Starting estrogen therapy in perimenopause was associated with reduced risks of breast cancer, heart attack, and stroke, study shows.
Declining estrogen levels during the menopause transition can have widespread physical and emotional effects on women. For many, hormone therapy provides relief from vasomotor and other bothersome symptoms. A new study presented at The Menopause Society’s 2025 Annual Meeting in Orlando suggests that when estrogen therapy is initiated may play a critical role in shaping long-term health outcomes.1,2
A large percentage of women experience menopausal symptoms, with hot flashes being the most common. Many begin experiencing symptoms during perimenopause—the transitional phase before the final menstrual period—when estrogen levels fluctuate and decline. Estrogen therapy is widely recognized as one of the most effective and generally safe approaches for managing these symptoms, but limited data exist on the long-term impact of initiating therapy during perimenopause compared with postmenopausal use or no therapy at all.
Researchers from Case Western Reserve University School of Medicine and University Hospitals in Cleveland conducted a retrospective cohort analysis using data from more than 120 million patient records in the TriNetX Research Network. Three cohorts were defined using ICD-10 codes:
Propensity score matching was applied to reduce selection bias and ensure comparability between groups. Outcomes of interest included breast cancer, heart attack, and stroke. The investigators calculated odds, risk, and hazard ratios for each outcome to determine the relative benefit or risk associated with different initiation timelines for estrogen therapy.
The findings revealed substantial differences in long-term outcomes based on the timing of estrogen initiation. Perimenopausal women who had used estrogen therapy for at least 10 years before menopause had approximately 60% lower odds of developing breast cancer, heart attack, and stroke compared with the other two groups.
Specifically, the odds ratios for Cohort 2 compared with Cohort 1 were 0.398 for breast cancer, 0.403 for heart attack, and 0.358 for stroke. When comparing Cohort 3 to Cohort 1, the odds ratios were 0.367, 0.374, and 0.371, respectively.
Women who began estrogen therapy after menopause had slightly lower odds of breast cancer and heart attack than those who never used hormones, but their likelihood of experiencing a stroke was 4.9% higher compared with non-users.
The study’s lead author, Ify Chidi, MPH, of Case Western Reserve University School of Medicine, emphasized the clinical significance of these findings:
“There has long been a debate about if and when estrogen therapy should begin, so hopefully the use of large-scale electronic health record data will help resolve that question,” said Chidi. “The goal of this study was to explore whether estrogen therapy could do more than relieve symptoms, and the results suggest that early initiation could be a key factor in reducing morbidity. Hopefully, these results start a larger conversation about prevention in women's health. If we can better understand the effect of hormones throughout menopause, we can improve the quality of life and reduce disease burden.”
Stephanie Faubion, MD, MBA, medical director for The Menopause Society, also noted the broader implications and limitations of the analysis:
“The findings of this study suggest lower risk and potentially greater benefit of estrogen-based therapy when started in perimenopause. While the observational study design is subject to known potential biases such as healthy user bias, these results may pave the way for additional research on the risks and benefits of hormone therapy when initiated earlier in the menopause transition.”
The results suggest that earlier initiation of estrogen therapy during perimenopause may provide a stronger protective effect against major health conditions, including cardiovascular disease and breast cancer, compared with starting therapy after menopause. However, researchers cautioned that as an observational study, the findings cannot establish causality.
Further clinical research is needed to confirm these results and to better characterize the long-term impact of hormone therapy when initiated at different stages of the menopause transition. The ongoing discussion surrounding hormone timing underscores the importance of individualized patient assessment, shared decision-making, and continued evaluation of long-term outcomes.
References
Get the latest clinical updates, case studies, and expert commentary in obstetric and gynecologic care. Sign up now to stay informed.
