Proteomic and metabolic signatures of female reproductive factors and risk of age‐related ocular diseases: A large prospective cohort study

Abstract Age‐related ocular diseases (ARODs), including cataract, primary open‐angle glaucoma (POAG), and age‐related macular degeneration (AMD), are leading causes of vision impairment and exhibit sex differences. We investigated associations between female reproductive factors and ARODs risk, and explored underlying proteomic and metabolomic pathways. This prospective cohort study included 265,276 women followed for a median of 13.4 years. We assessed 17 reproductive factors and derived a composite reproductive risk score (RRS). Cox models were used to examine associations between reproductive factors and incident ARODs. Proteomic and metabolomic profiling combined with mediation analysis identified biological pathways linking reproductive factors to ARODs. Shorter endogenous estrogen exposure was associated with higher risk of cataract (hazard ratio [HR] 1.21, 95% confidence interval [CI], 1.14–1.27) and AMD (HR 1.25, 95% CI, 1.09–1.45). Hormone replacement therapy (HRT) use increased risks of cataract (HR 1.11, 95% CI, 1.08–1.13), AMD (HR 1.15, 95% CI, 1.09–1.22), and POAG (HR 1.18, 95% CI, 1.11–1.25). Higher RRS was linked to elevated cataract (HR 1.14, 95% CI, 1.08–1.19) and POAG risk (HR 1.21, 95% CI, 1.06–1.38). Mechanistically, proteins involved in cytokine signaling (GDF15, SPP1) mediated the association between reproductive factors and cataract. Metabolites related to lipid metabolism (omega‐3 fatty acids) and energy homeostasis (creatine) contributed to broader metabolic mediation, explaining 29.3% (95% CI, 2.1%–56.5%) of the menopause–cataract link and 26.3% (95% CI, 15.7%–36.9%) of the HRT–cataract association. Female reproductive factors influence AROD risk through specific proteomic and metabolomic pathways, supporting integration of reproductive history into personalized eye care and identifying sex‐specific intervention targets.