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PubMed2005

[Effect of estradiol benzoate on the heat shock protein 70, 90 expressions in endometrial glandular epithelial cell].

OBJECTIVE: To explore the effect of estradiol benzoate on the expressions of heat shock protein (HSP) 70, 90 in endometrial glandular epithelial cell. METHODS: Normal endometrial glandular epithelial cells were isolated, and cultured by enzymolysis method and identified by electron microscopy and immunohistochemical analysis. The normal endometrial glandular epithelial cells were treated with culture medium only, estradiol benzoate (10(-9), 10(-8), 10(-7) or 10(-6) mol/L), estradiol benzoate (10(-9), 10(-8), 10(-7) or 10(-6) mol/L) and antiestrogen ICI 182780 (fulvestrant, faslodex, 1 micromol/L) and ICI 182780 only for 6, 12, 18, 24 hours respectively. The dose- and time-related effect of estradiol benzoate and ICI 182780 on the cell growth was measured by mononuclear cell direct cytotoxicity assay (methyl thiazolyl tetrazolium assay), and that on the expression of HSP70 and HSP90 in normal endometrial glandular epithelial cell in vitro was measured by immunohistochemical analysis and computerized image analysis system. RESULTS: Estradiol benzoate stimulated cell growth in a time- and dose-dependent manner and the effect was attenuated by the antiestrogen ICI 182780. The average cell growth rates of 10(-9), 10(-8), 10(-7), 10(-6) mol/L estradiol benzoate for 24 hours were (170 +/- 9)%, (207 +/- 11)%, (231 +/- 12)%, (257 +/- 10)%, which were significantly higher than those of 6 hours [(117 +/- 13)%, (129 +/- 10)%, (146 +/- 10)%, (176 +/- 6)%, P < 0.05] and that those estradiol + ICI 182780 for 24 hours [(137 +/- 4)%, (145 +/- 10)%, (151 +/- 9)%, (167 +/- 3)%, P < 0.05]. Estradiol benzoate treatment resulted in a time- and dose-dependent increase of the expression of HSP90 and decrease of HSP70 in human endometrial glandular epithelial cell. The expression of HSP90 in 10(-9), 10(-8), 10(-7), 10(-6) mol/L estradiol benzoate for 24 hours were (64.8 +/- 10.7)%, (75.9 +/- 12.6)%, (80.4 +/- 8.2)%, (83.2 +/- 7.6)%, which were significantly higher than that of the control [(28.0 +/- 3.3)%, (29.0 +/- 5.6)%, (29.0 +/- 5.0)%, (30.0 +/- 6.4)%, P < 0.05] and that of estradiol benzoate + ICI 182780 for 24 hours [(28.2 +/- 2.1)%, (29.7 +/- 3.2)%, (35.0 +/- 4.7)%, (34.7 +/- 6.5)%, P < 0.05]. The expression of HSP70 in 10(-9), 10(-8), 10(-7), 10(-6) mol/L estradiol benzoate for 24 hours were (38.4 +/- 5.7)%, (35.3 +/- 4.9)%, (32.5 +/- 3.1)%, (25.3 +/- 6.2)%, which were significantly lower than that of the control. The estradiol benzoate-induced effects on HSP70 levels were not attenuated by the antiestrogen ICI 182780. CONCLUSIONS: The effects of estradiol benzoate on the cell growth and HSP90 expression are estrogen receptor-dependent and the expression of HSP90 may be beneficial to the cell growth. The effect of estradiol on the expression of HSP70 is estrogen receptor-independent and the expression of HSP70 may protect the cell from damage.

Cell Proliferation↗
PubMed1991

Interleukin 1 alpha blocks estradiol-stimulated growth and down-regulates the estrogen receptor in MCF-7 breast cancer cells in vitro.

We studied the effect of interleukin 1 alpha (IL-1 alpha) on estradiol stimulation of cell growth and estrogen receptor (ER) content in MCF-7 human breast cancer cells in vitro to determine if IL-1 alpha altered cellular estradiol responsiveness. We found that IL-1 alpha blocked estradiol-stimulated growth of these cells in a dose-dependent manner (complete antagonism at 1000 units/ml: day 7 mean growth = vehicle, 47.7 micrograms DNA; estradiol 10(-10) M, 95.1; IL-1 alpha/estradiol, 44.6) and at all concentrations of estradiol from 10(-8) to 10(-11) M. IL-1 alpha in combination with trans-hydroxytamoxifen further inhibited estradiol-stimulated growth (vehicle = 44.8 micrograms DNA, estradiol = 108.3, estradiol/trans-hydroxytamoxifen = 47.8, IL-1 alpha/estradiol/trans-hydroxytamoxifen = 3.0, P less than 0.01). Inhibition with trans-hydroxytamoxifen was IL-1 alpha dose dependent (maximum = 97% at 1000 units/ml, P less than 0.01) and estradiol dose dependent (reversible with 10(-8) M estradiol, maximum inhibition at 10(-10) M estradiol). Concomitantly, IL-1 alpha down-regulated ER concentration by 38.0-43.7% (P less than 0.01) as measured by immunoreactivity or Scatchard analysis, respectively. This occurred as early as 3 h without a change in the Kd (vehicle = 0.23 nM, IL-1 alpha = 0.24 nM), persisted for at least 48 h, was dose dependent (maximum, 43.7% at 1000 units/ml, P less than 0.01), and was blocked by cycloheximide. IL-1 alpha, however, did not block estradiol stimulation of progesterone receptor content (vehicle = 221.9, IL-1 alpha = 238.9 fmol/mg protein) and did not block estradiol down-regulation of ER content. Furthermore, IL-1 alpha alone did not alter levels of ER mRNA and did not alter estradiol down-regulation of ER mRNA. These findings indicate that while IL-1 alpha antagonizes estradiol stimulation of growth and reduces ER content, its mechanism may involve other non-estrogen-regulated pathways.

Breast Neoplasms↗
PubMed1990

Induction and repression of specific estradiol sensitive proteins in the rat corpus luteum.

In the pregnant rat estradiol causes luteal cell hypertrophy and a dramatic increase in overall protein synthesis. The aim of this investigation was to determine whether estradiol induces the synthesis of specific proteins in luteal cell subcellular fractions and to examine estradiol-regulated translational products in order to identify a specific protein marker of estradiol action in the corpus luteum. Corpora lutea obtained from day 12 hypophysectomized-hysterectomized pregnant rats treated with or without estradiol (2 cm implant) for 3 days were incubated with Trans35S-label for 8 hours at 37 degrees C in an atmosphere of 95% O2 - 5% CO2. Nuclear, mitochondrial, microsomal and cytosolic subcellular compartments were obtained by differential centrifugation. RNA was extracted and translated using a rabbit reticulocyte lysate reaction mixture. Radiolabeled proteins were separated by SDS-PAGE, visualized by fluorography and quantified by densitometry. Estradiol-treatment significantly increased 35S-amino acid incorporation into luteal proteins. Specific estradiol-induced proteins within cellular fractions included mitochondrial 80, 50, and 32 x 10(-3) Mr proteins; microsomal 100, 80, 32 x 10(-3) Mr proteins; and cytosolic 80, 60, 50 and 14 x 10(-3) Mr proteins. Estradiol-treatment increased the secretion of two proteins (60 and 45 x 10(-3) Mr) while no major estradiol-induced proteins were noted in the nuclear fraction. In vitro translation of mRNA indicated that estradiol markedly enhances the message for a protein with apparent Mr 32 x 10(-3) Mr. The 32 x 10(-3) Mr translated protein appeared as the major estradiol-induced protein in mitochondrial and microsomal fractions. Estradiol also reduced the expression of a 38 x 10(-3) Mr protein (pI 7.0) in the cytosolic compartment. The major estradiol sensitive protein observed in luteal particulate and translation profiles was a 32 x 10(-3) Mr protein with a pI greater than or equal to 8.5. This protein may serve as a potential protein marker of estradiol action in the rat corpus luteum.

Animals↗
PubMed1996

Design and in vivo testing of 17 beta-estradiol-HP beta CD sublingual tablets.

17 beta-Estradiol is almost insoluble in water. The effect of various cyclodextrins and two different polymers, polyvinylpyrrolidone (PVP) and carboxymethylcellulose (CMC), on the aqueous solubility of 17 beta-estradiol was investigated. 17 beta-Estradiol was dissolved in aqueous 50% w/v 2-hydroxypropyl-beta- cyclodextrin (HP beta CD) solution containing 0.25% (w/v) CMC and the dry 17 beta-estradiol-HP beta CD complex formed by lyophilisation of the solution. Sublingual tablets from the dry complex were produced by direct compression. The dissolution of 17 beta-estradiol from tablets containing the drug in a lyophilised HP beta CD complex was determined. For reference the dissolution of 17 beta-estradiol was determined from tablets containing physical mixture of 17 beta-estradiol and HP beta CD or tablets containing 17 beta-estradiol without HP beta CD. Sublingual tablets containing 17 beta-estradiol-HP beta CD in the lyophilised complex demonstrated the fastest dissolution profile and those tablets were selected for further studies in humans. Six postmenopausal women received a sublingual tablet containing 17 beta-estradiol-HP beta CD complex equivalent to 100 micrograms 17 beta-estradiol. Blood samples were collected over a 12 h period and the 17 beta-estradiol plasma concentration was determined. 17 beta-Estradiol was rapidly absorbed from the sublingual tablets, resulting in a peak 17 beta-estradiol plasma concentration of 568 +/- 97 pmol/l 15 min after administration of the tablets, followed by a biphasic elimination.

Administration, Sublingual↗
PubMed1985

Comparison of hepatic impact of oral and vaginal administration of ethinyl estradiol.

The pronounced hepatic impact of oral ethinyl estradiol has been attributed by some to its so-called first-pass effect through the liver as only some 40% of ingested ethinyl estradiol reaches the systemic circulation. Others believe that ethinyl estradiol exerts its hepatic effects because of its chemical composition, specifically its 17 alpha-ethinyl group. In an attempt to resolve this controversy, a study was undertaken to determine whether vaginal administration of ethinyl estradiol can selectively reduce the hepatic effects of oral ethinyl estradiol. To compare the effects of oral and vaginal ethinyl estradiol, a group of postmenopausal subjects received either 5 micrograms of oral and 20 micrograms of vaginal ethinyl estradiol or 10 micrograms of oral and 50 micrograms of vaginal ethinyl estradiol in either sequence, respectively. Oral ethinyl estradiol was four to five times more potent than vaginal ethinyl estradiol. The potency ratios of the oral-vaginal ethinyl estradiol doses required to suppress follicle-stimulating hormone and luteinizing hormone were 4.4 and 3.2 and those to raise sex hormone-binding globulin binding capacity, corticosteroid-binding globulin binding capacity, and high-density lipoprotein cholesterol as well as lower low-density lipoprotein cholesterol were 3.5, 5.0, 4.2, and 4.2, respectively. These essentially equal oral-vaginal route potency ratios for both central nervous system and hepatic effects indicate that vaginal administration of ethinyl estradiol does not selectively reduce its hepatic impact in relation to its central nervous system effects. The pronounced hepatic effects of ethinyl estradiol are therefore attributed to its chemical composition.

Administration, Oral↗
PubMed1995

The effect of monophasic combinations of ethinyl estradiol and norethindrone on gonadotropins, androgens and sex hormone binding globulin: a randomized trial.

The effects of different monophasic combinations of ethinyl estradiol and norethindrone on FSH, LH, sex hormone binding globulin, total testosterone, androstenedione, and dehydroepiandrosterone sulfate levels in non-obese, non-hirsute women were compared. Retrospective analysis of frozen serum from a prospective randomized trial in which women received one of three oral contraceptive pills containing ethinyl estradiol 50 micrograms/norethindrone 1 mg, ethinyl estradiol 35 micrograms/norethindrone 1 mg or ethinyl estradiol 35 g/norethindrone 0.5 mg for nine cycles was conducted. Blood samples were obtained prior to treatment and during the third, sixth and ninth pill cycles. Ethinyl estradiol 50 micrograms/norethindrone 1 mg and ethinyl estradiol 35 micrograms/norethindrone 1 mg suppressed FSH, LH, and total testosterone and increased sex hormone binding globulin to a similar degree. Ethinyl estradiol 35 micrograms/norethindrone 0.5 mg resulted in less suppression of FSH, LH, and total testosterone, but greater elevation of sex hormone binding globulin. Dehydroepiandrosterone sulfate was suppressed to a similar degree with ethinyl estradiol 35 micrograms/norethindrone 1 mg and ethinyl estradiol 35 micrograms/norethindrone 0.5 mg, but ethinyl estradiol 50 micrograms/norethindrone 1 mg resulted in the least suppression of dehydroepiandrosterone sulfate. Ethinyl estradiol 35 micrograms/norethindrone 1 mg caused greater suppression of androstenedione than did the other two oral contraceptives. Oral contraceptive-induced changes in gonadotropins, androgens, and sex hormone binding globulin can be predicted by considering the relative amounts of estrogen and progestin in the pill. When combined with 1 mg of norethindrone, 50 micrograms of ethinyl estradiol did not result in greater suppression of FSH, LH, or total testosterone or in greater elevation of sex hormone binding globulin than did 35 micrograms of ethinyl estradiol.

Adolescent↗
PubMed1993

Specific beta estradiol binding in cartilage and serum from young mice and rats is age dependent.

Various studies have shown a direct effect of beta estradiol on cartilage and bone. Such effects point to the possibility that specific receptors to estradiol exist in the growth plate cartilage as well as in bone. 3H-estradiol specific binding (EB) was therefore investigated in the supernatant of cartilage homogenates from the epiphyses and ribs of young growing mice and rats. High levels of EB were observed in the cytosol fraction of cartilage homogenates in the late fetal stage and in young rats and mice. The EB levels decreased gradually from late fetal stage up to 14 days of age in both groups of animals independent of their sex. Nuclear binding of 3H estradiol was also demonstrated by autoradiography in the chondrocytes of proliferating and hypertrophic zones. Estradiol binding was inhibited by high doses of unlabelled beta-estradiol, but not by alpha estradiol. Binding was also inhibited by tamoxifen and DES but not by testosterone. High levels of estradiol binding (EBS) were also observed in serum from young animals, but not in animals 2 months of age or older. Study of estradiol binding in cartilage and in serum of rats of the same age showed a significant difference in estradiol binding between these two systems. The difference in estradiol binding between serum and cartilage was seen in the response to inhibitors, Scatchard analysis, and temperature dependence. The results of our study imply that there are specific receptors for 17 beta estradiol in growth plate cartilage; they originate from chondrocytes, and their amount decreases with age. The effects of estradiol on endochondral bone growth seems therefore to be receptor mediated.

Aging↗
PubMed1995

Modulation of natural killer cell-mediated cytotoxicity by tamoxifen and estradiol.

BACKGROUND: The nonsteroidal antiestrogenic drug, tamoxifen, inhibits the growth of estrogen receptor-positive tumors by interfering with the growth-stimulatory effect of estradiol. However, there is compelling evidence that tamoxifen treatment also is beneficial for patients with estrogen receptor-negative tumors. The hypothesis that tamoxifen is capable of enhancing the immunologic defense of tumor-bearing hosts was been investigated as a possible method for targeting receptor-negative neoplasms. METHODS: Natural killer (NK) cells in the spleen of female Fisher and Wistar-Furth rats were used against the YAC-1 murine lymphoma target in 51Cr-release assays. The effect of various concentrations of estradiol and tamoxifen (1 nM-1 microM) and of the metabolic inhibitors actinomycin D and cyclohexamide on target-cell killing was investigated. RESULTS: Tamoxifen enhanced and estradiol inhibited killing if applied for the entire 5 hours of the cytotoxic reaction. When applied jointly in this experimental setup, estradiol interfered with the enhancing effect of tamoxifen. Pretreatment of target cells with tamoxifen led to highly significant enhancement of cytotoxicity; estradiol also enhanced target cell killing, but to a lesser extent. After joint treatment, the level of cytotoxicity was comparable with that obtained with tamoxifen alone. Both pharmacologic (100 nM and 1 microM) and physiologic (1 or 10 nM) concentrations of estradiol and equimolar tamoxifen enhanced target cell lysis. However, pharmacological levels of estradiol inhibited effector cells when applied alone or in combination with tamoxifen. Highly significant enhancement of target-cell destruction occurred if both target and effector cells were pretreated with tamoxifen, whereas estradiol treatment of both cell types led to slight enhancement or no effect on cytotoxicity. Treatment of the target cells with actinomycin D or cycloheximide inhibited the lysis of untreated and tamoxifen- or estradiol-exposed cells. Treatment of YAC-1 target cells with tamoxifen or estradiol also enhanced the NK cell-mediated release of the nuclear label, 3H-thymidine, indicating DNA degradation. Similarly treated P815 cells resisted lysis by NK cells, but showed sensitization when the NK cells were stimulated by interleukin-2 for 48 hours before the lytic reaction. Estradiol and tamoxifen changed the kinetics of 3H-thymidine incorporation by YAC-1 cells, but the cells were capable of growing with the highest drug concentrations (1 microM) used in the cytotoxicity experiments. YAC-1 cells have no cytosolic estradiol receptors and are weakly positive for cytosolic progesterone receptors. CONCLUSIONS: These experiments indicate that NK cell-mediated target-cell destruction can be enhanced by tamoxifen primarily through sensitizing the target for lysis. Estradiol also sensitizes the target but inhibits the effector cells simultaneously so that little or no change results in cytolysis. Target-cell sensitization is not mediated by classical estrogen receptors and requires the active metabolic participation of the cells treated. A likely mechanism of this phenomenon is priming the target cell for apoptosis.

Animals↗
PubMedDate not supplied

Influence of estradiol on accessory reproductive organs in the castrated male rat. Effects of bromocriptine and flutamide.

Estradiol partially maintained the weights of the dorsolateral prostate and seminal vesicles in castrated adult male rats. One group of animals received subcutaneous injections of estradiol (0.01 mg/kg) daily, while a second group of animals received estradiol plus bromocriptine (4.0 mg/kg). Changes in weights of accessory reproductive organs were correlated with serum prolactin levels. Estradiol significantly increased serum prolactin levels while concomitant treatment with bromocriptine caused serum prolactin to remain at castrate levels. Bromocriptine slightly decreased, but did not abolish, the effect of estradiol on weights of the dorsolateral prostate and seminal vesicles. To determine if the effect of estradiol was mediated by androgen receptors in the dorsolateral prostate and seminal vesicles, a third group of animals was treated with flutamide. Flutamide, at a dosage (20 mg/kg) that abolished the effects of dihydrotestosterone on the weights of these tissues, produced no alternation of the effects of estradiol. Treatment of animals with a combination of flutamide, bromocriptine, and estradiol did not significantly alter organ weights from the results obtained with bromocriptine and estradiol. Scatchard plot analysis of the effect of estradiol treatment on cytosol binding of estradiol demonstrated increased quantities of estradiol binding in dorsolateral prostate and seminal vesicles which correlated with the changes in weights noted. Although part of the effect of estradiol on regression of male accessory reproductive organs of castrated rats may be mediated by prolactin, the principal effect appears to be a direct action on responsive tissues.

Anilides↗
PubMed1987

Requirement for prostaglandin F2 alpha in 17 beta-estradiol stimulation of DNA synthesis in rabbit endometrial cultures.

We have hypothesized that two of the endogenously synthesized endometrial prostaglandins (PGs), prostaglandin F2 alpha (PGF2 alpha), and prostaglandin E1 (PGE1), play a regulatory role in growth control of the rabbit endometrium. PGF2 alpha increases DNA synthesis and PGE1 inhibits that effect. Primary cultures of rabbit endometrial cells were used to examine the possible role of these PGs in the mechanism of action of 17 beta-estradiol on DNA synthesis. Towards this end, binding, second messenger and DNA synthesis experiments were performed. 17 beta-estradiol stimulation resulted in a time dependent (optimal: approximately 6 h) and 17 beta-estradiol concentration dependent (optimal: approximately 10(-7) M 17 beta-estradiol in phenol red-containing medium) increase in [3H]PGF2 alpha binding. Scatchard type analysis of the binding data revealed an increase in receptor number while the receptor affinity for [3H]PGF2 alpha remained the same as in the control treated cultures. This 17 beta-estradiol stimulated increase in PGF2 alpha receptor allowed a suboptimal concentration of PGF2 alpha (10(-9) M) to increase intracellular levels of inositol polyphosphates, while by itself this concentration of PGF2 alpha caused no significant change in intracellular inositol polyphosphate levels. 17 beta-estradiol, alone among the several studied steroid hormones, could increase [3H]PGF2 alpha binding. Proliferation studies revealed that, in these primary cultures of rabbit endometrium, 17 beta-estradiol could increase DNA synthesis but not in the presence of indomethacin, unless PGF2 alpha was added to the medium at a concentration (10(-10) M) near or above what is normally accumulated in the medium by these cultures. In the absence of 17 beta-estradiol stimulation, addition of these same low concentrations of PGF2 alpha had no effect on DNA synthesis. Apparently, through its effect on the PGF2 alpha receptor, 17 beta-estradiol enhances the PGF2 alpha stimulated DNA synthesis response approximately 100 fold. The DNA synthesis induced by 17 beta-estradiol can be inhibited by PGE1, as can PGF2 alpha-induced DNA synthesis. We propose that 17 beta-estradiol may be mediating its mitogenic effect through an alteration of the prostaglandin agonist:antagonist control of proliferation in rabbit endometrial cultures. In addition we suggest that, if 17 beta-estradiol acts to increase PGF2 alpha, receptors as part of its mode of action, this may be of importance in other tissues possessing both prostaglandin and 17 beta-estradiol receptors.

Animals↗
PubMed1998

Effects of 17 beta-estradiol on serum hormone concentrations and estrous cycle in female Crl:CD BR rats: effects on parental and first generation rats.

The recently passed Food Quality Protection Act of 1996 requires the U.S. EPA to implement screening strategies for endocrine active compounds (EACs) within the next 2 years. Interpreting results from screening tests is complicated by the absence of traditional dietary rodent bioassay data with model estrogenic compounds such as 17 beta-estradiol. Thus, a 90-day/one-generation reproduction study with 17 beta-estradiol was designed to: (1) provide such baseline data; (2) set dose levels for multigeneration reproduction and combined chronic toxicity/oncogenicity studies; and (3) evaluate various mechanistic/biochemical endpoints for inclusion in these follow-up studies. The current article describes the effects of dietary administration of 0, 0.05, 2.5, 10, and 50 ppm 17 beta-estradiol on the serum hormone concentrations and estrous cyclicity of female Crl:CD BR rats and evaluates a sampling strategy for measuring serum hormone levels in cycling female rats. Serum hormones were measured at three time points during a 90-day dietary exposure (1 week, 28 days, and 90 days) and in the F1 generation rats on postnatal day 98. Over the course of the 90-day feeding study for the P1 generation and from postnatal days 21 to 98 for the F1 generation, the estrous cycle was monitored daily in 10 rats/group. In P1 generation rats, dietary administration of 2.5, 10, and 50 ppm 17 beta-estradiol produced a dose-dependent increase in serum estradiol (E2) concentrations at all time points. In contrast, administration of 0.05, 2.5, 10, and 50 ppm 17 beta-estradiol produced a dose-dependent decrease in serum progesterone (P4) concentrations on test day 90, which correlated with an absence of corpora lutea and ovarian atrophy. At 10 and 50 ppm 17 beta-estradiol, serum luteinizing hormone (LH) concentrations were consistently decreased at all time points and were decreased at 2.5 ppm on test day 90. Serum prolactin (PRL) concentrations were increased at 50 ppm 17 beta-estradiol on test day 90. Serum follicle stimulating hormone (FSH) concentrations were either similar to the control levels or minimally changed at all time points. No F1 generation rats were produced at 10 or 50 ppm 17 beta-estradiol. In F1 generation rats, serum E2 concentrations were increased and P4 concentrations were decreased at a dietary concentration of 2.5 ppm 17 beta-estradiol, while serum concentrations of LH, FSH, and PRL were similar to the control. Dietary administration of 17 beta-estradiol at concentrations of 2.5 (both generations) and 10 and 50 ppm (P1 generation only) produced marked effects on the estrous cycle: decreased number of cycles, increased mean cycle length, and decreased number of normally cycling rats. The estrous cyclicity of rats fed 2.5 ppm 17 beta-estradiol appeared more severely affected in rats of the F1 generation than in rats of the P1 generation. Whether this increase in severity is related to an in utero exposure and/or greater mean daily intake of 17 beta-estradiol in the F1 generation rats in the postnatal period is unclear. Another goal of this study was to evaluate whether a single time point sampling strategy using cycling female rats could be used to detect compound-related changes in serum hormone concentrations. In evaluating a sampling strategy for measuring serum hormone levels, it appears that detection of compound-related alterations in serum hormone concentrations can be best detected by sampling during diestrus. Since the stage of the cycle dramatically influences hormone concentrations, large sample sizes (n = 50) are needed if serum hormone measurements are not matched with the stage of the cycle. The data indicate that this strategy of measuring serum hormone concentrations has utility in detecting compound-related effects within the confines of a traditional guideline study (subchronic, chronic, or multigenerational reproduction study).

Animals↗
PubMed1987

Postictal events in amygdala-kindled female rats with and without estradiol replacement.

This study investigated the effect of estradiol on ictal and postictal events in ovariectomized female rats kindled by daily amygdala stimulation during the presence or absence of estradiol replacement. Although ictal components of kindled seizures were not altered by estradiol, several postictal events such as myoclonic jerks were significantly increased by estradiol. Twelve days after kindling, estradiol-replaced rats with electrodes in the basal, lateral, or cortical amygdala nuclei developed brief postictal "bursts" of behavioral and EEG activity which developed into a secondary seizure in some rats. Rats without estradiol never displayed these postictal events. Pretreatment of rats with pentylenetetrazol, 20 mg/kg, 15 days after kindling, resulted in a further increase in the incidence of bursts and secondary seizures in the presence of estradiol; these events were most prominent in rats kindled in the absence of estradiol. Pentylenetetrazol also caused a significant increase in myoclonic jerks in estradiol-replaced rats, and postictal spikes in all rats. A series of five consecutive generalized seizures at 48-h intervals caused an increase in bursts in rats with estradiol replacement, but not in rats without estradiol. The results indicate that estradiol exerts excitatory effects during the postictal period following amygdala-kindled seizures and suggest that multiple regions mediate the postictal effects of estradiol, perhaps depending on the intraamygdala site of kindling stimulations.

Amygdala↗
PubMed1984

Effects of estradiol on myointimal thickenings from catheter injury and on organizing white mural non-occlusive thrombi.

The objective of this present study was to determine the effect of estradiol on the organization of white, mural, nonocclusive thrombus produced with a permanent, indwelling catheter in the abdominal aortae of rabbits and on myointimal thickenings produced by catheter injury but with only transient adhesion of platelets and no thrombosis in the thoracic aorta. Estradiol did not significantly alter the weight of thrombus or myointimal thickenings produced nor did it qualitatively or quantitatively alter Evans Blue uptake by the 7-day myointimal thickenings from injury or alter Evans Blue uptake by the 7-day thrombus. DNA synthesis measured in terms of [3H]thymidine incorporation into biochemical extractable DNA and expressed as dpm/mg DNA was 9 519 for the normal rabbit aortic wall without adventitia; 358 261 for myointimal thickenings including underlying aortic wall without estradiol treatment and 196 336 with estradiol; 55 840 for thrombus without estradiol and 55 250 with estradiol. Expressed as dpm/mg delipidated tissue the values were 62 for the normal rabbit aortic wall; 4 590 for myointimal thickenings without estradiol and 2 037 with estradiol; 1 421 for thrombus without estradiol and 1 403 with estradiol. Estradiol was effective in reducing DNA synthesis in the myointimal thickenings from injury but was not effective in reducing DNA synthesis in the 7-day thrombi. Estradiol significantly increased the influx or retention of [14C]cholesterol found at autopsy in both the organizing thrombi and the myointimal thickenings from injury after an oral dose of 14C-labelled cholesterol was administered 4 days prior to autopsy; however, estradiol did not significantly modify the final cholesterol concentration in the lesions.

Animals↗
PubMedDate not supplied

Estradiol replacement facilitates the acquisition of seizures kindled from the anterior neocortex in female rats.

Estradiol replacement facilitates kindling from a limbic region, the amygdala. This study determined if estradiol also interacts with kindling from a non-limbic region, the anterior neocortex. Ovariectomized female rats with estradiol replacement required 24 +/- 1.6 trials to kindle and accumulated 434 +/- 28 sec of afterdischarge (AD), significantly less than the 38 +/- 2.2 trials and 840 +/- sec in rats without estradiol. Estradiol replacement did not significantly alter the long series of focal cortical seizures preceding generalized seizures in spite of the early appearance of AD in the contralateral amygdala. Estradiol significantly advanced the onset of generalized seizures compared to rats without estradiol (19 +/- 0.6 versus 24 +/- 1.9 trials). Following secondary seizure generalization, estradiol rats rapidly completed late kindled seizure acquisition. In contrast, late kindling in rats without estradiol was slower as reflected by a 3-fold greater number of AD trials and AD seconds to complete kindling compared to rats with estradiol. One factor in the slower late kindling of rats without estradiol was the instability of generalized seizures which frequently regressed to focal or partial responses. The results provide further experimental evidence for a role for estradiol in catamenial epilepsy and suggest that the process of secondarily generalization of seizures is especially sensitive to estradiol.

Animals↗
PubMed2003

Controlled release of estradiol solubilized in carbopol/surfactant aggregates.

The potential of carbopol/surfactant dispersions as solubilizing and controlled release systems of estradiol (a poorly water-soluble drug) was evaluated. The solubilization of estradiol in the dispersions of Carbopol 934 (0.25%) and Pluronic F-127, Tween 80, sodium dodecylsulfate (SDS), or benzalkonium chloride (BkCl) was assessed, by differential scanning calorimetry (DSC) of films obtained by desiccation, as a decrease in estradiol melting temperature and enthalpy. The amounts of estradiol solubilized in carbopol/SDS and carbopol/Tween 80 aqueous dispersions were considerably greater (solubilization capacity: 1.3 and 9 times greater) than in the surfactant alone solutions and up to 100 times greater than in water. High aggregates/water equilibrium partition coefficients of estradiol in carbopol/SDS (1768 M(-1)) and carbopol/Tween 80 (14114 M(-1)) dispersions were found. Carbopol/(1%) SDS/(25 mg/dl) estradiol and carbopol/(0.1%) Tween 80/(5 mg/dl) estradiol dispersions had a pH of around 4, were easy flowing, and showed sustained release for at least 1 week. Estradiol diffusion coefficients were greater when the receptor medium was 0.3-1.0% SDS solution than when it was iso-osmotic NaCl solution or pH 7.5 phosphate buffer. At this pH, a viscoelastic gel is formed on the donor side of the membrane and the drug diffusion slowed down. When the receptor medium contains a surfactant, estradiol release seems to happen as a direct exchange between the carbopol/surfactant aggregates and the receptor surfactant micelles. If no surfactant is in the receptor fluid, estradiol/surfactant complexes migrate towards the receptor. Despite the low viscosity of these dispersions, estradiol diffusion coefficients were in the same order of magnitude as those obtained with a commercially available neutralized ethanol/water carbopol gel of estradiol (60 mg/dl). When the receptor medium had no surfactant, the low affinity of estradiol for water prevented drug diffusion from the commercial formulation. In summary, carbopol/surfactant aggregates act as efficient carriers of hydrophobic drugs; the affinity of estradiol for carbopol/surfactant aggregates, their dissociation, and the diffusivity of estradiol/surfactant complexes being key factors in the control of the drug release process.

Acrylic Resins↗
PubMed2005

17beta-estradiol inhibits outward potassium currents recorded in rat parabrachial nucleus cells in vitro.

Evidence is increasingly accumulating in support of a role for the steroid hormone 17beta-estradiol to modify neuronal functions in the mammalian CNS, especially in autonomic centers. In addition to its well known slowly developing and long lasting actions (genomic), estrogen can also rapidly modulate cell signaling events by affecting membrane excitability (non-genomic). Little, however, is known regarding the mechanism(s) by which 17beta-estradiol produces its rapid effects on neuronal membrane excitability. As potassium channels play a crucial role in cell excitability, we hypothesized that 17beta-estradiol caused excitability by modulating potassium flux through the neuronal cell membrane. We tested this hypothesis by examining the effects of 17beta-estradiol on outward potassium currents recorded in cells from the parabrachial nucleus of rats, in vitro. Bath application of 17beta-estradiol (10-100 microM) reversibly reduced voltage-activated outward potassium currents in a concentration-dependent manner. This effect was mimicked by BSA-17beta-estradiol but not mimicked by 17alpha-estradiol and was significantly reduced by ICI 182,780, a selective estrogen receptor antagonist. The inhibitory effect of 17beta-estradiol was dependent on extracellular potassium concentration, with more profound effects observed at lower concentrations. The 17beta-estradiol-induced inhibition of the outward current was blocked by pretreatment with the potassium channel blockers tetraethylammonium and 4-aminopyridine. The time constants of deactivation of tail currents were decreased by 17beta-estradiol over a range of test potentials (-140 to -80 mV). Finally, the inhibitory effect of 17beta-estradiol on the outward potassium currents was blocked following pre-incubation of slices in lavendustin A, a tyrosine kinase inhibitor. Taken together, these results suggest that 17beta-estradiol acts rapidly at an extracellular membrane receptor to reduce tetraethylammonium- and 4-aminopyridine-sensitive outward potassium currents by accelerating the closure of potassium channels. This may be the ionic basis of 17beta-estradiol-induced enhancement of neuronal excitability.

Animals↗
PubMed2006

Systemic and local administration of estradiol into the prefrontal cortex or hippocampus differentially alters working memory.

The influence of estradiol on learning and memory is dependent on a number of factors. The effects of physiological levels of estradiol on the acquisition of a spatial working memory task mediated by the prefrontal cortex (PFC) and the hippocampus were examined in Experiment 1. Ovariectomized Long-Evans rats received daily injections of estradiol or vehicle were tested on the win-shift version of the radial arm maze. A high dose of estradiol benzoate (5 microg) enhanced acquisition of the task, whereas a low dose of estradiol (0.3 microg) increased the number of errors committed over 17 days of testing. Experiment 2 was conducted to examine site-specific influences of estradiol on spatial working memory in well-trained rats. Saline and estradiol cyclodextrin (0.1 and 0.9 microg) were infused into the prelimbic region of the PFC or dorsal hippocampus 40 min prior to testing on the win-shift task. Infusions of estradiol into both brain areas attenuated saline-infusion disruptions in working memory. Specifically, the higher dose of estradiol facilitated working memory when infused into the PFC, whereas the lower dose of estradiol facilitated performance when infused into the dorsal hippocampus. Moreover, working memory was significantly impaired 24 h after infusions of estradiol into the dorsal hippocampus but not the PFC. These data provide further evidence for the notion that estradiol can dose-dependently alter memory processes and suggest that facilitation or disruptions of working memory by estradiol are site- and time-specific.

Analysis of Variance↗
PubMed2000

Activation of Ca(2+)-independent nitric oxide synthase by 17beta-estradiol in post-ischemic rat heart.

BACKGROUND: Nitric oxide (NO) donors or facilitation of endogenous NO production is cardioprotective. This study sought to determine whether enhanced myocardial NO production might contribute to estrogen-induced cardioprotection. METHODS: Ca(2+)-dependent and Ca(2+)-independent NOS activities (pmol min(-1) mg(-1) protein), NOS protein expression (quantitative immunoblot), cGMP content (pmol mg(-1) protein) and LV work (Joules) were measured in hearts isolated from ovariectomized rats that were either untreated or treated chronically with 17beta-estradiol (0.25 mg, 21 day release formulation). RESULTS: After 14 days, serum levels of 17beta-estradiol were 6+/-1 and 135+/-16 pg ml(-1) in untreated and 17beta-estradiol-treated animals, respectively. After 60 min aerobic working mode perfusion, Ca(2+)-dependent NOS (untreated, 1.47+/-0.36; 17beta-estradiol 1.13+/-0.25) and Ca(2+)-independent NOS (untreated, 0.45+/-0.24; 17beta-estradiol, 0.41+/-0.21) activities, eNOS and iNOS proteins and cGMP content (untreated, 0.64+/-0.08; 17beta-estradiol, 0.76+/-0.12) were not different in the two groups. After 60 min low-flow (0.5 ml min(-1)) ischemia and 30 min reperfusion, Ca(2+)-dependent NOS activities were again similar (untreated, 1.25+/-0.23; 17beta-estradiol, 0.78+/-0.27). However, after reperfusion, Ca(2+)-independent NOS activity (untreated, 0. 39+/-0.10; 17beta-estradiol, 1.36+/-0.36) was 3.5-fold higher (P=0. 008) and cGMP content (untreated, 0.30+/-0.03; 17beta-estradiol, 0. 49+/-0.07) was 1.6-fold higher (P=0.017) in hearts from 17beta-estradiol-treated animals. Although pre-ischemic function was similar, recovery of post-ischemic LV work was 2-fold greater (P=0.024) in the 17beta-estradiol group. CONCLUSION: The ability of ischemia and reperfusion in combination with chronic 17beta-estradiol to increase Ca(2+)-independent NOS activity and cGMP content supports a role for enhanced myocardial NO signaling in 17beta-estradiol-induced cardioprotection.

Animals↗