See related article, pages 245–254 Assessing benefits and risks of estrogen and hormone replacement therapy in postmenopausal women has been a long story with conflicting results and major changes in paradigms.1,2 Observational studies had consistently demonstrated a reduction in mortality and cardiovascular disease incidence in women on hormone replacement therapy compared to postmenopausal women not on replacement therapy. However, randomized trials have resulted in great disappointment because hormone replacement therapy for primary and secondary prevention of atherosclerotic disease were mostly associated with more risk (thromboembolism, malignancies, stroke) than benefit.1,3,4 However, the estrogen story has not been buried because of convincing preclinical data demonstrating a wide variety of cardiovasculoprotective action of estrogens.5 Among others, estrogen has major impact on the endothelium. The integrity of the endothelium effectively prevents atherosclerotic lesion formation and progression and has therefore come into the focus in vascular research. Estrogens trigger nitric oxide bioavailability through activation of endothelial nitric oxide synthase activity6 and reduce production of reactive oxygen species (Figure).7 Furthermore, estrogens accelerate endothelial cell regeneration after endothelial cell damage by mobilization of endothelial progenitor cells and activation of mature endothelial cells within the vessel wall.8–12 Nonendothelial cell-mediated effects of estrogens include effects on the inflammatory and immune system, the platelet cascade with prevention of arterial thrombosis (but promotion of venous thromboembolism) and beneficial effects on blood pressure (Figure).5 Additionally, novel clinical insights of estrogen replacement therapy have boosted and preserved the interest …