Continuous Combined Estrogen Plus Progestin and Endometrial Cancer

The Women's Health Initiative Randomized Trial

R. T. Chlebowski; G. L. Anderson; G. E. Sarto; R. Haque; C. D. Runowicz; A. K. Aragaki; C. A. Thomson; B. V. Howard; J. Wactawski-Wende; C. Chen; T. E. Rohan; M. S. Simon; S. D. Reed; J. E. Manson


J Natl Cancer Inst. 2016;108(3) 

In This Article

Abstract and Introduction


Background: While progestin addition to estrogen mitigates endometrial cancer risk, the magnitude of the effect on incidence, specific endometrial cancer histologies, and endometrial cancer mortality remains unsettled. These issues were assessed by analyses after extended follow-up of the Women's Health Initiative (WHI) randomized clinical trial evaluating continuous combined estrogen plus progestin use.

Methods: The WHI enrolled 16 608 postmenopausal women into a randomly assigned, double-blind, placebo-controlled trial. Women age 50 to 79 years with intact uteri with normal endometrial biopsy at entry were randomly assigned to once-daily 0.625mg conjugated equine estrogen plus 2.5mg medroxyprogesterone acetate (n = 8506) as a single pill or matching placebo (n = 8102). Follow-up beyond the original trial completion date required reconsent, obtained from 12 788 (83%) of surviving participants. Analyses were by intent-to-treat. All statistical tests were two-sided.

Results: After 5.6 years' median intervention and 13 years' median cumulative follow-up, there were fewer endometrial cancers in the combined hormone therapy compared with the placebo group (66 vs 95 case patients, yearly incidence, 0.06% vs 0.10%; hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.48 to 0.89, P = .007). While there were somewhat fewer endometrial cancers during intervention (25 vs 30, respectively; HR = 0.77, 95% CI = 0.45 to 1.31), the difference became statistically significant postintervention (41 vs 65, respectively; HR = 0.59, 95% CI = 0.40 to 0.88, P = .008), but hazard ratios did not differ between phases (P difference = .46). There was a statistically nonsignificant reduction in deaths from endometrial cancer in the estrogen plus progestin group (5 vs 11 deaths, HR = 0.42, 95% CI = 0.15 to 1.22).

Conclusion: In postmenopausal women, continuous combined estrogen plus progestin decreases endometrial cancer incidence.


Exogenous estrogen use increases endometrial cancer risk.[1–3] While combined estrogen plus progestin use results in less endometrial hyperplasia, an endometrial cancer precursor, than does estrogen alone,[4,5] the magnitude of estrogen plus progestin influence on estrogen-associated endometrial cancer risk has not been conclusively defined.[6] While a few case-control studies describe increased endometrial cancer risk with long-duration combined hormone therapy,[7,8] a recent meta-analysis of published cohort studies found a statistically significantly lower endometrial cancer risk with continuous combined estrogen plus progestin use.[6] Nonetheless, several recent menopause society[9,10] and task force[11] updates do not describe continuous estrogen plus progestin use as reducing endometrial cancer. In addition, the influence of continuous combined hormone therapy on types of endometrial cancer and endometrial cancer mortality remains unsettled.[12]

Against this background, in earlier reports from the Women's Health Initiative (WHI) randomized, placebo-controlled trial evaluating continuous combined estrogen plus progestin fewer endometrial cancers were seen with combined hormone therapy use, but the differences were not statistically significant.[13,14] Recently, with median cumulative follow-up of 13 years in this trial, estrogen plus progestin use was found to statistically significantly decrease endometrial cancer incidence.[15] In the current report, we extend that finding by providing analyses on estrogen plus progestin effects on endometrial cancer type, findings in relevant clinical subgroups, and information on endometrial cancer–related mortality.