title: Kisspeptin-54 at high doses acutely induces testicular degeneration in adult male rats via central mechanisms.
abstract: OBJECTIVE
  The kisspeptins are critical regulators of reproduction and a therapeutic target for reproductive disease. Intracerebroventricular (i.c.v.) or peripheral injection of kisspeptin potently stimulates the hypothalamic-pituitary gonadal (HPG) axis via gonadotrophin-releasing hormone (GnRH). However, little is known regarding the effects of kisspeptin administration on testicular function. We investigated the mechanism(s) of kisspeptin-induced testicular degeneration in the rat.
  
  
  METHODS
  Kisspeptin-54 (50 nmol.day(-1)) was continuously administered subcutaneously (6 h to 3 days) to male Wistar rats and reproductive hormones and testicular histology analysed. We also investigated the effects of a single subcutaneous injection of 0.5, 5 or 50 nmol kisspeptin-54. In order to determine whether the testicular degeneration observed is peripherally or centrally mediated, we investigated effects of i.c.v. injections of 5 nmol kisspeptin-54 and pre-administered a GnRH-receptor antagonist (cetrorelix) to rats peripherally treated with kisspeptin-54.
  
  
  RESULTS
  Continuous subcutaneous administration of kisspeptin-54 caused testicular degeneration after only 12 h, when gonadotrophins were still markedly raised, suggesting that the degeneration is independent of the desensitization of the HPG axis to kisspeptin-54. Furthermore, a single subcutaneous injection of kisspeptin-54 caused dose-dependent testicular degeneration. Continuous kisspeptin-54 administration is thus not required to cause testicular degeneration. Pretreatment with cetrorelix blocked kisspeptin-induced testicular degeneration, and a single i.c.v. injection of kisspeptin-54 caused testicular degeneration, suggesting it is GnRH-mediated.
  
  
  CONCLUSIONS
  Kisspeptin-induced testicular degeneration appears to be centrally mediated, and result from acute hyper-stimulation of the HPG axis. Doses must be carefully considered if kisspeptin is to be used therapeutically.
authors.affiliation: Department of Investigative Medicine, Hammersmith Hospital, Imperial College London, London, UK.
authors.forename: E L
authors.initials: EL
authors.lastname: Thompson
authors.forename: V
authors.initials: V
authors.lastname: Amber
authors.forename: G W H
authors.initials: GW
authors.lastname: Stamp
authors.forename: M
authors.initials: M
authors.lastname: Patterson
authors.forename: A E
authors.initials: AE
authors.lastname: Curtis
authors.forename: J H
authors.initials: JH
authors.lastname: Cooke
authors.forename: G F
authors.initials: GF
authors.lastname: Appleby
authors.forename: W S
authors.initials: WS
authors.lastname: Dhillo
authors.forename: M A
authors.initials: MA
authors.lastname: Ghatei
authors.forename: S R
authors.initials: SR
authors.lastname: Bloom
authors.forename: K G
authors.initials: KG
authors.lastname: Murphy
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D007265:Inhibins / Q000097:blood; D007276:Injections, Intraventricular; D007279:Injections, Subcutaneous; D008297:Male; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000008:administration & dosage / Q000502:physiology*; D000074502:Receptors, Kisspeptin-1; D013737:Testis / Q000187:drug effects* / Q000473:pathology; D013997:Time Factors
chemical_list: C492247:Kiss1r protein, rat; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; C422364:inhibin B; D007265:Inhibins