When it’s time for the sex talk, words matter

Abstract

In recent years, the traditional, unspoken assumption in published biomedical research studies that the young, healthy (usually white) male is the “default human” has received increasing scrutiny and criticism. The historical underrepresentation of female participants in biomedical research has been increasingly recognized and addressed, including with the current call for papers at the American Journal of Physiology-Heart and Circulatory Physiology. Our goal in the present Perspectives is to discuss the topic of terminology (man/woman vs. male/female) for human research participants when considering sex as a biological variable. This important consideration is consistent with the importance of gender identity and related topics to psychological, emotional, and physical health. Just as pronouns are important, so is appropriate terminology when referring to human research volunteers. Despite some disagreement regarding terminology between our two groups of authors, we provide consensus recommendations. Importantly, we all agree that the most vital aspect of the present discussion is the broader focus on sex as a biological variable and appropriate inclusion of biological sex in in vitro, preclinical, and human research studies.

INTRODUCTION

We are fortunate to live in an era when the historical underrepresentation of female participants in biomedical research is becoming recognized and addressed (1–3). Scientific journals, including the American Journal of Physiology-Heart and Circulatory Physiology (AJP-Heart and Circ), are progressively addressing and attempting to mitigate these disparities: case in point, this call for papers on “Sex as a Biological Variable.” In addition, AJP-Heart and Circ recently published their new policy requiring that consideration be given to the possible impact sex could have on results, interpretations, and conclusions in all articles submitted to the journal (4). In the present Perspectives article, we discuss the topic of terminology (man/woman vs. male/female) for human research participants when considering sex as a biological variable (see Fig. 1 for a schematic description). This is a relevant and important consideration in a time when gender identity and related topics are becoming increasingly recognized as essential to psychological, emotional, and physical health. Just as pronouns are important, so is appropriate terminology when referring to human research volunteers. Despite some disagreement regarding terminology among the authors, in our view, the most important aspect of the present discussion is the broader focus on sex as a biological variable, to bring attention to the fact that the young, healthy man is not the “default human.”

Figure 1.

Schematic summary of recommendations for describing sex as a biological variable (SABV). Step 1 visually depicts how to determine whether the independent variable of interest represents biological sex and/or gender. Step 2 depicts which nouns or adjectives to use when using SABV in animal, tissue, or cell models vs. human participants. In addition, recommendations are provided on which parameters to collect to adequately address SABV in human participants. Figure icons purchased through https://thenounproject.com/.

PERSPECTIVE 1

Perspective 1 (Gabrielle E.W. Giersch, Megan M. Wenner, Nisha Charkoudian): The words “man” and “woman” are the most appropriate nouns for referring to human participants in research studies.

When reporting results of human subjects’ research, the word “woman” is more specific and therefore more appropriate when referring to human participants. The use of “man” and “woman” as nouns to describe biological sex has been a frequent and common practice throughout recent decades (5–9). The word “female” can refer to the female of any species, whereas “woman” refers only to humans. This distinction is relevant, particularly when our goal in reporting results of human subjects’ research is to be as specific as possible. The use of these specific nouns still allows for the use of “male” and “female” as adjectives, particularly when describing the role of female sex hormones, estrogen and progesterone, which is appropriate and specific in that context.

In an era where gender identification is receiving increasing attention, it is both relevant and important to ensure the appropriate use of terminology. We must be clear in research methodology about both biological sex and gender identification, and the methods by which sex and gender are identified (e.g., self-reported gender identity, biological testing). In general, when reading or writing a scientific paper, the assumption is made that the word “women” refers to cis-gender women (i.e., women whose gender is consistent with their biological sex assigned at birth) and “men” refers to cis-gender men (i.e., men whose gender is consistent with their biological sex assigned at birth). This is something that should be more clearly specified in future methods, results, and discussion sections if transgender individuals are included in a participant group.

PERSPECTIVE 2

Perspective 2 (Austin T. Robinson, Joseph C. Watso, and Kanokwan Bunsawat): The words “male” and “female” (as nouns or adjectives) are most appropriate to distinguish between biological sexes in human research studies.

The terms “sex” and “gender” are often used interchangeably in human physiology studies (3). Animals are more commonly referred to as males/females and humans as men/women. The crux of our argument is that biological sex and gender identity are not synonymous. The National Institutes of Health (NIH), World Health Organization (WHO), and National Academy of Medicine define “sex” as the biological differences between females and males, including chromosomes, sex organs, and endogenous hormonal profiles (10–12). Conversely, “gender” refers to socially constructed characteristics of women and men, or girls and boys (10–12). These gender-related terms are shaped by established norms, behaviors, and roles within each historical and cultural context. Furthermore, these norms vary across societies and time. Importantly, the interactive influences of sex and gender in health and disease have been increasingly recognized and studied (3). Thus, it is critical to properly consider and acknowledge these factors in biomedical research.

Specifically, there seems to be confusion as to whether the sex or gender of human research participants should be reported and designated as males and females versus men and women. We recognize that these factors cannot be entirely separated. However, selecting the proper terminology largely depends on whether the measured outcomes are primarily affected by biological and/or psychosocial factors. There are several resources available through the NIH, Canadian Institutes of Health Research, and other organizations to help physiologists account for, and distinguish between, sex and gender in biomedical research (13). For instance, studies related to gender inequity in healthcare (14) or pay gap (15), or gender differences in health behaviors, should refer to the study participants as men and women, particularly if they were asked their gender identity. That said, differences in cardiovascular physiology (e.g., endothelial function, sympathetic neural outflow, cardiac function) are likely affected by social factors and health behaviors that can be influenced by gender norms. However, in human physiology studies, we are often parsing out the influence of sex, as opposed to gender, in health and disease (16–18). Thus, we conclude that physiology papers focused on “sex differences” should carefully refer to differences between males and females rather than “gender differences” unless the study is indeed focused on gender-related differences (19). Some investigators find using the descriptions “male human” or “female human” to be awkward, but when using male and female as adjectives, it is possible to be more specific (e.g., “female adults,” “female athletes,” “male participants,” “male patients with heart failure”).

REBUTTALS

Giersch et al. Rebuttal

The use of the term “woman” or “man” does not obviate the need for correct identification of both sex and gender in research studies. We agree that correct identification of both sex and gender (as distinct variables) is critical to appropriate identification and demographic characterization of human volunteers. For example, saying “we included 12 women” is assumed to refer to cis-gender women. Similarly, saying “we included 12 females” would also be assumed to refer to cis-gender women. Certainly, if authors were to say “we included 12 females” but three of them were transgender men, that is something that should be expanded upon in the methods and results, as transgender men (assigned female sex at birth) would potentially have different hormone profiles and other physiologically relevant differences from the other nine female participants.

It is not commonly accepted that the nouns “men” and “women” describe only gender. Both “men” and “women,” as well as “male” and “female,” are often used to describe either or both sex and gender. In a common example, these terms are often provided as the options when participants are asked to self-identify their gender. Given that the terms “male” and “female” are used in both contexts, the use of terminology specific to humans is most appropriate when reporting results of human subjects’ research.

Robinson et al. Rebuttal

The argument that identifying participants as men or women distinguishes them from animals is not a justifiable reason to identify human research participants by their gender as opposed to their biological sex. As our colleagues noted, the use of “men” and “women” as nouns to describe biological sex has been a frequent and common practice throughout recent decades (5–9). However, it is also common practice for authors in the field to use the terms “male” and “female” (20–25). We acknowledge the fact that both approaches being used in the past does not make one approach, versus the other, right or wrong per se. To avoid confusion, it may be helpful for researchers to clarify whether the study was conducted in animals or humans in the title and abstract of the paper when using “male” and “female.”

We agree that the terms “male” and “female” are sometimes (incorrectly) provided as options when participants are asked to self-identify their gender; however, that does not justify this practice or the implications of our contention. According to the definitions provided by the NIH, WHO, and others, any researchers, institutions, and companies interested in gender-related information should ask individuals whether they self-identify as “men,” “women,” or “nonbinary.” We also recognize that when identifying human participants as female or male, or as men and women, most readers may interpret this to mean the study was focused on cis-gender men or women. If a group studying “women” also included transgender women, the data would be confounded by divergent effects attributable to chromosomes, exogenous versus endogenous hormones, and other factors we still do not fully understand (26–28). However, that does not mean we should refer to participants by gender as opposed to sex, because, again, biological sex is our focus (see Fig. 1). In fact, it is paramount that we establish standardized language that considers the distinction between biological sex and gender to avoid misuse of terminology, which is particularly relevant for future publications in AJP-Heart and Circ (4). This standardized practice will improve communication and enhance potential interdisciplinary sex and gender-based research efforts within and outside our scientific discipline (3). Finally, it is worth noting that “laypeople” frequently deal with sex and gender issues (more often for trans and gender nonconforming people than for cis people) in their everyday lives. The least biomedical researchers can do is to critically reflect on the terminology for which we differentiate sex and gender.

CONCLUSIONS AND CONSENSUS RECOMMENDATIONS

Ultimately, we can agree that it is important to be specific when discussing sex differences in research; and going forward, we will need to appropriately identify research subjects based on sex and gender, as the transgender community becomes more represented in our research studies. Furthermore, the goal of our discussion is not to suggest that sex is binary (29), but rather to raise awareness and appreciation regarding the complex and diverse interactions between sex and gender on biomedical research in humans (e.g., transgender populations). These are important considerations, and if we can shed more light on them by having this conversation, we have all made a positive contribution. In consensus, we submit the following recommendations moving forward: 1) authors should use the Sex and Gender Equity in Research (SAGER) guidelines that recommend a detailed explanation in the methods section as to how the sex of human research participants was determined (e.g., self-reported, genetic/hormonal testing) (30, 31); 2) inclusion of sex as a biological variable should be considered for all research, per NIH and AJP-Heart and Circ guidance (4, 31); and 3) detailed participant demographics should be included in all methods sections to appropriately describe research participants (e.g., cis-gender, transgender, nonbinary, use of endogenous/exogenous hormones/hormonal blockers). A two-step approach to questioning has been proposed, whereby participants are asked both their sex assigned at birth and their current gender identity (19). See Table 1 and Fig. 1 for a list of suggested practices to characterize biological sex and gender identity.

Table 1.

Strategies to identify participants’ biological sex

Method/Suggested Additions
Self-reported
• Current gender identification
• Choices to include cis- and trans-
• Sex assigned at birth
• Use of exogenous hormones or hormone blockers
Genetic testing
• Karyotyping for sex determination (29)
In addition to a self-reported questionnaire (above)
Hormonal testing
• Laboratory-based measures of estrogen, progesterone, and testosterone (32)
In addition to a self-reported questionnaire (above)

The most cost-effective and noninvasive approach includes a two-step approach to determine 1) current gender identification and 2) biological sex assigned at birth. Additional ways to further characterize sex include asking about the use of exogenous hormones or hormone antagonists, karyotyping sex chromosomes, and measuring reproductive hormone concentrations.

GRANTS

This work was supported by National Heart, Lung, and Blood Institute Grants K01 HL147998 (to A.T.R.), R01 HL146558 (to M.M.W.), T32 HL139451 (to K.B.), and F32 HL154559 (to J.C.W.); Oak Ridge Institute for Science and Education Postdoctoral Fellowship; and Military Operational Medicine Research Program, U.S. Army Medical Research and Development Command (to N.C.).

DISCLAIMERS

The views, opinions, and/or findings contained in this article are those of the authors and should not be construed as an official US Department of the Army position, or decision, unless so designated by other official documentation. Approved for public release; distribution unlimited. Citations of commercial organizations and trade names in this report do not constitute an official Department of the Army endorsement or approval of the products or services of these organizations.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

A.T.R., M.M.W., and N.C. conceived and designed research; A.T.R. and K.B. prepared figures; A.T.R., M.M.W., K.B., J.C.W., G.E.W.G., and N.C. drafted manuscript; A.T.R., M.M.W., K.B., J.C.W., G.E.W.G., and N.C. edited and revised manuscript; A.T.R., M.M.W., K.B., J.C.W., G.E.W.G., and N.C. approved final version of manuscript.