Uterine Effects of Unopposed Estrogen Therapy in Menopausal Women

Summary and Comment |
April 5, 2007

Uterine Effects of Unopposed Estrogen Therapy in Menopausal Women

  1. Andrew M. Kaunitz, MD

Estrogen-only HT was associated with increased incidences of uterine bleeding, endometrial hyperplasia, and endometrial biopsies.

  1. Andrew M. Kaunitz, MD

Unlike estrogen-progestin menopausal hormone therapy, estrogen-only therapy is associated with little, if any, increase in breast cancer risk (Journal Watch Women’s Health Jan 22 2003 and Feb 22 2007). These observations have prompted increased interest in using estrogen-only HT to alleviate menopausal symptoms. To examine the effects of estrogen-only HT on endometrial thickness and uterine bleeding, investigators performed a combined analysis of two clinical trials involving 218 women with intact uteri who were randomized to receive oral micronized estradiol (1 mg/day) or placebo for 2 or 3 years. After baseline assessment of endometrial thickness, women kept records of uterine bleeding and underwent annual transvaginal ultrasound examinations; endometrial biopsy was performed if the endometrial thickness exceeded 5 mm.

Among women randomized to estradiol, the cumulative incidence of vaginal bleeding was 49% and 67% at 1 year and 3 years of treatment, respectively; by comparison, the 3-year cumulative bleeding incidence was 11% in the placebo group. Among estrogen users, those who were obese were more likely to experience bleeding than those who were not. During the study period, 44% of women in the estradiol group versus 14% in the placebo group had at least one endometrial thickness measurement that exceeded 5 mm. Estradiol recipients also were more likely than placebo recipients to require at least one endometrial biopsy (20.5% vs. 1.5% at 1 year; 48.2% vs. 4.3% at 3 years). Hyperplasia was diagnosed in 9.4% of women in the estradiol group and in none in the placebo group. Some women were diagnosed with hyperplasia after the conclusion of the studies; thus, the rate of hyperplasia after 3 years of estradiol therapy was 20%.


No participant was diagnosed with endometrial cancer during either study. Progestin use has been associated with increased risk for breast cancer and, in some women, mood changes; thus, symptomatic menopausal women with intact uteri might be particularly motivated to use unopposed estrogen therapy if they have a higher-than-average baseline risk for breast cancer or a history of dysphoria associated with progestin use. However, women with intact uteri who are considering estrogen-only therapy should be made aware of the increased risks for uterine bleeding, for needing one or more endometrial biopsies, and for being diagnosed with endometrial hyperplasia.


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