Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “ESTRADIOL”

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 577 records · Page 32Linked to original sources
PubMed1983

Role of decidual luteotropin and prolactin in the control of luteal cell receptors of estradiol.

In pseudopregnant rats, the luteotropic effect of estradiol depends on the presence of prolactin or decidual luteotropin. To determine if prolactin and decidual luteotropin regulate the functions of estradiol by maintaining luteal cell availability of estradiol receptors, decidual tissue was induced on Day 5 of pseudopregnancy. Control rats were hysterectomized on the same day. On Day 8, the rats were injected with 0.4 mg of ergocryptine (ECO) to inhibit prolactin secretion. Control rats were administered the vehicle only. On Day 9, in ECO-treated hysterectomized rats, serum progesterone declined from a control value of 50 +/- 7 to 7 +/- 2 ng/ml. In addition, luteal cell content of cytosolic and nuclear estradiol receptors was reduced by 95% and 48%, respectively. However, serum estradiol levels remained unchanged (vehicle treated: 23 +/- 7 pg/ml; ECO treated: 23 +/- 6 pg/ml). Administration of prolactin (250 micrograms/day, Days 7-9) to hysterectomized rats completely reversed the effect of ECO on serum progesterone levels and estradiol receptor content in both luteal compartments and had no effect on serum estradiol levels. In contrast, suppression of prolactin secretion in decidua-bearing rats had no effect on progesterone synthesis (vehicle treated: 54 +/- 6 ng/ml; ECO treated: 66 +/- 5 ng/ml) nor did it significantly decrease cytoplasmic and nuclear estradiol receptor content in luteal cells. These results suggest that 1) the availability of cytoplasmic receptors limits the biological responses of estradiol and 2) the synergistic luteotropic effect of prolactin or decidual luteotropin and estradiol involves the maintenance of luteal cell estradiol receptors by either prolactin or decidual luteotropin.

Animals↗
PubMed1996

Tyrosine kinase/p21ras/MAP-kinase pathway activation by estradiol-receptor complex in MCF-7 cells.

The mechanism by which estradiol acts on cell multiplication is still unclear. Under conditions of estradiol-dependent growth, estradiol treatment of human mammary cancer MCF-7 cells triggers rapid and transient activation of the mitogen-activated (MAP) kinases, erk-1 and erk-2, increases the active form of p21ras, tyrosine phosphorylation of Shc and p190 protein and induces association of p190 to p21ras-GAP. Both Shc and p190 are substrates of activated src and once phosphorylated, they interact with other proteins and upregulate p21ras. Estradiol activates the tyrosine kinase/p21ras/MAP-kinase pathway in MCF-7 cells with kinetics which are similar to those of peptide mitogens. It is only after introduction of the human wild-type 67 kDa estradiol receptor cDNA that Cos cells become estradiol-responsive in terms of erk-2 activity. This finding, together with the inhibition by the pure anti-estrogen ICI 182 780 of the stimulatory effect of estradiol on each step of the pathway in MCF-7 cells proves that the classic estradiol receptor is responsible for the transduction pathway activation. Transfection experiments of Cos cells with the estradiol receptor cDNA and in vitro experiments with c-src show that the estradiol receptor activates c-src and this activation requires occupancy of the receptor by hormone. Our experiments suggest that c-src is an initial and integral part of the signaling events mediated by the estradiol receptor.

Breast Neoplasms↗
PubMed1980

A comparison of the pharmacokinetic properties of three estradiol esters.

In order to assess the pharmacokinetics properties of estradiol cypionate, valerate and benzoate, the daily plasma levels of estradiol and estrone were analysed in groups of 10, 9 and 10 subjects, respectively, before and during 3 weeks after the intramuscular administration of a single dose of 5.0 mg in 1.0 ml arachis oil. In order to minimize the contribution of endogenous estrogens to the plasma levels, all subjects were receiving a combined oral contraceptive consisting of levonorgestrel (150 micrograms) and ethinyl estradiol (30 micrograms) for three months prior to the study and during the study period. The administration of estradiol cypionate gave significantly lower peak levels of estradiol and estrone than that of the valerate and benzoate. Peak plasma levels of estradiol and estrone were reached in approximately 4 days following the administration of estradiol cypionate and in a significantly shorter time (approximately 2 days) following the administration of both the valerate and benzoate. One hour after the injection of the esters, the average percentage increases in plasma estradiol and estrone levels were significantly higher in the valerate and benzoate groups compared to the subjects receiving estradiol cypionate. The average duration of elevated estrogen levels was shortest in the benzoate group (4-5 days) followed by the valerate (7-8 days) and cypionate (approximately 11 days). In none of the subjects studied were elevated estradiol and/or estrone levels encountered 2 weeks after the injection of the various esters. The data suggests that among the three esters studied, the valerate provides the most predictable pharmacokinetic behaviour.

Adult↗
PubMed2000

Estradiol induces a phasic Fos response in the hippocampal CA1 and CA3 regions of adult female rats.

Previous studies have shown that estradiol induces structural and functional changes in hippocampal CA1 pyramidal cells of the adult female rat. Estradiol increases the density of dendritic spines and axospinous synapses on CA1 pyramidal cells, and increases these cells' sensitivity to NMDA receptor-mediated synaptic input. Curiously, while estradiol effects are observed in CA1 pyramidal cells, the majority of the evidence indicates that these cells lack genomic estradiol receptors. In contrast, genomic estradiol receptors are expressed in at least some hippocampal interneurons in CA1. The goal of the present study was to determine which hippocampal neuronal populations are activated by estradiol, as determined by induction of c-Fos immunoreactivity, as well as the time-course of this activation. We quantified c-Fos expression in each of the major subdivisions of the hippocampus in adult female rats at various time points during the same estradiol treatment regimen known to regulate dendritic spines and synapses on CA1 pyramidal cells. Our results show a phasic estradiol-induced c-Fos response in the pyramidal cell layers of both CA1 and CA3. c-Fos was induced within 2 h of treatment, decreased at 6 and 12 h, and subsequently increased again at 24 h after treatment with estradiol. Double labeling for c-Fos and GAD 65 or GAD 67 suggests that c-Fos is induced primarily in principal cells, though a small proportion of GABAergic cells is also labeled. These estradiol-induced changes in c-Fos expression may reflect phasic neuronal activation and coupling to gene expression, which could be involved in estradiol's effects on excitatory synaptic connectivity in the hippocampus.

Animals↗
PubMed1992

Progestin receptors in substance P-immunoreactive neurons in the hypothalamus of male guinea pigs after behaviorally effective estradiol pulse treatment.

Pulsatile administration of estradiol effectively primes orchidectomized (ORCH) male guinea pigs to display progesterone-facilitated lordosis. In contrast, a single injection of estradiol benzoate (EB) is not behaviorally effective. In ovariectomized female guinea pigs, estradiol pulses induce progestin receptors selectively in substance P neurons in the ventrolateral hypothalamus (VLH), a site at which estradiol primes females to respond behaviorally to progesterone. To test the hypothesis that behaviorally effective estradiol pulses induce progestin receptors selectively in substance P neurons in the VLH in males, ORCH animals received a single injection of EB 40 h before, or two pulses of estradiol-17 beta, 39 and 11 h before perfusion. Colchicine was administered intracerebroventricularly prior to perfusion. The only difference found between the two estradiol treatment groups was a higher number of progestin receptor-immunoreactive (PR-IR) cells in the rostral VLH of estradiol pulse-treated males. There were no significant differences in the number of PR-IR cells in the mid- or caudal VLH, nor in the number of substance P-immunoreactive (SP-IR) neurons in the VLH/ventromedial hypothalamus (VMH) of animals receiving the two estradiol treatments. Furthermore, the percentage of PR-IR cells in the VLH also immunoreactive for SP did not differ between the estradiol pulse- (22%-25%) and the EB-injected animals (22%-32%). These data do not support the hypothesis that administration of behaviorally effective estradiol pulses, as compared to behaviorally ineffective EB injections, induce progestin receptors selectively in substance P neurons in the VLH of male guinea pigs.

Animals↗
PubMed2000

Methoxyestradiols mediate the antimitogenic effects of estradiol on vascular smooth muscle cells via estrogen receptor-independent mechanisms.

Estrogen receptors (ERs) are widely held to mediate the ability of 17 beta-estradiol (estradiol) to attenuate injury-induced proliferation of vascular smooth muscle cells (VSMCs) leading to vascular lesions. However, recent findings that estradiol prevents injury-induced vascular lesion formation in knock-out mice lacking either ER alpha or ER beta seriously challenge this concept. Here we report that the local metabolism of estradiol to methoxyestradiols, endogenous metabolites of estradiol with no affinity for ERs, is responsible for the ER-independent inhibitory effects of locally applied estradiol on rat VSMC growth. These finding imply that local vascular estradiol metabolism may be an important determinant of the cardiovascular protective effects of circulating estradiol. Thus, interindividual differences, either genetic or acquired, in the vascular metabolism of estradiol may define a given female's risk of cardiovascular disease and influence the cardiovascular benefit she receives from estradiol replacement therapy in the postmenopausal state. These findings also imply that nonfeminizing estradiol metabolites may confer cardiovascular protection in both women and men.

2-Methoxyestradiol↗
PubMed1993

Gluconeogenesis in hepatocytes of immature rainbow trout (Oncorhynchus mykiss): control by estradiol.

Estradiol treatment of starving immature rainbow trout dramatically alters the metabolic performance of isolated hepatocytes. One and two weeks postimplantation with estradiol, the rate of de novo glucose synthesis from [14C]alanine is reduced fourfold from 0.4 mumol/g/hr to 0.1 mumol/g/hr, compared with vehicle-injected control fish. After 6 weeks, the rate of glucose production on a gram wet weight basis is identical in both treatment groups, but significantly larger (by 80%) in the estradiol-treated group than in the controls, if expressed normalized to the hepatosomatic index (HSI). Estradiol treatment caused preferential partitioning of alanine carbon into oxidative pathways away from gluconeogenesis, indicated by a significantly lower ratio of glucose production over CO2 production in hepatocytes isolated from estradiol-treated animals. Incorporation of [14C]alanine into acid-precipitable protein is significantly larger in the estradiol-treated group after 2 weeks, and also after 6 weeks, when normalized to the HSI, indicating that part of the protein synthesized in the estradiol-treated groups is vitellogenin. No differences were detected between estradiol-treated animals and control animals in the activities of enzymes associated with gluconeogenesis [phosphoenolpyruvate carboxykinase, fructose 1,6-bisphosphatase (FBPase)] and amino acid metabolism (alanine and aspartate aminotransferases) in the time course investigated (expressed on a wet weight basis). Activities normalized to the HSI are higher in fish implanted with estradiol compared with controls at 2 and 6 weeks. In keeping with the increased potential of hepatocytes for CO2 production from alanine, estradiol treatment doubled and tripled the maximum activity of pyruvate kinase 1 and 2 weeks postimplantation, respectively. Fish were fasted to avoid erratic feeding due to treatments. Superimposed on estradiol actions are effects of starvation: a fourfold increase in the rate of gluconeogenesis, a threefold increase in oxidative flux, and a fivefold increase in the activity of FBPase--all normalized to hepatocyte weight.

Alanine↗
PubMed1994

Quercetin increases the severity of estradiol-induced tumorigenesis in hamster kidney.

Catechol estrogens have been postulated to mediate estradiol-induced kidney tumorigenesis in Syrian hamsters. As part of an examination of this postulate, we studied the influence of quercetin, a polyphenolic flavonoid, on the incidence and severity of estrogen-induced kidney tumors, on the metabolic activation of estradiol to catechol estrogens, and on the inactivation of catechol estrogens by catechol-O-methyltransferase-mediated O-methylation. None of the hamsters treated with 0.3 or 3% quercetin in the diet for 5.7 or 6.5 months, respectively, developed tumors, whereas all animals treated with estradiol developed kidney tumors. The coadministration of estradiol plus 3% quercetin significantly (p < 0.05) increased the mean number of large tumor nodules and the incidence of abdominal metastases over values obtained with hormone treatment alone. The coadministration of estradiol plus 0.3 or 3% quercetin for 16 days increased renal NADPH-dependent estradiol-4- but not estradiol-2-hydroxylase activities by 91 or 73%, respectively, over values obtained with hormone treatment alone. In vitro, quercetin and its structural analog, fisetin, strongly inhibited the catechol-O-methyltransferase-catalyzed O-methylation of 60 microM 4-hydroxyestradiol, with IC50 values of approximately 2-4 microM. Kinetic analyses of the enzyme inhibition by quercetin and fisetin revealed a mixed-type of inhibition (competitive plus non-competitive). Combined treatment of estradiol plus 3% quercetin decreased the rates of kidney catechol-O-methyltransferase-catalyzed O-methylation of 2- and 4-hydroxyestradiol by 34 and 22%, respectively, from values obtained with hormone treatment alone. Rates of hamster liver and kidney microsome-mediated estrogen quinone formation and quinone reduction (redox cycling) in estradiol plus 3% quercetin-treated hamsters were not markedly altered compared to values obtained in estradiol-treated animals. It is concluded that increased rates of formation of 4-hydroxyestradiol combined with an inhibition of the inactivation of this catechol estrogen by catechol-O-methyltransferase may result in elevated levels of this estrogen metabolite, specifically in the hamster kidney, where it may undergo metabolic redox cycling and generate potentially mutagenic free radicals. Thus, the potentiation by quercetin of estradiol-induced tumorigenesis in hamster kidney supports a role of 4-hydroxyestradiol in estrogen-induced carcinogenesis in this species.

Animals↗
PubMedDate not supplied

Pulsed estrogen therapy: pharmacokinetics of intranasal 17-beta-estradiol (S21400) in postmenopausal women and comparison with oral and transdermal formulations.

Pharmacokinetics of estradiol and estrone were assessed in postmenopausal women receiving S21400, a novel 17beta-estradiol formulation administered by nasal route; the results were compared with those obtained with oral and transdermal routes. Thirty six women received three treatments: a specified dose of 17beta-estradiol (100, 300 or 450 microg) given once and as 2 doses, 12 h apart, using three parallel dose groups in a randomised, crossover study. Thereafter, a reservoir patch (50 microg/day of 17beta-estradiol) or a tablet of 2 mg micronised 17beta-estradiol were randomly administered. Plasma concentrations of estradiol and estrone were measured by radioimmunoassays. Following intranasal dosing, estradiol was rapidly absorbed with plasma concentrations reaching maximal values (approximately 1400 pg/ml with a single 300 microg dose) after 10-30 min and returning within 12 h to levels of untreated postmenopausal women. Systemic exposure to estradiol was dose proportional and independent of the treatment regimen. Moreover, the dose of 300 microg gave an estimated 24 h systemic exposure to exogenous estradiol close to that of the 50 microg/day reservoir patch or the 2 mg tablet. The mean estrone to estradiol ratio was similar and 4-fold lower than those with the patch and the tablet, respectively. In conclusion, by this new route for estrogen replacement therapy, the nasal route, the pharmacokinetics of estradiol as S21400 were linear and displayed a 'pulsed' kinetic profile, different from those obtained with the usual routes of administration.

Administration, Cutaneous↗
PubMed2001

Binding of estradiol to synaptosomal mitochondria: physiological significance.

The subsynaptosomal distribution and specific binding of 17beta-estradiol in vitro to mitochondria isolated from presynaptic nerve endings of female rat brain were examined. 17Beta-estradiol is (i) distributed unequally in synaptosomes and mitochondria posses the highest capacity to bind estradiol with respect to the available amount of the hormone. (ii) Estradiol binds specifically to isolated synaptosomal mitochondria. A Michaelis-Menten plot of specific binding was sigmoidal within a concentration range of 0.1-5 nM of added estradiol, with a saturation plateau at 3 nM. Binding of higher estradiol concentrations demonstrated an exponential Michaelis-Menten plot, indicating non-specific binding to mitochondria. Vmax and Km for the sigmoidal-shape range were estimated as 46 +/- 6 fmol of estradiol/mg of mitochondrial proteins and 0.46 +/- 0.07 nM free estradiol respectively. (iii) Estradiol binding is not affected by the removal of ovaries. The results show that inhibition of Na-dependent Ca2+ efflux from mitochondria by estradiol occurs according to an affinity change of the translocator for Na+, at the same estradiol concentrations that show specific binding to mitochondrial membranes. These data imply that physiological concentrations of estradiol, acting on mitochondrial membrane properties, extragenomically modulate the mitochondrial, and consequently the synaptosomal content of Ca2+, and in that way exert a significant change in nerve cell homeostasis.

Animals↗
PubMed2002

[Are the acute effects of transdermal estradiol in postmenopausal women with coronary disease related to changes of the autonomic tone?].

The single application of estradiol in postmenopausal women with symptomatic coronary heart disease has an antiischemic effect, which seems to be mainly related to the relaxation of the vascular smooth muscle. Longterm replacement with estrogen in postmenopausal women reduces their increased sympathetic activity. The aim of the double-blinded study was to assess whether a single transdermal estradiol administration also has an effect on the sympathovagal balance and may additionally explain the acute effects of estradiol. Methods Fifteen women with symptomatic and angiographically proven coronary artery disease were cross-over randomized to two 100-microgram patches of estradiol or identical placebo. After one week the women received the opposite treatment. One day after patch application a 24-hour Holter-ECG recording was performed to assess the mean heart rate over 24 hours as well as time domain and frequency domain indices of the heart rate variability. Results The estradiol plasma concentration rose significantly from 354 +/- 176 pmol/l after placebo to 800 +/- 260 pmol/l after estradiol application. Heart rate during placebo was 74 +/- 15 bpm and during therapy 74 +/- 15 bpm. Heart rate variability was not different for time domain indices such as SDNN (estradiol: 64 +/- 31 ms; placebo: 65 +/- 33 ms) or for frequency domain indices such as LF (estradiol: 15.8 +/- 8.0 ms; placebo: 15.3 +/- 9.4 ms) and HF (estradiol: 12.1 +/- 8.5 ms; placebo: 12.9 +/- 9.9 ms). Conclusion A single transdermal application of estradiol did not modify heart rate or heart rate variability of women with coronary artery disease. The modulation of the autonomic tone does not seem to be a relevant mechanism of short-term estradiol effects.

Administration, Cutaneous↗
PubMed2005

Adaptation of estrogen-regulated genes in long-term estradiol deprived MCF-7 breast cancer cells.

First line treatment of hormone dependent breast cancer initially causes tumor regression but later results in adaptive changes and tumor re-growth. Responses to second line treatments occur but tumors again begin to progress after a period of 12???18??months. In depth understanding of the adaptive process would allow the identification of targets to abrogate the development of hormonal resistance and prolong the efficacy of endocrine therapy. We have developed a model system to examine adaptive changes in human MCF-7 breast cancer cells. Upon deprivation of estradiol for a prolonged period of time, a maneuver analogous to surgical oophorectomy in pre-menopausal women and use of aromatase inhibitors in post-menopausal patients, tumor cells adapt and become hypersensitive to estradiol. We reasoned that the expression pattern of multiple genes would change in response to estradiol deprivation and that cDNA microarrays would provide an efficient means of assessing these changes. Accordingly, we examined the transcriptional responses to estradiol in long-term estradiol deprived (LTED) MCF-7 cells with a cDNA microarray containing 1901 known genes and ESTs. To assess the changes induced by long-term estradiol deprivation, we compared the effects of estradiol administration in LTED cells with those in MCF-7 cells, which we had previously reported, and confirmed with real time PCR using the parental and LTED cells. Seven genes and one EST were induced by estradiol in LTED but not in wild type MCF-7 cells, whereas ten genes were down-regulated by estradiol only in LTED cells. The expression of seven genes increased concurrently and five decreased in response to estradiol in both cell types. From these observations, we generated testable hypotheses regarding several genes including DKFZP, RAP-1, ribosomal protein S6, and TM4SF1. Based upon the known functions of these genes and the patterns of observed changes, we postulate that divergent regulation of these genes may contribute to the different biologic responses to estrogen in these cell lines. These results provide targets for further mechanistic studies in our experimental system. Our findings indicate that long-term estradiol deprivation causes expression changes in multiple genes and emphasizes the complexity of the process of cellular adaptation.

Adaptation, Physiological↗
PubMed1985

Pharmacokinetics and pharmacodynamics of transdermal dosage forms of 17 beta-estradiol: comparison with conventional oral estrogens used for hormone replacement.

This open-label, multiple-crossover study compared the pharmacokinetics and pharmacodynamics of transdermal 17 beta-estradiol and two oral forms of estrogen replacement therapy in postmenopausal women. The transdermal systems delivered either 0.025, 0.05, or 0.1 mg/day; oral dosages were 2 mg of micronized 17 beta-estradiol or 1.25 mg of conjugated equine estrogens. Transdermal estradiol provided serum and urinary levels of estradiol conjugates typical of the early follicular phase of the premenopausal woman and an estradiol/estrone ratio that approximated 1. The increments of both serum and urinary estradiol showed dose proportionality. Serum levels of estradiol obtained 24 hours after oral administration of estrogens were in a range similar to the steady-state levels obtained with transdermal estradiol delivery. Oral estrogens, however, induced an excessive rise in estrone to levels far beyond those observed in premenopausal women. Continuous application of transdermal estradiol over 3 weeks did not result in any accumulation of estradiol or estradiol conjugates. After only three doses of oral estrogens, there were signs of retention of estrogens. Suppression of gonadotropins by oral and transdermal administration of estrogens was in a similar range. This observation supports the conclusions that levels of circulating estradiol are relevant to efficacy, and that excessively high levels of estrone after oral administration of estrogens merely represents a nonphysiologic precursor or metabolite pattern.

Administration, Oral↗
PubMed1993

Sustained-release subdermal estradiol implants: a new alternative in estrogen replacement therapy.

OBJECTIVE: This trial was a therapeutic and pharmacokinetic dose-finding study with subdermal implants that showed a constant in vitro daily release rate of estradiol. The aim was to find the daily release rate of estradiol that produces serum estradiol concentrations comparable with those obtained with transdermal estradiol at 0.05 mg/day. STUDY DESIGN: The study was an open crossover comparison of transdermal and subcutaneous delivery systems. Thirty-six postmenopausal (serum follicle-stimulating hormone concentration > 30 IU/L before commencing the study) were treated with transdermal estradiol for 4 weeks. Immediately after this transdermal estradiol delivery was replaced by either one or three estradiol implants. The serum concentrations of estrone, estradiol, follicle-stimulating hormone, and sex hormone-binding globulin were followed up for 8 weeks on implant therapy and compared with those during transdermal estrogen administration. To oppose the estrogen effect on the endometrium, each patient received an intrauterine device releasing a progestin, levonorgestrel. RESULTS: The serum estradiol concentrations achieved with three implants were comparable with those during transdermal administration of estradiol at 0.05 mg/day. Suppression of follicle-stimulating hormone was also better maintained with three implants compared with one. CONCLUSIONS: This study shows that constant release profiles can be achieved with nonbiodegradable estradiol implants. The results suggest that a single application should give sufficient estrogen substitution for more than a year.

Administration, Cutaneous↗
PubMed1990

Induction and inhibition of estradiol hydroxylase activities in MCF-7 human breast cancer cells in culture.

The effects of estradiol, progesterone, and tamoxifen on the activity of estradiol 2- and 16 alpha-hydroxylases were studied in human breast cancer cell cultures using a radiometric assay. After 5 days' exposure to these compounds, incubations in the presence of either [2-3H]estradiol or [16 alpha-3H]estradiol as substrate were carried out. In MCF-7 cells, estradiol (10(-8) M), progesterone (10(-6) M) and tamoxifen (10(-6) M) significantly increased 16 alpha-hydroxylase activity (estradiol; 21% progesterone 10% to 32%; tamoxifen 21% to 31%; P less than 0.01). Synergistic effects were observed when the cells were successively exposed to tamoxifen and progesterone. Simultaneous treatment with tamoxifen plus estradiol or estradiol plus progesterone showed no change from estradiol alone. On the other hand, although estradiol had no direct effects on 2-hydroxylase activity, tamoxifen decreased this enzymatic activity significantly at 10(-6) M (23% to 37%). Progesterone acted synergistically to further decrease this reaction. Treatment with only progesterone caused an increase in 2-hydroxylation. In contrast, a subline of MCF-7 cells with low estrogen receptor levels showed only minimal enzyme-hormone responses. Likewise, treatment of the estrogen receptor-negative MDA-MB-231 human breast cancer cell line with these compounds showed no effects on either 2- or 16 alpha-hydroxylase activity. In the progesterone receptor-rich T47D cell line, estradiol decreased both activities while progesterone increased both.(ABSTRACT TRUNCATED AT 250 WORDS)

Aryl Hydrocarbon Hydroxylases↗
PubMed1993

Effect of protein kinase-C inhibitor on estradiol-induced deoxyribonucleic acid synthesis in rats.

Effect of polymyxin B (PMB, protein kinase C inhibitor) on estradiol-induced thymidine incorporation into uterine DNA was studied in ovariectomized rats. Administration of estradiol to ovariectomized rats enhanced thymidine incorporation to uterine DNA 15-fold. Pretreatment of rats with PMB 1 hour before the administration of estradiol had a dose-dependent inhibitory effect on estradiol induced response. PMB had no effect on the basal levels of thymidine incorporation. The inhibitory effect of PMB was also observed with prostaglandin F2 alpha (PGF2 alpha)-induced thymidine incorporation. Time-course experiments indicate that PMB was effective in alleviating estradiol-induced response when administered 1 hour before or 5 minutes after estradiol administration. However, PMB did not antagonize estradiol-induced response when administered at 2, 4, 8, and 12 hours after estradiol administration. Polymyxin E (PME), which differs from PMB by one conservative amino acid substitution in the ring structure and is devoid of PKC activation, did not decrease estradiol- or PGE2 alpha-enhanced thymidine incorporation. It is concluded that estradiol-induced protein kinase-C activation may play a role in the stimulation of thymidine incorporation into uterine DNA and that this effect occurs within the first 2 hours of estradiol administration.

Animals↗
PubMed1983

Effect of estradiol-17 beta and prostaglandins on rat myometrial gap junctions.

The effects of estradiol-17 beta and indomethacin on myometrial gap junction development, plasma estradiol levels and uterine PGF2 alpha content were evaluated in immature and/or ovariectomized, mature rats. High doses of estradiol stimulated the development of gap junctions in the myometrium of animals from both groups. Concomitant injections of estradiol and indomethacin to ovariectomized rats potentiated the estradiol stimulation of gap junctions. Plasma estradiol levels were lower in ovariectomized rats treated with both estradiol and indomethacin than in animals treated with estradiol alone. Indomethacin also enhanced the uptake and retention of 3H-estradiol into uterine tissues. Uterine PGF2 alpha content of ovarectomized rats was stimulated with the initial injection of estradiol but thereafter, the PGF2 alpha content declined with repeated injections to values lower than that observed in controls. Prostaglandin F2 alpha content in tissues from rats treated with estradiol plus indomethacin were also higher than that observed in rats treated with indomethacin alone, however, the values obtained in both groups were significantly lower compared to those from control animals. These results are consistent with the hypothesis that steroid hormones and prostaglandins regulate myometrial gap junction formation. Regulation of myometrial gap junctions by prostaglandins is discussed with respect to a down regulation of the steroid-receptor mechanism and effects on cyclo-oxygenase or lipoxygenase products.

Animals↗
PubMed1990

Enhanced production of tissue-type plasminogen activator by estradiol in a novel type variant of human breast cancer MCF-7 cell line.

ES-1 cells, which showed a higher sensitivity to the cytocidal action of estradiol were isolated from a human breast cancer MCF-7 cell line. Growth of ES-1 cells was inhibited by a dose of 17-beta estradiol that stimulated the growth of the parental MCF-7 cells. Proteins secreted from MCF-7 and ES-1 cells when cultured with 17-beta estradiol were compared by sodium dodecyl sulfate-containing polyacrylamide gel electrophoresis (SDS-PAGE). Addition of estradiol to culture medium enhanced secretion of a protein of molecular mass of 52 kDa in media for both MCF-7 and ES-1 cell lines, but the secretion of a second 67 kDa protein was enhanced about 10-fold only in ES-1 cells. The analysis by SDS-PAGE of culture medium immunoprecipitated with anti-tissue-type plasminogen activator (t-PA) antibody demonstrated that the band of 67 kDa protein specifically secreted from estradiol-treated ES-1 cells contained t-PA. Zymography assays, quantitative immunoreactive assays, and Northern analysis showed about 5-fold specific increase by estradiol of t-PA with molecular mass of 65-70 kDa in ES-1 but not in its parental MCF-7 cells. Cellular level of the plasminogen activity was also specifically enhanced in ES-1 cells by estradiol, but only a slightly in MCF-7 cells. By contrast, another urokinase-type PA (u-PA) with molecular weight of 55 kDa showed very low level activity in both MCF-7 and ES-1 cell lines in the presence of estradiol. Formation of t-PA mRNA was specifically enhanced in ES-1 cells when ES-1 cells were treated for more than 12 h with 10(-8) M 17-beta estradiol. Estradiol did not elongate the lifetime of t-PA mRNA in ES-1 cells. A unique phenotype of ES-1 cells in response to estradiol is discussed in relation to activating expression of the t-PA gene.

Breast Neoplasms↗