Long-term systemic outcomes of postmenopausal hormone replacement therapy by age at menopause: a real-world cohort...

Does postmenopausal hormone replacement therapy (HRT), initiated within 1 year after menopause diagnosis, confer differential long-term health effects according to age at menopause?

Long-term postmenopausal HRT was associated with age-dependent clinical outcomes, with broadly consistent cardiovascular and skeletal associations across age groups, but more variable metabolic and oncological associations according to age at menopause.

The 'timing hypothesis' suggests that HRT initiated closer to menopause may have more favorable cardiometabolic associations than later initiation, but evidence across distinct age-at-menopause strata remains limited.

This retrospective new-user cohort study utilized de-identified data from the TriNetX Research Network, which provided access to electronic medical records for ∼111 million patients globally. To establish a relatively healthy baseline cohort, we included women aged 30-90 years without prior major systemic diseases who had a documented diagnosis of menopause. To ensure adequate time for the development of hard clinical endpoints, we required that the index event (initial menopause diagnosis) occurred at least 10 years before data extraction (31 December 2025), thereby guaranteeing a minimum follow-up period of one decade. To reduce immortal time bias and survivor bias inherent in prevalent-user designs, we employed a new-user, time-to-event cohort design. Women with a pre-existing history of type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), osteoporosis, compression fracture, venous thromboembolism (VTE), breast cancer, or colorectal cancer on or before the index date were excluded.

Women who initiated postmenopausal HRT containing estrogen and/or progestogen within 1 year after menopause diagnosis were propensity score-matched 1:1 with non-users using baseline demographic, clinical, and laboratory covariates. Primary matching yielded 83 670 matched pairs in women who experienced menopause at age ≤60 years and 12 175 matched pairs in women who experienced menopause at age >60 years. Time-to-event analyses using Cox proportional hazards regression were conducted across four clinically defined menopausal age strata: premature ovarian insufficiency (POI, <40 years), early menopause (40-45 years), normal menopause (46-60 years), and late menopause (>60 years). Hazard ratios (HRs) were calculated for incident T2DM, CVD, compression fracture, breast cancer, colorectal cancer, and VTE. Interaction P-values were calculated using the normal menopause group (46-60 years) as the reference for interaction testing. Sensitivity analyses were conducted in both the overall ≤60-year and >60-year cohorts using an alternative 1:1 matching strategy based only on age, race, and baseline BMI, excluding laboratory parameters.

In the overall matched cohort of women experiencing menopause at age ≤60 years, postmenopausal HRT was associated with lower hazards across all evaluated systemic endpoints. Compared with non-users, postmenopausal HRT was associated with lower hazards of T2DM (events: 3517 vs 4580; crude incidence: 4.20% vs 5.47%; HR: 0.595, 95% CI: 0.575-0.615) and CVD (events: 3960 vs 4413; crude incidence: 4.74% vs 5.29%; HR: 0.699, 95% CI: 0.688-0.709). Skeletal health was preserved, evidenced by a lower hazard of compression fractures (events: 426 vs 441; crude incidence: 0.51% vs 0.53%; HR: 0.780, 95% CI: 0.719-0.846). Furthermore, postmenopausal HRT was associated with lower hazards of breast cancer (events: 1281 vs 1504; crude incidence: 1.53% vs 1.80%; HR: 0.786, 95% CI: 0.743-0.831), colorectal cancer (events: 222 vs 276; crude incidence: 0.27% vs 0.33%; HR: 0.847, 95% CI: 0.738-0.971), and VTE (events: 1247 vs 1346; crude incidence: 1.49% vs 1.61%; HR: 0.859, 95% CI: 0.811-0.910). In the primary age-stratified model, the >60-year cohort showed a higher breast cancer hazard (HR: 1.151, 95% CI: 1.057-1.255); in the corresponding >60-year group sensitivity analysis, using alternative matching, the estimate remained directionally similar (HR: 1.218, 95% CI: 1.027-1.444). Across the remaining >60-year sensitivity outcomes, the direction of association was preserved, including continued lower hazards of T2DM, CVD, VTE, and compression fracture, while the colorectal cancer association remained neutral.

Important limitations include residual confounding, incomplete socioeconomic and screening data, limited details on HRT formulation, route, dose and duration, unavailable breast cancer subtype information, unavailable exact maximum follow-up duration, and the inability to directly incorporate standardized patient-level geography into the matching or regression models. Region-restricted inference was additionally constrained because the Europe, Middle East, and Africa (EMEA) > 60-year HRT cohort contained only 48 exposed users, precluding stable matched analysis.

While cardiovascular and skeletal associations appeared broadly consistent across menopausal ages, the associations with breast cancer in the older age group highlight the critical need for individualized prescribing. These real-world findings are most consistent with earlier initiation of postmenopausal HRT for symptomatic women and those with POI, while urging extreme caution with initiation in late-onset menopause.

No specific external funding was received. The study was supported by departmental funds from the Department of Obstetrics and Gynecology, Taichung Veterans General Hospital.

The authors declare no competing interests.

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