The effect of testosterone on somatic health in men
the Clinical manifestations of reducing the activity of sex hormones in men, currently called male hypogonadism, is well known since ancient times.They include loss of libido, and erectile function, decrease muscle mass and strength, mood changes and the nature of body hair. However, in the last 20 years began to accumulate information about what the consequences of hypogonadism are not limited to the above changes. In particular, there are a number of evidence of a link between hypogonadism and cardiovascular system (CVS). The issue is the subject of this work.
For a long time it was considered that testosterone has an adverse effect on the likelihood of developing the diseases for SSS. This view was based primarily on the fact that men are more likely to suffer similar diseases. Furthermore, it is known that estrogens, historically considered as antagonists of androgens, reduce the risk of developing cardiovascular disorders in women. The latter, in particular, proves the increase in such diseases after menopause.
In recent years this position has been subjected to severe revision . Methodologically correct studies performed have not confirmed the relationship between testosterone levels in blood and cardiovascular disease (CVD) in men [2, 3]. Some studies even have shown that a higher concentration of the hormone may have a beneficial effect [4, 5]. Treatment with testosterone also not associated with an increase in the frequency of myocardial infarction, angina or stroke [6, 7], moreover, it reduced the likelihood of these complications [8, 9]. A number of studies have also shown that testosterone levels in the blood of men back is associated with mortality from both CVD and all causes in General [10-12].
the Nature of the negative impact of reducing the level of testosterone on the development of CVD is not fully established. Nevertheless, existing data indicate that the adverse effect of hypogonadism on the cardiovascular system may be via the metabolic syndrome (MS). The latter is a well-known combination of various vascular risk factors, including disorders of glucose tolerance, obesity, hypertension, and dyslipidemia. The risk of developing MS in patients with hypogonadism significantly increased [13-15]. These data are so convincing that it even suggested the usefulness of hypogonadism in the number of diagnostic criteria of MS . At the same time continues the study of questions that arise after reviewing these epidemiological data. What is the cause and what the consequence: components of MS lead to the suppression of testicular function or hypogonadism contributes to their development? What are the mechanisms of these interactions? The unequivocal answer to these questions has not been received. The most probable is the existence of a bidirectional relationship between hypogonadism and MS.
insulin resistance (IR), a leading pathophysiological mechanism for the development of MS and its complications, correlated with the level of testosterone in the blood . Patients with hypogonadism have lower sensitivity to the action of insulin. There is reason to believe that hypogonadism contributes to the development of IR. In particular, signs of resistance to insulin action as identified in an experimental model of hypogonadism , and men with Klinefelter syndrome . In addition, the development changes characteristic of MS, including IR, dyslipidemia and obesity, occurs on the background of acute hypogonadism, caused by drug therapy . A similar situation occurs in particular in the treatment of prostate cancer (PCA) drugs from the group of analogues of gonadotropin-releasing hormone.
also of Significant interest is the relationship between hypogonadism and diabetes mellitus (DM) of the 2nd type. This question is studied long enough, and accumulated a number of important details, many of which are relevant in the context of the problem. In particular, men suffering from diabetes 2-type, not only more likely to have low levels of testosterone in the blood , but the presence of the latter in healthy men is predictor of development of diabetes in the future . In addition, the use of drugs of testosterone patients diabetes 2-type is associated with decreased expression of ER and better control over glucose level in the blood . The exact mechanism of such beneficial effects of testosterone has not been established but the possibility that it is associated with changes of the Constitution, primarily in the form of reducing the amount of adipose tissue.
At the same time, hyperinsulinemia may have an inhibitory effect on the endocrine function of the testes . In addition, it is shown that the suppression of insulin secretion leads to increased concentration of binding protein in the blood sex hormones . This in turn causes a decrease in the biological activity of testosterone. Suppression of insulin synthesis of the protein confirmed in experimental conditions . In General, the question of the impact of insulin on the synthesis of testosterone still far from being solved. It can be assumed that the various abnormalities in the synthesis of insulin can, although different, but have a negative impact on the biological activity of testosterone.
the Existence of an inverse Association between the adipose tissue and testosterone levels in the blood confirmed in many studies [25, 26]. This relationship, apparently, is complex.
Adipose tissue and especially its retroperitoneal part secretes a large number of biologically active substances, which allows a number of researchers to consider it as a separate component of the endocrine system [27, 28]. Many of these substances play an important role in the development of IR, however, they can also lead to hypogonadism. In particular, leptin, whose secretion by adipose tissue in MS is increased, can directly suppress the sensitivity of Leydig cells to luteinizing hormone as a result of interaction with specific receptors .
Another communication mechanism between adipose tissue and testosterone are known for a long time and is the conversion of androgens into estrogens in fat cells as a result of the action of the aromatase enzyme . Thus, adipose tissue can not only suppress secretion of testosterone and reduce its activity, while increasing the concentration of its natural antagonists.
it is Expected, however, and the existence of the reverse effect. In a number of experimental studies demonstrate that testosterone stimulates lipolysis in fat cells , inhibits the admission to them of the lipid molecules from the blood , and inhibits the differentiation of stem cells into adipocytes . All these data indicate that the level of testosterone in the blood affects the fatty tissue. Confirmation of the validity of assumptions of this kind are the results of the clinical studies that demonstrated the possibility of reducing the amount of adipose tissue in men treatment drugs testosterone, which will be discussed below.
based On the data presented above on the relationship between fat and testosterone proposed several theories to explain the development of hypogonadism in patients with obesity (and Vice versa). According to one of such theories , fat cells turn testosterone into estrogen and also synthesize substances that suppress the function of Leydig cells, leading to the development of hypogonadism. This in turn inhibits lipolysis and stimulates the capture of the fat cells of lipids from the blood, which leads to increase in adipose tissue and further increased metabolism of testosterone. In addition, due to elevated levels of estrogen and adipocytokines depressed hypothalamic-pituitary response to decreased testosterone levels. Such a hypothesis, in particular, explains the fact that men with obesity and hypogonadism is not marked compensatory increase in the level of luteinizing and follicular-stimulating hormones.
Disorders of lipid metabolism, manifested in the form of atherogenic dyslipidemia also correlates with the level of testosterone in the blood. That men with hypogonadism tend to increase total cholesterol (TC) and cholesterol of low-density lipoproteins (LDL) [34, 35], while the concentration of cholesterol of high density lipoproteins (HDL) in this group is reduced . These violations can be corrected through the use of testosterone. Also shown is the relationship of lowering the concentration of testosterone in the blood and hypertension .
the main mechanism for the development of CVD is endothelial dysfunction. All of the above vascular risk factors have a negative effect on the functional state of the endothelium that leads to the development of atherosclerosis and its complications. At the same time, hypogonadism can directly cause endothelial damage. In the experiment on rats Y. L. Lu et al. found that castration and the introduction of antagonists of 5-α-reductase, violates the conversion of testosterone to its biologically active form dihydrotestosterone are accompanied by pronounced changes in the endothelial cells . Microscopic examination of endothelial cells were shrunken, their shape is changed, and the intercellular connection is broken. In addition, many endothelial cells were covered with red blood cells. In the group of castrated animals, these changes were more pronounced, and they are partially subjected to reverse development with the introduction of testosterone.
it is also Assumed that testosterone and other androgens stimulate the proliferation in the bone marrow precursors of endothelial cells and their release into the bloodstream and the connection defects of the endothelium. In young men with hypogonadism, a decrease in the concentration of precursors of endothelial cells in the blood, replacement therapy led to a significant increase of these parameters . In addition, the biologically active form of testosterone – dihydrotestosterone stimulates proliferation of endothelial cells themselves, blood vessels. This effect of DHT illustrated in the experiments using aorta of the bull  and blood vessels .
Testosterone also affects the secretion of endothelial cells of various para - and autocrine mediators, and cytokines. In particular, it is shown that hypogonadism is accompanied by increased levels of endothelin-1, which has a marked vasoconstrictor effect . Treatment with testosterone was accompanied by a decrease in the concentration of the substance. Testosterone also suppresses the synthesis in the endothelium of many cytokines , having a negative effect on the function of these cells.
the Proliferation of smooth muscle cells of blood vessels is an important step in the development of atherosclerosis. This process is also influenced by the level of androgens in the blood. Testosterone and dihydrotestosterone have antiproliferative, proapoptotic action against smooth muscle cells of blood vessels [44, 45], which could give anti-atherogenic effect.
Presented above data about influence of androgen level on the development of MS indicate that alongside the direct effects on the endothelium testosterone can also exert influence indirectly through the development of various vascular disorders. The main practical consequence of this is a theoretical possibility that vascular risk factors and, therefore, prevent or slow the development of cardiovascular disorders by correcting reduced levels of testosterone. A similar effect can be achieved by the use of drugs of testosterone.
for a Long time there was no easy to use and effective products of testosterone, but for the moment, became available a number of new, highly effective, greatly expanding the possibilities of correction of levels of testosterone. Among these funds there are various forms of drugs, including oral (restrictions apply), for the/m injection, cutaneous application, as well as implanted pellets containing testosterone.
widely used in modern clinical practice are testosterone in the/m introduction. In most cases they allow to reach the maximum concentration of testosterone in the blood plasma within 72 h after injection. Over the next 10-21 days testosterone levels is progressively reduced. The most commonly used oil solution of testosterone enanthate and cypionate are administered in doses of 200 to 400 mg every 3-4 weeks. . A significant disadvantage of these drugs is the presence in their application to significant fluctuations in the level of testosterone in the blood. In the first days after the introduction of testosterone levels often greatly exceed physiological values, and the latter is inferior to them.
to overcome these disadvantages and to achieve a more convenient mode of appointment was created of testosterone undecanoate for the on/m introduction. This drug has a unique pharmacokinetic characteristics with its use of stable testosterone levels within the physiological values achieved within 3 d after injection and persists for about 12 weeks. . In this regard, the interval between the/m injections of testosterone undecanoate (10-14 weeks. or 4 p/year) is nearly 5 times that of testosterone enanthate or cypionate (2-3 weeks. or from 17 to 26 injections/year). This feature makes the drug more convenient for long-term substitution treatment.
One vial of the drug contains 1000 mg testosterone undecanoate in 4 ml castor oil. The contents of the ampoule should be administered very slowly (over about 60 s) deep in the gluteal region. After administration of testosterone undecanoate is gradually released into the blood where it is cleaved by serum esterases serum with formation of testosterone. The interval between the 1st and 2nd injections should be 6 weeks, between the subsequent 12 weeks. With the use of testosterone undecanoate it is recommended to measure testosterone in plasma 1 R/year.
Among the drugs testosterone for cutaneous application isolated patches and gels. The first patches containing testosterone, was proposed in the early 1990s and was intended for application on the skin of the scrotum. In addition to the inconvenience associated with fixation, the use of such patches is accompanied by elevated levels of dihydrotestosterone in the blood, due to the recovery of injected testosterone 5-α-reductase found in the skin of the scrotum . This deficiency deprived the patches for use outside of the scrotum, however, they will often (≈32% of cases) cause skin irritation, and in 12% of patients develop an allergic dermatitis . Containing testosterone gels cause less skin irritation and allow you to achieve an adequate level of hormone in the blood. Also suggested form for application on mucous cheeks.
currently, the ongoing development of drugs testosterone implanted subcutaneously in the form of pellets and microcapsules . These drugs significantly differ in duration of action (up to 6 months), but they also have significant drawbacks, the main of which is the need of surgical interventions during installation and removal.
Testosterone replacement therapy like any other form of treatment, involves risk of side effects and complications, determining contraindications to the prescribing of testosterone, and the volume of patient monitoring during the period of such treatment. The traditional concern associated with the use of testosterone is the ability to increase the risk of development and/or progression of prostate cancer. In this regard, before the beginning of, and periodically during the period of therapy is necessary to perform digital rectal examination and study of the level of prostate specific antigen in the blood. It should be noted that accumulated more and more evidence that normalization of testosterone levels is not accompanied by any appreciable negative effect on the course of prostate cancer . In addition, all the men before treatment and every 3 months. within 1 year of therapy and annually in the future, it is necessary to study the level of hematocrit. This is because testosterone stimulates erythropoiesis, in some patients, a significant increase in the number of erythrocytes may be accompanied by a dangerous increase in blood viscosity.
it Should be noted that one of the historically accepted wisdom of bias, restricting the use of testosterone, were fears of possible negative effects on the cardiovascular system. However, as we pointed out above, a better understanding of the true nature of the relationship between the level of testosterone in the blood and vascular risk factors have created the preconditions for the study of the possibility of correction as a result of substitution therapy with testosterone preparation.
In the literature widely presents the results of research into the effects of testosterone on the various elements of MS [21, 52-64]. The most extensively studied chemicals of testosterone to excess adipose tissue. In a number of studies have shown that hormone replacement therapy leads to an increase in muscle and decrease of fat mass. It should be noted that the decrease in fat mass is largely due to the most important from a clinical point of view, her abdominal part .
So, in a double-blind randomized study P. J. Snyder et al., 108 men over 65 years of age suffering from hypogonadism received treatment with testosterone or placebo for 36 months. . At the end of the study in the group treated with testosterone was shown to decrease fat mass by an average of 3 kg and increased lean body mass 1.9 kg. Among placebo significant changes were noted. The possibility of reducing the severity of or prevent the development of obesity and other MS components as a result of introduction of exogenous testosterone and confirmed in animal studies .
the Use of drugs of testosterone can also lead to normalization of blood pressure. The possibility of such actions shown in studies in men suffering from obesity and diabetes 2-type [60, 66]. Thus, it is noted that restoring the normal level of testosterone in the blood as a result of replacement therapy in patients with IR is accompanied by normalization of glucose level in the blood .
the Effect of treatment with testosterone on the lipid status is ambiguous. It has been shown that such treatment can lead to a decrease in the concentration of HDL cholesterol is potentially adverse effect. At the same time, the analysis of the different fractions of this form of lipoproteins showed that the use of testosterone mainly reduces the concentration of 3s shape having the lowest value for the anti-atherogenic properties of this type of lipoproteins [67, 68]. The levels of the other factions that are much more important, even increased.
meanwhile, the concentration of LDL cholesterol, with pronounced atherogenic activity, on the background of treatment with testosterone, according to most studies, decreased. It was also noted the decrease in level of total cholesterol.
In the studies by M. Zitzmann et al. studied the effect of testosterone treatment on lipid levels in the blood, and HELL in 66 men with hypogonadism . The treatment resulted in a significant decrease in LDL levels, and systolic and diastolic blood pressure. At the same time, the concentration of HDL cholesterol during the period of treatment increased.
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