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

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Abstract
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 [human chorionic gonadotropin] could induce ovulation in cycling animals given antiovulatory doses of 10 or 100 .mu.g [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; 20 IU hCG induced ovulation in all animals given 10 .mu.g antagonist, but 40 IU were required for the same effect in animals injected with 100 .mu.g. To test whether hormone secretion was differentially affected by the 2 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 .mu.g antagonist suppressed serum LH [luteinzing hormone], 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 .mu.g-treated animals. 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 [pregnant mare serum gonadotropin] was examined. When the antagonist was given 4 h before 50 IU hCG, the antagonist did not completely inhibit ovulation even at 100 or 1000 .mu.g/rat. When hCG was reduced to 30 IU, 100 .mu.g antagonist induced a partial inhibition of ovulation, and 1000 .mu.g induced a complete blockade. Apparently 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.