IN-VIVO EFFECTS OF A POTENT GNRH ANTAGONIST ORG-30850 - PHYSIOLOGICALEVIDENCE THAT DOWN-REGULATION OF GNRH RECEPTORS DOES NOT OCCUR

Objective: Our purpose was to determine the pituitary responsiveness t o exogenous GnRH in GnRH antagonist-suppressed overiectomized monkeys. Methods: This was a prospective experimental non-human primate study performed at the research laboratories of The Jones Institute for Repr oductive Medicine. Seventeen long-term ovariectomized cynomologus monk eys were studied. Interventions: The GnRH antagonist ORG 30850 was adm inistered to long-term ovariectomized monkeys assigned to one of six g roups: single subcutaneous injections in group A (n = 4), 0.3 mg/kg; g roup B (n = 4), 1.0 mg/kg; and group C (n = 3), 3.0 mg/kg; and six con secutive daily subcutaneous injections in group D (n = 2), 0.3 mg/kg; group E (n = 2), 1.0 mg/kg; and group F (n = 2), 3.0 mg/kg. Blood samp les were collected daily from 10 days before treatment until 22 days a fter treatment, then weekly for 6 additional weeks. Intravenous GnRH s timulation tests (10 mug/kg) were performed on the day after vehicle i njection (control) and the day after completion of treatment(s), and t hen at weekly intervals. The main outcome measures were serum levels o f LH, FSH, and ORG 30850. Results: Administration of ORG 30850 resulte d in suppression (P < .05) of LH and FSH in all treatment groups. Long -term suppression (greater than 2 weeks) was evident in all primates r eceiving a cumulative dose of at least 1 mg/kg. Paradoxically, the res ponsiveness of the pituitary to exogenous GnRH was accentuated during the time of maximal tonic LH/FSH suppression. Conclusions: ORG 30850 i s a potent long-acting GnRH antagonist. Furthermore, the present in vi vo demonstration of heightened pituitary responsiveness to exogenous G nRH emphasizes the divergent mechanisms of action of GnRH antagonists and GnRH agonists.