Sex Bias in Biomedical Research and Women’s Health (Episode 596)

Full Transcript: Episode 596

Lisa Hendrickson-Jack:

In today’s episode, I’m tackling a really interesting topic. This is kind of like a follow-up to the conversation that I had with Dr. Sarah Hill. For those of you who listened to that recent episode, you could tell that my mind was blown. And for many years, I’ve known that women are excluded from a lot of the studies that are done. A lot of our science, the vast majority of our science is based on the male body and male physiology. And I also knew that the majority of animal studies that have been done have also been done on male animals. But I feel like the conversation I had with Dr. Sarah Hill really sparked some more specific and nuanced details that I hadn’t really looked into. So, that’s what we’re doing in today’s episode. We’re taking a peek at how science has been done and delving a little bit deeper into these topics. And I’m also going to be talking about how even when women are studied and the specific goal of the study is to derive information about women, that there’s still room for improvement in terms of those study designs. So, hold on to your hats because today’s episode is going to be really interesting.

The paper that I’m going to be going over today is called Unmasking the Adverse Impacts of Sex Bias on Science and Research in Animal Welfare. So, that will be guiding the discussion and I’ll be bringing in a couple other interesting topics as well. So, one of the things that one of the themes that came out in my recent interview with Dr. Sarah Hill is just this idea that science really does need a do-over and it highlights I think the big piece for me at least that stood out was just really addressing the fact that women have not really been studied well although women have been studied and obviously there are studies that do include women and include female animals we haven’t really been studied well and we haven’t really been studied as women and what I mean by that obviously is that as women, we’re not on a daily circadian rhythm cycle. We don’t have similar hormones every single day. We have hormones that unfold over a menstrual cycle. And the average menstrual cycle, as we know, is about 29 days. But even within that, there’s a lot of variability. And if we look at cycle data, you can see the cycle length can vary significantly. Hormone fluctuations can vary quite a bit as well. And so, there’s a whole lot of implications of this. And in many ways, I’ve seen this in the research that I’ve looked at over the years where I’m highly critical of how they’re looking at the menstrual cycle, how they’re measuring hormones, how they’re determining and confirming ovulation, those types of things. And I think the big piece that I hadn’t researched because it’s not really part of the umbrella of the work that I’m doing, but one of the really interesting topics is how when they’re studying drugs, they’re not studying women or if they choose women, they’re studying them at a specific time of the cycle. And so therefore, they’re not testing how those drugs could be how they could interact differently with women in the pre-ovulatory phase versus the post-ovulatory phase under the influence of estrogen or progesterone and how that might affect how the drug functions. So I think that’s the piece that was really interesting. So this study is another review study and it’s kind of looking at the trajectory, the history, what has been done, why it’s like this, and they make a whole lot of really useful and important points. And so when they get into the history of it, they really do outline the historical over reliance on male animals in the drug development process. So they’re really kind of pointing out the fact that this is a known issue. It’s been known for a long time. And this process that the pharmaceutical industry undergoes to test certain drugs and have them approved has typically been done on male animals. And there’s a lot of beyond the obvious issue of women having higher side effects from these drugs. There’s other practical problems that arise as well. And so since the 1930s, there has been this kind of medical practice of excluding females and female animals because of this idea that their cycles are too variable or that it’s adding in some sort of additional just something that makes it too complicated for them to study. It’s like this is too complicated. Although that is certainly a cop-out because research is research and it really doesn’t take a genius to take some time and to sit down and think about what a specific methodology would be to accurately test both sexes. I feel like it is a cop-out and I do feel like it’s really not that hard to at least conceive of a study design and they do make some suggestions which we’ll get into. And so they kind of go through the years and they go through that it’s been well documented. According to the researchers they say and I quote this sex bias in biomedical research has been well documented. In a study across 10 fields of biology it was found that 80% of the animals that were used were male. And it was further found that even when both sexes were used, only one-third of studies analyzed the results by sex. So even when they include females, they’re not even separating the data and providing how it affected one sex over the other. So it’s really interesting how they’re doing this. It’s really shortcut research strategies here that we’re looking at and of course with profound implications and profoundly negative implications. So what we have when we look at this picture is that women are really underrepresented in the results and that also means that we do have a limited knowledge. There’s a whole lot more to learn about women and I think it gives us an important insight because when I talk about fertility awareness and I share that with people when I’m interviewed on other podcasts I had this really interesting experience when I was interviewed for Primally Pure. I was sitting there. I flew to California. So I was in their space, really nice space. Like there was mostly women involved in this process of bringing me there and interviewing me. But they had their tech guy, their sound guy, their lighting guy. So there was like five men in the room at least. And what was really interesting was that the topics I was talking about, the questions that they were asking in the discussion that arose once we finished recording, it was the men that were jumping in and like, “Hey, I didn’t know about that.” And I didn’t know that women aren’t even studied in science and things like that. So that really stood out to me because wow, this is information that I’ve known for a very long time. The average person doesn’t even realize that women aren’t studied.

So when we have that question of well why wasn’t I taught this and why wasn’t this part of my junior high school curriculum, right? Like why wasn’t this addressed? I think we really need to look at this kind of deep entrenched exclusion of female animals and women, human women in research and just kind of this assumption that we’re just like men and we’re just going to study like the standard which is a man and we’re just going to apply that to everybody else. And I think that that bias also then gives us an explanation as to why the menstrual cycle, the female body, fertility, all of those kinds of topics aren’t really addressed because they don’t really apply to men. And so therefore, since it’s not really part of the standard, why would it be included in the curriculum? Now, of course, we know why it should be, but for me, it really helps put things into a broader perspective because it is a systemic issue. And if we’re wanting it to change, then it’s not just that women have to go into male institutions. We often think that if you’re working with a female doctor, everything’s going to be better. That female doctor was trained in a male-dominated institution that the standard even of the studies and the testing that has laid out the medical program has been done on men. So you’re not going to have a woman come out different necessarily because the whole structure was built on the male body. So we know what we’re up against and at the end of the day what we need to do is just continue to deepen into this and learn about it and talk more about this. The more people that learn about this, the more interest there is in this field. And interestingly there are certain papers. So the researchers point out a paper that was done in 2010. So according to the study in 2010 Barry and Zucker conducted a survey of animal use in neuroscience and biomedical research and found that after 20 years of awareness of sex bias. So they’ve known about it for 20 years. The practice continued to be pervasive in animal studies. So even though it has been identified as an issue, it’s still pervasive. And they go on to say, “In 2020, when a 10-year follow-up study was concluded on sex reporting, there was some evidence of improvement, but sex bias remained pervasive. There was an increase in the proportion of studies that included both sexes, but no change in the proportion of studies that included data analyzed by sex.” So, what they’re saying is even though they’re including females more, they’re still not analyzing the data by sex, and they’re still doing certain practices that are making it really hard to really truly study the true differences in sex. So we’ve made some progress but certainly not enough.

So another aspect of this is something that Sarah Dr. Hill touched on in our interview which is how they actually do the research. And again this was fascinating. So it’s like oh we have to include women now. This is part of what we need to do. So let’s just take these female you know animals and just take their ovaries out and then we’ll just study them. And so that is wild that they do that because obviously that defeats the whole point of testing sex differences. So it is important to realize that that is what they have been doing for many years. And when they then include actual women, they can’t do that, but they can then study. They have chosen to include women, but they’ll include them during the first nine days of the cycle when there’s the least interaction of estrogen and progesterone. So again, we’re still not addressing it. So I think that is really interesting as well. So there was a couple of things that the researchers said that I found really interesting. So these researchers were taking the perspective from in my opinion based on reading the paper that they’re saying okay they’re excluding women because they’re saying that it’s going to cause too much variability. But one of the things that they were saying was that even when women are included there’s not necessarily that much variability. There was a couple of quotes that I found really interesting. One was that they can certainly incorporate the cycle and the hormone variation into the design which we’ll talk a little bit more about. But they said something interesting. They said empirical research across multiple rodent species and traits demonstrates that females are not more variable than males and for most traits female estrosity need not be considered. So I thought that was interesting. So what they’re saying is they’re overestimating how much the cycle would cause variability, and in certain studies it doesn’t even necessarily need to be considered. So that to me is interesting because I wonder how they came to that conclusion like it doesn’t really matter in a lot of cases. So I think that that’s an interesting perspective because they’re saying okay so maybe in certain situations they don’t need to consider the cycle they can just test women or female animals and in other studies they can incorporate the cycle into the design. And I think that the reason that that struck me as interesting is because until you actually test drug interactions when estrogen is high and progesterone is high or otherwise throughout the cycle, I don’t know that you could really say that it’s not relevant. So, that was just an interesting piece of information that I thought I would pull out of there.

So, this really made me think. So, there was a study that I talked about in the summer and I shared an episode and it was on PMDD. And in that study, essentially the researchers determined if you read through the whole study and you kind of look at their rationale, they tested certain things. They tested the hormone progesterone in the luteal phase and they compared women with PMDD versus the control group which did not have PMDD. And the researchers concluded that because the progesterone levels were not statistically significantly different between the PMDD group and the control group that progesterone was probably not the issue. And they hypothesized that maybe it’s just that the women are more sensitive. Like the women with PMDD because the levels aren’t different according to them, maybe the women just aren’t as sensitive to progesterone. The reason that I find that to be interesting is because when you look at the study design, they tested the women once, so one day in the luteal phase, and it was mid-luteal. And so based on my perspective of working with women over many years looking at the menstrual cycle chart, when a woman has issues with progesterone, it’s not necessarily mid-luteal that’s going to show up in the chart. So for anyone who’s not as familiar with this, if we look at the menstrual cycle, you have your period and then you ovulate and then in a healthy cycle 12 to 14 days after ovulation is going to be when the next period comes if you’re not pregnant. And so mid luteal would be about a week, let’s say 7 days after ovulation. But women who have PMS and PMDD symptoms, those typically are exacerbated during the week before her period. And so when a woman is charting, she could have a kind of normal-looking first half of that luteal phase, but then the progesterone can drop off after that. And I would argue that the biggest difference that you would see if you’re dealing with women who have PMS or PMDD versus the control group wouldn’t necessarily be mid luteal. It would be during the week before their period. And that even would be dependent on how like one of the signs of low progesterone is how long the luteal phase is at all. So I said 12 to 14 days is healthy. Well, some women have like a 10-day or a 9-day luteal and that would certainly indicate that their progesterone isn’t strong enough to even give them the full length of their luteal phase. So that in of itself is an indication that the progesterone levels are low. So if I go back to the study, they were saying, “Well, the levels aren’t different.” And I’m asking, well, your study design doesn’t allow you to fully evaluate if the levels are actually different because you only did one test on one day at the time of the cycle when it wouldn’t really be the best time to test that because the differences would show up in the latter part of the cycle. So I guess what I’m getting at with this point is that even in research that is specifically to do with women. So even when they’re studying women only to try to find results, I would go so far to say that they’re not necessarily taking the cycle as much into consideration as they should in many studies. And this is something that Lily and I talked about a lot when we were looking at different research because I would be looking at the study design and well, how are they testing? How are they confirming ovulation? Are they doing it based on the day? Are they just spot testing these women and things like that. There are certain practical implications when you’re looking at things like this because in order to truly test women based on what I’m seeing and to truly incorporate the menstrual cycle and the hormonal fluctuations, it would be a more complicated design. The participants would have to be more involved. They would potentially have to come multiple times throughout the pre-ovulatory and post-ovulatory phase. I would argue that in some cases it wouldn’t be sufficient just to test once and do a spot test on a certain day. They might have to have the women actually track their cycles and chart confirm ovulation and come not based on a date day 21 of the cycle but based on the actual date this many days after ovulation or come in for a series of tests. So, I just wanted to put that in there as well because I feel like even in studies currently that are being done on women to study events in women, there’s still room for improvement in the study design to actually get the results that we are curious about. And the reason why I thought of that PMDD study is because that topic came up in our fam group. One of our participants was like, “I heard your podcast.” And I was like, I was curious as to why the researchers were saying that the hormones aren’t the issue that instead it’s just these women are more sensitive. And so my response was, well, I don’t know. That’s what they came to. That was the conclusion based on their data. But I would love to see a study where they are actually testing and doing more of a series of progesterone testing and then comparing that series of tests amongst the different women because otherwise are you really getting a true value? And it could be that the women with PMDD are just more sensitive to the hormones. But how do you come to that conclusion if you haven’t fully tested the hypothesis by truly looking at those levels and seeing if they’re the same?

So what’s interesting then is how the researchers decided to approach like what were their recommendations. So they’re outlining this problem. They’re talking about the history. They’re saying it’s been like this for decades and since the 30s they’ve been doing research this way. So what are their recommendations? So I mean I think the most basic is that they are recommending that they include both sexes. Like imagine that and for that just to be the norm. And they are also encouraging the researchers to report sex specific results because one of the issues they identified was that even when they include female animals or women in these studies, they’re not necessarily dividing the results and showing if there are any differences based on sex. I mean again like basic I feel like we’re in kindergarten here. And they identify some of the practices that they have about taking out the ovaries of the animals, saying they should stop doing that because obviously if you do that, you’re not really testing, you’re not getting actual results that are useful. You’re just making it easier for yourself by trying to reduce variables. I think that one of the things that they talked about too is kind of reframing it differently, having one group of the male animals and then two groups of the female animals where one of the groups is in like the pre-ovulatory phase and one of the groups is in the post-ovulatory phase to actually be able to test. And I think that part of the resistance to that is that it would really change how we look at research and look at studies. It would be more expensive. It would be more complicated if we’re dealing with human women. It may be more difficult to find participants who are able to commit to more frequent testing or things like that. But ultimately I think that the paradigm has to change. They would have to embrace the cycles. So instead of avoiding hormones and considering them to be inconvenient. They would have to actually look at that as an important factor to be taken into consideration. So they would actually have to kind of change how they’re looking at it. And as I mentioned, they would have to I believe they would have to actually test during the times when the hormones are high. And it could be really helpful to have a good understanding of how the cycle works and have charting to be part of the process just so that you’re making sure that you’re testing. And again, the reason why this is a problem in these animal testing and drug testing is because what’s happening is they’re not testing these products when the women actually have hormones or when the animals are actually having their hormone levels at the highest points. And so therefore, they’re not seeing if there are any drug interactions and they’re not accounting for that. And so when drugs are coming on the market, their women are having all these side effects that they didn’t see in the animal studies, but that’s because they didn’t test them at these different times of their cycles. And one of the interesting aspects that kind of came out of this study was the implications for animal welfare. So that wasn’t something I was expecting to see, but by not testing female animals, they end up sacrificing a lot of them and having what they would call animal waste. So, even from an animal welfare standpoint, I mean, I’m not even getting into the should they be testing on animals conversation, but I’m just saying that by not including female animals, there’s a lot of female animals then that are discarded because they’re not even needed because they’re not looking at them. So, that was also an interesting piece that came out in the study.

So, I mean to wrap it up, I hope that this episode has been enlightening for you just to really explore this topic a little bit more, go a little bit deeper into it and think about the implications. There’s certainly implications in the interesting world that we live in with all the different pharmaceutical drugs coming out that are not being actually tested. And even when they’re being tested on women, it’s kind of like in name only. Like they’re kind of pretending to test on women, but they’re not really testing with female physiology, female hormones. They’re just kind of finding a way to fit female biological creatures into these studies without really exploring any of the variables that make them female in terms of the hormonal interplay. So that’s huge and that’s really helpful to know on a practical standpoint, from a practical level, it is helpful to know then that even when we’re looking at if you’ve been put on a certain medication or things like that, they may not have data. You may actually experience side effects that aren’t even listed because it wasn’t even tested and studied. So that’s terrifying. That’s a whole other level and a whole other layer that we would have to be thinking about. But I think it is knowledge is power. So it’s helpful to be aware of those things. But you know in addition to that even studies that are looking at women. So while I love research obviously I’ve been doing this research series for years now. I use a ridiculous number of citations in my books. I love to review research and actually provide evidence-based information. And that’s one of the draws for many of our fam practitioners in our programs. They love the depth of research that we go into and all the studies that we provide to back up all of our different recommendations. But with that said, we have to have a discerning eye. We have to be able to look at research not as gospel but as what it is. We have to understand that there are researchers bias and we need to be able to look at the study designs to critically think about how they have been what the researchers how they designed it why they did it this way and what the potential limitations are for designing studies a certain way. Now as someone who is not actively a researcher designing studies I do have some empathy for these researchers because obviously this is a more complicated design. It involves certainly a lot more. Like I said, if you’re designing a study this way, the participants would likely have to come in more frequently. It would likely be more expensive. You’d likely have to have a larger cohort of women. And from a practical standpoint, it might not always work. But I don’t need perfection. And I don’t think any of us need perfection. I feel like we need progress. And so the more that we can, interestingly, this particular study, the researchers are calling for change. So I think that is also really exciting. I think that this topic is going to be in the forefront a lot more and just to give a nod to Dr. Sarah Hill for bringing this even more to the forefront. I know she’s going to be out there really inspiring other researchers to look at this. I do think that it’s going to shift. I don’t think it’s going to be overnight, but I think the more that we can talk about it, learn about it, understand female physiology, and of course, understanding how the cycle works so that we can actually start to test it accurately, I think really and truly will only benefit from that level of research. So, with that said, if you wanted to take a peek at the studies that I mentioned in today’s episode, you’ll find it over at fertilityfriday.com/596. If this episode, if you can think of somebody who would really benefit from hearing it, if you have a friend or a colleague or a client who comes to mind, then I would highly encourage you to share. Again, fertilityfriday.com/596. And if you have been enjoying the episode, if you’ve been listening to the podcast for a while, but you haven’t had a chance to leave a review, I would highly encourage you to head over to Apple Podcast and leave a review and rating. I tried my best to read all of them, and I really appreciate all of you who have left a review. We have over 700 reviews at this point, which is just incredible. So, thank you to all of you who have done that. With that said, I’d like to wrap up here. I hope you have a wonderful week, weekend, whenever you tune in to the show. And of course, as always, until next time, be well and happy charting.