Behav Brain Res. 2001 Nov 29;126(1-2):115-26.
High levels of estradiol disrupt conditioned place preference learning, stimulus response learning and reference memory but have limited effects on working memory.
Galea LA, Wide JK, Paine TA, Holmes MM, Ormerod BK, Floresco SB.
Department of Psychology, The University of British Columbia, 2136 West Mall, Vancouver B.C., Canada V6T 1Z4. lgalesych.ubc.ca
The present study investigated the effects of high levels of estradiol in female rats on four different radial arm maze tasks: the hippocampus-dependent spatial working-reference memory task; the prefrontal cortex-hippocampus dependent delayed win-shift task; the striatum-dependent cued win-stay task; and the amygdala-dependent conditioned place preference task. Ovariectomized female rats were injected daily with either 10 microg of estradiol benzoate or sesame oil vehicle approximately 4 h prior to testing. In Experiment 1, treatment with estradiol disrupted learning on the spatial working-reference memory task by increasing the number of reference memory errors to reach criterion. In Experiment 2, treatment with estradiol had no significant effect on the delayed win-shift task. In Experiment 3, treatment with estradiol resulted in impaired performance on a striatum-dependent cued win-stay task. In Experiment 4, treatment with estradiol impaired the acquisition of a conditioned place-preference task. Taken together these findings suggest that high levels of estradiol inhibit reference memory, stimulus response learning, and amygdala-dependent appetitive conditioning while having little effect on working memory.
Gene Ther. 2001 Oct;8(20):1562-71.
Steroid hormone enhancement of gene delivery to a human airway epithelial cell line in vitro and mouse airways in vivo.
Wiseman JW, Goddard CA, Colledge WH.
Department of Physiology, University of Cambridge, Cambridge, CB2 3EG, UK.
Current liposome-based delivery protocols for gene therapy are relatively inefficient. In a pharmacological approach to enhance liposome-mediated gene delivery we have evaluated beta-estradiol and methyl-prednisolone as enhancing agents. We have shown that beta-estradiol in combination with lipoplex can significantly increase luciferase gene expression in sub-confluent, confluent and polarized human bronchial epithelial (16HBE) cells 23-fold, 100-fold and 900-fold, respectively, when compared with lipoplex alone. Similarly, incorporation of methyl-prednisolone into lipoplexes increases luciferase gene expression in confluent and polarized 16HBE cells 70.8-fold and 48-fold, respectively. Greater levels of gene expression were obtained when beta-estradiol (9.5-fold enhancement) or methyl-prednisolone (14-fold enhancement) were mixed with the liposome before addition of the plasmid compared with addition of the steroid after lipoplex formation. Beta-estradiol-containing lipoplexes were also evaluated in vivo where in the murine lung and nasal epithelium an eight-fold and 7.5-fold enhancement in gene expression were found compared with lipoplex alone. Incorporating beta-estradiol into lipoplexes increased both the total number of cells transfected and the amount of intracellular plasmid within the cell, including the nuclear compartment, compared with lipoplex alone. These results demonstrate the ability of steroids to enhance gene delivery in vitro and in vivo and thus may have the potential to improve gene therapy strategies.
Eur J Pharmacol. 2001 Nov 2;430(2-3):175-83.
Modulation by estrogens and xenoestrogens of recombinant human neuronal nicotinic receptors.
Nakazawa K, Ohno Y.
Division of Pharmacology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya, 158-8501, Tokyo, Japan. nakazawihs.go.jp
The effects of estrogens and xenoestrogens on human neuronal nicotinic acetylcholine receptor/channels were examined by expressing recombinant channels in Xenopus oocytes. When functional channels were expressed with alpha3 and beta4 subunits, estrogens (17beta-estradiol, 17alpha-estradiol, 17alpha-ethynylestradiol and diethylstilbestrol) and xenoestrogens (bisphenol A, p-nonylphenol and p-octylphenol) inhibited an ionic current activated by acetylcholine at concentrations up to 100 microM. When the subunit combination was changed to alpha4beta2, diethystilbestrol and the xenoestrogens inhibited the acetylcholine-activated current, but 17beta-estradiol or 17alpha-estradiol did not. For 17alpha-ethynylestradiol, the current through the alpha4beta2 receptor/channel was inhibited at 1 microM, but it was markedly enhanced at 10 and 100 microM. Tamoxifen (10 microM), an antiestrogen, itself inhibited the acetylcholine-activated current but did not antagonize the current modulations induced by the estrogens and the xenoestrogens. These and additional results suggest that human neuronal nicotinic acetylcholine receptors are the targets of non-genomic actions of estrogens and xenoestrogens.
Steroids. 2001 Dec;66(12):889-96.
Estradiol esterification in the human preovulatory follicle.
Cigliano L, Spagnuolo MS, Dale B, Balestrieri M, Abrescia P.
Dipartimento di Fisiologia Generale ed Ambientale, Universita di Napoli Federico II, Via Mezzocannone 8-80134 Napoli, Italy.
In the preovulatory follicle, the LH surge stimulates progesterone production, reduces estradiol synthesis, and scales up the permeability of the blood-follicle barrier. The purpose of this study was to investigate whether the extent of these changes is correlated with the levels of estradiol, estradiol esters, and cholesteryl esters in the follicular fluid. The follicular levels of progesterone, estradiol, estradiol linoleate, cholesterol, and cholesteryl linoleate were measured by HPLC. The estradiol linoleate/estradiol ratio, which reflects the efficiency of in vivo estradiol esterification, and the cholesteryl linoleate/cholesterol ratio were calculated and found negatively correlated. The estradiol level was positively correlated with the cholesteryl linoleate/cholesterol ratio while negatively correlated with the estradiol linoleate/estradiol ratio. The in vitro activity of lecithin-cholesterol acyltransferase, the enzyme esterifying both cholesterol and estradiol, was assayed by incubating the fluid with labeled substrates. This activity was not correlated with either the estradiol linoleate/estradiol or the cholesteryl linoleate/cholesterol ratio. The enzyme K(m) and V(max) values were lower with estradiol than with cholesterol. Higher estradiol linoleate/estradiol ratios and lower cholesteryl linoleate/cholesterol ratios were associated with higher level of Haptoglobin penetration into the follicle. This level, which was determined by ELISA, was found increased with increased progesterone concentration and, therefore, used as a marker of the LH-stimulated permeability of the blood-follicle barrier. Our data suggest that early preovulatory follicles contain more cholesteryl esters and less estradiol e
Circulation. 2001 Nov 20;104(21):2576-81.
Estrogen receptor-mediated, nitric oxide-dependent modulation of the immunologic barrier function of the endothelium: regulation of fas ligand expression by estradiol.
Amant C, Holm P, Xu Sh SH, Tritman N, Kearney M, Losordo DW.
Divisions of Cardiovascular Medicine and Cardiovascular Research, St Elizabeth's Medical Center, Boston, Massachusetts, USA.
BACKGROUND: Premenopausal women have a lower incidence of coronary artery disease than postmenopausal women or same-age men. Although the mechanisms of this apparent relative protection against atherosclerosis remain ill defined, estradiol, which is present in higher concentrations before menopause, is considered to play a central role. Recently, Fas ligand (FasL) expression by the vascular endothelium has been shown to inhibit the migration of inflammatory cells into the vessel wall, an event that is considered crucial for the development of atherosclerosis. METHODS AND RESULTS: The regulation of endothelial FasL expression by estradiol was investigated in vivo and in vitro. In an ovariectomized, cholesterol-clamped rabbit model, FasL expression was shown to be downregulated by elevations in serum cholesterol, which also resulted in invasion of the arterial wall by macrophages. Estradiol replacement resulted in restoration of FasL expression, with resultant inhibition of leukocyte traffic across the endothelium. Inhibition of NO production by addition of L-NAME to the drinking water of the estradiol-treated rabbits abrogated these effects. In vitro, estradiol is shown to regulate FasL expression at the transcriptional level via an estrogen receptor-mediated, NO-dependent mechanism. CONCLUSIONS: Estradiol transcriptionally regulates endothelial FasL expression by a mechanism involving at least one of the estrogen receptors. In an animal model of atherosclerosis, estradiol restores FasL expression, which is suppressed by atherogenic levels of serum cholesterol. The maintenance of endothelial FasL expressi
J Pharmacol Exp Ther. 2001 Dec;299(3):973-7.
2-Hydroxyestradiol attenuates the development of obesity, the metabolic syndrome, and vascular and renal dysfunction in obese ZSF1 rats.
Tofovic SP, Dubey RK, Jackson EK.
Center for Clinical Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
A pandemic of obesity is contributing importantly to the prevalence of the metabolic syndrome characterized by hypertension, insulin resistance, and hyperlipidemia. In turn, the metabolic syndrome is contributing to vascular disease and the accelerating epidemic of chronic renal failure. Currently, pharmacological approaches to attenuate obesity and its cardiovascular/renal sequelae are limited. The purpose of this study was to determine the effects of 2-hydroxyestradiol, a metabolite of 17beta-estradiol with minimal estrogenic activity, on the development of obesity, the metabolic syndrome, and heart, vascular, and renal dysfunction in obese ZSF1 rats, a well-characterized genetic model of obesity and the metabolic syndrome with concomitant heart, vascular, and kidney disease. ZSF1 rats were treated, beginning at 12 weeks of age, for 26 weeks with vehicle or 2-hydroxyestradiol (10 microg/kg/h). At baseline and after 24 weeks of treatment, animals were placed in metabolic cages, and food intake, water intake, urine output, and urinary excretion of proteins and glucose were determined. Next, in fasting animals, plasma cholesterol was measured, an oral glucose tolerance test was conducted, and total glycated hemoglobin levels were determined. At the end of the study, animals were anesthetized and instrumented for assessment of heart performance, renal hemodynamics, and mesenteric vascular reactivity. 2-Hydroxyestradiol attenuated the development of obesity and improved endothelial function, decreased nephropathy, decreased the severity of diabetes, lowered arterial blood pressure, and reduced plasma cholesterol. 2-Hydroxyestradiol may be an important lead for the developm
Horm Metab Res. 2003 Feb;35(2):76-80.
The effect of progesterone and synthetic progestins on serum- and estradiol-stimulated proliferation of human breast cancer cells.
Seeger H, Wallwiener D, Mueck AO.
Section of Endocrinology and Menopause, Department of Obstetrics and Gynecology, University of Tubingen, Germany.
The results from the Women's Health Initiative study on enhanced breast cancer risk in postmenopausal women using an estrogen/progestin combination clearly indicate the need for a comparison of different progestins with regard to cancer risk. To shed some light on this issue, we have investigated the influence of progesterone and various synthetic C19- and C21-progestins on cell proliferation of a human breast cancer cell line in vitro. Of special interested was the comparison of two different regimens commonly used in HRT, sequential and continuous combination with estradiol. We used the human breast cancer cell line MCF-7 as a model. Progesterone (P), chlormadinone acetate (CMA), dienogest (DNG), gestodene (GSD), 3-ketodesogestrel (KDG), levonorgestrel (LNG), medroxyprogesterone acetate (MPA), and norethisterone (NET) were investigated in the range of 0.01nm to 10 micro M alone and in combination with 10 nM estradiol. Cell proliferation was measured after 7 days using the ATP chemosensitivity test. Tested alone, CMA, DNG, GSD, KDG, MPA and NET significantly stimulated cell proliferation, but only at high dosages. Sequentially combined with estradiol, only CMA inhibited cell proliferation over the whole concentration range. Slight effects were found for DNG, GSD and KDG, whereas P and MPA only showed an effect at the highest concentration. NET had no significant effect on cell proliferation. Continuously combined, all progestins exhibited an inhibitory effect over the whole concentration range. The most prominent effects were found for P, CMA, GSD, and KDG. Only slight effects were found for DNG, MPA and NET. Our in vitro results indicate that the influence on breast cancer ri
Prostate. 2002 Dec 1;53(4):322-9.
Relationship of serum sex-steroid hormones and prostate volume in African American men.
Joseph MA, Wei JT, Harlow SD, Cooney KA, Dunn RL, Jaffe CA, Montie JE, Schottenfeld D.
Department of Epidemiology, The University of Michigan, Ann Arbor, Michigan 48109-2029, USA.
BACKGROUND: Previous epidemiologic investigations of the associations of sex-steroid hormones and benign prostatic hyperplasia (BPH) have focused on predominately white populations. The objective of this study was to evaluate potential associations of body mass index (BMI), cigarette smoking, use of alcohol, and endogenous sex-steroid hormones with prostate volume in a population-based sample of African American (AA) men, ages 40-79 yr. METHODS: A total of 369 AA men without clinical evidence of prostate cancer were identified in the Flint Men's Health Study by using a population-based sampling procedure. All subjects underwent a complete urologic evaluation that included prostate volume determination by transrectal ultrasonography and serum assays for androgens and estrogens. RESULTS: After age adjustment, BMI (weight (kg)/height (m)2) was positively correlated with increasing levels of androstanediol glucuronide (AG), estradiol (E2), estrone sulfate (E1S), and the ratios of E2:total testosterone (TT) and E2:free testosterone (FT); however, increasing BMI was negatively correlated with androstenedione (AD), FT, TT, and sex hormone-binding globulin (SHBG). Multivariable regression models demonstrated that prostate volume increased with age (P < 0.001) and BMI (P = 0.02) and decreased with increasing levels of SHBG (P = 0.01). Larger prostatic volumes were also marginally associated with increasing levels of TT (P = 0.058). CONCLUSION: Circulating serum levels of SHBG and endogenous sex-steroid hormones are correlated with prostate volume and potentially impact the natural history of BPH. However, longitudinal studies are needed to demonstrate the temporal relationships of hormones and
Horm Metab Res. 2001 Jun;33(6):337-42.
Effect of serotonin depletion by p-chlorophenylalanine on serum prolactin levels in estrogen-treated ovariectomized rats: insights concerning the serotoninergic, dopaminergic and opioid systems.
Mallmann ES, Ribeiro MF, Spritzer PM.
Division of Endocrinology, Hospital de Clinicas de Porto Alegre, Brazil.
The stimulatory effect of serotonin on prolactin secretion is well documented, and the administration of an inhibitor of serotonin synthesis (p-chlorophenylalanine - pCPA) has the expected inhibitory action on prolactin release in most experimental situations. However, there is evidence that in certain physiological or experimental conditions, activation of the serotoninergic system can also determine inhibition of prolactin secretion. The aim of the present study was to investigate the ability of estrogen to modify the effect of pCPA on prolactin secretion and to evaluate the participation of opioid and/or dopaminergic systems in regulating pCPA-induced prolactin secretion in estradiol-treated rats. We observed that pCPA administration (200 mg/kg/day, s.c., 2 days) to ovariectomized (OVX) female rats treated with estradiol benzoate (300 microg/week for 2 weeks, or 50 microg/week for 4 weeks, s.c.) causes a significant increase in serum prolactin, whereas no effect is observed in intact rats or in OVX rats without treatment. Bromocriptine administration completely reversed prolactin values previously increased by estradiol and by pCPA [OVX rats + estradiol = 86.50 ng/ml (68.90-175.02), OVX + estradiol + pCPA = 211.30 ng/ml (142.03-311.00), OVX + estradiol + pCPA + bromocriptine = 29.35 ng/ml (23.01 - 48.74), p<0.05. Naloxone administration partially reduced estrogen-induced high prolactin concentrations, but did not affect prolactin secretion stimulation determined by pCPA. Overall, the data from this report confirm the involvement of the dopaminergic system and, to a lesser degree, of endogenous opioids in prolactin secretion stimulation determine
Endocrinology. 2001 Aug;142(8):3554-7.
PPARalpha-dependent induction of liver microsomal esterification of estradiol and testosterone by a prototypical peroxisome proliferator.
Xu S, Zhu BT, Turan V, Rusyn I, Thurman R, Peters JM, Gonzalez FJ, Conney AH.
Laboratory for Cancer Research, Department of Chemical Biology, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
Fatty acyl-coenzyme A:estradiol acyltransferase in liver microsomes catalyzes the formation of estradiol fatty acid esters. These estrogen esters are extremely lipophilic and have prolonged hormonal activity because they are slowly metabolized and slowly release estradiol. Our previous studies showed that treatment of female rats with clofibrate or gemfibrozil (peroxisome proliferators commonly used as hypolipidemic drugs) markedly stimulated the liver microsomal esterification of estradiol. Although clofibrate administration is a potent inducer of liver microsomal fatty acyl-coenzyme A:estradiol acyltransferase in rats, it is a poor inducer in mice. In contrast to these observations, Wy-14,643 (an exceptionally potent prototypical peroxisome proliferator) is a strong inducer of fatty acyl-coenzyme A:estradiol acyltransferase in mice. To explore the role of PPARalpha in the induction of fatty acyl-coenzyme A:estradiol acyltransferase and fatty acyl-coenzyme A:testosterone acyltransferase activities by peroxisome proliferators, we fed 0.1% Wy-14,643 to female wild-type and PPARalpha null mice for 11 d. The liver microsomal acyl-coenzyme A:estradiol acyltransferase and acyl-coenzyme A:testosterone acyltransferase activities were increased 4- to 5-fold in wild-type mice fed Wy-14,643, but no increase was observed in null mice. These results demonstrate that induction of acyl-coenzyme A:estradiol acyltransferase and acyl-coenzyme A:testosterone acyltransferase activities by a prototypical peroxisome proliferator is dependent on PPARalpha.
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