The correlation between primary ovarian insufficiency, sex hormones and immune cells: a two-step Mendelian randomization study.

Background: Primary ovarian insufficiency (POI), a cause of female infertility, is characterized by elevated gonadotropin levels and fluctuating estrogen reductions, accompanied by irregular menstruation, osteoporosis, cardiovascular disease, and genitourinary syndrome of menopause. Previous studies have shown an association between POI and immune cells, but the causal relationship remains unclear. Sex hormones play a crucial role in immune regulation by influencing the function and levels of immune cells, suggesting they may be key mediators between POI and immune cells. Methods: Utilizing genome-wide association studies (GWAS), we conducted a comprehensive bidirectional two-sample Mendelian randomization (MR) analysis to explore the causal relationship between 731 immune cell traits and POI. Furthermore, a two-step MR analysis was employed to examine the potential mediating effects of sex hormones between these two systems. To ensure the robustness of our findings, we performed extensive sensitivity analyses, evaluating heterogeneity and horizontal pleiotropy. Results: After FDR adjustment (P Conclusions: Our study comprehensively assessed the correlation between immune cell phenotypes and POI in the European population, excluding the mediating role of sex hormones, thus providing valuable insights into the biological mechanisms of POI and informing early prevention and treatment strategies.