Take Home Message FIRST

• There are 8 forms of vitamin E
• The study just uses one form – alpha tocopherol
• Gamma tocopherol is more protective than alpha-tocopherol
• Tocotrienols may be also important for prostate cancer(CaP) protection
• One should be careful with making health decisions based from sound-bytes and headlines from the media.
• They typically do not have a medical expert on staff that critically reviews the research

 

What is Vitamin E

The term vitamin E describes a family of eight antioxidants (called isoforms)

4 – tocopherols (alpha-, beta-, gamma-, and delta-) and 4 tocotrienols (alpha-, beta-, gamma-, and delta-)

Alpha-tocopherol is the only form of vitamin E that was studied in the SELECT trial and it is the main form that is studied in most other clinical trials.

 

The SELECT trial

This was $175 million study to determine whether vitamin E (in the form alpha-tocopherol) and selenium (in the form of L-selenomethionine) can prevent prostate cancer. The trial was called the SELECT trial (SELenium and vitamin E Cancer prevention Trial).

The participants were randomly assigned to receive one of four interventions between August 2001 and June 2004 for a planned minimum follow-up of 7 years:

• L-selenomethionine (200 micrograms per day) and a vitamin E placebo;
• alpha–tocopherol (400 IU/day) and a selenium placebo;
• L-selenomethionine plus alpha-tocopherol; or
• placebo.

This study of the 35,000-man study was called for a halt when an early look at the data showed no benefit for the treatment. In this clinical trial, there were slightly more prostate cancers in men taking vitamin E alone and slightly more diabetes in men taking only selenium. But neither finding was statistically significant, meaning these findings were likely due to chance (Lippman et al. 2009).

The recent hoopla is about the study on JAMA indicating that extended follow-up of SELECT participants showed that healthy men with average risk of prostate cancer subjected to contemporary community standards of screening and biopsy who took a common dose and formulation of vitamin E (400 IU/d) have a significantly increased risk of prostate cancer. (Klein et al. 2011)

A Big Hole in the SELECT study from day one

This study reveals a fundamental problem confronting all researchers who seek to prove whether a certain supplement prevents a disease. There are too many factors involved in the development and progression of prostate cancer — including low levels of testosterone, increased levels of estrogen, co-existing diabetes or metabolic syndrome, and over-consumption of saturated fats (Malley et al. 2006).

This multitude of confounding factors makes it difficult to study just one or two compounds and expect to arrive at a validated finding. Reductionist studies are faulty and unnecessarily expensive as it relates to the study of supplementation.

Studying just alpha-tocopherol form of vitamin E is faulty in design, especially when there is some evidence indicating that other members of the vitamin E family are even more important.

Prior to and during the time the SELECT study began in the year 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, the alpha-tocopherol form of vitamin E depletes the cells of the more protective form of vitamin E, gamma tocopherol (Handelman et al. 1994).

 

The Link Between gamma-Tocopherol and CaP

Gamma-tocopherol is a form of vitamin E that is lacking in almost all commercial vitamin E supplements. When high doses of alpha-tocopherol vitamin E are consumed, it kicks out critically important gamma-tocopherol in the cells. While alpha-tocopherol inhibits the production of free radicals, it is the gamma-tocopherol form of vitamin E that is required to trap and neutralize free radicals. (Christen et al. 1997)

Furthermore, researchers reported that it could be dangerous to take high levels of alpha-tocopherol vitamin E without also consuming gamma-tocopherol.

In a 10,456 men study at the prestigious Johns Hopkins School of Public Health, men who had the highest blood levels of gamma-tocopherol were five times less likely to get prostate cancer (Helzlsouer et al. 2000).

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 also 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 five-fold lower risk of prostate cancer compared with men in the lowest quintile [lowest 20%]. 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).

How about the tocotrienols form of vitamin E

There are animal studies suggesting the beneficial aspects of all forms of tocotrienols and the prevention of prostate cancer

One report shows that mixed tocotrienols are effective in preventing and inhibiting prostate cancer growth in mice (Barve et al. 2010).

Mice studies do not conclusively mean that the results translate to humans. But CaP progression in certain mouse models closely resembles that in humans and therefore provides a useful tool to test the efficacy of preventive compounds.

My take on Vitamin E Study and the SELECT Trial

Researchers should seek nutritional experts to contribute to designing clinical trials. As a result of the faulty and grossly expensive SELECT trial, we will likely never see a better-designed study with gamma-tocopherol and tocotrienols in humans because “all forms of vitamin E are the same.” They are not.

References:

Lippman et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2009;301(1):39 -51.

Malley RL, Taneja SS. Obesity and prostate cancer. Can J Urol. 2006 Apr;13 Suppl 2:11-7.

Handelman, G.J., Epstein, W.L., Peerson, J., Spiegelman, D., Machlin, L.J., & Dratz, E.A. (1994). Human adipose alpha-tocopherol and gamma-tocopherol kinetics during and after 1 y of alpha-tocopherol supplementation. American Journal of Clinical Nutrition, 59(5), 1025-1032.

Klein et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2011 Oct 12;306(14):1549-56.

Christen S, et al. gamma-tocopherol traps mutagenic electrophiles such as NO(X) and complements alpha–tocopherol: physiological implications. Proc Natl Acad Sci U S A 1997 Apr 1;94(7):3217-22

Helzlsouer KJ, et al. Association Between alpha–Tocopherol, gamma-Tocopherol, Selenium, and Subsequent Prostate Cancer. J Natl Cancer Inst 2000 Dec 20;92(24):2018-2023.

Helzlsouer, K.J., Huang, H.Y., Alberg, A.J., Hoffman, S., Burke, A., & Norkus, E.P., et al. (2000). Association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer. Journal of National Cancer Institute, 92(24), 2018-2023.

Huang, H.Y., Alberg, A.J., Norkus, E.P., Hoffman, S.C., Comstock, G.W., Helzlsouer, K.J., et al. (2003). Prospective study of antioxidant micronutrients in the blood and the risk of developing prostate cancer. American Journal of Epidemiology, 157(4), 335-344.

Barve et al. Mixed tocotrienols inhibit prostate carcinogenesis in TRAMP mice. Nutr Cancer. 2010;62 (6): 789-94