Species differences in the sensitivity to a GnRH antagonist

The effects of the potent GnRH antagonist [Ac-D-NAL(2)1, 4F-D-Phe2, D-Trp3, D-Arg6]-GnRH (GnRH-A), on ovulation in mature rats and rabbits and on serum LH and FSH levels in ovariectomized rats, rabbits and mice were investigated. Dose-response studies showed that 1 microgram (4 micrograms/kg) of GnRH-A was sufficient to inhibit ovulation completely in cycling rats, while 500 micrograms (135 micrograms/kg) were required to inhibit mating induced ovulation in 8 of 11 rabbits. Two of the 3 rabbits which ovulated in spite of the antagonist treatment had delayed LH surges. The mean LH peak of these 3 rabbits was significantly (p less than 0.001) lower than that of controls. Pituitary response to GnRH-A, as measured by plasma gonadotropin levels following GnRH-A treatment in ovariectomized rabbits, rats and mice showed highest sensitivity of the rat to the inhibitory effects of the antagonist. Serum FSH levels were slightly suppressed in rats, but remained undiminished in rabbits and mice. The difference in the response of the three species to the antipituitary effects of GnRH-A is most likely due to differences in the affinity of the pituitary GnRH receptor to the antagonist.