Prompted by review of a number of posts related to methyl donors, I’ve become concerned about hypermethylation and its potential implications for my PCa. This is in light of what might very well already be an excessive supplement intake of methyl donors (L-Methylfolate, B12, TMG/BetaineHCL, Citicholine and choline/inositol). A reasonable question is “Why are you taking these?”
For background, stubbornly high homocysteine levels (11-16 umol/L have been a challenge for > 15 years despite following the usual folate, B12¸ B6, TMG and dietary suggestions. So, in frustration and after some research, I pressed my cardiologist to order B12 and MTHFR tests. Sure enough, I have two copies (homozygous) of the C6777T MTHFR mutation, which significantly limits my ability to process folate to support homocysteine conversion to methionine. As a result, I’ve increased my active folate intake considerably (5-10 mg) along with the other methyl donors, resulting in only a modest reduction in homocysteine thus far. Next homocysteine test is scheduled in mid-December
For others like me who are relatively new to the issues, here are several references (the first two from earlier posts on this forum):
A number of you appear to be considerably more knowledgeable about this, and I’d greatly appreciate your thoughts/comments. Thanks very much and have a nice Thanksgiving holiday.
Bill
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"On the contrary, vitamin B12, associated with an up to 3‐fold increase in risk, and possibly also folate, may even stimulate prostate cancer development."
"This case report illustrates the importance of the effects of supplements containing large amounts of folic acid, L-5-methyltetrahydrofolate, and cyanocobalamin on the metabolism of prostate cancer cells directly and/or B vitamin interference with docetaxel efficacy. Physicians caring for patients with prostate cancer undergoing watchful waiting, hormone therapy, and/or chemotherapy should consider the possible acceleration of tumor growth and/or metastasis and the development of drug resistance associated with supplement ingestion. "
Now, there may be an interaction effect between high alcohol consumption and low folate levels in men with your gene mutation. This indicates that it is wise to moderate your alcohol intake:
Thank you Allen. I've yet to dig into these studies, but a first quick review and your last comment hit me right between the eyes! In addition to my folate supplementation to address homocysteine and MTFHR deficiency, I just happen to very much enjoy wine. So some serious changes seem clearly in order in light of this new information.
I'll be having my circulating folate and B12 tested very shortly. I will also be following up pronto with my MO to discuss the above study results (which I'll be emailing to him today) and possible antifolate therapy. You've certainly helped me to move rapidly up the learning curve!
We're on the same page...I use L-5-Tetramethylfolate as well as high dose sublingual B12 melts. However, as I learn more about the implications of high levels of circulating folate and B12, more careful titration seems called for as I try to walk the line between PCa aggressiveness and high homocysteine. I'm not sure where to turn for professional guidance on this.
If you have a problem recycling homocysteine because of a MTHFR mutation, throwing a lot of methyl donors at it is not going to increase methionine (& therefore SAM) levels. i.e. hypermethylation should not be an issue.
If you were young & healthy (with no MTHFR mutation), you could certainly improve your methyl status by supplementing with SAMe. Obviously, I'm not suggesting that.
But how to lower homocysteine? Note that in intervention studies that used folic acid & B12, homocysteine levels did fall (at least for those with normal MTHFR), but cardiovascular risk was not improved. While homocysteine is associated with CVD, it may not be an important contributor.
Very interesting, Patrick. What are your thoughts about experimenting with elimination of folate and other methyl donor supplements to see what happens to my homocysteine? Based on a "very clean" catheterization result in 2012 and subsequent annual cardio exams/data, I consider PCa to be a more serious and current concern. Ditto for possible homocysteine => dementia & Alzheimer's implications.
Of course, I realize that you are not a physician. However, having reviewed your helpful frequent posts for some years on another PCa forum and more recently on this one, I very much respect your extensive knowledge and thoughtful analysis.
Presumably, it there was enough methionine in the diet, recycling homocysteine back to methionine would be pointless. What might be its fate? Homocysteine can be converted to cysteine. This requires vitamin B6 as a cofactor! Beyond ensuring that your B6 status is good, I doubt that there is anything tou could do to force the conversion to cysteine
I believe that doctors generally assume that there must be deficiency in one of the factors required for conversion to methionine. Below are some trials where clearly that was the thought &, given the results, B6/B9/B12 insufficiency is a common reason for elevated homocysteine. The downside with PCa is that supplementation might allow cells to become hypermethylated.
[1] 1999 - Germany
"Men and women (> or = 60 years) received either B-vitamins (400 micrograms folic acid {B9} + 1.65 mg pyridoxine {B6} + 3 micrograms cyanocobalamin {B12}) or a placebo daily for 4 weeks. Subjects in the vitamin group showed a significant decrease in plasma total homocysteine ..."
[2] 2002 - New Zealand
"A regular intake of as little as 100 microg folic acid per day was sufficient to lower tHcy in persons at the upper end of the normal range for tHcy"
[3] 2003 - U.K.
"Diet and supplement-based interventions led to an increase in measures of folate status and a reduction in plasma tHcy."
[4] 2003 - Netherlands
"The relative decrease in plasma homocysteine concentration was associated exponentially with increasing doses of folic acid. From the dose-response curve, the adequate daily dose of folic acid was estimated to be 392 micro g, which decreased plasma homocysteine concentrations 22%."
[5] 2003 - Sweden
etc.
I don't like to cite celebrity docs, but here is Dr. Weil:
"There is no treatment for elevated homocysteine apart from efforts to lower your levels by increasing your intake of B vitamins through the eating of more green leafy vegetables, fruits and more grain-based foods fortified with folic acid. So far, studies to determine whether lowering homocysteine levels can reduce the risk of heart disease haven’t shown a benefit, but this may be because the studies were too small or because homocysteine levels weren’t lowered enough." [6]
Forgot to mention the studies that found that lowering homocysteine did not lower CVD risk.
[1] 2006 - Norway.
"The mean total homocysteine level was lowered by 27 percent among patients given folic acid plus vitamin B12, but such treatment had no significant effect on the primary end point (risk ratio, 1.08; ...). Also, treatment with vitamin B6 was not associated with any significant benefit with regard to the primary end point (relative risk of the primary end point, 1.14; ...). In the group given folic acid, vitamin B12, and vitamin B6, there was a trend toward an increased risk (relative risk, 1.22; ...)."
"A harmful effect from combined B vitamin treatment was suggested."
[2] Norway.
"Mean plasma total homocysteine concentration was reduced by 30% after 1 year of treatment in the groups receiving folic acid and vitamin B(12). The trial was terminated early because of concern among participants due to preliminary results from a contemporaneous Norwegian trial suggesting adverse effects from the intervention."
"This trial did not find an effect of treatment with folic acid/vitamin B(12) or vitamin B(6) on total mortality or cardiovascular events. Our findings do not support the use of B vitamins as secondary prevention in patients with coronary artery disease."
[3] 2010 - U.K. - Meta-analysis.
"Individual participant data were obtained for a meta-analysis of 8 large, randomized, placebo-controlled trials of folic acid supplementation involving 37 485 individuals at increased risk of cardiovascular disease. The analyses involved intention-to-treat comparisons of first events during the scheduled treatment period. There were 9326 major vascular events (3990 major coronary events, 1528 strokes, and 5068 revascularizations), 3010 cancers, and 5125 deaths. Folic acid allocation yielded an average 25% reduction in homocysteine levels. During a median follow-up of 5 years, folic acid allocation had no significant effects on vascular outcomes, with rate ratios (95% confidence intervals) of 1.01 (0.97-1.05) for major vascular events, 1.03 (0.97-1.10) for major coronary events, and 0.96 (0.87-1.06) for stroke. Likewise, there were no significant effects on vascular outcomes in any of the subgroups studied or on overall vascular mortality. There was no significant effect on the rate ratios (95% confidence intervals) for overall cancer incidence (1.05 [0.98-1.13]), cancer mortality (1.00 [0.85-1.18]) or all-cause mortality (1.02 [0.97-1.08]) during the whole scheduled treatment period or during the later years of it. Dietary supplementation with folic acid to lower homocysteine levels had no significant effects within 5 years on cardiovascular events or on overall cancer or mortality in the populations studied."
Very helpful, Patrick! These studies further support my inclination to stop methyl donor supplements to avoid increasing my PCa's aggressiveness. There's still an issue with homocysteine=>AD/dementia, but that's definitely on the back burner.
"A group of experts reviewed literature evidence from the last 20 years. We here present a Consensus Statement, based on the Bradford Hill criteria, and conclude that elevated plasma total homocysteine is a modifiable risk factor for development of cognitive decline, dementia, and Alzheimer’s disease in older persons." ncbi.nlm.nih.gov/pmc/articl...
Of course, at only 79, I guess I don't yet fall into the "older persons" category.
The "homocysteine=>AD/dementia" might be explained, in a good many cases I suspect, by a B12 deficiency. It's certainly a concern of mine. How low can B12 go before there are repercussions.
Of course, a dozen or so years ago, when I became aware of hypermethylation, I was not concerned with long-term issues. (& perhaps I have even less reason to be now - LOL)
I suspected the same -- that this is not in the sweet spot (or likely even close) of most specialists (mine are at Penn). Found 5 ACAM members within 50 miles, 4 of whom don't appear to be very good fits based on their websites. I'll follow up with the other and, if necessary, I'll expand the search. Finding the right one -- even just for phone consultations -- is more important than distance.
Thanks, Patrick. These references seem clearly to support the generally accepted role of B6, B9(folate) and B12 in reducing homocysteine. Unfortunately, I’m playing this game with a bad hand: two copies (homozygous) of the C6777T MTHFR mutation, which significantly inhibits folate processing and homocysteine control.
Hence what looks like an excessive intake of methyl donors and, I assume, hypermethylation and increased PCa aggressiveness. Based on what I know now thanks to you and others on this forum, I’m inclined to severely cut back or eliminate my methyl intake rather than continue to feed my PCa. I’m also searching for an informed medical professional to advise on next steps.
However, your post makes me wonder if I fully understand the methionine cycle and the homocysteine <=> methionine conversion process described and depicted in the following two references:
“A molecule of methylfolate and a molecule of homocysteine also bind with the enzyme. A methyl group is passed from the methylfolate to the cob(I)alamin which then passes it on to the homocysteine, converting it into methionine…It should also be clear that taking methylcobalamin if you have a faulty MTHFR enzyme would be pointless.”
“In the Methionine Cycle, methionine is converted to SAMe (S−Adenosyl Methionine), which is a methyl donor for numerous reactions. In losing its methyl group, SAMe becomes SAH (S−Adenosyl Homocysteine), which is then converted to homocysteine. Homocysteine is either converted back to methionine, or it enters the transsulfuration pathway to form other sulfur-containing amino acids.”
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