Testosterone against male aging: is it worth it?

Until recently, such diseases characteristic of elderly and old men as atherosclerosis, hypertension, diabetes mellitus, disorders of the lower urinary tract and erectile dysfunction were considered separate diseases. However, recently there is more and more data indicating that these and other age-related diseases are closely interrelated and, as a rule, accompany a decrease in testosterone levels in an aging body. This indicates the need for an integrated approach to the treatment of diseases of elderly men and the inclusion of an analysis of the level of testosterone in blood plasma in the appropriate diagnostic protocols.

Comparison of age-related and classical hypogonadismSymptoms of hypogonadism include erectile dysfunction, accumulation of fat in the abdomen, mood swings, as well as a decrease in muscle strength and bone strength.

Usually hormone replacement therapy has pronounced positive effects on the condition of young patients with this disease. A comparison of data on similar symptoms developing in elderly men, as well as a statistically proven decrease in testosterone levels in old age, led to the emergence of the terms "age-related hypogonadism" and "age-related androgen deficiency" and assumptions that normalization of testosterone levels in the bloodstream can slow down the aging of the male body. However, to date, there is no reliable evidence that the symptoms described above are really manifestations of testosterone deficiency. Unfortunately, the data available today concerning the positive effect of testosterone replacement therapy on the health of aging men cannot be considered scientifically proven. The reason for this lies in the imperfection of the methods of conducting research, as a result of which they are obtained. Studies of this kind should be carried out by a double-blind method under the control of a placebo. In addition, to evaluate the results, it is necessary to use not data on the dynamics of surrogate markers of a particular disease, but the final clinical outcomes. For example, does the risk of developing diabetes mellitus and cardiovascular diseases decrease in patients who have had improvements in the symptoms of metabolic syndrome as a result of testosterone administration? Or – does the increased bone mineral density as a result of hormone therapy reduce the risk of fractures?

What does testosterone deficiency mean in old age?In a large number of healthy men, the testosterone level in the blood is 5-20% lower than the accepted normal values, so it is very difficult to draw a clear line between the hypogonadal and normal status of the body.

Moreover, the threshold level of the hormone at which a man begins to show symptoms of hypogonadism is very individual and varies from extremely low values to a value exceeding the lower limit of normal indicators for young men. The factors determining this symptomatic threshold are unknown, however, it is possible that genetic polymorphism of the androgen receptor plays an important role in this mechanism, causing variations in tissue sensitivity to testosterone. The effect of aging and acquired chronic diseases on the threshold level of testosterone has not yet been completely studied. At the same time, the results of most population studies indicate that obesity, various concomitant diseases and lifestyle have a pronounced effect on testosterone levels.

Thresholds and dose dependence of androgenic effectsEmpirical data confirming the concept of testosterone thresholds in the development of hypogonadism symptoms began to appear quite recently.

In addition, studies involving older men have shown that different symptoms of testosterone deficiency correspond to different threshold levels of the hormone circulating in the blood. Thus, according to one of the studies, the decrease in libido and muscle strength associated with testosterone levels was most pronounced when the hormone level decreased below 15 nmol/l, and the development of depression and type 2 diabetes mellitus – when its concentration in the blood was below 10 nmol/L. The authors of this work divided the patients into three groups according to the symptoms of testosterone deficiency they manifest: psychosomatic complaints, signs of metabolic syndrome and sexual problems. Since the patients of these groups differed in a number of indicators (testosterone content in the blood, age and body mass index), the observed symptoms could not be unambiguously associated with the hormonal background. The situation is further complicated by the multifactorial nature of the disorders observed with a decrease in testosterone levels. For example, the cause of erectile dysfunction, in addition to hypogonadism, may be disorders of the functioning of the arterial endothelium and nervous system, as well as psychological and other factors. And given the disagreement over the threshold for the development of symptoms of hypogonadism concentration of total testosterone in blood plasma (according to various data – from 7.5 to 12 nmol / l), the diagnosis of this disease can not be made only on the basis of the results of the analysis of hormonal status, without a comprehensive study of somatic and psychological aspects. (Total testosterone includes a free form of the hormone and a hormone complex with a carrier protein.)

Diagnosis of age-related hypogonadismThe decision on the diagnosis of age-related hypogonadism and the appointment of hormone therapy should be taken with great caution, taking into account the mutual dynamics of the increase in symptoms and changes in the level of testesterone in the patient's blood.

Testosterone is by no means a panacea for all the psychological and somatic problems that aging men face, and its uncontrolled use can have serious negative consequences.

If hypogonadism is suspected, patients should undergo a serious physiological and biochemical examination. Men of any age may have periods of transient decrease in testosterone levels, which must be excluded by a detailed study of clinical information and re-evaluation of hormonal status. It is also necessary to take into account risk factors for the development of hypogonadism, which include many chronic diseases (including diabetes, chronic obstructive pulmonary diseases, inflammatory joint diseases, kidney diseases and HIV-related diseases), obesity, metabolic syndrome and hemochromatosis.

Positive effects of Testosterone replacement therapyRestoring testosterone levels to normal values with the help of substitution therapy can reduce the manifestations of many symptoms of hypogonadism in young people.

There is evidence that hormone replacement therapy has a short-term positive effect on the health of older people, including their psychological state, sexual function, body weight, muscle strength, erythropoiesis, bone mineral density, cognitive function and the state of the cardiovascular system. The following are the main patterns identified in the study of the effect of hormone replacement therapy on the health of older men.

Metabolic syndrome, type 2 diabetes and cardiovascular diseasesMany symptoms of metabolic syndrome (obesity, hypertension, disorders of fat and carbohydrate metabolism and insulin resistance of tissues) are also characteristic of hypogonadism.

Low testosterone levels are also associated with surrogate markers of cardiovascular diseases and increased mortality from these diseases. According to the research results, the administration of testosterone to elderly men improved the indicators of fat and carbohydrate metabolism, which, together with diet correction and exercise, led to normalization of body weight and reduction of fat deposits in the abdomen.

Low testosterone levels in men are associated with an increased likelihood of developing cardiovascular diseases. However, there is no evidence that a high level of the hormone would correspond to a reduction in this risk. It is quite possible that the inverse correlation revealed by scientists between testosterone levels and the severity of coronary heart disease can be explained by the concomitant accumulation of fat in the abdominal area associated with an increased risk of problems in the cardiovascular system and the development of tissue sensitivity disorders to glucose and insulin-independent diabetes mellitus.

According to the results of studies conducted to date, the introduction of physiological doses of testosterone has a positive or neutral effect on the state of the cardiovascular system of older men. There is evidence of an improvement in the functional state of the vascular endothelium and blood supply to the myocardium, but none of the studies have shown the effect of therapy on the likelihood of developing diseases such as heart attack, stroke and angina pectoris, as well as on mortality rates from them.

Thus, despite the fact that a decrease in testosterone levels is associated with the development of metabolic syndrome and an increased risk of developing cardiovascular diseases, to study the effect of androgen replacement therapy on the frequency of these diseases and the mortality caused by them, it is necessary to conduct carefully planned clinical studies of adequate scale and duration.

Bone mineral densityOsteopenia, osteoporosis and increased bone fragility are characteristic of both young patients with hypogonadism and aging men with normal hormonal background.

With testosterone deficiency, the risk of fractures is doubled. However, the role of age-related hypogonadism in increasing the risk of fractures needs to be studied in detail, as well as the long-term effects of hormone therapy with testosterone. Testosterone increases the activity of bone–forming osteoblast cells and suppresses the activity of osteoclasts performing the opposite function. There is evidence that its administration in sufficient doses increases bone density (but does not ensure the achievement of normal values) in men of all age categories suffering from hypogonadism. However, in general, studies on the effect of testosterone replacement therapy have yielded contradictory results, which can be explained by insufficient sample volumes and the duration of observations.

Muscle mass and strengthThe aging process is accompanied by significant changes in the composition of the body, characterized by an increase in the amount of adipose tissue and its redistribution.

This can lead to physical disability and increased mortality. Maximum muscle strength proportional to the mass of muscle tissue regardless of age. Testosterone not only directly stimulates protein synthesis and muscle cell growth, but also increases the expression of insulin-like growth factor-1 (IGF-1), which has a similar effect. Therefore, an age-related decrease in testosterone levels may be one of the factors contributing to a decrease in muscle mass and, accordingly, physical strength.

The results of most of the work carried out to date indicate that the introduction of testosterone generally has a positive effect on the health of older men: it reduces the amount of adipose tissue, increases muscle mass, increases the strength of various muscle groups and generally improves physical capabilities. Only a small amount of data indicates that there is no effect of testosterone replacement therapy on the functional state of the muscles. Despite the fact that the introduction of testosterone is considered a promising approach to combating age-related physical weakness, at the present stage it is still impossible to speak unequivocally about the positive effect of such treatment on the physical condition of elderly men with a deficiency of this hormone.

Increased sex drive, sexual function and capabilitiesThe likelihood of developing erectile dysfunction increases significantly with age.

To maintain libido and ensure a normal erection, older men need a higher level of testosterone than young men. However, erectile dysfunction and/or decreased libido, both with normal and reduced testosterone levels, may be caused by other concomitant diseases or medications taken.

The introduction of adequate doses of testosterone can prevent premature outflow of blood from the cavernous bodies of the penis, which is a common cause of erectile dysfunction in old age. According to the results of a review of data obtained during randomized clinical trials, testosterone replacement therapy has a positive effect on the sexual health of older men with testosterone deficiency. The positive effects include not only an increase in self-esteem and sexual desire, but also the frequency of sexual acts and erections that occur during sleep.

The state of the urinary tractIn addition to improving sexual function, testosterone therapy has a positive effect on the functional state of the lower urinary tract of men with age-related hypogonadism, which is manifested by an increase in the capacity and elasticity of the bladder wall and a decrease in the pressure of its sphincter at maximum urine flow.

Mood, energy and quality of lifeMen over the age of 50 with a reduced level of free testosterone in the blood often complain of a deterioration in the quality of life, which is usually manifested by symptoms that echo the symptoms of deep depression, including decreased libido, increased anxiety, fatigue and irritability.

When studying the effect of testosterone replacement therapy on the severity of these symptoms, different groups of researchers obtained different results, ranging from a significant improvement in the quality of life to the absence of any recorded changes. The reason for this may be a genetic polymorphism of androgen receptors, which determines the population of men prone to depression when testosterone levels drop below a certain level.

Cognitive functionAge-related decrease in the level of free testosterone is a prognostic factor of deterioration of visual and verbal memory.

There is also evidence of a pronounced relationship between testosterone levels and a number of aspects of cognitive function, such as the ability to navigate in space and mathematical calculations. However, there are data contradicting these observations. For example, in men undergoing hormone therapy for the treatment of prostate cancer, suppression of endogenous testosterone synthesis and blocking of androgen receptors had a positive effect on verbal memory, but worsened the ability to navigate in space.

All clinical studies conducted to date on the effect of androgen replacement therapy on cognitive abilities and memory involved relatively small groups of patients and lasted relatively short. The data obtained contradict each other in some aspects, but in general they indicate that hormone therapy for men with hypogonadism, especially elderly patients, has a positive effect on their cognitive abilities.

Improvement of anemia symptomsIt is known that endogenous androgens stimulate the formation of red blood cells in the bone marrow, increase the number of reticulocytes and the level of hemoglobin in the blood, while castration has the opposite effect.

Testosterone deficiency leads to a decrease in hemoglobin levels by 10-20%, which may be the cause of anemia. For young men with hypogonadism, the content of erythrocytes and hemoglobin in the blood is lower than for healthy individuals of the same age. A similar decrease in these indicators can be observed in healthy older men.

Safety of testosterone administration to elderly menTo obtain reliable information about the effect of testosterone replacement therapy on the health of elderly men with hypogonadism, it is necessary to conduct clinical studies involving 5-7 thousand men, who must be monitored for at least 5-7 years.

Carrying out work of this scale is quite problematic, therefore, to date, to assess the safety of androgen replacement therapy, we have to be content with the results of smaller-scale studies. The main side effects of testosterone administration are described below.

Polycythemia
(a chronic disease of the blood system characterized by an increase in the absolute number of red blood cells, and in some cases also leukocytes and platelets).

In men who do not receive testosterone therapy, there is a non-linear relationship between the level of testosterone and the concentration of hemoglobin in blood plasma. Testosterone affects erythropoiesis through several mechanisms. It activates the synthesis of erythropoietin in the kidneys, and also directly stimulates the formation of colonies of erythrocyte progenitor cells in the bone marrow. The results of a number of studies indicate that an increase in the values of hemoglobin and hematocrit (the volume percentage of red blood cells relative to whole blood) and in the management of testosterone is dose-dependent. In addition, this effect is more pronounced in the treatment of elderly patients.

Elevated hematocrit is associated with a high risk of stroke and coronary heart disease. However, a large-scale meta-analysis of the results of placebo-controlled clinical trials in which elderly patients were injected with testosterone, in general, did not reveal a relationship between the increase in hematocrit caused by hormone therapy and the likelihood of stroke and other cardiovascular diseases. Thus, polycythemia is a controlled side effect of testosterone administration, provided that hemoglobin and hematocrit levels are monitored and an adequate dosage of the hormone is selected.

Functional state of the lower urinary tract and prostate diseasesWithin the framework of several studies, when monitoring the condition of men receiving hormone replacement therapy, no cases of difficulty urinating due to benign prostatic hyperplasia were detected.

At the same time, the frequency of complications such as urinary retention in the experimental groups was the same as in the control groups.

Despite the inconsistency of the data of individual studies, a meta-analysis of the results of studies on the possible effect of testosterone administration on the likelihood of prostate cancer also showed the absence of a pronounced relationship. However, according to its results, men undergoing hormone therapy are more likely to undergo prostate biopsy. The same applies to the safety of testosterone administration to elderly men who do not have a history of prostate cancer. At the same time, there are at least three publications according to which in 17 patients (in total in all works) who had previously been cured of prostate carcinoma, the administration of testosterone did not cause a recurrence of the tumor.

To date, it is considered that the administration of testosterone to older men is a reasonable practice, provided that existing recommendations are followed. This consensus is based on the opinion of experts, who, however, emphasize the existing need for long-term studies of the safety of therapy.

Diseases of the cardiovascular systemTen years ago, experts were of the opinion that androgens are an atherogenic factor, so it was believed that the introduction of testosterone could increase the risk of developing cardiovascular diseases.

Several studies conducted over the past decade have provided evidence that testosterone is not the cause of the development of diseases of the circulatory system. However, recent epidemiological studies have shown that low testosterone levels are a prognostic factor of mortality, and numerous review papers that have appeared over the past two years describe a reliable relationship between a reduced concentration of testosterone and the likelihood of developing diseases of the cardiovascular system.

The study of the results of testosterone replacement therapy did not reveal the development of side effects such as peripheral edema, exacerbations of hypertension and congestive heart failure. However, given that the existing data were obtained mainly from the observation of relatively healthy elderly men, in the treatment of patients with chronic diseases and generally painful individuals, it is necessary to take into account the possibility of fluid retention in the body.

Sudden respiratory arrest during sleep (apnea)Obstructive sleep apnea syndrome is characterized by snoring and repeated episodes of closure of the upper respiratory tract lumen, leading to a decrease in blood oxygen levels, fragmentation of sleep and increased daytime sleepiness.

This condition is characterized by a decrease in libido and (in 10-60% of cases) erectile dysfunction. In addition, it is associated with an increased risk of hypertension, arrhythmia, myocardial infarction, stroke and sudden death. Often, patients with sleep apnea syndrome suffer from obesity and metabolic syndrome, which may be the basis of problems in the sexual sphere.

As a rule, men with sleep apnea syndrome have a reduced level of testosterone in the blood plasma, but this can be explained by obesity and metabolic syndrome. A large meta-analysis of the results of placebo-controlled trials of hormone therapy for elderly men revealed no significant differences between the frequency of occurrence of night apnea in the experimental and control groups. Nevertheless, obstructive pulmonary disease in obese men or active smokers should be considered as a relative contraindication to hormone therapy.

Conclusions

To date, quite a lot of studies have been conducted, the results of which indicate that hormone replacement therapy reduces the symptoms of metabolic syndrome and increases bone mineral density, mood and sexual function in older men with reduced testosterone levels. However, only a few of these works were carried out according to generally accepted scientific standards. In addition, the comparison of the results of these studies is complicated by the lack of generally accepted normal indicators of hormone levels used for the diagnosis of hypogonadism. Another obstacle to an adequate interpretation of the results is a pronounced genetic polymorphism of androgen receptors, due to which the same testosterone levels can form completely different hormonal statuses in different men.

There is strong evidence that testosterone is not the main factor determining the development of prostate cancer in older men. Therefore, subject to the protocols developed by specialists, the administration of testosterone to patients with age-related hypogonadism is quite safe.

Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on Nature: Androgens and male aging: current evidence of safety and efficacy.

26.02.2010