Female Infertility and Risk for Later-Life Cardiovascular Disease: Lessons from a Mouse Model of Human Cardiovascular Disease

The potential link between female infertility during reproductive age and an increased risk of cardiovascular disease (CVD) later in life remains controversial. Female fertility is a complex process involving multiple steps, and disruptions at any stage can result in infertility. If only a specific subset of fertility dysfunctions—often challenging to diagnose—is associated with future CVD risk, this relationship may be masked by the heterogeneity of infertility causes. Identifying infertility factors that predispose women to CVD requires careful selection of study populations. To address this, we investigated fertility status in scavenger receptor class B, type I-deficient mice with hypomorphic apolipoprotein E mice, which represent the dominant pathologic foundation for human CVD. These female mice were healthy and active when fed a normal chow diet at reproductive age, but generated no offspring. The dysfunctional female fertility processes identified included degeneration of oocytes during the maturation processes prior to ovulation and impairment of implantation via dysfunctional decidualisation. The administration of probucol, a hypocholesterolaemic agent, significantly decreased the plasma total cholesterol level, as well as the size of high-density lipoprotein-like particles, and these alterations restored female fertility. These findings suggest that infertility caused by degeneration of oocytes during the maturation processes and defective uterine receptivity may contribute to CVD risk later in life. Women with unexplained infertility and recurrent implantation failure may represent an important cohort for future CVD risk assessment.