Unopposed estradiol therapy in postmenopausal women: results from two randomized trials.

OBJECTIVE

To estimate the rates of endometrial hyperplasia, bleeding episodes, and interventions among menopausal women receiving unopposed oral estradiol or placebo therapy with ultrasound monitoring over 3 years.

METHODS

Two-hundred eighteen healthy women with intact uteri enrolled in the Estrogen in the Prevention of Atherosclerosis Trial (EPAT) or the Women's Estrogen-Progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial (WELL-HART) were randomly assigned to either 1 mg of micronized 17beta-estradiol (n=96) or placebo (n=122) daily for up to 3 years in a double-blind fashion. Patients were followed with annual measurement of endometrial thickness using transvaginal ultrasonography. Logistic regression was used to identify predictors of uterine bleeding and endometrial biopsy.

RESULTS

Over the study periods, nine women (9.4% of patients, 95% confidence interval [CI] 3.6-15.2%) in the estradiol group developed hyperplasia. Eight of the nine cases (88.9%) of hyperplasia were simple without atypia. Women receiving estradiol were more likely than those receiving placebo to have at least one episode of uterine bleeding (67% versus 11% at 3 years, respectively, P<.001). Women in the estradiol group were also more likely to have an endometrial biopsy (48% versus 4% at 3 years, P<.001). Among women on estradiol, obesity (body mass index [BMI] greater than 30 kg/m(2)) significantly increased the odds of uterine bleeding compared with normal-weight patients (BMI 25 or less) (OR 3.7, 95% CI 1.2-11.8).

CONCLUSION

Short-term, unopposed estradiol therapy with gynecologic monitoring may be an option for the treatment of menopausal symptoms. Menopausal women choosing estradiol therapy, especially if obese, should anticipate uterine bleeding and the possibility of an endometrial biopsy.

CLINICAL TRIAL REGISTRATION

Clinicaltrials.gov, www.clinicaltrials.gov, NCT 00000559 and NCT 00115024.

LEVEL OF EVIDENCE

I.