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Persistence of an Intact Endometrial Matrix and Vessels Structure in Women Exposed to VA-2914, a Selective Progesterone Receptor Modulator

Department of Gynecology (S.R., G.B., A.B., J.-M.F., A.P.), Centre Hospitalier Universitaire, and Laboratory of Tumor and Development Biology (C.M., S.B., S.L., A.B., J.-M.F., A.P.), University of Liege, Tour de Pathologie (B23), Center of Experimental Cancer Research, ’GIGA-R’, B-4000 Liège, Belgium; Department of Obstetrics, Gynecology, Reproductive Medicine and Public Health (N.C.-B.), Hospital Tenon, Assistance Publique-Hôpitaux de Paris, Paris 75020, France; Equipe d’ Accueil 1533 Université Pierre et Marie Curie Université Paris 06 (N.C.-B., P.B.), 75005 Paris, France; and Endocrinology Unit (P.B.), Hospital Saint-Antoine, Assistance Publique-Hôpitaux de Paris, 75012 Paris, France

Address all correspondence and requests for reprints to: Jean-Michel Foidart, Département de Gynécologie et Obstétrique, Boulevard 12^e de Ligne, 1, B-4000 Liège, Belgium. E-mail: jmfoidart{at}ulg.ac.be.

Background: VA-2914 is a selective progesterone receptor modulator with potential contraceptive activity that induces amenorrhea, whereas progestins cause endometrial spotting and bleeding. This abnormal bleeding due to progestins is a consequence of focal stromal proteolysis by an increase in naked vessel size and density.

Objective: Our objective was to quantify the effects of VA-2914 on endometrial vascularization, fibrillar matrix, and vascular endothelial growth factor (VEGF)-A expression in endometrial biopsies from 41 women before and after 12 wk daily treatment with a placebo, or 2.5, 5, or 10 mg VA-2914.

Methods: Collagen fibrillar network was stained by silver impregnation. Vessel area, density, and structure were quantified with a computer-assisted image analysis system after double immunostaining using an anti-von Willebrand factor (endothelial cells) and an anti- smooth muscle actin (vascular smooth muscle cells) marker antibody. VEGF-A mRNAs were quantified by RT-PCR and localized by immunohistochemistry.

Results: The endometrial vessels, collagen network, and mRNA levels of VEGF-A were identical during the luteal phase at baseline and in VA-2914 treated women. VEGF-A distribution was unchanged.

Conclusions: VA-2914 does not alter the endometrial matrix and cells, and does not modify the endometrial vessel morphology as compared with baseline biopsies.