J Neurochem. 2001 Nov;79(4):796-803.
Brain region-specific up-regulation of mouse apolipoprotein E by pharmacological estrogen treatments.

Levin-Allerhand J, McEwen BS, Lominska CE, Lubahn DB, Korach KS, Smith JD.

The Rockefeller University, New York, New York 10021, USA.

Cerebral apolipoprotein E (apoE) has been implicated in neuronal protection and repair. Due to the variable levels and types of estrogen receptors within different brain regions, the effect of estrogen on apoE and the mechanism of this effect may vary within different regions. Ovariectomized female C57BL/6 mice were treated with pharmacological levels of 17 beta-estradiol or placebo for 5 days, resulting in supraphysiological plasma levels of estradiol in the treated mice. ApoE and glial fibrillary acidic protein (GFAP) levels were measured in the cortex, hippocampus and diencephalon. 17 beta-Estradiol up-regulated apoE but not GFAP in the cortex and diencephalon, whereas in the hippocampus, GFAP and apoE were equally up-regulated. Treatment of estrogen receptor (ER) alpha knockout mice with 17 beta-estradiol or treatment of C57BL/6 mice with 17 alpha-estradiol, a poor estrogen receptor agonist, specifically induced apoE in the cortex, but not in the diencephalon. These results indicate that 17 beta-estradiol effects on apoE are either directly or indirectly mediated by ER alpha in the diencephalon, while the effects in the cortex may be mediated by a non-classical mechanism or by ER beta. Measurement of mRNA levels in estrogen versus placebo-treated wild-type mice indicated that the effect of 17 beta-estradiol on apoE was not associated with changes in apoE mRNA levels.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11723172&dopt=Abstract estradiol




Hum Reprod. 2001 Dec;16(12):2533-9.
Human ovarian steroid secretion in vivo: effects of GnRH agonist versus antagonist (cetrorelix).

Garcia-Velasco JA, Isaza V, Vidal C, Landazabal A, Remohi J, Simon C, Pellicer A.

IVI-Madrid, Madrid, Spain. jgvelascvi.es

BACKGROUND: In order to investigate whether gonadotrophin-releasing hormone (GnRH) antagonists exert a significant effect on steroid secretion in vivo compared with GnRH agonists, concentrations of sex steroid hormones (oestradiol, progesterone and testosterone) were studied in follicular fluid from women undergoing ovarian stimulation and treated with either GnRH agonist or antagonist. In addition, the correlation between follicular fluid steroid hormone concentrations and variables of follicular and oocyte development was evaluated. METHODS: Microparticle enzyme immunoassay and radioimmunoassays were used. RESULTS: The mean (SEM) follicular fluid oestradiol concentration was significantly lower in patients treated with GnRH antagonist than in those treated with GnRH agonist (542.0 +/- 76.9 versus 873.0 +/- 105.1 pg/ml, P = 0.02), which correlates with the mean serum oestradiol concentrations found in these two groups. No significant differences were found between groups in follicular fluid progesterone concentrations. Women undergoing GnRH antagonist treatment showed similar concentrations of follicular fluid testosterone compared with GnRH agonist-treated women (14.8 +/- 1.1 versus 13.3 +/- 2.7 ng/ml). The oestradiol:testosterone ratio was markedly reduced in women treated with GnRH antagonist (49.1 +/- 2.3 versus 60.1 +/- 4.4, P = 0.04). In contrast, no differences were found either in the progesterone:testosterone ratio, or in the oestradiol:progesterone ratio. CONCLUSIONS: GnRH antagonist therapy in women undergoing ovarian stimulation had a significant effect on ovarian follicular steroidogenesis.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11726570&dopt=Abstract estradiol




Hum Reprod. 2001 Dec;16(12):2540-5.
Plasma prolactin/oestradiol ratio at 38 weeks gestation predicts the duration of lactational amenorrhoea.

Campino C, Torres C, Rioseco A, Poblete A, Pugin E, Valdes V, Catalan S, Belmar C, Seron-Ferre M.

Department of Endocrinologia, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Santiago, Chile.

BACKGROUND: Fully breastfeeding women experience an amenorrhoea of variable duration. Our aim was to identify in pregnancy, endocrine markers that could predict the duration of subsequent lactational amenorrhoea. METHODS: We studied 17 healthy women at 34 and 38 weeks gestation, and 1 and 3 months post-partum. The women fully breastfed until 6 months post-partum. During pregnancy, prolactin (PRL), oestrogens (total oestradiol, unconjugated oestrone, unconjugated oestriol), sex hormone binding globulin (SHBG), dehydroepiandrosterone sulphate (DHEA-S), progesterone and placental lactogen, and during post-partum PRL, oestrogens and SHBG, were measured. Free oestradiol in pregnancy and post-partum was calculated. RESULTS: Ten women experienced long (>6 months) and seven experienced short (<6 months) lactational amenorrhoea. At 38 weeks gestation, the women who experienced a long lactational amenorrhoea had twice as much PRL, about half the total oestradiol, lower SHBG concentration (P < 0.05, Student's t-test, Bonferroni modification) and similar free oestradiol concentration, compared with those who experienced short lactational amenorrhoea. The difference in PRL concentration persisted in post-partum postsuckling samples. CONCLUSION: At 38 weeks gestation, the ratio PRL/oestradiol identified all individual women according to the subsequent duration of their lactational amenorrhoea, suggesting that duration of lactational amenorrhoea is conditioned during pregnancy.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11726571&dopt=Abstract estradiol




Rev Neurol. 2001 Sep 1-15;33(5):425-7.
[Influence of estradiol on pyroglutamyl aminopeptidase activity in the frontal cortex of ovariectomized mice]

[Article in Spanish]

Garcia MJ, Martinez-Martos JM, Mayas MD, Ramirez M, Ramirez-Exposito MJ.

Area de Fisiologia. Dpto. Ciencias de la Salud; Universidad de Jaen. Jaen, Espana.

INTRODUCTION: Pyroglutamyl aminopeptidase (pGluAP) is an omega peptidase widely distributed in fluid and tissues which hydrolyses biological active peptides including thyrotropin releasing hormone (TRH). OBJECTIVES. The aim of present work is to study the influence of estradiol on soluble and membrane bound pGluAP activity in the frontal cortex of female mice. MATERIAL AND METHODS: Soluble and membrane bound pGluAP activities in frontal cortex of ovariectomized mice and ovariectomized mice injected with different doses of estradiol were measured using espectrophotometric assays. RESULTS: Soluble pGluAP activity in frontal cortex did not change after ovariectomy or after the administration of the different doses of estradiol. However, membrane bound pGluAP activity showed a significant increase after ovariectomy. After the administration of the lower dose of estradiol, membrane bond pGluAP activity returned to the same levels detected before the ovariectomy. CONCLUSION: Estradiol modifies membrane bound pGluAP activity which is the principal enzyme involved in the hydrolysis of TRH. Therefore, misregulation of estradiol levels may produce modifications in the neuromodulatory functions of TRH.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11727208&dopt=Abstract estradiol




Reproduction. 2001 Dec;122(6):875-81.
Expression of vascular endothelial growth factor (VEGF) receptors in rat corpus luteum: regulation by oestradiol during mid-pregnancy.

Sugino N, Kashida S, Takiguchi S, Karube-Harada A, Kato H.

Department of Obstetrics and Gynecology, Yamaguchi University School of Medicine, Minamikogushi 1-1-1, Ube 755-8505, Japan. obgyo.cc.yamaguchi-u.ac.jp

The aim of this study was to investigate the expression of vascular endothelial growth factor (VEGF) receptors, the fms-like tyrosine kinase (flt-1) and kinase insert domain-containing region (KDR), in corpora lutea obtained at different stages of the oestrous cycle and during pregnancy in rats. Immunohistochemistry revealed that both flt-1 and KDR were localized in luteal cells in addition to vascular endothelial cells, and that the intensity of staining was stronger in pregnant rats than in cyclic rats. Rats undergoing hypophysectomy-hysterectomy on day 12 of pregnancy were treated with oestradiol until day 15 of pregnancy to determine whether oestradiol is involved in expression of flt-1 and KDR mRNA in the corpus luteum during mid-pregnancy. The flt-1 and KDR mRNA contents in the corpus luteum were decreased significantly by hypophysectomy-hysterectomy, and these decreases recovered significantly after oestradiol treatment. Changes in the mass of the corpus luteum and serum progesterone concentrations paralleled the changes in expression of flt-1 and KDR mRNA. Developmental studies indicated that flt-1 and KDR mRNA contents in the corpus luteum were constant until day 15 of pregnancy but decreased significantly on day 21 of pregnancy. In conclusion, both flt-1 and KDR were expressed in luteal cells in addition to vascular endothelial cells, and expression was upregulated by oestradiol during mid-pregnancy. flt-1 and KDR may play a role in development of the corpus luteum and in production of progesterone during mid-pregnancy in rats.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11732982&dopt=Abstract estradiol




Blood Coagul Fibrinolysis. 2001 Dec;12(8):677-81.
Hypercoagulation in surgical postmenopausal women having hormone replacement with overdose estradiol.

He S, Bremme K, Silveira A, van Rooijen M, Blomback M.

Department of Surgical Sciences, Coagulation Research, Karolinska Institutet, Stockholm, Sweden. he_shahoo.com

A benefit of estradiol replacement preventing coronary heart disease (CHD) after menopause has been suggested by clinical investigations. In the department of gynecology at our hospital, we met by chance eight senior women who were hysterectomized due to different benign gynecological disorders. Acting on their own, they took a daily dose of estradiol valerate as high as 8-50 mg for 3 years, in comparison with 1-2 mg used in routine hormonal replacement therapy. We were interested to assess whether the overdose estrogen disturbs the hemostatic function, thus losing the favorable effect on CHD occurrence. Plasma levels of some procoagulants/anticoagulants were assayed in the eight women with replacement therapy and the results were compared with those of seven age-matched senior women and of 14 young healthy women with normal menstrual cycles. Using a new laboratory method recently developed by us, the overall hemostatic potential, shown as a single parameter (Abs-sum), was also determined. Results showed that high-dose estradiol activated coagulation and depressed fibrinolysis, leading to the net effect of elevated overall hemostatic potential. Thus, the overdose estradiol replacement may not be beneficial in preventing CHD after menopause, or it may even increase the risk due to the hypercoagulable state induced therefrom.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11734668&dopt=Abstract estradiol




Biochem Biophys Res Commun. 2001 Dec 14;289(4):796-800.
Role of ERK1/2 in the differential synthesis of progesterone and estradiol by granulosa cells.

Moore RK, Otsuka F, Shimasaki S.

Department of Reproductive Medicine, University of California at San Diego, School of Medicine, La Jolla, California 92093-0633, USA.

A major concept in mammalian ovarian physiology is that follicle-stimulating hormone (FSH) activates the granulosa cells (GCs) in the Graafian follicle to selectively produce estradiol, but not progesterone, during the follicular phase of the menstrual or estrous cycle. However, given the fact that FSH can induce production of both estradiol and progesterone by GCs cultured in vitro, it has been postulated for a long time that there is a factor present in the ovary that selectively prevents FSH-induced progesterone production. Here, we provide evidence that two members of the mitogen-activated protein kinase family, extracellular signal-regulated kinase-1 and -2 (ERK1/2) can differentially regulate FSH-stimulated estradiol and progesterone production. Using primary rat GCs from early antral follicles cultured in serum-free medium for 48 h, we found that the addition of a specific inhibitor of ERK1/2 activation, U0126, caused the attenuation or enhancement of FSH-induced progesterone or estradiol production, respectively, in a dose-dependent manner. Throughout the 48-h culture period in this culture system ERK1/2 molecules in their activated state (phospho-ERK1/2) were clearly detectable in GCs exposed to FSH. The addition of U0126 caused a decrease in the levels of phosphorylated but not unphosphorylated ERK1/2 which was maintained throughout the 48-h culture, suggesting that U0126 was continuously active to inhibit the phosphorylation of ERK1/2. The divergent regulation of FSH-induced progesterone and estradiol synthesis by U0126 was further supported by demonstrating that U0126 inhibits and stimulates FSH-induced mRNA levels of steroidogenic acute regulatory protein and P450 aromatase, respec




Kidney Int. 2001 Dec;60(6):2097-108.
Protein kinase CK2 mediates TGF-beta1-stimulated type IV collagen gene transcription and its reversal by estradiol.

Zdunek M, Silbiger S, Lei J, Neugarten J.

Nephrology Division, Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York 10467, USA.

BACKGROUND: We have previously shown that the transcription factor Sp1 mediates the stimulatory effects of transforming growth factor-beta1 (TGF-beta1) on type IV collagen gene transcription and protein synthesis, and that estradiol reverses these effects by down-regulating Sp1 activity. Protein kinase casein kinase II (CK2) phosphorylates Egr-1 and prevents its binding to Sp1. We hypothesized that TGF-beta1 stimulates CK2 activity, which in turn activates type IV collagen gene transcription via increased availability of free Sp1. METHODS: The effects of TGF-beta1 and of estradiol on murine mesangial cell type IV collagen gene transcription were measured using a reporter mini gene construct and on collagen IV protein synthesis by Western blotting. Nuclear Egr-1, phosphorylated Egr-1, Sp1, Egr-1/Sp1 complexes and unbound Sp1 were measured using co-immunoprecipitation and Western blotting techniques. RESULTS: TGF-beta1 stimulated CK2 activity in murine mesangial cells. Although TGF-beta1 failed to alter total Egr-1 protein, it increased phosphorylated Egr-1. This led to decreased Egr-1/Sp1 complex formation, increased unbound Sp1, increased binding of nuclear extracts to the collagen IV promoter, and increased type IV collagen gene transcription and protein synthesis. Physiologic concentrations of estradiol reversed these effects. CONCLUSIONS: These studies suggest that activation of CK2 mediates the stimulatory effect of TGF-beta1 on type IV collagen gene transcription. Moreover, the ability of estradiol to reverse TGF-beta1-stimulated type IV collagen synthesis is mediated by down-regulating CK2 activity, which ultimately limits the availability of unbound Sp1 t




J Steroid Biochem Mol Biol. 2001 Nov;78(5):451-8.
17beta-estradiol inhibits soluble guanylate cyclase activity through a protein tyrosine phosphatase in PC12 cells.

Chen ZJ, Che D, Vetter M, Liu S, Chang CH.

Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.

Besides its involvement in reproductive functions, estrogen protects against the development of cardiovascular diseases. The guanylate cyclase/cGMP system is known to exert potent effects on the regulation of blood pressure and electrolyte balance. We examined whether 17beta-estradiol can affect soluble guanylate cyclase in PC12 cells. The results indicate that 17beta-estradiol decreases cGMP levels in PC12 cells. 17beta-Estradiol decreases sodium nitroprusside (SNP)-stimulated, but not atrial natriuretic factor-stimulated cGMP formation in PC12 cells, indicating that 17beta-estradiol decreases cGMP levels by inhibiting the activity of soluble guanylate cyclase. 17beta-Estradiol also stimulates protein tyrosine phosphatase activities in PC12 cells and dephosphorylates at least three proteins. Addition of sodium vanadate, a protein tyrosine phosphatase inhibitor, blocks the inhibitory effects of 17beta-estradiol on soluble guanylate cyclase activity in PC12 cells. Furthermore, transfection of SHP-1, a protein tyrosine phosphatase, into PC12 cells inhibits both basal and SNP-stimulated guanylate cyclase activity. Amino acid analysis also reveals that the 70-kDa subunit of soluble guanylate cyclase contains the SHP-1 substrate consensus sequence. These results suggest that 17beta-estradiol inhibits soluble guanylate cyclase activity through SHP-1.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11738555&dopt=Abstract estradiol