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.