The hexanic extract (HE) of Serenoa repens (Permixon®) is indicated for the symptomatic treatment of benign prostatic hyperplasia (BPH). The drug is the n-hexane lipidosterolic extract of the American dwarf palm tree (also known as saw palmetto). The anti-inflammatory activity of HE S. repens has been demonstrated in vitro, in vivo and in men with prostatic inflammation. In randomized clinical trials, the efficacy of HE S. repens was similar to that of an α-blocker in terms of improving voiding and storage symptoms, increasing urinary flow rate and reducing prostate volume in men with BPH. HE S. repens was also as effective as 5α-reductase inhibitors and/or α-blockers at improving lower urinary tract symptoms (LUTS) and quality of life (QOL) in real-world observational studies. HE S. repens was generally well tolerated, with a lesser impact on male sexual function compared with other available therapies. Thus, HE S. repens is a useful option for the treatment of symptomatic BPH.
Plain Language Summary
BPH (enlargement of the prostate gland) compresses the urethra, leading to uncomfortable LUTS such as difficulty starting a urine stream, weak flow, incomplete bladder emptying, frequent urination, urgency, and waking at night to urinate. To avoid side effects often associated with other available treatments such as 5α-reductase inhibitors and α-blockers, plant extracts like HE Serenoa repens (Permixon®) are commonly used to treat the symptoms of BPH. HE S. repens is derived from a small palm tree native to America and has been shown to have anti-inflammatory effects in prostate inflammation. In clinical studies, HE S. repens was as effective as an α-blocker at improving urinary symptoms, increasing urinary flow rate and reducing prostate volume in men with BPH. In real-world studies, HE S. repens was as effective as 5α-reductase inhibitors and/or α-blockers at improving LUTS and QOL. European guidelines recommend HE S. repens as a treatment option for men with LUTS who want to avoid any potential side effects, especially those related to sexual function. HE S. repens was generally well tolerated, and is a useful option for the treatment of symptomatic BPH.
Hexanic lipidosterolic extract of the American dwarf palm tree with anti-inflammatory activity demonstrated in vitro, in vivo and in men with prostatic inflammation
The only S. repens extract that is approved for use under EMA well-established use criteria
Similar efficacy to 5α-reductase inhibitors and/or α-blockers in treating LUTS associated with BPH
Recommended by European guidelines as a treatment option for men with LUTS who want to avoid any potential adverse events, especially those related to sexual function
Benign prostatic hyperplasia (BPH) is characterized by proliferation of stromal and epithelial cells in the prostate transition zone, leading to enlargement of the prostate gland . This results in compression of the urethra, and is a common cause of lower urinary tract symptoms (LUTS) in men . The pathogenesis of BPH is not completely understood but is likely to be multifactorial . A persistent prostatic inflammatory status (PIS), also called chronic prostatic inflammation (CPI), has been shown to contribute to the development of BPH and increases the risk of (faster) disease progression. Therefore, inflammation is a key target of medical treatment for BPH .
LUTS are categorized as voiding symptoms (e.g. weak stream, hesitancy, straining, retention) and storage symptoms (e.g. frequency, urgency, nocturia) [3, 4]; these can lead to significant deterioration in quality of life (QOL) . Available treatments such as 5α-reductase inhibitors and α1-adrenergic receptor antagonists (α-blockers) are often associated with adverse events (AEs) including sexual dysfunction . Moreover, evidence for a reduction in persistent PIS with 5α-reductase inhibitors and α-blockers is limited . Phytotherapy is widely used in many regions for the treatment of LUTS . Extracts of the American saw palmetto or dwarf palm tree, Serenoa repens , have been traditionally used for the relief of LUTS associated with BPH . S. repens extracts are complex mixtures consisting mainly of free fatty acids . There are three main types of S. repens extracts: hexanic, supercritical CO2 and ethanolic [5, 7], each with differing phytochemical compositions .
The hexanic extract (HE) of S. repens (Permixon®) contains > 90% free fatty acids (lauric, oelic, myristic and palmitic acids) and 7% esterified fatty acids, while the rest is composed of phytosterols, flavonoids, alcohols and polyprenols . HE S. repens was first approved for the treatment of BPH in 1981 , and efficacy similar to that of the 5α-reductase inhibitor finasteride was established in early clinical trials  (previously reviewed in Drugs ). HE S. repens is the only extract of S. repens that is approved for use under EMA well-established use criteria, because of the quality of data available . Other (e.g. ethanolic) extracts have traditional use status [5, 6]. This article summarizes the pharmacological properties of HE S. repens and reviews more recent key clinical data relevant to its use in men with symptomatic BPH.
2 Pharmacodynamic Properties of HE S. repens
Several mechanisms of action have been proposed to explain the pharmacodynamic effects of HE S. repens on human prostatic tissue (Table 1), including anti-inflammatory activity (Sect. 2.1), anti-proliferative activity, and anti-androgenic activity.
2.1 Anti-inflammatory Activity
In vitro and in vivo studies have demonstrated that HE S. repens inhibits inflammatory cells and a range of inflammatory mediators and proteins, and was associated with down-regulation of genes that code markers of inflammation (Table 1) .
Importantly, HE S. repens also showed anti-inflammatory activity in a clinical trial in men with prostatic inflammation histologically confirmed by transrectal ultrasound-guided biopsy . In this study, patients were randomized to receive HE S. repens 320 mg/day or no treatment (i.e. control), with biopsies performed at baseline and 6 months. Inflammation was graded according to Irani’s scores for histological inflammation (extension of inflammatory cells; scores range from 0 to 3) and aggressiveness (effect of inflammatory cells on prostate tissue; scores range from 0 to 3). Among patients treated with HE S. repens, the mean inflammation and aggressiveness grading scores decreased significantly (both p = 0.001) from 1.55 for both at the first biopsy to 0.79 and 0.87 at the second biopsy. The mean reduction in inflammation grading (0.75 vs 0.21), aggressiveness grading (0.68 vs 0.20) and total Irani’s score (1.43 vs 0.41) was significantly (p ≤ 0.009) greater in the HE S. repens group compared with the control group. Immunohistochemical staining of biopsy samples for prostatic inflammation demonstrated significant (p < 0.001) reductions in the expression of antibodies specific for inflammatory cells (CD3, CD4, CD8, CD20 and CD163) after 6 months of treatment with HE S. repens, while there were no significant reductions in the expression of these antibodies in the control group .
As assessed using biomarkers of CPI, the anti-inflammatory activity of HE S. repens was more marked than that of tamsulosin in the exploratory phase IV PERMIN study in men with BPH-related LUTS  (Sect. 4.1.2). In this study, mRNA expression of the 29 most significant published BPH inflammation markers was quantified. Expression of each marker was normalized to KLK3, the gene that encodes prostate-specific antigen (PSA). Of the 29 genes investigated, 26 were detected at baseline. At day 90, there was a reduction in mean gene expression for 65% of markers in the HE S. repens group compared to 46% of markers in the tamsulosin group. When considering the 15 most commonly expressed genes, mean gene expression decreased for 80% of markers in the HE S. repens group and 33% of markers in the tamsulosin group .
3 Pharmacokinetic Properties of HE S. repens
Because HE S. repens is a complex mixture of several compounds (Sect. 1), its pharmacokinetic profile cannot be fully evaluated.
Plasma concentrations of an unspecified component of HE S. repens were measured in healthy young male volunteers (n = 12) who received a single oral dose of HE S. repens 320 mg in the fasting state [7, 13]. The maximum plasma concentration (Cmax) of 2.6 mg/L was achieved at 1.5 h post-dose . The mean area under the concentration-time curve was 8.2 mg/L⋅h and the elimination half-life was 1.9 h . In healthy volunteers (n = 24) who received a single dose of HE S. repens 160 mg containing 5 mg of radiolabeled lauric acid and myristic acid (active short-chain free fatty acids present in the extract), Cmax was observed at ≈ 3 h postdose . Tissue distribution of HE S. repens was assessed in rats after oral administration of the drug supplemented with radiolabeled oleic acid, lauric acid or β-sitosterol . Uptake of radioactivity was higher in the prostate gland than in the bladder or seminal vesicles, or more remote sites (e.g. liver) .
HE S. repens has been shown to inhibit CYP2C9, CYP2D6 and CYP3A4 in vitro; however, the clinical relevance of this is unknown . In healthy volunteers, HE S. repens did not appear to affect the pharmacokinetics of midazolam (a CYP3A4 substrate), caffeine (a CYP1A2 inducer), chlorzoxazone (a CYP2E1 inducer) or dextromethorphan (a CYP2D6 substrate) .
4 Therapeutic Efficacy of HE S. repens
The therapeutic efficacy of HE S. repens in men with symptomatic BPH was demonstrated in the randomized, double-blind, multicentre PERMAL  and PERMIN  studies comparing HE S. repens with the α-blocker tamsulosin (Sect. 4.1). Three open-label trials provide supportive evidence for the efficacy of HE S. repens in men with BPH. Briefly, in two small pilot studies, HE S. repens reduced infravesical obstruction and rapidly improved urodynamic parameters after 9 weeks of treatment  and improved clinical symptoms of BPH after 3 months of treatment . The long-term clinical efficacy of HE S. repens was demonstrated in a 2-year study . These open-label trials are not discussed further. The clinical efficacy of HE S. repens in real-world observational studies is discussed in Sect. 4.2.
4.1 Comparisons with Tamsulosin
4.1.1 PERMAL Study
HE S. repens was as effective as tamsulosin for the treatment of LUTS in men with BPH . Patients enrolled in the PERMAL study were men aged 50–85 years (mean 65.5 years) with LUTS secondary to BPH. All patients had an International Prostate Symptom Score (I-PSS) of ≥ 10, a maximum urinary flow rate (Qmax) of 5–15 mL/s for a voided volume of ≥ 150 mL with a post-voiding volume of < 150 mL, a prostate volume of ≥ 25 cm3, and a serum PSA level of < 4 ng/mL (or 4–10 mg/mL with a free/total PSA ratio of ≥ 15%). Following a 4-week placebo run-in period, patients were randomized to receive oral HE S. repens 320 mg/day (n = 350) or tamsulosin 0.4 mg/day (n = 354). The primary endpoint was the change in I-PSS total score from baseline to endpoint (12 months) in the per-protocol population .
At 12 months, HE S. repens and tamsulosin produced similar reductions from baseline in I-PSS total score (Table 2) . The two-sided 95% confidence interval (CI) for the difference between treatments in the mean absolute change in I-PSS at 12 months was − 0.894 to 0.895. The upper limit of the 95% CI did not exceed the non-inferiority criterion (+ 2), indicating that HE S. repens was non-inferior to tamsulosin. At 12 months, there was no significant difference between HE S. repens and tamsulosin in terms of the mean change from baseline in I-PSS irritative symptoms (− 1.7 vs − 1.5) and I-PSS obstructive symptoms (− 2.8 vs − 2.9). The I-PSS total score decreased in most (> 80%) patients in both groups. Overall, 67% of patients experienced a reduction of ≥ 3 points and 49% experienced a reduction of ≥ 5 points .
At 12 months, the change from baseline in Qmax was not significantly different between HE S. repens and tamsulosin (Table 2) . Qmax improved by 20% in 49% of HE S. repens and 55% of tamsulosin recipients, and by 50% in 28% of HE S. repens and 31% of tamsulosin recipients. At 6 weeks, 3 months and 12 months, the proportion of patients with a Qmax improvement of ≥ 3 mL/s was 25, 34 and 34% with HE S. repens and 33, 35 and 37% with tamsulosin, respectively. At 12 months, the change from baseline in sexual function score, prostate volume and PSA level did not significantly differ between patients receiving HE S. repens and those receiving tamsulosin (Table 2) .
A subset analysis of the PERMAL study compared the efficacy of HE S. repens and tamsulosin in patients with severe LUTS (i.e. I-PSS > 19; n = 124) . At 12 months, the mean improvement from baseline in I-PSS total score with HE S. repens versus that with tamsulosin approached statistical significance (Table 2). I-PSS irritative symptoms improved significantly (p < 0.05) more with HE S. repens than with tamsulosin (− 2.9 vs − 1.9), particularly among the most severely symptomatic patients (i.e. I-PSS > 21; n = 61). In terms of I-PSS obstructive symptoms, the change from baseline was − 4.9 with HE S. repens and − 3.9 with tamsulosin. The proportion of patients with an I-PSS response (i.e. ≥ 3-point reduction in I-PSS total score) was 80% with HE S. repens and 71% with tamsulosin. At 12 months, changes from baseline in Qmax, prostate volume and sexual function score were not significantly different between HE S. repens and tamsulosin (Table 2) .
4.1.2 PERMIN Study
The exploratory phase IV PERMIN study enrolled men aged 45–85 years with a > 12-month history of BPH-related LUTS . Other inclusion criteria included an I-PSS of ≥ 12, a prostate volume of ≥ 30 cm3 as determined by transrectal ultrasound, a Qmax of 5–15 mL/s for a voided volume of 150–500 mL, and a total PSA level of ≤ 4 ng/mL (or ≤ 10 mg/mL with a free/total PSA ratio of ≥ 25%). Following a 28- to 42-day washout period, patients were randomized to receive oral HE S. repens 320 mg/day (n = 102) or tamsulosin 0.4 mg/day (n = 104). The primary endpoint was mRNA expression associated with selected genes encoding biomarkers of prostate inflammation at day 90 (Sect. 2.1). Both HE S. repens and tamsulosin were associated with improvements in the secondary endpoints of I-PSS, Qmax, sexual function score and prostate volume (Table 2). There was no relationship between the change in clinical symptoms and the change in mRNA expression level. At day 90, the mean change from baseline in I-PSS total score with HE S. repens was − 6.4 in the subgroup of patients who overexpressed macrophage migration inhibitory factor (MIF) protein at baseline (> 3rd quartile), compared with − 4.5 in patients who did not overexpress MIF; this difference was not seen in the tamsulosin group (− 6.5 vs − 6.3) .
4.2 Observational Studies
Several observational studies in Europe have confirmed the efficacy of HE S. repens for the treatment of LUTS in men with BPH. For example, in two prospective, longitudinal studies conducted in real-life practice in Spain (QUALIPROST ) and France (PERSAT ), HE S. repens demonstrated similar efficacy to α-blockers [21, 22] and 5α-reductase inhibitors  in men aged ≥ 40 years with LUTS associated with BPH.
In the QUALIPROST study (n = 1713), 70% of patients received monotherapy with phytotherapy (of which 95% was HE S. repens), α-blockers (most commonly tamsulosin) or 5α-reductase inhibitors (most commonly dutasteride), 20% received combination therapy and 9% did not receive treatment (watchful waiting) . At 6 months, improvements in QOL and urinary symptoms were not significantly different between medical treatment groups (Table 3). Among patients with moderate-high baseline symptoms, all three monotherapies were associated with significantly greater improvements in QOL [assessed using the Benign Prostatic Hyperplasia Impact Index (BII)] than watchful waiting (Table 3). In terms of compliance, most (≈ 90%) patients in each medical treatment group took the medication with no difficulty . In a subset analysis, the efficacy of HE S. repens was similar to that of tamsulosin in men with moderate to severe LUTS associated with BPH . In patients who received monotherapy with HE S. repens 320 mg/day (n = 384) or tamsulosin 0.4 mg/day (n = 353), changes from baseline to 6 months in I-PSS total score, Qmax, prostate volume and PSA were not significantly different between treatment groups. Improvements in QOL (assessed using the BII and I-PSS 8) were also similar in both treatment groups .
In the PERSAT study (n = 759 evaluable), 50% of patients were treated with phytotherapy (of which 98% was HE S. repens) and 50% received an α-blocker (most commonly silodosin) . After 6 months, the proportion of patients with a ≥ 3-point reduction in total I-PSS score (primary endpoint) was 93% with phytotherapy and 94% with α-blockers. Overall, the mean change in total I-PSS score was − 10.0 points, with no significant difference between treatment groups. In terms of QOL, the proportion of patients bothered by their LUTS (i.e. I-PSS-QoL score of ≥ 4) decreased from 86% at baseline to 6% at 6 months in the phytotherapy group, and from 91% at baseline to 7% at 6 months in the α-blockers group. Overall, 93% of patients were satisfied with their prescribed treatment (95% with phytotherapy and 91% with α-blockers) . Similar results were seen among the subpopulation of patients who had no changes to their treatment during the study (n = 633) .
HE S. repens was also effective in patients with chronic benign prostate diseases with associated inflammation . A study conducted as part of routine clinical practice in Italy included 591 men aged 35–65 years with a clinical diagnosis of BPH or chronic prostatitis without infection, non-acute irritative dysuria symptoms, an I-PSS score of ≥ 13, a National Institute of Health-Chronic Prostatitis Symptom Index (NHI-CPSI) score of ≥ 2, a Qmax of < 12 mL/s, a post-voiding volume of < 150 mL, a digital rectal examination not suggestive of prostate cancer, and a total PSA of ≤ 4 ng/mL. HE S. repens improved bladder emptying and LUTS at 6 months, as evidenced by a significant (p < 0.001) increase from baseline in Qmax (from 10.7 to 13.7 mL/s) and significantly (p < 0.0001) improved scores on the I-PSS (from 17.8 to 12.2) and the NHI-CPSI (from 13.3 to 8.2). HE S. repens was also associated with an improvement in erectile function, as demonstrated by a significant (p < 0.0055) increase in International Index of Erectile Function-5 score (from 17.6 to 18.1) .
5 Tolerability of HE S. repens
HE S. repens was generally well tolerated in men with symptomatic BPH. In clinical trials, the most common adverse events (AEs) were headache and abdominal pain . Less common AEs included nausea, skin rash, reversible gynaecomastia, increased γ-glutamyltransferase and increased transaminases .
In the PERMAL study, AEs occurred in 66% of HE S. repens recipients and 67% of tamsulosin recipients . The most common (incidence ≥ 3% in any treatment group) AEs were rhinitis (9% with HE S. repens vs 12% with tamsulosin), headache (8 vs 11%), dizziness (3 vs 2%) and ejaculation disorders (1 vs 4%; p = 0.001). Rates of possibly treatment-related AEs (TRAEs; 22 vs 24%), serious AEs (8 vs 9%) and discontinuations due to AEs (8 vs 8%) were similar across both treatment groups . In the PERMIN study, the overall incidence of AEs was 29% with HE S. repens and 31% with tamsulosin . The most common (incidence > 2%) treatment-emergent AEs were retrograde ejaculation (4%), constipation (3%) and back pain (3%) with tamsulosin, while no AEs occurred in > 2% of HE S. repens recipients. AEs leading to treatment discontinuation (all of which were mild or moderate in severity) occurred in 8% of patients receiving HE S. repens and 3% of those receiving tamsulosin .
HE S. repens was better tolerated than α-blockers [21, 22] and 5α-reductase inhibitors  in the real-world QUALIPROST and PERSAT studies. In QUALIPROST, the overall incidence of AEs was 1% with HE S. repens, 16% with α-blockers and 14% with 5α-reductase inhibitors . For combination therapies, the incidence of AEs was 17% with HE S. repens + 5α-reductase inhibitors, 14% with HE S. repens + α-blockers, and 31% with α-blockers + 5α-reductase inhibitors . In PERSAT, potentially TRAEs were reported in 6% of phytotherapy recipients and 12% of patients receiving α-blockers; the most common TRAEs were ejaculation disorders (1 vs 4%) and asthenia (1 vs 3%) .
6 Dosage and Administration of HE S. repens
HE S. repens is approved under well-established use criteria in the EU for the symptomatic treatment of BPH . The recommended dosage is 320 mg once daily or 160 mg twice daily, administered orally. Long-term use is possible . Local prescribing information should be consulted for detailed information regarding contraindications, warnings and precautions, and drug interactions.
7 Place of HE S. repens in the Management of Symptomatic BPH
The main goals in the management of BPH are to relieve bothersome LUTS, improve QOL, and reduce disease progression and the development of complications . Therefore, management options for BPH are determined by symptom severity and the impact these symptoms have on QOL . They often consist of watchful waiting for patients with mild or non-bothersome LUTS and pharmacological treatment for patients with more severe symptoms [1, 27].
Pharmacotherapies for BPH-related LUTS include 5α-reductase inhibitors (e.g. dutasteride, finasteride), α-blockers (e.g. doxazosin, silodosin, tamsulosin) and phosphodiesterase type 5 inhibitors (e.g. tadalafil) [1, 3]. Muscarinic receptor antagonists (e.g. oxybutynin, tolterodine) are also strongly recommended by the European Association of Urology (EAU) as a treatment option for men with moderate to severe LUTS who mainly have bladder storage symptoms . However, the efficacy and tolerability of these pharmacological agents varies [1, 3]. There is ongoing interest in the use of phytotherapeutic agents, of which S. repens extracts are the most commonly prescribed and extensively studied [2, 28]. Recently updated EAU guidelines conclude that HE S. repens improves Qmax and nocturia, and now recommend HE S. repens as a treatment option for men with LUTS who want to avoid any potential AEs, especially those related to sexual function .
HE S. repens appears to have multiple mechanisms of action, including anti-inflammatory, anti-proliferative and anti-androgenic activity (Sect. 2). The effects of HE S. repens on inflammation (Sect. 2.1) are clinically relevant, given the known association between prostatic inflammation and the development/progression of BPH (Sect. 1). Indeed, the anti-inflammatory activity of HE S. repens has been demonstrated in vitro, in vivo, and in randomized clinical trials (Sect. 2.1).
Experience in randomized clinical trials has established the therapeutic efficacy of HE S. repens for the treatment of symptomatic BPH (Sect. 4.1). In the PERMAL and PERMIN studies, HE S. repens was as effective as tamsulosin in terms of improving voiding and storage symptoms, increasing urinary flow rate and reducing prostate volume in men with BPH (Sect. 4.1). The greater degree of improvement in urinary symptoms with HE S. repens in patients who overexpressed MIF protein at baseline versus those who did not (Sect. 4.1.2) suggests that patients with higher CPI and greater MIF expression may benefit most from treatment with HE S. repens . Additional studies to further investigate this finding would be of interest.
Data from several European observational studies were generally consistent with those seen in clinical trials (Sect. 4.2). In the real-world QUALIPROST and PERSAT studies, improvements in QOL observed with HE S. repens were similar to those observed with 5α-reductase inhibitors and/or α-blockers (Sect. 4.2). Despite their inherent limitations, such observational studies offer a better representation of real-life clinical practice than prospective clinical trials , confirming the efficacy of HE S. repens for the treatment of LUTS in men with BPH.
The clinical efficacy of HE S. repens in men with BPH-related LUTS has also been confirmed in various systematic reviews and network meta-analyses [29,30,31]. Generally, HE S. repens was associated with greater clinical benefits than placebo [29,30,31] and demonstrated similar efficacy to α-blockers and 5α-reductase inhibitors [30, 31]. However, the results of these indirect comparisons require cautious interpretation given the heterogeneity of the studies and patient populations assessed.
HE S. repens was generally well tolerated in clinical trials, with the most frequent AEs being headache, dizziness and ejaculation disorders (Sect. 5). However, it should be noted that the incidence of ejaculation disorders was significantly lower with HE S. repens than with tamsulosin (Sect. 5). Men with BPH are often dissatisfied with α-blocker and 5α-reductase inhibitor therapy due to ejaculation disorders and sexual dysfunction, respectively  and, in a real-world setting, the most common reason for prescribing HE S. repens was to avoid sexual dysfunction and ejaculation disorders (Sect. 4.2). Results of a sexual function questionnaire used in the PERMAL and PERMIN studies showed no significant differences between HE S. repens and tamsulosin (Sect. 4.1). However, pooled data from three randomized, double-blind studies (including PERMAL) demonstrated that HE S. repens had no negative impact on male sexual function in terms of interest in sex, quality of erection, achievement of orgasm and ejaculation, while tamsulosin and finasteride had a slight negative impact on sexual function (particularly ejaculation) . Moreover, in systematic reviews and meta-analyses, HE S. repens was associated with a significantly lower incidence of ejaculation disorders (p = 0.001)  and ejaculatory dysfunction (0.5 vs 4%; p = 0.007)  than tamsulosin, and numerically lower rates of decreased libido (2.2 vs 3%) and impotence (1.5 vs 2.8%) than finasteride .
Another key factor influencing physicians’ prescription of HE S. repens was patient acceptability (Sect. 4.2), the role of which is gaining greater importance in clinical decision-making . In the Adelphi Real World Permixon Study, which collected prescribing data from 200 physicians in France and Spain for 1197 patients with BPH, the main reasons for prescribing HE S. repens monotherapy aside from relief of urinary symptoms (including voiding and storage symptoms) were the avoidance of sexual dysfunction and ejaculation disorders, patient acceptability, value for money, familiarity with the drug, and reduction of inflammation . In the observational PERSAT study, almost all patients receiving HE S. repens were satisfied with their prescribed treatment (Sect. 4.2). According to current EAU guidelines for LUTS, the choice of treatment should always take into account factors such as patient values and preferences .
In conclusion, HE S. repens is an effective and generally well-tolerated treatment that is a useful option for men with symptomatic BPH.
Data Selection Hexanic Extract of Serenoa repens: 325 records identified
Excluded during initial screening (e.g. press releases; news reports; not relevant drug/indication; preclinical study; reviews; case reports; not randomized trial)
Excluded during writing (e.g. reviews; duplicate data; small patient number; nonrandomized/phase I/II trials)
Cited efficacy/tolerability articles
Cited articles not efficacy/tolerability
Search Strategy: EMBASE, MEDLINE and PubMed from 1946 to present. Clinical trial registries/databases and websites were also searched for relevant data. Key words were Permixon, Serenoa repens, saw palmetto extract, LUTS, benign prostatic hyperplasia, prostatic hypertrophy. Records were limited to those in English language. Searches last updated 7 February 2022
Yu ZJ, Yan HL, Xu FH, et al. Efficacy and side effects of drugs commonly used for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia. Front Pharmacol. 2020. https://doi.org/10.3389/fphar.2020.00658.
De Nunzio C, Salonia A, Gacci M, et al. Inflammation is a target of medical treatment for lower urinary tract symptoms associated with benign prostatic hyperplasia. World J Urol. 2020;38(11):2771–9.
Langan RC. Benign prostatic hyperplasia. Prim Care. 2019;46(2):223–32.
Strum SB. Serenoa repens (Saw palmetto) for lower urinary tract symptoms (LUTS): the evidence for efficacy and safety of lipidosterolic extracts. Part I. Uro. 2021;1:118–38.
Marti G, Joulia P, Amiel A, et al. Comparison of the phytochemical composition of Serenoa repens extracts by a multiplexed metabolomic approach. Molecules. 2019;24(2208):1–14.
European Medicines Agency. European Union herbal monograph on Serenoa repens (W. Bartram) small, fructus. 2014. https://www.ema.europa.eu/en/documents/herbal-monograph/draft-european-union-herbal-monograph-serenoa-repens-w-bartram-small-fructus_en.pdf. Accessed 8 Feb 2022.
European Medicines Agency. Assessment report on Serenoa repens (W. Bartram) small, fructus. Final. 2015. https://www.ema.europa.eu/en/documents/herbal-report/final-assessment-report-serenoa-repens-w-bartram-small-fructus_en.pdf. Accessed 8 Feb 2022.
De Monte C, Carradori S, Granese A, et al. Modern extraction techniques and their impact on the pharmacological profile of Serenoa repens extracts for the treatment of lower urinary tract symptoms. BMC Urol. 2014. https://doi.org/10.1186/1471-2490-14-63.
Carraro JC, Raynaud JP, Koch G, et al. Comparison of phytotherapy (Permixon®) with finasteride in the treatment of benign prostate hyperplasia: a randomized international study of 1,098 patients. Prostate. 1996;29(4):231–40.
Plosker GL, Brogden RN. Serenoa repens (Permixon®). A review of its pharmacology and therapeutic efficacy in benign prostatic hyperplasia. Drugs Aging. 1996;9(5):379–95.
Gravas S, Samarinas M, Zacharouli K, et al. The effect of hexanic extract of Serenoa repens on prostatic inflammation: results from a randomized biopsy study. World J Urol. 2019;37(3):539–44.
Latil A, Pétrissans MT, Rouquet J, et al. Effects of hexanic extract of Serenoa repens (Permixon® 160 mg) on inflammation biomarkers in the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia. Prostate. 2015;75(16):1857–67.
De di Valserra MB, Tripodi AS, Contos S, et al. Serenoa repens capsules: a bioequivalence study. Acta Toxicol Ther. 1994;15:21–39.
Raynaud JP, Girault J, Vinclair P, et al. Absorption of 2 of the main components of the lipido-sterolic extract of Serenoa repens (Permixon®) in human volunteers [abstract]. In: 5th International consultation on BPH. 2000.
Chevalier G, Benard P, Cousse H, et al. Distribution study of radioactivity in rats after oral administration of the lipido/sterolic extract of Serenoa repens (Permixon®) supplemented with [1-14C]-lauric acid, [1-14C]-oleic acid or [4-14C]-β-sitosterol. Eur J Drug Metab Pharmacokinet. 1997;22(1):73–83.
Debruyne F, Koch G, Boyle P, et al. Comparison of a phytotherapeutic agent (Permixon) with an α-blocker (tamsulosin) in the treatment of benign prostatic hyperplasia: a 1-year randomized international study. Eur Urol. 2002;41(5):497–506.
Al-Shukri SH, Deschaseaux P, Kuzmin IV, et al. Early urodynamic effects of the lipido-sterolic extract of Serenoa repens (Permixon®) in patients with lower urinary tract symptoms due to benign prostatic hyperplasia. Prostate Cancer Prostatic Dis. 2000;3(3):195–9.
Navarrete RV, Cardoso JVG, Barat A, et al. BPH and inflammation: pharmacological effects of Permixon on histological and molecular inflammatory markers. Results of a double blind pilot clinical assay. Eur Urol. 2003;44(5):549–55.
Pytel YA, Vinarov A, Lopatkin N, et al. Long-term clinical and biologic effects of the lipidosterolic extract of Serenoa repens in patients with symptomatic benign prostatic hyperplasia. Adv Ther. 2002;19(6):297–306.
Debruyne F, Boyle P, Da Silva FD, et al. Evaluation of the clinical benefit of Permixon and tamsulosin in severe BPH patients-PERMAL study subset analysis. Eur Urol. 2004;45(6):773–9.
Alcaraz A, Carballido-Rodriguez J, Unda-Urzaiz M, et al. Quality of life in patients with lower urinary tract symptoms associated with BPH: change over time in real-life practice according to treatment—the QUALIPROST study. Int Urol Nephrol. 2016;48(5):645–56.
de la Taille A, Bardin L, Castagné C, et al. Alpha-bloquants ou phytothérapie en traitement de première intention des SBAU/HBP en médecine générale: l’étude non interventionnelle PERSAT [Alpha-blockers or phytotherapy as first-line treatment of LUTS/BPH in general medicine: the PERSAT non-interventional study]. Prog Urol. 2020;30(10):522–31.
Alcaraz A, Rodriguez-Antolin A, Carballido-Rodriguez J, et al. Efficacy and tolerability of the hexanic extract of Serenoa repens compared to tamsulosin in moderate-severe LUTS-BPH patients. Sci Rep. 2021;11(1):19401.
de la Taille A, du Rieu QC, Bardin L. Alpha-bloquants ou Permixon® pendant 6 mois : résultats d’une sous-population de l’étude PERSAT [Alpha-blockers or Permixon® for 6 months: results from a subpopulation of the study PERSAT] [abstract no. CO-01]. Prog Urol. 2021;31(13):773.
Giulianelli R, Pecoraro S, Sepe G, et al. Multicentre study on the efficacy and tolerability of an extract of Serenoa repens in patients with chronic benign prostate conditions associated with inflammation. Arch Ital Urol Androl. 2012;84(2):94–8.
Edwards JL. Diagnosis and management of benign prostatic hyperplasia. Am Fam Physician. 2008;77(10):1403–10.
Gravas S, Cornu J, Gacci M, et al. EAU guidelines on management of non-neurogenic male lower urinary tract symptoms (LUTS), incl. benign prostatic obstruction (BPO). 2021. https://uroweb.org/guideline/treatment-of-non-neurogenic-male-luts/. Accessed 8 Feb 2022.
Geavlete P, Multescu R, Geavlete B. Serenoa repens extract in the treatment of benign prostatic hyperplasia. Ther Adv Urol. 2011;3(4):193–8.
Boyle P, Robertson C, Lowe F, et al. Updated meta-analysis of clinical trials of Serenoa repens extract in the treatment of symptomatic benign prostatic hyperplasia. BJU Int. 2004;93(6):751–6.
Novara G, Giannarini G, Alcaraz A, et al. Efficacy and safety of hexanic lipidosterolic extract of Serenoa repens (Permixon) in the treatment of lower urinary tract symptoms due to benign prostatic hyperplasia: systematic review and meta-analysis of randomized controlled trials. Eur Urol Focus. 2016;2(5):553–61.
Vela-Navarrete R, Alcaraz A, Rodríguez-Antolín A, et al. Efficacy and safety of a hexanic extract of Serenoa repens (Permixon®) for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH): systematic review and meta-analysis of randomised controlled trials and observational studies. BJU Int. 2018;122(6):1049–65.
Zlotta AR, Teillac P, Raynaud JP, et al. Evaluation of male sexual function in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) treated with a phytotherapeutic agent (Permixon®), tamsulosin or finasteride. Eur Urol. 2005;48(2):269–76.
Perry R, Milligan G, Anderson P, et al. Real-world use of Permixon® in benign prostatic hyperplasia–determining appropriate monotherapy and combination treatment. Adv Ther. 2012;29(6):538–50.
Ragab A, Ragab-Thomas JMF, Delhon A, et al. Effects of Permixon® (Sereprostat® in Spain) on phospholipase A2 activity and on arachidonic acid metabolism in cultured prostatic cells. Acta Medica. 1987:293-6.
Paubert-Braquet M, Mencia Huerta JM, Cousse H, et al. Effect of the lipidic lipidosterolic extract of Serenoa repens (Permixon®) on the ionophore A23187-stimulated production of leukotriene B4 (LTB4) from human polymorphonuclear neutrophils. Prostaglandins Leukot Essent Fatty Acids. 1997;57(3):299–304.
de la Taille A. Therapeutic approach: the importance of controlling prostatic inflammation. Eur Urol Suppl. 2013;12:116–22.
Latil A, Lantoine-Adam F, Aguilar L, et al. Anti-inflammatory properties of Permixon lipidosterolic extract of Serenoa repens: in vitro and in vivo results [abstract no. 630]. Eur Urol Suppl. 2010;9(2):209.
Latil A, Libon C, Templier M, et al. Hexanic lipidosterolic extract of Serenoa repens inhibits the expression of two key inflammatory mediators, MCP-1/CCL2 and VCAM-1, in vitro. BJU Int. 2012;110(6 Pt B):E301–7.
Latil A, Verscheure Y, Tisne-Versailles J, et al. Permixon lipidosterolic extract of Serenoa repens modifies prostate inflammatory status [abstract no. 352]. Eur Urol Suppl. 2009;8(4):208.
Sirab N, Robert G, Fasolo V, et al. Lipidosterolic extract of Serenoa repens modulates the expression of inflammation related-genes in benign prostatic hyperplasia epithelial and stromal cells. Int J Mol Sci. 2013;14(7):14301–20.
Bernichtein S, Pigat N, Camparo P, et al. Anti-inflammatory properties of lipidosterolic extract of Serenoa repens (Permixon®) in a mouse model of prostate hyperplasia. Prostate. 2015;75(7):706–22.
Silvestri I, Cattarino S, Agliano A, et al. Effect of Serenoa repens (Permixon®) on the expression of inflammation-related genes: analysis in primary cell cultures of human prostate carcinoma. J Inflamm. 2013;10(11):1–9.
Vacherot F, Azzouz M, Gil-Diez-De-Medina S, et al. Induction of apoptosis and inhibition of cell proliferation by the lipido-sterolic extract of Serenoa repens (LSESr, Permixon®) in benign prostatic hyperplasia. Prostate. 2000;45(3):259–66.
Vela-Navarrete R, Escribano-Burgos M, Farré AL, et al. Serenoa repens treatment modifies Bax/Bcl-2 index expression and caspase-3 activity in prostatic tissue from patients with benign prostatic hyperplasia. J Urol. 2005;173(2):507–10.
Bayne CW, Ross M, Donnelly F, et al. The selectivity and specificity of the actions of the lipido-sterolic extract of Serenoa repens (Permixon®) on the prostate. J Urol. 2000;164(3 Pt 1):876–81.
Habib FK, Ross M, Ho CK, et al. Serenoa repens (Permixon®) inhibits the 5α-reductase activity of human prostate cancer cell lines without interfering with PSA expression. Int J Cancer. 2005;114(2):190–4.
Di Silverio F, Monti S, Sciarra A, et al. Effects of long-term treatment with Serenoa repens (Permixon®) on the concentrations and regional distribution of androgens and epidermal growth factor in benign prostatic hyperplasia. Prostate. 1998;37(2):77–83.
During the peer review process, the manufacturer of the hexanic extract of Serenoa repens was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.
The preparation of this review was not supported by any external funding.
Authorship and Conflict of interest
Hannah Blair is a salaried employee of Adis International Ltd/Springer Nature, and declares no relevant conflicts of interest. All authors contributed to the review and are responsible for the article content.
Ethics approval, Consent to participate, Consent to publish, Availability of data and material, Code availability
The manuscript was reviewed by: M. Samarinas, Department of Urology, General Hospital of Larissa, Larissa, Greece; A. Wagg, Division of Geriatric Medicine, University of Alberta, Edmonton, AB, Canada.
The original online version of the article has been revised due to retrospective open access order.
Below is the link to the electronic supplementary material.
About this article
Cite this article
Blair, H.A. Hexanic Extract of Serenoa repens (Permixon®): A Review in Symptomatic Benign Prostatic Hyperplasia. Drugs Aging 39, 235–243 (2022). https://doi.org/10.1007/s40266-022-00924-3