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Absence of Nuclear Receptors for Oxysterols Liver X Receptor Induces Ovarian Hyperstimulation Syndrome in Mice

Unité Mixte de Recherche Centre National de la Recherche Scientifique 6247 (K.M., F.V., S.B., G.A., A.J.C.P., D.H.V., G.M., A.D., P.D., F.C., J.-M.A.L.), Institut National de la Santé et de la Recherche Médicale Unité 931, Clermont Université, Centre de Recherche en Nutrition Humaine d'Auvergne, 63177 Aubière Cedex, France; Centre Hospitalier Universitaire (G.M.), Service de Biochimie, 63003 Clermont-Ferrand, France; Centre Hospitalier Universitaire (P.D.), Service d'Anatomie Pathologique, Hôtel Dieu, 63058 Clermont-Ferrand, France; and Department of Animal Science (R.D.), McGill University, Sainte Anne de Bellevue Québec, Canada H9X 3V9

Address all correspondence and requests for reprints to: Jean-Marc A. Lobaccaro, Unité Mixte de Recherche Centre National de la Recherche Scientifique 6247 et Centre de Recherche en Nutrition Humaine d'Auvergne, 24 Avenue des Landais, 63177 Aubière Cedex, France. E-mail: j-marc.lobaccaro{at}univ-bpclermont.fr.

Ovarian hyperstimulation syndrome is a frequent complication occurring during in vitro fertilization cycles. It is characterized by a massive ovarian enlargement associated with an accumulation of extra vascular fluid. Here we show that liver X receptor (LXR)- and LXR-β deficient mice present many clinical and biological signs of ovarian hyperstimulation syndrome: ovarian enlargement, hemorrhagic corpora lutea, increased ovarian vascular permeability, and elevated estradiol. Ovulation stimulation resulted in excessive ovarian response to exogenous gonadotropins because follicle number and estradiol production were higher in transgenic mice. LXR deficiency also leads to perturbations in general inflammatory status, associated with ovarian il-6 deregulation. Upon treatment with the synthetic LXR agonist T09101317, serum estradiol and expression of star and cyp11a1 genes were markedly increased in wild-type mice, showing that LXRs are key regulators of ovarian steroidogenesis. These results suggest that LXRs control the ovulation by regulating endocrine and vascular processes.