Effect of 17ß-estradiol on Inflammatory-immune Responses in Post-menopausal Women According to Administration Route

Postmenopausal

Estrogen Replacement Therapy, menopausal women

The aim of this pilot study conducted in post-menopausal women is to evaluate the effect of 17ß-estradiol administration on inflammatory-immune cells, namely antigen-presenting cells (monocytes/dendritic cells), and more precisely on their activation by inflammatory stimuli. This study will allow us to determine our ability to recruit menopausal women and to characterize the optimal primary end-point among the numerous criteria tested

Although the beneficial effects of hormonal replacement therapy (HRT) against osteoporosis and climacteric symptoms have been clearly established, randomized studies recently revealed that the combined administration of oral estrogens and medroxyprogesterone acetate increases the incidence of coronary events and strokes during the first months of treatment. Furthermore, oral estrogens significantly enhance IL-6 and CRP secretion. This increase in the plasma concentration of inflammatory markers probably results from a direct effect of oral administration on the liver, since i twas not observed with estrogens administered by transdermal route. Our experimental data in ovariectomized mice demonstrated that the chronic subcutaneous administration of17ß-estradiol (E2) enhances the expression of pro-inflammatory cytokines by Th1 lymphocytes, Natural Killer T cells and monocytes/macrophages. This pro-inflammatory effect of E2 could play a role in the deleterious vascular effects observed in randomized studies, especially by favoring plaque instability. Our aim is to determine whether E2 administration in menopausal women leads to an inflammatory phenotype of circulating antigen-presenting cells, especially monocytes. Indeed, evaluating the inflammatory status at the cellular level probably gives more precise informations than plasma cytokine concentrations to predict the ability of estrogens to enhance inflammatory processes. We first propose a pilot study in order to determine enrollment feasibility, as well as the optimal biological endpoints to assess monocyte activation status. These latter criteria will be then used in a future randomized study comparing two routes of E2 administration (oral vs transdermal). The present study will include 34 menopausal women. After the inclusion visit, three visits will be performed with the collection of a 50 ml blood sample and the isolation of circulating immune cells (monocytes). The following criteria will be studied before (V1 and V2) and after 30 ± 3 days of E2 treatment (V3: 1. expression of surface activation molecules. 2. Secretion of cytokines in response to several Toll-like receptor stimuli. 3. IL-6 and CRP-US plasma concentrations. We will first assess the intra-individual variability (V1 and V2). At visit 2 (V2), the subjects will be randomized to receive E2 either by oral (n= 17) or transdermal (n= 17) route.

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