The Philip Morris Company introduced a new "women's only" cigarette in the late 1960s, coinciding with the resurgence of the feminist movement. Their Virginia Slims® brand was test-marketed in July 1968 and quickly gained popularity among young women (Figure 1). Marketing of women's cigarette brands was so effective that smoking initiation among teenaged girls who did not attend college nearly doubled from 1967 to 1973, while smoking initiation among teenaged boys remained unchanged.1 At least 20 to 30 years elapse between smoking initiation and the development of chronic obstructive pulmonary disease (COPD). Predictably, the death rate from COPD among women nearly tripled from 1980 to 2000.2 In part 1 of this article, we review the epidemiology of COPD and discuss sex differences in its pathophysiology. In part 2, to be published in a coming issue of The Journal of Respiratory Diseases, we will discuss the management of COPD in women. Epidemiology COPD is the fourth leading cause of death in the United States,3 and it continues to be associated with significant morbidity and societal expense. In 1993, COPD was associated with estimated costs of $23.9 billion, including $14.7 billion in direct medical costs and an additional $9.2 billion in indirect expenditures, such as loss of productivity and work time and premature mortality.4 From 1994 to 1996, nearly 8% of adults with COPD reported activity limitation related to their illness, and those with COPD were about twice as likely to have activity limitation as those without COPD.2 In 2000, about 10 million adults in the United States self-reported the presence of emphysema, chronic bronchitis, or physician- diagnosed COPD.2 However, data from the National Health and Nutrition Examination Survey (NHANES) III suggest that this estimate based on self-reports may be too conservative, and that COPD may be underdiagnosed by physicians.2 An overwhelming 24 million adults had spirometric evidence of impaired lung function. When examined closely, available data have identified some interesting trends in COPD-related illness in women. COPD was previously thought to represent a "man's disease"; the prevalence of and mortality associated with COPD in women seem to follow the recent increase in smoking in women relative to men. From 1980 to 1996, the trend for self-reported COPD increased among women but remained constant for men (Figure 2). Since 1987, the rate of self- reported COPD has been higher in women than in men.2 As the prevalence of COPD in women has increased, so has the burden on our health care system. While the number of emergency department visits for COPD has increased in both sexes, the gender gap has narrowed for hospitalizations. The estimated number of annual hospitalizations associated with COPD was higher in men than in women during the 1980s (Figure 3); however, since 1995, hospitalization rates have been similar.2 From 1980 to 2000, the overall number of deaths attributed to COPD increased by 67%.2 Coincident with this, the mortality rate from COPD increased in women. Since 1985, the rate of COPD- related deaths in women has steadily increased, and it nearly tripled from 1980 to 2000 (Figure 4). During this time, the death rate in men remained constant; in 2000, for the first time, the number of deaths from COPD was higher in women than in men.2 The increasing rates of hospitalization for COPD in both sexes and the steadily increasing number of COPD-related deaths in women are troublesome. To counter these trends, physicians and society must gain an increased awareness of the morbidity and mortality associated with this disease and should further investigate aspects of COPD that uniquely affect women. Pathophysiology Although there are many known and many unknown elements of the pathophysiology of COPD that differ between the sexes, 3 areas have been widely studied: airway size, susceptibility to COPD, and bronchial hyperreactivity (BHR). Airway size and flow rates: Resistance to flow through the airways is inversely proportional to the radius of the airway lumen to the fourth power. Women on average have airways that are 17% smaller than those in men.5 Further narrowing of the airways by the destructive effects of COPD or bronchoconstriction may make women more vulnerable than men to symptomatic airways obstruction. However, determinants of airflow rate are much more complicated than airway radius alone. Flow rate in the lungs also depends on elastic recoil and airway length. Airway length determines the effort-independent forced expiratory flow (FEF) rate.5 Larger lungs with longer airways tend to have slower flow rates. Therefore, the flow rates of girls and women, measured by the ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC), are generally higher than those of boys and men.5 This is complicated by the different effects of growth and aging on males and females. In young girls, the FEV1:FVC ratio is much greater than it is in boys of the same age and height. The gap between girls and boys decreases in adolescence as the ratio of residual volume to total lung capacity (TLC) increases in girls but not in boys. The net effect is that FEF rates standardized to FVC are higher in young and teenaged girls than in boys, but FEF rates standardized to TLC are not. In older adults, the changes in elastic recoil that result from aging occur at a later age in women than in men. Susceptibility: There is debate over whether women have an increased susceptibility to COPD. Much of this controversy springs from the differing variables used to evaluate susceptibility. When Chen and co-workers6 constructed a regression line from pack-years smoked and lung function (FVC, FEV1, and maximal mid-expiratory flow rate) for 1149 adults, women had a more precipitate decrease in lung function than did men. Xu and associates7 also demonstrated a greater decline in FEV1 in women in a study of 4554 persons stratified into light, moderate, and heavy smokers. When analyzing data from 13,897 persons who participated in the Copenhagen City Heart Study and the Glostrup Population Studies, Prescott and associates8 demonstrated that rate of decline in FEV1 per pack-year was greater for women than for men. Women also were noted to be at a greater risk for hospitalization for COPD. However, Nilsson9 and Anthonisen10 and their coworkers failed to demonstrate greater COPD susceptibility in women. Anthonisen and associates10 evaluated the continuing smokers from the Lung Health Study and found no difference between men and women in the rate of decline in FEV1 (percent of predicted).10 They concluded that the findings of increased susceptibility in other studies were spurious because the studies had failed to adequately correct for size, age, and sex. Connett and coworkers11 confirmed the findings of Anthonisen and coworkers10 when they divided the Lung Health Study cohort into continuing smokers and sustained quitters. Among continuing smokers, women lost slightly more FEV1 percent of predicted per year than did men (5.4% vs 5.0%, respectively). Nilsson and coworkers9 evaluated a questionnaire concerning smoking habits (which was sent out with the Swedish census in 1963) and death certificate data on a cohort of 55,930 persons through 1996 to determine susceptibility to COPD in men and women. They found no differences in susceptibility when sex differences in smoking were accounted for.9 Despite using similar methods, another study found results that conflicted with those of the Swedish survey, possibly because it did not correct for sex differences in smoking habits.12 In this study, Chen and coworkers12 evaluated Canadian National Population Health Survey data that required a response to the question "Do you have chronic bronchitis or emphysema diagnosed by a health professional?" In the Canadian survey, 3.5% of men and 8.2% of women responded that they had received a diagnosis of chronic bronchitis or emphysema. Bronchial hyperreactivity: BHR has significant predictive value for progression of COPD and death, and it has been linked to the rate of decline in FEV1 in both men and women.13 Persons who responded to the lowest doses of methacholine in the Lung Health Study (those with greater BHR) experienced the greatest annual declines in FEV1. Conversely, those who responded only to the highest dose of methacholine experienced the smallest annual decline in FEV1, regardless of sex. This study confirmed earlier findings by Postma and coworkers,14 who demonstrated a link between rate of decline in FEV1 and response to histamine. In another study, the relative risk of COPD- related death increased from 3.8 to 15.8 as the histamine threshold dose decreased from 32 mg/mL to 1 mg/mL.15 BHR may be more common in women than in men. Tashkin and coworkers13 demonstrated that BHR (determined by methacholine challenge) was present in 26% of men and 47% of women among the 5733 Lung Health Study participants. This finding has been confirmed in a large survey in Canada; BHR was more prevalent in women than in men at all 6 sites studied.16 Increased BHR in women has also been demonstrated by other investigators. Leynaert and coworkers17 showed an increased risk of BHR in women in Paris (odds ratio [OR], 5.2) and Montpellier, France, (OR, 2.2), when the analysis corrected for history of allergy, atopy, and percent of predicted FEV1. Similarly, in a large epidemiologic study (N = 1694) in Italy, Paoletti and coworkers18 noted increased BHR in women compared with men; their findings remained significant after correction for percent of predicted FEV1. However, other investigators have found no increase in BHR in women. Kanner and colleagues,19 who analyzed data from the Lung Health Study cohort, found that the uncorrected relative risk of BHR in women, compared with men, was 1.75; this value dropped to 1.06 when corrected for percent of predicted FEV1. Bakke and coworkers20 also failed to demonstrate sex differences in BHR. Diagnosis Gender bias appears to exist in the diagnosis and workup of COPD. Chapman and coworkers21 presented a standardized case of a smoker with cough and dyspnea to 192 physicians (154 men and 38 women). They found that COPD was diagnosed significantly more frequently if the patient was male (58%) than female (42%). A report by Watson and coworkers22 revealed that after adjusting for age, pack-years, country of residence, and severe dyspnea, women were more likely to receive smoking cessation counseling (OR, 1.57) but were less likely to have spirometry (OR, 0.84). Despite significantly fewer pack-years of smoking, women were more likely to report severe dyspnea than men with similar cough and less sputum production. As noted above, the evidence indicates that COPD is underdiagnosed. NHANES data reveal that of the 20 million Americans with COPD, only 10.5 million receive the diagnosis.2 The remaining 9.5 million have undocumented airway obstruction. 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