Reproductive Factors and Lung Cancer Risk among Never-Smoking Japanese Women with 21 Years of Follow-Up: A Cohort Study

Cancer Epidemiol Biomarkers Prev. 2021 Jun;30(6):1185-1192. doi: 10.1158/1055-9965.EPI-20-1399. Epub 2021 Apr 7.


Background: Previous studies have reported inconsistent associations between reproductive factors and lung cancer.

Methods: We used data from the Japan Public Health Center-based Prospective Study, which included 400 incident lung cancer cases (305 adenocarcinoma) among 42,615 never-smoking women followed for a median of 21 years, to examine the associations of reproductive and hormonal factors with lung cancer by histological type using Cox proportional hazards models.

Results: Longer fertility span (≥36 years vs. ≤32 years) was associated with increased risk of lung adenocarcinoma (HR, 1.48; 95% CI, 1.07-2.06, P trend = 0.01) but not with all lung cancer or nonadenocarcinoma. Similarly, late age at menopause (≥ 50 years) was associated with increased adenocarcinoma risk (vs. ≤ 47 years, HR, 1.41; 95% CI, 1.01-1.96, P trend 0.04). Compared with premenopausal women, women with natural menopause (HR, 1.99; 95% CI, 1.02-3.88) or surgical menopause (HR, 2.75; 95% CI, 1.33-5.67) were at increased risk of adenocarcinoma. In contrast, breastfeeding was associated with reduced risk of nonadenocarcinoma (HR, 0.51; 95% CI, 0.28-0.92). No significant association with parity, age at first birth, exogenous hormone use, or length of menstrual cycle was detected.

Conclusions: Reproductive factors may play a role in lung carcinogenesis. Future studies that include estrogen and progesterone biomarkers may help clarify the role of endogenous hormones in lung carcinogenesis.

Impact: Fertility span and age at menopause may be useful variables in developing risk prediction models for lung adenocarcinoma among nonsmoking women.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age Factors
  • Female
  • Follow-Up Studies
  • Humans
  • Japan / epidemiology
  • Lung Neoplasms / epidemiology*
  • Lung Neoplasms / etiology
  • Menopause*
  • Middle Aged
  • Non-Smokers / statistics & numerical data*
  • Prospective Studies
  • Reproductive History*
  • Risk Factors