This is a companion piece to "Foods/Supplements-Vitamins: Fish", that considers marine omega-3 from seafood & supplements, & attempts to explain why it may be important in PCa, in spite of conflicting studies.
Human studies have yielded confusing results. One might expect inconsistencies between populations. Scientists like to compare quartiles (or quintiles) of intake & compare top to bottom. In countries where fish intake is low, or the fish favored is not a good omega-3 source, & use of supplements is not widespread, the upper quartile range might actually be quite low. In contrast, in one of the Nordic countries where fish is a significant part of the diet, the lowest quartile range might be quite high.
Studies that assessed intake from food questionaires have to be somewhat ureliable. Studies that measured omega-3 in the blood are presumably reliable.
Here is an amusing warning from one of the omega-3 papers:
"One challenging aspect in cancer epidemiology is that any factor reducing cancer risk will usually promote life-expectancy, which in itself is a risk for cancer."
A. EICOSANOIDS.
Since study results are ambiguous, it's worthwhile explaining why marine omega-3 should be protective once PCa has developed. This is based on the role of eicosanoids.
"Eicosa" means 20. All fatty acids have a carbon backbone. The eicosanoids derive from fatty acids that are built on a chain of 20 carbons.
On the bad side, we have the pro-inflammatory omega-6, Arachidonic acid, which has a shorthand name of 20:4(n-6). This means that it has 20 carbons, and would be a saturated fat, but for 4 locations, where it is unsaturated. Which means that the fat molecule can bend at those points. The locations are 5, 8, 11, 14. The last location is 6 from the end, which makes it an omega-6; hence the "(n-6)".
In PCa, arachidonic acid is used to make inflammatory leukotriene, thromboxane and prostaglandin eicosanoids. All of them bad news. All of them, chronically activated.
On the good side, we have Eicosapentaenoic acid (EPA). This time "eicosa" is part of the name & from the rest of the name we might guess that shorthand for EPA is 20:5(n-3), because it is an omega-3. The 5 locations are 5, 8, 11, 14, 17. Notice that it is identical to arachidonic acid [AA], except for the extra desaturation at location 17 (which makes it an omega-3). Such a small difference, but with major implications.
The eicosanoid products of EPA are anti-inflammatory.
In addition, AA & EPA compete for the enzymes that make the downstream eicosanoid products. That is what makes balance so important. Studies have to consider the AA:EPA ratio IMO.
The COX & LOX enzymes act on AA to produce eicosanoids that increase inflammation, angiogenesis & tumor cell proliferation, while the same enzymes act on EPA to produce eicosanoids that lower inflammation, angiogenesis. metastasis & cell proliferation.
B. OMEGA-3 FATTY ACIDS - ALA, EPA & DHA.
In addition to EPA, the other omega-3 fatty acids of interest are alpha-linolenic acid [ALA] & Docosahexaenoic acid (DHA).
ALA is 18:3(n-3), with unsaturated locations at 9, 12, 15. EPA can be made from ALA by adding two carbons at the front & desaturating positions 5 & 8. But this does not happen to any great degree in the body & it is a mistake to view ALA as an alternative source to marine omega-3s. ALA seems to make PCa more aggressive. Best to avoid it.
DHA is 22:6(n-3); the unsaturated locations being at 4, 7, 10, 13, 16, 19. It can be made from EPA by adding two carbons at the front & desaturating position 4. Again, this does not happen to any great degree in the body. DHA is a major fatty acid in the brain. Yes - how did they know back then? - fish really is brain food.
All of the fatty acids described here are PUFAs - polyunsaturated fatty acids - i.e. they are unsaturated at more than one location.
From a practical perspective: avoid omega-3 & omega-6 fatty acids from vegetable oils & get 2,400-4,000 mg EPA+DHA from seafood or supplements daily. IMO
C. STUDIES - Neutral.
[Ca] (2004 - U.S.)
This study looked at fatty acids in red blood cells (erythrocytes).
"According to the results of this investigation, the ratio of {EPA + DHA to ALA} may be useful to estimate PUFA imbalances in cancer patients. EPA and DHA acid may be recommended as supplementation and in addition to current therapy during cancer treatment."
The statment above implies that we don't want ALA to be the dominant omega-3.
[Cb] (2006 - UK & Denmark)
This study looked at EPA, DHA & ALA in white blood cells (leukocytes), in comparison to prostate tissue. Basically, white blood cells reflect what one would find in normal & cancerous tissue, except that "men with prostate cancer had more ALA in prostate tissue than in leukocytes." "This is in accordance with the strong positive association between PSA and ALA levels in prostate tissue" & "lends support to the deleterious role of ALA in the development of prostate cancer."
[Cc] (2008 - Netherlands) This meta-analysis combined risk estimates across studies"
This "showed an increased risk of prostate cancer in men with a high intake or blood level of alpha-linolenic acid (ALA) (combined relative risk (RR) 1.36 ...). The association is stronger in the case-control studies (RR 1.84 ...) than in the prospective studies (RR 1.10 ...). Ecosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not significantly associated with prostate cancer.
[Cd] (1999 - Netherlands - Netherlands Cohort Study)
"The cohort study consisted of 58,279 men ages 55-69 years at baseline in 1986. After 6.3 years of follow-up, 642 incident prostate carcinoma cases were available for analysis."
"No associations were found for intake of arachidonic acid, eicosapentaenoic acid, or docosahexaenoic acid."
D. STUDIES - Negative.
[Da] (2007 - Sweden - Malmö Diet and Cancer cohort)
"We have studied 10,564 initially cancer-free men ... aged 45-73 years."
"During a mean follow-up of 11.0 years, 817 incidental PCa cases were diagnosed. Out of these, 281 were classified as advanced."
"... we observed positive associations between intakes of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and risk of PCa."
[Db] (1997 - Norway - Janus serum data bank) 141 matched cases.
PCa risk for the ratio AA:EPA by quartile: 1.0 (ref), 1.6, 0.6 & 0.8.
Obviously not a well-behaved risk relationship, but being in the top two quartiles of AA:EPA had lower risk than the bottom. Seems to say that AA protects against high(?) EPA.
[Dc] (2015 - U.S.) Prostate Cancer Prevention Trial (PCPT) - placebo arm.
"... we found that serum n-3 fatty acids were inversely, n-6 fatty acids were positively, and trans fatty acids were not associated with intraprostatic inflammation in controls."
However:
"In men with prostate cancer, there were no statistically significant associations of serum phospholipid fatty acids and intraprostatic inflammation; however, we could not rule out a possible ... inverse association for arachidonic acid."
So, why did omega-3 control prostatic inflammation in the controls, but not in cases?
"Given the direct association of intraprostatic inflammation with total and high-grade prostate cancer risk, our finding that serum n-3 fatty acids were inversely associated with intraprostatic inflammation in men without a diagnosis of prostate cancer is compatible with studies that have observed inverse associations of n-3 fatty acids and prostate cancer risk. This includes findings from both the Physician's Health study and the NIH-AARP study. However, our findings cannot explain the positive association of DHA, an n-3 fatty acid, with high-grade prostate cancer risk recently observed in the PCPT, SELECT, and EPIC studies"
[Dd] (2011 - U.S.) Prostate Cancer Prevention Trial (PCPT).
"Docosahexaenoic acid {DHA} was positively associated with high-grade disease (quartile 4 vs. 1: odds ratio (OR) = 2.50 ...)"
"The study findings are contrary to those expected ..."
"The primary limitation of the Prostate Cancer Prevention Trial is that almost all cases were local stage, and many would likely have never been diagnosed by standard clinical practice. It is important to note that most significant associations were for risk of clinically relevant, high-grade cancer only, which was defined very conservatively as a Gleason score of 8–10."
All I can think of is that these men had high levels due to supplementation, because they viewed thenselves to have a high risk for PCa, perhaps due to familial PCa.
[De] (2013 - U.S. - Selenium and Vitamin E Cancer Prevention Trial [SELECT])
"Compared with men in the lowest quartiles of LCω-3PUFA {long-chain omega-3 polyunsaturated fatty acids}, men in the highest quartile had increased risks for low-grade (HR = 1.44 ...), high-grade (HR = 1.71 ...), and total prostate cancer (HR = 1.43 ...). Associations were similar for individual long-chain ω-3 fatty acids."
"Higher linoleic acid (ω-6) was associated with reduced risks of low-grade (HR = 0.75 ...) and total prostate cancer (HR = 0.77, ...); however, there was no dose response."
"Findings for linoleic and arachidonic acids, the primary {omega-6} fatty acids associated with increased inflammation, were inconsistent: concentrations of linoleic acid above the lowest quartile were associated with reduced cancer risk, with no evidence of a linear trend, and concentrations of arachidonic acid were not associated with cancer risk."
[Df] (2008 - Denmark, Germany, Greece, Italy, Netherlands, Spain, Sweden, and the United Kingdom - the European Prospective Investigation into Cancer and Nutrition (EPIC)).
"There were significant positive associations between myristic, α-linolenic, and eicosapentaenoic acids and risk of high-grade prostate cancer."
"Danish men had the highest percent of eicosapentaenoic and Dutch men the highest n−3 docosapentaenoic acid (22:5n−3); these 2 fatty acids were lowest in men from Greece and Spain, respectively. The range in docosahexaenoic acid was >1 mol% across the countries and was highest in men from Spain and lowest among the Italian men."
"There was a suggestion of a positive association between eicosapentaenoic acid and the risk of prostate cancer, but neither the unadjusted nor the adjusted analysis was statistically significant. The multivariate RR for men in the highest quintile of docosahexaenoic acid was 1.39 ... in comparison with men in the lowest quintile, but the overall test for association was not statistically significant."
E. STUDIES - Positive.
[Ea] (2009 - Nigeria)
"In this population with high total plasma omega-3, we observed ... inverse risk reduction with EPA (0.4)"
{authors meant "inverse risk" or "risk reduction" - not "inverse risk reduction"}
[Eb] (2004 - U.S. - Health Professionals Follow-Up Study)
"A cohort of 47,866 US men aged 40-75 y with no cancer history in 1986 was followed for 14 y."
"During follow-up, 2965 new cases of total prostate cancer were ascertained, 448 of which were advanced prostate cancer."
"EPA and DHA intakes were related to lower prostate cancer risk. The multivariate RRs of total and advanced prostate cancer from comparisons of extreme quintiles of the combination of EPA and DHA were 0.89 ... and 0.74 .., respectively."
[Ec] (2004 - Jamaica)
This study looked at fatty acids in red blood cells (erythrocytes).
"Eicosapentaenoic acid (Omega3) levels decreased as PSA exceeded 10 ng/mL ..."
"Arachidonic acid (Omega6) levels decreased as PSA was < 2 ng/mL ..."
"In men with a PSA of > 10 ng/mL there was a positive correlation between the ratio of Omega6 to Omega3 PUFAs and PSA ..."
"there was also a negative correlation between the ratio of Omega3 to Omega6 PUFAs and PSA ..."
[Ed] (1999 - New Zealand)
This study looked at fatty acids in red blood cells (erythrocytes).
"Reduced prostate cancer risk was associated with high erythrocyte ... levels of EPA (multivariate relative risk = 0.59 ... upper vs lowest quartile) and DHA (multivariate relative risk = 0.62 ...)."
[F] Miscellaneous.
[Fa] (2013 - Iran)
"A total of 504 healthy men with serum PSA level ≤ 2·5 ng/ml were recruited into the study."
"Participants were randomly assigned to a daily dietary supplement containing n-3 fatty acids (1·12 g of EPA and 0·72 g of DHA per capsule) (group 1, n 126), n-6 fatty acid (600 mg γ-linolenic acid (GLA) each capsule) (group 2, n 126), CoQ10 (100 mg per capsule) (group 3, n 126) or a similar regimen of placebo (group 4, n 126) for 12 weeks. Study medication was administered as two capsules to be taken twice daily."
"EPA treatment significantly reduced serum PSA level by 30% ... from baseline. In contrast, GLA therapy significantly increased serum PSA concentration by 15% ... CoQ10 therapy also significantly reduced serum PSA level by 33% ..."
[G] Omega-3 & the Immune System.
There is an optimal intake of EPA+DHA. Barry Sears Zone product has 4g fish oil, delivering 2.4g (2,400 mg) EPA+DHA.
Last time I looked, the American Heart Association recommended up to 4g EPA+DHA for those with very high levels of triglycerides. I am sure that some go above 4g & I don't think that's wise. In fact, for men with a compromised immune system, 1.2g EPA+DHA (the dose suggested on the Life Extension product label) might be an appropriate maximum dose.
[Ga] (1998 - U.S.)
"n-3 PUFA have been shown to reduce the risk of cardiovascular and inflammatory diseases. However, they have also been shown to suppress T-cell-mediated immune function, an undesirable effect, especially in immuno-suppressed individuals. Studies have thus far suggested that this immuno-suppression may be in part attributable to increased lipid peroxidation and decreased antioxidant (especially vitamin E) levels, which can be prevented by appropriate vitamin E supplementation. Further well-designed human studies are needed to determine the appropriate levels of n-3 PUFA and vitamin E supplementation to optimize the beneficial anti-inflammatory effect of n-3 PUFA and minimize their suppressive effect on T-cell function."
[Gb] (1991 - U.S.)
"low doses of fish oil may have a mild immunosuppressive effect affecting both T and B cell functions"
The "low" dose used was "EPA dose of 2.4 g/day"
I wouldn't call that low. I would not take EPA by itself, since it tends to drive down DHA levels.
{This topic reminds me of how the flu shot can be ineffective in some men. Testosterone suppresses the immune sysem too. A man with high-normal T may fail to produce antibodies after the shot. Older men with low T do fine. Women have more active immune responses - & the downside is more autoimmune diseases. I mention this only because I don't think that anyone should panic over "a mild immunosuppressive effect" of marine omega-3.}
[H] Omega-3 & Insulin.
Bary Sears has long been involved in sports performance. He advocates omega-3 as a way to reduce inflammation in cells & increase oxygen delivery, & thus performance. Unfortunately, he had more effect on footballers than swimmers, who like to carb-up. With a high-carbohydrate diet, insulin levels will be high. Insulin causes inflammation. It is a growth factor for PCa. You can't realistically eliminate inflammation with fish oil if insulin isn't under control. Of course, Sears solution is the Zone diet he once made famous, which advocates a strict ratio of carb:fat:protein at every meal. It is not a low-fat diet.
-Patrick
[Ca] ncbi.nlm.nih.gov/pubmed/153...
[Cb] onlinelibrary.wiley.com/doi...
[Cc] ncbi.nlm.nih.gov/pubmed/189...
[Cd] ncbi.nlm.nih.gov/pubmed/104...
[Da] ncbi.nlm.nih.gov/pubmed/177...
[Db] onlinelibrary.wiley.com/doi...
[Dc] cancerpreventionresearch.aa...
[Dd] aje.oxfordjournals.org/cont...
[De] jnci.oxfordjournals.org/con...
[Df] ajcn.nutrition.org/content/...
[Ea] ncbi.nlm.nih.gov/pubmed/200...
[Eb] ajcn.nutrition.org/content/...
[Ec] onlinelibrary.wiley.com/doi...
[Ed] ncbi.nlm.nih.gov/pmc/articl...
[Fa] ncbi.nlm.nih.gov/pubmed/231...
