Low-Dose Vaginal Estrogen and Cardiovascular, Cerebrovascular, Cognitive, and Other Outcomes
Compared with oral systemic estrogen and estrogen-progestin, as studied in the WHI and forming the basis for the boxed warning, low-dose vaginal estrogen has lower systemic absorption and, similar to transdermal estradiol formulations, avoids "first-pass" liver metabolism and effects on hepatic enzymes. Lower-dose transdermal estradiol has been shown to have less risk of venous thromboembolism (VTE) and possibly stroke; thus, the significantly lower systemic absorption of low-dose vaginal estrogen makes it even less likely to increase risk of VTE and other cardiovascular events than oral systemic estrogen. The increased risks of coronary heart disease, stroke, and VTE, which have been reported with oral systemic hormone therapy, have not been reported with low-dose vaginal estrogen therapy. Moreover, long-term follow-up of women in the WHI trial of unopposed estrogen showed no increased risk of coronary events or all-cause mortality, indicating that low-dose vaginal estrogen is unlikely to affect these outcomes. The 2006 Cochrane review of VVA did not find evidence of an increased risk of VTE with low-dose estrogen, but data for women at high risk for these events are lacking. An increase in probable dementia was observed in the WHI among women aged 65 years or older who were treated with oral systemic estrogen-progestin therapy (equivocal results for systemic oral estrogen alone); there is no evidence that the minimal absorption of low-dose vaginal estrogen preparations would have the potential to affect dementia risk among women in any age group or would have biologic plausibility to do so.