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Best of The Neuroethics Blog: Dare to be Different: Defense of the Research of Sex Differences

Throughout the year, The Neuroethics Blog will be highlighting the most impactful, exciting, and popular posts from our nearly ten-year history.

Today's post is an update by Dr. Katy Renfro on her piece entitled Dare to be Different: Defense of the Research of Sex Differences, which was originally published on March 19, 2013 and is republished below.

Image courtesy of Pxhere
A great deal has evolved in the science and conversation of sex differences since my initial post over six years ago. The advancements in the study and discussion of sex, together with the gifts conferred by time, graduate training, and feedback from considerate mentors and colleagues, have also contributed to changes in my perspective on this field and on my original Neuroethics piece. 

Arguably the most notable of relatively recent events in the sex differences research and reporting domain is the 2016 implementation of the National Institutes of Health (NIH)’s Sex as a Biological Variable (SABV) policy. The policy stipulates that funding applications for research on vertebrate animals and humans include a discussion of how sex has been considered in study design and data analysis. In the case where a study is designed to include only one sex (i.e., exclusively study males or females), researchers are asked to provide sound justification for this design decision (National Institutes of Health, 2015). 

One of the primary NIH-stated goals of SABV is to correct the longstanding issue of exclusion of female animals from preclinical research. This aim references data such as those showing that a year’s worth of neuroscience studies published in top-tier journals were over four times as likely to have exclusively included male animals than female (Shansky & Woolley, 2016). The public health implications of female exclusion from preclinical trials became increasingly apparent over time as reports of adverse effects of pharmaceuticals in women (as compared to men) became more frequent (e.g., Government Accountability Office, 2001; U.S. Food and Drug Administration [FDA], 2018; FDA, 2019). Together, these data and the SABV adoption highlight one of the main points I attempted to make in my previous piece: we (still) cannot ignore sex, because when we do, there are negative public health consequences. And the sector of the public that disproportionately suffers is women. In not considering sex in research, what results is not equal consideration of the sexes, but rather a lack of consideration of females / women (e.g., Beery & Zucker, 2011). 

Many in the research community have supported SABV and similar policies adopted in Canada (Canadian Institutes of Health Research, 2017) and Europe (European Commission, 2018) as steps forward for scientific transparency and public health, but the response has been far from uniform (Prager et al., 2019; Shansky, 2019; McCarthy, Woolley, & Arnold, 2017; Rippon et al., 2014; Eliot & Richardson, 2016). Some scientists voiced concerns that policies such as these would unduly burden researchers by implicitly requiring them to increase their sample sizes to accommodate testing for sex effects (as discussed in Clayton, 2015 and Eliot & Richardson, 2016). Others worried SABV would lead to discovery of many false or trivial sex “differences,” and in doing so, would muddy and misguide the scientific literature. And a subset of scholars was wary that SABV-associated issues would reify the oft media-promoted conception that males and females are categorically different (Rippon et al., 2014; Maney, 2016). The latter concern is one that particularly resonates with me. 

Image courtesy of Pixabay
In my initial piece, I wrote in a way that endorsed the idea that a sex difference indicates a categorical difference, rather than a mean difference with a notable and important degree of overlap between males and females. The overlap -- the similarity between the sexes -- rarely receives equal media coverage as do the differences, but it warrants similar consideration and discussion (e.g., as discussed in Maney, 2016). And in interpreting a sex similarity or difference, we must not undervalue the role of context in the development and expression of that finding, which was a point I deemphasized in my original piece. Recognizing the nuance of sex in these ways is important not only for precise science, but also -- at a broader level -- for a more complete public understanding of others and for not erasing those who do not fit into “male” and “female” categories, such as the many intersex individuals born each year. 

In response to SABV policy concerns, the NIH has clarified that the goal of SABV is not to promote searching for sex differences. They note that sex effects might be explicitly tested for where there is scientific justification (e.g., when previous work suggests the endpoint of interest is differentially expressed in males and females), but that the overarching goal is to include sex as a variable of consideration so as to ensure the inclusion of females, the future replicability of work, and the potential for controlling for sex in analyses (Clayton, 2018). 

In cases where SABV yields detection of a sex difference that might have otherwise gone unnoticed or documented, I hope the research goes beyond the reporting of a difference. It does us no good moving forward to merely catalog differences -- we need to adopt measures and communication strategies that help us determine why those differences arise. I would be remiss to not acknowledge that there are many researchers -- biologists, psychologists, ethicists and more -- who are and have been working toward this end of unpacking sex differences (e.g., including but in no way limited to the researchers cited above, as well as work by Wallen, 1996, Fausto-Sterling, 2000, Hyde, 2005, Joel & McCarthy, 2017 [& for added, necessary emphasis: many, many researchers not listed here]). Ideally, their collective efforts (in addition to new efforts that result from SABV) will allow us to develop research-informed policy and medical services that mitigate sex/gender disparities in health.

References
  1. Beery, A. K., & Zucker, I. (2011). Sex bias in neuroscience and biomedical research. Neuroscience & Biobehavioral Reviews, 35(3), 565-572.
  2. Canadian Institutes of Health Research. (2017). Health portfolio sex and gender-based analysis policy. Retrieved from: https://www.canada.ca/en/health-canada/corporate/transparency/corporate-management-reporting/heath-portfolio-sex-gender-based-analysis-policy.html
  3. Clayton, J. A. (2015). Studying both sexes: a guiding principle for biomedicine. The FASEB Journal, 30(2), 519-524.
  4. Clayton, J. A. (2018). Applying the new SABV (sex as a biological variable) policy to research and clinical care. Physiology & behavior, 187, 2-5.
  5. Eliot, L., & Richardson, S. S. (2016). Sex in context: limitations of animal studies for addressing human sex/gender neurobehavioral health disparities. Journal of Neuroscience, 36(47), 11823-11830.
  6. European Commission. (2018). Participant portal H2020 online manual: Gender equality. Retrieved from: https://ec.europa.eu/research/participants/docs/h2020-funding-guide/cross-cutting-issues/gender_en.htm
  7. Fausto-Sterling, A. (2000). Sexing the body: Gender politics and the construction of sexuality. Basic Books.
  8. Government Accountability Office. (2001). Drug Safety: Most Drugs Withdrawn in Recent Years Had Greater Health Risks for Women. Retrieved from: https://www.gao.gov/new.items/d01286r.pdf
  9. Hyde, J. S. (2005). The gender similarities hypothesis. American psychologist, 60(6), 581.
  10. Joel, D., & McCarthy, M. M. (2017). Incorporating sex as a biological variable in neuropsychiatric research: where are we now and where should we be?. Neuropsychopharmacology, 42(2), 379.
  11. National Institutes of Health. (2015). NIH Policy on Sex as a Biological Variable. Retrieved from: https://orwh.od.nih.gov/sex-gender/nih-policy-sex-biological-variable
  12. Maney, D. L. (2016). Perils and pitfalls of reporting sex differences. Philosophical Transactions of the Royal Society B: Biological Sciences, 371(1688), 20150119.
  13. McCarthy, M. M., Woolley, C. S., & Arnold, A. P. (2017). Incorporating sex as a biological variable in neuroscience: what do we gain. Nat Rev Neurosci, 18(12), 707-708.
  14. Prager, E. M., Chambers, K. E., Plotkin, J. L., McArthur, D. L., Bandrowski, A. E., Bansal, N., ... & Graf, C. (2019). Improving transparency and scientific rigor in academic publishing. Journal of neuroscience research, 97(4), 377-390.
  15. Rippon, G., Jordan-Young, R., Kaiser, A., & Fine, C. (2014). Recommendations for sex/gender neuroimaging research: key principles and implications for research design, analysis, and interpretation. Frontiers in human neuroscience, 8, 650.
  16. Shansky, R. M., & Woolley, C. S. (2016). Considering sex as a biological variable will be valuable for neuroscience research. Journal of Neuroscience, 36(47), 11817-11822.
  17. Shansky, R. M. (2019). Are hormones a “female problem” for animal research?. Science, 364(6443), 825-826.
  18. U.S. Food and Drug Administration. (2018). Questions and Answers: Risk of next-morning impairment after use of insomnia drugs; FDA requires lower recommended doses for certain drugs containing zolpidem (Ambien, Ambien CR, Edluar, and Zolpimist). Retrieved from: https://www.fda.gov/drugs/drug-safety-and-availability/questions-and-answers-risk-next-morning-impairment-after-use-insomnia-drugs-fda-requires-lower#q10
  19. U.S. Food and Drug Administration. (2019). Understanding sex differences at FDA. Retrieved from: https://www.fda.gov/science-research/womens-health-research/understanding-sex-differences-fda
  20. Wallen, K. (1996). Nature needs nurture: the interaction of hormonal and social influences on the development of behavioral sex differences in rhesus monkeys. Hormones and Behavior, 30(4), 364-378.
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Dare to be Different: Defense of the Research of Sex Differences

In a recent article published in the journal Neuroethics, Dr. Rebecca Jordan-Young and Dr. Raffaella Rumiati argue that current research on sex differences is “both unscientific and far from politically neutral,” and should be abandoned.6 This article reflects many of the current conversations on the ethical implications of researching sex differences, which have largely focused on how results of these studies can be misappropriated to support sexist agendas. I cannot argue against the legitimacy of these concerns, and as researchers, we must always be careful to present our findings in a balanced and accurate manner so as to better combat misinterpretations and misrepresentations of data. However, we must also keep in mind that just as science has the potential to influence social and political conversations, this is a bidirectional relationship, and politics also have the power to misinform science.

In their paper, Jordan-Young and Rumiati argue that current research on
sex differences is "both unscientific and far from politically neutral."6
In their article, Dr. Jordan-Young and Dr. Rumiati offer two alternatives to sex difference research; the avenue they appear to more actively promote is to ignore sex differences altogether, in favor of researching differences between groups of people, such as socioeconomic or occupational classes. I believe this suggestion is an example of political motivations influencing science. Due to past and current sex/gender inequalities, there continues to be a strong push for leveling the sex/gender playing field. Although I am (of course) a strong supporter of equality between the sexes, I think it is misguided to push for the abandonment of a fruitful field of research because of the possible political implications of its results; indeed, I find the suggestion that we should halt inquiry in this area both unethical and unscientific.

Below, I provide rationale for why abandoning the study of sex differences would have ramifications for basic science research, and I then offer ways in which we as scientists can better address the potential political implications of the results of our studies.

Brain, body, and behavior

In Dr. Jordan-Young and Dr. Rumiati’s article, the researchers distinguish the body from the brain, asserting that although there are clear phenotypic differences between men and women that are due to hormonal effects, these differences are not representative of neural or behavioral differences. They support this claim by setting up a thought experiment: if a group of men and women were given images of male and female genitalia and were asked to categorize the images by sex, they would easily be able to do so; however, the same would not hold true for the brain—there are no gross, morphological indicators of the prototypical “male” and “female” human brain.

In response, I will propose another thought experiment. If one were to gather a group of men and women, and provide them with photographs of men and women’s gastrointestinal (GI) tissues (i.e. their stomachs), would they be able to categorize them by sex? I am fairly sure the group would perform this task at no better than chance. However, if one were to use modern scientific techniques to assess the pH and enzymatic profiles of these stomachs, and examine these profiles with help from the literature, it would become immediately apparent which belonged to the men and which belonged to the women, as men and women differ in acidity of gastric secretions and in activity of a number of gastric genes.8,5 In fact, if one were to assess activity of even just one enzyme: alcohol dehydrogenase, he/she would most likely be able to differentiate the GI tissues by sex, as this enzyme is much more active in men than women. If we take this a step further, and look for an alternate macro reflection of this difference that is not evident in the organ’s physical appearance, we could ask whether differences in this gene are related to behavioral sex differences, and the answer would be yes. When men and women drink comparable amounts of alcohol, men (due to greater enzymatic activity) have significantly lower blood alcohol content (BAC), and thus can drink markedly greater amounts before experiencing the adverse side effects of high alcohol consumption.4, 7, 2, 3

A different thought experiment: would it be possible
to categorize men and women's gastrointestinal 
tissues by sex?
Image courtesy of Dreamstime
Because researchers looked deeper than the organ’s physical appearance and revealed these sex differences, they then had clearer directions to follow when looking for the mechanisms underlying these differences, as a sex difference indicated that prenatal and/or circulating hormones could be at play. Indeed, it has been found that altering hormone levels affects expression of alcohol dehydrogenase (e.g. [1]). There are, of course, also environmental and other biological factors that modulate these sex differences in enzymatic activity and alcohol consumption (e.g. overall body size, regularity of alcohol consumption); however, recognizing that there is a sex difference allows for more careful investigation into underlying mechanisms, as one can use this information to generate hypotheses and design experiments that specifically examine the role of hormones. To ignore the sex difference would be to ignore an integral piece of the scientific picture.

Our internal organs cannot be completely divorced from our phenotypes; our body cannot be completely divorced from our brain, and both the brain and the body affect and are affected by our behavior. Just as recognition of sex differences provided a window into the mechanisms underlying alcohol consumption and alcohol-related disease prevalence, so it can provide us with clear avenues through which to explore the neural mechanisms of behavior. For example, there are reported sex differences in the prevalence of nearly every major mental illness4; ethically and scientifically, we cannot afford to deny these differences if we seek to better understand the basic biological mechanisms of illnesses such as depression, substance use disorders, and generalized anxiety disorder. Indeed, only after we understand the biological mechanisms of a disease can we better develop novel and effective treatments for it.

Conclusion and future directions

Knowledge always carries with it the potential for misuse; this is true for all scientific advancements, whether they be technological, chemical, or biological in nature. In using the example of these discoveries with the stomach, one could imagine that these results could be used to support differential regulations on alcohol consumption between the sexes, or to portray woman as “too pure” to consume alcohol “like a man.” However, it is these threats to equality that we should specifically work to eliminate—not the science of sex differences. The discovery of “difference” does not have to mean the discovery of ammunition to fuel societal inequalities. Indeed, difference itself carries with it no moral value or attribution of goodness/badness; it is culture that assigns value to these differences. Some of the strongest resources we have to combat misrepresentations of data are social media sources. As researchers, we should take on the responsibility of writing accurate and politically neutral pieces on our research so the public is presented with a clear picture of what we did in the experiment, what was found, and what it means. Through social media avenues, such as youtube videos, blogposts, or twitter links, we can promote these pieces and reach larger audiences. It should also be our responsibility to monitor the way our results are interpreted by outside sources and to counter misrepresentations—this is a responsibility that some researchers have already taken on (for example, see Dr. Lisa Diamond’s defense of her research on sexual fluidity against the National Association for Research and Therapy of Homosexuality’s misuse). In an increasingly “flattened” world, knowledge spreads within minutes; our job as scientists should not be to stop learning or to stop the dissemination of knowledge, but rather to make sure that we are among those disseminating it, so that it can be done so in a responsible manner.

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Katy Renfro completed her PhD in Psychology with a focus in Behavioral Neuroendocrinology at Emory University. In her dissertation work in Dr. Kim Wallen’s lab, Katy tested the relationship between oral contraceptive use and women’s neural and behavioral responses to natural rewards, such as food and sex. As a graduate student, Katy also worked in Dr. Greg Berns’ lab, where she studied sex similarities and differences in neural and behavioral response to cooperative economic games. Katy spent her time outside of the laboratory at Emory teaching, working as a learning specialist in the Office of Undergraduate Education, volunteering with science outreach organizations, and serving as a student representative to the International Academy of Sex Research.

References
  1. Aasmoe, L, & Aarbakke, J. (1999). Sex-dependent induction of alcohol dehydrogenase activity in rats. Biochemical Pharmacology, 57(9), 1067-1072.
  2. Baraona, E, Abittan, C S, Dohmen, K, et al. (2001). Gender differences in pharmacokinetics of alcohol. Alcoholism: Clinical and Experimental Research, 25(4), 502-507.
  3. Ceylan-Isik, A.F., McBride, S.M., & Ren, J. (2010). Sex differences in alcoholism: who is at a greater risk for development of alcoholic complication? Life Sciences, 87, 133-138.
  4. Eaton, N. R., Keyes, K. M., Krueger, R. F., et al. (2012). An invariant dimensional liability model of gender differences in mental disorder prevalence: Evidence from a national sample. Journal of abnormal psychology, 121(1), 282-288.
  5. Frezza, M, di Padova, C, Pozzato, G, et al. (1990). High blood alcohol levels in women. the role of decreased gastric alcohol dehydrogenase activity and first-pass metabolism. The New England Journal of Medicine, 322(2), 95-99.
  6. Gandhi, M., Aweeka, F., Greenblatt, R.M., Blaschke, T.F. (2004). Sex differences in pharmacokinetics and pharmacodynamics. Annual Review of Pharmacology and Toxicology, 44, 499-523.
  7. Jordan-Young, R. & Rumiati, R.I. (2012). Hardwired for sexism? Approaches to sex/gender in neuroscience. Neuroethics, 5(3), 305-315.
  8. National Institute on Alcohol Abuse and Alcoholism (1997). Factors influencing alcohol absorption and metabolism. Retrieved from: http://pubs.niaaa.nih.gov/publications/aa35.htm
  9. Whitley, H., & Lindsey, W. (2009). Sex-based differences in drug activity. American Family Physician, 80(11), 1254-1258.

Want to Cite this Post?

 Renfro, K. (2019). Best of The Neuroethics Blog: Dare to be different: Defense of the research of sex differences. The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2019/09/best-of-neuroethics-blog-dare-to-be.html
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