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

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.

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.

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.

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.

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.