The Effect of Different Doses of Micronized 17ss-Estradiol on C-Reactive Protein, Interleukin-6, and Lipids in Older Women

Abstract

Background. The authors evaluated the effect of 3 doses (0.25 mg/day, 0.5 mg/day, and 1 mg/day) of micronized 17β-estradiol (E₂) on C-reactive protein (CRP), interleukin-6 (IL-6), and lipids, compared with placebo, in healthy older women participating in an osteoporosis study. Methods. This randomized, double-blind, placebo-controlled study was conducted in a University clinical research center. Participants were healthy, community-living women older than 65 years. The primary outcome measure of the study was bone metabolism as estimated by serum and urine markers of bone turnover. For this analysis, the authors measured serum markers of CRP, IL-6, lipids, intracellular adhesion molecule-1, and E-selectin at baseline, after 12 weeks of treatment, and after 12 weeks with no treatment. Results. A significant dose-response effect of estrogen occurred on CRP levels. After 12 weeks of treatment, CRP decreased 59% in the 0.25 mg/day E₂ group and increased 65% in the 1 mg/day E₂ group, compared with placebo. The CRP level continued to be elevated (92%), compared with placebo, 12 weeks after treatment was discontinued in the 1 mg/day E₂ group. High-density lipoprotein (HDL) and HDL₂ cholesterol increased and low-density lipoprotein (LDL) cholesterol decreased at 12 weeks in the 1 mg/day E₂ group, with a significant dose-response effect. E-selectin decreased significantly in the 1 mg/day E₂ group 12 weeks after discontinuation of treatment (−7%), and there was a significant dose-response effect at this time. The 2 lower doses did not affect any of these parameters. Total and HDL₃ cholesterol, triglycerides, lipoprotein(a), intracellular adhesion molecule-1, and IL-6 did not change with any dose of E₂. Conclusions. C-reactive protein, an inflammation marker associated with increased risk for cardiovascular disease, decreased in women taking the lowest estrogen dose but increased in women assigned to the highest estrogen dose, suggesting decreased inflammation with lower dose E₂. However, with 3 months of treatment, 0.25 or 0.5 mg/day E₂ did not have the same beneficial effects on HDL or LDL cholesterol as did 1 mg/day E₂. These data suggest that estradiol doses have differential short-term effects on markers of cardiovascular disease. Low-dose E₂ decreased CRP, an important marker of inflammation, but did not affect lipid parameters, whereas the highest dose increased CRP and had a beneficial effect on lipid parameters. The long-term consequences of these effects are unknown, but it is possible that estradiol dose should be considered when risk:benefit ratios are evaluated for individual women before estrogen replacement therapy is initiated.