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PubMed1995

Origin of estradiol fatty acid esters in human ovarian follicular fluid.

The estradiol fatty acid esters are the most potent of the naturally occurring steroidal estrogens. These esters are present predominantly in fat, where they are sequestered until they are hydrolyzed by esterases. Thus they act as a preformed reservoir of estradiol. We have previously shown that ovarian follicular fluid from patients undergoing gonadotropin stimulation contains very high amounts of estradiol fatty acid esters (approximately 10(-7) M). The source of these esters is unknown. They can be formed by esterification of estradiol in the follicular fluid by lecithin:cholesterol acyltransferase (LCAT), or in the ovary by an acyl coenzyme A:acyltransferase. In order to determine which of these enzymatic processes is the source of the estradiol esters in the follicular fluid, we incubated [3H]estradiol with follicular fluid and cells isolated from human ovarian follicular fluid and characterized the fatty acid composition of the [3H]estradiol esters biosynthesized in each. In addition, we characterized the endogenous estradiol fatty acid esters in the follicular fluid and compared them to the biosynthetic esters. The fatty acid composition of the endogenous esters was different than those synthesized by the cellular acyl coenzyme A:acyltransferase, and the same as the esters synthesized by LCAT, demonstrating that the esters are produced in situ in the follicular fluid. Although the role of these estradiol esters in the ovary is not known, given their remarkable estrogenic potency it is highly probable that they have an important physiological role.

Chromatography, Thin Layer↗
PubMed1996

Roles of inhibin and estradiol in the regulation of follicle-stimulating hormone and luteinizing hormone secretion during the estrous cycle of the rat.

The relative contributions of inhibin and estradiol in the regulation of FSH and LH secretion were examined at various stages of the estrous cycle in the rat. At 1100 h on metestrus, diestrus, or estrus or at 0500 h on proestrus, rats were ovariectomized or given an injection of normal goat serum, antiserum to inhibin (inhibin-AS), antiserum to estradiol (estradiol-AS), or both antisera to examine the role of gonadal hormones in the regulation of tonic gonadotropin secretion. Plasma samples were collected before and at 6, 12, and 24 h after the treatments. Further, to examine the effects of the treatments on preovulatory gonadotropin surges, the five treatments described were carried out at 0500 h on proestrus and blood samples were collected from 1100 h to 2000 h on the same day at 1.5-h intervals. There was a significant rise in the concentration of plasma FSH after injection of inhibin-AS as well as after ovariectomy on each day of the estrous cycle. These treatments, however, had less effect on estrous FSH secretion. The rise in FSH was greater with immunoneutralization against both inhibin and estradiol than with immunoneutralization against inhibin alone on diestrus and proestrus. Basal levels of LH were increased at all stages of the cycle through immunoneutralization against inhibin and were also increased through immunoneutralization against estradiol except at estrus. Especially on diestrus, a remarkable increase in LH secretion was induced at 6 h after immunoneutralization against both inhibin and estradiol (1449.3 +/- 100.3% vs. control). The magnitude of the LH surge increased in inhibin-immunized rats, decreased in estradiol-immunized or ovariectomized rats, and remained at normal levels after injections of both antisera. The magnitude of the primary FSH surge increased very markedly in the inhibin-immunized group and decreased in the estradiol-immunized group. These results suggest that both estradiol and inhibin play a role in the regulation of LH secretion and that inhibin is a major regulator of FSH secretion during the estrous cycle of the rat. Furthermore, it is suggested that one or more extragonadal factors suppress estrous FSH secretion.

Animals↗
PubMed1998

Up-regulation of oxytocin receptor messenger ribonucleic acid and protein by estradiol in the cervix of ovariectomized rat.

Oxytocin receptor (OTR) regulation has been extensively studied in uterine myometrium and endometrium. However, studies in the cervix are limited. The present studies utilized in situ hybridization and immunocytochemistry to localize OTR mRNA and protein distribution in cervices of nonpregnant ovariectomized (OVX) rats and examined the effect of combined and independent treatments with estradiol and progesterone on cervical OTR. Thirteen nonpregnant rats were bilaterally OVX under general anesthesia. At least 7 days later, the rats were exposed to one of four different treatments 24 h prior to necropsy: 1) estradiol (50 microg, n = 4); 2) progesterone (10 mg, n = 3); 3) both estradiol (50 microg) and progesterone (10 mg) (n = 3); 4) corn oil vehicle (n = 3). After 24-h estradiol treatment, OTR mRNA increased significantly (p < 0.05) in smooth muscle cells of the rat cervix as a result of increased copy numbers of OTR mRNA per cell as well as an increased population of OTR mRNA-positive cells. Progesterone alone had no effect on OTR mRNA expression; however, progesterone combined with estradiol significantly inhibited the up-regulation of OTR mRNA by estradiol alone. The increase of OTR mRNA in cervical epithelial cells was minimal in all situations. Intensity of cervical OTR immunostaining in both the epithelial cells and cervical smooth muscle cells was also elevated after estradiol treatment. The anti-rat OTR antiserum used for immunocytochemistry was validated by Western blot analysis. In conclusion, OTR and OTR mRNA were localized in smooth muscle cells and in epithelial cells of rat cervix. Estradiol-dependent activation of OTR gene expression and active OTR synthesis in smooth muscle cells account for the increased OTR level in rat cervix in vivo, in which progesterone acted as an antagonist of estradiol on OTR gene expression.

Animals↗
PubMed2000

Effect of estradiol on estrogen receptor expression in rat uterine cell types.

In rodent uterus, both up- and down-regulation of estrogen receptor alpha (ERalpha) messenger ribonucleic acid (mRNA) and protein levels by estradiol has been demonstrated; however, it is not known which of the uterine compartments (endometrial epithelium, stroma, myometrium) respond to estradiol with autoregulation of ERalpha. The purpose of the present study was to investigate and compare the kinetics and cell type-specific effects of estradiol on uterine ERalpha expression in immature and adult rats. Ovariectomized female rats were injected s.c. with sesame oil or estradiol-17beta. Uteri were collected and analyzed for changes in ERalpha mRNA using RNase protection assays (RPA) and in situ hybridization using radiolabeled probes specific for ERalpha. Immunohistochemical analysis was performed with a polyclonal antibody specific to ERalpha. Expression of ERalpha in the uterine epithelial cells decreased at 3 and 6 h after estradiol administration to immature and adult rats, respectively. At 24 h, ERalpha mRNA levels in the immature and mature rat uterus were higher than pretreatment levels but returned to baseline by 72 h. Pretreatment with cycloheximide did not block the 3-h repressive effect of estradiol, suggesting that the estradiol-induced decrease in ERalpha mRNA occurs independent of new protein synthesis. A decrease in ERalpha mRNA and protein was also observed in uterine epithelia at 3 and 6 h after an estradiol injection to immature and adult rats, and intensity of both the in situ hybridization signal and the immunostaining in the epithelium increased at 24 and 72 h. However, the periluminal stromal cells in the adult uterus and the majority of stromal cells of the immature uterus appeared to have increased ERalpha expression. The results indicate that down-regulation of ERalpha in the epithelia and up-regulation of stromal ERalpha play a role in early events associated with estradiol-induced cell proliferation of the uterine epithelia.

Animals↗
PubMed2001

Chronic elevation of estradiol in young ovariectomized rats causes aging-like loss of steroid-induced luteinizing hormone surges.

This study was designed to test the hypothesis that the loss of LH surges in response to the stimulatory actions of estradiol and progesterone in middle-aged, persistent-estrous (PE) rats may be caused by chronic elevations in circulating estradiol. Five groups of regularly cycling young rats received an s.c. estradiol implant immediately after ovariectomy (Day 0). For determination of LH surges, blood samples were collected hourly between 1200-1900 h from each of the five groups at one of the following times: 3 days, or 1, 2, 4, or 8 wk later. On the next day, either progesterone (0.5 mg/100 g BW) or corn oil was injected s.c. at 1200 h, and samples were obtained as before. Incidence and amplitude of estradiol-induced LH surges decreased during the first 2 wk of estradiol treatment, after which no surges occurred. Progesterone enhanced the incidence and amplitude of estradiol-induced LH surges thus delaying their disappearance. These results support our hypothesis and demonstrate that the stimulatory actions of estradiol and progesterone on the LH surge sequentially diminish with time after exposure to estradiol in young rats. Thus, young rats chronically treated with estradiol may be a useful model for studying the mechanisms whereby LH surges are abolished in middle age during the hyperestrogenic state of PE.

Aging↗
PubMed2002

17beta-Estradiol protects isolated human pancreatic islets against proinflammatory cytokine-induced cell death: molecular mechanisms and islet functionality.

INTRODUCTION: Proinflammatory cytokines (PIC) (interleukin-1beta, interferon-gamma, and tumor necrosis factor alpha) are released after intraportal islet transplantation lead to functional suppression and islet apoptosis. Estradiol has been shown to promote survival of cells undergoing PIC-induced apoptosis. In this study, we evaluated the effects of estradiol on isolated human pancreatic islet (IHPI) survival after exposure to PIC and analyzed potential mechanisms of action. METHODS: Hand-picked, freshly isolated IHPI were incubated with PIC and estradiol. Viability was analyzed from single islet cells stained with ethidium bromide and acridine orange, apoptosis using a quantitative kit, NF-kappaB nuclear translocation using a promoter-Luciferase NF-kappaB responsive construct, mitochondrial permeability transition using the ApoAlert Mitochondrial kit, and caspase 9 by a fluorometric assay. In vitro functionality was examined by static incubation, and a limited number of islets were transplanted in nonobese diabetic, severe combined immunodeficient mice. RESULTS: 17beta-Estradiol induced a dose-dependent increase in islet viability, an effect partially reversed by the estrogen receptor antagonist ICI 182,780. In vitro, islets treated with estradiol presented higher stimulation index. Euglycemia was achieved in 6 of 12 animals that received estradiol-treated islets compared with 1 of 12 control animals. Lower NF-kappaB nuclear translocation, cytochrome release, and caspase 9 activation occurred in islets treated with estradiol. CONCLUSIONS: Estradiol promoted IHPI survival and improved functionality after PIC exposure in vitro and in vivo after transplantation. The molecular mechanisms involved included a decrease in NF-kappaB nuclear translocation, decrease in mitochondrial cytochrome release, and caspase 9 activation. The use of estradiol might be beneficial in clinical islet transplantation.

Animals↗
PubMed1997

Acute effects of 17 beta-estradiol on the coronary microcirculation: observations in sedated, closed-chest domestic swine.

OBJECTIVES: To test the hypotheses: that acute administration of 17 beta-estradiol dilates normal coronary microvessels in vivo; that coronary microvascular responses to acute estrogen stimulation exhibit sexual dimorphism; and that nitric oxide has a role in mediating these effects. METHODS: Measurements of hemodynamics, coronary flow velocity (Doppler), myocardial blood flow (microspheres) and oxygen consumption were made in closed-chest swine: group 1 consisted of castrated juvenile males, groups 2 and 3 of estrogen pretreated, castrated juvenile males, and group 4 of sexually mature females. 17 beta-Estradiol (2, 20 or 200 ng/kg) was given by intracoronary injection and data obtained 20-30 min later; additional measurements were made 1 h after the 200 ng/kg dose. The effect of L-NG-monomethylarginine (L-NMMA) on 17 beta-estradiol responses was also tested. Tissue and blood concentrations of 17 beta-estradiol, and concentrations of estrogen receptor in myocardium and coronary vessels were obtained. RESULTS: In estrogen-naive castrated males, 17 beta-estradiol had no effect on coronary flow velocity or myocardial blood flow, but 1 h after the 200 ng/kg dose there was an increase in diastolic coronary resistance compared with baseline (48 +/- 20 versus 41 +/- 17 mmHg/mkHz; P < 0.05). Estrogen pretreated castrated males also showed no change in myocardial blood flow after 17 beta-estradiol, but coronary flow velocity decreased (P < 0.05) compared with baseline 1 h after the 200 ng/kg dose (from 1.69 +/- 0.61 to 1.41 +/- 0.42 kHz) and diastolic coronary resistance increased significantly (P < 0.01) compared with control at this time (51 +/- 15 compared with 39 +/- 14 mmHg/mkHz). In sexually mature females, 17 beta-estradiol had no effect on myocardial blood flow but did cause a significant (P < 0.05) decrease in diastolic coronary vascular resistance compared with baseline (51 +/- 9 mmHg/mkHz) at both the 20 ng/kg and the 200 ng/kg doses (both 43 +/- 11 mmHg/mkHz). Coronary flow velocity also increased (P < 0.06) compared with baseline (1.34 +/- 0.26 mmHg/mkHz) after the 200 ng/kg dose (1.69 +/- 0.61 mmHg/mkHz). L-NMMA had no effect on flow responses to 17 beta-estradiol in any group. Classical estrogen receptors were not present in myocardium or coronary arteries from male or female swine. CONCLUSIONS: These results demonstrate that 17 beta-estradiol exerts a mild constrictor effect on the coronary microvessels of normal castrated, juvenile males whether estrogen-naive or estrogen-pretreated. In contrast, sexually mature normal females exhibit mild dilatation of the coronary microcirculation in response to acute estrogen stimulation. Nitric oxide does not appear to have a role in mediating the dilator response in females, and classical estrogen receptors are not involved. A direct membrane effect of the hormone (perhaps via alteration in potassium conductance) seems likely, and demonstrates sexual dimorphism.

Animals↗
PubMedDate not supplied

Influence of transdermal estradiol in the regulation of leptin levels of postmenopausal women: a double-blind, placebo-controlled study.

OBJECTIVE: To investigate whether the administration of transdermal estradiol is capable of modifying circulating levels of leptin. DESIGN: Forty postmenopausal women randomly received in a double-blind fashion, a transdermal patch containing either placebo or estradiol (50 microg/day). After 2 months of treatment, they were switched to the alternate treatment for another 2 months. Leptin levels were measured at the end of the placebo and estradiol administration. In a subset of 28 women an evaluation of body composition via bioelectrical impedance and an oral glucose tolerance test (OGTT; 75 g) were also performed at the end of the placebo and estradiol administration. Glucose, insulin, and leptin levels were measured in all OGTT samples. RESULTS: Leptin levels were related directly to body mass index (BMI), fat mass, and insulin, and inversely related to lean mass. In comparison to placebo, transdermal estradiol increased estradiol (from 77.8 +/- 8.4 pmol/l to 183.1 +/- 20.9 pmol/l; p < 0.0001) but did not significantly modify leptin (19.1 +/- 2.4 microg/l vs. 18.6 +/- 2 microg/l) or BMI. Estradiol did not modify fat mass or lean mass, significantly increased intracellular water (31.1 +/- 0.7% vs. 37.2 +/- 2.3%, p < 0.05), and decreased extracellular water (40.5 +/- 0.7% vs. 36.3 +/- 1.7%; p < 0.04). Leptin did not increase during OGTT, but a significant decrease, linearly related to BMI ( r = 0.519; p = 0.0189), was observed at the end of the test. CONCLUSIONS: Low doses of transdermal estradiol exert no influence on fasting leptin levels or BMI. The possibility that different doses of estradiol exert a more pronounced effect on circulating leptin needs to be addressed in comparative studies.

Administration, Cutaneous↗
PubMedDate not supplied

Percutaneous 17beta-estradiol gel for the treatment of vasomotor symptoms in postmenopausal women.

OBJECTIVE: To determine the efficacy and tolerability of two strengths of percutaneous 17beta-estradiol in a hydroalcoholic gel and placebo in controlling vasomotor symptoms of menopause. DESIGN: A total of 221 postmenopausal women were assigned randomly to treatment with percutaneous 17beta-estradiol gel 1.25 g (containing 0.75 mg of estradiol) or 2.5 g (containing 1.5 mg of estradiol) or placebo gel applied once daily for 12 weeks. The primary efficacy variable was the mean change from baseline in the frequency of moderate/severe hot flushes. In addition, the mean changes from baseline in the frequency and severity of all hot flushes were assessed. Safety and tolerability were evaluated from endometrial biopsy, adverse events, and laboratory tests. RESULTS: A significant reduction (P < 0.05) in the mean frequency of moderate-to-severe hot flushes and mean frequency and severity of all hot flushes was observed with both 17beta-estradiol gel groups compared with placebo. The mean number of moderate-to-severe hot flushes at the end of the study with 17beta-estradiol gel 2.5 g, 17beta-estradiol gel 1.25 g, and placebo gel was 2.0, 2.8 and 5.2, respectively. The overall incidence of adverse events was not significantly different among groups, though a higher incidence of estrogen-related adverse events was reported with the 17beta-estradiol gel 2.5-g dose. CONCLUSIONS: 17beta-estradiol gel was effective and well tolerated for alleviating moderate-to-severe hot flushes in postmenopausal women. Therapy may be initiated with the 1.25-g dose with an increase to the 2.5-g dose if needed.

Administration, Cutaneous↗
PubMed1999

Effects of 17beta-estradiol on tachycardia-induced changes of atrial refractoriness and cisapride-induced ventricular arrhythmia.

INTRODUCTION: Gender difference is known to be associated with the occurrence of arrhythmia. However, the effects of female sex hormone on atrial electrophysiology, and on the occurrence of torsades de pointes (TdP) induced by cisapride have been unclear. METHODS AND RESULTS: Two experiments were included in this study. In experiment 1, effective refractory periods (ERPs) from five epicardial atrial sites were measured before and after rapid atrial pacing at 800 beats/min for 30 minutes in dogs with pretreatment of verapamil (n = 10), 17beta-estradiol (n = 10), or without pretreatment (n = 10, control group). In experiment 2, limb-lead ECG and monophasic action potentials in the left and right ventricles were recorded before and after each dose of cisapride (2 to 6 mg/kg) during different ventricular rates in dogs with (n = 9) and without (n = 14) concomitant administration of 17beta-estradiol (0.3 microg/kg). After 17beta-estradiol administration, there were greater atrial ERPs in the study dogs than in the control group. The atrial ERPs were shortened significantly after rapid atrial pacing, but the degree was greater in the control group than in the dogs pretreated with verapamil or 17beta-estradiol. Moreover, the recovery of atrial ERPs was faster in dogs pretreated with verapamil or 17beta-estradiol than in the control group. In experiment 2, cisapride prolonged the QT interval and biventricular APD90 and induced early afterdepolarizations (EADs) in a dose-dependent manner. However, dogs receiving cisapride combined with 17beta-estradiol had a greater increase of ventricular repolarization and a higher incidence of EADs than those receiving cisapride only. Moreover, dogs receiving cisapride combined with 17beta-estradiol (3/9, 33%) had a greater incidence of TdP than those receiving cisapride only (0/14, 0%, P < 0.05). CONCLUSIONS: 17beta-estradiol has a significant effect on atrial electrophysiology, which may be related to the prevention of atrial fibrillation. However, the high incidence of TdP in dogs receiving cisapride combined with 17beta-estradiol suggests that the female sex hormone is an important risk factor of cisapride-induced proarrhythmia.

Action Potentials↗
PubMed1986

Estradiol-binding proteins from mycelial and yeast-form cultures of Paracoccidioides brasiliensis.

Paracoccidioides brasiliensis, the etiologic agent of paracoccidioidomycosis, causes disease much more frequently in men than it does in women, suggesting that the hormonal milieu of the host might influence P. brasiliensis pathogenicity. We recently demonstrated that cytosol from yeast cultures of P. brasiliensis contains a high-affinity, low-capacity, tritiated 17 beta-estradiol [( 3H]estradiol)-binding protein. Estradiol and, to a lesser degree, diethylstilbestrol (DES), inhibited the transformation of P. brasiliensis cultures from the mycelial to the yeast form, an event critical to the establishment of infection. Our current studies demonstrated a somewhat higher affinity (apparent dissociation constant [Kd], approximately equal to 6 to 12 nM) of the estrogen-binding protein for [3H]estradiol than was previously described for yeast cytosol. The presence of both high- and low-affinity estrogen-binding sites in yeast-form P. brasiliensis cytosol was detected after warming the cytosol to 37 degrees C. The high-affinity protein was labile to further heating (56 degrees C), although the low-affinity protein was stable. Additional experiments demonstrated the presence of an estrogen-binding protein in cytosol prepared from mycelial-form P. brasiliensis. This estrogen-binding protein had a slightly lower affinity for [3H]estradiol (Kd approximately equal to 13 nM), and its cytosol contained somewhat fewer binding sites (approximately equal to 78 fmol/mg of protein) than did yeast-form P. brasiliensis cytosol. Of particular interest was the finding that DES, a weak competitor for [3H]estradiol binding in yeast cytosol, displaced [3H]estradiol from the mycelial-form binding moiety. DES had a 50- to 100-fold-lower affinity for the [3H]estradiol-binding protein than did estradiol, consistent with its lower bioactivity in the mycelial-to-yeast-form transformation studies. The current results lend further support to our hypothesis that endogenous estrogens in the host, acting through the cytosol binding protein in the fungus, inhibit mycelial-to-yeast-form transformation, thus explaining the resistance of women to paracoccidioidomycosis.

Binding, Competitive↗
PubMed2006

Mitochondria play an important role in 17beta-estradiol attenuation of H(2)O(2)-induced rat endothelial cell apoptosis.

Studies have shown salutary effects of 17beta-estradiol following trauma-hemorrhage on different cell types. 17beta-Estradiol also induces improved circulation via relaxation of the aorta and has an anti-apoptotic effect on endothelial cells. Because mitochondria play a pivotal role in apoptosis, we hypothesized that 17beta-estradiol will maintain mitochondrial function and will have protective effects against H(2)O(2)-induced apoptosis in endothelial cells. Endothelial cells were isolated from rats' aorta and cultured in the presence or absence of H(2)O(2), a potent inducer of apoptosis. In additional studies, endothelial cells were pretreated with 17beta-estradiol. Flow cytometry analysis revealed H(2)O(2)-induced apoptosis in 80.9% of endothelial cells; however, prior treatment of endothelial cells with 17beta-estradiol resulted in an approximately 40% reduction in apoptosis. This protective effect of 17beta-estradiol was abrogated when endothelial cells were cultured in the presence ICI-182780, indicating the involvement of estrogen receptor (ER). Fluorescence microscopy revealed a 17beta-estradiol-mediated attenuation of H(2)O(2)-induced mitochondrial condensation. Western blot analysis demonstrated that H(2)O(2)-induced cytochrome c release from mitochondrion to cytosol and the activation of caspase-9 and -3 were decreased by 17beta-estradiol. These findings suggest that 17beta-estradiol attenuated H(2)O(2)-induced apoptosis via ER-dependent activation of caspase-9 and -3 in rat endothelial cells through mitochondria.

Animals↗
PubMed1998

Estradiol alters cholecystokinin stimulus-response coupling in rat pancreatic acini.

We have previously demonstrated that altered exocrine pancreatic stimulus-secretion coupling is associated with ovariectomy and chronic estradiol administration. To elucidate possible mechanisms underlying those effects we examined the ability of chronic administration of different doses of estradiol to regulate the CCK signal transduction pathway in isolated rat pancreatic acini. Doses of estradiol ranging from 0.5 to 119 micrograms/day were administered to ovariectomized rats for 18 days. Ovariectomy was associated with enhanced CCK-stimulated pancreatic amylase release, whereas estradiol dose dependently decreased the magnitude of CCK-stimulated amylase release. Ovariectomy was also associated with enhanced CCK receptor numbers on acinar cell membranes. Estradiol administration was associated with dose-dependent decreases in CCK receptor numbers. Neither ovariectomy nor estradiol administration affected CCK receptor affinity. Moreover, estradiol administration was associated with increased expression of the alpha-subunit of the heterotrimeric G protein Gq/11 (Galphaq/11). Recent findings (H. Ohnishi, S. A. Ernst, D. I. Yule, C. W. Baker, and J. A. Williams. J. Biol. Chem. 272: 16056-16061, 1997) demonstrate that Galphaq/11 may exert a tonic inhibitory effect on pancreatic enzyme release. In view of these findings, the increased expression of Galphaq/11 induced by estradiol likely contributes to the inhibition of pancreatic enzyme release. We conclude that the effect of estradiol to decrease pancreatic secretion is mediated through regulation of CCK receptor density and Galphaq/11 expression.

Amylases↗
PubMed1991

Effect of estradiol on tissue glycogen metabolism and lipid availability in exercised male rats.

The effect of 17 beta-estradiol 3-benzoate (10 micrograms.0.1 ml sunflower oil-1.100 g body wt-1) on exercise performance, tissue glycogen utilization, and lipid availability was determined in male rats. In experiment 1, estradiol or oil was administered 1 h or 1-6 days before a treadmill run to exhaustion. No differences in body weight between oil- and estradiol-administered animals were observed during the 6-day treatment. Animals receiving estradiol for 3-6 days ran significantly longer and completed more work than oil-administered animals. Significant degradation of red and white vastus muscle, myocardial, and liver glycogen was observed in all animals run to exhaustion. In experiment 2, animals were administered estradiol for 5 days and then run for 2 h. The submaximal run for 2 h significantly reduced tissue glycogen content in red and white vastus muscle, heart, and liver of oil-administered animals. The latter effect was attenuated in both vastus muscles, liver, and myocardial tissues in the estradiol-administered animals. Estradiol administration significantly increased plasma fatty acids and lowered plasma lactate during the submaximal run. These data indicate that when body weight remained constant between groups of male rats, estradiol administration for 3-6 days increased exercise performance. Furthermore, estradiol administration for 5 days resulted in greater lipid availability and less tissue glycogen utilization during submaximal running for 2 h.

Animals↗
PubMed2002

Direct actions of estradiol on the anterior pituitary gland are required for hypothalamus-dependent lactotrope proliferation and secretory surges of luteinizing hormone but not of prolactin in female rats.

Estradiol induces surges of prolactin (PRL) and luteinizing hormone (LH) secretion as well as lactotrope proliferation in female rats. We examined whether these hypothalamus-dependent events require the direct action of estradiol on the anterior pituitary gland by selective blockade of its peripheral actions, using ICI182,780 (ICI), an antiestrogen that cannot cross the blood-brain barrier. Injection of ICI into ovariectomized rats, at a dose of 250 microg/day for 4 days, almost completely inhibited estradiol-induced growth of the uterus, proliferation of lactotropes as determined by bromodeoxyuridine incorporation, and afternoon surges of LH secretion. However, ICI only partially inhibited estradiol-induced surges of PRL secretion and had no effect on estradiol-induced tonic inhibition of LH secretion even at the highest dose of 1,000 microg/day. The inhibitory effects of ICI found at 250 microg/day were attributable to its selective peripheral, but not central actions since ICI did not alter hypothalamic expression of progesterone receptors, an estradiol-dependent brain process. Estradiol-induced increases in the number of progesterone receptor-immunoreactive cells in the hypothalamic ventromedial nucleus and the medial preoptic area were not inhibited by this dose of ICI but were inhibited by 500 microg/day tamoxifen, an antiestrogen that can cross the blood-brain barrier. Treatment of cycling female rats with 250 microg/day ICI beginning from diestrus day 2 was also effective in blocking estrous lactotrope proliferation and preovulatory surges of LH secretion but not PRL secretion. Finally, in ovariectomized estradiol-treated pup-deprived lactating rats, ICI did not affect suckling-induced PRL secretion but completely blocked lactotrope proliferation. These results suggest that a direct estradiol action on the anterior pituitary gland is required for lactotrope proliferation and the positive feedback action on LH secretion but not for the secretory surges of PRL or for negative feedback.

Animals↗
PubMed2002

Ovariectomy-induced increases in hypothalamic serotonin-1A receptor function in rats are prevented by estradiol.

The present study investigated the effects of long-term estradiol withdrawal (ovariectomy) on hypothalamic serotonin-1A (5-HT(1A)) receptor signaling. Changes in neuroendocrine responses to the 5-HT(1A) agonist 8-OH-DPAT and levels of G(z) protein in the hypothalamus were used to examine 5-HT(1A) receptor signaling. Five days following ovariectomy, rats received daily injections of either 2 microg of beta-estradiol 3-benzoate or vehicle (subcutaneously) for 2, 4 or 14 days. Twenty-four hours after the last injection, and 15 min prior to sacrifice, rats were injected with (+/-)8-OH-DPAT (50 micro;g/kg, s.c.) or saline. Estradiol treatment did not alter basal corticotropin (ACTH) or oxytocin levels. Injection of (+/-)8-OH-DPAT produced significant increases in plasma ACTH and oxytocin levels. In the vehicle-treated rats, hormone responses to 8-OH-DPAT were enhanced in rats that received injections for 14 days compared with rats that received injections for either 2 or 4 days. Estradiol treatment for 4 or 14 days blunted this enhanced ACTH response to 8-OH-DPAT, whereas the oxytocin response to 8-OH-DPAT was only blunted after 14 daily injections of beta-estradiol 3-benzoate. The treatment with beta-estradiol 3-benzoate (2 microg/rat) did not reduce membrane-associated G(z) protein levels in the paraventricular nucleus of the hypothalamus. Hence, the inhibitory influence of a low dose of beta-estradiol 3-benzoate on 5-HT(1A) receptor signaling in the hypothalamus is not accompanied by a change in the levels of G(z) protein in the paraventricular hypothalamic nucleus. Results from the present study indicate a supersensitivity of 5-HT(1A) receptors after withdrawal of estradiol and suggest that estradiol suppresses 5-HT(1A) receptor signaling.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2002

Rapid uncoupling of serotonin-1A receptors in rat hippocampus by 17beta-estradiol in vitro requires protein kinases A and C.

17beta-Estradiol decreases R(+)8-OH-DPAT-stimulated [(35)S]GTPgammaS binding [an index of serotonin-1A (5-HT(1A)) receptor coupling] through the activation of estrogen receptors. We hypothesize that this occurs as a result of activation of protein kinase A (PKA) and/or protein kinase C (PKC) and phosphorylation of 5-HT(1A) receptors. Hippocampus from ovariectomized rats was incubated with 17beta-estradiol in HEPES buffer (37 degrees C). Cytosolic and membrane fractions were prepared to assess PKA and PKC activities, respectively. In separate experiments, membranes were prepared to measure R(+)8-OH-DPAT-stimulated [(35)S]GTPgammaS binding. 17beta-Estradiol (50 nM) increased PKA and PKC activities approximately 2- to 3-fold. PKC activity was elevated at 10, 30 and 60 min, whereas PKA activity was increased at 10 and 30 min. The ability of 17beta-estradiol to increase PKA and PKC was blocked by the estrogen receptor antagonist ICI 182,780 (1 microM). A selective PKA inhibitor (KT 5720, 60 nM) blocked 17beta-estradiol-stimulated PKA but NOT PKC activity. Conversely, the PKC inhibitor calphostin C (100 nM) blocked the increase in PKC activity produced by 17beta-estradiol but NOT the PKA response. The protein kinase inhibitors individually blocked the effects of 17beta-estradiol on R(+)8-OH-DPAT-stimulated [(35)S]GTPgammaS binding. By contrast, preincubation with the protein synthesis inhibitor cycloheximide (200 microM) or the mitogen activated protein (MAP) kinase kinase inhibitor PD 98059 (50 microM) was without effect. Incubation of hippocampus with 17beta-estradiol (50 nM, 60 min) caused the phosphorylation of a protein consistent with the 5-HT(1A) receptor. These studies demonstrate that 17beta-estradiol acts on estrogen receptors locally within the hippocampus through nongenomic mechanisms to activate PKA and PKC, phosphorylate 5-HT(1A) receptors and uncouple them from their G proteins.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2004

Relaxant effects of estradiol through non-genomic pathways in male and female pig bladder smooth muscle.

The precise effect of low estrogen levels on urinary bladder contractility remains controversial. The present study was designed to analyze the effect of 17beta-estradiol in bladder smooth muscle contractility and the involvement of specific estrogen receptor stimulation in this effect. Castrated male and female pig detrusor strips were mounted for tension recording in an organ bath, superfused with Krebs solution at 37 degrees C and stimulated electrically and pharmacologically. In order to verify the acute effect of 17beta-estradiol on muscle contractility, the strips were incubated with different concentrations of the hormone. Muscle contractions were induced by potassium chloride, acetylcholine chloride and electrical field stimulation. The involvement of the estrogen receptor in the effects of 17beta-estradiol was assessed by incubation of some strips with the selective estrogen receptor antagonist ICI 182.780 before estradiol was applied. Estradiol at a dose of 30 micromol/l elicited a lower amplitude of contractions induced by EFS, Ach and KCl in female as well as in castrated male pig bladder smooth muscle strips. The effects of 17beta-estradiol were stronger in contractions induced by potassium chloride than those induced by other forms of stimulation. Pre-treatment with the pure estrogen receptor antagonist had no effect on 17beta-estradiol-induced inhibition of muscle contractility. These observations suggest that 17beta-estradiol induces lower amplitude of contraction of female as well as castrated male pig detrusor which is not mediated by the classic estrogen receptor. Furthermore, we can conclude that estradiol has a stronger inhibitory effect on the depolarization of muscle cell membrane compared to a muscarinic receptor-induced contraction.

Acetylcholine↗