Effect of transdermal estradiol and oral conjugated equine estrogen on C-reactive protein in retinoid-placebo trial in healthy women.

Conjugated Equine Estrogen on C-Reactive Protein in Retinoid-Placebo Trial in Healthy Women To the Editor: In their interesting study, Decensi et al1 demonstrated that oral conjugated equine estrogen caused an increase in plasma C-reactive protein (CRP), whereas transdermal estradiol (E2) did not elevate CRP levels. The Heart and Estrogen/Progestin Replacement Study (HERS) and Women’s Health Initiative (WHI) trials demonstrated that oral hormone replacement therapy (HRT) did not reduce the risk of coronary artery disease (CAD) in postmenopausal women with or without coronary disease. Because elevated CRP is an independent risk factor for cardiovascular disease, a proinflammatory effect of oral estrogen might explain the increased risk of CAD during the first year of these recent trials. Accordingly, neutral effect of transdermal E2 on CRP might possibly be associated with a safer profile on early CAD risk. However, it is not clear whether oral estrogen stimulates systemic inflammatory responses or whether it simply stimulates hepatic synthesis of CRP without activation of inflammatory cytokines such as interleukin-6 (IL-6), which regulate hepatic CRP production. According to the WHI observational study,2 HRT-associated increases in CRP are due to a direct hepatic pass effect of oral estrogen and not to an effect of systemic inflammation because HRT did not increase plasma IL-6 concentrations. However, these data in this study are observational. A prospective randomized study by Herrington et al3 demonstrated that HRT increased plasma levels of CRP and IL-6 in postmenopausal women. Thus, oral estrogen replacement therapy (ERT) may exert a proinflammatory effect that could partially offset estrogen’s favorable effects and may lead to the increased risk of CAD. In contrast to oral ERT, transdermal E2 has been reported to depress IL-6 secretion in postmenopausal women.4 Accordingly, transdermal ERT can eliminate the adverse effects of oral ERT on inflammatory markers and could have a favorable effect on clinical outcome. Studies are needed to investigate whether transdermal ERT is effective for the risk of CAD in postmenopausal women with or without CAD.