A paper published recently from the Selenium and Vitamin E Cancer Prevention Trial (SELECT) in the Journal of the American Medical Association (JAMA. 306:1549-1556, 2011) concluded that “dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men.” This alarming news spread fast, and many men are now wondering if it is prudent to take vitamin E supplements in light of this new information.
To date, two large randomized, placebo-controlled trials (RCTs) have been conducted in healthy men to investigate the effect of vitamin E supplementation on prostate cancer: The Physicians’ Health Study (PHS) II and SELECT. PHS II (JAMA. 301:52-62, 2009) followed 14,641 healthy men, aged 50 years and older, given 400 International Units (IU) of synthetic vitamin E every other day for eight years. In SELECT, 35,533 healthy men, aged 50 and older, received 400 IU of synthetic vitamin E every day for seven years. In both trials, there was no benefit of taking vitamin E supplements on prostate cancer risk. After a median time of 5.5 years in SELECT, vitamin E supplementation was discontinued, yet follow-up of the study participants continued for 1.5 years in order to document additional events. Unexpectedly, the SELECT updated analysis published recently in JAMA found a 17% increased risk of being diagnosed with prostate cancer in men who had taken the vitamin E supplement compared to those who had received placebo. No biological mechanism was proposed to explain the increased incidence of prostate cancer.
Why Did They Look at Vitamin E in the First Place?
Vitamin E functions as a powerful, fat-soluble antioxidant in our cells and tissues. Antioxidants neutralize the effects of free radicals, highly reactive species that oxidize DNA, proteins, and lipids inside our cells, potentially causing damage and contributing to disease. In particular, oxidative DNA damage may cause mutations and, hence, increase the risk of certain cancers, including prostate cancer. Free-radical exposure is an unavoidable aspect of our lives, as these radicals are produced as a natural by-product of many biological processes, such as cellular respiration and inflammation, in addition to coming from our environment, particularly cigarette smoke. Antioxidants produced in the body and ingested in the diet are essential to reduce oxidative stress and counteract the potentially harmful effects of free radicals.
Some studies support a beneficial role for vitamin E in cancer and cardiovascular disease prevention. For example, the Women’s Health Study (JAMA. 294:56-65, 2005) followed 39,876 women who took 600 IU natural vitamin E every other day for ten years. The investigators found that supplemental vitamin E decreased cardiovascular-related deaths by 24% but had no effect on cardiovascular events, overall cancer incidence, or cancer-related deaths. In general, studies have reported mixed results, and the impact of vitamin E supplementation on chronic disease risk remains controversial.
Why Are the Results Different?
The Women’s Health Study (WHS), PHS II, and SELECT are RCTs, also referred to as clinical trials or intervention studies. In RCTs, individuals are randomly assigned to either treatment (vitamin E in this case) or placebo, and the impact of the intervention on disease incidence is evaluated after several years.
The important issues that emerge from these RCTs are vitamin E dose (200-400 IU/day), vitamin E form (natural vs. synthetic), and population studied. Synthetic vitamin E (all-rac-alpha-tocopherol or dl-alpha-tocopherol) has half the bioactivity of naturally occurring vitamin E (RRR-alpha-tocopherol or d-alpha-tocopherol)—hence, the “effective dose” in PHS II and SELECT was only 100 and 200 IU/day, respectively, and 300 IU/day in WHS. Higher doses may be needed to effectively reduce oxidative stress. In one dose-response study, significant reductions in plasma F2-isoprostanes (a marker of oxidative stress) occurred only at daily doses of at least 1,600 IU of natural-source vitamin E. Notably, this dose is above the tolerable upper intake level (UL) of 1,500 IU/day set by the Food and Nutrition Board of the Institute of Medicine.
The fact that the vitamin E doses used in the RCTs appear insufficient to lower oxidative stress may explain the lack of benefit with respect to cancer risk. It remains unknown whether oxidative stress plays a causal role in prostate cancer. Furthermore, it remains unexplained why vitamin E supplementation in SELECT was associated with a 17% increased risk of prostate cancer, whereas vitamin E supplementation in PHS II and WHS was not associated with increased risk of any type of cancer in men and women, respectively.
Finally, the population studied in SELECT was healthy males consuming a well-balanced diet, most of whom likely were not vitamin E deficient or under increased oxidative stress. Unfortunately, neither baseline vitamin E levels in the study participants’ blood nor their oxidative stress status was assessed. In situations of stress, disease, or deficiency, meeting an increased demand with vitamin E supplementation may be warranted. However, in healthy people, vitamin E supplementation shows no added benefit on disease risk, as confirmed by the RCTs discussed here. For example, a study on the effect of supplemental vitamin E on cancer risk in 29,000 Finnish male smokers (the Alpha-Tocopherol Beta-Carotene [ATBC] trial) reported in 1998 that daily supplements of 75 IU/day of synthetic vitamin E for five to eight years were associated with a 32% and 41% reduction in prostate cancer diagnosis and mortality, respectively, compared to unsupplemented smokers. However, among other limitations, the ATBC study was not designed to assess prostate cancer incidence as a primary endpoint. Since oxidative stress was not measured in the study subjects, the mechanism for the possible protective effect of low-dose vitamin E remains obscure. Factors other than oxidative stress play an important role in the etiology of prostate cancer, such as endogenous hormones, race, age, and dietary fat intake.
Based on the lack of conclusive evidence for a benefit of vitamin E supplementation in cancer and cardiovascular disease prevention in generally healthy adults and the potential for harm in certain subpopulations, the Linus Pauling Institute has revised its "Rx for Health" and no longer includes a recommendation for supplementation with 200 IU/day of natural-source vitamin E.
What to Do?
Vitamin E is an important micronutrient, and meeting daily recommendations is critical for optimum health. The Recommended Dietary Allowance (RDA) of vitamin E for adult men and women is 22.5 IU per day. Notably, more than 90% of individuals aged 2 years and older in the U.S. do not meet the daily requirement for vitamin E from food sources alone. Major sources of vitamin E in the American diet are vegetable oils, nuts, whole grains, and green leafy vegetables.
Taking all the issues discussed above into consideration, LPI recommends that generally healthy adults take a daily multivitamin/mineral supplement, which usually contains 30 IU of synthetic vitamin E, or 90% of the RDA.
