In this analysis of reproductive factors and lung cancer incidence, younger age at menopause and longer duration of oral contraceptive use were associated with increased risk. These associations were strongest among current smokers and small cell histology, which likely reflects the high proportion of current smokers within this histologic subtype. Increased risk was also seen with fewer children among never smokers and older age at first birth among current smokers.
The literature on hormonal factors and lung cancer has expanded in the past several years, reflecting the increased interest in this field. However, the methods of study design are heterogeneous across studies, which may explain the inconsistent reports in the literature. Despite the inconsistencies, several studies have reported an inverse association between age at menopause and lung cancer incidence. In a prospective analysis of the Shanghai Women’s Health Study with approximately 75,000 participating Chinese women who were lifetime non-smokers, the authors reported higher lung cancer risk with younger age at menopause [26
]. Other population based studies have also reported similar trends albeit not statistically significant [24
]. However, there also are reports of null association [16
] and one report of decreased risk with younger age at menopause [25
Regarding parity, two prospective cohort studies of never smokers have reported an inverse association in which decreased risk was seen with increasing parity [23
]. This is consistent with our results in which the inverse relationship was seen primarily in never smokers. The role of parity in other studies which include smokers is less clear. In regards to the age at first birth, literature is inconsistent with reports of decreased [19
] and increased [23
] risk with increasing age at first birth as well as reports of no significant association [16
]. The association with the use of oral contraceptives is inconsistent as well with a few reports of decreased risk [22
]. However, most studies report a null association [16
Our findings suggest that endogenous hormones during premenopausal years may have a protective role in lung cancer development. This is evident by the increased lung cancer risk with younger age at menopause and longer use of oral contraceptives in which the contraceptive mechanism is by suppressing ovulation and the release of endogenous hormones [34
]. The protective role appears to be greater among smokers and a possible mechanism may be the interaction between estrogen and cigarette smoke metabolism. CYP1A1 and CYP1B1
, members of the cytochrome P450 family of enzymes involved in phase I drug metabolism, are induced by cigarette smoking and they activate cigarette smoke carcinogens such as polycyclic aromatic hydrocarbons and also participate in estradiol metabolism [35
]. Several investigators have hypothesized that this interaction may be the mechanism by which smokers are found to have lower estrogen levels compared to nonsmokers [36
]. Conversely, there are reports of CYP1A1
upregulation by estrogen-α and estrogen-β receptors [35
]. The effect of estrogen on phase II metabolism enzymes is not clear although increased glutathione S-transferase (GSTT1
) mRNA expression has been associated with higher estradiol levels [35
]. This suggests that estrogen may influence the metabolism of smoking constituents and lead to differential lung cancer outcomes among smokers.
Another possible mechanism for the protective effect of premenopausal endogenous hormones may be the role of progesterone in lung cancer development. In a preclinical study by Ishibashi et al
, cellular proliferation was inhibited when lung cancer cell lines with progesterone receptors were incubated with progesterone [11
]. However, the literature on progesterone in lung cancer is limited and the role of progesterone and its interaction with estrogen in lung cancer remains unclear.
In regards to PMH use, we did not detect a significant association between PMH use and overall lung cancer incidence, although differential trends were seen in the various histologic subtypes. While reproductive factors reflect the effect of hormonal exposure during premenopausal years, the use of hormone replacement therapy exerts its effect during postmenopausal years. As described earlier, the literature on PMH use and lung cancer is conflicting with reports of protective, null and harmful associations [14
]. More recently, the Women’s Health Initiative investigators reported an increase in mortality and a nonsignificant increase in incidence of non-small cell lung cancer in the women who were randomized to the estrogen and progestin combination arm [41
]. A similar trend has been reported in a prospective cohort study of never smokers in which the majority of cases were adenocarcinoma [23
] and in two other case-control studies in which the primary outcome was adenocarcinoma [24
]. Also, the VITAL (Vitamins and Lifestyle) study recently reported an increased risk of lung cancer incidence with estrogen and progestin use [42
]. We did not detect a significant increased risk with estrogen and progestin use although a nonstatistically significant trend of increased risk was detected for squamous and adenocarcinoma. These findings in addition to the results of our analysis suggest that the role of postmenopausal hormones likely differ from that of premenopausal reproductive hormones and that the effect may vary in the different histologic subtypes.
There are many challenges in elucidating the role of hormones in lung carcinogenesis. One of the challenges is the fact that there are many situations in which a hormonal function could be altered. For instance, the action of the same hormone may vary in pre- versus postmenopausal women, smokers versus never smokers, and in the pathogenesis of tumors of various histologic subtypes. Furthermore, the effect of hormones may also depend on the receptor status of lung cancer cells. In a study by Schwartz et al
, the investigators found a protective association between PMH use and lung cancer but the association was seen primarily in lung cancers that harbored estrogen receptors [16
]. This suggests that the role of reproductive hormones as well as exogenous hormones may be restricted to those cancers that possess the receptors.
There are several strengths in this study. First, this study is prospective in design, which avoids the biases associated with retrospective studies, and the large number of cases and participants with long duration of follow up have allowed us to perform various subgroup analyses. Although the number of exposure variables and subgroups in this study increases the likelihood of chance findings, all analyses were hypothesis-driven and exposure variables were chosen a priori, thus no adjustment was made for multiple comparisons. Another strength of this study is that information on exposures and smoking variables was updated every two years, which reduces misclassification bias. A limitation is the small number of cases among never smokers. Accordingly, the lack of significant findings in never smokers may be due to the small number of cases.
In conclusion, the results of our study add to the increasing body of literature which indicates that female hormones may influence lung carcinogenesis. Their role is likely modest, especially in the presence of powerful risk factors such as smoking. However, additional research of this topic is warranted as it may lead to better understanding of lung cancer biology and possibly to development of novel therapeutic strategies. In order to achieve this goal, an integrative approach will be necessary spanning from molecular and clinical epidemiology research, to clinical prevention and therapeutic trials.