antibodies to receptors. Possible selective resistance of individual organs in relation to thyroid hormones. With selective resistance of the pituitary gland, for example, hyperthyroidism and goiter develop, recurring after surgical treatment. Resistance to cortisone was first described by A. S. M. Vingerhoeds et al. In 1976. Despite an increase in the content of cortisol in the blood, symptoms of Itenko-Cushing's disease were absent in patients, hypertension and hypokalemia were noted.

Rare hereditary diseases include cases of pseudohypoparathyroidism, clinically manifested as signs of parathyroid gland deficiency (tetany, hypocalcemia, hyperphosphataemia) with elevated or normal parathyroid hormone levels.

Insulin resistance is one of the important links in the pathogenesis of type II diabetes mellitus. At the heart of this process is a violation of the binding of insulin to the receptor and the transmission of the signal through the membrane into the cell. An important role in this is given to the kinase of the insulin receptor.

The basis of insulin resistance is a decrease in the absorption of glucose by tissues and, consequently, hyperglycemia, which leads to hyperinsulinemia. Increased insulin increases the absorption of glucose by peripheral tissues, reduces the formation of glucose by the liver, which can lead to normal glucose in the blood. With a decrease in the function of beta cells of the pancreas, glucose tolerance is impaired, and diabetes mellitus develops.

As it turned out in recent years, insulin resistance in combination with hyperlipidemia, arterial hypertension is an important factor in the pathogenesis of not only diabetes mellitus, but also many other diseases such as atherosclerosis, hypertension, obesity. This was first pointed out by Y. Reaven [Diabetes - 1988, 37-P. 1595-1607] and called this symptom complex metabolic syndrome "X".

Complex endocrine-metabolic disorders in tissues can depend on local processes.

Cellular hormones and neurotransmitters acted first as tissue factors, substances that stimulate the growth of cells, their movement in space, the strengthening or slowing down of certain biochemical and physiological processes in the body. Only after the formation of endocrine glands appeared a thin hormonal regulation. Many hormones of mammals are also tissue factors. Thus, insulin and glucagon act locally as tissue factors on cells within the islets. Consequently, the system of hormonal regulation under certain conditions plays a leading role in the processes of vital activity in order to maintain homeostasis in the body at a normal level.

In 1968, a major English pathologist and histochemist E. Pearce proposed a theory of the existence in the body of a specialized highly organized neuroendocrine cell system, the main specific property of which is the ability of its constituent cells to produce biogenic amines and polypeptide hormones (APUD-systems). The cells entering the APUD-system were called apudocytes. By the nature of the function, the biologically active substances of the system can be divided into two groups: compounds performing strictly defined specific functions (insulin, glucagon, ACTH, STH, melatonin, etc.), and compounds with diverse functions (serotonin, catecholamines, etc.).

These substances are produced in virtually all organs. Apodocytes act at the tissue level as regulators of homeostasis and control metabolic processes. Consequently, with pathology (the appearance of an abortion in certain organs), the symptoms of endocrine disease, corresponding to the profile of secreted hormones, develop. Diagnosis with a hoop is a significant challenge and is based on a general definition of blood hormones.

The measurement of hormone concentrations in the blood and urine is the most important means of evaluating endocrine functions. Analyzes of urine are in some cases more practical, but the level of hormones in the blood more accurately reflects the rate of their secretion. There are biological, chemical and carbonation methods for determining hormones. Biological methods, as a rule, are labor-intensive and of little specificity. The same shortcomings are inherent in many chemical methods. The most widely used are the carbonation methods based on the displacement of the labeled hormone from a specific bond with the carrier proteins, receptors or antibodies by the natural hormone contained in the sample analyzed. However, such definitions reflect only the physico-chemical or antigenic properties of hormones, and not their biological activity, which does not always coincide. In a number of cases, the determination of hormones is carried out under conditions of specific loads, which makes it possible to assess the reserve capabilities of a particular gland or the safety of feedback mechanisms. An obligatory prerequisite for the study of a hormone must be the knowledge of the physiological rhythms of its secretion. An important principle of assessing the hormone content is the simultaneous determination of a regulated parameter (for example, insulin and glycemia). In other cases, the level of the hormone is compared with the content of its physiological regulator (for example, in determining thyroxine and thyrotropic hormone - TSH). This contributes to differential diagnosis of close pathological conditions (primary and secondary hypothyroidism).

Modern diagnostic methods allow not only to identify endocrine disease, but also to determine the primary link of its pathogenesis, and, consequently, the origins of the formation of endocrine pathology.

[1], [2], [3], [4], [5], [6], [7], [8]