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At least 307 records · Page 17Linked to original sources
PubMed1988

Acquisition of estrogen-dependent progesterone receptors by normal mouse mammary gland. Ontogeny of mammary progesterone receptors.

Progesterone is known to stimulate cell proliferation of normal and neoplastic rodent mammary tissues. Recently we have observed that while progesterone is highly effective in sexually mature mice, no significant effect of progesterone can be demonstrated in immature, pubertal mammary gland. In the case of the adult gland, the mitogenic effects of progesterone appear to be related to the presence of E-dependent progesterone receptors (PgR). By contrast, immature mammary glands lack E-dependent PgR. The purpose of the present studies was to study the ontogeny of E-dependent PgR and the factors that lead to the acquisition of responsiveness to progesterone. The results obtained demonstrate that E-dependent PgR are first detectable at 7 weeks of age. Analysis of changes occurring in the mammary gland around this time indicate that E-dependent PgR are not acquired until the pubertal mammary epithelial growth phase has occurred. Furthermore both the growth phase and acquisition of PgR are dependent upon the presence of the ovaries. Analysis of concentration and subcellular distribution of both PgR and estrogen receptors indicate that there are no differences between pubertal and adult mice that could account for the absence of this estrogenic response and lack of E-dependent PgR in immature mammary gland.

Animals↗
PubMed1988

Transformation of human progesterone receptor in the presence of the progestin (R5020) and the antiprogestin (RU486).

We have examined and compared the binding characteristics and transformation in vitro of human uterine cytosolic progesterone receptor (PR) bound to either the progestin agonist, R5020 or the antiprogestin, RU486. Incubation of cytosol with 5-20 nM [3H]R5020 and [3H]RU486 yielded macromolecular complexes that sedimented in the 4S and 8S regions in 10-35% glycerol gradients. The 8S peaks of radioactivity due to macromolecular-bound [3H]R5020 or [3H]RU486 could be eliminated by a preincubation of the uterine cytosol with 1-2 microM progesterone or RU486. The [3H]R5020 binding in the 4S peak was not competable with either steroid. In contrast, the binding of [3H]RU486 in the 4S peak could be abolished by a pretreatment of uterine cytosol with excess RU486, but not progesterone. Selective fractionation of the cytosol with ammonium sulfate, in the presence of sodium molybdate, eliminated the non-specific 4S [3H]R5020 binder. The thermal (23 degrees C) transformation of the [3H]RU486-receptor complex, as a function of the loss of the area under the 8S peak, appeared to be comparable to that achieved with [3H]R5020-receptor complex. The 8S [3H]RU486 peak was reduced by only 46% compared to the [3H]R5020 peak, which was reduced by 60%. These results demonstrate that in human uterine cytosol, R5020 and RU486 bind in a specific and saturable manner to an 8S PR, which is susceptible to thermal 8S to 4S transformation. In addition, [3H]R5020 also interacts with a nonsaturable 4S macromolecule, whereas the 4S [3H]RU486 binder is saturable and specific for RU486. The above observations indicate the heterogeneity of the steroid binding components present in the human uterine cytosol, and suggest that caution should be taken when interpreting data which shows the presence of different molecular forms of the steroid receptors.

Binding, Competitive↗
PubMed1988

Description and analysis of differential sensitivity to glucocorticoids in Fao cells.

This study shows that the derived hepatoma cell line Fao displays different sensitivities for glucocorticoid induction of tyrosine aminotransferase (TAT), alanine aminotransferase (AAT) and gamma-glutamyltransferase (GGT). This was seen in the different behaviors of nine steroids with respect to these three effects: (1) in the presence of full agonists (dexamethasone or deacylcortivazol), half-maximal induction of GGT occurred at approx 5- to 6-fold higher agonist concentrations than those required for half-maximal induction of AAT and TAT; (2) in the presence of full antagonists (RU 486, R5020, or progesterone) the GGT response induced by an equal agonist concentration was inhibited at concentrations approx 4- to 5-fold lower than those required for an equivalent inhibition of TAT response; (3) in the presence of cortexolone, deoxycorticosterone, 11 beta-hydroxyprogesterone and dexamethasone-3'-oxetanone, there was a partial agonistic effect (30-50%) on TAT and AAT responses, whereas there was a mainly antagonistic effect (very weak agonistic effect: 0-10%) on GGT response; (4) regardless of the steroid or its full or partial agonist activity, a given TAT induction level (50%, for example) always corresponded to the same AAT and GGT induction levels (50 and 10% respectively). We provide evidence showing that the three above-mentioned biological responses are mediated via the same type of glucocorticoid receptor binding site. Consequently, this differential behavior probably originates from a phenomenon occurring after the common steps (activation, translocation) that follow the formation of the steroid-receptor complex. This leads us to propose a model in which this phenomenon is assumed to originate from a difference in the affinities of the activated receptor for the nuclear acceptor sites of the TAT and GGT genes.

Alanine Transaminase↗
PubMed1989

Receptor binding of NBD-labeled fluorescent estrogens and progestins in whole cells and cell-free preparations.

We have studied the interactions of four fluorescent steroid conjugates with either the estrogen or progesterone receptor, both in whole cells and cell-free receptor preparations. The fluorophore, nitrobenzoxadiazole (NBD), was conjugated with a synthetic progestin, with a steroidal estrogen, a non-steroidal estrogen, and with an antiestrogen. With all compounds, receptor-specific binding could be detected by fluorescence measurements following extraction from the protein into an organic solvent. In the native state, however, the NBD-ligand-receptor complex is essentially non-emissive, although these ligands fluoresce strongly when associated with non-specific binders such as albumin. The binding site concentrations and relative affinities determined by fluorescence (after extraction) correspond well with those determined by [3H]estradiol or [3H]R5020 binding to their respective receptors. In T47D breast cancer cells, the NBD-progestin showed receptor-mediated uptake and nuclear localization. These compounds have provided valuable information about the interactions of low and medium affinity ligands with their receptors; however, the successful use of fluorescent ligands for detecting steroid receptors under native-bound conditions, by "imaging" modalities (fluorescence microscopy and flow cytometry) will require the development of fluorophores that are emissive while receptor bound or assay protocols that enable the environment of ligands associated with the receptor to be controlled.

Affinity Labels↗
PubMed1989

Multihormone regulation of MMTV-LTR in transfected T-47-D human breast cancer cells.

Multihormonal regulation on the long terminal repeat (LTR) region of mouse mammary tumour virus (MMTV) has been studied using T-47-D human breast cancer cells stably transfected with the steroid sensitive LTR-C3 chimaeric gene. The specificity of steroid action on transfected LTR sequences has been compared with regulation of endogenous cellular markers. We conclude that the hormone response element of the LTR can be induced by physiological concentrations of androgen, progestin and glucocorticoid. 17 beta-Oestradiol did not regulate the LTR at physiological levels but an effect was found at 10(-6) M. This effect was not inhibited by antioestrogen nor was it reproduced by the synthetic oestrogen diethylstilboestrol suggesting such effects do not occur via the oestrogen receptor. The antioestrogens tamoxifen and transhydroxytamoxifen do not induce the LTR. No significant steroid competition was found in LTR regulation: whilst oestradiol did not act at physiological concentration it did not interfere with induction by androgen, progestin or glucocorticoid. Such gene regulation did not simply follow receptor status of the cells nor was it reflected in patterns of growth regulation by steroids. The implications of these findings on the mechanism of steroid hormone action are discussed.

Breast Neoplasms↗
PubMed1989

Inhibition of casein synthesis by progestagens in vitro: modulation in relation to concentration of hormones that synergize with prolactin.

We studied the effect of progesterone and its agonist, R 5020, on casein and transferrin production in pregnant rabbit mammary gland explant culture and its modulation by hormones that synergize with prolactin. The glands were obtained from rabbits on days 12-14 of gestation. The progestins had no effect alone, but significantly inhibited ovine and porcine prolactin stimulation of casein synthesis in a dose dependent manner. There were no effects on transferrin content of the tissue, demonstrating a specific effect of progesterone on casein synthesis. In approx 15% of the cultures, prolactin stimulated casein production to very high levels and the progestins lost their inhibitory action. Progestins were also ineffective when the tissue was cultured with prolactin and unphysiologically high levels of insulin (5 mg/l) or cortisol (280 nmol/l), which stimulated casein synthesis to higher levels than prolactin alone. The concentration of cortisol used was 10 times higher than the serum levels seen in rabbits at the stage of gestation studied (approx 10 ng/ml) and corresponded to levels seen at the end of gestation, a period when the glands are secreting milk and progesterone serum levels have commenced to decrease. Thus, when the prolactin effect upon casein synthesis had been potentiated, whether spontaneously or through synergism with insulin or corticoids, progestins were unable to inhibit it, as is the case in lactating tissues. The results show that utilization of unphysiological levels of hormones in culture may distort the response of the tissue, masking responses that are clearly seen in vivo.

Animals↗
PubMed1989

Progestins and androgens stimulate lipid accumulation in T47D breast cancer cells via their own receptors.

Using electron microscopy, in the human breast cancer cell line T47D, the synthetic progestin R5020, and 5 alpha-dihydrotestosterone were shown to increase significantly the number of lipid droplets per cell section compared to control cells or estradiol- and dexamethasone-treated cells. Lipid accumulation, as measured by Oil Red O dying and by [2-14C]acetate incorporation, was observed at concentrations as low as 10 pM R5020 and 1 nM 5 alpha-dihydrotestosterone, and was always more abundant after progestin treatment. The progestin antagonist RU486 inhibited, in a dose-dependent manner, lipid accumulation initiated by the two hormones, whereas the androgen antagonist flutamide inhibited only the effect initiated by 5 alpha-dihydrotestosterone. Cytoplasmic lipid droplets accumulation was not observed in the BT20 breast cancer cell line, which contains neither progesterone nor androgen receptors. These results indicate that progestins and androgens increase lipid accumulation by interacting with their own receptor. Chromatographic analysis of [2-14C]acetate labeled lipids showed that R5020 and 5 alpha-dihydrotestosterone enhanced the accumulation of cellular triglycerides at least in part by increasing their synthesis and decreased the quantity of lipids released into the medium. To conclude, we have shown that progestins and androgens, via their own receptor, can induce the same triglyceride accumulation in T47D cells. This effect follows fatty acid synthetase induction and precedes cell growth inhibition, two responses also triggered by progestin and androgen in these cells.

Acetates↗
PubMed1989

Comparative effects of 17 beta-estradiol, progestin R5020, tamoxifen and RU38486 on lactate dehydrogenase activity in MCF-7 human breast cancer cells.

The effects of 17 beta-estradiol (estradiol), synthetic progestin R5020 and their antagonists, tamoxifen (Tam) and synthetic RU38486 on lactate dehydrogenase (LDH) activity in MCF-7 human breast cancer cells during the growth period were studied. A specially developed quantitative cytochemical assay was used; LDH activity is expressed per cell, and is thus independent of the positive and negative growth effects of the hormones and antagonists. Estradiol and R5020 stimulated LDH activity after similar exposures (6-48 h) and the stimuli were concentration dependent over the range 10(-7) M to 10(-10) M. As for the antagonists, RU38486 stimulated LDH activity in much the same way as estradiol and R5020; Tam alone, on the other hand, does not stimulate LDH, but when added to estradiol, Tam inhibits estradiol mediated LDH activation. When present at half-stimulant concentration, estradiol + R5020 and estradiol + RU38486 exhibit additive effects on LDH activity. Thus LDH appears to be an interesting tool for the study of hormone and antagonist effects in MCF-7 breast cancer cells.

Breast Neoplasms↗
PubMed1990

Progestin binds to the glucocorticoid receptor and mediates antiglucocorticoid effect in rat adipose precursor cells.

The binding of progestin and glucocorticoid hormones was examined in the cytosol of rat adipose precursor cells. Progestin binding sites of high affinity and limited capacity were present in the cytosol of adipose precursor cells from female rats, but not from male rats, by using [3H]R5020 as radioligand. Glucocorticoid binding sites of high affinity and limited capacity were present in the cytosol of these cells from both male and female rats by using [3H]dexamethasone and [3H]triamcinolone acetonide as radioligands. The dissociation constants were in the physiological concentration range. Studies of competitive binding showed that progestin could compete with glucocorticoids at glucocorticoid binding sites. In a serum free medium glucocorticoid effect on cellular differentiation, monitored by glycerophosphate dehydrogenase (GPDH), was effectively counteracted by progesterone which by itself had no effect. These results demonstrate that progestin receptor exists only in rat adipose precursor cells from female rats, while glucocorticoid receptor exists in rat adipose precursor cells of both sexes. Glucocorticoid effects on cellular differentiation in these cells are mediated by the glucocorticoid receptor. Progestin binds to the glucocorticoid receptor and antagonizes glucocorticoid effect on cellular differentiation in these cells.

Adipose Tissue↗
PubMed1990

Luteolytic effect of the antiprogestin and antiglucocorticoid agent RU486 in rats.

Ovarian cells of pregnant rats were cultured with synthetic progestins (R5020, R2323), dexamethasone and RU486. Progesterone and 20 alpha-hydroxy-pregn-4-en-3-one (20 alpha-dihydroprogesterone) in the medium were measured by specific radioimmunoassay. Both R5020 and R2323 increased concentrations of these intrinsic progestins. RU486 decreased concentrations of progesterone, however, the addition of R5020 or R2323 counteracted this action. Immature hypophysectomized rats treated with pregnant mare serum gonadotropin (PMS) and human chorionic gonadotropin (hCG) were administered with RU486; the serum levels of progesterone and 20 alpha-dihydroprogesterone tended to decrease. R5020 and R2323 inhibited the effect of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), whereas RU486 did not. Inhibition of the cholesterol side chain cleavage enzyme (CSCC) by RU486 was more marked than that by R5020 or R2323. These results show that RU486 decreases progesterone synthesis in cultured ovarian cells. A part of the mechanism may involve an inhibition of CSCC.

Algestone↗
PubMed1987

Sexual differentiation of mammalian frontal cortex.

The pattern of distribution of the progesterone binding sites was examined in selected nuclei of the brain of male and female rat. In female rats the frontal cortex resulted to be the region with the highest concentration of 3H R5020 binding sites. However, in male rats the same region showed very little progestin binding activity. When female rats were androgenized via neonatal exposure to testosterone, the progestin binding activity of the frontal cortex became similar to that we observed in male rats. The present investigation indicates that sexual differentiation of the rat brain may include also brain regions not clearly involved in sex related functions like the frontal cortex.

Animals↗
PubMed1979

Binding of (3H)R5020 to progesterone receptor and serum contaminants in human endometrium.

The binding of [3H]R5020 to cytosol from human endometrium was utilized to evaluate the concentration of progesterone receptor by means of agar gel electrophoresis, using D-norgestrel as cold competitor. It was observed that radioligand binds predominantly to the receptor, and that serum contaminants such as albumin and corticosteroid-binding globulin do not interfere in the assay procedure.

Binding, Competitive↗
PubMed1986

Characterization of the nuclear progesterone receptor in human uterine leiomyoma.

Progesterone binding components were characterized and measured in the 0.4 M KCl nuclear extract of Premarin-primed human leiomyoma (LM) following progesterone injection (n = 5) using [3H]R5020 as the ligand. The receptor character of the binding was demonstrated by: high specificity for progesterone and R5020 binding, high saturable affinity (Kd approximately 2.5 nM) for R5020, sedimentation coefficient in high salt concentration (approximately 3 S), change of distribution of the receptor after progesterone administration, i.e. an increase in the nuclear and decrease in the cytosolic receptor levels. Similar results were demonstrated in the corresponding myometria and endometria. The characteristics of the nuclear progesterone receptor in all three tissues of the test group were similar to those of the cytosolic progesterone receptor in the test group and in the control group (no treatment before operation, n = 5). These results indicate that the nuclear progesterone receptor in human uterine LM shares similar characteristics to those of the myometrium and endometrium.

Cell Nucleus↗
PubMed1982

Changes in estrogen and progestin receptor binding resulting from retrochiasmatic knife cuts.

Retrochiasmatic frontolateral knife cuts (FLC) or sham operations (Sham) were performed with a Halasz-type knife. All animals were primed with estrogen plus 0.5 mg progesterone (P) and tested for lordosis both before and after surgery. Two weeks after the last test they received estradiol (E2) in Silastic capsules and were sacrificed 2 days later for determination of either nuclear estrogen receptors or cytosol progestin receptor binding in brain and pituitary (PIT). Rats which had received FLC showed significantly lower lordosis quotients relative to Shams, and relative to their own pre-surgery scores. Nuclear E2-receptor binding was significantly reduced in the hypothalamus (HYPO) following FLC, but not in preoptic area (POA) or PIT. No changes in cytosol P-receptor binding were observed in HYPO, POA or PIT following FLC. Our results suggest a positive correlation between the number of hypothalamic E2-receptors and the capacity to display lordosis, and emphasize the importance of anterolateral connections to the HYPO for the progesterone-induced facilitation of lordosis.

Animals↗
PubMed1984

The relationship between heat abbreviation and neural progestin receptors in female rats.

The purpose of this study was to determine whether changes in the levels of neural progestin receptors are associated with mating-induced heat abbreviation in the rat. Mating caused a decrease, 8-10 hr after stimulation, in the duration of sexual receptivity. No difference in the concentration of cytosol progestin receptors was found between mated and nonmated animals 8-10 hr after treatment. Mating caused a statistically significant decrease in the concentration of nuclear progestin receptors at that time. However, this difference was probably not related to heat abbreviation, because no difference in nuclear progestin receptor levels was found between animals mated with vaginal masks and animals mated without masks, while mated-masked animals were found to exhibit significantly higher levels of sexual receptivity than mated-nonmasked animals after treatment. In addition, mating either with or without masks caused a statistically significant increase in serum progesterone levels relative to that measured in nonmated animals. Therefore, it is suggested that mating, even in the absence of cervical-vaginal stimulation, may cause the release of adrenal progestins which, in turn, may influence the rate at which neural progestin receptors accumulate and are processed within cell nuclei. The results of the present study suggest that mating-induced heat abbreviation in the rat is not associated with decreased levels of neural cytosol or nuclear progestin receptors.

Animals↗
PubMed1987

Actions of progestins on estrous behaviour in female rats.

The present study evaluated the facilitative actions of progesterone and the synthetic progestin R 5020 on estrous responsiveness in ovariectomized, estrogen-primed female rats. The dose-response and time-response characteristics of the behavior facilitating actions of both progesterone and R 5020 were measured. The threshold doses for the facilitation of estrous behavior in estrogen-primed female rats were 1 microgram of R 5020 and 100 micrograms of progesterone. These doses of progestins facilitated estrous responsiveness with a similar time course that approached maximum at one hour. To examine the possible mechanism(s) of action of each progestin the synthetic progestin antagonist RU 38486 was used. The inhibitory effects of RU 38486 on estrous behavior facilitated by a threshold dose of progesterone or R 5020 were found to be almost identical. RU 38486 (5 mg) administered 1 hr prior to progesterone or R 5020 suppressed lordosis behavior by 44% and 47% respectively. These results suggest that progesterone and R 5020 facilitate estrous responsiveness through the same mechanism.

Animals↗
PubMed1979

Progesterone receptor in the rat ovary: further characterization and localization in the granulosa cell.

We have recently described a progesterone receptor in the cytosol of ovaries of hypophysectomized, estrogen-primed, immature rats. This progesterone receptor was shown to be a thermolabile, saturable protein, which is specific for progestins (R5020 and progesterone), and elutes at the void volume of a Sephadex G-200 column. In the present study, we performed a more detailed analysis of the biochemical properties of this receptor and examined its cellular localization within the ovary. Treatment of the ovary cytosol with protamine sulfate and N-ethyl maleimide abolishes the specific binding of 3H-R5020, indicating that the receptor is an acidic protein containing cysteine residues necessary for binding. Gel exclusion chromatography shows the progesterone receptor to have a mean Stokes radius of 86 A and a molecular weight of approximately 300,000 daltons. Kinetic analysis indicates that the receptor--R5020 complex dissociates very rapidly, with a t1/2 of 10 minutes. The cytosol of isolated granulosa cells bind 3H-R5020 specifically, demonstrating that the ovarian progesterone receptor is present in the granulosa cell.

Animals↗
PubMed1980

Sodium molybdate increases the amount of progesterone and estrogen receptor detected in certain human breast cancer cytosols.

When sodium molybdate is added at a final concentration of 20 mM, additional 8S and 4S progesterone (3H-R5020) receptor can be detected in the cytosols from a number of human breast cancers. Additional estrogen receptor also could be measured in some cytosols, and a quantitative temperature-dependent conversion of 8S to 4S binding molecules achieved. Sodium molybdate also prevented the loss of binding activity that occurred when cytosols were incubated at 30 degrees in the absence of added estradiol. In addition to increasing the amount of progesterone receptor, and to a lesser extent estrogen receptor that may be detected, elicidation of the mechanism by which this salt stabilized receptors should contribute to further understanding of how cytosol steroid receptor content and function is regulated.

Breast Neoplasms↗