Obesity Affects <scp>IVF</scp> Outcomes and Mevalonic Acid Rescues the Side Effects of Statins on Follicle Growth

The accelerating trend of obesity in women of childbearing age has become a significant issue in personal health, female fecundity, and offspring development. Simvastatin (SV) is a statin commonly prescribed oral agent for lipid-lowering therapy; however, its applicability in reproductively active women remains controversial. In this study, through clinical data analysis, we further confirmed that obesity reduces in vitro fertilization pregnancy success, with significant decreases in the number of retrieved oocytes, mature oocytes, and cleavage embryos. We found SV inhibited follicle development cultured in vitro. Based on our previously reported metabolomics data, mevalonic acid (MVA) was found to be a key metabolite in follicular development. In our in vitro follicle culture system, we demonstrated that the supplement of MVA in SV-added follicles recovered to grow similar to the untreated blank group, indicating the rescue effect of potential reproductive toxicity of SV. Both the downstream metabolites cholesterol and geranylgeraniol partially attenuated SV-induced apoptosis elevation and proliferation suppression in KGN cells. RNA sequencing results suggested that this rescue effect may be mediated through the TNF, PI3K-Akt, and JAK-STAT pathways. Our study shed light upon clinical practice for women of childbearing age who were treated with statins and might contribute to better health management in obesity populations.