Endothelial dysfunction, featuring reduced vascular endothelial-dependent dilation (EDD), is a significant predictor of cardiovascular (CV) events. Reduced EDD is characterized by the loss of nitric oxide (NO) production. EDD declines with aging in women at a slower rate compared to men but rapidly declines after menopause and quickly catches up to men, suggesting a beneficial effect of estrogen (E2). Our research has investigated the mechanisms underlying endothelial protection of E2 including how hormonal fluctuations during the peri-to early postmenopausal years contribute to endothelial dysfunction, and how these hormonal changes might interact with aging. Using a well described experimental model (systemic infusion of ascorbic acid; AA) to acutely reduce reactive oxygen species (ROS), our preliminary findings implicate oxidative stress as an underlying mechanism explaining the impaired EDD during the menopausal transition. Specifically we found improved EDD in response to AA in late peri- and postmenopausal women but not in pre- or early perimenopausal women. These data indicate that E2 may protect the vasculature from free radical injury during pre- and early perimenopausal years. In support of this concept, we demonstrated that AA can reverse the decrease in EDD that occurs in the setting of short-term E2 deficiency (3-days of gonadotropin releasing hormone antagonist; GnRHant) in pre-and early perimenopausal women.