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Follicle-Stimulating Hormone Increases Testicular Anti-Müllerian Hormone (AMH) Production through Sertoli Cell Proliferation and a Nonclassical Cyclic Adenosine 5'-Monophosphate-Mediated Activation of the AMH Gene

Centro de Investigaciones Endocrinológicas (Consejo Nacional de Investigaciones Científicas y Técnicas; C.L., P.B., R.R.), Hospital de Niños "R. Gutiérrez," C1425EFD Buenos Aires, Argentina; Unité de Recherches sur l’Endocrinologie du Développement (Intitut National de la Santé et de la Recherche Médicale; C.L.-C., J.N., M.D., J.-Y.P., N.J., R.R.), Département de Biologie, Ecole Normale Supérieure, 92120 Montrouge, France; and Departments of Pathology and Molecular and Cellular Biology (T.R.K., M.M.M.) and Department of Molecular and Human Genetics (M.M.M.), Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Dr. Rodolfo Rey, Centro de Investigaciones Endocrinológicas, Hospital de Niños, Gallo 1330, C1425EFD Buenos Aires, Argentina. E-mail: rodolforey{at}cedie.org.ar.

Anti-Müllerian hormone (AMH) production by testicular Sertoli cells is high before puberty and can be further induced by FSH. Our objective was to delineate the mechanisms by which FSH stimulates AMH production. Assay of serum AMH levels and histological morphometric analysis in prepubertal FSH-deficient transgenic mice showed that serum AMH and testicular mass were decreased owing to reduced Sertoli cell number. All parameters resumed normal values in mice treated with recombinant FSH. We also analyzed the ability of FSH and the factors involved in its signaling pathway to activate AMH transcription by transfecting AMH promoter-luc reporter constructs of different lengths in a prepubertal Sertoli cell line. Our results showed that FSH activates AMH transcription via adenylate cyclase, cAMP, and protein kinase A but involving a nonclassical cAMP-response pathway requiring nuclear factor-B and activating protein 2 binding sites, which lie more than 1.9 kb upstream of the AMH transcription start site. This is the first report showing the importance of distant sequences in the regulation of AMH expression. We conclude that prepubertal testicular AMH production is increased by FSH stimulation through Sertoli cell proliferation and an enhancement of AMH gene transcription.

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