Phytotherapeutica in common urological conditions in Western integrative medicine: a narrative review

Introduction

Phytotherapy, a scientifically based usage of plant extracts for treatment and prevention of disease, is as old as humanity. This knowledge was passed on from person to person in Ancient times, until the development of social structure and writing which helps for much wider distribution of knowledge. First written proof of phytotherapeutica dates 3000 B.C. The Egyptians was the first great civilization which left extensive body of knowledge on the medicinal use of plants (1). This legacy later was carried on and developed by Greek and Roman civilization in ancient Mediterranean. For millennia, the Chinese traditional medicine has the leading and most extensive experience in usage of plant extracts and compounds for urological conditions. The Renaissance marks peak in phytotherapy; modern technology led to unprecedented advancement in the development and use of active ingredients derived from plants in the recent years; at the present moment according to the World Health Organization approximately quarter of modern drugs in US originate from research on phytochemicals (2). Because of this widespread usage of phytotherapeutica urologists must have a solid knowledge on them, their benefits and potential adverse effects, as well as the new insights on the biochemical pathways that are enlightened by the discovery of specific active ingredients in plant extracts.

Phytotherapy has lot to offer in the treatment of benign urological diseases. Organizational factors, like differences in legislation in different countries and low motivation of pharmaceutical companies to perform proper randomized-controlled studies on plant based compounds, have significantly impaired the amount of available research needed for establishing the deserved evidence-based place of phytotherapeutica in Urology (3). This article focuses on those best-confirmed and most widely accepted plant-based medications, aiming to update the knowledge on the subject and outlining the future tendencies in their development.

Urological diseases are extremely common and tend to bear a significant health and social burden, while at the same time a lot of unanswered questions and unmet needs exist in their treatment (significant lack of knowledge on their etiology and pathophysiology, low efficacy of the accepted treatment options, toxicity in short or long-term, low compliance to therapeutic regiment). There are several reasons that urologists should be acquainted to the topic of phytotherapy. Substantial, yet still heterogeneous and controversial, database on efficacy of phytotherapy in conditions in Urology like BPH/LUTS. CP/CPPS, ED and sexual disorders, UTI and urolithiasis (the latter being subject of a separate article in this Special Series on Integrative Medicine in Urology) has been developed, making somewhat near its inclusion in international guidelines (1). Furthermore, the urologists must have knowledge regarding contraindication, toxicity and interactions of plant-based medications.

The objective of this article is to present as a narrative the best scientific evidence and contemporary trends on usage of phytotherapy for treatment of urological conditions in Western medicine. It aims to broaden the urologists’ knowledge on those widely accepted, well tolerated and effective therapeutic alternative used for a wide array of urological conditions. We present the following article in accordance with the Narrative Review reporting checklist (available at https://lcm.amegroups.com/article/view/10.21037/lcm-21-38/rc).

Methods

A literature review was performed in 5.2021 searching PubMed and Google Scholar for scientific articles published between January 1995 and May 2021. Inclusion criteria were Original articles in English on phytotherapy in benign urological conditions, excluding Letters to the Editor, Case report, Case series type of publications. The selection process begun with independent review search by all of the three authors, while the final list of included studies was reached by consensus.

The used keywords Included: ‘phytotherapy’, OR ‘BPH/LUTS’, OR ‘Serenoa repens’, OR ‘ED’, OR ‘CPPS’, OR ‘UTI’, OR ‘plant extracts’, OR ‘herbal medicines’. In the following table (Table 1) we present the characteristics of our search strategy.

Benign prostatic hyperplasia (BPH)

BPH is one of the most common urological diseases, observed in over 50 % of males over 50 years of age. Contemporary treatment options for BPH and resulting lower urinary tract symptoms (LUTS) include lifestyle modifications, medications and surgery.

The phytotherapeutic agents for BPH, which became increasingly popular since the late 20^th century, are highly heterogeneous group of medications, which contain different active ingredient(s) and in different concentrations in their various formulations (3). The use of phytotherapeutica in the treatment of BPH and LUTS has become widely popular and it’s prevalence in EU and USA is increasing, reaching up to 50 % in some countries (4), although specific recommendations on phytotherapy are lacking in the EAU and most of other major Guidelines due to product heterogeneity and lack of standardization, limited scientific background, and poor quality with significant potential bias of RCT and systematic reviews and meta-analyses on the subject. All of the aforementioned still prevents phytotherapy to fulfill the criteria of evidence-based medicine and hence be included into Guidelines for BPH/LUTS

The TRIUMPH Study studied the prescription practice in BPH/LUTS medication treatment in six European countries and concluded that despite significant differences in national policies, alpha-blockers were predominant in all countries as monotherapy (79%) followed by phytotherapy (16%) and 5-ARI (5). Another study in primary care (4) shows similar results. About 40% of men on medication therapy for LUTS/BPH in the US use phytotherapy as a monotherapy, or as a part of a combination treatment, with a trend to increase that percentage (6).

Mechanism of action of phytotherapeutica for BPH/LUTS is multi-factorial and still not sufficiently studied. Laboratory studies on cell cultures and animals have elucidated various possible mechanisms of action of the phytotherapeutica—anti-inflammatory, anti-androgenic, and estrogenic effects; decrease SHBG activity; inhibition of aromatase, lipoxygenase, growth factors, alpha-adrenoreceptors, 5-alpha reductase, M-cholinergic receptors, dihydropyridine and vanilloid receptors; and decrease oxidative stress (7-12).

More than three dozens plants and phytotherapeutic compounds are reported and used in the management of BPH/LUTS in the Western Urology, and among them the most popular are Serenoa repens, Pygeum africanum, Urtica dioica, Cucurbita pepo, Hypoxis rooperi, and Secale cereale (13).

Serenoa repens

Saw Palmetto (SP, SeR), [a.k.a. Serenoa repens, Dwarf palm plant (Sabal serrulatum)], represent the dried ripe fruits of a palm tree, native to North America. SeR has diuretic, uroantiseptic, endocrinological, and anabolic effects. SeR is by far the most widely used phytotherapeutic for BPH/LUTS, alleviating dysuria, urinary frequency, nocturia, and urine retention (14).

It is theorized that the main active substance in SeR are free fatty acids (FFAs), which have inhibitory activity on 5-alpha reductase type 1 and 2 (11,15-18). In an in vitro study FFA bind to adrenergic, muscarinic, and dihydropyridine receptors (19).

Inflammatory processes have a pivotal role in BPH/LUTS initiation and progression by activation of growth factors, increasing of oxidative stress, production of several cytokines, secretion of prostaglandins, leukotrienes and nitrates (20). Saw palmetto has a proven anti-inflammatory effect on the prostate and BPH-related LUTS, and its synergistic action with selenium (Se), and lycopene (Ly) increase its therapeutic properties.

The main obstacle in obtaining solid scientific evidence on SeR effectiveness in BPH/LUTS is the absence of standardization. There are numerous brands of SeR preparations, with significant variations in quality and quantity of active ingredients owing to the different origin of source plant and different extraction techniques (21,22).

In a recent updated Cochrane review (23) SeR extracts failed to show statistically significant improvement over placebo in LUTS scores or Qmax associated with BPH (23,24). However, in this review the heterogeneity between the studies regarding inclusion criteria is a source of significant bias. A significant variability exists in IPPS score of the patients, ranging from 6 (healthy) up to 32—patients with severe LUTS where medications are almost inevitably destined to fail.

In recent years, a lot of scientific interest has attracted the combination phytotherapy including SeR and other plant extracts for urinary symptoms (C. pepo, Epilobium parviflorum, lycopene, P. africanum) as well as the combination of selenium, lycopene and Serenoa, and significantly increased activity on alleviating LUTS/BPH is observed (25,26). In a systematic review of adverse events of SeR, the vast majority of them are mild, rare, and reversible, similar to those observed in placebo arms (27).

Some of the other commonly used phytotherapeutica for BPH/LUTS are:

Pygenum africanum

Native of Africa; plant source is the bark of African plum tree; main active ingredients are phytosterols and other sterols and steroid precursors and metabolites (28-30); several RCT and a meta-analysis confirm its efficacy (31-33).

Urtica dioica

Common or stinging nettle; native to Europe, Asia, parts of Africa and North America. This medicinal plant usage is known since medieval times as a diuretic and remedy for joint problems. Among its various medicinal usage are as a treatment for diabetes, hypotension, anemia. At the present moment it is also used in LUTS/BPH treatment, although rarely as monotherapy (34-36).

Cucurbita pepo

Also known as pumpkin; native of South-central America, universally spread and cultivated. Pumpkin seeds have therapeutic effect in a number of urological conditions like LUTS/BPH and urinary tract infections (UTIs). Although being widely used since ancient times, the active ingredients of pumpkins are scarcely studied. The Δ7-sterols, a specific active ingredient of pumpkin seeds, resemble the structure of DHT, presumably acting as a competitive inhibitor on DHT receptors (37). In other studies C. pepo extract has been found to have an effect on aromatase and 5-α-reductase Type II (38), as well as antioxidant and anti-inflammatory activity, immunological, antiviral, and antifungal properties (39).

Hypoxis rooperi

South African star grass (a.k.a. African potato, Hypoxis hemerocallidea, yellow star).

Native of South-East Africa. The main active ingredients of Hypoxis are thought to be the sterols, exerting antiandrogenic and anti-inflammatory effect (3).

Erectile dysfunction (ED) and fertility

ED is a prevalent condition with an increasing incidence rate—up to 31% of the male population is estimated to be affected (40) Standard ED treatments include prescription medications, vacuum pumps, implants and surgery, with inconsistent and sometimes unsatisfactory results. Even though the past 20 years saw major developments in the field of evidence-based sexual medicine, including the development of effective treatment options for ED, many patients still feel dissatisfied. A substantial percentage of the affected men resort to herbal-based therapy as an alternative to Western-based therapies. Many contemporary studies show phytotherapy as a viable treatment method in these cases.

Korean red ginseng

Korean ginseng has traditionally been used as an aphrodisiac since centuries. It has become one of the most popular herbal supplements taken for reproductive disorders, including sexual performance and ED (41).

Ginsenosides, which represents steroid-like saponins, are the unique active substances specific to ginseng species, along with polysaccharides, alkaloids, and phenolic molecules (42). The effect of ginseng necessitates saponin and non-saponin compounds to work synergistic (43). They result in endothelium NO synthesis, leading to vasodilation of the corpora cavernosa and hence improved erection (44). Ginseng has been shown to increase testosterone plasma levels in animal models.

Pygnogenol

Pinus pinaster (Maritime pine) is a tree species native to Southern France (45). Pygnogenol is extracted from the powdered Pinus pinaster bark. Procyanidins have significant antioxidant properties that have numerous health benefits (46).

Pygnogenol has significant antioxidant and anti-inflammatory properties. They have been shown to increase vascular NO synthesis and vasodilation which can improve symptoms of ED (47).

One double-blind RCT compared combination of L-arginine aspartate and Pygnogenol with placebo PRO (patients-reported outcomes), combined with monitoring of plasma testosterone concentration endothelial NO synthase activity (48). A one month intake of Pycnogenol normalises erectile function, with almost doubling the frequency of intercourse, as well as significant increase of e-NOS in spermatozoa and testosterone plasma levels. Another beneficial effect was the observed decrease of Cholesterol and normalization of blood pressure.

Lepidium meyenii

Lepidium meyenii (Maca or Peruvian bark), is native to the Central Andes Mountains of Peru (49). It has been used for >2,000 years for its medicinal purposes—extracts from the maca root have been known to improve erectile function even in healthy humans (50). In recent years it has become one of the most popular supplements for the improvement of sexual desire (51).

Research on animals shows that maca has beneficial effects on spermatogenesis and fertility, presumably owing to phytosterols or phytoestrogens. Recent clinical trials have also suggested its potential for improvement of sperm count and mobility and enhancing sexual function in humans (52). Macaridine, macamides, macaene, glucosinolates, maca alkaloid, and maca nutrients are some of the proposed active substances.

Contemporary literature lacks sufficient data to formulate a systematic review on the topic—additional research is needed before recommendations on efficacy and safety could be done.

Although reported as well tolerated Lepidium meyenii may have some psychological adverse effects, namely anxiety, mood changes, hallucinations, and potential for addiction (53).

CPPS

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is defined as pelvic or perineal pain, in the absence of UTI, lasting longer than 3 months. The pain can range from mild to debilitating, causing voiding difficulties. This condition vastly deteriorates the patient`s quality of life. There is no “gold standard” of treatment for this pathology. Because of the lack of specialized treatment (antibiotics, NSAIDs, and alpha-adrenolitics), phytotherapy has emerged as a safe efficient alternative for these patients providing numerous benefits with limited side effects.

Pollen extract (cernilton)

Cernilton (a standardized pollen extract mixture) is included in the therapeutic strategy for the treatment of CP/CPPS for almost 20 years (54). Its exact mechanism of action is largely unknown. Some authors suggest that the anti-inflammatory effect results from inhibition of cyclo-oxygenase and lipoxygenase.

One placebo-controlled study found that male patients with CP/CPPS receiving pollen extract for 12 weeks had significantly higher improvement in symptoms compared to placebo (55). The most substantial improvement was observed in pain relief, which is verified by the observed significant improvement in PRO such as total NIH-CPSI score and the QoL.

Quercetin

Quercetin is universally found in many fruits, vegetables, leaves, and grains. It has significant anti-neoplastic activity, as well as anti-inflammatory and oxidative stress reducing properties (56).

Quercetin has antioxidant properties, as free radical scavengers as well as inhibitor of xanthine oxidase, and anti-inflammatory properties. They modulate the activation of tyrosine kinase enzymes, which leads to inhibition of the division and growth of T cells and prostate cancer cells. Quercetin additionally has antimicrobial and antifungal properties.

In one study combination of quercetin with bromelain and papain led to improvement in the NIH symptom score from an average of 25.1 to 14.6, mean improvement of 44%. 82% of those patients reported at least a 25% improvement (57).

Piper methysticum (kava) root and Pedicularis spp. (lousewort)

Piper methysticum (kava) root and Pedicularis spp. (lousewort) are effective pelvic analgesics. Kava has traditionally been used as a medicinal herb in southern and western Pacific regions. It has been studied as an analgesic and systemic anxiolytic. It is indicated when pelvic pain is accompanied by concomitant anxiety, which is a substantial percentage of the affected patients. Lousewort has not been the subject of any clinical trials but historically it has been reported to have similar, if not superior, results than Kava. Both herbs are effective skeletal muscle relaxants.

UTI

UTI is an extremely common urological condition with significant morbidity and mortality, in addition to the negative effect on the QoL of the affected patients. Antibiotic therapy is the method of choice in symptomatic UTI. Bacterial resistance, antibiotics side effects, tendency of recurrence and other accompanying problems necessitates alternative approaches in controlling and preventing UTIs.

Western herbal medicines for lower UTI can be divided in two categories: those for symptomatic and antibacterial treatment during the acute episode and those used for prevention of recurrences.

The urinary bacterial pathogens use fimbria to attach to the glycolipids and glycoproteins found on the urothelium. That way they can evade being expelled by the urinary flow and successfully colonize the urinary tract. The bacteria also excrete hemolysin, and other biologically active substances, that injure the urothelium, allowing bacterial invasion, and increasing the risk of infection Uropathogens also can internalize into host epithelial cells and divide internally, providing a reservoir for recurrent infection. The focus of the phytotherapeutica used in UTI is to counteract on these mechanisms of evasion of the natural protective mechanisms of the urinary tract.

Arctostaphylos uva-ursi

Arctostaphylos uva-ursi (bearberry) is a plant species of the genus Arctostaphylos. Its leaves have been traditionally used as diuretics. It is approved in Germany as a therapeutic alternative for cystitis, especially in cases where E. coli is involved (58).

Its active ingredient is glycoside arbutoside, which is metabolised to hydroquinone glucuronide. In alkaline urine (such as in UTI), the hydroquinone glucuronide decomposes and hydroquinone (acting as a direct antimicrobial agent) is released. In addition the plant contains tannins, which could enhance the antibacterial effect of β-lactam antibiotics against methicillin-resistant S. aureus (MRSA).

There is data that long term use of synthetic hydroquinone could be carcinogenic. Hence the recommendation that this phytotherapeutica should not be used for more than 2 weeks.

Juniperus communis

Juniperus communis (juniper) belongs to the Cupressaceae family. The terpenoids contained in the leaves and berries are responsible for its antibacterial and diuretic effects. The main antibacterial activity of this plant results from terpinen-4-ol. This plant contains several other important active ingredients including oxygenated sesquiterpene, β-pinene, sabinene, monoterpene hydrocarbons, limonene, and myrcene (59).

Vaccinium macrocarpon (cranberry)

Vaccinium macrocarpon belongs to the Ericaceae family. It has been a subject to numerous studies, because of its effectiveness against E. coli (60). It exerts its effect through inhibition of the adhesion of type I and P-fimbria of the uropathogens to the uroepithelium, thus reducing the bacteria’s ability to attach to the bladder wall. Cranberry juice consumption limits the ability for formation of biofilm in both Gram-negative and Gram-positive bacteria.

Cranberry is reach in proanthocyanidins, which contribute to the anti-adhesion ability. Studies show additional effect against S. aureus, P. aeruginosa, K. pneumoniae, and P. mirabilis.

Other biologically active compounds include anthocyanidin, catechin, flavanols, myricetin, quercetin, and phenolics (61).

Cinnamon

Cinnamon belongs to the Lauraceae family and exerts significant antioxidant and antibacterial abilities. It contains bioactive molecules such as trans-cinnamaldehyde, eugenol, trans-cinnamyl acetate, and proanthocyanidins, which have beneficial effect in UTI treatment (62).

Amalaradjou et al. (63) reports that trans-cinnamaldehyde in the form of essential oil has inhibitory activity on biofilm formation of E. coli on urinary catheters, which is achieved by down regulating main genes of bacterial virulence. Additional mechanisms contribute to the antibacterial abilities of essential oils: (I) they are hydrophobic, hence their molecules target the lipid-containing bacterial cell membrane and mitochondria, altering their permeability and disrupting their function; (II) inhibitory activity on energy production and glucose uptake; and (III) inhibition of vital enzymes such as amino acid decarboxylases (64).

Echinacea angustifolia

Echinacea angustifolia (purple coneflower) root is a widely used immune stimulant. It is mainly utilized in treating and preventing infections in patients who are immunocompromised or when therapeutic failure is present with other agents (65). Purple coneflower should be avoided in patients with significant autoimmune diseases or those taking immunosuppressive drugs.

A short description of main characteristics of some of most popular phytotherapeutica in Western medicine, discussed in this article are presented in Table 2.

Conclusions

The therapeutic approaches for LUTS/BPH, ED, CP/CPPS and UTI at the present time are highly sophisticated and innovative, and more and more centered on the patients` expectations and concerns. Phytotherapy is one of the most widely used forms of treatment. Several concerns related to phytotherapeutica are that this type of treatment should not be used as an OTC without appropriate diagnostic work-up, and should be reserved for patients with mild or moderate symptoms.

Several conceptual problems generalized to phytotherapy and preventing it to take its deserved place in evidence-based medicine are the need to standardize the different source plants and extraction process, to better understand the mechanism of action of the different and frequently multiple active substances, to perform clinical trials with sophisticated design and protocol to evaluate the efficacy and safety of the various phytotherapica, and finally to obtain the highest level of evidence by running systematic reviews and meta-analyses, aiming to include phytotherapy in the most important international guidelines.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Noor NP Buchholz) for the series “Integrative Medicine Approaches to Common Urological Problems” published in Longhua Chinese Medicine. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://lcm.amegroups.com/article/view/10.21037/lcm-21-38/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://lcm.amegroups.com/article/view/10.21037/lcm-21-38/coif). The series “Integrative Medicine Approaches to Common Urological Problems” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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