title: Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: a novel hypothesis on the mechanism of hot flushes.
abstract: Despite affecting millions of individuals, the etiology of hot flushes remains unknown. Here we review the physiology of hot flushes, CNS pathways regulating heat-dissipation effectors, and effects of estrogen on thermoregulation in animal models. Based on the marked changes in hypothalamic kisspeptin, neurokinin B and dynorphin (KNDy) neurons in postmenopausal women, we hypothesize that KNDy neurons play a role in the mechanism of flushes. In the rat, KNDy neurons project to preoptic thermoregulatory areas that express the neurokinin 3 receptor (NK3R), the primary receptor for NKB. Furthermore, activation of NK₃R in the median preoptic nucleus, part of the heat-defense pathway, reduces body temperature. Finally, ablation of KNDy neurons reduces cutaneous vasodilatation and partially blocks the effects of estrogen on thermoregulation. These data suggest that arcuate KNDy neurons relay estrogen signals to preoptic structures regulating heat-dissipation effectors, supporting the hypothesis that KNDy neurons participate in the generation of flushes.
authors.affiliation: Department of Pathology and the Evelyn F. McKnight Brain Research Institute, University of Arizona College of Medicine, Tucson, AZ 85724, USA. nrance@email.arizona.edu
authors.forename: Naomi E
authors.initials: NE
authors.lastname: Rance
authors.forename: Penny A
authors.initials: PA
authors.lastname: Dacks
authors.forename: Melinda A
authors.initials: MA
authors.lastname: Mittelman-Smith
authors.forename: Andrej A
authors.initials: AA
authors.lastname: Romanovsky
authors.forename: Sally J
authors.initials: SJ
authors.lastname: Krajewski-Hall
mesh_terms: D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects / Q000502:physiology*; D004399:Dynorphins / Q000502:physiology*; D004958:Estradiol / Q000494:pharmacology; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D019584:Hot Flashes / Q000503:physiopathology*; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism*; D059648:Kisspeptins / Q000502:physiology*; D007986:Luteinizing Hormone / Q000378:metabolism; D008954:Models, Biological; D015287:Neurokinin B / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D010052:Ovariectomy; D017698:Postmenopause / Q000502:physiology; D011301:Preoptic Area / Q000378:metabolism; D051381:Rats; D018042:Receptors, Neurokinin-3 / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000098:blood supply; D013623:Tail / Q000098:blood supply; D014664:Vasodilation
chemical_list: D059648:Kisspeptins; D018042:Receptors, Neurokinin-3; D004958:Estradiol; D004399:Dynorphins; D015287:Neurokinin B; D007986:Luteinizing Hormone
keywords: Estrogen; GnRH; LH; Menopause; Reproduction; Thermoregulation