US Pharm. 2008;33(3)(OTC suppl):8-11.
By the age of 70, nearly 80% of men have benign prostatic hyperplasia (BPH), a prostate condition that can cause a variety of bothersome urinary symptoms.1 Two other common prostate disorders are prostatitis and prostate cancer. Men with prostate disorders may self-administer OTC products, vitamins, herbs, or supplements for their condition. One survey reported that 27% of men with prostate cancer used some form of alternative medicine.2 Another retrospective analysis found that 73% of men diagnosed with prostate cancer were using some type of dietary supplement.3 Many men utilize these alternative therapies without knowledge of their efficacy and risks, and they commonly do not inform their physicians about their use. The pharmacist is well positioned to answer patients' queries about prostate health and OTC treatments for prostate disease. This article will discuss some common nonprescription therapies that are used for prostate health.
Prostate cancer is prevalent among men. The male hormone testosterone can stimulate the growth of hormone-dependent prostate cancer cells. Known risks for prostate cancer include age, family history, African-American ethnicity, certain dietary factors, and obesity.4 Evidence suggests that men who eat a diet high in animal fat or red meat may be at increased risk for prostate cancer and that those who eat a diet rich in fruits and vegetables may have a lower risk.4
Products commonly taken for prostate cancer include vitamin E, selenium, and saw palmetto (discussion following). Selenium is a trace element that plays an important role as an antioxidant defense mechanism in the body. Vitamin E is a fat-soluble vitamin that also is an antioxidant. There has been some debate as to whether supplementation with selenium or vitamin E may have a protective effect and decrease the likelihood of prostate cancer development.3,4
Low selenium levels have been statistically correlated with prostate cancer, and supplementation with it can inhibit the growth of prostate carcinoma cells in vitro.5 Selenium is an essential component of the antioxidant enzyme glutathione peroxidase, which helps protect cells from oxidative damage. One proposed mechanism of action for selenium in improving prostate health is its effect on the endocrine system; it influences testosterone production, thereby evidencing a possible link to the pituitary-adrenal-gonadal axis.6
One large-scale, randomized, double-blind, placebo-controlled trial published by Clark et al in 1996 investigated the role of selenium in oncogenesis.5 The patients (N=1,312), all with a history of skin cancer, were studied to determine the incidence of cancer recurrence and of secondary endpoints, including all-cause cancer mortality. After randomization, patients received either 200 mcg of selenium or placebo daily for an average of 4.5 years. Selenium treatment did not protect against development of basal- or squamous-cell carcinoma, but the study was terminated early due to a statistically significant improvement in overall cancer mortality and other secondary endpoints such as lung, colon, and prostate cancer. The highest prostate cancer prevention rate was found in patients with the lowest baseline selenium levels. This study has been questioned, however, since its primary endpoint was to determine selenium's possible protective effects on skin cancer. The secondary endpoints (e.g., prostate cancer development) were not added until 1990, even though trial enrollment began in 1983. Thus, while the findings were intriguing, the authors suggested that selenium's effects be confirmed in a separate, appropriately designed trial before new recommendations regarding supplementation with it be made.
Another study, published by Yoshizawa et al (N=51,000), found a strong correlation between selenium levels and prostate cancer risk.7 Based on toenail selenium concentration, patients in the highest quartile of concentration had approximately half the risk of developing prostate cancer compared with the lowest quartile. After influencing factors such as family history, diet, and geographical region were controlled for, the difference was significant. A similar but smaller study conducted by Hardell et al found that serum selenium concentrations were significantly lower in men with prostate cancer than in those without it.8
A nested case-control study was performed by Peters et al within the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.9 Serum selenium concentrations were compared prospectively among 724 subjects with prostate cancer and 879 subjects without the disease; subjects were followed for up to eight years. Serum selenium was not associated with a significant decrease in prostate cancer risk overall. Higher serum selenium, however, was associated with significantly lower risks in subjects reporting a high vitamin E intake and in multivitamin users, indicating that combination therapy may decrease the risk of prostate cancer.
A large, randomized, double-blind study currently in progress, the Selenium and Vitamin E Cancer Prevention Trial (SELECT) is evaluating whether selenium and vitamin E reduce the risk of prostate cancer.10 A total of 32,400 healthy subjects will be randomized into four groups: vitamin E and selenium (200 mcg), vitamin E and placebo, selenium (200 mcg) and placebo, and placebo and placebo. Treatment will be given for seven to 12 years. Final results, expected in 2013, will clarify the relationship between these supplements and prevention of prostate cancer.
In summary, current evidence suggests that certain men may benefit from OTC selenium supplementation (200 mcg daily) to reduce the risk of prostate cancer. Men with a baseline selenium concentration below 122 ng/mL and a prostate-specific antigen (PSA) level less than 4 ng/mL appear to receive the greatest benefit from daily selenium supplementation. 5,11 However, results from the SELECT study are necessary to confirm that supplementation with 200 mcg of selenium is safe and effective in reducing the risk of prostate cancer among healthy men. Most of the research on selenium supplements has focused on prostate cancer prevention. At this time, it is unclear whether OTC selenium supplements should be used for the treatment of prostate cancer. The most recent evidence does not support the use of vitamin E in preventing prostate cancer.12
In BPH, the prostate gland becomes enlarged and may push against the urethra, causing various urinary symptoms, although not all men with an enlarged prostate experience symptoms. BPH occurs as men age, possibly due to an increased ratio of estrogen to testosterone in the bloodstream. BPH is not associated with an increased risk of cancer, although the two may occur simultaneously. Symptoms of BPH include a weak or slow urinary stream, inability to urinate or difficulty starting urination, frequent urination, urinary urgency, nocturia, and sensations of incomplete emptying after urination. Treatment is unnecessary for asymptomatic men; however, once pain or difficulty urinating is involved, treatment may be necessary.
The most common nonprescription agent used to alleviate symptoms of BPH is saw palmetto (Serenoa repens). 13 Extracted from the berry of the saw palmetto shrub, this substance is thought to inhibit 5-alpha reductase (5-AR), thus blocking the conversion of testosterone to dihydrotestosterone, which is responsible for stimulating growth of the prostate gland. Saw palmetto is generally well tolerated; side effects are infrequent, but include headache and gastrointestinal upset. No known drug interactions are associated with use of this herb.
Some studies found that saw palmetto led to an increase in urine flow rate in men with BPH compared to placebo, with effects comparable to finasteride.13,14 More recently, Bent et al conducted a randomized, double-blind, placebo-controlled study of 225 men with BPH who took standardized saw palmetto extract 160 mg or placebo twice daily for one year.15 Men with prostate cancer or urinary bladder problems were excluded. Subjects could participate if they had stopped taking alpha-blockers, 5-AR inhibitors, or saw palmetto for a specified length of time prior to the study. There was no significant difference between the saw palmetto and placebo groups in standardized objective urinary symptom scores (e.g., maximal urinary flow rate), prostate size, residual volume after voiding, quality of life, or serum PSA levels. The incidence of side effects was similar in the two groups. This study has cast considerable doubt on the effectiveness of saw palmetto for the treatment of BPH.
Similar results were found in a study undertaken by Marks et al.16 Patients with BPH (n=44) were treated for six months with either saw palmetto or placebo. In this study, saw palmetto did not produce a significant benefit in clinical parameters, prostate volume, or PSA versus placebo. Additionally, a meta-analysis published in 2002 suggested that saw palmetto may be effective for alleviating symptoms of BPH only in the short term.17
A new study that may prove useful for alternative-therapy recommendations is the Complementary and Alternative Medicine for Urological Symptoms (CAMUS) trial.18 The primary objective of this trial is to determine whether the phytotherapies S repens and Pygeum africanum (discussion following) can delay or prevent the progression of BPH. This randomized, double-blind, actively controlled efficacy study, which began in 2005, has enrolled 2,860 patients and will be completed in 2012. Participants are randomly assigned to one of four treatments: extract of S repens, extract of P africanum, tamsulosin, or placebo. Patients will have clinic visits every four months for four years. The following assessments will be performed at clinic visits: physical examination; digital rectal examination; medical follow-up (new diagnoses, treatments, hospitalizations); urinalysis; vital signs; PSA; uroflow measurement; and questionnaires related to prostate health, adverse events, and medications. The CAMUS trial will provide a solid comparison between some phytotherapies, placebo, and the currently recommended prescription-treatment drug class.
P africanum is a tall evergreen that grows in South and Central Africa. The powdered bark historically has been used in tea form for the relief of a variety of urinary disorders. Concentrated extracts of P africanum have been studied for its efficacy for BPH.19 As is the case with saw palmetto, however, methodologic problems such as short duration of follow-up, incomplete outcome assessment, and lack of product standardization have been identified in clinical trials.
The risks of saw palmetto are not known, although the herb is theorized to interact with 5-AR inhibitors based upon the supposed mechanism of action; this may produce abnormal or unexpected results. 20 Pharmacists should engage patients in a risk-versus-benefit discussion of saw palmetto. Men with new-onset obstructive urinary symptoms should be discouraged from self-medicating with saw palmetto; rather, these patients should be under medical supervision since the symptoms of BPH can mimic other disorders, such as prostate cancer and prostatitis.
Prostatitis--inflammation of the prostate gland--can be acute (bacterial) or chronic (bacterial or nonbacterial). Some symptoms of prostatitis are pain, urination problems, and fever. Recently, Kaplan et al published results of a one-year, randomized, single-blind trial comparing saw palmetto with finasteride in the treatment of prostatitis and chronic pelvic pain.21 Sixty-four men were randomized equally to the two treatment arms. All patients had previously been given antibiotics (nine to 93 weeks' duration), and 52 of them had been on alpha-blockers. At 12 months, the mean total National Institutes of Health Chronic Prostatitis Symptom Index score was significantly lower in the finasteride group (23.9 to 18.1), but not the saw palmetto group. In the finasteride arm, pain and quality of life were significantly improved at 12 months. The authors concluded that the patients who received saw palmetto had no tangible long-term improvement and that patients who received finasteride had significant, long-term improvement in all parameters except urination.
Diseases of the prostate gland normally produce urinary symptoms but may also cause pain, especially in the case of acute bacterial prostatitis and later stages of BPH. OTC analgesics such as acetaminophen and NSAIDs can be recommended to relieve pain in prostate disease. A working knowledge of the supplements utilized for prostate disorders will help the pharmacist field patients' questions about their use. In general, the pharmacist should refer patients who develop obstructive urinary symptoms to a physician for management.
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18. National Institute of Diabetes & Digestive & Kidney Diseases. The CAMUS study. www.niddk.nih.gov/patient/camus/CAMUS.htm. Accessed Feb. 21, 2008.
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