Benign prostatic hyperplasia (BPH) is one of the most common urologic conditions affecting the elderly male. Current management options for BPH and for lower urinary tract symptoms (LUTS) related to BPH include lifestyle changes, drugs, and surgical treatment. A comprehensive spectrum of drugs for the treatment of LUTS is available, ranging from adrenoceptor antagonists (alpha-blockers), 5-alpha-Reductase inhibitors (5-ARIs), phosphodiesterase type 5 inhibitor (PDE5-i), antimuscarinics, beta-3-adrenoceptor agonist, vasopressin analogs, and phytotherapeutic agents. Phytotherapy is commonly used as one form of treatment. Our concern is that it should be used in patients with mild-to-moderate grade of disease. The agent most widely used nowadays is the Serenoa repens while the other compounds are less used worldwide. Experimental and clinical studies suggest a crucial role for SeR as an alternative therapy (or as a complementary therapy) for the treatment of LUTS due to BPH.
KeywordsPhytotherapy, Benign prostatic hyperplasia, LUTS, Serenoa repens
Benign prostatic hyperplasia (BPH) is one of the most common urologic conditions affecting the elderly male [ ]. Current management options for BPH and for lower urinary tract symptoms (LUTS) related to BPH include lifestyle changes, drugs, and surgical treatment. A comprehensive spectrum of drugs for the treatment of LUTS is available, ranging from adrenoceptor antagonists (alpha-blockers), 5-alpha-reductase inhibitors (5-ARIs), phosphodiesterase type 5 inhibitor (PDE5-i), antimuscarinics, beta-3-adrenoceptor agonist, vasopressin analogs, and phytotherapeutic agents [ ].
Phytotherapy, a science-based medical practice based on the study of extracts of natural origin in the treatment and prevention of disease, probably born with men. The observation that animals preferred certain plants when they were injured or ill may have helped to guide primitive man in the search of cures for his ailments. Knowledge of the medicinal value of these plants was initially transferred on verbally, then with the development of society and written language, records on the use of medicinal plants were preserved in writing [ ]. The oldest written evidence of medicinal plants’ usage for preparation of drugs has been found on a Sumerian clay slab from Nagpur, approximately 5000 years old [ ]. The Egyptians had extensive knowledge of plants derived from their technique of embalming. The Ebers Papyrus (about 1550 BC) presents a large number of crude drugs that are still of great importance (castor seed, gum arabic, aloe, etc.). Knowledge of the virtues of medicinal plants later spread to Greece and other countries of the ancient Western World. The 15th, 16th, and 17th centuries were the great age of herbals; the use of, and search for, drugs and dietary supplements derived from plants have further accelerated in recent years. Pharmacologists, microbiologists, and botanists are combing the Earth for phytochemicals and leads that could be developed for treatment of various diseases; in fact, according to the World Health Organization, approximately 25% of modern drugs used in the United States have been derived from plants [ ].
Unfortunately, the interpretation and acceptance of such evidence for phytotherapeutic practices varies: in some countries, it is considered sufficient to license phytotherapeutic products as medicines, whereas in other countries, phytotherapy is viewed as a form of traditional medicine. While many consider herbal medicines with a well-defined use profile (one based on scientific and medical evidence) as phytotherapeutic products, others consider such products to be food supplements; the latter implies that medicines based on herbal substances are unproven therapies, and in some countries they are treated that way [ ].
The phytotherapeutic agents, which have gained widespread use since about 1990, are a heterogeneous group of products that may contain different concentrations of the active ingredient(s) [ ]. Despite The EAU Guidelines Panel have not made any specific recommendations on phytotherapy for the treatment of male LUTS because of product heterogeneity, limited regulatory framework, and methodological limitations of the published trials and metaanalyses, the use of phytotherapy for the treatment of BPH has become increasingly prevalent, especially in some countries where it use is as high as 50% of prescriptions [ ]. The TRIUMPH (TransEuropean Research Into the Use of Management Policies for LUTS suggestive of BPH in Primary Healthcare) Study compared the management of LUTS suggestive of BPH in real-life practice in six European countries (France, Germany, Italy, Poland, Spain, and the United Kingdom): although national levels of prescriptions varied from country to country, α-blockers were the most popular class in all countries (79%) followed by phytotherapy (16%) and 5-α-reductase (5%) [ ]. Similar data was published by Fourcade et al. in an observational, cross-sectional study that was carried out in primary care in Germany, France, Spain, and Portugal. Overall, α-blocker monotherapy was the most frequently prescribed treatment for LUTS/BPH (63%), phytotherapy given as monotherapy was the second most prescribed class of drugs (24%), and 5-α-reductase inhibitors were prescribed as monotherapy in only 4% of patients [ ]. In the United States, about 40% of men opting for nonsurgical therapy for BPH use herbal supplements alone or in conjunction with other medical preparation, and that number continues to grow [ ]. In the United States, in fact, the complementary and alternative medicines (CAMs) market is an extremely lucrative enterprise with revenues reaching close to US$ 6.4 billion in sales for the 2014 [ ]. The widespread availability of these products in health food stores, vitamin shops, traditional pharmacies, and supermarkets, as well as on numerous websites on the Internet, has contributed to their use and reflects the demand for these phytotherapeutic agents.
The different phytotherapeutic products are extracts from the roots, the leaves, the seeds, the bark, or the fruits of the various plants used. Although single plant preparations are available, many companies manufacture combination products (two or more plant extracts) or add vitamins in an attempt to improve efficacy, to improve marketability, and to provide a single product. In addition, the extraction procedure is not standardized so that different plant extracts from different producers cannot be reliably compared. The plant extracts contain a wide variety of chemical compounds, which include phytosterols, plant oils, fatty acids, and phytoestrogens (see Fig. 7.1 ) [ ].
Experimental data have suggested numerous possible mechanisms of action for the phytotherapeutic agents; study in vitro have demonstrated that plant extracts can have antiinflammatory, antiandrogenic, and estrogenic effects; decrease sexual hormone binding globulin; inhibit aromatase, lipoxygenase, growth factor-stimulated proliferation of prostatic cells, α-adrenoceptors, 5-α-reductase, muscarinic receptors, dihydropyridine and vanilloid receptors; and neutralize free radicals [ ]. These effects have not been confirmed in vivo, and the detailed mechanisms of action of plant extracts remain unclear (see Fig. 7.2 ).
There have been more than 30 phytotherapeutic compounds described for the management of BPH (see Fig. 7.3 ), the most widely used are Cucurbita pepo , Hypoxis rooperi , Pygeum africanum , Secale cereale, Urtica dioica , and Serenoa repens [ ].
Saw Palmetto (SP), also known as S. repens (SR) or Dwarf palm plant (also known by its botanical name of Sabal serrulatum), consist of the dried ripe fruit of a dwarf palm native to the West Indies and the South-Eastern United States (Florida, South Carolina). The plant itself is a bush with leaves having 18–24 sharp ending segments. The flowers are on short branches; the fruits are globular (2–3 × 1.5 cm), mono-seed, and bluish to black at maturity. The plant grows on dunes and pine forest. The fruit contains fatty acids and their glycerides (oleic, caprilic, myristic, lauric, stearic, palmitic, etc.), phytosterols (sitosterol, campesterol, cycloartenol), and sitosterol derivatives. Other constituents are organic acids (caffeic, chlorogenic, anthranilic, etc.) polysaccharides, tannin, sugars, volatile oil, and flavonoids. Extracts of the fruits are mainly prepared with hexane, ethanol, or supercritical CO 2 [ ].
The use of S . repens (Sr) originates from America where the Native Americans used it to manage genitourinary disturbances and enhance testicular function and breast size. The use of the whole berries as a tonic was later adopted by colonists. The first reports in the literature about use in urinary complaints date from the beginning of the 20th century. S . repens has been traditionally used as water and ethanol extracts. It is stated to possess diuretic, urinary antiseptic, endocrinological, and anabolic properties. Traditionally it has been used for chronic or subacute cystitis, testicular atrophy, sex hormone disorders, and most specifically for prostatic enlargement. Also inflammation of lactic glands in the breast, eczema, bronchial pathology, and cough are mentioned as indications in traditional medicine. It has been deemed to enhance sexual desire even if there is no scientific support for these traditional applications [ ].
S . repens is undisputedly the most common phytotherapeutic agent used for symptomatic management of BPH. Preparations are used to alleviate micturition disorders such as dysuria, urinary frequency, nocturia, and urine retention [ ].
Mechanism of Action
It is theorized that the chemically active component of S . repens extracts is mainly free fatty acids (FFA), with more than 90% comprising of oleic acid, lauric acid, myristic acid, and palmitic acid. FFA have been implicated in inhibition of both the type 1 and type 2 iso-enzymes of 5-α-reductase, an enzyme catalyzing the conversion of testosterone into dihydrotestosterone (DHT), thereby reducing growth of the prostate gland [ ]. Dose-dependent and noncompetitive inhibition of 5-α-reductase was observed in both the prostatic epithelium and the stroma in vitro experiments mainly due to FFA in the saponifiable fraction. The nonsaponifiable fraction, containing phytosterols, triterpenes, and fatty alcohols, and the hydrophilic components proved to be inactive. In a comparative study with finasteride, IC 50 values of between 5.6 and 40 μg/mL were obtained with the various lipophilic extracts (hexane, ethanol, hypercritical CO 2 ), compared to an IC 50 of 1 ng/mL for finasteride [ ] (see Fig. 7.4 ).
Abe et al. have also demonstrated in an in vitro experiment with rat liver that S . repens extract and in particular its major constituents, lauric acid, oleic acid, myristic acid, palmitic acid, and linoleic acid, exerted binding activities of α 1 -adrenergic, muscarinic, and 1,4-dihydropyridine (1,4-DHP) receptors and inhibited 5-α-reductase activity [ ]. In another study in vitro, Suzuki et al. have shown that Saw Palmetto extract exerts significant binding activities on alpha 1-adrenergic and muscarinic receptors in the rat lower urinary tract [ ].
As recently highlighted by De la Taille et al., inflammation has a key role in the pathogenesis and progression of BPH and therefore represents a rational target for BPH therapy. Scientific evidence supports the conclusion that hexanic extract of S . repens inhibits prostaglandin synthesis by blocking the activity of phospholipase A 2 in the arachidonic acid cascade and also acts by inhibiting the production of 5-lipoxygenase. In their study have demonstrated that addition of hexanic extract of S . repens decreased cell proliferation induced by FGF-2 in stromal and normal prostate cell lines and by IL-6 and IL-17 in the BPH-1 cell line. Exposure to hexanic extract of SeR, furthermore, led to significant underexpression of the human epidermal growth factor receptor 3 gene (ERBB3) and to significant overexpression of the human growth arrest-specific 1 gene (GAS1). These results would suggest, therefore, that hexanic extract of S . repens modifies the inflammatory status of BPH tissue through cytokine regulation and that reduction of inflammatory markers correlates significantly with improvement in clinical symptoms [ ].
Sirab et al. in 2013 explored the effects of the lipidosterolic extract of S. repens (LSESr) on the mRNA gene expression profiles of two representative models of BPH, BPH1 cell line and primary stromal cells derived from BPH. Treatment of these cells with the extract significantly altered gene expression patterns as assessed by comparative gene expression profiling on gene chip arrays. Lipidosterolic extract of the dwarf palm plant showed a dose-dependent cytotoxic effect in cultured human epithelial and stromal cells; both cells line respond similarly to LSESr. The expression changes were manifested 3 h following in vitro administration of the extract, suggesting a rapid action for this compound. Among the genes most consistently affected by the treatment, the authors found numerous genes involved in cellular metabolism, cell cycle and differentiation, apoptosis, organ morphogenesis, hormone secretion, angiogenesis, phosphorylation, signal transduction, cellular responses to pathogens, and external stimulus. Validation studies using quantitative real-time PCR confirmed the deregulation (up- or downregulation) of genes known to exhibit key roles in these biological processes including IL1β (interleukin 1-beta), IL1α (interleukin 1-alpha), CXCL6 (chemokine C-X-C motif ligand 6), IL1R1 (interleukin 1 receptor), PTGS2 (prostaglandin-endoperoxide-synthase 2), ALOX5 (arachidonate-5-lipoxygenase), GAS1 (growth arrest-specific 1), PHLDA1 (pleckstrin homology-like domain family A, member 1), IL6 (interleukin 6), IL8 (interleukin 8), NFkBIZ (nuclear factor of kappa light polypeptide gene enhancer in beta cells inhibitor zeta), NFKB1 (nuclear factor of kappa light polypeptide gene enhancer in beta-1 cells), TFRC (transferrin receptor), JUN (jun oncogene), CDKN1β (cyclin-dependent kinase inhibitor 1β), and ERBB3 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 3). Subsequent analyses also indicated that treatment with the lipidosterolic extract of S . repens can impede the stimulatory effects of certain pro-inflammatory cytokines such as IL6, IL17, and IL15 in these cells. These results, therefore, suggest that LSESr treatment in BPH epithelial and stromal cells modulates the expression of genes involved in inflammation, cell growth, and survival pathways [ ]. Recently, in a mouse model of prostate hyperplasia it was demonstrated that the daily administration of the lipidosterolic extract of S . repens Permixon significantly reduced the global inflammatory status of hyperplastic prostates by reducing the number of immune cell infiltrates and downregulating expression of several cytokines and chemokines such as CCR7, CXCL6, IL-6, and IL-17 [ ]. The effect of Saw Palmetto extract on prostate inflammatory status was first described by Vela Navarette et al., in their study, in fact, they have shown a significant reduction in the number of B-lymphocytes and other immune response markers (TNFα and IL-1β) after treatment [ ]. Similar antiinflammatory properties of the extract of S . repens were demonstrated studying the impact of the extract on monocyte chemo-attractant protein 1/chemokine (C-C motif) ligand 2 (MCP-1/CCL2) and vascular cell adhesion molecule 1 (VCAM-1) expression. After pretreatment with hexane LSESr, human prostate (epithelial and myofibroblastic) cells and vascular endothelial cells were stimulated with pro-inflammatory cytokines (IFN-γ, IL-17, TNF-α) known to be secreted by prostate-infiltrating CD4 + cells in BPH. MCP-1/CCL2 and VCAM-1 mRNA expression was quantified by real-time PCR. Hexanic LSESr decrease inflammation by blocking crucial steps of leukocyte adhesion and migration, by inhibiting MCP-1/CCL2 production by prostate stroma cells and by reducing MCP-1/CCL2 and VCAM-1 expression by vascular endothelial cells in an inflammatory environment [ ]. The antiinflammatory activity of S . repens in men with BPH-related LUTS was also evaluated by reduction of inflammation genes expression and by inhibition of prostate epithelial cell proliferation and antagonism with epidermal growth factor (EGF) receptor [ ].
As mentioned previously, several trials have suggested that inflammation have a key role in BPH development and progression through activation of the transcription factor nuclear factor-kappa B (NF-B), increase of vascular endothelial growth factor (VEGF) and transforming growth factor-β (TGF-β), oxidative stress increased, production of several cytokines, overexpression of inducible-cyclooxygenase (COX-2), inducible-nitric-oxide-synthase (iNOS) and 5-lipoxygenase (5-LOX), resulting in release of prostaglandins, nitrates, and leukotrienes [ ]. Although saw palmetto has a role in reducing the inflammation of the prostate and BPH-related LUTS, the combination of S . repens , selenium (Se), and lycopene (Ly) is more effective than S . repens alone to prevent hormone-dependent prostatic growth. In an experimental model on rats treated daily with testosterone propionate, in fact, Morgia et al. have shown that combined treatment with Ly-Se-SeR was more effective than S . repens alone for decreasing prostate weight and hyperplasia, increasing proapoptotic bcl-2-like protein 4 (Bax) and caspase-9, and reducing antiapoptotic Bcl-2 mRNA. Lycopene-Selenium- S . repens also markedly decreased epidermal growth factor and vascular endothelial growth factor expression. During testosterone-induced growth there was overexpression of the growth factor EGF, which was exactly prevented by treatment with SeR and to a greater extent by combined Ly-Se-SeR [ ]. In an in vitro and in vivo comparison study conducted by the same authors, it was demonstrated that the Ly-Se-SeR association caused a greater inhibitory effect on the expression of COX-2, 5-LOX, and iNOS expression. That association of plants extracts reduced oxidative stress and prostate pro-inflammatory phenotype, as well as hyperplasia, more efficiently than the single compounds; in particular the Ly-Se-SeR association showed a higher efficacy in reducing the loss of inhibitor κB-α (IκB-α), the increased Nuclear factor-kappa B (NF-κB) binding activity. The association of phytotherapeutic compounds was also the most effective treatment in reducing mRNA levels of Tumor necrosis factor-α (TNF-α) and caused a greater inhibitory effect on iNOS expression and nitrite release; Lycopene-Selenium- S . repens association was as effective in reducing malondialdehyde (MDA) [ ]. The triple therapeutic association, finally, may have an antiinflammatory activity that could be of interest in the treatment of prostatic chronic inflammation in BPH patients. In the “Flogosis and Profluss® in prostatic and genital disease (FLOG),” a multicenter study involving nine urological Italian centers, we have demonstrated a significant difference of flogosis between treated versus control with a reduction both of extension and grading of inflammation and inflammatory infiltrate (B-lymphocytes CD20, T-lymphocytes CD3–CD8, and macrophages CD68). This antiinflammatory activity could be of interest, therefore, in the treatment of chronic prostate inflammation in BPH patients [ ]. In 2014, finally, we have evaluated in an experimental model with BPH animals treated with testosterone the expression of four inhibitors of apoptosis proteins (IAPs) that influence apoptosis by direct inhibition of caspases and by the modulation of the transcription factors. BPH animals treated showed unchanged expression of cellular IAP-1 and cellular IAP-2 and increased expression of neuronal apoptosis inhibitory protein (NAIP), survivin, caspase-3, IL-6, and prostate specific membrane antigen (PSMA) levels when compared with sham animals. Immunofluorescence studies confirmed the enhanced expression of NAIP and survivin with a characteristic pattern of cellular localization. SeR-Se-Ly association showed the highest efficacy in reawakening apoptosis; additionally, this therapeutic cocktail significantly reduced IL-6 and PSMA levels. The administration of SeR, Se, and Ly significantly blunted prostate overweight and growth; moreover, the triple association was most effective in reducing prostate enlargement and growth by 43.3% in treated animals [ ].
Variability of Products and Extraction Techniques
A known difficulty in evaluating the literature pertaining to Saw Palmetto Berry is the absence of standard extraction and formulation. There are numerous branded S . repens products, and they differ both qualitatively and quantitatively because of differences in the source of the biological product and variations in the process used to extract the active ingredients. Several different extraction techniques with differences in terms of methodology, time, temperature, pressure, and solvents have been developed, also used in combination with other techniques in order to improve the recovery and, consequently, the pharmacological profile of their extracts. However, as a consequence of the differences among the extractive processes used by several companies, there is a discrepancy in the qualitative and quantitative composition of the extracts obtained from the same plant. Hence, despite the benefits obtained from SeR, the variety of the extractive techniques and strategies makes one extract different from another in terms of bioactives composition and this could affect the quality and the clinical effects of natural therapies of different brands even if derived from the same plant [ ]. In order to define the proportional content of the different types of S . repens , the National Institute of Health’s Office of Dietary Supplements and the Food and Drug Administration’s Center for Drug Evaluation and Research are collaborating with the National Institute of Standards and Technology (NIST) to develop standard reference materials (SRMs) for selected dietary supplements including Saw Palmetto. In the case of saw palmetto, two reference materials have been developed: SRM 3250 S . repens fruit and SRM 3251 S . repens extract. SRM 3250 has certified concentration values for specific phytosterols and fatty acids (free or as triglycerides). On the other hand, the extract SRM 3251 has certified concentration values for phytosterols, fatty acids (free or as triglycerides), β-carotene and its isomers, and γ- and δ-tocopherol [ ]. Numerous extraction techniques have been described and utilized; Permixon, for example, uses a hexanic (solvent) extraction method by which the bioactive compounds are dissolved from the ground plant and then extracted out for final collection ( n -hexane lipidosterolic extract). A second extraction technique utilizes supercritical fluid extraction, whereby CO 2 at low temperatures and pressures is used to recover essential oils; a third extraction technique is microwave-assisted extraction that utilizes solvents that absorb different electromagnetic radiation waves. Other extraction techniques include ultrasound-assisted extraction, ionic liquids, enzyme-assisted extraction, and pressurized liquid/fluid extraction [ ] (see Table 7.1 ). Among those listed the lipidosterolic extract of S . repens obtained by solvent (hexane) extraction is the most widely studied product in clinical and experimental trials. An understanding of the composition of different brands of S . repens is essential to comprehensive whether they are likely to be bioequivalent. To this end, Habib et colleagues compared 14 brands of S . repens : the examination highlighted significant differences in composition among the different brands. In particular, the concentration of FFA, which have been suggested as the main active ingredients of S . repens , ranged between 41% and 81%. Each of the individual FFAs analyzed was found in similar proportions in all the products assayed, with lauric and oleic acids present at the highest concentrations in every sample assayed [ ]. De monte et al., however, reported significant different in overall FFA content as well as differing proportions of the individual FFAs; Booker et al., furthermore, in 2014 demonstrated that only 9 of 57 Serenoa preparations contained the recommended dose of FFA as defined by the World Health Organization [ ].
|Extract (Composition)||Extraction Technique||Isolated Active Compound (%)|
|Sabal Select (> 90% free fatty acids or their esterified forms, 0.01%–0.15% fatty alcohols, 0.25%–0.50% total sterols, 0.15%–0.35% β-sitosterol)||Supercritical CO 2||Oleic acid (15%)|
|Lauric acid (15%)|
|Lauric acid (30.2%)|
|Oleic acid (28.5%)|
|Sabal Select (> 90% free fatty acids or their esterified forms, 0.01%–0.15% fatty alcohols, 0.25%–0.50% total sterols, 0.15%–0.35% β-sitosterol)||Supercritical CO 2||Myristic acid (12.1%)|
|Palmitic acid (9.1%)|
|Linoleic acid (4.6%)|
|Free fatty acids/mixed triglycerides ratio: ~ 55/45|
|Permixon||Oleic acid (36.0%), lauric acid (27.5%),|
|Free saturated and unsaturated fatty acids (> 90%)||Solvent (hexane) extraction||Myristic acid (12.0%)|
|Palmitic acid (9.7%)|
|Esterified FAs represent 7%, while the rest is composed of phytosterols, flavonoids, alcohols, and polyprenic compounds|
|Prostasan (95% total content of free fatty acids)||Solvent (96% ethanol) extraction||Not reported|
|Prostasan (95% total content of free fatty acids)||Solvent (96% ethanol) extraction||Not reported|
|Prostasan (86% total content of free fatty acids)||Solvent (96% ethanol) extraction||Not reported|
|Saw Palmetto Berry Powder (SPBE) (Madis Botanical, Inc., New Jersey)||Solvent (20% ethanol) extraction of (phyto)sterols||β-Sitosterol, stigmasterol, cholesterol|
|(90% free fatty acids, alcohols, and sterols)|
|PC-SPES||Solvent (70% ethanol) extraction||Not reported|
|Talso, Talso uno||Supercritical CO 2||Acid lipophilic compounds, fatty alcohols and sterols as main components|
|Prostamol Uno||Not reported||Saturated and unsaturated fatty acids and phytosteroids|
|Prostate EZE Max||Not reported||Serenoa repens standardized to fatty acids, Pygeum africanum standardized to β-sitosterol, Epilobium parvrflorum , Cucurbita pepo seed oil, lycopene|
|Profluss||Oily extract||Serenoa repens extract 85%, lycopene 6%, selenium|
|SeR||Solvent (ethanol) extraction||Not reported|
In consideration of the different compositions of the various brands of S . repens , in 2008 Scaglione et al. evaluated seven brands of S . repens available in Italy using a 5-α-reductase activity assay involving epithelial and fibroblast cells cocultured for 10 days. All extracts tested inhibited both isoforms of 5-α-reductase (I and II), although there was clear variation in potency between the different extracts and between different batches of the same extracts [ ]. More recently, the same author repeated this study comparing the potency of lipidosterolic extracts from 10 different brands with similar results [ ]. As highlighted by Raynaud and colleagues, the different efficacy of Serenoa repens in inhibiting the two isoform of 5-α-reductase depends on the length of the carbon chain and its saturation state. Particularly, lauric acid inhibits both 5-α-reductase type I and II, while myristic acid strongly inhibits only type II. Oleic acid and linoleic acid have a good activity on type I but not on type II while palmitic and stearic acids are inactive on both isoforms. Thus only the products with complete fatty acid compositions have the best inhibitory activity on 5-α-reductase [ ]. However, the inevitable conclusion is that with over 100 varieties of Saw Palmetto berry extract marketed, comparison of products is essentially impossible.
According to the European Association of Urology and to American Urological Association guidelines, the use of phytotherapy in treating LUTS and BPH has been popular in Europe and United States even if recent studies with more rigorous methods have generally failed to confirm a clinically important role for S . repens in the management of BPH and that more definitive evidence regarding the use of S . repens in BPH is needed.
Have been published several clinical studies and multiple metaanalyses and review on Saw Palmetto berry extract and its effect on BPH; many of initial systematic reviews, including those by Wilt in 1998 and Boyle in 2004, suggest an efficacy of SeR to improve urinary symptoms in treated patients against placebo. In the metaanalysis by Wilt and colleagues of 18 trials involving nearly three thousand patients using various S . repens monopreparations and combination products, the mean weighted difference for nocturia between patients and individuals taking a placebo was − 0.76 times per night. Boyle et al. carried out a metaanalysis of 17 studies (14 randomized clinical trial and 3 open-label trials) performed with the same commercially hexane extract (Permixon). In their study, the authors concluded that S . repens modestly but significantly improved peak urinary flow and nocturia: Permixon was associated with a mean reduction in the International Prostate Symptom Score (IPSS) of 4.78 points. The estimated effect of Permixon on peak urinary flow was an increase of 2.22 mL/s than placebo (where it was of 1.02 mL/s). The placebo effect is associated with a reduction in the mean number of episodes of nocturia of 0.63 which is further reduced to 1.01 episodes/night with Permixon therapy [ ]. In order to correct methodological issues of previous studies, Bent et. al in 2006 published a randomized double-blinded trial in which were evaluated 225 men over the age of 49 years who had moderate-to-severe symptoms of BPH treated for 1 year with saw palmetto extract (160 mg twice a day) or placebo. The authors reported no significant difference between the saw palmetto and placebo groups in the change in American Urological Association Symptom Index (AUASI) score, maximal urinary flow rate, prostate size, residual volume after voiding, quality of life, or serum prostate-specific antigen levels during the 1-year study [ ].
In 2011, the Complementary and Alternative Medicine for Urological Symptoms (CAMUS) study, a double-blind, multicenter, placebo-controlled randomized trial conducted by Barry et colleagues founded that S . repens ethanolic extract used at up three times of the standard daily dose (320 mg/day) had no greater effect than placebo on LUTS. The study, however, showed the safety and tolerability of Saw Palmetto extract even at double and triple doses compared to placebo [ ]. In the recent updated Cochrane review by Tacklind, MacDonald et al. 32 randomized controlled trials studying 5666 men with symptomatic BPH were evaluated to receive S . repens extract monotherapy for at least 4 weeks in comparison with placebo. Of the included trials, 12 used Permixon, five studies compared another standardized combination of SeR (160 mg) and U. dioica extracts (120 mg) known by the commercial name Prostagutt forte, fourteen trials used generic SeR alone or in combination with other phytotherapic (pumpkin seeds, vitamins A and E, nettle root, P. africanum ). The authors concluded that even if S . repens extracts are widely used to treat symptomatic BPH, it did not improve LUTS or Q max associated with BPH [ ]. However, the wide variation in inclusion criteria of patients in the studies is cause of concern. In some studies patients were included starting from a score 6 on the IPSS: considering that the scale ranges from 0 to 35, it may be questionable to include patients with a value of 6 who are nearly considered as healthy. On the other hand, may be doubtful to include patients with an IPSS of more than 32 for a drug treatment (see Table 7.2 ).
|Tacklind et al. [ ] |
|Serenoa repens , at double and triple doses, did not improve urinary flow measures or prostate size in men with LUTS BPH related||Update of former Cochrane analysis. Based on 2 recent studies with different conditions [ ]|
|Barry et al. [ ] |
|No difference between SR and PL for all parameters||Extensive exclusion list 369 patients treated with doses up to 3 × therapeutic dose. Ethanolic extract during 72 weeks|
|Shi et al. [ ] |
|Significant difference in % of patients improved: SR > PL (IPSS as primary outcome). Significantly higher flow rate and lower resistance for SR vs PL||94 patients treated during 3 months with, a nondefined extract of SR|
|Hizli and Uygur [ ] |
|IPSS: no difference between groups||60 patients divided in three groups: T, SR (hexane extract), T + SR. Duration: 6 months|
|Ulbricht et al. [ ] |
|Positive opinion about the therapeutic role of different SR preparations||Evidence-based systematic review of 33 studies with different preparations. Although several flaws were reported, the opinion of the authors is positive|
|Bent et al. [ ] |
|No difference between SR and PL for all parameters||Broad inclusion criteria. 225 patients treated with normal doses of CO 2 extract (different from extracts commercialized in EU) during 12 months|
|Boyle et al. [ ] |
|Significant improvement of urinary flow and nocturia||Metaanalysis of 17 published and nonpublished studies with the same hexane extract. Only 7 of them reported on IPSS|
|Willetts et al. [ ] |
|No difference between SR and PL for all parameters||Considerable difference of IPSS between both groups at baseline |
100 patients treated with normal doses of CO 2 extract (different from extracts commercialized in EU) during 3 months
|Debruyne et al. [ ] |
|Similar lowering of IPSS||704 patients treated with a hexane extract or T during 12 months|
|Glémain et al. [ ] |
|Lowering IPSS comparable in both groups||329 patients treated with T or T + SR standardized hexane extract during 52 weeks|
|Gerber et al. [ ] |
|SR significantly improves IPSS than PL||Responders to PL after 1 month were excluded. 85 patients were treated with an undefined extract during 6 months|
|Braeckman et al. [ ] |
|Urinary frequency, nocturia, urgency, dysuria, and urinary volume significantly improved vs PL. Quality of life rated by patients and doctors better than with PL||238 patients treated with a critical CO 2 extract or PL during 12 weeks|
|Carraro et al. [ ] |
|Similar IPSS||1098 patients treated with a hexane extract or finasteride during 26 weeks|
|Descotes et al. [ ] |
|Statistically significant improvement toward PL of dysuria, urinating frequency (day and night), and urinary flow rate||215 patients treated with a hexane extract during 4 weeks|
|Grasso et al. [ ] |
|No difference||63 patients treated with a nonspecified SR extract or alfuzosin during 3 weeks|
|Löbelenz et al. [ ] |
|No difference in urinary flow between SR and PL||60 patients were treated during 6 weeks with an undefined extract. Study with several flaws|
|Mattei et al. [ ] |
|SR: significant improvement vs baseline |
PL: no significant improvement vs baseline
|40 patients treated with a nondefined extract|
|Reece-Smith et al. [ ] |
|Significant improvement in both SR and PL of LUTS. No difference between groups||80 patients treated with a hexane extract or PL during 12 weeks|
|Cukier et al. [ ] |
|Urinary frequency and residual urinary volume significantly decreased with SR vs PL||168 patients treated with a hexane extract or PL during 10 weeks|
|Tasca et al. [ ] |
|Peak urinary flow increased and urinary frequency decreased significantly with SR vs PL||30 patients treated with a hexane extract or PL during 8 weeks|
|Champault et al. [ ] |
|Significant improvement by SR toward PL of nocturia, urinary flow rate, and residual volume||110 patients treated with a hexane extract or PL during 4 weeks|
|Emili et al. [ ] |
|Dysuria improved more in SR than in PL||30 patients treated with a hexane extract or PL during 4 weeks|
|Boccafoschi and Annoscia [ ] |
|Overall SR significantly better than PL||22 patients treated with a hexane extract or PL during 8.5 weeks|
In recent years, several studies have evaluated the combination therapy including saw palmetto and other plant extracts on urinary symptoms. In 2015 Marzano et al. published a comparative study to evaluate the effectiveness of cotreatment with S . repens (320 mg) plus Bromeline plus Nettle (Prostamev Plus) in comparison to S . repens alone in reducing the symptoms of prostatitis. After 2 months, the groups treated with Prostamev Plus in comparison to the groups treated with S . repens extract (saw palmetto) achieved better improvements of both IPSS, urinary flow and sexual life [ ]. In 2013, Coulson et al. published results from a phase II clinical trial on ProstateEZE Max a combination supplement of five commonly used plants extract including C. pepo , Epilobium parviflorum , lycopene, P. africanum , and S . repens . The authors found a significant reduction in the IPSS score in the active group of 36% compared to 8% for the placebo group after 3 months follow-up [ ]. As early as 2013, in fact, Minutoli et collaborators showed that the association of selenium, lycopene, and Serenoa increases their activity in BPH as recently reiterated by Russo, Salonia et al. [ ].
Selenium (Se) is a mineral essential in the diet of humans. The major dietary sources of Se are plant foods including Brazilian nuts, whole grains, wheat germ, soybean, sunflower seeds, and fish. In human body, the highest Se concentrations are in the liver, kidneys, and thyroid gland. Selenium is usually integrated into proteins to form selenoproteins as glutathione peroxidases, thioredoxin reductases, and iodothyronine deiodinases which are involved in several biological functions in both animals and humans [ ]. Although selenium could reduce the risk of developing prostate, lung, and colorectal cancer through epigenetic and antioxidant effect, its effectiveness has not yet been fully demonstrated [ ].
Lycopene (Ly) is the red pigment of tomatoes showing a potent antioxidant and antiinflammatory activity twice as effective as β-carotene and 10-fold more activity than α-tocopherol. Lycopene concentrations are known to be elevated in human semen and in prostate gland [ ]. The abundance of lycopene in prostatic tissue is indirectly implicated in the chemoprevention of pathologies as BPH and prostate cancer [ ].
With the aim to evaluate the efficacy and tolerability of combination therapy between S . repens (SeR), Lycopene (Ly), and Selenium (Se) + tamsulosin versus single therapies in patients with LUTS, in 2014 Morgia et al. conducted the PROCOMB trial, an Italian multicenter double-dummy randomized study of 225 men with an age of 55–80 years old. Patients were randomized in group A (SeR-Se-Ly), group B (tamsulosin 0.4 mg), group C (SeR-Se-Ly + tamsulosin 0.4 mg); the primary endpoints of the study were the reduction of IPSS, postvoid residual urine (PVR), and increase of Q max in group C versus monotherapy groups. Combination therapy has been demonstrated to be more effective than the individual monotherapies in terms of reduction of the IPSS and of increase of Q max after 1 year. The association of Ser-Se-Ly with 0.4 mg of tamsulosin decreased the IPSS score by 18.2% versus a 13.8% and 14.3% decrease for only tamsulosin and only herbal treatments, respectively. The proportions of men with a decrease of at least three points and decrease of 25% for IPSS were greater for Group C but the proportion of men with an increase of at least 3 mL/s and of 30% of Q max was not statistically different for combination therapy versus single monotherapies [ ]. The efficacy of Se-Ly-SeR (Profluss) versus SeR alone was also evaluated by the same group of authors in patients suffering from category IIIa chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS); IPSS improved significantly in both group but more in the combination group [ ]. Despite these findings, there is still significant heterogeneity in study design and methodological validity with small sample size and short-term follow-up. There is need for larger randomized placebo-controlled studies to better assess SeR + Se + Ly in BPH patients, but current data seem to demonstrate greater effectiveness of Serenoa + Lycopene + Selenium compared to monotherapy with Saw Palmetto extract.
Clinical trials of Saw Palmetto have consistently demonstrated that therapy at a dose of 320 mg/day is well tolerated with a side effect that is generally mild and include headache, decreased libido, and gastrointestinal problems [ ]. In a systematic review of adverse events of S . repens published in 2009, the majority of adverse events are mild, infrequent, and reversible, and similar to those with placebo. The most frequently reported adverse events are abdominal pain, diarrhea, nausea, fatigue, headache, decreased libido, and rhinitis [ ]. More serious adverse events such as death, liver damage, pancreatitis, and cerebral hemorrhage are reported in isolated case reports and data from spontaneous reporting schemes, but causality is questionable [ ]. There may be an increased response to anticoagulant treatment in patients who take SeR preparations. S . repens does not appear to have a clinically relevant effect on the majority of cytochrome P450 isoenzymes and no other interactions with S . repens have been found [ ].
The S . repens extract used in the CAMUS trial showed no evidence of toxicity at doses up to three times the usual clinical dose over an 18-month period. Participants were randomized to 320, 640, and 960 mg daily of an ethanolic S . repens extract or to an identical-appearing placebo in an escalating manner at 6-month intervals for a total of 18 months of follow-up. Adverse event assessments, vital signs, and blood and urine laboratory tests were obtained at regular intervals. There were no statistically significant differences between the groups in the rates of serious or nonserious adverse events, changes in vital signs, digital prostate examination findings, or study withdrawal rates. Overall, there were no significant intergroup differences in laboratory test abnormalities, while differences in individual laboratory tests were rare and small in magnitude. No evidence of significant dose-response phenomena was identified [ ].
S . repens inhibits both the type 1 and type 2 iso-enzymes of 5-α-reductase; furthermore, and this confirms the specificity and selectivity of SeR, 5-α-reductase activity is not inhibited after treatment with the plant extract in cells of nonprostate origin [ ]. However, in contrast to other 5-α-reductase inhibitors, SeR induces its effects without interfering with the cellular capacity of the prostate to secrete prostate-specific antigen (PSA) in vitro and in vivo [ ]. In 2013, Andriole et colleagues analyzed data on CAMUS trial demonstrating that Saw Palmetto extract did not alter PSA compared to placebo. PSA was shown, in fact, to be similar at baseline between treatment groups and the mean change during the trial for SPB and placebo was 0.23 and 0.16, respectively ( P = .5). They concluded that even at relatively high doses, Saw Palmetto berry did not affect serum PSA levels. Thus there is no concern that taking SPB may mask the ability to detect prostate cancer via PSA screening [ ].
Experimental and clinical studies suggest a crucial role for SeR as an alternative therapy (or as a complementary therapy) for the treatment of LUTS due to BPH. SrE, with its various ingredients, shows a wide range of biologic activities within the prostate and demonstrates a high specificity and selectivity for this organ. From in vitro experiments the following properties were identified: (1) inhibition of 5-α-reductase, (2) influence on androgen-receptor binding, (3) inhibition of alpha-receptor binding, (4) inhibition of eicosanoid synthesis, (5) spasmolytic effects, and (6) antiinflammatory effects. The activity can differ from one extract to another, probably dependent upon the content of fatty acids. Toxicity of the hexane extract appears low; there are no data on genotoxicity, carcinogenicity, or reproductive toxicity. As already said before, the main properties of SeR, confirmed in in vivo experiments, are its antiandrogenic, proapoptotic, and antiinflammatory effects, as well as its capacity to intercept each of these distinct pathways [ ] (see Fig. 7.5 ).