Exploring the Causal Relationship Between Sex Hormones and Depression by Means of Two-Sample Mendelian Randomization Analysis

Abstract

Background: To investigate the potential causal association between sex hormones and depression, a two-sample mendelian randomization (MR) analysis was conducted. Methods: Summary statistics from Genome-wide Association Study (GWAS) on sex hormones and depression were collected. Sex-specific instruments were used to analyze seven sex hormones, including progesterone (PROG) and bioavailable testosterone (BAT). The inverse variance weighted (IVW) method was employed as the primary analysis, and sensitivity analyses were conducted to assess the robustness of the findings. Results: The IVW analysis revealed genetically significant association between PROG and depression (odds ratio (OR): 0.95, 95% confidence interval (CI): 0.92–0.98, p = 0.002), which remained significant after Bonferroni correction (p < 0.0036). A nominally significant association was observed for BAT (OR: 0.90, 95% CI: 0.82–1.00, p = 0.049) and depression; however, this association did not survive Bonferroni correction. Upon stratification by gender, these associations were no longer significant (p > 0.05). Furthermore, no substantial associations were observed between depression and other sex hormones, including total testosterone (TT), estradiol (E2), follicle-stimulating hormone, prolactin, and luteinizing hormone (p > 0.05). Leave-one-out analyses and funnel plots (indicating balanced pleiotropy), confirmed the reliability of these findings, supporting the robustness of the results. Significant heterogeneity was observed in seven exposures: E2_Female, TT_Male, TT_Both, BAT_Both, BAT_Male, BAT_Female, and TT_Female. Additionally, Mendelian Randomization Pleiotropy Residual Sum and Outlier (MR-PRESSO) analysis identified outliers for BAT_Both, BAT_Female, E2_Female, TT_Both, and TT_Female; however, excluding these outliers did not alter the results. Conclusions: This study indicates a potential causal association between genetically predicted PROG levels and a decreased risk of depression. While BAT also suggested a potential protective effect, this association was considered suggestive after multiple testing correction and requires further validation.