Jillian L. Capodice, LAc introduces a variety of botanicals and supplements commonly known as “prostate-specific” and provides an overview on some of the available research.
Abstract: Various prostate conditions may affect many men over their lifetime. These common disorders include acute or chronic inflammation of the prostate gland, benign prostatic hyperplasia and prostate cancer. Complementary, alternative and integrative medicine strategies such as those that investigate and utilize botanicals and dietary supplements as potential preventive and therapeutic agents are important. While many promising agents are available, evidence-based research on both preclinical mechanism(s) of action and potential utility in the clinic must be determined before definitive recommendations can be made. This article briefly introduces a variety of botanicals and supplements commonly known as “prostate-specific” and provides a quick overview on some of the available research.
Disorders of the prostate may affect many men over their lifetime. These conditions range from mild inflammation of the prostate gland, to benign enlargement and prostate cancer. The aforementioned conditions all have significant prevalence and are vastly different pathological conditions; however one shared feature is that advances in preclinical and clinical research will enable us to learn more about the prevention and treatment of these diseases. Integrative medicine, which is the application of evidence-based complementary and alternative medicine (CAM) strategies into the clinic, includes biologic-based CAM therapies including botanicals and supplements and practitioner-based therapies such as acupuncture and massage. Many CAM therapies are popular and are in broad public use and investigation of them in an evidence-based manner is necessary for the sustainability of integrative medicine. This article introduces some of the botanicals and supplements associated with prostate health and begins to highlight research on each agent under investigation for the potential prevention and treatment of prostate cancer and other prostate disorders.
Background on Prostate Cancer and Prostate Terms
Prostate cancer (CaP) has been estimated to affect one in six men at some point during their lifetime and an estimated 218,890 new cases are predicted in 20071,2. Prostate cancer risk is associated with a number of factors including advanced age (increases with each decade >50), family history (father or siblings), race (greater prevalence in African American men) and lifestyle (e.g.: smoking). However an extremely important fact about prostate cancer is that it may be close to one hundred percent survivable if it is detected in its early stages3. This information coupled with epidemiologic data on the role of nutritional, dietary and lifestyle behaviors and cancer also illustrates prostate cancer as an excellent model for chemoprevention4. Chemoprevention is a term that was coined to define natural, synthetic or biologic agents used to reverse, suppress or prevent the development of the process of carcinogenesis6. Currently the only proven agent for CaP chemopreventive is the 5-α-reductase inhibitor finasteride5.
The study of finasteride as a chemopreventive agent was based on epidemiological evidence and observation on its clinical utility in reliving the symptoms of benign prostatic hyperplasia (BPH). The mechanism of action of finasteride is based on inhibition of the 5-α reductase enzyme which catalyzes the conversion of testosterone to dihydrotestosterone (DHT), thus sequestering DHT availability which fuels the growth of androgen dependant CaP5,7,8. While finasteride is the only proven cheompreventive agent for CaP, the mechanism of inhibition of the 5- α reductase enzyme has been hypothesized as a potential mechanism of action of various botanicals and supplements. I will discuss some of the pre-clinical and clinical data on these agents and stress that evidence-based research of these agents are necessary before definitive recommendations can be made. While this article is not designed to substitute as a visit to your health care professional, a few basic terms including the definition of the prostate, prostate specific antigen (PSA), biopsy and Gleason score are outlined in Table 1 in order to familiarize the reader with frequently mentioned terms. Table 2 further defines other conditions related to the prostate often referred to throughout this article including chronic prostatitis and benign prostatic hyperplasia (BPH).
A Primer on Herbal Products for Prostate Health: From A-Z
Anecdotal information and the impact of product marketing have suggested that botanicals and supplements may be efficacious in the prevention and treatment of various cancers, but to date, no agents have been validated as curative treatment or as prevention for any cancer. Promising preclinical and/or early phase clinical experimentation testing the anti-cancer potential and prostate health benefit(s) of many supplements and botanicals are both compelling and promising. Below we will outline some of the most common supplements and botanicals being studies for prostate cancer and prostate health. Table 3 provides a quick reference of all the botanicals and supplements mentioned in the article.
L-arginine is an essential amino acid that is present in the proteins of all life forms. It is synthesized in the kidneys and can also be found in some meats, vegetables, miso and yogurt. L-arginine is a precursor to the amino acids L-ornthine and L-proline, fundamental building blocks of collagen. Initial research on L-arginine was based on clinical observation of decreased arginine levels in patients with certain traumatic conditions including burns, sepsis and surgical trauma9,10. These observations spurred investigation on the potential anti-oxidant and cardio-protective activity of L-arginine as well as its potential chemopreventive ability11,12.
While L-arginine has found it way onto the list of many male-specific supplements, evidence-based research is sparse. Currently, no studies were found evaluating L-arginine for prostate health and only a handful of studies were found examining the potential activities of L-arginine. These include one study demonstrating growth inhibitory activity in a breast cancer cell line13 and research on the potential role of arginine and its role during immunosupression14. While these data are compelling, there is no substantial evidence at this time to support the benefits of L-arginine supplementation for the prevention or treatment of CaP and/or other prostate disorders.
Beta-sitosterol is one of the most abundant phytosterols in the diet and is commonly found in many plants, legumes and botanicals such as saw palmetto (Serona repens) and pygeum (Pygeum africanum). It is thought to be one of the key active ingredients in many of the prostate-specific herbs and is present in many combination products for male and prostate health. Preclinical research has demonstrated that beta-sitosterol inhibits the growth of prostate cancer cell lines15,16 and reduces xenograph tumor volumes (Awad et al 2001). Additionally, two clinical trials have reported preliminary efficacy of beta-sitosterol in the treatment of voiding symptoms related to BPH and demonstrate improvement in symptoms such as flow rate and decreased post void residual urine volume17,18,19. Further trials need to confirm these promising results and additional studies on botanicals containing beta-sitosterol (saw palmetto and pygeum) are mentioned below.
C: Curcumin (see: turmeric)
D: Vitamin D
Vitamin D is created by a reaction between UV light and the skin. Since it is not readily available in many sources, foods such as dairy products, breads and cereals are now fortified with vitamin D. Vitamin D is also available as a single supplement, an ingredient in some calcium supplements and in multi-vitamins made by numerous manufactures. The chemical structure is 1-α, 25-dihydroxyvitamin D or 1, 25(OH2)D9.
Previous epidemiological data had loosely correlated vitamin D deficiency with increased CaP risk though more recent studies have not found any association9. Current research and development of synthetic vitamin D analogs and vitamin D ligand receptors such as calcipotriol and calcitrol are underway. These agents may have inhibitory activity against prostate cancer cell lines and/ or synergistic activity with conventional chemotherapeutic agents21-24. Many of these preclinical and clinical investigations are underway and will further determine the utility of these agents.
E: Vitamin E, Essential Fatty Acids (see: fish oils, see omega-3)
Vitamin E is an antioxidant with potential cardio-protective and chemopreventive activity. Vitamin E describes 4 tocopherols and 4 tocotrienols but the most commonly supplemented form of vitamin E is a-tocopherol9.
While recent clinical data suggests that long-term (>4 years) and high-dose (>400IU) vitamin E supplementation may increase the risk of cardiovascular events in patients with diabetes mellitus and vascular disease, a large phase III trial entitled the Selenium and Vitamin E Cancer Prevention Trial (SELECT) is underway testing vitamin E supplementation (400 IU/day, all rac alpha-tochopheryl acetate) alone or in combination with the trace mineral, selenium (200 ug/day, L-selenomethionine) for prostate cancer chemoprevention25,26. The primary endpoint of the SELECT study is the clinical incidence of CaP as determined by a routine clinical work-up, including yearly digital rectal examination (DRE) and serum prostate specific antigen (PSA) levels. The final results of SELECT are anticipated in 201326.
F: Fish oils
Fish oils are tremendous sources of essential long-chain polyunsaturated fatty acids (LCPFA). These LCPFA’s are found in other plants including flax, evening primrose and algae; however fish oils are one of the richest sources of these lipids. Two of the most commonly studied fish oils are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
Both EPA and DHA are being examined for their potential anti-inflammatory activity and possible utility in chronic inflammatory conditions including cardiovascular disease and cancer27-29. Regarding prostate health, epidemiological studies have found conflicting evidence regarding fish oil supplementation and CaP incidence30,31. However preclinical investigations have also demonstrated that EPA and DHA are able to inhibit the growth of the prostate cancer cell line LNCaP and decrease mRNA levels of five up-regulated genes32. Recent in vivo data also suggest that rats fed a diet high in omega-3 stearidonic acid demonstrated decreased tumor growth, increased apoptosis and decreased proliferation in tumor cells33. While further research including placebo-controlled clinical trials will hopefully address these discordant results, no clear evidence is yet available suggesting the benefit of fish oil for prostate health.
G: Garlic, Ginger, Green Tea
Garlic (Allium sativum) is a commonly used herb in many cuisines and its posited health benefits are mainly derived from anecdotal evidence and a few epidemiological studies34,35. Recently, investigators have proposed hypotheses testing the anti-cancer potential of garlic but only a few preclinical studies were found testing garlic and diallyl trisulfide (an active component of garlic) for their potential inhibitory activity in the PC-3 and DU-145 prostate cancer cell lines36-38.
Ginger (Zingiber officinalis) is another well-known culinary herb that is also recognized to stimulate the digestive system and decrease subjective symptoms such nausea and motion sickness39,40. It has only been recently proposed as a powerful anti-inflammatory and potential anti-cancer agent in various preclinical cancer cell model systems including a colon cancer cell line and the epidermal mouse cell line JB6 often used to study tumor progression41. However no studies were found solely testing ginger or ginger products in a prostate cancer cell model system and only one study was found testing a combination formulation containing ginger called Zyflamend®, which exhibited inhibitory activities in the LNCaP cancer cell line42.
Green tea is a beverage that is traditionally drank in many Asian countries. There are many varieties of green tea and the most common plant is Camellia sinensis. Compositional analysis of green tea has revealed potent polyphenolic compounds termed catechins, which are further subdivided into flavan-3-ols. Green tea contains four major flavanols; (-)-epigallocatechin gallate (EGCG), (-)-epicatechin gallate (ECG), (-)-epigallocatechin (EGC) and (-)-epicatechin (EC) (Medical Economics 1998). EGCG is the most widely in studied both in vitro and in vivo chemoprevention studies.
In vitro studies have begun to elucidate the complex molecular mechanisms of action of ECGC and green tea polyphenols against prostate cancer cell lines and different investigators have demonstrated that inhibitory effects are due to induction of apoptosis43 inhibition of cell cycle progression44, and inhibition of key cell signaling pathways45. Many of these preclinical data have yielded translational phase I studies assessing the pharmacokinetics, safety and tolerability of green tea46 which have led to larger phase II and III clinical trials (currently underway) of green tea as a potential chemopreventive agent in breast, colon and prostate cancers47,48.
I: Isoflavones (soy isoflavones)
Soy isoflavones are considered phytoestrogens, plant-derived non-steroidal compounds with estrogen-like biological activity. Soy isoflavones consist of three main glycosylated aglycones, genistein, daidzein and glycitein, and each has been found to have both weak estrogenic and anti-estrogenic effects in vitro49. Pre clinical data have also demonstrated the anti-cancer activity of soy isoflavones in prostate, colon and breast cancer cell models50,51.
Initial clinical trials investigating the pharmacokinetic evaluation of genistein and daidzein demonstrated no clinically significant behavioral or physical changes regarding toxicity and rapid plasma and urine clearance of free and total genistein and daidzein ((1, 2, 4, 8, or 16 mg/kg body wt) in 30 healthy men) (t1/2 (elimination half-life) values of 3.2 h (free genistein) and 4.2 h (free daidzein))52. Other clinical trials tested the effect of various soy compounds on biomarkers. One pilot study confirmed a decreased percent change of free and total PSA ratios in prostate cancer patients consuming soy containing bread versus controls ((27.4% versus 15.6% respectively (p = 0.01))52. These and other promising investigations suggest that isoflavones may be potential prostate cancer chemopreventive agents and further clinical trials are necessary.
Lycopene is a member of the carotenoid family. It serves as an accessory light-gathering pigment and antioxidant in plants and algae and is responsible for giving vegetables and fruits their color. Lycopene is available in watermelons, papaya, pink guava, grapefruit, tomatoes and tomato-based products including tomato sauce, tomato juice and ketchup. Processed tomato products generally have more available dietary lycopene than fresh tomatoes9.
Regarding its role as a potential prostate cancer chemopreventive agent, a thorough meta-analysis of 11 case-control studies and 10 cohort studies assessed the use of tomato, tomato products, and/or lycopene and the relative risk of CaP53. The main findings were that the relative risk (RR) of prostate cancer among consumers of high amounts of raw tomato (5th quintile of intake) was 0.89, (95% CI 0.80–1.00) and less than nonfrequent users of tomato products (1st quartile of intake)52. In addition, lycopene intake from tomato products and particularly cooked tomato products seemed more bioavailable52-54. Based on these epidemiologic studies, current clinical trials are attempting to determine dose and response rates of supplemented lycopene. A recent phase I-II trial of lycopene supplementation in 36 men with biochemically relapsed prostate cancer (as determined by PSA) received daily lycopene supplementation of 15, 30, 45, 60, 90, and 120 mg/day for 1 year and demonstrated that lycopene was well tolerated in this patient population but supplementation at the doses used in the study did not result in any serum PSA response55. In conclusion, lycopene has potential as a potential chemopreventive agent although larger clinical trials are warranted.
O: Omega-3 Fatty Acids (Alpha-linoleic Acid)
Aloha-linoleic acid is an omega 3 fatty acid that contains 18 carbon atoms and 3 double bonds. It is also known as ALA9. ALA is metabolized to eicosapaentenoic acid (EPA) and docosahexaenoic acid (DHA) and EPA is a precursor to multiple eicosaniods which have both anti-inflammatory and anthi-arterogenic porpoerties. Numerous studies on prostate cancer risk have demonstrated conflicting results. Alpha-linolenic acid (ALA) is the most common omega-3 fatty acid in the Western diet however the relationship between dietary intake of ALA to prostate cancer risk remains unresolved. In 2004, Leitzman et al prospectivley evaluated the association between dietary intakes of alpha-linoleic and other fatty acids including, EPA (eicosanpentaenoic), DHA (docosahexaenoic), LA (linoleic), and AA (arachidonic acids and prostate cancer risk in 47,866 men56. Theses results demonstrate that of total cases, ALA intake was unrelated to risk, however, multivariate analyses demonstrated that in general, men with high intakes of ALA from meat and dairy were less likely to undergo CaP screening than those with greater ALA intakes from non-animal sources. However overall analysis determined that there was a weaker association for ALA intake (multivariate RR: 1.70; 95%CI:1.08,2.68;P for trend =0.04) than the authors previous report in 198657. Certain limitations regarding ALA studies and dietary intake vary depending on the oil type used in processed food versus sources from fish, meats, fruits, vegetables and grains. Moreover, studies of blood ALA levels are controversial due to low concentrations in most tissues including plasma and erythrocytes58. Based on the literature, at this time, it is difficult to make recommendations based on ALA intake, however it seems source of ALA intake and other risk factors including family history, genetic factors other dietary and lifestyle habits are all factors.
P: Pomegranate, pygeum
Pomegranate fruit (Punica granatum) is widely consumed as a fruit and juice and both anecdotal and epidemiological evidence suggest that the consumption of pomegranate juice may be a valuable cardioprotective agent and antioxidant59,60. Constitutional analysis of pomegranate seeds and husks reveals sugars, sterols, proteins, pectins and potent polyphenolic compounds including punicalagin and ellagic acid (of which punicalagin seems to be the most widely active and abundant)61.
Initial biochemical and cell based analysis has revealed preliminary effectiveness of pomegranate juice as a cardioprotective and anti-artherosclerotic agent and suggested it may have potential chemopreventive activity against human breast, colon, and prostate cancer cell62-64.
While there are only a few studies of pomegranate extract as a chemopreventive agent for prostate cancer, initial studies suggest that various elements of pomegranate juice (ellagic acid, lutieloin and caffeic acid from the juice and pericarp and steroidal chemicals 17-α estradiol, campesterol, gamma tocopherol, punicic acid) may act synergistically to enhance its antiproliferative activities in prostate cancer cell lines65. These same investigators also noted that pomegranate fractions may also inhibit the action of PC-3 prostate cancer cells across Matrigel ™ protein matrix membranes66.
While no human clinical trial data is available testing pomegranate juice as a potential chemopreventive, bioavailability data analysis suggests that ellagic acid and tannins found in pomegranate extracts are detectable in human plasma after oral consumption of pomegranate juice (180ml)67. In addition, pomegranate juice has been tested in a phase II trial of men with rising PSA following primary therapy for prostate cancer. This phase II study evaluated daily supplementation of 8 oz of pomegranate juice in men with a detectable PSA > 0.2 and < 5 ng/mL and Gleason score < or = 7, until disease progression. The results demonstrated a significant increase in mean PSA doubling time with treatment from a mean of 15 months at baseline to 54 months post treatment (p < 0.001) and corresponding laboratory effects on prostate cancer in vitro cell proliferation and apoptosis68. Together these promising in vitro and in vivo analyses of pomegranate juice demonstrate its promise as a chemopreventive agent for prostate cancer and its potential protective activity following prostate cancer treatment.
Pygeum (Pygeum africanum) is a tree commonly found in the mountains of central and southern Africa. Its bark is anecdotally known to offer relief from lower urinary tract disorders thus spurring its popularity as an herb for prostate health. Compositional analysis of pyguem has revealed antioxidants, ferrulic esters and beta-sitosterol (see: beta-sitosterol)9. Despite this compelling anecdotal evidence and a few positive case-reports, evidence-based research has yet to determine its efficacy for BPH or as a potential chemopreventive for CaP.
Resveratrol is a polyphenolic chemical known as 3,4′,5 trihydroxystilbene and exists in cis- and trans-stereoisomeric forms of which the trans-form is more active. It is most commonly known as a component found in grapes, grape skins and grapevines (resulting in higher resveratrol concentrations in red wines) but is also an active constituent in plants such as mulberries, peanuts and Polygnim cuspidatum (hu zhang in the traditional Chinese materia medica)69.
Initial biochemical analysis of resveratrol has suggested that both resveratrol and its synthetic analogues are able to inhibit growth of prostate and other cancer cell lines70,71. Molecular-based studies have similarly focused on the mechanistic effects of resveratrol and its ability to induce apoptosis and affect critical cell cycle signaling events in prostate cancer cell lines.
Despite the abundance of molecular data, only one in vivo study was found testing the effects of resveratrol and red wine consumption for its potential cardio-protective effects on platelet aggregation72. In addition, there were no Medline listed trials testing resveratrol in in vivo rodent or xenograph models of CaP or in human prostate cancer toxicity-based or chemoprevention clinical trials73,74. Finally, the question of whether resveratrol activity can be achieved at physiological doses has yet to be determined. Taken together, further analysis of the potential chemopreventive or therapeutic capability of resveratrol is warranted.
S: Saw palmetto
Saw palmetto (Serenoa repens) has received a great deal of attention in urology due to anecdotal evidence regarding its prostate specific properties. Compositional analysis has determined that beta-sitosterol, fatty acids and antioxidants may all contribute to its potential therapeutic activity9. Initial studies implied that the potential mechanism of action of saw palmetto might mimic the pharmaceutical 5-α reductase inhibitors though these data are weak75-76. Nevertheless ongoing studies on the mechanism, utility, and efficacy of saw palmetto as a potential chemopreventive agent may make clear the controversy surrounding this popular prostate herb. It is also important to note that a recent double-blind trial of saw palmetto for lower urinary tract symptoms demonstrated no significant effect of saw palmetto supplementation on American Urological Association Symptom Index scores (AUASI) (mean difference, 0.04 point; 95 percent confidence interval, -0.93 to 1.01) and maximal urinary flow rate (mean difference, 0.43 ml per minute; 95 percent confidence interval, -0.52 to 1.38)77.
T: Tomato products (see: lycopene), Turmeric
Turmeric (Curcuma longa) is a popular herb used in Indian and Asian cuisine and is widely know for giving curry its golden color. Composition of the herb includes antioxidants, essential oils and the well known potent polyphenolic compounds called curcuminoids. The major curcuminoids are curcumin, bisdemethoxycurcumin and demethoxycurcumin of which 75% of the total curcuminoids are curcumin9. There are many turmeric supplements available on the market with a wide variety of levels of standardization of curcumin and related curcuminoids. While the majority of in vitro analysis has been done on curcumin alone, it has been suggested that synergistic actions of the whole turmeric spice may exert additional potent antioxidant and chemopreventive activities.
Curcumin is a widely studied herb and initial analysis has focused on its antioxidant and anti-inflammatory activities78,79. Molecular analysis of curcumin has demonstrated its ability to induce apoptosis in LNCaP and PC-3 cell lines as well as the bone metastatic CaP cell lines C4-2B80-82. While there seems to be less in vivo data, some experimentation on curcumin has established that it was able to significantly inhibit LNCaP tumor size in nude mice, decrease cellular proliferation via BrdU analysis and inhibit angiogenesis as measured by CD31 antigen staining83. On the contrary, curcumin was not found to be effective against 3, 2’-dimethyl-4-aminobiphenol (DMAB) – and 2-amino-1-methylimidazo [4, 5-b] pyridine (PhIP)-induced rat ventral prostate cancer tumors84.
Despite the provocative in vitro and in vivo analysis, more confirmatory data regarding the mechanism of action of curcumin, its synergistic potential and its effect in human chemoprevention trials are necessary.
W: Wine (see: resveratrol)
Zinc is an essential element of human nutrition with multiple functions including presence in all organs, tissues, fluids and secretions and maintenance of biological membranes. Zinc is involved in sperm formation and testosterone metabolism, which may contribute to its reputation as an important mineral for men’s health. In addition, the potential immunomodulatory activity of zinc has been suggested. It is available in a wide variety of supplemental forms including zinc gluconate and zinc aspartae. It is also a common ingredient in many multivitamins. The controversy surrounding zinc supplementation as a risk factor for prostate cancer, a potential chemopreventive agent with inhibitory activity in the prostate and as a potential prognostic marker in combination with PSA is evident85-88. A recent analysis of trace mineral supplemtnation also reported mixed results from case–control and cohort studies. Kolonel et al studied the association between dietary Zn intake and risk and reported a statistically significant positive association between total Zn (including foods and supplement Zn) and prostate cancer risk among Hawaiian men over the age of 70 years but not among men under 70 years of age89,90. Conversely, a borderline inverse association between prostate cancer risk and Zinc supplementation found a statistically non-significant 37% decreased risk of prostate cancer in association with toenail Zn levels91. Currently there are no convincing answers regarding zinc supplementation as a chemopreventive agent for prostate cancer. Additional concern regarding zinc supplementation and its potential to decrease the absorption of concomitant intake of bisphosphonates and quinilone antibiotics commonly used in the treatment of CaP and chronic prostatitis respectively, is notable9,92. Until important preclinical and clinical studies are able to determine the effects of zinc, no ultimate recommendations can be made.
A variety of botanicals and supplements exist for the potential treatment of prostate health. While many of the abovementioned agents have strong anecdotal history and/or long use in traditional medical healing systems, evidence-based medicine and the necessity for rigorous research determining potential risk(s) and benefit(s) is necessary. However, one of the difficulties, surrounding the study of botanicals and supplements are the determination of active component(s), synergistic activity and concomitant use with pharmaceutical agents. The long term goals of the clinician, researcher and patient are to focus on education, awareness and research in order to facilitate integrative medicine. In the case of prostate cancer and prostate health, good diet, nutrition and botanical and dietary supplementation seems important and until all the research is done, it can’t hurt to add an extra cup of green tea and a nice tomato salad to one’s daily diet.
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Additional articles on this topic:
- Multivitamin Use and Risk of Prostate Cancer in the National Institutes of Health – AARP Diet and Health Study
- Prostate Health: Nutritional Support for Man’s Most Pressing Health Concerns
- Phase II Trial of Isoflavone in Prostate-Specific Antigen Recurrent Prostate Cancer After Previous Local Therapy
- Researchers Discover Common Variations in Gene Segments that Increase the Risk for Prostate Cancer
- Can Homeopathic Treatment Slow Prostate Cancer Growth?