Association of Smoking and Alcohol Consumption with Female Reproductive Diseases: A Mendelian Randomization Study on the Mediating Role of Circulating Metabolites.

BACKGROUND

Smoking and alcohol consumption have been consistently associated with adverse female reproductive outcomes; however, whether these associations reflect causal effects or are mediated by specific circulating metabolites remains unclear. We aimed to clarify the causal relationships between smoking- and alcohol-related behaviors and female reproductive disorders and to quantitatively assess metabolite-mediated effects.

METHODS

We conducted a large-scale two-sample Mendelian randomization (MR) study using genome-wide association data from up to 2.7 million individuals. Smoking behaviors (including smoking initiation, cigarette consumption, smoking cessation, and age at initiation) and alcohol consumption were evaluated in relation to multiple female reproductive disorders, including abnormal uterine bleeding, adenomyosis, endometrioid ovarian cancer, ovarian cysts, and female pelvic inflammatory diseases. To elucidate underlying mechanisms, we implemented a two-step MR-based mediation framework to quantify indirect effects through circulating metabolites.

RESULTS

Genetically predicted smoking initiation was associated with increased risks of abnormal uterine bleeding, endometrioid ovarian cancer, ovarian cysts, and inflammatory diseases of the female reproductive organs. Higher cigarette consumption was also causally associated with an increased risk of adenomyosis. Mediation analyses identified specific inflammatory and lipid-related metabolites as partial mediators of these associations. In particular, glycoprotein acetyls (GlycA) and four very low-density lipoprotein (VLDL) subtype markers jointly mediated 2.76-7.61% of the total effect of cigarettes per day on adenomyosis. Similarly, triglycerides across five lipoprotein subclasses mediated 1.08-1.77% of the total effect of smoking initiation on inflammatory diseases of the female reproductive organs.

CONCLUSION

This study provides genetically informed evidence supporting a potential causal role of smoking-related behaviors in female reproductive disorders. By identifying circulating metabolites as mediators, our findings reveal novel pathways linking smoking to gynecological disease risk and highlight metabolic dysregulation as a clinically relevant target for risk stratification and integrated smoking prevention or cessation strategies.