What do we know about phytotherapy of benign prostatic hyperplasia Olta Allkanjari, Annabella Vitalone PII: DOI: Reference:
S0024-3205(15)00075-2 doi: 10.1016/j.lfs.2015.01.023 LFS 14279
To appear in:
Life Sciences
Received date: Accepted date:
13 November 2014 21 January 2015
Please cite this article as: Allkanjari Olta, Vitalone Annabella, What do we know about phytotherapy of benign prostatic hyperplasia, Life Sciences (2015), doi: 10.1016/j.lfs.2015.01.023
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ACCEPTED MANUSCRIPT What do we know about phytotherapy of benign prostatic hyperplasia Olta Allkanjari1, Annabella Vitalone1 1
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Department of Physiology and Pharmacology - "Sapienza" University, P.le Aldo Moro 5, 00185 Rome, Italy
Corresponding author: Annabella Vitalone, PhD
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Department of Physiology and Pharmacology ―V. Erspamer‖, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome – Italy
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Phone: +39-06-49912904 Fax: +39-06-49912480
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E-mail: [email protected]
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Abstract
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Benign prostatic hyperplasia (BPH) is one of the most common urological diseases in aging men. Because of its long latency, BPH is a good target for prevention. The aim of the study has been to review the various options of treatment, currently available, in the field of phytotherapy. Watchful waiting, pharmacological therapy, and surgery are also helpful, depending on the severity of the disease. Although drug therapy (alpha1-blockers, 5alpha-reductase inhibitors) and surgery (prostatectomy,
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transurethral resection, etc.) seem to be the most effective for patients with moderate-severe BPH, herbal medicines (i.e., Serenoa repens, Pygeum africanum, Urtica dioica) are also commonly used in patients with mild-moderate symptoms. On the basis of preclinical studies several mechanisms of action have been postulated, including 5alpha-reductase inhibition, alphaadrenergic antagonism, dihydrotestoterone and estrogen receptors inhibition. Randomized clinical trials indicate significant efficacy in improving urinary symptoms and mild adverse effects for some of phytotherapeutic agents, while further clinical evidence is needed for others (e.g., Epilobium Spp., Secale cereale, Roystonea regia). Healthcare professionals should be constantly informed about BPH phytotherapy, taking into account the risks/benefits profile of the use of medicinal plants in the management of BPH.
Key words: Benign prostatic hyperplasia, Phytotherapy, Saw palmetto, Clinical efficacy, Safety profile, Review
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ACCEPTED MANUSCRIPT Chemical compounds: β-sitosterol (PubChem CID: 222284); Palmitic acid (PubChem CID: 985); Tamsulosin (PubChem CID: 129211); Finasteride (PubChem CID: 57363); Stigmasterol (PubChem CID: 5280794); Kaempferol (PubChem CID: 5280863); Lycopene (PubChem CID: 446925); Rooperol (PubChem CID: 6438989); N-docosanol
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(PubChem CID: 12620); Selenium (PubChem CID: 6326970).
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Introduction
Benign prostatic hyperplasia (BPH) is one of the most common urological diseases in aging men. It typically develops after the
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age of 40 years and ranges in prevalence from over 50% at 60 years to as high as 90% by 85 years of age. BPH is characterized by high morbidity and low mortality rate, and is considered a public health problem [1, 2]. The BPH natural history can be
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divided into pathological and clinical phase. The first phase is asymptomatic, and occurs at periurethral level with nodular
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hyperplasia [3]. The clinical phase occurs when the enlarged prostate gland compresses the urethra, this results in an increase of urine flow resistance associated with elasticity loss of tensile organ, and sometimes with the presence of inflammation (prostatitis). The condition determines symptoms associated with a clinical picture named "prostatism" [4] that is characterized by dynamic and static components. The first one affects stromal tissue and it is due to an increase of the smooth muscle tone of
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the bladder neck and of prostate stromal portion. The alpha1-receptors seem to be the mediators of this process. The obstructive symptoms induced by the dynamic component are terminal dribbling, sense of incomplete bladder emptying due to urinary retention, decreased force of the stream, urinary hesitancy or urinary flow intermittency. The other factor of the clinical phase (i.e., static component) involves the epithelial tissue which is affected by androgen-induced proliferation leading to prostate hypertrophy. The irritative symptoms caused by the static component are nocturia, incontinence, hematuria, urgency and increased frequency of voiding acts [5]. The symptoms described above can lead to anxiety, sleep disturbance [6], reduced mobility, difficulty in sexual relations and a compromised feeling of well-being, resulting in interruption of work and social activities, with a negative impact on the quality of life (QoL) [7]. The origin of BPH is not clearly defined. Three theories have been proposed to explain the causes of BPH development. The first one is based on the role of androgens, estrogens and growth factors. The prostate cells are able to convert about 90% of testosterone (TE) to dihydrotestosterone (DHT) by 5alpha-reductase. The latter binds to androgen receptors with higher affinity
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ACCEPTED MANUSCRIPT than TE, and it appears to act directly by stimulating protein synthesis, differentiation and prostate cell growth [8, 9]. DHT accumulates in prostate even when TE levels are low [10]. The binding of DHT to its receptor further stimulates the transcription and transduction of DNA specific segments, coding for growth factors (e.g., epidermal growth factor – EGF;
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insulin like growth factor – IGF; growth cheratinocitic factor), leading to an abnormal prostate cells proliferation [11]. Moreover, estrogens act in synergy with androgens in the development of BPH. Particularly, it has been observed an increase in
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the expression of aromatase (enzyme that catalyzes the peripheral conversion of androgens into estrogens) and estrogen receptors at the transition zone of hypertrophic prostate tissue [12]. The second postulate about BPH development is based on
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the presence of a small percentage of prostate cells androgen-independent that can self-renew in androgen-deficient conditions [3]. The third theory concerns the interactions between stroma and epithelium. Both of them are able to convert TE into DHT, allowing the production of various growth factors (fibroblast growth factor – FGF; endothelin-1 - ET1; transforming growth
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factor - TGF-β1; etc.), responsible of modulation, proliferation, apoptosis and secretory activity of both stromal (autocrine transmission) and epithelial portions (paracrine secretion) [3, 13, 14].
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In the pathogenesis of BPH some risk factors should also be taken into account, since this disease is more common in patients
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from North America and Europe, with large baseline prostate, with positive family history [15], and with previous inflammation of the prostate gland. Prostatitis, as well as oxidative stress, stimulates the inflammatory cascade associated with nuclear factor kappa-B (NF-ĸB), inducible nitric oxide synthase (iNOS), and 5-lipoxigenase (5-LOX) activation, cyclossigenase-2 (COX-2) over-expression, and cytokines and leukotrienes production [16].
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Therapeutic approaches currently available for the treatment of BPH consist in: watchful waiting, surgery, pharmacological therapy and the use of medicinal plants. The choice of treatment should be decided together with the patient and should be individualized, according to his personal preference and to the disease severity [17]. The main aim is to relieve symptoms and to improve patient’s QoL.
The watchful waiting (i.e., periodic revaluations of clinical conditions) and some changes in lifestyle is recommended for patients with mild symptoms who are not at risk of acute urinary retention [18]. In case of worsening of symptoms and as the post-void residual volume increases, pharmacological therapies are proposed. The two main classes of drugs are alpha1antagonists (prazosin, doxazosin, terazosin, alfuzosin, tamsulosin, silodosin) and 5alpha-reductase inhibitors (finasteride, dutasteride), often effectively used in combination as a recommended option for the treatment of patients at risk of BPH progression [19]. The target of alpha1-adrenergic antagonists is the dynamic component and they are considered as the mainstay of therapy [20]. The alpha1-blockers increase the volume and the stream force, improving symptoms and consequently
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ACCEPTED MANUSCRIPT patient’s QoL. The most common side effects are dizziness, tachycardia, postural hypotension [21], retrograde ejaculation (reversible after discontinuation of therapy) [19, 22]. The 5alpha-reductase inhibitors reduce the static component causing androgens reduction. They are more effective in patients with a significant enlargement of the prostate gland [23]. The use of
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finasteride increases the stream of urine and reduces BPH-related symptoms [24]. However, it causes numerous side effects as decreased libido, decreased volume of ejaculate, impotence and skin rash. Cases of gynecomastia have been also reported [25].
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The antimuscarinic drugs (tolterodine, fesoterodine) may also be used, in association with the two previous mentioned drugs classes, in severe conditions related to storage symptoms [22]. A more recent long-term pharmacological treatment of BPH of
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moderate degree consists in prostate antigen-specific antibodies (known as afala). This preparation promptly and effectively reduces irritative and obstructive symptoms and post-void residual volume, while increase urine flow [26]. Other recent and, in some cases, promising pharmacological therapies include the use of: 3-agonist (i.e., mirabegron); the association of 5-
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phosphodiesterase inhibitors (i.e., tadalafil) and alpha1-adrenergic antagonists; lonidamine (capable of inhibiting glycolysis and of causing cell apoptosis) and botulinum neurotoxin [27, 28, 29]. The latter approach, consisting in the intraprostatic injection
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of patients with urologic conditions [30].
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of botulinum toxin, is still of doubtful efficacy and safety and further studies are needed to determine its use in the management
In the worst cases of symptomatic BPH, invasive surgery (open prostatectomy - OP) or minimally invasive procedures (transurethral resection, transurethral microwave thermotherapy, laser ablation endoscopic, etc.) may be required. The type of surgery is based on the size of the prostate, the presence of painful symptoms and/or other concomitant diseases. OP is
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considered as the most effective as well as the most invasive procedure [5]. The incidence of its complications can range from retrograde ejaculation (81%) to urinary tract infections (3%) [31]. In recent years, the transurethral resection of the prostate (TURP) has become the ―gold standard‖ in patients with BPH, because this surgical approach allows obtaining an immediate removal of the obstruction and long-term improvement of the symptoms. However, also this procedure has been associated with side effects (e.g., incontinence, impotence, hemorrhages. The latter could be obviated by the use of intermittent clotting) [32]. Other minimally invasive procedures that improve the symptoms quickly and have a good cost/efficacy have been developed and the most practiced included the following: transurethral incision of the prostate (TUIP) that reduced the urethral compression and it is recommended when the gland weight is about 30 grams; transurethral electrovaporization of the prostate (TUVP) that represents a TURP modifications, consisting in the distruction of the hypertrophic prostate tissue; transurethral microwave therapy (TUMP), transurethral needle ablation (TUNA), and various types of endoscopic ablation by laser (ELAP). All of the above mentioned approaches are, in different extent, responsible for side effects such as: ineffectiveness or failure in
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ACCEPTED MANUSCRIPT the short term, high incidence of complications, need for a prolonged cauterizationtent, retrograde ejaculation, etc [32]. Because of many side effects of drug therapy and surgical procedures, and since the high morbidity and the long latency of BPH make it a good target for prevention [32], herbal medicines (also know as botanicals) are becoming a popular option in the
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treatment of this disease. Herbal products are usually derived from roots, berries or fruits of various plants, and are commercialized as extracts, that contain a wide range of chemical compounds (e.g., phytosterols, fatty acids, flavonoids). The
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most commonly used herbal remedies for mild-moderate BPH are Serenoa repens fruit extracts and Pygeum africanum bark extract [33, 34]. The herbal treatments generally show a great tolerance and plural numbers of action sites, many of which are in
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common with drugs such 5alpha-reductase inhibitors and alpha1-receptors antagonists. Many of herbal products currently used for BPH are sold in health food stores and are often, but not always, available as dietary supplement without medical prescription [32]. In particular, in the United States medicinal plants are regulated by the Dietary Supplement Health and
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Education Act as dietary supplements and are usually available without medical prescription [35]. In Italy, some of these herbal preparations are also registered as drugs and required prescription. In Germany and Austria, phytotherapy is the first-line
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treatment of mild to moderate urinary symptoms and represents more than 90% of all drugs prescribed for BPH treatment [36].
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Phytotherapy is generally less used in other countries, including Ireland, UK, Denmark, Norway, Finland, Sweden, Italy, Greece and Portugal. On the contrary, the number of phytotherapeutic prescriptions is particularly high in Belgium [37]. This review summarizes the preclinical and clinical evidences of the medicinal plants most widely used in the treatment of
Cucurbita pepo
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BPH. Particular attention was also devoted to the safety profile.
Cucurbita pepo L. belongs to the Cucurbitaceae family. It is an annual herbaceous plant native of South-central America, also known as pumpkin or Dubba. In traditional medicine, the oil of pumpkin seeds has been used for its antioxidant and antiinflammatory actions in the treatment of BPH and its urinary related problems [38].
Preclinical studies The chemical composition of pumpkin seeds consists of alpha-tocopherol, proteins, carbohydrates, fatty acids (palmitic, stearic, oleic and linoleic), non essential aminoacids (cucurbitine) and Δ5-Δ7-Δ8-phytosterols (including sitosterol, stigmasterol, etc.) [38, 39]. The Δ7-sterols have a chemical structure similar to DHT and can competitively inhibit the binding of DHT to its
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ACCEPTED MANUSCRIPT receptors. However, the active ingredient has not been yet identified and the data related to the mechanism of action are limited and not conclusive. Some studies carried out in rats show that pumpkin seeds extract can block the increase of prostate weight and protein synthesis induced by testosterone/prazosin [40], inhibiting testosterone-induced hypertrophy [41], and improves the
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function of the bladder (i.e tonic action, sphincter relax action) and urethra [42, 43]. The mechanism of action of pumpkin seed
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oil is supposed to be the 5alpha-reductase inhibition [41].
Clinical studies
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From a multicenter clinical trial conducted on thousands of patients with BPH treated with capsules of pumpkin seeds extract (500 mg), there was a decrease in the International Prostate Symptoms Score (IPSS) and an improvement of QoL [44]. A significant decrease in the levels of DHT, and a significant improvement in BPH urinary flow symptoms (i.e., time of the
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bladder emptying, residual volume, daily frequency of urination and nocturia) were also found in patients using a combination of pumpkin seeds and Serenoa repens [38]. This association (320 mg/day of each medicinal plant) was also effective in
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prostatic Korean patients in the amelioration of IPSS, QoL, PSA serum levels and maximum urine flow, while there were no
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differences in the prostate volume [45]. Other more recent multiple association involves the use of C. pepo seed oil (160 mg), Epilobium parviflorum extract (500 mg of dry herb), lycopene (2.1 mg), Pygeum africanum (15 g of dry stem) and Serenoa repens (660 mg of dry leaf). This herbal preparation, during three months of treatment, induces a significant reduction in IPSS, and day-and night time urinary frequency, in patients who presented medically diagnosed BPH [46]. However, further studies
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to confirm the efficacy of Cucurbita pepo in the treatment of BPH are needed. Regarding the safety of this plant, there is not indication of serious side effects, though it could be responsible of mild gastrointestinal problems (e.g., indigestion, diarrhea) [42], electrolytes loss (possibly due to its diuretic properties) [47], and alteration of International Normalized Ratio (INR, an indicator of prothrombin time). The last effect makes cucurbita contraindicated in case of anticoagulants concomitant therapies [38].
Epilobium spp.
Epilobium L. is a perennial herbaceous plant that belongs to the Onagraceae family. It consists of more than 200 species distributed in Europe, Asia, Africa, Australia, America, Tasmania and New Zealand [38]. The most common species include E. parviflorum, E. hirsutum, E. rosmarinifolium and E. angustifolium (commonly known as Willow herb). The part of the plant
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ACCEPTED MANUSCRIPT commonly used in various products is derived from the aerial flowered one. Traditional medicines consider the willow herb useful for fever, rheumatic complications, headache, and as a general pain releif, even if such uses are not supported by
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scientific evidence [38].
Preclinical studies
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The various species of this family are rich in flavonoids (myricitrin, isoquercitrin, quercitrin, guaiaverin, quercetin-3-O-β-Dglucuronide, etc.), dimeric macrocyclic ellagitannins (oenothein A and B) and sterols (β-sitosterol and its esters) [48, 49]. The
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common element in the various species of Epilobium is the presence of oenothein B which seems to play an important role in the inhibition of DNA synthesis, although other components may contribute to this effect [50]. The commercial Epilobium contained products, usually, consist on different plant species associations, so that the pharmacological standardization of this
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plant remains difficult. A study carried out by Bazylko et al. [51] has developed a simple, fast and selective method for the separation and quantitative determination of oenothein B and quercetin glucuronide of the E. angustifolium aqueous extract.
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Several studies confirm that the main tannic component of E. parviflorum is oenothein B, while the main flavonoid is myricitrin
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(myricitin-3-O-ramnoside). It was also found the presence of caffeic, chlorogenic, ellagic and gallic acid derivatives, myricitrin, quercitrin, kaempferol and their glycosides [52]. Epilobium is one of the various medicinal plants used in the treatment of BPH, although the exact mechanism of action has not yet been clarified. The activities observed in experimental studies consist in: high radical-scavenger, antioxidant activity [53], anti-inflammatory effect, analgesic property, anti-proliferative effect,
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inhibition of the activity of hyaluronidase and myeloperoxidase, lipoxygenase release possibly due to oenothein B content, and inhibitory effect on aromatase and 5alpha-reductase type 2 enzymes [49, 50, 54, 55]. The radical-scavenger and antioxidant activities have been found for both ethanol and aqueous extract of E. parviflorum; these were high (greater than that of Trolox® and ascorbic acid, used as positive controls), dose-dependent, and seem to be due to the presence of flavonoids [56]. The same finding was confirmed by other studies also for other Epilobium species [53, 57]. Regarding the anti-inflammatory activity, a potent inhibition of COX-1 and COX-2 has been found in vitro for the ethanolic (rather than aqueous) extract of E. parviflorum [56]. Furthermore, in vivo study on carrageenan-induced rat paw edema has been confirmed the high anti-inflammatory property, probably due to the inhibition of prostaglandin synthesis [58]. As regard the antiproliferative effect, an aspecific effect on the inhibition of cell proliferation has been found for various Epilobium species (E. angustifolium, rosmarinifolium, tetragonum) [50, 59]. This activity appeared to be related to interference on cell cycle progression from G0 to G1 phase, rather than to a cytotoxic effect [60]. Other results that may offer an explanation of the pharmacological use of willow herb in
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ACCEPTED MANUSCRIPT traditional medicine have shown an inhibition of 5alpha-reductase [61] and the induction of neutral endopeptidase (NEP) in prostate cells [59]. Moreover, antitumor activity due to the immune response enhancement mediated by the macrophages
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activation was found [62]. All of the previous mentioned activities indicate a key role of oenothein B [50, 59, 61, 62].
Clinical studies
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Although all the preclinical results could support the traditional use of different species of Epilobium for the treatment of BPH, and this plant is widely present in dietary supplements and cosmetic products used against androgenetic alopecia, further
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researches are needed. In particular those regarding the inhibition of prostatic cell proliferation, the anti-androgenic, antiinflammatory and analgesic properties that may be useful in the treatment of symptoms associated with BPH. In the literature, as previously discussed (see Section 3.2), there is only one clinical study regarding Epilobium parviflorum, used in association
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with various medicinal plants [46], whereas there are no published data regarding clinical efficacy and safety of Epilobium spp. used alone. However, although the lack of human studies, Epilobium extracts appear to be harmless to animals, but this data
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cannot be directly traduced in terms of clinical evidence [49].
Hypoxis roopery
Hypoxis roopery Moore belongs to the Hypoxidaceae (Amaryllidaceae) family. This is a perennial herbaceous plant native of
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South-East African regions, particularly of Kiwazulu Natal and of Transkei. It is also known as Hypoxis hemerocallidea, African potato or yellow star. The part of the plant usually used is made from a dark brown or black tuber which presents a yellow pulp [43]. Hypoxis roopery is traditionally known as a ―miracle‖ medicinal plant because it has been used for a wide array of human aliments, including cancers, diabetes, infections, nervous disorders, immune-related illnesses, heart weaknesses and urinary tract infections [63].
Preclinical studies The tuber contains mainly sterols (β-sitosterol and β-sitosterol glycoside), polysaccharides and lignans (mainly hypoxoside that should be converted to rooperol, its biologically active glycone) [38, 64]. The pharmacological effects of Hypoxis could be attributed to sterols [43]. In particular, β-sitosterol seems responsible for the increase of TGF- β1 expression and protein kinase C-alpha activity, in the stromal cells of human prostate [43]. However, this specific effect doesn’t appear clinically relevant in
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ACCEPTED MANUSCRIPT vivo, though it has been found an improvement of BPH related symptoms (post-void residual volume, increase of urine flow) [65]. The mechanism of action of this herb is not well known. From preclinical studies it doesn’t seem to inhibit 5alphareductase [66]. In vitro, rooperol has been shown to have anti-inflammatory activity, by inhibiting the cytokine production,
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COX-1 and COX-2 activity (ethanolic extract appared to be more potent than the aqueous one), by reducing the activity of transcription factors [56], and it might interfere with the synthesis of inflammatory mediators, such as prostaglandins [42, 67,
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68]. The antinflammatory effect was also recently confirmed at intestinal level, in mice, by an inhibition of epithelial cells proliferation and by a reduction in the expression of NF-ĸB in the colonic mucosa [69]. It has also been shown to have radical
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scavenger activity (that was equal for both ethanolic and acqueous extracts) [56]. As regards the safety of hypoxis extract, an in vivo study in mice, treated with 2000 mg/kg of hypoxis for 2 weeks, did not show any toxicity on various vital organs (brain, heart, lungs, liver, spleen, kidney and intestine), also confirmed at hystomorphological level [68]. On the other hand, the
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possibility of a negative interaction of Hypoxis with various isoforms of CYP450 (i.e., CYP1A2, 2A6, 2B6, 2C8, 2C9, 3A4 and 3A5) should be kept in mind. Indeed, the inhibition of presystemic metabolism could be achieved in the gastrointestinal tract
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when traditional doses of Hypoxis are taken [70].
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There is not enough data about the efficacy and safety of H. roopery. Clinical evaluations compared with placebo after 6 months of treatment with the whole plant extract, reported an increase in urinary flow, significant improvement in subjective
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complications, and a decreased post-void residual volume in patients with BPH [38]. Improvements in the IPSS score, with mild and infrequent adverse events were also found [71]. Those affect gastrointestinal (i.e., nausea, diarrhea) and cardiovascular (i.e., ventricular tachycardia) systems, and appear to be due to hypoxoside and rooperol, respectively [72]. In the recent years, the entire extract, phytosterols and other constituents of Hypoxis are finding new applications in the antioxidants, antiinflammatory, anti-diabetic, and anti-convulsionant fields [73].
Lycopersicum esculentum
Lycopersicum esculentum Mill. (also known as Solanum lycopersicum L.) belongs to the Solanaceae family.The tomato is an annual herbaceous plant that is native of the area between Mexico and Peru. It is commonly used as a food (tomato-based food:
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ACCEPTED MANUSCRIPT tomato paste, tomato sauce, tomato soups, etc.). Generally the tomatoes fruit and tomato-based products provide to the human body about 85% of lycopene, while the remaining 15% is obtained usually from the consumption of watermelon, apricot, peach,
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papaya and red berries [74].
Preclinical studies
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Lycopersicum esculentum contains glycoalkaloids (alpha-Tomatine), salicylates, flavones (apigenin and luteolin), polyphenolic compounds (quercetin, myricetin, kaempferol, naringenin and chlorogenic acid) and other carotenoids (phytoene and
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phytofluene) [75]. All green parts are toxic, as they contain solanine, a steroidal glicoalcaloid, which is not eliminated even by cooking processes. The ripe fruit is rich in nutrients, among which aminoacids, minerals (e.g., potassium), vitamins (A, B, C, D, E, K, and folate). A substance that has generated great interest among researchers is a polyunsaturated long-chain acyclic
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carotenoid, which is called lycopene. It contains 11 conjugated double bonds, linearly arranged in the trans configuration [76], while most of the lycopene that has been found in the prostate tissue has cys conformation [77]. The cys form is preferentially
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captured by benign and malignant prostate tissue and it is produced during cooking [77]. As lycopene has been correlated with
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a low frequency of adenocarcinoma [78], from 2003 was added to most multivitamins products as an agent for the prevention of cancer and has become the most commonly used carotenoid, among men of 45-65 years old [79]. In addition to lycopene, tomato contains lycopene cyclase (the enzyme that catalyzes the conversion of lycopene to β-carotene). The number of the mechanisms of action that have been proposed for the control of adenocarcinoma, as well as adenoma, is various, including:
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inhibition of growth factors-induced cell proliferation, interfereces in the progression of the cell cycle from G0/G1 to S phase, modulation of COX pathway, down-regulation of 5alpha-reductase type 1, pro-apoptotic activity (potentially due to alphatomatine) [80], inhibition of the synthesis of androgen receptor (which leads to a PSA reduction), and antioxidant activity [74, 76, 77, 78, 81]. The latter property consists in the high capacity of lycopene (compared to other carotenoids) to capture oxygen radicals otherwise responsible of DNA damage [76]. Other substances involved in the antioxidant effect are the tomato aglycone polyphenols (quercetin, naringenin and kaempferol), responsible also for the anticarcinogenic effects and the inhibition of cell proliferation, in a dose-dependent manner [77]. In vivo results indicated conflicting evidence related to the effect of tomato (or pure lycopene) on the reduction of plasmatic testosterone level. This could be explained by the duration of treatment, the differences in animal species or in the lycopene content [82]. However, as experimental studies indicate that the tomato extract is more effective in inhibiting carcinogenesis
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ACCEPTED MANUSCRIPT than lycopene alone, [83], this carotenoid does not appeared to be the only constituent of tomato to have effects on prostate [75]. In vivo pre-clinical assessment of lycopene showed good safety profile with a LD50 greater than 5000 mg/kg of body weight,
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and no acute dermal toxicity up to 2000 mg/kg of body weight. Those doses are about 300 times higher than those usually consumed in human [84]. Indeed, it was estimated a consumption of daily amount of lycopene about 8 mg [84], with benefits
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that become evident at approximately 7-35 mg/day [85, 86].
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Clinical studies
Regarding the clinical efficacy of tomato juice and in particular lycopene, a decrease in blood levels of PSA and in oxidative DNA damage, and an increase of cell apoptosis in patients with adenocarcinoma have been found [85, 87, 88]. To reach these
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effects, lycopene should be taken (at an average of 15 mg/day) for 3-6 months [88]. A good efficacy of low doses of lycopene (5 mg/day) was also found when this is associated with Serenoa repens [89].Common adverse effects induced by diet
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containing tomato products riched in lycopene are mild and reversible after discontinuation of therapy, and consist in
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gastrointestinal problems (dyspepsia, flatulence, etc.) [87] and dermatologic effects (itchy skin, etc.). In this context, should be hightlight that chronic exposure to high doses of tomato products can induce licopenemia, a reversible alteration consisting in yellow-orange skin discoloration. This adverse effect could be also associated with fatty hepatic cysts due to deposits of lycopene, which can cause abdominal pain and morphological and histological changes of liver parenchyma [84, 90].
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The Scientific Committee on Food of the European Commission has considered unacceptable the use as a food of lycopene synthetic preparations, because of their high sensitivity to oxygen and light, which form degradation products with mutagenic activity [74]. Moreover, lycopene induces phase І and ІІ metabolism enzymes and, even if helpful for the elimination from the body of carcinogens and toxins, particular attention must be devoted to concomitant use of pharmaceutical products [74]. In conclusion, though the data is very encouraging, the use of lycopene in the prevention or treatment of prostatic diseases is still premature.
Pinus pinaster
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ACCEPTED MANUSCRIPT Pinus pinaster Sol. belongs to the Pinaceae family. It is also known as the Maritime pine and lives spontaneously in the Western Mediterranean basin. The parts commonly used are gems, twigs and resin, from which the essential yellow oil with characteristic smell and resinous taste could be obtained, by distillation in steam.
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Preclinical studies The essential oil contains alpha-and beta-pinene with antiseptic properties, esters of borneol, d-limonene, aldehydes, oleoresin
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(or turpentine) that by distillation provides turpentine and rosin resin which is a transparent solid. It also contains diterpenes, coumarins and flavonoids. The needles are rich in vitamin C and flavonoids. The main and active component is the β-sitosterol,
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with chemical structure similar to that of cholesterol, which is also commonly found in legumes and vegetables and in particular in plants like Hypoxis, Pygeum or other genus. In vitro experiments have shown the effectiveness of β-sitosterol in inhibiting
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prostate cell proliferation [91, 92].
Clinical studies
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A randomized, double-blind and placebo study was conducted to evaluate the efficacy and safety of β-sitosterol (130 mg/day,
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for 6 months). In treated patients there was a significant improvement in the quality of life, in post-void residual volume, in the IPSS and in Qmax [91]. A systematic review also found a significant improvement of the urinary symptoms due to β-sitosterol [93]. Other authors have reported contradictory results regarding the efficacy of β-sitosterol, also in association with other plants and sustances, where a slight improvement was found though not statistically significant, therefore further clinical studies
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are needed [94]. The side effects induced by β-sitosterol are generally mild; however, impotence and gastrointestinal problems are presented to a greater extent compared to patients in the placebo group [93, 17].
Pygeum africanum
Pygeum africanum Hook belongs to the Rosaceae family. It is an evergreen tree native of the Central and South America mountains, the Madagascar and Comoros islands and the Gulf of Guinea. This plant is known even as: African Plum, Prunus africana, African cherry. Prunus africana is the only member of the genus widespread on the African continent and may be chemically distinctive. The major exporters of its bark (the part of the plant used) include Cameroon, Madagascar, Equatorial Guinea, and Kenya [95]. Young trees have smooth, reddish bark whereas older trees have dark, resinous bark with an intense smell of hydrocianic acid. It has the rare ability to regenerate its bark, as long as the vascular cambium is not destroyed [95, 96].
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Preclinical studies Pygeum africanum composition consists of phytosterols (β-sitosterol, β-sitosteryl glucoside, β-sitostenone), fatty acids,
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triterpenoid pentacyclic acids (ursolic, oleanolic and their homologs), alcohols (n-docosanol and its derivatives), esters of ferulic acid, linear acetogenins, nonacosane, entriacontane, glucopyranosyl ester of benzoic acid and β-D-glucopyranoside of
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diphenyl methyl alcohol, lignan isolariciresinol-9-hydroxy-7,8-dimethyl ether and proanthocyanidins [43, 97]. Two other important costituents isolated from the bark of Pygeum are N-butylbenzensolfonamide (NBBS) with anti-androgenic activity,
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and atraric acid, which mechanism of action is to inactivate the androgen receptor by inhibiting its nuclear translocation [98]. Pygeum inhibits the androgen and progesterone receptors, but not those of the glucocorticoids and estrogens; it inhibits the endogenous PSA expression and the prostate cancer cells growth [98]. Furthermore, the isolation of derivatives of docosanol
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from other plants (e.g,. Myoschilos oblongum), but also present in pygeum, has contribuited to highlight the inhibition of cell proliferation of human prostatic cells [99]. To confirm this mechanism of action, other studies evidenced a downregulation of
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TGF-β1 expression, and an inhibition of the proliferation of human prostatic fibroblasts and myofibroblasts [100]. Its
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antiproliferative effect has been demostrated also in rats through treatment with Tadenan® (Pygeum africanum extract), before and after administration of DHT [101]. Other studies performed with Tadenan® support the hypothesis that it might prevent the activation of metabolizing enzymes (or the formation of free radicals) or protect intracellular membranes against the destructive effects of free radicals reducing significantly the severity of both urinary bladder dysfunctions [43, 102].
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In animal models, pygeum regenerates the secretory activity of the prostate epithelium, modulates the contractility of the bladder and has anti-inflammatory activity related to the inhibition of 5-lipoxygenase, with a consequent decrease of leukotrienes production and other 5-lipoxygenase metabolites [103]. The anti-phlogistic action of pygeum could partially depend on its ability to reduce the number of neutrophils and the TGF-β expression in these cells [104]. Finally, Pygeum africanum has been demostrating in vivo a significant reduction of the incidence of prostate cancer, providing a preliminary evidence of its use as a supplement in persons who have a high risk to develop prostate cancer [105].
Clinical studies Pygeum africanum extract taken at daily dose of 100-200 mg, for about 1-2 months, improves significantly urinary symptoms (nocturia, frequency of micturition, etc.), flow parameters (i.e., maximum urinary flow rate and post-void residual urine), spermogram, the IPSS and consequently the QoL [106,107,108,109]. These benefits seem to remain almost unchanged even
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ACCEPTED MANUSCRIPT after 30 days of treatment, indicating a persistent clinical activity with a long term benefits [107]. It is also estabilished that single or fractionated dose of 100 mg/day are equivalent [109]. Regarding the effects of Pygeum africanum lipid-sterol extract on the gland size, there are conflicting results indicating its reduction [106, 107].
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Despite the different works mentioned above, a meta-analysis assessed that clinical trials of pygeum are of short duration, performed on very small groups of patients [110], and have often been conducted with different evaluation methods and on
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different extracts. However, it indicates that this drug is significantly more effective than placebo in relieving the symptoms of BPH patients. Further clinical trials are needed on a single type of standardized extract, for longer time and with validated
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methods in order to obtain conclusive information [111]. It has been reported that Pygeum africanum compared to watchful waiting, seems to improve significantly the urologic symptoms, and might be equally effective to Serenoa repens [17]. No information about the prevention of BPH long-term complications (such as acute urinary retention, renal failure or the need for
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surgery) has been reported. Finally, all clinical studies have concluded that pygeum-induced adverse effects are mild and comparable to placebo in frequency and type [107, 108, 111], and consisted in gastrointestinal problems (diarrhea, abdominal
Roystonea regia
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pain, constipation, nausea) and headache [43].
Roystonea regia Cook is a palm tree that belongs to the Arecaceae family. It is native of South Florida, Mexico and parts of
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Central America. In Cuba, it is also called palm criollo, while in India, where it is widely cultivated, is called Vakka [112]. The drug used for BPH is constituted by its mature fruits.
Preclinical studies
The extracts from its fruits contain a mixture of free fatty acids (oleic, lauric, palmitic and myristic acids in abundance), also known as D-004. Other acids (caprylic, capric, palmitoleic, stearic, linoleic and linolenic acids) are also found in lower concentrations. Preclinical studies have shown that the lipid extract of D-004 produced antioxidant effects in prostate tissue [113], inhibits competitively the prostatic 5alpha-reductase [114] and the simpatic-induced contraction of smooth muscle in ratisolated deferens tube [115]. In vivo studies have shown that oral treatment for 14 days with the lipid extract of Roystonea regia fruits could prevent and improve benign prostatic hyperplasia induced by testosterone, in rats. Experimental data indicate an antagonism of alpha1-adrenoceptors, and a decrease of prostate enlargement that seems dose-dependent and more efficient than
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ACCEPTED MANUSCRIPT that obtained with Serenoa repens, but largely less effective than tamsulosin [116,117,118]. On the other hand, the combination of D-004 and tamsulosin has been resulted much more effective (71%) than each of the monotherapies (57%) in preventing the urodynamic changes induced by phenylephrine in rats [119]. However, the mechanism leading to these effects requires further
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studies.
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Clinical studies
It is not yet possible to attribute to Roystonea clinical efficacy, even if the family to which it belongs and the antagonism of
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alpha1-adrenoceptors offer good basis for further studies. A randomized, double-blind study on healthy volunteers indicated a significant antioxidant effect on plasmatic oxidative markers of D-004 (320 mg/day), taken for 6 weeks [120]. Informations in
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the literature concerning the safety of Roystonea are currently very limited; only 2 cases of dyspepsia were reported [120].
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Secale cereale
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Secale cereale L. is an annual or biannual herbaceous plant that belongs to the Graminaceae family and is widespread in temperate zones. It is also known by the names of rye, common rye and rye pollen. The drug is made from the pollen and the extract is obtained from a microbial digestion of pollen of various plants, especially from Secale cereale from Sweden and
Preclinical studies
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Switzerland. The extraction process involves the sequential use of water and organic solvents [43].
The common presence of proteins, carbohydrates, vitamins, minerals and β-sterols (in the acetone-soluble fraction) has been reported [121], however the active ingredient is still not known. Moreover, the composition of commercial products (tablets and capsules) is highly variable, making it difficult to interpret the results. One of the most famous products, used by millions of people, prepared from the Secale cereale pollen extract is Cernilton® (each dose is standardized in 60 mg of cernitina T60 water soluble fraction, and 3 mg of Cernitina GBX - acetone soluble fraction). It is registered as herbal drug throughout Western Europe (i.e., Switzerland, Austria, Germany, Spain, Greece), Japan, Korea and Argentina; while in the U.S. is used as a dietary supplement. Several mechanisms of action have been proposed for pollen extracts, including: relaxation of urethral sphincteric smooth muscle tone [122], increase of the bladder muscles contraction [123], increase of the apoptosis in epithelial cells of prostate gland, inhibition of the 5alpha-reductase, increase of the serum and prostatic levels of zinc, the block of the
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ACCEPTED MANUSCRIPT alpha-adrenergic receptors, inhibition of prostaglandins and leukotrienes biosynthesis [43]. From an in vivo study, it has been suggested that a therapy with Secale cereale pollen extract may retard the growth of prostate cancer by increased apoptosis of
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tumor cells in animal models [124], but it can’t yet be recommended as a successful treatment for prostate disorders.
Clinical studies
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The pollen of Secale cereale seems useful in relieving urinary symptoms of BPH and prostatitis, but the improvement is modest and the evidence is limited [42, 93]. Two systematic reviews have compared the activity of Cernilton® with placebo or other
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types of herbal preparations used in BPH. A modest and subjective improvement in urologic symptoms was found when pollen is used for 24 weeks. However, it did not improve urinary flow, prostate size or the residual urine volume compared with placebo [43,125]. Although results suggest that Cernilton offers modest benefits to patients with BPH, the studies evaluated in
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this review were limited by several factors, as reported below [126,127]. The duration of treatment was short (i.e., 24 weeks). The dosages of Cernilton® have not been reported in all of these studies and the standardization of the preparation is unknown.
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Other studies, that have evaluated the clinical efficacy and safety of pollen extract, have suggested that it is well tolerated and
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improves modestly all urologic symptoms including nocturia. However, the administration of tamsulosin hydrochloride alone and in combination with pollen extract appeared more effective than the administration of pollen extract alone, in patients with urinary symptoms associated with BPH [128]. The long-term efficacy, safety and the capacity of Secale cereale pollen extract to prevent the complications of BPH are not known. One recent randomized clinical trial indicated that the long-term
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administration of 750 mg of Cernilton (Prostate®) may improve the symptoms of BPH and prevent its clinical progression better and faster than only 375 mg of the same product [129]. A total of 240 patients who presented a value of IPSS greater than 7, were treated orally with 750 mg of Prostate® (Cernilton) the first year and 375 mg for the next three. After the first year of treatment with Cernilton, the volume of the prostate, the incidence of urinary retention and the need of surgery were reduced. On the other hand, many other parameters (i.e., IPSS, prostate volume, residual urine, post-urination, Qmax) improved only after 4 years of treatment [129]. However, no adverse effects were observed. A previous multi-center, randomized clinical trial conducted versus placebo in 906 patients with BPH, have highlighted that, after 6 months of treatment, Cernilton® has the same efficacy of alpha1-antagonists and 5alpha-reductase inhibitors in improving IPSS, QoL, Qmax and residual urine. This effect was greater in patients with a high IPSS baseline. Conversly, Cernilton® was less effective than 5alpha-reductase inhibitors in the reduction of prostate size [130]. The pollen extract is also efficacious in men with inflammatory prostatitis and chronic pelvic pain syndrome in improving total symptoms, pain and QoL, without significant side effects [131]. Common side effects
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ACCEPTED MANUSCRIPT in using pollen exctracts are of allergic type, including respiratory reactions, skin hypersensitivity, and gastrointestinal symptoms [42, 93].
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Serenoa repens
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Serenoa repens Small. is a small palm, of the Aricaceae family. It is also known as Sabal serrulata, saw palmetto, Ju-zhong, Dwarf palm. Its habitat is in the West India and in the Southeastern part of the United States, especially in South Carolina,
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Florida, and Southern California. The drug consists of the dried ripe fruits; these drupes of soapy and unpleasant taste are similar to black olives of which, in therapy, is used the lyposterolic extract. Traditional medicine describes the use of dwarf palm since 1800 for the treatment of variety problems of the prostate and, without any scientific evidences, for other indications
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including breast enlargement, sperm production, and sexual potency [132]. From the twentieth century, the fruit of Serenoa has been recommended by many urologists to treat difficulties of micturition associated with BPH, so that it became one of the 10
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top-selling drugs in the United States [133]. Only in this country, in 2002, about 2.5 million adults have been using saw
Preclinical studies
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palmetto [134].
The liposterolic extract of Serenoa repens consists in a complex mixture of long-chain alcohols, fatty acids and their glycerides
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(oleic, caprylic, myristic, lauric, stearic, palmitic, linoleic acid), carbohydrates (galactose, arabinose and uronic acid), phytosterols (beta-sitosterol, beta-sitosterol-3-O-glucoside, beta-sitosterol-3-O-diglucoside, campestrol, cicloartenol), flavonoids (isoquercetin, kaempferol-3-O-glucoside), resins, tannins, pigments, essential oils and organic acids (caffeic, chlorogenic and anthranilic acid) [133]. The SPE (saw palmetto extract, also known as Serenoa repens purified extract) contains predominantly saturated and unsaturated fatty acids (90%), among which the main constituents are oleic and lauric acids; both represent more than 50% of the content of SPE. In addition, there are also myristic, palmitic and linoleic acid [135]. It is thought that the phytosterols and free fatty acids are the pharmacologically active constituents. In vitro results suggest two probable mechanisms: the non-competitive inhibition of 5alpha-reductase (both isoforms І and ІІ), which leads to decreased prostatic DHT content and inhibition of DHT binding to the androgen receptors, present in the cytosol of prostate cells [136]. The anti-androgenic effects of lipophilic extract also consist in inhibiting the 3-ketosteroid reductase responsible for the DHT conversion to another androgenic metabolite [137]. Inhibition of 5alpha-reductase by Serenoa extract depends, at least in part,
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ACCEPTED MANUSCRIPT to its free fatty acids content. Currently, there are no accepted guidelines for a standardized content of saw palmetto extracts in commercial products, even though the WHO has recommended that its composition should be 80-95% of fatty acids and sterols combined, or 85-95% of fatty acids and more than 0.2% sterols [134]. In order to analyze the binding affinity of fatty acids of
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SPE to various receptors (i.e., alpha1-adrenergic, muscarinic and dihydropyridine 1.4 calcium channels), it was shown that fatty acids inhibited prazosin and isradipine binding, in the central nervous system, in a dose-dependent manner. The affinity of
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oleic, linoleic and myristic acid for each receptor was higher than that of the SPE. The results suggest that the oleic and lauric acids antagonize receptors in a non-competitive manner [138]. Other important role of the fatty acids content (with the
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exception of palmitic acid) is the inhibition of both type 1 and 2 isoenzymes of 5alpha-reductase. This is the most noticeable effect of whole SPE, and occurs in a dose-dependent manner [138]. A stronger inhibition of 5alpha-reductase in prostate cancer cells was also found when Serenoa berries extract was associated with astaxanthin (carotenoid) [139]. The inhibition of both
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types of 5 alpha-reductase was also confirmed by other studies, even if with very different potency. The high variability in commercial products appeared due to different extraction processes that lead to qualitative and quantitative differences in the
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active ingredients [140,141]. In order to obtain reproducible biological activity, it is consequently necessary the standardization
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of every product in the commercial processing. Additionally to 5alpha-reductase inhibition, Serenoa seems to have antiinflammatory effects by inhibiting the synthesis of pro-inflammatory metabolites of arachidonic acid, through the blockade of COX and 5alpha-lipoxygenase enzymes [136] and by modulating the expression of infiammation related-genes [142]. It has been also reported a spasmolytic action on bladder muscle, by blocking calcium channels, by activating the Na+/Ca2+ exchanger
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[43], and through the antagonism of acetylcholine-induced contraction [143]. All these mechanisms support the clinical effectiveness of the SPE for the treatment of lower urinary tract symptoms, as they lead to significant relieves of urodynamic symptoms, increasing bladder capacity and extending the time of urination [144]. Other mechanisms of action of SPE include: inhibition of estrogen nuclear receptors and growth factors involved in prostate cell proliferation (EGF, FGF), anti edematous effects and alpha-adrenergic receptor blockade through a non-competitive antagonism [133]. About the last effect, unexpectedly, it has also been reported that serenoa stimulates the noradrenaline release causing contraction of the prostate smooth muscle. This sympathomimetic effect could be due to the constitutive presence of some amines, even if it is not been confirmed neither in vivo, nor in clinical trials probably because of the metabolism of these substances by hepatic enzymes [145]. Several studies have found that SPE suppresses the growth and induces apoptosis of prostatic epithelial cells, by inhibition of signal transduction pathways IGF1-activated and through the inactivation of the STAT 3 signals [146]. The increase of Bax/Bcl-2 ratio, caspase-3 activity, expression of p53 protein and a decrease in the expression of p21 and p27
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ACCEPTED MANUSCRIPT proteins appear to be also involved [147,148]. However, contrasting evidence regarding apoptosis has been reported, as the reduction of prostate size was achieved only at high doses [132, 149]. Regarding the safety of serenoa, an in vivo study has been shown no signs of liver toxicity [150] and no significant differences in body weight, enzymatic activity and levels of
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malondialdehyde, compared to placebo [150]. In order to increase the therapeutic activity in BPH, Serenoa repens is frequently associated with lycopene and selenium (an element able to promote an optimal antioxidant/oxidant balance). An association
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containing lycopene, selenium and Serenoa repens, commercialized as a dietary supplement named Profluss®, has been studied in vitro and in vivo for its efficacy in BPH. An inhibition of COX-2, 5-lipoxygenase, inducible nitric oxide synthase, and a
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reduction of NF-ĸB and mRNA that synthetize for TNF-alpha, has been found. The association of lycopene, selenium and Serenoa repens had more powerful anti-inflammatory and antiproliferative effects, compared to either compound alone, in reducing prostate weight and hyperplasia, in the suppression of cell proliferation induced by various growth factors (e.g., EGF,
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VEGF, TNF-alpha) [151], and in promoting apoptosis [152].
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Clinical studies
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In relation to the clinical efficacy, Serenoa repens seems useful in the treatment of mild and moderate BPH if patients are treated with standardized products (90% free fatty acids), at a dose of 160 mg twice daily, for at least three months [132]. On the other hand, it is contraindicated in advanced BPH with severe urinary retention and should not be used without consulting the physician [133]. The clinical efficacy of S. repens appeared superior to placebo and comparable to 5alpha-reductase
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inhibitors and alpha1-antagonists. Various studies are discussed below. A meta-analysis of 18 controlled clinical studies conducted for periods ranging from 4 to 48 weeks, showed a therapeutic efficacy of Serenoa extracts significantly superior to placebo and identical to finasteride [153]. Favorable effects on IPSS, LUTS, urine flow, nocturia and dysuria, have been also reported [154]. However, other studies have not reached to the same conclusion, pointing negative results on the improvement of urinary symptoms associated with BPH [134]. Furthermore, S. repens does not seem neither to reduce the prostate size and urinary flow measures [155], nor to change the levels of prostatespecific antigen (PSA), testosterone, DHT, follicle stimulating hormone (FSH), estradiol, and luteinizing hormone (LH) [133, 156]. Compared to finasteride (5 mg/g), Serenoa repens (320 mg/day) produces similar improvements in urinary flow, IPSS, and quality of life. Finasteride seemed to have a slightly higher effect on the peak urinary flow, whereas saw palmetto extract affected libido and impotence in a significantly lower manner [157].
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ACCEPTED MANUSCRIPT As regards the alpha1-antagonists, serenoa seems to have comparable efficacy to tamsulosin in improving bladder function [17]. On the other hand, the efficacy of prazosin in improving urine flows, micturition nocturnal frequency and post-void residual volume appared superior than saw palmetto [149]. The combination therapies ofserenoa with tamsulosin and serenoa
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with lycopene, selenium and tamsulosin increase Qmax and decrease IPSS, resulting more effective than the single therapies [158,159].
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As mentioned above, noteworthy is that serenoa is often associated with other medicinal plant extracts and/or elements, and a lot of clinical studies have been confirming its efficacy in improving the maximum urine flow, urinary resistance, IPSS score,
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quality of life, pain, urgency and nocturia [160,161,162,163,164]. These studies regard combinations as: Prostataplex® (serenoa plus vitamin A, plant sterols, lycopene, pumpkin seed oil, palm oil and selenium) [160], a mixture of 320 mg/die of serenoa and 240 mg/die of nettle root extracts [161], IPB-tre® (320 mg of Serenoa repens, 120 mg of Urtica dioica and 5 mg of Pinus
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pinaster) [162], Pluvio® (160 mg of fluid lipid-sterolic extract of Serenoa repens standardized in 85% of fatty acids, 300 mg of dry extract of Urtica dioica standardized in 0.8% of β-sitosterol, 166,7 mg of avocado and soya standardized in 30% of
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and 320 mg of Serenoa repens oil extract) [164].
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phytosterols, 1 mg of vitamin B1,5 mg of vitamin E and 7,5 mg of zinc) [163], Profluss® (5 mg of lycopene, 50 µg of selenium
The randomized studies compared with placebo (320 patients; 30 days-1 year) [162], finasteride (543 patients; 48 weeks) [161], watchful wating (120 patients; 6 months) [163], and serenoa alone (108 patients; 8 weeks) [164] have been reporting either positive results in the reduction of prostate volume [160, 162,163] or improvement in men with LUTS associated with BPH or
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chronic nonbacterial prostatitis [160,161,162,163,164]; although conflicting results have been found about the effect on PSA level [163,164]. Regarding the safety of the associations mentioned above, most of the studies have reported no serious and/or medium side effects [156, 162, 163,164]. Recently, an association of Serenoa repens, Pinus massoniana Bark Extract (PMBE) and Crocus sativus (named IDIProst® Gold), has been shown to better improve urinary and sexual function when compared with Serenoa repens alone [165]. Probably, the association of PMBE and Crocus sativus to serenoa produced a synergistic effect due to pharmacological properties of the other medicinal plants, including: nitric oxide activity, antioxidant effect and free radical scavenging properties of PMBE, increase of eNOS activity and promotion of the diffusion of oxygen into tissues induced by Crocus sativus [165]. The adverse effects of serenoa are generally mild and include headache, decreased libido, sexual dysfunction, ejaculation disorders, gastrointestinal problems (especially nausea and diarrhea if ingested on empty stomach or in large amount, respectively) [17, 133, 153]. Effects involving the sexual sphere are probably due to serenoa action on 5alpha-reductase. The
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ACCEPTED MANUSCRIPT urinary tract infections, ejaculation problems and impotence have been reported in 2% of patients treated in long-term with the dwarf palm, but in all cases its tolerability was better than finasteride [133]. However, other studies have demonstrated no negative impact on male sexual function [166] and do not support the relationship between serious clinical adverse effects and
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the use of dwarf palm extract [167]. The confirm is given also by the CAMUS trial that showed no evidence of toxicity of saw palmetto extract used at doses up to 3 times the usual clinical dose (160 mg, 2 times a day) during an 18-month period [168].
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Other case reports of greater severity were reported in the literature, including: high risk of bleeding, hepatitis and pancreatitis. In particular, it was reported cases of hematuria and coagulopathy in patients taking Serenoa [169], and a case of significant
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bleeding in a man hospitalized for surgery of meningiomas [170]. However, serenoa did not interefere in platelet aggregation and there are no data about the increase of pro-thrombin time (PT) or partial thromboplastin time (PTT) [171]. Regarding the probable implication of Serenoa in acute hepatitis and pancreatitis, a case of a 55 year old man who had taken serenoa
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intermittently for about 4 years has been reported [172]. A second case of 65 years old man who had started, a week before, a treatment with Saw palmetto (160 mg, 2 times a day) for difficulty in urination has documented acute pancreatitis [173]. A case
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of liver injury (cholestasis and fatty liver)in a 58 years old male who had taken during the last week a Serenoa repens
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commercial preparation (900 mg dry extract/day) has been reported [174]. The enrollment of specific patients in clinical trials, does not allow having unique information about potential drug interactions; among the exclusion criteria are men treated with alpha-blockers, diuretics and other drugs [133]. Among the possible pharmacodynamic interactions, has been reported an increase in bleeding time for the use of inhibitors of COX-2 and aspirin [97]. In addition, given its mechanism of action,
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Serenoa repens can theoretically interact with all hormonal therapies [43]. It is worth mentioning that Serenoa repens was part of medicinal plants present in PC Spes, sold in the United States for "prostate health". In 2002, the California Department of Health Services reported that different lots of the product, in addition to presenting a high variability in the concentrations of its components were contaminated by indomethacin, warfarin, alprazolam and diethylstilbestrol [175]. The healthcare professionals should therefore evaluate carefully the quality of herbal products, before recommending to a patient.
Urtica dioica
Urtica dioica L. belongs to the Urticaceae family. It is also known by the names of stinging nettle, common nettle and ortiga. It is an herbaceous plant, thorny that commonly grows all over the world, in regions where the climate is humid and temperate.
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ACCEPTED MANUSCRIPT The drug used in BPH is made from the roots, but fresh and dried flower parts are traditionally used for other purposes, such as joint pain, urinary tract infections and as diuretics. For external use the nettle is used as a remedy for hair loss, against seborrhea and dandruff of the scalp [38]. U. dioica has been ranked among the 16 most commonly used medicinal plants in the North of
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the Iberian Peninsula. Traditionally, is used as a depurative, for acne, diarrhea, diabetes, and to improve circulation and low
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blood pressure [176].
Preclinical studies
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The leaves contain sterols (beta-sitosterol, hydroxy-sitosterol), flavonoids (rutin, kaempferol, quercetin), minerals (calcium, potassium), tannins, acids (salicylic, malic acid) and amines (histamine) [43]. It has been reported that, in the root, elements particularly important are the presence of lectines (mixture of isolectines from 0.2 to 0.6%), polysaccharides (glucans,
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glucogalacturonans, arabinogalactan acid), idroxycumarins (scopoletin), ceramides, lignans (secoisolariciresinol -9-Oglucoside, (-)-3,4-divanililtetraidrofuran, neo-olivile), sterols and their glycosides (beta-sitosterol, stigmasterol, campestrol),
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phenols (p-hydroxy benzaldehyde), monoterpendiols and their glycosides, fatty triterpene, fenilpropans (homovanillilic alcohol
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and its 41-O-glycoside) [177].
In the treatment of BPH, a number of mechanisms of action of the root have been postulated, including light diuretic and potent anti-inflammatory activities probably due to the presence of scopoletin. The root extract, in vitro, inhibits the binding of the sex hormone binding globulin (SHBG) to its receptor in the membrane of human prostatic cells. The SHBG has the function to
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regulate the concentration of free androgens and estrogens in the plasma, and interference at its receptors on the membrane of prostate cells, would prevent these hormones to interact, themselves, with their receptors [178]. The lignans contained in the stinging nettle seem to have a high affinity for SHBG [38]. The polysaccharides and lectins can block the binding between the epidermal growth factor, secreted by the prostate tissue, and its receptors, with suppression of prostate cellular metabolism and its growth [43]. In addition, the lectines may contribute to the prostatic anti-proliferative and anti-inflammatory activities [38]. The polysaccharides stimulate the activity of T lymphocytes and the complement activation [179]. Both malic and caffeic acids show anti-inflammatory activity, in vitro and in vivo, through inhibition of COX and lipoxygenase. The nettle extract inhibits TNF activity [180], prostate cells proliferation [181], and aromatase activity [182]. The aqueous extract of the leaves of stinging nettle inhibits the activity of adenosine deaminase (ADA), the key enzyme in the nucleotides metabolism. The inhibition is dose-dependent and it might be one of the mechanisms that lead to improvements of patients symptoms [183].
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ACCEPTED MANUSCRIPT Animal studies indicate that U. dioica inhibits markedly platelets aggregation and improves the lipid profile; the constituents responsible for this potent effect seem to be the flavonoids [184,185]. It was found also that the methanol extract of stinging nettle significantly inhibited the prostate growth induced experimentally [186,187]. Ortica seems to inhibit the 5alpha-reductase
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activity, probabbly due to the presence of scopoletin and beta-sitosterol, at least in vivo [188].
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Clinical studies
A clinical study, randomized, double-blind, compared to placebo analyzed the effect of Urtica dioica roots aqueous extract (120
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mg, 3 times/day). The results showed a significant improvement in LUTS, Qmax, and IPSS, after sixth months of treatment. These improvements were maintained also after 18 months of treatment [189]. No significant difference was observed between the groups in the levels of PSA and testosterone, but the treated group showed a moderate reduction of the prostate size [189].
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Other study carried out with a higher dosage of urtica (459 mg), did not confirm the previous finding [190]. Other randomized trials have evaluated the effects of an association called PRO 160/120 and consisting in 160 mg of Serenoa
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repens standardized fruit extract and 120 mg of Urtica dioica root extract. A total of 257 patients with moderate and severe
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symptoms were treated with PRO 160/120 or placebo (one capsule, 2 times a day, for six months). The efficacy of the treatment was superior to placebo for attenuation of inflammatory and obstructive symptoms [191]. The same combination was tested on 140 patients, for fifteen months, and was compared toward tamsulosin (0.4 mg/day). This study found the effectiveness of PRO 160/120 and tamsulosin in the treatment of LUTS caused by BPH, and both treatments were well tolerated [192]. Another
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randomized, double-blind study, confirm the effectiveness and tollerability of PRO 160/120 versus finasteride in increasing urine flow, improve symptoms related to bladder emptying, but not in reducing the prostate volume [193]. The nettle (300 mg) has also been evaluated in combination with Pygeum africanum (25 mg), in six months of treatment and no significant differences were found in various parameters (i.e., IPSS, QoL, Qmax) and clinical improvement [194]. The nettle extract is generally well tolerated [189] and may result in only occasional mild gastrointestinal effects. There have been reports of diarrhea and respiratory system diseases of moderate intensity, but the effects do not differ from those observed in the placebo [191]. Rarely have been reported edema and urticaria related to allergic reactions induced by the plant [38]. U. dioica contains tannins, which can interact with concomitant intake of iron, causing a reduction of the effects in patients who need iron supplements. It is therefore, recommended to separate for at least two hours the times of administration of these components [38].
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ACCEPTED MANUSCRIPT Miscellany
Other numerous medicinal plants have been proposed in the treatment of benign prostatic hyperplasia-related symptoms,
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including the following: Zea mays (cornsilk), Allium sativum (garlic), Echinacea Spp., Althea officinalis (marshmallow), Equisetum arvense (horsetail), Lactuca scariola, Asteracantha longifolia, Argyreia speciosa and Parmellia perlata for their
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antimicrobial activity, helpful in preventing the chronic urinary infections [42; 195]; Arctostaphylos uva-ursi (uva-ursi) in the treatment of prostatitis; Opuntia ficus-indica (prickly pear) useful in controlling the prostate enlargement for its antioxidant and
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antiproliferative activities on prostate cells [42, 196]; Curculigo orchioides (black musli) for dysuria and poluria, and in the management of prostatic enlargement [195]; Telfairia occidentalis for the inhibition of hormonal induction of BPH [197]; Mucuna pruriens for its anti-inflammatory capacity in various prostatic affections; Vaccaria segatalis for the ameliorating the
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prostate pathomorphology and prostatic and testicular indexes [198]; etc. These medicinal plants and many others are of growing recent scientific interest [199]. Most of the mentioned herbal remedies are probably more effective for prevention
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and/or for the treatment of BPH-related symptoms, rather than for a direct effect on the prostate gland. Moreover, active
value is still unknown.
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ingredients and biochemical mechanism of action of some of above mentioned plants still need investigation, and their clinical
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An overview of the medicinal plants described in this review is reported in Table 1.
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ACCEPTED MANUSCRIPT Table 1. Medicinal plants used in the treatment of benign prostatic hyperplasia, their mechanism of action, and clinical safety and efficacy (if known). Postulated mechanism/s of
Clinical
(common name)
action
efficacy
Cucurbita pepo
Inhibition of DHT binding to the
(pumpkin, dubba)
androgen receptor
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Botanical name
Safety
+
ND2
ND
ND
ND
ND
++3
Anti-proliferative activity
+/−4
+/−
Pygeum africanum
Inhibition of nuclear translocation
++
++
(prunus africanus, african cherry)
of the androgen receptor
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+1
5alpha-reductase inhibition Radical-scavenger and anti-
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Epilobium Spp. (willow herb)
oxidant activity
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anti-androgenic activity
(african potato, yellow star)
(tomato)
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Lycopersicum esculentum
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Hypoxis roopery
anti-inflammatory activity anti-proliferative activity analgesic property Anti-proliferative activity anti-inflammatory activity radical-scavenger activity Anti-proliferative and proapoptotic activity own-regulation of 5alphareductase anti-oxidant activity anti-inflammatory activity
Pinus pinaster (maritime pine)
inhibition of cell proliferation
25
ACCEPTED MANUSCRIPT pro-apoptotic activity anti-inflammatory activity anti-oxidant activity 5alpha-reductase inhibition
(palm criollo, vakka)
alpha1-adrenoceptors antagonism
ND
ND
ND
++
++
+
+
+
ND
ND
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Roystonea regia
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antioxidant activity
5alpha-reductase inhibition
(common rye, rye pollen)
pro-apoptotic activity
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Secale cereale
alpha-adrenergic receptors block
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anti-inflammatory activity
Serenoa repens
Urtica dioica (stinging nettle, ortiga)
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(sabal serrulata, saw palmetto)
spasmolytic activity 5alpha-reductase inhibition inhibition of DHT binding to androgen receptors anti-inflammatory activity spasmolytic activity anti-proliferative activity sympathomimetic effects alpha1-adrenoceptors antagonism Anti-proliferative activity anti-inflammatory activity inhibition of SHBG inhibition of aromatase
Zea mays (cornsilk), Allium sativum (garlic), Echinacea Spp., Althea
Antimicrobial activity
officinalis (marshmallow), Equisetum arvense (horsetail), Lactuca
anti-oxidant activity
scariola, Asteracantha longifolia, Parmellia perlata, Arctostaphylos
anti-proliferative activity
uva-ursi (uva-ursi), Opuntia ficus-indica (prickly pear), Curculigo
anti-androgenic activity
orchioides (black musli), Telfairia occidentalis, Vaccaria segatalis.
anti-inflammatory activity
26
ACCEPTED MANUSCRIPT 1
: efficacious/safe, 2: not determined, 3: very efficacious and/or very safe, 4: contrasting evidences
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Conclusions and perspective
Depending on the severity of the disease, the various treatment options currently available are: watchful waiting, drug therapy,
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surgery and the use of medicinal plants. Although drug therapy (alpha1-blockers, inhibitors of 5alpha-reductase) and surgery (prostatectomy, transurethral resection, etc.) seem to be the most effective choices for patients with moderate to severe BPH,
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herbal medicine can be useful in patients with mild to moderate symptoms. Medicinal plants most commonly used in BPH are: Serenoa repens Small. (Arecaceae Family), Pygeum africanum Hook (Rosaceae family), Urtica dioica L. (Urticaceae family), Cucurbita pepo L. (Cucurbitaceae family), Epilobium spp. L. (Onagraceae family), Secale cereale L. (Gramineafamily e),
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Hypoxis roopery Moore (Hypoxidaceae family), Roystonea regia Cook (Arecaceae family), Pinus pinaster Sol (Pinaceae family) and Lycopersicum esculentum Mill. (Solanaceae family). The last two medicinal plants are primarily used for their
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extraction products, β-sitosterol and lycopene respectively. Serenoa repens, Pygeum africanum, Curcubita pepo, and Urtica
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dioica are the most prevalent plants used to treat BPH.The various extraction procedures of plant based medicinals, the different drugs used, their mechanism of action (sometimes poorly characterized), make difficult, quite impossible the comparison between the various products. At the same time, whether in vitro or in vivo studies have been reported some pharmacological actions of certain active substances, this does not necessarily mean that the same substances have beneficial effects in the
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clinical practice. However, there is emerging evidence that various plant extracts are well tolerated and allow to obtain an improvement in symptoms of urinary tract BPH-related. S. repens in human studies showes an effectiveness higher than placebo, equivalent to tamsulosin and in combination to U. dioica reveales equal effects to finasteride in improving symptoms of lower urinary tract and with less side effects. Regarding the safety of serenoa, gastrointestinal problems, headache, liver disease, pancreatitis, and sexual dysfunction have been reported. Pygeum africanum as serenoa is registered (at least in Italy) as a phytotherapic medicine, and moderate evidence indicates that its use improves the parameters of the urinary stream. Pygeum seems a safe drug. Urtica dioica shows promising efficacy that is higher if it is taken in combination with other medicinal plants and nutraceuticals such as serenoa, pine, lycopene, etc. The effectiveness of Cucurbita pepo is based on preliminary data and further confirmation is needed, especially related to long-term effects. Pumpkin is safe enough except some evidence which advice against its association with anticoagulants. Because of the lack of clinical trials on the use of various species of Epilobium, no data are currently available on its effectiveness and safety; although in experimental studies they did not induce a
27
ACCEPTED MANUSCRIPT particular toxicity. Secale cereale seems effective in urinary symptoms of BPH, but its effects have to be confirmed by clinical evidence. In relation to its adverse effects abdominal pain, nausea and hypersensitivity , were found. Very limited data are available about the clinical use of Hypoxis roopery and Roystonea regia. Regarding lycopene, recent research confirms its
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ability in the prevention and progression of BPH; the mechanisms of action could possibly be proposed in the prevention of adenocarcinoma. Furthermore, the effectiveness of tomato extract seems higher than that of lycopene alone. The tomato
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consumed in normal quantities of a Mediterranean diet can be considered, in absence of specific allergic symptoms, a safe food. Regarding the associations of plants, they seem more effective than the plants alone; However, the use of multi-component
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products does not play in favor of the safety. Zea mays (cornsilk), Allium sativum (garlic), Echinacea Spp., Althea officinalis (marshmallow), Equisetum arvense (horsetail), Lactuca scariola, Asteracantha longifolia, Parmellia perlata, Arctostaphylos uva-ursi (uva-ursi), Opuntia ficus-indica (prickly pear), Curculigo orchioides (black musli), Telfairia occidentalis, Vaccaria
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segatalis and many other plants are of growing scientific interest in the field of BPH phytotherapy, but nowadays most of them result more effective for prevention and/or for the treatment of BPH-related symptoms, rather than for an effect on prostate
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gland enlargement. However, the effect obtained with drugs (as pure chemicals) is reached at much lower doses than those
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needed to obtain the same effect with the use of a phytocomplex. Moreover, regarding other plants, many products are not standardized and, data relating to their safety are not always available and their clinical efficacy is generally based on a short duration treatment of a small number of patients. It should be also important to remember that in many cases the analytical, pharmacological or clinical markers are unknown, and the effects of some herbal products could be unforeseeable. This
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disadvantage, along with that phytotherapy usually requires at least few weeks before to have any efficacy, should be taken into account in the choice of treatment. In conclusion, because of the impact of BPH symptoms on health and QoL, a greater communication between the patient and his doctor allows to facilitate the diagnosis and to personalize the treatment, and healthcare professionals should try to be constantly informed about the possible risks and benefits of BPH herbal medicine.
Conflict of Interest Statement
The authors declare that there are no conflicts of interest.
Acknowledgements
28
ACCEPTED MANUSCRIPT
This study was supported by the ―Enrico and Enrica Sovena Foundation‖, Rome, Italy.
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[176] M.I. Calvo, S. Akerreta, R.Y. Cavero, Pharmaceutical ethnobotany in the Riverside of Navarra (Iberian Peninsula), J. Ethnopharmacol. 135(1) (2011) 22-33.
[177] J.E. Chrubasik, B.D. Roufogalis, H. Wagner, S. Chrubasik, A comprehensive review on the stinging nettle effect and
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[181] L. Konrad, H.H. Müller, C. Lenz, H. Laubinger, G. Aumüller, J.J. Lichius, Antiproliferative effect on human prostate cancer cells by a stinging nettle root (Urtica dioica) extract, Planta. Med. 66(1) (2000) 44-47. [182] D. Gansser, G. Spiteller, Aromatase inhibitors from Urtica dioica roots, Planta. Med. 61(2) (1995) 138-140. [183] I. Durak, H. Biri, E. Devrim, S. Sözen, A. Avci, Aqueous extract of Urtica dioica makes significant inhibition on adenosine deaminase activity in prostate tissue from patients with prostate cancer, Cancer. Biol. Ther. 3(9) (2004) 855-897. [184] M. El Haouari, M. Bnouham, M. Bendahou, M. Aziz, A. Ziyyat, A. Legssyer, H. Mekhfi, Inhibition of rat platelet aggregation by Urtica dioica leaves extracts, Phytother. Res. 20(7) (2006) 568-572. [185] C.F. Daher, K.G. Baroody, G.M. Baroody, Effect of Urtica dioica extract intake upon blood lipid profile in the rats, Fitoterapia. 77(3) (2006) 183-188. [186] J.J. Lichius, C. Muth, The inhibiting effects of Urtica dioica root extracts on experimentally induced prostatic hyperplasia in the mouse, Planta. Med. 63(4) (1997) 307-310.
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ACCEPTED MANUSCRIPT [187] L.W. Chung, J. Matsuura, A.K. Rocco, T.C. Thompson, G.J. Miller, M.N. Runner, Tissue interactions and prostatic growth: a new mouse model for prostatic hyperplasia, Ann. N. Y. Acad. Sci. 438 (1984) 394-404. [188] A. Nahata, V.K. Dixit, Ameliorative effects of stinging nettle (Urtica dioica) on testosterone-induced prostatic
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[191] N. Lopatkin, A. Sivkov, S. Schläfke, P. Funk, A. Medvedev, U. Engelmann, Efficacy and safety of a combination of
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[194] E.A. Melo, E.B. Bertero, L.A. Rios, D. Mattos Jr., Evaluating the efficiency of a combination of Pygeum africanum and stinging nettle (Urtica dioica) extracts in treating benign prostatic hyperplasia (BPH): double-blind, randomized, placebo controlled trial, Int. Braz. J. Urol. 28(5) (2002) 418-425. [195] R. Jeyaraman, P.S. Patki, Clinical Evaluation of Efficacy and Safety of a Herbal Formulation in Benign Prostatic Hyperplasia: A Single Blind, Randomized, Placebo-Controlled Study, Open. J. Urol. 2 (2012) 157-163. [196] R.A. Chavez-Santoscoy, J.A. Gutierrez-Uribe, S.O. Serna-Saldívar, Phenolic composition, antioxidant capacity and in vitro cancer cell cytotoxicity of nine prickly pear (Opuntia spp.) juices, Plant. Foods. Hum. Nutr. 64(2) (2009) 146-152. [197] C.E. Ejike, L.U. Ezeanyika, Inhibition of the experimental induction of benign prostatic hyperplasia: a possible role for fluted pumpkin (Telfairia occidentalis Hook f.) seeds, Urol. Int. 87(2) (2011) 218-224. [198] H. Zhang, Y. Jing, G. Wu, Inhibitory effects of crude polysaccharides from Semen vaccariae on benign prostatic hyperplasia in mice, J. Ethnopharmacol. 145(2) (2013) 667-669.
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ACCEPTED MANUSCRIPT [199] H. Azimi, A.A. Khakshur, I. Aghdasi, M. Fallah-Tafti, M. Abdollahi, A review of animal and human studies for management of benign prostatic hyperplasia with natural products: perspective of new pharmacological agents, Inflamm.
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Graphical abstract
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S0024-3205(15)00075-2 doi: 10.1016/j.lfs.2015.01.023 LFS 14279
To appear in:
Life Sciences
Received date: Accepted date:
13 November 2014 21 January 2015
Please cite this article as: Allkanjari Olta, Vitalone Annabella, What do we know about phytotherapy of benign prostatic hyperplasia, Life Sciences (2015), doi: 10.1016/j.lfs.2015.01.023
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ACCEPTED MANUSCRIPT What do we know about phytotherapy of benign prostatic hyperplasia Olta Allkanjari1, Annabella Vitalone1 1
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Department of Physiology and Pharmacology - "Sapienza" University, P.le Aldo Moro 5, 00185 Rome, Italy
Corresponding author: Annabella Vitalone, PhD
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Department of Physiology and Pharmacology ―V. Erspamer‖, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome – Italy
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Phone: +39-06-49912904 Fax: +39-06-49912480
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E-mail: [email protected]
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Abstract
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Benign prostatic hyperplasia (BPH) is one of the most common urological diseases in aging men. Because of its long latency, BPH is a good target for prevention. The aim of the study has been to review the various options of treatment, currently available, in the field of phytotherapy. Watchful waiting, pharmacological therapy, and surgery are also helpful, depending on the severity of the disease. Although drug therapy (alpha1-blockers, 5alpha-reductase inhibitors) and surgery (prostatectomy,
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transurethral resection, etc.) seem to be the most effective for patients with moderate-severe BPH, herbal medicines (i.e., Serenoa repens, Pygeum africanum, Urtica dioica) are also commonly used in patients with mild-moderate symptoms. On the basis of preclinical studies several mechanisms of action have been postulated, including 5alpha-reductase inhibition, alphaadrenergic antagonism, dihydrotestoterone and estrogen receptors inhibition. Randomized clinical trials indicate significant efficacy in improving urinary symptoms and mild adverse effects for some of phytotherapeutic agents, while further clinical evidence is needed for others (e.g., Epilobium Spp., Secale cereale, Roystonea regia). Healthcare professionals should be constantly informed about BPH phytotherapy, taking into account the risks/benefits profile of the use of medicinal plants in the management of BPH.
Key words: Benign prostatic hyperplasia, Phytotherapy, Saw palmetto, Clinical efficacy, Safety profile, Review
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ACCEPTED MANUSCRIPT Chemical compounds: β-sitosterol (PubChem CID: 222284); Palmitic acid (PubChem CID: 985); Tamsulosin (PubChem CID: 129211); Finasteride (PubChem CID: 57363); Stigmasterol (PubChem CID: 5280794); Kaempferol (PubChem CID: 5280863); Lycopene (PubChem CID: 446925); Rooperol (PubChem CID: 6438989); N-docosanol
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(PubChem CID: 12620); Selenium (PubChem CID: 6326970).
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Introduction
Benign prostatic hyperplasia (BPH) is one of the most common urological diseases in aging men. It typically develops after the
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age of 40 years and ranges in prevalence from over 50% at 60 years to as high as 90% by 85 years of age. BPH is characterized by high morbidity and low mortality rate, and is considered a public health problem [1, 2]. The BPH natural history can be
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divided into pathological and clinical phase. The first phase is asymptomatic, and occurs at periurethral level with nodular
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hyperplasia [3]. The clinical phase occurs when the enlarged prostate gland compresses the urethra, this results in an increase of urine flow resistance associated with elasticity loss of tensile organ, and sometimes with the presence of inflammation (prostatitis). The condition determines symptoms associated with a clinical picture named "prostatism" [4] that is characterized by dynamic and static components. The first one affects stromal tissue and it is due to an increase of the smooth muscle tone of
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the bladder neck and of prostate stromal portion. The alpha1-receptors seem to be the mediators of this process. The obstructive symptoms induced by the dynamic component are terminal dribbling, sense of incomplete bladder emptying due to urinary retention, decreased force of the stream, urinary hesitancy or urinary flow intermittency. The other factor of the clinical phase (i.e., static component) involves the epithelial tissue which is affected by androgen-induced proliferation leading to prostate hypertrophy. The irritative symptoms caused by the static component are nocturia, incontinence, hematuria, urgency and increased frequency of voiding acts [5]. The symptoms described above can lead to anxiety, sleep disturbance [6], reduced mobility, difficulty in sexual relations and a compromised feeling of well-being, resulting in interruption of work and social activities, with a negative impact on the quality of life (QoL) [7]. The origin of BPH is not clearly defined. Three theories have been proposed to explain the causes of BPH development. The first one is based on the role of androgens, estrogens and growth factors. The prostate cells are able to convert about 90% of testosterone (TE) to dihydrotestosterone (DHT) by 5alpha-reductase. The latter binds to androgen receptors with higher affinity
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ACCEPTED MANUSCRIPT than TE, and it appears to act directly by stimulating protein synthesis, differentiation and prostate cell growth [8, 9]. DHT accumulates in prostate even when TE levels are low [10]. The binding of DHT to its receptor further stimulates the transcription and transduction of DNA specific segments, coding for growth factors (e.g., epidermal growth factor – EGF;
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insulin like growth factor – IGF; growth cheratinocitic factor), leading to an abnormal prostate cells proliferation [11]. Moreover, estrogens act in synergy with androgens in the development of BPH. Particularly, it has been observed an increase in
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the expression of aromatase (enzyme that catalyzes the peripheral conversion of androgens into estrogens) and estrogen receptors at the transition zone of hypertrophic prostate tissue [12]. The second postulate about BPH development is based on
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the presence of a small percentage of prostate cells androgen-independent that can self-renew in androgen-deficient conditions [3]. The third theory concerns the interactions between stroma and epithelium. Both of them are able to convert TE into DHT, allowing the production of various growth factors (fibroblast growth factor – FGF; endothelin-1 - ET1; transforming growth
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factor - TGF-β1; etc.), responsible of modulation, proliferation, apoptosis and secretory activity of both stromal (autocrine transmission) and epithelial portions (paracrine secretion) [3, 13, 14].
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In the pathogenesis of BPH some risk factors should also be taken into account, since this disease is more common in patients
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from North America and Europe, with large baseline prostate, with positive family history [15], and with previous inflammation of the prostate gland. Prostatitis, as well as oxidative stress, stimulates the inflammatory cascade associated with nuclear factor kappa-B (NF-ĸB), inducible nitric oxide synthase (iNOS), and 5-lipoxigenase (5-LOX) activation, cyclossigenase-2 (COX-2) over-expression, and cytokines and leukotrienes production [16].
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Therapeutic approaches currently available for the treatment of BPH consist in: watchful waiting, surgery, pharmacological therapy and the use of medicinal plants. The choice of treatment should be decided together with the patient and should be individualized, according to his personal preference and to the disease severity [17]. The main aim is to relieve symptoms and to improve patient’s QoL.
The watchful waiting (i.e., periodic revaluations of clinical conditions) and some changes in lifestyle is recommended for patients with mild symptoms who are not at risk of acute urinary retention [18]. In case of worsening of symptoms and as the post-void residual volume increases, pharmacological therapies are proposed. The two main classes of drugs are alpha1antagonists (prazosin, doxazosin, terazosin, alfuzosin, tamsulosin, silodosin) and 5alpha-reductase inhibitors (finasteride, dutasteride), often effectively used in combination as a recommended option for the treatment of patients at risk of BPH progression [19]. The target of alpha1-adrenergic antagonists is the dynamic component and they are considered as the mainstay of therapy [20]. The alpha1-blockers increase the volume and the stream force, improving symptoms and consequently
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ACCEPTED MANUSCRIPT patient’s QoL. The most common side effects are dizziness, tachycardia, postural hypotension [21], retrograde ejaculation (reversible after discontinuation of therapy) [19, 22]. The 5alpha-reductase inhibitors reduce the static component causing androgens reduction. They are more effective in patients with a significant enlargement of the prostate gland [23]. The use of
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finasteride increases the stream of urine and reduces BPH-related symptoms [24]. However, it causes numerous side effects as decreased libido, decreased volume of ejaculate, impotence and skin rash. Cases of gynecomastia have been also reported [25].
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The antimuscarinic drugs (tolterodine, fesoterodine) may also be used, in association with the two previous mentioned drugs classes, in severe conditions related to storage symptoms [22]. A more recent long-term pharmacological treatment of BPH of
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moderate degree consists in prostate antigen-specific antibodies (known as afala). This preparation promptly and effectively reduces irritative and obstructive symptoms and post-void residual volume, while increase urine flow [26]. Other recent and, in some cases, promising pharmacological therapies include the use of: 3-agonist (i.e., mirabegron); the association of 5-
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phosphodiesterase inhibitors (i.e., tadalafil) and alpha1-adrenergic antagonists; lonidamine (capable of inhibiting glycolysis and of causing cell apoptosis) and botulinum neurotoxin [27, 28, 29]. The latter approach, consisting in the intraprostatic injection
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of patients with urologic conditions [30].
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of botulinum toxin, is still of doubtful efficacy and safety and further studies are needed to determine its use in the management
In the worst cases of symptomatic BPH, invasive surgery (open prostatectomy - OP) or minimally invasive procedures (transurethral resection, transurethral microwave thermotherapy, laser ablation endoscopic, etc.) may be required. The type of surgery is based on the size of the prostate, the presence of painful symptoms and/or other concomitant diseases. OP is
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considered as the most effective as well as the most invasive procedure [5]. The incidence of its complications can range from retrograde ejaculation (81%) to urinary tract infections (3%) [31]. In recent years, the transurethral resection of the prostate (TURP) has become the ―gold standard‖ in patients with BPH, because this surgical approach allows obtaining an immediate removal of the obstruction and long-term improvement of the symptoms. However, also this procedure has been associated with side effects (e.g., incontinence, impotence, hemorrhages. The latter could be obviated by the use of intermittent clotting) [32]. Other minimally invasive procedures that improve the symptoms quickly and have a good cost/efficacy have been developed and the most practiced included the following: transurethral incision of the prostate (TUIP) that reduced the urethral compression and it is recommended when the gland weight is about 30 grams; transurethral electrovaporization of the prostate (TUVP) that represents a TURP modifications, consisting in the distruction of the hypertrophic prostate tissue; transurethral microwave therapy (TUMP), transurethral needle ablation (TUNA), and various types of endoscopic ablation by laser (ELAP). All of the above mentioned approaches are, in different extent, responsible for side effects such as: ineffectiveness or failure in
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ACCEPTED MANUSCRIPT the short term, high incidence of complications, need for a prolonged cauterizationtent, retrograde ejaculation, etc [32]. Because of many side effects of drug therapy and surgical procedures, and since the high morbidity and the long latency of BPH make it a good target for prevention [32], herbal medicines (also know as botanicals) are becoming a popular option in the
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treatment of this disease. Herbal products are usually derived from roots, berries or fruits of various plants, and are commercialized as extracts, that contain a wide range of chemical compounds (e.g., phytosterols, fatty acids, flavonoids). The
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most commonly used herbal remedies for mild-moderate BPH are Serenoa repens fruit extracts and Pygeum africanum bark extract [33, 34]. The herbal treatments generally show a great tolerance and plural numbers of action sites, many of which are in
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common with drugs such 5alpha-reductase inhibitors and alpha1-receptors antagonists. Many of herbal products currently used for BPH are sold in health food stores and are often, but not always, available as dietary supplement without medical prescription [32]. In particular, in the United States medicinal plants are regulated by the Dietary Supplement Health and
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Education Act as dietary supplements and are usually available without medical prescription [35]. In Italy, some of these herbal preparations are also registered as drugs and required prescription. In Germany and Austria, phytotherapy is the first-line
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treatment of mild to moderate urinary symptoms and represents more than 90% of all drugs prescribed for BPH treatment [36].
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Phytotherapy is generally less used in other countries, including Ireland, UK, Denmark, Norway, Finland, Sweden, Italy, Greece and Portugal. On the contrary, the number of phytotherapeutic prescriptions is particularly high in Belgium [37]. This review summarizes the preclinical and clinical evidences of the medicinal plants most widely used in the treatment of
Cucurbita pepo
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BPH. Particular attention was also devoted to the safety profile.
Cucurbita pepo L. belongs to the Cucurbitaceae family. It is an annual herbaceous plant native of South-central America, also known as pumpkin or Dubba. In traditional medicine, the oil of pumpkin seeds has been used for its antioxidant and antiinflammatory actions in the treatment of BPH and its urinary related problems [38].
Preclinical studies The chemical composition of pumpkin seeds consists of alpha-tocopherol, proteins, carbohydrates, fatty acids (palmitic, stearic, oleic and linoleic), non essential aminoacids (cucurbitine) and Δ5-Δ7-Δ8-phytosterols (including sitosterol, stigmasterol, etc.) [38, 39]. The Δ7-sterols have a chemical structure similar to DHT and can competitively inhibit the binding of DHT to its
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ACCEPTED MANUSCRIPT receptors. However, the active ingredient has not been yet identified and the data related to the mechanism of action are limited and not conclusive. Some studies carried out in rats show that pumpkin seeds extract can block the increase of prostate weight and protein synthesis induced by testosterone/prazosin [40], inhibiting testosterone-induced hypertrophy [41], and improves the
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function of the bladder (i.e tonic action, sphincter relax action) and urethra [42, 43]. The mechanism of action of pumpkin seed
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oil is supposed to be the 5alpha-reductase inhibition [41].
Clinical studies
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From a multicenter clinical trial conducted on thousands of patients with BPH treated with capsules of pumpkin seeds extract (500 mg), there was a decrease in the International Prostate Symptoms Score (IPSS) and an improvement of QoL [44]. A significant decrease in the levels of DHT, and a significant improvement in BPH urinary flow symptoms (i.e., time of the
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bladder emptying, residual volume, daily frequency of urination and nocturia) were also found in patients using a combination of pumpkin seeds and Serenoa repens [38]. This association (320 mg/day of each medicinal plant) was also effective in
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prostatic Korean patients in the amelioration of IPSS, QoL, PSA serum levels and maximum urine flow, while there were no
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differences in the prostate volume [45]. Other more recent multiple association involves the use of C. pepo seed oil (160 mg), Epilobium parviflorum extract (500 mg of dry herb), lycopene (2.1 mg), Pygeum africanum (15 g of dry stem) and Serenoa repens (660 mg of dry leaf). This herbal preparation, during three months of treatment, induces a significant reduction in IPSS, and day-and night time urinary frequency, in patients who presented medically diagnosed BPH [46]. However, further studies
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to confirm the efficacy of Cucurbita pepo in the treatment of BPH are needed. Regarding the safety of this plant, there is not indication of serious side effects, though it could be responsible of mild gastrointestinal problems (e.g., indigestion, diarrhea) [42], electrolytes loss (possibly due to its diuretic properties) [47], and alteration of International Normalized Ratio (INR, an indicator of prothrombin time). The last effect makes cucurbita contraindicated in case of anticoagulants concomitant therapies [38].
Epilobium spp.
Epilobium L. is a perennial herbaceous plant that belongs to the Onagraceae family. It consists of more than 200 species distributed in Europe, Asia, Africa, Australia, America, Tasmania and New Zealand [38]. The most common species include E. parviflorum, E. hirsutum, E. rosmarinifolium and E. angustifolium (commonly known as Willow herb). The part of the plant
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ACCEPTED MANUSCRIPT commonly used in various products is derived from the aerial flowered one. Traditional medicines consider the willow herb useful for fever, rheumatic complications, headache, and as a general pain releif, even if such uses are not supported by
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scientific evidence [38].
Preclinical studies
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The various species of this family are rich in flavonoids (myricitrin, isoquercitrin, quercitrin, guaiaverin, quercetin-3-O-β-Dglucuronide, etc.), dimeric macrocyclic ellagitannins (oenothein A and B) and sterols (β-sitosterol and its esters) [48, 49]. The
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common element in the various species of Epilobium is the presence of oenothein B which seems to play an important role in the inhibition of DNA synthesis, although other components may contribute to this effect [50]. The commercial Epilobium contained products, usually, consist on different plant species associations, so that the pharmacological standardization of this
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plant remains difficult. A study carried out by Bazylko et al. [51] has developed a simple, fast and selective method for the separation and quantitative determination of oenothein B and quercetin glucuronide of the E. angustifolium aqueous extract.
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Several studies confirm that the main tannic component of E. parviflorum is oenothein B, while the main flavonoid is myricitrin
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(myricitin-3-O-ramnoside). It was also found the presence of caffeic, chlorogenic, ellagic and gallic acid derivatives, myricitrin, quercitrin, kaempferol and their glycosides [52]. Epilobium is one of the various medicinal plants used in the treatment of BPH, although the exact mechanism of action has not yet been clarified. The activities observed in experimental studies consist in: high radical-scavenger, antioxidant activity [53], anti-inflammatory effect, analgesic property, anti-proliferative effect,
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inhibition of the activity of hyaluronidase and myeloperoxidase, lipoxygenase release possibly due to oenothein B content, and inhibitory effect on aromatase and 5alpha-reductase type 2 enzymes [49, 50, 54, 55]. The radical-scavenger and antioxidant activities have been found for both ethanol and aqueous extract of E. parviflorum; these were high (greater than that of Trolox® and ascorbic acid, used as positive controls), dose-dependent, and seem to be due to the presence of flavonoids [56]. The same finding was confirmed by other studies also for other Epilobium species [53, 57]. Regarding the anti-inflammatory activity, a potent inhibition of COX-1 and COX-2 has been found in vitro for the ethanolic (rather than aqueous) extract of E. parviflorum [56]. Furthermore, in vivo study on carrageenan-induced rat paw edema has been confirmed the high anti-inflammatory property, probably due to the inhibition of prostaglandin synthesis [58]. As regard the antiproliferative effect, an aspecific effect on the inhibition of cell proliferation has been found for various Epilobium species (E. angustifolium, rosmarinifolium, tetragonum) [50, 59]. This activity appeared to be related to interference on cell cycle progression from G0 to G1 phase, rather than to a cytotoxic effect [60]. Other results that may offer an explanation of the pharmacological use of willow herb in
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ACCEPTED MANUSCRIPT traditional medicine have shown an inhibition of 5alpha-reductase [61] and the induction of neutral endopeptidase (NEP) in prostate cells [59]. Moreover, antitumor activity due to the immune response enhancement mediated by the macrophages
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activation was found [62]. All of the previous mentioned activities indicate a key role of oenothein B [50, 59, 61, 62].
Clinical studies
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Although all the preclinical results could support the traditional use of different species of Epilobium for the treatment of BPH, and this plant is widely present in dietary supplements and cosmetic products used against androgenetic alopecia, further
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researches are needed. In particular those regarding the inhibition of prostatic cell proliferation, the anti-androgenic, antiinflammatory and analgesic properties that may be useful in the treatment of symptoms associated with BPH. In the literature, as previously discussed (see Section 3.2), there is only one clinical study regarding Epilobium parviflorum, used in association
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with various medicinal plants [46], whereas there are no published data regarding clinical efficacy and safety of Epilobium spp. used alone. However, although the lack of human studies, Epilobium extracts appear to be harmless to animals, but this data
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cannot be directly traduced in terms of clinical evidence [49].
Hypoxis roopery
Hypoxis roopery Moore belongs to the Hypoxidaceae (Amaryllidaceae) family. This is a perennial herbaceous plant native of
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South-East African regions, particularly of Kiwazulu Natal and of Transkei. It is also known as Hypoxis hemerocallidea, African potato or yellow star. The part of the plant usually used is made from a dark brown or black tuber which presents a yellow pulp [43]. Hypoxis roopery is traditionally known as a ―miracle‖ medicinal plant because it has been used for a wide array of human aliments, including cancers, diabetes, infections, nervous disorders, immune-related illnesses, heart weaknesses and urinary tract infections [63].
Preclinical studies The tuber contains mainly sterols (β-sitosterol and β-sitosterol glycoside), polysaccharides and lignans (mainly hypoxoside that should be converted to rooperol, its biologically active glycone) [38, 64]. The pharmacological effects of Hypoxis could be attributed to sterols [43]. In particular, β-sitosterol seems responsible for the increase of TGF- β1 expression and protein kinase C-alpha activity, in the stromal cells of human prostate [43]. However, this specific effect doesn’t appear clinically relevant in
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ACCEPTED MANUSCRIPT vivo, though it has been found an improvement of BPH related symptoms (post-void residual volume, increase of urine flow) [65]. The mechanism of action of this herb is not well known. From preclinical studies it doesn’t seem to inhibit 5alphareductase [66]. In vitro, rooperol has been shown to have anti-inflammatory activity, by inhibiting the cytokine production,
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COX-1 and COX-2 activity (ethanolic extract appared to be more potent than the aqueous one), by reducing the activity of transcription factors [56], and it might interfere with the synthesis of inflammatory mediators, such as prostaglandins [42, 67,
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68]. The antinflammatory effect was also recently confirmed at intestinal level, in mice, by an inhibition of epithelial cells proliferation and by a reduction in the expression of NF-ĸB in the colonic mucosa [69]. It has also been shown to have radical
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scavenger activity (that was equal for both ethanolic and acqueous extracts) [56]. As regards the safety of hypoxis extract, an in vivo study in mice, treated with 2000 mg/kg of hypoxis for 2 weeks, did not show any toxicity on various vital organs (brain, heart, lungs, liver, spleen, kidney and intestine), also confirmed at hystomorphological level [68]. On the other hand, the
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possibility of a negative interaction of Hypoxis with various isoforms of CYP450 (i.e., CYP1A2, 2A6, 2B6, 2C8, 2C9, 3A4 and 3A5) should be kept in mind. Indeed, the inhibition of presystemic metabolism could be achieved in the gastrointestinal tract
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when traditional doses of Hypoxis are taken [70].
Clinical studies
There is not enough data about the efficacy and safety of H. roopery. Clinical evaluations compared with placebo after 6 months of treatment with the whole plant extract, reported an increase in urinary flow, significant improvement in subjective
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complications, and a decreased post-void residual volume in patients with BPH [38]. Improvements in the IPSS score, with mild and infrequent adverse events were also found [71]. Those affect gastrointestinal (i.e., nausea, diarrhea) and cardiovascular (i.e., ventricular tachycardia) systems, and appear to be due to hypoxoside and rooperol, respectively [72]. In the recent years, the entire extract, phytosterols and other constituents of Hypoxis are finding new applications in the antioxidants, antiinflammatory, anti-diabetic, and anti-convulsionant fields [73].
Lycopersicum esculentum
Lycopersicum esculentum Mill. (also known as Solanum lycopersicum L.) belongs to the Solanaceae family.The tomato is an annual herbaceous plant that is native of the area between Mexico and Peru. It is commonly used as a food (tomato-based food:
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ACCEPTED MANUSCRIPT tomato paste, tomato sauce, tomato soups, etc.). Generally the tomatoes fruit and tomato-based products provide to the human body about 85% of lycopene, while the remaining 15% is obtained usually from the consumption of watermelon, apricot, peach,
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papaya and red berries [74].
Preclinical studies
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Lycopersicum esculentum contains glycoalkaloids (alpha-Tomatine), salicylates, flavones (apigenin and luteolin), polyphenolic compounds (quercetin, myricetin, kaempferol, naringenin and chlorogenic acid) and other carotenoids (phytoene and
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phytofluene) [75]. All green parts are toxic, as they contain solanine, a steroidal glicoalcaloid, which is not eliminated even by cooking processes. The ripe fruit is rich in nutrients, among which aminoacids, minerals (e.g., potassium), vitamins (A, B, C, D, E, K, and folate). A substance that has generated great interest among researchers is a polyunsaturated long-chain acyclic
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carotenoid, which is called lycopene. It contains 11 conjugated double bonds, linearly arranged in the trans configuration [76], while most of the lycopene that has been found in the prostate tissue has cys conformation [77]. The cys form is preferentially
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captured by benign and malignant prostate tissue and it is produced during cooking [77]. As lycopene has been correlated with
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a low frequency of adenocarcinoma [78], from 2003 was added to most multivitamins products as an agent for the prevention of cancer and has become the most commonly used carotenoid, among men of 45-65 years old [79]. In addition to lycopene, tomato contains lycopene cyclase (the enzyme that catalyzes the conversion of lycopene to β-carotene). The number of the mechanisms of action that have been proposed for the control of adenocarcinoma, as well as adenoma, is various, including:
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inhibition of growth factors-induced cell proliferation, interfereces in the progression of the cell cycle from G0/G1 to S phase, modulation of COX pathway, down-regulation of 5alpha-reductase type 1, pro-apoptotic activity (potentially due to alphatomatine) [80], inhibition of the synthesis of androgen receptor (which leads to a PSA reduction), and antioxidant activity [74, 76, 77, 78, 81]. The latter property consists in the high capacity of lycopene (compared to other carotenoids) to capture oxygen radicals otherwise responsible of DNA damage [76]. Other substances involved in the antioxidant effect are the tomato aglycone polyphenols (quercetin, naringenin and kaempferol), responsible also for the anticarcinogenic effects and the inhibition of cell proliferation, in a dose-dependent manner [77]. In vivo results indicated conflicting evidence related to the effect of tomato (or pure lycopene) on the reduction of plasmatic testosterone level. This could be explained by the duration of treatment, the differences in animal species or in the lycopene content [82]. However, as experimental studies indicate that the tomato extract is more effective in inhibiting carcinogenesis
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ACCEPTED MANUSCRIPT than lycopene alone, [83], this carotenoid does not appeared to be the only constituent of tomato to have effects on prostate [75]. In vivo pre-clinical assessment of lycopene showed good safety profile with a LD50 greater than 5000 mg/kg of body weight,
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and no acute dermal toxicity up to 2000 mg/kg of body weight. Those doses are about 300 times higher than those usually consumed in human [84]. Indeed, it was estimated a consumption of daily amount of lycopene about 8 mg [84], with benefits
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that become evident at approximately 7-35 mg/day [85, 86].
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Clinical studies
Regarding the clinical efficacy of tomato juice and in particular lycopene, a decrease in blood levels of PSA and in oxidative DNA damage, and an increase of cell apoptosis in patients with adenocarcinoma have been found [85, 87, 88]. To reach these
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effects, lycopene should be taken (at an average of 15 mg/day) for 3-6 months [88]. A good efficacy of low doses of lycopene (5 mg/day) was also found when this is associated with Serenoa repens [89].Common adverse effects induced by diet
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containing tomato products riched in lycopene are mild and reversible after discontinuation of therapy, and consist in
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gastrointestinal problems (dyspepsia, flatulence, etc.) [87] and dermatologic effects (itchy skin, etc.). In this context, should be hightlight that chronic exposure to high doses of tomato products can induce licopenemia, a reversible alteration consisting in yellow-orange skin discoloration. This adverse effect could be also associated with fatty hepatic cysts due to deposits of lycopene, which can cause abdominal pain and morphological and histological changes of liver parenchyma [84, 90].
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The Scientific Committee on Food of the European Commission has considered unacceptable the use as a food of lycopene synthetic preparations, because of their high sensitivity to oxygen and light, which form degradation products with mutagenic activity [74]. Moreover, lycopene induces phase І and ІІ metabolism enzymes and, even if helpful for the elimination from the body of carcinogens and toxins, particular attention must be devoted to concomitant use of pharmaceutical products [74]. In conclusion, though the data is very encouraging, the use of lycopene in the prevention or treatment of prostatic diseases is still premature.
Pinus pinaster
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ACCEPTED MANUSCRIPT Pinus pinaster Sol. belongs to the Pinaceae family. It is also known as the Maritime pine and lives spontaneously in the Western Mediterranean basin. The parts commonly used are gems, twigs and resin, from which the essential yellow oil with characteristic smell and resinous taste could be obtained, by distillation in steam.
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Preclinical studies The essential oil contains alpha-and beta-pinene with antiseptic properties, esters of borneol, d-limonene, aldehydes, oleoresin
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(or turpentine) that by distillation provides turpentine and rosin resin which is a transparent solid. It also contains diterpenes, coumarins and flavonoids. The needles are rich in vitamin C and flavonoids. The main and active component is the β-sitosterol,
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with chemical structure similar to that of cholesterol, which is also commonly found in legumes and vegetables and in particular in plants like Hypoxis, Pygeum or other genus. In vitro experiments have shown the effectiveness of β-sitosterol in inhibiting
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prostate cell proliferation [91, 92].
Clinical studies
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A randomized, double-blind and placebo study was conducted to evaluate the efficacy and safety of β-sitosterol (130 mg/day,
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for 6 months). In treated patients there was a significant improvement in the quality of life, in post-void residual volume, in the IPSS and in Qmax [91]. A systematic review also found a significant improvement of the urinary symptoms due to β-sitosterol [93]. Other authors have reported contradictory results regarding the efficacy of β-sitosterol, also in association with other plants and sustances, where a slight improvement was found though not statistically significant, therefore further clinical studies
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are needed [94]. The side effects induced by β-sitosterol are generally mild; however, impotence and gastrointestinal problems are presented to a greater extent compared to patients in the placebo group [93, 17].
Pygeum africanum
Pygeum africanum Hook belongs to the Rosaceae family. It is an evergreen tree native of the Central and South America mountains, the Madagascar and Comoros islands and the Gulf of Guinea. This plant is known even as: African Plum, Prunus africana, African cherry. Prunus africana is the only member of the genus widespread on the African continent and may be chemically distinctive. The major exporters of its bark (the part of the plant used) include Cameroon, Madagascar, Equatorial Guinea, and Kenya [95]. Young trees have smooth, reddish bark whereas older trees have dark, resinous bark with an intense smell of hydrocianic acid. It has the rare ability to regenerate its bark, as long as the vascular cambium is not destroyed [95, 96].
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Preclinical studies Pygeum africanum composition consists of phytosterols (β-sitosterol, β-sitosteryl glucoside, β-sitostenone), fatty acids,
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triterpenoid pentacyclic acids (ursolic, oleanolic and their homologs), alcohols (n-docosanol and its derivatives), esters of ferulic acid, linear acetogenins, nonacosane, entriacontane, glucopyranosyl ester of benzoic acid and β-D-glucopyranoside of
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diphenyl methyl alcohol, lignan isolariciresinol-9-hydroxy-7,8-dimethyl ether and proanthocyanidins [43, 97]. Two other important costituents isolated from the bark of Pygeum are N-butylbenzensolfonamide (NBBS) with anti-androgenic activity,
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and atraric acid, which mechanism of action is to inactivate the androgen receptor by inhibiting its nuclear translocation [98]. Pygeum inhibits the androgen and progesterone receptors, but not those of the glucocorticoids and estrogens; it inhibits the endogenous PSA expression and the prostate cancer cells growth [98]. Furthermore, the isolation of derivatives of docosanol
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from other plants (e.g,. Myoschilos oblongum), but also present in pygeum, has contribuited to highlight the inhibition of cell proliferation of human prostatic cells [99]. To confirm this mechanism of action, other studies evidenced a downregulation of
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TGF-β1 expression, and an inhibition of the proliferation of human prostatic fibroblasts and myofibroblasts [100]. Its
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antiproliferative effect has been demostrated also in rats through treatment with Tadenan® (Pygeum africanum extract), before and after administration of DHT [101]. Other studies performed with Tadenan® support the hypothesis that it might prevent the activation of metabolizing enzymes (or the formation of free radicals) or protect intracellular membranes against the destructive effects of free radicals reducing significantly the severity of both urinary bladder dysfunctions [43, 102].
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In animal models, pygeum regenerates the secretory activity of the prostate epithelium, modulates the contractility of the bladder and has anti-inflammatory activity related to the inhibition of 5-lipoxygenase, with a consequent decrease of leukotrienes production and other 5-lipoxygenase metabolites [103]. The anti-phlogistic action of pygeum could partially depend on its ability to reduce the number of neutrophils and the TGF-β expression in these cells [104]. Finally, Pygeum africanum has been demostrating in vivo a significant reduction of the incidence of prostate cancer, providing a preliminary evidence of its use as a supplement in persons who have a high risk to develop prostate cancer [105].
Clinical studies Pygeum africanum extract taken at daily dose of 100-200 mg, for about 1-2 months, improves significantly urinary symptoms (nocturia, frequency of micturition, etc.), flow parameters (i.e., maximum urinary flow rate and post-void residual urine), spermogram, the IPSS and consequently the QoL [106,107,108,109]. These benefits seem to remain almost unchanged even
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ACCEPTED MANUSCRIPT after 30 days of treatment, indicating a persistent clinical activity with a long term benefits [107]. It is also estabilished that single or fractionated dose of 100 mg/day are equivalent [109]. Regarding the effects of Pygeum africanum lipid-sterol extract on the gland size, there are conflicting results indicating its reduction [106, 107].
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Despite the different works mentioned above, a meta-analysis assessed that clinical trials of pygeum are of short duration, performed on very small groups of patients [110], and have often been conducted with different evaluation methods and on
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different extracts. However, it indicates that this drug is significantly more effective than placebo in relieving the symptoms of BPH patients. Further clinical trials are needed on a single type of standardized extract, for longer time and with validated
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methods in order to obtain conclusive information [111]. It has been reported that Pygeum africanum compared to watchful waiting, seems to improve significantly the urologic symptoms, and might be equally effective to Serenoa repens [17]. No information about the prevention of BPH long-term complications (such as acute urinary retention, renal failure or the need for
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surgery) has been reported. Finally, all clinical studies have concluded that pygeum-induced adverse effects are mild and comparable to placebo in frequency and type [107, 108, 111], and consisted in gastrointestinal problems (diarrhea, abdominal
Roystonea regia
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pain, constipation, nausea) and headache [43].
Roystonea regia Cook is a palm tree that belongs to the Arecaceae family. It is native of South Florida, Mexico and parts of
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Central America. In Cuba, it is also called palm criollo, while in India, where it is widely cultivated, is called Vakka [112]. The drug used for BPH is constituted by its mature fruits.
Preclinical studies
The extracts from its fruits contain a mixture of free fatty acids (oleic, lauric, palmitic and myristic acids in abundance), also known as D-004. Other acids (caprylic, capric, palmitoleic, stearic, linoleic and linolenic acids) are also found in lower concentrations. Preclinical studies have shown that the lipid extract of D-004 produced antioxidant effects in prostate tissue [113], inhibits competitively the prostatic 5alpha-reductase [114] and the simpatic-induced contraction of smooth muscle in ratisolated deferens tube [115]. In vivo studies have shown that oral treatment for 14 days with the lipid extract of Roystonea regia fruits could prevent and improve benign prostatic hyperplasia induced by testosterone, in rats. Experimental data indicate an antagonism of alpha1-adrenoceptors, and a decrease of prostate enlargement that seems dose-dependent and more efficient than
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ACCEPTED MANUSCRIPT that obtained with Serenoa repens, but largely less effective than tamsulosin [116,117,118]. On the other hand, the combination of D-004 and tamsulosin has been resulted much more effective (71%) than each of the monotherapies (57%) in preventing the urodynamic changes induced by phenylephrine in rats [119]. However, the mechanism leading to these effects requires further
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studies.
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Clinical studies
It is not yet possible to attribute to Roystonea clinical efficacy, even if the family to which it belongs and the antagonism of
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alpha1-adrenoceptors offer good basis for further studies. A randomized, double-blind study on healthy volunteers indicated a significant antioxidant effect on plasmatic oxidative markers of D-004 (320 mg/day), taken for 6 weeks [120]. Informations in
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the literature concerning the safety of Roystonea are currently very limited; only 2 cases of dyspepsia were reported [120].
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Secale cereale
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Secale cereale L. is an annual or biannual herbaceous plant that belongs to the Graminaceae family and is widespread in temperate zones. It is also known by the names of rye, common rye and rye pollen. The drug is made from the pollen and the extract is obtained from a microbial digestion of pollen of various plants, especially from Secale cereale from Sweden and
Preclinical studies
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Switzerland. The extraction process involves the sequential use of water and organic solvents [43].
The common presence of proteins, carbohydrates, vitamins, minerals and β-sterols (in the acetone-soluble fraction) has been reported [121], however the active ingredient is still not known. Moreover, the composition of commercial products (tablets and capsules) is highly variable, making it difficult to interpret the results. One of the most famous products, used by millions of people, prepared from the Secale cereale pollen extract is Cernilton® (each dose is standardized in 60 mg of cernitina T60 water soluble fraction, and 3 mg of Cernitina GBX - acetone soluble fraction). It is registered as herbal drug throughout Western Europe (i.e., Switzerland, Austria, Germany, Spain, Greece), Japan, Korea and Argentina; while in the U.S. is used as a dietary supplement. Several mechanisms of action have been proposed for pollen extracts, including: relaxation of urethral sphincteric smooth muscle tone [122], increase of the bladder muscles contraction [123], increase of the apoptosis in epithelial cells of prostate gland, inhibition of the 5alpha-reductase, increase of the serum and prostatic levels of zinc, the block of the
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ACCEPTED MANUSCRIPT alpha-adrenergic receptors, inhibition of prostaglandins and leukotrienes biosynthesis [43]. From an in vivo study, it has been suggested that a therapy with Secale cereale pollen extract may retard the growth of prostate cancer by increased apoptosis of
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tumor cells in animal models [124], but it can’t yet be recommended as a successful treatment for prostate disorders.
Clinical studies
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The pollen of Secale cereale seems useful in relieving urinary symptoms of BPH and prostatitis, but the improvement is modest and the evidence is limited [42, 93]. Two systematic reviews have compared the activity of Cernilton® with placebo or other
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types of herbal preparations used in BPH. A modest and subjective improvement in urologic symptoms was found when pollen is used for 24 weeks. However, it did not improve urinary flow, prostate size or the residual urine volume compared with placebo [43,125]. Although results suggest that Cernilton offers modest benefits to patients with BPH, the studies evaluated in
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this review were limited by several factors, as reported below [126,127]. The duration of treatment was short (i.e., 24 weeks). The dosages of Cernilton® have not been reported in all of these studies and the standardization of the preparation is unknown.
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Other studies, that have evaluated the clinical efficacy and safety of pollen extract, have suggested that it is well tolerated and
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improves modestly all urologic symptoms including nocturia. However, the administration of tamsulosin hydrochloride alone and in combination with pollen extract appeared more effective than the administration of pollen extract alone, in patients with urinary symptoms associated with BPH [128]. The long-term efficacy, safety and the capacity of Secale cereale pollen extract to prevent the complications of BPH are not known. One recent randomized clinical trial indicated that the long-term
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administration of 750 mg of Cernilton (Prostate®) may improve the symptoms of BPH and prevent its clinical progression better and faster than only 375 mg of the same product [129]. A total of 240 patients who presented a value of IPSS greater than 7, were treated orally with 750 mg of Prostate® (Cernilton) the first year and 375 mg for the next three. After the first year of treatment with Cernilton, the volume of the prostate, the incidence of urinary retention and the need of surgery were reduced. On the other hand, many other parameters (i.e., IPSS, prostate volume, residual urine, post-urination, Qmax) improved only after 4 years of treatment [129]. However, no adverse effects were observed. A previous multi-center, randomized clinical trial conducted versus placebo in 906 patients with BPH, have highlighted that, after 6 months of treatment, Cernilton® has the same efficacy of alpha1-antagonists and 5alpha-reductase inhibitors in improving IPSS, QoL, Qmax and residual urine. This effect was greater in patients with a high IPSS baseline. Conversly, Cernilton® was less effective than 5alpha-reductase inhibitors in the reduction of prostate size [130]. The pollen extract is also efficacious in men with inflammatory prostatitis and chronic pelvic pain syndrome in improving total symptoms, pain and QoL, without significant side effects [131]. Common side effects
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ACCEPTED MANUSCRIPT in using pollen exctracts are of allergic type, including respiratory reactions, skin hypersensitivity, and gastrointestinal symptoms [42, 93].
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Serenoa repens
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Serenoa repens Small. is a small palm, of the Aricaceae family. It is also known as Sabal serrulata, saw palmetto, Ju-zhong, Dwarf palm. Its habitat is in the West India and in the Southeastern part of the United States, especially in South Carolina,
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Florida, and Southern California. The drug consists of the dried ripe fruits; these drupes of soapy and unpleasant taste are similar to black olives of which, in therapy, is used the lyposterolic extract. Traditional medicine describes the use of dwarf palm since 1800 for the treatment of variety problems of the prostate and, without any scientific evidences, for other indications
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including breast enlargement, sperm production, and sexual potency [132]. From the twentieth century, the fruit of Serenoa has been recommended by many urologists to treat difficulties of micturition associated with BPH, so that it became one of the 10
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top-selling drugs in the United States [133]. Only in this country, in 2002, about 2.5 million adults have been using saw
Preclinical studies
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palmetto [134].
The liposterolic extract of Serenoa repens consists in a complex mixture of long-chain alcohols, fatty acids and their glycerides
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(oleic, caprylic, myristic, lauric, stearic, palmitic, linoleic acid), carbohydrates (galactose, arabinose and uronic acid), phytosterols (beta-sitosterol, beta-sitosterol-3-O-glucoside, beta-sitosterol-3-O-diglucoside, campestrol, cicloartenol), flavonoids (isoquercetin, kaempferol-3-O-glucoside), resins, tannins, pigments, essential oils and organic acids (caffeic, chlorogenic and anthranilic acid) [133]. The SPE (saw palmetto extract, also known as Serenoa repens purified extract) contains predominantly saturated and unsaturated fatty acids (90%), among which the main constituents are oleic and lauric acids; both represent more than 50% of the content of SPE. In addition, there are also myristic, palmitic and linoleic acid [135]. It is thought that the phytosterols and free fatty acids are the pharmacologically active constituents. In vitro results suggest two probable mechanisms: the non-competitive inhibition of 5alpha-reductase (both isoforms І and ІІ), which leads to decreased prostatic DHT content and inhibition of DHT binding to the androgen receptors, present in the cytosol of prostate cells [136]. The anti-androgenic effects of lipophilic extract also consist in inhibiting the 3-ketosteroid reductase responsible for the DHT conversion to another androgenic metabolite [137]. Inhibition of 5alpha-reductase by Serenoa extract depends, at least in part,
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ACCEPTED MANUSCRIPT to its free fatty acids content. Currently, there are no accepted guidelines for a standardized content of saw palmetto extracts in commercial products, even though the WHO has recommended that its composition should be 80-95% of fatty acids and sterols combined, or 85-95% of fatty acids and more than 0.2% sterols [134]. In order to analyze the binding affinity of fatty acids of
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SPE to various receptors (i.e., alpha1-adrenergic, muscarinic and dihydropyridine 1.4 calcium channels), it was shown that fatty acids inhibited prazosin and isradipine binding, in the central nervous system, in a dose-dependent manner. The affinity of
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oleic, linoleic and myristic acid for each receptor was higher than that of the SPE. The results suggest that the oleic and lauric acids antagonize receptors in a non-competitive manner [138]. Other important role of the fatty acids content (with the
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exception of palmitic acid) is the inhibition of both type 1 and 2 isoenzymes of 5alpha-reductase. This is the most noticeable effect of whole SPE, and occurs in a dose-dependent manner [138]. A stronger inhibition of 5alpha-reductase in prostate cancer cells was also found when Serenoa berries extract was associated with astaxanthin (carotenoid) [139]. The inhibition of both
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types of 5 alpha-reductase was also confirmed by other studies, even if with very different potency. The high variability in commercial products appeared due to different extraction processes that lead to qualitative and quantitative differences in the
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active ingredients [140,141]. In order to obtain reproducible biological activity, it is consequently necessary the standardization
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of every product in the commercial processing. Additionally to 5alpha-reductase inhibition, Serenoa seems to have antiinflammatory effects by inhibiting the synthesis of pro-inflammatory metabolites of arachidonic acid, through the blockade of COX and 5alpha-lipoxygenase enzymes [136] and by modulating the expression of infiammation related-genes [142]. It has been also reported a spasmolytic action on bladder muscle, by blocking calcium channels, by activating the Na+/Ca2+ exchanger
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[43], and through the antagonism of acetylcholine-induced contraction [143]. All these mechanisms support the clinical effectiveness of the SPE for the treatment of lower urinary tract symptoms, as they lead to significant relieves of urodynamic symptoms, increasing bladder capacity and extending the time of urination [144]. Other mechanisms of action of SPE include: inhibition of estrogen nuclear receptors and growth factors involved in prostate cell proliferation (EGF, FGF), anti edematous effects and alpha-adrenergic receptor blockade through a non-competitive antagonism [133]. About the last effect, unexpectedly, it has also been reported that serenoa stimulates the noradrenaline release causing contraction of the prostate smooth muscle. This sympathomimetic effect could be due to the constitutive presence of some amines, even if it is not been confirmed neither in vivo, nor in clinical trials probably because of the metabolism of these substances by hepatic enzymes [145]. Several studies have found that SPE suppresses the growth and induces apoptosis of prostatic epithelial cells, by inhibition of signal transduction pathways IGF1-activated and through the inactivation of the STAT 3 signals [146]. The increase of Bax/Bcl-2 ratio, caspase-3 activity, expression of p53 protein and a decrease in the expression of p21 and p27
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ACCEPTED MANUSCRIPT proteins appear to be also involved [147,148]. However, contrasting evidence regarding apoptosis has been reported, as the reduction of prostate size was achieved only at high doses [132, 149]. Regarding the safety of serenoa, an in vivo study has been shown no signs of liver toxicity [150] and no significant differences in body weight, enzymatic activity and levels of
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malondialdehyde, compared to placebo [150]. In order to increase the therapeutic activity in BPH, Serenoa repens is frequently associated with lycopene and selenium (an element able to promote an optimal antioxidant/oxidant balance). An association
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containing lycopene, selenium and Serenoa repens, commercialized as a dietary supplement named Profluss®, has been studied in vitro and in vivo for its efficacy in BPH. An inhibition of COX-2, 5-lipoxygenase, inducible nitric oxide synthase, and a
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reduction of NF-ĸB and mRNA that synthetize for TNF-alpha, has been found. The association of lycopene, selenium and Serenoa repens had more powerful anti-inflammatory and antiproliferative effects, compared to either compound alone, in reducing prostate weight and hyperplasia, in the suppression of cell proliferation induced by various growth factors (e.g., EGF,
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VEGF, TNF-alpha) [151], and in promoting apoptosis [152].
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Clinical studies
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In relation to the clinical efficacy, Serenoa repens seems useful in the treatment of mild and moderate BPH if patients are treated with standardized products (90% free fatty acids), at a dose of 160 mg twice daily, for at least three months [132]. On the other hand, it is contraindicated in advanced BPH with severe urinary retention and should not be used without consulting the physician [133]. The clinical efficacy of S. repens appeared superior to placebo and comparable to 5alpha-reductase
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inhibitors and alpha1-antagonists. Various studies are discussed below. A meta-analysis of 18 controlled clinical studies conducted for periods ranging from 4 to 48 weeks, showed a therapeutic efficacy of Serenoa extracts significantly superior to placebo and identical to finasteride [153]. Favorable effects on IPSS, LUTS, urine flow, nocturia and dysuria, have been also reported [154]. However, other studies have not reached to the same conclusion, pointing negative results on the improvement of urinary symptoms associated with BPH [134]. Furthermore, S. repens does not seem neither to reduce the prostate size and urinary flow measures [155], nor to change the levels of prostatespecific antigen (PSA), testosterone, DHT, follicle stimulating hormone (FSH), estradiol, and luteinizing hormone (LH) [133, 156]. Compared to finasteride (5 mg/g), Serenoa repens (320 mg/day) produces similar improvements in urinary flow, IPSS, and quality of life. Finasteride seemed to have a slightly higher effect on the peak urinary flow, whereas saw palmetto extract affected libido and impotence in a significantly lower manner [157].
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ACCEPTED MANUSCRIPT As regards the alpha1-antagonists, serenoa seems to have comparable efficacy to tamsulosin in improving bladder function [17]. On the other hand, the efficacy of prazosin in improving urine flows, micturition nocturnal frequency and post-void residual volume appared superior than saw palmetto [149]. The combination therapies ofserenoa with tamsulosin and serenoa
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with lycopene, selenium and tamsulosin increase Qmax and decrease IPSS, resulting more effective than the single therapies [158,159].
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As mentioned above, noteworthy is that serenoa is often associated with other medicinal plant extracts and/or elements, and a lot of clinical studies have been confirming its efficacy in improving the maximum urine flow, urinary resistance, IPSS score,
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quality of life, pain, urgency and nocturia [160,161,162,163,164]. These studies regard combinations as: Prostataplex® (serenoa plus vitamin A, plant sterols, lycopene, pumpkin seed oil, palm oil and selenium) [160], a mixture of 320 mg/die of serenoa and 240 mg/die of nettle root extracts [161], IPB-tre® (320 mg of Serenoa repens, 120 mg of Urtica dioica and 5 mg of Pinus
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pinaster) [162], Pluvio® (160 mg of fluid lipid-sterolic extract of Serenoa repens standardized in 85% of fatty acids, 300 mg of dry extract of Urtica dioica standardized in 0.8% of β-sitosterol, 166,7 mg of avocado and soya standardized in 30% of
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and 320 mg of Serenoa repens oil extract) [164].
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phytosterols, 1 mg of vitamin B1,5 mg of vitamin E and 7,5 mg of zinc) [163], Profluss® (5 mg of lycopene, 50 µg of selenium
The randomized studies compared with placebo (320 patients; 30 days-1 year) [162], finasteride (543 patients; 48 weeks) [161], watchful wating (120 patients; 6 months) [163], and serenoa alone (108 patients; 8 weeks) [164] have been reporting either positive results in the reduction of prostate volume [160, 162,163] or improvement in men with LUTS associated with BPH or
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chronic nonbacterial prostatitis [160,161,162,163,164]; although conflicting results have been found about the effect on PSA level [163,164]. Regarding the safety of the associations mentioned above, most of the studies have reported no serious and/or medium side effects [156, 162, 163,164]. Recently, an association of Serenoa repens, Pinus massoniana Bark Extract (PMBE) and Crocus sativus (named IDIProst® Gold), has been shown to better improve urinary and sexual function when compared with Serenoa repens alone [165]. Probably, the association of PMBE and Crocus sativus to serenoa produced a synergistic effect due to pharmacological properties of the other medicinal plants, including: nitric oxide activity, antioxidant effect and free radical scavenging properties of PMBE, increase of eNOS activity and promotion of the diffusion of oxygen into tissues induced by Crocus sativus [165]. The adverse effects of serenoa are generally mild and include headache, decreased libido, sexual dysfunction, ejaculation disorders, gastrointestinal problems (especially nausea and diarrhea if ingested on empty stomach or in large amount, respectively) [17, 133, 153]. Effects involving the sexual sphere are probably due to serenoa action on 5alpha-reductase. The
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ACCEPTED MANUSCRIPT urinary tract infections, ejaculation problems and impotence have been reported in 2% of patients treated in long-term with the dwarf palm, but in all cases its tolerability was better than finasteride [133]. However, other studies have demonstrated no negative impact on male sexual function [166] and do not support the relationship between serious clinical adverse effects and
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the use of dwarf palm extract [167]. The confirm is given also by the CAMUS trial that showed no evidence of toxicity of saw palmetto extract used at doses up to 3 times the usual clinical dose (160 mg, 2 times a day) during an 18-month period [168].
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Other case reports of greater severity were reported in the literature, including: high risk of bleeding, hepatitis and pancreatitis. In particular, it was reported cases of hematuria and coagulopathy in patients taking Serenoa [169], and a case of significant
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bleeding in a man hospitalized for surgery of meningiomas [170]. However, serenoa did not interefere in platelet aggregation and there are no data about the increase of pro-thrombin time (PT) or partial thromboplastin time (PTT) [171]. Regarding the probable implication of Serenoa in acute hepatitis and pancreatitis, a case of a 55 year old man who had taken serenoa
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intermittently for about 4 years has been reported [172]. A second case of 65 years old man who had started, a week before, a treatment with Saw palmetto (160 mg, 2 times a day) for difficulty in urination has documented acute pancreatitis [173]. A case
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of liver injury (cholestasis and fatty liver)in a 58 years old male who had taken during the last week a Serenoa repens
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commercial preparation (900 mg dry extract/day) has been reported [174]. The enrollment of specific patients in clinical trials, does not allow having unique information about potential drug interactions; among the exclusion criteria are men treated with alpha-blockers, diuretics and other drugs [133]. Among the possible pharmacodynamic interactions, has been reported an increase in bleeding time for the use of inhibitors of COX-2 and aspirin [97]. In addition, given its mechanism of action,
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Serenoa repens can theoretically interact with all hormonal therapies [43]. It is worth mentioning that Serenoa repens was part of medicinal plants present in PC Spes, sold in the United States for "prostate health". In 2002, the California Department of Health Services reported that different lots of the product, in addition to presenting a high variability in the concentrations of its components were contaminated by indomethacin, warfarin, alprazolam and diethylstilbestrol [175]. The healthcare professionals should therefore evaluate carefully the quality of herbal products, before recommending to a patient.
Urtica dioica
Urtica dioica L. belongs to the Urticaceae family. It is also known by the names of stinging nettle, common nettle and ortiga. It is an herbaceous plant, thorny that commonly grows all over the world, in regions where the climate is humid and temperate.
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ACCEPTED MANUSCRIPT The drug used in BPH is made from the roots, but fresh and dried flower parts are traditionally used for other purposes, such as joint pain, urinary tract infections and as diuretics. For external use the nettle is used as a remedy for hair loss, against seborrhea and dandruff of the scalp [38]. U. dioica has been ranked among the 16 most commonly used medicinal plants in the North of
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the Iberian Peninsula. Traditionally, is used as a depurative, for acne, diarrhea, diabetes, and to improve circulation and low
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blood pressure [176].
Preclinical studies
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The leaves contain sterols (beta-sitosterol, hydroxy-sitosterol), flavonoids (rutin, kaempferol, quercetin), minerals (calcium, potassium), tannins, acids (salicylic, malic acid) and amines (histamine) [43]. It has been reported that, in the root, elements particularly important are the presence of lectines (mixture of isolectines from 0.2 to 0.6%), polysaccharides (glucans,
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glucogalacturonans, arabinogalactan acid), idroxycumarins (scopoletin), ceramides, lignans (secoisolariciresinol -9-Oglucoside, (-)-3,4-divanililtetraidrofuran, neo-olivile), sterols and their glycosides (beta-sitosterol, stigmasterol, campestrol),
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phenols (p-hydroxy benzaldehyde), monoterpendiols and their glycosides, fatty triterpene, fenilpropans (homovanillilic alcohol
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and its 41-O-glycoside) [177].
In the treatment of BPH, a number of mechanisms of action of the root have been postulated, including light diuretic and potent anti-inflammatory activities probably due to the presence of scopoletin. The root extract, in vitro, inhibits the binding of the sex hormone binding globulin (SHBG) to its receptor in the membrane of human prostatic cells. The SHBG has the function to
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regulate the concentration of free androgens and estrogens in the plasma, and interference at its receptors on the membrane of prostate cells, would prevent these hormones to interact, themselves, with their receptors [178]. The lignans contained in the stinging nettle seem to have a high affinity for SHBG [38]. The polysaccharides and lectins can block the binding between the epidermal growth factor, secreted by the prostate tissue, and its receptors, with suppression of prostate cellular metabolism and its growth [43]. In addition, the lectines may contribute to the prostatic anti-proliferative and anti-inflammatory activities [38]. The polysaccharides stimulate the activity of T lymphocytes and the complement activation [179]. Both malic and caffeic acids show anti-inflammatory activity, in vitro and in vivo, through inhibition of COX and lipoxygenase. The nettle extract inhibits TNF activity [180], prostate cells proliferation [181], and aromatase activity [182]. The aqueous extract of the leaves of stinging nettle inhibits the activity of adenosine deaminase (ADA), the key enzyme in the nucleotides metabolism. The inhibition is dose-dependent and it might be one of the mechanisms that lead to improvements of patients symptoms [183].
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ACCEPTED MANUSCRIPT Animal studies indicate that U. dioica inhibits markedly platelets aggregation and improves the lipid profile; the constituents responsible for this potent effect seem to be the flavonoids [184,185]. It was found also that the methanol extract of stinging nettle significantly inhibited the prostate growth induced experimentally [186,187]. Ortica seems to inhibit the 5alpha-reductase
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activity, probabbly due to the presence of scopoletin and beta-sitosterol, at least in vivo [188].
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Clinical studies
A clinical study, randomized, double-blind, compared to placebo analyzed the effect of Urtica dioica roots aqueous extract (120
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mg, 3 times/day). The results showed a significant improvement in LUTS, Qmax, and IPSS, after sixth months of treatment. These improvements were maintained also after 18 months of treatment [189]. No significant difference was observed between the groups in the levels of PSA and testosterone, but the treated group showed a moderate reduction of the prostate size [189].
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Other study carried out with a higher dosage of urtica (459 mg), did not confirm the previous finding [190]. Other randomized trials have evaluated the effects of an association called PRO 160/120 and consisting in 160 mg of Serenoa
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repens standardized fruit extract and 120 mg of Urtica dioica root extract. A total of 257 patients with moderate and severe
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symptoms were treated with PRO 160/120 or placebo (one capsule, 2 times a day, for six months). The efficacy of the treatment was superior to placebo for attenuation of inflammatory and obstructive symptoms [191]. The same combination was tested on 140 patients, for fifteen months, and was compared toward tamsulosin (0.4 mg/day). This study found the effectiveness of PRO 160/120 and tamsulosin in the treatment of LUTS caused by BPH, and both treatments were well tolerated [192]. Another
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randomized, double-blind study, confirm the effectiveness and tollerability of PRO 160/120 versus finasteride in increasing urine flow, improve symptoms related to bladder emptying, but not in reducing the prostate volume [193]. The nettle (300 mg) has also been evaluated in combination with Pygeum africanum (25 mg), in six months of treatment and no significant differences were found in various parameters (i.e., IPSS, QoL, Qmax) and clinical improvement [194]. The nettle extract is generally well tolerated [189] and may result in only occasional mild gastrointestinal effects. There have been reports of diarrhea and respiratory system diseases of moderate intensity, but the effects do not differ from those observed in the placebo [191]. Rarely have been reported edema and urticaria related to allergic reactions induced by the plant [38]. U. dioica contains tannins, which can interact with concomitant intake of iron, causing a reduction of the effects in patients who need iron supplements. It is therefore, recommended to separate for at least two hours the times of administration of these components [38].
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ACCEPTED MANUSCRIPT Miscellany
Other numerous medicinal plants have been proposed in the treatment of benign prostatic hyperplasia-related symptoms,
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including the following: Zea mays (cornsilk), Allium sativum (garlic), Echinacea Spp., Althea officinalis (marshmallow), Equisetum arvense (horsetail), Lactuca scariola, Asteracantha longifolia, Argyreia speciosa and Parmellia perlata for their
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antimicrobial activity, helpful in preventing the chronic urinary infections [42; 195]; Arctostaphylos uva-ursi (uva-ursi) in the treatment of prostatitis; Opuntia ficus-indica (prickly pear) useful in controlling the prostate enlargement for its antioxidant and
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antiproliferative activities on prostate cells [42, 196]; Curculigo orchioides (black musli) for dysuria and poluria, and in the management of prostatic enlargement [195]; Telfairia occidentalis for the inhibition of hormonal induction of BPH [197]; Mucuna pruriens for its anti-inflammatory capacity in various prostatic affections; Vaccaria segatalis for the ameliorating the
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prostate pathomorphology and prostatic and testicular indexes [198]; etc. These medicinal plants and many others are of growing recent scientific interest [199]. Most of the mentioned herbal remedies are probably more effective for prevention
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and/or for the treatment of BPH-related symptoms, rather than for a direct effect on the prostate gland. Moreover, active
value is still unknown.
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ingredients and biochemical mechanism of action of some of above mentioned plants still need investigation, and their clinical
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An overview of the medicinal plants described in this review is reported in Table 1.
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ACCEPTED MANUSCRIPT Table 1. Medicinal plants used in the treatment of benign prostatic hyperplasia, their mechanism of action, and clinical safety and efficacy (if known). Postulated mechanism/s of
Clinical
(common name)
action
efficacy
Cucurbita pepo
Inhibition of DHT binding to the
(pumpkin, dubba)
androgen receptor
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Botanical name
Safety
+
ND2
ND
ND
ND
ND
++3
Anti-proliferative activity
+/−4
+/−
Pygeum africanum
Inhibition of nuclear translocation
++
++
(prunus africanus, african cherry)
of the androgen receptor
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+1
5alpha-reductase inhibition Radical-scavenger and anti-
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Epilobium Spp. (willow herb)
oxidant activity
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anti-androgenic activity
(african potato, yellow star)
(tomato)
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Lycopersicum esculentum
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Hypoxis roopery
anti-inflammatory activity anti-proliferative activity analgesic property Anti-proliferative activity anti-inflammatory activity radical-scavenger activity Anti-proliferative and proapoptotic activity own-regulation of 5alphareductase anti-oxidant activity anti-inflammatory activity
Pinus pinaster (maritime pine)
inhibition of cell proliferation
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ACCEPTED MANUSCRIPT pro-apoptotic activity anti-inflammatory activity anti-oxidant activity 5alpha-reductase inhibition
(palm criollo, vakka)
alpha1-adrenoceptors antagonism
ND
ND
ND
++
++
+
+
+
ND
ND
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Roystonea regia
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antioxidant activity
5alpha-reductase inhibition
(common rye, rye pollen)
pro-apoptotic activity
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Secale cereale
alpha-adrenergic receptors block
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anti-inflammatory activity
Serenoa repens
Urtica dioica (stinging nettle, ortiga)
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(sabal serrulata, saw palmetto)
spasmolytic activity 5alpha-reductase inhibition inhibition of DHT binding to androgen receptors anti-inflammatory activity spasmolytic activity anti-proliferative activity sympathomimetic effects alpha1-adrenoceptors antagonism Anti-proliferative activity anti-inflammatory activity inhibition of SHBG inhibition of aromatase
Zea mays (cornsilk), Allium sativum (garlic), Echinacea Spp., Althea
Antimicrobial activity
officinalis (marshmallow), Equisetum arvense (horsetail), Lactuca
anti-oxidant activity
scariola, Asteracantha longifolia, Parmellia perlata, Arctostaphylos
anti-proliferative activity
uva-ursi (uva-ursi), Opuntia ficus-indica (prickly pear), Curculigo
anti-androgenic activity
orchioides (black musli), Telfairia occidentalis, Vaccaria segatalis.
anti-inflammatory activity
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ACCEPTED MANUSCRIPT 1
: efficacious/safe, 2: not determined, 3: very efficacious and/or very safe, 4: contrasting evidences
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Conclusions and perspective
Depending on the severity of the disease, the various treatment options currently available are: watchful waiting, drug therapy,
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surgery and the use of medicinal plants. Although drug therapy (alpha1-blockers, inhibitors of 5alpha-reductase) and surgery (prostatectomy, transurethral resection, etc.) seem to be the most effective choices for patients with moderate to severe BPH,
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herbal medicine can be useful in patients with mild to moderate symptoms. Medicinal plants most commonly used in BPH are: Serenoa repens Small. (Arecaceae Family), Pygeum africanum Hook (Rosaceae family), Urtica dioica L. (Urticaceae family), Cucurbita pepo L. (Cucurbitaceae family), Epilobium spp. L. (Onagraceae family), Secale cereale L. (Gramineafamily e),
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Hypoxis roopery Moore (Hypoxidaceae family), Roystonea regia Cook (Arecaceae family), Pinus pinaster Sol (Pinaceae family) and Lycopersicum esculentum Mill. (Solanaceae family). The last two medicinal plants are primarily used for their
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extraction products, β-sitosterol and lycopene respectively. Serenoa repens, Pygeum africanum, Curcubita pepo, and Urtica
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dioica are the most prevalent plants used to treat BPH.The various extraction procedures of plant based medicinals, the different drugs used, their mechanism of action (sometimes poorly characterized), make difficult, quite impossible the comparison between the various products. At the same time, whether in vitro or in vivo studies have been reported some pharmacological actions of certain active substances, this does not necessarily mean that the same substances have beneficial effects in the
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clinical practice. However, there is emerging evidence that various plant extracts are well tolerated and allow to obtain an improvement in symptoms of urinary tract BPH-related. S. repens in human studies showes an effectiveness higher than placebo, equivalent to tamsulosin and in combination to U. dioica reveales equal effects to finasteride in improving symptoms of lower urinary tract and with less side effects. Regarding the safety of serenoa, gastrointestinal problems, headache, liver disease, pancreatitis, and sexual dysfunction have been reported. Pygeum africanum as serenoa is registered (at least in Italy) as a phytotherapic medicine, and moderate evidence indicates that its use improves the parameters of the urinary stream. Pygeum seems a safe drug. Urtica dioica shows promising efficacy that is higher if it is taken in combination with other medicinal plants and nutraceuticals such as serenoa, pine, lycopene, etc. The effectiveness of Cucurbita pepo is based on preliminary data and further confirmation is needed, especially related to long-term effects. Pumpkin is safe enough except some evidence which advice against its association with anticoagulants. Because of the lack of clinical trials on the use of various species of Epilobium, no data are currently available on its effectiveness and safety; although in experimental studies they did not induce a
27
ACCEPTED MANUSCRIPT particular toxicity. Secale cereale seems effective in urinary symptoms of BPH, but its effects have to be confirmed by clinical evidence. In relation to its adverse effects abdominal pain, nausea and hypersensitivity , were found. Very limited data are available about the clinical use of Hypoxis roopery and Roystonea regia. Regarding lycopene, recent research confirms its
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ability in the prevention and progression of BPH; the mechanisms of action could possibly be proposed in the prevention of adenocarcinoma. Furthermore, the effectiveness of tomato extract seems higher than that of lycopene alone. The tomato
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consumed in normal quantities of a Mediterranean diet can be considered, in absence of specific allergic symptoms, a safe food. Regarding the associations of plants, they seem more effective than the plants alone; However, the use of multi-component
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products does not play in favor of the safety. Zea mays (cornsilk), Allium sativum (garlic), Echinacea Spp., Althea officinalis (marshmallow), Equisetum arvense (horsetail), Lactuca scariola, Asteracantha longifolia, Parmellia perlata, Arctostaphylos uva-ursi (uva-ursi), Opuntia ficus-indica (prickly pear), Curculigo orchioides (black musli), Telfairia occidentalis, Vaccaria
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segatalis and many other plants are of growing scientific interest in the field of BPH phytotherapy, but nowadays most of them result more effective for prevention and/or for the treatment of BPH-related symptoms, rather than for an effect on prostate
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gland enlargement. However, the effect obtained with drugs (as pure chemicals) is reached at much lower doses than those
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needed to obtain the same effect with the use of a phytocomplex. Moreover, regarding other plants, many products are not standardized and, data relating to their safety are not always available and their clinical efficacy is generally based on a short duration treatment of a small number of patients. It should be also important to remember that in many cases the analytical, pharmacological or clinical markers are unknown, and the effects of some herbal products could be unforeseeable. This
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disadvantage, along with that phytotherapy usually requires at least few weeks before to have any efficacy, should be taken into account in the choice of treatment. In conclusion, because of the impact of BPH symptoms on health and QoL, a greater communication between the patient and his doctor allows to facilitate the diagnosis and to personalize the treatment, and healthcare professionals should try to be constantly informed about the possible risks and benefits of BPH herbal medicine.
Conflict of Interest Statement
The authors declare that there are no conflicts of interest.
Acknowledgements
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This study was supported by the ―Enrico and Enrica Sovena Foundation‖, Rome, Italy.
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Graphical abstract
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