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Experience of using the drug "Nebido" in patients with age-related androgen deficiency

Unfortunately, the lack of universal clinical markers makes the diagnosis of androgen deficiency difficult. The most reliable biochemical marker is free testosterone, but its determination is an extremely labor-intensive technique. As a rule, it is determined by a calculation method based on total testosterone and sex steroid binding globulin, measured in nmol/l. Clinical symptoms of androgen deficiency may be masked by concomitant somatic pathology. Nevertheless, its diagnosis in older men should be carried out as widely as possible. Testosterone, as you know, is the most important sex hormone responsible for the health and activity of a man throughout his life. Together with dihydrotestosterone, androstenedione and their metabolites, it creates the tone of the central nervous system, subcortical formations, supporting the functional activity of the gonads and providing copulatory function. With its deficiency, cardiovascular diseases, obesity, atherosclerosis, insulin resistance and type 2 diabetes mellitus, osteopenia and osteoporosis, anemia, dry skin, decreased muscle mass and strength, erectile dysfunction, as well as autonomic disorders, which include fluctuations in blood pressure, develop. , cardialgia, dizziness, increased sweating, sudden flushing of the face and neck and the notorious “hot flashes”. The actions of testosterone in some organs occur after the peripheral conversion of testosterone to estradiol, which then binds to estrogen receptors in the nuclei of target cells (eg, pituitary gland, adipose tissue, brain, bone and Leydig cells). The decrease in testosterone production is based on a decrease in its synthesis by Leydig cells due to deterioration in the blood supply to testicular tissue, as well as a decrease in the number of receptors for luteinizing hormone on their surface, which arise and progress with age [3]. With age, the size of the pituitary gland also decreases, thereby disrupting the neuroregulatory link of testosterone synthesis. An MRI of the brain performed on 153 men aged 50 to 70 years showed a progressive decrease in the size of the pituitary gland starting at age 56. More than 80% of patients with age-related androgen deficiency have a good response to the administration of human chorionic gonadotropin (hCG), expressed in an increase in endogenous testosterone synthesis by Leydig cells [4]. However, in the sports medicine literature, there is data that indicates possible limitations in the use of hCG drugs. The duration of hCG injections should be limited to only a very short number of weeks. If hCG is taken by athletes for many weeks and even in very high doses, then hypofunction of the gonads may develop. According to B. Phillips, taking hCG should be limited to a period of three weeks, with a pause of at least 6 months. HCG can be used, for example, for 2–3 weeks in the middle of treatment and for 2–3 weeks at the end. It should be remembered that long-term use of hCG suppresses the body's production of gonadotropins for a long time, so the drugs should be used only for a short time. In addition, when taking hCG, side effects may develop (feeling lightheaded, weight gain, gastrointestinal disorders). Other reasons also play a significant role in the development of androgen deficiency, since it has been shown that men with concomitant somatic pathologies have lower testosterone levels in the blood than healthy men of the same age [5,6]. In addition to physiological factors, hypogonadism can be caused by taking certain medications (antihypertensives, hypnotics, antipsychotics, glucocorticoids, antiulcer drugs, antiallergens), which are often prescribed to the elderly, increasing the age-related decrease in free testosterone levels. According to the decision of a working meeting of the Austrian Society of Urology (1994), the changes that occur as a result of testosterone deficiency in men were proposed to be called “partial androgen deficiency in older men,” or PADAM syndrome (partial androgen deficiency in aging males). Recently, domestic authors are increasingly inclined to the term “age-related hypogonadism.” The consequences of age-related hypogonadism are confirmed by a number of serious studies. Work carried out by Polish scientists, which studied the correlation between the level of free testosterone in a group of patients with atherosclerotic lesions of the coronary arteries confirmed by coronary angiography and in a group of healthy men, established a significantly low level of testosterone in patients with androgen deficiency [7]. At the same time, the level of triglycerides and low-density lipoproteins (LDL) in patients with testosterone deficiency was statistically significantly higher than in healthy people, and the levels of total cholesterol and high-density lipoprotein (HDL) cholesterol were practically the same. Research by W. Barud. et al [8] also found a positive correlation between testosterone and HDL cholesterol levels. Consequently, low testosterone concentration plays an unconditional role in the pathogenesis of atherosclerosis. The role of obesity in the development of cardiovascular pathology is beyond doubt. The cause of androgen deficiency in obesity is leptin produced by white adipose tissue, which stimulates the secretion of gonadotropin-releasing hormone [9]. Resistance of central structures to leptin in obese patients leads to disruption of the rhythm of gonadotropin-releasing hormone secretion, which may be another reason for the development of hypogonadotropic hypogonadism. Age-related androgen deficiency contributes to the development of osteopenia and osteoporosis. From the age of 40, men begin to experience physiological loss of bone mass. At the beginning, there is a slight loss of 0.3–0.5% per year. With the development of PADAM syndrome in men, bone loss accelerates to 2 and even 3% per year (depending on the location of the bones), continuing at this rate until 75–80 years. The histomorphometric heterogeneity of hypogonal osteoporosis in men may reflect a gradual transition from osteoclast- to osteoblast-dependent bone loss over time. Testosterone deficiency may also reduce calcitonin secretion and impair calcitriol synthesis [10]. Despite the fact that estrogens are more effective in preventing the growth of metabolic markers, testosterone has an independent effect on bone tissue, stimulating periosteal bone growth, and the degree of their influence depends on the sensitivity of androgen receptors on osteoclasts [11]. Androgens inhibit the action of interleukin-6 [12]. It is difficult to overestimate the role of hypogonadism in patients with type 2 diabetes mellitus. Findings from the Massachusetts Study of Aging Men, which examined the prevalence of sexual dysfunction in the general population and in patients with diabetes, established a relationship between levels of free testosterone, sex steroid binding globulin (SHBG), and the risk of developing insulin resistance and type 2 diabetes. A prospective follow-up of 1,709 men aged 40–70 years over 7–10 years revealed a risk of developing type 2 diabetes of 1.58 per 1 standard deviation decrease in free testosterone (3.9 ng/dL) and, accordingly, 1.89 to reduce SHBG by 1 standard deviation (15.8 nmol/L) [13]. If the examined patients had diabetes mellitus, a complication such as erectile dysfunction was noted in more than 55% of patients. The risk of erectile dysfunction in type 2 diabetes mellitus is observed 3 times more often than in the general population [14]. The prevalence of androgen deficiency in patients with type 2 diabetes mellitus is up to 75% [15]. In men of any age, androgens play a significant role in inducing gender-appropriate behavior, controlling sexual behavior, and influencing erection and libido. This mechanism is associated exclusively with the activity of androgen receptors. A decrease in testosterone levels leads to a decrease in libido and potency. Normal testosterone levels promote the release of dopamine in the preoptic area both during the copulation phase and in the preceding arousal phase. This mechanism is determined by the production of nitric oxide under the influence of testosterone, which affects the release of dopamine [12]. Currently, a negative feedback relationship between testosterone levels and chronic depression is considered proven. When treating patients with androgen deficiency with testosterone drugs, a significant improvement in mood and the disappearance of depressive syndrome were noted [16]. The prevalence of hypogonadism is quite high. According to various authors, it can reach from 10 to 35% (Fig. 1) [17]. A US study of 890 men demonstrated a progressive increase with age in the incidence of low total testosterone and low free testosterone index (testosterone/sex steroid binding globulin ratio) [18]. Thus, there is no doubt about the possibility of prescribing testosterone replacement therapy to patients with androgen deficiency. In this case, two issues are considered: the safety of the drug and the choice of its dosage form. The widespread introduction of hormone replacement therapy into practice is limited by the existing myth about the negative effect of testosterone on the prostate gland, especially in older men. No less controversial is the opinion about the negative impact of androgens on the lipid spectrum, although the above studies do not confirm this. As for the effect of androgen replacement therapy on the prostate gland, a number of studies have shown that a clear dependence of the state of the prostate in old age on testosterone levels has not been established. Testosterone replacement therapy does not contribute to the development of benign hyperplasia and prostate cancer, since the goal of treatment is to maintain only the physiological level of the hormone in the blood[18]. It is known that testosterone is metabolized in the liver and is quickly destroyed in it, therefore, when taken orally, high doses are required. Thus, modified analogues of the hormone and forms for its parenteral administration are used as drug therapy. The routes of administration of the drug are as follows: oral, transdermal and injection. Without diminishing the importance of individual medications, we note some inconveniences of their use. The oral form is testosterone undecanoate. The drug has a short half-life, does not create hyperconcentrations, however, for a total of about 6 hours a day, the testosterone level while taking the drug does not exceed 12 nmol/l (with a normal range of 12–33 nmol/l). The frequency of administration is 3 times a day, which creates a number of inconveniences for the patient. Recently, testosterone patches and gels have become widespread. However, their use also has a number of limitations. For most patients, discomfort occurs due to the inability to shower after applying the drug for several hours (decrease in drug concentration), which largely changes their habits. Our experience suggests that a quarter of all patients violate the prescribed treatment regimen, forgetting to apply the gel daily, which leads to instability in the concentration of testosterone in the blood. Existing buccal forms of testosterone have not found widespread use in practice. In our study, we used an injectable form of testosterone undecanoate, obtained by esterification of natural testosterone at the 17b position. This drug is known in our country under the name “Nebido”. It was developed to long-term increase serum testosterone concentrations in men to physiological levels. One ampoule contains 1000 mg of testosterone undecanoate in 4 ml of oil solution (castor oil). The indication for use was laboratory confirmed hypogonadism (total testosterone level below 12 nmol/l). Contraindications for the use of Nebido are the same as for any other form of testosterone: androgen-dependent prostate carcinoma, malignant neoplasm of the mammary gland in men; hypercalcemia as a marker of malignant tumor growth; existing or history of liver tumor; hypersensitivity to any of the components of the drug. The following administration method was used: 1000 mg of testosterone undecanoate was administered per injection, the interval between the first and second injections was 6 weeks. subsequent intervals between injections are 12 weeks. The contents of one ampoule of the drug were injected deep into the gluteal muscle very slowly over about 1 minute. Compliance with this rule minimized the discomfort associated with the introduction of Nebido. The study was conducted over 30 weeks. A total of 42 patients aged from 59 to 72 years (mean age 65.5±7.0 years) took part in our study. 20 patients suffered from diabetes mellitus from 6 to 15 years; 22 patients had no disturbances in carbohydrate metabolism. Before the examination, all patients filled out an androgen deficiency questionnaire; the reduction in androgen levels was previously assessed using the Morley scale. All patients had sexual dysfunction and laboratory-confirmed hypogonadism (total testosterone levels below 12 nmol/l). All patients were prescribed the drug "Nebido" according to the above method. Efficacy was assessed after 5 days, 6, 18 and 30 weeks from the start of therapy. Both groups were comparable in age, body mass index and the presence of concomitant somatic pathology, namely arterial hypertension and stable angina (functional class I–III). All patients with diabetes mellitus received similar therapy with oral hypoglycemic drugs, which did not change throughout the study. All men had erectile dysfunction, the severity of which was determined according to the International Index of Erectile Dysfunction (the average level was 12 points, which corresponds to its average severity (the norm is 21–25 points). All patients underwent ultrasound diagnostics of the penile arteries and the PSA level was determined ( repeatedly during the entire study period). The level of depression was assessed before and after the study using the Beck Depression Inventory (BDI). All patients underwent a hormonal examination to determine the level of total testosterone; free testosterone was determined by the calculation method. To exclude hypogonadotropic hypogonadism in all patients examined the levels of total testosterone, luteinizing hormone, follicle-stimulating hormones, prolactin and estradiol in the blood serum. Before the start of therapy, all patients, as a result of androgen deficiency, showed a decrease in libido, varying degrees of sexual dysfunction, decreased performance, weakness, drowsiness, fatigue, depression reactions. In addition, all patients had abdominal obesity (OB/WC index was more than 1.2). Plasma testosterone concentrations were assessed after 5 days, 6, 18 and 30 weeks from the start of therapy. Thus, after 5 days from the start of treatment, the concentration of total testosterone reached normal values (Fig. 2). According to our estimates, there were no changes in testosterone levels during the observation period. Convenient pharmacokinetics of the drug ensured stable serum testosterone concentrations in men within the physiological norm. In patients with diabetes mellitus, the initial average blood testosterone level was lower than in patients without carbohydrate metabolism disorders, but after 30 weeks from the start of treatment it was even slightly higher than in the group of patients without diabetes mellitus. We assessed the levels of glycated hemoglobin, total serum cholesterol, triglycerides, LDL, HDL and body mass index in patients treated with Nebido. These indicators were assessed at 6, 18 and 30 weeks from the start of therapy. Their dynamics are shown in Table 1. While taking the drug "Nebido", there were no supraphysiological peak testosterone concentrations during the entire period of therapy. As can be seen from the presented data, all patients experienced a significant improvement in their lipid profile during Nebido therapy. This was expressed in a significant decrease in the content of total cholesterol, LDL and triglycerides. Positive dynamics are demonstrated by both the level of glycated hemoglobin and body mass index. Table 2 shows similar results of treatment with Nebido in patients without diabetes. The results differ slightly from those given above, but the positive effect of the treatment can be seen quite clearly. The level of blood pressure in patients with arterial hypertension during the study has not changed significantly. All patients were carried out bone densitometry, the method of determining the mineral density of bone tissue (MPTT) was an X -ray bickendon absorphytiometry of the distal bones of the forearm (DTH 200 OSTEOMETER Corporation) (Denmark). In the presence of clinical and laboratory signs of androgenic deficiency, low MPCT was detected in 85% of cases in patients with concomitant diabetes and 77.2% of cases without carbohydrate metabolism. During the initial examination, patients of both groups had a bone mass density below the average -reservoir indicators by more than 1.0 SDS. After 30 weeks from the onset of treatment, 70.5% of patients in a group with diabetes had an increase in bone mass density from the initial indicators by 0.25 SDS, in other cases of significant changes in the bone tissue were not detected. In patients without diabetes mellitus, bone density increased by the same level in 38.8% of cases, in 61.2% of cases did not change significantly. The level of blood pressure in patients with arterial hypertension during the study has not changed significantly. The state of the prostate gland, including ultrasound and the determination of the PSA concentration, was checked at the beginning of the study, after 18 and 30 weeks from the beginning of therapy. In the course of clinical studies, not a single patient developed cancer or benign prostate hyperplasia. The average PSA values did not increase significantly. In only one patient, the PSA level reached 4 μg/l, but he did not stop treatment. The volume of the prostate gland increased slightly, but remained within physiological limits. All patients have an improvement in sexual activity, an increase in libido, a decrease in total body weight and percentage of adipose tissue. The international erectile dysfunction index increased and amounted to an average of 17 points. The level of depression on the Bek scale has significantly decreased - on average from 21 points to 11. Thus, Nebido therapy has an undoubted positive effect on the lipid spectrum, body weight, compensation for type 2 diabetes, sexual function and mood. Its use in patients with acquired androgen deficiency effectively, safely and significantly improves the quality of their life. To restore the level of testosterone, only 4 injections per year are required, while there is no supraophysiological increase in testosterone after its administration. The unconditional effect, convenience and safety of use from the point of view of a practical doctor allow you to give a “Nebido” preference in the treatment of androgen deficiency.

Literature 1. Veliev E.I. “Androgen deficiency conditions in men—the view of a urologist.” Materials of the National Congress “Man and Medicine”, 2006, Moscow. 2. Morales A, Lunenfeld B. Androgen replacement therapy in aging men with secondary hypogonadism. Draft recommendations for endorsement by ISSAM. Aging males 2001;4;151–62. 3. Snyder PJ, Lawrence DA. Treatment of male hypogonadism with testosterone enanthate.J Clin Endocrinol Metab. 1980 Dec;51(6):1335–9. 4. Kalinchenko S.Yu., Kozlov G.I., Goncharov N.P., Novolodskaya Yu.V. Age-related changes in the hypothalamic-pituitary-testicular axis in men. The second scientific conference with international participation dedicated to the 80th anniversary of the birth of Professor Mikhail Grigorievich Kolpakov. Russia, Novosibirsk, October 15 – 17, 2002. 5. A multicenter trial comparing the luteinizing hormone releasing hormone analog Zoladex, with Zoladex plus flutamide in the treatment of advanced prostate cancer. Eur Urol. 1990;18 Suppl 3:28–9. 6. Vertkin A.L. et al. “Erectile dysfunction: cardiac aspects.” MEDpress-inform, 2005, 144 p. 7. Sieminska L et al. Serum free testosterone in men with coronary artery atherosclerosis. Med Sci Monit. 2003; 9(5): CR 214–218. 8. Barud W. et al. Association of obesity and insulin resistance with serum testosterone, sex hormone binding globulin and estradiol in older males. Pol Merkuriusz Lek. 2005 Mar;18(105):295–7. 9. Kim S.–C., Ahn S.–Y., Park S.–H. et al. // J. Korean Med. Sci. – 1995. – Vol. 10. – N 1. 10. Baillie SP Davison CE, Johnson FJ, Francis RM Pathogenesis of vertebral crush fractures in men. Age Aging. 1992. N° 21. P. 139–141. 11. Pederson L., Kremer M. Judd J., Pascoe D., Spelsberg TC, Riggs BL, Oursler M J. Androgens regulate bone resorption activity of isolated osteoclasts in vitro. Proc Natl Acad Sci USA, 1999. 12. I.I. Dedov, S.Yu. Kalinchenko. Age-related androgen deficiency in men. Moscow, “Practical Medicine”, 2006, 239 p. 13. Feldman HA, Golstein I., Hatzichristou DG etal. Impotence and its medical and psychological correlates: results of the Massachusetts Male Aging Study // J. Urol. (Baltimore). 1994. Vol. 151. P. 54–61. 14. Hakim L S., Goldstein I. Diabetic sexual dysfunction //Endocrinol. Metab. Clin. N. Am. – 1996. – Vol. 25. –P. 379–400. 15. Kalinchenko S.Yu. The role of correction of hypogonadism in the treatment of type 2 diabetes mellitus in men. Materials of the Fifth Moscow City Congress of Endocrinologists, March 23–24, 2006. 16. Burris AS, Banks SM, Carter CS, Davidson JM, Sher-ins RJ. A long–term, prospective study of the physiologic and behavioral effects of hormone replacement in untreated hypogonadal men. J Androl.Jul-Aug 1992; 13(4): 297–304. 17. Plymate S. Hypogonadism. Endocrinol Metab Clin North Am 1994; 23:749–772. 18. Yarman SM, Metter EJ, Tobin JDF et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J.Clin. Endocrinol Metab 2001;86:724–31. 19. Segal A.S. Long-term administration of testosterone preparations: safety assessment. Symposium “Nebido - modern possibilities in the correction of androgen deficiency in men” Moscow, April 21, 2006.

Reviews from experts

Replacement therapy is always a risk. Moreover, there is a risk of delayed action. It is impossible to immediately draw clear conclusions based on taking one course. Observations are required for at least 2-3 months after completion of the course.

We offer reviews from doctors:

As we can see, even experts have mixed opinions about the drug. Only one thing is clear: the degree of effectiveness of the drug depends on many factors. The main one is individual medical indicators.

How the drug works: description

Low testosterone levels cause a phenomenon called hypogonadism, a pathology of the testicles. Which, in turn, is fraught with negative processes of various forms: from increased fatigue and depression to decreased libido and lack of erection.

The mechanism of action of the drug is based on the injection of an oil solution of testosterone undecanoate ester. After some time, the active substance is broken down, releasing testosterone as a result of a chemical reaction.

The intramuscular injection of testosterone is intended to compensate for the deficiency of the hormone in the body and normalize all related processes. A positive result is when the examination shows a reduction in symptoms characteristic of hypogonadism.