Early natural menopause is associated with poor lung health and increased mortality among female smokers

Abstract

Background: Early natural menopause has been regarded as a biomarker of reproductive and somatic aging. Cigarette smoking is the most harmful factor for lung health and also an established risk factor for early menopause. Understanding the effect of early menopause on health outcomes in middle-aged and older female smokers is important to develop preventive strategies.

Objective: This study aimed to examine the associations of early menopause with multiple lung health and aging biomarkers, lung cancer risk, and all-cause and cause-specific mortality in postmenopausal women who were moderate or heavy smokers.

Study design: This study was conducted on postmenopausal women with natural (n=1038) or surgical (n=628) menopause from the Pittsburgh Lung Screening Study. The Pittsburgh Lung Screening Study is a community-based research cohort of current and former smokers, screened with low-dose computed tomography and followed up for lung cancer. Early menopause was defined as occurring before 45 years of age. The analyses were stratified by menopause types because of the different biological and medical causes of natural and surgical menopause. Statistical methods included linear model, generalized linear model, linear mixed-effects model, and time-to-event analysis.

Results: The average age of the 1666 female smokers was 59.4±6.7 years, with 1519 (91.2%) of the population as non-Hispanic Whites and 1064 (63.9%) of the population as current smokers at baseline. Overall, 646 (39%) women reported early menopause, including 198 (19.1%) women with natural menopause and 448 (71.3%) women with surgical menopause (P<.001). Demographic variables did not differ between early and nonearly menopause groups, regardless of menopause type. Significant associations were identified between early natural menopause and higher risk of wheezing (odds ratio, 1.65; P<.01), chronic bronchitis (odds ratio, 1.73; P<.01), and radiographic emphysema (odds ratio, 1.70; P<.001) and lower baseline lung spirometry in an obstructive pattern (-104.8 mL/s for forced expiratory volume in the first second with P<.01, -78.6 mL for forced vital capacity with P=.04, and -2.1% for forced expiratory volume in the first second-to-forced vital capacity ratio with P=.01). In addition, early natural menopause was associated with a more rapid decline of forced expiratory volume in the first second-to-forced vital capacity ratio (-0.16% per year; P=.01) and incident airway obstruction (odds ratio, 2.02; P=.04). Furthermore, women early natural menopause had a 40% increased risk of death (P=.023), which was mainly driven by respiratory diseases (hazard ratio, 2.32; P<.001). Mediation analyses further identified that more than 33.3% of the magnitude of the associations between early natural menopause and all-cause and respiratory mortality were explained by baseline forced expiratory volume in the first second. Additional analyses in women with natural menopause identified that the associations between continuous smoking and subsequent lung cancer risk and cancer mortality were moderated by early menopause status, and females with early natural menopause who continued smoking had the worst outcomes (hazard ratio, >4.6; P<.001). This study did not find associations reported above in female smokers with surgical menopause.

Conclusion: Early natural menopause was found to be a risk factor for malignant and nonmalignant lung diseases and mortality in middle-aged and older female smokers. These findings have strong public health relevance as preventive strategies, including smoking cessation and chest computed tomography screening, should target this population (ie, female smokers with early natural menopause) to improve their postmenopausal health and well-being.

Keywords: early menopause; lung aging; lung cancer; mortality; smoker.

Figure 1.. Interactions between early natural menopause and continuous smoking for affecting lung cancer incidence and cancer mortality.

Kaplan-Meier curve showed that females with early menopause who continued smoking had the highest lung cancer risk (1A) and cancer mortality (1B) compared to other three combinations. With females with non-continuous smoking & non-early menopause as the reference, hazard ratios for lung cancer were 0.87 (95%CI=0.39–1.96, P=0.73) for non-continuous smoking & early menopause, 2.05 (95%CI=1.26–3.35, P<0.01) for continuous smoking & non-early menopause, and 4.65 (95%CI=2.55–8.49, P<0.001) for continuous smoking & early menopause. With females with non-continuous smoking & non-early menopause as the reference, hazard ratios for cancer mortality are 0.91 (95%CI=0.43–1.95, P=0.81) for non-continuous smoking & early menopause, 1.55 (95%CI=0.94–2.56, P=0.09) for continuous smoking & non-early menopause, and 4.61 (95%CI=2.63–8.07, P<0.001) for continuous smoking & early menopause.

Figure 1.. Interactions between early natural menopause and continuous smoking for affecting lung cancer incidence and cancer mortality.

Kaplan-Meier curve showed that females with early menopause who continued smoking had the highest lung cancer risk (1A) and cancer mortality (1B) compared to other three combinations. With females with non-continuous smoking & non-early menopause as the reference, hazard ratios for lung cancer were 0.87 (95%CI=0.39–1.96, P=0.73) for non-continuous smoking & early menopause, 2.05 (95%CI=1.26–3.35, P<0.01) for continuous smoking & non-early menopause, and 4.65 (95%CI=2.55–8.49, P<0.001) for continuous smoking & early menopause. With females with non-continuous smoking & non-early menopause as the reference, hazard ratios for cancer mortality are 0.91 (95%CI=0.43–1.95, P=0.81) for non-continuous smoking & early menopause, 1.55 (95%CI=0.94–2.56, P=0.09) for continuous smoking & non-early menopause, and 4.61 (95%CI=2.63–8.07, P<0.001) for continuous smoking & early menopause.