Selenium

Prompted by a recent comment from Joel.

While selenium research has become a bit complicated, it has always been clear in one regard:- selenium deficency is a PCa risk factor, and there is no dose-related benefit once sufficiency has been achieved.  

Populations around the world vary tremendously in terms of selenium status. It all depends on the ground on which their food is grown or raised. In the U.S., vast amounts of land have poor selenium levels. Selenium maps:

google.com/search?q=seleniu...

google.com/search?q=seleniu...

"Buy Local" campaigns are all very well, but one should be aware of what local land can & cannot deliver. Fortunately for Americans who haven't given up eating bread, the wheat belt provides sufficient amounts of selenium. Canadians are OK too. Pity the British who lost access to Canadian wheat when the country joined the European Union in 1973. Daily intake used to be ~60 μg, but is now ~30 μg. According to the Linus Pauling Institute, we need 55 (micrograms) / day. (The UK says 75 μg.)

It's common for studies to group subjects by selenium status into quintiles (five groups) or quartiles (four). It would be more useful to isolate selenium-deficient men as a separate group. In American studies [A.1] [A.2] the bottom quintile may have contained a significant number of selenium-sufficient men.

In contrast, in the Dutch study [A.3], both the first & second quintiles appear to be deficient. 

"Selenium intakes in Northern Europe have generally dropped considerably over recent decades. In the 1970s intakes were around 60-70 μg per day whereas now intakes are estimated at only 30 μg for women and 40 μg per day for men, which is about half the current recommended amount. It is believed that the reason may be a greater reliance on homegrown instead of imported wheat from Canada and America, which contains up to 50 times more selenium than the European equivalent. Interestingly Finland introduced selenium into fertiliser in the 1980s and levels have increased correspondingly." [X.1]

[A] Toe-nail selenium status & risk

[A.1] Giovannucci / Health Professionals Follow-Up Study (1998) 

181 PCa cases had an average selenium level of 0.82 μg/g, whereas healthy matched controls averaged 0.96 μg/g. Basically, advanced PCa risk was reduced by 45% by not being in the bottom quintile.

[A.2] Washington County, Maryland “CLUE II" study.

Similar to [A.1] in that risk was reduced by almost half by not being in the bottom quintile.

[A.3] Netherlands Cohort Study.

Comparing quintiles with the first, the PCa risk factors were:

1.00 1.05 0.69 0.75 0.69

Again we see the lack of benefit of higher levels once sufficiency has been established.

[B] Plasma selenium status & risk

Generally considered to be an inferior way to measure selenium status.

[B.1] Baltimore Longitudinal Study of Aging registry, including 52 with known prostate cancer and 96 age matched controls. Comparing quartiles with the first, the risk factors were:

1.00 0.15 0.21 0.24

Not so well-behaved, but, again, the bottom group is to be avoided.

[B.2] Denmark: 'Diet, Cancer and Health' cohort.

"784 cases ... Two-thirds (n 525) of the cases had advanced disease at the time of diagnosis, and among these 170 had high-grade disease ..."

"Plasma Se was not associated with total or advanced prostate cancer risk, but higher Se levels were associated with a lower risk of high-grade disease ..." 23% less risk.

Danes have "a relatively low Se intake", so this study appears to say that deficiency increases the risk for high-grade disease.

The SELECT study. [the Selenium and Vitamin E Chemoprevention Trial]

"Between 2001 and 2004, 35,533 men ... were randomly assigned to the four study arms" [S.2]

For the two selenium arms: 200 µg/day from L-selenomethionine. To my mind, this was a poor choice. While it does have good bioavailability, the methionine component is problematic. Methionine is an essential amino acid & selenomethionine is readily incorporated into protein. This casts into doubt the amount available for prostate uptake.

The study recruited men from the United States, Canada and Puerto Rico. Overall, a population with good selenium status. A very large majority of the men would therefore be unlikely to see benefit. Selenium-deficient men would probably benefit, but the numbers might be swamped by the vast majority who received no benefit. In addition, men at the high end of sufficiency might be driven to a level where PCa risk actually increases. IMO, a fatal mistake to not measure baseline toenail levels, so as to identify the deficient & over-sufficient populations.  

Mark Moyad, writing at the start of the study (2002), seemed to predict failure:

"Selenium supplements provided a benefit only for those individuals who had lower levels of baseline plasma selenium. Other subjects, with normal or higher levels, did not benefit and may have an increased risk for prostate cancer." [S.1]

Results from 2008 [S.2]:

- placebo arm: 416/8,696 cases

- selenium only: 432/8,752 cases

- selenium+E: 437/8,703 cases

Clearly, no benefit.

Of those "graded by central lab" with lesser cancer:

- Gleason score <7:

   ... placebo arm: 240/365 cases = 66%

   ... selenium only: 217/361 cases = 60%

- Gleason score =3+4:

  ... placebo arm: 80/365 cases = 22%

  ... selenium only: 105/361 cases = 29%

Not at all encouraging. A total of 320 men in the placebo arm & 322 in the selenium arm. Almost the same number, but 30% more GS=3+4 cases in the intervention arm. Significant in that this is the dividing line between surveillance & treatment for many.

"The trial was prematurely terminated in 2008, 18 months before its intended minimum follow-up length. The selenium and vitamin E doses and formulations used in SELECT were found to be ineffective, and concern was raised about a possible trend in developing type 2 diabetes mellitus among the study participants taking selenium" [S.3]

In my view, SELECT was a huge misuse of money. (The vitamin E part of the study was even more screwed-up than the selenium.)

One of my bugbears is cadmium, which is a common pollutant. Selenium opposes cadmium. Other reasons are sometimes hypothesized for selenium's protection, & the cadmium connection is usually missed. From a 2005 German study [X.2]:

"Because Se is known to interact with cadmium (Cd), it has been suggested that its cancer protective action could be attributable in part to its interaction with Cd, a toxic and suspected carcinogenic element, which is found in many foods, in drinking water, and in the environment. Cadmium is considered a significant prostate cancer risk factor as it stimulates the growth of prostate epithelial cells and promotes their malignant transformation. Accordingly, prostate cancer risk is determined not only by Se status, but also the degree of Cd exposure. Determinations of Se and Cd in 129 prostates of deceased men aged 15-99 yr revealed Cd to accumulate in the prostate. Whereas the atomic Se/Cd ratios of the prostates of young men were invariably >1, indicating a stoichiometric excess of Se over Cd, they were found to decline with age, approaching the 1:1 ratio in elderly nonsmokers, a fact suggestive of the formation of a 1:1 Cd-Se complex. The associated physiological inactivation of Se could account for the increase of the prostate cancer risk with advancing age."

One confusing aspect of more recent research is the association of genetic variations with selenium PCa risk. This makes the subject way too complicated. I no longer supplement for PCa, but I would for deficiency. My chosen form would be sodium selenite. It is inorganic & has poor bioavailability, but there are some interesting studies.

-Patrick

[A.1] jnci.oxfordjournals.org/con...

[A.2] jnci.oxfordjournals.org/con...

[A.3] cebp.aacrjournals.org/conte...

[B.1] ncbi.nlm.nih.gov/pubmed/116...

[B.2] ncbi.nlm.nih.gov/pubmed/269...

[S.1] ncbi.nlm.nih.gov/pubmed/119...

[S.2] ncbi.nlm.nih.gov/pmc/articl...

[S.3] ncbi.nlm.nih.gov/pmc/articl...

[X.1] eufic.org/article/en/diet-r...

[X.2] ncbi.nlm.nih.gov/pubmed/157...

4 Replies

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  • There was a study back in the nineties where men taking selenium and Vitamin E supplements were accidently found to have a lower incident of PC. I took this to heart for many years after my diagnoses until my PSA began to rise again.  

  • Magnus,

    You may be thinking of Larry Clark's original study [1], published in 1997?  That study did not use E.  The SELECT study, which did include E, did not start until 2002 & reported only much later.

    Clark's focus was on skin cancer & involved "Seven dermatology clinics in the eastern United States."

    "After a total follow-up of 8271 person-years, selenium treatment did not significantly affect the incidence of basal cell or squamous cell skin cancer."

    "Analysis of secondary end points revealed that, compared with controls, patients treated with selenium had a nonsignificant reduction in all-cause mortality (108 deaths in the selenium group and 129 deaths in the control group"

    "and significant reductions in total cancer mortality (29 deaths in the selenium treatment group and 57 deaths in controls"

    "total cancer incidence (77 cancers in the selenium group and 119 in controls"

    "and incidences of lung, colorectal, and prostate cancers"

    Unlike the SELECT study, Clark used "Se-enriched yeast (200 micrograms Se/day)" [2]

    A 1998 paper gives more PCa info [3].

    "There were 13 prostate cancer cases in the selenium-treated group and 35 cases in the placebo group"

    "Restricting the analysis to the 843 patients with initially normal levels of prostate-specific antigen (< or = 4 ng/mL), only four cases were diagnosed in the selenium-treated group and 16 cases were diagnosed in the placebo group after a 2 year treatment lag"

    In 2002, there is more to say.  The 52% PCa reduction was statistically significant, unlike the reductions in lung (26%) & colorectal (54%) cancer.

    The paper contains a warning, that should have been heeded by SELECT, which had begun recruiting:

    "Participants with baseline plasma selenium concentrations in the lowest two tertiles (<121.6 ng/ml) experienced reductions in total cancer incidence, whereas those in the highest tertile showed an elevated incidence."

    And here's something I hadn't realized:

    "The protective effect of selenium was confined to males ... and was most pronounced in former smokers."

    Cigarette smoke contains a large amount of cadmium.  Selenium would have conjoined with the cadmium to form a complex that effectively neutralized the cadmium.  (I'm glad that I mentioned cadmium in the post.)

    Clearly, all future selenium studies should take into account smoking status.

    In 2003 [5]:

    Selenium supplementation "continued to significantly reduce the overall incidence ..." 

    "The protective effect of {selenium supplementation} appeared to be confined to those with a baseline PSA level of <or= 4 ng/mL"  65% reduction.

    "Participants with baseline plasma selenium concentrations only in the lowest two tertiles (< 123.2 ng/mL) had significant reductions in prostate cancer incidence."

    In 2008 [6], a report on:

    "a small substudy in Macon, GA, which began in 1989 and randomized 424 patients to 400-mcg/day of Se or to matched placebo"

    "The 200-mcg/day Se treatment decreased total cancer incidence by a statistically significant 25%; however, 400-mcg/day of Se had no effect on total cancer incidence."

    One might read into this that benefit at the low end was entirely countered by harm at the high end.

    It is odd to see Larry's name on these later papers:

    "Clark LC  Arizona Cancer Center, College of Medicine, University of Arizona, Tucson, USA."

    He died in 2000 of PCa, age 51:

    tandfonline.com/doi/abs/10....

    uanews.arizona.edu/story/wo...

    laprp.com/files/pdf/The_Gho...

    -Patrick

    [1] ncbi.nlm.nih.gov/pubmed/897...

    [2] ncbi.nlm.nih.gov/pubmed/931...

    [3] ncbi.nlm.nih.gov/pubmed/963...

    [4] ncbi.nlm.nih.gov/pubmed/121...

    [5] ncbi.nlm.nih.gov/pubmed/126...

    [6] ncbi.nlm.nih.gov/pubmed/184...

  • Thanks for the clarification. I'm getting up in years and the memory is not what it used to be.

  • Your posts are always amazing. As I begin to read them I know it's you writing without looking to see who is writing. I always appreciate your personal take on the subject, usually at the end. Thank you. Genie

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