Direct and Indirect Inhibition of Ovulation in Rats by an Antagonist of Luteinizing Hormone-Releasing Hormone*

The importance of a central or peripheral site of action in the blockade of ovulation induced by LHRH antagonists was investigated. To determine if hCG could induce ovulation in cycling animals given antiovulatory doses of 10 or 100 micrograms N-Ac-D-p-Cl-Phe1,D-p-Cl-Phe2,D-Trp3,D-Arg6,D-Ala10 LHRH, the antagonist was injected at 1200 h of proestrus followed by varying doses of hCG at 1600 h. hCG did induce ovulation in animals given the analog, which suggested that the antagonist acted primarily at the hypothalamus-pituitary level to inhibit ovulation; however, 20 IU hCG induced ovulation in all animals given 10 micrograms antagonist, but 40 IU were required for the same effect in animals injected with 100 micrograms. To test whether hormone secretion was differentially affected by the two doses of antagonist, animals were injected with antagonist at 1200 h of proestrus, and groups were killed at 1- or 2-h intervals through 2100 h. Both 10 and 100 micrograms antagonist suppressed serum LH, FSH, progesterone, and estradiol levels to the same degree. Therefore, no differences in these hormones were detected that could account for the increased hCG required to induce ovulation in the 100 micrograms-treated animals. We next examined the ability of the antagonist to inhibit ovulation in animals hypophysectomized at day 24 of age and injected with 25 IU PMSG 7 days later and 30 or 50 IU hCG 48 h after PMSG. When the antagonist was given 4 h before 50 IU hCG, the antagonist did not completely inhibit ovulation even at 100 or 1000 micrograms/rat. When hCG was reduced to 30 IU, 100 micrograms antagonist induced a partial inhibition of ovulation, and 1000 micrograms induced a complete blockade. These results suggest that the LHRH antagonists primarily act centrally to inhibit ovulation, but they make the ovaries less responsive to hCG stimulation and can directly inhibit ovulation at high doses.