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-estradiol metabolites
1 Center for Clinical Pharmacology, 3 Department of Medicine, and 4 Department of Pharmacology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213; and 2 Clinic for Endocrinology, Department of Obstetrics and Gynecology, University Hospital Zurich, 8091 Zurich, Switzerland
17
-Estradiol (estradiol), the most abundant
endogenous estrogen, affords cardiovascular protection. However, in a
given cohort of postmenopausal women, estradiol replacement therapy
provides cardiovascular protection in only a subset. The reasons for
this variable action can only be understood once the mechanisms by which estradiol induces its cardiovascular protective effects are
known. Because most biological effects of estradiol are mediated via
estrogen receptors (ERs) and the heart and blood vessels contain both
ER-
and ER-, the prevailing view is that ERs mediate
estradiol-induced cardiovascular protection. However, recent findings
that estradiol protects against vascular injury in arteries of mice
lacking either ER- or ER- seriously challenges this concept. Thus
other non-ER mechanisms may be operative. Endogenous estradiol is
enzymatically converted to several nonestrogenic metabolites, and some
of these metabolites induce potent biological effects via
ER-independent mechanisms. Therefore, it is conceivable that the
cardiovascular protective effects of estradiol are mediated via its
endogenous metabolites. On the basis of the evidence cited in this
review, the cardiovascular protective effects of estradiol are both ER dependent and independent. The purpose of this article is to review the
evidence regarding the cardiovascular protective effects of estradiol
metabolites and to discuss the cellular, biochemical, and molecular
mechanisms involved.
estrone; methoxyestradiol; catecholestradiol; hydroxyestradiol; mitogenesis; menopause; vascular smooth muscle; endothelium; cardiac fibroblasts
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