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LE Magazine January 2007

Saw Palmetto

Phytotherapy for benign prostatic hyperplasia.

OBJECTIVE: To systematically review the existing evidence regarding the efficacy and safety of phytotherapeutic compounds used to treat men with symptomatic benign prostatic hyperplasia (BPH). DESIGN: Randomized trials were identified searching MEDLINE (1966--1997), EMBASE, Phytodok, the Cochrane Library, bibliographies of identified trials and review articles, and contact with relevant authors and drug companies. The studies were included if men had symptomatic benign prostatic hyperplasia, the intervention was a phytotherapeutic preparation alone or combined, a control group received placebo or other pharmacologic therapies for BPH, and the treatment duration was at least 30 days. Key data were extracted independently by two investigators. RESULTS: A total of 44 studies of six phytotherapeutic agents (Serenoa repens, Hypoxis rooperi, Secale cereale, Pygeum africanum, Urtica dioica, Curcubita pepo) met inclusion criteria and were reviewed. Many studies did not report results in a method allowing meta-analysis. Serenoa repens, extracted from the saw palmetto, is the most widely used phytotherapeutic agent for BPH. A total of 18 trials involving 2939 men were reviewed. Compared with men receiving placebo, men taking Serenoa repens reported greater improvement of urinary tract symptoms and flow measures. Serenoa repens decreased nocturia (weighted mean difference (WMD) = -0.76 times per evening; 95% CI = -1.22 to -0.32; n = 10 studies) and improved peak urine flow (WMD = 1.93 ml s(-1); 95% CI = 0.72 to 3.14, n = 8 studies). Men treated with Serenoa repens rated greater improvement of their urinary tract symptoms versus men taking placebo (risk ratio of improvement = 1.72; 95% CI = 1.21 to 2.44, n = 8 studies). Improvement in symptoms of BPH was comparable to men receiving the finasteride. Hypoxis rooperi (n = 4 studies, 519 men) was also demonstrated to be effective in improving symptom scores and flow measures compared with placebo. For the two studies reporting the International Prostate Symptom Score, the WMD was -4.9 IPSS points (95% CI = -6.3 to -3.5, n = 2 studies) and the WMD for peak urine flow was 3.91 ml s(-1) (95% CI = 0.91 to 6.90, n = 4 studies). Secale cereale (n = 4 studies, 444 men) was found to modestly improve overall urological symptoms. Pygeum africanum (n = 17 studies, 900 men) may be a useful treatment option for BPH. However, review of the literature has found inadequate reporting of outcomes which currently limit the ability to estimate its safety and efficacy. The studies involving Urtica dioica and Curcubita pepo are limited although these agents may be effective combined with other plant extracts such as Serenoa and Pygeum. Adverse events due to phytotherapies were reported to be generally mild and infrequent. CONCLUSIONS: Randomized studies of Serenoa repens, alone or in combination with other plant extracts, have provided the strongest evidence for efficacy and tolerability in treatment of BPH in comparison with other phytotherapies. Serenoa repens appears to be a useful option for improving lower urinary tract symptoms and flow measures. Hypoxis rooperi and Secale cereale also appear to improve BPH symptoms although the evidence is less strong for these products. Pygeum africanum has been studied extensively but inadequate reporting of outcomes limits the ability to conclusively recommend it. There is no convincing evidence supporting the use of Urtica dioica or Curcubita pepo alone for treatment of BPH. Overall, phytotherapies are less costly, well tolerated and adverse events are generally mild and infrequent. Future randomized controlled trials using standardized preparations of phytotherapeutic agents with longer study durations are needed to determine their long-term effectiveness in the treatment of BPH.

Public Health Nutr. 2000 Dec;3(4A):459-72

Serenoa repens (Permixon) inhibits the 5alpha-reductase activity of human prostate cancer cell lines without interfering with PSA expression.

The phytotherapeutic agent Serenoa repens is an effective dual inhibitor of 5alpha-reductase isoenzyme activity in the prostate. Unlike other 5alpha-reductase inhibitors, Serenoa repens induces its effects without interfering with the cellular capacity to secrete PSA. Here, we focussed on the possible pathways that might differentiate the action of Permixon from that of synthetic 5alpha-reductase inhibitors. We demonstrate that Serenoa repens, unlike other 5alpha-reductase inhibitors, does not inhibit binding between activated AR and the steroid receptor-binding consensus in the promoter region of the PSA gene. This was shown by a combination of techniques: assessment of the effect of Permixon on androgen action in the LNCaP prostate cancer cell line revealed no suppression of AR and maintenance of PSA protein expression at control levels. This was consistent with reporter gene experiments showing that Permixon failed to interfere with AR-mediated transcriptional activation of PSA and that both testosterone and DHT were equally effective at maintaining this activity. Our results demonstrate that despite Serenoa repens effective inhibition of 5alpha-reductase activity in the prostate, it did not suppress PSA secretion. Therefore, we confirm the therapeutic advantage of Serenoa repens over other 5alpha-reductase inhibitors as treatment with the phytotherapeutic agent will permit the continuous use of PSA measurements as a useful biomarker for prostate cancer screening and for evaluating tumour progression.

Int J Cancer. 2005 Mar 20;114(2):190-4

Effect of permixon on human prostate cell growth: lack of apoptotic action.

BACKGROUND: Permixon, a phytotherapeutic agent derived from the saw palmetto or Serenoa repens plant, is a lipid/sterol extract that is believed to interfere with 5alpha-reductase activity, thus inhibiting prostate growth. In this study, we investigated the magnitude and specificity of the effect of Permixon on cell proliferation and apoptosis in human prostate cancer cells. METHODS: The effect of Permixon was examined in androgen-independent PC-3 prostate cancer cells, androgen-sensitive LNCaP prostate cancer cells, and MCF-7 breast cancer cells in vitro. Cell growth, apoptosis induction, and cell proliferation was studied after exposure to Permixon at two concentrations (10 and 100 microg/ml). Cell proliferation and cell cycle progression were determined after 24 hr on the basis of (3)[H]-thymidine incorporation assay and flowcytometric analysis, respectively. Apoptosis induction was evaluated in treated and untreated cultures using the Hoescht staining and caspase-3 activation. RESULTS: Exposure of prostate and breast cancer cells to a high dose of Permixon (100 microg/ml) resulted in a significant decrease in the rate of cell growth; an effect that was not time-dependent and was not associated with cell cycle arrest. Permixon treatment (at either high or low dose) had no effect on apoptosis induction in prostate cancer cell lines (P > 0.6). Furthermore, in vitro Permixon was a weak inhibitor of 5alpha-reductase activity type 2 in prostatic homogenates. CONCLUSIONS: The results indicate the ability of Permixon to affect prostate cancer cell growth without inducing apoptosis or cell cycle arrest. This effect was not prostate-specific and was only manifested at high concentrations of Permixon. Furthermore our findings indicate that Permixon is weak inhibitor of 5alpha-reductase compared to finasteride. This study challenges previous evidence on the anti-growth effect of Permixon in the prostate and its ability to inhibit 5alpha-reductase activity, while questioning apoptosis as a mechanism of action of this phytotherapeutic against prostate growth, a concept that may have therapeutic significance.

Prostate. 2004 Sep 15;61(1):73-80

Tissue effects of saw palmetto and finasteride: use of biopsy cores for in situ quantification of prostatic androgens.

OBJECTIVES: To determine the effects of a saw palmetto herbal blend (SPHB) compared with finasteride on prostatic tissue androgen levels and to evaluate needle biopsies as a source of tissue for such determinations. METHODS: Prostate levels of testosterone and dihydrotestosterone (DHT) were measured on 5 to 10-mg biopsy specimens (18-gauge needle cores) in three groups of men with symptomatic benign prostatic hyperplasia: 15 men receiving chronic finasteride therapy versus 7 untreated controls; 4 men undergoing prostate adenomectomy to determine sampling variability (10 specimens each); and 40 men participating in a 6-month randomized trial of SPHB versus placebo, before and after treatment. RESULTS: Prostatic tissue DHT levels were found to be several times higher than the levels of testosterone (5.01 versus 1.51 ng/g), that ratio becoming reversed (1.05 versus 3.63 ng/g) with chronic finasteride therapy. The finasteride effect was statistically significant for both androgens (P <0.01), and little overlap of individual values between finasteride-treated and control patients was seen. In the randomized trial, tissue DHT levels were reduced by 32% from 6.49 to 4.40 ng/g in the SPHB group (P <0.005), with no significant change in the placebo group. CONCLUSIONS: For control versus finasteride-treated men, the tissue androgen values obtained with needle biopsy specimens were similar-both for absolute values and the percentage of change-to those previously reported using surgically excised volumes of prostatic tissue. The quantification of prostatic androgens by assay of needle biopsies is thus feasible and offers the possibility of serial studies in individual patients. The SPHB-induced suppression of prostatic DHT levels, modest but significant in a randomized trial, lends an element of support to the hypothesis that inhibition of the enzyme 5-alpha reductase is a mechanism of action of this substance.

Urology. 2001 May;57(5):999-1005

Saw palmetto for the treatment of men with lower urinary tract symptoms.

PURPOSE: A comprehensive review of the literature on the use of saw palmetto in men with lower urinary tract symptoms is provided. MATERIALS AND METHODS: A literature search of studies that have assessed the mechanism of action and clinical results of saw palmetto in men with benign prostatic hyperplasia was performed. RESULTS: A variety of potential mechanisms of action of saw palmetto have been demonstrated through in vitro studies, including 5-alpha reductase inhibition, adrenergic receptor antagonism and intraprostatic androgen receptor blockade. Clinical evidence of the relevance of these effects is largely unavailable. The use of saw palmetto in men with benign prostatic hyperplasia is safe with no recognized adverse effects. No effect on serum prostate specific antigen has been noted. Placebo controlled trials and meta-analyses have suggested that saw palmetto leads to subjective and objective improvement in men with lower urinary tract symptoms. However, most studies are significantly limited by methodological flaws, small patient numbers and brief treatment intervals. CONCLUSIONS: Evidence suggests that saw palmetto may have a significant effect on urinary flow rates and symptom scores compared to placebo in men with lower urinary tract symptoms. However, large scale, placebo controlled trials are needed to assess the efficacy of saw palmetto.

J Urol. 2000 May;163(5):1408-12

A randomized, double-blind, placebo-controlled trial to determine the effectiveness of botanically derived inhibitors of 5-alpha-reductase in the treatment of androgenetic alopecia.

BACKGROUND: Androgenetic alopecia (AGA) is characterized by the structural miniaturization of androgen-sensitive hair follicles in susceptible individuals and is anatomically defined within a given pattern of the scalp. Biochemically, one contributing factor of this disorder is the conversion of testosterone (T) to dihydrotestosterone (DHT) via the enzyme 5-alpha reductase (5AR). This metabolism is also key to the onset and progression of benign prostatic hyperplasia (BPH). Furthermore, AGA has also been shown to be responsive to drugs and agents used to treat BPH. Of note, certain botanical compounds have previously demonstrated efficacy against BPH. Here, we report the first example of a placebo-controlled, double-blind study undertaken in order to examine the benefit of these botanical substances in the treatment of AGA. OBJECTIVES: The goal of this study was to test botanically derived 5AR inhibitors, specifically the liposterolic extract of Serenoa repens (LSESr) and beta-sitosterol, in the treatment of AGA. Subjects: Included in this study were males between the ages of 23 and 64 years of age, in good health, with mild to moderate AGA. RESULTS: The results of this pilot study showed a highly positive response to treatment. The blinded investigative staff assessment report showed that 60% of (6/10) study subjects dosed with the active study formulation were rated as improved at the final visit. CONCLUSIONS: This study establishes the effectiveness of naturally occurring 5AR inhibitors against AGA for the first time, and justifies the expansion to larger trials.

J Altern Complement Med. 2002 Apr;8(2):143-52

Saw palmetto and benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a common health issue that affects 8% of all men at the age of 40, 60% of men in their 70s, and 90% of those greater than 80 years of age. One-fourth of these men will develop moderate to severe lower urinary tract symptoms that greatly affect their quality of life. Recent evidence suggests that the use of saw palmetto leads to improvements in urinary function for those suffering from BPH. The favorable comparison of saw palmetto with tamsulosin, a well-known first line agent in the treatment of urinary tract symptoms, demonstrates promise towards a beneficial effect of this herbal agent, with very few, if any, adverse effects. However, what degree of this beneficial activity is due to placebo effects is yet to be determined. In addition, the precise mechanism of action of saw palmetto in men with BPH remains unclear.

Am J Chin Med. 2004;32(3):331-8