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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Cardiovascular Pharmacology of Estradiol Metabolites

Raghvendra K. Dubey, Stevan P. Tofovic and Edwin K. Jackson
Journal of Pharmacology and Experimental Therapeutics February 2004, 308 (2) 403-409; DOI: https://doi.org/10.1124/jpet.103.058057
Raghvendra K. Dubey
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Stevan P. Tofovic
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Edwin K. Jackson
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Abstract

A discussion of the role of endogenous estradiol metabolites in mediating important biological actions of estradiol is essentially nonexistent in standard textbooks of pharmacology and endocrinology. Indeed, the prevailing view is that all biological effects of estradiol are initiated by binding of estradiol per se to estrogen receptors and that estradiol metabolites are more or less irrelevant. This orthodox view, which is most likely incorrect, is the fundamental premise (an estrogen is an estrogen is an estrogen) underlying the design of important clinical trials such as the Heart and Estrogen/Progestin Replacement Study and the Women's Health Initiative Study. Accumulating data provide convincing evidence that some metabolites of estradiol, the major estrogen secreted by human ovaries, are biologically active and mediate multiple effects on the cardiovascular and renal systems that are largely independent of estrogen receptors. More specifically, metabolites of estradiol, particularly catecholestradiols and methoxyestradiols, induce multiple estrogen receptor-independent actions that protect the heart, blood vessels, and kidneys from disease. These protective effects are mediated in part by the inhibition of the ability of vascular smooth muscle cells, cardiac fibroblasts, and glomerular mesangial cells to migrate, proliferate, and secrete extracellular matrix proteins, as well as by an improvement in vascular endothelial cell function. The purpose of this review is to highlight the cardiovascular and renal pharmacology of catecholestradiols and methoxyestradiols. The take home message is simple: that when it comes to cardiovascular and renal protection, the concept that all estrogenic compounds are created equal may not be true.

Footnotes

  • Supported in part by Swiss National Science Foundation Grant 32-64040.00.

  • DOI: 10.1124/jpet.103.058057.

  • ABBREVIATIONS. CYP450, cytochrome P450; COMT, catechol-O-methyltransferase; ER, estrogen receptor; SHBG, serum hormone binding globulin; VSMC, vascular smooth muscle cell; LDL, low-density lipoprotein; NO, nitric oxide; ERK, extracellular-signal regulated kinase; MAP kinase, mitogen-activated protein kinase; PDGF, platelet-derived growth factor; IGF-1, insulin-like growth factor-1; ICI 182,780, fulvestrant.

    • Received October 29, 2003.
    • Accepted December 1, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 308 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 308, Issue 2
1 Feb 2004
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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Cardiovascular Pharmacology of Estradiol Metabolites

Raghvendra K. Dubey, Stevan P. Tofovic and Edwin K. Jackson
Journal of Pharmacology and Experimental Therapeutics February 1, 2004, 308 (2) 403-409; DOI: https://doi.org/10.1124/jpet.103.058057

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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Cardiovascular Pharmacology of Estradiol Metabolites

Raghvendra K. Dubey, Stevan P. Tofovic and Edwin K. Jackson
Journal of Pharmacology and Experimental Therapeutics February 1, 2004, 308 (2) 403-409; DOI: https://doi.org/10.1124/jpet.103.058057
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  • Article
    • Abstract
    • Estradiol Synthesis (Fig. 1)
    • Estradiol Metabolism (Fig. 1)
    • General Pharmacology of Catecholestradiols and Methoxyestradiols
    • Effects of Catecholestradiols and Methoxyestradiols on Key Cell Types in the Cardiovascular and Renal Systems
    • Effects of Catecholestradiols and Methoxyestradiols on Plasma Lipids
    • Evidence That Local Conversion of Estradiol and Catecholestradiols to Methoxyestradiols Mediates the Inhibitory Effects of Estradiol and Catecholestradiols on Cardiovascular Cells
    • Clinical Implications
    • Conclusion
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