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[en] The synthesis of two novel radiolabelled estrogen derivatives, [125I](E)-3-methoxy-17α-iodovinylestra-1,3,5(10),6-tetraen-17β-ol (E[125I]IVDE) and [125I](Z)-3-methoxy-17α-iodovinylestra-1,3,5(10),6-tetraen-17β-ol (Z[125I]IVDE), was carried out aiming to study the influence of the introduction of a C6-C7 double bond on the biological properties of the estradiol molecule. 3-Methoxyestra-1,3,5(10),6-tetraen-17-one was synthesised starting from a suitably protected estrone and subsequently converted into the 17α-ethynyl derivative. The radioiodinated derivatives were stereoselectively formed by radioiododestannylation of the corresponding tributylstannyl precursors. The biodistribution of the novel [125I]iodovinylestradiol derivatives was evaluated in immature female mice. Biological data indicated that the Z-isomer, owing to its higher in vivo uptake by the target tissue, has the preferable configuration for further development of similar compounds for estrogen receptor detection.
[en] Over the past decade, educational programmes have been the main focus of the activities of the International Union of Toxicology (IUTOX). The IUTOX educational programmes are dynamic and have been growing in scope and frequency each year. It is envisaged that this growth will continue with guidance from our member societies and the continuing support of our sponsors. Presently, IUTOX is engaged in the following educational programmes: (1) International congresses that provide the opportunity for direct communication of current toxicological information. Fellowships are sponsored to facilitate attendance at these congresses for toxicologists in need. (2) Workshops that permit interaction on a more localised level of topics of more regional interest. Workshops have served to help stimulate formation of toxicology societies by bringing together sufficient scientists to facilitate these discussions. (3) Continuing educational (CE) programmes at member society meetings. Topics are prioritised based on input received from the local societies. Programmes often are those from CE courses given at meetings, such as conferences of the US Society of Toxicology (US SOT) and EUROTOX from the previous year. (4) Biennial Risk Assessment Summer School (RASS), an intensive week-long interaction between senior toxicologists who serve as faculty with attendees providing individual training. (5) Dissemination of donated printed toxicological books from publishers and syllabi from continuing education courses to regional locations. (6) Web-based interactive training programmes in regions where formal toxicological educational programmes are limited or lacking. (7) Preparation and distribution of monographs on selected topics of very current interest. Monographs on environmental oestrogens and genetically-modified foods have been published. The recent activities in each of these programmes are reviewed in this paper
[en] A product is prepared by the action of tritiated methanol on 11β-hydroxy-estra-4,9-dien-3,17-dione, the action of an aromatisation agent on the (11β)-11-methoxy-3H3-estra-4,9-dien-3,17-dione formed and the action of an ethynylation agent on the resulting (11β)-3-hydroxy-11-methoxy-3H3-estra-1,3,5(10)-trien-17-one giving (11β, 17α)-11-methoxy-3H3-19-norpregna-1,3,5(10)-trien-20-yne-3,17 diol, the free hydroxyl function or functions of this product may be etherified or esterified as the case may be. The tritiated methanol acts in the presence of perchloric acid. The aromatisation agent is palladium hydroxide and the operation is carried out in methanol. The ethynylation agent is acetylene and the reaction takes place in the presence of sodium t-amylate in toluene. This product allows the study and determination of the estrogen specific receptor present in the tissue cells of target organs for the action of estrogens: uterus, vagina, hypophysis, hypothalamus and tumours, of the breast and prostate for example, in both animals and man. Not being fixed by the plasma proteins binding such hormones as testosterone and estradiol in women the product is an ideal indicator of the tissular estrogen receptor with which it forms a complex of strong affinity and great stability, especially since it interacts with the tissular receptors of no other steroid hormone groups (glucocorticoids, androgen or progestogen mineralocorticosteroids)
[fr]Procede de preparation d'un produit caracterise en ce que l'on fait agir le methanol tritie sur la 11β-hydroxy-estra-4,9-dien-3,17-dione, soumet la (11β)-11-methoxy-3H3-estra-4,9-dien-3,17-dione resultant a l'action d'un agent d'aromatisation, fait agir sur la (11β)-3-hydroxy-11-methoxy-3H3-estra-1,3,5(10)-trien-17-one resultant un agent d'ethynylation et obtient le (11β, 17α)-11-methoxy-3H3-19-norpregna-1,3,5(10)-trien-20-yne-3,17-diol, dont on peut, le cas echeant, etherifier ou esterifier la ou les fonctions hydroxyles libres. On fait agir le methanol tritie en presence de l'acide perchlorique. L'agent d'aromatisation est l'hydroxyde de palladium et on opere dans le methanol. L'agent d'ethynylation est l'acetylene et on opere en presence de t-amylate de sodium dans le toluene. Ce produit permet l'etude et le dosage du recepteur specifique estrogene present dans les cellules des tissus des organes cibles de l'action des estrogenes, comme l'uterus, le vagin, l'hypophyse, l'hypothalamus et les tumeurs, comme par exemple du sein, de la prostate, aussi bien chez l'animal que chez l'homme. En effet comme ce produit ne se fixe pas sur les proteines plasmatiques liant les hormones tels que la testosterone et l'estradiol chez la femme c'est un marqueur de choix du recepteur tissulaire des estrogenes avec lequel il forme un complexe de forte affinite et de grande stabilite, d'autant qu'il n'a aucune interaction avec les recepteurs tissulaires des autres classes d'hormones steroidiennes (glucocorticoides, mineralocorticosteroides androgenes ou progestogenes)
[en] We evaluated the efficacy and safety of the aromatase inhibitor exemestane in patients with advanced, persistent or recurrent endometrial carcinoma. We performed an open-label one-arm, two-stage, phase II study of 25 mg of oral exemestane in 51 patients with advanced (FIGO stage III-IV) or relapsed endometrioid endometrial cancer. Patients were stratified into subsets of estrogen receptor (ER) positive and ER negative patients. Recruitment to the ER negative group was stopped prematurely after 12 patients due to slow accrual. In the ER positive patients, we observed an overall response rate of 10%, and a lack of progression after 6 months in 35% of the patients. No responses were registered in the ER negative patients, and all had progressive disease within 6 months. For the total group of patients, the median progression free survival (PFS) was 3.1 months (95% CI: 2.0-4.1). In the ER positive patients the median PFS was 3.8 months (95% CI: 0.7-6.9) and in the ER negative patients it was 2.6 months (95% CI: 2.1-3-1). In the ER positive patients the median overall survival (OS) time was 13.3 months (95% CI: 7.7-18.9), in the ER negative patients the corresponding numbers were 6.1 months (95% CI: 4.1-8.2). Treatment with exemestane was well tolerated. Treatment of estrogen positive advanced or recurrent endometrial cancer with exemestane, an aromatase inhibitor, resulted in a response rate of 10% and lack of progression after 6 months in 35% of the patients. Trial identification number (Clinical Trials.gov): http://www.clinicaltrials.gov/NCT01965080. Nordic Society of Gynecological Oncology: NSGO–EC–0302. EudraCT number: 2004-001103-35
[en] 17α-Ethinylestradiol (EE2) is a synthetic estrogen used primarily in birth control pills and in hormone replacement therapy. Owing to its occurrence in surface waters at concentrations frequently greater than 1 ng/l and its projected future use, EE2 is expected to pose a significant risk to aquatic organisms. This study was conducted to obtain long-term exposure data necessary for the establishment of water quality criteria and to investigate mechanisms associated with toxic effects. In a multigeneration experiment, Chinese rare minnows (Gobiocypris rarus) were constantly exposed to environmentally relevant concentrations of the synthetic estrogen EE2. Mortality, deformities, reproductive parameters, plasma vitellogenin and histopathology were assessed. The results showed that, in the F0 generation, all endpoints were significantly affected at concentrations higher than 0.2 ng/l EE2. No F1 phenotypic males developed to maturity at 0.2 ng/l and, when adult females of this exposure group were crossed with unexposed males, no F2 fertile eggs were produced. Kidney histopathology and ultrastructure suggest anomalies possibly associated with increased vitellogenin accumulation. We concluded that the reproduction of the F1 minnows was completely inhibited at the lowest concentration tested, 0.2 ng/l EE2, a concentration frequently detected in surface waters. Growth effects may be related to increased energy requirements including the energy used in VTG synthesis. Reproductive effects are presumably associated with male feminization and the occurrence of testis-ova in males; however, ovarian degeneration observed in females may also have contributed to reproductive failure
[en] Oestrogen receptors were measured in the cytoplasmic fraction of tummours from patients with breast cancer. Receptors were detected in 48% of patients, and 52% showed no receptors. A follow-up study of a small group of patients on hormone therapy is reported
[en] Although the radioreceptor method is widely used for estrogen receptor assay in human tissue, it has several limitations and a number of alternative methods are being explored. An immunohistochemical method of estrogen receptor assay using a specific antibody to estradiol has been proposed as a suitable alternative. The present study was designed to evaluate the validity of this method in detecting true estrogen receptors in human tumor tissue. Using radioiodinated antibody to estrogen, we have demonstrated that the estrogen antibody can detect the estrogen when it is bound to 4S type receptor but is unable to bind to estrogen when the hormone is bound to 8S type receptor. Our observations suggest that the immunohistochemical method of detection of intracellular cytosolic receptor for estrogen is not a suitable alternative to the currently used radioreceptor method
[en] An estrogen radioimmunoassay was used to study the problem of blanks in steroid assays. Negligible binding (1.5 percent) in the non-antibody tubes prevailed throughout the study. The assay was validated using accepted procedures. Both water and solvent blanks had estrogen concentrations of 7-9 pg/tube. However, neither water nor solvent blanks showed a dose-related response, indicating that they were 'real' blanks. Exogenous estradiol, when added to water and solvent in quantities less than the estimated blank, was not quantitatively recovered. However, exogenous estradiol added to the water solvent in quantities greater than the blank estimate was quantitatively recovered. The sensitivity of the reference standard curve was 6-10 pg/tube, approximately the same as the blank estimate. These results indicated that the estimates of water and solvent blanks were measures of the assay sensitivity. In such circumstances, it is suggested that blank estimates should not be subtracted from sample values. If the blank estimates are high, attention should be directed towards improving the sensitivity of the assay
[en] Gene expression profiling of tumors using DNA microarrays is a promising method for predicting prognosis and treatment response in cancer patients. It was recently reported that expression profiles of sporadic breast cancers could be used to predict disease recurrence better than currently available clinical and histopathological prognostic factors. Having observed an overlap in those data between the genes that predict outcome and those that predict estrogen receptor-α status, we examined their predictive power in an independent data set. We conclude that it may be important to define prognostic expression profiles separately for estrogen receptor-α-positive and estrogen receptor-α-negative tumors
[en] The increasing availability and use of sports supplements is of concern as highlighted by a number of studies reporting endocrine disruptor contamination in such products. The health food supplement market, including sport supplements, is growing across the Developed World. Therefore, the need to ensure the quality and safety of sport supplements for the consumer is essential. The development and validation of two reporter gene assays coupled with solid phase sample preparation enabling the detection of estrogenic and androgenic constituents in sport supplements is reported. Both assays were shown to be of high sensitivity with the estrogen and androgen reporter gene assays having an EC50 of 0.01 ng mL-1 and 0.16 ng mL-1 respectively. The developed assays were applied in a survey of 63 sport supplements samples obtained across the Island of Ireland with an additional seven reference samples previously investigated using LC-MS/MS. Androgen and estrogen bio-activity was found in 71% of the investigated samples. Bio-activity profiling was further broken down into agonists, partial agonists and antagonists. Supplements (13) with the strongest estrogenic bio-activity were chosen for further investigation. LC-MS/MS analysis of these samples determined the presence of phytoestrogens in seven of them. Supplements (38) with androgen bio-activity were also selected for further investigation. Androgen agonist bio-activity was detected in 12 supplements, antagonistic bio-activity was detected in 16 and partial antagonistic bio-activity was detected in 10. A further group of supplements (7) did not present androgenic bio-activity when tested alone but enhanced the androgenic agonist bio-activity of dihydrotestosterone when combined. The developed assays offer advantages in detection of known, unknown and low-level mixtures of endocrine disruptors over existing analytical screening techniques. For the detection and identification of constituent hormonally active compounds the combination of biological and physio-chemical techniques is optimal.