Suppression by LH-releasing hormone (LHRH) of the augmenting effect of estradiol on the secretion of LH and FSH by the rat pituitary gland.

Estradiol sensitizes the pituitary gland for the gonadotropin-releasing activity of LHRH. LHRH desensitizes the pituitary gland and does so in a dose-dependent manner. Moreover, LHRH dose-dependently suppresses the sensitizing effect of EB. In rats with an LHRH concentration in the plasma of about 90 pg/ml, the sensitizing effect of estradiol is absent.

Plasma gonadotrophin concentrations, pituitary gonadotrophin content and pituitary responsiveness to LHRH in rats treated with LHRH and oestradiol benzoate.

Suppression of gonadotrophin secretion during prolonged treatment with a high dose of LHRH was studied. Long-term ovariectomized rats were infused for 6 days with various doses of LHRH (25, 50, 100, 250 or 500 ng/h) with or without simultaneous treatment with oestradiol benzoate (OB; 3 micrograms/s.c. injection); a further group was treated with OB only. The effects of these treatments were studied on plasma concentrations of LH and FSH, the pituitary content of LH and FSH and on LH and FSH secretion in vitro (perifusion) in the unstimulated state and following maximal LHRH stimulation (1 microgram LHRH/ml perifusion medium). Administration of LHRH caused a dose-dependent reduction in plasma concentrations of LH and FSH and depleted the pituitary LH/FSH stores. Treatment with OB lowered the plasma concentration of LH to about 30% and that of FSH to about 65% of the control values. Administration of OB plus a low dose of LHRH (25 or 50 ng/h) markedly stimulated the secretion of LH but not of FSH, so that the plasma concentrations of LH were fully restored to the control value. With higher rates of LHRH infusion, OB caused no enhancement of the plasma concentrations of LH and FSH. The experiments in vitro revealed a sensitizing, i.e. stimulatory effect, of OB on LHRH-stimulated LH and FSH secretion. However, the higher the rate of infusion of LHRH the smaller the sensitizing effect. Interpolation from dose-response curves showed that an LHRH infusion rate of about 150 ng/h (which would establish a plasma concentration of LHRH of about 68 pmol/l) would have no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Minor interference of low-dose pulses of GnRH with the positive effect of oestradiol on the pituitary gland.

In the ovariectomized rat we investigated the effects of prolonged treatment with oestradiol and 'physiological' pulses of exogenous GnRH on the GnRH-responsiveness of the pituitary gland. Rats were for 20 h pre-treated with either GnRH (3-ng pulses of 3 min duration every 20 min) or saline and for 19 h with either oestradiolbenzoate (OB; 3 micrograms/sc injection) or oil. Then LH and FSH responses were evoked by continuous test infusions of GnRH at the rates of either 60, 100, 150 or 1000 ng/h, lasting 10 h. It appeared that, irrespective of pre-treatment with either GnRH or saline, OB caused an increase of the maximal LH and FSH responses (that is the responses to the maximal stimulus of 1000 ng GnRH/h), and an increase of the GnRH-sensitivity of the pituitary gland, as far as the FSH secretion is concerned. GnRH pulses caused, irrespective of pre-treatment with OB or oil, a decrease of the GnRH-sensitivity of the pituitary gland, as well as a decrease of the maximal FSH response and of the pituitary FSH content. It was concluded that low-dose pulses of exogenous GnRH desensitize the pituitary gland and deplete the pituitary FSH stores, but do not change the positive effect of oestradiol on the maximal gonadotropin response.

Decidua and the control of corpus luteum function, follicular development and pituitary LHRH-responsiveness in pseudopregnant and pregnant rats.

The mid-pregnancy rescue of corpora lutea can be mimicked in the pseudopregnant rat by induction of decidual tissue in the uterus: in such rats, around day 10, there is neither luteolysis, nor resumption of follicle-development or increase of the pituitary responsiveness to LHRH. The results suggest that the mid-pregnancy rescue of corpora lutea is caused by a maternal factor.

Studies on the modulation of the desensitization of the pituitary gland by luteinizing hormone-releasing hormone in the ovariectomized rat.

In ovariectomized rats the desensitization of the LH cells in vivo, which develops during constant rate infusion of LHRH, 1) does not depend on a concomitant depletion of the pituitary LH stores, 2) proceeds normally when the hypothalamo-pituitary connection has been severed and 3) is a process in which LH itself is not involved.

Clomiphene citrate can mimic the augmentative (positive) but not the depressing (negative) effect of estradiol on the LHRH-stimulated release of LH and FSH by the pituitary gland of the long-term ovariectomized rat.

In the long-term ovariectomized rat, both estradiol benzoate (EB) and clomiphene citrate enhance the release of LH induced by luteinizing hormone-releasing hormone (LHRH). EB also enhances the release of FSH. In rats pretreated with LHRH, EB strongly depresses the LHRH-induced LH/FSH release, but clomiphene enhances this release, regardless of the presence of EB.

Progesterone and the control of functional luteolysis, of secretion of prolactin and of pituitary LHRH responsiveness. A study with pseudopregnant rats kept in alternating and constant lighting conditions.

The effect of exogenous progesterone (P) on the corpus luteum function (in terms of the secretion of P and 20-alpha-dihydroprogesterone (DHP), on the secretion of prolactin (Prl) and on the pituitary responsiveness to LHRH was studied in pseudopregnant (PSP) rats kept in alternating and constant lighting conditions (LD-PSP and LL-PSP rats, respectively). Rats were rendered pseudopregnant by appropriately timed stimulation of the cervix uteri (LL rats first received an ovulatory dose of hCG). LH responses were induced by constant rate infusion of LHRH (104 ng/h for 21 h). P was delivered by subcutaneously inserted Silastic implants; control rats received sham implants. In both LD-and LL-PSP rats the plasma P and DHP levels were high on day 8 of PSP. On day 12, however, the plasma P levels had fallen but the DHP levels had risen, demonstrating that between days 8 and 12 functional luteolysis had occurred and that neither the production of P and DHP, nor the timing of luteolysis are under the control of the lighting conditions. On day 12 of PSP the pituitary responsiveness to LHRH was much higher than on day 8. Moreover, on days 8/9 of PSP peaks of Prl were seen in all rats, but on days 11/12 such peaks were largely absent. In LD-PSP rats 'nocturnal' Prl peaks were seen on days 8/9 in all 9 experimental animals, but 'diurnal' peaks were seen in only 4 of these animals. Also, the diurnal peaks were on average much lower than the nocturnal peaks.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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 LHRH 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 micrograms/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 microgram/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.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of the LH-releasing activities of LH-RH and its agonistic analogue buserelin in the ovariectomized rat.

LH-RH and the potent agonistic analogue (D-Ser(But)6-des-Gly10)-LH-RH(1-9)-ethylamide (HOE-766 or buserelin) were at several doses either infused or injected intravenously in 5-weeks-ovariectomized rats, which had been treated with either 3 micrograms estradiol-benzoate (EB) or with oil, 24 h previously. Blood samples for assay of LH were taken during the subsequent 24 h. Pituitary glands were removed at the end of the experiments. Buserelin, when infused, was slightly more effective than LH-RH on releasing LH. When injected, however, buserelin was at the higher dose ranges increasingly more effective as an LH-releasing agent than LH-RH. EB-treatment increased the LH response of the pituitary gland to both peptides in an identical way. It was concluded that buserelin derives its high potency not from its intrinsic LH-releasing activity, which is only slightly greater than that of LH-RH, but from a longer duration of action.

Control of follicle-stimulating hormone secretion by steroid-free bovine follicular fluid in the ovariectomized rat.

The effects of steroid-free bovine follicular fluid (bFF) and sodium phenobarbitone on spontaneous LH releasing hormone (LHRH)-induced secretion of FSH and LH were studied in ovariectomized rats. Luteinizing hormone releasing hormone was administered by infusion to rats anaesthetized with phenobarbitone. Bovine follicular fluid reduced FSH release and synthesis. Luteinizing hormone release remained unaffected after bFF treatment. Phenobarbitone reduced both FSH and LH release. The observed suppressive effects of bFF and phenobarbitone on FSH secretion were additive, suggesting that the basal release of FSH has an LHRH-dependent and an LHRH-independent component. Furthermore, bFF did not affect pituitary responsiveness of LH secretion to LHRH and reduced the responsiveness of FSH secretion only when administered some time before the LHRH challenge. The present observations support the view that in the ovariectomized rat the pituitary gland is the only site of action of inhibin-like activity as present in bFF.

Changes in pituitary LH content and LH secretion in the long-term ovariectomized rat during prolonged infusion of LRH.

LH secretion and the depletion of the pituitary LH stores caused by continuous infusion of LRH, were studied in the 5-weeks ovariectomized rat. After 1 day of infusion at the rate of 416 ng/h, pituitary LH content decreased to about 40% of its initial value. Upon continuation of the infusion the LH content increased slowly until, after 7 days, it increased to about 54% of the original value. The plasma LH concentrations, after having reached peak values of 7122 +/- 291 ng/ml after 2 h of infusion, declined to a plateau at about 300 ng/ml but it took 5 days to reach this value. When after either 2 or 8 days of LRH infusion at the rate of 416 ng/h the infusion was changed to a 'supramaximal' rate of 10,400 ng/h for 24 h, a transient secondary rise of LH secretion was induced. The magnitude of the secondary response, was essentially the same after 2 or 8 days of LRH infusion, but these secondary responses were significantly smaller than the LH-response during a similar LRH-infusion in previously untreated ovariectomized rats.

Recovery of the pituitary gland from LRH-induced refractoriness to LRH in the ovariectomized rat.

Recovery of the pituitary gland from LRH-induced refractoriness to LRH was studied in 5-weeks ovariectomized rats. Rats first received over a period of 48 h an infusion of LRH at a rate of 416 ng/h. After discontinuation of this infusion pituitary LH content had decreased to about 50% of its original value and the rate of LH secretion decreased markedly. Over a period of 72 h after discontinuation of the infusion plasma LH values rose to pre-infusion values but pituitary LH content showed such a recovery only partly. In another series of experiments a second infusion of LRH was given during 24 h and again at a rate of 416 ng/h, starting 3, 12, 24 or 72 h after discontinuation of the first infusion. It induced rises of LH secretion which were smaller than those following the first infusion, indicating refractoriness of the pituitary gland to LRH. However, the LH responses became progressively larger with increasing time intervals after the end of the first infusion. This stimulation of LH release was accompanied by a further decrease of pituitary LH content which was still depressed after the first infusion. Comparison of plasma LH levels and pituitary LH content indicated that pituitary responsiveness to LRH can recover independently from pituitary LH content. It can also be concluded that the absolute value of the blood LRH concentration can not be the sole determining factor of LH secretion.