Section Editors: Franklin Lowe, MD, MPH
Sven Wenske, MD
Introduction
National Center for Complementary and Alternative Medicine (NCCAM), a division of the National Institutes of Health (NIH), conducts and support research and provides information about complementary health. In a recent national survey, 38% of adults used some form of complementary and alternative medicine (1). “Complementary medicine” refers to use of Complementary and Alternative Medicine (CAM) together with conventional medicine, such as using acupuncture in addition to usual care to help lessen pain. Most use of CAM by Americans is complementary. “Alternative medicine” refers to use of CAM in place of conventional medicine. “Integrative medicine” combines treatments from conventional medicine and CAM for which there is some high-quality evidence of safety and effectiveness. It is also called integrated medicine.
CAM practices are often grouped into broad categories, such as natural products, mind and body medicine, and manipulative and body-based practices. Although these categories are not formally defined, they are useful for discussing CAM practices and some CAM practices may fit into more than 1 category. This chapter provides an overview of some of the CAM practices that are used or are related to the practice of urology.
Mind and Body Medicine
Mind and body practices focus on the interactions among the brain, mind, body, and behavior, with the intent to use the mind to affect physical functioning and promote health. Many CAM practices embody this concept in different ways. Meditation techniques, yoga, and acupuncture are some of these techniques.
Acupuncture, the application of solid needles inserted into defined spots in the skin, has been described thousands of years ago as part of ancient Chinese medicine. Although its main application has been to treat a variety of chronic conditions, such as back pain, obesity, addictions, and many others, more recently acupuncture has found its way into modern medicine and is nowadays part of daily clinical routine in many urologic practices. Especially urologic diseases that are difficult to treat, such as premature ejaculation, lower urinary tract symptoms (LUTS) and overactive bladder (OAB), chronic prostatitis/chronic pelvic pain syndrome (CPPS), or side effects (eg, hot flashes) of androgen-deprivation therapy (ADT) for advanced/metastatic prostate cancer, are the primary targets of acupuncture in urology (2).
Results from a clinical study in patients with LUTS or CPPS, 1 of the most difficult to treat urologic conditions, or patients with increased urinary frequency and urgency after radical prostatectomy, showed good results of acupuncture in decreasing symptoms and improving quality of life (3). Good success has also been reported in studies on patients that receive acupuncture for hot flashes, 1 of the most common side effects of ADT. A randomized placebo-controlled study showed recently the effects of acupuncture in the treatment of premature ejaculation in comparison to placebo and the standard treatment using paroxetine (4). Whereas paroxetine reduced the validated Premature Ejaculation Diagnostic Tool (PEDT) score from 17 to 10.5, acupuncture achieved a reduction from 16 to 11, which was significantly better than placebo. Usually, treatments are being applied twice per week for the 1st 6 wk. If patients respond to the treatment and if symptoms improve, the treatment frequency is reduced to once per week, and continues for a total of 12 wk. After that, a maintenance treatment schedule may be needed to prevent recurrent or increasing symptoms.
While the mechanisms of acupuncture are still not entirely understood, the main hypothesis is that certain neurotransmitters (eg, serotonin, endorphins) are being released under needle stimulation, and that there exists an alternative connective tissue communication system unrelated to the peripheral and central nervous systems.
In addition to acupuncture, also pelvic floor muscle training (PFMT), relaxation, and yoga have all been shown to decrease muscle contractions and stress of the pelvic floor. One analysis from Stanford University studied the treatment of intra- and extrapelvic myofascial trigger point release therapy, and training in paradoxical relaxation including cognitive behavioral methods in patients with CPPS, with good results (5).
Overall, especially after exhausting standard treatments for common benign urologic disorders, acupuncture and other complementary and integrative therapies offer good alternative treatment approaches with limited potential for adverse events.
Manipulative and Body-Based Practices
Manipulative and body-based practices focus primarily on the structures and systems of the body, including the bones and joints, soft tissues, and circulatory and lymphatic systems. 2 commonly used therapies fall within this category: Spinal manipulation and massage therapy. Limited data is available but the literature suggests that 2 methods of manual therapy (myofascial physical therapy and global therapeutic massage) may benefit patients with urologic CPPS (6).
ACTIVE HEXOSE CORRELATED COMPOUND (AHCC)
AHCC is derived from the mycelia (branches) of shiitake (Lentinula edodes) of the basidiomycete mushroom family. It has been derived through hybridization of different shiitake subtypes. Characteristic for AHCC is its high content of α-glucans (a carbohydrate) and its low molecular weight, which renders it highly absorbable in the body. 1st described in an animal model in 1998, AHCC was shown to enhance immune response in an in vivo adenocarcinoma model in rats (12). Numerous subsequent human clinical studies have been performed on AHCC, showing that AHCC increases the activity of natural killer (NK) cells, T-cells, and dendritic cells that are all essential components of the human immune system. However, AHCC was also shown to act as an immune regulator through downregulation of an overactive immune system, thereby supporting the body's normal response to inflammatory processes during which the immune system may be upregulated. AHCC found urologic application in humans in a more recent study from 2009, where it was found to be beneficial in the treatment of castrate-resistant prostate cancer, reflected in a significant PSA response in a patient with metastatic castrate-resistant disease (13). As a complementary immunotherapy in patients with cancer, viral and nonviral hepatitis, HIV, and other immunocompromised patients, AHCC is being widely used, especially in Asia.
AFRICAN PLUM (Pygeum africanum)
The extract, tadenan, is derived from the bark of the African plum tree and is taken for the treatment of benign prostatic hypertrophy (BPH) and LUTS. Pygeum is usually found in most combination prostate health formulations. Its mode of action is thought to be via inhibition of fibroblast growth and anti-inflammatory effects. Some inconclusive data show a decrease in symptoms and an increase in flow rate. However, the T-IPSS study, a randomized double-blind, placebo-controlled trial using tadenan was completed but never released or published (11). Only some minor gastrointestinal side effects have been noted with this product.
BAZOTON (Radix urticae)
This plant extract has been used in the treatment of benign prostatic hypertrophy (BPH). The active ingredients are thought to include its steroid–glycoside composition. It is an inhibitor of sex-steroid-binding globulin. There is a paucity of clinical data that show it decreases symptom scores, and it has little effect on flow rates. Side effects are minor and usually related to its smell and taste.
BROCCOLI SEED EXTRACT (Sulforaphane)
Multiple epidemiologic mouse models and cell-based studies indicate that the broccoli-derived isothiocyanate Sulforaphane [(-)-1-isothiocyanato-(4R)-methylsulfinylbutane] may affect the development of various types of cancers and especially prostate tumors. A recent analysis by Traka et al. (15) in PTEN-deficient mice showed that sulforaphane had positive effects to counteract changes downstream of PTEN loss. The PTEN is a tumor suppressor gene, and its deletion in an epithelial stem cell can be an early initiating event leading to prostatic intraepithelial neoplasia (PIN), and subsequently to cancer. The authors also found a significant overlap in changes in gene expression induced by sulforaphane in mouse prostate tissue with PTEN loss, with that induced in prostate tissue of men consuming a broccoli-rich diet.
CAPSAICIN (capsicum)
Capsaicin is the main pungent ingredient of hot peppers. It has been used as an intravesical therapy for overactive bladder (OAB). The mode of action is by selective activation of sensory nerve fibers and by a neurotoxic effect on afferent C fibers. Multiple studies have documented its efficacy in terms of symptom improvement and urodynamic changes (16). Adverse effects include suprapubic pain, hematuria, and incontinence, which are all self-limiting.
COMMON NATURAL PRODUCTS USED IN UROLOGY
This area of CAM includes use of a variety of herbal medicines (also known as botanicals), vitamins, minerals, and other “natural products.” Many are sold over the counter as dietary supplements. Some uses of dietary supplements – eg, taking a multivitamin to meet minimum daily nutritional requirements or taking calcium to promote bone health – are not thought of as CAM. The World Health Organization has estimated that 80% of the world's population uses some type of herbal medicine. Women are more likely than men to use complementary and alternative medicine (7).
These common agents are not US Food and Drug Administration (FDA) approved, but are available through health food stores and other commercial outlets. Phytotherapies and other supplements are under study, but few have undergone trials in the United States. Most have not demonstrated any significant efficacy, and many of these products are sold as part of combination therapies, and sold under various trade names. There have been growing concerns about the potential toxicities of these products and their interactions with standard pharmaceuticals. According to the FDA, manufacturers of dietary supplements can make claims about how their products affect the structure or function of the body, but they may not claim to prevent, treat, cure, mitigate, or diagnose a disease without prior FDA approval. The FDA does monitor many of these compounds for undisclosed ingredients that can impact their efficacy. Limited data is available on the substances in urology. However, there is an increasing amount of peer-reviewed literature that provides some support for a few of these alternative therapies while others have not been able to clearly demonstrate efficacy (8). A challenge for any natural compound is standardization of the product (9). The large NIH-sponsored CAMUS trial studied increasing doses of saw palmetto on lower urinary tract function. Unfortunately when subject to rigorous study parameters, increasing doses of a saw palmetto fruit extract did not reduce LUTS more than placebo (10).
CRANBERRY JUICE AND SUPPLEMENTS (Vaccinium macrocarpon)
Cranberry is widely used to prevent UTIs; it was originally believed that this fruit acidified the urine (17). However, cranberry appears to work by inhibiting the adhesion of type I and P-fimbriated uropathogens (eg, uropathogenic Escherichia coli) to the uroepithelium, thus impairing colonization and subsequent infection. It contains a unique blend of organic acids – quinic, malic, and citric – as well as nondialyzable polymeric compounds that provide this antibacterial adherence effect.
Studies using cranberry juice, cranberry–lingonberry juice, and cranberry tablets compared with placebo for preventing UTIs, bacteriuria, or pyuria concluded that cranberry juice and cranberry products significantly reduced UTIs among women with recurrent infections (18,19). Recommended doses range from 90 to 480 mL of cranberry cocktail twice daily or 15–30 mL of unsweetened 100% cranberry juice daily. The frozen concentrate has almost 30 times the strength of the juice, and 30–45 mL BID has been used. Capsule doses range between 1 and 6 capsules of 300–400 mg concentrated extract BID. High pediatric doses of >300 mL daily have been associated with adverse effects such as hypersensitivity or gastrointestinal distress such as diarrhea.
The findings of several reviews support the potential use of cranberry products in the prophylaxis of recurrent UTIs in young and middle-aged women, but it should not be used as a substitute for antibiotics, as it is an ineffective treatment for established infections. Patients with a history of nephrolithiasis should avoid the use of cranberry products (possible increases in urinary calcium and oxalate concentration). Due to the heterogeneity of clinical study designs and the lack of consensus regarding the dosage regimen and formulation to use, cranberry products cannot be broadly recommended for the prophylaxis of recurrent UTIs at this time. Note that it may potentiate anticoagulant effects of warfarin.
FLAXSEED (Linum usitatissimum)
Flaxseed is a member of the genus Linum in the family Linaceae, and contains high levels of dietary fiber as well as lignans, an abundance of micronutrients and ω-3 fatty acids. The lignans in flaxseed may provide some health benefits against cancers that are sensitive to hormones, such as breast and prostate. Some reports have published the effect of flaxseed on lowering PSA and androgens. A randomized trial analyzing prostatectomy specimens in men randomized to flaxseed supplementation 3 wk before surgery showed significant differences in tumor proliferation rate, index, and apoptotic rate between men that had been randomized to take flaxseed supplements vs. those that stayed on normal diet (20,21). An effect on biochemical outcome and prostate cancer mortality has not been shown.
GINKGO BILOBA
Primarily used for memory deficits, dementia, and neurologic dysfunction, ginkgo biloba is also promoted as a treatment for impotence and selective serotonin reuptake inhibitor (SSRI)-induced sexual dysfunction, with a recommended dose range of 60–80 mg standardized dry extract orally BID or TID (22). Studies have shown small cognition benefits with dementia, but no other demonstrated benefit in healthy adults (23). Use cautiously with aspirin (ASA), salicylates, and warfarin.
GOSHA-JINKI-GAN (GJG)
Gosha-jinki-gan (GJG) is a traditional Chinese blended herbal medicine composed of 10 different herbs. In canine studies, bladder contraction mediated by pelvic nerve stimulation and induced by acetylcholine administration was significantly inhibited by administration of 100 mg/kg GJG; effects were similar to that seen with 0.1 mg atropine. Human studies have reported mild improvements in International Prostate Symptom Scores (IPSS) and OAB symptoms in some patients (7). Mild adverse events include nausea, diarrhea, and urinary frequency.
GREEN TEA
In addition to several potent antioxidants, such as epigallocatechin-3-gallate (EGCG), in green tea, mainly its polyphenolic compounds have been suggested to decrease prostate cancer development and decelerate prostate cancer progression in several in vitro and in vivo animal studies (24,25). High green tea consumption in Japan may at least partially explain the low prostate cancer prevalence in Japanese men, as green tea plays a major role in the Asian diet. Despite the fact that results in human studies have mostly been controversial, some well-designed studies have also demonstrated a significant reduction in incidence of prostate cancer incidence in men with high-grade PIN who drink green tea. However, the protective role of tea in prostate cancer is still controversial (26).
HEATHER (Calluna vulgaris)
The medicinal portion of common heather consists of the entire herb (leaves, flower, roots) ground and boiled to create a product that is taken for its diuretic properties in the treatment of kidney ailments and BPH/LUTS. Active compounds are thought to include flavonoids and sitosterols. The claimed efficacy has never been documented. No clinical trials are available.
HORNY GOAT WEED (Epimedium)
Epimedium is a Chinese herbal remedy promoted as a safe and natural alternative to sildenafil citrate (27,28). However, extracts of epimedium are strongly estrogenic due to the presence of novel potent phytoestrogens of the prenyl-flavone family. It has been reported to cause tachyarrhythmias.
LYCOPENE
Lycopene is a major carotenoid component of tomato, red pepper, and other red fruits and vegetables. The pigment acts basically as an antioxidant, protecting cells against damage from free radicals. In several studies it was found to have potential anticancer activity in many types of cancer, as numerous studies reported on inverse associations between lycopene intake and prostate cancer prevalence and grade (29). Overall, the protective effect of lycopene is unclear, as controversial results have been published. When taken, lycopene is better absorbed by the body when it is consumed in cooked, instead of raw or fresh products (30).
MODIFIED CITRUS PECTIN (MCP)
Pectin, a carbohydrate consisting of thousands of polysaccharide molecules, is found abundantly in the peels of apples, citrus fruits, and plums, but is also found in most other plants. Regular pectin is not absorbable by the human body, but in modified citrus pectin (MCP) the pectin has been altered through breaking of its long polysaccharide chains. It has been shown to inhibit cancer growth and breast and prostate cancer metastases in animal models, and was found to suppress cancerous proliferation and induce apoptosis of prostate cancer cells in vitro (31). MCP showed also antimetastatic properties, and potential for increasing apoptotic responses of tumor cells to chemotherapy by inhibiting antiapoptotic functions of galectin-3, and has therefore been established in the literature for its potential use in the treatment of multiple human malignancies (prostate, colon, breast, liver, and melanoma).
ω-3 FATTY ACIDS (FISH OIL)
These naturally occurring compounds, ω-3 fatty acids, polyunsaturated essential fatty acids, cannot be produced by the human body, but are required for normal performance of numerous organs and cell functions. However, there is a wide range of conflicting results in the literature on health benefits, especially in the cancer prevention and treatment.
One of the most extensive reviews of the literature on this topic from MacLean et al. (32) from 2006 in the Journal of the American Medical Association concluded that there is no association between ω-3 fatty acids and the prevention or the prevalence of cancer. A more recent analysis concluded similarly, also taking into account difficulties in assessing patient's exact dietary habits, but ω-3 fatty acids were consequently deemed neither a risk factor nor a beneficial factor with regard to cancers (33). However, as ω-3 fatty acids improve appetite and help gain weight, they may be of benefit in patients with advanced cancer and cachexia, as this may contribute to improved quality of life.
PC-SPES
This product is no longer commercially available because of issues associated with quality control. It was found to be tainted with diethylstilbestrol, warfarin, and alprazolam. It was used for treatment of prostate cancer, particularly in hormone-refractory patients. It consisted of 8 Chinese herbs (Chrysanthemum, Isatis, licorice, Ganoderma lucidum, Panax pseudoginseng, Rabdosia rubescens, Scutellaria[skullcap], and saw palmetto berry) (34). It had potent antiestrogenic effects. Its use was associated with deep venous thrombosis, breast tenderness, loss of libido, and decreased PSA and testosterone levels. Other companies have made similar combinations but have not achieved a widespread usage (35).
PANAX GINSENG (Korean red ginseng)
This product has been used for numerous indications in traditional Chinese medicine. It is frequently used for decreased libido and erectile dysfunction. It reportedly has androgenic effects and stimulation, although improvements in penile endothelial L-arginine–nitric oxide activity have been suggested (36,37). Clinical trials are not conclusive of its effectiveness.
PERMIXON (Serenoa repens)
This is the branded saw palmetto extract produced in France. It is the lipidosterolic extract of the dried fruit (berry) of the dwarf palm. It is the most widely studied of all phytotherapies for the treatment of BPH/LUTS. From in vitro studies, it has been postulated to have many mechanisms of action including antiprostaglandin, antiandrogenic, and antiestrogenic effects (38). It has almost no effect upon prostate size and no effect upon PSA levels (39). There are no known significant health risks or adverse effects.
POMEGRANATE (Punica granatum)
Pomegranate juice is known for its high vitamin C content, as well as vitamin B5 (pantothenic acid), potassium, and natural phenols, such as ellagitannins and flavonoids with extremely effective free radical-scavenging properties.
Increasing evidence shows that pomegranate juice has potential to inhibit growth and reduce the invasion of prostate cancer cells both in vitro and in vivo. A phase II clinical trial, in which patients with rising PSA after primary treatment with curative intent of prostate cancer were given 8 oz of pomegranate juice per day, showed that the mean PSA doubling time increased significantly in men under treatment with pomegranate juice from 15 to 54 mo (p < 0.001) (40). Several subsequent studies have shown that pomegranate juice affects many of the cellular processes involved in cell death and also affects signaling pathways that could inhibit cell migration and invasion (41).
PUMPKIN SEED (Cucurbita pepo)
Fresh and dried seeds are taken whole or ground for the treatment of BPH or OAB. Active compounds are thought to be phytosterols (42,43). There are no recent clinical trials and therefore no evidence establishing its efficacy. There are no known side effects.
RESVERATROL
Resveratrol is a potent antioxidant found in wine, especially in high concentration in Pinot noir, but also in grapes and berries. Research has demonstrated that it inhibits cancer growth through reduction of cell proliferation and metastasis, and induction of cell apoptosis. On a molecular level, it has been shown that mechanisms involved are inhibition of Akt and suppression of IGF-1 receptor expression (44). These antitumor effects of resveratrol were observed in in vitro and in vivo xenograft studies with the common prostate cancer cell lines PC3, DU145, and LNCaP.
RYE POLLEN (Secale cereale)
A pollen extract obtained by microbial digestion and extraction by water and organic solvents. Cernilton is the branded product. Active ingredients are thought to be β-sitosterols (45). It is used for the treatment of BPH and prostatitis and CPPS (46). In vitro inhibition of epithelial and stromal cell growth has been demonstrated (45). No long-term conclusive clinical studies exist. Side effects are reportedly minimal.
SAW PALMETTO BERRY (Serenoa repens, Sabal serrulata)
There are many different extraction processes and therefore many different brands of saw palmetto. The composition of these brands is variable. A recent NIH-sponsored double-blind, placebo-controlled study using the Indena brand showed no statistical difference between placebo and saw palmetto berry for treatment of BPH/LUTS. Permixon brand is the most widely studied product (see “Permixon” above). Minimal side effects are associated with saw palmetto. Saw palmetto berry extract (SPBE) compounds are also sold for “prostate health.” SPBE includes ingredients such as β-sitosterol and stigmasterol with no reliable clinical data to support their use. A recent large meta-analysis documented no significant clinical benefit of Serenoa repens on LUTS or prostate volume (10). Saw palmetto extract does not affect serum prostate-specific antigen more than placebo, even at relatively high dose (47). In addition it appears safe with the saw palmetto extract used in the CAMUS trial showed no evidence of toxicity at doses up to 3 times the usual clinical dose during an 18-mo period.
SELENIUM
A trace mineral that may prevent the development of prostate cancer. Epidemiologic studies suggest a chemopreventive effect (48). 1 study of patients with high-grade PIN suggested that selenium reduced the incidence of prostate cancer on subsequent biopsy. The National Cancer Institute–sponsored SELECT trial was a 10-yr prospective trial that began in 2001 of over 35,000 men studying the prostate cancer chemopreventive effects of selenium and vitamin E alone and in combination (49). The data monitoring safety board (DMSB) halted the trial in the fall of 2008. Their concerns were that the supplements did not appear to offer any benefit. In particular, there was a statistically nonsignificant trend to increasing prostate cancer with vitamin E alone and increased diabetes risk in men on selenium alone.
SOUTH AFRICAN STAR GRASS (Hypoxis rooperi)
This extract is taken for BPH/LUTS. The active compound is thought to be β-sitosterols, which are thought to induce apoptosis by transforming growth factor (TGF)-β1; this is unproven clinically (50). Initial studies showed dramatic improvements in symptom scores and flow rates; however, confirmatory studies are still needed (51). Adverse effects are believed to be minimal.
STINGING NETTLE (Urtica dioica, Urticae radix)
Bazoton is a branded form of this extract; (see Bazoton section above). The clinical evidence of the effectiveness of nettle root is based primarily on open studies, and the significance of this must be confirmed (14, 52). Minimal toxicity is associated with stinging nettle use.
VITAMIN D3 (Cholecalciferol)
As a fat-soluble vitamin, vitamin D3 plays a key role in overall health, as it mainly maintains calcium and phosphate homeostasis. However, it has also been shown to exhibit antineoplastic effects on various types of cancer, such as colon, breast, and prostate cancers (53).
The Institute of Medicine (IOM) has reviewed and updated the dietary reference intakes (DRIs) for vitamin D. It found that there is strong evidence to support the use of vitamin D with calcium for bone health but that it was lacking for other health conditions. Dosages for patient with various health issues differ. The recommended daily allowance (RDA), as set in 2011, is based on age, as follows: For those 1–70 yr of age, 600 IU daily; for those 71 yr and older, 800 IU daily; and for pregnant and lactating women, 600 IU daily. The IOM further recommended that serum 25(OH)D levels of 20 ng/mL (50 nmol/L) is adequate, and levels >50 ng/mL (125 nmol/L) could have potential adverse effects. However, dosages for urologic patients may differ based on underlying health disorders and concomitant medications (underlying osteopenia, ADT, therapy with RANK-ligand inhibitors [Denosumab] or bisphos-phonates in patients with metastatic prostate cancer, etc.).
VITAMIN E (γ-TOCOPHEROL)
Vitamin E, another fat-soluble essential vitamin, was initially thought to prevent prostate cancer risk. However, the National Cancer Institute–sponsored SELECT trial, studying prostate cancer chemopreventive effects of selenium and vitamin E, reported in 2009 controversial results with no benefits of vitamin E supplementation (see “Selenium”) (54). Moreover, the follow-up publication in 2011 even reported a significantly increased prostate cancer risk in healthy men with dietary supplementation with vitamin E (55). In addition, vitamin E supplementation above dosages of >400 IU per day were found to significantly increase risks of cardiovascular events.
YOHIMBINE (PAUSINYSTALIA YOHIMBE) YOCON, YOHIMEX
An extract of the bark of the yohimbe tree has been used for erectile dysfunction and decreased libido. The mechanism of action is as an α-adrenergic antagonist. Conflicting studies show both positive and no effect when compared to placebo (56). It appears to have greatest utility for men with psychogenic impotence. Despite the advent of phosphodiesterase 5 (PDE5) inhibitors, there is still widespread utilization of this over-the-counter product. Side effects include anxiety, tremors, dizziness, hypertension, and tachycardia. Do not use with antidepressants (eg, MAOIs or similar agents).
ZYFLAMEND
Zyflamend, a formulation containing 10 different herbs, is a dietary supplement marketed for the support of cardiovascular and joint function and healthy inflammation response. It is thought to have anti-inflammatory, antiangiogenic, and antiproliferative properties. Several in vitro studies have shown that Zyflamend decreases COX-1 and COX-2 enzymatic activity, induces apoptosis, and reduces androgen receptor expression in LNCaP cells (57). Moreover, it was found to inhibit arachidonic acid pathways, in human prostate cancer PC3 cells. Moreover, it also inhibits the proliferation of oral squamous carcinoma, pancreatic cancer, and melanoma cells in vitro. In an animal model, it inhibited the growth of both hormone-naïve and castrate-resistant prostate cancer, and reduced the expression of PSA. However, the latter could not be shown in a phase I clinical trial in men with PIN at Columbia University Medical Center, where Zyflamend was well tolerated, but did not lead to any significant changes in serum PSA levels (58).
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