title: Effects of an antagonist of neurokinin receptors 1, 2 and 3 on reproductive hormones in male beagle dogs.
abstract: BACKGROUND
  SCH 206272, a neurokinin 1, 2, and 3 receptor antagonist, administered to beagle dogs results in testicular toxicity. Therefore, a series of experiments were conducted to determine whether this observed toxicity was associated with changes in reproductive hormones and hypothalamic gonadotrophin releasing hormone (GnRH) levels.
  
  
  METHODS
  Male beagle dogs were administered 30 mg/kg SCH 206272 for up to 7 days. Blood samples were collected at the end of the dosing period for reproductive hormone analysis. Male reproductive organs were stained with hematoxylin and eosin and the hypothalamus was stained for GnRH.
  
  
  RESULTS
  Intact male dogs exhibited SCH 206272-related decreases in pulsatility and magnitude of luteinizing hormone (LH) and testosterone, which were associated with seminiferous tubule degeneration, oligospermia, and epithelial atrophy in the prostate gland. Neutered dogs also exhibited SCH 206272-related decreases in LH and FSH. In a subsequent reversibility study, intact male dogs exhibited decreased LH, testosterone, and FSH, which exhibited recovery by 2 weeks post-dosing; however, seminiferous tubule degeneration and oligospermia did not exhibit recovery by 2 weeks post-dosing. Dogs administered SCH 206272 also exhibited an increase in mean number of GnRH-containing neurons in the hypothalamus and an increase in GnRH mRNA/neuron, which exhibited recovery by 2 weeks post-dosing.
  
  
  CONCLUSIONS
  SCH 206272-dosed dogs exhibited rapid decreases in reproductive hormones and subsequent testicular pathology. Collectively, these changes in hormone levels suggest that the observed SCH 206272-related reproductive tract findings are the result of alterations in hypothalamic-pituitary-gonadal function. However, a direct effect on the testes cannot be definitively ruled out.
authors.affiliation: Merck Research Laboratories, Summit, New Jersey, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Enright
authors.forename: Michael W
authors.initials: MW
authors.lastname: Leach
authors.forename: Georges
authors.initials: G
authors.lastname: Pelletier
authors.forename: Fernand
authors.initials: F
authors.lastname: LaBrie
authors.forename: Barry S
authors.initials: BS
authors.lastname: McIntyre
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Losco
mesh_terms: D000081:Acetamides / Q000633:toxicity*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004285:Dogs; D004958:Estradiol / Q000097:blood; D005640:Follicle Stimulating Hormone / Q000097:blood; D015870:Gene Expression / Q000187:drug effects; D007987:Gonadotropin-Releasing Hormone / Q000097:blood / Q000235:genetics; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007986:Luteinizing Hormone / Q000097:blood*; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D020411:Oligonucleotide Array Sequence Analysis; D009919:Orchiectomy; D010880:Piperidines / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors*; D020127:Recovery of Function; D013737:Testis / Q000187:drug effects* / Q000378:metabolism; D013739:Testosterone / Q000097:blood*
chemical_list: D000081:Acetamides; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D012333:RNA, Messenger; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; C472346:SCH 206272; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D004958:Estradiol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone