J Mol Endocrinol. 2004 Aug;33(1):243-52.
Tissue-specific estrogenic and non-estrogenic effects of a xenoestrogen, nonylphenol.

Watanabe H, Suzuki A, Goto M, Lubahn DB, Handa H, Iguchi T.

Center for Integrative Bioscience, Okazaki National Research Institutes, 5-1 Higashiyama, Myodaiji, Okazaki 444-8585, Japan.

Alkylphenols perturb the endocrine system and are considered to have weak estrogenic activities. Although it is known that nonylphenol can bind weakly to the estrogen receptor, it is unclear whether all reported effects of nonylphenol are attributable to its estrogen receptor-binding activity. In order to examine whether alkylphenols have similar effects to the natural hormone, estradiol, we used a mouse model to examine the effects of nonylphenol on gene expression and compared it with estradiol. DNA microarray analysis revealed that, in the uterus, most of the genes activated by this alkylphenol at a high dose (50 mg/kg) were also activated by estradiol. At lower doses, nonylphenol (0.5 mg/kg and 5 mg/kg) had little effect on the genes that were activated by estradiol. Thus, we concluded that the effects of nonylphenol at a high dose (50 mg/kg) were very similar to estradiol in uterine tissue. Moreover, since evaluation of estrogenic activity by gene expression levels was comparable with the uterotrophic assay, it indicated that analysis of gene expression profiles can predict the estrogenic activities of chemicals. In contrast to the similar effects of nonylphenol and estradiol observed in the uterus, in the liver, gene expression was more markedly affected by nonylphenol than by estradiol. This indicated that, in the liver, nonylphenol could activate another set of genes that are distinct from estrogen-responsive genes. These results indicated that nonylphenol has very similar effects to estradiol on gene expression in uterine but not in liver tissue, indicating that tissue-specific effects should be considered in order to elucidate the distinct effects of alkylphenols.

PMID




Prostaglandins Leukot Essent Fatty Acids. 2002 Dec;67(6):453-9.
Nuclear receptor agonists stimulate release of arachidonic acid from rat liver cells.

Levine L.

Department of Biochemistry, Brandeis University, Waltham, MA 02454, USA. llevinrandeis.edu

Release of arachidonic acid (AA) from rat liver cells is stimulated after a 6 h incubation with compounds that are members of the nuclear receptor superfamily, including vitamin D(3), clofibrate, 22(R) OH cholesterol, farnesol, progesterone, testosterone, 17beta-estradiol, hydrocortisone, 3,3'5 triiodothyronine, juvenile hormone III, WY14643, L -thyroxine, the tyrosine analog of thiazolidinediones, GW7845, tamoxifen, hydroxytamoxifen, 17alpha-estradiol and D -thyroxine. Squaline, lanosterol, cholesterol and the 17beta-estradiol antagonist, ICI-182,780, do not stimulate. ICI-182,780 inhibits the release stimulated by 17beta-estradiol, vitamin D(3), 22(R) OH cholesterol, celecoxib or indomethacin. Actinomycin D abolishes the release stimulated by 15-deoxy-delta(12,14) PGJ(2), but is less effective at inhibiting the release stimulated by all of the agonists listed above as well as the release stimulated by 9-cis retinoic acid, all trans -retinoic acid, the thiazidinedione, ciglitazone and the non-steroidal anti-inflammatory drugs, indomethacin and celecoxib. Based on the effects of the 17beta-estradiol antagonist, ICI-182,780, the release of AA appears to be a membrane effect and may not be mediated by the classical estrogen receptors. From the results obtained with actinomycin D, some stimulations may require transcription.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12468267&dopt=Abstract estradiol




J Clin Endocrinol Metab. 2004 Aug;89(8):3922-31.
Catecholamines block the antimitogenic effect of estradiol on human coronary artery smooth muscle cells.

Dubey RK, Jackson EK, Gillespie DG, Zacharia LC, Imthurn B.

Department of Obstetrics and Gynecology, Clinic for Endocrinology, University Hospital Zurich, Switzerland. raghvendra.dubesz.ch

Sequential conversion of estradiol to catecholestradiols and methoxyestradiols by cytochrome-P(450) (CYP450) and catechol-O-methyltransferase (COMT), respectively, contributes to the antimitogenic effects of estradiol on vascular smooth muscle cell (SMC) growth via estrogen receptor-independent mechanisms. Because catecholamines are also substrates for COMT, we hypothesize that catecholamines may abrogate the vasoprotective effects of estradiol by competing for COMT and inhibiting methoxyestradiol formation. To test this hypothesis, we investigated the antimitogenic/inhibitory effects of estradiol on human coronary artery SMC growth (cell number, DNA synthesis, collagen synthesis, and SMC migration) and ERK1/2 phosphorylation in the presence and absence of catecholamines. Norepinephrine, epinephrine, isoproterenol, and OR486 (COMT inhibitor) abrogated the inhibitory effects of estradiol on SMC growth and ERK1/2 phosphorylation. The interaction of catecholamines with estradiol was not affected by phentolamine or propanolol, alpha- and beta-adrenoceptor antagonists, respectively. The antimitogenic effects of 2-hydroxy-estradiol, but not 2-methoxyestradiol, were abrogated by epinephrine, isoproterenol, and OR486. Catecholamines inhibited the conversion of both estradiol and 2-hydroxy-estradiol to 2-methoxyestradiol, and SMCs expressed CYP1A1 and CYP1B1. Our findings suggest that catecholamines within the coronary arteries may abrogate the antivasoocclusive effects of estradiol by blocking the conversion of catecholestradiols to methoxyestradiols. The interaction between catecholamines and estradiol metabolism may importantly define the cardiovascular effects of e




J Clin Endocrinol Metab. 2004 Aug;89(8):3973-8.
Estradiol negative feedback regulates nocturnal luteinizing hormone and follicle-stimulating hormone secretion in prepubertal female rhesus monkeys.

Wilson ME, Fisher J, Chikazawa K.

Division of Psychobiology, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, Georgia 30329, USA. markmy.emory.edu

In recent years, animal models of puberty in children have focused on factors responsible for the developmental increase in gonadotropin secretion independent of gonadal negative feedback. Although the testis may play little if any role in timing the initial increase in gonadotropin secretion in the male, the situation may be different for the female. The present study tested the hypothesis that removal of endogenous estradiol by ovariectomy would produce an immediate increase in nocturnal but not daytime LH and FSH concentrations, an effect reversed by estradiol replacement. Morning (1000 and 1030 h) and evening (2200 and 2230 h) concentrations of bioactive LH and, in selected samples, immunoreactive FSH were evaluated in young juvenile female rhesus monkeys (n = 7) before and after ovariectomy at 13 months of age. Evening but not morning concentrations of gonadotropins were significantly increased within 2 wk of ovariectomy, whereas estradiol replacement returned these to presurgical levels and to those observed in age-matched, gonadally intact females (n = 7). By 145 d after ovariectomy, or approximately 17 months of age, evening as well as morning concentrations of LH were significantly higher than concentrations seen immediately after surgery. Estradiol replacement at approximately 18 months of age suppressed both morning and evening LH but not to the degree seen during a similar treatment after ovariectomy. These data support the hypothesis that, for the female, the developmental rise in diurnal gonadotropin secretion is controlled by a gonad-independent mechanism as well as a gonadal negative feedback inhibition.




Mol Endocrinol. 2004 Nov;18(11):2700-13. Epub 2004 Aug 05.
Mitogenic activity of estrogens in human breast cancer cells does not rely on direct induction of mitogen-activated protein kinase/extracellularly regulated kinase or phosphatidylinositol 3-kinase.

Gaben AM, Saucier C, Bedin M, Redeuilh G, Mester J.

Institut National de la Sante et de la Recherche Medicale, Unite 482, 184 rue du Faubourg Saint Antoine, 75012 Paris, France. gabet-antoine.inserm.fr.

We have addressed the question of rapid, nongenomic mechanisms that may be involved in the mitogenic action of estrogens in hormone-dependent breast cancer cells. In quiescent, estrogen-deprived MCF-7 cells, estradiol did not induce a rapid activation of either the MAPK/ERK or phosphatidylinositol-3 kinase (PI-3K)/Akt pathway, whereas the entry into the cell cycle was documented by the successive inductions of cyclin D1 expression, hyperphosphorylation of the retinoblastoma protein (Rb), activity of the promoter of the cyclin A gene, and DNA synthesis. However, pharmacological inhibitors of the src family kinases, 4-amino-5-(4-methylphenyl)-7-(t-butyl) pyrazolo[3,4-d] pyrimidine (PP1) or of the PI-3K (LY294002) did prevent the entry of the cells into the cell cycle and inhibited the late G1 phase progression, whereas the inhibitor of MAPK/ERK activation (U0126) had only a partial inhibitory effect in the early G1 phase. In agreement with these results, small interfering RNA targeting Akt strongly inhibited the estradiolinduced cell cycle progression monitored by the activation of the promoter of the cyclin A gene. The expression of small interfering RNA targeting MAPK 1 and 2 also had a clear inhibitory effect on the estradiol-induced activation of the cyclin A promoter and also antagonized the estradiol-induced transcription directed by the estrogen response element. Finally, transfection of the estrogen receptor into NIH3T3 fibroblasts did not confer to the cells sensitivity to a mitogenic action of estradiol. We conclude that the induction of the cell




Cancer Epidemiol Biomarkers Prev. 2004 Aug;13(8):1296-301.
Associations between reproductive and menstrual factors and postmenopausal sex hormone concentrations.

Chubak J, Tworoger SS, Yasui Y, Ulrich CM, Stanczyk FZ, McTiernan A.

Cancer Prevention Research Program, Fred Hutchinson Cancer Research Center, P.O. Box 19024, M4-B402, Seattle, WA 98109-1024, USA.

Reproductive and menstrual characteristics, as well as high circulating estrogen concentrations, are associated with risk of hormone-related cancers in postmenopausal women. To explore possible etiologic relationships between menstrual/reproductive characteristics and risk of hormone-related cancers, we examined associations between menstrual/reproductive factors and serum concentrations of free estradiol, total estradiol, estrone, sex hormone binding globulin (SHBG), and follicle stimulating hormone (FSH). This study was conducted in 173 postmenopausal women using data from the prerandomization visit of an exercise clinical trial. Participants were sedentary, overweight/obese, and not on hormone therapy. Women > or =20 years past menopause had 23% lower total estradiol and 30% lower free estradiol concentrations than women within 4 years of menopause (P for trend = 0.04 and 0.02, respectively). Nulliparous women had 19% higher FSH concentrations than parous women (P = 0.02). Among parous women, parity was positively associated with SHBG and negatively associated with free estradiol concentrations. Women with > or =4 children had 20% lower free estradiol and 38% higher SHBG concentrations compared with women with one birth (P for trend = 0.02 and 0.01, respectively). Total number of months spent breast-feeding was modestly and inversely associated with serum FSH concentrations (P for trend = 0.07). Our results suggest that menstrual/reproductive characteristics may be associated with postmenopausal hormone concentrations; verification of these results in other studies may elucidate how these variables influence risk of hormone-related cancers.




Ginecol Obstet Mex. 2004 Mar;72:95-102.
[Bone mineral density and 17 beta-estradiol correlation in postmenopausal women]

[Article in Spanish]

Cardenas Morales BE, Perez Campos E, Gatica Valdez N.

Facultad de Medicina y Cirugia de la Universidad Autonoma Benito Juarez de Oaxaca, Mexico. becar200otmail.com

BACKGROUND: With the increased life-expectancy reached during 20th century, women will spend a very important part of their lives in the estrogenic deficiency state accompanying menopause. OBJECTIVES: To detect serum 17beta-estradiol levels, bone mineral density values, and to see the correlation between both parameters as well as with postmenopausal period. MATERIAL AND METHODS: A transversal study with ambulatory, community-dwelling postmenopausal women from Oaxaca de Juarez, Oax. was performed. RESULTS: We studied 70 women with spontaneous menopause, medium values were: age, 55.9 +/- 5.4 yr; menopause age, 48 +/- 3 yr; postmenopausal period, 7.9 +/- 5.3 yr; body mass index, 28.3 +/- 5.4, and serum 17beta-estradiol by radioimmunoassay, 62.78 +/- 25.83 pg/mL. Quantitative calcaneous ultrasound was used to measure bone mineral density and we found 30 women with normal level (-1.0 to 1.4 SD), 29 with osteopenia (-1.1 to -2.3 SD) and only 2 subjects with osteoporosis (-2.7 to 2.8 SD). CONCLUSIONS: Statistical analysis shows that bone mineral density and postmenopausal period were significantly correlated (p<0.05) as well as serum 17beta-estradiol levels with postmenopausal period; nevertheless, no correlation between bone mineral density and serum 17beta-estradiol or body mass index (p>0.05) was found. On the other hand, it is remarkable high serum 17beta-estradiol levels found in this group, related with postmenopausal status. These latter results are different from those reported in the literature.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15310101&dopt=Abstract estradiol




Prescrire Int. 2002 Dec;11(62):163-5.
Intranasal estradiol: new formulation. Intranasal oestrogen delivery system: just a gimmick.

[No authors listed]

(1) Many oral and transdermal (patch and gel) estradiol preparations are already available for controlling menopausal symptoms due to oestrogen deficiency. (2) Marketing authorization has now been granted in Europe for an intranasal delivery system, which produces a high, brief plasma estradiol peak. (3) According to two clinical trials, the symptomatic effects of 300 micrograms of estradiol daily by the intranasal route is similar to that of 50 micrograms /day transdermally (unblinded trial) and 2 mg/day orally (double-blind trial). (4) The most frequent side effects are intranasal reactions (in approximately 50% of patients), breast pain (30-40% of patients), and metrorrhagia (approximately 7% of cycles). (5) The long-term consequences of such high plasma estradiol peaks, including the risk of breast cancer, are unknown. (6) Intranasal estradiol is not reimbursed in France, unlike other oestrogen preparations for use in menopausal women. (7) In practice, oral and transdermal delivery systems, with which we have lengthy experience, are adequate for relieving menopausal symptoms. The intranasal route offers no proven advantage, and its long-term risks are unknown.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12469692&dopt=Abstract estradiol




Behav Brain Res. 2004 Nov 5;155(1):45-53.
High level estradiol impairs and low level estradiol facilitates non-spatial working memory.

Wide JK, Hanratty K, Ting J, Galea LA.

Department of Psychology and Neuroscience Program, The University of British Columbia, 2136 West Mall, Vancouver, BC, Canada V6T 1Z4.

The present study investigated the effect of different doses of estradiol treatment on performance in the non-spatial delayed alternation T-maze a task in which performance is mediated by the integrity of the prefrontal cortex (PFC). Ovariectomized (OVX) female rats were injected with estradiol benzoate (0.3 microg/0.1 ml sesame oil (EB0.3), 5 microg/0.1 ml sesame oil (EB5) or 10 microg/0.1 ml sesame oil (EB 10)) or vehicle (sesame oil, 0.1 ml). Approximately 2 h after each injection, animals were trained daily on the T-maze with an initial delay of 10 s (short delay). Following a month with no treatment animals were re-trained at a 40 s delay (long delay). Days to reach criterion (one error per day for three consecutive days), mean total errors, errors across days, change in performance across training (short subtracted from long delay), and latency to reach goal arm, were scored. At the short delay, there was a weak effect for the low dose of estradiol (EB0.3 low-to-medium physiological) to significantly decrease the number of working memory errors compared to controls. However at the longer delay the higher doses of estradiol EB5 (high physiological) and to a lesser extent EB10 (suupraphysiological) significantly increased the number of working memory errors compared to controls. These data demonstrate the differential effect of estradiol during short and long delays on prefrontal cortex dependent working memory. High levels of estradiol impair PFC-dependent working memory at longer delays, while low level estradiol weakly facilitates PFC-dependent working memory at a shorter delay. These data suggest that estradiol's facilitatory effects on working memory may not be mediated through the