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PubMed2004

Effects of 17-beta-estradiol treatment of female zebra finches on offspring sex ratio and survival.

Treatment of female zebra finches (Taeniopygia guttata) with 17-beta-estradiol leads to a female-biased sex ratio in their offspring at the age of independence [Horm. Behav. 35 (1999) 135]. It is unclear whether this is due to a bias of the primary sex ratio or to sex-specific survival. We replicated this experiment and found again a significantly higher total number of daughters than sons at independence in the estradiol-treated group. This was due to higher embryonic survival of daughters compared with sons in the estradiol-treated group and the reverse in the control group. There was no effect of the hormone treatment on the primary sex ratio. Treatment with 17-beta-estradiol led to a significantly shorter hatching time and to heavier offspring at day 7 after hatching. This weight was correlated with maternal plasma estradiol levels on the day of the first egg, which were significantly higher in the estradiol-treated group than in the control group. The results do not support the idea that maternal estradiol levels influence the primary sex ratio. They indicate that maternal estradiol differentially affects survival of sons and daughters via an influence on the embryonic environment, possibly enhancing offspring growth.

Animals↗
PubMed2003

Influence of estradiol, stress, and 5-HT2A agonist treatment on brain-derived neurotrophic factor expression in female rats.

BACKGROUND: Estradiol affects neuronal plasticity, mood, and cognition. We examined the effects of the estrous cycle, acute and chronic estradiol treatments on BDNF mRNA expression in the hippocampus and cortex of female rats. The roles of 5-HT2A receptors and of stress on the BDNF mRNA regulation were also explored. METHODS: BDNF mRNA levels were measured using in situ hybridization at proestrus and estrus, and following acute and chronic estradiol treatment of acutely and chronically ovariectomized (OVX) female rats. Some rats were pretreated with 5-HT2A agonist and antagonist, and another group was subjected to two-hour immobilization stress. RESULTS: BDNF mRNA levels in the dentate gyrus and the medial prefrontal cortex were decreased during estrus, when estradiol levels are highest. Acute estradiol treatment decreased hippocampal BDNF mRNA in acutely OVX rats, but neither acute nor chronic estradiol had effect in chronically OVX rats. Estradiol pretreatment reduced the 5-HT2A receptor-mediated cortical upregulation in BDNF mRNA and did not effect the stress-induced down-regulation of BDNF mRNA in the dentate gyrus. CONCLUSIONS: The duration of the estradiol treatment and the duration of the ovarian hormone deprivation are important factors in the regulation of BDNF synthesis and possibly in the functional outcome of estrogen treatment.

Animals↗
PubMed2001

Minimal androgenic activity of a new oral contraceptive containing norethindrone acetate and graduated doses of ethinyl estradiol.

The pharmacokinetics and androgenic activity of Estrostep, a new oral contraceptive providing low-dose estrogen in a graduated sequence with a constant dose of progestin, were characterized in an open-label, nonrandomized study in 17 normally cycling women treated for three cycles with Estrostep. Women received 1 mg of norethindrone acetate daily combined with 20 microg of ethinyl estradiol daily for the first 5 days (1/20), 30 microg of ethinyl estradiol daily for the next 7 days (1/30), and 35 microg of ethinyl estradiol daily for 9 days (1/35). No medication was given for 7 days in each cycle to allow for withdrawal bleeding. Serial blood samples for the measurement of ethinyl estradiol and norethindrone concentrations were collected on days 5, 12, and 21 of the third treatment cycle for the 1/20, 1/30, and 1/35 dose, respectively. Sex hormone-binding globulin (SHBG) and free testosterone were measured at baseline, on day 1 of cycles 2 and 3 (SHBG only), and on days 5, 12, and 21 of cycle 3. Mean steady-state plasma ethinyl estradiol and norethindrone concentrations increased over cycle 3. The increases in ethinyl estradiol concentrations were proportional to dose. The increases in norethindrone concentrations were related to ethinyl estradiol-dependent increases in SHBG concentrations, which were 218%, 253%, and 296% of baseline values on days 5, 12, and 21, respectively. Mean plasma free testosterone concentrations decreased 47%, 60%, and 64% below baseline on days 5, 12, and 21 of cycle 3, respectively. Graduated ethinyl estradiol doses combined with a constant norethindrone acetate dose progressively increase SHBG and decrease free testosterone, which overrides any theoretic concerns of androgenic activity of norethindrone acetate. Although true androgenic activity can be determined only by assessing endpoints such as acne, hirsutism, and lipids in large controlled trials, the observed changes in circulating SHBG and free testosterone concentrations indicate that Estrostep has little, if any, intrinsic androgenic activity.

Adult↗
PubMed2000

Failure of the combination of sequential oral and transdermal estradiol plus norethisterone acetate to affect plasma homocysteine levels.

OBJECTIVE: A high level of plasma homocysteine may be deleterious to vascular health. We therefore compared the effect of combinations of sequential oral and transdermal estradiol plus norethisterone acetate on plasma homocysteine. DESIGN: Prospective, randomized study. SETTING: Outpatient department of obstetrics and gynecology in a university hospital. PATIENT(S): Forty-two healthy, nonsmoking postmenopausal women starting hormone replacement therapy (HRT) to control climacteric symptoms. INTERVENTION(S): In a randomized order, the women started using either oral HRT (2 mg of estradiol on days 1-12, 2 mg of estradiol plus 1 mg of norethisterone acetate (NETA) on days 13-22, and 1mg of estradiol on days 23-28; n = 21) or transdermal HRT (50 microg/d of estradiol on days 1-28 and 250 microg/d of norethisterone acetate on days 15-28, n = 21) for 1 year. MAIN OUTCOME MEASURE(S): Fasting plasma levels of homocysteine were measured before the treatment and during the combined estradiol-plus-NETA phases of the sixth and 12th treatment cycles. RESULT(S): Basal homocysteine levels in the oral group (8.2 +/- 3.1 micromol/L, mean plusmn;SD) and transdermal group (8.7 plusmn; 1.8 micromol/L, mean plusmn;SD) were not affected by the estradiol-plus-NETA combination. CONCLUSION(S): Neither an oral nor a transdermal combination of sequential estradiol and NETA causes significant changes in plasma homocysteine in Finnish postmenopausal women with normal baseline homocysteine levels.

Administration, Cutaneous↗
PubMed2001

Magnitude and variability of sequential estradiol and progesterone concentrations in women using depot medroxyprogesterone acetate for contraception.

OBJECTIVE: To describe the magnitude and variability of sequential serum estradiol and progesterone concentrations throughout one depot medroxyprogesterone (DMPA) injection interval. DESIGN: Prospective study. SETTING: Family planning and women's health clinics. PATIENT(S): Thirty-one women, ages 19 to 46, using DMPA for contraception. INTERVENTION(S): Serum for estrogen and progesterone was collected weekly throughout one DMPA injection interval. MAIN OUTCOME MEASURE(S): Serum estradiol and progesterone concentrations; estradiol patterns produced from data plotted across the entire DMPA injection interval. RESULT(S): The average daily estradiol concentrations ranged from 7.9 to 69.1 pg/mL, with a mean of 18.9 +/- 12.9 and a median of 15.4 pg/mL. Average daily progesterone concentrations ranged from 0.14 to 1.1 ng/mL, with a mean of 0.40 +/- 0.19 ng/mL and a median of 0.36 ng/mL. Two general patterns of estradiol concentrations were identified. One pattern, observed in approximately one third of the participants, reflected estradiol concentrations that were extremely low (mean, 12.7 +/- 3.6 pg/mL; median, 13.4 pg/mL) and consistently flat across the DMPA injection interval. The second pattern, seen in the remaining participants, reflected estradiol concentrations that were higher (mean, 22.2 +/- 14.9 pg/mL; median, 17.3 pg/mL) and quite variable. CONCLUSION(S): This study demonstrated that estradiol concentrations were lower than the 40 to 50 pg/mL reported in most studies and, for the majority of women, varied substantially across the DMPA injection interval.

Adult↗
PubMed1997

The incidence of renal anomalies at full term in fetal rats is synergistically increased by estradiol (but not testosterone) supplementation on day 18 of alcoholic gestation.

BACKGROUND/PURPOSE: Fetal alcohol syndrome is characterized by facial dysmorphology, mental and growth retardation, and somatic anomalies including hydronephrosis. The authors sought to determine the influence of exogenous testosterone or estradiol on the incidence of hydronephrosis in a rodent model of fetal alcohol syndrome (FAS). METHODS: Pregnant rats were fed a liquid diet containing 35% ethanol-derived calories from gestation day 6 through 15, with exogenous testosterone or estradiol supplementation on day 18. On day 20, fetal kidneys were examined for evidence of hydronephrosis, and fetal serum estradiol concentrations were determined by radioimmunoassay. RESULTS: Maternal estrogen supplementation resulted in very high fetal serum estradiol levels that were not additionally increased by alcoholism. Despite this fact, the expression of renal malformations was highest in the alcoholic, estradiol-supplemented offspring. Additionally, the rate of renal malformations was significantly higher in the estrogen-supplemented alcoholic group than in the strictly estradiol animals, yet the fetal serum estradiol concentrations did not differ between the two groups. CONCLUSIONS: This suggests that ethanol may act synergistically with estradiol to increase the rate of renal anomalies including hydronephrosis. Such damage may persist via a suppression of normal testosterone-stimulated renal growth and development. FAS includes significant renal anomalies characterized by hydronephrosis in both animal models and affected children. Although the long-term functional sequelae of hydronephrosis and reflux are well known, the progression of renal disease in FAS children remains to be documented.

Animals↗
PubMed2001

Hydrocortisone modulates the effect of estradiol on endothelial nitric oxide synthase expression in human endothelial cells.

The interaction between hydrocortisone and estradiol on the regulation of endothelial nitric oxide synthase (eNOS) expression was investigated in human umbilical vein endothelial cells (HUVECs). Following incubation in medium containing dextran-coated-charcoal-stripped serum (DCC-stripped medium) for 4 days, incubation of HUVECs with 0.1 nM estradiol for 24 hr in the absence of hydrocortisone increased levels of eNOS mRNA measured by ribonuclease protection assay above control (0 nM estradiol). 2 microM hydrocortisone applied for 24 hr preceding and during estradiol application inhibited the estradiol-elicited increase in eNOS mRNA levels, reducing mRNA levels from 134% +/- 14% of control to 85% +/- 5% of control. Significant (ANOVA, p<0.01) reductions of estradiol-mediated increases of mRNA levels occurred over a range of hydrocortisone concentrations (10 nM, p<0.05; 2 microM, p<0.05; n=3-12). In the presence of 2 microM hydrocortisone, 10 nM estradiol significantly reduced eNOS mRNA levels to 59% +/- 3% of control. The ability of hydrocortisone to block or reverse the estradiol-mediated increase in eNOS mRNA levels may provide a link between elevated hydrocortisone levels and decreased NO production, potentially contributing to the development of hypertension and cardiovascular disease in vivo and antagonizing cardioprotective effects of estrogens.

Dose-Response Relationship, Drug↗
PubMed2002

17Beta-estradiol inhibits high-voltage-activated calcium channel currents in rat sensory neurons via a non-genomic mechanism.

There is increasing evidence that estrogen influences electrical activity of neurons via stimulation of membrane receptors. Although the presence of intracellular estrogen receptors and their responsiveness in dorsal root ganglion (DRG) primary sensory neurons were reported, rapid electrical responses of estrogen in DRG neurons have not been reported yet. Therefore the current study was initiated to examine the rapid effects of estrogen on Ca2+ channels and to determine its detailed mechanism in female rat DRG neurons using whole-cell patch-clamp recordings. Application of 17beta-estradiol (1 microM) caused a rapid inhibition on high-voltage-activated (HVA)-, but not on low-voltage-activated (LVA)-Ca2+ currents. This rapid estrogen-mediated inhibition was reproducible and dose-dependent. This effect was also sex- and stereo-specific; it was greater in cells isolated from intact female rats and was more effective than that of 17alpha-estradiol, the stereoisomer of the endogenous 17alpha-estradiol. In addition, ovariectomy reduced the inhibition significantly but this effect was restored by administration of estrogen in ovariectomized subjects. Occlusion experiments using selective blockers revealed 17beta-estradiol mainly targeted on both L- and N-type Ca2+ currents. Overnight treatment of cells with pertussis toxin profoundly reduced 17beta-estradiol-mediated inhibition of the currents. On the other hand, estradiol conjugated to bovine serum albumin (EST-BSA) produced a similar extent of inhibition as 17beta-estradiol did. These results suggest that 17beta-estradiol can modulate L- and N-type HVA Ca2+ channels in rat DRG neurons via activation of pertussis toxin-sensitive G-protein(s) and non-genomic pathways. It is likely that such effects are important in estrogen-mediated modulation of sensory functions at peripheral level.

Animals↗
PubMed1998

Estradiol and progesterone alter ethanol-induced effects on mu-opioid receptors in specific brain regions of ovariectomized rats.

This study was conducted to evaluate the effects of estradiol and progesterone on ethanol-induced alterations of mu-opioid receptor binding kinetics in specific brain regions. Female ovariectomized rats were injected with ethanol (3 g/kg, i.p.), estradiol (50 microg/kg, s.c.) and/or progesterone (5 mg/kg, s.c.), or ethanol plus estradiol and/or progesterone daily for 7 days. Control animals received saline and olive oil. Brains were immediately removed and the cortex, hippocampus, hypothalamus, and midbrain were dissected and assayed for mu-opioid receptor binding kinetics. In the hypothalamus, ethanol alone and in combination with estradiol and/or progesterone significantly decreased Bmax. Ethanol alone also decreased Bmax in the midbrain and cortex. When administered with estradiol only, ethanol increased Bmax and Kd in the hippocampus. The administration of estradiol alone and progesterone alone decreased Bmax in the hypothalamus, while not affecting Bmax in any of the other brain regions. However, when estradiol and progesterone were combined, Bmax, as well as Kd, increased in the cortex. Progesterone alone and in combination with estradiol also increased Kd in the midbrain. In addition, Kd significantly increased following administration of ethanol in combination with either of the hormones, or both, in the midbrain and cortex. These results clearly indicate that the female hormones modulate the effects of ethanol on binding kinetics of mu-opioid receptors in specific brain regions. The present findings may in part explain sex differences in alcohol effects.

Animals↗
PubMed1998

Catalase prevents estradiol-induced chondrocyte cytotoxicity.

Osteoarthritis is a common geriatric disease and estrogen may play an important role in this disease. Estradiol may cause chondrocyte damage as suggested by in vitro and in vivo data. One of the possible mechanisms of estradiol-induced chondrocyte damage was thought to be related to free radicals. Whether catalase, a known free radical scavenger, can prevent estradiol-induced chondrocyte damage was tested using a chondrocyte culture system. The results of this study suggest that catalase can significantly reduce the estradiol-induced damage to chondrocytes. Apparently, catalase alters the molecular structure of estradiol as indicated by the absorption spectrum of estradiol with time. The modified estradiol may decrease its toxicity to the chondrocytes. However, the contents of free radicals in the treated chondrocytes have no significant difference from the untreated control cells. Studies to further investigate the mechanism or prevention of estradiol-induced chondrocyte damage in osteoarthritis are warranted.

Animals↗
PubMed1996

Postprandial reduction in high-density lipoprotein cholesterol concentrations in postmenopausal women: improvement by 17beta-estradiol.

The aim of the study was to characterize postprandial high-density lipoprotein (HDL) cholesterol metabolism in postmenopausal women and to evaluate the effect of replacement therapy with 17beta-estradiol. Sixteen healthy normolipidemic (plasma cholesterol, 5.39 +/- 0.68 mmol/L; plasma triglycerides [TGds], 1.24 +/- 0.55 mmol/L) postmenopausal women received an oral vitamin A fat tolerance test (50 g fat with 60,000 IU vitamin A/m2 body surface area). Various blood samples were taken before the test, at hourly intervals up to 8 hours, and 24 hours after ingestion of the fat load for determination of HDL cholesterol, HDL TG, and HDL apolipoprotein (apo) A-I concentrations. TG and vitamin A concentrations were also measured. A subgroup of six women were treated with 2 mg micronized 17beta-estradiol orally each day for 6 weeks, after which the oral vitamin A fat tolerance test was repeated. A reduction in plasma HDL cholesterol concentrations was observed 3 to 8 hours after ingestion of the fat load, and the minimal postprandial HDL cholesterol concentration was, on average, 31.7% (P = .04) lower than the fasting HDL cholesterol concentration. HDL cholesterol had returned to the initial value 24 hours after the fat load. The decrease in postprandial HDL cholesterol concentrations was attenuated by treatment with 17beta-estradiol. The area under the curve (AUC) for the postprandial reduction in HDL cholesterol improved substantially by 66% during 17beta-estradiol (-2.4 +/- 2.6 mmol x h x L(-1) before 17beta-estradiol and - 1.1 +/- 1.2 mmol x h x L(-1)_ during 17beta-estradiol, P = .038). In conclusion, HDL cholesterol concentrations decreased by 32% in the postprandial state in normolipidemic postmenopausal women, indicating that HDL cholesterol must be measured in the fasting state. Replacement therapy with 17beta-estradiol reduced the postprandial decrease in HDL cholesterol by 66%. This effect of 17beta-estradiol can be beneficial in reducing the risk of coronary artery disease.

Aged↗
PubMed2002

Role of 17beta-estradiol administration on insulin sensitivity in the rat: implications for the insulin receptor.

The role of 17beta-estradiol in the early steps of insulin action is only partially known, although its effect on glucose homeostasis has been reported. In this paper, we attempt to prove the influence of 17beta-estradiol on the insulin receptor of ovariectomized rats treated with different hormonal doses. Our results show that high doses of estradiol impair insulin sensitivity while low doses improve it. We think that these results are the consequence of changes at a molecular level, because high doses of estradiol produced lower expression of the insulin receptor gene, lower content of this receptor in target tissues, and lower phosphorylation of insulin receptor in these tissues. However, low doses of estradiol seem to produce just the opposite. The possible existence of consensus response elements in the insulin receptor gene promoter to estradiol could be controlling the expression of this gene, this control being dose and timing dependent. Moreover, we cannot discard a possible effect of estradiol on the activity of protein tyrosine phosphatases, and therefore, on the activity of the insulin receptor. These new findings improve knowledge about the possible risk for insulin resistance in women taking oral contraceptives or receiving hormonal replacement therapy around the menopause, but could also open the door towards the possible utilization of 17beta-estradiol in some diabetes cases.

Adipose Tissue↗
PubMed1981

Estradiol-17 beta inhibition of androgen uptake, metabolism and binding in epididymis of adult male rats in vivo: a comparison with cyproterone acetate.

The effects of estradiol-17 beta on androgen uptake, metabolism and binding were studied in rat epididymis in vivo in comparison with cyproterone acetate. Steroids (250 ug/100 g body weight) were injected 5 min prior to 3H-testosterone in castrate rats. Estradiol-17 beta inhibited 3H-testosterone uptake into epididymal cytosol by 58% as compared to 38% by cyproterone acetate. 3H-Testosterone uptake into epididymal nuclei was inhibited 95% by estradiol-17 beta and 83% by cyproterone acetate. Total bound radioactivity in cytosol fractions was reduced to a greater extent by estradiol-17 beta than cyproterone acetate when either 3H-testosterone or 3H-dihydrotestosterone was injected. Binding of 3H-dihydrotestosterone to nuclear receptors was completely abolished by estradiol-17 beta; whereas approximately 20% binding remained in the nuclear extract after cyproterone acetate treatment. Metabolism of 3H-testosterone in vivo was also altered by estradiol-17 beta, resulting in diminished conversion to 3H-dihydrotestosterone. Cyproterone acetate, on the other hand, did not affect 3H-testosterone metabolism. Estradiol-17 beta and cyproterone acetate inhibited in vitro binding of 3H-dihydrotestosterone to the intracellular cytoplasmic receptor, but not the intraluminal androgen binding protein (ABP). These data suggest that estradiol-17 beta may have a more potent antiandrogenic effect on the epididymis than cyproterone acetate due to inhibition of 5 alpha reduction of testosterone as well as binding to the androgen receptor.

Animals↗
PubMed2003

Suppression of circulating concentrations of FSH and LH by inhibin and estradiol during the initiation of follicle deviation in mares.

The role of estradiol and inhibin in suppression of FSH and LH during the initiation of follicle deviation was examined in mares. In Experiment 1, the two largest follicles (F1, F2) were retained during a wave and the rest were ablated as they reached > or =10 mm. The largest follicle was left intact (control, n=12) or was ablated when it reached > or =20.0 mm (Day 0; expected beginning of deviation). The second largest follicle continued growing (n=9) or regressed (n=4) after F1 ablation. Circulating estradiol and total inhibin decreased after Day 0 in the F2-regressing group, whereas estradiol increased after Day 0.5 and inhibin was unaltered in the control and F2-growing groups. Circulating FSH decreased in the control group and increased in the F2-regressing group after Day 0. In the F2-growing group, FSH increased between Days 0 and 0.5 and then decreased. Circulating LH increased between Days 0 and 2 in the F2-regressing group and between Days 0 and 0.5 in the F2-growing group. In Experiment 2, 0 or 1 follicle was retained in a wave followed by administration of 0 or 1 mg of estradiol at the expected beginning of deviation (Hour 0; 2 x 2 factorial design, n=4-6/group). Circulating total inhibin was higher and FSH was lower at Hour 0 in the 1-follicle than in the 0-follicle groups. Follicle-stimulating hormone decreased after Hour 0 in the 1-mg but not in the 0-mg groups, and the decrease in the 0-follicle/1-mg group was not to the level of that in the 1-follicle/1-mg group. Circulating LH was not affected by follicle number but was reduced by estradiol. Results supported the hypotheses that F1 near the beginning of deviation produces inhibin and estradiol and that the increase in circulating estradiol at the beginning of deviation induces FSH suppression in combination with other follicle substances (presumably inhibin). Results also indicated that the increase in estradiol induces suppression of LH.

Animals↗
PubMed2000

Effect of estradiol and progesterone on oviductal LH-receptors and LH-dependent relaxation of the porcine oviduct.

We have previously shown that the porcine oviduct possesses immunoreactive and functional LH receptors and that LH causes relaxation of the oviduct, especially during the periovulatory stage of estrous cycle. The current studies were undertaken to investigate the effects of estradiol and progesterone on LH receptor protein and LH-stimulated motility of the oviduct in steroid-primed ovariectomized gilts. Twenty-one cross-bred gilts were ovariectomized at 6 m.o. of age. Four weeks later gilts received daily intramuscular injection of either 2 mL corn oil (control n = 4), estradiol benzoate (EB) 1.5 mg (n = 6), progesterone 50 mg (n = 5), or 1.5 mg EB plus 50 mg progesterone (n = 6) for 4 consecutive days. The gilts were slaughtered on Day 5 after the first injection of steroids or vehicle. Rings of isthmus and ampulla were collected from each oviduct and placed in a tissue chamber perfused with Kreb's solution for 60 min. The mechanical activity was recorded for 30 min after LH treatment. Immunoreactivity of LHR in the Fallopian tube sections were detected in the epithelium of the tubal mucosa, smooth muscle cells and the blood vessel endothelium. Western blotting showed that porcine oviducts contain 75, 48 and 45 kDa immunoreactive LH receptor proteins, like the corpus luteum (CL). The lowest receptor expression was found in controls and in gilts treated with estradiol or progesterone. Combined treatment with estradiol and progesterone resulted in a significant increase of LH receptor protein concentrations when compared with control animals. In vitro LH treatment affected oviduct contractility of combined estradiol and progesterone treated gilts but not the oviduct of the remaining groups. It also caused a decrease in amplitude, frequency and areas under the curve (AUC) of ampulla (P < 0.05) and the amplitude and AUC of isthmus (P < 0.001) in combined estradiol and progesterone-primed gilts. These results indicate that estradiol and progesterone together, but not separately, increase LH receptor protein in the porcine oviduct and that combined estradiol and progesterone priming is necessary for LH-induced relaxation of the porcine oviduct.

Animals↗
PubMed2003

Estradiol enhances the neurotoxicity of glutamate in GT1-7 cells through an estrogen receptor-dependent mechanism.

Glutamate plays an important role in neuroendocrine regulation of reproduction through acting on the N-methyl-D-asparate receptor (NMDAR) in the preoptic area (POA). However, a larger dose of glutamate is neurotoxic. Estradiol (E2) increases the responsiveness of neurons to glutamate through activation and/or expression of NMDAR. In order to investigate whether estradiol modulates the neurotoxic effect of glutamate on the neurons through estrogen receptor (ER), immortalized GT1-7 cells, which simultaneously express ER and NMDAR were used. Tamoxifen and ICI 182,780, ER antagonist, were used to investigate whether the ER is involved in the effect of estradiol on glutamate-induced neurotoxicity. MK-801, a NMDAR antagonist, was used to confirm the enhancement of NMDAR-mediated neurotoxicity by estradiol. Neurotoxicity was evaluated by cell viability and LDH efflux. Cell death was observed by flow cytometry and DNA fragmentation. The results showed that: (1) estradiol (10 nM, incubated for 3 days) significantly enhanced the glutamate-induced neuronal death; (2) the percentages of necrosis and apoptosis were elevated after glutamate treatment, and estradiol significantly enhanced the glutamate-induced cell death; (3) glutamate-induced DNA fragmentation was enhanced by E2-pretreatment; (4) the induction of cell death and increase of LDH efflux after glutamate treatment were also enhanced by E2-pretreatment; (5) both the tamoxifen and ICI 182,780 abolished the estradiol-enhanced NMDAR expression and neurotoxicity of glutamate; (6) higher dose of MK-801 (2 microM) was needed in E2-pretreated cells than in non-E2-pretreated group to block the glutamate-induced neurotoxicity. These results suggested that pretreatment of estradiol might enhance the expression of NMDAR and subsequent glutamate-induced neurotoxicity on the GT1-7 cells through an ER-dependent manner.

Animals↗
PubMed2000

Impact of estradiol blood concentrations on skin capillary Laser Doppler flow in premenopausal women.

OBJECTIVE AND METHOD: Estradiols are known to prevent cardiovascular diseases, but the underlying mechanisms remain unclear. We assessed the finger skin capillary blood flow in 20 premenopausal women with oral contraception noninvasively by Laser Doppler flowmetry (LDF). Blood flow was registered both under basal conditions and after 2 min of arterial occlusion. Furthermore, the combination with a beat-to-beat online finger blood pressure monitor allowed the calculation of the regional peripheral resistance (RPR). All measurements were performed in the menstrual phase. LDF and RPR were correlated to the estradiol whole blood levels. RESULTS: Both baseline (r(2)=0.826; P<0.01) and vasodilation (r(2)=0.747; P<0.01) blood flux were significantly correlated to the corresponding estradiol concentrations. A multiple stepwise regression analysis (with age, height, weight, duration of oral contraception, nicotine pack years and estradiol levels in the equation) showed positive correlations between estradiol levels and (a) baseline (P<0.05) or (b) vasodilation (P<0.05) Laser Doppler flux or (c) time to reach the peak flux (r(2)=0.31; P<0.05). Furthermore, the minimal local vascular resistance was negatively correlated to the estradiol levels (r(2)=0.45; P<0.05). CONCLUSION: The study provides evidence that both the baseline and the vasodilation capillary blood flux in women in the menstrual phase depend on the estradiol whole blood levels. Furthermore, the local vascular resistance shows a negative correlation to the hormonal state. Functional or structural alterations of the microvasculature may therefore contribute to the estradiol-associated cardiovascular protection.

Adult↗
PubMed2002

Estradiol enhances Akt activation in cortical explant cultures following neuronal injury.

We have previously demonstrated that estradiol reduces cell death in cortical explant cultures following injury induced by metabolic inhibition in a receptor-dependent fashion. In this study, we examined whether cell death involves apoptosis and assessed the potential mediators of estradiol's actions. Cortical explant cultures were generated from postnatal day 3 rat pups. On day 7 in vitro, explants were injured by exposure to 1 mM 2-DG/2 mM KCN for 2 h to model the metabolic inhibition observed during ischemia. Explants were fixed in 4% paraformaldehyde at 2, 6, 10 and 24 h following the injury period and 18-microm thick sections were cut on a cryostat and stained with cresyl violet to assess cell death. The same sections were also labeled by TUNEL to determine whether cell death occurred by apoptosis. Other sections were used for immunohistochemistry to determine whether cells that stained positive for activated caspase 3 were also immunopositive for NeuN, a neuronal marker, or GFAP, an astrocyte marker. Protein was extracted for Western blot analysis from a separate set of explants collected at 0, 0.5, 1, 2 and 4 h following the conclusion of the injury. Estradiol treatment significantly reduced the number of cells undergoing apoptotic cell death as indicated by nuclear condensation visualized by cresyl violet staining (P<0.05). TUNEL staining revealed that the majority of pyknotic and fragmented nuclei were also TUNEL positive. Furthermore, caspase 3 activation appeared to be restricted to neurons. To examine a possible mechanism by which estradiol prevents apoptosis, we examined the level of activation of Akt kinase, which mediates antiapoptotic signals. Potential activation was measured by phosphorylation of Akt at Ser473 by Western blot analysis. In the absence of estradiol, pAkt levels were significantly increased at 2 h following the termination of injury. Explants that were pretreated with estradiol exhibited elevated levels of pAkt at 1 h following injury. Treatment with ICI 182,780 prevented the effect of estradiol. These studies suggest that estradiol prevents injury-induced apoptosis and that Akt activation may mediate these protective effects.

Alzheimer Disease↗