Iron Supplements Improve Unexplained Fatigue in Premenopausal Women

A reader (thanks, Dan!) pointed out a follow-up study to one I had included in VeganHealth’s article Iron, about iron supplementation in women with unexplained fatigue who have low iron stores but do not technically have anemia. I updated the article:

“Two studies from Switzerland have shown that iron supplementation can reduce fatigue in premenopausal women (1, 2) whose hemoglobin levels are above 120 g/l (and thus not diagnosed with anemia). The most recent, from 2012 (2), was a double-blinded, randomized controlled trial in which 80 mg of ferrous sulfate (an iron supplement) per day for 12 weeks increased hemoglobin in women who had average serum ferritin levels of 22.5 µg/l. This increase in hemoglobin was matched with a 50% reduction in symptoms of fatigue (compared to only 19% for placebo). Improvements in hemoglobin were seen after 6 weeks.”

This study got me thinking… I remember back around 2001 when I was doing my dietetic internship at Georgia State. I was able to spend some time working at a couple of alternative health clinics that specialized in helping people with chronic fatigue. At that time, they were putting pretty much everyone on a low carb diet, which translated to more meat. I actually don’t know if many people made any sort of recovery from the fatigue – my memory is that one person I counseled had made a significant recovery while another hadn’t made any improvement, but I have no idea what the success rates were for the clinics. To the extent that a low carb diet helped, I wonder if it was merely due to the women getting more heme iron and curing an undetected deficiency.

Improving iron status is worth considering for anyone with fatigue whose hemoglobin is on the lower end of normal and who has a serum ferritin less than 50 µg/l.

Iron does seem to be a possible culprit in three of higher profile cases of young women becoming ex-vegan that come to mind, and perhaps it’s something to which our movement needs to be paying more attention.

While the studies above used iron supplements to increase iron status, don’t forget that adding a significant amount of vitamin C to meals has been shown to be better for increasing iron absorption than increasing iron (more info).

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References

1. Verdon F, Burnand B, Stubi CL, Bonard C, Graff M, Michaud A, Bischoff T, de Vevey M, Studer JP, Herzig L, Chapuis C, Tissot J, Pécoud A, Favrat B. Iron supplementation for unexplained fatigue in non-anaemic women: double blind randomised placebo controlled trial. BMJ. 2003 May 24;326(7399):1124. | link

2. Vaucher P, Druais PL, Waldvogel S, Favrat B. Effect of iron supplementation on fatigue in nonanemic menstruating women with low ferritin: a randomized controlled trial. CMAJ. 2012 Aug 7;184(11):1247-54. | link

16 Responses to “Iron Supplements Improve Unexplained Fatigue in Premenopausal Women”

  1. Dan Says:

    Prof. Leo Zacharski, the PI of FeAST (hematologist), came to our institution to give Grand Rounds on the subject of iron toxicity. He postulated that one of the mechanisms by which vegetarian diets reduce mortality is that they often induce a state of relative (subclinical) iron deficiency, or at least correct the relative (subclinical) heme iron overload intake seen in carnivores. He mentioned that iron was extremely pro-oxidative in the body and he tries to take long-term users off it as soon as possible. He sees many seniors taking iron for years for no good reason. Iron is also an essential nutrient for some disease-causing pathogens in the body including one in the gut that can’t live without it (can’t recall which species).

    I think putting non-anemic post-menopausal women with lowish ferritins on iron replacement to treat a surrogate marker (ferritin level), albeit accompanied by clinical improvement (in fatigue), might be dangerous if it leads to long-term iron overload, cardiovascular disease, diabetes and infections. We just don’t know.

    About 20 years ago, every post-menopausal woman in this country was being encouraged by their doctor to start estrogen to protect their bones and hearts. These women had low estrogen levels because they were post-menopausal – so just replace the deficiency. Look where that got us. When the definitive trials were done, there was an excess of heart attacks, strokes, blood clots and cancer in the groups receiving estrogen. This was shown in several very large trials. How humbling.

    We simply do not have the long-term randomized data to support iron supplementation as being safe or even effective. Since Zacharski’s FeAST trial demonstrated such a large reduction in cancer mortality with body iron reduction (through phlebotomy), what does adding iron to the system do? The converse? That’s what worries me.

    Fortunately, supplemental iron is difficult to tolerate, leading to a lot of GI symptoms, and therefore many people do not persist well with it. Sure, if it helps a pre-menopausal vegan women with an intact menstruating uterus tolerate the diet better, I am all for it. For all others, I would investigate the cause of the iron deficiency (this usually requires scoping the GI tract) and only treat if symptomatic anemia is present.

    My father’s case is a good one to consider. He has had mild anemia (Hg 12-12.5 g/dL) for many years (has been pesco-lacto-vegetarian for about 40 years – no egg intake). His ferritins have always been low. Recently he underwent colonoscopy and upper gastrointestinal endoscopy which demonstrated a small ulcer and biopsy-positivity for Helicobacter pylori infection, which was treated with PPIs and antibiotics. I think in his case it was a good idea to rule out cancer (as he is 77 and otherwise in great health). I told him not to start supplemental iron just to treat his numbers (ferritin, hemoglobin), and I confirmed this input with another academic hematologist (not Leo Zacharski). He is not fatigued and maintains a vigorous travel and exercise schedule as well as work. His low iron state is probably vasculoprotective. The lessons from his case are 1) don’t assume all iron deficiency in vegetarians is dietary; 2) don’t start iron just because you have a low ferritin or borderline anemia – obviously significant fatigue should be present, and a trial of iron should be evaluated.

    Jack, I was not aware that low carb diets fix fatigue. It is possible they do this by reducing insulin/glucose swings, or by inducing ketosis which can have a very pleasant uplifting effect in the CNS (the brain thrives on ketone bodies). Speaking here of the ketotic euphoria of very low carb diets. But I have also discovered that low carb diets can exacerbate mood disorders (perhaps through depleting serotonin in the synaptic clefts), trigger insomnia, and mania in bipolar disorder. My guess is that any dietary approach that eliminates junk food, fast food and processed food to a great extent will relieve “industrial additive-induced fatigue syndrome”. Much fatigue is due to poor sleep hygiene.

    (sorry for the length of this post!! no need to reply)

  2. Jack Norris RD Says:

    Dan,

    Your comments require a response.

    > I was not aware that low carb diets fix fatigue.

    I guess I wasn’t clear in my post but I tried to say that I don’t know whether their diet had much of a success rate and I didn’t mean to imply that low carb diets cure chronic fatigue; I’m skeptical that they do. And if they do, then perhaps it has nothing to do with the macronutrient ratio but rather it’s the addition of heme iron.

    I also was not even suggesting that people start taking iron supplements, but rather that they increase vitamin C to improve iron absorption. But, if that doesn’t fix things, then a short-term, relatively modest iron supplement could also help improve iron status. I’d rather accept what is a slightly increased risk of cancer, assuming there really is one at small doses, than spend the next 40 years fatigued.

    If you have peripheral artery disease, then it’s probably worth being more careful.

  3. Dan Says:

    Jack,
    I agree. A six month course of iron is not like putting someone on estrogen for ten years. It’s a relatively short-term intervention which even in an older person is likely not to increase risk for malignancy or cardiovascular events, especially since it is so poorly tolerated and little gets absorbed.

    I was wondering if I could get your take on something. The recommendations on your sister website are great and far-reaching but if you put all of the recommendations for strict vegans together, and added the requisite RDIs for each essential vitamin, nutrient and mineral, one would obviously have to consume a lot of functional foods (diverse assortment of foods) each day. It’s not just that people don’t have the time, skill or knowledge to prepare such a wide variety of foods to ensure they are meeting the recommended daily intake for each essential dietary component (let alone fiber, protein, essential fatty acids, etc) — it’s more that some many different types of foods would be necessary to consume to balance it all. This would be a full time job! Do you think it is far easier to just take a few supplements rather than stressing out over whether the diet is including enough calcium, omega-3′s, iron, D, B12, C, B, A, D, E, K, iodine, zinc, lysine, etc, etc? What the body can’t manufacture, it needs from the diet. If it’s not in the diet, supplements could provide it. Dietary recommendations are becoming overwhelming with the number of different recommended food types. That is why peacounter has been so helpful – it tells you exactly where you are missing a given micro or macronutrient (in my case, it led me to discover I was getting enough vitamin A and choline).

  4. Jack Norris RD Says:

    Dan,

    In case you haven’t noticed my summary of recommendations:

    http://veganhealth.org/articles/dailyrecs

    > it is far easier to just take a few supplements rather than stressing out over whether the diet is including enough calcium, omega-3′s, iron, D, B12, C, B, A, D, E, K, iodine, zinc, lysine, etc, etc?

    I don’t think it’s all that difficult and if you eat a lot of greens, that takes care of many of these nutrients. But where you might come up short, I think it’s fine to take a supplement to make up the difference.

    Unless you have iron deficiency, you don’t need to worry about iron (or vitamin C).

  5. Andreas Says:

    Dan,

    The higher amount of lysine found in meat does not add up to the lower quantity of lysine that animals eat themselves. Humans and all other plant eaters have bacteria in their gut which produce Lysine and other amino acids from fiber/amino acids or from converting Aspartic Acid found in saliva into Lysine. Eating gluten impedes on this mechanism.

    http://www.ncbi.nlm.nih.gov/pubmed/16444817
    http://ajcn.nutrition.org/content/76/6/1317.full

    Example of Lysine Biosynthesis: Bifidobacterium breve (found in human gastrointestinal tract)
    http://www.genome.jp/kegg-bin/show_pathway?org_name=bbru&mapno=00300&mapscale=&show_description=hide

    If a person eats meat and gets a parasite….
    http://www.ncbi.nlm.nih.gov/pubmed/14668277

    Like Jack said, leafy greens and I suggest finding fresh greens and chewing them well. I also suggest eating instinctively by not portion controlling leafy greens, just eat as many as you feel like and you will know when you’ve had enough.

    One thing I want to point out is that the human body does not work the same way it does when eating animal products. Vegans have more fiber(including cellulose) digesting bacteria in their guts than vegetarians and omnivores.

    http://rheumatology.oxfordjournals.org/content/41/8/950.full
    http://www.nature.com/ejcn/journal/v66/n1/full/ejcn2011141a.html
    http://www.hablemosclaro.org/pdf/noticias/A_vegan_diet_alters_the_human_colonic_faecal_microbiota.pdf

  6. Dan Says:

    Speaking of supplements and cancer risk, here is an interesting trial:

    J Natl Cancer Inst. 2009 Mar 18;101(6):432-5. doi: 10.1093/jnci/djp019. Epub 2009 Mar 10.
    Folic acid and risk of prostate cancer: results from a randomized clinical trial.
    Figueiredo JC, Grau MV, Haile RW, Sandler RS, Summers RW, Bresalier RS, Burke CA, McKeown-Eyssen GE, Baron JA.
    Source
    Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, USA. janefigu@usc.edu
    Abstract
    Data regarding the association between folate status and risk of prostate cancer are sparse and conflicting. We studied prostate cancer occurrence in the Aspirin/Folate Polyp Prevention Study, a placebo-controlled randomized trial of aspirin and folic acid supplementation for the chemoprevention of colorectal adenomas conducted between July 6, 1994, and December 31, 2006. Participants were followed for up to 10.8 (median = 7.0, interquartile range = 6.0-7.8) years and asked periodically to report all illnesses and hospitalizations. Aspirin alone had no statistically significant effect on prostate cancer incidence, but there were marked differences according to folic acid treatment. Among the 643 men who were randomly assigned to placebo or supplementation with folic acid, the estimated probability of being diagnosed with prostate cancer over a 10-year period was 9.7% (95% confidence interval [CI] = 6.5% to 14.5%) in the folic acid group and 3.3% (95% CI = 1.7% to 6.4%) in the placebo group (age-adjusted hazard ratio = 2.63, 95% CI = 1.23 to 5.65, Wald test P = .01). In contrast, baseline dietary folate intake and plasma folate in nonmultivitamin users were inversely associated with risk of prostate cancer, although these associations did not attain statistical significance in adjusted analyses. These findings highlight the potential complex role of folate in prostate cancer and the possibly different effects of folic acid-containing supplements vs natural sources of folate.

    It turns out they used 1 mg of folic acid in this study. I’m a bit concerned as I have a very strong family history of prostate ca. I started a B100 complex for angular stomatitis which contains 0.4 mg of folic acid. On the plus side, I eat very little grain and thus consume much less enriched flour than the average person.

    I have also read elsewhere that folic acid may act as a promoter for colon cancer in people who have pre-existing colonic polyps (which is how virtually all colorectal cancers begin). There is some evidence that rates of colon cancer spiked right after mandatory fortification of the grain supply with folic acid was instituted.

    The guidelines for screening for prostate cancer changed quite recently to drop PSA testing in average-risk men. Perhaps I should consume half a tablet of the B100 complex instead of a full tablet per day.

    It’s strange because PHS II recently reported that multivitamin use, in a very large randomized trial, reduced cancer rates by about 9% (and no effect on prostate cancer). This was published in JAMA just recently. http://www.ncbi.nlm.nih.gov/pubmed/23162860

    We see again the weathervane of nutrition research, even at its highest quality (RCTs) — and the wind blows in both directions.

  7. Andreas Says:

    Dan,

    http://chriskresser.com/folate-vs-folic-acid
    http://www.greenmedinfo.com/blog/synthetic-folic-acid-may-contribute-colorectal-cancer2

    Mushrooms are rich in B Vitamins.

  8. Dan Says:

    Here is a study suggesting omega-3 supplements increased cancer risk in women. It is virtually impossible to overdose on specific micronutrients from normal, balanced dietary intake, unlike the case with supplements. I am very careful about recommending supplements to my patients, unless they have documented dietary deficiencies (most of my patients aren’t vegan, though). I have pretty much stopped prescribing omega-3 in my practice for cardioprotection, since the last 5 trials were all negative (SU.FOL.OM3, ORIGIN, Alpha-Omega, OMEGA, and the latest from Italy a few weeks ago in N.Engl.J.Med).

    B Vitamin and/or ω-3 Fatty Acid Supplementation and Cancer
    Ancillary Findings From the Supplementation With Folate, Vitamins B6 and B12, and/or Omega-3 Fatty Acids (SU.FOL.OM3) Randomized Trial
    Valentina A. Andreeva, PhD; Mathilde Touvier, PhD; Emmanuelle Kesse-Guyot, PhD; Chantal Julia, MD; Pilar Galan, MD; Serge Hercberg, MD

    Arch Intern Med. 2012;172(7):540-547. doi:10.1001/archinternmed.2011.1450.
    Background To advance knowledge about the cancer-chemopreventive potential of individual nutrients, we investigated the effects of B vitamin and/or ω-3 fatty acid supplements on cancer outcomes among survivors of cardiovascular disease.

    Methods This was an ancillary study of the Supplementation With Folate, Vitamins B6 and B12 and/or Omega-3 Fatty Acids (SU.FOL.OM3) secondary prevention trial (2003-2009). In all, 2501 individuals aged 45 to 80 years were randomized in a 2 × 2 factorial design to one of the following 4 daily supplementation groups: (1) 5-methyltetrahydrofolate (0.56 mg), pyridoxine hydrochloride (vitamin B6; 3 mg) and cyanocobalamin (vitamin B12; 0.02 mg); (2) eicosapentaenoic and docosahexaenoic acid (600 mg) in a 2:1 ratio; (3) B vitamins and ω-3 fatty acids; or (4) placebo. Overall and sex-specific hazard ratios (HRs) and 95% CIs regarding the cancer outcomes were estimated with Cox proportional hazards models.

    Results After 5 years of supplementation, incident cancer was validated in 7.0% of the sample (145 events in men and 29 in women), and death from cancer occurred in 2.3% of the sample. There was no association between cancer outcomes and supplementation with B vitamins (HR, 1.15 [95% CI, 0.85-1.55]) and/or ω-3 fatty acids (HR, 1.17 [95% CI, 0.87-1.58]). There was a statistically significant interaction of treatment by sex, with no effect of treatment on cancer risk among men and increased cancer risk among women for ω-3 fatty acid supplementation (HR, 3.02 [95% CI, 1.33-6.89]).

    Conclusion We found no beneficial effects of supplementation with relatively low doses of B vitamins and/or ω-3 fatty acids on cancer outcomes in individuals with prior cardiovascular disease.

  9. Dan Says:

    Andreas, I am taking a B100 complex to treat angular stomatitis. It contains 400 micrograms of folic acid. This is on top of the 1200 micrograms that my diet is already providing me with (according to peacounter.com). I am not overly concerned that an increase from 1200 micrograms to 1600 micrograms is going to give me prostate or colon cancer. There are conflicting data on folic acid and cancer risk. A very recent, large, comprehensive, individual patient data (IPD) meta-analysis in the Lancet showed no increase in the risk of any kind of cancer in the folic acid randomized trials, although the accompanying editorial complained that the trials did not run long enough, and the meta-analysis itself did not try to dissect out early versus late effects (it’s widely believed that folic acid could act as more of a tumor promoter rather than tumor initiator, thus long-term folic acid may be bad). Again we see the weathervane of nutritional research…

    Perhaps I’ll go with mushrooms instead.

  10. Jack Norris RD Says:

    Dan,

    There’s a theory that folic acid is a lot more dangerous than folate from food when it comes to cancer. Does any of the research you’ve read differentiate between them? Apparently, “folic acid” is not simply folate plus a hydrogen (as many -ates/-acids are) but are actually different molecules.

  11. Dan Says:

    Jack, here is what UpToDate says (which most doctors use – for what it’s worth):

    [snip - due to copyright concerns. - Jack]

    (doesn’t really answer your question though)

  12. Jack Norris RD Says:

    Dan,

    Thanks for the info. Are you a medical doctor? Sorry if you’ve already let us know.

  13. Dan Says:

    Yes I am.

  14. Andreas Says:

    Dan,

    2 years ago I developed angular stomatitis a month after going vegan; cured it with a methylcobalamin 1000mcg B12 supplement and I was obviously borderline B12 deficient on a meat rich diet. It could of been a folate deficiency but its very unlikely since I was eating a lot of leafy greens, vegetables and beans from the get go.

    I’ve read a source which states that 97% of the industrial microbial production of B12 is sent to animal feed and knowing what I know about B12; I strongly believe everyone except me needs to supplement with B12.

  15. Dan Says:

    Andreas,

    As far as I know, there is no difference in the oral bioavailability (absorption) of methylcobalamin vs cyanocobalamin. I was on a very meat rich diet and my B12 levels exceeded 600. On a pesco-vegetarian diet, they came down to 500 then 400. On a lacto-vegetarian diet, I have not tested them for adequacy. Three years ago, I was deficient while occasionally eating meat (105 and 205). But the meat intake numbers prove I can absorb B12 from meat, so I am assuming I can absorb the supplemental form adequately in the B100 complex I am taking. If I notice anything out of the ordinary, I will get a B12 level done to ensure I am absorbing the 100 micrograms I am taking. Otherwise, I prefer to minimize any bloodwork, as unnecessary.

    I don’t eat a lot of leafy greens – just green pepper, green onion (shallots), cucumber skins – and so I may be folate deficient, but peacounter does not indicate this to be so. There are probably other sources of folate in my diet than these minimal greens.

  16. Gauri Says:

    Jack, here’s more about fatigue and iron deficiency in premenopausal women.

    http://bit.ly/waMKm2

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