title: Kisspeptin restores pulsatile LH secretion in patients with neurokinin B signaling deficiencies: physiological, pathophysiological and therapeutic implications.
abstract: Pulsatile gonadotropin-releasing hormone (GnRH) is crucial to normal reproductive function and abnormalities in pulse frequency give rise to reproductive dysfunction. Kisspeptin and neurokinin B (NKB), neuropeptides secreted by the same neuronal population in the ventral hypothalamus, have emerged recently as critical central regulators of GnRH and thus gonadotropin secretion. Patients with mutations resulting in loss of signaling by either of these neuroendocrine peptides fail to advance through puberty but the mechanisms mediating this remain unresolved. We report here that continuous kisspeptin infusion restores gonadotropin pulsatility in patients with loss-of-function mutations in NKB (TAC3) or its receptor (TAC3R), indicating that kisspeptin on its own is sufficient to stimulate pulsatile GnRH secretion. Moreover, our findings suggest that NKB action is proximal to kisspeptin in the reproductive neuroendocrine cascade regulating GnRH secretion, and may act as an autocrine modulator of kisspeptin secretion. The ability of continuous kisspeptin infusion to induce pulsatile gonadotropin secretion further indicates that GnRH neurons are able to set up pulsatile secretion in the absence of pulsatile exogenous kisspeptin.
authors.affiliation: Faculté de Médecine Paris-Sud UMR-S693, Université Paris-Sud, Le Kremlin-Bicêtre, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Young
authors.forename: Jyothis T
authors.initials: JT
authors.lastname: George
authors.forename: Javier A
authors.initials: JA
authors.lastname: Tello
authors.forename: Bruno
authors.initials: B
authors.lastname: Francou
authors.forename: Jerome
authors.initials: J
authors.lastname: Bouligand
authors.forename: Anne
authors.initials: A
authors.lastname: Guiochon-Mantel
authors.forename: Sylvie
authors.initials: S
authors.lastname: Brailly-Tabard
authors.forename: Richard A
authors.initials: RA
authors.lastname: Anderson
authors.forename: Robert P
authors.initials: RP
authors.lastname: Millar
mesh_terms: D000328:Adult; D012734:Disorders of Sex Development / Q000097:blood / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy; D004958:Estradiol / Q000097:blood; D005260:Female; D006801:Humans; D007265:Inhibins / Q000097:blood; D059648:Kisspeptins / Q000008:administration & dosage*; D007986:Luteinizing Hormone / Q000097:blood / Q000378:metabolism*; D008297:Male; D009154:Mutation / Q000502:physiology; D015287:Neurokinin B / Q000172:deficiency* / Q000235:genetics; D011673:Pulsatile Flow / Q000187:drug effects; D018042:Receptors, Neurokinin-3 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013739:Testosterone / Q000097:blood
chemical_list: D059648:Kisspeptins; D018042:Receptors, Neurokinin-3; C422364:inhibin B; D013739:Testosterone; D004958:Estradiol; D007265:Inhibins; D015287:Neurokinin B; D007986:Luteinizing Hormone