Sex Hormones and Chronic Obstructive Pulmonary Disease: A Cross-Sectional Study and Mendelian Randomization Analysis

Dongru Du,1– 3,* Bi Ran,1– 3,* Dan Xu,1– 3 Lian Liu,1– 3 Xueru Hu,1– 3 Tingting Zeng,1– 3 Yongchun Shen,1– 3 Fengming Luo1– 4 1Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 2State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 3Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 4Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, Sichuan University, Chengdu, 610200, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yongchun Shen; Fengming Luo, Tel +86 28 8542 2350, Fax +86 28 8558 2944, Email shen_yongchun@126.com; fengmingluo@outlook.comBackground: Sex steroid hormones, including testosterone and estradiol, play significant roles in various aspects of pulmonary health and diseases. However, although there were a few studies trying to link sex hormones with COPD, their effect remained limited due to small sample size and insufficient causal results. This study aims to investigate the association between sex hormones and chronic obstructive pulmonary disease (COPD) based on the National Health and Nutrition Examination Survey (NHANES) database and evaluate causality via a two-sample Mendelian randomization (MR).Methods: Data from NHANES 2013– 2016 were enrolled for the cross-sectional study. The association between sex hormones and COPD was evaluated via multivariable logistic regression. Sex-stratified analysis, subgroup analyses and interaction tests were performed to further evaluate the correlation. For MR analysis, data were collected from genome-wide association studies and FinnGen datasets. The inverse-variance-weighted (IVW) approach, along with four other approaches, was applied in the analysis. Further sensitivity analysis was conducted to assess the existence of pleiotropy and heterogeneity.Results: 7,617 eligible participants were enrolled in the cross-sectional analysis. Negative associations were observed in both testosterone-COPD (OR 0.770, 95% CI 0.626, 0.948, p = 0.018) and estradiol-COPD (OR 0.794, 95% CI 0.688, 0.915, p = 0.005) relationships after covariate adjustments. However, the results from IVW-MR analysis showed that no causal relationship was observed in either the testosterone-COPD (OR 0.83, 95% CI 0.53, 1.29, p = 0.407) or estradiol-COPD (OR 0.74, 95% CI 0.23, 2.38, p = 0.616) relationship, which was also supported by the other four approaches (all p values > 0.05).Conclusion: Although a significant negative association was observed between sex hormones and COPD, the results of MR analysis did not support the causality of this relationship. Our study suggested that sex hormones may indirectly rather than directly affect the development of COPD via potential covariates, which warranted further investigations.Keywords: sex steroid hormones, testosterone, estradiol, chronic obstructive pulmonary disease, NHANES, Mendelian randomization