Издательство ООО Сударыня - PARTIAL ANDROGEN DEFICIENCY AMONG AGING MEN Influence on the growth of metabolic syndrome and pathology of the prostate gland - Издательско-полиграфические работы в Санкт-Петербурге - Широкий спектр полиграфических услуг. Современное оборудование для всех стадий технологического процесса печати, допечатной подготовки и послепечатной обработки.
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St. Petersburg Medical Academy of Post-Graduate Studies
A.V. Pechersky
PARTIAL ANDROGEN DEFICIENCY AMONG AGING MEN Influence on the growth of metabolic syndrome and pathology of the prostate gland

Third Edition
St. Petersburg, Russia, 2007
Author – PhD, Senior Lecturer of the Department of Surgical Diseases of the St. Petersburg Medical Academy of Post-Graduate Studies A.V. Pechersky
Reviewers:
Head Urologist of the Health Committee of the City Administration of St. Petersburg, Russia, Head of the Department of Urology of the St. Petersburg State Medical Academy of I.I. Mechnikov, Professor B.K. Komyakov, MD, PhD;
Head of the urology course of the Medical Faculty of St. Petersburg State University, Professor A.I. Gorelov, MD, PhD

This monograph is written about an important modern medical problem – partial age-related androgen deficiency (andropause). The beakdown of tissue renewal among men of older age groups is analyzed as the main etiological factor of development of partial age-related androgen deficiency. The link between this pathology and the development of metabolic syndrome, malignant hyperplasia, and cancer of the prostate gland in men of older age-groups is shown in this book. A whole series of additions has been made to the third edition.
This textbook is meant for urologists, endocrinologists, oncologists, and doctors of combined specializations.

TABLE OF CONTENTS
List of abbreviations….5
Introduction...7
Breakdown of tissue renewal among people of older age groups as the main reason for development of partial age-related androgen defiency…….9
Change in adenohypophysis regulation among aging men with partial androgen deficiency.….50
Influence of a change in the level of testosterone on the activity of 5a-reductase, aromatase and the levels of cell growth factors…..54
Influence of partial androgen deficiency among aging men on carbohydrate metabolism....61
The influence of age-specific decreases in testosterone production on mineral metabolism.….67
The influence of partial androgen deficiency among aging men on the immune system…….70
Change in the expression of receptors of steroid hormone in the presence of partial androgen deficiency among aging mеn …77
Influence of partial age-related androgen deficiency on the impulse regime of incretion of several hormones………….84
The role of testosterone in regulating the expression of genes of several proliferation factors....91
Extragonadal testosterone production among aging men with partial androgen deficiency.……96
Role of partial androgen deficiency among aging men in the development of benign hyperplasia and prostate cancer...101
Diagnostics of partial androgen deficiency among aging men..…108
Methods for correcting partial androgen deficiency among aging men……112
Conclusion...124
Bibliography……129

LIST OF ABBREVIATIONS
ACTH - adrenocorticotropic hormone
AR - androgen receptors
BPH - benign prostatic hyperplasia
DNA – desoxyribonucleic acid
EGF - epidermal growth factor
ER - estrogen receptors
FSH - follicle-stimulating hormone
IGF-I, IGF-II – insulin-like growth factor I and II
IL-1α – interleukin-1α
IL-1β – interleukin-1β
IL-6 – interleukin-6
IL-7 – interleukin-7
INFγ – interferon-γ
LH - luteinizing hormone
PADAM - partial androgen deficiency of aging men
PCR method – polymerase chain reaction method
PR - progesterone receptors
PSA - prostate-specific antigen
PTH - parathyroid hormone
STH - somatotropic hormone
TGFβ - transforming growth factor-β
Th - T-helpers
TNFα - tumor necrosis factor-α
bFGF - basic fibroblast growth factor

Key words: adrenocorticotropic hormone, androgen blockade, globulin, benign prostatic hyperplasia, connecting genital hormones, 5a-dihydrotestosterone, epidermal growth factor, 17b-estradiol, follicle-stimulating hormone, insulin-like growth factor-1, insulin, interleukin-1α, interleukin-1β, luteinizing hormone, main fibroblast growth factor, pluripotent stem cells, prostate cancer, PSA, regeneration, somatotropic hormone, free testosterone, total testosterone, transforming growth factor-β, tumor necrosis factor-α

INTRODUCTION
Yurii Kerkis named the development of biochemical imbalance to be the main reason for age-related changes in older men in 1940. This imbalance is accompanied by a change in the correlation of the resulting products of physiological processes and reactions.
Support of the biochemical balance in the body is determined genetically, and is formed through the process of natural selection. Species with reproductive advantages are most fit for the fight for survival (Green N. et al., 1993), since they provide for the birth and growth of independent life for an adequate number of offspring. At the end of the reproductive period the parent individuals stop having any influence on the survival of the species; their fate becomes of no value to evolution. At this time the final stage of ontogenesis begins, which is outside the influence of natural selection. It is precisely in this period that we can observe the development of biochemical imbalance (including hormonal imbalance). Although people can keep their social function in their old-age, the period of optimal functionality for human reproduction, as set by evolution, ends at the age of 35-40 years.
Committed cell-precursors and differentiated cells can be divided a limited number of times (Alberts B. et al., 1994) and aren’t capable of ensuring regeneration of tissues during the whole process of ontogenesis. The renewal of tissues during the whole long period is impossible without the participation of a specialized system which is responsible for regeneration. The given system is made up of pluripotent stem cells which are capable of differentiating themselves into all types of somatic cells, and into a line of genital cells. These stem cells are also capable of reproducing themselves over the whole lifespan of the organism. The results of our research allow us to conclude that pluripotent stem cells make up a universal regeneration mechanism which was formed during the process of evolution.
After 40 years of age people show a reduction in their pool of pluripotent stem cells (Teplyashin A.S. et al., 2005). The reduction in intensity of processes of tissue renewal of endocrinal organs has a negative effect on these organs’ function. Men show a reduction in the amount of testosterone circulating in their blood. The latter phenomenon received the name partial androgen deficiency of aging men (PADAM)) (Bremner W.J. et al., 1983; Gray A. et al., 1991; Teplashin A.S. et al., 2005). A whole series of compensatory-adaptive reactions is formed in order to compensate for the lack of testosterone. This series of reactions affects endocrine, paracrine, and autocrine levels (Pechersky A.V. et al., 2003).
PADAM triggers abnormality in the mechanisms of regulation in the system of the gonads-hypophysis-hypothalamus, and in particular an increase in the activity of the hypophysis (Dilman V.M., 1973; Vermeulen A., Kaufman J.M., 1998). In the presence of PADAM the natural cycle of development of cells with androgen receptors breaks down. There is a compensatory increase in the formation of 5α-dihydrotestosterone, which has more affinity to the androgen receptor than does testosterone. The levels of 17β-estradiol and other factors which stimulate mitotic activity also increase (Pechersky A.V. et al., 2002; Pechersky A.V. et al., 2003), which leads to an increase in the risk of development of oncological pathology (Bershtein L.M., 2000; Lopatkin N.A., 1998; Puskar D.Yu., 2002).
A decrease in the testosterone level is accompanied by the development of a series of cardiovascular diseases (Neri R.O., Kassem N., 1984; Lund F., Rasmussen F., 1988; Micksche M., 1990).

BREAKDOWN IN TISSUE RENEWAL AMONG PEOPLE OF OLDER AGE GROUPS AS THE MAIN REASON FOR THE DEVELOPMENT OF PARTIAL AGE-RELATED ANDROGEN DEFICIENCY

Cells of any type can form in an adult organism from the ovule and cells of the embryo of mammals (up to the 8-cell stage). Activation of the ovule is a stage in the realization of the development program whose gradual unfolding leads to the formation of a new individual. The development program has a rigid order of biological processes through which each successive stage is initiated by the preceding stage. Any interference in the given process from the beginning of meiosis of the oogonium and spermatogonium to the formation of the adult individual will lead to a breakdown in the mechanism formed by evolution. For example, a breakdown in the above-mentioned order when introducing the nucleus of the differentiated cell into the cytoplasm of the ovule after eliminating its own nucleus (when cloning) makes it impossible for a full-fledged individual to develop.
The later separations of cells of the embryo of mammals (after the 8-cell stage) are accompanied by the beginning of their differentiation (Alberts B. et al., 1994). In parallel to the development of various organs and tissues one can also note the formation of structures which are responsible for their renewing. One of these structures is the formation of pluripotent stem cells. Pluripotent stem cells are formed when implementing the development program of the fertilized ovule, which is one of the pathways of differentiation of cells of the embryo.
Among vertebrates the majority of populations of differentiated cells are subject to renewal – these cells are constantly dying and being replaced by new cells. In some cases newly differentiated cells of the adult organism can be formed from simple doubling, whereby two daughter cells of the same type are formed (for example, hepatocytes). The final state of differentiation is incompatible with cell division in a series of tissues. Renewal of cells in these tissues can take place through cells of the cambial zone (for example, basal cells of the epidermis, spermatogoniums). Cambial cells are specialized cell-predecessors which can divide, yet already show the beginning signs of differentiation. They give descendants when being separated, part of which continues differentiation, while another part of which remains low-differentiated.
Committed cells-predecessors and differentiated cells, having started the differentiation pathway or having finished it, can divide a limited number of times (Alberts B. et al., 1994) and are not capable of ensuring tissue regeneration during the whole period of ontogenesis. Renewal of tissues over such a long period is impossible without the participation of a specialized system which is responsible for regeneration. The given system is represented by pluripotent stem cells, which are capable of differentiating themselves into all types of somatic cells and into a line of genital cells, and are also capable of renewing themselves over the whole life-cycle of the organism. The population of pluripotent stem cells is heterogeneous: cells with similar characteristics can be found according to data from a number of authors (Toma J.G. et al., 2001; Zuk P.A. et al., 2002; Teplyashin A.S. et al., 2005) when there is a primary localization of pluripotent stem cells in the bone marrow and in other derivatives of the mesoderm: in fatty tissue, in muscles, and in the heart and dermis. It’s possible that such a special organization of the system allows the system to be as effective as possible at supporting the processes for tissue regeneration, and is also connected to the possibility of separate parts of the process complimenting each other and being inter-replaceable.
Such a structure has self-regulation mechanisms which are typical of the system. The quantity of pluripotent stem cells and cambial cells-predecessors, as well as their ratio to differentiated cells is regulated by the macroorganism. The ratio of the given cells is determined by the concrete tasks of reparation. The cell has a set of molecules in its proliferate state which allow the cell to pass through the restriction point. These “molecules allowing separation”, which determine the proliferate state of the cell, are quickly broken down in the period of absence of serum, and are synthesized for a significantly longer time after serum is added (Alberts B. et al., 1994). The given factors, which are reversible with proliferation and rest, make it possible to integrate the cell into the integral organism. Outside the microorganism, without the presence of the organism’s constantly-changing regulatory factors, pluripotent stem cells are subject to death, which is proven by significant difficulties that arise when cultivating stem cells “in vitro”. From these positions one can state that the creation of constant lines of embryonal stem cells, which aren’t subject to aging in the culture in the absence of the regulating influence of the macroorganism, and which have lost their connection to the microorganism, is apparently related to certain genetic changes which bring the given cells closer to malignant ones. The use of such cells in clinical practice can be accompanied by an increase in the risk of development of carcinogenesis. Furthermore, attempts to receive pluripotent stem cells from embryonal cells which are programmed to implement the development program will be accompanied by a regular formation of teratomas, which has been proven by a whole series of researchers (Alberts B. et al., 1994). Pluripotent stem cells are a separate branch of differentiation of embryonal cells, and their formation is impossible outside of the developing embryo. Any attempts at reproducing the effects of regulatory factors “in vitro” for separate embryonal cells look to be unpromising considering the extreme difficulty at repeating the sequence of actions of regulatory factors of the development program.
In certain cases teratomas develop when cultivating the spermatogonium as they show signs of stem cells (Alberts B. et al., 1994; Krylova T.A. et al., 2005). The sporadic nature of the appearance of teratomas, apparently, is conditioned by the difficulty of the isolated separation of the spermatogonium. It’s likely that the make-up of cultivated cells is heterogeneous, and that one can’t exclude the possibility of the presence of cells which begin meiotic division (spermatocytes). The appearance of teratomas testifies to the fact that the development program is launched not from the moment when the ovum is fertilized, but from the beginning of meiosis. Considering that pluripotent stem cells and spermatogonium make up separate branches of the differentiation of cells of the embryo and that they are meant for executing various functions, then receiving full-fledged stem cells from spermatogoniums is unlikely.
The basal membrane, which underlies the epithelial layer, does not prevent the migration of a whole series of cells through the membrane, including macrophages and cells which support regeneration. Cells which keep their connection with the basal membrane also keep contact with the underlying connective tissue, which executes control over differentiation of epithelial cells.
Considering that dissociated cells are aggregated with cells of their own tissue more easily in the experiment, pluripotent stem cells, apparently, will aggregate with low-differentiated cells-predecessors of the cambial zone to a larger degree, thereby adding to their numbers. The following differentiation of cells in the cambial zone will promote replacement of old cells.
It’s likely that the differentiation process of stem cells is regulated by the development program: its according part is initiated by the cell environment during the migration of stem cells. Each cell of a many-celled organism contains a certain set of surface receptors which give it the possibility to react in a specific way to the complementary set of signal molecules, and which allow the cell to connect with in a certain way with other cells and with the extra cellular matrix. The given set of receptors represents a “morphogenetic code” which determines the organization of cells in tissues (Alberts B. et al., 1994). The strict sequence of the appearance of expression of receptors to cell growth factors and, perhaps, a similarly strict regulation of the formation (autocrinally or paracrinally) of cell growth factors at various stages of the differentiation of cells confirms the given conclusion. An example of such is the alternation of expression of receptors to various growth factors when differentiating T- and B-lymphocytes, as shown in the work by Roitt I. et al. (2000). The universality of the regeneration mechanism, which operates by means of pluripotent stem cells, is proven by the gradual replacement of the recipient’s cells with cells of the donor when transplanting stem cells of peripheral blood among the patients with sharp myeloblast leucosis, chornic myeloleukemia, or myelodysplastic syndrome after preliminary conditioning. For example, one year after transplantation, when comparing blood samples of the patient and his closest relative (mother), the material was found to be not consanguinity. Furthermore, when the blood groups of the donor and recipient don’t coincide then the blood groups of recipients one year after transplantation were always the same as that of the donor. Analogous data were received when studying the quickly regenerating cheek epithelium. In 6 cases the patients studied showed two types of cells in the cheek epithelium 1 year after transplantation of peripheral stem cells. These two types of cells had differing genotypes. Of these six cases, in 5 of them the share of cells in the cheek epithelium which belonged to the opposite sex to that of the recipient (the donor’s sex) equaled from 50% to 80%. And in one case all 100% of the cells in the cheek epithelium had a genotype that was not consanguinity to that of the recipient’s mother (Pechersky A.V. et al., 2007). Affirmation of the universality of the regeneration mechanism, which is done by means of pluripotent stem cells, is proven by long-term results of local radiation impact. Despite the atrophy of cambial cells the percentage of irreversible late radiolesions is relatively small. According to data collected by V.M. Vinogradov (2004), this percentage does not exceed 5%. Irreversible changes in the given zone can be prevented only by restoration of its cambial zones through migration of cells capable of making the according differentiation (stem cells).
The formation and regeneration of tissues, which are made by way of cell migration, make up a more difficult mechanism as compared with separation and detention of offspring of cells-founders in the epithelial layer. Formation and regeneration of tissues made through cell migration are widespread in nature, including various stages of ontogenesis in man. An example can be taken from mix-amoebas (Dictyostelium discoideum): eukaryotic organisms which live as separately moving cells. Mix-amoebas produce chemotactic substances when going hungry which attract other cells, and which turn into aggregation centers. Cell aggregation is completed by the formation of a many-celled worm-like creature – a plasmoid which may include as many as 100,000 mix-amoebas. One should note that the plasmodium, which is a transitional form from one-celled to many-celled organisms, is a chimeric individual that consists of cells with various genomes. Other examples come from cells of the primary mesenchyma of amphibians which enter the cavity of the blastula and which move along the wall, stretching on the long appendices-filopodiums released by them. In vertebrate embryos the cells of the nervous crib migrate from the epithelial (nerve) tube and are differentiated into a series of tissues, including elements of the peripheral nervous system. All components of the limbs among young vertebrate embryos (besides the epidermis) are produced by migrating cells. These cells should first finish their long journey through the embryonic connective tissue before reaching their destination and taking part in the formation of structures of the limbs. The formation of a chemical agent which attracts the migrating cells by way of chemotaxis and/or the formation of adhesive molecules of the fibrinonectin type, which determine the direction of migration, serve as the basis for cell migration (Alberts B. et al., 1994).
Chemotactic factors play a decisive role in the migration of stem cells (Roitt I., et al., 2000). The movement of mobile cells towards higher concentrations of nourishing substrates, for example sugars and amino acids, lies in the basis of chemotaxis. Apparently the above-mentioned nourishing substrates, which determine the direction of movement of one-celled organisms during hunger in many-celled organisms, acquire the role of signal molecules of chemotaxis. The zone of its influence expands quite quickly during the formation of a center of aggregation since the cells aggregated together not only respond to the chemotactic signal but also starts themselves to excrete analogous substances. The advantage of such a system for transferring the chemotactic signal comes from the fact that as the signal is distributed from the center it is constantly renewed, and doesn’t weaken at large distances. That said its concentration changes all the time. Unlike the given model, a signal dispersed by means of diffusion grows constantly weaker, and is permanent. Cells, in their movements, pick up the spatial gradients of various substances, focusing on exactly the changes in concentration of the chemoattractant, and not on its consistent size (Alberts B. et al., 1994). For this reason a many-timed re-translation of the chemotactic signal, accompanied by a change in its content in the medium, is more effective.
The reactions of natural immunity are initiated by a series of chemical structures, including end sugars of glycoprotein membranes containing end mannose. Under normal conditions end sugars are blocked by sialic acid, which defends cells from phagocytosis by macrophages. The defense of end carbohydrate remainders of glucoconjugate membranes is broken down in old cells as a result of desialation of the cell surface: free mannose appears. The given cells thereby become accessible for recognition. When macrophages come in contact with old cells they become active, and the first line of immune defense is engaged – the reaction of natural immunity. Inflammation – a phylogenetically older process – lies in their basis (Yarilin A.A., 1999).
Elimination of old cells by macrophages can be done both through phagocytosis and by means of extracellular killing: contact-induced apoptosis and the transfer of toxic material into cell-targets. Protein-perforin is a key factor of cell-directed cytolysis. Perforin permeates into the membrane of cell-targets together with participation of Ca++ and forms pores in the membrane for the penetration of granzines which launch apoptosis. Necrosis or apoptosis and the following lysis of the cell are accompanied by the development of demarcation inflammation. Necrotic processes (necrosis, apoptosis) take place over the course of all of ontogenesis as a manifestation of normal vital functions of the organism. Death and the breakdown of old cells with following regeneration is constantly taking place in the organism (Strukov A.I., Serov V.V., 1993; Yarilin A.A., 1999).
Products of incretion of macrophages, activated T-cells, and also epithelial and endothelial cells, and cells of the stroma of hemopoietic and lymphoid organs are very important for regulation of the development of inflammation. A special role is played by incretion of cell growth factors, colony-stimulating and chemotactic factors, and also interleukin (Yarilin A.A ., 1999).
The most well-known cell growth factors which regulate proliferation and differentiation of cells include epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), insulin-like growth factor I and II (IGF-I, IGF-II), transforming growth factor-β (TGFβ) and others (Alberts B. Et al., 1994). The specific combination of cell growth factors promotes proliferation of fibroblasts as well as proliferation and differentiation of low-differentiated cells-predecessors and stem cells which promote restoration of tissue defects at the same time as necrosis (or apoptosis) (Yarilin A.A., 1999). The specificity of regulation of differentiation made by the cell environment in the strict sequence of local formation of cell growth factors and the same strict regulation of the sequence of receptors which determined by the according part of the development program. Incretion of cell growth factors continues until the complete restoration of damaged tissue. Colony-stimulating factors serve as strong stimulators of hematosis, including increasing stimulation of pluripotent stem cells of the bone marrow with their sped-up transition into the bloodstream, while chemotactic factors ensure their directed migration for regeneration of damaged parts of the tissue.
Activated macrophages and monocytes in the area of inflammation increte IL-1 (α and β forms), and tumor necrosis factor-α (TNFα). Tumor necrosis factor-α not only leads to apoptosis of cells, but is also capable of activating lipoprotein lipase in cells-targets, which can lead to cachexy. Under conditions of inflammation endothelial cells and fibroblasts increte IL-7, which leads to expression of the gene bcl-2. Expression of genes which increase the resistance of cells to the death under the apoptosis mechanism, which allows cells to remain under the influence of highly-active products which are formed under inflammation (Yarilin A.A., 1999).
Molecules of the major histocompatibility complex (MHC I class) are connected and represented on the surface of cell by peptide fragments of endogenous proteins. The formation of the complex of the antigenic peptide with the MHC I class molecule is a continuously flowing process. Of the presented peptides, 90% are common for the majority of various cells of the organism (due to the great number of biochemical processes which are common for all cells, and, respectively, for the majority of common identical proteins (Alberts B. et al., 1994)) and 10% are differ between them (Yarilin A.A., 1999). Apparently the majority of the differing peptides of various cells reflect tissue- and cell-specific information. It’s interesting that the share in their make-up of foreing peptides is very small (about 1%).
The majority of the given peptides come from signal sections of proteins and the very molecules of the MHC I class. Regulating the composition of the given antigens during processing in endosomes, the cell determines the character of the interaction with other cells which have complimentary receptors. The given mechanism promotes integration of each separately-taken cell in the integral organism. It’s natural that a series of chemoattractants, which are molecules of the MHC I class and which have tissue- and cell-specific behavior, ensure the directed migration of stem cells into strictly determined tissues, such as, for example, according to data from I. Roitt, et al. (2000), into the thymus.
The directed migration of pluripotent stem cells is impossible without the formation of specific chemoreceptor. Their appearance should be preceded by a series of interim stages. At first the antigens must be bound together and delivered into lymphatic nodes or other lymphoid organs by antigen-presenter cells. This stage is caused by the desialation of glycoproteins in old and intensively proliferating cells which contain end mannose. Antigen-presenter cells conduct endocytosis of the antigen. There is fragmentation of proteins in endosomes or lysosomes (the whole protein molecule can’t be identified by the T - lymphocyte without processing by helper cells). Endosomes, which contain peptide antigens, are joined with endosomes which contain “empty” (not containing antigen peptide) molecules of the MHC II class. Trimerous complexes of molecules which form as part of the MHC II class and antigen peptides are lifted to the surface of cells as part of the membranes of the endosomes. Antigen-presenter cells lose their ability to connect new antigens during processing of the antigen; an expression of helping molecules CD 80/86, which take part in the presentation of the antigen peptide to T-helpers, appear on the their surface (Yarilin A.A., 1999).
Lymphocytes are connected to endothelial cells of postcapillary venules in secondary lymphocyte organs, and come through between endothelial cells and go through the gland into the lymphatic vessels (Alberts B. et al., 1994). Such a constant circulation ensures the meeting between lymphocytes and antigen-presenter cells, and, through their mediation, makes it possible to ensure contact of T-helpers with T-killers and with pluripotent stem cells, with the formation of the according receptors in them.
The quantity of constantly-dying according cells is significantly higher than the number of microorganisms which enter into the inner medium of the organism. It’s interesting that molecules of the MHC II class most of all form complexes with autologous peptides (with products of the MHC I class and other proteins): 90% of them are common to the majority of various cells in the organism, while 10% vary amongst each other and only 1% of the latter are made up of foreing antigens. The presentation of 99% autologous peptides by molecules of the MHC II class (Alberts B. et al., 1994) testifies to the following formation of a significant share of complimentary receptors to precisely autoantigens.
Binding together of T-helpers with the complex of antigens – molecules of the MHC II class of the antigen-presenting cell with the participation of helper molecules leads to activation of T-helpers. The base of T-cell recognition is immunodominance – the dependence of activation of receptors of T-cells on the relationship of the antigen peptide to the MHC molecule (the degree of difference of the antigen from the organism’s own molecules). Ir-l gene control of the character and intensity of the immune response to antigens is done through this mechanism. The predominance of autoantigens during the formation of complexes with molecules of the MHC II class testifies to the fact that T-cells more often have to identify “the changed one of their own”, and significantly less often have to identify the “outsider” (Yarilin A.A., 1999). Apparently identification by T-helpers of “the changed one of their own” can lead to activation of not only T-killers, but also to activation of pluripotent stem cells (with the formation of specific receptors for antigens presented by molecules of the MHC I class) for simultaneous (with destruction of the changed cells) reparation of the damaged part of the tissue. The ratio of types of activated cells is determined, perhaps, by the degree of difference in the presented antigen from its own molecules.
The activation of pluripotent stem cells with the formation of complementary receptors, apparently, is also made by means of antigen-presenting cells. The likelihood of a meeting of T-helpers and pluripotent stem cells (during their constant circulation through secondary lymphoid organs) with antigen-presenting cells is considerably higher as compared to the possibility of contact between them themselves. It would seem, by analogy with the process for activation of cytotoxic T-cells, that the next stage should be the rendering by T-helpers (through the T-cell receptor and the molecules of the MHC II class with the presented antigen along with participation of helping molecules and interferon γ) of an activating effect on the antigen-presenting cells. The activated antigen-presenting cells receives the possibility through the MHC II class molecule with the antigen (by analogy to the interaction with T-cell receptor of the cytotoxic T-cell) to connect with the receptors of the pluripotent stem cells with the succeeding formation of the tissue-specific receptors on its surface. That said the cytotoxic cells and, apparently, the pluripotent stem cells, receive helping molecules of adhesion and inter-cell interaction (expression of the adhesion molecules CD 2, CD 58, integrin receptors ICAM-1, and others), which provide solid contact with the cells-targets. The appearance of tissue-specific “homing-receptors” determines the pathway of migration of lymphocytes (Yarilin A.A., 1999) and, perhaps, of stem cells to the places of inflammation, including the places of death of old cells. T-suppressors (Ts) can regulate the given processes. The main cells-targets of T-suppressors are T-helpers. Activation by T-helpers (Th1) (through the mediation of antigen-presenting cells) of cytotoxic T-cells is accompanied by the paracrine and autocrine formation of IL-2. Among other functions, IL-2 is capable of guarding activated cells from apoptosis. Thus, activated T-killers have expression of the bcl-2 gene and several other analogous genes.
Simultaneously, expression of the Fas-receptor appears on T-lymphocytes and on antigen-presenting cells, through which the signal that induces apoptosis enters the cell. All of the given changes in the expression of membrane molecules are characteristic of memory T-cells being formed. These cells are a variety of effector T-cells. The balance of the expression of Bcl-2 and that of the Fas-receptor determines the fate of these cells: the fast death of effector cells after the execution of their functions or the prolonged life-span of memory cells. It’s important that cells require repeat contact with the specific antigen in order to support the expression of the bcl-2 gene. For example, memory T-cells die quite quickly in a medium which doesn’t contain the according antigen (Yarilin A.A., 1999).
Apparently the expression of the bcl-2 gene also allows it to avert the development of apoptosis of stem cells which migrate into the regeneration area after the contact with T-helpers mediated by antigen-presenting cells. Intensification of bcl-2 gene expression among committed stem cells take place when these cells migrate between endothelial cells, which produce IL-7, in the space between cells. The expression of the gene bcl-2 makes it possible for stem cells, which are quite sensitive to unfavorable conditions in their environment, to survive under conditions of the effect of highly active products (active forms of nitrogen and oxygen, TNFα, INFγ and others), which form, in particular, during the death of older cells and the development of the accompanying inflammation.
In accordance with the theory of clonal selection each stem cell, which is committed to producing one certain antigen-specific chemoreceptor, should form a family of clone of cells which have identical antigen specificity, analogous to cells of immunological memory. For pluripotent stem cells this is a step towards unipotency. In this case even a single antigen determinant will, as a rule, activate many clones, each of which will have surface receptors which have their own special, individual relation to the given determinant (Alberts B. et al., 1994).
Apparently, when using preparations made from various animal tissues, man has at least several clones of stem cells which carry complementary receptors to the common fragments of tissue-specific peptides of xenogeneic preparations. Binding of the antigen with the receptor leads to intensive proliferation of the according clone of stem cells. The directed migration of stem cells in the tissue, the cells of which contain tissue-specific peptides that are complimentary to their receptors in the complex with molecules of the MHC I class, will promote stimulation of regeneration of the given tissues. For example, in an experiment on rats with cross circulation damage to the liver in one of them lead to simulation of processes of liver regeneration for both animals (Alberts B. et al., 1994); a whole series of widely-used preparations made from various tissues of animals (the liver, prostate, cartilage, cornea, and others) stimulates regeneration of the according tissues in man (Mashkovsky M.D., 2002).
The formation of chemoattractant, which include antigens of the MHC I class, and the formation among pluripotent stem cells of receptors complimentary to them (through presentation of autoantigens by molecules of the MHC II class), looks to be the most suitable explanation of directed migration of pluripotent stem cells to certain cells and tissues.
The participation of pluripotent stem cells and the possible mediation of antigen-presenting cells and T-helpers/T-suppressors in the complex with molecules of the MHC I class/II class make it possible to suppose that exactly this immune system is responsible for regeneration of tissues in the organism. The signification prevalence of autoantigens (99%) among peptides represented by molecules of the MHC II class, as well as the significant prevalence of sub-populations of CD4+-lymphocytes (helpers) over CD8+-killers in the blood and the lymph shows that participation in the regeneration process is the most important (and perhaps the leading) function of the immune system.
It’s likely that after transplantation of any type of allogenic (or, theoretically, of xenogenic) organ a gradual process of replacement of donor cells with stem cells of the recipient begins, with their subsequent differentiation. In this case the cell environment of the donor’s organ conducts the direction of differentiation of the stem cells entering the organism. The given model may turn out to be simpler than attempts to grow tissues “in vitro”. One can approximately judge the intensity of replacement of the cells of the donor’s organ with the recipient’s cells based on the speed at which tissues are renewed in normal conditions. For example, the speed of renewal of bone tissue equals about 10% per year (Alberts B. et al., 1994). Inhabitation of the thymus by stem cells is necessary not only for the subsequent formation of T-cells, but also for keeping the epithelium of the thymus in a normal functioning state – for formation of the epithelial reticulum and the cortico- medullary structure of the thymus in ontogenesis (Yarilin A.A., 1999).
Epithelial cells of the thymus make up a microenvironment for developing thymocytes and serve as sources of signals which are generated under direct cell contacts. Interaction of molecules of the MHC II class of epithelial cells and receptors of T-cells serve as the base for these contacts, as well as participation of helping molecules. Molecules of the MHC II class play a leading role among epithelial cells in the process of positive selection of thymocytes, and in the process of negative selection of thymocytes among macrophages and dendritic cells (Yarilin A.A., 1999). Cells of the microenvironment of the thymus transfer information to T-lymphocytes on antigens of their own tissues during the process of the given contacts, as well as, apparently, form for them the type of response to the presented antigens. The latter is more important when separating antigens of a cell damaged by a virus or of foreign tissue (with activation of T-killers to a greater degree) from autoantigens of dead, old cells (with the subsequent activation of pluripotent stem cells with the formation of tissue-specific receptors for directed migration and renewal of tissues).
The constant renewal of the thymus’ own cells through stem cells with the subsequent transfer of information from newly-formed cells of the microenvironment of the thymus to T-lymphocytes and their subsequent selection makes it possible to constantly renew data about T-lymphocytes’ own antigens. Considering the evolution of the genome – its gradual development and perfection as a result of various genetic recombinations (Alberts B. et al., 1994) (and, accordingly, of changes in autoantigens), the given mechanism ensures the according synchronous changes in the immune system throughout ontogenesis, and also makes it possible to keep a unity of changes taking place for the majority of tissues in the organism (thanks to their simultaneous renewal by cells with the new characteristics).
When transplanting allogenic pluripotent stem cells epithelial cells of the microenvironment of the thymus will form, among other ways, from transplanted cells. Accordingly, T-lymphocytes will additionally start to view the donor’s antigens as “their own” during the study process. The given pattern, apparently, determines the development of immunological tolerance, which, according to a number of authors (Alberts B. et al., 1994), develops during transplantation of tissues or organs after preliminary blood transfusions (or transplantation of pluripotent stem cells/bone marrow) from a single donor, as well as after preliminary transplantation of cells of the embryo in the experiment.
Blood transfusion (or transplantation of stem cells/bone marrow, or cells of the embryo), apparently leads to formation of a chimeric individual. The given individual, in particular, will have two types of pluripotent stem cells with two various genotypes. The subsequent migration of stem cells of these two types into the thymus and the renewal of its own cells of the microenvironment will lead to formation of T-lymphocytes which view both antigens of their own organism and those of the donor as “their own”. The lack of a rejection reaction among patients 1 year after transplantation of stem cells of peripheral blood to cheek cells of the epithelium in 50% - 100% of all cases having the genotype of the donor proves this conclusion (Pechersky A.V. et al., 2007). Theoretically the chimeric recipient can be given any tissues or organs from the original donor without risk of later rejection.
The notion of the immortality of pluripotent stem cells – their ability to divide any number of times – is relative to a significant degree. The proliferate behavior of cells over the whole period of ontogenesis is managed by long-term inner-cell programs. The interactions between long-term and short-term control mechanisms are determined, apparently, by the development program, which is implemented through cell growth factors, colony-stimulating factors, and products which form under the expression of proto-oncogenes and other factors. For example, the speed of cell division and the number of divisions needed by the pluripotent stem cell before the beginning of differentiation depends on the various combination of colony-stimulating factors. The likelihood of transition to a state of calm (G0) is increased with the number of cell divisions. The cells of many-celled organisms of many types transition to the state of G0 as a result of final differentiation, thereby losing their ability to divide independently from external stimuli (Alberts B. et al., 1994). With age the quantity of cells which according to marking data can be considered to be pluripotent stem cells, gradually decreases (Teplyashin A.S. et al., 2005). The presence of long-term inner-cell programs testifies in favor of the fact that the development program not only leads to the formation of an adult individual, but also determines this individual’s development over all of ontogenesis. Several million new cells should be formed each second in order to support the organism in a normal state (Alberts B. et al., 1994). That said each second there is necrosis (or apoptosis) of a similar number of old cells which leads to a multitude of local areas of inflammation. Among older persons the necrotizing old cells are not replaced by an adequate number of low-differentiated cells-predecessors (or stem cells), which makes it impossible to finish the regeneration process. Considering that the solidity of the cell population is directly proportional to the concentration of growth factors in the medium, this category of people show a compensatory increase in the formation of cell growth factors (for stimulation of proliferation of low-differentiated cells of the cambial zone) and an increase in the formation of colony-stimulating factors (for stimulation of proliferation of pluripotent stem cells). Production of the given factors in order to have as additional a stimulating effect on proliferation of cells. Accordingly, one can note an increase in the expression of proliferation factors among people of older age groups (Ki67 and others) in the majority of tissues (Pechersky A.V. et al., 2005), as well as an increase in the share of committed forms of stem cells of the bone marrow (Teplyashin A.S. et al., 2005).
The increased production of growth factors among people of older age groups doesn’t lead to the formation of an adequate quantity of cells-predecessors which can provide a replacement for dead, old cells. Furthermore, with age the quantity of cells of the cambial zones only decreases. Thus the given stimulation increases as a person’s age increases, and becomes constant.
The given changes are naturally accompanied by development of a constantly-raised expression of genes of the according growth factors and their receptors; thus there is a transformation of proto-oncogenes which are responsible, under normal conditions, for separation of cells in response to the action of growth factors, into oncogenes. For example, the oncogene erbB begins to code the pared-down variant of the receptor of the epidermal growth factor (EGF). The given receptor loses its EGF-conjunctive external domain, but keep its inner-cell domain with tyrosine-specific with protein kinase activity. Cells with such defective receptors behave themselves in such a way as if some signal from epidermal growth factor for proliferation is constantly acting on them (Alberts B. et al., 1994).
One should note that the compensatory transformation of proto-oncogenes into oncogenes, when there is a long absence of the effect on the regulating signal, is a particular example of the overall reaction of the organism in such situations. For example, when there is stenosis of the renal artery over a long period of time, there is then hypertrophy of cells of the juxteglomerular apparatus (with an increase in them of the quantity of increting granules), accompanied by the maximum formation of renin; production of the hormone becomes non-regulated. The retention of high intensity of renin production by transformed cells after eliminating stenosis testifies to accompanying genetic changes (Tareeva I.E., 1995). Epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), insulin-like growth factors I and II (IGF-I, IGF-II), as well as a series of other factors all have expressed mitotic activity and are promoter factors of carcinogenesis (Bershtein L.M., 2000). The constantly increased levels of cell growth factors, which stimulate proliferation of cambial cells, blockage of the development of apoptosis (caused by expression of the gene bcl-2 among committed stem cells after activation by T-helpers, as well as cells of the cambial zone which form in the process of their differentiation), and the transformation of proto-oncogenes into oncongenes can lead to metaplasia (and in the future to their malignant transformation).
Metaplasia is indirect and begins after reproduction of cambial cells which are changed under the influence of the above-mentioned factors, and which differentiated into a new type of the epithelium (for example, into keratinizing flat, instead of prismatic) (Strukov A.I., Serov V.V., 1993). Analogously to clonal selection of lymphocytes, each changed non-differentiated cambial cell forms a family which gives metaplasia cells their start.
An increase in the deficit of pluripotent stem cells and the according decrease in the number of cambial cells of the tissues in people of older age groups is accompanied by an increase in the intensity of formation of cell growth factors and the development of the expression of an even greater number of oncogenes, which lead to the appearance of new, changed to a greater degree, non-differentiated cambial cells. Considering the scale of the above-mentioned changes, which take place in the majority of tissues, the risk of carcinogenesis increases with age. Under these conditions the development of a cancerous growth is a pre-determined process. The concrete localization of the tumor and the time it takes to appear will depend on separate initiating factors and the individual particularities of the individual. The given conclusion is proven by data collected by A.I. Strukov and V.V. Serov (1993) on the possibility of the appearance of a tumor in any tissue and in any organ.
Thus malignant growth of the epithelium is caused by long-term increased stimulation of mitotic activity of non-differentiated cells of the cambial zones as a result of an insufficient amount of the latter. Despite the increase in compensatory stimulation, the inadequacy of cambial cells progresses with age.
It’s likely that just one division of malignant cells is not enough to ensure progression of growth of the tumor. Stem cells, which constantly supplement the cell composition of the cambial zone, apparently continue to enter the zone with changed cambial cells (metaplased or cancerous cells), transforming themselves into these others under the influence of the cell environment. Data from a series of authors (Strukov A.I., Serov V.V., 1993; Alberts B. et al., 1994) about the beginning of intensive growth of the tumor after the beginning of its vascularization, making it possible to significantly increase the flow of stem cells into this area, as well as to expose stem cells and cells-predecessors among cells of malignant tumors, confirm this conclusion.
The malignant transformation of cambial cells, which increases the number of their divisions, is aimed at compensation of a chronic lack of cambial cells and of pluripotent stem cells among people of older age groups. This conclusion is proven by the similarity of malignant cells to stem cells, for example the appearance among them of embryonal antigens (Strukov A.I., Serov V.V., 1993).
The factors studied, which are formed during the death of old cells and at the same time as inflammation takes place, apparently not only lead to malignant transformation of cells, but also to future growth of the tumor. For example, along the periphery of the tumor there continues to be a zone of perifocal (demarcative) inflammation. Among other cells in this zone, there are macrophages, which fulfill the role of local regulators of inflammation (Strukov A.I., Serov V.V., 1993; Serov V.V., Paukov V.S., 1995). Analogously to osteoclasts (forming from monocytes and being a variety of macrophages), which destroy the bone matrix when renewing the bone tissue (Alberts B. et al., 1994), macrophages of the zone of perifocal inflammation, separating hydrolytic enzymes, lyse the surrounding tissues (they destroy the endothelium, basal membranes, fibronectin, collagen, elastin, the bone matrix, and other structures), freeing space for tumorous cells. The accumulation of cytokinins, which have growth activity in relation to cells of the endothelium (vascular growth factor, and others, increted by macrophages), determine their proliferation and the formation of new vessels – angiogenesis. The endothelium in turn produces IL-1, basic fibroblast growth factor, and platelet-derived growth factor under conditions of inflammation, thereby strengthening proliferation, as well as IL-7, which leads to expression of the gene bcl-2. Expression of the gene bcl-2, which increases the resistance of cells to death under the apoptosis mechanism, screens the endothelium and migrating stem cells from highly-active products which form during inflammation (Yarilin A.A., 1999).
An important component of inflammation is necrosis, which develops as a result of thrombosis of the vessels around the inflamed part of the tissues. Adaptive changes of the endothelium in the region of the inflammation are accompanied by inner and outer-vessel coagulation of fibrinogen and the formation of the thrombocyte thrombus. Coagulation factors are expressed and adhere on the surfaces of the activated endothelium, thrombocytes, and leucocytes, thereby leading to the development of fibrin (Alberts B. et al., 1994; Serov V.V., Paukov V.S., 1995). Thus tumors are often subject to necrosis and pitting (Strukov A.I., Serov V.V., 1993). Considering the fact that the regeneration process is not yet completed during necrosis of old stells in the majority of tissues and according local areas of inflammation among people of older age groups, the risk of the development of thrombus increases.
During mitosis cells are rounded and lose their solid link with one another (due to the reduction in cell adhesiveness and the loss of focal contacts), which seriously breaks down the integrity of the tissue, which is made up of such cells (Alberts B. et al., 1994). For this reason metastasis begins more quickly among tumors with the greatest intensity of separation of malignant cells. The direction of the metastasis of malignant cells (Strukov A.I., Serov V.V., 1993) is determined by the according tissue-specific receptors on their surface. The given status testifies in favor of the fact that malignant cells, which cover the deficit in pluripotent stem and cambial cells, acquiring similarity with pluripotent stem cells, repeat the pathway and mechanisms of migration of stem cells during metastasis. The formation of specific receptors on the surface of tumorous cells should be preceded by the bond of T-helpers with complexes of the antigen (products of MHC I class and other peptides of dead cells) - molecule of the MHC II class on the surface of antigen-presenting cells in secondary lymphoid organs, activation of T-helpers, and the subsequent (through the mediation of antigen-presenting cells) interaction of T-helpers with tumorous cells.
Apparently, activation by T-helpers of malignant cells with the formation of tissue-specific receptors on their surface (complimentary to specific antigens of the molecules of the MHC I class of old and dead cells) is accompanied by the beginning identification as these cells as “their own” together with simultaneous (with the help of T-suppressors) suppression of the response of cytotoxic cells to the tumorous antigens. The given processes can be lead to development of the failure of the immune response in the case of tumors. The appearance of “homing-receptors” determines the migration pathways of malignant cells into a certain zone of inflammation on the place of the death of the old cells. The predominance of death of old cells over the processes of regeneration in the majority of tissues of people of older age groups, and the appearance of tissue-specific chemoattractants (as which molecules of the MHC I class serve) determine the potential regions of metastasis. In accordance with the theory on clonal selection, each malignant cell, committed to the production of one certain antigen-specific chemoreceptor, should form a family or clone of cells which have identical antigen specificity. In order for there to be contact of malignant cells with T-helpers these cells must constantly circulate through secondary lymphoid organs. Tumorous cells are attached to endothelial cells of postcapillary venules, and are come through between them and fall through the gland into lymphatic vessels and further through the according groups of glands and vessels into the thoracic duct, through which they return to the blood. Apparently the given circulation takes place constantly, leading to dissemination of the tumor.
In an analogous way, the long-running inflammatory process may lead to malignant transformation of tissues. The long-term effect of alteration factors, the death of a large number of cells, the reciprocal stimulation of proliferation of cambial cells due to an increase in formation of cell growth factors, as well as the blocking of the development of apoptosis become the main pathogenetic factors of malignant transformation. The malignant degeneration of chronic ulcers of the stomach, the mucus cavity of the mouth (among people with a chronic bite) and other examples (Napalkov N.P., 1989) confirm the given conclusion.
Under conditions when death of old cells predominates over regeneration processes among people of older age groups, then, apparently, formation of both pluripotent stem cells of the bone marrow and stem cells of the fatty and several other types of tissue is stimulated. It’s possible that the appearance of adipose tumors in a series of organs, which do not normally contain adipocytes (for example, the formation of adipose tumors in the kidneys) is caused by a compensatory migration of stem cells, as well as by their committed forms, from fatty tissue. Transformation into adipocytes of fibroblasts related to them (Alberts B. Et al., 1994), apparently, would lead to fatty degeneration of tissues (such as, for example, under metabolic syndrome). The involvement of fatty tissues in the compensation processes leads to an increase in the tissue’s mass (Pechersky A.V. et al., 2006).
When tissue is damaged cell growth factors, acting in various combinations, selectively regulate the proliferation and differentiation of each of the many-numbered cell types of the high animals (Alberts B. et al., 1994). Under conditions of a lack of pluripotent stem cells, and, consequently, of cambial cells in the region of necrosis (or apoptosis) and the impossibility of completing the regeneration of the given piece of tissue, cell growth factors will increase, leading to intensive proliferation of fibroblasts. In these conditions the quantity of fibroblasts will be significantly higher than the quantity of cambial cells, leading to formation of a scar. The ratio of cambial cells and fibroblasts determines the intensity of the scar tissue. Apparently, under migration of an adequate number of stem cells and the formation of an adequate number of cambial cells, the area of necrosis (or apoptosis) may renew itself completely without the development of fibrous tissue.
The data received in the study prove this conclusion. We observed a reliable decrease in the width of the papillary and reticulate sections of the dermis among people of older age groups as a result of the breakdown in the regeneration process, as well as a reduction in the size of hair follicles, the average quantity of cambial epithelial cells of the matrix of the hair bulb and endothelial cells of blood capillaries. The average quantity of fibroblasts was higher in people of older age groups due to the intensive stimulation by cell growth factors, while part of the hair follicles were replaced by scar tissue (Pechersky A.V. et al., 2007).
The systemic character of the changes taking place in people of older age groups is proven by the development of atrophy and fibrous changes in other tissues and organs. In particular, among men one can note atrophy of the testicles, which shows itself through the development of fibrosis of the basal membrane of tubular testicles, the reduction in the quantity of Leidig cells, and other changes. Atrophy is developed in other endocrine organs as well, for example one can see a reduction in the size of the hypophyis (Dedov I.I., Kalinchenko S.Yu., 2006). Involution changes of the aging kidney are expressed by a reduction in its mass and volume, and by progression of the accretion of joining-tissue components. After 40 years of age there is sclerosis of about 10% of the nephrons each ten years (1% per year) (Tareeva I.E., 1995). The overall mechanisms of regeneration, which depend on the quantity of the pool of pluripotent stem cells and the speed at which this pool decreases with age, determine the equal intensity of sclerosis of the majority of tissues among people of older age groups. The rate at which the general testosterone level decreases among aging men: 0,4 – 2,8% per year (Dedov I.I., Kalinchenko S.Yu., 2006) accord to these values of the intensity of sclerosis of tissues.
The age involution of the thymus is accompanied by a decrease in its mass, as well as by the replacement of the epithelial compartment by joining tissue and fibroblasts products - adipocytes. After 50-60 years one can observe a decrease in the number of T-cells in the blood and organs (to a greater degree of T-helpers). The age-related decrease in T-helpers may have a negative effect on the formation of tissue-specific receptors of pluripotent stem cells and, consequently, on the regeneration process. Among populations of thymocytes the most reduction effects comes on the quantity of immature cortical CD4+CD8+. Nevertheless, there continues to be constant release of bone-marrow predecessors into the thymus, and mature T-cells continue to emigrate from the thymus, although the intensity of this process decreases (Yarilin A.A., 1999). The age-related decrease in pluripotent stem cells has a negative effect not only on the settlement of the thymus with lymphoid elements, but also on the support of the normal functional status of the epithelium of the thymus – on the formation of the epithelial reticulum and the cortico-medullary structure of the thymus.
Nervous tissue has a series of particularities. Unlike neurons, which can’t divide after differentiation, the majority of neuroglial cells keep their ability to divide over their whole life (Alberts B. et al., 1994). As differentiated cells they have a limited number of divisions, and, consequently, need replenishment of their numbers over the whole period of ontogenesis. Apparently the age-related decrease in pluripotent stem cells will also lead to a breakdown of the renewal process of the given cells with activation of macrophages (microglials).
During embryonal development immature neurons which don’t form axon and dendrites migrate from their birthplace to radial glial cells. Neurons are layered in the cortex of the brain in accordance with the succession of their migration. Cells which formed later migrate further then cells which formed earlier. Radial glial cells direct migration of neurons, and are kept in the majority of areas of the head and spine until the end of the development period. They disappear after the laying of the main nervous structures, and aren’t kept almost anywhere in the mature nervous system (Alberts B. et al., 1994). The size and volume of the brain in man increases by several times from birth to it’s the brain’s final formation. In particular, the thickness of the cortex equals only 20% at birth of the final size of the brain achieved later in life (Klossovsky B.N. et al., 1977). Apparently, the post-natal development of the central nervous system is also connected to migration of stem cells. It’s possible that the migration of stem cells continues over the whole of ontogenesis with the aim of renewing the structures of the central nervous system. In this case fragments of the dead neurons (which carry, in particular, molecules of the MHC I class, for a certain cell) can become chemoattractants which allow stem cells which are migrating and which have begun differentiation to reestablish the prior links of dead neurons. Considering the commonness of malignant pluripotent stem cells, the metastasis into the brain of malignant tumors of other localizations serves as an indirect proof of the renewal of the structure of the central nervous system through migration of stem cells.
One must note that age-related changes of the brain are in many ways analogous to age-related changes of other organs. Senile (pre-senile) dementia is connected to progressing atrophy of the brain. The illness is caused by cerebral amyloidosis, which is found in 100% of all cases. The illness is often accompanied by arthrosclerosis and type II diabetes, which are initiated by the age-related decrease in production of sex hormones to a significant degree (Pechersky A.V. et al., 2003; Pechersky A.V. et al., 2006). Just as in the above-illustrated examples of age-related changes, the leading role in pathogenesis of amyloidosis belongs to activation of macrophages, which in turn activate a whole series of cells, including fibroblasts and endotheliocytes. Activation of the given cells is accompanies by production of protein by the fibril of the amyloid. The resorption of the amyloid (amyloidoclasia) is found extremely rarely (due to the lack of methods capable of creating a backwards development of the processes which led to the disease) among local forms of amyloidosis and is caused by phagocytic activity macrophages (Strukov A.I., Serov V.V., 1993).
The reduction in the intensity of the processes for renewing tissues of the endocrine organs has a negative influence on their functions. One can observe a decrease in the levels of a series of increted hormones (testosterone, somatotrope hormone, and others) (Dedov I.I., Kalinchenko S.Yu., 2006). The reduction in testosterone production leads to the appearance of so-called partial androgen deficiency of aging men (PADAM), and initiates the development of metabolic sybdrome (X-syndrome) to a significant degree (Pechersky A.V. et al., 2003; Pechersky A.V. et al., 2006). At the same time the high compensatory capabilities of the central nervous system help ensure keeping stereotypical reactions of its structures. For example, an increase in the level of somatotrope hormone under the increased formation of estrogens (Lavin, 1999) can be found in people of older age groups despite the reduction in the size of the hypophysis. After making orchidectomy among men as concerns prostate cancer the according increase in estrone is accompanied by an increase in the level of somatotrope hormone (Pechersky A.V. et al., 2003).
The age-related decrease in testosterone production has a significant influence on factors of the extra-cell environment which regulate cell aging. Apoptosis develops in cells of normal mouse embryos (which are capable of division in the according conditions without signs of aging) when adding the blood serum of an older individual (Alberts B. et al., 1994). Some of the leading inductors of apoptosis are glucocorticoids and tumor necrosis factor-α (TNFα), (Yarilin A.A., 1999); their levels increased under PADAM (Pechersky A.V. et al., 2003; Pechersky A.V. et al., 2006).
Ca++ takes part in the activation of phagocytes, in the perforin-dependent cytolysis mechanism, and in the formation of nitrogen oxide (which causes, to a significant degree, bactericidal activity of phagocytes). Mg++ takes part in the alternative activation of the compliment (Yarilin A.A., 1999). The increase in levels of Ca++ and Mg++ in the blood serum among patients with PADAM can be seen as a component of the immune system response to the increase in proliferation activity (Pechersky A.V. et al., 2003; Pechersky A.V. et al., 2006) and the increase in the number of old cells.
Ca++ and Mg++ take part in the differentiation of cells and the spatial organization of tissues, having an influence on the mechanisms for inner-cell adhesion (Alberts B. Et al., 1994). The given functions are important under conditions of increased stimulation of cells of the cambial zones among people of older age groups.
PADAM breaks down the development of cells with androgen receptors. A whole series of compensatory-adaptive reactions takes place in order to compensate for the inadequacy of mytogenic action of testosterone. These reactions concern endocrinal, paracrinal, and autocrinal levels (Vasilyev Yu.M., 1997; Bershtein L.M., 2000; Pechersky A.V. et al., 2003). The given compensatory changes are expressed by the intensification of incretion of cells growth factors (bFGF, IGF-1, EGF and others), the increase in aromatase and 5α-reductase, the increase in the level of endocrine division activators (somatotrope hormone, insulin, vitamin D) (Pechersky A.V. et al., 2003). The compensatory-adaptive reactions which take place under the reduction in testosterone production are aimed at increasing mitotic activity of cells (Pechersky A.V. et al., 2002; Pechersky A.V. et al., 2003; Pechersky A.V. et al., 2005).
Androgen-dependent cells are found in the worse situation during age-related decrease in testosterone production: the increase in the level of promoter factors of carcinogenesis in the blood plasma, which accompanies the death of old cells, accompanies the breakdown in the development of cells when going through the androgen-dependent stage (Pechersky A.V. et al., 2005). Accordingly, the share of prostate cancer equals a significant part of all oncological illnesses in men of older age groups (Pushkar D.Yu., 2002). The given changes are combined with processes which accompany the death of old cells among people of older age groups, thereby increasing the risk of development of carcinogenesis.
When patients have partial age-related androgen deficiency then their development of androgen-related cells is broken down, which is morphologically expressed by atrophy of the given cells (Lopatkin N.A., 1998; Ryde C.M. et al., 1992; Sporn M.B., 1996; Bersthein L.M., 2000; Pechersky A.V. et al., 2005). An earlier-made study showed that androgen receptors in the skin of the parietal in men (in the epidermis, the dermis (among fibroblasts), in the hair follicle and in the seat glands) (Pechersky A.V. et al., 2007). Accordingly, we found changes among the persons studied from older age groups in the development of androgen-dependent tissues and of separate cells: a decrease in the thickness of the papillary and reticulate layers of the dermis, of the average quantity of cambial epithelial cells of the matrix of the hair bulb, of the sizes of the hair follicles and the majority of fibroblasts of the hair papillary, as well as the appearance of deformed and hyperchromic nuclei among fibroblasts (which testify to degenerative changes in cells) (Pechersky A.V. et al., 2007). The data received in the study make it possible to state that the age-related decrease in the pool of pluripotent stem cells and the subsequent reduction in the formation of sex hormones are the main reasons for development of age-related changes of the skin, as well as of baldness and gray hair.
As our study made showed, stem cells of peripheral blood among men have androgen receptors and, likewise, are androgen-dependent. The age-related reduction in production of sex hormones has a negative impact on the development and proliferation of pluripotent stem cells which are dependent on the levels of these hormones, which is an additional negative factor which is capable of reducing their quantity. The subsequent breakdown in the regeneration of tissues of the gonads (the testicles in men with a reduction in Leidig cells, which increte testosterone) testifies to the formation of a vicious circle with the phenomenon of mutual dependency (Pechersky A.V. et al., 2007).
The receptor apparatus, which accepts the signal, and the increting cells and tissues form a unified inter-related system (Kettyle W.M., Arky R.A., 2001). The disintegration of receptors and their replacement with new ones is done continuously. When there is a lack of ligand, or when there is a reduction in its content then the time off the half-life of the according receptor increases (Alberts B. et al., 1994). It’s typical of people of older age groups as compared with the control group that there was a greater expression of androgen receptors in the epidermis, dermis (fibroblasts), hair follicles, and sweat glands among the former, which prove the presence of androgen deficit in these people (Pechersky A.V. et al., 2007).
Fibroblasts take part in the formation of the specialized architectonics of the connective tissue according to its local functions. An inter-cellular matrix is formed due to the activity of fibroblasts. This matrix contains collagen of the I and III types. The majority of types of connective tissue are made from these types of collagen. The ratio changes in favor of type I as a measure of the maturing of the connective tissue. The base of immature argyrophilic collagenous fibers is type III collagen (Serov V.V., Paukov V.S., 1995). Thus, type III collagen starts to predominate in people of older age groups when there is an increase in the level of cell growth factors and, accordingly, an increase in the stimulation of proliferation of fibroblasts in the majority of types of connective tissue. The predominance of type III collagen was discovered by Ettinger A.P. and co-authors (2006) in their study of skin among patients of older age groups with post-operations ventral hernias.
The break-up and replacement of collagen and other macromolecules of the territorial matrix occurs continuously under normal conditions. Collagens split into specific extracellular enzymes – collagenases (Alberts B. et al., 1994). Among people of older age-groups there is a breakdown of fibroblast renewal due to migration of an inadequate number of stem cells. The activity of a number of enzymes which take part in the splitting of connective tissue structures also decreases (for example, elastase (A.V. Pechersky et al., 2006)).
Excess stimulation of fibroblasts by cell growth factors and, accordingly, an increase in the share of non-mature argyrophil collagenous fiber and an increase in TNFα levels, products of the respiratory burst and over-oxidation, as well as a reduction in testosterone production, which has a negative effect on development of androgen-dependent fibroblasts, leading to development of degenerative changes such as a reduction in size and the appearance of a deformed and hyperchromic nucleus, all lead to a breakdown in connective tissue structure among people of older age groups. Accordingly, the collagen and elastic fibers among patients studied from older age groups were of a finer and more branchy type as compared to those of the control group: one could observe a decrease in thickness and an increase in the quantity of their diagonal and diagonal-transverse sections (Pechersky A.V. et al., 2007). The reduction in strength characteristics of connective tissue promotes the development of hernias of various localities, aneurism of the vessels, and other illnesses. The change in the structure of the inter-cellular matrix breaks down the processes for transferring the signal and conditions for migration of cells.
The conclusions made are proven by a series of well-known illnesses. The reduction in the number of divisions of cells among patients with early-aging syndrome – Werner syndrome – which is shown, for example, under cultivation, leads to a lack of cambial and pluripotent stem cells. The formation of a whole series of cell growth factors, including fibroblast growth factor, increases in a compensatory way in response to the lack of formation of an adequate number of pluripotent stem cells so as to compensate for necrotizing old cells. It is indicative that fibroblasts taken from patients with Werner’s syndrome turn out to be insensitive to fibroblast growth factor and several other growth factors (Alberts B. Et al., 1994). Considering that de-sensitizing of the according receptors of cells-targets is developed under the long-term effect of the according stimulus, the de-sensitizing of receptors of fibroblast growth factor is the result of the increase in its level over a long term.
Considering the fact that under chemotaxis cells react not to constant size, but rather to the change in the concentration of chemoattractant in the medium (Alberts B. Et al., 1994), constantly-increased levels of chemotactic factors in the place of necrosis (or apoptosis) of old cells leads to de-sensitizing of the according receptors of stem cells, preventing their entrance into the given area.
Accordingly, among patients with Werner’s syndrome, the breakdowns in regeneration of tissues have a systemic character. The atrophic changes in a series of endocrinal glands are accompanied by development of their inadequacy (hypogonadism and other pathology). Hypogonadism promotes the development of osteoporosis (Pechersky A.V. et al., 2006), while atrophy of cartilage tissue leads to the development of arthritis. As a result patients show limitations in the mobility of their joints. The increase in promoter factors of carcinogenesis and hormonal imbalance are accompanied by a high risk of development of oncological illnesses. The reduction in the number of cambial cells – hair follicles, is deepened by hypogonadism. The reduction in the formation of testosterone has a negative effect on the development of androgen-dependent skin cells, including cells of the hair follicles. The synthesis of pigment by the cells of hair bulbs is broken down. Patients show of early diffuse baldness and gray hair. Atrophic changes in the skin are characteristic of the given syndrome. The inadequacy of steroid hormones is accompanied by an increase in the formation of their predecessor – cholesterol. The activation of factors of cell immunity in response to the increase in mitotic activity promotes progression of atherosclerosis (Pechersky A.V. et al., 2006). The given pathological processes are characteristic of the clinical flow of Werner’s syndrome (Kryazheva S.S., 1976).
The selective damage of T-helpers among people with AIDS, apparently, hinders the formation of specific receptors of pluripotent stem cells. Information of antigen-presenting cells, which carry the complex of the antigen (including peptides of the dead cells) - MHC II class molecule, isn’t taken into account and doesn’t transform into the according receptor of pluripotent stem cells to the chemoattractant, which is represented by components of the MHC I class molecules. It’s likely that under these conditions the majority of pluripotent stem cells, not having tissue-specific receptors, remains uncalled for, and subsequently dies out. In an analogous way as in people of older age groups, the process of renewal the cell contents of cambial zones is broken down in patients with AIDS, which makes an additional negative contribution into the development of exhaustion, dementia, and tumors.
Thus, pluripotent stem cells are a universal mechanism for regeneration, which is formed during the evolution process. The age-related decrease in the quantity of pluripotent stem cells breaks down the processes of tissue regeneration, including tissues of endocrine organs. The hormonal imbalance that develops intensifies the changes taking place. The mutual load of the developing pathological processes leads to the formation of a vicious circle. Thus, among people of older age groups there is a greater risk of the development of oncological diseases. Furthermore, atrophic and sclerotic processes progress in the majority of tissues, and destructive changes of the connective tissue increase (with the decrease in solidity characteristics). Transplantation of allogenic stem cells can be a prospective way of making reverse development of the given pathological processes.

CHANGE IN ADENOHYPOPHYSIS REGULATION AMONG AGING MEN WITH PARTIAL ANDROGEN DEFICIENCY

As a result of the interaction of neurohumoral regulatory processes, the age-related decrease in testosterone production among aging men is reflected in the entire system of hypothalamic-pituitary regulation. The violation of regulatory mechanisms in the presence of PADAM is a particular case of a compensatory reaction made by the structures of the central nervous system and endocrine glands, which is characteristic of hypoproduction of one or several hormones.
A decreased testosterone level stimulates not only incretion of LH, but the incretion of gonadotropin-releasing hormone as well (Lavin N., 1999), and, secondarily, of FSH. Among some patients with partial age-related androgen deficiency the levels of LH and FSH don’t exceed normal values, even despite the low level of testosterone. In the presence of PADAM one can observe an increase in the activity of 5α-reductase and aromatase, and, accordingly, an increase in the levels of 5a-dihydrotestosterone and 17b-estradiol as well (Pechersky A.V. et al., 2002; Pechersky A.V. et al., 2003). The increased levels of 5a-dihydrotestosterone and 17b-estradiol suppress the incretion of LH, FSH and gonadotropin-releasing hormone by the principle of negative feedback, as well as suppress the incretion of (Lavin N., 1999). Testosterone and 5α-dihydrotestosterone connect with one and the same receptor. The affinity of binding together of the androgen receptor is higher for 5α-dihydrotestosterone than that of testosterone (Lavin N., 1999). For this reason the reduction in testosterone production among patients with PADAM and the responsive increase in 5α-dihydrotestosterone and 17b-estradiol can be unaccompanied by an increase in LH and FSH among some patients. The expressed increase in LH and FSH levels can be seen when there is a significant reduction in testosterone and, consequently, in a significant decrease in 5α-dihydrotestosterone and 17b-estradiol (such as, for example, after orchidectomy) (Pechersky A.V. et al., 2003).
Additionally, a series of peptides (IGF-1, epidermal growth factor) and hormones (corticosteroids), which fill the role of estromedins – intermediaries of the effect of estradiol, can have a suppressing. (Lippman M. E., Dickson R. B., 1989; Bershtein L.M., 2000). Receptors of corticosteroids are homologous to individual areas of estrogen receptors. They can change into forms that activate both corticosteroid-sensitive and estrogen-sensitive elements of the genome (Tsai M. J. et al., 1998). The levels of the given factors increase when production of testosterone is decreased (Pechersky A.V. et al., 2003). The incretion of LH and FSH using the negative feedback mechanism can be assisted by extragonadal testosterone production (Pechersky A.V. et al., 2005).
Loss of the rhythm of gonadotropin-releasing incretion by the hormone among patients with PADAM, as well as its long and constant (in tonic regime) effect leads to de-synthesis of the according receptors on gonadotropin cells and to suppression of the incretion of LH and FSH, despite the deficit in testosterone (Lavin N., 1999; Montanari E. et al., 1995; Pechersky A.V. et al., 2006).
When the level of testosterone is decreased, one can observe an increase in the level of prolactin (Pechersky A.V. et al., 2003). An increase in the production of 17b-estradiol leads to a reduction in the content of prolactin-inhibiting factor – dopamine, in the hypothalamus. Thus, estrogens have a direct activating influence on the incretion of prolactin by the hypophysis (Pankov A.Yu., 1983; Lavin N., 1999; Kettail V.M., Arki R.A., 2001).
An increase in 17β-estradiol leads to an increase in the concentration of thyroxin-connected globulin. The reciprocal decrease in free Т3 and Т4 promotes intensification of the formation of thyrotropin-releasing hormone and TTH. The incretion of common Т3 and Т4 is intensified. The production of thyrotropin-releasing hormone and TTH keeps increasing until the normal concentration of free Т3 and Т4 is restored. Thyrotropin-releasing hormone stimulates the incretion of lactotropic cells of the adenohypophysis, which leads to an increase in prolactin (Lavin N., 1999).
An increase in the level of STH is also connected to an increase in 17β-estradiol. This is proven by the results of functional trials with estrogens. In these trials one can observe an intensification of the incretion of STH (Lavin N., 1999). An increase in the level of STH causes an increase in the formation of IGF-1. An increase in the level of IGF-1 accompanies insulin resistance and a growth of tolerance to glucose (Lavin N., 1999).
PADAM leads to the development of insulin resistance (Pechersky A.V. et al., 2003; Pechersky A.V. et al., 2006). Hyperglycemia develops in response, and this leads to growth in the level of insulin. This insulin together with a decrease in sensitivity of hypothalamic centers to the slowdown of glucose leads to a incretion of growth hormone-releasing factor and corticoliberin by neurons of the hypothalamus into the portal system of the hypophysis, as well as suppresses incretion of somatostatin. Growth hormone-releasing factor stimulates the incretion of somatotropic hormone – the contrinsular horome. An increase in the concentration of STH leads to an increase in the production of IGF-1 in the liver. Resistance to insulin is accompanied by resistance to IGF-1 too, which is capable of connecting to insulin receptors. The formation of STH is additionally stimulated by vitamin D (Jakob F. et al., 1995; Shozu M. et al., 1991; Bershtein L.M., 1998; Lavin N., 1999; Bershtein L.M., 2000; Kettail V.M., Arki R.A., 2001), the level of which also increases when the level of testosterone goes down (Pechersky A.V. et al., 2003). Corticotropin-releasing hormone creates a surge of adrenocorticotropic hormone which increases the incretion of another contrinsular hormone, cortisol, in the adrenal cortex. A vicious circle is formed. An increase in the production of glucocorticoids suppresses the formation of dopamine and reduces the inhibiting effect of dopamine on the synthesis of prolactin (Lavin N., 1999).

INFLUENCE OF A CHANGE IN THE LEVEL OF TESTOSTERONE ON THE ACTIVITY OF 5α-REDUCTASE, AROMATSE, AND THE LEVELS OF CELL GROWTH FACTORS

A significant part of the tissues in the body have testosterone receptors. The natural development of androgen-dependent cells is broken among patient with PADAM. After this the transformation from androgen-independent transitory-proliferate cells into the androgen-dependent pool of transitional cells (Lopatkin N.A., 1998) requires the presence of the physiologically necessary level of testosterone further development. The insufficiency of the mitogenetic activity of testosterone leads to the formation of a series of compensatory-adaptive reactions which have an effect on endocrine, paracrine, and autocrine regulation levels (Pechersky A.V. et al., 2000; Pechersky A.V. et al., 2003).
Results of experimental research on the testosterone-sensitive cell line of fibroblasts of the foreskin of male patients testifies to a minimal accumulation of biologically active metabolite of testosterone (5α-dihydrotestosterone and 17β-estradiol) during incubation of cells in a medium with a concentration of testosterone as close as possible to the concentration’s normal content in the blood plasma among men (7.0 ng/ml (24,29 nmol/l)). In mediums with an increased or reduced level of testosterone (as compared to normal physiological values) one can observe an increase in the formation of 5α-dihydrotestosterone and 17β-estradiol and, consequently, there is an increase in the activity of 5α-reductase and aromatase. Thus, when the concentration of testosterone is lowered to 3 ng/ml (10.41 nmol/l), and the level of 5α-dihydrotestosterone is raised, on average, to 1.8 times, then, at 1 ng/ml (3.47 nmol/l) it is raised by 3.3 times. The level of the content of 5α-dihydrotestosterone also increases when the concentrations of testosterone in the blood are higher: at a concentration of 12 ng/ml (41.64 nmol/l) - by 2.9 times, at a concentration of 24 ng/ml (83.28 nmol/l) – by 4.9 times, and at a concentration of 600 ng/ml (2082.0 nmol/l) – by 10.5 times. Similar changes are characteristic for incretions in the incubational medium of 17β-estradiol (Pechersky A.V. et al., 2005).
An increase in the activity of 5α-reductase and aromatase is determined by the physiological role of testosterone, estrogens, and 5α-dihydrotestosterone. Testosterone also takes part in the cell growth and cell differentiation processes (Lopatkin N.A., 1998; Kettail V.M., Arki R.A., 2001). Testosterone and 5α-dihydrotestosterone, which connect with one and the same inner-cell receptor (Lavin N., 1999), stimulate proliferative activity (Zezerov V.G., Severin E.S., 1998). Estrogens induce an intensive mitogenesis in tissues which contain cells with specific receptors (Burrows H., Horning E., 1952). An increase in the activity of 5α-reductase and aromatase is caused by a PADAM, and is directed at compensating for the lack of mitogenetic activity by testosterone (Pechersky A.V. et al., 2002; Pechersky A.V. et al., 2003; Pechersky A.V. et al., 2005). The physiological activity of 5α-dihydrotestosterone exceeds that of testosterone by 5-10 times (Dedov I.I., Kalinchenko S.Yu., 2006) due to the higher affinity of binding of 5α-dihydrotestosterone with the androgen receptor (Lavin N., 1999). Thus, during an age-related decrease in testosterone production the increase in the share of 5α-dihydrotestosterone decreases the negative manifestation of the given state. That said 5α-dihydrotestosterone can not completely replace testosterone. 5α-Dihydrotestosterone, unlike testosterone, is formed in tonic regime, and its production does not accord with the impulse formation of LH. Furthermore, the growing decrease in testosterone production with age, despite the increased activity of 5α-reductase, limits the formation of 5α-dihydrotestosterone and the manifestation of the given compensatory mechanism. Thus, when the testosterone level goes down considerably (after orchidectomy among patients with prostate cancer) then this leads to a decrease in production of 5α-dihydrotestosterone and 17β-estradiol as well since they are formed from testosterone. The drop in the levels of testosterone and 17β-estradiol is accompanied by a compensatory increase in aromatase activity, which is proven by the increase in estrone (Pechersky A.V. et al., 2003). Estrone, like 17β-estradiol, is formed under the influence of aromatase (Lavin N., 1999). The formation of estrone from suprarenal androgen – androstenedion makes it possible to estimate aromatase activity even when there is a significant reduction in testosterone after orchidectomy. Thus, despite the reduction in 17β-estradiol, aromatase activity, on the contrary, increases. Considering that both aromatase and 5α-reductase activity increases when testosterone decreases (Pechersky A.V. et al., 2002; Pechersky A.V. et al., 2005), the increase in aromatase activity after orchidectomy testifies to growth of 5α-reductase activity as well. The given changes combine with suppression of TGFβ formation (Pechersky A.V. et. al., 2003) – the factor which is responsible for cells going through the cell differentiation stages and onset of apoptosis (Lopatkin N.A., 1998, Yarilin A.A., 1999; Bershtein L.M., 2000).
An increase in the level of 5α-dihydrotestosterone and aromatase is considered to be the main increase in the pathogenesis of the development of a whole series of tumorous diseases, including malign hyperplasia and cancer of the prostate gland (McKinlay J.B. еt al., 1989; Partin A.W. еt al., 1991; Stoner E., 1992; Montanari E. еt al., 1995; Lopatkin N.A., 1998; Bershtein L.M., 1998; Bershtein L.M., 2000). Stimulation of 5-reductase and aromatase activity is accompanied by a compensatory hyperplasia of tissues which contain the given enzymes. In particular, one can observe benign hyperplasia of the prostate gland and an increase in the portion of fatty tissue and overall obesity.
On the contrary, the restoration of the testosterone level to its physiological value leads to a decrease in the activity of 5α-reductase and aromatase, and helps prevent the above-mentioned illnesses (Pechersky A.V. et al., 2002; Pechersky A.V. et al., 2005).
Changes in endocrine regulation, which are caused by a decrease in testosterone production, are directed at exponentiation of the effect of estrogens. An increase in prolactin and glucocorticoids, which can be observed among patients with PADAM, leads to an increase in aromatase activity and intensification of the effect of estrogens. Glucocorticoids stimulate the activity of aromatase in the culture of stromal cells separated from fatty tissue (Mendelson C. R., Simpson E. R., 1987; Ryde C.M. et al., 1992; Bershtein L.M., 2000), insulin (Lueprasitsakul P., Longcope C., 1990), and vitamin D (Jakob F. et al., 1995; Bershtein L.M., 1998), the levels of which increase when testosterone production goes down (Pechersky A.V. et al., 2003), thereby making an effect of mutual intensifaction.
In addition to the modulation of antitumoral resistance, and of autoimmune, inflammatory and allergic reactions on the biosynthesis of steroids (including the activity of aromatase), cytokines can also have an influence (Purohit A., Ghilchik M. W., Duncan L., Wang D., Reed M. J. et al., 1995; Reed M. J. et al., 1995; Abbas A. K. et al., 1996). Among the regulators of aromatase activity one can include interleukin 1 and the necrosis factor of tumors -  (Belizario J. E. et al., 1991; McPheron A. C. et al., 1997). An increase in the incretion of interleukin -1 and interleukin-1 correlates with an increase in the activity of aromatase (Pacifici R. et al., 1991). The given changes can be observed among patients with PADAM (Pechersky A.V. et al., 2003). Thus the activity of aromatase and 5-reductase depends on the testosterone level. Any change in the testosterone level leads to an increase in activity of the given enzymes (Pechersky A.V. et al., 2002; Pechersky A.V. et al., 2003; Pechersky A.V. et al., 2005).
A decrease in the level, and, accordingly, of the mitotic activity of testosterone is compensated for not only by an increase in aromatase and 5α-reductase activity, but also by an additional intensification in the production of peptide growth factors (Pechersky A.V. et al., 2003). The given changes are caused by the lack of endocrinal activators of division (Vasilyev Yu. M., 1997; Bershtein L.M., 2000).
5-Dihydrotestosterone induces synthesis of insulin-like growth factor, epidermal growth factor, and fibroblast growth factor (Zezerov E.G., Severin E.S., 1998).
Estrogens induce the expression of a whole series of estrogen-dependent genes, among which one can find genes of peptide growth factors, and of receptors of progesterone and oncogenes (Bershtein L.M., 2000).
An increase in the level of progesterone leads to a shift in the sensitivity of tissues from steroids to peptide growth factors (Lange C. A. et al., 1999; Bershtein L.M., 2000). The given changes can be seen as a compensatory reaction which develops when there is a lack of steroid hormones.
An increase in the level of STH intensifies the formation IGF-1. The IGF-1 receptor is similar to the receptor for insulin, thus IGF-1 can connect with receptors of insulin and activate them. An increase in the levels of IGF-1 and insulin among patients with PADAM is a compensatory response to the development of insulin resistance (Pechersky A.V. et al., 2003). Considering the participation of insulin, along with IGF-1, in increasing the mitotic activity of cells insulin resistance can be seen as a mechanism for increasing the levels of insulin, STH, IGF-1 and, acordingly, their mitotic activity. An increase in the levels of the indicators is characteristic of the stage of promotion of tumorous growth (Yam D. et al., 1996; Bershtein L.M., 2000).
IGF-1, epidermal growth factor, and a series of other peptides can add to the effect of estradiol, hooking onto estrogen receptors. Estromedins, along with other properties of estrogens, have an expressed induction of mitogenesis in tissues (Lippman M. E., Dickson R. B., 1989; Lavin N., 1999; Bershtein L.M., 2000; Trapeznikova M. F., et al., 2004). IGF-1-connecting proteins inhibit the interaction between IGF-1 and insulin with receptors, and thereby suppress the influence of IGF-1 and insulin on cell-targets (Lavin N., 1999). Some serine proteases (prostate-specific antigen (PSA), inhibitor-1 of the activator of plasminogen) destroy IGF-connecting protein-3 (Alessi M. C., 1997; Bershtein L.M., 2000). At this point the increased level of 5-dihydrotestosterone not only increases the synthesis of IGF-1 (Zezerov V.G., Severin E.S., 1998), but also, through the stimulation of the formation of PSA, strengthens its effect.
When the level of testosterone is reduced one can observe an increase in the level of bFGF (Pechersky A.V. et al., 2003), which is the strongest stimulating influence on the proliferation of the epithelium. In terms of mitotic activity bFGF is stronger than EGF and some other growth factors (Lopatkin N.A., 1998).
An increase in aromatase and 5α-reductase activity and the level of the majority of growth factors shows that compensatory-adaptive reactions, which develop when the level of testosterone goes down, are directed at increasing mitotic activity in the cells. The intensity of these reactions is proportional to the intensity of the decrease in the production of testosterone.
When there is an increase in the testosterone level (under large doses of testosterone preparations prescribed in the experiment), then the increase in 5α-reductase and aromatase activity also, apparently, has a compensatory role, since the main way to lower the level of testosterone is to increase the intensity of its metabolism (Wilson J.D., 1975). In this case two of the interim products are 5α- dihydrotestosterone and 17β-estradiol. When there is artificial creation of high testosterone levels then the formation of 5α-dihydrotestosterone and 17β-estradiol is not restricted to the quantity of the original product. For this reason their formation significantly exceeds the analogous process in men with PADAM. High levels of testosterone, 5α-dihydrotestosterone and 17β-estradiol, each of which has high mytogenic activity, lead to formation of prostate cancer in animal experiments (Lopatkin N.A., 1998; Prehn R.T., 1999).
Thus any change in the testosterone level (both as a decrease under PADAM, or as an increase when large doses of androgen preparations are prescribed) leads to an increase in the formation of 5α-dihydrotestosterone and 17β-estradiol, increase in proliferate activity, and a break down in regulation of cell growth, which significantly increases the risk of cancerogenesis (Pechersky A.V. et al., 2002; Pechersky A.V. et al., 2003; Pechersky A.V. et al., 2005; Pechersky A.V. et al., 2007).

THE INFLUENCE OF PARTIAL ANDROGEN DEFICIENCY AMONG AGING MEN ON CARBOHYDRATE METABOLISM

Regulation based on the principle of inverse feedback is typical of many-stepped enzymatic processes: when the level of the final product goes down, the intensity of preceding reactions goes up, and the increase in the levels of the preceding substrates stimulates the formation of the product of the last stage (the so-called “activation by the predecessor”). This regularity is characteristic of all living organisms. Cholesterol is the main predecessor of the formation for steroid hormones (in particular for testosterone), and at earlier stages – glucose (Berezov T.T., Korovkin B.F., 2004). When testosterone production goes down with age there is a compensatory increase in cholesterol and glucose levels – substrates for the subsequent synthesis of testosterone (Pechersky A.V. et al., 2002; Pechersky A.V. et al., 2006).
Standard genetically-determined variants of the functioning of the endocrine system apparently formed as evolution of the human body went on. Some of these variants come as compensatory reactions in the presence of pathological states of the body. Resistance to insulin and leptin, which are accompanied by hyperphagia, an increase in glucose in the blood plasma, and an increase in the capacity of the fatty depots, is a widespread phenomenon in the animal world. The development of resistance to insulin and leptin in the summer months makes it possible to increase the mass of fatty tissue in animals for later use in the winter period (Florant G.L. et al., 2004). This state develops temporarily under physiological conditions, and doesn’t result in any negative consequences.
The mechanism of insulin resistance which is formed in the process of phylogenesis is employed for a compensatory increase in the levels of the predecessors of testosterone – cholesterol and glucose – when there is an age-related reduction in testosterone production. Considering that after forty years of age the decrease in testosterone production in men only progresses further and further, resistance to insulin among such men is a constant attribute which leads to a whole series of complications.
Insulin resistance, which develops in patients with PADAM (Pechersky A.V. et al., 2003), upsets the transport and utilization of glucose. A blockade of insulin receptors of cells in the liver promotes an increase in the production of glucose (thanks to an increase in gluconeogenesis). Insulin resistance in skeletal muscles also induces an increase in the level of glucose in the blood since the utilization of glucose in the muscles is one of the main mechanisms of its metabolism. As a response to a disruption of the transport and metabolism of glucose and an increase in the level of insulin, neurons of the hypothalamus increte growth hormone-releasing factor and corticotrophin-releasing hormone into the portal system of the hypophysis, leading to an increase in the level of anti-insular hormone, like STH (Lavin N., 1999; Kettail V.M., Arki R.A., 2001) and cortisol (Lavin N., 1999).
The level of glucagon in the presence of insulin-dependent sugar diabetes increases constantly, and doesn’t go down after a patient eats (Karpishenko A.I., 2001).
Insulin receptors are also additionally activated by IGF-1. An increase in the level of estrogens in the presence of PADAM further increases the incretion of STH, which in turn stimulates the formation of IGF-1 (Lavin, 1999; Pechersky A.V. et al., 2003). An increase in the levels of insulin, STH, and IGF-1, and, consequently, of their mitotic activity among patients with PADAM, is a compensatory reaction to the development of insulin resistance (Pechersky A.V. et al., 2003).
IGF-1– connecting proteins restrain the interaction of IGF-1 and insulin with receptors, thereby inhibiting their influence on cell-targets (Lavin N., 1999). A reduction in the level of IGF-1– connecting proteins intensifies the influence of IGF-1 and insulin (Cohen P. et al., 1994; Bershtein L.M., 2000). Insulin suppresses synthesis of IGF-1– connecting proteins (Rutanen E. M. et al., 1994; Bershtein L.M., 2000). Thus hyperinsulinism helps overcome insulin resistance.
Insulin, which is an inductor of key enzymes of glycolysis, and a repressor of the main enzymes of gluconeogenesis, controls the correlation of activity of these processes (Berezov T.T., Korovkin V.F., 1982). Glucocorticoids serve as an inductor of the enzymes of gluconeogenesis and as a repressor of the enzymes of gluconeogenesis (Karpishenko A.I., 2001). Therefore, in the presence of insulin resistance, which is accompanied by an increase in the incretion of corticosteroids and a decrease in the influence of insulin, the intensity of gluconeogenesis by means of the stimulation of the corresponding enzymes in the liver and the kidneys increases (Berezov T.T., Korovkin V.F., 1982). Insulin resistance, and the increase in insulin which accompanies it, leads to dislipoproteinemia, especially to hypertriglyceridemia, since the surplus of insulin stimulates lipogenesis and the synthesis of low-density lipoprotein in the liver (Lavin N., 1999).
Among patients with insulin-dependent sugar diabetes (2nd-type diabetes) and obesity, the level of glucose in the blood plasma can remain within normal ranges before the stage of decompensation β-cells, despite the activation of gluconeogenesis and the infringement of the utilization of glucose (or exceed the normal levels in insignificant amounts). At the same time the level insulin in such patients increases from 1.5-3 times (Ginzburg M.M., Kryukov N.N., 2002). An exhaustion of β-cells is induced (Lavin N., 1999).
Insulin sensitivity of adipocytes is inversely proportional to the sizes of the cell. Hyperinsulinemia, which precedes obesity, leads to growth of the content of lipids in the cell, as well as to an increase in the sizes of adipocytes. The larger the adipocyte, the less sensitive it is to insulin, which testifies to the fact that the capacity of fatty depots is reduced. Fat depots are depots of the second type after glycogen of the liver for the utilization of glucose, the surplus quantity of which remains in them, transforming itself into fatty acids glycerin, and then into triglycerides. An increase in the correlation of the circumference of the waist to the circumference of the hips testifies to the presence of insulin resistance (Bershtein L.M., 2000). Compensatorily, STH intensifies cell proliferation, which, among other things, helps increase the amount of cells of fatty tissue (Cliorin A.I., 1989). Thus, the replication of preadipocytes, with the resulting transformation of the preadipocytes into real fatty cells, as well as hyperinsulinemia, which leads to an additional quantity of lipids entering fatty cells, increases the capacity of fat depots and promotes the development of obesity.
An intensification of aromatase activity in the presence of PADAM, or in other words an increase of the aromatization of testosterone and androstenedione (Pechersky A. et al., 2002; Pechersky A. et al., 2003), is combined with a significant increase in the body mass among men. An increase in the level of estrogens in the blood and the intensification of their usurpation by the tissues of the organism can be observed among men suffering from obesity (Schneider J. et al., 1979; Schneider J. et al., 1983; Zumoff В. et al., 1981; Bershtein L.M., 1998). An increase in the level of estrogens formed stimulates an increase in the quantity and sizes of the adipocytes, as well as in the quantity of stromal cells of fatty tissue (Hirsch J. et al., 1991; Bershtein L.M., 1998). Stromal cells of fatty tissue are themselves capable of synthesizing both estrogens and androgens, in particular 5α- dihydrotestosterone and androstenedione (Perel E. et al., 1986). Their incretion, in turn, has a stimulating effect on the development of fatty tissue, and a vicious circle is formed. Lymphocytes and macrophages, which also have aromatase activity, add to the given effect (Bershtein L.M., 1998).
An increased level of glucocorticoids, IGF-1, epidermal growth factor and a series of other peptides which activate estrogen receptors, supplement the effect of estradiol, which is connected with an increase of the number and sizes of adipocytes, and of the quantity of stromal cells in the fatty tissue. This effect is the result of homology of individual parts of their receptors to estrogen receptors (Lippman M. E., Dickson R. B., 1989; Tsai M. J. et al., 1998; Bershtein L.M., 2000). An increase in the level of regulating factor is accompanied by the activation of the according receptors (Kettail V.M. Arki R.A., 2001). The increase in glucocorticoid production is accompanied not only by an increase in the expression of corticosteroid receptors but also by an increase in the expression of homologous estrogen receptors (Bershtein L.M., 2000., Tsai M. J. et al., 1998). An increase in the number and size of adipocytes exponentiates the effect of the aromatase held in them.
Thus, the development of insulin resistance among men with PADAM, which is accompanied by an increase in the levels of glucose, cholesterol, triglycerides, insulin, STH, IGF-1, adrenocorticotropic hormone, and cortisol, as well as by an increased share of fatty tissue, is caused, to a significant degree, by testicular insufficiency. An inverse development of the above-mentioned pathological processes is impossible without correction of age-related androgen deficiency.

THE INFLUENCE OF AGE-SPECIFIC DECREASES IN TESTOSTERONE PRODUCTION ON MINERAL METABOLISM

After 30 years of age the mass of bony tissue among all people is slowly reduced. The speed of the loss of bone mass is higher among women than among men (Lavin N., 1999). An increase in the risk of osteoporosis among men with primary hypogonadism and among women with a deficit of estrogens in the period of menopause results from a rise in the threshold of sensitivity of the cells of the parathyroid glands to calcium, as a result of which the mechanism of suppression of the incretion of parathyroid hormone comes as an answer to hypercalcemia. As a result the cells of the parathyroid glands increte a surplus amount of PTH. Accordingly, the level of the incretion of calcitonin is reduced. Incretion is influenced by changes in the concentration of magnesium (Mg++) in the blood (Lavin N., 1999).
A surplus of PTH speeds up the resorption of bone tissue and increases the washing out of calcium from the bones, which leads to hypercalcemia. The resorption of phosphates in the kidneys is reduced under the influence of a surplus of PTH, and phosphaturia and hypophosphatemia arise. The tubular absorption of calcium is increased, but this effect of PTH is balanced out by an increased glomerular filtration of calcium as a result of hypercalcemia; thus calcium in the urine increases (Lavin N., 1999). PTH receptors are present on the osteoblasts and osteocytes, but are not present on osteoclasts. Nevertheless, when the level of PTH increases, osteoclasts are activated, and the resorption of bone tissue is accelerated. This effect of PTH is mediated by osteoblasts: under the influence of PTH osteoblasts begin to increte IGF-1 and cytokines (interleukin-1 and others), which in their turn activate osteoclasts. This is assisted by the enhanced proliferation of cells-predecessors of osteoclasts, which have PTH receptors (Lavin N., 1999). When the level of PTH is constantly high, the resorption of bone tissue predominates over its formation, which leads to osteopenin. Stimulation of IGF-1 when PTH incretion increases (Lavin N., 1999) has the effect of additionally increasing the level of IGF-1 among patients with PADAM (Pechersky A.V. et. al., 2003).
Insulin resistance accompanies an age-related decrease in testosterone production (Pechersky A. et al., 2003). A disruption of the hormonal action of insulin in the presence of insulin resistance is accompanied by a decrease in the activity of osteoblasts, which promotes osteoporosis and hypercalcemia (Lavin N., 1999).
The incretion of corticotropin-releasing hormone into the portal system of the hypophysis during a blockade of insulin receptors promotes a incretion of adrenocorticotropic hormone, which strengthens the incretion of cortisol in the cortex of the adrenal glands. Cortisol suppresses the activity of the osteoblasts (Lavin N., 1999).
A surplus of PTH and hypophosphatemia stimulate synthesis of 1.25 (ОН)2 D3 in the renal tubules. The levels of calcitonin, estrogens and insulin also influence the formation of 1.25 (ОН)2 D3 (Lavin N., 1999). Under the influence of 1.25 (ОН)2 D3 the absorption of calcium in the intestines is increased, which strengthens hypercalcemia even more (Lavin N., 1999). When the level of testosterone is decreased, the level of 25-OHVitD3 is increased (Pechersky A.V. et al., 2003).
Calcitonin slows down the resorption of bone tissue by reducing the activity of osteoclasts and by stimulating osteoblasts. When the level of sex hormones is decreased, especially in women with a deficit of estrogens, as conditioned by menopause, and in men with deficit of androgens due to PADAM, the incretion of calcitonin is decreased, which promotes a faster resorption of bone tissue (Lavin N., 1999).
Surplus formation of thyroid hormones, as conditioned by the increase in the level of 17β-estradiol, stimulates osteoclasts, which additionally leads to an intensification of the resorption of bone tissue (Lavin N., 1999).
When PTH incretion increases one can observe an increase in the activity of alkaline phosphatase. Alkaline phosphatase is produced in the bones by osteoblasts and the content of alkaline phosphatase increases during periods of increased osteoblast activity. The activity of osteoblasts and that of osteoclasts are closely linked between themselves, thus any intensification in the metabolic processes in the bones leads to an increase in the concentration of alkaline phosphatase (Lavin N., 1999; Kettail V.M., Arki R.A., 2001).
Older people are sensitive to even light hypercalcemia. The peak of hypercalcemia comes at 60-70 years of age. Damage of the central nervous system, of the cardiovascular system, of the kidneys, and of the stomach-intestine tract is strongest in the medical picture. The strength of the bone tissue remains comparatively stable until the 50-year age bracket, after which the strength of the bones of representatives of both sexes begins to decrease. Among women this process becomes much faster during menopause. Among men a steep drop in the curve of the reduction of the bone mass isn’t observed since, unlike women, in the period of andropause there is not a sudden decrease in the content of sex hormones among men. A prescription of estrogens prevents hypercalcemia and a further loss of bone mass among women (Lavin N., 1999; Kettail V.M., Arki R.A., 2001). Among men, a prescription of androgen-replacement therapy seems to be a promising way to prevent osteoporosis.
PTH receptors are found not only in bone tissue and the kidneys, but in many other tissues and organs in which PTH takes part in the metabolism of calcium and phosphorus (Lavin N., 1999). Apparently, an increase in the threshold of sensitivity to calcium during menopause among women, and during PADAM among men, is distributed not only to parathyroid glands, but to the remaining tissues which contain PTH receptors. An illusion of hypocalcemia is created, which compensatorily promotes an intensive synthesis of PTH by the parathyroid glands, as well as outside-thyroid production of the analogue of PTH – PTH-like peptides made by the periphery tissues. The stimulation of the synthesis of PTH promotes hyperplasia (and, more rarely, of adenoma) of the parathyroid glands (Lavin N., 1999).

THE INFLUENCE OF PARTIAL ANDROGEN DEFICIENCY AMONG AGING MEN ON THE IMMUNE SYSTEM

Reactions of natural immunity are initiated by a series of chemical structures including end sugars of the membrane glycoproteins that contain mannose. Protection from end carbohydrate remainders of membrane glycoproteins is broken down among old, proliferative, malignant cells – free mannose appears on the surface of these cells. The given cells become accessible to identification. (Yarilin A.A., 1999).
The above-mentioned changes among patients with PADAM are stipulated by an increase in the level of a series of mytogenic factors: STH, insulin, bFGF and others. At the same time an increase in production of IL-2 can be observed too, as well as in the expression of its receptor (CD25+). An increase in the expression of the receptor IL-2(CD25+) adds to the effect made by IL-2, thereby linking them into a single system (Pechersky A.V. et al., 2006). IL-2 supports the proliferate phase of the immune response – an increase in the pool of specific cytoxic effectors and cells that make non-specific cytotoxicity as compared to cell targets (Yarilin A.A., 1999; Roitt I. et al., 2000).
Activation of macrophages has various influences on the development of a series of products: incretion of the activator of plasminogen, a factor which activates platelets, cytokines (including IL-1α, IL-1β, IL-6, and TNFα), hormones (ACTH, STH), products of the active form of oxygen and nitrogen and overoxidation, is intensified, while the formation of elastase, on the contrary, goes down (Yarilin A.A., 1999). The decrease in the formation of a series of enzymes of neutrophils, such as elastase, is the result of long-term stimulation made by means of IL-2, TNFα, and INFγ.
TNFα, hydrolases (acid phosphatase, alkaline phosphatases, serine proteinases and esterases), components of the compliment, and highly-active forms of oxygen and nitrogen are all responsible for influencing the cytolytic (including anti-tumor) activity of monocytes, macrophages, neutrophils, and cytotoxic Т-cells (Yarilin A.A., 1999; Roitt I. et al., 2000).
TNFα contains an expressed cytotoxicity, which is shown in the destruction of tumorous cells. In addition to regulatory and cytotoxic activity, TNFα also connects with specific highly-active membrane receptors, especially with TNF-R1, which gives a domain for cell death, thereby helping the program of apoptosis to be started (Yarilin A.A., 1999; Roitt I., Brostoff J., 2000).
Acid phosphatase, which has cytolytic activity, is found in macrophages, in primary (auzorophile) granules of neutrophils, and in several other cells of the immune system (Yarilin A.A., 1999; Roitt I. Et al., 2000). Alkaline phosphatase also has cytolytic activity. Alkaline phosphatase is found in secondary (specific) granules of neutrophils and, together with other highly-active substances and enzymes, is capable of provoking the death of tumorous cells (Yarilin A.A., 1999).
The formation of free radicals, peroxides, and other highly active products is accompanied by a high rate of glucose consumption. The oxidation of glucose through the pentose-phosphate path is accompanied by an accumulation of NADPH; the interaction of the latter with oxygen molecules leads to the formation of superoxide-anion (O2-). In following reactions hydrogen peroxide is formed (H2O2), as well as hydroxyl-radical (OH-) and other products which provoke lysis (Yarilin A.A., 1999; Roitt I. et al., 2000). An ncreased level of glucose, which is necessary for this process, is supported thanks to insulin resistance. When the level of testosterone goes down the level of insulin goes up regularly, which points to an intensification of the given compensatory mechanism (Pechersky A.V. et al., 2003; Pechersky A.V. et al., 2006). In men over 40 years old one can observe a slow and steady increase in the level of PSA. PSA is serine proteinase – an enzyme which belongs to the class of hydrolases. α1-Antichemotripsin and α2-macroglobulin connect PSA, turning it into a non-active form (Loran O.B. et. al., 1999; Bershtein L.M., 2000).
Besides the epithelium of the prostate gland, serine proteinases are formed by a whole series of cells. Granules of macrophages, neutrophils, and cytotoxic Т- cells also contain serine and esterases of a chemotripsin type. Regulation of the activity of proteinases is done by their inhibitors, which are increted by macrophages: α-antichemotripsin and α2-macroglobulin. Serine proteinases participate in the antibody-independent alternative way of activating the complement. Besides the expression of cytotoxicity, serine proteinases can also stimulate the launch of a program of apoptosis in cell-targets, influencing the paths of inner-cell signaling (Yarilin A.A., 1999; Roitt I. et al., 2000).
An increase in PSA, which is more often used as a diagnostic criterion that testifies to a incretion of malignant cells of the epithelium of acinuses, in the presence of prostate cancer, which have grown over the surrounding tissues, and have entered into the bloodstream, is in fact a addition of the compensatory reaction of the system of the compliment and cell immunity.
An increase in the levels of the given indicators testifies to the response antitumoral cell immunity in response to an increase in proliferative activity among patients with PADAM. The given reaction is directed at the utilization of the newly-formed atypical cells and at the regulation of apoptosis (Pechersky A.V. et al., 2003).
The above-named cytokines can not only modulate antitumoral resistance and autoimmune, and inflammatory reactions, but also have an influence on the biosynthesis of steroids, including aromatase activity (Purohit A. et al., 1995; Reed M. J. et al., 1995; Abbas A. K. et al., 1996; Bershtein L.M., 1998). An increase in the incretion of interleukin -1 and interleukin-1 correlates with an increase in the activity of aromatase (Pacifici R. et al., 1991).
When the testosterone level goes down the increase in IL-1β и TNFα is combined with the suppression of the formation of TGFβ, a factor which suppresses Th1 immune response, which is responsible for the sequential movement by a cell through the stages of differentiation and the onset of apoptosis (Pechersky A. et al., 2003).
Participation of the protein-degrading enzymes of neutrophils in the development of the vascular component of the inflammatory reaction makes for a change in the contractibility and permeability of small vessels. For example, serine proteinase, which is made by neutrophils, leads to the formation of angiotensin II from angiotensinogen of the plasma. Specific granules of neutrophils increte enzymes that similar to proteases of the system of the compliment, and which are capable of chipping off vasoactive peptide C5a from the C5 molecule. Low-molecular cationic proteins make for aggregation of thrombocytes.
Peroxidation of low-density and very low-density lipoproteins by products of the active form of oxygen and nitrogen, increted by neutrophils, leads to formation of their peroxide-modified forms that have high atherogenicity. Activation of macrophages makes it possible for macrophages to takeover the products formed. High concentrations of esterified and free cholesterol are collected in the cytoplasm or arterial macrophages, thereby transforming them into foamy cells. When these cells are destroyed cholesterol is then collected in the walls of the arteries (Berezov T.T., Korovkin B.F., 2004).
An increase in adhesive interactions, an increase in formation of the activator of plasminogen (a factor which activates platelets), an increase in TNFα of the products of the active form of oxygen and nitrogen and overoxidation, and a change in the properties of the endothelium, contractibility, and penetrability of small vessels all have an influence on the vascular-platelet hemostasis, thereby increasing the risk of platelet formation (Ragimov A.A. et al., 2005).
A reduction in elastase activity, an increase in the levels of TNFα, products of the active form of oxygen and nitrogen and overoxidation lead to a breakdown in the structure of the connective tissue and have a negative influence on the restoration of its compenents among older men. This promotes the development of such diseases as hernias at various locations, aneurisms of blood vessels, and several others.
Increased values of IL-1α, IL-1β, TNFα, acid phosphatase and alkaline phosphatase, as well as of the value of peroxidation of lipids, PSA, calcium and magnesium when testosterone production goes down testifies to the development of a compensatory reaction of anti-tumor cell immunity in response to an increase in proliferative activity among patients with PADAM. This reaction is aimed at utilization of the atypical cells that form and at regulating apoptosis.
Correction of testosterone levels among patients with PADAM, which initiates a response to the natural immunity, leads to the development of such diseases and pathological states as atherosclerosis, primary hypertension and an increase in the risk of thrombosis. It also promotes development of pathology of the connective tissue (with a decrease in the tissue’s strength), and cardiovascular and brain irregularities.
Correction in testosterone level among patients with PADAM, which leads to a decrease in the levels of mytogenic factors (STH, insulin, main fibroblast growth factor) leads to the reverse development of compensatory reactions to natural cell immunity: a decrease in the levels of IL-1, TNFα, Ca++, Mg++ and a decrease in the value of peroxidation of lipids (thiobarbutic acid-active products). The given changes are accompanied by an increase in the elastase activity of neutrophils and of elastase of the blood serum. One can also observe an increase in the number of lymphocytes, which is most likely a result of the androgen dependency of the given cells (Pechersky A.V. et al, 2006).

CHANGE IN THE EXPRESSION OF RECEPTORS OF STEROID HORMONE IN THE PRESENCE OF PARTIAL ANDROGEN DEFICIENCY AMONG AGING MEN

The development of competent cells is broken down already during the testosterone-dependent stage among patients with PADAM. The onset of apoptosis becomes more difficult. These processes precede malignant growth; they are reflected by changes seen in the peritumurous zone (in tissues not included in malignant growth). The malignant transformation of a whole series of tissues is accompanied by the appearance of hormonal acticity in these tissues (Lavin N., 1999).
In order to compensate for the lack of endocrinal activators of division, and in particular a lack of mitogenic activity of tesotosterone, a whole complex of compensatory-adaptive reactions is formed, including intensification of incretion of peptide growth factors by cells, an increase in aromatase and 5α-reductase activity, an increase in the levels of endocrinal activators of separation (somatotropic hormone, insulin, vitamin D), as well as an increase in the production of testosterone itself (Pechersky A.V. et al., 2003; Pechersky A.V. et al., 2005)). The given factors have a significant influence on the development of cancer of the prostate gland, bladder, rectum, and several other organs (Fernandez E. et al., 1996; Lopatkin N.A., 1998; Bershtein L.M., 2000).
An increase in the level of testosterone is achieved not only thanks to hypophysial stimulation of Leydig cells, but also through a synthesis of testosterone by other tissues, for which such a function is not common in normal conditions. This conclusion is proven by the synthesis by fatty tissue cells of androgens (5α- dihydrotestosterone and androstenedione) and estrogens (Perel E. et al., 1986). The testosterone level is significantly greater in peritumorous tissues (in tissues not involved in tumorous growth) of the prostate gland and in tissues of tumors of the prostate gland, bladder, and straight intestine than the levels of testosterone in the blood serum of the according patients. An excess in the level of testosterone in tumorous tissue over analogous levels in the tissue of the peritumorous zone in patients with prostate cancer, shows that there is an intensification of the production of testosterone outside the gonads in the presence of an increase in the mitotic activity of the cells (Pechersky A.V. et al., 2005).
Thus, extragonadal production of testosterone is directed at compensation of partial age-related androgen deficiency. The largest expression of the given compensatory-adaptive reaction is made in the presence of a malignant transformation of the tissues that have been drawn into the compensation processes. The increase in expression of AR in the tissues of the peritumorous zone among patients with prostate cancer as compared to analogous data from the prostate gland among young men testifies to the fact there is not an adequate restoration of regulation by using testosterone (Pechersky A.V. et al., 2005). The receptor apparatus, which accepts the signal, along with incretions, cells, and tissues make up a united, interdependent system (Neveu P.J., Le Moal M., 1990; Besedovsky H.O., Del Rey A., 1996; Bershtein L.M., 1998, Kettail V.M., Arki R.A., 2001). The disintegration of receptors and their replacement with new receptors takes place without stop. When the ligand is absent or when it is contents are reduced the half-life time of the accompanying receptor increases (Alberts B. et al., 1994). Accordingly, the decrease in the level of regulating factor is accompanied by an increase in the expression of its receptors. The expression of AR and ER, which is manifested in the peritumorous tissue of the prostate gland, as well as the expression of ER, which is manifested in the peritumorous tissue of the rectum, supplement an increase in 5α-reductase and aromatase activity, which are observed when the level of testosterone goes down (Pechersky A.V. et al., 2005). The N-end section of the androgen receptor contains glutamic iterations. The increase in the length of such iterations weakens the interaction of the receptor with androgens, while a decrease in length strengthens interaction. Mutations of the N-end section of the androgen receptor are expressed in primary foci and metastases of cancer of the prostate gland. When there is a more expressed decrease in the level of testosterone one can note a relatively small number of the above-mentioned iterations (Dedov I.I., Kalinchenko S.Yu., 2006), which testifies to the intensification of interaction of the receptor with androgens under an age-related reduction in testosterone production.
Lymphocytic-magrophagic infiltration promotes intensification of steroidogenesis in the tumorous tissue (Borkowski A. et al., 1978; Bershtein L.M., 1998). Lymphocytes and macrophages can synthesize testosterone from androstenedione (Milewich L. at al., 1982; Coddington C.C. et al., 1988; Bershtein L.M., 1998), as well as possess aromatase activity, thereby transforming androgens into estrogens (Frisch R.E. et al., 1980; Mor G. et al., 1998; Lea C.K. et al., 1997; Bershtein L.M., 1998). Lymphocytic and marcophagal infiltration of tumors of the prostate gland, bladder, and rectum, as well as in the peritumorous zone of the given organs supplements the overall compensatory reaction, which is directed at increasing mitotic activity, expression, to which the rate of the decrease in testosterone is proportional (Pechersky A.V. et al., 2003; Pechersky A.V. et al., 2005). Participation of lymphocytes and macrophages in the process of steroidogenesis proves the conception of the unity of immune and neuroendocrine regulation (Besedovsky H.O., Del Rey A., 1996; Weigent D.A., Blalock J.E., 1987; Korneva E.A., Shkhinek E.K., 1988; Bershtein L.M., 1998).
Disruptions in the process of differentiation of androgen-dependent transition cells, resulting from PADAM, are expressed morphologically by atrophy of the given cells. In particular, one can observe atrophy of the epithelium of acinuses of the prostate gland (Lopatkin N.A., 1998; Ryde C.M. et al., 1992; Sporn M.B., 1996; Bershtein L.M., 2000). The given changes are made in the tissues of the peritumorous zone of the prostate gland. Atrophy of the epithelium of the glands of the peritumorous zone among patients with prostate cancer testifies to the inadequacy of extragonadal production of testosterone and of the increase in the formation of 5α-dihydrotestosterone as compensation reactions in the presence of PADAM (Pechersky A.V. et al., 2005).
Extragonadal synthesis of steroid hormones is conditioned by hormonal and autocrinal-paracrinal factors. Prolactin (Pankov, A. Yu. 1983), insulin (Lueprasitsakul P., Longcope C., 1990), vitamin D (Jakob F. et al., 1995; Shozu M. et al., 1996; Bershtein L.M., 1998), insulin-like growth factor-1(IGF-1) (Mendelson C.R., Simpson E.R., 1987; Ryde C.M. et al., 1992; Bershtein L.M., 2000), main growth factor of fibroblasts (bFGF), and epidermal growth factor (EGF) (Mendelson C.R., Simpson E.R., 1987) all have a significant influence on this process. An increase in the level of the given factors is characteristic of metabolic syndrome (X-syndrome) and can be observed when the level of testosterone goes down (Pechersky A.V. et al., 2003).
In the presence of PADAM the increased levels of STH, insulin, estradiol, 5α-dihydrotestosterone, vitamin D, bFGF, IGF-1, and EGF, which are all factors that promote carcinogenesis, stimulate cell proliferation (Pechersky A.V. et al., 2002; Pechersky A.V. et al., 2003). There is an expression of Ki67 in the peritumorous zone among patients with prostate cancer, which reflects the intensity of cell proliferation, as well as the expression of bcl-2, which characterizes inhibition of apoptosis. Thus, atrophic changes in androgen-dependent cells (the result of PADAM) are accompanied by an increased risk of blastomatous transformation of these cells, and can be seen as a pre-cancer process (Pechersky A.V. et al., 2005). An increase in the above-named mytogenic factors in the blood plasma involves androgen-independent tissues into the compensation process in the presence of the development of PADAM. Thus, among cancer patients with PADAM there is extragonadal production of testosterone by the tumorous tissue not only of the prostate gland but also of the bladder and rectum (Pechersky A.V. et al., 2005). Immunohistochemical research of the tissues of the bladder and rectum do not show any signs of AR in these tissues. Considering that extragonadal testosterone production is stimulated by promoting factors of carcinogenesis and is accompanied by increased mitotic activity, there is a natural expression of Ki67 in the peritumorous zones of the given patients (Pechersky A.V. et al., 2005).
An increased expression of p53, which makes for normalization of cell growth, and which is shown in the peritumorous zone of patients with cancer of the prostate, bladder, and rectum, is a compensatory response under the conditions of increased proliferative activity of cells under PADAM (Pechersky A.V. et al., 2003, Pechersly A.V. et al., 2005). The expression of p53 in the presence of PADAM among patients supplements an increase in the levels of cytotoxic factors of anti-tumorous cell immunity: the necrosis factor of tumors-α (TNFα), acid phosphatase, alkaline phosphatase, serine proteinase (including PSA), and active forms of oxygen, nitrogen and others (Pechersky A.V. et al., 2003). When there is a significant increase in the number of atypical cells the effectiveness of these factors becomes inadequate; the conditions for development of a malignant tumor arise.
The dependency of cell immunity on PADAM is proven by the expression of AR, ER, PR, and bcl-2 of lymphocytes and macrophages of the infiltrate of the tumors and peritumorous tissues (Pechersky A.V. et al., 2005). The presence of AR (Pechersky A.V. et al., 2005) and ER (Jakob F. Et al., 1992; Cutolo M. et al., 1996; Pechersky A.V. et al., 2005) on the surface of lymphocytes and macrophages testifies to their androgen and estrogen dependency and explains why decompensation of anti-tumor immunity in the presence of a significant decrease in testosterone levels take place (Pechersky A.V. et al., 2003). Thus, extragonadal testosterone production by a whole series of tumors and tissues, which is accompanied by an increase in proliferative activity, is a result of partial androgen deficiency among aging men (PADAM). The given changes are directed at compensation of testicular inadequacy and are a partial expression of metabolic syndrome (X-syndrome). At the same time, the capabilities of the immune system, which utilizes a-typical cells, become inadequate.
The above-described pathological processes concern all organs and tissues of the body, including both androgen-dependent and androgen-independent ones, thereby raising the risk of their tumorous transformation.

THE INFLUENCE OF PARTIAL ANDROGEN DЕFICIENCY AMONG AGING MEN ON THE IMPULSE MODE OF THE INCRETION OF SOME HORMONES AND MITOTIC ACTIVITY

The endocrine and nervous systems function in a coordinated way, thereby supporting the consistency of the body’s inner environment. Although there is an obvious difference in the mechanisms by which these two systems pass along information, each of the two systems features the release of chemical substances as a way of making communication between cells. The endocrine system is a continuation of the central nervous system. Neuroincretorial cells of the hypothalamus combine characteristics of both systems: they get information from higher-lying parts of the central nervous system through synaptic transfers and, at the same time, synthesize hormones which are transported along with the current of axoplasma to the hypophysis. The sensory stimulus is transformed into hormone incretion; such a transformation is called a neuroendocrinal response (Green P. et al., 1993).
Sending information to the central nervous system is done with the help of a frequency pulse code. This code uses both the frequency of the transfer of nerve impulses, and the quantity of nerve impulses in “formed packages” (Gubanov N.I., 1978; Utepbergenov A.A., 1978). J. Furth was one of the first researchers to use methods of analysis from cybernetics for evaluating the function of the hypophysis (1967). Regulation of the rhythm of incretion of hormones of the hypothalamus is done by the suprachiasmatic core of the middle brain (Kettail V.M. et al., 2001; Арки Р.А., 2001). The suprachiasmatic core serves not only as a pacemaker for rhythms, but is also one of the most important centers for integration of the brain. Axons of afferent neurons end in the suprachiasmatic core. These afferent neurons are located in more than 20 sections of the brain (Ugryumov M.V., 1999).
The system of regulation of rhythms includes three components: neuron-pacemakers, an afferent regulation unit which adapts the work of the pacemaker, and an efferent unit which transfers commands of the pacemaker to the functional target (Klein D.C. et al., 1991).
The success of the transfer of the biological signal depends not only on the level of the hormone but also on the frequency of the incretion of the hormone. This conclusion is confirmed by the dependency of the correlation of formation of LH and FSH levels on the frequency of incretion of gonadotropin-releasing of the hormone (Lavin N., 1999). The pulse of the rhythm of the formation of hormones from the point of view of cybernetics is related to “discrete messages”, which are capable of sending a significantly large volume of information, unlike “non-stop messages”, which have a constantly changing size (Gubanov N.I., 1978; Utepbergenov A.A., 1978).
Information from the central nervous system, which is transferred in the form of nerve impulses which follow one after another at regular intervals and are united into packets, is transformed into an impulse rhythm of formation of hormones (Pechersky A.V. et al, 2002). The ability of neurons of the suprachiasmatic core (unlike neurons of other sections of the brain, which have endogenic rhythm) to transform a series of rhythms into single impulses (Mirmiran M. et al., 1992) allows this to be achieved.
Incretion of the majority of hormones of the adenohypophysis has an impulse character which complies with the short period of their decomposition. Unlike other hormones of the front part of the hypophysis, prolactin is formed in tonic mode (Lavin N., 1999). This type of incretion is made up of a "continuous message" and, accordingly, caries less information. The incretion mode of prolactin is determined by regulation by dopamine (DA), which also forms in tonic mode (Kettail V.M., Arki R.A., 2001). Prolactin is a phylogenetically older hormone, and its incretion mode is less complete as compared to that of other hormones of the adenohypophysis, which have an impulse incretion mode. As a result, the volume of information carried through incretion of prolactin is significantly inferior to the analogous value for the majority of other hormones which formed at later stage of evolution (Pechersky A.V. et al., 2002; Pechersky A.V. et al., 2006).
The development of PADAM is accompanied by a breakdown in the impulse regime of hormone incretion by the adenohypophysis. These changes lead to limitation and distortion of the information being transferred, which regulates a whole series of physiological processes including proliferate activity (Pechersky A.V. et al., 2002; Pechersky A.V. et al., 2006). For example, LH is the stimulator of synthesis of IGF-1 in Sertoli cells. IGF-1 strengthens the expression of LH receptors on Leydig cells, and thereby activates steroidogenesis. FSH has a slowing-down influence on the creation of transformation growth factors in Sertoli cells. Transformation growth factors reject steroidogenesis in Leydig cells (Lavin N., 1999). In relation to this, the frequency of the rhythm of formation of gonadotropin-releasing hormone, which determines the correlation between LH and FSH, has a direct influence on the level of cell growth factors, and, accordingly, on cell proliferation (Pechersky A.V. et al., 2002; Pechersky A.V. et al., 2006).
As testosterone production goes down as men get older the agreement between the central and peripheral core of the hypothalamus-hypophysis-gonad system is broken down. When changes in the testes take place as men get older (smaller quantity of Leydig cells), those patients who have PADAM demonstrate that the impulse incretion of gonadotropin-releasing hormone and LH isn’t accompanied by an adequate impulse incretion of testosterone. The central nervous system understands this state to be an even deeper manifestation of androgen deficit. There is thus a compensatory increase in the levels of gonadotropin-releasing hormone, LH, and FSH, using a mechanism of inverse feedback (Lavin N., 1999). Despite the increase in the level of testosterone, the mode for testosterone incretion becomes non-physiological, and gradually becomes tonic. The reaction of Leydig cells in tonic mode to the impulse formation of gonadotropin-releasing hormone and LH among men with PADAM is accompanied by a gradual transition to a tonic regime of hormone incretion by the hypophysis and hypothalamus. Apparently, a decrease in impulse incretion of hypothalamus-hypophysis hormones is additionally determined by the suppression of activity of neuron-pacemakers of the suprachiasmatic core due to the transition to tonic regime of the periphery endocrine organs (testosterone) and, accordingly, changes in the characteristics of the afferent signal which is received as part of the mechanism for negative inverse feedback.
The long and continuous (in the tonic mode) influence of gonadotropin-releasing hormone leads to de-sythesization of this hormone's receptors on gonadotropin cells, and to suppression of the incretion of LH and FSH, despite the remaining deficit of testosterone (Montanari E. et al. 1995; Lavin N., 1999). Thus, among those patients studied with PADAM the original levels of LH and FSH don’t exceed the normal referential interval.
The use of analogues of gonadotropin-releasing hormone, which have a suppressing influence on gonadotropin cells of the hypophysis as well as on Leydig cells (Lavin N., 1999), is based on this effect.
Suppression of the impulse incretion of gonadotropin-releasing hormone, in turn, is reflected in the correlation of LH and FSH, and in the formation of cell growth factors. A vicious circle is formed.
Melatonin together with a change in the expression of its receptors in the suprachiasmatic core has a significant influence on regulation of neuron-pacemakers (Klein D.C. et al., 1991).
An increased level of prolactin, which is observed among patients with PADAM (Pechersky A.V. et al., 2003), leads to suppression of the impulse incretion of gonadotropin-releasing hormone and, consequentially, of the impulse rhythm of production of LH, FSH, and testosterone, as well as to suppression of impulse incretion of STH (Lavin N., 1999). Cortisol has an influence on the regulation of rhythms of the suprachiasmatic core, which is proven by the high concentration of receptors of corticosteroids in the suprachiasmatic core (De Kloet E.R. et al., 1988). Any deviation in production of cortisol from the norm, whether it be a significant decrease in production (when patients have adrenalectomy) (Arduinin D. et al., 1986, 1987), or an increase in cortisol levels together with a reduced amplitude of its impulse incretion (when patients have PADAM) (Pechersky A.V. et al., 2006), has a suppressive effect on neurons-pacemakers of the suprachiasmatic core. Insulin resistance, which goes along with PADAM (Pechersky A.V. et al., 2003), leads to the exhaustion of β cells and to a breakdown in the impulse incretion of insulin (Lavin N., 1999). One can see a significantly lower amplitude of fluctuations in insulin levels among patients with PADAM (Pechersky A.A. et al., 2006).
The transfer of the hormonal signal which regulates mitotic activity is sent through G-protein. G-protein in its activated form stimulates the synthesis of cyclical adenosine monophosphate from adenosine triphosphate through adenylate cyclase, and stimulates the synthesis of cyclical guanosine monophosphate from guanosine triphosphate through guanylate cyclase. Adenosine monophosphate and guanosine monophosphate launch the mechanism for activiating inner-cell proteins. The phosphorylation-dephosphorylation process is the fundamental mechanism for making the biological effect of “secondary" messengers within cells. Phosphorylation is the most important post-translation modification of protein molecules that activates or inhibits the fermentive activity of protein molecules. Dephosphorylation leads to inactivation of the ferment, and to a return to the original state by stopping the transfer of the mitotic signal. Hormonal regulation of mitotic activity of normocytes is discreet and impulsive. The change from the impulse formation of hormones to a tonic incretion regime inhibits the onset of the physiologically necessary dephosphorylation phase. The signal chain, which caries the mitogenic signal, takes on a continually active state (“the pressed button effect”). The cell is thereby held in a regime of constant mitotic activity. The activity of adenylate cyclase and guanylate cyclase gets an additional stimulus from ions of Ca++ and free radicals – products of peroxide oxidation of lipids (Karpishenko A.I., 2001; Beryezov T.T., Korovkin B.F., 2004). The levels of the latter go up among patients with age-related deficiency of testosterone production (Pechersky A.V. et al., 2003; Pechersky A.V. et al., 2006).
The daily dose of the testosterone preparation which enters the blood plasma when making androgen-replacement therapy among patients with PADAM shouldn’t exceed the average daily production of testosterone in healthy men: 5-7 mg/day (Lavin N., 1999; Morales A. et al., 2006). Giving a larger dose per day leads to suppression of the body’s own production of testosterone, with loss of incretion rhythm. Thus, restoration of regulation, which should be done by testosterone, won’t take place. In this way the physiological rhythm of incretion of hormones helps the neuroendocrine system to complete its main function, which is integration of various biological processes into a single organism. These processes take place on the molecular, cell, tissue, organ, and system levels. An age-related decrease in the production of peripheral hormones (especially during PADAM) leads to a loss of impulse rhythm and the establishment of a tonic incretion mode for a whole series of hormones, as well as to an increase in mitotic activity. The reverse development of these changes can be observed in men of older age groups with PADAM who are given androgen-replacement therapy. The restoration of the physiological regime of incretion of testosterone, in turn, is the main criteria by which the success of androgen-replacement therapy can be judged.

THE ROLE OF TESTOSTERONE IN REGULATION OF THE EXPRESSION OF GENES OF SEVERAL PROLIFERATION FACTORS

Due to the inter-dependence of neurohumoral regulatory processes (Lavin, 1999), inadequate testosterone production as a result of a reduction in the number of cell-producers of testosterone (Leydig cells) leads not only to an increase in the formation of LH, but has an influence on the entire endocrinal regulation system as well. An entire series of genetically determined compensatory-adaptive reactions takes place. These changes are combined with an increase or a decrease in the expression of the according genes (Pechersky A.V. et al., 2005).
The receptor apparatus which accepts the signal, together with cells, tissues and organs that make incretions form a unified interdependent system. Activation of receptors on the cell membrane increases the effect of the according regulating factor (Lavin N., 1999; Kettyle V.M., Arki R.A., 2001). The expression of AR and ER is added to by increased 5α-reductase and aromatase activity. This increase is observed when the testosterone level goes down (Pechersky A.V. et al., 2005). The fact that this reaction is typical is proven by the significantly higher level of the expression of the ER gene among patients with PADAM (Pechersky A.V. et al., 2006).
A decrease in the production of testosterone among men with PADAM and, correspondingly, a reduction in testosterone mytogenic activity, is compensated for by an increase in the synthesis of peptide growth factors, such as bFGF and several others (Pechersky A.V. et al., 2003). The main growth factor of fibroblasts, bFGF, has the most expressed stimulatory effect on proliferation of the cells of the epithelia. In terms of its mytogenic activity bFGF is stronger than EGF and a series of other cell growth factors (Lopatkin N.A., 1998). The expression of bFGF and EGF genes increases among patients with PADAM (Pechersky A.V. et al., 2006).
A decrease in the quantity of insulin receptors (insulin resistance) leads to a reactionary increase in the level of insulin. At this point insulin-independent sugar diabetes (type 2 diabetes) starts to develop. Insulin increases mytotic cell activity Lavin, 1999). From this point of view insulin resistance can be seen as a mechanism for increasing the level of insulin, and correspondingly, for increasing its mytogenic activity. A low level of the expression of the gene for insulin receptors among patients with PADAM testifies to the fact that the number of insulin receptors is reduced when testosterone production goes down (Pechersky A.V. et al., 2006).
The increase in the level of expression of these genes in men with PADAM is accompanied by an increase in the level of estrogens, bFGF, EGF, and insulin in the blood plasma. This increase stimulates proliferative activity (Pechersky et al., 2003; Pechersky et al., 2005).
Increased levels of mitogenic factors in the blood plasma have an effect both on androgen-dependent and androgen-independent cells of the organism.
Patients with PADAM regularly show an increased expression of the anti-apoptotic gene bcl-2, which allows one to speak of an increased risk of blastomatosis transformation during PADAM (Pechersky A.V. et al., 2006).
The given changes represent a series of compensatory-adaptive reactions which develop among men with PADAM, and have a systematic character.
Apparently the male organism has formed standard genetically-determined variants of functioning of the endocrinal and paracrinal-autocrinal regulation systems over the course of evolution. These variations match both normal conditions and the majority of pathological states a man can have, one of which is a reduction in the production of testosterone. The absence of adequate incretion of testosterone by Leydig cells in response to LH activity is accompanied by an increase in the expression of the ER, bFGF, EGF, and bcl-2 genes, as well as by a decrease in expression of the gene for insulin receptors (Pechersky A.V. et al., 2006).
The change in the pattern of gene expression takes place during the process of phylogenesis and depends on the level to which testosterone production has deviated from physiological norms. The new variations of the functioning of the endocrinal and paracrinal-autocrinal regulation systems, which arise when testosterone production decreases, are made through a mechanism of negative feedback.
The necessary level of testosterone is formed in the body as a response to LH incretion when androgen-replacement therapy in patients with PADAM is made properly. Autocrine-paracrine interaction is also normalized thanks to the obstruction-free passage of androgen-dependent cells through the testosterone-dependent cell development stage. When testosterone regulation is rehabilitated there is no longer any need for compensatory-adaptive reactions to take place in the body, as happens in men with PADAM. Instead one can observe the inverse: a decrease in the expression of the ER, bFGF, EGF, and bcl-2 genes, and an increase in the expression of the IR gene (Pechersky A.V. et al., 2006).
The inverse development of the expression of the given genes when PADAM is corrected points to the significant role of an age-related decrease in testosterone production at increasing the risk of the development of carcinogenesis among men in older age groups as well as to the reversibility of the given changes.
In conclusion, the normalization of testosterone production through androgen-replacement therapy helps make a decrease in both proliferative activity and insulin resistance among older men. These changes suggest that metabolic syndrome is possibly reversed (X-syndrome), which represents to a significant degree a phylogenetically-formed response to a decrease in sex hormones production. Taking this into consideration, attempts to change the expression of individual genes without taking into effect the systematic nature and succession of the changes that take place seem hardly promising.

EXTRAGONDAL TESTOSTERONE PRODUCTION AMONG AGING MEN WITH PARTIAL ANDROGEN DEFICIENCY

A whole series of compensatory-adaptive reactions aimed at increasing mytotic cell activity takes place in order to make up for a lack of endocrinal cell-division factors (Vasilyev Yu. M., 1997; Bershtein, L.M. 2000). The intensity of these reactions is proportional to the amount by which the testosterone level drops. The given compensatory changes are expressed both by intensification of the incretion of various mytogenic factors, and by an increase in the production of testosterone itself (Pechersky A.V. et al., 2003; Pechersky A.V. et al., 2005).
The increase in testosterone production is achieved both thanks to hypophyseal stimulation of Leydig cells and thanks to the process of testosterone synthesis by other tissues, for which such a function should be abnormal.
Extragonadal synthesis of steroid hormones is caused by hormonal and autocrinal-paracrinal factors which have mytogenic activity (Mendelson C.R., Simpson E.R., 1987; Lueprasitsakul P., Longcope C., 1990; Jakob F. et al., 1995; Shozu M. et al., 1996; Bersthein L.M., 1998; Ryde C.M. et al., 1992; Bersthein L.M., 2000).
Each of the eukaryotic cells (with minor exceptions) is a carrier of the individual’s entire genetic information. While the genome is almost identical for all cells in the organism, their proteom and metabolom are determined by inner and outer physiological factors. The fact that cells are included in compensatory reactions means that this process is capable of modulating their metabolom, which is proven by the hormonal activity of a significant number of non-endocrinic cells in the organism. Potentially any cell in the organism can have hormonal activity. For example, patients with PADAM have extra-gonadal testosterone production (Pechersky A.V. et al., 2005), while analogues of hypophysial hormones can be formed by cells of the cancerous tumor of the prostate gland (Franklin R.B., Costello L.C., 1990; Costello L.C., Franklin R.B., 1994; Naz R.K., 1997), extra-gonadal production of estrogens is done by fatty tissue and several other types of tissues among women (Bershtein L.M., 1998) in the menopause period, rennin is synthesized by myocytes of the wall that brings arterioles transformed into epitheliod cells, and by deep-colony forming cells of the kidney when there is an expressed and long-term ischemia of its tissues (Tareeva I.E., 1995) and other examples.
Hormonal activity among tissues which are neither endocrinal or neuroendocrinal by nature is a result of either a lack of the corresponding endocrine factor (for example, extragonadal production of androgens among men with PADAM (Pechersky A.V. et al., 2005) and of estrogens among women (Bersthein L.M., 1998) during the menopause period) or by the hormone formed taking part in the chain of compensatory-adaptive reactions. An example of the latter is the synthesis of prolactin by tissue of cancerous tumors in the prostate gland (Franklin R.B., Costello L.C., 1990; Costello L.C., Franklin R.B., 1994), which leads to an increase in aromatase activity (Pankov A.Yu, 1983).
Apparently the situational expression of compensatory hormonal activity by the majority of cells and tissues (including tumorous ones) forms a diffuse endocrine system (APUD-system) (Pechersky A.V. et al., 2005).
The strongest expression of extragonadal production of testosterone among men in the andropause period is achieved when there is a significant increase in mitotic activity of cells; when there is a malignant transformation (Pechersky A.V. et al., 2005). The malignant transformation of cells is the most expressed manifestation of compensatory changes as PADAM develops. This given effect, apparently, has an influence on the pathophysiological role of the cancerous tumor.
Extragonadal testosterone production is directed at compensating for partial age-related androgen deficiency. Among some patients with PADAM extragonadal testosterone production allows men to support their total testosterone level within the range of a normal referent interval despite the fact that these patients belong to older age groups. In some cases among older men the level of total testosterone is significantly higher than the upper level of the norm. Extragonadal testosterone production makes it harder to diagnose PADAM.
The compensatory incretion of hormones by non-endocrinal cells and tissues is not a regulated process however (Tareeva I.E., 1995; Lavin N., 1999; Kettyle V.M., Arky R.A., 2001) and is not adequate. This is evidenced by the signs of a lack of testosterone regulation among patients with PADAM in the form of atrophy of androgen-dependent tissues and the expression of AR in these tissues (Pechersky A.V. et al., 2005).
Endocrinal tissues have a whole series of unique enzymes for synthesis of the according hormones. For example, a series of peptide hormones from the hypophysis have oligosaccharide chains with a high amount of mannose. These chains end both with sialic acid and with sulphates. Analogous hormones which aren’t made by the hypophysis and for which transferase of the hypophysis doesn’t play a role in development have only sialic acid at the end of their oligosaccharide chains. Biological activity is determined for the most part by the speed at which the hormone is taken out of the body, rather than by the hormone’s quantitative amounts. Peptide hormones with oligosaccharide chains that end with sulfate have a shorter period of half-breaking. This allows them to support the physiological impulse regime of regulation and to support the necessary sensitivity of their receptors. The forms of hormones that hold sialic acid or free mannose for the most part have a longer period of half-breaking. This particularity doesn’t give them the chance to support the regulatory process in full; the biological activity of the given isoforms of hormones is much lower in these cases (Szkudlinski M.W. et al., 1993). A breakdown in the defense of ending carbohydrate remainders of a whole series of chemical structures together with the appearance of free mannose on their surface (Yarilin А.А., 1999) is characteristic of men of older age groups (Pechersky A.V. et al., 2006).
Prescribing of androgen-replacement therapy using testosterone preparations leads to the reverse development of the above-mentioned compensatory-adaptive reactions and to a decrease in extragonadal testosterone production. This conclusion is proven by results from a ten-year study of the use of a preparation of testosterone undecanoate. These results show an absence of a significant increase in the total testosterone level after the beginning of androgen-replacement therapy (Gooren L.J.G.,1994).
Thus, extragonadal testosterone production by a whole series of tissues is the result of partial age-related androgen deficiency (PADAM). These changes are directed at compensating for the inadequacy of testosterone production by the testicles. The restoration of regulation made by testosterone which is made possible when adequate androgen-replacement therapy is conducted takes away the need to to make a complex of compensatory-adaptive reactions that develop among patients with PADAM. The reverse development of these pathological processes is observed, including a reduction in extragonadal production of testosterone production. The latter is proven by the absence of an increase in total testosterone or a reduction in total testosterone production among patients.

THE ROLE OF PARTIAL ANDROGEN DEFICIENCY AMONG AGING MEN IN THE DEVELOPMENT OF BENIGN HYPERPLASIA AND PROSTATE CANCER

Processes of growth and differentiation of cells of the prostate gland that contain androgen receptors depend on testosterone (Lopatkin N.A., 1998; Kettail V.M., Arki R.A., 2001). In the presence of PADAM the development of androgen-independent transitory-proliferate cells into the androgen-dependent pool of transitional cells (Lopatkin N.A., 1998), which requires the presence of a physiologically necessary level of testosterone for their future development, is accompanied by a breakdown in their differentiation. The risk of their neoplastic transformation increases (Russo J., Russo I. H., 1997; Bershtein L.M., 2000; Pechersky A.V. et al., 2000; Pechersky A.V. et al., 2005).
The increase in 5α-reductase and aromatase activity under partial age-related androgen deficiency promotes an increase in production of 5α-dihydrotestosterone and 17β-estradiol (Pechersky A.V. et al., 2002; Pechersky A.V. et al., 2003; Pechersky A.V. et al., 2005).
The greater affinity of linking of 5α-dihydrotestosterone with the androgen receptor determines the higher physiological activity of 5α-dihydrotestosterone, which is 5-10 times higher than testosterone (Lavin N., 1999). Thus, when there is an age-related reduction in testosterone production, the increase in the share of 5α- dihydrotestosterone reduces the negative manifestations of the given state.
In the prostate gland more than 90% of testosterone is irreversibly transformed into 5α-dihydrotestosterone, and the concentration of 5α-dihydrotestosterone in the prostate exceeds the concentration of testosterone by 5 times. The ratio in the blood plasma is the reverse: there is 10 times less 5α-dihydrotestosterone than testosterone (Dedov I.I., Kalinchenko S.Yu., 2006) in the blood plasma.
The high dependency of prostate gland cells on the formation of testosterone under conditions of an even small decrease in testosterone production leads to a compensatory increase in production of 5α-dihydrotestosterone, especially in the transit zone of the prostate gland, where the content of 5α-dihydrotestosterone in the presence of BPH is 2-3 times higher than in other parts of the organ (Lopatkin N.A., 1998; Lavin N., 1999).
That said, 5α-dihydrotestosterone does not serve as a complete replacement of testosterone: unlike testosterone, it is formed in tonic regime, while production of 5α-dihydrotestosterone does not correspond to the impulsive formation of LH. Moreover, the greater decrease in testosterone production as men get older limits the formation of 5α-dihydrotestosterone and the manifestation of the given compensatory mechanism even though there is an increase in 5α-reductase activity.
The stimulating effect of 5α-dihydrotestosterone is made, mainly, on the epithelial cells. 17β-estradiol stimulates estrogen receptors located both in cells of the stroma and in cells of the epithelium of the prostate gland, with more of them being found in the stroma.
The greatest activity of aromatase in the prostate gland in the presence of its malignant hyperplasia can also be observed in the transit zone, in which there is an accumulation of 17-estradiol and estrone. Their induction of growth in stromal cells, which contain estrogen receptors, for a second time leads to proliferation of the epithelium with the formation of new glandular structures (Lopatkin N.A., 1998).
An increase in the formation of 5α-dihydrotestosterone and 17β-estradiol among patients with PADAM is supplemented by the activation of a series of hormones, cell growth factors, and cytokines. There is an increase in the levels of STH, IGF-1, insulin, bFGF and other factors (Pechersky A.V. et al., 2002; Pechersky A.V. et al., 2003). bFGF has the most expressed stimulating influence on the proliferation of the epithelium of the prostate gland, exceeding EGF and several other growth factors (Lopatkin N.A., 1998). An increase in the expression of genes of peptide growth factors under the influence of estrogens (Bershtein L.M., 2000) also promotes the development of benign hyperplasia and prostate cancer. Insulin, together with IGF-1, increases the mitotic activity of cells (Yam D. et al., 1996; Bershtein L.M., 2000) including cells of the prostate gland. These factors are the most important in pathogenesis of the development of benign hyperplasia and prostate cancer (McKinlay J.B. еt al., 1989; Partin A.W. еt al., 1991; Stoner E., 1992; Montanari E. еt al., 1995; Lopatkin N.A., 1998).
An increase in aromatase, 5α-reductase activity and the levels of the majority of growth factors shows that the developing compensatory-adaptive reactions in the presence of partial age-related androgen deficiency are directed at an increase in the mitotic activity of cells, while their expression is proportional to the level of the decrease in the production of testosterone (Pechersky A.V. et al., 2003).
Stimulation of aromatase and 5-reductase activity is accompanied by compensatory hyperplasia of tissues which contain the given enzymes. In particular one can observe hyperplasia of the paraurethral glands of the prostate with an increase not only in the number of glandular cells, but also in their volume. An increase in the average size of cells of the glandular epithelium of the prostate with age has been noted by L.M. Bershtein (2000).
Thus an increase in the number and size of adenomatosis-transformed cells of the prostate gland which contain 5α-reductase is a compensatory reaction aimed at increasing the formation of 5α-dihydrotestosterone during a decrease in testosterone production.
An increase in proliferate activity of the cells of the prostate gland is accompanied by extragonadal testosterone production, which is also aimed at compensating age-related androgen deficiency. The strongest expression of the given compensatory-adaptive reactions is made in the presence of their malignant transformation.
Breakdowns in the process of development of androgen-dependent transitional cells, which are the result of PADAM, are morphologically shown through their atrophy, which is observed both in the presence of benign hyperplasia (Lopatkin N.A., 1998; Ryde C.M. et al., 1992; Sporn M.B., 1996; Bershtein L.M., 2000), and in the presence of cancer (in tissues not included in malignant growth) of the prostate gland. Atrophy of the epithelium of the acinuses together with an increase in the expression of AR in the tissues of the peritumorous zone among patients with prostate cancer testifies to the inadequacy of such compensatory reactions under the development of PADAM as extragonadal testosterone production and an increase in the formation of 5α-dihydrotestosterone (Pechersky A.V. et al., 2005).
An increase in the expression of Ki67 and bcl-2 of atrophically-changed androgen-dependent tissues of the prostate gland points to the increased risk of their blastomatous transformation (Pechersky A.V. et al., 2005). The given changes make it possible to consider atrophic changes of the prostate gland, caused by PADAM, to be part of pre-cancer processes. Aromatase and 5α-reductase increases when making an androgen blockade among patients with prostate cancer even despite the significant decrease in the testosterone level and its metabolites: 5α-dihydrotestosterone and 17β-estradiol (Pechersky A.V. et al., 2002; Pechersky A.V. et al., 2003; Pechersky A.V. et al., 2005). A decrease in the level of testosterone and 5α-dihydrotestosterone after the beginning of the androgen blockade is compensated for not only by an increase in aromatase activity and 5α-reductase activity, but also by an additional increase in the levels of STH, IGF-1, insulin, 25-OHVitD3, estrone, and bFGF, which have an expressed mytogenic effect. These changes are caused by a lack of endocrine activators of separation (Vasilyev Yu. M., 1997; Bershtein L.M., 2000). An increase in the levels of the given factors is characteristic for the promotion stage of tumorous growth (Yam D. et al., 1996; Bershtein L.M., 2000). The given changes combine with suppression of the formation of TGFβ (Pechersky A.V. et al., 2003) – a factor which is responsible for the sequential passing by the cell through the stages of differentiation and the onset of apoptosis (Lopatkin N.A., 1998; Yarilin A.A., 1999; Bershtein L.M., 2000).
Cytotoxic factors of cell immunity (TNFα, hydrolases (acid phosphatase, alkaline phosphatase, serine proteinases and esterases), and the components of the compliment) utilize the newly-formed a-typical cells and launch a program of apoptosis (Yarilin A.A., 1999; Roitt I. et al., 2000).
After 40 years of age one can observe in men a gradual increase in the level of PSA-serine proteinase, which belongs to the class of hydrolases (Loran O.B. et al., 1999; Bershtein L.M., 2000), and, accordingly, have not only cytotoxide activity but also take part in the launch of the program of apoptosis in cell-targets. Thus an increase in PSA, besides its diagnostic meaning, which testifies to the entrance of an incretion of malignant cells of the epithelium of acinuses of the prostate gland which have overgrown the surrounding tissues into the bloodstream, also supplements the compensatory reaction of the system of the compliment and of cell immunity to the increase in mitotic activity (Pechersky A.V. et al., 2003). When there is a significant increase in the number of atypical cells the effective of these factors becomes inadequate. After the androgen blockade is begun one can notice that the initially high levels of cytotoxic factors of cell immunity (acid phosphatase, alkaline phosphatase, and TNFα) decrease. The decrease in both regulatory factors and the majority of cytotoxic factors of cell immunity testifies to the decompensation of the mechanisms of anti-tumor immunity among patients given an androgen blockade (Pechersky A.V. et al., 2003).
Thus the decrease in the testosterone level leads to an increase in mitotic activity, a breakdown in regulation of cell differentiation and the onset of apoptosis, and also (when there is a significant decrease in the level of testosterone) to decompensation of anti-tumor immunity.
The given changes, which arise after the beginning of implementation of the androgen blockade, create the conditions for growth of a new tumor from the low-differentiated androgen-independent epithelial cells, despite the dystrophic changes taking place in androgen-dependent cancer cells of the primary tumor.
Keeping in mind the many-stagedness of carcinogenesis (Bershtein L.M., 2000) and the good close effect, one can look at androgen blockades as a promising method for treating patients under the condition that the androgen blockade is conducted under relatively short courses of treatment, and that the hormonal balance in the body is restored to normal after the androgen blockade is finished. Considering that it’s impossible to restore hormonal balance without testosterone production by the body’s own Leydig cells (Pechersky A.V. et al., 2002), one can recommend only a pharmacological androgen blockade thanks to the fact that it is reversible.
Thus an age-related decrease in testosterone production can be viewed as the main factor promoting the development of benign hyperplasia and cancer of the prostate gland. The development of benign hyperplasia and prostate cancer, together with insulin resistance and osteoporosis, is a partial manifestation of metabolic syndrome (X-syndrome), which is made up of a series of compensatory-adaptive reactions the development of which in men of older age groups is caused to a significant degree by a decrease in testosterone production.
When PADAM is corrected (when making androgen-replacement therapy) the compensatory reactions that had been developing become unnecessary; one can observe their reverse development, including a decrease in the size of benign hyperplasia of the prostate gland (Pechersky A.V. et al., 2002). The effectiveness of this therapy depends on the degree of restoration of physiological regulation made by means of testosterone.

DIAGNOSTICS OF PARTIAL ANDROGEN DEFICIENCY AMONG AGING MEN

The reduction in testosterone production in men older than 40 years of age takes place at an average rate of 0.4 – 2.8% per year. Most of all free testosterone production is reduced (1.2 – 2.5% per year). A reduction in the level of total testosterone is found in only 7 – 30% of all cases. At 80 years of age the average level of total testosterone is 40% lower than the same figure at 25 years of age, while free testosterone is 60% lower than at age 25. Thus one can most often speak of partial rather than absolute androgen deficiency (Vermeulen A., Kaufman J.M., 1998; Feldman H.R. et al., 2002; Vermeulen A., Kaufman J.M., 2002; Dedov I.I., Kalinchenko S.Yu., 2006). The stronger drop in free testosterone level makes for the high diagnostic significance of this figure.
Extragonadal testosterone production, which compensates for PADAM, makes diagnostics of free testosterone harder (Pechersky A.V. et al., 2005).
A decrease in testosterone production leads to corresponding changes in hypothalamus-hypophysis regulation. The level of testosterone depends on the formation of luteinizing hormone, (LH) of the hypophysis. When the level of testosterone in the blood plasma is either raised or decreased using the mechanism of negative feedback the level of LH is changed accordingly. Analogously the level of thyrotropic hormone is used in diagnostics of the euthyroid state and when evaluating the use of the replacement therapy (Whitley R.J. et al., 1994).
A decreased level of testosterone stimulates the incretion of LH as well as the incretion of gonadotropin-releasing hormone (Lavin N., 1999), and, (secondarily) a incretion of FSH. However, when making primary analysis some patients with partial age-related androgen deficiency do not show LH and FSH levels that exceed normal values. In the presence of PADAM one can observe increased activity of 5α-reductase and aromatase, and, subsequently, an increase in the levels of 5α- dihydrotestosterone and 17β-estradiol (Pechersky A.V. et al., 2002; Pechersky A.V. et al., 2003). Increased levels of 5α-dihydrotestosterone and 17β-estradiol suppress the incretion of LH, FSH, and gonadotropin-releasing hormone based on the principle of negative feedback (Lavin N., 1999). For this reason the reduction in the production of testosterone in the presence of PADAM and the ensuing responsive increase in the levels of 5α- dihydrotestosterone and 17β-estradiol thanks to an increase in the activity of 5α-reductase and aromatase (Pechersky A.V. et al., 2002) might not be accompanied by increased levels of LH and FSH in some patients (Pechersky A.V. et al., 2003).
Testosterone inhibits production of globulin for connecting sex hormones by the liver. A decrease in testosterone level leads to an increase in the level of globulin for connecting sex hormones in the plasma (Dedov I.I., Kalinchenko S.Yu., 2006). An analogous effect can be observed when the level of estrogens increases (Lavin N., 1999). After 40 years of age the level of globulin for connecting sex hormones in each man increases by 1.3% per year (Feldman H.R. et al., 2002). As a result the amount of testosterone that is available to cell targets (free testosterone and testosterone connected with albumin) goes down even more. At the same time the level of total testosterone in the blood serum remains close to the norm (Lavin N., 1999).
Incretion of gonadotropin-releasing hormone by the hypothalamus, as well as of LH and FSH by the hypophysis, take places on average every 90 minutes. Testosterone incretion is also characteristically impulsive and takes place every 90 mintues (Lavin N., 1999). In normal a state the amplitude of fluctuations in the incretion of LH, FSH and total testosterone can more than double (the minimum value of hormone is different from the maximum level by 100% or more) (Lavin N., 1999). When the number of Leydig cells goes down among men of older age groups the impulse incretion of gonadotropin-releasing hormone and LH is not accompanied by an impulse formation of an adequate amoung of testosterone, and the regime of testosterone incretion transforms from an impulse regime to a tonic one (Bremner W.J. et al., 1983; Lavin N., 1999). In order to make diagnostics of the breakdown in the rhythym of incretion one should measure hormone levels by taking five samples in the blood serum, taken at an interval of 20 minutes each (Pechersky A.V. et al., 2002) – a period of time that covers the whole average period of impulse incretion (Lavin N., 1999).
Thus, 5α-dihydrotestosterone, 17β-estradiol, total testosterone, free testosterone, globulin, which connects sex hormones, LH, and FSH are a united inter-dependent system. The age-related decrease in the incretion of testosterone concerns all levels of this system. The given values and the estimate of the rhythym of incretion of part of them objectively reflect PADAM. They can be used both in primary diagnostics of partial age-related androgen deficiency and in evaluating the effectiveness of using androgen-replacement therapy.
A decrease in the levels of common and free testosterone, and an increase in the levels of 5α-dihydrotestosterone, 17β-estradiol, globulin, which connects sex hormones, LH and FSH, and a decrease in the amplitude of the fhythym of incretion of LH, FSH and total testosterone will testify to a lack of testosterone. Conversely, a normalization of the given values will point to the adequacy of the androgen-replacement therapy provided (Pechersky A.V. et al., 2002).

METHODS FOR CORRECTING PARTIAL ANDROGEN DEFICIENCY AMONG AGING MEN

Therapy for treating partial age-related androgen deficiency should be aimed at the eliminating the hormonal system’s imbalance which forms as a result of certain of the system’s parts getting out of balance.
Replenishment of the pool of pluripotent stem cells in people of older age groups will help promote their adequate entry into cambial zones with the subsequent replacement of old necrotizing cells with an adequate quantity of committed cells. Apparently, behind this there is a reverse development of the pathological processes (including changes in endocrine organs) described above. The positive clinical dynamics among oncological patients when transplanting their own cultured pluripotent stem cells, or when making therapy with the use of colony enhancing factor, proves the given conclusion (Konstantinova M.M., 2004).
There must be support of a normal quantity of cells in the pool of pluripotent stem cells in order to ensure that the constant process of tissue renewal in people of older age groups can go on unharmed. Cultivation of the patient’s own pluripotent stem cells with their subsequent transplantation is not very promising. Under this method the transplanted cells don’t have a proliferate advantage above the patient’s other pluripotent stem cells (they all accord to one and the same age stage of the development program). The use of the given method is limited by the difficulty of implementation (making its many-time use more difficult), as well as by the temporary nature of the increase in the quantity of pluripotent stem cells in the peripheral blood after transplantation. The use of autologic stem cells is justified only when they are prepared ahead of time at a younger age (for example at 18-25 years of age). The given method is restricted however by the cost of specialized storage of stem cells, while the effectiveness of this method is inversely proportional to the age at which the cells are gathered.
The use of pharmacological preparations of colony-stimulating factor, as well as of preparations which stimulate formation of colony-stimulating factors by macrophages (preparations containing microbe lipopolysaccharides, autohemotherapy (the use of cups) and other methods) is expedient only under constant use. The prescription of this therapy using separate courses can’t guarantee the permanency of the normal quantity of cells in the pluripotent stem cell pool. Furthermore, pluripotent stem cells in people of older age groups constantly undergo increased stimulation due to the excess formation of colony enhancing factors. The additional stimulation of proliferation speeds up the exhaustion of their pool, which will require an increase in the dose of preparations used in the therapy process. The given therapy will become ineffective at a certain point. Artificial transformation of cells (which relate to other directions of differentiation) into pluripotent stem cells also doesn’t seem to be promising. The given cells form, thereby avoiding the many-staged differentiation pathway of embryo cells into pluripotent stem cells, as firmly determined by the development program. For this reason these cells can’t be a full-fledged alternative to pluripotent stem cells. Furthermore, there use may increase the risk of development of oncological illnesses.
The potential possibility of renewal of epithelium cells of the thymus (conducting the study of T-lymphocytes) through transplantation of allogenic stem cells with their subsequent perception of tissue-specific antigens of the immune system of the recipient as “their own” makes it possible to consider transplantation of allogenic pluripotent stem cells as the most promising way of supporting a normal quantity of the pool of pluripotent stem cells among people of older age groups. After transplantation pluripotent stem cells form their own pool, which takes part in the renewal of the majority of the quantity of tissues of the organism. The individual becomes a chimera.
One must note that chimerism is widespread in living nature: the appearance of many-celled organisms through unification of one-celled became possible forms thanks to chimerism. Seizure by the eukaryotic cell of the procariotic cell led to the appearance of mitochondrions–organellas of eucariotic cells, which have their own DNA (Alberts B. Et al., 1994). The appearance of the rhesus-conflict at birth of an Rh+ child by a Rh- mother (Roitt I., et al., 2000) testifies to the fact that the cells of the baby fall into the mother’s blood at birth. Apparently, besides red blood cells, all components of the child’s blood enter the mother’s blood, including pluripotent stem cells, which will lead to chimerism of the mother. Considering the widespreadness of chimerism in natural conditions, artificial formation of the chimeral individual may be used for solving a whole series of practical medical tasks.
The effectiveness of transplantation of allogenic pluripotent stem cells to people of older age groups will depend on the difference between the age of the donor and the age of the recipient. In this case the most important stage is that of the long-term inner-cell program, where the donor’s cells and the recipients cells are located. The presence of long-term inner-cell programs of pluripotent stem cells, which determine their proliferation potential (their capability to support the necessary quantity of their own pool), differs pluripotent stem cells of young people significantly from the according cells of older people.
Bone marrow can be used in order to transplant pluripotent stem cells, apparently, as well as peripheral pluripotent stem cells or whole blood (in which there is always a certain amount of pluripotent stem cells). Considering the development of subsequent immunological tolerance, transplantation of the given mediums can be fulfilled many times for achieving normalization of the pool of pluripotent stem cells.
From these positions the transfusion of the donor’s umbilical blood, in the cells of which the expression of all common antigens of the MHC I class is suppressed, with the exception of HLA-G (which makes it possible to prevent the danger of the rejection of the placenta and fetus, which have the father’s genes) (Roitt I. et al., 2000), doesn’t give much of an advantage. Furthermore, the amount of umbilical blood of one donor, as a rule, is not enough to form the necessary pool of pluripotent stem cells in the recipient. Conducting the subsequent transplantations of bone marrow (or pluripotent stem cells, or whole blood) from the given person looks impossible considering the ethic and legal limitations connected to his age.
When there is a significant difference in age between the donor and the recipient the proliferate potential of pluripotent stem cells of the donor will gradually exceed the analogous figure for the recipient. This leads to domination of the pool of pluripotent stem cells of the donor in response to the formation of colony-stimulating factors of the recipient, as well as to constant renewal due to the predominance of cells of the recipient’s tissues. Thus, under these conditions the optimal situation is to use pluripotent stem cells from one donor for transplantation (or, what is less desirable, from a limited number of donors).
The participation of transplanted pluripotent stem cells in the renewal of the majority of tissues of the organism, including tissues of endocrinal organs, requires taking a whole series of additional factors into account. Transplantation of bone marrow or stem cells of peripheral blood or whole blood from the donor of one sex to a recipient of the other sex may have a negative influence on regulation of sex hormones. There is greater risk of the development of various cardio-vascular diseases when increasing the formation of hormones of the opposite sex. The vicinity of cells from individuals of various sexes in one tissue, most likely, is also accompanied by various reactions. The analogous incompabatability reactions, apparently, may arise under transplantation of bone marrow or stem cells of peripheral blood from the donor to the recipient who have various blood groups.
The differences connected with the sex of a person and blood group manifested themselves early on in the evolution process. The formation of all regulatory systems of man’s body during the process of phylogenesis took place taking into account these factors. For example, antigens of the 0AB system are present not only on red blood cells, but also on many other cells in the body too, and are expressed by a large number of microorganisms. Antigens of the 0AB system are localized in the carbohydrate part of glycoproteins. The structure of these carbohydrates, just as of carbohydrates which determine the Louis near blood group system, depends on the expression of genes which determine the activity of enzymes that transport terminal sugars during synthesis of oligosaccharide molecules (Roitt I., et al., 2000). For this reason the transplantation of pluripotent stem cells in the group of stem cells of peripheral blood or the bone marrow, or of whole blood, should be done from the donor to the recipient of one sex which have equal blood groups.
A reduction in the percentage of cells replaced in the female patient with a developed reaction of “transplant against its carrier” as compared with data of patients without registered complications (Pechersky A.V. et al., 2007) testifies to the negative influence of the reactions of incompatibility on the process of renewal of tissues by stem cells. In an analogous way to Werner syndrome, the breakdown of the process for renewal of tissues can have a series of complications, including development of cataracts.
It’s possible that the formation of the chimeric individual through the transplantation of bone marrow or stem cells of peripheral blood or whole blood will make it possible to solve a whole series of tasks. The development of immunological tolerance will make it possible to transplant any tissues or organs from the primary donor.
Transplantation of allogenic organs or tissues without the preliminary formation of the chimerism in the recipient will be accompanied by a gradual replacement of cells of the donor organ by stem cells of the recipient with their subsequent differentiation. One can exclude the parallel inclusion of cambial cells into the differentiation process of the transplanted donor’s organ through the preliminary use of cytostatic drugs. The process of replacement of the donor’s organ by the recipient’s stem cells can be made even faster by making courses with the use of preparations of colony-stimulating factors, and also, by using preparations which contain xenogenic chemoattractants of transplanted organs or tissues (for ensuring the aim of their migration). The use of hyaluronic acid preparations for improving migration of stem cells is promising. Hyaluronic acid represents one of the groups of glucoseaminoglycane. Attracting water, and thereby leading to swelling of the inter-cellular matrix, hyaluronic acid lightens the migration of cells, thereby easing there regeneration (Alberts B. et al., 1994).
When tissue is damaged, apparently, just the stoppage in the action of the damaging agent and removing the necrotizing cells (for example, thanks to the use of proteolytic enzymes) is not enough. One can significantly improve regeneration and reduce the expression of scaring of the damaged tissue by stimulating the formation of an additional quantity of pluripotent stem cells when using colony stimulating factors or using preparations which initiate the formation of colony stimulating factors by macrophages (medicinal means which contain microbal lipopolysaccharides, autohemotherapy (the use of cups)). The given effect can be accompanied by the use of preparations which ensure the migration of stem cells into the region of damage (preparations which contain xenogenic chemoattractants of the damaged organ or tissue), as well as by the prescription of hyaluronic acid, which improve the migration of stem cells through the inter-cell space.
Apparently, another potential way to treat patients with various hereditary diseases, including Werner syndrome, could be transplantation into these patients of bond marrow or peripheral stem cells, or whole blood from healthy donors of the same sex as the recipient who have the same blood group after the preliminary conditioning.
The tropics of infectious disease pathogens are determined to a significant degree by the presence of the corresponding receptors in cells-targets. Mutation of the given receptors, which can be observed in a certain part of the population, makes for resistance to infection. For example, mutation of the gene that codes the CCR5 receptor marked as ∆32, leads to resistance to Human Immunodeficiency Virus (HIV) infection among homozygotes. The CCR5∆32 mutant allele is found among 12-18% of European people in the heterozygous state, and in 1% in the homozygous state (Belozerov E.S., Bulankov Yu.I., 2006). Transplantation of pluripotent stem cells from people with resistance to infection to patients leads to the appearance of cells and tissues in the latters which are unreceptive to the given pathogens.
The breakdown in the process of renewal of endocrinal organs leads to the development of hormonal imbalance, which have a significant effect on factors of the extra-cell medium, regulating cell aging. Patients need to have the according correction in order to increase the effectiveness of transplantation of pluripotent stem cells. In particular, when there is an age-related reduction in testosterone production that leads to an increase in the levels of such inductors of apoptosis as glucocorticoids, tumor necrosis factor-α (TNFα), active forms of oxygen and nitrogen (Pechersky A.V. et al., 2003; Pechersky A.V. et al., 2006), it is recommended that patients be given preliminary androgen-replacement therapy.
In order to perform androgen-replacement therapy one can use the following preparations: peroral preparations of testosterone (Andriol (testosterone undecanoate)), injection forms of testosterone (Nebido, Sustanon-250, Omnadren-250), and preparations of testosterone in the form of gels (Androgel, Testogel) and plasters. Peroral preparations of testosterone (Andriol (testosterone undecanoate)), are absorbed in the rectum and enter the bloodstream through the lymphatic system without primary metabolism in the liver (Nieschlag E. et al., 1975; Loran O.B. et al., 1999), which allows for these preparations to be used for a long time with the goal of performing replacement therapy in the presence of an age-related decrease in testosterone production.
In order to conduct diagnostics of possible side reactions, it is recommended that androgen-replacement therapy be performed only when the levels of creatinine, urea, common bilirubin, glucose, the activity of alanine aminotransferase and aspartate aminotransferase, and other methods of analysis which are included in the “A Practical Guide to Screening and Monitoring of Male Patients Who Have Received Therapy Using Testosterone” are kept under control (Morales A. еt al., 1996). In order to exclude cancer of the prostate gland all patients are given preliminary finger and ultrasound rectal research of the prostate gland, an analysis of their PSA level and, if needed, a biopsy of the prostate gland.
A decrease in testosterone production in men over 40 years old is the result of natural processes of aging, and is proven by morphological changes in the testicles. Besides irreversible morphological changes of the testicles, the decrease in the incretory function of the testicles is connected to functional breakdowns. Thus in order to keep a normal level of testosterone the organism is required to use all of the remaining potential of the Leydig cells thanks to an increase in the production of LH by the hypophysis (McKinlay J.B. et al., 1989). The long-term (over the course of many years) functioning of the remaining Leydig cells at their limit of capability inescapably leads to a reduction in their functionality (Veldhuis J.D. et al., 1992). Changes in the Leydig cells under the influence of the long-term hyperstimulation of LH can be reversible to a significant degree. An example can be the temporary character of the reduction in the functionality of the testicles in sterile men after therapy using gonadotropin preparations (Pepperell R.J. et al., 1986).
The restoration of reversible changes in the Leydig cells can be aided by a series of medicinal means (nicotinamide, cytochrome С, vitamin Е, mildronate and others), a part of which is the coenzymes of biological oxidation in the cells of people and animals.
The use of these preparations allows for an increase in the share of personal physiological synthesis of testosterone by the gonads in addition to the exogenous introduction of the hormone.
An exogenous introduction of testosterone in patients with PADAM leads to a decrease in the level of LH and a decrease in the levels of hormonal and autocrine-paracrine factors that stimulate both gonadal and extragonadal synthesis of steroid hormones. A decrease in the level of the given factors leads to a reverse development of compensatory-adaptive reactions that are directed at hyperstimulation of the production of testosterone. Therefore the prescription of small doses of the preparations of testosterone may not be accompanied by a significant increase in the level of common testosterone, which is proven by the results of ten years of use of testosterone undecanoate (Gooren L.J.G., 1994).
When calculating the daily dose of testosterone that enters the blood plasma when making androgen-replacement thereapy among patients with PADAM, one must keep in mind average daily testosterone production among men (5 - 7 mg/day) (Lavin N., 1999; Morales A. et al., 2006), as well as the age dynamic of the decrease in testosterone (approximately 0.4%-2.8% per year for common testosterone) (Dedo I.I., Kalinchenko S. Yu., 2006). Exceeding this figure using exogenous testosterone will lead to suppression of the body’s own production of the hormone, and to a loss in the rhythym of testosterone incretion. In this case androgen-replacement therapy will stop fulfilling its main role – restoration of regulation made by means of testosterone. Considering that about half of the mass of testosterone undecanoate, as well as part of the preparation, is lost when being located and absorbed in the gastrointestinal tract, the most optimal size per capsule of testosterone undecanoate is a dose of 40 mg per day. The optimal daily dose for transdermal gel testosterone preparations, apparently, is 10 - 15 mg of testosterone per day considering that losses due to absorbation equal about 90% (Pechersky A., 2006).
Optimal androgen-replacement therapy should make the level of introduced exogenous testosterone as close as possible to the daily physiological fluctuations in testosterone, with a maximum level in early morning hours and then a gradual drop throughout the rest of the day.
Normalization of the content of LH and other hormonal and autocrinal-paracrinal factors when androgen-replacement therapy is made is optimal for the functioning of Leydig cells. In this case, one doesn’t observe either their depletion as a result of hyperstimulation or a decrease in their function due to hypostimulation. Thus, if in the future the level of LH and other values that characterize the state of testosterone regulation will be kept within the norm, there won’t be a need to use therapy that improves the state of the patient’s own Leydig cells. Due to unavoidable accumulation of irreversible changes in the testicles, patients with PADAM need constant monitoring, and, in certain cases, an increase in the dose of exogenous testosterone.
Thus, replacement therapy using preparations of testosterone in the presence of partial age-related androgen deficiency leads to a decrease in the levels of 5α-dihydrotestosterone, 17β-estradiol, and a series of cell growth factors, to restore neurohumoral regulation in the gonad-hypophysis-hypothalamus system. Androgen-replacement therapy can be used to reduce the risk of both malignant hyperplasia and cancer of the prostate gland, and can also help prevent such diseases and pathological states as type 2 diabetes, obesity, atherosclerosis, osteoporosis, atrophic changes in the skin, a decrease in sexual activity, and psycho-emotional and autonomic abnormalities (Morita R. et al., 1979; Rousseau P.C., 1986; Wu S.Z., Weng X., 1993; Vermuelen A., Kaufman J.M., 1998; Pechersky A. et al., 2002; Pechersky A. et al., 2003). Replacement therapy should be made without stopping until the number of Leydig cells is resoted. A stoppage in replacement therapy or the prescription of replacement therapy in separate courses can lead to a renewal of the above-named pathological processes.

CONCLUSION

A decrease in the pool of pluripotent stem cells among men after 40 years of age (Teplyashin A.S. et al. 2005) leads to a reduction in the intensity of processes for renewing tissues, including tissues of endocrinal organs. PADAM develops as a result among men (Bremner W.J. et al., 1983; Gray A. et al., 1991). A whole series of compensatory-adaptive reactions takes place in order to compensate for the lack of tesosterone production. These reactions concern endocrinal, paracrinal, and autocrinal levels (Pechersky A.V. et al., 2003).
Due to the interdependence of neurohumoral regulatory processes, the age-related decrease in testosterone production has an influence on the entire system of hypothalamus- hypophysial regulation, including the impulse mode of incretion of a whole series of hormones, and also on the activity of growth factors and oncogenes.
A decrease in testosterone production disrupts the natural development cycle of cells that have androgen receptors. Any change in the testosterone level (both as a decrease in the presence of PADAM, or as an increase when large doses of androgen preparations are prescribed by a doctor) leads to an increase in the activity of aromatase and 5α-reductase. Stimulation of 5α-reductase and aromatase activity is accompanied by compensatory hyperplasia of the tissues which contain the given enzymes. In particular there is formation of an adenoma of the paraurethral glands that contain 5α-reductase in the prostate gland, and an increase in the share of fatty tissue that contains aromatase. Contrarily, restoration of the testosterone level to its normal physiological value leads to a reduction in the activity of 5α-reductase and aromatase activity, and aids in prevention of both benign hyperplasia of the prostate gland and obesity.
An increase in aromatase and 5α-reductase activity, as well as of the level of the majority of growth factors shows that the compensatory-adaptive reactions that develop in the presence of PADAM are directed at raising mitotic activity of cells, while their expression is proportional to the level of the decrease in testosterone production. These pathological processes concern all organs and tissues of the human body, including both androgen-dependent and androgen-independent ones, thereby raising the risk of a tumorous transformation.
Extragonadal production of testosterone allows the level of testosterone in the body to be kept within the normal range of the referential interval among the majority of patients with PADAM. However, compensatory incretion of hormones by non-endocrinal tissues and cells (including tumorous ones), is impossible to regulate and, furthermore, is inadequate. Signs of inadequacy of testosterone regulation, which are expressed in patients with prostate cancer in the form of atrophy of the prostate’s tissues and the expression of androgen receptors in these tissues, confirm the inadequacy of the given compensatory mechanism.
Regulation based on the principle of inverse feedback is typical of many-stepped enzymatic processes: when the level of the final product goes down, the intensity of preceding reactions goes up. “Activation by the predecessor” is characteristic of these processes: the increase in the levels of the preceding substrates stimulates the formation of the product of the last stage. This regularity is characteristic of all living organisms. The main predecessor of the formation for steroid hormones (in particular for testosterone) is cholesterol, and at earlier stages – glucose. When testosterone production goes down with age there is a compensatory increase in cholesterol and glucose levels – substrates for the subsequent synthesis of testosterone.
Apparently the male organism has formed standard genetically-determined variants of the functioning of the endocrinal system over the course of evolution. Some of them can be used as compensatory reactions in the presence of a series of pathological processes.
Resistance to insulin and leptin, which are accompanied by hyperphagia, an increase in glucose in the blood plasma, and an increase in the capacity of the fatty depots, is a widespread phenomenon in the animal world. The development of resistance to insulin and leptin in the summer months makes it possible to increase the mass of fatty tissue in animals for later use in the winter period. This state develops temporarily under physiological conditions, and doesn’t result in any negative consequences.
The mechanism of insulin resistance which is formed in the process of phylogenesis is employed for a compensatory increase in the levels of the predecessors of testosterone – cholesterol and glucose – when there is an age-related reduction in testosterone production. Considering that after forty years of age the decrease in testosterone production in men only progresses further and further, resistance to insulin among such men is a constant attribute which leads to a whole series of complications.
An increase in the level of cytotoxic factors of cell immunity (TNFα, hydrolase, components of the compliment, and highly-active forms of oxygen and nitrogen) testifies to the fact that there is development of a compensatory reaction of anti-tumor cell immunity in response to the increase in the proliferate activity among patients with PADAM. The given reaction is directed at utilizing the newly formed atypical cells and at regulating apoptosis. In the presence of a significant increase in the number of atypical cells, the effectiveness of the given factors becomes inadequate. Thus the age-related decrease in the number of pluripotent stem cells breaks down the processes of tissue replacement, including tissues of the endocrinal organs. The growing hormonal imbalance intensifies the changes taking place. The interelated rejection of the pathological processes that develop leads to the formation of a vicious circle. Partial age-related androgen deficit causes the development of benign hyperplasia and prostate cancer to a significant degree, as well as insulin resistance (type 2 diabetes) and osteoporosis. The increase in proliferative activity among patients with PADAM, which intiates the response of natural immunity, leads to the development of suc illnesses and pathological states as atherosclerosis, essential hypertension, an increase in the risk of the formation of thrombosis, the development of pathology of the connective tissue, and strong cardiovascular and brain abnormalities. The given diseases are partial expressions of metabolic syndrome (X-syndrome).
Thus, the risk of the development of oncological diseases increases among people of older age groups, and there is progression of atrophic and sclerotic processes in the majority of tissues. There is also an increase in destructive changes in connecting tissue (with a reduction in their strength characteristics). A promising way to reverse the development of pathological processes may be to transplant allogenic pluripotent stem cells and to combine transplantation with various methods of correctin of age-related inadequacy of sex hormones.

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