Effect of estradiol on the secretion of LH in the GnRH-pretreated rat after treatment with the GnRH-antagonist, Org 30093

Abstract

Abstract. LH responses induced in the long-term ovariectomized rat by GnRH or GnRH agonistic analogue are augmented by E2. The augmentation by E2 does not occur during, but after termination of GnRH pretreatment. In this study it was investigated whether the augmenting effect of E2 develops also in the GnRH-pretreated rat when the animals were treated with GnRH antagonistic analogue. Two weeks after ovariectomy rats were treated for 10 days with 250 ng GnRH/h (GnRH-rats), released by sc implanted osmotic minipumps. Control rats received a Silastic 'sham pump'. Rats were simultaneously treated with solvent (oil) or estradiol benzoate (EB, 3 μg, sc). Each group of rats was divided into two subgroups, one receiving solvent, the other the GnRH antagonist, Org 30093 (ANT, 100 μg/injection) on 3 consecutive days. In Experiment 1, the pituitary LH content and the LH secretion following stimulation with the agonistic GnRH analogue buserelin, were measured, in Experiment 2, the plasma concentrations of LH before and after cessation of ANT treatment. The effects of treatment with GnRH, EB and ANT were studied on the basis of 1) the height of the maximal LH response and 2) the halfmaximally effective dose (ed 50) of buserelin. Experiment 1 revealed that GnRH depleted the pitutiary gland to about 42% of its original LH content. In EB-treated GnRH-rats the depletion was even stronger (to 14%). After ANT treatment, the pituitary glands of the GnRH-rats were (partly) repleted (oil: to 65%; EB: to 31%). ANT and EB had no effect on the pituitary LH content in control rats. EB increased the maximal LH response in control rats but not in GnRH-rats. ANT increased the maximal LH response to buserelin in oil-injected control rats as well as in oil- and EB-treated GnRH-rats. In these latter two groups, the increase of the maximal LH response was equally large. However, there was an effect of EB on the ed 50 of buserelin during ANT treatment, the pituitary gland of the EB-treated GnRH-rats had become more sensitive to GnRH. Experiment 2 revealed that GnRH pretreatment reduced the plasma LH concentrations to about 49% of the control levels. EB and ANT, too, lowered the plasma LH concentrations (to about 25%). Neither EB nor ANT, alone or in combination, changed the plasma LH concentrations in GnRH-rats. After cessation of ANT treatment, the plasma LH levels of the oil-injected control rats slowly returned to pretreatment levels, but those of the EB-treated control rats remained suppressed. In the GnRH-rats the reverse was seen: after cessation of ANT treatment, peaks of LH appeared in the plasma of the EB-treated rats, but not in the oil-injected. It is concluded that 1) treatment with ANT is not fully equivalent to termination of GnRH administration because it antagonizes the effects of GnRH only in part: 2) ANT has an intrinsic augmenting effect on the pituitary GnRH-responsiveness, and 3) owing to E2-induced sensitization of the pituitary gland, peaks of LH appear in the plasma of GnRH-rats but not of control rats after termination of ANT treatment.