Multiple Inhibitory Actions of Luteinizing Hormone-Releasing Hormone Agonist on Luteinizing Hormone/Human Chorionic Gonadotropin Receptor-Mediated Ovarian Responses*

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Abstract
The administration to female rats of the LHRH agonist, [des-GlyNH210]LHRH ethylamide, as either a single dose or repeated injections resulted in a decrease in the binding of 125I-labeled hCG to ovarian plasma membranes. An ovarian cell suspension prepared from the agonist-injected group of rats also responded to hCG with a decreased ability to accumulate cAMP and progesterone compared with the saline-treated controls. The receptor loss was due to a decreased number of hormone-binding sites rather than to a change in the affinity of the receptor for the hormone. Preincubation of ovarian cells with the agonistic analog in vitro also caused an inhibition of progesterone synthesis in response to hCG, cholera toxin, and 8-Bromo-cAMP, suggesting a direct inhibitory effect of the analog on ovarian steroidogenesis. Prior exposure to the agonistic analog, however, had no effect on cAMP accumulation by the ovarian cells in response to either hCG or cholera enterotoxin, further suggesting that the site of inhibitory action lies at a point after cAMP accumulation. In summary, the present study demonstrates that 1) the inhibition of ovarian steroidogenesis observed in response to the injection of the LHRH agonist is primarily due to down-regulation of ovarian hCG/LH receptors with a resultant decrease in cAMP accumulation, and this effect may be caused by the pulses of LH release from the pituitary, and 2) the direct inhibitory effect on steroidogenesis observed under in vitro conditions is independent of gonadotropin receptor, and the site of this inhibitory action lies at a point after cAMP accumulation.