This case-control study is among only a few observational studies to have comprehensively examined the relationship between reproductive and hormonal factors and lung cancer in women in the U.S. After controlling for exposure to active and passive exposure to cigarette smoke, education, and income, the results using hospital-based and population-based controls did not differ substantially. We found that greater number of live births was associated with a reduced risk of non-small cell lung cancer. Other reproductive and hormonal factors, including long-term use of oral contraceptive and menopausal hormone therapy, were not associated with risk. Although we hypothesized that greater exposure to endogenous or exogenous estrogens would be associated with an increased risk of lung cancer, especially among current smokers, the results overall were not stronger among current compared to former or never smokers.
We observed that, compared to women who had one or two births, women with five or more births had a significantly lower risk of lung cancer, regardless of smoking status. Our results are in agreement with two recent prospective studies, one among non-smoking women in the Singapore Chinese Health Study12
and another among non-smoking women in Shanghai13
, both having found significant inverse relationships between parity and risk of lung cancer. Two hospital-based case-control studies also observed inverse associations with parity, including one conducted in Singapore, particularly among lifetime never-smokers17
and another conducted among non-smoking and smoking women in the Czech Republic18
. However, other epidemiologic studies found either null8,9,14-16
or positive associations10-11
. We did not identify any potential common biases arising from these studies that could clearly explain the range of inconsistent findings. While confounding by cigarette smoking may be the most obvious explanation, analyses restricted to never-smoking women have yielded positive11
, and, including the current study, inverse associations12,13,17
between parity and risk of lung cancer. These contradictory findings may have arisen due to chance alone, as the number of lung cancer cases was typically low. It is plausible that a greater number of births may reduce the risk of lung cancer through a decline in circulating estrogens after pregnancy. For instance, among 216 healthy postmenopausal women in the Nurses’ Health Study, higher parity was associated with reduced levels of estrone sulfate, and older ages at first birth were associated with lower percent bioavailable estradiol33
No clear patterns emerge from the scant evidence on lung cancer risk in relation to other reproductive factors, such as menstrual cycle regularity, type of menopause, and ages at menarche, first, and last birth8,9,11-21
. Some studies indicate that women who reach menopause naturally at relatively young ages are at slightly increased risk of lung cancer9,13,15,16
, which may partly reflect smoking behaviors since smokers tend to reach menopause at earlier ages34
. Nonetheless, two of these studies were conducted among never-smoking women9,13
. The present study shows that women who reached natural menopause before age 50 were at slightly increased risk (vs. 50-54, OR=1.50, 95% CI 0.97, 2.31), though the results were weaker among former and never smokers. Future studies examining serum estrogens and lung cancer may help to more fully understand the role of reproduction, endogenous hormones, and lung cancer risk.
Few studies have examined the association between oral contraceptive use and risk of lung cancer, but these have yielded mostly null results8,10-12,14,21
. A case-control study in Germany showed a reduced risk with use of oral contraceptives, particularly among smokers15
; however, no relationship was observed with increasing duration of use. Our findings also do not suggest that oral contraceptive use influences the risk of lung cancer in women, even among current smokers.
The evidence as a whole for hormone therapy is equivocal, with some studies providing evidence of a positive association8
, some showing inverse associations14,15,23-29
, or no overall association9-13,19,22,23
. Combined estrogen and progestin was not associated with lung cancer in a randomized controlled trial, the Women’s Health Initiative, though follow-up for this study was only 5.2 years35
. Differences in the results across studies may be attributable to a variety of factors, including recall or selection biases, differences in outcome (i.e., total lung cancer or a particular histologic type), or differences in definition or categorization of menopausal hormone therapy. However, our study provides evidence that uncontrolled confounding by cigarette smoking may be partially responsible for some of the reported inverse associations between HRT use and lung cancer in women. For instance, we observed a significantly reduced risk for the use of menopausal hormone therapy when comparing cases to population controls, which was attenuated after the adjustment for other factors, specifically cigarette smoking status, duration, and intensity. In contrast, age-adjusted comparisons of lung cancer cases to hospital controls, who were matched to cases by pack-years of smoking, showed no association with risk.
Recent clinical and laboratory evidence suggests that estrogen may directly or indirectly influence the risk of lung cancer, though the potential mechanisms in humans are unclear. Estrogen receptors, including ERα and ERβ, are expressed in normal and cancerous human lung tissue36
. Activation of ERα induces lung differentiation and maturation, while stimulation of ERβ by estradiol leads to proliferation of lung cancer cells37
. Estrogen receptor α (ERα) appears to play a direct role in the up-regulation of cytochrome p450 (CYP) enzymes in the liver, which oxidize components of cigarette smoke (i.e., polycyclic aromatic hydrocarbons (PAHs) such as benzo[a
]pyrene (BP) into carcinogenic derivatives38
. The metabolism of nicotine and cotinine by CYP enzymes is accelerated in women compared to men, particularly during pregnancy or when taking estrogen-only birth control pills7
. Estrogen may also aid in the formation of PAH-related DNA adducts39
. Laboratory studies in rodents support a role of estrogen in the promotion of non-small cell lung cancer40
. While this evidence suggests that greater exposure to endogenous and exogenous estrogen would, if anything, lead to an increased risk of lung cancer, in general, this hypothesis has not been strongly supported by results from epidemiologic studies.
The ability to compare results using both population and hospital controls was a major strength of this study. In general, case-control studies are prone to several biases, including differential recall of past exposures between cases and controls, greater likelihood of population controls comprising healthy volunteers, and the inclusion of hospital controls who are more or less likely to be hospitalized due to the exposure of interest (Berkson’s bias)41
. These types of biases were unlikely to have strongly influenced findings from the present study given that hospital- and population-based controls were not recruited based on their reproductive history or hormone use, and despite the greater similarities of the cases to the hospital compared to population controls in terms of smoking, education, and household income, the results did not differ substantially between the two groups after adjustment for smoking and other covariates. A detailed questionnaire regarding lung cancer risk factors and reproductive history, which allowed us to control for active and passive smoking, income, and education, and to examine a variety of reproductive and hormonal exposures, was an additional strength of this study. Given the wide range of smoking behaviors among the women in this study, we were able to directly address the hypothesis that cigarette smoking modifies the association between endogenous and exogenous estrogen exposure and lung cancer risk.
This study suggests that, in general, endogenous and exogenous hormone exposure was not associated with lung cancer risk after accounting for active and passive cigarette smoking and indicators of socioeconomic status. However we observed that a higher parity was associated with lower lung cancer risk among never, former, and current smokers. The question of whether the inverse association between number of births and lung cancer risk may be explained by hormonal changes during or after pregnancy warrants further investigation.
Novelty and impact of the paper Although estrogen may promote lung tumor growth directly or by modulating cigarette metabolism, epidemiologic evidence linking reproductive and hormonal factors with lung cancer risk has been inconsistent. Our study finds a protective role for parity, confirming results from two recent prospective studies of nonsmoking women and supporting the need for a more comprehensive investigation of the hormonal role of pregnancy in lung carcinogenesis.