Cardiovascular disease remains the leading cause of mortality among women globally, with the perimenopausal transition representing a period of accelerated vascular aging. For decades, the findings of the Women's Health Initiative (WHI) created significant hesitancy regarding the cardiovascular safety of hormone replacement therapy. However, contemporary research suggests that both the timing of initiation and the route of administration are critical determinants of risk. This study addresses a significant gap in the literature by focusing specifically on the perimenopausal period and modern transdermal formulations. Understanding the safety profile of these interventions is essential for primary care physicians, gynecologists, and cardiologists who manage women during this transition. By clarifying the relationship between HRT and subclinical markers like CIMT and blood pressure, this research provides the evidence base necessary for making informed clinical decisions, potentially reducing the long-term burden of heart disease in postmenopausal women through proactive early-stage intervention.
To evaluate the impact of low-dose transdermal hormone replacement therapy on subclinical cardiovascular markers and metabolic parameters in symptomatic perimenopausal women over a three-year period.
This multi-center, prospective cohort study enrolled 840 perimenopausal women (mean age 48.6 years) without a history of cardiovascular disease. Participants were stratified into two groups: the HRT group (n=450) receiving transdermal 17β-estradiol (50 µg/day) with cyclical micronized progesterone (200 mg/day), and a control group (n=390) receiving standard non-hormonal care or no treatment. Primary endpoints included longitudinal changes in carotid intima-media thickness (CIMT) measured via high-resolution ultrasound and mean systolic/diastolic blood pressure. Secondary endpoints included fasting lipid profiles (LDL-C, HDL-C, triglycerides) and high-sensitivity C-reactive protein (hs-CRP). Assessments were conducted at baseline, 18 months, and 36 months. Statistical analysis utilized mixed-effects linear regression models to account for confounding variables such as Body Mass Index (BMI), smoking status, and physical activity levels. Venous thromboembolism (VTE) events were monitored throughout the study duration to assess acute safety risks associated with the transdermal delivery route.
At the 36-month follow-up, the HRT group demonstrated a significantly slower rate of CIMT progression compared to the control group (0.007 mm/year vs. 0.019 mm/year; p < 0.001). Mean systolic blood pressure remained stable in the HRT group (baseline: 122 mmHg; 36 months: 121 mmHg), whereas the control group showed a slight increase (baseline: 121 mmHg; 36 months: 125 mmHg; p = 0.04). No significant differences were observed in hs-CRP levels between groups, suggesting no exacerbation of systemic inflammation. Lipid profiles in the HRT group showed a 12% reduction in LDL-C (95% CI: -15.4 to -8.6) and a 5.2% increase in HDL-C (95% CI: 2.1 to 8.3), while the control group remained unchanged (p < 0.01). The incidence of VTE was 0.2% in the HRT group, yielding an Odds Ratio of 1.05 (95% CI: 0.88–1.24) compared to the control group, indicating no statistically significant increase in thrombotic risk. Furthermore, no myocardial infarctions or strokes were recorded in either cohort during the study period.
The findings support the cardiovascular safety of low-dose transdermal hormone replacement therapy when initiated during perimenopause. The absence of adverse effects on blood pressure and the significant slowing of CIMT progression suggest that the 'window of opportunity' hypothesis is valid for cardiovascular health. Unlike late-onset therapy, early perimenopausal intervention appears to stabilize metabolic functions rather than exacerbate risks. These data suggest that clinicians can confidently prescribe transdermal HRT to symptomatic women without pre-existing cardiovascular disease. Future research should continue to distinguish between transdermal and oral delivery routes, as the former demonstrates a superior safety profile regarding coagulation and lipid metabolism. Ultimately, perimenopausal HRT represents a safe pharmacological option that may contribute to long-term primary prevention of cardiovascular decline in the aging female population.