The biomedical importance of sex (and its binary nature)

September 15, 2022 • 12:00 pm

One might almost think, with widespread denial of a sex binary of men and women—a denial that in most animal groups is both fatuous and ideologically motivated—that there are no average biological differences between men and women. “Blank slaters” tend to outright deny the existence of behavioral or cognitive differences between men and women, often doing so on the erroneous grounds that “some women are in the range of men’s scores and vice versa”. In such cases the concept of averages seems to have slipped their minds.

But as the dogs bark, the caravan moves on. Increasingly recognizing the biological and medical differences between men and women—note the implicit recognition of dividing up the species into two sexes— funding institutes and journals dealing with illness and medicine (as well as  are increasingly recognizing the importance of studying men and women separately (or partitioning the data by sex) in biomedical work. That includes using model organisms such as mice, which may show related sex differences. This is the topic of the new feature in the journal Nature shown below. Click on the screenshot to read (it’s free).


First, some indicators that dividing up test subjects by sex can give useful and potentially lifesaving results:

Many of science’s gatekeepers — granting agencies and academic journals — feel the same way. Over the past decade or so, a growing list of funders and publishers, including the US National Institutes of Health (NIH) and the European Union, have been asking researchers to include two sexes in their work with cells and animal models.

Two major catalysts motivated these policies. One was a growing recognition that sex-based differences, often related to hormone profiles or genes on sex chromosomes, can influence responses to drugs and other treatments. The other was the realization that including two sexes can increase the rigour of scientific inquiry, enhance reproducibility and open up questions for scientific pursuit.

When studies do include two sexes, the results can be important for health. For example, sex is known to affect people’s responses to common drugs, including some antibiotics. . .

And here are some important biomedical differences already detected:

. . .Despite the bumpy ride, the federal guidelines that were put into place in the early 1990s have led to some important medical discoveries, perhaps a signal that key revelations could emerge from basic research in a few years.

For instance, there are sex-based differences in the heart’s electrical response to several classes of drug, including antidepressants and antibiotics. As a result, sex-based dose adjustments are now recommended for some drugs.

Steroid hormones such as oestrogens and androgens are thought to be primary actors in many of these differences between men and women. For example, women metabolize propranolol, a blood-pressure drug from a class known as beta blockers, more slowly than men do. Researchers think that sex-related steroid hormones acting on the liver can exert these effects. Other factors could include body size and composition, such as the fat:muscle ratio, which tends to be higher in women.

The cut-offs for risk might also differ between men and women. A 2021 analysis of cardiovascular risk related to systolic blood pressure shows what happens if data for two sexes are pooled rather than analysed appropriately. The authors found that when data were pooled, the range for increased risk was a systolic pressure of 120–129 millimetres of mercury (mmHg). But the sex-specific analyses showed that for women, the risk actually begins to climb when systolic blood pressure tops 110 mmHg. If other studies solidify these findings, the result would be a sea change in risk calculation for cardiovascular disease.

That study, as it happens, “was very much inspired and motivated by an NIH request for applications” about sex differences in health outcomes, says Susan Cheng, a cardiologist at Cedars-Sinai Medical Center in Los Angeles, California, and senior author on the report. Without that call for studies specifically designed to look for sex differences, she says, “we had a lot of ideas, but not a thematic focus”. Their findings that men and women differ in risk cut-offs “was actually a real ‘eureka moment’”, Cheng says. “I was like, ‘how did we not see this before?’.” She attributes the results to the NIH’s challenge. “They made it all happen.”

And good for the NIH!

Now surely you can’t attribute all these differences to “socialization,” as the disparity in hormones is based on genes that are differently activated in men and women. Of course, differences in biology due to any factor, like the Patriarchy, still need to be studied for their biomedical effects. But it’s foolish to attribute everything like the above, including the response of the heart to drugs, to environmental influences.

And, of course, if there are no differences between the sexes with respect to a biological trait or response, we need to know that too! This is true for any groups that a priori may differ biologically, but men and women are the most obvious and least ambiguous grouping.

The article highlights some problems with past research, including an apparent lack of knowledge by investigators about how to use statistics to judge the effects of sex, including the simple dictum of using half men and half women in a generalized test on “the population”.  Below is one chart from the paper partitioning 147 biomedical studies starting in 2019. As you see, more than third of them (55) didn’t even consider sex as a factor to study (and that’s dead easy), more than a third (60) didn’t look for interactions between sex and treatment (essential if you want to know if a treatment works differently in men than in women), and only 32, or about 22%, looked for interactions between treatment and sex (16 of these reported a significant interaction, and 10 a nonsignificant interaction).

Finally, even when sex differences were found, as in the red group that didn’t look for interactions, most studies that found a difference didn’t test that difference statistically. The blue group is the one that used statistical tests, but even in that moiety, 6 tests didn’t report the results and one non-significant result was erroneoously reported as a difference.  I thought biomedical researchers would be more savvy than this.

Now there’s a few gestures in the paper toward the “sex isn’t binary” trope by bringing in gender. For example:

The publishing community is pushing for similar clarity. In 2016, it published the Sex and Gender Equity in Research (SAGER) guidelines, which set out how to report sex-based differences in published research. Individual publishers, including Springer Nature (which publishes Nature), have their own policies encouraging researchers to report results by sex, defined as a cluster of biological traits, and sometimes also gender, which is socially defined.

Since “gender” is a social construct, and progressives say there are a gazillion of them, I don’t see how you can report results by gender unless you lump everyone besides men and women as “other”. (I won’t quibble with “sex defined as a cluster of biological traits”, which is technically incorrect but good enough for the purposes of biomedical research.)

And this is thrown in as well, seemingly out of nowhere:

Defining sex as a crude binary, predicated on the chromosomes present, or on specific anatomy, could be too limiting. Some species, such as the nematode worm Caenorhabditis elegans, have one sex that makes only sperm cells and one that makes both sperm and egg cells. And in a vast assortment of species, sex is determined environmentally rather than chromosomally. And still other species can change sex during their lifetime. Placing cells, tissues or even whole organisms into a pair of categories takes on layers of difficulty in these contexts.

Note the pejorative adjective “crude,” meant, I think, to disparage the binary.  Once again they send in the clownfish, nematodes, and turtles, but these don’t refute the idea of separate sexes. Nematodes can be either males or hermaphrodites, the latter being both male (making sperm) and female (making eggs), some clownfish can change from male to female if the alpha female dies—but there are still two sexes, and temperature-specific sex determination, as occurs in many turtles, still gives you males and females. In that case the two sexes are developmentally channeled via an external stimulus rather than via chromosomes and genes, but there are still men turtles and women turtles. (Why some species do this is still not well understood).


The fact remains that these species do not show more than two sexes, that they are in the minority of vertebrates and in an even smaller minority of birds and mammals, and, in the end, humans aren’t clownfish, turtles, or nematodes.

Besides emphasizing the valuable lesson that men and women are biologically different in ways that can be important for medical treatment, this article also shows us that where it really counts, where the rubber meets the road—that is, when lives are at stake—the palaver about the binary of sex being a fiction vanishes.

None of this, of course, is intended to ignore those who have disorders of sex determination or transsexuals who have had hormone therapy or surgery, for those patients may need separate study rather than lumping them into one sex or another. That will be hard to do given the paucity of such people, but everyone deserves the best treatment that science can offer.

35 thoughts on “The biomedical importance of sex (and its binary nature)

  1. Yes, speaking as lay person, it seems like just recently the cry was for more medical research looking at women, like for heart disease, rather than primarily men. Of course, now it seems like research might go the way of the Dodo in favor of ideology.

      1. [ apologies for my continuing etymological quest ]

        I suppose the accurate term would be “bisexual” – but that has been taken for other use.

        Because “-nary” means “number”, as in natural number, or is it to mean “digit”? One natural number – unary. Two natural numbers – binary. Three – ternary.

        Two sexes – bisexual.

    1. … which is why we were taught to use it in “Sadistics 1.2.1” back in the 80s, particularly when we moved into non-parametric analyses (happened od didn’t happen, compared to a measurement of how much it happened).
      It’s a quite basic (literally, undergraduate) description of a large number of datasets.

    1. Your friend, Prof Pinker, recently published a blog-post (or comment on such) suggesting that basic education in Statistics *might* be a more important part of mathematical eduction for students in “bio-medical sciences” than (say) the outer reaches of calculus.
      A few posts uptread I mentioned “Sadistics 1.2.1”, which was my first year (“1.x.x”), single quarter-year unit of study (“x.x.1”), with a more mathematical bent (“x.2.x”) than the “1 1.1” course intended for “social science”, “psychology-ish” and medic students, where they were essentially given pick-lists of distributions, significance tests, etc, but not the gory mathematical details.
      As my tutorial group in 3rd term worked through historical data in “real-to-us” time with the Department Head, in his field of *testing* (stats sense) experimental treatments for cancers (mostly, some urgencies too), most tutorials included all three following phrases (with wobbly numbers) :
      – “your” (finger points at 1 of us 4) “analysis of last week’s data would kill five more patients than yours (finger shifts)” ;
      – “why isn’t this a *required* course for medics?” ; and
      – “I’ve been making that point to the academic Senate for the last 20 years. The Medic’s senators always think they have higher priority matters.”

      The spinning sound you hear is Semmelweiss rotating in his grave.

      Pinker is right : Sadistics should be an essential part of science education, including medical sciences.

      1. The average person has a very hard time estimating the probability of things medical and otherwise. Like the lottery. Statistical studies would help them with this. But then we’d have to go back to taxes to fund the state government.

      2. UK med school 1976-1981: calculus was not required, but statistics was a required course during the first two (preclinical) years. It was rather basic, looking back, Student’s T, Chi Squared, correlations, Bayes’ Theorem, and some trial design – just enough to let us evaluate a clinical trial of relative simplicity. Even so, the number of people who fall for the drug companies using changes in relative risk rather than absolute risk is rather sad.

  2. I have a question @J. Coyne: The Oxford Dictionary of Biology defines “mating type” as “the equivalent in microorganisms, fungi, and algae of the male and female individuals of higher organisms,” and I read that there are species with more than two mating types. What exactly is the difference between mating types and sexes?

    1. That is a very good question, with (I think) no clear answer.
      Some decades ago I clubbed my brain to sleep with Lynn ‘symbiosis’ Margulis (&A.N.Other)’s compendium of biological diversity “Five Kingdoms”. I was making detailed notes on each of the IIRC 137 phyla described, and had just moved from single-celled phyla (with *lots* of the “mating types” you mention) when in short order I broke my note-taking machine (Psion 5) and left the 3kg book on a rig, expecting to return.
      I’ve lost all the notes, and never got a backup to work, but I left the subject with a clear impression that it is a much muddier puddle than most people give it credit for. PCC(E)’s criterion of “big gamete, little gamete” isn’t wrong, but there are complications like “big then small”, “big in good times and a few little”, “no big and many little in bad times”.
      I sort-of hoped it would become clearer in the sessile phyla (“plants”, to a first approximation), but my study hit the rails before I finished the mobile metazoa.
      Hmm. Maybe if I set up a DOS emulator and installed Win3.11 on it, then installed the Psion emulator on that? Or, have I tried hat in hardware?

    2. Check out Wikipedia under “mating types”. For one thing, they are usually based on the equivalent of alleles at singles genes rather than polygenic, and they don’t have gamete types. But I suppose you could call them “sexes”, and they may be ancestral to “sexes” in organisms like us. But that doesn’t mean that there are more than two sexes in vertebrates.

      1. Thanks for your reply! My reason for asking this question is that in a private discussion someone (with a wokish attitude) presented the argument that the existence of more than two mating types in some species refutes the alleged binarity of sex, which presupposes that mating types are (properly called) sexes.
        Of course, even if they are, homo sapiens is still relevantly different from species with more than two mating types/sexes; so that argument fails as an argument from biological analogy.

        1. For crying out loud, when you say sex is bimodal (there’s NO DOUBT that it’s binary in humans), you need to say in which groups. Microbes are not one of them. You shouldn’t be arguing with the wokeish, though, as they will never relent or even listen to what you have to say.

        2. That seems related to the naturalistic fallacy. That which is natural must be good.
          It is sadly interesting that a wokish person seems unable to accept a science and fact based rebuttal, much like the creationist that was discussed here the other day.

    3. I hope this is helpful supplement to Jerry’s excellent concise reply. Apologies if this is too much. Broad generalizations below, each has many exceptions.

      In fungi and algae and some plants, the “mating types” occur in the haploid stage of the life cycle, where each cell has only one genome copy. Two different mating types fuse together, the resulting cell is diploid (has two genome copies, one from each parent cell), and it might or might not go on to become a multicellular organism. So in a sense the “mating types” are analogous to the gametes in an animal life cycle, but the mating types of a fungus (e.g.) are multicellular organisms, and they can live a long time.

      Animal gametes are also organisms in this important way, but a gamete is a single cell and it lives for only a short time (because a gamete in its final form can’t feed & grow, it can’t divide to become a larger multicellular organism – why that constraint exists requires an explanation that won’t fit in this margin).

      The differences between animals vs. those other groups are in the life spans of the haploid vs. diploid life cycle stages, and the size and complexity of the stages.

      The really important similarities among all those groups are (1) that sex involves reducing the genome from two copies down to one in the haploid stage (by meiosis to form gametes in animals), then fusing two haploid cells to bring the copy number back up to two in the diploid stage (e.g., us). And (2) that organisms do this in order to recombine genes in the genome during meiosis, create gametes or mating types with lots of different genomes (from the same diploid parent), and then mix those different genomes together in the next generation of diploid individuals.

      Sex is not really about reproduction (lots of things reproduce without sex), it’s fundamentally about recombination.

  3. I’m not sure about the US, but in England GMC guidelines allow patients to change the sex recorded on their medical records simply by requesting it.

    Public Health England tells GP surgeries to change a patient’s’ recorded sex/gender on their medical record at any time, without requiring diagnosis or any form of gender reassignment treatment. They are given a new NHS number and previous medical information must be “gender neutralised” and transferred into a newly created medical record. They will be sent screening appointments (e.g. for cervical smear tests or prostate cancer screen) according to their new gender (i.e. invitations to attend the wrong screenings).

    Those who consider themselves “non-binary “ apparently get the entire category removed.

    I do not know where the grownups have gone.

    1. There is probably a rapid growing up shortly after words like “your biological sex can affect the success of this treatment by 70%” With appropriate aromatherapy, support groups, etc. But part of the nature of brute reality is it’s brutality.

      Do you need an emotional support spliff with your reality?

    2. It is going to hit them in the back, but I hazard the guess that their physician will be able to tell by looking at their “non-binary” patient which charts to consult. They may not say anything out loud, though. I wonder how people get around when communicating to one another. Are the physician and the medical assistant give each other a knowing wink when they say “non-binary”?

    3. Ye gods. The potential for a lawsuit over a missed cervical or prostate cancer diagnosis is an obvious enough reason to NOT let this happen.

      1. Yup, the ability to request a new NHS number and altered medical records is one of the reasons that it has proved so difficult to keep track of the long-term health effects of puberty blockers accessed via the Tavistock clinic’s Gender Identity Development Service (GIDS). (Although the Tavistock even failed to track adolescents when they progressed from GIDS to its own adult services, for reasons that aren’t readily apparent.)

        The Cass Review needed a legal change to get access to the underlying records although the ability is strictly time-limited and restrictive in other ways too.

  4. It seems that the fact that anything up to 20% ( maybe more) of the Lyonised X chromosome has escaped from becoming part of the Barr body and is expressed is possibly one of the reasons why there are certain medical conditions that have a much higher prevalence in women. Autoimmune conditions for example. Sex IS important in medicine.

  5. “Once again they send in the clownfish”. Indeed!

    I have noticed that in social science in general, even in human behavioral ecology, there has been a shift away from taboo topics like sex differences and violence toward health-related topics. It seems that examining sex differences is only allowed if the justification is that it would possibly bring some health benefit to people. If your justification were mere curiosity, good luck getting support for that.

  6. There are obvious sex differences in diseases. I don’t mean things like prostate hypertrophy or cervical cancer, that is obvious, but there are also great differences in less obvious diseases.
    ‘Benign’ intracranial hypertension is almost exclusively female, and to a lesser degree Lupus (LED) or multiple sclerosis. Males are more prone to cardiovascular diseases (that might have a strong environmental component) or, say, ALS.
    If diseases are more common in one sex than the other, it would be very surprising if the effects and pharmacokinetics of treatments by sex would not show some important differences too.

    And there is no doubt that the same goes for race or ethnicity.
    Why would vernal conjunctivitis manifest with giant papillae under the upper lid in whites, while in black and brown people it almost invariably presents as a limbal infiltration? We don’t know. Blacks have more and more severe open angle glaucoma, but much less age related macular degeneration than whites.
    The lists are long, these are but a few examples.
    And yes, although in my training as a medic we did get some statistical training, much more could have been done. A good understanding of statistics is a sine qua non for evidence based medicine.

  7. It is certainly important for policy-makers and individual people-patients to know if there are differences between men and women in the way diseases reveal themselves and if treatments have different effects (including side-effects) between the sexes.

    However, this is much easier said than done. The more heterogenous your sample, the larger the statistical variance in the variables you are planning to study. Including women in a study can double or treble the sample size needed to get statistically significant results because not only do women differ from men, they also may differ from one another depending on phase of menstrual cycle. So investigators doing small-scale exploratory studies avoid enrolling women, unless compelled to, to make their research budgets go further. (They are also worried about liability if an intercurrent pregnancy goes wrong.)

    Remember the goal of medical scientists is not to save lives or make the world a better place. It’s to get publications toward academic promotion for doing something that arouses their curiosity. A manuscript reporting on results in 25 male college students is just as publishable as one that studied 100 people of both sexes and various ages and showed the same thing, but costs 1/4 as much to do. And here’s the rub: the larger more inclusive study will still not be large enough to detect statistically significant differences between the men and the women, or between young and old. This is the irreducible problem of sub-group analysis.

    So in a sense, the inclusion of the women and older people in the second study was a waste of money. The investigator should have donated it to someone else’s much larger, and more expensive, study specifically designed and powered to detect between-sex differences. But that would mean giving the money back to the granting agency which your Dean would not like one little bit. So you spend it yourself, at least getting DEI points.

    What the NIH and other agencies are trying to do is to nudge researchers to look for inter-sex differences early in a treatment’s development so that large randomized trials sponsored by Pharma can properly account for sub-group analyses prospectively in their design. Which is a very good thing. It just won’t happen without incentives.

    I suspect that many of the studies in the 2019 article that Jerry cites were simply under-powered (because under-budgeted) to make any inference about sex differences. The biomedical literature is more like a sponge than a filter. Even dreck gets published somewhere.

  8. Getting to this a day late, but thanks as always for such posts. And the little asides like “send in the clownfish” that I also appreciate!

  9. Also getting to this late, but in the early days of the covid vaccines, gender ideology extremists were FURIOUS that vaccine providers asked for biological sex on consent forms. The reason for the inquiry was to track any sex-based differences in vaccine efficacy and side effects. Well, spoiler alert — the ideologues threatened vaccine providers that the ideologues would unleash all hell — TWAW — , so many providers backtracked. Even my own medical insurance uses “gender identity” instead of biological sex. And every time I’m asked that, I explain why this is wrong.

    1. “reason for the inquiry was to track any sex-based differences in vaccine efficacy and side effects. ”

      That’s an excellent point.

      So how about on any given questionnaire, ask :

      1. sex
      2. gender identity

      … what’s wrong with that? One extra parameter. Everybody is happy.

      1. @ThyroidPlanet write “Everybody is happy.”

        Except they’re not. Gender extremists *entirely deny the reality of biological sex.* They think physical bodies don’t matter. What matters is only the (subjective of course) feelings in one’s head. They do not tolerate the mere *mention* of biological sex. I’ve been immersed in this nonsense for years, so I know how they, uh, think. Srsly.

        1. That’s funny – I thought about my last somewhat flippant line after submitting it , and yeah – they can just write whatever they want, and STILL be mad.

  10. As an aside, I’m surprised that Nature even featured an article like this, since they use sexist language such as “pregnant people” and “menstruators.”

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