by Nathan Huey
figures by Daniel Utter
Sex is one of the most obvious candidates for a first step towards individualized healthcare. It is both unambiguous in the majority of cases as well as a significant factor in the development and progression of a host of diseases. Today, many medical professionals feel that first honing in on sex-specific treatment options is the most productive way to move forward with the larger effort of implementing precision medicine.
In the past, however, ignoring sex differences has resulted in widespread healthcare inequality, biased studies, and dangerous conclusions.
Fortunately, that isn’t the end of the story. Improvements made in the state of sex-specific research over the last few decades allow us to look optimistically towards a future with treatments better attuned to our biology.
In this article, it will hopefully become clear why incorporating sex-specific knowledge represents an important first step towards personalizing therapy. To this end, we’ll first examine several of the specific mechanisms by which sex can influence disease in the context of a case study.
A closer look at lung disease
Chronic obstructive pulmonary disorder (COPD) is a lung disease that makes breathing much more difficult and affects hundreds of millions of people each year globally. It provides an illustrative example of some of the different ways that sex can influence human illness (Figure 1).
Body size, hormones, and genetics
To begin with, females tend to be smaller than males, and this includes the female respiratory system. That means that per-cigarette, female airways receive more exposure to smoke. This likely sensitizes them to its harmful effects when compared with males who smoke just as often. Smoking is the primary risk factor for COPD and, as such, any differences that modify the effect of cigarette smoke on the body are relevant to COPD.
Another mediator of the effect of cigarette smoke may the sex-specific hormones estrogen and progesterone. Both are generally found in higher concentrations for females compared to males. It has been hypothesized that estrogens lead to the accumulation of toxic byproducts when cigarette smoke is metabolized. In addition, progesterone could contribute to the inflammatory response in airways, leading to more serious and sustained damage for females. It may also partly explain why this kind of damage is observed more frequently in female cases of COPD in contrast to male cases, for which damage of the air sacs is more common.
Finally, genetics also play a significant role in the development of COPD. Multiple genes have been associated with COPD. Mutations in these genes can predispose individuals to early onset COPD and may even make them more sensitive to the effects of smoking with respect to developing lung disease. A recent study has implied that the set of genes associated with COPD risk for males may actually be different than the COPD risk gene set in females. In other words, the genetic/biochemical foundation of the disease itself may be different for males and females. In the future, this might imply that different genetic tests for females and males would be more useful to assess the likelihood of developing COPD than a single standard test.
These three factors represent only a fraction of the ways that sex can influence disease. One important takeaway is that if sickness is different depending on sex, treatment should also be sex-specific. Despite its importance, it wasn’t until relatively recent times that sex was acknowledged as a salient feature of human illness.
Sexual disparities in clinical studies
Historically, the default model for medical research has been male. The Physician’s Health Study, for example, was initiated in 1982 to examine the effect of aspirin on cardiovascular disease. The study was very large, enrolling over 22,000 participants. Not a single one of them was female. In the ‘70s, the FDA even banned women in childbearing age from being enrolled in phase I clinical trials. This ban was lifted 20 years later, in 1993.
For many years, it was simply assumed that women would react to drugs and exposures (like cigarette smoke) in a reasonably similar way as men do. Their inclusion in clinical studies would thereby only introduce unnecessary complications from the female hormonal cycle. Although this made studies with men in this sense simpler, it unfortunately caused them to be ungeneralizable to the population at large.
Why is this an issue?
Imagine the FDA just approved a new drug based solely on studies done in mice. Although mice share ~90% of our genes, many people may still be uncomfortable taking the drug themselves without human data. Without knowing the effects on similar organisms, there still remains some uncertainty in the outcome. Differences in the underlying biology of people or organisms could lead to unexpected and potentially unwanted reactions.
While the physiological differences between men and women are obviously less significant than those between humans and mice, many females face a conceptually similar dilemma today.
For example, if the standard dose of a drug is calculated for a male with average body size and metabolism, giving females that same dose might lead to a higher rate of accidental overdose. This could be caused by differences in body size as well as in how male and female bodies process the drug. In particular, females have higher body fat content, meaning that fat-soluble drugs tend to be metabolized more slowly. Sex differences also exist in how the liver and kidneys function to break down and remove drugs from the body.
Cardiovascular disease is another classical example of the danger of ignoring sex-differences in research and diagnosis. Men and women not only exhibit a different prevalence of heart disease, but also different symptoms, comorbidities, and response to treatment. For example, women are more likely to report pain associated with heart attack somewhere other than the chest than men. Medical professionals in the past have focused research efforts on cardiovascular disease exclusively in men (as in the Physicians’ Health Study), disregarding the distinct features of the disease in women. As a result, many women have been misdiagnosed or have received inappropriate treatment over the years.
Sex differences for the benefit of (wo)mankind
Health inequities like these are exactly what the Office of Research on Women’s Health (ORWH) at the National Institutes of Health (NIH) was established to mitigate. Since the creation of this office in 1993, the inclusion of female study subjects in all studies is mandatory for NIH-approved research unless a convincing argument for their exclusion can be made.
In 1998, the FDA enacted the Investigational New Drug Applications and New Drug Applications rule, which allows them to reject filing new drug applications if sex differences aren’t adequately considered in the determination of potential risks and efficacy leading up to clinical trials.
Today, the importance of accounting for the variability between male and female biology in research is widely recognized. There exists a clear contribution of biological sex to health outcomes across a wide spectrum of conditions.
Discovering how sex makes a difference is key to developing useful sex-based therapies (Figure 2). This knowledge could help focus efforts on the most important features of an illness, which may display meaningful differences across the biological sexes. In this way, the actual causes of disease can be more effectively targeted on an individual level.
Nathan Huey is a 2nd year PhD student in the Biostatistics Department at Harvard. He studies new statistical methodologies for identifying sex-specific genetic risk factors of COPD.
Dan Utter is a 4th year PhD student in Organismic and Evolutionary Biology at Harvard.
For more information:
- For a wealth of resources related to the science and policy of sex-differences visit the website of the NIH’s Office of Research on Women’s Health.
- To read an excellent nuanced discussion of the important distinction between the concepts of “sex” and “gender” and their effects on health, check out this article by Krista Conger from Stanford Medicine.
- For more information about the different factors that contribute to COPD and to learn more about how genetic risk factors are identified, visit this webpage.
- For a great conversation about the topics of “sex” and “gender” in modern society, listen to this episode of Sam Harris’ “Waking Up Podcast”.