Inflammatory Biomarkers, Hormone Replacement Therapy, and Incident Coronary Heart Disease

Abstract

Context Postmenopausal hormone replacement therapy (HRT) has been shown to elevate C-reactive protein (CRP) levels. Several inflammatory biomarkers, including CRP, are associated with increased cardiovascular risk. However, whether the effect of HRT on CRP represents a clinical hazard is unknown. Objectives To assess the association between baseline levels of CRP and interleukin 6 (IL-6) and incident coronary heart disease (CHD) and to examine the relationship between baseline use of HRT, CRP, and IL-6 levels as they relate to subsequent vascular risk. Design, Setting, and Participants Prospective, nested case-control study of postmenopausal women, forming part of the Women's Health Initiative, a large, nationwide, observational study. Among 75343 women with no history of cardiovascular disease or cancer, 304 women who developed incident CHD were defined as cases and matched by age, smoking status, ethnicity, and follow-up time with 304 study participants who remained event free during a median observation period of 2.9 years. Main Outcome Measure Incidence of first myocardial infarction or death from CHD. Results Median baseline levels of CRP (0.33 vs 0.25 mg/dL; interquartile range [IQR], 0.14-0.71 vs 0.10-0.47; PϽ.001) and IL-6 (1.81 vs 1.47 pg/mL; IQR, 1.30-2.75 vs 1.05-2.15; PϽ.001) were significantly higher among cases compared with controls. In matched analyses, the odds ratio (OR) for incident CHD in the highest vs lowest quartile was 2.3 for CRP (95% confidence interval [CI], 1.4-3.7; P for trend=.002) and 3.3 for IL-6 (95% CI, 2.0-5.5; P for trend Ͻ.001). After additional adjustment for lipid and nonlipid risk factors, both inflammatory markers were significantly associated with a 2-fold increase in odds for CHD events. As anticipated, current use of HRT was associated with significantly elevated median CRP levels. However, there was no association between HRT and IL-6. In analyses comparing individuals with comparable baseline levels of either CRP or IL-6, those taking or not taking HRT had similar CHD ORs. In analyses stratified by HRT, we observed a positively graded relationship between plasma CRP levels and the OR for CHD among both users and nonusers of HRT across the full spectrum of baseline CRP. Conclusions These prospective findings indicate that CRP and IL-6 independently predict vascular events among apparently healthy postmenopausal women and that HRT increases CRP. However, use or nonuse of HRT had less importance as a predictor of cardiovascular risk than did baseline levels of either CRP or IL-6.

Increased Levels of C-Reactive Protein After Oral Hormone Replacement Therapy May Not Be Related to an Increased Inflammatory Response

“…16 Therefore, it seems likely that HRT may increase CRP through an IL-6 -independent and TNF␣-independent mechanism. 17,18 In accordance with our findings, Pradhan et al 19 in a prospective analysis from the Women's' Health Initiative (WHI) have reported that long-term HRT use was associated with increased CRP levels and with a decrease in IL-6 and that baseline levels of CRP and IL-6 are independently associated with cardiovascular risk in postmenopausal women. Early observational studies have suggested that HRT may reduce cardiovascular risk.…”

Insulin resistance with hormone replacement therapy: associations with markers of inflammation and adiposity

“…We found that combination HRT increased CRP by 17.8%, but did not change IL-6, suggesting that a generalized pro-inflammatory effect with HRT is not occurring. Our finding that HRT increases CRP is consistent with previous reports (20)(21)(22)(57)(58)(59). Our finding that HRT did not affect IL-6 is consistent with another randomized trial (57), but not with a crosssectional study that found lower levels of IL-6 with HRT (58).…”

“…Limitations include our relatively small sample size. However, CRP and IL-6 have been shown to correlate strongly with markers of insulin sensitivity (18,60). In our volunteers, CRP, IL-6, and leptin correlated strongly with glucose disposal at baseline (r= −0.382, −0.338, −0.561, respectively, all P's<0.01).…”

“…Specifically, high sensitivity C-reactive protein (CRP) and interleukin 6 (IL-6) are associated with increased cardiovascular events in these women (16,18). Because adipose tissue produces , it is possible that circulating markers of inflammation mediate the effect of fat on insulin sensitivity.…”

C‐Reactive Protein Identifies Low‐Risk Metabolically Healthy Obese Persons: The European Prospective Investigation of Cancer–Norfolk Prospective Population Study

“…We found similar associations for abdominally obese participants with elevated CRP levels showing an increased risk for CHD compared with abdominally obese participants with low CRP levels. Previous studies linking CRP levels to CHD were performed largely in populations with a lower prevalence of obesity than that of the current US population 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32. In the 2 largest published studies of CRP and CHD disease,25, 27 the mean body mass index (in  kg/m 2 ) of participants ranged from 25 to 26, lower than the recently reported mean of 28.7 in US adults,33 indicating the clinical need for data regarding CRP in obese populations.…”