Figure 7. Schematic model for the effects of postmenopausal iron accumulation with or without hormone replacement therapy (HRT) on atherosclerosis (AS) severity through modulating estrogen receptor α (ERα) expression.

Iron accumulation occurs naturally and gradually after menopause. In early postmenopausal (EPM), iron retention was mild, and ERα was responsive to HRT application to achieve protective effects. However, when iron overload is significant in late postmenopausal (LPM), Mdm2 is upregulated along with ERα downregulation. This negative correlation is potentiated by the application of HRT and iron accumulation with aging. Therefore, HRT use avails to aggravate the progression of AS in the LPM period. Iron chelation, however, reverses the adverse effect of HRT and attenuates the accelerated development of AS, suggesting a protective role of appropriate iron restriction in the LPM stage.