Focus on preclinical sex differences will not address women’s and men’s health disparities

Abstract

Last spring, the US National Institutes of Health (NIH) announced a new policy calling for the use of both male and female materials-animals, tissues, cells, and cell lines-in preclinical research (1). Canada and the European Union have recently instituted similar policies. Advocates argue that requiring analysis of sex in preclinical research will advance scientific understanding of sex differences in human health outcomes, such as higher rates of adverse drug events (ADE) in women compared with men (2). We disagree.To be useful in addressing health disparities, sex-linked variables in preclinical materials must effectively model differences between human men and women. In the absence of evidence that this is so, the addition of sex as a variable in all preclinical studies is likely to introduce conceptual and empirical errors into research. Biomedical research institutions and funders can better remedy sex differences in health outcomes by focusing on the scientific study of the interaction of sex and gender variables in health outcomes in human populations.Sex differences in rates of ADE may be a result of biological factors, gender-related social factors, or a combination of sex-and gender-related variables. "Sex" refers to chromosomal complement, reproductive organs, or specific hormones related to sexual reproduction. "Gender" refers to sociocultural norms, expectations, and practices ascribed to males and females (3). Gendered factors, such as women's propensity to take multiple pharmaceuticals simultaneously (polypharmacy) compared with men, and their greater likelihood to see medical doctors than men, play a well-documented role in sex differences in health outcomes (4-6).Take the case of zolpidem (Ambien). In 2013, the Food and Drug Administration issued an unprecedented advisory reducing the recommended zolpidem dosage for women, following reports of higher numbers of ADE in women compared to men (7). Since then, researchers have sought the biological basis for this sex difference in reports of zolpidem-related ADE. Surprisingly, experimental studies of sex differences in the pharmacokinetics and pharmacodynamics of zolpidem in human men and women found that body weight, not sex, is the culprit. Women clear zolpidem from their system more slowly than men, but body weight eliminates the statistical significance of sex as a variable in clearance of zolpidem (8). Because body weight, not sex, is the independent biological variable, sex-based preclinical research protocols would likely not have predicted sex differences in rates of ADE with zolpidem.The zolpidem case provides an example of the need for studies aimed at uncovering the embodied interaction of human sex-and gender-related variables in sex differences in ADE. Weight is distributed differentially across male and female bodies. In presentday American populations, weight may interact with gender-related variables. For example, higher rates of zolpidem use and polypharmacy in women compared to men, as well as biopsychosocial factors, such as wome...

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