Uterine and vaginal effects of unopposed ultralow-dose transdermal estradiol.

OBJECTIVE: To investigate uterine effects of unopposed ultralow-dose transdermal estradiol administered to postmenopausal women for 2 years. METHODS: Postmenopausal women (n = 417), aged 60-80 years, with a uterus and with bone mineral density that was normal for age (z score >or=-2.0) were randomly assigned to receive unopposed transdermal estradiol (14 microg per day) or identical placebo patch. We evaluated effects on endometrial histology, vaginal bleeding, and vaginal epithelial cell maturation. RESULTS: At baseline, estradiol and placebo groups were similar in age (67 +/- 5 years) and in median baseline serum estradiol level (4.8 pg/mL, interquartile range 2.7, 8.0 pg/mL). In the estradiol group, median estradiol level increased to 8.6 pg/mL, (interquartile range 4.4, 13.9 pg/mL, P < .001). In the estradiol group, focal atypical endometrial hyperplasia developed in 1 woman, and adenosarcoma of the uterus developed in 1 woman. The placebo group had no endometrial hyperplasia. Endometrial proliferation occurred in 8.5% of the estradiol group and in 1.1% of the placebo group (P = .06). Incidence of vaginal bleeding was 12.4% in the estradiol group and 8.6% in the placebo group (P = .3). Vaginal epithelial cells showed greater maturation in the estradiol group than in the placebo group (P < .001) but less than typically observed with standard doses of estrogen. CONCLUSION: During 2 years of treatment with ultralow-dose unopposed estradiol, treatment and placebo groups had similar rates of endometrial hyperplasia, endometrial proliferation, and vaginal bleeding. This therapy apparently causes little or no endometrial stimulation. LEVEL OF EVIDENCE: I.