Background:
Benign prostatic hyperplasia (BPH) is a disease that affects the quality of life by causing lower urinary tract symptoms (LUTS) in men. Electroacupuncture (EA) and moxibustion therapy have been suggested as an adjunct therapy for improving LUTS in patients with BPH, but clinical studies evaluating the effectiveness of EA and its cotreatment with electronic moxibustion (EM) in patients who have been prescribed alpha blockers have yet to be reported. Therefore, this study aimed to evaluate the effectiveness and safety of EA and EM.
Methods:
Twenty-eight patients diagnosed with BPH were randomized to treatment group (TG, n = 14) or control group (CG, n = 14). The TG continued to use the previously prescribed alpha blocker and received the cotreatment of EA and EM 3 times a week for 6 weeks. The CG continued to use the previously prescribed alpha blocker alone for 6 weeks. The primary outcome was the mean change in the international prostate symptom score (IPSS) from baseline to week 6. The secondary outcomes were IPSS at week 3 and 12, clinical relevance, IPSS life satisfaction, EuroQol-Five dimensions, average urinary flow rate, maximum urinary flow rate, and prostate volume.
Results:
The IPSS decreased at all time points with a statistically significant difference between the 2 groups (3W: P = .0313; 6W: P = .0010; 12W: P = .0304). Based on the minimal clinically important difference (MCID, 3 points), there were significant differences between the TG and the CG at week 3, 6, and 12 (3W: P = .0461; 6W: P = .0123; 12W: P = .0216). Significant group × week interaction effects were found for the IPSS score (P = .0018), as determined from analyses using repeated measures analysis of variance. There were no significant differences between the 2 groups in IPSS life satisfaction, EuroQol-Five dimensions, average urinary flow rate, maximum urinary flow rate, and prostate volume.
Conclusion:
EA and its cotreatment with EM might have a beneficial effect as an adjunct therapy in improving LUTS in patients with BPH. Large-scale randomized controlled trials are warranted to confirm the effectiveness and safety of EA and its cotreatment with EM.
Keywords: benign prostatic hyperplasia, electroacupuncture, electronic moxibustion, randomized controlled trial
1. Introduction
Benign prostatic hyperplasia (BPH) occurs in men as they age, and it causes lower urinary tract symptoms (LUTS) in 40% to 70% of men aged 60 years or older and thus affects quality of life.[1] Patients with BPH seek treatment because the consequent LUTS alters their quality of life, such as causing symptoms including sensation of incomplete bladder emptying, frequent urination, nocturia, urinary urgency, and intermittent stream, as well as sleep disturbances and restrictions in prolonged traveling.[2,3]
Based on the international prostate symptom score (IPSS), BPH patients with moderate or severe symptoms are primarily recommended pharmacological therapy, and surgical treatment can be considered if adequate improvement of LUTS is not achieved with pharmacological therapy.[4] However, the adverse reactions of tamsulosin, an alpha blocker used to treat BPH, include rhinitis (6.6%), vertigo (4.4%), and abnormal ejaculation (2.8%),[5] and 5-alpha reductase inhibitors have been associated with sexual function-related adverse events, such as erectile dysfunction, reduced libido, and retrograde ejaculation.[6,7] Furthermore, surgical treatment is not a viable option for older patients, patients with a severe existing condition, and in cases in which pharmacological therapy involving anti-platelet agents and anti-coagulants cannot be suspended.[4] Thus, there is still a need for safe and effective treatment for patients who do not adequately respond to pharmacological therapy and for whom surgical treatment is not a good alternative.
Recently, complementary and alternative medicine treatments, namely electroacupuncture (EA) and moxibustion, have been proposed as an adjuvant therapy for LUTS caused by BPH, and in Asian countries, several studies have assessed the effectiveness and safety of EA in patients with BPH.[8–10] In addition, a meta-analysis of the effectiveness of moxibustion on BPH showed that moxibustion intervention increased the maximum urinary flow rate (Qmax), reduced prostate volume, and improved patients’ perceived symptoms and quality of life.[11] However, no randomized controlled trial has been conducted to assess the effectiveness of EA and its cotreatment with electronic moxibustion (EM) in BPH patients prescribed alpha blockers. Thus, this study aimed to evaluate the effectiveness and safety of EA and EM in patients diagnosed with BPH who still have persistent LUTS despite using alpha blockers.
2. Methods
2.1. Study design and setting
This study is a 2-arm parallel-design, assessor-blinded, randomized controlled trial. The subjects were recruited from patients who visited the Daejeon Korean Medical Hospital of Daejeon University in the Republic of Korea between November 2019 and May 2020. The trial subjects were given an adequate explanation and a written information sheet about the study by the Korean medicine doctor (KMD) and clinical research coordinator on the first visit and signed a written consent. The subjects were randomized to treatment group (TG) or control group (CG) at a 1:1 ratio. The TG continued using alpha blockers as previously prescribed and underwent 18 sessions of combined EA and EM therapy over a 6-week period (3 sessions per week). The CG continued using alpha blockers as previously prescribed for 6 weeks. The study flow chart is illustrated in Figure 1, and the study protocol was published in 2020.[12]
Figure 1.
Study flow chart. FAS = full analysis set, PP = per protocol.
This study was approved by the institutional review board at Daejeon Korean Medical Hospital of Daejeon University (DJDSKH-19-BM-13) and was registered with the Clinical Research Information Service managed by the Korea Disease Control Agency (identifier: KCT0004411). This study was conducted in accordance with the Korean Clinical Practice Guidelines and declaration of Helsinki.
2.2. Recruitment
Of patients who visited the Daejeon Korean Medical Hospital of Daejeon University, eligible subjects per the inclusion and exclusion criteria were recruited by posting the recruitment advertisement on the hospital’s bulletin board, bus stops, subway stations, newspapers, and apartment bulletin boards. The subjects who voluntarily signed the informed consent to participate in the trial underwent a demographic survey, history taking, vital sign measurement, laboratory testing, and electrocardiography.
2.2.1. Inclusion criteria.
Men aged between 50 and 79 years, those who have been diagnosed with BPH and are on alpha blockers. Patients with a total score between 8 and 19 in the IPSS. Patients who have voluntarily decided to participate in the study via written informed consent with a sufficient explanation on the purpose and process of the study. Patients who can fill out the measurement data for patient preparation on their own or with the aid of a guardian or the investigator.
2.2.2. Exclusion criteria.
Those who are diagnosed with BPH and using medications other than alpha blocker for treatment purpose (5-alpha-reductase inhibitors, anticholinesterases, antidiuretic hormones, etc). Patients with a total serum prostate specific antigen (PSA) level ≥4 ng/mL (although PSA levels are ≥4 ng/mL, the patient may enroll if the prostate biopsy confirms that it is not prostate cancer). Patients with a medical history of disorders other than BPH with suspected urinary disorders or other causes (e.g., neurogenic bladder, urethral stenosis, bladder stones, acute/chronic renal failure, acute/chronic prostatitis, and urinary tract infections) that may cause change in urinary flow rate. Patients diagnosed with urogenital malignancies, such as prostate and bladder cancers. Patients with history of prostate surgery (including transurethral resection of the prostate, balloon dilatation, heat therapy, and stents) or who have received or planned other invasive procedures for prostate treatment. Patients with a history of acute urinary retention. Patients who have clinically significant kidney or liver disease or have a hematological finding. Patients who have clinically significant urinalysis findings or hematuria on urinalysis. Patients who use pacemakers. Patients with severe underlying diseases (uncontrolled hypertension, cardiovascular disease, malignant tumors, etc) who are undergoing active treatment for this. Patients with severe diabetes (uncontrolled diabetes) or diabetic neuropathy. Patients with local skin disease at the EM treatment site. Patients who have a significant neuropsychiatric history or are currently have a neuropsychiatric disease. Patients who are deemed inappropriate by the study investigator for reasons other than the above.
2.3. Interventions
2.3.1. EA and its cotreatment with EM.
The TG continued using their prescribed alpha blockers and underwent 18 sessions of combined EA and EM therapy for 6 weeks at 3 sessions per week. Disposable sterile stainless steel needles of 0.25 × 40 mm or 0.30 × 60 mm were used (DONGBANG Medical Co., Ltd., Chungcheongnam-do, Republic of Korea) depending on the acupuncture point. At each session, EA was performed with the patient in the prone position, followed by EA and EM in the supine position. With the patient in the prone position, the KMD located and inserted disposable sterile needles into bilateral BL33 and BL35 obliquely. After inserting the needles, electric stimulation was applied at 16Hz at bilateral BL33 to BL35 for 15 minutes. Then, with the patient in the supine position, the KMD located and inserted disposable sterile needles into bilateral SP6 and SP9 straightly, followed by electric stimulation at 16 Hz for 15 minutes. When performing EA on SP6 and SP9 in the supine position, a gauze was placed on CV4, and EM was performed at 45ºC for 15 minutes. Because each patient has different levels of sensitivity and tolerance to heat stimulation, a gauze was placed between the EM and skin when the patient complained of the treatment being too hot. All EA and EM treatments were performed by a KMD with at least 2 years of clinical experience.
2.3.2. Alpha blocker.
The patients in the CG continued to take their previously prescribed alpha blocker. However, use of any other western medical treatment (e.g., 5-alpha reductase inhibitor, anti-cholinergic agents, anti-diuretic hormone) to improve symptoms of BPH was prohibited during the study period. The patients were instructed to notify the investigator in case of any changes or additions to the previously prescribed medications other than the alpha blocker. After the completion of the clinical trial, up to 3 sessions of EA and EM therapy were offered to patients in the CG upon request.
2.4. Outcomes
Primary outcome was set as the average change of total IPSS at 6W compared to the baseline (1W). A score of 0–5 is given depending on the severity of each symptom, and the total IPSS is classified as: mild (0–7), moderate (8–19), and severe (20–35).[4] The secondary outcomes were: average change of total IPSS at 3W and 12W, clinical relevance at 3W, 6W, and 12W, IPSS quality-of-life (QoL) score and EuroQol-Five dimensions (EQ-5D) score at 6W and 12W, average urinary flow rate (Qave) and Qmax at 6W and 12W, and prostate volume at 6W. Clinical relevance was assessed using minimal clinically important difference (MCID).[13] The MCID for IPSS over 4 to 6 weeks is 3 according to the American Urological Association Guideline,[14] and we compared the percentage of subjects who had a reduction of IPSS by at least 3 points at 3W, 6W, and 12W. IPSS QoL score measures QoL as a result of BPH, and the subjects choose the score that best represents their QoL in relation to urinary symptoms from 0 (delighted) to 6 (terrible). The EQ-5D is the most widely used QoL questionnaire, and we used the Korean version of the EQ-5D index in this study.[15,16] Prostate volume was obtained from abdominal ultrasound commissioned to an external medical center (a radiology clinic) and was recorded in the case report form. Safety was assessed based on adverse event detected by observation and patients’ report of symptoms.
2.5. Sample size
Sample size was determined based on similar studies[8,9] and researchers’ past research experiences in hypothesizing the anticipated average change and standard deviation of IPSS, due to the lack of studies that involved both EA and EM therapy with alpha blockers. For a 2-tailed test at a significance level of .05, type 2 error of 0.1 (10%), power of 0.9 (90%), and withdrawal of 20% with anticipated mean difference of IPSS of 4.34 and standard deviation (SD) of 5.23, the sample size was determined to be 78, with 39 in each group.
2.6. Randomization and blinding
Randomization was performed using a randomization table created by an uninvolved statistician using the SAS® version 9.4 (SAS institute. Inc., Cary, NC) software, and the created randomization table was stored in confidentiality by a statistician not involved in the performance and assessment of this clinical trial. Blinding of the personnel and participants was not possible for this study, and risk of bias was controlled for as much as possible by excluding the study personnel from the assessment and blinding the assessor. The assessment was performed by a KMD in the research team, and the KMD was blinded from subject allocation.
2.7. Statistical methods
All statistical analyses were performed using a 2-tailed test with a significance level set at 5%. The SAS® Version 9.4 (SAS institute. Inc.) software was used, and missing values were addressed with multiple imputation. For the efficacy analysis, full analysis set (FAS) and per-protocol (PP) were used, where the primary analysis was performed using the FAS, and secondary analyses were performed using the PP set. For intergroup comparisons, continuous data were presented as mean and SD and analyzed with an independent t-test or Wilcoxon rank sum test, with 95% confidence interval (CI) presented when necessary. Categorical data were presented as frequency and percentage and analyzed using a chi-square test or Fisher exact test. The primary endpoint is the average change of IPSS at 6W compared to the baseline, and it was analyzed using analysis of covariance (ANCOVA). The secondary endpoints were analyzed using the same technique. The changes of the parameters before and after the treatment were analyzed using a paired t test or Wilcoxon signed-rank test. The differences in the trends over sessions were analyzed using repeated measures analysis of variance, followed by the Dunnett procedure as a post hoc test for multiple comparison, with the Greenhouse–Geisser Epsilon used for adjusting for the assumption of sphericity.
3. Results
3.1. Patients recruitment
Of 36 patients, 28 were determined to be eligible for the inclusion and exclusion criteria. The subjects were randomly allocated to the TG or CG at a 1:1 ratio. Twenty-two out of 28 enrolled subjects completed the trial, and 6 withdrew from the study. All 6 withdrawn subjects (1 in TG, 5 in CG) withdrew their consent to participate in the study (Fig. 1). While we targeted to enroll 78 subjects, there were internal circumstances of the study in recruiting subjects, and thus the study was completed with 28 subjects.
3.2. Baseline characteristics
There were no significant differences in age, height, weight, obesity, employment status, marital status, exercise status and duration, drinking history, and medical history between the 2 groups. The duration of BPH statistically significantly differed between the TG (39.71 months) and CG (19.71 months) in the FAS analysis but did not significantly differ between the 2 groups in the PP analysis. There were no significant differences between the 2 groups in the outcomes, namely IPSS, IPSS QoL, EQ-5D, Qmax, and prostate volume. Qave significantly differed between the TG (7.57 mL/s) and CG (5.29 mL/s) in the FAS analysis but not in the PP analysis (Table 1).
Table 1.
Demographics and baseline characteristics.
| Characteristics | FAS analysis | PP analysis | ||||
|---|---|---|---|---|---|---|
| Treatment group (n = 14) | Control group (n = 14) | P value | Treatment group (n = 13) | Control group (n = 10) | P value | |
| Age (yr)† | 63.64 (60.21, 67.07) | 64.50 (61.02, 67.98) | .7077 | 63.92 (60.24, 67.60) | 64.50 (60.46, 68.54) | .8185 |
| Height (cm)† | 169.2 (166.0, 172.3) | 169.5 (166.8, 172.2) | .8565 | 168.5 (165.4, 171.7) | 169.2 (165.8, 172.6) | .7494 |
| Weight (kg)† | 73.56 (70.02, 77.11) | 73.36 (68.03, 78.68) | .9448 | 72.99 (69.37, 76.61) | 73.11 (67.11, 79.11) | .9690 |
| BMI (kg/m2)† | 25.70 (24.72, 26.68) | 25.51 (23.85, 27.17) | .8298 | 25.69 (24.63, 26.76) | 25.51 (23.72, 27.30) | .8388 |
| Job‡ | ||||||
| Yes | 7 (50.00%) | 9 (64.29%) | .7036 | 6 (46.15%) | 6 (60.00%) | .6802 |
| No | 7 (50.00%) | 5 (35.71%) | 7 (53.85%) | 4 (40.00%) | ||
| Married‡ | ||||||
| Yes | 13 (92.86%) | 12 (85.71%) | .9999 | 12 (92.31%) | 8 (80.00%) | .5596 |
| No | 1 (7.14%) | 2 (14.29%) | 1 (7.69%) | 2 (20.00%) | ||
| Exercise‡ | ||||||
| Yes | 10 (71.43%) | 8 (57.14%) | .6946 | 10 (76.92%) | 7 (70.00%) | .9999 |
| No | 4 (28.57%) | 6 (42.86%) | 3 (23.08%) | 3 (30.00%) | ||
| Exercise time (min/wk)† | 451.0 (211.1, 690.9) | 461.3 (138.1, 784.4) | .9527 | 451.0 (211.1, 690.9) | 458.6 (72.6, 844.6) | .9675 |
| Drinking‡ | ||||||
| Yes | 7 (50.00%) | 7 (50.00%) | .9999 | 7 (53.85%) | 5 (50.00%) | .9999 |
| No | 7 (50.00%) | 7 (50.00%) | 6 (46.15%) | 5 (50.00%) | ||
| Duration of BPH (mo)† | 39.71 (23.99, 55.44) | 19.71 (9.82, 29.61) | .0281* | 42.69 (27.06, 58.33) | 22.70 (9.02, 36.38) | .0534 |
| Medical history‡ | ||||||
| Hypertension | ||||||
| Yes | 2 (14.29%) | 3 (21.43%) | .9999 | 2 (15.38%) | 2 (20.00%) | .9999 |
| No | 12 (85.71%) | 11 (78.57%) | 11 (84.62%) | 8 (80.00%) | ||
| Myocardial infarction | ||||||
| Yes | 1 (7.14%) | 0 (0.00%) | .9999 | 1 (7.69%) | 0 (0.00%) | .9999 |
| No | 13 (92.86%) | 14 (100.00%) | 12 (92.31%) | 10 (100.00%) | ||
| Diabetes | ||||||
| Yes | 0 (0.00%) | 2 (14.29%) | .4815 | 0 (0.00%) | 2 (20.00%) | .1779 |
| No | 14 (100.00%) | 12 (85.71%) | 13 (100.00%) | 8 (80.00%) | ||
| Other | ||||||
| Yes | 1 (7.14%) | 2 (14.29%) | .9999 | 1 (7.69%) | 0 (0.00%) | .9999 |
| No | 13 (92.86%) | 12 (85.71%) | 12 (92.31%) | 10 (100.00%) | ||
| IPSS | 15.00 (12.05, 17.95) | 15.29 (11.31, 19.26) | .9017 | 15.31 (12.17, 18.44) | 16.60 (11.36, 21.84) | .6249 |
| IPSS QoL | 4.79 (4.22, 5.35) | 4.93 (4.31, 5.55) | .7152 | 4.85 (4.25, 5.44) | 5.20 (4.75, 5.65) | .3354 |
| EQ-5D | 0.898 (0.863, 0.932) | 0.885 (0.834, 0.936) | .6579 | 0.897 (0.860, 0.935) | 0.867 (0.797, 0.937) | .3774 |
| Q ave | 7.57 (6.04, 9.10) | 5.29 (3.60, 6.97) | .0395* | 7.39 (5.78, 9.00) | 6.06 (3.92, 8.20) | .2730 |
| Q max | 15.47 (12.87, 18.07) | 12.26 (8.52, 15.99) | .1393 | 15.46 (12.63, 18.30) | 13.67 (8.88, 18.46) | .4581 |
| Prostate volume | 35.00 (24.52, 45.49) | 28.88 (22.83, 34.92) | .2842 | 35.45 (24.08, 46.82) | 27.73 (20.67, 34.79) | .2534 |
| Transverse diameter (width) | 4.79 (4.35, 5.23) | 4.55 (4.29, 4.80) | .2998 | 4.77 (4.29, 5.24) | 4.49 (4.15, 4.82) | .3297 |
| Anterior posterior diameter (height) | 3.43 (3.01, 3.85) | 3.03 (2.78, 3.29) | .0939 | 3.43 (2.97, 3.89) | 2.99 (2.66, 3.32) | .1232 |
| Length | 3.89 (3.44, 4.34) | 3.90 (3.59, 4.20) | .9663 | 3.94 (3.47, 4.41) | 3.86 (3.52, 4.19) | .7607 |
Data expressed either n (%) or mean (95% confidence interval).
BMI = body mass index, BPH = benign prostatic hyperplasia, EQ-5D = European Quality of life Five Dimensions questionnaire, FAS = full analysis set, IPSS = International Prostate Symptom Score, PP = per protocol, Qave = average urinary flow rate, Qmax = maximum urinary flow rate, QoL = quality of life.
Independent t test.
Fisher exact test.
Significant difference.
3.3. Clinical outcomes
3.3.1. Primary outcome: IPSS at week 6.
In the FAS analysis, the IPSS statistically significantly decreased by 6.21 at 6W compared to the baseline in the TG (P < .0001), and the reduction was statistically significantly greater in the TG compared to the CG (P = .0010). In the PP analysis, the IPSS statistically significantly decreased by 6.38 at 6W compared to the baseline in the TG (P < .0001), and the change was statistically significantly different between the 2 groups (P = .0025) (Table 2).
Table 2.
Changes in IPSS.
| IPSS | FAS analysis | PP analysis | ||||||
|---|---|---|---|---|---|---|---|---|
| Treatment group (n = 14) | Control group (n = 14) | Mean difference | P value† | Treatment group (n = 13) | Control group (n = 10) | Mean difference | P value† | |
| Baseline | 15.00 (12.05, 17.95) | 15.29 (11.31, 19.26) | 15.31 (12.17, 18.44) | 16.60 (11.36, 21.84) | ||||
| Week 3 | 10.57 (7.01, 14.14) | 13.71 (9.83, 17.59) | −2.84 (−5.43, −0.26) | .0313* | 10.77 (6.91, 14.62) | 15.40 (9.81, 20.99) | −3.29 (−6.35, −0.23) | .0363* |
| Difference | −4.43 (−6.50, −2.36) | −1.57 (−3.22, 0.07) | −4.54 (−6.78, −2.30) | −1.20 (−3.16, 0.76) | ||||
| P value‡ | .0005* | .0611 | .0009* | .1995 | ||||
| Week 6 | 8.79 (5.78, 11.80) | 13.85 (10.57, 17.14) | −4.80 (−7.67, −1.94) | .0010* | 8.92 (5.37, 12.48) | 15.30 (10.78, 19.82) | −5.28 (−8.45, −2.10) | .0025* |
| Difference | −6.21 (−8.32, −4.10) | −1.43 (−3.47, 0.61) | −6.38 (−8.82, −3.95) | −1.30 (−3.59, 0.99) | ||||
| P value‡ | <.0001* | .1686 | <.0001* | .2308 | ||||
| Week 12 | 8.51 (5.54, 11.48) | 12.37 (8.55, 16.18) | −3.76 (−7.16, −0.36) | .0304* | 8.70 (5.56, 11.84) | 13.93 (9.47, 18.39) | −4.27 (−7.83, −0.72) | .0184* |
| Difference | −6.49 (−8.68, −4.30) | −2.92 (−5.60, −0.24) | −6.61 (−8.90, −4.31) | −2.67 (−5.55, 0.22) | ||||
| P value‡ | <.0001* | .0332* | <.0001* | .0700 | ||||
Data expressed as mean (95% confidence interval).
FAS = full analysis set, IPSS = International Prostate Symptom Score, PP = per protocol.
Analysis of covariance.
Paired t test.
Significant difference.
3.3.2. Secondary outcomes: IPSS at weeks 3 and 12.
In the FAS analysis, the IPSS statistically significantly decreased by 4.43 and 6.49 at 3W and 12W, respectively, compared to the baseline in the TG (3W: P = .0005; 12W: P < .0001) and statistically significantly decreased by 2.92 at 12W compared to the baseline in the CG (P = .0332). The amount of change statistically significantly differed between the 2 groups (3W: P = .0313; 12W: P = .0304). In the PP analysis, the IPSS statistically significantly decreased by 4.54 and 6.61 at 3W and 12W, respectively, compared to the baseline in the TG (3W: P = .0009; 12W: P < .0001), and there were statistically significant differences between the 2 groups (3W: P = .0363; 12W: P = .0184) (Table 2).
3.3.3. Secondary outcomes: clinical relevance.
The percentage of subjects whose IPSS decreased by at least 3 points, the MCID, was analyzed. At 3W, 6W, and 12W, the TG showed a higher reduction rate than the CG, and the difference was statistically significant (3W: P = .0461; 6W: P = .0123; 12W: P = .0216) (Table 3).
Table 3.
Analysis of MCID (PP).
| n† | %‡(95% CI) | P value | |
|---|---|---|---|
| Week3 | |||
| Treatment group (N = 14) | 8 | 57.14% | .0461* |
| Control group (N = 14) | 2 | 15.38% | |
| Week6 | |||
| Treatment group (N = 13) | 10 | 76.92% | .0123* |
| Control group (N = 10) | 2 | 20.00% | |
| Week12 | |||
| Treatment group (N = 11) | 9 | 81.82% | .0216* |
| Control group (N = 9) | 2 | 22.22% | |
CI = confidence interval, MCID = minimal clinically important difference, PP = per protocol.
Number of patients with the decrease on the IPSS score more than 3 points.
Ratio of n to N.
Significant difference.
3.3.4. Secondary outcomes: IPSS QoL and EQ-5D.
The IPSS QoL score statistically significantly decreased by 1.22 and 1.86 at 6W (P = .0005) and 12W (P < .0001), respectively, compared to the baseline in the TG and statistically significantly decreased by 0.88 at 12W (P = .0174) compared to the baseline in the CG (n = 14 vs 14). However, the difference between the 2 groups was not statistically significant. The EQ-5D score statistically significantly increased by 0.032 at 12W compared to the baseline in the TG (P = .0149), with no statistically significant change in the CG (n = 14 vs 14). The difference between the 2 groups was not statistically significant (Additional File 1, Supplemental Digital Content 1, http://links.lww.com/MD/H212).
3.3.5. Secondary outcomes: Q ave and Q max.
There were no statistically significant differences in the changes of Qave and Qmax at 6W and 12W compared to the baseline between the 2 groups in both the FAS and PP analyses (Additional File 2, Supplemental Digital Content 2, http://links.lww.com/MD/H213).
3.3.6. Secondary outcomes: prostate volume.
There were no statistically significant differences in the change of prostate volume at 6W compared to the baseline in both the FAS and PP analyses. In the TG, prostate volume was statistically significantly decreased by 3.98 (P = .0002), transverse diameter by 0.26 (P = .0163), and anterior posterior diameter by 0.27 (P = .0002) at 6W compared to the baseline, with no statistically significant changes in the CG (n = 14 vs 14) (Additional File 3, Supplemental Digital Content 3, http://links.lww.com/MD/H214).
3.3.7. Analysis of trends over time.
Repeated measures analysis of variance was performed to analyze the changes in the trends over time. There was a significant time and group interaction for the IPSS (P = .0018), and the changes in the IPSS over time significantly differed between the 2 groups at 3W, 6W, and 12W (3W: P = .0380; 6W: P = .0014; 12W: P = .0102) (Fig. 2). The trends of IPSS QoL score and EQ-5D score over time did not significantly differ between the 2 groups. There were significant changes in Qave (P = .0371) and Qmax (P = .0075) over time, but the time and group interaction was not significant.
Figure 2.
Change over time in the IPSS. *P value <.05 by ANCOVA, †P value <.05 by RM ANOVA post-hoc, *Significant difference.
3.3.8. Adverse events.
During the study period, no procedure-related adverse events were observed in 28 subjects (14 in the TG, 14 in the CG).
4. Discussion
BPH causes LUTS, such as storage symptoms and voiding symptoms, as a result of enlarged prostates and increased smooth muscle tension,[17,18] which in turn disturb activities of daily living and alter individuals’ lifestyle.[19] Hence, based on meta-analyses[11,14] and clinical trials[9,10,20–25] on the effectiveness of acupuncture and moxibustion therapies for BPH, this study was designed to assess effectiveness and safety of EA and its cotreatment with EM as an adjuvant therapy for BPH.
In this study, patients diagnosed with BPH and have moderate LUTS despite the use of alpha blockers were enrolled. The TG continued to take their previously prescribed alpha blocker and additionally underwent combined EA and EM therapy for 6 weeks at 3 sessions per week. The duration of BPH statistically significantly differed between the TG (39.71 months) and the CG (19.71 months) in the FAS analysis, with no significant differences in the PP analysis.
At 6W, the IPSS decreased by 6.21 in the TG and 1.43 in the CG, with a statistically significant difference between the 2 groups (n = 14 vs 14, P = .0010). At all time points, including 3W and 12W, the TG showed a significantly greater reduction of the IPSS (n = 14 vs 14, 3W: P = .0313; 12W: P = .0304), and the reduction of the IPSS was continued until the 12W follow-up after the completion of the intervention. To assess clinical relevance, we analyzed the percentage of subjects whose IPSS decreased by at least 3 points[14]—the MCID—between the 2 groups. At all time points, the TG showed a statistically significantly higher percentage of subjects with the reduction compared to the CG (3W: P = .0461; 6W: P = .0123; 12W: P = .0216). This shows the potential of combined EA and EM therapy on improving LUTS in patients with BPH.
Regarding QoL, the EQ-5D score and IPSS QoL score did not statistically significantly differ between the 2 groups at 6W and 12W. Patients with BPH experience sleep disturbances and other types of discomfort due to LUTS, such as sensation of incomplete bladder emptying, frequent urination, and nocturia,[2,3] and these symptoms has a toll on their mental health, such as by causing depression or anxiety, thereby deteriorating the patients’ health-related QoL.[19,26] While the TG showed a significant reduction of IPSS at 6W and 12W compared to the CG, their IPSS was still 8 or higher, indicating moderate LUTS, which may be the reason underlying the absence of significant difference in QoL between the 2 groups.
The baseline Qave statistically significantly differed between the 2 groups in the FAS analysis (TG: 7.57, CG: 5.29) but not in the PP analysis. Qave and Qmax at 6W and 12W did not statistically significantly differ between the 2 groups. This is inconsistent with the results of a meta-analysis[14] of the efficacy of acupuncture therapy in patients with BPH that the acupuncture group had an increase of 2 mL/s (MCID)[27] or higher in Qmax at 4W to 6W, and that the difference between the 2 groups was significant. Uroflowmetry provides information about Qave, Qmax, and urine output.[28–30] Patients are instructed to urinate in a relaxed environment when they feel the urge to urinate, and significant results can be only obtained with a minimum urine output of 150 mL or higher.[4] However, in this study, some subjects were too tense and thus were unable to urinate comfortably, and some subjects urinated before arriving at the hospital; as a result, some of the urine outputs were <150 mL. In addition, as Qmax changes according to urine output,[1] and uroflowmetry has validity issues, where repeated tests lead to large variations,[4] these factors are suspected to have affected the study outcomes. Further studies should address these limitations and obtain more accurate data.
While prostate volume did not statistically significantly differ between the 2 groups, prostate volume was reduced by 3.98 (P = .0002), transverse diameter by 0.26 (P = .0163), and anterior posterior diameter by 0.27 (P = .0002) in the TG after the intervention compared to the baseline, showing statistically significant changes (n = 14 vs 14). 5-Alpha reductase inhibitors, which reduces prostate size by inducing apoptosis of prostate epithelial cells,[31] show their clinical efficacy after a minimum of 6 to 12 months of treatment, and patients who have taken 5-alpha reductase inhibitors for 2 to 4 years show about 15% to 30% decrease in the IPSS, 1.5 to 2.0 mL/s increase in Qmax, and 18% to 28% reduction in prostate volume.[6,32–40] Considering the fact that prostate volume, transverse diameter, and anterior posterior diameter were altered with a relatively short intervention period of 6 weeks in this study, this shows the potential that EA and EM treatment might affect prostate volume. As the number of patients included in this trial was quite small, large-scale randomized controlled trials are warranted to evaluate the effect of EA and EM treatment on prostate volume.
Regarding changes in trends over time, there was no significant time and group interaction effect for IPSS QoL score, EQ-5D score, Qave, and Qmax, but there was a significant time and group interaction for IPSS, suggesting that the TG has a greater improvement of perceived LUTS compared to the CG (P = .0018). Furthermore, the 2 groups showed significant differences in the changes over time, suggesting that combined EA and EM treatment may be effective in improving LUTS in patients with BPH throughout a 12-week period (3W: P = .0380; 6W: P = .0014; 12W: P = .0102).
During the study period, no procedure-related adverse events were observed, and there were no significant differences in the clinical pathology examination for safety assessment between the 2 groups. According to a meta-analysis of the efficacy of acupuncture therapy on BPH,[14] 2 studies reported that no adverse events occurred in the TG,[9,22] and one of these studies reported that 2 cases of mild hematoma occurred in the sham acupuncture group (CG).[9] Another study observed one case of depression and fatigue after acupuncture treatment,[20] and one study reported 2 cases of an urge to have a bowel movement following acupuncture treatment that were spontaneously lost within 3 days.[23] Taken together, combined EA and EM treatment can be considered a relatively safe intervention. However, because the number of patients included in this trial was quite small, large-scale randomized controlled trials are warranted to evaluate the safety of EA and its cotreatment with EM.
This study has the following limitations. First, this study did not collect all the set sample sizes. This study was conducted with the aim of recruiting 78 subjects but completed with 28 subjects due to the first COVID-19 outbreak during the subject recruitment period. Although this study could not draw firm clinical conclusions due to not collecting all the set sample sizes, the results of this study might be used for future full-sized randomized controlled trial. So we reported the results of this study as a pilot study. Second, due to the marked difference in the intervention techniques for the 2 groups, it was impossible to completely control for the relevant risk of bias by blinding the intervention personnel and subjects. Further studies are needed to employ a sham intervention to neutralize the placebo effect. Third, BPH is a progressive disease,[41,42] and thus longer-term studies are needed to assess the continued effects of combined EA and EM treatment.
Despite these limitations, this study is the first study—to our best knowledge—to assess the effectiveness and safety of EA and its cotreatment with EM as an adjuvant therapy for BPH patients with persistent moderate LUTS despite the use of an alpha blocker. The results of this study suggest that 6 weeks of combined EA and EM treatment might be clinically effective in improving perceived LUTS in patients with BPH. Future full-sized randomized controlled trials are warranted to confirm the hypothesis of this pilot study.
5. Conclusion
EA and its cotreatment with EM might be effective as an adjuvant treatment for improving LUTS in patients with BPH. Large-scale randomized controlled trials are warranted to confirm the effectiveness and safety of EA and its cotreatment with EM.
Author contributions
YIK and CHH determined the study design as principal investigators and were responsible for the final decision to submit this manuscript for publication. HBK, JHJ, EK, and YCP participated in the design of the study. HBK drafted the manuscript. JHJ and YIK conducted intervention. JHJ and EK revised the manuscript. OK determined the statistical analysis procedures. YEC and CY provided technical advice and made critical revisions to the study plan. All authors read and approved the final manuscript.
Conceptualization: Hyo Bin Kim, Young Il Kim.
Formal analysis: Ojin Kwon.
Funding acquisition: Chang-Hyun Han.
Investigation: Chang-Hyun Han, Young Il Kim.
Methodology: Hyo Bin Kim, Ju Hyun Jeon, Eunseok Kim, Yang Chun Park.
Project administration: Changsop Yang.
Supervision: Chang-Hyun Han, Young Il Kim.
Validation: Young Eun Choi.
Writing – original draft: Hyo Bin Kim.
Writing – review & editing: Ju Hyun Jeon, Eunseok Kim.
Supplementary Material
Abbreviations:
- ANCOVA =
- analysis of covariance
- BPH =
- benign prostatic hyperplasia
- CG =
- control group
- CI =
- confidence interval
- EA =
- electroacupuncture
- EM =
- electronic moxibustion
- EQ-5D =
- EuroQol-Five Dimension
- FAS =
- full analysis set
- IPSS =
- international prostate symptom score
- KIOM =
- Korea Institute of Oriental Medicine
- KMD =
- Korean Medicine doctor
- LUTS =
- lower urinary tract symptoms
- MCID =
- minimal clinically important difference
- PP =
- per protocol
- PSA =
- prostate specific antigen
- Qave =
- average urinary flow rate
- Qmax =
- maximum urinary flow rate
- QoL =
- quality of life
- SD =
- standard deviation
- TG =
- treatment group
HBK and C-HH contributed equally to this study.
This study was approved by the Institutional Review Boards of the hospitals to which the participating research centers belong: Daejeon University Daejeon Korean Medicine Hospital (DJDSKH-19-BM-13). The study was performed in accordance with the approved protocol, and written informed consent was obtained from every participant.
This trial was registered with the Clinical Research Information Service of South Korea (KCT0004411) on October 31, 2019.
This study was financially supported by grants from project KSN2022210 of the Korea Institute of Oriental Medicine (KIOM), Republic of Korea.
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Supplemental Digital Content is available for this article.
How to cite this article: Kim HB, Han C-H, Jeon JH, Kim E, Kwon O, Choi YE, Yang C, Park YC, Kim YI. Effectiveness and safety of electroacupuncture and its cotreatment with electronic moxibustion in the treatment of patients with moderate benign prostatic hyperplasia using alpha blocker: An assessor-blinded, randomized, controlled pilot study. Medicine 2022;101:36(e30386).
Contributor Information
Hyo Bin Kim, Email: omdkim01@dju.kr.
Chang-Hyun Han, Email: chhan@kiom.re.kr.
Ju Hyun Jeon, Email: kmdjeon@dju.kr.
Eunseok Kim, Email: omdkim01@dju.kr.
Ojin Kwon, Email: cheda1334@kiom.re.kr.
Young Eun Choi, Email: wowo9129@kiom.re.kr.
Changsop Yang, Email: yangunja@kiom.re.kr.
Yang Chun Park, Email: omdpyc@dju.kr.
References
- [1].The Korean Prostate Society. Guideline of Benign Prostatic Hyperplasia. Seoul: Medrang, 2010. [Google Scholar]
- [2].Kim DH, Kwon HY. Clinical characteristics of frequency-anxiety syndrome. Korean J Urol. 2001;42:858–63. [Google Scholar]
- [3].Lee NR, Kim KH, Kwak YH, et al. Effects of the symptoms, anxiety, and depression on the quality of sleep of benign prostate hyperplasia patients. J Korea Contents Assoc. 2015;15:338–49. [Google Scholar]
- [4].Yeo JK, Choi H, Bae JH, et al. Korean clinical practice guideline for benign prostatic hyperplasia. Investig Clin Urol. 2016;57:30–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [5].Shim SR, Kim JH, Choi H, et al. General effect of low-dose tamsulosin (0.2 mg) as a first-line treatment for lower urinary tract symptoms associated with benign prostatic hyperplasia: a systematic review and meta-analysis. Curr Med Res Opin. 2015;31:353–65. [DOI] [PubMed] [Google Scholar]
- [6].McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med. 2003;349:2387–98. [DOI] [PubMed] [Google Scholar]
- [7].Naslund MJ, Miner M. A review of the clinical efficacy and safety of 5α-reductase inhibitors for the enlarged prostate. Clin Ther. 2007;29:17–25. [DOI] [PubMed] [Google Scholar]
- [8].Yang T, Liu Z, Zhang XQ, et al. Evaluation on therapeutic effects of electro acupuncture for benign prostatic hyperplasia: a prospective randomized controlled study. Chin J Rehabil Med. 2008;23:1028–31. [Google Scholar]
- [9].Wang Y, Liu B, Yu J, et al. Electroacupuncture for moderate and severe benign prostatic hyperplasia: a randomized controlled trial. PLoS One. 2013;8:e59449. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [10].Yu J-S, Shen K-H, Chen W-C, et al. Effects of electroacupuncture on benign prostate hyperplasia patients with lower urinary tract symptoms: a single-blinded, randomized controlled trial. Evid Based Complement Alternat Med. 2011;2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [11].Bae G, Lee S, Hong J, et al. Moxibustion for benign prostatic hyperplasia: a systematic review and meta-analysis. J Intern Korean Med. 2018;39:372–88. [Google Scholar]
- [12].Kim HB, Kim YI, Jeon JH, et al. Effectiveness and safety of electroacupuncture and its cotreatment with electronic moxibustion in the treatment of patients with moderate benign prostatic hyperplasia using alpha blocker: study protocol for an assessor-blinded, randomized controlled clinical trial. Medicine (Baltim). 2020;99:e19678. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [13].Jaeschke R, Guyatt GH, Sackett DL, et al. Users’ guides to the medical literature: III. How to use an article about a diagnostic test B. What are the results and will they help me in caring for my patients? JAMA. 1994;271:703–7. [DOI] [PubMed] [Google Scholar]
- [14].Zhang W, Ma L, Bauer BA, et al. Acupuncture for benign prostatic hyperplasia: a systematic review and meta-analysis. PLoS One. 2017;12:e0174586. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [15].Seong SS, Choi CB, Sung YK, et al. Health-related quality of life using EQ-5D in Koreans. J Korean Rheum Assoc. 2004;11:254–62. [Google Scholar]
- [16].Kim MH, Cho YS, Uhm WS, et al. Cross-cultural adaptation and validation of the Korean version of the EQ-5D in patients with rheumatic diseases. Qual Life Res. 2005;14:1401–6. [DOI] [PubMed] [Google Scholar]
- [17].Byun SS, Jeong H, Jo MK, et al. Relative proportions of tissue components in the prostate: are they related to the development of symptomatic BPH in Korean men? Urology. 2005;66:593–6. [DOI] [PubMed] [Google Scholar]
- [18].Bailey K, Abrams P, Blair PS, et al. Urodynamics for Prostate Surgery Trial; Randomised Evaluation of Assessment Methods (UPSTREAM) for diagnosis and management of bladder outlet obstruction in men: study protocol for a randomised controlled trial. Trials. 2015;16:567. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [19].Hunter DJW, McKee M, Black NA, et al. Health status and quality of life of British men with lower urinary tract symptoms: results from the SF-36. Urology. 1995;45:962–71. [DOI] [PubMed] [Google Scholar]
- [20].Liu X. Study on electroacupuncture efficacy and specificities of BL33 (Zhong Liao) for treatment of benign prostatic hyperplasia [MSc thesis]. China Academy of Chinese Medical Sciences, 2012. Available at: http://www.cnki.net/KCMS/detail/detail.aspx?dbcode=CMFD&QueryID=7&CurRec= 2&dbname=CMFD2012&filename=1012362862.nh&urlid=&yx=&v=MDU3MDlObktyWkViUElSOGVY MUx1eFlTN0RoMVQzcVRyV00xRnJDVVJMMmZadVp0RkNyaFZyM05WRjI2SExDK0g=. [Google Scholar]
- [21].Zheng RW. Electroacupuncture for benign prostatic hyperplasia-a randomised controlled trial and a MRS mechanism study [MSc thesis]. Beijing University of Chinese Medicine, 2016. Available at: http://www.cnki.net/KCMS/detail/detail.aspx?dbcode=CDFD&QueryID=15&CurRec=1&dbname= CDFDLAST2016&filename=1016069128.nh&urlid=&yx=&v=MjYzNzkxRnJDVVJMMmZadVp0RkNya FZiN0xWRjI2R0xPK0Y5RE9wNUViUElSOGVYMUx1eFlTN0RoMVQzcVRyV00=. [Google Scholar]
- [22].Yang T. Effects of electroacupuncture for symptomatic benign prostatic hyperplasia [MSc thesis]. China Academy of Chinese Medical Sciences, 2010. Available at: http://www.cnki.net/KCMS/detail/ detail.aspx?dbcode=CMFD&QueryID=19&CurRec=3&dbname=CMFD2011&filename=2010180441. nh&urlid=&yx=&v=MDkzNTdidkxWMTI2SHJLd0h0WElycEViUElSOGVYMUx1eFlTN0RoMVQzcVRy V00xRnJDVVJMMmZadVp0RkNyaFY=. [Google Scholar]
- [23].Yu XH. The clinical curative effect obervation on treating benign prostatic hyperplasia with electro-acu- puncture [MSc thesis]. Hei Long Jiang Traditional Chinese Medicine University, 2005. Available at: http://www.cnki.net/KCMS/detail/detail.aspx?dbcode=CMFD&QueryID=19&CurRec=9&dbname= CMFD0506&filename=2005120538.nh&urlid=&yx=&v=MTgyNjg3RGgxVDNxVHJXTTFGckNVUkwyZ lp1WnRGQ3JoVzc3TVYxMjdHN0s2SHRUUHA1RWJQSVI4ZVgxTHV4WVM=. [Google Scholar]
- [24].Wang K. Observation on therapeutic effect of electroacupuncture for benign prostatic hyperplasia [MSc thesis]. Hei Long Jiang Traditional Chinese Medicine University, 2006. Available at: http://www. cnki.net/KCMS/detail/detail.aspx?dbcode=CMFD&QueryID=19&CurRec=8&dbname=CMFD0506& filename=2006113971.nh&urlid=&yx=&v=MTAxOTgzS1YxMjdHTEs1SGRqTHJwRWJQSVI4ZVgxT HV4WVM3RGgxVDNxVHJXTTFGckNVUkwyZlp1WnRGQ3JoVzc=. [Google Scholar]
- [25].Du L. Abdomen acupuncture for benign prostatic hyperplasia. J Integr Tradit Chinese Med West Med. 2012;21:1637–8. [Google Scholar]
- [26].Kim JS, Moon VN. Factors influencing health-related quality of life in patients with benign prostatic hyperplasia. J Korean Acad Nurs. 2010;40:287–97. [DOI] [PubMed] [Google Scholar]
- [27].National Institute for Health and Clinical Excellence: Guidance. The Management of Lower Urinary Tract Symptoms in Men (Clinical Guideline 97.). London, UK: Royal College of Physicians, 2010. [PubMed] [Google Scholar]
- [28].Rowant D, James ED, Kramer AEJL, et al. Urodynamic equipment: technical aspects: produced by the international continence society working party on urodynamic equipment. J Med Eng Technol. 1987;11:57–64. [DOI] [PubMed] [Google Scholar]
- [29].Grino PB, Bruskewitz R, Blaivas JG, et al. Maximum urinary flow rate by uroflowmetry: automatic or visual interpretation. J Urol. 1993;149:339–41. [DOI] [PubMed] [Google Scholar]
- [30].Witjes WPJ, De La Rosette J, Zerbib M, et al. Computerized artifact detection and correction of uroflow curves: towards a more consistent quantitative assessment of maximum flow. Eur Urol. 1998;33:54–63. [DOI] [PubMed] [Google Scholar]
- [31].Rittmaster RS, Norman RW, Thomas LN, et al. Evidence for atrophy and apoptosis in the prostates of men given finasteride. J Clin Endocrinol Metab. 1996;81:814–9. [DOI] [PubMed] [Google Scholar]
- [32].Lepor H, Williford WO, Barry MJ, et al. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. N Engl J Med. 1996;335:533–9. [DOI] [PubMed] [Google Scholar]
- [33].Kirby RS, Roehrborn C, Boyle P, et al. Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) trial. Urology. 2003;61:119–26. [DOI] [PubMed] [Google Scholar]
- [34].Andersen JT, Ekman P, Wolf H, et al. Can finasteride reverse the progress of benign prostatic hyperplasia? A two-year placebo-controlled study. Urology. 1995;46:631–7. [DOI] [PubMed] [Google Scholar]
- [35].Nickel JC, Fradet Y, Boake RC, et al. Efficacy and safety of finasteride therapy for benign prostatic hyperplasia: results of a 2-year randomized controlled trial (the PROSPECT study). PROscar Safety Plus Efficacy Canadian Two year Study. CMAJ. 1996;155:1251–9. [PMC free article] [PubMed] [Google Scholar]
- [36].McConnell JD, Bruskewitz R, Walsh P, et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med. 1998;338:557–63. [DOI] [PubMed] [Google Scholar]
- [37].Marberger MJ, Group PS. Long-term effects of finasteride in patients with benign prostatic hyperplasia: a double-blind, placebo-controlled, multicenter study. Urology. 1998;51:677–86. [DOI] [PubMed] [Google Scholar]
- [38].Roehrborn CG, Boyle P, Nickel JC, et al. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology. 2002;60:434–41. [DOI] [PubMed] [Google Scholar]
- [39].Roehrborn CG, Siami P, Barkin J, et al. The effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the CombAT study. J Urol. 2008;179:616–21; discussion 621. [DOI] [PubMed] [Google Scholar]
- [40].Roehrborn CG, Siami P, Barkin J, et al. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study. Eur Urol. 2010;57:123–31. [DOI] [PubMed] [Google Scholar]
- [41].Roehrborn CG. BPH progression: concept and key learning from MTOPS, ALTESS, COMBAT, and ALF-ONE. BJU Int. 2008;101:17–21. [DOI] [PubMed] [Google Scholar]
- [42].Emberton M, Andriole GL, De La Rosette J, et al. Benign prostatic hyperplasia: a progressive disease of aging men. Urology. 2003;61:267–73. [DOI] [PubMed] [Google Scholar]
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