title: Human GnRH deficiency: a unique disease model to unravel the ontogeny of GnRH neurons.
abstract: Evolutionary survival of a species is largely a function of its reproductive fitness. In mammals, a sparsely populated and widely dispersed network of hypothalamic neurons, the gonadotropin-releasing hormone (GnRH) neurons, serve as the pilot light of reproduction via coordinated secretion of GnRH. Since it first description, human GnRH deficiency has been recognized both clinically and genetically as a heterogeneous disease. A spectrum of different reproductive phenotypes comprised of congenital GnRH deficiency with anosmia (Kallmann syndrome), congenital GnRH deficiency with normal olfaction (normosmic idiopathic hypogonadotropic hypogonadism), and adult-onset hypogonadotropic hypogonadism has been described. In the last two decades, several genes and pathways which govern GnRH ontogeny have been discovered by studying humans with GnRH deficiency. More importantly, detailed study of these patients has highlighted the emerging theme of oligogenicity and genotypic synergism, and also expanded the phenotypic diversity with the documentation of reversal of GnRH deficiency later in adulthood in some patients. The underlying genetic defect has also helped understand the associated nonreproductive phenotypes seen in some of these patients. These insights now provide practicing clinicians with targeted genetic diagnostic strategies and also impact on clinical management.
authors.affiliation: Harvard Reproductive Endocrine Sciences Center of Excellence, Reproductive Endocrine Unit of the Department of Medicine of the Massachusetts General Hospital and Endocrine Division of the Brigham and Women's Hospital, Boston, MA 02114, USA.
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Balasubramanian
authors.forename: Andrew
authors.initials: A
authors.lastname: Dwyer
authors.forename: Stephanie B
authors.initials: SB
authors.lastname: Seminara
authors.forename: Nelly
authors.initials: N
authors.lastname: Pitteloud
authors.forename: Ursula B
authors.initials: UB
authors.lastname: Kaiser
authors.forename: William F
authors.initials: WF
authors.lastname: Crowley
mesh_terms: D000818:Animals; D016326:Extracellular Matrix Proteins / Q000172:deficiency / Q000235:genetics; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D005768:Gastrointestinal Hormones / Q000235:genetics / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000172:deficiency* / Q000235:genetics*; D006801:Humans; D007006:Hypogonadism / Q000235:genetics; D007031:Hypothalamus / Q000254:growth & development*; D017436:Kallmann Syndrome / Q000235:genetics*; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D000857:Olfaction Disorders / Q000235:genetics; D010641:Phenotype; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000074502:Receptors, Kisspeptin-1; D011966:Receptors, LHRH / Q000235:genetics / Q000378:metabolism; D018042:Receptors, Neurokinin-3 / Q000235:genetics / Q000378:metabolism; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C076266:ANOS1 protein, human; D016326:Extracellular Matrix Proteins; D005768:Gastrointestinal Hormones; C118688:KISS1R protein, human; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C423608:PROK2 protein, human; C470838:PROKR2 protein, human; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D011966:Receptors, LHRH; D018042:Receptors, Neurokinin-3; D018000:Receptors, Peptide; D014157:Transcription Factors; C118437:negative elongation factor; D007987:Gonadotropin-Releasing Hormone; D005346:Fibroblast Growth Factors