Blockade of LH and FSH secretion by LH-releasing hormone, by the LH-releasing hormone analogue, buserelin, and by combined treatment with LH-releasing hormone and oestradiol benzoate

ABSTRACT The LH and FSH release-stimulating (experiment 1) and -blocking (experiment 2) effects of LH-releasing hormone (LHRH) and of the LHRH analogue d-Ser(But)6-des-Gly10-LHRH-ethylamide (buserelin), as well as the effect of combined treatment with LH RH and oestradiol benzoate (OB; experiment 3) on the 'supra-maximally' LHRH-stimulated release of LH and FSH were studied in rats ovariectomized for 2 weeks. Pretreatment with LHRH (250 or 500 ng/h) or buserelin (250 ng/h) for 6 days was effected by means of subcutaneously implanted Alzet osmotic minipumps; control rats received a 'sham pump', i.e. a piece of silicone elastomer with the dimensions of a minipump. Oestradiol benzoate (3 μg/injection) or solvent was injected subcutaneously 75 and 27 h before the induction of LH/FSH responses. Experiment 1 revealed that after infusion of LHRH and buserelin, both at the rate of 1 μg/h, plasma LHRH concentrations were established which were about twice as low as the plasma buserelin concentrations. This might suggest that buserelin has a longer half-life than LHRH. As an LH and FSH release-stimulating substance, however, it appeared that buserelin was about as effective as LHRH. Experiment 2, however, suggested that as an LH/FSH release-blocking agent buserelin was much more effective than LHRH. In addition, after buserelin pretreatment the pituitary glands contained much less LH and FSH than after LHRH pretreatment at both dose levels used. However, this may also (at least partly) be due to the fact that buserelin has a longer half-life so that after infusion of buserelin and LHRH at the same rate the plasma concentrations of buserelin are higher than those of LHRH; after buserelin infusion the pituitary gland is therefore stimulated at a higher intensity. Experiment 3 showed that in OB-injected, sham-implanted rats the LHRH-stimulated secretion of LH and FSH was significantly higher than in the oil-injected, sham-implanted rats. In the LHRH-pretreated rats (LHRH: 250 ng/h for 6 days), however, the already depressed LHRH-stimulated secretion of LH and FSH was still further depressed by OB treatment. These latter results suggest that the increase of the pituitary LHRH responsiveness during exposure to oestrogen requires a reduction of the LHRH stimulation, which is normally caused by the negative feedback of oestrogen on the hypothalamus. J. Endocr. (1984) 103, 301–309