Prostate Cancer, Nutrition, and Dietary Supplements (PDQ®)—Health Professional Version - National Cancer Institute

Prostate Cancer, Nutrition, and Dietary Supplements (PDQ®)–Health Professional Version

Vitamin E

Overview

Most dietary vitamin E comes from gamma-tocopherol. Food sources of vitamin E include vegetable oil, nuts, and egg yolks.
Research suggests that vitamin E may protect against a number of chronic diseases, such as cardiovascular disease.
Studies suggest that alpha-tocopherol –associated protein (TAP) may have capabilities as a tumor suppressor in prostate cancer.
The Selenium and Vitamin E Cancer Prevention Trial (SELECT), a large multicenter clinical trial, was initiated by the National Institutes of Health (NIH) in 2001 to examine the effects of selenium and/or vitamin E on the development of prostate cancer.
In 2011, updated results from SELECT showed that men who took vitamin E alone had a 17% increase in prostate cancer risk compared with men who took placebo.
In 2014, an analysis of SELECT results showed that men who had high selenium status at baseline and who were randomly assigned to receive selenium supplementation had an increased risk of high-grade prostate cancer, but vitamin E supplementation had no effect among men with high selenium status.

General Information and History

Vitamin E was discovered in 1922 as a factor essential for reproduction.[1]

Vitamin E occurs in eight different forms: four tocopherols (alpha-, beta-, gamma-, and sigma-) and four tocotrienols (alpha-, beta-, gamma-, and sigma-).[2] Compared with other tocopherols, alpha-tocopherol (the form of vitamin E commonly found in dietary supplements) is the most abundant in the body and the most biologically active. Most dietary vitamin E comes from gamma-tocopherol. Food sources of vitamin E include vegetable oil, nuts, and egg yolks.[3]

The bioavailability of vitamin E depends on a number of factors, such as the food matrix containing vitamin E (e.g., low- or high-fat food).[4] Vitamin E is delivered to tissues by high- and low-density lipoproteins (HDL and LDL, respectively). Delivery by LDL occurs via an endocytic pathway, while the protein’s ATP -binding cassette, subfamily 1 and scavenger receptor class B type 1 (SR-BI) are involved in HDL vitamin E transport.[5]

Research suggests that vitamin E may protect against a number of chronic diseases, such as cardiovascular disease.[1] Many of vitamin E’s health benefits have been ascribed to its actions as a powerful antioxidant; as with other antioxidants, vitamin E protects cell membranes by interfering with reactions that would form lipid hydroperoxide products.[5] Vitamin E also has nonantioxidant functions: it has been shown to modulate signaling pathways and gene expression.[3]

Human Studies

Epidemiologic studies

The National Institutes of Health-American Association of Retired Persons (NIH-AARP) Diet and Health Study was initiated to examine whether supplemental vitamin E and dietary tocopherol intakes may prevent prostate cancer. Participants in the study completed food-frequency questionnaires and were monitored for 5 years. No association between vitamin E supplements and prostate cancer risk was found. However, a reduction in the risk of advanced prostate cancer was observed with high intakes of gamma-tocopherol.[6]

In a 2010 study, levels of trace elements and vitamin E were measured in prostate cancer patients. Prostate cancer patients had significantly lower levels of plasma vitamin E than did healthy controls. In addition, there was an inverse association between prostate-specific antigen levels and plasma vitamin E.[7]

Studies suggest that alpha-tocopherol–associated protein (TAP) may have capabilities as a tumor suppressor in prostate cancer. In a 2007 study, prostate cancer specimens, which had been obtained from radical prostatectomy, were examined for TAP expression. Results showed reduced TAP expression in prostate cancer tissue and lower levels of TAP were associated with higher clinical stage and larger tumor size.[8]

A study published in 2011 examined serum alpha-tocopherol and supplemental vitamin E intake with sex steroid hormones in participants in the Third National Health and Nutrition Examination Survey (NHANES III). Results showed an inverse association between serum alpha-tocopherol levels and sex steroid hormones, but only in smokers.[9]

Serum alpha-tocopherol and gamma-tocopherol levels and prostate cancer risk were examined in participants in the Prostate, Lung, Colorectal and Ovarian (PLCO) Screening Trial. An inverse relationship was observed between alpha-tocopherol levels and prostate cancer, but only in current and recently former smokers.[10] A meta-analysis of nine nested case-control studies, representing approximately 370,000 men from several countries, also found an inverse relationship between blood alpha-tocopherol levels and prostate cancer risk, but in all patients studied rather than limited to a smoking subset.[11] No association was seen with gamma-tocopherol levels in this analysis. The risk of prostate cancer decreased by 21% for every 25 mg/L increase in blood alpha-tocopherol levels.

The North Carolina-Louisiana Prostate Cancer Project investigated racial and geographic differences in prostate cancer aggressiveness.[12] The effects of food intake of tocopherols, vitamin E supplementation, and adipose tissue biomarkers of tocopherol were studied. In 1,023 African American men and 1,079 white men studied with incident prostate cancer, inverse associations were observed between dietary sources of tocopherol and prostate cancer aggressiveness that were statistically significant in white men but not in African American men.

Intervention Studies

The Physicians’ Health Study II investigated whether vitamin C or vitamin E prevents prostate cancer and other cancers in men. Participants in the study were randomly assigned to receive vitamin E (synthetic alpha-tocopherol, 400 IU qod) and/or vitamin C (synthetic ascorbic acid, 500 mg /d) supplements and were monitored for an average of 8 years. The overall rates of prostate cancer were very similar in the vitamin E supplement and placebo groups, suggesting that vitamin E may not prevent prostate cancer. Furthermore, vitamin E did not have an effect on total cancer or mortality in these participants.[13]

Although not primarily designed for this purpose, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study has been a resource for researchers investigating prostate cancer and vitamin E.[14] A long follow-up study of participants in the ATBC Study was conducted. Baseline serum alpha-tocopherol levels and dietary intake of vitamin E had been assessed and participants were monitored for up to 19 years. Findings revealed that while there was no association between dietary vitamin E levels and prostate cancer risk, higher serum alpha-tocopherol levels may be associated with a decreased risk for developing advanced prostate cancer.[15] In a 2009 study, blood samples obtained from participants in the ATBC Study were analyzed and genotyped. Results showed that geneticvariations in the TTPA and SEC14L2 genes were associated with serum alpha-tocopherol but did not directly affect prostate cancer risk. However, results suggested that polymorphismsin SEC14L2 may influence the effect of alpha-tocopherol supplementation on prostate cancer risk.[16] One study also focused on the ATBC Study and investigated whether serum alpha-tocopherol levels affected survival time in men diagnosed with prostate cancer. Serum alpha-tocopherol levels were assessed at baseline and 3 years later. Higher serum alpha-tocopherol levels, at both baseline and the 3-year point, were associated with improved prostate cancer survival.[17]

A 2011 study examined links between serum alpha- and gamma-tocopherols and risk of prostate cancer among participants in the Carotene and Retinol Efficacy Trial (CARET). CARET was a randomized, placebo-controlled study that investigated whether daily supplementation of beta-carotene and retinyl palmitate would reduce the risk of lung cancer in heavy smokers and asbestos -exposed workers. Results indicated that among current smokers, higher levels of serum alpha- and gamma-tocopherols were associated with reduced risk of aggressive prostate cancer. In addition, findings suggested there may be an interaction between myeloperoxidase (MGO) G-463A genotype, serum alpha-tocopherol level, and prostate cancer risk. Specific genotypes were associated with increased prostate cancer risk in subjects with low levels of serum alpha-tocopherol, while those same genotypes along with higher levels of alpha-tocopherol were associated with reduced risk of prostate cancer.[18]

The Selenium and Vitamin E Cancer Prevention Trial (SELECT)

On the basis of findings from earlier studies,[14,19] the SELECT, a large multicenter clinical trial, was initiated by the NIH in 2001 to examine the effects of selenium and/or vitamin E on the development of prostate cancer. SELECT was a phase III, randomized, double-blind, placebo-controlled, population-based trial.[20] More than 35,000 men, aged 50 years or older, from more than 400 study sites in the United States, Canada, and Puerto Rico were randomly assigned to receive vitamin E (all-rac-alpha-tocopherol acetate, 400 IU/d) and a placebo, selenium (L-selenomethionine, 200 µg/d) and a placebo, vitamin E and selenium, or two placebos daily for 7 to 12 years. The primary endpoint of the clinical trial was incidence of prostate cancer.[20]

Initial results of SELECT were published in 2009. There were no statistically significant differences in rates of prostate cancer in the four groups. In the vitamin E–alone group, there was a nonsignificant increase in rates of prostate cancer (P = .06); in the selenium–alone group, there was a nonsignificant increase in incidence of diabetes mellitus (P = .16). On the basis of those findings, the data and safety monitoring committee recommended that participants stop taking the study supplements.[21]

Updated results were published in 2011. When compared with placebo, the rate of prostate cancer detection was significantly greater in the vitamin E–alone group (P = .008) and represented a 17% increase in prostate cancer risk. There was also greater incidence of prostate cancer in men who had taken selenium than in men who had taken placebo, but those differences were not statistically significant.[22]

Toenail selenium levels were assayed in a two-case cohort study of a subset of SELECT participants. Vitamin E supplementation (alone) had no effect among men with high selenium status at baseline but increased the risks of total (63%; P = .02), low-grade (46%; P= .09), and high-grade (111%; P = .008) prostate cancer among men with lower baseline selenium status. The authors concluded that men older than 55 years should avoid supplementation with either vitamin E or selenium at doses exceeding dietary recommendations.[23] In a case-cohort analysis of 1,434 men in the SELECT who underwent analysis of single nucleotide polymorphisms in 21 genes, investigators found support for the hypothesis that genetic variation in selenium and vitamin E metabolism/transport genes may influence the risk of overall- and high-grade prostate cancer and that selenium or vitamin E supplementation may modify an individual's response to those risks.[24]

The dose and form of vitamin E used in SELECT may have contributed to the results. On the basis of the results of the ATBC Study, all-rac-alpha-tocopheryl acetate was the form of vitamin E used in SELECT. The dose used in SELECT (400 IU) was higher than that in the ATBC Study. SELECT researchers opted for the higher dose because it was found in vitamin supplements, there was evidence for benefits of higher doses (including reductions in Alzheimer’s disease and age-related macular degeneration), and it was thought the higher dose would be more protective against prostate cancer than a lower dose.[25] Following the results of SELECT, it has been posited that high levels of alpha-tocopherol may affect levels of gamma-tocopherol, another form of vitamin E that may have chemopreventiveeffects.[26] Another important difference between the ATBC Study and SELECT that may explain the findings was the smoking status of study participants. Participants in the ATBC Study were smokers, while 7.5% of SELECT participants used tobacco products.[27]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Adverse Effects

Alpha-tocopherols have been deemed Generally Recognized as Safe by the U.S. Food and Drug Administration.[28]

In the Physicians’ Health Study II, there were no significant adverse effects reported for gastrointestinal tract symptoms, fatigue, drowsiness, skin discoloration or rashes, or migraine. However, participants who took vitamin E (alpha-tocopherol, 400 IU qod) experienced a greater number of hemorrhagic strokes than did participants who took placebo.[13] An increase in hemorrhagic strokes among participants in the vitamin E group (alpha-tocopherol, 50 mg/d) also was noted in the ATBC Study.[14]

In the initial report of results from SELECT, there were no significant differences between incidences of less severe adverse effects (e.g., alopecia, dermatitis, and nausea) experienced by the groups that received vitamin E (rac-alpha-tocopheryl acetate, 400 IU/d) and those experienced by the other treatment groups.[21] Follow-up analysis of SELECT participants revealed an increased risk of prostate cancer among men in the vitamin E–alone group.[22]

References

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Crispen PL, Uzzo RG, Golovine K, et al.: Vitamin E succinate inhibits NF-kappaB and prevents the development of a metastatic phenotype in prostate cancer cells: implications for chemoprevention. Prostate 67 (6): 582-90, 2007. [PUBMED Abstract]
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Adaramoye OA, Akinloye O, Olatunji IK: Trace elements and vitamin E status in Nigerian patients with prostate cancer. Afr Health Sci 10 (1): 2-8, 2010. [PUBMED Abstract]
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Mondul AM, Rohrmann S, Menke A, et al.: Association of serum α-tocopherol with sex steroid hormones and interactions with smoking: implications for prostate cancer risk. Cancer Causes Control 22 (6): 827-36, 2011. [PUBMED Abstract]
Weinstein SJ, Peters U, Ahn J, et al.: Serum α-tocopherol and γ-tocopherol concentrations and prostate cancer risk in the PLCO Screening Trial: a nested case-control study. PLoS One 7 (7): e40204, 2012. [PUBMED Abstract]
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Antwi SO, Steck SE, Su LJ, et al.: Dietary, supplement, and adipose tissue tocopherol levels in relation to prostate cancer aggressiveness among African and European Americans: The North Carolina-Louisiana Prostate Cancer Project (PCaP). Prostate 75 (13): 1419-35, 2015. [PUBMED Abstract]
Gaziano JM, Glynn RJ, Christen WG, et al.: Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians' Health Study II randomized controlled trial. JAMA 301 (1): 52-62, 2009. [PUBMED Abstract]
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Weinstein SJ, Wright ME, Lawson KA, et al.: Serum and dietary vitamin E in relation to prostate cancer risk. Cancer Epidemiol Biomarkers Prev 16 (6): 1253-9, 2007. [PUBMED Abstract]
Wright ME, Peters U, Gunter MJ, et al.: Association of variants in two vitamin e transport genes with circulating vitamin e concentrations and prostate cancer risk. Cancer Res 69 (4): 1429-38, 2009. [PUBMED Abstract]
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Cheng TY, Barnett MJ, Kristal AR, et al.: Genetic variation in myeloperoxidase modifies the association of serum α-tocopherol with aggressive prostate cancer among current smokers. J Nutr 141 (9): 1731-7, 2011. [PUBMED Abstract]
Clark LC, Combs GF Jr, Turnbull BW, et al.: Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 276 (24): 1957-63, 1996. [PUBMED Abstract]
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Lippman SM, Klein EA, Goodman PJ, 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 301 (1): 39-51, 2009. [PUBMED Abstract]
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 306 (14): 1549-56, 2011. [PUBMED Abstract]
Kristal AR, Darke AK, Morris JS, et al.: Baseline selenium status and effects of selenium and vitamin e supplementation on prostate cancer risk. J Natl Cancer Inst 106 (3): djt456, 2014. [PUBMED Abstract]
Chan JM, Darke AK, Penney KL, et al.: Selenium- or Vitamin E-Related Gene Variants, Interaction with Supplementation, and Risk of High-Grade Prostate Cancer in SELECT. Cancer Epidemiol Biomarkers Prev 25 (7): 1050-1058, 2016. [PUBMED Abstract]
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