1 Institute of Radiation Hygiene, BfSFederal Office for Radiation Protection, Neuherberg, Germany.
2 Tumour Centre, University of Regensburg, Regensburg, Germany.
3 Institute of Epidemiology, GSFNational Research Center for Environment and Health, Neuherberg, Germany.
4 Institute of Biometry, Epidemiology and Data Information Processing, School of Veterinary Medicine, University of Hannover, Hannover.
Correspondence: Dr Michaela Kreuzer, BfS-Institute of Radiation Hygiene, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany. E-mail: mkreuzer{at}bfs.de
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Abstract |
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Methods We used data of a case-control study on lung cancer conducted from 1990 to 1996 in Germany, including 811 histologically confirmed female cases and 912 female population controls. Information on various menstrual and reproductive factors, use of oral contraceptives (OC), hormone replacement therapy (HRT), and smoking was gathered through personal interviews using a structured questionnaire. Odds ratios (OR) and 95% CI adjusted for age, region, smoking, and education were calculated via logistic regression.
Results A reduction in lung cancer risk was observed with the use of OC (OR = 0.69; 95% CI: 0.510.92), but no trend in risk with increasing duration of use, age at first use, or calendar year of first use was present. A history of HRT was associated with a reduced risk (OR = 0.83; 95% CI: 0.641.09), particularly after long duration (7 years) (OR = 0.59; 95% CI: 0.370.93). No clear association was found with regard to age at menarche, length of menstrual cycle, number of live-births, and age at menopause. Overall results did not differ much by histological cell subtype. The reduction in lung cancer risk associated with the use of exogenous hormones was primarily seen among smoking women.
Conclusions Our data provide evidence for a possible role of hormonal factors in the aetiology of lung cancer in women.
Accepted 14 December 2002
Differences in the histological distribution of lung carcinoma between men and women, which cannot be fully explainedby differences in smoking habits,1 and a possibly greater susceptibility of women to tobacco carcinogens than men,2,3 indicate that sex-specific hormones may play a role in the genesis of lung cancer. Siegfried4 hypothesized that oestrogens may possibly influence lung cancer development, either through direct promotion by oestrogen of cell proliferation in the lung, or as a result of the influence of estrogen on lung-carcinogen metabolism or development of lung diseases that predispose to lung cancer. Evidence for an association between hormonal factors and lung cancer among women is available from several lines. First, possible biological evidence was given by some experimental studies indicating the presence of steroid receptors in some lung tumour types.58Second, a familial aggregation of cancers of the reproductive system among female lung cancer patients9,10 in addition to an increased risk oflung cancer in female survivors of a primary cancer of the reproductive organs1117 have been described, indicating a possibly endocrine-related common aetiology of cancers of the lung and the reproductive organs. Third, some menstrual1820 and reproductive factors18,2123 have been associated with lung cancer risk in women. Women having ever used oral contraceptives (OC) was suggestive of a reduced lung cancer risk.23 Inconsistent results have been provided with respect to oestrogen replacement therapy.21,2426 A positive synergism between smoking and oestrogen replacement therapy was reported by Taioli and Wynder21 and was hypothesized as a possible explanation for a heightened smoking risk of women compared with men.
The aim of the present analysis of the data of a case-control study on lung cancer in Germany was to examine the relation of various hormonal factors in the aetiology of lung cancer in women. Particular emphasis was given on estimating these effects separately in smokers and non-smokers and for different histological types. Findings of this study on other risk factors have been published previously.2730
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Materials and Methods |
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A total of 4276 cases (3465 men and 811 women) and 4629 controls (3717 men and 912 women) were personally interviewed by trained interviewers. A structured questionnaire was used to obtain information on demographic characteristics, residential history, active and passive (non-smokers only) smoking history, job history, personal and family medical history, dietary habits, and endocrine factors. Subjects were defined as smokers if they had ever smoked regularly (at least one cigarette per day) for 6 months. Active and former smokers were summarized as smokers and were compared with non-smokers. One-year radon measurements were performed in the current residence.30
Among women, detailed information on hormonal factors such as age at first and last menstrual period, average length of menstrual cycle, age at first pregnancy, and number of full-term pregnancies was collected. Menopausal status could be determined only indirectly by cessation of menstrual periods. Women reporting that they had still their menstrual periods at the date of interview were defined as premenopausal women. Those reporting cessation of menstruation were asked about age at last menstrual period defined as age at menopause in the analyses and about cause of menopause (natural, surgery, radiation therapy, hormonal therapy, or others) including information on age at genital surgery. To assess the role of exogenous hormones women were asked about having ever used OC, age at first use, and duration of use in years. In addition, they were asked whether they had ever used hormones other than OC as, for example, oestrogen replacement therapy in menopause. For positive response, information was recorded on age at first use, and duration of use in years, but not on type of hormones or dosage.
The statistical analyses were based on multivariate techniques for case-control studies. Conditional logistic regression models were used to estimate odds ratios (OR) and 95% CI with strata for age and region and adjusting for educational level (<10 years, 10 years of school attendance), cumulative tobacco smoke (log(packyear+1)), and years since stopping smoking (current smoker/quit <5 years ago or quit >5 years ago). As additional potential confounders for the association of endocrine factors and lung cancer risk we quantified variables for occupational exposure to known or suspected lung carcinogens as described previously,28 exposure to environmental tobacco smoke in terms of the summary indicator of ETS-exposure (low, medium, or high) for non-smokers,29 and time-weighted average radon exposure in the current residence as continuous variable.30 Since risk estimates were little affected by these confounder variables we present OR adjusted for age, region, smoking, and education only. Trend tests were performed using the continuous variable in the regression model and presenting the corresponding two-sided P-value. For categorization of variables tertiles of the distribution among controls was used. Subgroup analyses were performed after stratification for smokers and non-smokers and by histological type using unconditional logistic regression models. Potential differences in OC and hormone replacement therapy (HRT) use or other factors between women from East and West Germany were considered by repeating all analyses separately for each study area and discussing differences if present.
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Results |
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In Table 5, risk estimates concerning use of hormones stratified for smokers and non-smokers and for histological cell type are given. Substantially more women used OC among smokers (55% of the controls and 38% of the cases) than among non-smokers (31% and 27%, respectively). This may partly be due to the fact that smoking women belong to a younger generation than non-smoking women. Smoking seems to modify lung cancer risk associated with the use of OC. Among smokers, the OR was significantly reduced for users compared with lifetime non-users (OR = 0.50; 95% CI: 0.340.74); whereas no effect was present among non-smoking women (OR = 1.18; 95% CI: 0.781.79). For all major histological cell types a reduction in risk was observed, which was most pronounced for small cell lung cancer. In all groups, however, no decrease in lung cancer risk with increasing duration of use was apparent. In the group of smoking women, lung cancer risk by calendar year of first OC use was associated with similar risk estimates at each category, showing OR of 0.47, 0.51, and 0.47 for women who started to use OC in the 1960s, 1970s, and 1980s, respectively. The corresponding OR in the group of non-smoking women were 1.41, 0.88 and 1.63, respectively.
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Due to the lack of information on composition of HRT, we analysed separately the group of women with surgical menopause, who are likely to have had hysterectomy and consequently their HRT therapy may have consisted of oestrogens only (Table 6). A positive history of HRT was associated with a reduced lung cancer risk of OR = 0.8 for all women and among both smoking and non-smoking women. Again long-term users (
7 years) showed consistently lowered risk estimates over all sub-groups.
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Discussion |
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Overall we found no clear association between age at natural (or both natural and surgical) menopause and lung cancer risk, and only weak evidence for earlier ages at natural menopause among smoking cases compared with smoking controls. A significant reduction in risk associated with late age at natural and surgical menopause was reported by Wu et al.,23 while Taioli and Wynder21 noted a significant reduction in lung cancer risk with early age at natural and surgical menopause (40 years). No relation was found in a case-control study among Chinese women.22 An anti-oestrogenic effect of smoking has been reported, leading to a 1- to 2-year earlier occurrence of natural menopause among smoking women compared with non-smoking women.32,33 This was confirmed in our study, showing a mean age at natural menopause of 50.7 years among non-smoking controls, and 49.8 years and 49.0 years among smokers of <20 pack-years and >20 pack-years, respectively. In the present study among postmenopausal women, type of menopause was associated with an 1.13-fold non-significantly increased lung cancer risk among women with surgical menopause (not shown). No information was available on type of surgery such as removal of ovaries. Two previous reports found an increase in lung cancer risk after hysterectomy,23,34 being highest among women whose ovaries remained intact.23 A hysterectomy had been suspected as risk factor for lung cancer, because of the potential of trauma-associated lung embolism.23
Few epidemiological studies examined the role of the use of OC in the aetiology of lung cancer. Wu-Williams et al.22 noted an OR of 0.8 (95% CI: 0.51.2) for lung cancer among women who had used OC as compared with non-users. This finding is consistent with that reported by Taioli et al.,21 (OR = 0.8; 95% CI: 0.51.5). A significant trend of reduction in risk of adenocarcinoma with increasing duration of use was noted by Wu et al.,23 although based on short-term users only (averaging 45 months among cases and 61 months in controls). All these studies controlled for smoking and made no distinction in risk between smokers and non-smokers. Our overall smoking adjusted risk estimate is in accordance with previous studies (OR = 0.7; 95% CI: 0.50.9), yet we found a significant interaction between smoking status and risk of lung cancer associated with the use of OC, showing a reduction in risk by 50% in smokers only. It is unclear whether this finding is spurious, because no doseresponse relationship regarding duration of use was present. Also, women who started to use OC in the 1960s, the years with the highest level of oestrogens in OC, showed a similar lung cancer risk than those who started later when oestrogen levels were drastically reduced. It cannot be excluded that part of the observed reduced risk among smokers may be explained by residual confounding through social class. Differences between East and West German women were not present, neither with respect to the proportion of OC users, duration of use, nor the risk estimates. The use of OC was inversely associated with age at first pregnancy among both smokers and non-smokers. Among smokers, at each level of age at first pregnancy a reduced lung cancer risk with the use of OC was found, indicating that OC use seems to be an independent risk factor.
Inconsistent findings were available with respect to lung cancer risk associated with HRT. In a large population-based cohort of women who had received HRT,25 a 30% excess risk for lung cancer was observed (95% CI: 0.91.7), which, however, could also have been due to a higher prevalence of smokers in the cohort than in the background population. Two previous case-control studies found no association between HRT and lung cancer.18,23 Ettinger et al.26 reported a lower risk of death from lung cancer in a female cohort of long-term postmenopausal oestrogen replacement hormone users compared with age-matched postmenopausal non-users (relative risk = 0.22; 95% CI: 0.041.15, adjusted for current smoking). Our results indicate a lowered lung cancer risk with HRT, particularly among long-term users and independent of cell type. It is difficult to evaluate this effect without data on dosage and composition of hormones. When we limited the analyses to women with surgical menopause, who are most likely to have received oestrogens only, we found a reduction in risk by 50% for long-term users over all sub-groups. The reduction in risk was more pronounced among women starting in the years before 1980 than among those starting later, where probably levels of oestrogens were reduced. It should be noted that use of HRT differed between East and West German women. East German women were treated much less with HRT (16% among controls) than West German women (37% among controls) and for a shorter time period. Lung cancer risk associated with a positive history of HRT differed slightly between East German (OR = 1.10; 95% CI: 0.611.96) and West German women (OR = 0.80; 95% CI: 0.591.08).
A 70% significant excess risk of adenocarcinoma (95% CI: 1.02.8) for HRT users versus non-users including a non-significant increase in lung cancer risk with increasing duration of use was demonstrated by Taioli et al.21 Interestingly, the increase in risk was primarily seen among smokers, while no effect was present among non-smokers.21 Some studies which provided evidence for a higher susceptibility of lung cancer in women than men given a similar level of tobacco smoke3 hypothesized that this observed positive synergism between HRT and smoking might be some possible explanation. Our results contradict a positive synergism of HRT with smoking. Several factors may contribute to these differences. First our study subjects were more likely to report long-term use than those of Taioli;21 second, composition and dosage of hormones may differ in both studies (unfortunately both studies did not collect this information); third, differences in smoking habits or residual confounding due to social class may produce different risk estimates.
There is increasing evidence that oestrogens may play a role in the genesis of lung cancer, yet the mechanism is unclear. Experimental studies suggest the presence of oestrogen and other steroid receptors in lung tissue.58,35,36 Steroids are known to be involved in the differentiation and metabolism of pulmonary epithelial cells. The presence of these receptors has been suggested as indicative of their common role in the regulation of cancer growth in various organs36 and of potential hormonal responsiveness of these tumours.20 Since adenocarcinomas showed a significantly higher incidence of steroid receptors compared with other lung cancer cell types,4 some investigators hypothesized that the greater proportion of adenocarcinoma among female compared with male cases1 may be in part due to endocrine-related factors. In addition, a greater proportion of oestrogen receptors has been detected in females than in males.37 In the present study, however, no major differences in risk by histologic type associated with the various hormonal factors were observed.
One of the main strengths of this study is the large sample size of lung cancer cases and controls that made the overall risk estimates relatively stable and allowed stratification by smoking status and histology. All interviews were conducted with the subjects themselves in face-to-face interviews, in contrast to studies in which surrogates were used. All cases were histologically or cytologically verified as tumours that originated in the lung. In addition, an independent review of about 75% of the diagnosed material was completed, in order to classify the cell type uniformly. Moreover, we controlled for most potential confounders.
Nevertheless, there are several limitations in our study. Some potential methodological problems concern the low response rate among controls and recruitment of cases. In Germany, cancer patients had to be recruited via study hospitals, since no overall cancer registry existed, thus the extent of representativeness of our cases is not measurable. In previous analyses based on the former East German cancer registry we estimated a coverage of about 50% for the eastern study area. A selection bias due to the poor response among controls cannot be completely ruled out. In a sub-sample of refusals, a non-response-analysis was conducted. Non-response was mainly due to refusal of long-term measurements of radon (1 year) required in the subjects homes (38%), no time for interview and organization of the measurement (13%), followed by illness (13%) and other reasons. As the controls tended to be more highly educated than the cases and there may be a positive correlation between low social class and some of the hormonal factors such as young age at first pregnancy and less frequent use of hormones, special attention has been given to a potential selection bias by controlling for educational level. However, uncontrolled residual confounding by differential socioeconomic status and life style cannot be excluded and could have resulted in somewhat lowered risk estimates. Another potential weakness of our study is the lack of information on type and dosage of hormones. Since this study was primarily conducted to investigate the effects of residential radon on lung cancer risk, no detailed information on hormones was collected. Some of the observed differences in risk between smokers and nonsmokers might be explained by differences in type and dosage of hormones.
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Conclusion |
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KEY MESSAGES
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Acknowledgments |
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References |
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