Monday, January 31, 2011

Iron-deficiency is not something you get just for being a lady

This post was chosen as an Editor's Selection for ResearchBlogging.orgWhen I was thirteen years old, I got my period. Soon after, I remember going with my mother to the nurse practitioner's office -- her name was Debbie. Debbie told me that once girls got their periods, they were more likely to be anemic, and I would have to watch out for it. She suggested I start to take an iron supplement.

Something about that conversation irked me, even when I discovered that I was slightly anemic a few years later. I disliked the implication that one could be pathological just by being female. And I didn't understand how it was that menses, which is only about thirty milliliters of blood loss per menses, could have such a profound impact on women's iron status.

When I was in college, I studied this in a bit more depth in my undergraduate thesis. I discovered two important studies:

First, most people assume that the sex difference in iron stores in males and females, which begins at puberty, is due to the onset of the period and looks like this:
Figure 1. Made-up data to demonstrate the assumed way the sex difference in hemoglobin is produced.
However, the sex difference in iron status in males and females derives from an increase in male iron stores at puberty, not a decrease in female iron stores. This has to do with oxygen transport and testosterone (Bergstrom et al 1995). This means that the difference that occurs at puberty actually looks like this:
Figure 2. Made-up data to demonstrate the actual way the sex difference in hemoglobin is produced.
Second, the main culprit for iron-deficiency anemia (IDA) in men is upper-gastrointestinal bleeding, so when men present with IDA the first thing they do is an endoscopy. When women present with IDA they give her iron supplements and tell her to go home because it's just her ladybusiness. Kepczyk et al (1999) decided to actually do endoscopies on women for whom a gynecological source was diagnosed by a specialist for their IDA. They found a whopping eighty-six percent of these women had a gastrointestinal disease that was likely causing their IDA. Therefore, menses likely had nothing to do with their IDA, and the assumption that menses made them pathological actually obstructed a correct diagnosis.

The majority of the women in that study were bleeding internally, and no one had figured it out until then because they had periods.

When I went to graduate school, I wanted to study menstrual and endometrial functioning because the assumption that it inherently causes disease seems to lead to a life of frustration with the medical system for many women. I figured it would be good for us to better understand variation in this part of the body... so that's what I did. I went to rural Poland, where my colleague Dr. Grazyna Jasienska has a lovely field site perfect for testing my questions about the endometrium: I wanted a non-industrial population, but couldn't choose one so remote that I didn't have access to a hospital, since the women would need to do ultrasounds for me to image their endometria. Then, I didn't set out to test specific questions about IDA, but Dr. Jasienska wanted to do some blood tests on my subjects for a related study, and happened to do a full work-up on them.

Without meaning to, I ended up with two very useful pieces of evidence: measurements of their endometrial thickness, and their iron status. I also knew their dietary iron intake since I did 24-hour diet recalls. I realized that I had the evidence in front of me to test the relationship between menstruation and anemia directly, rather than indirectly like other studies I had read.

It was a matter of some simple correlations (Clancy et al 2006):
Figure 3. Red blood cells (RBC) and hemoglobin (Hg) are positively correlated with endometrial thickness (from Clancy et al 2006). Click to embiggen!
Take a look at the p-values for the relationship between endometrial thickness (ET) and red blood cells (RBC), and ET and hemoglobin (Hg): both are statistically significant. What's more, the relationships are positive. That means that the thicker the endometria, the better the iron status. I'll admit, when I ran these stats my hypothesis was simply that there would be no relationship, likely meaning that the effect of ET on iron status was at most neutral. But a positive effect? At least in this test, there is no support for the prevailing medical assumption that menses is correlated with IDA.

I was reminded of this study of mine recently, because it was cited by someone else studying something a bit different (vanity Google Scholaring will get you that). Elizabeth Miller, a graduate student (though she may have since defended) at the University of Michigan, wrote a very interesting paper on maternal hemoglobin depletion, which is the situation where pregnancy and lactation deplete iron stores. Miller (2010) studied this phenomenon in two populations in northern Kenya, a settled population and a more pastoral one, as a way to understand the differential impact of interbirth interval, energetic constraint, and dietary iron intake on maternal depletion. I'm going to focus just on the part of this study related to issues of menses and IDA.

Miller found that iron stores slowly increase in lactating mothers with months since birth, but also that the more children these women had, the lower their hemoglobin. This makes sense in terms of where iron needs to be allocated during pregnancy and lactation, and how women with many children might not have enough time or resource to replete their iron before having their next kid.

But the really cool finding, to me, was that resumption of menses after pregnancy was positively associated with hemoglobin. Resumption of periods after pregnancy is highly variable, and largely dependent on energy availability and lactation practices. These results, that iron stores increase once you start getting your period again, indicate again that menses is not having a negative effect on iron stores. So this is the second study I know of to show a positive relationship between menses and iron status.

Ladies, unless you are menorrhagic (bleeding more than 120 milliliters each cycle) your period is not doing you wrong. If you have iron-deficiency anemia and your doctor is insisting it's because you slough off your endometrium from time to time without doing a single test to confirm it, you may want to insist on an endoscopy. It could save your life.

References

Bergström E, Hernell O, Persson LA, & Vessby B (1995). Serum lipid values in adolescents are related to family history, infant feeding, and physical growth. Atherosclerosis, 117 (1), 1-13 PMID: 8546746

Clancy, K., Nenko, I., & Jasienska, G. (2006). Menstruation does not cause anemia: Endometrial thickness correlates positively with erythrocyte count and hemoglobin concentration in premenopausal women American Journal of Human Biology, 18 (5), 710-713 DOI: 10.1002/ajhb.20538

Kepczyk, M. (1999). A prospective, multidisciplinary evaluation of premenopausal women with iron-deficiency anemia The American Journal of Gastroenterology, 94 (1), 109-115 DOI: 10.1016/S0002-9270(98)00661-3

Miller EM (2010). Maternal hemoglobin depletion in a settled northern Kenyan pastoral population. American journal of human biology : the official journal of the Human Biology Council, 22 (6), 768-74 PMID: 20721981

47 comments:

  1. LOVE this post (and your blog)! Go science *fist in the air*!!

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  2. Jamie Sukowicz (Anth 249)January 31, 2011 at 6:34 PM

    I found this article really interesting. Attributing iron deficiencies to menses seems like the simplest explanation, but I’m glad that you indicated that these menses are not the only difference between men and women in terms of their likelihood at being iron-deficient. I had never thought of the fact that iron (or any other sort of nutrient, mineral, etc) could increase or decrease in someone without an external cause (such as a diet change), but the increase in iron that men have through puberty is definitely something that should be noted. Although many women and men lead similar lifestyles in terms of activity, work, leisure, and diet, it is important to note that biological differences exist regardless of similar lifestyles. I never realized that iron deficiency could have such a severe cause or outcome, nor would I have thought that such a serious condition could be so easily disregarded due to the fact that women bleed a little each month. It is good to know that studies like this are working to spread awareness and encourage people to seek out additional opinions if their initial doctor’s visit does not yield the results they had hoped for.

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  3. This was an outstanding post - thanks! Such a great example of what science should be about: questioning and testing our assumptions.

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  4. Awesome, thank you for writing this. I'm curious if you have considered the effect of birth control on this correlation. For example, my ob mentioned that a hormonal iud will keep the endometrium thin.....

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  5. Thanks, everyone! Jamie, nice to see you visiting! :)

    RSB, what an interesting question. While I don't know that it has been explicitly measured, it is generally assumed that hormonal contraceptives keep the endometrium from proliferating as much as it would, and the same is true with IUDs. So likely the endometria are thinner for these women. For women with menorrhagia and IDA this would be a great solution (and I'm pretty sure is used as such). But for women who have fairly normal blood loss, it shouldn't impact things too much. Nice twist either way!

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  6. Very interesting. It's interesting to see that there is a positive correlation between endometrial thickness and iron supply. But something that I think may be overlooked is erythropoiesis due to the thickening of the endometrium. At least to me it seems perfectly possible that there would be a large spike in red blood cells to nourish the thickened endometrium. So that could be the source of the correlation between increased iron content, hemoglobin, and endometrial thickness.

    And I love how microbes that we once thought were harmless can come back to bite us years later! It turns out that 50% of us have H.pylori living in our upper GI tract and this is now known to be the leading cause of gastric ulcers, a serious condition that can lead to an upper GI bleed. So if an upper GI bleed is the main source of anemia in both men and women then the answer might be in the normal flora of the gut! Pretty wicked!

    I think there is an important message here though. Doctors should not just shrug off a patient because they think a condition is within the realms of normal physiology. The patient knows their body best and the doctor should make sure that the patient is treated according to their concerns.

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  7. This is interesting information! I've been reading up on anemia during pregnancy because that's one of the things I'm currently testing for in my field site but haven't come across anything like this. So cool!

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  8. I've been passing the link to this around like crazy. I'm fairly chronically anemic, and it took years to work out why for exactly that problem.

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  9. I'm curious -- this is a very medical/bio post, but your designation is in Anthropology. How's that work? (I'm guessing an interesting career path)

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  10. Anon - thanks for writing. I am a biological anthropologist, which means I study humans in light of evolution. My work is in the sub-disciplines human biology and evolutionary medicine. So I have a lot of training in physiology, evolutionary theory, etc, and run a lab that runs endocrinology and biomarker assays.

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  11. Also, Erica, where is your field site and what work do you do? Sounds interesting!

    Ray, interesting question! Though I wonder how to assess RBC that is in endometrial tissue or how that might impact serum measurements of them. My suspicion is that menstrual blood loss is simply an assessment of health, that the more you have (to a certain extent) the more energy you likely can allocate to reproduction. Since hemoglobin is often used as an assessment of health in public health studies, I think this is just a correlation without causation... or rather, it's not being energy constrained that increases both of these things, even if one isn't dependent on the other.

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  12. Fascinating post. Thanks for writing!

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  13. I love this post - a clear example of not only a misdiagnosis within the realm of medical possibility, but also a stereotyping and transformation of "female as sex" to "female as condition" - or worse, illness.

    As someone whose knowledge of medicine is cursory at best, it's kind of shocking to see that this field which in my mind is comprised totally of pinpoint diagnoses, sterile environments, and (above all) empirical data, is sometimes just as dependent on sex and gender stereotypes as, say, popular media. The problem seems to be: if those who know better (i.e., medical professionals) won't even challenge it, how do the rest of us have any hope at all?

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  14. Tom, thanks for stopping by. You ask: "The problem seems to be: if those who know better (i.e., medical professionals) won't even challenge it, how do the rest of us have any hope at all?"

    Being the perennial optimist, I think that more patients are taking on more responsibility for their health, even as they are uncomfortable and disappointed in a system that requires them to be like this. I guess the issue is, while once upon a time we trusted our doctors' words in all things, it wasn't a good idea back then either, so lamenting that past doesn't do us much good. Don't get me wrong -- I have those same feelings and frustrations, and I resent constantly having to prove my expertise when I am in a doctor's office, but I am trying to hold that up against the reality that they didn't know more back then, we just had a more hierarchical system that led to greater trust.

    So... medical professionals will start to challenge these things. But only if we point them out and try to make them.

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  15. Very nice post! I will be teaching anemia next week to nursing students and will pass this along.

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  16. Would a fecal occult blood test catch the upper GI bleeding? I'm a first year med student so I have no idea about how real world gyno visits go, but we've been trained that no abdominal or gynecological exam is complete without a rectal exam (which includes an FOBT).

    I would have thought that anemic girls should have a greater chance of getting properly diagnosed. (assuming that all gynos perform the test and the test works in this case).

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  17. Professor Clancy, I wonder if you have read or heard of the book "Sex, Time, and Power" by Dr. Leonard Shlain. He had a very interesting hypothesis about iron levels in human females. He made the observation that in no other animal is there regular shedding of a core mineral in three distinct phases of life - menstruation, breastfeeding and menopause are all marked with iron loss.

    He wonders "what could the evolutionary benefit to this be? You would think this would be a disadvantage."

    The argument that Shlain puts together is highly original and fascinating that involves ...sex, time and power. But in short he makes the case that this iron shedding is an evolved trait because it causes group bonding. Men bring heme-iron rich food to women and women bring childrearing and gathered foods to the party.

    I hope you take a look at the book and see the breadth of his speculations.

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  18. Jim: I just googled for fecal occult blood test and upper gastrointestinal bleeding and up pops a Wikipedia article.

    http://en.wikipedia.org/wiki/Fecal_occult_blood

    Apparently there's more than one kind of fecal occult blood test, and some of them are better at catching upper GI bleeding than others.

    I'm trying to remember if I had a rectal exam at my last gyn appointment (with a general practitioner). I'm drawing a blank. This was mentioned in the Wikipedia article but I'm not sure how applicable it is to office visits:

    http://www.annemergmed.com/article/S0196-0644(07)01333-9/abstract

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  19. Wow, this post is fantastic. I find it very interesting the ways in which science is limited by unquestioned cultural assumptions.

    This is why I really don't like the sound of the conclusions drawn in Sex, Time, and Power - or most other evolutionary psychology or bioanthropology. It's too pat to say that there's a natural adaptive reason why women have lower iron - so they get to sit at home and wait for the brave men to come home and bond with them over iron-rich snacks? That whole conclusion is just covered in man-the-hunter type sexism.

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  20. Also, I've never had a rectal exam before (I'm 27 and female), neither in a gyno checkup or any other sort of physical exam.

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  21. Oh boy is this ever a brilliant post. The data's important because it's really interesting how assumptions about lady parts meant no one bothered to check for what would otherwise be an obvious and parallel reason for anemia.

    But what I really like is how your two charts illustrate what happens when you drop the assumption that (relatively affluent, euro/american, military-age) men are baseline/normal/reference against which the rest of humanity varies. As soon as you switch the frame of reference suddenly men are the variable. And looking at the second chart we're *really variable.*

    This isn't just significant for reasons of gender-blind assumptions. You look at the second chart and suddenly a sex-specific illness like hemochromatosis stops looking so inexplicable.

    That's still kind of academic compared to the consequences of neglecting to consider GI bleeding in women. If women are already "borderline anemic" (now a.k.a. "normal") then identifying and dealing with significant causes like that instead of assuming along with Aristotle that a couple of teaspoons of undiluted blood lost in menses was making the difference. (Hello? Even though donating a whole pint in 20 minutes doesn't?)

    Again a very cool, cool post.

    figleaf

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  22. I think part of this problem involves the medical definition of "menses" which focuses on blood loss, when in reality the majority of blood in the uterus is recycled back into the body and not actually lost.

    This is an amazing find and also a good argument for Anthropologists to be accepting of both scientific and humanistic theories.

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  23. Excellent post! This should be required reading for all women (and everyone really). It's amazing how little we know about women's health. Here is another really interesting study on health statistics and the effects it can have on women: http://www.psychologicalscience.org/journals/pspi/pspi_8_2_article.pdf. One part explains that 1 out of 10 women who tested positive in a mammogram actually had breast cancer, but gynecologists will unnecessarily alarm the other 9 women because they are unable to accurately analyze statistics.

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  24. Pat Bowne -- you just made my day. You are EXACTLY the audience I hoped to reach with this post.

    Jim, that is a wonderful question (about fecal blood testing) but I don't have any idea. My apologies! And I second the commenter in suspecting that, in reality, rectal exams are incredibly rare even if you are taught you're supposed to do them. I've never had one as a part of my normal yearly gynecological work-up. Ever.

    mjs, thanks for sharing the info about that book. I haven't read it, but to be honest, at least from your description, it looks like evolutionary storytelling. At least in my work, and with my interests, I tend to look at more mechanistic hypotheses (meaning, trying to empirically understand relationships between different aspects of environment and physiology). I also share some concerns similar to diggingellen about it. There was so much variability in our ancestral diet that seeing things in a strict savanna, hunter/gatherer dynamic is probably too simple, so that already begins to diminish the argument.

    figleaf, thanks for your comments! You nailed it on the head when you said: "But what I really like is how your two charts illustrate what happens when you drop the assumption that (relatively affluent, euro/american, military-age) men are baseline/normal/reference against which the rest of humanity varies. As soon as you switch the frame of reference suddenly men are the variable. And looking at the second chart we're *really variable.*" Just remember, the data was made up in order to represent trends. While I found evidence of the trends I describe and I fully back my interpretation, no one had good longitudinal data or graphs to demonstrate this.

    modestgrrl - exactly! We resorb tons, which is why I study the endometrium and am interested in how it behaves in the days leading up to menses. To me, it looks like we resorb more if we have more energetic constraint. But that is a WHOLE different post :).

    Anonymous - thanks for the link, I will definitely read it!

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  25. Wow, thank you for this. My mom had her uterus taken out for anemia. The doctors involved never questioned it was anything other than period-related.

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  26. Subscribing... Nearly every woman in my mother's family ends up getting a hysterectomy once they reach about 40. Some for anemia, some for menorrhagia. At 30, I have low ferritin... and migraines which have me taking a lot of NSAIDs. Thanks for being one of the itty bitty handful of people posting information on this.

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  27. I also have had the inverse told to me: that if I'm not anemic, then no matter how heavy my bleeding is it's not significant enough to warrant medical investigation. I had to actually measure the milileters and present my own dug-up data on average flow versus mine before I could get anywhere (and still am not that far) with my docs. Currently the fact that I'm not anemic is a major obstacle in getting a PCOS diagnosis, which otherwise is well-supported by my symptoms.

    Also, side note, I was anemic in high school. At 16 I became a vegetarian, and kept dutifully taking my iron supplements. At 19 when I got mono but they took ages to figure it out, they checked for anemia, and found I had *too much* iron, and forbade me from even multivitamins containing iron. They were astonished that this was the case even though I wasn't eating meat.

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  28. Kelly, Ghost, Anon, thanks for writing. Anon, I agree: I know women who have had the total opposite experience where they've suffered menorrhagia (very heavy bleeding) and low iron and the doc either says it's part of being a woman, or to just take iron.

    That's interesting that not being anemic would keep you from having a PCOS diagnosis - I wasn't aware that was a criterion.

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  29. Fascinating post!

    I've had menorrhagia and dysmenorrhoea for most of my menstruating years, and chronic fatigue for half of those, but it took roughly a decade to get a doctor who had the sense to say, wait a minute, did we actually ever test your iron levels? And she found out I had IDA, and now I'm being treated and my energy level overall is up (despite having something else that causes chronic fatigue as well - it's a vast improvement even then). Doctors' treatment of their patients can be wildly variable.

    Had I been male and presented with the multitude of health issues I do, I'm fairly certain I wouldn't have been treated like a hypochondriac for twenty years before getting an accurate diagnosis (and I'm only twenty-five now).

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  30. Interesting and enlightening and validating on many levels ~ thank you for this with us all! Peace.

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  31. My husband calls doctors "tech support for people" with the basic problem being that it's hard to turn people off and back on again to see if a restart will fix it ;p

    Doctors have a list of symptoms that are supposed to match with a list of diseases--kind of an ultimate matching test. It does get more complicated than that, but that's a pretty basic sum-up.

    Which is why second opinions are powerful--if a doctor has never seen a disease in action, he will be less helpful than one who has.

    Good luck with this (as someone who's borderline anemic :)

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  32. Trialia, what you and a few other commenters have said is making me realize I need to make sure I write at least one other post on the "other" side of this story -- that is, how very real and debiliatating some reproductive pathologies can be for women.

    Walk in the Woods, thank you.

    And Anon, I like your husband's analogy! Sometimes I wish we could do a hard restart :).

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  33. This is fascinating. But it appears to contradict something I've read in the past: namely, that people in general do less well on math tests when they're slightly anemic, and that this explains the drop-off in girls' math scores around puberty. (Until puberty, girls outperform boys in math, if anything.)

    Could boys' improvement in math be due to their increase in iron stores?

    Are pubescent girls actually anemic?

    -- Beth

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  34. Hi Beth, that's interesting. It sounds like correlation not causation, and if you have a link to the study (or even a pop sci article on the study) I would really enjoy reading it! I'm not sure what the mechanism would be for a correlation between iron stores and math scores.

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  35. KBHC: Here's one:

    Halterman JS, Kaczorowski JM, Aligne CA, et al. Iron deficiency and cognitive achievement among school-aged children and adolescents in the United States. Pediatrics June 2001:107(6), pp 1381-1386.

    And an ABC News article about the same study:
    http://abcnews.go.com/Health/story?id=117414&page=1

    which clarifies that there doesn't have to actually be anemia for the effects to be seen; a mild deficiency shows an effect. It also posits that the combination of rapid growth + menses could = iron deficiency; another article suggested diet may be partly to blame:

    http://toyourhealth.com/mpacms/tyh/article.php?id=465

    This page suggests that heavier-than-normal menstrual bleeding may be the cause:

    http://www.anemia.org/patients/feature-articles/content.php?contentid=000348

    “An important risk factor for iron deficiency anemia is heavier than normal menstrual bleeding, which affects about 10% of women in the United States. Adolescent females often do not get enough iron to keep up with menstrual losses. They especially do not want to talk about how heavy their periods are."

    Anecdotally, as a teenager I immediately denied heavy periods when my (male) doctor asked. Part of this was that I had no idea what normal was (and this was not explained to me). I later learned that my periods were indeed heavy.

    -- Beth

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  36. Really interesting post (and comments too). I didn't realise that I had been guilty of what is unfortunately a classic teacher error - repeating what I had been told by textbooks in good faith. I will now be more accurate when teaching - thank you!

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  37. Just found this, via a link from a friend. Thank you for it, it has given me a couple new things to think about. And now, I'm going to go arrange to have a chat with my doctor about my continuing mild anemia. I believe I shall be taking your paper with me.

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  38. Beth, thanks so much! I'll check those out. And yes, heavy menstrual bleeding may certainly cause anemia. However many women are assumed to have anemia due to *normal* menstrual bleeding. Further, as the Kepczyk et al article illustrates, sometimes it's assumed to be the cause and, without testing, ends up masking a more serious cause.

    Also, again, take a look at the results I found: thicker endometria were associated with *more* hemoglobin. So menses shouldn't lead to iron deficiency, even in a subclinical sense. So again, it's important to *not* assume that menses has anything to do with variation in iron, at least in a negative sense (again, if anything, heavier blood loss, up to a point and within the normal range, should be correlated with higher stores of iron).

    IanH and luna-the-cat, thanks for your comments!

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  39. As someone with chronic anemia, this article smacked me right between the eyes. I have been referred to OBGYN after OBGYN, and every time they try to talk me into surgery to stop my period, because I cannot take the pill for other medical reasons. Surgery. To stop my period. Before I was even 40. I kept thinking there had to be a better way.

    If anemia IS a result of GI bleeds however, wouldn't there be other noticeable symptoms? How long can you bleed from your gut without knowing it?

    In any case, I love the title and thesis of this article. Thank you for sharing it.

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  40. Hello, loved the article, I have been anemic for so long and finally found out 2 years ago that I have celiac disease. Many gi disorders including celiac disease (an intolerance to wheat gluten that attacks the small intestine) cause anemia due to the guts inability to absorb iron from the diet, not internal bleeding. Doctors are more aware of it now and some will test you for celiac if you have unexplained anemia. If you google celiac and iron deficiency you will find quite a lot of articles. I'm sure other upper gi diseases work the same way, causing absorption issues rather than bleeding.

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  41. By the way, here is a basic article on celiac and iron deficiency. http://celiacdisease.about.com/od/symptomsofceliacdisease/a/CeliacAnemia.htm

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  42. Thanks Anon! Yes, I am gluten intolerant and iron deficient -- that was the explanation for my iron deficiency, not normal menstruation. I hope to eventually write a post on this exact topic -- so glad to meet someone else in a similar situation!

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  43. So the anemia symptoms are getting bad again. Migraines. Dizziness. Fatigue. Loss of appetite. Sensitivity to temperature. Shakiness. Ear ringing. Impair vision upon standing. Just everything. I cant take to iron because it messes up my stomach but that’s the only thing than makes the other symptoms go away.

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