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MK Lindberg
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SL Alatalo
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JM Halleen
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S Mohan
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JA Gustafsson
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C Ohlsson
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There are two known estrogen receptors, estrogen receptor-alpha (ER alpha) and estrogen receptor-beta (ER beta), which may mediate the actions of estrogen. The aim of the present study was to compare fat content, skeletal growth and adult bone metabolism in female mice lacking ER alpha (ERKO), ER beta (BERKO) or both ERs (DERKO). We demonstrate that endogenous estrogens decrease the fat content in female mice via ER alpha and not ER beta. Interestingly, the longitudinal bone growth was decreased in ERKO, increased in BERKO, but was intermediate in DERKO females, demonstrating that ER alpha and ER beta exert opposing effects in the regulation of longitudinal bone growth. The effects on longitudinal bone growth were correlated with similar effects on serum levels of IGF-I. A complex regulation of the trabecular bone mineral density (BMD), probably caused by a disturbed feedback regulation of estrogen and testosterone, was observed in female ER-inactivated mice. Nevertheless, a partial functional redundancy for ER alpha and ER beta in the maintenance of the trabecular BMD was observed in the female mice at 60 days of age. Thus, ER alpha and ER beta may have separate effects (regulation of fat), opposing effects (longitudinal bone growth) or partial redundant effects (trabecular BMD at 60 days of age), depending on which parameter is studied.

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Y Ninomiya
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Y Arao
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T Kometani
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S Hiwatashi
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T Yamasaki
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T Erikawa
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H Yamaguchi
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T Hasegawa
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S Masushige
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S Kato
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Abstract

We examined vitamin A-deficient chicks to determine whether vitamin A affects the estrogen-induced development of the chick oviduct. When oviduct development was stimulated for 5 days with the synthetic estrogen, diethylstilbestrol, the wet weight of the oviduct in vitamin A-deficient chicks was only half that in control chicks. The DNA content in this tissue showed that the decreased oviduct weight in the vitamin A-deficient chicks was caused by the decreased proliferation of oviduct cells. However, the estrogen-induced expression of the ovalbumin gene was not affected by the vitamin A deficiency, suggesting that estrogen-induced cytodifferentiation is not affected by vitamin A. To clarify the vitamin A action on estrogen-induced development in the oviduct, transcripts of nuclear estrogen receptor (ER) and all-trans-retinoic acid (RARα, β and γ) receptors, which exert the effects of estrogen and vitamin A, were measured. The ER, RARα and RARβ genes, but not that of RARγ, were expressed during oviduct development, indicating that estrogen and vitamin A may control the expression of target genes through their cognate receptors. Thus, we have shown that vitamin A is involved in estrogen-induced cell proliferation but not in cytodifferentiation of the chicken oviduct.

Journal of Endocrinology (1996) 148, 257–265

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AL Ochoa
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NA Mitchner
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CD Paynter
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RE Morris
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N Ben-Jonathan
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Vascular endothelial growth factor (VEGF), an endothelial cell mitogen and permeability factor, participates in tumor angiogenesis, but less is known about its regulation or function in normal vascular homeostasis. In the uterus, which undergoes cyclic changes in its vasculature, VEGF is induced by estrogen. Since the pituitary gland contains highly permeable capillaries and is estrogen-responsive, our objectives were to localize VEGF expression within the pituitary and to determine whether it is regulated by estrogen in both the pituitary and the somatolactotrope cell line, GH(3). Ovariectomized rats were injected with estradiol, and pituitaries and uteri were subjected to in situ hybridization or quantitative reverse transcription-polymerase chain reaction (RT-PCR). VEGF expression was strong and punctate in the neural lobe, weaker and diffuse in the anterior lobe and undetectable in the intermediate lobe. Two VEGF isoforms, 164 and 120, were detected in all tissues. In the posterior pituitary, VEGF expression was 3- to 6-fold higher than in the anterior pituitary or uterus and was unaltered by estrogen. In contrast, anterior pituitary VEGF was induced by estrogen within 1 h, peaked at 3 h, and returned to basal levels by 24 h. Similar dynamics, albeit 10-fold higher, were seen in the uterus. Translated VEGF proteins were detected by Western blot in both the anterior pituitary and uterus. GH(3) cells also showed a dose- and time-dependent induction of VEGF expression by estrogen. In conclusion: (1) VEGF expression is higher in the neural lobe than in the anterior lobe and is undetectable in the intermediate lobe, (2) the expression of VEGF164 and VEGF120 is rapidly upregulated by estrogen in the anterior pituitary but is unchanged in the posterior pituitary, and (3) the pituitary lactotrope cell line, GH(3), also increases VEGF expression in response to estradiol.

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AG Gunin
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V Emelianov
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AS Tolmachev
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A Tolmacheva
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The aim of this work was to examine the role of prolactin and dopaminergic drugs, which affect prolactin secretion, on proliferative and morphogenetic reactions in the uterus under continuous estrogen treatment. Ovariectomized mice received injections of estradiol dipropionate (2 microg per 100 g, weekly) or vehicle and daily injections of prolactin (0.25 mg/100 g) or saline (0.05 ml) for 30 days. Other groups of mice received injections of estradiol or vehicle and injections of saline, and were allowed to drink bromocriptine (25 mg/l), metoclopramide (25 mg/l), or only tap water for 30 days. Prolactin administration results in a decrease in the incidence of abnormal glands with abnormal epithelium, the incidence of atypical hyperplasia, uterine weight, proliferation (the number of mitotic and bromodeoxyuridine-labeled cells) and the levels of estrogen receptor-alpha, but causes an increase in the level of beta-catenin in uterine tissues of estrogen-treated mice. The effect of metoclopramide, which increases prolactin secretion, is principally similar to prolactin, but much less expressed. Bromocriptine, which reduces prolactin levels, increases uterine weight, proliferation, the levels of estrogen receptor-alpha, the incidence of abnormal glands with abnormal epithelium, the incidence of complex and atypical hyperplasia, and decreases the level of beta-catenin in uterine structures of estrogen-treated mice. In the absence of estradiol, none of the treatments used had any effect on the parameters tested. Thus, prolactin or metoclopramide produce antiestrogenic effects in the uterus of mice and prevent the formation of atypical hyperplasia which has an unfavorable prognosis, but bromocriptine has the opposite effect. Estrogen receptor-alpha and beta-catenin were associated with the actions of prolactin, metoclopramide and bromocriptine on estrogen-dependent processes in the uterus.

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RS Ishimaru
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K Leung
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L Hong
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PS LaPolt
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Previous studies demonstrated inhibitory effects of nitric oxide (NO) and cGMP on ovarian steroidogenesis. This study examined the effects of NO on estrogen levels and cAMP accumulation from immature cultured rat granulosa cells. Granulosa cells were incubated with media alone (control), FSH or FSH plus increasing concentrations of the NO generator, (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA/NO). While FSH increased estrogen levels 15-fold compared with controls, DETA/NO inhibited FSH-stimulated aromatase activity in a dose-dependent manner. Time-course studies revealed that the inhibitory effects of DETA/NO on aromatase activity persisted throughout the 72 h culture period. Treatment with DETA/NO also inhibited the stimulatory effects of forskolin on estrogen production, indicating that NO can influence steroidogenesis by actions downstream of the FSH receptor. Incubation of cells with FSH plus DETA/NO increased cGMP accumulation over 100-fold, compared with cells treated with media or FSH alone. In this regard, a cGMP analog mimicked the inhibitory effects of NO on FSH- and forskolin-stimulated estrogen production, indicating a potential mechanism of NO action. NO also decreased FSH-stimulated (cAMP) accumulation from cultured cells, indicating an antagonistic effect of NO on the second messenger mediating FSH actions. These findings demonstrate that NO inhibits estrogen production from rat granulosa cells, potentially reflecting actions on the second messengers cGMP and cAMP.

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S Ho Hong
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H Young Nah
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J Yoon Lee
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M Chan Gye
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C Hoon Kim
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M Kyoo Kim
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The steroid hormone, estrogen, plays an important role in various physiological events which are mediated via its nuclear estrogen receptors, ERalpha and ERbeta. However, the molecular mechanisms that are regulated by estrogen in the uterus remain largely unknown. To identify genes that are regulated by estrogen, the ovariectomized mouse uterus was exposed to 17beta-estradiol (E2) for 6 h and 12 h, and the data were analyzed by cDNA microarray. The present study confirms previous findings and identifies several genes with expressions not previously known to be influenced by estrogen. These genes include small proline-rich protein 2A, receptor-activity-modifying protein 3, inhibitor of DNA binding-1, eukaryotic translation initiation factor 2, cystatin B, decorin, secreted frizzled-related protein 2, integral membrane protein 2B and chemokine ligand 12. The expression patterns of several selected genes identified by the microarray analysis were confirmed by RT-PCR. In addition, laser capture microdissection (LCM) was conducted to determine the expression of selected genes in specific uterine cell types. Analysis of early and late responsive genes using LCM and cDNA microarray not only suggests direct and indirect effects of E2 on uterine physiological events, but also demonstrates differential regulation of E2 in specific uterine cell types. These results provide a basic background on global gene alterations or genetic pathways in the uterus during the estrous cycle and the implantation period.

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E R Simpson
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S E Bulun
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J E Nichols
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Y Zhao
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Introduction

Estrogen biosynthesis is catalyzed by an enzyme known as aromatase P450 (Thompson & Siiteri 1974a, Mendelson et al. 1985, Nakajin et al. 1986, Kellis & Vickery 1987) (P450arom, the product of the CYP19 gene (Nelson et al. 1993)). CYP19 is a member of the P450 superfamily of genes which currently contains over 300 members in some 36 gene families (Nelson et al. 1993). Typically, these enzymes catalyze the insertion of oxygen atoms derived from molecular oxygen into organic molecules to form hydroxyl groups. In the case of P450arom, three such attacks by molecular oxygen give rise to loss of the C19 angular methyl group of the steroid substrate as formic acid, with concomitant aromatization of the A-ring to give the phenolic A-ring characteristic of estrogens (Thompson & Siiteri 1974b).

Estrogen biosynthesis in humans occurs in a number of tissue sites of expression including the granulosa cells and

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M Campbell-Thompson
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KK Reyher
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LB Wilkinson
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A sexual dimorphism in gastric acid secretion has been known for many years, with women secreting less acid ( approximately 40%) than men. The mechanisms mediating this sex difference are unknown, but a role for estrogens is suggested from animal models. Two estrogen receptor (ER) subtypes, ER alpha and ER beta, mediate genomic effects of estrogens, and mRNA for both subtypes has been detected in the rat stomach. The objective of this study was to determine the cellular distribution of ER alpha and ER beta proteins in the rat stomach. ER alpha and ER beta proteins were detected in nuclei of fundic parietal cells and epithelial cells in the progenitor zone. In the antrum, several cells were immunoreactive for ER beta in regions containing stem and neuroendocrine cell types but ER alpha protein was not detected in antral glands. Both ER alpha and ER beta proteins were expressed in enteric neurons within the nucleus and cytoplasm, with specific punctate staining for ER alpha in cell bodies and fibers. These studies are the first to show differences between ER alpha and ER beta proteins in the epithelial cellular distribution in the fundus and antrum and to detect co-expression in enteric neurons. These results suggest that estrogens may inhibit gastric acid secretion via genomic effects in fundic parietal cells through either ER subtype and in antral neuroendocrine cells via ER beta. Moreover, co-expression of ER alpha and ER beta in enteric neurons indicates that estrogenic effects could also be mediated through neurogenic reflexes. Our findings imply that direct regulation of multiple cell types by estrogens may contribute to the modulation of gastric functions that have been recognized during the estrous cycle and between the sexes.

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H Shimizu
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Y Shimomura
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Y Nakanishi
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T Futawatari
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K Ohtani
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N Sato
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M Mori
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Abstract

The decrease in estrogen in menopausal women increases body fat. The present studies were undertaken to investigate the involvement of estrogen in leptin production in vivo. In the first study, expression of ob gene mRNA in white adipose tissue was measured at 2 and 8 weeks after ovariectomy in rats. In the second, serum leptin concentration was measured in total body fat of 87 weight-matched human subjects (29 men, 29 premenopausal and 29 postmenopausal women). In the third, changes in serum leptin concentration with the menstrual cycle were determined, ob gene expression decreased in subcutaneous and retroperitoneal white adipose tissue of ovariectomized rats 8 weeks after the operation, while ovariectomy increased ob gene expression in mesenteric white adipose tissue. Serum leptin concentration was decreased by ovariectomy. Estradiol supplement reversed the effect of ovariectomy on ob gene expression and circulating leptin levels. In humans, serum leptin concentration was higher in premenopausal women than in men, and in postmenopausal women it was lower than in premenopausal women, but still higher than in men. In 13 premenopausal women, serum leptin levels were significantly higher in the luteal phase than in the follicular phase. The present studies strongly indicate that estrogen regulates leptin production in rats and human subjects in vivo. Regional variation in the regulation of ob gene expression by estrogen was found.

Journal of Endocrinology (1997) 154, 285–292

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T Usui
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Y Ikeda
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T Tagami
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K Matsuda
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K Moriyama
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K Yamada
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H Kuzuya
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S Kohno
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A Shimatsu
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Some plant compounds or herb mixtures are popular alternatives to conventional therapies and contain organic compounds that bind to some nuclear receptors, such as the estrogen receptor (ER), to exert various biological effects. We studied the effect of various herbal extracts on ERalpha and ERbeta isoforms. One herbal extract, Rhei rhizoma (rhubarb), acts as an agonist to both ERalpha and ERbeta. The phytochemical lindleyin, a major component of rhubarb, might contribute to this estrogenic activity through ERalpha and ERbeta. 4-Hydroxytamoxifen, an ER antagonist, completely reversed the estrogenic activity of lindleyin. Lindleyin binds to ERalpha in vitro, as demonstrated using a fluorescent polarization assay. The in vivo effect of rhubarb extract was studied using a vitellogenin assay system in the freshwater fish, Japanese medaka (Oryzias latipes). There were marked increases in serum vitellogenin levels in male medaka exposed to rhubarb extract. We conclude that lindleyin, a component of some herbal medicines, is a novel phytoestrogen and might trigger many of the biological responses evoked by the physiological estrogens.

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