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Neuroendocrine Phenotype Analysis in Five Patients with Isolated Hypogonadotropic Hypogonadism due to a L102P Inactivating Mutation of GPR54

Pediatric Endocrine Unit (Y.T.-R., O.A.), Ha’Emek Medical Center, Afula 18101, Israel; Technion Faculty of Medicine (Y.T.-R.), 31905 Haifa, Israel; Maternité Pellegrin (M.C.-D.), Centre Hospitalier Universitaire Bordeaux, 33076 Bordeaux, France; Institut National de la Santé et de la Recherche Médicale U690, Hôpital Robert Debré (A.I., C.A., N.d.R.), 75019 Paris, France; and Université Paris 11 (N.d.R.), Faculté de Médecine Paris Sud, 94275 Le Kremlin Bicêtre, France

Address all correspondence and requests for reprints to: Dr. Nicolas de Roux, Institut National de la Santé et de la Recherche Médicale U690, Hopital Robert Debré, 48 Bd Serrurier, 75735 Paris Cedex 19, France. E-mail: deroux{at}rdebre.inserm.fr.

Context: Loss of function of the G protein-coupled receptor of kisspeptins (GPR54) was recently described as a new cause of isolated hypogonadotropic hypogonadism. In vivo studies performed in several species have confirmed the major role of kisspeptins in neuroendocrine regulation of the gonadotropic axis and therefore sexual maturation.

Objective: The objective of this study was to specify the exact contribution of kisspeptins and GPR54 to the initiation of puberty in humans.

Design: Detailed neuroendocrine descriptions were performed in five patients with isolated hypogonadotropic hypogonadism bearing a new GPR54-inactivating mutation.

Results: A homozygous mutation (T305C) leading to a leucine substitution with proline (L102P) was found in the five affected patients. This substitution completely inhibited GPR54 signaling. Phenotypic analysis revealed variable expressivity in the same family, either partial or complete gonadotropic deficiency. LH pulsatility analysis showed peaks with normal frequency but low amplitude. Repeated GnRH tests performed between 12 and 21 yr of age in one affected male revealed progressive changes in pituitary response from an early pubertal to an almost full pubertal pattern. Double GnRH test stimulations performed at a 120-min interval showed reduced dynamic pituitary response in GPR54-mutated patients.

Conclusion: GPR54 inactivation does not impede neuroendocrine onset of puberty; rather, it delays and slows down pubertal maturation of the gonadotropic axis. The L102P loss of function mutation in GPR54 results in a more quantitative than qualitative defect of gonadotropic axis activation.

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