Elsevier

Life Sciences

Volume 126, 1 April 2015, Pages 42-56
Life Sciences

Review article
What do we know about phytotherapy of benign prostatic hyperplasia?

https://doi.org/10.1016/j.lfs.2015.01.023Get rights and content

Abstract

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, transurethral resection, etc.) seem to be 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, alpha-adrenergic antagonism, dihydrotestosterone and estrogen receptor inhibition. Randomized clinical trials indicate significant efficacy in improving urinary symptoms and mild adverse effects for some 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 risk/benefit profile of the use of medicinal plants in the management of BPH.

Introduction

Benign prostatic hyperplasia (BPH) is one of the most common urological diseases in aging men. It typically develops after the age of 40 years and ranges in prevalence from over 50% at 60 years to as high as 90% by 85 years of age [1]. BPH is characterized by high morbidity and low mortality rate, and is considered a public health problem [2]. The BPH natural history can be divided into the pathological and clinical phases. The first phase is asymptomatic, and occurs at the periurethral level with nodular 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 the loss of elasticity 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 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 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; insulin like growth factor — IGF), leading to abnormal prostate cell proliferation [11]. Moreover, estrogens act in synergy with androgens in the development of BPH. Particularly, an increase in the expression of aromatase (an enzyme that catalyzes the peripheral conversion of androgens into estrogens) and estrogen receptors at the transition zone of hypertrophic prostate tissue has been observed [12]. The second postulate about BPH development is based on 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 factor — TGF-β1; etc.), responsible for modulation, proliferation, apoptosis and secretory activities of both stromal (autocrine transmission) and epithelial portions (paracrine secretion) [3], [13], [14].

In the pathogenesis of BPH some risk factors should also be taken into account, since this disease is more common in patients 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, cyclooxygenase-2 (COX-2) over-expression, and cytokine and leukotriene production [16].

Therapeutic approaches currently available for the treatment of BPH consist of: 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.

Watchful waiting (i.e., periodic revaluations of clinical conditions) and some changes in lifestyle are recommended for patients with mild symptoms who are not at risk of acute urinary retention [18]. In the case of worsening of symptoms and as the post-void residual volume increases, pharmacological therapies are proposed. The two main classes of drugs are alpha1-antagonists (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 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 androgen reduction. They are more effective in patients with a significant enlargement of the prostate gland [23]. The use of finasteride increases the stream of urine and reduces BPH-related symptoms [24]. However, it causes numerous side effects such as decreased libido, decreased volume of ejaculate, impotence and skin rash. Cases of gynecomastia have been also reported [25]. The antimuscarinic drugs (tolterodine, fesoterodine) may also be used, in association with the two previously mentioned drug classes, in severe conditions related to storage symptoms [22]. A more recent long-term pharmacological treatment of BPH of 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: β3-agonist (i.e., mirabegron); the association of 5-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 of an intraprostatic injection of botulinum toxin, is still of doubtful efficacy and safety and further studies are needed to determine its use in the management of patients with urologic conditions [30].

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 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, this procedure has also 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 g; transurethral electrovaporization of the prostate (TUVP) that represents TURP modifications, consisting in the destruction 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 abovementioned approaches are, in different extent, responsible for side effects such as: ineffectiveness or failure in the short term, high incidence of complications, need for a prolonged catheterization, 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 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 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 great tolerance and plural numbers of action sites, many of which are in common with drugs such 5alpha-reductase inhibitors and alpha1-receptor antagonists. Many of the 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 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 require prescription. In Germany and Austria, phytotherapy is the first-line treatment of mild to moderate urinary symptoms and represents more than 90% of all the drugs prescribed for BPH treatment [36]. 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 BPH. Particular attention was also devoted to their safety profile.

Section snippets

Cucurbita pepo

C. 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 anti-inflammatory actions in the treatment of BPH and its urinary related problems [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, Epilobium hirsutum, Epilobium rosmarinifolium and Epilobium angustifolium (commonly known as willow herb). The part of the plant commonly used in various products is derived from the aerial flowered one. Traditional medicines consider the

Hypoxis rooperi

H. rooperi Moore belongs to the Hypoxidaceae (Amaryllidaceae) family. This is a perennial herbaceous plant native of South-East African regions, particularly of KwaZulu 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]. H. rooperi is traditionally known as a “miracle” medicinal plant because it has been used for a wide array of human

Lycopersicum esculentum

L. 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 food (tomato-based food: tomato paste, tomato sauce, tomato soups, etc.). Generally the tomato fruit and tomato-based products provide to the human body about 85% of lycopene, while the remaining 15% is usually obtained from the consumption of watermelon, apricot, peach, papaya and red

Pinus pinaster

P. 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 the gems, twigs and resin, from which the essential yellow oil with characteristic smell and resinous taste could be obtained, by distillation in steam.

P. africanum

P. africanum Hook belongs to the Rosaceae family. It is an evergreen tree native of the Central and South American mountains, the Madagascar and Comoros islands and the Gulf of Guinea. This plant is known even as: African Plum, Prunus africana and African cherry. P. 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

Roystonea regia

R. regia Cook is a palm tree that belongs to the Arecaceae family. It is native of South Florida, Mexico and parts of Central America. In Cuba, it is also called palm criollo, while in India, where it is widely cultivated, it is called Vakka [112]. The drug used for BPH is constituted by its mature fruits.

Secale cereale

S. 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 S. cereale from Sweden and Switzerland. The extraction process involves the sequential use of water and organic solvents [43].

S. repens

S. repens Small. is a small palm, of the Aricaceae family. It is also known as Sabal serrulata, saw palmetto, Ju-zhong and Dwarf palm. Its habitat is in West India and in the Southeastern part of the United States, especially in South Carolina, Florida, and Southern California. The drug consists of the dried ripe fruits; these drupes of soapy and unpleasant taste are similar to black olives which, in therapy, uses the lyposterolic extract. Traditional medicine describes the use of dwarf palm

Urtica dioica

U. dioica L. belongs to the Urticaceae family. It is also known by the names of stinging nettle, common nettle and ortiga. It is a thorny herbaceous plant that commonly grows all over the world, in regions where the climate is humid and temperate. 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 and urinary tract infections and as diuretics. For external use the nettle is used as a remedy for hair loss,

Conclusions and perspective

Depending on the severity of the disease, the various treatment options currently available are: watchful waiting, drug therapy, 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, herbal medicine can be useful in patients with mild to moderate symptoms. Medicinal plants most commonly used in BPH

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgments

This study was supported by the “Enrico and Enrica Sovena Foundation”, Rome, Italy.

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