Causal Relationship Between Metabolites and Vasomotor Symptoms in Menopause: A Two-Sample Mendelian Randomization Analysis Study

Abstract Objective: Perimenopause represents a critical phase in a woman's reproductive journey characterized by a myriad of challenges, with vasomotor symptoms (VMS) emerging as a significant hurdle. This study endeavors to explore the potential causal associations between metabolites and VMS during perimenopause, aiming to elucidate the biological processes influencing VMS manifestation and inform personalized therapeutic strategies. Methods: Leveraging a two-sample Mendelian randomization (MR) analysis, comprehensive genome-wide association studies (GWAS) datasets were utilized to discern specific metabolites implicated in VMS etiology adhering to STROBE-MR guidelines. The primary metabolite dataset, derived from the metabolite GWAS, includes genetic association evidence for 486 metabolites across 7,824 individuals. VMS GWAS summary statistics, with 14,261 cases and 77,767 controls, form the basis for causal inference. Rigorous quality control measures ensure the integrity of associations, and assumptions crucial to MR analysis are addressed, including relevance, independence, and exclusion restriction. Protein-protein interaction(PPI) network and enrichment analysis were constructed to explore potential regulatory pathways associated with VMS. Results: MR analysis identified 12 metabolites associated with VMS among which mannose, isoleucine, stearate, myristate, ascorbate, 3-dehydrocarnitine, 4-androsten-3beta,17beta-diol disulfate 1 and 10-undecenoate show inverse associations, suggesting potential protective effects. Conversely, inosine, myristate, gamma-glutamyl leucine, glucose, and serine display positive associations, indicating contributory effects in pathogenesis. Biological network analysis elucidated the molecular pathways linking these metabolites to VMS, highlighting the involvement of diverse biological processes such as neuroactive ligand-receptor interaction, lipid metabolism, hormonal responses, and immune modulation. Furthermore, protein-protein interaction networks identified hub genes central to VMS regulation, including MME, CCND1, TNF, ITGB1, PTGS2, HSP90AA1, CTSB, PPARG, PPARA, and CXCL8, shedding light on potential regulatory mechanisms. Conclusion: This study highlighted the complexity of perimenopausal VMS and the importance of holistic therapies. Targeted interventions focusing on specific metabolites and pathways served as potential approach for symptom relief. Acknowledging limitations in analyses and datasets, future research should prioritize diverse cohorts to enhance understanding and treatment of VMS.