"Pitfalls" of testosterone therapy
The article was published in the journal "Digest of Urology" No. 2/2018.
In the next issue of the program "An hour with a leading urologist" Stepan Sergeevich Krasnyak, an employee of the Department of Andrology and Human Reproduction of the Lopatkin Research Institute of Urology and Interventional Radiology of the Ministry of Health of Russia, spoke about the problems associated with the appointment of hormone replacement therapy with testosterone drugs in men.
As Stepan Sergeyevich noted at the beginning of his speech, the topic of testosterone therapy is extremely ambiguous and raises many questions both among doctors and patients. The prevalence of testosterone therapy is growing rapidly today, but the negative aspects of such treatment, according to the guest of the program, are often forgotten.
S.S. Krasnyak recalled the main areas of influence of testosterone on the male body. In particular, this hormone provokes the growth of body hair, participates in the synthesis of serum proteins in the liver, causes penis enlargement and triggers spermatogenesis, affects thinking and mood, promotes an increase in strength and muscle mass, participates in the synthesis of erythropoietin from the kidneys, and also supports the growth of bones in length and an increase in their density. Accordingly, the less testosterone in the body, the less pronounced the male sexual characteristics. Fortunately, according to Stepan Sergeevich, usually the decrease in the amount of this hormone is reversible.
The border of norm and pathology
It's no secret that testosterone levels tend to decrease with age. However, is this process normal or pathological, and where is the boundary that allows you to distinguish between these two states? Most often, problems with testosterone occur in men over the age of 45-50 years. There are a number of criteria for detecting age-related hypogonadism. Among them, a decrease in serum testosterone (total <11 nmol/l, free <220 pmol/l), erectile dysfunction, decreased libido and the frequency of morning erections (EMAS data). The doctor stressed that testosterone preparations are prescribed for the treatment of hypogonadism as such, not sexual dysfunction or obesity. The threshold level of testosterone for the appointment of hormone replacement therapy is 9.7—10.4 and 6.9 nmol / l.
Stepan Sergeyevich noted the importance of a personalized approach to the patient: there are people with high sensitivity of receptors, in whom even low testosterone levels do not cause distinct clinical manifestations. Accordingly, the question arises whether hormone therapy is necessary for such patients. Current clinical recommendations say that, as a rule, it is not necessary. In practice, according to the lecturer, it is necessary to proceed from a combination of clinical symptoms, probably associated with low testosterone levels, and its laboratory confirmation. At the same time, it is important to avoid uncontrolled and excessive administration / intake of testosterone.
In general, cases of mismatch of symptoms (20-40% of the general population) and low circulating testosterone levels (in 20% of men > 70 years old) are quite common. According to these criteria, only 2% aged 40 to 80 years have age-related hypogonadism and really need testosterone therapy.
Hormone replacement therapy – billions of dollars
Today, testosterone replacement therapy is widely used worldwide for the treatment of hypogonadism and related isolated symptoms. The disturbing aspect of this trend, however, is that it has formed without any serious scientific evidence, swinging benefits and risks of this type of therapy.
Today, injectable and gel testosterone preparations are mainly being tried on. In the United States, the volume of sales of testosterone preparations doubled between 2005 and 2010 and continues to grow. Similar trends are observed all over the world. From 2000 to 2011, the total sales of testosterone in the world increased 12-fold to $1.8 billion. According to forecasts, in 2018, the volume of sales of testosterone drugs in the United States alone will amount to $ 3.8 billion. Involuntarily, as Stepan Sergeyevich noted, the question arises: have men become so much more likely to suffer from hypogonadism lately? It is possible that there is a large-scale excess treatment.
The doctor also spoke about the presence of scattered, but numerous data indicating a trend towards an increase in the number of patients suffering from obesity associated with testosterone intake.
Substitution therapy, Stepan Sergeyevich stressed, should be offered to the patient only after a conversation that in the long term the beneficial and adverse effects of this treatment are unknown to him. So, in 2017, at the congress of the American Urological Association, the so-called urological "court" was held, where, with the participation of practicing lawyers, the case of prescribing testosterone drugs to a patient with a high risk of cardiovascular diseases was investigated, which eventually led to his death. Interestingly, practically no somatic diseases are contraindications to the appointment of hormone therapy. However, the doctor stressed, this does not mean that it is necessary to prescribe it to everyone, including the most severe patients. Patients with a high risk of concomitant diseases must necessarily undergo specialized studies.
Attention is also drawn to the fact that many of the currently available studies on the topic included men without symptoms of hypogonadism, while various testosterone thresholds, drugs, and dosage regimens were used for evaluation. Thus, it is very difficult to bring together data that would allow an objective assessment of the safety of testosterone therapy.
About the pitfalls
At least, there are absolute contraindications for the appointment of HRT. These are prostate and breast cancers, as well as liver tumors. Relative contraindications include prostate-specific antigen (PSA) levels >4 ng/ml (or 3 ng/ml in men at high risk of prostate cancer); hematocrit >50%; pronounced lower urinary tract symptoms caused by benign prostatic hyperplasia (above 19 points on the IPSS scale); and poorly controlled stagnation of heart failure and sleep apnea.
There is a number of evidence that testosterone preparations increase the volume of the prostate gland, eventually causing a moderate increase in PSA levels in older men. In 2005, the Gerontological Journal published a report according to which the total number of adverse events associated with the prostate gland (prostate biopsies, cancer, serum PSA levels above 4 ng/ml, an increase in IPSS scores) turned out to be significantly higher in the group of patients receiving testosterone than in those who received placebo (odds ratio 1.90; 95% CI 1.11–3.24; p<0.05). There is also data showing the results of the use of testosterone preparations in patients with locally advanced and metastatic prostate cancer (prostate cancer). According to these data, the levels of total testosterone and sex hormone binding globulin significantly differed in patients with aggressive and non-aggressive forms of the disease: testosterone levels were significantly higher in patients with aggressive forms of prostate cancer. It is unclear whether it is possible to talk about a causal relationship here, but the fact of correlation has been revealed.
Another significant factor is hepatotoxicity. It is because of it that oral forms of testosterone preparations are banned in most countries today. The development of hepatic insufficiency, benign and malignant neoplasms of the liver, intrahepatic cholestasis, hepatic purpura, hepatocellular adenoma and carcinoma were associated with their reception.
In addition, such a factor as polycythemia is noted. A very common complication of taking testosterone preparations is erythrocytosis (hematocrit greater than 50%). Two meta-analyses performed in recent years have shown significant negative effects of testosterone therapy in this respect compared to placebo. There is a correlation between high testosterone levels and high hemoglobin levels. Erythrocytosis is more often dose-dependent and develops in older men during therapy with injectable forms of testosterone. The risk of such complications is especially high in the presence of other chronic diseases, for example, chronic obstructive pulmonary disease. Therefore, when prescribing testosterone preparations, control blood tests should be performed.
As for the effect of testosterone preparations on the cardiovascular system, this issue remains controversial. Due to the steady increase in cardiovascular mortality rates, it is particularly acute. There is, in particular, evidence that testosterone intake correlates with the progression of heart failure, but the causal relationship remains a matter of debate. The use of testosterone in coronary heart disease is believed to have a stimulating atherogenic effect due to its negative effect on the lipid profile. However, it has been proven that normal physiological testosterone levels are beneficial for the male heart, and low levels are associated with an unfavorable risk of ischemic disease outcomes. But, as S.S. Krasnyak emphasized, it is impossible to guarantee that a particular patient will achieve exactly the physiological level of testosterone without serious fluctuations.
In 2006, the New England Journal of Medicine published a study involving 106 elderly men at the average age of 74 with low levels of total testosterone, mobility limitations, high prevalence of arterial hypertension, obesity, diabetes mellitus, pre-existing heart disease and hyperlipidemia. For 6 months, patients were treated with testosterone in daily doses from 5 to 15 g. A placebo group was also isolated. The frequency of cardiovascular events was significantly higher in patients taking testosterone preparations (23% vs. 5%). Thus, Stepan Sergeevich summed up, it is impossible to assert the safety of such therapy, especially long-term, in patients with existing diseases.
Testosterone and fertility
Another serious issue is the effect of testosterone preparations on male fertility. There is evidence of a decrease in the volume of patients' testicles and a decrease in the number of spermatozoa up to their complete absence (azoospermia) against the background of taking testosterone preparations. At the same time, the number of spermatozoa most often returns to the initial level within 6 months after discontinuation of therapy, but this does not always happen. This is especially important for young men, some of whom take hormonal medications to achieve rapid improvement in external physical and athletic performance. Today, there are even developments in the use of testosterone preparations as a means of male contraception.
Other factors
Mental changes are also an important factor: psychotic symptoms, excessive libido and aggression, in addition to physical and psychological dependence with withdrawal syndrome are quite rare, but still noted by attending physicians in patients taking testosterone. In this sense, as the doctor noted, the hormone, like many things in the world, has dark and bright sides. Taking testosterone can increase a patient's level of enterprise and courage, but it can also lead to aggression and suspicion. A lot depends on the innate qualities of the man himself.
A well—known side effect of testosterone preparations is gynecomastia. It is associated with the aromatization of testosterone into estradiol in peripheral adipose and muscle tissue. At the same time, the ratio of estradiol to testosterone, as a rule, remains normal.
In addition, testosterone replacement therapy is associated with an exacerbation of sleep apnea. Its severe forms are a relative contraindication for the appointment of therapy. In case of occurrence or exacerbation of obstructive apnea, a reduction in the dosage of the drug or discontinuation of therapy is required.
Like any anabolic steroids, testosterone preparations can cause nitrogen, sodium and water retention — a mineralocorticoid effect. Edema in such cases can worsen the condition of patients with heart, liver and kidney diseases.
The phenomenon of hyperandrogenism in patients' sexual partners is associated with the use of cutaneous forms of testosterone. Transdermal forms of drugs can be associated with a number of skin reactions, mainly erythema and itching, which are also common when using patches. Intramuscular injections of testosterone, in turn, can cause local soreness and hematomas.
Non-drug ways to increase testosterone
In addition to hormone replacement therapy, physical exercises, proper nutrition and regular visits to a urologist contribute to maintaining and increasing testosterone levels at any age. Also, control over stress levels plays a sick role. For example, reducing working hours helps many patients. If there are large amounts of overtime work, the working day should be reduced to 10 hours. It is useful to spend at least 2 hours a day doing something you love and not related to work: for example, reading or listening to music.
Regarding physical activity, there is a recent Japanese study (Kumagawa et al., 2015), which showed that after 12 weeks, against the background of high physical activity, there is a significant increase in testosterone levels without prescribing hormone replacement therapy. Another study involving 83 men (Trumble, Benjamin C. et al.) showed that one hour of chopping wood increases testosterone levels by 48% (P <0.001). Another work was carried out with the participation of 30 young men aged 18-27 years (Devi S. et al., 2014). They practiced on an exercise bike for 15 minutes a day with a pulse of 125-150 beats per minute. After 12 weeks of such classes, an increase in testosterone levels up to 20% was observed.
There is also evidence that testosterone levels correlate well with waist circumference. Thus, getting rid of excess fat mass in any case will lead to an adjustment in the level of this hormone. It is weight loss that can be considered as a first-line therapeutic measure in patients with hypogonadism caused by obesity. There is a possibility that with successful weight loss, the appointment of hormone replacement therapy in the future will not be required for a man.
In the XXI century, prolongation of life and maintenance of its quality come to the fore among the tasks of medicine. Accordingly, patients should be given a number of simple recommendations that will help reduce the risk of developing metabolic syndrome and the appearance of problems with testosterone levels. First of all, a man should change his diet and give up excessive alcohol consumption, and approach this systematically, and not as a temporary measure. However, the doctor stressed, the patient does not need to be severely restricted in the use of fats, including saturated fats: they are involved in the production of sex steroids, including testosterone. There is evidence of a strong correlation between the level of high-density lipoproteins (HDL) and free testosterone (Heller, R.).
There are also a number of phytopreparations that have an evidence base in terms of increasing testosterone levels. For example, it has been shown that 14-day consumption of eureka longleaf extract increases the level of circulating testosterone by 30.2%. According to the results of another study, the same extract increased the number of men with normal testosterone levels from 35.5 to 90.8%. In addition, 6-week use of Peruvian maca extract showed an increase in testosterone production by Leydig cells (Ohta Y. et al., 2016).
Stepan Sergeyevich, however, noted that he understands the skepticism of some doctors regarding methods other than hormone replacement therapy. But, as he recalled, a lot of the active substances of the drugs synthesized today were initially obtained from plant raw materials. Therefore, the use of herbal preparations in addition to changing the amount of physical activity, adjusting nutrition and reducing the level of daily stress may well bring results.
About the author:
Stepan Sergeevich Krasnyak is an employee of the Department of Andrology and Human Reproduction of the N. A. Lopatkin Research Institute of Urology and Interventional Radiology of the Ministry of Health of the Russian Federation
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