[Hypogonadotropic hypogonadism: new aspects in the regulation of hypothalamic-pituitary-gonadal axis].
Hypogonadotropic hypogonadism (HH) is defined by the absence of sex steroid synthesis associated with the lack of appropriate gonadotrophin secretion. This leads to a variable degree of impuberism, often diagnosed during childhood or adolescence. Genetics of HH involve many genes. However, molecular defects have been identified in only 30 % of patients. Kallmann syndrome (KS) is defined by the association of HH and anosmia. Six genes are involved in KS (KAL1, FGFR1, FGF8, PROK2, PROKR2 and CHD7). However, genetics of KS is complex, because of the variability of the phenotype for a similar molecular defect. Otherwise, heterozygous anomalies are frequently described. Identification in the same patient of several mutations in some of these genes (digenism) could account for this variability. Autosomal recessive transmission is frequently observed in familial cases of HH without anosmia. Molecular alterations have been identified for several neuropeptides or their corresponding receptors, which are involved in the physiology of the gonadotropic axis : GNRHR, KISS1R/GPR54, neurokinin B (TAC3), TACR3 and GNRH1 (and PROK2, PROKR2 and CHD7). Anomalies of leptin or its receptor are also involved in HH cases. A new negative regulating element has been recently identified in humans : RFRP3, which is ortholog of the avian GnIH (gonadotrophin inhibitory hormone). Recent progress about these neuropeptides leads to a new model of comprehension of the gonadotropic axis physiology, from a linear model to a network model, which regulates the central element of regulation of the gonadotropic axis, represented by the GnRH neurons.
Service d'Explorations Fonctionnelles Endocriniennes, Hôpital d'Enfants Armand Trousseau, APHP, 26 avenue du Dr Arnold Netter 75571 Paris cedex 12, France. frederic.brioude@trs.aphp.fr
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D004265:DNA Helicases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D051524:Fibroblast Growth Factor 8 / Q000235:genetics; D005768:Gastrointestinal Hormones / Q000235:genetics; D006066:Gonads / Q000378:metabolism*; D006801:Humans; D007006:Hypogonadism / Q000235:genetics / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism*; D017436:Kallmann Syndrome / Q000235:genetics / Q000378:metabolism; D020738:Leptin / Q000235:genetics; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D009479:Neuropeptides / Q000235:genetics; D000857:Olfaction Disorders / Q000235:genetics; D010902:Pituitary Gland / Q000378:metabolism*; D010905:Pituitary Hormone Release Inhibiting Hormones / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D054411:Receptors, Leptin / Q000235:genetics; D018000:Receptors, Peptide / Q000235:genetics
C076266:ANOS1 protein, human; D004268:DNA-Binding Proteins; D016326:Extracellular Matrix Proteins; C496456:FGF8 protein, human; D005768:Gastrointestinal Hormones; D020738:Leptin; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C423608:PROK2 protein, human; C470838:PROKR2 protein, human; D010905:Pituitary Hormone Release Inhibiting Hormones; D043562:Receptors, G-Protein-Coupled; D054411:Receptors, Leptin; D018000:Receptors, Peptide; D051524:Fibroblast Growth Factor 8; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D004265:DNA Helicases; C491434:CHD7 protein, human