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Journal of the Society for Gynecologic Investigation
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In Vivo Effects of a Potent GnRH Antagonist ORG 30850

Physiologic Evidence That Down-Regulation of GnRH Receptors Does Not Occur

Keith Gordon

Richard T. Scott

Robert F. Williams

Douglas R. Danforth

Hubert J. J. Loozen

Helenius J. Kloosterboer

Gary D. Hodgen

OBJECTIVE: Our purpose was to determine the pituitary responsiveness to exogenous GnRH in GnRH antagonist-suppressed ovariectomized monkeys.

METHODS: This was a prospective experimental non-human primate study performed at the research laboratories of The Jones Institute for Reproductive Medicine . Seventeen long-term ovariectomized cynomolgus monkeys were studied.

INTERVENTIONS: The GnRH antagonist ORG 30850 was administered to long-term ovari ectomized monkeys assigned to one of six groups: single subcutaneous injections in group A (n = 4), 0.3 mg/kg; group B (n = 4), 1.0 mg/kg; and group C (n = 3), 3.0 mg/kg; and six consecutive 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 samples were collected daily from 10 days before treatment until 22 days after treatment, then weekly for 6 additional weeks. Intravenous GnRH stimulation tests (10 µglkg) were performed on the day after vehicle injection (control) and the day after completion of treatment(s), and then at weekly intervals. The main outcome measures were serum levels of LH, FSH, and ORG 30850.

RESULTS: Administration of ORG 30850 resulted in suppression (P < .05) of LH and FSH in all treatment groups. Long-term suppression (greater than 2 weeks) was evident in all primates receiving a cumulative dose of at least 1 mg/kg. Paradoxically, the responsiveness of the pituitary to exogenous GnRH was accentuated during the time of maximal tonic LHlFSH suppression.

CONCLUSIONS: ORG 30850 is a potent long-acting GnRH antagonist. Furthermore, the present in vivo demonstration of heightened pituitary responsiveness to exogenous GnRH em phasizes the divergent mechanisms of action of GnRH antagonists and GnRH agonists . (J Soc Gynecol Invest 1994;1: 290-6)

Key Words: GnRH antagonist • non-human primate • ORG 30850 • down-regulation • GnRH receptors.

Journal of the Society for Gynecologic Investigation, Vol. 1, No. 4, 290-296 (1994)
DOI: 10.1177/107155769400100408
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