Evidence of GnRH antagonist escape in obese women.

CONTEXT: 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). DESIGN: This was an interventional study. SETTING: The study was conducted at a university clinical and translational research center. PARTICIPANTS: Regularly menstruating obese (n = 10) and normal-weight (n = 10) women participated in the study. INTERVENTIONS: A frequent blood sampling study was performed after a GnRH antagonist was administered, followed by recombinant LH. MAIN OUTCOMES MEASURED: 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.