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

The views expressed are those of the author and are not necessarily those of Scientific American.


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I am away on vacation this week. I have decided to share my most popular post to date with the Scientific American audience, in the hopes of getting a few more people excited about physiology, women’s health, and culture. Enjoy!

When 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 visually represent the assumed way the sex difference in hemoglobin is produced. No, I can’t find real data in the literature but yes, if you find any send it along and I’ll update the post.

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 visually represent the actual way the sex difference in hemoglobin is produced. See caveat from Figure 1.

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 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

Kate Clancy About the Author: Dr. Kate Clancy is an Assistant Professor of Anthropology at the University of Illinois. She studies the evolutionary medicine of women’s reproductive physiology, and blogs about her field, the evolution of human behavior and issues for women in science. Find her comment policy here. Follow on Twitter @KateClancy.

The views expressed are those of the author and are not necessarily those of Scientific American.





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  1. 1. user5454 6:18 pm 07/27/2011

    There are plenty of historical examples of doctors being too quick to attribute pathology to women’s bodies, so I’m definitely on board with the idea of being careful about not doing that, and the etiology of IDA in women seems like an issue worth drawing attention to. However, this article’s conclusions seem very disproprotionate to its evidence to the point of very serious irresponsibility.

    Look at the title of the Bergstrom paper which she claims (or at least implies) is the basis for her graphs. That doesn’t seem like the title of paper that has discovered something novel and important about IDA, and I can’t find the words “iron” or “oxygen” anywhere in the full text.

    The Kepczyk paper, which she cites as the “whopping 86% of women” who had GI disease, has a total sample size of 17. It was performed by a gastroenterologist, who appears to be both an author and a lead evaluator, with a convenience sample and no blinding at all. The 86% figure comes from 6 out of 7 patients, who had what sound like very common and minor problems. There is no attempt at all to show that the GI problems were the true cause of the anemia.

    I can’t really comment on the author’s own work, but overall I’m not seeing *anything* that comes even close justifying the author’s recommendation of demanding an endoscopy–which, after all is not a risk, pain, or monetarily free procedure– much less the claim that you might *die* if you don’t. Printing those claims based on such flimsy evidence in Scientific American, a publication that people could reasonably trust for advice on this subject, seems deeply irresponsible.

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  2. 2. Bora Zivkovic 9:26 pm 07/27/2011

    Great blog post – I can see why it was the most popular on your old blog.

    Not sure how to respond to the technical questions by user5454, but am baffled by his/her use of “she” instead of “you” when addressing you in a comment. Also, this commenter probably missed that this is an independent blog hosted by SA, and that SA does not tell bloggers what to blog about and how.

    Link to this
  3. 3. kclancy 9:34 pm 07/27/2011

    user5454, just in case you are new to blogs, you are welcome to address me (the blogger, or blog post author) directly. I’m sorry to hear you feel this post is irresponsible, but I’m also sorry to say that you’re wrong.

    On the Bergstrom paper, I’m happy to send you the pdf if you don’t have access yourself. Also please see the captions under the figures – I am going on well-established evidence about how testosterone works, but I also do suffer from the fact that this hasn’t been studied in the literature (or if it has, I haven’t found it in the ten years I’ve been studying this topic). I do think that this is the weakest part of the blog post, but I also felt I had to somehow visually represent how the data is projected to look to help people understand why the two ways of thinking about puberty and iron are so different.

    The Kepczyk paper is a relatively small sample size (though honestly, really not that small for a medical paper), but the their results are very significant. I think the chances of the results being all false positives to be incredibly small. I’m not sure why the lead author being a gastroenterologist is a bad thing.

    Next, let’s revisit the last paragraph that troubles you so much:

    “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.”

    My issue here is that women with unresolved iron-deficiency who menstruate a normal amount never receive any additional testing. And this could mask GI bleeding, but it could also mask celiac disease or bowel cancer. And all of these diseases, often iron deficiency is the first sign that something is wrong. If doctors stop pursuing iron deficiency in women after asking “do you menstruate?” they are doing women a disservice. And yes, in some cases, getting it checked out further could really save their lives.

    Finally, I’d be happy to have you comment on my own work, since you take issue with my analysis of the literature. Feel free to contact me if you’d like pdfs of my paper or the paper where I’m cited that I reference here.

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  4. 4. KDCosta 9:47 pm 07/27/2011

    “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.”

    I’m not clear how User5454 reads this as demanding an endoscopy, and frames this as an irresponsible recommendation. What Kate has done is highlight a popular misdiagnosis and present a scientific basis for seeking an alternative diagnosis. It is no different, in my opinion, from recommendations made elsewhere. Kate does not say march into your doctor’s office and demand an endoscopy. But she provides a basis for speaking with health professionals who are often rushed, and let’s face it, who sometimes don’t listen as well as they should. It is up to us to be our own health advocates. The more information we have to make informed health decisions the better – particularly when the information is as well reasoned as this.

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  5. 5. kclancy 9:51 pm 07/27/2011

    Thanks Bora and Krystal!

    Link to this
  6. 6. user5454 11:26 pm 07/27/2011

    Thanks for the response! I really appreciate you being willing to discuss your post, and I hope I’ll be able to convince you to at least add some caveats to it.

    “On the Bergstrom paper, I’m happy to send you the pdf if you don’t have access yourself.”

    I appreciate the offer, but I have access to it. Can you point me to the part of the paper that you’re citing? I’ve read the abstract and searched for key terms (“iron”, “oxygen”, “tesosterone”, etc) and I can’t find reference to anything related to your post at all. I’m also generally skeptical that a paper which, as you claim, definitively overturns common knowledge and practice of medicine wouldn’t even mention that finding in its abstract.

    “Also please see the captions under the figures ”

    I know your figure are just made-up visual representations, and I think that’s totally fine.

    “I am going on well-established evidence about how testosterone works, but I also do suffer from the fact that this hasn’t been studied in the literature.”

    I don’t understand. How can something be well-established without being studied in the literature?

    “The Kepczyk paper is a relatively small sample size (though honestly, really not that small for a medical paper)…”

    17 might be an ok sample size for a very rare condition, but it’s tiny for a condition as common as IDA. But “tiny” vs “not so tiny” is somewhat subjective, so I won’t go any farther except to suggest that it would be more honest to replace the phrase “a whopping 86%”, which conceals the real numbers involved, to “a whopping 6 out of 7″.

    “…but the their results are very significant. I think the chances of the results being all false positives to be incredibly small.”

    This perhaps my biggest qualm. Are their results significant? I don’t see any statistical analysis in their paper at all. They don’t even attempt to show a significant correlation between these GI findings and anemia, much less that they contributed to it, much less that the GI findings were the root it, much less that the expense and risk of finding and treating the GI disease would provide any real clinical benefit to the patient.

    “I’m not sure why the lead author being a gastroenterologist is a bad thing.”

    The problem is that he’s both the lead author and an evaluator. But blinding is a very basic principle in clinical studies, and the fact that he was unblinded and had every reason to want the study to show exactly it showed does leave it open to a very real possibility of bias, even if he was acting in perfectly good faith.

    As for your own research, as you describe it, you haven’t shown anything but correlation, right? Couldn’t high hemoglobin easy be causing the return of menses?

    In short, my objection is this: you’re making a suggestion that (a potentially very large number of) people “insist” on a medical test (albeit in certain circumstances) that you haven’t even begun to evaluate the diagnostic or clinical value of because you believe that a large number of doctors are stubbornly (and perhaps paternalistically) wrong about a basic issue of physiology. I think your evidence for this extraordinary claim is weak, but as a member of the academic community, I think you will succeed in reducing some patients trust in their doctors and perhaps even in getting them to insist on procedures they don’t need.

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  7. 7. kellyoakes 9:05 am 07/28/2011

    Great post! I remember finding it on your old blog after my doctor told me that I was iron deficient but that it was “perfectly normal” given that I was a woman. I felt like I’d been fobbed off, and this post helped me realise that feeling sceptical about what they said wasn’t necessarily just paranoia on my part.

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  8. 8. kclancy 10:37 am 07/28/2011

    Hi user5454, I am on vacation and so putting a lot of time into this is hard. But, my daughter happened to be vomiting all night, and since I couldn’t sleep I did a little research.

    First: you are right, I cited the wrong Bergstrom paper, and I can’t seem to find the correct one in my reference manager. I know it is a paper by Bergstrom that I first read this but will have to dig up the correct citation. In the meantime, I did some lit review and found additional evidence to support the idea that testosterone increases iron:

    http://journals.humankinetics.com/pes-back-issues/PESVolume7Issue3August/IronandHematologicalStatusAmongAdolescentAthletesTrackedThroughPuberty

    http://archinte.ama-assn.org/cgi/content/abstract/166/13/1380

    The above papers show that pubertal rises in testosterone are correlated with rises in iron, and that higher iron in older adults is associated with higher testosterone in men and women. So, this doesn’t rule out that menstrual blood loss may in some women lower their iron (particularly if it is heavy) but it certainly provides an additional factor to consider in the sex difference in iron. In fact, while I have found one paper (Milman et al 1999 if memory serves) that suggests a slight dip in iron at menarche, iron goes up in boys and girls shortly after, as it generally increases with age through adolescence.

    As for Kepczyk et al, I still think it is an important example of testing a medical assumption. You don’t need to do stats to measure the percentage of women with IDA who have upper GI bleeding. But, Kepczyk et al isn’t the only group to find that endoscopy is important in premenopausal women: Bini et al (1998) has found the same:

    http://www.sciencedirect.com/science/article/pii/S0002934398002605

    And this paper demonstrates the importance of looking at GI causes of IDA regardless of GI symptoms:

    http://www.sciencedirect.com/science/article/pii/S000293430100883X

    Finally, yes, my work demonstrates a correlation… but how few studies demonstrate causality? I’m not sure the point you are making about the association I’ve found. I still find it pretty interesting that the women that should have the heaviest menses had the highest iron… particularly when it was an opportunistic study, where I didn’t expressly set out to test this. I don’t try to explain the causality, just show that our assumption, that the reverse relationship should exist, doesn’t in my sample.

    If I have the time later this summer, I may try and write a follow up post expressly about puberty and iron, because after the research I did last night it is even more interesting than I first thought!

    Link to this
  9. 9. user5454 3:05 pm 07/28/2011

    Hi Dr. Clancy,
    Thanks a lot for continuing to look into it. I’m very sorry to hear about your daughter.

    While I haven’t had the chance to thoroughly review all of it, the new evidence you’ve presented for both your points certainly seems a lot more compelling. It’s enough to convince me that testosterone is correlated (and perhaps causal) of higher iron stores and that there is at least a very good chance that menstruation doesn’t entirely explain increased anemia in pubescent women.

    The studies regarding endoscopy are also much more compelling. Their sample sizes are 10 and 40 times larger than the original study you cited, but equally importantly they set out to systematically address very specific clinical questions. Unlike the previous study, they also actually found some patients with clinically relevant disease (including some actual cancers). They stop far short of recommending that every woman with anemia with no explanation other than menstruation absolutely be subjected to endoscopy regardless of age or other aspects of the clinical picture, but the assertion that one of them makes in its introduction that “The standard evaluation of a patient with iron deficiency anemia includes a complete evaluation of the gastrointestinal tract to identify a source of bleeding.” certainly seems to reflect a much higher degree of consensus in the medical field on this issue than I gathered from your post.

    So while I’m still far from convinced that a patient should insist on endoscopy against their doctor’s advice, or that the average anemic woman should live in fear of cancer if she doesn’t, those assertions seem much more reasonable now than they did. I just hope that you understand my reaction when I believed that the papers you cited were the best evidence you could find for your belief.

    Enjoy your vacation, and thanks again for taking the time to discuss your work. I hope your daughter is feeling much better!

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