Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Promegestone”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 649 records · Page 36Linked to original sources
PubMed2001

Transactivation of progestin- and estrogen-responsive promoters by 19-nor progestins in African Green Monkey Kidney CV1 cells.

New and more potent progestins and antiprogestins suitable for reproductive therapy and contraception are currently the target of intensive research. The design of such drugs has been hampered by the complex technology required for screening these compounds at the molecular level. To solve this problem, we developed an in vitro cell system that allows detection of the progestagenic effects of a given compound using a PRE2-TATA-CAT reporter vector transiently introduced in a cell line stably transfected with the rabbit progesterone receptor (PR). The African Green Monkey Kidney CV1 (AGMK-CV1) cell line was chosen because these cells do not express endogenous steroid receptors; the selected clone stably expressing the rabbit PR has been maintained in our laboratory for more than 2 yr without detectable losses in PR content and progestagenic response. The presence and function of the PR were assessed by immunohistochemical and saturation analyses as well as by monitoring transactivation of the PRE2-TATA-CAT reporter gene. In this cell line, the PR is expressed at a concentration of 0.170 fmol/mg of protein, and the receptor is localized within the cell nucleus in either the presence or absence of the potent synthetic progestin R5020. This PR-expressing cell system allowed study of the in vitro progestational activity of several 19-nor progestins. The antiprogestin RU486 inhibited CAT activity induced by R5020; norethisterone (NET), levonorgestrel (LNG), and gestodene (GSD) induced PRE2-TATA-CAT activity at concentrations similar to those of R5020, whereas NET A-ring-reduced metabolites induced CAT activity at an extent lower than (5alpha-NET) or similar (3beta,5alpha-NET) to that of the precursor compound. The PRE2-TATA-CAT induction by 17beta-estradiol was also analyzed and no crossreactivity was detected. However, when the ERE-VitA2-TK-CAT (estrogen-responsive element-vitellogenin A2-thymidine kinase promoter-CAT) reporter vector and the estradiol receptor alpha or beta were cotransfected, CAT activity was induced in the presence of 17beta-estradiol, and NET tetrahydro-reduced derivatives. The results indicate that this AGMK-CV1-PR cell assay system appears to be suitable for measuring the effects of different synthetic progestins at the transcriptional level. In this assay system, NET, LNG, and GSD exhibit potent progestational effects at the transcriptional level. In the particular case of NET, the assay system allowed us to determine that the single or multiple hormonal transcriptional effects of this compound are partially mediated by its A-ring-reduced derivatives.

Animals↗
PubMed2002

The angiogenic factor Cyr61 is induced by the progestin R5020 and is necessary for mammary adenocarcinoma cell growth.

Cyr61 is a secreted pro-angiogenic factor that belongs to an emerging family of growth regulators classified as CCN (CTGF/Cyr61/NOV). Work in our laboratory has focused on sex steroid regulation of Cyr61 and its role in hormonal carcinogenesis. In this study, both Cyr61 mRNA and protein were induced by the progestin, R5020, in T47D mammary adenocarcinoma cells in a dose- and time-dependent fashion. Cyr61 gene induction by R5020 was transcriptionally regulated by progesterone receptor (PR) as the antiprogestin, RU486, and actinomycin D blocked induction completely. Moreover, Cyr61 was upregulated by epidermal growth factor (EGF) but not by R5020 in the PR-MDA-MB-431 mammary adenocarcinoma cell line, underscoring the necessity of PR. The functional significance of progestin induction of Cyr61 in breast cancer cell growth was demonstrated by anti-Cyr61 neutralizing antibodies, which diminished R5020 and EGF-dependent DNA synthesis by 30%. Moreover, anti-Cyr61 neutralizing antibodies reduced the synergistic effects of R5020 and EGF on T47D cell growth by 30%. Accordingly, protein lysates generated from stage II invasive ductal carcinomas (n = 20) were analyzed in order to determine the relevance of Cyr61 expression in the context of breast tumorigenesis. Remarkably, increased Cyr61 protein expression was observed in greater than 50% of primary breast tumor lysates that were progesterone receptor (PR)+ but estrogen receptor negative. Taken together, our data suggest that in addition to its proangiogenic activity, Cyr61 may be a novel mediator of progesterone activity in enhancing growth-factor-driven tumor growth in breast cancer.

Adenocarcinoma↗
PubMed1985

[Studies of progestin specific binding protein in the human prostate (II): The possibility of non-specific binding protein disturbance for the accurate quantitative assay of 4S specific binding protein].

The R5020 specific binding protein in the human prostate was studied to elucidate the cause for the poorer reproducibility of 4S high affinity complex sediment than that of 7-8S high affinity complex sediment. The sucrose density gradient, with a low ionic strength buffer including sodium molybdate, was used. Charcoal assay is one of the most common methods used in steroid receptor studies. However, there is a possibility that the high amount of non-specific binding protein common in the human prostate disturbs the charcoal function which removes the free and also the loosely bound steroids from low affinity protein. In the sucrose density gradient process, charcoal treatment is necessary to obtain the apparent 7-8S peak from the 4S one because 7-8S is covered with huge 4S when the charcoal treatment is not performed. 4S complex is proved to be more sensitive than 7-8S to this form of treatment in this study. In addition, the R5020 specific binding protein is found in not only 7-8S complex but also 4S. The dissociation constant of 4S protein is identified with that in 7-8S in the low range of [3H]-R5020(0.4-5.2 nM) using Scatchard plots, but not in the high range (1.3-10.4 nM). Thus, it seems possible that the high amount of non-specific binding protein disturbs the accurate quantification of specific binding protein in 4S. In conclusion, the poor reproducibility of 4S complex through charcoal treatment is caused by the presence of the high amount of non-specific binding protein in the human prostate.

Animals↗
PubMed1995

Effects of steroid hormones on fibrinolytic system in cultured human endometrial cells.

In a primary human endometrial cell culture, the addition of progesterone resulted in an approximately 2-fold increase in the amount of tissue-type plasminogen activator (t-PA) released into the culture media, with the minimal effective dose being 10(-7) M. In contrast, progesterone significantly reduced the release of urokinase-type PA (u-PA). Endometrial cells are known to release a major PA inhibitor, PAI-1. Progesterone stimulated the release of PAI-1. These observed effects of progesterone seem to be mediated through the progestin receptor in that R5020, a specific ligand for progestin receptor, mimicked the effects of progesterone, and RU486, an antagonist of progesterone, completely eliminated the effects of progesterone. It is notable that estradiol, when added alone or in combination with progesterone, caused no discernible effect on the release of PAs and PAI-1. These results suggest that progesterone is a key hormone in regulating the PA/plasmin system in the human endometrium, thereby playing a pivotal role in implantation and ensuing embryonal development.

Cells, Cultured↗
PubMed1980

Specific progestin binding in vitro by anterior pituitary and brain tissues of male rats.

Using a highly potent synthetic-progestin, R5020 (17 alpha, 21-dimethyl-19-nor-4, 9-pregnadiene-3, 20-dione), the characterization of progestin binding components was attempted in cytosols from the anterior pituitary and various brain tissues of castrated or castrated-adrenalectomized male rats. In both types of operated rats, estrogen administration increased the number of binding sites of R5020 in the anterior pituitary and hypothalamus-preoptic area, but not in the cerebral cortex, amygdala-hippocampus nor in the cerebellum. After incubation of the anterior pituitary cytosol with [3H]-R5020 with or without various unlabeled steroids, a specific progestin binding was found in the 7-8S region with a binding capacity of 250 fmoles/mg protein and equilibrium dissociation constant of 8 nM. A specific progestin binding was also found in the cytosol from hypothalamus-preoptic area sedimenting in the 7S region with a binding capacity of 150 fmoles/mg protein and a dissociation constant of 6 nM. Specific binding components in these tissues were heat-labile and protein in nature. Little or no 7S binding was found in the other brain tissues. Although 4-5S binding in the cerebral cortex and 4S bind ng in the amygdala-hippocampus and cerebellum were found, binding specificity in those tissues was low. It was concluded that the pituitary gland and hypothalamus-preoptic area of male rats contained progestin receptor in their cytoplasms.

Adrenal Glands↗
PubMed1981

Progestin-binding protein in human benign prostatic hypertrophy.

Cytosols from human benign prostatic hypertrophy contained progestin-binding components which bound to R 5020, ORG 2058 and progesterone in high affinity fashion. Most of the protein bound to R 5020 was recovered in the precipitate with 0-30% saturation of ammonium sulfate. The R 5020-binding protein showed sedimentation coefficients of 3.6S and 8.4S, and was eluted in the void volume of a Sephadex G-200 column. This protein was clearly distinguished from the dihydrotestosterone-binding protein by its precipitability by ammonium sulfate, heat stability and susceptibility to delipidization. R 5020 and ORG 2058 binding were markedly inhibited by the addition of R 1881, therefore, most of the binding to progestin in cytosols from the benign prostatic hypertrophy seems to be also the sites for R 1881. Although nuclear extract by 0.4 M KCl showed R 1881 binding, the extract did not contain the R 5020-binding protein, and this suggested that the progestin-binding protein observed in the cytosols does not seem to be the steroid receptor.

Carrier Proteins↗
PubMed1983

Changes in concentration of hypothalamic cytosolic progestin receptors at the initiation of pseudopregnancy in rats.

Pseudopregnancy (psp) can be induced by a single injection of progesterone in cyclic rats and the administration of anti-progesterone serum can block the establishment of psp in cervically stimulated rats. To further investigate neuroendocrine mechanisms for the initiation of either psp or prolactin (PRL) surges in connection with the neurotropic action of progesterone, cytosolic progestin receptors (PRc) were identified and measured in preoptic (POA) and basal hypothalamic (BH) areas. Chronological determinations of PRc concentrations in both areas revealed large fluctuations in the morning of the estrous day but not in the morning of the diestrous day. The differences between the maximal and the minimal PRc concentrations observed were more than 100-fold in POA and 3-fold in BH. Cervical stimulation applied in the afternoon of the proestrous day significantly altered the changing pattern of PRc concentrations in POA but not in BH. One of the two peaks of PRc concentrations in POA was magnified and advanced earlier to 0300 h, and then the 1st PRL surge peaking at 0700 h occurred. This PRL release seemed to stimulate progesterone secretion and an elevation of peripheral progesterone levels coincided with the 2nd peak of PRc concentrations in POA at 0900 h. This coincidence may be a prerequisite for the further continuation of PRL surges. These results strongly suggest that the spontaneous oscillation of the PRc concentration in hypothalamic neurons is involved in the regulation of PRL secretion and that cervical stimulation shifts the phase and changes the amplitude.

Animals↗
PubMed1986

Inhibition of the binding of R-5020 and rat uterine progesterone receptors by long chain fatty acids.

Long chain fatty acids were known to interfere with the binding between rat uterine estrogen receptors and estradiol. The effect of long chain fatty acids on the binding between rat progesterone receptors and 3H-R5020 was studied. The binding was inhibited by palmitic acid, palmitooleic acid, arachidonic acid and docosahexaenoic acid. Docosahexaenoic acid was the strongest inhibitor and palmitic acid was the weakest inhibitor. The inhibitory effect of palmitic acid and arachidonic acid was dose dependent. In rat uterine cytosols, there existed an arachidonic acid binding factor which was distinct from progesterone receptor. The inhibitory mechanisms of long chain fatty acids was not clear, but the inhibitory effect was stronger if the number of carbon atoms increased with the number of double bonds.

Animals↗
PubMed1986

Properties of progestin-binding protein in benign hypertrophic human prostate.

RU 27987 is a new ligand for progesterone receptor and binds in high affinity to nuclei of target tissues of progesterone. Using this compound, progestin-binding components in the benign hypertrophic human prostate were studied, and compared with those examined with R 5020, a conventional ligand, in the study of progesterone receptor. In cytosols, the binding affinity of RU 27987 was higher than that of R 5020, and the number of maximum binding sites for RU 27987 seemed to be large but correlated well with those of R 5020. The binder for RU 27987 sedimented at 8.6 S, and the binding was specific to progestational steroids, indicating that binding properties of this binder in the cytosols are identical to those for R 5020. Although there was no binding with R 5020 in the nuclear extract, a small amount of specific binding with RU 27987 was detected. However, the cytosol bound with RU 27987 was not retained in DNA Sepharose and no specific binder for RU 27987 in the nuclear extract was observed in a sucrose density gradient centrifugation. From these observations, it was assumed that the nuclear binding observed was attributable to contamination of the cytosolic binder. The results obtained in the present study suggest that the progestin-binding component in the benign prostatic hypertrophy is not the progesterone receptor but a high affinity binder for progestins whose physiological role is not clear at present.

Alpha-Globulins↗
PubMed1988

Effect of phosphatidyl inositol on progesterone receptors in rat uterine cytosol.

It was reported that unsaturated long chain fatty acids, such as arachidonic acid, oleic acid and docosahexaenoic acid inhibit the binding between progesterone and estrogen receptors and steroid hormones. Most of the long chain fatty acids are contained in phospholipids within the cells. The effect of phospholipids on the binding between R5020 and progesterone receptors was studied. Phosphatidyl ethanolamine and sphingomyelin had no effect on binding, but phosphatidyl inositol and phosphatidyl serine inhibited the binding 53% and 34% respectively. The effect of phosphatidyl inositol on the binding between R5020 and progesterone receptors was dose dependent. Scatchard analysis revealed that the addition of phospholipid markedly decreased the number of binding sites from 1398 fmol/mgp to 258 fmol/mgp, but the dissociation constant was little affected.

Animals↗
PubMed2001

Trimegestone: expanding therapeutic choices for the treatment of the menopause.

UNLABELLED: Trimegestone is a novel norpregnane progestin, which has a potent progesterone receptor and very low androgen receptor affinities but no detectable affinity to oestrogen receptor. Trimegestone has been developed for use in conjunction with oestrogen for postmenopausal hormone replacement therapy (HRT). The dose of trimegestone required for endometrial safety was optimised in a dose ranging study. Oral trimegestone was administered at 0.05, 0.1, 0.25 and 0.5 mg/day, days 15 - 28 along with continuous oral micronised oestradiol at 2 mg daily. The majority of women in the four dose groups experienced relief of climacteric symptoms by the end of the third treatment cycle. The incidence of pre-menstrual tension-like symptoms was low and did not differ between the four dose groups. After 6 months of treatment, the bleeding pattern showed a clear dose-dependent modulation such that the higher the dose of trimegestone administered the more predictable was the day of onset of bleeding and the shorter and lighter the bleeding episodes became. This was further confirmed in another study comparing trimegestone in 0.5 and 0.25 mg doses to norethisterone acetate, where women on the 0.5 mg dose experienced more favourable bleeding pattern compared with the lower dose of 0.25 mg or to norethisterone acetate. In the dose ranging study, 96% of endometrial specimens obtained at the end of the study had secretory changes. The lipoprotein profile measured at baseline, 3 and 6 months during the dose ranging study confirmed the fact that trimegestone, irrespective of the dose, did not negate the beneficial effects of oestrogen on lipids. CONCLUSION: trimegestone is an effective and well-tolerated new progestin, which does not negate the beneficial effects of oestrogen on lipids.

Female↗
PubMed2003

Regulation of nuclear receptor and cofactor expression in breast cancer cell lines.

OBJECTIVE: The aim of this study was to compare the expression profile of nuclear receptors (NRs) and cofactors in different breast cancer cell lines as well as their regulation by estradiol, insulin and progestin R5020. METHODS: Expression of NRs and cofactors were determined from MCF-7, T-47D and ZR-75-1 breast cancer cell lines. Multiprobe ribonuclease protection assay and real-time RT-PCR were used to quantitate mRNA levels of steroid receptors, vitamin D receptors (VDR) and retinoic acid receptors (RAR) and cofactors: amplified in breast cancer-1, cyclic AMP response element binding protein (CBP), p300/CBP-associated factor, p300, nuclear receptor corepressor and silencing mediator of repressed transcription. RESULTS: Basal expression levels of NRs and cofactors varied depending on the cell line. Cell line-specific regulation of androgen receptor, estrogen receptor-alpha (ERalpha), RARalpha, RARgamma and VDR expression was observed after estradiol treatment. Likewise, differences in the regulation of ERalpha, RARalpha and VDR expression after R5020 treatment were observed. We did not observe significant regulation of cofactor expression after estradiol, insulin or progestin treatment in any cell line analyzed. CONCLUSIONS: The results showed that not only is the expression profile of the NRs and cofactors cell line specific but also the regulation of NR expression. Thus the determinants of the ligand action (receptor and cofactor expression) varied considerably among different cell clones of the breast cancer cells. This suggested a gradient of NR-ligand sensitivities in the hormone-dependent breast cancers, which produces an additional challenge in developing novel ligands for hormone replacement therapy and breast cancer treatment.

Acetyltransferases↗
PubMed1984

Changes during the menstrual cycle in cytosolic and nuclear concentrations of progestagen receptor in the human Fallopian tube.

[3H]R5020 was bound to cytosolic and nuclear samples of human Fallopian tube with high affinity and specificity. The cytoplasmic and nuclear concentrations of progestagen receptor varied, throughout the menstrual cycle, in the ampulla, isthmus and fimbria. Concentrations were higher at the late proliferative stage of the cycle than at the early proliferative and late secretory stages. A positive linear regression was observed between cytosolic and nuclear progestagen receptor concentrations and plasma oestradiol levels. A negative linear relationship was observed between cytosolic progestagen receptor concentration and plasma progesterone levels during the secretory stages of the menstrual cycle.

Cell Nucleus↗
PubMed2002

Identification of genes differentially regulated by glucocorticoids and progestins using a Cre/loxP-mediated retroviral promoter-trapping strategy.

Glucocorticoids and progestins are two classes of steroid hormone with very distinct biological functions. However, the glucocorticoid receptor (GR) and the progesterone receptor (PR) share many structural and functional similarities. One way that glucocorticoids and progestins can exert different biological effects is through their different abilities to regulate the expression of certain target genes. A strategy employing a retroviral promoter-trap and Cre/loxP-mediated site-specific recombination has been developed to identify genes that are differentially regulated by glucocorticoids and progestins. A mouse fibroblast cell line (4F) stably expressing both GR and PR and containing a single copy of a multifunctional selection plasmid is generated. This line is transduced with a self-inactivating retroviral promoter-trap vector carrying coding sequences for Cre-recombinase (Cre) in the U3 region. Integration of the provirus places Cre expression under the control of a genomic flanking sequence. Activation of Cre expression from integration into active genes results in a permanent switch between the selectable marker genes that converts the cells from neomycin-resistant to hygromycin-resistant. Selection for hygromycin resistance after hormone treatment yields recombinants in which Cre sequences in the U3 region are expressed from hormone-inducible upstream cellular promoters. Because Cre-mediated recombination is a permanent event, the expression of the selectable marker genes is independent of ongoing Cre expression. Thus this system permits the identification of genes that are transiently or weakly induced by hormone.

Animals↗
PubMed1982

Characterization and properties of a progesterone receptor in the uterus of the quokka (Setonix brachyurus).

A progesterone receptor system, with a high specificity for progestins, was detected in the uterine tissue of the marsupial, Setonix brachyurus (quokka), using the synthetic progestin 17 alpha, 21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione (R5020). The apparent equilibrium dissociation constant of the ligand binding to the cytosolic component was 2.2 nmol/l, and to the nuclear component 4.8 nmol/l. Significant loss of binding ability of the receptor occurred when cytosol was pretreated with dextran-coated charcoal. All binding studies were performed, therefore, in the presence of endogenous steroid which was demonstrated to affect the dissociation constant but have no effect on the estimation of the concentration of binding sites. Cytosolic binding was increased sixfold by oestradiol-17 beta treatment in vivo, and the translocation of the bound complex into the nucleus was effected by progesterone. It is suggested that the binding component described plays a role in the action of progesterone on the uterine tissue of the quokka.

Animals↗