Hormone therapy in postmenopausal women and risk of endometrial hyperplasia or endometrial cancer.
Level 1 - systematic review of randomized trials
Systematic review and meta-analysis of randomized controlled trials
PubMed 41128095 · doi:10.1002/14651858.CD000402.pub5
What was done
This Cochrane systematic review update searched multiple databases through July 22, 2024, for randomized controlled trials evaluating hormone therapy regimens in postmenopausal women administered for at least one year. Eligible regimens included unopposed estrogen, continuous combined estrogen-progestogen, and sequential combined estrogen-progestogen, compared against placebo or each other. The primary critical outcomes were histologically diagnosed endometrial hyperplasia and endometrial cancer at one year and beyond one year. Risk of bias was evaluated with Cochrane RoB 1, and evidence certainty was graded using GRADE.
What was found
The review included 72 RCTs involving 40,652 women. There were too few events across trials to draw conclusions regarding endometrial cancer. For endometrial hyperplasia: - Unopposed estrogen versus placebo: probably increased risk at 1 year (OR 5.86, 95% CI 4.09 to 8.40; 6 RCTs, n=2,493; moderate certainty) and after 1 year (OR 8.97, 95% CI 6.78 to 11.87; 9 RCTs, n=2,539; moderate certainty). - Continuous combined versus placebo: may have little to no effect at 1 year (OR 0.51, 95% CI 0.08 to 3.38; 4 RCTs, n=3,893; low certainty); uncertain after 1 year (OR 0.25, 95% CI 0.04 to 1.40; 4 RCTs, n=789; very low certainty). - Sequential combined versus placebo: may increase risk at 1 year (OR 5.53, 95% CI 2.60 to 11.76; 4 RCTs, n=1,030; low certainty) with little difference after 1 year (OR 2.30, 95% CI 0.76 to 6.99; 3 RCTs, n=534; low certainty). - Unopposed estrogen versus continuous combined: substantially higher risk with unopposed estrogen at 1 year (OR 21.90, 95% CI 16.76 to 28.62; 11 RCTs, n=7,856; moderate certainty) and after 1 year (OR 16.78, 95% CI 11.01 to 25.55; 3 RCTs, n=1,191; moderate certainty). - Unopposed estrogen versus sequential combined: higher risk at 1 year (OR 17.19, 95% CI 11.27 to 26.22; 5 RCTs, n=2,354) and after 1 year (OR 19.21, 95% CI 11.95 to 30.90; 2 RCTs, n=417). - Direct comparisons between continuous and sequential combined regimens, as well as most progestogen dose comparisons, lacked sufficient events to draw firm conclusions.
Why it matters
This review provides clear, pooled trial evidence quantifying the magnitude of endometrial hyperplasia risk from unopposed estrogen and confirms the protective necessity of adding continuous progestogen in postmenopausal women with an intact uterus.
Limits
Trials reported too few incident cases to assess endometrial cancer risk directly. Several comparisons suffered from low event counts, small sample sizes, and substantial statistical heterogeneity (I² up to 70%), leading to low or very low GRADE certainty for sequential regimens and specific progestogen dose comparisons.
Cited by
- supports Administering unopposed estrogen without progesterone in women with an intact uterus increases the risk of endometrial hyperplasia and endometrial cancer.