title: Evidence of GnRH antagonist escape in obese women.
abstract: BACKGROUND
  Assisted reproductive technology (ART) cycle cancelation rates are increased among overweight and obese women; however, the reasons for this are not completely clear. Premature luteinization due to inadequate endogenous gonadotropin suppression is a possibility for this higher risk of cancellation.
  
  
  OBJECTIVE
  The objective of the study was to investigate the impact of female obesity on the pharmacokinetics of cetrorelix (GnRH antagonist).
  
  
  METHODS
  This was an interventional study.
  
  
  METHODS
  The study was conducted at a university clinical and translational research center.
  
  
  METHODS
  Regularly menstruating obese (n = 10) and normal-weight (n = 10) women participated in the study.
  
  
  METHODS
  A frequent blood sampling study was performed after a GnRH antagonist was administered, followed by recombinant LH.
  
  
  METHODS
  Pharmacokinetics of cetrorelix in obese vs normal weight women were measured.
  
  
  RESULTS
  Five of the obese women (50%) and none of the normal-weight women had a rebound of LH (defined as >50% increase in LH level from nadir) over the 14-hour postdose observation period. The obese group had a significantly decreased distributional half-life of cetrorelix compared with the normal-weight group (8.1 ± 1.6 vs 12.7 ± 6.2 hours, P = .02). The obese group exhibited increased clearance of cetrorelix compared with the normal-weight group (25.8 ± 6.8 vs 20.1 ± 8.3 L/h, P = .058).
  
  
  CONCLUSIONS
  The altered pharmacokinetics of cetrorelix in obese women may lead to premature ovulation during ART, and this could be one of the mechanisms that results in increased cycle cancelation in this group of women. In accordance with the higher gonadotropin requirements for obese women undergoing ART, weight-based dosing of GnRH antagonists may be required.
authors.affiliation: Divisions of Reproductive Endocrinology and Infertility (L.W.R., J.L., J.C., A.J.P., N.S.) and Basic Reproductive Sciences (A.P.B.) and Departments of Pharmaceutical Sciences (E.L.B.-P.) and Biostatistics and Informatics (A.A.A.), University of Colorado, Aurora, Colorado 80045.
authors.forename: Lauren W
authors.initials: LW
authors.lastname: Roth
authors.forename: Erica L
authors.initials: EL
authors.lastname: Bradshaw-Pierce
authors.forename: Amanda A
authors.initials: AA
authors.lastname: Allshouse
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lesh
authors.forename: Justin
authors.initials: J
authors.lastname: Chosich
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Bradford
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Polotsky
authors.forename: Nanette
authors.initials: N
authors.lastname: Santoro
mesh_terms: D000328:Adult; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D006727:Hormone Antagonists / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects*; D007986:Luteinizing Hormone / Q000097:blood; D009765:Obesity / Q000097:blood / Q000378:metabolism*; D010062:Ovulation Induction / Q000379:methods
chemical_list: D006727:Hormone Antagonists; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; C062876:cetrorelix