The present systematic review indicates that female compared with male smokers experienced a faster decline in lung function beyond age 45 to 50 years. This trend was evident even in female smokers who smoked only a modest amount of cigarettes (<15 g/day). In non- or ex-smokers, there were no significant gender-related changes in FEV1% pred over time. However, there was considerable heterogeneity in the results across the studies (see table 2 and figure 3) and as such these data should be interpreted cautiously. Additional prospective longitudinal studies powered specifically on gender-related changes in lung function in the post-menopausal age group are needed to confirm these observations.
The findings from the present study are consistent with other studies, which were not included in this review [21–29]. Prescott and colleagues reported similar findings from two independent population samples: Copenhagen City Heart Study (CCHS) and Glostrup Population Studies (GPS) . In both samples, when adjusted for pack-years of smoking, female smokers had a faster decline in lung function compared with male smokers. In the CCHS, the estimated excess loss of FEV1 was 7.4 ml per pack-year in female current smokers and 6.3 ml per pack-year in male current smokers. In the GPS, the estimated excess loss of FEV1 was 10.5 ml per pack-year in the female current smokers and 8.4 ml per pack-year in the male current smokers. Importantly, in both samples, even after adjustments of daily tobacco consumption and years of smoking, female smokers had a higher risk of hospitalization for COPD compared with male smokers (relative risk, RR, 1.5, 95% confidence interval, CI, 1.2–2.1 in the CCHS and RR, 3.6, 95% CI, 1.4–9.0 in the GPS) . Furthermore, women with impaired lung function (FEV1 < 40% pred) had a higher risk of death from all causes (RR, 5.0 for women, 2.7 for men) and of deaths from obstructive lung diseases (RR, 57 for women, 34 for men,) compared with men . Xu and colleagues studied 1 618 male and 1 669 female adults aged 40–69 yrs in the Beijing Respiratory Health Study . Although female never smokers had better lung function than did male never smokers, female current smokers had significantly lower lung function compared with male smokers . In a genetics study of early onset COPD, Silverman and colleagues found that female first-degree current or ex-smoking relatives of the probands were almost two times more likely to demonstrate mild airflow limitation (FEV1 <80% predicted) and over three times more likely to have severe airflow limitation (FEV1 <40% predicted) than did male relatives .
Although the present study did not evaluate effects of smoking cessation on lung function in men and women, data from the Lung Health Study indicates that female quitters may experience larger gains in lung function than do male sustained quitters. In that study, female sustained quitters experienced a 2.5 fold larger improvement in FEV1% pred than did male sustained quitters after one year of smoking cessation . These data, in conjunction with results of the present systematic review, suggest that female smokers have increased susceptibility for COPD, especially after age 45 to 50 years. With smoking cessation, however, female quitters may experience a larger recovery of their lung function than do male quitters.
Although our study was not designed to evaluate the effects of smoking in adolescent youths, previous studies indicate that smoking may also have a greater (negative) impact on lung growth in female than male youngsters. Gold et al  found that among adolescents, smoking five or more cigarettes a day, as compared with never smokers, was associated with a 1.09% per year reduction in the growth rate of FEV1 in girls, while for boys, smoking reduced FEV1 growth by only 0.20%/yr. Patel et al  found that exposure to cigarette smoke during childhood was an independent risk factor for the development of obstructive airways disease in women but not in men. Thus, the relationship between gender, age and FEV1 changes may be U-shaped.
The mechanisms responsible for the increased susceptibility of women to cigarette smoke are largely unknown. There is now a general consensus that inflammation is at the heart of the pathobiology of COPD and that the inflammatory process involves both the lung (airways and parenchyma) and the systemic circulation [32–34]. The intensity of the inflammatory process in the airways and in the systemic circulation is associated with severity of FEV1 impairment [33, 34]. Whether women are more likely to demonstrate airway inflammation compared with men is unknown. Interestingly, women in the general population are known to have higher circulating C-reactive protein levels, a marker of systemic inflammation, but only after ~50 years of age . Since active smoking amplifies systemic inflammation, independent of other factors , smoking-inflammation pathway may be an important contributor to the increased risk observed in women in the peri and post-menopausal periods. Further research is needed to confirm this hypothesis.
Another potential mechanism may relate to bronchial hyperresponsiveness. In the Lung Health Study, there was a higher prevalence of bronchial hyperresponsiveness among women than among men (85% in women versus 59% of the men) . In another population-based study, Leynaert and coworkers demonstrated increased prevalence of bronchial hyperresponsiveness in women, even after adjustments for respiratory symptoms, atopy, or lung function parameters . Paoletti et al  also found increased risk of bronchial hyperresponsiveness among women compared with men independent of baseline lung function. In women, they observed that current smokers had significantly more reactive airways than did non- or ex-smokers. However, in men, smoking status made no material impact on bronchial responsiveness . These data may be clinically relevant since bronchial hyperresponsiveness has been associated with increased risk of both COPD progression  and COPD mortality .
Additionally, cigarette smoke may modify hormonal status in women, which may affect lung function. Women who are active smokers become relatively estrogen deficient compared with non-smokers because cigarette smoke induces cytochrome P450 isoenzymes CYP1A1 and CYP1A2, which alter estrogen metabolism leading to increased production of inactive catechols . Hormone replacement therapy in the post-menopausal period is associated with improved lung function, reducing the risk of airflow obstruction by ~25% . Hormone replacement therapy also reduces bronchial hyperresponsiveness in post-menopausal women .
An alternative hypothesis for higher susceptibility of females to smoking may be differences in lung development between females and males. Interestingly, relative to male rates, female rates of obstructive airway diseases increase sharply during adolescence . Before pubescence, girls have smaller lung volumes than do boys but generate higher flows . During teenage years, airways and lung volumes demonstrate isotropic growth in boys. In girls, however, airway growth becomes disproportionately smaller relative to lung volume growth, indicating dysanapsis . Thus, for any given lung volume and size, women have smaller airways compared with men, which may make the airways more susceptible to the adverse effects of cigarette smoke.
There were several limitations to the study. Firstly, we used only a crude marker of smoking (i.e. self-report of smoking). Since male smokers generally smoke more cigarettes than do female smokers and have a longer smoking history, we may have underestimated the true effects of cigarette smoking in the female population . Secondly, as with most systematic reviews, publication bias is a source of concern. Figure 3 indicates that there were no material differences in results between large and small studies, suggesting that publication bias did not significantly affect the results.