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At least 235 records · Page 13Linked to original sources
PubMed1986

Antiprogestin-receptor complexes: differences in the interaction of the antiprogestin RU38,486 and the progestin R5020 with the progesterone receptor of human breast cancer cells.

In order to understand the molecular basis for antiprogestin action, we have compared the interaction of the antiprogestin [3H]RU38, 486 (RU486) and the progestin [3H]R5020 with the progesterone receptor (PR). In both MCF-7 and T47D human breast cancer cells, we have observed marked differences in the sedimentation properties of the PR on high salt sucrose gradients: while the R5020-receptor complexes sediment at approximately 4 S (4.4 +/- 0.1 S), the RU486-receptor sediments as a prominent 6 S species as well as a 4 S species. This binding is abolished by excess unlabelled R5020, RU486 or progesterone, but is unaffected by excess unlabelled hydrocortisone or dexamethasone, indicating that both the 4 S and 6 S species represent the PR and not glucocorticoid receptor. Although the relative distribution of 4 S and 6 S forms is not altered by treatment with DNAse or RNAse, exposure to 10 mM thioglycerol or to 3 M urea results in conversion of the 6 S to the 4 S form, suggesting that disulfide bonds and hydrophobic interactions are important in maintaining the integrity of the 6 S form. These findings suggest that the 6 S antiprogestin complex is formed as a result of the interaction of PR units with each other or with a different protein. This change in receptor association state may be an important aspect of the antiprogestin activity of RU486.

Binding, Competitive↗
PubMed1986

Progestin-induced down regulation of nuclear estrogen receptor in uterine decidual cells: analysis of receptor synthesis and turnover by the density-shift method.

The density-shift method was used to study the effect of the synthetic progestin, R5020, (17,21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione) on the turnover and synthesis of nuclear estrogen receptor in hamster decidual cells. Newly-synthesized receptor was labeled with dense [2H, 13C, 15N] amino acids and separated from pre-existing receptor by density-gradient centrifugation. Progestin increased receptor turnover within 3 h of treatment and blocked estradiol-induced receptor synthesis at 6 h and 9 h. Thus, progestin down regulates estrogen receptor by increasing receptor turnover and inhibiting estrogen-induced receptor replenishment.

Animals↗
PubMed1992

Rat lung possesses the mineralocorticoid receptor.

Lung cytosol from male, adrenalectomized rats was screened for the mineralocorticoid receptor (MCR) by a polyclonal antiserum raised in the rabbit against rat renal antigen. Western blot analysis revealed a single 98 kDa band, like the MCR purified biochemically. The MCR could also be photolabelled for the first time by 3H-R 5020 in this very 98 kDa region that was displaced by RU 26752 specific to MCR. Immune IgG was able to precipitate the MCR-3H-RU 26752 complex, and to displace the same to high molecular weight regions during gel permeation chromatography on Sephacryl columns. Thus, MCR mediated actions need to be redefined. Furthermore, the technique of photochemical labelling forms a novel tool to assess MCR specificity, and to dissect its structure and function.

Animals↗
PubMed1979

Cytoplasmic progestin-receptors in guinea pig brain: characteristics and relationship to the induction of sexual behavior.

The synthetic progestin, R 5020, was used to measure cytoplasmic progestin receptors in the brain and pituitary gland of ovariectomized guinea pigs. Progestin receptors with a dissociation constant of 0.1--0.3 nM were measured by gel filtration in all brain regions studied, pituitary gland and the uterus. The receptor is progestin-specific; biologically potent progestins compete well against [3H]R 5020 for binding, but androgens, glucocorticoids and estrogens do not. The concentration of the cytoplasmic progestin receptor in hypothalamus-preoptic area-septum and midbrain is decreased in vivo by behaviorally effective doses of progesterone. In the pituitary gland, hypothalamus, preoptic area-septum and midbrain, but not other brain regions, the concentration of progestin receptors increases after estradiol benzoate-priming. The increase in the concentration of cytoplasmic progestin receptors in hypothalamus-preoptic area-septum is dependent on the dose of estradiol benzoate injected. After a single injection of a dose of estradiol benzoate routinely used to facilitate the display of sexual receptivity (1.6 microgram estradiol benzoate/animal), the latency to an increase and subsequent decrease in cytoplasmic progestin receptors in the hypothalamus-preoptic area-septum correlates well with the previously reported time course for progesterone's facilitation of sexual receptivity after estradiol benzoate injection. The experiments are consistent with the notion that brain progestin receptors mediate at least some of the behavioral effects of progesterone.

20-alpha-Dihydroprogesterone↗
PubMed1981

Estrogen-sensitive progestin binding sites in the brain of the lizard, Anolis carolinensis.

Cytosol binding sites for the synthetic progestin [3H]R5020 have been identified in the brain and oviduct from untreated and estrogen primed ovariectomized female lizards (Anolis carolinensis). Competition of various unlabeled steroids at either 10 nM (brain) or 10 and 100 nM (oviduct) revealed that progestins were effective competitors whereas two glucocorticoids as well as testosterone and estradiol were ineffective. The apparent dissociation constant (Kd) of the receptor for [3H]R5020 in the hypothalamus and telencephalon of the brain was determined to be 0.7-0.8 nM. The concentration of binding sites in the hypothalamus was approximately twice as great as in the telencephalon. The dissociation constant of the binding site for [3H]R5020 in the oviduct was determined to be 1.4-1.7 nM. Although sucrose density gradient centrifugation of brain cytosols labeled with [3H]R5020 failed to reveal a discretely sedimenting peak of radioactivity, oviduct cytosol gradients contained two broad peaks of [3H]R5020 binding at 3-6S and 8-9S. The concentration of [3H]R5020 binding sites in both the oviduct and hypothalamus was found to increase after estrogen treatment. Scatchard analysis of oviduct cytosol [3H]R5020 binding showed that estrogen priming increased binding levels 3-fold. Single point assays with 0.4 nM [3H]R5020 demonstrated that estrogen priming increased binding by 55% in hypothalamus but did not alter binding in cytosol from the telencephalon sample. These results suggest that the [3H]R5020 binding sites identified in the brain and oviduct of the lizard A. carolinensis may correspond to cytoplasmic progestin receptors. Furthermore, the finding of an estrogen-induced increase in the concentration of these receptors in the hypothalamus and oviduct indicate that the capability of estrogen to modulate the concentration of progestin receptor is present in a representative of a vertebrate class whose progenitors gave rise to birds and mammals.

Animals↗
PubMed1981

Temporal relationship between cell nuclear progestin receptor levels and sexual receptivity following intravenous progesterone administration.

This study was designed to assess the temporal relationship between the appearance and retention of cell nuclear progestin receptors in hypothalamus and the facilitation and decline of feminine sexual behavior following an i.v. injection of progesterone (P). Nuclear translocation of progestin receptors preceded the earliest appearance of behavior. The behavioral effects of P outlasted the nuclear progestin receptor elevation by several hours. Our results are consistent with the idea that P-induced effects on feminine sexual behavior involve genomic activation.

Animals↗
PubMed1983

Topographic distribution of progestin target cells in hamster brain and pituitary after injection of [3H]R5020.

The topographic distribution of progestin concentrating cells in the female hamster brain and pituitary was studied by thaw-mount autoradiography. Fifteen minutes after injection of [3H]R5020, a synthetic progestin, nuclear uptake and concentration of radioactivity was found in certain cells of the forebrain and midbrain, as well as in the anterior pituitary. Competition studies with unlabeled R5020 abolished and with progesterone reduced the nuclear uptake of radioactivity. In the forebrain, radioactively labeled cells are observed in n. septi lateralis, n. interstitialis striae terminalis, n. preopticus medialis and lateralis, n. periventricularis hypothalami, organum subfornicale, n. arcuatus hypothalami, n. ventromedialis hypothalami, n. dorsomedialis hypothalami and n. premammillaris ventralis. In the midbrain a few labeled cells are found in the griseum centrale. In the anterior pituitary, labeled cells are identified by immunostaining as luteinizing hormone-producing cells. The results of the autoradiographic study demonstrate nuclear progestin binding sites and suggest genomic action of progestin on the labeled structures, probably related to the modulation of gonadotropin secretion and sexual behavior in the brain and pituitary.

Animals↗
PubMed1989

Sex differences in cytosolic progestin receptors in microdissected regions of the hypothalamus/preoptic area of guinea pigs.

Cytosolic progestin receptors (CPRs) were measured in microdissected nuclei of the hypothalamus and preoptic area of male and female guinea pigs. Adult gonadectomized animals were given 3 daily injections of 20 micrograms/day estradiol benzoate (EB) or oil vehicle. 24 h later, animals were sacrificed and cytosolic progestin receptors were measured using the synthetic progestin 3H-R5020. CPR levels did not differ significantly between oil treated males and oil treated females in any brain areas examined. With EB treatment, males showed significant increases in CPRs in most of the brain areas in which females showed increases, i.e. in the medial preoptic area, the periventricular part of the preoptic area, the periventricular part of the anterior hypothalamus, the ventromedial nucleus of the hypothalamus, the periventricular part of the medial hypothalamus and the arcuate-median eminence. However, EB treated males showed significantly lower CPR levels than EB treated females in both the periventricular part of the preoptic area and the periventricular part of the medial hypothalamus.

Animals↗
PubMed1989

Progestins affect reproductive behavior and androgen receptor dynamics in male guinea pig brain.

The present study extends previous studies of ours by comparing the anti-androgenic effect of a progestin agonist (R5020) with progesterone (P). Intact male guinea pigs treated with P (1 and 10 mg/day) and R5020 (100 micrograms/day) had greater latency to mount and lower numbers of mounts and intromissions compared to controls. Ejaculation and plasma testosterone concentration were not affected. Specific brain regions were analyzed for androgen receptor (AR) content. Progestins produced fewer (P less than 0.01) nuclear AR in hypothalamus-preoptic area and pituitary without associated changes in cytosolic AR. These data are best interpreted by postulating an effect of P on AR dynamics mediated through the P receptor and not by competition for androgen binding to its receptor.

Animals↗
PubMed1990

Progestin receptors in the ventromedial nucleus of the hypothalamus and arcuate nucleus-median eminence are decreased by idazoxan.

Steroid-dependent lordosis behavior in ovariectomized (OVX) guinea pigs is attenuated by alpha 1- and/or alpha 2-noradrenergic (NE) receptor antagonists. Correlated with the decrease in lordosis after alpha 1-NE receptor blockade by prazosin is a decrease in 'cytosol' progestin receptors in the ventromedial hypothalamic nucleus (VMN). We examined whether a presumed alpha 2-NE receptor blocker (idazoxan, IDA) also affects progestin receptors. A decrease in 'cytosol' progestin receptors was found after IDA treatment of OVX, estrogen-treated guinea pigs in the VMN and the arcuate nucleus-median eminence (ARC-ME). Apparently, either prazosin or IDA can inhibit lordosis behavior and decrease 'cytosol' progestin receptors in the VMN. In contrast, idazoxan but not prazosin, decrease 'cytosol' progestin receptors in the ARC-ME.

Adrenergic alpha-Antagonists↗
PubMed1987

Evaluation of RU-27987 as a ligand to determine the progesterone receptor.

RU-27987, a synthetic progestin, which was recently developed by Roussel Uclaf, Paris, was tested for its validity as a ligand to determine the progesterone receptor in breast cancer. The results were compared to those obtained with R-5020 and ORG-2058, two ligands that are already in use worldwide. The intra- and interassay variation of receptor determination was similar for all 3 ligands. Receptor levels were analyzed with each of the 3 progestins in control cytosols and in 26 mammary carcinoma samples. A good correlation between receptor levels was found although the values of ORG-2058 were somewhat lower, but not significantly. This resulted in a lower proportion of receptor positive samples for ORG-2058 (11/26) compared to R-5020 (13/26) and RU-27987 (14/26). The affinity to the progesterone and to the glucocorticoid receptor, as well as the precision of the Scatchard plot analysis were comparable for the 3 ligands tested. Intra- and interassay variation of receptor determination were also similar. We therefore conclude, that RU-27987 is a suitable ligand to determine progesterone receptor in mammary carcinoma.

Breast Neoplasms↗
PubMed1986

Effect of the antiprogestin RU486 on progesterone production by cultured human granulosa cells: inhibition of the ovarian 3B-hydroxysteroid dehydrogenase.

Recent studies suggest that the antiprogestin RU486 may have a direct effect on human ovarian luteal function. To further examine this possibility, we have studied the effect of RU486 on ovarian steroidogenesis using human granulosa cells obtained from women undergoing in vitro fertilization. RU486 at concentrations of 0.1, 2, 5, 10 and 100 nM was incubated with 10(5) granulosa cells over 72 hours. Significant suppression of progesterone production occurred following treatment of cultured cells with 2, 5, 10, and 100 nM RU486 at 24 hours (p less than 0.05) and 48 hours (p less than 0.01). At 72 hours, significant decreases in progesterone production were observed with 10 nM (p less than 0.05) and 100 nM RU486 (p less than 0.01). The greatest effect of RU486 on progesterone production occurred at 24 hours of incubation (slope = -8.03) compared with 48 (slope = -4.71) or 72 (slope = -2.31) hours (p less than 0.01). Maximal suppression of progesterone production occurred using 10 nM RU486 with no further significant suppression observed with 100 nM RU486. Other steroids (R5020, DHA) failed to suppress progesterone production suggesting that the observed inhibitory effect on progesterone was specific to RU486. To better understand how RU486 decreases progesterone production in granulosa cell cultures, we measured human ovarian 3B-hydroxysteroid dehydrogenase (3BHSD) in the presence and absence of RU486 in vitro. A significant dose-dependent decrease in the activity of 3BHSD was observed at concentrations of RU486 that were equal to or greater than substrate concentration. Taken together, these findings suggest that RU486 may directly affect human ovarian progesterone production through a mechanism that involves a reduction in 3BHSD activity.

3-Hydroxysteroid Dehydrogenases↗