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The Cochrane Database of Systematic Reviews logoLink to The Cochrane Database of Systematic Reviews
. 2023 Jun 22;2023(6):CD001423. doi: 10.1002/14651858.CD001423.pub4

Serenoa repens for the treatment of lower urinary tract symptoms due to benign prostatic enlargement

Juan VA Franco 1,✉, Leonel Trivisonno 2, Nadia J Sgarbossa 2, Gustavo Ariel Alvez 3, Cecilia Fieiras 3, Camila Micaela Escobar Liquitay 4, Jae Hung Jung 5
Editor: Cochrane Urology Group
PMCID: PMC10286776  PMID: 37345871

Abstract

Background

Benign prostatic hyperplasia (BPH) is a non‐malignant enlargement of the prostate, which can lead to obstructive and irritative lower urinary tract symptoms (LUTS). The pharmacologic use of plants and herbs (phytotherapy) for the treatment of LUTS associated with BPH is common. The extract of the berry of the American saw palmetto or dwarf palm plant, Serenoa repens (SR), which is also known by its botanical name of Sabal serrulatum, is one of several phytotherapeutic agents available for the treatment of BPH.

Objectives

To assess the effects of Serenoa repens in the treatment of men with LUTS consistent with BPH.

Search methods

We performed a comprehensive search of multiple databases (the Cochrane Library, MEDLINE, Embase, Scopus, Web of Science, and LILACS), trials registries, other sources of grey literature, and conference proceedings published up to 16 September 2022, with no restrictions on language or publication status.

Selection criteria

We included randomized controlled trials of participants with BPH who were treated with Serenoa repens or placebo/no treatment.

Data collection and analysis

Two review authors independently assessed studies for inclusion at each stage and undertook data extraction and risk of bias assessment and GRADE assessment of the certainty of the evidence. We considered review outcomes measured up to 12 months after randomization as short term, and beyond 12 months as long term. Our main outcomes included urologic symptom scores, quality of life, and adverse events.

Main results

For this update, we narrowed the review question to only comparisons with placebo. We included 27 studies (of which 9 were new) involving a total of 4656 participants, 19 studies comparing Serenoa repens with placebo, and 8 studies comparing Serenoa repens in combination with other phytotherapeutic agents versus placebo. Most studies included men aged > 50 (mean age range 52 to 68) with moderate urologic symptoms (International Prostate Symptom Score [IPSS] range 8 to 19). Ten studies were funded by the pharmaceutical industry; two studies were funded by government agencies; and the remaining studies did not specify funding sources.

Serenoa repens versus placebo or no intervention

Results for this comparison are based on predefined sensitivity analyses limited to studies at low risk of bias. Serenoa repens results in little to no difference in urologic symptoms at short‐term follow‐up (3 to 6 months; IPSS score range 0 to 35, higher scores indicate worse symptoms; mean difference (MD) −0.90, 95% confidence interval (CI) −1.74 to −0.07; I2 = 68%; 9 studies, 1681 participants; high‐certainty evidence). Serenoa repens results in little to no difference in the quality of life at short‐term follow‐up (3 to 6 months; IPSS quality of life domain range 0 to 6, higher scores indicate worse quality of life; MD −0.20, 95% CI −0.40 to −0.00; I2 = 39%; 5 studies, 1001 participants; high‐certainty evidence). Serenoa repens probably results in little to no difference in adverse events (1 to 17 months; risk ratio (RR) 1.01, 95% CI 0.77 to 1.31; I2 = 18%; 12 studies, 2399 participants; moderate‐certainty evidence). Based on 164 cases per 1000 men in the placebo group, this corresponds to 2 more (38 fewer to 51 more) per 1000 men in the Serenoa repens group.

Serenoa repens results in little to no difference in urologic symptoms at long‐term follow‐up (12 to 17 months, IPSS score, MD 0.07, 95% CI −0.75 to 0.88; I2 = 34%; 3 studies, 898 participants; high‐certainty evidence). Serenoa repens results in little to no difference in quality of life at long‐term follow‐up (12 to 17 months, IPSS quality of life, MD −0.11, 95% CI −0.41 to 0.19; I2 = 65%; 3 studies, 882 participants; high‐certainty evidence). There were no data on long‐term adverse events for this comparison.

Serenoa repens in combination with other phytotherapy versus placebo or no intervention

Different phytotherapeutic agents that include Serenoa repens may result in little to no difference in urologic symptoms compared to placebo at short‐term follow‐up (12 to 24 weeks, IPSS score, MD −2.41, 95% CI −4.54 to −0.29; I2 = 67%; 4 studies, 460 participants; low‐certainty evidence). We are very uncertain about the effects of these agents on quality of life (very low‐certainty evidence). These agents may result in little to no difference in the occurrence of adverse events; however, the CIs included substantial benefits and harms (12 to 48 weeks, RR 0.91, 95% CI 0.58 to 1.41; I2 = 0%; 4 studies, 481 participants; low‐certainty evidence). Based on 132 cases per 1000 men in the placebo group, this corresponds to 12 fewer (55 fewer to 54 more) per 1000 men in the combined phytotherapeutic agents with Serenoa repens group.

Authors' conclusions

Serenoa repens alone provides little to no benefits for men with lower urinary tract symptoms due to benign prostatic enlargement. There is more uncertainty about the role of Serenoa repens in combination with other phytotherapeutic agents.

Keywords: Aged, Humans, Male, Middle Aged, Plant Extracts, Plant Extracts/adverse effects, Prostatic Hyperplasia, Prostatic Hyperplasia/complications, Prostatic Hyperplasia/drug therapy, Quality of Life, Serenoa

Plain language summary

Serenoa repens for benign prostatic hyperplasia

Review question

Does Serenoa repens alone or in combination with other phytotherapeutic agents improve symptoms in men with benign prostatic enlargement?

Background

An enlarged prostate may cause bothersome urinary tract symptoms, such as having to urinate often during the day or night, having a weak stream, and the feeling of not completely emptying the bladder. Besides other common drug interventions, using plants and herbs (phytotherapy) is common and has been growing steadily in most Western countries. The extract of the berry of the American saw palmetto, or dwarf palm plant, Serenoa repens, which is also known by its botanical name of Sabal serrulatum, is one of several phytotherapeutic agents available for the treatment of this condition.

Study characteristics

We found 27 studies with 4656 men comparing Serenoa repens alone or in combination with other herbal products to a placebo (participants are made to believe they received treatment when in fact they did not). Most studies included men over 50 with moderate symptoms. Ten studies were funded by pharmaceutical organizations; two studies received government funding; and the remaining studies did not specify funding sources.

Key results

Based on the most trustworthy studies, Serenoa repens alone results in little to no difference in urinary tract symptoms or quality of life compared to placebo at three to six months. This treatment is also likely not associated with adverse events. Results were similar at 12 to 17 months.

Serenoa repens in combination with other herbal products may result in little to no difference in urinary tract symptoms, but there is more uncertainty about effects on quality of life and adverse events.

The findings of this review are current to 16 September 2022.

Certainty of the evidence

The certainty of the evidence is primarily high or moderate for Serenoa repens alone, but low for Serenoa repens in combination with other agents, meaning our confidence in the results is high, moderate, or low.

Summary of findings

Summary of findings 1. Serenoa repens compared to placebo or no intervention.

Serenoa repens compared to placebo or no intervention
Patient or population: lower urinary tract symptoms due to benign prostatic hyperplasia
Setting: outpatient (Australia, Asia, Europe, and the USA)
Intervention: Serenoa repens
Comparison: placebo/no treatment
Outcomes № of participants
(studies) Certainty of the evidence
(GRADE) Relative effect
(95% CI) Anticipated absolute effects* (95% CI)
Risk with placebo/no treatment Risk difference with Serenoa repens
Urologic symptom score
Measured by IPSS scores (range 0 to 35)
Higher scores indicate worse symptoms.
Follow‐up: 3 to 6 months
MCID: 3 points		 1681
(9 RCTs)		 ⊕⊕⊕⊕
Higha MD −0.90
(−1.74 to −0.07)		 The mean score was 14.33. MD 0.90 lower (1.74 lower to 0.07 lower)
Quality of life
Measured by IPSS‐QoL score (range 0 to 6)
Follow‐up: 3 to 6 months
MCID: 0.5 points		 1001
(5 RCTs)		 ⊕⊕⊕⊕
Higha MD −0.20
(−0.40 to 0.00)		 The mean score was 3.11. MD 0.20 lower (0.40 lower to 0.00 lower)
Adverse events
Cumulative incidence
Follow‐up: 1 to 17 months
MCID: relative risk reduction/increase of 0.25		 2399
(12 RCTs)		 ⊕⊕⊕⊝
Moderateb RR 1.01
(0.77 to 1.31)		 164 per 1000 2 more per 1000 (38 fewer to 51 more)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; IPSS: International Prostate Symptom Score; MCID: minimal clinically important difference; MD: mean difference; QoL: quality of life; RCT: randomized controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
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aWe did not downgrade the certainty of the evidence for risk of bias as these results were robust following sensitivity analysis excluding studies at high risk of bias. 
bWe did not downgrade the certainty of the evidence for risk of bias as these results were robust following sensitivity analysis excluding studies at high risk of bias. We downgraded one level due to imprecision as the CI included little to no benefit and also harms (based on a 25% relative risk reduction).

Summary of findings 2. Serenoa repens in combination with other phytotherapy versus placebo or no intervention.

Serenoa repens in combination with other phytotherapy versus placebo or no intervention
Patient or population: lower urinary tract symptoms due to benign prostatic hyperplasia
Setting: outpatient (Europe/USA)
Intervention: Serenoa repens with other phytotherapy
Comparison: placebo/no intervention
Outcomes № of participants
(studies) Certainty of the evidence
(GRADE) Relative effect
(95% CI) Anticipated absolute effects* (95% CI)
Risk with placebo/no treatment Risk difference with Serenoa repens
Urologic symptom score
Measured by IPSS scores (range 0 to 35)
Higher scores indicate worse symptoms.
Follow‐up: 12 to 24 weeks
MCID: 3 points		 460
(4 RCTs)		 ⊕⊕⊝⊝
Lowa,b MD −2.41
(−4.54 to −0.29)		 The mean score was 12. MD 2.41 lower (4.54 lower to 0.29 lower)
Quality of life
Measured by IPSS‐QoL score (range 0 to 6)
Follow‐up: 2 to 6 months
MCID: 0.5 points		 265
(2 RCTs)		 ⊕⊝⊝⊝
Very lowc,d,e 1 study reported improvements (P < 0.05), while the other did not.
Adverse events
Cumulative incidence
Follow‐up: 12 to 48 weeks
MCID: relative risk reduction/increase of 0.25		 481
(4 RCTs)		 ⊕⊕⊝⊝
Lowf RR 0.91
(0.58 to 1.41)		 132 per 1000 12 fewer per 1000
(55 fewer to 54 more)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; IPSS: International Prostate Symptom Score; MCID: minimal clinically important difference; MD: mean difference; QoL: quality of life; RCT: randomized controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
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aDowngraded one level due to concerns about inconsistency: high statistical inconsistency (I2 = 67%).
bDowngraded one level due to imprecision: wide CI including substantial benefit and little to no effect.
cDowngraded one level due to risk of bias: high risk of bias in included studies.
dDowngraded one level due to inconsistency: the included studies reported different effects.
eDowngraded one level due to imprecision: the included studies reported P values, and we are uncertain about effect sizes.
fDowngraded two levels due to imprecision: CI includes substantial benefits and harms.

Background

Description of the condition

Description of the condition

The prostate gland is an organ approximately the size of a walnut located below the urinary bladder encircling the urethra (Leissner 1979). Benign prostatic hyperplasia (BPH) is a histological diagnosis defined as an increased number of epithelial and stromal cells in the prostate; this may cause prostatic enlargement and, subsequently, compression of the urethra and obstruction (Roehrborn 2008). BPH may therefore develop with or without lower urinary tract symptoms (LUTS) in men aged over 40 years (Dunphy 2015). BPH acquires clinical significance when associated with bothersome LUTS (Roehrborn 2008). 'Symptom bother' typically correlates with the increased number and severity of symptoms, which relate to both quality of life impairment and treatment seeking (Agarwal 2014). Self‐administered questionnaires (e.g. the International Prostate Symptom Score [IPSS]) include the quality of life domain to evaluate the relative degree of bother across all LUTS (Barry 1995). Increased LUTS severity is associated with worsening men's overall distress using the man's perception of bladder condition, which is a single‐item global question (ranging from 1 [causes no problems at all] to 6 [causes severe problems]) (Chapple 2017). In this Cochrane Review, we consider the term BPH as prostatic enlargement with LUTS to define the disease condition and potential need for intervention.

BPH can progress and cause serious consequences such as acute urinary retention, infection, and upper urinary tract deterioration. BPH also negatively impacts public health and a reduction in a person's quality of life (Kozminski 2015; Martin 2014). In Europe, 30% of men over 50 years of age, equivalent to 26 million men, are affected by bothersome LUTS, including storage symptoms (such as urinary frequency, urgency, and nocturia) or voiding symptoms (such as urinary hesitancy, weak urinary stream, straining to void, and prolonged voiding), or both. The yearly reported associated number of medical prescriptions is estimated to be around 11.6 million for 74 million people at risk from 2004 to 2008 (Cornu 2010). According to an international study involving 7588 men, the prevalence of LUTS was 18% in 40‐year‐olds, 29% of men in their 50s, 40% of men in their 60s, and 56% of men in their 70s (Homma 1997). In the USA, an estimated eight million men over 50 years of age have BPH (Roehrborn 2008). More recent data show that the lifetime prevalence of BPH was 26.2% (95% confidence interval 22.8 to 29.6%) (Lee 2017).

Diagnosis

Initial evaluation of LUTS suggestive of BPH includes patient history and physical examination, which may include a digital rectal examination, urinalysis, prostate‐specific antigen (PSA), and IPSS (Gravas 2022; Lerner 2021). A digital rectal examination may be performed to assess the prostate for size and any lesions suspicious of cancer. PSA is secreted by the prostate gland and is found to be abnormally elevated in conditions such as prostate cancer, BPH, infection, or inflammation of the prostate (Gravas 2022; Lerner 2021). The IPSS is used to assess urinary symptom severity and quality of life. It is also used to document subjective responses to treatment. Measurements of maximum flow rate (Qmax) and postvoid residual (PVR) are also used in diagnosis and treatment decisions (Gravas 2022; Lerner 2021). A low Qmax and a large PVR predict an increased risk of symptom progression (Crawford 2006). Further evaluations may be needed for differential diagnosis or pre‐surgical assessments (Gravas 2022; Lerner 2021).

Treatment

Treatment decisions are based on symptoms and the degree of bother noted by the patient. Initial treatment options for BPH include conservative management (watchful waiting and lifestyle modification) and medication (alpha‐blockers and 5‐alpha reductase inhibitors) (Gravas 2022; Lerner 2021). If patients have been refractory to conservative and medical treatment, and BPH causes subsequent complications, such as acute urinary retention, recurrent urinary tract infection, bladder stones or diverticula, hematuria, or renal insufficiency, surgical options are considered (Gravas 2022; Lerner 2021). Currently, guidelines do not recommend the routine use of Serenoa repens, but they state that in instances where patients want to avoid adverse side effects of other treatments, these patients should be informed of its modest benefits (Gravas 2022).

Description of the intervention

There are about 30 phytotherapeutic compounds available for the treatment of BPH, and one of the most widely used is an extract from the berry of the American saw palmetto or dwarf palm plant, Serenoa repens, which is also known by its botanical name of Sabal serrulatum. The extracts can be classified as hexane, ethanolic, and supercritical carbon dioxide. The hexane extract (commercially known as Permixon) is proposed to have a higher biological activity and the lowest variability from batch to batch in free fatty acid content, possibly suggesting a higher efficacy and fewer adverse events (Habib 2004; Scaglione 2008).

Serenoa repens is usually taken in a daily dose of 320 mg, although some studies have investigated higher doses (Barry 2011). The most frequently reported adverse events are minor gastrointestinal symptoms, genitourinary problems, musculoskeletal complaints, and upper respiratory tract infections.

How the intervention might work

The causes of LUTS related to BPH are not entirely known; however, it is theorized that a combination of prostatic cellular proliferation (BPH) and smooth muscle dysfunction are likely reasons (Roehrborn 2020). The purported mechanisms of action for Serenoa repens include:

  • alteration in cholesterol metabolism (Christensen 1990);

  • antiestrogenic and antiandrogenic effects (Dreikorn 1990; Marwick 1995), with Serenoa repens (Permixon) acting as a weak surrogate 5‐ARI inhibiting the conversion of testosterone to dihydrotestosterone (DHT), Dedhia 2008, and the dependent inhibition of 5‐ARI in the stroma and epithelium of the prostate (Weisser 1996);

  • anti‐inflammatory effects by a decrease in available sex hormone‐binding globulin (Di Silverio 1993);

  • pro‐apoptotic properties and inhibition of cellular proliferation (Vacherot 2000; Vela‐Navarrete 2005);

  • the relaxation of smooth muscles of the detrusor and the prostate via alpha‐1 adrenergic receptors (Roehrborn 2020);

  • placebo effect (Roehrborn 2020).

Why it is important to do this review

Phytotherapy is widely used for the relief of lower urinary symptoms attributed to BPH. Since the last update (Tacklind 2012), several new trials have been published. Whereas some newer non‐Cochrane reviews have been published, none has included GRADE methods (Novara 2016; Russo 2021; Vela‐Navarrete 2018).

Objectives

To assess the effects of Serenoa repens in the treatment of men with LUTS consistent with BPH.

Methods

Criteria for considering studies for this review

Types of studies

The methods for this update have been extensively modified since its last publication to meet current methodological expectations; please refer to the Differences between protocol and review section. We included parallel‐group randomized controlled trials (RCTs). We excluded cluster‐RCTs, as these study designs are not relevant in this setting. We included the first phase of cross‐over studies. We did not include single‐armed studies. We included studies regardless of their publication status or language.

Types of participants

We defined the eligible participant population as men over the age of 40 years with a prostate volume of 20 mL or greater (as assessed by ultrasound or cross‐sectional imaging), with lower urinary tract symptoms (LUTS) as determined by International Prostate Symptom Scores (IPSS) of eight or over, and a maximum flow rate (Qmax) of less than 15 mL/second, as measured by non‐invasive uroflowmetry, invasive pressure flow studies, or both (Dunphy 2015; EAU 2022; McNicholas 2016; McVary 2011). We based the age limit on the fact that the prevalence of BPH increases in middle‐aged and older men and is infrequent in younger men (Barry 1997; EAU 2022; Egan 2016). We included studies in which only a subset of participants was relevant to this review (i.e. studies in which more than 75% of participants were relevant to this review) if data were available separately for the relevant subset.

We excluded studies of men with active urinary tract infection, bacterial prostatitis, chronic renal failure, untreated bladder calculi or large diverticula, prostate cancer, and urethral stricture disease, as well as those who had undergone prior prostate, bladder neck, or urethral surgery. We also excluded studies of people with other conditions that affect urologic symptoms, such as neurogenic bladder due to spinal cord injury, multiple sclerosis, or central nervous system disease.

Types of interventions

Experimental intervention

  • Serenoa repens alone (hexanic and non‐hexanic extract)

  • Serenoa repens in combination with other phytotherapy

Comparator intervention

  • Placebo or no intervention

Comparisons

  • Serenoa repens versus placebo or no intervention

  • Serenoa repens in combination with other phytotherapy versus placebo or no intervention

To establish fair comparisons, we required that concomitant interventions be the same in the experimental and comparator groups.

Types of outcome measures

We did not use measurement of the outcomes assessed in this review as an eligibility criterion.

Primary outcomes

  • Urologic symptom scores (continuous outcome)

  • Quality of life (continuous outcome)

  • Adverse events

Secondary outcomes

We did not include secondary outcomes.

Method and timing of outcome measurement

We considered the clinically important differences for the review outcome measures to rate the overall certainty of evidence in the summary of findings tables following a minimally contextualized approach (Jaeschke 1989; Johnston 2013). We considered outcomes measured up to and including 12 months after randomization as short term, and later than 12 months as long term. For adverse events, the timing of outcome assessment was not well‐defined across studies, and outcome data were not disaggregated by follow‐up, so we did not divide them into short and long term.

Urologic symptom scores

Mean change from baseline or final mean value, measured using a validated scale (such as IPSS). We considered the improvement of an IPSS score of three points as the minimal clinically important difference (MCID) to assess the efficacy and comparative effectiveness (Barry 1995). If possible, we used different thresholds of MCID based on the severity of IPSS, with a threshold of three points for men with mild LUTS, five for moderate LUTS, and eight for severe LUTS (Barry 1995).

Quality of life

Mean change from baseline or final mean value measured as a validated scale (such as IPSS‐quality of life or BPH Impact Index). No threshold has been established for IPSS quality of life in the literature. However, we used an MCID of 0.5 to assess the efficacy and comparative effectiveness. A BPH Impact Index score of one as an MCID was used to indicate improvement (Barry 2013; Franco 2021; Rees 2015).

Adverse events

The number of participants experiencing at least one adverse event (e.g. gastrointestinal discomfort). There were no reported thresholds in adverse events, thus we considered a clinically important difference a risk ratio reduction or increase of at least 25% (Guyatt 2011).

Search methods for identification of studies

Electronic searches

We searched the following sources from the inception of each database to the date of search with no restrictions on the language of publication:

  • the Cochrane Central Register of Controlled Trials (CENTRAL; www.cochranelibrary.com/) (2022, Issue 9) searched 16 September 2022;

  • MEDLINE (Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to 16 September 2022);

  • Embase (www.embase.com/) from 1974 to 16 September 2022;

  • Scopus (www.scopus.com/home.uri) from 1966 to 16 September 2022;

  • Science Citation Index Expanded (SCI‐E) Web of Science Clarivate (www.webofscience.com; from 1970 to 16 September 2022);

  • Latin American and Caribbean Literature in Health Sciences (LILACS; lilacs.bvsalud.org/es/; from 1982 to 16 September 2022);

  • ClinicalTrials.gov (www.clinicaltrials.gov) (searched 16 September 2022);

  • World Health Organization International Clinical Trials Registry Platform (ICTRP) (www.who.int/trialsearch) (searched 16 September 2022).

Details of the search strategies are provided in Appendix 1.

Searching other resources

We attempted to identify other potentially eligible trials and ancillary publications by searching the reference lists of retrieved included trials, reviews, meta‐analyses, and health technology assessment reports. We contacted the study authors of included trials to identify further studies that we may have missed. We contacted drug/device manufacturers for ongoing or unpublished trials. We searched abstract proceedings of relevant meetings of the American Urological Association, the European Association of Urology, and the International Continence Society from 2020 to 2022 for unpublished studies (see Appendix 2).

Data collection and analysis

Selection of studies

We used Covidence to identify and remove potential duplicate records (Covidence). Two review authors (out of LT, NJS, GAA, and CF) scanned abstracts, titles, or both to determine which studies should be assessed further using the same software. Two review authors (out of LT, NJS, GAA, and CF) investigated all potentially relevant records as full text, mapped records to studies, and classified studies as included studies, excluded studies, studies awaiting classification, or ongoing studies following the criteria for each provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022a). Any discrepancies were resolved through consensus or recourse to a third review author (JVAF or JHJ). We documented the reasons for exclusion of excluded studies. We presented a PRISMA flow diagram showing the process of study selection (Page 2021).

Data extraction and management

We developed a dedicated data abstraction form that we pilot‐tested ahead of time. For studies that fulfilled our inclusion criteria, two review authors (out of LT, NJS, GAA, and CF) independently abstracted the following information.

  • Study design

  • Study dates

  • Study settings and country

  • Participant inclusion and exclusion criteria (e.g. age, baseline IPSS)

  • Participant details, baseline demographics (e.g. age, prostate size, IPSS)

  • Numbers of participants by study and by study arm

  • Details of relevant experimental intervention (e.g. dose, posology, type of Serenoa repens extract)

  • Definitions of relevant outcomes and methods (e.g. type of instrument, such as IPSS) and timing of outcome measurement (e.g. in months), as well as relevant subgroups (e.g. based on age, prostate volume, and the severity of LUTS)

  • Study funding sources

  • Declarations of interest by primary investigators

For dichotomous outcomes, we presented numbers of events and totals for populations in a 2 × 2 table and summary statistics with corresponding measures of variance. We obtained the means and standard deviations or data necessary for continuous outcomes to calculate this information. Any disagreements were resolved by discussion or in consultation with a third review author (JVAF or JHJ) if required.

We provided information about potentially relevant studies, including the trial identifiers, in tables. In addition, we contacted the authors of included studies to obtain key missing data as needed.

Dealing with duplicate and companion publications

In the event of duplicate publications, companion documents, or multiple reports of a primary study, we maximized the yield of information by mapping all publications to unique studies and collating all available data. We used the most complete data set aggregated across all known publications. In case of doubt, we prioritized the publication reporting the most extended follow‐up associated with our primary or secondary outcomes.

Assessment of risk of bias in included studies

Two review authors (out of LT, NJS, GAA, CF) independently assessed the risk of bias for the results of the main outcomes (those included in the summary of findings table, see below) in each included study using the recently developed revision of the Cochrane risk of bias tool, RoB 2 (Flemyng 2023; Higgins 2022b). Any disagreements were resolved by discussion or by involving another review author (JVAF). We assessed the risk of bias according to the following domains, focusing on the effect of assignment to the intervention at baseline:

  • the randomization process;

  • deviations from intended interventions;

  • missing outcome data;

  • measurement of the outcome;

  • selection of the reported results.

Answers to signaling questions and supporting information collectively lead to a domain‐level judgment of 'low risk,' 'some concerns,' or 'high risk' of bias. These domain‐level judgments informed an overall risk of bias judgment for the outcome based on the algorithm in the guidance document of RoB 2.

We provided a quote from the study report together with a justification for our judgment in the risk of bias table. We aimed to source published protocols in order to assess selective reporting. Where information on risk of bias related to unpublished data or correspondence with a trialist, we noted this in the risk of bias table. When considering treatment effects, we took into account the risk of bias for the studies that contributed to that outcome. We made summary assessments of the risk of bias for each important outcome across domains and an overall narrative across studies.

We used a Microsoft Excel spreadsheet tool to manage data supporting the answers to the signaling questions and risk of bias judgments (Microsoft Excel 2023). All of these data are publicly available as supplementary material in the Open Science Framework platform.

Measures of treatment effect

We expressed dichotomous data as risk ratios (RRs) with 95% confidence intervals (CIs). We expressed continuous data as mean differences (MDs) with 95% CIs, unless different studies used different measures to assess the same outcome, in which case we re‐expressed the data as standardized mean differences (SMDs) with 95% CIs.

Unit of analysis issues

Where multiple trial arms were reported in a single trial, we would include only the treatment arms relevant to the review topic. Had two comparisons from the same trial (e.g. drug A versus placebo and drug B versus placebo) been combined in the same meta‐analysis, we would have followed the guidance in Section 6.2 of the Cochrane Handbook (Higgins 2022a). Our preferred approach was to combine groups to create a single pair‐wise comparison.

Dealing with missing data

We contacted investigators or study sponsors to verify key study characteristics and to obtain missing numerical outcome data where possible (e.g. when a study was available as an abstract only).

Where numerical outcome data were missing, such as standard deviations or correlation coefficients, and they could not be obtained from the authors, we calculated them from other available statistics such as 95% CI or P values, according to the methods described in the Cochrane Handbook (Higgins 2022a). If this was not possible, and the missing data could have introduced serious bias, we planned to explore the impact of including such studies in the overall assessment of results by a sensitivity analysis.

Assessment of heterogeneity

We identified heterogeneity (inconsistency) through visual inspection of the forest plots to assess the amount of overlap of CIs, and by using the I2 statistic, which quantifies inconsistency across studies to assess the impact of heterogeneity on the meta‐analysis. We interpreted the I2 statistic as follows (Deeks 2022):

  • 0% to 40%: may not be important;

  • 30% to 60%: may indicate moderate heterogeneity;

  • 50% to 90%: may indicate substantial heterogeneity;

  • 75% to 100%: considerable heterogeneity.

In the case of heterogeneity, we attempted to identify possible reasons for it by examining individual study and subgroup characteristics.

Assessment of reporting biases

We attempted to obtain study protocols to assess selective outcome reporting. When we included 10 or more studies in a meta‐analysis, we used funnel plots to assess small‐study effects (Page 2022). Several explanations can be offered for the asymmetry of a funnel plot, including true heterogeneity of effect with respect to study size, poor methodological design (and hence bias of small studies), and publication bias. We therefore used caution in our interpretation of results.

Data synthesis

Unless there was good evidence for homogeneous effects across studies, we summarized data using a random‐effects model. We interpreted random‐effects meta‐analyses with due consideration of the whole distribution of effects. We also performed statistical analyses according to the statistical guidelines contained in the Cochrane Handbook (Higgins 2022a). For dichotomous outcomes, we used the Mantel‐Haenszel method. For continuous outcomes, we used the inverse variance method. We used Review Manager Web software to perform the analyses (RevMan Web 2022).

Subgroup analysis and investigation of heterogeneity

We expected the following characteristics to potentially introduce clinical heterogeneity, and carried out subgroup analyses to investigate interactions.

  • Type of Serenoa repens preparation (hexanic versus non‐hexanic extract)

  • Participant age (less than 65 years versus 65 years or more)

  • Severity of LUTS based on IPSS (score less than or equal to 19 [moderately symptomatic] versus greater than 19 [severely symptomatic])

These subgroup analyses are based on the following observations.

  • Other reviews highlight that there might be different effects of different Serenoa repens extracts (Russo 2021).

  • Age is a well‐known risk factor for BPH surgery. Older men have a higher rate of postoperative complications compared with younger men (Bhojani 2014; Pariser 2015). The age cut‐off is based on the World Health Organization's (WHO) definition of old age (WHO 2002).

  • The relationship between changes in IPSS scores and patient global ratings of improvement is influenced by the baseline scores (Barry 1995).

Sensitivity analysis

We performed sensitivity analyses to explore the influence of the following factors (when applicable) on effect size:

  • restricting the analysis to RCTs by considering risk of bias, restricting to studies with an overall low risk of bias.

If the sensitivity analyses provided moderate‐ to high‐certainty evidence, we would draw our main conclusions (summary of findings tables) based on this estimate. This is a similar approach to the previous version of this review (Tacklind 2012).

Summary of findings and assessment of the certainty of the evidence

We presented the overall certainty of the evidence for each outcome according to the GRADE approach (Guyatt 2008). For each comparison, two review authors (JVAF and LT) independently rated the certainty of the evidence for each outcome as 'high,' 'moderate,' 'low,' or 'very low,' using GRADEpro GDT software (GRADEpro GDT). Any discrepancies were resolved by consensus or if needed by arbitration from a third review author (JHJ). For each comparison, we presented a summary of the evidence for the main outcomes in the summary of findings table, which provides key information about the best estimate of the magnitude of effect in relative terms and absolute differences for each relevant comparison of alternative management strategies; numbers of participants and studies addressing each important outcome; and the rating of our overall confidence in the effect estimates for each outcome (Schünemann 2022).

We considered five criteria, not only related to internal validity (overall risk of bias, inconsistency, imprecision, and publication bias) but also external validity (directness of results), for downgrading the certainty of the evidence for a specific outcome (Schünemann 2022). We included the following comparisons.

  • Serenoa repens versus placebo or no intervention

  • Serenoa repens in combination with other phytotherapy versus placebo or no intervention

Each summary of findings table includes the following outcomes.

  • Urologic symptom scores

  • Quality of life

  • Adverse events

We followed GRADE guidance for detailed footnotes and language to describe the certainty of the evidence (Santesso 2016; Santesso 2020).

Results

Description of studies

Results of the search

For this update, we narrowed the focus of the review questions, focusing on the effects of Serenoa repens versus placebo or in combination with other psychotherapeutic agents versus placebo. As a result, we excluded 7 of 32 studies included in the previous update because they were not included in this focused review question (Braeckman 1997; Carraro 1996; Debruyne 2002; Engelmann 2006; Pannunzio 1986; Roveda 1994; Sökeland 1997), and moved another 7 older studies to awaiting classification because of missing full text (see Characteristics of studies awaiting classification) (Cukier 1985; Emili 1983; Gabric 1987; Löbelenz 1992; Mattei 1990; Mohanty 1999; Tasca 1985). A total of 18 studies from the previous version of this review were relevant to our review question.

We conducted a de novo search and identified 14,362 records from electronic databases. We found no relevant records in additional sources. After removing duplicates, we screened the titles and abstracts of the remaining 6957 records, of which 6870 were excluded. We assessed 87 full‐text articles and excluded 49 records for various reasons (see Excluded studies). We identified nine new studies through this search (Argirović 2013; BASTA 2010; Carbin 1990; Coulson 2013; Hong 2009; Iacono 2015; Ryu 2015; Sudeep 2020; Ye 2019). Considering the 18 relevant studies from the previous version of the review, we included 27 studies with 4656 participants in this update. A PRISMA flow diagram illustrating the flow of literature through the assessment process is presented in Figure 1.

1.

1

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Study flow diagram.

Included studies

See Characteristics of included studies and Table 3.

1. Summary of the characteristics of included studies.
Study Trial period Country n Follow‐up Brand and daily dosage (when available) Co‐intervention Age mean (SD) IPSS mean (SD) Prostate volume mean (SD)
I C I C I C
Studies comparing Serenoa repens with placebo
Argirović 2013 2008 to 2010 Serbia 199 6 months Prostamol Uno 320 mg Tamsulosin 65.9 (7.4) 56.8 (7.7) 15.6 (3.2) 16.2 (4.9) 31.2 (4.2) 38.6 (11.6)
BASTA 2010 2006 to 2008 International 1011 12 months Permixon* 320 mg daily
Prostamol Uno 320 mg		 None 64.61 (7.69)
65.14 (7.67)		 64.14 (7.69) N/A N/A N/A N/A
Barry 2011 2008 to 2010 USA 369 72 weeks Prosta Urgenin Uno 320 mg None 61.25 (8.72) 60.7 (8.08) 14.42 (4.29) 14.69 (4.75) N/A N/A
Bauer 1999 N/A Germany/Italy 101 6 months Talso Uno 320 mg daily None 66.1 9.6 8.9 34.5 31.7
Bent 2006 2001 to 2004 USA 225 14 months Carbon dioxide extract 320 mg None 62.9 (8.0) 63.0 (7.4) 15.7 (5.7) 15.0 (5.3) 34.7 (13.9) 33.9 (15.2)
Boccafoschi 1983 N/A Italy 22 60 days Permixon* 320 mg None 68 (55 to 80) 68 (54 to 78) N/A N/A N/A N/A
Champault 1984 N/A France 110 30 days Permixon* 320 mg None N/A N/A N/A N/A N/A N/A
Descotes 1995 1995 France 176 30 days Permixon* 320 mg None 65.6 (8.4) 67 (7.6) N/A N/A N/A N/A
Gerber 2001 1999 to 2000 USA 85 6 months SR 320 mg None 64.6 (± 9.9) 65.3 (± 9.7) 16.7 (± 4.9) 15.8 (± 4.8) N/A N/A
Glémain 2002 N/A France 329 52 weeks Permixon* 320 mg Tamsulosin 65.2 (7.9) 64.4 (7.7) 16.2 (5.2) 16.3 (5.6) 40.8 (16.5) 38.6 (15)
Hizli 2007 2005 Turkey 60 6 months Permixon* 320 mg Tamsulosin 60.2 (6.3) 58.9 (5.7) 15.6 (3.2) 16.2 (4.7) 31.2 (4.2) 38.6 (11.6)
Hong 2009 N/A Korea 62 12 months SR 320 mg None 52.0 53.1 18.3 15.4 26.1 23.2
Mandressi 1983 N/A Italy 60 1 month Permixon* 320 mg None N/A N/A N/A N/A N/A N/A
Reece Smith 1986 N/A UK 70 12 weeks Permixon* 320 mg None 66.15 (5.86) 67.03 (6.03) N/A N/A N/A N/A
Ryu 2015 2012 to 2013 Korea 120 12 months Permixon* 320 mg Tamsulosin 62.5 (1.21) 63.4 (1.44) 19.6 (0.73) 20 (0.85) 30.1 (0.93) 30.2 (0.67)
Shi 2008 N/A China 94 3 months Prostataplex (dosing not reported) None 65.91 64.04 16.85 14.46 47.72 48.38
Sudeep 2020 N/A India 99 12 weeks VISPO/SPO 400 mg None 57.76 (7.25) 55.18 (8.56) 20.00 (4.41) 20.00 (3.74) N/A N/A
Willetts 2003 1999 to 2000 Australia 100 12 weeks Carbon dioxide extract 320 mg None 62.1 (1.2) 63.9 (1.3) N/A N/A N/A N/A
Ye 2019 2014 to 2016 China 354 24 weeks SR 320 mg None 61.47 (5.20) 60.32 (5.96) 14.42 (3.88) 14.34 (4.08) 37.0 (19.7) 37.3 (25.4)
Studies comparing phytotherapy containing Serenoa repens with placebo
Carbin 1990 1990 Sweden/Denmark 55 3 months Curbicin
(PSO 480 mg + SR 480 mg)		 None 62.0 (6.7) 61.2 (5.8) N/A N/A N/A N/A
Coulson 2013 N/A Australia 60 3 months ProstateEZE Max
(PSO 160 mg, epilobium 500 mg, lycopene 2.1 mg, pygeum 15 g + SR 660 mg)		 None 63 (10.1) 64.9 (9.6) 19.5 18 N/A N/A
Iacono 2015 N/A Italy 185 6 months Tradamixina
(Eisenia 80 mg, Tribulus 100 mg, chitosan oligosaccharide (Biovis) 100 mg + SR 320 mg)		 None 64.2 (8.6) 20.6 (5.4) N/A N/A N/A
Lopatkin 2005 1997 to 2000 Russia 257 24 weeks PRO 160/120
(Sabal‐Urtica 240 mg + SR 320 mg)		 None 67 (7) 68 (6) 17.4 (3.3) 17.8 (3.3) 43.5 (17.6) 44.8 (17.6)
Marks 2000 1997 to 1998 USA 44 6 months Nettle root 240 mg, PSO 480 mg, lemon 99 mg, vitamin A 570 IU + SR 318 mg None 65.1 (8.1) 62.9 (9.3) 18.1 (7.2) 16.6 (5.3) 58.5 (29.8) 55.6 (26.7)
Metzker 1996 N/A Germany 40 12 months Prostagutt forte
(Sabal‐Urtica 240 mg + SR 320 mg)		 None 66.0 65.1 18.6 19.0 N/A N/A
Morgia 2014 2011 to 2012 Italy 225 12 months Profluss
(selenium and lycopene + SR 320 mg)		 Tamsulosin 65 66 20 19 45 45
Preuss 2001 N/A USA 144 3 months Cernitin AF
(Cernitin 378 mg, vitamin E 100 IU + SR with beta‐sitosterol 286 mg)		 None N/A N/A 18.9 17.1 N/A N/A
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(*) Hexanic extract of Serenoa repens; C: control; I: intervention; IPSS: International Prostate Symptom Score; IU: international units; N/A: not available (not described); PSO: pumpkin seed oil; SR: Serenoa repens;SD: standard deviation

Study design and settings

All studies were RCTs. The median sample size was 100 participants (interquartile range 61 to 212), and the median follow‐up was 24 weeks (interquartile range 12 to 52). Studies were conducted in Serbia (Argirović 2013), the USA (Barry 2011; Bent 2006; Gerber 2001; Marks 2000; Preuss 2001), Germany (Bauer 1999; Metzker 1996), Italy (Boccafoschi 1983; Iacono 2015; Mandressi 1983; Morgia 2014), France (Champault 1984; Descotes 1995; Glémain 2002), Turkey (Hizli 2007), Korea (Hong 2009; Ryu 2015), the UK (Reece Smith 1986), China (Shi 2008; Ye 2019), India (Sudeep 2020), Sweden (Carbin 1990), Australia (Coulson 2013; Willetts 2003), and Russia (Lopatkin 2005), and one study was conducted in more than one country (BASTA 2010).

Participants

Most studies included men aged > 50 (mean age range 52 to 68), and a few studies included men with a mean age > 65 (Boccafoschi 1983; Descotes 1995; Glémain 2002; Lopatkin 2005; Marks 2000; Reece Smith 1986). Most studies included men with moderate urologic symptoms (IPSS range 8 to 19), with only three studies including a mean score of 20 or more (Iacono 2015; Morgia 2014; Sudeep 2020). Less than half of the studies reported prostate size, which was mostly small to moderate size (mean size range 26.1 to 58.5 mL) (Argirović 2013; Bauer 1999; Bent 2006; Glémain 2002; Hizli 2007; Hong 2009; Lopatkin 2005; Marks 2000; Morgia 2014; Ryu 2015; Shi 2008; Ye 2019).

Interventions and comparisons

We included 27 studies for the following comparisons.

The most commonly used daily dose was 320 mg daily, either as a single dose or 160 mg twice daily. For the comparisons to placebo, one study did not specify the dosing (Shi 2008), and one study used a 200 mg extract twice daily (400 mg daily total; Sudeep 2020). Whereas the doses of Serenoa repens in combined treatment with another phototherapy usually ranged from 286 to 320, one study included a higher dose of 480 mg daily (Carbin 1990).

Co‐interventions were described in five studies, and in all cases included tamsulosin (Argirović 2013; Glémain 2002; Hizli 2007; Morgia 2014; Ryu 2015).

Outcomes

Twenty‐one studies reported data on urologic symptoms (Argirović 2013; Barry 2011; BASTA 2010; Bauer 1999; Bent 2006; Coulson 2013; Gerber 2001; Glémain 2002; Hizli 2007; Hong 2009; Iacono 2015; Lopatkin 2005; Marks 2000; Metzker 1996; Morgia 2014; Preuss 2001; Ryu 2015; Shi 2008; Sudeep 2020; Willetts 2003; Ye 2019), but only a subset of 12 of these studies reported data on quality of life (Argirović 2013; Barry 2011; Bent 2006; Gerber 2001; Glémain 2002; Hizli 2007; Hong 2009; Metzker 1996; Morgia 2014; Ryu 2015; Willetts 2003; Ye 2019). Twenty‐four studies reported data on adverse events (Argirović 2013; Barry 2011; BASTA 2010; Bauer 1999; Bent 2006; Boccafoschi 1983; Carbin 1990; Champault 1984; Coulson 2013; Descotes 1995; Gerber 2001; Glémain 2002; Hizli 2007; Lopatkin 2005; Marks 2000; Metzker 1996; Morgia 2014; Preuss 2001; Reece Smith 1986; Ryu 2015; Shi 2008; Sudeep 2020; Willetts 2003; Ye 2019). One study did not report any outcomes relevant to this review (Mandressi 1983).

Funding sources

Ten studies were funded by the pharmaceutical industry (BASTA 2010; Coulson 2013; Gerber 2001; Lopatkin 2005; Marks 2000; Morgia 2014; Preuss 2001; Sudeep 2020; Willetts 2003; Ye 2019); two studies were funded by government agencies (Barry 2011; Bent 2006); and the remaining studies did not specify funding sources.

Excluded studies

See Characteristics of excluded studies.

We excluded 49 studies for the following reasons.

Studies awaiting classification

See Characteristics of studies awaiting classification.

We identified 24 studies (7 from the previous version of the review) with no available full text (Aliaev 2007; Anonymous 2005; Bercovich 2010; Buck 2002; Carreras 1987; Cukier 1985; Dathe 1991; Diehl 2005; Emili 1983; Fabricius 1993; Gabric 1987; Green 2000; Löbelenz 1992; Martínez 1987; Mattei 1990; Mohanty 1999; Neumann 1993; Razumov 2001; Sekikawa 2020; Tasca 1985; Tkachuk 2002; Vahlensieck 1993; Vinarov 2009; Wehr 1995).

Ongoing studies

We also identified five ongoing studies (ISRCTN84633360; JPRN‐UMIN000023274; JPRN‐UMIN000027902; NCT00497939; NCT02121613). See Characteristics of ongoing studies.

Risk of bias in included studies

The risk of bias assessments for each result in Table 1 and Table 2, including all domain judgments and support for judgment, is located in the risk of bias section, at the side of all forest plots. The signaling questions' responses can be found on the Open Science Framework storage (osf.io/65m8e).

The risk of bias of outcomes across all results and domains was mostly 'some concerns' due to a lack of prespecification of outcomes and analysis plans. We assessed three studies as at overall low risk of bias (Barry 2011; Bent 2006; Sudeep 2020). We assessed three studies as at high risk of bias due to missing outcome data or bias in the measurement of the outcome (due to lack of blinding), in addition to some concerns regarding selective reporting (Hizli 2007; Hong 2009; Ryu 2015).

Effects of interventions

See: Table 1; Table 2

1. Serenoa repens versus placebo or no intervention (short term)

Results for this comparison are based on predefined sensitivity analyses limited to studies at low risk of bias. See Table 1.

1.1. Urologic symptoms

Serenoa repens results in little to no difference in urologic symptoms at short‐term follow‐up (3 to 6 months; mean difference (MD) −0.90, 95% confidence interval (CI) −1.74 to −0.07; I2 = 68%; 9 studies, 1681 participants; high‐certainty evidence). All heterogeneity was explained by a single study of 304 participants that compared Serenoa repens to placebo and showed a difference in IPSS scores of −2.77 (95% CI −3.71 to −1.83) (Ye 2019), which is statistically significant but clinically unimportant. We did not downgrade the certainty of the evidence for inconsistency, considering a minimally contextualized approach and our predefined MCID. We also did not downgrade for risk of bias, since our main analysis was based on a sensitivity analysis excluding studies at high risk of bias (Analysis 1.1). However, this analysis did not materially differ from the analysis including all studies (Analysis 1.2).

1.1. Analysis.

1.1

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Comparison 1: Serenoa repens versus placebo or no intervention, Outcome 1: Urologic symptom score (short term—sensitivity analysis)

1.2. Analysis.

1.2

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Comparison 1: Serenoa repens versus placebo or no intervention, Outcome 2: Urologic symptom score (short term—all studies)

One study with 101 participants found a reduction of urologic symptoms with Serenoa repens (P < 0.01) (Bauer 1999). Another study with 1011 participants found a decrease in urologic symptoms with Serenoa repens compared to placebo at 12 months follow‐up (P = 0.04) (BASTA 2010).

1.2. Quality of life

Serenoa repens results in little to no difference in quality of life at short‐term follow‐up (3 to 6 months, MD −0.20, 95% CI −0.40 to −0.00; I2 = 39%; 5 studies, 1001 participants; high‐certainty evidence). We did not downgrade the certainty of the evidence for risk of bias since, our main analysis was based on a sensitivity analysis excluding studies at high risk of bias (Analysis 1.3). However, this analysis did not materially differ from the analysis including all studies (Analysis 1.4).

1.3. Analysis.

1.3

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Comparison 1: Serenoa repens versus placebo or no intervention, Outcome 3: Quality of life (short term—sensitivity analysis)

1.4. Analysis.

1.4

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Comparison 1: Serenoa repens versus placebo or no intervention, Outcome 4: Quality of life (short term—all studies)

1.3. Adverse events

Serenoa repens probably results in little to no difference in adverse events (1 to 17 months, risk ratio (RR) 1.01, 95% CI 0.77 to 1.31; I2 = 18%; 12 studies, 2399 participants; moderate‐certainty evidence). Based on 164 cases per 1000 men in the placebo group, this corresponds to 2 more (38 fewer to 51 more) per 1000 men in the Serenoa repens group. We did not downgrade the certainty of the evidence for risk of bias, since our main analysis was based on a sensitivity analysis excluding studies at high risk of bias (Analysis 1.5). However, this analysis did not materially differ from the analysis including all studies (Analysis 1.6). Nonetheless, we downgraded one level due to imprecision.

1.5. Analysis.

1.5

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Comparison 1: Serenoa repens versus placebo or no intervention, Outcome 5: Adverse events (sensitivity analysis)

1.6. Analysis.

1.6

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Comparison 1: Serenoa repens versus placebo or no intervention, Outcome 6: Adverse events

We did not incorporate three studies into the meta‐analysis because they reported no adverse events in either the treatment or control group (Bauer 1999; Shi 2008; Sudeep 2020).

The most commonly reported adverse events were headache, gastrointestinal disorders (e.g. diarrhea, nausea and vomiting, stomach upset), upper respiratory symptoms (e.g. rhinitis), ejaculation disorders, musculoskeletal symptoms (e.g. arthralgia in the knees and muscular arm pain), and dizziness. Many of these symptoms may be attributable to co‐interventions (alpha‐blockers).

Few studies in each category precluded subgroup analyses according to age, symptom severity, prostate size, and type of extract (see Included studies).

1.4. Subgroup analysis
1.4.1. Type of Serenoa repens preparation

We were unable to detect differences in urologic symptoms when comparing the effects of hexanic versus non‐hexanic extract (P = 0.23, see Analysis 1.7).

1.7. Analysis.

1.7

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Comparison 1: Serenoa repens versus placebo or no intervention, Outcome 7: Urologic symptom score (subgroup analysis—hexanic vs non‐hexanic extract)

1.4.2. Other subgroup analyses

Few studies in each category precluded subgroups based on participant age and severity of lower urinary tract symptoms (see Included studies).

1.5. Sensitivity analysis

We conducted a sensitivity analysis excluding studies at overall high risk of bias. Given that these analyses provided moderate‐ to high‐certainty evidence, we incorporated them into the main results and summary of findings table (see above outcomes 1.1, 1.2, and 1.3 and Analysis 1.1; Analysis 1.3; Analysis 1.5).

2. Serenoa repens versus placebo or no intervention (long term)

2.1. Urologic symptoms

Serenoa repens results in little to no difference in urologic symptoms at long‐term follow‐up (12 to 17 months, MD 0.07, 95% CI −0.75 to 0.88; I2 = 34%; 3 studies, 898 participants; high‐certainty evidence). We did not downgrade the certainty of the evidence for risk of bias, since our main analysis was based on a sensitivity analysis excluding studies at high risk of bias (Analysis 1.8). However, this analysis did not materially differ from the analysis including all studies (Analysis 1.9).

1.8. Analysis.

1.8

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Comparison 1: Serenoa repens versus placebo or no intervention, Outcome 8: Urologic symptom score (long term—sensitivity analysis)

1.9. Analysis.

1.9

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Comparison 1: Serenoa repens versus placebo or no intervention, Outcome 9: Urologic symptom score (long term—all studies)

2.2. Quality of life

Serenoa repens results in little to no difference in quality of life at long‐term follow‐up (12 to 17 months, MD −0.11, 95% CI −0.41 to 0.19; I2 = 65%; 3 studies, 882 participants; high‐certainty evidence). We did not downgrade the certainty of the evidence for risk of bias, since our main analysis was based on a sensitivity analysis excluding studies at high risk of bias (Analysis 1.10). However, this analysis did not materially differ from the analysis including all studies (Analysis 1.11). 

1.10. Analysis.

1.10

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Comparison 1: Serenoa repens versus placebo or no intervention, Outcome 10: Quality of life (long term—sensitivity analysis)

1.11. Analysis.

1.11

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Comparison 1: Serenoa repens versus placebo or no intervention, Outcome 11: Quality of life (long term—all studies)

2.3. Adverse events

None of the included studies reported this outcome.

2.4. Subgroup analysis

Few studies in each category precluded these subgroup analyses (see Included studies).

2.5. Sensitivity analysis

We conducted a sensitivity analysis excluding studies at overall high risk of bias. Given that these analyses provided high‐certainty evidence, we incorporated them into the main results and summary of findings table (see above outcomes 2.1 and 2.2 and Analysis 1.8; Analysis 1.10).

3. Serenoa repens in combination with other phytotherapy versus placebo or no intervention

See Table 2.

3.1. Urologic symptoms

Different phytotherapeutic agents that include Serenoa repens may result in little to no difference in urologic symptoms compared to placebo at short‐term follow‐up (12 to 24 weeks, MD −2.41, 95% CI −4.54 to −0.29; I2 = 67%; 4 studies, 460 participants; low‐certainty evidence; Analysis 2.1). The certainty of the evidence is low due to imprecision and inconsistency.

2.1. Analysis.

2.1

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Comparison 2: Serenoa repens in combination with other phytotherapy versus placebo or no intervention, Outcome 1: Urologic symptom score

3.1.1. Studies not included in meta‐analysis

One study with 60 participants found a 36% reduction in the total IPSS median score in the active group (Serenoa repens, lycopene, Prunus africana, Epilobium parviflorum, and Cucurbita pepo) compared to 8% in the placebo group at three months follow‐up (P < 0.05) (Coulson 2013). Another study with 225 participants found a greater decrease in IPSS scores for combination therapy (Serenoa repens, lycopene, and selenium) compared to control at 12‐month follow‐up (median change 2.0, range −3 to −1, P < 0.01) (Morgia 2014). One study reported as an abstract did not provide comparative data (only a decrease in IPSS in the intervention group) (Iacono 2015).

3.2. Quality of life

We are very uncertain about the effects of these agents on quality of life (very low‐certainty evidence). In one study with 40 participants, 84.2% of participants in the intervention group had improvements in their quality of life after six months of treatment compared to 11.1% of participants in the placebo group (P < 0.001) (Metzker 1996). Another study with 225 participants found little to no difference in quality of life scores (median change 0, range −0.1 to 1) (Morgia 2014). The certainty of the evidence is very low due to risk of bias, inconsistency, and imprecision.

3.3. Adverse events

Different phytotherapeutic agents that include Serenoa repens may result in little to no difference in occurrence of adverse events; however, the CIs included substantial benefits and harms (12 to 48 weeks, RR 0.91, 95% CI 0.58 to 1.41; I2 = 0%; 4 studies, 481 participants; low‐certainty evidence; Analysis 2.2). Based on 132 cases per 1000 men in the placebo group, this corresponds to 12 fewer (55 fewer to 54 more) per 1000 men in the combined phytotherapeutic agents with Serenoa repens group. We did not incorporate two studies into the meta‐analysis because they reported no adverse events in either the treatment or control group (Carbin 1990; Coulson 2013). The certainty of the evidence is low due to severe imprecision.

2.2. Analysis.

2.2

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Comparison 2: Serenoa repens in combination with other phytotherapy versus placebo or no intervention, Outcome 2: Adverse events

Another study with 225 participants reported no significant differences in treatment‐related adverse events (P = 0.67) (Morgia 2014).

The most commonly reported adverse events were headache, gastrointestinal disorders (e.g. diarrhea, nausea and vomiting, dyspepsia), upper respiratory symptoms (e.g. rhinitis), ejaculation disorders, musculoskeletal symptoms (e.g. arthralgia in the knees and pain), and dizziness. Many of these symptoms may be attributable to co‐interventions (alpha‐blockers).

3.4. Subgroup analysis

Few studies in each category precluded these subgroup analyses (see Included studies).

3.5. Sensitivity analysis

We were unable to conduct a sensitivity analysis because the meta‐analyses did not include studies at overall high risk of bias.

Discussion

Summary of main results

For this update, we narrowed the review question and included 27 studies (of which 9 were new studies) with 4656 participants, 19 studies comparing Serenoa repens with placebo and 8 studies comparing Serenoa repens in combination with other phytotherapeutic agents versus placebo.

Serenoa repens versus placebo or no intervention

Based on predefined sensitivity analyses limited to studies at low risk of bias, Serenoa repens results in little to no difference in urologic symptoms and quality of life at short‐term follow‐up. Serenoa repens probably results in little to no difference in adverse events.

Serenoa repens results in little to no difference in urologic symptoms and quality of life at long‐term follow‐up. There were no data on long‐term adverse events for this comparison.

Serenoa repens in combination with other phytotherapy versus placebo or no intervention

Phytotherapeutic agents with various agents, including Serenoa repens, may result in little to no difference in urologic symptoms compared to placebo at short‐term follow‐up. We are very uncertain about the effects of these agents on quality of life. These agents may result in little to no difference in the occurrence of adverse events; however, the confidence intervals included substantial benefits and harms.

Overall completeness and applicability of evidence

While there has been a growing body of research since the last update of this review, our conclusions remain unchanged. Clinical practice guidelines have since deprioritized Serenoa repens in their treatment pathways.

  • The 2021 Guideline of the American Urological Association focuses on the treatment of LUTS attributed to BPH using common surgical techniques and minimally invasive surgical therapies, thus the information on the different types of medical interventions is not deepened, much less the use of Serenoa repens (Lerner 2021).

  • A previous version of this guideline from 2010 mentioned that the available data do not suggest that Serenoa repens has a clinically significant effect on LUTS secondary to BPH (McVary 2011). Furthermore, it adds that no dietary supplement, combined herbal medicine, or other unconventional therapy is recommended to manage LUTS secondary to BPH due to the paucity of high‐quality published trials (McVary 2011).

  • The European Association of Urology guidelines on the management of non‐neurogenic male LUTS recommends several therapeutic and surgical interventions in men with BPH (EAU 2022). This guideline recommends offering the hexane extract of Serenoa repens to men with LUTS who want to avoid possible adverse events, especially those related to sexual function (weak recommendation), informing the patient that the magnitude of efficacy may be modest (strong recommendation) (EAU 2022). Our review offers a further cautionary note about the use of Serenoa repens.

  • The Korean Urological Association guidelines for the evidence‐based diagnosis and treatment of BPH provide basic information on diagnostic testing, drug therapy, and surgical treatment, but do not mention Serenoa repens as a management option (Yeo 2016).

Considering cut‐off points of 40 mL and 80 mL for small, medium, and large prostates, all studies included men with small‐ to average‐size prostates and moderate urologic symptoms. We found no studies in men with large prostates, and only a few studies of men with more severe urologic symptoms (see Table 3). This evidence is therefore only be applicable to this population (Franco 2023).

Few studies included co‐interventions such as tamsulosin (Argirović 2013; Glémain 2002; Hizli 2007; Morgia 2014; Ryu 2015). However, this did not contribute to statistical heterogeneity when analyzing the outcomes of adverse events. Nonetheless, many of those adverse events described narratively (see footnotes in Analysis 1.5 and Analysis 2.2) include dizziness and ejaculatory disorders, which are typically associated with alpha‐blockers (Mansbart 2022).

Quality of the evidence

The overall certainty of the evidence was high for the main comparison, except for adverse events, for which we identified imprecision. We followed a similar approach to previous versions of this review, excluding studies at high risk of bias from our primary analysis. For the second comparison, however, we had additional concerns about precision and inconsistency across outcomes.

Not all studies provided full details of critical outcomes such as urologic symptoms, quality of life, and adverse events, which would be desirable considering men’s values and preferences (Dahm 2021).

Potential biases in the review process

We could not locate the full text of seven of the original studies in the review, which could not be re‐analyzed using the updated methods (Cukier 1985; Emili 1983; Gabric 1987; Löbelenz 1992; Mattei 1990; Mohanty 1999; Tasca 1985). We contacted the original authors of the review and updates, and they did not hold copies of those studies. In addition to our existing library resources, we also posted a task in Cochrane TaskExchange (currently known as Cochrane Engage) to ask for help on this issue, without success. Based on the characteristics described in the previous version of the review (and available in the Characteristics of studies awaiting classification section), these studies primarily focused on non‐validated outcome measures and Qmax, which would not have contributed to the main analyses of this review. Moreover, we identified 17 additional references that were also assessed as awaiting classification because we could not retrieve a full text to determine their eligibility. These references were mostly from the 1980s and 1990s, so it is likely that their outcomes would not be able to be incorporated into our main analyses.

Although reporting of the timing of adverse events has improved in recent years, we were unable to identify the timing of their occurrence in the included reports, as required by the CONSORT‐Harms statement (Junqueira 2023; Phillips 2019). We therefore did not disaggregate data according to the length of follow‐up of the studies, since most of them described adverse events that were related to treatment initiation (gastrointestinal intolerance) or the effect of co‐interventions (e.g. dizziness and hypotension due to tamsulosin), which resulted in our assumption that they were all short term.

We could not incorporate the results of five studies in our meta‐analyses due to missing data (missing standard deviation or standard error), but we reported these results separately (BASTA 2010; Bauer 1999; Coulson 2013; Iacono 2015; Morgia 2014). Finally, we could not perform many predefined funnel plots and subgroup and sensitivity analyses due to the scarcity of data, low heterogeneity across comparisons, and few trials included in each comparison.

Agreements and disagreements with other studies or reviews

A recent systematic review and network meta‐analysis on the same topic included 22 randomized clinical trials with multiple comparisons of hexanic and non‐hexanic extracts of Serenoa repens with alpha‐adrenergic agonists and placebo (Russo 2021). While the authors concluded that there were clinically insignificant improvements in IPSS at 12 weeks, their confidence intervals included little to no difference compared to placebo (MD −0.47, 95% CI −2.69 to 1.74 for hexanic extract; MD −1.69, 95% CI −4.36 to 0.98 for non‐hexanic extract). Moreover, the authors reported greater improvements in hexanic extracts than in non‐hexanic extracts. Still, the quantitative estimate included little to no difference between subgroups, similar to the findings of our review (MD −2.16, 95% CI −5.64 to 1.30). Finally, this review was limited due to fewer studies comparing Serenoa repens with placebo (7 in that review compared to 15 in ours), with a substantial imprecision in their results.

Another systematic review included seven randomized clinical trials comparing hexanic extract (restricted to the Permixon formulation) with placebo for the outcomes of nocturia, Qmax,and adverse events, but did not assess IPSS (Novara 2016). The authors found a decrease in the episodes of nocturia that may be clinically insignificant (MD −0.31, range −0.59 to −0.03); however, the findings on adverse events were similar to ours.

Finally, a systematic review including 15 randomized clinical trials and 12 observational studies comparing Permixon with placebo assessed nocturia, Qmax,and adverse events, but did not assess IPSS (Vela‐Navarrete 2018). This review also found a small reduction in nocturia that may be clinically insignificant (MD −0.64, range −0.98 to −0.31), and similar results regarding adverse events.

Whereas the dose for almost all studies was 320 mg daily, higher concentrations may result in small but positive improvements in LUTS symptoms, as described in a single study that included doses of 400 mg (Sudeep 2020). The data were insufficient to conduct a subgroup analysis.

Authors' conclusions

Implications for practice.

Serenoa repens alone provides little to no benefits for men with lower urinary tract symptoms due to benign prostatic enlargement. There is more uncertainty about the role of Serenoa repens in combination with other phytotherapeutic agents.

Implications for research.

Considering the uncertainties about the effects of Serenoa repens in higher doses or combined with other herbal treatments, future high‐quality, placebo‐controlled randomized controlled trials are needed in this area that focus on patient‐important outcomes, including urologic symptoms, quality of life, and adverse events.

Feedback

Anna Rita Bilia, et al, 31 August 2009

Summary

Feedback: Quality of a herbal medicinal product is essential. Both the safety profile and the efficacy of a multi‐component herbal medicinal product are irrevocably linked to quality. Quality should be assessed according to the monographs reported in the European Pharmacopoeia or in other Pharmacopoeias or pharmaceutical reference books [1, 2]. These record the methods to define the quality of multi‐component herbal drugs and also of defined selected extracts, according to classification of active constituents, pharmacologically active markers and quality markers [3, 4]. Additionally, pharmacopeial methods are fully validated to perform correctly under the given analytical proceedings irrespectively of the environment where they are performed (ICH guideline Q2(R1); www.ich.org).

Quality of a defined multi‐component herbal extract is strictly related to the quality of the botanical source (herbal drug) defined by the botanical name of the plant according to the binomial system (genus, species, variety and author) and the part used (e.g. leaf, root or fruit). In addition other factors should be considered such as the method of preparation (extraction process, solvents used; solubility and stability of the plant constituents), the drug extract ratio (DER), time and temperature operations, which could be crucial not only for safety but also for the efficacy of the product [5‐8]. Ideally, in analogy with the analytical procedures for testing, also the production‐process should be fully validated, in order to guarantee consistency of the final product, as far as possible.

For these reasons the final mix of constituents in a multi‐component extract may exert different activities and in some circumstances, may even have a different safety profile from another type of extract, that is derived from the identical herb. These facts are taken into consideration and documented for well‐defined herbal extracts in a new series of published European Community Monographs, authorised by the EMEA [9]. It is noteworthy that, among the various types of plant products, e.g. food and botanical products, on the world market, only Herbal Medicinal Products are produced under rigid quality systems, such as Good Sourcing Practices (GSP), Good Agricultural Practices (GAP), Good Field Collection Practices (GFCP), Good Processing Practices (GPP), as well as Good Manufacturing Practices (GMP). As a consequence the quality can be assessed and the final product can be considered reproducible.

According to the above arguments, it is crucial to realise, that the identical botanical source cannot guarantee the bioequivalence of its various multi‐component extracts and of the resulting different Herbal Medicinal Products. The situation in the Cochrane review on Serenoa repens [10] leaves no doubt, that various different Serenoa extracts (not always defined) and their subsequently varying final medicinal products, have been summarised, then analysed, in order to obtain the final conclusions of the review. This left the reader to assume, that both comparable (bioequivalent) and non‐comparable products were included and compared in this study, in spite of the fact, that they might have exerted different, e.g. non‐comparable safety and/or efficacy profiles.

Considering statements and definitions mentioned above, the Cochrane Review on Serenoa repens [10] has been evaluated by the contributors to the present 'Letter to the editor.' Four in part‐related problems were encountered. In the following four comments, these problems have been addressed.

Feedback 1. Problem, missing conclusion regarding studies with a positive control Serenoa alone, was compared in 4 of the 30 investigated clinical trials with known BPH drugs, such as Finasteride, Tamsulosin and Gestonorone caproate as positive controls. Reported in the review were a few minor differences and many comparable results for the various evaluated symptoms and no difference for the overall urinary symptom scores, between treatments with either Serenoa extract or these BPH drugs in different studies with up to 1098 patients. This apparently demonstrated, that the efficacy of these drugs was not different from that of the Serenoa products. Selected results are shown here, to exemplify the commentary: 1 study compared Serenoa to finasteride (MD, mean difference, ‐0,40 Points, 95% CI ‐0.57 to 1.37, P > 0.05); 2 studies compared Serenoa to tamsulosin (WMD, weighted mean difference, ‐0.52 points, 95% CI ‐1.91 to 0.88, P > 0.05).

The reader of the review, even without being in the position to repeat the full statistical analysis, could conclude, that efficacy of Serenoa should be similar or comparable to these BPH drugs. The final statement of the authors, that "Sereoa is not different from placebo", is in clear contradiction to these reports. This contradiction has not been addressed, nor discussed, by the authors of the review.

Conclusion to comment 1

Contradictions described here, unless resolved, prohibit a final conclusion about the efficacy of Serenoa repens products.

Comment 2. Problem, chemical complexity of a multi‐component plant‐extract; 'non‐equivalence' of analysed products The authors of the review appear to have treated the various Serenoa fruit preparations, derived from different extracts, used in the 30 clinical trials, which they analysed, as if these extracts were identical single chemical entities. i.e. the authors appear not to have considered in their analysis, that components of different multi‐component preparations vary, according to their extraction procedure, the solvent used, the drug‐extract‐ratio, the total constituents probably vary, the co‐active constituents probably vary and the standardization can vary. Thus the doses can vary.

The authors have stated in the review, that "of the 15 trials (in true only 14 appeared to have been actually analysed in the review), that were placebo‐controlled and compared to Serenoa repens monotherapy, 7 utilized the commercialized Permixon®, which assured that our comparators were equivalent" [page 13]. Thus the reader may conclude, that 7 out of 14 placebo‐controlled trials were included in this analysis, that were 'non‐equivalent' (i.e. 50% of the comparators). This causes concern about the validity of the authors' statement as well as the authors' conclusions.

Comment 3. Problem, variation of dose

The dosage relates directly to the composition of a multi‐component extract (see comment 2 as well). Thus, the dosage between studies can vary, even if identical amounts are given. Naturally, the dosage must also vary, if the administered amount differs. The 'daily dose' of an extract administered, varied from study to study, in the 30 studies analysed: from 20 drops, 100 mg, 160 mg, 212 mg, 286 mg, 320 mg (a number of studies), 480 mg up to 640 mg, mostly applied in two portions. There was no statistical evaluation in the review taking these different dosages that were used in the 30 clinical trials, into account.

The BPH treatments using non‐identical Serenoa preparations at strongly varying dosages, were summarized and investigated in the review, as if identical treatments with defined dosages, had been used. This is, as if one would assume, that apples, pears and even lemons will taste the same, merely because they are round.

Conclusion to comments 2 and 3

The statistical comparative analysis by the authors of the review, focuses on clinical symptom‐scores of BPH in 30 trials, but they have omitted to fully address the consequences of analysing heterogenous Serenoa preparations administered in heterogenous dosage schemes, in those trials. For example the 7 'non‐equivalent' placebo‐controlled trials should not have been considered as a valid part of a comparative clinical analysis of the placebo‐controlled studies.

Comment 4. Problem, studies conducted with Serenoa‐containing combination products.

Nine (9) of 30 analysed studies, were conducted with combination products containing Serenoa repens extracts, besides one or more other potentially active phytotherapeutic agent (there was no consideration of the dosage, the various extracts were not defined, in the Cochrane review).

Conclusion to comment 4

These studies do not give evidence concerning the efficacy of Serenoa. Any efficacy or lack of efficacy cannot be attributed to Serenoa, such as would be the case in mono‐therapy, but could be influenced by the other plant components in each product. The reader may conclude, that these studies do not qualify for a comparative analysis and cannot support a conclusive statement concerning the activity of Serenoa repens.

Summarising conclusions from comments 1‐4

‐Of 30 analysed studies, 7 placebo‐controlled studies with "non‐comparable" Serenoa products and 9 studies with combination products, could be deleted for good reasons, possibly leaving 14 studies for a revision of the comparative analysis.

‐The authors final conclusion in this review "Sereoa is not different from placebo," does not appear to have been corroborated by rigorous scientific reasoning. Even without repeating the full statistical evaluation (which appears to be necessary as well), the authors final conclusion regarding the efficacy of Serenoa repens, needs to be reconsidered.

References

  1. Saw Palmetto Fruit. Sabalis serrulatae fructus. European Pharmacopoeia. Council of Europe.

  2. Saw palmetto. USP, United States Pharmacopeia.

  3. Guideline on declaration of herbal substances and herbal preparations in herbal medicinal products/traditional herbal medicinal products in the SPC (Summary of product characteristics). EMEA adopted guideline. London, 26 July 2007 Doc. Ref: EMEA/HMPC/CHMP/CVMP/287539/2005

  4. Reflection papers on markers used for quantitative and qualitative analyses of herbal medicinal products and traditional herbal medicinal products. EMEA adopted guideline. London, 15 July 2008. Doc. Ref. EMEA/HMPC/253629/2007

  5. Gaedcke F, Steinhoff B. In: Herbal medicinal products. Scientific and regulatory basis for development, quality assurance and marketing authorisation. CRC Press, Boca Raton, 2003.

  6. Guideline on specifications: test procedures and acceptance criteria for herbal substances, herbal preparations and herbal medicinal products/traditional herbal medicinal products. EMEA adopted guideline. London 30 March 2006. CPMP/QWP/2819/00 Rev 1. EMEA/CVMP/814/00 Rev 1

  7. Guideline on quality of herbal medicinal products/traditional herbal medicinal products. London, 30 March 2006. EMEA adopted guideline. CPMP/QWP/2819/00 Rev 1. EMEA/CVMP/814/00 Rev 1.

  8. Vlietinck A, Pieters L, Apers S. Legal requirements for the quality of herbal substances and herbal preparations for the manufacturing of herbal medicinal products in the European Union. Planta Med 2009;75:683‐8.

  9. a) about European Community Monographs http://www.emea.europa.eu/htms/human/hmpc/hmpcmonographs.htm ; b) homepage of HMPC (Herbal Medicinal Product Committee of EMEA) http://www.emea.europa.eu/htms/human/hmpc/index.htm; c) about HMPC documents (Herbal Medicinal Product Committee of EMEA) http://www.emea.europa.eu/htms/human/hmpwp/working.htm.

  10. Tacklind J, MacDonald R, Rutks I, Wilts TJ. Serenoa repens for benign prostatic hyperplasia (Review). The Cochrane Collaboration, The Cochrane Library 2009, Issue 2, pp.1‐56. Publishers John Wiley & Sons, Ltd.

Submitter agrees with default conflict of interest statement:

I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback.

Reply

Thank you for your comments.

The reviewer remarks that we are acting non‐scientifically by lumping, for example, Permixon® and generic Serenoa repens, is mistaken. Others have made claims that Serenoa repens (whether generic or as Permixon®) alleviates symptoms associated with BPH. We have merely tested their hypothesis.

The reviewer makes two excellent points on bio equivalency and dosages, and in a forthcoming update we will address both. However, we disagree with the reviewers' suggestion that we should have utilized only the Permixon® trials. We conducted a systematic review of the evidence related to all of these products.

The Permixon® trials, which the reviewer urges us to use exclusively, are of almost uniformly poor quality. For example, the 7 RCTs that compared Permixon® to placebo had study populations of 22, 30, 60, 80, 110, 168, and 215. These trials were conspicuously underpowered, with the possible exception of the last two. Follow‐up for the 7 Permixon®‐versus‐placebo trials, measured in weeks, was 4, 4, 4, 4, 8.5, 10 and 12. Only one of the six Permixon® trials that were compared to an active control (or combination therapy with either Permixon® or the active control) utilized a placebo arm.

The reviewer states: "The reader of the review, even without being in the position to repeat the full statistical analysis, could conclude that efficacy of Serenoa should be similar or comparable to these BPH drugs. The final statement of the authors that 'Serenoa is not different from placebo,' is in clear contradiction to these reports." We are not contradictory, but the evidence is ambiguous, as we put it in the review. For example, Carraro [1] (Permixon® versus finasteride) reported a decrease in IPSS symptom scores for both arms (‐37% versus ‐39%, respectively); unfortunately, he did not include a placebo arm. Carraro's trial was certainly well powered (N = 1098), but follow‐up was only 26 weeks.

The consequence of the reviewers' recommendation to use only the Permixon® trials would eliminate the highest quality trial of the thirty, and Bent’s NEJM trial [2] (Serenoa repens versus placebo) is methodologically superior to all of the other twenty‐nine. Bent writes "these studies [previous RCTs] are limited by the small numbers of subjects enrolled, their short duration, their failure to use standard outcome measures, and the lack of information from participants concerning how effectively the placebo was blinded."

After 12‐month follow‐up Bent reported "[b]oth groups also had a small decrease in the AUASI score. . . : the score decreased by 0.68 in the saw palmetto group (95 percent confidence interval, ‐1.37 to 0.01) and by 0.72 in the placebo group (95 percent confidence interval, ‐1.40 to ‐0.04) ( Table 3 ( Barry 2011 ; Bent 2006 ; Braeckman 1997a ; Cukier 1985 ; Mohanty 1999a). There was, however, no significant difference between groups in the mean change in AUASI scores over time (difference in mean change, 0.04 point; 95 percent confidence interval, ‐0.93 to 1.01)."

Can these results be extrapolated to European populations using Permixon®? We think so. Nevertheless, we welcome an equivalent European trial utilizing Permixon® when it becomes available.

References

  1. Carraro J‐C, Raynaud J‐P, Koch G, Chisholm GD, Di Silverio F, Teillac P, Da Silva FC, Cauquil J, Chopin DK, Hamdy FC, et al. Comparison of phytotherapy (Permixon®) with finasteride in the treatment of benign prostate hyperplasia: a randomized international study of 1,098 patients. The Prostate 1996;29:231‐40.

  2. Bent S, Kane C, Shinohara K, Neuhaus J, Hudes ES, Goldberg H, Avins AL. Saw palmetto for benign prostatic hyperplasia. The New England Journal of Medicine 2006;354(6):557‐66.

Contributors

The consumers

Corresponding author: Prof. Dr. Anna Rita Bilia, Phytolab, University of Florence, Department of Pharmaceutical Sciences, via Ugo Schiff 6, I‐50019 Sesto Fiorentino (Florence), Italy. E‐mail: ar.bilia@unifi.it.

Co‐contributors names and addresses:

S. F.A.J. Horsten, PhD., Steenmarteakker 1, NL‐3994 GE Houten;

S. Sturm, PhD., University of Innsbruck, Inst. of Pharmacy/Pharmacognosy, A‐6020 Innsbruck;

M. Frater‐Schröder, PhD., Schwand, CH‐9642 Ebnat‐Kappel.

The authors

James Tacklind

Rod MacDonald

Indy Rutks

Tim Wilt

(2009)

What's new

Date Event Description
22 June 2023 New search has been performed Updated search (replacement of previous search) and updated methods (harmonizing with other reviews on this topic), with a narrower focus (comparisons and outcomes)
22 June 2023 New citation required but conclusions have not changed Incorporation of nine new studies by a new author team
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History

Protocol first published: Issue 1, 1998
Review first published: Issue 1, 1999

Date Event Description
31 July 2016 Amended Under Abstract/Search methods, deleted Google Scholar
24 June 2013 Amended Editorial changes requested by Prostatic Diseases and Urologic Cancers Group
4 March 2013 Amended Under 'Serenoa repens alone or in combination versus placebo,' changed "There were 25 trials" to "24" trials. Added Carbin 1990 to the list. Under 'Serenoa repens alone or in combination versus active control,' we deleted Carbin 1990 from this listing. We changed "of 10 trials comparing SR" to "of 9 trials." We changed "Three trials reported nocturia" to "Two trials." Deleted Carbin 1990 from Analysis 1.5 because it was combination therapy not monotherapy
31 October 2012 New search has been performed Search updated 27 January 2012; two new studies included.
31 October 2012 New citation required but conclusions have not changed Two new studies included. Byline changed; conclusions not changed.
6 May 2011 Amended For this update (2012) we added adverse events (harms) to 'Secondary outcomes.'
4 March 2010 Amended Under 'Feedback/1 Anna Rita Bilia, et al, 31 August 2009/Summary/Reply,' a clause read: "and by 0.72 in the placebo group (95 percent confidence interval, ‐1.40 to ‐0.04) ('Table 3')." It has been changed to "and by 0.72 in the placebo group (95 percent confidence interval, ‐1.40 to ‐0.04) ('Table 3')."
29 September 2008 New citation required and conclusions have changed We have modified our findings of the efficacy of Serenoa repens.
10 July 2008 New search has been performed This is a substantial update with nine new trials.
25 March 2008 Amended Converted to new review format
21 December 2007 New citation required and conclusions have changed Substantive amendment
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Notes

The text in the Background section and the Methods has been recycled from other Cochrane Reviews from the senior author (Franco 2021). Most of the evidence up to December 2020 was extracted and published as an open‐access non‐Cochrane review in which fewer databases were consulted (Trivisonno 2021), from which we also recycled text for the Discussion.

Acknowledgements

Acknowledgements from the authors

Juan Víctor Ariel Franco is a PhD candidate in the Programme of Methodology of Biomedical Research and Public Health, Universitat Autònoma de Barcelona (Spain).

We thank the authors of the previous version of this review: James Tacklind, Roderick MacDonald, Indy Rutks, Judith Stanke, and Timothy Wilt.

Acknowledgements from the previous version of this review

This work was partially funded by the National Center for Complementary and Alternative Medicine (NCCAM) Grant Number R24 AT001293 and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grant Number 1R01 DK063300‐01A2. The authors are employees of the US Department of Veterans Affairs. The contents of this systematic review are solely the responsibility of the authors and do not necessarily represent the official views of the NCCAM, the National Institutes of Health, or the Department of Veterans Affairs. We also wish to thank Maurizio Tiso, Margaret Haugh, Rich Crawford, Tatyana Shamilyan, Philipp Dahm, Yelena Slinin, and Joan Barnes for their work in translating and abstracting data from non‐English language studies.

Editorial and peer‐reviewer contributions

The Cochrane Urology Group supported the authors in the development of this review.

The following people conducted the editorial process for this article:

  • Sign‐off Editor (final editorial decision): Philipp Dahm, MD, Urology Section, Minneapolis VA Health Care System, Minneapolis, Minnesota, USA;

  • Handling Editor (selected peer reviewers, provided editorial guidance to authors, and made editorial decisions): Muhammad Imran Omar, MD, University of Aberdeen, Aberdeen, UK;

  • Managing Editor (selected peer reviewers, collated peer‐reviewer comments, provided editorial guidance to authors, edited the article): Jennifer Mariano, Cochrane Urology, USA;

  • Copy Editor (copy‐editing and production): Lisa Winer, Cochrane Copy Edit Support;

  • Peer reviewers (provided comments and recommended an editorial decision): Brendan Brwne, Emory University Department of Urology (clinical/content review), Michael Lardas, 2nd Department of Urology, Sismanoglio General Hospital, Athens, Greece (clinical/content review). One additional peer reviewer provided clinical/content peer review, but chose not to be publicly acknowledged.

The authors JVAF and JHJ are contact editors for the Cochrane Urology Group but were excluded from the editorial processing of this article.

Appendices

Appendix 1. Search strategies

1. Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library .

#1 MeSH descriptor: [Prostatic Hyperplasia] explode all trees

#2 MeSH descriptor: [Prostatism] explode all trees

#3 (Prostat*near/3 hyperplasia*):ti,ab,kw

#4 ((Prostat* near/3 hypertroph*)):ti,ab,kw

#5 ((Prostat* near/3 adenoma*)):ti,ab,kw

#6 (BPH or BPO or BPE):ti,ab,kw

#7 (prostat* near/3 enlarg*):ti,ab,kw

#8 (Prostatism):ti,ab,kw

#9 (Bladder* near/3 obstruct*):ti,ab,kw

#10 (BOO):ti,ab,kw

#11 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10

#12 (phytoterap*):ti,ab,kw

#13 (Herb* near/3 Therap*):ti,ab,kw

#14 MeSH descriptor: [Plant Extracts] explode all trees

#15 (plant*):ti,ab,kw

#16 MeSH descriptor: [Serenoa] explode all trees

#17 (serenoa):ti,ab,kw

#18 (sabal*):ti,ab,kw

#19 (Phytomedicin*):ti,ab,kw

#20 (phytosterol*):ti,ab,kw

#21 (sitosterols*):ti,ab,kw

#22 (permixon):ti,ab,kw

#23 ("saw palmetto"):ti,ab,kw

#24 #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23

#25 #11 AND #24

2. Medline (Ovid)

1. exp Prostatic Hyperplasia/

2. exp Prostatism/

3.exp Urinary Bladder Neck Obstruction/

4. (Prostat* adj3 hyperplasia*).tw.

5. (Prostat* adj3 hypertroph*).tw.

6. (Prostat* adj3 adenoma*).tw.

7. (BPH or BPO or BPE).tw.

8. (prostat* adj3 enlarg*).tw.

9. Prostatism.tw.

10. (Bladder* adj3 obstruct*).tw.

11. BOO.tw.

12 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11

13 phytoterap*.tw.

14 (Herb* adj3 Therap*).tw.

15 exp Plant Extracts/

16 plant*.tw.

17 exp Serenoa/

18 serenoa.tw.

19 sabal*.tw.

20 Phytomedicin*.tw.

21 phytosterol*.tw.

22 sitosterols*.tw.

23 permixon.tw

24 "saw palmetto".tw.

25 13 or 14 or 15 or 16 0r 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24

26 12 and 25

3. Embase (Elsevier.com)

#26. #12 AND #25

#25. #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 )

#24. 'saw palmetto':ti,ab,kw

#23. permixon:ti,ab,kw

#22. sitosterols*:ti,ab,kw

#21. phytosterol*:ti,ab,kw

#20. phytomedicin*:ti,ab,kw

#19. sabal*:ti,ab,kw

#18. serenoa:ti,ab,kw

#17. 'serenoa'/exp

#16. plant*:ti,kw

#15. 'plant extract'/exp

#14. (herb* NEAR/3 therap*):ti,ab,kw

#13. phytoterap*:ti,ab,kw

#12. #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11

#11. boo:ti,ab,kw

#10. (bladder* NEAR/3 obstruct*):ti,ab,kw

#9. prostatism:ti,ab,kw

#8. (prostat* NEAR/3 enlarg*):ti,ab,kw

#7. bph:ti,ab,kw OR bpo:ti,ab,kw OR bpe:ti,ab,kw

#6. (prostat* NEAR/3 adenoma*):ti,ab,kw

#5. (prostat* NEAR/3 hypertroph*):ti,ab,kw

#4. (prostat* NEAR/3 hyperplasia*):ti,ab,kw

#3. 'bladder obstruction'/exp

#2. 'prostatism'/exp

#1. 'prostate hypertrophy'/exp

4. Scopus

TITLE‐ABS‐KEY ( ( "Prostatic Hyperplasia" OR prostatism OR "Urinary Bladder Neck Obstruction" OR bph OR bpo OR bpe OR boo OR "Bladder obstruction" ) ) AND TITLE‐ABS‐KEY ( ( "Plant Extracts" OR plant* OR serenoa OR sabal* OR phytomedicin* OR phytosterol* OR sitosterols* OR permixon OR "saw palmetto" )

5. Science Citation Index Expanded (SCI‐E) Web of Science Clarivate

1: Ti=("Prostatic Hyperplasia" OR Prostatism OR "Urinary Bladder Neck Obstruction" OR BPH OR BPO OR BPE OR BOO OR "Bladder obstruction")

2: AB=("Prostatic Hyperplasia" OR Prostatism OR "Urinary Bladder Neck Obstruction" OR BPH OR BPO OR BPE OR BOO OR "Bladder obstruction")

3: #2 OR #1

4: TI=("Plant Extracts" OR plant* OR serenoa OR sabal* OR Phytomedicin* OR phytosterol* OR sitosterols* OR permixon OR "saw palmetto")

5: AB=("Plant Extracts" OR plant* OR serenoa OR sabal* OR Phytomedicin* OR phytosterol* OR sitosterols* OR permixon OR "saw palmetto") 1304899

6: #4 OR #5

7: #3 AND #6

6. Latin American and Caribbean Literature in Health Sciences (LILACS)

título, resumen, asunto: ("Prostatic Hyperplasia" OR "Hiperplasia prostática" OR Prostatism OR prostatismo OR "Urinary Bladder Neck Obstruction" OR "Obstrucción del cuello de la vejiga urinaria" OR "Obstrução do colo da bexiga urinária" OR BPH OR BPO OR BPE OR BOO) AND (phytotherapy OR fitoterapia OR "Plant Extracts" OR "Extratos de plantas" OR "Extractos de plantas" OR plants OR plantas OR serenoa OR sabal OR Phytomedicine OR Fitomedicina OR phytosterol OR fitosterol OR sitosterols OR sitoesteroles OR sitoesteróis OR permixon OR permixon OR "saw palmetto" OR "saw palmetto" OR Palma)

7. ClinicalTrials.gov

#1 phytoterap* OR Serenoa OR permixon OR "saw palmetto" OR sitosterols* OR sabal* OR Plant Extracts

8. World Health Organization International Clinical Trials Registry Platform (ICTRP)

#1 phytoterap* OR Serenoa OR permixon OR "saw palmetto" OR sitosterols* OR sabal* OR Plant Extracts

Appendix 2. Searches in conference proceedings

Conference Website (last access 29 Dec 2022)
American Urology Association 2020 https://www.aua2020.org/abstracts
American Urology Association 2021 https://www.aua2021.org/abstracts
American Urology Association 2022 https://www.auanet.org/AUA2022/publications
International Continence Society 2020 https://www.ics.org/2020/programme#Abstracts
International Continence Society 2021 https://www.ics.org/2021/programme
International Continence Society 2022 https://www.ics.org/2022/programme
European Association of Urology 2020, 2021, 2022 https://resource‐centre.uroweb.org/
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Appendix 3. Methods from the previous version of the review

Criteria for considering studies for this review

Types of studies

Randomized, controlled clinical trials.

Types of participants

Men with lower urinary tract symptoms (LUTS) consistent with benign prostatic hyperplasia (BPH).

Types of interventions

Comparison of preparations of SR with placebo or medical therapies for BPH with a treatment duration of at least 30 days.

Types of outcome measures
Primary outcomes

  • Urologic symptom scores (Boyarsky, American Urologic Association Symptom Index (AUA), and the International Prostate Symptom Score (IPSS)), with validated scores taking precedence over non validated ones. Both the AUA and IPSS use an identical scale of zero to 35, with mild symptoms scored 1 to 8, medium 9 to 18, and severe ≥ 19.

Secondary outcomes

  • Change in peak urine flow (mL/s).

  • Change in prostate size (measured in cubic centimeters (cc)).

  • Nocturia (times/evening).

  • Overall physician or patient assessment of urinary symptoms.

  • Adverse events (harms).

Search methods for identification of studies

See Appendices.

Electronic searches

We electronically searched the Cochrane Central Register of Controlled trials (CENTRAL), (including the database of the Cochrane Prostatic Diseases and Urologic Cancers Group) MEDLINE® (from 2008 to 2011), EMBASE (from 2001 to 1 January 2012), Web of Science®, Scopus, BIOSIS Previews®, LILACS, http://clinicaltrial.gov/, http://www.controlled‐trials.com/, and http://www.who.int/ictrp/en/.

Searching other resources

We handsearched systematic reviews, references, clinical‐practice guidelines, and conference abstracts.

Data collection and analysis

We assessed mean urologic symptom scores (IPSS, AUA), nocturia (# times), peak urine flow (mL/s), and prostate size (cc). The number and per cent of men reporting specific harms were also evaluated.

For the primary analysis (of the stated primary and secondary outcomes), all trials including SR in mono preparations and in combination were analyzed separately (e.g., SR versus placebo or active controls, SR + Urtica dioica versus placebo or controls). We pooled studies that were deemed clinically similar and provided sufficient information.

Selection of studies

In this update, two review authors (JT, RM) decided on eligibility.

Data extraction and management

Two review authors (JT, RM) independently assessed study characteristics and extracted data. Missing or additional information was sought from authors/sponsors. Extracted data were reviewed by the principal review author and discrepancies were resolved by discussion.

Assessment of risk of bias in included studies

As a measure of overall methodologic study quality – and bias – we assessed scales and criteria developed by Schulz and The Cochrane Collaboration (Cochrane Handbook 2011; Schulz 1995). The following seven criteria were addressed.

  • Selection bias I (Was there an articulated rule for allocating interventions based on chance?).

  • Selection bias II (Was there any foreknowledge of the allocation of interventions by anyone?).

  • Blinding bias I (During the course of the trial were study participants and personnel blinded to the knowledge of who received which intervention?).

  • Blinding bias II (Were the outcome assessors blinded to who received the intervention and who did not?).

  • Attrition bias (Did the trial assess all patients, or account for those not assessed?).

  • Reporting bias (Were outcomes selectively reported?).

  • Other bias (Were arms assessed differently?).

Each criterion was answered by 'low risk', 'unclear risk', and 'high risk', and summarized here (Figure 1; Figure 1). For the main outcome, we also assessed the quality of evidence in the summary of findings Table for the main comparison using GRADEPro (GRADEPro 2008).

Measures of treatment effect

We performed our statistical analysis according to the Cochrane Handbook for Systematic Reviews of Interventions (Cochrane Handbook 2011). Dichotomous outcomes were expressed using risk ratios (RR) or absolute risk reductions (RD), using the Mantel‐Haenszel method. Continuous outcomes were expressed as mean differences (MD), or, for unequal scales, standardized mean differences (SMD). To minimize the uncertainty of the pooled‐effect estimate, we used an inverse variance method, which allowed larger trials with smaller SEM (standard error of the mean) more weight over smaller trials with larger SEM.

All outcome measures utilized 95% confidence intervals (CI), with a P value of ≤ 0.05 considered to be statistically significant.

Unit of analysis issues

Quasi‐randomized trials were not included.

Dealing with missing data

To assess the per cent change of patients' urologic symptoms, a modified intention‐to‐treat (ITT) was performed (i.e., men who dropped out or were lost to follow‐up were considered to have had worsening symptoms) (Lavori 1992). The denominator for the modified ITT analysis included the number randomized to treatment at baseline and the numerator included the number completing the trial and showing improvement.

Assessment of heterogeneity

We assessed for heterogeneity by using the I₂ statistic. If a meta‐analysis had an I₂ of > 50%, we conducted a descriptive sensitivity analysis.

Assessment of reporting biases

To minimize reporting bias, we cross‐referenced trials and their protocols, compared systematic reviews to their included studies, and contacted authors.

Data synthesis

Assuming some level of unexplained heterogeneity among trials, we used a random‐effects model to adjust for effect size inconsistency.

Subgroup analysis and investigation of heterogeneity

We conducted no a priori analyses by subgroup. For investigation of heterogeneity, see Assessment of heterogeneity.

Sensitivity analysis

See Assessment of heterogeneity.

Previous search methods (appendix)

A. We searched Google Scholar using all combinations of the following categories:

  1. prostatic hyperplasia OR bph OR benign prostatic hyperplasia;

  2. serenoa repens OR s. repens OR sabal serrulata OR saw palmetto;

  3. rct OR randomized controlled trial OR randomised controlled trial.

Restrictions were by years (2008 to 2011) and category (Medicine, Pharmacology, and Veterinary Science).

B. We searched Ovid MEDLINE® from 2008 to 2011 by crossing an optimally sensitive search strategy for trials from The Cochrane Collaboration with the following MeSH search terms.

  1. prostatic hyperplasia.mp.

  2. phytosterols.mp.

  3. plant extracts.mp.

  4. sitosterols.mp.

  5. serenoa repens.mp.

  6. sabal serrulata.mp.

  7. saw palmetto.mp.

  8. or/2‐7

  9. 1 and 8

  10. limit 9 to randomized controlled trial

  11. limit 11 to yr="2008 ‐ 2011"

We included all subheadings (Dickersin 1994).

C. We also searched the following using the same key terms we used for the Ovid MEDLINE® search and limited by the dates 2008 to 2011:

  1. The Cochrane Library, including the database of the Cochrane Prostatic Diseases and Urologic Cancers Group, the Cochrane Field for Complementary Medicine, and the Cochrane Central Register of Controlled Trials (CENTRAL);

  2. Web of Science®;

  3. CINAHL®;

  4. BIOSIS Previews®;

  5. LILACS;

  6. http://clinicaltrial.gov/;

  7. http://www.controlled-trials.com/;

  8. http://www.who.int/ictrp/en/.

D. EMBASE was searched from 2001 to 1 January 2012 using the following strategy.

Set Items Description
S1 8684 PROSTATIC (W) HYPERPLASIA
S2 7071 BPH/TI,AB
S3 240 SAW (W) PALMETTO
S4 179 SERENOA (W) REPENS
S5 150 PERMIXON
S6 31 SABAL (W) SERRULATA
S7 252 (S1 OR S2) AND (S3 OR S4 OR S5 OR S6)
S8 276370 RANDOMIZED (W) CONTROLLED (W) TRIAL? OR RANDIMISED (W)CONTROLLE‐D (W) TRIAL?
S9 11351 RCT?
S10 51 S7 AND (S8 OR S9)
S11 37 S10/2001:2011
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There were no language restrictions.

Data and analyses

Comparison 1. Serenoa repens versus placebo or no intervention.

Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1.1 Urologic symptom score (short term—sensitivity analysis) 9 1681 Mean Difference (IV, Random, 95% CI) ‐0.90 [‐1.74, ‐0.07]
1.2 Urologic symptom score (short term—all studies) 12 1841 Mean Difference (IV, Random, 95% CI) ‐0.77 [‐1.44, ‐0.11]
1.3 Quality of life (short term—sensitivity analysis) 5 1001 Mean Difference (IV, Random, 95% CI) ‐0.20 [‐0.40, 0.00]
1.4 Quality of life (short term—all studies) 8 1161 Mean Difference (IV, Random, 95% CI) ‐0.16 [‐0.32, 0.00]
1.5 Adverse events (sensitivity analysis) 12 2399 Risk Ratio (M‐H, Random, 95% CI) 1.01 [0.77, 1.31]
1.6 Adverse events 14 2539 Risk Ratio (M‐H, Random, 95% CI) 0.95 [0.72, 1.26]
1.7 Urologic symptom score (subgroup analysis—hexanic vs non‐hexanic extract) 12 1841 Mean Difference (IV, Random, 95% CI) ‐0.77 [‐1.44, ‐0.11]
1.7.1 Hexanic extract 3 437 Mean Difference (IV, Random, 95% CI) ‐0.27 [‐0.99, 0.44]
1.7.2 Non‐Hexanic extract 9 1404 Mean Difference (IV, Random, 95% CI) ‐0.99 [‐1.91, ‐0.07]
1.8 Urologic symptom score (long term—sensitivity analysis) 3 898 Mean Difference (IV, Random, 95% CI) 0.07 [‐0.75, 0.88]
1.9 Urologic symptom score (long term—all studies) 5 1018 Mean Difference (IV, Random, 95% CI) 0.01 [‐0.58, 0.59]
1.10 Quality of life (long term—sensitivity analysis) 3 882 Mean Difference (IV, Random, 95% CI) ‐0.11 [‐0.41, 0.19]
1.11 Quality of life (long term—all studies) 5 1002 Mean Difference (IV, Random, 95% CI) ‐0.12 [‐0.37, 0.13]
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Comparison 2. Serenoa repens in combination with other phytotherapy versus placebo or no intervention.

Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
2.1 Urologic symptom score 4 460 Mean Difference (IV, Random, 95% CI) ‐2.41 [‐4.54, ‐0.29]
2.2 Adverse events 4 481 Risk Ratio (M‐H, Random, 95% CI) 0.91 [0.58, 1.41]
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Characteristics of studies

Characteristics of included studies [ordered by study ID]

Argirović 2013.

Study characteristics
Methods Study design: parallel‐group randomized trial
Study dates: June 2008 to September 2010
Setting: outpatient, single center, national
Country: Serbia
Participants Inclusion criteria: men > 50 years of age, a total IPSS of 7 to 18, QoL > 3, Qmax of 5 to 15 mL/s, with PVR < 150 mL, prostate volume < 50 mL, measured by transrectal ultrasound (TRUS) and serum PSA 1.5 to 4 ng/mL
Exclusion criteria: significant bladder outlet obstruction (PVR > 200 mL, Qmax < 5 mL/s), 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
Sample size: 199 participants
Age (years):
Group 1 (SD): 65.9 ± 7.4
Group 2 (SD): 56.8 ± 7.7
IPSS score (baseline)
Group 1 (SD): 15.6 ± 3.2
Group 2 (SD): 16.2 ± 4.9
Prostate size:
Group 1 (SD): 31.2 ± 4.2
Group 2 (SD): 38.6 ± 11.6
Interventions Group 1 (n = 81): Serenoa repens (Prostamol Uno) 320 mg daily
Group 2 (n = 87): only co‐intervention
Co‐interventions: tamsulosin (Tamsol) 0.4 mg
A third group of only Serenoa repens (without tamsulosin) was not included in the analysis as it was not relevant to this review.
Outcomes Urinary symptoms

  • How measured: IPSS

  • Time points measured: 0, 3, and 6 months

  • Time points reported: 6 months


Quality of life

  • How measured: IPSS‐QoL score

  • Time points measured: 0, 3, and 6 months

  • Time points reported: 6 months


Adverse events

  • How measured: not reported

  • Time points measured: not reported

  • Time points reported: 6 months

  • Other outcomes measured in the trial: Qmax, prostate volume, PSA, IPSS obstructive and irritative subscore and postvoiding residual volume
Notes Funding sources: not available
Conflict of interest: not available
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Barry 2011.

Study characteristics
Methods Study design: parallel‐group randomized trial
Study dates: June 2008 to October 2010
Setting: multicenter, outpatient, national
Country: USA
Participants Inclusion criteria:

  • Men ≥ 45 years old

  • Qmax ≥ 4 mL/s

  • AUASI scores ≥ 8 and ≤ 24 at 2 screening visits


Exclusion criteria:

  • Prior invasive treatment for BPH

  • Recent alpha‐blocker (alpha‐blocker (1 month), 5‐alpha reductase inhibitor (3 months), or phytotherapy including saw palmetto extract (3 months) treatment; recent treatment with other medications affecting LUTS

  • Creatinine > 2.0 mg/dL

  • Liver function tests more than 3 times normal

  • Coagulopathy or anticoagulation

  • Recent unstable medical conditions

  • Neurologic conditions affecting urination

  • Recent prostatitis or repeated urinary tract infections

  • Prostate or bladder cancer or a PSA level > 10 ng/mL

  • Recent or planned genitourinary instrumentation

  • Severe incontinence

  • Recent diuretic initiation or dose change

  • Medical conditions likely to prevent completion


Sample size: 369 randomized participants
Age (years):
Group 1 mean (SD): 61.25 (8.72)
Group 2 mean (SD): 60.7 (8.08)
IPSS/AUASI score (baseline):
Group 1 mean (SD): 14.42 (4.29)
Group 2 mean (SD): 14.69 (4.75)
Prostate size:
Group 1: not available
Group 2: not available
Interventions Group 1 (n = 176): one, two, and then three 320 mg chocolate‐colored gelcaps daily containing a standardized saw palmetto fruit extract with dose escalations at 24 and 48 weeks. Saw palmetto extract used was standardized to a reference chromatogram (with 85% to 95% fatty acids as marker substances). The phytotherapy used in this trial was a proprietary lipidic ethanolic extract of ripe, dried saw palmetto berries, Serenoa repens (W.Bartram) Small (Arecaceae), manufactured by Rottapharm/Madaus, Cologne, Germany and sold as PROSTAURGENIN UNO capsules.
Group 2 (n = 181): an identical number of placebo gelcaps escalated similarly
Co‐interventions: none
Outcomes Urinary symptoms

  • How measured: AUASI score

  • Time points measured: 12, 24, 36, 48, 60, and 72 weeks

  • Time points reported: 72 weeks

  • Subgroups: age (61 years) and AUASI baseline score (16)


Quality of life

  • How measured: IPSS‐QoL/BPH impact index

  • Time points measured: 12, 24, 36, 48, 60, and 72 weeks

  • Time points reported: 72 weeks

  • Subgroups: none


Adverse events

  • How measured: blood counts, basic blood chemistries, coagulation tests, electrocardiogram, and urinalysis

  • Time points measured: 4 weeks after each dose increase and at the end of the study, and 30 days of treatment discontinuation

  • Time points reported: 72 weeks

  • Subgroups: none


Other outcomes measured in the trial: Qmax, a global assessment of improvement, PVR, PSA, erectile and ejaculatory function, incontinence, sleep quality, NIH‐CPSI
Notes Funding sources: this study was funded by co‐operative agreements from the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases: U01 DK63795, U01 DK63797, U01 DK63825, U01 DK63835, U01 DK63866, U01 DK63833, U01 DK63862, U01 DK63840, U01 DK63883, U01 DK63831, U01 DK63778, and U01 DK63788. Support was also provided by the National Center for Complementary and Alternative Medicine and the Office of Dietary Supplements, NIH. Rottapharm/Madaus, Cologne, Germany donated the saw palmetto fruit extract and matching placebo.
Declarations of interest: Rottapharm/Madaus had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation or approval of the manuscript. Rottapaharm/Madaus provided nonbinding comments to the authors on a draft of the manuscript. Individual authors:

  • Barry serves on the Board of and receives salary support as President of the not‐for‐profit (501[3]c) Foundation for Informed Medical Decision Making (http://www.fimdm.org), which develops content for patient education programs. The foundation has an arrangement with a for‐profit company, Health Dialog, to co‐produce and market these programs to healthcare organizations.

  • Nickel reports receiving consultation funds from GlaxoSmithKline, Pfizer, Watson, Astellas, Ferring, Taris, Triton, Farr Labs, Trillium, Cernelle, and Johnson & Johnson; has provided expert testimony for GlaxoSmithKline; and has received payment for development of educational presentations from the Canadian Urological Association.

  • Crawford reports receiving payment for lectures from Ferring Pharmaceuticals.

  • Andriole reports receiving consultation funds from Amgen, Bayer, Caris, France Foundation, GenProbe, GlaxoSmithKline, Steba Biotech, Ortho‐Clinical Diagnostics, and Ferring Pharmaceuticals, and has received royalties from “Up to Date.” He reports receiving payment for the development of educational presentations from Amgen, and has stock/stock options in Envisioneering Medical, Viking Medical, Augmenix, and Cambridge Endo. Dr Andriole reports receiving travel/accommodations/meeting expenses from Amgen, Augmenix, Bayer, Cambridge Endo, Caris, France Foundation, GenProbe, Myriad Genetics, Steba Biotech, and Ortho Clinical Diagnostics.

  • Naslund reports receiving payment for lectures from Glaxo and Sanofi as well as payment for the development of educational presentations for the France Foundation.

  • Lee reports that funds were paid to her institution for consultancy to Merck.

  • McVary reports receiving consultancy funds from Lilly/ICOS, Allergan, NIDDK, Watson Pharmaceuticals, and NeoTract, as well as payment for lectures from GlaxoSmithKline.
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BASTA 2010.

Study characteristics
Methods Study design: parallel‐group randomized trial
Study dates: December 2006 to November 2008
Setting: outpatient, multicenter
Country: Germany, Lithuania, Romania, Slovak Republic, Poland, and Russia
Participants Inclusion criteria:

  • Male patients, 50 years or older

  • IPSS ≥ 13

  • Stable IPS score over the 4‐week run‐in period allowing a deviation of ± 2 points to be assessed at the randomization visit (V2)

  • PSA < 10.0 ng/mL

  • Maximum urinary flow (Qmax) ≤ 15 mL/s

  • Residual urinary volume ≤ 100 mL

  • Voided volume > 150 mL

  • Prostate volume > 30 mL

  • Diagnosis of BPH upon palpation

  • QoL ≥ 3 (assessed by QoL question of the IPSS)


Exclusion criteria (men with a history of the following):

  • Prostate cancer

  • Any other malignancy

  • Bladder neck or prostate surgery

  • Lower urinary tract infection (> 10,000 CFU/mL urine)

  • Cystolithiasis

  • Irradiation of the pelvis

  • Any disorders causing micturition disturbances, including prostatitis, neurogenic voiding disturbances

  • Urethral stricture

  • Previous venereal infections

  • Systemic immunological disorder

  • Diabetes mellitus

  • Diabetic polyneuropathy

  • Neurologic disorders

  • Abnormal liver and kidney function (twice the upper normal limit of serum aminotransferases and/or bilirubin, creatinine > 160 µmol/L), assessed at the screening visit

  • Treatment for BPH with an alpha‐blocker or any phytotherapeutic agent within 6 weeks before randomization

  • Treatment for BPH with a 5‐alpha‐reductase inhibitor within 6 months before randomization

  • Diuretics or drugs with antiandrogenic or alpha‐receptor properties administered during the preceding 6 months for non‐urological diseases (hypertension, cerebrovascular insufficiency) before randomization

  • Anticholinergic agents, anti‐inflammatory drugs (NSAIDs, steroids) or any medication affecting detrusor, external or internal sphincter muscle

  • Other medications to treat bladder dysfunction: tolterodine HCL, propiverine HCL, solifenacin succinate, and trospium chloride within 6 weeks before randomization

  • Known hypersensitivity to study drug

  • Drug abuse

  • Participation in another clinical trial in the previous 3 months


Sample size: 1011 participants
Age (years):
Group 1 mean (SD): 65.14 (7.67)
Group 2 mean (SD): 64.61 (7.69)
Group 4 mean (SD): 64.14 (7.69)
IPSS score (baseline): not available
Prostate size (cm3): not available
Interventions Group 1 (n = 334; per‐protocol set): ethanol extract of Sabal serrulata (Prostamol) once daily 320 mg orally for 12 months
Group 1 (n = 330; per‐protocol set): hexane extract of Sabal serrulata (Permixon) once daily 2 x 160 mg orally for 12 months
Group 2 (n = 126; per‐protocol set): placebo of similar characteristics for 12 months
Co‐interventions: none
Outcomes Urinary symptoms

  • How measured: IPSS

  • Time points measured: baseline and 7 visits until 12 months

  • Time points reported: narrative description at 12 months

  • Subgroups: severity (narrative)


Quality of life

  • How measured: quality of life index

  • Time points measured: baseline and 7 visits until 12 months

  • Time points reported: narrative description at 12 months

  • Subgroups: none


Adverse events

  • How measured: MedDRA classification, including plausibility (possible/probable or unrelated)

  • Time points measured: possibly the cumulative incidence

  • Time points reported: possibly the cumulative incidence

  • Subgroups: none


Other outcomes measured in the trial: PVR and Qmax
Notes Funding sources: Berlin‐Chemie AG (Menarini Group)
Declarations of interest: not reported
Unpublished data only from the clinical trial registry: www.clinicaltrialsregister.eu/ctr-search/trial/2006-003532-30/results
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Bauer 1999.

Study characteristics
Methods Study design: parallel‐group randomized trial
Study dates: not available
Setting: outpatient, multicenter, international
Country: Germany/Italy
Participants Inclusion criteria: confirmed diagnosis of BPH with enlargement of the prostate, symptoms of obstruction, and a maximum flow of < 15 mL/s
Exclusion criteria: men treated for BPH within 1 month of the trial start; prostate cancer; acute urinary tract infection; chronic prostatitis; neurogenic bladder
Sample size: 101 participants
Age (years): mean 66.1
IPSS score (baseline): Sabal extract 9.6; placebo 8.9
Prostate size: Sabal extract 34.5 cm3; placebo 31.7 cm3
Interventions Group 1 (n = not available): Sabal extract (LG166/S ‐ Talso Uno) 160 mg twice daily
Group 2 (n = not available): matching placebo
Outcomes Urinary symptoms

  • How measured: IPSS

  • Time points measured: 6 months

  • Time points reported: 6 months (graphic/% ‐ unusable data)


Adverse events

  • How measured: not reported

  • Time points measured: possibly the cumulative incidence

  • Time points reported: narratively


Other outcomes measured in the trial: Qmax, prostate volume, and sexual function
Notes Funding sources: Sanofi (industry)
Conflicts of interest: not available
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Bent 2006.

Study characteristics
Methods Study design: parallel group randomized trial
Study dates: July 2001 to May 2004
Setting: multicenter, outpatient, national
Country: USA
Participants Inclusion criteria:

  • Men > 49 years old

  • AUASI ≥ 8

  • Qmax < 15 mL/s


Exclusion criteria:

  • Qmax < 4 mL/s

  • Residual volume > 250 mL

  • History of:

    • prostate cancer;

    • surgery for BPH;

    • urethral stricture;

    • neurological bladder.

  • Creatinine > 2.0 mg/dL

  • PSA > 4.0 ng/dL

  • Users of medications known to affect urination

  • Severe concomitant disease


Sample size: 225 participants
Age (years):
Group 1 mean (SD): 62.9 (8.0)
Group 2 mean (SD): 63.0 (7.4)
AUASI score (baseline):
Group 1 mean (SD): 15.7 (5.7)
Group 2 mean (SD): 15.0 (5.3)
Prostate size (mL):
Group 1 mean (SD): 34.7 (13.9)
Group 2 mean (SD): 33.9 (15.2)
Interventions Group 1 (n = 112): saw palmetto carbon dioxide extract capsules, 160 mg twice daily orally for 14 months
Group 2 (n = 113): placebo capsules twice a day orally for 14 months
Co‐interventions: none
Outcomes Urinary symptoms

  • How measured: AUASI

  • Time points measured: 1, 3, 6, 9, and 12 months

  • Time points reported: 1, 3, 6, 9, and 12 months

  • Subgroups: AUASI score (20) and PSA levels (1.4 ng/dL)


Quality of life

  • How measured: BPH Impact Index/36‐Item Short‐Form Health Survey (SF‐36)

  • Time points measured: 1, 3, 6, 9, and 12 months

  • Time points reported: 1, 3, 6, 9, and 12 months

  • Subgroups: none


Adverse events

  • How measured: not described (classified as serious/non‐serious)

  • Time points measured: possibly at 12‐month follow‐up

  • Time points reported: possibly at 12‐month follow‐up

  • Subgroups: none


Other outcomes measured in the trial: Qmax, prostate size, PVR, PSA, creatinine, testosterone, and other laboratory values
Notes Funding sources: supported by a grant (1 RO1 DK56199‐01, to Dr Avins) from the National Institute of Diabetes and Digestive and Kidney Diseases and a grant (1 K08 ATO1338‐01, to Dr Bent) from the National Center for Complementary and Alternative Medicine
Declarations of interest: Dr Kane reports receiving consulting fees from American Medical Systems and Intuitive Surgical and lecture fees from Merck and TAP. Dr Shinohara reports having received lecture fees from GlaxoSmithKline and Pfizer. Dr Avins reports receiving grant support from Merck.
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Boccafoschi 1983.

Study characteristics
Methods Study design: double‐blind, controlled clinical trial
Study dates: not available
Setting: outpatient, single center and national
Country: Italy
Participants Inclusion criteria: not available
Exclusion criteria: not available
Sample size: 22 randomized participants
Age (years):
Group 1 mean (range): 68 (55 to 80)
Group 2 mean (range): 68 (54 to 78)
IPSS score (baseline): not available
Prostate size: not available
Interventions Group 1 (n = 11): Permixon 160 mg, 2 capsules orally (1 in the morning and the other in the evening) for 60 days (total dose per day: 320 mg)
Group 2 (n = 11): placebo 2 capsules orally (1 in the morning and the other in the evening) for 60 days
Co‐interventions: none
Outcomes Adverse events

  • How measured: not described

  • Time points measured: 60 days

  • Time points reported: 60 days

  • Subgroups: none


Other outcomes measured in the trial: dysuria, nocturia, and urinary frequency
Notes Funding: not specified
Conflicts of interest: not specified
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Carbin 1990.

Study characteristics
Methods Study design: parallel‐group randomized trial
Study dates: not available
Setting: outpatient, multicenter, international
Country: Sweden/Denmark
Participants Inclusion criteria:

  • Men between 50 and 80 years old

  • Presence of BPH

  • Prostate examination

  • Acid phosphatase determination


Exclusion criteria: need for surgery or residual urine > 300 mL
Sample size: 55
Age (years):
Group 1 mean (SD): 62.0 (± 6.7)
Group 2 mean (SD): 61.2 (± 5.8)
IPSS/AUASI score (baseline):
Group 1 mean (SD): 6.8 (± 1.4)
Group 2 mean (SD): 6.6 (± 1.3)
Prostate size: not available
Interventions Group 1 (n = 26): Curbicin contains 160 mg of standardized extract PS6 from Cucurbita pepo L. seeds (80 mg) and Sabal serrulata fruits (80 mg). The tablets were swallowed whole in a dose of 2 tablets 3 times a day (possibly 3 months).
Group 2 (n = 27): placebo tables were identical in smell, consistency, shape, color, and taste to the active compound (possibly 3 months)
Co‐interventions: none
Outcomes Adverse events

  • How measured: not described (they were reported in a sentence: “No untoward side effects were reported”)

  • Time points measured: not available (possibly 3 months)

  • Time points reported: not available

  • Subgroups: none


Other outcomes measured in the trial: Qmax, micturition time, residual volume, diurnal frequency, nocturnal frequency, and duration of illness. Subjective symptoms such as dysuria and global assessment of the therapy were evaluated with a scale: much better, better, the same, worse.
Notes Funding sources: not available
Declarations of interest: not available
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Champault 1984.

Study characteristics
Methods Study design: parallel‐group, double‐blind, placebo‐controlled randomized trial
Study dates: study dates not available
Setting: outpatient, single center, national
Country: France
Participants Inclusion criteria: not available
Exclusion criteria:

  • Patients with an acute or unstable episode

  • Adenomas requiring early surgery

  • Carcinoma of the prostate

  • Prostatic syndromes associated with other genitourinary conditions


Sample size: 110 outpatients randomized
Age (years): not available
IPSS score (baseline): not available
Prostate size: not available
Interventions Group 1 (n = 55): hexane extract of Serenoa repens (PA109/Permixon) 320 mg per day (2 x 80 mg x 2) orally for 30 days
Group 2 (n = 55): placebo 320 mg per day (2 x 80 mg x 2) orally for 30 days
Co‐interventions: none
Outcomes Adverse events

  • How measured: standard blood chemistry

  • Time points measured: 30 days

  • Time points reported: 30 days

  • Subgroups: none


Other outcomes measured in the trial: dysuria, patient self‐rating and physician’s rating, Qmax
Notes Funding sources: not available
Declarations of interest: not available
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Coulson 2013.

Study characteristics
Methods Study design: randomized, double‐blind, placebo‐controlled clinical trial
Study dates: study dates not available
Setting: outpatient, single center, national
Country: Australia
Participants Inclusion criteria:

  • Healthy males between 40 and 80 years old

  • Medically diagnosed BPH

  • IPSS > 8


Exclusion criteria:

  • Use of any therapy for BPH or other urological symptoms within the last 30 days

  • Recently started a bladder‐training program

  • Urogenital surgery within the last 6 months

  • Bladder biopsy and/or cystoscopy and biopsy within the past 30 days

  • An indwelling catheter or practiced self‐catheterization

  • Medically diagnosed with chronic persistent local pathology (i.e. interstitial cystitis, bladder stones)

  • Were receiving/prescribed anticoagulation therapy

  • Diagnosed with severe renal and/or hepatic insufficiency

  • Diagnosed with genital anatomical deformities

  • Uncontrolled diabetes mellitus

  • History of spinal cord injury

  • Uncontrolled psychiatric disorder and/or abnormal secondary sexual characteristics

  • Diagnosed prostatic cancer

  • Current or a history of chronic alcohol and/or illicit drug abuse

  • Had participated in any other clinical trial during the last 30 days


Sample size: 60 randomized participants
Age (years):
Group 1 mean (SD): 63 (10.1)
Group 2 mean (SD): 64.9 (9.6)
IPSS score (baseline):
Group 1 median: 19.5
Group 2 median: 18
Prostate size: not available
Interventions Group 1 (n = 32): ProstateEZE Max is a commercially available capsule‐form herbal formulation containing Cucurbita pepo seed oil (160 mg), Epilobium parviflorum extracts (equivalent to 500 mg dry herb), lycopene (2.1 mg), Prunus africana (equivalent to 15 g dry stem, standardized to ‐sitosterol), and Serenoa repens (equivalent to 660 mg of dry leaf per capsule) with the excipients lecithin, hydrogenated vegetable oil and beeswax and soya oil in a blue soft gel capsule. Administered as 1 capsule per day with food for 3 months
Group 2 (n = 25): the placebo product contained the same amounts of lecithin, hydrogenated vegetable oil, and beeswax, but had higher levels of soya oil in the same soft gel capsule. Administered as 1 capsule per day with food for 3 months
Co‐interventions: none
Outcomes Urinary symptoms

  • How measured: IPSS

  • Time points measured: 1, 2, and 3 months

  • Time points reported: 1, 2, and 3 months

  • Subgroups: none


Adverse events

  • How measured: participant plasma electrolytes (PE), liver function tests (LFT), and PSA

  • Time points measured: 3 months

  • Time points reported: 3 months

  • Subgroups: none


Other outcomes measured in the trial: daytime and nighttime urinary frequency
Notes Funding sources: funding and study medication for the project were received from the clinical trial sponsor, Totally Natural Products, Sydney, Australia
Declarations of interest: funding and study medication for the project were received from the clinical trial sponsor, Totally Natural Products, Sydney, Australia. The sponsor had no involvement in the collection, analysis or interpretation of the data, writing of the report, or the decision to submit the paper for publication.
Retrospectively registered: ACTRN12610000168055
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Descotes 1995.

Study characteristics
Methods Study design: double‐blind, placebo‐controlled randomized trial
Study dates: not available
Setting: outpatient, multicenter and national
Country: France
Participants Inclusion criteria:

  • Dysuria

  • Daytime and nocturnal urinary frequency of at least 8 weeks’ standing

  • Qmax ≥ 5 mL/s


Exclusion criteria:

  • Excessively mild symptoms of BPH (nocturnal urinary frequency < 2) of recent onset (< 8 weeks)

  • Excessively severe symptoms of BPH such as:

    • Qmax < 5 mL/s;

    • incontinence;

    • bladder distension;

    • acute urinary retention;

    • other complication of BPH.

  • Associated urogenital infection

  • Hematuria

  • Diabetes

  • Neuropathy

  • Pelvic cancer

  • History of surgery for BPH or that could have induced dysuria


Sample size: 176 randomized participants
Age (years):
Group 1 mean (SD): 65.6 (8.4)
Group 2 mean (SD): 67 (7.6)
IPSS score (baseline): not available
Prostate size: not available
Interventions Group 1 (n = 82): Permixon 160 mg orally twice daily (morning and evening) for 30 days
Group 2 (n = 94): placebo orally twice daily (morning and evening) for 30 days
Co‐interventions: none
Outcomes Adverse events

  • How measured: not described (the treatment tolerability was graded on a 3‐point scale)

  • Time points measured: 0 and 30 days

  • Time points reported: 0 and 30 days

  • Subgroups: none


Other outcomes measured in the trial: patient‐based global efficacy and physician‐based global efficacy, improvement of dysuria, Qmax
Notes Funding sources: not available
Declarations of interest: 1 author (P Deschaseaux) works in Laboratoires Pierre Fabre, which manufactures Permixon
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Gerber 2001.

Study characteristics
Methods Study design: parallel‐group randomized trial
Study dates: January 1999 to July 2000
Setting: outpatient, multicenter, national
Country: USA
Participants Inclusion criteria:

  • Men ≥ 45 years old

  • IPSS score ≥ 8


Exclusion criteria: men were ineligible if they had:

  • prostate surgery;

  • prostate cancer or urethral stricture disease;

  • recently been treated with finasteride, saw palmetto or alternative therapy for BPH (6 months), or alpha‐receptor blocker (1 month).


Sample size: 85
Age (years):
Group 1 mean (SD): 64.6 (± 9.9)
Group 2 mean (SD): 65.3 (± 9.7)
IPSS/AUASI score (baseline):
Group 1 mean (SD): 16.7 (± 4.9)
Group 2 mean (SD): 15.8 (± 4.8)
Prostate size: not available
Interventions Group 1 (n = 41): men received saw palmetto 160 mg twice daily. The saw palmetto product was standardized to contain 85% to 95% fatty acids and sterols and was manufactured by Nutraceutical, Ogden, Utah.
Group 2 (n = 44): the only other ingredients in the saw palmetto and placebo capsules were extra‐virgin olive oil, gelatin, and glycerin
Co‐interventions: none
Outcomes Urinary symptoms

  • How measured: IPSS score

  • Time points measured: 2, 4, and 6 months

  • Time points reported: 2, 4, and 6 months

  • Subgroups: none


Quality of life

  • How measured: IPSS QoL

  • Time points measured: 2, 4, and 6 months

  • Time points reported: 2, 4, and 6 months

  • Subgroups: none


Adverse events

  • How measured: not described (they were reported in a sentence: “The only other adverse reaction reported was mild gastric distress by 1 patient in the saw palmetto group.”)

  • Time points measured: not available (possibly 2, 4, and 6 months)

  • Time points reported: not available

  • Subgroups: none


Other outcomes measured in the trial: sexual function, Qmax
Notes Funding sources: the study drug and placebo were provided by Nutraceutical Corp., Ogden, Utah
Declarations of interest: not available
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Glémain 2002.

Study characteristics
Methods Study design: parallel‐group randomized trial
Study dates: not available
Setting: outpatient, multicenter and national
Country: France
Participants Inclusion criteria:

  • Men above 50 years old

  • IPSS ≥ 13

  • LUTS

  • Diagnosed BPH

  • Qmax of 7 to 15 mL/s for a voided volume of at least 120 mL


Exclusion criteria:

  • History of surgical intervention in the bladder, prostate, or pelvic area

  • PVR > 300 mL

  • Ailments that could affect urination or the final evaluation (bladder disease, prostate cancer, urinary tract infection, urethral stricture)

  • Stopping treatment for BPH for less than 15 days (for alpha‐blockers) or less than 1 month (for plant extract or finasteride)

  • Hepatic insufficiency

  • Cardiovascular or cerebrovascular event

  • Neurological disease

  • Allergy to alpha‐blockers

  • Life‐threatening pathology


Sample size: 329 randomized participants
Age (years):
Group 1 mean (SD): 64.4 (7.7)
Group 2 mean (SD): 65.2 (7.9)
IPSS score (baseline):
Group 1 mean (SD): 16.3 (5.6)
Group 2 mean (SD): 16.2 (5.2)
Prostate size:
Group 1 mean (SD): 38.6 (15)
Group 2 mean (SD): 40.8 (16.5)
Interventions Group 1 (n = 161): placebo orally after breakfast and dinner for 52 weeks
Group 2 (n = 165): Serenoa repens 160 mg orally (Permixon) after breakfast and dinner for 52 weeks
Co‐interventions: tamsulosin (Omix LP 0.4 mg) orally after breakfast
Outcomes Urinary symptoms

  • How measured: IPSS score

  • Time points measured: 0, 4, 13, 26, 39, and 52 weeks

  • Time points reported: 0, 4, 13, 26, 39, and 52 weeks

  • Subgroups: none


Quality of life

  • How measured: IPSS‐QoL and UROLIFE BPH QoL9

  • Time points measured: 0, 4, 13, 26, 39, and 52 weeks

  • Time points reported: 0, 4, 13, 26, 39, and 52 weeks

  • Subgroups: none


Adverse events

  • How measured: not described (classified as serious/non‐serious)

  • Time points measured: not available (possibly 52 weeks)

  • Time points reported: not available (possibly 52 weeks)

  • Subgroups: none


Other outcomes measured in the trial: sexual function was assessed using the Brief Male Sexual Function Inventory (BMSFI), Qmax
Notes Funding sources: not available
Declarations of interest: not available
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Hizli 2007.

Study characteristics
Methods Study design: open‐label prospective study
Study dates: May 2005 to November 2005
Setting: outpatient, multicenter, national
Country: Turkey
Participants Inclusion criteria:

  • IPSS ≥ 10

  • Qmax 5 to 15 mL/s

  • PVR ≤ 150 mL

  • Prostate volume ≥ 25 cm3

  • PSA ≤ 4 ng/mL


Exclusion criteria:

  • History of bladder disease likely to affect micturition

  • Urethral stenosis

  • Prostate cancer

  • Pelvic radiotherapy

  • Repeated infection of the urinary tract or chronic bacterial prostatitis, or any other disease that causes urinary problems

  • Men with clinically significant cardiovascular disease

  • Hematuria

  • Insulin‐dependent diabetes mellitus

  • A history of severe hepatic failure or abnormal liver function tests

  • Concomitant medication

  • Hypersensitivity to 1 of the study drugs

  • Having participated in another clinical trial in the previous 3 months


Sample size: 60 randomized participants
Age (years):
Group 1 mean (SD): 58.9 (5.7)
Group 2 mean (SD): 56.8 (7.8)
Group 3 mean (SD): 60.2 (6.3)
IPSS score (baseline):
Group 1 mean (SD): 16.2 (4.7)
Group 2 mean (SD): 18.0 (4.9)
Group 3 mean (SD): 15.6 (3.2)
Prostate size:
Group 1 mean (SD): 38.6 (11.6)
Group 2 mean (SD): 35.2 (10.3)
Group 3 mean (SD): 31.2 (4.2)
Interventions Group 1 (n = 20): tamsulosin 0.4 mg once a day for 6 months
Group 2 (n = 20): Serenoa repens (Permixon) 320 mg once a day for 6 months is the lipidosterolic extract of Serenoa repens
Group 3 (n = 20): Serenoa repens 320 mg plus tamsulosin 0.4 mg once a day for 6 months
Co‐interventions: tamsulosin (for comparison of group 2 and 3)
Outcomes Urinary symptoms

  • How measured: IPSS

  • Time points measured: 2, 4, and 6 months

  • Time points reported: 2, 4, and 6 months

  • Subgroups: none


Quality of life

  • How measured: IPSS‐QoL

  • Time points measured: 2, 4, and 6 months

  • Time points reported: 2, 4, and 6 months

  • Subgroups: none


Adverse events

  • How measured: not described

  • Time points measured: during the 6‐month treatment period

  • Time points reported: during the 6‐month treatment period

  • Subgroups: none


Other outcomes measured in the trial: PSA, Qmax, and acute urinary retention
Notes Funding sources: not available
Declarations of interest: not available
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Hong 2009.

Study characteristics
Methods Study design: placebo‐controlled randomized trial
Study dates: not available
Setting: outpatient, single center, national
Country: Korea
Participants Inclusion criteria: BPH patients with an IPSS of 8 or more
Exclusion criteria: any major diseases. BPH‐related treatment (5‐a‐reductase inhibitor, a‐receptor blocker, or urogenital surgery)
Sample size: 62 randomized participants
Age (years):
Group 1 mean (SD): 52 (1.8)
Group 2 mean (SD): 53.1 (4.29)
IPSS score (baseline):
Group 1 mean (SD): 18.3 (2.0)
Group 2 mean (SD): 15.4 (2.8)
Prostate size:
Group 1 mean (SD): 26.1 (1.7)
Group 2 mean (SD): 23.2 (2.3)
Interventions Group 1 (n = 13): saw palmetto oil, 320 mg/day. Men took 2 capsules per day in the morning and in the evening after a meal over a 12‐month period.
Group 2 (n = 7): placebo, control, sweet potato starch, 320 mg/day. Men took 2 capsules per day in the morning and in the evening after a meal over a 12‐month period.
Co‐interventions: none
Outcomes Urinary symptoms

  • How measured: IPSS

  • Time points measured: 0, 3, 6, 9, and 12 months

  • Time points reported: 0, 3, 6, 9, and 12 months

  • Subgroups: none


Quality of life

  • How measured: IPSS‐QoL

  • Time points measured: 0, 3, 6, 9, and 12 months

  • Time points reported: 0, 3, 6, 9, and 12 months

  • Subgroups: none


Adverse events

  • How measured: clinical examination

  • Time points measured: weekly

  • Time points reported: not reported

  • Subgroups: none


Other outcomes measured in the trial: Qmax and other uroflowmetry parameters; PSA.
Notes Funding sources: not available
Declarations of interest: not available
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Iacono 2015.

Study characteristics
Methods Study design: parallel‐group randomized trial
Study dates: not available
Setting: outpatient, single center, national
Country: Italy
Participants Inclusion criteria: men affected by lower urinary tract symptoms due to BPH
Exclusion criteria: not specified
Sample size: 185 participants
Age (years): mean 64.5 (SD 8.6)
IPSS score (baseline):
Group 1 (SD): 20.6 (5.4)
Group 2 (SD): not available
Prostate size: not available
Interventions Group 1 (n = 95): Tramaxadina (Alga Ecklonia bicylis 80 mg, Tribulus terrestris 100 mg, chitosan oligosaccharide (Biovis) 100 mg) and Serenoa repens 320 mg daily for 6 months
Group 2 (n = 90): placebo
Outcomes Urinary symptoms

  • How measured: IPSS

  • Time points measured: not reported

  • Time points reported: 6 months (only for the intervention group)
Notes Funding sources: not available
Conflict of interest: not available
Study available only as an abstract of the 17th Annual Congress of the European Society for Sexual Medicine, 2015 February 5‐7; Copenhagen.
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Lopatkin 2005.

Study characteristics
Methods Study design: parallel‐group randomized trial
Study dates: not available
Setting: outpatient, multicenter, national
Country: possibly Germany or Russia
Participants Inclusion criteria:

  • Male outpatients 50 ≥ years old suffering from symptomatic BPH

  • Maximum urinary flow rate < 15 mL/s

  • Change in maximum urinary flow between screening and end of run‐in period ≤ 3 mL/s

  • Urinary output > 100 mL at baseline

  • IPSS total score ≥ 14

  • IPSS QoL ≥ 4


Exclusion criteria:

  • Mental condition interfering with the ability to give informed consent or to complete the self‐ratings

  • Previous or scheduled surgery involving pelvis or urinary tract

  • Urethral stricture disease or a history of pelvic radiation therapy

  • PSA > 10 ng/mL

  • Large residual urine > 350 mL

  • Symptomatic urinary tract infection

  • Chronic bacterial prostatitis

  • Patients with diabetes mellitus, diabetic neuropathy, or prostate carcinoma

  • Serious general and specific risks

  • Concomitant medication affecting the micturition pattern


Sample size: 257 randomized participants
Age (years):
Group 1 mean (SD): 68 (7)
Group 2 mean (SD): 67 (7)
IPSS score (baseline):
Group 1 mean (SD): 18 (4)
Group 2 mean (SD): 18 (3)
Prostate size:
Group 1 mean (SD): 44.9 (18.1) cm3
Group 2 mean (SD): 46.4 (19.2) cm3
Interventions Group 1 (n = 127): PRO 160/120 mg (Sabal fruit extract WS 1473 90% ethanol and Urtica root dry extract WS 1031, respectively) orally daily in the morning and in the evening for 24 weeks
Group 2 (n = 126): placebo orally daily in the morning and in the evening for 24 weeks
Co‐interventions: none
Outcomes Urinary symptoms

  • How measured: IPSS score

  • Time points measured: day 0 and weeks 16 and 24

  • Time points reported: day 0 and weeks 16 and 24

  • Subgroups: none


Quality of life

  • How measured: IPSS‐QoL

  • Time points measured: day 0 and weeks 16 and 24

  • Time points reported: not reported

  • Subgroups: none


Adverse events

  • How measured: not described

  • Time points measured: possibly at week 24

  • Time points reported: possibly at week 24

  • Subgroups: none


Other outcomes measured in the trial: prostate size, Qmax, and urinary retention
Notes Funding sources: Wilmar Schwabe GmbH & Co. KG, Karlsruhe (Germany)
Conflicts of interest: not available
At 24 weeks all men were unblinded and received the experimental treatment, with follow‐up to 48 and 96 months (no control group).
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Mandressi 1983.

Study characteristics
Methods Study design: double‐blind parallel‐group randomized trial
Study dates: not available
Setting: outpatient, single center, national
Country: Italy
Participants Inclusion criteria:

  • Men between 50 and 80 years old with prostate adenoma diagnosed

  • Men were never treated for prostate adenoma and no other diseases present


Exclusion criteria: not available
Sample size: 60 randomized participants
Age (years): not available
IPSS score (baseline): not available
Prostate size: not available
Interventions Group 1 (n = 19): Serenoa repens (Permixon 160 mg twice daily)
Group 2 (n = 15): placebo (capsule)
Group 3 (n = 15): Pygeum africanum
Co‐interventions: none
Outcomes This study did not report any outcomes relevant to this review.
Other outcomes: individual symptom scales
Notes Funding sources: not available
Declarations of interest: not available
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Marks 2000.

Study characteristics
Methods Study design: parallel‐group randomized trial
Study dates: September 1997 to January 1998
Setting: outpatient
Country: USA
Participants Inclusion criteria:

  • Men aged 45 to 80 years

  • Clinical diagnosis of BPH based on moderate to severe symptoms and palpation of an enlarged prostate gland on rectal examination at the screening visit

  • IPSS 9 or more

  • Question 5 rating of 1 or more

  • 2 of any of questions 1 to 4, 6 or 7 rating of 3 or more

  • PSA < 15 ng/mL

  • Prostate volume 30 cm3 or more


Exclusion criteria:

  • History of:

    • allergy to saw palmetto;

    • any illness or condition that may confound the results of the study or pose additional risk to the patient;

    • treatment with any investigational drug;

    • drug or alcohol abuse or dependence;

    • bladder surgery or procedure for BPH;

    • neurogenic bladder;

    • chronic prostatitis or repeat urinary tract infection;

    • recurrent acute urinary retention episodes.

  • Concurrent use of a‐adrenergic receptor antagonists and/or any hormonal therapy that may affect the prostate and use of finasteride or prostate phytotherapy

  • Evidence of urethral stricture or radiotherapy to the pelvis


Sample size: 44 participants
Age (years):
Group 1 mean (SD): 65.1 (8.1)
Group 2 mean (SD): 62.9 (9.3)
IPSS score (baseline):
Group 1 mean (SD): 18.1 (7.2)
Group 2 mean (SD): 16.6 (5.3)
Prostate size (cm3):
Group 1 mean (SD): 58.5 (29.8)
Group 2 mean (SD): 55.6 (26.7)
Interventions Group 1 (n = 21): saw palmetto berry lipoidal extract and other herbs (nettle root extract 80 mg; pumpkin seed oil extract 160 mg; lemon extract 33 mg; vitamin A 190 international units), 106 mg, 3 times daily with meals, orally for 6 months
Group 2 (n = 23): placebo capsules (glycerin, yellow wax, lecithin, and soybean oil), 3 times daily with meals, orally for 6 months
Co‐interventions: none
Outcomes Urinary symptoms

  • How measured: IPSS, uroflowmetry, and bladder scan

  • Time points measured: 6, 12, 18, and 24 weeks

  • Time points reported: 6, 12, 18, and 24 weeks

  • Subgroups: none


Quality of life

  • How measured: quality of life index

  • Time points measured: 6, 12, 18, and 24 weeks

  • Time points reported: none (measured but not reported)

  • Subgroups: none


Adverse events

  • How measured: a panel of 26 standard blood test

  • Time points measured: complete follow‐up

  • Time points reported: complete follow‐up

  • Subgroups: none


Other outcomes: postvoid residual urine volume, total serum PSA, free serum PSA, % free PSA, testosterone, dihydrotestosterone, estradiol, whole prostate volume, transition zone prostate volume, Qmax, urinary retention
Notes Funding sources: supported by an unrestricted educational grant from the Nutrilite Division of Amway Corp., Buena Park, California. Financial interest and/or other relationship with Nutrilite Division of Amway Corp.
Declarations of interest: saw palmetto extract capsules were provided and blinding was done by the Nutrilite Division of Amway Corp., Buena Park, California
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Metzker 1996.

Study characteristics
Methods Study design: double‐blind, parallel‐group randomized trial
Study dates: not available
Setting: inpatient, single center, national
Country: Germany
Participants Inclusion criteria:

  • BPH stage 1 to 2 according to Alken

  • Minimum volume of urination > 150 mL

  • Qmax 20 mL/s


Exclusion criteria:

  • Age < 50

  • Need for the instrumental intervention of the lower urinary tract except for single catheterization

  • Symptomatic urinary tract infection

  • Concomitant medication that could interfere with the evaluation of efficacy

  • Another serious organic disease


Sample size: 40 randomized participants
Age (years):
Group 1 mean (SD): 66.0 (52.4 to 84.0)
Group 2 mean (SD): 65.1 (52.8 to 80.6)
IPSS score (baseline):
Group 1 mean (SD): 18.6 (15.0 to 22.2)
Group 2 mean (SD): 19.0 (15.1 to 22.9)
Prostate size: not available
Interventions Group 1 (n = 20): Sabal‐Urtica (Prostagutt forte) capsule twice a day for 1 year. 1 capsule of Prostagutt forte contains: WS 1473 extract of saw palmetto fruits, 160 mg and WS 1031 dry extract of nettle root, 120 mg.
Group 2 (n = 20): placebo capsule twice a day for 1 year
Co‐interventions: none
Outcomes Urinary symptoms

  • How measured: IPSS

  • Time points measured: day 0 and 24 and 48 weeks

  • Time points reported: day 0 and 24 and 48 weeks

  • Subgroups: none


Quality of life

  • How measured: AUASI

  • Time points measured: day 0 and 24 weeks

  • Time points reported: day 0 and 24 weeks (narrative)

  • Subgroups: none


Adverse events

  • How measured: not reported

  • Time points measured: day 0 and 24 weeks

  • Time points reported: cumulative at 24 weeks (narrative)

  • Subgroups: none


Other outcomes measured in the trial: blood pressure, Qmax, residual volume
Notes Funding sources: not available
Conflicts of interest: not available
After 24 weeks, all men were offered the interventional treatment (no control group).
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Morgia 2014.

Study characteristics
Methods Study design: parallel‐group randomized trial
Study dates: March 2011 to March 2012
Setting: outpatient, multicenter and national
Country: Italy
Participants Inclusion criteria:

  • Age between 55 and 80 years old

  • Digital rectal examination negative for prostate nodules

  • PSA ≤ 4 ng/mL

  • IPSS ≥ 12

  • Prostate volume ≤ 60 cm3 (assessed by ultrasound)

  • Qmax ≤ 15 mL/s

  • Postvoid residual urine < 150 mL


Exclusion criteria:

  • Prostate cancer

  • Previous bladder cancer

  • Diabetes mellitus

  • Neurogenic disorders

  • Severe liver disease

  • History of orthostatic hypotension or syncope

  • Symptomatic urinary tract infection

  • Anti‐androgens

  • Antidepressants (neuroleptics, anticholinergics) therapy

  • Recent treatment with alpha blocker (within 1 month) or phytotherapy including saw palmetto extract (within 3 months)

  • Previous medical therapy with 5‐alpha‐reductase inhibitors or surgical treatment for LUTS/BPH

  • Patients with catheters or with an episode of acute retention of urine in the last 4 weeks


Sample size: 225 randomized participants
Age (years):
Group 1 median (range): 65 (56 to 76)
Group 2 median (range): 66 (56 to 79)
IPSS score (baseline):
Group 1 median (range): 20 (12 to 35)
Group 2 median (range): 19 (12 to 33)
Prostate size:
Group 1 median (range): 45 (20 to 60)
Group 2 median (range): 45 (20 to 60)
Interventions Group 1 (n = 75): Serenoa repens 320 mg, selenium, lycopene (Profluss) for 1 year
Group 2 (n = 79): placebo for 1 year
Co‐interventions: tamsulosin 0.4 mg
Outcomes Urinary symptoms

  • How measured: IPSS

  • Time points measured: 0, 1, 3, 6, and 12 months

  • Time points reported: 6 and 12 months

  • Subgroups: none


Quality of life

  • How measured: IPSS‐QoL

  • Time points measured: 0, 1, 3, 6, and 12 months

  • Time points reported: 6 and 12 months

  • Subgroups: none


Adverse events

  • How measured: not described

  • Time points measured: along the 12‐month trial

  • Time points reported: 12 months

  • Subgroups: none


Other outcomes measured in the trial: International Index of Erectile Function (IIEF‐5), PVR, prostate volume, PSA and Ejaculation Questionnaire (EjQ), Qmax
Notes Funding sources: Konpharma provided support for this study
Declarations of interest: the authors declare no conflicts of interest. This study has been designed and conducted independently.
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Preuss 2001.

Study characteristics
Methods Study design: parallel‐group, double‐blind, placebo‐controlled randomized trial
Study dates: not available
Setting: outpatient, multicenter, national
Country: USA
Participants Inclusion criteria:

  • Diagnosis of BPH

  • No evidence of cancer by digital rectal or PSA examinations, or both

  • Qmax between 5 and 15 mL/s for a voided volume in excess of 100 mL

  • Patient must read, speak, and clearly understand English, and written informed consent to participate in the trial had to be obtained


Exclusion criteria:

  • Age greater than 80 years

  • The presence of any tumor, malformation, or infection of the genitourinary tract, any severe concomitant medical condition

  • Severe laboratory abnormalities

  • Medical treatment for BPH with finasteride (Proscar) within the last 4 weeks

  • Patients currently being treated with antibiotics for genitourinary tract infections


Sample size: 144 randomized participants
Age (years): not available
AUASI score (baseline):
Group 1 mean (SD): 18.9
Group 2 mean (SD): 17.7
Prostate size: not available
Interventions Group 1 (n = 75): Cernitin 378 mg, saw palmetto complex and phytosterol (saw palmetto fruit standardized to 40% to 50% free fatty acids and B‐sitosterol standardized to 43%) 286 mg, and vitamin E 100 international units once a day for 3 months
Group 2 (n = 69): placebo once a day for 3 months
Co‐interventions: none
Outcomes Urinary symptoms

  • How measured: AUASI

  • Time points measured: the first day and in the third month

  • Time points reported: the first day and in the third month

  • Subgroups: none


Adverse events

  • How measured: not described

  • Time points measured: possibly at 3‐month follow‐up

  • Time points reported: possibly at 3‐month follow‐up

  • Subgroups: none


Other outcomes measured in the trial: PSA, Qmax, and nocturia
Notes Funding sources: Rexall/Sundown, Inc., Boca Raton, FL through the National Research Council for Health, Washington, DC and Meridian ID
Declarations of interest: not available
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Reece Smith 1986.

Study characteristics
Methods Study design: parallel‐group randomized trial
Study dates: not available
Setting: inpatient, multicenter, national
Country: UK
Participants Inclusion criteria:

  • Difficulty in micturition

  • Impairment of urinary stream

  • Urinary urgency

  • Urinary hesitancy

  • Urinary intermittency

  • Terminal dribbling

  • A sensation of incomplete voiding

  • Average daytime micturitions

  • Average nocturnal micturitions

  • Libido


Exclusion criteria:

  • Malignant prostatic disease

  • Symptoms did not fulfill the entry criteria


Sample size: 70 randomized participants
Age (years):
Group 1 mean (SD): 66.15 (5.86)
Group 2 mean (SD): 67.03 (6.03)
IPSS score (baseline): not available
Prostate size: not available
Interventions Group 1 (n = 33): Permixon (2 capsules of 160 mg) once a day for 12 weeks. Contains fruits of Serenoa repens, a kind of palm tree
Group 2 (n = 37): placebo once a day for 12 weeks
Co‐interventions: none
Outcomes Adverse events

  • How measured: not described

  • Time points measured: possibly at 12 weeks follow‐up

  • Time points reported: possibly at 12 weeks follow‐up

  • Subgroups: none


Other outcomes measured in the trial: blood studies, urinary retention, and Qmax.
Notes Funding sources: not available
Declarations of interest: not available
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Ryu 2015.

Study characteristics
Methods Study design: randomized controlled trial
Study dates: March 2012 to March 2013
Setting: outpatient, single center, national
Country: Korea
Participants Inclusion criteria:

  • Men between 50 and 80 years old

  • IPSS > 10 points

  • Qmax 5 to 15 mL/s for a voided volume of at least 150 mL

  • Postvoiding volume < 150 mL

  • Prostate volume > 25 cm3

  • PSA < 4 ng/mL


Exclusion criteria:

  • History of bladder diseases such as:

    • micturition;

    • urethral stenosis;

    • prostate cancer;

    • pelvic radiotherapy;

    • repeated infection of urinary tract.

    • chronic bacterial prostatitis.

  • Patients with clinically significant cardiovascular disease

  • Hematuria

  • Insulin‐dependent diabetes mellitus

  • History of severe hepatic failure or abnormal liver function test

  • Known hypersensitivity to 1 of the study drugs

  • Medical history of BPH during the past 12 months


Sample size: 120 randomized participants
Age (years):
Group 1 mean (SD): 62.5 (1.21)
Group 2 mean (SD): 63.4 (1.44)
IPSS score (baseline):
Group 1 mean (SD): 19.6 (0.73)
Group 2 mean (SD): 20 (0.85)
Prostate size:
Group 1 mean (SD): 30.1 (0.93)
Group 2 mean (SD): 30.2 (0.67)
Interventions Group 1 (n = 60): Serenoa repens (Permixon) 320 mg/day for 12 months
Group 2 (n = 60): only the co‐intervention
Co‐interventions: tamsulosin 0.2 mg/day
Outcomes Urinary symptoms

  • How measured: IPSS score

  • Time points measured: 0, 6, and 12 months

  • Time points reported: 0, 6, and 12 months

  • Subgroups: none


Quality of life

  • How measured: LUTS‐related quality of life scores

  • Time points measured: 0, 6, and 12 months

  • Time points reported: 0, 6, and 12 months

  • Subgroups: none


Adverse events

  • How measured: not described

  • Time points measured: 0, 6, and 12 months

  • Time points reported: 12 months

  • Subgroups: none


Other outcomes measured in the trial: PSA and prostate volume, Qmax
Notes Funding sources: not available
Declarations of interest: not available
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Shi 2008.

Study characteristics
Methods Study design: parallel‐group randomized trial
Study dates: not available
Setting: outpatient, multicenter, national
Country: China
Participants Inclusion criteria:

  • Newly diagnosed LUTS associated with BPH based on urological symptoms

  • A digital rectal examination that showed an enlarged prostate but no signs of prostate cancer

  • Serum creatinine > 160 μmol/L

  • Bacterial count < 100,000/mL

  • PSA ≤ 4 ng/mL

  • IPSS > 12

  • Uroflowmetry with MFR < 15 mL/s and voiding volume > 150 mL


Exclusion criteria:

  • A history of prostate cancer

  • The use of any drugs, herbs, or other non‐prescription preparations for LUTS associated with BPH within 4 weeks of screening, including: finasteride, alpha‐ or beta‐blockers, diuretics, calcium channel blockers, or anticholinergic drugs

  • Abnormal laboratory parameters, including: PSA > 4 ng/mL, serum creatinine > 160 μmol/L, a urine bacterial count > 100,000/mL, BUN > 8 mg/dL, MFR > 15 mL/s, and voiding volume < 150 mL

  • Patient's inability to understand or follow the study protocol

  • Current or previous participation in another clinical trial

  • BPH is judged by a urologist to require surgical treatment, previous bladder or prostate surgery

  • Micturition problems associated with an identified bladder pathology urethral stricture

  • Recurrent urinary tract infections

  • Known renal, hepatic, or cardiac insufficiency

  • Diabetes mellitus

  • Recent myocardial infarction

  • Known alcohol abuse

  • Known sensitivity to the ingredients in the product

  • Significant depression or other psychiatric disease noted during the initial screening

  • Any other cancer in the last 5 years except skin cancer

  • Being on anticoagulation therapy


Sample size: 94 randomized participants
Age (years):
Group 1 mean (SD): 65.91 (63.77 to 68.05)
Group 2 mean (SD): 64.04 (61.57 to 66.52)
IPSS score (baseline):
Group 1 mean (SD): 16.85 (14.92 to 18.77)
Group 2 mean (SD): 14.46 (13.13 to 15.78)
Prostate size:
Group 1 mean (SD): 47.72 (45.38 to 50.06)
Group 2 mean (SD): 48.38 (46.25 to 50.52)
Interventions Group 1 (n = 46): 2 Prostataplex soft gels daily for 12 weeks. The main active ingredient of Prostataplex soft gel is saw palmetto. Other components include soybean oil, beeswax, soy lecithin, gelatin, glycerin, deionized water, titanium dioxide, US Federal Food, Drug and Cosmetic Act carmine red, and natural vanilla flavor.
Group 2 (n = 48): 2 placebo soft gels for 12 weeks. The main ingredient of the placebo soft gel was corn oil. Other components include gelatin, glycerin, purified water and titanium dioxide, and the Federal Food, Drug and Cosmetic Act red, yellow, and blue.
Co‐interventions: none
Outcomes Urinary symptoms

  • How measured: IPSS

  • Time points measured: 2 weeks and 3 months

  • Time points reported: 2 weeks and 3 months

  • Subgroups: none


Quality of life

  • How measured: IPSS‐QoL

  • Time points measured: 2 weeks and 3 months

  • Time points reported: 2 weeks and 3 months

  • Subgroups: none


Adverse events

  • How measured: not described

  • Time points measured: 3 months follow‐up

  • Time points reported: 3 months follow‐up

  • Subgroups: none


Other outcomes measured in the trial: PSA, BUN and creatinine, Qmax and urinary retention
Notes Funding sources: not available
Declarations of interest: not available
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Sudeep 2020.

Study characteristics
Methods Study design: double‐blind, parallel‐group randomized trial
Study dates: not available
Setting: outpatient, single center, national
Country: India
Participants Inclusion criteria:

  • IPSS score > 7

  • Aging Male Symptoms (AMS) score ≥ 27 and responding positively to question 1 or 7 or any other 3 questions of the Androgen Deficiency in the Aging Male (ADAM) questionnaire


Exclusion criteria:

  • Neurogenic bladder dysfunction

  • Prostatic cancer

  • Prostatitis

  • Hematuria

  • Diabetes

  • Any other chronic illness


Sample size: 99 randomized participants
Age (years):
Group 1 mean (SD): 57.76 (7.25)
Group 2 mean (SD): 55.18 (8.56)
Group 3 mean (SD): 57.48 (7.04)
IPSS score (baseline):
Group 1 mean (SD): 20.00 (4.41)
Group 2 mean (SD): 20.00 (3.74)
Group 3 mean (SD): 19.45 (3.82)
Prostate size: not available
Interventions Group 1 (n = 33): saw palmetto extract VISPO (containing 3% beta‐sitosterol ‐ 200 mg of Serenoa repens extract) 500 mg doses twice daily for 12 weeks
Group 2 (n = 33): placebo (maltodextrin) for 12 weeks
Group 3 (n = 33): saw palmetto oil SPO (0.2% beta‐sitosterol ‐ 200 mg of Serenoa repens extract) for 12 weeks
Co‐interventions: none
Outcomes Urinary symptoms

  • How measured: IPSS

  • Time points measured: 0, 6, and 12 weeks

  • Time points reported: 0, 6, and 12 weeks

  • Subgroups: none


Adverse events

  • How measured: not described

  • Time points measured: possibly at 12 weeks follow‐up

  • Time points reported: possibly at 12 weeks follow‐up

  • Subgroups: none


Other outcomes measured in the trial: urinary retention, Qmax, PSA, 5‐alpha‐reductase, testosterone, AMS, and ADAM
Notes Funding sources: Vidya Herbs Private Ltd
Declarations of interest: none
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Willetts 2003.

Study characteristics
Methods Study design: parallel‐group, double‐blind randomized controlled trial
Study dates: January 1999 to March 2000
Setting: outpatient, national
Country: Australia
Participants Inclusion criteria:

  • At least 3 symptoms of prostatism

  • Aged < 80 years

  • No significant medical condition

  • Maximum urinary flow rate of 5 to 15 mL/s for a voided volume of 150 mL, and a normal serum PSA level (< 4 ng/mL) within the previous 3 months


Exclusion criteria:

  • Insulin‐dependent diabetes, severe cardiopulmonary disease, or significant central nervous system disease

  • Men were not permitted to have used the following in the previous 4 weeks: androgens, 5‐alpha‐reductase inhibitors, alpha‐blockers, or herbal preparations for urinary problems

  • History of prostate cancer or adenomas, urethral, bladder, ureteric, or renal abnormalities, urogenital surgery, renal stones, strictures or scarring, acute urinary retention, or allergy to study treatment


Sample size: 100 participants
Age (years):
Group 1 mean (SEM): 62.1 (1.2)
Group 2 mean (SEM): 63.9 (1.3)
IPSS score (baseline): not reported
Prostate size: not reported
Interventions Group 1 (n = 50): Serenoa repens extract (2 x 160 mg of carbon dioxide extract; Blackmores Ltd, Sydney, Australia) 2 capsules per day for 12 weeks
Group 2 (n = 50): placebo (paraffin oil), 2 capsules per day for 12 weeks
Co‐interventions: none
Outcomes Urinary symptoms

  • How measured: IPSS

  • Time points measured: 0 and 12 weeks

  • Time points reported: not reported

  • Subgroups: none


Quality of life

  • How measured: IPSS‐QoL

  • Time points measured: 0 and 12 weeks

  • Time points reported: 0 and 12 weeks

  • Subgroups: none


Adverse events

  • How measured: cumulative incidence

  • Time points measured: not specified

  • Time points reported: possibly at 12 weeks

  • Subgroups: none


Other outcomes measured in the trial were: Qmax and sexual function
Notes Funding sources: Blackmores Ltd provided funding for this study
Declarations of interest: not available
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Ye 2019.

Study characteristics
Methods Study design: parallel‐group randomized trial
Study dates: March 2014 to June 2016
Setting: outpatient, multicenter, national
Country: China
Participants Inclusion criteria:

  • Men ≥ 45 years old

  • Qmax ≥ 4 mL/s

  • AUASI score ≥ 8 and ≤ 24 at 2 screening visits

  • Participants on therapy with alpha‐adrenergic blockers, 5‐alpha‐reductase inhibitors, Chinese patent drug, and herbal medicine for BPH were withdrawn for 2 weeks


Exclusion criteria:

  • Refractory to medical treatment

  • BPH complications

  • IPSS of 20 to 35

  • Suspected or confirmed prostatic cancer, neurogenic bladder dysfunction, urethral stricture, congenital or anatomic abnormality of the genital organ, and a history of surgery or trauma that would affect the evaluation of the efficacy of the drug

  • Diabetes mellitus, severe cardiovascular disease, sexually transmitted disease, malignant tumor, peptic ulcer, hemorrhagic disease, mental diseases, acrasia, alcohol dependence, and drug abuse

  • Patients on drugs affecting the bladder or sexual function, those with insufficiency of liver or kidney, and those with a history of allergic reactions to the study drug or similar drugs

  • Patients who participated in another clinical trial in the past 3 months


Sample size: 354
Age (years):
Group 1 mean (SD): 61.47 (± 5.20)
Group 2 mean (SD): 60.32 (± 5.96)
IPSS/AUASI score (baseline):
Group 1 mean (SD): 14.42 (± 3.88)
Group 2 mean (SD): 14.34 (± 4.08)
Prostate size:
Group 1: 37.01 (± 19.68)
Group 2: 37.30 (± 25.40)
Interventions Group 1 (n = 159): Serenoa repens extract 320 mg (160 mg twice daily soft capsule) manufactured by TAD Pharma GmbH
Group 2 (n = 166): placebo 160 mg twice daily soft capsule
Outcomes Urinary symptoms

  • How measured: IPSS score

  • Time points measured: 2, 4, 12, and 24 weeks

  • Time points reported: 2, 4, 12, and 24 weeks

  • Subgroups: none


Quality of life

  • How measured: IPSS QoL

  • Time points measured: 2, 4, 12, and 24 weeks

  • Time points reported: 2, 4, 12, and 24 weeks

  • Subgroups: none


Adverse events:

  • How measured: narratively

  • Time points measured: not available (possibly 2, 4, 12, and 24 weeks)

  • Time points reported: not available

  • Subgroups: none


Other outcomes measured in the trial: voiding symptoms, prostate volume, urinary frequency, and total PSA level. Other parameters assessed were MSF‐4 score, IIEF, and Qmax.
Notes Funding sources: Serenoa Repens was provided by TAD Pharma GmbH
Declarations of interest: the authors report no conflicts of interest
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AUASI: American Urological Association Symptom Index; BPH: benign prostatic hyperplasia; BUN: blood urea nitrogen; CFU: colony‐forming units; HCL: hydrochloride; IIEF: International Index of Erectile Function; IPSS: International Prostate Symptom Score; LUTS: lower urinary tract symptoms; MedDRA: Medical Dictionary for Regulatory Activities; MFR: maximum flow rate; MSF‐4: Male Sexual Function 4‐item; NIH‐CPSI: National Institutes of Health Chronic Prostatitis Symptom Index; PSA: prostate‐specific antigen; PVR: postvoid residual; Qmax: peak urinary flow; QoL: quality of life; SD: standard deviation; SEM: standard error of the mean

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion
Adriazola Semino 1992 Wrong study design/comparison: Serenoa repens vs active control (Prazosin). No indication of randomization
Al‐Shukri 2000 Wrong study design: non‐randomized study
Alcaraz 2022 Wrong study design: observational study
Ali 2020 Wrong comparison: Serenoa repens vs alpha‐blockers
Aliaev 2009 Wrong study population: men had chronic abacterial prostatitis
Authié 1987 Wrong study design: non‐randomized study
Bartsch 1998 Wrong comparison: Serenoa repens vs finasteride
Braeckman 1997 Wrong comparison: different doses of Serenoa repens
Cai 2013 Wrong comparison: IDIProst vs Serenoa repens
Carraro 1996 Wrong comparison: Serenoa repens vs finasteride
Comar 1986 Comparison with mepartricin
CTRI/2012/10/003049 Wrong comparison: different doses of phytotherapy
CTRI/2020/09/027521 Wrong comparison: Serenoa repens vs SAW‐1720
Debruyne 2002 Wrong comparison: with alpha‐blocker
Di Maida 2020 Wrong study design: non‐randomized comparative study
Di Silverio 1992 Tissue study investigating the antiestrogenic effect of Serenoa repens vs placebo
Duborija‐Kovacevic 2010 Wrong comparison: Serenoa repens vs doxazosin and finasteride
Engelmann 2006 Wrong comparison: Serenoa repens vs tamsulosin
EUCTR2011‐005307‐33‐FR Wrong comparison: Serenoa repens vs tamsulosin
Gerber 1998 Wrong study design: no control group
Giannakopoulos 2002 Wrong study design: no control group
Giulianelli 2012 Wrong study design: observational study
Grasso 1995 Wrong comparison: Serenoa repens vs alpha‐blocker
Gurzhenko 2020 Wrong study design: observational study
Guzman 2016 Wrong comparison: D‐004 vs Serenoa repens
Hamdv 1997 Wrong comparison: Serenoa repens vs finasteride
Ju 2015 Wrong study design: no comparison
Latil 2015 Wrong comparison: Serenoa repens vs alpha‐blockers
Morgia 2013 Wrong study population: men subject to histologic sampling
Morgia 2018 Wrong comparison: Serenoa repens vs tadalafil
NCT00797394 Wrong comparison: Serenoa repens as a co‐intervention
Pannunzio 1986 Wrong comparison: Serenoa repens vs gestonorone caproate
Pavone 2010 Wrong study design: not a randomized controlled trial
Pecoraro 2004 Wrong population: study focused on the use of the drug as preoperative adjuvant treatment
Popa 2005 Wrong study design: independent re‐analysis of the included study Metzker 1996
Romaniuk 2013 Wrong comparison: Serenoa repens vs doxazosin and finasteride
Roveda 1994 Wrong comparison: Serenoa repens oral vs rectal route
Sinescu 2011 Wrong study design: non‐randomized study
Stepanov 1999 Wrong study design: no control group
Strauch 1994 Wrong comparison: Serenoa repens vs finasteride
Suardi 2014 Wrong patient population: men with prostatitis
Sökeland 1997 Wrong comparison: Serenoa repens vs finasteride
Taieb 2010 Wrong study design: observational study
Vela‐Navarrete 2005 Study focused on tissue samples of the prostate.
Veltri 2002 Wrong study population: study focused on prostatic tissue
Vinarov 2010 Wrong study design: no active or placebo control
Weisser 1997 Wrong study population: prostatic tissue (enzyme study)
Yamanishi 2004 Wrong comparison: Serenoa repens vs alpha‐blockers
Zlotta 2005 Wrong study design: re‐analysis of previous studies
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Characteristics of studies awaiting classification [ordered by study ID]

Aliaev 2007.

Methods Not available
Participants Not available
Interventions Not available
Outcomes Not available
Notes Full text not available.
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Anonymous 2005.

Methods Not available
Participants Not available
Interventions Not available
Outcomes Not available
Notes Full text not available.
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Bercovich 2010.

Methods Not available
Participants Not available
Interventions Not available
Outcomes Not available
Notes Full text not available.
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Buck 2002.

Methods Not available
Participants Not available
Interventions Not available
Outcomes Not available
Notes Full text not available.
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Carreras 1987.

Methods Not available
Participants Not available
Interventions Not available
Outcomes Not available
Notes Full text not available.
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Cukier 1985.

Methods Multisite study
Randomization: numbered or coded identical containers administered sequentially
Blinding: participants, providers
Participants Geographic region: France
Study setting: community
N = 168
Baseline IPSS: NR
Baseline prostate volume: NR
Mean age (range): 69 (NR) years
Race: white
Diagnostic criteria: patients with "prostatism" or for whom surgery was not indicated (no mechanical or infectious complications)
Interventions Control: matching placebo
Treatment: Permixon 160 mg twice daily
Study duration: 10 weeks
Lost to follow‐up: 13%
Outcomes Symptom score (# of daily mictions)
Dysuria (4‐point scale)
Bladder residual volume
Nocturia
Dropouts due to side effects: NR
Notes Exclusions: symptoms for at least 6 months
Full text not available for this update.
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Dathe 1991.

Methods Not available
Participants Not available
Interventions Not available
Outcomes Not available
Notes Full text not available.
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Diehl 2005.

Methods Not available
Participants Not available
Interventions Not available
Outcomes Not available
Notes Full text not available.
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Emili 1983.

Methods Single‐site study
Randomization: noted, but method not stated
Blinding: participants, providers
Participants Geographic region: Italy
Study setting: community
N = 30
Baseline symptom score: NR
Baseline prostate volume: NR
Mean age (range): NR (44 to 78) years
Race: white
Diagnostic criteria: men with manageable BPH
Interventions Control: matching placebo
Treatment: Permixon 160 mg twice daily
Study duration: 4 weeks
Lost to follow‐up: n = 0
Outcomes Peak urine flow
Mean urine flow
Bladder residual volume
Prostate size (qualitative scale used)
Nocturia
Dropouts due to side effects: none
Notes Exclusions: prior treatment for BPH
Full text not available for this update.
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Fabricius 1993.

Methods Not available
Participants Not available
Interventions Not available
Outcomes Not available
Notes Full text not available.
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Gabric 1987.

Methods Multisite study
Randomization: unclear
Blinding: participants, providers
Participants Geographic region: Croatia
Study setting: community
N = 30
Baseline IPSS: NR
Baseline prostate volume: NR
Mean age (range): 65 (40 to 82) years
Race: white
Diagnostic criteria: BPH, stages I, II (Vahlensieck)
Interventions Control: placebo
Treatment: Prostagutt forte (SR + Urtica dioica) 20 drops 3 times daily
Study duration: 6 weeks
Lost to follow‐up: none
Outcomes Physician rating of improvement
Peak urine flow
Bladder residual volume
Dropouts due to side effects: none
Notes Exclusions: stage IV prostate adenoma, bacterial prostatitis, cystitis, urethritis
Full text not available for this update.
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Green 2000.

Methods Not available
Participants Not available
Interventions Not available
Outcomes Not available
Notes Full text not available.
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Löbelenz 1992.

Methods Multisite study
Randomization: computer‐generated randomization code
Blinding: participants, providers
Participants Geographic region: Germany
Study setting: community
N = 60
Baseline IPSS: NR
Baseline prostate volume: NR
Mean age (range): NR (48 to 82) years
Race: white
Diagnostic criteria: BPH, stages I, II; peak urine flow < 20 mL/s
Interventions Control: matching placebo
Treatment: Sabal extract 100 mg daily
Study duration: 6 weeks
Lost to follow‐up: n = 0
Outcomes Peak urine flow
Mean urine flow
Dropouts due to side effects: n = 0
Notes Exclusions: NR
Full text not available for this update.
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Martínez 1987.

Methods Not available
Participants Not available
Interventions Not available
Outcomes Not available
Notes Full text not available.
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Mattei 1990.

Methods Single‐site study
Randomization: noted, but method not stated
Blinding: participants, providers
Participants Geographic region: Italy
Study setting: community
N = 40
Baseline symptom score: NR
Baseline prostate volume: Talso (SR extract) 36 mm (diameter); placebo 37 mm
Mean age (range): NR (45 to 72) years
Race: white
Diagnostic criteria: men with manageable BPH
Interventions Control: matching placebo
Treatment: Talso (SR extract) 160 mg twice daily
Study duration: 13 weeks
Lost to follow‐up: 5%
Outcomes Dysuria (symptom score 0 to 4)
Bladder residual volume (incomplete emptying ‐ symptom score 0 to 4)
Discomfort (pollakiuria ‐ symptom score 0 to 4)
Daytime frequency
Nocturia
Prostate size
Dropouts due to side effects: 1 participant from each group due to "stomach pains"; relation to therapy unclear
Notes Exclusions: urogenital disease, prostate cancer
Full text not available for this update.
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Mohanty 1999.

Methods Site not described.
Randomization not described.
Blinding: double‐blind
Participants Geographic region: NR
Study setting: clinic
N = 75
Baseline modified Boyarsky: NR
Baseline prostate volume: SR 28.78 mL; placebo 29.89 mL
Mean age (range): NR (40 to 90) years
Race: NR
Diagnostic criteria: BPH grades I or II; symptomatic; without surgical indication; took no BPH drug treatment for last 30 days
Interventions Control: matching placebo, 1 capsule twice daily
Treatment: SR, 1 capsule twice daily
Study duration: 2 months
Lost to follow‐up: SR n = 2; placebo n = 0
Outcomes Modified Boyarsky (range 0 to 27; higher score indicates worse symptoms)
Frequency
Nocturia
Peak urine flow
Residual volume
Prostate size (ultrasound)
Adverse events
Notes Exclusions: men with prostate conditions other than BPH (carcinoma of the prostate, infective prostatitis); serious renal, hepatic, and cardiac conditions
Full text not available for this update.
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Neumann 1993.

Methods Not available
Participants Not available
Interventions Not available
Outcomes Not available
Notes Full text not available.
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Razumov 2001.

Methods Not available
Participants Not available
Interventions Not available
Outcomes Not available
Notes Full text not available.
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Sekikawa 2020.

Methods Double‐blind randomized controlled trial
Participants Key inclusion criteria:

  • Healthy Japanese men 40 or more years old

  • Those who have nocturia at least twice

  • Those who are considered as appropriate for the study by the principal investigator

  • Those whose high‐sensitivity PSA level is less than 3.0 ng/mL (40 to 64 years old); less than 3.5 ng/mL (65 to 70 years old); or less than 4.0 ng/mL (more than 70 years old) at screening (before consumption)

  • Those who have 8 to 19 points on the IPSS at screening (before consumption) and do not need the treatment

  • Select those who have relatively high score on the IPSS


Key exclusion criteria:

  • At least 1 previous medical history or under the treatment of malignant tumor, heart failure or myocardial infarction

  • Men who have a pacemaker or an implantable cardioverter defibrillator

  • Currently under treatment for cardiac arrhythmia, hepatic disorder, renal disorder, cerebrovascular disorder, rheumatism, diabetes mellitus, dyslipidemia, hypertension, or other chronic diseases

  • Those who need treatment for diseases related to urination, e.g. benign prostatic hypertrophy, overactive bladder, and urolithiasis

  • Those who use or take "Foods for Specified Health Uses" and "Foods with Function Claims" daily

  • Currently taking medications (including herbal medicines) and dietary supplements

  • Those who are allergic to medications and/or the test food related products

  • Those enrolled in other clinical trials within the last 3 months before agreement to participate in this trial or who plan to participate another trial during this trial

  • Considered to be ineligible to participate in the study based on the evaluation of the principal physician
Interventions Intervention: capsule containing saw palmetto extract with 200 mL of water daily for 8 weeks
Control: placebo, same posology
Outcomes Primary outcomes
IPSS: change after 8 weeks
Key secondary outcomes*

  1. IPSS

  2. Overactive Bladder Symptom Score (OABSS)

  3. Original questionnaires (Likert scale)

  4. Ultrasonography of postvoid residual volume of urine


*1,2,3 Assess these at screening (before consumption) and 4 and 8 weeks after consuming.
*4 Assess at screening (before consumption) and 8 weeks after consuming.
Notes  
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Tasca 1985.

Methods Single‐site trial
Randomization: noted, but method not stated
Blinding: participants, providers
Participants Geographic region: Italy
Study setting: community
N = 30
Baseline symptom score: NR
Baseline prostate volume: NR
Mean age (range): 61.5 (49 to 81) years
Race: white
Diagnostic criteria: stage I and II prostatic adenomas
Interventions Control: matching placebo
Treatment: PA109 (Permixon) 160 mg twice daily
Study duration: 8 weeks
Lost to follow‐up: 10%
Outcomes Dysuria (% reporting)
Peak urine flow
Mean urine flow
Total voided volume
Pollakiuria ‐ daytime (% reporting)
Pollakiuria ‐ nocturnal (% reporting)
Urgency (% reporting)
Dropouts due to side effects: 1 participant from the treatment group
Notes Exclusions: details not provided
Full text not available for this update.
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Tkachuk 2002.

Methods Not available
Participants Not available
Interventions Not available
Outcomes Not available
Notes Full‐text not available
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Vahlensieck 1993.

Methods Not available
Participants Not available
Interventions Not available
Outcomes Not available
Notes Full‐text not available for this update
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Vinarov 2009.

Methods Not available
Participants Not available
Interventions Not available
Outcomes Not available
Notes Full‐text not available
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Wehr 1995.

Methods Not available
Participants Not available
Interventions Not available
Outcomes Not available
Notes Full‐text not available
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IPSS: International Prostate Symptom Score

Characteristics of ongoing studies [ordered by study ID]

ISRCTN84633360.

Study name Permixon (R) 320 mg once a day open label treatment for patients participating in the placebo controlled study
Methods Randomized controlled trial
Participants Participant inclusion criteria: not available. However, condition of interest was benign prostatic hyperplasia.
Interventions Permixon 320 mg once a day vs placebo
Outcomes Primary outcome measure: not provided at time of registration
Secondary outcome measures: not provided at time of registration
Starting date Recruitment start date: 20 February 2000
Recruitment end date: 19 February 2004
Contact information Mr T Terry
University Hospitals of Leicester
c/o Research and Development Office
Leicester General Hospital NHS Trust
Leicester
LE1 4PW
United Kingdom
+44 (0)116 258 4109
research@lri.org.uk
(contacted on 30 December 2022)
Notes  
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JPRN‐UMIN000023274.

Study name A clinical trial to investigate the effect of the foods containing plant extract
Methods Double‐blind randomized controlled trial
Participants Inclusion criteria: men aged 50 to 80 giving written informed consent
Key exclusion criteria:

  • Serious historical disease, marked impairment, or treatment in the liver, kidney, heart, lung, gastrointestinal tract, blood, endocrine system, or metabolism system

  • Previous medical history of drug or food allergy, or both

  • Constant use of oral medicines, functional foods and/or supplements

  • Ineligible due to the physician's judgment

  • Participation in other clinical trials
Interventions Intervention: food containing plant extract for 8 weeks
Control: food without plant extract for 8 weeks
Outcomes Primary outcomes
Change from baseline of IPSS total score at 4‐ and 8‐week consumption
Key secondary outcomes

  • Change from baseline of IPSS2 score at 4‐ and 8‐week consumption

  • Change from baseline of BPH Impact Index total score at 4‐ and 8‐week consumption

  • Change from baseline of PSA at 8‐week consumption
Starting date 23 July 2016
Contact information Masayuki Sugimoto
Email: info.food@kb‐clinic.com
Takashi Sone
Email: t.sone@kb‐clinic.com
(contacted both on 30 December 2022)
Notes  
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JPRN‐UMIN000027902.

Study name A verification study on improvement of problems with urination due to ingestion of the food containing saw palm extracts
Methods Double‐blind randomized controlled trial
Participants Key inclusion criteria:

  1. Japanese men aged 40 to less than 70 years old

  2. Those who wake up for urination at least twice during nocturnal sleep

  3. Those who have problems with urination, e.g. urinary urgency, frequent urination, and urinary incontinence

  4. Those who are considered as appropriate for the study by the principal investigator

  5. Those whose high‐sensitivity PSA level is less than 3.0 ng/mL (40 to 65 years old) or less than 3.5 ng/mL (65 to 70 years old) at screening and examination before ingestion

  6. Those with IPSS score of less than 20 at screening and examination before ingestion and do not need the treatment

  7. If number of people who passed 6. exceed the sample size, select those who have relatively high IPSS score


Key exclusion criteria:

  1. At least 1 previous medical history or under the treatment of malignant tumor, heart failure or myocardial infarction

  2. Currently under treatment for cardiac arrhythmia, hepatic disorder, renal disorder, cerebrovascular disorder, rheumatism, diabetes mellitus, dyslipidemia, hypertension, or other chronic diseases

  3. Those who need the treatment for diseases related to urination, e.g. benign prostatic hypertrophy, overactive bladder, and urolithiasis

  4. Those who use or take "Foods for Specified Health Uses" and "Foods with Functional Claims" daily

  5. Currently taking medicines or herbal medicines, or both

  6. Those who are allergic to medicines and/or the test food related products

  7. Those who had participated in another clinical test for 3 months when signing the informed consent form for this trial

  8. Considered as inappropriate for this test by the principal investigator
Interventions Intervention: saw palmetto extracts containing capsule B, once a day for 12 weeks. Swallowing a capsule after breakfast with water or warm water (approximately 200 mL) without chewing. If the participant forgets to ingest the test food, they would take it as soon as they remember within the day.
Control: placebo, same posology for 12 weeks
Outcomes Primary outcomes
IPSS: assessed at 0, 4, 8, and 12 weeks after consuming
Key secondary outcomes*
1. King's Health Questionnaire (KHQ)
2. Overactive Bladder Symptom Score (OABSS)
3. Subjective symptoms
3‐1. Visual analogue scale: pleasantness of waking, sleep quality
3‐2. Diary: frequency of urination per day, frequency of urination at night
3‐3. Interview sheet: time required for urination
*1,2 Assessed at 0, 4, 8, and 12 weeks after consuming.
*3‐2 Keep it from a week before consuming to 12 weeks after consuming.
*3‐1,3‐3 Assessed at 0 and 12 weeks after consuming.
Starting date 24 June 2017
Contact information Kazuo YAMAMOTO
CEO, ORTHOMEDICO Inc.
2F Sumitomo Fudosan Korakuen Bldg., 1‐4‐1 Koishikawa, Bunkyo‐ku, Tokyo
Telephone: 03‐3818‐0610
Email: kazu@orthomedico.jp
(contacted on 30 December 2022)
Notes The description of this study is identical to the registry of Sekikawa 2020.
Open in a new tab

NCT00497939.

Study name The effectiveness of saw palmetto and sanmiaoshan on benign prostatic hyperplasia in Chinese patients
Methods Cross‐over randomized controlled trial
Participants Inclusion criteria:

  • Age between 50 and 80 years old

  • Clinically diagnosed as having BPH

  • Suffered from lower urinary tract symptoms with IPSS >= 8

  • Detectable prostatic enlargement determined by DRE

  • Urinary flow between 5 and 15 mL/s in a total void volume >= 150 mL

  • Serum PSA level < 4 ng/mL or between 4 and 10 ng/mL with per cent free PSA > 25% or >= 4 with cancer excluded by biopsy


Exclusion criteria:

  • Acute retention of urine

  • Congestive heart failure, unstable angina, arrhythmia, myocardial infraction

  • Prostatic surgery

  • Prostatic malignancy

  • Gastrointestinal disease

  • Renal impairment with serum creatinine > 140 umol/L

  • Hepatic disorder
Interventions Saw palmetto and sanmiaoshan capsule plus alpha‐blockers
Outcomes Primary outcomes

  • Differences in IPSS between the study medication and placebo groups (baseline, 6 months, end of washout period, and 6 months after cross‐over)

  • Differences in Qmax between the study medication and placebo groups (baseline, 6 months, end of washout period, and 6 months after cross‐over)


Secondary outcomes

  • Differences in IPSS and Qmax at baseline and at the end of treatment drug/placebo treatment (baseline and after washout and end of the study)

  • Mean urinary flow rate, postvoid residual volume, prostate volume, PSA and GHQ score between study medication group and placebo group (baseline, 6 months, end of washout period, and 6 months after cross‐over)

  • Mean urinary flow rate, postvoid residual volume, prostate volume, PSA and GHQ score between study medication group and baseline, and placebo group and baseline (baseline, 6 months, end of washout period, and 6 months after cross‐over and end of the study)
Starting date January 2006
Contact information Annie YF Wong
Tel: (852) 2632 2501
anniewong@surgery.cuhk.edu.hk
(contacted on 30 December 2022)
Notes  
Open in a new tab

NCT02121613.

Study name PERmixon® in LUTS Evaluation Study (PERLES)
Methods Quadruple‐blinded randomized controlled trial
Participants Inclusion criteria:

  • Male subject

  • Between 45 and 85 years old

  • Bothersome LUTS due to BPH such as frequency (daytime or nighttime), urgency, sensation of incomplete voiding, delayed urination, or weak stream

  • Naive to any prior treatment for LUTS due to BPH

  • Prostate enlargement at DRE suggestive of BPH

  • IPSS > 12 at enrollment visit and at inclusion visit

  • QoL IPSS score ≥ 3 evaluated at enrollment visit and at inclusion visit


Exclusion criteria:

  • Urological history such as urethral stricture disease and/or bladder neck disease, active (at enrollment and/or inclusion or recurrent urinary tract infection, stone in bladder or urethra)

  • Any neurologic or psychiatric disease/disorder interfering with detrusor or sphincter muscle

  • Insulin‐dependent diabetes mellitus and uncontrolled non‐insulin‐dependent diabetes mellitus

  • Known severe renal insufficiency or creatinine clearance < 30 mL/min

  • Known liver insufficiency or clinically significant abnormal liver function tests

  • History of, or concomitant, cardiac arrhythmia or angina pectoris

  • Orthostatic hypotension at enrollment or inclusion visit

  • Known hypersensitivity to 1 of the constituents of the study drugs

  • Is participating in another clinical trial
Interventions Experimental: Permixon 160 mg and placebo
Drug: Permixon 160 mg. Oral administration, 160 mg twice daily
Drug: placebo matching Permixon 160 mg. Oral administration, twice daily
Drug: placebo matching Tamsulosine LP. Oral administration, daily
Placebo comparator: placebo
Drug: placebo matching Permixon 160 mg. Oral administration, twice daily
Drug: placebo matching Tamsulosine LP. Oral administration, daily
Tamsulosine LP and placebo: active control arm
Drug: Tamsulosine LP. Oral administration, 0.4 mg daily
Drug: placebo matching Permixon 160 mg. Oral administration, twice daily
Outcomes IPSS score change from baseline to 180 days
Starting date Completed study (unpublished)
Contact information Study Director: Karim Keddad, MD (Pierre Fabre Medicament)
No other contact information available.
Notes  
Open in a new tab

DRE: digital rectal examination; IPSS: International Prostate Symptom Score; LUTS: lower urinary tract symptoms; QoL: quality of life

Differences between protocol and review

2023 update: The Methods section has been extensively modified to fit current methodological standards, including the incorporation of RoB 2 for risk of bias assessment (we chose a 'replacement approach' as defined by Methodological Expectations of Cochrane Intervention Reviews (MECIR) criteria UR3). The previous version of the protocol can be found in Appendix 3. This is a similar approach to that used in other updates (Franco 2021).

We adjusted the wording of the Objectives to fit those of other reviews by the Cochrane Review Group, and we focused on the main critical outcomes for pharmacological treatments: urologic symptoms, quality of life, and adverse events. We provided greater specifications as to the study designs and population included in our update. We narrowed the scope of the comparisons to placebo or no treatment.

2012 update: The previous authors added adverse events (harms) to Secondary outcomes.

Contributions of authors

Research conception and design: Juan Víctor Ariel Franco and Jae Hung Jung.

Data acquisition: Camila Micaela Escobar Liquitay (search strategy), Leonel Fabrizio Trivisonno, Cecilia Fieiras, Nadia Sgarbossa, and Gustavo Ariel Alvez.

Statistical analysis: Juan Víctor Ariel Franco and Jae Hung Jung.

Data analysis and interpretation: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript: All authors.

Administrative, technical, or material support: Juan Víctor Ariel Franco.

Supervision: Juan Víctor Ariel Franco.

Approval of the final manuscript: All authors.

Sources of support

Internal sources

  • Instituto Universitario Hospital Italiano de Buenos Aires, Argentina

    Provides a salary for her work in Cochrane to CMEL

  • Heinrich‐Heine‐University Düsseldorf, Germany

    Provides a salary for his work in Cochrane to JVAF

External sources

  • No sources of support provided

Declarations of interest

JVAF: none known.

LT: none known.

NJS: none known.

GAA: none known.

CF: none known.

CMEL: none known.

JHJ: none known.

JVAF and JHJ are contact editors for the Cochrane Urology Group but were excluded from the editorial processing of this article.

New search for studies and content updated (no change to conclusions)

References

References to studies included in this review

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Lopatkin 2005 {published data only}

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Preuss 2001 {published data only}

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References to studies excluded from this review

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CTRI/2020/09/027521 {published data only}

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Debruyne 2002 {published data only}

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Gerber 1998 {published data only}

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Hamdv 1997 {published data only}

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NCT00797394 {unpublished data only}

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Pannunzio 1986 {published data only}

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References to studies awaiting assessment

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