Low-Dose Vaginal Estrogen and Breast-Related Outcomes
Assessment of the potential biologic effects of low-dose vaginal estrogen on breast tissue can be approached by considering three separate endpoints: mammographic breast density, breast cancer, and breast pain. Although we could find no studies examining the endpoint of breast density in relation to low-dose vaginal estrogens, a 2-year placebo-controlled randomized trial examining a transdermal preparation delivering estradiol 14 µg/day showed no difference in breast density at 2 years compared with placebo. Regarding breast cancer, a large-scale observational study of Finnish women, including 18,314 users of vaginal estrogen, indicated no increase in the risk of breast cancer associated with vaginal estrogen use. Moreover, no increased risk would be expected based on the results of the unopposed estrogen arm of the WHI. With 7.2 years of oral conjugated equine estrogens (0.625 mg/d), the hazard ratios (95% CIs) were 0.79 (0.61-1.02) for the intervention phase and 0.79 (0.65-0.97) for the 13-year cumulative follow-up phase, suggesting no increased risk of breast cancer with unopposed conjugated equine estrogens across this time frame. Evidence that this finding applies to other formulations of estrogen remains inconclusive. However, one would not expect that an even lower dose of unopposed estrogen given vaginally, and with minimal systemic absorption, would have an adverse effect on breast cancer risk. Regarding breast pain, this symptom has been reported with intermediate doses of vaginal estrogen. However, in a study of low-dose vaginal estrogen (Estring), only 1 of 108 women complained of breast pain while the ring was in place. Reports on the use of 10 µg of low-dose vaginal estrogen make no mention of breast pain. Based on these collective findings, it is improbable that these products exert important biologic effects on the breast.