Published Online
on August 11, 2003

A more recent version of this article appeared on October 1, 2003

This Article Full Text (PDF) All Versions of this Article: 42/4/657    most recent 01.HYP.0000085560.02979.0Cv1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Miller, A. P. Articles by Oparil, S. Search for Related Content PubMed PubMed Citation Articles by Miller, A. P. Articles by Oparil, S. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Hormone Replacement Therapy Related Collections Animal models of human disease Pathophysiology Risk Factors Growth factors/cytokines Epidemiology Mechanism of atherosclerosis/growth factors

Submitted on May 12, 2003
Revised on June 9, 2003

Hormone Replacement Therapy and Inflammation. Interactions in Cardiovascular Disease

Andrew P. Miller^*; Yiu-Fai Chen; Dongqi Xing; Wenguang Feng; and Suzanne Oparil

From the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham.

^* To whom correspondence should be addressed. E-mail: apmiller{at}uab.edu.

Abstract--Inflammation plays a central role in the pathogenesis of many forms of vascular disease, including atherosclerosis. Atherogenesis begins with endothelial damage, and the damaged endothelium expresses adhesion molecules, chemokines, and proinflammatory cytokines that direct atherosclerotic plaque formation and spill into the circulation as biomarkers of atherosclerotic disease risk. Menopausal hormone therapy, including a variety of estrogen preparations with or without a progestin, has negative modulatory effects on most of these soluble inflammatory markers, including E-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and tumor necrosis factor-, inconsistent effects on interleukin-6, and stimulatory effects on transforming growth factor-, a vasoprotective cytokine. In contrast, C-reactive protein, a circulating proinflammatory cytokine produced in both liver and atherosclerotic arteries, increases in response to oral conjugated estrogens but not to transdermal estrogen. Although C-reactive protein is clearly linked to increased cardiovascular disease risk in women, the hormone-induced rise in this biomarker is not associated with increased risk and may be related to a first-pass effect of C-reactive protein production in the liver after oral estrogen absorption. Many important questions about the effects of ovarian hormones on vascular inflammation and the pathogenesis of vascular disease cannot be answered in human subjects. Insights from fundamental mechanistic studies in animal models are needed to delineate the cellular/molecular events that determine whether these hormones protect or injure blood vessels.

Key words: atherosclerosis • leukocytes • vessels • women • risk factors

This article has been cited by other articles:

				L.-Y. C. Wing, Y.-C. Chen, Y.-Y. Shih, J.-C. Cheng, Y.-J. Lin, and M. J. Jiang Effects of Oral Estrogen on Aortic ROS-Generating and -Scavenging Enzymes and Atherosclerosis in apoE-Deficient Mice Experimental Biology and Medicine, September 1, 2009; 234(9): 1037 - 1046. [Abstract] [Full Text] [PDF]

				M. Abu-Taha, C. Rius, C. Hermenegildo, I. Noguera, J.-M. Cerda-Nicolas, A. C. Issekutz, P. J. Jose, J. Cortijo, E. J. Morcillo, and M.-J. Sanz Menopause and Ovariectomy Cause a Low Grade of Systemic Inflammation that May Be Prevented by Chronic Treatment with Low Doses of Estrogen or Losartan J. Immunol., July 15, 2009; 183(2): 1393 - 1402. [Abstract] [Full Text] [PDF]

				D. Xing, S. Nozell, Y.-F. Chen, F. Hage, and S. Oparil Estrogen and Mechanisms of Vascular Protection Arterioscler Thromb Vasc Biol, March 1, 2009; 29(3): 289 - 295. [Abstract] [Full Text] [PDF]

				R. Marfella, C. Di Filippo, M. Portoghese, F. Ferraraccio, B. Crescenzi, M. Siniscalchi, M. Barbieri, C. Bologna, M. R. Rizzo, F. Rossi, et al. Proteasome Activity as a Target of Hormone Replacement Therapy-Dependent Plaque Stabilization in Postmenopausal Women Hypertension, April 1, 2008; 51(4): 1135 - 1141. [Abstract] [Full Text] [PDF]

				M. Subramanian and C. Shaha Up-Regulation of Bcl-2 through ERK Phosphorylation Is Associated with Human Macrophage Survival in an Estrogen Microenvironment J. Immunol., August 15, 2007; 179(4): 2330 - 2338. [Abstract] [Full Text] [PDF]

				M. Schumacher, R. Guennoun, A. Ghoumari, C. Massaad, F. Robert, M. El-Etr, Y. Akwa, K. Rajkowski, and E.-E. Baulieu Novel Perspectives for Progesterone in Hormone Replacement Therapy, with Special Reference to the Nervous System Endocr. Rev., June 1, 2007; 28(4): 387 - 439. [Abstract] [Full Text] [PDF]

				J. L. Turgeon, M. C. Carr, P. M. Maki, M. E. Mendelsohn, and P. M. Wise Complex Actions of Sex Steroids in Adipose Tissue, the Cardiovascular System, and Brain: Insights from Basic Science and Clinical Studies Endocr. Rev., October 1, 2006; 27(6): 575 - 605. [Abstract] [Full Text] [PDF]

				C. Bolego, E. Vegeto, C. Pinna, A. Maggi, and A. Cignarella Selective Agonists of Estrogen Receptor Isoforms: New Perspectives for Cardiovascular Disease Arterioscler Thromb Vasc Biol, October 1, 2006; 26(10): 2192 - 2199. [Abstract] [Full Text] [PDF]

				J. E. Ostberg, M. J. H. Attar, V. Mohamed-Ali, and G. S. Conway Adipokine Dysregulation in Turner Syndrome: Comparison of Circulating Interleukin-6 and Leptin Concentrations with Measures of Adiposity and C-Reactive Protein J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2948 - 2953. [Abstract] [Full Text] [PDF]

				T. C. Register, J. A. Cann, J. R. Kaplan, J. K. Williams, M. R. Adams, T. M. Morgan, M. S. Anthony, R. M. Blair, J. D. Wagner, and T. B. Clarkson Effects of Soy Isoflavones and Conjugated Equine Estrogens on Inflammatory Markers in Atherosclerotic, Ovariectomized Monkeys J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1734 - 1740. [Abstract] [Full Text] [PDF]

				C. Maric, K. Sandberg, and C. Hinojosa-Laborde Glomerulosclerosis and Tubulointerstitial Fibrosis are Attenuated with 17{beta}-Estradiol in the Aging Dahl Salt Sensitive Rat J. Am. Soc. Nephrol., June 1, 2004; 15(6): 1546 - 1556. [Abstract] [Full Text] [PDF]

				J. L. Turgeon, D. P. McDonnell, K. A. Martin, and P. M. Wise Hormone Therapy: Physiological Complexity Belies Therapeutic Simplicity Science, May 28, 2004; 304(5675): 1269 - 1273. [Abstract] [Full Text] [PDF]