Testosterone replacement therapy against male aging: is it worth it?

Until recently, such diseases typical for elderly and old men as atherosclerosis, hypertension, diabetes mellitus, disorders of the lower urinary tract, and erectile dysfunction were considered to be separate diseases. Recently, however, there is increasing evidence that these and other age-related diseases are closely interrelated and, as a rule, are accompanied by 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 the analysis of plasma testosterone levels in the appropriate diagnostic protocols.

Comparison of age and classic hypogonadism

Symptoms of hypogonadism include erectile dysfunction, accumulation of fat in the abdomen, mood swings, and 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. Comparison of data on the development of similar symptoms in elderly men, as well as statistically proven decrease in testosterone levels in old age has led to the emergence of the terms “age hypogonadism” and “age androgen deficiency” and the assumption that normalization of testosterone 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, currently available data on the positive effects of testosterone replacement therapy on the health status of aging men cannot be considered scientifically proven. The reason for this lies in the imperfection of the research methods in which they were obtained. Studies of this kind should be carried out double-blind under the control of placebo. In addition, to evaluate the results, it is necessary to use not the data on the dynamics of surrogate markers of a particular disease, but the final clinical outcomes. For example, does the risk of diabetes and cardiovascular disease decrease in patients who have improved symptoms of metabolic syndrome as a result of testosterone? Or – does the increased bone density as a result of hormone therapy reduce the risk of fractures? had an improvement in the symptoms of metabolic syndrome as a result of testosterone? Or – does the increased bone density as a result of hormone therapy reduce the risk of fractures?

What does testosterone deficiency mean in old age?

A large number of healthy men testosterone levels in the blood are 5–20% lower than the accepted normal values, so it is very difficult to draw a clear line between the hypogonadic 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 that exceeds the lower limit of normal values ​​for young men. The factors determining this symptomatic threshold are unknown, however, it is possible that the genetic polymorphism of the androgen receptor, which causes variations in the sensitivity of tissues to testosterone, plays an important role in this mechanism. The effect of aging and acquired chronic diseases on the threshold level of testosterone has not yet been completely studied.

Thresholds and dose dependence of androgenic effects

Empirical evidence supporting the concept of threshold values ​​of testosterone in the development of symptoms of hypogonadism, began to appear quite recently. In addition, studies involving older men have shown that different threshold levels of the hormone circulating in the blood correspond to various symptoms of testosterone deficiency. Thus, according to one study, the decrease in libido and muscle strength associated with testosterone levels was most pronounced when the hormone level dropped below 15 nmol / l, and the development of depression and type 2 diabetes mellitus when its concentration in the blood is 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 linked 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 impaired functioning of the arterial endothelium and the nervous system, as well as psychological and other factors. And given the disagreements over the threshold for the development of symptoms of hypogonadism plasma concentration of total testosterone (according to various sources – from 7.5 to 12 nmol / l), the diagnosis of this disease cannot be made only on the basis of the results of the analysis of hormonal status, without a comprehensive study of somatic and psychological aspects.

Diagnosis of age-related hypogonadism

The 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 testosterone in the patient’s blood. Testosterone is by no means a panacea for all the psychological and somatic problems faced by aging men, and its uncontrolled use can have serious negative consequences.

If hypogonadism is suspected, patients should undergo a serious physiological and biochemical examination. In men of any age, periods of transient decrease in testosterone levels are possible, which must be eliminated with the help of a detailed study of clinical information and a reassessment of hormonal status. Risk factors for the development of hypogonadism, which include many chronic diseases (including diabetes, chronic obstructive pulmonary diseases, inflammatory diseases of the joints, kidney diseases and diseases associated with HIV), obesity, metabolic syndrome and hemochromatosis, must also be considered

The positive effects of testosterone replacement therapy

Restoration of testosterone to normal values ​​with the help of replacement 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 status of older people, including their psychological state, sexual function, body weight, muscle strength, erythropoiesis, bone mineral density, cognitive function and cardiovascular status system. Below are the main patterns identified in the study of the effect of hormone replacement therapy on the health status of older men.

Metabolic syndrome, type 2 diabetes and cardiovascular diseases

Many of the symptoms of metabolic syndrome (obesity, hypertension, disorders of fat and carbohydrate metabolism, and insulin resistance) are also characteristic of hypogonadism. Low testosterone is also associated with surrogate markers of cardiovascular diseases and increased mortality from these diseases. According to research results, the introduction of testosterone to older men improved the indicators of fat and carbohydrate metabolism, which, together with the correction of diet and exercise, led to the normalization of body weight and a decrease in fat deposits in the abdominal area.

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 hormone would correspond to a reduction in this risk. It is quite possible that the inverse correlation between testosterone levels and the severity of coronary heart disease identified by scientists can be explained by the concomitant accumulation of fat in the abdomen associated with an increased risk of problems in the cardiovascular system and the development of disorders of tissue sensitivity to glucose and non-insulin dependent 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 cardiovascular system of older men. There is evidence of an improvement in the functional state of the vascular endothelium and myocardial blood supply, but none of the studies have shown the effect of therapy on the likelihood of developing diseases such as heart attack, stroke and angina, 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, thoroughly planned clinical studies of adequate scale and duration are needed to study the effect of androgen replacement therapy on the incidence of these diseases and the resulting mortality.

Bone mineral density

Osteopenia, osteoporosis, and increased bone fragility are characteristic of both young patients with hypogonadism and aging men with normal hormonal levels. With a shortage of testosterone, the risk of fracture is doubled. However, the role of age-related hypogonadism in increasing the risk of fractures needs detailed study, as well as the long-term effects of hormone therapy with testosterone. Testosterone increases the activity of bone-forming cells – osteoblasts and inhibits 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.

Muscle mass and strength

The aging process is accompanied by significant changes in body composition, characterized by an increase in the amount of adipose tissue and its redistribution. This can lead to disability and increased mortality. Maximum muscle strength is proportional to muscle mass, regardless of age. Testosterone not only directly stimulates the synthesis of proteins and the growth of muscle cells, but also increases the expression of insulin-like growth factor-1 (IGF-1), which has a similar effect. Therefore, a decrease in testosterone levels associated with age can be one of the factors contributing to a decrease in muscle mass and, consequently, physical strength.

The results of most of the works carried out to date indicate that the introduction of testosterone in general has a positive effect on the health status of older men: it reduces the amount of adipose tissue, increases muscle mass, increases the strength of various muscle groups and generally improves physical abilities. Only a small amount of data indicates the absence of influence of testosterone replacement therapy on the functional state of the muscles. Despite the fact that the introduction of testosterone is considered to be a promising approach to combating age-related physical weakness, at the present stage it is still impossible to clearly speak about the positive impact of such treatment on the physical condition of elderly men with deficiency of this hormone.

Increased sexual desire, sexual function and abilities

The likelihood of developing erectile dysfunction increases significantly with age. Older men require a higher level of testosterone than younger ones to maintain libido and ensure normal erection. However, erectile dysfunction and / or decreased sexual desire, both at normal and at 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 a review of data from randomized clinical trials, testosterone replacement therapy has a positive effect on the sexual health of older men with testosterone deficiency. Positive effects include not only an increase in self-esteem and sexual desire, but also the frequency of sexual intercourse and erections occurring during sleep.

Urinary tract condition

In addition to improving sexual function, testosterone therapy has a positive effect on the functional state of the lower urinary tract in 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 life

Men over 50 years old with reduced levels of free testosterone in the blood often complain of a deterioration in the quality of life, which usually manifests symptoms that are in common with symptoms of deep depression, including decreased sexual desire, increased anxiety, fatigue and irritability. When studying the effect of testosterone replacement therapy near me on the severity of these symptoms, different groups of researchers obtained varying 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 the androgen receptor, which determines the population of men susceptible to the development of depression with a decrease in testosterone levels below a certain level.

Cognitive function

An age-related decrease in free testosterone is a prognostic factor in the deterioration of visual and verbal memory. There is also evidence of a pronounced relationship between testosterone levels and a number of aspects of the cognitive function, such as spatial orientation and mathematical calculations. However, there are contradictory data. For example, in men who underwent hormonal therapy for the treatment of prostate cancer, suppression of the synthesis of endogenous testosterone and blocking of androgen receptors had a positive effect on verbal memory, but impaired the ability to orient in space.

All the 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 time. The data obtained at the same time contradict each other in some aspects, however, in general, they indicate that hormone therapy of men with hypogonadism, especially elderly patients, has a positive effect on their cognitive abilities.

Improving anemia symptoms

It 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 level by 10-20%, which may be the cause of the development of anemia. Young men with hypogonadism are characterized by lower than in healthy individuals of the same age, the content of red blood cells and hemoglobin in the blood. A similar decrease in these indicators can be observed in healthy elderly men.

The safety of testosterone administration in older men

To obtain reliable information on the effect of testosterone replacement therapy on the health status of elderly men with hypogonadism, it is necessary to conduct clinical studies with the participation of 5-7 thousand men, monitoring of which must be carried out for at least 5-7 years. Conducting work of this magnitude is quite problematic, so today, to assess the safety of androgen replacement therapy, one has to be content with the results of smaller studies. The main side effects of testosterone administration are described below.

Polycythemia
(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 testosterone levels and plasma hemoglobin concentration. Testosterone affects erythropoiesis through several mechanisms. It activates the synthesis of erythropoietin in the kidneys, as well as 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 hemoglobin and hematocrit values ​​(the volume percentage of erythrocytes relative to whole blood) and in the administration 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 clinical trials conducted under placebo-control, in which testosterone was administered to elderly patients, did not, in general, reveal a relationship between hormone-induced hematocrit increase 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 appropriate dosage of the hormone is selected.

The functional state of the lower urinary tract and diseases of the prostate gland

Within the framework of several works, when observing the condition of men receiving hormone replacement therapy, there were no cases of difficulty urinating due to benign prostatic hyperplasia. At the same time, the frequency of development of such complications as urinary retention in the experimental groups was the same as in the control groups.

Despite the inconsistency of data from individual studies, a meta-analysis of the results of studies on the possible effect of testosterone administration on the likelihood of developing prostate cancer also showed the absence of a pronounced correlation. However, according to his results, men undergoing hormone therapy are more likely to undergo prostate biopsy. The same applies to the safety of testosterone administration in older 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 (cumulatively in all studies), previously cured of prostate carcinoma, administration of testosterone did not cause recurrence of the tumor.

Today, it is believed that the introduction of testosterone to older men is appropriate practice, subject to compliance with existing guidelines. This consensus is based on the opinions of experts, who, however, emphasize the existing need for long-term studies of the safety of therapy.

Diseases of the cardiovascular system

Ten years ago, experts were of the opinion that androgens are an atherogenic factor, so it was believed that the introduction of testosterone may increase the risk of developing cardiovascular diseases. Several studies over the past decade have provided evidence that testosterone is not the cause of circulatory disease. However, recent epidemiological studies have shown that low testosterone is a prognostic factor in mortality, and numerous survey papers that have appeared over the past two years describe a significant relationship between a reduced testosterone concentration and the likelihood of developing cardiovascular diseases.

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

Sudden stop breathing in sleep (apnea)

The syndrome of obstructive sleep apnea is characterized by snoring and repeated episodes of closing the lumen of the upper respiratory tract, leading to a decrease in oxygen levels in the blood, sleep fragmentation 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, arrhythmias, myocardial infarction, stroke and sudden death. Patients with sleep apnea often suffer from obesity and metabolic syndrome, which may underlie problems in the sexual sphere.

As a rule, plasma testosterone levels are reduced in men with sleep apnea, but this can be explained by obesity and metabolic syndrome. A large meta-analysis of the results of placebo-controlled trials of hormonal therapy in elderly men did not reveal significant differences between the incidence of sleep apnea in the experimental and control groups. However, obstructive pulmonary disease in obese men or active smokers should be considered as a relative contraindication to hormone therapy.

findings

To date, quite a lot of research has been conducted, the results of which indicate that hormone replacement therapy reduces the symptoms of the metabolic syndrome and increases bone mineral density, mood and sexual function in elderly men with reduced testosterone levels. However, only a few of these works are carried out according to generally accepted scientific standards. In addition, the comparison of the results of these studies is hampered by the absence of generally accepted normal hormone levels used to diagnose hypogonadism. Another obstacle for an adequate interpretation of the results is the 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 compliance with the protocols developed by specialists, the administration of testosterone to patients with age-related hypogonadism is fairly safe.

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