Causal relationship between physical activity and common gynecologic conditions: a two-sample Mendelian randomization study

OBJECTIVE: While physical activity (PA) patterns are epidemiologically linked to gynecologic pathologies, establishing causality remains uncertain. This Mendelian randomization (MR) study evaluated causal relationships between PA phenotypes and gynecologic disorders. METHODS: Using European-ancestry female genome-wide association study (GWAS) data, we analyzed eight gynecologic disorders and four PA instruments. Primary inverse-variance weighted (IVW) estimates were supplemented by sensitivity analyses (MR-Egger, weighted median, MR-PRESSO) to address pleiotropy and heterogeneity. RESULTS: Our MR revealed subtype-specific effects: walking for pleasure [OR = 0.63, 95% CI: 0.41-0.96], strenuous sports [OR = 0.34, 95% CI: 0.16-0.74], and other exercises [OR = 0.70, 95% CI: 0.49-0.99]) reduced ER+ breast cancer (BC) risk, while leisure screen time increased risk (OR = 1.08, 95% CI: 1.004-1.163). Only other exercises protected against ER- BC (OR = 0.60, 95% CI: 0.38-0.96). Exercise frequency inversely correlated with endometrial cancer (EC) (walking: OR = 0.20; strenuous sports: OR = 0.06; other exercises: OR = 0.41) and endometriosis (ES) (strenuous sports: OR = 0.17; other exercises: OR = 0.26), but was positively associated with sedentary behavior (EC: OR = 1.36). Ovarian cyst (OCS) risk decreased with walking (OR = 0.34) and other exercises (OR = 0.28), yet increased with screen time (OR = 1.23). Paradoxically, walking showed strong positive (OR = 31.48) and strenuous exercise inverse (OR = 0.004) associations with polycystic ovary syndrome (PCOS). No causal links emerged for cervical cancer (CC), ovarian cancer (OC), or uterine fibroids (UF). CONCLUSION: This first MR evidence demonstrates PA's differential causal effects on gynecologic disorders, particularly highlighting exercise modality-specific protection against ER+ BC, EC, and ES. Paradoxical PCOS associations warrant mechanistic investigation. Findings underscore PA as a modifiable preventive factor and advocate for subtype-tailored exercise guidelines in women's health.