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PubMed2002

Dehydroepiandrosterone and alpha-estradiol limit the functional alterations of rat brain mitochondria submitted to different experimental stresses.

The effects of dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), alpha-estradiol and beta-estradiol on the main functions of purified rat brain mitochondria were investigated in basal conditions and after being submitted to various stresses including anoxia-reoxygenation, uncoupling and apoptosis. In basal conditions, DHEA (1 microM) and alpha-estradiol (1 microM) inhibited the respiratory control ratio (RCR) from 3.1 to 2.3 (25%). After anoxia-reoxygenation, DHEA (1 microM) and alpha-estradiol (1 microM) reversed significantly (P<0.01) the RCR decrease from 1.4 to 2.0 (21.5%) by restoring the state 4. This effect was observed when DHEA was added either before anoxia or before reoxygenation and when alpha-estradiol was added before anoxia. The mitochondrial membranes damaged after the anoxia-reoxygenation were 70 and 50%, respectively, protected by DHEA and alpha-estradiol at 1 microM. They also limited by about 50%, the cytochrome c release induced by the anoxia-reoxygenation. The oxygen consumption of mitochondria in presence of NADH (130 microM) and cytochrome c (5 microM) was significantly inhibited by DHEA and alpha-estradiol with high EC(50) of 30 and 22 pM, respectively. At 1 microM, they also inhibited the 10 microM carbonyl cyanide m-chlorophenylhydrazone-induced uncoupling to about 35% whereas beta-estradiol only decreased it to 9%. Our results indicated that DHEA and alpha-estradiol partly preserved the mitochondrial functions altered by an anoxia-reoxygenation with a concentration-dependent effect. The mechanism involved was independent of the classical genomic effect of steroids, the antioxidant properties but implicated a direct action on the mitochondrial membranes.

Adenosine Triphosphatases↗
PubMed2003

Estradiol inhibits atp-induced intracellular calcium concentration increase in dorsal root ganglia neurons.

Estrogen has been implicated in modulation of pain processing. Although this modulation occurs within the CNS, estrogen may also act on primary afferent neurons whose cell bodies are located within the dorsal root ganglia (DRG). Primary cultures of rat DRG neurons were loaded with Fura-2 and tested for ATP-induced changes in intracellular calcium concentration ([Ca(2+)](i)) by fluorescent ratio imaging. ATP, an algesic agent, induces [Ca(2+)](i) changes via activation of purinergic 2X (P2X) type receptors and voltage-gated Ca(2+) channels (VGCC). ATP (10 microM) caused increased [Ca(2+)](i) transients (226.6+/-16.7 nM, n = 42) in 53% of small to medium DRG neurons. A 5-min incubation with 17 beta-estradiol (100 nM) inhibited ATP-induced [Ca(2+)](i) (164+/-14.6 nM, P<0.05) in 85% of the ATP-responsive DRG neurons, whereas the inactive isomer 17 alpha-estradiol had no effect. Both the mixed agonist/antagonist tamoxifen (1 microM) and specific estrogen receptor antagonist ICI 182780 (1 microM) blocked the estradiol inhibition of ATP-induced [Ca(2+)](i) transients. Estradiol coupled to bovine serum albumin, which does not diffuse through the plasma membrane, blocked ATP-induced [Ca(2+)](i), suggesting that estradiol acts at a membrane-associated estrogen receptor. Attenuation of [Ca(2+)](i) transients was mediated by estrogen action on VGCC. Nifedipine (10 microM), an L-type VGCC antagonist mimicked the effect of estrogen and when co-administered did not increase the estradiol inhibition of ATP-induced [Ca(2+)](i) transients. N- and P-type VGCC antagonists omega-conotoxin GVIA (1 microM) and omega-agatoxin IVA (100 nM), attenuated the ATP-induced [Ca(2+)](i) transients. Co-administration of these blockers with estrogen induced a further decrease of the ATP-induced [Ca(2+)](i) flux. Together, these results suggest that although ATP stimulation of P2X receptors activates L-, N-, and P-type VGCC, estradiol primarily blocks L-type VGCC. The estradiol regulation of this ATP-induced [Ca(2+)](i) transients suggests a mechanism through which estradiol may modulate nociceptive signaling in the peripheral nervous system.

Adenosine Triphosphate↗
PubMed2000

Effects of treatment with 17beta-estradiol on the hypercholesterolemic rabbit middle cerebral artery.

OBJECTIVE: The effects of acute and long-term treatment with 17beta-estradiol on the vasomotor responses of rabbit middle cerebral artery (RMCA) were investigated. METHODS: For 8 weeks, male rabbits consumed standard chow (control group), standard chow+1% cholesterol (cholesterol group) or 1% cholesterol chow+17beta-estradiol (i.m. injection 700 microg per week) (estradiol group). The RMCA was precontracted with high K(+) solution and exposed to agonists. RESULTS: Acute exposure to 17beta-estradiol strongly induced relaxation of the RMCA isolated from either control or cholesterol groups. This effect was endothelium independent. Incubation with 17beta-estradiol shifted the calcium contraction curve to the right. High cholesterol diet impaired the relaxation induced by acetylcholine and did not alter relaxation to sodium nitroprusside or to papaverine. Chronic treatment with 17beta-estradiol restored this impaired relaxation to acetylcholine. This protective effect of estradiol was significantly reduced in the presence of N(omega) nitro-L-arginine methyl ester, a constitutive nitric oxide-synthase inhibitor and was not modified in the presence of aminoguanidine, an inducible nitric oxide-synthase inhibitor. Neither tetrabutylammonium, a blocker of calcium-activated K(+) channels, nor glibenclamide, a blocker of ATP-sensitive K(+) channels, affected concentration-response to acetylcholine in the RMCA of the estradiol group, whereas 4-aminopyridine, a blocker of voltage-dependent K(+) channels strongly inhibited this relaxation. CONCLUSIONS: These results suggest that acute effects of 17beta-estradiol in the RMCA is mediated through blockade of calcium entry into vascular smooth muscle cells, while chronic treatment with this hormone seems to be mediated by release of nitric oxide which activates voltage-dependent potassium channels.

Animals↗
PubMed2001

Effect of estradiol valerate alone or in association with cyproterone acetate upon vascular function of postmenopausal women at increased risk for cardiovascular disease.

OBJECTIVES: a large body of evidence has been accumulated suggesting that impairment of vascular endothelial function is an initial step in the development of atherosclerosis. Recent studies have shown that estrogen replacement therapy in postmenopausal women (PMW) improves endothelium-dependent, flow-mediated dilatation (FMD) while the cyclical adjunct of a progestin may reverse this effect. METHODS: the purpose of this study was to evaluate endothelium-dependent, FMD in the brachial artery and the plasma levels of Endothelin-1 in menopausal females treated with estradiol valerate with and without cyclical cyproterone acetate in 20 PMW (mean age 64+/-6 years) with more than one risk factor for coronary artery disease. After a baseline evaluation, PMW entered a double-blinded, placebo controlled single cross-over study and were randomized to receive either estradiol valerate (2 mg) for 21 days or estradiol valerate (2 mg) for 11 days and estradiol valerate (2 mg) and cyproterone acetate (1 mg) for 10 days. Patients were crossed-over the complementary treatment 7 days after completing the first treatment phase. The study of forearm blood flow was repeated at the end of each treatment period. RESULTS: estradiol valerate significantly increased FMD as compared with baseline (12+/-3 vs. 7+/-4%, P<0.01) the adjunct of cyproterone acetate did not affect the effect of estradiol valerate upon FMD (12+/-3 vs. 11+/-4%, P=NS). Similarly reactive hyperemic flow increased after estradiol valerate alone (24%) or in association with cyproterone acetate (24%) compared with baseline. Plasma levels of Endothelin-1 were significantly reduced by estradiol valerate alone or in association with cyproterone acetate. CONCLUSIONS: in conclusion hormone replacement therapy with estradiol valerate and cyproterone acetate improves endothelial function and reduces plasma levels of Endothelin-1 in PMW at risk of coronary artery disease. These effects may be relevant for cardioprotection.

Brachial Artery↗
PubMed1997

Estradiol delivery by vaginal rings: potential for hormone replacement therapy.

OBJECTIVES: To determine if delivery of estradiol from elastomeric vaginal rings gives estradiol blood levels in the range associated with effective estrogen replacement therapy and to determine the relation between in vitro estradiol release from the rings and blood levels in vivo. Secondary objectives related to changes in lipoprotein cholesterol, changes in climacteric symptoms, and evaluation of acceptability to users. METHODS: Three ring variants releasing approximately 100, 150 and 200 micrograms/day of estradiol in vitro were used through 22 days in 21 postmenopausal women, 7 on each dose levels. Blood samples for measurement of estradiol were taken at 3-4 day intervals. Lipoprotein cholesterol was measured before and at the end of treatment. Women were questioned about climacteric symptoms and about their satisfaction with the ring. RESULTS: Mean serum estradiol levels for the three groups of rings were 63 +/- 6, 94 +/- 5 and 136 +/- 13 pg/ml for the 100, 150 and 200 micrograms/day rings, respectively. FSH levels declined during ring use and the maturation values of cells collected on vaginal swabs markedly increased. Total and LDL cholesterol were significantly reduced and HDL cholesterol was not significantly changed. All women reported relief of postmenopausal symptoms. Vaginal discomfort during the first 3 days of use was reported by 12 women but overall satisfaction with the method was high. CONCLUSIONS: Women using the vaginal rings attained estradiol blood levels compatible with control of climacteric symptoms and bone loss. The relation between in vitro estradiol release and blood levels in vivo was essentially identical for all 3 doses. The use of vaginal rings to deliver estradiol for hormone replacement therapy is judged to merit further evaluation.

Administration, Intravaginal↗
PubMed2000

Efficacy and tolerability of a new 7-day transdermal estradiol patch versus placebo in hysterectomized women with postmenopausal complaints.

OBJECTIVES: To investigate the efficacy and tolerability of a continuously applied 7-day-Estradiol patch (Fem7, Merck KGaA, Germany) delivering 50 microg estradiol per day in the treatment of hysterectomized women with postmenopausal complaints compared with placebo. DESIGN: A multicentre, randomized, double-blind study with an initial screening phase (phase I), a 3-month double-blind placebo-controlled phase (phase II) and a 3-month open follow-up phase (phase III). METHODS: 186 patients were randomized for a 3-cycle placebo-controlled study followed by a 3-cycle open follow-up (total duration; 6 months). The changes in Kupperman Index (primary efficacy variable), hot flushes and urogenital symptom score were studied from baseline to the end of the study. In addition, skin tolerability was assessed and patients were also asked to grade the subjective acceptance of therapy. RESULTS: A reduction in Kupperman Index was observed in both groups, and at each cycle of the placebo-controlled treatment phase the 7-day-Estradiol patch was superior compared with placebo (last value vs. baseline P = 0.0006). From the second treatment week onwards a distinct difference was noted in the reduction of hot flushes from baseline between the 7-day-Estradiol patch group and the placebo group. The difference between the groups was statistically significant for each cycle and at the end of the controlled treatment phase (mean weekly hot flush reduction at the end of the placebo-controlled treatment phase: -32.5 for the 7-day-Estradiol patch vs. -22.0 for placebo, P = 0.0025). The efficacy of the 7-day-Estradiol patch within the application period did not show any difference between days 1-3 and 4-7. Subjective acceptance of the 7-day-Estradiol patch was good and 72.4% of patients who took active medication throughout the study were willing to consider continuing its use. CONCLUSIONS: The 7-day-Estradiol patch is well tolerated and provides effective relief of moderate to severe vasomotor symptoms in hysterectomized women, with a rapid onset of action and 7-day duration of therapeutic effect. Although a placebo effect was observed, the 7-day-Estradiol patch significantly reduced hot flushes and other menopausal symptoms throughout the application period.

Administration, Cutaneous↗
PubMed2003

Microemulsions for topical delivery of estradiol.

Estradiol has been widely used for the treatment of hormonal insufficiencies. Due to its extensive first pass metabolism after oral administration, transdermal administration of estradiol in gels and emulsions has been used to improve its bioavailability, prolong activity and to optimize metabolic profile. The purpose of this study was to investigate microemulsions as delivery systems for estradiol. Various o/w microemulsions were used to deliver estradiol across human abdominal skin in vitro. Trasdermal flux of estradiol was determined using Franz-type diffusion cells and the samples were analyzed by high-performance liquid chromatography (HPLC). The permeation data showed that microemulsion formulations increased estradiol flux 200-700-fold over the control, but permeability coefficients were decreased by 5-18 times. The superior transdermal flux of estradiol was due to 1500-fold improvement in solubilization of estradiol by microemulsions. The results suggest that microemulsions are potential vehicles for improved topical delivery of estradiol.

Adjuvants, Pharmaceutic↗
PubMed2002

17beta-Estradiol inhibits cytokine induction of the human E-selectin promoter.

Estradiol has been shown to decrease levels of the cell adhesion molecule E-selectin in cultured cells and in women on hormone replacement therapy. We set out to determine if the mechanism of estradiol action on E-selectin is at the level of its promoter. It was found that estradiol repressed the cytokine-stimulated induction of luciferase activity driven by the human E-selectin promoter in a reporter plasmid (hE-sel-LUC) in co-transfected human hepatoma cells (Hep G2) and human umbilical cord endothelial cells (ECV-304). Repression by estradiol was dependent on the presence of transfected estrogen receptor (ER) alpha or beta expression vectors. The ER antagonist ICI-182,780 blocked the repression by estradiol, confirming the receptor-dependence of the effect. The intact DNA-binding domain of ERalpha was required for estradiol repression of the cytokine-induced stimulation of the promoter in each cell line as demonstrated by the inability of an ER construct with two point mutations in the DNA-binding domain to inhibit reporter activity. Mutation of the NFK-B site at -94 to -85 within the E-selectin promoter led to less stimulation of hE-sel-LUC by interleukin one beta (IL-1beta). Estradiol did not inhibit this IL-1beta stimulated luciferase activity, indicating that the NFK-B site is necessary for ER-mediated inhibition of this promoter. Mutation of the AP-1 site at -500 to -494 within the E-selectin promoter had no effect on the ability of IL-1beta to stimulate its transcription, and estradiol repressed this activation in an ER-dependent manner with identical efficacy and potency in comparison with the wild-type promoter. Therefore, the E-selectin promoter is down-regulated by estradiol working through either ERalpha or ERbeta and requires the NFK-B site at -94 to -85 within the promoter.

Base Sequence↗
PubMed1997

Mechanism for maintenance of high breast tumor estradiol concentrations in the absence of ovarian function: role of very high affinity tissue uptake.

Breast tumors from postmenopausal women contain levels of estradiol similar to those in premenopausal patients even though serum estradiol levels fall by an order of magnitude upon cessation of ovarian function. The present study sought to examine enhanced uptake from plasma as one potential mechanism for maintenance of high tissue estradiol levels in postmenopausal patients. Accordingly, we used osmotic minipumps to continuously infuse estradiol (E2) at rates producing serum concentrations ranging from pre- to postmenopausal levels for two weeks to oophorectomized Sprague-Dawley rats bearing nitrosomethylurea-induced mammary tumors. We then measured E2 concentrations in various tissues and sera and reasoned that tissue affinities for estradiol could be directly calculated from in vivo measurements by adapting Scatchard analysis to steroid infusion data. Using this method, we demonstrated a very high affinity estradiol binding component with a Kd two orders of magnitude higher (i.e., 0.35 x 10(-12) M) than determined with standard in vitro techniques. A second estradiol binding component with the expected Kd of 1 x 10(-10) M was also present. Estradiol bound to both classes of binding sites could be 98% displaced with diethylstilbestrol within a 6-hr period. In vivo steroid binding off-times calculated from log-linear slopes averaged approximately 60 min. These data demonstrated that the actual E2 binding affinity in target tissues in vivo, especially at low estrogen concentrations, is much higher than usually estimated from standard, in vitro estrogen receptor assays. These observations provide one mechanism to explain why estradiol concentrations remain high in breast cancer tissue from postmenopausal women and consequently can stimulate tumor proliferation.

Animals↗
PubMed1997

17 beta-Estradiol enhances the outgrowth and survival of neocortical neurons in culture.

Results of this investigation demonstrate that exposure to 17 beta-estradiol differentially and significantly regulates cortical nerve cell outgrowth depending on the cortical region. Parietal and occipital neurons treated with 1 nM 17 beta-estradiol showed a greater magnitude of neuronal outgrowth whereas outgrowth of temporal cortex neurons was decreased in the presence of 1 nM 17 beta-estradiol. Frontal cortex neurons showed a consistent enhancement of neuronal outgrowth that did not reach statistical significance. The dose response profile for 17 beta-estradiol regulation of the macromorphological features exhibited a bimodal dose response relationship whereas the dose response profile for 17 beta-estradiol regulation of the micromorphological features exhibited a dose response more characteristic of an inverted V-shaped function. An antagonist to the NMDA receptor antagonist, AP5, abolished the growth promoting effect of 17 beta-estradiol whereas the nuclear estrogen receptor antagonist ICI 182,780 did not. Lastly, neocortical neurons exposed to 17 beta-estradiol exhibited greater viability and survival than control neurons over a two week period. These data indicate that 17 beta-estradiol can enhance the growth and viability of select populations of neocortical neurons and that the growth promoting effects of 17 beta-estradiol can be blocked by an antagonist to the NMDA glutamate receptor and not by an antagonist to the estrogen nuclear receptor.

Animals↗
PubMed1999

Antiarrhythmic effect and its underlying ionic mechanism of 17beta-estradiol in cardiac myocytes.

1. The effects of oestrogens on action potential and membrane currents were examined in single guinea-pig atrial myocytes. 2. 17Beta-estradiol (3-10 microM) shortened the action potential duration without significant changes in the resting membrane potential. E-4031 (1 microM) markedly prolonged the action potential duration and induced early afterdepolarization, and 17beta-estradiol (10 microM) abolished it. 3. When cells were perfused in isoproterenol-containing solution, action potentials due to abnormal automaticity caused by membrane depolarization developed, and were also inhibited by 17beta-estradiol. 4. Under voltage clamp conditions, the voltage-dependent Ca2+ currents consisted of both T-(I(Ca,T)) and L-type (I(Ca,L)). 17Beta-estradiol reduced I(Ca,L) concentration-dependently, while it (10 microM) suppressed I(Ca,T) only by approximately 10%. 17Beta-estradiol did not affect time courses of I(Ca,L) inactivation, but it shifted the steady-state inactivation curve to more negative potentials. 5. 17Beta-estradiol (10 microM) did not affect the time-dependent K+ current (I(K)), referred to as I(Kr) and I(Ks) and inwardly rectifying K+ current. However, 17beta-estradiol (30 microM) or diethylstilbestrol (10 microM) inhibited K+ currents. 6. DES and ethinylestradiol (EES) also suppressed I(Ca,L), but testosterone and progesterone failed to inhibit I(Ca,L) The potency of the inhibitory effect on I(Ca,L) was DES> EES> 17beta-estradiol. 7. 17Beta-estradiol and DES also inhibited the cyclic AMP-enhanced I(Ca,L), but cyclic GMP in the pipette or pretreatment of L-NAME could not block the effects of oestrogen on I(Ca,L). 8 These results suggest that oestrogen specifically has antiarrhythmic effects, possibly by acting the L-type Ca2+ channels. The antiarrhythmic effects of oestrogens may contribute to the cardioprotective actions of oestrogens.

Action Potentials↗
PubMed2005

Acute impairment of contractile responses by 17beta-estradiol is cAMP and protein kinase G dependent in vascular smooth muscle cells of the porcine coronary arteries.

The aim of the present study was to investigate the involvement of adenosine 3',5'-cyclic monophosphate (cAMP) cascade in the acute impairment of contraction by 17beta-estradiol in porcine coronary arteries, and to elucidate the signaling pathway leading to the activation of this cascade by the hormone. Isometric tension was recorded in isolated rings of porcine coronary arteries. The contraction to U46619 was reduced significantly following 30 min incubation with 1 nM 17beta-estradiol or 1 nM isoproterenol. There was no additive effect when 17beta-estradiol and isoproterenol were administered together. The effect of 17beta-estradiol was mimicked by both the cyclic AMP analogue 8-Br-cAMP and the guanosine 3',5'-cyclic monophosphate (cyclic GMP) analogue 8-Br-cGMP. In rings with and without endothelium, the modulatory effect of 17beta-estradiol was abolished by the adenylyl cyclase inhibitor, SQ 22536, but was unaffected by the guanylyl cyclase inhibitor, ODQ. Both the cAMP antagonist Rp-8-Br-cAMPS and the cGMP antagonist inhibitor Rp-8-Br-cGMPS inhibited the effect of 17beta-estradiol. The effect of 17beta-estradiol was unaffected by the protein kinase A inhibitor, KT5720, but was abolished by the protein kinase G (PKG) inhibitor, KT5823, which also abolished the effect of isoproterenol. These data support our earlier findings that 17beta-estradiol (1 nM) acutely impairs contractile responses of porcine coronary arteries in vitro. This acute effect of 17beta-estradiol involves cAMP in vascular smooth muscles and the activation of PKG.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2003

Effect of estradiol on estrogen receptor-alpha gene expression and activity can be modulated by the ErbB2/PI 3-K/Akt pathway.

Epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), and heregulin-beta1 (HRG-beta1), can modulate the expression and activity of the estrogen receptor-alpha (ER-alpha) via the phosphatidylinositol 3-kinase (PI 3-K)/Akt pathway in the ER-alpha-positive breast cancer cell line, MCF-7. Estradiol can also rapidly activate PI 3-K/Akt in these cells (nongenomic effect). The recent study examines whether Akt is involved in the ER-alpha regulation by estradiol (genomic effect). Stable transfection of parental MCF-7 cells with a dominant-negative Akt mutant, as well as the PI 3-K inhibitors wortmannin and LY 294,002, blocked the effect of estradiol on ER-alpha expression and activity by 70-80 and 55-63%, respectively. Stable transfection of MCF-7 cells with a constitutively active Akt mimicked the effect of estradiol. The changes in ER-alpha expression and activity were abrogated in response to estradiol by an arginine to cysteine mutation in the pleckstrin homology (PH) domain of Akt (R25C), suggesting the involvement of this amino acid in the interaction between Akt and ER-alpha. Experiments employing selective ErbB inhibitors demonstrate that the effect of estradiol on ER-alpha expression and activity is mediated by ErbB2 and not by EGFR. Moreover, anchorage-dependent and -independent growth assays, cell cycle and membrane ruffling analyses showed that Akt exerts estrogen-like activity on cell growth and membrane ruffling and that a selective ErbB2 inhibitor, but not anti-ErbB2 antibodies directed to the extracellular domain, can block these effects. In the presence of constitutively active Akt, tamoxifen only partially inhibits cell growth. In contrast, in cells stably transfected with either a dominant-negative Akt or with R25C-Akt, as well as in parental cells in the presence of a selective ErbB2 inhibitor, the effect of estradiol on anchorage-dependent and -independent cell growth was inhibited by 50-75 and 100%, respectively. Dominant-negative Akt inhibited membrane ruffling by 54%; however, R25C-Akt did not have any effect, suggesting that kinase activity plays an important role in this process. Scatchard analysis demonstrated a 67% reduction in estrogen-binding capacity in cells transfected with constitutively active Akt. No change in binding affinity of estradiol to the receptor was observed upon transfection with either Akt mutant. Taken together, our results suggest that estradiol treatment results in binding to membrane ER-alpha and interaction with a heterodimer containing ErbB2, leading to tyrosine phosphorylation. This results in the activation of PI 3-K and Akt. Akt, in turn, may interact with nuclear ER-alpha, altering its expression and activity.

Androstadienes↗
PubMed2000

Nongenomic inhibition of catecholamine secretion by 17beta-estradiol in PC12 cells.

We investigated the effects of 17beta-estradiol, an estrogen, on [(3)H]norepinephrine ([(3)H]NE) secretion in PC12 cells. Pretreatment with 17beta-estradiol reduced 70 mM K(+)-induced [(3)H]NE secretion in a concentration-dependent manner with a half-maximal inhibitory concentration (IC(50)) of 2 +/- 1 microM. The 70 mM K(+)-induced cytosolic free Ca(2+) concentration ([Ca(2+)](i)) rise was also reduced when the cells were treated with 17beta-estradiol (IC(50) = 15 +/- 2 microM). Studies with voltage-sensitive calcium channel (VSCC) antagonists such as nifedipine and omega-conotoxin GVIA revealed that both L- and N-type VSCCs were affected by 17beta-estradiol treatment. The 17beta-estradiol effect was not changed by pretreatment of the cells with actinomycin D and cycloheximide for 5 h. In addition, treatment with pertussis or cholera toxin did not affect the inhibitory effect of 17beta-estradiol. 17beta-Estradiol also inhibited the ATP-induced [(3)H]NE secretion and [Ca(2+)](i) rise. In PC12 cells, the ATP-induced [Ca(2+)](i) rise is known to occur through P2X(2) receptors, the P2Y(2)-mediated phospholipase C (PLC) pathway, and VSCCs. 17beta-Estradiol pretreatment during complete inhibition of the PLC pathway and VSCCs inhibited the ATP-induced [Ca(2+)](i) rise. Our results suggest that 17beta-estradiol inhibits catecholamine secretion by inhibiting L- and N-type Ca(2+) channels and P2X(2) receptors in a nongenomic manner.

Adenosine↗
PubMed2003

17beta-estradiol inhibits the production of RANTES in human keratinocytes.

A chemokine, regulated upon activation, normal T cell expressed and secreted (RANTES) attracts T helper-1 cells and macrophages. The production of RANTES is enhanced in keratinocytes of psoriatic skin lesions, which may contribute to the inflammatory infiltrate. It is known that estrogen regulates the natural course of psoriasis. We examined the in vitro effects of 17beta-estradiol on RANTES production by human keratinocytes. 17beta-estradiol inhibited tumor necrosis factor-alpha or interleukin-1beta-induced RANTES secretion, mRNA expression, and promoter activity in keratinocytes, and these effects of 17beta-estradiol were counteracted by estrogen receptor antagonist ICI 182 780. Two nuclear factor kappaB elements on RANTES promoter were required for tumor necrosis factor-alpha or interleukin-1beta-induced transcription and involved in the inhibition by 17beta-estradiol. 17beta-estradiol inhibited nuclear factor kappaB transcriptional activity, whereas it did not inhibit DNA binding of nuclear factor kappaB or phosphorylation or degradation of the inhibitor of nuclear factor kappaB alpha in tumor necrosis factor-alpha or interleukin-1beta-stimulated keratinocytes. 17beta-estradiol-induced inhibition of nuclear factor kappaB transcriptional activity and RANTES promoter activity was rescued by overexpression of a coactivator cyclic AMP response element-binding protein (CREB) or nuclear factor kappaB p65 but not by steroid receptor coactivator-1 or nuclear factor kappaB p50. The overexpression of CREB-binding protein rescued 17beta-estradiol-induced inhibition of transcription mediated by a chimeric protein, GAL4-p65286-551, which contained GAL4 DNA binding domain fused to C-terminal transactivating domain of p65 (amino acids 286-551). The transfection of estrogen receptor alpha or estrogen receptor beta into estrogen receptor-negative SKBR3 cells resulted in 17beta-estradiol-mediated inhibition of transcription via GAL4-p65286-551. These results suggest that 17beta-estradiol-bound estrogen receptor may inhibit nuclear factor kappaB-dependent transcription of RANTES gene by competing with p65 for limiting amounts of CREB-binding protein.

CREB-Binding Protein↗
PubMed2002

Low circulating estradiol and adrenal androgens concentrations in men on glucocorticoids: a potential contributory factor in steroid-induced osteoporosis.

Reductions in circulating estradiol concentrations could be implicated in the pathogenesis of steroid-induced osteoporosis (SIOP) in men. We assessed serum estradiol and adrenal androgens (dehydroepiandrosterone sulfate [DHEAS] and androstenedione) in 77 men (group A: idiopathic osteoporosis [IOP], n = 38, aged [mean +/- SD] 57.7 +/- 12.1 years; group B: SIOP, n = 39, aged 55.3 +/- 13.1 years). We also studied the relationship between bone mineral density (BMD) and serum estradiol in the group of men with SIOP. In group B, we observed a higher prevalence of low serum testosterone concentrations (<9.0 nmol/L) (P =.0052), which was significantly correlated with steroid dosage (r = -0.42, P =.0089) and estradiol concentrations (r = 0.42, P =.012). There was a significant positive association between BMD at the lumbar spine and serum estradiol (P =.004) in the men with SIOP (group B). A high proportion of subjects had low serum estradiol concentrations (<48 pmol/L) in both groups (group A: 44.7 %, group B: 36 %). Serum adrenal androgens concentrations were also significantly suppressed in group B (serum androstenedione-group A: 4.99 +/- 1.8; Group B: 2.1 +/- 1.6 nmol/L; P =.0001). Serum DHEAS was undetectable in 59% of patients in group B versus 6% in group A (P =.001). Reductions in androstenedione also correlated with steroid dosage (r = -0.35, P =.01). In conclusion, the data show that adrenal androgens synthesis is markedly suppressed in men with SIOP. The clinical relevance of this finding remains to be determined. This study also shows a positive association between serum estradiol and BMD and a high prevalence of low serum estradiol in men with SIOP. Low serum estradiol may contribute to bone loss in men with SIOP.

Adult↗
PubMed1996

Large and small cells of the porcine corpus luteum: differential capacity to secrete estradiol and aromatize exogenous androgen during mid- and late luteal phase.

It has been demonstrated previously that aromatization capacity of luteal cells increased as the luteal phase progresses, suggesting that estradiol secretion by regressing corpora lutea could play an active role in regulation of the estrus cycle. To determine whether a specific luteal subpopulation is responsible for this process, luteal cells collected from mature (8-10 days after ovulation) corpora lutea were separated at unit gravity into small (14-26 microns) and large (26-38 microns) cell types. Aliquots of separated cells were incubated overnight in M199 medium alone (= control) or in medium containing: 10 M-5 T, 10(-6) M or 10(-7) M T or 0.1 x 10(-3) M, 0.5 x 10(-3) M or 1 x 10(-3) M aromatase inhibitor CGS 16949A. Both cell types were capable of estradiol production without the addition of substrates. The endogenous content of estradiol was always higher in large granulosa-derived luteal cells (LC) than in small theca-derived luteal cells (SC), and was higher in the late (LLP) than in the mid-luteal (MLP) phase. Both types of cells responded to testosterone by increasing estradiol secretion. Adding aromatase inhibitor to LC isolated from MLP and LLP decreased testosterone-stimulated estradiol secretion. On the other hand, aromatase inhibitor had no effect on testosterone-stimulated estradiol secretion by SC isolated during MLP, and inhibited testosterone-stimulated estradiol secretion by SC isolated during LLP. These data are the first to show the ability of both populations of porcine luteal cells to aromatize exogenous testosterone. The observed lack of aromatase inhibitor influence upon basal secretion of estradiol by SC separated from mature corpora lutea, and the decrease of testosterone-stimulated estradiol secretion by SC isolated from regressing corpora lutea, indicate that cytodifferentiation during luteinization could cause expression of P450arom in theca-derived luteal cells.

Androgens↗
PubMed1999

The inhibition of low density lipoprotein oxidation by 17-alpha estradiol.

The inhibition of LDL-oxidation by 17-alpha estradiol was assessed in vitro by the determination of the duration of the lag-phase in copper ion-induced oxidation and compared to that of 17-beta estradiol, estriol, and probucol. Addition of 0.2, 0.4, and 1 micromol/l of the test substances prolonged the lag-phase of LDL-oxidation 1.3-(+/-0.09 SD), 1.7-(+/-0.14 SD), and 2.7-(+/-0.25 SD) fold for 17-alpha estradiol; 1.4-(+/-0.14 SD), 1.8-(+/-0.1 SD), and 2.6-(+/-0.16 SD) fold for 17-beta estradiol; 1.1-(+/-0.07 SD), 1.4-(+/-0.11 SD), and 1.6-(+/-0.11 SD) fold for estriol as well as 1.4-(+/-0.14 SD), 1.6-(+/-0.1 SD), and 3.0-(+/-0.21) fold for probucol, thus proving that 17-alpha estradiol is as effective as 17-beta estradiol or similar to probucol and more effective than estriol (n = 6 in all cases). These data demonstrate that 17-alpha estradiol is able to delay LDL-oxidation, hence providing a basis for clinical examination of the protective effects of 17-alpha estradiol against atherosclerosis in patients where hormonal effects of 17-beta estradiol are undesirable.

Antioxidants↗