Normal structure of the gonadotropin-releasing hormone (GnRH) gene in patients with GnRH deficiency and idiopathic hypogonadotropic hypogonadism.

Idiopathic hypogonadotropic hypogonadism (IHH) is a genetic disorder in which a lack of hypothalamic GnRH secretion forms the basis for impaired gonadotropin release. Several lines of evidence, including an animal model of GnRH deficiency, suggest that an abnormality at the level of the GnRH gene might be responsible for the secretory defect in patients with IHH. We examined 13 patients (11 males and 2 females) with IHH documented by standard clinical and biochemical criteria, including apulsatile basal LH secretion which was reversed by administration of pulsatile GnRH. The structure of the GnRH gene in these patients was determined using Southern blot analyses. In every case EcoRI digestion revealed a 10-kilobase fragment including the entire GnRH gene, eliminating deletion of the gene as a cause of IHH. Multiple restriction enzymes (Xba I, BglII, BamHI, PstI, TaqI, RsaI, EcoRV, and BglI) and hybridization probes to exons 2 and 4 of the gene were used to search for polymorphisms or relatively small deletions or rearrangements in the GnRH gene. Polymorphisms were not identified, and deletions or rearrangements involving more than 200 basepairs were excluded. We conclude that a major rearrangement of the GnRH gene is not a common basis for IHH in humans.