title: First evidence of ovulation induced by oral LH agonists in healthy female volunteers of reproductive age.
abstract: BACKGROUND
  Two new low-molecular-weight LH agonists (Org 43553 and Org 43902) were shown to induce ovulation in preclinical experiments.
  
  
  OBJECTIVE
  Our objective was to assess the safety, pharmacokinetics, and pharmacodynamics of Org 43553 and Org 43902 when administered to healthy females.
  
  
  METHODS
  Org 43553 and 43902 studies were randomized, placebo-controlled, single-rising-dose first-in-human trials, which included 159 healthy female volunteers. Part 1 of the studies assessed the safety and pharmacokinetics. Part 2 evaluated the pharmacodynamics effect of a single oral dose of Org 43553 (25-900 mg) or Org 43902 (30-300 mg) to induce ovulation after the development of a large preovulatory follicle, whereas the endogenous LH surge was suppressed due to GnRH antagonist treatment while follicular development was supported with recombinant FSH.
  
  
  RESULTS
  Org 43553 and 43902 were safe and well tolerated. Both compounds showed a fast absorption after oral intake, with peak concentrations reached within 0.5 to 1 hour. The elimination half-life of Org 43553 was 30 to 47 hours and that of Org 43902 was 17 to 22 hours. Ovulation induction confirmed by midluteal progesterone rise ≥15 nmol/L was proven in both studies, also when excluding subjects with an endogenous LH rise. The minimal effective dose for ovulation induction was 300 mg in both studies and resulted in an ovulation rate of 83% and 82%, respectively.
  
  
  CONCLUSIONS
  These first proof-of-concept studies both demonstrated that a single oral intake of an low-molecular-weight LH agonist induces ovulation of the preovulatory follicle in pituitary-suppressed female volunteers of reproductive age.
authors.affiliation: MSD, Molenstraat 11, 5342 CC, Oss, The Netherlands. mireille.gerrits@merck.com
authors.forename: Mireille
authors.initials: M
authors.lastname: Gerrits
authors.forename: Bernadette
authors.initials: B
authors.lastname: Mannaerts
authors.forename: Hester
authors.initials: H
authors.lastname: Kramer
authors.forename: Samira
authors.initials: S
authors.lastname: Addo
authors.forename: Rob
authors.initials: R
authors.lastname: Hanssen
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D005260:Female; D006262:Health; D006805:Human Experimentation; D006801:Humans; D007986:Luteinizing Hormone / Q000819:agonists* / Q000031:analogs & derivatives; D008875:Middle Aged; D010062:Ovulation Induction / Q000379:methods*; D010865:Pilot Projects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D012098:Reproduction / Q000187:drug effects / Q000502:physiology; D013876:Thiophenes / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: C526583:5-amino-2-methylsulfanyl-4-(3-(2-morpholin-4-ylacetylamino)phenyl)thieno(2,3-d)pyrimidine-6-carboxylic acid tert-butylamide; D011743:Pyrimidines; D013876:Thiophenes; D007986:Luteinizing Hormone