How Selenium, Vitamin E Increase Prostate Cancer Risk

New data from the much publicized Selenium and Vitamin E Cancer Prevention Trial (SELECT), which sought to determine whether these supplements could protect against the development of prostate cancer, confirm that both antioxidants can be risky business for men.

As previously reported, men receive no preventive benefit from either selenium or vitamin E supplements; in fact, for certain men, these supplements actually increased the risk for prostate cancer.

The new study, published online February 22 in the Journal of the National Cancer Institute, explored which men who take these supplements are most at risk for prostate cancer, and why.

However, the ongoing public health message from the trial remains the same, said a trial investigator.

"Men using these supplements should stop, period. Neither selenium nor vitamin E supplementation confer any known [health] benefits — only risks," said lead author Alan Kristal, DrPH, from the Fred Hutchinson Cancer Research Center in Seattle, in a press statement.

"Many people think that dietary supplements are helpful or at the least innocuous. This is not true," he added.

The cohort of 4856 men was culled from SELECT, the larger phase 3 placebo-controlled trial in which more than 35,000 men were randomized to high-dose vitamin E (400 IU/day) and/or selenium (200 µg/day) supplements.

SELECT began in 2001 and was expected to run for 12 years, but it was stopped early, in 2008, after participants had been on the supplements for an average of 5 years. The results demonstrated that there was no protective effect from selenium and suggested that vitamin E increased prostate cancer risk.

Although the use of the supplements stopped, the study actually continued. After 2 years of follow-up, the men who took vitamin E had a statistically significant 17% increased risk for prostate cancer, as previously reported.

Notably, the rate of prostate cancer detection was higher in the groups that received either supplement alone or a combination of the 2 than in the placebo group (but the difference was significant only in the vitamin E group).

Selenium is a nonmetallic trace element found in plant in foods such as rice, wheat, and Brazil nuts, and in seafood and meat. In a previous large skin cancer prevention trial, it was associated with a reduced risk for prostate cancer. According to the National Cancer Institute, it is an antioxidant that might help control cell damage that can lead to cancer.

Vitamin E is found in a wide range of foods, especially vegetables, vegetable oils, nuts, and egg yolks. Like selenium, vitamin E is considered an antioxidant.

Key: Increased Risk Depends on Baseline Selenium
In this new case–cohort study, 1739 men diagnosed with prostate cancer during SELECT were compared with 3117 men who were not.

Dr. Kristal and colleagues found that baseline selenium status alone, in the absence of supplementation, was not associated with prostate cancer risk.

However, they also found that the effects of the supplements differed substantially between men with low levels at baseline and those with high levels.

Specifically, selenium supplementation increased the risk for prostate cancer in men who already had high selenium levels at baseline.

Before SELECT even began, there was evidence that selenium supplementation would not benefit men who already had an adequate intake of the nutrient.

For this reason, at baseline, the investigators measured the concentration of selenium in the toenails of participants. The plan was to test whether supplementation would benefit only the subset of men with low selenium levels at baseline, they explain.

Instead, they found that men with high selenium levels at baseline who took selenium supplements increased their risk for high-grade cancer by 91% (P = .007). In other words, the levels of selenium in these men became toxic.

The investigators also report that vitamin E increased prostate cancer risk in men, but only in those with low selenium levels at baseline.

Specifically, in the men with low levels of selenium randomized to receive vitamin E alone, the total risk for prostate cancer increased by 63% (P = .02) and the risk for high-grade cancer increased by 111% (P = .01).

This might explain why, in the 2008 SELECT results, only the men randomized to receive vitamin E alone, not those who received both vitamin E and selenium, had an increased risk for prostate cancer.

There is some evidence from basic science to support the idea of a meaningful dynamic. "An interaction between vitamin E and selenium has long been hypothesized because of their activities in preventing lipid peroxidation," Dr. Kristal and colleagues write.

Selenium, whether from dietary sources or supplements, might protect men from the harmful effects of vitamin E, they suggest. So selenium, at low levels, is not necessarily harmful to men.

Nevertheless, these new results are consistent with the medical literature on supplements and cancer, the investigators report. The message is that nothing good is gained in healthy people.

The literature "suggests that effects of supplementation are dependent upon the nutrient status of the target population, such that supplementation of populations with adequate nutrient status, leading to supraphysiological exposure, has either no effect or increases cancer risk," they write.

Adding Flavanols to Dark Chocolate Doesn't Improve Health Benefits

Excuses for regularly indulging in dark chocolate keep accumulating, with the added possibility that its ingredients, thought to promote relaxed arteries, also have biochemical effects that may discourage atherosclerosis. But special flavanol-enriched formulations of dark chocolate may do little to enhance its vascular benefits, suggests a report published in the March 2014 issue of the FASEB Journal.

In a randomized, double-blind study, eating dark chocolate—acutely and over weeks—not only improved objective measures of endovascular function, it also improved biochemical markers that reflect leukocyte activation, inflammation, and other signs of atherogenesis.

The study further compared normal- vs high-flavanol dark-chocolate consumption by its participants, a few dozen overweight and mildly obese middle-aged male volunteers. It saw few important differences in vascular functional or biochemical effects following ingestion of either formulation of chocolate.

Changes in endothelial function were reflected in improved flow-mediated dilation (FMD), blood pressure, and augmentation index (AIX), while "changes in leukocyte-cell counts, plasma cytokines, and leukocyte adherence markers after chocolate consumption point toward a less-activated state of cellular adherence and, hence, a less atherogenic milieu," according to the authors, led by Dr Diederik Esser (Top Institute Food and Nutrition and Wageningen University, the Netherlands).

"Extra flavanols did not augment these effects," they write, "but did affect taste and had a negative effect on the motivation to eat chocolate."

Beneficial vascular changes and even improved clinical outcomes have long been attributed to consumption of flavanol- and polyphenol-rich foods like chocolate, red wine, cinnamon, and tea in both observational and interventional studies. Chocolate itself has been associated with improved blood pressure and cerebral perfusion and a reduction in stroke, heart failure, and other cardiovascular-event outcomes.

Acute Chocolate Effects
In a double-blind crossover randomization, 29 men consumed 70 g of chocolate on each of two days separated by at least one week. On one occasion, the chocolate contained normal levels of flavanols, and on the other it was supplemented with extra flavanols.

Ingestion of both types of chocolate decreased AIX (indicating decreased central aortic pressure) but didn't affect FMD (reflecting endothelial function). Similarly, hematocrit and counts of thrombocytes, lymphocytes, monocytes, and neutrophils went up within two hours. Plasma soluble intercellular adhesion molecule (sICAM) 3, interleukin (IL)-1β, and von Willebrand factor levels went up, and plasma IL-6 levels fell two hours after ingestion of both kinds of chocolate. Insulin also went up after both chocolates, but more so after the high-flavanol kind.

The Four-Week Crossover Trial
The same 29 subjects plus an additional 15 participated in a second double-blind experiment in which four weeks of 70 g per day of either high- or low-flavanol chocolate was followed by a four-week washout period and then crossover to four weeks of the other kind of chocolate. They followed certain dietary restrictions to minimize background flavanol intake.

Four weeks of consuming chocolate of either kind elevated fasting FMD by a percentage point and dropped AIX to a similar extent; both measures reverted to baseline after the washout period. The literature suggests a significant 13% reduction in cardiovascular-event risk for every 1% rise in FMD after chocolate consumption, according to the authors.

In a novel finding, four weeks of chocolate consumption significantly lowered counts of circulating leukocytes, suggesting decreased inflammation; also, "leukocytes can transmigrate through the endothelium and therefore play a crucial role in the formation of atherosclerosis."

Chocolate also lowered protein expression of lymphocytes CD62L and CD11b, monocyte CD62L, and neutrophils CD66b and CD11c. "These cell-surface molecules are involved in leukocyte recruitment and adherence to the endothelium during the initial steps of atherosclerosis," the group writes.

"A minor but significant" 0.1-mL rise in fasting plasma glucose and 0.3-mL increase in plasma free fatty acids was evident after four weeks of chocolate of either kind.

Taking the High-Fat Challenge
"High-fat-challenge" tests conducted after each four-week period of chocolate intake required drinking a 95 fat-gram shake of yogurt, canola oil, and other ingredients followed by endothelial-function and metabolic marker tests at 1.5 and 3.0 hours to assess postprandial responses.

Consumption of the high-fat shake was followed by average declines in FMD by 1.8 percentage points, in AIX by four percentage points, and in diastolic blood pressure by 2 mm Hg, regardless of whether the background chocolate contained normal or high flavanol levels. Also seen at postprandial testing were rises in hematocrit; counts of thrombocytes, lymphocytes, monocytes, and neutrophils; plasma concentrations of sICAM1, soluble vascular cell adhesion molecule (sVCAM) 1, sICAM3, P-selectin, IL-8, and tumor necrosis factor-alpha (TNF-α); and expression of lymphocytes CD11c and CD11b, monocyte CD11c and CD11b, and neutrophils CD62l and CD11b adhesion molecules. At the same time, monocyte CD62l expression and IL-6 plasma levels fell.

"Our results indicate that flavanol-enriched chocolate was not healthier than regular dark chocolate with respect to vascular health markers," according to Esser et al.

Limits on flavanol absorption didn't account for the similar effects, they determined, based on plasma and urine measures of flavanol intake; normal-flavanol–level chocolate may simply attain maximal flavanol effects on vascular health, the group writes.