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1 University of British Columbia, Vancouver, British Columbia, Canada; and 2 University of Toronto, Toronto, Ontario, Canada
Correspondence and requests for reprints should be addressed to Don D. Sin, M.D., The James Hogg iCAPTURE Center for Cardiovascular and Pulmonary Research, St. Paul's Hospital, Room 368A, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6 Canada. E-mail: dsin{at}mrl.ubc.ca
ABSTRACT
There is a worldwide epidemic of chronic obstructive pulmonary disease (COPD) in women. Some large epidemiologic studies suggest that female smokers may have increased susceptibility to COPD. The biological mechanisms to explain these observations are far from certain. However, the susceptibility to the effects of cigarette smoke in women could be due to a greater deposition of toxic substances in the lung, impaired clearance of the toxins that are deposited, and/or an exaggerated biologic response to these toxins. The latter effect could be due to an increased ability to convert certain xenobiotics to more toxic metabolites or to a decreased ability to conjugate and excrete metabolites of these toxins. Female hormones, in particular estrogen, can up-regulate certain cytochrome P450 enzymes without altering detoxifying enzymes, leading to a disturbance in the balance between metabolism and conjugation. This article reviews this and other potential mechanisms that may confer increased susceptibility of COPD to female smokers.
Key Words: gender • COPD, susceptibility • cigarette smoke
In the United States and in many other Western nations, there are more women than men with chronic obstructive pulmonary disease (COPD) (1). The rising incidence of women with COPD in the Western world is largely unexplained. Because cigarette smoking is the single most important risk factor for COPD, one plausible explanation is that the epidemic is being driven by the increasing rates of smoking in women since World War II. Although this is true, in nearly all age categories there continues to be more male than female smokers, and even among smokers, men tend to smoke more cigarettes per day than women (2). A recent systematic review of all published large cohort studies indicated that women who smoke have faster decline in lung function compared with male smokers, especially after 45 years of age (3). The rate of decline among ex- and never-smokers, on the other hand, was similar between men and women regardless of age. These data suggest another plausible explanation for the rising epidemic of COPD in women: Female smokers are biologically more susceptible to COPD.
CLINICAL STUDIES
Silverman and colleagues (4) performed a genetic linkage study using the Boston early-onset COPD cohort. Of the 84 probands with severe early-onset COPD, 71% were women. In this cohort, the female probands on average smoked fewer cigarettes than the male probands, although there was no major difference in lung function between men and women. Most importantly, of the 348 first-degree relatives studied, the female first-degree relatives who smoked had significantly lower FEV1/FVC (as percent predicted) (P = 0.009) and significantly greater bronchodilator responsiveness (as a percentage of baseline FEV1) (P = 0.002) compared with male first-degree relatives who smoked (4). In never-smokers, no sex-related differences in lung function were observed. In another study, Prescott and colleagues showed that female smokers had faster decline in lung function compared with male smokers: –7.4 ml/pack-year in women versus –6.3 ml/pack-year in men in the Copenhagen City Heart Study and –10.5 ml/pack-year in women versus –8.1 ml/pack-year in men in the Glostrup Population Study (5). Because women have smaller lungs, these differences translate into larger differences in percent predicted lung function. Similar results were reported by Dransfield and colleagues who showed that female smokers had greater loss in FEV1 compared with male smokers, adjusted for pack-years of smoking (–1.21%/pack-year in women vs. –0.98%/pack-year in men; P = 0.001) (6). Women had two to three times the risk of COPD hospitalization compared with men. In a Danish population-based registry study, Ringbaek and colleagues showed that women with COPD had higher mortality than men with COPD, with a rate ratio of 1.8 over a mean follow-up of 13.3 years (7).
The good news is that when women stop smoking, they recover more lung function than do male ex-smokers. In the first year after smoking cessation, women experience a greater increase in FEV1 than do male ex-smokers (3.7% of predicted in women vs. 1.6% predicted in men; P < 0.001) (8). Women's increased susceptibility to COPD seems to start early in childhood. During childhood, girls experience a larger reduction in lung function when exposed to environmental tobacco smoke compared with boys (9). Similarly, exposure to air pollution causes greater reduction in lung growth in girls compared with boys (10). Gold and colleagues showed in an adolescent population that girls who smoked five or more cigarettes per day demonstrated slower growth in their FEV1 and FVC compared with girls who did not smoke (–1.09%/yr for FEV1 and –0.76%/yr for FVC). In contrast, boys who smoked five or more cigarettes per day experienced no or trivial reductions in their FEV1 or FVC compared with nonsmoking boys (–0.20%/yr for FEV1 and –0.03%/yr for FVC) (11).
COPD PHENOTYPES AND GENDER
There are two major phenotypes in COPD: emphysema and airway disease. Using the National Emphysema Treatment Trial data, Martinez and colleagues showed that female patients with COPD had more airway disease, characterized by increased thickening of the airway wall relative to the luminal size, whereas men had more emphysema, especially involving the outer peel of the lung (12). For similar lung function (i.e., similar FEV1 percent predicted), women had greater dyspnea, higher modified BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) scores, worse health, and worse functional performance status compared with men (13). Female patients with COPD also demonstrated greater bronchodilator reversibility and airway hyperresponsiveness compared with men, which supports the concept that airway disease is more relevant in women, whereas parenchymal disease may be more relevant in men (14, 15).
OXIDANT STRESS IN FEMALE SMOKERS
The susceptibility to the effects of cigarette smoke in women could be due to a greater deposition of toxic substances in the lung, impaired clearance of the toxins that are deposited, and/or an exaggerated biologic response to these toxins. The latter effect could be due to an increased ability to convert certain xenobiotics to more toxic metabolites or to a decreased ability to conjugate and excrete metabolites of these toxins (Figure 1). Tobacco smoke contains more than 4,000 chemicals, including nitrosamine, NNK (4-[methylnitrosamino]-1-[3-pyridyl]-1-butanone), minor alkaloids (e.g., nornicotine, anatabine, and anabasine), N-nitroso derivatives, and polycyclic aromatic hydrocarbons (PAHs). With smoking, these chemicals are rapidly absorbed and metabolized in the body via oxidation (first phase) and conjugation (second phase). The oxidative phase occurs in a two-step process mediated largely by cytochrome P450 (CYP) (step 1) and aldehyde oxidase enzymes (step 2) (16). Up-regulation of the oxidative phase without a concomitant increase in the conjugation phase can lead to oxidative stress. Female smokers have increased lung expression of CYP enzymes compared with male smokers. In one study, female lungs had 2.4 times more mRNA for CYP enzymes than did male lungs (P = 0.016) (17).
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and ERβ. They are ligand-binding transcription factors and members of the nuclear receptor family. ER is expressed more frequently in women than in men, whereas ERβ is expressed with similar frequency in men and women. The two main CYP enzymes that are up-regulated by cigarette smoke are CYP1A1 and CYP1B1, which are regulated by ER (18). Stimulation of estrogen receptor in the lungs increases protein expression of CYP1A1 by twofold (17). The increased CYP expression is also related to increased estradiol-β expression (19). CYPs are also involved in the bioactivation of 17β-estradiol, resulting in a positive feedback loop (20). Neither ER nor ERβ materially affects the expression of detoxifying enzymes such as glutathione S-transferase, which are responsible for neutralizing the harmful effects of active intermediate species generated by the CYP enzymes in the phase I reactions (18). Taken together, these data suggest that female hormones may accelerate metabolism of cigarette smoke, likely through the CYP pathways, into various metabolites. Some of these metabolites, especially those that are related to N-nitroso derivatives and PAH, are potent oxidants and oxidizers. Because estrogen does not modify detoxifying enzymes such as glutathione S-transferase, female smokers experience increased oxidative stress in the lungs, which may lead to lung injury. These hormonal effects may explain why female smokers demonstrate accelerated metabolism of nicotine. Benowitz and colleagues (21), for instance, injected nicotine and cotinine intravenously and found that women compared with men had faster plasma clearance of nicotine and cotinine, greater conversion of nicotine to cotinine, and significantly higher trans-3' hydroxycotinine-d2 (3HC-d2) to cotinine-d2 ratio (0.27–0.19; P < 0.001) and 3HC-d4 to cotinine-d4 ratio (0.32–0.21; P < 0.001). The 3HC to cotinine ratios were particularly elevated among women who used estrogen-only oral contraceptives. Other studies (especially animal studies) have shown that female subjects have accelerated metabolism of other components of cigarette smoke, such as PAH and nitroso compounds.
ANIMAL STUDIES
Animal studies support a sex-related difference in xenobiotic metabolism. For instance, when mice were injected with naphthalene (NP) (200 mg/kg), a PAH found in sidestream smoke, there was more airway injury in female compared with male mice (22). There was also greater accumulation of NP metabolites and a higher expression of CYP enzymes in the lungs of the female mice (23). The NP metabolites are biologically active and induce a brisk inflammatory response and cause oxidative stress in the airways through a process called metabolic bioactivation (24). Other PAHs in cigarette smoke also undergo metabolic bioactivation in the airways mediated by CYP enzymes and cause oxidative stress and airway injury in various animal models (25).
OXIDATIVE STRESS AND DNA DAMAGE
Increased oxidant stress has been implicated in the pathogenesis of COPD. With oxidative DNA damage, the body produces antibodies to the damaged DNA. One such marker of DNA oxidative stress is anti–5-hydroxymethyl-2'-deoxyuridine (HMdU) autoantibody (26). Mooney and colleagues showed in 140 heavy smokers that the titers for the anti-HMdU autoantibodies were 50% higher in women than in men after adjustment for cigarettes smoked per day. With smoking cessation, the autoantibody titers decreased significantly over time in women but not in men (26).
Cigarette smoke may also cause DNA mutations leading to one of the common complications of COPD, lung cancer. One of the salient gene mutations that are thought to promote lung carcinogenesis is a G:C substitution in the p53 gene, which can arise in response to exposure to certain components of cigarette smoke, such as benzo[a]pyrene. Kure and colleagues found that female patients with lung cancer had an increased frequency of this mutation and a higher hydrophobic DNA adduct level compared with male patients, even though the level of exposure to carcinogens from cigarette smoking was lower in women than in men (27). Similar findings have been reported by other groups (28). In addition, women have a DNA repair capacity that is 10 to 15% lower than that in men (P < 0.001) (29). Due to the increased burden of DNA adducts and mutations, women who have reduced DNA repair capacity have significantly higher risk of developing lung cancer than do men with reduced DNA repair capacity. For example, when a woman has a DNA repair capacity that is lower than 7.0%, her risk of lung cancer increases by approximately sevenfold, whereas in men, the risk is increased by only twofold (29). Taken together, these data suggest that female smokers experience greater oxidative stress and are more susceptible to genetic mutations, which may predispose them to some complications of COPD, including lung cancer.
GENDER DIFFERENCES IN BRONCHIAL HYPERRESPONSIVENESS AND INHALATIONAL PATTERNS
Bronchial hyperresponsiveness (BHR) has been associated with increased risk of COPD progression and COPD mortality (30). Approximately 87% of female smokers with mild to moderate COPD demonstrate increased bronchial responsiveness, whereas only 63% of male smokers demonstrate BHR (15). In men, the major risk factors for BHR are asthma and atopy, whereas in women, the single most important risk factor is cigarette smoking (31). In men, smoking status has little or no effect on BHR (31). Although there are many factors that govern BHR, airway inflammation plays a significant role in the process. There is a general consensus that inflammation and oxidative stress are important components in the pathobiology of COPD, which may contribute to COPD progression, systemic inflammation, oxidative stress, and associated morbidity and mortality (32). BHR may also increase the deposition of small aerosolized particles by 19% (33). Moreover, the manner in which a cigarette is smoked may be an important determinant of the altered bronchial reactivity observed in cigarette smokers. Taylor and colleagues studied 20 smokers and found that inhalation patterns were related to the provocative concentration of histamine that caused a 20% fall in FEV1 (PC20) and to the cough threshold for inhaled citric acid. Histamine PC20 values were inversely correlated with depth and rate of inhalation. Cough threshold was inversely correlated with greater cigarette consumption and with depth of inhalation. Female smokers tend to inhale deeper and breath-hold for a longer time than male smokers, which may predispose them to more airway damage (34).
CONCLUSIONS
COPD is a silent epidemic in women. Emerging data suggest that women tend to have more airway disease, whereas men tend to develop more emphysema. There are compelling biological reasons why female smokers might be more susceptible to COPD compared with male smokers. There is a dearth of clinical and experimental studies that have specifically addressed causes and mechanisms underlying the growing burden of COPD in women. Sex-related differences in xenobiotic metabolism, sex hormones, airway inflammation and responsiveness, and particle deposition are some of the potential mechanistic pathways that should be evaluated to better understand the biological differences that may predispose women to a higher risk of COPD.
FOOTNOTES
This article was based on a round table discussion at the "Toward a Research Agenda on Gender and Chronic Obstructive Pulmonary Disease" conference, which was sponsored by the Canadian Institutes of Health Research (Institute of Gender and Health), by the Canadian Tobacco Control Research Initiative, and by ICEBERGS (http://www.icebergs.ubc.ca).
Conflict of Interest Statement: D.D.S. has received honoraria for speaking engagements from AstraZeneca (AZ) in 2003 ($4,000), in 2004 ($3,000), in 2005 ($11,000) and from GlaxoSmithKline (GSK) in 2003 ($4,000), in 2004 ($8,000), in 2005 ($6,500), and in 2006 ($10,000). He has also received unrestricted research funding as either the principal investigator or co-principal investigator from GSK in 2003 for $80,000 and in 2004 for 1.5 million. He has also received $3,500 from GSK for consultancy work in 2004 and $1,500 in 2006. S.B.-Z.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. H.C. received $11,000 in 2005 for serving on an advisory board for GSK. He is the coinvestigator on two multicenter studies sponsored by GSK and has received travel expenses to attend meetings related to the project. He has three contract service agreements with GSK to quantify the CT scans in subjects with COPD. A percentage of his salary between 2003 and 2006 ($15,000/yr) derives from contract funds provided to Peter D. Paré by GSK for the development of validated methods to measure emphysema and airway disease using computed tomography. He is the coinvestigator (D. Sin, principal investigator) on a Canadian Institutes of Health-Industry (Wyeth) partnership grant. There is no financial relationship between any industry and the current study. P.D.P. is the principal investigator of a project funded by GSK to develop CT-based algorithms to quantitate emphysema and airway disease in COPD. With collaborators he has received 
$300,000 to develop and validate these techniques. The funds he has applied solely to the research to support programs and technicians. He is also principal investigator of a Merck Frosst–supported research program to investigate gene expression in the lungs of patients who have COPD. He and collaborators have received $200,000 for this project. These funds have supported the technical personnel and expendables involved in the project.
(Received in original form June 28, 2007; accepted in final form August 1, 2007)
REFERENCES
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