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Abstract

Volume 14, Issue 1 (January 2012) 14, 49–56; 10.1038/aja.2011.68

New understandings of the genetic basis of isolated idiopathic central hypogonadism

Marco Bonomi1,2, Domenico Vladimiro Libri2,3, Fabiana Guizzardi2, Elena Guarducci4, Elisabetta Maiolo5, Elisa Pignatti6, Roberta Asci7, Luca Persani1,2,3 and on behalf of the Idiopathic Central Hypogonadism Study Group of the Italian Societies of Endocrinology and Pediatric Endocrinology and Diabetes*

1 Division of Endocrinology and Metabolism, Istituto Auxologico Italiano IRCCS, 20149 Milan, Italy
2 Lab of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, 20149 Milan, Italy
3 Department of Medical Sciences, University of Milan, 20122 Milan, Italy
4 Department of Clinical Pathophysiology, Unit of Andrology, University of Florence, 50134 Florence, Italy
5 Lab of Human and Medical Genetics, Ospedale Galliera, 16128 Genova, Italy
6 Department of Medicine, Endocrinology, Metabolism and Geriatrics, University of Modena and Reggio Emilia, 41126 Modena, Italy
7 CEINGE, University Federico II Naples and Dept. of Clinical and Experimental Medicine, Second University of Naples, 80131 Naples, Italy

* The Idiopathic Central Hypogonadism Study Group of the Italian Societies of Endocrinology and Paediatric Endocrinology and Diabetes: Gianluca Aimaretti (Novara), Monica Altobelli (Bergamo), Giorgio Arnaldi (Ancona), Maurizia Baldi (Genoa), Luigi Bartalena (Varese), Luciano Beccaria (Lecco), Paolo Beck-Peccoz (Milan), Giuseppe Bellastella (Naples), Giorgio Borretta (Cuneo), Fabio Buzi (Brescia), Salvo Cannavò (Messina), Marco Cappa (Rome), Anna Cariboni (Milan), Tommaso Ciampani (Varese), Alessandro Cicognani (Bologna), Mariangela Cisternino (Pavia), Sabrina Corbetta (Milan), Nicola Corciulo (Lecce), Renato Cozzi (Milan), Angela Valentina D'Elia (Udine), Ettore Degli Uberti (Ferrara), Mario De Marchi (Turin), Gianni Forti (Florence), Natascia di Iorgi (Genoa), Andrea Fabbri (Rome), Alberto Ferlin (Padua), Rossella Gaudino (Verona), Enrico Grosso (Turin), Csilla Krausz (Florence), Fabio Lanfranco (Turin), Daniela Larizza (Pavia), Paolo Limone (Turin), Mario Maggi (Florence), Roberto Maggi (Milan), Mohammad Maghnie (Genoa), Antonio Mancini (Rome), Giorgia Mandrile (Turin), Marco Marino (Modena), Maria Antonietta Mencarelli (Siena), Nicola Migone (Turin), Giovanni Neri (Rome), Lucia Perroni (Genova), Elisa Pignatti (Modena), Alba Pilotta (Brescia), Angela Ida Pincelli (Monza), Alessandro Pizzocaro (Milan), Alfredo Pontecorvi (Rome), Giorgio Radetti (Bolzano), Paola Razzore (Turin), Gianni Russo (Milan), Filippo Salvini (Milan), Andrea Secco (Genoa), Maria Segni (Rome), Manuela Simoni (Modena), Agostino Sinisi (Naples), Riccardo Vigneri (Catania), and Giovanna Weber (Milan).

Correspondence: Dr L Persani, (luca.persani@unimi.it)

Received 1 July 2011; Revised 6 September 2011; Accepted 6 September 2011; Published online 5 December 2011

Abstract

Idiopathic hypogonadotropic hypogonadism is a rare disease that is characterized by delayed/absent puberty and/or infertility due to an insufficient stimulation of an otherwise normal pituitary-gonadal axis by gonadotrophin-releasing hormone (GnRH) action. Because reduced or normal luteinizing hormone (LH)/follicle-stimulating hormone (FSH) levels may be observed in the affected patients, the term idiopathic central hypogonadism (ICH) appears to be more appropriate. This disease should be distinguished from central hypogonadism that is combined with other pituitary deficiencies. Isolated ICH has a complex pathogenesis and is fivefold more prevalent in males. ICH frequently appears in a sporadic form, but several familial cases have also been reported. This finding, in conjunction with the description of numerous pathogenetic gene variants and the generation of several knockout models, supports the existence of a strong genetic component. ICH may be associated with several morphogenetic abnormalities, which include osmic defects that, with ICH, constitute the cardinal manifestations of Kallmann syndrome (KS). KS accounts for approximately 40% of the total ICH cases and has been generally considered to be a distinct subgroup. However, the description of several pedigrees, which include relatives who are affected either with isolated osmic defects, KS, or normo-osmic ICH (nICH), justifies the emerging idea that ICH is a complex genetic disease that is characterized by variable expressivity and penetrance. In this context, either multiple gene variants or environmental factors and epigenetic modifications may contribute to the variable disease manifestations. We review the genetic mechanisms that are presently known to be involved in ICH pathogenesis and provide a clinical overview of the 227 cases that have been collected by the collaborating centres of the Italian ICH Network.

Keywords: central hypogonadism; congenital hypogonadism; GnRH; hypogonadotropic hypogonadism; hypothalamus–pituitary–gonadal axis; Kallmann syndrome; male infertility

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