In vivo effects of a potent GnRH antagonist ORG 30850: physiologic evidence that down-regulation of GnRH receptors does not occur.
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.


METHODS
The GnRH antagonist ORG 30850 was administered to long-term ovariectomized 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 micrograms/kg) 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 LH/FSH suppression.


CONCLUSIONS
ORG 30850 is a potent long-acting GnRH antagonist. Furthermore, the present in vivo demonstration of heightened pituitary responsiveness to exogenous GnRH emphasizes the divergent mechanisms of action of GnRH antagonists and GnRH agonists.
Gordon
K
K
Department of Obstetrics and Gynecology, Jones Institute for Reproductive Medicine, Eastern Virginia Medical School, Norfolk 23507, USA.
Scott
R T
RT
Williams
R F
RF
Danforth
D R
DR
Loozen
H J
HJ
Kloosterboer
H J
HJ
Hodgen
G D
GD
D000818:Animals; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004353:Drug Evaluation, Preclinical; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology*; D007986:Luteinizing Hormone / Q000097:blood; D008252:Macaca fascicularis; D010052:Ovariectomy; D010053:Ovary / Q000502:physiology*; D010902:Pituitary Gland / Q000187:drug effects; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors*
D006727:Hormone Antagonists; D011966:Receptors, LHRH; C067622:Org 30850; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone