When thinking of women’s health, it can be easy to go straight to menstruation, pregnancy, and menopause. Researchers are just starting to grasp how big a part sex-specific differences play in our bodies.
Sex-specific differences have started to get more attention over the past decade or so. What changed?
Shannon Dunn. We’ve known about how sex influences health for a while now. This was driven by the research of several pioneers in the field who were using both sexes of animals or humans in research for decades and organisations such as the society for Women’s Health Research. For example, in my field, two scientists Dr. Rhonda Voskuhl (UCLA), and Dr. Halina Offner (University of Oregon) performed seminal work in the 1990s and 2000s that described how females mounted stronger autoimmune responses in the lab animal model of multiple sclerosis and defined how sex steroids including testosterone, estradiol and sex chromosomes (XX vs XY) controll these sex differences. But for the most part, until recently, it was common to focus on only studying one sex both in lab and human studies.
Over the past decade, however, things have begun to change, partly thanks to these and other pioneers getting together and pushing for new policies. Research bodiesnow ask researchers to carry out their studies in both males and females. For example, in 2009, the government of Canada implimented a Sex- and Gender-Based Analysis Plus policy (SGBA Plus; the plus includes the intersection of gender with other cultural variables) to guide research. For biological sciences, it meant that researchers were now expected to conduct research in both males and females. In 2016, the US National Institutes of Health followed suit and published the ‘Sex as a Biological Variable’ policy in 20161.
These policies aren’t infallible. A recent review of grant abstracts that were funded by the government of Canada revealed that only a small percentage (<2%) of grant descriptions mentioned sex or female-specific health research2. Still, these policies mean that reviewers are being asked to consider this when deciding who gets funded. I think the wave is going in the right direction. Interesting research is starting to emerge from this push. As more researchers pay attention to sex differences, more often than not, they are noticing sex differences in their results.
What do we know about how sex differences can influence health?
There are many ways in which sex differences can influence health. I’ll focus on the immune response, which is what I study. Females tend to have a more robust immune response than males. Depending on the context, this can be a good or a bad thing. Women, for instance, are disproportionately more likely to have autoimmune disorders — estimates suggest 78% of people with autoimmune disease in the US are women3. Women may also be more likely to reject organ transplants and to be more prone to asthma after puberty than males4.
On the other end of the spectrum, this proclivity towards inflammation can be protective, for instance in the context of cancer. Studies suggest that men are almost two-fold more likely to die from malignant cancers than women. Female immune cells may also be more resistant to exhaustion56. A series of high-profile papers over the past few years found that female immune cells tended to stay active longer than male cells in the face of cancer. Interestingly, one team of researchers were able to shift the sex difference by modulating the levels of androgens. That was a really cool finding that has a high potential to change how women and men with cancer are treated.
Females also seem to be better at warding off infections than males and often develop better T cell and antibody responses to vaccination7. Male bias, for its part, seems to encourage the activity of regulatory T cells, which can ward off autoimmunity. Males may also be more prone to develop another pro-inflammatory response called T helper 17 which may play a role in the development of hypertension by acting on the kidneys and the spleen.
Can you give us an example of a mechanism driving these sex differences?
There are subtleties in the immune system that make it more active in females and less active in males. One example, which has been attracting a lot of recent attention, is the differential expression of genes off the X chromosome in male and females. For example, toll-like receptor 7 (TLR7), a molecule carried by immune cells that senses viruses is more highly expressed in certain female immune cells. That may be in part because most women carry two copies of this X‑encoded gene which is incompletely silenced: in most female immune cells, the second copy of X encoded genes are silenced. TLR‑7 seems to be an exception.
Jean Charles Guery, for instance, showed that female plasmacytoid dendritic cells produce more type‑I interferon than male cells. This is in part due to females having higher levels of expression of this TLR‑7. And if I was going to pick one cytokine to fight off viruses, I would say type‑I interferons. So this finding provides an explanation for how females’ innate immune systems react more strongly against viruses. There’s also evidence that estradiol, a hormone that is higher in females than in males, can turn on this same pathway, highlighting the complexity of this regulation.
Conversely, androgens like testosterone, in general, suppress immune response by binding the androgen receptor on a variety of immune cells, including macrophages, neutrophils, B cells, and some T cells8.
Those sex biases can also act on neurodegeneration, is that right?
Yes, that’s right. Two-thirds of Americans with Alzheimer’s are women. At age 45, women’s lifetime risk of Alzheimer’s disease dementia is about twice as high as men’s. That’s partly because they live longer, but sex differences also could play a role here9.
For instance, Marina Lynch and colleagues found clear sex differences in microglia, the cells found in the brain that are thought to help control the development of amyloid plaques. We still don’t quite understand the mechanisms leading to Alzheimer’s. But one very clear-cut thing that’s emerging from recent research is that female microglia seemingly don’t do as well in fighting off the formation of the amyloid plaques.
What’s next for this field of research?
When we talk about sex differences, we mean how health is influenced by sex chromosomes—the most common combination being XX or XY—and any downstream cascading events, like the formation of the gonads and different levels of sex steroids.
The big next step will be getting a better grasp of gender-based differences. Some human studies have at least started recording gender identity, which is certainly a step forward. We’re also starting to see studies looking at the influence of hormone therapy, given as part of gender-affirming care for trans people, on the immune system and other organs. But to fully understand the influence of gender on health, we need a more well-rounded appreciation of what gender means, which means placing it within a wider context of culture, religion, ethnicity, and more. Also, identifying factors that are following thousands of participants can really help to better understand gender based analysis.
For example, being a woman can mean different things when taken in the context of other cultural, religion, and societal differences. For example, a woman who is single, has high income, but a moderate stress job, can afford high quality healthy food, and does yoga daily, may have a very different health outcome than a women who is under stress trying to put food on the table and carrying for six children and elderly parents. Similarly, a man’s cultural background may mean he has more pressure than others to not only support his own family but to send money home to his extended family, which could mean more stress and exposure to work-related factors. That’s where large population health studies that are startng to try to measure these
Another big challenge for the field will be understanding how sex influences response to treatment. I think most people studying the sex differences are starting to appreciate that a female body is different from a male body — but it hasn’t quite trickled down to clinical care and for the most part, everyone receives the same medication.Women have also historically been underrepresented in clinical trials, notably following the 1977 recommendation from the US Food and Drug Administration that women of childbearing age be excluded. Clinical trials have to be better geared to measure the outcomes of the effects of medications and treatments on men and women.
