OBJECTIVE: Current hormone therapy in postmenopausal women is associated with uterotrophic activity and cancer-promoting effects. In this experimental study, we compared the effects of the selective estrogen-receptor (ER) beta agonist biochanin A, and the selective ERalpha agonist ethinylestradiol, on the development of intimal hyperplasia after balloon injury and on uterus morphology. DESIGN: Female F344 rats with or without prior ovariectomy were used for aortic denudations. Animals remained untreated or received oral biochanin A (100 mg/kg) or ethinylestradiol (100 microg/kg). After 14 days, aortas and uteri were harvested for histologic and immunohistochemical analyses. Computerized assessments of aortic adhesion molecule expression, and isometric relaxation experiments, and uteri were analyzed. In vitro studies with smooth muscle cells and endothelial cells were performed to further investigate the effects of hormone treatment on cell proliferation, migration and adhesion molecule expression. RESULTS: Among untreated rats, ovariectomized animals tended to show greater neointimal hyperplasia and increased expression of the adhesion molecules 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1). Biochanin A treatment reduced neointima formation, inhibited VCAM-1 up-regulation, and improved the vascular relaxation response. No effect was observed on uterus growth or histology. Ethinylestradiol also reduced aortic neointima formation and inhibited VCAM-1 up-regulation, but failed to improve endothelial function and significantly induced uterus growth. Both agents showed antiproliferative and weak antimigratory effects on smooth muscle cells, and reduced VCAM-1 expression on stimulated endothelial cells in vitro. CONCLUSIONS: The ERbeta agonist biochanin A shows vasculoprotective effects without uterotrophic activity. Because hormone therapy may have cancer-promoting side effects, administration of ERbeta-selective agents might be alternatively used to reduce the risk of cardiovascular disease in postmenopausal women.
