Gender-specific Causal Relationship between Sex Hormones and Carpal Tunnel Syndrome: A Mendelian Randomisation Study

Background: Observational studies have shown a correlation between sex hormones and the risk of developing carpal tunnel syndrome (CTS), but it remains unclear whether these associations are causal. Aims: We aimed to investigate the potential causal relationships between a range of sex hormones and the risk of CTS using a Mendelian randomisation (MR) approach. Methods: We selected exposure-related genetic instruments from genome-wide association studies summary data using significance thresholds. The CTS summary data were obtained from two sources: the UK Biobank (UKB) (12,887 cases and 443,461 controls) and the FinnGen consortium (17,198 cases and 273,097 controls). The random-effects inverse variance-weighted method was used as the primary approach for causal analysis, along with complementary weighted median, MR-Egger and MR-PRESSO tests for sensitivity analysis. Fixed-effect model was used to meta-analyse the results from the UKB and FinnGen. Results: The meta-analysis of the MR results from FinnGen and UKB identified potential risk factors that may increase the risk of CTS. These factors include lower sex hormone-binding globulin (SHBG) levels (both: odds ratio [OR] =0.628, P < 0.0001; female: OR = 0.601, P < 0.0001; male: OR = 0.717, P < 0.0001) and lower body mass index-adjusted SHBG levels (both: OR = 0.748, P < 0.0001; female: OR = 0.718, P < 0.0001; male: OR = 0.753, P < 0.0001). In males, higher total testosterone (TT) levels (OR = 0.912, P = 0.0052) may decrease the risk of CTS, whereas higher bioavailable testosterone (BAT) levels (OR = 1.370, P < 0.0001) may increase the risk of CTS in females. Oestradiol (E2), progesterone, the ratio of testosterone to oestradiol, androstendione, aldosterone and 17-hydroxyprogesterone showed no significant causal relationship with CTS risk. Conclusion: This MR study provides insights into the potential role of SHBG, TT and BAT in the development of CTS, highlighting the importance of conducting gender-specific genetic analyses.