The hypothalamus-pituitary-testicular axis (hypogalamo-pituitary-gonadal system) is a hormonally interconnected organ system. The testes (testicles) of mammals are the site of germ cell formation and androgen production (Rommerts, 2004). Testosterone, a steroid that contains 19 carbon atoms and is secreted by the testes, is an androgen predominant in most mammals. Testosterone plays an important role in mammalian reproduction: it is necessary to maintain sexual function, the development of germ cells and secondary genitalia. In adult animals, it has additional effects on muscle and bone tissue, hematopoietic processes, blood clotting, plasma lipid levels, carbohydrate and protein metabolism, psychosexual and cognitive functions. During the formation of sex in the mammalian fetus, testosterone leads to the masculinization of Wolf structures and causes the formation of external genitalia in the form of a scrotum and penis. In addition, an increase in testosterone levels during puberty stimulates somatic growth and virilization in boys.

The production of androgens in the testes is mainly regulated by luteinizing hormone (LH), whereas the formation of germ cells requires the coordinated action of follicle-stimulating hormone (FSH) and a high intra-testicular concentration of testosterone, which is produced by Leydig cells under the influence of LH (Rommerts, 2004). The paracrine interaction between Sertoli cells and germ cells is also an important component of the regulation of spermatogenesis, although the exact role of Sertoli cells in the regulation of germ cell development is poorly understood.

The function of the testes is regulated by a group of direct and feedback mechanisms that function at the level of the hypothalamus, pituitary gland and testes. Thus, the undulating secretion of gonadoliberin (gonadotropin-releasing hormone) stimulates the secretion of LH and FSH, which in turn is regulated by a feedback chain involving sex hormones, including sex steroids, as well as inhibin and activin.

Testosterone can be converted into estrogens under the influence of aromatase. "Attention" Mainly estrogens, not testosterone, suppress the hypothalamus-pituitary-testicular axis and reduce the secretion of endogenous testosterone when exogenous drugs are administered.

Migration of gonadoliberin-producing neurons during fetal development. Neurons producing hydrocarbons excrete organic substances (Schwantzel-Fukuda, Pfaff, 1989) and migrate beyond organic compounds. At first glance, we will touch on our final placement in the hypothalamus at this point. Such an orderly migration of gonadoliberin-producing neurons requires coordinated action of molecules that determine the direction of adhesion proteins, such as the product of the kalig-1 gene and the fibroblast growth receptor, as well as enzymes that help neuronal cells make their way in the intercellular space. Mutation of any of these proteins can interfere with the migration process and lead to gonadoliberin deficiency. In a group of patients, a violation of such ontogenetic migration of gonadoliberin-producing neurons to their final location in the hypothalamus leads to a disease called idiopathic hypogonadotropic hypogonadism, which is characterized by gonadoliberin deficiency and impaired gonadotropin secretion by the pituitary gland (Legouis et al., 1991).

The hypothalamus as the integrating center of the male reproductive system is the integrating center of the reproductive system and coordinates regulatory signals from higher centers and feedback signals from the gonads (Knobil, 1980; Crowley et al., 1991). The hypothalamus receives information from the central nervous system, which reflects the influence of emotions; stress, light, olfactory stimuli, temperature and other external factors. Feedback signals from gonads include steroid hormones (testosterone and estradiol) and protein hormones (inhibin and activin).

Regulation of LH and FSH by undulating gonadoliberin secretion. Mr. Doliberin is one of the main regulators who deals with gonadotropin secretion and applies secretion with cells both in vitro and in vivo. The billionaire's free-exchange secretion apparatus is important for maintaining normal secretion of LH and its pituitary gland (Belchetz et al., 1978; Knobil, 1980; Shupnik, 1990; Crowley et al., 1991; Weiss et al., 1992). Continuous administration of gonadoliberin or the use of long—acting gonadoliberin agonists leads to a decrease in LH and FSH secretion, a phenomenon known as negative regulation (Belchetz et al., 1978; Knobil, 1980). The gonadoliberin secretion operator (studio and part of the secretory release) represents the collective and qualitative composition of the secreted gonadotropins (Belchets et al., 1978; Heisknleder et al., 1988, 1991; Kim et al., 1988a, 1988b; Yuan et al., 1988; Shupnik, 1990; Weiss et al., 1992). A noticeable increase in the frequency of gonadoliberin emissions also leads to a loss of sensitivity of gonadotropic cells and a subsequent decrease in the secretion of LH and FSH (Belchetz et al., 1978; Merccr et al., 1988; Shupnik, 1990). The electrophysiological activity of hypothalamic neurons producing gonadoliberin is interrelated with its periodic secretory emissions.

Initial administration of gonoliberin induces transcription of the LH-r gene in vitro (Vikrman et al., 1989; Shupnik, 1990; Weiss et al., 1992). The recent introduction of Mr. doliberin combines the transcription of the tolko a gene, but not of Mr. R-a united LGBT (Heisknleder et al., 1988). The initial application of hybridization also replaces the polyliberianism of the MRNA of the state corporation (Weiss et al., 1992). A particle of statistical analysis, which is a global method, contains important significance for the digital regulation of the LH-R and PH-beta genes (Haiscnlcdcrct et al., 1988). A higher frequency enhances a-genes and LH-beta, and a lower frequency enhances FSH—beta, which became the basis for the assumption that changes in the frequency of gonadoliberin emissions may be one of the mechanisms for regulating the production of two functionally different gonadotropins using a single hypothalamic releasing hormone (Haiscnlcdcr et al., 1988). The initial integration of heraldry or the introduction of an agonistic control system leads to a decrease in the level of mRNK LH-p, while the level of mRNK LH-a remains improved (Haiscnlcdcr et al., 1988; Kim et al., 1988a. 1988b; Yuan et al., 1988).

A significant part of the information regarding the physiology of gonadoliberin secretion was obtained by studying the wave-like nature of changes in LH and FSH levels in normal men and women, as well as by studying the effects of hormone replacement therapy using gonadoliberin in patients with idiomatic hypogonadotronous hypogonadism (Urban CT al., 1988; Crowley CT al., 1991). Studies of such patients with hypothalamic gonadoliberin deficiency show that periodic intravenous administration of this hormone in the amount of 25 ng-kg'1 makes it possible to reproduce normal undulating secretion of LH with all the features of ce (Crowley CT al., 1991). The peak level of radioliberin after intensive administration of such a dose of the hormone (500-1000 mg-ml4) resembles someone who can be surrounded by care. The technique, if possible, is made from the portal system of hypnosis (Crowley et al., 1991). In a man with idiomatic hypothetical syndrome, the optometric interval can be increased by 2 hours (Crowley et al., 1991). Increasing the efficiency of the use of genetic engineering equipment is associated with the gradual convergence of the government with the genetic engineering production of neurons (Armature et al., 1976). A decrease in the pulse rate of gonadoliberin or an increase in the interval between them increases the amplitude of the subsequent secretory release of LH. It is a linear system consisting of a logarithmic base consisting of heraldry and collectively secreted LG, SGS and a free a-company (Spratt et al., 1986; Whitcomb et al., 1990). In adult men, the amplitude of an increase in LH levels in response to gonadoliberium significantly exceeds the amplitude of an increase in FSH levels.

Intelligent blood collection in healthy men and women has become a publicly available study in the field of education (Urban et al., 1988). Researchers representing the collective standard of living among men, according to one recent study (Urban ct al., 1988), observe what is happening in the following way; the interval between secretory emissions is 55 minutes, the duration of LH peaks is 40 minutes, the amplitude of LH peaks is 37% of the initial level (an increase of 1.8 mMU-ml-1) - Significant variability in the parameters of changes in LH levels in healthy men and women normally necessitates precautions when interpreting small deviations in the frequency and amplitude of hormone fluctuations. The frequency of blood sampling and the approach used to quantify the parameters of fluctuations in hormone levels can have a significant impact on the likelihood of their erroneous assessment (Gorodskiy et al., 1988).

The effect of gonadoliberin on gonadotropic cells is carried out through their binding to specific membrane receptors, which leads to receptor aggregation and calcium-dependent release of LH (coed et Al., 1981, 1982).

Functional structure and development of the pituitary gland
Extensive data from immunocytological studies indicate that the secretion of LH and FSH in the pituitary gland occurs in cells of the same type (Moricrty, 1973; Kovacs ct al., 1985). Gonadotropin cells secreting LH and FSH account for approximately 10-15% of the total number of cells of the adenohypophysis (anterior pituitary) (Moricrty, 1973; Kovacs et al., 1985) and are scattered throughout the adenohypophysis near blood capillaries. They are easily found in the pituitary gland of the fetus and immature individuals (Childs ct al., 1981), however, their number remains small until puberty. Castration leads to an increase in the number as well as the size of gonadotropic cells. Adenohypophysis cells originate from common multipotent cells or progenitor cells. Genetic analysis of mutations associated with disorders of pituitary function that occur during the development of the body has revealed the molecular mechanisms of pituitary development and the isolation of individual cell lines (Ingraham et al., 1988; Scully, Rosenfield, 2002). The development of the pituitary embryo and its various cell types is controlled by the time-coordinated expression of a number of transcription factors containing the homeodomain. Three homeobox-containing genes Lbx3, Lbx4 and Titfl play an important role in early organogenesis (Scully, Rosenfeld, 2002). For cellular specialization and proliferation of differentiated cells, the expression of transcription factors Pitl and Propl is necessary: Pitl contains a POU-specific and DNA-binding POU-homeocomponent (Scully, Rosenfeld, 2002). The Propl gene encodes a transcription factor with a single DNA-binding component. Pitl mutations are associated with deficiency of somatotropic hormone (STH), thyroid stimulating hormone (TSH) and prolactin, and Propl mutations in addition to deficiency of STH, prolactin and TSH are associated with a lack of LH and FSH. The expression of Propl and Pitl is preceded by the expression of the HESX1 gene, mutations in which are associated with septoptic dysplasia and panhypopituitarism (Parks et al., 1999).

Biochemical structure and molecular biology of LH and FSH
The family of pituitary hormones having a glycoprotein nature includes LH, FSH, TSH and chorionic gonadotropin (HCG) (Sairam, 1983; Ryan ct al., 1987; Gharib ct al., 1990). All these hormones are heterodimers consisting of a- and P-components. The primary sequence of the p-components of LH, FSH, TSH and HCG of various types is almost identical, the biological specificity of hormones is determined by heterogeneous P-components. The significant homology between the two components indicates their common origin from a common ancestral gene. Each subunit individually has no biological activity, they can have any effect only after the formation of a heterodimer. As part of the heterodimer, they are connected by disulfide bonds, the location of cysteine residues is of great importance for the correct laying and formation of the three-dimensional structure of the glycoprotein (Sairam, 1983; Ryan et al., 1987; Gharib et al., 1990); the a-component of LH contains two carbohydrate chains associated with asparagine residues, whereas their p-component may include one or two (Table 21.1) (Baezinger, 1990); The P-component of HCG also contains O-linked oligosaccharides, which are not present in the composition of the LH dimer (Cole ct al., 1984). Despite the fact that free unbound a-subunits are secreted by the pituitary gland into the bloodstream, it is generally believed that the secretion of free P-components in this way practically does not occur. The emergence of chorionic gonadotropin as an independent gonadotropin in the course of evolutionary development occurred relatively recently (Komfeld, Kornfcld, 1976; Fiddcs ct al., 1984). Unlike LH, which can be found in the pituitary gland of a significant number of species, HCG is found only in the placenta of some mammalian species, namely horses, baboons and humans (Fiddcs et al., 1984); the a- and p-components of LH and FSH are encoded by different genes (Fiddes et al., 1984). The human p-component LH-HCG gene cluster includes seven HCG-like genes, one of which is the liLH—beta gene (Fiddes ct al., 1984). The general organization of the LH p-subunit gene, consisting of four exons and three nitrons, is similar to the structure of the genes of the p-subunits of other glycoprotein hormones.

The regulatory role of LG
Testosterone secretion by Leydig cells is controlled by LH, which binds to G-protein coupled receptors on Leydig cells and activates the cyclic adenosine monophosphate (cAMP) signaling pathway. The luteinizing hormone receptor-choriopic gonadotropin (LH-HCG receptor) is characterized by homology with other G-protein coupled receptors such as rhodopsin, adrenergic, FSH and TSH receptors (McFarland et al., 1989; Sprengel et al., 1990). G-protein coupled receptors are transmembrane proteins with a common structural motif including seven membrane-penetrating domains. These seven domains are located at the carboxyl end of the molecule, which also contains a small area with cytoplasmic localization. Its sequence contains several serine and threonine residues that can undergo phosphorylation (McFarland et al., 1989; Sprengel et al., 1990).

Luteinizing hormone stimulates the activity of the side-chain cleavage enzyme (Simpson, 1979; Mori, Marsh, 1982), an enzyme associated with cytochrome P450, which catalyzes the conversion of cholesterol into pregnenolone, which limits the rate of the stage of testosterone biosynthesis. This hormone increases the supply of cholesterol to the enzyme that cleaves side chains, thus increasing the efficiency of the reaction of converting cholesterol to pregnenolone (Simpson, 1979; Mori, Marsh, 1982). Steroidogenesis acute regulatory protein (STAR) makes cholesterol available for the side chain cleavage complex and regulates the rate of testosterone biosynthesis (Clark, Stocco, 1996). The peripheral benzodiazipine receptor, a mitochondrial cholesterol-binding protein that participates in cholesterol transport and is represented in high concentration on the outer mitochondrial membrane, is also proposed as an active regulator of the steroidogenesis process. Long-term effects of LH include stimulation of gene expression and synthesis of a number of key enzymes of the steroid biosynthesis pathway, including the enzyme that cleaves side chains, 3-p-hydroxysteroid dehydrogenase, 17-a-hydroxylase and 17,20-lyase (Simpson, 1979; Mori, Marsh, 1982). Despite the fact that LH also activates the phospholipase C signaling pathway, it remains unclear how important this is for LH-mediated stimulation of testosterone production. In addition, insulin-like growth factor I is involved in the control of steroidogenesis in Leydig cells; proteins binding insulin-like growth factor; inhibins, activins, transforming growth factor-p, epidermal growth factor, interleukin-1, the main fibroblast growth factor, gonadoliberium, vasopressin and another group of poorly characterized mitochondrial proteins.

The regulatory role of FSH is that males
FSH binds to specific Sertoli cell receptors and stimulates the production of a number of proteins, including inhibin-like peptides, transferrin, androgen binding protein, androgen receptor and 7-glutamyltranspeptidase. At the same time, the role of FSH in regulating the process of spermatogenesis remains poorly understood. The point of view is changing, according to which LH acts on Leydig cells, stimulating the production of testosterone in large volume (Boccabella, 1963; Steinberger, 1971; Sharpe, 1987). Testosterone then penetrates into spermatogony and spermatocytes, initiating the process of their meiotic division. It is assumed that FSH is necessary for spermogenesis, i.e. the maturation process during which spermatozoa grow into mature spermatozoa. Unambiguously, these animal experiments and studies of patients with idiopathic hypogonadism after treatment with gonadotropins show that FSH plays a more important role in maintaining normal spermatogenesis.

In rats and non-human primates, testosterone alone can support spermatogenesis if it occurs after removal of the pituitary gland or cutting of the legs of the pituitary gland (Marshall et al., 1983; Sharpe et al., 1988; Stager et al., 2004). However, if testosterone is injected slowly for some time (several weeks or months) after such an operation, its effectiveness in restoring spermatogenesis is significantly reduced. Spermatogenesis, which is maintained in male rodents and non-human primates with the pituitary gland removed by the administration of testosterone, is qualitative, but not completely normal (Marshall et al., 1983; Sharpe et al., 1988; Stager et al., 2004). Its combination with FSH proved to be more effective for the second initiation of spermatogenesis compared to testosterone (Stager et al., 2004). Thus, despite the fact that LH itself can support or re-initiate spermatogenesis, FSH is necessary for almost normal sperm production.

In men who have LH and FSH deficiency in the prepubescent period, LH or human chorionic gonadotropin alone cannot initiate spermatogenesis (Bardin et al., 1969; Matsumoto et al., 1983, 1984; Finkel et al., 1985). However, if gonadotropin deficiency develops after puberty has occurred in the patient, LH and hCG can independently initiate repeated normal spermatogenesis (Finkel et al., 1985). Thus, FSH is necessary to initiate the process of spermatogenesis, but after that, a sufficiently high dose of testosterone is required to maintain it. This fact suggests that FSH can take part in a certain kind of “programming" that occurs during puberty, after which LH can independently support the processes of development and maturation of germ cells.

The concentration of androgens in the testes is much higher than in the blood serum, but there are quite diverse opinions regarding the high level of testosterone in the testes (Sharpe, 1987; Sharpe et al., 1988; Stager et al., 2004). For example, the stimulating effect of exogenous testosterone on spermatogenesis is not associated with a proportional increase in its internal level. In obese adults with removed himphysis or after administration of gonadoliberin antagonists who injected testosterone, there is a direct relationship between testosterone levels in the testes and spermatogenesis (Stager et al., 2004). The method of postmortem collection of testicular tissues affects the assessment of the internal concentration of testosterone (Stager et al., 2004). Thus, the interaction between the intrafamilial concentration of testosterone, FSH and spermatogenesis remains poorly understood. Androgens of the receptor are found on Sertoli cells and peritubular cells, on some Leydig cells and endothelial cells of individual arteries. At the same time, we are not aware of the presence of androgen receptors on germ cells. It is assumed that the attraction of androgens to spermatogenesis is mediated through Sertoli cells, if it is possible that testosterone can also indirectly act on the development of germ cells. Testosterone is injected into the secretion of proteins by both spherical spermatids and Sertoli cells. The maximum expression of androgen receptors is observed at stages VI-VII of the spermatogenic epithelium, testosterone regulates the apoptosis of germ cells depending on the stage of their development.

To transduce the FSH signal to germ cells, a Sertoli cell site is required, FSH receptors are located on this type of cell, but not on germ cells. The FSH receptor is also a G-protein-coupled polypeptide consisting of a glycosylated extracellular domain that connects to a C-terminal site containing 7 transmembrane sites (Sprengel et al., 1990).

Reverse regulation by testosterone
Testosterone plays an important role in the regulation of gonadotropin secretion in males after feedback. In a number of experimental animals, LH and post-FSH levels sharply increase after castration (Yamamoto et al., 1970; Badger et al., 1978). After castration, a layer of LG-A and I mRNAs (Gharib et al., 1986) and FSH-r (Gharib et al., 1987) hangs, while changes in the FSH-a Community are less pronounced.

Post-castration inclusion of LH in blood pregnancy and damage to LH-r mRNA has developed both a change in gonadotropic cell rings and hypertrophy of individual gonadotropins (Childs et al., 1987). The introduction of testosterone, starting immediately after or immediately after castration, can weaken the post-castration growth of LH-a and-r mRNA, as well as the level of LH in the child's blood, only unknowingly affects the level of FSH-r mRNA (Gharib et al., 1986, 1987).

Testosterone oxidizes the complex attraction to the secretion and synthesis of FSH
The overall effect of in vivo testosterone use in men is normally a decrease in serum FSH levels (Swerdloff et al., 1979; Winters et al., 1979). The unambiguously direct effect of testosterone on the release of FSH on the pituitary bladder stimulates (Steinberg, Chowdhury, 1977; Bhasin et al., 1987; Gharib et al., 1987). In the culture of isolated pituitary cells, testosterone increases the release of FSH in the middle (Steinberg, Chowdhury, 1977). This is accompanied by a 3-4-fold increase in the level of FSH-r mRNA (Gharib et al., 1990). In intact male mice, blocking the action of gonadoliberin by administration of its testosterone antagonist causes the formation of FSH in a dose-dependent manner (Bhasin et al., 1987). It has been shown that in castrated animals that were injected with a gonadoliberin antagonist, the administration of testosterone in post-increasing doses is accompanied by an increase in the level of FSH in the child's body. These data indicate that the stimulating effect of testosterone on serum FSH levels is mediated not so much by exposure to the gonadal FSH inhibitor as by indirect effects on the pituitary gland level. Testosterone causes the formation of FSH-r mRNA, but not LH-R. At the same time, in intact males, live testosterone stimulates gonadoliberin secretion of FSH, which as a result leads to the removal of FSH levels in the child's body.

When administered to humans and rats, testosterone normally supplies LH secretion (Santen, 1975; Matsumoto et al., 1984; Veldhuis et al., 1984). Similar feeding effects are manifested directly at the hypothalamic level — this closure confirms the fact of a decrease in testosterone levels in secretory LH frequencies in men with normal gonads (Matsumoto, Bremncr, 1984; Schckter et al., 1989; Finkclstcin et al., 1991a). Androgens are not oxidized by direct action on an LH-r mRNA sample in a monolayer culture of rat pituitary cells. Similarly, in male rats, after administration of the gonadoliberin antagonist, the administration of testosterone, in post-increasing doses, leads only to an increase in FSH-r mRNA, but not LH-r mRNA (Bhasin et al., 1987). Unlike rats, in humans suffering from idiomatic hypogonadotropic hypogonadism, the amplitude of LH fluctuations caused and supported by periodic administration of gonadoliberin decreases after administration of testosterone, which indicates that in humans testosterone is additionally oxidized by respiration at the pituitary gland level, slowing down LH secretion in response to stimulation by gonadoliberin (Matsumoto et al., 1984; Schekter et al., 1989; Finkelstein et al., 1991a). These studies show that male testosterone or one of its metabolites inhibits gonadotropin secretion at the pituitary and hypothalamus levels.

The inhibitory effect of testosterone is mediated by the absence of testosterone and is mediated by its metabolites estradiol and dihydrotestosterone. The use of aromatase or 5-a-reductase inhibitors is accompanied by an increase in LH concentration, which is consistent with the idea of the role of estradiol and dihydrotestosterone in enhancing the inhibitory effect of testosterone in the feedback loop (Santen, 1975; Finkelstein et al., 1991b; Gormley, Rittmaster, 1992). The unambiguously non-aromatizable androgen dihydrotestosterone is also amenable to LH secretion due to the assumption that testosterone aromatization is not necessary to describe its inhibitory effects on LH secretion (Santen, 1975). Similarly, there is no substance for the administration of testosterone secretion of LH and 5-a testosterone recovery (Gormley, Rittmaster, 1992). The activity of testosterone at the hypothalamic level increases in areas of the opioergic pathways (Veldhuis et al., 1984).

Feeding with estrogen feedback
Estrogens can be oxidized by both stimulating and feeding attraction to the synthesis and secretion of gonadotropin, depending on the dose, duration of action and attraction, or on the effects of gonadoliberin and other physiological factors. In animal experiments, it is shown that the stimulating effect of estrogens on the synthesis and secretion of gonadotropin in vivo indirectly affects the pituitary bladder, whereas inhibition occurs on the hypothalamic bladder (Neill et al., 1977; Clarke, Cummins, 1982; Zmeili et al., 1986; Saade et al., 1989; Shupnik et al., 1989; Yamaji et al., 1992). The use of estrogens leads to the removal of rhythmic fluctuations in the frequency of the LH bladder, which promotes growth on the hypothalamus bladder (Shupnik et al., 1989). Estradiol treatment of sections of the hypothalamus slows down the expression of gonadoliberin mRNA (Hall, Miller, 1986). Finally, transcription of all three gonadotropin subunits is negatively regulated by estradiol in vivo, even though its direct effect on the pituitary gland in vitro is stimulating (Neill et al., 1977; Clarke, Cummins, 1982; Saade et al., 1989). Estradiol reduces the amplitude of LH fluctuations in healthy men and men with gonadoliberin deficiency containing gonadoliberin (Finkelstein et al., 1991b). These studies prove that male estradiol inhibits the synthesis and secretion of LH by acting directly on the surface of the pituitary gland.

Inhibin, activin and follistatin
The hypothesis that a peptide of gonadal origin selectively regulates FSH secretion was isolated more than 70 years ago (McCulIagh, 1932), however, the structure of inhibin-like peptides was finally characterized by lichen in 1985 (Ling et al., 1985; Buiger, Igarashi, 1988; Vale et al., 1988; Ying, 1988). Inhibins contain some dimeric proteins, which include one common a component and one or two p components: RA or Pb. Heterodimer A:Rd forms inhibin a, and heterodimer a:Rv-inhibin B (Vale et al., 1988). Inhibins A and B are equally subordinate to the FSH sector, the sisters of the converting form of inhibin in the blood of a man are inhibin B. In addition, the components of RA can form homodimers called activin A, or heterodimers with beta-activin AB components (Mason et al., 1985). Both activins, A and B, stimulate the secretion of FSH in vitro.

Inhibin-like proteins are widespread in various organs and have significant homology with members of the protein family, which includes the Muller inhibitory substance, transforming growth factor-p, bone tissue proteins, as well as the decapentaplegic gene complex in drosophila (Vale et al., 1988; Ying, 1988), all of which play an important role as growth regulators and differentiation in various mechanisms. One activin interacts with erythropoietin, stimulating erythropoiesis. In addition, activin is an important regulator of genes containing a homeobox. In the testes, it regulates the increase in spermatogony volume (Mather et al., 1990).

The role of inhibins in the body of adult male animals remains unclear
Studies using immuno-neutralization in rats have shown that the administration of an antimingibin vaccine leads to increased FSH damage only in females and in males of the prepubescent period, but not in adult males (Rivier et al., 1986). These data were questioned about the role of inhibin in vivo as a regulator of FSH in adult males. It was shown that after the destruction of Leydig cells in adult male rats with the help of a specific toxin ethandimethanesulfonate, the use of antiangibic acid leads to the growth of FSH cells in the blood (Culler, Negro-Vilar, 1990). This result shows that, under normal conditions, testosterone plays a more important role in the regulation of FSH in adult males and the effect of inhibin can only be detected when testosterone damage is removed. In fact, using specific, dual research methods, an inverse relationship was established between the level of inhibin b and the level of FSH in the blood of healthy men and women, as well as in men with impaired germ cell development.

Although, according to the first hypothesis, inhibin was dispersed as a selective FSH inhibitor, under certain conditions it can also regulate LH levels (Vale et al., 1988). Unicellular both FSH and LH regulate inhibin production by Sertoli cells in male rats and humans (McLachlan et al., 1988; Keman ct al., 1989; Krummen et al., 1989); both FSH and LH increase the level of inhibin-a mRNA (Krummen et al., 1989, 1990). The effect of FSH on the production of inhibin subjects is created at cAMP sites (Najmabadi et al., 1993).

Follistatin is one class of FSH inhibitors (Ueno et al., 1987), which includes glycosylated polypeptides related by homology to pancreatic secretory inhibitory protein and human epidermal growth factor (hEFR). Visual follistatin consists of four domains, three of them are very similar in succession to each other, as well as to hEFR and PSTI. The physiological role of follistatins is unknown, and an increasing number of data indicate that their effect may be directly in the supply of FSH secretion. Follistatins are potential inhibitors of estrogen production in granulosa cells and can bind activin. In addition, they can act as binding proteins for other growth-regulating proteins, such as myostatin.

Activins regulate gonadal function in men and women (Vale et al., 1988). In the testes, activins enhance LH-stimulated testosterone production, while it is administered as inhibins. In granulose layer cells, activins increase aromatase activity, but inhibit progesterone synthesis (Vale et al., 1988; Ying, 1988). Activin can also act as an autocrine/paracrine indicator in the pituitary gland and modulate the expression of the FSH-A gene.

Fetal development. Gonadoliberium is found in the hypothalamus of the fetus as early as 6 weeks after the onset of pregnancy (Lee R.A., 1988). At the 10th week of embryo development, detectable amounts of Lh and FSH are contained in the pituitary gland, and at the 11th — 12th week, changes in LH levels in response to gonadoliberin can be detected. The level of LH and FSH reaches its peak value around the 20th week (Clements et al., 1980; Lee P.A. 1988). In the second half of pregnancy, there is a gradual decrease in serum levels of LH and FSH. The mechanism of this phenomenon is unknown, but it may be due to some factors acting in the second half of pregnancy. Increased secretion of sex steroids by the gonads of the fetus, an increase in the level of estrogens in the maternal body, as well as the formation of negative feedback mechanisms — all this can contribute to the tonic inhibition of the hypothalamus and pituitary gland by sex steroids (Winter et al., 1975; Sizonenko, 1979).

Placental chorionic gonadotropin plays an important role in stimulating the production of androgens by the testes of the embryo in early pregnancy (Lee R.A., 1988). An increased level of androgens is necessary for the differentiation of Wolf structures in male embryos. In addition, FSH stimulates the differentiation and development of seminal tubules. These data are consistent with the fact that in individuals with idiopathic hypogonadotropic hypogonadism, normal differentiation of the genital ducts and external genitalia occurs, since placental chorionic gonadotropin stimulates the testes of the fetus to produce sufficient amounts of androgens, even in the absence of pituitary LH and FSH. However, due to FSH deficiency, these patients have underdevelopment or delayed development of the seminal tubules. In particular, in the second half of pregnancy, the lowering of the testes depends on the level of androgens, which is regulated by pituitary LH during this period (Husmann, 1991).

The postnatal period and childhood years. After childbirth, the level of LH and FSH increases again, although not for long (Winter et al., 1975; Sizonenko, 1979). In the first 6 months of postnatal life, LH and FSH are detected in detectable amounts in the blood (Winter et al., 1975). During this short period of reactivation of the hypothalamic-pituitary system, the rhythmic nature of LH and FSH secretion can be observed (Winter et al., 1975; Jakachi et al., 1982). Serum levels of LH and FSH peak by the age of 2-3 months and then decrease to undetectable amounts by 9-12 months, similar changes occur with testosterone levels. Thus, this short period of postpartum life, when the content of gonadotropin and sex steroids has not yet decreased to a minimum, provides an opportunity to assess the functioning of the hypothalamic-pituitary-gonadal system.

In childhood, the hypothalamic-pituitary-gonadal system is in a state of inactivity until puberty (Lee R.A. et al., 1976; Apter et al., 1978). At the same time, the pituitary gland and testes retain the ability to respond to gonadoliberin and chorionic gonadotropin. The response of the pituitary gland to gonadoliberin stimulation at prepubescent age is relatively weakened. In addition, at this time, gonadoliberium stimulates a more significant increase in FSH levels compared to LH. This distinguishes children from adults, in whom a single stimulation with gonadoliberin causes a more pronounced increase in LH levels. During puberty, LH and FSH levels increase (Sizonenko, 1979). Activation of FSH secretion precedes an increase in LH secretion. The early stages of puberty are characterized by rhythmic secretion of LH during sleep (Jakachi et al., 1982).

The use of highly sensitive bidirectional immunoradiometric, immunofluorimetric and chemiluminescent analysis showed that, starting from the age of 7 years and until the end of puberty of the body, the average concentration of L G increases by more than 100 times, FSH — by 7 times, and estradiol — by 12 times (Apter et al., 1989). The increase in FSH levels occurs gradually, while the level of LH increases very sharply. Changes in FSH precede an increase in LH concentration. The mechanisms of controlling low gonadoliberin levels in childhood and triggering its secretion at puberty remain unknown.

Changes in reproductive function during aging. There is a general opinion that with aging, the level of testosterone in the blood serum of men progressively decreases (Fig. 21.6) (Pirke, Doerr, 1973; Dai et al., 1981; Gray et al., 1991; Simon et al., 1992; Zmuda et al., 1997; Ferrini, Barret-Connor, 1998; Harman et al., 2001; Feldman et al., 2002; Matsumoto, 2002). In almost 25% of men over the age of 70, serum testosterone levels are in the range characteristic of hypogonadism (Harman et al., 2001). Since the level of sex hormone binding globulin (sar hormone binding globulin, SHBG) increases with age, the decrease in free and bioavailable testosterone during aging is more significant than the decrease in total testosterone (Pirke, Doerr, 1973; Tenover et al., 1987; Ferrini, Barret-Connor, 1998; Harman et al. al., 2001). The daily rhythm of testosterone secretion, which is observed in young men, noticeably weakens with age. Despite the fact that in the last decades of life there has been a decrease in the average level of total, free and bioavailable testosterone, in many older men its serum content remains within the normal range. The level of estradiol and estrone in the blood either does not change or increases slightly due to increased aromatization of androgen into estrogen in peripheral organs (Pirke, Doerr, 1973; Ferrini, Barret-Connor, 1998).

Age-related changes in reproductive hormones are additionally influenced by concomitant diseases, changes in body composition and medication intake. Despite the fact that data on the relationship between age and androgen levels in blood serum are in fact mainly the results of ascertaining studies, an age-related decrease in testosterone levels has also been confirmed in several clinical studies (Zmuda et al., 1997; Harman ct al., 2001; Feldman et al., 2002). Some of these works have been criticized for choosing older men whose health was better than that of the general population. However, even after adjusting for morbidity, blood sampling time for analysis, variability of analysis methods and the effect of medications taken, testosterone levels in older men are lower compared to younger men.

An age-related decrease in testosterone levels occurs due to defects at all levels of the hypothalamic-pituitary-gonadal system. The secretion of androgens in the testes of older men is weakened due to disorders at the level of the genital glands. This is confirmed by an increase in FSH and LH levels (Kaufman, VErmeulen, 1997; Morlcy et al., 1997; Feldman et al., 2002), a weakening of the testosterone response to chorionic gonadotropin and a decrease in Leydig cell mass in older men (Longcope, 1973). The level of the free a-subunit in the blood is also increased in older men (Harman et al., 1982).LH secretion in older men occurs less regularly compared to younger men (Pincus et al., 1997). In older men, there is also a weakening of synchrony between LH and testosterone secretion (Pincus et al., 1997). Thus, the aging of the body is accompanied by violations of the regulatory feedback mechanisms that control the flow of information between the components of the hypothalamic-pituitary-testicular system, as well as a change in the established nature of rhythmic hormone secretion (Pincus et al., 1997).

The secretion of testosterone. In males of most mammalian species, 95% of testosterone in the circulatory system is the result of its secretion in the testes. Men are older than men aged 3 to 10 years (Horton, 1978). Her direct secretion by the adrenal glands and the conversion of hadrostendiopa in the peripheral organs add up to another 500 mcg of testosterone per day. Human testes produce a small amount of dihydrotestosterone (about 70 micrograms per pack), the bulk of which is in the blood as a result of its transformation from space (Longcope, Fineberg, 1985).

The tester works in tandem with a heterogeneous group of cells, which includes wonderful Leydig cells, and members of the public, and extraordinary Leydig cells (Prince, 2001). Studies of hypogonadotropic mice have shown that the development of Sertoli and Leydig cells in the fetus does not depend on gonadotropins, but their presence is necessary for the normal differentiation and proliferation of a population of mature Leydig cells. In men 46,Xy with an inactivating mutation of the L G receptor, there is ambiguity in the formation of genital organs, expressed to varying degrees, and the absence of Leydig cells, which indicates the important role of LH in regulating the development of Leydig cells (Dufau, 1988; Huhtaniemi, Toppari, 1995). The number of Sertoli cells after birth is regulated by gonadotropins.

Androgen transport in the body: 98% of testosterone circulating in the circulatory system is associated with plasma proteins — sex hormone binding globulin (SHBG) and albumin (Vermeulen, 1988; Rosner, 1991); SHBG binds testosterone with much greater sensitivity compared to albumin. Only 0.5—3.0% of testosterone is in an unbound state. Although, according to the generally accepted point of view, only the unbound fraction has biological activity, the hormone associated with albumin easily dissociates in capillaries and may also have bioavailability (Pardridge, 1987). It was obvious that the androgens associated with albumin and SHBG represent a single control system in the carpet treatment system for seeds or years (Pardridge, 1987). Moreover, these researchers considered that the complex of the SBG field system can be almost seamlessly introduced into Jehovah's Witnesses due to the barrenage system and published through plasma memory. "This point of view is not shared by everyone" (Pardridge, 1987).

SHBG glycoprotein is synthesized in the liver and represents a highly qualified researcher (Vermeulen, 1988; Rosnr, 1991). The production of SHBG in the liver is regulated by insulin, thyroid hormones, nutritional factors, as well as the ratio of androgens and estrogens; it participates in the transport of sex steroids into plasma, and its concentration is the main factor regulating their distribution between protein-bound and free states. The integration of SHBG into the system occurs after the adoption of androgens, the acceptance of obesity, the gypsum community and necrotic syndrome (Roner, 1991). Conversely, estrogen intake, hyperthyroidism, many types of inflammatory diseases and aging are accompanied by an increase in SHBG levels. The locus associated with the concentration of SHBG in the genome of the Negroid and Caucasoid races was mapped at position lq44, in the genome of the Negroid race, several additional loci are found to correlate with the concentration of this globulin, which indicates a multigenic regulation of the level of SHBG (Larrea et al., 1995). The relationship of testerone with SHBG or albumin is not important for its state — chris with SHBG demiurge and albumin are sterile, you do not observe the usual soldering guide.

Testosterone metabolism occurs mainly in the liver (50-70%), although degradation processes are also observed in other peripheral tissues, in particular in the prostate and skin. Testosterone enters the liver from the blood and undergoes a series of chemical reactions there involving 5-a- and 5-r-reductases, 3-a- and 3-r-hydroxysteroid dehydrogenases and 17-(3-hydroxysteroid dehydrogenase, as a result of which it turns into androsterone, ethio-cholanolone (both of these metabolites are inactive), as well as in dihydrotestosterone and 3-a-androstanediol. Before excretion in the kidneys, these compounds undergo glucuropidation or sulfation. Free and bound androsterone and etiocholanolone are the main metabolites of testosterone found in urine.

Testosterone as a prohormone: the role of dihydrotestosterone and estradiol in mediating the action of androgens. Testosterone undergoes chemical transformations in many peripheral tissues into active metabolites — 17-p-estradiol and 5-a-dihydrotestosterone (Wilson et al., 1993; Grumbach, Auchus, 1999). Aromatization A-since he is a 17-year-old radiol. However, the restoration of the ct-4 double bond can convert testosterone into 5-a-dihydrotestosterone. The action of testosterone in many tissues is carried out through these metabolites, for example, the effect of testosterone on the resorption of trabecular bone tissue, sexual differentiation of the brain, plasma lipid levels, the development of atherosclerosis and some types of behavior is mediated by its conversion to estrogen (Grumbach, Auchus, 1999). Studies on mice with mutation of the a-gene of the estrogen receptor, the P-receptor of estrogen or aromatase allow for a better understanding of the role of estrogens in the body of male mammals (Jones et al., 2000). These estrogen-deficient models show significant abnormalities in spermatogenesis and fertility, increased testosterone and LH levels, decreased bone mass and increased body fat, which indicates the importance of estrogens in the regulation of bone mass, gonadotropin, body composition and spermatogenesis (Smith et al., 1994; Carani et al., 1997). There are reports of rare cases of inactivating mutations of the CYPI9 aromatase gene in humans (Carani et al., 1997). In women with the CYP19 gene mutation, masculinization, inability to sexual development, elevated levels of androgens, LH and FSH, polycystic ovaries and high growth are observed. Men with a mutation of the CYP19 aromatase gene have osteonorosis, accelerated metabolic processes in bone tissue, delayed fusion of the epiphysis, high growth, as well as increased testosterone levels and reduced estradiol (Carani et al., 1997).

Two isoenzymes of 5-a-steroid reductase have been characterized (Wilson et al., 1993; Russell Wilson, 1994); 5-a-rsductase of type 1 steroids is expressed in many types of somatic tissues, has an optimum pH of 8.0, the gene of this enzyme is mapped at the chromosomal locus 5p15; 5-a-rsductase of type 2 steroids It is expressed in the prostate and other tissues of the genital organs, has an optimum pH of 5.0, and the ce gene is located at the 2p23 locus (Wilson T. El., 1993). From the point of view of the 5-a-reductase type 1 gene, I have underdevelopment of the cervix and a violation of reproductive age (Wilson et al., 1993).

In order for testosterone to have an effect on the prostate and sebaceous glands, it is necessary to restore its 5-a to dihydrotestosterone. Dihydrosterone plays a role in the pathogenesis of benign organ hyperplasia and androgenic care (Wilson et al., 1993). Type 2 isoenzyme is the predominant form in the prostate and is involved in the pathophysiology of benign prostatic hypertrophy, hirsutism and possibly baldness in men. During embryonic development, testosterone controls the differentiation of the Wolf ducts into the epididymis, outgrowing tubules and seminal vesicles. Dihydrotestosterone is also required to form structures from the urogenital sinus and genital tubercle, such as the scrotum, penis and spongy part of the male urethra. Despite the fact that both testosterone and dihydrotestosterone have anabolic effects on muscle tissue, the activity of 5-a-reductase in skeletal muscle is very low or absent and it is unknown whether the restoration of testosterone to dihydrotestosterone is a prerequisite for mediating the effects of androgens on muscles. Similarly, the question remains unclear which androgen — testosterone or dihydrotestosterone affects the sexual function of men.

Extensive information on the role of dehydrotestosterone has been obtained from studies of patients with autosomal recessive deficiency of 5-a-reductase steroids. In male children from 46.With the disease, normal internal male genitalia are present at birth, including my testicles, while they have abnormalities in the formation of external genitalia, or the presence of female genitalia (Kai et al., 1993; Mcndonca CT al., 1996). Eventually, with its help, such people have partial virtualization and major development of the computer system (Cai et al., 1993). Many, but not all, people with a 46-year-old disorder develop male gender identification, even if they were raised as girls. The peculiarities of their development indicate that testosterone itself is able to stimulate psychosexual behavior, libido, the development of the Wolf ducts in the embryonic state, the formation of muscles, coarsening of the voice, spermatogenesis, as well as hair loss in the armpits and pubis. At the same time, dihydrotestosterone is necessary for the formation and growth of the prostate gland, the formation of external genitalia, male type of facial and body hair, or the development of male type of baldness. All individuals with 5-a-reductase deficiency studied to date were characterized by the presence of a mutation in the 5-a-reductase gene of steroids type 2— a form of the enzyme predominant in prostate tissues (Tsai CT al., 1993; Mcndonca CT al., 1996).

The mechanism of action of androgens. Most of the effects of testosterone and dihydrotestosterone are mediated by the binding of these steroids to the intracellular androgen receptor, which acts as a ligand-dependent transcription factor (Zhou ct al., 1994; Lee D.K., Chang, 2003). The affinity of binding to the androgen receptor in testosterone is two times less than that of dihydrotestosterone, despite the fact that the maximum binding capacity of the receptor for both of these androgens is the same. The receptor complex with dihydrotestosterone is characterized by higher thermal stability and lower dissociation rate. This may provide higher capabilities of dihydrotestosterone in implementing the effects of androgen in some androgen-sensitive tissues, such as the prostate gland.

The androgen receptor is characterized by homology with other nuclear receptors, including glucocorticoid, progesterone and mineralcorticoid receptors (Zhoukt al., 1994; Lee D.K., Chang, 2003). The predominant form of the androgen receptor contains 919 amino acid residues, has a molecular weight of 110-114 " and consists of three conservative functional domains: a steroid-binding domain, a DNA-binding domain and a domain that activates transcription. The most conservative of these is the central cysteine-rich DN-binding domain. A single copy of the receptor gene occupies a 90-tn section in the chromosomal locus Xq 11-12. In the absence of its ligand, the androgen receptor protein is distributed in the nucleus and cytoplasm. The binding of androgen to the receptor causes it to move to the nucleus — the amino acid sequence located between 617-633 amino acid residues of the receptor is responsible for moving to the nucleus and the function of transactivation. There is scattered evidence that some effects of androgens can be mediated through membrane receptors in other ways without affecting the genome.

Binding of the receptor to the androgen leads to conformational changes in this protein. There is also evidence that the binding of antiandrogens to the receptor can cause another type of conformational changes (Zhou et al., 1994; Lee D.K., Chang, 2003). The androgen receptor can use two transactivation domains, AF, and AF, respectively. The transactivation component AF (including the so-called regions 1 and 5) is located in the amino terminal part of the receptor, whereas AF2 is located in its carboxylic terminal, hormone-dependent component. In an intact receptor, both AF and AF are hormone-dependent and are influenced by nuclear receptor coactivators. At the same time, in the shortened androgen receptor, which has lost the hormone-binding domain, AF, becomes constitutively active. The binding of the hormone to the receptor leads to the formation of a complex with tissue-specific coactivators and co-receptors that determine the specificity of the hormone's action.

Mutations in the androgen receptor gene are associated with a wide range of phenotypic disorders (Brinkman, 2001). Individuals with a complete lack of androgen sensitivity, which is observed in male pseudohermaphroditism, are characterized by the presence of external female genitalia, a blind vaginal pocket and well-developed mammary glands. Patients with other androgen receptor mutations may have a male phenotype and less pronounced disorders such as hypospadnia, gynecomastia, and infertility (McPhaul et al., 1993).

The length of the CAG and GCC repeats in exon 1 of the androgen receptor gene is correlated with the transcriptional activity of the receptor protein. Deviations in the length of the polyglutamine tract in exon 1 of the androgen receptor are associated with spinal and bulbar muscular atrophy, also known as Kennedy's disease. Although some studies have reported the relationship of polyglutamine and polyglycine tract length polymorphism with male infertility and prostate cancer risk, its existence has not been definitively confirmed (Casclla et al., 2001).

Since antiquity, people have known about the close relationship between the energy balance and the nature of nutrition with the function of the reproductive system in men and women. The onset of puberty, the duration of the reproductive period, the number of offspring and the age of menopause are all related to body weight and composition, in particular the amount of body fat (Frisch, McArthur, 1974; Van Der Spruy, 1985; Frisch, 1989; Foster, Nagatani, 1999). Optimal nutrition is necessary for normal reproductive function: both calorie restriction of the diet and subsequent weight loss, as well as excessive food intake and obesity lead to impaired reproductive function. The temporal features of puberty are significantly more strongly associated with the development and growth of the human body than with chronological age (Penny et al., 1978; Frisch, 1989). In the animal kingdom, during periods of food scarcity, small animals with short lifespans may not even have time to reach puberty before death (Foster, Nagatani, 1999). In animals with a longer life span, in the absence of proper nutrition, puberty may be delayed. Malnutrition caused by starvation, eating disorders and physical exertion leads to a decrease in body weight, as well as changes in its composition and hormone levels, which can disrupt reproductive function (Penny et al., 1978; Bates et al., 1982; Rock et al., 1996). As a rule, a decrease in body weight and changes in its composition due to malnutrition are associated with a decrease in gonadotropin secretion, a decrease in LH and FSH levels also correlates with the degree of weight loss (Fig. 21.7) (Penny et al., 1978). At the same time, hypogonadotropic and hypergonadotronic hypogonadism may be observed in cachexia associated with chronic diseases such as acquired immunodeficiency syndrome (Arver et al., 1999). In general, all these observations provide strong evidence that energy balance is an important factor determining the function of the reproductive system in all mammals.


Leptin is a hunger hormone and its role in weight loss
We do not know the exact nature of the biochemical pathways that combine energy metabolism and the reproductive system, two essential elements of biological systems that determine the survival of any species. According to the most common hypothesis, the mediators of metabolic signals regulating hypothalamic gonadoliberin secretion are leptin and neuropeptide Y (Aubert et al., 1988; Clarke, Henry, 1999; Cunningham et al., 1999; Foster, Nagatani, 1999). Leptin, a product of the obese gene, is a hormone circulating in the circulatory system, which is secreted by adipose tissue cells and has a central effect, regulating the activity of the effector system of the central nervous system, which is responsible for maintaining energy balance (Schwartz et al., 1999). Leptin stimulates LH secretion by activating nitric oxide synthase in gonadotropic cells (McCann et al., 1988) and suppresses the secretion of neuropeptide Y. Neuropeptide Y has a tonic suppressive effect on the secretion of leptin and gonadoliberin. Leptin also stimulates the production of nitric oxide (NO) in the mediobasal hypothalamus, NO stimulates the secretion of gonadoliberin by hypothalamic gonadoliberin-secreting neurons (McCann et al., 1988). Recent data indicate the existence of additional regulatory pathways, including energy homeostasis associated with galanine-like peptide (GALP), food intake and secretion of gadoliberin in the hypothalamus (see Figure 21.7) (Seth et al., 2004). The total effect of leptin is to stimulate the hypothalamic secretion of gonadoliberia (Schwartz et al., 1999).

Restriction of the energy value of the mammalian diet is associated with a decrease in leptin levels and a subsequent drop in LH levels (Schwartz et al., 1999). Administration of leptin to starving mice restores the suppression of gonadotropin secretion that accompanies malnutrition (Schwartz et al., 1999). However, mutant ob/ob mice with leptin deficiency are characterized by hypogonadotropic hypogoiadism and infertility, and administration of leptin to such mice restores their gonadotropin secretion and ability to fertilize (Mohamed-Ali et al., 1998; Schwartz et al., 1999). Thus, energy deficiency and a decrease in body weight are associated with impaired gonadoliberin secretion, which is partly due to changes in the activity of neuropeptide Y, galpin-like peptide (GALP) and a subsequent decrease in leptin secretion. Although it has been established that leptin is an important metabolic factor that unites the energy balance and the reproductive system, it remains unclear whether it is the primary signal for triggering gonadoliberin secretion at the beginning of puberty. An increasing amount of evidence suggests that leptin is necessary, but not sufficient for the initiation of puberty.

A hungry winter in Denmark. During World War II, from October 1944 to May 1945, the German army restricted the supply of food to a number of Danish cities (Figure 21.8), which led to a significant decrease in average daily food intake to less than 1,000 kcal (Stein et al., 1973). Studies have shown that 50% of women who were starved developed amenorrhea, decreased the frequency of conception, and increased the rate of perinatal mortality, congenital malformations and schizophrenia (Stein et al., 1973). Thus, optimal energy consumption with food is an important condition for the normal ability to reproduce offspring and prenatal development of the fetus.

The relationship between body weight and fertility in the Kung San tribe. The Kung San tribe, which lives in Botswana, hunts and feeds on the gifts of nature (Van Der Walt et al., 1978). The body weight of men and women of the tribe varies throughout the year depending on the availability of food. In the summer months, which are abundant in food, their body weight increases, and in the winter months it reaches minimum values. The number of births in the tribe reaches a peak 9 months after the peak of body weight (Van Der Walt et al., 1978). This is another example of how the availability of food regulates the ability to reproduce offspring in nature.

The Minnesota experiment on the effects of starvation. In the late 40s, an experiment was conducted on the campus of the University of Minnesota to study the effects of starvation, in which 32 volunteers participated. The energy value of their diet during the experiment was approximately 1,600 kcal per day"1 (6,688 MJ day-1), which is about two thirds of normal energy requirements (Keys et al., 1950). The participants in the experiment lost an average of 23% of their initial body weight, more than 70% of adipose tissue and 24% of non-fat tissue. The decrease in the energy value of the diet and the subsequent loss of body weight initially led to a loss of libido and a decrease in the amount of prostate secretion, as well as sperm motility and viability. A decrease in sperm production was already observed with a decrease in body weight by about 25% below the normal value for this growth. The restoration of normal body weight was accompanied by the restoration of reproductive function.

Men with chronic diseases often have androgen deficiency, defined as a decrease in testosterone levels. Thus, even after the advent of powerful antiviral therapy, androgen deficiency continues to be a common complication after HIV infection. In one of the studies of 150 HIV-infected men who visited our clinic in 1997, about one third had serum levels of total and free testosterone at a level characteristic of hypogonadism (Arver et al., 1999). Other studies have also noted a significant prevalence of hypogonadism in HIV-infected men (Dobs et al., 1996; Grinspooon et al., 1996). A survey of HIV-infected men showed that many of them had testosterone levels reduced to 20% (Reitschei et al., 2000). Thus, androgen deficiency continues to be a widespread phenomenon in HIV-infected men.

According to the results of our study, 20% of HIV-infected men with low testosterone levels had elevated levels of LH and FSH, i.e. gingonadotropic hypogonadism (Arver et al., 1999). This pattern can be explained by primary testicular dysfunction in these patients. The remaining 80% had normal or decreased levels of LH and FSH. Men with hypogonadotronic hypogonadism had either a central defect at the level of the hypothalamus or pituitary gland, or a double defect affecting both the testes and hypothalamic-pituitary centers. The pathophysiology of hypohopadism in HIV infection is quite complex and includes defects at various levels of the hypothalamic-pituitary-seminal system.

A recent study showed that men with chronic obstructive pulmonary disease have reduced levels of total and free testosterone (Casaburi et al., 1996). Similarly, hypogonadism is very common in patients with cancer, with the last stage of renal failure, who are on hemodialysis, as well as in liver diseases (Handelsman, Dong, 1993; Singh et al., 2001). In previous years, it was reported that two thirds of men with end-stage renal failure have low levels of total and free testosterone (Handelsman, Dong, 1993). According to the results of a later study, of 39 men with end-stage renal failure who were on hemodialysis and not diabetic, 24 had total free testosterone levels below the lower limit of the normal range (Singh et al., 2001). Men on hemodialysis have a high incidence of impaired sexual function and spermatogenesis (Handelsman, Dong, 1993). In addition, such patients experience a decrease in muscle mass and an increase in adipose tissue mass, as well as a marked decrease in muscle strength and physical capabilities (Kopple, 1999; Johansen et al., 2001). Although it is known that androgen deficiency can contribute to the complex pathophysiology of impaired sexual function and sarcopenia in men on hemodialysis, nothing is known about whether these physiological shifts can be reversed with hormone replacement therapy.

The pathophysiology of hypogonadism in chronic diseases is a multifactorial phenomenon — defects can occur at all levels of the hypothalamic-pituitary-testicular system (Bross et al., 1998). Improper or insufficient nutrition, mediators and products of the systemic inflammatory response, medications such as ketoconazole, and metabolic disorders caused by systemic diseases can all contribute to a decrease in testosterone production.

Low testosterone levels correlate with a poor prognosis of the disease. Low testosterone levels correlate with an unfavorable prognosis of the course of the disease in HIV-infected men. Serum testosterone levels in men who lost body weight were lower compared to those with stable body weight (Coodlcy et al., 1994). Longitudinal studies of HIV-infected homosexual men have revealed a progressive decrease in serum testosterone levels, much more pronounced in HIV-infected men with developing acquired immunodeficiency syndrome (AIDS). A decrease in testosterone levels in the blood serum of HIV-infected men occurred at the beginning of a chain of events ending in exhaustion (Dobs et al., 1996). Their testosterone levels correlated with muscle mass and the ability to withstand physical exertion (Grinspoon et al., 1996). Despite the fact that patients with HIV infection may experience a decrease in the mass of both fat and muscle tissue, it is the decrease in the latter that is an important aspect of weight loss associated with exhaustion. HIV-infected men often have impaired sexual function. In the case of an increase in their life expectancy, the fragility of the body and impaired sexual function of the mo|ut become one of the important aspects of ensuring the quality of life.

Similarly, muscle mass, strength and other indicators, as well as physical performance, are markedly reduced in patients on hemodialysis (Johansen et al., 2001). The ability to tolerate physical activity is weakened (Kopple, 1999; Johansen et al., 2001), the maximum oxygen consumption is reduced by almost 2 times compared to the calculated level for healthy individuals] Despite the complexity of the etiology of sarcopenia and end-stage renal failure, a decrease in testosterone levels, which contributes to the loss of muscle mass and the development of various disorders, is potentially reversible.

The data from literary sources regarding the effect of physical exercise on testicular function are to a certain extent contradictory, since the studies conducted differ significantly in type, type, intensity and duration of physical exercise. Moreover, only a few studies have monitored the effect of caloric intake and the initial level of motor activity, so it is not surprising that men who engaged in physical exercise had both an increase and a decrease in testosterone levels in the blood. These men differ significantly from women, in whom intensive aerobic exercise is accompanied by persistent menstrual irregularities and the production of ovarian estrogens (Frisch, Revelle, 1970; Mahna et al., 1973; Warren, 1980; Baker et al., 1981; Veldhuis et al., 1985; Loucks et al., 1989; Cumming, 1996). Girls who practice ballet dancing and perform significant physical activity often experience delayed menarche (Frisch et al., 1980). Such irregularities in the regularity of the menstrual cycle, impaired gonadotropin secretion and elevated cortisol levels are often noted in women who run (Baker et al., 1981; Villanueva et al., 1986). At the same time, the literature data on the effect of physical exercise on reproductive function in men are more scattered and less unambiguous (MacConnie et al., 1986; Scarda, Burge, 1998).

In a broad sense, training regimes can be divided into those using endurance exercises and those performing strength exercises. Despite the fact that serum testosterone levels may increase in anticipation of sports or endurance exercises, the authors of most studies agree that moderate-intensity endurance exercises have a weak or clinically insignificant effect on blood testosterone levels (Scarda, Burge, 1998; Smiilos et al., 2003). However, endurance training exercises with a very high level of physical activity, an example of which is long-distance running, especially in combination with significant energy expenditure and weight loss, cause a drop in serum testosterone levels (Remes et al., 1979; Hakkincn ct al., 1985; MacConnie et al., 1986; Dressendorfer, Wade, 1991; Skarda, Burge, 1998). For example, men who run and run an average of about 92 km weekly have a 10% lower bone density of the lumbar vertebrae compared to the control group of men who do not run (Frost, 1992). In general, there is a negative correlation between the length of the distance run and the bone density of the lumbar vertebrae and femur: the longer the length of the distance run, the greater the energy consumption and the lower the bone density. In one of the reports on the results of a study of men participating in a 15-day 400 km race, there was a noticeable decrease in testosterone levels and an increase in cortisone levels (Dressen-A dorfer, Wade, 1991). After that, it is not surprising that the lowest testosterone levels are observed in army recruits undergoing intensive training in preparatory camps.

It is noteworthy that men who run 20-30 km weekly have higher bone density compared to their peers from the control group who did not run (Frost, 1992; Burrows et al., 2003). There are also similar reports that people engaged in rowing have a higher density of mineral tissue compared to those who lead a sedentary lifestyle. In another study, the bone density of athletes engaged in triathlon and those from the control group who lead a sedentary lifestyle was the same. Thus, physical endurance exercises below the average and average intensity levels can have a positive effect on the density of mineral tissue and at the same time have virtually no effect on testosterone levels. Excessively intense endurance exercises lower testosterone levels and reduce bone density (Heinonen et al., 1995; Burrows ct al., 2003).

There is a consensus that long-distance runners may have significant energy and nutritional deficiencies, which may themselves affect bone density regardless of the effect of physical activity on testosterone levels (Burrows et al., 2003). Indeed, some studies have suggested that only behaviors that entail malnutrition are associated with a decrease in bone density and an increased risk of fractures. Moreover, some of the destructive effects of a decrease in sex hormones on bone density can be compensated by the direct positive effect of physical exercise and motor activity on the bone apparatus.

It has been suggested that the effect of physical exercise on bone density largely depends on the force applied to the limbs during exercise (Frost, 1992). Frost admitted that only training regimes in which the forces applied to the limbs exceed a certain threshold level and are able to cause a bone remodeling reaction, while long-distance running, in which the forces acting on the limbs are relatively small (only 5-10 times the body weight) and therefore not they stimulate an increase in bone density. According to this hypothesis, the amount of load on the bone is much more important than the type of motor activity or duration of exercise, therefore, marathon runners or soldiers undergoing training in training camps, due to a significant energy deficit, can expect a decrease in testosterone levels and the absence of balancing its effects of positive effects on the bone apparatus, and in general, lower bone density.

Previous studies have found no changes and only a slight increase in total serum testosterone as a result of strength training (Remes et al., 1979; Truls ct al., 2000; Ahtiaincn ct al., 2003). Small changes in testosterone concentration, which were reported in some studies, did not persist after the end of classes. In fact, some researchers have noted a significant decrease in free testosterone levels during recovery from physical exertion. The concentration of SHBG during strength training did not change significantly. Some studies have reported an increase in the ratio of testosterone to cortisol during progressive training aimed at maximizing strength. The individual hormonal response to strength exercises is characterized by significant variability.

Anabolic drugs may only be used by a doctor's prescription and are contraindicated in children. The information provided does not call for the use or distribution of potent substances and is aimed solely at reducing the risk of complications and side effects.