Abstract
RATIONALE: Reduced circulating estrogen levels around the time of menopause can induce symptoms that affect health and well-being. Estrogen therapy is the most effective treatment, but may be associated with some adverse health outcomes, including endometrial pathology. This is an update of a review first published in 1999 and last updated in 2012. OBJECTIVES: • To assess the effects of hormone therapy regimens for protecting postmenopausal women against endometrial hyperplasia and endometrial cancer. • To define the lowest effective dose(s) of progestogen used in combination with estrogen therapy for protecting the endometrium. SEARCH METHODS: We searched for trials in the Cochrane Gynaecology and Fertility Group specialized register, CENTRAL (containing output from two trial registers and CINAHL), MEDLINE, Embase, and PsycINFO to 22 July 2024. We also checked references and contacted study authors to identify additional studies. ELIGIBILITY CRITERIA: Interventions of interest were unopposed estrogen, continuous combined estrogen and progestogen, and sequential combined estrogen and progestogen, administered for at least one year. These interventions could be compared head to head or with placebo. Trials had to report rates of endometrial hyperplasia or endometrial cancer (histologic diagnosis). OUTCOMES: Our critical outcomes were endometrial hyperplasia and endometrial cancer at one year and after one year. Our important outcomes were adherence to therapy, requirement for additional interventions, and withdrawal due to adverse events. RISK OF BIAS: We used the original Cochrane risk of bias tool (RoB 1). SYNTHESIS METHODS: Where meta-analysis was possible, we calculated odds ratios (ORs) with 95% confidence intervals (CIs). We used GRADE to assess the certainty of evidence for each outcome. INCLUDED STUDIES: This update included 72 studies (involving 40,652 women) conducted worldwide. There were 42 multicenter trials. SYNTHESIS OF RESULTS: There were too few studies with events to draw conclusions about endometrial cancer. The results for endometrial hyperplasia are presented below. Unopposed estrogen versus placebo Unopposed estrogen probably increases the risk of endometrial hyperplasia at one year compared with placebo (22-43 events/1000 women versus 5 events/1000 women; OR 5.86, 95% CI 4.09 to 8.40; I² = 0%; 6 RCTs, 2493 women; moderate-certainty-evidence). Unopposed estrogen probably increases the risk of endometrial hyperplasia after one year (40-68 events/1000 women versus 6 events/1000 women; OR 8.97, 95% CI 6.78 to 11.87; I² = 49%; 9 RCTs, 2539 women; moderate-certainty-evidence). Continuous combined estrogen plus progestogen versus placebo Continuous combined therapy may have little to no effect on the risk of endometrial hyperplasia at one year compared with placebo (0-16 events/1000 women versus 5 events/1000 women; OR 0.51, 95% CI 0.08 to 3.38; I² = 48%; 4 RCTs, 3893 women; low-certainty-evidence). We are unsure about the effect of continuous combined therapy after one year (OR 0.25, 95% CI 0.04 to 1.40; I² = 47%; 4 RCTs, 789 women; very low-certainty evidence). Sequential combined estrogen plus progestogen versus placebo Sequential combined therapy may increase the risk of endometrial hyperplasia at one year compared with placebo (6-27 events/1000 women versus 2 events/1000 women; OR 5.53, 95% CI 2.60 to 11.76; I² = 0%; 4 RCTs, 1030 women; low-certainty-evidence). Sequential combined therapy may result in little to no difference in the risk of endometrial hyperplasia after one year (16-97 events/1000 women versus 20 events/1000 women; OR 2.30, 95% CI 0.76 to 6.99; I² = 0%; 3 RCTs, 534 women; low-certainty-evidence). Unopposed estrogen versus continuous combined estrogen plus progestogen Unopposed estrogen probably increases the risk of endometrial hyperplasia at one year compared with continuous combined therapy (46-75 events/1000 women versus 3 events /1000 women; OR 21.90, 95% CI 16.76 to 28.62; I² = 53%; 11 RCTs, 7856 women; moderate-certainty-evidence). Unopposed estrogen probably increases the risk of endometrial hyperplasia after one year compared with continuous combined therapy (33-73 events/1000 women versus 3 events/1000 women; OR 16.78, 95% CI 11.01 to 25.55; I² = 69%; 3 RCTs, 1191 women; moderate-certainty-evidence). Unopposed estrogen versus sequential combined estrogen plus progestogen Unopposed estrogen may increase the risk of endometrial hyperplasia at one year compared with sequential combined therapy (156-301 events/1000 women versus 16 events/1000 women; OR 17.19, 95% CI 11.27 to 26.22; I² = 70%; 5 RCTs, 2354 women; low-certainty-evidence). Unopposed estrogen may increase the risk of endometrial hyperplasia after one year compared with sequential combined treatment (379-612 events/1000 women versus 49 events/1000 women; OR 19.21, 95% CI 11.95 to 30.90; I² = 15%; 2 RCTs, 417 women; low-certainty-evidence). Continuous combined estrogen plus progestogen versus sequential combined estrogen plus progestogen All analyses had insufficient events to draw conclusions. Continuous combined estrogen plus progestogen - dose comparisons We are unsure about the effect of moderate-dose estrogen plus low-dose progestogen compared with moderate-dose estrogen plus moderate-dose progestogen on the risk of endometrial hyperplasia at one year (OR 1.18, 95% CI 0.24 to 5.84; I² = 36%; 2 RCTs, 2363 women; very low-certainty-evidence). The remaining dose comparisons had insufficient events to draw conclusions. Sequential combined estrogen plus progestogen - dose comparisons Moderate-dose estrogen plus low-dose progestogen may result in little to no difference in the risk of endometrial hyperplasia at one year compared with moderate-dose estrogen plus moderate-dose progestogen (3-32 events/1000 women versus 6 events/1000 women; OR 1.66, 95% CI 0.49 to 5.65; I² = 0%; 4 RCTs, 1072 women; low-certainty-evidence). The remaining dose comparisons had insufficient events to draw conclusions. AUTHORS' CONCLUSIONS: Unopposed estrogen probably increases the risk of endometrial hyperplasia versus placebo and continuous combined therapy at one year and later. Sequential combined therapy may increase the risk of endometrial hyperplasia at one year versus placebo. The evidence is less certain for continuous versus sequential combined regimens and dose comparisons of continuous and sequential combined regimens. The trials had few events, and long-term follow-up was challenging. For endometrial cancer, events were rare and trials were underpowered to draw meaningful conclusions. FUNDING: This review had no dedicated funding. REGISTRATION: Original review (1999) DOI: 10.1002/14651858.CD000402 Review update (2004) DOI: 10.1002/14651858.CD000402.pub2 Review update (2009) DOI: 10.1002/14651858.CD000402.pub3 Review update (2012) DOI: 10.1002/14651858.CD000402.pub4.