Regulation of hormone secretion by the testes

The important physiological role of the testicles explains the complexity of ordering their functions. Three hormones of the anterior pituitary gland have a direct influence on them: follicle-stimulating hormone, luteinizing hormone and prolactin. As already noted, LH and FSH are glycoproteins consisting of 2 polypeptide subunits, with the a-subunit in both hormones (and TSH) being the same, and the biological specificity of the molecule is determined by the beta-subunit, which acquires activity after combining with the alpha-subunit of any animal species. Prolactin contains only one polypeptide chain. The synthesis and secretion of luteinizing hormone and follicle-stimulating hormone are in turn controlled by the hypothalamic factor - gonadotropin-releasing hormone (or luliberin), which is a decapeptide and is produced by the nuclei of the hypothalamus in the portal vessels of the pituitary gland. There is evidence of the involvement of monoaminergic systems and prostaglandins (E series) in the regulation of lulliberin production.

By binding to specific receptors on the surface of pituitary cells, luliberin activates adenylate cyclase. With the participation of calcium ions, this leads to an increase in the content of cAMP in the cell. It is still unclear whether the pulsating nature of the secretion of pituitary luteinizing hormone is due to hypothalamic influences.

LH-releasing hormone stimulates the secretion of both luteinizing hormone and follicle-stimulating hormone. Their ratio depends on the conditions under which the pituitary gland secretes these hormones. Thus, on the one hand, an intravenous injection of LH-releasing hormone leads to a significant increase in the blood level of luteinizing hormone, but not follicle-stimulating hormone. On the other hand, a long-term infusion of releasing hormone is accompanied by an increase in the content of both gonadotropins in the blood. Apparently, the effect of LH-releasing hormone on the pituitary gland is modulated by additional factors, including sex steroids. LH-releasing hormone primarily controls the sensitivity of the pituitary gland to such modeling effects and is necessary not only to stimulate the secretion of gonadotropins, but also to maintain it at a relatively low (basal) level. Prolactin secretion, as noted above, is regulated by other mechanisms. In addition to the stimulating effect of TRH, pituitary lactotrophs also experience the inhibitory effect of hypothalamic dopamine, which simultaneously activates the secretion of gonadotropins. However, serotonin increases prolactin production.

Luteinizing hormone stimulates the synthesis and secretion of sex steroids by Leydig cells, as well as the differentiation and maturation of these cells. Follicle-stimulating hormone probably enhances their reactivity to luteinizing hormone by inducing the appearance of LH receptors on the cell membrane. Although follicle-stimulating hormone is traditionally considered a hormone that regulates spermatogenesis, without interaction with other regulators it does not initiate or maintain this process, which requires the combined effect of follicle-stimulating hormone, luteinizing hormone, and testosterone. Luteinizing hormone and follicle-stimulating hormone interact with specific receptors on the membrane of Leydig and Sertoli cells, respectively, and through activation of adenylate cyclase increase the content of cAMP in the cells, which activates the phosphorylation of various cellular proteins. The effects of prolactin in the testicles are less studied. Its high concentrations slow down spermatogenesis and steroidogenesis, although it is possible that in normal quantities this hormone is necessary for spermatogenesis.

Feedback loops that close at different levels are also of great importance in the regulation of testicular functions. Thus, testosterone inhibits the secretion of OH. Apparently, this negative feedback loop is mediated only by free testosterone, and not by testosterone bound in serum to sex hormone-binding globulin. The mechanism of the inhibitory effect of testosterone on the secretion of luteinizing hormone is quite complex. It may also involve intracellular conversion of testosterone into either DHT or estradiol. It is known that exogenous estradiol suppresses the secretion of luteinizing hormone in much smaller doses than testosterone or DHT. However, since exogenous DHT still has this effect and is not aromatized, the latter process is obviously not necessary for the manifestation of the inhibitory effect of androgens on the secretion of luteinizing hormone. Moreover, the very nature of the change in the pulse secretion of luteinizing hormone under the influence of estradiol, on the one hand, and testosterone and DHT, on the other, is different, which may indicate a difference in the mechanism of action of these steroids.

As for follicle-stimulating hormone, large doses of androgens are capable of inhibiting the secretion of this pituitary hormone, although physiological concentrations of testosterone and DHT do not have this effect. At the same time, estrogens inhibit the secretion of follicle-stimulating hormone even more intensively than luteinizing hormone. It has now been established that the cells of the vas deferens produce a polypeptide with a molecular weight of 15,000-30,000 daltons, which specifically inhibits the secretion of follicle-stimulating hormone and changes the sensitivity of FSH-secreting pituitary cells to luliberin. This polypeptide, the source of which is apparently the Sertoli cells, is called inhibin.

Feedback between the testicles and the centers regulating their function is also closed at the hypothalamus level. The hypothalamus tissue contains receptors for testosterone, DHT, and estradiol, which bind these steroids with high affinity. The hypothalamus also contains enzymes (5a-reductase and aromatase) that convert testosterone into DHT and estradiol. There is also evidence of a short feedback loop between gonadotropins and the hypothalamic centers that produce luliberin. An ultrashort feedback loop within the hypothalamus itself cannot be ruled out, according to which luliberin inhibits its own secretion. All of these feedback loops may include activation of peptidases that inactivate luliberin.

Sex steroids and gonadotropins are necessary for normal spermatogenesis. Testosterone initiates this process by acting on spermatogonia and then stimulating meiotic division of primary spermatocytes, resulting in the formation of secondary spermatocytes and young spermatids. Maturation of spermatids into spermatozoa is carried out under the control of follicle-stimulating hormone. It is not yet known whether the latter is necessary to maintain spermatogenesis that has already begun. In an adult with pituitary insufficiency (hypophysectomy), after resumption of spermatogenesis under the influence of luteinizing hormone and follicle-stimulating hormone replacement therapy, sperm production is maintained by injections of LH alone (in the form of human chorionic gonadotropin). This occurs despite the almost complete absence of follicle-stimulating hormone in the serum. Such data allow us to assume that it is not the main regulator of spermatogenesis. One of the effects of this hormone is to induce the synthesis of a protein that specifically binds testosterone and DHT, but is capable of interacting with estrogens, albeit with less affinity. This androgen-binding protein is produced by Sertoli cells. Animal experiments suggest that it may be a means of creating a high local concentration of testosterone, which is necessary for normal spermatogenesis. The properties of androgen-binding protein from human testicles are similar to those of sex hormone-binding globulin (SHBG), which is present in blood serum. The main role of luteinizing hormone in the regulation of spermatogenesis is to stimulate steroidogenesis in Leydig cells. The testosterone secreted by them, along with follicle-stimulating hormone, ensures the production of androgen-binding protein by Sertoli cells. In addition, as already noted, testosterone directly affects spermatids, and this action is facilitated in the presence of this protein.

The functional state of the fetal testes is regulated by other mechanisms. The main role in the development of Leydig cells at the embryonic stage is played not by the pituitary gonadotropins of the fetus, but by the chorionic gonadotropin produced by the placenta. Testosterone secreted by the testes during this period is important for determining the somatic sex. After birth, stimulation of the testes by the placental hormone ceases, and the level of testosterone in the blood of the newborn drops sharply. However, after birth, boys experience a rapid increase in the secretion of pituitary LH and FSH, and already in the 2nd week of life, an increase in the concentration of testosterone in the blood serum is noted. By the 1st month of postnatal life, it reaches a maximum (54-460 ng%). By the age of 6 months, the level of gonadotropins gradually decreases and up until puberty remains as low as in girls. T levels also fall, and prepubertal levels are approximately 5 ng%. At this time, the overall activity of the hypothalamic-pituitary-testicular axis is very low, and gonadotropin secretion is suppressed by very low doses of exogenous estrogens, a phenomenon not observed in adult males. The testicular response to exogenous human chorionic gonadotropin is preserved. Morphological changes in the testicles occur at approximately six years of age. The cells lining the walls of the seminiferous tubules differentiate, and tubular lumens appear. These changes are accompanied by a slight increase in the levels of follicle-stimulating hormone and luteinizing hormone in the blood. Testosterone levels remain low. Between 6 and 10 years of age, cell differentiation continues, and the diameter of the tubules increases. As a result, the size of the testicles increases slightly, which is the first visible sign of impending puberty. If the secretion of sex steroids does not change in the prepubertal period, then the adrenal cortex at this time produces increased amounts of androgens (adrenarche), which can participate in the mechanism of puberty induction. The latter is characterized by abrupt changes in somatic and sexual processes: body growth and skeletal maturation accelerate, secondary sexual characteristics appear. The boy turns into a man with a corresponding restructuring of sexual function and its regulation.

During puberty, there are 5 stages:

• I - prepuberty, the longitudinal diameter of the testicles does not reach 2.4 cm;
• II - early increase in the size of the testicles (up to 3.2 cm in maximum diameter), sometimes sparse hair growth at the base of the penis;
• III - the longitudinal diameter of the testicles exceeds 3.3 cm, obvious pubic hair growth, the beginning of an increase in the size of the penis, possible hair growth in the armpit area and gynecomastia;
• IV - full pubic hair, moderate hair in the armpit area;
• V - full development of secondary sexual characteristics.

After the testicles begin to increase in size, pubertal changes continue for 3-4 years. Their nature is influenced by genetic and social factors, as well as various diseases and medications. As a rule, pubertal changes (stage II) do not occur until the age of 10. There is a correlation with bone age, which at the beginning of puberty is approximately 11.5 years.

Puberty is associated with changes in the sensitivity of the central nervous system and hypothalamus to androgens. It has already been noted that in prepubertal age the CNS has a very high sensitivity to the inhibitory effects of sex steroids. Puberty occurs during a period of some increase in the threshold of sensitivity to the action of androgens by the mechanism of negative feedback. As a result, hypothalamic production of luliberin, pituitary secretion of gonadotropins, synthesis of steroids in the testicles increase, and all this leads to the maturation of the seminiferous tubules. Simultaneously with a decrease in the sensitivity of the pituitary gland and hypothalamus to androgens, the reaction of pituitary gonadotrophs to hypothalamic luliberin increases. This increase relates mainly to the secretion of luteinizing hormone, and not follicle-stimulating hormone. The level of the latter doubles approximately at the time of the appearance of pubic hair. Since follicle-stimulating hormone increases the number of receptors for luteinizing hormone, this ensures the testosterone response to the increase in luteinizing hormone levels. From the age of 10, there is a further increase in the secretion of follicle-stimulating hormone, which is accompanied by a rapid increase in the number and differentiation of epithelial cells of the tubules. The level of luteinizing hormone increases somewhat more slowly until the age of 12, and then there is a rapid increase, and mature Leydig cells appear in the testicles. Maturation of the tubules continues with the development of active spermatogenesis. The concentration of follicle-stimulating hormone in the blood serum characteristic of adult men is established by 15, and the concentration of luteinizing hormone - by 17 years.

A noticeable increase in serum testosterone levels is recorded in boys from about the age of 10. The peak concentration of this hormone occurs at the age of 16. The decrease in the content of SGBT that occurs during puberty in turn contributes to an increase in the level of free testosterone in the serum. Thus, changes in the rate of genital growth occur even during the period of low levels of this hormone; against the background of its slightly increased concentration, the voice changes and hair growth occurs in the armpits, facial hair growth is noted already at a fairly high ("adult") level. An increase in the size of the prostate gland is associated with the appearance of nocturnal emissions. Libido arises at the same time. In the middle of puberty, in addition to a gradual increase in the content of luteinizing hormone in the serum and an increase in the sensitivity of the pituitary gland to luliberin, characteristic increases in the secretion of luteinizing hormone associated with nocturnal sleep are recorded. This occurs against the background of a corresponding increase in the level of testosterone at night and its pulsed secretion.

It is known that during puberty, numerous and varied transformations of metabolism, morphogenesis and physiological functions occur, caused by the synergistic influence of sex steroids and other hormones (STH, thyroxine, etc.).

After its completion and up to 40-50 years of age, the spermatogenic and steroidogenic functions of the testicles are maintained at approximately the same level. This is evidenced by the constant rate of testosterone production and the pulsating secretion of luteinizing hormone. However, during this period, vascular changes in the testicles gradually increase, leading to focal atrophy of the seminiferous tubules. From about the age of 50, the function of the male gonads begins to slowly fade. The number of degenerative changes in the tubules increases, the number of germinal cells in them decreases, but many tubules continue to carry out active spermatogenesis. The testicles can be reduced in size and become softer, the number of mature Leydig cells increases. In men over 40, the levels of luteinizing hormone and follicle-stimulating hormone in the serum increase significantly, while the rate of testosterone production and the content of its free form decrease. However, the overall testosterone level remains the same for several decades, as the binding capacity of SGLB increases and the metabolic clearance of the hormone slows down. This is accompanied by an accelerated conversion of testosterone into estrogens, the total content of which in the serum increases, although the level of free estradiol also decreases. In the testicular tissue and the blood flowing from them, the amount of all intermediate products of testosterone biosynthesis decreases, starting with pregnenolone. Since in old and senile age the amount of cholesterol cannot limit steroidogenesis, it is believed that mitochondrial processes of converting the former into pregnenolone are disrupted. It should also be noted that in old age, the level of luteinizing hormone in plasma, although elevated, apparently this increase is inadequate to the decrease in testosterone content, which may indicate changes in the hypothalamic or pituitary centers regulating gonadal function. The very slow decline in testicular function with age leaves open the question of the role of endocrine changes as causes of male menopause.

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