Mutation analysis of the KAL Gene in Female Patients with Gonadotropin-Releasing Hormone Deficiency

Isolated gonadotropin-releasing hormone (GnRH) deficiency, including Kallmann's syndrome (KS) and idiopathic hypogonadotropic hypogonadism (IHH), is a congenital disorder, which is characterized by a functional deficit in hypothalamic GnRH secretion. Despite recent advances in the understanding of the pathogenesis of the X-linked form of KS as the identification of the KAL gene (Xp22.3), the genetic basis of the sporadic form in female patients remains unclear. Although most searches for mutations in X chromosome have been reported in males, the newly recognized phenomenon of inheritance, such as genomic imprinting and uniparental disomy, raises the possibility of a female phenotype in the X- linked genetic defect. Here, the molecular study of the coding region of the KAL gene (exon 5 to 14) in 10 unrelated females with KS (n=6) or IHH (n=4) is reported. None of the subjects had familial histories of delayed puberty or hypogonadism. Samples from 4 healthy, unrelated female volunteers were used for identification of polymorphisms. PCR of the 10 exons of the KAL gene was performed on genomic DNA. The PCR products of the 10 exons were subject to single strand conformation polymorphism (SSCP) analysis to identify possible mutations. In an SSCP analysis of the amplified fragments (fragment size: 147 to 302bp), no mutations or polymorphisms were found in any of the 10 patients and 4 controls. In conclusion, it is unlikely that KAL gene mutations are a clinically significant cause of sporadic GnRH deficiency in female patients, indicating the existence of defects in unidentified genes that result in the expression of the phenotypes in females.

Secondary Amenorrhea Caused by Hydrocephalus Due to Aqueductal Stenosis : Report of Two Cases

Amenorrhea is rarely presented as a manifestation of endocrinological disturbances in patients of chronic hydrocephalus. We describe two cases of secondary amenorrhea caused by hydrocephalus due to aqueductal stenosis. Two female patients of age 30 and 20 yr presented with amenorrhea and increasing headache. Magnetic resonance images revealed marked, noncommunicating hydrocephalus without any tumorous lesion. In one patient, emergent extraventricular drainage was necessary because of progressive neurological deterioration. Each patient underwent surgical intervention for the hydrocephalus-ventriculoperitoneal shunt and endoscopic third ventriculostomy. Both resumed normal menstruation continuing so far with further normal menstrual bleeding. These two cases and others reported in the literature indicated that the surgical intervention for hydrocephalus resolves amenorrhea in all the cases of amenorrhea due to hydrocephalus. The suspected role of the surgery is the correction of increased intracranial pressure, which is an important pathogenetic factor in the development of amenorrhea.