Normosmic idiopathic hypogonadotropic hypogonadism: update on the genetic background and future challenges.

PURPOSE OF REVIEW: What controls puberty remains largely unknown, and current gene mutations account for only about one-third of the apparently genetic cases of idiopathic hypogonadotropic hypogonadism. Lately, important developments have occurred in this field. RECENT FINDINGS: The neuroendocrine control of reproduction in all mammals is governed by a hypothalamic neural network of approximately 1500 gonadotropin-releasing hormone (GnRH) secreting neurons that control the activity of the reproductive axis across life. Recently, the syndrome of human GnRH deficiency, either with anosmia, termed Kallmann syndrome, or with a normal sense of smell, termed normosmic idiopathic hypogonadotropic hypogonadism, has proven to be important disease models that have revealed much about the abnormalities that can befall the GnRH neurons as they differentiate, migrate, form networks, mature and senesce. Mutations in several genes responsible for these highly coordinated developmental processes have thus been unearthed by the study of this prismatic disease model. These genetic studies have opened up a new chapter in the physiology and the pharmacology of the gonadotropic axis.

Molecular defects of the GnRH-receptor gene in Chinese patients with idiopathic hypogonadotropic hypogonadism and the severity of hypogonadism.

BACKGROUND: Human mutations in the gonadotropin-releasing hormone receptor (GnRHR) gene cause normosmic idiopathic hypogonadotropic hypogonadism (IHH). At least 19 different mutations have been identified in this G-protein-coupled receptor, which consist mostly of missense mutations. OBJECTIVES: To identify and determine the frequency of mutations in the coding region of the gonadotropin-releasing hormone receptor (GnRHR) gene in forty Chinese patients with normosmic idiopathic hypogonadotropic hypogonadism (IHH) and establish genotype/phenotype correlations where possible. METHODS: The diagnosis of HH was based on absent or incomplete sexual development after 17 years of age in girls and 18 years in boys associated with low or normal levels of LH in both sexes and low levels of testosterone in males and of estradiol in females. All patients presented with a normal sense of smell in an olfactory specific test. Forty IHH patients and 40 controls were screened for mutations in the coding sequence of the GnRHR gene. The coding region of the GnRHR gene was amplified by PCR and directly sequenced. RESULTS: A missense mutation, serine 168 arginine (S168R), located in the fourth transmembrane domain of the GnRHR gene, was identified as being in a homozygous state in one male with complete HH. The S168R mutation has been previously shown to be a cause in the complete loss of receptor function because hormone binding to the receptor is completely impaired. In another patient, a compound heterozygous mutation (Gln106Arg and Arg262Gln) was identified in a male with partial HH. The Gln106Arg mutation is located in the first extracellular loop of GnRH-R, this mutation decreases but not does eliminate GnRH binding; while Arg262Gln mutation is located in the third extracellular loop of GnRH-R and only decreases signal transduction. A good correlation between genotype and phenotype was found in our patients. The patient, who was homozygous for the completely inactivating S168R mutation, had complete HH. In addition, the affected patient who was compound heterozygous for the Glnl06Arg--Arg262Gln mutations - has partial HH. CONCLUSIONS: GnRHR mutations can be classified into partial or complete loss of function mutations. Partially inactivating substitutions of the GnRHR frequently found in familial hypogonadotrophic hypogonadism are Q106R and R262Q. Comparison of compound heterozygous with homozygous patients suggests that their phenotype and the response to GnRH is determined by the GnRHR variant with the less severe loss of function.