title: Neurokinin 3 Receptor Antagonism Reveals Roles for Neurokinin B in the Regulation of Gonadotropin Secretion and Hot Flashes in Postmenopausal Women.
abstract: Neurokinin B (NKB) and kisspeptin are obligate for normal gonadotropin secretion, and links between gonadotropin-releasing hormone (GnRH) pulsatility and vasomotor symptoms have been proposed. Using a selective NKB receptor (NK3R) antagonist, the role of NKB in the hypergonadotropic state in menopausal women was explored.
  
  
  
  Eleven postmenopausal women were administered the NK3R antagonist MLE4901 at 40 mg twice daily orally for 7 days. Ten-minute blood sampling for 8 h was performed before and on the last day of NK3R antagonist treatment for luteinising hormone (LH) pulsatility analysis with kisspeptin-10 (0.3 µg/kg i.v. bolus) administered at 6 h on both days. Hot flash frequency and severity were self-reported for 7 days before and during NK3R antagonist administration.
  
  
  
  LH fell from 29.3 ± 4.1 to 24.4 ± 3.8 IU/L (p < 0.05) after 7 days of NK3R antagonist treatment, with no change in follicle-stimulating hormone (FSH). Basal (non-pulsatile) LH secretion was reduced (549.0 ± 70.8 vs. 366.1 ± 92.1 IU/L/6 h, p = 0.006), and while the LH pulse frequency did not change in the group as a whole (from 0.8 ± 0.1 to 0.7 ± 0.1 pulses/h, ns), it did fall in the 8 women with hot flashes (from 1.0 ± 0.1 to 0.7 ± 0.1 pulses/h, p < 0.05). These women also reported a reduction in hot flash frequency (from 3.4 ± 1.2 to 1.0 ± 0.6 hot flashes/day, p = 0.008) whilst taking the NK3R antagonist. Kisspeptin-10 did not affect LH secretion with or without the NK3R antagonist.
  
  
  
  The administration of an NK3R antagonist indicates a role for NKB in the regulation of LH/GnRH in postmenopausal women, whereas the lack of response to kisspeptin may reflect the hypo-oestrogenic state. These data support a link of LH/GnRH pulsatility and vasomotor symptoms with NK3R antagonism as a potential therapeutic approach.
authors.forename: Karolina
authors.initials: K
authors.lastname: Skorupskaite
authors.forename: Jyothis T
authors.initials: JT
authors.lastname: George
authors.forename: Johannes D
authors.initials: JD
authors.lastname: Veldhuis
authors.forename: Robert P
authors.initials: RP
authors.lastname: Millar
authors.forename: Richard A
authors.initials: RA
authors.lastname: Anderson
mesh_terms: D000284:Administration, Oral; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D006062:Gonadotropins / Q000378:metabolism*; D019584:Hot Flashes / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D059648:Kisspeptins / Q000378:metabolism / Q000627:therapeutic use; D007986:Luteinizing Hormone / Q000097:blood; D008875:Middle Aged; D015287:Neurokinin B / Q000378:metabolism*; D010507:Periodicity; D017698:Postmenopause / Q000187:drug effects* / Q000378:metabolism; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D006062:Gonadotropins; C106628:KISS1 protein, human; D059648:Kisspeptins; D018042:Receptors, Neurokinin-3; D007987:Gonadotropin-Releasing Hormone; D015287:Neurokinin B; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone
keywords: Gonadotropin-releasing hormone; Hot flashes; Kisspeptin; Luteinising hormone pulsatility; Menopause; Neurokinin B