Oral Administration of 17β-Estradiol Over 3 Months Without Progestin Co-Administration Does Not Improve Coronary Flow Reserve in Post-Menopausal Women: A Randomized Placebo-Controlled Cross-Over CMR Study

Abstract

Several large epidemiological outcome studies did not demonstrate a benefit of combined estrogen-progestin replacement treatment (HRT) on cardiovascular events in elderly postmenopausal women. Whether progestin antagonism is responsible for these negative results or the natural estrogen 17ss-estradial (E2) itself is not effective in the coronary circulation is unknown. To assess the effect of 3 months of E2 treatment on the coronary circulation, i.e., on coronary flow reserve (CFR), in postmenopausal women without established coronary artery disease (CAD). In a double-blind placebo-controlled cross-over design postmenopausal women (60 +/- 5 years, n = 14) were randomized to either start with placebo or E2 (Estrofem, Novo Nordisk, Copenhagen, Denmark) 2 mg/d given orally over 3 months and to switch thereafter for another 3 months of therapy. At baseline, a stress echocardiography was performed to exclude CAD. CFR was determined by coronary sinus CMR flow measurements (with motion-adapted gating and interactive acquisition window control; spatial/temporal resolution of 0.8 x 0.9 mm2/25-30 ms) which were performed at rest and during vasodilation (dipyridamole 0.56 mg/kg over 4 minutes IV) at baseline, and after 3 and 6 months of therapy, respectively. Hemodynamics such as heart rate and systolic and diastolic blood pressure were not different for the control and E2 group. For CFR and for resting and hyperemic coronary sinus blood flow, no differences between the placebo and E2 group were found (2-way ANOVA for repeated measurements). Reproducibility of phase-contrast CMR measurements of CFR was -1.1 +/- 4.9%. In elderly postmenopausal women without significant CAD, oral administration of E2 over 3 months without a progestin co-administration does not improve CFR. This finding yields partly explanation for some large epidemiological trials which could not demonstrate a clinical cardiovascular benefit of HRT in elderly women.