Regulation of secretion of testicular hormones

The important physiological role of testicles explains the complexity of ordering their functions. Direct influence on them have three hormones of the anterior lobe of the pituitary: 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 determines the beta subunit, which acquires activity after integration with an alpha subunit of any kind animals. Prolactin also contains only one polypeptide chain. The synthesis and secretion of luteinizing hormone and follicle-stimulating hormone are in turn under the control of the hypothalamic factor-gonadotropin-releasing hormone (or lylyberin), which is a decapeptide and produced by the nuclei of the hypothalamus in the portal vessels of the pituitary gland. There are data on the participation of monoaminergic systems and prostaglandins (series E) in the regulation of the production of luliberin.

Connecting with specific receptors on the surface of the pituitary cells, lyuliberin activates the adenylate cyclase. With the participation of calcium ions, this leads to an increase in the content of cAMP in the cell. It is not yet clear whether the pulsating nature of the secretion of the pituitary luteinizing hormone is due to hypothalamic influences.

Luliberin stimulates the secretion of both luteinizing hormone and follicle-stimulating hormone. The ratio of them depends on the conditions in which the pituitary gland secretes these hormones. Thus, on the one hand, intravenous injection of lylyberyrin leads to a significant increase in the level of luteinizing hormone in the blood, but not follicle-stimulating hormone. On the other hand, a prolonged infusion of the releasing hormone is accompanied by an increase in the content in the blood of both gonadotropins. Apparently, the influence of lylybyrin on the pituitary is modulated by additional factors, including sex steroids. Luliberin 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. The secretion of prolactin, as noted above, is regulated by other mechanisms. In addition to the stimulating effect of TRH, the pituitary lactotrophs test the inhibitory effect of hypothalamic dopamine, which simultaneously activates the secretion of gonadotropins. However, serotonin increases the production of prolactin.

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, in all probability, enhances their reactivity to luteinizing hormone, inducing the appearance of LH-receptors on the cell membrane. Although follicle-stimulating hormone is traditionally considered a hormone that regulates spermatogenesis, but without interacting with other regulators, it does not trigger and support 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, and through the 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 testicles are less studied. Its high concentrations slow down spermato- and steroidogenesis, although it is possible that in normal amounts this hormone is necessary for spermatogenesis.

In the regulation of testicular functions, feedbacks, closing at different levels, are also of great importance. Thus, testosterone inhibits the secretion of OG Apparently, this negative feedback loop is mediated only by free testosterone, rather than bound in serum with sex hormone-binding globulin. The mechanism of the inhibitory effect of testosterone on the secretion of luteinizing hormone is quite complicated. Intracellular conversion of testosterone into either DHT or estradiol may also participate in it. It is known that exogenous estradiol inhibits the secretion of luteinizing hormone in much smaller doses than testosterone or DHT. However, since exogenous DHT still possesses such an action and does not undergo aromatization, the latter process is obviously not yet 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 impulse secretion of the luteinizing hormone under the action 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 the follicle-stimulating hormone, large doses of androgens are able to inhibit the secretion of this pituitary hormone, although the physiological concentrations of testosterone and DHT have no such 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 to 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, whose source is apparently Sertoli cells, was called inhibin.

Feedback between the testicles and the centers of regulation of their function is closed and at the level of the hypothalamus. In the tissue of the hypothalamus, testosterone receptors for DHT and estradiol, which bind these steroids with high affinity, are found. In the hypothalamus, enzymes (5a-reductase and aromatase) are also present in converting testosterone to DHT and estradiol. There is also evidence of the existence of a short feedback loop between gonadotropins and hypothalamic centers producing lyuliberin. It is not excluded and ultrashort feedback within the hypothalamus, according to which lylyberin inhibits its own secretion. All of these feedback loops may include the activation of peptidases inactivating lylyberyrin.

Sexual steroids and gonadotropins are necessary for normal spermatogenesis. Testosterone triggers this process, acting on spermatogonia and then stimulating the meiotic division of primary spermatocytes, resulting in the formation of secondary spermatocytes and young spermatids. Maturation of spermatids in spermatozoa is carried out under the control of follicle-stimulating hormone. It is not yet known whether the latter is necessary to maintain the already started spermatogenesis. In an adult with pituitary insufficiency (hypophysectomy), after resumption of spermatogenesis under the influence of replacement therapy with luteinizing hormone and follicle-stimulating hormone, sperm production is supported by injections of only LH (in the form of chorionic gonadotropin). This occurs despite the almost complete absence of follicle-stimulating hormone in the serum. Such data suggest that it is not the main regulator of spermatogenesis. One of the effects of this hormone is the induction of protein synthesis, specifically binding testosterone and DHT, but capable of, although with a lower affinity, interact with estrogens. This androgen-binding protein is produced by Sertoli cells. Experiments on animals allow us to consider it as a means of creating a high local concentration of testosterone, necessary for the normal course of spermatogenesis. The properties of androgen-binding protein from human testicles are similar to those of sex hormone-binding globulin (GGSG) present in serum. The main role of luteinizing hormone in the regulation of spermatogenesis is to stimulate steroidogenesis in Leydig cells. The secreted testosterone along with follicle-stimulating hormone provides the production of androgen-binding protein by Sertoli cells. In addition, as already noted, testosterone directly affects the spermatids, and this effect is facilitated in the presence of this protein.

The functional state of the testes of the fetus 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 released testes during this period is important for determining the somatic sex. After birth, stimulation of the testes with placental hormone ceases, and the testosterone level in the blood of the newborn falls sharply. However, after birth, the boys develop a rapid increase in the secretion of hypophyseal LH and FSH, and already at the second week of life there is an increase in the concentration of testosterone in the blood serum. By the 1st month of postnatal life, it reaches a maximum (54-460 ng%). By the age of 6 months, the level of gonadotropins is gradually decreasing and up to puberty remains as low as that of girls. The T content also decreases, and its level in the prepubertal period is approximately 5 ng%. At this time, the overall activity of the hypothalamic-pituitary-testicular system is very low, and the secretion of gonadotropins is inhibited by very low doses of exogenous estrogens, which is not observed in adult men. The reaction of testicles to exogenous chorionic gonadotropin is preserved. Morphological changes in testicles occur around the age of six. The cells lining the walls of the vas deferens differentiate, and the luminescence of the tubules appears. These changes are accompanied by a slight increase in the level of follicle-stimulating hormone and luteinizing hormone in the blood. The testosterone content remains low. Between 6 and 10 years, the differentiation of cells continues, 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 induction of puberty. The latter is characterized by dramatic changes in somatic and sexual processes: body growth and maturation of the skeleton are accelerated, secondary sexual characteristics appear. The boy turns into a man with a corresponding reorganization of sexual function and its regulation.

During the pubertal period, there are 5 stages:

• I - prepubertate, 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 by the maximum diameter), sometimes a rare hair in the base of the penis;
• III - the longitudinal diameter of the testicles exceeds 3.3 cm, obvious pubic hair embolization, the beginning of the increase in the size of the penis, axillary region and gynecomastia are possible;
• IV - complete pubis hair, moderate hairiness of the axillary region;
• V - full development of secondary sexual characteristics.

After the testicle size increases, pubertal shifts 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 years. There is a correlation with bone age, which at the beginning of pubertal is approximately 11.5 years.

The pubertal period is associated with changes in the sensitivity of the central nervous system and the hypothalamus to androgens. It has already been noted that at the prepubertal age the CNS has a very high sensitivity to the inhibitory effects of sex steroids. Pueblerata occurs during a period of a certain increase in the threshold of sensitivity to the action of androgens by the mechanism of negative feedback. As a result, hypothalamic production of lyuliberin, pituitary secretion of gonadotropins, synthesis of steroids in testicles increase, and all this leads to maturation of the vas deferens. Simultaneously with a decrease in the sensitivity of the pituitary and hypothalamus to androgens, the reaction of gonadotrophs of the pituitary gland to hypothalamic lyuliberin increases. This increase is mainly related to the secretion of luteinizing hormone, rather than follicle-stimulating hormone. The level of the latter increases by about half at the time of pubic haemorrhage. Because follicle-stimulating hormone increases the number of receptors to the luteinizing hormone, it provides a testosterone response to an increase in the level of luteinizing hormone. 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 tubular epithelial cells. The level of luteinizing hormone increases slightly more slowly to 12 years, and then there is a rapid increase in it, and in testicles mature Leydig cells appear. The maturation of tubules continues with the development of active spermatogenesis. Characteristic for adult men, the concentration of follicle-stimulating hormone in the serum is set to 15, and the concentration of luteinizing hormone - to 17 years.

A marked increase in testosterone levels in the serum is recorded in boys from about 10 years of age. The peak concentration of this hormone falls on 16 years. In the course of puberty, a decrease in the content of the SGSG, in turn, increases the level of free testosterone in the serum. Thus, changes in the growth rate of the genitals take place even during the low level of this hormone; on the background of a slightly increased concentration of it, the voice changes and the hair of the axillary trunks develops, the facial hair is already noted at a sufficiently high ("adult") level. The increase in the size of the prostate gland is associated with the appearance of nocturnal pollutions. At the same time there is libido. In the middle of the pubertal period, in addition to a gradual increase in the luteinizing hormone content in the serum and an increase in the sensitivity of the pituitary to lyuliberin, characteristic increases in luteinizing hormone secretion associated with nighttime sleep are recorded. This occurs against the background of a corresponding increase in testosterone levels at night and impulse its secretion.

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

At its end and up to 40-50 years, the spermatogenic and steroidogenic functions of the testicles are maintained at approximately the same level. This is evidenced by a constant rate of testosterone production and pulsatile secretion of luteinizing hormone. However, during this period, the vascular changes in testicles gradually increase, leading to focal atrophy of the vas deferens. Approximately from the age of 50, the function of male gonads begins to slowly fade. The number of degenerative changes in the tubules increases, the number of hermetic cells in them decreases, but many tubules continue to carry out active spermatogenesis. The testes can be reduced and become softer, the number of mature Leydig cells is increased. In men over the age of 40, the levels of luteinizing hormone and follicle-stimulating hormone in the serum increase significantly, while the testosterone production and the content of its free form decrease. However, the total level of testosterone remains for a number of decades, as the binding capacity of the GGSG 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 testicle tissue and the blood flowing from them, the amount of all intermediate products of testosterone biosynthesis, starting with pregnenolone, decreases. Since in the elderly and old age the amount of cholesterol can not limit steroidogenesis, it is believed that the mitochondrial processes of the transformation of the first into pregnenolone are violated. It should also be noted that in the elderly, the level of luteinizing hormone in plasma, although increased, but apparently, this growth is inadequate to a decrease in testosterone, which may indicate changes in the hypothalamic or pituitary centers of the regulation of gonadal function. The very slow decrease in testicular functions with age leaves open the question of the role of endocrine changes as the causes of men's menopause.

[1], [2], [3], [4], [5], [6], [7]