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Complementary and alternative medicine in men’s health
Review
Complementary and alternative medicine in men’s health Keywords Complementary and alternative medicine Benign prostatic hyperplasia Prostate cancer Erectile dysfunction
Jinsung Park, Dong Wook Shin and Tai Young Ahn Abstract The use of complementary and alternative medicine (CAM) for the management of urologic disease is increasing worldwide. Meanwhile, with the aging of populations, men’s health is becoming an important issue. Numerous dietary and phytotherapeutic agents have been used for the treatment of benign prostatic hyperplasia, prostate cancer, and sexual dysfunction. Despite increasing evidence, the exact mechanisms of action, efficacy, and safety of CAM are currently unknown. Most CAM studies have been criticized due to flaws in methodology and small sample sizes. Considering these circumstances, it is important for urologists to become knowledgeable about the scientific evidence for CAM. This article reviews the effects of CAM on men’s health, focusing on clinical evidence. We conclude that, when performed properly, CAM is beneficial in improving men’s health and well-being. ß 2008 WPMH GmbH. Published by Elsevier Ireland Ltd.
Introduction
Jinsung Park, MD Department of Urology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea Dong Wook Shin, MD Quality of Cancer Care Branch, National Cancer Control Research Institute, National Cancer Center, Seoul, Korea Tai Young Ahn, MD, PhD Department of Urology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
E-mail: [email protected]
Online 23 October 2008
The use of complementary and alternative medicine (CAM) for the management of urologic disease is increasing worldwide. Although the exact definitions vary, CAM includes a broad set of practices that do not conform to the conventional practice model of the dominant medical community. Since CAM comprises hundreds of medical methods it is a confusing term. Strictly speaking, the term ‘alternative medicine’ implies health care practices that are not readily integrated into the dominant health care model, whereas the term CAM implies that they are used to complement one another. Despite the distinction in terminology, CAM is often regarded as alternative medicine and the two terms are used interchangeably. Despite public preference for the holistic approach of CAM, it has yet to be readily adopted by urologists. The most important reason for this reticence is the lack of scientific evidence, which is mainly due to missing prerequisites such as personal, financial, and spatial resources. Furthermore, the academic world is often very negative towards
ß 2008 WPMH GmbH. Published by Elsevier Ireland Ltd.
CAM. Most CAM studies to date have been performed on a small scale and are rarely blinded or controlled. Another important issue is that of safety. Most CAM products do not undergo stringent clinical development and adverse-event reporting, which is mandatory for approved pharmaceutical agents. Moreover, the quality-control process does not apply to some over-the-counter herbal products. Nearly half of the American and European populations use some form of CAM, with the expectation of health benefits [1]. However, most patients do not inform their physicians of CAM use. Furthermore, the cost for individual patients, as well as for society as a whole, is substantial [1]. In this regard, it is not appropriate for urologists to ignore or suppress the use of CAM without a scientific basis for such a decision. Rather, urologists should be familiar with the increasing scientific evidence to ensure proper patient guidance, regardless of their own personal beliefs, on the benefits of CAM. There are many well-written review articles that focus on the use of CAM in areas of
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Review urology. However, most of them include preclinical evidence of therapeutic benefits, which usually turn out to be not effective in clinical trials. In this article, we will summarize the scientific evidence for CAM use in men’s health from a clinical viewpoint, including treatments for benign prostatic hyperplasia (BPH), prostate cancer, and sexual dysfunction.
Benign prostatic hyperplasia The effects of diet, including fat, fruits, and vegetables, on the incidence and clinical course of BPH have been investigated in several studies [2–5]. Lagiou et al. reported that a highfat diet is associated with increased risk of BPH, which can be reduced by fruit intake [2]. Although the exact mechanisms vary, excessive calories and saturated fat, especially from dairy products and red meat, promote obesity and prostate cell growth by increasing the production of insulin growth factor type-1 (IGF-1) and inflammatory arachidonic acid by-products [5–7]. In contrast, dietary fibers and antioxidants found in fruits and vegetables, particularly tomatoes and cruciferous vegetables, and phytoestrogens found in soy protein, prevent prostate disease by counteracting free radical damage, blocking the harmful effects of IGF-1 and excess sex hormones, reducing serum cholesterol levels, and preventing aromatase activity [2,8–10]. Bravi et al. reported that specific types of food, such as cereals, bread, eggs, and poultry, increase blood glucose and cause hyperinsulinemia, promote IGF, and, subsequently, prostatic cell growth and BPH [4]. Garlic (Allium sativum) and its preparations have been used to treat BPH symptoms owing to anti-inflammatory and antioxidant effects [11].
The use of phytotherapeutic agents (where ‘phyto’ indicates ‘plant’) for lower urinary tract symptoms (LUTS) due to BPH has increased in the United States and throughout the world over the past 10 years [12]. Buck reported that phytotherapy improved BPH symptoms in up to 70% of patients [13], which may explain why 50% of German urologists prefer plant-based therapies to synthetic medications for men with symptomatic BPH [14]. Currently, there are more than 30 botanical compounds available for BPH treatment. The most commonly used compounds are shown in Table 1 [15]. Plant extracts contain phytosterols (b-sitosterol, campestrol, stigmasterol, d5-sterol, d-7-sterol), phytoestrogens (lignans, flavonoids, isoflavonoids (genistein, daidzein)), fatty acids (lauric and myristic acid), lectins, plant oils, polysaccharides, lupenone, lupeol, and terpenoids [15]. Experimental data suggest several mechanisms of action for phytotherapeutic agents, including anti-androgenic effects, androgen and estrogen receptor inhibition, 5a-reductase inhibition, anti-inflammatory effects, interference with prostaglandin metabolism, inhibition of phospholipase A2 and 5-lipoxygenase, blockade of arachidonic acid release, suppression of prostate cell metabolism and growth, inhibition of growth factor or prolactininduced prostatic cell proliferation, aromatase inhibition, protection of bladder and detrusor function, reduced levels of sex hormone-binding globulin, and induction of apoptosis [15–17]. However, it is unclear which, if any, of these proposed mechanisms is responsible for the clinical responses. The most popular extract in terms of sales revenue and clinical trial investigation is that from the dried berry of saw palmetto (botanical names, Serenoa repens and Sabal serrulata).
Table 1 Origin of phytotherapeutic preparations currently used for treatment of LUTS/BPH Plant (species)
Part used
American dwarf palm/saw palmetto (Serenoa repens/Sabal serrulata) African plum tree (Pygeum africanum, Prunus africana) South African star grass (Hypoxis rooperi) Pine (Pinus), spruce (Picea) Stinging nettle (Urtica dioica) Rye (Secale cereale) Pumpkin (Cucurbita pepo)
Fruit Bark Root Root Root Pollen Seed
LUTS/BPH, lower urinary tract symptom/benign prostatic hyperplasia.
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Review Serenoa repens (Permixon1, Pierre Fabre Medicament, Boulogne, France) is one of most commonly used phytotherapeutic agents for treating urologic disorders, and has been approved as a treatment for BPH in France and Germany. Fruits from this plant contain b-sitosterol, fatty acids, and antioxidants. Several meta-analyses have integrated the results from individual S. repens studies [18,19]. Wilt et al. integrated data from double-blinded and placebo-controlled analyses showing that S. repens improves urinary symptom scores by 28% and nocturia by 25% (10 studies), and peak urinary flow rate by 24%, compared with placebo (8 studies) [18]. However, the efficacy of S. repens on BPH is still a controversial issue. Recently, Bent et al. reported that saw palmetto did not improve symptoms or objective measures of BPH in a double-blind, randomized trial [20]. It should be noted that most published placebo-controlled studies are flawed because none met the generally accepted criteria developed by the International Consultation on BPH for assessing treatment results in men with LUTS. However, Zlota et al. reported that Permixon has no negative impact on male sexual function; this is in contrast to both Finasteride and Tamsulosin, which have a slight impact on sexual function, especially on ejaculation [21]. An extract from the African prune tree (Pygeum africanum) was reported to be effective in treating LUTS and obstructed bladder. Two recent clinical trials using P. africanum (Tadenan1, Laboratories Debat, Saint-Cloud, France) revealed an approximately 40% reduction in the International Prostate Symptom Score (IPSS) and improvement in the urinary flow rates of approximately 18% over baseline [22,23]. Based on a meta-analysis of 18 clinical trials, Ishani et al. demonstrated that men receiving P. africanum were more than twice as likely to be rated with symptom improvement by their physician, compared with men receiving placebo (65% versus 30%, relative risk (RR) = 2.1) [24]. However, another study did not show any efficacy with P. africanum [25]. Most studies advocating efficacy were flawed owing to the small sample size or the absence of a placebo arm, and the use of different methods. Therefore, more placebo-controlled studies with long-term follow-up are required. South African star grass (Hypoxis rooperi: Harzol1, Hoyer-Madaus GmbH & Co., Monheim,
Germany) has been shown to significantly improve voiding parameters in a 6-month double-blind, placebo-controlled trial, and an open-label follow-up study [26,27]. Azuprostat1 (Azupharma GmbH, Gerlinger, Germany), a combination of b-sitosterols from Hypoxis rooperi, pine (Pinus), and spruce (Picea), is also effective for BPH, as shown by a 6-month randomized, placebo-controlled trial [28]. No additional reports on the effects of H. rooperi have been published since the year 2000. Even fewer relevant clinical studies have been published on the other extracts listed in Table 1, specifically those from Urtica dioica, Cucurbita pepo, Secale cereale, and Opuntia. In a systematic review and meta-analysis, MacDonald et al. concluded that Secale cereale (Cernilton1, AB Cevenelle, Stockholm, Sweden) modestly improves overall urologic symptoms, including nocturia, but additional trials are required to evaluate its clinical effectiveness [29]. Among the mushroom extracts, Reishi mushroom (Ganoderma lucidum) displayed the strongest 5a-reductase inhibitory activity, interfering with prostate growth in a rat model [30], whereas Phellinus linteus induced prostate enlargement [31]. Thus, BPH patients should ingest this compound with care.
Prostate cancer CAM use is prevalent among 33–43% of prostate cancer patients [32–34]. Men at high risk for prostate cancer also show a high prevalence of CAM use [35]. Tomato contains a variety of carotenoids, among which lycopene is the most abundant. A large-scale cohort study by Giovannucci et al. demonstrated that total intake of tomatobased food is inversely associated with cancer risk [36]. Based on epidemiologic data, as well as preclinical evidence of antioxidant [37] and antitumor effects [38], lycopene and other carotenoids have been the focus of several clinical trials as potential chemopreventive agents for prostate cancer. In an open-label, non-controlled trial, Chen et al. examined the effects of tomato sauce-based pasta dishes on lycopene uptake, oxidative DNA damage, and prostatespecific antigen (PSA) levels in 32 patients awaiting radical prostatectomy [9]. Compared with baseline levels, oxidative DNA damage in prostate tissue and serum PSA levels were
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Review significantly reduced after therapeutic intervention [9]. Purified lycopene supplementation has also been examined in several clinical trials, and Matlaga et al. reported marked PSA reductions (even to nadir) [39]. In a phase II randomized trial performed before radical prostatectomy by Kucuk et al., the lycopene supplementation group displayed decreased tumor volume and lower plasma PSA levels, compared with the control group [40]. Ansari et al. performed a randomized controlled trial in 54 patients with advanced prostate cancer in which the combination of lycopene and orchiectomy was compared with orchiectomy alone. Reduced PSA levels, more complete response, and increased survival were observed in the combination treatment group compared to the orchiectomy alone group [41]. However, in a recent dose-escalating phase I/ II trial, although well tolerated, lycopene supplementation (dose range of 15–90 mg/day) did not result in a PSA response [42]. Ansari & Gupta also performed an open-label, singlearm trial examining the effects of lycopene on 20 patients with hormone-refractory prostate cancer (HRPC) and showing clinical and biochemical evidence of disease progression [43]. As most patients displayed stable tumor responses, improved general performance status, decreased bone pain, and reduced urinary tract symptoms, the investigators concluded that lycopene is effective and safe for HRPC [43]. However, recent evidence does not support the preventive effect of tomato carotenoids on the development of prostate cancer. In a large cohort study by Kirsh et al., lycopene was not associated with reduced prostate cancer risk [44]. Bunker et al. recently published data from an unblinded, randomized, phase I clinical trial investigating lycopene supplementation in Tobago men at high risk for prostate cancer [45]. In the lycopene group, serum PSA levels reduced during the first month of treatment, but returned to the randomization level by month 4, indicating that the PSA-lowering responses observed during previous 3-week studies in men were transient and this may, therefore, not be an appropriate endpoint for long-term studies [45]. Despite several conflicting results, increased consumption of tomato and lycopene supplements may generally be regarded as safe and possibly beneficial. This recommendation is consistent with current health guidelines to
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increase fruit and vegetable consumption. The relatively low cost and negligible toxicity make it an attractive complementary or alternative therapeutic option, particularly when conventional therapy is contraindicated or refused. Preclinical evidence of antitumor activity [46], and epidemiologic evidence of prostate cancer prevention with vitamin D [47–50] led to several phase I and II clinical trials. Liu et al. performed phase I [51] and phase II [52] trials with vitamin D in patients with advanced prostate cancer. No objective response was observed, and hypercalcemia and increased creatinine levels were major toxicities, resulting in termination of treatment. Phase I/II studies by Schwartz et al. on HRPC revealed no tumor response, but did show decreased parathyroid hormone levels, which may prevent skeletal complications [53]. Analyses by Beer et al. using vitamin D (calcitriol) in combination with docetaxel for advanced prostate cancer revealed a synergistic effect of vitamin D and chemotherapeutic agents [54,55]. In a recent epidemiological study, sunlight exposure was associated with increased survival of prostate cancer patients [56]. Selenium, known for its antioxidant and antitumor activities [57,58], was associated with decreased incidences of colorectal, lung, and prostate cancer in the Nutritional Prevention of Cancer Trial [59], with the most significant effects being on prostate cancer [60,61]. Similarly, vitamin E has antioxidant and antitumor properties [62,63]. In an a-tocopherol, bcarotene cancer prevention study involving 29,133 male smokers, vitamin E supplementation reduced the risk of developing prostate cancer, although the primary endpoint was lung cancer incidence [64]. Another study by Chan et al. confirmed this finding [65]. A largescale, prospective, randomized trial in more than 35,000 men (SELECT: selenium and vitamin E cancer prevention trial) is ongoing, with results expected in 2013 [66]. The finding that prostate cancer is not prevalent in areas such as China, together with preclinical evidence of the antitumor effects of green tea on prostate cancer cells [67], has prompted several clinical trials. In a small Italian study that examined the preventive effect of green tea in a high-risk group with high-grade prostatic intraepithelial neoplasia (pre-malignant lesions of prostate cancer), a significantly lower incidence was observed in
Review the green tea group compared with the nongreen tea group (incidence: 3% versus 30%, respectively) [68,69]. A larger, confirmatory, study is ongoing in the United States. Isoflavones, such as daidzein and genistein, have attracted considerable interest owing to epidemiological evidence of prostate cancer risk reduction [70] and preclinical evidence of antitumor activity [71]. In a randomized trial on early prostate cancer patients, the isoflavone group contained lower levels of free testosterone and PSA compared with the placebo group [72]. In open-label, phase II, nonrandomized clinical trials on patients with recurring PSA, soy milk has been shown to decrease the PSA velocity, suggesting activity in prostate cancer [73]. Modified citrus pectin (MCP) has shown antitumor and anti-metastatic activities in preclinical studies [74]. In a phase II pilot study by Guess et al., MCP treatment significantly prolonged the PSA doubling time [75]. PC-SPES (named from prostate cancer (PC) and the Latin, spes, for hope), is an eight-herb Chinese formulation, consisting of isatis (Isatis indigotica), either liquorice (Glycyrrhiza glabra) or Gan coa (G. uralensis), Chinese skullcap (Scutellaria baicalensis), reishi (Ganoderma lucidum), saw palmetto (Serenoa repens or Sabal serrulata), Asian ginseng (Panax ginseng), denodrantherm (Denodrantherma morifolium) and rabdosia (Rabdosia rubescens). The compound has gained popularity as a therapy for prostatic cancer, supported by preclinical evidence of estrogenic and antineoplastic effects [76] and favorable results from small-scale clinical studies on advanced prostate cancer patients [77–79]. However, the US Food and Drug Administration (FDA) advised against the use of this Chinese phytomedicine in February 2002, owing to the relatively high levels of diethylstilbesterol and warfarin, which can cause estrogenic and hemorrhagic complications. The compound is no longer marketed in the US. Several dietary supplements have been tested in clinical trials, with disappointing results. In mixed-cancer trials involving advanced prostate cancer patients, shark cartilage was inactive and had no salutary effect on the quality of life [80]. Other dietary supplements that have been used to treat prostate cancer patients, based solely on preclinical evidence, include silibinin [81,82], and a grape seed extract [83].
Sexual dysfunction: erectile dysfunction and premature ejaculation Although erectile dysfunction (ED) is an important health problem for which a plethora of CAM treatments are endorsed, the benefit of CAM use for ED is largely unknown, and welldesigned large-scale CAM-based clinical trials are limited at present. L-arginine, a precursor of nitric oxide (NO) that has been reported to increase NO levels in preclinical studies [84,85], has been examined in several clinical trials, either alone or in combination with other agents. In a doubleblinded, randomized, placebo-controlled trial, oral administration of arginine improved subjective sexual performance in patients with low urinary nitrate or nitrite (NOx) levels at baseline [86]. However, in another randomized, placebo-controlled cross-over trial in mixed-type impotence patients, L-arginine showed no benefits compared with placebo [87]. L-arginine has also been examined with other agents, including yohimbine [88,89] and pycnogenol [90]. Korean red ginseng (Panax ginseng) has been investigated in a double-blind, placebo-controlled, cross-over study by Hong et al. [91]. Patients in the Korean red ginseng group exhibited a higher mean International Index of Erectile Function score, particularly in terms of penetration and maintenance, and higher penile tip rigidity on RigiScan. Although the data are not conclusive, Korean red ginseng is recommended as a cost-effective alternative to phosphodiesterase type 5 (PDE-5) inhibitors [92]. The National Center for Complimentary and Alternative Medicine (NCCAM) is supporting trials to further clarify the beneficial effects of Asian ginseng for various indications. In a 12-week, double-blind, placebo-controlled trial involving 32 healthy male volunteers and their partners, deer velvet induced no significant differences in sexual behavior or hormonal levels [93]. Ginko biloba has been tested for antidepressant-induced sexual dysfunction. An open trial by Cohen & Bartlik supported its effectiveness [94], whereas in a placebo-controlled study, both the gingko and placebo groups showed improvement, suggesting a significant placebo effect in this population [95].
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Review Yohimbine, the bark extract of the yohimbe tree from western Africa, was evaluated in a three-arm clinical trial comprising placebo, yohimbine, and a combination of yohimbine and L-arginine. Yohimbine itself was effective, although the combination had a more significant effect [88]. Yohimbine may increase blood pressure and heart rate, and cause harmful drug interactions with a monoamine oxidase inhibitor or tricyclic antidepressant. Other commercial agents that claim to enhance sexual performance were prohibited in 2006 by the US FDA, these include Zimaxx, Libidus, Neophase, Nasutra, Vigor-25, Actra-Rx (Yilishen), and 4EVERON. These compounds contain variations of active ingredients in drugs prescribed for ED (notably PDE-5 inhibitors such as sildenafil) and may dangerously lower blood pressure when administered in combination with certain prescription medicines. Acupuncture in various formats (with or without moxibustion and with or without Chinese drug injections [96]) has been used to treat ED (mainly non-organic or psychogenic) [97,98]. In a randomized, controlled pilot trial in patients with psychogenic ED, a satisfactory response was achieved in 68.4% of the treatment group and 9% of the placebo group [99].
Limited studies on CAM have investigated its efficacy in premature ejaculation. Yoga had a similar efficacy to fluoxetine in a comparative trial in patients with premature ejaculation [100].
Conclusions Although concerns for the effects of CAM on men’s health are increasing, the exact mechanisms of action remain controversial. In addition, clinical efficacy and safety data based on well-designed clinical trials with no methodological flaws are lacking. Therefore, further randomized placebo-controlled trials of longer study duration are needed to evaluate the efficacy and safety of CAM in men’s health treatments. Based on increasing evidence, we propose that urologists have a responsibility to their patients to gain knowledge about the advantages and disadvantages of CAM. Furthermore, they should advise against therapies that are without merit or may cause harm, and recommend those that prevent chronic illness, reduce treatmentrelated side effects and improve men’s health and well-being.
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Review [56] Lim HS, Roychoudhuri R, Peto J, Schwartz G, Baade P, Moller H. Cancer survival is dependent on season of diagnosis and sunlight exposure. Int J Cancer 2006;119:1530–6. [57] Webber MM, Perez-Ripoll EA, James GT. Inhibitory effects of selenium on the growth of du-145 human prostate carcinoma cells in vitro. Biochem Biophys Res Commun 1985;130:603–9. [58] Jiang C, Wang Z, Ganther H, Lu J. Caspases as key executors of methyl seleniuminduced apoptosis (anoikis) of du-145 prostate cancer cells. Cancer Res 2001;61: 3062–70. [59] Clark LC, Combs Jr GF, Turnbull BW, Slate EH, Chalker DK, Chow J, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 1996;276:1957–63. [60] Combs Jr GF, Clark LC, Turnbull BW. An analysis of cancer prevention by selenium. Biofactors 2001;14:153–9. [61] Combs Jr GF. Status of selenium in prostate cancer prevention. Br J Cancer 2004;91: 195–9. [62] Gunawardena K, Murray DK, Meikle AW. Vitamin E and other antioxidants inhibit human prostate cancer cells through apoptosis. Prostate 2000;44:287–95. [63] Israel K, Yu W, Sanders BG, Kline K. Vitamin E succinate induces apoptosis in human prostate cancer cells: role for Fas in vitamin E succinate-triggered apoptosis. Nutr Cancer 2000;36:90–100. [64] Heinonen OP, Albanes D, Virtamo J, Taylor PR, Huttunen JK, Hartman AM, et al. Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst 1998;90:440–6. [65] Chan JM, Stampfer MJ, Ma J, Rimm EB, Willett WC, Giovannucci EL. Supplemental vitamin E intake and prostate cancer risk in a large cohort of men in the united states. Cancer Epidemiol Biomarkers Prev 1999; 8:893–9. [66] Klein EA, Thompson IM, Lippman SM, Goodman PJ, Albanes D, Taylor PR, et al. Select: the next prostate cancer prevention trial. Selenum and Vitamin E Cancer Prevention Trial. J Urol 2001;166:1311–5. [67] Gupta S, Hastak K, Ahmad N, Lewin JS, Mukhtar H. Inhibition of prostate carcinogenesis in tramp mice by oral infusion of green tea polyphenols. Proc Natl Acad Sci USA 2001;98:10350–5. [68] Bettuzzi S, Brausi M, Rizzi F, Castagnetti G, Peracchia G, Corti A. Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial
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[80] Miller DR, Anderson GT, Stark JJ, Granick JL, Richardson D. Phase I/II trial of the safety and efficacy of shark cartilage in the treatment of advanced cancer. J Clin Oncol 1998;16:3649–55. [81] Zi X, Agarwal R. Silibinin decreases prostate-specific antigen with cell growth inhibition via g1 arrest, leading to differentiation of prostate carcinoma cells: implications for prostate cancer intervention. Proc Natl Acad Sci USA 1999; 96:7490–5. [82] Singh RP, Deep G, Blouin MJ, Pollak MN, Agarwal R. Silibinin suppresses in vivo growth of human prostate carcinoma pc3 tumor xenograft. Carcinogenesis 2007; 28:2567–74. [83] Agarwal C, Singh RP, Agarwal R. Grape seed extract induces apoptotic death of human prostate carcinoma DU145 cells via caspases activation accompanied by dissipation of mitochondrial membrane potential and cytochrome c release. Carcinogenesis 2002;23:1869–76. [84] Moody JA, Vernet D, Laidlaw S, Rajfer J, Gonzalez-Cadavid NF. Effects of long-term oral administration of L-arginine on the rat erectile response. J Urol 1997;158: 942–7. [85] Gur S, Kadowitz PJ, Trost L, Hellstrom WJ. Optimizing nitric oxide production by time dependent L-arginine administration in isolated human corpus cavernosum. J Urol 2007;178:1543–8. [86] Chen J, Wollman Y, Chernichovsky T, Iaina A, Sofer M, Matzkin H. Effect of oral administration of high-dose nitric oxide donor L-arginine in men with organic erectile dysfunction: results of a double-blind, randomized, placebo-controlled study. BJU Int 1999;83:269–73. [87] Klotz T, Mathers MJ, Braun M, Bloch W, Engelmann U. Effectiveness of oral L-arginine in first-line treatment of erectile dysfunction in a controlled crossover study. Urol Int 1999;63:220–3. [88] Lebret T, Herve JM, Gorny P, Worcel M, Botto H. Efficacy and safety of a novel combination of L-arginine glutamate and yohimbine hydrochloride: a new oral therapy for erectile dysfunction. Eur Urol 2002;41:608–13: discussion 13. [89] Kernohan AF, McIntyre M, Hughes DM, Tam SW, Worcel M, Reid JL. An oral yohimbine/L-arginine combination (NMI 861) for the treatment of male erectile dysfunction: a pharmacokinetic, pharmacodynamic and interaction study with intravenous nitroglycerine in healthy male subjects. Br J Clin Pharmacol 2005;59:85–93. [90] Stanislavov R, Nikolova V. Treatment of erectile dysfunction with pycnogenol and L-arginine. J Sex Marital Ther 2003;29: 207–13.
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[98] Aydin S, Ercan M, Caskurlu T, Tasci AI, Karaman I, Odabas O, et al. Acupuncture and hypnotic suggestions in the treatment of non-organic male sexual dysfunction. Scand J Urol Nephrol 1997;31:271–4. [99] Engelhardt PF, Daha LK, Zils T, Simak R, Konig K, Pfluger H. Acupuncture in the treatment of psychogenic erectile dysfunction: first results of a prospective randomized placebo-controlled study. Int J Impot Res 2003;15:343–6. [100] Dhikav V, Karmarkar G, Gupta M, Anand KS. Yoga in premature ejaculation: a comparative trial with fluoxetine. J Sex Med 2007;4:1726–32.
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Complementary and alternative medicine in men’s health Keywords Complementary and alternative medicine Benign prostatic hyperplasia Prostate cancer Erectile dysfunction
Jinsung Park, Dong Wook Shin and Tai Young Ahn Abstract The use of complementary and alternative medicine (CAM) for the management of urologic disease is increasing worldwide. Meanwhile, with the aging of populations, men’s health is becoming an important issue. Numerous dietary and phytotherapeutic agents have been used for the treatment of benign prostatic hyperplasia, prostate cancer, and sexual dysfunction. Despite increasing evidence, the exact mechanisms of action, efficacy, and safety of CAM are currently unknown. Most CAM studies have been criticized due to flaws in methodology and small sample sizes. Considering these circumstances, it is important for urologists to become knowledgeable about the scientific evidence for CAM. This article reviews the effects of CAM on men’s health, focusing on clinical evidence. We conclude that, when performed properly, CAM is beneficial in improving men’s health and well-being. ß 2008 WPMH GmbH. Published by Elsevier Ireland Ltd.
Introduction
Jinsung Park, MD Department of Urology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea Dong Wook Shin, MD Quality of Cancer Care Branch, National Cancer Control Research Institute, National Cancer Center, Seoul, Korea Tai Young Ahn, MD, PhD Department of Urology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
E-mail: [email protected]
Online 23 October 2008
The use of complementary and alternative medicine (CAM) for the management of urologic disease is increasing worldwide. Although the exact definitions vary, CAM includes a broad set of practices that do not conform to the conventional practice model of the dominant medical community. Since CAM comprises hundreds of medical methods it is a confusing term. Strictly speaking, the term ‘alternative medicine’ implies health care practices that are not readily integrated into the dominant health care model, whereas the term CAM implies that they are used to complement one another. Despite the distinction in terminology, CAM is often regarded as alternative medicine and the two terms are used interchangeably. Despite public preference for the holistic approach of CAM, it has yet to be readily adopted by urologists. The most important reason for this reticence is the lack of scientific evidence, which is mainly due to missing prerequisites such as personal, financial, and spatial resources. Furthermore, the academic world is often very negative towards
ß 2008 WPMH GmbH. Published by Elsevier Ireland Ltd.
CAM. Most CAM studies to date have been performed on a small scale and are rarely blinded or controlled. Another important issue is that of safety. Most CAM products do not undergo stringent clinical development and adverse-event reporting, which is mandatory for approved pharmaceutical agents. Moreover, the quality-control process does not apply to some over-the-counter herbal products. Nearly half of the American and European populations use some form of CAM, with the expectation of health benefits [1]. However, most patients do not inform their physicians of CAM use. Furthermore, the cost for individual patients, as well as for society as a whole, is substantial [1]. In this regard, it is not appropriate for urologists to ignore or suppress the use of CAM without a scientific basis for such a decision. Rather, urologists should be familiar with the increasing scientific evidence to ensure proper patient guidance, regardless of their own personal beliefs, on the benefits of CAM. There are many well-written review articles that focus on the use of CAM in areas of
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Review urology. However, most of them include preclinical evidence of therapeutic benefits, which usually turn out to be not effective in clinical trials. In this article, we will summarize the scientific evidence for CAM use in men’s health from a clinical viewpoint, including treatments for benign prostatic hyperplasia (BPH), prostate cancer, and sexual dysfunction.
Benign prostatic hyperplasia The effects of diet, including fat, fruits, and vegetables, on the incidence and clinical course of BPH have been investigated in several studies [2–5]. Lagiou et al. reported that a highfat diet is associated with increased risk of BPH, which can be reduced by fruit intake [2]. Although the exact mechanisms vary, excessive calories and saturated fat, especially from dairy products and red meat, promote obesity and prostate cell growth by increasing the production of insulin growth factor type-1 (IGF-1) and inflammatory arachidonic acid by-products [5–7]. In contrast, dietary fibers and antioxidants found in fruits and vegetables, particularly tomatoes and cruciferous vegetables, and phytoestrogens found in soy protein, prevent prostate disease by counteracting free radical damage, blocking the harmful effects of IGF-1 and excess sex hormones, reducing serum cholesterol levels, and preventing aromatase activity [2,8–10]. Bravi et al. reported that specific types of food, such as cereals, bread, eggs, and poultry, increase blood glucose and cause hyperinsulinemia, promote IGF, and, subsequently, prostatic cell growth and BPH [4]. Garlic (Allium sativum) and its preparations have been used to treat BPH symptoms owing to anti-inflammatory and antioxidant effects [11].
The use of phytotherapeutic agents (where ‘phyto’ indicates ‘plant’) for lower urinary tract symptoms (LUTS) due to BPH has increased in the United States and throughout the world over the past 10 years [12]. Buck reported that phytotherapy improved BPH symptoms in up to 70% of patients [13], which may explain why 50% of German urologists prefer plant-based therapies to synthetic medications for men with symptomatic BPH [14]. Currently, there are more than 30 botanical compounds available for BPH treatment. The most commonly used compounds are shown in Table 1 [15]. Plant extracts contain phytosterols (b-sitosterol, campestrol, stigmasterol, d5-sterol, d-7-sterol), phytoestrogens (lignans, flavonoids, isoflavonoids (genistein, daidzein)), fatty acids (lauric and myristic acid), lectins, plant oils, polysaccharides, lupenone, lupeol, and terpenoids [15]. Experimental data suggest several mechanisms of action for phytotherapeutic agents, including anti-androgenic effects, androgen and estrogen receptor inhibition, 5a-reductase inhibition, anti-inflammatory effects, interference with prostaglandin metabolism, inhibition of phospholipase A2 and 5-lipoxygenase, blockade of arachidonic acid release, suppression of prostate cell metabolism and growth, inhibition of growth factor or prolactininduced prostatic cell proliferation, aromatase inhibition, protection of bladder and detrusor function, reduced levels of sex hormone-binding globulin, and induction of apoptosis [15–17]. However, it is unclear which, if any, of these proposed mechanisms is responsible for the clinical responses. The most popular extract in terms of sales revenue and clinical trial investigation is that from the dried berry of saw palmetto (botanical names, Serenoa repens and Sabal serrulata).
Table 1 Origin of phytotherapeutic preparations currently used for treatment of LUTS/BPH Plant (species)
Part used
American dwarf palm/saw palmetto (Serenoa repens/Sabal serrulata) African plum tree (Pygeum africanum, Prunus africana) South African star grass (Hypoxis rooperi) Pine (Pinus), spruce (Picea) Stinging nettle (Urtica dioica) Rye (Secale cereale) Pumpkin (Cucurbita pepo)
Fruit Bark Root Root Root Pollen Seed
LUTS/BPH, lower urinary tract symptom/benign prostatic hyperplasia.
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Review Serenoa repens (Permixon1, Pierre Fabre Medicament, Boulogne, France) is one of most commonly used phytotherapeutic agents for treating urologic disorders, and has been approved as a treatment for BPH in France and Germany. Fruits from this plant contain b-sitosterol, fatty acids, and antioxidants. Several meta-analyses have integrated the results from individual S. repens studies [18,19]. Wilt et al. integrated data from double-blinded and placebo-controlled analyses showing that S. repens improves urinary symptom scores by 28% and nocturia by 25% (10 studies), and peak urinary flow rate by 24%, compared with placebo (8 studies) [18]. However, the efficacy of S. repens on BPH is still a controversial issue. Recently, Bent et al. reported that saw palmetto did not improve symptoms or objective measures of BPH in a double-blind, randomized trial [20]. It should be noted that most published placebo-controlled studies are flawed because none met the generally accepted criteria developed by the International Consultation on BPH for assessing treatment results in men with LUTS. However, Zlota et al. reported that Permixon has no negative impact on male sexual function; this is in contrast to both Finasteride and Tamsulosin, which have a slight impact on sexual function, especially on ejaculation [21]. An extract from the African prune tree (Pygeum africanum) was reported to be effective in treating LUTS and obstructed bladder. Two recent clinical trials using P. africanum (Tadenan1, Laboratories Debat, Saint-Cloud, France) revealed an approximately 40% reduction in the International Prostate Symptom Score (IPSS) and improvement in the urinary flow rates of approximately 18% over baseline [22,23]. Based on a meta-analysis of 18 clinical trials, Ishani et al. demonstrated that men receiving P. africanum were more than twice as likely to be rated with symptom improvement by their physician, compared with men receiving placebo (65% versus 30%, relative risk (RR) = 2.1) [24]. However, another study did not show any efficacy with P. africanum [25]. Most studies advocating efficacy were flawed owing to the small sample size or the absence of a placebo arm, and the use of different methods. Therefore, more placebo-controlled studies with long-term follow-up are required. South African star grass (Hypoxis rooperi: Harzol1, Hoyer-Madaus GmbH & Co., Monheim,
Germany) has been shown to significantly improve voiding parameters in a 6-month double-blind, placebo-controlled trial, and an open-label follow-up study [26,27]. Azuprostat1 (Azupharma GmbH, Gerlinger, Germany), a combination of b-sitosterols from Hypoxis rooperi, pine (Pinus), and spruce (Picea), is also effective for BPH, as shown by a 6-month randomized, placebo-controlled trial [28]. No additional reports on the effects of H. rooperi have been published since the year 2000. Even fewer relevant clinical studies have been published on the other extracts listed in Table 1, specifically those from Urtica dioica, Cucurbita pepo, Secale cereale, and Opuntia. In a systematic review and meta-analysis, MacDonald et al. concluded that Secale cereale (Cernilton1, AB Cevenelle, Stockholm, Sweden) modestly improves overall urologic symptoms, including nocturia, but additional trials are required to evaluate its clinical effectiveness [29]. Among the mushroom extracts, Reishi mushroom (Ganoderma lucidum) displayed the strongest 5a-reductase inhibitory activity, interfering with prostate growth in a rat model [30], whereas Phellinus linteus induced prostate enlargement [31]. Thus, BPH patients should ingest this compound with care.
Prostate cancer CAM use is prevalent among 33–43% of prostate cancer patients [32–34]. Men at high risk for prostate cancer also show a high prevalence of CAM use [35]. Tomato contains a variety of carotenoids, among which lycopene is the most abundant. A large-scale cohort study by Giovannucci et al. demonstrated that total intake of tomatobased food is inversely associated with cancer risk [36]. Based on epidemiologic data, as well as preclinical evidence of antioxidant [37] and antitumor effects [38], lycopene and other carotenoids have been the focus of several clinical trials as potential chemopreventive agents for prostate cancer. In an open-label, non-controlled trial, Chen et al. examined the effects of tomato sauce-based pasta dishes on lycopene uptake, oxidative DNA damage, and prostatespecific antigen (PSA) levels in 32 patients awaiting radical prostatectomy [9]. Compared with baseline levels, oxidative DNA damage in prostate tissue and serum PSA levels were
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Review significantly reduced after therapeutic intervention [9]. Purified lycopene supplementation has also been examined in several clinical trials, and Matlaga et al. reported marked PSA reductions (even to nadir) [39]. In a phase II randomized trial performed before radical prostatectomy by Kucuk et al., the lycopene supplementation group displayed decreased tumor volume and lower plasma PSA levels, compared with the control group [40]. Ansari et al. performed a randomized controlled trial in 54 patients with advanced prostate cancer in which the combination of lycopene and orchiectomy was compared with orchiectomy alone. Reduced PSA levels, more complete response, and increased survival were observed in the combination treatment group compared to the orchiectomy alone group [41]. However, in a recent dose-escalating phase I/ II trial, although well tolerated, lycopene supplementation (dose range of 15–90 mg/day) did not result in a PSA response [42]. Ansari & Gupta also performed an open-label, singlearm trial examining the effects of lycopene on 20 patients with hormone-refractory prostate cancer (HRPC) and showing clinical and biochemical evidence of disease progression [43]. As most patients displayed stable tumor responses, improved general performance status, decreased bone pain, and reduced urinary tract symptoms, the investigators concluded that lycopene is effective and safe for HRPC [43]. However, recent evidence does not support the preventive effect of tomato carotenoids on the development of prostate cancer. In a large cohort study by Kirsh et al., lycopene was not associated with reduced prostate cancer risk [44]. Bunker et al. recently published data from an unblinded, randomized, phase I clinical trial investigating lycopene supplementation in Tobago men at high risk for prostate cancer [45]. In the lycopene group, serum PSA levels reduced during the first month of treatment, but returned to the randomization level by month 4, indicating that the PSA-lowering responses observed during previous 3-week studies in men were transient and this may, therefore, not be an appropriate endpoint for long-term studies [45]. Despite several conflicting results, increased consumption of tomato and lycopene supplements may generally be regarded as safe and possibly beneficial. This recommendation is consistent with current health guidelines to
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increase fruit and vegetable consumption. The relatively low cost and negligible toxicity make it an attractive complementary or alternative therapeutic option, particularly when conventional therapy is contraindicated or refused. Preclinical evidence of antitumor activity [46], and epidemiologic evidence of prostate cancer prevention with vitamin D [47–50] led to several phase I and II clinical trials. Liu et al. performed phase I [51] and phase II [52] trials with vitamin D in patients with advanced prostate cancer. No objective response was observed, and hypercalcemia and increased creatinine levels were major toxicities, resulting in termination of treatment. Phase I/II studies by Schwartz et al. on HRPC revealed no tumor response, but did show decreased parathyroid hormone levels, which may prevent skeletal complications [53]. Analyses by Beer et al. using vitamin D (calcitriol) in combination with docetaxel for advanced prostate cancer revealed a synergistic effect of vitamin D and chemotherapeutic agents [54,55]. In a recent epidemiological study, sunlight exposure was associated with increased survival of prostate cancer patients [56]. Selenium, known for its antioxidant and antitumor activities [57,58], was associated with decreased incidences of colorectal, lung, and prostate cancer in the Nutritional Prevention of Cancer Trial [59], with the most significant effects being on prostate cancer [60,61]. Similarly, vitamin E has antioxidant and antitumor properties [62,63]. In an a-tocopherol, bcarotene cancer prevention study involving 29,133 male smokers, vitamin E supplementation reduced the risk of developing prostate cancer, although the primary endpoint was lung cancer incidence [64]. Another study by Chan et al. confirmed this finding [65]. A largescale, prospective, randomized trial in more than 35,000 men (SELECT: selenium and vitamin E cancer prevention trial) is ongoing, with results expected in 2013 [66]. The finding that prostate cancer is not prevalent in areas such as China, together with preclinical evidence of the antitumor effects of green tea on prostate cancer cells [67], has prompted several clinical trials. In a small Italian study that examined the preventive effect of green tea in a high-risk group with high-grade prostatic intraepithelial neoplasia (pre-malignant lesions of prostate cancer), a significantly lower incidence was observed in
Review the green tea group compared with the nongreen tea group (incidence: 3% versus 30%, respectively) [68,69]. A larger, confirmatory, study is ongoing in the United States. Isoflavones, such as daidzein and genistein, have attracted considerable interest owing to epidemiological evidence of prostate cancer risk reduction [70] and preclinical evidence of antitumor activity [71]. In a randomized trial on early prostate cancer patients, the isoflavone group contained lower levels of free testosterone and PSA compared with the placebo group [72]. In open-label, phase II, nonrandomized clinical trials on patients with recurring PSA, soy milk has been shown to decrease the PSA velocity, suggesting activity in prostate cancer [73]. Modified citrus pectin (MCP) has shown antitumor and anti-metastatic activities in preclinical studies [74]. In a phase II pilot study by Guess et al., MCP treatment significantly prolonged the PSA doubling time [75]. PC-SPES (named from prostate cancer (PC) and the Latin, spes, for hope), is an eight-herb Chinese formulation, consisting of isatis (Isatis indigotica), either liquorice (Glycyrrhiza glabra) or Gan coa (G. uralensis), Chinese skullcap (Scutellaria baicalensis), reishi (Ganoderma lucidum), saw palmetto (Serenoa repens or Sabal serrulata), Asian ginseng (Panax ginseng), denodrantherm (Denodrantherma morifolium) and rabdosia (Rabdosia rubescens). The compound has gained popularity as a therapy for prostatic cancer, supported by preclinical evidence of estrogenic and antineoplastic effects [76] and favorable results from small-scale clinical studies on advanced prostate cancer patients [77–79]. However, the US Food and Drug Administration (FDA) advised against the use of this Chinese phytomedicine in February 2002, owing to the relatively high levels of diethylstilbesterol and warfarin, which can cause estrogenic and hemorrhagic complications. The compound is no longer marketed in the US. Several dietary supplements have been tested in clinical trials, with disappointing results. In mixed-cancer trials involving advanced prostate cancer patients, shark cartilage was inactive and had no salutary effect on the quality of life [80]. Other dietary supplements that have been used to treat prostate cancer patients, based solely on preclinical evidence, include silibinin [81,82], and a grape seed extract [83].
Sexual dysfunction: erectile dysfunction and premature ejaculation Although erectile dysfunction (ED) is an important health problem for which a plethora of CAM treatments are endorsed, the benefit of CAM use for ED is largely unknown, and welldesigned large-scale CAM-based clinical trials are limited at present. L-arginine, a precursor of nitric oxide (NO) that has been reported to increase NO levels in preclinical studies [84,85], has been examined in several clinical trials, either alone or in combination with other agents. In a doubleblinded, randomized, placebo-controlled trial, oral administration of arginine improved subjective sexual performance in patients with low urinary nitrate or nitrite (NOx) levels at baseline [86]. However, in another randomized, placebo-controlled cross-over trial in mixed-type impotence patients, L-arginine showed no benefits compared with placebo [87]. L-arginine has also been examined with other agents, including yohimbine [88,89] and pycnogenol [90]. Korean red ginseng (Panax ginseng) has been investigated in a double-blind, placebo-controlled, cross-over study by Hong et al. [91]. Patients in the Korean red ginseng group exhibited a higher mean International Index of Erectile Function score, particularly in terms of penetration and maintenance, and higher penile tip rigidity on RigiScan. Although the data are not conclusive, Korean red ginseng is recommended as a cost-effective alternative to phosphodiesterase type 5 (PDE-5) inhibitors [92]. The National Center for Complimentary and Alternative Medicine (NCCAM) is supporting trials to further clarify the beneficial effects of Asian ginseng for various indications. In a 12-week, double-blind, placebo-controlled trial involving 32 healthy male volunteers and their partners, deer velvet induced no significant differences in sexual behavior or hormonal levels [93]. Ginko biloba has been tested for antidepressant-induced sexual dysfunction. An open trial by Cohen & Bartlik supported its effectiveness [94], whereas in a placebo-controlled study, both the gingko and placebo groups showed improvement, suggesting a significant placebo effect in this population [95].
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Review Yohimbine, the bark extract of the yohimbe tree from western Africa, was evaluated in a three-arm clinical trial comprising placebo, yohimbine, and a combination of yohimbine and L-arginine. Yohimbine itself was effective, although the combination had a more significant effect [88]. Yohimbine may increase blood pressure and heart rate, and cause harmful drug interactions with a monoamine oxidase inhibitor or tricyclic antidepressant. Other commercial agents that claim to enhance sexual performance were prohibited in 2006 by the US FDA, these include Zimaxx, Libidus, Neophase, Nasutra, Vigor-25, Actra-Rx (Yilishen), and 4EVERON. These compounds contain variations of active ingredients in drugs prescribed for ED (notably PDE-5 inhibitors such as sildenafil) and may dangerously lower blood pressure when administered in combination with certain prescription medicines. Acupuncture in various formats (with or without moxibustion and with or without Chinese drug injections [96]) has been used to treat ED (mainly non-organic or psychogenic) [97,98]. In a randomized, controlled pilot trial in patients with psychogenic ED, a satisfactory response was achieved in 68.4% of the treatment group and 9% of the placebo group [99].
Limited studies on CAM have investigated its efficacy in premature ejaculation. Yoga had a similar efficacy to fluoxetine in a comparative trial in patients with premature ejaculation [100].
Conclusions Although concerns for the effects of CAM on men’s health are increasing, the exact mechanisms of action remain controversial. In addition, clinical efficacy and safety data based on well-designed clinical trials with no methodological flaws are lacking. Therefore, further randomized placebo-controlled trials of longer study duration are needed to evaluate the efficacy and safety of CAM in men’s health treatments. Based on increasing evidence, we propose that urologists have a responsibility to their patients to gain knowledge about the advantages and disadvantages of CAM. Furthermore, they should advise against therapies that are without merit or may cause harm, and recommend those that prevent chronic illness, reduce treatmentrelated side effects and improve men’s health and well-being.
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