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Characterization of Endozepines in the Human Testicular Tissue: Effect of Triakontatetraneuropeptide on Testosterone Secretion

European Institute for Peptide Research (Institut Fédératif de Recherche Multidisciplinaires sur les Peptides 23) (C.D., H.L., M.-C.T., H.V., J.-M.K.), Laboratory of Cellular and Molecular Neuroendocrinology, Institut National de la Santé et de la Recherche Medicale, Unité 413, Unité Affiliée Centre National de la Recherche Scientifique, University of Rouen, 76821 Mont-Saint-Aignan, France; and Department of Endocrinology and Metabolic Diseases (H.L., J.-M.K.), Centre Hospitalier Universitaire of Rouen, 76031 Rouen, France

Address all correspondence and requests for reprints to: Dr. Hubert Vaudry, Laboratory of Cellular and Molecular Neuroendocrinology, Institut Fédératif de Recherche Multidisciplinaires sur les Peptides 23, Institut National de la Santé et de la Recherche Medicale, Unité 413, Unité Affiliée Centre National de la Recherche Scientifique, University of Rouen, 76821 Mont-Saint-Aignan Cedex, France. E-mail: hubert.vaudry{at}univ-rouen.fr.

Previous studies have shown that endozepines, i.e. endogenous ligands of benzodiazepine (BZD) receptors, stimulate steroidogenesis in adrenocortical and Leydig cells. In the present report, we have investigated the presence and action of endozepines in the human testis. Immunohistochemical labeling revealed the occurrence of endozepine-like immunoreactivity in Leydig, Sertoli, and germ cells. HPLC analysis combined with a specific RIA resolved two immunoreactive peaks that coeluted with synthetic octadecaneuropeptide (ODN) and triakontatetraneuropeptide (TTN). RT-PCR amplification showed that the mRNA encoding the endozepine precursor diazepam-binding inhibitor is expressed in the human testis. The action of endozepines on testosterone production was studied in vitro using perifused human testicular fragments. Administration of TTN provoked a dose-dependent increase in testosterone secretion, whereas ODN had no effect. The stimulatory action of TTN on testosterone production was totally blocked by flunitrazepam, a peripheral-type BZD receptor antagonist/central-type BZD receptor (CBR) agonist. Conversely, the CBR agonist clonazepam and the CBR antagonist flumazenil did not affect testosterone secretion. Collectively, these results suggest that, in the human testicular tissue, TTN may exert an intracrine and/or paracrine control of steroidogenesis through activation of a peripheral-type BZD receptor.

This work was supported by the Centre Hospitalier Universitaire of Rouen, Institut National de la Santé et de la Recherche Medicale, Unité 413, Institut Fédératif de Recherche Multidisciplinaires sur les Peptides 23, and the Conseil Régional de Haute-Normandie. C.D. was the recipient of a fellowship from the Société d’Andrologie de Langue française.

Abbreviations: BZD, Benzodiazepine; CBR, central-type BZD receptor; DBI, diazepam-binding inhibitor; hCG, human chorionic gonadotropin; KRB, Krebs-Ringer buffer; ODN, octadecaneuropeptide; PB, phosphate buffer; PBR, peripheral-type BZD receptor; TFA, trifluoroacetic acid; TTN, triakontatetraneuropeptide.