C-Reactive Protein and Estrogen
Abstract & Commentary
Synopsis: Postmenopausal hormone replacement therapy rapidly and markedly increased the concentration of C-reactive protein, which may be a negative effect of estrogen, but reduces E-selection, which may be anti-inflammatory.
Sources: Ridner PM, et al. Circulation 1999;100:713-716; Cushman M, et al. Circulation 1999;100:717-722.
Considerable observational epidemiological data suggest that hormone replacement therapy reduces cardiovascular events in women. However, the recently published HERS (Heart and Estrogen Replacement Study) failed to demonstrate a reduction in coronary events in women with known coronary artery disease (CAD) assigned to hormone replacement therapy vs. placebo (Hulley S, et al. JAMA 1998;280:605-613). Recent pathophysiological studies have linked atherosclerosis to inflammation and the inflammatory marker C-reactive protein has predicted increased risk of CAD in studies involving women. Cross-sectional studies of long-term users of hormones have shown elevated C-reactive protein levels (see Ridner and colleagues). Thus, the lack of secondary prevention benefit in HERS could be due to enhanced inflammation caused by estrogen use. Accordingly, Cushman and colleagues (second source document) tested the effects of hormone therapy on several inflammatory factors (C-reactive protein, E-selectin, Von Willebrand factor, and factor VIIIc) in 383 women, a subset of the 875 women enrolled in the postmenopausal estrogen progestin interventions (PEPI) trial. PEPI was a three-year randomized, double-blind, placebo-controlled trial comparing four hormone regimens on cardiovascular risk factors. The main trial results have been published and showed beneficial effects on serum lipids and lipoproteins. The subgroup had the inflammatory factors measured at baseline, 12, and 36 months. All four hormone regimens resulted in a sustained increase in C-reactive protein of 85%, but a decrease in E-selectin of 18% vs. placebo (P < 0.002). Van Willebrand and factor VIIIc were unchanged. Cushman et al conclude that postmenopausal hormone replacement therapy rapidly and markedly increased the concentration of C-reactive protein, which may be a negative effect of estrogen but reduces E-selectin, which may be anti-inflammatory. Clinical trials of cardiovascular outcomes will be needed to assess the significance of these findings.
Comment by Michael H. Crawford, MD
After encouraging observational data on estrogens for secondary prevention, the cardiology community was deeply disappointed with the results of HERS, the first randomized clinical trial of secondary prevention with hormone replacement therapy. The results of this subgroup of PEPI may provide at least a partial explanation for the results of HERS. Of interest is the fact that coronary events were increased early in the five-year HERS, but seemed to decrease in the last two years of follow-up. This was interpreted as showing that the beneficial lipid effects of hormone therapy may take time to manifest benefit in women with known CAD. The early and marked increase in C-reactive protein may have augmented this time separation of benefits from hormones in HERS. Unfortunately, the C-reactive protein effects were sustained for the three years of PEPI, suggesting that they would probably not decrease in another two years, but you never know. Also, the potential beneficial effects of reduced E-selectin levels may take time to be of benefit. In support of this concept, the changes in E-selectin and LDL cholesterol were correlated.
The major limitation of this study is the inability to assess the effects of inflammatory protein changes on cardiovascular risk. PEPI was not designed to evaluate clinical end points and there were too few women in PEPI with CAD to study outcome effects. However, to the extent that inflammatory protein pathways are casually related to cardiovascular events, these findings are of considerable interest and support the negative results of HERS.
The potential reason for the negative findings in the Heart and Estrogen Replacement Study of secondary prevention is that estrogen:
a. increases LDL cholesterol.
b. increases the Von Willebrand factor.
c. increases C-reactive protein.
d. All of the above
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