By Deborah Borfitz

July 30, 2019 | A new theory is uniting full lines of evidence from anthropology, immunology, and evolution to explain sex differences in the risk for autoimmune diseases and certain cancers. An interdisciplinary team of scientists at Arizona State University (ASU) have coined it the Pregnancy Compensation Hypothesis and describe the phenomenon in the July 1 issue of Trends in Genetics.

In a nutshell, the hypothesis holds that evolution shaped the maternal body to compensate in multiple ways for the unique pregnancy environment—to at the same time tolerate a genetically distinct individual and placenta, while also surviving exposure to an assortment of parasites and pathogens, says Melissa Wilson, assistant professor with ASU's School of Life Sciences and senior author of the paper. Life in urban industrialized society, marked by fewer pregnancies over a women's reproductive career and fewer foreign organisms to fend off, is a "mismatch" to those ancestral mammalian adaptations.

That could explain why autoimmune diseases such as multiple sclerosis, lupus and rheumatoid arthritis are eight times more common in women than men, Wilson proposes. It could also be the reason women are less likely to get non-reproductive cancers, including melanoma, colon, kidney and lung cancer. Thyroid cancer is the sole exception and has been increasing in prevalence among women over time and across populations, she adds, and it is probably no coincidence that the thyroid helps to prime the immune system during pregnancy.

"It's not that evolution is happening faster or slower, it's that it did a really good job on us," Wilson continues. "As a medical community, we must think about how it shaped our body's systems so we can better understand and interpret how they're responding in our current environments. I think then we'll be able to make better progress than we have in the last several decades."

The Pregnancy Compensation Hypothesis appears to be passing the street test. Wilson says she has personally received dozens of emails, phone calls, Facebook messages and tweets—almost all from women—saying the theory makes sense to them based on their personal experience and observations, even if their doctor dismissed their individual experiences as "crazy."

As of 2016, the National Institutes of Health (NIH) will no longer fund research that does not consider sex as a biological variable, Wilson points out. The Pregnancy Compensation Hypothesis is an attempt to explain known sex differences in immune function and the role of hormones.

Testable Predictions

ASU scientists are now working to build collaborations and start actively testing the Pregnancy Compensation Hypothesis, which Wilson sees as a practical framework for viewing patients and conducting clinical research. By partnering with organizations having access to large electronic medical record databases, researchers could test the prediction that women who get pregnant more often have lower rates of autoimmune disease. "We don't have that exact answer yet, but we do know that in over 75% of women with certain autoimmune diseases—specifically, rheumatoid arthritis and MS [multiple sclerosis]—symptoms go away when they’re pregnant."

The unifying theory leads to a slew of testable predictions across mammals and species that have fully formed invasive placentas, Wilson says. Researchers might think about conducting experiments in collaboration with zoos that house animals whose immune systems, like those of women, are no longer contending with a placenta throughout their reproductive life.

Being female and being pregnant may turn out to be extremely important variables when it comes to immune response, she continues, although studies in both humans and animals have up to now been conducted predominantly on men. A movement is now underway to include pregnant women in research and, effective this year, the policy of the NIH is that studies include people across the lifespan.

Based on the Pregnancy Compensation Hypothesis, sex differences in immune function prior to puberty should be largely genetically based, Wilson says. But during the reproductive years there should be a "really big shift" in immune response between typical males and typical females that recedes again at menopause.

Although Wilson and her ASU colleagues focused on autoimmune diseases and cancer in their Trends in Genetics paper, she says, heart disease certainly follows that pattern. Women typically don’t experience much cardiac disease prior to menopause, but their risk is on par with men by the time they hit their mid-70s. After learning that parasites can potentially metabolize cholesterols, Wilson says she got to thinking that the human immune system may be responding to fluctuations in lipid levels, which are known to be directly involved in cardiac disease.

Who knows, one day people may be treated with therapeutic parasites, Wilson continues. In fact, the hygiene hypothesis suggests a lack of exposure to pathogens as the reason for increases in all autoimmune diseases in men and women. In clinical trials, people with MS have been given parasitic worms "to give their bodies something to respond to," with mixed results.

Getting an immune system boost from pathogens and parasites might depend on exposure during development so the body has an opportunity to develop a response to them, Wilson adds. Pregnancy and the placenta may be similarly "priming" the immune system, and perhaps whatever it's fending off can in the future be given to people early in their life to prevent disease onset.

"I'm optimistic the field is going to move rather quickly," Wilson says. "I think we'll be able to say not only why there are sex differences but when they start to occur"—and intervene before then.

Next Steps

One target for collaboration is the UK Biobank, which has genetic information as well as health records, says Wilson. Healthcare in the US is largely privatized, so there's no comparable data pool to mine for associations between genetics and autoimmune disease.

ASU researchers have instead been working with the Tsimané, a Bolivian natural fertility population whose women give birth to an average of eight or nine children and are also exposed to parasites and pathogens, Wilson says. "We're looking at gene expression across men and women in that population… [and] differences in their immune system."

One of Wilson's goals is to start a collaboration looking at expression in the immune system of an industrialized population, to see if observed sex differences are the same as in the subsistence Tsimané population. Her suspicion is that evolution of the human immune system, as expressed in the genes, will look different in the two groups.

Additionally, ASU researchers are looking at sex differences between 30 collected placentas that largely represent the genotype of the offspring rather than the mom, Wilson continues. Based on earlier studies by Katie Hinde (now an associate professor of evolutionary biology and senior sustainability scientist at ASU) looking at the composition of milk in lactating rhesus monkeys, large differences might be seen based on the offspring's sex. In other words, the sex of the offspring may be directly shaping the maternal immune system.

The immune system of both sexes is regulated by hormones impacted by the relatively sedentary lifestyle of all industrialized populations, says Wilson. Less activity along with greater access to calories can both lead to higher levels of reproductive hormones that may exacerbate immune response. But that’s a study for another day, she adds, so researchers can't yet say if going to the gym more regularly could help stave off hormone-associated diseases such as diabetes and rheumatoid arthritis.

"Going forward, we need to systematically collect environmental variables like pathogenic exposure, levels of stress and reproductive hormones, and parity," says Wilson. In the absence of universal healthcare coverage in the US, the information will be difficult to collect and likely require the involvement of private health companies, she adds. Systematic discrimination, socioeconomic disparities, and lack of data-sharing with consumers will all need addressing.

On the bright side, several health startups have emerged that are taking health measurements and immediately sharing back the results so people can make more informed health decisions. "That's where I'd like to see us going," says Wilson. "I don't want to be a researcher who is just taking and not giving back. We don't have a right to other people's data. I'm not owed that by anyone."

ASU could be collaborating with a company interested in healthcare inequities within the year, says Wilson. That could help researchers with the inherently difficult work of teasing apart the role of stress, exercise, and diet on disease risk.