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G Emons

Publications and source records attributed to G Emons.

At least 73 records · Page 4Linked to original sources
PubMed1994

Modulatory action of progesterone and progesterone antagonists on hypothalamic-pituitary function.

The ability of ovarian steroids to sensitize and desensitize the pituitary gonadotroph to hypothalamic gonadotrophin-releasing hormone (GnRH) is essential for their modulatory actions on gonadotrophin secretion. The time-dependent actions of progesterone on GnRH-stimulated gonadotrophin secretion from cultured pituitary cells obtained from female rats were examined. Progesterone induced an acute stimulatory effect on luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion in cell perifusion studies, from as early as 50 min after the onset of progesterone treatment. Long-term incubation (52 h) of pituitary cells in static culture reduced the responsiveness of the gonadotroph to GnRH. The antiprogestins RU486, ZK 98.299, and ZK 98.734 blocked both the acute facilitatory and the long-term inhibitory action of progesterone. In the absence of progesterone, the antiprogestins per se induced marked inhibitory and stimulatory effects on GnRH-stimulated LH secretion. In brief, short-term treatment of non-oestrogen-primed cells with antiprogestins was ineffective (ZK compounds) or reduced LH secretion (RU486), while long-term treatment was stimulatory. Oestrogen-primed cells exerted exclusively inhibitory effects on GnRH-induced LH secretion. In conclusion, antiprogestins are effective antagonists of progesterone actions in the gonadotroph. However, they exert diverse actions on gonadotrophin secretion in the absence of progesterone, which might interfere with their antagonistic properties.

Animals↗
PubMed1994

The use of luteinizing hormone releasing hormone agonists and antagonists in gynaecological cancers.

The use of agonistic analogues of luteinizing hormone releasing hormone (LHRH) is an established therapy for hormone-dependent metastatic pre-menopausal breast cancer. Their mechanism of action in this disease is the suppression of ovarian oestrogen production (medical castration). In the treatment of post-menopausal metastatic breast cancer, LHRH agonists also have some effect, although minor, probably through a suppression of ovarian androgen production. Convincing evidence has been accumulated that LHRH analogues can directly inhibit the proliferation of breast cancer cells in vitro. The clinical impact of these findings, however, is still controversial. Experimental data and several pilot clinical trials suggest that in epithelial ovarian cancer and sex-cord-stromal tumours of the ovary, LHRH agonists might have antitumour activity through the suppression of gonadotrophin secretion (selective medical hypophysectomy). Phase III clinical trials, evaluating this hypothesis, are in progress. Direct antiproliferative effects of LHRH analogues on epithelial ovarian cancer cells have been demonstrated in vitro. In endometrial cancer, experimental and early clinical results support the concept of a direct antiproliferative activity of LHRH analogues. Recently, potent antagonistic analogues of LHRH, devoid of relevant side-effects have become available for clinical testing. These new antagonists might be superior to agonistic LHRH analogues with respect to the rapidity and efficacy of selective medical hypophysectomy and medical castration. Modern LHRH antagonists might also permit a better exploitation of direct antitumour effects. A further therapeutic improvement in gynaecological oncology might result from a combination of LHRH agonists or antagonists with other peptide hormone analogues such as agonists of somatostatin or antagonists of bombesin/gastrin releasing peptide which have antitumour activity. Since 50% of breast cancers and 80% of epithelial ovarian cancers and endometrial cancers have high affinity binding sites for LHRH, cytotoxic LHRH analogues might provide a targeted chemotherapy, which would be more efficacious and less toxic than conventional regimens.

Adult↗
PubMed1994

Expression of luteinizing hormone releasing hormone and its mRNA in human endometrial cancer cell lines.

Recent results have shown that specific binding sites for luteinizing hormone-releasing hormone (LHRH) are present in biopsy samples of human endometrial cancer and in the human endometrial cancer cell lines Ishikawa and HEC-1A. The proliferation of these cell lines was retarded by LHRH analogs. The present study was undertaken to determine whether these endometrial tumor cells also produce LHRH or an LHRH-like peptide which could serve as natural ligand for the LHRH binding sites. Using a specific antibody, LHRH-immunoreactivity was detected in extracts of Ishikawa (426 +/- 84 fmol/10(6) cells) and HEC-1A (368 +/- 41 fmol/10(6) cells) cells. LHRH-like bioactivity of these samples was assessed in a rat pituitary cell culture system. The release of luteinizing hormone induced by endometrial cancer cell extracts corresponded to that obtained with comparable amounts of authentic LHRH. The expression of the mRNA for LHRH could be demonstrated by reverse transcriptase - polymerase chain reaction using specific primers according to the published sequence and by subsequent Southern blot analysis. The presence of immuno- and bioactive LHRH-like factors and the demonstration of expression of the mRNA for LHRH in two human endometrial cancer cell lines supports the concept of an autocrine regulatory system based on LHRH in endometrial cancer.

Base Sequence↗
PubMed1993

High affinity binding and direct antiproliferative effects of LHRH analogues in human ovarian cancer cell lines.

Recently, specific binding sites for luteinizing hormone releasing hormone (LHRH) and its analogues have been demonstrated in biopsy samples of human epithelial ovarian cancer. Their biological significance remained obscure. In this study we ascertained whether such LHRH-binding sites are also present in the human epithelial ovarian cancer cell lines EFO-21 and EFO-27 and if they could mediate antiproliferative effects of LHRH analogues. Using [125I, D-Trp6]LHRH, a high affinity/low capacity binding site was detected in both lines: EFO-21 (Kd1 = 1.5 x 10(-9) M; binding capacity (Bmax1) = 4.9 fmol/10(6) cells) and EFO-27 (Kd1 = 1.7 x 10(-9) M; Bmax1 = 3 fmol/10(6) cells). In addition, a second class of low affinity/high capacity binding sites (EFO-21: Kd2 = 7.5 x 10(-6) M; Bmax2 = 24 pmol/10(6) cells; EFO-27: Kd2 = 4.3 x 10(-6) M; Bmax2 = 14.5 pmol/10(6) cells) was demonstrated. Specific binding of [125I, D-Trp6]LHRH was displaced with nearly equal efficiency by unlabeled [D-Trp6]LHRH, the LHRH-antagonists SB-75 and Hoe-013, and by native LHRH but not by unrelated peptides such as oxytocin and somatostatin. In the presence of 10(-5) M agonist [D-Trp6]LHRH, the proliferation of both cell lines was significantly reduced to 77% of controls after 24 h and to approx. 60% after 6 days. Lower concentrations (10(-9) M) of the agonist, significantly decreased the proliferation to 87.5% for EFO-21 and 86% for EFO-27 after 6 days. These antiproliferative effects were enhanced by increasing doses of [D-Trp6]LHRH and were maximal at 10(-5) M (EFO-21: 65.5% of control, EFO-27: 68% of control). Similar dose-dependent antiproliferative effects were obtained in EFO-21 line with the LHRH-antagonists SB-75 and Hoe-013, while these analogues had no effects on the proliferation of EFO-27 cells. SB-75 partly antagonized the antiproliferative effect of [D-Trp6]LHRH in a dose dependent way in the EFO-27 line. These data suggest that LHRH analogues can directly inhibit the in vitro proliferation of human ovarian cancer cells. This effect might be mediated through the high affinity LHRH binding sites.

Cell Division↗
PubMed1993

Ovarian steroids modulate endothelin-induced luteinizing hormone secretion from cultured rat pituitary cells.

It has been demonstrated that endothelins (ETs) induce LH secretory responses in cultured rat pituitary cells. Because estradiol and progesterone are known to be potent modulators of GnRH-induced gonadotropin secretion, we examined whether these steroids also influence the secretory responses of gonadotrophs to ETs. Cultured female rat pituitary cells were treated for 48 h with vehicle (0.2% ethanol), 1 nM estradiol alone, or a combination of 1 nM estradiol and 100 nM progesterone or for 48 h with 1 nM estradiol and a further 4 h with 100 nM progesterone and subsequently stimulated with 10 pM-100 nM ET-1 or ET-3. Forty-eight-hour estradiol treatment led to enhanced LH secretory responses to both ETs. This action was facilitated by short term progesterone treatment (3-fold vs. vehicle), while long term progesterone treatment was inhibitory. Perifusion experiments were performed to study the kinetics of individual and pulsatile LH secretory responses after steroid exposure of pituitary cells. ET-1 induced immediate biphasic LH responses that were augmented by long term estradiol treatment. Two-hour progesterone exposure led to marked increases in LH secretion, whereas 48-h progesterone treatment was inhibitory. Estradiol and progesterone were able to modulate both the initial spike and the secondary plateau phase of the secretory profile in response to ET-1, although these actions did not always reach statistical significance. The steroid treatment paradigms employed also induced inhibitory and stimulatory effects in cells that were stimulated with ET-3 in a pulsatile fashion. In these experiments it could be demonstrated that the facilitatory action of progesterone was present after 50 min of treatment and was maximum after 150 min (5-fold enhancement). The present data support the hypothesis that ETs are involved in the physiological regulation of gonadotropin secretion and demonstrate that ovarian steroids can act as potent modulators of ET-induced LH secretion.

Animals↗
PubMed1993

High affinity binding and direct antiproliferative effects of luteinizing hormone-releasing hormone analogs in human endometrial cancer cell lines.

Although specific binding sites for LH-releasing hormone (LHRH) and its analogs have been demonstrated in biopsy samples of human endometrial cancer, their biological significance remains obscure. In this study we evaluated whether binding sites for LHRH are also present in the human endometrial cancer cell lines HEC-1A and Ishikawa and if such sites could mediate antiproliferative effects of LHRH analogs. Using [125I,D-Trp6]LHRH as a ligand, a high affinity/low capacity binding site was detected in both lines: HEC-1A line, dissociation constant (Kd)1 = 5.7 x 10(-9) mol/L, binding capacity (Bmax)1 = 78 fmol/10(6) cells; Ishikawa line, Kd1 = 4.2 x 10(-9) mol/L, Bmax1 = 29 fmol/10(6) cells. In addition, a second class of low affinity/high capacity binding sites for LHRH was demonstrated (HEC-1A line, Kd2 = 1.4 x 10(-6) mol/L, Bmax2 = 21 pmol/10(6) cells; Ishikawa, Kd2 = 4 x 10(-6) mol/L, Bmax2 = 32 pmol/10(6) cells). In the presence of 10(-5) mol/L agonist [D-Trp6]LHRH (triptorelin), the proliferation of HEC-1A and Ishikawa cell lines was significantly reduced to 76 +/- 2% and 88 +/- 4% of controls, respectively, after 24 h and to 64 +/- 2% and 62 +/- 2%, respectively, after 6 days. Dose-response experiments showed that lower concentrations (10(-9) mol/L) of the agonist decreased the proliferation to 80 +/- 1% for the HEC-1A line and 71 +/- 2% of controls for the Ishikawa line after 6 days. Antiproliferative effects are enhanced by increasing the doses of triptorelin and were maximal in this series of experiments at 10(-5) mol/L, the proliferation in the HEC-1A line being 62 +/- 1% and in the Ishikawa line 52 +/- 2% of controls, respectively. Similar time- and dose-dependent antiproliferative effects were obtained in both cell lines with the LHRH antagonist SB-75 (cetrorelix). These data suggest that LHRH analogs can directly inhibit the proliferation of human endometrial cancer cells in vitro. This direct action could be mediated through the high affinity LHRH binding sites.

Amino Acid Sequence↗
PubMed1992

Effects of progesterone on gonadotropin-releasing hormone receptor concentration in cultured estrogen-primed female rat pituitary cells.

Acute (0.5-4 h) treatment of estradiol (E)-primed female rat pituitary cells with progesterone (P) augments gonadotropin-releasing hormone (GnRH)-induced LH release, whereas chronic (48 h) P-treatment reduces pituitary responsiveness to the hypothalamic decapeptide. Dispersed E-primed (48 h, 1 nM) rat pituitary cells were cultured for 4 or 48 h in the presence of 100 nM P to assess the effects of the progestagen on GnRH receptors and on gonadotrope responsiveness to the decapeptide. P-treatment (4 h) significantly augmented GnRH-receptor concentrations (4.44 +/- 0.6 fmol/10(6) cells) as compared to cells treated only with E (2.6 +/- 0.5 fmol/10(6) cells). Parallel significant changes in GnRH-induced LH secretion were observed. The acute increase in GnRH-receptor number was nearly maximal (180% of receptor number in cells treated with E alone) within 30 min of P addition. Chronic P-treatment (48 h) significantly reduced pituitary responsiveness to GnRH as compared to E-treatment. The GnRH-receptor concentrations (3.9 +/- 0.6 fmol/10(6) cells), however, remained elevated above those in E-primed cells. GnRH-receptor affinity was not influenced by any of the different treatments. These results indicate that the acute facilitatory P-effect on GnRH-induced LH release is at least chronologically closely related to an increase in GnRH-receptor concentration. The chronic negative P-effect on pituitary responsiveness to GnRH, however, shows no relation to changes in available GnRH receptors.

Animals↗
PubMed1992

Modulatory actions of estradiol and progesterone on phorbol ester-stimulated LH secretion from cultured rat pituitary cells.

We compared the ability of estradiol and progesterone to modulate gonadotropin-releasing hormone (GnRH) and protein kinase C (PKC)-mediated luteinizing hormone (LH) secretion. Long-term (48 h) treatment of rat pituitary cells with 1 nM estradiol enhanced GnRH and phorbol ester (TPA)-stimulated LH secretion. This positive effect was facilitated by additional short-term (4 h) treatment with progesterone (100 nM). However, long-term progesterone treatment, which inhibited GnRH-stimulated LH secretion, did not influence TPA-stimulated gonadotropin release. These steroid actions occurred without an effect on the total amount of LH in the cell cultures (total LH = LH secreted + LH remaining in the cell) and neither the secretagogues nor the steroids altered total LH. Since GnRH or TPA-induced LH secretion depends on Ca2+ influx into the gonadotroph, we also analyzed the effects of estradiol and progesterone under physiological extracellular Ca2+ concentrations and in the absence of extracellular Ca2+. The steroids were able to influence GnRH or TPA-induced LH secretion under both conditions. However, when TPA was used as stimulus in Ca(2+)-deficient medium the relative changes induced by estradiol and progesterone were more pronounced, possibly indicating that the extracellular Ca(2+)-independent component of PKC-mediated LH secretion is more important for the regulation of the steroid effects. It is concluded that estradiol and progesterone might mediate their modulatory actions on GnRH-stimulated LH secretion via an influence on PKC. This effect can occur independently from de novo synthesis of LH and Ca2+ influx into gonadotrophs.

Animals↗
PubMed1992

[In vivo and in vitro effects of GnRH analogs on ovarian Leydig cell tumor].

A 65-year old patient, suspected to be suffering from an androgen producing ovarian tumour, was treated preoperatively with the GnRH agonist triptorelin (500 micrograms/day s.c.) for 7 days. After an initial rise, gonadotrophin levels were suppressed under this treatment. The elevated serum testosterone concentrations were reduced by approx. 50% by the triptorelin injections. After the extirpation of the tumour (histologically a Leydig cell tumour of the ovary without signs of malignancy), primary cell cultures which secreted testosterone and androstenedione were prepared. Coincubation of the tumour cells with the GnRH agonist triptorelin had no effect on their androgen secretion. Treatment of the tumour cells with high concentrations (10(-5) M) of a GnRH antagonist, however, resulted in a 100% increase of their testosterone and androstenedione secretion. GnRH-binding sites of low affinity (Ka = 0.54 x 10(5) M-1) and high capacity (B max = 1364 x 10(-12) M/mg membrane protein) were identified in the tumour. These findings suggest that GnRH analogues might modify androgen secretion of sex-cord stromal tumours of the ovary via the suppression of endogenous gonadotrophin secretion and possibly also via direct effects on the tumour cells.

Aged↗
PubMed1992

Intracellular actions of gonadotropic and peptide hormones and the therapeutic value of GnRH-agonists in ovarian cancer.

During the last two decades, considerable experimental evidence has been collected indicating that epithelial ovarian cancer might be gonadotropin dependent. LH and FSH receptors have been described in some of these tumors. The proliferation of ovarian cancer cells could be stimulated in vitro by gonadotropins. Suppression of endogenous LH and FSH secretion by GnRH-agonist treatment inhibited the growth of experimental or heterotransplanted ovarian cancers in various animal models. A number of recent phase II clinical trials have shown that the application of GnRH-agonists can lead to remission or stable disease in patients with relapsed advanced ovarian cancer. At present, prospective controlled clinical studies are being performed to assess the efficacy of GnRH-agonist treatment in addition to conventional surgical and cytostatic therapy in ovarian cancer in FIGO stages III and IV. Also, direct effects of GnRH analogues on ovarian cancer seem possible: a GnRH-like protein has been found in the human ovary. Our group discovered and partially characterized a specific GnRH-binding site (mol. wt 63.2 kDa) in ovarian cancer which is very similar to other human extrapituitary GnRH-binding sites of the low affinity, high capacity type, e.g. in breast cancer or the placenta. Recently, other groups have described also high affinity GnRH-agonist binding sites in ovarian cancer as well as in other extrapituitary tissues. First results from our laboratory indicate that the proliferation of certain ovarian cancer cell lines in vitro is reduced by both agonistic and antagonistic analogues of GnRH. Other authors were able to inhibit gonadotropin-induced in vitro proliferation of ovarian cancer cell lines by co-incubation with a GnRH-agonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Modulation of cytoplasmic calcium signaling in rat pituitary gonadotrophs by estradiol and progesterone.

The stimulatory action of GnRH on gonadotropin secretion from cultured rat pituitary cells is modulated by estradiol (E) and progesterone (P). Since secretory responses to GnRH are initiated by phosphoinositide hydrolysis and Ca2+ mobilization, the effects of gonadal steroids on the pattern of Ca2+ signaling were analyzed in single pituitary gonadotrophs. Increasing concentrations of GnRH elicited a spectrum of [Ca2+]i signals in single gonadotrophs, ranging from subthreshold to threshold-oscillatory and biphasic (spike & plateau) responses. In E-treated gonadotrophs, short-term P treatment shifted subthreshold [Ca2+]i responses to oscillatory and oscillatory to biphasic responses, whereas long-term P treatment shifted oscillatory to subthreshold [Ca2+]i response profiles. These changes parallel the effects of P on GnRH-induced LH release, and indicate that the modulatory effects of ovarian steroids on gonadotropin secretion include a significant action on the Ca2+ signaling pathway.

Animals↗
PubMed1992

Acute effects of oestradiol and progesterone on melittin- and gonadotrophin-releasing hormone-induced LH secretion.

It is well established that oestradiol and progesterone modulate gonadotrophin-releasing hormone (GnRH)-induced LH secretion from cultured rat pituitary cells. Short-term oestradiol and long-term progesterone treatment exert inhibition, while short-term progesterone and long-term oestradiol treatment lead to enhancement of GnRH-stimulated LH secretion. There are several lines of evidence to suggest that the steroid effects might be mediated via a mechanism involving modulation of the GnRH signal-transduction system. To evaluate the role of arachidonic acid, which serves as an intracellular signal transducer by itself or its lipoxygenase metabolites, in the mediation of oestradiol and progesterone actions, we examined their effects on melittin (activator of phospholipase (A2)-stimulated LH secretion. When pituitary cells from adult female rats were treated for 48 h with 1 nmol oestradiol/l or 1 nmol oestradiol/l plus 100 nmol progesterone/l, GnRH (1 nmol/l)-induced LH secretion was stimulated or inhibited respectively. However, melittin (10-300 nmol/l)-stimulated LH secretion remained unaffected after such treatment. Short-term treatment with oestradiol inhibited GnRH-induced LH secretion while progesterone treatment of oestradiol-primed cells led to a stimulatory effect. Interestingly, melittin-stimulated LH secretion was influenced in the same way after the short treatment paradigm. Perifusion studies were performed to assess the kinetics of these acute steroid actions further. Four separate perifusion chambers were continuously perifused with medium and stimulated for 2 min with 1 nmol GnRH/l or 1 mumol melittin/l every 50 min in a pulsatile fashion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Specific low affinity binding sites for gonadotropin-releasing hormone in human endometrial carcinomata.

Specific low-affinity high-capacity binding sites for gonadotropin-releasing hormone (GnRH) have recently been discovered in human breast and ovarian carcinomata. We checked whether similar binding sites are present in human endometrial cancer. Plasma membrane preparations were incubated with [125I,D-Ala6-desGly10]-GnRH-ethylamide in the presence or absence of unlabelled GnRH agonists or other peptides. GnRH-binding could be demonstrated in all 12 tumor samples tested. The mathematical analysis of the binding data was consistent with a single class of low affinity (Ka = (0.8-1.4) x 10(5) M-1) and high-capacity (Bmax = (134-142) x 10(-12) M/mg membrane protein) binding sites. Native GnRH had a similar affinity to the binding sites as the GnRH agonist used. Other peptides such as oxytocin, somatostatin and thyrotropin-releasing hormone did not crossreact with the binding sites. A photolabelled derivative of [D-Lys6]-GnRH was prepared with the bifunctional photolabile reagent (4-azidobenzyl)-N-hydroxysuccinimide. Photoaffinity labelling of endometrial carcinoma membranes and subsequent sodium dodecyl sulfate electrophoresis in 10% polyacrylamide gel revealed the presence of a single molecular mass component of 62 +/- 1.9 kDa. The appearance of this photolabelled binding site could be largely suppressed by the addition of unlabelled GnRH-agonist (10(-4) M) and thus represents the specific binding site for GnRH in endometrial cancer.

Affinity Labels↗
PubMed1990

LHRH-receptors and LHRH-agonist treatment in ovarian cancer: an overview.

Considerable evidence exists that ovarian cancer might be gonadotrophin-dependent. Receptors for LH and FSH have been discovered in these tumors. Proliferation of ovarian cancer cells in vitro could be stimulated by gonadotrophins. Withdrawal of LH and FSH in animal models of ovarian cancer inhibited growth of these tumors. Phase-II clinical studies have shown that suppression of endogenous gonadotrophins by LHRH-agonists can be beneficial in women with advanced ovarian cancer. Respective controlled clinical trials are performed at present. Also direct effects of LHRH analogues on ovarian tumors have been reported. An LHRH like protein was found in human ovarian tissue. We discovered a specific LHRH binding site (mol. wt 63.2 kDa) in ovarian cancer tissue which is very similar to other human extrapituitary LHRH binding sites, of the low-affinity, high-capacity type, e.g. in breast cancer and the placenta. In the latter tissues, LHRH or a related substance has been proposed as an autocrine regulator of cellular function. If this was also the case in ovarian cancer, direct effects of LHRH analogs on the tumor cells could be used as additional therapeutical points of attack.

Animals↗
PubMed1990

Modulatory actions of the new antiprogestins ZK 98.299 and ZK 98.734 and of RU 486 on luteinizing hormone secretion and progesterone effects in pituitary gonadotrophs.

The effects of the antiprogestins (APs) ZK 98.299, ZK 98.734 and RU 486 on GnRH-stimulated LH secretion and their antagonistic activity on progesterone (P) actions were investigated in cultured pituitary cells from adult female Wistar rats. P (100 nM) was able to exert a facilitatory effect on GnRH (1 nM)-induced LH secretion after short-term (4 h) treatment of estradiol-primed (1 nM, 48 h) rat pituitary cells. When the APs (10 pM-10 microM) were introduced during the 4 h incubation period with P the facilitatory effect of P was totally abolished at concentrations greater than 10 nM (ZK 98.299, ZK 98.734) and greater than 1 nM (RU 486). Also the APs were shown to block the inhibitory action of P which occurs after long-term incubation of pituitary cells with this steroid. However at concentrations greater than 10 nM (ZK 98.734, RU 486) and greater than 100 nM (ZK 98.299) this antagonistic action of the APs was lost. To evaluate whether the APs have direct effects on GnRH-induced LH secretion in the absence of exogenous P pituitary cells cultivated for 48 h with or without 1 nM estradiol were incubated for 4 or 24 h with increasing concentrations of the APs (10 pM-10 microM). Four hour treatment of non-estradiol-primed cells with ZK 98.299 or ZK 98.734 was without any effect on the LH response to a 1 nM GnRH-stimulus. Only the highest concentration of RU 486 (10 microM) reduced the LH response. Twenty-four hour treatment of the cultures with the APs led to enhancement of GnRH-stimulated LH secretion by up to 113, 37 and 33% for ZK 98.734, ZK 98.299 and RU 486, respectively. When estradiol-primed cells were used for the same experiments we observed exclusively inhibitory effects on GnRH-induced LH secretion after 4 and 24 h treatment periods. It is concluded that these new APs are potent inhibitors of P-actions, but also per se they induce diverse effects on GnRH-stimulated LH secretion in cultured rat pituitary cells which have to be taken into account.

Animals↗