Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mode of action of activin A on the anterior pituitary gland (AP) was investigated using primary cultured cells. The AP cells were cultured with activin A (1 ng/ml) at various cell densities for 24-96 h, and further incubated for 3 h with activin A-free medium. When the cells were pretreated with activin A for 48 h, follicle-stimulating hormone (FSH) secretion during the following 3-h incubation was increased only at a density of 1 x 10(5) cells/200 mm2, but not at 2 x 10(5) or 4 x 10(5) cells/200 mm2. A longer pretreatment (96 h) was required in order to induce this response at a density of 2 x 10(5) cells/200 mm2. Luteinizing hormone (LH) secretion was not affected by activin A. Thus, the FSH secretory activity of the primary culture of AP was stimulated by activin A in a cell density-dependent manner. Furthermore, it was found that treatment with activin A (10 ng/ml) for 72 h increased the number of immunoreactive FSH cells by 25-41%, and that these newly induced FSH cells were low responders to gonadotropin-releasing hormone stimulation. The proportions of immunoreactive LH, thyroid-stimulating hormone, prolactin or growth hormone cells were not affected. From these results, we conclude that activin A increases FSH secretion by changing the cell population of pituitary gonadotropes.
Mol Cell Endocrinol 1990 Mar 05
PMID:Activin A increases the number of follicle-stimulating hormone cells in anterior pituitary cultures. 210 11

Follicle-stimulating hormone (FSH)-suppressing protein (FSP) or follistatin, a novel gonadal glycoprotein hormone, has been shown to have chronic inhibitory effects on the secretion of both FSH and luteinizing hormone (LH) in response to gonadotropin-releasing hormone (GnRH) in vitro. The present study was designed to investigate the acute effects of bovine FSP on GnRH-stimulated gonadotropin secretion and to examine the potential subcellular sites of this action of FSP using cultured pituitary cells. Anterior pituitaries from adult male Sprague-Dawley rats were enzymatically dispersed and cultured for 48 h, after which the cells were treated with bovine FSP for 6 h, followed by a 4 h stimulation with secretagogues in the continued presence of FSP. Results showed that the 35 kDa form of bovine FSP (0.1-3 nM) dose-dependently suppressed GnRH-stimulated FSH and LH secretion, with inhibition of 38 and 25%, respectively, at 3 nM. In addition, FSP suppressed gonadotropin secretion in response to activators of protein kinase C (phorbol 12-myristate 13-acetate (PMA) and mezerein) and a calcium ionophore (A23187). However, FSP had no effect on gonadotropin secretion evoked by melittin, an activator of phospholipase A2. Furthermore, 35 kDa bovine FSP did not compete with GnRH for GnRH binding sites in a direct competition study and treatment of cultured pituitary cells with FSP (0.1-3 nM) for 10 h did not alter the number of GnRH binding sites on the cell membranes. Finally, similar inhibitory effects on gonadotropin secretion in response to GnRH, PMA and mezerein were obtained with the 31 and 39 kDa forms of bovine FSP, each at a concentration of 1 nM. We conclude from the present study that FSP acutely inhibits GnRH-stimulated gonadotropin secretion in cultured pituitary cells, and that FSP exerts its action beyond the GnRH receptor, possibly by affecting the protein kinase C and/or the calcium-calmodulin systems.
Mol Cell Endocrinol 1990 Jul 30
PMID:Acute inhibitory effect of follicle-stimulating hormone-suppressing protein (FSP) on gonadotropin-releasing hormone-stimulated gonadotropin secretion in cultured rat anterior pituitary cells. 212 65

The LHRH agonists are antigonadotropic agents for reversible ovarian suppression in gynaecology and in oncology. In oncology, pituitary inhibition is maintained with high release rates preferably by implant or microcapsule injection. The pharmacokinetics of buserelin after injection, infusion, and during implant treatment (controlled release) are described. The release rate is monitored by urinary buserelin excretion (fractional excretion of 30% of the daily dose). During therapy, LHRH agonists in serum are measured by specific radioimmunoassays, with or without extraction. A more convenient non-invasive procedure is to measure the amount of buserelin in 24-h urine samples (during injections or nasal spray), or the urinary buserelin/creatinine ratio in morning urine samples (during infusions or implants). After high dose injection, buserelin has a half-life of 80 min, therapeutic plasma concentrations are maintained for 8-12 h. In long-term maintenance with buserelin implants (polylactide-glycolide, 75:25), serum concentrations and urinary excretion showed an extended plateau phase indicating a suitable dose interval of 2-3 months. In endometriosis and leiomyoma, the minimum release rate (urinary buserelin) required for maintenance of steroid suppression was established (buserelin excretion of about 0.5 microgram/g creatinine). Buserelin implants in prostate carcinoma are effective for 2 or 3 months, after a single dose of 6.6 or 10 mg buserelin, respectively. A consistent suppression of serum testosterone secretion was confirmed for more than 2 yr. Buserelin microparticles are effective in rhesus monkeys to completely suppress follicular maturation and oestrogen secretion during 4-6 weeks after a single dose of 3.6 mg buserelin. Recent results on the controlled release of an LHRH antagonist (Hoe 013) from biodegradable microparticles in rats with DMBA-induced mammary tumours indicate that tumour suppression by LHRH antagonists is well tolerated and highly effective. The local tolerance at the injection site of antagonist microparticles is excellent as in the case of LHRH agonists like buserelin.
J Steroid Biochem Mol Biol 1990 Dec 20
PMID:Pharmacokinetics and endocrine effects of slow release formulations of LHRH analogues. 212 37

A new depot formulation of the LHRH analogue Zoladex (goserelin acetate) has been developed which releases the drug over a period of at least 3 months as judged by measurement of drug content in depots at intervals after insertion in male rats and by the suppression of oestrogen secretion and oestrus in female rats. This formulation is based on the lactide/glycolide polymer system used for the standard 1-month Zoladex depot, but the dose has been increased to 10.8 mg and the characteristics have been modified to enable a longer release of drug to be achieved. Thirty-eight patients with histologically proven, locally advanced (stage T3 or T4) and/or metastatic prostate cancer were treated with this new longer acting LHRH analogue depot formulation containing 10.8 mg Zoladex. After initial increase of serum testosterone in the first week of therapy, castration levels were reached in all patients after 4 weeks and this was maintained for more than 14 weeks. At the time of depot exhaustion, when escape from castration levels of androgen occurred, all patients received a single injection of a standard 1-month depot containing 3.6 mg Zoladex which restored castration levels of androgen thus showing that the pituitary gland was again suppressed. The tolerance and acceptability of the longer-acting depot is high and comparable to the 1-month depot. Taking into account social and psychological factors, patients with advanced prostate carcinoma will soon be able to be treated with a longer acting LHRH depot formulation every 3 months an alternative of the 1-month depot now widely used clinically.
J Steroid Biochem Mol Biol 1990 Dec 20
PMID:A new extra long acting depot preparation of the LHRH analogue Zoladex. First endocrinological and pharmacokinetic data in patients with advanced prostate cancer. 214 7

This prospective randomized phase III trial compares orchidectomy as standard androgen-deprivative therapy of advanced (metastatic) prostatic cancer with treatment using the LHRH agonist Buserelin administered as nasal spray 3 daily doses of 400 micrograms, and combined with cyproterone acetate (CPA) 3 daily doses of 50 mg orally for 2 weeks initially to prevent flare-up of the disease, or continuously as complete androgen blockade. The trial was closed to entry in September 1989 when 367 patients were recruited. Patients were stratified for performance status (WHO) and metastatic status prior to randomization. According to patient and disease characteristics spreading of patients over the 3 arms was without statistical significant differences. Ineligibility was 5 and 4% of the patients were only partly evaluable. In March 1990 a first, preliminary analysis was performed. At that time 207 patients were off-study for progression or death and median follow-up was 1 yr. As to time-to-progression and survival there were no significant differences between the 3 arms. The meaning of this in regard to results of other trials with complete androgen blockade is discussed.
J Steroid Biochem Mol Biol 1990 Dec 20
PMID:Orchidectomy versus Buserelin in combination with cyproterone acetate, for 2 weeks or continuously, in the treatment of metastatic prostatic cancer. Preliminary results of EORTC-trial 30843. 214 9

The stimulatory effect of exogenously administered potato 5-lipoxygenase (0.1-0.3 U/2 ml) on luteinizing hormone (LH) release was demonstrated in rat anterior pituitary cells in a superfusion system. Nordihydroguaiaretic acid (NDGA), an inhibitor of 5-lipoxygenase, abolished the effect of the enzyme on LH secretion. The secretory effect on LH after 5-lipoxygenase administration was biphasic and dependent on Ca2+ indicating that 5-lipoxygenase affects LH release through its oxygenation reaction. Another series of experiments demonstrated that activation of 5-lipoxygenase, expressed as production of leukotriene (LT) B4 and C4 (728 +/- 127 pg/10(6) cells and 178 +/- 23 pg/10(6) cells, respectively) occurs in rat pituitary cells after addition of Ca2+ ionophore A23187. However, LTB4 and LTC4 were not formed by pituitary cells that had previously been desensitized by gonadotropin-releasing hormone (GnRH), the physiological ligand of LH release. These results are consistent with a role of 5-lipoxygenase metabolites in the mechanism of GnRH-induced LH secretion.
Mol Cell Endocrinol 1990 Feb 12
PMID:Exogenous action of 5-lipoxygenase by its metabolites on luteinizing hormone release in rat pituitary cells. 215 15

Dispersed estradiol-treated rat pituitary cells were used to characterize progesterone (P) modulation of luteinizing hormone (LH) secretion in response to a variety of pharmacologic secretagogues which influence cell biochemistry. Acute (less than 3 h) and chronic (24 h) exposures to P prior to secretagogue challenge respectively enhanced and inhibited Ca2+ ionophore (A23187)-stimulated and gonadotropin-releasing hormone (GnRH)-stimulated LH release in similar quantitative fashion without any effect on concurrent prolactin release. Similar responses were also noted with cholera toxin-stimulated secretion. However, when protein kinase C activators such as phorbol esters and dioctanoylglycerol were used to trigger LH release, chronic exposure to P did not inhibit, but rather enhanced, LH release. Again, P had no effect on prolactin release. 'Washout' studies indicated that chronic treatments with P would suppress LH secretion stimulated by these compounds, but only when the steroid was cleared from the cells 4 h beforehand. These studies provide further evidence that P specifically modulates gonadotroph secretory function via mechanisms which bypass GnRH receptors. Moreover, they suggest that P exerts many different actions within the gonadotroph and question the role of protein kinase C in GnRH action.
Mol Cell Endocrinol 1990 Mar 26
PMID:Progesterone modulation of gonadotropin secretion by dispersed rat pituitary cells in culture. III. A23187, cAMP, phorbol ester and DiC8-stimulated luteinizing hormone release. 216 Mar 82

The regulation of rat gonadotropin-releasing hormone (GnRH) receptors in male rat pituitary, hippocampus and testis was studied, in vivo, under steady-state conditions during treatment with D-Trp6 GnRH (triptorelin, slow-release form, at 300 micrograms/kg/month). GnRH receptors were characterized on tissue sections by quantitative autoradiography using 125I-GnRHa as a tracer. Castrating doses of triptorelin strongly down-regulated pituitary GnRH receptors (50% of reduction after 8 h, 80% on days 1-30); in contrast, only a transient decrease (20% at 8 h) was observed in the hippocampus with a rapid return to control levels. Triptorelin induced a marked (2-fold) increase in GnRH receptors in testicular interstitial tissue during 5 days with a return to control value by day 20. Administration of a GnRH antagonist (BIM 21009, 1 mg/kg/24 h) induced a rapid reduction of pituitary and testicular receptors to undetectable levels at 24 h, while hippocampal receptors were strongly reduced only. This indicates that GnRH receptors with similar pharmacology are differently controlled in various tissues and that brain receptors are likely to be also regulated by GnRH agonists and antagonists.
Mol Cell Endocrinol 1990 Mar 26
PMID:GnRH receptors in rat brain, pituitary and testis; modulation following surgical and gonadotropin-releasing hormone agonist-induced castration. 216 Mar 86

Pituitary GH3 cells were transfected with a human growth hormone-releasing hormone (hGRH) precursor minigene fused to the promoter region of either a cytomegalic immediate early gene (pCMV) or the mouse metallothionein-1 gene (mMT) to examine the molecular heterogeneity of the translation products. Expression of the hGRH message occurred following transfection of the cells with each fusion gene. Extracts of pCMV-hGRH-transfected GH3 cells as well as the culture medium contained detectable levels of immunoreactive (ir)-hGRH peptides. Analysis of molecular heterogeneity by reverse-phase high performance liquid chromatography and radioimmunoassay indicated that both mature forms of hGRH (hGRH(1-44)-NH2 and hGRH(1-40)-OH) were synthesized in the cells, although hGRH(1-44)-NH2 was the primary form secreted into the medium. A high molecular weight form of ir-hGRH, believed to represent the hGRH precursor (or a partially processed form of the precursor) was detected in cells and, in smaller amounts, in the medium. Several ir-hGRH peptides, presumed cleavage products of the mature forms of hGRH, were also found. The efficiency of processing of the hGRH precursor and metabolism of the mature hormonal forms in transfected cells grown in the presence of four different peptidase inhibitors varied with the inhibitor present. Transfected GH3 cells, therefore, possess all of the necessary enzymes for and are capable of processing the hGRH precursor to mature GRH and provide a model to study hGRH biosynthesis.
Mol Cell Endocrinol 1990 Jun 18
PMID:Expression of a cytomegalovirus-human growth hormone-releasing hormone precursor fusion gene in transfected GH3 cells. 216 57

We have examined the pharmacology of the voltage-sensitive Ca2+ channels (VSCCs) that mediate gonadotropin secretion from primary cultures of rat pituitary cells, stimulated by either cell depolarization or by binding of gonadotropin-releasing hormone (GnRH). We also measured single-cell [Ca2+]i transients using fura-2 in gonadotropes identified by a reverse hemolytic plaque assay employing an antiserum to luteinizing hormone (LH). Cell depolarization evoked by either 50 mM K+ or 30 microM veratridine induced 2- to 6-fold increases in gonadotropin secretion over basal levels. GnRH caused 6- to 20-fold increases in follicle-stimulating hormone (FSH) and LH secretion, respectively, with maximal stimulation at 100 nM GnRH. K(+)- or GnRH-induced FSH release was largely prevented by co-incubation with 1 mM CdCl. Tetrodotoxin (TTX, 5 microM) prevented the veratridine-, but not the K(+)- or GnRH-induced, stimulation of FSH secretion. Nitrendipine (Ntd, 1 microM) produced 35-50% inhibition (NS) of both FSH and LH release stimulated by either 50 mM K+ or 100 nM GnRH. Ntd also inhibited the K(+)-induced [Ca2+]i rise (greater than 90%), as well as the secondary, plateau phase of the GnRH-induced elevation of [Ca2+]i (100% inhibition). Omega-conotoxin (omega-CgTx, 100 nM) partially suppressed FSH and LH release (NS) due to both K+ (33% each) and GnRH (44% and 18%, respectively). omega-CgTx showed variable effects on [Ca2+]i transients evoked by K+ or GnRH ranging from clear inhibition to no effect. We conclude that influx of extracellular Ca2+ is one of several fundamental events underlying the depolarization- or receptor-activated release of LH and FSH, and that this influx can be inhibited by dihydropyridine-sensitive ('L') Ca2+ channels. Two classes of L-channels may exist in gonadotropes, that differ in their sensitivity to omega-CgTx.
Mol Cell Endocrinol 1990 Jul 09
PMID:Nitrendipine and omega-conotoxin modulate gonadotropin release and gonadotrope [Ca2+]i. 217 Feb 11


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