The endocrine, and according to modern data, the neuroendocrine system regulates and coordinates the activity of all organs and systems, ensuring the adaptation of the organism to the constantly changing factors of the external and internal environment, the result of which is the maintenance of homeostasis, which, as you know, is necessary to maintain the normal functioning of the organism. In recent years, it has been clearly shown that the neuroendocrine system performs these functions in close interaction with the immune system.
The endocrine system is represented by the endocrine glands, which are responsible for the formation and release of various hormones into the bloodstream. Endocrine glands, or endocrine glands, are subdivided into classical (pituitary, thyroid and parathyroid glands, pancreatic islet apparatus, adrenal cortex and medulla, testes, ovaries, pineal gland) and non-classical (thymus, heart, liver, kidneys, central nervous system, placenta, skin, gastrointestinal tract), which are shown in Fig. 1 (see color insert).
It has been established that the central nervous system (CNS) takes part in the regulation of the secretion of hormones of all endocrine glands, and hormones, in turn, affect the function of the central nervous system, modifying its activity and state. Nervous regulation of the body’s endocrine functions is carried out both through pituitary (hypothalamic) hormones and through the influence of the autonomic nervous system. In addition, a sufficient amount of monoamines and peptide hormones are secreted in various areas of the central nervous system, many of which are also secreted in the endocrine cells of the gastrointestinal tract. These hormones include vasoactive intestinal peptide (VIP), cholecystokinin, gastrin, neurotensin, met-, leenkephalin, etc.
In the hypothalamus, the proper hypothalamic (vasopressin, oxytocin, neurotensin) and pituitary hormones (somatostatin, thyroliberin, or thyrotropin-releasing hormone, gonadotropin-releasing hormone, or gonadotropin-releasing hormone, or luliberin, or corticoliberin-releasing hormone) The latter are released into the portal system of the pituitary gland, reach the cells of the anterior lobe of the pituitary gland, inhibiting or enhancing their secretory activity, and thereby change the rate of secretion of tropic hormones of the pituitary gland.
The immune system and the thymus gland (thymus) also produce a large number of hormones that can be categorized into cytokines, or lymphokines, and thymic hormones. Cytokines that are secreted by immunocompetent cells include g-interferon, interleukin 1, 2, 3, 4, 5, 6, 7, 9, 10, 11 and 12; tumor necrosis factor, granulocyte colony-stimulating factor, granulocytomacrophage colony-stimulating factor, macrophage colony-stimulating factor, leukemic inhibitory factor, oncostatin M, stem cell factor, etc. It must be emphasized that activated lymphocytes and other immunocompetent cells secrete as epidermal transforming growth factor, somatomedins, or insulin-like growth factors 1 and 2 (IGF 1 and 2), as well as various polypeptide hormones (ACTH, TSH, LH, FSH, STH, prolactin, chorionic gonadotropin, somatostatin, VIP, oxytocin, vasopressin, , corticoliberin, somatoliberin, substance P, etc.).
Specific thymic hormones were isolated from the thymus gland: thymosin (5th fraction), thymosin a-1, thymosin a-7, thymosin a-11, thymosin b-4, b-8, thymosin b-9, thymosin b-10, thymic humoral factor, thymopoietin, thymulin, thymic factor X, thymostimulin. In addition, the above-listed lymphokines (interleukin 1, 2, 4, 6, 7, tumor necrosis factor, etc.), neuropeptides (neurotensin, substance P, VIP, cholecystokinin, somatostatin, oxytocin, vasopressin, neurotensins, methenkephalin, ACTH, atrial natriuretic peptide).
Cycotines and thymic hormones exercise their specific action in an autocrine or paracrine way, affecting the differentiation of T cells, increasing the number of T suppressors or cytotoxic T cells, restoring the reactivity of T cells, affecting hematopoietic cells and thus taking part in the integrating role of neuroendocrine – the immune system in the body.
Much data has accumulated on gastrointestinal hormones that are secreted by cells or cell clusters located in the tissues of the gastrointestinal tract. More than 30 hormones of this group have been isolated and described. Endocrine cells of the gastrointestinal tract secrete gastrin, gastrin-releasing peptide, secretin, cholecystokinin, somatostatin, GIP, VIP, substance P, motilin, galanin, glucagon gene peptides (glycentin, oxyntomodulin, glucagon-like peptide 1 and 2), neurotensin N YY, pancreatic polypeptide, neuropeptide Y, chromogranins (chromogranin A and related peptides – pancreatin and chromostatin; chromogranin B and related peptide GAWK and secretogranin II). Structurally similar to VIP are the peptide histidine isoleucine (PHI), the peptide histidine methionine (PHM), the pituitary adenylate cyclase activating peptide (PACAP), which is detected in two forms (PACAP 27 and PACAP 38), and having a 68% homologous structure with the VIP , although encoded by different genes. All these hormones, like VIP, carry out a biological effect through an increase in cAMP and have an effect close to that of VIP.
Similar in structure to the gastrin-releasing peptide neuromedin B, neuromedin U8 and U25, which have a biological effect similar to the gastrin-releasing peptide. Described peptides related to the calcitonin gene (CGRP). If the α-peptide related to the calcitonin gene is a neuropeptide and represents the main form of the hormone in the central nervous system and in the endings of the sensory nerves, then the β-peptide related to the calcitonin gene is localized in the nerve endings of the gastrointestinal tract and the pancreas.
Opioid peptides (enkephalins and endorphins) are detected in neurons of the gastrointestinal tract and are represented by two groups of peptides: leu- and methenkephalins, derivatives of preproenkephalin A, and dynorphins, derivatives of preproenkephalin B.
Endothelin 1, 2, and 3, initially isolated from endothelial cells, are also localized in the cells of the gastrointestinal tract. Moreover, a new peptide was isolated, which is structurally similar to endothelin and named vasoactive intestinal constrictor peptide (VIC). It is possible that all these hormones, in addition to their physiological role, are involved in the pathogenesis of various diseases of the gastrointestinal tract, in particular gastric ulcer.
Secretory endocrine cells of the gastrointestinal tract belong to the APUD-system (amine content, precursor uptake, decarboxilation, which means the content of amines, absorption of precursors and decarboxylation). A characteristic property of these cells is their ability to absorb and accumulate precursors of biogenic amines, followed by their decarboxylation, resulting in the formation of biologically active substances and polypeptide hormones.
A little more than 30 years have passed since the discovery of a new class of biologically active compounds – prostaglandins (Pg), acting in concentrations of 10-11 mol / l. First, PgE2, PgF2, PgD2 were identified, which are called “classic” prostaglandins and have a wide spectrum of action. Thus, prostaglandins of the E2 series affect the state of the cardiovascular system, gastrointestinal tract, reproductive system and respiratory system, are mediators of inflammation, fever and certain types of pain. Fa series prostaglandins act on the female reproductive, respiratory and digestive systems.
In 1975 thromboxanes were described, and in 1976 – prostacyclins (prostaglandin 12), which are derivatives of prostaglandins and are involved in the processes of aggregation and disaggregation of platelets. The initial product for the synthesis of prostaglandins in vivo is arachidonic acid. 1979 – 1980 another chain of transformations of arachidonic acid into leukotrienes (leukotriene A4, B4, C4, D4, E4), synthesized in polymorphonuclear leukocytes and participating in inflammatory reactions, was discovered.
The listed compounds are formed from arachidonic acid, which is present in cell membranes as one of the constituent phospholipids. Cleavage of arachidonic acid from phosphotidylcholinarachidonate of the phospholipid part of the membrane occurs with the participation of phospholipase A2. There are two main pathways (cyclooxygenase and lipoxygenase) for the oxidation of arachidonic acid. The end products of the first pathway are prostaglandins and thromboxanes, and of the second, hydroxyeicosatetraenoic acid (HETE) and leukotrienes. In addition to cyclooxygenase and lipooxygenase, a third enzyme, epoxygenase, has been identified, which oxidizes arachidonic acid to epoxyeicosatrienoic acid (EET) and dihydroxyeicosatrienoic acid (DHET). All metabolites of arachidonic acid are called eicosanoids.
The role of eicosanoids in the body is great. They are involved in the mechanisms of insulin secretion, in the regulation of glucose production by the liver, in the processes of lipolysis, metabolism in bone tissue in normal conditions and with metastases, in reproductive function (regulation of luteolysis, contraction of uterine muscles during childbirth and abortion), in the regulation of the function of the adenohypophysis, hormonal function the gastrointestinal tract, kidneys, lungs, in the processes of inflammation, blood coagulation and the mechanisms of development of atherosclerosis.
The kidneys, performing the main excretory function, are also a kind of endocrine gland. Juxtaglomerular cells secrete the hormone renin into the bloodstream, under the influence of which angiotensinogen is converted into angiotensin, and the latter promotes the synthesis and release of aldosterone. Another hormone, erythropoietin, is formed in the kidneys, which stimulates the development and release of red blood cells from the bone marrow. Here, under the influence of 1-hydroxylase, the biologically less active form of 25 (OH) vitamin D is hydroxylated into the active form-1, 25 (OH) 2 of vitamin D.
Recently, it has been established that the heart is also an endocrine gland. Initially, atrial natriuretic hormone was isolated from the atrium, and now it has been established that there is an atrial natriuretic system in myocytes, consisting of a prohormone, which includes 126 amino acid residues, and is involved in lowering blood pressure and has natriuretic, diuretic, potassiumuretic properties. From the prohormone are formed: pro-atrial natriuretic hormone (1-30); long acting sodium stimulant (31-67); vascular dilator (79-98); potassium uretic stimulant (99-126 amino acid residues). The listed peptides are released into circulation as an N-terminal peptide of 98 amino acids and a C-terminal peptide of 28 amino acids, i.e. actually atrial natriuretic hormone. Both peptides are released simultaneously in response to central hypervolemia and increased heart rate (over 125 beats per minute). The N-terminal peptide (1-98) under the influence of proteases is cleaved into peptides consisting of 1-30, 31-67, 79-98 amino acid residues, which have a biological effect.
The brain natriuretic peptide is secreted in the central nervous system. Both atrial and brain natriuretic peptides are detected, in addition to the heart and brain, in other tissues (adrenal glands, kidneys, uterus, etc.), although the concentration of these hormones in the tissues is only 1/1000 of the hormone level in the heart. This indicates that natriuretic peptides have paracrine or autocrine functions here. The neuroendocrine system provides regulation, coordination and integration of various body functions. The unity and interconnection of the nervous and endocrine mechanisms of regulation can be clearly seen on the example of the hypothalamus, special cells of which perceive afferent and efferent nerve impulses and transmit them further already by hormonal means – through the secretion of pituitary and hypothalamic hormones into the portal system of the pituitary gland. Consequently, in the hypothalamus, nerve impulses are converted into humoral signals. Other endocrine cells, in particular cells of the APUD system, have the ability to form not only hormones, but also neurotransmitters, or neurotransmitters.
Thus, it is more correct to speak not about the endocrine system, but about the neuroendocrine system of the body, or the immune-neuroendocrine system. The functional activity and morphological structure of the endocrine glands are controlled and regulated by the central nervous system. Back in 1935 A.D. Speransky wrote that “the humoral factor is one of the types of reflection of nervous influences in peripheral tissues, without which no nervous function is known to us at all.” Modern research has fully confirmed this position.
The functional activity of the endocrine system depends not only on the ability of the endocrine glands to produce the required amount of hormones. Most of the hormones secreted by the peripheral endocrine glands are delivered to the corresponding target organs or tissues in a protein-bound state. Thus, glucocorticoids – adrenal cortex hormones, progesterone and aldosterone – are bound by glucocorticoid-binding proteins, the main of which is transcortin. Thyroid hormones are bound by thyroxine-binding globulins (a-2 globulin with a molecular weight of 54 kDa), transthyretin, which was previously called prealbumin (a glycoprotein with a molecular weight of 55 kDa), and albumin with a molecular weight of 66.5 kDa. Testosterone, dihydrotestosterone and estradiol circulate in the central circulation in combination with sex hormone binding globulin, which is a glycoprotein with a molecular weight of 90 kDa.
In this case, blood proteins perform mainly a transport function. Transport proteins do not bind the corresponding hormones to the same extent. Thus, transcortin binds to the same extent (about 90%) cortisol and progesterone, and globulin, which binds sex hormones, binds testosterone more strongly (about 98%) than estradiol. About 50% of the circulating aldosterone is associated with proteins. Most of calcitriol is in a complex with a protein that binds vitamin D, and the 25-OH D3 fraction binds to this protein more strongly than 1, 25 (OH) 2D3. Thyroid hormones circulate in the blood almost entirely in protein-bound form. Free form for T4 is 0.04% and for T3 – 0.4%. About 68% of T4 and 80% of T3 are associated with thyroxine-binding globulin, 11% of T4 and 9% of T3 with transthyretin, and 21% of T4 and 11% of T3 circulating in the blood are associated with albumin.
The hormones associated with them are biologically inactive, i.e. unable to complex with the corresponding receptor. In order for the hormone to interact with the receptor, the hormones must dissociate from the fraction associated with blood proteins. As a rule, the fraction of the free hormone makes up a small part of its total amount circulating in the circulatory system, but it is this fraction that provides the biological effect inherent in this hormone. A change in the amount of blood proteins that bind hormones leads to the development of pathological conditions caused by an excess or deficiency of the effect of the corresponding hormone.
Transport proteins, in addition to their specific function of transferring the hormone to the site of its action, perform the function of depositing the hormone in the bloodstream. The protein-bound hormone is in constant equilibrium with the free biologically active form of the hormone, and as the level of the free hormone decreases, the latter is released from the protein-bound form, thus maintaining a constant concentration of the free fraction in the peripheral blood. In addition, transport proteins affect the rate of clearance of the hormone, which is carried out in the liver and kidneys.
Fat-soluble (lipophilic) hormones (steroids, iodothyronines, and calcitriol) passively pass through the cell plasma membrane and then bind (complex) with cytosolic proteins and nuclear receptors. Water-soluble (hydrophilic) hormones (polypeptide, glycoprotein, protein and catecholamines), after complexing with membrane receptors, exert their effect through secondary messengers.
An important condition for the normal functioning of the endocrine system is also the state of the target tissue. So it is customary to call a tissue that is sensitive to the action of this hormone and responds with a specific effect on this action. The ability of target tissues to respond to the corresponding hormone is determined by the presence of receptors that interact with this hormone. For example, adrenocorticotropic hormone (ACTH) circulates throughout the body, but only the adrenal glands have receptors that can complex with it. Therefore, the adrenal gland is the target organ or tissue for ACTH; here the hormone exerts its biological effect – it stimulates the processes of steroidogenesis. A change in the functional state of the receptor apparatus leads to the appearance of the same symptoms that manifest excessive or insufficient secretion of the corresponding hormones.
The endocrine function of the body is provided by systems that include:
1) endocrine glands secreting hormone;
2) hormones and their transport routes;
3) the corresponding organs or target tissues that respond to the action of hormones and are provided with normal receptor and post-receptor mechanisms.
The endocrine system of the body as a whole maintains constancy in the internal environment, which is necessary for the normal course of physiological processes. In addition, the endocrine system, together with the nervous and immune systems, provide reproductive function, growth and development of the body, the formation, utilization and storage (“in reserve” in the form of glycogen or fatty tissue) energy.
Hormones and their mechanism of action
Originally, the term “hormone” meant chemicals that are secreted by the endocrine glands into the lymphatic or blood vessels, circulate in the blood and have an effect on various organs and tissues located at a considerable distance from the place of their formation. It turned out, however, that some of these substances (for example, norepinephrine), circulating in the blood as hormones, act as a neurotransmitter (neurotransmitter), while others (somatostatin) are both hormones and neurotransmitters. In addition, certain chemical substances are secreted by endocrine glands or cells in the form of prohormones and only at the periphery are converted into biologically active hormones (testosterone, thyroxine, angiotensinogen, etc.).
Hormones, in the broad sense of the word, are biologically active substances and carriers of specific information, with the help of which communication between various cells and tissues is carried out, which is necessary for the regulation of numerous functions of the body. The information contained in hormones reaches its addressee due to the presence of receptors, which translate it into post-receptor action (influence), accompanied by a certain biological effect.
Currently, the following options for the action of hormones are distinguished:
1) hormonal, or hemocrine, i.e. action at a considerable distance from the place of formation;
2) isocrine, or local, when a chemical substance synthesized in one cell has an effect on a cell located in close contact with the first, and the release of this substance is carried out into the interstitial fluid and blood;
3) neurocrine, or neuroendocrine (synaptic and nonsynaptic) action, when a hormone, released from nerve endings, performs the function of a neurotransmitter or neuromodulator, i.e. a substance that alters (usually enhances) the action of a neurotransmitter;
4) paracrine – a type of isocrine action, but at the same time the hormone formed in one cell enters the intercellular fluid and affects a number of cells located in the immediate vicinity;
5) juxtacrine – a kind of paracrine action, when the hormone does not enter the intercellular fluid, and the signal is transmitted through the plasma membrane of a nearby other cell;
6) autocrine action, when the hormone released from the cell affects the same cell, changing its functional activity;
7) solinocrine action, when a hormone from one cell enters the lumen of the duct and thus reaches another cell, exerting a specific effect on it (for example, some gastrointestinal hormones).
The synthesis of protein hormones, like other proteins, is under genetic control, and typical mammalian cells express genes that encode 5,000 to 10,000 different proteins, and some highly differentiated cells up to 50,000 proteins. Any protein synthesis begins with transposition of DNA segments, then transcription, post-transcriptional processing, translation, post-translational processing and modification. Many polypeptide hormones are synthesized in the form of large prohormone precursors (proinsulin, proglucagon, proopiomelanocortin, etc.). The conversion of prohormones into hormones is carried out in the Golgi apparatus.
By their chemical nature, hormones are divided into protein, steroid (or lipid) and amino acid derivatives.
Protein hormones are subdivided into peptide ones: ACTH, somatotropic (STH), melanocyte-stimulating (MSH), prolactin, parathyroid hormone, calcitonin, insulin, glucagon, and proteid – glucoproteins: thyrotropic (TTG), follicle-stimulating, lymphocyte-stimulating (FSH) Pituitary hormones and hormones of the gastrointestinal tract belong to oligopeptides, or small peptides. Steroid (lipid) hormones include corticosterone, cortisol, aldosterone, progesterone, estradiol, estriol, testosterone, which are secreted by the adrenal cortex and gonads. This group includes vitamin D sterols – calcitriol. Derivatives of arachidonic acid are, as already indicated, prostaglandins and belong to the group of eicosanoids. Adrenaline and norepinephrine, synthesized in the adrenal medulla and other chromaffin cells, as well as thyroid hormones are derivatives of the amino acid tyrosine. Protein hormones are hydrophilic and can be transported by the blood in a free state or in a state partially bound to blood proteins. Steroid and thyroid hormones are lipophilic (hydrophobic), have a low solubility, their main amount circulates in the blood in a protein-bound state.
Hormones carry out their biological action by complexing with receptors – information molecules that transform a hormonal signal into hormonal action. Most hormones interact with receptors located on the plasma membranes of cells, while other hormones interact with receptors located intracellularly, i.e. with cytoplasmic and nuclear.
Protein hormones, growth factors, neurotransmitters, catecholamines and prostaglandins belong to the group of hormones for which receptors are located on the plasma membranes of cells. Plasma receptors, depending on their structure, are subdivided into:
1) receptors, the transmembrane segment of which consists of seven fragments (loops);
2) receptors, the transmembrane segment of which consists of one fragment (loop or chain);
3) receptors, the transmembrane segment of which consists of four fragments (loops).
The hormones, the receptor of which consists of seven transmembrane fragments, include: ACTH, TSH, FSH, LH, chorionic gonadotropin, prostaglandins, gastrin, cholecystokinin, neuropeptide Y, neuromedin K, vasopressin, adrenaline (a-1 and 2, b-1 and 2), acetylcholine (M1, M2, M3 and M4), serotonin (1A, 1B, 1C, 2), dopamine (D1 and D2), angiotensin, substance K, substance P, or neurokinin types 1, 2 and 3, thrombin , interleukin-8, glucagon, calcitonin, secretin, somatoliberin, VIP, pituitary adenylate cyclase activating peptide, glutamate (MG1 – MG7), adenine.
The second group includes hormones that have one transmembrane fragment: STH, prolactin, insulin, somatomammotropin, or placental lactogen, IGF-1, neural growth factors, or neurotrophins, hepatocyte growth factor, atrial natriuretic peptide types A, B and C, oncostatin, erythropoietin, ciliary neurotrophic factor, leukemic inhibitory factor, tumor necrosis factor (p75 and p55), neural growth factor, interferons (a, b and g), epidermal growth factor, neurodifferentiating factor, fibroblast growth factors, platelet growth factors A and B, macrophage colony-stimulating factor, activin, inhibin, interleukins-2, 3, 4, 5, 6 and 7, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, low density lipoprotein, transferrin, IGF-2, urokinase plasminogen activator.
The third group hormones, the receptor of which has four transmembrane fragments, include acetylcholine (nicotinic muscle and nerve), serotonin, glycine, g-aminobutyric acid.
Membrane receptors are integral components of plasma membranes. The binding of the hormone to the corresponding receptor is characterized by high affinity, i.e. a high degree of receptor affinity for this hormone.
The biological effect of hormones interacting with receptors localized on the plasma membrane is carried out with the participation of a “secondary messenger”, or transmitter.
Depending on what substance performs its function, hormones can be divided into the following groups:
1) hormones that
have a biological effect with the participation of cyclic adenosine monophosphate (cAMP);
2) hormones that act with the participation of cyclic guanidine monophosphate (cGMP);
3) hormones mediating their action with the participation of ionized calcium or phosphatidylinositides (inositol triphosphate and diacylglycerol) or both compounds as an intracellular secondary messenger;
4) hormones that exert their effect by stimulating the cascade of kinases and phosphatases.
The mechanisms involved in the formation of secondary messengers operate through the activation of adenylate cyclase, guanylate cyclase, phospholipase C, phospholipase A2, tyrosine kinases, Ca2 + channels, etc.
Corticoliberin, somatoliberin, VIP, glucagon, vasopressin, LH, FSH, TSH, chorionic gonadotropin, ACTH, parathyroid hormone, type E, D and I prostaglandins, b- adrenergic catecholamines have a hormonal effect through the activation of the receptor Adenylase through stimulation of the catecholase adenylase system. At the same time, another group of hormones, such as somatostatin, angiotensin II, acetylcholine (muscarinic effect), dopamine, opioids, and a2-adrenergic catecholamines, inhibit the adenylate cyclase-cAMP system.
In the formation of secondary messengers for hormones such as gonadoliberin, thyroliberin, dopamine, thromboxanes A2, endoperoxides, leukotrienes, agniotensin II, endothelin, parathyroid hormone, neuropeptide Y, a1-adrenergic catecholamines, the system of acetylchinipholines, B , Ca2 + -dependent protein kinase C. Insulin, macrophage colony-stimulating factor, platelet-derived growth factor mediate their action through tyrosine kinase, and atrial natriuretic hormone, histamine, acetylcholine, bradykinin, endothelium-derived factor or nitric oxide, which in turn mediates the action of the mediator and acetylcholine via guanylate cyclase. It should be noted that the division of hormones according to the principle of activating systems or one or another secondary messenger is conditional, since many hormones, after interacting with the receptor, simultaneously activate several secondary messengers.
Most hormones interacting with plasma receptors with 7 transmembrane fragments activate secondary messengers through binding to guanylate nucleotide proteins or G-proteins or regulatory proteins (G-proteins), which are heterotrimeric proteins consisting of a-, b-, g-subunits … More than 16 genes encoding the a-subunit have been identified, several genes for the b- and g-subunits. Different types of a-subunits have non-identical effects. Thus, the as subunit inhibits adenylate cyclase and Ca2 + channels, the aq subunit inhibits phospholipase C, the ai subunit inhibits adenylate cyclase and Ca2 + channels and stimulates phospholipase C, K + channels and phosphodiesterase; The b-subunit stimulates phospholipase C, adenylate cyclase and Ca2 + channels, while the g-subunit stimulates K + channels, phosphodiesterase and inhibits adenylate cyclase. The exact function of other subunits of regulatory proteins has not yet been established.
Hormones complexing with a receptor having one transmembrane fragment activate intracellular enzymes (tyrosine kinase, guanylate cyclase, serine-threonine kinase, tyrosine phosphatase). Hormones, the receptors of which have 4 transmembrane fragments, transmit the hormonal signal through ion channels.