Differential effects of oral versus transdermal estrogen replacement therapy on C-reactive protein in postmenopausal women.
OBJECTIVE
We investigated whether the route of estrogen replacement therapy (ET) is the major determinant of C-reactive protein (CRP) in postmenopausal women.


BACKGROUND
Recent studies demonstrated that oral ET causes a sustained increase in CRP, implicating a proinflammatory effect. Because CRP is synthesized in the liver, we hypothesized that estrogen-induced CRP elevation is related to first-pass hepatic metabolism.


METHODS
In 21 postmenopausal women, we conducted a randomized, crossover, placebo-controlled study to compare the effects of transdermal versus oral ET on CRP and inflammatory cytokines. We measured CRP, interleukin (IL)-1-beta, IL-6, and tumor necrosis factor-alpha before and after eight weeks of transdermal estradiol (E(2)) (100 microg/day), oral conjugated estrogen (CEE) (0.625 mg/day), or placebo. Insulin-like growth factor-1 (IGF-1), a hepatic-derived anabolic peptide, was also measured.


RESULTS
Transdermal E(2) had no effect on CRP or IGF-1 levels. In contrast, eight weeks of oral conjugated estrogens caused a more than twofold increase in CRP and a significant reduction in IGF-1 (p < 0.01) in the same women. The magnitude of increase in CRP was inversely correlated to the decrease in IGF-1 (r = -0.49, p = 0.008). Neither transdermal E(2) nor oral CEE had any effects on the plasma concentrations of cytokines that promote CRP synthesis.


CONCLUSIONS
In postmenopausal women, oral but not transdermal ET increased CRP by a first-pass hepatic effect. An increase in CRP levels is accompanied by a reduction in IGF-1, an anti-inflammatory growth factor. Because CRP is a powerful predictor of an adverse prognosis in otherwise healthy postmenopausal women, the route of administration may be an important consideration in minimizing the adverse effects of ET on cardiovascular outcomes.
Vongpatanasin
Wanpen
W
Donald W. Reynolds Cardiovascular Clinical Research Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75390, USA. wanpen.vongpatanasin@utsouthwestern.edu
Tuncel
Meryem
M
Wang
Zhongyun
Z
Arbique
Debbie
D
Mehrad
Borna
B
Jialal
Ishwarlal
I
D000279:Administration, Cutaneous; D000284:Administration, Oral; D000704:Analysis of Variance; D002097:C-Reactive Protein / Q000378:metabolism*; D018592:Cross-Over Studies; D015914:Estrogen Replacement Therapy / Q000379:methods*; D004967:Estrogens / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism*; D008593:Menopause / Q000097:blood* / Q000378:metabolism; D008875:Middle Aged
D004967:Estrogens; D008055:Lipids; D007334:Insulin-Like Growth Factor I; D002097:C-Reactive Protein