Int J Gynecol Cancer. 1992 Mar;2(2):101-106.
Characterization of an estradiol-independent but estradiol-responsive growth phenotype in a human endometrial adenocarcinoma heterotransplanted into nude mice.

Horvath G, Ferno M, Baldetorp B, Cameron R, Ranstam J.

Gynecologic Section, General Section, Department of Oncology, Department of Pathology, and Department of Community Health Sciences, University Hospital, S-221 85 Lund, Sweden.

The tumor growth phenotype was characterized in relation to concentration of circulating estradiol, estradiol receptor (ER) activation and progesterone receptor (PgR) induction. Ten tumor pieces from an ER and PgR positive human endometrial adenocarcinoma grown in non-oophorectomized nude mice for one year were randomly selected to grow during a preparation phase of 4 weeks either in oophorectomized nude mice - to adapt tumor growth to the absence of estradiol (group A), or in non-oophorectomized nude mice (group B). For the experimental phase, tumor pieces from each group were again randomly assigned to either of two subgroups (i.e., 4 subgroups in all): with estradiol treatment (subgroups A+ and B+), or without (subgroups A- and B-) as control subgroups. There were no differences in take rate or tumor growth rate between the control subgroups (A- vs. B-), indicating tumor growth to be estradiol-independent. The tumor was estradiol-sensitive, however, as tumor growth could be stimulated by estradiol. Despite its estradiol-independence of growth, the tumor's estradiol-binding capacity varied according to whether the host animals were oophorectomized or not; and despite the similar growth patterns during the experimental phase, the values of high affinty bound ER (ER activation) were greater for tumors grown in non-oophorectomized mice during the preparation phase than for those grown in oophorectomized mice. Thus, our findings show that an ovarain (estradiol) independent but responsive phenotype of tumor growth is present in human endometrial adenocarcinomas growing i




J Neuroendocrinol. 2001 Sep;13(9):761-8.
Oestradiol increases phosphorylation of a dopamine- and cyclic AMP-regulated phosphoprotein (DARPP-32) in female rat brain.

Auger AP, Meredith JM, Snyder GL, Blaustein JD.

Center for Neuroendocrine Studies, Neuroscience and Behavior Program, Tobin Hall, University of Massachusetts, Amherst, MA, USA. aauge00maryland.edu

Recent studies suggest that oestrogen and progestin receptors may be activated by the neurotransmitter dopamine, as well as by their respective ligands. Because intracerebroventricular infusion of D(1), but not D(2), dopaminergic receptor agonists increases oestrous behaviour in oestradiol-primed rats, we wanted to determine if treatment with oestradiol alters the activity of D(1) receptor-associated processes in steroid receptor-containing areas in female rat brain. One D(1) receptor-associated phosphoprotein that may be influenced by oestradiol is a dopamine- and cyclic AMP-regulated phosphoprotein, Mr = 32,000 (DARPP-32). Because DARPP-32 is phosphorylated in response to dopamine acting via a cAMP-dependent protein kinase, it provides a useful marker to examine where in the brain a particular stimulus might be altering the activity of D(1) receptor-containing neurones. To determine if oestradiol alters the phosphorylation of DARPP-32, we stained immunocytochemically brain sections of female rats treated with behaviourally relevant doses of oestradiol or oil vehicle with an antibody that detects only the threonine 34-phosphorylated form of DARPP-32. Behaviourally effective doses of oestradiol increase the phosphorylation of DARPP-32 within the medial preoptic nucleus, bed nucleus of the stria terminalis, paraventricular nucleus of the hypothalamus and the ventromedial nucleus of the hypothalamus, 48 h after treatment. These data suggest that oestradiol increases the activity of D(1) dopamine receptor-associated processes in oestrogen receptor-containing areas of female rat forebrain.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11578525&dopt=Abstract estradiol [PubMed - indexed for MEDL




J Neurosci. 2001 Oct 15;21(20):RC176.
17-beta-estradiol induces an inhibitor of active caspases.

Zhang Y, Tounekti O, Akerman B, Goodyer CG, LeBlanc A.

Departments of Neurology and Neurosurgery and Pediatrics, McGill University, Montreal, Quebec, Canada H3A 2T5.

We have shown previously that caspase-6 activity is lethal to human neurons (LeBlanc et al., 1999; Zhang et al., 2000). Here we find that 17-beta-estradiol but not 17-alpha-estradiol prevents caspase-6-mediated neuronal cell death. 17-beta-estradiol-treated neuronal extracts directly inhibit recombinant active caspase-6, caspase-3, caspase-7, and caspase-8 in vitro. We conclude that 17-beta-estradiol induces a caspase inhibitory factor (CIF) that is preventing neuronal apoptosis. The induction of CIF occurs within 10 min of 17-beta-estradiol exposure to neurons, does not require de novo protein synthesis, and involves mitogen-activated protein kinase activation. The effect is antagonized by the estrogen receptor antagonist tamoxifen. In contrast, 17-beta-estradiol does not induce CIF or prevent caspase-mediated cell death in cultured astrocytes. CIF does not act through oxidation of the caspase active site. CIF activity copurifies with proteins of between 12 and 14 kDa in size. Our results indicate that 17-beta-estradiol induces an inhibitor of active caspases through a receptor-mediated nongenomic pathway and provide an additional mechanism for the neuroprotective action of 17-beta-estradiol that is likely highly relevant to the understanding of the role of estrogen against Alzheimer's disease.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11588206&dopt=Abstract estradiol




Life Sci. 2001 Aug 24;69(14):1609-17.
Different role of endothelium/nitric oxide in 17beta-estradiol- and progesterone-induced relaxation in rat arteries.

Chan HY, Yao X, Tsang SY, Chan FL, Lau CW, Huang Y.

Department of Physiology, Chinese University of Hong Kong, People's Republic of China.

The present study was aimed to examine the different role of endothelium/nitric oxide in relaxation induced by two female sex hormones, 17beta-estradiol and progesterone in rat isolated aortas and mesenteric arteries. The isometric force of each ring was measured with Grass force-displacement transducers in the organ bathes. 17beta-Estradiol induced both endothelium-dependent and -independent relaxation in the rat aortas but only the endothelium-independent relaxation in the rat mesenteric arteries. In contrast. progesterone induced both endothelium-dependent and -independent relaxation in the rat mesenteric arteries but only endothelium-independent relaxation in rat aortas. N(G)-Nitro-L-arginine methyl ester and methylene blue attenuated the relaxant response to 17beta-estradiol in the aortic rings or to progesterone in the mesenteric arteries. Pretreatment with L-arginine antagonized the effect of N(G)-nitro-L-arginine methyl ester on sex hormone-induced relaxation. The endothelium contribution to relaxation seems to only relate to lower concentrations of 17beta-estradiol and progesterone. In summary, the present results clearly demonstrate a different role of the functional endothelium in the relaxant response to 17beta-estradiol or progesterone in the conduit vessel (aorta) and the resistance vessels (mesenteric artery). Nitric oxide contributes largely to the endothelium-dependent relaxation induced by 17beta-estradiol in the isolated aortas or by progesterone in the mesenteric arteries.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11589501&dopt=Abstract estradiol




Life Sci. 2001 Aug 24;69(14):1651-60.
Estrogen prevents destabilization of endothelial nitric oxide synthase mRNA induced by tumor necrosis factor alpha through estrogen receptor mediated system.

Sumi D, Hayashi T, Jayachandran M, Iguchi A.

Department of Geriatrics, Nagoya University Graduate School of Medicine, Japan.

17beta-estradiol up-regulates endothelial nitric oxide synthase (eNOS) expression in cultured endothelial cells. To clarify the role of mRNA stabilization in upregulation of eNOS expression, endothelial cells were incubated with actinomycin D as transcriptional inhibitor. Up to 10 hours incubation with 17beta-estradiol alone did not affect significantly the stability of eNOS mRNA. As tumor necrosis factor-alpha (TNF-alpha) is associated with the progression of atherosclerosis, we examined the effect of 17beta-estradiol on eNOS mRNA destabilization with TNF-alpha. After 10 hours co-incubation with TNF-alpha, relative intensity of eNOS mRNA decreased to 50% of the intensity at the start time of incubation, however, it remained significantly 1.6 times in the presence of 17beta-estradiol. This inhibitory effect of 17beta-estradiol was abolished by the treatment of estrogen receptor antagonist, ICI 182,780. This is the first finding that 17beta-estradiol stabilizes eNOS mRNA destabilized by TNF-alpha through estrogen receptor mediated mechanism.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11589505&dopt=Abstract estradiol




Environ Toxicol Chem. 2001 Oct;20(10):2142-51.
Substances with estrogenic activity in effluents of sewage treatment plants in southwestern Germany. 2. Biological analysis.

Korner W, Spengler P, Bolz U, Schuller W, Hanf V, Metzger JW.

Institute of Organic Chemistry, University of Tubingen, Germany. wolfgang.koernefu.bayern.de

The proliferation test with human estrogen receptor-positive MCF-7 breast cancer cells (E-Screen assay) was applied for quantitative determination of total estrogenic activity in 24-h composite effluent samples from 16 municipal and two industrial sewage treatment plants (STPs) in the state of Baden-Wurttemberg, southwestern Germany. The estrogenic efficacy relative to the positive control, 17beta-estradiol, was between 26 and 74% (median, 48%) for the 16 municipal STPs. Estradiol equivalent concentrations (EEQs) were between 0.2 and 7.8 ng/L (median, 1.6 ng/L) and, thereby, were lower than those found in a pilot study, which revealed EEQs of greater than 10 ng/L in the effluents of two other STPs. The EEQs in 14 of the 16 effluent samples were very similar (0.9-3.3 ng/L), indicating a rather constant input of estrogenic substances via STPs into rivers. Additional activated charcoal filtration turned out to be very efficient in further eliminating estrogenic activity from effluents. The EEQs of the E-Screen assay and those calculated from the results of extensive chemical analysis using the estradiol equivalency factors determined for 13 natural and synthetic estrogenic substances were comparable for most of the effluent samples. 17beta-Estradiol, 17alpha-ethinylestradiol, and, to a lesser extent, estrone contributed to 90% or more of the EEQ value.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11596742&dopt=Abstract estradiol




Biochim Biophys Acta. 2003 May 12;1640(2-3):113-8.
17beta-estradiol inhibits NADPH oxidase activity through the regulation of p47phox mRNA and protein expression in THP-1 cells.

Sumi D, Hayashi T, Matsui-Hirai H, Jacobs AT, Ignarro LJ, Iguchi A.

Department of Geriatrics, Nagoya University Graduate School of Medicine, 65, Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan.

In this report, we demonstrate that NADPH oxidase is activated by tumor necrosis factor-alpha (TNF-alpha) plus interferon-gamma (IFN-gamma) in human monocytic cells (THP-1 cells) differentiated with phorbol ester (PMA) and that physiological concentration of 17beta-estradiol inhibits NADPH oxidase activity in THP-1 cells stimulated with TNF-alpha plus IFN-gamma. This effect is mediated by estrogen receptor based on estrogen receptor antagonist (ICI 182, 780) that diminishes inhibition by 17beta-estradiol. This inhibition is specific in 17beta-estradiol because 17alpha-estradiol, testosterone and progesterone do not inhibit NADPH oxidase activity. Activation of NADPH oxidase induced by TNF-alpha plus IFN-gamma is caused by up-regulation of p47(phox) (cytosolic component of NADPH oxidase) expression. 17beta-Estradiol prevents the up-regulation of p47(phox) mRNA and protein expression. This prevention of p47(phox) expression depends on the inhibition of NF-kappaB activation. Our results implicate that 17beta-estradiol has an anti-atherosclerotic effects through the improvement of nitric oxide (NO) bioavailability caused by the regulation of superoxide (O(2)(-)) production.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12729920&dopt=Abstract estradiol




J Cardiovasc Pharmacol. 2001 Nov;38(5):657-65.
Tamoxifen is an acute, estrogen-like, coronary vasodilator of porcine coronary arteries in vitro.

Hutchison SJ, Chou TM, Chatterjee K, Sudhir K.

Division of Cardiology, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada. stuart.hutchinsotoronto.ca

Tamoxifen is a mixed estrogen antagonist and agonist. Observational data from breast cancer studies associate tamoxifen use with lesser rates of myocardial infarction. The authors sought to determine the acute vasoactive properties of tamoxifen compared with estradiol. Isolated coronary ring segments from female pigs were studied in organ baths. KCl-precontracted ring segments were exposed to increasing doses of both tamoxifen and estradiol (log-9-log-5 M ). Ring segments were also exposed to tamoxifen and estradiol in the presence of inhibitors of nitric oxide, glybenclamide, the hormone receptor antagonists ICI 182,780 and flutamide, and after de-endothelialization. Tamoxifen caused acute dilation of coronary arteries but less than estradiol. Tamoxifen-and estradiol-induced acute vasodilation was not nitric oxide- or endothelium-dependent, but was adenosine triphosphate-sensitive potassium channel-dependent. Tamoxifen-induced vasorelaxation was inhibited by antagonism of the classic estrogen receptor and antagonism of the androgen receptor with flutamide, whereas estrogen-induced vasorelaxation was inhibited partially by classic estrogen receptor antagonism but not by androgen receptor antagonism. Tamoxifen attenuated both the sensitivity of vasoconstriction to endothelin-1 and the maximal response. Tamoxifen and estradiol are both acute coronary vasodilators, with similar mechanisms of action. Tamoxifen also attenuates coronary vasoconstriction. Such properties may account for some of the observed cardiovascular clinical benefits seen in observational studies of tamoxifen use.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11602812&dopt=Abstract estradiol




J Biotechnol. 2001 Dec 14;92(1):47-59.
Strategies to modulate BHK cell proliferation by the regulation of IRF-1 expression.

Carvalhal AV, Moreira JL, Carrondo MJ.

Instituto de Biologia Experimental e Tecnologica/Instituto de Tecnologia Quimica e Biologica IBET/ITQB, Apartado 12, P-2781-901 Oeiras, Portugal.

Activation of the constitutively expressed interferon-regulatory-factor-1/estrogen receptor fusion protein (IRF-1-hER) in BHK cells was accomplished through the addition of estradiol to the culture medium, which enabled IRF-1 to gain its transcriptional activator function and inhibit cell growth. With the addition of 100 nM estradiol at the beginning of the exponential phase of a cell suspension culture, IRF-1 activation led to a rapid cell growth inhibition but also to a significant decrease in cell viability. To apply this concept in industry, a reduction of the time span of estradiol exposure is required. Cycles of estradiol addition and removal were performed in 2-l stirred tank bioreactors operated under perfusion, where an initial step addition of 100 nM estradiol was performed, followed, after 48-72 h, by a slow dilution with estradiol-free fresh medium (perfusion rate varying between 0.7 and 1.4 per day). Cell growth inhibition was successfully achieved for three consecutive cycles. Diluting the estradiol by perfusing medium without estradiol to concentrations lower than 10 nM led to cell growth and viability recovery independently of the perfusion rate used. These observations permitted the definition of operational strategies for regulated IRF-1 BHK cell growth by pulse estradiol addition, followed by a period of 48 h in the presence of estradiol and by fast perfusion to estradiol concentrations lower than 10 nM. Cell growth response to IRF-1 activation and following estradiol removal by perfusion was also evaluated with an IRF-1-hER regulated clone expressing constitutively Factor VII, where the time of estradiol exposure and perfusion rate were varied. This clone presented a