"We show that geraniol, a monoterpene found in essential oils of fruits and herbs caused inhibition of Caco-2 cells growth and blocked cancer cell differentiation. Geraniol at 400 ìM prevented the formation of brush-border membranes and inhibited the expression of intestinal hydrolases (sucrase, lactase, alkaline phosphatase). When combined with geraniol (400 ìM), the antiproliferative and cytotoxic effects of 5-FU (5 ìM) were increased by 2-fold."

Saw Palmetto Extract - New Actions and Localized Effect on DHT Discovered

Reviewed by: R. Reichert

Reference: Paubert-Braquet M, Cousse H, Raynaud JP, et al. Effect of the lipidosterolic extract of Serenoa repens (Permixon(R)) and its major components on basic fibroblast growth factor-induced proliferation of cultures of human prostate biopsies. Eur Urol 1998; 33:340-47.

Summary: Prostate tissue samples that had been biopsied from patients with benign prostatic hyperplasia (BPH) were cultured in vitro with several different types of media for a maximum of 72 hours. Biopsies were cultured in the presence or absence of basic fibroblast growth factor (b-FGF) or epidermal growth factor (EGF). Lovastatin was or was not added after 30 minutes and geraniol was added after 24 hours. Aiposterolic extract of saw palmetto (Permixon(R)) or its components (e.g. unsaturated fatty acids, the unsaponified fraction, hexacosanol and lupenone) at doses of 1, 10, and 30 ng/ml were also added after a 24 hour time period. Radioactively labeled thymidine was added to the culture media after 36, 48, 60 and 71 hours in order to assess cell proliferation. Histological specimens were then prepared and examined using autoradiography.

Results demonstrated that b-FGF significantly increased prostatic tissue growth by 100 to 250% in five out of six specimens (p < 0.05 and p < 0.01). Similar percentage increases in EGF were recorded as for b-FGF, but in only three out of five specimens tested (p < 0.01 and p < 0.001). For both b-FGF and EGF-treated specimens, incorporation of thymidine occurred primarily in the glandular epithelium. Lovastatin completely inhibited both the basal and the growth-factor stimulated proliferation of prostatic cells. Average b-FGF and EGF cell proliferation was 40 to 90% and 80 to 95% respectively. Adding geraniol to the incubation medium enhanced prostate cell proliferation induced by b-FGF and EGF.
When separately compared to b-FGF, the saw palmetto extract did not significantly inhibit basal cell proliferation at any dose. However, when saw palmetto was incubated with either b-FGF or EGF, it significantly inhibited both b-FGF- and EGF- induced cell proliferation respectively at the highest dose of 30 ug/ml (p < 0.01 and p < 0.05). Similarily, lupenone (in contrast to b-FGF) had a minimal, nonsignificant effect on basal cell proliferation. However, incubation with b-FGF markedly inhibited b-FGF-induced cell proliferation at all three concentrations tested (p < 0.001). Furthermore, hexacosanol and the unsaponifiable fractions of saw palmetto had comparable outcomes. Hexacosanol at all doses, alone or when combined with b-FGF, markedly inhibited b-FGF-induced cell proliferation (p < 0.05; p < 0.01), but was ineffective on basal cell proliferation at doses of 1, 10 and 30 ug/ml when compared to b-FGF individually. Similar results to those of hexacosanol were obtained with the unsaponified fraction of saw palmetto. Except in once case, the unsaturated fatty acid portion did not affect basal or b-FGF-induced prostate cell proliferation.

Reference: Di Silverio F, Monti S, Sciarra A, et al. Effects of long-term treatment with Serenoa repens (Permixon(R)) on the concentrations and regional distribution of androgens and epidermal growth factor in benign prostatic hyperplasia. The Prostate 1998; 37:77-83.

Summary: Twenty-five men with BPH (average 68 ñ 6 years) were randomly assigned to one of two treatment groups. The group that received no therapy served as a control while the other group was given 320 mg/day of the liposterolic extract of saw palmetto (Permixon(R)) for three months. Before beginning the trial, patients had lower urinary tract symptoms for at least one to three years, plus an enlarged prostate (average 44 ñ 12 ml) as measured by transrectal ultrasound, a maximum urinary flow rate of less than 15 ml/sec and a post-void urinary volume of greater than 150 ml. After 90 days, all patients underwent suprapubic biopsies from three prostatic regions: periurethral, subscapular and intermediate. Each protastic region was evaluated with radioimmunoassay for levels of testosterone (T), dihydrotestosterone (DHT), and epidermal growth factor (EGF).

The results demonstrate that, in contrast to the control group, those who were treated with saw palmetto had statistically significant reductions in prostatic DHT and EGF levels along with an increase in T levels. Moreover, these latter changes were regionally distinct, with those employing the herb exhibiting significantly lower DHT (2,363ñ 553 pg/g tissue, p < 0.001) and EGF (6.98 ñ 2.48 ng/g tissue, p < 0.001) values in the periurethral zone. T values in the saw palmetto group were significantly elevated in all three prostatic regions tested, with the highest values seen in the periurethral (1,023 ñ 101 pg/g tissue, p < 0.001) area. By comparison, those individuals in the untreated group had lower T, and higher DHT and EGF values in the periurethral area (615 ñ 62 pg/g tissue, 7,317 ñ 551 pg/g tissue, and 20.9 ñ 3.3 ng/g tissue, respectively).

Comments/Opinions: The first paper, by Dr. Monique Paubert-Braquet and colleagues from the Bio-Inova EuroLab Research Laboratories, in Plaisir, France, suggests that a liposterolic extract of saw palmetto (Serenoa repens) inhibits the in vitro production of prostatic growth factors such as b-FGF and EGF. Recent work on the molecular aspects of BPH suggests that prostatic tissue or epithelial growth is stimulated by various growth factors, such as EGF, insulin growth factor (IGF) I and II, and keratinocyte growth factor (KGF). KGF is a member of the fibroblast growth factor (FGF) family. According to Dr. M. R. Freeman and associates, b-FGF or FGF-2 is a pleiotropic polypeptide that stimulates human prostatic fibroblast growth, induces endothelial cell production, initiates neovascularization in vivo, and is a significant tumor angiogenesis factor.(1) Normally these growth-promoting agents are counterbalanced by growth-restraining factors such as transforming growth factor-á (TGF-á). However, androgens like testosterone exert an antagonistic effect on TGF-á, thereby shifting this tissue/growth inhibitory balance in favor of prostate gland hyperplasia.(2)

This evidence suggests that saw palmetto may have a far more complex mechanism of action than the often and widely reported inhibition of 5à-reductase (5-AR). Although saw palmetto's inhibition of this enzyme has been confirmed by numerous in vitro studies, its effectiveness as a 5-AR inhibitor and hence a dihydrotestosterone (DHT) antagonist is not beyond question. This controversy has been most evident in one controlled clinical study comparing the drug finasteride (Proscar(R)) to a liposterolic extract of saw palmetto (Permixon(R)) in 32 healthy volunteers.(3) The investigators found that after 12 hours of therapy with 5 mg of finasteride, serum dihydrotestosterone (DHT) levels were reduced by 65%. In comparison to the drug, saw palmetto extract had no effect on serum DHT and therefore, according to the researchers, had no impact on 5-AR.

However, the evidence presented in the second review again places the aforementioned conclusions regarding 5-AR, DHT and saw palmetto in considerable doubt. In the study by Dr. F. Silverio and associates from the Department of Urology, University of Rome, saw palmetto extract, at the recommended therapeutic dose of 320 mg per day, induces a 50% reduction in DHT and a 125% increase in T in BPH tissue when compared to the control group. These latter facts combined, the authors note, demonstrate the ability of saw palmetto to inhibit 5-AR. By comparison, in the study above(3) the drug finasteride decreased DHT by 66% and increased T by 170% with respect to a control group in tissue samples taken from BPH patients. In addition, for those patients employing saw palmetto there was 50% reduction in EGF values when contrasted to the control group. This again compares favorably to the 60% EGF reduction seen in patients taking finasteride. Moreover, this decrease in EGF is in agreement with the results obtained by Dr. M. Paubert-Braquet, who noted the saw palmetto inhibited both b-FGF and EGF when they were incubated together. Interestingly, Dr. Silverio notes that the tissue distribution of T, DHT and EGF is highest in the zone adjacent to the urethra, and that stimulation of this area can ultimately lead to prostatic hyperplasia.

What is remarkable about these facts is that unlike finasteride, which seems to exert a more generalized mode of action on prostate tissue, saw palmetto is very zone-specific in its effects, causing sharp declines in periurethral DHT and EGF. Clinically, this reinforces the notion that saw palmetto, a viable treatment for the lower urinary tract symptoms associated with BPH and is unlikely to cause significant reductions in prostate size. However, despite the successful results in this study, one has to question why the authors did not measure tissue levels of TGF-á, along with both types 1 and 2 5-AR. Furthermore, it would have been interesting to see if the prostatic tissue results correlated with a reduction in BPH symptomatology (e.g. decrease in prostatic volume and an increase in peak urinary flow rates).

While the latter study concludes that saw palmetto's effectiveness in treating BPH is region-specific, it also demonstrates that its mechanism of action should not be restricted to just 5-AR inhibition. Both papers suggest that other mechanisms of action, such as interference with prostatic growth factors (e.g. EGF), anti-estrogenic and aromatase inhibition, as well as anti-inflammatory actions, need to be given much more research attention by the scientific community.

(1) Freeman MR, Gleave ME, Chung LWK. Stromal-epithelial interactions: molecular aspects and relevance to benign prostatic hyperplasia. In: Kirby R, McConnell JD, Fitzpatrick JM,, eds. Textbook of Benign Prostatic Hyperplasia. Oxford, England: Isis Medical Media Ltd, 1996: 57-74.

(2) Griffiths K. Molecular control of prostate growth. In: Kirby R, McConnell JD, Fitzpatrick JM, et. al., eds. Textbook of Benign Prostatic Hyperplasia. Oxford, England: Isis Medical Media Ltd, 1996: 23-56.
(3) Strauch G, Perles P, Vergult G, et al. Comparison of finasteride (Proscar(R)) and Serenoa repens (Permixon(R)) in the inhibition of 5à-reductase in healthy male volunteers. Eur Urol 1994; 26:247-52.

Natural Product Research Consultants, Inc.
By R. Reichert


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