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1 Pharmaceutical Outcomes Programme, BC Children's Hospital and BC Women's Hospital & Health Centre, Vancouver, British Columbia, Canada; 2 Division of Respiratory and Critical Care Medicine, Kingston General Hospital, Queen's University, Kingston, Ontario, Canada; 3 Department of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Correspondence and requests for reprints should be addressed to Pat Camp, Ph.D., P.T., Pharmaceutical Outcomes Programme, BC Children's and BC Women's Hospital & Health Centre of British Columbia, E423-4480 Oak Street, Vancouver, BC, V6H 3V4 Canada. E-mail: pgcamp{at}interchange.ubc.ca
ABSTRACT
Chronic diseases have a variable impact on men and women due to the complex interaction between biological sex and environmental risk factors to which men and women are differentially exposed. Sex differences have not been adequately explored in chronic obstructive pulmonary disease (COPD), as most studies have either had small sample sizes or not enough women to allow for accurate comparisons. This article will address sex differences in susceptibility, expression of COPD subtypes, and activity-related breathlessness, and will identify key areas for further investigation.
Key Words: chronic obstructive pulmonary disease • gender • susceptibility • phenotypes • breathlessness
Chronic diseases have a variable impact on men and women due to the complex interaction between biological sex and environmental risk factors to which men and women are differentially exposed. Sex differences have not been adequately explored in chronic obstructive pulmonary disease (COPD), as most studies have either had small sample sizes or not enough women to allow for accurate comparisons. For example, the number of women in key COPD clinical trials has ranged from 0 to 35%. Recent work has suggested that while the overall prevalence and incidence of COPD are higher in men (1–3), the incidence of COPD in younger age groups (i.e., age 55–59) is now much higher in women (3). Women may be more susceptible to developing COPD, are more likely to express the airway-predominant subtype, and report more severe symptoms and activity intolerance. This paper will address these themes and will identify key areas for further investigation.
WOMEN AND SUSCEPTIBILITY TO THE EFFECTS OF SMOKING
One common message is that women are more susceptible to the effects of smoking and COPD development. To conceptualize this, it is helpful to address COPD susceptibility in general. Data on differential effects of risk factors for in utero lung development that may ultimately result in COPD are scarce. After birth, three general mechanisms may lead to COPD:
Women often have similar levels of impaired lung function despite having smoked much less, suggesting that one or a combination of the above factors is involved. Silverman and coworkers (4) reported that female current and ex-smokers were more likely to have a reduced FEV1/FVC than their male counterparts. Gan and colleagues (5) provided further evidence for accelerated decline in lung function in women who smoke in their meta-analysis of 11 studies, measuring percent predicted forced expiratory volume in 1 second (FEV1% predicted) over time. Female smokers had, with increasing age, a faster yearly decline of FEV1% predicted than male smokers. This was most apparent after the age of 50 years and did not occur in ex- and never-smokers. In contrast, a recent analysis of the Framingham Offspring Cohort by Kohansal and coworkers (6) found that female smokers actually had a lower decline of FEV1 compared with male smokers. The Gan study (5) and the Kohansal study (6) used different methods to calculate rate of decline, making direct comparisons difficult. With respect to lung development, Gold and colleagues (7) studied over 12,000 girls and boys aged 10 to 18 years in six areas of the United States. They found that girls who smoked at least 5 cigarettes per day had 1.09% slower growth in FEV1 per year compared with never-smokers, whereas this value was only 0.20% in boys.
Recent studies have suggested that an autoimmune component may be present in COPD development (8). Autoimmune diseases affect 8% of the population, 78% of whom are women. Women are known to respond to infection, vaccination, and trauma with increased antibody production and a T helper (Th)2-predominant immune response, whereas a Th1 response is predominant in men. The onset of menopause also alters the immune system in healthy women (9), yet the impact of this on lung function in women who smoke is unknown. Other mechanisms underlying differential disease susceptibility may include sex differences in nicotine metabolism and other cigarette by-products, and the influence of sex hormones on the biological response to risk factors.
Environmental risk factors that may preferentially impact women have not been well explored. It is not clear how type of cigarette, in conjunction with airway and parenchymal lung development, inhalation strength, and other behavioral aspects of smoking, differ in women and men. Another important, yet largely ignored risk factor is exposure to environmental tobacco smoke (ETS). Women may be more likely to have ETS exposure, and a greater proportion of never-smokers with COPD are women (10). When not accounting for ETS exposure, studies may suggest that women have decreased lung function for a given amount smoked, when in fact their total cigarette smoke exposure may be higher than their calculated pack-years.
In summary, there is some evidence that women may be more susceptible to cigarette smoke and more likely to develop COPD. However, susceptibility has been characterized in many different ways, including prevalence, FEV1%predicted, lung function decline, or mortality. The lack of a consistent methodology has resulted in conflicting studies with little consensus on the issue of COPD susceptibility in women versus men. Longitudinal cohort studies from birth onward are needed to fully appreciate how sex differences in biological determinants interact with environmental factors and impact COPD susceptibility, and these studies should measure lung function, genetic and environmental factors, and multiple biomarkers.
WOMEN WITH COPD HAVE LESS EMPHYSEMA AND MORE AIRWAY DISEASE
There exist two main subtypes of COPD: large airway disease with mucous production and remodeling of the small airways, and parenchymal destruction leading to loss of elastic recoil. Martinez and coworkers (11) measured differences in emphysema (using CT) and airway wall thickness (using histologic samples) in patients undergoing lung volume reduction surgery and found that men had increased emphysema with larger emphysematous spaces, while women had thicker airway walls. Other studies have also reported increased CT-measured emphysema severity in men (12, 13). Why men may have more emphysema is not clear, but the larger lung volumes and airway lumen in men may increase the likelihood of deposition of the smallest inhaled particles in the alveolar regions instead of the airways. However, the lack of normative values of lung density in men versus women means we cannot conclude with certainty that an increased susceptibility to emphysema is apparent in men. Reference values for lung density measures for both men and women are clearly needed. In addition, we have little understanding of how other factors, such as age or smoking status, affect sex-specific susceptibility to a particular COPD subtype over time.
SEX DIFFERENCES IN ACTIVITY-RELATED BREATHLESSNESS IN HEALTH AND IN COPD
Healthy women report breathlessness more frequently than age-matched men and also have greater perceived intensity of exertional breathlessness (14). Recent studies in COPD similarly suggest that women are more symptomatic and report poorer quality of life than their male counterparts for a similar level of airway obstruction (15). Sex differences in perceived symptoms are multifactorial and include biological, sociocultural, environmental, and psychological influences. We will focus on physiologic factors (see Figure 1).
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E) during cycle exercise, the work of breathing is increased (likely reflecting increase airway resistance) in young women compared with age-matched men. However, this sex difference disappears when E is expressed as a percentage of baseline maximal ventilatory capacity—that is, when the reduced ventilatory reserve in women is accounted for (16).
The effects of aging on respiratory system function (i.e., changes in respiratory system compliance, respiratory muscle strength, and ventilation–perfusion relations) is broadly similar in men and women, but the sensory consequence of the aging process is greater in women given their reduced ventilatory reserve (17). Sex differences in intensity ratings of breathlessness at a standardized power output or E during exercise in both young and older individuals are no longer evident when work rates are expressed as % of predicted maximum or E is expressed as % of maximal ventilatory capacity (17). Thus, regardless of age, healthy women experience greater breathlessness than men during a standardized physical task because the E and fractional contractile respiratory muscle effort required to support this task represents a higher fraction of their maximum compared with men (18). In men, relatively less effort needs to be expended to drive E, given their naturally larger lungs and stronger respiratory muscles. It follows that a plausible mechanistic explanation for sex differences in activity-related breathlessness is the existence of differences in fractional respiratory muscular effort and concomitant central corollary discharge from respiratory motor centers in the brain to the somato-sensory cortex.
Women who develop mild-to-moderate COPD show greater airway hyperresponsiveness to methacholine than men matched for FEV1, differences that disappear when the reduced baseline airways diameter in women is accounted for (19). The physiologic and clinical implications of relatively increased airway hyperresponsiveness in women and of possible sex differences in the pathological manifestations of COPD are currently unknown (11). There is evidence that the sex differences in respiratory sensation described in health persist and become amplified as the pathophysiologic effects of COPD further erode the relatively reduced maximal ventilatory reserve in women (20). The physiologic underpinnings of sex differences in symptom perception during physical activity in COPD are currently poorly understood. de Torres and colleagues (21) found that in an population of men with COPD, dyspnea during exercise was explained primarily by respiratory factors such as PaO2 and DLCO, whereas for women with similar levels of airflow obstruction, dyspnea was explained primarily by respiratory center factors. Potential contributory factors that deserve systematic study include fundamental sex differences in: (1) airway structure and function (including dysanapsis), (2) resting and dynamic ventilatory mechanics during exercise, (3) ventilatory control and its humoral influences, and (4) qualitative and affective dimensions of breathlessness.
It appears that there are differential effects of environmental and biological factors on the development of COPD in men and women, whereas physiologic differences may also contribute to the perception of breathlessness that is associated with COPD and hinders an individual's quality of life. There remain many important areas for further research, including:
FOOTNOTES
P.G.C. is supported by a CIHR team grant (ICEBERGS).
Conflict of Interest Statement: P.G.C. received lecture fees from AstraZeneca (AZ) and GlaxoSmithKline (GSK) up to $1,000. Her spouse owns stocks or options with Pfizer $1,001–$5,000 and she has received grant support from GSK (UBC and St. Paul's Hospital receives grants from GSK $100,001 or more). D.E.O. served on the Board or Advisory Board for and received lecture fees from GSK, Boehringer Ingelheim (BI), and Pfizer Canada $1,001–$5,000. He received grant support from GSK $100,001 or more, Pfizer Canada $50,001–$100,000, Merck Frosst $100,001 or more, BI, and Novartis $50,001–$100,000. D.S.P. served as a consultant for Altana up to $1,000 and served on the Board or Advisory Board for BI up to $1,000. She received lecture fees from GlaxoSmithKline $1,001–$5,000 and Chiesi up to $1,000 and received grant support from Altana and GlaxoSmithKline $100,001 or more. She receives royalties from Springer, Bohn Stafleu, and Van Gorkum up to $1,000.
(Received in original form April 9, 2009; accepted in final form June 8, 2009)
REFERENCES
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