Relative potencies of gonadotropin-releasing hormone agonists and antagonists on ovarian and pituitary functions

The abilities of various agonistic and antagonistic analogs of GnRH to modulate ovarian estrogen production were compared with their relative potencies to regulate pituitary LH release. Granulosa cells from immature hypophysectomized rats were cultured for 2 days in the presence of FSH and aromatase substrate (delta 4-androstenedione), with or without various concentrations of GnRH agonists or 10(-8) M GnRH plus various concentrations of selected GnRH antagonists. FSH treatment increased estrogen production, whereas concomitant treatment with various GnRH agonists resulted in dose-dependent decreases in estrogen production. des-Gly10-[D-Ser(TBu)6] Pro9-NHEt-GnRH proved most potent at both the ovarian and pituitary levels, being 170- and 190-fold greater than those values for the GnRH decapeptide, respectively. In general, the ovarian and pituitary potencies of all 10 agonists studied were comparable, with a correlation coefficient of 0.98. When added together with 10(-8) M GnRH, the GnRH antagonists caused dose-dependent blockage of the inhibitory effect of GnRH. Among 7 antagonists tested, [Ac-D-Phe1,D-p-cl-Phe2,D-TYrp3,6]GnRH was shown to be most potent at the pituitary level (half maximal inhibitory dose ratio: IDR50 antagonist/GnRH = 0.17) and blocked the GnRH inhibition at the ovarian level with an IDR50 value of 4.4. The potencies of the antagonists to block the GnRH effect at the pituitary and ovarian levels were comparable, yielding a correlation coefficient of 0.97. Although one cannot rule out subtle differences in the specificities of the respective GnRH target tissues due to minor disparities between pituitary and ovarian potencies of some analogs, the present results demonstrate an overall agreement of responsiveness between ovarian granulosa cells and pituitary gonadotrophs to GnRH agonists and antagonists.