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Sample records for estrogen synthase aromatase

  1. Nicotine Blocks Brain Estrogen Synthase (Aromatase): In Vivo Positron Emission Tomography Studies in Female Baboons

    Energy Technology Data Exchange (ETDEWEB)

    Biegon, A.; Biegon, A.; Kim, S.-W.; Logan, J.; Hooker, J.M.; Muench, L.; Fowler, J.S.

    2010-01-12

    Cigarette smoking and nicotine have complex effects on human physiology and behavior, including some effects similar to those elicited by inhibition of aromatase, the last enzyme in estrogen biosynthesis. We report the first in vivo primate study to determine whether there is a direct effect of nicotine administration on brain aromatase. Brain aromatase availability was examined with positron emission tomography and the selective aromatase inhibitor [{sup 11}C]vorozole in six baboons before and after exposure to IV nicotine at .015 and .03 mg/kg. Nicotine administration produced significant, dose-dependent reductions in [{sup 11}C]vorozole binding. The amygdala and preoptic area showed the largest reductions. Plasma levels of nicotine and its major metabolite cotinine were similar to those found in cigarette smokers. Nicotine interacts in vivo with primate brain aromatase in regions involved in mood, aggression, and sexual behavior.

  2. Ekspresi Gen CYP19 Aromatase, Estrogen, Androgen pada penderita Periodontitis Agresif

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    Dahlia Herawati

    2016-11-01

    Full Text Available Kepadatan tulang tubuh ditentukan oleh gen CYP19 aromatase, hormon estrogen dan androgen. Pada periodontitis agresif terjadi perkembangan cepat kerusakan tulang alveolar, dan kerusakan tulang alveoler tersebut tidak diimbangioleh regenerasi tulang. Tujuan penelitian ini adalah menunjukkan ekspresi gen CYP19 aromatase, estrogen, androgen pada penderita periodontitis agresif agar dapat untuk menjadi pertimbangan pada saat melakukan perawatan periodontal. Metode penelitian, pemeriksaan ekspresi gen aromatse CYP19 berasal dari spesimen tulang alveolar menggunakan imunohistokimia, pengukuran hormon estrogen dan androgen dari serum menggunakan Vidas: Elfa. Hasil penelitian ekspresi gene CYP19 aromatase pada periodontitis agresif menunjukkan gambaran lebih rendah densitasnya dibandingkan pada nonperiodontitis. Estrogen dan androgen pad aperiodontitis agresif ada kecenderungan lebih rendah dibandingkan pada nonperiodontitis. Kesimpulan regenerasi tulang alveoler pad a periodontitis agresif terhambat karena sedikitnya gen CYP19 aromatase dan hormon estrogen dan androgen yang berperan pada pembentukan tulang alveoler kurang memadai.

  3. Aromatase expression increases the survival and malignancy of estrogen receptor positive breast cancer cells.

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    Keya De Mukhopadhyay

    Full Text Available In postmenopausal women, local estrogen produced by adipose stromal cells in the breast is believed to support estrogen receptor alpha (ERα positive breast cancer cell survival and growth. This raises the question of how the ERα positive metastatic breast cancer cells survive after they enter blood and lymph circulation, where estrogen level is very low in postmenopausal women. In this study, we show that the aromatase expression increased when ERα positive breast cancer cells were cultured in suspension. Furthermore, treatment with the aromatase substrate, testosterone, inhibited suspension culture-induced apoptosis whereas an aromatase inhibitor attenuated the effect of testosterone suggesting that suspended circulating ERα positive breast cancer cells may up-regulate intracrine estrogen activity for survival. Consistent with this notion, a moderate level of ectopic aromatase expression rendered a non-tumorigenic ERα positive breast cancer cell line not only tumorigenic but also metastatic in female nude mice without exogenous estrogen supplementation. The increased malignant phenotype was confirmed to be due to aromatase expression as the growth of orthotopic tumors regressed with systemic administration of an aromatase inhibitor. Thus, our study provides experimental evidence that aromatase plays an important role in the survival of metastatic ERα breast cancer cells by suppressing anoikis.

  4. Structure-activity relationships of estrogen derivatives as aromatase inhibitors. Effects of heterocyclic substituents.

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    Numazawa, Mitsuteru; Komatsu, Sachiko; Tominaga, Takako; Yamashita, Kouwa

    2008-09-01

    Aromatase, which is responsible for the conversion of androgens to estrogens, is a potential therapeutic target for the selective lowering estrogen level in patients with estrogen-dependent breast cancer. We prepared and tested series of the pyridine- and other heterocyclic ring-containing derivatives of 2- and 4-aminoestrones, estrone, and estradiol, compounds 5, 10, 12 and 15. The isonicotinyl derivatives of 2- and 4-aminoestrone, compounds 5c and 10c, were fairly potent competitive inhibitors of aromatase (K(i), 2.1+/-0.14 and 1.53+/-0.08 microM for 5c and 10c, respectively) and other compounds did not show, to a significant extent, the aromatase inhibitory activity. This result suggests that the isonicotinyl-substituted derivatives 5c and 10c would be accessible to the active site of aromatase.

  5. Effects of currently used pesticides in assays for estrogenicity, androgenicity, and aromatase activity in vitro

    DEFF Research Database (Denmark)

    Andersen, Helle Raun; Vinggaard, Anne; Rasmussen, Thomas Høj

    2002-01-01

    Twenty-four pesticides were tested for interactions with the estrogen receptor (ER) and the androgen receptor (AR) in transactivation assays. Estrogen-like effects on MCF-7 cell proliferation and effects on CYP19 aromatase activity in human placental microsomes were also investigated. Pesticides...... to their frequent use in Danish greenhouses. In addition, the metabolite mercaptodimethur sulfoxide, the herbicide tribenuron-methyl, and the organochlorine dieldrin, were included. Several of the pesticides, dieldrin, endosulfan, methiocarb, and fenarimol, acted both as estrogen agonists and androgen antagonists....... Prochloraz reacted as both an estrogen and an androgen antagonist. Furthermore, fenarimol and prochloraz were potent aromatase inhibitors while endosulfan was a weak inhibitor. Hence, these three pesticides possess at least three different ways to potentially disturb sex hormone actions. In addition...

  6. Structure-activity relationships of 2-, 4-, or 6-substituted estrogens as aromatase inhibitors.

    Science.gov (United States)

    Numazawa, Mitsuteru; Ando, Momoko; Watari, Yoko; Tominaga, Takako; Hayata, Yasuko; Yoshimura, Akiko

    2005-06-01

    Aromatase, which is responsible for the conversion of androgens to estrogens, is a potential therapeutic target for the selective lowering of estrogen levels in patients with estrogen-dependent breast cancer. To develop a novel class of aromatase inhibitors, we tested series of 2- and 4-substituted (halogeno, methyl, formyl, methoxy, nitro, and amino) estrones (7 and 9), as well as series of 6alpha- and 6beta-substituted (alkyl, phenalkyl, and alkoxy) estrones (13 and 14), and their estradiol analogs (8, 10, 11, and 12) as aromatase inhibitors. All of the inhibitors examined blocked the androstenedione aromatization in a competitive manner. Introduction of halogeno and methyl functions at C-2 of estrone as well as that of a phenalkyl or methyl function at the C-6alpha or C-6beta position markedly increased affinity to aromatase (apparent K(i) value=0.10-0.66 microM for the inhibitors versus 2.5 microM for estrone). 6alpha-Phenylestrone (13c) was the most powerful inhibitor among the estrogens studied, and its affinity was comparable to that of the androgen substrate androstenedione. Estradiol analogs were much weaker inhibitors than the corresponding estrone compounds in each series, indicating that the 17-carbonyl group plays a critical role in the formation of a thermodynamically stable enzyme-inhibitor complex.

  7. Germline genetic predictors of aromatase inhibitor concentrations, estrogen suppression and drug efficacy and toxicity in breast cancer patients.

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    Hertz, Daniel L; Henry, N Lynn; Rae, James M

    2017-04-01

    The third-generation aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, are highly effective for the treatment of estrogen receptor-positive breast cancer in postmenopausal women. AIs inhibit the aromatase (CYP19A1)-mediated production of estrogens. Most patients taking AIs achieve undetectable blood estrogen concentrations resulting in drug efficacy with tolerable side effects. However, some patients have suboptimal outcomes, which may be due, in part, to inherited germline genetic variants. This review summarizes published germline genetic associations with AI treatment outcomes including systemic AI concentrations, estrogenic response to AIs, AI treatment efficacy and AI treatment toxicities. Significant associations are highlighted with commentary about prioritization for future validation to identify pharmacogenetic predictors of AI treatment outcomes that can be used to inform personalized treatment decisions in patients with estrogen receptor-positive breast cancer.

  8. Diminished androgen and estrogen receptors and aromatase levels in hypogonadal diabetic men: reversal with testosterone.

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    Ghanim, Husam; Dhindsa, Sandeep; Abuaysheh, Sanaa; Batra, Manav; Kuhadiya, Nitesh D; Makdissi, Antoine; Chaudhuri, Ajay; Dandona, Paresh

    2018-03-01

    One-third of males with type 2 diabetes (T2DM) have hypogonadism, characterized by low total and free testosterone concentrations. We hypothesized that this condition is associated with a compensatory increase in the expression of androgen receptors (AR) and that testosterone replacement reverses these changes. We also measured estrogen receptor and aromatase expression. This is a randomized double-blind placebo-controlled trial. Thirty-two hypogonadal and 32 eugonadal men with T2DM were recruited. Hypogonadal men were randomized to receive intramuscular testosterone or saline every 2 weeks for 22 weeks. We measured AR, ERα and aromatase expression in peripheral blood mononuclear cells (MNC), adipose tissue and skeletal muscle in hypogonadal and eugonadal males with T2DM at baseline and after 22 weeks of treatment in those with hypogonadism. The mRNA expression of AR, ERα (ESR1) and aromatase in adipose tissue from hypogonadal men was significantly lower as compared to eugonadal men, and it increased significantly to levels comparable to those in eugonadal patients with T2DM following testosterone treatment. AR mRNA expression was also significantly lower in MNC from hypogonadal patients compared to eugonadal T2DM patients. Testosterone administration in hypogonadal patients also restored AR mRNA and nuclear extract protein levels from MNC to that in eugonadal patients. In the skeletal muscle, AR mRNA and protein expression are lower in men with hypogonadism. Testosterone treatment restored AR expression levels to that comparable to levels in eugonadal men. We conclude that, contrary to our hypothesis, the expression of AR, ERα and aromatase is significantly diminished in hypogonadal men as compared to eugonadal men with type 2 diabetes. Following testosterone replacement, there is a reversal of these deficits. © 2018 European Society of Endocrinology.

  9. Increased Sclerostin Levels after Further Ablation of Remnant Estrogen by Aromatase Inhibitors

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    Wonjin Kim

    2015-03-01

    Full Text Available BackgroundSclerostin is a secreted Wnt inhibitor produced almost exclusively by osteocytes, which inhibits bone formation. Aromatase inhibitors (AIs, which reduce the conversion of steroids to estrogen, are used to treat endocrine-responsive breast cancer. As AIs lower estrogen levels, they increase bone turnover and lower bone mass. We analyzed changes in serum sclerostin levels in Korean women with breast cancer who were treated with an AI.MethodsWe included postmenopausal women with endocrine-responsive breast cancer (n=90; mean age, 57.7 years treated with an AI, and compared them to healthy premenopausal women (n=36; mean age, 28.0 years. The subjects were randomly assigned to take either 5 mg alendronate with 0.5 µg calcitriol (n=46, or placebo (n=44 for 6 months.ResultsPostmenopausal women with breast cancer had significantly higher sclerostin levels compared to those in premenopausal women (27.8±13.6 pmol/L vs. 23.1±4.8 pmol/L, P0.05.ConclusionSerum sclerostin levels increased with absolute deficiency of residual estrogens in postmenopausal women with endocrine-responsive breast cancer who underwent AI therapy with concurrent bone loss.

  10. New Insights Into the Role of Estrogens in Male Fertility Based on Findings in Aromatase-Deficient Zebrafish.

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    Tang, Haipei; Chen, Yu; Liu, Yun; Yin, Yike; Li, Gaofei; Guo, Yin; Liu, Xiaochun; Lin, Haoran

    2017-09-01

    It has been demonstrated that estrogens are indispensable for male fertility in mammals. Aromatase (encoded by CYP19) catalyzes the final step of estradiol biosynthesis. However, less is known about the role of aromatase in male fertility in nonmammalian species. Fish aromatase is encoded by two separate genes: the gonad-specific cyp19a1a and the brain-specific cyp19a1b. In a recent study, we used transcription activatorlike effector nucleases to systematically generate cyp19a1a and cyp19a1b mutant lines and a cyp19a1a;cyp19a1b double-mutant line in zebrafish and demonstrated that cyp19a1a was indispensable for sex differentiation. In this study, we focused on male fertility in these aromatase-deficient zebrafish. Our results showed that all aromatase-deficient male fish had normal fertility even at 1 year after fertilization. Interestingly, we observed more spermatozoa in the cyp19a1a and double-mutant males than in the wild-type and cyp19a1b mutant males. The whole-body androgen levels, follicle-stimulating hormone β and luteinizing hormone β protein levels in the pituitary, and transcript levels of genes known to be involved in spermatogenesis and steroidogenesis in the testes were significantly higher in the cyp19a1a mutant and aromatase double-mutant males than in the wild-type and cyp19a1b mutant males. These results might explain why more spermatozoa were observed in these fish. Collectively, our findings indicate that estrogens are not needed to achieve and maintain normal fertility in male zebrafish. This finding challenges the traditional view that estrogens are indispensable for male fertility. Copyright © 2017 Endocrine Society.

  11. Inhibition of estrone sulfatase by aromatase inhibitor-based estrogen 3-sulfamates.

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    Numazawa, Mitsuteru; Tominaga, Takako; Watari, Yoko; Tada, Yasue

    2006-05-01

    Our rationale is based on the finding that estrone 3-sulfamate (EMATE, 2d), a typical estrone sulfatase (ES) inhibitor, can be hydrolyzed and the pharmacological effect of the free estrogen contributes to the bioactivity of the sulfamate. A number of 3-sulfamoylated derivatives of the good aromatase inhibitors, 2- and 4-halogeno (F, Cl, and Br) estrones and their estradiol analogs as well as 6beta-methyl and phenyl estrones, were synthesized and evaluated as inhibitors of ES in human placental microsomes in comparison with the lead compound EMATE. Among them, 2-chloro- and 2-bromoestrone 3-sulfamates (2b and 2c), along with their estradiol analogs 3b and 3c, were powerful competitive inhibitors with K(i)'s ranging between 4.0 and 11.3 nM (K(i) for EMATE, 73 nM). These four sulfamates as well as the 2-fluoro analogs 2a and 3a inactivated ES in a time-dependent manner more efficiently than EMATE, and 2-halogeno estrone sulfamates 2 also caused a concentration-dependent loss of ES activity. The results may be useful for developing a new class of drugs having a dual function, ES inhibition and aromatase inhibition, for the treatment of breast cancer.

  12. New steroidal aromatase inhibitors: Suppression of estrogen-dependent breast cancer cell proliferation and induction of cell death

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    Roleira Fernanda MF

    2008-07-01

    Full Text Available Abstract Background Aromatase, the cytochrome P-450 enzyme (CYP19 responsible for estrogen biosynthesis, is an important target for the treatment of estrogen-dependent breast cancer. In fact, the use of synthetic aromatase inhibitors (AI, which induce suppression of estrogen synthesis, has shown to be an effective alternative to the classical tamoxifen for the treatment of postmenopausal patients with ER-positive breast cancer. New AIs obtained, in our laboratory, by modification of the A and D-rings of the natural substrate of aromatase, compounds 3a and 4a, showed previously to efficiently suppress aromatase activity in placental microsomes. In the present study we have investigated the effects of these compounds on cell proliferation, cell cycle progression and induction of cell death using the estrogen-dependent human breast cancer cell line stably transfected with the aromatase gene, MCF-7 aro cells. Results The new steroids inhibit hormone-dependent proliferation of MCF-7aro cells in a time and dose-dependent manner, causing cell cycle arrest in G0/G1 phase and inducing cell death with features of apoptosis and autophagic cell death. Conclusion Our in vitro studies showed that the two steroidal AIs, 3a and 4a, are potent inhibitors of breast cancer cell proliferation. Moreover, it was also shown that the antiproliferative effects of these two steroids on MCF-7aro cells are mediated by disrupting cell cycle progression, through cell cycle arrest in G0/G1 phase and induction of cell death, being the dominant mechanism autophagic cell death. Our results are important for the elucidation of the cellular effects of steroidal AIs on breast cancer.

  13. Determination and confirmation of selective estrogen receptor modulators (SERMs), anti-estrogens and aromatase inhibitors in bovine and porcine urine using UHPLC-MS/MS.

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    Meijer, Thijs; Essers, Martien L; Kaklamanos, George; Sterk, Saskia S; van Ginkel, Leendert A

    2017-04-01

    Selective estrogen receptor modulators (SERMs), anti-estrogens and aromatase inhibitors are prohibited in human sports doping. However, they also present a risk of being used illegally in animal husbandry for fattening purposes. A method was developed and validated using UHPLC-MS/MS for the determination and confirmation of SERMs, anti-estrogens and aromatase inhibiters in bovine and porcine urine. This method was used in a survey of more than 200 bovine and porcine urine samples from Dutch farms. In 18 out of 103 porcine urine samples (17%) and two out of 114 bovine samples (2%) formestane, an aromatase inhibitor, was detected. None of the other compounds was detected. From human doping control it is known that formestane can, in some cases, be of natural origin. Analyses of reference samples from untreated bovine and porcine animals demonstrated the presence of formestane in bovine animals, but not yet in porcine animals. Future research will focus on whether the detected formestane in porcine and bovine urine is from endogenous or exogenous origin, using GC-c-IRMS.

  14. Expression of estrogen receptors (α, β), cyclooxygenase-2 and aromatase in normal endometrium and endometrioid cancer of uterus.

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    Knapp, P; Chabowski, A; Błachnio-Zabielska, A; Walentowicz-Sadłecka, M; Grabiec, M; Knapp, P A

    2013-01-01

    Endometrial cancer (EC) is one of the most common malignancies of the female genital tract, but the etiology, especially its metabolism is still investigated. The aim of this study was to evaluate the presence and relative expression of Estrogen Receptors (α, β), Cyclooxygenase-2 and Aromatase in both endometrial cancer and normal mucosa. Two groups of women were selected for the study: 1) patients with endometrioid endometrial cancer (FIGO I; G1 - G3) (n=35) and 2) subjects with normal endometrial tissue (control group, n=29). The expression of Estrogen Receptors (ERα, β), Cyclooxygenase-2 (COX-2), Aromatase were estimated by Western blot analysis. Furthermore, the associations between FIGO classification (stage: Ia, Ib), tumor grade (G) and expression of ERα, β, COX-2, aromatase proteins were evaluated. Overall and disease-free survival curves were generated according to the Kaplan-Meier method. Median follow-up time of the patients examined in this study was 39 months. The relative expression of each examined protein was markedly higher in the endometrial cancer tissue as compared to the healthy endometrium. The trends towards greater expression along with a tumor progression was noticed (FIGO stage: Ia vs. Ib). Analysis of endometrial cancer risk factors and their influence on survival curves showed only an inverse significant correlations between obesity (BMI: 36.2; n=21) and disease-free survival in EC group (p=0.00872), but there was no significant association between obesity and overall survival (p=0.358). Endometrioid endometrial cancer shows relatively higher expression of either ER, COX-2 and aromatase comparing to healthy mucosa, suggesting their involvement in tumor development and progression.

  15. Variable aromatase inhibitor plasma concentrations do not correlate with circulating estrogen concentrations in post-menopausal breast cancer patients.

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    Hertz, Daniel L; Speth, Kelly A; Kidwell, Kelley M; Gersch, Christina L; Desta, Zeruesenay; Storniolo, Anna Maria; Stearns, Vered; Skaar, Todd C; Hayes, Daniel F; Henry, N Lynn; Rae, James M

    2017-10-01

    The aromatase inhibitors (AI) exemestane (EXE), letrozole (LET), and anastrozole suppress estrogen biosynthesis, and are effective treatments for estrogen receptor (ER)-positive breast cancer. Prior work suggests that anastrozole blood concentrations are associated with the magnitude of estrogen suppression. The objective of this study was to determine whether the magnitude of estrogen suppression, as determined by plasma estradiol (E2) concentrations, in EXE or LET treated patients is associated with plasma AI concentrations. Five hundred post-menopausal women with ER-positive breast cancer were enrolled in the prospective Exemestane and Letrozole Pharmacogenetic (ELPh) Study conducted by the COnsortium on BReast cancer phArmacogomics (COBRA) and randomly assigned to either drug. Estrogen concentrations were measured at baseline and after 3 months of AI treatment and drug concentrations were measured after 1 or 3 months. EXE or LET concentrations were compared with 3-month E2 concentration or the change from baseline to 3 months using several complementary statistical procedures. Four-hundred patients with on-treatment E2 and AI concentrations were evaluable (EXE n = 200, LET n = 200). Thirty (7.6%) patients (EXE n = 13, LET n = 17) had 3-month E2 concentrations above the lower limit of quantification (LLOQ) (median: 4.75; range: 1.42-63.8 pg/mL). EXE and LET concentrations were not associated with on-treatment E2 concentrations or changes in E2 concentrations from baseline (all p > 0.05). Steady-state plasma AI concentrations do not explain variability in E2 suppression in post-menopausal women receiving EXE or LET therapy, in contrast with prior evidence in anastrozole treated patients.

  16. Dopamine D1 receptor activation regulates the expression of the estrogen synthesis gene aromatase B in radial glial cell

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    Lei eXing

    2015-09-01

    Full Text Available Radial glial cells (RGCs are abundant stem-like non-neuronal progenitors that are important for adult neurogenesis and brain repair, yet little is known about their regulation by neurotransmitters. Here we provide evidence for neuronal-glial interactions via a novel role for dopamine to stimulate RGC function. Goldfish were chosen as the model organism due to the abundance of RGCs and regenerative abilities of the adult central nervous system. A close anatomical relationship was observed between tyrosine hydroxylase-positive catecholaminergic cell bodies and axons and dopamine-D1 receptor expressing RGCs along the ventricular surface of telencephalon, a site of active neurogenesis. A primary cell culture model was established and immunofluorescence analysis indicates that in vitro RGCs from female goldfish retain their major characteristics in vivo, including expression of glial fibrillary acidic protein and brain lipid binding protein. The estrogen synthesis enzyme aromatase B is exclusively found in RGCs, but this is lost as cells differentiate to neurons and other glial types in adult teleost brain. Pharmacological experiments using the cultured RGCs established that specific activation of dopamine D1 receptors up-regulates aromatase B mRNA through a cyclic adenosine monophosphate-dependent molecular mechanism. These data indicate that dopamine enhances the steroidogenic function of this neuronal progenitor cell.

  17. Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens

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    Morishima, Akira; Grumbach, M.M.; Simpson, E.R. [Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)]|[Univ. of California, San Francisco, CA (United States)] [and others

    1995-12-01

    The aromatase enzyme complex catalyzes the conversion of androgens to estrogens in a wide variety of tissues, including the ovary, testis, placenta, brain, and adipose tissue. Only a single human gene encoding aromatase P450 (CYP19) has been isolated; tissue-specific regulation is controlled in part by alternative promoters in a tissue-specific manner. We report a novel mutation in the CYP19 gene in a sister and brother. The 28-yr-old XX proband, followed since infancy, exhibited the cardinal features of the aromatase deficiency syndrome as recently defined. She had nonadrenal female pseudohermaphrodism at birth and underwent repair of the external genitalia, including a clitorectomy. Her adult height is 177.6 cm (+2.5 SD). Her only sibling, and XY male, was studied at 24 yr of age. During both pregnancies, the mother exhibited signs of progressive virilization that regressed postpartum. The height of the brother was 204 cm (+3.7 SD) with eunuchoid skeletal proportions, and the weight was 135.1 kg (+2.1 SD). He was sexually fully mature and had macroorchidism. The bone age was 14 yr at a chronological age of 24 3/12 yr. Bone mineral densitometric indexes of the lumbar spine (cancellous bone) and distal radius (cortical bone) were consistent with osteoporosis; the distal radius was -4.7 SD below the mean value for age- and sex-matched normal men; indexes of bone turnover were increased. Analysis of genomic DNA in transformed lymphoblasts from both the sister and brother indicated a homozygous single base change at base pair 1123 (C{r_arrow}T) in exon IX of the CYP19 gene, a highly conserved region, that results in a cysteine instead of an arginine at position 375 (R375C). The parents are obligate heterozygotes in this consanguineous pedigree. Expression of the mutant complementary DNA showed that the R375C mutation had 0.2% the aromatase activity of the wild-type enzyme. 44 refs., 7 figs., 4 tabs.

  18. Two natural products, trans-phytol and (22E)-ergosta-6,9,22-triene-3β,5α,8α-triol, inhibit the biosynthesis of estrogen in human ovarian granulosa cells by aromatase (CYP19)

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Jiajia [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); Yuan, Yun [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang (China); Lu, Danfeng; Du, Baowen [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); Xiong, Liang; Shi, Jiangong [State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (China); Yang, Lijuan [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); Liu, Wanli [MOE Key Laboratory of Protein Science, School of Life Sciences, Tsinghua University, Beijing 100084 (China); Yuan, Xiaohong [School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang (China); Zhang, Guolin, E-mail: zhanggl@cib.ac.cn [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu (China); Wang, Fei, E-mail: wangfei@cib.ac.cn [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu (China)

    2014-08-15

    Aromatase is the only enzyme in vertebrates to catalyze the biosynthesis of estrogens. Although inhibitors of aromatase have been developed for the treatment of estrogen-dependent breast cancer, the whole-body inhibition of aromatase causes severe adverse effects. Thus, tissue-selective aromatase inhibitors are important for the treatment of estrogen-dependent cancers. In this study, 63 natural products with diverse structures were examined for their effects on estrogen biosynthesis in human ovarian granulosa-like KGN cells. Two compounds—trans-phytol (SA-20) and (22E)-ergosta-6,9,22-triene-3β,5α,8α-triol (SA-48)—were found to potently inhibit estrogen biosynthesis (IC{sub 50}: 1 μM and 0.5 μM, respectively). Both compounds decreased aromatase mRNA and protein expression levels in KGN cells, but had no effect on the aromatase catalytic activity in aromatase-overexpressing HEK293A cells and recombinant expressed aromatase. The two compounds decreased the expression of aromatase promoter I.3/II. Neither compound affected intracellular cyclic AMP (cAMP) levels, but they inhibited the phosphorylation or protein expression of cAMP response element-binding protein (CREB). The effects of these two compounds on extracellular regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinases (MAPKs), and AKT/phosphoinositide 3-kinase (PI3K) pathway were examined. Inhibition of p38 MAPK could be the mechanism underpinning the actions of these compounds. Our results suggests that natural products structurally similar to SA-20 and SA-48 may be a new source of tissue-selective aromatase modulators, and that p38 MAPK is important in the basal control of aromatase in ovarian granulosa cells. SA-20 and SA-48 warrant further investigation as new pharmaceutical tools for the prevention and treatment of estrogen-dependent cancers. - Highlights: • Two natural products inhibited estrogen biosynthesis in human ovarian granulosa cells. • They

  19. Relevance of estrogenic and aromatase inhibiting effects of mixtures of xenoestrogens for human exposure

    NARCIS (Netherlands)

    van Meeuwen, J.A.

    2008-01-01

    BACKGROUND. Daily humans are exposed to various sources of estrogen-like compounds (xenoestrogens), such as food (naturally occurring, residues or contaminants), clothes and cosmetics. Non-governmental organisations give the impression that this causes adverse effects on human health and the

  20. Structural and functional analysis of two di-domain aromatase/cyclases from type II polyketide synthases.

    Science.gov (United States)

    Caldara-Festin, Grace; Jackson, David R; Barajas, Jesus F; Valentic, Timothy R; Patel, Avinash B; Aguilar, Stephanie; Nguyen, MyChi; Vo, Michael; Khanna, Avinash; Sasaki, Eita; Liu, Hung-Wen; Tsai, Shiou-Chuan

    2015-12-15

    Aromatic polyketides make up a large class of natural products with diverse bioactivity. During biosynthesis, linear poly-β-ketone intermediates are regiospecifically cyclized, yielding molecules with defined cyclization patterns that are crucial for polyketide bioactivity. The aromatase/cyclases (ARO/CYCs) are responsible for regiospecific cyclization of bacterial polyketides. The two most common cyclization patterns are C7-C12 and C9-C14 cyclizations. We have previously characterized three monodomain ARO/CYCs: ZhuI, TcmN, and WhiE. The last remaining uncharacterized class of ARO/CYCs is the di-domain ARO/CYCs, which catalyze C7-C12 cyclization and/or aromatization. Di-domain ARO/CYCs can further be separated into two subclasses: "nonreducing" ARO/CYCs, which act on nonreduced poly-β-ketones, and "reducing" ARO/CYCs, which act on cyclized C9 reduced poly-β-ketones. For years, the functional role of each domain in cyclization and aromatization for di-domain ARO/CYCs has remained a mystery. Here we present what is to our knowledge the first structural and functional analysis, along with an in-depth comparison, of the nonreducing (StfQ) and reducing (BexL) di-domain ARO/CYCs. This work completes the structural and functional characterization of mono- and di-domain ARO/CYCs in bacterial type II polyketide synthases and lays the groundwork for engineered biosynthesis of new bioactive polyketides.

  1. Longitudinal changes of trabecular bone score after estrogen deprivation: effect of menopause and aromatase inhibition.

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    Pedrazzoni, M; Casola, A; Verzicco, I; Abbate, B; Vescovini, R; Sansoni, P

    2014-09-01

    To examine the effects of the menopausal transition and treatment with aromatase inhibitors (AI) on trabecular bone score (TBS, a newly proposed index of bone architecture derived from DXA vertebral scans) and vertebral bone mineral density (BMD). Retrospective cohort study on 29 women who became postmenopausal during a mean follow-up of 2.9 years (MP group) and 34 women treated with AI during a mean follow-up of 2.1 years (AI group). BMD was measured by DXA and TBS with a specific software. TBS decreased after menopause, but the change was significantly lower than that of the lumbar BMD (-4.6 vs. -6.8 %; mean difference: 2.2 %; p = 0.016). An even larger difference was observed in the AI group (-2.1 vs. -5.9 %; mean difference: 3.8 %; p = 0.002). The decrease of TBS induced by menopause or treatment with AI is significantly lower than that of lumbar BMD.

  2. Assessment of xenoestrogens using three distinct estrogen receptors and the zebrafish brain aromatase gene in a highly responsive glial cell system.

    Science.gov (United States)

    Le Page, Yann; Scholze, Martin; Kah, Olivier; Pakdel, Farzad

    2006-05-01

    The brain cytochrome P450 aromatase (Aro-B) in zebrafish is expressed in radial glial cells and is strongly stimulated by estrogens (E2); thus, it can be used in vivo as a biomarker of xenoestrogen effects on the central nervous system. By quantitative real-time polymerase chain reaction, we first confirmed that the expression of Aro-B gene is robustly stimulated in juvenile zebrafish exposed to several xenoestrogens. To investigate the impact of environmental estrogenic chemicals on distinct estrogen receptor (ER) activity, we developed a glial cell-based assay using Aro-B as the target gene. To this end, the ER-negative glial cell line U251-MG was transfected with the three zebrafish ER subtypes and the Aro-B promoter linked to a luciferase reporter gene. E2 treatment of U251-MG glial cells cotransfected with zebrafish ER-alpha and the Aro-B promoter-luciferase reporter resulted in a 60- to 80-fold stimulation of luciferase activity. The detection limit was xenoestrogens leads to an enhancement of the estrogenic potency, even when each single agent might be present at low effect concentrations. In conclusion, we demonstrate that our bioassay provides a fast, reliable, sensitive, and efficient test for evaluating estrogenic potency of endocrine disruptors on ER subtypes in a glial context.

  3. Changes in the expression of aromatase, estrogen receptor α and β in mandibular condylar cartilage of rats induced by disordered occlusion

    Directory of Open Access Journals (Sweden)

    Yu Shibin

    2012-09-01

    Full Text Available Abstract Background Estrogens play an important role in modulating the morphology and function of temporomandibular joints (TMJs, which is suggested to act via estrogen receptors (ERs. The present study was to investigate the expression of aggrecan, collagen type II (Col II, Col X, aromatase, ERα and ERβ in degenerative changes of mandibular condylar cartilage. Methods Forty male and 40 female 8-week-old rats were enrolled in this study. In experimental groups, the disordered occlusion was created by moving the first molars mesially and the third ones distally. Immunohistochemistry and real-time PCR were performed at the end of the second or fourth week. Results Degenerative changes, characterized by interrupted continuity of hypertrophic layer, pyknotic and eosinophilic lesion with few nuclei, areas filled with eosinophilic nuclei, were observed in more joints from female experimental groups than male ones. However, thickening changes in hypertrophic layer were only found in male experimental groups. The gene expression of Col II, Col X and aggrecan increased in 4-wk male experimental subgroup (both P Conclusions Mandibular condylar cartilage responses differently to the disordered occlusion in male and female rats. The levels of locally synthesized estrogen, ERα and ERβ may have limited attribution, if any, to the sex-specific cartilage response.

  4. Seasonal expression of androgen receptor, aromatase, and estrogen receptor alpha and beta in the testis of the wild ground squirrel (Citellus dauricus Brandt

    Directory of Open Access Journals (Sweden)

    Q. Li

    2015-02-01

    Full Text Available The aim of this study was to investigate the seasonal expression of androgen receptor (AR, estrogen receptors α and β (ERα and ERβ and aromatase cytochrome P450 (P450arom mRNA and protein by real-time PCR and immunohistochemistry in the wild ground squirrel (WGS testes. Histologically, all types of spermatogenic cells including mature spermatozoa were identified in the breeding season (April, while spermatogonia and primary spermatocytes were observed in the nonbreeding season (June, and spermatogonia, primary spermatocytes and secondary spermatocytes were found in pre-hibernation (September. AR was present in Leydig cells, peritubular myoid cells and Sertoli cells in the breeding season and pre-hibernation with more intense staining in the breeding season, whereas AR was only found in Leydig cells in the nonbreeding season; P450arom was expressed in Leydig cells, Sertoli cells and germ cells during the breeding season, whereas P450arom was found in Leydig cells and Sertoli cells during pre-hibernation, but P450arom was not present in the nonbreeding season; stronger immunohistochemical signal for ERα was present in Sertoli cells and Leydig cells during the breeding season; ERβ was only expressed in Leydig cells of the breeding season. Consistent with the immunohistochemical results, the mean mRNA level of AR, P450arom, ERα and ERβ were higher in the testes of the breeding season when compared to pre-hibernation and the nonbreeding season. These results suggested that the seasonal changes in spermatogenesis and testicular recrudescence and regression process in WGSs might be correlated with expression levels of AR, P450arom and ERs, and that estrogen and androgen may play an important autocrine/paracrine role to regulate seasonal testicular function.

  5. Genetics Home Reference: aromatase excess syndrome

    Science.gov (United States)

    ... In affected males, the increased aromatase and subsequent conversion of androgens to estrogen are responsible for the ... in each cell is sufficient to cause the disorder. In some cases, an affected person inherits the ...

  6. Dienogest, a synthetic progestin, inhibits prostaglandin E2 production and aromatase expression by human endometrial epithelial cells in a spheroid culture system.

    Science.gov (United States)

    Shimizu, Yutaka; Mita, Shizuka; Takeuchi, Takashi; Notsu, Tatsuto; Mizuguchi, Kiyoshi; Kyo, Satoru

    2011-01-01

    Prostaglandin E(2) (PGE(2)) is a major mediator in the pathophysiology, and pathogenesis of gynecological diseases associated with abnormal endometrial disease with proliferation and inflammation, such as endometriosis. In this study, we investigated the effect of dienogest, a selective progesterone receptor agonist, on PGE(2) production and the expression of aromatase, an estrogen synthase, in human immortalized endometrial epithelial cells. Compared with monolayer culture, the cells showed enhanced PGE(2) production and expression of the PGE(2) synthases cyclooxygenase-2 (COX-2), and microsomal prostaglandin E(2) synthase-1 (mPGES-1) in a spheroid culture system. Dienogest inhibited PGE(2) production and this effect was reversed by RU486, a progesterone receptor antagonist. Dienogest inhibited the PGE(2) synthases mRNA and protein expression, and the nuclear factor-κB activation. Moreover, the suppressive effect of dienogest on PGE(2) production was sustained 24h after the drug was withdrawn. Dienogest but not COX inhibitors inhibited aromatase expression. These results suggest that progesterone receptor activation reduces the gene expressions of COX-2, mPGES-1, and aromatase. Our findings suggest that the pharmacological mechanism of dienogest includes the direct inhibition of PGE(2) synthase and aromatase expression and may contribute to the therapeutic effect on the progression of endometriosis. Copyright © 2010 Elsevier Inc. All rights reserved.

  7. Modulation of Aromatase Activity as a Mode of Action for Endocrine Disrupting Chemicals in a Marine Fish

    Science.gov (United States)

    The steroidogenic enzyme aromatase catalyzes the conversion of androgens (androstenedione and testosterone) to estrogens (estrone and estradiol) and therefore plays a central role in reproduction. In contrast to most vertebrates, teleost fish have two distinct forms of aromatase....

  8. Teratogenicity and brain aromatase-induction of monosodium ...

    African Journals Online (AJOL)

    Teratogenicity and brain aromatase-induction of monosodium glutamate in estrogen-responsive mosaic transgenic zebra fish Danio rerio. Tamer Said Abdelkader, Chang Seo-Na, Kim Tae-Hyun, Song Juha, Kim Dongso, Jae-Hak Park ...

  9. Substituted androstanes as aromatase inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Levina, Inna S [N.D.Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow (Russian Federation)

    1998-11-30

    The synthesis and structure-activity relationships of inhibitors of steroid aromatase which catalyses the last stage of a multistep biotransformation of cholesterol into estrogens, viz., aromatisation of C{sub 19}-steroids into C{sub 18}-phenolic steroids, are discussed. Compounds of the androstane series which are structurally related to the natural substrate, viz., androst-4-ene-3,17-dione, are the subjects of consideration. The review encompasses problems of synthesis of various substituted androstanes and their aromatase-inhibiting activities and structural requirements for selective specific aromatase inhibitors based on in vitro and in vivo structure-activity studies of compounds synthesised, their biological properties and the results of clinical trials. Special attention is paid to practical applications of aromatase inhibitors in the treatment of hormone-dependent mammary and ovarian tumours as well as benign prostatic tumours. In writing this report, the author has used all the information currently available in the chemical, biochemical, endocrinological and medicinal literature as well as in patents. The bibliography includes 173 references.

  10. Substituted androstanes as aromatase inhibitors

    Science.gov (United States)

    Levina, Inna S.

    1998-11-01

    The synthesis and structure-activity relationships of inhibitors of steroid aromatase which catalyses the last stage of a multistep biotransformation of cholesterol into estrogens, viz., aromatisation of C19-steroids into C18-phenolic steroids, are discussed. Compounds of the androstane series which are structurally related to the natural substrate, viz., androst-4-ene-3,17-dione, are the subjects of consideration. The review encompasses problems of synthesis of various substituted androstanes and their aromatase-inhibiting activities and structural requirements for selective specific aromatase inhibitors based on in vitro and in vivo structure-activity studies of compounds synthesised, their biological properties and the results of clinical trials. Special attention is paid to practical applications of aromatase inhibitors in the treatment of hormone-dependent mammary and ovarian tumours as well as benign prostatic tumours. In writing this report, the author has used all the information currently available in the chemical, biochemical, endocrinological and medicinal literature as well as in patents. The bibliography includes 173 references.

  11. Rapid Modulation of Aromatase Activity in the Vertebrate Brain

    Directory of Open Access Journals (Sweden)

    Thierry D. Charlier

    2013-01-01

    Full Text Available Numerous steroid hormones, including 17β-estradiol (E2, activate rapid and transient cellular, physiological, and behavioral changes in addition to their well-described genomic effects. Aromatase is the key-limiting enzyme in the production of estrogens, and the rapid modulation of this enzymatic activity could produce rapid changes in local E2 concentrations. The mechanisms that might mediate such rapid enzymatic changes are not fully understood but are currently under intense scrutiny. Recent studies in our laboratory indicate that brain aromatase activity is rapidly inhibited by an increase in intracellular calcium concentration resulting from potassium-induced depolarization or from the activation of glutamatergic receptors. Phosphorylating conditions also reduce aromatase activity within minutes, and this inhibition is blocked by the addition of multiple protein kinase inhibitors. This rapid modulation of aromatase activity by phosphorylating conditions is a general mechanism observed in different cell types and tissues derived from a variety of species, including human aromatase expressed in various cell lines. Phosphorylation processes affect aromatase itself and do not involve changes in aromatase protein concentration. The control of aromatase activity by multiple kinases suggests that several amino acids must be concomitantly phosphorylated to modify enzymatic activity but site-directed mutagenesis of several amino acids alone or in combination has not to date revealed the identity of the targeted residue(s. Altogether, the phosphorylation processes affecting aromatase activity provide a new general mechanism by which the concentration of estrogens can be rapidly altered in the brain.

  12. Androgen and estrogen receptor mediated mechanisms of testosterone action in male rat pelvic autonomic ganglia

    Science.gov (United States)

    Purves-Tyson, T.D.; Arshi, M.S.; Handelsman, D. J.; Cheng, Y.; Keast, J. R.

    2007-01-01

    Although male reproductive function is primarily androgen dependent, many studies suggest that estrogens have direct actions on the male reproductive organs. Pelvic autonomic neurons provide the motor control of the internal reproductive organs and the penis and various properties of these neurons are affected by endogenous androgens. However, the possible role of estrogens at this site has not been examined. Here we have investigated the significance of estrogens produced by aromatisation of testosterone in the physiological actions of androgens on adult male rat pelvic ganglion neurons. RT-PCR studies showed that aromatase and both estrogen receptors (ERα and ERβ) are expressed in these ganglia. Western blotting also showed that aromatase is expressed in male pelvic ganglia. Using immunohistochemical visualisation, ERα was predominantly expressed by nitric oxide synthase (NOS)-positive parasympathetic pelvic ganglion neurons. In vivo studies showed that the decrease in pelvic ganglion soma size caused by gonadectomy could be prevented by administration of testosterone (T) or dihydrotestosterone (DHT), but not 17β-estradiol (E2), showing that this maintenance action of testosterone is mediated entirely by androgenic mechanisms. However, in vitro studies of cultured pelvic ganglion neurons revealed that T, DHT and E each stimulated the growth of longer and more complex neurites in both noradrenergic and cholinergic NOS-expressing neurons. The effects of T were attenuated by either androgen or estrogen receptor antagonists, or by inhibition of aromatase. Together these studies demonstrate that estrogens are likely to be synthesised in the male pelvic ganglia, produced from testosterone by local aromatase. The effects of androgens on axonal growth are likely to be at least partly mediated by estrogenic mechanisms, which may be important for understanding disease-, aging- and injury-induced plasticity in this part of the nervous system. PMID:17629410

  13. Androgen and estrogen receptor-mediated mechanisms of testosterone action in male rat pelvic autonomic ganglia.

    Science.gov (United States)

    Purves-Tyson, T D; Arshi, M S; Handelsman, D J; Cheng, Y; Keast, J R

    2007-08-10

    Although male reproductive function is primarily androgen dependent, many studies suggest that estrogens have direct actions on the male reproductive organs. Pelvic autonomic neurons provide the motor control of the internal reproductive organs and the penis and various properties of these neurons are affected by endogenous androgens. However, the possible role of estrogens at this site has not been examined. Here we have investigated the significance of estrogens produced by aromatization of testosterone (T) in the physiological actions of androgens on adult male rat pelvic ganglion neurons. Reverse transcriptase polymerase chain reaction (RT-PCR) studies showed that aromatase and both estrogen receptors (ERalpha and ERbeta) are expressed in these ganglia. Western blotting also showed that aromatase is expressed in male pelvic ganglia. Using immunohistochemical visualization, ERalpha was predominantly expressed by nitric oxide synthase (NOS)-positive parasympathetic pelvic ganglion neurons. In vivo studies showed that the decrease in pelvic ganglion soma size caused by gonadectomy could be prevented by administration of T or dihydrotestosterone (DHT), but not 17beta-estradiol (E2), showing that this maintenance action of testosterone is mediated entirely by androgenic mechanisms. However, in vitro studies of cultured pelvic ganglion neurons revealed that T, DHT and E each stimulated the growth of longer and more complex neurites in both noradrenergic and cholinergic NOS-expressing neurons. The effects of T were attenuated by either androgen or estrogen receptor antagonists, or by inhibition of aromatase. Together these studies demonstrate that estrogens are likely to be synthesized in the male pelvic ganglia, produced from T by local aromatase. The effects of androgens on axonal growth are likely to be at least partly mediated by estrogenic mechanisms, which may be important for understanding disease-, aging- and injury-induced plasticity in this part of the

  14. 3D-QSAR Study of Steroidal and Azaheterocyclic Human Aromatase Inhibitors using Quantitative Profile of Protein-Ligand Interactions

    Science.gov (United States)

    Aromatase is a member of the cytochrome P450 superfamily responsible for a key step in the biosynthesis of estrogens. As estrogens are involved in the control of important reproduction-related processes, including sexual differentiation and maturation, aromatase is a potential ta...

  15. Aromatase and neuroinflammation in rat focal brain ischemia.

    Science.gov (United States)

    Zhong, Yu H; Dhawan, Jasbeer; Kovoor, Joel A; Sullivan, John; Zhang, Wei X; Choi, Dennis; Biegon, Anat

    2017-11-01

    Accumulating evidence suggests that expression of aromatase, the enzyme responsible for the conversion of androgens to estrogens, is transiently upregulated in rat stroke models. It was further suggested that increased aromatase expression is linked to neuroinflammation and that it is neuroprotective in females. Our goal was to investigate aromatase upregulation in male rats subjected to experimental stroke in relationship to neuroinflammation, infarct and response to treatment with different putative neuroprotective agents. Intact male rats were subjected to transient (90min) middle cerebral artery occlusion (MCAO) and administered selfotel (N-methyl-d-aspartic acid (NMDA) receptor competitive antagonist), TPEN (a zinc chelator), a combination of the two drugs or vehicle, injected immediately after reperfusion. Animals were killed 14days after MCAO and consecutive brain sections used to measure aromatase expression, cerebral infarct volume and neuroinflammation. Quantitative immunohistochemistry (IHC) demonstrated increased brain aromatase expression in the peri-infarct area relative to contralesional area, which was partially abrogated by neuroprotective agents. There was no correlation between aromatase expression in the peri-infarct zone and infarct volume, which was reduced by neuroprotective agents. Microglial activation, measured by quantitative autoradiography, was positively correlated with infarct and inversely correlated with aromatase expression in the peri-infarct zone. Our findings indicate that focal ischemia upregulates brain aromatase in the male rat brain at 14days post surgery, which is within the time frame documented in females. However, the lack of negative correlation between aromatase expression and infarct volume and lack of positive correlation between microgliosis and aromatase do not support a major role for aromatase as a mediator of neuroprotection or a causal relationship between microglial activation and increased aromatase

  16. Aromatase, brain sexualization and plasticity: the fish paradigm.

    Science.gov (United States)

    Le Page, Yann; Diotel, Nicolas; Vaillant, Colette; Pellegrini, Elisabeth; Anglade, Isabelle; Mérot, Yohann; Kah, Olivier

    2010-12-01

    In contrast to mammals, teleost fish have a very labile genetic sex determination. Sex differentiation is influenced by a combination of hormonal, social and environmental factors and teleost fishes exhibit many examples of hermaphroditism. This means that the brain of fish is not irreversibly sexualized early in life. This review aims at highlighting some unique features of fish that may explain their brain sexual plasticity. Unlike mammals, in which brain aromatase activity decreases after birth, adult teleosts exhibit an intense aromatase activity due to strong expression of one of two aromatase genes (aromatase A or cyp19a1a and aromatase B or cyp19a1b) that arose from a gene duplication event. Interestingly, aromatase B is only expressed in radial glial cells (RGC) of adult fish. These cells persist throughout life and act as progenitors in the brain of both developing and adult fish. In agreement with the fact that brain aromatase activity is correlated with sex steroid levels, the high expression of cyp19a1b is due to an autoregulatory loop through which estrogens and aromatizable androgens upregulate aromatase expression. Given the well-established roles of estrogens and aromatase on brain sexualization, these features suggest that the brain of fish conserves properties of embryonic mammalian brain throughout life - high neurogenic activity and high aromatase expression in progenitor cells correlated with sex steroid levels. The permanent dialogue between the brain and the gonad would permit sex changes and thus the emergence of a variety of reproductive strategies. Other hypotheses are also discussed. © 2010 The Authors. European Journal of Neuroscience © 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  17. Quantitative analysis of long-form aromatase mRNA in the male and female rat brain.

    Science.gov (United States)

    Tabatadze, Nino; Sato, Satoru M; Woolley, Catherine S

    2014-01-01

    In vitro studies show that estrogens acutely modulate synaptic function in both sexes. These acute effects may be mediated in vivo by estrogens synthesized within the brain, which could fluctuate more rapidly than circulating estrogens. For this to be the case, brain regions that respond acutely to estrogens should be capable of synthesizing them. To investigate this question, we used quantitative real-time PCR to measure expression of mRNA for the estrogen-synthesizing enzyme, aromatase, in different brain regions of male and female rats. Importantly, because brain aromatase exists in two forms, a long form with aromatase activity and a short form with unknown function, we targeted a sequence found exclusively in long-form aromatase. With this approach, we found highest expression of aromatase mRNA in the amygdala followed closely by the bed nucleus of the stria terminalis (BNST) and preoptic area (POA); we found moderate levels of aromatase mRNA in the dorsal hippocampus and cingulate cortex; and aromatase mRNA was detectable in brainstem and cerebellum, but levels were very low. In the amygdala, gonadal/hormonal status regulated aromatase expression in both sexes; in the BNST and POA, castration of males down-regulated aromatase, whereas there was no effect of estradiol in ovariectomized females. In the dorsal hippocampus and cingulate cortex, there were no differences in aromatase levels between males and females or effects of gonadal/hormonal status. These findings demonstrate that long-form aromatase is expressed in brain regions that respond acutely to estrogens, such as the dorsal hippocampus, and that gonadal/hormonal regulation of aromatase differs among different brain regions.

  18. Aromatase is abundantly expressed by neonatal rat penis but downregulated in adulthood.

    Science.gov (United States)

    Jesmin, S; Mowa, C N; Sakuma, I; Matsuda, N; Togashi, H; Yoshioka, M; Hattori, Y; Kitabatake, A

    2004-10-01

    Although synthesis of estrogen by male gonads has been well documented for over half a century, it is only recently that the role of estrogen in male reproductive events has gained appreciation. We recently reported abundant expression of estrogen receptor (ER)-alpha and -beta in different cell types of the rat penis, whose levels diminished with advancing age. The present study, which builds on data from the ER study, was designed to determine whether the penis is capable of generating its own local estrogen by examining evidence of the expression of aromatase, a microsomal enzymatic complex which irreversibly converts androgens to estrogens, using immunohistochemistry, Western blotting, in situ hybridization and real-time PCR analyses. Secondly, the effects of sex steroid hormones on penile aromatase were examined. Discrete aromatase immunoreactive cells were localized in primordial corpus cavernosum, corpus spongiosus and os penis, blood vessels and sensory corpuscle of glans penis. In situ hybridization signals corresponded with immunohistochemical findings. Western blot, enzyme immunoassay and real-time PCR analyses of rat penile samples revealed an age-dependent expression of aromatase and estrogen, with levels at week 1 almost resembling those of the ovary, but they decreased sharply by week 8, and decreased further by week 35. This expression pattern was strikingly similar to that of ER-alpha reported previously. Testosterone and diethylstilbesterol administered prenatally upregulate levels of aromatase mRNA and protein, and estrogen postnatally. Dihydrotestosterone upregulated aromatase mRNA and protein, but not estrogen. We conclude that estrogen acts via ER in a paracrine and/or autocrine manner to regulate penile events, particularly during development, and that estrogen synthesis is regulated by estrogen and androgens.

  19. Relation among Aromatase P450 and Tumoral Growth in Human Prolactinomas

    Directory of Open Access Journals (Sweden)

    María José García-Barrado

    2017-11-01

    Full Text Available The pituitary gland is part of hypothalamic-pituitary–gonadal axis, which controls development, reproduction, and aging in humans and animals. In addition, the pituitary gland is regulated mainly by hormones and neurotransmitters released from the hypothalamus and by systemic hormones secreted by target glands. Aromatase P450, the enzyme responsible for the catabolization of aromatizable androgens to estrogens, is expressed in different parts of body, including the pituitary gland. Moreover, aromatase P450 is involved in sexual dimorphism where alteration in the level of aromatase can initiate a number of diseases in both genders. On the other hand, the direct actions of estrogens, mainly estradiol, are well known for stimulating prolactin release. Numerous studies have shown that changes in the levels of estrogens, among other factors, have been implicated in the genesis and development of prolactinoma. The pituitary gland can produce estradiol locally in several types of endocrine cells, and it is possible that aromatase could be responsible for the maintenance of the population of lactotroph cells and the modulation of the action of central or peripheral regulators. Aromatase overexpression due to inappropriate gene regulation has clinical effects such as the pathogenesis of prolactinomas. The present study reports on the synthesis of pituitary aromatase, its regulation by gonadal steroids, and the physiological roles of aromatase on pituitary endocrine cells. The involvement of aromatase in the pathogenesis of pituitary tumors, mainly prolactinomas, through the auto-paracrine production of estradiol is reviewed.

  20. Estrogens, Genetic Polymorphisms and Breast Cancer Risk

    National Research Council Canada - National Science Library

    Okobia, Michael N; Bunker, Clareann H; Kuller, Lewis; Ferrell, Robert E; Anyanwu, Stanley N; Ezeome, Emmanuel R; Uche, Emmanuel E

    2004-01-01

    ... cancer in Nigerian women. A case-control study is being undertaken to investigate the exposure level to estrogen and its metabolites in these women by examining the genotype frequencies of the genes encoding aromatase...

  1. Comment. The Comparative and Evolutionary Biology of Vertebrate Aromatase

    Science.gov (United States)

    Aromatase is the enzyme responsible for the synthesis of estrogens from androgens. It is doubtful that there are many other genes that have such a broad and profound influence on reproduction and survival of species. The expression of this enzyme in various tissues controls both directly and indirec...

  2. Estrogens and male reproduction: a new concept

    Directory of Open Access Journals (Sweden)

    S. Carreau

    2007-06-01

    Full Text Available The mammalian testis serves two main functions: production of spermatozoa and synthesis of steroids; among them estrogens are the end products obtained from the irreversible transformation of androgens by a microsomal enzymatic complex named aromatase. The aromatase is encoded by a single gene (cyp19 in humans which contains 18 exons, 9 of them being translated. In rats, the aromatase activity is mainly located in Sertoli cells of immature rats and then in Leydig cells of adult rats. We have demonstrated that germ cells represent an important source of estrogens: the amount of P450arom transcript is 3-fold higher in pachytene spermatocytes compared to gonocytes or round spermatids; conversely, aromatase activity is more intense in haploid cells. Male germ cells of mice, bank voles, bears, and monkeys express aromatase. In humans, we have shown the presence of a biologically active aromatase and of estrogen receptors (alpha and ß in ejaculated spermatozoa and in immature germ cells in addition to Leydig cells. Moreover, we have demonstrated that the amount of P450arom transcripts is 30% lower in immotile than in motile spermatozoa. Alterations of spermatogenesis in terms of number and motility of spermatozoa have been described in men genetically deficient in aromatase. These last observations, together with our data showing a significant decrease of aromatase in immotile spermatozoa, suggest that aromatase could be involved in the acquisition of sperm motility. Thus, taking into account the widespread localization of aromatase and estrogen receptors in testicular cells, it is obvious that, besides gonadotrophins and androgens, estrogens produced locally should be considered to be physiologically relevant hormones involved in the regulation of spermatogenesis and spermiogenesis.

  3. Estrogen regulation of testicular function

    Directory of Open Access Journals (Sweden)

    Akingbemi Benson T

    2005-09-01

    Full Text Available Abstract Evidence supporting a role for estrogen in male reproductive tract development and function has been collected from rodents and humans. These studies fall into three categories: i localization of aromatase and the target protein for estrogen (ER-alpha and ER-beta in tissues of the reproductive tract; ii analysis of testicular phenotypes in transgenic mice deficient in aromatase, ER-alpha and/or ER-beta gene; and, iii investigation of the effects of environmental chemicals on male reproduction. Estrogen is thought to have a regulatory role in the testis because estrogen biosynthesis occurs in testicular cells and the absence of ERs caused adverse effects on spermatogenesis and steroidogenesis. Moreover, several chemicals that are present in the environment, designated xenoestrogens because they have the ability to bind and activate ERs, are known to affect testicular gene expression. However, studies of estrogen action are confounded by a number of factors, including the inability to dissociate estrogen-induced activity in the hypothalamus and pituitary from action occurring directly in the testis and expression of more than one ER subtype in estrogen-sensitive tissues. Use of tissue-specific knockout animals and administration of antiestrogens and/or aromatase inhibitors in vivo may generate additional data to advance our understanding of estrogen and estrogen receptor biology in the developing and mature testis.

  4. Comprehensive and Automated Linear Interaction Energy Based Binding-Affinity Prediction for Multifarious Cytochrome P450 Aromatase Inhibitors

    NARCIS (Netherlands)

    van Dijk, Marc; Ter Laak, Antonius M; Wichard, Jörg D; Capoferri, Luigi; Vermeulen, Nico P E; Geerke, Daan P

    2017-01-01

    Cytochrome P450 aromatase (CYP19A1) plays a key role in the development of estrogen dependent breast cancer, and aromatase inhibitors have been at the front line of treatment for the past three decades. The development of potent, selective and safer inhibitors is ongoing with in silico screening

  5. Cytochrome P450 aromatase expression in human seminoma

    Directory of Open Access Journals (Sweden)

    Montanaro Daniela

    2005-12-01

    Full Text Available Abstract Background The enzyme cytochrome P450 aromatase, catalysing the conversion of androgens into estrogens, has been detected in normal human testicular cells suggesting a physiological role of local estrogen biosynthesis on spermatogenesis control. Estrogens, regulating cell growth and apoptosis, can also be involved in tumorigenesis process, but the possible link between estrogens and testicular neoplastic process is, up to now, scarcely known. This study examined aromatase expression in human seminoma, which is the most common germ cell tumour of the testis. Methods The tumour-bearing testes were obtained from 20 patients with classic seminoma undergoing to therapeutic orchidectomy. Paraffin embedded tissues were processed for immunohistochemistry using a mouse monoclonal antibody generated against human placental cytochrome P450 arom, as primary antibody, and a biotinylated goat-anti-mouse IgG, as secondary antibody. Furthermore, Western blot analysis of seminoma extracts was carried out. Results Intense P450 arom immunoreactivity was observed in the seminoma cells and Western blot analysis confirmed the immunodetection. A strong immunostaining was also detected in cells of intratubular germ cell neoplasia (IGCN, adjacent to seminoma. Conclusion The present study demonstrated, for the first time in human, aromatase expression in neoplastic cells of seminoma suggesting a relation between local estrogen biosynthesis and germ cell tumorigenesis. The P450 arom immunolocalization in the cells of IGCN, representing the common precursor of most germ cell tumors, seems to support these findings.

  6. Genome-wide epigenetic profiling of breast cancer tumors treated with aromatase inhibitors

    NARCIS (Netherlands)

    Nevedomskaya, E.; Wessels, L.; Zwart, W.

    2014-01-01

    Aromatase inhibitors (AI) are extensively used in the treatment of estrogen receptor-positive breast cancers, however resistance to AI treatment is commonly observed. Apart from Estrogen receptor (ER?) expression, no predictive biomarkers for response to AI treatment are clinically applied. Yet,

  7. Presence of aromatase inhibitors in cycads.

    Science.gov (United States)

    Kowalska, M T; Itzhak, Y; Puett, D

    1995-07-28

    Cycads, the most primitive of the living gymnosperms, have been used and continue to be used for food and medicinal purposes by many cultures, although toxins must be removed before ingestion. In our quest to identify tropical plants that contain inhibitors of the cytochrome P-450 aromatase and thus may be efficacious in treating estrogen-dependent tumors, we have screened extracts from 5 species of cycad folia encompassing 3 genera: Cycas cairnsiana F. Muell., Cycas revoluta Thunb., Cycas rumphii Miq., Dioon spinulosum Dyer and Encephalartos ferox Bertol. All extracts were found to contain inhibitors of the human enzyme.

  8. Inhibition of human aromatase complex (CYP19) by antiepileptic drugs

    DEFF Research Database (Denmark)

    Jacobsen, Naja Wessel; Halling-Sørensen, Bent; Birkved, Franziska Maria A Kramer

    2008-01-01

    Antiepileptic drugs and epilepsy are often associated with sexual disorder in women such as hyperandrogenism, menstrual disorders and ovarian cysts. In children, until puberty, a hormone imbalance may influence many aspects of development, e.g. growth and sexual maturation. The aromatase complex...... is the enzyme system that converts androgens to estrogens and consequently an inhibition may induce a hormone imbalance. Twelve antiepileptic drugs, used in mono or polytherapy for the treatment of children, were tested for their ability to inhibit aromatase (CYP19) with commercially available microsomes from...

  9. [Development of aromatase inhibitors and analysis of their inhibitory activities].

    Science.gov (United States)

    Numazawa, M

    1998-12-01

    Inhibitors of aromatase are of interest in the treatment of advanced estrogen-dependent breast cancers. In addition, the inhibitors are promising to play as conformational and catalytic probes for the active site of this enzyme, aromatase. There fore, we synthesized a number of steroidal aromatase inhibitors, including suicide substrates, and also studied the mechanism for a time-dependent inactivation of aromatase by the suicide substrates. The mechanism for the aromatase inactivation by 6-oxo-androstenedione (AD) (1), one of the first discovered suicide substrates, was explored using the 19-substituted analogs 2-5 as well as stereo- and/or regio-specifically labeled [3H, 14C]-compound 1. The results indicated that the 4 beta,5 beta-epoxy-19-oxo derivative 7 is a reactive electrophile that irreversibly binds to the active site of aromatase. Studies on the aromatase inhibition by regioisomers of AD, 4-en-6-one 17, 5-en-4-one 18 and 5-en-7-one 19, revealed that the C-3 carbonyl function is not essential for the tight binding of an inhibitor to the active site. 3-Deoxy AD (22) and its 6 alpha,7 alpha-cyclopropano steroid 24 as well as some of 6-alkyl-ADs are among the most potent competitive inhibitors reported so for (K(m) for AD/Ki > 6). Structure-activity relationships of the 6-alkyl-ADs and their 3-deoxy-, delta 1-, delta 6-, and delta 1,6-analogs as aromatase inhibitors showed that aromatase has a hydrophobic binding pocket with a limited accessible volume in the active site in the region corresponding to the beta-side rather than the alpha-side of the C-6 position of the substrate. The 6-alkyl-ADs and their delta 1-analogs were converted into the corresponding estrogens with human placental aromatase, whereas the 3-deoxy steroids 22 and 25 were metabolized to the corresponding 19-oxygenated compounds. The relative apparent K(m) values for the androgens are different from the relative Ki values, indicating that there is a difference between the ability to serve

  10. Management of sexual dysfunction in postmenopausal breast cancer patients taking adjuvant aromatase inhibitor therapy

    OpenAIRE

    Derzko, C.; Elliott, S.; Lam, W.

    2007-01-01

    Treatment with aromatase inhibitors for postmenopausal women with breast cancer has been shown to reduce or obviate invasive procedures such as hysteroscopy or curettage associated with tamoxifen-induced endometrial abnormalities. The side effect of upfront aromatase inhibitors, diminished estrogen synthesis, is similar to that seen with the natural events of aging. The consequences often include vasomotor symptoms (hot flushes) and vaginal dryness and atrophy, which in turn may result in cys...

  11. Puerarin activates endothelial nitric oxide synthase through estrogen receptor-dependent PI3-kinase and calcium-dependent AMP-activated protein kinase

    Energy Technology Data Exchange (ETDEWEB)

    Hwang, Yong Pil; Kim, Hyung Gyun [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of); Hien, Tran Thi [College of Pharmacy, Chosun University, Gwangju (Korea, Republic of); Jeong, Myung Ho [Heart Research Center, Chonnam National University Hospital, Gwangju (Korea, Republic of); Jeong, Tae Cheon, E-mail: taecheon@ynu.ac.kr [College of Pharmacy, Yeungnam University, Gyungsan (Korea, Republic of); Jeong, Hye Gwang, E-mail: hgjeong@cnu.ac.kr [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of)

    2011-11-15

    The cardioprotective properties of puerarin, a natural product, have been attributed to the endothelial nitric oxide synthase (eNOS)-mediated production of nitric oxide (NO) in EA.hy926 endothelial cells. However, the mechanism by which puerarin activates eNOS remains unclear. In this study, we sought to identify the intracellular pathways underlying eNOS activation by puerarin. Puerarin induced the activating phosphorylation of eNOS on Ser1177 and the production of NO in EA.hy926 cells. Puerarin-induced eNOS phosphorylation required estrogen receptor (ER)-mediated phosphatidylinositol 3-kinase (PI3K)/Akt signaling and was reversed by AMP-activated protein kinase (AMPK) and calcium/calmodulin-dependent kinase II (CaMKII) inhibition. Importantly, puerarin inhibited the adhesion of tumor necrosis factor (TNF)-{alpha}-stimulated monocytes to endothelial cells and suppressed the TNF-{alpha} induced expression of intercellular cell adhesion molecule-1. Puerarin also inhibited the TNF-{alpha}-induced nuclear factor-{kappa}B activation, which was attenuated by pretreatment with N{sup G}-nitro-L-arginine methyl ester, a NOS inhibitor. These results indicate that puerarin stimulates eNOS phosphorylation and NO production via activation of an estrogen receptor-mediated PI3K/Akt- and CaMKII/AMPK-dependent pathway. Puerarin may be useful for the treatment or prevention of endothelial dysfunction associated with diabetes and cardiovascular disease. -- Highlights: Black-Right-Pointing-Pointer Puerarin induced the phosphorylation of eNOS and the production of NO. Black-Right-Pointing-Pointer Puerarin activated eNOS through ER-dependent PI3-kinase and Ca{sup 2+}-dependent AMPK. Black-Right-Pointing-Pointer Puerarin-induced NO was involved in the inhibition of NF-kB activation. Black-Right-Pointing-Pointer Puerarin may help for prevention of vascular dysfunction and diabetes.

  12. Imaging of aromatase distribution in rat and rhesus monkey brains with [{sup 11}C]vorozole

    Energy Technology Data Exchange (ETDEWEB)

    Takahashi, Kayo [Division of Pharmacology, Department of Neuroscience, Uppsala University, Uppsala SE-75124 (Sweden); Uppsala Imanet, Uppsala SE-75109 (Sweden)]. E-mail: kayo.takahashi@uppsala.imanet.se; Bergstroem, Mats [Uppsala Imanet, Uppsala SE-75109 (Sweden); Department of Pharmaceutical Biosciences, Uppsala University, Uppsala SE-75124 (Sweden); Fraendberg, Pernilla [Uppsala Imanet, Uppsala SE-75109 (Sweden); Vesstroem, Eva-Lotta [Uppsala Imanet, Uppsala SE-75109 (Sweden); Watanabe, Yasuyoshi [Department of Physiology, Osaka City University Graduate School of Medicine, Osaka 545-8585 (Japan); Langstroem, Bengt [Uppsala Imanet, Uppsala SE-75109 (Sweden)

    2006-07-15

    Aromatase is an enzyme that converts androgens to estrogens and may play a role in mood and mental status. The aim of this study was to demonstrate that brain aromatase distribution could be evaluated with a novel positron emission tomography (PET) tracer [{sup 11}C]vorozole. Vorozole is a nonsteroidal aromatase inhibitor that reversibly binds to the heme domain of aromatase. In vitro experiments in rat brain, using frozen section autoradiography, illustrated specific binding in the medial amygdala (MA), the bed nucleus of stria terminalis (BST) and the preoptic area (POA) of male rat brain. Specific binding in female rat brain was found in the MA and the BST; however, the signals were lower than those of males. The K {sub d} of [{sup 11}C]vorozole binding to aromatase in MA was determined to be 0.60{+-}0.06 nM by Scatchard plot analysis using homogenates. An in vivo PET study in female rhesus monkey brain demonstrated the uptake of [{sup 11}C]vorozole in the amygdala, where the uptake was blocked by the presence of excess amounts of unlabeled vorozole. Thus, this tracer has a high affinity for brain aromatase and could have a potential for in vivo aromatase imaging. This technique might enable the investigation of human brain aromatase in healthy and diseased persons.

  13. Triclocarban and Triclosan Inhibit Human Aromatase via Different Mechanisms

    OpenAIRE

    Li, Huitao; Zhao, Yu; Chen, Lanlan; Su, Ying; Li, Xiaoheng; Jin, Lixu; Ge, Ren-Shan

    2017-01-01

    Human aromatase (CYP19A1) is an important enzyme, which produces estrogen from androgen for maintaining the female reproductive function and pregnancy. Triclocarban and triclosan are antimicrobial chemicals added to personal care, household, and industrial products. They could be endocrine disruptors and may disrupt human CYP19A1 activity. In the present study, we investigated the effects of triclocarban and triclosan on estradiol production and human CYP19A1 activity in JEG-3 cells. Tricloca...

  14. Direct Regulation of Aromatase B Expression by 17β-Estradiol and Dopamine D1 Receptor Agonist in Adult Radial Glial Cells

    OpenAIRE

    Xing, Lei; Esau, Crystal; Trudeau, Vance L.

    2016-01-01

    Aromatase cytochrome P450arom (cyp19) is the only enzyme that has the ability to convert androgens into estrogens. Estrogens, which are produced locally in the vertebrate brain play many fundamental roles in neuroendocrine functions, reproductive functions, socio-sexual behaviors, and neurogenesis. Radial glial cells (RGCs) are neuronal progenitor cells that are abundant in fish brains and are the exclusive site of aromatase B expression and neuroestrogen synthesis. Using a novel in vitro RGC...

  15. Overexpression of aromatase alone is sufficient for ovarian development in genetically male chicken embryos.

    Directory of Open Access Journals (Sweden)

    Luke S Lambeth

    Full Text Available Estrogens play a key role in sexual differentiation of both the gonads and external traits in birds. The production of estrogen occurs via a well-characterised steroidogenic pathway, which is a multi-step process involving several enzymes, including cytochrome P450 aromatase. In chicken embryos, the aromatase gene (CYP19A1 is expressed female-specifically from the time of gonadal sex differentiation. To further explore the role of aromatase in sex determination, we ectopically delivered this enzyme using the retroviral vector RCASBP in ovo. Aromatase overexpression in male chicken embryos induced gonadal sex-reversal characterised by an enlargement of the left gonad and development of ovarian structures such as a thickened outer cortex and medulla with lacunae. In addition, the expression of key male gonad developmental genes (DMRT1, SOX9 and Anti-Müllerian hormone (AMH was suppressed, and the distribution of germ cells in sex-reversed males followed the female pattern. The detection of SCP3 protein in late stage sex-reversed male embryonic gonads indicated that these genetically male germ cells had entered meiosis, a process that normally only occurs in female embryonic germ cells. This work shows for the first time that the addition of aromatase into a developing male embryo is sufficient to direct ovarian development, suggesting that male gonads have the complete capacity to develop as ovaries if provided with aromatase.

  16. Menopause Is a Determinant of Breast Aromatase Expression and Its Associations With BMI, Inflammation, and Systemic Markers.

    Science.gov (United States)

    Brown, Kristy A; Iyengar, Neil M; Zhou, Xi Kathy; Gucalp, Ayca; Subbaramaiah, Kotha; Wang, Hanhan; Giri, Dilip D; Morrow, Monica; Falcone, Domenick J; Wendel, Nils K; Winston, Lisle A; Pollak, Michael; Dierickx, Anneloor; Hudis, Clifford A; Dannenberg, Andrew J

    2017-05-01

    Most estrogen-dependent breast cancers occur after menopause, despite low levels of circulating estrogens. Breast expression of the estrogen-biosynthetic enzyme, aromatase, is proposed to drive breast cancer development after menopause. However, the effects of menopause on breast aromatase expression are unknown. To determine the effect of menopause on breast aromatase expression in relation to body mass index (BMI), white adipose tissue inflammation (WATi), and systemic markers of metabolic dysfunction. Cross-sectional study of 102 premenopausal (age 27 to 56) and 59 postmenopausal (age 45 to 74) women who underwent mastectomy for breast cancer treatment/prevention. Breast tissue was assessed for the presence of crown-like structures and the expression and activity of aromatase. Systemic markers examined include interleukin (IL)-6, insulin, glucose, leptin, adiponectin, high-sensitivity C-reactive protein (hsCRP), cholesterol, and triglycerides. Multivariable analysis was performed for aromatase messenger RNA (mRNA) in relation to BMI, WATi, and blood markers. Postmenopausal women had higher BMI and more breast WATi than premenopausal women. Fasting levels of IL-6, glucose, leptin, hsCRP, and homeostatic model assessment 2 insulin resistance score were higher in the postmenopausal group. BMI was positively correlated with aromatase mRNA in both pre- and postmenopausal women. Aromatase levels were higher in breast tissue of postmenopausal women, with levels being higher in inflamed vs noninflamed, independent of BMI. Adipocyte diameter and levels of leptin, hsCRP, adiponectin, and high-density lipoprotein cholesterol were more strongly correlated with aromatase in postmenopausal than premenopausal women. Elevated aromatase in the setting of adipose dysfunction provides a possible mechanism for the higher incidence of hormone-dependent breast cancer in obese women after menopause. Copyright © 2017 Endocrine Society

  17. Inhibition of aromatase activity by methyl sulfonyl PCB metabolites in primary culture of human mammary fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Berg, M. van den; Heneweer, M.; Geest, M. de; Sanderson, T. [Inst. for Risk Assessment Sciences and Utrecht Univ. (Netherlands); Jong, P. de [St. Antonius Hospital, Nieuwegein (Netherlands); Bergman, A. [Stockholm Univ., Stockholm (Sweden)

    2004-09-15

    Methyl sulfonyl PCB metabolites (MeSO2-PCBs) are persistent contaminants and are ubiquitously present in humans and the environment. Lipophilicity of MeSO2- PCB metabolites is similar to the parent compounds and they have been detected in human milk, adipose, liver and lung tissue. 4- MeSO2-PCB-149 is the most abundant PCB metabolite in human adipose tissue and milk at a level of 1.5 ng/g lipids. Human blood concentration of 4-MeSO2-PCB-149 is approximately 0.03 nM. 3- MeSO2-PCB-101 is the predominant PCB metabolite in muscle and blubber in wildlife, such as otter, mink and grey seal. In the environment, they have been linked to chronic and reproductive toxicity in exposed mink. Additionaly, some MeSO{sub 2}-PCBs have been shown to be glucocorticoid receptor (GR) antagonists. Since approximately 60% of all breast tumors are estrogen responsive, exposure to compounds that are able to alter estrogen synthesis through interference with the aromatase enzyme, can lead to changes in estrogen levels and possibly to accelerated or inhibit breast tumor growth. Therefore, it is important to identify exogenous compounds that can alter aromatase activity in addition to those compounds which have direct interaction with the estrogen receptor (ER). Aromatase (CYP19) comprises the ubiquitous flavoprotein, NADPH-cytochrome P450 reductase, and a unique cytochrome P450 that is exclusively expressed in estrogen producing cells. Previous studies have revealed that expression of the aromatase gene is regulated in a species- and tissue specific manner. In healthy breast tissue, the predominantly active aromatase promoter region I.4 is regulated by glucocorticoids and class I cytokines. Therefore, it is important to investigate possible aromatase inhibiting properties of MeSO{sub 2}-PCBs (as anti glucocorticoids?) in relevant human tissues. We used primary human mammary fibroblasts because of their role in breast cancer development. We compared the results in primary fibroblasts with

  18. Estrogen metabolizing enzymes : biomarkers of exposure, effect and susceptibility for carcinogenesis

    NARCIS (Netherlands)

    Duursen, Majorie Beatrix Maria van

    2005-01-01

    In the etiology of breast cancer, estrogens and its metabolites play a key role as tumor initiators and promoters. Co-expression of estrogen synthesizing enzymes (aromatase and steroid sulfatase) and estrogen metabolizing enzymes (CYP1A1 and CYP1B1) in breast tissue makes it plausible that locally

  19. Glucocorticoid-induction of hypothalamic aromatase via its brain-specific promoter.

    Science.gov (United States)

    Brooks, D C; Zhao, H; Yilmaz, M B; Coon V, J S; Bulun, S E

    2012-10-15

    In the brain, a 36-kb distal promoter (I.f) regulates the Cyp19a1 gene that encodes aromatase, the key enzyme for estrogen biosynthesis. Local estrogen production in the brain regulates critical functions such as gonadotropin secretion and sexual behavior. The mechanisms that control brain aromatase production are not well understood. Here we show that the glucocorticoid dexamethasone robustly increases aromatase mRNA and protein by up to 98-fold in mouse hypothalamic cell lines in a dose- and time-dependent fashion. Using deletion mutants of the brain-specific promoter I.f and chromatin immunoprecipitation-PCR, we isolated a distinct region (-500/-200 bp) which becomes enriched in bound glucocorticoid receptor upon dexamethasone stimulation. A glucocorticoid antagonist or siRNA based knockdown of glucocorticoid receptor ablated dexamethasone stimulation of aromatase expression. Our findings demonstrate how glucocorticoids alter aromatase expression in the hypothalamus and might indicate a mechanism whereby glucocorticoid action modifies gonadotropin pulses and the menstrual cycle. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  20. Endocrine disrupting potentials of Bisphenol A, Bisphenol A dimethacrylate, 4-n-Nonyl-phenol and 4-Octylphenol assessed in cell model systems for effects on the estrogen-, androgen-, aryl hydrocarbon-receptor and aromatase activity

    DEFF Research Database (Denmark)

    Bonefeld-Jørgensen, Eva Cecilie; Long, Manhai; Hofmeister, Marlene V

    (RLU). Effects on the Androgen receptor (AR) trans-activation were investigated by co-transfection of the CHO-K1 hamster cells using the reporter vector MMTV-LUC and the AR expression vector pSVAR0. Effects on the CYP19 aromatase, an important enzyme in the steroid synthesis pathway involved...... of endogenous steroid metabolism potentially alters neuronal and reproductive system development: effects of environmental plasticizers. Program "Quality of Life and Management of Living Resources". (Contract no. QLK4-CT-2002-02637). http://endomet.bham.ac.uk                                                                                                                                                                                                                         ....

  1. Diabetes alters aromatase enzyme levels in sciatic nerve and hippocampus tissues of rats.

    Science.gov (United States)

    Burul-Bozkurt, Nihan; Pekiner, Can; Kelicen, Pelin

    2010-04-01

    Diabetes mellitus (DM) is associated with increased risk of impaired cognitive function. Diabetic neuropathy is one of the most common and important complications of DM. Estrogens prevent neuronal loss in experimental models of neurodegeneration and accelerate nerve regeneration. Aromatase catalyzes the conversion of androgens to estrogens and expressed in a variety of tissues including neurons. Although insulin is known to regulate the activity of aromatase there is no study about the effects of diabetes on this enzyme. Present study was designed to investigate the effects of experimental diabetes on aromatase expression in nervous system. Gender-based differences were also investigated. Rats were injected with streptozotocin to induce diabetes. At the end of 4 and 12 weeks sciatic nerve and hippocampus homogenates were prepared and evaluated for aromatase proteins. Aromatase expressions in sciatic nerves of both genders were decreased in 4 weeks of diabetes, but in 12 weeks the enzyme levels were increased in females and reached to control levels in male animals. Aromatase levels were not altered in hippocampus at 4 weeks but increased at 12 weeks in female diabetic rats. No significant differences were observed at enzyme levels of hippocampus in male diabetic rats. Insulin therapy prevented all diabetes-induced changes. In conclusion, these results indicated for the first time that, DM altered the expression of aromatase both in central and peripheral nervous systems. Peripheral nervous system is more vulnerable to damage than central nervous system in diabetes. These effects of diabetes differ with gender and compensatory neuroprotective mechanisms are more efficient in female rats.

  2. In Silico Prediction of Chemicals Binding to Aromatase with Machine Learning Methods.

    Science.gov (United States)

    Du, Hanwen; Cai, Yingchun; Yang, Hongbin; Zhang, Hongxiao; Xue, Yuhan; Liu, Guixia; Tang, Yun; Li, Weihua

    2017-05-15

    Environmental chemicals may affect endocrine systems through multiple mechanisms, one of which is via effects on aromatase (also known as CYP19A1), an enzyme critical for maintaining the normal balance of estrogens and androgens in the body. Therefore, rapid and efficient identification of aromatase-related endocrine disrupting chemicals (EDCs) is important for toxicology and environment risk assessment. In this study, on the basis of the Tox21 10K compound library, in silico classification models for predicting aromatase binders/nonbinders were constructed by machine learning methods. To improve the prediction ability of the models, a combined classifier (CC) strategy that combines different independent machine learning methods was adopted. Performances of the models were measured by test and external validation sets containing 1336 and 216 chemicals, respectively. The best model was obtained with the MACCS (Molecular Access System) fingerprint and CC method, which exhibited an accuracy of 0.84 for the test set and 0.91 for the external validation set. Additionally, several representative substructures for characterizing aromatase binders, such as ketone, lactone, and nitrogen-containing derivatives, were identified using information gain and substructure frequency analysis. Our study provided a systematic assessment of chemicals binding to aromatase. The built models can be helpful to rapidly identify potential EDCs targeting aromatase.

  3. Potential contribution of aromatase inhibition to the effects of nicotine and related compounds on the brain

    Directory of Open Access Journals (Sweden)

    Anat eBiegon

    2012-11-01

    Full Text Available Cigarette smoking continues to be a major public health problem, and while smoking rates in men have shown some decrease over the last few decades, smoking rates among girls and young women are increasing. Practically all of the important aspects of cigarette smoking are sexually dimorphic. Women become addicted more easily than men, while finding it harder to quit. Nicotine replacement appears to be less effective in women. This may be linked to the observation that women are more sensitive than men to non-nicotine cues or ingredients in cigarettes. The reasons for these sex differences are mostly unknown. Several lines of evidence suggest that many of the reported sex differences related to cigarette smoking may stem from the inhibitory effects of nicotine and other tobacco alkaloids on estrogen synthesis via the enzyme aromatase (cyp19a gene product. Aromatase is the last enzyme in estrogen biosynthesis, catalyzing the conversion of androgens to estrogens. This review provides a summary of experimental evidence supporting brain aromatase as a potential mediator and/or modulator of nicotine actions in the brain, contributing to sex differences in smoking behavior. Additional research on the interaction between tobacco smoke, nicotine and aromatase may help devise new, sex specific methods for prevention and treatment of smoking addiction.

  4. Long-term treatment with the pure anti-estrogen fulvestrant durably remodels estrogen signaling in BG-1 ovarian cancer cells.

    OpenAIRE

    Badia, Eric; Docquier, Aurélie; Busson, Muriel; Lapierre, Marion; Pujol, Pascal; Balaguer, Patrick; Cavailles, Vincent

    2012-01-01

    International audience; Most ovarian cancers are estrogen-positive and hormonal treatments using anti-estrogens or aromatase inhibitors are under investigation for treating the tumors that are resistant to conventional therapies. In this study, the long-term effects of two anti-estrogens, namely 4-hydroxytamoxifen and fulvestrant (or ICI182,780), were investigated in ERα-positive BG1 epithelial ovarian cancer cells. To this aim, cells were grown in the presence of anti-estrogen concentrations...

  5. Investigation of aromatase inhibitory activity of metal complexes of 8-hydroxyquinoline and uracil derivatives

    Directory of Open Access Journals (Sweden)

    Prachayasittikul V

    2014-08-01

    Full Text Available Veda Prachayasittikul,1 Ratchanok Pingaew,2 Chanin Nantasenamat,3 Supaluk Prachayasittikul,3 Somsak Ruchirawat,4,5 Virapong Prachayasittikul1 1Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand; 2Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok, Thailand; 3Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand; 4Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 5Chulabhorn Graduate Institute, Bangkok, Thailand Purpose: Estrogens play important roles in the pathogenesis and progression of breast cancer as well as estrogen-related diseases. Aromatase is a key enzyme in the rate-limiting step of estrogen production, in which its inhibition is one strategy for controlling estrogen levels to improve prognosis of estrogen-related cancers and diseases. Herein, a series of metal (Mn, Cu, and Ni complexes of 8-hydroxyquinoline (8HQ and uracil derivatives (4–9 were investigated for their aromatase inhibitory and cytotoxic activities. Methods: The aromatase inhibition assay was performed according to a Gentest™ kit using CYP19 enzyme, wherein ketoconazole and letrozole were used as reference drugs. The cytotoxicity was tested on normal embryonic lung cells (MRC-5 using 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay. Results: Only Cu complexes (6 and 9 exhibited aromatase inhibitory effect with IC50 0.30 and 1.7 µM, respectively. Cytotoxicity test against MRC-5 cells showed that Mn and Cu complexes (5 and 6, as well as free ligand 8HQ, exhibited activity with IC50 range 0.74–6.27 µM. Conclusion: Cu complexes (6 and 9 were found to act as a novel class of aromatase inhibitor. Our findings suggest that these 8HQ–Cu–uracil complexes are promising agents that could be potentially developed as a selective anticancer agent for breast cancer

  6. Mechanisms underlying differential response to estrogen-induced apoptosis in long-term estrogen-deprived breast cancer cells

    OpenAIRE

    SWEENEY, ELIZABETH E.; FAN, PING; JORDAN, V. CRAIG

    2014-01-01

    Models of long-term estrogen-deprived breast cancer cells are utilized in the laboratory to mimic clinical aromatase inhibitor-resistant breast cancer and serve as a tool to discover new therapeutic strategies. The MCF-7:5C and MCF-7:2A subclones were generated through long-term estrogen deprivation of estrogen receptor (ER)-positive MCF-7 cells, and represent anti-hormone-resistant breast cancer. MCF-7:5C cells paradoxically undergo estrogen-induced apoptosis within seven days of estrogen (e...

  7. Use of heterologous expressed polyketide synthase and small molecule foldases to make aromatic and cyclic compounds

    DEFF Research Database (Denmark)

    2016-01-01

    A method for producing individual or libraries of tri- to pentadecaketide-derived aromatic compounds of interest by heterologous expression of polyketide synthase and aromatase/cyclase in a recombinant host cell.......A method for producing individual or libraries of tri- to pentadecaketide-derived aromatic compounds of interest by heterologous expression of polyketide synthase and aromatase/cyclase in a recombinant host cell....

  8. Aromatase Inhibitor-Induced Erythrocytosis in a Patient Undergoing Hormonal Treatment for Breast Cancer

    Directory of Open Access Journals (Sweden)

    Sri Lakshmi Hyndavi Yeruva

    2015-01-01

    Full Text Available Aromatase inhibitors (AIs are most commonly used for breast cancer patients with hormone receptor positive disease. Although the side effect profile of aromatase inhibitors is well known, including common side effects like arthralgia, bone pain, arthritis, hot flashes, and more serious problems like osteoporosis, we present a case of an uncommon side effect of these medications. We report the case of a postmenopausal woman on adjuvant hormonal therapy with anastrozole after completing definitive therapy for stage IIIB estrogen receptor-positive breast cancer, who was referred to hematology service for evaluation of persistent erythrocytosis. Primary and known secondary causes of polycythemia were ruled out. On further evaluation, we found that her erythrocytosis began after initiation of anastrozole and resolved after it was discontinued. We discuss the pathophysiology of aromatase inhibitor-induced erythrocytosis and reference of similar cases reported in the literature.

  9. The planetary biology of cytochrome P450 aromatases.

    Science.gov (United States)

    Gaucher, Eric A; Graddy, Logan G; Li, Tang; Simmen, Rosalia C M; Simmen, Frank A; Schreiber, David R; Liberles, David A; Janis, Christine M; Benner, Steven A

    2004-08-17

    Joining a model for the molecular evolution of a protein family to the paleontological and geological records (geobiology), and then to the chemical structures of substrates, products, and protein folds, is emerging as a broad strategy for generating hypotheses concerning function in a post-genomic world. This strategy expands systems biology to a planetary context, necessary for a notion of fitness to underlie (as it must) any discussion of function within a biomolecular system. Here, we report an example of such an expansion, where tools from planetary biology were used to analyze three genes from the pig Sus scrofa that encode cytochrome P450 aromatases-enzymes that convert androgens into estrogens. The evolutionary history of the vertebrate aromatase gene family was reconstructed. Transition redundant exchange silent substitution metrics were used to interpolate dates for the divergence of family members, the paleontological record was consulted to identify changes in physiology that correlated in time with the change in molecular behavior, and new aromatase sequences from peccary were obtained. Metrics that detect changing function in proteins were then applied, including KA/KS values and those that exploit structural biology. These identified specific amino acid replacements that were associated with changing substrate and product specificity during the time of presumed adaptive change. The combined analysis suggests that aromatase paralogs arose in pigs as a result of selection for Suoidea with larger litters than their ancestors, and permitted the Suoidea to survive the global climatic trauma that began in the Eocene. This combination of bioinformatics analysis, molecular evolution, paleontology, cladistics, global climatology, structural biology, and organic chemistry serves as a paradigm in planetary biology. As the geological, paleontological, and genomic records improve, this approach should become widely useful to make systems biology statements about

  10. Adult-onset hypogonadotropic hypogonadism caused by aberrant expression of aromatase in an adrenocortical adenocarcinoma.

    Science.gov (United States)

    Advani, Andrew; Johnson, Sarah J; Nicol, Moira R; Papacleovoulou, Georgia; Evans, Dean B; Vaikkakara, Suresh; Mason, J Ian; Quinton, Richard

    2010-01-01

    Estrogen-secreting adrenal cancers are extremely rare, with feminizing symptoms attributed to aromatase expression in the adrenal tumor. We describe a case of hypogonadotropic hypogonadism as a consequence of aberrant aromatase expression in a patient with adrenocortical adenocarcinoma. A 54 year-old man presented with a two month history of gynecomastia and reduced libido. Endocrine biochemistry at presentation showed hypogonadotropic hypogonadism (LH 2.4 U/L, FSH E(1), 821 pmol/L) and estradiol (E(2), 797 pmol/L) and subclinical ACTH-independent hypercortisolism (serum cortisol post 1mg overnight dexamethasone suppression test, 291 nmol/L). A right adrenal mass was identified on CT scanning and the patient underwent an open adrenalectomy. Post-operative evaluation showed normalization of serum levels of E(1) (95 pmol/L), E(2 )(109 pmol/L), testosterone (11.4 nmol/L), LH (4.1 U/L) and FSH (5.9 IU/L), and of cortisol dynamics. Immunohistochemistry of the adrenal cancer confirmed aberrant expression of aromatase in most, although not all, carcinoma cells. Transcripts associated with utilization of promoters II, I.1 and I.3 were prominently represented in the tumor aromatase mRNA. This case highlights that clinical features of feminizing adrenocortical carcinomas can be secondary to estrogen production by aberrantly transcribed and translated aromatase within the tumor. Even in males, gonadotropin secretion is subject to predominantly estrogen-mediated feedback-inhibition. The diagnosis of adrenocortical adenocarcinoma should be considered in men presenting with low testosterone and gonadotropins, particularly in the presence of feminizing features.

  11. Managing Aromatase Inhibitors in Breast Cancer Survivors: Not Just for Oncologists

    OpenAIRE

    Files, Julia A.; Ko, Marcia G.; Pruthi, Sandhya

    2010-01-01

    The role of the general internist in the care of breast cancer survivors is increasing as the number of women living with breast cancer continues to rise. Most breast cancers occurring in women older than 50 years are estrogen receptor– and/or progesterone receptor–positive, and adjuvant endocrine therapy plays an important role in the treatment plan. Aromatase inhibitors are becoming the preferred endocrine therapy, and general internists caring for breast cancer survivors need to be familia...

  12. Sexual dimorphism in the glucose homeostasis phenotype of the Aromatase Knockout (ArKO) mice.

    Science.gov (United States)

    Van Sinderen, Michelle; Steinberg, Gregory; Jorgensen, Sebastian B; Honeyman, Jane; Chow, Jenny D Y; Simpson, Evan R; Jones, Margaret E E; Boon, Wah Chin

    2017-06-01

    We investigated the effects of estrogens on glucose homeostasis using the Aromatase Knockout (ArKO) mouse, which is unable to convert androgens into estrogens. The ArKO mouse is a model of total estrogen ablation which develops symptoms of metabolic syndrome. To determine the development and progression of whole body state of insulin resistance of ArKO mice, comprehensive whole body tolerance tests were performed on WT, ArKO and estrogen administrated mice at 3 and 12 months of age. The absence of estrogens in the male ArKO mice leads to hepatic insulin resistance, glucose and pyruvate intolerance from 3 to 12 months with consistent improvement upon estrogen treatment. Estrogen absence in the female ArKO mice leads to glucose intolerance without pyruvate intolerance or insulin resistance. The replacement of estrogens in the female WT and ArKO mice exhibited both insulin sensitizing and resistance effects depending on age and dosage. In conclusion, this study presents information on the sexually dimorphic roles of estrogens on glucose homeostasis regulation. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Estrogen enhances wound healing in the penis of rats.

    Science.gov (United States)

    Mowa, C N; Hoch, R; Montavon, C L; Jesmin, S; Hindman, G; Hou, G

    2008-10-01

    Estrogen receptor (ER) alpha and beta and aromatase are expressed in various cell-types and compartments of the penis, including the epidermis of glans penis. Here, we hypothesize that estrogen helps maintain the viability and integrity of glans penis and test the hypothesis by treating lesioned glans penis with either 17beta-estradiol or vehicle only. Estrogen was found to facilitate wound healing and increase vascular endothelial growth factor (VEGF) immunoreactivity compared to control, as revealed by scanning electron microscopy, histology, and immunohistochemistry. We conclude that estrogen plays a role in maintaining glans penis integrity, in part, by facilitating penile healing, possibly via up-regulating VEGF levels.

  14. Management of sexual dysfunction in postmenopausal breast cancer patients taking adjuvant aromatase inhibitor therapy.

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    Derzko, C; Elliott, S; Lam, W

    2007-12-01

    Treatment with aromatase inhibitors for postmenopausal women with breast cancer has been shown to reduce or obviate invasive procedures such as hysteroscopy or curettage associated with tamoxifen-induced endometrial abnormalities. The side effect of upfront aromatase inhibitors, diminished estrogen synthesis, is similar to that seen with the natural events of aging. The consequences often include vasomotor symptoms (hot flushes) and vaginal dryness and atrophy, which in turn may result in cystitis and vaginitis. Not surprisingly, painful intercourse (dyspareunia) and loss of sexual interest (decreased libido) frequently occur as well. Various interventions, both non-hormonal and hormonal, are currently available to manage these problems. The purpose of the present review is to provide the practitioner with a wide array of management options to assist in treating the sexual consequences of aromatase inhibitors. The suggestions in this review are based on recent literature and on the recommendations set forth both by the North American Menopause Association and in the clinical practice guidelines of the Society of Gynaecologists and Obstetricians of Canada. The complexity of female sexual dysfunction necessitates a biopsychosocial approach to assessment and management alike, with interventions ranging from education and lifestyle changes to sexual counselling, pelvic floor therapies, sexual aids, medications, and dietary supplements-all of which have been reported to have a variable, but often successful, effect on symptom amelioration. Although the use of specific hormone replacement-most commonly local estrogen, and less commonly, systemic estrogen with or without an androgen, progesterone, or the additional of an androgen in an estrogenized woman (or a combination)-may be highly effective, the concern remains that in patients with estrogen-dependent breast cancer, including those receiving anti-estrogenic adjuvant therapies, the use of these hormones may be

  15. The planetary biology of cytochrome P450 aromatases

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    Gaucher Eric A

    2004-08-01

    Full Text Available Abstract Background Joining a model for the molecular evolution of a protein family to the paleontological and geological records (geobiology, and then to the chemical structures of substrates, products, and protein folds, is emerging as a broad strategy for generating hypotheses concerning function in a post-genomic world. This strategy expands systems biology to a planetary context, necessary for a notion of fitness to underlie (as it must any discussion of function within a biomolecular system. Results Here, we report an example of such an expansion, where tools from planetary biology were used to analyze three genes from the pig Sus scrofa that encode cytochrome P450 aromatases–enzymes that convert androgens into estrogens. The evolutionary history of the vertebrate aromatase gene family was reconstructed. Transition redundant exchange silent substitution metrics were used to interpolate dates for the divergence of family members, the paleontological record was consulted to identify changes in physiology that correlated in time with the change in molecular behavior, and new aromatase sequences from peccary were obtained. Metrics that detect changing function in proteins were then applied, including KA/KS values and those that exploit structural biology. These identified specific amino acid replacements that were associated with changing substrate and product specificity during the time of presumed adaptive change. The combined analysis suggests that aromatase paralogs arose in pigs as a result of selection for Suoidea with larger litters than their ancestors, and permitted the Suoidea to survive the global climatic trauma that began in the Eocene. Conclusions This combination of bioinformatics analysis, molecular evolution, paleontology, cladistics, global climatology, structural biology, and organic chemistry serves as a paradigm in planetary biology. As the geological, paleontological, and genomic records improve, this approach should

  16. Molecular Bases and Phenotypic Determinants of Aromatase Excess Syndrome

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    Maki Fukami

    2012-01-01

    Full Text Available Aromatase excess syndrome (AEXS is a rare autosomal dominant disorder characterized by gynecomastia. This condition is caused by overexpression of CYP19A1 encoding aromatase, and three types of cryptic genomic rearrangement around CYP19A1, that is, duplications, deletions, and inversions, have been identified in AEXS. Duplications appear to have caused CYP19A1 overexpression because of an increased number of physiological promoters, whereas deletions and inversions would have induced wide CYP19A1 expression due to the formation of chimeric genes consisting of a noncoding exon(s of a neighboring gene and CYP19A1 coding exons. Genotype-phenotype analysis implies that phenotypic severity of AEXS is primarily determined by the expression pattern of CYP19A1 and the chimeric genes and by the structural property of the fused exons with a promoter function (i.e., the presence or the absence of a natural translation start codon. These results provide novel information about molecular mechanisms of human genetic disorders and biological function of estrogens.

  17. DIFERENSIASI KELAMIN TIGA GENOTIPE IKAN NILA YANG DIBERI BAHAN AROMATASE INHIBITOR

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    Didik Ariyanto

    2016-11-01

    Full Text Available Penggunaan hormon sintetik 17 a-metiltestosterone untuk sex reversal ikan konsumsi sudah dilarang. Salah satu bahan yang terbukti efektif dalam sex reversal adalah bahan aromatase inhibitor. Bahan ini dapat digunakan dalam proses pembalikan kelamin karena menghambat sekresi enzim aromatase yang bertanggung jawab dalam konversi hormon androgen menjadi estrogen. Tingginya kadar androgen dalam tubuh akan mengarahkan proses diferensiasi kelamin ke arah kelamin jantan. Penelitian ini bertujuan mengetahui pengaruh pemberian bahan aromatase inhibitor terhadap diferensiasi kelamin tiga genotipe ikan nila. Bahan utama yang digunakan adalah larva ikan nila genotipe XX, XY, dan YY yang diberi bahan aromatase inhibitor, khususnya imidazole. Penambahan hormon sintetik 17a-metiltestosterone digunakan sebagai kontrol (+. Pemberian imidazole dilakukan melalui pakan pada larva ikan nila yang berumur 7 hari setelah menetas, selama 28 hari. Selanjutnya benih dipelihara dalam hapa pendederan selama 60 hari di kolam tanah. Pada akhir pendederan dilakukan identifikasi jenis kelamin, bobot individu rata-rata, dan sintasan. Hasil penelitian menunjukkan bahwa imidazole efektif meningkatkan rasio kelamin jantan pada ikan nila genotipe XX dan YY, tetapi tidak pada genotipe XY. Sampai akhir tahap pendederan, semua genotipe dan perlakuan yang berbeda tidak memberikan efek yang berbeda nyata terhadap laju pertumbuhan maupun nilai sintasan, kecuali pada genotipe YY

  18. Gas chromatography-mass spectrometric study of 19-oxygenation of the aromatase inhibitor 19-methylandrostenedione with human placental microsomes.

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    Numazawa, Mitsuteru; Nagaoka, Masao; Handa, Wakako; Yamada, Akane

    2006-06-01

    To gain insight into the catalytic function of aromatase, we studied 19-oxygenation of 19-methyl-substituted derivative of the natural substrate androstenedione (AD), compound 1, with human placental aromatase by use of gas chromatography-mass spectrometry (GC-MS). Incubation of the 19-methyl derivative 1 with human placental microsomes in the presence of NADPH under an aerobic condition did not yield a detectable amount of [19S]19-hydroxy product 2 or its [19R]-isomer 3 when the product was analyzed as the bis-methoxime-trimethylsilyl (TMS) derivative by GC-MS; moreover, the production of estrogen was not detected as the bis-TMS derivative of estradiol (detection limit: about 3 ng and 10 pg per injection for the 19-ol and estradiol, respectively). The results reveal that the 19-methyl steroid 1 does not serve as a substrate of aromatase, although it does serve as a powerful inhibitor of the enzyme.

  19. Aromatase, oestrogens and human male reproduction

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    Carreau, Serge; Wolczynski, Slaweck; Galeraud-Denis, Isabelle

    2010-01-01

    In most mammalian species aromatase is encoded by a single gene (Cyp19), which contains 18 exons, nine of them being translated. In man, the presence of a biologically active aromatase and oestrogen receptors (ERα and ERβ) has been reported in Leydig cells, and also in immature germ cells and ejaculated spermatozoa. Concerning aromatase, the amount of transcript and enzymatic activity are decreased in immotile compared with motile sperm. We have amplified aromatase mRNA by real-time polymerase chain reaction in spermatozoa from asthenospermic, teratospermic and asthenoteratospermic men and recorded, respectively, 44, 52 and 67 per cent decreases of the amount of transcripts compared with fertile donors. A high degree of correlation (r = −0.64) between the abnormal spermatozoa (especially microcephaly and acrosome malformations) and aromatase/GAPDH transcript ratio has been observed. Idiopathic infertility is a wide health problem and no treatment is currently available. In humans, even if the role of oestrogens in spermatogenesis is still a matter of debate, the observations of decreased sperm number and motility in men genetically deficient in aromatase, together with our data and those reported in the literature, may suggest a role for aromatase/oestrogens not only during the development and maintenance of spermatogenesis but also in the final maturation of spermatozoa. PMID:20403870

  20. Effect of β-agonist on the dexamethasone-induced expression of aromatase by the human monocyte cells

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    Masatada Watanabe

    2017-02-01

    Full Text Available Emerging evidence suggests that sex steroids are important for human skin health. In particular, estrogen improves skin thickness, elasticity and moisture of older women. The major source of circulating estrogen is the ovary; however, local estrogen synthesis and secretion have important roles in, for example, bone metabolism and breast cancer development. We hypothesized that infiltrated peripheral monocytes are one of the sources of estrogen in skin tissues. We also hypothesized that, during atopic dermatitis under stress, a decline in the hypothalamus–pituitary–adrenal axis (HPA and facilitation of the (hypothalamus–sympathetic–adrenomedullary system (SAM attenuates estrogen secretion from monocytes. Based on this hypothesis, we tested aromatase expression in the human peripheral monocyte-derived cell line THP-1 in response to the synthetic glucocorticoid dexamethasone (Dex, the synthetic β-agonist isoproterenol (Iso and the β-antagonist propranolol (Pro. Dex mimics glucocorticoid secreted during excitation of the HPA, and Iso mimics catecholamine secreted during excitation of the SAM. We found that aromatase activity and the CYP19A1 gene transcript were both upregulated in THP-1 cells in the presence of Dex. Addition of Iso induced their downregulation and further addition of Pro rescued aromatase expression. These results may suggest that attenuation of estrogen secretion from peripheral monocytes could be a part of the pathology of stress-caused deterioration of atopic dermatitis. Further examination using an in vitro human skin model including THP-1 cells might be a valuable tool for investigating the therapeutic efficacy and mechanism of estrogen treatment for skin health.

  1. Potential role of aromatase inhibitors in the treatment of endometriosis

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    Abu Hashim H

    2014-07-01

    Full Text Available Hatem Abu HashimDepartment of Obstetrics and Gynecology, Faculty of Medicine, Mansoura University, Mansoura, EgyptAbstract: Endometriosis is an estrogen-dependent chronic inflammatory disease affecting 5%–10% of reproductive-age women, with a prevalence of 5%–50% in infertile women and >33% of women with chronic pelvic pain. Third-generation aromatase inhibitors (AIs are approved adjuvants for the treatment of estrogen receptor-positive breast cancer. Molecular studies have revealed the presence of aromatase P450, the key enzyme in the biosynthesis of ovarian estradiol, inside the endometriotic tissue, indicating local synthesis of estradiol. Thereby, AIs represent an appealing medical option for the management of different aspects of this enigmatic disease, especially pelvic pain and infertility. Accordingly, this review aims to evaluate the potential role of AIs in the treatment of endometriosis-associated symptoms, mainly pain and infertility. Notably, several studies have demonstrated that the combination of AIs with conventional therapy as oral contraceptive pills, progestins, or gonadotropin-releasing hormone analogs can be used to control endometriosis-associated pain and pain recurrence in premenopausal women, particularly those with pain due to rectovaginal endometriosis refractory to other medical or surgical treatment. Some case reports have shown promising results in the treatment of postmenopausal endometriosis as first-line treatment, when surgery is contraindicated, or as second-line treatment in the case of postoperative recurrence. Third-generation AIs, especially letrozole, have challenged clomiphene citrate as an ovulation-induction agent in patients with polycystic ovary syndrome and in cases of unexplained infertility. However, few studies are available regarding the use of AIs to treat endometriosis-associated infertility. Therefore, larger multicenter randomized trials using AIs for the treatment of endometriosis

  2. Organizing effects of sex steroids on brain aromatase activity in quail.

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    Charlotte A Cornil

    2011-04-01

    Full Text Available Preoptic/hypothalamic aromatase activity (AA is sexually differentiated in birds and mammals but the mechanisms controlling this sex difference remain unclear. We determined here (1 brain sites where AA is sexually differentiated and (2 whether this sex difference results from organizing effects of estrogens during ontogeny or activating effects of testosterone in adulthood. In the first experiment we measured AA in brain regions micropunched in adult male and female Japanese quail utilizing the novel strategy of basing the microdissections on the distribution of aromatase-immunoreactive cells. The largest sex difference was found in the medial bed nucleus of the stria terminalis (mBST followed by the medial preoptic nucleus (POM and the tuberal hypothalamic region. A second experiment tested the effect of embryonic treatments known to sex-reverse male copulatory behavior (i.e., estradiol benzoate [EB] or the aromatase inhibitor, Vorozole on brain AA in gonadectomized adult males and females chronically treated as adults with testosterone. Embryonic EB demasculinized male copulatory behavior, while vorozole blocked demasculinization of behavior in females as previously demonstrated in birds. Interestingly, these treatments did not affect a measure of appetitive sexual behavior. In parallel, embryonic vorozole increased, while EB decreased AA in pooled POM and mBST, but the same effect was observed in both sexes. Together, these data indicate that the early action of estrogens demasculinizes AA. However, this organizational action of estrogens on AA does not explain the behavioral sex difference in copulatory behavior since AA is similar in testosterone-treated males and females that were or were not exposed to embryonic treatments with estrogens.

  3. Managing arthralgia in a postmenopausal woman taking an aromatase inhibitor for hormonesensitive early breast cancer: a case study

    International Nuclear Information System (INIS)

    Bryce, Jane; Bauer, Martina; Hadji, Peyman

    2012-01-01

    In order to reduce the risk of recurrence, adjuvant treatment with an aromatase inhibitor (AI) is recommended for postmenopausal women following surgery for hormone receptor-positive breast cancer. AIs are associated with improved disease-free survival compared with tamoxifen. The adverse events associated with AIs resemble those of menopause, such as bone density loss and musculoskeletal symptoms. We examine the case of a postmenopausal woman who was prescribed anastrozole, a nonsteroidal AI, as adjuvant therapy following surgery for estrogen and progesterone receptor-positive (ER and PgR+) breast cancer. A 58-year-old postmenopausal woman diagnosed with ER and PgR+ breast cancer was prescribed anastrozole as adjuvant therapy following a right-inferior quadrantectomy. After experiencing joint pain and stiffness, she was prescribed paracetamol and a topical nonsteroidal anti-inflammatory drug. She was also counseled on nonpharmacological interventions. However, she continued to experience symptoms, and reported that she was not taking anastrozole regularly. The case study patient ultimately found relief by switching to letrozole, another aromatase inhibitor. This approach is supported by recent studies examining the benefits of switching strategies between aromatase inhibitors in order to relieve symptoms of arthralgia/myalgia. Both adherence and strategies for managing aromatase inhibitor-associated arthralgia are key to deriving maximal clinical benefit from AI therapy. Switching from one aromatase inhibitor to another may provide a viable option in managing adverse events and enhancing adherence to medication

  4. Influence of Triazine Herbicide Exposure on Guppies (Poecilia sphenops) Aromatase Activities, Altered Sex Steroid Concentration and Vitellogenin Induction.

    Science.gov (United States)

    Vasanth, S; Arul, G; Karthikeyeni, S; Kumar, T S V; Vignesh, V; Manimegalai, M; Bupesh, G; Thirumurugan, R; Subramanian, P

    2015-01-01

    Atrazine, a herbicide is one the most toxic and sustaining pollutants in aquatic environment. It is detectable in surface water and in underground sources of drinking water. Many studies indicate that atrazine might be a potent endocrine disrupting xenobiotic. There are limited studies have revealed that the effects of atrazine on sex steroids hormones, vitellogenin and induction of aromatase, gonadosomatic index and hepatosomatic index. In this study, juvenile Poecilia sphenops fish was exposed to three different (0.83, 1.25 and 2.5 ppm) concentration of atrazine for 100 d. Changes in plasma and gonadal content and concentrations of sex steroids and vitellogenin protein in poecilia sphenops under laboratory conditions were assessed. The low level of the atrazine show estrogenic effect in males, as determined by a shortage of testosterone induction. Present study suggests that low induction of plasma vitellogenin and aromatase in male fish become suitable biomarkers of exposure to estrogenic chemicals.

  5. Limonoids and their anti-proliferative and anti-aromatase properties in human breast cancer cells.

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    Kim, Jinhee; Jayaprakasha, Guddadarangavvanahally K; Patil, Bhimanagouda S

    2013-02-01

    Lemons are a widely used citrus crop and have shown several potential health benefits. In the present study, the mechanism and effectiveness of the anti-cancer and anti-aromatase properties of limonoids were investigated for the first time. Defatted lemon (Citrus lemon L. Burm) seed powder was extracted with ethyl acetate (EtOAc) and methanol (MeOH) for 16 h each, successively. These extracts were fractionated using 1D (silica) and 2D (ion exchange and SP-70 columns) column chromatography to obtain nine limonoids. The compounds were identified by TLC, HPLC, and LC-MS techniques. A panel of 9 purified limonoids, including limonin, nomilin, obacunone, limonexic acid (LNA), isolimonexic acid (ILNA), nomilinic acid glucoside (NAG), deacetyl nomilinic acid glucoside (DNAG), limonin glucoside (LG) and obacunone glucoside (OG) as well as 4 modified compounds such as limonin methoxime (LM), limonin oxime (LO), defuran limonin (DL), and defuran nomilin (DN), were screened for their cytotoxicity on estrogen receptor (ER)-positive (MCF-7) or ER-negative (MDA-MB-231) human breast cancer cells. We further tested the mechanism of the anti-proliferative activity of limonoids using an in vitro aromatase enzyme assay and western blot with anti-caspase-7. Among the tested limonoids, 11 limonoids exhibited cytotoxicity on MCF-7 whereas 8 limonoids showed cytotoxicity against the MDA-MB-231 cell lines. Although most of the limonoids showed anti-aromatase activity, the inhibition of proliferation was not related to the anti-aromatase activity. On the other hand, the anti-proliferative activity was significantly correlated with caspase-7 activation by limonoids. Our findings indicated that the citrus limonoids may have potential for the prevention of estrogen-responsive breast cancer (MCF-7) via caspase-7 dependent pathways.

  6. Aromatase imaging with [N-methyl-C-11]vorozole PET in healthy men and women

    International Nuclear Information System (INIS)

    Biegon, Anat; Fowler, Joanna S.; Alexoff, David L.; Kim, Sung Won; Logan, Jean; Pareto, Deborah; Schlyer, David; Wang, Gene-Jack

    2015-01-01

    Aromatase, the last and obligatory enzyme catalyzing estrogen biosynthesis from androgenic precursors, can be labeled in vivo with (11)C-vorozole. Aromatase inhibitors are widely used in breast cancer and other endocrine conditions. The present study aims to provide baseline information defining aromatase distribution in healthy men and women, against which its perturbation in pathological situations can be studied. Methods: (11)C-vorozole (111-296 MBq/subject) was injected I.V in 13 men and 20 women (age range 23 to 67). PET data were acquired over a 90 minute period. Each subject had 4 scans, 2/day separated by 2-6 weeks, including brain and torso or pelvis scans. Young women were scanned at 2 discrete phases of the menstrual cycle (midcycle and late luteal). Men and postmenopausal women were also scanned following pretreatment with a clinical dose of the aromatase inhibitor letrozole.Time activity curves were obtained and standard uptake values (SUV) calculated for major organs including brain, heart, lungs, liver, kidneys, spleen, muscle, bone and male and female reproductive organs (penis, testes, uterus, ovaries). Organ and whole body radiation exposures were calculated using Olinda software. Results: Liver uptake was higher than all other organs, but was not blocked by pretreatment with letrozole. Mean SUVs in men were higher than in women, and brain uptake was blocked by letrozole. Male brain SUVs were also higher than all other organs (ranging from 0.48±0.05 in lungs to 1.5±0.13 in kidneys). Mean ovarian SUVs (3.08±0.7) were comparable to brain levels and higher than all other organs. Furthermore, ovarian SUVs In young women around the time of ovulation (midcycle) were significantly higher than those measured in the late luteal phase, while aging and cigarette smoking reduced (11)C-vorozole uptake. Conclusions: PET with (11)C-vorozole is useful for assessing physiological changes in estrogen synthesis capacity in the human body. Baseline levels in

  7. Aromatase imaging with [N-methyl-11C]vorozole PET in healthy men and women.

    Science.gov (United States)

    Biegon, Anat; Alexoff, David L; Kim, Sung Won; Logan, Jean; Pareto, Deborah; Schlyer, David; Wang, Gene-Jack; Fowler, Joanna S

    2015-04-01

    Aromatase, the last and obligatory enzyme catalyzing estrogen biosynthesis from androgenic precursors, can be labeled in vivo with (11)C-vorozole. Aromatase inhibitors are widely used in breast cancer and other endocrine conditions. The present study aimed to provide baseline information defining aromatase distribution in healthy men and women, against which its perturbation in pathologic situations can be studied. (11)C-vorozole (111-296 MBq/subject) was injected intravenously in 13 men and 20 women (age range, 23-67 y). PET data were acquired over a 90-min period. Each subject had 4 scans, 2 per day separated by 2-6 wk, including brain and torso or pelvis scans. Young women were scanned at 2 discrete phases of the menstrual cycle (midcycle and late luteal). Men and postmenopausal women were also scanned after pretreatment with a clinical dose of the aromatase inhibitor letrozole. Time-activity curves were obtained, and standardized uptake values (SUV) were calculated for major organs including brain, heart, lungs, liver, kidneys, spleen, muscle, bone, and male and female reproductive organs (penis, testes, uterus, ovaries). Organ and whole-body radiation exposures were calculated using OLINDA software. Liver uptake was higher than uptake in any other organ but was not blocked by pretreatment with letrozole. Mean SUVs were higher in men than in women, and brain uptake was blocked by letrozole. Male brain SUVs were also higher than SUVs in any other organ (ranging from 0.48 ± 0.05 in lungs to 1.5 ± 0.13 in kidneys). Mean ovarian SUVs (3.08 ± 0.7) were comparable to brain levels and higher than in any other organ. Furthermore, ovarian SUVs in young women around the time of ovulation (midcycle) were significantly higher than those measured in the late luteal phase, whereas aging and cigarette smoking reduced (11)C-vorozole uptake. PET with (11)C-vorozole is useful for assessing physiologic changes in estrogen synthesis capacity in the human body. Baseline levels

  8. Estrogenic activities in rodent estrogen-free diets.

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    Ciana, Paolo; Brena, Andrea; Sparaciari, Paolo; Bonetti, Elena; Di Lorenzo, Diego; Maggi, Adriana

    2005-12-01

    Diets lacking soy and alpha-alpha derivatives that are considered to be estrogen-free by standard bioassays (uterotrophic assay and vaginal opening) have been revealed to contain considerable amounts of compounds able to transcriptionally activate the estrogen receptors (ERs) and stimulate luciferase expression in several organs of the ERE-Luc reporter mouse. By molecular imaging, we show that ER activation is present in nonreproductive organs to an extent similar to that observed with the administration of 17beta-estradiol, and it is not influenced by orchiectomy or treatment with an aromatase inhibitor. This, together with the use of a completely synthetic diet, proves that the activation of ERs observed is due to estrogenic compounds present in commercial diets and that it is not a secondary event determined by food consumption and metabolism. The pervasiveness of estrogenic compounds in nature poses the question of how relevant and necessary is the daily ingestion of natural compounds active through the ERs for the maintenance of a correct metabolism in both male and female mammals.

  9. Effects of testosterone and its metabolites on aromatase-immunoreactive cells in the quail brain: relationship with the activation of male reproductive behavior.

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    Balthazart, J; Foidart, A; Absil, P; Harada, N

    1996-01-01

    The enzyme aromatase converts testosterone (T) into 17 beta-estradiol and plays a pivotal role in the control of reproduction. In particular, the aromatase activity (AA) located in the preoptic area (POA) of male Japanese quail is a limiting step in the activation by T of copulatory behavior. Aromatase-immunoreactive (ARO-ir) cells of the POA are specifically localized within the cytoarchitectonic boundaries of the medial preoptic nucleus(POM), a sexually dimorphic and steroid-sensitive structure that is a necessary and sufficient site of steroid action in the activation of behavior. Stereotaxic implantation of aromatase inhibitors in but not around the POM strongly decreases the behavioral effects of a systemic treatment with T of castrated males. AA is decreased by castration and increased by aromatizable androgens and by estrogens. These changes have been independently documented at three levels of analysis: the enzymatic activity measured by radioenzymatic assays in vitro, the enzyme concentration evaluated semi-quantitatively by immunocytochemistry and the concentration of its messenger RNA quantified by reverse transcription-polymerase chain reaction (RT-PCR). These studies demonstrate that T acting mostly through its estrogenic metabolites regulates brain aromatase by acting essentially at the transcriptional level. Estrogens produced by central aromatization of T therefore have two independent roles: they activate male copulatory behavior and they regulate the synthesis of aromatase. Double label immunocytochemical studies demonstrate that estrogen receptors(ER) are found in all brain areas containing ARO-ir cells but the extent to which these markers are colocalized varies from one brain region to the other. More than 70% of ARO-ir cells contain detectable ER in the tuberal hypothalamus but less than 20% of the cells display this colocalization in the POA. This absence of ER in ARO-ir cells is also observed in the POA of the rat brain. This suggests that

  10. Study on the effect of aromatase inhibitors and antiestrogens on the sex differentiation of broiler chicks

    Directory of Open Access Journals (Sweden)

    E.A Valizadeh

    2011-02-01

    Full Text Available During the development of chick embryo, the genotype of the zygote determines the nature of the gonads, which thereafter creates the male or female phenotype. Differentiation of gonads during the period called “critical period for sexual differentiation “is accompanied with beginning of secretion of sexual hormones. Every change in the rate of steroidal hormones concentration during this critical period, affects on the structure of gonads. Therefore, injection of aromatase inhibitors (which blocks the synthesis of estrogen from testostron in 5th day of incubation into the eggs, causes the production of males with female genotype. These sex reversal females have bilateral testes with complete spermatogenesis, having normal physical appearance and behavior. In this study, 14-α-hydroxy 3,6,17, androstan-trion inhibitor (1mg/egg was injected into the eggs. Furthermore, the effect of three anti-estrogens (which blocks the estrogen receptor Tamoxifen, and Clomiphen Citrate and GAR79 were studied. Injection of aromatase inhibitors into the eggs during incubation period caused statistically significant (p

  11. Estrogen biosynthesis in human uterine adenomyosis

    International Nuclear Information System (INIS)

    Urabe, Mamoru; Yamamoto, Takara; Kitawaki, Jo; Honjo, Hideo; Okada, Hiroji

    1989-01-01

    Estrogen biosynthesis (aromatiase activity) was investigated in human adenomyosis tissue and compared with that of the normal myometrium, endometrium, and endometrical cancer tissues. Homogenates were incubated with [1,2,6,7- 3 H]androstenedione and NADPH at 37 deg. C for 1 h. After stopping the enzymatic reaction with ethyl acetate, [4- 14 C]estrone and [4- 14 C]estradiol-17β were added to the incubated sample. Estrone and estradiol were purified and identified by Bio-Rad AG1-X2 column chromatography, thin-layer chromatography and co-crystallization. Estrogen formed in the incubated sample was calculated from the 3 H/ 14 C ratio of the final crystal. The value for estrone formed from androstenedione was 52-132 fmol . h -1. g -1 wet weight. Aromatase activity in the adenomyosis tissues was higher than that in normal endometrial or myometrial tissues, but lower than that found in myometrial or endometrial tumour tissue. Furthermore, we investigated the effect of danazol, progresterone, and medroxyprogesterone acetate on adenomyosis cells in primary cultures. Aromatase activity in adenomyosis was blocked by danazol, but stimulated by progesterone and MPA. These results indicate that aromatase activity in adenomyosis may contribute to the growth of the ectopic endometrial tissue which occurs in this disease. (author)

  12. Direct regulation of aromatase B expression by 17β-estradiol and dopamine D1 receptor agonist in adult radial glial cells

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    Lei eXing

    2016-01-01

    Full Text Available Aromatase cytochrome P450arom (cyp19 is the only enzyme that has the ability to convert androgens into estrogens. Estrogens, which are produced locally in the vertebrate brain play many fundamental roles in neuroendocrine functions, reproductive functions, socio-sexual behaviors and neurogenesis. Radial glial cells (RGCs are neuronal progenitor cells that are abundant in fish brains and are the exclusive site of aromatase B expression and neuroestrogen synthesis. Using a novel in vitro RGC culture preparation we studied the regulation of aromatase B by 17β-estradiol (E2 and dopamine (DA. We have established that activation of the dopamine D1 receptor (D1R by SKF 38393 up-regulates aromatase B gene expression most likely through the phosphorylation of cyclic AMP response element binding protein (CREB. This up-regulation can be enhanced by low concentration of E2 (100 nM through increasing the expression of D1R and the level of p-CREB protein. However, a high concentration of E2 (1 μM and D1R agonist together failed to up-regulate aromatase B, potentially due to attenuation of esr2b expression and p-CREB levels. Furthermore, we found the up-regulation of aromatase B by E2 and DA both requires the involvement of esr1 and esr2a. The combined effect of E2 and DA agonist indicates that aromatase B in the adult teleost brain is under tight control by both steroids and neurotransmitters to precisely regulate neuroestrogen levels.

  13. Unique distribution of aromatase in the human brain: in vivo studies with PET and [N-methyl-11C]vorozole.

    Science.gov (United States)

    Biegon, Anat; Kim, Sung Won; Alexoff, David L; Jayne, Millard; Carter, Pauline; Hubbard, Barbara; King, Payton; Logan, Jean; Muench, Lisa; Pareto, Deborah; Schlyer, David; Shea, Colleen; Telang, Frank; Wang, Gene-Jack; Xu, Youwen; Fowler, Joanna S

    2010-11-01

    Aromatase catalyzes the last step in estrogen biosynthesis. Brain aromatase is involved in diverse neurophysiological and behavioral functions including sexual behavior, aggression, cognition, and neuroprotection. Using positron emission tomography (PET) with the radiolabeled aromatase inhibitor [N-methyl-(11)C]vorozole, we characterized the tracer distribution and kinetics in the living human brain. Six young, healthy subjects, three men and three women, were administered the radiotracer alone on two separate occasions. Women were scanned in distinct phases of the menstrual cycle. Specificity was confirmed by pretreatment with a pharmacological (2.5 mg) dose of the aromatase inhibitor letrozole. PET data were acquired over a 90-min period and regions of interest placed over selected brain regions. Brain and plasma time activity curves, corrected for metabolites, were used to derive kinetic parameters. Distribution volume (V(T)) values in both men and women followed the following rank order: thalamus > amygdala = preoptic area > medulla (inferior olive) > accumbens, pons, occipital and temporal cortex, putamen, cerebellum, and white matter. Pretreatment with letrozole reduced V(T) in all regions, though the size of the reduction was region-dependent, ranging from ∼70% blocking in thalamus andpreoptic area to ∼10% in cerebellum. The high levels of aromatase in thalamus and medulla (inferior olive) appear to be unique to humans. These studies set the stage for the noninvasive assessment of aromatase involvement in various physiological and pathological processes affecting the human brain.

  14. Unique Distribution of Aromatase in the Human Brain: In Vivo Studies With PET and [N-Methyl-11C]Vorozole

    Energy Technology Data Exchange (ETDEWEB)

    Biegon, A.; Biegon, A.; Kim, S.W.; Alexoff, D.; Millard, J.; Carter, P.; Hubbard, B.; King, P.; Logan, J.; Muench, L.; Pareto, D.; Schlyer, D.; Shea, C.; Telang, F.; Wang, G.-J.; Xu, Y.; Fowler, J.

    2010-10-01

    Aromatase catalyzes the last step in estrogen biosynthesis. Brain aromatase is involved in diverse neurophysiological and behavioral functions including sexual behavior, aggression, cognition, and neuroprotection. Using positron emission tomography (PET) with the radiolabeled aromatase inhibitor [N-methyl-{sup 11}C]vorozole, we characterized the tracer distribution and kinetics in the living human brain. Six young, healthy subjects, three men and three women, were administered the radiotracer alone on two separate occasions. Women were scanned in distinct phases of the menstrual cycle. Specificity was confirmed by pretreatment with a pharmacological (2.5 mg) dose of the aromatase inhibitor letrozole. PET data were acquired over a 90-min period and regions of interest placed over selected brain regions. Brain and plasma time activity curves, corrected for metabolites, were used to derive kinetic parameters. Distribution volume (V{sub T}) values in both men and women followed the following rank order: thalamus > amygdala = preoptic area > medulla (inferior olive) > accumbens, pons, occipital and temporal cortex, putamen, cerebellum, and white matter. Pretreatment with letrozole reduced VT in all regions, though the size of the reduction was region-dependent, ranging from {approx}70% blocking in thalamus andpreoptic area to {approx}10% in cerebellum. The high levels of aromatase in thalamus and medulla (inferior olive) appear to be unique to humans. These studies set the stage for the noninvasive assessment of aromatase involvement in various physiological and pathological processes affecting the human brain.

  15. Frequency of Polymorphism in Aromatase Enzyme Coding Gene with Prostate Cancer Risk in North Indian Population

    Directory of Open Access Journals (Sweden)

    KH Onsory

    2015-10-01

    Full Text Available Background: A series of biochemical reactions are involved in the endogenous production of estrogens. Their final and rate-limiting step is catalyzed by aromatase belonging to the class XIX of cytochrome P450. CYP19 is a key enzyme for estrogen synthesis in males. It catalyzes the irreversible conversion of androstenedione and testosterone to estrone and estradiol-17β, respectively. Aromatase P450 is present in the endoplasmic reticulum of estrogen-reproducing cells in which it is expressed. The effects of the resulting estrogens are mediated through the estrogen receptor. One of the most important polymorphism, is a C to T variation in exon 7 resulting in an Arg264Cys amino acid exchange, has been shown to be very common in Asia. The purpose of this study was to determine the association of CYP19 gene polymorphism with the prostate cancer risk among the studied population. Methods: PCR-RFLP analysis of CYP19 gene was on 100 prostate cancer patients and an equal number of matching controls. The data was analyzed using the computer software SPSS for windows (version 19. Results: The frequency of CT genotype was higher in patients (37% as compared to controls (21.2% and this incidence was statistically significant (OR, 2.10; 95 % CI, 1.02-4.34; P=0.044. Stratification of patients according to the risk factors, resulted in a slightly improved OR in individuals carrying CT compared to CC genotype (OR, 2.35 95% CI, 1.11-4.96; P=0.024. The TT genotype was not significantly associated with prostate cancer risk (OR, 0.63; 95% CI, 0.16-2.50; P=0.519. Conclusion: It seems that CT genotype is more associated with cancer prostate compare with other genotypes. It appears to be an increased risk of prostate cancer associated with the Arg264Cys substitution in the CYP19 gene.

  16. Des-acyl ghrelin inhibits the capacity of macrophages to stimulate the expression of aromatase in breast adipose stromal cells.

    Science.gov (United States)

    Au, CheukMan C; Docanto, Maria M; Zahid, Heba; Raffaelli, Francesca-Maria; Ferrero, Richard L; Furness, John B; Brown, Kristy A

    2017-06-01

    Des-acyl ghrelin is the unacylated form of the well-characterized appetite-stimulating hormone ghrelin. It affects a number of physiological processes, including increasing adipose lipid accumulation and inhibiting adipose tissue inflammation. Breast adipose tissue inflammation in obesity is associated with an increase in the expression of the estrogen biosynthetic enzyme, aromatase, and is hypothesized to create a hormonal milieu conducive to tumor growth. We previously reported that des-acyl ghrelin inhibits the expression and activity of aromatase in isolated human adipose stromal cells (ASCs), the main site of aromatase expression in the adipose tissue. The current study aimed to examine the effect of des-acyl ghrelin on the capacity of mouse macrophages (RAW264.7 cells) and human adipose tissue macrophages (ATMs) to stimulate aromatase expression in primary human breast ASCs. RAW264.7 cells were treated with 0, 10 and 100pM des-acyl ghrelin following activation with phorbol 12-myristate 13-acetate, and cells and conditioned media were collected after 6 and 24h. The effect of des-acyl ghrelin on macrophage polarization was examined by assessing mRNA expression of pro-inflammatory M1-specific marker Cd11c and anti-inflammatory M2-specific marker Cd206, as well as expression of Tnf and Ptgs2, known mediators of the macrophage-dependent stimulation of aromatase. TNF protein in conditioned media was assessed by ELISA. The effect of RAW264.7 and ATM-conditioned media on aromatase expression in ASCs was assessed after 6h. Results demonstrate des-acyl ghrelin significantly increases the expression of Cd206 and suppresses the expression of Cd11c, Tnf and Ptgs2 in activated RAW264.7 cells. Treatment of RAW264.7 and ATMs with des-acyl ghrelin also significantly reduces the capacity of these cells to stimulate aromatase transcript expression in human breast ASCs. Overall, these findings suggest that in addition to direct effects on aromatase in ASCs, des-acyl ghrelin also

  17. Central Administration of Indomethacin Mitigates the Injury-Induced Upregulation of Aromatase Expression and Estradiol Content in the Zebra Finch Brain.

    Science.gov (United States)

    Pedersen, Alyssa L; Brownrout, Jenna L; Saldanha, Colin J

    2017-08-01

    Injury to the vertebrate brain causes neuroinflammation, characterized in part by increases in prostaglandins. In rodents and songbirds, brain injury also induces the transcription and translation of aromatase in reactive astrocytes around the site of damage. Interestingly, this induction is more rapid in female zebra finches relative to males. Induced aromatization is neuroprotective, as inhibition of aromatase and estrogen replacement, increases and decreases the extent of damage, respectively. Although the consequences of induced astrocytic aromatization are intensely studied, little is known about what factors induce aromatase. Inflammation is sufficient to induce astrocytic aromatase suggesting that the link between inflammation and aromatase expression may be causal. To test this hypothesis, adult male and female zebra finches received bilateral mechanical injuries through which either the cyclooxygenase (COX)-1/2 inhibitor indomethacin or vehicle was administered into contralateral hemispheres. Subjects were killed either 6 or 24 hours after injury. In both sexes, an enzyme immunoassay for prostaglandin E2 (PGE2) revealed that indomethacin decreased PGE2 relative to the contralateral hemisphere at both time points, suggesting that the dose and mode of administration used were successful in affecting neuroinflammation locally. Indomethacin reduced aromatase expression and 17β-estradiol (E2) content at 6 hours but not 24 hours following injury in females. However, in males, the inhibitory effect of indomethacin on aromatase and E2 was apparent at 24 but not 6 hours after treatment. These data suggest that COX activity, perhaps via consequent prostaglandin secretion, may induce aromatase expression and central E2, an effect that is detectable in temporally distinct patterns between sexes. Copyright © 2017 Endocrine Society.

  18. Currently used pesticides and their mixtures affect the function of sex hormone receptors and aromatase enzyme activity

    Energy Technology Data Exchange (ETDEWEB)

    Kjeldsen, Lisbeth Stigaard; Ghisari, Mandana; Bonefeld-Jørgensen, Eva Cecilie, E-mail: ebj@mil.au.dk

    2013-10-15

    The endocrine-disrupting potential of pesticides is of health concern, since they are found ubiquitously in the environment and in food items. We investigated in vitro effects on estrogen receptor (ER) and androgen receptor (AR) transactivity, and aromatase enzyme activity, of the following pesticides: 2-methyl-4-chlorophenoxyacetic acid (MCPA), terbuthylazine, iodosulfuron-methyl-sodium, mesosulfuron-methyl, metsulfuron-methyl, chlormequat chloride, bitertanol, propiconazole, prothioconazole, mancozeb, cypermethrin, tau fluvalinate, malathion and the metabolite ethylene thiourea (ETU). The pesticides were analyzed alone and in selected mixtures. Effects of the pesticides on ER and AR function were assessed in human breast carcinoma MVLN cells and hamster ovary CHO-K1 cells, respectively, using luciferase reporter gene assays. Effects on aromatase enzyme activity were analyzed in human choriocarcinoma JEG-3 cells, employing the classical [{sup 3}H]{sub 2}O method. Five pesticides (terbuthylazine, propiconazole, prothioconazole, cypermethrin and malathion) weakly induced the ER transactivity, and three pesticides (bitertanol, propiconazole and mancozeb) antagonized the AR activity in a concentration-dependent manner. Three pesticides (terbuthylazine, propiconazole and prothioconazole) weakly induced the aromatase activity. In addition, two mixtures, consisting of three pesticides (bitertanol, propiconazole, cypermethrin) and five pesticides (terbuthylazine, bitertanol, propiconazole, cypermethrin, malathion), respectively, induced the ER transactivity and aromatase activity, and additively antagonized the AR transactivity. In conclusion, our data suggest that currently used pesticides possess endocrine-disrupting potential in vitro which can be mediated via ER, AR and aromatase activities. The observed mixture effects emphasize the importance of considering the combined action of pesticides in order to assure proper estimations of related health effect risks

  19. Association of Variants in Candidate Genes with Lipid Profiles in Women with Early Breast Cancer on Adjuvant Aromatase Inhibitor Therapy.

    Science.gov (United States)

    Santa-Maria, Cesar A; Blackford, Amanda; Nguyen, Anne T; Skaar, Todd C; Philips, Santosh; Oesterreich, Steffi; Rae, James M; Desta, Zeruesenay; Robarge, Jason; Henry, Norah Lynn; Storniolo, Anna M; Hayes, Daniel F; Blumenthal, Roger S; Ouyang, Pamela; Post, Wendy S; Flockhart, David A; Stearns, Vered

    2016-03-15

    Aromatase inhibitors can exert unfavorable effects on lipid profiles; however, previous studies have reported inconsistent results. We describe the association of single-nucleotide polymorphisms (SNP) in candidate genes with lipid profiles in women treated with adjuvant aromatase inhibitors. We conducted a prospective observational study to test the associations between SNPs in candidate genes in estrogen signaling and aromatase inhibitor metabolism pathways with fasting lipid profiles during the first 3 months of aromatase inhibitor therapy in postmenopausal women with early breast cancer randomized to adjuvant letrozole or exemestane. We performed genetic association analysis and multivariable linear regressions using dominant, recessive, and additive models. A total of 303 women had complete genetic and lipid data and were evaluable for analysis. In letrozole-treated patients, SNPs in CYP19A1, including rs4646, rs10046, rs700518, rs749292, rs2289106, rs3759811, and rs4775936 were significantly associated with decreases in triglycerides by 20.2 mg/dL and 39.3 mg/dL (P < 0.00053), respectively, and with variable changes in high-density lipoprotein (HDL-C) from decreases by 4.2 mg/dL to increases by 9.8 mg/dL (P < 0.00053). Variants in CYP19A1 are associated with decreases in triglycerides and variable changes in HDL-C in postmenopausal women on adjuvant aromatase inhibitors. Future studies are needed to validate these findings, and to identify breast cancer survivors who are at higher risk for cardiovascular disease with aromatase inhibitor therapy. ©2015 American Association for Cancer Research.

  20. Potential effect of Olea europea leaves, Sonchus oleraceus leaves and Mangifera indica peel extracts on aromatase activity in human placental microsomes and CYP19A1 expression in MCF-7 cell line: Comparative study.

    Science.gov (United States)

    Shaban, N Z; Hegazy, W A; Abdel-Rahman, S M; Awed, O M; Khalil, S A

    2016-08-29

    Aromatase inhibitors (AIs) provide novel approaches to the adjuvant therapy for postmenopausal women with estrogen-receptor-positive (ER+) breast cancers. In this study, different plant extracts from Olea europaea leaves (OLE), Sonchus oleraceus L. (SOE) and Mangifera indica peels (MPE) were prepared to identify phytoconstituents and measure antioxidant capacities. The effects of these three extracts on aromatase activity in human placental microsomes were evaluated. Additionally, the effects of these extracts on tissue-specific promoter expression of CYP19A1 gene in cell culture model (MCF-7) were assessed using qRT-PCR. Results showed a concentration-dependent decrease in aromatase activity after treatment with OLE and MPE, whereas, SOE showed a biphasic effect. The differential effects of OLE, SOE and MPE on aromatase expression showed that OLE seems to be the most potent suppressor followed by SOE and then MPE. These findings indicate that OLE has effective inhibitory action on aromatase at both the enzymatic and expression levels, in addition to its cytotoxic effect against MCF-7 cells. Also, MPE may be has the potential to be used as a tissue-specific aromatase inhibitor (selective aromatase inhibitor) and it may be promising to develop a new therapeutic agent against ER+ breast cancer.

  1. Vaginal atrophy in breast cancer survivors: role of vaginal estrogen therapy.

    Science.gov (United States)

    Mariani, Luciano; Gadducci, Angiolo; Vizza, Enrico; Tomao, Silverio; Vici, Patrizia

    2013-01-01

    Early menopause and related vaginal atrophy is a well known side-effect of hormone adjuvant treatment in breast cancer patients, particularly during aromatase-inhibitors therapy. Due to estrogens contra-indication, proper therapy for such symptom remains often an inadequately addressed clinical problem. After an accurate assessment of the risk/benefit ratio, vaginal low-dose estrogen treatment (better with estriol) [corrected] may have a role in controlling vaginal atrophy in selected and informed breast cancer women.

  2. Aromatase inactivation by 2-substituted derivatives of the suicide substrate androsta-1,4-diene-3,17-dione.

    Science.gov (United States)

    Takahashi, Madoka; Handa, Wakako; Umeta, Hiromi; Ishikawa, Saki; Yamashita, Kouwa; Numazawa, Mitsuteru

    2009-09-01

    To gain the structure-activity relationship of Delta(1)-androstenediones (Delta(1)-ADs) as mechanism-based inactivator of aromatase, series of 2-alkyl- and 2-alkoxy-substituted Delta(1)-ADs (6 and 9) as well as 2-bromo-Delta(1)-AD (14) were synthesized and tested. All of the inhibitors examined blocked aromatase in human placental microsomes in a competitive manner. In a series of 2-alkyl-Delta(1)-ADs (6), n-hexyl compound 6f was the most powerful inhibitor with an apparent K(i) value of 31 nM. The inhibitory activities of 2-alkoxy steroids 9 decreased in relation to length of the alkyl chain up to n-hexyloxy group (K(i): 95 nM for methoxy 9a). All of the alkyl steroids 6 along with the alkoxy steroid 9, except for the ethyl and n-propyl compounds 6b and 6c, caused a time-dependent inactivation of aromatase. The inactivation rates (k(inact): 0.020-0.084 min(-1)) were comparable to that of the parent compound Delta(1)-AD. The inactivation was prevented by the substrate AD, and no significant effect of l-cysteine on the inactivation was observed in each case. The results indicate that the 2-hexyl compound 6f act as the most powerful mechanism-based inactivator of aromatase among Delta(1)-AD analogs and may be submitted to the preclinical study in estrogen-dependent breast cancer.

  3. Studies on the catalytic function of aromatase: aromatization of 6-alkoxy-substituted androgens.

    Science.gov (United States)

    Numazawa, Mitsuteru; Ando, Momoko; Zennyoji, Rika

    2002-09-01

    To gain insight into the catalytic function of aromatase, we studied aromatization of a series of 6alpha- and 6beta-ether-substituted (methoxy, ethoxy, and n-butoxy) androst-4-ene-3,17-dione (AD) steroids (1 and 2) and their androsta-1,4-diene-3,17-dione (ADD) derivatives (3 and 4) with human placental aromatase by gas chromatography-mass spectrometry (GC-MS). Among the steroids examined, 6beta-methoxy and 6beta-ethoxyADDs (4a and 4b) are suicide substrates of aromatase. All of the steroids were found to be converted into the corresponding 6-alkoxy estrogens. Introduction of the alkoxy groups at C-6 of AD or ADD decreased the ability of these to serve as a substrate of aromatase. In 6alpha-alkoxy steroid series, compounds 1 and 3, the aromatization rate increased by elongating the 6-methoxy group up to the n-butoxy group whereas, in the 6beta-isomers series, 2 and 4, the rate decreased due to this structural modification. 6beta-Alkoxy steroids, 2 and 4, including the suicide substrates, were extremely poor substrates for the aromatization reaction. Apparent K(m) values obtained for 6alpha-alkoxy compounds 1 and 3 were similar to each other, ranging from 92 to 111nM, as shown by their previously-obtained K(i) values. The findings indicate that the stereochemistry as well as the bulkiness of the 6-ether-substituent play an important role in the ability to serve as a substrate. It is also predicted that the aromatization reaction and the mechanism-based inactivation reaction would be related and have a definite partition number which is characteristic to the compound in a series of suicide substrates.

  4. Metabolism of 19-methyl-substituted steroids by human placental aromatase

    International Nuclear Information System (INIS)

    Beusen, D.D.; Carrell, H.L.; Covey, D.F.

    1987-01-01

    The 19-methyl analogues of androstenedione and its aromatization intermediates (19-hydroxyandrostenedione and 19-oxoandrostenedione) were evaluated as substrates of microsomal aromatase in order to determine the effect of a 19-alkyl substituent on the enzyme's regiospecificity. Neither the androstenedione analog [10-ethylestr-4-ene-3,17-dione (1c) nor the 19-oxoandrostenedione analog [10-acetylestr-4-ene-3,17-dione (3c)] was converted to estrogens or oxygenated metabolites by placental microsomes. In contrast, both analogues of 19-hydroxyandrostenedione [10-[(1S)-1-hydroxyethyl] extr-4-ene-3,17-dione (2c) and 10-[(1R)-1-hydroxyethyl]estr-4-ene-3,17-dione (2e)] were converted to the intermediate analog 3c in a process requiring O 2 and either NADH or NADPH. No change in enzyme regiospecificity was detected. The absolute configuration of 2e was determined by X-ray crystallography. Experiments with 18 O 2 established that 3c generated from 2c retained little 18 O ( 18 O (≅ 70%). All four 19-methyl steroids elicited type I difference spectra from placental microsomes in addition to acting as competitive inhibitors of aromatase. Pretreatment of microsomes with 4-hydroxyandrostenedione (a suicide inactivator of aromatase) abolished the metabolism of 2c and 2e to 3c, as well as the type I difference spectrum elicited by 2c and 2e. The failure of 2c, 2e, and 3c to undergo aromatization was rationalized in the context of a mechanistic proposal for the third oxygenation of aromatase requiring hydrogen abstraction at C 1 of 19,19-dihydroxyandrostenedione, homolytic cleavage of the C 10 -C 19 bond, and oxygen rebound at C 19

  5. Aromatase inhibitors in stimulated IVF cycles

    DEFF Research Database (Denmark)

    Papanikolaou, Evangelos G; Polyzos, Nikolaos P; Humaidan, Peter

    2011-01-01

    Aromatase inhibitors have been introduced as a new treatment modality that could challenge clomiphene citrate as an ovulation induction regiment in patients with PCOS. Although several randomized trials have been conducted regarding their use as ovulation induction agents, only few trials are ava...

  6. The effects of the standardized extracts of Ginkgo biloba on steroidogenesis pathways and aromatase activity in H295R human adrenocortical carcinoma cells

    Science.gov (United States)

    2016-01-01

    Objectives Aromatase inhibitors that block estrogen synthesis are a proven first-line hormonal therapy for postmenopausal breast cancer. Although it is known that standardized extract of Ginkgo biloba (EGb761) induces anti-carcinogenic effects like the aromatase inhibitors, the effects of EGb761 on steroidogenesis have not been studied yet. Therefore, the effects of EGb761 on steroidogenesis and aromatase activity was studied using a H295R cell model, which was a good in vitro model to predict effects on human adrenal steroidogenesis. Methods Cortisol, aldosterone, testosterone, and 17β-estradiol were evaluated in the H295R cells by competitive enzyme-linked immunospecific assay after exposure to EGb761. Real-time polymerase chain reaction were performed to evaluate effects on critical genes in steroid hormone production, specifically cytochrome P450 (CYP11/ 17/19/21) and the hydroxysteroid dehydrogenases (3β-HSD2 and 17β-HSD1/4). Finally, aromatase activities were measured with a tritiated water-release assay and by western blotting analysis. Results H295R cells exposed to EGb761 (10 and 100 μg/mL) showed a significant decrease in 17β-estradiol and testosterone, but no change in aldosterone or cortisol. Genes (CYP19 and 17β-HSD1) related to the estrogen steroidogenesis were significantly decreased by EGb761. EGb761 treatment of H295R cells resulted in a significant decrease of aromatase activity as measured by the direct and indirect assays. The coding sequence/ Exon PII of CYP19 gene transcript and protein level of CYP19 were significantly decreased by EGb761. Conclusions These results suggest that EGb761 could regulate steroidogenesis-related genes such as CYP19 and 17β-HSD1, and lead to a decrease in 17β-estradiol and testosterone. The present study provides good information on potential therapeutic effects of EGb761 on estrogen dependent breast cancer. PMID:27188280

  7. The effects of the standardized extracts of on steroidogenesis pathways and aromatase activity in H295R human adrenocortical carcinoma cells

    Directory of Open Access Journals (Sweden)

    Mijie Kim

    2016-05-01

    Full Text Available Objectives Aromatase inhibitors that block estrogen synthesis are a proven first-line hormonal therapy for postmenopausal breast cancer. Although it is known that standardized extract of Ginkgo biloba (EGb761 induces anti-carcinogenic effects like the aromatase inhibitors, the effects of EGb761 on steroidogenesis have not been studied yet. Therefore, the effects of EGb761 on steroidogenesis and aromatase activity was studied using a H295R cell model, which was a good in vitro model to predict effects on human adrenal steroidogenesis. Methods Cortisol, aldosterone, testosterone, and 17β-estradiol were evaluated in the H295R cells by competitive enzyme-linked immunospecific assay after exposure to EGb761. Real-time polymerase chain reaction were performed to evaluate effects on critical genes in steroid hormone production, specifically cytochrome P450 (CYP11/ 17/19/21 and the hydroxysteroid dehydrogenases (3β-HSD2 and 17β-HSD1/4. Finally, aromatase activities were measured with a tritiated water-release assay and by western blotting analysis. Results H295R cells exposed to EGb761 (10 and 100 μg/mL showed a significant decrease in 17β-estradiol and testosterone, but no change in aldosterone or cortisol. Genes (CYP19 and 17β-HSD1 related to the estrogen steroidogenesis were significantly decreased by EGb761. EGb761 treatment of H295R cells resulted in a significant decrease of aromatase activity as measured by the direct and indirect assays. The coding sequence/ Exon PII of CYP19 gene transcript and protein level of CYP19 were significantly decreased by EGb761. Conclusions These results suggest that EGb761 could regulate steroidogenesis-related genes such as CYP19 and 17β-HSD1, and lead to a decrease in 17β-estradiol and testosterone. The present study provides good information on potential therapeutic effects of EGb761 on estrogen dependent breast cancer.

  8. Triclocarban and Triclosan Inhibit Human Aromatase via Different Mechanisms

    Directory of Open Access Journals (Sweden)

    Huitao Li

    2017-01-01

    Full Text Available Human aromatase (CYP19A1 is an important enzyme, which produces estrogen from androgen for maintaining the female reproductive function and pregnancy. Triclocarban and triclosan are antimicrobial chemicals added to personal care, household, and industrial products. They could be endocrine disruptors and may disrupt human CYP19A1 activity. In the present study, we investigated the effects of triclocarban and triclosan on estradiol production and human CYP19A1 activity in JEG-3 cells. Triclocarban and triclosan reduced estradiol production in JEG-3 cells. Triclocarban and triclosan inhibited human CYP19A1 with IC50 values of 15.81 and 6.26 μM, respectively. Triclosan competitively inhibited CYP19A1, while triclocarban noncompetitively inhibited this enzyme. Docking study showed that triclosan bound to the steroid-binding pocket of CYP19A1, while triclocarban was off this target, suggesting a different mechanism. In conclusion, triclocarban and triclosan are inhibitors of human CYP19A1.

  9. Insight into the binding interactions of CYP450 aromatase inhibitors with their target enzyme: a combined molecular docking and molecular dynamics study.

    Science.gov (United States)

    Galeazzi, Roberta; Massaccesi, Luca

    2012-03-01

    CYP450 aromatase catalyzes the terminal and rate-determining step in estrogen synthesis, the aromatization of androgens, and its inhibition is an efficient approach to treating estrogen-dependent breast cancer. Insight into the molecular basis of the interaction at the catalytic site between CYP450 aromatase inhibitors and the enzyme itself is required in order to design new and more active compounds. Hence, a combined molecular docking-molecular dynamics study was carried out to obtain the structure of the lowest energy association complexes of aromatase with some third-generation aromatase inhibitors (AIs) and with other novel synthesized letrozole-derived compounds which showed high in vitro activity. The results obtained clearly demonstrate the role of the pharmacophore groups present in the azaheterocyclic inhibitors (NSAIs)-namely the triazolic ring and highly functionalized aromatic moieties carrying H-bond donor or acceptor groups. In particular, it was pointed out that all of them can contribute to inhibition activity by interacting with residues of the catalytic cleft, but the amino acids involved are different for each compound, even if they belong to the same class. Furthermore, the azaheterocyclic group strongly coordinates with the Fe(II) of heme cysteinate in the most active NSAI complexes, while it prefers to adopt another orientation in less active ones.

  10. Time-dependent aromatase inactivation by 4 beta,5 beta-epoxides of the natural substrate androstenedione and its 19-oxygenated analogs.

    Science.gov (United States)

    Numazawa, Mitsuteru; Yoshimura, Akiko; Tachibana, Mii; Shelangouski, Momoko; Ishikawa, Maya

    2002-03-01

    Aromatase catalyzes the conversion of androgens to estrogens through three sequential oxygenations. To gain insight into the catalytic function of aromatase and its aromatization mechanism, we studied the inhibition of human placental aromatase by 4 beta,5 beta-epoxyandrostenedione (5) as well as its 19-hydroxy and 19-oxo derivatives (6 and 7, respectively), and we also examined the biochemical aromatization of these steroids. All of the epoxides were weak competitive inhibitors of aromatase with apparent K(i) values ranging from 5.0 microM to 30 microM. The 19-methyl and 19-oxo compounds 5 and 7 inactivated aromatase in a time-dependent manner with k(inact) of 0.048 and 0.110 min(-1), respectively, in the presence of NADPH. In the absence of NADPH, only the former inhibited aromatase with a k(inact) of 0.091 min(-1). However, 19-hydroxy steroid 6 did not cause irreversible inactivation either in the presence or absence of NADPH. Gas chromatography-mass spectrometric analysis of the metabolite produced by a 5-min incubation of the three epoxides with human placental microsomes in the presence of NADPH under air revealed that all three compounds were aromatized to produce estradiol with rates of 8.82, 0.51, and 1.62 pmol/min/mg protein for 5, 6, and 7, respectively. In each case, the aromatization was efficiently prevented by 19-hydroxyandrost-4-en-17-one, a potent aromatase inhibitor. On the basis of the aromatization and inactivation results, it seems likely that the two pathways, aromatization and inactivation, may proceed, in part, through a common intermediate, 19-oxo compound 7, although they may be principally different.

  11. Improved synthesis and molecular modeling of 4beta,19-dihydroxyandrost-5-en-17-one, an excellent inhibitor of aromatase.

    Science.gov (United States)

    Numazawa, Mitsuteru; Yamada, Keiko; Watari, Yoko; Ando, Momoko

    2002-05-01

    4Beta,19-dihydroxyandrost-5-en-17-one (6) is an excellent competitive inhibitor of estrogen synthetase (aromatase). Alternate, improved synthesis of this inhibitor was established. Treatment of 19-(tert-butyldimethylsilyloxy)androst-4-en-17-one (8) with m-chloroperbenzoic acid gave a 1.4:1 mixture of 4alpha,5alpha-epoxide 9 and its 4beta,5beta-isomer 10. The mixture was reacted with diI. HClO4 in dioxane to produce principally 4beta,5alpha-diol 11 (80%) of which acetylation followed by dehydration with SOCl2 yielded 4beta,19-diacetoxy-5-ene compound 14 in good yield. Alkaline hydrolysis of diacetate 14 gave 4beta,19-diol 6. The minimum energy conformation of the powerfull aromatase inhibitor 6 was obtained with the PM3 method and compared with that of the structurally related diol steroid, 4-ene-5beta,19-diol 3, a weak competitive inhibitor.

  12. Estrogen Injection

    Science.gov (United States)

    ... class of medications called hormones. It works by replacing estrogen that is normally produced by the body. ... your doctor about eating grapefruit and drinking grapefruit juice while using this medicine.

  13. Estrogen Test

    Science.gov (United States)

    ... and Iron-binding Capacity (TIBC, UIBC) Trichomonas Testing Triglycerides Troponin Tryptase Tumor Markers Uric Acid Urinalysis Urine ... in men and play a role in bone metabolism and growth in both sexes. Estrogen tests measure ...

  14. Celecoxib increases miR-222 while deterring aromatase-expressing breast tumor growth in mice

    International Nuclear Information System (INIS)

    Wong, Tsz Yan; Li, Fengjuan; Lin, Shu-mei; Chan, Franky L; Chen, Shiuan; Leung, Lai K

    2014-01-01

    Breast cancer is one of the most deadly diseases in women. Inhibiting the synthesis of estrogen is effective in treating patients with estrogen-responsive breast cancer. Previous studies have demonstrated that use of cyclooxygenase (COX) inhibitors is associated with reduced breast cancer risk. In the present study, we employed an established mouse model for postmenopausal breast cancer to evaluate the potential mechanisms of the COX-2 inhibitor celecoxib. Aromatase-expressing MCF-7 cells were transplanted into ovariectomized athymic mice. The animals were given celecoxib at 1500 ppm or aspirin at 200 ppm by oral administration with androstenedione injection. Our results showed that both COX inhibitors could suppress the cancer xenograft growth without changing the plasma estrogen level. Protein expression of ERα, COX-2, Cyclin A, and Bcl-xL were reduced in celecoxib-treated tumor samples, whereas only Bcl-xL expression was suppressed in those treated with aspirin. Among the breast cancer-related miRNAs, miR-222 expression was elevated in samples treated with celecoxib. Further studies in culture cells verified that the increase in miR-222 expression might contribute to ERα downregulation but not the growth deterrence of cells. Overall, this study suggested that both celecoxib and aspirin could prevent breast cancer growth by regulating proteins in the cell cycle and apoptosis without blocking estrogen synthesis. Besides, celecoxib might affect miR expression in an undesirable fashion

  15. Modulation of Estrogen Chemical Carcinogenesis by Botanical Supplements used for Postmenopausal Women’s Health

    Science.gov (United States)

    Snelten, Courtney S.; Dietz, Birgit; Bolton, Judy L.

    2012-01-01

    Breast cancer risk has been associated with long-term estrogen exposure including traditional hormone therapy (HT, formally hormone replacement therapy). To avoid traditional HT and associated risks, women have been turning to botanical supplements such as black cohosh, red clover, licorice, hops, dong gui, and ginger to relieve menopausal symptoms despite a lack of efficacy evidence. The mechanisms of estrogen carcinogenesis involve both hormonal and chemical pathways. Botanical supplements could protect women from estrogen carcinogenesis by modulating key enzymatic steps [aromatase, P4501B1, P4501A1, catechol-O-methyltransferase (COMT), NAD(P)H quinone oxidoreductase 1 (NQO1), and reactive oxygen species (ROS) scavenging] in estradiol metabolism leading to estrogen carcinogenesis as outlined in Figure 1. This review summarizes the influence of popular botanical supplements used for women’s health on these key steps in the estrogen chemical carcinogenesis pathway, and suggests that botanical supplements may have added chemopreventive benefits by modulating estrogen metabolism. PMID:24223609

  16. Neural stem cell sex dimorphism in aromatase (CYP19 expression: a basis for differential neural fate

    Directory of Open Access Journals (Sweden)

    Jay Waldron

    2010-11-01

    Full Text Available Jay Waldron1, Althea McCourty1, Laurent Lecanu1,21The Research Institute of the McGill University Health Centre, Montreal, Canada; 2Department of Medicine, McGill University, Quebec, CanadaPurpose: Neural stem cell (NSC transplantation and pharmacologic activation of endogenous neurogenesis are two approaches that trigger a great deal of interest as brain repair strategies. However, the success rate of clinical attempts using stem cells to restore neurologic functions altered either after traumatic brain injury or as a consequence of neurodegenerative disease remains rather disappointing. This suggests that factors affecting the fate of grafted NSCs are largely understudied and remain to be characterized. We recently reported that aging differentially affects the neurogenic properties of male and female NSCs. Although the sex steroids androgens and estrogens participate in the regulation of neurogenesis, to our knowledge, research on how gender-based differences affect the capacity of NSCs to differentiate and condition their neural fate is lacking. In the present study, we explored further the role of cell sex as a determining factor of the neural fate followed by differentiating NSCs and its relationship with a potential differential expression of aromatase (CYP19, the testosterone-metabolizing enzyme.Results: Using NSCs isolated from the subventricular zone of three-month-old male and female Long-Evans rats and maintained as neurospheres, we showed that differentiation triggered by retinoic acid resulted in a neural phenotype that depends on cell sex. Differentiated male NSCs mainly expressed markers of neuronal fate, including ßIII-tubulin, microtubule associated protein 2, growth-associated protein 43, and doublecortin. In contrast, female NSCs essentially expressed the astrocyte marker glial fibrillary acidic protein. Quantification of the expression of aromatase showed a very low level of expression in undifferentiated female NSCs

  17. Testosterone-induced adult neurosphere growth is mediated by sexually-dimorphic aromatase expression

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    Mark Ian Ransome

    2015-07-01

    Full Text Available We derived adult neural stem/progenitor cells (NSPCs from the sub-ventricular zone of male and female mice to examine direct responses to principal sex hormones. In the presence of epidermal growth factor (EGF and fibroblast growth factor-2 (FGF2 NSPCs of both sexes expressed nestin and sox2 and could be maintained as neurospheres without addition of any sex hormones. The reverse was not observed; neither testosterone (T, 17β-oestradiol (E2 nor progesterone (P4 was able to support neurosphere growth in the absence of EGF and FGF2. 10nM T, E2 or P4 induced nestin(+ cell proliferation within 20 minutes and enhanced neurosphere growth over 7 days irrespective of sex, which was abolished by Erk inhibition with 20M U0126. Maintaining neurospheres with each sex hormone did not affect subsequent neuronal differentiation. However, 10nM T, E2 or P4 added during differentiation increased III tubulin(+ neuron production with E2 being more potent compared to T and P4 in both sexes. Androgen receptor (AR inhibition with 20M flutamide but not aromatase inhibition with 10M letrozole reduced basal and T-induced neurosphere growth in females, while only concurrent inhibition of AR and aromatase produced the same effect in males. This sex-specific effect was supported by higher aromatase expression in male neurospheres compared to females measured by Western blot and green fluorescent protein reporter. 10M menadione induced oxidative stress, impaired neurosphere growth and up-regulated aromatase expression in both sexes. However, under oxidative stress letrozole significantly exacerbated impaired neurosphere growth in males only. While both E2 and T could prevent oxidative stress-induced growth reduction in both sexes, the effects of T were dependent on innate aromatase activity. We show for the first time that intrinsic androgen and estrogen signalling may impact the capacity of NSPCs to produce neural progenitors under pathological conditions of

  18. The use of a unique co-culture model of fetoplacental steroidogenesis as a screening tool for endocrine disruptors: The effects of neonicotinoids on aromatase activity and hormone production.

    Science.gov (United States)

    Caron-Beaudoin, Elyse; Viau, Rachel; Hudon-Thibeault, Andrée-Anne; Vaillancourt, Cathy; Sanderson, J Thomas

    2017-10-01

    Estrogen biosynthesis during pregnancy is dependent on the collaboration between the fetus producing the androgen precursors, and the placenta expressing the enzyme aromatase (CYP19). Disruption of estrogen production by contaminants may result in serious pregnancy outcomes. We used our recently developed in vitro co-culture model of fetoplacental steroidogenesis to screen the effects of three neonicotinoid insecticides on the catalytic activity of aromatase and the production of steroid hormones. A co-culture of H295R human adrenocortical carcinoma cells with fetal characteristics and BeWo human choriocarcinoma cells which display characteristics of the villous cytotrophoblast was exposed for 24h to various concentrations of three neonicotinoids: thiacloprid, thiamethoxam and imidacloprid. Aromatase catalytic activity was determined in both cell lines using the tritiated water-release assay. Hormone production was measured by ELISA. The three neonicotinoids induced aromatase activity in our fetoplacental co-culture and concordingly, estradiol and estrone production were increased. In contrast, estriol production was strongly inhibited by the neonicotinoids. All three pesticides induced the expression of CYP3A7 in H295R cells, and this induction was reversed by co-treatment of H295R cells with exogenous estriol. CYP3A7 is normally expressed in fetal liver and is a key enzyme involved in estriol synthesis. We suggest that neonicotinoids are metabolized by CYP3A7, thus impeding the 16α-hydroxylation of fetal DHEA(-sulfate), which is normally converted to estriol by placental aromatase. We successfully used the fetoplacental co-culture as a physiologically relevant tool to highlight the potential effects of neonicotinoids on estrogen production, aromatase activity and CYP3A7 expression during pregnancy. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Is basic research providing answers if adjuvant anti-estrogen treatment of breast cancer can induce cognitive impairment?

    NARCIS (Netherlands)

    Buwalda, Bauke; Schagen, Sanne B.

    2013-01-01

    Adjuvant treatment of cancer by chemotherapy is associated with cognitive impairment in some cancer survivors. Breast cancer patients are frequently also receiving endocrine therapy with selective estrogen receptor modulators (SERMs) and/or aromatase inhibitors (AIs) to suppress the growth of

  20. Evidence for an Elevated Aspartate pKa in the Active Site of Human Aromatase*

    Science.gov (United States)

    Di Nardo, Giovanna; Breitner, Maximilian; Bandino, Andrea; Ghosh, Debashis; Jennings, Gareth K.; Hackett, John C.; Gilardi, Gianfranco

    2015-01-01

    Aromatase (CYP19A1), the enzyme that converts androgens to estrogens, is of significant mechanistic and therapeutic interest. Crystal structures and computational studies of this enzyme shed light on the critical role of Asp309 in substrate binding and catalysis. These studies predicted an elevated pKa for Asp309 and proposed that protonation of this residue was required for function. In this study, UV-visible absorption, circular dichroism, resonance Raman spectroscopy, and enzyme kinetics were used to study the impact of pH on aromatase structure and androstenedione binding. Spectroscopic studies demonstrate that androstenedione binding is pH-dependent, whereas, in contrast, the D309N mutant retains its ability to bind to androstenedione across the entire pH range studied. Neither pH nor mutation perturbed the secondary structure or heme environment. The origin of the observed pH dependence was further narrowed to the protonation equilibria of Asp309 with a parallel set of spectroscopic studies using exemestane and anastrozole. Because exemestane interacts with Asp309 based on its co-crystal structure with the enzyme, its binding is pH-dependent. Aromatase binding to anastrozole is pH-independent, consistent with the hypothesis that this ligand exploits a distinct set of interactions in the active site. In summary, we assign the apparent pKa of 8.2 observed for androstenedione binding to the side chain of Asp309. To our knowledge, this work represents the first experimental assignment of a pKa value to a residue in a cytochrome P450. This value is in agreement with theoretical calculations (7.7–8.1) despite the reliance of the computational methods on the conformational snapshots provided by crystal structures. PMID:25425647

  1. Dietary administration of the licorice flavonoid isoliquiritigenin deters the growth of MCF-7 cells overexpressing aromatase.

    Science.gov (United States)

    Ye, Lan; Gho, Wai M; Chan, Franky L; Chen, Shiuan; Leung, Lai K

    2009-03-01

    Licorice is the sweet-tasting rhizomes of a bean plant and is quite commonly used in Western countries for culinary purposes, while it is a medicinal herb in China. Many flavonoids have been isolated from licorice, and their pharmacological properties may be applicable in preventive medicine. Overexposure to estrogen has been implicated in the etiology of breast cancer, and cytochrome P450 (CYP) 19 enzyme, or aromatase, catalyzes the rate-limiting reaction. Phytocompounds that are able to inhibit this enzyme may potentially suppress breast cancer development. In the present study the licorice flavonoid isoliquiritigenin (ILN) was shown to be an aromatase inhibitor in recombinant protein and MCF-7 cells stably transfected with CYP19 (MCF-7aro). ILN displayed a K(i) value of around 3 muM, and it also blocked the MCF-7aro cell growth pertaining to the enzyme activity in vitro. Subsequently, the compound administered in diet was given to ovariectomized athymic mice transplanted with MCF-7aro cells. This mouse model is widely accepted for studying postmenopausal breast cancer. The phytochemical significantly deterred the xenograft growth without affecting the body weight. Subsequently, the flavonoid's effect on CYP19 transcriptional control in vitro was also investigated. At the mRNA level, ILN could also suppress the expression in wild-type MCF-7 cells. Reporter gene assay and real-time PCR verified that the transactivity of CYP19 driven by promoters I.3 and II was suppressed in these cells. Deactivation of C/EBP could be the underlying molecular mechanism. Our study demonstrated that ILN was an inhibitor of aromatase and a potential chemopreventive agent against breast cancer.

  2. Computational drug designing of fungal pigments as potential aromatase inhibitors

    Directory of Open Access Journals (Sweden)

    Nighat Fatima

    2014-12-01

    Full Text Available The existing aromatase inhibitors produced unwelcome effects impose the discovery of novel drugs with privileged selectivity, a reduced amount of toxicity and humanizing potency. In this study, we illuminate the binding mode of polyketide azaphilanoid pigments monascin, ankaflavin, monascorubrin and monascorubramine isolated from Monascus fungus to the aromatase by molecular docking. The 3-dimensional structure of aromatase enzyme (PDB: 4KQ8 was obtained from the Protein Data Bank. PatchDock docking software was used to analyze structural complexes of the aromatase with monascus pigments. Comparatively, the AutoGrid model presented the most briskly constructive binding mode of monascin to aromatase. Docked energies in kcal/mol are: monascin;-13.2; monascorubramine:-12.8, monascorubrin:-12.3; ankaflavin: -10.5. These outcomes exposed these ligands could be potential drugs to treat hormone dependent breast cancer.

  3. The effect of aromatase inhibitors on bone metabolism

    DEFF Research Database (Denmark)

    Folkestad, Lars; Bjarnason, Nina H; Bjerregaard, Jon Kroll

    2009-01-01

    Aromatase inhibitors increase the disease-free survival in patients with receptor-positive breast cancer. Aromatase is a cytochrome P450 enzyme complex catalysing the conversion of androgens to oestrogens. These properties cause a significant increase in bone loss. In this MiniReview, we present...... data from the aromatase inhibitor studies and the studies designed to investigate aromatase inhibitor effect on bone metabolism. At the cellular level, oestrogen has profound effects on both osteoblasts and osteoclasts. Oestrogen decreases the osteoblastic production of resorptive cytokines...... in comparison with tamoxifen. We conclude that treatment with aromatase inhibitors leads to an increased bone loss and thus an increase in the risk of fractures in women with breast cancer....

  4. Effects of Neonicotinoids on Promoter-Specific Expression and Activity of Aromatase (CYP19) in Human Adrenocortical Carcinoma (H295R) and Primary Umbilical Vein Endothelial (HUVEC) Cells.

    Science.gov (United States)

    Caron-Beaudoin, Élyse; Denison, Michael S; Sanderson, J Thomas

    2016-01-01

    The enzyme aromatase (CYP19; cytochrome P450 19) in humans undergoes highly tissue- and promoter-specific regulation. In hormone-dependent breast cancer, aromatase is over-expressed via several normally inactive promoters (PII, I.3, I.7). Aromatase biosynthesizes estrogens, which stimulate breast cancer cell proliferation. The placenta produces estrogens required for healthy pregnancy and the major placental CYP19 promoter is I.1. Exposure to certain pesticides, such as atrazine, is associated with increased CYP19 expression, but little is known about the effects of neonicotinoid insecticides on CYP19. We developed sensitive and robust RT-qPCR methods to detect the promoter-specific expression of CYP19 in human adrenocortical carcinoma (H295R) and primary umbilical vein endothelial (HUVEC) cells, and determined the potential promoter-specific disruption of CYP19 expression by atrazine and the commonly used neonicotinoids imidacloprid, thiacloprid, and thiamethoxam. In H295R cells, atrazine concentration-dependently increased PII- and I.3-mediated CYP19 expression and aromatase catalytic activity. Thiacloprid and thiamethoxam induced PII- and I.3-mediated CYP19 expression and aromatase activity at relatively low concentrations (0.1-1.0 µM), exhibiting non-monotonic concentration-response curves with a decline in gene induction and catalytic activity at higher concentrations. In HUVEC cells, atrazine slightly induced overall (promoter-indistinct) CYP19 expression (30 µM) and aromatase activity (≥ 3 µM), without increasing I.1 promoter activity. None of the neonicotinoids increased CYP19 expression or aromatase activity in HUVEC cells. Considering the importance of promoter-specific (over)expression of CYP19 in disease (breast cancer) or during sensitive developmental periods (pregnancy), our newly developed RT-qPCR methods will be helpful tools in assessing the risk that neonicotinoids and other chemicals may pose to exposed women. © The Author 2015

  5. Thymoquinone Defeats Diabetes-Induced Testicular Damage in Rats Targeting Antioxidant, Inflammatory and Aromatase Expression

    Directory of Open Access Journals (Sweden)

    Mustafa S. Atta

    2017-04-01

    Full Text Available Antioxidants have valuable effects on the process of spermatogenesis, particularly with diabetes mellitus (DM. Therefore, the present study investigated the impact and the intracellular mechanisms by which thymoquinone (TQ works against diabetes-induced testicular deteriorations in rats. Wistar male rats (n = 60 were randomly allocated into four groups; Control, Diabetic (streptozotocin (STZ-treated rats where diabetes was induced by intraperitoneal injection of STZ, 65 mg/kg, Diabetic + TQ (diabetic rats treated with TQ (50 mg/kg orally once daily, and TQ (non-diabetic rats treated with TQ for 12 weeks. Results revealed that TQ significantly improved the sperm parameters with a reduction in nitric oxide (NO and malondialdehyde (MDA levels in testicular tissue. Also, it increased testicular reduced glutathione (GSH levels and superoxide dismutase (SOD activity. Interestingly, TQ induced downregulation of testicular inducible nitric oxide synthase (iNOS and nuclear factor kappa-B (NF-κB and significantly upregulated the aromatase protein expression levels in testicles in comparison with the diabetic rats. In conclusion, TQ treatment exerted a protective effect against reproductive dysfunction induced by diabetes not only through its powerful antioxidant and hypoglycemic effects but also through its downregulation of testicular iNOS and NF-κB along with upregulation of aromatase expression levels in diabetic rats.

  6. Benzalacetone Synthase

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    Ikuro eAbe

    2012-03-01

    Full Text Available Benzalacetone synthase, from the medicinal plant Rheum palmatum (Polygonaceae (RpBAS, is a plant-specific chalcone synthase (CHS superfamily of type III polyketide synthase (PKS. RpBAS catalyzes the one-step, decarboxylative condensation of 4-coumaroyl-CoA with malonyl-CoA to produce the C6-C4 benzalacetone scaffold. The X-ray crystal structures of RpBAS confirmed that the diketide-forming activity is attributable to the characteristic substitution of the conserved active-site "gatekeeper" Phe with Leu. Furthermore, the crystal structures suggested that RpBAS employs novel catalytic machinery for the thioester bond cleavage of the enzyme-bound diketide intermediate and the final decarboxylation reaction to produce benzalacetone. Finally, by exploiting the remarkable substrate tolerance and catalytic versatility of RpBAS, precursor-directed biosynthesis efficiently generated chemically and structurally divergent, unnatural novel polyketide scaffolds. These findings provided a structural basis for the functional diversity of the type III PKS enzymes.

  7. Three-dimensional quantitative structure-activity relationships of steroid aromatase inhibitors

    Science.gov (United States)

    Oprea, Tudor I.; García, Angel E.

    1996-06-01

    Inhibition of aromatase, a cytochrome P450 that converts androgens to estrogens, is relevant in the therapeutic control of breast cancer. We investigate this inhibition using a three-dimensional quantitative structure-activity relationship (3D QSAR) method known as Comparative Molecular Field Analysis, CoMFA [Cramer III, R.D. et al., J. Am. Chem. Soc., 110 (1988) 5959]. We analyzed the data for 50 steroid inhibitors [Numazawa, M. et al., J. Med. Chem., 37 (1994) 2198, and references cited therein] assayed against androstenedione on human placental microsomes. An initial CoMFA resulted in a three-component model for log(1/Ki), with an explained variance r2 of 0.885, and a cross-validated q2 of 0.673. Chemometric studies were performed using GOLPE [Baroni, M. et al., Quant. Struct.-Act. Relatsh., 12 (1993) 9]. The CoMFA/GOLPE model is discussed in terms of robustness, predictivity, explanatory power and simplicity. After randomized exclusion of 25 or 10 compounds (repeated 25 times), the q2 for one component was 0.62 and 0.61, respectively, while r2 was 0.674. We demonstrate that the predictive r2 based on the mean activity (Ym) of the training set is misleading, while the test set Ym-based predictive r2 index gives a more accurate estimate of external predictivity. Using CoMFA, the observed differences in aromatase inhibition among C6-substituted steroids are rationalized at the atomic level. The CoMFA fields are consistent with known, potent inhibitors of aromatase, not included in the model. When positioned in the same alignment, these compounds have distinct features that overlap with the steric and electrostatic fields obtained in the CoMFA model. The presence of two hydrophobic binding pockets near the aromatase active site is discussed: a steric bulk tolerant one, common for C4, C6-alpha and C7-alpha substitutents, and a smaller one at the C6-beta region.

  8. Sex-Dependent Regulation of Aromatase-Mediated Synaptic Plasticity in the Basolateral Amygdala.

    Science.gov (United States)

    Bender, Roland A; Zhou, Lepu; Vierk, Ricardo; Brandt, Nicola; Keller, Alexander; Gee, Christine E; Schäfer, Michael K E; Rune, Gabriele M

    2017-02-08

    The basolateral amygdala (BLA) integrates sensory input from cortical and subcortical regions, a function that requires marked synaptic plasticity. Here we provide evidence that cytochrome P450 aromatase (AROM), the enzyme converting testosterone to 17β-estradiol (E2), contributes to the regulation of this plasticity in a sex-specific manner. We show that AROM is expressed in the BLA, particularly in the basolateral nucleus (BL), in male and female rodents. Systemic administration of the AROM inhibitor letrozole reduced spine synapse density in the BL of adult female mice but not in the BL of male mice. Similarly, in organotypic corticoamygdalar slice cultures from immature rats, treatment with letrozole significantly reduced spine synapses in the BL only in cultures derived from females. In addition, letrozole sex-specifically altered synaptic properties in the BL: in acute slices from juvenile (prepubertal) female rats, wash-in of letrozole virtually abolished long-term potentiation (LTP), whereas it did not prevent the generation of LTP in the slices from males. Together, these data indicate that neuron-derived E2 modulates synaptic plasticity in rodent BLA sex-dependently. As protein expression levels of AROM, estrogen and androgen receptors did not differ between males and females and were not sex-specifically altered by letrozole, the findings suggest sex-specific mechanisms of E2 signaling. SIGNIFICANCE STATEMENT The basolateral amygdala (BLA) is a key structure of the fear circuit. This research reveals a sexually dimorphic regulation of synaptic plasticity in the BLA involving neuronal aromatase, which produces the neurosteroid 17β-estradiol (E2). As male and female neurons in rodent BLA responded differently to aromatase inhibition both in vivo and in vitro , our findings suggest that E2 signaling in BLA neurons is regulated sex-dependently, presumably via mechanisms that have been established during sexual determination. These findings could be

  9. Effects of the aromatase inhibitor Letrozole on serum immunoglobulin and lysozyme levels in immunized rainbow trout (Oncorhynchus mykiss Walbaum females

    Directory of Open Access Journals (Sweden)

    Paria Akbary

    2013-12-01

    Full Text Available Letrozole is a synthetic aromatase inhibitor and interfere in the committed step in the synthesis of endogenous estrogens from androgens. Also estrogens regulate the immune system in teleost. Changes of 17- β- esrtradiol (E2, serum immunoglobulin and lysozyme levels were measured using a method based on the ability of lysozyme to lyse the bacterium Micrococcus lysodeikticus, enzyme-linked immunosorbent assay (ELISA and ELISA respectively. Twelve broodstocks were injected weekly with 2.5 mg kg-1 letrozole (an endocrine disrupter component two months before spawning season and vaccinated intraperitoneally (i.p with a bacterin (inactivated L. garviae one month before spawning. Twelve broodstocks for vaccination and twelve female rainbow trout as control group were also immiunised (i.p with the bacterin and injected (i.p with PBS, respectively. In the group received 2.5 mg AI kg-1 per week, serum E2 levels were significantly lower than that of other groups. Total immunoglobulin level and lysozyme activity were significantly higher in the parents received 2.5 mg kg-1 per week and were immunized with 10-9 cells ml-1 Lactococcus garvieae  compared to the group which immunized with L. garvieae and the control (non- immunized. The present study, suggests that aromatase inhibitors such as letrozole may be a potential tool to regulate the synthesis of E2, is involved in the hormone- immune system interaction in rainbow trout.

  10. Estrogen and Bazedoxifene

    Science.gov (United States)

    ... medications called estrogen agonist–antagonists. Estrogen works by replacing estrogen that is normally produced by the body. ... eat large amounts of grapefruit or drink grapefruit juice while taking this medication.

  11. The SEEM: selective estrogen enzyme modulators in breast cancer.

    Science.gov (United States)

    Pasqualini, J R; Ebert, C; Chetrite, G S

    1999-12-01

    Human breast cancer tissue contains all the enzymes (estrone sulfatase, 17 beta-hydroxysteroid dehydrogenase, aromatase) involved in the last steps of estradiol biosynthesis. This tissue also contains sulfotransferase for the formation of the biologically inactive estrogen sulfates. In the past years, it has been demonstrated that various progestins (promegestone, nomegestrol acetate, medrogestone) as well as tibolone and its metabolites are potent inhibitors of sulfatase and 17 beta-hydroxysteroid dehydrogenase activities. It was also shown that medrogestone, nomegestrol acetate, promegestone or tibolone can stimulate the sulfotransferase activity for the local production of estrogen sulfates. All these data, in addition to numerous agents which can block the aromatase action, lead to the new concept of Selective Estrogen Enzyme Modulators (SEEM) which can largely apply to breast cancer tissue. The exploration of various progestins and other active agents in trials with breast cancer patients, showing an inhibitory effect on sulfatase and 17 beta-hydroxysteroid dehydrogenase, or a stimulatory effect on sulfotransferase, will provide a new option in the treatment of this disease.

  12. Aromatase inhibition by 4 beta,5 beta-epoxides of 16 alpha-hydroxyandrostenedione and its 19-oxygenated analogs, potential precursors of estriol production in the feto-placental unit.

    Science.gov (United States)

    Numazawa, Mitsuteru; Yoshimura, Akiko; Watari, Yoko; Matsuzaki, Hisao

    2002-12-01

    To gain insight into the nature of the substrate binding site and the catalytic function of aromatase, we studied the inhibition of androstenedione aromatization by 4beta,5beta-epoxy-16alpha-hydroxyandrostenedione (4) and its 19-hydroxy and 19-oxo derivatives, 5 and 6, as well as the biochemical aromatization of these steroids in human placental microsomes. The 19-methyl and 19-oxo compounds, 4 and 6, were weak competitive inhibitors of aromatase, with apparent K(i) values of 246 microM and 270 microM, respectively, whereas the 19-hydroxy compound 5 inhibited aromatase in a non-competitive manner with the K(i) of 135 microM. The 19-methyl compound 4 inactivated aromatase in a time-dependent manner with k(inact) of 0.213 min(-1) in the presence of NADPH in air, but the other two did not cause it. The conversion of the three epoxides into estrogen, as well as 19-oxygenation of 19-methyl steroid 4 with human placental microsomes in the presence of NADPH in air, were not detected by gas chromatography-mass spectrometry. The present results are consistent with the two binding sites theory in the active site of aromatase.

  13. Estrogen, Progesterone and Epithelial Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Ho Shuk-Mei

    2003-10-01

    Full Text Available Abstract Ovarian carcinoma (OCa continues to be the leading cause of death due to gynecologic malignancies and the vast majority of OCa is derived from the ovarian surface epithelium (OSE and its cystic derivatives. Epidemiological evidence strongly suggests that steroid hormones, primarily estrogens and progesterone, are implicated in ovarian carcinogenesis. However, it has proved difficult to fully understand their mechanisms of action on the tumorigenic process. New convincing data have indicated that estrogens favor neoplastic transformation of the OSE while progesterone offers protection against OCa development. Specifically, estrogens, particularly those present in ovulatory follicles, are both genotoxic and mitogenic to OSE cells. In contrast, pregnancy-equivalent levels progesterone are highly effective as apoptosis inducers for OSE and OCa cells. In this regard, high-dose progestin may exert an exfoliation effect and rid an aged OSE of pre-malignant cells. A limited number of clinical studies has demonstrated efficacies of antiestrogens, aromatase inhibitors, and progestins alone or in combination with chemotherapeutic drugs in the treatment of OCa. As a result of increased life expectancy in most countries, the number of women taking hormone replacement therapies (HRT continues to grow. Thus, knowledge of the mechanism of action of steroid hormones on the OSE and OCa is of paramount significance to HRT risk assessment and to the development of novel therapies for the prevention and treatment of OCa.

  14. 6beta,19-Bridged androstenedione analogs as aromatase inhibitors.

    Science.gov (United States)

    Komatsu, Sachiko; Yaguchi, Ayaka; Yamashita, Kouwa; Nagaoka, Masao; Numazawa, Mitsuteru

    2009-11-01

    Inhibition of aromatase is an efficient approach for the prevention and treatment of breast cancer. New 6beta,19-bridged steroid analogs of androstenedione, 6beta,19-epithio- and 6beta,19-methano compounds 11 and 17, were synthesized starting from 19-hydroxyandrostenedione (6) and 19-formylandrost-5-ene-3beta,17beta-yl diacetate (12), respectively, as aromatase inhibitors. All of the compounds including known steroids 6beta,19-epoxyandrostenedione (4) and 6beta,19-cycloandrostenedione (5) tested were weak to poor competitive inhibitors of aromatase and, among them, 6beta,19-epoxy steroid 4 provided only moderate inhibition (K(i): 2.2 microM). These results show that the 6beta,19-bridged groups of the inhibitors interfere with binding in active site of aromatase.

  15. Use of the granulosa cell aromatase bioassay for measurement of bioactive follicle-stimulating hormone in urine and serum samples of diverse species.

    Science.gov (United States)

    Dahl, K D; Hsueh, A J

    1987-01-01

    Ovarian steroids and growth factors are intragonadal modulators which augment a key endpoint of follicle-stimulating hormone (FSH) action in granulosa cells: the induction of aromatase activity. Studies of these paracrine hormones that enhance FSH-stimulated estrogen biosynthesis by cultured rat granulosa cells, have led to the development of a sensitive and specific in vitro bioassay for FSH. This newly developed granulosa cell aromatase bioassay (GAB) allows for the measurement of bioactive FSH levels in serum and urine of humans and animals with various physiological and pathological conditions. These studies have demonstrated that the GAB assay is useful in detecting possible changes in the molecular forms of FSH. The adaptation of this method for urine samples allows for the measurement of bio-FSH levels in situations where venipuncture is not practical or in species for which specific radioimmunoassays are not available.

  16. The anti-aromatase effect of progesterone and of its natural metabolites 20alpha- and 5alpha-dihydroprogesterone in the MCF-7aro breast cancer cell line.

    Science.gov (United States)

    Pasqualini, J R; Chetrite, G

    2008-01-01

    Progesterone is metabolized in the normal breast mainly into 4-ene-pregnenes (e.g. 20alpha-dihydroprogesterone, 20alphaDHP) but, in contrast, in breast cancer tissue the 5alpha-dihydropregnanes (e.g. 5alpha-dihydroprogesterone, 5alphaDHP) are prevalent. In the present study the effect of progesterone and its main metabolites 20alphaDHP and 5alphaDHP on the aromatase activity in a stable aromatase-expressing estrogen receptor-positive human breast cancer cell line, MCF-7aro, was explored. The MCF-7aro cells were stripped of endogenous steroids and incubated with physiological concentrations of [3H]-testosterone ([3H]-testos: 5 x 10(-9)M) alone or in the presence of progesterone, 20alphaDHP or 5alphaDHP (5 x 10(-6) or 5 x 10(-8)M) for 24 h at 37 degrees C. The cellular radioactivity uptake was determined in the ethanolic supernatant and the DNA content in the remaining pellet. [3H]-Estradiol (E2), [3H]-estrone (E1) and [3H]-testos were characterized by thin layer chromatography and quantified using the corresponding standard. Aromatase activity was present at a high level in the MCF-7aro cells after incubation with [3H]-testos when the concentration of [3H]-E2 was 3.70 pmol/mg DNA; 20alphaDHP at concentrations of 5 x 10(-6)M or 5 x 10(-8)M significantly inhibited this conversion by 50.3% and 36.5%, respectively. No significant effect was found with the metabolite 5alphaDHP or the parent hormone, progesterone. The MCF-7aro cell line shows high detectable aromatase activity. The present data indicate that the progesterone metabolite 20alphaDHP, found mainly in normal breast tissue, can act as an anti-aromatase agent.

  17. Androgens and estrogens in benign prostatic hyperplasia: past, present and future

    Science.gov (United States)

    Nicholson, Tristan M.; Ricke, William A.

    2011-01-01

    Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) are common clinical problems in urology. While the precise molecular etiology remains unclear, sex steroids have been implicated in the development and maintenance of BPH. Sufficient data exists linking androgens and androgen receptor pathways to BPH and use of androgen reducing compounds, such as 5α-reductase inhibitors which block the conversion of testosterone into dihydrotestosterone, are a component of the standard of care for men with LUTS attributed to an enlarged prostate. However, BPH is a multifactorial disease and not all men respond well to currently available treatments, suggesting factors other than androgens are involved. Testosterone, the primary circulating androgen in men, can also be metabolized via CYP19/aromatase into the potent estrogen, estradiol-17β. The prostate is an estrogen target tissue and estrogens directly and indirectly affect growth and differentiation of prostate. The precise role of endogenous and exogenous estrogens in directly affecting prostate growth and differentiation in the context of BPH is an understudied area. Estrogens and selective estrogen receptor modulators (SERMs) have been shown to promote or inhibit prostate proliferation signifying potential roles in BPH. Recent research has demonstrated that estrogen receptor signaling pathways may be important in the development and maintenance of BPH and LUTS; however, new models are needed to genetically dissect estrogen regulated molecular mechanisms involved in BPH. More work is needed to identify estrogens and associated signaling pathways in BPH in order to target BPH with dietary and therapeutic SERMs. PMID:21620560

  18. Genome-wide epigenetic profiling of breast cancer tumors treated with aromatase inhibitors

    Directory of Open Access Journals (Sweden)

    Ekaterina Nevedomskaya

    2014-12-01

    Full Text Available Aromatase inhibitors (AI are extensively used in the treatment of estrogen receptor-positive breast cancers, however resistance to AI treatment is commonly observed. Apart from Estrogen receptor (ERα expression, no predictive biomarkers for response to AI treatment are clinically applied. Yet, since other therapeutic options exist in the clinic, such as tamoxifen, there is an urgent medical need for the development of treatment-selective biomarkers, enabling personalized endocrine treatment selection in breast cancer. In the described dataset, ERα chromatin binding and histone marks H3K4me3 and H3K27me3 were assessed in a genome-wide manner by Chromatin Immunoprecipitation (ChIP combined with massive parallel sequencing (ChIP-seq. These datasets were used to develop a classifier to stratify breast cancer patients on outcome after AI treatment in the metastatic setting. Here we describe in detail the data and quality control metrics, as well as the clinical information associated with the study, published by Jansen et al. [1]. The data is publicly available through the GEO database with accession number GSE40867.

  19. Estrogenic effects in vitro and in vivo of the fungicide fenarimol

    DEFF Research Database (Denmark)

    Andersen, Helle Raun; Bonefeld-Jørgensen, Eva C.; Nielsen, Flemming

    2006-01-01

    in fenarimol-treated animals. To our knowledge, only two other pesticides (o.p-DDT and methoxychlor) have previously been reported to induce an estrogenic response in the rodent uterotrophic bioassay. A pronounced xenoestrogenicity in serum samples from rats treated with fenarimol and estradiol benzoate (E2B......) separately or in combination was observed, demonstrating the usefulness of this approach for estimating the integrated internal exposure to xenoestrogens. The MCF-7 cell proliferation assay was used to investigate further the dose-response curves for the estrogenic, antiestrogenic, and aromatase inhibiting...

  20. Testosterone Represses Estrogen Signaling by Upregulating miR-22: A Mechanism for Imbalanced Steroid Hormone Production in Preeclampsia.

    Science.gov (United States)

    Shao, Xuan; Liu, Yanlei; Liu, Ming; Wang, Yongqing; Yan, Liying; Wang, Hao; Ma, Liyang; Li, Yu-Xia; Zhao, Yangyu; Wang, Yan-Ling

    2017-04-01

    Preeclampsia, a multisystem syndrome occurring during mid- to late gestation in humans, is a leading cause of maternal and perinatal morbidity and mortality. Patients usually present with high circulating testosterone and reduced estradiol production, but the mechanisms remain unclear. Revealing the mechanism that modulating the imbalance of testosterone and estradiol in preeclampsia is of great value in understanding the cause of the disease. The placenta is the predominant source of steroid hormone production during gestation, and we observed markedly increased 17β-HSD3 (17β-hydroxysteroid dehydrogenase 3) levels and downregulated aromatase expression, the key enzymes responsible for synthesis of testosterone and estradiol, respectively, in preeclamptic placentas compared with controls. Furthermore, we found a significant upregulation of microRNA (miR)-22 in preeclamptic placentas. In a trophoblast cell line, JEG-3 cells, testosterone repressed the expression of aromatase and estrogen receptor α and the production of estradiol while promoting miR-22 expression. miR-22 directly targeted and inhibited estrogen receptor α expression while indirectly decreasing aromatase expression and estradiol production by interfering with estrogen receptor α signaling. Furthermore, inhibition of miR-22 expression significantly reversed the inhibitory effect of testosterone on de novo estradiol synthesis in human trophoblastic cells. The findings reveal a mechanism underlying the balanced production of androgen and estrogen modulated by miR-22 in the human placenta and provide new insights into the pathogenesis of preeclampsia from the aspect of endocrine regulation. © 2017 American Heart Association, Inc.

  1. Screening of selected pesticides for inhibition of CYP19 aromatase activity in vitro

    DEFF Research Database (Denmark)

    Vinggaard, A.M.; Hnida, C.; Breinholt, V.

    2000-01-01

    than 50 mu M. The positive control 4-hydroxyandrostendione (1 mu M) caused an inhibition of aromatase activity by 74%. The compounds, which did not affect the aromatase activity, were bromopropylate, chlorfenvinphos. chlorobenzilate, chlorpyrifos, diuron, heptachlor, iprodion, linuron, pentachlorphenol...

  2. [Effects of aromatase inhibitor on sexual differentiation of SDN-POA in rats].

    Science.gov (United States)

    Ohe, E

    1994-03-01

    The sexually dimorphic nucleus of the preoptic area (SDN-POA) of male rats is larger than that of females, the difference being caused by the perinatal effect of estrogen converted from androgen. To investigate the role of estrogen formation in the SDN-POA during the critical period of this sexual differentiation, CGS16949A (0.5 mg/kg, sc) was injected into the mothers in the late gestational age(F) or into neonates for 14 days from birth(N). Animals were sacrificed on the 20th. day of gestation and 7 days after birth, and fetal and neonatal brain aromatase activities (AA) as well as serum levels of testosterone(T) and corticosterone(B) were measured. On the 30th day after birth, the offspring of treated mothers and neonatally treated rats were sacrificed and the cross-sectional areas of the SDN-POA were evaluated by image processor NEXUS 6800. In group F, CGS16949A markedly suppressed brain AA in vitro (fetal hypothalamus: IC50 1.4nM) and in vivo in both the hypothalamus and amygdala. However, the levels of T and B did not show any significant change in group F. The same depression of AA was also observed in group N on the 7th day after birth. In CGS-treated males in groups F and N, the SDN-POA area markedly decreased to that of control females. The area in males in group F was not significantly different from that in females. These results suggest that estrogen converted from androgen plays a dominant role in the development of sexual dimorphism of the SDN-POA, and that the brain AA in the pre- and postnatal period is important in this process.

  3. Comparison of the effect of cortisol on aromatase activity and androgen metabolism in two human fibroblast cell lines derived from the same individual

    DEFF Research Database (Denmark)

    Svenstrup, B; Brünner, N; Dombernowsky, P

    1990-01-01

    The effect of preincubation with cortisol on estrogen and androgen metabolism was investigated in human fibroblast monolayers grown from biopsies of genital and non-genital skin of the same person. The activity in the cells of aromatase, 5 alpha-reductase, 17 beta-hydroxysteroid oxidoreductase...... and 3 alpha-hydroxysteroid oxidoreductase was investigated by isolating estrone, estradiol, estriol, dihydrotestosterone, androstanedione, androsterone, 3 alpha-androstanediol, testosterone and androstenedione after incubation of the cells with [14C]testosterone or [14C]androstenedione. For experiments...

  4. Aromatase inhibitors, efficacy and metabolic risk in the treatment of postmenopausal women with early breast cancer

    Directory of Open Access Journals (Sweden)

    Stefano Gonnelli

    2008-12-01

    Full Text Available Stefano Gonnelli1, Roberto Petrioli21Department of Internal Medicine, Endocrine-Metabolic Science and Biochemistry, University of Siena, Italy (Dir. R. Nuti.; 2Department of Human Pathology and Oncology, Medical Oncology Section, University of Siena, Italy (Dir. G. FranciniAbstract: The third-generation aromatase inhibitors (AIs, letrozole, anastrozole and exemestane, are becoming the first choice endocrine drugs for post-menopausal women with breast cancer, since they present greater efficacy when compared with tamoxifen in both adjuvant and metastatic setting. In particular, several large and well designed trials have suggested an important role for AIs in the adjuvant treatment of postmenopausal women with estrogen-receptor positive breast cancer either in the upfront, sequential or extended adjuvant mode. Overall, AIs are associated with a small but significant improvement in disease free survival. The expanding use of AIs in the treatment of early breast cancer means that individual patients will be exposed to the agents for longer durations, making it increasingly important to establish their long-term safety. This review focused on the effects of AIs on bone metabolism, serum lipids and cardiovascular risk. AIs have adverse effects on bone turnover with a reduction of bone mineral density and an increase in the rate of fragility fractures. With respect to tamoxifen AIs present lower thrombotic risk and a less favorable impact on lipid profile, whereas the true effects on cardiovascular risk still remain to be clarified. An adequate monitoring of bone mineral density (BMD and lipid profile could be recommended for post-menopausal women candidate to AIs.Keywords: breast cancer, aromatase inhibitors, bone loss, lipids, cardiovascular risk

  5. CYP11A1 expression in bone is associated with aromatase inhibitor-related bone loss.

    Science.gov (United States)

    Rodríguez-Sanz, M; García-Giralt, N; Prieto-Alhambra, D; Servitja, S; Balcells, S; Pecorelli, R; Díez-Pérez, A; Grinberg, D; Tusquets, I; Nogués, X

    2015-08-01

    Aromatase inhibitors (AIs) used as adjuvant therapy in postmenopausal women with hormone receptor-positive breast cancer cause diverse musculoskeletal side effects that include bone loss and its associated fracture. About half of the 391 patients treated with AIs in the Barcelona-Aromatase induced bone loss in early breast cancer cohort suffered a significant bone loss at lumbar spine (LS) and/or femoral neck (FN) after 2 years on AI-treatment. In contrast, up to one-third (19.6% LS, 38.6% FN) showed no decline or even increased bone density. The present study aimed to determine the genetic basis for this variability. SNPs in candidate genes involved in vitamin D and estrogen hormone-response pathways (CYP11A1, CYP17A1, HSD3B2, HSD17B3, CYP19A1, CYP2C19, CYP2C9, ESR1, DHCR7, GC, CYP2R1, CYP27B1, VDR and CYP24A1) were genotyped for association analysis with AI-related bone loss (AIBL). After multiple testing correction, 3 tag-SNPs (rs4077581, s11632698 and rs900798) located in the CYP11A1 gene were significantly associated (Pbone tissue and primary osteoblasts was demonstrated by RT-PCR. Both common isoforms of human cholesterol side-chain cleavage enzyme (encoded by CYP11A1 gene) were detected in osteoblasts by western blot. In conclusion, the genetic association of CYP11A1 gene with AIBL and its expression in bone tissue reveals a potential local function of this enzyme in bone metabolism regulation, offering a new vision of the steroidogenic ability of this tissue and new understanding of AI-induced bone loss. © 2015 Society for Endocrinology.

  6. Estrogen, Estrogen Receptor and Lung Cancer

    Directory of Open Access Journals (Sweden)

    Li-Han Hsu

    2017-08-01

    Full Text Available Estrogen has been postulated as a contributor for lung cancer development and progression. We reviewed the current knowledge about the expression and prognostic implications of the estrogen receptors (ER in lung cancer, the effect and signaling pathway of estrogen on lung cancer, the hormone replacement therapy and lung cancer risk and survival, the mechanistic relationship between the ER and the epidermal growth factor receptor (EGFR, and the relevant clinical trials combining the ER antagonist and the EGFR antagonist, to investigate the role of estrogen in lung cancer. Estrogen and its receptor have the potential to become a prognosticator and a therapeutic target in lung cancer. On the other hand, tobacco smoking aggravates the effect of estrogen and endocrine disruptive chemicals from the environment targeting ER may well contribute to the lung carcinogenesis. They have gradually become important issues in the course of preventive medicine.

  7. Studies on estrogen biosynthesis using radioactive and stable isotopes

    International Nuclear Information System (INIS)

    Wright, J.N.; Akhtar, M.

    1990-01-01

    The conversion of androgens into estrogen involves three distinct generic reactions which are catalyzed by a single P450 enzyme (aromatase or P450(aromatase)). The first step in the process is the conversion of 19-methyl into a hydroxymethyl group which requires NADPH + O2, thus representing the well-known hydroxylation process. The next stage, converting the -CH2OH into -CHO, also requires NADPH + O2 and may be rationalized either through a second hydroxylation reaction producing a gem-diol, CH(OH)2 (which dehydrates to the aldehyde), or via another route. The final stage in the process again uses NADPH + O2, culminating in the release of C-19 as formate. Our extensive studies using precursors containing 2H, 3H, and 18O have shown that the carbonyl oxygen of the 19-aldehyde group is the one that was introduced in the first step as the hydroxyl group. The aldehydic oxygen along with another, from O2, used in the third step of the process, is incorporated into the released formate. It was found that at each stage of the process, oxygen atoms were introduced or transferred as whole numbers. In light of these data, mechanisms in which H2O is used to promote the C-10-C-19 bond cleavage or those in which the conversion of the 19-oxoandrostenedione into estrogen is considered to occur via the sequence -CHO----(-)CH(OH)2----estrogen are eliminated. In addition, our mechanistic analysis makes it unlikely that 1 beta-, 2 beta-, or 10 beta-hydroxysteroids serve as intermediates in estrogen biosynthesis. We consider a free radical mechanism for the hydroxylation process. 40 references

  8. Abnormal lipid/lipoprotein metabolism and high plasma testosterone levels in male but not female aromatase-knockout mice.

    Science.gov (United States)

    Amano, Akiko; Kondo, Yoshitaka; Noda, Yoshihiro; Ohta, Mitsuhiro; Kawanishi, Noriaki; Machida, Shuichi; Mitsuhashi, Kazuteru; Senmaru, Takafumi; Fukui, Michiaki; Takaoka, Osamu; Mori, Taisuke; Kitawaki, Jo; Ono, Masafumi; Saibara, Toshiji; Obayashi, Hiroshi; Ishigami, Akihito

    2017-05-15

    Sex steroid hormones, such as estrogen and testosterone, are believed to play important roles in lipid metabolism. To elucidate the effects of estrogen depletion on lipid metabolism in male and female mice, we used aromatase-knockout (ArKO) mice, in which Cyp19 gene disruption prevented estrogen synthesis in vivo. These mice were divided into the following 4 groups: male and female ArKO mice and male and female wild-type (WT) mice. These mice were fed a normal-fat diet (13.6% fat) ad libitum. At 159 days after birth, the mice were tested for liver and plasma lipid content and hepatic hormone receptor- and lipid/lipoprotein metabolism-related gene expression. Interestingly, we found that hepatic steatosis was accompanied by markedly elevated plasma testosterone levels in male ArKO mice but not in female ArKO mice. Plasma lipoprotein profiles exhibited concurrent decreases in LDL- and small dense LDL-triglyceride (TG) levels in male ArKO mice. Moreover, male mice, but not female mice, exhibited marked elevations in androgen receptor (AR), sterol regulatory element-binding protein 1 (SREBP1), and CD36 expression. These results strongly suggest that Cyp19 gene disruption, which induces a sexually dimorphic response and high plasma testosterone levels in male mice, also induces hepatic steatosis. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Androgens and estrogens in skeletal sexual dimorphism

    Science.gov (United States)

    Laurent, Michaël; Antonio, Leen; Sinnesael, Mieke; Dubois, Vanessa; Gielen, Evelien; Classens, Frank; Vanderschueren, Dirk

    2014-01-01

    Bone is an endocrine tissue expressing androgen and estrogen receptors as well as steroid metabolizing enzymes. The bioactivity of circulating sex steroids is modulated by sex hormone-binding globulin and local conversion in bone tissue, for example, from testosterone (T) to estradiol (E2) by aromatase, or to dihydrotestosterone by 5α-reductase enzymes. Our understanding of the structural basis for gender differences in bone strength has advanced considerably over recent years due to increasing use of (high resolution) peripheral computed tomography. These microarchitectural insights form the basis to understand sex steroid influences on male peak bone mass and turnover in cortical vs trabecular bone. Recent studies using Cre/LoxP technology have further refined our mechanistic insights from global knockout mice into the direct contributions of sex steroids and their respective nuclear receptors in osteoblasts, osteoclasts, osteocytes, and other cells to male osteoporosis. At the same time, these studies have reinforced the notion that androgen and estrogen deficiency have both direct and pleiotropic effects via interaction with, for example, insulin-like growth factor 1, inflammation, oxidative stress, central nervous system control of bone metabolism, adaptation to mechanical loading, etc., This review will summarize recent advances on these issues in the field of sex steroid actions in male bone homeostasis. PMID:24385015

  10. Social interaction influences blood cortisol values and brain aromatase genes in the protandrous false clown anemonefish, Amphiprion ocellaris.

    Science.gov (United States)

    Iwata, Eri; Mikami, Kyohei; Manbo, Jun; Moriya-Ito, Keiko; Sasaki, Hideaki

    2012-12-01

    Anemonefish, Amphiprion spp., are socially controlled, protandrous sex changers with a monogamous mating system. Under certain conditions, sexually immature anemonefish with ambisexual gonads differentiate directly into males or females. Formation and maintenance of social rank in a group are considered key requirements for the induction of sex change or differentiation. Generally, each animal living in a social group experiences a different level of social stress in accordance with its social rank, and we hypothesize that the stress situation of individual anemonefish influences its sex determination. Groups of three sexually immature anemonefish were placed into each of five experimental tanks and kept for 10 days to allow for social rank formation and behavioral observation. The fish were then euthanized, and blood and brain samples were collected from each fish. The social rank of each individual was distinguishable from day 1 of the experiment. Aggressive behaviors were most frequent and blood Cortisol values were higher in dominant individuals. The transcription of mRNA for stress-related genes, i.e., those encoding for glucocorticoid and arginine vasotocin receptors, was higher in the brains of dominant individuals than in other social ranks. Furthermore, we detected higher transcription levels of gonad and brain aromatase genes, which encode the enzyme that converts androgens into estrogens, in the brains of dominant individuals. These results suggest that social rank reflects the blood Cortisol value, which in turn leads to sex differentiation by manipulating transcription of genes, including aromatase genes, in the brain.

  11. Estrogens and aging skin

    OpenAIRE

    Thornton, M. Julie

    2013-01-01

    Estrogen deficiency following menopause results in atrophic skin changes and acceleration of skin aging. Estrogens significantly modulate skin physiology, targeting keratinocytes, fibroblasts, melanocytes, hair follicles and sebaceous glands, and improve angiogenesis, wound healing and immune responses. Estrogen insufficiency decreases defense against oxidative stress; skin becomes thinner with less collagen, decreased elasticity, increased wrinkling, increased dryness and reduced vascularity...

  12. High progesterone levels during the luteal phase related to the use of an aromatase inhibitor in breast cancer patients

    DEFF Research Database (Denmark)

    Alviggi, C; Marci, R; Vallone, R

    2017-01-01

    cancer, several studies have demonstrated that progesterone could expand a transformation-sensitive stem cell population in the mammary glands. The estrogen negative feedback effect on the hypothalamus-pituitary axis and the disruption of steroid biosynthesis and could represent an intriguing reason......OBJECTIVE: To evaluate the hormonal profile in three breast cancer patients who underwent controlled ovarian stimulation in the presence of the aromatase inhibitor letrozole. PATIENTS AND METHODS: In IVF University referral center, a case series of three breast cancer patients who underwent...... behind this phenomenon. Our results highlight the need to evaluate further the increase in progesterone levels in the luteal phase in women with breast cancer undergoing COS with letrozole....

  13. A positive feedback pathway of estrogen biosynthesis in breast cancer cells is contained by resveratrol

    International Nuclear Information System (INIS)

    Wang Yun; Ye Lan; Leung, Lai K.

    2008-01-01

    Cytochrome P450 (CYP) 19 enzyme or aromatase catalyses the rate-determining step of estrogen synthesis. The transcriptional control of CYP19 gene is highly specific in different cell types, for instance, Promoter I.3/II is commonly used for regulation in breast cancer cells. Recently, a positive feedback pathway for estrogen synthesis has been identified in ERα expressing SK-BR-3 cells. CYP19 mRNA abundance and activity are increased in this pathway and the promoter usage is switched from Promoter I.3/II to I.1 through a non-genomic process. In the present study, effect of the phytocompound resveratrol on this Promoter I.1-controlled expression of aromatase was investigated. Results indicated that resveratrol reduced the estradiol-induced mRNA abundance in SK-BR-3 cells expressing ERα. Luciferase reporter gene assays revealed that resveratrol could also repress the transcriptional control dictated by Promoter I.1. Since the ERE-driven luciferase activity was not repressed by resveratrol, the nuclear events of estrogen were unlikely to be suppressed by resveratrol. Instead the phytochemical reduced the amount of ERK activated by estradiol, which could be the pathway responsible for Promoter I.1 transactivation and the induced CYP19 expression. The present study illustrated that resveratrol impeded the non-genomic induction of estrogen on CYP19

  14. Effects of low dose treatment of tributyltin on the regulation of estrogen receptor functions in MCF-7 cells

    Energy Technology Data Exchange (ETDEWEB)

    Sharan, Shruti; Nikhil, Kumar; Roy, Partha, E-mail: paroyfbs@iitr.ernet.in

    2013-06-01

    Endocrine disrupting chemicals are the natural/synthetic compounds which mimic or inhibit the actions of endogenous hormones. Organotin compounds, such as tributyltin (TBT) are typical environmental contaminants and suspected endocrine-disrupting chemical. The present study evaluates the estrogenic potential of this compound in vitro in ER (+) breast adenocarcinoma, MCF-7 cell line. Our data showed that tributyltin chloride (TBTCl) had agonistic activities for estrogen receptor-α (ER-α). Its estrogenic potential was checked using cell proliferation assay, aromatase assay, transactivation assay, and protein expression analysis. Low dose treatment of TBTCl had a proliferative effect on MCF-7 cells and resulted in up-regulation of aromatase enzyme activity and enhanced estradiol production in MCF-7 cells. Immunofluorescence staining showed translocation of ER-α from cytoplasm to nucleus and increased expression of ER-α, 3β-HSD and aromatase on treatment with increasing doses of TBTCl. Further, to decipher the probable signaling pathways involved in its action, the MCF-7 cells were transfected with different pathway dependent luciferase reporter plasmids (CRE, SRE, NF-κB and AP1). A significant increase in CRE and SRE and decrease in NF-κB regulated pathway were observed (p < 0.05). Our results thus showed that the activation of SRE by TBTCl may be due to ligand dependent ER-α activation of the MAPK pathway and increased phosphorylation of ERK. In summary, the present data suggests that low dose of tributyltin genomically and non-genomically augmented estrogen dependent signaling by targeting various pathways. - Highlights: • Tributyltin chloride is agonistic to ER-α in MCF-7 cell line at low doses. • Tributyltin chloride up regulated aromatase activity and estradiol production. • Tributyltin chloride also activates MAPK pathway inducing ERK activation.

  15. Intratumoral estrogen production and actions in luminal A type invasive lobular and ductal carcinomas.

    Science.gov (United States)

    Takagi, Mayu; Miki, Yasuhiro; Miyashita, Minoru; Hata, Shuko; Yoda, Tomomi; Hirakawa, Hisashi; Sagara, Yasuaki; Rai, Yoshiaki; Ohi, Yasuyo; Tamaki, Kentaro; Ishida, Takanori; Suzuki, Takashi; Ouchi, Noriaki; Sasano, Hironobu

    2016-02-01

    The great majority of invasive lobular carcinoma (ILC) is estrogen-dependent luminal A type carcinoma but the details of estrogen actions and its intratumoral metabolism have not been well studied compared to invasive ductal carcinoma (IDC). We first immunolocalized estrogen-related enzymes including estrogen sulfotransferase (EST), estrogen sulfatase (STS), 17β-hydroxysteroid dehydrogenase (HSD) 1/2, and aromatase. We then evaluated the tissue concentrations of estrogens in ILC and IDC and subsequently estrogen-responsive gene profiles in these tumors in order to explore the possible differences and/or similarity of intratumoral estrogen environment of these two breast cancer subtypes. The status of STS and 17βHSD1 was significantly lower in ILCs than IDCs (p = 0.022 and p < 0.0001), but that of EST and 17βHSD2 vice versa (p < 0.0001 and p = 0.0106). In ILCs, tissue concentrations of estrone and estradiol were lower than those in IDCs (p = 0.0709 and 0.069). In addition, the great majority of estrogen response genes tended to be lower in ILCs. Among those genes above, FOXP1 was significantly higher in ILCs than in IDCs (p = 0.002). FOXP1 expression was reported to be significantly higher in relapse-free IDC patients treated with tamoxifen. Therefore, tamoxifen may be considered an option of endocrine therapy for luminal A type ILC patients. This is the first study to demonstrate the detailed and comprehensive status of intratumoral production and metabolism of estrogens and the status of estrogen response genes in luminal A-like ILC with comparison to those in luminal A-like IDCs.

  16. Estrogen deficiency results in enhanced expression of Smoothened of the Hedgehog signaling in the thymus and affects thymocyte development.

    Science.gov (United States)

    Li, Chun-Lin; Toda, Katsumi; Saibara, Toshiji; Zhang, Ting; Ono, Masafumi; Iwasaki, Shinji; Maeda, Takashi; Okada, Teruhiko; Hayashi, Yoshihiro; Enzan, Hideaki; Shizuta, Yutaka; Onishi, Saburo

    2002-05-01

    Aromatase is an essential enzyme for estrogen synthesis. We investigated the role of estrogen in thymocyte development using aromatase-deficient (ArKO) mice. Like its role as a regulator of bone metabolism through regulating osteoprotegerin (OPG) production, estrogen is involved in the processes of thymocyte development although aromatase mRNA was not detectable in the thymus. Thymic regression and reduced cellularity were evident in ArKO mice. The major difficulties in thymocyte development of ArKO mice were observed during the CD44+ CD25- stage at the cortico-medullary junction and during the CD44- CD25- stage at the subcapsular region where the estrogen receptor was expressed in the stromal cells. The proportion of thymocytes during the CD44+ CD25- stage was reduced. The progression of CD44- CD25+ cells to the CD44- CD25- stage was accelerated in ArKO mice possibly due to insufficient osteoprotegerin production in estrogen-deficiency. However, the expression of Smoothened of the Hedgehog signaling was enhanced in CD4- CD8- double negative cells. This enhancement may result in impaired progression of CD44- CD25- cells to the CD4+ CD8+ double positive stage and impaired proliferation of CD4+ CD8+ double positive cells since Smoothened (Smo) is known to arrest cells as non-proliferating cells. This could be the reason why the proportion of CD3+ TCRbeta(high) cells during the late phase of thymocyte maturation was reduced in ArKO mice. From these observations, we propose that estrogen supports thymocyte development and maturation at many stages through many regulatory pathways including the sonic hedgehog- and the osteoprotegerin ligand (OPGL)-mediated signaling.

  17. Which patients benefit most from adjuvant aromatase inhibitors?

    DEFF Research Database (Denmark)

    Viale, G; Regan, M M; Dell'Orto, P

    2011-01-01

    On average, aromatase inhibitors are better than tamoxifen when used as initial or sequential therapy for postmenopausal women with endocrine-responsive early breast cancer. Because there may be contraindications to their use based on side-effects or cost, we investigated subgroups in which aroma...

  18. DNA methylation of the gonadal aromatase (cyp19a promoter is involved in temperature-dependent sex ratio shifts in the European sea bass.

    Directory of Open Access Journals (Sweden)

    Laia Navarro-Martín

    2011-12-01

    Full Text Available Sex ratio shifts in response to temperature are common in fish and reptiles. However, the mechanism linking temperature during early development and sex ratios has remained elusive. We show in the European sea bass (sb, a fish in which temperature effects on sex ratios are maximal before the gonads form, that juvenile males have double the DNA methylation levels of females in the promoter of gonadal aromatase (cyp19a, the enzyme that converts androgens into estrogens. Exposure to high temperature increased the cyp19a promoter methylation levels of females, indicating that induced-masculinization involves DNA methylation-mediated control of aromatase gene expression, with an observed inverse relationship between methylation levels and expression. Although different CpGs within the sb cyp19a promoter exhibited different sensitivity to temperature, we show that the increased methylation of the sb cyp19a promoter, which occurs in the gonads but not in the brain, is not a generalized effect of temperature. Importantly, these effects were also observed in sexually undifferentiated fish and were not altered by estrogen treatment. Thus, methylation of the sb cyp19a promoter is the cause of the lower expression of cyp19a in temperature-masculinized fish. In vitro, induced methylation of the sb cyp19a promoter suppressed the ability of SF-1 and Foxl2 to stimulate transcription. Finally, a CpG differentially methylated by temperature and adjacent to a Sox transcription factor binding site is conserved across species. Thus, DNA methylation of the aromatase promoter may be an essential component of the long-sought-after mechanism connecting environmental temperature and sex ratios in vertebrate species with temperature-dependent sex determination.

  19. Aromatase inhibitors for prevention of breast cancer in postmenopausal women: a narrative review.

    Science.gov (United States)

    Behan, Lucy Ann; Amir, Eitan; Casper, Robert F

    2015-03-01

    The increasing incidence of breast cancer (BC) worldwide has resulted in widespread interest in primary prevention therapies. A number of large randomized trials have shown that selective estrogen receptor modulators can reduce the relative risk for BC by 30% to 40% in high-risk women. In early-stage BC, aromatase inhibitors (AIs) showed a 35% relative reduction in the risk of contralateral BCs compared with tamoxifen. In this narrative review, we discuss the role of AIs in the primary prevention of BC and novel research on combination hormone therapy-medical therapy for the primary prevention of BC. Using PubMed/Medline, we comprehensively searched for studies of BC primary prevention using AIs, including studies of novel methods of prevention using combination hormone therapy-BC prevention. Two large multicenter, prospective, randomized, placebo-controlled trials have evaluated AIs--anastrozole (International Breast Cancer Intervention Study II) and exemestane (Mammary Prevention 3)--for BC risk reduction in women at increased risk for BC, which we summarize. We identified five studies (three completed and two ongoing) of combination AI-hormone therapy that are undergoing investigation for BC risk reduction. AIs are effective at BC risk reduction, although long-term follow-up data are required to assess whether this risk reduction will result in reduced mortality. Combination hormone therapy-AI for BC risk reduction is experimental and warrants further investigation.

  20. Expression of P450-aromatase in the goat placenta throughout pregnancy.

    Science.gov (United States)

    Mondragon, J A; Ocadiz-Delgado, R; Miranda, C; Valencia, J; Rosales, A M; Gariglio, P; Romano, M C

    2007-09-01

    The enzyme P450-aromatase (P450-Aro) is essential for the conversion of androgens to estrogens. The objective was to study the expression and distribution of P450-Aro in goat placentae throughout pregnancy. For this purpose, we used reverse transcription-polymerase chain reaction (RT-PCR) with primers derived from the ovarian cDNA sequence found by our group. The expression of P450-Aro mRNA was first detected by in vitro RT-PCR in cotyledons at 4 months and was still present at term. Based on in situ RT-PCR, cotyledon microvilli expressed P450-Aro mRNA early in pregnancy; the signal was detected in the syncytiotrophoblast and in non-fused cytotrophoblasts inside the microvilli, but was scarce in the interstitial cells of the villous core. In the last 2 months of pregnancy (including at term), the expression of P450-Aro mRNA was still detected in the syncytiotrophoblast. However, P450-Aro was never detected in the caruncule (regardless of stage of pregnancy). In conclusion, P450-Aro was expressed in the goat placenta microvilli starting early in pregnancy; the expression and distribution of the enzyme increased throughout pregnancy and was still present at term.

  1. Direct and indirect endocrine disruption : aromatase and estrogen receptor-mediated processes in breast cancer development

    NARCIS (Netherlands)

    Heneweer, Marjoke

    2005-01-01

    Endocrine disrupting chemicals (EDCs) have been defined by the World Health Organization as: “exogenous substances or mixtures that alters function(s) of the endocrine system and causes adverse health effects in an intact organism, or its progeny, or (sub)populations”. Synthetic, as well as,

  2. Effects of Nutrition Relevant Mixtures of Phytoestrogens on Steroidogenesis, Aromatase, Estrogen, and Androgen Activity

    DEFF Research Database (Denmark)

    Taxvig, Camilla; Engell-Kofoed, Anders Elleby; Sonne-Hansen, Katrine

    2010-01-01

    Phytoestrogens (PEs) are naturally occurring plant components produced in a large range of plants. They can induce biologic responses in vertebrates by mimicking or modulating the action or production of endogenous hormones. This study examined mixtures of 12 food relevant PEs for effects...... in the MCF7 cells of the isoflavonoid mixture and coumestrol was supported by an observed increase in progesterone receptor protein expression as well as a decreased ER expression. Overall, the results support that nutrition-relevant concentrations of PEs both alone and in mixtures possess various endocrine...

  3. Effects of xenoestrogens on the expression of vitellogenin (vtg) and cytochrome P450 aromatase (cyp19a and b) genes in zebrafish (Danio rerio) larvae.

    Science.gov (United States)

    Wang, Jingxian; Shi, Xiongjie; Du, Yongbin; Zhou, Bingsheng

    2011-01-01

    In the present study, expression levels of vitellogenin (vtg) and cytochrome P450 aromatase genes (cyp19a and cyp19b) in zebrafish larvae during the early stages of development were investigated by quantitative real time-PCR assay. The results indicated that vtg gene transcription was induced seven days after zebrafish larvae fertilization, whereas the expression of cyp19a and cyp19b genes was detected as early as 3 and 4 days post-fertilization (dpf). Investigations into the effects of 17β-estradiol (E2) exposure on the expression of these genes showed that both vtg and cyp19b were upregulated by E2 in zebrafish larvae as early as four dpf, whereas no variation was observed in cyp19a gene expression. The estrogenic potential of pharmaceutical estrogen (DES), phenol estrogen (BPA) and the brominated flame retardants, TBBPA, DE-71 and 4-BP, were evaluated by analyzing the expression of these three genes in zebrafish larvae. The results demonstrated that natural estrogen, endocrine disrupting compounds and brominated flame retardants act as endocrine disrupters through different mechanisms. We have demonstrated for the first time that the polybrominated diphenyl ether mixture, DE-71, acts as an endocrine disrupter by upregulation of cyp19b gene expression at a relatively low concentration. These results indicate that analysis of vtg and cyp19b gene expression in zebrafish during early embryogenesis and organogenesis represents the basis of a sensitive and fast bioassay for the routine assessment of xenoestrogen effects.

  4. Ovarian aromatase loss-of-function mutant medaka undergo ovary degeneration and partial female-to-male sex reversal after puberty.

    Science.gov (United States)

    Nakamoto, Masatoshi; Shibata, Yasushi; Ohno, Kaoru; Usami, Takeshi; Kamei, Yasuhiro; Taniguchi, Yoshihito; Todo, Takeshi; Sakamoto, Takashi; Young, Graham; Swanson, Penny; Naruse, Kiyoshi; Nagahama, Yoshitaka

    2018-01-15

    Although estrogens have been generally considered to play a critical role in ovarian differentiation in non-mammalian vertebrates, the specific functions of estrogens during ovarian differentiation remain unclear. We isolated two mutants with premature stops in the ovarian aromatase (cyp19a1) gene from an N-ethyl-N-nitrosourea-based gene-driven mutagenesis library of the medaka, Oryzias latipes. In XX mutants, gonads first differentiated into normal ovaries containing many ovarian follicles that failed to accumulate yolk. Subsequently, ovarian tissues underwent extensive degeneration, followed by the appearance of testicular tissues on the dorsal side of ovaries. In the newly formed testicular tissue, strong expression of gsdf was detected in sox9a2-positive somatic cells surrounding germline stem cells suggesting that gsdf plays an important role in testicular differentiation during estrogen-depleted female-to-male sex reversal. We conclude that endogenous estrogens synthesized after fertilization are not essential for early ovarian differentiation but are critical for the maintenance of adult ovaries. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Estrogens and development

    Energy Technology Data Exchange (ETDEWEB)

    McLachlan, J.A.; Newbold, R.R.

    1987-11-01

    The normal development of the genital organs of mammals, including humans, is under hormonal control. A role for the female sex hormone estrogen in this process is still unclear. However, exposure of experimental animals or humans to the potent exogenous estrogen, diethylstilbestrol (DES), results in persistent differentiation effects. Since many chemicals in the environment are weakly estrogenic, the possibility of hormonally altered differentiation must be considered.

  6. Estrogens in breast cancer

    International Nuclear Information System (INIS)

    Terzieff, V.; Vázquez, A.

    2004-01-01

    The prolonged exposure to estrogen increases the risk of cancer breast, the precise role of estrogen in the carcinogenesis process is unclear. They are capable of inducing cell proliferation through different channels receptor Estrogen (ER) known, for example through MAPkinasa sensitivity the promoter of proliferation effect depends on the level of RE, or type to â, integrity (mutations may alter its function) and ligand. The different types of estrogens and related compounds have different profile of affinity for RE and effect end. The modulatory role of progestogens proliferation is very complex, and the interaction between the effector pathways of progestin’s, estrogens, EGF and IGF family - maybe others - determines the final effect .. Estrogens are mutagenic per se weak, but is now known for its hepatic metabolism occur highly reactive species such as quinones, and catechol, powerful mutagens in vitro. Direct or indirect genotoxicity probably explains Part of the effects of estrogen on tumor cells. The use of hormone replacement (HTR) increases the risk of CM, as proportional to the time of use. The combination with progestin seems to be increased risk (R R 2). It is unclear the role of phyto estrogens in the prevention the CM. In the male breast is known that the proliferative response to parenchymal different hormonal maneuvers is different. The effect is minimal castration are and maximum with the combination of estrogen and progesterone. It is unclear, however, the risk of the population exposed to hormone therapy for cancer prostate or otherwise

  7. Regulation of P450 oxidoreductase by gonadotropins in rat ovary and its effect on estrogen production

    Directory of Open Access Journals (Sweden)

    Uesaka Miki

    2008-12-01

    Full Text Available Abstract Background P450 oxidoreductase (POR catalyzes electron transfer to microsomal P450 enzymes. Its deficiency causes Antley-Bixler syndrome (ABS, and about half the patients with ABS have ambiguous genitalia and/or impaired steroidogenesis. POR mRNA expression is up-regulated when mesenchymal stem cells (MSCs differentiate into steroidogenic cells, suggesting that the regulation of POR gene expression is important for steroidogenesis. In this context we examined the regulation of POR expression in ovarian granulosa cells by gonadotropins, and its possible role in steroidogenesis. Methods Changes in gene expression in MSCs during differentiation into steroidogenic cells were examined by DNA microarray analysis. Changes in mRNA and protein expression of POR in the rat ovary or in granulosa cells induced by gonadotropin treatment were examined by reverse transcription-polymerase chain reaction and western blotting. Effects of transient expression of wild-type or mutant (R457H or V492E POR proteins on the production of estrone in COS-7 cells were examined in vitro. Effects of POR knockdown were also examined in estrogen producing cell-line, KGN cells. Results POR mRNA was induced in MSCs following transduction with the SF-1 retrovirus, and was further increased by cAMP treatment. Expression of POR mRNA, as well as Cyp19 mRNA, in the rat ovary were induced by equine chorionic gonadotropin and human chorionic gonadotropin. POR mRNA and protein were also induced by follicle stimulating hormone in primary cultured rat granulosa cells, and the induction pattern was similar to that for aromatase. Transient expression of POR in COS-7 cells, which expressed a constant amount of aromatase protein, greatly increased the rate of conversion of androstenedione to estrone, in a dose-dependent manner. The expression of mutant POR proteins (R457H or V492E, such as those found in ABS patients, had much less effect on aromatase activity than expression of wild

  8. Role of Estrogens in the Size of Neuronal Somata of Paravaginal Ganglia in Ovariectomized Rabbits

    Science.gov (United States)

    Hernández-Aragón, Laura G.; García-Villamar, Verónica; Carrasco-Ruiz, María de los Ángeles; Nicolás-Toledo, Leticia; Ortega, Arturo; Cuevas-Romero, Estela; Martínez-Gómez, Margarita

    2017-01-01

    We aimed to determine the role of estrogens in modulating the size of neuronal somata of paravaginal ganglia. Rabbits were allocated into control (C), ovariectomized (OVX), and OVX treated with estradiol benzoate (OVX + EB) groups to evaluate the neuronal soma area; total serum estradiol (E2) and testosterone (T) levels; the percentage of immunoreactive (ir) neurons anti-aromatase, anti-estrogen receptor (ERα, ERβ) and anti-androgen receptor (AR); the intensity of the immunostaining anti-glial cell line-derived neurotrophic factor (GDNF) and the GDNF family receptor alpha type 1 (GFRα1); and the number of satellite glial cells (SGCs) per neuron. There was a decrease in the neuronal soma size for the OVX group, which was associated with low T, high percentages of aromatase-ir and neuritic AR-ir neurons, and a strong immunostaining anti-GDNF and anti-GFRα1. The decrease in the neuronal soma size was prevented by the EB treatment that increased the E2 without affecting the T levels. Moreover, there was a high percentage of neuritic AR-ir neurons, a strong GDNF immunostaining in the SGC, and an increase in the SGCs per neuron. Present findings show that estrogens modulate the soma size of neurons of the paravaginal ganglia, likely involving the participation of the SGC. PMID:28316975

  9. Role of Estrogens in the Size of Neuronal Somata of Paravaginal Ganglia in Ovariectomized Rabbits

    Directory of Open Access Journals (Sweden)

    Laura G. Hernández-Aragón

    2017-01-01

    Full Text Available We aimed to determine the role of estrogens in modulating the size of neuronal somata of paravaginal ganglia. Rabbits were allocated into control (C, ovariectomized (OVX, and OVX treated with estradiol benzoate (OVX + EB groups to evaluate the neuronal soma area; total serum estradiol (E2 and testosterone (T levels; the percentage of immunoreactive (ir neurons anti-aromatase, anti-estrogen receptor (ERα, ERβ and anti-androgen receptor (AR; the intensity of the immunostaining anti-glial cell line-derived neurotrophic factor (GDNF and the GDNF family receptor alpha type 1 (GFRα1; and the number of satellite glial cells (SGCs per neuron. There was a decrease in the neuronal soma size for the OVX group, which was associated with low T, high percentages of aromatase-ir and neuritic AR-ir neurons, and a strong immunostaining anti-GDNF and anti-GFRα1. The decrease in the neuronal soma size was prevented by the EB treatment that increased the E2 without affecting the T levels. Moreover, there was a high percentage of neuritic AR-ir neurons, a strong GDNF immunostaining in the SGC, and an increase in the SGCs per neuron. Present findings show that estrogens modulate the soma size of neurons of the paravaginal ganglia, likely involving the participation of the SGC.

  10. Novel drugs that target the estrogen-related receptor alpha: their therapeutic potential in breast cancer

    International Nuclear Information System (INIS)

    May, Felicity EB

    2014-01-01

    The incidence of breast cancer continues to rise: 1.7 million women were diagnosed with and 521,000 women died from breast cancer in 2012. This review considers first current treatment options: surgery; radiotherapy; and systemic endocrine, anti-biological, and cytotoxic therapies. Clinical management includes prevention, early detection by screening, treatment with curative intent, management of chronic disease, and palliative control of advanced breast cancer. Next, the potential of novel drugs that target DNA repair, growth factor dependence, intracellular and intercellular signal transduction, and cell cycle are considered. Estrogen-related receptor alpha has attracted attention as a therapeutic target in triple-negative breast cancers with de novo resistance to, and in breast cancers with acquired resistance to, endocrine therapies such as antiestrogens and aromatase inhibitors. Estrogen-related receptor alpha is an orphan receptor and transcription factor. Its activity is regulated by coregulator proteins and posttranslational modification. It is an energy sensor that controls adaptation to energy demand and may facilitate glycolytic metabolism and mitochondrial oxidative respiration in breast cancer cells. Estrogen-related receptor alpha increases breast cancer cell migration, proliferation, and tumor development. It is expressed at high levels in estrogen receptor-negative tumors, and is proposed to activate estrogen-responsive genes in endocrine-resistant tumors. The structures and functions of the ligand-binding domains of estrogen receptor alpha and estrogen-related receptor alpha, their ability to bind estrogens, phytoestrogens, and synthetic ligands, and the effects of ligand agonists, antagonists, and inverse agonists on biological activity, are evaluated. Synthetic ligands of estrogen-related receptor alpha have activity in preclinical models of metabolic disorders, diabetes, osteoporosis, and oncology. The clinical settings in which these novel

  11. Engineered biosynthesis of regioselectively modified aromatic polyketides using bimodular polyketide synthases.

    Science.gov (United States)

    Tang, Yi; Lee, Taek Soon; Khosla, Chaitan

    2004-02-01

    Bacterial aromatic polyketides such as tetracycline and doxorubicin are a medicinally important class of natural products produced as secondary metabolites by actinomyces bacteria. Their backbones are derived from malonyl-CoA units by polyketide synthases (PKSs). The nascent polyketide chain is synthesized by the minimal PKS, a module consisting of four dissociated enzymes. Although the biosynthesis of most aromatic polyketide backbones is initiated through decarboxylation of a malonyl building block (which results in an acetate group), some polyketides, such as the estrogen receptor antagonist R1128, are derived from nonacetate primers. Understanding the mechanism of nonacetate priming can lead to biosynthesis of novel polyketides that have improved pharmacological properties. Recent biochemical analysis has shown that nonacetate priming is the result of stepwise activity of two dissociated PKS modules with orthogonal molecular recognition features. In these PKSs, an initiation module that synthesizes a starter unit is present in addition to the minimal PKS module. Here we describe a general method for the engineered biosynthesis of regioselectively modified aromatic polyketides. When coexpressed with the R1128 initiation module, the actinorhodin minimal PKS produced novel hexaketides with propionyl and isobutyryl primer units. Analogous octaketides could be synthesized by combining the tetracenomycin minimal PKS with the R1128 initiation module. Tailoring enzymes such as ketoreductases and cyclases were able to process the unnatural polyketides efficiently. Based upon these findings, hybrid PKSs were engineered to synthesize new anthraquinone antibiotics with predictable functional group modifications. Our results demonstrate that (i) bimodular aromatic PKSs present a general mechanism for priming aromatic polyketide backbones with nonacetate precursors; (ii) the minimal PKS controls polyketide chain length by counting the number of atoms incorporated into the

  12. Engineered biosynthesis of regioselectively modified aromatic polyketides using bimodular polyketide synthases.

    Directory of Open Access Journals (Sweden)

    Yi Tang

    2004-02-01

    Full Text Available Bacterial aromatic polyketides such as tetracycline and doxorubicin are a medicinally important class of natural products produced as secondary metabolites by actinomyces bacteria. Their backbones are derived from malonyl-CoA units by polyketide synthases (PKSs. The nascent polyketide chain is synthesized by the minimal PKS, a module consisting of four dissociated enzymes. Although the biosynthesis of most aromatic polyketide backbones is initiated through decarboxylation of a malonyl building block (which results in an acetate group, some polyketides, such as the estrogen receptor antagonist R1128, are derived from nonacetate primers. Understanding the mechanism of nonacetate priming can lead to biosynthesis of novel polyketides that have improved pharmacological properties. Recent biochemical analysis has shown that nonacetate priming is the result of stepwise activity of two dissociated PKS modules with orthogonal molecular recognition features. In these PKSs, an initiation module that synthesizes a starter unit is present in addition to the minimal PKS module. Here we describe a general method for the engineered biosynthesis of regioselectively modified aromatic polyketides. When coexpressed with the R1128 initiation module, the actinorhodin minimal PKS produced novel hexaketides with propionyl and isobutyryl primer units. Analogous octaketides could be synthesized by combining the tetracenomycin minimal PKS with the R1128 initiation module. Tailoring enzymes such as ketoreductases and cyclases were able to process the unnatural polyketides efficiently. Based upon these findings, hybrid PKSs were engineered to synthesize new anthraquinone antibiotics with predictable functional group modifications. Our results demonstrate that (i bimodular aromatic PKSs present a general mechanism for priming aromatic polyketide backbones with nonacetate precursors; (ii the minimal PKS controls polyketide chain length by counting the number of atoms

  13. Aromatase activity in receptor negative breast and endometrial cancer

    NARCIS (Netherlands)

    Berstein, LM; Kovalevskij, A; Larionov, A; Tsyrlina, E; Vasilyev, D; Zimarina, T; Thijssen, JHH

    Among the factors for estrogen and progesterone receptors (ER and PR) negativity of tumors of reproductive tissue special attention., is attracted by ability of the tumor produce estrogens (as intratumoral regulators of ER and PR) through reaction of aromatization. 101 samples of tumor tissue (64

  14. Somatic and psychological effects of low-dose aromatase inhibition in men with obesity-related hypogonadotropic hypotestosteronemia

    NARCIS (Netherlands)

    Loves, S.; Jong, J. de; Sorge, A. van; Telting, D.; Tack, C.J.J.; Hermus, A.R.; Westerterp, K.; Boer, H. de

    2013-01-01

    INTRODUCTION: Reduced testosterone levels are frequently observed in obese men. Increased aromatase activity may be an etiological factor. OBJECTIVE: In this study, we evaluate the clinical effects of aromatase inhibition in obesity-related hypogonadotropic hypotestosteronemia (OrHH). METHODS:

  15. Bisphenol A exposure during adulthood alters expression of aromatase and 5α-reductase isozymes in rat prostate.

    Directory of Open Access Journals (Sweden)

    Beatriz Castro

    Full Text Available The high incidence of prostate cancer (PCa and benign prostatic hypertrophy (BPH in elderly men is a cause of increasing public health concern. In recent years, various environmental endocrine disruptors, such as bisphenol A (BPA, have been shown to disrupt sexual organs, including the prostate gland. However, the mechanisms underlying these effects remain unclear. Because androgens and estrogens are important factors in prostate physiopathology, our objective was to examine in rat ventral prostate the effects of adult exposure to BPA on 5α-Reductase isozymes (5α-R types 1, 2, and 3 and aromatase, key enzymes in the biosynthesis of dihydrotestosterone and estradiol, respectively. Adult rats were subcutaneously injected for four days with BPA (25, 50, 300, or 600 µg/Kg/d dissolved in vehicle. Quantitative RT-PCR, western blot and immunohistochemical analyses showed lower mRNA and protein levels of 5α-R1 and 5α-R2 in BPA-treated groups versus controls but higher mRNA levels of 5α-R3, recently proposed as a biomarker of malignancy. However, BPA treatment augmented mRNA and protein levels of aromatase, whose increase has been described in prostate diseases. BPA-treated rats also evidenced a higher plasma estradiol/testosterone ratio, which is associated with prostate disease. Our results may offer new insights into the role of BPA in the development of prostate disease and may be of great value for studying the prostate disease risk associated with exposure to BPA in adulthood.

  16. Bisphenol A exposure during adulthood alters expression of aromatase and 5α-reductase isozymes in rat prostate.

    Science.gov (United States)

    Castro, Beatriz; Sánchez, Pilar; Torres, Jesús M; Preda, Ovidiu; del Moral, Raimundo G; Ortega, Esperanza

    2013-01-01

    The high incidence of prostate cancer (PCa) and benign prostatic hypertrophy (BPH) in elderly men is a cause of increasing public health concern. In recent years, various environmental endocrine disruptors, such as bisphenol A (BPA), have been shown to disrupt sexual organs, including the prostate gland. However, the mechanisms underlying these effects remain unclear. Because androgens and estrogens are important factors in prostate physiopathology, our objective was to examine in rat ventral prostate the effects of adult exposure to BPA on 5α-Reductase isozymes (5α-R types 1, 2, and 3) and aromatase, key enzymes in the biosynthesis of dihydrotestosterone and estradiol, respectively. Adult rats were subcutaneously injected for four days with BPA (25, 50, 300, or 600 µg/Kg/d) dissolved in vehicle. Quantitative RT-PCR, western blot and immunohistochemical analyses showed lower mRNA and protein levels of 5α-R1 and 5α-R2 in BPA-treated groups versus controls but higher mRNA levels of 5α-R3, recently proposed as a biomarker of malignancy. However, BPA treatment augmented mRNA and protein levels of aromatase, whose increase has been described in prostate diseases. BPA-treated rats also evidenced a higher plasma estradiol/testosterone ratio, which is associated with prostate disease. Our results may offer new insights into the role of BPA in the development of prostate disease and may be of great value for studying the prostate disease risk associated with exposure to BPA in adulthood.

  17. Aromatase Expression in the Hippocampus of AD Patients and 5xFAD Mice

    Directory of Open Access Journals (Sweden)

    Janine Prange-Kiel

    2016-01-01

    Full Text Available Numerous studies show that 17β-estradiol (E2 protects against Alzheimer’s disease (AD induced neurodegeneration. The E2-synthesizing enzyme aromatase is expressed in healthy hippocampi, but although the hippocampus is severely affected in AD, little is known about the expression of hippocampal aromatase in AD. To better understand the role of hippocampal aromatase in AD, we studied its expression in postmortem material from patients with AD and in a mouse model for AD (5xFAD mice. In human hippocampi, aromatase-immunoreactivity was observed in the vast majority of principal neurons and signal quantification revealed higher expression of aromatase protein in AD patients compared to age- and sex-matched controls. The tissue-specific first exons of aromatase I.f, PII, I.3, and I.6 were detected in hippocampi of controls and AD patients by RT-PCR. In contrast, 3-month-old, female 5xFAD mice showed lower expression of aromatase mRNA and protein (measured by qRT-PCR and semiquantitative immunohistochemistry than WT controls; no such differences were observed in male mice. Our findings stress the importance of hippocampal aromatase expression in neurodegenerative diseases.

  18. Uso de inibidores da aromatase no tratamento do câncer de mama e osteoporose = The use of aromatase inhibitors for breast cancer treatment and osteoporosis

    Directory of Open Access Journals (Sweden)

    Cassol, Lina Barbosa

    2005-01-01

    Conclusão: Estratégias diagnósticas, preventivas e, eventualmente, terapêuticas de osteoporose devem ser empregadas precocemente em pacientes com câncer de mama tratadas com inibidores da aromatase

  19. Mass spectrometric analysis of oxygenations in aromatization of androst-4-ene-3,6,17-trione, a suicide substrate of aromatase, by placental microsomes. Isotope effect and stereochemistry.

    Science.gov (United States)

    Numazawa, Mitsuteru; Takahashi, Madoka; Nagaoka, Masao; Handa, Wakako; Yamashita, Kouwa

    2007-01-01

    Aromatase catalyzes the conversion of androstenedione (AD) to estrone through three sequential oxygenations of the 19-methyl group. 6-OxoAD (1) is one of the typical suicide substrates of aromatase, which is converted by aromatase to 6-oxoestrone through 19-alcohol (19-ol) and 19-aldehyde (19-al) intermediates 2 and 3. To study the deuterium isotope effect on the conversion of 19-ol 2 to 19-al 3 as well as the stereochemistry of the 19-hydrogen removal in this conversion, we initially synthesized [19,19-(2)H(2)] and [19S- or 19R-(2)H] 19-ols 2, starting from the corresponding deuterium-labeled 19-hydroxyAD derivatives. In incubation of non-labeled and [19,19-(2)H(2)]-labeled 19-ol 2 or that of their 1:1 mixture with human placental microsomes in the presence of NADPH under air, there was no significant deuterium-isotope effect on the production of the aromatized product 6-oxoestrone or on the conversion of 19-ol 2 to 19-al 3, based on gas chromatography-mass spectrometric analysis of the estrogen product or liquid chromatography-mass spectrometric (LC-MS) analysis of the deuterium contents of the product 19-al 3 and the recovered 19-ol 2. Moreover, in the incubations of [19S-(2)H] 19-ol 2 and its 19R isomer, LC-MS analysis of the product 3 demonstrated that the 19-pro-R hydrogen atom was stereospecifically removed in the conversion of 19-ol 2 to 19-al 3. These findings indicate that the 19-oxygenation of 19-ol 2 would proceed in the same mechanism as that involved in the AD aromatization.

  20. Estrogen-dependent seasonal adaptations in the immune response of fish.

    Science.gov (United States)

    Szwejser, Ewa; Verburg-van Kemenade, B M Lidy; Maciuszek, Magdalena; Chadzinska, Magdalena

    2017-02-01

    Clinical and experimental evidence shows that estrogens affect immunity in mammals. Less is known about this interaction in the evolutionary older, non-mammalian, vertebrates. Fish form an excellent model to identify evolutionary conserved neuroendocrine-immune interactions: i) they are the earliest vertebrates with fully developed innate and adaptive immunity, ii) immune and endocrine parameters vary with season, and iii) physiology is constantly disrupted by increasing contamination of the aquatic environment. Neuro-immuno-endocrine interactions enable adaption to changing internal and external environment and are based on shared signaling molecules and receptors. The presence of specific estrogen receptors on/in fish leukocytes, implies direct estrogen-mediated immunoregulation. Fish leukocytes most probably are also capable to produce estrogens as they express the cyp19a and cyp19b - genes, encoding aromatase cytochrome P450, the enzyme critical for conversion of C19 steroids to estrogens. Immunoregulatory actions of estrogens, vary among animal species, and also with dose, target cell type, or physiological condition (e.g., infected/non-infected, reproductive status). They moreover are multifaceted. Interestingly, season-dependent changes in immune status correlate with changes in the levels of circulating sex hormones. Whereas E2 circulating in the bloodstream is perhaps the most likely candidate to be the physiological mediator of systemic immune-reproductive trade-offs, leukocyte-derived hormones are hypothesized to be mainly involved in local tuning of the immune response. Contamination of the aquatic environment with estrogenic EDCs may violate the delicate and precise allostatic interactions between the endogenous estrogen system and the immune system. This has negative effects on fish health, but will also affect the physiology of its consumers. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. The role of estrogen in bone growth and formation: changes at puberty

    Directory of Open Access Journals (Sweden)

    Divya Singh

    2010-12-01

    Full Text Available Divya Singh1, Sabyasachi Sanyal2, Naibedya Chattopadhyay11Division of Endocrinology, 2Division of Drug Target Discovery and Development, Central Drug Research Institute (Council of Scientific and Industrial Research, Lucknow, Uttar Pradesh, IndiaAbstract: A high peak bone mass (PBM at skeletal maturity is a good predictor for lower rate of fracture risks in later life. Growth during puberty contributes significantly to PBM achievement in women and men. The growth hormone (GH/insulin-like growth factor 1 (IGF-1 axis has a critical role in pubertal bone growth. There is an increase in GH and IGF-1 levels during puberty; thus, it is assumed that sex steroids contribute to higher GH/IGF-1 action during growth. Recent studies indicate that estrogen increases GH secretion in boys and girls, and the major effect of testosterone on GH secretion is via aromatization to estrogen. Estrogen is pivotal for epiphyseal fusion in young men and women. From studies of individuals with a mutated aromatase gene and a case study of male patient with defective estrogen receptor-alpha (ER-α, it is clear that estrogen is indispensable for normal pubertal growth and growth plate fusion. ER-α and estrogen receptor-beta (ER-β have been localized in growth plate and bone. ER knockout studies have shown that ER-α-/- female mice have reduced linear appendicular growth, while ER-β-/- mice have increased appendicular growth. No such effect is seen in ER-β-/- males; however, repressed growth is seen in ER-α-/- males, resulting in shorter long bones. Thus, ER-β represses longitudinal bone growth in female mice, while it has no function in the regulation of longitudinal bone growth in male mice. These findings indicate that estrogen plays a critical role in skeletal physiology of males as well as females.Keywords: peak bone mass, puberty, estrogen, growth plate

  2. Inhibitory effect of Sphagnum palustre extract and its bioactive compounds on aromatase activity

    Directory of Open Access Journals (Sweden)

    Hee Jeong Eom

    2016-09-01

    Full Text Available Sphagnum palustre (a moss has been traditionally used in Korea for the cure of several diseases such as cardiac pain and stroke. In this research, the inhibitory effect of S. palustre on aromatase (cytochrome P450 19, CYP19 activity was studied. [1β-3H] androstenedione was used as a substrate and incubated with S. palustre extract and recombinant human CYP19 in the presence of NADPH. S. palustre extract inhibited aromatase in a concentration-dependent manner (IC50 value: 36.4 ± 8.1 µg/mL. To elucidate the major compounds responsible for the aromatase inhibitory effects of S. palustre extract, nine compounds were isolated from the extract and tested for their inhibition of aromatase activity. Compounds 1, 6, and 7 displayed aromatase inhibition, while the inhibition by the other compounds was negligible.

  3. Red versus white wine as a nutritional aromatase inhibitor in premenopausal women: a pilot study.

    Science.gov (United States)

    Shufelt, Chrisandra; Merz, C Noel Bairey; Yang, YuChing; Kirschner, Joan; Polk, Donna; Stanczyk, Frank; Paul-Labrador, Maura; Braunstein, Glenn D

    2012-03-01

    An increased risk of breast cancer is associated with alcohol consumption; however, it is controversial whether red wine increases this risk. Aromatase inhibitors (AIs) prevent the conversion of androgens to estrogen and occur naturally in grapes, grape juice, and red, but not white wine. We tested whether red wine is a nutritional AI in premenopausal women. In a cross-over design, 36 women (mean age [SD], 36 [8] years) were assigned to 8 ounces (237 mL) of red wine daily then white wine for 1 month each, or the reverse. Blood was collected twice during the menstrual cycle for measurement of estradiol (E2), estrone (E1), androstenedione (A), total and free testosterone (T), sex hormone binding globulin (SHBG), luteinizing hormone (LH), and follicle stimulating hormone (FSH). Red wine demonstrated higher free T vs. white wine (mean difference 0.64 pg/mL [0.2 SE], p=0.009) and lower SHBG (mean difference -5.0 nmol/L [1.9 SE], p=0.007). E2 levels were lower in red vs. white wine but not statistically significant. LH was significantly higher in red vs. white wine (mean difference 2.3 mIU/mL [1.3 SE], p=0.027); however, FSH was not. Red wine is associated with significantly higher free T and lower SHBG levels, as well as a significant higher LH level vs. white wine in healthy premenopausal women. These data suggest that red wine is a nutritional AI and may explain the observation that red wine does not appear to increase breast cancer risk.

  4. Estrogenic effects of several BPA analogs in the developing zebrafish brain

    Directory of Open Access Journals (Sweden)

    Joel eCano-Nicolau

    2016-03-01

    Full Text Available Important set of studies have demonstrated the endocrine disrupting activity of Bisphenol A (BPA. The present work aimed at defining estrogenic-like activity of several BPA structural analogs, including BPS, BPF, BPAF, and BPAP, on 4-day or 7-day post-fertilization (dpf zebrafish larva as an in vivo model. We measured the induction level of the estrogen-sensitive marker cyp19a1b gene (Aromatase B, expressed in the brain, using three different in situ/in vivo strategies: 1 Quantification of cyp19a1b transcripts using RT-qPCR in wild type 7-dpf larva brains exposed to bisphenols ; 2 Detection and distribution of cyp19a1b transcripts using in situ hybridization on 7-dpf brain sections (hypothalamus; and 3 Quantification of the cyp19a1b promoter activity in live cyp19a1b-GFP transgenic zebrafish (EASZY assay at 4-dpf larval stage. These three different experimental approaches demonstrated that BPS, BPF or BPAF exposure, similarly to BPA, significantly activates the expression of the estrogenic marker in the brain of developing zebrafish. In vitro experiments using both reporter gene assay in a glial cell context and competitive ligand binding assays strongly suggested that up-regulation of cyp19a1b is largely mediated by the zebrafish estrogen nuclear receptor alpha (zfERα. Importantly, and in contrast to other tested bisphenol A analogs, the bisphenol AP (BPAP did not show estrogenic activity in our model.

  5. Effects of bisphenol A-related diphenylalkanes on vitellogenin production in male carp (Cyprinus carpio) hepatocytes and aromatase (CYP19) activity in human H295r adrenocortical carcinoma cells

    International Nuclear Information System (INIS)

    Letcher, Robert J.; Sanderson, J. Thomas; Bokkers, Abraham; Giesy, John P.; Berg, Martin van den

    2005-01-01

    The present study investigated the effects of the known xenoestrogen bisphenol A (BPA) relative to eight BPA-related diphenylalkanes on estrogen receptor (ER)-mediated vitellogenin (vtg) production in hepatocytes from male carp (Cyprinus carpio), and on aromatase (CYP19) activity in the human adrenocortical H295R carcinoma cell line. Of the eight diphenylalkanes, only 4,4'-(hexafluoropropylidene)diphenol (BHF) and 2,2'-bis(4-hydroxy-3-methylphenyl)propane (BPRO) induced vtg, i.e., to a maximum of 3% to 4% (at 100 μM) compared with 8% for BPA relative to the maximum induction by 17β-estradiol (E2, 1 μM). Bisphenol A diglycidyl ether (BADGE) was a potent antagonist of vtg production with an IC50 of 5.5 μM, virtually 100% inhibition of vtg at 20 μM, and an inhibitive (IC50) potency about one-tenth that of the known ER antagonist tamoxifen (IC50, 0.6 μM). 2,2'-Diallyl bisphenol A, 4,4'-(1,4-phenylene-diisopropylidene)bisphenol, BPRO, and BHF were much less inhibitory with IC50 concentrations of 20-70 μM, and relative potencies of 0.03 and 0.009 with tamoxifen. Bisphenol ethoxylate showed no anti-estrogenicity (up to 100 μM), and 4,4'-isopropylidene-diphenol diacetate was only antagonistic at 100 μM. When comparing the (anti)estrogenic potencies of these bisphenol A analogues/diphenylalkanes, anti-estrogenicity occurred at lower concentrations than estrogenicity. 4,4'-Isopropylidenebis(2,6-dimethylphenol) (IC50, 2.0 μM) reduced E2-induced (EC50, 100 nM) vtg production due to concentration-dependent cytotoxicity as indicated by a parallel decrease in MTT activity and vtg, whereas the remaining diphenylalkanes did not cause any cytotoxicity relative to controls. None of the diphenylalkanes (up to 100 μM) induced EROD activity indicating that concentration-dependent, CYP1A enzyme-mediated metabolism of E2, or any Ah-receptor-mediated interaction with the ER, was not a likely explanation for the observed anti-estrogenic effects. At concentrations as great as 100

  6. Evidence for the prevention of bone loss in elderly and old early non-metastatic breast cancer patients treated with aromatase inhibitors

    DEFF Research Database (Denmark)

    Gunmalm, V.; Jørgensen, N. R.; Abrahamsen, B.

    2017-01-01

    Breast cancer (BC) is the most common cancer amongst women worldwide. Bone health is emerging as an important issue for BC survivors. In this literature study, we focus on agents for preventing bone loss in early non-metastatic estrogen receptor positive BC in treatment with aromatase inhibitors...... (AI) and to assess the evidence for antiresorptive treatment of bone loss in early non-metastatic breast cancer. We included randomized controlled trials (RCT's) comparing: (a) bisphosphonates and control; (b) different bisphosphonates; (c) denosumab and control and (d) bisphosphonates vs. denosumab...... in early non-metastatic BC women in AI treatment. Among antiresorptives, zoledronic acid currently has the highest evidence for prevention of AI associated bone loss in early non-metastatic BC. Data on fracture prevention among all patients, elderly and old is sparse. More randomized controlled studies...

  7. The effect of estrogen on the sexual interest of castrated males: Implications to prostate cancer patients on androgen-deprivation therapy.

    Science.gov (United States)

    Wibowo, Erik; Wassersug, Richard J

    2013-09-01

    Androgen deprivation therapy (ADT) for prostate cancer (PCa) treatment causes sexual dysfunction. We review here the effects of estrogen on the sexual performance of androgen-deprived males. The major findings are: 1. Estrogen receptors are present in brain centers that are important for sexual behavior; as well as in male reproductive organs, in a pattern suggesting that estrogen may have some role in orgasmic function and genital skin sensitivity. 2. Estrogen restores sexual interest above castrate levels in many vertebrates including reptiles, birds and mammals; but multiple factors contribute to the magnitude of this effect. 3. Data from castrated men, aromatase-deficient men, male-to-female transsexuals, and men on antiandrogens all suggest that estrogen can maintain some libido in androgen-deprived men. We discuss the general benefits of estrogen therapy to quality of life of men on ADT, the potential risks of this treatment, and possible treatment regimes for estrogen therapy in males. Unless contraindicated, we propose that PCa patients on ADT would benefit from supplemental parenteral estrogen. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  8. Aromatase inhibitors in the treatment of deep endometriosis

    Directory of Open Access Journals (Sweden)

    Simone Ferrero

    2009-09-01

    Full Text Available Recent case reports and pilot studies suggested that aromatase inhibitors might be effective in treating pain symptoms related to the presence of endometriosis. We present the case of a 32-year-old woman who suffered dysmenorrhea, dyspareunia, chronic pelvic pain, and dyschezia caused by rectovaginal endometriosis. Pain symptoms recurred after treatment with the oral contraceptive pill; the patient refused surgery. Therefore a double-drug regimen including letrozole (2.5 mg/day and norethisterone acetate (2.5 mg/day was offered to the patient. The scheduled length of treatment was six months. This double-drug regimen determined a quick and significant improvement in all pain symptoms. During treatment, the patient complained mild arthralgia. After the interruption of treatment, pain symptoms quickly recurred and at 6-month follow-up their intensity was similar to baseline values. Operative laparoscopy was performed, the presence of rectovaginal endometriosis was confirmed and all visible endometriotic lesions were excised. Aromatase inhibitors might be offered when pain symptoms caused by endometriosis persist during the administration of other hormonal therapies and the patient refuses surgery. However, women must be informed that these drugs determine only a temporary relief of pain symptoms and might cause adverse effects (such as arthralgia.

  9. VASCULAR AGING IN WOMEN: IS ESTROGEN THE FOUNTAIN OF YOUTH?

    Directory of Open Access Journals (Sweden)

    Susana eNovella

    2012-06-01

    Full Text Available Aging is a physiological process associated with structural and functional changes in vasculature, including endothelial dysfunction, arterial stiffening and remodeling, impaired angiogenesis, and defective vascular repair, and with an increasing prevalence of atherosclerosis. The risk of cardiovascular disease differs between men and women, remaining lower in women during their fertile years and reaching values similar to their male peers after menopause. Menopause is marked by the loss of endogenous estrogen production. Therefore, estrogens have been implicated in premenopausal protection from cardiovascular disease, an assumption supported by experimental and some clinical studies, where estrogen induces protective effects in vascular endothelium. Indeed, estradiol promotes endothelial vasodilator synthesis, including NO production through increased expression and activity of endothelial nitric oxide synthase, and modulates prostacyclin and thromboxane A2 release; the thromboxane A2 pathway plays a key role in regulating vascular tone in females in both normal and in pathophysiologic states.Contrary to experimental results, some clinical trials found no cardiovascular benefit from estrogen replacement therapy in aged postmenopausal women. These discrepancies could be due to the Timing Hypothesis which suggests that estrogen-mediated vascular benefits may occur only before the detrimental effects of aging are established in the vasculature. Thus, there is still a gap in the knowledge, understanding, and general awareness of mechanisms for cardiovascular aging in women.In this review, we discuss clinical and experimental data on the effects of aging, estrogens and hormonal replacement therapy on vascular function of females to delve into how menopause and aging contribute jointly to vascular aging and how estrogen modulates the vascular responses at different ages.

  10. International Union of Basic and Clinical Pharmacology. XCVII. G Protein–Coupled Estrogen Receptor and Its Pharmacologic Modulators

    Science.gov (United States)

    2015-01-01

    Estrogens are critical mediators of multiple and diverse physiologic effects throughout the body in both sexes, including the reproductive, cardiovascular, endocrine, nervous, and immune systems. As such, alterations in estrogen function play important roles in many diseases and pathophysiological conditions (including cancer), exemplified by the lower prevalence of many diseases in premenopausal women. Estrogens mediate their effects through multiple cellular receptors, including the nuclear receptor family (ERα and ERβ) and the G protein–coupled receptor (GPCR) family (GPR30/G protein–coupled estrogen receptor [GPER]). Although both receptor families can initiate rapid cell signaling and transcriptional regulation, the nuclear receptors are traditionally associated with regulating gene expression, whereas GPCRs are recognized as mediating rapid cellular signaling. Estrogen-activated pathways are not only the target of multiple therapeutic agents (e.g., tamoxifen, fulvestrant, raloxifene, and aromatase inhibitors) but are also affected by a plethora of phyto- and xeno-estrogens (e.g., genistein, coumestrol, bisphenol A, dichlorodiphenyltrichloroethane). Because of the existence of multiple estrogen receptors with overlapping ligand specificities, expression patterns, and signaling pathways, the roles of the individual receptors with respect to the diverse array of endogenous and exogenous ligands have been challenging to ascertain. The identification of GPER-selective ligands however has led to a much greater understanding of the roles of this receptor in normal physiology and disease as well as its interactions with the classic estrogen receptors ERα and ERβ and their signaling pathways. In this review, we describe the history and characterization of GPER over the past 15 years focusing on the pharmacology of steroidal and nonsteroidal compounds that have been employed to unravel the biology of this most recently recognized estrogen receptor. PMID

  11. Attempted replication of SNPs in RANKL and OPG with musculoskeletal adverse events during aromatase inhibitor treatment for breast cancer.

    Science.gov (United States)

    Dempsey, Jacqueline M; Xi, Jingyue; Henry, N Lynn; Rae, James M; Hertz, Daniel L

    2018-02-01

    Aromatase inhibitor (AI) therapy is highly efficacious in the treatment of estrogen receptor-positive breast cancer; however, in a subset of patients AI use is discontinued due to drug-induced musculoskeletal adverse events (MS-AE). Several studies have investigated the role of germline single nucleotide polymorphisms (SNPs) on patients' risk of MS-AEs; however, no associations have yet to be validated for translation into clinical practice. This study attempted to replicate SNPs in RANKL ( rs7984870 ) and OPG ( rs2073618 ) on the risk of AI-induced MS-AEs and screen for secondary associations with MS-AE-related treatment discontinuation and serum and urine markers of bone health. Previously reported associations were not replicated with our primary hypothesis, change in MS-AE from baseline to 3 mo; however, patients homozygous for the G allele of rs7984870 in RANKL had lower risk of MS-AE-associated treatment discontinuation in analyses of secondary phenotypes without statistical correction.

  12. Periodontal Health in Women With Early-Stage Postmenopausal Breast Cancer Newly on Aromatase Inhibitors: A Pilot Study.

    Science.gov (United States)

    Taichman, L Susan; Inglehart, Marita R; Giannobile, William V; Braun, Thomas; Kolenic, Giselle; Van Poznak, Catherine

    2015-07-01

    Aromatase inhibitor (AI) use results in low estrogen levels, which in turn affect bone mineral density (BMD). Periodontitis, alveolar bone loss, and tooth loss are associated with low BMD. The goal of this study is to assess the prevalence of periodontitis and perceived oral health and evaluate salivary biomarkers in postmenopausal women who are survivors of early-stage (I to IIIA) breast cancer (BCa) and receive adjuvant AI therapy. Participants included 58 postmenopausal women: 29 with BCa on AIs and 29 controls without BCa diagnoses. Baseline periodontal status was assessed with: 1) periodontal probing depth (PD); 2) bleeding on probing (BOP); and 3) attachment loss (AL). Demographic and dental utilization information was gathered by questionnaire. Linear regression modeling was used to analyze the outcomes. No differences were found in mean PD or number of teeth. The AI group had significantly more sites with BOP (27.8 versus 16.7; P = 0.02), higher worst-site AL (5.2 versus 4.0 mm; P tobacco use, dental insurance, and previous radiation and chemotherapy exposure demonstrated that AI use increased AL by >2 mm (95% confidence interval, 0.46 to 3.92). Median salivary osteocalcin and tumor necrosis factor-α levels were significantly higher in the AI group than the control group. This first investigation of the periodontal status of women initiating adjuvant AI therapy identifies this population as having an increased risk for periodontitis.

  13. Brief exposure of embryos to steroids or aromatase inhibitor induces sex reversal in Nile tilapia (Oreochromis niloticus).

    Science.gov (United States)

    Gennotte, Vincent; Mafwila Kinkela, Patrick; Ulysse, Bernard; Akian Djétouan, Dieudonné; Bere Sompagnimdi, Frédéric; Tomson, Thomas; Mélard, Charles; Rougeot, Carole

    2015-01-01

    This study aimed to develop sex reversal procedures targeting the embryonic period as tools to study the early steps of sex differentiation in Nile tilapia with XX, XY, and YY sexual genotypes. XX eggs were exposed to masculinizing treatments with androgens (17α-methyltestosterone, 11-ketotestosterone) or aromatase inhibitor (Fadrozole), whereas XY and YY eggs were subjected to feminizing treatments with estrogen analog (17α-ethynylestradiol). All treatments consisted of a single or double 4-hr immersion applied between 1 and 36 hour post-fertilization (hpf). Concentrations of active substances were 1000 or 2000 μg l(-1) in XX and XY, and 2000 or 6500 μg l(-1) in YY. Masculinizing treatments of XX embryos achieved a maximal sex reversal rate of 10% with an exposure at 24 hpf to 1000 μg l(-1) of 11-ketotestosterone or to 2000 μg l(-1) of Fadrozole. Feminization of XY embryos was more efficient and induced up to 91% sex reversal with an exposure to 2000 μg l(-1) of 17α-ethynylestradiol. Interestingly, similar treatments failed to reverse YY fish to females, suggesting either that a sex determinant linked to the Y chromosome prevents the female pathway when present in two copies, or that a gene present on the X chromosome is needed for the development of a female phenotype. © 2014 Wiley Periodicals, Inc.

  14. Analysis of the rs10046 Polymorphism of Aromatase (CYP19 in Premenopausal Onset of Human Breast Cancer

    Directory of Open Access Journals (Sweden)

    Karin Zins

    2014-01-01

    Full Text Available The CYP19 gene encodes aromatase, an enzyme catalyzing the conversion of androgens to estrogens. Studies analyzing associations between single nucleotide polymorphisms in CYP19 and breast cancer risk have shown inconsistent results. The rs10046 polymorphism is located in the 3' untranslated region of the CYP19 gene, but the influence of this polymorphism on breast cancer risk is unclear. In this study, we investigated the impact of rs10046 SNP on breast cancer risk, age at onset and association with clinical characteristics in an Austrian population of 274 breast cancer patients and 253 controls. The results show that a significantly increased fraction of patients with the TT genotype of rs10046 develop breast cancer under the age of 50 (41.8% of TT patients, compared to 26.6% of C carriers; p = 0.018, Chi-square test. No rs10046 genotypes were significantly associated with increased breast cancer risk or patient characteristics other than age at onset. These results suggest that the rs10046 polymorphism in the CYP19 gene may have an effect on breast cancer susceptibility at an age under 50 in the investigated population.

  15. Estrogen receptor α functions in the regulation of motivation and spatial cognition in young male rats.

    Science.gov (United States)

    Meyer, Katrin; Korz, Volker

    2013-01-01

    Estrogenic functions in regulating behavioral states such as motivation, mood, anxiety, and cognition are relatively well documented in female humans and animals. In males, however, although the entire enzymatic machinery for producing estradiol and the corresponding receptors are present, estrogenic functions have been largely neglected. Therefore, and as a follow-up study to previous research, we sub-chronically applied a specific estrogen receptor α (ERα) antagonist in young male rats before and during a spatial learning task (holeboard). The male rats showed a dose-dependent increase in motivational, but not cognitive, behavior. The expression of hippocampal steroid receptor genes, such as glucocorticoid (GR), mineralocorticoid (MR), androgen (AR), and the estrogen receptor ERα but not ERβ was dose-dependently reduced. The expression of the aromatase but not the brain-derived neurotrophic factor (BDNF) encoding gene was also suppressed. Reduced gene expression and increased behavioral performance converged at an antagonist concentration of 7.4 µmol. The hippocampal and blood serum hormone levels (corticosterone, testosterone, and 17β-estradiol) did not differ between the experimental groups and controls. We conclude that steroid receptors (and BDNF) act in a concerted, network-like manner to affect behavior and mutual gene expression. Therefore, the isolated view on single receptor types is probably insufficient to explain steroid effects on behavior. The steroid network may keep motivation in homeostasis by supporting and constraining the behavioral expression of motivation.

  16. Estrogen receptor α functions in the regulation of motivation and spatial cognition in young male rats.

    Directory of Open Access Journals (Sweden)

    Katrin Meyer

    Full Text Available Estrogenic functions in regulating behavioral states such as motivation, mood, anxiety, and cognition are relatively well documented in female humans and animals. In males, however, although the entire enzymatic machinery for producing estradiol and the corresponding receptors are present, estrogenic functions have been largely neglected. Therefore, and as a follow-up study to previous research, we sub-chronically applied a specific estrogen receptor α (ERα antagonist in young male rats before and during a spatial learning task (holeboard. The male rats showed a dose-dependent increase in motivational, but not cognitive, behavior. The expression of hippocampal steroid receptor genes, such as glucocorticoid (GR, mineralocorticoid (MR, androgen (AR, and the estrogen receptor ERα but not ERβ was dose-dependently reduced. The expression of the aromatase but not the brain-derived neurotrophic factor (BDNF encoding gene was also suppressed. Reduced gene expression and increased behavioral performance converged at an antagonist concentration of 7.4 µmol. The hippocampal and blood serum hormone levels (corticosterone, testosterone, and 17β-estradiol did not differ between the experimental groups and controls. We conclude that steroid receptors (and BDNF act in a concerted, network-like manner to affect behavior and mutual gene expression. Therefore, the isolated view on single receptor types is probably insufficient to explain steroid effects on behavior. The steroid network may keep motivation in homeostasis by supporting and constraining the behavioral expression of motivation.

  17. Estrogen Effects on Wound Healing.

    Science.gov (United States)

    Horng, Huann-Cheng; Chang, Wen-Hsun; Yeh, Chang-Ching; Huang, Ben-Shian; Chang, Chia-Pei; Chen, Yi-Jen; Tsui, Kuan-Hao; Wang, Peng-Hui

    2017-11-03

    Wound healing is a physiological process, involving three successive and overlapping phases-hemostasis/inflammation, proliferation, and remodeling-to maintain the integrity of skin after trauma, either by accident or by procedure. Any disruption or unbalanced distribution of these processes might result in abnormal wound healing. Many molecular and clinical data support the effects of estrogen on normal skin homeostasis and wound healing. Estrogen deficiency, for example in postmenopausal women, is detrimental to wound healing processes, notably inflammation and re-granulation, while exogenous estrogen treatment may reverse these effects. Understanding the role of estrogen on skin might provide further opportunities to develop estrogen-related therapy for assistance in wound healing.

  18. Estrogens, Neuroinflammation, and Neurodegeneration

    Science.gov (United States)

    Villa, Alessandro; Vegeto, Elisabetta; Poletti, Angelo

    2016-01-01

    Inflammatory activation of microglia is a hallmark of several disorders of the central nervous system. In addition to protecting the brain against inflammatory insults, microglia are neuroprotective and play a significant role in maintaining neuronal connectivity, but the prolongation of an inflammatory status may limit the beneficial functions of these immune cells. The finding that estrogen receptors are present in monocyte-derived cells and that estrogens prevent and control the inflammatory response raise the question of the role that this sex steroid plays in the manifestation and progression of pathologies that have a clear sex difference in prevalence, such as multiple sclerosis, Parkinson's disease, and Alzheimer's disease. The present review aims to provide a critical review of the current literature on the actions of estrogen in microglia and on the involvement of estrogen receptors in the manifestation of selected neurological disorders. This current understanding highlights a research area that should be expanded to identify appropriate replacement therapies to slow the progression of such diseases. PMID:27196727

  19. Anaerobic biotransformation of estrogens

    International Nuclear Information System (INIS)

    Czajka, Cynthia P.; Londry, Kathleen L.

    2006-01-01

    Estrogens are important environmental contaminants that disrupt endocrine systems and feminize male fish. We investigated the potential for anaerobic biodegradation of the estrogens 17-α-ethynylestradiol (EE2) and 17-β-estradiol (E2) in order to understand their fate in aquatic and terrestrial environments. Cultures were established using lake water and sediment under methanogenic, sulfate-, iron-, and nitrate-reducing conditions. Anaerobic degradation of EE2 (added at 5 mg/L) was not observed in multiple trials over long incubation periods (over three years). E2 (added at 5 mg/L) was transformed to estrone (E1) under all four anaerobic conditions (99-176 μg L -1 day -1 ), but the extent of conversion was different for each electron acceptor. The oxidation of E2 to E1 was not inhibited by E1. Under some conditions, reversible inter-conversion of E2 and E1 was observed, and the final steady state concentration of E2 depended on the electron-accepting condition but was independent of the total amount of estrogens added. In addition, racemization occurred and E1 was also transformed to 17-α-estradiol under all but nitrate-reducing conditions. Although E2 could be readily transformed to E1 and in many cases 17-α-estradiol under anaerobic conditions, the complete degradation of estrogens under these conditions was minimal, suggesting that they would accumulate in anoxic environments

  20. Anaerobic biotransformation of estrogens

    Energy Technology Data Exchange (ETDEWEB)

    Czajka, Cynthia P. [Department of Microbiology, University of Manitoba, Winnipeg, MB, R3T 2N2 (Canada); Londry, Kathleen L. [Department of Microbiology, University of Manitoba, Winnipeg, MB, R3T 2N2 (Canada)]. E-mail: londryk@cc.umanitoba.ca

    2006-08-31

    Estrogens are important environmental contaminants that disrupt endocrine systems and feminize male fish. We investigated the potential for anaerobic biodegradation of the estrogens 17-{alpha}-ethynylestradiol (EE2) and 17-{beta}-estradiol (E2) in order to understand their fate in aquatic and terrestrial environments. Cultures were established using lake water and sediment under methanogenic, sulfate-, iron-, and nitrate-reducing conditions. Anaerobic degradation of EE2 (added at 5 mg/L) was not observed in multiple trials over long incubation periods (over three years). E2 (added at 5 mg/L) was transformed to estrone (E1) under all four anaerobic conditions (99-176 {mu}g L{sup -1} day{sup -1}), but the extent of conversion was different for each electron acceptor. The oxidation of E2 to E1 was not inhibited by E1. Under some conditions, reversible inter-conversion of E2 and E1 was observed, and the final steady state concentration of E2 depended on the electron-accepting condition but was independent of the total amount of estrogens added. In addition, racemization occurred and E1 was also transformed to 17-{alpha}-estradiol under all but nitrate-reducing conditions. Although E2 could be readily transformed to E1 and in many cases 17-{alpha}-estradiol under anaerobic conditions, the complete degradation of estrogens under these conditions was minimal, suggesting that they would accumulate in anoxic environments.

  1. Correlation between aromatase expression in the eutopic endometrium of symptomatic patients and the presence of endometriosis

    Directory of Open Access Journals (Sweden)

    Maia Jr H

    2012-02-01

    Full Text Available Hugo Maia Jr1,2, Clarice Haddad1,2, Julio Casoy11CEPARH, 2Itaigara Memorial Day Hospital, Salvador, Bahia, BrazilObjective: To investigate whether aromatase expression in the eutopic endometrium correlates with the presence and severity of endometriosis in patients with infertility and/or dysmenorrhea undergoing laparoscopy and hysteroscopy.Patients: The study involved 106 patients of reproductive age with symptoms of dysmenorrhea and infertility. Sixteen endometriosis-free asymptomatic patients were used as a control group.Methods: Concomitant laparoscopy and hysteroscopy was carried out in all cases. An endometrial biopsy was taken to determine aromatase p450 expression by immunohistochemistry. Endometriosis was staged according to the American Society of Reproductive Medicine classification.Results: Endometriosis was diagnosed by laparoscopy in 92/106 symptomatic patients. In this group, aromatase expression was detected in the eutopic endometrium of 66/92 patients with endometriosis (72% and in 13/14 (95% patients in the symptomatic, endometriosis-free group (P = 0.09. Aromatase expression was not detected in any patients from the control group. In the endometriosis group, aromatase expression was detected in the eutopic endometrium of 28/45 patients (62% with American Society of Reproductive Medicine classification stage 1 of the disease, in 11/14 patients (78% with stage II, 14/20 patients (70% with stage III, and in 12/13 patients (92% with stage IV; however, the difference was only statistically significant between stages I and IV (P = 0.04.Conclusion: Aromatase expression in the endometrium was associated with the presence of dysmenorrhea and infertility irrespective of the presence of endometriosis. When endometriosis was present, however, there was a tendency for aromatase expression to be positively correlated with dysmenorrhea severity.Keywords: aromatase, endometrium, endometriosis, Cox-2, dysmenorrhea

  2. Probing the active site of aromatase with 2-methyl-substituted androstenedione analogs.

    Science.gov (United States)

    Numazawa, Mitsuteru; Watari, Yoko; Yamada, Keiko; Umemura, Nao; Handa, Wakako

    2003-08-01

    To gain insight into the spatial nature of the androstenedione (AD) binding (active) site of aromatase in relation to the catalytic function of the enzyme, we synthesized 2,2-dimethylAD (4), 2beta- and 2alpha-methylADs (5 and 6), 19-oxygenated derivatives of compounds 4 and 6, and 2-methyleneAD (17), and we then tested their inhibitory activity as well as their aromatase reaction (aromatization for 2-methyl and 2-methylene analogs or 19-oxygenation for 2,2-dimethyl steroids) with human placental aromatase. 2-Methyl and 2-methylene steroids 5, 6, and 17 were good competitive inhibitors of aromatase (K(i)=22-68nM), but less effective compared to the 2,2-dimethyl analog 4 (K(i)=8.8nM), indicating that a combination of 2beta- and 2alpha-methyl moieties is essential for the formation of a thermodynamically stable inhibitor-aromatase complex. A series of 2alpha-methyl steroids were good substrates for aromatase, whereas 2beta-methyl steroid 5 was an extremely poor substrate, and a series of 2,2-dimethyl steroids did not serve as substrate, suggesting that a 2beta-methyl moiety of the 2,2-dimethyl and 2beta-methyl steroids would prevent the aromatase reaction probably due to steric hindrance in each case. The 2-methylene compound 17 was also aromatized to produce 2-methylestrogen with a low conversion rate where the 1,4-diene structure may have been created before the C(10)-C(19) bond cleavage. Kinetic analysis of the aromatization of androgens revealed that a good substrate was not essentially a good inhibitor for aromatase.

  3. Structural basis for androgen specificity and oestrogen synthesis in human aromatase

    Energy Technology Data Exchange (ETDEWEB)

    Ghosh, Debashis; Griswold, Jennifer; Erman, Mary; Pangborn, Walter; (HWMRI)

    2009-03-06

    Aromatase cytochrome P450 is the only enzyme in vertebrates known to catalyse the biosynthesis of all oestrogens from androgens. Aromatase inhibitors therefore constitute a frontline therapy for oestrogen-dependent breast cancer. In a three-step process, each step requiring 1 mol of O{sub 2}, 1 mol of NADPH, and coupling with its redox partner cytochrome P450 reductase, aromatase converts androstenedione, testosterone and 16{alpha}-hydroxytestosterone to oestrone, 17{beta}-oestradiol and 17{beta},16{alpha}-oestriol, respectively. The first two steps are C19-methyl hydroxylation steps, and the third involves the aromatization of the steroid A-ring, unique to aromatase. Whereas most P450s are not highly substrate selective, it is the hallmark androgenic specificity that sets aromatase apart. The structure of this enzyme of the endoplasmic reticulum membrane has remained unknown for decades, hindering elucidation of the biochemical mechanism. Here we present the crystal structure of human placental aromatase, the only natural mammalian, full-length P450 and P450 in hormone biosynthetic pathways to be crystallized so far. Unlike the active sites of many microsomal P450s that metabolize drugs and xenobiotics, aromatase has an androgen-specific cleft that binds the androstenedione molecule snugly. Hydrophobic and polar residues exquisitely complement the steroid backbone. The locations of catalytically important residues shed light on the reaction mechanism. The relative juxtaposition of the hydrophobic amino-terminal region and the opening to the catalytic cleft shows why membrane anchoring is necessary for the lipophilic substrates to gain access to the active site. The molecular basis for the enzyme's androgenic specificity and unique catalytic mechanism can be used for developing next-generation aromatase inhibitors.

  4. Estrogen-regulated expression of cyp19a1a and cyp19a1b genes in swim-up fry of Labeo rohita.

    Science.gov (United States)

    Gupta, Shreyasi; Moulik, Sujata Roy; Pal, Puja; Majumder, Suravi; Das, Sumana; Guha, Payel; Juin, Subir Kumar; Panigrahi, Ashis Kumar; Mukherjee, Dilip

    2017-09-15

    P450 aromatase is the terminal enzyme in the steroidogenic pathway and catalyzes the conversion of androgens to estrogens. The expression of cyp19a1 genes in brain and gonad of Indian major carp, Labeo rohita swim-up fry was measured by quantitative real-time polymerase chain-reaction. Results demonstrated that cyp19a1b and cyp19a1a predominate in brain and gonad respectively. Treatment of fry with an aromatase inhibitor fadrozole for 6days attenuated brain cyp19a1b expression, but not cyp19a1a of gonad. Fadrozole also attenuated brain aromatase activity. Treatment with 17β-estradiol (E2) for 6days resulted in up-regulation of brain cyp19a1b transcripts in a dose- and time-dependent manner, but not cyp19a1a. Whole-body concentration of vitellogenin also increased in response to E2. Altogether, these results indicate L. rohita swim-up fry can be used to detect environmental estrogens either using vitellogenin induction or cyp19a1b gene expression. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Geranyl diphosphate synthase from mint

    Energy Technology Data Exchange (ETDEWEB)

    Croteau, R.B.; Wildung, M.R.; Burke, C.C.; Gershenzon, J.

    1999-03-02

    A cDNA encoding geranyl diphosphate synthase from peppermint has been isolated and sequenced, and the corresponding amino acid sequence has been determined. Accordingly, an isolated DNA sequence (SEQ ID No:1) is provided which codes for the expression of geranyl diphosphate synthase (SEQ ID No:2) from peppermint (Mentha piperita). In other aspects, replicable recombinant cloning vehicles are provided which code for geranyl diphosphate synthase or for a base sequence sufficiently complementary to at least a portion of the geranyl diphosphate synthase DNA or RNA to enable hybridization therewith (e.g., antisense geranyl diphosphate synthase RNA or fragments of complementary geranyl diphosphate synthase DNA which are useful as polymerase chain reaction primers or as probes for geranyl diphosphate synthase or related genes). In yet other aspects, modified host cells are provided that have been transformed, transfected, infected and/or injected with a recombinant cloning vehicle and/or DNA sequence encoding geranyl diphosphate synthase. Thus, systems and methods are provided for the recombinant expression of geranyl diphosphate synthase that may be used to facilitate the production, isolation and purification of significant quantities of recombinant geranyl diphosphate synthase for subsequent use, to obtain expression or enhanced expression of geranyl diphosphate synthase in plants in order to enhance the production of monoterpenoids, to produce geranyl diphosphate in cancerous cells as a precursor to monoterpenoids having anti-cancer properties or may be otherwise employed for the regulation or expression of geranyl diphosphate synthase or the production of geranyl diphosphate. 5 figs.

  6. Geranyl diphosphate synthase from mint

    Energy Technology Data Exchange (ETDEWEB)

    Croteau, Rodney Bruce (Pullman, WA); Wildung, Mark Raymond (Colfax, WA); Burke, Charles Cullen (Moscow, ID); Gershenzon, Jonathan (Jena, DE)

    1999-01-01

    A cDNA encoding geranyl diphosphate synthase from peppermint has been isolated and sequenced, and the corresponding amino acid sequence has been determined. Accordingly, an isolated DNA sequence (SEQ ID No:1) is provided which codes for the expression of geranyl diphosphate synthase (SEQ ID No:2) from peppermint (Mentha piperita). In other aspects, replicable recombinant cloning vehicles are provided which code for geranyl diphosphate synthase or for a base sequence sufficiently complementary to at least a portion of the geranyl diphosphate synthase DNA or RNA to enable hybridization therewith (e.g., antisense geranyl diphosphate synthase RNA or fragments of complementary geranyl diphosphate synthase DNA which are useful as polymerase chain reaction primers or as probes for geranyl diphosphate synthase or related genes). In yet other aspects, modified host cells are provided that have been transformed, transfected, infected and/or injected with a recombinant cloning vehicle and/or DNA sequence encoding geranyl diphosphate synthase. Thus, systems and methods are provided for the recombinant expression of geranyl diphosphate synthase that may be used to facilitate the production, isolation and purification of significant quantities of recombinant geranyl diphosphate synthase for subsequent use, to obtain expression or enhanced expression of geranyl diphosphate synthase in plants in order to enhance the production of monoterpenoids, to produce geranyl diphosphate in cancerous cells as a precursor to monoterpenoids having anti-cancer properties or may be otherwise employed for the regulation or expression of geranyl diphosphate synthase or the production of geranyl diphosphate.

  7. Polyketide synthase from Fusarium

    DEFF Research Database (Denmark)

    Kvesel, Kasper; Wimmer, Reinhard; Sørensen, Jens Laurids

    Fungi produce a wide array of secondary metabolites, with interesting bioactivities by help of a number of enzyme complexes. Polyketide synthases (PKS) are a class of multidomain enzymes, producing a class of secondary metabolites called polyketides1,2. Only few structures of PKS’s have been...

  8. Aromatase inhibitor treatment limits progression of peritoneal endometriosis in baboons.

    Science.gov (United States)

    Langoi, David; Pavone, Mary Ellen; Gurates, Bilgin; Chai, Daniel; Fazleabas, Asgerally; Bulun, Serdar E

    2013-03-01

    To determine the effect of inhibiting aromatase activity on endometrial lesion growth and aromatase expression in a baboon model of induced endometriosis. Prospective study. Primate research institute. Sixteen olive baboons. Sixteen olive baboons with induced endometriosis were examined with laparoscopy 10 months after disease inoculation. Animals in group 1 (n = 10) were treated with 1.25 mg/d of the aromatase inhibitor (AI) letrozole, and animals in group 2 (n = 6) were given a placebo for a total of 6 months. Total number of endometriotic lesions, morphology, and volume of lesions, as well as semiquantitative reverse transcription-polymerase chain reaction and quantitative polymerase chain reaction for levels of aromatase cytochrome messenger RNA were measured. Ovarian volumes were evaluated before treatment initiation and every 2 months during the study. Treatment of group 1 animals with an AI significantly decreased lesion volume from baseline measurements, whereas the placebo-treated animals showed an increase in lesion volume. Aromatase messenger RNA levels in lesions in the AI-treated animals were significantly lower compared with the placebo-treated animals. Ovarian volumes were significantly increased at 6 months of AI treatment compared with pretreatment volumes. These findings suggest that suppression of aromatase cytochrome P450 may inhibit the in vivo growth of endometriotic lesions in baboons. Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  9. Uso de inibidores da aromatase no tratamento do câncer de mama e osteoporose = The use of aromatase inhibitors for breast cancer treatment and osteoporosis

    Directory of Open Access Journals (Sweden)

    Cassol, Lina Barbosa

    2005-01-01

    Full Text Available Objetivos: Nos últimos anos, os inibidores da aromatase têm emergido como uma alternativa ao tamoxifen no tratamento hormonal de pacientes pósmenopáusicas com câncer de mama, expressando receptores hormonais. Apesar de os inibidores da aromatase possuírem, em geral, um perfil de efeitos colaterais favorável, existem preocupações sobre seu impacto em longo prazo sobre a massa óssea e o desenvolvimento de osteoporose. Essa revisão descreve a relação dos estrógenos com o metabolismo ósseo, o mecanismo de ação e dados clínicos sobre os principais inibidores da aromatase, o impacto dessas drogas no desenvolvimento de osteoporose e as estratégias diagnósticas, preventivas e terapêuticas de osteoporose que devem ser aplicadas em pacientes com câncer de mama recebendo inibidores da aromatase. Fonte dos dados: A presente revisão baseou-se em artigos publicados nos últimos cinco anos, selecionados a partir de uma busca no Medline e de referências da bibliografia selecionada. Síntese dos dados: O tratamento com inibidores da aromatase associa-se a aumento na incidência de osteoporose e fraturas. Conclusão: Estratégias diagnósticas, preventivas e, eventualmente, terapêuticas de osteoporose devem ser empregadas precocemente em pacientes com câncer de mama tratadas com inibidores da aromatase

  10. Prognostic and predictive importance of the estrogen receptor coactivator AIB1 in a randomized trial comparing adjuvant letrozole and tamoxifen therapy in postmenopausal breast cancer

    DEFF Research Database (Denmark)

    Alkner, S; Jensen, M-B; Rasmussen, B B

    2017-01-01

    PURPOSE: To evaluate the estrogen receptor coactivator amplified in breast cancer 1 (AIB1) as a prognostic marker, as well as a predictive marker for response to adjuvant tamoxifen and/or aromatase inhibitors, in early estrogen receptor-positive breast cancer. METHOD: AIB1 was analyzed...... with immunohistochemistry in tissue microarrays of the Danish subcohort (N = 1396) of the International Breast Cancer Study Group's trial BIG 1-98 (randomization between adjuvant tamoxifen versus letrozole versus the sequence of the two drugs). RESULTS: Forty-six percent of the tumors had a high AIB1 expression. In line...... with previous studies, AIB1 correlated to a more aggressive tumor-phenotype (HER2 amplification and a high malignancy grade). High AIB1 also correlated to higher estrogen receptor expression (80-100 vs. 1-79%), and ductal histological type. High AIB1 expression was associated with a poor disease-free survival...

  11. Regulation of ovarian steroid biosynthesis by estrogen during proestrus in the rat.

    Science.gov (United States)

    Banks, P K; Meyer, K; Brodie, A M

    1991-09-01

    Studies were performed to test the hypothesis that the rapid decline in estradiol (E2) levels on proestrus before ovulation was due to a reduction in androgen substrate for aromatase, and that this decline in androgen was regulated by an estrogen receptor-mediated mechanism. Aromatase activity, concentrations of E2, androstenedione (A), testosterone (T), and progesterone (P4) in follicular, corpora lutea, and ovarian homogenates as well as peripheral E2, A, P4, and LH were measured in cycling rats from 1400-2000 h on proestrus. These parameters were also recorded after the expected E2 surge in animals treated at 1900 h on diestrous day 2 with the antiestrogen keoxifene (20 mg/kg), with or without an ovulatory dose of PMSG at 1600 h on proestrus. In a second experiment, P-450-17 alpha-hydroxylase/C17,20-lyase (P-450(17 alpha] activity was measured in a group of control rats at 1500, 1700, and 1900 h. Aromatase activity remained unchanged, even though serum and ovarian E2 levels were reduced from peak values at 1500 h to basal values at 1800 h (P less than 0.01). Peripheral A as well as ovarian androgens (specifically follicular but not luteal) A and T were also reduced over this time period (P less than 0.01). Although total ovarian P4 remained unchanged, follicular levels rose from 1400-2000 h (P less than 0.01). These reductions in androgens and E2 levels coincided with a marked reduction in follicular P-450(17 alpha) activity. Treatment with keoxifene with or without PMSG prevented the fall in peripheral E2 and A and the increase in peripheral P4 seen in controls. Ovarian and follicular E2, A, and to a lesser extent T were also remained at values similar to those during the E2 surge. Follicular P4 was reduced by both treatments. Neither treatment had any effect on aromatase. These results indicate that the fall in peripheral and ovarian E2 levels before ovulation was due to a decline in aromatizable androgen, through an inhibition of follicular P-450(17 alpha

  12. Estrogenic compounds -endocrine disruptors

    OpenAIRE

    Munteanu Constantin; Hoteteu Mihai

    2011-01-01

    Endocrine disruptors (polychlorinated biphenyls, dichlorodiphenyl-trichloroethane [DDT], dioxin, and some pesticides) are estrogen-like and anti-androgenic chemicals in the environment. They mimic natural hormones, inhibit the action of hormones, or alter the normal regulatory function of the endocrine system and have potential hazardous effects on male reproductive axis causing infertility. Although testicular and prostate cancers, abnormal sexual development, undescended testis, chronic inf...

  13. Estrogen receptor alpha is cell cycle-regulated and regulates the cell cycle in a ligand-dependent fashion.

    Science.gov (United States)

    JavanMoghadam, Sonia; Weihua, Zhang; Hunt, Kelly K; Keyomarsi, Khandan

    2016-06-17

    Estrogen receptor alpha (ERα) has been implicated in several cell cycle regulatory events and is an important predictive marker of disease outcome in breast cancer patients. Here, we aimed to elucidate the mechanism through which ERα influences proliferation in breast cancer cells. Our results show that ERα protein is cell cycle-regulated in human breast cancer cells and that the presence of 17-β-estradiol (E2) in the culture medium shortened the cell cycle significantly (by 4.5 hours, P fashion. These results provide the rationale for an effective treatment strategy that includes a cell cycle inhibitor in combination with a drug that lowers estrogen levels, such as an aromatase inhibitor, and an antiestrogen that does not result in the degradation of ERα, such as tamoxifen.

  14. Leptin, its receptor and aromatase expression in deep infiltrating endometriosis.

    Science.gov (United States)

    Gonçalves, Helder F; Zendron, Carolina; Cavalcante, Fernanda S; Aiceles, Verônica; Oliveira, Marco Aurélio P; Manaia, Jorge Henrique M; Babinski, Márcio A; Ramos, Cristiane F

    2015-08-05

    The aim of this study was to evaluate the leptin levels in the serum and peritoneal fluid (PF) and the protein expression in three different peritoneal ectopic implants in patients who underwent surgery for deep infiltrating endometriosis. All patients had been treated at the Department of Gynecology of the Pedro Ernesto University Hospital, Rio de Janeiro. The study group consisted of 15 patients who underwent surgery for adnexal masses and infertility, while the control group consisted of ten women who underwent surgery for tubal ligation. Peritoneal fluid and samples tissues were collected during surgery. Serum samples were obtained before anesthesia. In this study, the leptin levels in the serum and peritoneal fluid (PF) were evaluated by ELISA. The protein expression of leptin and its receptors (ObR) and aromatase enzyme were evaluated by Western blot analysis of the intestine, uterosacral ligament and vaginal septum in the ectopic implants. The t-test and one-way ANOVA with Holm-Sìdak post-test were used, and p endometriosis = 19.2 ng/mL ± 1.84, p endometriosis = 7.71 ng/mL ± 0.59, p = 0.18). Comparing women with and without ovarian implants, the leptin levels in both the serum and PF were significantly higher in women without ovarian implants (serum: with ovarian implant = 15.85 ± 1.99; without ovarian implant = 23.14 ± 2.60; ng/mL, p = 0.04; PF: with ovarian implant = 4.28 ± 1.30; without ovarian implant = 11.18 ± 2.98;ng/mL, p = 0.048). The leptin, ObR and aromatase protein expression levels were increased in lesions in the vaginal septum and were decreased in the intestine lesions. This study reports several interesting associations between the leptin levels in serum, peritoneal fluid, and tissue samples and the localization of the ectopic endometrium. Although this study does not provide a clear picture of the role of leptin in the development and progression of peritoneal implants

  15. Cleaning up polyketide synthases.

    Science.gov (United States)

    Kwan, Jason C; Schmidt, Eric W

    2012-03-23

    Complex biosynthetic enzymes such as polyketide synthases make mistakes. In this issue of Chemistry & Biology, Jensen et al. report that a discrete family of acyltransferases is responsible for error correction, hydrolyzing key biosynthetic intermediates from a multi-enzyme complex. This activity might find use in understanding polyketide biosynthesis, particularly in uncultivated organisms and in tailoring the synthesis of small molecules. Copyright © 2012 Elsevier Ltd. All rights reserved.

  16. Hybrid polyketide synthases

    Energy Technology Data Exchange (ETDEWEB)

    Fortman, Jeffrey L.; Hagen, Andrew; Katz, Leonard; Keasling, Jay D.; Poust, Sean; Zhang, Jingwei; Zotchev, Sergey

    2016-05-10

    The present invention provides for a polyketide synthase (PKS) capable of synthesizing an even-chain or odd-chain diacid or lactam or diamine. The present invention also provides for a host cell comprising the PKS and when cultured produces the even-chain diacid, odd-chain diacid, or KAPA. The present invention also provides for a host cell comprising the PKS capable of synthesizing a pimelic acid or KAPA, and when cultured produces biotin.

  17. Aromatase reaction of 3-deoxyandrogens: steric mode of the C-19 oxygenation and cleavage of the C10-C19 bond by human placental aromatase.

    Science.gov (United States)

    Numazawa, Mitsuteru; Nagaoka, Masao; Sohtome, Norishige

    2005-08-16

    Aromatase is a cytochrome P-450 enzyme complex that catalyzes the conversion of androst-4-ene-3,17-dione (AD) to estrone and formic acid through three sequential oxygenations of the 19-methyl group. To gain insight into the catalytic function of aromatase as well as the mechanism of the hitherto uncertain third oxygenation step, we focused on the aromatase-catalyzed 19-oxygenation of 3-deoxyandrogens: 3-deoxy-AD (1), which is a very powerful competitive inhibitor but poor substrate of aromatase, and its 5-ene isomer 4, which is a good competitive inhibitor and effective substrate of the enzyme. In incubations of their 19S-(3)H-labeled 19-hydroxy derivatives 2 and 5 and the corresponding 19R-(3)H isomers with human placental microsomes in the presence of NADPH under air, the radioactivity was liberated in both water and formic acid. The productions of (3)H(2)O and (3)HCOOH were blocked by the substrate AD or the inhibitor 4-hydroxy-AD, indicating that these productions are due to a catalytic function of aromatase. A comparison of the (3)H(2)O production from S-(3)H substrates 2 and 5 with that from the corresponding R-(3)H isomers revealed that the 19-pro-R hydrogen atom was stereospecifically (pro-R:pro-S = 100:0) removed in the conversion of 5-ene substrate 5 into the 19-oxo product 6, whereas 75:25 stereoselectivity for the loss of the pro-R and pro-S hydrogen atoms was observed in the oxygenation of the other substrate, 2. The present results reveal that human placental aromatase catalyzes three sequential oxygenations at C-19 of 3-deoxyandrogens 1 and 4 to cause the cleavage of the C(10)-C(19) bond through their 19-hydroxy (2 and 5) and 19-oxo (3 and 6) intermediates, respectively, where there is a difference in the stereochemistry between the two androgens in the second 19-hydroxylation. It is implied that the aromatase-catalyzed 19-oxygenation of 5-ene steroid 4 but not the 4-ene isomer 1 would proceed in the same steric mechanism as that involved in the AD

  18. Estrogen effects on the breast

    International Nuclear Information System (INIS)

    Berkowitz, J.E.; Goldblum, L.E.; Gatewood, O.M.B.; Gayler, B.W.

    1988-01-01

    Estrogen is frequently used in postmenopausal women for the treatment of menopausal symptoms and for prevention of osteoporosis. Little mention of estrogen effects on the postmenopausal breast is found in the literature. It has been suggested that estrogen replacement therapy may cause proliferative changes in the breast, manifested by mammographically dense breasts. The authors present five patients in whom the fibroglandular tissue dramatically increased after initiation of hormonal therapy. One patient's mammogram returned to baseline 2 weeks after discontinuation of treatment. Recognition of the estrogen effect is important since appearing densities are cause for suspicion in the postmenopausal breast and since very dense breasts can obscure masses

  19. In vitro and in vivo estrogenic activity of BPA, BPF and BPS in zebrafish-specific assays.

    Science.gov (United States)

    Le Fol, Vincent; Aït-Aïssa, Selim; Sonavane, Manoj; Porcher, Jean-Marc; Balaguer, Patrick; Cravedi, Jean-Pierre; Zalko, Daniel; Brion, François

    2017-08-01

    Bisphenol A (BPA) is a widely used chemical that has been extensively studied as an endocrine-disrupting chemical (EDC). Other bisphenols sharing close structural features with BPA, are increasingly being used as alternatives, increasing the need to assess associated hazards to the endocrine system. In the present study, the estrogenic activity of BPA, bisphenol S (BPS) and bisphenol F (BPF) was assessed by using a combination of zebrafish-specific mechanism-based in vitro and in vivo assays. The three bisphenols were found to efficiently transactivate all zebrafish estrogen receptor (zfER) subtypes in zebrafish hepatic reporter cell lines (ZELH-zfERs). BPA was selective for zfERα while BPS and BPF were slightly more potent on zfERβ subtypes. We further documented the estrogenic effect in vivo by quantifying the expression of brain aromatase using a transgenic cyp19a1b-GFP zebrafish embryo assay. All three bisphenols induced GFP in a concentration-dependent manner. BPS only partially induced brain aromatase at the highest tested concentrations (>30µM) while BPA and BPF strongly induced GFP, in an ER-dependent manner, at 1-10µM. Furthermore, we show that BPF strongly induced vitellogenin synthesis in adult male zebrafish. Overall, this study demonstrates the estrogenic activity of BPA, BPF and BPS in different cell- and tissue-contexts and at different stages of development. Differences between in vitro and in vivo responses are discussed in light of selective ER activation and the fate of the compounds in the models. This study confirms the relevance of combining cellular and whole-organism bioassays in a unique model species for the hazard assessment of candidate EDCs. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Genetic Polymorphisms in the Long Noncoding RNA MIR2052HG Offer a Pharmacogenomic Basis for the Response of Breast Cancer Patients to Aromatase Inhibitor Therapy.

    Science.gov (United States)

    Ingle, James N; Xie, Fang; Ellis, Matthew J; Goss, Paul E; Shepherd, Lois E; Chapman, Judith-Anne W; Chen, Bingshu E; Kubo, Michiaki; Furukawa, Yoichi; Momozawa, Yukihide; Stearns, Vered; Pritchard, Kathleen I; Barman, Poulami; Carlson, Erin E; Goetz, Matthew P; Weinshilboum, Richard M; Kalari, Krishna R; Wang, Liewei

    2016-12-01

    Genetic risks in breast cancer remain only partly understood. Here, we report the results of a genome-wide association study of germline DNA from 4,658 women, including 252 women experiencing a breast cancer recurrence, who were entered on the MA.27 adjuvant trial comparing the aromatase inhibitors (AI) anastrozole and exemestane. Single-nucleotide polymorphisms (SNP) of top significance were identified in the gene encoding MIR2052HG, a long noncoding RNA of unknown function. Heterozygous or homozygous individuals for variant alleles exhibited a ∼40% or ∼63% decrease, respectively, in the hazard of breast cancer recurrence relative to homozygous wild-type individuals. Functional genomic studies in lymphoblastoid cell lines and ERα-positive breast cancer cell lines showed that expression from MIR2052HG and the ESR1 gene encoding estrogen receptor-α (ERα) was induced by estrogen and AI in a SNP-dependent manner. Variant SNP genotypes exhibited increased ERα binding to estrogen response elements, relative to wild-type genotypes, a pattern that was reversed by AI treatment. Further, variant SNPs were associated with lower expression of MIR2052HG and ERα. RNAi-mediated silencing of MIR2052HG in breast cancer cell lines decreased ERα expression, cell proliferation, and anchorage-independent colony formation. Mechanistic investigations revealed that MIR2052HG sustained ERα levels both by promoting AKT/FOXO3-mediated ESR1 transcription and by limiting ubiquitin-mediated, proteasome-dependent degradation of ERα. Taken together, our results define MIR2052HS as a functionally polymorphic gene that affects risks of breast cancer recurrence in women treated with AI. More broadly, our results offer a pharmacogenomic basis to understand differences in the response of breast cancer patients to AI therapy. Cancer Res; 76(23); 7012-23. ©2016 AACR. ©2016 American Association for Cancer Research.

  1. Genomic risk prediction of aromatase inhibitor-related arthralgia in patients with breast cancer using a novel machine-learning algorithm.

    Science.gov (United States)

    Reinbolt, Raquel E; Sonis, Stephen; Timmers, Cynthia D; Fernández-Martínez, Juan Luis; Cernea, Ana; de Andrés-Galiana, Enrique J; Hashemi, Sepehr; Miller, Karin; Pilarski, Robert; Lustberg, Maryam B

    2018-01-01

    Many breast cancer (BC) patients treated with aromatase inhibitors (AIs) develop aromatase inhibitor-related arthralgia (AIA). Candidate gene studies to identify AIA risk are limited in scope. We evaluated the potential of a novel analytic algorithm (NAA) to predict AIA using germline single nucleotide polymorphisms (SNP) data obtained before treatment initiation. Systematic chart review of 700 AI-treated patients with stage I-III BC identified asymptomatic patients (n = 39) and those with clinically significant AIA resulting in AI termination or therapy switch (n = 123). Germline DNA was obtained and SNP genotyping performed using the Affymetrix UK BioBank Axiom Array to yield 695,277 SNPs. SNP clusters that most closely defined AIA risk were discovered using an NAA that sequentially combined statistical filtering and a machine-learning algorithm. NCBI PhenGenI and Ensemble databases defined gene attribution of the most discriminating SNPs. Phenotype, pathway, and ontologic analyses assessed functional and mechanistic validity. Demographics were similar in cases and controls. A cluster of 70 SNPs, correlating to 57 genes, was identified. This SNP group predicted AIA occurrence with a maximum accuracy of 75.93%. Strong associations with arthralgia, breast cancer, and estrogen phenotypes were seen in 19/57 genes (33%) and were functionally consistent. Using a NAA, we identified a 70 SNP cluster that predicted AIA risk with fair accuracy. Phenotype, functional, and pathway analysis of attributed genes was consistent with clinical phenotypes. This study is the first to link a specific SNP/gene cluster to AIA risk independent of candidate gene bias. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  2. [Advances in isoprene synthase research].

    Science.gov (United States)

    Gou, Yan; Liu, Zhongchuan; Wang, Ganggang

    2017-11-25

    Isoprene emission can lead to significant consequence for atmospheric chemistry. In addition, isoprene is a chemical compound for various industrial applications. In the organisms, isoprene is produced by isoprene synthase that eliminates the pyrophosphate from the dimethylallyl diphosphate. As a key enzyme of isoprene formation, isoprene synthase plays an important role in the process of natural emission and artificial synthesis of isoprene. So far, isoprene synthase has been found in various plants. Isoprene synthases from different sources are of conservative structural and similar biochemical properties. In this review, the biochemical and structural characteristics of isoprene synthases from different sources were compared, the catalytic mechanism of isoprene synthase was discussed, and the perspective application of the enzyme in bioengineering was proposed.

  3. Relevance of pituitary aromatase and estradiol on the maintenance of the population of prolactin-positive cells in male mice.

    Science.gov (United States)

    García-Barrado, María José; Blanco, Enrique J; Catalano-Iniesta, Leonardo; Sanchez-Robledo, Virginia; Iglesias-Osma, María Carmen; Carretero-Hernández, Marta; Rodríguez-Cobos, Javier; Burks, Deborah Jane; Carretero, José

    2016-07-01

    In previous studies we demonstrated the expression of aromatase in pituitary cells. This expression is gender related, and is also associated with the presence of prolactinomas. To ascertain the relevance of aromatase in modulating the populations of prolactin-positive pituitary cells an immunocytochemical and morphometric study of prolactin-positive pituitary cells was carried out using the pituitary glands of adult male and female aromatase-knockout (ArKO) mice. Additionally has been determined if pituitary aromatase is involved in a gender-linked differentiated regulation of the prolactin-producing pituitary cells. Compared to wild-type mice, the knockout animals of both genders showed a significant decrease (pprolactin cells, as well as in the percentages of the prolactin-positive cells and the proliferating prolactin cells. Our results suggest that estradiol is responsible for the maintenance of the population of prolactin cell in males and, so as not to disturb the endocrine reproductive environment, estradiol is synthesized inside the pituitary by circulating testosterone via means of aromatase P450, which acts in paracrine way. This new role for pituitary aromatase may well explain the previous findings establishing that the pituitary expression of aromatase is higher in males than in females, and the association between the development of prolactinomas and the increased expression of aromatase in tumours. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Estrogenic compounds -endocrine disruptors

    Directory of Open Access Journals (Sweden)

    Munteanu Constantin

    2011-11-01

    Full Text Available Endocrine disruptors (polychlorinated biphenyls, dichlorodiphenyl-trichloroethane [DDT], dioxin, and some pesticides are estrogen-like and anti-androgenic chemicals in the environment. They mimic natural hormones, inhibit the action of hormones, or alter the normal regulatory function of the endocrine system and have potential hazardous effects on male reproductive axis causing infertility. Although testicular and prostate cancers, abnormal sexual development, undescended testis, chronic inflammation, Sertoli-cell-only pattern, hypospadias, altered pituitary and thyroid gland functions are also observed, the available data are insufficient to deduce worldwide conclusions.

  5. An Arabidopsis callose synthase

    DEFF Research Database (Denmark)

    Ostergaard, Lars; Petersen, Morten; Mattsson, Ole

    2002-01-01

    in the Arabidopsis mpk4 mutant which exhibits systemic acquired resistance (SAR), elevated beta-1,3-glucan synthase activity, and increased callose levels. In addition, AtGsl5 is a likely target of salicylic acid (SA)-dependent SAR, since AtGsl5 mRNA accumulation is induced by SA in wild-type plants, while...... expression of the nahG salicylate hydroxylase reduces AtGsl5 mRNA levels in the mpk4 mutant. These results indicate that AtGsl5 is likely involved in callose synthesis in flowering tissues and in the mpk4 mutant....

  6. ESTROGEN IN THE LIMBIC SYSTEM

    NARCIS (Netherlands)

    ter Horst, Gert J.; Litwack, G

    2010-01-01

    Estrogens are a group of steroid hormones that function as the primary female sex hormone. Estrogens not only have an important role in the regulation of the estrous or menstrual cycle but also control, for example, bone formation, the cardiovascular system, and cognitive functions. Estradiol (E2),

  7. Tumor estrogen content and clinico-morphological and endocrine features of endometrial cancer.

    Science.gov (United States)

    Berstein, L M; Tchernobrovkina, A E; Gamajunova, V B; Kovalevskij, A J; Vasilyev, D A; Chepik, O F; Turkevitch, E A; Tsyrlina, E V; Maximov, S J; Ashrafian, L A; Thijssen, J H H

    2003-04-01

    To compare estrogen concentrations in endometrial cancer tissue with those in macroscopically normal endometrium and with certain morphological characteristics of the tumor and endocrine parameters in patients. The estradiol content was evaluated by radioimmunoassay after homogenization and extraction in 78 adenocarcinomas (61 from postmenopausal patients). Higher concentrations of estradiol in tumor tissue samples than in macroscopically normal endometrium were found in patients of both reproductive and postmenopausal age. This difference was the same in patients with either endometrial carcinoma type I or type II. No association between tumor steroid receptor levels, estradiol concentrations in blood serum, and timing of menopause with intratumoral estradiol contents was discovered. Estradiol concentrations in tumor tissues correlated positively with the clinical stage of disease and rate of tumor invasion (in patients with peripheric/lower type of fat topography), and negatively with tumor differentiation stage (in patients with central/upper type of fat topography) and the percentage of intact double-stranded DNA in normal endometrium. Tumor estrogen content in endometrial cancer has clinical significance that is modified in the presence of certain endocrine characteristics related to insulin resistance. The role of local estrogen production (aromatase activity) in this setting deserves special study.

  8. Dynamics of Aromatase and Physiological Indexes in Male Fish as Potential Biomarkers of Anthropogenic Pollution.

    Science.gov (United States)

    Guyón, N F; Roggio, M A; Amé, M V; Wunderlin, D A; Bistoni, M A

    2016-11-01

    Endocrine disruption on aquatic wildlife is being increasingly reported, and the changes in gene aromatase expression are used as indicators. However, natural fluctuations in brain and gonadal aromatase expression and physiological indexes have not been previously measured in a fish species (Jenynsia multidentata) throughout a complete reproductive cycle, nor the biological effects of anthropogenic inputs on these responses. Accordingly, males were monthly collected over a year in both, a reference and a contaminated site. Physicochemical analyses of water samples were done and reflected a strong anthropogenic impact. Brain aromatase fluctuates along the reproductive cycle of this species and, noticeably, the increase of brain gene expression begins with a 1 month delay in the contaminated site. This mismatch is also evidenced for testes weight. Hepatosomatic index also revealed adverse effects in the polluted site. In turn, the alterations observed in biological responses could be affecting the reproduction of this fish species.

  9. Monoterpene synthases from common sage (Salvia officinalis)

    Energy Technology Data Exchange (ETDEWEB)

    Croteau, Rodney Bruce (Pullman, WA); Wise, Mitchell Lynn (Pullman, WA); Katahira, Eva Joy (Pullman, WA); Savage, Thomas Jonathan (Christchurch 5, NZ)

    1999-01-01

    cDNAs encoding (+)-bornyl diphosphate synthase, 1,8-cineole synthase and (+)-sabinene synthase from common sage (Salvia officinalis) have been isolated and sequenced, and the corresponding amino acid sequences has been determined. Accordingly, isolated DNA sequences (SEQ ID No:1; SEQ ID No:3 and SEQ ID No:5) are provided which code for the expression of (+)-bornyl diphosphate synthase (SEQ ID No:2), 1,8-cineole synthase (SEQ ID No:4) and (+)-sabinene synthase SEQ ID No:6), respectively, from sage (Salvia officinalis). In other aspects, replicable recombinant cloning vehicles are provided which code for (+)-bornyl diphosphate synthase, 1,8-cineole synthase or (+)-sabinene synthase, or for a base sequence sufficiently complementary to at least a portion of (+)-bornyl diphosphate synthase, 1,8-cineole synthase or (+)-sabinene synthase DNA or RNA to enable hybridization therewith. In yet other aspects, modified host cells are provided that have been transformed, transfected, infected and/or injected with a recombinant cloning vehicle and/or DNA sequence encoding (+)-bornyl diphosphate synthase, 1,8-cineole synthase or (+)-sabinene synthase. Thus, systems and methods are provided for the recombinant expression of the aforementioned recombinant monoterpene synthases that may be used to facilitate their production, isolation and purification in significant amounts. Recombinant (+)-bornyl diphosphate synthase, 1,8-cineole synthase and (+)-sabinene synthase may be used to obtain expression or enhanced expression of (+)-bornyl diphosphate synthase, 1,8-cineole synthase and (+)-sabinene synthase in plants in order to enhance the production of monoterpenoids, or may be otherwise employed for the regulation or expression of (+)-bornyl diphosphate synthase, 1,8-cineole synthase and (+)-sabinene synthase, or the production of their products.

  10. Estrogen Effects on Wound Healing

    Directory of Open Access Journals (Sweden)

    Huann-Cheng Horng

    2017-11-01

    Full Text Available Wound healing is a physiological process, involving three successive and overlapping phases—hemostasis/inflammation, proliferation, and remodeling—to maintain the integrity of skin after trauma, either by accident or by procedure. Any disruption or unbalanced distribution of these processes might result in abnormal wound healing. Many molecular and clinical data support the effects of estrogen on normal skin homeostasis and wound healing. Estrogen deficiency, for example in postmenopausal women, is detrimental to wound healing processes, notably inflammation and re-granulation, while exogenous estrogen treatment may reverse these effects. Understanding the role of estrogen on skin might provide further opportunities to develop estrogen-related therapy for assistance in wound healing.

  11. Comparative study on individual aromatase inhibitors on cardiovascular safety profile: a network meta-analysis

    Directory of Open Access Journals (Sweden)

    Zhao XH

    2015-09-01

    Full Text Available Xihe Zhao,1 Lei Liu,2 Kai Li,1 Wusheng Li,1 Li Zhao,1 Huawei Zou1 1Department of Oncology, 2Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China Abstract: The third-generation aromatase inhibitors (AIs: anastrozole, letrozole, and exemestane have now become standard adjuvant endocrine treatment for postmenopausal estrogen receptor-positive breast cancer complementing chemotherapy and surgery. Because of the absence of direct head-to-head comparisons of these AIs, an indirect comparison is needed for individual treatment choice. In this network systemic assessment, the cardiovascular (CV side effects in using anastrozole, letrozole, and exemestane based on original studies on AIs vs placebo or tamoxifen were compared. We integrated all available direct and indirect evidences. The odds ratio (OR of severe CV events for indirect comparisons between exemestane and anastrozole was 1.41 (95% confidence interval [CI] =0.49–2.78, letrozole and anastrozole was 1.80 (95% CI =0.40–3.92, and letrozole and exemestane was 1.46 (95% CI =0.34–3.4. OR of subgroup risk for AIs and tamoxifen were all >1 except for thrombolism risk subgroup. The results showed that the total and severe CV risk ranking is letrozole, exemestane, and anastrozole in descending order. None of the AIs showed advantages in CV events than tamoxifen except for thromboembolism event incidence. Keywords: CV risk, breast cancer, AI, network meta-analysis

  12. Effects of transferrin on aromatase activity in porcine granulosa cells in vitro.

    Directory of Open Access Journals (Sweden)

    Małgorzata Duda

    2009-01-01

    Full Text Available Proliferating cells have an absolute requirement for iron, which is delivered by transferrin with subsequent intracellular transport via the transferrin receptor. Recent studies have reported that transferrin plays a crucial role in the local regulation of ovarian function, apart from its iron-binding characteristic. Therefore, the present study was undertaken to explore the possible role of transferrin in porcine granulosa cells function by examining its influence on aromatase activity, the most important indicator of follicular cell differentiation. In the first series of studies, pig granulosa cells isolated from small, immature follicles were cultured in the presence of transferrin alone (10 microg/ml or 100 microg/ml or with the addition of FSH (100ng/ml. The second series of studies was undertaken to determine transferrin-stimulated granulosa cells ability to aromatize exogenous testosterone (1x10(-7M. One hour after the establishment of cultures an aromatase inhibitor CGS16949A was added to test its influence on estradiol production. After 48 hours, cultures were terminated and cells were processed for immunocytochemical staining of aromatase. Media were frozen for further estradiol level analysis. Positive immunostaining for aromatase was found in all granulosa cell cultures. The intensity of immunostaining was always stronger in cultures supplemented with FSH whereas the addition of transferrin had no effect. Granulosa cells in vitro synthesized the highest amount of estradiol after the addition of FSH and exogenous testosterone as measured radioimmunologically. Concomitant treatment with FSH and transferrin caused an inhibition of FSH-stimulated aromatase activity. The production of estradiol also declined in the presence of FSH, testosterone and transferrin. This study demonstrates that transferrin had a dose-dependent inhibitory effect on FSH-stimulated aromatase activity, which was confirmed by radioimmunoassay. Our results indicate

  13. Screening of selected pesticides for inhibition of CYP19 aromatase activity in vitro

    DEFF Research Database (Denmark)

    Vinggaard, A.M.; Hnida, C.; Breinholt, V.

    2000-01-01

    Many pesticides are able to block or activate the steroid hormone receptors and/or to affect the levels of sex hormones, thereby potentially affecting the development or expression of the male and female reproductive system or both. This emphasizes the relevance of screening pesticides for a wide......, and triadimenol were identified as weak aromatase inhibitors. In conclusion, seven out of 22 tested pesticides turned out to be weak to moderate aromatase inhibitors in vitro, indicating the relevance of elucidating the endocrine effects in vivo of these compounds....

  14. Genetic variants of estrogen beta and leptin receptors may cause gynecomastia in adolescent.

    Science.gov (United States)

    Eren, Erdal; Edgunlu, Tuba; Korkmaz, Huseyin Anil; Cakir, Esra Deniz Papatya; Demir, Korcan; Cetin, Esin Sakalli; Celik, Sevim Karakas

    2014-05-15

    Gynecomastia is a benign breast enlargement in males that affects approximately one-third of adolescents. The exact mechanism is not fully understood; however, it has been proposed that estrogen receptors and aromatase enzyme activity may play important roles in the pathogenesis of gynecomastia. While many studies have reported that aromatase enzyme (CYP19) gene polymorphism is associated with gynecomastia, only one study has shown a relationship between estrogen receptor (ER) alpha and beta gene polymorphism and gynecomastia. Thus, the aim of this study was to evaluate the relationships between CYP19 (rs2414096), ER alpha (rs2234693), ER beta (rs4986938), leptin (rs7799039), and leptin receptor (rs1137101) gene polymorphisms and gynecomastia. This study included 107 male adolescents with gynecomastia and 97 controls. Total serum testosterone (T) and estradiol (E2) levels were measured, and DNA was extracted from whole blood using the PCR-RFLP technique. The polymorphic distributions of CYP19, ER alpha, ER beta, leptin and leptin receptor genes were compared. The median E2 level was 12.41 (5.00-65.40) pg/ml in the control group and 16.86 (2.58-78.47) pg/ml in the study group (pgynecomastia and leptin receptor rs1137101 (p=0.002) and ER beta receptor rs4986938 gene polymorphisms (p=0.002). According to our results, increased E2 level and ER beta gene rs4986938 polymorphism might explain why some adolescents have gynecomastia. Leptin receptor gene rs1137101 polymorphism might affect susceptibility to gynecomastia. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. [Estrogens, progestins and blood lipids].

    Science.gov (United States)

    Tikkanen, M J

    1984-01-01

    Progestins and estrogens can affect blood lipids and, as a result, contribute to cardiovascular disease. Since the very first studies, scientists have treated progestins and estrogens separately instead of studying their combined effect. Studies have shown that oral contraceptives (OCs) increase the risk of heart attack and brain hemorrhage. Heart attacks are 3-4 times more likely to occur in women aged 25-49 who are using OCs than those who are not. The risk diminishes after use is discontinued, but women aged 40-49 with a long history of OC use remain twice as prone to heart attacks even after giving up these contraceptives. OCs can cause problems with clotting, resulting in coronary and other arterial complications, increasing atherogenic risk. The effect of steroids on clotting and blood pressure must be studied before it can be determined how cardiovascular disease can be prevented. The author advocates the use of natural and synthetic estrogens in small quantities. He recommends the following in particular: progestins of the pregnal series, desogestrel, and a combination of 19-nortestosterone and estrogen. Synthetic estrogens (mestronol, ethinylestradio) increase high density lipoprotein (HDL) cholesterol levels, and androgens reduce them. Except for desogestrel, currently available progestins are related to androgens. It was discovered in 1977 that progestins in the pregnal series can cause tumors in the breast glands of beagles. Synthetic estrogens increase triglyceride levels by accelerating very low density lipoprotein (VLDL) synthesis. Currently available OCs which contain fewer estrogens, do not affect triglyceride levels to any significant degree. Conjugated estrogens are widely used in Anglo-Saxon countries and can cause hypertriglyceridemia. All other estrogens used to treat symptoms of menopause increase HDL cholesterol and reduce atherogenic LDL cholesterol.

  16. Estrogen and gastrointestinal malignancy.

    LENUS (Irish Health Repository)

    Hogan, A M

    2012-02-01

    The concept that E2 exerts an effect on the gastrointestinal tract is not new and its actions on intestinal mucosa have been investigated for at least three decades. An attempt to consolidate results of these investigations generates more questions than answers, thus suggesting that many unexplored avenues remain and that the full capabilities of this steroid hormone are far from understood. Evidence of its role in esophageal, gastric and gallbladder cancers is confusing and often equivocal. The most compelling evidence regards the protective role conferred by estrogen (or perhaps ERbeta) against the development and proliferation of colon cancer. Not only has the effect been described but also many mechanisms of action have been explored. It is likely that, along with surgery, chemotherapy and radiotherapy, hormonal manipulation will play an integral role in colon cancer management in the very near future.

  17. Dienogest inhibits aromatase and cyclooxygenase-2 expression and prostaglandin E₂ production in human endometriotic stromal cells in spheroid culture.

    Science.gov (United States)

    Yamanaka, Kaoruko; Xu, Bing; Suganuma, Izumi; Kusuki, Izumi; Mita, Shizuka; Shimizu, Yutaka; Mizuguchi, Kiyoshi; Kitawaki, Jo

    2012-02-01

    To determine the effect of dienogest (DNG) on the expression of aromatase and cyclooxygenase-2 (COX-2) and the production of prostaglandin E(2) (PGE(2)) in human endometriotic stromal cells (ESCs). Experimental study in vitro. University hospital. Seventeen patients with ovarian endometrioma. ESCs from chocolate cyst linings of ovaries were treated with DNG. Expression of aromatase and COX-2 evaluated in spheroid cultures of human ESCs by real-time quantitative polymerase chain-reaction and immunocytochemistry, production of PGE(2) quantified by enzyme-linked immunosorbent assay (ELISA), and nuclear factor kappa B (NF-κB) DNA-binding examined by ELISA and immunocytochemistry. The pharmaceutical actions of DNG on the expression of aromatase and COX-2 and the production of PGE(2) were examined using spheroid cultures of human ESCs. More aromatase, COX-2, and PGE(2) were expressed in spheroid cultures than in conventional ESCs monolayers. In the spheroid cultures, DNG (10(-7) M) and progesterone (10(-7) M) inhibited the expression of aromatase, COX-2, and PGE(2). DNG also inhibited NF-κB DNA-binding activity and reduced the immunocytochemical protein expression of aromatase, COX-2, and NF-κB p50 nuclear localization. Because DNG inhibits aromatase and COX-2 expression as well as PGE(2) production in ESCs, these pharmacologic features might contribute to a therapeutic effect of DNG on endometriosis. Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  18. Effect-directed analysis for estrogenic compounds in a fluvial sediment sample using transgenic cyp19a1b-GFP zebrafish embryos.

    Science.gov (United States)

    Fetter, Eva; Krauss, Martin; Brion, François; Kah, Olivier; Scholz, Stefan; Brack, Werner

    2014-09-01

    Xenoestrogens may persist in the environment by binding to sediments or suspended particulate matter serving as long-term reservoir and source of exposure, particularly for organisms living in or in contact with sediments. In this study, we present for the first time an effect-directed analysis (EDA) for identifying estrogenic compounds in a sediment sample using embryos of a transgenic reporter fish strain. In the tg(cyp19a1b-GFP) transgenic zebrafish strain, the expression of GFP (green fluorescent protein) in the brain is driven by an oestrogen responsive element in the promoter of the cyp19a1b (aromatase) gene. The selected sediment sample of the Czech river Bilina had already been analysed in a previous EDA using the yeast oestrogen screening assay and had revealed fractions containing estrogenic compounds. When normal phase HPLC (high performance liquid chromatography) fractionation was used for the separation of the sediment sample, the biotest with transgenic fish embryos revealed two estrogenic fractions. Chemical analysis of candidate compounds in these sediment fractions suggested alkylphenols and estrone as candidate compounds responsible for the observed estrogenic effect. Alkylphenol concentrations could partially explain the estrogenicity of the fractions. However, xenoestrogens below the analytical detection limit or non-targeted estrogenic compounds have probably also contributed to the sample's estrogenic potency. The results indicated the suitability of the tg(cyp19a1b-GFP) fish embryo for an integrated chemical-biological analysis of estrogenic effects. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Dienogest reduces proliferation, aromatase expression and angiogenesis, and increases apoptosis in human endometriosis.

    Science.gov (United States)

    Miyashita, Mariko; Koga, Kaori; Takamura, Masashi; Izumi, Gentaro; Nagai, Miwako; Harada, Miyuki; Hirata, Tetsuya; Hirota, Yasushi; Fujii, Tomoyuki; Osuga, Yutaka

    2014-09-01

    Dienogest is a novel progestin that is highly selective for progesterone receptors and inhibits endometriosis. However, it remains unknown how the administration of dienogest to patients with endometriosis impacts on their lesion tissues. The aim of this study was to evaluate the in vivo effect of dienogest on endometriosis tissue. We collected endometrioma tissues from patients treated with dienogest (N = 7) or not treated (N = 11, controls). Cell proliferation, aromatase expression and blood vessel density were evaluated by staining for Ki67, aromatase and the von Willebrand factor, respectively. Apoptosis was detected using the TUNEL assay. The proportion of Ki67 and aromatase positive epithelial cells was significantly lower in the dienogest group than in controls (p dienogest group (p dienogest group compared with controls (p = 0.20). Our study demonstrates that endometrioma taken from patients treated with dienogest show remarkable histological features such as reduction of proliferation, aromatase expression and angiogenesis, and increase of apoptosis. This study clarified the impact of dienogest on local histological events that explain its therapeutic effect on endometriosis.

  20. Discrete Fourier Transform-Based Multivariate Image Analysis: Application to Modeling of Aromatase Inhibitory Activity.

    Science.gov (United States)

    Barigye, Stephen J; Freitas, Matheus P; Ausina, Priscila; Zancan, Patricia; Sola-Penna, Mauro; Castillo-Garit, Juan A

    2018-02-12

    We recently generalized the formerly alignment-dependent multivariate image analysis applied to quantitative structure-activity relationships (MIA-QSAR) method through the application of the discrete Fourier transform (DFT), allowing for its application to noncongruent and structurally diverse chemical compound data sets. Here we report the first practical application of this method in the screening of molecular entities of therapeutic interest, with human aromatase inhibitory activity as the case study. We developed an ensemble classification model based on the two-dimensional (2D) DFT MIA-QSAR descriptors, with which we screened the NCI Diversity Set V (1593 compounds) and obtained 34 chemical compounds with possible aromatase inhibitory activity. These compounds were docked into the aromatase active site, and the 10 most promising compounds were selected for in vitro experimental validation. Of these compounds, 7419 (nonsteroidal) and 89 201 (steroidal) demonstrated satisfactory antiproliferative and aromatase inhibitory activities. The obtained results suggest that the 2D-DFT MIA-QSAR method may be useful in ligand-based virtual screening of new molecular entities of therapeutic utility.

  1. 4- and 6-(p-Sulphamoylphenyl)androstenediones: Studies of aromatase inhibitor-based oestrone sulphatase inhibition.

    Science.gov (United States)

    Watari, Yoko; Yamaguchi, Satoshi; Takahashi, Madoka; Nagaoka, Masao; Numazawa, Mitsuteru

    2010-12-01

    4-(p-Sulphamoylphenyl)androstenedione (3) and 6alpha-p-sulphamoylphenyl analogues 12-14 were synthesised and tested as aromatase inhibitors as well as oestrone sulphatase inhibitors in human placental microsomes. All of the p-sulphamoylphenyl compounds synthesised were powerful inhibitors of aromatase with apparent K(i) values ranging between 30 and 97nM. In addition, the aromatase inhibitory activities of 6alpha-p-hydroxyphenyl compounds 9-11, which may be produced from their respective sulphamoylphenyl compounds by action of oestrone sulphatase, were also high in a range of 23 and 75nM of the K(i) values. On the other hand, all of the sulphamoylphenyl compounds were poor inhibitors of oestrone sulphatase with more than about 200microM of IC(25) values. Although the present findings of the oestrone sulphatase inhibition are disappointing, such attempts may be valuable to develop a new class of drugs having a dual function, aromatase inhibitor and oestrone sulphatase inhibitor, for the treatment of oestrogen-dependent breast cancer. Copyright 2010 Elsevier Inc. All rights reserved.

  2. Molecular cloning of P450 aromatase from the leopard gecko and its expression in the ovary.

    Science.gov (United States)

    Endo, Daisuke; Park, Min Kyun

    2005-07-01

    In this study, we identified the cDNA of P450 aromatase in the leopard gecko, a lizard with temperature-dependent sex determination. The cDNA encodes a putative protein of 505 amino acids. The deduced amino acid sequence of leopard gecko aromatase cDNA showed 80% identity with that of turtles, 70% with humans and 77% with chickens. This is the first report of the identification of P450 aromatase cDNA in squamata species. It has been reported that this gene is expressed in different layers of cells in the ovary of mammalian species and avian species. Thus, we also investigated cells expressing the mRNA of this gene in the ovary of the leopard gecko by RT-PCR and in situ hybridization. The mRNA expression of leopard gecko P450 aromatase was localized in both the thecal and granulosa cell layers in the ovary. The expression in thecal and granulosa cell layers was examined in the largest follicle, second largest follicle and third largest follicle by RT-PCR. A higher level of mRNA expression was observed in the granulosa cell layer of the second largest follicle than in other cell layers. This result may reflect the characteristics of follicles in species with automonochronic ovulation.

  3. Is aromatase cytochrome P450 involved in the pathogenesis of endometrioid endometrial cancer?

    NARCIS (Netherlands)

    Jongen, VHWM; Thijssen, JHH; Hollema, H; Donker, GH; Santema, JG; Van Der Zee, AGJ; Heineman, MJ

    2005-01-01

    Prospectively, the relationship between androgen levels in the utero-ovarian circulation, aromatase activity in endometrial and body fat tissue, and the presence or absence of endometrioid endometrial cancer was studied in postmenopausal women. In 43 women with endometrioid endometrial cancer and 8

  4. SCA-1 Labels a Subset of Estrogen-Responsive Bipotential Repopulating Cells within the CD24+ CD49fhi Mammary Stem Cell-Enriched Compartment

    Directory of Open Access Journals (Sweden)

    Genevieve V. Dall

    2017-02-01

    Full Text Available Estrogen stimulates breast development during puberty and mammary tumors in adulthood through estrogen receptor-α (ERα. These effects are proposed to occur via ERα+ luminal cells and not the mammary stem cells (MaSCs that are ERαneg. Since ERα+ luminal cells express stem cell antigen-1 (SCA-1, we sought to determine if SCA-1 could define an ERα+ subset of EpCAM+/CD24+/CD49fhi MaSCs. We show that the MaSC population has a distinct SCA-1+ population that is abundant in pre-pubertal mammary glands. The SCA-1+ MaSCs have less stem cell markers and less in vivo repopulating activity than their SCA-1neg counterparts. However, they express ERα and specifically enter the cell cycle at puberty. Using estrogen-deficient aromatase knockouts (ArKO, we showed that the SCA-1+ MaSC could be directly modulated by estrogen supplementation. Thus, SCA-1 enriches for an ERα+, estrogen-sensitive subpopulation within the CD24+/CD49fhi MaSC population that may be responsible for the hormonal sensitivity of the developing mammary gland.

  5. Estradiol coupling to human monocyte nitric oxide release is dependent on intracellular calcium transients: evidence for an estrogen surface receptor.

    Science.gov (United States)

    Stefano, G B; Prevot, V; Beauvillain, J C; Fimiani, C; Welters, I; Cadet, P; Breton, C; Pestel, J; Salzet, M; Bilfinger, T V

    1999-10-01

    We tested the hypothesis that estrogen acutely stimulates constitutive NO synthase (cNOS) activity in human peripheral monocytes by acting on an estrogen surface receptor. NO release was measured in real time with an amperometric probe. 17beta-estradiol exposure to monocytes stimulated NO release within seconds in a concentration-dependent manner, whereas 17alpha-estradiol had no effect. 17beta-estradiol conjugated to BSA (E2-BSA) also stimulated NO release, suggesting mediation by a membrane surface receptor. Tamoxifen, an estrogen receptor inhibitor, antagonized the action of both 17beta-estradiol and E2-BSA, whereas ICI 182,780, a selective inhibitor of the nuclear estrogen receptor, had no effect. We further showed, using a dual emission microfluorometry in a calcium-free medium, that the 17beta-estradiol-stimulated release of monocyte NO was dependent on the initial stimulation of intracellular calcium transients in a tamoxifen-sensitive process. Leeching out the intracellular calcium stores abolished the effect of 17beta-estradiol on NO release. RT-PCR analysis of RNA obtained from the cells revealed a strong estrogen receptor-alpha amplification signal and a weak beta signal. Taken together, a physiological dose of estrogen acutely stimulates NO release from human monocytes via the activation of an estrogen surface receptor that is coupled to increases in intracellular calcium.

  6. Estrogenic and anti-androgenic effects of the herbicide tebuthiuron in male Nile tilapia (Oreochromis niloticus).

    Science.gov (United States)

    de Almeida, Milena Devechi; Pereira, Thiago Scremin Boscolo; Batlouni, Sergio Ricardo; Boscolo, Camila Nomura Pereira; de Almeida, Eduardo Alves

    2018-01-01

    Tebuthiuron is a phenylurea herbicide widely used in agriculture that can reach the aquatic environments, possibly posing negative effects to the aquatic biota. Phenylurea herbicides, such as diuron, are known to cause estrogenic and anti-androgenic effects in fish, but no such effects were yet reported for tebuthiuron exposure. Thus, the aim of this study was to evaluate if tebuthiuron, at environmentally relevant concentrations (100 and 200ng/L) and after 25days of exposure have estrogenic and/or anti-androgenic effects on male of Nile tilapia (Oreochromis niloticus), through the evaluation of plasmatic testosterone (T) and estradiol (E 2 ) levels, brain aromatase (CYP19) levels (western-blot), and by evaluating the histology of the testicles. When compared to the control group, plasmatic T levels decreased about 76% in the animals exposed to 200ng/L of tebuthiuron, while E 2 levels increased about 94%, which could be related to a significant increase (77%) in CYP19A1 levels, an enzyme that catalyzes the conversion of androgens into estrogens. Histological analyses of the testicles also demonstrated that tebuthiuron at both tested concentrations caused a decrease in the diameter of the seminiferous tubules and in the diameter of the lumen. Therefore, the gonadosomatic index (GSI) was reduced by 36% % in the animals exposed 200ng/L to tebuthiuron. Indeed, the relative frequency of spermatocytes and spermatids increased respectively 73% (200ng/L) and 61% (100ng/L) in the tebuthiuron exposed animals, possibly due to the impairment of sperm release into the lumen, that was decreased 93% (200ng/L) in the treated animals compared to the control. These results confirm that tebuthiuron causes estrogenic and anti-androgenic effects in Nile tilapias at environmentally relevant concentrations. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Studies directed towards a mechanistic evaluation of inactivation of aromatase by the suicide substrates androsta-1,4-diene-3,17-diones and its 6-ene derivatives aromatase inactivation by the 19-substituted derivatives and their enzymic aromatization.

    Science.gov (United States)

    Numazawa, Mitsuteru; Nagaoka, Masao; Handa, Wakako; Ogawa, Yoko; Matsuoka, Satomi

    2007-01-01

    To gain insight into the mechanistic features for aromatase inactivation by the typical suicide substrates, androsta-1,4-diene-3,17-dione (ADD, 1) and its 6-ene derivative 2, we synthesized 19-substituted (methyl and halogeno) ADD and 1,4,6-triene derivatives 8 and 10 along with 4,6-diene derivatives 9 and tested for their ability to inhibit aromatase in human placental microsomes as well as their ability to serve as a substrate for the enzyme. 19-Methyl-substituted steroids were the most powerful competitive inhibitors of aromatase (K(i): 8.2-40 nM) in each series. Among the 19-substituted inhibitors examined, 19-chloro-ADD and its 6-ene derivatives (7b and 9b) inactivated aromatase in a time-dependent manner in the presence of NADPH in air while the other ones did not. The time-dependent inactivation was blocked by the substrate AD and required NADPH. Only the time-dependent inactivators 7b and 9b in series of 1,4-diene and 1,4,6-triene steroids as well as all of 4,6-diene steroids 9, except for the methyl compound 9a, served as a substrate for aromatase to yield estradiol and/or its 6-ene estradiol with lower conversion rates compared to the corresponding parent steroids 1,4-diene, 1,4,6-triene and 4,6-diene derivatives. The present findings strongly suggest that the aromatase reaction, 19-oxygenation, at least in part, would be involved in the time-dependent inactivation of aromatase by the suicide substrates 1 and 2, where the 19-substitutent would play a critical role in the aromatase reaction probably though steric and electronic reasons.

  8. Design, synthesis, and biological evaluation of resveratrol analogues as aromatase and quinone reductase 2 inhibitors for chemoprevention of cancer

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Bin; Hoshino, Juma; Jermihov, Katie; Marler, Laura; Pezzuto, John M.; Mesecar, Andrew D.; Cushman, Mark (Hawaii); (Purdue); (UIC)

    2012-07-11

    A series of new resveratrol analogues were designed and synthesized and their inhibitory activities against aromatase were evaluated. The crystal structure of human aromatase (PDB 3eqm) was used to rationalize the mechanism of action of the aromatase inhibitor 32 (IC{sub 50} 0.59 {mu}M) through docking, molecular mechanics energy minimization, and computer graphics molecular modeling, and the information was utilized to design several very potent inhibitors, including compounds 82 (IC{sub 50} 70 nM) and 84 (IC{sub 50} 36 nM). The aromatase inhibitory activities of these compounds are much more potent than that for the lead compound resveratrol, which has an IC{sub 50} of 80 {mu}M. In addition to aromatase inhibitory activity, compounds 32 and 44 also displayed potent QR2 inhibitory activity (IC{sub 50} 1.7 {mu}M and 0.27 {mu}M, respectively) and the high-resolution X-ray structures of QR2 in complex with these two compounds provide insight into their mechanism of QR2 inhibition. The aromatase and quinone reductase inhibitors resulting from these studies have potential value in the treatment and prevention of cancer.

  9. The application of estrogen receptor-1 mutations' detection through circulating tumor dna in breast cancer

    Directory of Open Access Journals (Sweden)

    Binliang Liu

    2017-01-01

    Full Text Available Breast cancer is the most common cancer in women worldwide. Endocrine therapy is the cornerstone of treatment for patients with hormone receptor-positive advanced breast cancer. Unfortunately, although most patients initially respond to endocrine treatment, they will eventually acquire resistance to endocrine therapy. The mechanisms of endocrine resistance are complicated. In particular, the estrogen receptor-1 (ESR1 mutation has been recognized as an important topic in recent years. Mutation of ESR1 leads to complete aromatase inhibitor resistance and partial resistance to estrogen receptor agonists and antagonists. Therefore, during clinical treatment, it is of great importance to continuously monitor ESR1 mutations before and after endocrine therapy. Conventional tissue biopsies have unavoidable disadvantages, and therefore, the use of circulating tumor DNA (ctDNA has become more prevalent because it is noninvasive and convenient, has excellent sensitivity, and can quickly assess the overall situation of the tumor. The current methods for detecting ctDNA ESR1 mutations mainly include droplet digital polymerase chain reaction and next-generation sequencing techniques. Based on their advantages and disadvantages, we can establish an initial ESR1 mutation monitoring system. However, developing robust methods to monitor ESR1 mutation, detecting endocrine drug resistance, and evaluating prognoses for guiding clinical treatment strategies require long-term exploration. In this review, we will summarize recent concepts and advancements regarding ESR1 mutation monitoring, ctDNA detection technology, and their application in endocrine therapy of breast cancer.

  10. Mixture interactions of xenoestrogens with endogenous estrogens.

    Science.gov (United States)

    There is growing concern of exposure to fish, wildlife, and humans to water sources contaminated with estrogens and the potential impact on reproductive health. These environmental estrogens originate from various sources including concentrated animal feedlot operations (CAFO), m...

  11. Pharmacogenetics and aromatase inhibitor induced side effects in breast cancer patients.

    Science.gov (United States)

    Sini, Valentina; Botticelli, Andrea; Lunardi, Gianluigi; Gori, Stefania; Marchetti, Paolo

    2017-06-01

    This paper reviews genetic variations mainly related to the onset of adverse events during aromatase inhibitors in early breast cancer. Genetic variability could occur at different steps. The analysis included studies that involved breast cancer patients, treated with an aromatase inhibitor, genotyped for CYP19A1 and/or CYP17A1 and/or CYP27B1 and/or TCLA1, and/or RANK/RANKL/OPG and/or ESR1/ESR2, and assessed for toxicity profile. Twenty-two articles were included for the analysis. Three studies evaluated outcomes and adverse events; 19 studies assessed only side effects. Functional variations may be useful in predicting the onset of toxicities. The identification of polymorphisms at increased risk of toxicity may enable patient management. However, more data are needed to be applied in the individualization of treatment in daily practice.

  12. Estrogenic and pregnancy interceptory effects of Achyranthes ...

    African Journals Online (AJOL)

    ... the dose of 200 mg/kg body weight also exhibited estrogenic activity. Histological studies of the uterus were carried out to confirm this estrogenic activity. Keywords: Achyranthes aspera; antifertility; anti-implantation; estrogenic; uterotropic. The African Journal of Traditional, Complementary and Alternative Medicines Vol.

  13. Short Stature in Chronic Kidney Disease Treated with Growth Hormone and an Aromatase Inhibitor

    OpenAIRE

    Susan R. Mendley; Fotios Spyropoulos; Debra R. Counts

    2015-01-01

    We describe an alternative strategy for management of severe growth failure in a 14-year-old child who presented with advanced chronic kidney disease close to puberty. The patient was initially treated with growth hormone for a year until kidney transplantation, followed immediately by a year-long course of an aromatase inhibitor, anastrozole, to prevent epiphyseal fusion and prolong the period of linear growth. Outcome was excellent, with successful transplant and anticipated complete correc...

  14. Neoadjuvant therapy of endometrial cancer with the aromatase inhibitor letrozole: endocrine and clinical effects.

    Science.gov (United States)

    Berstein, Lev; Maximov, Sergei; Gershfeld, Eduard; Meshkova, Irina; Gamajunova, Vera; Tsyrlina, Evgenia; Larionov, Alexei; Kovalevskij, Anatolii; Vasilyev, Dmitry

    2002-11-15

    To investigate the short-term hormonal and clinical effects of the aromatase inhibitor letrozole (Femara) in patients with endometrial cancer. Ten previously untreated, post-menopausal patients (mean age 59 years) with endometrial cancer, predominantly stage I disease, received letrozole 2.5mg per day for 14 days before surgery. Clinical, sonographic, morphologic, cytologic, and hormonal-metabolic parameters (blood estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), glucose, and cholesterol by radioimmunoassay, enzyme immune assay, or enzyme-colorimetric methods; tumor progesterone receptors by ligand-binding assay; and aromatase activity by 3H-water release assay) were evaluated before and after treatment. Treatment was well-tolerated in all patients. In two patients, pain relief in the lower part of the belly and/or decrease in intensity of uterine discharge was reported. In the three cases, substantial decreases in endometrial M-echo (ultrasound) signal were noted; the mean value of this parameter after treatment was 31.1% lower than before treatment. Blood estradiol concentration decreased by an average of 37.8% after letrozole therapy, and tumor progesterone receptor levels and aromatase activity decreased by 34.4 and 17.5%, respectively. Treatment with letrozole did not influence surgery. These data show that short-term treatment with letrozole in the neoadjuvant setting resulted in some positive clinical changes. Longer-term and larger-scale trials of neoadjuvant letrozole in endometrial cancer are warranted.

  15. Estrogen has opposing effects on vascular reactivity in obese, insulin-resistant male Zucker rats

    Science.gov (United States)

    Brooks-Asplund, Esther M.; Shoukas, Artin A.; Kim, Soon-Yul; Burke, Sean A.; Berkowitz, Dan E.

    2002-01-01

    We hypothesized that estradiol treatment would improve vascular dysfunction commonly associated with obesity, hyperlipidemia, and insulin resistance. A sham operation or 17beta-estradiol pellet implantation was performed in male lean and obese Zucker rats. Maximal vasoconstriction (VC) to phenylephrine (PE) and potassium chloride was exaggerated in control obese rats compared with lean rats, but estradiol significantly attenuated VC in the obese rats. Estradiol reduced the PE EC50 in all groups. This effect was cyclooxygenase independent, because preincubation with indomethacin reduced VC response to PE similarly in a subset of control and estrogen-treated lean rats. Endothelium-independent vasodilation (VD) to sodium nitroprusside was similar among groups, but endothelium-dependent VD to ACh was significantly impaired in obese compared with lean rats. Estradiol improved VD in lean and obese rats by decreasing EC50 but impaired function by decreasing maximal VD. The shift in EC50 corresponded to an upregulation in nitric oxide synthase III protein expression in the aorta of the estrogen-treated obese rats. In summary, estrogen treatment improves vascular function in male insulin-resistant, obese rats, partially via an upregulation of nitric oxide synthase III protein expression. These effects are counteracted by adverse factors, such as hyperlipidemia and, potentially, a release of an endothelium-derived contractile agent.

  16. PENGARUH RANGSANGAN HORMON AROMATASE INHIBITOR DAN OODEV TERHADAP PERUBAHAN KELAMIN DAN PERKEMBANGAN GONAD IKAN KERAPU SUNU, Plectropomus leopardus

    Directory of Open Access Journals (Sweden)

    Hirmawan Tirta Yudha

    2018-01-01

    Full Text Available Permasalahan utama yang dihadapi dalam penyediaan calon induk ikan kerapu sunu Plectropomus leopardus hasil budidaya yang bersifat hermaprodit sekuensial adalah keterlambatan dalam perkembangan gonad dan perubahan gonad dari betina menjadi jantan. Manipulasi hormonal merupakan cara yang paling efektif dan efisien dalam memacu perkembangan reproduksi dan pematangan gonad. Tujuan dari penelitian ini adalah untuk mendapatkan dosis hormon aromatase inhibitor dan oodev yang tepat untuk memacu perubahan kelamin dan perkembangan gonad ikan kerapu sunu. Ikan uji yang digunakan sebanyak 35 ekor F-1 dengan bobot rerata 2,3 ± 0,28 kg. Penelitian dilakukan selama dua bulan. Induksi hormon dilakukan melalui penyuntikan setiap dua minggu sekali dengan empat dosis aromatase inhibitor dan oodev yang berbeda; A (aromatase inhibitor 1 mg kg-1 ikan, O (oodev 1 mL kg-1 ikan, AO1 (aromatase inhibitor 0,1 mg kg-1 ikan + oodev 1 mL kg-1 ikan, AO2 (aromatase inhibitor 1 mg kg-1 ikan + oodev 1 mL kg-1 ikan, dan K (plasebo. Hasil penelitian menunjukkan bahwa kombinasi aromatase inhibitor 1 mg kg-1 ikan dan oodev 1 mL kg-1 ikan efektif untuk merangsang perubahan kelamin. Perlakuan tersebut dapat meningkatkan konsentrasi testosteron dalam darah (2,819 ng/mL setelah delapan minggu pemeliharaan. Berdasarkan hasil histologi gonad dan observasi terhadap ekspresi gen terkait reproduksi menggunakan gen target DMRT1 dan SOX3 menunjukkan bahwa perlakuan hormon AO2 (Aromatase inhibitor 1 mg kg-1 ikan + oodev 1 mL kg-1 ikan terbukti dapat memacu perubahan kelamin dari betina menjadi jantan dan kematangan gonad pada ikan kerapu sunu Plectropomus leopardus. The main problems faced in providing prospective broodstock of protogynous hermaphrodite coral trout grouper Plectropomus leopardus are lateness of gonadal development and gonadal sex reversal from female to male. Hormonal manipulation is the most effective way to induce reproductive development and gonadal maturation. The present

  17. Environmental Estrogens and Breast cancer

    Directory of Open Access Journals (Sweden)

    llmiawati llmiawati

    2014-12-01

    Full Text Available Background: Recent studies revealed that various man-made chemicals disrupting properties with endocrine- contribute in the development of breast cancer.objective: To review the state of the science of the endocrine-disrupting chemicals (EDC and their role in the development of breast cancer.Methods: Key papers on experimental and epidemiologic studies examining the associations between EDC and breast cancer were searched throJgh the Google Sch-olar and pubMedusing Results: EDC effects depend on the level and timing of exposure, with critical window on developmentalstages. Diethylstilbestrol(DES and bispIenolA(BpA aretwo thoroughlystudied environmental estrogenic compounds. Epidemiological studies showed increased breast cancer incident in women exposed to DES during gestation. ExperimentalstuQies revealed that BPA induces architectural and gene expression froRte changes ir i"J"rt r;;;"ry gtand, with the stroma of fetal mammary gland as the primary target. ihe effects of these environmental estrogens are mostly mediated through the estrogen ieceptors a and B. Their exposure may further sensitize the mammary tissuelo the hit or otner carcinogens. Epigenome alteration in the mammary gland has also been implicated in its neoplastic dLvelopre"nt.Conclusions: Fetal and perinatal stages are the critical exposure windows to environmental estrogens and multiple mechanism is irnplicated in the development of breast cancer resulted from this exposure.

  18. Molecular imaging of estrogen receptors

    NARCIS (Netherlands)

    van Kruchten, Michel

    2015-01-01

    For patients with estrogen receptor (ER) positive breast cancer, endocrine therapy plays a major role in both the adjuvant and palliative setting. For adequate treatment decision-making it is crucial to obtain up-to-date information on the ER-status of the tumor(s), since ER-expression is the sole

  19. Synthesis and PET studies of [11C-cyano]letrozole (Femara), an aromatase inhibitor drug

    Energy Technology Data Exchange (ETDEWEB)

    kil K. E.; Biegon A.; Kil, K.-E.; Biegon, A.; Ding, Y.-S.; Fischer, A.; Ferrieri, R.A.; Kim, S.-W.; Pareto, D.; Schueller, M.J.; Fowler, J.S.

    2008-11-10

    Aromatase, a member of the cytochrome P450 family, converts androgens such as androstenedione and testosterone to estrone and estradiol respectively. Letrozole (1-[bis-(4-cyanophenyl)methyl]-1H-1,2,4-triazole, Femara{reg_sign}) is a high affinity aromatase inhibitor (K{sub i}=11.5 nM) which has FDA approval for breast cancer treatment. Here we report the synthesis of carbon-11 labeled letrozole and its assessment as a radiotracer for brain aromatase in the baboon. Letrozole and its precursor (4-[(4-bromophenyl)-1H-1,2,4-triazol-1-ylmethyl]benzonitrile, 3) were prepared in two-step syntheses from 4-cyanobenzyl bromide and 4-bromobenzyl bromide, respectively. The [{sup 11}C]cyano group was introduced via the tetrakis(triphenylphosphine)palladium(0) catalyzed coupling of [{sup 11}C]cyanide with the bromo-precursor (3). PET studies in the baboon brain were carried out to assess regional distribution and kinetics, reproducibility of repeated measures and saturability. The free fraction of letrozole in the plasma, log D, and the [{sup 11}C-cyano]letrozole fraction in the arterial plasma were also measured. [{sup 11}C-cyano]Letrozole was synthesized in 60 min with a radiochemical yield of 79-80%, with a radiochemical purity greater than 98% and a specific activity of 4.16 {+-} 2.21 Ci/{micro}mol at the end of bombardment (n=4). PET studies in the baboon revealed initial rapid and high uptake and initial rapid clearance followed by slow clearance of carbon-11 from the brain with no difference between brain regions. The brain kinetics was not affected by co-injection of unlabeled letrozole (0.1 mg/kg). The free fraction of letrozole in plasma was 48.9% and log D was 1.84. [{sup 11}C-cyano]Letrozole is readily synthesized via a palladium catalyzed coupling reaction with [{sup 11}C]cyanide. Although it is unsuitable as a PET radiotracer for brain aromatase as revealed by the absence of regional specificity and saturability in brain regions, such as amygdala, which are known

  20. Synthesis and PET studies of [(11)C-cyano]letrozole (Femara), an aromatase inhibitor drug.

    Science.gov (United States)

    Kil, Kun-Eek; Biegon, Anat; Ding, Yu-Shin; Fischer, Andre; Ferrieri, Richard A; Kim, Sung Won; Pareto, Deborah; Schueller, Michael J; Fowler, Joanna S

    2009-02-01

    Aromatase, a member of the cytochrome P450 family, converts androgens such as androstenedione and testosterone into estrone and estradiol, respectively. Letrozole (1-[bis-(4-cyanophenyl)methyl]-1H-1,2,4-triazole; Femara) is a high-affinity aromatase inhibitor (K(i)=11.5 nM) that has Food and Drug Administration approval for breast cancer treatment. Here we report the synthesis of carbon-11-labeled letrozole and its assessment as a radiotracer for brain aromatase in the baboon. Letrozole and its precursor (4-[(4-bromophenyl)-1H-1,2,4-triazol-1-ylmethyl]benzonitrile) were prepared in a two-step synthesis from 4-cyanobenzyl bromide and 4-bromobenzyl bromide, respectively. The [(11)C]cyano group was introduced via tetrakis(triphenylphosphine)palladium(0)-catalyzed coupling of [(11)C]cyanide with the bromo precursor. Positron emission tomography (PET) studies in the baboon brain were carried out to assess regional distribution and kinetics, reproducibility of repeated measures and saturability. Log D, the free fraction of letrozole in plasma and the [(11)C-cyano]letrozole fraction in arterial plasma were also measured. [(11)C-cyano]Letrozole was synthesized in 60 min with a radiochemical yield of 79-80%, with a radiochemical purity greater than 98% and a specific activity of 4.16+/-2.21 Ci/mumol at the end of bombardment (n=4). PET studies in the baboon revealed initial rapid and high uptake and initial rapid clearance, followed by slow clearance of carbon-11 from the brain, with no difference between brain regions. Brain kinetics was not affected by coinjection of unlabeled letrozole (0.1 mg/kg). The free fraction of letrozole in plasma was 48.9%, and log D was 1.84. [(11)C-cyano]Letrozole is readily synthesized via a palladium-catalyzed coupling reaction with [(11)C]cyanide. Although it is unsuitable as a PET radiotracer for brain aromatase, as revealed by the absence of regional specificity and saturability in brain regions such as amygdala, which are known to

  1. Synthesis and PET studies of [{sup 11}C-cyano]letrozole (Femara), an aromatase inhibitor drug

    Energy Technology Data Exchange (ETDEWEB)

    Kil, Kun-Eek [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Department of Chemistry, Stony Brook University, Stony Brook, NY 11794 (United States); Biegon, Anat [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Ding, Yu-Shin [Department of Radiology, Yale University School of Medicine, New Haven, CT 06520-8048 (United States); Fischer, Andre [Johannes-Gutenberg Universitaet Mainz, Institut fuer Organische Chemie, 55128 Mainz (Germany); Ferrieri, Richard A.; Kim, Sung Won; Pareto, Deborah; Schueller, Michael J. [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Fowler, Joanna S. [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Department of Chemistry, Stony Brook University, Stony Brook, NY 11794 (United States)], E-mail: fowler@bnl.gov

    2009-02-15

    Introduction: Aromatase, a member of the cytochrome P450 family, converts androgens such as androstenedione and testosterone into estrone and estradiol, respectively. Letrozole (1-[bis-(4-cyanophenyl)methyl]-1H-1,2,4-triazole; Femara) is a high-affinity aromatase inhibitor (K{sub i}=11.5 nM) that has Food and Drug Administration approval for breast cancer treatment. Here we report the synthesis of carbon-11-labeled letrozole and its assessment as a radiotracer for brain aromatase in the baboon. Methods: Letrozole and its precursor (4-[(4-bromophenyl)-1H-1,2,4-triazol-1-ylmethyl]benzonitrile) were prepared in a two-step synthesis from 4-cyanobenzyl bromide and 4-bromobenzyl bromide, respectively. The [{sup 11}C]cyano group was introduced via tetrakis(triphenylphosphine)palladium(0)-catalyzed coupling of [{sup 11}C]cyanide with the bromo precursor. Positron emission tomography (PET) studies in the baboon brain were carried out to assess regional distribution and kinetics, reproducibility of repeated measures and saturability. Log D, the free fraction of letrozole in plasma and the [{sup 11}C-cyano]letrozole fraction in arterial plasma were also measured. Results: [{sup 11}C-cyano]Letrozole was synthesized in 60 min with a radiochemical yield of 79-80%, with a radiochemical purity greater than 98% and a specific activity of 4.16{+-}2.21 Ci/{mu}mol at the end of bombardment (n=4). PET studies in the baboon revealed initial rapid and high uptake and initial rapid clearance, followed by slow clearance of carbon-11 from the brain, with no difference between brain regions. Brain kinetics was not affected by coinjection of unlabeled letrozole (0.1 mg/kg). The free fraction of letrozole in plasma was 48.9%, and log D was 1.84. Conclusion: [{sup 11}C-cyano]Letrozole is readily synthesized via a palladium-catalyzed coupling reaction with [{sup 11}C]cyanide. Although it is unsuitable as a PET radiotracer for brain aromatase, as revealed by the absence of regional specificity

  2. Dysregulated estrogen receptor signaling in the hypothalamic-pituitary-ovarian axis leads to ovarian epithelial tumorigenesis in mice.

    Directory of Open Access Journals (Sweden)

    Mary J Laws

    2014-03-01

    Full Text Available The etiology of ovarian epithelial cancer is poorly understood, mainly due to the lack of an appropriate experimental model for studying the onset and progression of this disease. We have created a mutant mouse model in which aberrant estrogen receptor alpha (ERα signaling in the hypothalamic-pituitary-ovarian axis leads to ovarian epithelial tumorigenesis. In these mice, termed ERαd/d, the ERα gene was conditionally deleted in the anterior pituitary, but remained intact in the hypothalamus and the ovary. The loss of negative-feedback regulation by estrogen (E at the level of the pituitary led to increased production of luteinizing hormone (LH by this tissue. Hyperstimulation of the ovarian cells by LH resulted in elevated steroidogenesis, producing high circulating levels of steroid hormones, including E. The ERαd/d mice exhibited formation of palpable ovarian epithelial tumors starting at 5 months of age with 100% penetrance. By 15 months of age, 80% of ERαd/d mice die. Besides proliferating epithelial cells, these tumors also contained an expanded population of luteinized stromal cells, which acquire the ability to express P450 aromatase and synthesize E locally. In response to the elevated levels of E, the ERα signaling was accentuated in the ovarian epithelial cells of ERαd/d mice, triggering increased ERα-dependent gene expression, abnormal cell proliferation, and tumorigenesis. Consistent with these findings, treatment of ERαd/d mice with letrozole, an aromatase inhibitor, markedly reduced circulating E and ovarian tumor volume. We have, therefore, developed a unique animal model, which serves as a useful tool for exploring the involvement of E-dependent signaling pathways in ovarian epithelial tumorigenesis.

  3. Effects of triclosan on hormones and reproductive axis in female Yellow River carp (Cyprinus carpio): Potential mechanisms underlying estrogen effect.

    Science.gov (United States)

    Wang, Fan; Guo, Xiangmeng; Chen, Wanguang; Sun, Yaowen; Fan, Chaojie

    2017-12-01

    Triclosan (TCS), a member of the class of compounds called pharmaceutical and personal care products (PPCPs), is a broad antibacterial and antifungal agent found in a lot of consumer products. However, TCS hormone effect mechanism in teleost female fish is not clear. Female Yellow River carp (Cyprinus carpio) were exposed to 1/20, 1/10 and 1/5 LC 50 TCS (96h LC 50 of TCS to carp) under semi-static conditions for 42days. Vitellogenin (Vtg), 17β-estradiol (E 2 ), testosterone(T), estrogen receptor (Er), gonadotropin (GtH), and gonadotropin-releasing hormone (GnRH) levels were measured by enzyme-linked immunosorbent assay (ELISA). Meanwhile, we also examined the mRNA expressions of aromatase, GtHs-β, GnRH, and Er by quantitative real-time PCR (qRT-PCR). The results indicated that 1/5 LC 50 TCS induced Vtg in hepatopancreas of female carps by interference with the hypothalamic-pituitary-gonadal (HPG) axis at multiple potential loci through three mechanisms: (a) TCS exposure enhanced the mRNA expression of hypothalamus and gonadal aromatase which converts androgens into estrogens, subsequently increasing serum concentrations of E 2 to induce Vtg in hepatopancreas; (b) TCS treatment increased GnRH and GtH-β mRNA expression and secretion, causing the disturbance of reproductive endocrine and the increase of E 2 to induce Vtg in hepatopancreas; (c) TCS exposure enhanced synthesis and secretion of Er, then it bound to Er to active Vtg synthesis. These mechanisms showed that TCS may induce Vtg production in female Yellow River carp by Er-mediated and non-Er-mediated pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Reducing endogenous estrogen during prepuberal life does not affect boar libido or sperm fertilizing potential.

    Science.gov (United States)

    Berger, Trish; Conley, Alan J

    2014-09-01

    Increasing sperm production per breeding male has economic significance with increasing use of artificial insemination. Manipulations to increase sperm production in livestock will only be useful if libido and sperm fertilizing capacity are not adversely affected. Reducing endogenous estrogens in the postnatal interval increases the number of Sertoli cells and hence testicular sperm production capacity. These experiments were designed to evaluate the effects of reducing endogenous estrogens on libido and sperm fertilizing capacity. Boars were treated with an aromatase inhibitor, letrozole, to reduce testicular estrogen production between 1 and 6 weeks of age or between 11 and 16 weeks of age, and the littermates to these boars were treated with the canola oil vehicle. Letrozole treatment did not affect time to first mount at 22 weeks of age, regardless of whether the treatment occurred from 1 to 6 weeks of age (118 seconds vs. 233 seconds, SEM = 161 for letrozole-treated and vehicle-treated boars, respectively) or from 11 to 16 weeks of age (107 seconds vs. 67 seconds, SEM = 63 for letrozole-treated and vehicle-treated boars, respectively). Similarly, sperm fertilizing ability and in vivo fertility were equivalent in letrozole-treated boars and their vehicle-treated littermates. Surprisingly, the increase in Sertoli cell numbers observed in the letrozole-treated boars at 20 weeks of age (5.8 vs. 4.3 billion, SEM = 0.5; P libido or sperm fertilizing capacity. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Intrinsic mechanism of estradiol-induced apoptosis in breast cancer cells resistant to estrogen deprivation.

    Science.gov (United States)

    Lewis, Joan S; Meeke, Kathleen; Osipo, Clodia; Ross, Eric A; Kidawi, Noman; Li, Tianyu; Bell, Eric; Chandel, Navdeep S; Jordan, V Craig

    2005-12-07

    We previously developed an estrogen receptor (ER)-positive breast cancer cell line (MCF-7:5C) that is resistant to long-term estrogen deprivation and undergoes rapid and complete apoptosis in the presence of physiologic concentrations of 17beta-estradiol. Here, we investigated the role of the mitochondrial apoptotic pathway in this process. Apoptosis in MCF-7:5C cells treated with estradiol, fulvestrant, or vehicle (control) was investigated by annexin V-propidium iodide double staining and 4',6-diamidino-2-phenylindole (DAPI) staining. Apoptosis was also analyzed in MCF-7:5C cells transiently transfected with small interfering RNAs (siRNAs) to apoptotic pathway components. Expression of apoptotic pathway intermediates was measured by western blot analysis. Mitochondrial transmembrane potential (psim) was determined by rhodamine-123 retention assay. Mitochondrial pathway activity was determined by cytochrome c release and cleavage of poly(ADP-ribose) polymerase (PARP) protein. Tumorigenesis was studied in ovariectomized athymic mice that were injected with MCF-7:5C cells. Differences between the treatment groups and control group were determined by two-sample t test or one-factor analysis of variance. All statistical tests were two-sided. MCF-7:5C cells treated with estradiol underwent apoptosis and showed increased expression of proapoptotic proteins, decreased psim, enhanced cytochrome c release, and PARP cleavage compared with cells treated with fulvestrant or vehicle. Blockade of Bax, Bim, and p53 mRNA expression by siRNA reduced estradiol-induced apoptosis relative to control by 76% [95% confidence interval (CI) = 73% to 79%, P estradiol-induced apoptosis in long-term estrogen-deprived breast cancer cells. Physiologic concentrations of estradiol could potentially be used to induce apoptosis and tumor regression in tumors that have developed resistance to aromatase inhibitors.

  6. Glycogen Synthase Kinase-3β

    DEFF Research Database (Denmark)

    Munkholm, Klaus; Lenskjold, Toke; Jacoby, Anne Sophie

    2016-01-01

    Evidence indicates a role for glycogen synthase kinase-3β (GSK-3β) in the pathophysiology of mood disorders and in cognitive disturbances; however, the natural variation in GSK-3β activity over time is unknown. We aimed to investigate GSK-3β activity over time and its possible correlation...

  7. STRUCTURAL ENZYMOLOGY OF POLYKETIDE SYNTHASES

    OpenAIRE

    Tsai, Shiou-Chuan (Sheryl); Ames, Brian Douglas

    2009-01-01

    This chapter describes structural and associated enzymological studies of polyketide synthases, including isolated single domains and multidomain fragments. The sequence–structure–function relationship of polyketide biosynthesis, compared with homologous fatty acid synthesis, is discussed in detail. Structural enzymology sheds light on sequence and structural motifs that are important for the precise timing, substrate recognition, enzyme catalysis, and protein–protein interactions leading to ...

  8. Pause menopause with Rhodiola rosea, a natural selective estrogen receptor modulator.

    Science.gov (United States)

    Gerbarg, Patricia L; Brown, Richard P

    2016-06-15

    Menopausal women are challenged by the adverse effects of estrogen loss on energy, mood, cognitive function, and memory. These stresses are compounded by increased risks for cardiovascular disease, osteoporosis, and cancer. Known to have neuroprotective, cardio-protective, anti-oxidative and anti-carcinogenic effects, Rhodiola rosea extracts have also been shown to improve energy, mood, cognitive function and memory. We propose that R. rosea be investigated for use as a potential selective estrogen receptor modulator (SERM) in the prevention and treatment of menopause-related fatigue, stress, depression, cognitive decline, memory impairment, cardiovascular disease, osteoporosis and cancer. This paper briefly reviews the relationship between estrogen decline and menopause-related health risks, the molecular mechanisms underlying estrogenic effects on health, and the evidence indicating beneficial effects of R. rosea extracts on these mechanisms and health risks. Mechanisms include non-genomic and genomic effects, for example: activation of intra-cellular signal transduction pathways by binding to estrogen receptors, ERα-mediated activation of endothelial nitric oxide synthase with increased nitric oxide release; and anti-inflammatory effects, counteracting TNFα by inhibiting nuclear factor-Kappa-B (NF-KB) and protection of osteoblasts from hydrogen peroxide. A clinical case illustrating treatment of a menopausal woman with R. rosea is presented. Risks, benefits, gaps in knowledge, and future directions are discussed. Numerous lines of evidence indicate that R. rosea should be investigated as a potential selective estrogen receptor modulator (SERM) to prevent, delay or mitigate menopause-related cognitive, psychological, cardiovascular and osteoporotic conditions. Copyright © 2015 Elsevier GmbH. All rights reserved.

  9. Effect of high intratesticular estrogen on global gene expression and testicular cell number in rats

    Directory of Open Access Journals (Sweden)

    He Zuping

    2010-06-01

    Full Text Available Abstract Background The identification of estrogen receptors alpha and beta and aromatase in the testis has highlighted the important role of estrogens in regulating spermatogenesis. There is a wealth of information on the deleterious effects of fetal and neonatal exposure of estrogens and xenoestrogens in the testis, including spermiation failure and germ cell apoptosis. However, very little is known about gene transcripts affected by exogenous estradiol exposure in the testis. The objective of the present study was to unveil global gene expression profiles and testicular cell number changes in rats after estradiol treatment. Methods 17beta-estradiol was administered to adult male rats at a dose of 100 micrograms/kg body weight in saline daily for 10 days; male rats receiving only saline were used as controls. Microarray analysis was performed to examine global gene expression profiles with or without estradiol treatment. Real time RT-PCR was conducted to verify the microarray data. In silico promoter and estrogen responsive elements (EREs analysis was carried out for the differentially expressed genes in response to estradiol. Quantitation of testicular cell number based on ploidy was also performed using flow cytometry in rats with or without estradiol treatment. Results We found that 221 genes and expressed sequence tags (ESTs were differentially expressed in rat testes treated with estradiol compared to the control; the microarray data were confirmed by real time RT-PCR. Gene Ontology analysis revealed that a number of the differentially expressed genes are involved in androgen and xenobiotic metabolism, maintenance of cell cytoskeleton, endocytosis, and germ cell apoptosis. A total of 33 up-regulated genes and 67 down-regulated genes showed the presence of EREs. Flow cytometry showed that estradiol induced a significant decrease in 2n cells (somatic and germ cells and 4n cells (pachytene spermatocytes and a marked increase in the number of

  10. To modulate and be modulated: estrogenic influences on auditory processing of communication signals within a socio-neuro-endocrine framework.

    Science.gov (United States)

    Yoder, Kathleen M; Vicario, David S

    2012-02-01

    Gonadal hormones modulate behavioral responses to sexual stimuli, and communication signals can also modulate circulating hormone levels. In several species, these combined effects appear to underlie a two-way interaction between circulating gonadal hormones and behavioral responses to socially salient stimuli. Recent work in songbirds has shown that manipulating local estradiol levels in the auditory forebrain produces physiological changes that affect discrimination of conspecific vocalizations and can affect behavior. These studies provide new evidence that estrogens can directly alter auditory processing and indirectly alter the behavioral response to a stimulus. These studies show that: 1) Local estradiol action within an auditory area is necessary for socially relevant sounds to induce normal physiological responses in the brains of both sexes; 2) These physiological effects occur much more quickly than predicted by the classical time-frame for genomic effects; 3) Estradiol action within the auditory forebrain enables behavioral discrimination among socially relevant sounds in males; and 4) Estradiol is produced locally in the male brain during exposure to particular social interactions. The accumulating evidence suggests a socio-neuro-endocrinology framework in which estradiol is essential to auditory processing, is increased by a socially relevant stimulus, acts rapidly to shape perception of subsequent stimuli experienced during social interactions, and modulates behavioral responses to these stimuli. Brain estrogens are likely to function similarly in both songbird sexes because aromatase and estrogen receptors are present in both male and female forebrain. Estrogenic modulation of perception in songbirds and perhaps other animals could fine-tune male advertising signals and female ability to discriminate them, facilitating mate selection by modulating behaviors.

  11. Potential effects of environmental contaminants on P450 aromatase activity and DNA damage in swallows from the Rio Grande and Somerville, Texas

    Science.gov (United States)

    Sitzlar, M.A.; Mora, M.A.; Fleming, J.G.W.; Bazer, F.W.; Bickham, J.W.; Matson, C.W.

    2009-01-01

    Cliff swallows (Petrochelidon pyrrhonota) and cave swallows (P. fulva) were sampled during the breeding season at several locations in the Rio Grande, Texas, to evaluate the potential effects of environmental contaminants on P450 aromatase activity in brain and gonads and DNA damage in blood cells. The tritiated water-release aromatase assay was used to measure aromatase activity and flow cytometry was used to measure DNA damage in nucleated blood cells. There were no significant differences in brain and gonadal aromatase activities or in estimates of DNA damage (HPCV values) among cave swallow colonies from the Lower Rio Grande Valley (LRGV) and Somerville. However, both brain and gonadal aromatase activities were significantly higher (P future studies. ?? 2008 Springer Science+Business Media, LLC.

  12. Aromatase excess syndrome: a rare autosomal dominant disorder leading to pre- or peri-pubertal onset gynecomastia.

    Science.gov (United States)

    Fukami, Maki; Miyado, Mami; Nagasaki, Keisuke; Shozu, Makio; Ogata, Tsutomu

    2014-03-01

    Overexpression of CYP19A1 encoding aromatase results in a rare genetic disorder referred to as aromatase excess syndrome (AEXS). Male patients with AEXS manifest pre- or peri-pubertal onset gynecomastia, gonadotropin deficiency, and advanced bone age, while female patients are mostly asymptomatic. To date, 30 male patients with molecularly confirmed AEXS have been reported. A total of 12 types of submicroscopic rearrangements, i.e., two simple duplications, four simple deletions, two simple inversions, and four complex rearrangements, have been implicated in AEXS. Clinical severity of AEXS primarily depends on the types of the rearrangements. AEXS appears to account for a small number of cases of pre- or peri-pubertal onset gynecomastia, and should be suspected particularly when gynecomastia is associated with an autosomal dominant inheritance pattern, characteristic hormone abnormalities and/or advanced bone age. Treatment with an aromatase inhibitor appears to benefit patients with AEXS, although long-term safety of this class of drugs remains unknown.

  13. A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom)

    Energy Technology Data Exchange (ETDEWEB)

    Conte, F.A.; Grumbach, M.M. [Univ. of California, San Francisco, CA (United States); Ito, Y.; Fisher, C.R.; Simpson, E.R. [Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)

    1994-06-01

    The authors report the features of a new syndrome of aromatase deficiency due to molecular defects in the CYP19 (P450arom) gene in a 46,XX female. At birth, the patient presented with a nonadrenal form of female pseudohermaphrodism. At 17 months of age, laparotomy revealed normal female internal genital structures; the histological appearance of the ovaries was normal. FSH concentrations were markedly elevated at 9.4 ng/mL LER 869, and estrone and estradiol levels were undetectable (<37 pmol/L). By 14 yr of age, she had failed to exhibit breast development. The clitoris has enlarged to 4 x 2 cm, and pubic hair was Tanner stage IV. The plasma concentration of testosterone was elevated at 3294 pmol/L, as was androstenedione at 9951 pmol/L. Plasma estradiol levels were below 37 pmol/L. ACTH and dexamethasone tests indicated a nonadrenal source of testosterone and androstenedione. Plasma gonadotropin levels were in the castrate range. Pelvic sonography and magnetic resonance imaging showed multiple 4- to 6-cm ovarian cysts bilaterally. Despite increased circulating androgens and clitoral growth, the bone age was 10 yr at chronologic age 14 2/12 yr. Estrogen replacement therapy resulted in a growth spurt, breast development, menarche, suppression of gonadotropin levels, and resolution of the cysts. The clinical findings suggested the diagnosis of P450arom deficiency. Analyses of genomic DNA from ovarian fibroblasts demonstrated two single base changes in the coding region of the P450arom gene, one at 1303 basepairs (C-T), R435C, and the other at 1310 basepairs (G-A), C437Y, in exon 10. The molecular genetic studies indicate that the patient is a compound heterozygote for these mutations. Expression of these mutations showed that the R435C mutation had 1.1% the activity of the wild-type P450arom enzyme, whereas the C437Y mutation demonstrated no activity. 32 refs., 6 figs., 2 tabs.

  14. Nongenomic Signaling Pathways of Estrogen Toxicity

    Science.gov (United States)

    Watson, Cheryl S.; Jeng, Yow-Jiun; Kochukov, Mikhail Y.

    2010-01-01

    Xenoestrogens can affect the healthy functioning of a variety of tissues by acting as potent estrogens via nongenomic signaling pathways or by interfering with those actions of multiple physiological estrogens. Collectively, our and other studies have compared a wide range of estrogenic compounds, including some closely structurally related subgroups. The estrogens that have been studied include environmental contaminants of different subclasses, dietary estrogens, and several prominent physiological metabolites. By comparing the nongenomic signaling and functional responses to these compounds, we have begun to address the structural requirements for their actions through membrane estrogen receptors in the pituitary, in comparison to other tissues, and to gain insights into their typical non-monotonic dose-response behavior. Their multiple inputs into cellular signaling begin processes that eventually integrate at the level of mitogen-activated protein kinase activities to coordinately regulate broad cellular destinies, such as proliferation, apoptosis, or differentiation. PMID:19955490

  15. Cellular Expression of Cyclooxygenase, Aromatase, Adipokines, Inflammation and Cell Proliferation Markers in Breast Cancer Specimen.

    Directory of Open Access Journals (Sweden)

    Samar Basu

    Full Text Available Current evidences suggest that expression of Ki67, cyclooxygenase (COX, aromatase, adipokines, prostaglandins, free radicals, β-catenin and α-SMA might be involved in breast cancer pathogenesis. The main objective of this study was to compare expression/localization of these potential compounds in breast cancer tissues with tissues collected adjacent to the tumor using immunohistochemistry and correlated with clinical pathology. The breast cancer specimens were collected from 30 women aged between 49 and 89 years who underwent breast surgery following cancer diagnosis. Expression levels of molecules by different stainings were graded as a score on a scale based upon staining intensity and proportion of positive cells/area or individually. AdipoR1, adiponectin, Ob-R, leptin, COX-1, COX-2, aromatase, PGF2α, F2-isoprostanes and α-SMA were localised on higher levels in the breast tissues adjacent to the tumor compared to tumor specimens when considering either score or staining area whereas COX-2 and AdipoR2 were found to be higher considering staining intensity and Ki67 on score level in the tumor tissue. There was no significant difference observed on β-catenin either on score nor on staining area and intensity between tissues adjacent to the tumor and tumor tissues. A positive correlation was found between COX-1 and COX-2 in the tumor tissues. In conclusion, these suggest that Ki67, COXs, aromatase, prostaglandin, free radicals, adipokines, β-catenin and α-SMA are involved in breast cancer. These further focus the need of examination of tissues adjacent to tumor, tumor itself and compare them with normal or benign breast tissues for a better understanding of breast cancer pathology and future evaluation of therapeutic benefit.

  16. Short Stature in Chronic Kidney Disease Treated with Growth Hormone and an Aromatase Inhibitor

    Directory of Open Access Journals (Sweden)

    Susan R. Mendley

    2015-01-01

    Full Text Available We describe an alternative strategy for management of severe growth failure in a 14-year-old child who presented with advanced chronic kidney disease close to puberty. The patient was initially treated with growth hormone for a year until kidney transplantation, followed immediately by a year-long course of an aromatase inhibitor, anastrozole, to prevent epiphyseal fusion and prolong the period of linear growth. Outcome was excellent, with successful transplant and anticipated complete correction of height deficit. This strategy may be appropriate for children with chronic kidney disease and short stature who are in puberty.

  17. Estrogenic activity, estrogens, and calcium in runoff post-layer litter application from rainfall simulated events

    Science.gov (United States)

    Estrogens in runoff from fields fertilized with animal wastes have been implicated as endocrine disruptors of fish in recipient surface waters. The goal of this study was to measure estrogenic activity in runoff post-application of animal waste with the greatest potential for estrogenic activity - ...

  18. CERAPP: Collaborative Estrogen Receptor Activity Prediction Project

    Data.gov (United States)

    U.S. Environmental Protection Agency — Data from a large-scale modeling project called CERAPP (Collaborative Estrogen Receptor Activity Prediction Project) demonstrating using predictive computational...

  19. Genetic Polymorphisms, Estrogens, and Breast Density

    National Research Council Canada - National Science Library

    Maskarinec, Gertraud

    2003-01-01

    .... We have completed two investigations that addressed the following specific aims: 1. To examine the association between polymorphism in genes coding for metabolism and biosynthesis of estrogens...

  20. Estrogens and Cognition: Friends or Foes?

    Science.gov (United States)

    Korol, Donna L.; Pisani, Samantha L.

    2015-01-01

    Estrogens are becoming well known for their robust enhancement on cognition particularly for learning and memory that relies upon functioning of the hippocampus and related neural systems. What is also emerging is that estrogen modulation of cognition is not uniform, at times enhancing yet at other times impairing learning. This review explores the bidirectional effects of estrogens on learning from a multiple memory systems view, focusing on the hippocampus and striatum, whereby modulation by estrogens sorts according to task attributes and neural systems engaged during cognition. We highlight our findings that show the ability to solve hippocampus-sensitive tasks typically improves under relatively high estrogen status while the ability to solve striatum-sensitive tasks degrades with estrogen exposures. Though constrained by dose and timing of exposure, these opposing enhancements and impairments of cognition can be observed following treatments with different estrogenic compounds including the hormone estradiol, the isoflavone genistein found in soybeans, and agonists that are selective for specific estrogen receptors, suggesting that activation of a single receptor type is sufficient to produce the observed shifts in learning strategies. Using this multi-dimensional framework will allow us to extend our thinking of the relationship between estrogens and cognition to other brain regions and cognitive functions. PMID:26149525

  1. Ovariectomy and subsequent treatment with estrogen receptor agonists tune the innate immune system of the hippocampus in middle-aged female rats.

    Directory of Open Access Journals (Sweden)

    Miklós Sárvári

    Full Text Available The innate immune system including microglia has a major contribution to maintenance of the physiological functions of the hippocampus by permanent monitoring of the neural milieu and elimination of tissue-damaging threats. The hippocampus is vulnerable to age-related changes ranging from gene expression to network connectivity. The risk of hippocampal deterioration increases with the decline of gonadal hormone supply. To explore the impact of hormone milieu on the function of the innate immune system in middle-aged female rats, we compared mRNA expression in the hippocampus after gonadal hormone withdrawal, with or without subsequent estrogen replacement using estradiol and isotype-selective estrogen receptor (ER agonists. Targeted profiling assessed the status of the innate immune system (macrophage-associated receptors, complement, inhibitory neuronal ligands, local estradiol synthesis (P450 aromatase and estrogen reception (ER. Results established upregulation of macrophage-associated (Cd45, Iba1, Cd68, Cd11b, Cd18, Fcgr1a, Fcgr2b and complement (C3, factor B, properdin genes in response to ovariectomy. Ovariectomy upregulated Cd22 and downregulated semaphorin3A (Sema3a expression, indicating altered neuronal regulation of microglia. Ovariectomy also led to downregulation of aromatase and upregulation of ERα gene. Of note, analogous changes were observed in the hippocampus of postmenopausal women. In ovariectomized rats, estradiol replacement attenuated Iba1, Cd11b, Fcgr1a, C3, increased mannose receptor Mrc1, Cd163 and reversed Sema3a expression. In contrast, reduced expression of aromatase was not reversed by estradiol. While the effects of ERα agonist closely resembled those of estradiol, ERβ agonist was also capable of attenuating the expression of several macrophage-associated and complement genes. These data together indicate that the innate immune system of the aging hippocampus is highly responsive to the gonadal hormone milieu

  2. Structural Basis of Catalysis in the Bacterial Monoterpene Synthases Linalool Synthase and 1,8-Cineole Synthase

    OpenAIRE

    Karuppiah, Vijaykumar; Ranaghan, Kara E.; Leferink, Nicole G. H.; Johannissen, Linus O.; Shanmugam, Muralidharan; Ní Cheallaigh, Aisling; Bennett, Nathan J.; Kearsey, Lewis J.; Takano, Eriko; Gardiner, John M.; van der Kamp, Marc W.; Hay, Sam; Mulholland, Adrian J.; Leys, David; Scrutton, Nigel S.

    2017-01-01

    Terpenoids form the largest and stereochemically most diverse class of natural products, and there is considerable interest in producing these by biocatalysis with whole cells or purified enzymes, and by metabolic engineering. The monoterpenes are an important class of terpenes and are industrially important as flavors and fragrances. We report here structures for the recently discovered Streptomyces clavuligerus monoterpene synthases linalool synthase (bLinS) and 1,8-cineole synthase (bCinS)...

  3. Immunoexpression of androgen receptors and aromatase in testes of patient with Klinefelter's syndrome.

    Directory of Open Access Journals (Sweden)

    Stanisław Fracki

    2005-02-01

    Full Text Available Klinefelter's syndrome (47, XXY is the most common chromosome aneuploidy in men and is usually characterized by underdeveloped testes and sterility. The aim of the present study was to detect cellular distribution of androgen receptors (AR and aromatase in testes of patient with KS. The tissue sections were processed for morphological and immunohistochemical staining. Additionally, levels of FSH, LH, PRL, estradiol, and testosterone were measured in the plasma. Morphological analysis revealed a complete absence of spermatogenesis. No germ cells were present in seminiferous tubules. In some tubules, nests of apparently degenerating Sertoli cells were found. In the interstitium, Leydig cell hyperplasia was observed. Using immunohistochemistry, nuclear AR staining was detected in Sertoli cells and peritubular cells, whereas in Leydig cells the staining was exclusively cytoplasmic. The immunostaining of aromatase was detected in the cytoplasm of Sertoli cells and Leydig cells. Increased levels of gonadotropins and decreased level of testosterone concomitantly with the cytoplasmic localization of AR in Leydig cells might contribute to the impaired testicular function in patient with KS.

  4. Long-term safety of aromatase inhibitors in the treatment of breast cancer

    Directory of Open Access Journals (Sweden)

    Jean-Marc A Nabholtz

    2008-03-01

    Full Text Available Jean-Marc A NabholtzBreast Cancer Research Institute La Prandie, Valojoulx, FranceAbstract: Following promising data for metastatic breast cancer in terms of efficacy and safety profile, third-generation aromatase inhibitors (AI, anastrozole, letrozole, and exemestane, underwent a full development in early setting. If recent results consistently show the superiority of these agents over tamoxifen, the therapeutic strategies of AIs in adjuvant setting are still debated. Beyond the choice of clinical strategy, the long duration of exposure to AI in adjuvant setting required a full determination of the long-term toxicity profile of these agents. While all three AIs have either favorable (decreased incidence of hot flashes, gynecologic and thromboembolic side-effects or unfavorable (skeletal complications, arthralgia, musculoskeletal pain, sexual dysfunction class adverse events, some variability between AIs has been reported in side-effects as well as gastrointestinal, urogenital, neurologic, and visual disturbances, confirming the lack of interchangeability between the three AIs. The overall therapeutic index of AIs appears today superior to that of tamoxifen with proven improved efficacy and better toxicity profile. This review will explore the results from the available adjuvant AIs trials with a particular emphasis on safety profiles, quality of life, and therapeutic index, helping to define the present role of AIs in the adjuvant management of postmenopausal patients with breast cancer.Keywords: breast cancer, aromatase inhibitors, adjuvant, safety profile

  5. Genomic profiling of ER+ breast cancers after short-term estrogen suppression reveals alterations associated with endocrine resistance

    Science.gov (United States)

    Giltnane, J.M.; Hutchinson, K.E.; Stricker, T.P.; Formisano, L.; Young, C.D.; Estrada, M.V.; Nixon, M.J.; Du, L.; Sanchez, V.; Ericsson, P. Gonzalez; Kuba, M.G.; Sanders, M.E.; Mu, X.J.; Van Allen, E.M.; Wagle, N.; Mayer, I.; Abramson, V.; Gómez, H.; Rizzo, M.; Toy, W.; Chandarlapaty, S.; Mayer, E.L.; Christiansen, J.; Murphy, D.; Fitzgerald, K.; Wang, K.; Ross, J.S.; Miller, V.A.; Stephens, P.J.; Yelensky, R.; Garraway, L.; Shyr, Y.; Meszoely, I.; Balko, J.M.; Arteaga, C.L.

    2017-01-01

    Proliferative inhibition of estrogen-receptor positive (ER+) breast cancers after short-term antiestrogen therapy correlates with long-term patient outcome. We profiled 155 ER+/HER2– early breast cancers from 143 patients treated with the aromatase inhibitor letrozole for 10-21 days before surgery. Twenty-one percent of tumors remained highly proliferative suggesting these tumors harbor alterations associated with intrinsic endocrine therapy resistance. Whole-exome sequencing revealed a correlation between 8p11-12 and 11q13 gene amplifications, including FGFR1 and CCND1, respectively, and high Ki67. We corroborated these findings in a separate cohort of serial pre-treatment, post-neoadjuvant chemotherapy, and recurrent ER+ tumors. Combined inhibition of FGFR1 and CDK4/6 reversed antiestrogen resistance in ER+ FGFR1/CCND1 co-amplified CAMA1 breast cancer cells. RNA sequencing of letrozole-treated tumors revealed intrachromosomal ESR1 fusion transcripts and gene expression signatures in cancers with high Ki67, indicative of enhanced E2F-mediated transcription and cell cycle processes. These data suggest short-term pre-operative estrogen deprivation followed by genomic profiling can be used to identify druggable alterations potentially causal to intrinsic endocrine therapy resistance. PMID:28794284

  6. Estrogen-like and tissue-selective effects of 7-methoxycoumarin from Ficus umbellata (Moraceae): an in vitro and in vivo study.

    Science.gov (United States)

    Zingue, Stéphane; Michel, Thomas; Nde, Chantal Beatrice Magne; Njuh, Amstrong Nang; Cisilotto, Julia; Ndinteh, Derek Tantoh; Clyne, Colin; Fernandez, Xavier; Creczynski-Pasa, Tânia Beatriz; Njamen, Dieudonné

    2017-08-02

    Ficus umbellata is a medicinal plant previously shown to endow estrogenic properties. Its major component was isolated and characterized as 7-methoxycoumarin (MC). Noteworthy, coumarins and the respective active metabolite 7-hydroxycoumarin analogs have shown aromatase inhibitory activity, which is of particular interest in the treatment of estrogen-dependent cancers. The present work aimed at evaluating the estrogenic/antiestrogenic effects of MC in vitro and in vivo. To do so, in vitro assays using E-screen and reporter gene were done. In vivo, a 3-day uterotrophic assay followed by a postmenopausal-like rat model to characterize MC as well as F. umbellata aqueous extract in ovariectomized Wistar rats was performed. The investigations focused on histological (vaginal and uterine epithelial height) and morphological (uterine wet weight, vagina stratification and cornification) endpoints, bone mass, biochemical parameters and lipid profile. MC induced a significant (p < 0.05) MCF-7 cell proliferation at a concentration of 0.1 μM, but did not inhibit the effect induced by estradiol in both E-screen and reporter gene assays. In vivo, MC treatment did not show an uterotrophic effect in both rat models used. However, MC (1 mg/kg) induced a significant increase (p < 0.01) of vaginal epithelial height. No significant change was observed with MC in abdominal fat weight, serum lipid levels and bone weight. These results suggest that MC has a weak estrogenic activity in vitro and in vivo that accounts only in part to the estrogenicity of the whole plant extract. MC could be beneficial with regard to vagina dryness as it showed a tissue specific effect without exposing the uterus to a potential tumorigenic growth.

  7. Lipoxin A₄ prevents the progression of de novo and established endometriosis in a mouse model by attenuating prostaglandin E₂ production and estrogen signaling.

    Directory of Open Access Journals (Sweden)

    Rajesh Kumar

    Full Text Available Endometriosis, a leading cause of pelvic pain and infertility, is characterized by ectopic growth of endometrial-like tissue and affects approximately 176 million women worldwide. The pathophysiology involves inflammatory and angiogenic mediators as well as estrogen-mediated signaling and novel, improved therapeutics targeting these pathways are necessary. The aim of this study was to investigate mechanisms leading to the establishment and progression of endometriosis as well as the effect of local treatment with Lipoxin A4 (LXA₄, an anti-inflammatory and pro-resolving lipid mediator that we have recently characterized as an estrogen receptor agonist. LXA₄ treatment significantly reduced endometriotic lesion size and downregulated the pro-inflammatory cytokines IL-1β and IL-6, as well as the angiogenic factor VEGF. LXA₄ also inhibited COX-2 expression in both endometriotic lesions and peritoneal fluid cells, resulting in attenuated peritoneal fluid Prostaglandin E₂ (PGE₂ levels. Besides its anti-inflammatory effects, LXA₄ differentially regulated the expression and activity of the matrix remodeling enzyme matrix metalloproteinase (MMP-9 as well as modulating transforming growth factor (TGF-β isoform expression within endometriotic lesions and in peritoneal fluid cells. We also report for first time that LXA₄ attenuated aromatase expression, estrogen signaling and estrogen-regulated genes implicated in cellular proliferation in a mouse model of disease. These effects were observed both when LXA₄ was administered prior to disease induction and during established disease. Collectively, our findings highlight potential targets for the treatment of endometriosis and suggest a pleotropic effect of LXA₄ on disease progression, by attenuating pro-inflammatory and angiogenic mediators, matrix remodeling enzymes, estrogen metabolism and signaling, as well as downstream proliferative pathways.

  8. Effects of estrogen on the vascular system

    Directory of Open Access Journals (Sweden)

    R.C. Tostes

    2003-09-01

    Full Text Available The cardiovascular protective actions of estrogen are partially mediated by a direct effect on the vessel wall. Estrogen is active both on vascular smooth muscle and endothelial cells where functionally competent estrogen receptors have been identified. Estrogen administration promotes vasodilation in humans and in experimental animals, in part by stimulating prostacyclin and nitric oxide synthesis, as well as by decreasing the production of vasoconstrictor agents such as cyclooxygenase-derived products, reactive oxygen species, angiotensin II, and endothelin-1. In vitro, estrogen exerts a direct inhibitory effect on smooth muscle by activating potassium efflux and by inhibiting calcium influx. In addition, estrogen inhibits vascular smooth muscle cell proliferation. In vivo, 17ß-estradiol prevents neointimal thickening after balloon injury and also ameliorates the lesions occurring in atherosclerotic conditions. As is the case for other steroids, the effect of estrogen on the vessel wall has a rapid non-genomic component involving membrane phenomena, such as alteration of membrane ionic permeability and activation of membrane-bound enzymes, as well as the classical genomic effect involving estrogen receptor activation and gene expression.

  9. Quantum chemical studies of estrogenic compounds

    Science.gov (United States)

    Quantum chemical methods are potent tools to provide information on the chemical structure and electronic properties of organic molecules. Modern computational chemistry methods have provided a great deal of insight into the binding of estrogenic compounds to estrogenic receptors (ER), an important ...

  10. EADB: An Estrogenic Activity Database for Assessing ...

    Science.gov (United States)

    Endocrine-active chemicals can potentially have adverse effects on both humans and wildlife. They can interfere with the body’s endocrine system through direct or indirect interactions with many protein targets. Estrogen receptors (ERs) are one of the major targets, and many endocrine disruptors are estrogenic and affect the normal estrogen signaling pathways. However, ERs can also serve as therapeutic targets for various medical conditions, such as menopausal symptoms, osteoporosis, and ER-positive breast cancer. Because of the decades-long interest in the safety and therapeutic utility of estrogenic chemicals, a large number of chemicals have been assayed for estrogenic activity, but these data exist in various sources and different formats that restrict the ability of regulatory and industry scientists to utilize them fully for assessing risk-benefit. To address this issue, we have developed an Estrogenic Activity Database (EADB; http://www.fda.gov/ScienceResearch/ BioinformaticsTools/EstrogenicActivityDatabaseEADB/default. htm) and made it freely available to the public. EADB contains 18,114 estrogenic activity data points collected for 8212 chemicals tested in 1284 binding, reporter gene, cell proliferation, and in vivo assays in 11 different species. The chemicals cover a broad chemical structure space and the data span a wide range of activities. A set of tools allow users to access EADB and evaluate potential endocrine activity of

  11. Estrogen, aging and the cardiovascular system.

    Science.gov (United States)

    Stice, James P; Lee, Jennifer S; Pechenino, Angela S; Knowlton, Anne A

    2009-01-01

    Estrogen is a powerful hormone with pleiotropic effects. Estrogens have potent antioxidant effects and are able to reduce inflammation, induce vasorelaxation and alter gene expression in both the vasculature and the heart. Estrogen treatment of cultured cardiac myocytes and endothelial cells rapidly activates NFkappaB, induces heat-shock protein (HSP)-72, a potent intracellular protective protein, and protects cells from simulated ischemia. In in vivo models, estrogens protect against ischemia and trauma/hemorrhage. Estrogens may decrease the expression of soluble epoxide hydrolase, which has deleterious effects on the cardiovascular system through metabolism of epoxyeicosatrienoic acids. Natural (endogenous) estrogens in premenopausal women appear to protect against cardiovascular disease and yet controlled clinical trials have not indicated a benefit from estrogen replacement postmenopause. Much remains to be understood in regards to the many properties of this powerful hormone and how changes in this hormone interact with aging-associated changes. The unexpected negative results of trials of estrogen replacement postmenopause probably arise from our lack of understanding of the many effects of this hormone.

  12. Producing biofuels using polyketide synthases

    Science.gov (United States)

    Katz, Leonard; Fortman, Jeffrey L; Keasling, Jay D

    2013-04-16

    The present invention provides for a non-naturally occurring polyketide synthase (PKS) capable of synthesizing a carboxylic acid or a lactone, and a composition such that a carboxylic acid or lactone is included. The carboxylic acid or lactone, or derivative thereof, is useful as a biofuel. The present invention also provides for a recombinant nucleic acid or vector that encodes such a PKS, and host cells which also have such a recombinant nucleic acid or vector. The present invention also provides for a method of producing such carboxylic acids or lactones using such a PKS.

  13. Breast Cancer, Aromatase Inhibitor Therapy, and Sexual Functioning: A Pilot Study of the Effects of Vaginal Testosterone Therapy

    Directory of Open Access Journals (Sweden)

    Melissa Dahir, DNP, IF

    2014-04-01

    Conclusions: The use of a compounded testosterone vaginal cream applied daily for 4 weeks improves reported sexual health quality of life in women with breast cancer taking AIs. Dahir M and Travers‐Gustafson D. Breast cancer, aromatase inhibitor therapy, and sexual functioning: A pilot study of the effects of vaginal testosterone therapy. Sex Med 2014;2:8–15.

  14. Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials

    NARCIS (Netherlands)

    Dowsett, M.; Forbes, J. F.; Bradley, R.; Ingle, J.; Aihara, T.; Bliss, J.; Boccardo, F.; Coates, A.; Coombes, R. C.; Cuzick, J.; Dubsky, P.; Gnant, M.; Kaufmann, M.; Kilburn, L.; Perrone, F.; Rea, D.; Thurlimann, B.; van de Velde, C.; Pan, H.; Peto, R.; Davies, C.; Gray, R.; Burrett, J.; Clarke, M.; Duane, F.; Evans, V.; Gettins, L.; Godwin, J.; Liu, H.; McGale, P.; MacKinnon, E.; McHugh, T.; James, S.; Morris, P.; Read, S.; Taylor, C.; Wang, Y.; Wang, Z.; Bergh, J.; Pritchard, K.; Albain, K.; Anderson, S.; Arriagada, R.; Barlow, W.; Bergsten-Nordstrom, E.; Buyse, M.; Cameron, D.; Coleman, R.; Correa, C.; Costantino, J.; Davidson, N.; Di Leo, A.; Ewertz, M.; Forbes, J.; Gelber, R.; Geyer, C.; Gianni, L.; Goldhirsch, A.; Hayes, D.; Hill, C.; Janni, W.; Martin, M.; Norton, L.; Ohashi, Y.; Paik, S.; Perez, E.; Piccart, M.; Pierce, L.; Raina, V.; Ravdin, P.; Robertson, J.; Rutgers, E.; Sparano, J.; Swain, S.; Viale, G.; von Minckwitz, G.; Wang, X.; Whelan, T.; Wilcken, N.; Winer, E.; Wolmark, N.; Wood, W.; Abe, O.; Abe, R.; Enomoto, K.; Kikuchi, K.; Koyama, H.; Masuda, H.; Nomura, Y.; Sakai, K.; Sugimachi, K.; Toi, M.; Tominaga, T.; Uchino, J.; Yoshida, M.; Haybittle, J. L.; Leonard, C. F.; Calais, G.; Garaud, P.; Collett, V.; Delmestri, A.; Sayer, J.; Harvey, V. J.; Holdaway, I. M.; Kay, R. G.; Mason, B. H.; Bartsch, R.; Fesl, C.; Fohler, H.; Greil, R.; Jakesz, R.; Lang, A.; Luschin-Ebengreuth, G.; Marth, C.; Mlineritsch, B.; Samonigg, H.; Singer, C. F.; Steger, G. G.; Stoger, H.; Canney, P.; Yosef, H. M. A.; Focan, C.; Peek, U.; Oates, G. D.; Powell, J.; Durand, M.; Mauriac, L.; Dolci, S.; Larsimont, D.; Nogaret, J. M.; Philippson, C.; Piccart, M. J.; Masood, M. B.; Parker, D.; Price, J. J.; Lindsay, M. A.; Mackey, J.; Hupperets, P. S. G. J.; Bates, T.; Blamey, R. W.; Chetty, U.; Ellis, I. O.; Mallon, E.; Morgan, D. A. L.; Patnick, J.; Pinder, S.; Olivotto, I.; Ragaz, J.; Berry, D.; Broadwater, G.; Cirrincione, C.; Muss, H.; Weiss, R. B.; Abu-Zahra, H. T.; Portnoj, S. M.; Bowden, S.; Brookes, C.; Dunn, J.; Fernando, I.; Lee, M.; Poole, C.; Spooner, D.; Barrett-Lee, P. J.; Mansel, R. E.; Monypenny, I. J.; Gordon, N. H.; Davis, H. L.; Sestak, I.; Lehingue, Y.; Romestaing, P.; Dubois, J. B.; Delozier, T.; Griffon, B.; Mace Lesec'h, J.; Brain, E.; de La Lande, B.; Mouret-Fourme, E.; Mustacchi, G.; Petruzelka, L.; Pribylova, O.; Owen, J. R.; Harbeck, N.; Janicke, F.; Meisner, C.; Schmitt, M.; Thomssen, C.; Meier, P.; Shan, Y.; Shao, Y. F.; Zhao, D. B.; Chen, Z. M.; Pan, H. C.; Howell, A.; Swindell, R.; Burrett, J. A.; Cutter, D.; Kerr, A.; Mannu, G.; Albano, J.; de Oliveira, C. F.; Gervasio, H.; Gordilho, J.; Ejlertsen, B.; Jensen, M.-B.; Johansen, H.; Mouridsen, H.; Palshof, T.; Gelman, R. S.; Harris, J. R.; Henderson, C.; Shapiro, C. L.; Christiansen, P.; Moller, S.; Mouridsen, H. T.; Trampisch, H. J.; Dalesio, O.; de Vries, E. G. E.; Rodenhuis, S.; van Tinteren, H.; Comis, R. L.; Davidson, N. E.; Robert, N.; Sledge, G.; Solin, L. J.; Sparano, J. A.; Tormey, D. C.; Dixon, J. M.; Forrest, P.; Jack, W.; Kunkler, I.; Rossbach, J.; Klijn, J. G. M.; Treurniet-Donker, A. D.; van Putten, W. L. J.; Rotmensz, N.; Veronesi, U.; Bartelink, H.; Bijker, N.; Bogaerts, J.; Cardoso, F.; Cufer, T.; Julien, J. P.; van de Velde, C. J. H.; Cunningham, M. P.; Huovinen, R.; Joensuu, H.; Costa, A.; Bonadonna, G.; Valagussa, P.; Goldstein, L. J.; Bonneterre, J.; Fargeot, P.; Fumoleau, P.; Kerbrat, P.; Luporsi, E.; Namer, M.; Eiermann, W.; Hilfrich, J.; Jonat, W.; Kreienberg, R.; Schumacher, M.; Bastert, G.; Rauschecker, H.; Sauer, R.; Sauerbrei, W.; Schauer, A.; Blohmer, J. U.; Costa, S. D.; Eidtmann, H.; Gerber, B.; Jackisch, C.; Loibl, S.; de Schryver, A.; Vakaet, L.; Belfiglio, M.; Nicolucci, A.; Pellegrini, F.; Pirozzoli, M. C.; Sacco, M.; Valentini, M.; McArdle, C. S.; Smith, D. C.; Stallard, S.; Dent, D. M.; Gudgeon, C. A.; Hacking, A.; Murray, E.; Panieri, E.; Werner, I. D.; Carrasco, E.; Segui, M. A.; Galligioni, E.; Leone, B.; Vallejo, C. T.; Zwenger, A.; Lopez, M.; Erazo, A.; Medina, J. Y.; Horiguchi, J.; Takei, H.; Fentiman, I. S.; Hayward, J. L.; Rubens, R. D.; Skilton, D.; Scheurlen, H.; Sohn, H. C.; Untch, M.; Dafni, U.; Markopoulos, C.; Fountzilas, G.; Mavroudis, D.; Klefstrom, P.; Blomqvist, C.; Saarto, T.; Gallen, M.; Tinterri, C.; Margreiter, R.; de Lafontan, B.; Mihura, J.; Roche, H.; Asselain, B.; Salmon, R. J.; Vilcoq, J. R.; Andre, F.; Delaloge, S.; Koscielny, S.; Michiels, S.; Rubino, C.; A'Hern, R.; Ellis, P.; Yarnold, J. R.; Benraadt, J.; Kooi, M.; van de Velde, A. O.; van Dongen, J. A.; Vermorken, J. B.; Castiglione, M.; Colleoni, M.; Collins, J.; Gelber, R. D.; Lindtner, J.; Price, K. N.; Regan, M. M.; Rudenstam, C. M.; Senn, H. J.; Thuerlimann, B.; Bliss, J. M.; Chilvers, C. E. D.; Hall, E.; Marty, M.; Possinger, K.; Schmid, P.; Wallwiener, D.; Foster, L.; George, W. D.; Stewart, H. J.; Stroner, P.; Borovik, R.; Hayat, H.; Inbar, M. J.; Peretz, T.; Robinson, E.; Bruzzi, P.; del Mastro, L.; Pronzato, P.; Sertoli, M. R.; Venturini, M.; Camerini, T.; de Palo, G.; Di Mauro, M. G.; Formelli, F.; Amadori, D.; Martoni, A.; Pannuti, F.; Camisa, R.; Cocconi, G.; Colozza, A.; Passalacqua, R.; Aogi, K.; Takashima, S.; Ikeda, T.; Inokuchi, K.; Sawa, K.; Sonoo, H.; Sadoon, M.; Tulusan, A. H.; Kohno, N.; Miyashita, M.; Takao, S.; Ahn, J.-H.; Jung, K. H.; Korzeniowski, S.; Skolyszewski, J.; Ogawa, M.; Yamashita, J.; Bastiaannet, E.; van de Water, W.; van Nes, J. G. H.; Christiaens, R.; Neven, P.; Paridaens, R.; van den Bogaert, W.; Braun, S.; Martin, P.; Romain, S.; Janauer, M.; Seifert, M.; Sevelda, P.; Zielinski, C. C.; Hakes, T.; Hudis, C. A.; Wittes, R.; Giokas, G.; Kondylis, D.; Lissaios, B.; de la Huerta, R.; Sainz, M. G.; Ro, J.; Altemus, R.; Camphausen, K.; Cowan, K.; Danforth, D.; Lichter, A.; Lippman, M.; O'Shaughnessy, J.; Pierce, L. J.; Steinberg, S.; Venzon, D.; Zujewski, J. A.; D'Amico, C.; Lioce, M.; Paradiso, A.; Chapman, J.-A. W.; Gelmon, K.; Goss, P. E.; Levine, M. N.; Meyer, R.; Parulekar, W.; Pater, J. L.; Pritchard, K. I.; Shepherd, L. E.; Tu, D.; Ohno, S.; Bass, G.; Brown, A.; Bryant, J.; Dignam, J.; Fisher, B.; Mamounas, E. P.; Redmond, C.; Wickerham, L.; Hozumi, Y.; Baum, M.; Jackson, I. M.; Palmer, M. K.; Ingle, J. N.; Suman, V. J.; Bengtsson, N. O.; Emdin, S.; Jonsson, H.; Lythgoe, J. P.; Kissin, M.; Erikstein, B.; Hannisdal, E.; Jacobsen, A. B.; Varhaug, J. E.; Gundersen, S.; Hauer-Jensen, M.; Host, H.; Nissen-Meyer, N. N.; Mitchell, A. K.; Robertson, J. F. R.; Ueo, H.; Di Palma, M.; Mathe, G.; Misset, J. L.; Levine, M.; Morimoto, K.; Takatsuka, Y.; Crossley, E.; Harris, A.; Talbot, D.; Taylor, M.; di Blasio, B.; Ivanov, V.; Paltuev, R.; Semiglazov, V.; Brockschmidt, J.; Cooper, M. R.; Falkson, C. I.; Hadji, P.; Makris, A.; Parton, M.; Pennert, K.; Powles, T. J.; Smith, I. E.; Gazet, J. C.; Browne, L.; Graham, P.; Corcoran, N.; Clack, G.; van Poznak, C.; Businico, A.; Deshpande, N.; di Martino, L.; Douglas, P.; Lindtner, A.; Notter, G.; Bryant, A. J. S.; Ewing, G. H.; Firth, L. A.; Krushen-Kosloski, J. L.; Nissen-Meyer, R.; Anderson, H.; Killander, F.; Malmstrom, P.; Ryden, L.; Arnesson, L.-G.; Carstensen, J.; Dufmats, M.; Fohlin, H.; Nordenskjold, B.; Soderberg, M.; Carpenter, J. T.; Murray, N.; Royle, G. T.; Simmonds, P. D.; Crowley, J.; Gralow, J.; Hortobagyi, G.; Livingston, R.; Martino, S.; Osborne, C. K.; Ravdin, P. M.; Adolfsson, J.; Bondesson, T.; Celebioglu, F.; Dahlberg, K.; Fornander, T.; Fredriksson, I.; Frisell, J.; Goransson, E.; Iiristo, M.; Johansson, U.; Lenner, E.; Lofgren, L.; Nikolaidis, P.; Perbeck, L.; Rotstein, S.; Sandelin, K.; Skoog, L.; Svane, G.; af Trampe, E.; Wadstrom, C.; Maibach, R.; Hakama, M.; Holli, K.; Isola, J.; Rouhento, K.; Saaristo, R.; Safra, T.; Brenner, H.; Hercbergs, A.; Yoshimoto, M.; Paterson, A. H. G.; Fyles, A.; Meakin, J. W.; Panzarella, T.; Bahi, J.; Reid, M.; Spittle, M.; Bishop, H.; Bundred, N. J.; Forsyth, S.; Pinder, S. E.; Deutsch, G. P.; Kwong, D. L. W.; Pai, V. R.; Senanayake, F.; Martin, A. L.; Rubagotti, A.; Hackshaw, A.; Houghton, J.; Ledermann, J.; Monson, K.; Tobias, J. S.; Carlomagno, C.; de Laurentiis, M.; de Placido, S.; Williams, L.; Bell, R.; Coleman, R. E.; Dodwell, D.; Hinsley, S.; Marshall, H. C.; Solomayer, E.; Fehm, T.; Horsman, J. M.; Lester, J.; Winter, M. C.; Broglio, K.; Buzdar, A. U.; Hsu, L.; Love, R. R.; Ahlgren, J.; Garmo, H.; Holmberg, L.; Liljegren, G.; Lindman, H.; Warnberg, F.; Asmar, L.; Jones, S. E.; Aft, R.; Gluz, O.; Liedtke, C.; Nitz, U.; Litton, A.; Wallgren, A.; Karlsson, P.; Linderholm, B. K.; Chlebowski, R. T.; Caffier, H.; Brufsky, A. M.; Llombart, H. A.

    2015-01-01

    Background The optimal ways of using aromatase inhibitors or tamoxifen as endocrine treatment for early breast cancer remains uncertain. Methods We undertook meta-analyses of individual data on 31 920 postmenopausal women with oestrogen-receptor-positive early breast cancer in the randomised trials

  15. Review of hormone-based treatments in postmenopausal patients with advanced breast cancer focusing on aromatase inhibitors and fulvestrant

    DEFF Research Database (Denmark)

    Kümler, Iben; Knoop, Ann S; Jessing, Christina A R

    2016-01-01

    . However, overall survival was not significantly increased. CONCLUSION: Conventional treatment with an aromatase inhibitor or fulvestrant may be an adequate treatment option for most patients with hormone receptor-positive advanced breast cancer. Mammalian target of rapamycin (mTOR) inhibition and cyclin...

  16. Structure-activity relationships of 2alpha-substituted androstenedione analogs as aromatase inhibitors and their aromatization reactions.

    Science.gov (United States)

    Numazawa, Mitsuteru; Handa, Wakako; Hasegawa, Chie; Takahashi, Madoka

    2005-12-01

    Aromatase catalyzes the conversion of androstenedione (1a, AD) to estrone through three sequential oxygenations of the 19-methyl group. To gain insight into the spatial nature of the AD binding (active) site of aromatase in relation to the catalytic function of the enzyme, we tested for the ability of 2alpha-substituted (halogeno, alkyl, hydroxy, and alkoxy) ADs (1b-1i) to inhibit aromatase in human placental microsomes as well as their ability to serve as a substrate for the enzyme. All of the steroids inhibited the enzyme in a competitive manner with the apparent K(i)'s ranging from 45 to 1150 nM. 2alpha-Halogeno (F, Cl, and Br) and 2alpha-alkyl (CH3 and CH2CH3) steroids 1b-1f were powerful to good inhibitors (Ki=45-171 nM) whereas steroids 1g-1i, having an oxygen function (hydroxy or alkoxy) at C-2alpha, were poor inhibitors (Ki=670-1150 nM). Aromatization of some of the steroids with placental microsomes was analyzed by gas chromatography-mass spectrometry, indicating that the aromatization rate of the bromide 1d was about two-fold that of the natural substrate AD and that of 2alpha-methoxide 1h was similar to that of AD. Kinetic analysis of the aromatization of androgens revealed that a good substrate was not essentially a good inhibitor for aromatase.

  17. Anti-aromatase effect of resveratrol and melatonin on hormonal positive breast cancer cells co-cultured with breast adipose fibroblasts

    NARCIS (Netherlands)

    Chottanapund, Suthat; Van Duursen, M. B M; Navasumrit, Panida; Hunsonti, Potchanee; Timtavorn, Supatchaya; Ruchirawat, Mathuros; Van den Berg, Martin

    2014-01-01

    Targeting the estrogen pathway has been proven effective in the treatment for estrogen receptor positive breast cancer. There are currently two common groups of anti-estrogenic compounds used in the clinic; Selective Estrogen Receptor Modulators (SERMs, e.g. tamoxifen) and Selective Estrogen Enzyme

  18. Expression of aromatase in the embryonic brain of the olive ridley sea turtle (Lepidochelys olivacea), and the effect of bisphenol-A in sexually differentiated embryos.

    Science.gov (United States)

    Gómez-Picos, Patsy; Sifuentes-Romero, Itzel; Merchant-Larios, Horacio; Hernández-Cornejo, Rubí; Díaz-Hernández, Verónica; García-Gasca, Alejandra

    2014-01-01

    Brain aromatase participates in several biological processes, such as regulation of the reproductive-endocrine axis, memory, stress, sexual differentiation of the nervous system, male sexual behavior, and brain repair. Here we report the isolation and expression of brain aromatase in olive ridley sea turtle (Lepidochelys olivacea) embryos incubated at male- and female-promoting temperatures (MPT and FPT, respectively), at the thermosensitive period (TSP) and the sex-differentiated period. Also, aromatase expression was assessed in differentiated embryos exposed to bisphenol-A (BPA) during the TSP. BPA is a monomer of polycarbonate plastics and is considered an endocrine-disrupting compound. Normal aromatase expression was measured in both forebrain and hindbrain, showing higher expression levels in the forebrain of differentiated embryos at both incubation temperatures. Although no significant differences were detected in the hindbrain, expression was slightly higher at MPT. BPA did not affect aromatase expression neither in forebrains or hindbrains from embryos incubated at MPT, whereas at FPT an inverted U-shape curve was observed in forebrains with significant differences at lower concentrations, whereas in hindbrains a non-significant increment was observed at higher concentrations. Our data indicate that both incubation temperature and developmental stage are critical factors affecting aromatase expression in the forebrain. Because of the timing and location of aromatase expression in the brain, we suggest that brain aromatase may participate in the imprinting of sexual trends related to reproduction and sexual behavior at the onset of sex differentiation, and BPA exposure may impair aromatase function in the female forebrain.

  19. Labeled estrogens as mammary tumor probes

    International Nuclear Information System (INIS)

    Feenstra, A.

    1981-01-01

    In this thesis estrogens labeled with a gamma or positron emitting nuclide, called estrogen-receptor binding radiopharmaceuticals are investigated as mammary tumour probes. The requirements for estrogen-receptor binding radiopharmaceuticals are formulated and the literature on estrogens labeled for this purpose is reviewed. The potential of mercury-197/197m and of carbon-11 as label for estrogen-receptor binding radiopharmaceuticals is investigated. The synthesis of 197 Hg-labeled 4-mercury-estradiol and 2-mercury-estradiol and their properties in vitro and in vivo are described. It appears that though basically carbon-11 labeled compounds are very promising as mammary tumour probes, their achievable specific activity has to be increased. (Auth.)

  20. Modulation of Δ9-tetrahydrocannabinol-induced MCF-7 breast cancer cell growth by cyclooxygenase and aromatase

    International Nuclear Information System (INIS)

    Takeda, Shuso; Yamamoto, Ikuo; Watanabe, Kazuhito

    2009-01-01

    Δ 9 -Tetrahydrocannabinol (Δ 9 -THC), a major constituent of marijuana, has been shown to stimulate the growth of MCF-7 breast cancer cells through cannabinoid receptor-independent signaling [Takeda, S., Yamaori, S., Motoya, E., Matsunaga, T., Kimura, T., Yamamoto, I., Watanabe, K., 2008. Δ 9 -Tetrahydrocannabinol enhances MCF-7 cell proliferation via cannabinoid receptor-independent signaling. Toxicology 245, 141-146]. Although the growth of MCF-7 cells is known to be stimulated by 17β-estradiol (E 2 ), the interaction of Δ 9 -THC and E 2 in MCF-7 cell growth is not fully clarified so far. In the present study, by using E 2 -sensitive MCF-7 cells that have expressed cyclooxygenase-2 (COX-2) and cytochrome P450 19 (aromatase), we studied whether or not COX-2 and aromatase are involved in Δ 9 -THC-mediated MCF-7 cell proliferation. It was shown that Δ 9 -THC-induced MCF-7 cell growth was inhibited by COX-2 inhibitors and was stimulated by arachidonic acid (a COX substrate). However, the growth of MCF-7 cells induced by Δ 9 -THC was not stimulated by PGE 2 , and the expression of aromatase was not affected by COX-2 inhibitors, arachidonic acid, and PGE 2 , suggesting that there is a disconnection between COX-2 (PGE 2 ) and aromatase in Δ 9 -THC-mediated MCF-7 cell proliferation. On the other hand, Δ 9 -THC-induced MCF-7 cell growth was elevated by two kinds of aromatase inhibitors. Taken together with the evidence that Δ 9 -THC-induced MCF-7 cell proliferation was interfered with testosterone (an aromatase substrate) and exogenously provided E 2 , it is suggested that (1) the growth stimulatory effects of Δ 9 -THC are mediated by the product(s) of COX-2 except for PGE 2 , (2) the action of Δ 9 -THC is modulated by E 2 , and (3) COX-2 and aromatase are individually engaged in the proliferation of MCF-7 cells induced by Δ 9 -THC.

  1. Management of adenomyosis in infertile women: comparison between laparotomic resection and administration of aromatase inhibitor (Experience in 55 cases

    Directory of Open Access Journals (Sweden)

    Rajuddin Rajuddin

    2006-03-01

    Full Text Available The objective of this study was to observe the results of adenomyosis mangement with resection and administration of aromatase inhibitor. Cases of ademyosis in infertile women were collected for three years (January 1999 to December 2001 and the diagnoses were confirmed using transvaginal USG. Cases were grouped into two groups, i.e. group 1 (undergoing laparotomic resection and group 2 (receiving treatment with aromatase inhibitor of anastrozole. Both groups were evaluated for changes in clinical symptoms, rate of successful pregnancy, and postoperative recurrency rate. During three years as many as 1619 infertility cases were managed, and among which 66 (4.07% cases of adenomyosis were diagnosed with transvaginal USG. As many as 55 cases were analyzed, i.e., 32 cases underwent resection and 23 cases received aromatase inhibitor. Of 32 cases of surgical resection, the histopathological results showed 30 (93.75% cases of adenomyosis and 2 (6.25% cases of uterus myoma. In the group undergoing resection three cases (9.4% were successfully pregnant, i.e., two cases had live birth, one case ended up with 6-week abortion. Moreover, 25 (78.1% cases were not pregnant and 4 (12.5% cases had recurrency, while 24 (75.35% cases experienced disappearance of symptoms yet not pregnant. On the other hand, of 23 cases in the group receiving aromatase inhibitor 2 (8.6% cases were able to be pregnant, one case had live birth and another case ended up with abortion, while 14 (59.1% cases had disappearance of symptoms yet not pregnant. During three months of treatment with aromatase inhibitor, a reduction in the lesion size between 7.31 mm3 and 25.90 mm3 were observed with CI 95% (p < 0.001. In conclusion, treatment with aromatase inihibitor did not heal lesions, but only reduced the size of adenomyosis lesions. On the other hand, resection could heal lesions, yet recurrency of disease may occur (12.5% after one postoperative year. (Med J Indones 2006; 15

  2. The Relationship between Estrogen and Nitric Oxide in the Prevention of Cardiac and Vascular Anomalies in the Developing Zebrafish (Danio Rerio

    Directory of Open Access Journals (Sweden)

    Benjamin G. Sykes

    2016-10-01

    Full Text Available It has been known that both estrogen (E2 and nitric oxide (NO are critical for proper cardiovascular system (CVS function. It has also been demonstrated that E2 acts as an upstream effector in the nitric oxide (NO pathway. Results from this study indicate that the use of a nitric oxide synthase (NOS inhibitor (NOSI which targets specifically neuronal NOS (nNOS or NOS1, proadifen hydrochloride, caused a significant depression of fish heart rates (HR accompanied by increased arrhythmic behavior. However, none of these phenotypes were evident with either the inhibition of endothelial NOS (eNOS or inducible NOS (iNOS isoforms. These cardiac arrhythmias could also be mimicked by inhibition of E2 synthesis with the aromatase inhibitor (AI, 4-OH-A, in a manner similar to that of nNOSI. In both scenarios, by using an NO donor (DETA-NO in either NO + nNOSI or E2 + AI co-treatments, fish could be significantly rescued from decreased HR and increased arrhythmias. However, the addition of an NOS inhibitor (L-NAME to the E2 + AI co-treatment fish prevented the rescue of low heart rates and arrhythmias, which strongly implicates the NO pathway as a downstream E2 targeted molecule for the maintenance of healthy cardiomyocyte contractile conditions in the developing zebrafish. Cardiac arrhythmias could be mimicked by the S-nitrosylation pathway inhibitor DTT (1,4-dithiothreitol but not by ODQ (1H-[1–3]oxadiazolo[4,3-a]quinoxalin-1-one, the inhibitor of the NO receptor molecule sGC in the cGMP-dependent pathway. In both the nNOSI and AI-induced arrhythmic conditions, 100% of the fish expressed the phenotype, but could be rapidly rescued with maximum survival by a washout with dantrolene, a ryanodine Ca2+ channel receptor blocker, compared to the time it took for rescue using a control salt solution. In addition, of the three NOS isoforms, eNOS was the one most implicated in the maintenance of an intact developing fish vascular system. In conclusion, results

  3. Novel Selective Estrogen Mimics for the Treatment of Tamoxifen-Resistant Breast Cancer

    Science.gov (United States)

    Molloy, Mary Ellen; Perez White, Bethany E.; Gherezghiher, Teshome; Michalsen, Bradley T.; Xiong, Rui; Patel, Hitisha; Zhao, Huiping; Maximov, Philipp Y.; Jordan, V. Craig; Thatcher, Gregory R. J.; Tonetti, Debra A.

    2014-01-01

    Endocrine-resistant breast cancer is a major clinical obstacle. The use of 17β-estradiol (E2) has re-emerged as a potential treatment option following exhaustive use of tamoxifen (TAM) or aromatase inhibitors although side effects have hindered its clinical usage. Protein kinase C alpha (PKCα) expression was shown to be a predictor of disease outcome for patients receiving endocrine therapy and may predict a positive response to an estrogenic treatment. Here, we have investigated the use of novel benzothiophene selective estrogen mimics (SEMs) as an alternative to E2 for the treatment of TAM-resistant breast cancer. Following in vitro characterization of SEMs, a panel of clinically relevant PKCα-expressing, TAM-resistant models were used to investigate the antitumor effects of these compounds. SEM treatment resulted in growth inhibition and apoptosis of TAM-resistant cell lines in vitro. In vivo SEM treatment induced tumor regression of TAM-resistant T47D:A18/PKCα and T47D:A18-TAM1 tumor models. T47D:A18/PKCα tumor regression was accompanied by translocation of ERα to extranuclear sites, possibly defining a mechanism through which these SEMs initiate tumor regression. SEM treatment did not stimulate growth of E2-dependent T47D:A18/neo tumors. Additionally, unlike E2 or TAM, treatment with SEMs did not stimulate uterine weight gain. These findings suggest the further development of SEMs as a feasible therapeutic strategy for the treatment of endocrine-resistant breast cancer without the side effects associated with E2. PMID:25205655

  4. Neoadjuvant letrozole for postmenopausal estrogen receptor-positive, HER2-negative breast cancer patients, a study from the Danish Breast Cancer Cooperative Group (DBCG)

    DEFF Research Database (Denmark)

    Skriver, Signe Korsgaard; Laenkholm, Anne-Vibeke; Rasmussen, Birgitte Bruun

    2018-01-01

    and received neoadjuvant chemotherapy. Eight patients received adjuvant chemotherapy due to lack of response. CONCLUSION: Neoadjuvant aromatase inhibitor therapy is an acceptable strategy in selected postmenopausal patients with ER-rich and HER2-negative early breast cancer with ductal histology and should......INTRODUCTION: Neoadjuvant endocrine treatment (NET) is a low-toxicity approach to achieve operability in locally advanced breast cancer, and to facilitate breast conservation in early breast cancer, particular in patients with highly estrogen receptor (ER) positive and HER2-negative disease. Here......, we report the results obtained by neoadjuvant letrozole in patients with early breast cancer in a phase-II design. MATERIAL AND METHODS: A total of 119 postmenopausal women with ER-positive, HER2-negative operable breast cancer were assigned to four months of neoadjuvant letrozole before definitive...

  5. Heterooligomeric phosphoribosyl diphosphate synthase of Saccharomyces cerevisiae

    DEFF Research Database (Denmark)

    Hove-Jensen, Bjarne

    2004-01-01

    The yeast Saccharomyces cerevisiae contains five phosphoribosyl diphosphate (PRPP) synthase-homologous genes (PRS1-5), which specify PRPP synthase subunits 1-5. Expression of the five S. cerevisiae PRS genes individually in an Escherichia coli PRPP-less strain (Deltaprs) showed that a single PRS...

  6. Estrogen

    Science.gov (United States)

    ... pharmacist if you are allergic to aspirin or tartrazine (a food color additive). Ask your pharmacist or ... cause growth to slow or stop early in children who take large doses for a long time. ...

  7. The interaction between aromatase, metalloproteinase 2,9 and cd44 in breast cancer A interação entre aromatase, metalloproteinase 2, 9 e cd44 no câncer de mama

    Directory of Open Access Journals (Sweden)

    Fábio Bagnoli

    2010-01-01

    Full Text Available OBJECTIVE: This study intends to verify the expression levels and correlation of aromatase, matrix metalloproteinase 2 (MMP-2, matrix metalloproteinase 9 (MMP-9 and CD44 in ductal carcinoma in situ (DCIS and infiltrating ductal carcinoma (IDC when both are found in the same breast. METHODS: One hundred and ten cases were evaluated by tissue microarray (TMA and immunohistochemically screened with anti-aromatase polyclonal antibodies, anti-MMP-2 monoclonal antibodies, anti-MMP-9 policlonal antibodies and anti-CD44 monoclonal antibodies. RESULTS: Aromatase was expressed in IDC and DCIS in 63 (57.3% and 60 (67% of the cases respectively; MMP-2 was similarly expressed in IDC and DCIS in 15 (13.60% cases; MMP-9 was positively expressed in IDC and DCIS in 83 (75.50% and 82 (74.50% cases, respectively; CD44 was positively expressed in IDC and DCIS in 49 (44.50% and 48 (42.60% of the cases, respectively; all of them were highly correlated (pOBJETIVO: O objetivo desse estudo é verificar as expressões e correlações da aromatase, metalloproteinase 2 da matriz (MMP2, metalloproteinase 9 da matriz (MMP-9 e CD44 no carcinoma ductal in situ (CDIS e carcinoma ductal infiltrativo (CDI quando ambos estão presentes simultaneamente na mesma mama. MÉTODOS: Foram avaliados 110 casos pelo método de tissue microarray (TMA e através da utilização de anticorpos policlonais antiaromatase, anticorpos monoclonais anti-MMP-2, anticorpos policlonais anti-MMP-9 e anticorpos monoclonais anti-CD44. RESULTADOS: A aromatase estava expressa de forma positiva no CDI e CDIS em 63 (57,3% e 60 (67% casos, respectivamente. A expressão de MMP-2 estava expressa de forma positiva em 15 (13,6% casos tanto no CDI, quanto no CDIS. A expressão da MMP-9 estava expressa de forma positiva em 83 (75,5% e 82 (74,5% casos de CDI e CDIS, respectivamente. A expressão de CD44 estava expressa de forma positiva em 49 (44,5% e 48 (42,6% casos de CDI e CDIS, respectivamente. Todos eles

  8. Reversibility of endocrine disruption in zebrafish (Danio rerio) after discontinued exposure to the estrogen 17α-ethinylestradiol

    Energy Technology Data Exchange (ETDEWEB)

    Baumann, Lisa, E-mail: lisa.baumann@vetsuisse.unibe.ch [Centre for Fish and Wildlife Health, Vetsuisse Faculty, University of Bern, PO Box 8466, CH-3001 Bern (Switzerland); Aquatic Ecology and Toxicology Section, Centre for Organismal Studies, University of Heidelberg, Im Neuenheimer Feld 230, D-69120 Heidelberg (Germany); Knörr, Susanne, E-mail: susanne.knoerr@gmx.de [Aquatic Ecology and Toxicology Section, Centre for Organismal Studies, University of Heidelberg, Im Neuenheimer Feld 230, D-69120 Heidelberg (Germany); Keiter, Susanne, E-mail: susanne.keiter@cos.uni-heidelberg.de [Aquatic Ecology and Toxicology Section, Centre for Organismal Studies, University of Heidelberg, Im Neuenheimer Feld 230, D-69120 Heidelberg (Germany); Rehberger, Kristina, E-mail: k.rehberger@stud.uni-heidelberg.de [Aquatic Ecology and Toxicology Section, Centre for Organismal Studies, University of Heidelberg, Im Neuenheimer Feld 230, D-69120 Heidelberg (Germany); Volz, Sina, E-mail: s.volz@stud.uni-heidelberg.de [Aquatic Ecology and Toxicology Section, Centre for Organismal Studies, University of Heidelberg, Im Neuenheimer Feld 230, D-69120 Heidelberg (Germany); Schiller, Viktoria, E-mail: schiller@molbiotech.rwth-aachen.de [Fraunhofer Institute for Molecular Biology and Applied Ecology, Forckenbeckstr. 6, D-52074 Aachen (Germany); Fenske, Martina, E-mail: martina.fenske@ime.fraunhofer.de [Fraunhofer Institute for Molecular Biology and Applied Ecology, Forckenbeckstr. 6, D-52074 Aachen (Germany); Holbech, Henrik, E-mail: hol@biology.sdu.dk [Department of Biology, University of Southern Denmark, Campusvej 55, DK-5230 Odense M (Denmark); Segner, Helmut, E-mail: helmut.segner@vetsuisse.unibe.ch [Centre for Fish and Wildlife Health, Vetsuisse Faculty, University of Bern, PO Box 8466, CH-3001 Bern (Switzerland); Braunbeck, Thomas, E-mail: braunbeck@uni-hd.de [Aquatic Ecology and Toxicology Section, Centre for Organismal Studies, University of Heidelberg, Im Neuenheimer Feld 230, D-69120 Heidelberg (Germany)

    2014-08-01

    The aim of the present study was to investigate the persistence of the feminizing effects of discontinued 17α-ethinylestradiol (EE2) exposure on zebrafish (Danio rerio). An exposure scenario covering the sensitive phase of sexual differentiation, as well as final gonad maturation was chosen to examine the estrogenic effects on sexual development of zebrafish. Two exposure scenarios were compared: continuous exposure to environmentally relevant concentrations (0.1–10 ng/L EE2) up to 100 days post-hatch (dph) and developmental exposure up to 60 dph, followed by 40 days of depuration in clean water. The persistence of effects was investigated at different biological organization levels from mRNA to population-relevant endpoints to cover a broad range of important parameters. EE2 had a strong feminizing and inhibiting effect on the sexual development of zebrafish. Brain aromatase (cyp19b) mRNA expression showed no clear response, but vitellogenin levels were significantly elevated, gonad maturation and body growth were inhibited in both genders, and sex ratios were skewed towards females and undifferentiated individuals. To a large extent, all of these effects were reversed after 40 days of recovery, leading to the conclusion that exposure to the estrogen EE2 results in very strong, but reversible underdevelopment and feminization of zebrafish. The present study is the first to show this reversibility at different levels of organization, which gives better insight into the mechanistic basis of estrogenic effects in zebrafish. - Highlights: • Zebrafish were exposed to 17α-ethinylestradiol during their sexual differentiation. • Reversibility of effects was investigated after depuration of 40 days. • Morphological and physiological parameters were compared. • Zebrafish were able to recover at all different levels from mRNA to population.

  9. Reversibility of endocrine disruption in zebrafish (Danio rerio) after discontinued exposure to the estrogen 17α-ethinylestradiol

    International Nuclear Information System (INIS)

    Baumann, Lisa; Knörr, Susanne; Keiter, Susanne; Rehberger, Kristina; Volz, Sina; Schiller, Viktoria; Fenske, Martina; Holbech, Henrik; Segner, Helmut; Braunbeck, Thomas

    2014-01-01

    The aim of the present study was to investigate the persistence of the feminizing effects of discontinued 17α-ethinylestradiol (EE2) exposure on zebrafish (Danio rerio). An exposure scenario covering the sensitive phase of sexual differentiation, as well as final gonad maturation was chosen to examine the estrogenic effects on sexual development of zebrafish. Two exposure scenarios were compared: continuous exposure to environmentally relevant concentrations (0.1–10 ng/L EE2) up to 100 days post-hatch (dph) and developmental exposure up to 60 dph, followed by 40 days of depuration in clean water. The persistence of effects was investigated at different biological organization levels from mRNA to population-relevant endpoints to cover a broad range of important parameters. EE2 had a strong feminizing and inhibiting effect on the sexual development of zebrafish. Brain aromatase (cyp19b) mRNA expression showed no clear response, but vitellogenin levels were significantly elevated, gonad maturation and body growth were inhibited in both genders, and sex ratios were skewed towards females and undifferentiated individuals. To a large extent, all of these effects were reversed after 40 days of recovery, leading to the conclusion that exposure to the estrogen EE2 results in very strong, but reversible underdevelopment and feminization of zebrafish. The present study is the first to show this reversibility at different levels of organization, which gives better insight into the mechanistic basis of estrogenic effects in zebrafish. - Highlights: • Zebrafish were exposed to 17α-ethinylestradiol during their sexual differentiation. • Reversibility of effects was investigated after depuration of 40 days. • Morphological and physiological parameters were compared. • Zebrafish were able to recover at all different levels from mRNA to population

  10. Crosstalk between Wnt/β-catenin and estrogen receptor signaling synergistically promotes osteogenic differentiation of mesenchymal progenitor cells.

    Directory of Open Access Journals (Sweden)

    Yanhong Gao

    Full Text Available Osteogenic differentiation from mesenchymal progenitor cells (MPCs are initiated and regulated by a cascade of signaling events. Either Wnt/β-catenin or estrogen signaling pathway has been shown to play an important role in regulating skeletal development and maintaining adult tissue homeostasis. Here, we investigate the potential crosstalk and synergy of these two signaling pathways in regulating osteogenic differentiation of MPCs. We find that the activation of estrogen receptor (ER signaling by estradiol (E2 or exogenously expressed ERα in MPCs synergistically enhances Wnt3A-induced early and late osteogenic markers, as well as matrix mineralization. The E2 or ERα-mediated synergy can be effectively blocked by ERα antagonist tamoxifen. E2 stimulation can enhance endochondral ossification of Wnt3A-transduced mouse fetal limb explants. Furthermore, exogenously expressed ERα significantly enhances the maturity and mineralization of Wnt3A-induced subcutaneous and intramuscular ectopic bone formation. Mechanistically, we demonstrate that E2 does not exert any detectable effect on β-catenin/Tcf reporter activity. However, ERα expression is up-regulated within the first 48h in AdWnt3A-transduced MPCs, whereas ERβ expression is significantly inhibited within 24h. Moreover, the key enzyme for the biosynthesis of estrogens aromatase is modulated by Wnt3A in a biphasic manner, up-regulated at 24h but reduced after 48h. Our results demonstrate that, while ER signaling acts synergistically with Wnt3A in promoting osteogenic differentiation, Wnt3A may crosstalk with ER signaling by up-regulating ERα expression and down-regulating ERβ expression in MPCs. Thus, the signaling crosstalk and synergy between these two pathways should be further explored as a potential therapeutic approach to combating bone and skeletal disorders, such as fracture healing and osteoporosis.

  11. Aromatase inhibitors - a viable option for recurrent granulosa cell tumour of ovary: overview and case report

    International Nuclear Information System (INIS)

    Munem, A.A.; Bahrani, B.A.; Mehdi, I.

    2012-01-01

    Granulosa cell tumour of the ovary in adults is a rare tumour of low malignant potential affecting middle aged peri or post menopausal patients. These tumours are often diagnosed at an early stage, due to their hormonally active nature. They, however, have unique distinguishing histologic features and behaviour of frequent and late local or systemic relapses. The diagnosis can be challenging with unusual presentations. There is high association of endometrial carcinoma. Surgery is the mainstay of management in early low risk disease, while radiotherapy and systemic platinum based chemotherapy are employed in higher stage with poor prognostic indices. Survival is good in early stage disease. Recurrent, progressive, and treatment refractory disease is not infrequent and poses management challenge. Endocrine manipulation and hormone treatment are employed in few cases with equivocal results, as reported in literature. We present a case of recurrent and treatment refractory GCT in a postmenopausal patient, managed by aromatase inhibitor Anastrozole with reasonable efficacy. (author)

  12. New insights about the evaluation of human sperm quality: the aromatase example.

    Directory of Open Access Journals (Sweden)

    A Saad

    2010-01-01

    Full Text Available Male contribution to the couple's infertility is at first evaluated by the routine examination of semen parameters upon optical microscopy providing valuable information for a rational initial diagnosis and for a clinical management of infertility. But the different forms of infertility defined according to the WHO criteria especially teratozoospermia are not always related to the chromatin structure or to the fertilization capacity. New investigations at the molecular level (transcript and protein could be developed in order to understand the nature of sperm malformation responsible of human infertility and thus to evaluate the sperm quality. The profile analysis of spermatozoal transcripts could be considered as a fingerprint of the past spermatogenic events. The selection of representative transcripts of normal spermatozoa remains complex because a differential expression (increased, decreased or not modified levels of specific transcripts has been revealed between immotile and motile sperm fractions issued from normozoospermic donors. Microarrays tests or real-time quantitative PCR could be helpful for the identification of factors involved in the male infertility. Differences in the expression of specific transcripts have been reported between normal and abnormal semen samples. With the aromatase example, we have noted a negative strong correlation between the amount of transcript and the percentage of abnormal forms especially in presence of head defects. Immunocytochemical procedures using fluorescent probes associated with either confocal microscopy or flow cytometry can be also helpful to proceed with further investigations about the localization of proteins in the compartmentalized spermatozoa or the acrosome reaction. The dual location of aromatase both in the equatorial segment, the mid-piece and the tail could explain the double role of this enzyme in acrosome reaction and motility.

  13. Prevention of aromatase inhibitor-induced bone loss with alendronate in postmenopausal women: The BATMAN Trial.

    Science.gov (United States)

    Lomax, Anna J; Yee Yap, Saw; White, Karen; Beith, Jane; Abdi, Ehtesham; Broad, Adam; Sewak, Sanjeev; Lee, Chooi; Sambrook, Philip; Pocock, Nicholas; Henry, Margaret J; Yeow, Elaine G; Bell, Richard

    2013-12-01

    Postmenopausal women on aromatase inhibitors (AI) are at risk of aromatase inhibitor-associated bone loss (AIBL) and fractures. In 2005 Osteoporosis Australia proposed an algorithm for bisphosphonate intervention. Three hundred and three postmenopausal women with early breast cancer (EBC) were enrolled (osteoporotic, n=25; osteopaenic, n=146; normal bone mineral density (BMD), n=126). Weekly alendronate (70 mg) treatment efficacy as triggered by the algorithm in preventing bone loss was evaluated. All patients received anastrozole (1 mg daily), calcium and vitamin D. All osteoporotic patients received alendronate at baseline. Eleven out of the 146 (7.5%) osteopaenic patients commenced alendronate within 18 months of participation and eleven commenced after. One hundred and twenty four out of the 146 (84.9%) osteopaenic patients and all 126 with normal baseline BMD did not trigger the algorithm. At three years, lumbar spine mean BMD increased (15.6%, p<0.01) in the osteoporotic group. BMD in the osteopaenic group with early intervention significantly increased at three years (6.3%, p=0.02). No significant change was seen in the late intervention group. No change was observed in those with osteopaenia without alendronate. There was a significant drop in lumbar spine (-5.4%) and hip (-4.5%) mean BMD, in the normal BMD group, none of whom received alendronate. Fracture data will be presented. In postmenopausal women with endocrine-responsive EBC, BMD improved over time when a bisphosphonate is administered with anastrozole in osteoporotic patients using an osteoporosis schedule. Subjects with normal baseline BMD experienced the greatest BMD loss, although none became osteoporotic.

  14. Molecular basis of aromatase deficiency in an adult female with sexual infantilism and polycystic ovaries

    Energy Technology Data Exchange (ETDEWEB)

    Ito, Y.; Fisher, C.R.; Simpson, E.R. (Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)); Conte, F.A.; Grumbach, M.M. (Univ. of California, San Francisco, CA (United States))

    1993-11-15

    The authors identified two mutations in the CYP19 gene responsible for aromatase deficiency in an 18-year-old 46,XX female with ambiguous external genitalia at birth, primary amenorrhea and sexual infantilism, and polycystic ovaries. The coding exons, namely exons II-X, of the CYP19 gene were amplified by PCR from genomic DNA and sequenced directly. Direct sequencing of the amplified DNA from the patient revealed two single-base changes, at bp 1303 (C[yields]T) and bp 1310 (G[yields]A) in exon X, which were newly found missense mutations and resulted in codon changes of R435C and C437Y, respectively. Subcloning followed by sequencing confirmed that the patient is a compound heterozygote. The results of restriction fragment length polymorphism analysis and direct sequencing of the amplified exon X DNA from the patient's mother indicate maternal inheritance of the R435C mutation. Transient expression experiments showed that the R435C mutant protein had [approx]1.1% of the activity of the wild type, whereas C437Y was totally inactive. Cysteine-437 is the conserved cysteine in the heme-binding region believed to serve as the fifth coordinating ligand of the heme iron. To the authors' knowledge, this patient is the first adult to have described the cardinal features of a syndrome of aromatase deficiency. Recognition that such defects exist will lead to a better understanding of the role of this enzyme in human development and disease.

  15. Crystal structure of riboflavin synthase

    Energy Technology Data Exchange (ETDEWEB)

    Liao, D.-I.; Wawrzak, Z.; Calabrese, J.C.; Viitanen, P.V.; Jordan, D.B. (DuPont); (NWU)

    2010-03-05

    Riboflavin synthase catalyzes the dismutation of two molecules of 6,7-dimethyl-8-(1'-D-ribityl)-lumazine to yield riboflavin and 4-ribitylamino-5-amino-2,6-dihydroxypyrimidine. The homotrimer of 23 kDa subunits has no cofactor requirements for catalysis. The enzyme is nonexistent in humans and is an attractive target for antimicrobial agents of organisms whose pathogenicity depends on their ability to biosynthesize riboflavin. The first three-dimensional structure of the enzyme was determined at 2.0 {angstrom} resolution using the multiwavelength anomalous diffraction (MAD) method on the Escherichia coli protein containing selenomethionine residues. The homotrimer consists of an asymmetric assembly of monomers, each of which comprises two similar {beta} barrels and a C-terminal {alpha} helix. The similar {beta} barrels within the monomer confirm a prediction of pseudo two-fold symmetry that is inferred from the sequence similarity between the two halves of the protein. The {beta} barrels closely resemble folds found in phthalate dioxygenase reductase and other flavoproteins. The three active sites of the trimer are proposed to lie between pairs of monomers in which residues conserved among species reside, including two Asp-His-Ser triads and dyads of Cys-Ser and His-Thr. The proposed active sites are located where FMN (an analog of riboflavin) is modeled from an overlay of the {beta} barrels of phthalate dioxygenase reductase and riboflavin synthase. In the trimer, one active site is formed, and the other two active sites are wide open and exposed to solvent. The nature of the trimer configuration suggests that only one active site can be formed and be catalytically competent at a time.

  16. Differential modulation of nitric oxide synthases in aging: therapeutic opportunities

    Directory of Open Access Journals (Sweden)

    Stêfany Bruno De Assis Cau

    2012-06-01

    Full Text Available Vascular aging is the term that describes the structural and functional disturbances of the vasculature with advancing aging. The molecular mechanisms of aging-associated endothelial dysfunction are complex, but reduced nitric oxide (NO bioavailability and altered vascular expression and activity of NO synthase (NOS enzymes have been implicated as major players. Impaired vascular relaxation in aging has been attributed to reduced endothelial NOS (eNOS-derived NO, while increased inducible NOS (iNOS expression seems to account for nitrosative stress and disrupted vascular homeostasis. Although eNOS is considered the main source of NO in the vascular endothelium, neuronal NOS (nNOS also contributes to endothelial cells-derived NO, a mechanism that is reduced in aging. Pharmacological modulation of NO generation and expression/activity of NOS isoforms may represent a therapeutic alternative to prevent the progression of cardiovascular diseases. Accordingly, this review will focus on drugs that modulate NO bioavailability, such as nitrite anions and NO-releasing non-steroidal anti-inflammatory drugs, hormones (dehydroepiandrosterone and estrogen, statins, resveratrol and folic acid, since they may be useful to treat/to prevent aging-associated vascular dysfunction. The impact of these therapies on life quality in elderly and longevity will be discussed.

  17. Clinical instability of breast cancer markers is reflected in long-term in vitro estrogen deprivation studies

    International Nuclear Information System (INIS)

    Milosevic, Jelena; Klinge, Johanna; Borg, Anna-Lena; Foukakis, Theodoros; Bergh, Jonas; Tobin, Nicholas P

    2013-01-01

    Long-term estrogen deprivation models are widely employed in an in vitro setting to recapitulate the hormonal milieu of breast cancer patients treated with endocrine therapy. Despite the wealth information we have garnered from these models thus far, a comprehensive time-course analysis of the estrogen (ER), progesterone (PR), and human epidermal growth factor 2 (HER-2/neu) receptors on the gene and protein level, coupled with expression array data is currently lacking. We aimed to address this knowledge gap in order to enhance our understanding of endocrine therapy resistance in breast cancer patients. ER positive MCF7 and BT474 breast cancer cells were grown in estrogen depleted medium for 10 months with the ER negative MDA-MB-231 cell line employed as control. ER, PR and HER-2/neu expression were analysed at defined short and long-term time points by immunocytochemistry (ICC), and quantitative real-time RT-PCR (qRT-PCR). Microarray analysis was performed on representative samples. MCF7 cells cultured in estrogen depleted medium displayed decreasing expression of ER up to 8 weeks, which was then re-expressed at 10 months. PR was also down-regulated at early time points and remained so for the duration of the study. BT474 cells generally displayed no changes in ER during the first 8 weeks of deprivation, however its expression was significantly decreased at 10 months. PR expression was also down-regulated early in BT474 samples and was absent at later time points. Finally, microarray data revealed that genes and cell processes down-regulated in both cell lines at 6 weeks overlapped with those down-regulated in aromatase inhibitor treated breast cancer patients. Our data demonstrate that expression of ER, PR, and cell metabolic/proliferative processes are unstable in response to long-term estrogen deprivation in breast cancer cell lines. These results mirror recent clinical findings and again emphasize the utility of LTED models in translational research

  18. Estrogen, Estrogen Receptors and Rupture of Brain Aneurysms: Brief Review of the Literature

    Directory of Open Access Journals (Sweden)

    Navas-Marrugo Sandy Zuleica

    2014-10-01

    Full Text Available Estrogen, is involved in much of the life women lives, having great importance in many functions of the female body including the definition of secondary sexual characters, but also has been linked as protective factor regard to catastrophic events such as cerebral aneurysms, probably related to estrogen deficiency and described high incidence in menopausal women. It is known the effects of estrogen on vascular physiology and pathophysiologic mechanisms with potential therapeutic implications. We present a brief review focused in the role of estrogens and the rupture of cerebral aneurysms.

  19. Breast Cancer Associated Estrogen Receptors: Catechol Estrogen Receptors in ER-Minus Mice

    National Research Council Canada - National Science Library

    Lubahn, Dennis

    1999-01-01

    Our research will lead to a better understanding of the developmental, physiological, and biochemical roles of endogenous and environmental estrogens in breast cancer causation, prognosis and treatment...

  20. Breast Cancer Associated Estrogen Receptors: Catechol Estrogen Receptors in ER-Minus Mice

    National Research Council Canada - National Science Library

    Lubahn, Dennis

    1998-01-01

    Our research will lead to a better understanding of the developmental, physiological, and biochemical roles of endogenous and environmental estrogens in breast cancer causation, prognosis and treatment...

  1. Local Transformations of Androgens into Estradiol by Aromatase P450 Is Involved in the Regulation of Prolactin and the Proliferation of Pituitary Prolactin-Positive Cells

    Science.gov (United States)

    Carretero Hernández, Marta; Iglesias Osma, María Carmen; Carretero, Manuel; Herrero, Julio J.

    2014-01-01

    In previous studies we demonstrated the immunohistochemical expression of aromatase in pituitary cells. In order to determine whether pituitary aromatase is involved in the paracrine regulation of prolactin-producing pituitary cells and the physiological relevance of pituitary aromatase in the control of these cells, an in vivo and in vitro immunocytochemical and morphometric study of prolactin-positive pituitary cells was carried out on the pituitary glands of adult male rats treated with the aromatase antagonist fadrozole. Moreover, we analyzed the expression of mRNA for the enzyme in pituitary cells of male adult rats by in situ hybridization. The aromatase-mRNA was seen to be located in the cytoplasm of 41% of pituitary cells and was well correlated with the immunocytochemical staining. After in vivo treatment with fadrozole, the size (cellular and nuclear areas) of prolactin cells, as well as the percentage of prolactin-positive cells and the percentage of proliferating-prolactin cells, was significantly decreased. Moreover, fadrozole decreased serum prolactin levels. In vitro, treatment with fadrozole plus testosterone induced similar effects on prolactin-positive cells, inhibiting their cellular proliferation. Our results suggest that under physiological conditions aromatase P450 exerts a relevant control over male pituitary prolactin-cells, probably transforming testosterone to estradiol in the pituitary gland. PMID:24978194

  2. Breast Cancer and Estrogen-Alone Update

    Science.gov (United States)

    ... Current Issue Past Issues Research News From NIH Breast Cancer and Estrogen-Alone Update Past Issues / Summer 2006 ... hormone therapy does not increase the risk of breast cancer in postmenopausal women, according to an updated analysis ...

  3. Estrogens, Genetic Polymorphisms and Breast Cancer Risk

    National Research Council Canada - National Science Library

    Okobia, Michael N; Bunker, Clareann H; Kuller, Lewis; Ferrell, Robert E; Anyanwu, Stanley N; Ezeome, Emmanuel R; Uche, Emmanuel E

    2004-01-01

    This study is aimed at evaluating the role of polymorphisms in the genes encoding enzymes responsible for the biosynthesis and degradation of estrogens and its metabolites in susceptibility to breast...

  4. Conjugated estrogens and breast cancer risk.

    Science.gov (United States)

    Campagnoli, C; Ambroggio, S; Biglia, N; Sismondi, P

    1999-12-01

    Available epidemiologic data suggest the possibility that the use of oral conjugated equine estrogens (CEE) 0.625 mg/day as a first-choice dose could be associated with a very limited (if any) breast cancer risk increase. Some biological peculiarities of oral CEE back the possibility of a limited detrimental effect on breast tissue, due to either direct or indirect actions. Direct actions. Some experimental findings suggest that the 17 alpha-dihydroderivatives of equilenin and equilin (15% of the CEE components) have a non-estrogenic or even an anti-estrogenic effect on breast tissue. This could partially counterbalance the stimulatory action of the other CEE components. Indirect actions. Oral estrogens, through their metabolic and hepatocellular effects (emphasized by the first liver passage) cause a sharp increase in sex hormone binding globulin (SHBG) level which is followed by a lower quantity of both estrogen and androgen in the free, bioavailable, form. More importantly, they cause a decrease in circulating insulin-like growth factor I (IGF-I) activity, due to both a reduction in IGF-I synthesis by the liver and an increase in IGF-binding protein-1 level. A strong relationship between breast cancer risk and the concentration of circulating IGF-I in premenopausal women has been recently found. Actually, estrogens and IGF-I have a synergistic effect on cell proliferation, and IGF-I is necessary for maximum estrogen-receptor activation in breast cancer cell lines. The possibility does exist that the SHBG level increase and the IGF-I bioavailability decrease, caused by oral CEE, balance the increased estrogen stimulation on breast tissue.

  5. Structural Basis of Catalysis in the Bacterial Monoterpene Synthases Linalool Synthase and 1,8-Cineole Synthase

    Science.gov (United States)

    2017-01-01

    Terpenoids form the largest and stereochemically most diverse class of natural products, and there is considerable interest in producing these by biocatalysis with whole cells or purified enzymes, and by metabolic engineering. The monoterpenes are an important class of terpenes and are industrially important as flavors and fragrances. We report here structures for the recently discovered Streptomyces clavuligerus monoterpene synthases linalool synthase (bLinS) and 1,8-cineole synthase (bCinS), and we show that these are active biocatalysts for monoterpene production using biocatalysis and metabolic engineering platforms. In metabolically engineered monoterpene-producing E. coli strains, use of bLinS leads to 300-fold higher linalool production compared with the corresponding plant monoterpene synthase. With bCinS, 1,8-cineole is produced with 96% purity compared to 67% from plant species. Structures of bLinS and bCinS, and their complexes with fluorinated substrate analogues, show that these bacterial monoterpene synthases are similar to previously characterized sesquiterpene synthases. Molecular dynamics simulations suggest that these monoterpene synthases do not undergo large-scale conformational changes during the reaction cycle, making them attractive targets for structured-based protein engineering to expand the catalytic scope of these enzymes toward alternative monoterpene scaffolds. Comparison of the bLinS and bCinS structures indicates how their active sites steer reactive carbocation intermediates to the desired acyclic linalool (bLinS) or bicyclic 1,8-cineole (bCinS) products. The work reported here provides the analysis of structures for this important class of monoterpene synthase. This should now guide exploitation of the bacterial enzymes as gateway biocatalysts for the production of other monoterpenes and monoterpenoids. PMID:28966840

  6. Estrogen receptor transcription and transactivation: Estrogen receptor alpha and estrogen receptor beta - regulation by selective estrogen receptor modulators and importance in breast cancer

    International Nuclear Information System (INIS)

    S Katzenellenbogen, Benita; A Katzenellenbogen, John

    2000-01-01

    Estrogens display intriguing tissue-selective action that is of great biomedical importance in the development of optimal therapeutics for the prevention and treatment of breast cancer, for menopausal hormone replacement, and for fertility regulation. Certain compounds that act through the estrogen receptor (ER), now referred to as selective estrogen receptor modulators (SERMs), can demonstrate remarkable differences in activity in the various estrogen target tissues, functioning as agonists in some tissues but as antagonists in others. Recent advances elucidating the tripartite nature of the biochemical and molecular actions of estrogens provide a good basis for understanding these tissue-selective actions. As discussed in this thematic review, the development of optimal SERMs should now be viewed in the context of two estrogen receptor subtypes, ERα and ERβ, that have differing affinities and responsiveness to various SERMs, and differing tissue distribution and effectiveness at various gene regulatory sites. Cellular, biochemical, and structural approaches have also shown that the nature of the ligand affects the conformation assumed by the ER-ligand complex, thereby regulating its state of phosphorylation and the recruitment of different coregulator proteins. Growth factors and protein kinases that control the phosphorylation state of the complex also regulate the bioactivity of the ER. These interactions and changes determine the magnitude of the transcriptional response and the potency of different SERMs. As these critical components are becoming increasingly well defined, they provide a sound basis for the development of novel SERMs with optimal profiles of tissue selectivity as medical therapeutic agents

  7. Alcohol consumption negates estrogen-mediated myocardial repair in ovariectomized mice by inhibiting endothelial progenitor cell mobilization and function.

    Science.gov (United States)

    Mackie, Alexander R; Krishnamurthy, Prasanna; Verma, Suresh K; Thorne, Tina; Ramirez, Veronica; Qin, Gangjian; Abramova, Tatiana; Hamada, Hiromichi; Losordo, Douglas W; Kishore, Raj

    2013-06-21

    We have shown previously that estrogen (estradiol, E2) supplementation enhances voluntary alcohol consumption in ovariectomized female rodents and that increased alcohol consumption impairs ischemic hind limb vascular repair. However, the effect of E2-induced alcohol consumption on post-infarct myocardial repair and on the phenotypic/functional properties of endothelial progenitor cells (EPCs) is not known. Additionally, the molecular signaling of alcohol-estrogen interactions remains to be elucidated. This study examined the effect of E2-induced increases in ethanol consumption on post-infarct myocardial function/repair. Ovariectomized female mice, implanted with 17β-E2 or placebo pellets were given access to alcohol for 6 weeks and subjected to acute myocardial infarction. Left ventricular functions were consistently depressed in mice consuming ethanol compared with those receiving only E2. Alcohol-consuming mice also displayed significantly increased infarct size and reduced capillary density. Ethanol consumption also reduced E2-induced mobilization and homing of EPCs to injured myocardium compared with the E2-alone group. In vitro, exposure of EPCs to ethanol suppressed E2-induced proliferation, survival, and migration and markedly altered E2-induced estrogen receptor-dependent cell survival signaling and gene expression. Furthermore, ethanol-mediated suppression of EPC biology was endothelial nitric oxide synthase-dependent because endothelial nitric oxide synthase-null mice displayed an exaggerated response to post-acute myocardial infarction left ventricular functions. These data suggest that E2 modulation of alcohol consumption, and the ensuing EPC dysfunction, may negatively compete with the beneficial effects of estrogen on post-infarct myocardial repair.

  8. Evidence of a correlation of estrogen receptor level and avian osteoclast estrogen responsiveness.

    Science.gov (United States)

    Pederson, L; Kremer, M; Foged, N T; Winding, B; Ritchie, C; Fitzpatrick, L A; Oursler, M J

    1997-05-01

    Isolated osteoclasts from 5-week-old chickens respond to estradiol treatment in vitro with decreased resorption activity, increased nuclear proto-oncogene expression, and decreased lysosomal enzyme secretion. This study examines osteoclasts from embryonic chickens and egg-laying hens for evidence of estrogen responsiveness. Although osteoclasts from both of these sources express estrogen receptor mRNA and protein, estradiol treatment had no effect on resorption activity. In contrast to the lack of effect on resorption, estradiol treatment for 30 minutes resulted in steady-state mRNA levels of c-fos and c-jun increasing in osteoclasts from embryonic chickens and decreasing in osteoclasts from egg-laying hens. These data suggest that a nuclear proto-oncogene response may not be involved in estradiol-mediated decreased osteoclast resorption activity. To examine the influence of circulating estrogen on osteoclast estrogen responsiveness, 5-week-old chickens were injected with estrogen for 4 days prior to sacrifice. Estradiol treatment of osteoclasts from these chickens did not decrease resorption activity in vitro. Transfection of an estrogen receptor expression vector into osteoclasts from the estradiol-injected chickens and egg-laying hens restored estrogen responsiveness. Osteoclasts from 5-week-old chickens and estradiol treated 5-week-old chickens transfected with the estrogen receptor expression vector contained significantly higher levels of estrogen receptor protein and responded to estradiol treatment by decreasing secretion of cathepsins B and L and tartrate-resistant acid phosphatase. In contrast, osteoclasts from embryonic chickens, egg-laying hens, and estradiol-treated 5-week-old chickens either untransfected or transfected with an empty expression vector did not respond similarly. These data suggest that modulation of osteoclast estrogen responsiveness may be controlled by changes in the osteoclast estrogen receptor levels.

  9. Temperature- vs. estrogen-induced sex determination in Caiman latirostris embryos: Both females, but with different expression patterns of key molecules involved in ovarian development.

    Science.gov (United States)

    Canesini, Guillermina; Stoker, Cora; Galoppo, Germán H; Durando, Milena L; Tschopp, María V; Luque, Enrique H; Muñoz-de-Toro, Mónica M; Ramos, Jorge G

    2018-04-01

    Caiman latirostris is a species with temperature dependent sex determination (TSD), which implies that the incubation temperature of the eggs is the main factor that determines the sex during a thermo-sensitive period (TSP). However, estrogens play a critical role in this process. The administration of 17β-estradiol (E 2 ) previous to TSP overrides the effects of male incubation temperature, producing phenotypic females. This effect has been defined as sex reversal or estrogen-induced sex determination (E 2 SD). The aim of the present study is to describe similarities and differences in the effects of TSD and E 2 SD treatment conditions on ovary development. Our results show that the two treatment conditions studied are able to produce different ovaries. Treatment with E 2 modified the expression pattern of estrogen receptor alpha and progesterone receptor, and expression of the enzyme aromatase. Moreover, in E 2 SD females, the proliferation/apoptosis dynamic was also altered and high expression of TAp63 was observed suggesting the presence of greater DNA damage in germ cells. To the best of our knowledge, this is the first report that describes the morphology of the female gonad of C. latirostris in three stages of embryonic development and shows the expression of TAp63 during the gonad development of a reptile. It is important to emphasize that the changes demonstrated in E 2 SD female gonads of embryos show that environmental compounds with proven estrogenic activity alter the follicular dynamics of C. latirostris in neonatal as much as in juvenile animals, endangering their reproductive health and possibly bringing consequences to ecology and evolution. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. A pilot randomized trial to prevent sexual dysfunction in postmenopausal breast cancer survivors starting adjuvant aromatase inhibitor therapy.

    Science.gov (United States)

    Advani, Pragati; Brewster, Abenaa M; Baum, George P; Schover, Leslie R

    2017-08-01

    A randomized pilot trial evaluated the hypothesis that early intervention lessens sexual dysfunction in the first year on aromatase inhibitors. A secondary aim was comparing the efficacy of two vaginal moisturizers. Fifty-seven postmenopausal women with early stage breast cancer starting aromatase inhibitors were randomized to three treatment groups. All received a handout on managing sexual and other side effects. The Usual Care group received no additional therapy. The Active Treatment groups received a 6-month supply of a vaginal moisturizer (hyaluronic acid-based in Active Group-H and prebiotic in Active Group-P) and a vaginal lubricant and dilator, plus access to an educational website and phone coaching. Questionnaires completed at baseline, 6, and 12 months included the Female Sexual Function Index (FSFI), Menopausal Sexual Interest Questionnaire (MSIQ), Female Sexual Distress Scale-Revised (FSDS-R), and a menopausal symptom scale. Forty-nine women (86%) provided follow-up data. Mean age was 59 and 77% were non-Hispanic Caucasian. Sexual function was impaired at baseline, but remained stable over 12 months for all groups. The combined active treatment group had less dyspareunia (P = 0.07) and sexual distress (P = 0.02) at 6 months than the Usual Care group. At 6 months, the Active-H group improved significantly more than the Active-P group on FSFI total score (P = 0.04). Sexual counseling helped women maintain stable sexual function on aromatase inhibitors. Active intervention resulted in better outcomes at 6 months. This promising pilot trial suggests a need for more research on preventive counseling to maintain sexual function during aromatase inhibitor treatment.

  11. Structure-activity relationships and docking studies of synthetic 2-arylindole derivatives determined with aromatase and quinone reductase 1.

    Science.gov (United States)

    Prior, Allan M; Yu, Xufen; Park, Eun-Jung; Kondratyuk, Tamara P; Lin, Yan; Pezzuto, John M; Sun, Dianqing

    2017-12-15

    In our ongoing effort of discovering anticancer and chemopreventive agents, a series of 2-arylindole derivatives were synthesized and evaluated toward aromatase and quinone reductase 1 (QR1). Biological evaluation revealed that several compounds (e.g., 2d, IC 50  = 1.61 μM; 21, IC 50  = 3.05 μM; and 27, IC 50  = 3.34 μM) showed aromatase inhibitory activity with half maximal inhibitory concentration (IC 50 ) values in the low micromolar concentrations. With regard to the QR1 induction activity, 11 exhibited the highest QR1 induction ratio (IR) with a low concentration to double activity (CD) value (IR = 8.34, CD = 2.75 μM), while 7 showed the most potent CD value of 1.12 μM. A dual acting compound 24 showed aromatase inhibition (IC 50  = 9.00 μM) as well as QR1 induction (CD = 5.76 μM) activities. Computational docking studies using CDOCKER (Discovery Studio 3.5) provided insight in regard to the potential binding modes of 2-arylindoles within the aromatase active site. Predominantly, the 2-arylindoles preferred binding with the 2-aryl group toward a small hydrophobic pocket within the active site. The C-5 electron withdrawing group on indole was predicted to have an important role and formed a hydrogen bond with Ser478 (OH). Alternatively, meta-pyridyl analogs may orient with the pyridyl 3'-nitrogen coordinating with the heme group. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Fungal type III polyketide synthases.

    Science.gov (United States)

    Hashimoto, Makoto; Nonaka, Takamasa; Fujii, Isao

    2014-10-01

    This article covers the literature on fungal type III polyketide synthases (PKSs) published from 2005 to 2014. Since the first discovery of fungal type III PKS genes in Aspergillus oryzae, reported in 2005, putative genes for type III PKSs have been discovered in fungal genomes. Compared with type I PKSs, type III PKSs are much less abundant in fungi. However, type III PKSs could have some critical roles in fungi. This article summarizes the studies on fungal type III PKS functional analysis, including Neurospora crassa ORAS, Aspergillus niger AnPKS, Botrytis cinerea BPKS and Aspergillus oryzae CsyA and CsyB. It is mostly in vitro analysis using their recombinant enzymes that has revealed their starter and product specificities. Of these, CsyB was found to be a new kind of type III PKS that catalyses the coupling of two β-keto fatty acyl CoAs. Homology modelling reported in this article supports the importance of the capacity of the acyl binding tunnel and active site cavity in fungal type III PKSs.

  13. Terpene synthases from Cannabis sativa.

    Directory of Open Access Journals (Sweden)

    Judith K Booth

    Full Text Available Cannabis (Cannabis sativa plants produce and accumulate a terpene-rich resin in glandular trichomes, which are abundant on the surface of the female inflorescence. Bouquets of different monoterpenes and sesquiterpenes are important components of cannabis resin as they define some of the unique organoleptic properties and may also influence medicinal qualities of different cannabis strains and varieties. Transcriptome analysis of trichomes of the cannabis hemp variety 'Finola' revealed sequences of all stages of terpene biosynthesis. Nine cannabis terpene synthases (CsTPS were identified in subfamilies TPS-a and TPS-b. Functional characterization identified mono- and sesqui-TPS, whose products collectively comprise most of the terpenes of 'Finola' resin, including major compounds such as β-myrcene, (E-β-ocimene, (--limonene, (+-α-pinene, β-caryophyllene, and α-humulene. Transcripts associated with terpene biosynthesis are highly expressed in trichomes compared to non-resin producing tissues. Knowledge of the CsTPS gene family may offer opportunities for selection and improvement of terpene profiles of interest in different cannabis strains and varieties.

  14. Pemodelan Molekul Turunan p-Metoksi sinnamoil Hidrazida Sebagai Inhibitor Checkpoint Kinase 1 dan Inhibitor Aromatase secara In silico

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    Galih Satrio Putra

    2017-08-01

    Full Text Available The development of anticancer drugs from ethyl p-methoxycinnamate (EPMC derivatives continues to obtain compounds that have high ability of cancer cells apoptosis and minimal side effects. p-Methoxycinnamoyl hydrazide derivate compounds from EPMC structure modification were docked into the ligand-binding pocket of Check point kinase 1 enzymes (2YWP and the aromatase enzyme (3S7S using software Molegro Virtual Docker (MVD Ver.5.5. We compared the Rerank score of native ligand with derivate compounds of p-Methoxycinnamoyl hydrazide. Rerank scores of compounds 4b and 4c (-99.98 Kcal/mol and -99.80 Kcal/mol were lower than the native ligand A42 in inhibiting the enzyme checkpoint kinase 1. Rerank values of p-Methoxycinnamoyl hydrazide derivate compounds were greater than the native ligand EXM in inhibiting the enzyme aromatase. p-Methoxycinnamoyl hydrazide derivate compounds, especially compounds 4b and 4c, had anticancer mechanism by inhibiting the enzyme pathway checkpoint kinase 1 and had not activity in inhibiting the aromatase enzyme.

  15. Fecal microbial determinants of fecal and systemic estrogens and estrogen metabolites: a cross-sectional study

    Directory of Open Access Journals (Sweden)

    Flores Roberto

    2012-12-01

    Full Text Available Abstract Background High systemic estrogen levels contribute to breast cancer risk for postmenopausal women, whereas low levels contribute to osteoporosis risk. Except for obesity, determinants of non-ovarian systemic estrogen levels are undefined. We sought to identify members and functions of the intestinal microbial community associated with estrogen levels via enterohepatic recirculation. Methods Fifty-one epidemiologists at the National Institutes of Health, including 25 men, 7 postmenopausal women, and 19 premenopausal women, provided urine and aliquots of feces, using methods proven to yield accurate and reproducible results. Estradiol, estrone, 13 estrogen metabolites (EM, and their sum (total estrogens were quantified in urine and feces by liquid chromatography/tandem mass spectrometry. In feces, β-glucuronidase and β-glucosidase activities were determined by realtime kinetics, and microbiome diversity and taxonomy were estimated by pyrosequencing 16S rRNA amplicons. Pearson correlations were computed for each loge estrogen level, loge enzymatic activity level, and microbiome alpha diversity estimate. For the 55 taxa with mean relative abundance of at least 0.1%, ordinal levels were created [zero, low (below median of detected sequences, high] and compared to loge estrogens, β-glucuronidase and β-glucosidase enzymatic activity levels by linear regression. Significance was based on two-sided tests with α=0.05. Results In men and postmenopausal women, levels of total urinary estrogens (as well as most individual EM were very strongly and directly associated with all measures of fecal microbiome richness and alpha diversity (R≥0.50, P≤0.003. These non-ovarian systemic estrogens also were strongly and significantly associated with fecal Clostridia taxa, including non-Clostridiales and three genera in the Ruminococcaceae family (R=0.57−0.70, P=0.03−0.002. Estrone, but not other EM, in urine correlated significantly with

  16. The estrogen receptor of the gastropod Nucella lapillus: Modulation following exposure to an estrogenic effluent?

    Energy Technology Data Exchange (ETDEWEB)

    Castro, L. Filipe C. [CIIMAR, Centre of Marine and Environmental Research, Laboratory of Cellular and Molecular Studies, University of Porto, Rua dos Bragas 177, 4050-123 Porto (Portugal)], E-mail: filipe.castro@ciimar.up.pt; Melo, C. [CIIMAR, Centre of Marine and Environmental Research, Laboratory of Cellular and Molecular Studies, University of Porto, Rua dos Bragas 177, 4050-123 Porto (Portugal); Guillot, R.; Mendes, I.; Queiros, S.; Lima, D. [CIIMAR, Centre of Marine and Environmental Research, Laboratory of Environmental Toxicology, University of Porto, Rua dos Bragas 177, 4050-123 Porto (Portugal); Reis-Henriques, M.A. [CIIMAR, Centre of Marine and Environmental Research, Laboratory of Environmental Toxicology, University of Porto, Rua dos Bragas 177, 4050-123 Porto (Portugal); ICBAS, Instituto Ciencias Biomedicas Abel Salazar, University of Porto, Largo Professor Abel Salazar 2, 4099-003 Porto (Portugal); Santos, M.M. [CIIMAR, Centre of Marine and Environmental Research, Laboratory of Environmental Toxicology, University of Porto, Rua dos Bragas 177, 4050-123 Porto (Portugal)], E-mail: santos@ciimar.up.pt

    2007-10-30

    The molecular targets of estrogenic endocrine disrupting chemicals have been studied in detail in vertebrates. The lack of basic endocrine knowledge impairs similar approaches for invertebrates. Evidence indicates that the signalling pathways of invertebrates may also be a target of estrogenic chemicals (ECs). In fact, the exposure to effluents containing ECs has been reported to impact mollusc reproduction. Despite the reported estrogen independence of the mollusc nuclear estrogen receptor (ER), its role in EC-induced toxicity has not been investigated in vivo. Therefore, we have cloned the ER of the gastropod Nucella lapillus and evaluated the effects of a mixture of estrogenic chemicals (sewage effluent) on its expression in the ovary. Here, we show that the exposure to a raw domestic/industrial effluent, impact ER expression with a simultaneous reproductive maturation. These results highlight the need to further investigate the role of ER on the reproductive process in prosobranch gastropods and whether this signalling pathway is prone to disruption by ECs.

  17. Do microRNAs Mediate Estrogen-Dependent Repression of Genes

    National Research Council Canada - National Science Library

    Nakshatri, Harikrishna; Collins, Nikail R

    2008-01-01

    Estrogen receptor alpha (ERa) mediates transcriptional effects of estrogen. Estrogen inducible proteins c-Myc and E2F family are required for optimal ERa activity and secondary estrogen response, respectively...

  18. Use of aromatase inhibitors to treat endometriosis-related pain symptoms: a systematic review

    Directory of Open Access Journals (Sweden)

    Venturini Pier L

    2011-06-01

    Full Text Available Abstract This systematic review aims to assess the efficacy of aromatase inhibitors (AIs in treating pain symptoms caused by endometriosis. A comprehensive literature search was conducted to identify all the published studies evaluating the efficacy of type II nonsteroidal aromatase inhibitors (anastrozole and letrozole in treating endometriosis-related pain symptoms. The MEDLINE, EMBASE, PubMed, and SCOPUS databases and the Cochrane System Reviews were searched up to October 2010. This review comprises of the results of 10 publications fitting the inclusion criteria; these studies included a total of 251 women. Five studies were prospective non-comparative, four were randomized controlled trials (RCTs and one was a prospective patient preference trial. Seven studies examined the efficacy of AIs in improving endometriosis-related pain symptoms, whilst three RCTs investigated the use of AIs as post-operative therapy in preventing the recurrence of pain symptoms after surgery for endometriosis. All the observational studies demonstrated that AIs combined with either progestogens or oral contraceptive pill reduce the severity of pain symptoms and improve quality of life. One patient preference study demonstrated that letrozole combined with norethisterone acetate is more effective in reducing pain and deep dyspareunia than norethisterone acetate alone. However, letrozole causes a higher incidence of adverse effects and does not improve patients' satisfaction or influence recurrence of symptoms after discontinuation of treatment. A RCT showed that combining letrozole with norethisterone acetate causes a lower incidence of adverse effects and lower discontinuation rate than combining letrozole with triptorelin. Two RCTs demonstrated that, after surgical treatment of endometriosis, the administration of AIs combined with gonadotropin releasing hormone analogue for 6 months reduces the risk of endometriosis recurrence when compared with gonadotropin

  19. Structure-activity relationships of 3-deoxy androgens as aromatase inhibitors. Synthesis and biochemical studies of 4-substituted 4-ene and 5-ene steroids.

    Science.gov (United States)

    Nagaoka, Masao; Watari, Yoko; Yajima, Hiromi; Tsukioka, Kaoru; Muroi, Yasuyo; Yamada, Keiko; Numazawa, Mitsuteru

    2003-08-01

    As part of our investigation into the structure-activity relationship of a novel class of aromatase inhibitors, two series of 3-deoxy androgens, androst-5-en-17-ones with a non-polar alkoxy (5 and 6), alkyl (20-22), or phenylalkyl (23 and 24) group at C-4beta and 4-acyloxyandrost-4-en-17-ones (29-32, and 34) were synthesized and evaluated. The 4beta-alkyl and 4beta-phenylalkyl compounds were obtained through reaction of 4alpha,5alpha-epoxy steroid (8) with RMgBr (R: alkyl and phenylalkyl) followed by dehydration of the 4beta-substituted 5alpha-hydroxy products (15-19) with SOCl(2) as key reactions. Acylation of 4alpha,5alpha-diol (25) with (RCO)(2)O in pyridine and subsequent dehydration with SOCl(2) gave the 4-acyloxy steroids. All of the steroids studied, except for 4-acetoxy-19-ol (34) that was a non-competitive inhibitor of human placental aromatase, blocked aromatase activity in a competitive manner. 4-Benzoyloxy- and 4-acetoxy steroids (31) and (32) were the most powerful inhibitors of aromatase (K(i)=70 and 60nM, respectively). Elongation of an acetoxy group in a series of 4-acyloxy steroids or a methyl group in a series of 4beta-alkyl steroids decreased affinity for aromatase principally in relation to carbon number of the acyl or alkyl function. The present findings are potentially useful for understanding the spatial and electronic nature of the binding site of aromatase as well as for developing effective aromatase inhibitors.

  20. The role of estrogens at men. Part 1. General and developmental endocrinology, physiology and pathophysiology of estrogens at men

    Directory of Open Access Journals (Sweden)

    I. A. Tyuzikov

    2015-02-01

    Full Text Available Estrogens (female sex hormones are important sex hormones for women and men, although traditionally the problems associated with impaired synthesis and metabolism of estrogens are considered, especially in relation to the female population. However, presented an overview allows for a different look at the role and significance of estrogens for men. In the first part of the literature review highlights issues of general endocrinology and age of estrogens and the results of clinical and experimental studies, reflecting the physiological functionsof estrogens and pathophysiologic consequences of violations of the synthesis and metabolism of estrogens in male organism.

  1. The role of estrogens at men. Part 1. General and developmental endocrinology, physiology and pathophysiology of estrogens at men

    Directory of Open Access Journals (Sweden)

    I. A. Tyuzikov

    2014-01-01

    Full Text Available Estrogens (female sex hormones are important sex hormones for women and men, although traditionally the problems associated with impaired synthesis and metabolism of estrogens are considered, especially in relation to the female population. However, presented an overview allows for a different look at the role and significance of estrogens for men. In the first part of the literature review highlights issues of general endocrinology and age of estrogens and the results of clinical and experimental studies, reflecting the physiological functionsof estrogens and pathophysiologic consequences of violations of the synthesis and metabolism of estrogens in male organism.

  2. Synthesis and PET studies of [11C-cyano]letrozole (Femara®), an aromatase inhibitor drug

    Science.gov (United States)

    Kil, Kun-Eek; Biegon, Anat; Ding, Yu-Shin; Fischer, Andre; Ferrieri, Richard A.; Kim, Sung Won; Pareto, Deborah; Schueller, Michael J.; Fowler, Joanna S.

    2011-01-01

    Introduction Aromatase, a member of the cytochrome P450 family, converts androgens such as androstenedione and testosterone to estrone and estradiol respectively. Letrozole (1-[bis-(4-cyanophenyl)methyl]-1H-1,2,4-triazole, Femara®) is a high affinity aromatase inhibitor (Ki=11.5 nM) which has FDA approval for breast cancer treatment. Here we report the synthesis of carbon-11 labeled letrozole and its assessment as a radiotracer for brain aromatase in the baboon. Methods Letrozole and its precursor (4-[(4-bromophenyl)-1H-1,2,4-triazol-1-ylmethyl]benzonitrile, 3) were prepared in two-step syntheses from 4-cyanobenzyl bromide and 4-bromobenzyl bromide, respectively. The [11C]cyano group was introduced via the tetrakis(triphenylphosphine)palladium(0) catalyzed coupling of [11C]cyanide with the bromo-precursor (3). PET studies in the baboon brain were carried out to assess regional distribution and kinetics, reproducibility of repeated measures and saturability. The free fraction of letrozole in the plasma, log D, and the [11C-cyano]letrozole fraction in the arterial plasma were also measured. Results [11C-cyano]Letrozole was synthesized in 60 min with a radiochemical yield of 79–80%, with a radiochemical purity greater than 98% and a specific activity of 4.16±2.21 Ci/μmol at the end of bombardment (n=4). PET studies in the baboon revealed initial rapid and high uptake and initial rapid clearance followed by slow clearance of carbon-11 from the brain with no difference between brain regions. The brain kinetics was not affected by co-injection of unlabeled letrozole (0.1 mg/kg). The free fraction of letrozole in plasma was 48.9% and log D was 1.84. Conclusion [11C-cyano]Letrozole is readily synthesized via a palladium catalyzed coupling reaction with [11C]cyanide. Although it is unsuitable as a PET radiotracer for brain aromatase as revealed by the absence of regional specificity and saturability in brain regions, such as amygdala, which are known to contain

  3. Enzymic aromatization of 6-alkyl-substituted androgens, potent competitive and mechanism-based inhibitors of aromatase.

    Science.gov (United States)

    Numazawa, M; Yoshimura, A; Oshibe, M

    1998-01-01

    To gain insight into the relationships between the aromatase inhibitory activity of 6-alkyl-substituted androgens, potent competitive inhibitors, and their ability to serve as a substrate of aromatase, we studied the aromatization of a series of 6alpha- and 6beta-alkyl (methyl, ethyl, n-propyl, n-pentyl and n-heptyl)-substituted androst-4-ene-3,17-diones (ADs) and their androsta-1,4-diene-3,17-dione (ADD) derivatives with human placental aromatase, by gas chromatography-mass spectrometry. Among the inhibitors examined, ADD and its 6alpha-alkyl derivatives with alkyl functions less than three carbons long, together with 6beta-methyl ADD, are suicide substrates of aromatase. All of the steroids, except for 6beta-n-pentyl ADD and its n-heptyl analogue as well as 6beta-n-heptyl AD, were found to be converted into the corresponding 6-alkyl oestrogens. The 6-methyl steroids were aromatized most efficiently in each series, and the aromatization rate essentially decreased in proportion to the length of the 6-alkyl chains in each series, where the 6alpha-alkyl androgens were more efficient substrates than the corresponding 6beta isomers. The Vmax of 6alpha-methyl ADD was approx. 2.5-fold that of the natural substrate AD and approx. 3-fold that of the parent ADD. On the basis of this, along with the facts that the rates of a mechanism-based inactivation of aromatase by ADD and its 6alpha-methyl derivative are similar, it is implied that alignment of 6alpha-methyl ADD in the active site could favour the pathway leading to oestrogen over the inactivation pathway, compared with that of ADD. The relative apparent Km values for the androgens obtained in this study are different from the relative Ki values obtained previously, indicating that there is a difference between the ability to serve as an inhibitor and the ability to serve as a substrate in the 6-alkyl androgen series. PMID:9405288

  4. Estrogenicity of glabridin in Ishikawa cells.

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    Melissa Su Wei Poh

    Full Text Available Glabridin is an isoflavan from licorice root, which is a common component of herbal remedies used for treatment of menopausal symptoms. Past studies have shown that glabridin resulted in favorable outcome similar to 17β-estradiol (17β-E2, suggesting a possible role as an estrogen replacement therapy (ERT. This study aims to evaluate the estrogenic effect of glabridin in an in-vitro endometrial cell line -Ishikawa cells via alkaline phosphatase (ALP assay and ER-α-SRC-1-co-activator assay. Its effect on cell proliferation was also evaluated using Thiazoyl blue tetrazolium bromide (MTT assay. The results showed that glabridin activated the ER-α-SRC-1-co-activator complex and displayed a dose-dependent increase in estrogenic activity supporting its use as an ERT. However, glabridin also induced an increase in cell proliferation. When glabridin was treated together with 17β-E2, synergistic estrogenic effect was observed with a slight decrease in cell proliferation as compared to treatment by 17β-E2 alone. This suggest that the combination might be better suited for providing high estrogenic effects with lower incidences of endometrial cancer that is associated with 17β-E2.

  5. Aromatase deficiency causes altered expression of molecules critical for calcium reabsorption in the kidneys of female mice *.

    NARCIS (Netherlands)

    Oz, O.K.; Hajibeigi, A.; Howard, K.; Cummins, C.L.; Abel, M. van; Bindels, R.J.M.; Word, R.A.; Kuro-o, M.; Pak, C.Y.; Zerwekh, J.E.

    2007-01-01

    Kidney stones increase after menopause, suggesting a role for estrogen deficiency. ArKO mice have hypercalciuria and lower levels of calcium transport proteins, whereas levels of the klotho protein are elevated. Thus, estrogen deficiency is sufficient to cause altered renal calcium handling.

  6. Classical and Nonclassical Estrogen Receptor Action on Chromatin Templates

    National Research Council Canada - National Science Library

    Nordeen, Steven

    2000-01-01

    .... Using newly-developed approaches, I investigated mechanisms of estrogen/estrogen receptor action on chromatin templates in vitro in order to better understand the role of chromatin in steroid-regulated gene expression...

  7. Classical and Nonclassical Estrogen Receptor Action on Chromatin Templaces

    National Research Council Canada - National Science Library

    Nordeen, Steve

    2001-01-01

    .... Using newly-developed approaches, I investigated mechanisms of estrogen/estrogen receptor action on chromatin templates in vitro in order to better understand the role of chromatin in steroid-regulated gene expression...

  8. Ozonation of estrogenic chemicals in biologically treated sewage

    DEFF Research Database (Denmark)

    Hansen, Kamilla Marie Speht; Andersen, Henrik Rasmus; Ledin, Anna

    2010-01-01

    The present study shows that ozonation of effluents from municipal wastewater treatment plants (WWTPs) is likely to be a future treatment solution to remove estrogens and xeno-estrogens. The required ozone dose and electrical energy for producing the ozone were determined in two WWTP effluents...... for removal of 17 estrogenic chemicals. The estrogenic compounds included parabens, industrial phenols, sunscreen chemicals, and steroid estrogens. The obtained values of Electrical Energy per Order (EEOs) for the treatment of the estrogens were in the range 0.14–1.1 kWh/m3 corresponding to 1.7–14 g O3/m3....... It is furthermore suggested that UV-absorbance is a useful parameter for online control of the ozone dose in a full scale application since the absorbance of the WWTP effluents and the remaining concentration of the estrogens and xeno-estrogens correlated well with the applied ozone dose....

  9. Aromatic Polyketide Synthases (Purification, Characterization, and Antibody Development to Benzalacetone Synthase from Raspberry Fruits).

    Science.gov (United States)

    Borejsza-Wysocki, W.; Hrazdina, G.

    1996-03-01

    p-Hydroxyphenylbutan-2-one, the characteristic aroma compound of raspberries (Rubus idaeus L.), is synthesized from p-coumaryl-coenzyme A and malonyl-coenzyme A in a two-step reaction sequence that is catalyzed by benzalacetone synthase and benzalacetone reductase (W. Borejsza-Wysocki and G. Hrazdina [1994] Phytochemistry 35: 623-628). Benzalacetone synthase condenses one malonate with p-coumarate to form the pathway intermediate p-hydroxyphenylbut-3-ene-2-one (p-hydroxybenzalacetone) in a reaction that is similar to those catalyzed by chalcone and stilbene synthases. We have obtained an enzyme preparation from ripe raspberries that was preferentially enriched in benzalacetone synthase (approximately 170-fold) over chalcone synthase (approximately 14-fold) activity. This preparation was used to characterize benzalacetone synthase and to develop polyclonal antibodies in rabbits. Benzalacetone synthase showed similarity in its molecular properties to chalcone synthase but differed distinctly in its substrate specificity, response to 2-mercaptoethanol and ethylene glycol, and induction in cell-suspension cultures. The product of the enzyme, p-hydroxybenzalacetone, inhibited mycelial growth of the raspberry pathogen Phytophthora fragariae var rubi at 250 [mu]M. We do not know whether the dual activity in the benzalacetone synthase preparation is the result of a bifunctional enzyme or is caused by contamination with chalcone synthase that was also present. The rapid induction of the enzyme in cell-suspension cultures upon addition of yeast extract and the toxicity of its product, p-hydroxybenzalacetone, to phytopathogenic fungi also suggest that the pathway may be part of a plant defense response.

  10. PERFORMANSI TIGA GENOTIPE IKAN NILA YANG DIBERI PAKAN AROMATASE INHIBITOR PADA TAHAP PEMBESARAN

    Directory of Open Access Journals (Sweden)

    Didik Ariyanto

    2016-11-01

    Full Text Available Ikan nila jantan XY mempunyai laju pertumbuhan lebih cepat dibanding ikan betina XX, sehingga budidaya ikan nila tunggal kelamin jantan lebih menguntungkan. Salah satu metode produksi massal benih ikan nila tunggal kelamin jantan adalah melalui sex reversal, yaitu dengan menambahkan hormon sintetik 17a-metiltestosteron (mt atau dapat juga dengan memberikan bahan aromatase inhibitor (AI. Penelitian ini bertujuan untuk mengevaluasi performansi benih tiga genotipe (XX, XY, dan YY ikan nila yang diberi bahan AI pada tahap pembesaran. Bahan utama adalah benih ikan nila genotipe XX, XY, dan YY yang diberi bahan AI. Benih dengan penambahan hormon mt digunakan sebagai kontrol (+. Sebagai pembanding digunakan populasi campuran antara jantan dan betina. Benih berumur 95 hari setelah menetas dengan bobot rata-rata 20 g/ekor dipelihara dalam jaring yang ditempatkan di kolam pembesaran selama 120 hari. Hasil penelitian menunjukkan bahwa populasi tunggal kelamin jantan genotipe XY maupun jantan hasil sex reversal genotipe XX mempunyai laju pertumbuhan dan hasil panen lebih baik dibandingkan populasi campuran XX-XY. Semua perlakuan dan genotipe yang berbeda tidak memberikan dampak yang berbeda nyata terhadap nilai keragaman ukuran, sintasan, maupun nilai food conversion ratio, kecuali pada genotipe YY. Organ reproduksi pada semua genotipe dan perlakuan berkembang normal

  11. Aromatase inhibitors induced autoimmune disorders in patients with breast cancer: A review

    Directory of Open Access Journals (Sweden)

    George Zarkavelis

    2016-09-01

    Full Text Available Subacute cutaneous lupus erythematosus (SCLE is characterized by particular cutaneous manifestations such as non-scaring plaques mainly in sunlight exposed parts of the body along with specific serum autoantibodies (i.e. antinuclear antibodies (ANA, Ro/SSa, La/SSb. It is considered either idiopathic or drug induced. The role of chemotherapeutic agents in causing SCLE has been investigated with the taxanes being the most common anticancer agents. However, recent data emerging point toward antiestrogen therapies as a causative factor not only for SCLE but also for a variety of autoimmune disorders. This is a report of a case of a 42 year old woman who developed clinical manifestations of SCLE after letrozole treatment in whom remission of the cutaneous manifestations was noticed upon discontinuation of the drug. In addition, an extensive review of the English literature has been performed regarding the association of antiestrogen therapy with autoimmune disorders. In conclusion, Oncologists should be aware of the potential development of autoimmune reactions in breast cancer patients treated with aromatase inhibitors.

  12. Synaptic long-term potentiation and depression in the rat medial vestibular nuclei depend on neural activation of estrogenic and androgenic signals.

    Directory of Open Access Journals (Sweden)

    Mariangela Scarduzio

    Full Text Available Estrogenic and androgenic steroids can be synthesised in the brain and rapidly modulate synaptic transmission and plasticity through direct interaction with membrane receptors for estrogens (ERs and androgens (ARs. We used whole cell patch clamp recordings in brainstem slices of male rats to explore the influence of ER and AR activation and local synthesis of 17β-estradiol (E2 and 5α-dihydrotestosterone (DHT on the long-term synaptic changes induced in the neurons of the medial vestibular nucleus (MVN. Long-term depression (LTD and long-term potentiation (LTP caused by different patterns of high frequency stimulation (HFS of the primary vestibular afferents were assayed under the blockade of ARs and ERs or in the presence of inhibitors for enzymes synthesizing DHT (5α-reductase and E2 (P450-aromatase from testosterone (T. We found that LTD is mediated by interaction of locally produced androgens with ARs and LTP by interaction of locally synthesized E2 with ERs. In fact, the AR block with flutamide prevented LTD while did not affect LTP, and the blockade of ERs with ICI 182,780 abolished LTP without influencing LTD. Moreover, the block of P450-aromatase with letrozole not only prevented the LTP induction, but inverted LTP into LTD. This LTD is likely due to the local activation of androgens, since it was abolished under blockade of ARs. Conversely, LTD was still induced in the presence of finasteride the inhibitor of 5α-reductase demonstrating that T is able to activate ARs and induce LTD even when DHT is not synthesized. This study demonstrates a key and opposite role of sex neurosteroids in the long-term synaptic changes of the MVN with a specific role of T-DHT for LTD and of E2 for LTP. Moreover, it suggests that different stimulation patterns can lead to LTD or LTP by specifically activating the enzymes involved in the synthesis of androgenic or estrogenic neurosteroids.

  13. Estrogen-associated severe hypertriglyceridemia with pancreatitis.

    Science.gov (United States)

    Aljenedil, Sumayah; Hegele, Robert A; Genest, Jacques; Awan, Zuhier

    Estrogen, whether therapeutic or physiologic, can cause hypertriglyceridemia. Hypertriglyceridemia-induced pancreatitis is a rare complication. We report 2 women who developed estrogen-associated severe hypertriglyceridemia with pancreatitis. The first patient developed pancreatitis secondary to hypertriglyceridemia associated with in vitro fertilization cycles. Marked reduction in her triglyceride was achieved with dietary restrictions and fibrate. The second patient developed pancreatitis secondary to hypertriglyceridemia during her pregnancies. She was noncompliant with the treatment; therefore, her triglyceride remained high after delivery. In both patients, no hypertriglyceridemia-associated genes mutations were identified, although the second patient had strong polygenic susceptibility to hypertriglyceridemia. Estrogen-induced severe hypertriglyceridemia with pancreatitis can be a life-threatening condition. Screening in high-risk patients is crucial to prevent subsequent complications. Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.

  14. Efficacy and mechanism of action of Proellex, an antiprogestin in aromatase overexpressing and Letrozole resistant T47D breast cancer cells.

    Science.gov (United States)

    Gupta, Akash; Mehta, Rajeshwari; Alimirah, Fatouma; Peng, Xinjian; Murillo, Genoveva; Wiehle, Ronald; Mehta, Rajendra G

    2013-01-01

    Aromatase inhibitors (AI) are considered as a first line therapy for ER+PR+ breast cancers. However, many patients acquire resistance to AI. In this study, we determined the response of antiprogestin CDB-4124 (Proellex) on the aromatase overexpressing and Letrozole resistant cell lines and also studies its mechanism of action in inhibition of breast cancer cell proliferation. For these studies we generated aromatase overexpressing T47D (T47Darom) and respective control (T47Dcon) breast cancer cell lines by stable transfection with plasmid containing CYP19A1 gene, or empty vector respectively. Letrozole resistant cell line (T47DaromLR) was generated by incubating T47Darom for 75 weeks in the presence of 10 μM Letrozole. Cell proliferation was determined by MTT or crystal violet assays. Gene expressions were quantified by QRT-PCR whereas proteins were identified by western blot analyses, flow cytometry and immunofluorescence staining. Aromatase activity was determined by estradiol ELISA. The effects of Proellex on the anchorage independent growth were measured by soft agar colony formation. Statistical differences between the various groups were determined by Student's 't' test or ANOVA followed by Bonferroni's post hoc test. Results showed that T47Darom and T47DaromLR cell lines had significantly higher aromatase expression (mRNA; 80-90 fold and protein) and as a result exhibited increased aromatization of testosterone to estradiol as compared to T47Dcon. Both these cell lines showed enhanced growth in the presence of Testosterone (50-60%). In T47DaromLR cells increased PR-B and EGFR expression as compared to T47Dcon cells was observed. Proellex and other known aromatase inhibitors (Letrozole, Anastrozole, and Exemestane) inhibited testosterone induced cell proliferation and anchorage independent growth of T47Darom cells. Cell growth inhibition was significantly greater when cells were treated with Proellex alone or in combination with other AIs as compared to AIs

  15. Estrogenic and anti-estrogenic activity of 23 commercial textile dyes.

    Science.gov (United States)

    Bazin, Ingrid; Ibn Hadj Hassine, Aziza; Haj Hamouda, Yosra; Mnif, Wissem; Bartegi, Ahgleb; Lopez-Ferber, Miguel; De Waard, Michel; Gonzalez, Catherine

    2012-11-01

    The presence of dyes in wastewater effluent of textile industry is well documented. In contrast, the endocrine disrupting effects of these dyes and wastewater effluent have been poorly investigated. Herein, we studied twenty-three commercial dyes, usually used in the textile industry, and extracts of blue jean textile wastewater samples were evaluated for their agonistic and antagonistic estrogen activity. Total estrogenic and anti-estrogenic activities were measured using the Yeast Estrogen Screen bioassay (YES) that evaluates estrogen receptor binding-dependent transcriptional and translational activities. The estrogenic potencies of the dyes and wastewater samples were evaluated by dose-response curves and compared to the dose-response curve of 17β-estradiol (E2), the reference compound. The dose-dependent anti-estrogenic activities of the dyes and wastewater samples were normalized to the known antagonistic effect of 4-hydroxytamoxifen (4-OHT) on the induction of the lac Z reporter gene by E2. About half azo textile dyes have anti-estrogenic activity with the most active being Blue HFRL. Most azo dyes however have no or weak estrogenic activity. E2/dye or E2/waste water ER competitive binding assays show activity of Blue HFRL, benzopurpurine 4B, Everzol Navy Blue FBN, direct red 89 BNL 200% and waste water samples indicating a mechanism of action common to E2. Our results indicate that several textile dyes are potential endocrine disrupting agents. The presence of some of these dyes in textile industry wastewater may thus impact the aquatic ecosystem. Copyright © 2012 Elsevier Inc. All rights reserved.

  16. Estrogen and Growth Hormone and their Roles in Reproductive Function

    OpenAIRE

    Hüseyin Baki ÇİFTCİ

    2013-01-01

    The aim of this study was to review the effect of estrogen on growth hormone secretion and the roles of estrogen and growth hormone in reproductive function. Estrogen is the main hormone affecting growth, development, maturation and functioning of reproductive tract as well as the sexual differentiation and the behavior. Growth hormone is also important factor in sexual maturation and attainment of puberty. The impact of estrogen on growth hormone secretion has been reported in rodents and pr...

  17. Epigenetic control of gonadal aromatase (cyp19a1 in temperature-dependent sex determination of red-eared slider turtles.

    Directory of Open Access Journals (Sweden)

    Yuiko Matsumoto

    Full Text Available In the red-eared slider turtle (Trachemys scripta, a species with temperature-dependent sex determination (TSD, the expression of the aromatase gene during gonad development is strictly limited to the female-producing temperature. The underlying mechanism remains unknown. In this study, we identified the upstream 5'-flanking region of the aromatase gene, gonad-specific promoter, and the temperature-dependent DNA methylation signatures during gonad development in the red-eared slider turtle. The 5'-flanking region of the slider aromatase exhibited sequence similarities to the aromatase genes of the American alligator, chicken, quail, and zebra finch. A putative TATA box was located 31 bp upstream of the gonad-specific transcription start site. DNA methylation at the CpG sites between the putative binding sites of the fork head domain factor (FOX and vertebrate steroidogenic factor 1 (SF1 and adjacent TATA box in the promoter region were significantly lower in embryonic gonads at the female-producing temperature compared the male-producing temperature. A shift from male- to female-, but not from female- to male-, producing temperature changed the level of DNA methylation in gonads. Taken together these results indicate that the temperature, particularly female-producing temperature, allows demethylation at the specific CpG sites of the promoter region which leads the temperature-specific expression of aromatase during gonad development.

  18. Estrogenic activity of flavonoids in mice. The importance of estrogen receptor distribution, metabolism and bioavailability

    DEFF Research Database (Denmark)

    Breinholt, Vibeke; Hossaini, A.; Svendsen, Gitte W.

    2000-01-01

    The in vivo estrogenic potential of the flavonoids apigenin, kaempferol, genistein and equol was investigated in immature female mice. Genistein and equol, administered by gavage for 4 consecutive days [post-natal day (PND) 17-20, 100 mg/kg body weight], was found to significantly increase uterine...... or lower potency. Bioavailability, metabolism, the ability to alter ER alpha distribution in the uterus and the estrogenic potential of parent compound and metabolites may thus contribute to the differences in in vivo estrogenicity of dietary flavonoids....

  19. Estrogen and colorectal cancer incidence and mortality.

    Science.gov (United States)

    Lavasani, Sayeh; Chlebowski, Rowan T; Prentice, Ross L; Kato, Ikuko; Wactawski-Wende, Jean; Johnson, Karen C; Young, Alicia; Rodabough, Rebecca; Hubbell, F Allan; Mahinbakht, Ali; Simon, Michael S

    2015-09-15

    The preponderance of observational studies describe an association between the use of estrogen alone and a lower incidence of colorectal cancer. In contrast, no difference in the incidence of colorectal cancer was seen in the Women's Health Initiative (WHI) randomized, placebo-controlled trial with estrogen alone after a mean intervention of 7.1 years and cumulative follow-up of 13.2 years. This study extends these findings by providing detailed analyses of the effects of estrogen alone on the histology, grade, and stage of colorectal cancer, relevant subgroups, and deaths from and after colorectal cancer. The WHI study was a randomized, double-blind, placebo-controlled trial involving 10,739 postmenopausal women with prior hysterectomy. Participants were assigned to conjugated equine estrogen at 0.625 mg/d (n = 5279) or a matching placebo (n = 5409). Rates of colorectal cancer diagnoses and deaths from and after colorectal cancer were assessed throughout the study. Colorectal cancer rates in the estrogen-alone and placebo groups were comparable: 0.14% and 0.12% per year, respectively (hazard ratio [HR], 1.13; 95% confidence interval [CI], 0.83-1.58; P = .43). Bowel screening examinations were comparable between the 2 groups throughout the study. The grade, stage, and location of colorectal cancer did not differ between the randomization groups. There were more colorectal cancer deaths in the estrogen-alone group (34 [0.05%] vs 24 [0.03%]; HR, 1.46, 95% CI, 0.86-2.46; P = .16), but the difference was not statistically significant. The colorectal cancer incidence was higher for participants with a history of colon polyp removal in the estrogen-alone group (0.23% vs 0.02%; HR, 13.47; nominal 95% CI, 1.76-103.0; P colorectal cancer or deaths from or after colorectal cancer. A possibly higher risk of colorectal cancer in women with prior colon polyp removal who use estrogen alone requires confirmation. © 2015 American Cancer Society.

  20. The differential association of conjugated equine estrogen and esterified estrogen with activated protein C resistance in postmenopausal women

    NARCIS (Netherlands)

    Smith, N.L.; Heckbert, S.R.; Doggen, Catharina Jacoba Maria; Lemaitre, R.N.; Reiner, A.P.; Lumley, T.; Meijers, J.C.M.; Psaty, B.M.; Rosendaal, F.R.

    2006-01-01

    Objectives: Clinical trials have demonstrated that oral conjugated equine estrogen (CEE) therapy with or without medroxyprogesterone (MPA) increases venous thrombotic risk but this safety issue has not been investigated for other oral estrogens. Based on observational study findings that esterified

  1. The differential association of conjugated equine estrogen and esterified estrogen with activated protein C resistance in postmenopausal women

    NARCIS (Netherlands)

    Smith, N. L.; Heckbert, S. R.; Doggen, C. J.; Lemaitre, R. N.; Reiner, A. P.; Lumley, T.; Meijers, J. C. M.; Psaty, B. M.; Rosendaal, F. R.

    2006-01-01

    OBJECTIVES: Clinical trials have demonstrated that oral conjugated equine estrogen (CEE) therapy with or without medroxyprogesterone (MPA) increases venous thrombotic risk but this safety issue has not been investigated for other oral estrogens. Based on observational study findings that esterified

  2. Estrogen Metabolism and Breast Cancer Risk – A Review | Okobia ...

    African Journals Online (AJOL)

    This paradigm shift is necessitated by evidence of estrogen induced carcinogenesis in several animal and human models following exposure to these estrogen metabolites. This review examines some of the available evidence relating these estrogen metabolites to animal and human breast carcinogenesis. African Journal ...

  3. Xenoestrogens elicit a modulation of endocannabinoid system and estrogen receptors in 4NP treated goldfish, Carassius auratus.

    Science.gov (United States)

    Pomatto, Valentina; Palermo, Francesco; Mosconi, Gilberto; Cottone, Erika; Cocci, Paolo; Nabissi, Massimo; Borgio, Luca; Polzonetti-Magni, Alberta M; Franzoni, Maria Fosca

    2011-10-01

    Based on pharmacological, behavioral and neuroanatomical studies, the endocannabinoids appear to be pivotal in some important neuroendocrine regulations of both vertebrates and invertebrates. Interestingly, a well developed endocannabinoid system was recently demonstrated by us in different bonyfish brain areas which control reproduction, energy balance and stress. Fish in particular are very sensitive to different types of stressors which can heavily affect their reproductive activity and negatively reverberate on aquaculture. Since recent new data have been reported on endocrine disruptors (EDs) impact on zebrafish receptor CB1 expression, in the present research we have investigated the response of the endocannabinoid system to acute treatment with an environmental stressor such as the xenoestrogen nonylphenol (4NP) in the brain and peripheral tissues of the goldfish Carassius auratus. First of all the estrogenic effects induced by 4NP were demonstrated by a dose-dependent increase of plasma levels and gene expression of the biomarker vitellogenin, then changes in cannabinoid receptors and anandamide degradative enzyme, the fatty acid amide hydrolase (FAAH), were analysed by means of Real Time PCR. As the exposure to EDs may lead to an activation of estrogen receptors and affects the Aromatase (AROB) transcription, changes in mRNA levels for ER subtypes and AROB were also evaluated. Our results confirm in goldfish the effect of 4NP on ERα and ERβ1 receptors and point out a different sensitivity of CB1 and CB2 for this compound, suggesting distinct roles of these cannabinoid receptors in some adaptive processes to contrast stress induced by xenoestrogen exposure. Copyright © 2011 Elsevier Inc. All rights reserved.

  4. Bacillus caldolyticus prs gene encoding phosphoribosyldiphosphate synthase

    DEFF Research Database (Denmark)

    Krath, Britta N.; Hove-Jensen, Bjarne

    1996-01-01

    The prs gene, encoding phosphoribosyl-diphosphate (PRPP) synthase, as well as the flanking DNA sequences were cloned and sequenced from the Gram-positive thermophile, Bacillus caldolyticus. Comparison with the homologous sequences from the mesophile, Bacillus subtilis, revealed a gene (gca......D) encoding N-acetylglucosamine-l-phosphate uridyltransferase upstream of prs, and a gene homologous to ctc downstream of prs. cDNA synthesis with a B. caldolyticus gcaD-prs-ctc-specified mRNA as template, followed by amplification utilising the polymerase chain reaction indicated that the three genes are co......-transcribed. Comparison of amino acid sequences revealed a high similarity among PRPP synthases across a wide phylogenetic range. An E. coli strain harbouring the B. caldolyticus prs gene in a multicopy plasmid produced PRPP synthase activity 33-fold over the activity of a haploid B. caldolyticus strain. B. caldolyticus...

  5. Effect of combining in vitro estrogenicity data with kinetic characteristics of estrogenic compounds on the invivo predictive value

    NARCIS (Netherlands)

    Punt, A.; Brand, W.; Murk, A.J.; Wezel, van A.P.; Schriks, M.; Heringa, M.B.

    2013-01-01

    With the ultimate aim of increasing the utility of in vitro assays for toxicological risk assessment, a method was developed to calculate in vivo estrogenic potencies from in vitro estrogenic potencies of compounds by taking into account systemic availability. In vitro estrogenic potencies of three

  6. Molecular analysis of human endometrium: Short-term tibolone signaling differs significantly from estrogen and estrogen + progestagen signaling

    NARCIS (Netherlands)

    P. Hanifi-Moghaddam (Payman); B. Boers-Sijmons (Bianca); A.H.A. Klaassens (Anet); F.H. van Wijk (Heidy); M.A. den Bakker (Michael); M.C. Ott; G.L. Shipley; H.A.M. Verheul (Herman); H.J. Kloosterboer (Helenius); C.W. Burger (Curt); L.J. Blok (Leen)

    2007-01-01

    textabstractTibolone, a tissue-selective compound with a combination of estrogenic, progestagenic, and androgenic properties, is used as an alternative for estrogen or estrogen plus progesterone hormone therapy for the treatment of symptoms associated with menopause and osteoporosis. The current

  7. Estrogenicity of food-associated estrogenic compounds in the fetuses of female transgenic mice upon oral and IP maternal exposure

    NARCIS (Netherlands)

    Veld, ter M.G.R.; Zawadzka, E.; Rietjens, I.M.C.M.; Murk, A.J.

    2009-01-01

    The present study investigated to what extent seven food-associated in vitro estrogenic compounds can induce estrogenic effects in the fetuses of pregnant female mice with an estrogen receptor (ER)-mediated luciferase (luc) reporter gene system. The luc-induction was determined either 8 h after

  8. Estrogen Receptor Alpha Distribution and Expression in the Social Neural Network of Monogamous and Polygynous Peromyscus.

    Directory of Open Access Journals (Sweden)

    Bruce S Cushing

    Full Text Available In microtine and dwarf hamsters low levels of estrogen receptor alpha (ERα in the bed nucleus of the stria terminalis (BST and medial amygdala (MeA play a critical role in the expression of social monogamy in males, which is characterized by high levels of affiliation and low levels of aggression. In contrast, monogamous Peromyscus males display high levels of aggression and affiliative behavior with high levels of testosterone and aromatase activity. Suggesting the hypothesis that in Peromyscus ERα expression will be positively correlated with high levels of male prosocial behavior and aggression. ERα expression was compared within the social neural network, including the posterior medial BST, MeA posterodorsal, medial preoptic area (MPOA, ventromedial hypothalamus (VMH, and arcuate nucleus in two monogamous species, P. californicus and P. polionotus, and two polygynous species, P. leucopus and P. maniculatus. The results supported the prediction, with male P. polionotus and P. californicus expressing higher levels of ERα in the BST than their polygynous counter parts, and ERα expression was sexually dimorphic in the polygynous species, with females expressing significantly more than males in the BST in both polygynous species and in the MeA in P. leucopus. Peromyscus ERα expression also differed from rats, mice and microtines as in neither the MPOA nor the VMH was ERα sexually dimorphic. The results supported the hypothesis that higher levels of ERα are associated with monogamy in Peromyscus and that differential expression of ERα occurs in the same regions of the brains regardless of whether high or low expression is associated with social monogamy. Also discussed are possible mechanisms regulating this differential relationship.

  9. Estrogenic and anti-estrogenic activities of Cassia tora phenolic constituents.

    Science.gov (United States)

    El-Halawany, Ali Mahmoud; Chung, Mi Hwa; Nakamura, Norio; Ma, Chao-Mei; Nishihara, Tsutomu; Hattori, Masao

    2007-10-01

    Through an estrogenic activity bioassay-guided fractionation of the 70% ethanolic extract of Cassia tora seeds two new phenolic triglucosides, torachrysone 8-O-[beta-D-glucopyranosyl(1-->3)-O-beta-D-glucopyranosyl(1-->6)-O-beta-D-glucopyranoside] (1) and toralactone 9-O-[beta-D-glucopyranosyl-(1-->3)-O-beta-D-glucopyranosyl-(1-->6)-O-beta-D-glucopyranoside] (2), along with seven known compounds were isolated. The structures of the new compounds were elucidated on the basis of spectroscopic and chemical evidence. The estrogenic activity of the fractions and the isolated compounds were investigated using the estrogen-dependent proliferation of MCF-7 cells. In addition, the yeast two hybrid assay expressing estrogen receptor alpha (ERalpha) and beta (ERbeta) and the ERalpha competitor screening assay (ligand binding screen) were used to verify the binding affinities of the isolated compounds to ER. Furthermore, a naringinase pre-treatment of the 70% alcoholic extract of Cassia tora seeds resulted in a significant increase in its estrogenic activity. From the naringinase pre-treated extract six compounds were isolated, among which 6-hydroxymusizin and aurantio-obtusin showed the most potent estrogenic activity, while torachrysone, rubrofusarin and toralactone showed a significant anti-estrogenic activity. Finally, the structure requirements responsible for the estrogenic activity of the isolated compounds were studied by investigating the activity of several synthetic compounds and chemically modifying the isolated compounds. The basic nucleus 1,3,8-trihyroxynaphthalene (T(3)HN) was found to play a principal role in the binding affinity of these compounds to ER.

  10. Estrogenic effects of fusarielins in human breast cancer cell lines

    DEFF Research Database (Denmark)

    Søndergaard, Teis; Klitgaard, Louise Graabæk; Purup, Stig

    2012-01-01

    from fungi that bind to the estrogen receptors and induce an estrogenic response in targeted cells. All four tested fusarielins stimulate MCF-7 cell proliferation with fusarielin H as the most potent, able to stimulate cell proliferation 4-fold in a resazurin metabolism assay at 25 μM. MDA-MB-231 cells...... without the estrogen receptor-α and MCF-10a cells without estrogen receptors were not stimulated by fusarielins. Furthermore, the stimulation was prevented in MCF-7 cells when fusarielins were incubated in the presence of the estrogen receptor antagonist fulvestrant. These observations suggest...

  11. Estrogens in the breast tissue: a systematic review

    Science.gov (United States)

    Colditz, Graham A.

    2013-01-01

    The role of estrogens in breast carcinogenesis has been investigated at the level of whole body (plasma) and cell (molecular, receptors, etc.). Growing attention focused on the breast tissue being an intracrine organ, with potentially important local estrogen production in the breast. However, very little is known about the local breast tissue estrogen levels. Understanding the role of the tissue estrogens in breast carcinogenesis might open new avenues in breast cancer prevention. This systematic review summarizes published studies that measured local estrogen levels in the breast and offers suggestions for strategies to fill gaps in our existing scientific knowledge. PMID:21286801

  12. [Pharmacodynamics of synthetic estrogens. A review].

    Science.gov (United States)

    Sojo-Aranda, I; Cortés-Gallegos, V

    1990-10-01

    Some details about the function of natural and synthetical hormonas are reviewed, particularly estrogens as ethynyl estradiol and its 3, Methyl ether (mestranol); its peripheral concentration vs tissular hormonal contents, a relationship of biological importance as the first step in its hormonal action and the cumulative local effects that could explain some intra and extracellular phenomena.

  13. [Pharmacodynamics of synthetic estrogens. Review article].

    Science.gov (United States)

    Sojo-Aranda, I; Cortés-Gallegos, V

    1990-10-01

    Some details about the function of natural and synthetical hormonas are reviewed, particularly estrogens as ethynyl estradiol and its 3, Methyl ether (mestranol); its peripheral concentration vs tissular hormonal contents, a relationship of biological importance as the first step in its hormonal action and the cummulative local effects that could explain some intra and extracellular phenomena.

  14. Expression of Estrogen and Progesterone Receptors among ...

    African Journals Online (AJOL)

    Study design: This is a descriptive study to detect the level of Estrogen (ER) and Progesterone (PR) receptors in a sample of biopsies from Sudanese women with breast cancer presented at Khartoum teaching Hospital Material and Methods: Forty biopsies from breast cancer patients were examined with immunostaining

  15. Urinary estrogen metabolites and breast cancer

    DEFF Research Database (Denmark)

    Dallal, Cher M; Stone, Roslyn A; Cauley, Jane A

    2013-01-01

    Background: Circulating estrogens are associated with increased breast cancer risk, yet the role of estrogen metabolites in breast carcinogenesis remains unclear. This combined analysis of 5 published studies evaluates urinary 2-hydroxyestrone (2-OHE1), 16a-hydroxyestrone (16a-OHE1......), and their ratio (2:16a-OHE1) in relation to breast cancer risk. ¿Methods: Primary data on 726 premenopausal women (183 invasive breast cancer cases and 543 controls) and 1,108 postmenopausal women (385 invasive breast cancer cases and 723 controls) were analyzed. Urinary estrogen metabolites were measured using...... premenopausal 2:16a-OHE1 was suggestive of reduced breast cancer risk overall (study-adjusted ORIIIvsI=0.80; 95% CI: 0.49-1.32) and for estrogen receptor negative (ER-) subtype (ORIIIvsI=0.33; 95% CI: 0.13-0.84). Among postmenopausal women, 2:16a-OHE1 was unrelated to breast cancer risk (study-adjusted ORIIIvs...

  16. Xeno-estrogenic compounds in precipitation

    NARCIS (Netherlands)

    Peters, R.J.B.; Beeltje, H.; Delft, R.J. van

    2008-01-01

    The exposure to some chemicals can lead to hormone disrupting effects. Presently, much attention is focused on so-called xeno-estrogens, synthetic compounds that interact with hormone receptors causing a number of reactions that eventually lead to effects related to reproduction and development. The

  17. Targeted estrogen delivery reverses the metabolic syndrome

    NARCIS (Netherlands)

    Finan, Brian; Yang, Bin; Ottaway, Nickki; Stemmer, Kerstin; Müller, Timo D.; Yi, Chun-Xia; Habegger, Kirk; Schriever, Sonja C.; García-Cáceres, Cristina; Kabra, Dhiraj G.; Hembree, Jazzminn; Holland, Jenna; Raver, Christine; Seeley, Randy J.; Hans, Wolfgang; Irmler, Martin; Beckers, Johannes; de Angelis, Martin Hrabě; Tiano, Joseph P.; Mauvais-Jarvis, Franck; Perez-Tilve, Diego; Pfluger, Paul; Zhang, Lianshan; Gelfanov, Vasily; DiMarchi, Richard D.; Tschöp, Matthias H.

    2012-01-01

    We report the development of a new combinatorial approach that allows for peptide-mediated selective tissue targeting of nuclear hormone pharmacology while eliminating adverse effects in other tissues. Specifically, we report the development of a glucagon-like peptide-1 (GLP-1)-estrogen conjugate

  18. Estrogen Levels in the three Trimesters

    African Journals Online (AJOL)

    estrogen levels in first, second and third trimesters of pregnant albino rats. MATERIALS AND METHODS. TEST SUBJECTS. 20 female albino rats and 6 male albino rats, with initial weight of 165-180g were purchase from the animal house of Department of Animal and. Environmental Biology , University of Benin,. Benin city ...

  19. Effect of low dose exposure to the herbicide atrazine and its metabolite on cytochrome P450 aromatase and steroidogenic factor-1 mRNA levels in the brain of premetamorphic bullfrog tadpoles (Rana catesbeiana).

    Science.gov (United States)

    Gunderson, Mark P; Veldhoen, Nik; Skirrow, Rachel C; Macnab, Magnus K; Ding, Wei; van Aggelen, Graham; Helbing, Caren C

    2011-03-01

    The transcriptional regulator steroidogenic factor 1 (SF-1) and the enzyme cytochrome P450 aromatase (CYP19) play a central role in modulation of a broad range of tissue-specific developmental processes associated with hormone homeostasis that includes differentiation of the central nervous system. SF-1 and CYP19 expression may be targeted by a variety of endocrine disruptive agents prevalent within the environment. In the present study, we cloned and characterized partial sequences for bullfrog (Rana catesbeiana) SF-1 and CYP19 and examined the effects of a 48h exposure to 1 and 100μg/l of the herbicide atrazine (ATZ) and its major metabolite desethylatrazine (DEA), as well as 5ng/l of the estrogenic chemical, 17α-ethynylestradiol (EE(2)), and 673ng/l of the thyroid hormone, 3,5,3'-triiodothyronine (T(3)), on SF-1 and CYP19 mRNA abundance in the brains of premetamorphic bullfrog tadpoles. Quantitative RT-PCR analysis showed an increase in CYP19 mRNA following a 48h exposure to EE(2) but not T(3) while no significant changes in SF-1 transcript levels occurred. We observed a strong positive correlation between CYP19 and SF-1 transcript abundance in the ATZ-exposed animals which was not evident with DEA- or hormone-exposed tadpoles. Our results are intriguing in light of reported behavioral changes in ATZ-exposed frogs and suggest that further research is warranted to examine the relationship and role of CYP19 and SF-1 in amphibian brain development. Copyright © 2011 Elsevier B.V. All rights reserved.

  20. Ultra-low-dose estriol and Lactobacillus acidophilus vaginal tablets (Gynoflor(®)) for vaginal atrophy in postmenopausal breast cancer patients on aromatase inhibitors: pharmacokinetic, safety, and efficacy phase I clinical study.

    Science.gov (United States)

    Donders, Gilbert; Neven, Patrick; Moegele, Maximilian; Lintermans, Anneleen; Bellen, Gert; Prasauskas, Valdas; Grob, Philipp; Ortmann, Olaf; Buchholz, Stefan

    2014-06-01

    Phase I pharmacokinetic (PK) study assessed circulating estrogens in breast cancer (BC) patients on a non-steroidal aromatase inhibitor (NSAI) with vaginal atrophy using vaginal ultra-low-dose 0.03 mg estriol (E3) and Lactobacillus combination vaginal tablets (Gynoflor(®)). 16 women on NSAI with severe vaginal atrophy applied a daily vaginal tablet of Gynoflor(®) for 28 days followed by a maintenance therapy of 3 tablets weekly for 8 weeks. Primary outcomes were serum concentrations and PK of E3, estradiol (E2), and estrone (E1) using highly sensitive gas chromatography-mass spectrometry. Secondary outcomes were clinical measures for efficacy and side effects; microscopic changes in vaginal epithelium and microflora; and changes in serum FSH, LH, and sex hormone-binding globulin. Compared with baseline, serum E1 and E2 did not increase in any of the women at any time following vaginal application. Serum E3 transiently increased after the first application in 15 of 16 women, with a maximum of 168 pg/ml 2-3 h post-insertion. After 4 weeks, serum E3 was slightly increased in 8 women with a maximum of 44 pg/ml. The vaginal atrophy resolved or improved in all women. The product was well tolerated, and discontinuation of therapy was not observed. The low-dose 0.03 mg E3 and Lactobacillus acidophilus vaginal tablets application in postmenopausal BC patients during AI treatment suffering from vaginal atrophy lead to small and transient increases in serum E3, but not E1 or E2, and therefore can be considered as safe and efficacious for treatment of atrophic vaginitis in BC patients taking NSAIs.

  1. The expression of estrogen receptors and the effects of estrogen on human periodontal ligament cells.

    Science.gov (United States)

    Cao, M; Shu, L; Li, J; Su, J; Zhang, W; Wang, Q; Guo, T; Ding, Y

    2007-06-01

    Osteoporotic women exhibit high frequency of alveolar bone loss and low bone density. Estrogen deficiency, which is vital in the pathogenesis of postmenopausal osteoporosis, has received increasing attention in the studies related to the periodontal diseases. Similar to most hormones, estrogen exerts its influence by binding to specific receptors, estrogen receptor (ER)-alpha and -beta. The periodontal ligament cells (PDLcs) are very important in maintaining the integrity of the periodontal tissue, which is the connective tissue located between the alveolar bone and the root surface of tooth. In this study, we evaluated the effects of estrogen deficiency on the alveolar bone in ovariectomized rats by histometric measurement of attachment level in vivo. Using the reverse transcriptase polymerase chain reaction (RT-PCR) and Western-blot procedure, we also detected mRNA and protein products of ERs and investigated the effects of estrogen on bone-forming capability by monitoring alkaline phosphatase (ALP) activity and osteocalcin production in cultured human PDLcs. Our results demonstrated that both ER-alpha and -beta were expressed in PDLcs. Moreover, when exposed to 17-beta estradiol, PDLcs exhibited positive modulation on ALP activity and osteocalcin production. The study suggests that estrogen and ERs may play an important role in periodontal diseases. (c) 2007 Prous Science. All rights reserved.

  2. Perfluorinated chemicals: Differential toxicity, inhibition of aromatase activity and alteration of cellular lipids in human placental cells

    Energy Technology Data Exchange (ETDEWEB)

    Gorrochategui, Eva; Pérez-Albaladejo, Elisabet [Department of Environmental Chemistry, IDAEA–CSIC, 08034 Barcelona, Catalonia (Spain); Casas, Josefina [Department of Biomedicinal Chemistry, IQAC–CSIC, 08034 Barcelona, Catalonia (Spain); Lacorte, Sílvia, E-mail: slbqam@cid.csic.es [Department of Environmental Chemistry, IDAEA–CSIC, 08034 Barcelona, Catalonia (Spain); Porte, Cinta, E-mail: cinta.porte@cid.csic.es [Department of Environmental Chemistry, IDAEA–CSIC, 08034 Barcelona, Catalonia (Spain)

    2014-06-01

    The cytotoxicity of eight perfluorinated chemicals (PFCs), namely, perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorododecanoic acid (PFDoA), perfluorobutanesulfonate (PFBS), perfluorohexanesulfonate (PFHxS) and perfluorooctanesulfonate (PFOS) was assessed in the human placental choriocarcinoma cell line JEG-3. Only the long chain PFCs – PFOS, PFDoA, PFNA, PFOA – showed significant cytotoxicity in JEG-3 cells with EC50 values in the range of 107 to 647 μM. The observed cytotoxicity was to some extent related to a higher uptake of the longer chain PFCs by cells (PFDoA > PFOS ≫ PFNA > PFOA > PFHxA). Moreover, this work evidences a high potential of PFOS, PFOA and PFBS to act as aromatase inhibitors in placental cells with IC50s in the range of 57–80 μM, the inhibitory effect of PFBS being particularly important despite the rather low uptake of the compound by cells. Finally, exposure of JEG-3 cells to a mixture of the eight PFCs (0.6 μM each) led to a relative increase (up to 3.4-fold) of several lipid classes, including phosphatidylcholines (PCs), plasmalogen PC and lyso plasmalogen PC, which suggests an interference of PFCs with membrane lipids. Overall, this work highlights the ability of the PFC mixture to alter cellular lipid pattern at concentrations well below those that generate toxicity, and the potential of the short chain PFBS, often considered a safe substitute of PFOS, to significantly inhibit aromatase activity in placental cells. - Highlights: • Eight perfluorinated chemicals of different chain lengths have been selected. • Long chain ones – PFOS, PFDoA, PFNA, PFOA – were cytotoxic in placenta cells. • The uptake of long chain perfluorinated chemicals by cells was comparatively higher. • PFOS, PFOA and the short chain PFBS significantly inhibited aromatase activity. • A mixture of perfluorinated chemicals significantly altered placenta cell

  3. Perfluorinated chemicals: Differential toxicity, inhibition of aromatase activity and alteration of cellular lipids in human placental cells

    International Nuclear Information System (INIS)

    Gorrochategui, Eva; Pérez-Albaladejo, Elisabet; Casas, Josefina; Lacorte, Sílvia; Porte, Cinta

    2014-01-01

    The cytotoxicity of eight perfluorinated chemicals (PFCs), namely, perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorododecanoic acid (PFDoA), perfluorobutanesulfonate (PFBS), perfluorohexanesulfonate (PFHxS) and perfluorooctanesulfonate (PFOS) was assessed in the human placental choriocarcinoma cell line JEG-3. Only the long chain PFCs – PFOS, PFDoA, PFNA, PFOA – showed significant cytotoxicity in JEG-3 cells with EC50 values in the range of 107 to 647 μM. The observed cytotoxicity was to some extent related to a higher uptake of the longer chain PFCs by cells (PFDoA > PFOS ≫ PFNA > PFOA > PFHxA). Moreover, this work evidences a high potential of PFOS, PFOA and PFBS to act as aromatase inhibitors in placental cells with IC50s in the range of 57–80 μM, the inhibitory effect of PFBS being particularly important despite the rather low uptake of the compound by cells. Finally, exposure of JEG-3 cells to a mixture of the eight PFCs (0.6 μM each) led to a relative increase (up to 3.4-fold) of several lipid classes, including phosphatidylcholines (PCs), plasmalogen PC and lyso plasmalogen PC, which suggests an interference of PFCs with membrane lipids. Overall, this work highlights the ability of the PFC mixture to alter cellular lipid pattern at concentrations well below those that generate toxicity, and the potential of the short chain PFBS, often considered a safe substitute of PFOS, to significantly inhibit aromatase activity in placental cells. - Highlights: • Eight perfluorinated chemicals of different chain lengths have been selected. • Long chain ones – PFOS, PFDoA, PFNA, PFOA – were cytotoxic in placenta cells. • The uptake of long chain perfluorinated chemicals by cells was comparatively higher. • PFOS, PFOA and the short chain PFBS significantly inhibited aromatase activity. • A mixture of perfluorinated chemicals significantly altered placenta cell

  4. Estrogen and its role in gastrointestinal health and disease.

    LENUS (Irish Health Repository)

    Hogan, Aisling M

    2012-02-01

    INTRODUCTION: While the concept of a role of estrogen in gastrointestinal (in particular, colonic) malignancy has generated excitement in recent years, no review has examined the role of this potent and omnipresent steroid hormone in physiological states or its contribution to the development of benign pathological processes. Understanding these effects (and mechanisms therein) may provide a platform for a deeper understanding of more complex disease processes. METHODS: A literature search was conducted using the PubMed database and the search terms were "estrogen," "estrogen AND gastrointestinal tract," "estrogen AND colon," "estrogen AND esophagus," "estrogen AND small intestine," "estrogen AND stomach," "estrogen AND gallbladder," and "estrogen AND motility." Bibliographies of extracted studies were further cross-referenced. In all, 136 full-text articles were selected for review. A logical organ-based approach was taken to enable extraction of data of clinical relevance and meaningful interpretation thereof. Insight is provided into the hypotheses, theories, controversies, and contradictions generated over the last five decades by extensive investigation of estrogen in human, animal, and cell models using techniques as diverse as autoradiographic studies of baboons to human population analysis. CONCLUSIONS: Effects from esophagus through to the colon and rectum are summarized in this first concise collection of data pertaining to estrogenic actions in gastrointestinal health and disease. Mechanisms of these actions are discussed where possible. Undoubtedly, this hormone exerts many actions yet to be elucidated, and its potential therapeutic applications remain, as yet, largely unexplored.

  5. Identification of an estrogenic hormone receptor in Caenorhabditis elegans

    International Nuclear Information System (INIS)

    Mimoto, Ai; Fujii, Madoka; Usami, Makoto; Shimamura, Maki; Hirabayashi, Naoko; Kaneko, Takako; Sasagawa, Noboru; Ishiura, Shoichi

    2007-01-01

    Changes in both behavior and gene expression occur in Caenorhabditis elegans following exposure to sex hormones such as estrogen and progesterone, and to bisphenol A (BPA), an estrogenic endocrine-disrupting compound. However, only one steroid hormone receptor has been identified. Of the 284 known nuclear hormone receptors (NHRs) in C. elegans, we selected nhr-14, nhr-69, and nhr-121 for analysis as potential estrogenic hormone receptors, because they share sequence similarity with the human estrogen receptor. First, the genes were cloned and expressed in Escherichia coli, and then the affinity of each protein for estrogen was determined using a surface plasmon resonance (SPR) biosensor. All three NHRs bound estrogen in a dose-dependent fashion. To evaluate the specificity of the binding, we performed a solution competition assay using an SPR biosensor. According to our results, only NHR-14 was able to interact with estrogen. Therefore, we next examined whether nhr-14 regulates estrogen signaling in vivo. To investigate whether these interactions actually control the response of C. elegans to hormones, we investigated the expression of vitellogenin, an estrogen responsive gene, in an nhr-14 mutant. Semi-quantitative RT-PCR showed that vitellogenin expression was significantly reduced in the mutant. This suggests that NHR-14 is a C. elegans estrogenic hormone receptor and that it controls gene expression in response to estrogen

  6. Estrogen-gut microbiome axis: Physiological and clinical implications.

    Science.gov (United States)

    Baker, James M; Al-Nakkash, Layla; Herbst-Kralovetz, Melissa M

    2017-09-01

    Low levels of gonadal circulating estrogen observed in post-menopausal women can adversely impact a diverse range of physiological factors, with clinical implications for brain cognition, gut health, the female reproductive tract and other aspects of women's health. One of the principal regulators of circulating estrogens is the gut microbiome. This review aims to shed light on the role of the gut microbiota in estrogen-modulated disease. The gut microbiota regulates estrogens through secretion of β-glucuronidase, an enzyme that deconjugates estrogens into their active forms. When this process is impaired through dysbiosis of gut microbiota, characterized by lower microbial diversity, the decrease in deconjugation results in a reduction of circulating estrogens. The alteration in circulating estrogens may contribute to the development of conditions discussed herein: obesity, metabolic syndrome, cancer, endometrial hyperplasia, endometriosis, polycystic ovary syndrome, fertility, cardiovascular disease (CVD) and cognitive function. The bi-directional relationship between the metabolic profile (including estrogen levels) and gut microbiota in estrogen-driven disease will also be discussed. Promising therapeutic interventions manipulating the gut microbiome and the metabolic profile of estrogen-driven disease, such as bariatric surgery and metformin, will be detailed. Modulation of the microbiome composition subsequently impacts the metabolic profile, and vice versa, and has been shown to alleviate many of the estrogen-modulated disease states. Last, we highlight promising research interventions in the field, such as dietary therapeutics, and discuss areas that provide exciting unexplored topics of study. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. The effects of chronic testosterone administration on body weight, food intake, and adipose tissue are changed by estrogen treatment in female rats.

    Science.gov (United States)

    Iwasa, Takeshi; Matsuzaki, Toshiya; Yano, Kiyohito; Yanagihara, Rie; Tungalagsuvd, Altankhuu; Munkhzaya, Munkhsaikhan; Mayila, Yiliyasi; Kuwahara, Akira; Irahara, Minoru

    2017-07-01

    In females, estrogens play pivotal roles in preventing excess body weight (BW) gain. On the other hand, the roles of androgens in female BW, appetite, and energy metabolism have not been fully examined. We hypothesized that androgens' effects on food intake (FI) and BW regulation change according to the estrogens' levels. To evaluate this hypothesis, the effects of chronic testosterone administration in ovariectomized (OVX) female rats with or without estradiol supplementation were examined in this study. Chronic testosterone administration decreased BW, FI, white adipose tissue (WAT) weight, and adipocyte size in OVX rats, whereas it increased BW, WAT weight, and adipocyte size in OVX with estradiol-administered rats. In addition, chronic testosterone administration increased hypothalamic CYP19a1 mRNA levels in OVX rats, whereas it did not alter CYP19a1 mRNA levels in OVX with estradiol-administered rats, indicating that conversion of testosterone to estrogens in the hypothalamus may be activated in testosterone-administered OVX rats. Furthermore, chronic testosterone administration decreased hypothalamic TNF-α mRNA levels in OVX rats, whereas it increased hypothalamic IL-1β mRNA levels in OVX with estradiol-administered rats. On the other hand, IL-1β and TNF-α mRNA levels in visceral and subcutaneous WAT and liver were not changed by chronic testosterone administration in both groups. These data indicate that the effects of chronic testosterone administration on BW, FI, WAT weight, and adipocyte size were changed by estradiol treatment in female rats. Testosterone has facilitative effects on BW gain, FI, and adiposity under the estradiol-supplemented condition, whereas it has inhibitory effects in the non-supplemented condition. Differences in the responses of hypothalamic factors, such as aromatase and inflammatory cytokines, to testosterone might underlie these opposite effects. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Dopaminergic regulation of mate competition aggression and aromatase-Fos colocalization in vasotocin neurons.

    Science.gov (United States)

    Kabelik, David; Kelly, Aubrey M; Goodson, James L

    2010-01-01

    Recent experiments demonstrate that aggressive competition for potential mates involves different neural mechanisms than does territorial, resident-intruder aggression. However, despite the obvious importance of mate competition aggression, we know little about its regulation. Immediate early gene experiments show that in contrast to territorial aggression, mate competition in finches is accompanied by the activation of neural populations associated with affiliation and motivation, including vasotocin (VT) neurons in the medial bed nucleus of the stria terminalis (BSTm) and midbrain dopamine (DA) neurons that project to the BSTm. Although VT is known to facilitate mate competition aggression, the role of DA has not previously been examined. We now show that in male zebra finches (Taeniopygia guttata), mate competition aggression is inhibited by the D(2) agonist quinpirole, though not the D(1) agonist SKF-38393 or the D(4) agonist PD168077. The D(3) agonist 7-OH-DPAT also inhibited aggression, but only following high dose treatment that may affect aggression via nonspecific binding to D(2) receptors. Central VT infusion failed to restore D(2) agonist-inhibited aggression in a subsequent experiment, demonstrating that D(2) does not suppress aggression by inhibiting VT release from BSTm neurons. In a final experiment, we detected D(2) agonist-induced increases in immunofluorescent colocalization of the product of the immediate early gene c-fos and the steroid-converting enzyme aromatase (ARO) within VT neurons of the BSTm. Thus, although VT and DA appear to influence mate competition aggression independently, BSTm VT neurons are clearly influenced by the activation of D(2) receptors, which may modify future behaviors.

  9. Patterns of bone density evaluation in a community population treated with aromatase inhibitors.

    Science.gov (United States)

    Ligibel, Jennifer A; O'Malley, A James; Fisher, Maxine; Daniel, Gregory W; Winer, Eric P; Keating, Nancy L

    2012-08-01

    Aromatase inhibitors (AIs) increase the risk of bone loss and fracture. Guidelines recommend routine bone density screening for women on AIs, but there are few data regarding the incorporation of these guidelines into clinical practice. We assessed bone density testing in a community-based cohort of breast cancer patients treated with AIs. By means of encounter and pharmacy data from WellPoint plans in the HealthCore Integrated Research Database, we assessed bone density testing among 9,138 women aged ≥50 years with breast cancer who were treated with AIs between 2002 and 2008. We used multivariable logistic regression to identify factors associated with baseline bone density testing in women initiating an AI, and among a subset of 2,086 women treated with AIs for at least 2 years, with testing during the first 2 years of therapy. Only 41.6 % of women underwent bone density testing when initiating AI therapy. Rates of bone density testing increased over time, but were lower for women who were older, lived in the Northeast (vs. other regions), had been treated with prior proton pump inhibitor or tamoxifen therapy, lived in areas with lower educational attainment, or were enrolled in a health maintenance organization (vs. other insurance types) (all P < 0.05). Among women treated with AIs for at least 2 years, 59.9 % of women underwent bone density testing during the first 2 years of AI therapy. Rates of testing were lower for women living in the Midwest or West (vs. Northeast), living in areas with lower education levels, enrolled in health maintenance organizations (vs. other insurance types), and with prior tamoxifen use. In conclusion, most women initiating AI therapy, and 40 % of those on long-term therapy, did not undergo recommended bone density evaluation in this community-based population. Attention is needed to insure that unnecessary fractures are avoided in breast cancer patients taking AIs.

  10. New selective estrogen and androgen receptor modulators.

    Science.gov (United States)

    Clarke, Bart L; Khosla, Sundeep

    2009-07-01

    The present review focuses on the most significant recent findings regarding selective estrogen receptor modulators (SERMs) and selective androgen receptor modulators (SARMs). SERMs, which interact with estrogen receptor-alpha and estrogen receptor-beta in multiple tissues, continue to generate clinical interest in potential applications in as many disorders as the tissues in which the two known receptors are found. SARMs have been demonstrated to have fewer clinical applications to date, but continue to be investigated for use in multiple disorders in which androgen receptor modulation is likely to be important. Both types of compounds hold great promise for therapeutic use in multiple hormonal disorders involving tissue-specific effects mediated by estrogen or androgen receptors. Although SERMs have been available for clinical use for 50 years, recent investigation has focused on large randomized clinical trials for newer indications of older agents or smaller clinical trials of newer agents with improved clinical activity and reduced side effects in specific tissues. In particular, the large, prospective, randomized, controlled, multiyear Study of Tamoxifen and Raloxifene and Raloxifene Use in the Heart clinical trials have recently shown interesting similarities and differences between tamoxifen and raloxifene in estrogen-responsive tissues. Lasofoxifene and arzoxifene are two newer SERMs that have recently been demonstrated to improve bone mineral density and lower serum cholesterol values compared with older SERMs in smaller clinical trials. SARMs are a newer category of drug still being investigated mostly at the basic and preclinical level, with fewer clinical trials available for review. SARMs are currently being investigated mostly for use in prostate cancer at different stages but hold promise for multiple other applications. Recent clinical trials indicate that SERMs are useful in treatment of disorders of bone and mineral metabolism and breast cancer

  11. Androgen priming using aromatase inhibitor and hCG during early-follicular-phase GnRH antagonist down-regulation in modified antagonist protocols

    DEFF Research Database (Denmark)

    Løssl, Kristine; Andersen, A N; Loft, A

    2006-01-01

    Temporary exposure of follicles to increased levels of androgens may enhance their sensitivity to FSH. The aim of this study was to increase the intraovarian androgen level using aromatase inhibitors and hCG before controlled ovarian stimulation (COH) and to test this concept clinically.......Temporary exposure of follicles to increased levels of androgens may enhance their sensitivity to FSH. The aim of this study was to increase the intraovarian androgen level using aromatase inhibitors and hCG before controlled ovarian stimulation (COH) and to test this concept clinically....

  12. Ki67 Proliferation Index as a Tool for Chemotherapy Decisions During and After Neoadjuvant Aromatase Inhibitor Treatment of Breast Cancer: Results From the American College of Surgeons Oncology Group Z1031 Trial (Alliance).

    Science.gov (United States)

    Ellis, Matthew J; Suman, Vera J; Hoog, Jeremy; Goncalves, Rodrigo; Sanati, Souzan; Creighton, Chad J; DeSchryver, Katherine; Crouch, Erika; Brink, Amy; Watson, Mark; Luo, Jingqin; Tao, Yu; Barnes, Michael; Dowsett, Mitchell; Budd, G Thomas; Winer, Eric; Silverman, Paula; Esserman, Laura; Carey, Lisa; Ma, Cynthia X; Unzeitig, Gary; Pluard, Timothy; Whitworth, Pat; Babiera, Gildy; Guenther, J Michael; Dayao, Zoneddy; Ota, David; Leitch, Marilyn; Olson, John A; Allred, D Craig; Hunt, Kelly

    2017-04-01

    Purpose To determine the pathologic complete response (pCR) rate in estrogen receptor (ER) -positive primary breast cancer triaged to chemotherapy when the protein encoded by the MKI67 gene (Ki67) level was > 10% after 2 to 4 weeks of neoadjuvant aromatase inhibitor (AI) therapy. A second objective was to examine risk of relapse using the Ki67-based Preoperative Endocrine Prognostic Index (PEPI). Methods The American College of Surgeons Oncology Group (ACOSOG) Z1031A trial enrolled postmenopausal women with stage II or III ER-positive (Allred score, 6 to 8) breast cancer whose treatment was randomly assigned to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For the trial ACOSOG Z1031B, the protocol was amended to include a tumor Ki67 determination after 2 to 4 weeks of AI. If the Ki67 was > 10%, patients were switched to neoadjuvant chemotherapy. A pCR rate of > 20% was the predefined efficacy threshold. In patients who completed neoadjuvant AI, stratified Cox modeling was used to assess whether time to recurrence differed by PEPI = 0 score (T1 or T2, N0, Ki67 2) versus PEPI > 0 disease. Results Only two of the 35 patients in ACOSOG Z1031B who were switched to neoadjuvant chemotherapy experienced a pCR (5.7%; 95% CI, 0.7% to 19.1%). After 5.5 years of median follow-up, four (3.7%) of the 109 patients with a PEPI = 0 score relapsed versus 49 (14.4%) of 341 of patients with PEPI > 0 (recurrence hazard ratio [PEPI = 0 v PEPI > 0], 0.27; P = .014; 95% CI, 0.092 to 0.764). Conclusion Chemotherapy efficacy was lower than expected in ER-positive tumors exhibiting AI-resistant proliferation. The optimal therapy for these patients should be further investigated. For patients with PEPI = 0 disease, the relapse risk over 5 years was only 3.6% without chemotherapy, supporting the study of adjuvant endocrine monotherapy in this group. These Ki67 and PEPI triage approaches are being definitively studied in the ALTERNATE trial (Alternate Approaches for

  13. Class II recombinant phosphoribosyl diphosphate synthase from spinach

    DEFF Research Database (Denmark)

    Krath, B N; Hove-Jensen, B

    2001-01-01

    to other PRPP synthases the activity of spinach PRPP synthase isozyme 3 is independent of P(i), and the enzyme is inhibited by ribonucleoside diphosphates in a purely competitive manner, which indicates a lack of allosteric inhibition by these compounds. In addition spinach PRPP synthase isozyme 3 shows...

  14. Evolutionary and mechanistic insights from the reconstruction of (+)-humulene synthases from a modern (+)-Germacrene A Synthase

    OpenAIRE

    Gonzalez Gonzalez, Veronica; Touchet, Sabrina; Grundy, Daniel J.; Faraldos, Juan A.; Allemann, Rudolf Konrad

    2014-01-01

    Germacrene A synthase (GAS) from Solidago canadensis catalyzes the conversion of farnesyl diphosphate (FDP) to the plant sesquiterpene (+)-germacrene A. After diphosphate expulsion, farnesyl cation reacts with the distal 10,11-double bond to afford germacrene A (>96%) and

  15. Endothelial nitric oxide synthase gene polymorphisms associated ...

    African Journals Online (AJOL)

    Endothelial nitric oxide synthase (NOS3) is involved in key steps of immune response. Genetic factors predispose individuals to periodontal disease. This study's aim was to explore the association between NOS3 gene polymorphisms and clinical parameters in patients with periodontal disease. Genomic DNA was obtained ...

  16. Glutamate synthase: An archaeal horizontal gene transfer?

    Indian Academy of Sciences (India)

    (GOGAT) which is a key enzyme in ammonia assimilation in bacteria, algae and plants. It catalyzes the reductive transamidation of amido nitrogen from glutamine to 2-oxoglutarate to form two molecules of glutamate (Temple et al 1998). Glutamate synthases differ according to their molecular weights, subunit compositions, ...

  17. Relationship between endothelial nitric oxide synthase gene ...

    African Journals Online (AJOL)

    Introduction: Endothelial nitric oxide synthase (eNOS), the enzyme in charge of nitric oxide production, plays a crucial role in vascular biology. However, the impact of single nucleotide polymorphisms (SNPs) affecting the gene encoding for eNOS (eNOS) on coronary artery diseases remains under debate and no data were ...

  18. Producing alpha-olefins using polyketide synthases

    Energy Technology Data Exchange (ETDEWEB)

    Fortman, Jeffrey L.; Katz, Leonard; Steen, Eric J.; Keasling, Jay D.

    2018-01-02

    The present invention provides for a polyketide synthase (PKS) capable of synthesizing an .alpha.-olefin, such as 1-hexene or butadiene. The present invention also provides for a host cell comprising the PKS and when cultured produces the .alpha.-olefin.

  19. Expression of Deinococcus geothermalis trehalose synthase gene ...

    African Journals Online (AJOL)

    A novel trehalose synthase gene from Deinococcus geothermalis (DSMZ 11300) containing 1692 bp reading-frame encoding 564 amino acids was amplified using polymerase chain reaction (PCR). The gene was ligated into pET30Ek/LIC vector and expressed after isopropyl β-D-thiogalactopyranoside induction in ...

  20. Cloning and expression of pineapple sucrosephosphate synthase ...

    African Journals Online (AJOL)

    A 1132-base pairs (bp) polymerase-chain-reaction product of sucrose-phosphate synthase (SPS) (EC 2.3.1.14) from pineapple (Ananas comosus cv. Comte de paris) fruit was cloned and nominated as Ac- SPS1. The sequence encodes a putative 377 amino acids protein containing two serine conserved features that had ...

  1. Activation of estrogen response elements is mediated both via estrogen and muscle contractions in rat skeletal muscle myotubes

    DEFF Research Database (Denmark)

    Wiik, A.; Hellsten, Ylva; Berthelson, P.

    2009-01-01

    then differentiated into myotubes and subjected to either estrogen or electrical stimulation. Activation of the ERE sequence was determined by measurement of luciferase activity. The results show that both ERalpha and ERbeta are expressed in myotubes from rats. Both estrogen stimulation and muscle contraction......The aim of the present study was to investigate the activation of estrogen response elements (EREs) by estrogen and muscle contractions in rat myotubes in culture and to assess whether the activation is dependent on the estrogen receptors (ERs). In addition, the effect of estrogen and contraction...... increased (P muscle contraction. Use of ER antagonists showed that, whereas the estrogen-induced transactivation is mediated via ERs, the effect of muscle contraction...

  2. Estradiol prodrugs (EP) for efficient oral estrogen treatment and abolished effects on estrogen modulated liver functions.

    Science.gov (United States)

    Elger, W; Wyrwa, R; Ahmed, G; Meece, F; Nair, H B; Santhamma, B; Killeen, Z; Schneider, B; Meister, R; Schubert, H; Nickisch, K

    2017-01-01

    Oral compared to parenteral estrogen administration is characterized by reduced systemic but prominent hepatic estrogenic effects on lipids, hemostatic factors, GH-/IGF I axis, angiotensinogen. In order to avoid such adverse metabolic effects of oral treatment, estradiol (E2) prodrugs (EP) were designed which bypass the liver tissue as inactive molecules. Carbone17-OH sulfonamide [-O 2 -NH 2 ] substituted esters of E2 (EC508, others) were synthesized and tested for carbonic anhydrase II (CA-II) binding. CA II in erythrocytes is thought to oppose extraction of EP from portal vein blood during liver passage. Ovariectomized (OVX, day minus 14) rats were orally treated once daily from day 1-3. Sacrifice day 4. Uteri were dissected and weighed. Cholesterol fractions and angiotensinogen were determined in plasma. Oral E2 and ethinyl estradiol (EE) generated dose related uterine growth and important hepatic estrogenic effects. EP induced uterine growth at about hundred-fold lower doses. This was possible with almost absent effects on plasma cholesterol or angiotensinogen. Preliminary pharmacokinetic studies with EC508 used intravenous and oral administration in male rats. Resulting blood levels revealed complete oral bioavailability. Further high blood- but low plasma concentrations indicated erythrocyte binding of EC508 in vivo as potential mechanism of low extraction at liver passage. Very high systemic estrogenicity combined with markedly lower or absent adverse hepatic estrogenic effects is evidence for a systemic release of E2 from sulfonamide EP. In conclusion, tested oral EP bypass the liver in erythrocytes furnishing systemic estradiol at hydrolysis. This mechanism avoids the hepatic estrogenic impact of conventional oral estrogen therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Yeast Estrogen Screen Assay as a Tool for Detecting Estrogenic Activity in Water Bodies

    Directory of Open Access Journals (Sweden)

    Mirjana Bistan

    2012-01-01

    Full Text Available The presence of endocrine-disrupting compounds in wastewater, surface water, groundwater and even drinking water has become a major concern worldwide, since they negatively affect wildlife and humans. Therefore, these substances should be effectively removed from effluents before they are discharged into surface water to prevent pollution of groundwater, which can be a source of drinking water. Furthermore, an efficient control of endocrine-disrupting compounds in wastewater based on biological and analytical techniques is required. In this study, a yeast estrogen screen (YES bioassay has been introduced and optimized with the aim to assess potential estrogenic activity of waters. First, assay duration, concentration of added substrate to the assay medium and wavelength used to measure the absorbance of the substrate were estimated. Several compounds, such as 17-β-estradiol, 17-α-ethinylestradiol, bisphenol A, nonylphenol, genisteine, hydrocortisone, dieldrin, atrazine, methoxychlor, testosterone and progesterone were used to verify its specificity and sensitivity. The optimized YES assay was sensitive and responded specifically to the selected estrogenic and nonestrogenic compounds in aqueous samples. Potential estrogenicity of influent and effluent samples of two wastewater treatment plants was assessed after the samples had been concentrated by solid-phase extraction (SPE procedure using Oasis® HLB cartridges and methanol as eluting solvent. Up to 90 % of relative estrogenic activity was detected in concentrated samples of influents to wastewater treatment plants and estrogenic activity was still present in the concentrated effluent samples. We found that the introduced YES assay is a suitable screening tool for monitoring the potential estrogenicity of effluents that are discharged into surface water.

  4. Estrogen Deficiency and the Origin of Obesity during Menopause

    Directory of Open Access Journals (Sweden)

    Fernando Lizcano

    2014-01-01

    Full Text Available Sex hormones strongly influence body fat distribution and adipocyte differentiation. Estrogens and testosterone differentially affect adipocyte physiology, but the importance of estrogens in the development of metabolic diseases during menopause is disputed. Estrogens and estrogen receptors regulate various aspects of glucose and lipid metabolism. Disturbances of this metabolic signal lead to the development of metabolic syndrome and a higher cardiovascular risk in women. The absence of estrogens is a clue factor in the onset of cardiovascular disease during the menopausal period, which is characterized by lipid profile variations and predominant abdominal fat accumulation. However, influence of the absence of these hormones and its relationship to higher obesity in women during menopause are not clear. This systematic review discusses of the role of estrogens and estrogen receptors in adipocyte differentiation, and its control by the central nervous systemn and the possible role of estrogen-like compounds and endocrine disruptors chemicals are discussed. Finally, the interaction between the decrease in estrogen secretion and the prevalence of obesity in menopausal women is examined. We will consider if the absence of estrogens have a significant effect of obesity in menopausal women.

  5. Estrogen replacement therapy and cardioprotection: mechanisms and controversies

    Directory of Open Access Journals (Sweden)

    M.T.R. Subbiah

    2002-03-01

    Full Text Available Epidemiological and case-controlled studies suggest that estrogen replacement therapy might be beneficial in terms of primary prevention of coronary heart disease (CHD. This beneficial effect of estrogens was initially considered to be due to the reduction of low density lipoproteins (LDL and to increases in high density lipoproteins (HDL. Recent studies have shown that estrogens protect against oxidative stress and decrease LDL oxidation. Estrogens have direct effects on the arterial tissue and modulate vascular reactivity through nitric oxide and prostaglandin synthesis. While many of the effects of estrogen on vascular tissue are believed to be mediated by estrogen receptors alpha and ß, there is evidence for `immediate non-genomic' effects. The role of HDL in interacting with 17ß-estradiol including its esterification and transfer of esterified estrogens to LDL is beginning to be elucidated. Despite the suggested positive effects of estrogens, two recent placebo-controlled clinical trials in women with CHD did not detect any beneficial effects on overall coronary events with estrogen therapy. In fact, there was an increase in CHD events in some women. Mutations in thrombogenic genes (factor V Leiden, prothrombin mutation, etc. in a subset of women may play a role in this unexpected finding. Thus, the cardioprotective effect of estrogens appears to be more complicated than originally thought and requires more research.

  6. Estrogen therapy: the dangerous road to Shangri-La.

    Science.gov (United States)

    1976-11-01

    The use of estrogens almost tripled during the 1965-75 period, with usage concentrated as a cure-all for aging, for the degenerative diseases associated with aging, and for the emotional difficulties of middle age. 3 separate studies published in the last year have shown a high level of association between estrogen use and the development of endometrial cancer. Results of these studies coupled with the significant recent increase in the incidence of cancer in women over 50 who are in the high socioeconomic groups--the groups most likely to use estrogen therapy--emphasize the association. The U.S. FDA has proposed a modification in the labeling for estrogens, and a package insert for patients which would warn of possible hazards of estrogen therapy. It is recommended that estrogen be used only for vasomotor symptoms and vaginal atrophy. The lowest possible effective dosage should be used and for the shortest possible amount of time. Earlier studies had suggested that estrogen replacement therapy might protect against breast cancer; most recent studies suggest the opposite. In addition, estrogen may trigger high blood pressure and increase some blood clotting. Women with high blood pressure or a family history of early heart attacks are contraindicated from using estrogen therapy. Even for the treatment of osteoporosis, there may be safer alternative therapies. Women are cautioned as to their own responsibilities when taking estrogens.

  7. In vivo imaging of brain aromatase in female baboons: [11C]vorozole kinetics and effect of the menstrual cycle.

    Science.gov (United States)

    Pareto, Deborah; Biegon, Anat; Alexoff, David; Carter, Pauline; Shea, Coreen; Muench, Lisa; Xu, Youwen; Fowler, Joanna S; Kim, Sunny W; Logan, Jean

    2013-01-01

    The aim of this work was to quantify the brain distribution of the enzyme aromatase in the female baboon with positron emission tomography and the tracer [11C]vorozole using three different quantification methods for estimating the total distribution volume (V(T)): a graphical method, compartment modeling, and a tissue to plasma ratio. The graphical model and the compartment modeling gave similar estimates to the data and similar values (correlation R  =  .988; p  =  .0001). [11C]Vorozole shows a rapid uptake by the brain followed by a relatively constant accumulation, suggesting the possibility of using the tissue to plasma ratio as an estimate of V(T). The highest uptake of [11C]vorozole in the baboon brain was measured in the amygdala, followed by the preoptic area and hypothalamus, basal ganglia, and cortical areas. Pretreatment studies with vorozole or letrozole showed a generalized decrease in brain accumulation and V(T). The results suggested that the physiologic changes in gonadal hormone levels accompanying the menstrual cycle had a significant effect on brain aromatase V(T).

  8. Co-Formulants in Glyphosate-Based Herbicides Disrupt Aromatase Activity in Human Cells below Toxic Levels

    Directory of Open Access Journals (Sweden)

    Nicolas Defarge

    2016-02-01

    Full Text Available Pesticide formulations contain declared active ingredients and co-formulants presented as inert and confidential compounds. We tested the endocrine disruption of co-formulants in six glyphosate-based herbicides (GBH, the most used pesticides worldwide. All co-formulants and formulations were comparably cytotoxic well below the agricultural dilution of 1% (18–2000 times for co-formulants, 8–141 times for formulations, and not the declared active ingredient glyphosate (G alone. The endocrine-disrupting effects of all these compounds were measured on aromatase activity, a key enzyme in the balance of sex hormones, below the toxicity threshold. Aromatase activity was decreased both by the co-formulants alone (polyethoxylated tallow amine—POEA and alkyl polyglucoside—APG and by the formulations, from concentrations 800 times lower than the agricultural dilutions; while G exerted an effect only at 1/3 of the agricultural dilution. It was demonstrated for the first time that endocrine disruption by GBH could not only be due to the declared active ingredient but also to co-formulants. These results could explain numerous in vivo results with GBHs not seen with G alone; moreover, they challenge the relevance of the acceptable daily intake (ADI value for GBHs exposures, currently calculated from toxicity tests of the declared active ingredient alone.

  9. Co-Formulants in Glyphosate-Based Herbicides Disrupt Aromatase Activity in Human Cells below Toxic Levels

    Science.gov (United States)

    Defarge, Nicolas; Takács, Eszter; Lozano, Verónica Laura; Mesnage, Robin; Spiroux de Vendômois, Joël; Séralini, Gilles-Eric; Székács, András

    2016-01-01

    Pesticide formulations contain declared active ingredients and co-formulants presented as inert and confidential compounds. We tested the endocrine disruption of co-formulants in six glyphosate-based herbicides (GBH), the most used pesticides worldwide. All co-formulants and formulations were comparably cytotoxic well below the agricultural dilution of 1% (18–2000 times for co-formulants, 8–141 times for formulations), and not the declared active ingredient glyphosate (G) alone. The endocrine-disrupting effects of all these compounds were measured on aromatase activity, a key enzyme in the balance of sex hormones, below the toxicity threshold. Aromatase activity was decreased both by the co-formulants alone (polyethoxylated tallow amine—POEA and alkyl polyglucoside—APG) and by the formulations, from concentrations 800 times lower than the agricultural dilutions; while G exerted an effect only at 1/3 of the agricultural dilution. It was demonstrated for the first time that endocrine disruption by GBH could not only be due to the declared active ingredient but also to co-formulants. These results could explain numerous in vivo results with GBHs not seen with G alone; moreover, they challenge the relevance of the acceptable daily intake (ADI) value for GBHs exposures, currently calculated from toxicity tests of the declared active ingredient alone. PMID:26927151

  10. Local feedback loop of ghrelin-GH in the pig ovary: action on estradiol secretion, aromatase activity and cell apoptosis.

    Science.gov (United States)

    Rak, Agnieszka; Gregoraszczuk, Ewa Łucja

    2008-06-01

    Ghrelin is recognized as an important regulator of growth hormone (GH) secretion, food intake and a factor which controls reproduction. In the present studies, the effect of GH and insulin-like growth factor (IGF-I) on ghrelin synthesis and secretion and the effects of ghrelin on GH synthesis and secretion in cultured whole porcine follicles were studied. Ghrelin and GH levels were measured in the follicular wall and in the culture medium. Moreover, the action of combined treatment with ghrelin and GH on estradiol secretion, aromatase activity and cell apoptosis were examined. We demonstrated that ghrelin increased GH secretion but not GH synthesis by ovarian follicles. GH stimulated both ghrelin synthesis and secretion in the ovarian follicles. The increase in estradiol secretion, aromatase activity and the decrease in caspase-3 activity were noted in ghrelin alone- and ghrelin in combination with GH-treated cells. In culture treated with combination of both these hormones, all investigated parameters were similar to those noted in ghrelin alone-treated cells. In conclusion, our study provides novel evidence for the gonadal feedback loop between GH and ghrelin secretion in the ovary. However, results of the presented research suggest independent action of GH and ghrelin in the ovary.

  11. Src Is a Potential Therapeutic Target in Endocrine-Resistant Breast Cancer Exhibiting Low Estrogen Receptor-Mediated Transactivation.

    Science.gov (United States)

    Guest, Stephanie K; Ribas, Ricardo; Pancholi, Sunil; Nikitorowicz-Buniak, Joanna; Simigdala, Nikiana; Dowsett, Mitch; Johnston, Stephen R; Martin, Lesley-Ann

    2016-01-01

    Despite the effectiveness of endocrine therapies in estrogen receptor positive (ER+) breast cancer, approximately 40% of patients relapse. Previously, we identified the Focal-adhesion kinase canonical pathway as a major contributor of resistance to estrogen deprivation and cellular-sarcoma kinase (c-src) as a dominant gene in this pathway. Dasatinib, a pan-src inhibitor, has recently been used in clinical trials to treat ER+ patients but has shown mixed success. In the following study, using isogenic cell line models, we provide a potential explanation for these findings and suggest a sub-group that may benefit. A panel of isogenic cell lines modelling resistance to aromatase inhibitors (LTED) and tamoxifen (TAMR) were assessed for response to dasatinib ± endocrine therapy. Dasatinib caused a dose-dependent decrease in proliferation in MCF7-TAMR cells and resensitized them to tamoxifen and fulvestrant but not in HCC1428-TAMR. In contrast, in estrogen-deprived conditions, dasatinib increased the proliferation rate of parental-MCF7 cells and had no effect on MCF7-LTED or HCC1428-LTED. Treatment with dasatinib caused a decrease in src-phosphorylation and inhibition of downstream pathways, including AKT and ERK1/2 in all cell lines tested, but only the MCF7-TAMR showed a concomitant decrease in markers of cell cycle progression. Inhibition of src also caused a significant decrease in cell migration in both MCF7-LTED and MCF7-TAMR cells. Finally, we showed that, in MCF7-TAMR cells, in contrast to tamoxifen sensitive cell lines, ER is expressed throughout the cell rather than being restricted to the nucleus and that treatment with dasatinib resulted in nuclear shuttling of ER, which was associated with an increase in ER-mediated transcription. These data suggest that src has differential effects in endocrine-resistant cell lines, particularly in tamoxifen resistant models, with low ER genomic activity, providing further evidence of the importance of patient selection

  12. Estrogen and estrogen receptor alpha promotes malignancy and osteoblastic tumorigenesis in prostate cancer.

    Science.gov (United States)

    Mishra, Sweta; Tai, Qin; Gu, Xiang; Schmitz, James; Poullard, Ashley; Fajardo, Roberto J; Mahalingam, Devalingam; Chen, Xiaodong; Zhu, Xueqiong; Sun, Lu-Zhe

    2015-12-29

    The role of estrogen signaling in regulating prostate tumorigenesis is relatively underexplored. Although, an increasing body of evidence has linked estrogen receptor beta (ERß) to prostate cancer, the function of estrogen receptor alpha (ERα) in prostate cancer is not very well studied. We have discovered a novel role of ERα in the pathogenesis of prostate tumors. Here, we show that prostate cancer cells express ERα and estrogen induces oncogenic properties in prostate cancer cells through ERα. Importantly, ERα knockdown in the human prostate cancer PacMetUT1 cells as well as pharmacological inhibition of ERα with ICI 182,780 inhibited osteoblastic lesion formation and lung metastasis in vivo. Co-culture of pre-osteoblasts with cancer cells showed a significant induction of osteogenic markers in the pre-osteoblasts, which was attenuated by knockdown of ERα in cancer cells suggesting that estrogen/ERα signaling promotes crosstalk between cancer and osteoblastic progenitors to stimulate osteoblastic tumorigenesis. These results suggest that ERα expression in prostate cancer cells is essential for osteoblastic lesion formation and lung metastasis. Thus, inhibition of ERα signaling in prostate cancer cells may be a novel therapeutic strategy to inhibit the osteoblastic lesion development as well as lung metastasis in patients with advanced prostate cancer.

  13. Use of vaginal estrogen in Danish women

    DEFF Research Database (Denmark)

    Meaidi, Amani; Goukasian, Irina; Lidegaard, Oejvind

    2016-01-01

    our result to the prevalence of urogenital atrophy-related symptoms reported in the literature, our study suggests an under-diagnosis and under-treatment of this condition. Teaching women and primary-care physicians about symptomatic urogenital atrophy and its treatment options may increase......INTRODUCTION: We know little about the use of vaginal estrogen in perimenopausal and postmenopausal women. We aimed to assess the prevalence of vaginal estrogen use in Denmark. MATERIAL AND METHODS: The study was designed as a nationwide cross-sectional study of all Danish women aged 40-79 years......, living in Denmark during the period 2007-2013. The Danish Prescription Register delivered data permitting us to assess the prevalence, age and regional geographical belonging of women purchasing prescribed vaginal estradiol. The number of women using over-the-counter vaginal estriol products...

  14. Estrogen and phytoestrogens: Effect on eNOS expression and in vitro vasodilation in cerebral arteries in ovariectomized Watanabe heritable hyperlipidemic rabbits

    DEFF Research Database (Denmark)

    Lund, Claus O.; Mortensen, Alicja; Nilas, Lisbeth

    2007-01-01

    Objectives: To evaluate the effect of estrogen replacement therapy or soy isoflavones supplement on endothelium-dependent relaxation in vitro and gene expression of endothelial nitric oxide synthase (eNOS) in cerebral arteries in a rabbit model of human hypercholesterolemia. Study design: Thirty...... cholesterol was significantly higher at termination in the SoyLife(R) group (P lipoprotein (LDL) cholesterol was comparable in all treatment groups. Neither treatment influenced the endothelium-dependent responses to carbamylcholine chloride or L-NAME or the endothelium...

  15. Aromatase Inhibitors and the Risk of Colorectal Cancer in Post-Menopausal Women with Breast Cancer.

    Science.gov (United States)

    Khosrow-Khavar, F; Yin, H; Barkun, A; Bouganim, N; Azoulay, L

    2017-12-27

    A large trial of post-menopausal women with breast cancer reported an imbalance in colorectal cancer events with aromatase inhibitors (AIs), compared with tamoxifen in the adjuvant setting. This unexpected signal was observed within 3 years of randomization. To date, no observational studies have examined this important safety question in the natural setting of clinical practice. Thus, the objective of this study was to determine whether AIs, when compared with tamoxifen, are associated with increased risk of colorectal cancer in post-menopausal women with breast cancer. Using the United Kingdom Clinical Practice Research Datalink, we identified women, at least 55 years of age, with breast cancer newly-treated with either AIs or tamoxifen between January 1, 1996 and September 31, 2015, with follow-up until September 31, 2016. High-dimensional propensity score-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of incident colorectal cancer associated with AIs when compared with tamoxifen overall, by cumulative duration of use, and time since initiation. All exposures were lagged by one year for latency considerations. A total of 9701 and 8893 patients initiated AIs and tamoxifen as first-line hormonal therapy (median follow-up of 2.4 and 2.9 years, respectively). Compared with tamoxifen, AIs were not associated with an increased risk of colorectal cancer (incidence rates of 150 per 100,000 person-years in both groups; adjusted HR: 0.90, 95% CI: 0.53-1.52). Similarly, there was no evidence of an association with cumulative duration of use (p-heterogeneity=0.54), and time since initiation (p-heterogeneity=0.66). In this first population-based study, the use of AIs was not associated with an increased risk of colorectal cancer. These findings should provide reassurance to the concerned stakeholders. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical

  16. Testosterone vs. aromatase inhibitor in older men with low testosterone: effects on cardiometabolic parameters.

    Science.gov (United States)

    Dias, J P; Shardell, M D; Carlson, O D; Melvin, D; Caturegli, G; Ferrucci, L; Chia, C W; Egan, J M; Basaria, S

    2017-01-01

    Testosterone (T) replacement is being increasingly offered to older men with age-related decline in testosterone levels. The effects of long-term testosterone replacement and aromatase inhibition (AI) on glucose homeostasis and cardiometabolic markers were determine in older non-diabetic men with low testosterone levels. Men ≥65 years, mean age 71 ± 3 years with serum total T testosterone gel (TT) (n = 10), 1 mg anastrozole (n = 10) or placebo (n = 9) daily for 12 months. Homeostatic Model Assessment of insulin resistance (HOMA IR ) was the primary outcome. Secondary outcomes included OGIS in response to OGTT, fasting lipids, C-reactive protein (CRP), adipokines, and abdominal and mid-thigh fat by computed tomography. All outcomes were assessed at baseline and 12 months. After 12 months, absolute changes in HOMA IR in both treatment arms (TT group: -0.05 ± 0.21); (AI group: 0.15 ± 0.10) were similar to placebo (-0.11 ± 0.26), as were CRP and fasting lipid levels. Adiponectin levels significantly decreased in the TT group (-1.8 ± 0.9 mg/L, p = 0.02) and abdominal subcutaneous fat (-60.34 ± 3.19 cm 2 , p = 0.003) and leptin levels (-1.5 ± 1.2 ng/mL, p = 0.04) were significantly lower with AI. Mid-thigh subcutaneous fat was reduced in both treatment arms (TT group: -4.88 ± 1.24 cm 2 , p = 0.008); (AI group: -6.05 ± 0.87 cm 2 , p = 0.0002). In summary, in this proof-of-concept trial, changes in HOMA IR AI were similar in all three groups while the effects of intervention on subcutaneous fat distribution and adipokines were variable. Larger efficacy and safety trials are needed before AI pharmacotherapy can be considered as a treatment option for low T levels in older men. © 2016 American Society of Andrology and European Academy of Andrology.

  17. Tracking evolution of aromatase inhibitor resistance with circulating tumour DNA analysis in metastatic breast cancer.

    Science.gov (United States)

    Fribbens, C; Garcia Murillas, I; Beaney, M; Hrebien, S; O'Leary, B; Kilburn, L; Howarth, K; Epstein, M; Green, E; Rosenfeld, N; Ring, A; Johnston, S; Turner, N

    2018-01-01

    Selection of resistance mutations may play a major role in the development of endocrine resistance. ESR1 mutations are rare in primary breast cancer but have high prevalence in patients treated with aromatase inhibitors (AI) for advanced breast cancer. We investigated the evolution of genetic resistance to the first-line AI therapy using sequential ctDNA sampling in patients with advanced breast cancer. Eighty-three patients on the first-line AI therapy for metastatic breast cancer were enrolled in a prospective study. Plasma samples were collected every 3 months to disease progression and ctDNA analysed by digital droplet PCR and enhanced tagged-amplicon sequencing (eTAm-Seq). Mutations identified in progression samples by sequencing were tracked back through samples before progression to study the evolution of mutations on therapy. The frequency of novel mutations was validated in an independent cohort of available baseline plasma samples in the Study of Faslodex versus Exemestane with or without Arimidex (SoFEA) trial, which enrolled patients with prior sensitivity to AI. Of the 39 patients who progressed on the first-line AI, 56.4% (22/39) had ESR1 mutations detectable at progression, which were polyclonal in 40.9% (9/22) patients. In serial tracking, ESR1 mutations were detectable median 6.7 months (95% confidence interval 3.7-NA) before clinical progression. Utilising eTAm-Seq ctDNA sequencing of progression plasma, ESR1 mutations were demonstrated to be sub-clonal in 72.2% (13/18) patients. Mutations in RAS genes were identified in 15.4% (6/39) of progressing patients (4 KRAS, 1 HRAS, 1 NRAS). In SoFEA, KRAS mutations were detected in 21.2% (24/113) patients although there was no evidence that KRAS mutation status was prognostic for progression free or overall survival. Cancers progressing on the first-line AI show high levels of genetic heterogeneity, with frequent sub-clonal mutations. Sub-clonal KRAS mutations are found at high frequency. The genetic

  18. Differential responsiveness of luteinized human granulosa cells to gonadotropins and insulin-like growth factor I for induction of aromatase activity

    International Nuclear Information System (INIS)

    Christman, G.M.; Randolph, J.F. Jr.; Peegel, H.; Menon, K.M.

    1991-01-01

    The objective of this study was to examine the in vitro responsiveness of cultured luteinized human granulosa cells over time to insulin-like growth factor 1 (IGF-1), human follicle-stimulating hormone (FSH), and human chorionic gonadotropin (hCG) for the induction of aromatase activity. Granulosa cells were retrieved from preovulatory follicles in patients undergoing in vitro fertilization. Cells were cultured for a period of 72 hours or 10 days. The ability of hCG, human FSH, and/or IGF-I to induce aromatase activity was assayed by the stereospecific release of tritium from [1B-3H]androstenedione. Short-term cultures (72 hours) demonstrated a marked rise in aromatase activity in response to human FSH and IGF-I, whereas a smaller response to hCG was observed. In contrast, 10-day cultures demonstrated responsiveness predominantly to hCG rather than human FSH for the induction of aromatase activity with no remarkable effect of IGF-I. Luteinized human granulosa cells undergo a transformation from an initial human FSH and IGF-I responsive state to an hCG responsive state in long-term cultures

  19. Short-term androgen priming by use of aromatase inhibitor and hCG before controlled ovarian stimulation for IVF. A randomized controlled trial

    DEFF Research Database (Denmark)

    Lossl, K; Andersen, C Yding; Loft, A

    2008-01-01

    Temporary exposure of follicles to increased levels of androgens may augment follicular responsiveness. The present study tested whether short-term androgen priming by aromatase inhibitor and human chorionic gonadotrophin (hCG) before controlled ovarian stimulation (COS) increases the number of top......-quality embryos after IVF/ICSI....

  20. Comparison of the effect of cortisol on aromatase activity and androgen metabolism in two human fibroblast cell lines derived from the same individual

    DEFF Research Database (Denmark)

    Svenstrup, B; Brünner, N; Dombernowsky, P

    1990-01-01

    with 14C-labeled substrate the cells were incubated in medium, charcoal stripped of steroids without Phenol Red. Preincubation from 6 to 36 h with cortisol in concentrations of 10(-8) - 10(-6) M showed maximal stimulation of aromatase activity after 12 h preincubation with cortisol in concentrations of 0...

  1. Synthesis and biochemical properties of 6-bromoandrostenedione derivatives with a 2,2-dimethyl or 2-methyl group as aromatase inhibitors.

    Science.gov (United States)

    Numazawa, Mitsuteru; Handa, Wakako; Yamada, Keiko

    2004-11-01

    To gain insight into the mechanism for irreversible inactivation of aromatase by 6beta-bromoandrostenedione (1), one of the earliest discovered suicide substrates, in relation to the catalytic function of the enzyme, the 2,2-dimethyl derivative of compound 1, steroid 4, and its 6alpha-isomer 5, as well as 2-methyl-1,4-diene steroid 8 and its 6alpha-bromide 10, were synthesized. All of the steroids inhibited aromatase activity in human placental microsomes with apparent K(i)'s ranging between 10 and 81 nM. The 2,2-dimethyl-6beta- and 6alpha-bromo steroids 4 and 5 were extremely powerful inhibitors (K(i): 14 and 10 nM, respectively), but these two did not cause a time-dependent inactivation of aromatase in the presence of NADPH; in contrast, the 2-methyl-1,4-diene steroids 8 and 10 caused time-dependent inactivation with apparent k(inact) of 0.035 and 0.071 min(-1), respectively, in a suicide manner. These results indicate that the 2,2-dimethyl function of the 6beta-bromide 4 would prevent the inactivation of aromatase caused by inhibitor 1 in a suicide manner, probably through steric activity, whereas the 2-methyl group of steroid 8 did not significantly affect the suicidal inactivation by the parent 1,4-diene steroid, a typical suicide substrate.

  2. Depsidones inhibit aromatase activity and tumor cell proliferation in a co-culture of human primary breast adipose fibroblasts and T47D breast tumor cells

    NARCIS (Netherlands)

    Chottanapund, Suthat; Van Duursen, M. B.M.|info:eu-repo/dai/nl/181957701; Zwartsen, Anne; Timtavorn, Supatchaya; Navasumrit, Panida; Kittakoop, Prasat; Sureram, Sanya; Ruchirawat, Mathuros; Van den Berg, Martin|info:eu-repo/dai/nl/08660466X

    2017-01-01

    Naturally occurring depsidones from the marine fungus Aspergillus unguis are known to have substantial anti-cancer activity, but their mechanism of action remains elusive. The purpose of this study was to examine the anti-aromatase activity of two common depsidones, unguinol and aspergillusidone A,

  3. Depsidones inhibit aromatase activity and tumor cell proliferation in a co-culture of human primary breast adipose fibroblasts and T47D breast tumor cells.

    Science.gov (United States)

    Chottanapund, Suthat; Van Duursen, M B M; Zwartsen, Anne; Timtavorn, Supatchaya; Navasumrit, Panida; Kittakoop, Prasat; Sureram, Sanya; Ruchirawat, Mathuros; Van den Berg, Martin

    2017-01-01

    Naturally occurring depsidones from the marine fungus Aspergillus unguis are known to have substantial anti-cancer activity, but their mechanism of action remains elusive. The purpose of this study was to examine the anti-aromatase activity of two common depsidones, unguinol and aspergillusidone A, in a co-culture system of human primary breast adipose fibroblasts and hormonal responsive T47D breast tumor cells. Using this in vitro model it was shown that these depsidones inhibit the growth of T47D tumor cells most likely via inhibition of aromatase (CYP19) activity. The IC 50 values of these depisidones were compared with the aromatase inhibitors letrozole and exemestane. Letrozole and exemestane had IC 50 values of respectively, 0.19 and 0.14 μM, while those for Unguinol and Aspergillusidone A were respectively, 9.7 and 7.3 μM. Our results indicate that among the depsidones there maybe aromatase inhibitors with possible pharmacotherapeutical relevance.

  4. Androgen priming using aromatase inhibitor and hCG during early-follicular-phase GnRH antagonist down-regulation in modified antagonist protocols

    DEFF Research Database (Denmark)

    Løssl, Kristine; Andersen, A N; Loft, A

    2006-01-01

    Temporary exposure of follicles to increased levels of androgens may enhance their sensitivity to FSH. The aim of this study was to increase the intraovarian androgen level using aromatase inhibitors and hCG before controlled ovarian stimulation (COH) and to test this concept clinically....

  5. Estrogen and xenoestrogens in breast cancer.

    Science.gov (United States)

    Fernandez, S V; Russo, J

    2010-01-01

    There is growing concern that estrogenic environmental compounds that act as endocrine-disrupting chemicals might potentially have adverse effects on hormone-sensitive organs such as the breast. This concern is further fueled by evidence indicating that natural estrogens, specifically 17beta-estradiol, are important factors in the initiation and progression of breast cancer. We have developed an in vitro-in vivo model in which we have demonstrated the carcinogenicity of E2 in human breast epithelial cells MCF-10F. Hypermethylation of NRG1, STXBP6, BMP6, CSS3, SPRY1, and SNIP were found at different progression stages in this model. The use of this powerful and unique model has provided a tool for exploring whether bisphenol A and butyl benzyl phthalate have relevance in the initiation of breast cancer. These studies provide firsthand evidence that the natural estrogen 17beta-estradiol and xenoestrogenic substances like bisphenol A are able to induce neoplastic transformation in human breast epithelial cells.

  6. Menopausal bone loss and estrogen replacement.

    Science.gov (United States)

    Meema, S; Meema, H E

    1976-07-01

    Throughout adult life the bone mineral mass of the radius is greater in males than in females. In males, it decreases after 60 years of age, while in females, it decreases earlier, at approximately 50 years, and the loss is greater. At the average age of 67 years, one half of the normal white female population has less than the normal amount of bone in the radius. Premenopausal women over the age of 50 do not show any decline of bone mineral mass, while in postmenopausal women, regardless of age, there is a loss of bone mass related to the number of years after menopause. Castrated women have significantly less bone mass than premenopausal women of the same average age. No decrease in cortical thickness of the radius was found in oophorectomized women treated with estrogens after castration. In a long-term, follow-up study, untreated postmenopausal women (after a natural or an artifical menopause) showed a significant loss of bone mass, while estrogen-treated, postmenopausal women showed no such loss. Estrogen treatment thus appears to prevent postmenopausal bone loss.

  7. Modulators of androgen and estrogen receptor activity.

    Science.gov (United States)

    Clarke, Bart L; Khosla, Sundeep

    2010-01-01

    This review focuses on significant recent findings regarding modulators of androgen and estrogen receptor activity. Selective androgen receptor modulators (SARMs) interact with androgen receptors (ARs), and selective estrogen receptor modulators (SERMs) interact with estrogen receptors (ERs), with variable tissue selectivity. SERMs, which interact with both ERб and ERв in a tissue-specific manner to produce diverse outcomes in multiple tissues, continue to generate significant interest for clinical application. Development of SARMs for clinical application has been slower to date because of potential adverse effects, but these diverse compounds continue to be investigated for use in disorders in which modulation of the AR is important. SARMs have been investigated mostly at the basic and preclinical level to date, with few human clinical trials published. These compounds have been evaluated mostly for application in different stages of prostate cancer to date, but they hold promise for multiple other applications. Publication of the large STAR and RUTH clinical trials demonstrated that the SERMs tamoxifen and raloxifene have interesting similarities and differences in tissues that contain ERs. Lasofoxifene, bazedoxifene, and arzoxifene are newer SERMs that have been demonstrated in clinical trials to more potently increase bone mineral density and lower serum cholesterol values than tamoxifen or raloxifene. Both SARMs and SERMs hold great promise for therapeutic use in multiple disorders in which tissue-specific effects are mediated by their respective receptors.

  8. The role of estrogen in bipolar disorder, a review

    DEFF Research Database (Denmark)

    Meinhard, Ninja; Kessing, Lars Vedel; Vinberg, Maj

    2014-01-01

    BACKGROUND: It appears that the female reproductive events and hormonal treatments may impact the course of bipolar disorder in women. In particular, childbirth is known to be associated with onset of affective episodes in women with bipolar disorder. During the female reproductive events the sex...... estrogen levels and women with bipolar disorder including studies of the anti manic effects of the selective estrogen receptor modulator tamoxifen. METHOD: A systematically literature search on PubMed was conducted: two studies regarding the connection between serum estrogen levels and women with bipolar...... disorder were identified. Furthermore, four studies were found concerning the antimanic effects of tamoxifen. RESULTS: Both studies in the estrogen studies showed very low levels of estrogen in women with postpartum psychosis and significant improvement of symptoms after treatment with estrogen. The four...

  9. The role of estrogen in bipolar disorder, a review

    DEFF Research Database (Denmark)

    Meinhard, Ninja; Kessing, Lars Vedel; Vinberg, Maj

    2014-01-01

    Background: It appears that the female reproductive events and hormonal treatments may impact the course of bipolar disorder in women. In particular, childbirth is known to be associated with onset of affective episodes in women with bipolar disorder. During the female reproductive events the sex...... estrogen levels and women with bipolar disorder including studies of the anti manic effects of the selective estrogen receptor modulator tamoxifen. Method: A systematically literature search on PubMed was conducted: two studies regarding the connection between serum estrogen levels and women with bipolar...... disorder were identified. Furthermore, four studies were found concerning the antimanic effects of tamoxifen. Results: Both studies in the estrogen studies showed very low levels of estrogen in women with postpartum psychosis and significant improvement of symptoms after treatment with estrogen. The four...

  10. Engineering of plant type III polyketide synthases.

    Science.gov (United States)

    Wakimoto, Toshiyuki; Morita, Hiroyuki; Abe, Ikuro

    2012-01-01

    Members of the chalcone synthase superfamily of type III polyketide synthases (PKSs) catalyze iterative condensations of CoA thioesters to produce a variety of polyketide scaffolds with remarkable structural diversity and biological activities. The homodimeric type III PKSs share a common three-dimensional overall fold with a conserved Cys-His-Asn catalytic triad; notably, only a slight modification of the active site dramatically expands the catalytic repertoire of the enzymes. In addition, the enzymes exhibit extremely promiscuous substrate specificities, and accept a variety of nonphysiological substrates, making the type III PKSs an excellent platform for the further production of unnatural, novel polyketide scaffolds with promising biological activities. This chapter summarizes recent advances in the engineering of plant type III PKS enzymes in our laboratories, using approaches combining structure-based enzyme engineering and precursor-directed biosynthesis with rationally designed substrate analogs. Copyright © 2012 Elsevier Inc. All rights reserved.

  11. Estrogen Enhances the Expression of the Multidrug Transporter Gene ABCG2—Increasing Drug Resistance of Breast Cancer Cells through Estrogen Receptors

    Directory of Open Access Journals (Sweden)

    Fung-Wei Chang

    2017-01-01

    Full Text Available Background: Multidrug resistance is a major obstacle in the successful therapy of breast cancer. Studies have proved that this kind of drug resistance happens in both human cancers and cultured cancer cell lines. Understanding the molecular mechanisms of drug resistance is important for the reasonable design and use of new treatment strategies to effectively confront cancers. Results: In our study, ATP-binding cassette sub-family G member 2 (ABCG2, adenosine triphosphate (ATP synthase and cytochrome c oxidase subunit VIc (COX6C were over-expressed more in the MCF-7/MX cell line than in the normal MCF7 cell line. Therefore, we believe that these three genes increase the tolerance of MCF7 to mitoxantrone (MX. The data showed that the high expression of COX6C made MCF-7/MX have more stable on mitochondrial membrane potential (MMP and reactive oxygen species (ROS expression than normal MCF7 cells under hypoxic conditions. The accumulation of MX was greater in the ATP-depleted treatment MCF7/MX cells than in normal MCF7/MX cells. Furthermore, E2 increased the tolerance of MCF7 cells to MX through inducing the expression of ABCG2. However, E2 could not increase the expression of ABCG2 after the inhibition of estrogen receptor α (ERα in MCF7 cells. According to the above data, under the E2 treatment, MDA-MB231, which lacks ER, had a higher sensitivity to MX than MCF7 cells. Conclusions: E2 induced the expression of ABCG2 through ERα and the over-expressed ABCG2 made MCF7 more tolerant to MX. Moreover, the over-expressed ATP synthase and COX6c affected mitochondrial genes and function causing the over-expressed ABCG2 cells pumped out MX in a concentration gradient from the cell matrix. Finally lead to chemoresistance.

  12. Targeting Epigenetics Therapy for Estrogen Receptor-Negative Breast Cancers

    Science.gov (United States)

    2015-10-01

    AWARD NUMBER: W81XWH-13-1-0400 TITLE: Targeting Epigenetics Therapy for Estrogen Receptor-Negative Breast Cancers PRINCIPAL INVESTIGATOR...Targeting Epigenetics Therapy for Estrogen Receptor-Negative Breast Cancers 5b. GRANT NUMBER W81XWH-13-1-0400 5c. PROGRAM ELEMENT NUMBER 6...negative breast cancer, epigenetics , nuclear hormone receptor, estrogen Overall Project Summary Flavin-dependent, lysine-specific protein

  13. Engineering cotton (+)-delta-cadinene synthase to an altered function: germacrene D-4-ol synthase.

    Science.gov (United States)

    Yoshikuni, Yasuo; Martin, Vincent J J; Ferrin, Thomas E; Keasling, Jay D

    2006-01-01

    The combined approaches of rational design and random mutagenesis were applied to generate a sesquiterpene synthase with an altered activity. Due to the lack of a convenient screen for sesquiterpene synthase activity, a high-throughput dual-activity screen was used by fusing (+)-delta-cadinene synthase to chloramphenicol acetyltransferase (CAT). The gene encoding (+)-delta-cadinene synthase was mutagenized using error-prone PCR. The resulting mutant fusion proteins were screened for CAT activity and altered sesquiterpene selectivity. Twenty-one clones producing (+)-delta-cadinene and germacrene D-4-ol in different ratios were isolated from the library. Analysis using a homology model of (+)-delta-cadinene synthase suggested that the G helix plays a very important role in (+)-delta-cadinene formation. Reconstruction of the G helix using site-directed, saturation mutagenesis yielded a mutant, N403P/L405H, that maintained its specific activity and showed higher selectivity to germacrene D-4-ol in vivo (up to 93%).

  14. Computational estimation of rainbow trout estrogen receptor binding affinities for environmental estrogens

    International Nuclear Information System (INIS)

    Shyu, Conrad; Cavileer, Timothy D.; Nagler, James J.; Ytreberg, F. Marty

    2011-01-01

    Environmental estrogens have been the subject of intense research due to their documented detrimental effects on the health of fish and wildlife and their potential to negatively impact humans. A complete understanding of how these compounds affect health is complicated because environmental estrogens are a structurally heterogeneous group of compounds. In this work, computational molecular dynamics simulations were utilized to predict the binding affinity of different compounds using rainbow trout (Oncorhynchus mykiss) estrogen receptors (ERs) as a model. Specifically, this study presents a comparison of the binding affinity of the natural ligand estradiol-17β to the four rainbow trout ER isoforms with that of three known environmental estrogens 17α-ethinylestradiol, bisphenol A, and raloxifene. Two additional compounds, atrazine and testosterone, that are known to be very weak or non-binders to ERs were tested. The binding affinity of these compounds to the human ERα subtype is also included for comparison. The results of this study suggest that, when compared to estradiol-17β, bisphenol A binds less strongly to all four receptors, 17α-ethinylestradiol binds more strongly, and raloxifene has a high affinity for the α subtype only. The results also show that atrazine and testosterone are weak or non-binders to the ERs. All of the results are in excellent qualitative agreement with the known in vivo estrogenicity of these compounds in the rainbow trout and other fishes. Computational estimation of binding affinities could be a valuable tool for predicting the impact of environmental estrogens in fish and other animals.

  15. Effect of a hormone-releasing intrauterine system (Mirena® on aromatase and Cox-2 expression in patients with adenomyosis submitted or not, to endometrial resection

    Directory of Open Access Journals (Sweden)

    Maia R

    2012-04-01

    Full Text Available Hugo Maia Jr1,2, Clarice Haddad1, Julio Casoy1, Rebeca Maia1, Nathanael Pinheiro3, Elsimar M Coutinho11Centro de Pesquisa e Assistência em Reprodução Humana (CEPARH, 2Itaigara Memorial Day Hospital, 3IMAGEPAT, Salvador, Bahia, BrazilObjective: To investigate the effect of a levonorgestrel-releasing intrauterine system (Mirena® on aromatase and cyclooxygenase-2 (Cox-2 expression in the endometrium of patients with adenomyosis who were submitted to endometrial resection at the time of insertion, compared to a group not submitted to endometrial resection and a group of controls with adenomyosis not submitted to any previous hormonal treatment.Patients and methods: Patients with adenomyosis (n = 89 were included in this study. Twenty-two patients had been using Mirena® for 5 years but had not been submitted to endometrial resection prior to insertion of the device. Twenty-four patients were submitted to endometrial resection at the time of Mirena® insertion. The remaining 43 patients with adenomyosis had undergone no previous hormonal treatment and served as a control group. Cox-2 and aromatase expression were determined in the endometrium by immunohistochemistry.Results: Use of Mirena® for 5 years reduced aromatase expression in the endometrium; however, this reduction was significantly greater in the uteri previously submitted to endometrial resection. The reduction in Cox-2 expression was significant only in the uteri submitted to endometrial resection followed by the insertion of Mirena®.Conclusion: Endometrial resection followed by the insertion of Mirena® was associated with greater rates of amenorrhea in patients with adenomyosis, which in turn were associated with a more effective inhibition of aromatase and Cox-2 expression in the endometrium.Keywords: aromatase, Mirena®, adenomyosis, Cox-2, endometrium, levonorgestrel

  16. Reinvestigation of the synthesis and evaluation of [N-methyl-{sup 11}C]vorozole, a radiotracer targeting cytochrome P450 aromatase

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sung Won [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States)], E-mail: swkim@bnl.gov; Biegon, Anat; Katsamanis, Zachary E. [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Ehrlich, Carolin W. [Johannes-Gutenberg Universitaet Mainz, Institut fuer Organische Chemie, Duesbergweg 10-14, Mainz (Germany); Hooker, Jacob M.; Shea, Colleen [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Muench, Lisa [National Institute on Alcoholism and Alcohol Abuse, Bethesda, MD (United States); Xu Youwen; King, Payton; Carter, Pauline; Alexoff, David L. [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Fowler, Joanna S. [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Department of Psychiatry, Mount Sinai School of Medicine, New York, NY (United States); Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY (United States)

    2009-04-15

    Introduction: We reinvestigated the synthesis of [N-methyl-{sup 11}C]vorozole, a radiotracer for aromatase, and discovered the presence of an N-methyl isomer which was not removed in the original purification method. Herein we report the preparation and positron emission tomography (PET) studies of pure [N-methyl-{sup 11}C]vorozole. Methods: Norvorozole was alkylated with [{sup 11}C]methyl iodide as previously described and also with unlabeled methyl iodide. A high-performance liquid chromatography (HPLC) method was developed to separate the regioisomers. Nuclear magnetic resonance (NMR) spectroscopy ({sup 13}C and 2D-nuclear Overhauser effect spectroscopy NMR) was used to identify and assign structures to the N-methylated products. Pure [N-methyl-{sup 11}C]vorozole and the contaminating isomer were compared by PET imaging in the baboon. Results: Methylation of norvorozole resulted in a mixture of isomers (1:1:1 ratio) based on new HPLC analysis using a pentafluorophenylpropyl bonded silica column, in which vorozole coeluted one of its isomers under the original HPLC conditions. Baseline separation of the three labeled isomers was achieved. The N-3 isomer was the contaminant of vorozole, thus correcting the original assignment of isomers. PET studies of pure [N-methyl-{sup 11}C]vorozole with and without the contaminating N-3 isomer revealed that only [N-methyl-{sup 11}C]vorozole binds to aromatase. [N-methyl-{sup 11}C]Vorozole accumulated in all brain regions with highest accumulation in the aromatase-rich amygdala and preoptic area. Accumulation was blocked with vorozole and letrozole consistent with reports of some level of aromatase in many brain regions. Conclusions: The discovery of a contaminating labeled isomer and the development of a method for isolating pure [N-methyl-{sup 11}C]vorozole combine to provide a new scientific tool for PET studies of the biology of aromatase and for drug research and development.

  17. Selectivity of natural, synthetic and environmental estrogens for zebrafish estrogen receptors

    Energy Technology Data Exchange (ETDEWEB)

    Pinto, Caroline [Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204-5056 (United States); Grimaldi, Marina; Boulahtouf, Abdelhay [Institut de Recherche en Cancérologie de Montpellier, Institut National de la Santé de la Recherche Médicale U896, Institut Régional de Cancérologie de Montpellier, Université Montpellier 1, 34298 Montpellier (France); Pakdel, Farzad [Institut de Recherche sur la Santé, Environnement et Travail (IRSET), INSERM U1085, Université de Rennes 1, Rennes (France); Brion, François; Aït-Aïssa, Sélim [Unité Écotoxicologie In Vitro et In Vivo, INERIS, Parc ALATA, 60550 Verneuil-en-Halatte (France); Cavaillès, Vincent [Institut de Recherche en Cancérologie de Montpellier, Institut National de la Santé de la Recherche Médicale U896, Institut Régional de Cancérologie de Montpellier, Université Montpellier 1, 34298 Montpellier (France); Bourguet, William [U1054, Centre de Biochimie Structurale, CNRS UMR5048, Université Montpellier 1 et 2, 34290 Montpellier (France); Gustafsson, Jan-Ake [Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204-5056 (United States); Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Huddinge (Sweden); and others

    2014-10-01

    Zebrafish, Danio rerio, is increasingly used as an animal model to study the effects of pharmaceuticals and environmental estrogens. As most of these estrogens have only been tested on human estrogen receptors (ERs), it is necessary to measure their effects on zebrafish ERs. In humans there are two distinct nuclear ERs (hERα and hERβ), whereas the zebrafish genome encodes three ERs, zfERα and two zfERβs (zfERβ1 and zfERβ2). In this study, we established HeLa-based reporter cell lines stably expressing each of the three zfERs. We first reported that estrogens more efficiently activate the zfERs at 28 °C as compared to 37 °C, thus reflecting the physiological temperature of zebrafish in wildlife. We then showed significant differences in the ability of agonist and antagonist estrogens to modulate activation of the three zfER isotypes in comparison to hERs. Environmental compounds (bisphenol A, alkylphenols, mycoestrogens) which are hER panagonists and hERβ selective agonists displayed greater potency for zfERα as compared to zfERβs. Among hERα selective synthetic agonists, PPT did not activate zfERα while 16α-LE2 was the most zfERα selective compound. Altogether, these results confirm that all hER ligands control in a similar manner the transcriptional activity of zfERs although significant differences in selectivity were observed among subtypes. The zfER subtype selective ligands that we identified thus represent new valuable tools to dissect the physiological roles of the different zfERs. Finally, our work also points out that care has to be taken in transposing the results obtained using the zebrafish as a model for human physiopathology. - Highlights: • Zebrafish is increasingly used to study the effects of estrogens. • We assessed the activity of pharmaceutical and environmental estrogens on zfERs. • Environmental estrogens displayed greater potency for zfERα compared to zfERβs. • hERβ selective agonists displayed greater potency for zf

  18. Estrogenic activity of flavonoids in mice. The importance of estrogen receptor distribution, metabolism and bioavailability

    DEFF Research Database (Denmark)

    Breinholt, Vibeke; Hossaini, A.; Svendsen, Gitte W.

    2000-01-01

    The in vivo estrogenic potential of the flavonoids apigenin, kaempferol, genistein and equol was investigated in immature female mice. Genistein and equol, administered by gavage for 4 consecutive days [post-natal day (PND) 17-20, 100 mg/kg body weight], was found to significantly increase uterine...... weights and the overall uterine concentration of estrogen receptor alpha (ER alpha). In kaempferol- and equol-exposed mice the cytosolic ER alpha concentration was significantly increased as compared to the solvent control, which is speculated to result in an increased sensitivity of the uterus...

  19. Estrogen receptor mRNA in mineralized tissues of rainbow trout: calcium mobilization by estrogen.

    Science.gov (United States)

    Armour, K J; Lehane, D B; Pakdel, F; Valotaire, Y; Graham, R; Russell, R G; Henderson, I W

    1997-07-07

    RT-PCR was undertaken on total RNA extracts from bone and scales of the rainbow trout, Oncorhynchus mykiss. The rainbow trout estrogen receptor (ER)-specific primers used amplified a single product of expected size from each tissue which, using Southern blotting, strongly hybridized with a 32P-labelled rtER probe under stringent conditions. These data provide the first in vivo evidence of ER mRNA in bone and scale tissues of rainbow trout and suggest that the effects of estrogen observed in this study (increased bone mineral and decreased scale mineral contents, respectively) may be mediated directly through ER.

  20. CTP synthase forms cytoophidia in the cytoplasm and nucleus

    Energy Technology Data Exchange (ETDEWEB)

    Gou, Ke-Mian [MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT (United Kingdom); State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193 (China); Chang, Chia-Chun [Institute of Biotechnology, National Taiwan University, Taipei, Taiwan, ROC (China); Shen, Qing-Ji [MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT (United Kingdom); Sung, Li-Ying, E-mail: liyingsung@ntu.edu.tw [Institute of Biotechnology, National Taiwan University, Taipei, Taiwan, ROC (China); Agricultural Biotechnology Research Center, Academia Sinica, Taipei 115, Taiwan, ROC (China); Liu, Ji-Long, E-mail: jilong.liu@dpag.ox.ac.uk [MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT (United Kingdom)

    2014-04-15

    CTP synthase is an essential metabolic enzyme responsible for the de novo synthesis of CTP. Multiple studies have recently showed that CTP synthase protein molecules form filamentous structures termed cytoophidia or CTP synthase filaments in the cytoplasm of eukaryotic cells, as well as in bacteria. Here we report that CTP synthase can form cytoophidia not only in the cytoplasm, but also in the nucleus of eukaryotic cells. Both glutamine deprivation and glutamine analog treatment promote formation of cytoplasmic cytoophidia (C-cytoophidia) and nuclear cytoophidia (N-cytoophidia). N-cytoophidia are generally shorter and thinner than their cytoplasmic counterparts. In mammalian cells, both CTP synthase 1 and CTP synthase 2 can form cytoophidia. Using live imaging, we have observed that both C-cytoophidia and N-cytoophidia undergo multiple rounds of fusion upon glutamine analog treatment. Our study reveals the coexistence of cytoophidia in the cytoplasm and nucleus, therefore providing a good opportunity to investigate the intracellular compartmentation of CTP synthase. - Highlights: • CTP synthase forms cytoophidia not only in the cytoplasm but also in the nucleus. • Glutamine deprivation and Glutamine analogs promotes cytoophidium formation. • N-cytoophidia exhibit distinct morphology when compared to C-cytoophidia. • Both CTP synthase 1 and CTP synthase 2 form cytoophidia in mammalian cells. • Fusions of cytoophidia occur in the cytoplasm and nucleus.

  1. Estrogens and Androgens in Skeletal Physiology and Pathophysiology

    Science.gov (United States)

    Almeida, Maria; Laurent, Michaël R.; Dubois, Vanessa; Claessens, Frank; O'Brien, Charles A.; Bouillon, Roger; Vanderschueren, Dirk

    2016-01-01

    Estrogens and androgens influence the growth and maintenance of the mammalian skeleton and are responsible for its sexual dimorphism. Estrogen deficiency at menopause or loss of both estrogens and androgens in elderly men contribute to the development of osteoporosis, one of the most common and impactful metabolic diseases of old age. In the last 20 years, basic and clinical research advances, genetic insights from humans and rodents, and newer imaging technologies have changed considerably the landscape of our understanding of bone biology as well as the relationship between sex steroids and the physiology and pathophysiology of bone metabolism. Together with the appreciation of the side effects of estrogen-related therapies on breast cancer and cardiovascular diseases, these advances have also drastically altered the treatment of osteoporosis. In this article, we provide a comprehensive review of the molecular and cellular mechanisms of action of estrogens and androgens on bone, their influences on skeletal homeostasis during growth and adulthood, the pathogenetic mechanisms of the adverse effects of their deficiency on the female and male skeleton, as well as the role of natural and synthetic estrogenic or androgenic compounds in the pharmacotherapy of osteoporosis. We highlight latest advances on the crosstalk between hormonal and mechanical signals, the relevance of the antioxidant properties of estrogens and androgens, the difference of their cellular targets in different bone envelopes, the role of estrogen deficiency in male osteoporosis, and the contribution of estrogen or androgen deficiency to the monomorphic effects of aging on skeletal involution. PMID:27807202

  2. Estrogen signaling in the proliferative endometrium: implications in endometriosis

    Directory of Open Access Journals (Sweden)

    Rita de Cássia Pereira da Costa e Silva

    2016-02-01

    Full Text Available SUMMARY Even though the physiological role of estrogen in the female reproductive cycle and endometrial proliferative phase is well established, the signaling pathways by which estrogen exerts its action in the endometrial tissue are still little known. In this regard, advancements in cell culture techniques and maintenance of endometrial cells in cultures enabled the discovery of new signaling mechanisms activated by estrogen in the normal endometrium and in endometriosis. This review aims to present the recent findings in the genomic and non-genomic estrogen signaling pathways in the proliferative human endometrium specifically associated with the pathogenesis and development of endometriosis.

  3. Estrogen-related and other disease diagnoses preceding Parkinson's disease

    DEFF Research Database (Denmark)

    Latourelle, Jeanne C; Dybdal, Merete; Destefano, Anita L

    2010-01-01

    Estrogen exposure has been associated with the occurrence of Parkinson's disease (PD), as well as many other disorders, and yet the mechanisms underlying these relations are often unknown. While it is likely that estrogen exposure modifies the risk of various diseases through many different...... mechanisms, some estrogen-related disease processes might work in similar manners and result in association between the diseases. Indeed, the association between diseases need not be due only to estrogen-related factors, but due to similar disease processes from a variety of mechanisms....

  4. Treatment of wastewater having estrogen activity by ionizing radiation

    International Nuclear Information System (INIS)

    Kimura, Atsushi; Taguchi, Mitsumasa; Ohtani, Yoshimi; Shimada, Yoshitaka; Hiratsuka, Hiroshi; Kojima, Takuji

    2007-01-01

    Decomposition of endocrine disrupting chemicals (EDCs) in wastewater was investigated by use of 60 Co γ-ray. Estrogen activities of wastewaters were estimated by the yeast two-hybrid assay based on human or medaka estrogen receptors. The dose required for the elimination of estrogen activity of wastewater below 1 ng dm -3 was about 200 Gy (J kg -1 ). The elimination dose of the estrogen activity depended on the amounts of total organic carbons in wastewater. The economic cost of the treatment process of EDCs using electron beam was estimated at 17 yen m -3

  5. Breast Cancer and Estrogen Biosynthesis in Adipose Tissue

    Science.gov (United States)

    1998-10-01

    virilization during pregnancy may or may not be a consistent presentation, because, to date, two of three moth - ers of aromatase-deficient fetuses were...diagnosis was made based upon high plasma estrone (Ej) and estradiol (E2) levels. After detailed endocrine preoper- ative testing and catheterization of...the catheter in this vein. In the preoperative period, LH and FSH were almost un- detectable (0.5 IU/L and 0.4 IU, respectively) and did not

  6. Vitellogenin, a Marker of Estrogen Mimicking Contaminants in Fishes: Characterization, Quantification and Interference by Anti-Estrogens

    OpenAIRE

    Palumbo, Amanda J.

    2008-01-01

    Vitellogenin (Vg), the estrogen inducible protein precursor to egg yolk, serves as an indicator of exposure to estrogen mimicking environmental contaminants. Vg was isolated by size exclusion and ion exchange chromatography from plasma of California halibut (Paralichthys californicus) treated with estrogen. MALDI TOF mass spectrometry (MS) analysis resulted in a molecular mass of 188 kDa. MS/MS de novo sequencing provided evidence that California halibut has more than one form of Vg. Similar ...

  7. Expression profiles of estrogen-regulated microRNAs in breast cancer cells

    OpenAIRE

    Katchy, Anne; Williams, Cecilia

    2016-01-01

    Molecular signaling through both estrogen and microRNAs are critical for breast cancer development and growth. The activity of estrogen is mediated by transcription factors, the estrogen receptors. Here we describe a method for robust characterization of estrogen-regulated microRNA profiles. The method details how to prepare cells for optimal estrogen response, directions for estrogen treatment, RNA extraction, microRNA large-scale profiling and subsequent confirmations.

  8. Estrogens and cognition: Friends or foes?: An evaluation of the opposing effects of estrogens on learning and memory.

    Science.gov (United States)

    Korol, Donna L; Pisani, Samantha L

    2015-08-01

    This article is part of a Special Issue "Estradiol and cognition". Estrogens are becoming well known for their robust enhancement on cognition particularly for learning and memory that relies upon functioning of the hippocampus and related neural systems. What is also emerging is that estrogen modulation of cognition is not uniform, at times enhancing yet at other times impairing learning. This review explores the bidirectional effects of estrogens on learning from a multiple memory systems view, focusing on the hippocampus and striatum, whereby modulation by estrogens sorts according to task attributes and neural systems engaged during cognition. We highlight our findings showing that the ability to solve hippocampus-sensitive tasks typically improves under relatively high estrogen status while the ability to solve striatum-sensitive tasks degrades with estrogen exposures. Though constrained by dose and timing of exposure, these opposing enhancements and impairments of cognition can be observed following treatments with different estrogenic compounds including the hormone estradiol, the isoflavone genistein found in soybeans, and agonists that are selective for specific estrogen receptors, suggesting that activation of a single receptor type is sufficient to produce the observed shifts in learning strategies. Using this multi-dimensional framework will allow us to extend our thinking of the relationship between estrogens and cognition to other brain regions and cognitive functions. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Localization of nitric oxide synthase in human skeletal muscle

    DEFF Research Database (Denmark)

    Frandsen, Ulrik; Lopez-Figueroa, M.; Hellsten, Ylva

    1996-01-01

    The present study investigated the cellular localization of the neuronal type I and endothelial type III nitric oxide synthase in human skeletal muscle. Type I NO synthase immunoreactivity was found in the sarcolemma and the cytoplasm of all muscle fibres. Stronger immunoreactivity was expressed...... in the sarcolemma as well as the cytoplasm of type I muscle fibres. NADPH diaphorase activity confirmed a higher level of NO synthase activity in the sarcolemma as well as the cytoplasm of type I muscle fibers. Histochemical staining for cytochrome oxidase showed a staining pattern similar to that observed for type...... I NO synthase immunoreactivity and NADPH diaphorase activity. Type III NO synthase immunoreactivity was observed both in the endothelium of larger vessels and of microvessels. The results establish that human skeletal muscle expresses two different constitutive isoforms of NO synthase in different...

  10. Do estrogen or selective estrogen receptor modulators improve quality of life for women with postmenopausal osteoporosis?

    Science.gov (United States)

    Gold, Deborah T; Silverman, Stuart L

    2007-03-01

    Osteoporotic fractures result in significant deficits in health-related quality of life (HRQOL). The accumulation of deficits resulting from osteoporosis and fractures is now recognized as a major cause of reduced HRQOL in women after the menopause and in later life. Some of these same postmenopausal women may also have deficits in HRQOL related to vasomotor symptoms during the menopausal transition. Although estrogen therapy has not been shown to improve overall HRQOL in late postmenopausal women in randomized, controlled trials, it may improve menopausal symptoms. In contrast, selective estrogen receptor modulators (SERMs) such as raloxifene may increase vasomotor symptoms. Although estrogen is not indicated for the primary prevention of osteoporosis, estrogen therapy may be considered for the postmenopausal woman at risk of osteoporotic fracture who is symptomatic and who is not at high risk of breast cancer or cardiovascular events. Raloxifene decreases risk of invasive breast cancer and may be considered in women at high risk of breast cancer. Decision making about osteoporosis treatment should also consider the impact of the treatment on HRQOL.

  11. Functional plasticity of paralogous diterpene synthases involved in conifer defense

    OpenAIRE

    Keeling, Christopher I.; Weisshaar, Sabrina; Lin, Roy P. C.; Bohlmann, Jörg

    2008-01-01

    The diversity of terpenoid compounds produced by plants plays an important role in mediating various plant–herbivore, plant–pollinator, and plant–pathogen interactions. This diversity has resulted from gene duplication and neofunctionalization of the enzymes that synthesize and subsequently modify terpenes. Two diterpene synthases in Norway spruce (Picea abies), isopimaradiene synthase and levopimaradiene/abietadiene synthase, provide the hydrocarbon precursors for most of the diterpene resin...

  12. Geranyl diphosphate synthase molecules, and nucleic acid molecules encoding same

    Science.gov (United States)

    Croteau, Rodney Bruce [Pullman, WA; Burke, Charles Cullen [Moscow, ID

    2008-06-24

    In one aspect, the present invention provides isolated nucleic acid molecules that each encode a geranyl diphosphate synthase protein, wherein each isolated nucleic acid molecule hybridizes to a nucleic acid molecule consisting of the sequence set forth in SEQ ID NO:1 under conditions of 5.times.SSC at 45.degree. C. for one hour. The present invention also provides isolated geranyl diphosphate synthase proteins, and methods for altering the level of expression of geranyl diphosphate synthase protein in a host cell.

  13. Are previous episodes of bacterial vaginosis a predictor for vaginal symptoms in breast cancer patients treated with aromatase inhibitors?

    DEFF Research Database (Denmark)

    Gade, Malene R; Goukasian, Irina; Panduro, Nathalie

    2018-01-01

    Objective To estimate the prevalence of vaginal symptoms in postmenopausal women with breast cancer exposed to aromatase inhibitors, and to investigate if the risk of vaginal symptoms is associated with previous episodes of bacterial vaginosis. Methods Patients from Rigshospitalet and Herlev...... University Hospital, Denmark, were identified through the register of Danish Breast Cancer Cooperation Group and 78 patients participated in the study. Semiquantitave questionnaires and telephone interview were used to assess the prevalence of vaginal symptoms and previous episode(s) of bacterial vaginosis....... Multivariable logistic regression models were used to assess the association between vaginal symptoms and previous episodes of bacterial vaginosis. Results Moderate to severe symptoms due to vaginal itching/irritation were experienced by 6.4% (95% CI: 2.8-14.1%), vaginal dryness by 28.4% (95% CI: 19...

  14. Isoflavones: estrogenic activity, biological effect and bioavailability.

    Science.gov (United States)

    Vitale, Daniela Cristina; Piazza, Cateno; Melilli, Barbara; Drago, Filippo; Salomone, Salvatore

    2013-03-01

    Isoflavones are phytoestrogens with potent estrogenic activity; genistein, daidzein and glycitein are the most active isoflavones found in soy beans. Phytoestrogens have similarity in structure with the human female hormone 17-β-estradiol, which can bind to both alpha and beta estrogen receptors, and mimic the action of estrogens on target organs, thereby exerting many health benefits when used in some hormone-dependent diseases. Numerous clinical studies claim benefits of genistein and daidzein in chemoprevention of breast and prostate cancer, cardiovascular disease and osteoporosis as well as in relieving postmenopausal symptoms. The ability of isoflavones to prevent cancer and other chronic diseases largely depends on pharmacokinetic properties of these compounds, in particular absorption and distribution to the target tissue. The chemical form in which isoflavones occur is important because it influences their bioavailability and, therefore, their biological activity. Glucose-conjugated isoflavones are highly polar, water-soluble compounds. They are hardly absorbed by the intestinal epithelium and have weaker biological activities than the corresponding aglycone. Different microbial families of colon can transform glycosylated isoflavones into aglycones. Clinical studies show important differences between the aglycone and conjugated forms of genistein and daidzein. The evaluation of isoflavone metabolism and bioavailability is crucial to understanding their biological effects. Lipid-based formulations such as drug incorporation into oils, emulsions and self-microemulsifying formulations have been introduced to increase bioavailability. Complexation with cyclodextrin also represent a valid method to improve the physicochemical characteristics of these substances in order to be absorbed and distributed to target tissues. We review and discuss pharmacokinetic issues that critically influence the biological activity of isoflavones.

  15. Bu-Shen-Ning-Xin Decoction ameliorated the osteoporotic phenotype of ovariectomized mice without affecting the serum estrogen concentration or uterus

    Directory of Open Access Journals (Sweden)

    Wang L

    2015-08-01

    Full Text Available Ling Wang,1,2,* Xue-Min Qiu,1,2,* Yu-Yan Gui,1,2 Ying-Ping Xu,1,2 Hans-Jürgen Gober,3 Da-Jin Li1 1Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, IBS, Fudan University Shanghai Medical College, 2Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, People’s Republic of China; 3Department of Pharmacy, Wagner Jauregg Hospital and Children’s Hospital, Linz, Austria *These authors contributed equally to this work Introduction: Bu-Shen-Ning-Xin Decoction (BSNXD, a traditional Chinese medicinal composition, has been used as a remedy for postmenopausal osteoporosis, but its effects on bone metabolism and the uterus have not been reported.Purpose: We aimed to determine the respective effects of BSNXD on the bones and the uterus of ovariectomized (OVX mice to evaluate the efficacy and safety of this herbal formula.Materials and methods: Postmenopausal osteoporosis animal models that were generated by ovariectomy were treated with BSNXD. Dual-energy X-ray absorptiometry was performed to analyze the bone mineral density, and histomorphometric analysis was performed to measure the parameters related to bone metabolism. Calcein labeling was performed to detect bone formation. The uteruses from the mice were weighed, and the histomorphometry was analyzed. Drug-derived serum was prepared to assess the 17-β-estradiol concentration via enzyme immunoassay.Results: BSNXD administration ameliorated the osteoporotic phenotype of OVX mice, as evidenced by an increase in the bone mineral density and bone volume; these effects could not be abolished by the administration of the aromatase inhibitor letrozole. Moreover, BSNXD had no effect on the serum estrogen concentration or uterus.Conclusion: These results suggest that BSNXD has ameliorating effects on bone loss due to estrogen deprivation without affecting the peripheral blood estrogen concentration or the uterus in OVX mice. Keywords

  16. Use of Aromatase Inhibitors in Large Cell Calcifying Sertoli Cell Tumors: Effects on Gynecomastia, Growth Velocity, and Bone Age

    Science.gov (United States)

    Crocker, Melissa K.; Gourgari, Evgenia; Stratakis, Constantine A.

    2014-01-01

    Context: Large cell calcifying Sertoli cell tumors (LCCSCT) present in isolation or, especially in children, in association with Carney Complex (CNC) or Peutz-Jeghers Syndrome (PJS). These tumors overexpress aromatase (CYP19A1), which leads to increased conversion of delta-4-androstenedione to estrone and testosterone to estradiol. Prepubertal boys may present with growth acceleration, advanced bone age, and gynecomastia. Objective: To investigate the outcomes of aromatase inhibitor therapy (AIT) in prepubertal boys with LCCSCTs. Design: Case series of a very rare tumor and chart review of cases treated at other institutions. Setting: Tertiary care and referral center. Patients: Six boys, five with PJS and one with CNC, were referred to the National Institutes of Health for treatment of LCCSCT. All patients had gynecomastia, testicular enlargement, and advanced bone ages, and were being treated by their referring physicians with AIT. Interventions: Patients were treated for a total of 6–60 months on AIT. Main Outcome Measures: Height, breast tissue mass, and testicular size were all followed; physical examination, scrotal ultrasounds, and bone ages were obtained, and hormonal concentrations and tumor markers were measured. Results: Tumor markers were negative. All patients had decreases in breast tissue while on therapy. Height percentiles declined, and predicted adult height moved closer to midparental height as bone age advancement slowed. Testicular enlargement stabilized until entry into central puberty. Only one patient required unilateral orchiectomy. Conclusions: Patients with LCCSCT benefit from AIT with reduction and/or elimination of gynecomastia and slowing of linear growth and bone age advancement. Further study of long-term outcomes and safety monitoring are needed but these preliminary data suggest that mammoplasty and/or orchiectomy may be foregone in light of the availability of medical therapy. PMID:25226294

  17. Comparison of pharmacokinetics of newly discovered aromatase inhibitors by a cassette microdosing approach in healthy Japanese subjects.

    Science.gov (United States)

    Kusuhara, Hiroyuki; Takashima, Tadayuki; Fujii, Hisako; Takashima, Tsutomu; Tanaka, Masaaki; Ishii, Akira; Tazawa, Shusaku; Takahashi, Kazuhiro; Takahashi, Kayo; Tokai, Hidekichi; Yano, Tsuneo; Kataoka, Makoto; Inano, Akihiro; Yoshida, Suguru; Hosoya, Takamitsu; Sugiyama, Yuichi; Yamashita, Shinji; Hojo, Taisuke; Watanabe, Yasuyoshi

    2017-12-01

    The aim of the present study is to investigate the pharmacokinetics of our newly developed aromatase inhibitors (cetrozole and TMD-322) in healthy subjects by a cassette microdose strategy. A cocktail of cetrozole and TMD-322 was administered intravenously or orally (1.98 μg for each drug) to six healthy volunteers in a crossover fashion. Anastrozole (1.98 μg) was also included in the oral cocktail. Total body clearance and bioavailability were 12.1 ± 7.1 mL/min/kg and 34.9 ± 32.3% for cetrozole, and 16.8 ± 3.5 mL/min/kg and 18.4 ± 12.2% for TMD-322, respectively. The area under the plasma concentration-time curves of cetrozole and TMD-322 after oral administration was markedly lower than that of anastrozole because of their high hepatic clearance. Two subjects out of six exhibited 4- and 17-fold larger exposure of cetrozole than the others following intravenous and oral administration, respectively. Such variation was not observed for TMD-322 and anastrozole. Extensive metabolism of cetrozole and TMD-322 was observed in the CYP2C19 expression system among the test CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). We report the first clinical investigation of our aromatase inhibitors by a cassette microdose strategy in healthy Japanese subjects. This strategy offers an optional approach for candidate selection as a phase zero study in drug development. Copyright © 2017. Published by Elsevier Ltd.

  18. Clinical significance of Phosphatidyl Inositol Synthase overexpression in oral cancer

    International Nuclear Information System (INIS)

    Kaur, Jatinder; Sawhney, Meenakshi; DattaGupta, Siddartha; Shukla, Nootan K; Srivastava, Anurag; Ralhan, Ranju

    2010-01-01

    We reported increased levels of Phosphatidyl Inositol synthase (PI synthase), (enzyme that catalyses phosphatidyl inositol (PI) synthesis-implicated in intracellular signaling and regulation of cell growth) in smokeless tobacco (ST) exposed oral cell cultures by differential display. This study determined the clinical significance of PI synthase overexpression in oral squamous cell carcinoma (OSCC) and premalignant lesions (leukoplakia), and identified the downstream signaling proteins in PI synthase pathway that are perturbed by smokeless tobacco (ST) exposure. Tissue microarray (TMA) Immunohistochemistry, Western blotting, Confocal laser scan microscopy, RT-PCR were performed to define the expression of PI synthase in clinical samples and in oral cell culture systems. Significant increase in PI synthase immunoreactivity was observed in premalignant lesions and OSCCs as compared to oral normal tissues (p = 0.000). Further, PI synthase expression was significantly associated with de-differentiation of OSCCs, (p = 0.005) and tobacco consumption (p = 0.03, OR = 9.0). Exposure of oral cell systems to smokeless tobacco (ST) in vitro confirmed increase in PI synthase, Phosphatidylinositol 3-kinase (PI3K) and cyclin D1 levels. Collectively, increased PI synthase expression was found to be an early event in oral cancer and a target for smokeless tobacco

  19. Divinyl ether synthase gene and protein, and uses thereof

    Science.gov (United States)

    Howe, Gregg A [East Lansing, MI; Itoh, Aya [Tsuruoka, JP

    2011-09-13

    The present invention relates to divinyl ether synthase genes, proteins, and methods of their use. The present invention encompasses both native and recombinant wild-type forms of the synthase, as well as mutants and variant forms, some of which possess altered characteristics relative to the wild-type synthase. The present invention also relates to methods of using divinyl ether synthase genes and proteins, including in their expression in transgenic organisms and in the production of divinyl ether fatty acids, and to methods of suing divinyl ether fatty acids, including in the protection of plants from pathogens.

  20. Vitis vinifera terpenoid cyclases: functional identification of two sesquiterpene synthase cDNAs encoding (+)-valencene synthase and (-)-germacrene D synthase and expression of mono- and sesquiterpene synthases in grapevine flowers and berries.

    Science.gov (United States)

    Lücker, Joost; Bowen, Pat; Bohlmann, Jörg

    2004-10-01

    Valencene is a volatile sesquiterpene emitted from flowers of grapevine, Vitis vinifera L. A full-length cDNA from the cultivar Gewürztraminer was functionally expressed in Escherichia coli and found to encode valencene synthase (VvVal). The two major products formed by recombinant VvVal enzyme activity with farnesyl diphosphate (FPP) as substrate are (+)-valencene and (-)-7-epi-alpha-selinene. Grapevine valencene synthase is closely related to a second sesquiterpene synthase from this species, (-)-germacrene D synthase (VvGerD). VvVal and VvGerD cDNA probes revealed strong signals in Northern hybridizations with RNA isolated from grapevine flower buds. Transcript levels were lower in open pre-anthesis flowers, flowers after anthesis, or at early onset of fruit development. Similar results were obtained using a third probe, (-)-alpha-terpineol synthase, a monoterpenol synthase. Sesquiterpene synthase and monoterpene synthase transcripts were not detected in the mesocarp and exocarp during early stages of fruit development, but transcripts hybridizing with VvVal appeared during late ripening of the berries. Sesquiterpene synthase transcripts were also detected in young seeds.

  1. How does the estrogen receptor work?

    International Nuclear Information System (INIS)

    Gross, Jennifer M; Yee, Douglas

    2002-01-01

    In breast cancer, interruption of estrogen receptor (ER)-α function is an effective therapeutic strategy. Despite the clinical benefit of interruption of ER-α function, the precise biological action of ER-α in breast tumors is not completely understood. Results of a recent study show that ER-α promotes growth of breast cancer cells by targeting expression of signaling components of the insulin-like growth factor system. Intriguingly, the authors of this study raise the possibility that unliganded ER-α itself may affect gene expression and breast cancer biology, and they suggest a potential mechanism for ER-α to stimulate proliferation in breast cancer

  2. Computational method for discovery of estrogen responsive genes

    DEFF Research Database (Denmark)

    Tang, Suisheng; Tan, Sin Lam; Ramadoss, Suresh Kumar

    2004-01-01

    of human genes are functionally well characterized. It is still unclear how many and which human genes respond to estrogen treatment. We propose a simple, economic, yet effective computational method to predict a subclass of estrogen responsive genes. Our method relies on the similarity of ERE frames...

  3. Toxicogenomics-based in vitro alternatives for estrogenicity testing

    NARCIS (Netherlands)

    Wang, S.

    2013-01-01

    Testing chemicals for their endocrine-disrupting potential, including interference with estrogen receptor signaling, is an important aspect to assess the safety of currently used and newly developed chemicals. The standard test for disruption of normal estrogen function is the in vivo uterotrophic

  4. The Endocrine Role of Estrogens on Human Male Skeleton

    Directory of Open Access Journals (Sweden)

    Vincenzo Rochira

    2015-01-01

    Full Text Available Before the characterization of human and animal models of estrogen deficiency, estrogen action was confined in the context of the female bone. These interesting models uncovered a wide spectrum of unexpected estrogen actions on bone in males, allowing the formulation of an estrogen-centric theory useful to explain how sex steroids act on bone in men. Most of the principal physiological events that take place in the developing and mature male bone are now considered to be under the control of estrogen. Estrogen determines the acceleration of bone elongation at puberty, epiphyseal closure, harmonic skeletal proportions, the achievement of peak bone mass, and the maintenance of bone mass. Furthermore, it seems to crosstalk with androgen even in the determination of bone size, a more androgen-dependent phenomenon. At puberty, epiphyseal closure and growth arrest occur when a critical number of estrogens is reached. The same mechanism based on a critical threshold of serum estradiol seems to operate in men during adulthood for bone mass maintenance via the modulation of bone formation and resorption in men. This threshold should be better identified in-between the ranges of 15 and 25 pg/mL. Future basic and clinical research will optimize strategies for the management of bone diseases related to estrogen deficiency in men.

  5. Comparing predicted estrogen concentrations with measurements in US waters.

    Science.gov (United States)

    The range of exposure rates to the steroidal estrogens estrone (E1), beta-estradiol (E2), estriol (E3), and ethinyl estradiol (EE2) in the aquatic environment was investigated by modeling estrogen introduction via municipal wastewater from sewage plants across the US. Model predi...

  6. Estrogens, MSI and Lynch syndrome-associated tumors

    NARCIS (Netherlands)

    Ferreira, Ana Monteiro; Westers, Helga; Albergaria, Andre; Seruca, Raquel; Hofstra, Robert M. W.

    2009-01-01

    Estrogens play a major role in the biology of hormone-responsive tissues but also in the normal physiology of various non-typical hormone-responsive tissues. In disease, estrogens have been associated with tumor development, in particular with tumors such as breast, endometrium, ovary and prostate.

  7. Fate of estrogens in biological treatment of concentrated black water

    NARCIS (Netherlands)

    Mes, de T.Z.D.

    2007-01-01

    Feminisation of male fish is for a large part due to compounds entering surface waters via wastewater. For domestic wastewater, two natural estrogens, estrone and 17-estradiol and the synthetic estrogen, constituent of the contraceptive pill, are mainly responsible for this effect. These compounds

  8. Chrysanthemyl diphosphate synthase operates in planta as a bifunctional enzyme with chrysanthemol synthase activity

    DEFF Research Database (Denmark)

    Yang, Ting; Gao, Liping; Hu, Hao

    2014-01-01

    Chrysanthemyl diphosphate synthase (CDS) is the first path-way-specific enzyme in the biosynthesis of pyrethrins, the most widely used plant-derived pesticide. CDS catalyzes c1′-2-3 cyclopropanation reactions of two molecules of dimethylallyl diphosphate (DMAPP) to yield chrysanthemyl diphosphate...

  9. Impaired ATP synthase assembly associated with a mutation in the human ATP synthase subunit 6 gene.

    NARCIS (Netherlands)

    Nijtmans, L.G.J.; Henderson, N.S.; Attardi, G.; Holt, L.J.

    2001-01-01

    Mutations in human mitochondrial DNA are a well recognized cause of disease. A mutation at nucleotide position 8993 of human mitochondrial DNA, located within the gene for ATP synthase subunit 6, is associated with the neurological muscle weakness, ataxia, and retinitis pigmentosa (NARP) syndrome.

  10. Temperature Shift Alters DNA Methylation and Histone Modification Patterns in Gonadal Aromatase (cyp19a1 Gene in Species with Temperature-Dependent Sex Determination.

    Directory of Open Access Journals (Sweden)

    Yuiko Matsumoto

    Full Text Available The environment surrounding the embryos has a profound impact on the developmental process and phenotypic outcomes of the organism. In species with temperature-dependent sex determination, gonadal sex is determined by the incubation temperature of the eggs. A mechanistic link between temperature and transcriptional regulation of developmental genes, however, remains elusive. In this study, we examine the changes in DNA methylation and histone modification patterns of the aromatase (cyp19a1 gene in embryonic gonads of red-eared slider turtles (Trachemys scripta subjected to a temperature shift during development. Shifting embryos from a male-producing temperature (MPT to a female-producing temperature (FPT at the beginning of the temperature-sensitive period (TSP resulted in an increase in aromatase mRNA expression while a shift from FPT to MPT resulted in decreased expression. DNA methylation levels at CpG sites in the promoter of the aromatase gene were high (70-90% at the beginning of TSP, but decreased in embryos that were incubated at constant FPT and those shifted from MPT to the FPT. This decrease in methylation in the promoter inversely correlated with the expected increase in aromatase expression at the FPT. The active demethylation under the FPT was especially prominent at the CpG site upstream of the gonad-specific TATA box at the beginning of TSP and spread downstream of the gene including exon1 as the gonad development progressed. In embryos incubated at FPT, the promoter region was also labeled by canonical transcriptional activation markers, H3K4me3 and RNA polymerase II. A transcriptional repression marker, H3K27me3, was observed in temperature-shifted gonads of both temperature groups, but was not maintained throughout the development in either group. Our findings suggest that DNA hypomethylation and H3K4me3 modification at the aromatase promoter may be a primary mechanism that releases a transcriptional block of aromatase to

  11. Long-term use of estrogens: benefit or risk

    Directory of Open Access Journals (Sweden)

    Bogusława Pietrzak

    2015-03-01

    Full Text Available Estrogens are widely used in hormone replacement therapy, gynecology, urogynecology and rarely in dermatology. Non-therapeutic use of estrogens is very widespread. Estrogens are used as contraceptives, which cause a lot of serious side effects. A common clinical problem is skin hyperpigmentation (melasma, occurring mainly in women who take contraceptives with high doses of estrogens. But low doses of estrogens may also cause skin side effects. The mechanism of melasma development is very complicated and not fully understood. It is very likely that UV radiation and genetic background can affect melasma development. Effective therapy should lead to prevention or alleviation of relapses. Treatment should also reduce the area of lesions and improve the appearance of skin. There is no effective and universal pattern of treatment, in which only one substance or method is used. A combination of different methods is used to optimize the therapy. An important role is attributed to prevention, especially protection from UV radiation.

  12. Estrogen, Angiogenesis, Immunity and Cell Metabolism: Solving the Puzzle

    Directory of Open Access Journals (Sweden)

    Annalisa Trenti

    2018-03-01

    Full Text Available Estrogen plays an important role in the regulation of cardiovascular physiology and the immune system by inducing direct effects on multiple cell types including immune and vascular cells. Sex steroid hormones are implicated in cardiovascular protection, including endothelial healing in case of arterial injury and collateral vessel formation in ischemic tissue. Estrogen can exert potent modulation effects at all levels of the innate and adaptive immune systems. Their action is mediated by interaction with classical estrogen receptors (ERs, ERα and ERβ, as well as the more recently identified G-protein coupled receptor 30/G-protein estrogen receptor 1 (GPER1, via both genomic and non-genomic mechanisms. Emerging data from the literature suggest that estrogen deficiency in menopause is associated with an increased potential for an unresolved inflammatory status. In this review, we provide an overview through the puzzle pieces of how 17β-estradiol can influence the cardiovascular and immune systems.

  13. Ontogeny of the mouse estrogen receptor: the pelvic region

    Energy Technology Data Exchange (ETDEWEB)

    Holderegger, C.; Keefer, D.

    1986-10-01

    The appearance of estrogen receptors was examined during the course of fetal and neonatal development in the pelvic region of the mouse; /sup 3/H-diethylstilbestrol (DES) was administered via the maternal circulation to developing mice on days 4, 7, 10, 13, 14, 15, and 17 of gestation or to neonates on the day of birth. Localization of the ligand was monitored autoradiographically. The earliest appearance of estrogen receptors occurred in the mesenchyme around the genital ducts on day 13 of pregnancy. On subsequent days, estrogen-concentrating cells appeared in certain mammary-gland cells, connective-tissue strands, in perichondrium associated with specific developing bones, skin, interstitial tissue of the testis, in a sheath of cells surrounding the colon, and in the urethra. The significance of cells containing estrogen receptors in these locations is discussed in reference to a transplacental action of estrogens and the clinical ramifications of DES.

  14. The Critical Role of Estrogen in Menopausal Osteoporosis

    Directory of Open Access Journals (Sweden)

    Mrinali Sharma

    2017-12-01

    Full Text Available Osteoporosis is a bone disorder, which causes a reduction in the mass and density of bone tissue, and implants a greater possibility for skeletal fractures to occur. This bone disease is especially relevant for women suffering from menopause. Due to this general prevalence, osteoporosis requires continual intervention in the pharmacological and medicinal industry for better treatment alternatives for patients. A focal point for many scientific research studies for osteoporosis has been estrogen. As a hormone, estrogen exhibits a fluctuating capacity in the woman's body, and this has been proclaimed to be a qualifying explanation as to why women develop osteoporosis after menopause. The purpose of this paper is to interpret estrogen's capacity to treat menopausal osteoporosis. Thus, in this article, estrogen’s significance in bone health and different forms, derivatives, and the combinations of estrogen is examined in terms of efficiency in treating osteoporosis. [J Contemp Med 2017; 7(4.000: 418-427

  15. The dynamics of estrogen receptor activity.

    Science.gov (United States)

    Ciana, P; Scarlatti, F; Biserni, A; Ottobrini, L; Brena, A; Lana, A; Zagari, F; Lucignani, G; Maggi, A

    2006-07-20

    In the latest few years, the merging of imaging and animal engineering technologies has led to the generation of innovative tools that provide the opportunity to look into the dynamics of specific molecular events in living animals during their entire life under a completely renewed perspective. These tools will have a profound impact not only on basic research, but also on drug discovery and development allowing to depict the activity of any therapeutic agents in all their designed targets as well as in the organs where they may cause undesired effects. Along this research line, our laboratory has recently described the first animal model reporting the state of activity of estrogen receptors (ERs) in real time: the ERE-luc reporter mouse. The application of optical imaging to the ERE-luc has allowed an unprecedented in depth view of estrogen signaling in all of its target tissues. For example, the analysis of the state of activity of ERs in the physiological setting of the estrous cycle has provided compelling evidence that hormone-independent mechanisms are responsible for activating ERs in non-reproductive organs. This discovery may pave the way to a rational basis for the development of novel, more selective and effective treatments for menopause.

  16. Epigenetic regulation of estrogen-dependent memory

    Science.gov (United States)

    Fortress, Ashley M.; Frick, Karyn M.

    2014-01-01

    Hippocampal memory formation is highly regulated by post-translational histone modifications and DNA methylation. Accordingly, these epigenetic processes play a major role in the effects of modulatory factors, such as sex steroid hormones, on hippocampal memory. Our laboratory recently demonstrated that the ability of the potent estrogen 17β-estradiol (E2) to enhance hippocampal-dependent novel object recognition memory in ovariectomized female mice requires ERK-dependent histone H3 acetylation and DNA methylation in the dorsal hippocampus. Although these data provide valuable insight into the chromatin modifications that mediate the memory-enhancing effects of E2, epigenetic regulation of gene expression is enormously complex. Therefore, more research is needed to fully understand how E2 and other hormones employ epigenetic alterations to shape behavior. This review discusses the ep