Sex Hormones and the Risk of Nasal Polyps: A Two‐Sample Mendelian Randomization Study

ABSTRACT Objective The pathophysiological roles of sex hormones in airway inflammation have drawn much attention recently. We aimed to explore the causal effect of sex hormones on chronic rhinosinusitis (CRS) and nasal polyps (NP) via a Mendelian randomization (MR) study. Methods Genetic traits for serum bioavailable testosterone (BioT), total testosterone (ToT), sex hormone‐binding globulin (SHBG), and estradiol were extracted from a genome‐wide association study (GWAS) containing 425,097 European individuals from the UK Biobank, while outcome data were obtained from the FinnGen data set. Two‐sample MR analysis was performed to assess the association of sex hormones and NP or CRS with the inverse variance weighted method as the main analysis, together with sensitivity analyses. Results Genetically predicted BioT levels showed a possible inverse association with both NP (OR = 0.669, p = 0.009) and CRS (OR = 0.792, p = 0.014) in the overall population, though these associations were marginally above the traditional significance threshold after multiple testing correction (FDR = 0.054). Sex‐stratified analyses revealed potentially stronger protective associations in females, with higher BioT associated with lower odds of NP. No significant causal effects of estradiol or SHBG on NP or CRS were identified in the available GWAS data. Conclusion Our MR analyses suggest a possible inverse relationship between genetically predicted serum BioT levels and the risk of both CRS and NP, with potentially stronger effects in females. Further observational and experimental studies are necessary to validate these genetic associations and explore the potential immunomodulatory mechanisms by which testosterone may influence sinonasal inflammation.