Am J Physiol Heart Circ Physiol. 2002 Dec;283(6):H2644-9. Epub 2002 Jul 26.
Estradiol reduces F2alpha-isoprostane production in cultured human endothelial cells.

Hermenegildo C, Garcia-Martinez MC, Tarin JJ, Cano A.

Research Unit, Hospital Clinic Universitari de Valencia, Spain. carlos.hermenegildv.es

Free radical-generated F(2alpha)-isoprostanes are a group of compounds with vasoconstrictor properties. To investigate whether estradiol exerts antioxidant actions modifying F(2alpha)-isoprostane production, cultured human umbilical vein endothelial cells were exposed to estradiol and other compounds and F(2alpha)-isoprostanes were measured in culture medium. Exposure to 1 and 10 nM estradiol for 24 h reduced F(2alpha)-isoprostane production by 36 and 49%, respectively (P < 0.001 vs. control). Exposure to antiestrogens alone (ICI-182780 or EM-652) slightly reduced F(2alpha)-isoprostanes (P < 0.05 vs. control), but much less than exposure to estradiol (P < 0.05). ICI-182780 reversed the estradiol-induced reduction of F(2alpha)-isoprostane concentration (P < 0.05). Along with time-course analysis, these results suggest that estradiol effects were mediated through estrogen receptor-dependent and -independent mechanisms. Progestogens alone (progesterone or medroxyprogesterone acetate) did not modify F(2alpha)-isoprostane production at any of the tested concentrations (1, 10, and 100 nM). Progesterone completely reversed estradiol-induced reduction of F(2alpha)-isoprostane production (P < 0.05 vs. control and estradiol), but medroxyprogesterone acetate did not (P < 0.05 vs. control).

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12388318&dopt=Abstract estradiol




Metabolism. 2002 Nov;51(11):1397-401.
Effect of ovariectomy and estradiol replacement on skeletal muscle enzyme activity in female rats.

Beckett T, Tchernof A, Toth MJ.

Department of Medicine, University of Vermont, Burlington, VT 05405, USA.

In female rats, ovariectomy (OVX) is associated with increased body fat and insulin resistance, and estradiol replacement prevents these alterations. These metabolic changes related to the estrogen-deficient state might be due, in part, to alterations in skeletal muscle substrate metabolism. We tested the hypothesis that estradiol affects the regulation of enzymes involved in substrate oxidation and storage within skeletal muscle. Specifically, we examined enzymes involved in the regulation of glycogen synthesis (glycogen synthase [GS]), glycolysis (phosphofructokinase [PFK]), tricarboxylic acid cycle activity (citrate synthase [CS]), and beta-oxidation (beta-hydroxyacyl-CoA dehydrogenase [beta-HADH]). Twenty-two, female Sprague-Dawley rats (7 to 8 weeks old) were separated into 3 groups: OVX + placebo (P; n = 8), OVX + estradiol (E(2); n = 8), and sham-operated (S; n = 6). Rats from E(2) and P groups were pair-fed to the S group to control for OVX-induced changes in food intake. After 16 days, activities of GS, PFK, CS, and beta-HADH were measured in vastus medialis muscle. GS fractional velocity was significantly lower (P <.05) in P (mean +/- SE; 39.7% +/- 6.2%) compared with both S (61.9% +/- 8.8%) and E(2) (65.8% +/- 8.4%) rats. In addition, E(2) rats (41.4 +/- 2.0) had significantly higher (P <.05) CS activity than P (34.9 +/- 2.0) and S (33.9 +/- 1.4 micromol/min/g) groups. There was no effect of OVX or estradiol replacement on beta-HADH or PFK. Our results suggest that, independent of alterations in food intake, estradiol availability affects the regulation of enzymes involved in nonoxidative glucose disposal (GS) and oxidative metabolism (CS) in skeletal muscle. Copyright 2002, Elsevier Science (USA). All rights reserved.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1&dopt=Abstract




Metabolism. 2002 Nov;51(11):1458-62.
Low circulating estradiol and adrenal androgens concentrations in men on glucocorticoids: a potential contributory factor in steroid-induced osteoporosis.

Hampson G, Bhargava N, Cheung J, Vaja S, Seed PT, Fogelman I.

Department of Chemical Pathology, St Thomas' Hospital, London, UK.

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




Int J Androl. 2002 Dec;25(6):345-51.
Seminal plasma androgen/oestrogen balance in infertile men.

Luboshitzky R, Kaplan-Zverling M, Shen-Orr Z, Nave R, Herer P.

Endocrine Institute, Haemek Medical Center, Afula, Israel. luboshitzky_lalit.org.il

The hypothesis that the balance between oestrogen and androgen in seminal plasma is important for normal fertility was investigated. We determined the concentrations of oestradiol and testosterone in blood and seminal plasma from 62 infertile men and 32 normozoospermic men. Infertile men were classified according to semen analysis (concentration, motility and morphology): asthenozoospermia, oligozoospermia and oligoteratoasthenozoospermia. Serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were determined in all participants. For all subjects, mean testosterone levels were lower and mean oestradiol were higher in seminal plasma than in blood. Seminal plasma testosterone levels were lower in the infertile groups vs. control men ( p < 0.0002). Oligpzoospermic and oligoteratoasthenozoospermic men had significantly higher seminal plasma oestradiol levels compared with controls ( p < 0.03). The three infertile groups had significantly lower seminal plasma testosterone/oestradiol ratio than control men ( p < 0.001). Sperm analysis data (concentration, motility and morphology) significantly correlated with seminal plasma testosterone/oestradiol ratio. The findings of elevated seminal plasma oestradiol, decreased testosterone and testosterone/oestradiol ratio in infertile men, and the significant correlation between hormone levels and sperm analysis data suggest that the local balance between androgen and oestrogen is important for spermatogenesis.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12406366&dopt=Abstract estradiol




Neuroendocrinology. 2002 Oct;76(4):214-22.
Estrogenic properties of raloxifene, but not tamoxifen, on D2 and D3 dopamine receptors in the rat forebrain.

Landry M, Levesque D, Di Paolo T.

Molecular Endocrinology and Oncology Research Center and Faculte de Pharmacie, Universite Laval, Sainte-Foy, Que., Canada.

The present study investigated the estrogenic specificity of the modulation of dopamine D(2) and D(3) receptors by comparing the effects of estradiol with tamoxifen or raloxifene. These compounds have estrogenic and/or antiestrogenic activity depending on the target tissue. Two weeks after ovariectomy of female rats, we observed a 60% decrease in the uterine weight, which was prevented by a replacement therapy of 2 weeks with 17beta-estradiol. A tamoxifen or raloxifene treatment of 2 weeks increased uterine weights by 35 and 15%, respectively, but significantly less than estradiol treatment. Ovariectomy decreased dopamine D(2) receptor specific binding (20%) in the dorsolateral part of the anterior striatum and these receptors were left unchanged in the other parts of the striatum as well as in the olfactory tubercle and the nucleus accumbens. 17beta-Estradiol and raloxifene, but not tamoxifen treatment prevented this decrease. Ovariectomy left dopamine D(3) receptor specific binding unchanged. However, estradiol and raloxifene treatment decreased dopamine D(3) receptor binding in the islands of Calleja, the core and shell of the nucleus accumbens and the dorsal part of the anterior striatum, compared with ovariectomized rats. Our results show that raloxifene, but not tamoxifen, has an agonist estrogenic activity on dopamine receptors. Furthermore, estradiol and raloxifene have opposite effects on specific binding to dopamine D(2) and D(3) receptors. Copyright 2002 S. Karger AG, Basel

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12411738&dopt=Abstract estradiol




Arch Toxicol. 2002 Nov;76(11):613-20. Epub 2002 Aug 08.
Immature uterotrophic assay of estrogenic compounds in rats given diets of different phytoestrogen content and the ovarian changes with ICI 182,780 or antide.

Yamasaki K, Sawaki M, Noda S, Wada T, Hara T, Takatsuki M.

Chemicals Assessment Center, Chemicals Evaluation and Research Institute, 3-822, Ishii, Hita, Oita 0877-0061, Japan. yamasaki-kanjeri.jp

To investigate the influence of phyotestrogens in the diet, an immature uterotrophic assay of ethinylestradiol, bisphenol A, 4-nonylphenol or genistein was performed in rats given the formula MF diet, modified NIH-07 open formula diet, or modified NIH-07 phytoestrogen-lowered-diet (study 1). The chemicals were administered subcutaneously from 20 days of age for 3 days. Doses of ethinylestradiol, bisphenol A, 4-nonylphenol or genistein were 0.06-0.6 micro g/kg per day, 1-10 mg/kg per day, 10-100 mg/kg per day or 1-20 mg/kg per day, respectively. In another study, an immature uterotrophic assay of genistein and ethinylestradiol together with ICI 182,780 or antide was performed to compare the ovarian changes with these chemicals (study 2). Doses of genistein or ethinylestradiol were 30 mg/kg per day or 0.6 micro g/kg per day, respectively, and these chemicals were injected subcutaneously from 20 days of age for 3 days. In study 1, there were no essential differences in the uterus weights among the various phytoestrogen-content diets. In study 2, the ovary weights in rats given genistein were significantly higher than in the controls, whereas the ovary weights in rats given ethinylestradiol were lower than in the controls. The ovary weights in the ICI 182,780 plus genistein group were significantly higher than in the genistein group, but decrease of the ovary weights was detected in the antide plus genistein group. There was no significant difference in ovary weights between the ICI 182,780 plus ethinylestradiol group and the ethinylestradiol group, but decrease of ovary weights was detected in antide pl




Physiol Behav. 2002 Nov;77(2-3):217-25.
High levels of estradiol impair spatial performance in the Morris water maze and increase 'depressive-like' behaviors in the female meadow vole.

Galea LA, Lee TT, Kostaras X, Sidhu JA, Barr AM.

Department of Psychology and Neuroscience Program, The University of British Columbia, Vancouver, British Columbia, Canada. lgalesych.ubc.ca

The present study investigated sex differences and the effect of a high level of estradiol in the female meadow vole on performance in the forced swim test (FST) and the Morris water maze in meadow voles. Female meadow voles were ovariectomized (OVX) and administered either vehicle (sesame oil) or estradiol for 2 days prior to performing the FST. Four days following the FST, all animals were run in the Morris water maze. Results indicated that estradiol-injected female meadow voles showed more 'depressive-like' behaviors in the FST (greater time spent immobile and less time spent swimming) than vehicle-treated female or male meadow voles. In addition, estradiol-treated females had impaired performance (greater latencies and distance swam to reach the hidden platform) than both vehicle-treated female and male meadow voles, consistent with previous data. Despite the fact that estradiol administration increased 'depressive-like' behaviors in the FST and impaired performance in the Morris water maze, there was no correlation between the two behaviors indicating that 'depressive-like' behaviors did not account for the differences seen in spatial performance in the Morris water maze. To our knowledge, this is the first demonstration in rodents indicating that estradiol-mediated changes in behavior in the FST is not indicative of subsequent performance in the Morris water maze.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12419397&dopt=Abstract estradiol




Pancreas. 2003 Apr;26(3):e59-66.
Estradiol alleviates acinar cell apoptosis and chronic pancreatitis in male Wistar Bonn/Kobori rats.

Nakamura S, Yamada T, Hashimoto T, Takahashi S, Sogawa M, Ohara H, Nakazawa T, Sano H, Kuno A, Joh T, Nomura T, Arakawa T, Itoh M.

Department of Comprehensive Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

AIMS: To quantitatively determine the influence of estradiol on acinar cell apoptosis and chronic pancreatitis; assess its effects on infiltration of CD4 and CD8 T cells in the pancreas; investigate the role of testosterone on chronic pancreatitis in 20-week-old male WBN/Kob rats; and determine the impact of estradiol on proliferation of splenocytes derived from these animals in vitro. METHODOLOGY AND FINDINGS: Treatment with high (0.4 mg x kg x week) but not low (0.1 mg x kg x week) doses of estradiol for 10 weeks significantly decreased the number of apoptotic acinar cells stained with an anti-single strand DNA antibody, histologic scores, and pancreatic myeloperoxidase activity in 20-week-old WBN/Kob rats, in comparison with control values. The high doses also significantly attenuated the increase in pancreatic hydroxyproline content, an indicator of collagen deposition, at 20 weeks. They caused significant decreases in the numbers of CD4 and CD8 T cells infiltrating the pancreas. Both doses suppressed levels of testosterone but without any influence on the serum corticosterone concentrations. Androgen receptors could not be immunohistochemically identified in the pancreas at 20 weeks, and dietary treatment with flutamide, an androgen receptor antagonist, did not influence the chronic pancreatitis. Estradiol significantly reduced 1% phytohemagglutinin-induced incorporation of bromodeoxyuridine into the splenocytes in vitro. CONCLUSIONS: We conclude that estradiol dose-dependently attenuates acinar cell apoptosis and development of chronic pancreatitis, independent of any change in endogenous corticosterone and




Neuroscience. 2002;115(2):415-24.
Dehydroepiandrosterone and alpha-estradiol limit the functional alterations of rat brain mitochondria submitted to different experimental stresses.

Morin C, Zini R, Simon N, Tillement JP.

Departement de Pharmacologie, Faculte de Medecine de Paris XII, 8 rue du General Sarrail, F-94010 Creteil, France. ch.moriniv-paris12.fr

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