Lower urinary tract symptoms (LUTS) are widespread in men and are associated with a significant decrease in the quality of life [1][2][3]. According to modern ideas about urodynamics, LUTS are conditionally divided into symptoms of storage, voiding (emptying), and post-voiding. According to Choi et al., nocturia, urgency with the risk of urine loss, as well as storage symptoms in young people have the strongest impact on the quality of life of patients suffering from LUTS [4]. It has been found that the symptoms of accumulation to a greater extent than the symptoms of emptying affect the psychological health of patients, contributing to the development of depression and anxiety disorders [5][6]. Along with this, many patients are disappointed in the proposed treatment and prefer not to consult a doctor [7].

According to the guidelines of the American Urological Association together with the Society for Urodynamics and Women's Pelvic Medicine (AUA/SUFU), the first line of treatment for patients with accumulation symptoms should be behavioral therapy aimed at bladder training [8]. In addition, body mass index correction, restriction of caffeine and alcohol, pelvic floor muscle training, and restriction of fluid intake in the evening are often used strategies. The next line of therapy, which doctors and patients often resort to (while bypassing the first one), is drug therapy. According to the guidelines of the European Association of Urologists, the main group of drugs used for the treatment of LUTS are alpha-blockers (1A-level of evidence) [9]. In addition, competitive inhibitors of M-receptors and inhibitors of 5-alpha reductase, as well as combination therapy can be used [2][10]. The effectiveness of this therapy is not unambiguous. In particular, Kasyan et al. reported that, although alpha-blockers are first-line medicines in the treatment of LUTS, they have a negligible effect on accumulation symptoms. Thus, this has the strongest impact on the patient's life quality [10]. In turn, the use of cholinolytics is associated with the presence of side effects and insufficient effectiveness, which leads to the independent termination of the course of treatment by patients [11]. In addition, Yu et al. reported that to date there is no universal approach to the treatment of LUTS and that therapy should be selected for each patient individually [12].

Thus, today there is a need to search for new types of LUTS therapy, which can play the role of concomitant therapy and collectively improve the results of treatment.

The study aimed to test the hypothesis that the use of the peripheral magnetic neuromodulation (PMN) method in men with LUTS will help to reduce subjective and objective clinical symptoms and improve the patients’ life quality.

A prospective randomized study involved 68 men. The average age was 39 ± 9.3 years. The criteria for inclusion of patients were age over 18 years, as well as the presence of LUTS, mainly accumulation phases (urgency, nocturia, imperative urges, frequent daytime urination), as well as post-voiding symptoms (feeling of incomplete emptying of the bladder, periodic leakage of urine after the act of urination). All the patients filled out a standard informed consent form. The exclusion criteria were contraindications to the use of the PNM, namely, the presence in the patient's body of metal elements or objects made with the use of ferromagnets, convulsive seizures in the anamnesis, or taking medicines that can provoke convulsive seizures. Also, it is important to consider the presence of implanted devices that control the physiological functions of the body, such as a pacemaker, cochlear implant, etc., as well as pelvic tumors in the anamnesis. Patients with pronounced fixed infravesical obstruction, confirmed by the data of the obstructive uroflowmetry line determined by the standard Liverpool nomogram, and/or with the presence of a residual urine volume of more than 50 ml were excluded as well. Additional exclusion criteria were the presence of prostatic specific antigen (PSA) of blood more than 4.0 ng/ml, the presence of urinary tract infections, and chronic diseases of the cardiovascular system in the decompensation stage.

The study took place during the period from March to October 2021 based on the North-West Center for Evidence-Based Medicine. Patients who met the inclusion criteria in the absence of exclusion criteria were randomized in a 1:1 ratio for magnetic neuromodulation or drug therapy.

Treatment protocol. The subjects in the main group received 10 sessions of non-invasive peripheral neuromodulation by using the BTL Emsella magnetic stimulator (BTL Corp., UK) according to the protocol “Strengthening pelvic floor muscles” with trapezoidal frequency modulation in the range from 1 to 10 Hz. Patients in the control group underwent a month-long course of drug therapy with alpha-1 blocker (tamsulosin) according to the standard regimen of 0.4 mg/day.

The examination algorithm included the collection of anamnesis, physical examination with the determination of body mass index, filling out a standard validated questionnaire for the assessment of symptoms of the lower urinary tract “International Prostate Symptom Score/IPSS”, filling out a urination diary [13]. Laboratory and instrumental methods included a general urinalysis, a blood test for PSA, uroflowmetry with the determination of the volume of residual urine by ultrasound (ultrasound). The results were evaluated on equal terms (10 days and 1 month) in both groups, followed by a comparison of effectiveness.

The primary endpoint of the study was defined as a decrease in the severity of lower urinary tract symptoms, such as frequent urination during the day, nocturia, and urgency. The primary endpoint of effectiveness was assessed by using an IPSS questionnaire and a urination diary. Improvement of urodynamic parameters, such as maximum urine flow rate (Qmax), average urine flow rate (Q ave), post-void residual (PVR) urine volume, were the secondary endpoint of the study. Secondary endpoints were evaluated by using non-invasive urodynamic studies, such as uroflowmetry, and the determination of residual urine volume by ultrasound. Clinical symptoms and urodynamic parameters are described in the study following the standardized terminology of the International Continence Society [14]. The study was registered on ClinicalTrials.gov (NCT04807569) before the inclusion of patients.

Statistical analysis. According to the authors’ calculations, to confirm a 10% decrease (from 30 to 20%) of the LUTS manifestations (at a time when according to IPSS, the significance level is 0.05, and the power of 80%), at least 62 subjects are to be included in the study. To compensate for possible data loss, the sample size has been increased by 10%. As a result, the total sample size is 68 patients, with a 1:1 ratio of 34 patients in each group.

Categorical variables are described as absolute numbers and percentages. To compare the dynamics before and after treatment, the conjugacy tables were analyzed by using the exact Fisher criterion. Quantitative variables were described as mean ± standard deviation, 95% confidence intervals for averages, or as median and quartiles. To compare quantitative signs before and after treatment, the paired Wilcoxon rank criterion was used. The unpaired Mann-Whitney rank criterion was used in the analysis between the groups. The differences were considered significant at p < 0.05. Calculations were performed by using the R language – R Core Team (2021) (R Foundation for Statistical Computing, Vienna, Austria).

The analysis of the results of treatment of patients was carried out according to the “protocol” model. As a result, 67 (98.5%) of the subjects were included in the final database. One patient from the drug therapy group dropped out of the study for personal reasons. The body mass index of the respondents was 28.1 ± 2.9 kg/m2 in the PMN group and 26.3 ± 2.6 kg/m2 in the drug therapy group. The average score according to the IPSS questionnaire was 18.1 ± 4 and 19.3 ± 5.1 in the PMN group and the drug group, respectively (p = 0.12). There was no significant difference in the initial parameters of uroflowmetry (Q max = 14.7 ml/s for the PMN group and 14.36 ml/s for the drug therapy group) (p = 0.64).

Results for 10 days. An interim analysis showed that in the magnetic stimulation group, relief of symptoms occurred in 21 (61.7%) patients. At the same time, the average IPSS score showed a decrease from 18.1 ± 2.1 to 16.9 ± 3.2 points, which turned out to be statistically significant (p = 0.037). The number of urinations per day decreased from 14 (6 – 20) to 10 (6 – 14) times (p < 0.001). Objective indicators of uroflowmetry have not changed.

In the group of drug therapy, the dynamics of subjective and objective indicators were not noted.

Results for 1 month. According to the data obtained 1 month after the start of treatment, 22 (64.7%) of the subjects in the PMN group noted an improvement. The average score of the IPSS questionnaire in this group was 16.6 ± 3.7 points, while before the start of treatment it was 18.1 ± 4 points (Figure 1). Thus, there was a statistically significant decrease in the severity of symptoms (p = 0.032). According to the urination diary, the median number of urinations per day changed from 14 (6 – 20) times to 9 (6 – 14) times (p < 0.001). Objective indicators such as Q max (14.7 ± 2.5 ml/s before treatment, 15.3 ± 2.9 ml/s after the full course) (p = 0.43) and Q ave (7.84 ± 1.58 ml/s before treatment and 8.82 ± 1.91 ml/s after the full course) (p = 0.22) did not show any dynamics. The volume of residual urine according to ultrasound showed a statistically significant decrease (20 ml (0 – 30) before the start of treatment, 15 ml (0 – 20) after the full course) (p = 0.002). At the same time, there were no dynamics in all these indicators compared to the control 10 days after the start of treatment.

In the drug therapy group, an improvement in the subjective state was noted in 25 (73.5%) patients. IPSS score changed from 19.27 ± 5.08 to 15.4 ± 4.85 points, showing a significant decrease (p <0.001). The number of urinations per day changed from 13 (6 – 19) times to 10 (6 – 14) times (p <0.001). According to uroflowmetry, Q max increased from 14.36 ± 2.82 ml/s to 15.94 ± 2.71 ml/s (p = 0.032), while the average urination rate did not change (p = 0.17). The volume of residual urine also showed a statistically significant decrease (30 ml (0 – 40) before the start of treatment, 0 ml (0 – 20) after the full course) (p < 0.001).

PMN is a method that has proven itself in the treatment of stress urinary incontinence in women [15][16]. In addition, a few studies are demonstrating the effectiveness of PMN in the treatment of symptoms of bladder hyperactivity such as frequent urination and urgency [17][18]. The method is based on the generation of eddy currents in the electromagnetic field of the coil, which changes the transmembrane potential of neurons, promotes the release of neurotransmitters into the synaptic cleft, and causes a motor response in the form of muscle contraction [19]. However, to date, there are no uniform magnetic stimulation protocols applicable for the treatment of specific nosologies. As for this study, a protocol was chosen that was created based on earlier studies, as well as the empirical selection of the most comfortable stimulation mode for the patient [20]. It should be noted that to date, the effect of peripheral magnetic stimulation on the function of the lower urinary tract has not been fully studied. One of the possible mechanisms leading to a decrease in the subjective perception of LUTS may be pelvic floor muscle training. In a randomized clinical trial (RCT), Tibaek et al. demonstrated that pelvic floor muscle training in men suffering from LUTS can significantly improve the quality of life and reduce the intensity of accumulation symptoms [21]. PMN promotes multiple contraction and relaxation of the pelvic floor muscles, essentially being a method of hardware training. Thus, arbitrary control over the muscles of the genitourinary diaphragm is enhanced and the intervals between urination are increased. Another possible mechanism is to act directly on the preganglionic neurons of the sympathetic nervous system through a system of insertion neurons (interneurons). Under the influence of an impulse, the fibers of the genital nerve are excited, from where it is transmitted to the spinal cord, and then, presumably, moves retrograde through interneurons [22]. The excitation of postganglionic sympathetic fibers in the subcutaneous nerve leads to the release of norepinephrine, which has a relaxing effect on the bladder, leading to an increase in the functional capacity of the bladder and an increase in the intervals for urination [23][24]. Such a mechanism is based on a system of somatovisceral integrations in the spinal cord and, presumably, underlies the therapeutic effect of tibial neuromodulation [23]. In addition, during RCT, Yamanishi et al. compared the urodynamic effects of magnetic and electrical stimulation on the symptoms of detrusor hyperactivity [25]. In both groups, there was a significant increase in such urodynamic parameters as the first urge to urinate and the maximum cystometric capacity. Inhibition of detrusor contractions has also been reported in animal studies and healthy volunteers [26][27]. In this study, it was also possible to demonstrate an increase in the intervals between urination in patients in the PMN group both for 10 days after treatment and for 1 month. It is worth noting that magnetic stimulation demonstrated a statistically significant decrease in the frequency of urination per day for 10 days, while in the tamsulosin group the greatest effect was achieved a month after the start of therapy. This finding suggests that the combined use of PMN and drug therapy can give the best effect on the treatment of patients with LUTS.

Even though the authors obtained statistically significant differences in the level of residual urine, as well as in the maximum and average urination rates before and after treatment in the tamsulosin group, these indicators are characterized by variability. These differences cannot be considered as clinically significant ones. According to clinical guidelines, the volume of residual urine less than 50 ml is usually regarded as normal. [8][9]. Along with this, according to the IPSS questionnaire, the scores for the question “How often during the last month have you had a feeling of incomplete emptying of the bladder after urination?” changed from 4 (2 – 5) to 2 (1 – 4) (p = 0.036), which indicates a subjective decrease in the intensity of post-voiding symptoms.

Limitations. The results of this study should be perceived in light of several limitations. Firstly, this study did not imply placebo control. Secondly, there was no delayed follow-up of patients after the course of treatment, therefore there is no data on the duration of the effect and the development of late side effects. Nevertheless, the data obtained during the study suggest that the early effect of magnetic neuromodulation in combination with the delayed effect of taking tamsulosin may in combination achieve the best result for patients suffering from LUTS. Thus, PMN can be offered as an option within the framework of combination therapy or as an independent method in case it is impossible to prescribe medications.

The study demonstrated the promising possibilities of PMN in male patients suffering from LUTS. Thus, the PMN-method may be preferable for patients dissatisfied with drug therapy. However, additional randomized placebo-controlled studies are required to confirm these hypotheses.