Does the addition of Serenoa repens to tamsulosin improve its therapeutical efficacy in benign prostatic hyperplasia ?

Background/Aim. It has been observed that a large number of patients with low urinary tract symptoms due to benign prostatic hyperplasia (LUTS/BPH)) has been treated with a combination of tamsulosin (TAM) + Serenoa repens (SR) (TAM + SR). The aim of this study was to compare a combination TAM + SR with TAM and SR alone, to see if there was any difference in efficacy and tolerance of each in patients with LUTS/BPH. Methods. In this prospective study patients had to have prostate volume (PV) < 50 mL, International Prostate Symptom Score (IPSS) of 7–18, Quality of Life score (QoLs) > 3, a maximal flow rate (Qmax) of 5–15 mL/s, with post voiding residual volume (PVR) < 150 mL and serum prostatic antigen (PSA) < 4 ng/mL. TAM (0.4 mg) was administered once a day, SR (320 mg) daily or SR (320 mg) + TAM (0.4 mg) daily for a median period of 6 months. Results. A total of 297 patients were recruited, whereas 265 patients were fully available: 87 into the group TAM, 97 into the group SR and 81 into the group TAM + SR. There was no statistically significant difference between the treatment groups in the sense of demographic and other baseline parameters. No difference was found among the 3 treatment groups, neither in the major endpoint of the study in the sense of a change between baseline and final evaluation in total IPSS, obstructive and irritative subscores, improvement of QoLs, increase in Qmax, nor for the second endpoint including diminution of PV, PSA and PVR. During the treatment period 20 (23%) of the patients managed with TAM and 17 (21%) with TAM + SR had drugtreated with related adverse reactions. No adverse effect was detected in the group SR. Conclusion. Treatment of BPH by both SR and TAM seems to be efficacious alone. None of them had superiority over another and, additionally, a combined therapy (TAM + SR) does not provide extra benefits. Furthermore, SR is a well-tolerated agent that can be used alternatively in the treatment of LUTS/BPH.


Introduction
Low urinary tract symptoms (LUTS) are frequently associated with benign prostatic hyperplasia (BPH) caused by cellular hyperplasia of both glandular and stromal elements.With an aging population the number of men affected by BPH is likely to increase 1,2 .Symptoms severity appears to be dependent, at least in part, on smooth muscle tone in the prostate and bladder neck ³.Since medical inhibitors, including alpha-blockers (ABs) 4 , alpha-reductase inhibitors (5-ARIs) and phytotherapeutic agents offer an attractive alternative to surgery, the number of transurethral resections of the prostate has declined in recent years 5,6 .However, the tolerability of these agents varies.Some ABs are associated with cardiovascular adverse events (AEs) (postural hypotension, dizziness, and headache) and 5-ARIs can lead to sexual dysfunction 7 .Conversely, a drug with high affinity for alpha 1A-adrenoreceptors (tamsulosin) (TAM) may be more prostate specific and may maintain the therapeutic response in the treatment of symptomatic BPH with less effect on blood pressure and fewer cardiovascular AEs 8 .In selected patients, a combination of AB and 5-ARI is the most effective form of BPH medical therapy to reduce the risk of clinical progression, i.e. acute urinary retention (AUR) and BPHrelated surgery 9 .On the other hand, increasing attention has been focused on the use of phytotherapeutic agents to alleviate the symptoms of BPH.The most described and studied phytotherapeutic agent for the medical treatment of BPH is etahnolic extract of Serenoa repens (SR) (Sabal serrulata) derived from the berry of the American dwarf palm tree [10][11][12] .The antiandrogenic, antiproliferative and anti-inflammatory complementary activities of SR extracts could constitute an advantage over ABs to treated symptomatic BPH where both "obstruction" and "irritation" are involved.
The aim of this prospective pilot study was to test the hypothesis that the efficacy of combination TAM + SR is superior to TAM and SR alone for the relief of LUTS/BPH.The main endpoints of the study were changes in the total International Prostate Symptom Score (IPSS), Quality of a life score (QoLs), maximal flow rate (Qmax) and post voiding residual volume (PVR) from baseline to the last observation carried forward.This was applied only in naive patients suffering from LUTS/BPH without previous treatment with ABs, 5-ARIs or phytotherapy.

Methods
Between June 2008 and September 2010, 297 men aged 50-87 years, with symptomatic BPH were included in the study containing 3 regimens: TAM (Tamsol ® ) 0.4 mg daily (n = 98), SR (Prostamol uno ® ) and TAM 0.4 mg + SR 320 mg daily (n = 92), to compare the efficacy of each of these treatment regimens.All the patients signed informed consent form before any treatment.Pre-treatment procedures consisted of collection of the medical history (including urologic history), check of concomitant medications, physical examination [including digital rectal examination (DRE)], routine laboratory tests [urine analysis, urine culture, creatinine, prostate specific antigen (PSA)], total IPSS, irritative and obstructive subscores, QoLs, prostate volumen (PV), Qmax and PVR.The study was specially designed for medical treatment of patients suffering from low risk of AUR and BPH-related surgery.Inclusion criteria were men > 50 years of age, a total IPSS of 7-18, QoLs >3, Qmax of 5-15 mL/s, with PVR < 150 mL, PV < 50 mL, measured by transrectal ultrasound (TRUS) and serum PSA 1.5-4 ng/mL.TRUSguided biopsies of the prostate were performed in patients with PSA > 4 ng/mL, abnormal DRE, and/or suspicious echogenicity on TRUS.The subjects with a significant bladder outlet obstruction (BOO) were excluded a priori from the study (PVR > 200 mL, Qmax < 5 mL/s).Patients were excluded from the study if they had the history of bladder disease likely to affect micturition, urethral stenosis, prostate and/or bladder cancer, bladder stone, previous pelvic radiotherapy, recurrent urinary retention, neurogenic lower urinary tract dysfunction, repeated infection of the urinary tract, chronic bacterial prostatitis, or any other disease that can cause urinary problems.Assessment visits were performed head to head and were scheduled at randomization (day 0), and latter at months 3 and 6.PV and PSA were measured at selection and at endpoint, whereas the total IPSS, obstructive and irritative subscore, Qols, Qmax and PVR were evaluated at baseline and later every 3 months.Responders were defined on the basis of IPSS and Qmax by decrease of > 25% and increase of > 30% from baseline, respectively.The patients without subjective and objective improvement were rejected from the study within 3 months from the initiation of the treatment, after both patients and physicians had agreed about that.
The Kruskal-Wallis test was used for comparison of the groups and the Wilcoxon signed-rank test for analysis of the baseline and a 6-month treatment parameters.A p value < 0.05 was considered statistically significant.Data processing was done by SPSS package for Windows version 11.0.

Results
A total of 87, 97 and 81 patients were fully available regarding the treatment regimen, according to TAM, SR and TAM + SR, respectively.The main reason for study discontinuation was voluntary withdrawal (1.3%), protocol violation (2.4%), lack of efficacy (3.03%) and other reasons (2.7%).Four (1.3%) patients were lost to follow-up (Table 1).
The treatment groups had comparable distribution in terms of age, body mass index, a total IPSS, irritative and obstructive subscores, QoLs, Qmax, PVR, PV and PSA (Table 2).The mean age was 64.9 ± 7.6 years.
After 6 months of the treatment, the mean decrease in IPSS was -4.6, -6.1 and -4.9 in the TAM, SR and TAM + SR groups respectively.The difference between IPSS values at baseline and 6 months later were significant in each group (p < 0.05).The patients in the group SR had a greater reduction in symptoms than the other group.However, statistical analysis did not reveal this expected difference between the treatment regimens (p = 0.1).This difference between the groups in the mean total IPSS decrease was not observed in the irritative part -1.7, -1.8 and -1.9 (p = 0.6) and the obstructive part -1.5, -1.4 and -1.3 (p = 0.5), for TAM, SR and TAM + SR, respectively.For the QoLs, the group TAM had an initial mean score of 3.5, which decreased for 2.1; the group SR 4.2 which decreased to 2.6; the group TAM + SR had the initial mean score of 3.5 which decreased for 2.2 after 6 months.The 3 groups had lower mean score after the treatment but the difference was not significant (p = 0.1).Six months following the treatment, the mean increase in Qmax was similar in both TAM and SR group (3.7 mL/s for TAM, 3.2 mL/s for SR), but was slightly greater in the group TAM + SR (4.2 mL/s).The patients in each group improved flow rates and the difference between the Qmax values at baseline and 6 months later was statistical significance in each group (p < 0.005), although the difference was not statistically significant among groups with regard to increase in Qmax values (p = 0.3).The improvement of PVR volume was not statistically different among the groups which decreased by 29.6, 28.1 and 25.4 mL, respectively (p = 0.4).Six months following the treatment the mean PV had decreased by 1.0, 0.7 and 0.8 mL, respectively.The difference was not significant (p = 0.6).The decrease in PSA was more pronounced in the groups SR, but the difference was not statistically significant (p = 0.25) (Table 3).At endpoint, the percentage of patients negatively affected by urinary symptoms (feeling mostly dissatisfied, unhappy, and terrible) was reduced by > 50% in the groups TAM, SR and TAM + SR (from 66.7% to 34.5%, from 63.1% to 34.7% and from 64.2% to 22.7%, respectively) (p < 0.001) (Table 4).
During a 6-month treatment period, 20 (23%) of the patients managed with TAM and 17 (21%) patients with TAM + SR, had some degree of drug related AEs.For most of these patients (79%) the AEs were mild.The most frequently reported AEs were reduced or absent ejaculations during orgasm and a headache.The mean improvement of total IPSS was greater in the men experiencing ejaculatory disorders (10.7%) than in those who did not (-7.3 ± 3.3 vs -6.1 ± 2.3) (p = 0.04) but not regarding Qmax (-4.0 ± 2.3 vs -3.4 ± 2.5) (p = 0.07).A headache was reported by a slightly higher percentage of subjects in the group TAM + SR (6.1%) compared to the group TAM (5.9%), but without statistically significant difference.However, these AEs did not result in withdrawal from the study.No AE, were detected in the group SR (Table 5).

Discussion
The use of phytotherapy in treating LUTS/BPH has been popular in Europe for many years and has recently spread in the USA.In some studies the efficacy of SR was found to be equivalent to 5-ARI and Abs ¹² , ¹³.However, recently updated Cochrane report summarized the clinical results of 30 randomized trials comprising 5.222 men.SR was compared as mono or combination preparations either with placebo, other plant extracts (Pygeum africanum, Ustica di-oica), the 5-ARI (finasteride), or AB (TAM).The mean follow-up of these trials varied between 4 and 60 weeks.The Cochrane report concluded that SR was not superior to placebo, finasteride, or TAM with regard to IPSS improvement, increase in Qmax or prostate size reduction.For nocturia SR was significantly better than placebo (mean weight difference -0.78) 14 .
Direct comparative randomized controlled trials have shown the superior efficacy of ABs over placebo, whereas the combination of 5-ARI and an AB was more effective than the AB alone 15 .Although the combination of an AB and SR was frequently used in some European countries, including Serbia, at the time of preparing this study, its superior efficacy over AB and SR alone had not been fully investigated.Therefore, this question was addressed to direct comparative trial.
The results of our study demonstrate that TAM and SR are equivalent to a combination TAM + SR in the management of these patients.After 6 months, all the treatment groups induced practically the same mean reduction in total IPSS (-4.6 vs -6.1 vs -4.9 points) with 2/3 of men responding to the treatment by a decrease of 3 points or more.For all the treatment groups the mean percentage change from baseline and after 6-months was similar (28.4% for TAM, 33.9% for SR and 31.4% for TAM + SR).This data correlates with the results reported in other series 14,16 .However, the difference in total IPSS in TAM vs the group TAM + SR was slightly higher in the study of Glemain et al. 17 (-5.2vs -6.0).The greatest improvement in total IPSS was observed in those patients with greatest severity of disease 18 .No differences were observed among the treatment groups from baseline to  endpoint of the study in terms of irritative and obstructive symptoms, corresponding with data providing from other studies 16,17 .We reported the improvement in QoLs of -2.1, -2.6 and -2.2 in each group.However, the improvement of QoLs was lower for TAM vs TAM + SR, -1.0 vs -1.3, in the study reported by Glemain et al. 17 .
In the present study, the mean increase in Qmax (3.7 mL/s, 3.2mL/s and 4.2 mL/s) strongly correlates with data providing from Hizli and Uygur 16 , whereas mean changes of 1.3mL/s (TAM) and 1.2mL/s (TAM+SR) are reported in other study 17 .
Limited studies have evaluated PVR in measuring the response to treatment 16 .We measured PVR to assess the efficacy of treatment regimens and found a mean decrease of 23.6 mL, 28.1 mL and 25.4 mL, respectively.
We found that the addition of SR has no significant effect on PSA levels, consistent with earlier results 19 .In fact, decreasing PSA would not be a desire result of a BPH medication, because it may mask or delay the detection of prostatic carcinoma.This is in contrast with 5-ARI 15 .
PV was found to be decreased by SR in 3 uncontrolled stdies [20][21][22] , but this was not confirmed in controlled studies 10,11 .We found the mean decrease in PV of -1.0 mL, -0.7 mL and 0.8 mL for the groups TAM, SR and TAM + SR, respectively, but they were not statistically significant.TAM efficacy does not depend on prostate size and is similar across age group.However, TAM does not reduce prostate size 23 .
The occurrence of AEs was similar in the groups TAM and TAM + SR (23% vs 21%).Retrograde ejaculation was the most common TAM related AE (10.7%).The mean improvement of IPSS was greater in the men experiencing this AE than in the men who did not.For the older BPH patients who experienced retrograde ejaculation, it might be a small trade for the rapid and significant relief of urinary symptoms that treatment with TAM offered.Retrograde ejaculation is a characteristic AE of ABs with the occurrence in 4%-11% of patients and that has been shown to be reversible after administration of the drug has been stopped 24 .In short, our results confirm that AEs are commonly associated with TAM, whereas SR is a well-tolerated agent used for LUTS/BPH.
The best of our knowledge shows that only one study has compared TAM and SR alone with combination of TAM +S R in treatment of LUTS/BPH 16,17 .The number of 60 pa-tients included in this study (20 in each group) with followup of 6 months, is too small to be absolutely confident about these results.The OCOS trial included 329 patients managed with TAM (n = 161) and TAM + SR (n = 168) with the mean follow-up of 52 weeks.No statistically significant difference was found between these groups, neither for the change in IPSS between the baseline and final evaluation, nor for the improvement of the irritative and obstructive subscore, QoLs and Qmax.However, the group SR was not included in this study 17 .
Although the efficacy of the 3 treatment groups can only be reliably determined with placebo-controlled studies, clinically relevant information can still be gained from comparative trials, and for this reason a placebo group was not included in the present study.The follow-up was relatively short (6 months) in comparison to 12 months in other trials 11,14,17 .There is also a financial implication with the use of SR because reimbursement of cost by health insurance in Europe, including Serbia, is not contemplated.However, trials exploring efficacy of new AB silodosin have a followup of only 3 months 25,26 .We investigate currently the combination of AB with phytotherapeutical agent isoflavone extracted from red clover (trifolium pretense) during the treatment period of 3 months in patients with mild and moderate symptomatic BPH.
Overall, it appears that phytotherapy with SR is as valid pharmacotherapy as Abs in management of men with LUTS/BPH.Indeed, it may have less adverse effects and be better tolerated.What is certain is that urologist should be aware and informed about phytotherapy as it inevitably becomes part of the standard medical therapy for men with LUTS/BPH.

Conclusion
We find that treatment of BPH with both TAM and SR alone seems to be equally effective in reducing urinary obstruction, in proving symptomatology and QoLs, whereas a combined therapy (TAM + SR) does not provide extra benefits.Furthermore, SR is a well-tolerated agent that can be used alternatively in treatment of LUTS/BPH.The limitation of our study is a relatively short follow-up.Large prospective randomized studies with longer follow-up periods are needed to clarify more the efficacy of SR in treatment of BPH.

Table 3 Mean changes and ameliration rate in efficacy parameters from baseline to endpoint of the study
SD-standard deviation, TAM -tamsulosin; SR -Serenoa repens; IPPS -International Prostate Symptom Score; QoL -Quality of life; Qmax -maximal flow rate; PVR -post-voiding residual volume; PV -prostate volume; PSA -prostate specific antigen.

Table 1 Reasons for premature discontinuation per the treatment group
TAM -tamsulosin; SR -Serenoa repens; n -number of patients.

Table 4 Summary of quality of life scores related to urinary simptoms
n -number of patients; TAM -tamsulosin.