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Female smokers beyond the perimenopausal period are at increased risk of chronic obstructive pulmonary… Gan, Wen Q; Man, SF P; Postma, Dirkje S; Camp, Patricia; Sin, Don D Mar 29, 2006

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ralssBioMed CentRespiratory ResearchOpen AcceResearchFemale smokers beyond the perimenopausal period are at increased risk of chronic obstructive pulmonary disease: a systematic review and meta-analysisWen Qi Gan1,2, SF Paul Man1,2, Dirkje S Postma3, Patricia Camp1 and Don D Sin*1,2Address: 1James Hogg iCAPTURE Center for Cardiovascular and Respiratory Research, University of British Columbia, Vancouver, B.C., Canada, 2Department of Medicine (Pulmonary Division), University of British Columbia, Vancouver, B.C., Canada and 3Department of Pulmonology, University Hospital, University of Groningen, Groningen, The NetherlandsEmail: Wen Qi Gan - wgan@mrl.ubc.ca; SF Paul Man - pman@providencehealth.bc.ca; Dirkje S Postma - d.s.postma@int.umcg.nl; Patricia Camp - pcamp@unix.infoserve.net; Don D Sin* - dsin@mrl.ubc.ca* Corresponding author    AbstractBackground: Recent reports indicate that over the next decade rates of chronic obstructivepulmonary disease (COPD) in women will exceed those in men in the western world, though inmost jurisdictions, women continue to smoke less compared with men. Whether female adultsmokers are biologically more susceptible to COPD is unknown. This study reviewed the availableevidence to determine whether female adult smokers have a faster decline in forced expiratoryvolume in one second (FEV1) compared with male adult smokers and whether age modifies therelationship between cigarette smoke and lung function decline.Methods: A systematic review and a meta-analysis was performed of population-based cohortstudies that had a follow-up period of at least 3 years, measured FEV1 on at least two different timepoints, and presented FEV1 data stratified by gender and smoking status in adults.Results: Of the 646 potentially relevant articles, 11 studies met these criteria and were includedin the analyses (N = 55 709 participants). There was heterogeneity in gender-related results acrossthe studies. However, on average current smokers had a faster annual decline rate in FEV1%predicted compared with never and former smokers. Female current smokers had with increasingage a significantly faster annual decline in FEV1% predicted than male current smokers (linearregression analysis, R2 = 0.56; p = 0.008). Age did not materially affect the rate of decline in FEV1%predicted in male and female former and never smokers (p = 0.775 and p = 0.326, respectively).Conclusion: As female smokers age, they appear to experience an accelerated decline in FEV1%predicted compared with male smokers. Future research powered specifically on gender-relatedchanges in lung function is needed to confirm these early findings.Published: 29 March 2006Respiratory Research2006, 7:52 doi:10.1186/1465-9921-7-52Received: 20 January 2006Accepted: 29 March 2006This article is available from: http://respiratory-research.com/content/7/1/52© 2006Gan et al; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 9(page number not for citation purposes)BackgroundChronic obstructive pulmonary disease (COPD) is amajor cause of death in North America and Europe andthe only major disease for which the morbidity and mor-Respiratory Research 2006, 7:52 http://respiratory-research.com/content/7/1/52tality are still increasing in these continents [1,2].Although COPD is currently the 4th-leading cause of mor-tality and the 12th-leading cause of disability, by the year2020 it will be the 3rd-leading cause of death and the 5th-leading cause of disability worldwide [3,4]. Strikingly, thisprojected increase in COPD-related morbidity and mor-tality will be driven largely by the female population, atrend that started 20 years ago [5]. Some have ascribedthis trend to increased smoking rates in women over thepast two decades [6]. However, there are likely to be otherfactors involved. While female smoking rates have indeedincreased relative to male rates since the 1970's, femalesmoking rates continue to be lower than those for men[5,7]. For example, in the US in 2003, 19% of adultwomen smoked versus 24% of adult men [8]. Moreover,even when women smoke, they consume on averagefewer cigarettes per day and have lower serum cotininelevels compared with men, indicating that cigarette smokeexposure per se cannot account for the rising COPD bur-den in women [9]. These data raise the possibility thatfemale smokers may be biologically more susceptible toCOPD compared to male smokers. We conducted a sys-tematic review and a meta-analysis to determine whetherfemale smokers do or do not have increased susceptibilityto COPD compared with male smokers. Additionally,since age is a major determinant of changes in lung func-tion [10], we sought to determine whether age modifiedMethodsSearch for relevant studiesUsing PUBMED (1966–January 2006) and EMBASE(1980–January 2006) electronic databases, we conducteda comprehensive literature search to identify studiesrelated to the decline of lung function published beforeJanuary 2006. We used lung function sensitive terms(forced expiratory volume, vital capacity) combined withdesign sensitive terms (cohort studies, longitudinal stud-ies, follow-up studies, prospective studies), and smokingsensitive terms (smoke, cigarette, smoking) in oursearches. The electronic searches were supplemented byscanning of the reference lists from retrieved articles toidentify additional studies that may have been missedduring the electronic search. We also contacted the pri-mary authors of retrieved studies for additional data and/or clarification of data, where necessary.Study selection and data abstractionThe primary objective of this study was to compare theannual decline of lung function, measured as percent pre-dicted forced expiratory volume in one second (FEV1 %pred), which is an important phenotype of COPD [11],between men and women stratified according to smokingstatus. To mitigate methodological biases, we limited oursearch to studies that: (1) were population-based; (2)employed a longitudinal cohort design; (3) had a follow-Table 1: Characteristics of studies included in meta-analyses*Source Project name Sample size Women (%) Average age at baseline (year)Duration of follow up (year)Viegi et al,22 2001 Po River Delta Epidemiologic Study, North Italy1774 51 32 8Chinn et al,12 2005 European Community Respiratory Health Survey II, 27 centers, 26 were in western Europe and one was in the USA6654 51 34 9Rijcken et al,13 1995 Vlagtwedde-Vlaardingen study in the Netherlands1619 43 39 25Jedrychowski et al,14 1986Cracow Study in Cracow, Poland 1364 64 40 13James et al,15 2005 Busselton Health Study in Busselton, Western Australia9317 51 42 29Tashkin et al,16 1984 UCLA Population Studies in Los Angeles County, USA2401 54 46 5Sherrill et al,17 1996 Tucson Epidemiology Study of Obstructive Lung Disease in Tucson, Arizona, USA477 41 48 8Connett et al,23 2003† Lung Health Study, 10 centres, nine in the USA, one in Canada5346 37 48 5Xu et al,18 1992 Six Cities Study in the USA 12 080 55 49 6Vestbo et al,19 1996 Copenhagen City Heart Study, Denmark9435 57 53 5Griffith et al,20 2001 Cardiovascular Health Study in the USA 5242 57 73 7Symbols: *: Order in table: average age at baseline; †: The participants were smokers with mild-to-moderate COPD.Page 2 of 9(page number not for citation purposes)the relationship between smoking and lung functiondecline in both men and women.up of at least 3 years; (4) measured FEV1 on at least twodifferent time points; and (5) presented FEV1 data strati-Respiratory Research 2006, 7:52 http://respiratory-research.com/content/7/1/52fied by gender and smoking status. We excluded cross-sec-tional studies, or studies that evaluated occupationalexposures on lung function. We also excluded studieswhose primary focus was on secondhand smoke expo-sures. From each retrieved article, two independent inves-tigators abstracted the following information: projectname, sample size, average age at baseline, proportional-ity of women, duration of follow up, and annual declinerate of FEV1 % pred stratified by gender and smoking sta-tus (Table 1, Table 2). Any questions or discrepanciesregarding these data were resolved through iteration andconsensus.Statistical analysisWe used the annual change in the rate of FEV1% predreported in the studies to conduct the primary analyses.Annual changes in FEV1% pred were calculated by sub-tracting the final FEV1% pred from the baseline value anddividing the difference by the number of years of follow-up. For studies that only provided absolute FEV1 values[12-20], we calculated FEV1% pred by applying a pub-lished prediction equation to the absolute values [21].The reported baseline mean age and height were used inthese calculations. For studies that did not report data onthe subjects' height [12,14,17-19], we imputed 174 cm formen and 161 cm for women because the populations ofthese studies had similar race and age profiles as thosereported in James's study (Table 2) [15]. We compared theannual changes in FEV1% pred between women and menacross smoking status by using male values as the referent.A positive value denoted a larger decline in women, whilea negative value denoted a larger decline in men. Wedecline in lung function since the incidence of obstructiveairways disease in women increases sharply in the post-menopausal period [5]. We used both unweighted andweighted linear regression techniques to assess gender-related differences in the annual decline of FEV1% pred. Inthe weighted analysis, we used the sample size of men andwomen in each smoking category as the weights. All testswere two-tailed in nature and were performed using statis-tical software SAS (version 9.1, SAS Institute, Carey, N.C).ResultsA summary of the search strategy is shown in Figure 1. Theoriginal search yielded 466 and 180 citations in PUBMEDand EMBASE, respectively. The abstracts of these articleswere selected and reviewed. Of these, 67 articles wereretrieved for a detailed review. After excluding studies thatused identical cohorts (n = 41) and studies that had insuf-ficient data (n = 15), we were left with 11 original studiesthat met the inclusion criteria. The baseline characteristicsof these studies are summarized in Table 1. Collectively,there were 55 709 participants in these studies, 52% werewomen, and the baseline average age of the cohorts variedfrom 32 to 73 years. The duration of follow-up rangedfrom 5 to 29 years.Table 2 summarizes the annual decline in FEV1% pred inboth men and women according to smoking status. Ingeneral, older cohorts experienced a faster decline inFEV1% pred/yr compared with younger cohorts and cur-rent smokers had a faster decline in FEV1% pred/yr com-pared with never smokers. Former smokers had similardecline rates in FEV1% pred/yr as never smokers. ThereTable 2: Annual decline rate in FEV1% pred/yr in men and women according to smoking statusSource Average age at baseline (year)Never smokers Former smokers Current smokersWomen Men Difference* Women Men Difference* Women Men Difference*Viegi et al,22 2001 32 NA NA NA -0.12 -0.21 0.09 0.12 0.13 -0.01C hinn et al,12 2005 34 0.78 0.76 0.02 0.91 0.76 0.15 0.88 0.84 0.04Rijcken et al,13 1995 39 0.83 0.96 -0.13 0.89 0.87 0.02 0.97 1.11 -0.14Jedrychow ski et al,14 198640 1.35 1.13 0.22 NA NA NA 1.41 1.46 -0.05James et al,15 2005 42 0.87 0.91 -0.04 0.99 1.01 -0.02 1.05 1.22 -0.17Tashkin et al,16 198446 1.51 1.70 -0.19 1.36 1.65 -0.29 1.97 2.15 -0.18Sherrill et al,17 1996 48 0.50 0.44 0.06 0.49 0.85 -0.36 0.66 0.49 0.17Connett et al,23 200348 NA NA NA 0.37 0.07 0.30 1.20 1.05 0.15Xu et al,18 1992 49 1.08 0.98 0.10 1.11 0.89 0.22 1.42 1.37 0.05Each cell represents annual change in FEV1% pred/yr, unless otherwise indicated.Symbols: *:A positive number denotes a larger decline in FEV1% pred in women; a negative number denotes a large decline in FEV1% pred in men; †: Never smokers and former smokers were combined as non-smokers in the article since they did not differ in FEV1% pred decline.Page 3 of 9(page number not for citation purposes)hypothesized that age might be an important modifier forthe relationship between smoking and gender-relatedwere four studies that provided data on lung functionchanges stratified by the mean daily consumption of ciga-Respiratory Research 2006, 7:52 http://respiratory-research.com/content/7/1/52rettes [15,18,19,22]. There was a dose-dependent acceler-ation in the decline of FEV1% pred/yr (Table 3).In current smokers, with increasing age, women had a sig-nificantly faster decline in FEV1% pred/yr compared withmen (R2 = 0.56; p = 0.008), while in former and neversmokers, age did not significantly modify the rate ofdecline in FEV1% pred/yr between men and women (p =0.775 and p = 0.326, respectively) (Figure 2). There wereno material differences in the results between theweighted and unweighted analyses. The three average age-difference in FEV1% pred/yr regression lines diverged at~45 to 50 years of age. As a sensitivity assessment, werepeated the analysis after excluding the study by Griffithand colleagues [20], which appeared to an outlier in Fig-ure 3. In the sensitivity analysis, female compared withmale smokers still had a faster decline in FEV1% pred/yr(R2 = 0.40; p = 0.050), while in former smokers and neversmokers, there were no gender differences (in formersmokers, R2 = 0.14; p = 0.323; in never smokers, R2 = 0.28and p = 0.179).DiscussionThe present systematic review indicates that female com-pared with male smokers experienced a faster decline inlung function beyond age 45 to 50 years. This trend wasevident even in female smokers who smoked only a mod-est amount of cigarettes (<15 g/day). In non- or ex-smok-ers, there were no significant gender-related changes inFEV1% pred over time. However, there was considerableheterogeneity in the results across the studies (see table 2and figure 3) and as such these data should be interpretedcautiously. Additional prospective longitudinal studiespowered specifically on gender-related changes in lungfunction in the post-menopausal age group are needed toconfirm these observations.The findings from the present study are consistent withother studies, which were not included in this review [21-29]. Prescott and colleagues reported similar findingsfrom two independent population samples: CopenhagenCity Heart Study (CCHS) and Glostrup Population Stud-ies (GPS) [24]. In both samples, when adjusted for pack-years of smoking, female smokers had a faster decline inlung function compared with male smokers. In the CCHS,the estimated excess loss of FEV1 was 7.4 ml per pack-yearin female current smokers and 6.3 ml per pack-year inmale current smokers. In the GPS, the estimated excessloss of FEV1 was 10.5 ml per pack-year in the female cur-rent smokers and 8.4 ml per pack-year in the male currentsmokers. Importantly, in both samples, even after adjust-Table 3: Annual decline rate in FEV1% pred/yr for female and male current smokers stratified by the daily amount of cigarette consumptionSource Average age at baseline (year)Never smokers < 15 g/day 15 g/dayWomen Men Difference* Women Men Difference* Women Men Difference*Viegi et al,22 2001 32 NA NA NA 0.08 0.12 -0.04 0.22 0.15 0.07James et al,15 2005 42 0.87 0.91 -0.04 0.97 1.12 -0.15 1.13 1.26 -0.13Xu et al,18 1992 49 1.08 0.98 0.10 1.16 0.97 0.19 1.51 1.44 0.07Vestbo et al,1 1996 53 1.00 0.83 0.17 1.23 0.98 0.25 1.32 1.22 0.10Total -- 0.99 0.91 0.08 1.10 0.95 0.15 1.35 1.23 0.12Flow diagram of study selectionigure 1Flow diagram of study selection.Search results : N=646PUBMED: n=466EMBASE:  n=180Did not meet criteria or duplicate articles:n=579Studies retrieved: n=67Identical cohort used: n=41Insufficient data: n=15Studies included in analyses : n=11Page 4 of 9(page number not for citation purposes)Each cell represents annual change in FEV1% pred, unless otherwise indicated.Symbols: *: A positive number denotes a larger decline in FEV1% pred in women; a negative number denotes a larger decline in FEV1% pred in men.Respiratory Research 2006, 7:52 http://respiratory-research.com/content/7/1/52ments of daily tobacco consumption and years of smok-ing, female smokers had a higher risk of hospitalizationfor COPD compared with male smokers (relative risk, RR,1.5, 95% confidence interval, CI, 1.2–2.1 in the CCHSand RR, 3.6, 95% CI, 1.4–9.0 in the GPS) [24]. Further-more, women with impaired lung function (FEV1 < 40%pred) had a higher risk of death from all causes (RR, 5.0for women, 2.7 for men) and of deaths from obstructivelung diseases (RR, 57 for women, 34 for men,) comparedwith men [25]. Xu and colleagues studied 1 618 male and1 669 female adults aged 40–69 yrs in the Beijing Respira-tory Health Study [28]. Although female never smokershad better lung function than did male never smokers,female current smokers had significantly lower lung func-female first-degree current or ex-smoking relatives of theprobands were almost two times more likely to demon-strate mild airflow limitation (FEV1 <80% predicted) andover three times more likely to have severe airflow limita-tion (FEV1 <40% predicted) than did male relatives [29].Although the present study did not evaluate effects ofsmoking cessation on lung function in men and women,data from the Lung Health Study indicates that femalequitters may experience larger gains in lung function thando male sustained quitters. In that study, female sustainedquitters experienced a 2.5 fold larger improvement inFEV1% pred than did male sustained quitters after oneyear of smoking cessation [30]. These data, in conjunctionUnweighted analysis of the relationship between age and gender-related differences in the annual decline in FEV1% pred according to smok ng statusFigu e 2Unweighted analysis of the relationship between age and gender-related differences in the annual decline in FEV1% pred according to smoking status Abbreviation: FEV1: forced expiratory volume in one second.Difference in FEV1% pred/yearFaster in men           Faster in women-0.4-0.3-0.2- 35 40 45 50 55 60 65 70 75R2=0.56, P=0.008R2=0.14, P=0.326R2 =0.01, P=0.775Average age at baseline (year)CurrentNeverCurrentNever FormerFormerDifference in FEV1% pred/yearFaster in men           Faster in womenPage 5 of 9(page number not for citation purposes)tion compared with male smokers [28]. In a genetics studyof early onset COPD, Silverman and colleagues found thatwith results of the present systematic review, suggest thatfemale smokers have increased susceptibility for COPD,Respiratory Research 2006, 7:52 http://respiratory-research.com/content/7/1/52especially after age 45 to 50 years. With smoking cessa-tion, however, female quitters may experience a largerrecovery of their lung function than do male quitters.Although our study was not designed to evaluate theeffects of smoking in adolescent youths, previous studiesindicate that smoking may also have a greater (negative)impact on lung growth in female than male youngsters.Gold et al [31] found that among adolescents, smokingfive or more cigarettes a day, as compared with neversmokers, was associated with a 1.09% per year reductionin the growth rate of FEV1 in girls, while for boys, smokingreduced FEV1 growth by only 0.20%/yr. Patel et al [27]found that exposure to cigarette smoke during childhoodThus, the relationship between gender, age and FEV1changes may be U-shaped.The mechanisms responsible for the increased susceptibil-ity of women to cigarette smoke are largely unknown.There is now a general consensus that inflammation is atthe heart of the pathobiology of COPD and that theinflammatory process involves both the lung (airways andparenchyma) and the systemic circulation [32-34]. Theintensity of the inflammatory process in the airways andin the systemic circulation is associated with severity ofFEV1 impairment [33,34]. Whether women are morelikely to demonstrate airway inflammation comparedwith men is unknown. Interestingly, women in the gen-Weighted analysis of the relationship between age and gender-related differences in the annual decline in FEV1% pred for cur-rent smokersFigure 3Weighted analysis of the relationship between age and gender-related differences in the annual decline in FEV1% pred for current smokers The regression line is weighted by the numbers of current smokers. The diameter of each circle is proportional to the number of current smokers in each study. Abbreviation: FEV1: forced expiratory volume in one second.-0.4-0.3-0.2- 35 40 45 50 55 60 65 70 75Difference in FEV1% pred/yearFaster in men          Faster in womenAverage age at baseline (year)Chinn12Rijcken13Jedrychowski14James15Tashkin16Sherrill17Connett23Xu18Vestbo19Griffith20Viegi22R2=0.53, P=0.011Difference in FEV1% pred/yearFaster in men          Faster in womenPage 6 of 9(page number not for citation purposes)was an independent risk factor for the development ofobstructive airways disease in women but not in men.eral population are known to have higher circulating C-reactive protein levels, a marker of systemic inflamma-Respiratory Research 2006, 7:52 http://respiratory-research.com/content/7/1/52tion, but only after ~50 years of age [35]. Since activesmoking amplifies systemic inflammation, independentof other factors [36], smoking-inflammation pathwaymay be an important contributor to the increased riskobserved in women in the peri and post-menopausal peri-ods. Further research is needed to confirm this hypothesis.Another potential mechanism may relate to bronchialhyperresponsiveness. In the Lung Health Study, there wasa higher prevalence of bronchial hyperresponsivenessamong women than among men (85% in women versus59% of the men) [37]. In another population-basedstudy, Leynaert and coworkers demonstrated increasedprevalence of bronchial hyperresponsiveness in women,even after adjustments for respiratory symptoms, atopy,or lung function parameters [38]. Paoletti et al [39] alsofound increased risk of bronchial hyperresponsivenessamong women compared with men independent of base-line lung function. In women, they observed that currentsmokers had significantly more reactive airways than didnon- or ex-smokers. However, in men, smoking statusmade no material impact on bronchial responsiveness[39]. These data may be clinically relevant since bronchialhyperresponsiveness has been associated with increasedrisk of both COPD progression [40] and COPD mortality[41].Additionally, cigarette smoke may modify hormonal sta-tus in women, which may affect lung function. Womenwho are active smokers become relatively estrogen defi-cient compared with non-smokers because cigarettesmoke induces cytochrome P450 isoenzymes CYP1A1and CYP1A2, which alter estrogen metabolism leading toincreased production of inactive catechols [42]. Hormonereplacement therapy in the post-menopausal period isassociated with improved lung function, reducing the riskof airflow obstruction by ~25% [43]. Hormone replace-ment therapy also reduces bronchial hyperresponsivenessin post-menopausal women [44].An alternative hypothesis for higher susceptibility offemales to smoking may be differences in lung develop-ment between females and males. Interestingly, relative tomale rates, female rates of obstructive airway diseasesincrease sharply during adolescence [45]. Before pubes-cence, girls have smaller lung volumes than do boys butgenerate higher flows [46]. During teenage years, airwaysand lung volumes demonstrate isotropic growth in boys.In girls, however, airway growth becomes disproportion-ately smaller relative to lung volume growth, indicatingdysanapsis [47]. Thus, for any given lung volume and size,women have smaller airways compared with men, whichmay make the airways more susceptible to the adverseThere were several limitations to the study. Firstly, weused only a crude marker of smoking (i.e. self-report ofsmoking). Since male smokers generally smoke more cig-arettes than do female smokers and have a longer smok-ing history, we may have underestimated the true effectsof cigarette smoking in the female population [9]. Sec-ondly, as with most systematic reviews, publication bias isa source of concern. Figure 3 indicates that there were nomaterial differences in results between large and smallstudies, suggesting that publication bias did not signifi-cantly affect the results.ConclusionWe found that beyond age 45 to 50 years, female smokersappear to experience an accelerated decline in FEV1%pred/yr compared with male smokers. Additional pro-spective longitudinal studies powered specifically on gen-der-related changes in lung function in the post-menopausal age group are needed to confirm these obser-vations. In view of the growing incidence of smoking andthe COPD in the female population, there is an urgentneed to promote smoking abstinence and cessation in thefemale population.AbbreviationsCCHS: Copenhagen City Heart StudyCOPD: chronic obstructive pulmonary diseaseFEV1: forced expiratory volume in one secondGPS: Glostrup Population StudiesPred: predictedRR: relative riskYr: yearCompeting interestsThis project is supported by ICEBERGS (InterdisciplinaryCapacity Enhancement: Bridging Excellence in Respira-tory Disease and Gender Studies), which is funded by theCanadian Institutes of Health Research (IGH / ICRH), theCanadian Lung Association, and the Heart and StrokeFoundation of Canada.Authors' contributionsAll authors have made substantial intellectual contribu-tion to the interpretation of the results and drafting of themanuscript.AcknowledgementsPage 7 of 9(page number not for citation purposes)effects of cigarette smoke. 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