Disruption of the mechanism of action of hormones

Changes in tissue reactions to a particular hormone may be associated with the production of an abnormal hormonal molecule, a deficiency of receptors or enzymes that respond to hormonal stimulation. Clinical forms of endocrine diseases have been identified in which shifts in hormone-receptor interactions are the cause of pathology (lipoatrophic diabetes, some forms of insulin resistance, testicular feminization, neurogenic diabetes insipidus).

Common features of the action of any hormones are a cascade amplification of the effect in the target cell; regulation of the speed of pre-existing reactions, rather than initiation of new ones; comparatively long-term (from a minute to a day) preservation of the effect of nervous regulation (fast - from a millisecond to a second).

For all hormones, the initial stage of action is binding to a specific cellular receptor, which initiates a cascade of reactions that lead to changes in the amount or activity of a number of enzymes, which forms the physiological response of the cell. All hormone receptors are proteins that non-covalently bind hormones. Since any attempt to present this problem in any detail requires a thorough coverage of the fundamental issues of biochemistry and molecular biology, only a brief summary of the relevant issues will be given here.

First of all, it should be noted that hormones are capable of influencing 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 (which is often called the trophic effect), as well as changing the blood flow through the organ (adrenocorticotropic hormone - ACTH, for example, not only stimulates the biosynthetic and secretory activity of adrenal cortex cells, but also increases blood flow in the steroid-producing glands).

At the level of an individual cell, hormones typically control one or more rate-limiting steps in cellular metabolic reactions. Almost always, such control involves increased synthesis or activation of specific protein enzymes. The specific mechanism of this influence depends on the chemical nature of the hormone.

Hydrophilic hormones (peptide or amine) are believed to not penetrate the cell. Their contact is limited to receptors located on the outer surface of the cell membrane. Although convincing evidence of the "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. Binding of the hormone to the receptor initiates a series of intramembrane processes leading to the cleavage of the active catalytic unit from the enzyme adenylate cyclase located on the inner surface of the cell membrane. In the presence of magnesium ions, the active enzyme converts adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP). The latter activates one or more cAMP-dependent protein kinases present in the cell cytosol, which promote the phosphorylation of a number of enzymes, which causes their activation or (sometimes) inactivation, and can also change the configuration and properties of other specific proteins (for example, structural and membrane proteins), as a result of which protein synthesis at the ribosome level is enhanced, transmembrane transfer processes are changed, etc., i.e., the cellular effects of the hormone are manifested. 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. The enzyme that destroys intracellular cAMP, i.e. converts it into an inactive compound (5'-AMP), is phosphodiesterase. The above scheme is the essence of the so-called second messenger concept, first proposed in 1961 by E. V. Sutherland et al. based on the analysis of the effect of hormones on the breakdown of glycogen in liver cells. The first messenger is considered to be the hormone itself, approaching the cell from the outside. The effects of some compounds may also be associated with a decrease in the level of cAMP in the cell (through inhibition of adenylate cyclase activity or an increase in phosphodiesterase activity). It should be emphasized that cAMP is not the only second messenger known to date. This role can also be played by other cyclic nucleotides, such as cyclic guanosine monophosphate (cGMP), calcium ions, metabolites of phosphatidylinositol, and possibly prostaglandins formed as a result of the hormone's action on the phospholipids of the cell membrane. In any case, the most important mechanism of action of second messengers is the phosphorylation of intracellular proteins.

Another mechanism is postulated for 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 the methods of penetration of these hormones into the cell currently remains debatable, the classical scheme is based on their free penetration as lipophilic compounds. However, once in the cell, steroid and thyroid hormones reach the object of their action - the cell nucleus - in different ways. The former interact with cytosolic proteins (receptors), and the resulting complex - steroid-receptor - is translocated into the nucleus, where it reversibly binds to DNA, acting as a gene activator and changing transcription processes. As a result, specific mRNA appears, which leaves the nucleus and causes the synthesis of specific proteins and enzymes on ribosomes (translation). Thyroid hormones that enter the cell behave differently, directly binding to the chromatin of the cell nucleus, whereas cytosolic binding not only does not promote, but even hinders the nuclear interaction of these hormones. In recent years, data have appeared on the fundamental similarity of the mechanisms of cellular action of steroid and thyroid hormones and that the described discrepancies between them may be associated with errors in the research methodology.

Particular attention is also paid to the possible role of a specific calcium-binding protein (calmodulin) in modulating cellular metabolism after exposure to hormones. The concentration of calcium ions in the cell regulates many cellular functions, including the metabolism of cyclic nucleotides themselves, the mobility of the cell and its individual organelles, endo- and exocytosis, axonal flow, and the release of neurotransmitters. The presence of calmodulin in the cytoplasm of virtually all cells suggests its significant role in regulating many cellular activities. Available data indicate that calmodulin may act as a calcium ion receptor, i.e. the latter acquire physiological activity only after binding to calmodulin (or similar proteins).

Resistance to a 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 caused by changes in cell membrane receptors or disruption of the connection with intracellular proteins. These disorders are caused by the formation of abnormal receptors and enzymes (usually congenital pathology). Acquired resistance is associated with the development of antibodies to receptors. Selective resistance of individual organs to thyroid hormones is possible. 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 the increased content of cortisol in the blood, the patients did not have symptoms of Itsenko-Cushing's disease, hypertension and hypokalemia were observed.

Rare hereditary diseases include cases of pseudohypoparathyroidism, clinically manifested by signs of parathyroid gland insufficiency (tetany, hypocalcemia, hyperphosphatemia) with elevated or normal levels of parathyroid hormone in the blood.

Insulin resistance is one of the important links in the pathogenesis of type II diabetes mellitus. This process is based on the disruption of insulin binding to the receptor and signal transmission through the membrane into the cell. Insulin receptor kinase plays a significant role in this.

Insulin resistance is based on decreased glucose uptake by tissues and, consequently, hyperglycemia, which leads to hyperinsulinemia. Increased insulin levels enhance glucose uptake by peripheral tissues, reduce glucose production by the liver, which can lead to normal blood glucose levels. When pancreatic beta cell function decreases, 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 he called this symptom complex metabolic syndrome "X".

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

Cellular hormones and neurotransmitters initially acted as tissue factors, substances stimulating cell growth, their movement in space, strengthening or slowing down certain biochemical and physiological processes in the body. Only after the formation of endocrine glands did fine hormonal regulation arise. Many mammalian hormones are also tissue factors. Thus, insulin and glucagon act locally as tissue factors on cells inside the islets. Consequently, the hormonal regulation system under certain conditions plays a leading role in life processes to maintain homeostasis in the body at a normal level.

In 1968, the prominent English pathologist and histochemist E. Pearce put forward a theory about the existence in the body of a specialized, highly organized neuroendocrine cellular system, the main specific property of which is the ability of its constituent cells to produce biogenic amines and polypeptide hormones (APUD system). The cells included in the APUD system are called apudocytes. By the nature of the function, the biologically active substances of the system can be divided into two groups: compounds that perform strictly defined specific functions (insulin, glucagon, ACTH, STH, melatonin, etc.), and compounds with a variety of functions (serotonin, catecholamines, etc.).

These substances are produced in almost all organs. Apudocytes act as homeostasis regulators at the tissue level and control metabolic processes. Consequently, in case of pathology (apudomas appearing in certain organs), symptoms of an endocrine disease develop, corresponding to the profile of secreted hormones. Diagnosis of apudomas presents significant difficulties and is generally based on determining the content of hormones in the blood.

Measuring hormone concentrations in blood and urine is the most important means of assessing endocrine functions. Urine tests are more practical in some cases, but the level of hormones in the blood more accurately reflects the rate of their secretion. There are biological, chemical and saturation methods for determining hormones. Biological methods are usually labor-intensive and of low specificity. The same disadvantages are inherent in many chemical methods. The most widely used are saturation methods based on the displacement of the labeled hormone from a specific bond with carrier proteins, receptors or antibodies by the natural hormone contained in the analyzed sample. However, such determinations reflect only the physicochemical or antigenic properties of hormones, and not their biological activity, which does not always coincide. In some cases, hormone determinations are carried out under specific loads, which allows us to assess the reserve capacity of a particular gland or the integrity of feedback mechanisms. A prerequisite for studying a hormone is knowledge of the physiological rhythms of its secretion. An important principle of hormone content assessment is the simultaneous determination of the regulated parameter (for example, insulin and glycemia). In other cases, the hormone level is compared with the content of its physiological regulator (for example, when determining thyroxine and thyroid-stimulating hormone - TSH). This facilitates differential diagnostics of closely related pathological conditions (primary and secondary hypothyroidism).

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

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