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CLINICAL STUDY: HORMONE REPLACEMENT THERAPY

Divergent effects of hormone therapy on serum markers of inflammation in postmenopausal women with coronary artery disease on appropriate medical management

^a Cardiology Branch, National Heart, Lung and Blood Institute, Bethesda, Maryland, USA
^b Office of Biostatistics Research, National Heart, Lung and Blood Institute, Bethesda, Maryland, USA
^c Immunopathology Section, National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA
^d Clinical Pathology Department, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA

Manuscript received November 24, 1999; revised manuscript received May 5, 2000, accepted July 10, 2000.

Reprint requests and correspondence: Dr. Richard O. Cannon III, National Institutes of Health, Building 10, Room 7B15, 10 Center Drive MSC-1650, Bethesda, Maryland 20892-1650
cannonr{at}nih.gov

OBJECTIVES

The goal of our study was to determine whether hormone therapy alters markers of inflammation in postmenopausal women with chronic stable coronary artery disease (CAD) on appropriate medical management.

BACKGROUND

Hormone therapy reduces some markers of inflammation associated with atherosclerosis risk (cell adhesion molecules) but increases levels of another marker of inflammation—C-reactive protein—in healthy postmenopausal women.

METHODS

Ten women (average age 66 years; range 59 to 76 years) with CAD on medical management (including aspirin [9], statin lipid-lowering therapy [7], angiotensin-converting enzyme inhibitors [3]) were randomly assigned to conjugated equine estrogens 0.625 mg (combined with medroxyprogesterone acetate 2.5 mg daily in five women with uterus intact) or placebo(s) daily for one month with crossover to the alternate therapy after one month off of hormone treatment in a double-blind study. At the end of each treatment phase, the following markers of inflammation were measured in serum: interleukin-6, C-reactive protein, E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and matrix metalloproteinase-9.

RESULTS

Hormone therapy significantly lowered serum levels of cell adhesion molecules E-selectin (46.9 ± 18.3 vs. 56.3 ± 20.6 ng/mL, p = 0.006), intercellular adhesion molecule-1 (282 ± 74 vs. 304 ± 78 ng/mL, p = 0.013) and vascular cell adhesion molecule-1 (605 ± 218 vs. 657 ± 214 ng/mL, p = 0.01) but increased levels of matrix metalloproteinase-9 (648 ± 349 vs. 501 ± 285 ng/mL, p = 0.02). Interleukin-6 (4.33 ± 4.78 vs. 3.04 ± 1.47 pg/mL, p = 0.283) and C-reactive protein (0.88 ± 1.13 vs. 0.61 ± 0.50 mg/dL, p = 0.358) were not significantly elevated on hormone therapy compared with placebo values.

CONCLUSIONS

Hormone therapy has divergent effects on serum markers of inflammation in women with CAD. Reduction in levels of cell adhesion molecules may reduce attachment of white blood cells to the vessel wall, but increases in matrix metalloproteinase-9 within the vessel wall could digest and weaken fibrous caps of vulnerable plaques, thus provoking thrombosis.

Abbreviations and Acronyms   AP-1 = activator protein-1   CAD = coronary artery disease   CEE = conjugated equine estrogens   CRP = C-reactive protein   ICAM-1 = intercellular adhesion molecule-1   IL-6 = interleukin-6   MI = myocardial infarction   MMP = matrix metalloproteinases   MPA = medroxyprogesterone acetate   PAI-1 = plasminogen activator inhibitor-1   VCAM-1 = vascular cell adhesion molecule-1

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