New insights in the genetics of isolated hypogonadotropic hypogonadism

Isolated gonadotropic deficiency or isolated hypogonadotropic hypogonadism is defined as a low sexual hormone secretion by the gonads associated with low LH and FSH plasma levels. Kallmann syndrome is defined as a congenital isolated gonadotropic deficiency associated with anosmia whereas the phenotype of the idiopathic form is limited to the gonadotropic axis. For several years, it has been known that mutations of the KAL-1 gene or loss-of-function mutations of GnRH receptor did not explain all familial cases of isolated gonadotropic deficiency with or without anosmia. Thus the existence of other genes playing a major role in the physiology of the gonadotropic axis was highly suggested. In 2003, fibroblast growth factor receptor 1 (FGFR1) and GPR54 were shown to be two of these genes. FGFR1 loss-of-function mutations were reported in Kallmann syndrome whereas inactivating mutations of GPR54 were described in the idiopathic form of the gonadotropic deficiency. These genetic studies have opened up a new chapter in the physiology and the pharmacology of the gonadotropic axis.