Jin-Sung Yuk

Objective: To evaluate the association between various types and durations of menopausal hormone therapy (MHT) and the risk of endometrial cancer. Methods: This nationwide retrospective population‐based cohort study used the Korean National Health Insurance Service database from 2007 to 2020. Eligible participants, defined as women aged over 40 years who sought care for menopausal symptoms, were enrolled during 2011–2014 and followed for the development of endometrial cancer until the end of 2020. After propensity score matching, participants were categorized as MHT users or non‐users. MHT regimens were classified as tibolone, combined estrogen‐progestogen therapy by the manufacturer (CEPM), combined estrogen‐progestogen therapy by a physician (CEPP), and others. Results: The incidence of endometrial cancer was 19 per 100 000 person‐years (95% confidence interval [CI]: 17–21) in both MHT and non‐MHT groups. Use of manufacturer‐combined estrogen and progestogen therapy was associated with a significantly lower risk of endometrial cancer (hazard ratio [HR] 0.592, 95% CI: 0.437–0.801), while physician‐combined therapy showed no significant association (HR 1.474, 95% CI: 0.472–4.607). Tibolone use was not associated with increased risk when used for four years or less (HR 0.9, 95% CI: 0.61–1.314), but showed a significantly increased risk when used for more than four years (HR 1.518, 95% CI: 1.152–1.999). In duration‐based analysis, MHT therapy use between three and six years was also associated with increased risk (HR 1.499, 95% CI: 1.061–2.117). Conclusion: Endometrial cancer risk in postmenopausal women is influenced by hormone therapy type and duration. Combined estrogen–progestogen regimens are associated with lower risk, whereas prolonged tibolone use is associated with higher risk, supporting individualized and duration‐based monitoring.

Supplementary Table 2. Characteristics of pre-propensity score-matched MHT and non-MHT groups in women

Supplementary Table 6. Hazard ratios of cancer risk associated with tibolone.

Supplementary Table 7. Hazard ratios of cancer risk associated with combined estrogen/progestogen.

Supplementary Table 5. Hazard ratios of cancer risk associated with MHT use by age group.

Supplementary Table 9. Hazard ratios of cancer risk associated with MHT use by duration

Supplementary Table 1. Cancer classification by anatomic site.

Supplementary Table 4. Total cancer incidence per 100,000 person-years by use of menopausal hormone therapy.

Background:To investigate menopausal hormone therapy’s (MHT) overall cancer risks in postmenopausal women.Methods:This retrospective cohort study used South Korea’s National Health Insurance System data, focusing on women aged 40 or older diagnosed with initial menopause (2011–2014), comparing an MHT group (≥6 months) with a propensity score–matched non-MHT group for cancer incidence until 2020.Results:We matched 138,445 women per group, followed for a median of 7.9 years. Breast (28%), thyroid (23%), and colorectal (8%) cancers predominated. MHT increased the overall cancer risk [hazard ratio (HR) 1.104; 95% confidence interval (CI), 1.064–1.145], especially estrogen plus progestogen therapy (EPT; HR, 1.172; 95% CI, 1.119–1.227) and estrogen-alone therapy (ET; HR, 1.142; 95% CI, 1.05–1.244), but not tibolone. Breast (HR, 1.568; 95% CI, 1.448–1.697), colorectal (HR, 1.157; 95% CI, 1.018–1.315), brain (HR, 1.618; 95% CI, 1.6–2.258), and renal (HR, 1.378; 95% CI, 1.053–1.803) cancers were more common in MHT; uterine cancer decreased (HR, 0.865; 95% CI, 0.763–0.981).Conclusions:MHT increased overall cancer risk, with EPT and ET elevating risks, unlike tibolone. MHT users faced higher risks of breast, brain, renal, and colorectal cancers but a lower risk of uterine cancer.Impact:These findings suggest considering lower-potency progestogens in current estrogen/progestogen therapy. This change might increase endometrial cancer risk but reduce breast cancer risk, potentially lowering overall cancer risk.

Supplementary Figure S1 shows Kaplan–Meier overall survival curves comparing (A) MHT users versus nonusers and (B) survival by MHT regimen (tibolone, estrogen plus progestogen, and estrogen alone), with hazard ratios, 95% confidence intervals, and log-rank p values reported.