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Summary

Chung et al. [1] have recently published a systematic review and meta-analysis aimed at determining the association of early and late menopause onset with the risk of developing lung cancer. The authors reviewed and obtained through PubMed, EMBASE and Scopus database search studies analyzing this possible association. A total of twenty-eight studies were included in at least one meta-analysis, of age at menopause (lowest vs. highest; n=26), early menopause (≤45 vs. ≥50/51 years or middle; n=11), late menopause (≥55 vs. <50 years or middle; n=6), or continuous (per additional year; n=6). Pooled relative risks (RRs) or odds ratios (ORs) and their corresponding 95% confidence intervals (CI) were estimated using a random-effects meta-analysis. The authors found that early menopause was linked with lung cancer in both cohort (RR 1.26, 95% CI: 1.10-1.41; n=6) and case-control studies (OR 1.38, 95% CI: 1.11-1.66; n=5). As determined in three large cohort studies the increased risk was primarily evident among smokers (RR 1.38, 95% CI: 1.10-1.66) but not among non-smokers (RR 1.02, 95% CI: 0.63-1.40). In four case-control studies it was found that late menopause was also associated with lung cancer (OR 1.29, 95% CI: 1.08-1.51). Contrary to this, the association was mainly observed among non-smokers (OR 1.35, 95% CI: 1.11-1.59) but not among smokers (OR 1.05, 95% CI: 0.75-1.36). The authors conclude that there is an increased risk of lung cancer in women who present an early menopause onset (≤45 years); however, the risk is primarily among smokers. There is a need for large prospective cohort studies to confirm the association between late menopause (≥55 years) and lung cancer risk among non-smokers.

Commentary

Lung cancer is the leading cause of death due to malignancy among men and the second among women after breast cancer, contributing in 2018 to almost 14% of the total of cancer deaths in women [2]. During the last two decades, the higher incidence of lung cancer found in men as compared to women has changed, situation that has not been fully explained by gender differences in smoking habits [2]. Indeed, women who smoke seem to have increased their susceptibility to develop lung cancer compared to men who smoke [3], and women who have never smoked are twice as likely to develop lung cancer as men who have never smoked. Recent meta-analyses have found a relationship between lung cancer and menstrual and reproductive factors [4]. Longer length of menstrual cycles, higher parity and later age at first birth have been related to a lower risk of lung cancer, while postmenopause and induced menopause related to a higher risk of lung cancer [1]. Despite this, none of the previous reviews have found an association between age at menopause onset and the risk of lung cancer [4]. All studies have been based on the comparison of the highest age range (50 to 55 years) with the lowest category (40 to 50 years) of menopause onset. Cigarette consumption is a main risk factor for both early menopause and lung cancer and has an important influence on histological subtypes; however, none of the reviews performed meta-analyses separately for smokers and non-smokers and different subtypes. Adenocarcinoma is the most common type in women and non-smokers, while squamous cell carcinoma is the most common type in men and smokers; small cell carcinoma is the most aggressive form of lung cancer and is typically caused by smoking.

Several studies have found that the higher risk of lung cancer among women with younger age at menopause has been primarily evident among ever or current smokers; while other studies have found similar risk between smokers and non-smokers. Various age cut-off points for menopause onset could cause inconsistencies, as well as different types of lung cancer, or a non-linear association. Early menopause onset (<45 years) is associated with an increased risk of all-cause mortality, cardiovascular disease, and type 2 diabetes, while late menopause (≥55 years) is related to a higher risk of breast cancer [5]. The authors of the present commented meta-analysis aimed at examining the association of early and late menopause with lung cancer risk, and the analysis was further stratified by smoking status and histological subtypes where data were available. Recent reviews have found that menstrual and reproductive factors are related to lung cancer risk, but evidence on a possible association with age at menopause is inconsistent. Authors found that the increased risk of lung cancer related to an early menopause (≤45 years) was basically evident among smokers but not among non-smokers; contrary to this, the higher risk of lung cancer associated with late menopause (≥55 years) was mainly observed among non-smokers but not among smokers. The authors acknowledge, that their meta-analysis is the first to examine the associations of both early and late menopause onset with lung cancer risk and that significant limitations of previous meta-analyses have been the inconsistent classification of exposure variables, especially those with more than two age categories.

We agree with the authors, that there is a need for large prospective cohort studies in order to confirm the association between late menopause (≥55 years) and lung cancer risk among non-smokers. In addition, investigation can focus on the underlying molecular mechanisms, specifically looking at the interaction between tobacco carcinogens and exo- and endogenous sex hormones in lung cancer development.

Peter Chedraui, MD, PhD
Instituto de Investigación e Innovación en Salud Integral
Universidad Católica de Santiago de Guayaquil, Guayaquil, Ecuador

References

  1. Chung HF, Gete DG, Mishra GD. Age at menopause and risk of lung cancer: A systematic review and meta-analysis. Maturitas. 2021 Nov;153:1-10. doi: 10.1016/j.maturitas.2021.07.010.
    https://pubmed.ncbi.nlm.nih.gov/34654521/
  2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424.
    https://pubmed.ncbi.nlm.nih.gov/30207593/
  3. Stapelfeld C, Dammann C, Maser E. Sex-specificity in lung cancer risk. Int J Cancer. 2020;146(9):2376-2382.
    https://pubmed.ncbi.nlm.nih.gov/31583690/
  4. Huang J, Yue N, Shi N, et al. Influencing factors of lung cancer in nonsmoking women: systematic review and meta-analysis. J Public Health (Oxf). 2021 Jan 12:fdaa254. doi: 10.1093/pubmed/fdaa254.
    https://pubmed.ncbi.nlm.nih.gov/33429425/
  5. Rojas K, Stuckey A. Breast Cancer Epidemiology and Risk Factors. Clin Obstet Gynecol. 2016;59(4):651-672.
    https://pubmed.ncbi.nlm.nih.gov/27681694/

 


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If you would like to add a comment or contribute to a discussion based on this issue, please contact Menopause Live Editor, Peter Chedraui, at peter.chedraui@cu.ucsg.edu.ec.

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