The effects of exogenous estrogen on coronary heart disease are controversial. Substantial observational data support a protective effect and several randomized clinical trials have demonstrated that estrogen produces a more favorable lipid profile. Yet, when administered for secondary prevention in the Heart and Estrogen/Progestin Replacement Study (HERS) and Estrogen Replacement and Atherosclerosis (ERA) trials, estrogen had no overall benefit. In HERS, estrogen use was associated with an increase in early events but a late reduction in risk. These conflicting data suggest the need for additional exploration of the effect of estrogen on the risk factors and precipitants of coronary heart disease. Peripheral blood markers of inflammation, specifically C-reactive protein (CRP) and interleukins, have been increasingly recognized as predictors of cardiovascular events and suggest new pathophysiologic mechanisms. However, the effects of estrogen upon inflammatory markers and their subsequent impact upon endothelial function are still unclear. This study will use data from the NHLBI-funded Postmenopausal Estrogen Progestin Intervention (PEPI) randomized clinical trial to assess the effect of conjugated equine estrogens (CEE) with or without progestins upon two peripheral blood inflammatory markers, CRP and IL-6, and their subsequent effects on other cardiovascular risk factors. We will also examine the relation of exogenous CEE on sex hormone-binding globulin (SHBG), a hepatic protein whose production is independent of inflammation but is stimulated by CEE. Assays for IL-6, CRP, and SHBG will be performed on longitudinal stored serum samples and these results will be linked to extensive socio-demographic, lifestyle, and clinical information already collected in the PEPI clinical trial. We hypothesize that CEE will create unfavorable risk profiles of inflammatory markers (higher IL-6 and higher CRP) during the first year of therapy but these patterns will change toward more favorable profiles (lower IL-6 despite continued higher CRP) with continued treatment. We also hypothesize that the continued stimulation of CRP beyond the first year will be through a non- inflammatory effect on liver protein production (similar to estrogen's stimulation of sex hormone-binding globulin SHBG) rather than IL-6 mediated. These findings may provide substantial insight into why CEE appears to promote early but protect against late cardiovascular effects.
| Crandall, C; Palla, S; Reboussin, B et al. (2006) Cross-sectional association between markers of inflammation and serum sex steroid levels in the postmenopausal estrogen/progestin interventions trial. J Womens Health (Larchmt) 15:14-23 |
| Hu, Peifeng; Greendale, Gail A; Palla, Shana L et al. (2006) The effects of hormone therapy on the markers of inflammation and endothelial function and plasma matrix metalloproteinase-9 level in postmenopausal women: the postmenopausal estrogen progestin intervention (PEPI) trial. Atherosclerosis 185:347-52 |
| Reuben, David B; Palla, Shana L; Hu, Peifeng et al. (2006) Progestins affect mechanism of estrogen-induced C-reactive protein stimulation. Am J Med 119:167.e1-8 |
