In vivo administration of a GnRH antagonist to male mice: effects on pituitary gonadotropin secretion in vitro.
The potent luteinizing hormone-releasing hormone antagonist [N-Ac-D-p-Cl-Phe1,2,D-Trp3,D-Arg6,D-Ala10]GnRH (4 mg/kg) was administered sc once or daily for 21 days to immune-deficient (nude) and normal immune-competent (NIC) male mice derived from the same genetic background. Effects of in vivo pretreatment with the antagonist on gonadotropin secretion from hemipituitary glands from both types of mice were studied in vitro in the presence or absence of synthetic GnRH. Treatment with the GnRH antagonist caused differential effects on release of FSH and LH from and amounts of FSH and LH in hemipituitary glands. Pituitary FSH secretion was effectively inhibited, whereas effects on pituitary LH were less evident or nonsignificant under these experimental conditions. Long-term treatment with the antagonist caused larger effects on pituitary secretion and content of FSH, when compared with short-term treatment. No significant effects of duration of treatment on secretion or pituitary content of LH were detected. Addition of synthetic GnRH to the incubation medium caused stimulation of gonadotropin release. Therefore, it was concluded that the high doses of this GnRH antagonist were not able to block GnRH receptors effectively in the pituitary glands of nude and NIC male mice. The incomplete suppression of LH secretion by this high dose of the GnRH antagonist may partly explain the inability of the antagonist to suppress plasma testosterone levels and the growth of androgen-dependent tumours in male mice.
Ultee-van Gessel
A M
AM
Department of Biochemistry, Erasmus University, Rotterdam, The Netherlands.
van Steenbrugge
G J
GJ
Leemborg
F G
FG
Schroeder
F H
FH
de Jong
F H
FH
D000818:Animals; D005640:Follicle Stimulating Hormone / Q000378:metabolism*; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives*; D007279:Injections, Subcutaneous; D007986:Luteinizing Hormone / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D010903:Pituitary Gland, Anterior / Q000378:metabolism*
D007987:Gonadotropin-Releasing Hormone; C035819:LHRH, N-Ac-(4-Cl-Phe)(1,2)-Trp(3)-Arg(6)-AlaNH2(10)-; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone