title: Differential effects of oral versus transdermal estrogen replacement therapy on C-reactive protein in postmenopausal women.
abstract: 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.
authors.affiliation: Donald W. Reynolds Cardiovascular Clinical Research Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75390, USA. wanpen.vongpatanasin@utsouthwestern.edu
authors.forename: Wanpen
authors.initials: W
authors.lastname: Vongpatanasin
authors.forename: Meryem
authors.initials: M
authors.lastname: Tuncel
authors.forename: Zhongyun
authors.initials: Z
authors.lastname: Wang
authors.forename: Debbie
authors.initials: D
authors.lastname: Arbique
authors.forename: Borna
authors.initials: B
authors.lastname: Mehrad
authors.forename: Ishwarlal
authors.initials: I
authors.lastname: Jialal
mesh_terms: 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
chemical_list: D004967:Estrogens; D008055:Lipids; D007334:Insulin-Like Growth Factor I; D002097:C-Reactive Protein