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Improving bph symptoms and sexual dysfunctions with a saw palmetto preparation? results from a pilot trialPHYTOTHERAPY RESEARCHPhytother. Res. (2012)Published online in Wiley Online Library(wileyonlinelibrary.com) DOI: 10.1002/ptr.4696 Improving BPH symptoms and sexualdysfunctions with a saw palmetto preparation?Results from a pilot trial Andreas Suter,1,4* Reinhard Saller,2 Eugen Riedi3 and Michael Heinrich41Medical Department, A. Vogel Bioforce AG, Roggwil, Switzerland2Institute of Natural Medicine, Zurich University Hospital, Zurich, Switzerland3Urological practice, Chur, Switzerland4School of Pharmacy, University of London, University College London, London, United Kingdom In elderly men, benign prostatic hyperplasia (BPH) is a major risk factor for sexual dysfunctions (SDys).
Additionally, the standard treatments for BPH symptoms, alpha blockers and 5-alpha-reductase inhibitors, causeSDys themselves. Preparations from saw palmetto berries are an efﬁcacious and well-tolerated symptomatictreatment for mild to moderate BPH and have traditionally been used to treat SDys. We conducted an openmulticentric clinical pilot trial to investigate whether the saw palmetto berry preparation ProstasanW inﬂuencedBPH symptoms and SDys. Eighty-two patients participated in the 8-week trial, taking one capsule of 320 mg sawpalmetto extract daily. At the end of the treatment, the International Prostate Symptom Score was reduced from14.4 Æ 4.7 to 6.9 Æ 5.2 (p < 0.0001); SDys measured with the brief Sexual Function Inventory improved from22.4 Æ 7.2 to 31.4 Æ 9.2 (p < 0.0001), and the Urolife BPH QoL-9 total improved from 162.7 Æ 47.9 to105.0 Æ 56.3 (p < 0.0001). Investigators’ and patients’ assessments conﬁrmed the good efﬁcacy, and treatmentwas very well tolerated and accepted by the patients. Correlation analyses conﬁrmed the relationship betweenimproved BPH symptoms and reduced SDys. This was the ﬁrst trial with saw palmetto to show improvementin BPH symptoms and SDys as well. Copyright 2012 John Wiley & Sons, Ltd.
Keywords: benign prostatic hyperplasia; sexual dysfunctions; clinical trial; saw palmetto; Serenoa repens.
and clinically signiﬁcant association between LUTS and various types of sexual dysfunctions in ageing menworldwide. From epidemiological data, Rosen et al.
The prostate is a ﬁbromuscular glandular organ that lies (2005) concluded that, compared with patients without between the urinary bladder and the pelvic ﬂoor and BPH-symptoms, patients with BPH-symptoms were at surrounds the prostatic urethra (Dixon, 2005). Starting a 3.7-fold higher risk of developing erectile dysfunction around the age of 40, the prostatic tissue enclosing the during the 2-year period following the onset of BPH- urethra starts growing; this nonmalignant growth is symptoms. Additionally, the severity of the LUTS known as benign prostate hyperplasia (BPH) (Isaacs symptoms was correlated with more frequent and more and Coffey, 1989). It leads to constriction of the severe occurrence of erectile and ejaculatory dysfunctions urethra and gives rise to associated lower urinary tract symptoms (LUTS), such as urgency, frequency, noc- The main medical treatments for BPH symptoms turia, incomplete bladder emptying and weak urine include alpha blockers such as tamsulosin, doxazosin stream. LUTS occur in about one third of all men in and alfuzosin (Novara et al., 2006) that provide fast their 60s and half of men older than 80 (McVary, relief of the LUTS symptoms (Kaplan, 2004) or the 2006), even though the histological presence of BPH is 5-alpha-reductase-inhibitors ﬁnasteride and dutasteride, observed in more than 90% of men in this age group which lead to symptom relief after 6–9 months and are most favourable in patients with large prostates (Dull In addition to obstructive and irritative symptoms, et al., 2002). Both treatment options show beneﬁcial BPH also negatively inﬂuences sexual functions (Gur effects on the BPH symptoms; however, they also each et al., 2008). Epidemiological studies show that, along have a signiﬁcant negative impact on sexual functions.
with the general ageing process, BPH-related LUTS The main sexual dysfunction reported under alpha are a key factor in development of erectile dysfunctions blocker therapy is retrograde or abnormal ejaculation, and ejaculatory disorders (Braun et al., 2003; Boyle which occurs in 4–18% of patients taking tamsulosin, with et al., 2004), representing a stronger risk factor than rise to 30% during long-term use (Carbone and Hodges, diabetes, hypertension, heart disease or hyperlipidemia 2003). Studies on 5-alpha-reductase inhibitors report (Rosen et al., 2003). Overall, there appears to be a clear sexual dysfunctions with a frequency of 2.1–38%,with erectile dysfunctions being most prominent, followedby decreased libido and ejaculatory disorders (Erdemir * Correspondence to: Andreas Suter, A. Vogel Bioforce AG, MedicalDepartment, Roggwil, Switzerland.
et al., 2008). Sexual dysfunctions are the most often reported adverse events under 5-alpha-reductase- Copyright 2012 John Wiley & Sons, Ltd.
inhibition, with similar frequencies reported for ﬁnasteride willingness to honestly answer questions on sexuality and dutasteride (Naslund and Miner, 2007).
and written informed consent given by the patient.
Preparations made from the berries of saw palmetto Exclusion criteria included lack of libido because of a Serenoa repens (W. Bartram) Small (synonym Sabal psychiatric disease or a depressive mood, occurrence of serrulata (Michx.) Schult.f.) have a long standing use in lack of libido in the judgement of the investigator within the treatment of mild to moderate BPH symptoms.
the last 2 months, patients with severe vascular disorders The plant, which is indigenous to Florida, was ﬁrst used (microangiopathies), severe diabetes mellitus, patients by white settlers in the United States not only for treat- with hypertension who were on a stable antihypertensive ment of LUTS but, interestingly, also as a treatment for medication for less than 2 months, known neuropathies, erectile dysfunctions, to improve testicular atrophy and known poor compliance of the patient, participation in sperm production, and as a genitourinary and sexual a clinical trial within the last 2 months prior to the study stimulant (Bennett and Hicklin, 1998). More than 30 start, alcohol and drug abuse and planned surgeries controlled clinical trials have been conducted to investi- within the observation period. The participants were gate BPH treatment with saw palmetto preparations, prohibited from regular application (>1 unit/2 weeks) of which generally consist of 320 mg lipophilic berry phosphodiesterase-5-phosphodiesterase-5-inhibitors (PDE) extract per day (Ulbricht et al., 2006). Compared with inhibitors and intake of PDE-5-inhibitors less than 4 days placebo, the studies demonstrate good efﬁcacy of long- prior to the ﬁrst study visit. If not taken continuously for term saw palmetto use to treat BPH symptoms; the 3 months as stable medication, the following concomitant results are similar to ﬁnasteride (Carraro et al., 1996) medications were also not allowed: 5-alpha-reductase in- and tamsulosin (Debruyne et al., 2004), but saw hibitors, alpha-antagonists, nonsteroidal anti-inﬂammatory palmetto has a much better safety proﬁle than these drugs (NSAIDs) (synthetics and phytochemicals), para- substances particularly in regards to sexual dysfunctions cetamol and synthetic antidepressive agents.
(Wilt et al., 2002). As modes of action, in vitro andin vivo inhibition of both isoforms of the 5-alpha-reductase (Habib et al., 2005; Abe et al., 2009) and anti-inﬂammatory activities (Breu et al., 1992; Iglesias-Gato et al., 2011) have been reported, as well as This was an open clinical trial with total study duration inhibition of autonomous receptors in the lower urinary of 9 weeks per patient, which consisted of a 1-week untreated run-in phase and a subsequent treatment It is very desirable to ﬁnd a treatment that not only period of 8 weeks. At each visit, efﬁcacy parameters improves the symptoms of BPH but also has no negative were recorded as detailed in the succeeding text. The or possibly even a beneﬁcial impact on sexual dysfunctions run-in phase was carried out to observe if BPH (Skolarus and Wei, 2009). With this as a goal, we carried symptoms and sexual dysfunctions remained stable.
out a clinical pilot trial investigating whether a standar- The test medication was a lipophilic saw palmetto berry dized saw palmetto product inﬂuenced sexual dysfunctions extract with a daily dosage of one capsule, containing in patients with mild to moderate BPH.
320 mg extract (ProstasanW, batch nr. 025070, drugextractant ratio 9–12 : 1, extractant ethanol 96% V/V;manufactured by A. Vogel Bioforce AG, Roggwil,Switzerland. The berries are from A. Vogel Bioforce’sown organic certiﬁed cultivation in Florida, USA.) The extract complied with the provisions of the EuropeanPharmacopoeia for saw palmetto fruit. One capsule of this batch contained 275 mg fatty acids, which comprisedof 29.5% lauric acid, 39.2% oleic and linoleic acid, The study was carried out between June 2009 and 13.5% myristic acid and 10% palmitic acid.
October 2010 in two urological and four general At the second visit, each patient received one bottle practices in Switzerland, in patients with at least moder- with 90 capsules and compliance was checked by count- ate BPH symptoms and sexual dysfunctions, such as ing the remaining tablets at the ﬁnal study visit.
erectile dysfunctions or lack of drive. The trial was Changes in BPH symptoms were evaluated using the approved by the relevant cantonal ethical committees IPSS, sexual dysfunctions with the bSFI and the Urolife and was carried out in accordance with the provisions BPH Quality of Life-9 (Urolife QoL-9) questionnaire.
of good clinical practice and the ethical obligations of The bSFI is a validated instrument with two questions the Declaration of Helsinki. The Swiss regulatory about sexual drive, three on erections, two on ejacula- authority Swissmedic notiﬁed the study that is registered tion, four on problem assessment and one question on in the international clinical trial registry ClinicalTrials.
the overall satisfaction. Each question is rated on a gov, identiﬁer number NCT01021267.
corresponding scale from 0 (most severe problem) to 4 Inclusion criteria were as follows: male patients (no problem) (O’Leary et al., 1995). The Urolife QoL-9 between 18–80 years of age with International Prostate questionnaire is also a validated score with one question Symptom Score (IPSS) >7, presence of BPH symptoms each on desire, erection and satisfaction; each is rated on for at least 2 months, patients suffering from sexual a 100 mm visual analogue scale, ranging from 0 (most dysfunction (erectile dysfunction and/or decrease of severe problem) to 100 (no problem at all) (Lukacs libido) for at least 2 months, sexual drive component et al., 1997). Two questionnaires were used instead of of the brief Sexual Function Inventory (bSFI) <5, only one to achieve a better validity of changes in sexual desire and possibility of sexual activity (masturbation, dysfunctions. No validated German version was avail- sexual partnership), no organic impairment preventing able for either questionnaire, and thus they were ﬁrst sexual practice (physical or vascular impairment, etc.), translated to German by two independent translators.
Copyright 2012 John Wiley & Sons, Ltd.
SAW PALMETTO IN BPH AND SEXUAL DYSFUNCTIONS From these two translated versions, one German version Table 1. Demographic baseline characteristics of the per protocol was compiled, which was then re-translated to English by two other translators, to be compared with the originalversion. The German version was then corrected and used by a German speaking doctor in his daily practice.
Based on his experiences, further corrections were made, and ﬁnal versions of the German scores were completed. At end of the treatment, global assessment of efﬁcacy by the patient and the investigator was given on a 4-point scale (very good, good, moderate or bad).
Safety parameters included the occurrence of adverse events and the global assessment of safety by the patient and the investigator at the end of the treatment as very good, good, moderate or poor. Additionally, questions were asked about the patients’ daily routines. The patients were asked if they would take the medication again, how important it was for them to use herbaltreatment, and whether they would prefer a herbal remedy during the treatment period was assessed as good when over a synthetic compound. Investigators were asked 80–120% of the test medication was taken; 78.6% of the if they would use the test medication again and were patients fulﬁlled this criterion, only 7.1% of the patients asked to provide reasons if they answered afﬁrmatively.
took less than 80% of the medication.
As this was an open clinical pilot trial, descriptive statistics There were no signiﬁcant differences between the were used using Excel (Microsoft Corporation, Redmond, intention to treat population and the per protocol popu- Washington, USA) and SAS Version 9.2 (SAS Institute, lation in all parameters; therefore, the results of per Enhanced Logging Facilities, Cary, NC, USA). For the protocol population will be shown. There were also no outcome measures, IPSS, bSFI and Urolife QoL, within statistical changes in the efﬁcacy parameters during the group comparisons of changes from visit 1 to visit 2, from time period without treatment (between visit 1 and visit visit 1 to visit 3, and from visit 2 to visit 3, were performed 2), showing that the symptoms were stable and did not using the Wilcoxon test for paired differences. Correla- alter within a short time frame; thus, only results from tions between changes in IPSS and bSFI, IPSS and Urolife visit 2 (the start of treatment) and visit 3 (the end of QoL-9, and bSFI and Urolife QoL-9 were analysed by calculating Pearson’s coefﬁcient of correlation.
The IPSS was reduced by 51%, from 14.4 Æ 4.7 to6.9 Æ 5.2, after 8 weeks of treatment (p < 0.0001) (Fig. 1).
A score from 0 to 7 is deﬁned as mild, from 8 to 19 as moderate and from 20 to 35 as severe BPH symptoms.
A total of 82 patients were recruited, forming the At the beginning of the treatment, 18.8% of all patients intention-to-treat population. Thirteen patients had at had severe and 78.3% had moderate symptoms; by the least one major protocol deviation and were excluded ﬁnal visit, this shifted to 63.8% patients with mild, 31.9% from the per protocol population, which was used for with moderate, and only 4.3% with severe symptoms.
ﬁnal analysis. Deviations included one patient with IPSS Looking at the single items contributing to the score, <7 at inclusion, one with sexual drive component of they were all signiﬁcantly improved to the same extent, bSFI >5 at inclusion, four patients with disallowedconcomitant medication and seven patients who didnot return to the participating practice after the ﬁrstvisit. Reasons for discontinuation of treatment includedone instance of the death of a patient’s wife, two adverseevents (nausea that was seen as related to the studymedication and an unrelated transient ischemic attack)and in four cases the patients did not show up at all tothe follow-up visits. The patients were 57.3 Æ 11.1 yearsold and baseline characteristics as well as the agedistribution in the population were without pathological ﬁndings. Details are shown in Table 1.
One centre recruited the majority of the patients (n = 54), and the other ﬁve centres the remaining 15patients. The baseline characteristics of the patients Figure 1. Change of International Prostate Symptom Score (IPSS) from this one centre did not differ signiﬁcantly between the start and the end of treatment (per protocol population, from those that form the other centres. Compliance Copyright 2012 John Wiley & Sons, Ltd.
and none was superior to another. The average nycturia the single centre experienced at least some improve- score changed from 1.7 Æ 1.1 to 1.0 Æ 0.8, the obstructive subscore from 8.1 Æ to 3.9 to 3.7 Æ 3.7, and the irritativesubscore from 6.3 Æ 2.6 to 3.2 Æ 2.3.
The Urolife QoL-9 total score saw an improvement from 162.7 Æ 47.9 to 105.0 Æ 56.3 (p < 0.0001) (Fig. 3).
Contrary to the bSFI, the improvements in QoL-9 were The total bSFI score improved from 22.4 Æ 7.2 to signiﬁcant at all centres. All three single questions were 31.4 Æ 9.2 (p < 0.0001) (Fig. 2). The single item scores also statistically signiﬁcantly improved, as detailed in for sexual drive, erectile function, ejaculatory function, problem assessment and sexual satisfaction were eachalso signiﬁcantly improved (p < 0.0001) (Table 2). Thebiggest relative improvements in single questions wereseen in the problem assessment domain, where ‘getting Assessments by investigators and patients and keeping an erection’ improved by 64%, and ‘havingproblems with lack of drive’ and ‘ejaculation’ each The majority of the patients rated the efﬁcacy as improved by 54%. ‘Feeling sexual drive within the last very good (22%) or good (54%) and only 15% saw a 30 days’ improved by 47%, and ‘having an erection ﬁrm small effect. The investigators assessed efﬁcacy more enough to have sexual intercourse’ was scored as 42% favourably, reporting 38% of the cases as being very better, which, in absolute values, is a change from below good, 44% good and only 7% patients with unchanged ‘fairly often’ to ‘usually’.
condition. When asked on what parameters the study There was a centre effect, as mean values of the medication had the best effect, 8% of the patients indi- centre with the most patients exhibited a signiﬁcant cated erectile function, 26% libido and 66% erectile improvement, whereas the other 15 patients pooled together from the other centres only exhibited a trend Of the total 82 patients, 62 patients would take the (p = 0.12). Of these 15 patients, eight saw an improve- capsules again (data are missing from six patients); and ment, four no change and three a worsening of their in 91% of all cases, the investigators would use the state, whereas the vast majority of the patients from Figure 2. Improvement of brief Sexual Function Inventory (bSFI) at Figure 3. Improvement of the Urolife benign prostate hyperplasia the start and the end of therapy (per protocol population, n = 69; (BPH) quality of life-9 (QoL-9) total score between the start and the end of therapy (per protocol population, n = 69; p < 0.0001).
Table 2. Single item scores of the bSFI and Urolife BPH QoL BPH, benign prostate hyperplasia; bSFI, brief sexual function inventory.
Copyright 2012 John Wiley & Sons, Ltd.
SAW PALMETTO IN BPH AND SEXUAL DYSFUNCTIONS Similarly, investigators regarded tolerability in 90.8%of the cases as very good and 5.3% as good.
In this pilot trial, we wanted to assess if a saw palmettoberry preparation had an inﬂuence on both, prostatesymptoms and sexual dysfunctions. We ﬁrst examinedthe improvement in BPH symptoms as measured withthe IPSS, which is the standard instrument to measureseverity of BPH symptoms (Simpson, 1997). Weobserved a greater than 50% reduction, indicating agood treatment response that was in the efﬁcacy rangeobserved for saw palmetto treatments in other trials on Figure 4. Single item scores of the brief Sexual Function Inventory BPH and larger than the effect of placebo. A survey of (bSFI) at the start and the end of treatment, normalized to a scale seven clinical trials for a lipophilic saw palmetto prepar- of 0–10 (0 = worst state, 10 = best) (n = 69).
ation describes the observation of a total of 2555patients that were observed with average treatment For 61% of the patients, it was very important that duration of 300 days and a mean initial IPSS value of the medication was of herbal origin and 97% of them 14.72. At the end of the treatment, IPSS was reduced would, given the same efﬁcacy and safety, prefer herbal to a synthetic drug. Investigators stated that the most clinical trials, 320 mg lipophilic saw palmetto berry important reason to apply this saw palmetto preparation extract was used daily and, after 6 months, the IPSS was the good safety observed in 95% of all cases, followed by the efﬁcacy observed in 93% of patients.
(Bauer et al., 1999) with respective reductions underplacebo of 13.9% and 13.6%.
Secondly and more importantly, we assessed whether the treatment had a positive inﬂuence on concomitantsexual dysfunctions. Four previous clinical trials of saw We carried out correlation analyses to assess if changes palmetto treatment for BPH also evaluated changes in in IPSS, bSFI and Urolife QoL-9 were associated. There sexual dysfunctions as a secondary parameter, with was a negative correlation between changes in the IPSS mixed results. However, the patients in these trials had score and the bSFI (Pearson’s rho = À0.366; p = 0.002) mainly BPH symptoms, not necessarily sexual dysfunc- and a positive correlation between changes in the IPSS tions (SDys) as well. Using the International Index of Erectile Function (IIEF), Willetts et al. (2003) observed p = 0.002), indicating that less urinary problems were a trend of improvement, with an increase from 51.5 to associated with better assessment of sexual function.
55.1 after 12 weeks of saw palmetto treatment compared Furthermore, there was a high negative correlation with a small decrease from 49.4 to 48.7 with placebo between the bSFI and Urolife QoL-9, showing that both (Willetts et al., 2003), and Sinescu et al. (2011) reported questionnaires were valid for evaluating sexual dysfunc- a signiﬁcant improvement of the IIEF from 44.4 to 50.8 tions and consequently assessed changes to the same after 24 months of treatment (Sinescu et al., 2011). In the degree (Pearson’s rho = À0.607; p < 0.0001).
trial conducted by Gerber et al. (2001), the patients had Subgroup analyses conﬁrmed these ﬁndings, showing to ﬁll out a non-speciﬁed ‘sexual function question- that patients with a higher IPSS at inclusion (IPSS 20–35) naire’; results indicated no change with either placebo exhibited better improvements in their bSFI (p = 0.029) or saw palmetto treatment (Gerber et al., 2001). In an and in their Urolife QoL-9 (p = 0.032) values than did open trial, Bauer et al. (1999) asked if the treatment patients with lower IPSS (8–19). Comparing younger had an inﬂuence on patients ‘sexual activity’; responses patients (21–50 years) to older patients (51–80 years) did indicated that it mostly remained unchanged with two not show a signiﬁcant difference regarding changes of patients reporting an increase (Bauer et al., 1999).
IPSS, bSFI and Urolife QoL-9, or did concomitant Taken together, data from these trials are insufﬁcient medication have an inﬂuence on these parameters.
to convincingly show that saw palmetto had a positiveinﬂuence on BPH-related SDys.
To determine this, it was important to conﬁrm at inclusion that the patients in our trial deﬁnitely sufferedfrom SDys; all the patients in our trial had obvious Five patients reported six adverse events, including SDys, based on comparisons of the initial values from nausea, eructation and acid regurgitation, all of which the bSFI and the Urolife QoL-9 in our trial with were mild in nature and seen as related to the study epidemiological. O’Leary et al. (2003) observed an medication, and two incidents of a transient ischemic average total bSFI score of 27.7 in a population of attack in the same patient and a mild pruritus, which 1883, >50-year-old men in the United States (O’Leary were not related to the study medication. From the total et al., 2003), whereas in our study the same age group 82 patients, data from six patients were missing on the had a lower initial value of 20.1. In another study, the safety assessment; from the remaining patients, 89.5% patients with ages of 36.9 Æ 12.0 years displayed an rated tolerability as very good and 6.6% as good.
average total bSFI of 33.5 Æ 2.2 (Collins et al., 2002) Copyright 2012 John Wiley & Sons, Ltd.
compared with the total initial bSFI of 26.3 Æ 6.6 from 24.9 to 27.14, and subdomains for erection and observed in our 21–50-year-old patients. A large study satisfaction did not change signiﬁcantly (Kim et al., of 2829 LUTS patients with an average age of 65.9 years 2010). In a large open trial with 839 enrolled patients evaluated Urolife QoL-9 scores and found an initial total suffering from LUTS caused by BPH, 10 mg alfuzosin value of 8.8 Æ 0.1 (scale 0–30) (Lukacs et al., 2000), was taken daily for 2 years. The initial IPSS of 15.5 was whereas in our study an initial score of 170.3 Æ 47.0 (scale reduced by 7 points, whereas the total initial bSFI value 0–300) was recorded for the 51–80 year patient group.
of 21.5 improved only slightly during the treatment period, leading to the assessment by the authors that success regarding improvement of SDys in this the treatment at least ‘did not have any deleterious study population. Both scores for SDys changed sig- effect on sexual dysfunctions’ (Elhilali et al., 2006). A niﬁcantly, the bSFI by 40.2% and the Urolife QoL-9 further open clinical trial with 10 mg alfuzosin showed, by 35.5%. Looking at the subscores, ‘sexual drive’ besides a signiﬁcant improvement of the IPSS after and ‘erectile function’, almost the same degree of 1 year of treatment, a signiﬁcant improvement of the improvement was seen for both scores, with 35.3% bother score of the Danish Prostatic Symptom Score and 37% in the bSFI and 33.9% and 36.7% in the questionnaire for sexual dysfunction (van Moorselaar Urolife QoL-9, respectively. The major difference et al., 2005) whereas a study comparing tamsulosin/ between these two scores is caused by the more solifenacin either alone or in combination in patients weighted problem assessment domain of the bSFI. It with LUTS also saw improved IPSS, but observed no has been shown that both questionnaires are equally signiﬁcant changes in the IIEF (Seo et al., 2011). The sensitive in assessing sexual dysfunctions, which was IPSS reductions of about 6 to 7 points found in these also substantiated by the correlation analysis. Inter- studies with alpha-blockers were similar to those estingly, we observed that it was almost impossible observed in placebo-controlled trials (van Kerrebroeck for patients to ﬁll out the bSFI without doctor’s help, et al., 2000; Nordling, 2005), but were not superior to whereas the Urolife QoL-9 was quite easy for the improvements in IPSS seen in our study. This is in patients to ﬁll out alone. In summary, we have shown line with the trials of Debruyne et al. (2004) and Zlotta for the ﬁrst time that a saw palmetto intervention in et al. (2005), which showed similar IPSS reductions patients with BPH and SDys had a beneﬁcial inﬂu- following treatment with a saw palmetto preparation ence on both BPH symptoms and on SDys.
and tamsulosin (Debruyne et al., 2004; Zlotta et al., Our efﬁcacy results are of further importance when 2005). The main difference between our results considering the other available options for simultaneous and those of the cited studies on alpha blockers is treatment of LUTS and SDys. It is currently debated that patients under saw palmetto treatment may whether alpha blockers or PDE inhibitors may be experience an improvement in their SDys, whereas beneﬁcial for treating symptoms of both disorders.
this effect cannot be expected from alpha-blocking Experimental models have shown that a1-adrenergic agents may improve erectile dysfunctions by inﬂuencing It also remains doubtful whether PDE-5 inhibitors the balance between contraction and relaxation of the are a good treatment for both LUTS and SDys corpus cavernosum smooth muscle, of which, relaxation together. Clinical data for PDE-5 inhibitors has shown leads to an erection (Hellstrom and Kendirci, 2006). On a good improvement on erectile dysfunctions, but a the other hand, experimental data also indicates that small effect on BPH symptoms. McVary et al. (2007) NO synthase and NO could play important roles in saw a signiﬁcant improvement in the IPSS following tissue from the urethra, corpus cavernosum, prostate, 12 weeks of treatment with 100 mg sildenaﬁl, with an vas deferens and bladder neck (Ehren et al., 1994).
IPSS change of À6.3 versus À1.9 with placebo, as well Reduced concentrations of NOS/NO in the prostate as a signiﬁcant improvement of the IIEF erectile func- and bladder increase smooth muscle tone and may tion domain (McVary et al., 2007). In the trial of improve prostatic cell proliferation (Mirone et al., 2011), Roehrborn et al. (2008), the application of different indicating that PDE-5-inhibitors, which increase the NO dosages of tadalaﬁl demonstrated that an increased concentration, may have positive effects on LUTS.
dosage correlated with increased IPSS improvement, Initial clinical trials have been carried out with alpha from +3.9 at 2.5 mg to +5.2 at 20 mg, with a dose of blockers or PDE-5-inhibitors (Kaminetsky, 2006).
5 mg showing the best beneﬁt/risk ratio. After the Clinical data with alpha blockers, however, has shown treatment period of 12 weeks, improvement was also seen a good treatment effect on BPH symptoms but only a in the IIEF erectile function subdomain (Roehrborn et al., small positive inﬂuence on SDys. In a clinical trial where 2008). Vardenaﬁl (20 mg) taken twice daily for 8 weeks patients with moderate to severe BPH symptoms took improved the IPSS by 5.9 points, compared with 10 mg alfuzosin for 6 months, the IPSS decreased from placebo with 3.6 points; signiﬁcant changes were also 18.93 to 9.59 points, and the Male Sexual Health seen in the IIEF erectile dysfunction (ED), and the Questionnaire (MSHQ) ejaculation subscore improved Urolife QoL-9 improved by 27% compared with 7% from 23.09 to 21.54; this was statistically signiﬁcant, but under placebo (Stief et al., 2008). Although IPSS was the clinical relevance remains doubtful with an improve- improved in these trials, interestingly, changes in ﬂow ment only of about 7%. The overall number of patients rates were never reported. In total, clinical data for with moderate to severe erectile dysfunctions decreased PDE-5-inhibitors show a smaller improvement in LUTS from 35% to 22% (Leungwattanakij et al., 2010). These than that observed in our trial following saw palmetto results were not conﬁrmed in another trial where treatment, and our trial demonstrates better effects on patients with BPH symptoms took 10 mg alfuzosin daily ED. Interestingly, when assessing a broader spectrum for 12 weeks. Results of this trial showed that IPSS of SDys, as with the Urolife QoL-9 and not ED alone, decreased signiﬁcantly from 17.92 to 12.07, but the the results of our trials are at least comparable with MSHQ ejaculatory subdomain worsened signiﬁcantly Copyright 2012 John Wiley & Sons, Ltd.
SAW PALMETTO IN BPH AND SEXUAL DYSFUNCTIONS One solution that has been discussed in the litera- Association guideline for treatment of BPH symp- ture for concomitant reduction of BPH symptoms toms also advocates using a combination of alpha- and ED is the combination of an alpha blocker with blockers and 5-alpha-reductase inhibitors (McVary a PDE-5-inhibitor. Data from three such clinical et al., 2011), a protocol designed to achieve better studies are presently available. One small trial inves- efﬁcacy, but without fully considering the additive tigated alfuzosin, sildenaﬁl or the combination on side effect rates of these two drugs as shown in LUTS and EDs. After 12 weeks of treatment, initial combination trials (Mirone et al., 2011).
values of IPSS, which were between 16.9 and 17.8, Our present trial has some limitations; it was were reduced signiﬁcantly in all treatment groups designed as an uncontrolled pilot trial to elucidate if with the largest reduction (24.1%) in the combination any effect of a saw palmetto treatment would be group. The IIEF erectile function score was signiﬁ- observed. Consequently, the size of the placebo effect cantly improved by the combination and sildenaﬁl, can only be estimated. Furthermore, there was a but not in the alfuzosin group (Kaplan et al., 2007).
strong centre effect, as one centre recruited substan- Another combination trial with sildenaﬁl or tamsulosin tially more patients than the others, and these other showed comparable results, with the largest IPSS centres did have fewer responders than the main improvement observed with the combination (À40.1%), centre. Subgroup analysis did not unveil any signiﬁcant differences in patient characteristics between these (À28.2%); the IIEF improved signiﬁcantly with centres; however, these analyses were limited by the sildenaﬁl and the combination but not with tamsulosin low number of patients in the other ﬁve centres to- (Tuncel et al., 2010). In further trial, 100 mg udenaﬁl gether. A further placebo-controlled clinical trial with was added to a stable alpha-blocking therapy in a more balanced patient distribution in the centres patients with BPH and ED for 8 weeks. The IPSS was would be the next step to conﬁrm our ﬁndings.
reduced by 2.8 points, and the IIEF-5 improved bymore than 5 points, indicating that a combination oradd-on therapy of udenaﬁl may be beneﬁcial (Chunget al., 2009). Comparing these data with the results of our trial, with an IPSS-reduction of 51% andimproved SDys by 40.1% as measured with the bSFI, This is the ﬁrst trial ever to indicate that saw palmetto the saw palmetto treatment yielded efﬁcacy results similar treatment had not only a good efﬁcacy in reducing to the combination of an alpha blocker and a PDE-5- BPH symptoms but also a concomitant effect on SDys.
We demonstrated that a saw palmetto treatment was Phosphodiesterase-5-inhibitors are expensive treat- as effective in reducing BPH symptoms as an alpha ments; therefore, a cost-beneﬁt assessment is warranted blocker or a 5-alpha-reductase inhibitor, but that, in for further extensive PDE-prescription. In the USA, a contrast to those treatments, saw palmetto was asso- single dose of 25 mg sildenaﬁl costs about eight times ciated with an improvement of SDys as measured with as much as an alpha-blocking agent like 1 mg doxazosin the bSFI and the Urolife QoL-9 score. Compared with (Stafford and Radley, 2002) or 30 times more than PDE-5-inhibitors, the saw palmetto treatment did not 0.4 mg tamsulosin in Germany (Schneider and Richling, have the same efﬁcacy in improving ED, but did have 2008), whereas the cost for a daily dosage of Prostasan the same treatment effect for overall change of SDys, is in the lower range of an alpha blocker. These differ- with a better reduction in IPSS. The cost of daily treat- ences in price, in addition to the only moderate efﬁ- ment with saw palmetto is much cheaper than with many cacy, make it doubtful if PDE-5-inhibitors should be other medications, for example, in Switzerland, the cost advocated as standard treatments for BPH symptoms.
would be 0.75 Swiss francs for saw palmetto versus When looking at safety and tolerability, our data 22.30 Swiss francs for 100 mg sildenaﬁl (Stebler, 2009).
were in accordance with the previous ﬁndings and In our trial, we observed the same efﬁcacy results as have indicated that saw palmetto was very well tolerated, been seen for combination therapy with alpha blocker in contrast to the standard treatments for LUTS. A and PDE-5-inhibitor, but with much better tolerability major problem for patients taking an alpha blocker of the saw palmetto treatment. Based on these promising and/or a 5-alpha-reductase inhibitor is the occurrence results, which are also reﬂected by the good acceptance of sexual adverse effects that cause many men to of patients and investigators, we consider saw palmetto discontinue treatment (Roehrborn, 2004). Study data to be the ﬁrst line treatment for patients with mild and show that 2–16% of all patients under alpha reduc- moderate BPH symptoms, as it may also improve con- tase inhibitor therapy experience EDs, decreased comitant SDys, while having a very good tolerability libido and decreased volume of ejaculate (twice the frequency seen with placebo), whereas alpha-blockingagents, particularly tamsulosin, have been frequentlylinked with ejaculatory disorders in around 10% of all patients (Gacci et al., 2011). In daily practice, theincidence rates may even be higher than in clinical We would like to thank the following investigators for participating in trials. In a large epidemiological study carried out with this trial: Daniel Borer, Moerigen; Eva Ditrych, Bern; Simon Feldhaus,Brunnen; Manfred Hoesle, Zurich; and Felix Trinkler, Zollikon.
urologists and internal medicine physicians in theUnited States, doctors estimated that 18–27% of thepatients taking an alpha-blocking medication suffer from ejaculatory disorders and 16–22% of men takinga 5-alpha-reductase-inhibitor suffer from EDs (Seftel The study was ﬁnanced by A.Vogel Bioforce AG, where A. Suter is et al., 2007). Nevertheless, the latest American Urology Copyright 2012 John Wiley & Sons, Ltd.
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SURVEY ON SCHOOL-BASED MEASURES FOR IMMIGRANT CHILDREN 1. NATIONAL DEFINITIONS AND DEMOGRAPHIC CONTEXT OF IMMIGRATION 1.1. National definitions and legislative sources Immigrants in Slovenia can be classified into four categories (1): 1. Slovene citizens who immigrated to Slovenia because of the disintegration of former Yugoslavia (e.g. officers of the Yugoslav Army and their fa