Tumors of the apud system. Diffuse endocrine system Patterns of development of DES cells

Introduction…………………………………………………………………………..3

Brief description of tumors of the APUD system……………………….4-5

Carcinoid and its classifications………………………………………….……..4-6

Macroscopic and microscopic picture……………………………6-8

Etiology and pathogenesis………………………………………………………...9

Course and forecast………………………………………………………………10

Diagnosis of carcinoid tumors………………………………………..10-11

Conclusion……………………………………………………………………12

Bibliography……………………………………………………………….

Introduction

The concept of "neuroendocrine tumors" (NET) combines a heterogeneous group of neoplasms of various localizations, originating from cells of the diffuse neuroendocrine system (DNES), capable of producing neurospecific polypeptide hormones and biogenic amines. Most often, these tumors occur in the broncho-pulmonary system, in various parts of the gastrointestinal tract and in the pancreas (gastroenteropancreatic), in some endocrine glands (in the pituitary gland, medullary thyroid cancer, pheochromocytoma of the adrenal and extra-adrenal localization). These include highly differentiated carcinoids (synonymous with carcinoid tumor). NETs are among the relatively rare neoplasms. The increased interest in this problem of clinicians (first of all, oncologists, surgeons and endocrinologists), pathologists and other specialists noted in the last two decades is explained by the undoubted increase in the frequency of detection of these tumors, the existing difficulties in their early recognition (due to insufficient familiarity of doctors of various specialties with the features of clinical manifestations or the absence for the vast majority of regions of the ability to provide a comprehensive examination with the determination of common and specific biochemical markers, hormones and vasoactive peptides, conducting modern diagnostic studies), disagreements in the clinical and morphological criteria for making a diagnosis and assessing prognostic factors, the lack of generally recognized standards of treatment and objective assessment their results.

Brief description of tumors of the APUD system

Apudoma is a tumor originating from cellular elements located in various organs and tissues (mainly endocrine cells of the pancreas, cells of other parts of the gastrointestinal tract, C-cells of the thyroid gland), producing polypeptide hormones.

The term "APUD" (an abbreviation of the English words: Amine - amines, Precursor - precursor, Uptake - absorption, Decarboxylation - decarboxylation) was proposed in 1966 to refer to the general properties of a variety of neuroendocrine cells that can accumulate tryptophan, histidine and tyrosine, transforming them by decarboxylation mediators: serotonin, histamine, dopamine. Any cell of the APUD system is potentially capable of synthesizing many peptide hormones.

Most cells develop from the neural crest, but under the influence of external stimulating factors, many endodermal and mesenchymal cells can acquire the properties of cells of the gastroenteropancreatic endocrine system (APUD system).

Localization of cells of the APUD system:

1. Central and peripheral neuroendocrine organs (hypothalamus, pituitary gland, peripheral ganglia of the autonomic nervous system, adrenal medulla, paraganglia).

2. Central nervous system (CNS) and peripheral nervous system (glial cells and neuroblasts).

3. Neuroectodermal cells in the composition of the endocrine glands of endodermal origin (C-cells of the thyroid gland).

4. Endocrine glands of endodermal origin (parathyroid glands, pancreatic islets, single endocrine cells in the walls of the pancreatic ducts).

5. Mucosa of the gastrointestinal tract (enterochromaffin cells).

6. The mucous membrane of the respiratory tract (neuroendocrine cells of the lungs).

7. Skin (melanocytes).

The following types of apudoma are currently described:

· VIPoma - characterized by the presence of watery diarrhea and hypokalemia as a result of islet cell hyperplasia or a tumor, often malignant, originating from pancreatic islet cells (usually the body and tail), which secrete vasoactive intestinal polypeptide (VIP).

· gastrinoma - a gastrin-producing tumor, in 80% of cases located in the pancreas, much less often (15%) - in the wall of the duodenum or jejunum, antrum, peripancreatic lymph nodes, in the gates of the spleen, extremely rarely (5%) - extraintestinally (omentum, ovaries, biliary system).

· Glucagonoma - a tumor, more often malignant, originating from alpha cells of the pancreatic islets.

· Carcinoid ;

· Neurotensinoma - a tumor of the pancreas or ganglia of the sympathetic chain that produces neurotensin.

· PPoma - pancreatic tumor secreting pancreatic polypeptide (PP).

· Somatostatinoma - a malignant slow-growing tumor, characterized by an increase in the level of somatostatin.

The collection of single hormone-producing cells is called the diffuse endocrine system. A significant number of these endocrinocytes are found in the mucous membranes of various organs and associated glands. They are especially numerous in the organs of the digestive system. The cells of the diffuse endocrine system in the mucous membranes have a wide base and a narrower apical part. In most cases, they are characterized by the presence of argyrophilic dense secretory granules in the basal sections of the cytoplasm.

Secretory products of cells of the diffuse endocrine system have both local (paracrine) and distant endocrine effects. The effects of these substances are very diverse.

At present, the concept of a diffuse endocrine system is synonymous with the concept of an APUD system. Many authors recommend using the latter term, and calling the cells of this system "apudocytes". APUD is an abbreviation made up of the initial letters of words denoting the most important properties of these cells - Amine Precursor Uptake and Decarboxylation, - absorption of amine precursors and their decarboxylation. By amines is meant the group neuroamines- catecholamines (eg adrenaline, norepinephrine) and indolamines (eg serotonin, dopamine).

There is a close metabolic, functional, structural relationship between monoaminergic and peptidergic mechanisms of endocrine cells of the APUD system. They combine the production of oligopeptide hormones with the formation of neuroamine. The ratio of the formation of regulatory oligopeptides and neuroamines in different neuroendocrine cells can be different.

Oligopeptide hormones produced by neuroendocrine cells have a local (paracrine) effect on the cells of the organs in which they are localized, and a distant (endocrine) effect on the general functions of the body up to higher nervous activity.

Endocrine cells of the APUD series show a close and direct dependence on nerve impulses coming to them through sympathetic and parasympathetic innervation, but do not respond to tropic hormones of the anterior pituitary gland.

According to modern concepts, APUD-series cells develop from all germ layers and are present in all tissue types:

1. neuroectoderm derivatives (these are neuroendocrine cells of the hypothalamus, pineal gland, adrenal medulla, peptidergic neurons of the central and peripheral nervous system);
2. derivatives of the skin ectoderm (these are cells of the APUD series of the adenohypophysis, Merkel cells in the skin epidermis);
3. derivatives of the intestinal endoderm are numerous cells of the gastroenteropancreatic system;
4. mesoderm derivatives (eg, secretory cardiomyocytes);
5. derivatives of the mesenchyme - for example, mast cells of the connective tissue.

The cells of the APUD system, located in various organs and tissues, have a different origin, but have the same cytological, ultrastructural, histochemical, immunohistochemical, anatomical, and functional features. More than 30 types of apudocytes have been identified.

Examples of APUD-series cells located in the endocrine organs are parafollicular cells of the thyroid gland and chromaffin cells of the adrenal medulla, and in non-endocrine cells - enterochromaffin cells in the mucous membrane of the gastrointestinal tract and respiratory tract (Kulchitsky cells).

(see also from general histology)

Some terms from practical medicine:

• pheochromocytoma, chromaffin tumor, pheochromoblastoma, chromaffinoma, chromaffinocytoma - a hormonally active tumor originating from mature cells of chromaffin tissue, more often from the adrenal medulla;
• carcinoid, argentaffinoma, tumor carcinoid enterochromaffinoma - the general name of benign and malignant tumors, the morphological substrate of which are intestinal argentaffinocytes or cells resembling them in structure; carcinoid occurs in the appendix, less often in the stomach, small intestine or bronchi;
• carcinoid syndrome, enterodermatocardiopathic - a combination of chronic enteritis, fibrous valvulitis of the heart valve, telangiectasia and skin pigmentation, periodically accompanied by vasomotor disorders and sometimes asthma-like attacks; due to excessive intake of serotonin produced by carcinoid into the blood;

In 1968 The English histochemist Pierce put forward the concept of the existence in the body of a special highly organized diffuse system of endocrine cells, the specific function of which is the production of biogenic amines and peptide hormones, the so-called APUD system. This made it possible to significantly expand and, in a certain sense, revise the prevailing views on the hormonal regulation of vital processes. Since the spectrum of biogenic amines and peptide hormones is quite wide and includes many vital substances (serotonin, melatonin, histamine, catecholamines, pituitary hormones, gastrin, insulin, glucagon, etc.), the significant role of this system in maintaining homeostasis becomes obvious, and its study is becoming more and more relevant.

At first, the APUD theory was met with criticism, especially its position that APUD cells originate exclusively from the neuroectoderm, more precisely, from the crest of the embryonic neural tube. The reason for this initial misconception, apparently, is that apudocytes, in addition to peptides and amines, contain neuron-specific enzymes and substances: enolase (NSE), chromogranin A, synaptophysin, etc. and also exhibit other "neurocrestopathic" properties. Later, the authors and supporters of the APUD theory recognized that apudocytes have a different origin: some from the crest of the neural tube, others, for example, pituitary and skin apudocytes, develop from the ectoderm, while apudocytes of the stomach, intestines, pancreas, lungs, thyroid gland, a number of other organs are derivatives of the mesoderm. It has now been proven that in ontogeny (or under conditions of pathology) structural and functional convergence of cells of different origins can occur.

In the 70s-80s of the last century, through the efforts of many researchers, including R. Gilleman, who was awarded the Nobel Prize precisely for the discovery of peptide neuroendocrine regulation in the ANN, the APUD theory was transformed into the concept of a diffuse peptidergic neuroendocrine system (DPNES). Cells belonging to this system have been identified in the CNS and ANS, cardiovascular, respiratory, digestive systems, urogenital tract, endocrine glands, skin, placenta, i.e. virtually everywhere. The ubiquitous representation of these "chimeric" cells or transducers, combining the properties of nervous and endocrine regulation, fully corresponded to the main idea of ​​the APUD theory, that in terms of structure and function, DPNES serves as a link between the nervous and endocrine systems.

The APUD theory was further developed in connection with the discovery of humoral effectors of the immune system - cytokines. chemokines. integrins. defensins, etc. The relationship between DPNES and the immune system became apparent when it was found that these substances are formed not only in the organs and cells of the immune system, but also in apudocytes. On the other hand, it turned out that cells of the immune system have APUD characteristics. As a result, a modern version of APUD theory has emerged. According to this version, the human body has a multifunctional and widespread, in other words, diffuse neuroimmunoendocrine system (DNIES), which connects the nervous, endocrine and immune systems into a single complex, with duplicating and partly interchangeable structures and functions (Table 11.1). The physiological role of DNIES is the regulation of virtually all biological processes, at all levels - from subcellular to systemic. It is no coincidence that the primary pathology of DNIES is distinguished by its brightness and variety of clinical and laboratory manifestations, and its secondary (i.e., reactive) disorders accompany virtually any pathological process.

On the basis of the DNIES concept, a new integral biomedical discipline has been formed - neuroimmunoendocrinology, which approves a systemic, rather than nosological, approach to human pathology. The basis of "nosologism" is the postulate, according to which each disease or syndrome has a specific cause, a clear pathogenesis, and characteristic clinical, laboratory and morphological stigmata. The DNIES concept removes these methodological blinkers, making it possible to integrally interpret the causes and mechanisms of the pathological process.

The theoretical significance of the DNIES theory is that it helps to understand the nature of such physiological and pathological conditions as apoptosis, aging, inflammation, neurodegenerative diseases and syndromes, and osteoporosis. Oncopathologists, including hemoblastoses, autoimmune disorders. Its clinical relevance is explained by the fact that functional and/or morphological damage to apudonitis is accompanied by hormonal-metabolic, neurological, immunological and other severe disorders. The corresponding clinical-laboratory-morphological syndromes and their associations are presented in Table 11.2.

In his first articles, Peirce combined 14 cell types producing 12 hormones and located in the pituitary gland, stomach, intestines, pancreas, adrenal glands and paraganglia into the APUD system. Later, this list expanded, and more than 40 types of apudocytes are currently known (table).

In recent years, the presence of peptide hormones in the cells of the central and peripheral nervous system has been discovered. Such nerve cells are designated by the term "peptidergic neurons".

Table 11.1.

The collection of single hormone-producing cells is called the diffuse endocrine system (DES). Among single hormone-producing cells, two independent groups are distinguished: I - neuroendocrine cells of the APUD-series (of nervous origin); II - cells of non-nervous origin.

The first group includes secretory neurocytes formed from neuroblasts of the neural crest, which have the ability to simultaneously produce neuroamines, as well as synthesize protein hormones, i.e., having signs of both nerve and endocrine cells, therefore called neuroendocrinecells. These cells are characterized by the ability to take up and decarboxylate amine precursors.

According to modern concepts, APUD-ssria cells develop from all germ layers and are present in all tissue types:

1) derivatives of neuroectoderm (neuroendocrine cells neurosecretory nuclei of the hypothalamus, epiphysis, adrenal medulla, leptidergic neurons of the central and peripheral nervous system); 2) derivatives of the skin ectoderm (cells of the APUD series of the adenohypophysis, Merkel cells in the epidermis); 3) derivatives of the intestinal endoderm - enterinocytes - cells of the gastroenteropancreatic system; 4) derivatives of the mesoderm (secretory cardiomyocytes develop from the myoepicardial plate); 5) derivatives of the mesenchyme - mast cells

The APUD-series cells are characterized by the following features: the presence of specific granules, the presence of amines (catecholamines or serotonin), the absorption of amino acids - precursors of amines, the presence of an enzyme - decarboxylase of these amino acids.

APUD-series cells are found in the brain and in many organs - in endocrine and non-endocrine. APUD-series cells are found in most organs and systems - in the gastrointestinal fact, genitourinary system, skin, endocrine organs (thyroid gland), uterus, thymus, paraganglia, etc.

According to morphological, biochemical and functional characteristics, more than 20 types of APU D-series cells have been isolated, designated by the letters of the Latin alphabet A. B, C, D, etc. It is customary to allocate endocrine cells of the gastroenteropancreatic system into a special group.

Description of the endocrine cells of various organs is given in the relevant chapters.

Examples of neuroendocrine cells of this group located in the endocrine organs are parafollicular cells of the thyroid gland and chromaffin cells of the adrenal medulla, and in non-eidocrine cells - enteronitis (enterochromaffin cells) in the mucous membrane of the gastrointestinal tract.

One-sided hormones produced by neuroendocrine cells have a local effect on the cells of the organs in which they are localized. but mainly distant (endocrine) - on the general functions of the body up to higher nervous activity

A common topographic feature of these cells is their location near blood vessels.

The ratio of the formation of regulatory oligopeptides and neuroamines in different neuroendocrine cells can be different.

Endocrine cells of the APUD-series show a close and direct dependence on nerve impulses coming to them through sympathetic and parasympathetic innervation, but do not respond to the throne hormones of the anterior pituitary gland; their condition and activity after hypophysectomy is not disturbed.

The second group includes single hormone-producing cells or their accumulation, originating not from neuroblasts, but from other sources. This group includes a variety of cells of endocrine and non-endocrine organs that secrete steroid and other hormones: insulin (B-cells), glucagon (A-cells), enteroglucagon (L-cells), peptides (D-cells, K-cells) , secretin (S-cells), etc. These also include Leydig cells (glandulocytes) of the testis, producing testosterone and cells of the granular layer of ovarian follicles, producing estrogens and progesterone, which are steroid hormones (these cells are of mesodermal origin). The production of these hormones is activated by adenohypophyseal gonadotropins, and not by nerve impulses.

Moscow Medical Academy named after I.M. Sechenov

Department of Histology, Cytology and Embryology

Ddiffuse endocrine system

Fulfilled

Scientific adviser:

A bit of history

Development of DES cells

Patterns of development of DES cells:

The structure of the diesel power plant

DES cell regeneration

· Conclusion

· Bibliography

A special place in endocrinology and in the mechanisms of hormonal regulation is occupied by the diffuse endocrine system (DES), or the APUD system - the abbreviation Amine Precursor Uptake and Decarboxylation - the absorption of the amine precursor and its decarboxylation. DES is understood as a complex of receptor-endocrine cells (apudocytes), the bulk of which is located in the border tissues of the digestive, respiratory, urogenital and other body systems and which produce biogenic amines and peptide hormones.

A bit of history

In 1870, R. Heidenhain published data on the existence of chromaffin cells in the gastric mucosa. In subsequent years, they, as well as argentophilic cells, were found in other organs. Their functions remained unexplained for several decades. The first evidence of the endocrine nature of these cells was presented in 1902 by Beilis and Starling. They conducted experiments on a deneurated and isolated loop of the jejunum with preserved blood vessels. It was found that with the introduction of acid into the intestinal loop, devoid of any nerve connections with the rest of the body, pancreatic juice is secreted. It was obvious that the impulse from the intestines to the pancreas, causing the secretory activity of the latter, was transmitted not through the nervous system, but through the blood. And since the introduction of acid into the portal vein did not cause pancreatic secretion, it was concluded that the acid causes the formation of some substance in the epithelial cells of the intestine, which is washed out of the epithelial cells with the blood stream and stimulates the secretion of the pancreas.

In support of this hypothesis, Baylis and Starling carried out an experiment that finally confirmed the existence of endocrinocytes in the intestine. The mucous membrane of the jejunum was ground with sand in a weak solution of hydrochloric acid, filtered. The resulting solution was injected into the jugular vein of the animal.

In a few moments the pancreas responded with a stronger secretion than before.

In 1968, the English histologist E. Pierce proposed the concept of the existence of cells of the APUD series, which have common cytochemical and functional features. The acronym APUD is made up of the initial letters of the most important characteristics of cells. It has been established that these cells secrete biogenic amines and peptide hormones and have a number of common features:

1) absorb amine precursors;

Development of DES cells

According to modern concepts, APUD-series cells develop from all germ layers and are present in all tissue types:

1. neuroectoderm derivatives (these are neuroendocrine cells of the hypothalamus, pineal gland, adrenal medulla, peptidergic neurons of the central and peripheral nervous system);

2. derivatives of the skin ectoderm (these are cells of the APUD series of the adenohypophysis, Merkel cells in the epidermis of the skin);

3. derivatives of the intestinal endoderm are numerous cells of the gastroenteropancreatic system;

4. derivatives of the mesoderm (for example, secretory cardiomyocytes);

5. derivatives of the mesenchyme - for example, mast cells of the connective tissue.

Patterns of development of DES cells:

1. Early differentiation of DES cells in the organs of the digestive and respiratory systems even before the appearance of specific target cells. These data suggest that the early development of endocrine cells in certain tissues is due to the participation of their hormones in the regulation of the mechanisms of embryonic histogenesis.

2. The most intensive development of the endocrine apparatus of the digestive and respiratory systems during the period of the most pronounced growth and differentiation of tissues.

3. The appearance of DES cells in those places of organs and tissues where they are not found in adults. An example of this is the detection of cells secreting gastrin in the embryonic pancreas and their disappearance in it in the postnatal period. In Zollinger-Ellison syndrome, gastrin-secreting cells differentiate again in the pancreas.

DPP structure

DES cells, located in the epithelium of the mucous membranes of the digestive canal, airways and urinary tract, are endoepithelial, unicellular glands that do not form conglomerates.

In the intestine, between the basement membranes of cells and the underlying blood vessels and nerve endings, there is a layer of connective tissue; no special relationships between endocrine type cells and capillaries have been found.

DES cells localized in the epithelium are large, triangular or pear-shaped. They are characterized by light eosinophilic cytoplasm; secretory granules, as a rule, are concentrated on the basal surface of the cell or along the lower part of its lateral surface. In the upper part of the lateral surface, the epithelial cells are connected by tight junctions, which prevents the diffusion of secretory products into the lumen of the gastrointestinal tract, at least under physiological conditions. At the same time, bubbles are often found directly under the cell surface that faces the intestinal lumen. The exact functional significance of these vesicles is not known. It is very likely that they are a transport system, the direction of which will be established only in experiments with a labeled transport object or its predecessors. It is possible that these vesicles form on the surface facing the lumen of the gastrointestinal tract and allow the cell to absorb the contents of the lumen, including secretogenic ones; perhaps they originate from the reticulum (or even the lamellar complex).

All DES cells contain the endoplasmic reticulum, the Golgi apparatus, free ribosomes, and numerous mitochondria. It is most difficult to classify actively functioning cells, the granules of which are at different stages of the secretory conveyor and therefore differ in size, density, and content even in one cell. Features of the formation, maturation and disintegration of granules for each type of endocrine cells are individual, as well as the size and morphology of mature secretory granules.

All DES cells can be divided into two types according to the features of secretion: open and closed.

endocrine cells open type always with one end facing the cavity of a hollow organ. Cells of this type are in direct contact with the contents of these organs. Most of these cells are located in the mucous membrane of the pyloric part of the stomach and small intestine. The top of the cell is provided with numerous microvilli. In functional terms, they are a kind of biological antennas, in the membranes of which receptor proteins are embedded. It is they who perceive information about the composition of food, inhaled air and the end products of metabolism excreted from the body. In close proximity to the receptor complex is the Golgi apparatus. Thus, cells of the open type perform a receptor function - in response to irritation, hormones are released from the secretory granules of the basal part of the cells.

In the mucous membrane of the fundus of the stomach, endocrine cells do not come into contact with the contents of the lumen. These are endocrine cells. closed type. They do not contact with the external environment, but perceive information about the state of the internal environment and maintain its constancy by isolating their homons. It is believed that closed-type endocrine cells respond to physiological stimuli (mechanical, thermal), and open-type cells respond to chemical stimuli: the type and composition of chyme.

The response of cells of open and closed types is the release or accumulation of hormones. Based on this, we can conclude that DES cells perform two main functions: receptor - perception of information from external and internal environments of the body and effector - secretion of hormones in response to specific stimuli. Speaking about the paracrine and endocrine effects of DES hormones, we can conditionally distinguish three levels of their implementation: intraepithelial paracrine influences; effects in the underlying connective, muscle and other tissues; and, finally, distant endocrine influences. This suggests that each DES cell is the center of the paracrine-endocrine region. The study of the microenvironment of endocrine cells is essential for understanding not only the principles of hormonal regulation, but also for explaining local morphological changes under the action of various factors.

Returning to the analysis of the functional significance of DES, it should be emphasized once again that DES cells perform both receptor and effector (hormonal) functions. This makes it possible to express a new concept, according to which DES cells act as a kind of diffusely organized "sense organ".

The specific activity of DES is not limited to the regulation of external metabolism and the barrier function of epithelial tissues. Thanks to its hormones, it communicates with other regulatory systems of the body. Their analysis made it possible to formulate the concept primary response systems, alertsand body protection (SPROSO). Its essence lies in the fact that the entry of any substances from the external environment through the epithelium into the internal environment of the body and the removal of metabolites from the internal environment through the epithelial tissues into the external environment is carried out under the control of SPROSO. It includes the following links: endocrine , represented by DES cells; nervous , consisting of peptidergic neurons of the sense organs and the nervous system, and local immune defense, formed by macrophages, lymphocytes, plasmocytes and tissue basophils.

DES cell regeneration

Recovery processes that develop in DES cells after exposure to factors that lead to a sharp functional stress of the endocrine apparatus are characterized by the following spectrum of structural and functional reactions:

1. Activation of the secretory process. The transition of most endocrinocytes from a state of physiological rest to active secretion, which in itself is already one of the forms of a compensatory reaction, in some cases is accompanied by the implementation of an additional mechanism of secretion in the cells. At the same time, the formation and maturation of hormone-containing granules is carried out in the cisterns of the granular endoplasmic reticulum without the participation of the Golgi complex.

2. The ability of endocrinocytes to regenerate by mitosis. This reaction has not been sufficiently studied and remains unclear. No mitotic figures were found in the endocrine apparatus of the gastrointestinal tract under conditions of experimental and clinical pathology. Even with regard to the cells of the pancreatic islets, the most studied in this regard, there is still no single point of view. Since there are no cambial elements in the pancreatic islets, specialized cells undergo mitotic division. There is evidence that reparative regeneration of the islets during partial resection of the pancreas is carried out due to mitotic cell division.

3. Mitosis of cambial cells of the epithelial layer with their subsequent differentiation according to the endocrine type.

Conclusion

The production of vital chemicals by apudocytes determines their importance in the regulation of vital processes in normal and pathological conditions.

Since DES plays a significant role in the regulation of homeostasis, it can be assumed that the study of the dynamics of its functional state can be used in the future to develop methods for directed correction of homeostasis disturbances in various pathological conditions. Therefore, the study of DES is a rather promising problem in medicine.

Bibliography

1. Yu.I. Afanasiev, N.A. Yurina, E.F. Kotovsky. Histology (textbook). - M.: Medicine, 1999.

2. I.I. Dedov, G.A. Melnichenko, V.V. Fadeev. Endocrinology. - M.: Medicine, 2000.

3. APUD-system: achievements and prospects of study in oncoradiology and pathology. Obninsk, 1988

4. Physiology. Ed. K.V. Sudakov. - M: Medicine, 2000.

5. Yaglov V.V. Actual problems of DES biology. 1989, Volume XCVI, pp. 14-30.