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PubMed2001

Short-term estradiol replacement in postmenopausal women selectively mutes somatostatin's dose-dependent inhibition of fasting growth hormone secretion.

How estradiol stimulates pulsatile GH secretion in the human is not well understood. Here, we test the clinical hypothesis that estradiol stimulates GH secretion, in part, by opposing somatostatin's inhibition of GH release. To this end, 13 estrogen-withdrawn postmenopausal women received placebo or 1 mg micronized estradiol-17beta orally, twice daily for 14 days, in a prospectively randomized, patient-blinded, within-subject cross-over design. For each intervention, the dose-dependent suppressive actions of somatostatin were evaluated by infusing 0 (saline), 3, 10, 30, 100, or 300 microg/1.73 m(2).h somatostatin-14 continuously, iv, for 3 h, on separate mornings, in the fasting state, 48 h apart. Blood was sampled at 10-min intervals for 2 h before, for 3 h concurrently with, and for 1 h after each infusion. Serum GH concentrations were quantitated in an ultrasensitive chemiluminescence-based assay (detection threshold, 0.005 microg/L). In the estrogen-deficient milieu, constant iv somatostatin infusions inhibited steady-state serum GH concentrations (valley mean during the last 60 min of the infusion interval) in a dose-dependent manner (P < 10(-4) interventional effect). Maximally effective doses of somatostatin reduced the latter by 89 +/- 6.1% (mean +/- SEM) below the subject-specific preinfusion baseline. Estrogen administration increased the serum estradiol concentration from 12 +/- 1 to 245 +/- 35 pg/mL [42 +/- 4 to 920 +/- 110 pmol/L] (P < 10(-4)); decreased serum concentrations of LH (P = 0.018), FSH (P < 10(-4)), and insulin-like growth factor-I (P = 0.003); and elevated the fasting (6-h mean) serum GH concentration from 0.41 +/- 0.07 to 0.87 +/- 0.27 (P = 0.011). Estradiol supplementation did not alter somatostatin's maximal suppression of GH by 89 +/- 4.7% (P < 10(-4) below subject-specific preinfusion baseline), thus signifying unchanging somatostatin efficacy. In contrast, estradiol replacement significantly elevated the half-maximally inhibitory dose of infused somatostatin by 13.5-fold, from 0.43 (0.38-0.48, 95% group statistical confidence intervals) (placebo) to 6.0 (5.2-7.0) (estradiol) microg/1.73 m(2)/h (P < 10(-4)), denoting muting of somatostatin's inhibitory potency. The latter inference was confirmed by a concomitant 4-fold decrease in the exponential steepness of the somatostatin inhibitory dose-response function; viz., mean 1.42 (1.49 to 1.33) (placebo) vs. 0.34 (0.62 to 0.26) (estradiol) slope units (P < 10(-4)). The foregoing effects were specific, because estrogen did not alter somatostatin's dose-dependent enhancement (P < 10(-4)) of the orderliness of GH release patterns, as quantitated via the approximate entropy regularity statistic. In summary, short-term replacement of estradiol to midfollicular phase levels in postmenopausal women selectively reduces the potency, but not the efficacy, of somatostatin's dose-dependent inhibition of GH release. Estrogen supplementation does not modify somatostatin's reciprocal enhancement of the quantifiable orderliness (approximate entropy) of the GH secretory process. Accordingly, we postulate that estradiol can facilitate pulsatile GH secretion, in part, by opposing the repressive actions of somatostatin.

Cross-Over Studies↗
PubMed2003

Estradiol rapidly activates Akt via the ErbB2 signaling pathway.

Previously, we have demonstrated that the two mitogenic growth factors epidermal growth factor and IGF-I can activate Akt and estrogen receptor-alpha (ERalpha) in the hormone-dependent breast cancer cell line, MCF-7. In this report we now show that estradiol can also rapidly activate phosphatidylinositol 3-kinase (PI 3-K)/Akt and that this effect is mediated by the ErbB2 signaling pathway. Treatment of cells with estradiol resulted in phosphorylation of Akt and a 9-fold increase in Akt activity in 10 min. Akt activation was blocked by wortmannin and LY 294,002, two inhibitors of PI 3-K; by genistein, a protein tyrosine kinase inhibitor and an ER agonist; by AG825, a selective ErbB2 inhibitor; and by the antiestrogens ICI 182,780 and 4-hydroxy-tamoxifen; but not by rapamycin, an inhibitor of the ribosomal protein kinase p70S6K; nor by AG30, a selective epidermal growth factor receptor inhibitor. Akt activation by estradiol was abrogated by an arginine-to-cysteine mutation in the pleckstrin homology domain of Akt (R25C). Growth factors also activated Akt in the ER-negative variant of MCF-7, MCF-7/ADR, but estradiol did not induce Akt activity in these cells. Transient transfection of ERalpha into these cells restored Akt activation by estradiol, suggesting that estradiol activation of Akt requires the ERalpha. Estradiol did not activate Akt in MCF-7 cells stably transfected with an anti-ErbB2-targeted ribozyme, further confirming a role for ErbB2. In vitro kinase assays using immunoprecipitation and anti-Akt1, -Akt2, and -Akt3-specific antibodies demonstrated that Akt1 is activated by estradiol in MCF-7 cells whereas Akt3 is the activated isoform in ER-negative MDA-MB231 cells, implying that selective activation of Akt subtypes plays a role in the actions of estradiol. Taken together, our data suggest that estradiol, bound to membrane ERalpha, interacts with and activates an ErbB dimer containing ErbB2, inducing activation of PI 3-K/Akt.

Androstadienes↗
PubMed1990

Estradiol decreases retention of rhodamine 123 fluorescence in GH4C1 pituitary tumor cells.

Rhodamine 123 is a lipophilic cationic fluorescent dye that localizes in mitochondria. We found that 17 beta-estradiol changes the ability of GH4C1 cells, clonal rat pituitary tumor cells, to retain rhodamine 123. Cells incubated with 10 micrograms/ml rhodamine 123 for 30 min at 37 C took up about equal amounts of rhodamine 123, as determined by fluorescence microscopy, regardless of whether they had been treated with estradiol. After three 5-min washes at 37 C, cells treated with 1 nM estradiol for 7 days before incubation with rhodamine 123 had lost more fluorescence than untreated cells. We further characterized the effect by flow cytometry. The difference in fluorescence between control and treated cells ranged from 50- to 500-fold. The effect of estradiol was maximal at 10(-10) M and took a week to develop fully. The effect is specific for estradiol, because estradiol and diethylstilbestrol reduced retention of rhodamine 123 fluorescence at 10(-10) M, but the same concentrations of dihydrotestosterone, progesterone, dexamethasone, and cholesterol did not. To test if the effect on rhodamine 123 fluorescence was caused by activation of the multidrug resistance transport system, we examined the effect of estradiol on the retention of daunomycin, a known substrate of the transport system. Estradiol treatment caused a 3-fold decrease in daunomycin fluorescence. We isolated clones resistant to estradiol-induced loss of rhodamine 123 fluorescence by flow cytometry and found that two clones still showed an estradiol-induced decrease in daunomycin fluorescence equivalent to that of the parent line.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1980

[Plasma estradiol concentration and uterine estrogen receptor in adult rats after steroid administration (author's transl)].

Interaction of estradiol and testosterone was studied at the level of cytoplasmic and nuclear estrogen receptors in the uterus of the adult rat. 55 Sprague-Dawley strain rats, 10 weeks old, were divided into 4 groups. Group I. 5 intact rats (proestrus). Group II. 30 rats were injected with long acting estradiol (ED: 1mg/0.2ml of estradiol dipropionate). Each 5 rats were sacrificed on day 1, 3, 5, 7, 11 and 14 days respectively after the ED injection. Group III. 10 rats were injected with ED. Vehicle (0.2ml of dimethyl sulfoxide) and 1mg/ 0.2ml of testosterone were injected from the 3rd day of the ED injection for 5 days into each 5 rats respectively. Group IV. 10 rats were injected with ED. The rats were treated similarly to Group III except that vehicle or testosterone injections began from the 7th day. Plasma estradiol was determined by RIA. The DCC method for cytoplasmic receptor assay and the pellet exchange method for nuclear receptor assay were used. As to unbound receptor assay, the material was incubated with tritiated estradiol at 0 degrees C for 2 hours. Incubation at 30 degrees C for 1 hour was added to the above for bound receptor assay. Plasma estradiol levels increased 1 day after the ED injection and remained very high for 7 days and decreased to five times that of intact rats 14 days after the injection. Plasma estradiol levels were not influenced by injections of vehicle or testosterone. In group II, cytoplasmic estrogen receptor decreased 1 day after the ED injection and remained low for 7 days and then returned gradually. In nucleus bound receptor increased. Fluctuation of estrogen receptors in uterine cytoplasma and nucleus was in accordance with the concentration of plasma estradiol. In Groups III and IV, there was no significant difference in cytoplasmic and nuclear estrogen receptors between vehicle and testosterone injections. Plasma estradiol levels and uterine cytoplasmic and nuclear estrogen receptors of the ED-treated rats were not influenced by testosterone injections. It is supposed that interaction of estradiol and testosterone may occur in the protein or DNA synthesis mechanism after the receptor level.

Animals↗
PubMed2003

Estradiol levels in girls with Turner's syndrome compared to normal prepubertal girls as determined by an ultrasensitive assay.

Based on growing evidence that estradiol is produced in small amounts even in the prepubertal ovary, we hypothesized that estradiol levels in girls with Turner's syndrome (TS) are lower than in normal prepubertal girls secondary to the lack of normally functioning ovaries. Estradiol levels in untreated girls with TS have not been previously well defined because of the lack of adequate sensitivity of previously available estradiol assays. We utilized an ultrasensitive assay to study estradiol levels in 34 girls with TS and 34 normal age-matched prepubertal girls between the ages of 5 and 12 years. The average estradiol level in the girls with TS (6.4 +/- 4.9 pmol/l estradiol equivalents) was significantly lower than in the normal prepubertal girls (12.7 +/- 10.8 pmol/l estradiol equivalents; p < 0.01). Girls with TS were significantly shorter, and weighed less than the normal prepubertal girls, as expected. The estradiol level was not significantly correlated with height, bone age, or degree of bone age delay. In conclusion, girls with TS have significantly lower estradiol levels than normal age-matched prepubertal girls. This report is consistent with the hypothesis that the lack of normal ovarian function in girls with TS is evident even before puberty.

Age Determination by Skeleton↗
PubMed1990

Effects of enclomiphene on estradiol-induced changes in LH secretion in ewes.

Experiments were conducted to characterize the ability of the antiestrogen enclomiphene (ENC) to block the effects of estradiol on secretion of LH in ovariectomized ewes. To determine whether ENC could block an estradiol-induced LH surge, ewes (n = 4/group) were administered 10 to 250 mg ENC followed 30 min later by 25 micrograms estradiol. Ten or 25 mg ENC suppressed the estradiol-induced LH surge in one of four ewes, whereas 100- or 250-mg doses suppressed the LH surge in three and four of four ewes, respectively. In ewes that received a single treatment of 100 mg ENC plus 25 micrograms estradiol, serum concentrations of LH remained below 1 ng/ml for 3 wk. Compared with untreated ewes, the number of pituitary GnRH receptors was elevated (P less than .05) at 12 d and 28 d, but pituitary content of LH had decreased (P less than .05) by 28 d in ewes treated with 100 mg ENC. To determine whether ENC could block the inhibitory effects of estradiol on serum concentrations of LH, ewes received injections of .03, .1, 1 or 10 mg ENC every 4 d. Half the ewes treated with each dose also received estradiol implants. Injection of .03, .1 or 1 mg ENC alone did not affect serum concentrations of LH, whereas the 10-mg dose decreased serum concentrations of LH below 1 ng/ml by wk 1 of treatment. No dose prevented the inhibition of serum concentrations of LH caused by estradiol implants. In ovariectomized ewes, ENC was antagonistic to estradiol; it prevented the positive effects of estradiol required to induce an LH surge.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Effects of long-term administration of pituitary-derived bovine growth hormone and estradiol on growth in steers.

Sixty-three Friesian steers (9 mo old, 257 kg; n = 15 or 16/treatment) were employed in a 2 x 2 factorial to test bovine growth hormone (bGH) and estradiol (Compudose implant). Steers received daily subcutaneous injections of vehicle or bGH (40 micrograms/kg body weight) for 22 wk. Steers were slaughtered 8 wk after the end of bGH treatment (wk 30). Steers had ad libitum access to silage plus a fixed amount (4 to 5.5 kg/d) of concentrate. Average daily gain (ADG) and feed conversion efficiency (FCE) improved (P less than .05) in response both to bGH and to estradiol during wk 0 to 22. Although bGH did not affect ADG or FCE during wk 23 to 30, estradiol improved (P less than .05) them; bGH and estradiol appeared additive (nonsignificant interactions) during wk 0 to 22. At slaughter, estradiol increased (P less than .05) carcass weight and carcass and leg length while decreasing (P less than .05) conformation score and percentage of kidney, knob and channel fat (KHP); bGH decreased (P less than .05) KHP. Although both bGH and estradiol increased (P less than .01) plasma GH, their effects were not additive. Both bGH and estradiol increased (P less than .01) plasma somatomedin-C and decreased (P less than .01) plasma urea nitrogen concentrations; effects were additive. Estradiol, but not bGH, increased (P less than .05) plasma glucose, whereas neither bGH nor estradiol altered plasma creatinine and nonesterified fatty acids. In summary, both bGH and estradiol improved growth and FCE, and their effects appeared to be additive. It is likely that some of their effects were mediated by somatomedin-C.

Animals↗
PubMed1996

The effect of estrone and estradiol treatment on endometrial total protein, uteroferrin, and retinol-binding protein secretion during midpregnancy or midpseudopregnancy in swine.

It has been hypothesized that conceptus estrogens influence endometrial protein secretion during pregnancy in swine. To test this hypothesis, the effect of estrone and estradiol treatment from d 30 to 60 of pregnancy or pseudopregnancy on endometrial protein secretion was investigated. Pregnant (P; n = 16) and pseudopregnant (PP) gilts (n = 18) received either sham treatment or estrone or estradiol implants (5 mg/d release rate; 60 d release) on d 30 of P or PP. Blood samples were collected on d 30, 40, 50, and 60 to measure estrone and estradiol. On d 60, gilts were hysterectomized. For P gilts, endometrium in apposition to one placenta from each uterine horn was collected. For PP gilts, each uterine horn was flushed with 40 mL of leucine-deficient minimal essential medium (MEM), and endometrial tissue was collected from each horn. Endometrial tissues were incubated in MEM in the presence of 50 microCi of [3H]leucine to examine protein secretion. Estrone and estradiol treatments increased both plasma and endometrial concentrations of estrone (P < .01 except endometrium for P gilts) and estradiol (P < .01, respectively). Endometrium from P gilts secreted more nondialyzable macromolecules (NDM), acid phosphatase activity (AP, a measure of uteroferrin), and retinol-binding protein (RBP) in culture than did endometrium from PP gilts. Estrone treatment increased (P < .01) endometrial NDM from P gilts but not that from PP gilts; estradiol had no effect. Both estrone and estradiol increased (P = .069) endometrial secretion of AP of PP but not of P gilts. Endometrial secretion of RBP was not affected by either estrone or estradiol treatment. Neither estrone nor estradiol affected total protein or AP and estrone treatment decreased (P < .05) RBP in uterine flushings from PP gilts. These data indicate that endometrium from P pigs secretes more protein than endometrium from PP pigs but neither estrone nor estradiol completely mimics the effect of pregnancy.

Acid Phosphatase↗
PubMed2003

Oxytocin-induced secretion of prostaglandin F2alpha in postpartum beef cows: effects of progesterone and estradiol-17beta treatment.

The purpose of the present study was to determine the effect of progesterone or progesterone + estradiol-17beta on oxytocin-induced prostaglandin F2alpha (PGF2alpha) secretion in postpartum beef cows. Thirty-four anestrous postpartum beef cows were ovariectomized (d 32 [Groups 1 to 3] or d 23 [Groups 4 to 6] postpartum [d 0 = parturition]) and allotted to six treatments (Group 1; negative control) to simulate short (Groups 2 through 5) or normal (Group 6) length estrous cycles. Steroid treatments for the respective groups were as follows: Group 1) no estradiol-17beta or progesterone treatment (n = 8; negative control); Group 2) progesterone (d 34 to 40; n = 6); Group 3) estradiol-17beta (d 32 to 33) and progesterone (d 34 to 40; n = 6); Group 4) progesterone (d 23 to 29), no estradiol-17beta (d 32 to 33), and progesterone (d 34 to 40; n = 5); Group 5) progesterone (d 23 to 29), estradiol-17beta (d 32 to 33), and progesterone (d 34 to 40; n = 5); and Group 6) progesterone (d 23 to 29), estradiol-17beta (d 32 to 33), and progesterone (d 34 to 50; n = 4; positive control). Oxytocin (100 IU) was injected (i.v.) at the end of each treatment to test the ability of the postpartum uterus to secrete PGF2alpha as measured by a stable metabolite of PGF2alpha, 15keto-13,14 dihydro-PGF2alpha (PGFM). Peak concentrations ofPGFM (P < 0.08) and total PGFM secreted (area under the curve; P < 0.05) were increased on d 6 following first (Group 2) or second (Group 4) exposure to progesterone and were similar to peak concentrations and total PGFM secreted 16 d following a simulated normal estrous cycle (Group 6). Administration of estradiol-17beta before first progesterone exposure (Group 3) did not reduce peak concentrations of PGFM or total PGFM secreted relative to the preceding groups. Peak concentrations of PGFM (P < 0.08) and total PGFM secreted (P < 0.05) were reduced following a second progesterone exposure, provided that cows were pretreated with estradiol-17beta (Group 5). In summary, oxytocin-induced release of PGFM was inhibited on d 6 following second exposure to progesterone only when cows were pretreated with estradiol-17beta. Therefore, estradiol-17beta and progesterone were both associated with the timing of PGF2, secretion in postpartum cows.

Animals↗
PubMed1980

Sexual behavior, seminal pH and accessory sex gland weights in geldings administered testosterone and(or) estradiol-17 beta.

Sixteen stallions were castrated and 30 days later assigned to one of four treatments: (1) testosterone propionate (175 microgram/kg body weight), (2) 17 beta-estradiol-3-benzoate (44 micrograms/kg body weight), (3) a combination of both steroids or, (4) vehicle only. These dosage were administered every other day for 18 days. The dosages were then doubled and continued for 20 days. Concentrations of testosterone and estradiol in serum decreased rapidly after castration and stabilized within about 6 hours. Mean concentrations of testosterone and estradiol maintained by the steroids were 1.4 and 90 pg/ml, respectively, during treatment at the lower dosage, and 2.6 and 186 pg/ml during treatment at the higher dosage. Libido and the ability to ejaculate were gradually lost after castration. Testosterone restored both aspects of sexual behavior within 2 weeks. Estradiol effectively restored libido at the higher dosage, but was less effective in restoring the ability to ejaculate. The pH of gel-free semen increased after castration and was subsequently decreased by treatment with testosterone or the combination of both steroids. Estradiol had no effect on seminal pH. Weights of the seminal vesicles, ampullae and prostate were greater in geldings treated with testosterone or with both steroids than in estradiol-treated or control geldings. Since estradiol alone was able to restore libido in geldings, it is possible that the maintenance of libido in intact stallions involves either estradiol secreted directly by the testes or estradiol arising from aromatization in peripheral tissues. Treatment with estradiol at either concentration, did not appear to affect the size or function of sex glands in geldings.

Animals↗
PubMed1986

Fate and residues of [4-14C]estradiol-17 beta after intramuscular injection into Holstein steer calves.

Radiocarbon-labeled estra-1,3,5(10)-triene-3,17 beta-diol [4-14C-estradiol-17 beta; beta-estradiol] was suspended in commercial peanut oil and administered to each of three Holstein steer calves (142 to 170 kg body weight) by deep injection into neck muscle via 2.0 ml peanut oil carrier. The dosages were equivalent to .27 to .29 mg beta-estradiol/kg body weight. After dosing, radiocarbon was rapidly and almost totally eliminated in urine and feces. Most of the administered radiocarbon had been eliminated after 2 d, and by 11 d after treatment no radiocarbon was detectable in urine or feces of any calf. Of the total dose, 42.1 +/- 3.8% was excreted in urine and 57.7 +/- 5.2% was eliminated in feces. Analysis of noninjection site tissue samples (blood, brain, fat, kidney, liver and muscle) collected at sacrifice 14 d after treatment showed that none contained detectable radiocarbon residues, with the sensitivity limit for most tissues being 6 ppb beta-estradiol equivalent. Certain sections of muscle taken from the injection site area did contain detectable radiocarbon residues (as much as 69 ppb beta-estradiol equivalent), but total injection site area residues in each calf comprised less than .07% of the total administered dose. Radiocarbon in urine consisted primarily of alpha-estradiol, with much lesser amounts of estrone. Both compounds occurred as nonconjugates and as glucuronides. beta-Estradiol was not detected in urine. Radiocarbon in feces included primarily alpha-estradiol but also beta-estradiol and estrone, each in non-conjugated form. The fact that most of the intramuscular-administered beta-estradiol was eliminated in the feces strongly suggests a major role for biliary excretion in the disposition of this steroid by steer calves.

Animals↗
PubMed1999

Lack of effects of transdermal estradiol on diastolic function: a randomized placebo-controlled double-blind short-term trial.

OBJECTIVE: Limited information is available on the effects of transdermal estradiol on diastole. The present study was a randomized double-blind placebo-controlled trial designed to investigate the short-term effects of transdermal estradiol on left ventricular diastolic function in postmenopausal women. METHODS: The study included 45 women aged 50.8 +/- 3.6 years (25 randomized to the study group and 20 to placebo), who underwent Doppler echocardiography and determination of the plasma estradiol level after 4 and 8 weeks of transdermal estradiol administration in a dose of 50 micrograms per 24 h. RESULTS: There were no modifications in heart rate. Systolic blood pressure dropped in the study patients after 8 weeks (p < 0.03); diastolic blood pressure remained unchanged. Estradiol levels were 67 +/- 36 pg/ml at 4 weeks and 70 +/- 49 pg/ml at 8 weeks in the study group. Basal values of peak early and peak atrial velocities, acceleration time and rate, deceleration time and rate, early/atrial velocity ratio and pressure half-time were not significantly different between the estradiol and placebo groups. Doppler values remained unchanged after both 4 and 8 weeks in women receiving estradiol. Women with relatively high serum 17 beta-estradiol levels (> 100 pg/ml) at 4 or 8 weeks of treatment did not present more pronounced changes in the Doppler-derived parameters compared with patients with low hormone levels. CONCLUSION: The results showed a lack of short-term effects of transdermal estradiol on left ventricular diastolic function in postmenopausal women, irrespective of serum estradiol levels.

Administration, Cutaneous↗
PubMed2000

Neonatal estradiol exposure alters mouse mammary estrogen receptor alpha expression.

The rate of prepubertal ductal morphogenesis as well as the incidence of hyperplastic growth in the adult mouse mammary gland is enhanced by 5 days of neonatal estradiol exposure. It is unknown whether estradiol acts through its nuclear receptor to affect growth in the neonatal gland. Immunohistochemical analysis indicates that estrogen receptor alpha (ER) is present in both the mammary epithelium and stroma before estradiol exposure is initiated at day 1. By 7 days of age, the frequency of ER-positive epithelial and stromal cells is significantly reduced in mammary glands of estradiol-exposed mice compared to controls. Coincident with this decrease in mammary ER is growth inhibition of the estradiol-exposed gland. At day 21, the exposed glands exhibit precocious epithelial outgrowth while significantly fewer stromal cells express ER compared to controls. By day 35, the exposed epithelium fills the fat pad while the exposed stromal cells express significantly more ER. To study the function of mammary ER, we have established mammary epithelial cell lines from oil and estradiol treated mice. Two cell lines from oil-treated and two from estradiol-exposed glands maintain ER expression in culture. Transient transfection of these ER-positive cell lines with a reporter vector containing an estrogen response element (ERE) demonstrates that the immunodetected ER is functional as a transcription factor in response to 100 nM estradiol. The in vitro transcriptional activity in response to estradiol is anti-estrogen sensitive, requires the presence of the ERE, and is independent of neonatal treatment in vivo. Our data indicate that neonatal estradiol exposure alters ER expression and mammary growth, but does not alter ER function.

Animals↗
PubMed1999

Estradiol modulates bcl-2 in cerebral ischemia: a potential role for estrogen receptors.

We have shown that physiological levels of estradiol exert profound protective effects on the cerebral cortex in ischemia induced by permanent middle cerebral artery occlusion. The major goal of this study was to begin to elucidate potential mechanisms of estradiol action in injury. Bcl-2 is a proto-oncogene that promotes cell survival in a variety of tissues including the brain. Because estradiol is known to promote cell survival via Bcl-2 in non-neural tissues, we tested the hypothesis that estradiol decreases cell death by influencing bcl-2 expression in ischemic brain injury. Furthermore, because estradiol may protect the brain through estrogen receptor-mediated mechanisms, we examined expression of both receptor subtypes ERalpha and ERbeta in the normal and injured brain. We analyzed gene expression by RT-PCR in microdissected regions of the cerebral cortex obtained from injured and sham female rats treated with estradiol or oil. We found that estradiol prevented the injury-induced downregulation of bcl-2 expression. This effect was specific to bcl-2, as expression of other members of the bcl-2 family (bax, bcl-x(L), bcl-x(S), and bad) was unaffected by estradiol treatment. We also found that estrogen receptors were differentially modulated in injury, with ERbeta expression paralleling bcl-2 expression. Finally, we provide the first evidence of functional ERbeta protein that is capable of binding ligand within the region of the cortex where estradiol-mediated neuroprotection was observed in cerebral ischemia. These findings indicate that estradiol modulates the expression of bcl-2 in ischemic injury. Furthermore, our data suggest that estrogen receptors may be involved in hormone-mediated neuroprotection.

Animals↗
PubMed1999

Adrenomedullin and nitric oxide in menstrual and in vitro fertilization cycles. Relationship to estradiol.

BACKGROUND: Estradiol has marked systemic vasodilator effects which may be partially mediated by nitric oxide. Recently, a new vasodilator peptide, adrenomedullin, having potent vasodilatory action which is mediated at least in part by nitric oxide, has been isolated. This study investigated whether a relationship exists between circulating levels of estradiol, adrenomedullin, and nitrite/nitrate (the two stable oxidation products of NO metabolism) both in the spontaneous menstrual cycle and IVF cycles. METHODS: Ten normal ovulatory infertile patients were included in this prospective longitudinal study. Circulating levels of estradiol, adrenomedullin, and nitrite/nitrate were investigated. Follicular fluid concentrations of adrenomedullin and nitrite/nitrate, as well as estradiol, were also determined in IVF cycles. RESULTS: Serum nitrite/nitrate levels were significantly elevated in the late follicular phase compared to cycle day 3 of the spontaneous menstrual cycle thus paralleling plasma estradiol. However, no significant change in serum nitrite/nitrate concentration was found associated to multifollicular development and supraphysiological levels of estradiol in IVF cycles. Adrenomedullin plasma levels did not show significant variation either in menstrual or IVF cycles. No correlation was found between plasma estradiol levels and nitrite/nitrate serum concentrations or adrenomedullin plasma levels nor between circulating adrenomedullin and nitrite/nitrate both in menstrual and IVF cycles. Follicular fluid concentrations of estradiol and adrenomedullin but not nitrite/nitrate were significantly higher than those found in plasma or serum. Neither estradiol follicular fluid concentration correlated with those of adrenomedullin or nitrite/nitrate nor a relationship was observed between adrenomedullin and nitrite/nitrate. CONCLUSIONS: Circulating levels of nitrite/nitrate show a significant increase during the late follicular phase in the normal menstrual cycle which is unrelated to adrenomedullin. In addition, this does not necessarily indicate a cause and effect relationship between nitrite/nitrate and estradiol levels given that no increase in nitrite/nitrate was observed from a hypoestrogenic to a hyperestrogenic state during IVF cycles. Further studies are necessary to clarify this subject. Also, the biological and clinical significance of the presence of adrenomedullin in the human follicular fluid remains to be elucidated.

Adrenomedullin↗
PubMed2000

17beta-estradiol acts separately on the LDL particle and artery wall to reduce LDL accumulation.

Estrogen replacement therapy has been shown to attenuate atherogenesis, although the mechanisms for this effect are incompletely defined. Previously, we showed that 17-beta estradiol (estradiol) attenuated oxidant stress-induced increases in vascular low density lipoprotein (LDL) accumulation. It was unclear whether estradiol's effect was imparted on the lipoprotein particle or the artery wall. To examine this, we chronically treated rats with the following sex hormones: low estradiol, high estradiol, progesterone, low estradiol + progesterone, placebo, or control. Carotid arteries (n = 8/group) were isolated and perfused with fluorescently labeled LDL. Rates of LDL accumulation were measured before and after treatment with 10 ng/ml tumor necrosis factor-alpha (TNF) using quantitative fluorescence microscopy. We observed a 50% decrease in basal LDL accumulation rates (P < 0.01) and a 25% decrease in endothelial layer permeability (P < 0.01) in arteries from estradiol-treated animals. There was no effect of hormone replacement on rate of TNF-induced LDL accumulation (P = 0.451), while incubation of LDL with 65 pg/ml estradiol attenuated the TNF effect (P < 0.01). These experiments suggest two independent mechanisms of anti-atherogenic protection by estradiol: 1) decreased endothelial layer permeability; and 2) incorporation of estradiol into the LDL particle and prevention of LDL binding to the artery wall.

Animals↗
PubMed2001

[Prognostic value assessment of the early response of blood estradiol, FSH, and LH using leuprolide acetate during ovarian hyperstimulation in assisted reproduction].

OBJECTIVE: Evaluate the prognostic value of the early response of the serum estradiol FSH y LH action of leuprolide acetate during the folicular phase, used as an adjuvant to ovarian stimulation in IVF-ET. STUDY DESIGN: Were analyzed 31 cycles of stimulation in 26 patients with sterility primary and secondary. Where measured estradiol, FSH, LH on cycle day 2 to 5 for to establish the patterns of response to GnRHa administration. Were compared the response patterns in relation to the number of oocyte captured, estradiol in the day of application of hCG, number of embryos and fertilization rate using (t-student, wilcoxon test and X2). RESULTS: Where observed four distincts patterns of response of estradiol. Pattern A: 133 cycles, presented a prompt elevation of estradiol, followed by a fall on the 4th cycle's day. Pattern B: 9 cycles delayed elevation of the estradiol, followed by a fall on the 6th cycles day. Pattern C: 7 cycles showed persistent elevation of the estradiol. Pattern D: 2 cycles no response of the estradiol (canceled cycles). Was found a significative difference in the estradiol level the day of application of hCG, number of captured oocytes and number of embrions in the pattern A in relation with B and C. No significative difference were found in the fertilization rate. The seric level of FSH and LH were no predictives. We concluded that the response pattern of the estradiol to the leuprolide acetate is the good prognosis indicator of the results of IVF-ET.

Adult↗
PubMed2002

Estradiol in elderly men.

The role of estrogens in male physiology has become more evident, as a consequence of the discovery of human models of estrogen deficiency such as estrogen resistance or aromatase deficiency. In males, testosterone is the major source of plasma estradiol, the main biologically active estrogen, only 20% of which is secreted by the testes. Plasma estrone, 5% of which is converted to plasma estradiol, originates from tissue aromatization of, mainly adrenal, androstenedione. The plasma concentration of estradiol in males is 2-3 ng/dl and its production rate in blood is 25-40 micrograms/24 h; both of these values are significantly higher than in postmenopausal women. Plasma levels of estradiol do not necessarily reflect tissue-level activity as peripherally formed estradiol is partially metabolized in situ; thus, not all enters the general circulation, with a fraction remaining only locally active. Of the factors influencing plasma estradiol levels, plasma testosterone is a major determinant. However, the age-associated decrease in testosterone levels is scarcely reflected in plasma estradiol levels, as a result of increasing aromatase activity with age and the age-associated increase in fat mass. Free and bioavailable estradiol levels do decrease modestly with age as does the ratio of free testosterone to free estradiol, the latter testifying to the age-associated increased aromatization of testosterone. Estradiol levels are highly significantly positively related to body fat mass and more specifically to subcutaneous abdominal fat, but not to visceral (omental) fat. Indeed, aromatase activity in omental fat is only one-tenth of the activity in gluteal fat. Estrogens in males play an important role in the regulation of the gonadotropin feedback, several brain functions, bone maturation, regulation of bone resorption and in lipid metabolism. Moreover, they affect skin metabolism and are an important factor determining sex interest in man.

Adrenal Glands↗