Official Title: “Effect of 17ß-Estradiol on Inflammatory-Immune Responses in Post-Menopausal Women According to Administration Route: Pilot Study”

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

Study Type: Interventional

Study Design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Pharmacodynamics Study

Study Primary Completion Date: September 2009

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.

Intervention(s) in this Clinical Trial

• Drug: oestradiol
  • oestradiol 2 mg oral route 30 days
• Drug: oestradiol
  • oestradio transdermal patch 60ug by 24 hours 30 days

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • oestradiol by oral administration
• Experimental: 2
  • oestradiol par patch

Primary Measures

• To determine the feasibility of a future multicentric randomized trial : estimation of the number of subjects required
  • Time Frame: 1 month
    Safety Issue?: No

Inclusion Criteria:

• Women with confirmed menopause (duration : 1 to 5 years)
• No contra-indication of hormonal replacement therapy due to medical history
• Mammogram without significant abnormality (< 12 months)
• Normal body mass index (BMI) (19 ≤ IMC ≤ 25 kg/m2)
• No treatment with estrogens and/or progestatives and/or SERM (specific moduator of estrogen receptor) and/or phytoestrogènes ongoing or stopped for less than 3 months
• No clinical or biological abnormality or treatment indicating the presence of an infectious or inflammatory disease.
• No participation to another clinical study during the 3 months before the inclusion
• Ability to sign the consent form.

Gender Eligibility for this Clinical Trial: Female

Minimum Age for this Clinical Trial: 45 Years

Maximum Age for this Clinical Trial: 60 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: University Hospital, Toulouse

Overall Clinical Trial Officials and Contacts

Pierre GOURDY Principal Investigator Hospital University Toulouse  

Overall Contact: Pierre GOURDY, MD 33-56-132-2685 gourdy.p@chu-toulouse.fr

Information obtained from ClinicalTrials.gov on August 29, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00701337

Study ID Number: 0507402

ClinicalTrials.gov Identifier: NCT00701337

Health Authority: France: Afssaps - French Health Products Safety Agency