title: Neurokinin B Receptor Antagonism in Women With Polycystic Ovary Syndrome: A Randomized, Placebo-Controlled Trial.
abstract: Polycystic ovary syndrome (PCOS), the most common endocrinopathy in women, is characterized by high secretion levels of LH and T. Currently, there is no treatment licensed specifically for PCOS.
  
  
  
  The objective of this study was to investigate whether a targeted therapy would decrease LH pulse frequency in women with PCOS, subsequently reducing serum LH and T concentrations and thereby presenting a novel therapeutic approach to the management of PCOS.
  
  
  
  This study is a double-blind, double-dummy, placebo-controlled, phase 2 trial.
  
  
  
  University hospitals and private clinical research centers were included.
  
  
  
  Women with PCOS aged 18-45 years participated.
  
  
  
  Intervention included AZD4901 (a specific neurokinin-3 [NK3] receptor antagonist) at a dose of 20, 40, or 80 mg/day or matching placebo for 28 days.
  
  
  
  Change from baseline in the area under the LH serum concentration-time curve over 8 hours (area under the curve) on day 7 relative to placebo was measured.
  
  
  
  Of a total 67 randomized patients, 65 were evaluable. On day 7, the following baseline-adjusted changes relative to placebo were observed in patients receiving AZD4901 80 mg/day: 1) a reduction of 52.0% (95% confidence interval [CI], 29.6-67.3%) in LH area under the curve; 2) a reduction of 28.7% (95% CI, 13.9-40.9%) in total T concentration; and 3) a reduction of 3.55 LH pulses/8 hours (95% CI, 2.0-5.1) (all nominal P < .05).
  
  
  
  The NK3 receptor antagonist AZD4901 specifically reduced LH pulse frequency and subsequently serum LH and T concentrations, thus presenting NK3 receptor antagonism as a potential approach to treating the central neuroendocrine pathophysiology of PCOS.
authors.affiliation: Diabetes Trials Unit (J.T.G.), Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford, United Kingdom; AstraZeneca, Waltham, Massachusetts (R.K., M.L.S.) Mereside, Alderley Park, Macclesfield, Cheshire, United Kingdom (J.M., S.M., L.W.), Wilmington, Delaware (R.D.F.); and Gaithersburg Maryland (T.W.H.); Endocrine Research Unit (J.V.), Mayo Clinic College of Medicine, Center for Translational Science Activities, Rochester, Minnesota; MRC Centre for Reproductive Health (K.S., R.A.A.), The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Jyothis T
authors.initials: JT
authors.lastname: George
authors.affiliation: Diabetes Trials Unit (J.T.G.), Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford, United Kingdom; AstraZeneca, Waltham, Massachusetts (R.K., M.L.S.) Mereside, Alderley Park, Macclesfield, Cheshire, United Kingdom (J.M., S.M., L.W.), Wilmington, Delaware (R.D.F.); and Gaithersburg Maryland (T.W.H.); Endocrine Research Unit (J.V.), Mayo Clinic College of Medicine, Center for Translational Science Activities, Rochester, Minnesota; MRC Centre for Reproductive Health (K.S., R.A.A.), The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Rahul
authors.initials: R
authors.lastname: Kakkar
authors.affiliation: Diabetes Trials Unit (J.T.G.), Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford, United Kingdom; AstraZeneca, Waltham, Massachusetts (R.K., M.L.S.) Mereside, Alderley Park, Macclesfield, Cheshire, United Kingdom (J.M., S.M., L.W.), Wilmington, Delaware (R.D.F.); and Gaithersburg Maryland (T.W.H.); Endocrine Research Unit (J.V.), Mayo Clinic College of Medicine, Center for Translational Science Activities, Rochester, Minnesota; MRC Centre for Reproductive Health (K.S., R.A.A.), The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Jayne
authors.initials: J
authors.lastname: Marshall
authors.affiliation: Diabetes Trials Unit (J.T.G.), Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford, United Kingdom; AstraZeneca, Waltham, Massachusetts (R.K., M.L.S.) Mereside, Alderley Park, Macclesfield, Cheshire, United Kingdom (J.M., S.M., L.W.), Wilmington, Delaware (R.D.F.); and Gaithersburg Maryland (T.W.H.); Endocrine Research Unit (J.V.), Mayo Clinic College of Medicine, Center for Translational Science Activities, Rochester, Minnesota; MRC Centre for Reproductive Health (K.S., R.A.A.), The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Scott
authors.affiliation: Diabetes Trials Unit (J.T.G.), Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford, United Kingdom; AstraZeneca, Waltham, Massachusetts (R.K., M.L.S.) Mereside, Alderley Park, Macclesfield, Cheshire, United Kingdom (J.M., S.M., L.W.), Wilmington, Delaware (R.D.F.); and Gaithersburg Maryland (T.W.H.); Endocrine Research Unit (J.V.), Mayo Clinic College of Medicine, Center for Translational Science Activities, Rochester, Minnesota; MRC Centre for Reproductive Health (K.S., R.A.A.), The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Finkelman
authors.affiliation: Diabetes Trials Unit (J.T.G.), Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford, United Kingdom; AstraZeneca, Waltham, Massachusetts (R.K., M.L.S.) Mereside, Alderley Park, Macclesfield, Cheshire, United Kingdom (J.M., S.M., L.W.), Wilmington, Delaware (R.D.F.); and Gaithersburg Maryland (T.W.H.); Endocrine Research Unit (J.V.), Mayo Clinic College of Medicine, Center for Translational Science Activities, Rochester, Minnesota; MRC Centre for Reproductive Health (K.S., R.A.A.), The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Tony W
authors.initials: TW
authors.lastname: Ho
authors.affiliation: Diabetes Trials Unit (J.T.G.), Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford, United Kingdom; AstraZeneca, Waltham, Massachusetts (R.K., M.L.S.) Mereside, Alderley Park, Macclesfield, Cheshire, United Kingdom (J.M., S.M., L.W.), Wilmington, Delaware (R.D.F.); and Gaithersburg Maryland (T.W.H.); Endocrine Research Unit (J.V.), Mayo Clinic College of Medicine, Center for Translational Science Activities, Rochester, Minnesota; MRC Centre for Reproductive Health (K.S., R.A.A.), The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Johannes
authors.initials: J
authors.lastname: Veldhuis
authors.affiliation: Diabetes Trials Unit (J.T.G.), Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford, United Kingdom; AstraZeneca, Waltham, Massachusetts (R.K., M.L.S.) Mereside, Alderley Park, Macclesfield, Cheshire, United Kingdom (J.M., S.M., L.W.), Wilmington, Delaware (R.D.F.); and Gaithersburg Maryland (T.W.H.); Endocrine Research Unit (J.V.), Mayo Clinic College of Medicine, Center for Translational Science Activities, Rochester, Minnesota; MRC Centre for Reproductive Health (K.S., R.A.A.), The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Karolina
authors.initials: K
authors.lastname: Skorupskaite
authors.affiliation: Diabetes Trials Unit (J.T.G.), Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford, United Kingdom; AstraZeneca, Waltham, Massachusetts (R.K., M.L.S.) Mereside, Alderley Park, Macclesfield, Cheshire, United Kingdom (J.M., S.M., L.W.), Wilmington, Delaware (R.D.F.); and Gaithersburg Maryland (T.W.H.); Endocrine Research Unit (J.V.), Mayo Clinic College of Medicine, Center for Translational Science Activities, Rochester, Minnesota; MRC Centre for Reproductive Health (K.S., R.A.A.), The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Anderson
authors.affiliation: Diabetes Trials Unit (J.T.G.), Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford, United Kingdom; AstraZeneca, Waltham, Massachusetts (R.K., M.L.S.) Mereside, Alderley Park, Macclesfield, Cheshire, United Kingdom (J.M., S.M., L.W.), Wilmington, Delaware (R.D.F.); and Gaithersburg Maryland (T.W.H.); Endocrine Research Unit (J.V.), Mayo Clinic College of Medicine, Center for Translational Science Activities, Rochester, Minnesota; MRC Centre for Reproductive Health (K.S., R.A.A.), The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Stuart
authors.initials: S
authors.lastname: McIntosh
authors.affiliation: Diabetes Trials Unit (J.T.G.), Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford, United Kingdom; AstraZeneca, Waltham, Massachusetts (R.K., M.L.S.) Mereside, Alderley Park, Macclesfield, Cheshire, United Kingdom (J.M., S.M., L.W.), Wilmington, Delaware (R.D.F.); and Gaithersburg Maryland (T.W.H.); Endocrine Research Unit (J.V.), Mayo Clinic College of Medicine, Center for Translational Science Activities, Rochester, Minnesota; MRC Centre for Reproductive Health (K.S., R.A.A.), The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Webber
mesh_terms: D000293:Adolescent; D000328:Adult; D000634:Aminoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood* / Q000187:drug effects; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D011085:Polycystic Ovary Syndrome / Q000188:drug therapy*; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D013739:Testosterone / Q000097:blood*; D055815:Young Adult
chemical_list: C555357:3-((methylsulfonyl)amino)-2-phenyl-N-(1-phenylpropyl)quinolin-4-carboxamide; D000634:Aminoquinolines; D018042:Receptors, Neurokinin-3; D013449:Sulfonamides; D013739:Testosterone; D007986:Luteinizing Hormone