The concept of yin/yang suggests that a whole is the sum of its parts, with the parts having both female (yin) and male (yang) components. Does this abstract idea have relevance to the study of chronic obstructive pulmonary disease (COPD)? Specifically, would sex- and gender-related scientific insights really have implications for how we treat men and women with COPD?

In a 2001 report, “Exploring the Biological Contributions to Human Health: Does Sex Matter?”, the Institute of Medicine posited that, in considering human disease, “Sex does matter. It matters in ways that we did not expect. Undoubtedly it matters in ways that we have not begun to imagine” (1). From a historical perspective, COPD has been considered to occur more frequently in men, which has been attributed to differences in smoking rates (2, 3). From a public health perspective, the investigation of sex and gender differences in COPD is timely, because in 2000, the number of women dying of COPD surpassed the number of men (4). Whether this is the consequence of secular trends in smoking behaviors or differential susceptibility to features of COPD is unclear, but this ominous observation is motivation to investigate further.

The article by Martinez and colleagues in this issue of the Journal (pp. 243–252) (5) found there were differences in densitometric measures of emphysema and differences in reported symptoms in men and women with advanced COPD. In an analysis of computed tomography (CT) scan data from the National Emphysema Treatment Trial (NETT), women had statistically less whole lung emphysema, with smaller emphysematous lesions and less peripheral emphysematous destruction despite similar FEV₁. It is unclear whether these CT findings are just statistically significant or if these differences are clinically meaningful. The authors subsequently observed in a subset of histological sections that airways of women had smaller lumens and thicker walls. Although the integration of CT findings with lung histology is crucial, we need to be mindful of how some of these findings may be secondary to normal baseline difference in airways in male versus female lungs.

Although any categorization will likely fail to be absolute, in studying COPD we should dichotomize findings of male–female differences into those that are potentially sex-related (i.e., genetic, hormonal, anatomic, and other biological influences) versus those that are potentially gender-related (i.e., secondary to environmental, social, and/or cultural factors that may influence exposure histories and lifestyle choices). The approach of considering together CT scan data and histological observations (sex-specific features) with depression and dyspnea symptoms (gender-specific features) is a novel and important component of the study by Martinez and coworkers.

One of the most provocative observations is that women enrolled in NETT reported fewer pack-years of smoking than men, but had similarly severe COPD. Recently, a meta-analysis demonstrated that beyond age 45, female current smokers had a faster annual decline in FEV₁ than male current smokers (6). In this context, the observations by Martinez and colleagues raise several important questions. If women had similar pack-year histories, would they have the same amount of emphysema as men, or are women more predisposed to have more airway disease? With refinement of CT scan airway phenotypes, will we detail more differences between men and women with COPD? Do women with similarly severe disease by GOLD (Global Initiative for Chronic Obstructive Lung Disease) staging do worse clinically because of the physiologic impact of having more airway disease? Or, is it that women have more systemic sequelae related to COPD, as manifested by a higher prevalence of depression, decreased functional capacity, and more body mass loss—features demonstrated by this and other studies (7, 8).

One limitation of this study is that enrollment in NETT was selective and included only individuals with severe emphysema, so the generalizability may be limited. Reporting bias may account for some of the apparent clinical heterogeneity between men and women. Lastly, this analysis is retrospective and cross-sectional; it is relevant to investigate these sex and gender differences longitudinally and to assess for any differences in treatment effect in NETT. Martinez and colleagues propose that this work is “hypothesis generating” and caveat their observations with the suggestion that some of the emphysema and histological airway differences may be secondary to normal anatomic difference between adult male and female lungs. This is an appropriately reserved position, but we still need to commend the authors for their comprehensive approach to the NETT data and their suggestion that their findings should lead to other studies of “complex interactions between biological and sociocultural factors” (9).

Several lines of data suggest that genetic interactions may be important to the sex/gender differences observed in COPD. First, in families of individuals with severe, early-onset COPD, a female predominance among COPD cases was observed, indicating a potential gene-by-sex interaction (10). Murine data suggest that genes may interact with smoking and sex-specific factors for the development of emphysema, with some inbred strains of mice demonstrating a female predominance of emphysematous destruction of the lung in response to cigarette smoke exposure (Steven D. Shapiro, personal communication). Relevant to the current analysis, distributional features of emphysema in the NETT subjects have been associated with genetic variation (11). As such, the next wave of research should focus on biological, hormonal, and genetic factors that may drive sex and gender differences in COPD.

Teasing apart the etiology of sex and gender difference will require time, but “an additional and more general reason for studying differences between the sexes is that these differences, like other forms of biological variation, can offer important insights into underlying biological mechanisms” (1). Studying the yin and yang of COPD will lead to insights about COPD pathophysiology as a whole. What is not debatable is that there are sex and gender differences in COPD to consider in both research and clinical care of patients. The study of male–female differences should be multidisciplinary and collaborative, as there are lessons to learn from animal models, human studies, and patient care. The article by Martinez and colleagues should convince us that sex and gender matter in the study of COPD; using improved phenotyping with CT scanning and concerted initiatives in COPD research, we will likely discover that sex and gender matter to COPD in ways that we have not yet imagined.

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