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(Circulation. 1999;100:717-722.)
© 1999 American Heart Association, Inc.

Clinical Investigation and Reports

Effect of Postmenopausal Hormones on Inflammation-Sensitive Proteins

The Postmenopausal Estrogen/Progestin Interventions (PEPI) Study

Mary Cushman, MD, MSc; Claudine Legault, PhD; Elizabeth Barrett-Connor, MD; Marcia L. Stefanick, PhD; Craig Kessler, MD; Howard L. Judd, MD; Pamela A. Sakkinen, MD, MPH; Russell P. Tracy, PhD

From the Departments of Medicine (M.C.), Pathology (M.C., P.A.S., R.P.T.) and Biochemistry (R.P.T.), University of Vermont, Burlington; Department of Public Health Sciences (C.L.), Wake Forest University School of Medicine, Winston-Salem, NC; Department of Family and Preventive Medicine (E.B.-C.), University of California, San Diego, La Jolla, Calif; Stanford Center for Research in Disease Prevention (M.L.S.), Stanford University, Palo Alto, Calif; Department of Medicine, Division of Hematology/Oncology (C.K.), Georgetown University, Washington, DC; and Department of Obstetrics and Gynecology (H.L.J.), University of California, Los Angeles.

Correspondence and reprint requests to Mary Cushman, MD, MSc, Department of Medicine, University of Vermont, 55A South Park Drive, Colchester, VT 05446. E-mail mcushman{at}salus.uvm.edu

Background—Observational studies in healthy women suggest postmenopausal hormone therapy reduces risk of coronary events. In contrast, in a recent clinical trial of women with coronary disease, a subgroup analysis demonstrated increased risk during the early months of therapy. Because higher levels of inflammation factors predict vascular disease outcomes, the effect of hormones on these factors is of interest.

Methods and Results—Four inflammation-sensitive factors, C-reactive protein, soluble E-selectin, von Willebrand factor antigen, and coagulation factor VIIIc were measured at baseline, 12, and 36 months in 365 participants of the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial, a randomized, placebo-controlled trial of the effects of 4 hormone preparations on cardiovascular disease risk factors. Compared with placebo, all 4 active preparations resulted in a large sustained increase in the concentration of C-reactive protein and a decrease in soluble E-selectin (P=0.0001). There were no effects of treatment on concentrations of von Willebrand factor or factor VIIIc. There were no differences in effects among treatment arms. Relative to placebo, when combining active treatment arms, final concentrations of C-reactive protein were 85% higher whereas E-selectin was 18% lower compared with baseline.

Conclusions—Postmenopausal hormones rapidly increased the concentration of the inflammation factor C-reactive protein. Such an effect may be related to adverse early effects of estrogen therapy. In contrast, hormones reduced the concentration of soluble E-selectin, and this might be considered an anti-inflammatory effect. Because PEPI was not designed to assess clinical endpoints, studies of the impact of hormone-mediated changes in inflammation on risk of subsequent coronary events are needed.

Key Words: risk factors • hormones • inflammation • coagulation • women

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