Causality and potential drug targets for hyperandrogenism and anovulation-related infertility: two-sample Mendelian randomization and colocalization analyses

Excessive androgens may lead to abnormal folliculogenesis and anovulation. To explore the link between hyperandrogenism (HA) and anovulation - related infertility, we performed a two - sample Mendelian randomization analysis, followed by multiple validations. We also delineated potential pathogenic pathways and assessed druggability. The inverse variance weighted (IVW) combined with the meta analysis results showed sex hormone-binding globulin (SHBG, IVW: OR1 = 0.561; 95% CI: 0.363 to 0.866; P1 = 0.009; meta: OR = 0.817, P = 0.023) and bioavailable testosterone (BIOT, meta: OR = 1.298, P = 0.019) were associated with anovulation-related female infertility. Single-cell analysis revealed upregulated androgen synthesis in granulosa and theca cells, with divergent receptor signaling. CD74, CYP11A1, and HLA-DRB1 may be potential therapeutic targets aimed at HA and anovulation-related infertility. Our findings indicated SHBG appears a protective factor of anovulation-related infertility. The druggabilities of CD74, CYP11A1, and HLA-DRB1 shed light on future research on safer, less toxic agents for the treatment of HA-related anovulatory infertility.