If you have side effects from medications, did you ever think about the possible reasons for those side effects? Did you ever consider that how your response to treatment might be determined by your biological sex — as male or female?
Young, healthy adult males are the most convenient group for clinical testing. Traditionally, the menstrual cycle was often viewed as a potential confounding factor and researchers chose to ignore rather than to embrace it. Within the last 30–40 years, government regulations have mandated that pharmaceutical drugs or new therapies must be tested in both males and females. And in National Institutes of Health-funded research, scientists have to justify not including both males and females in studies. Embracing these differences is part of the goal of precision medicine — an individualized way to treat patients based on sex, genes, environment and lifestyle.
I’ll use the term sex differences to define differences between biological males (with an XY chromosome) and biological females (with an XX chromosome). Circulating levels of sex hormones, such as estrogen and testosterone, which are produced by reproductive organs, are another determinant of sex differences.
My first foray into this research was, like most scientific discoveries, an accident. My graduate work focused on the role of brain inflammation in Alzheimer’s disease. I wanted to understand how a common risk factor for Alzheimer’s disease, the E4 allele of the apolipoprotein E gene, predisposed certain individuals to develop Alzheimer’s disease but not others. I obtained a baffling and equivocal set of results and thought my graduate career was over.
I realized that I had combined males and females into a single experimental group rather than stratifying them. At the time, it was known that more women than men were diagnosed with Alzheimer’s disease. Researchers thought the reasons could be women’s longer life expectancy or more frequent health checkups. I thought that my experiments might provide clues to explain the reasons for the difference.
I carefully redesigned the experiment with sex differences in mind. The next set of results revealed an exciting result, namely that the apolipoprotein E4 allele significantly increased the level of inflammation in males with a negligible effect on inflammation in females. In fact, the levels of inflammation were higher in most females even in the absence of the E4 allele. These findings have since been confirmed by many other research groups in smaller studies, and more recently in a very large study of many individuals with Alzheimer’s disease across the United States.
A recent clinical study that I’ve led at West Virginia University in conjunction with the Department of Emergency Medicine explores sex differences further. The goal of our study was to identify blood-based biomarkers to predict sepsis outcome and potentially, neurological outcomes in sepsis patients admitted to Ruby Memorial Hospital’s Emergency Department.
With financial support from the West Virginia Clinical and Translational Science Institute, we found that a potential biomarker was much higher in the sepsis patient population compared to a control group of patients who were also ill but did not have a sepsis diagnosis. When we stratified our results by sex, we found that our potential biomarker was only elevated in male sepsis patients compared to male controls, with negligible differences between female sepsis patients and female controls. These results suggest that a precision medicine approach which incorporates sex differences can be applied to sepsis patients in the Emergency Department. We hope to expand this finding to more include more sepsis patients at Ruby and to include other hospitals across the state.
Candice Brown is an assistant professor at the Rockefeller Neuroscience Institute researching interactions between the brain and the immune system in neurological disorders. She holds a PhD in genetics and genomics from Duke University.