title: Interactions Between Neurokinin B and Kisspeptin in Mediating Estrogen Feedback in Healthy Women.
abstract: Kisspeptin and neurokinin B (NKB) are obligate for normal gonadotropin secretion, but their hierarchy is unexplored in normal women.
  
  
  
  To investigate the interaction between kisspeptin and NKB on estrogen-regulated LH secretion.
  
  
  
  Women were treated with neurokinin-3 receptor (NK3R) antagonist followed by transdermal estradiol to induce LH secretion 48 hours later, with kisspeptin-10 or vehicle infusion during estrogen administration in a 2-way crossover study.
  
  
  
  Clinical research facility.
  
  
  
  Healthy females with regular menses.
  
  
  
  NK3R antagonist AZD4901 40 mg twice daily orally was taken from cycle day 4-6 for 6 days (n = 10, with 10 no treatment controls). Transdermal estradiol patches (200 μg/d) were applied after 5 days of NK3R antagonist treatment. At 24-hour estradiol treatment, women were randomized to 7-hour kisspeptin-10 (4 μg/kg/h) or vehicle iv infusion, with the alternate infusion in a subsequent cycle.
  
  
  
  Plasma gonadotropin and estradiol secretion.
  
  
  
  After an initial suppression, LH secretion was increased 48 hours after estradiol treatment. Kisspeptin-10 increased LH secretion during the inhibitory phase, and LH remained elevated beyond the discontinuation of kisspeptin-10 infusion. NK3R antagonist decreased LH pulse frequency (0.5 ± 0.2 vs 0.7 ± 0.2 pulses/h, P < .05) and stimulated FSH response to kisspeptin-10 infusion (10.7 ± 11.0 vs 5.0 ± 3.6 IU/L, P < .05) with a nonsignificant rise in LH. The duration of LH response was blunted, with LH being lower at 48 hours (7.5 ± 4.8 vs 15.0 ± 11.4 IU/L, P < .05).
  
  
  
  These data demonstrate that NKB signaling regulates GnRH/LH secretion in normal women, and is predominantly proximal to kisspeptin in mediating estrogenic positive and negative feedback on LH secretion.
authors.affiliation: MRC Centre for Reproductive Health (K.S., J.T.G., R.A.A.), The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom; Endocrine Research Unit (J.D.V.), Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota 55905; and Mammal Research Unit and Centre for Neuroendocrinology (R.P.M.), University of Pretoria, 0028 Pretoria, South Africa and MRC Receptor Biology Unit, Institute for Infectious Diseases and Molecular Medicine, University of Cape Town, 7925 Observatory, South Africa.
authors.forename: Karolina
authors.initials: K
authors.lastname: Skorupskaite
authors.affiliation: MRC Centre for Reproductive Health (K.S., J.T.G., R.A.A.), The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom; Endocrine Research Unit (J.D.V.), Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota 55905; and Mammal Research Unit and Centre for Neuroendocrinology (R.P.M.), University of Pretoria, 0028 Pretoria, South Africa and MRC Receptor Biology Unit, Institute for Infectious Diseases and Molecular Medicine, University of Cape Town, 7925 Observatory, South Africa.
authors.forename: Jyothis T
authors.initials: JT
authors.lastname: George
authors.affiliation: MRC Centre for Reproductive Health (K.S., J.T.G., R.A.A.), The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom; Endocrine Research Unit (J.D.V.), Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota 55905; and Mammal Research Unit and Centre for Neuroendocrinology (R.P.M.), University of Pretoria, 0028 Pretoria, South Africa and MRC Receptor Biology Unit, Institute for Infectious Diseases and Molecular Medicine, University of Cape Town, 7925 Observatory, South Africa.
authors.forename: Johannes D
authors.initials: JD
authors.lastname: Veldhuis
authors.affiliation: MRC Centre for Reproductive Health (K.S., J.T.G., R.A.A.), The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom; Endocrine Research Unit (J.D.V.), Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota 55905; and Mammal Research Unit and Centre for Neuroendocrinology (R.P.M.), University of Pretoria, 0028 Pretoria, South Africa and MRC Receptor Biology Unit, Institute for Infectious Diseases and Molecular Medicine, University of Cape Town, 7925 Observatory, South Africa.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Millar
authors.affiliation: MRC Centre for Reproductive Health (K.S., J.T.G., R.A.A.), The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom; Endocrine Research Unit (J.D.V.), Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota 55905; and Mammal Research Unit and Centre for Neuroendocrinology (R.P.M.), University of Pretoria, 0028 Pretoria, South Africa and MRC Receptor Biology Unit, Institute for Infectious Diseases and Molecular Medicine, University of Cape Town, 7925 Observatory, South Africa.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Anderson
mesh_terms: D000293:Adolescent; D000328:Adult; D018592:Cross-Over Studies; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology*; D004967:Estrogens / Q000008:administration & dosage / Q000494:pharmacology*; D025461:Feedback, Physiological / Q000502:physiology*; D005260:Female; D006801:Humans; D059648:Kisspeptins / Q000008:administration & dosage / Q000494:pharmacology*; D007986:Luteinizing Hormone / Q000378:metabolism*; D008875:Middle Aged; D015287:Neurokinin B / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000502:physiology*; D055815:Young Adult
chemical_list: D004967:Estrogens; C106628:KISS1 protein, human; D059648:Kisspeptins; D018377:Neurotransmitter Agents; D018039:Receptors, Tachykinin; C102505:neurokinin receptor 4; D004958:Estradiol; D015287:Neurokinin B; D007986:Luteinizing Hormone