title: Chronic subcutaneous administration of kisspeptin-54 causes testicular degeneration in adult male rats.
abstract: The kisspeptins are KiSS-1 gene-derived peptides that signal through the G protein-coupled receptor-54 (GPR54) and have recently been shown to be critical regulators of reproduction. Acute intracerebroventricular or peripheral administration of kisspeptin stimulates the hypothalamic-pituitary-gonadal (HPG) axis. This effect is thought to be mediated via the hypothalamic gonadotropin-releasing hormone (GnRH) system. Chronic administration of GnRH agonists paradoxically suppresses the HPG axis after an initial agonistic stimulation. We investigated the effects of continuous peripheral kisspeptin administration in male rats by use of Alzet minipumps. Initially we compared the effects of acute subcutaneous administration of kisspeptin-10, -14, and -54 on the HPG axis. Kisspeptin-54 produced the greatest increase in plasma LH and total testosterone at 60 min postinjection and was used in the subsequent continuous administration experiments. Chronic subcutaneous long-term administration of 50 nmol kisspeptin-54/day for 13 days decreased testicular weight. Histological examination showed degeneration of the seminiferous tubules associated with a significant decrease in the circulating levels of the testes-derived hormone, inhibin B. Plasma free and total testosterone were also lower, although these changes did not reach statistical significance. Further studies examined the effects of shorter periods of continuous kisspeptin administration. Subcutaneous administration of 50 nmol kisspeptin-54 for 1 day increased plasma LH and testosterone. This effect was lost after 2 days of administration, suggesting a downregulation of the HPG axis response to kisspeptin following continuous administration. These findings indicate that kisspeptin may provide a novel tool for the manipulation of the HPG axis and spermatogenesis.
authors.affiliation: Department of Metabolic Medicine, Hammersmith Hospital, Imperial College London, London, United Kingdom.
authors.forename: Emily L
authors.initials: EL
authors.lastname: Thompson
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Murphy
authors.forename: Michael
authors.initials: M
authors.lastname: Patterson
authors.forename: Gavin A
authors.initials: GA
authors.lastname: Bewick
authors.forename: Gordon W H
authors.initials: GW
authors.lastname: Stamp
authors.forename: Annette E
authors.initials: AE
authors.lastname: Curtis
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Cooke
authors.forename: Preeti H
authors.initials: PH
authors.lastname: Jethwa
authors.forename: Jeannie F
authors.initials: JF
authors.lastname: Todd
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Ghatei
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Bloom
mesh_terms: D000367:Age Factors; D000818:Animals; D004704:Endocrinology / Q000379:methods*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D015918:Infusion Pumps, Implantable; D007279:Injections, Subcutaneous; D059648:Kisspeptins; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D010902:Pituitary Gland / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013737:Testis / Q000187:drug effects* / Q000473:pathology*; D013739:Testosterone / Q000097:blood; D025521:Tumor Suppressor Proteins / Q000494:pharmacology*
chemical_list: C106628:KISS1 protein, human; D059648:Kisspeptins; D009842:Oligopeptides; D025521:Tumor Suppressor Proteins; D013739:Testosterone; D007986:Luteinizing Hormone