Science is set up in a way that systematically penalizes research on females and female-related health issues…but not necessarily for the reasons you think. Although there was a time and place in history when women weren’t believed to be worthy of study, this is far less true now than it was even 25 years ago. Academics tend to skew more left than right, and the overwhelming majority of scientists that I have met in my career—both women and men—are fully supportive of women, women’s rights, and proponents of women’s inclusion in science. Although others might perceive the gender equality landscape somewhat differently from the way I do, all else being equal, I think that most researchers would be just as inclined to study women and things that are important to women as they are to study things that are important to men. This is particularly true given the growing number of women in science.
But all else isn’t equal.
Women are harder to study than men, and because science is extremely competitive and demands a rapid pace of publication, when there aren’t checks and balances in the system to ensure that women get studied, few people will study them. Because females’ hormones change cyclically, biomedical research using females as participants has to account for cycle phase. Although this might not sound like that big of a deal to have to do, the logistics of exercising this kind of control when collecting data on a large number of participants is nightmarishly tricky and can easily triple the amount of time and money it takes to answer a research question.
Just to give you a sense for what this sort of thing looks like in terms of day-to-day lab operations, I’ll tell you about a study that we did recently looking at the relationship between immune function and decision-making in women and men. Although the immune system seems like a good candidate for being a ‘gender-neutral’ body system (like a spleen or lungs or something), its activities are actually quite variable depending on sex and cycle phase. Maintaining a pregnancy is something that has required women’s bodies to find an immunological loophole to prevent their immune systems from attacking the implanting embryo because embryos have more than a few things in common with the things that immune systems are programmed to destroy. It has different genes from mom’s (one of the hallmarks of pathogens), its cells divide rapidly (one of the hallmarks of cancer), and it syphons resources from mom’s body (one of the hallmarks of parasites). These types of cues—especially when all occurring at the same time—usually send the immune system into search and destroy mode. To keep this from happening, women’s sex hormones actually modify immunological function based on cycle phase and pregnancy status.
Now, what all of this meant for us and our research was that we needed to be very specific about the cycle phase of the women we included in our study to make sure that their immune systems would be doing roughly the same thing at the time of the study. First, we needed to make sure that all of the women in the study were at the same phase in their cycle, so that we could accurately compare them to each other. Second, we needed to make sure the cycle phase we chose was one that would minimize the unique impact of their sex hormones on their immune system functioning so that we could compare them to men. Using these two criteria as our guides, we chose to include only naturally cycling women who were in the early follicular phase of their cycles.
Women are harder to study than men, and because science…demands a rapid pace of publication, when there aren’t checks and balances in the system to ensure that women get studied, few people will study them.
Our first methodological challenge was that we needed to recruit only non-pill-taking women to participate in the study. This was not an easy feat given that the overwhelming majority of women ages 18–25 located in proximity to a university campus (where most of our participants hailed from) are on the pill. Next, we had to schedule all of these women to come into the lab 4 to 7 days after starting their periods. This meant that for each woman, there were only four days each month in which they were eligible to participate, and these days were not always easy to predict. Women’s cycles can have a mind of their own, sometimes, and not all women are great at keeping track of where they are with everything on any given day. To make sure that women would be where we needed them to be in their cycles when they came in the lab, we found that the best way to schedule them was to have them contact us as soon as they started their periods, and then we’d schedule them to come in 4 to 7 days later. If the woman’s calendar wouldn’t allow for a session to be scheduled on one of those four days (which happened frustratingly often—life is busy and often scheduled more than a week in advance), we had to wait until the next month and try again.
Once we were able to find a day that worked for our female participant’s schedule, we then had to scramble to put together an on-the-fly research team to collect her data. This was a lot more complicated than it might sound because each of our testing sessions required the assistance of eight researchers, many of whom had to schedule around classes and other experiments that they were running. And if we were able to get that to work—if the stars aligned, the light shone down from the heavens, and angels sang—we would be able to collect data from our female participant and all was right with the world. We then repeated this exercise 79 times until data collection on women was complete.
Compare this to the process we had to follow to run men through the study.
First, we had to call the men and schedule a session based on the days in which we planned to have a research team assembled (a perk of being able to schedule far in advance). Second, our team of already-assembled researchers had to run them through the study.
That was it.
If we’d only used men in our study, we would have been able to complete data collection in two to three months and it would have cost roughly $12,000.00. Including women and exercising control over their cycle phase meant that data collection took nine months and cost nearly $30,000.00. And if we would have wanted to look at how women’s immune / behavior relationships differ across the cycle—looking at multiple cycle phases rather than just one—or to see how these women differ from women on the pill, the cost and logistical nightmare could have been doubled, tripled, or quadrupled. (You can divide the cycle up into as few as two phases (estrogen dominant half; progesterone dominant half) and as many as four (menstrual, early follicular, ovulatory, and luteal). Doing research using women as participants—and doing so in a way that recognizes the pervasive role women’s sex hormones play in pretty much everything their bodies do—is incredibly challenging. And because of this, many researchers simply steer clear of studying issues that require women as participants or require thoughtful control of their cycles.
This is why, as recently as 1986, papers were being published with titles like “Normal Human Aging,” that included data only on men. And, although things have gotten better since congress made it necessary for NIH-funded clinical trials to include (some) women in their research, this issue is far from solved. Females continue to be understudied in all phases of research, including pre-clinical research on non-human animals and cells.
Females continue to be understudied in all phases of research, including pre-clinical research on non-human animals and cells.
For example, a colleague of mine who uses mice to study Alzheimer’s Disease (a disease that afflicts considerably more women than men), was just asked for the first time ever by a reviewer, why they didn’t include female mice in one their studies. And this is 2018. This, despite the fact that he’s been in the field for nearly 30 years and has routinely tested only males. (Although this is now changing based on the reviewers asking for data on females. When the system changes, research practices change.)
According to his take on the state of the field, at least 90 percent of the research he reads on the mechanisms that contribute to Alzheimer’s Disease is done exclusively on male mice. And the primary reasons for this are that a) females make the results too nuanced (since males and females almost never respond the same way to treatments) and b) the results from females are mechanistically messier (since it is possible that their sex hormones may have influenced their results). These two issues make studies that include females harder to get published, disinclining researchers from studying them at all.
This shouldn’t be okay. All (as in, ALL) medical research is first tested using animal models. These models are important in helping researchers study new cancer cures, the progression of Alzheimer’s disease, autoimmune issues, mental illness, PTSD, and pretty much anything else that might go right or wrong in the human body (including the brain). These models are the foundational bedrock of biomedical research. And because females are harder to study (and the results taken from females can be more difficult to interpret because of cycle phase), the overwhelming majority of this research has been done using only male animals. Only males. There is little doubt in my mind that there are major medical breakthroughs in women’s health that have been overlooked because females have been routinely excluded from the front lines of animal research. Female rodents have typically been studied second (after finding promising results in males) or not all. If something didn’t work in males, it was just assumed not to work, without ever testing it in females.
There is little doubt in my mind that there are major medical breakthroughs in women’s health that have been overlooked because females have been routinely excluded from the front lines of animal research.
The inclusion of females in research—and done in such a way that accounts for cyclically changing hormones—is not something that should be left up to the goodwill of the researchers running the studies. When science is done this way, women and women’s issues lose. There is so much pressure put on scientists to publish, publish, publish, that many (and I have been as guilty of this as anyone else) choose to do what’s fast, cheap, and easy, rather than do what’s right. If the top research journals will publish your research without including female participants, would you go through all of the trouble when it might ultimately shoot you in the foot? Or would you do the easier thing and collect data on men and then simply include a caveat telling the reader that the results need to be ‘further explored in women’? I ask these questions not to excuse science (or myself in my own research practices), but to explain how we’ve gotten to this place. It should come as absolutely no surprise that research has ignored women for so long because the establishment—the journal publishers, the reviewers, and the funding agencies—have rewarded it.
Although things are changing for the better (in the U.S., federal agencies will no longer fund clinical trials involving humans that do not include women and the NIH has new policies to increase inclusion of female animals and female-derived cells in pre-clinical work), there’s still a long way to go. Animal research using only males is still funded by many agencies, is readily publishable, and continues to be the norm in many disciplines. And many biomedical research journals still don’t require researchers to use females in their research or to even report the sex of the participants used in the studies. Thoughtful, carefully-done research on females still takes longer, costs more, and is oftentimes harder to interpret than research conducted only on males. So, when people’s careers depend on their publication rate—rather than the need for answers to the questions they’re asking—women, and the issues they care about most, lose.
Many research and publishing policies that are in place are relics of a time when people didn’t appreciate the breadth of the differences between men and women. It used to be thought that the results of research done on males would be easily generalizable to women, because women were thought of as smaller versions of men, differing only in our reproductive organs. But now that we know better, we need to do better. When it is de rigueur for all scientists to have to include females in their studies (and do so in a way that takes into account women’s changing hormonal status), more females will be studied. And when more females are studied, female-specific health issues—including the birth control pill—will also be studied.
Reprinted from This Is Your Brain on Birth Control: The Surprising Science of Women, Hormones, and the Law of Unintended Consequences by arrangement with Avery, an imprint of Penguin Publishing Group, a division of Penguin Random House LLC. Copyright © 2019, Sarah E. Hill, PhD.
