Do selenium and vitamin E really increase the risk of prostate cancer?
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Reference
Klein EA, Thompson IM Jr, Tangen CM, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2011;306(14):1549-1556.
Design
The SELECT (Selenium and Vitamin E Cancer Prevention Trial) includes a total of 35,533 men from 427 study sites in the United States, Canada, and Puerto Rico who were randomized between August 22, 2001, and June 24, 2004. The primary analysis included 34,887 men who were randomly assigned to 1 of 4 treatment groups: 8,752 to receive selenium; 8,737 to receive vitamin E; 8,702 to receive both agents; and 8,696 to receive placebo. Analysis reflects the final data collected by the study sites on their participants through July 5, 2011.
Participants
35,533 Canadian and American men
Study Parameters Assessed
The study enrolled healthy men at average risk of prostate cancer based on a baseline prostate-specific antigen (PSA) level of ≤4 ng/mL and normal digital rectal examination (DRE), commencing at age 50 years for black men or at age 55 years for all others. Men were randomized into 1 of 4 groups: selenium (200 μg/d from L-selenomethionine) and a vitamin E placebo, vitamin E (400 IU/d of all rac-α-tocopherol acetate) and a selenium placebo, selenium plus vitamin E, or placebo.
Participants without prostate cancer were monitored every 6 months with an annual limited physical examination including blood pressure, weight, and smoking status; participants who developed prostate cancer during the study were monitored annually thereafter. Participants were recommended to undergo PSA and DRE testing and prostate biopsy based on the standard of care in their community and in accordance with the participant's preference. To facilitate adherence, a multivitamin containing no selenium or vitamin E was offered. All participants were required to provide written informed consent, and the local institutional review board of each study site approved the study. Follow-up continued in an unblinded fashion at study sites from October 2008 until July 2011.
Key Findings
- The rate of prostate cancer detection was greater in all treatment groups when compared with placebo but was statistically significant only in the vitamin E alone group.
- Prostate cancer risk did not increase when vitamin E and selenium were taken together.
- Those who took vitamin E alone were at a 17% higher risk of developing prostate cancer.
- Vitamin E alone or with selenium did not reduce the risk of other cancers or diseases.
Practice Implications
Vitamin E, like many vitamins, has several isoforms that occur naturally in foods. These isoforms are called vitamers, and include 4 tocopherols and 4 tocotrienols, each labeled alpha, beta, delta, or gamma. The above study used a single vitamer, alpha-tocopherol, which may be one reason for the negative findings. Evidence indicates other vitamers of E play a more prominent role in reducing the risk of cancer, including prostate cancer (CaP).
Evidence indicates other vitamers of E play a more prominent role in reducing the risk of cancer, including prostate cancer.
Before and during the time the SELECT study was recruiting patients (beginning in 2000), emerging research demonstrated that the alpha-tocopherol component of vitamin E does not protect people from CaP without the other major component of vitamin E, gamma-tocopherol. In fact, evidence suggests alpha tocopherol depletes cells of the more protective form of vitamin E, gamma tocopherol.1
Lesson
You shouldn’t study alpha-tocopherol without gamma tocopherol.
Gamma-tocopherol is a form of vitamin E that is lacking in many commercial vitamin E supplements. Consuming high doses of alpha-tocopherol depletes the cell of critically important gamma-tocopherols. Although alpha-tocopherol inhibits the production of free radicals, it is gamma-tocopherol that is required to trap and neutralize free radicals.2
In a study of 10,456 men done at Johns Hopkins School of Public Health, men who had the highest blood levels of gamma-tocopherol were 5 times less likely to develop prostate cancer.3 In addition to the finding that higher levels of gamma-tocopherol significantly reduced prostate cancer risk, the study also showed that selenium and alpha-tocopherol reduced prostate cancer incidence, but only when gamma-tocopherol levels are high.
The most provocative study found that men with the highest plasma gamma-tocopherol concentrations had a highly significant 5-fold lower risk of prostate cancer compared with men in the lowest quintile (lowest 20%].4 This effect was not significant for plasma alpha-tocopherol concentrations. Other researchers have also found that gamma-tocopherol offers a protective effect against prostate cancer (Huang et al. 2003).
In addition to tocopherols, tocotrienols have also been shown to have possible preventative effects for prostate cancer. One report showed that a combination of all 4 tocotrienols is effective in preventing and inhibiting prostate cancer growth in mice.5 Since these vitamers of E often occur together in foods, it would not be surprising to find out they are synergistic in effect.
Lastly, the data from the current study support the theory that selenium and vitamin E together cause no increase in prostate cancer. Products that contain mixed tocopherols and/or tocotrienol along with selenium may still be beneficial for reduction of prostate cancer risk. Studies such as the SELECT trial that used single agents in isolation may not reflect best practices of supplement application as we know them today.
For more research involving integrative oncology, click here.
About the Author
References
1. Handelman GJ, Epstein WL, Peerson J, Spiegelman D, Machlin LJ, Dratz EA. Human adipose alpha-tocopherol and gamma-tocopherol kinetics during and after 1 y of alpha-tocopherol supplementation. Am J Clin Nutr. 1994;59(5):1025-1032.
2. Christen S, Woodall AA, Shigenaga MK, Southwell-Keely PT, Duncan MW, Ames BN. Gamma-tocopherol traps mutagenic electrophiles such as NO(X) and complements alpha–tocopherol: physiological implications. Proc Natl Acad Sci USA. 1997;94(7):3217-3222.
3. Helzlsouer KJ, Huang HY, Alberg AJ, et al. Association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer. J Natl Cancer Inst. 2000;92(24):2018-2023.
4. Huang HY, Alberg AJ, Norkus EP, et al. Prospective study of antioxidant micronutrients in the blood and the risk of developing prostate cancer. Am J Epidemiol. 2003;157(4):335-344.
5. Barve A, Khor TO, Reuhl K, Reddy B, Newmark H, Kong AN. Mixed tocotrienols inhibit prostate carcinogenesis in TRAMP mice. Nutr Cancer. 2010;62(6):789-794