Highlight
- Unopposed estrogen significantly increases risk of endometrial hyperplasia compared to placebo and combined regimens.
- Continuous combined estrogen–progestogen appears protective against hyperplasia within one year.
- Sequential combined regimens may increase short-term hyperplasia risk over placebo.
- Evidence for impact on endometrial cancer remains inconclusive due to rare events and limited power.
Background
Menopause marks a substantial drop in circulating estrogen, often producing vasomotor symptoms, urogenital atrophy, and reduced bone density. Hormone therapy (HT) remains the most effective intervention for symptom control, yet concerns over adverse outcomes—including endometrial hyperplasia and endometrial cancer—necessitate precision in regimen choice. This updated Cochrane review (originally published in 1999, last updated in 2012) re-evaluates the evidence regarding endometrial safety across various HT protocols for postmenopausal women.
Study Design
The systematic review incorporated randomized controlled trials (RCTs) identified through multiple bibliographic databases and clinical trial registers up to July 22, 2024. Eligible participants were postmenopausal women receiving unopposed estrogen, continuous combined estrogen–progestogen, or sequential combined estrogen–progestogen for ≥1 year, compared either head-to-head or against placebo. Critical outcomes included histologically confirmed endometrial hyperplasia and endometrial cancer at one year and beyond. Additional outcomes addressed adherence, need for further interventions, and discontinuation due to adverse events. Risk of bias was appraised via the Cochrane RoB 1 tool, and findings graded using GRADE methodology.
Key Findings
Unopposed Estrogen vs Placebo
Six RCTs (n = 2,493) demonstrated that unopposed estrogen probably increases the one-year incidence of endometrial hyperplasia from 5/1000 to between 22–43/1000 women (OR 5.86, 95% CI 4.09–8.40, moderate certainty). After one year, nine RCTs (n = 2,539) showed risk elevation to 40–68/1000 women versus placebo (OR 8.97, 95% CI 6.78–11.87, moderate certainty).
Continuous Combined Therapy vs Placebo
Four RCTs (n = 3,893) indicate little to no difference at one year (0–16/1000 vs 5/1000; OR 0.51, 95% CI 0.08–3.38, low certainty). Long-term impact remains uncertain due to sparse data (very low certainty).
Sequential Combined Therapy vs Placebo
Four RCTs (n = 1,030) suggest sequential regimens may moderately raise one-year hyperplasia risk (6–27/1000 vs 2/1000; OR 5.53, 95% CI 2.60–11.76, low certainty). After one year, data point towards minimal difference (low certainty).
Unopposed Estrogen vs Continuous Combined Therapy
Eleven RCTs (n = 7,856) revealed a substantial increase in one-year hyperplasia risk with unopposed estrogen compared to continuous combined regimens (46–75/1000 vs 3/1000; OR 21.90, 95% CI 16.76–28.62, moderate certainty). Long-term outcomes align with these findings.
Unopposed Estrogen vs Sequential Combined Therapy
Five RCTs (n = 2,354) found unopposed estrogen may increase hyperplasia risk at one year (156–301/1000 vs 16/1000; OR 17.19, 95% CI 11.27–26.22, low certainty), with consistency after one year noted.
Continuous vs Sequential Combined Therapy
Evidence remains inconclusive, with events too scarce to support firm conclusions.
Dose Comparisons
Differential impacts of moderate versus low-dose progestogens within combined regimens lack robust evidence, with low or very low certainty results and insufficient events to definitively guide clinical practice.
Endometrial Cancer Outcomes
Across included trials, events of endometrial cancer were rare. The evidence base remains underpowered for definitive conclusions on cancer risk modulation by HT regimens.
Expert Commentary
The updated synthesis places particular emphasis on the protective role of progestogens when combined with estrogen. Continuous combined therapy appears most favorable for minimizing hyperplasia, fitting current guideline recommendations in women with an intact uterus. In contrast, unopposed estrogen—whether short term or long term—carries substantial risk for proliferative endometrial changes, underlining its unsuitability outside specialized indications.
Sequential combined therapy’s modest risk elevation may reflect periods of unopposed estrogen exposure inherent to its regimen design. Progestogen dose comparisons, a clinically pertinent aspect, remain poorly supported by evidence, signaling an area for targeted research.
Conclusion
For endometrial safety in postmenopausal hormone therapy, continuous combined estrogen–progestogen regimens offer superior short-term protection against hyperplasia compared with unopposed estrogen or placebo. Sequential combined regimens may raise short-term risk but can still mitigate dangers versus unopposed estrogen. Current evidence cannot elucidate long-term cancer risk differences due to limited event rates and follow-up duration. Clinical decision-making should continue to weigh symptom control benefits against endometrial safety, with careful consideration of regimen composition, duration, and progestogen dosage.
Funding and Registration
The review received no dedicated funding. Registered under original DOI 10.1002/14651858.CD000402 in 1999, with subsequent updates including July 2024 search cutoff.
References
Kim D, Jordan V, Casciola F, Ferguson M, Humphries A, Bofill Rodriguez M, Wise MR. Hormone therapy in postmenopausal women and risk of endometrial hyperplasia or endometrial cancer. Cochrane Database Syst Rev. 2025 Oct 23;10(10):CD000402. doi: 10.1002/14651858.CD000402.pub5. PMID: 41128095; PMCID: PMC12548017.
