J Invest Dermatol. 2002 Mar;118(3):519-29.
17beta-estradiol enhances vascular endothelial growth factor production and dihydrotestosterone antagonizes the enhancement via the regulation of adenylate cyclase in differentiated THP-1 cells.

Kanda N, Watanabe S.

Department of Dermatology, Teikyo University, School of Medicine, Tokyo, Japan. nmed.teikyo-u.ac.jp

We studied the in vitro effects of sex hormones on vascular endothelial growth factor (VEGF) production in differentiated THP-1 monocytic cells. Phorbol-12-myristate-13-acetate differentiated THP-1 into macrophage-like cells. 17beta-estradiol (10 (-9) M) increased VEGF secretion of controls 3.1-fold in differentiated THP-1 and this effect of 17beta-estradiol was antagonized by dihydrotestosterone, although dihydrotestosterone alone did not alter VEGF secretion. 17beta-estradiol increased steady-state mRNA level of VEGF and the increase was counteracted by dihydrotestosterone in differentiated THP-1, although dihydrotestosterone alone did not alter the VEGF mRNA level. Progesterone did not affect the constitutive and 17beta-estradiol-induced VEGF secretion and mRNA level. Transient transfection revealed that 17beta-estradiol enhanced chloramphenicol acetyl transferase expression driven by VEGF promoter and the enhancement was antagonized by dihydrotestosterone. Adenylate cyclase inhibitor suppressed 17beta-estradiol-induced enhancement of VEGF secretion, mRNA level, and promoter activity, whereas dihydrotestosterone-induced suppression on the effects of 17beta-estradiol was counteracted by 3',5'-adenosine cyclic monophosphate (cAMP) analog. 17beta-estradiol increased intracellular cAMP level by activating adenylate cyclase, while dihydrotestosterone reduced the basal and 17beta-estradiol-increased cAMP level by inhibiting adenylate cyclase. Transfection with 5'-deleted VEGF promoters demonstrated that the region between -88 and -66 bp may be involved in the transcriptional regulation by each hormone. The mutation within activator protein-2




Reproduction. 2003 May;125(5):733-41.
Effect of oestradiol treatment on mast cell populations and microflora in the vaginal cul-de-sac of seasonally anoestrous brushtail possums (Trichosurus vulpecula).

Mahoney PM, Hurst PR, McLeod BJ, McConnell MA, Thompson EG.

Department of Anatomy and Structural Biology, University of Otago, PO Box 56, Dunedin, New Zealand. trish.mahonetonebow.otago.ac.nz

Mast cell populations in the vaginal cul-de-sac of female brushtail possums do not appear to be related to microbial invasion but changes in their density occur at oestrus, indicating a hormonal influence. The present study examined the effect of treatment with oestradiol on microflora and on mast cell numbers and their spatial location in cul-de-sac tissue of seasonally anoestrous brushtail possums. Tissue was collected from seasonally anoestrous brushtail possums (n = 6 per group) that were either untreated (anoestrous group) or were subjected to 6 days of treatment with oestradiol (oestradiol group) administered via subcutaneous implants or with the oil vehicle alone (control group). Tissue was collected aseptically for microbiological procedures and the fractionator and optical disector were used to quantify mast cell populations. Microflora populations were low (< 4.0 x 10(4) organisms g(-1)) and numbers of mast cells were similar in all groups. Mast cell density was greatest in epithelial and connective tissues from seasonally anoestrous and control animals and lowest in oestradiol-treated possums, in which there was a significant increase in cul-de-sac mass and volume. There is an inverse relationship between circulating oestrogen concentrations and mast cell density in possum cul-de-sac tissue, which is probably the result of an increase in tissue volume.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12713436&dopt=Abstract estradiol




JOP. 2001 Jul;2(4):140-9.
Effect of treatment with different doses of 17-beta-estradiol on insulin receptor substrate-1.

Gonzalez C, Alonso A, Grueso NA, Diaz F, Esteban MM, Fernandez S, Patterson AM.

Department of Functional Biology, Physiology Area, University of Oviedo. Oviedo, Spain. tinoorreo.uniovi.es

CONTEXT: Ovarian hormones modulate insulin sensitivity, but their exact role remains unclear. OBJECTIVE: We tried to determine whether different doses of 17-beta-estradiol cause changes in the regulation of insulin receptor substrate (IRS-1) levels, and if so, the possible implications in insulin sensitivity. DESIGN: Ovariectomized rats were treated with different doses of 17-beta-estradiol at 6, 11 and 16 days. MAIN OUTCOME MEASURES: Immunoprecipitation and Western blotting for IRS-1 were performed in different tissues. RESULTS: We found that estradiol treatment has an influence on the amount of IRS-1 but that it acts in different ways depending on the tissue studied, on the length of treatment, and on the doses employed. CONCLUSIONS: Our results suggest that low concentrations of 17-beta-estradiol could be responsible for the upregulation of insulin receptor substrate 1, increasing insulin sensitivity in muscle and adipose tissue. However, insulin receptor substrate 1 is downregulated with high concentrations of 17-beta-estradiol, thus these high hormone plasma levels could favour insulin resistance in peripheral tissues. The role of 17-beta-estradiol seems to modulate insulin receptor substrate 1 levels in insulin dependent tissues, but in a different manner in each tissue. These novel findings are important for improving knowledge about the possible risk for insulin resistance in women taking oral contraceptives or receiving hormone replacement therapy at menopause.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11875250&dopt=Abstract estradiol




Br J Cancer. 2002 Feb 1;86(3):367-71.
Ethnic differences in ovulatory function in nulliparous women.

Haiman CA, Pike MC, Bernstein L, Jaque SV, Stanczyk FZ, Afghani A, Peters RK, Wan P, Shames L.

Department of Preventive Medicine, USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA. haimasc.edu

African-American women have a long-standing approximately 20% higher breast cancer incidence rate than USA White women under age 40 while rates among Latinas are lower than those of Whites. The reasons for this are not clear, however they may be due to ethnic differences in circulating oestradiol and progesterone levels. In a cross-sectional study, we investigated whether anovulation frequency and circulating serum oestradiol and/or progesterone levels vary among normally cycling nulliparous African-American (n=60), Latina (n=112) and non-Latina White (n=69) women. Blood and urine specimens were collected over two menstrual cycles among healthy 17- to 34-year-old women. Frequency of anovulation was greater among White women (nine out of 63, 14.3%) than African-American women (four out of 56, 7.1%) or Latina women (seven out of 102, 6.9%), although these differences were not statistically significant. African-American women had 9.9% (P=0.26) higher follicular phase oestradiol concentrations than Latina women and 17.4% (P=0.13) higher levels than White women. African-American women also had considerably higher levels of luteal phase oestradiol (vs Latinas, +9.4%, P=0.14; vs Whites, +25.3%, P=0.003) and progesterone (vs Latinas, +15.4%, P=0.07; vs Whites, +36.4%, P=0.002). Latina women were also observed to have higher follicular oestradiol, and luteal oestradiol and progesterone levels than White women (follicular oestradiol: +6.8%, P=0.48; luteal oestradiol: +14.6%, P=0.04; luteal progesterone: +18.2%, P=0.06). These results suggest that exposure to endogenous steroid hormones may be greater for young African-American and Latina women than for W




Gynecol Obstet Fertil. 2002 Jan;30(1):36-41.
[Comparison of predictive values of inhibins A and B, and plasma estradiol in IVF patients treated with GnRH agonists and recombinant FSH]

[Article in French]

Millot F, Antoine JM, Merviel P, Mathieu E, Carpeau J, Uzan S.

Service de biochimie et hormonologie, hopital Tenon, 4, rue de la Chine, 75970 Paris, France. francoise.millonn.ap-hop-paris.fr

The objectives of this study were to determine the mean plasma inhibin A and B kinetics in normoovulatory patients treated by GnRH agonist and rec-FSH and to compare their predictive value with that of plasma estradiol on retrieved oocytes number and pregnancy rate. The study was carried out retrospectively in 36 normoovulatory IVF patients stimulated by GnRH agonist from D21 and rec-FSH from D2 of the following cycle. Two groups of 18 patients (having obtained or not a pregnancy) were paired for age and cause of infertility. Estradiol was measured by direct immunoassay. Inhibin A and B were measured by ELISA (Serotec Limited, Oxford, UK). Inhibin A was correlated with estradiol until P-2 (P0: day of follicles aspiration). Inhibin B rose earlier, its concentration reached its maximum at P-5. Plasma estradiol and inhibin A kinetics were not different among pregnant and nonpregnant women. There was a trend for a broader plasma Inhibin B surface under the curve in pregnant than in nonpregnant women. Estradiol and Inhibin A were correlated to the oocytes number at the end of stimulation (P-2 and D10). Inhibin B was correlated earlier than estradiol and inhibin A, at P-8 and D7. Plasma inhibin A did not demonstrate a better predictive value than estradiol neither of the oocytes number nor the chance of pregnancy. Inhibin B could be useful for early decision of cycle cancellation or stimulation adjustment.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11875863&dopt=Abstract estradiol




Hypertension. 2002 Feb;39(2 Pt 2):412-7.
Methoxyestradiols mediate the antimitogenic effects of locally applied estradiol on cardiac fibroblast growth.

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

Department of Obstetrics and Gynecology, Clinic for Endocrinology, University Hospital Zurich, Switzerland. rahk.usz.ch

Estradiol inhibits cardiac fibroblast growth and may protect against cardiac remodeling associated with heart disease. However, the mechanisms by which estradiol attenuates cardiac fibroblast growth remain unclear. Because cardiac fibroblasts express cytochrome P450s (CYP450s) and catechol-O-methyltransferase (COMT) capable of converting estradiol to hydroxyestradiols and methoxyestradiols, respectively, and because hydroxyestradiols and methoxyestradiols (estradiol metabolites with little affinity for estrogen receptors) are potent inhibitors of cardiac fibroblast growth, we hypothesized that the antimitogenic effects of estradiol are mediated via hydroxyestradiols and/or methoxyestradiols. The inhibitory effects of estradiol (1 to 100 nmol/L) on serum-stimulated (3)H-thymidine incorporation (DNA synthesis), (3)H-proline incorporation (collagen synthesis), and cell number (proliferation) were enhanced (P<0.005) by CYP450 inducers 3-methylcholanthrene (10 micromol/L) and phenobarbital (10 micromol/L). Moreover, the inhibitory effects of estradiol were blocked by the CYP450 inhibitor 1-aminobenzotriazole (10 micromol/L) and the COMT inhibitors quercetin (10 micromol/L) and OR486 (10 micromol/L). In contrast to estradiol, the modulators of CYP450 and COMT were poor ligands for estrogen receptors (binding affinity less-than-or-equal 0.0001% versus estradiol). In cardiac fibroblasts, both quercetin and OR486 inhibited the metabolism of hydroxyestradiol to methoxyestradiol and blocked the inhibitory effects of hydroxyestradiol on cardiac fibroblast proliferation and DNA and collagen synthesis. The abrogating effects of quercetin and OR486 on the metabol




Hypertension. 2002 Feb;39(2 Pt 2):418-24.
Role of methoxyestradiols in the growth inhibitory effects of estradiol on human glomerular mesangial cells.

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

Department of Obstetrics and Gynecology, University Hospital Zurich, Switzerland. rahk.usz.ch

Metabolism of locally applied 17beta-estradiol (estradiol) to methoxyestradiols contributes to the growth inhibiting effects of estradiol on vascular smooth muscle cells via an estrogen receptor (ER)-independent mechanism. Because vascular smooth muscle cells are phenotypically similar to glomerular mesangial cells, it is feasible that estradiol inhibits glomerular mesangial cell growth via a similar mechanism, and this possibility was investigated. In human glomerular mesangail cells, estradiol concentration dependently (1 to 100 nmol/L) inhibited serum-induced proliferation (cell number) and DNA ((3)[H]-thymidine incorporation) and collagen ((3)[H]-proline incorporation) synthesis. The inhibitory effects of estradiol were mimicked by 2-hydroxyestradiol and 2-methoxyestradiol, metabolites of estradiol with little affinity for ERs. 2-Hydroxyestradiol and 2-methoxyestradiol were more potent growth inhibitors than estradiol. The inhibitory effects of estradiol were enhanced by CYP450 inducers 3-methylcholanthrene (10 micromol/L) and phenobarbital (10 micromol/L) and blocked by the CYP450 inhibitor 1-aminobenzotriazole (10 micromol/L). The growth inhibitory effects of estradiol were also blocked by quercetin (10 micromol/L) and OR 486 (10 micromol/L) inhibitors of catechol-O-methyltransferase (converts catecholestradiols to methoxyestradiols). ICI182780 (ER antagonist with ER binding affinity similar to estradiol) blocked the growth inhibitory effects of estradiol (1 to 100 nmol/L) only at concentrations (>50 micromol/L) that inhibited estradiol metabolism to catecholestradiols. The growth inhibitory effects of 2-hydroxyestradiol were abrogated by quercetin and OR486 (two structu




J Endocrinol Invest. 2002 Jan;25(1):4-10.
Implications of estradiol and progesterone in pulmonary vasodilatation in cirrhotic patients.

Aller R, Moya JL, Avila S, Villa J, Moreira V, Barcena R, Boxeida D, de Luis DA.

Service of Gastroenterology, Hospital Ramon y Cajal, Madrid, Spain.

The derangement of sex hormone serum levels in cirrhotic patients is well-delineated, and increased levels of progesterone and estradiol have been associated to hyperventilation in cirrhotic patients. These hormones have a well-known role in the regulation of vascular tone. The aim of this study was to evaluate whether sex hormone levels contribute to pulmonary vasodilatation (PV) and gas exchange abnormalities in cirrhosis. Contrast transesophageal echocardiography, arterial blood gases, parameters of liver function, pulmonary function test, estradiol and progesterone levels were determined in 45 male cirrhotic patients. Nineteen of 45 patients (42.2%) presented PV. Hyperventilation (pressure arterial of CO2< or =35 mmHg) was correlated to progesterone levels (p<0.05) and pressure arterial of CO2 was high in patients with PV (p<0.005) and Child class B and C (p<0.01). Hypoxemia (pressure arterial of O2<80 mmHg) had inverse correlation with progesterone (p<0.05) and estradiol (p<0.05) levels and pressure arterial of O2 was low in patients with Child class B and C (p<0.05). PV was present in patients with high estradiol levels (p<0.05), high progesterone levels (p<0.005) and Pugh class B and C (p<0.05). Logistic regression analysis identified progesterone as the sole independent factor associated to PV (p<0.0005). Multivariate linear regression showed that PV was the sole independent factor related to both pressure arterial of CO2 (p<0.05) and pressure arterial of O2 (p<0.01) levels. PV was independently associated to gas exchange abnormalities in cirrhosis. Progesterone and estradiol were related with PV in cirrhotic patients.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11885576&dopt=Abstract estradiol [PubMed - indexed for M




Arch Med Res. 2002 Mar-Apr;33(2):148-51.
Enhanced sister-chromatid exchange rate in human lymphocytes exposed to 17beta estradiol in vitro.

Djelic N, Djelic D.

Department of Biology, Faculty of Veterinary Medicine, University of Belgrade, Bul. JNA #18, Belgrade, 11000 Serbia, Yugoslavia. ndjeliet.bg.ac.yu

BACKGROUND: Epidemiologic data and animal experiments strongly implicate that steroid hormones are involved in the process of malignant transformation due to their capability to stimulate mitotic division and/or elevate the level of mutations in susceptible cells. METHODS: The objectives of this investigation were to evaluate the effects of 17beta estradiol in sister-chromatid exchange (SCE) test on cultured human peripheral blood lymphocytes. The lowest concentration of 17beta estradiol used in this experiment (10(-10) M) was calculated as comparable with the physiologic blood level of 17beta estradiol in women. Three experimental concentrations corresponded to minimal (7 x 10(-8) M), average (3.5 x 10(-6) M), and maximal (7 x 10(-6) M) therapeutic doses in human medicine. In addition, the highest concentrations exceed maximal therapeutic dose 10-fold (7 x 10(-5) M) and 30-fold (2.1 x 10(-4) M), respectively. RESULTS: The obtained results indicate that estradiol significantly elevates SCE per cell frequency at all concentrations applied except at the lowest one. However, estradiol has not influenced mitotic activity of cultured human lymphocytes significantly. CONCLUSIONS: It can be concluded that 17beta estradiol expressed genotoxic effects and therefore might represent a human health risk.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11886713&dopt=Abstract estradiol