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Sample records for aromatase

  1. Molecular characterization of aromatase

    OpenAIRE

    Hong, Yanyan; Li, Hongzhi; Yuan, Yate-Ching; Chen, Shiuan

    2009-01-01

    Aromatase is an estrogen synthetase. Estrogens are female sex hormones involved in the development and growth of breast tumors. It has been of significant interest to elucidate the structure-function relationship of aromatase since its inhibitors have shown great promise in fighting breast cancer. Aromatase belongs to the cytochrome P450 family, and forms an electron-transfer complex with its partner, NADPH-cytochrome P450 reductase. Because of the membrane-bound character and heme-binding in...

  2. Update on Aromatase Inhibitors

    Directory of Open Access Journals (Sweden)

    Seifert-Klauss V

    2015-01-01

    Full Text Available Aromatase inhibitors (AI block the last phase of estrogen production in many types of tissues which express the enzym aromatase, among them muscle, liver, adrenal, brain and fat. The enzyme catalyzes the last step of the biosynthesis of the estrogens, i. e. the aromatisation of testosterone to estradiol and of androstendion to estrone. Aromatase is localized in the membrane of the endoplasmatic reticulum and is also produced in the placenta and the gonads. Mutations in the gene CYP19A1, which codes for aromatase, can lead either to lack or excess of aromatase. Gene polymorphisms also influence the amount of bioavailable estrogen and bone density.br Indications: AI are approved for the treatment of postmenopausal women with hormone receptor positive breast cancer, both in the adjuvant setting as well as after recurrence and in progressive disease. In premenopausal and in perimenopausal women AI cause an increased sensitivity of the ovaries to follicle stimulating hormone (FSH and can thereby lead to a boosted estrogen answer – this effect is particularly pronounced in early perimenopausal women – so that these situations demand a combination with GnRH-analogue if AI treatment is to be initiated. Alternatively, tamoxifene may be used in premenopausal patients, with or without GnRH analogues. Treatment of premenopausal patients with hormone receptor positive breast cancer with aromatase inhibiting therapy alone constitutes an absolute contraindication. Aromatase inhibitors do not lead to estrogen receptor downregulation or block the receptor such as tamoxifene. An exceptional application is the application in reproductive medicine in women who do not have hormone receptor positive breast cancer: because of the higher sensitivity induced by AI-co-therapy, FSH-doses and -costs for assisted reproduction are reduced, and ovarian hyperstimulation syndrome (OHSS may be avoided. For premenopausal diseases which are said to be positively affected by

  3. Genetics Home Reference: aromatase excess syndrome

    Science.gov (United States)

    ... males, the increased aromatase and subsequent conversion of androgens to estrogen are responsible for the gynecomastia and limited bone growth characteristic of aromatase excess syndrome . Increased estrogen in females can cause symptoms ...

  4. Molecular Docking of Aromatase Inhibitors

    Directory of Open Access Journals (Sweden)

    Virapong Prachayasittikul

    2011-04-01

    Full Text Available Aromatase is an enzyme that plays a critical role in the development of estrogen receptor positive breast cancer. As aromatase catalyzes the aromatization of androstenedione to estrone, a naturally occurring estrogen, it is a promising drug target for therapeutic management. The undesirable effects found in aromatase inhibitors (AIs that are in clinical use necessitate the discovery of novel AIs with higher selectivity, less toxicity and improving potency. In this study, we elucidate the binding mode of all three generations of AI drugs to the crystal structure of aromatase by means of molecular docking. It was demonstrated that the docking protocol could reliably reproduce the interaction of aromatase with its substrate with an RMSD of 1.350 Å. The docking study revealed that polar (D309, T310, S478 and M374, aromatic (F134, F221 and W224 and non-polar (A306, A307, V370, L372 and L477 residues were important for interacting with the AIs. The insights gained from the study herein have great potential for the design of novel AIs.

  5. Genetics Home Reference: aromatase deficiency

    Science.gov (United States)

    ... regulating bone growth and blood sugar levels. During fetal development, aromatase converts androgens to estrogens in the placenta, ... link between the mother's blood supply and the fetus. This conversion in the ... sexual development in female fetuses. After birth, the conversion of ...

  6. Natural Products as Aromatase Inhibitors

    OpenAIRE

    Balunas, Marcy J.; Su, Bin; Brueggemeier, Robert W.; Kinghorn, A. Douglas

    2008-01-01

    With the clinical success of several synthetic aromatase inhibitors (AIs) in the treatment of postmenopausal estrogen receptor-positive breast cancer, researchers have also been investigating also the potential of natural products as AIs. Natural products from terrestrial and marine organisms provide a chemically diverse array of compounds not always available through current synthetic chemistry techniques. Natural products that have been used traditionally for nutritional or medicinal purpos...

  7. Aromatase inhibitors in the treatment of endometriosis.

    Science.gov (United States)

    Słopień, Radosław; Męczekalski, Błażej

    2016-03-01

    Endometriosis is a chronic inflammatory condition in which foci of endometrial tissue grow outside of the uterine cavity. Endometriosis was estimated to affect 176 million women of childbearing potential all over the world in 2010. The presence of extrauterine endometrial tissue is associated with pain and infertility. Typical symptoms of endometriosis include dysmenorrhoea, dyspareunia, heavy menstrual periods (menorrhagia), pelvic pain that is not related to menstrual cycles, dysuria, and chronic fatigue. Medical treatments for endometriosis include combined oral contraceptive pills, danazol, gestrinone, medroxyprogesterone acetate, and gonadotropin-releasing hormone agonists (aGnRHs). A new class of medications called aromatase inhibitors has been identified in recent years as potential therapeutic agents for endometriosis. This article provides general information about aromatase inhibitors, their use in gynaecology, and their adverse effects. In particular, the paper discusses the use of aromatase inhibitors in the treatment of endometriosis in postmenopausal women. Unlike oral contraceptives, gestagens, aGnRHs, and danazol, which suppress ovarian oestrogen synthesis, aromatase inhibitors inhibit mainly extra-ovarian synthesis of oestrogens. Therefore, the use of aromatase inhibitors seems to be particularly relevant in older patients, as most of the body's oestrogen is produced outside the ovaries after menopause. The paper discusses also the use of aromatase inhibitors in the treatment of pain associated with endometriosis and infertility caused by endometriosis. PMID:27095958

  8. Aromatase inhibitors in the treatment of endometriosis

    Science.gov (United States)

    Męczekalski, Błażej

    2016-01-01

    Endometriosis is a chronic inflammatory condition in which foci of endometrial tissue grow outside of the uterine cavity. Endometriosis was estimated to affect 176 million women of childbearing potential all over the world in 2010. The presence of extrauterine endometrial tissue is associated with pain and infertility. Typical symptoms of endometriosis include dysmenorrhoea, dyspareunia, heavy menstrual periods (menorrhagia), pelvic pain that is not related to menstrual cycles, dysuria, and chronic fatigue. Medical treatments for endometriosis include combined oral contraceptive pills, danazol, gestrinone, medroxyprogesterone acetate, and gonadotropin-releasing hormone agonists (aGnRHs). A new class of medications called aromatase inhibitors has been identified in recent years as potential therapeutic agents for endometriosis. This article provides general information about aromatase inhibitors, their use in gynaecology, and their adverse effects. In particular, the paper discusses the use of aromatase inhibitors in the treatment of endometriosis in postmenopausal women. Unlike oral contraceptives, gestagens, aGnRHs, and danazol, which suppress ovarian oestrogen synthesis, aromatase inhibitors inhibit mainly extra-ovarian synthesis of oestrogens. Therefore, the use of aromatase inhibitors seems to be particularly relevant in older patients, as most of the body's oestrogen is produced outside the ovaries after menopause. The paper discusses also the use of aromatase inhibitors in the treatment of pain associated with endometriosis and infertility caused by endometriosis. PMID:27095958

  9. Aromatase inhibitors in men: effects and therapeutic options

    Directory of Open Access Journals (Sweden)

    de Jong Frank H

    2011-06-01

    Full Text Available Abstract Aromatase inhibitors effectively delay epiphysial maturation in boys and improve testosterone levels in adult men Therefore, aromatase inhibitors may be used to increase adult height in boys with gonadotropin-independent precocious puberty, idiopathic short stature and constitutional delay of puberty. Long-term efficacy and safety of the use of aromatase inhibitors has not yet been established in males, however, and their routine use is therefore not yet recommended.

  10. Developmental regulation of aromatase activity in the rat hypothalamus

    Energy Technology Data Exchange (ETDEWEB)

    Lephart, E.D.

    1989-01-01

    The brain of all mammalian species studied thus far contain an enzymatic activity (aromatase) that catalyzes the conversion of androgens to estrogens. The activity is highest during prenatal development and contributes to the establishment of sex differences which determine adult gonadotropin secretion patterns and reproductive behavior. The studies presented in this dissertation represent a systematic effort to elucidate the mechanism(s) that control the initiation of and contribute to maintaining rat hypothalamic aromatase activity during pre- and postnatal development. Aromatase enzyme activity was measured by the {sup 3}H{sub 2}O release assay or by traditional estrogen product isolation. Brain aromatase mRNA was detected by hybridization to a cDNA encoding rat aromatase cytochrome P-450. In both males and females the time of puberty was associated with a decline in hypothalamic aromatase activity. This decline may represent a factor underlying the peri-pubertal decrease in the sensitivity to gonadal steroid feedback that accompanies completion of puberty. The results also indicate that androgens regulate brain aromatase levels during both the prepubertal and peri-pubertal stages of sexual development and that this regulation is transiently lost in young adults. Utilizing a hypothalamic organotypic culture system, aromatase activity in vitro was maintained for as long as two days. The results of studies of a variety of hormonal and metabolic regulators suggest that prenatal aromatase activity is regulated by factor(s) that function independently from the classical cyclic AMP and protein kinase C trans-membrane signaling pathways.

  11. Aromatase inhibitors and anti-synthetase syndrome.

    Science.gov (United States)

    Mascella, Fabio; Gianni, Lorenzo; Affatato, Alessandra; Fantini, Manuela

    2016-09-01

    Adjuvant therapy in postmenopausal women with endocrine-responsive breast cancer (BC) is actually centered on the use of anti-aromatase inhibitors (AI). Several reports, however, are emerging in literature associating the use of this drugs to rheumatic disorders. This case report describes the first case of anti-synthetase syndrome diagnosis after treatment with anti-estrogen agents in a patient with pre-existing rheumatoid arthritis. PMID:27225465

  12. Melatonin modulates aromatase activity and expression in endothelial cells.

    Science.gov (United States)

    Alvarez-García, Virginia; González, Alicia; Martínez-Campa, Carlos; Alonso-González, Carolina; Cos, Samuel

    2013-05-01

    Melatonin is known to suppress the development of endocrine-responsive breast cancers by interacting with the estrogen signaling pathways. Paracrine interactions between malignant epithelial cells and proximal stromal cells are responsible for local estrogen biosynthesis. In human breast cancer cells and peritumoral adipose tissue, melatonin downregulates aromatase, which transforms androgens into estrogens. The presence of aromatase on endothelial cells indicates that endothelial cells may contribute to tumor growth by producing estrogens. Since human umbilical vein endothelial cells (HUVECs) express both aromatase and melatonin receptors, the aim of the present study was to evaluate the ability of melatonin to regulate the activity and expression of aromatase on endothelial cells, thus, modulating local estrogen biosynthesis. In the present study, we demonstrated that melatonin inhibits the growth of HUVECs and reduces the local biosynthesis of estrogens through the downregulation of aromatase. These results are supported by three lines of evidence. Firstly, 1 mM of melatonin counteracted the testosterone-induced cell proliferation of HUVECs, which is dependent on the local biosynthesis of estrogens from testosterone by the aromatase activity of the cells. Secondly, we found that 1 mM of melatonin reduced the aromatase activity of HUVECs. Finally, by real‑time RT-PCR, we demonstrated that melatonin significantly downregulated the expression of aromatase as well as its endothelial-specific aromatase promoter region I.7. We conclude that melatonin inhibits aromatase activity and expression in HUVECs by regulating gene expression of specific aromatase promoter regions, thereby reducing the local production of estrogens. PMID:23450505

  13. Origin of aromatase inhibitory activity via proteochemometric modeling.

    Science.gov (United States)

    Simeon, Saw; Spjuth, Ola; Lapins, Maris; Nabu, Sunanta; Anuwongcharoen, Nuttapat; Prachayasittikul, Virapong; Wikberg, Jarl E S; Nantasenamat, Chanin

    2016-01-01

    Aromatase, the rate-limiting enzyme that catalyzes the conversion of androgen to estrogen, plays an essential role in the development of estrogen-dependent breast cancer. Side effects due to aromatase inhibitors (AIs) necessitate the pursuit of novel inhibitor candidates with high selectivity, lower toxicity and increased potency. Designing a novel therapeutic agent against aromatase could be achieved computationally by means of ligand-based and structure-based methods. For over a decade, we have utilized both approaches to design potential AIs for which quantitative structure-activity relationships and molecular docking were used to explore inhibitory mechanisms of AIs towards aromatase. However, such approaches do not consider the effects that aromatase variants have on different AIs. In this study, proteochemometrics modeling was applied to analyze the interaction space between AIs and aromatase variants as a function of their substructural and amino acid features. Good predictive performance was achieved, as rigorously verified by 10-fold cross-validation, external validation, leave-one-compound-out cross-validation, leave-one-protein-out cross-validation and Y-scrambling tests. The investigations presented herein provide important insights into the mechanisms of aromatase inhibitory activity that could aid in the design of novel potent AIs as breast cancer therapeutic agents.

  14. 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 ...... 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.......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...

  15. Neuroinflammation induces glial aromatase expression in the uninjured songbird brain

    Directory of Open Access Journals (Sweden)

    Saldanha Colin J

    2011-07-01

    Full Text Available Abstract Background Estrogens from peripheral sources as well as central aromatization are neuroprotective in the vertebrate brain. Under normal conditions, aromatase is only expressed in neurons, however following anoxic/ischemic or mechanical brain injury; aromatase is also found in astroglia. This increased glial aromatization and the consequent estrogen synthesis is neuroprotective and may promote neuronal survival and repair. While the effects of estradiol on neuroprotection are well studied, what induces glial aromatase expression remains unknown. Methods Adult male zebra finches (Taeniopygia guttata were given a penetrating injury to the entopallium. At several timepoints later, expression of aromatase, IL-1β-like, and IL-6-like were examined using immunohisotchemistry. A second set of zebra birds were exposed to phytohemagglutinin (PHA, an inflammatory agent, directly on the dorsal surface of the telencephalon without creating a penetrating injury. Expression of aromatase, IL-1β-like, and IL-6-like were examined using both quantitative real-time polymerase chain reaction to examine mRNA expression and immunohistochemistry to determine cellular expression. Statistical significance was determined using t-test or one-way analysis of variance followed by the Tukey Kramers post hoc test. Results Following injury in the zebra finch brain, cytokine expression occurs prior to aromatase expression. This temporal pattern suggests that cytokines may induce aromatase expression in the damaged zebra finch brain. Furthermore, evoking a neuroinflammatory response characterized by an increase in cytokine expression in the uninjured brain is sufficient to induce glial aromatase expression. Conclusions These studies are among the first to examine a neuroinflammatory response in the songbird brain following mechanical brain injury and to describe a novel neuroimmune signal to initiate aromatase expression in glia.

  16. Committee Opinion No. 663: Aromatase Inhibitors in Gynecologic Practice.

    Science.gov (United States)

    2016-06-01

    Aromatase inhibitors have been used for the treatment of breast cancer, ovulation induction, endometriosis, and other estrogen-modulated conditions. For women with breast cancer, bone mineral density screening is recommended with long-term aromatase inhibitor use because of risk of osteoporosis due to estrogen deficiency. Based on long-term adverse effects and complication safety data, when compared with tamoxifen, aromatase inhibitors are associated with a reduced incidence of thrombosis, endometrial cancer, and vaginal bleeding. For women with polycystic ovary syndrome and a body mass index greater than 30, letrozole should be considered as first-line therapy for ovulation induction because of the increased live birth rate compared with clomiphene citrate. Lifestyle changes that result in weight loss should be strongly encouraged. Aromatase inhibitors are a promising therapeutic option that may be helpful for the management of endometriosis-associated pain in combination therapy with progestins. PMID:27214191

  17. Committee Opinion No. 663 Summary: Aromatase Inhibitors in Gynecologic Practice.

    Science.gov (United States)

    2016-06-01

    Aromatase inhibitors have been used for the treatment of breast cancer, ovulation induction, endometriosis, and other estrogen-modulated conditions. For women with breast cancer, bone mineral density screening is recommended with long-term aromatase inhibitor use because of risk of osteoporosis due to estrogen deficiency. Based on long-term adverse effects and complication safety data, when compared with tamoxifen, aromatase inhibitors are associated with a reduced incidence of thrombosis, endometrial cancer, and vaginal bleeding. For women with polycystic ovary syndrome and a body mass index greater than 30, letrozole should be considered as first-line therapy for ovulation induction because of the increased live birth rate compared with clomiphene citrate. Lifestyle changes that result in weight loss should be strongly encouraged. Aromatase inhibitors are a promising therapeutic option that may be helpful for the management of endometriosis-associated pain in combination therapy with progestins. PMID:27214185

  18. Aromatase inhibitor strategies in metastatic breast cancer

    Directory of Open Access Journals (Sweden)

    Heather L McArthur

    2009-07-01

    Full Text Available Heather L McArthur, Patrick G MorrisBreast Cancer Medicine Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USAAbstract: Despite ongoing therapeutic innovations, metastatic breast cancer (MBC remains a treatable but incurable disease. In the developed world, a diagnosis of MBC without a preceding diagnosis of early stage disease is a rare event. However, approximately one-third of women with early stage breast cancer ultimately experience a distant recurrence. Because the majority of breast cancers express estrogen and/or progesterone receptors and are accordingly considered hormone-sensitive, therapeutic strategies that interfere with hormone-mediated tumorigenesis have been a cornerstone of the breast cancer management paradigm for decades. Historically, the selective estrogen receptor modulator tamoxifen has been the most extensively studied and widely used hormone maneuver in breast cancer. However, a recent therapeutic innovation, namely the successful development of third-generation aromatase inhibitors (AIs, has had a dramatic impact on the treatment paradigm for women with hormone-sensitive MBC. Because of the demonstrated efficacy in postmenopausal breast cancer patients, the generally favorable side-effect profile, and the convenience of oral administration, AIs are now in widespread clinical use. Currently, there are three clinically available third-generation AIs: two reversible, nonsteroidal AIs, letrozole and anastrozole; and one irreversible, steroidal AI, exemestane. All three agents are at least as efficacious as tamoxifen as monotherapy for postmenopausal women with hormone-sensitive MBC. Current clinical research aims to improve upon existing strategies by evaluating AIs in combination with systemic chemotherapy regimens and/or novel targeted agents. It is hoped that these therapeutic innovations will lead to ongoing improvements in quality of life parameters and ideally survival for women

  19. Aromatase inhibitors and antiepileptic drugs: a computational systems biology analysis

    Directory of Open Access Journals (Sweden)

    Mustata Gabriela

    2011-06-01

    Full Text Available Abstract Background The present study compares antiepileptic drugs and aromatase (CYP19 inhibitors for chemical and structural similarity. Human aromatase is well known as an important pharmacological target in anti-breast cancer therapy, but recent research demonstrates its role in epileptic seizures, as well. The current antiepileptic treatment methods cause severe side effects that endanger patient health and often preclude continued use. As a result, less toxic and more tolerable antiepileptic drugs (AEDs are needed, especially since every individual responds differently to given treatment options. Methods Through a pharmacophore search, this study shows that a model previously designed to search for new classes of aromatase inhibitors is able to identify antiepileptic drugs from the set of drugs approved by the Food and Drug Administration. Chemical and structural similarity analyses were performed using five potent AIs, and these studies returned a set of AEDs that the model identifies as hits. Results The pharmacophore model returned 73% (19 out of 26 of the drugs used specifically to treat epilepsy and approximately 82% (51 out of 62 of the compounds with anticonvulsant properties. Therefore, this study supports the possibility of identifying AEDs with a pharmacophore model that had originally been designed to identify new classes of aromatase inhibitors. Potential candidates for anticonvulsant therapy identified in this manner are also reported. Additionally, the chemical and structural similarity between antiepileptic compounds and aromatase inhibitors is proved using similarity analyses. Conclusions This study demonstrates that a pharmacophore search using a model based on aromatase inhibition and the enzyme's structural features can be used to screen for new candidates for antiepileptic therapy. In fact, potent aromatase inhibitors and current antiepileptic compounds display significant - over 70% - chemical and structural similarity

  20. Cytochrome P450 aromatase expression in human seminoma

    OpenAIRE

    Montanaro Daniela; Aquila Saveria; Romeo Francesco; Rago Vittoria; Andò Sebastiano; Carpino Amalia

    2005-01-01

    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 ...

  1. Medial Amygdalar Aromatase Neurons Regulate Aggression in Both Sexes

    Directory of Open Access Journals (Sweden)

    Elizabeth K. Unger

    2015-02-01

    Full Text Available Aromatase-expressing neuroendocrine neurons in the vertebrate male brain synthesize estradiol from circulating testosterone. This locally produced estradiol controls neural circuits underlying courtship vocalization, mating, aggression, and territory marking in male mice. How aromatase-expressing neuronal populations control these diverse estrogen-dependent male behaviors is poorly understood, and the function, if any, of aromatase-expressing neurons in females is unclear. Using targeted genetic approaches, we show that aromatase-expressing neurons within the male posterodorsal medial amygdala (MeApd regulate components of aggression, but not other estrogen-dependent male-typical behaviors. Remarkably, aromatase-expressing MeApd neurons in females are specifically required for components of maternal aggression, which we show is distinct from intermale aggression in pattern and execution. Thus, aromatase-expressing MeApd neurons control distinct forms of aggression in the two sexes. Moreover, our findings indicate that complex social behaviors are separable in a modular manner at the level of genetically identified neuronal populations.

  2. Metformin Reverses Development of Pulmonary Hypertension via Aromatase Inhibition.

    Science.gov (United States)

    Dean, Afshan; Nilsen, Margaret; Loughlin, Lynn; Salt, Ian P; MacLean, Margaret R

    2016-08-01

    Females are more susceptible to pulmonary arterial hypertension than males, although the reasons remain unclear. The hypoglycemic drug, metformin, is reported to have multiple actions, including the inhibition of aromatase and stimulation of AMP-activated protein kinase. Inhibition of aromatase using anastrazole is protective in experimental pulmonary hypertension but whether metformin attenuates pulmonary hypertension through this mechanism remains unknown. We investigated whether metformin affected aromatase activity and if it could reduce the development of pulmonary hypertension in the sugen 5416/hypoxic rat model. We also investigated its influence on proliferation in human pulmonary arterial smooth muscle cells. Metformin reversed right ventricular systolic pressure, right ventricular hypertrophy, and decreased pulmonary vascular remodeling in the rat. Furthermore, metformin increased rat lung AMP-activated protein kinase signaling, decreased lung and circulating estrogen levels, levels of aromatase, the estrogen metabolizing enzyme; cytochrome P450 1B1 and its transcription factor; the aryl hydrocarbon receptor. In human pulmonary arterial smooth muscle cells, metformin decreased proliferation and decreased estrogen synthesis by decreasing aromatase activity through the PII promoter site of Cyp19a1 Thus, we report for the first time that metformin can reverse pulmonary hypertension through inhibition of aromatase and estrogen synthesis in a manner likely to be mediated by AMP-activated protein kinase. PMID:27296990

  3. Motion and flexibility in human cytochrome p450 aromatase.

    Directory of Open Access Journals (Sweden)

    Wenhua Jiang

    Full Text Available The crystal structures of human placental aromatase in complex with the substrate androstenedione and exemestane have revealed an androgen-specific active site and the structural basis for higher order organization. However, X-ray structures do not provide accounts of movements due to short-range fluctuations, ligand binding and protein-protein association. In this work, we conduct normal mode analysis (NMA revealing the intrinsic fluctuations of aromatase, deduce the internal modes in membrane-free and membrane-integrated monomers as well as the intermolecular modes in oligomers, and propose a quaternary organization for the endoplasmic reticulum (ER membrane integration. Dynamics of the crystallographic oligomers from NMA is found to be in agreement with the isotropic thermal factors from the X-ray analysis. Calculations of the root mean square fluctuations of the C-alpha atoms from their equilibrium positions confirm that the rigid-core structure of aromatase is intrinsic regardless of the changes in steroid binding interactions, and that aromatase self-association does not deteriorate the rigidity of the catalytic cleft. Furthermore, NMA on membrane-integrated aromatase shows that the internal modes in all likelihood contribute to breathing of the active site access channel. The collective intermolecular hinge bending and twisting modes provide the flexibility in the quaternary association necessary for membrane integration of the aromatase oligomers. Taken together, fluctuations of the active site, the access channel, and the heme-proximal cavity, and a dynamic quaternary organization could all be essential components of the functional aromatase in its role as an ER membrane-embedded steroidogenic enzyme.

  4. Aromatase inhibitors in stimulated IVF cycles

    Directory of Open Access Journals (Sweden)

    Tournaye Herman

    2011-06-01

    Full Text Available Abstract 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 available regarding their efficacy in IVF stimulated cycles. Current available evidence support that letrozole may have a promising role in stimulated IVF cycles, either when administered during the follicular phase for ovarian stimulation. Especially for women with poor ovarian response, letrozole appears to have the potential to increase clinical pregnancy rates when combined with gonadotropins, whereas at the same time reduces the total gonadotropin dose required for ovarian stimulation. However, given that in all of the trials letrozole has been administered in GnRH antagonist cycles, it is intriguing to test in the future how it may perform when used in GnRH agonist cycles. Finally administration of letrozole during luteal phase in IVF cycles offers another treatment modality for patients at high risk for OHSS taking into account that it drastically reduces estradiol levels

  5. Aromatase immunolocalization in human ductuli efferentes and proximal ductus epididymis.

    Science.gov (United States)

    Carpino, A; Romeo, F; Rago, V

    2004-03-01

    Abstract Cytochrome P450 aromatase is a terminal enzyme that catalyses the conversion of androgens into oestrogens. This study investigated the immunohistochemical localization of aromatase in human efferent ductules and proximal ductus epididymis using a mouse anti-human monoclonal P450arom IgG as primary antibody and a goat anti-mouse biotinylated IgG as secondary antibody. A strong immunoreaction was observed in the epithelial cell cytoplasm of both ductuli efferentes and proximal ductus epididymis, whereas the smooth muscle cells were immunonegative in the two regions. The results show, for the first time in humans, that epithelial cells of ductuli efferentes and proximal caput epididymis express aromatase, suggesting that locally produced oestrogens may have a role in epididymal function. PMID:15032911

  6. 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 ...... with valproate and phenobarbital. When adding carbamazepine to a range of valproate concentrations no additional inhibition was seen. The data for some of the AEDs show that side effects on steroid synthesis in humans due to inhibition of aromatase should be considered....

  7. Potential utility of natural products as regulators of breast cancer-associated aromatase promoters

    Directory of Open Access Journals (Sweden)

    Walker Larry A

    2011-06-01

    Full Text Available Abstract Aromatase, the key enzyme in estrogen biosynthesis, converts androstenedione to estrone and testosterone to estradiol. The enzyme is expressed in various tissues such as ovary, placenta, bone, brain, skin, and adipose tissue. Aromatase enzyme is encoded by a single gene CYP 19A1 and its expression is controlled by tissue-specific promoters. Aromatase mRNA is primarily transcribed from promoter I.4 in normal breast tissue and physiological levels of aromatase are found in breast adipose stromal fibroblasts. Under the conditions of breast cancer, as a result of the activation of a distinct set of aromatase promoters (I.3, II, and I.7 aromatase expression is enhanced leading to local overproduction of estrogen that promotes breast cancer. Aromatase is considered as a potential target for endocrine treatment of breast cancer but due to nonspecific reduction of aromatase activity in other tissues, aromatase inhibitors (AIs are associated with undesirable side effects such as bone loss, and abnormal lipid metabolism. Inhibition of aromatase expression by inactivating breast tumor-specific aromatase promoters can selectively block estrogen production at the tumor site. Although several synthetic chemical compounds and nuclear receptor ligands are known to inhibit the activity of the tumor-specific aromatase promoters, further development of more specific and efficacious drugs without adverse effects is still warranted. Plants are rich in chemopreventive agents that have a great potential to be used in chemotherapy for hormone dependent breast cancer which could serve as a source for natural AIs. In this brief review, we summarize the studies on phytochemicals such as biochanin A, genistein, quercetin, isoliquiritigenin, resveratrol, and grape seed extracts related to their effect on the activation of breast cancer-associated aromatase promoters and discuss their aromatase inhibitory potential to be used as safer chemotherapeutic agents for

  8. Aromatase inhibitors for subfertile women with polycystic ovary syndrome (Review)

    NARCIS (Netherlands)

    Franik, S.; Kremer, J.A.M.; Nelen, W.L.D.M.; Farquhar, C.

    2014-01-01

    BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea). It affects about 4% to 8% of women worldwide and often leads to anovulatory subfertility. Aromatase inhibitors (AIs) are a novel class of drugs that wer

  9. 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...

  10. Aromatase, estrogen receptors and brain development in fish and amphibians.

    Science.gov (United States)

    Coumailleau, Pascal; Pellegrini, Elisabeth; Adrio, Fátima; Diotel, Nicolas; Cano-Nicolau, Joel; Nasri, Ahmed; Vaillant, Colette; Kah, Olivier

    2015-02-01

    Estrogens affect brain development of vertebrates, not only by impacting activity and morphology of existing circuits, but also by modulating embryonic and adult neurogenesis. The issue is complex as estrogens can not only originate from peripheral tissues, but also be locally produced within the brain itself due to local aromatization of androgens. In this respect, teleost fishes are quite unique because aromatase is expressed exclusively in radial glial cells, which represent pluripotent cells in the brain of all vertebrates. Expression of aromatase in the brain of fish is also strongly stimulated by estrogens and some androgens. This creates a very intriguing positive auto-regulatory loop leading to dramatic aromatase expression in sexually mature fish with elevated levels of circulating steroids. Looking at the effects of estrogens or anti-estrogens in the brain of adult zebrafish showed that estrogens inhibit rather than stimulate cell proliferation and newborn cell migration. The functional meaning of these observations is still unclear, but these data suggest that the brain of fish is experiencing constant remodeling under the influence of circulating steroids and brain-derived neurosteroids, possibly permitting a diversification of sexual strategies, notably hermaphroditism. Recent data in frogs indicate that aromatase expression is limited to neurons and do not concern radial glial cells. Thus, until now, there is no other example of vertebrates in which radial progenitors express aromatase. This raises the question of when and why these new features were gained and what are their adaptive benefits. This article is part of a Special Issue entitled: Nuclear receptors in animal development.

  11. Aromatase inhibitors for subfertile women with polycystic ovary syndrome (Review)

    OpenAIRE

    Franik, S.; Kremer, J.A.M.; Nelen, W.L.D.M.; Farquhar, C

    2014-01-01

    BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea). It affects about 4% to 8% of women worldwide and often leads to anovulatory subfertility. Aromatase inhibitors (AIs) are a novel class of drugs that were introduced for ovulation induction in 2001. Over the last ten years clinical trials have reached differing conclusions as to whether the AI letrozole is at least as effective as the first-line tr...

  12. Selective inhibition of aromatase by a dihydroisocoumarin from Xyris pterygoblephara.

    Science.gov (United States)

    Endringer, Denise C; Guimarães, Keller G; Kondratyuk, Tamara P; Pezzuto, John M; Braga, Fernão C

    2008-06-01

    Aromatase is a well-established target for the chemoprevention of breast cancer. The dihydroisocoumarin (3 R,4 R)-(-)-6-methoxy-1-oxo-3-pentyl-3,4-dihydro-1 H-isochromen-4-yl acetate (1) (IC 50 = 1.6 +/- 0.1 microM), isolated from aerial parts of Xyris pterygoblephara, showed aromatase inhibitory activity. The specificity of 1 was evaluated by inhibition assays with cytochrome P450 enzymes. CYP1A1 was inhibited modestly (IC 50 = 38.0 +/- 2.0 microM), while CYP2C8 and CYP3A4 enzymes were not affected. Dihydroisocoumarin 1 showed weak antiproliferative activity against MCF-7 (IC 50 = 66.9 +/- 2.3 microM) and LNCaP (IC 50 = 57.5 +/- 2.0 microM) cells and was inactive against LU-1 and HepG2 cells in culture. These results demonstrate the potential of dihydroisocoumarin 1 to serve as a selective aromatase inhibitor. PMID:18462007

  13. Cytochrome P450 aromatase expression in human seminoma

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    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.

  14. Combining Computational and Biochemical Studies for a Rationale on the Anti-Aromatase Activity of Natural Polyphenols

    OpenAIRE

    Neves, Marco A. C.; Dinis, Teresa C. P.; Colombo, Giorgio; Melo, M. Luísa Sá e

    2007-01-01

    Aromatase, an enzyme of the cytochrome P450 family, is a very important pharmacological target, particularly for the treatment of breast cancer. The anti-aromatase activity of a set of natural polyphenolic compounds was evaluated in vitro. Strong aromatase inhibitors including flavones, flavanones, resveratrol, and oleuropein, with activities comparable to that of the reference anti-aromatase drug aminoglutethimide, were identified. Through the application of molecular modeling techniques bas...

  15. Synthesis of highly-labeled with tritium steroid hormones and their use for estimation of aromatase activity

    International Nuclear Information System (INIS)

    Highly-labeled steroids - progesterone, estradiol, and androsterone are synthesized. They are used for determination of aromatase activity in different pathologies. It is shown that high activity of aromatase in endometrium in patients with endometrium neoplasms without myome deteriorates disease prognosis. At the same time high aromatase activity in endometrium in patients with endometrium neoplasms with myome has frequently opportune result

  16. Aromatase enzyme expression in acromegaly and its possible relationship with disease prognosis.

    Science.gov (United States)

    Selek, Alev; Cetinarslan, Berrin; Gurbuz, Yesim; Tarkun, Ilhan; Canturk, Zeynep; Cabuk, Burak

    2015-05-01

    The purpose of this study was to evaluate aromatase enzyme expression in growth hormone (GH) secreting adenomas and comparison with prolactinomas, nonfunctional adenomas, and normal pituitary tissues. Also the impact of its expression on clinical and prognostic features was evaluated. 38 acromegaly, 26 prolactinoma, and 31 nonfunctional pituitary adenoma and 11 normal pituitary gland samples from autopsies were included. Aromatase and estrogen receptor-alpha (ERα) were evaluated by Immunohistochemical method; demographic, pre- and postoperative features of the patients were noted. Aromatase was expressed in varying degrees in all cases in study including controls. Aromatase expression in patients with acromegaly was significantly higher than patients with prolactinoma, nonfunctional adenoma, and controls (p = 0.04, p = 0.01 and p acromegaly, aromatase expression was negatively correlated with ER-alpha (p = 0.02, r = -0.34). Also, Ki-67 immunohistochemical results were negatively correlated with aromatase expression (p = 0.03, r = -0.27) while positively correlated with ER expression (p acromegaly. In patients with acromegaly and prolactinoma, aromatase expression was negatively correlated with Ki-67 score, and also it was higher in patients with complete postoperative remission than without remission. Therefore, aromatase expression may be a good prognostic marker predominantly in acromegaly.

  17. 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

    aromatase activity. Furthermore, exposure of the H295R cells to isoflavonoids caused a decrease in testosterone production, and various mixtures of PEs significantly stimulated MCF-7 human breast adenocarcinoma cell growth and induced aromatase activity in JEG-3 choriocarcinoma cells. The estrogenic effect...

  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. 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.

  20. Developing steroidal aromatase inhibitors-an effective armament to win the battle against breast cancer.

    Science.gov (United States)

    Yadav, Mange Ram; Barmade, Mahesh A; Tamboli, Riyaj S; Murumkar, Prashant R

    2015-11-13

    Breast cancer, an emerging disease among the women population, occurs due to overexpression of estrogens. The enzyme aromatase plays a key rate limiting role in the biosynthesis of estrogens. Certain clinical advantages of the use of exemestane, a steroidal aromatase inhibitor over non-steroidal aromatase inhibitors have drawn the attention of researchers for the development of novel steroidal aromatase inhibitors.The current review is a humble attempt to compile the reports by various researchers till date on the synthesis of steroidal aromatase inhibitors. It has been tried to encompass the structural modifications carried out by various researchers in the steroid ring system by taking up the functional group modifications on rings A, B, ring A/B junction, ring-D, ring modifications, bridged derivatives and heterocyclic ring-fused derivatives in a systematic way.

  1. Aromatase inhibitors in the treatment of deep endometriosis

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    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.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    Vinggaard, A M; Hnida, C; Breinholt, V; Larsen, J C

    2000-06-01

    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 range of hormone-mimicking effects. Twenty-two pesticides were tested for their ability to affect CYP19 aromatase activity in human placental microsomes using the classical [(3)H](2)O method. Prochloraz, imazalil, propioconazole, fenarimol, triadimenol, triadimefon (all fungicides), and dicofol (an acaricide) gave rise to a statistically significant inhibition of aromatase activity. The IC(50)s of prochloraz, imazalil, propioconazole fenarimol, triadimenol, and triadimefon were calculated from dose-response curves to be 0.04, 0.34, 6.5, 10, 21 and 32 microM, respectively. The IC(50) of dicofol was greater than 50 microM. The positive control 4-hydroxyandrostendione (1 microM) 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, procymidon, propyzamide, quintozen, tetrachlorvinphos and tetradifon. With the purpose of comparing the results for fenarimol obtained with the microsomal system with data from an intact cell system, an aromatase assay based on JEG-3 cells was established. 4-Hydroxyandrostendione (1 microM) inhibited the aromatase activity in JEG-3 cells by 94%. The IC(50) for fenarimol in this system was 2 microM, slightly lower than that observed in the microsomal system. For the first time, fenarimol has been demonstrated to inhibit aromatase activity in human tissues and, furthermore, propioconazole, triadimefon, 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

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

    Directory of Open Access Journals (Sweden)

    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

  5. Use of Network Inference to Unravel the Mechanisms of Action and Specificity of Aromatase Inhibitors

    Science.gov (United States)

    The vertebrate hypothalamus-pituitary-gonadal (HPG) axis is controlled through various feedback mechanisms in order to maintain a dynamic homeostasis during changing environmental conditions, including exposure to chemical stressors. In this study, three aromatase inhibitors, fad...

  6. 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.

  7. Effects of aromatase inhibition on spatial working memory and hippocampal astrocyte numbers

    OpenAIRE

    José I. Arias; Héctor González-Pardo; Nélida M. Conejo; Jorge L. Arias

    2012-01-01

    Sex hormones are known to induce the sexual differentiation of the brain during early development in mammals. Testosterone secreted by males already during gestation is classically believed to contribute to brain and behavioural sexual differentiation thanks to its conversion to estradiol by the enzyme aromatase. However, there is evidence suggesting that aromatase inhibition may also impair cognitive functions in women receiving hormonal treatment for breast cancer. In order to evaluate the ...

  8. A feasibility study of a Nordic walking intervention for women experiencing aromatase inhibitor associated arthralgia

    OpenAIRE

    Fields, Jo

    2015-01-01

    Background: Women taking AIs (Aromatase Inhibitors) as treatment for breast cancer commonly experience joint pain and stiffness (aromatase inhibitor associated arthralgia; AIAA) which can lead to early discontinuation of treatment. Exercise is often recommended and there is preliminary evidence it might prove helpful. Nordic Walking is a popular form of exercise in women with breast cancer, and based on a biopsychosocial model, could provide additional benefits over normal walking alone. Ther...

  9. Bilateral De Quervain Syndrome after Aromatase Inhibitor Administration: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Konstantinos Papadimitriou

    2012-01-01

    Full Text Available Aromatase inhibitors are widely used as one of the main treatment options of both early and advanced hormone receptor-positive breast cancer in postmenopausal women. Unfortunately, musculoskeletal symptoms are often presented in patients treated with aromatase inhibitors (AIs, and, although the pathogenesis is unknown, postulated mechanisms have been described. Herein, to our knowledge, we present the first report of bilateral De Quervain syndrome related with AIs therapy with a review of the relevant literature.

  10. 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

  11. Constitutional genetic variation at the human aromatase gene (Cyp19) and breast cancer risk

    OpenAIRE

    Siegelmann-Danieli, N; Buetow, K H

    1999-01-01

    The activity of the aromatase enzyme, which converts androgens into oestrogens and has a major role in regulating oestrogen levels in the breast, is thought to be a contributing factor in the development of breast cancer. We undertook this study to assess the role of constitutional genetic variation in the human aromatase gene (Cyp19) in the development of this disease. Our genotyping of 348 cases with breast cancer and 145 controls (all Caucasian women) for a published tetranucleotide repeat...

  12. Aromatase expression is linked to estrogenic sensitivity of periurethral muscles in female rabbits.

    Science.gov (United States)

    de los Ángeles Carrasco-Ruiz, María; García-Villamar, Verónica; López-García, Kenia; Sánchez-García, Octavio; Pacheco, Pablo; Cuevas, Estela; Martínez-Gómez, Margarita; Castelán, Francisco

    2015-06-01

    Beyond its role in the conversion of androgens to estrogens, the expression of aromatase could influence on the estrogenic signalling in targeted tissues. Considering the well-defined biochemical and physiological differences between the pubococcygeus (Pcm) and bulbospongiosus (Bsm) muscles in female rabbits, it is presently hypothesized that the aromatase expression is differentially linked to the estrogen sensitivity of each muscle. To this end, serum estradiol levels and the aromatase expression, presence of ERα and ERβ and morphometry were evaluated in the Pcm and Bsm of female rabbits allocated in control, ovariectomized (OVX) and OVX treated with estradiol benzoate (OVX + EB) groups. Aromatase expression was high in the Pcm. Independently to serum estradiol, ovariectomy increased aromatase expression in the Pcm while decreased it in the Bsm. The EB treatment avoided the effect of ovariectomy only in the Pcm. The number of immunoreactive nuclei anti-ERα and anti-ERβ was high in the Pcm of OVX and OVX + EB rabbits, while those in the Bsm remained unchanged. The number of peripheral nuclei per fibre and the cross-sectional area-to-myonucleus ratio were modified only in the Pcm. Our findings support aromatase expression in the Pcm, and Bsm of rabbits is differentially linked to estrogenic sensitivity of each muscle.

  13. 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.

  14. P450-aromatase activity and expression in human testicular tissues with severe spermatogenic failure.

    Science.gov (United States)

    Lardone, M C; Castillo, P; Valdevenito, R; Ebensperger, M; Ronco, A M; Pommer, R; Piottante, A; Castro, A

    2010-08-01

    There is evidence that impaired spermatogenesis is associated with an imbalance in the oestradiol/testosterone ratio and with Leydig cell (LC) dysfunction. In testis, P450-aromatase, encoded by CYP19, is responsible for the conversion of testosterone to oestradiol. The aims of this study were to quantify CYP19 mRNA expression, aromatase activity and protein localization, and to measure the oestradiol to testosterone ratio in testicular tissues of men with spermatogenic impairment. Twenty-four men with complete Sertoli cell-only syndrome (SCOS), 14 with focal SCOS, 14 with maturation arrest (MA), 8 with mixed atrophy and 30 controls with normal spermatogenesis were subjected to testicular biopsy. All subjects underwent a physical examination, cytogenetic and serum hormonal studies. Testicular CYP19 mRNA was quantified using real time RT-PCR. Testicular aromatase activity was measured using the (3)H(2)0 assay and protein expression was evaluated using immunohistochemistry. In cases, serum testosterone and oestradiol were normal, but the testosterone/LH ratio was lower compared with controls (p < 0.05). Aromatase was localized in the Leydig, Sertoli and germ cells of all tissues, although stronger intensity was observed in LC. Aromatase mRNA and activity were not altered in cases and correlated positively with LC number (r = 0.516 and r = 0.369; p < 0.008). The intratesticular oestradiol/testosterone ratio was elevated (p = 0.005) in complete SCOS patients compared with controls. In conclusion, testicular aromatase seems to be normal in most subjects with impaired spermatogenesis. However, an altered intratesticular oestradiol/testosterone ratio in some patients with complete SCOS suggests that aromatase is increased, which might contribute to Leydig cell dysfunction.

  15. Combined down-regulation by aromatase inhibitor and GnRH-agonist in IVF patients with endometriomas-A pilot study

    DEFF Research Database (Denmark)

    Lossl, Kristine; Løssl, Kristine; Loft, Anne;

    2009-01-01

    OBJECTIVE: The key enzyme in the biosynthesis of estradiol, aromatase, has been demonstrated within endometriosis. Combined administration of aromatase inhibitor and GnRH-agonist may efficiently suppress estrogen biosynthesis through a combined pituitary, ovarian, peripheral and "in situ" action...

  16. Purification of human placental aromatase cytochrome P-450 with monoclonal antibody and its characterization

    International Nuclear Information System (INIS)

    A simple and efficient method is described for the purification of microsomal aromatase cytochrome P-450 from human placenta. The enzyme was solubilized with Emulgen 913 and sodium cholate and subjected to chromatography on a column of Sepharose 4B couples with a specific monoclonal antibody, followed by hydroxyapatite column chromatography. The specific cytochrome P-450 content of purified aromatase was 13.1 (12-14.8) nmol/mg of protein. Aromatase assays were carried out with reconstituted systems of bovine liver P-450 reductase and dilauroyl-L-α-phosphatidylcholine with [1β-3H,4-14C]androstenedione as substrate. The total recovery of purified aromatase activity was 32.2%, and P-450 recovery was 17.6%. The very high Km value for 16α-hydroxytestosterone aromatization gives a reasonable indication that estriol is not the directly aromatized product in the fetoplacental unit of human pregnancy. The aromatase P-450 was subjected to SDS-polyacrylamide gel electrophoresis in increasing quantities. Silver stain detection techniques indicated a single band having a molecular mass of 55 kDa with greater than 97% purity. The stability analysis showed a half-life of over 4 years on storage at -80C

  17. 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.

  18. Transgenic Chickens Overexpressing Aromatase Have High Estrogen Levels but Maintain a Predominantly Male Phenotype.

    Science.gov (United States)

    Lambeth, Luke S; Morris, Kirsten R; Wise, Terry G; Cummins, David M; O'Neil, Terri E; Cao, Yu; Sinclair, Andrew H; Doran, Timothy J; Smith, Craig A

    2016-01-01

    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-characterized steroidogenic pathway, which is a multistep 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. Ectopic overexpression of aromatase in male chicken embryos induces gonadal sex reversal, and male embryos treated with estradiol become feminized; however, this is not permanent. To test whether a continuous supply of estrogen in adult chickens could induce stable male to female sex reversal, 2 transgenic male chickens overexpressing aromatase were generated using the Tol2/transposase system. These birds had robust ectopic aromatase expression, which resulted in the production of high serum levels of estradiol. Transgenic males had female-like wattle and comb growth and feathering, but they retained male weights, displayed leg spurs, and developed testes. Despite the small sample size, this data strongly suggests that high levels of circulating estrogen are insufficient to maintain a female gonadal phenotype in adult birds. Previous observations of gynandromorph birds and embryos with mixed sex chimeric gonads have highlighted the role of cell autonomous sex identity in chickens. This might imply that in the study described here, direct genetic effects of the male chromosomes largely prevailed over the hormonal profile of the aromatase transgenic birds. This data therefore support the emerging view of at least partial cell autonomous sex development in birds. However, a larger study will confirm this intriguing observation. PMID:26556534

  19. Sex differences in brain aromatase activity: genomic and non-genomic controls

    Directory of Open Access Journals (Sweden)

    Jacques eBalthazart

    2011-09-01

    Full Text Available Aromatization of testosterone into estradiol in the preoptic area plays a critical role in the activation of male copulation in quail and in many other vertebrate species. Aromatase expression in quail and in other birds is higher than in rodents and other mammals, which has facilitated the study of the controls and functions of this enzyme. Over relatively long time periods (days to months, brain aromatase activity and transcription are markedly (4-6 fold increased by genomic actions of sex steroids. Initial work indicated that the preoptic aromatase activity is higher in males than in females and it was hypothesized that this differential production of estrogen could be a critical factor responsible for the lack of behavioral activation in females. Subsequent studies revealed, however, that this enzymatic sex difference might contribute but is not sufficient to explain the sex difference in behavior. Studies of aromatase activity, immunoreactivity and mRNA concentrations revealed that sex differences observed when measuring enzymatic activity are not necessarily observed when one measures mRNA concentrations. Discrepancies potentially reflect post-translational controls of the enzymatic activity. Aromatase activity in quail brain homogenates is rapidly inhibited by phosphorylation processes. Similar rapid inhibitions occur in hypothalamic explants maintained in vitro and exposed to agents affecting intracellular calcium concentrations or to glutamate agonists. Rapid changes in aromatase activity have also been observed in vivo following sexual interactions or exposure to short-term restraint stress and these rapid changes in estrogen production modulate expression of male sexual behaviors. These data suggest that brain estrogens display most if not all characteristics of neuromodulators if not neurotransmitters. Many questions remain however concerning the mechanisms controlling these rapid changes in estrogen production and their behavioral

  20. Transgenic Chickens Overexpressing Aromatase Have High Estrogen Levels but Maintain a Predominantly Male Phenotype.

    Science.gov (United States)

    Lambeth, Luke S; Morris, Kirsten R; Wise, Terry G; Cummins, David M; O'Neil, Terri E; Cao, Yu; Sinclair, Andrew H; Doran, Timothy J; Smith, Craig A

    2016-01-01

    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-characterized steroidogenic pathway, which is a multistep 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. Ectopic overexpression of aromatase in male chicken embryos induces gonadal sex reversal, and male embryos treated with estradiol become feminized; however, this is not permanent. To test whether a continuous supply of estrogen in adult chickens could induce stable male to female sex reversal, 2 transgenic male chickens overexpressing aromatase were generated using the Tol2/transposase system. These birds had robust ectopic aromatase expression, which resulted in the production of high serum levels of estradiol. Transgenic males had female-like wattle and comb growth and feathering, but they retained male weights, displayed leg spurs, and developed testes. Despite the small sample size, this data strongly suggests that high levels of circulating estrogen are insufficient to maintain a female gonadal phenotype in adult birds. Previous observations of gynandromorph birds and embryos with mixed sex chimeric gonads have highlighted the role of cell autonomous sex identity in chickens. This might imply that in the study described here, direct genetic effects of the male chromosomes largely prevailed over the hormonal profile of the aromatase transgenic birds. This data therefore support the emerging view of at least partial cell autonomous sex development in birds. However, a larger study will confirm this intriguing observation.

  1. 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

  2. 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

    . 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...... assay. Vinclozolin reacted as a potent AR antagonist and dichlorvos as a very weak one. Methomyl, pirimicarb, propamocarb, and iprodion weakly stimulated aromatase activity. Although the potencies of the pesticides to react as hormone agonists or antagonists are low compared to the natural ligands...

  3. 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

    range of hormone-mimicking effects. Twenty-two pesticides were tested for their ability to affect CYP19 aromatase activity in human placental microsomes using the classical [H-3](2)O method. Prochloraz, imazalil, propioconazole, fenarimol, triadimenol, triadimefon tall fungicides), and dicofol tan...... acaricide) gave rise to a statistically significant inhibition of aromatase activity. The IC(50)s of prochloraz, imazalil, propioconazole fenarimol, triadimenol, and triadimefon were calculated from dose-response curves to be 0.04, 0.34, 6.5, 10, 21 and 32 mu M, respectively, The IC50 Of dicofol was greater...

  4. Xanthones from the Botanical Dietary Supplement Mangosteen (Garcinia mangostana) with Aromatase Inhibitory Activity

    OpenAIRE

    Balunas, Marcy J.; Su, Bin; Brueggemeier, Robert W.; Kinghorn, A. Douglas

    2008-01-01

    Twelve xanthone constituents of the botanical dietary supplement, mangosteen (the pericarp of Garcinia mangostina) were screened using a non-cellular, enzyme-based microsomal aromatase inhibition assay. Of these compounds, garcinone D (3), garcinone E (5)α-mangostin (8), and γ-mangostin (9) exhibited dose-dependent inhibitory activity. In a follow-up cell-based assay using SK-BR-3 breast cancer cells that express high levels of aromatase, the most potent of these four xanthones was γ-mangosti...

  5. In situ aromatase expression in primary tumor is associated with estrogen receptor expression but is not predictive of response to endocrine therapy in advanced breast cancer

    DEFF Research Database (Denmark)

    Lykkesfeldt, Anne E; Henriksen, Katrine L; Rasmussen, Birgitte B;

    2009-01-01

    whether in situ carcinoma cell aromatization is the primary source of estrogen production for tumor growth and whether the aromatase expression is predictive of response to endocrine therapy. Due to methodological difficulties in the determination of the aromatase protein, COX-2, an enzyme involved...... of advanced breast cancer. Semi-quantitative immunohistochemical (IHC) analysis was performed for ER, PR, COX-2 and aromatase using Tissue Microarrays (TMAs). Aromatase was also analyzed using whole sections (WS). Kappa analysis was applied to compare association of protein expression levels. Univariate...... TMAs. Expression of COX-2 and aromatase did not predict response to endocrine therapy. Aromatase in combination with high PR expression may select letrozole treated patients with a longer TTP. CONCLUSION: TMAs are not suitable for IHC analysis of in situ aromatase expression and we did not find COX-2...

  6. Molecular simulations of aromatase reveal new insights into the mechanism of ligand binding.

    Science.gov (United States)

    Park, Jiho; Czapla, Luke; Amaro, Rommie E

    2013-08-26

    CYP19A1, also known as aromatase or estrogen synthetase, is the rate-limiting enzyme in the biosynthesis of estrogens from their corresponding androgens. Several clinically used breast cancer therapies target aromatase. In this work, explicitly solvated all-atom molecular dynamics simulations of aromatase with a model of the lipid bilayer and the transmembrane helix are performed. The dynamics of aromatase and the role of titration of an important amino acid residue involved in aromatization of androgens are investigated via two 250-ns long simulations. One simulation treats the protonated form of the catalytic aspartate 309, which appears more consistent with crystallographic data for the active site, while the simulation of the deprotonated form shows some notable conformational shifts. Ensemble-based computational solvent mapping experiments indicate possible novel druggable binding sites that could be utilized by next-generation inhibitors. In addition, the effects of protonation on the ligand positioning and channel dynamics are investigated using geometrical models that estimate the opening width of critical channels. Significant differences in channel dynamics between the protonated and deprotonated trajectories are exhibited, suggesting that the mechanism for substrate and product entry and the aromatization process may be coupled to a "locking" mechanism and channel opening. Our results may be particularly relevant in the design of novel drugs, which may be useful therapeutic treatments of cancers such as those of the breast and prostate. PMID:23927370

  7. A Study to Evaluate Genetic Predictors of Aromatase Inhibitor Musculoskeletal Symptoms (AIMSS) | Division of Cancer Prevention

    Science.gov (United States)

    E1Z11 is a study to determine whether certain genetic information can predict which breast cancer patients will discontinue treatment with AIs due to the development of musculoskeletal symptoms (MSS). Women with stage 1-111 breast cancer who are prescribed the aromatase inhibitor anastrozole as treatment may join. |

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

    Science.gov (United States)

    Biegon, Anat; Alia-Klein, Nelly; Fowler, Joanna S

    2012-01-01

    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 and many effects of nicotine are sexually dimorphic (reviewed by Pogun and Yararbas, 2009). 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.

  9. 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.

  10. Inhibitory Aromatase Effects of Flavonoids from Ginkgo Biloba Extracts on Estrogen Biosynthesis.

    Science.gov (United States)

    Park, Yong Joo; Choo, Wun Hak; Kim, Ha Ryong; Chung, Kyu Hyuck; Oh, Seung Min

    2015-01-01

    Ginkgo biloba extract (GBE) is a popular phytomedicine and has been used for disorders of the central nervous system, cardiovascular, renal, respiratory, and circulatory diseases. Although GBE is a complex mixture of over 300 compounds, its major components are 24% flavonoids and 6% terpene lactones. In this study, we tested the inhibitory effects of the three major flavonoids (kaempferol, quercetin, and isorhamnetin) from GBE, independently and as mixtures, on aromatase activity using JEG-3 cells (human placental cells) and recombinant proteins (human placental microsome). In both systems, kaempferol showed the strongest inhibitory effects among the three flavonoids; the flavanoid mixtures exerted increased inhibitory effects. The results of exon I.1-driven luciferase reporter gene assays supported the increased inhibitory effects of flavonoid mixtures, accompanied by suppression of estrogen biosynthesis. In the RT-PCR analysis, decreased patterns of aromatase promoter I.1 mRNA expressions were observed, which were similar to the aromatase inhibition patterns of flavonoids and their mixtures. The present study demonstrated that three flavonoids synergistically inhibit estrogen biosynthesis through aromatase inhibition, decrease CYP19 mRNA, and induce transcriptional suppression. Our results support the usefulness of flavonoids in adjuvant therapy for breast cancer by reducing estrogen levels with reduced adverse effects due to estrogen depletion. PMID:26434836

  11. 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

  12. Direct Effects, Compensation, and Recovery in Female Fathead Minnows Exposed to a Model Aromatase Inhibitor

    Science.gov (United States)

    The paper reports on the effects of a model aromatase inhibitor, fadrozole, on molecular and biochemical endpoints within the fathead minnow reproductive axis. Unlike previous studies, this work incorporated extensive time-course characterization over the course of an 8 d exposu...

  13. Estrogen receptors α and β and aromatase as independent predictors for prostate cancer outcome

    Science.gov (United States)

    Grindstad, Thea; Skjefstad, Kaja; Andersen, Sigve; Ness, Nora; Nordby, Yngve; Al-Saad, Samer; Fismen, Silje; Donnem, Tom; Khanehkenari, Mehrdad Rakaee; Busund, Lill-Tove; Bremnes, Roy M.; Richardsen, Elin

    2016-01-01

    Androgens are considered important in normal prostate physiology and prostate cancer (PCa) pathogenesis. However, androgen-targeted treatment preventing PCa recurrence is still lacking. This indicates additional mediators contributing to cancer development. We sought to determine the prognostic significance of estrogen receptors, ERα and -β, and the aromatase enzyme in PCa. Tissue microarrays were created from 535 PCa patients treated with radical prostatectomy. Expression of ERα, ERβ and aromatase were evaluated using immunohistochemistry. Representative tumor epithelial (TE) and tumor stromal (TS) areas were investigated separately. Survival analyses were used to evaluate the markers correlation to PCa outcome. In univariate analyses, ERα in TS was associated with delayed time to clinical failure (CF) (p = 0.042) and PCa death (p = 0.019), while ERβ was associated with reduced time to biochemical failure (BF) (p = 0.002). Aromatase in TS and TE was associated with increased time to BF and CF respectively (p = 0.016, p = 0.046). Multivariate analyses supported these observations, indicating an independent prognostic impact of all markers. When stratifying the analysis according to different surgical centers the results were unchanged. In conclusion, significant prognostic roles of ERα, ERβ and aromatase were discovered in the in PCa specimens of our large multicenter cohort. PMID:27610593

  14. The effect of opiates on the activity of human placental aromatase/CYP19.

    Science.gov (United States)

    Zharikova, Olga L; Deshmukh, Sujal V; Kumar, Meena; Vargas, Ricardo; Nanovskaya, Tatiana N; Hankins, Gary D V; Ahmed, Mahmoud S

    2007-01-15

    Aromatase, cytochrome P450 19, is a key enzyme in the biosynthesis of estrogens by the human placenta. It is also the major placental enzyme that metabolizes the opiates L-acetylmethadol (LAAM), methadone, and buprenorphine (BUP). Methadone and BUP are used in treatment of the opiate addict and are competitive inhibitors of testosterone conversion to estradiol (E(2)) and 16alpha-hydroxytestosterone (16-OHT) to estriol (E(3)) by aromatase. The aim of this investigation is to determine the effect of 20 opiates, which can be administered to pregnant patients for therapeutic indications or abused, on E(2) and E(3) formation by placental aromatase. Data obtained indicated that the opiates increased, inhibited, or had no effect on aromatase activity. Their effect on E(3) formation was more pronounced than that on E(2) due to the lower affinity of 16-OHT than testosterone to aromatase. The K(i) values for the opiates that inhibited E(3) formation were sufentanil, 7 +/- 1 microM; LAAM, 13 +/- 8 microM; fentanyl, 25 +/- 5 microM; oxycodone, 92 +/- 22 microM; codeine, 218 +/- 69 microM; (+)-pentazocine, 225 +/- 73 microM. The agonists morphine, heroin, hydromorphone, oxymorphone, hydrocodone, propoxyphene, meperidine, levorphanol, dextrorphan, and (-)-pentazocine and the antagonists naloxone and naltrexone caused an increase in E(3) formation by 124-160% of control but had no effect on E(2) formation. Moreover, oxycodone and codeine did not inhibit E(2) formation and the IC(50) values for fentanyl, sufentanil, and (+)-pentazocine were >1000 microM. It is unlikely that the acute administration of the opiates that inhibit estrogen formation would affect maternal and/or neonatal outcome. However, the effects of abusing any of them during the entire pregnancy are unclear at this time. PMID:17118343

  15. Product of aromatase activity in intact LNCaP and MCF-7 human cancer cells.

    Science.gov (United States)

    Castagnetta, L A; Granata, O M; Bellavia, V; Amodio, R; Scaccianoce, E; Notarbartolo, M; Follari, M R; Miceli, M D; Carruba, G

    1997-04-01

    We investigated conversion rates of androgens to estrogens in cultured, hormone-responsive prostate (LNCaP) and breast (MCF-7) human cancer cells. For this purpose, we adopted an intact cell analysis, whereby cells were incubated for different incubation times in the presence of close-to-physiological (1 nM) or supraphysiological (1 microM) concentrations of labelled androgen precursors, i.e. testosterone (T) and androstenedione (delta4Ad). The aromatase activity, as measured by estrogen formation, was detected in LNCaP cells (0.5 pmol/ml), even though to a significantly lower extent than in MCF-7 cells (5.4 pmol/ml), using 1 microM T after 72 h incubation. Surprisingly, LNCaP cells displayed a much higher aromatase activity when T was used as a substrate with respect to delta4Ad. In either cell line, T transformation to delta4Ad was relatively low, attaining only 2.8% in LNCaP and 7.5% MCF-7 cells. However, T was mostly converted to conjugates (over 95%), glucuronides and some sulphates, in LNCaP cells, whereas it was only partly converted to sulphates (<10%) in MCF-7 cells. Aromatase activity seems to be inconsistent in LNCaP cells, being strongly affected by culture conditions, especially by fetal calf serum (FCS). Further studies should assess the regulation of aromatase expression by serum or growth factors in different human cancer cells, also using anti-aromatase and/or anti-estrogen compounds, in different culture conditions.

  16. Effects of Pharmaceuticals Used for Breast Cancer Treatment on Reproduction and Aromatase Activity in a Marine Fish

    Science.gov (United States)

    Laboratory experiments were conducted with the marine fish cunner (Tautogolabrus adspersus) to evaluate whether four pharmaceuticals used in breast cancer treatment have an impact on reproduction or aromatase activity. Tamoxifen binds to estrogen receptors, while anastrozole, let...

  17. EFFECTS OF INCUBATION TEMPERATURE AND ESTROGEN EXPOSURE ON AROMATASE ACTIVITY IN THE BRAIN AND GONADS OF EMBRYONIC ALLIGATORS

    Science.gov (United States)

    During embryogenesis, incubation temperature and the hormonal environment influence gonadal differentiation of some reptiles, including all crocodilians. Current evidence suggests that aromatase, the enzyme that converts androgens to estrogens, has a role in sexual differentiatio...

  18. Post-proliferative immature radial glial cells female-specifically express aromatase in the medaka optic tectum.

    Directory of Open Access Journals (Sweden)

    Akio Takeuchi

    Full Text Available Aromatase, the key enzyme responsible for estrogen biosynthesis, is present in the brain of all vertebrates. Much evidence has accumulated that aromatase is highly and exclusively expressed in proliferating mature radial glial cells in the brain of teleost fish even in adulthood, unlike in other vertebrates. However, the physiological significance of this expression remains unknown. We recently found that aromatase is female-specifically expressed in the optic tectum of adult medaka fish. In the present study, we demonstrated that, contrary to the accepted view of the teleost brain, female-specific aromatase-expressing cells in the medaka optic tectum represent a transient subset of post-proliferative immature radial glial cells in the neural stem cell lineage. This finding led us to hypothesize that female-specific aromatase expression and consequent estrogen production causes some sex difference in the life cycle of tectal cells. As expected, the female tectum exhibited higher expression of genes indicative of cell proliferation and radial glial maturation and lower expression of an anti-apoptotic gene than did the male tectum, suggesting a female-biased acceleration of the cell life cycle. Complicating the interpretation of this result, however, is the additional observation that estrogen administration masculinized the expression of these genes in the optic tectum, while simultaneously stimulating aromatase expression. Taken together, these results provide evidence that a unique subpopulation of neural stem cells female-specifically express aromatase in the optic tectum and suggest that this aromatase expression and resultant estrogen synthesis have an impact on the life cycle of tectal cells, whether stimulatory or inhibitory.

  19. 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

  20. 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.

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

    International Nuclear Information System (INIS)

    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 (IC50 0.59 μM) 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 (IC50 70 nM) and 84 (IC50 36 nM). The aromatase inhibitory activities of these compounds are much more potent than that for the lead compound resveratrol, which has an IC50 of 80 μM. In addition to aromatase inhibitory activity, compounds 32 and 44 also displayed potent QR2 inhibitory activity (IC50 1.7 μM and 0.27 μM, 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.

  2. Xanthones from the botanical dietary supplement mangosteen (Garcinia mangostana) with aromatase inhibitory activity.

    Science.gov (United States)

    Balunas, Marcy J; Su, Bin; Brueggemeier, Robert W; Kinghorn, A Douglas

    2008-07-01

    Twelve xanthone constituents of the botanical dietary supplement mangosteen (the pericarp of Garcinia mangostana) were screened using a noncellular, enzyme-based microsomal aromatase inhibition assay. Of these compounds, garcinone D (3), garcinone E (5), alpha-mangostin (8), and gamma-mangostin (9) exhibited dose-dependent inhibitory activity. In a follow-up cell-based assay using SK-BR-3 breast cancer cells that express high levels of aromatase, the most potent of these four xanthones was gamma-mangostin (9). Because xanthones may be consumed in substantial amounts from commercially available mangosteen products, the consequences of frequent intake of mangosteen botanical dietary supplements require further investigation to determine their possible role in breast cancer chemoprevention.

  3. Aromatase Inhibitors for Endometriosis-Associated Infertility; Do We Have Sufficient Evidence?

    Science.gov (United States)

    Abu Hashim, Hatem

    2016-01-01

    Orally active aromatase inhibitors (AIs) have gained attention for treatment of infertile women with endometriosis in whom aromatase p450 is aberrantly expressed. This review aimed to critically appraise and summarize the available evidence concerning the use of AIs for management of endometriosis-associated infertility. PubMed was searched to May 2015 with the following key words: endometriosis, infertility and aromatase. Priority was given for randomized controlled trials (RCTs) followed by other study designs. Main outcome measures were as follows: rates of clinical pregnancy, miscarriage and live birth as well as endocrine outcomes. Eighty-two abstracts were screened and six original articles were included. A RCT demonstrated that post-operative letrozole treatment did not improve spontaneous pregnancy rate. Another RCT reported no superiority of letrozole superovulation over clomiphene citrate (each combined with intrauterine insemination) in minimalmild endometriosis and previous laparoscopic treatment. Anastrozole significantly inhibited the growth of endometriotic cells and their estrogen production in culture. In assisted reproductive technology (ART) cycles, dual suppression (Agonist/anastrozole) was tested in a pilot study with a pregnancy rate of 45% however, high pregnancy loss (30%) occurred. A retrospective study showed that letrozole may improve endometrial receptivity in endometriotic patients undergoing in vitro fertilization (IVF). An opposite view from an in vitro study showed lower estradiol production and aromatase expression in cultured granulosa cells from endometriotic women undergoing IVF and marked reduction under letrozole. In conclusion, current evidence is limited. More trials are warranted to enhance our knowledge and provide a clear and unequivocal evidence to guide our clinical management of infertile women with endometriosis using AIs. PMID:27695608

  4. Synthesis of Triphenylethylene Bisphenols as Aromatase Inhibitors That Also Modulate Estrogen Receptors.

    Science.gov (United States)

    Lv, Wei; Liu, Jinzhong; Skaar, Todd C; O'Neill, Elizaveta; Yu, Ge; Flockhart, David A; Cushman, Mark

    2016-01-14

    A series of triphenylethylene bisphenol analogues of the selective estrogen receptor modulator (SERM) tamoxifen were synthesized and evaluated for their abilities to inhibit aromatase, bind to estrogen receptor α (ER-α) and estrogen receptor β (ER-β), and antagonize the activity of β-estradiol in MCF-7 human breast cancer cells. The long-range goal has been to create dual aromatase inhibitor (AI)/selective estrogen receptor modulators (SERMs). The hypothesis is that in normal tissue the estrogenic SERM activity of a dual AI/SERM could attenuate the undesired effects stemming from global estrogen depletion caused by the AI activity of a dual AI/SERM, while in breast cancer tissue the antiestrogenic SERM activity of a dual AI/SERM could act synergistically with AI activity to enhance the antiproliferative effect. The potent aromatase inhibitory activities and high ER-α and ER-β binding affinities of several of the resulting analogues, together with the facts that they antagonize β-estradiol in a functional assay in MCF-7 human breast cancer cells and they have no E/Z isomers, support their further development in order to obtain dual AI/SERM agents for breast cancer treatment. PMID:26704594

  5. Ligula intestinalis infection is associated with alterations of both brain and gonad aromatase expression in roach (Rutilus rutilus).

    Science.gov (United States)

    Boulange-Lecomte, C; Geraudie, P; Forget-Leray, J; Gerbron, M; Minier, C

    2011-09-01

    The tapeworm Ligula intestinalis commonly infests roach (Rutilus rutilus) and is responsible for the inhibition of gonad development. In order to better understand the effect of the plerocercoid on fish physiology, and to discriminate parasitization effects from those of endocrine-disrupting compounds (EDC), Cyp19b and Cyp19a aromatase expression was investigated by real-time quantitative polymerase chain reaction (PCR) in brain and gonads of ligulosed roach, caught from a reference site. Data were compared to reproductive and endocrine endpoints previously reported in a larger cohort study (including the sampled population of the present one), such as gonadosomatic index, Fulton index, gonadal histology, plasma sex steroid levels and brain aromatase activity. A decrease in Cyp19b expression in the brain of infected fish was demonstrated, in agreement with the reduction of aromatase activity previously described. In contrast, Cyp19a expression in the gonads appeared to be enhanced in ligulosed fish, in accordance with the presence of immature but differentiated sexual tissues. Together these results show that: (1) L. intestinalis infestation results in an alteration of aromatase expression which, in particular, may have profound effects on the fish brain; and (2) L. intestinalis infection must be considered as a major confounding factor in ecotoxicological studies using aromatase expression as an EDC biomarker. Moreover, the concordance between activity and expression--investigated for the first time in the same population--gives a functional relevance to the transcript aromatase dosage in the brain. Finally, quantitative PCR was confirmed as a sensitive approach, enabling aromatase status to be defined in the poorly developed gonads of ligulosed individuals. PMID:21062527

  6. Aromatase inhibition attenuates desflurane-induced preconditioning against acute myocardial infarction in male mouse heart in vivo.

    Directory of Open Access Journals (Sweden)

    Virginija Jazbutyte

    Full Text Available The volatile anesthetic desflurane (DES effectively reduces cardiac infarct size following experimental ischemia/reperfusion injury in the mouse heart. We hypothesized that endogenous estrogens play a role as mediators of desflurane-induced preconditioning against myocardial infarction. In this study, we tested the hypothesis that desflurane effects local estrogen synthesis by modulating enzyme aromatase expression and activity in the mouse heart. Aromatase metabolizes testosterone to 17β- estradiol (E2 and thereby significantly contributes to local estrogen synthesis. We tested aromatase effects in acute myocardial infarction model in male mice. The animals were randomized and subjected to four groups which were pre-treated with the selective aromatase inhibitor anastrozole (A group and DES alone (DES group or in combination (A+DES group for 15 minutes prior to surgical intervention whereas the control group received 0.9% NaCl (CON group. All animals were subjected to 45 minutes ischemia following 180 minutes reperfusion. Anastrozole blocked DES induced preconditioning and increased infarct size compared to DES alone (37.94 ± 15.5% vs. 17.1 ± 3.62% without affecting area at risk and systemic hemodynamic parameters following ischemia/reperfusion. Protein localization studies revealed that aromatase was abundant in the murine cardiovascular system with the highest expression levels in endothelial and smooth muscle cells. Desflurane application at pharmacological concentrations efficiently upregulated aromatase expression in vivo and in vitro. We conclude that desflurane efficiently regulates aromatase expression and activity which might lead to increased local estrogen synthesis and thus preserve cellular integrity and reduce cardiac damage in an acute myocardial infarction model.

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

    International Nuclear Information System (INIS)

    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 (Ki=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 [11C]cyano group was introduced via tetrakis(triphenylphosphine)palladium(0)-catalyzed coupling of [11C]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 [11C-cyano]letrozole fraction in 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. 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: [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

  8. Inhibition of human placental aromatase activity by hydroxylated polybrominated diphenyl ethers (OH-PBDEs)

    International Nuclear Information System (INIS)

    Polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants in many different polymers, resins and substrates. Due to their widespread production and use, their high binding affinity to particles, and their lipophilic properties, several PBDE congeners can bioaccumulate in the environment. As a result, PBDEs and their hydroxylated metabolites (OH-PBDEs) have been detected in humans and various wildlife samples, such as birds, seals, and whales. Furthermore, certain OH-PBDEs and their methoxylated derivatives (MeO-PBDEs) are natural products in the marine environment. Recently, our laboratory focused on the possible effects on steroidogenesis of PBDEs and OH-PBDEs, e.g. in the human adrenocortical carcinoma (H295R) cell line indicating that some OH-PBDEs can significantly influence steroidogenic enzymes like CYP19 (aromatase) and CYP17. In the present study, human placental microsomes have been used to study the possible interaction of twenty two OH-PBDEs and MeO-PBDEs with aromatase, the enzyme that mediates the conversion of androgens into estrogens. All OH-PBDE derivates showed significant inhibition of placental aromatase activity with IC50 values in the low micromolar range, while the MeO-PBDEs did not have any effect on this enzyme activity. Enzyme kinetics studies indicated that two OH-PBDEs, 5-hydroxy-2,2',4,4'-tetrabromodiphenyl ether (5-OH-BDE47) and 6-hydroxy-2,2',4,4'-tetrabromodiphenyl ether (6-OH-BDE47), had a mixed-type inhibition of aromatase activity with apparent Ki/Ki' of 7.68/0,02 μM and 5.01/0.04 μM respectively. For comparison, some structurally related compounds, a dihydroxylated polybrominated biphenyl, which is a natural product (2,2'-dihyroxy-3,3',5,5'-tetrabromobiphenyl (2,2'-diOH-BB80)) and its non-bromo derivative were also included in the study. Again inhibition of aromatase activity could be measured, but their potency was significantly less than those observed for the OH-PBDEs. These results show that a wide range of

  9. 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

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

    International Nuclear Information System (INIS)

    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

  11. Brain aromatase (Cyp19A2) and estrogen receptors, in larvae and adult pejerrey fish Odontesthes bonariensis: Neuroanatomical and functional relations

    Science.gov (United States)

    Strobl-Mazzulla, P. H.; Lethimonier, C.; Gueguen, M.M.; Karube, M.; Fernandino, J.I.; Yoshizaki, G.; Patino, R.; Strussmann, C.A.; Kah, O.; Somoza, G.M.

    2008-01-01

    Although estrogens exert many functions on vertebrate brains, there is little information on the relationship between brain aromatase and estrogen receptors. Here, we report the cloning and characterization of two estrogen receptors, ?? and ??, in pejerrey. Both receptors' mRNAs largely overlap and were predominantly expressed in the brain, pituitary, liver, and gonads. Also brain aromatase and estrogen receptors were up-regulated in the brain of estradiol-treated males. In situ hybridization was performed to study in more detail, the distribution of the two receptors in comparison with brain aromatase mRNA in the brain of adult pejerrey. The estrogen receptors' mRNAs exhibited distinct but partially overlapping patterns of expression in the preoptic area and the mediobasal hypothalamus, as well as in the pituitary gland. Moreover, the estrogen receptor ??, but not ??, were found to be expressed in cells lining the preoptic recess, similarly as observed for brain aromatase. Finally, it was shown that the onset expression of brain aromatase and both estrogen receptors in the head of larvae preceded the morphological differentiation of the gonads. Because pejerrey sex differentiation is strongly influenced by temperature, brain aromatase expression was measured during the temperature-sensitive window and was found to be significantly higher at male-promoting temperature. Taken together these results suggest close neuroanatomical and functional relationships between brain aromatase and estrogen receptors, probably involved in the sexual differentiation of the brain and raising interesting questions on the origin (central or peripheral) of the brain aromatase substrate. ?? 2008 Elsevier Inc.

  12. Managing arthralgia in a postmenopausal woman taking an aromatase inhibitor for hormone-sensitive early breast cancer: a case study

    Directory of Open Access Journals (Sweden)

    Bryce J

    2012-03-01

    Full Text Available Jane Bryce1, Martina Bauer2, Peyman Hadji21National Cancer Institute, Naples, Italy; 2Philipps University of Marburg, Marburg, GermanyBackground: 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.Purpose: 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.Methods and sample: 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.Results: 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.Conclusions: 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.Keywords: adherence, anastrozole, aromatase inhibitor, arthralgia, breast cancer, letrozole

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

    International Nuclear Information System (INIS)

    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 [3H]2O 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. - Highlights:

  14. 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

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

    Directory of Open Access Journals (Sweden)

    Charlotte A Cornil

    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.

  16. Everolimus downregulates estrogen receptor and induces autophagy in aromatase inhibitor-resistant breast cancer cells

    OpenAIRE

    Lui, Asona; New, Jacob; Ogony, Joshua; Thomas, Sufi; Lewis-Wambi, Joan

    2016-01-01

    Background mTOR inhibition of aromatase inhibitor (AI)-resistant breast cancer is currently under evaluation in the clinic. Everolimus/RAD001 (Afinitor®) has had limited efficacy as a solo agent but is projected to become part of combination therapy for AI-resistant breast cancer. This study was conducted to investigate the anti-proliferative and resistance mechanisms of everolimus in AI-resistant breast cancer cells. Methods In this study we utilized two AI-resistant breast cancer cell lines...

  17. 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

  18. Aromatase inhibitor-associated bone loss and its management with bisphosphonates in patients with breast cancer

    Directory of Open Access Journals (Sweden)

    Bauer M

    2012-06-01

    Full Text Available M Bauer,1 J Bryce,2 P Hadji11University of Marburg, Marburg, Germany; 2National Cancer Institute, Naples, ItalyAbstract: Postmenopausal women have an increased risk of osteopenia and osteoporosis due to loss of the bone-protective effects of estrogen. Disease-related processes may also contribute to the risk of bone loss in postmenopausal women with breast cancer. One of the most common and severe safety issues associated with cancer therapy for patients with breast cancer is bone loss and the associated increase in risk of fractures. This paper reviews the recent literature pertaining to aromatase inhibitor (AI-associated bone loss, and discusses suggested management and preventative approaches that may help patients remain on therapy to derive maximum clinical benefit. A case study is presented to illustrate the discussion. We observed that AIs are in widespread use for women with hormone receptor-positive breast cancer and are now recommended as adjuvant therapy, either as primary therapy or sequential to tamoxifen, for postmenopausal women. AIs target the estrogen biosynthetic pathway and deprive tumor cells of the growth-promoting effects of estrogen, and AI therapies provide benefits to patients in terms of improved disease-free survival. However, there is a concern regarding the increased risk of bone loss with prolonged AI therapy, which can be managed in many cases with the use of bisphosphonates and other interventions (eg, calcium, vitamin D supplementation, exercise.Keywords: aromatase inhibitors, bisphosphonates, bone loss, breast cancer, estrogen

  19. Gossypol enantiomers potently inhibit human placental 3β-hydroxysteroid dehydrogenase 1 and aromatase activities.

    Science.gov (United States)

    Dong, Yaoyao; Mao, Baiping; Li, Linxi; Guan, Hongguo; Su, Ying; Li, Xiaoheng; Lian, Qingquan; Huang, Ping; Ge, Ren-Shan

    2016-03-01

    Gossypol is a chemical isolated from cotton seeds. It exists as (+) or (-) enantiomer and has been tested for anticancer, abortion-inducing, and male contraception. Progesterone formed from pregnenolone by 3β-hydroxysteroid dehydrogenase 1 (HSD3B1) and estradiol from androgen by aromatase (CYP19A1) are critical for the maintenance of pregnancy or associated with some cancers. In this study we compared the potencies of (+)- and (-)-gossypol enantiomers in the inhibition of HSD3B1 and aromatase activities as well as progesterone and estradiol production in human placental JEG-3 cells. (+) Gossypol showed potent inhibition on human placental HSD3B1 with IC50 value of 2.3 μM, while (-) gossypol weakly inhibited it with IC50 over 100 μM. In contrast, (-) gossypol moderately inhibited CYP19A1 activity with IC50 of 23 μM, while (+) gossypol had no inhibition when the highest concentration (100 μM) was tested. (+) Gossypol enantiomer competitively inhibited HSD3B1 against substrate pregnenolone and showed mixed mode against NAD(+). (-) Gossypol competitively inhibited CYP19A1 against substrate testosterone. Gossypol enantiomers showed different potency related to their inhibition on human HSD3B1 and CYP19A1. Whether gossypol enantiomer is used alone or in combination relies on its application and beneficial effects. PMID:26709042

  20. Aromatase, adiposity, aging and disease. The hypogonadal-metabolic-atherogenic-disease and aging connection.

    Science.gov (United States)

    Cohen, P G

    2001-06-01

    In males, aging, health and disease are processes that occur over physiologic time and involve a cascade of hormonal, biochemical and physiological changes that accompany the down-regulation of the hypothalamic-anterior pituitary-testicular axis. As aging progresses there are relative increases of body fat and decreases in muscle mass. The increased adipose tissue mass is associated with the production of a number of newly generated factors. These include aromatase, leptin, PAI-1, insulin resistance, and the dyslipidemias, all of which can lead to tissue damage. Fatty tissue becomes the focal point for study as it represents the intersection between energy storage and mobilization. The increase in adipose tissue is associated with an increase in the enzyme aromatase that converts testosterone to estradiol and leads to diminished testosterone levels that favor the preferential deposition of visceral fat. As the total body fat mass increases, hormone resistance develops for leptin and insulin. Increasing leptin fails to prevent weight gain and the hypogonadal-obesity cycle ensues causing further visceral obesity and insulin resistance. The progressive insulin resistance leads to a high triglyceride-low HDL pattern of dyslipidemia and increased cardiovascular risk. All of these factors eventually contribute to the CHAOS Complex: coronary disease, hypertension, adult-onset diabetes mellitus, obesity and/or stroke as permanent changes unfold. Other consequences of the chronic hypogonadal state include osteopenia, extreme fatigue, depression, insomnia, loss of aggressiveness and erectile dysfunction all of which develop over variable periods of time. PMID:11399122

  1. Arthralgia during aromatase inhibitor treatment in early breast cancer patients: prevalence, impact, and recognition by healthcare providers

    NARCIS (Netherlands)

    Boonstra, A.; Zadelhoff, J. van; Timmer-Bonte, J.N.H.; Ottevanger, P.B.; Beurskens, C.H.G.; Laarhoven, H.W.M. van

    2013-01-01

    BACKGROUND: : Many breast cancer patients experience arthralgia symptoms during aromatase inhibitor (AI) treatment, which leads to poor compliance and a lower quality of life. OBJECTIVE: : The research questions of this study were as follows: (1) What is the incidence of arthralgia during AI treatme

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

    International Nuclear Information System (INIS)

    Δ9-Tetrahydrocannabinol (Δ9-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. Δ9-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 (E2), the interaction of Δ9-THC and E2 in MCF-7 cell growth is not fully clarified so far. In the present study, by using E2-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 Δ9-THC-mediated MCF-7 cell proliferation. It was shown that Δ9-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 Δ9-THC was not stimulated by PGE2, and the expression of aromatase was not affected by COX-2 inhibitors, arachidonic acid, and PGE2, suggesting that there is a disconnection between COX-2 (PGE2) and aromatase in Δ9-THC-mediated MCF-7 cell proliferation. On the other hand, Δ9-THC-induced MCF-7 cell growth was elevated by two kinds of aromatase inhibitors. Taken together with the evidence that Δ9-THC-induced MCF-7 cell proliferation was interfered with testosterone (an aromatase substrate) and exogenously provided E2, it is suggested that (1) the growth stimulatory effects of Δ9-THC are mediated by the product(s) of COX-2 except for PGE2, (2) the action of Δ9-THC is modulated by E2, and (3) COX-2 and aromatase are individually engaged in the proliferation of MCF-7 cells induced by Δ9-THC.

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

    Science.gov (United States)

    Kjeldsen, Lisbeth Stigaard; Ghisari, Mandana; Bonefeld-Jørgensen, Eva Cecilie

    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 [(3)H](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.

  4. Paternal Retrieval Behavior Regulated by Brain Estrogen Synthetase (Aromatase) in Mouse Sires that Engage in Communicative Interactions with Pairmates

    Science.gov (United States)

    Akther, Shirin; Huang, Zhiqi; Liang, Mingkun; Zhong, Jing; Fakhrul, Azam A. K. M.; Yuhi, Teruko; Lopatina, Olga; Salmina, Alla B.; Yokoyama, Shigeru; Higashida, Chiharu; Tsuji, Takahiro; Matsuo, Mie; Higashida, Haruhiro

    2015-01-01

    Parental behaviors involve complex social recognition and memory processes and interactive behavior with children that can greatly facilitate healthy human family life. Fathers play a substantial role in child care in a small but significant number of mammals, including humans. However, the brain mechanism that controls male parental behavior is much less understood than that controlling female parental behavior. Fathers of non-monogamous laboratory ICR mice are an interesting model for examining the factors that influence paternal responsiveness because sires can exhibit maternal-like parental care (retrieval of pups) when separated from their pups along with their pairmates because of olfactory and auditory signals from the dams. Here we tested whether paternal behavior is related to femininity by the aromatization of testosterone. For this purpose, we measured the immunoreactivity of aromatase [cytochrome P450 family 19 (CYP19)], which synthesizes estrogen from androgen, in nine brain regions of the sire. We observed higher levels of aromatase expression in these areas of the sire brain when they engaged in communicative interactions with dams in separate cages. Interestingly, the number of nuclei with aromatase immunoreactivity in sires left together with maternal mates in the home cage after pup-removing was significantly larger than that in sires housed with a whole family. The capacity of sires to retrieve pups was increased following a period of 5 days spent with the pups as a whole family after parturition, whereas the acquisition of this ability was suppressed in sires treated daily with an aromatase inhibitor. The results demonstrate that the dam significantly stimulates aromatase in the male brain and that the presence of the pups has an inhibitory effect on this increase. These results also suggest that brain aromatization regulates the initiation, development, and maintenance of paternal behavior in the ICR male mice. PMID:26696812

  5. CREB-regulated transcription co-activator family stimulates promoter II-driven aromatase expression in preadipocytes.

    Science.gov (United States)

    Samarajeewa, Nirukshi U; Docanto, Maria M; Simpson, Evan R; Brown, Kristy A

    2013-08-01

    The dramatically increased prevalence of breast cancer after menopause is of great concern and is correlated with elevated local levels of estrogens. This is mainly due to an increase in aromatase expression driven by its proximal promoter II (PII). We have previously demonstrated that the CREB co-activator CRTC2 binds directly to PII and stimulates its activity via mechanisms involving LKB1-AMPK in response to prostaglandin E(2) (PGE(2)). There are three members of the CRTC family (CRTC1-3) and this study aimed to characterize the role of other CRTCs in the activation of aromatase PII. The expression and subcellular localization of CRTCs were examined in preadipocytes using qPCR and immunofluorescence. Under basal conditions, CRTC1 expression was the lowest, whereas CRTC3 transcripts were present at higher levels. Basally, CRTC2 and CRTC3 were mainly cytoplasmic and PGE(2) caused their nuclear translocation. Reporter assays and chromatin immunoprecipitation (ChIP) were performed to assess the effect of CRTCs on PII activity and binding. Basal PII activity was significantly increased with all CRTCs. Forskolin (FSK)/phorbol 12-myristate 13-acetate (PMA), to mimic PGE(2), resulted in a further significant increase in PII activity with all CRTCs, with CRTC2 and CRTC3 having greater effects. This was consistent with ChIP data showing an increased binding of CRTCs to PII with FSK/PMA. Moreover, gene silencing of CRTC2 and CRTC3 significantly reduced the FSK/PMA-mediated stimulation of aromatase activity. Interestingly, CRTCs acted cooperatively with CREB1 to increase PII activity, and both CREs were found to be essential for the maximal induction of PII activity by CRTCs. Phosphorylation of CRTC2 at its AMPK target site, Ser 171, dictated its subcellular localization, and the activation of aromatase PII in preadipocytes. In conclusion, this study demonstrates that aromatase regulation in primary human breast preadipocytes involves more than one CRTC.

  6. 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

  7. Induction of Female-to-Male Sex Change in Adult Zebrafish by Aromatase Inhibitor Treatment

    Science.gov (United States)

    Takatsu, Kanae; Miyaoku, Kaori; Roy, Shimi Rani; Murono, Yuki; Sago, Tomohiro; Itagaki, Hideyuki; Nakamura, Masaru; Tokumoto, Toshinobu

    2013-12-01

    This study investigated whether undifferentiated germ and/or somatic stem cells remain in the differentiated ovary of a species that does not undergo sex changes under natural conditions and retain their sexual plasticity. The effect of aromatase inhibitor (AI)-treatment on sexually mature female zebrafish was examined. A 5-month AI treatment caused retraction of the ovaries after which testes-like organs appeared, and cyst structures filled with spermatozoa-like cells were observed in sections of these tissues. Electron microscopic observations revealed that these cells appeared as large sperm heads without tails. Sperm formation was re-examined after changing the diet to an AI-free food. A large number of normal sperm were obtained after eight weeks, and no formation of ovarian tissue was observed. Artificial fertilization using sperm from the sex-changed females was successful. These results demonstrated that sex plasticity remains in the mature ovaries of this species.

  8. 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.

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

    Directory of Open Access Journals (Sweden)

    Stefano Gonnelli

    2008-11-01

    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

  10. 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

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

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    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.

  12. Differential expression of genes for aromatase and estrogen receptor during the gonadal development in chicken embryos.

    Science.gov (United States)

    Nakabayashi, O; Kikuchi, H; Kikuchi, T; Mizuno, S

    1998-04-01

    In birds, differentiation of embryonic gonads is not as strictly determined by the genetic sex as it is in mammals, and can be influenced by early manipulation with a sex steroid hormone. Thus administration of an aromatase inhibitor induces testis development in the genetic female, and administration of estrogen induces a left ovotestis in the genetic male embryo. Another feature of avian gonadogenesis is that only the left ovary develops in most species. Molecular mechanisms underlying these features at the level of gene expression have not been elucidated. In this paper, we present evidence that a gene for aromatase cytochrome P-450, an enzyme required for the last step in the synthesis of estradiol-17beta, is expressed in medullae of the left and right gonads of a female chicken embryo, but not in those of a male chicken embryo, and that an estrogen receptor gene is expressed only in epithelium (and cortex later, in the female) of the left, not the right, gonad of both sexes, but the expression in the male left gonad is temporary and restricted to an early stage of development. Differential expression of these two genes serves well to explain the above features of gonadal development in birds. Furthermore, in ovo administration of estradiol-17beta from the 5th to the 14th day of incubation does not cause expression of the estrogen receptor gene in the right gonad of chicken embryos of either sex, suggesting that the absence of expression of the estrogen receptor gene in the right gonad is not the result of down-regulation, but may be regarded as an important cause of the unilateral ovarian development. PMID:9584834

  13. Characterization of Aromatase Expression in the Adult Male and Female Mouse Brain. I. Coexistence with Oestrogen Receptors α and β, and Androgen Receptors

    OpenAIRE

    Davor Stanić; Sydney Dubois; Hui Kheng Chua; Bruce Tonge; Nicole Rinehart; Malcolm K Horne; Wah Chin Boon

    2014-01-01

    Aromatase catalyses the last step of oestrogen synthesis. There is growing evidence that local oestrogens influence many brain regions to modulate brain development and behaviour. We examined, by immunohistochemistry, the expression of aromatase in the adult male and female mouse brain, using mice in which enhanced green fluorescent protein (EGFP) is transcribed following the physiological activation of the Cyp19A1 gene. EGFP-immunoreactive processes were distributed in many brain regions, in...

  14. 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.

  15. 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.

  16. Farnesoid X Receptor, through the Binding with Steroidogenic Factor 1-responsive Element, Inhibits Aromatase Expression in Tumor Leydig Cells*

    OpenAIRE

    Catalano, Stefania; Malivindi, Rocco; Giordano, Cinzia; Gu, Guowei; Panza, Salvatore; Bonofiglio, Daniela; Lanzino, Marilena; Sisci, Diego; Panno, Maria Luisa; Andò, Sebastiano

    2009-01-01

    The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that regulates bile acid homeostasis. It is expressed in the liver and the gastrointestinal tract, but also in several non-enterohepatic tissues including testis. Recently, FXR was identified as a negative modulator of the androgen-estrogen-converting aromatase enzyme in human breast cancer cells. In the present study we detected the expression of FXR in Leydig normal and tumor cell lines and in rat testes tissue. ...

  17. Advances in breast cancer treatment and prevention: preclinical studies on aromatase inhibitors and new selective estrogen receptor modulators (SERMs)

    OpenAIRE

    Schiff, Rachel; Chamness, Gary C.; Brown, Powel H.

    2003-01-01

    Intensive basic and clinical research over the past 20 years has yielded crucial molecular understanding into how estrogen and the estrogen receptor act to regulate breast cancer and has led to the development of more effective, less toxic, and safer hormonal therapy agents for breast cancer management and prevention. Selective potent aromatase inhibitors are now challenging the hitherto gold standard of hormonal therapy, the selective estrogen-receptor modulator tamoxifen. Furthermore, new s...

  18. Brain aromatase and circulating corticosterone are rapidly regulated by combined acute stress and sexual interaction in a sex specific manner

    OpenAIRE

    Dickens, M.J.; Balthazart, J.; Cornil, C. A.

    2012-01-01

    Neural production of 17β-oestradiol via aromatisation of testosterone may play a critical role in rapid, non-genomic regulation of physiological and behavioural processes. In brain nuclei implicated in the control of sexual behaviour, sexual or stressfull stimuli induce respectively a rapid inhibition or increase in preoptic aromatase activity (AA). Here, we tested quail that were either non-stressed or acutely stressed (15 min restraint) immediately prior to sexual interaction (5 min) with s...

  19. Dietary Polyphenols Suppress Elevated Levels of Proinflammatory Mediators and Aromatase in the Mammary Gland of Obese Mice

    OpenAIRE

    Subbaramaiah, Kotha; Sue, Erika; Bhardwaj, Priya; Du, Baoheng; Hudis, Clifford A.; Giri, Dilip; Kopelovich, Levy; Zhou, Xi Kathy; Dannenberg, Andrew J.

    2013-01-01

    In postmenopausal women, obesity is a risk factor for the development of hormone receptor-positive breast cancer driven by estrogen. After menopause, aromatization of androgen precursors in adipose tissue is a major synthetic source of estrogen. Recently, in mouse models and women, we identified an obesity-inflammation-aromatase axis. This obesity induced inflammation is characterized by crown-like structures (CLS) consisting of dead adipocytes encircled by macrophages in breast white adipose...

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

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    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

  1. 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

  2. Postmenopausal Breast Cancer, Aromatase Inhibitors, and Bone Health: What the Surgeon Should Know.

    Science.gov (United States)

    Baatjes, K J; Apffelstaedt, J P; Kotze, M J; Conradie, M

    2016-09-01

    Breast cancer, as the most common malignancy in women, remains a major public health issue despite countless advances across decades. Endocrine therapy is the cornerstone of treatment of the hormone-sensitive subtype of breast cancer. The use of aromatase inhibitors (AIs) in the postmenopausal women has extended the survival beyond that of Tamoxifen, but harbors a subset of side effects, most notably accelerated bone loss. This, however, does not occur in all women undergoing treatment. It is vital to identify susceptible patients early, to limit such events, employ early treatment thereof, or alter drug therapy. International trials on AIs, predominantly performed in North American and European females, provide little information on what to expect in women in developing countries. Here, surgeons often prescribe and manage endocrine therapy. The prescribing surgeon should be aware of the adverse effect of the endocrine therapy and be able to attend to side effects. This review highlights clinical and biochemical factors associated with decrease in bone mineral density in an, as yet, unidentified subgroup of postmenopausal women. In the era of personalized medical care, appropriate management of bone health by surgeons based on these factors becomes increasingly important. PMID:27189076

  3. Vaginal estrogen products in hormone receptor-positive breast cancer patients on aromatase inhibitor therapy.

    Science.gov (United States)

    Sulaica, Elisabeth; Han, Tiffany; Wang, Weiqun; Bhat, Raksha; Trivedi, Meghana V; Niravath, Polly

    2016-06-01

    Atrophic vaginitis represents a major barrier to compliance with aromatase inhibitor (AI) therapy in breast cancer (BC) survivors. While local estrogen therapy is effective for postmenopausal vaginal dryness, the efficacy of such therapies has not been evaluated systematically in hormone receptor-positive (HR+) BC patients on AI therapy. Furthermore, the potential risk of breast cancer recurrence with vaginal estrogen therapy represents a long-term safety concern for the patients with HR + BC. Unfortunately, there is no standardized assay to measure very low concentrations of estradiol (E2) in these women being treated with AI therapy. This makes it difficult to evaluate even indirectly the potential risk of BC recurrence with vaginal estrogen therapy in HR + BC patients on AI therapy. In this review, we describe available assays to measure very low concentrations of E2, discuss the Food and Drug Administration-approved vaginal estrogen products on the market, and summarize published and ongoing clinical trials evaluating the safety and efficacy of vaginal estrogen in HR + BC patients on AI therapy. In the absence of any randomized controlled clinical trials, this review serves as a summary of available clinical data and ongoing studies to aid clinicians in selecting the best available option for their patients. PMID:27178335

  4. Masculinization of female golden rabbitfish Siganus guttatus using an aromatase inhibitor treatment during sex differentiation.

    Science.gov (United States)

    Komatsu, Toru; Nakamura, Shigeo; Nakamura, Masaru

    2006-08-01

    To elucidate the involvement of endogenous estrogen (estradiol-17beta; E2) and the decisive factor (somatic or germinal element) in the ovarian differentiation of tropical marine teleosts, the effect of the aromatase inhibitor (AI) fadrozole on gonadal sex differentiation in the golden rabbitfish Siganus guttatus (Bloch) was examined for different dosages and periods of treatment. Fadrozole interrupted ovarian cavity formation at a dose of 500 microg g(-1) diet, while there was little effect at 10 or 100 microg g(-1). The gonads from both the 30-day and 90-day administration (500 microg g(-1) diet) groups were significantly biased toward testes (P=0.002 and <0.0001, respectively), which suggests strongly that E2 is involved in early ovarian differentiation and that its suppression is an indispensable condition for testicular differentiation in S. guttatus. The results from the two different AI treatment periods imply that the initial feminization of somatic gonadal elements determines subsequent ovarian differentiation, including oogenesis: a conclusion supported by the considerable time lag between ovarian cavity formation and subsequent oogenesis during normal ovarian differentiation in S. guttatus.

  5. 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.

  6. A Case of Erythrocytosis in a Patient Treated with an Aromatase Inhibitor for Breast Cancer

    Directory of Open Access Journals (Sweden)

    Abhinav Iyengar

    2013-01-01

    Full Text Available A previously healthy 79-year-old female was referred to hematology for further evaluation of erythrocytosis. Two years earlier she had been diagnosed with ER/PR-positive ductal carcinoma of the breast and was receiving hormonal therapy with exemestane. No secondary cause of erythrocytosis was identified. Serum erythropoietin (EPO level was normal, and molecular testing for the JAK2 V617F and exon 12 mutations was negative. A bone marrow biopsy showed a mild increase in erythropoiesis, and no spontaneous erythroid colonies were demonstrated. Erythrocytosis is common reason for referral to a hematologist. The myeloproliferative disorder, polycythemia vera, and the rare congenital polycythemias represent primary erythrocytosis. Common secondary causes include smoking, obstructive sleep apnea, and other pulmonary diseases. Erythrocytosis is well described with certain classes of drugs, including androgens. We hypothesize that exemestane contributed to the development of erythrocytosis in our patient. To our knowledge, erythrocytosis has not been previously described in association with aromatase inhibitors. These drugs prevent the conversion of androstenedione and testosterone to estrogen; thus the physiologic mechanisms may be similar to those responsible for erythrocytosis seen with exogenous androgens. These mechanisms are not well understood, but may include altered iron metabolism by a reduction in hepcidin levels.

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

    Science.gov (United States)

    Zhao, Xihe; Liu, Lei; Li, Kai; Li, Wusheng; Zhao, Li; Zou, Huawei

    2015-01-01

    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. PMID:26491345

  8. Aromatase inhibition remodels the clonal architecture of estrogen-receptor-positive breast cancers

    Science.gov (United States)

    Miller, Christopher A.; Gindin, Yevgeniy; Lu, Charles; Griffith, Obi L; Griffith, Malachi; Shen, Dong; Hoog, Jeremy; Li, Tiandao; Larson, David E.; Watson, Mark; Davies, Sherri R; Hunt, Kelly; Suman, Vera J.; Snider, Jacqueline; Walsh, Thomas; Colditz, Graham A.; DeSchryver, Katherine; Wilson, Richard K.; Mardis, Elaine R.; Ellis, Matthew J.

    2016-01-01

    Resistance to oestrogen-deprivation therapy is common in oestrogen-receptor-positive (ER+) breast cancer. To better understand the contributions of tumour heterogeneity and evolution to resistance, here we perform comprehensive genomic characterization of 22 primary tumours sampled before and after 4 months of neoadjuvant aromatase inhibitor (NAI) treatment. Comparing whole-genome sequencing of tumour/normal pairs from the two time points, with coincident tumour RNA sequencing, reveals widespread spatial and temporal heterogeneity, with marked remodelling of the clonal landscape in response to NAI. Two cases have genomic evidence of two independent tumours, most obviously an ER− ‘collision tumour', which was only detected after NAI treatment of baseline ER+ disease. Many mutations are newly detected or enriched post treatment, including two ligand-binding domain mutations in ESR1. The observed clonal complexity of the ER+ breast cancer genome suggests that precision medicine approaches based on genomic analysis of a single specimen are likely insufficient to capture all clinically significant information. PMID:27502118

  9. Vaginal estrogen products in hormone receptor-positive breast cancer patients on aromatase inhibitor therapy.

    Science.gov (United States)

    Sulaica, Elisabeth; Han, Tiffany; Wang, Weiqun; Bhat, Raksha; Trivedi, Meghana V; Niravath, Polly

    2016-06-01

    Atrophic vaginitis represents a major barrier to compliance with aromatase inhibitor (AI) therapy in breast cancer (BC) survivors. While local estrogen therapy is effective for postmenopausal vaginal dryness, the efficacy of such therapies has not been evaluated systematically in hormone receptor-positive (HR+) BC patients on AI therapy. Furthermore, the potential risk of breast cancer recurrence with vaginal estrogen therapy represents a long-term safety concern for the patients with HR + BC. Unfortunately, there is no standardized assay to measure very low concentrations of estradiol (E2) in these women being treated with AI therapy. This makes it difficult to evaluate even indirectly the potential risk of BC recurrence with vaginal estrogen therapy in HR + BC patients on AI therapy. In this review, we describe available assays to measure very low concentrations of E2, discuss the Food and Drug Administration-approved vaginal estrogen products on the market, and summarize published and ongoing clinical trials evaluating the safety and efficacy of vaginal estrogen in HR + BC patients on AI therapy. In the absence of any randomized controlled clinical trials, this review serves as a summary of available clinical data and ongoing studies to aid clinicians in selecting the best available option for their patients.

  10. 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

  11. Reduced estradiol synthesis by letrozole, an aromatase inhibitor, is protective against development of pentylenetetrazole-induced kindling in mice.

    Science.gov (United States)

    Rashid, Davood; Panda, B P; Vohora, Divya

    2015-11-01

    Neurosteroids, such as testosterone and their metabolites, are known to modulate neuronal excitability. The enzymes regulating the metabolism of these neurosteroids, thus, may be targeted as a noval strategy for the development of new antiepileptic drugs. The present work targeted two such enzymes i,e aromatase and 5α-reductase in order to explore the potential of letrozole (an aromatase inhibitor) on pentylenetetrazole (PTZ)-induced kindling in mice and the ability of finasteride (a 5α-reductase inhibitor) to modulate any such effects. PTZ (30 mg/kg, i.p.), when administered once every two days (for a total of 24 doses) induced kindling in Swiss albino mice. Letrozole (1 mg/kg, p.o.), administered prior to PTZ, significantly reduced the % incidence of kindling, delayed mean onset time of seizures and reduced seizure severity score. Letrozole reduced the levels of plasma 17β-estradiol after induction of kindling. The concurrent administration of finasteride and letrozole produced effects similar to letrozole on PTZ-kindling and on estradiol levels. This implies that the ability of letrozole to redirect the synthesis of dihydrotestosterone (DHT) and 5α-androstanediol from testosterone doesn't appear to play a significant role in the protective effects of letrozole against PTZ kindling. Letrozole, however, increased the levels of 5α-DHT in mice plasma. The aromatase inhibitors, thus, may be exploited for inhibiting the synthesis of proconvulsant (17β-estradiol) and/or redirecting the synthesis of anticonvulsant (DHT and 5α-androstanediol) neurosteroids.

  12. Rapid increase in aggressive behavior precedes the decrease in brain aromatase activity during socially mediated sex change in Lythrypnus dalli

    OpenAIRE

    Black, Michael P; Balthazart, Jacques; Baillien, Michelle; Grober, Matthew S.

    2010-01-01

    In the bluebanded goby, Lythrypnus dalli, removal of the male from a social group results in a rapid behavioral response where one female becomes dominant and changes sex to male. In a previous study, within hours of male removal, aromatase activity in the brain (bAA) of dominant females was almost 50% lower than that of control females from a group in which the male had not been removed. For those females that displayed increased aggressive behavior after the male was removed, the larger the...

  13. Evaluation of the quality and accuracy of information regarding aromatase inhibitors available on the internet.

    Science.gov (United States)

    Beaton, Ceri; Codd, Rhodri J; Holland, Phillip A; Gateley, Christopher A

    2008-01-01

    The internet is commonly used by patients to access medical information, particularly where new treatments become available and are highlighted in the press. There is however, no regulation of the quality or accuracy of the information presented on web sites. The aim of this study was to evaluate the quality and accuracy of the information concerning the aromatase inhibitors (AIs). The three most popular search engines: Google, Yahoo, and MSN were utilized. The top ten "hits" for the generic and proprietary names of each AIs: anastrozole (Arimidex), exemestane (Aromasin), and letrozole (Femara) were evaluated using a 12-point score by a single assessor. The accuracy of the information provided was compared with the National Institute for Health and Clinical Excellence guidelines. The mean score for the 180 web sites was only 6.13 out of 12 (0-11). If we consider a score of 9 or more out of 12 (> or =75%) for a web site to represent good quality information, then 51 (28%) of pages scored well. Google was slightly better than Yahoo and MSN; with the highest percentage of web sites scoring well. In evaluating hits according to type of web sites, 50 (28%) were charity web sites and 30 (17%) were drug company web sites and both groups scored significantly higher than the overall mean (charity p = 0.014, drug company p = 0.001). Only 2 of 180 hits gave accurate statistical evidence regarding the benefits of AIs over tamoxifen. We have found that the quality and accuracy of information concerning AIs provided on the Internet is poor and patients using it are unlikely to find accurate information. It is therefore our duty as healthcare providers to guide patients, so as to avoid them from being overwhelmed by irrelevant and conflicting information. PMID:18537915

  14. Hepatic glucose intolerance precedes hepatic steatosis in the male aromatase knockout (ArKO mouse.

    Directory of Open Access Journals (Sweden)

    Michelle L Van Sinderen

    Full Text Available Estrogens are known to play a role in modulating metabolic processes within the body. The Aromatase knockout (ArKO mice have been shown to harbor factors of Metabolic syndrome with central adiposity, hyperinsulinemia and male-specific hepatic steatosis. To determine the effects of estrogen ablation and subsequent replacement in males on whole body glucose metabolism, three- and six-month-old male ArKO mice were subjected to whole body glucose, insulin and pyruvate tolerance tests and analyzed for ensuing metabolic changes in liver, adipose tissue, and skeletal muscle. Estrogen-deficient male ArKO mice showed increased gonadal adiposity which was significantly reduced upon 17β-estradiol (E2 treatment. Concurrently, elevated ArKO serum leptin levels were significantly reduced upon E2 treatment and lowered serum adiponectin levels were restored to wild type levels. Three-month-old male ArKO mice were hyperglycemic, and both glucose and pyruvate intolerant. These phenotypes continued through to 6 months of age, highlighting a loss of glycemic control. ArKO livers displayed changes in gluconeogenic enzyme expression, and in insulin signaling pathways upon E2 treatment. Liver triglycerides were increased in the ArKO males only after 6 months of age, which could be reversed by E2 treatment. No differences were observed in insulin-stimulated ex vivo muscle glucose uptake nor changes in ArKO adipose tissue and muscle insulin signaling pathways. Therefore, we conclude that male ArKO mice develop hepatic glucose intolerance by the age of 3 months which precedes the sex-specific development of hepatic steatosis. This can be reversed upon the administration of exogenous E2.

  15. 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...... 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...... and for investigations of the in vitro regulation of the enzymes involved....

  16. 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)

    International Nuclear Information System (INIS)

    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 (IC50: 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 inhibited

  17. 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

  18. 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).

  19. Brain cytochrome P450 aromatase activity in roach (Rutilus rutilus): seasonal variations and impact of environmental contaminants.

    Science.gov (United States)

    Geraudie, Perrine; Hinfray, Nathalie; Gerbron, Marie; Porcher, Jean-Marc; Brion, François; Minier, Christophe

    2011-10-01

    P450 aromatase catalyses the conversion of C19 androgens to C18 estrogens which is thought to be essential for the regulation of the reproductive function. In this study, brain aromatase activity (AA) was measured monthly over a reproductive cycle in wild roach (Rutilus rutilus) sampled in a reference site in Normandy. AA peaked during the breeding season, reaching 35 fmol mg(-1)min(-1) in both male and female fish, and was low during the rest of the year except for a significant rise in October. AA was correlated with ovary maturation (measured either as gonado-somatic index or by histological analysis of the gonads) and plasma sex-steroid levels (11-ketotestosterone in males and 17-β-estradiol in females). Measurements of AA in polluted sites showed that activity was significantly upregulated in sites with fish showing high levels of plasma vitellogenin and large proportion of intersexuality (20-50%) thus suggesting the occurrence of estrogenic compounds and their involvement in AA modulation. PMID:21820384

  20. 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

  1. Aromatase inhibitors with or without gonadotropin-releasing hormone analogue in metastatic male breast cancer: a case series

    Science.gov (United States)

    Zagouri, F; Sergentanis, T N; Koutoulidis, V; Sparber, C; Steger, G G; Dubsky, P; Zografos, G C; Psaltopoulou, T; Gnant, M; Dimopoulos, M-A; Bartsch, R

    2013-01-01

    Background: Data regarding the safety and effectiveness of aromatase inhibitors (AIs) as monotherapy or combined with gonadotropin-releasing hormone (GnRH) analogue in male breast cancer are scarce. Methods: In this retrospective chart review, cases of male breast cancer patients treated with AIs with or without a GnRH analogue were evaluated. Results: Twenty-three men were included into this case series. Aromatase inhibitors in combination with or without a GnRH analogue were given as first-line therapy in 60.9% and as second-line therapy in 39.1% of patients, respectively. All patients had visceral metastases, whereas in five of them bone lesions coexisted. In all cases AIs were tolerated well, and no case of grade 3 and 4 adverse events was reported. A partial response was observed in 26.1% of patients and stable disease in 56.5%. Median overall survival (OS) was 39 months and median progression-free survival (PFS) was 13 months. Regarding OS and PFS, no significant effects of GnRH analogue co-administration or type of AI were noted. Conclusion: Our study shows that AIs with or without GnRH analogues may represent an effective and safe treatment option for hormone-receptor positive, pretreated, metastatic, male breast cancer patients. PMID:23722469

  2. Weight gain and inflammation regulate aromatase expression in male adipose tissue, as evidenced by reporter gene activity.

    Science.gov (United States)

    Polari, L; Yatkin, E; Martínez Chacón, M G; Ahotupa, M; Smeds, A; Strauss, L; Zhang, F; Poutanen, M; Saarinen, N; Mäkelä, S I

    2015-09-01

    Obesity and white adipose tissue (WAT) inflammation are associated with enhanced aromatization in women, but little is known about the regulation of aromatase (CYP19A1) gene expression in male WAT. We investigated the impact of weight gain and WAT inflammation on the regulation of CYP19A1 in males, by utilizing the hARO-Luc aromatase reporter mouse model containing a >100-kb 5'-region of the human CYP19A1 gene. We show that hARO-Luc reporter activity is enhanced in WAT of mice with increased adiposity and inflammation. Dexamethasone and TNFα, as well as forskolin and phorbol 12-myristate 13-acetate, upregulate hARO-Luc activity, suggesting the involvement of promoters I.4 and I.3/II. Furthermore, we show that diet enriched with antioxidative plant polyphenols attenuates WAT inflammation and hARO-Luc activity in obese males. In conclusion, our data suggest that obesity-associated WAT inflammation leads to increased peripheral CYP19A1 expression in males, and that polyphenol-enriched diet may have the potential to attenuate excessive aromatization in WAT of obese men. PMID:26054748

  3. 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.

  4. 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.

  5. 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)

    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

  6. Age-related decrease in aromatase and estrogen receptor(ERαand ERβ) expression in rat testes: protective effect of low caloric diets

    Institute of Scientific and Technical Information of China (English)

    Khaled Hamden; Dorothee Silandre; Christelle Delalande; Abdefattah El Feki; Serge Carreau

    2008-01-01

    Aim: To examine the effects on rat aging of caloric restriction (CR1) and undernutrition (CR2) on the body and on testicular weights, on two enzymatic antioxidants (superoxide dismutase and catalase), on lipid peroxidation and on the expression of testicular aromatase and estrogen receptors (ER). Methods: CR was initiated in 1-month-old rats and carried on until the age of 18 months. Results: In control and CR2 rats an age-related decrease of the aromatase and of ER (α and β) gene expression was observed; in parallel a diminution of testicular weights, and of the total number and motility of epididymal spermatozo was recorded. In addition, aging in control and CR2 rats was accom-panied by a significant decrease in testicular superoxide dismutase, catalase activities, and an increase in lipid peroxidation level (thiobarbituric acid reactive substance), associated with alterations of spermatogenesis. Conversely, caloric restriction-treatment exerted a protective effect and all the parameters were less affected by aging. Conclusion:These results indicate that during aging, a low caloric diet (not undernutrition) is beneficial for spermatogenesis and likely improves the protection of the cells via an increase of the cellular antioxidant defense system in which aromatase/ER could play a role.

  7. Isolation and characterization of goat ovarian aromatase cDNA: assessment of the activity using an intact cell system and placental expression.

    Science.gov (United States)

    Bobes, Raúl José; Miranda, Carolina; Pérez-Martinez, Mario; Luu-The, Van; Romano, Marta C

    2004-08-01

    Goat ovarian follicles produce estrone and estradiol from androgens. The synthesis of C18 estrogens from C19 androgens requires cytochrome P450 aromatase, but little information about this key enzyme is available in the goat. We report here for the first time the cDNA sequence of the goat ovarian aromatase, the activity of the enzyme in a cell system, and its expression in the term goat placenta. A cDNA library from goat ovarian poly(A)+ RNA was constructed. Human aromatase cDNA was selected as probe to screen the library; several clones were isolated, but none was complete. The longest clone was 3.1 kb long, but it lacked the sequence coding for a few amino acids in the NH(2)-terminal. To obtain the missing sequence, we performed reverse amplification of the cDNA end (RACE). Sequence analysis indicated that goat aromatase possessed a very long 3'-untranslated region ( approximately 1790 bp), and a polyadenylation signal (AATAAA) located at position 3320 downstream from the ATG start codon. The coding region of goat cDNA was inserted in an expression vector and transfected into HEK-293 cells that were cultured in presence of [14C]-androstenedione, steroids extracted and further separated by TLC. The transfected cells efficiently transformed [14C]-androstenedione into estrone. This activity was inhibited by 4-hydroxyandrostenedione. We also investigated the presence of mRNA for P450 aromatase in the goat placenta, using reverse transcription-polymerase chain reaction (RT-PCR) and primers derived from the cDNA ovarian sequence and confirmed the expression of the mRNA in term placenta.

  8. 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.

  9. Reinvestigation of the synthesis and evaluation of [N-methyl-11C]vorozole, a radiotracer targeting cytochrome P450 aromatase

    International Nuclear Information System (INIS)

    Introduction: We reinvestigated the synthesis of [N-methyl-11C]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-11C]vorozole. Methods: Norvorozole was alkylated with [11C]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 (13C and 2D-nuclear Overhauser effect spectroscopy NMR) was used to identify and assign structures to the N-methylated products. Pure [N-methyl-11C]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-11C]vorozole with and without the contaminating N-3 isomer revealed that only [N-methyl-11C]vorozole binds to aromatase. [N-methyl-11C]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-11C]vorozole combine to provide a new scientific tool for PET studies of the biology of aromatase and for drug research and development.

  10. Gene expression alterations associated with outcome in aromatase inhibitor-treated ER+ early-stage breast cancer patients

    DEFF Research Database (Denmark)

    Gravgaard Thomsen, Karina Hedelund; Lyng, Maria Bibi; Elias, Daniel;

    2015-01-01

    Aromatase inhibitors (AI), either alone or together with chemotherapy, have become the standard adjuvant treatment for postmenopausal, estrogen receptor-positive (ER+) breast cancer. Although AIs improve overall survival, resistance is still a major clinical problem, thus additional biomarkers...... predictive of outcome of ER+ breast cancer patients treated with AIs are needed. Global gene expression analysis was performed on ER+ primary breast cancers from patients treated with adjuvant AI monotherapy; half experienced recurrence (median follow-up 6.7 years). Gene expression alterations were validated...... by qRT-PCR, and functional studies evaluating the effect of siRNA-mediated gene knockdown on cell growth were performed. Twenty-six genes, including TFF3, DACH1, RGS5, and GHR, were shown to exhibit altered expression in tumors from patients with recurrence versus non-recurrent (fold change ≥1.5, p

  11. 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.

  12. Aromatase inhibition abolishes courtship behaviours in the ring dove (Streptopelia risoria) and reduces androgen and progesterone receptors in the hypothalamus and anterior pituitary gland.

    Science.gov (United States)

    Belle, M D C; Sharp, P J; Lea, R W

    2005-08-01

    The aim of this study was to determine in the ring dove, the effects of aromatase inhibition on the expression of aggressive courtship and nest-soliciting behaviours in relation to the distribution of cells containing immunoreactive androgen (AR) and progesterone (PR) receptor in the hypothalamus and pituitary gland. Isolated sexually experienced ring doves were transferred in opposite sex pairs to individual breeding cages, and then injected with the aromatase inhibitor, fadrozole (four males and four females), or saline vehicle (four males and four females) for 3 days at 12 hourly intervals. Saline-injected control males displayed aggressive courtship behaviours (bow-cooing and hop-charging) and nest-soliciting throughout the study, and control females displayed nest-soliciting. By day 3, fadrozole treatment resulted in the disappearance of all these behaviours and in a decrease or disappearance of AR and PR in the anterior pituitary gland, and in the nucleus preopticus paraventricularis magnocellularis (PPM), nucleus preopticus medialis (POM), nucleus hypothalami lateralis posterioris (PLH), and ventral, lateral and dorsal nucleus tuberalis in the hypothalamus (VTu, LTu, DTu). In the nucleus preopticus anterior (POA), fadrozole treatment decreased AR in both sexes and decreased PR in females but not in males. Cells containing co-localized nuclear AR and PR were found in all hypothalamic areas examined, and in the anterior pituitary gland. Fadrozole is suggested to reduce the local availability of estrogen required indirectly for the induction of AR, and except in cells containing PR in the male POA, for the direct induction of PR. It is suggested that aggressive courtship behaviour is terminated by "cross talk" between aromatase-independent PR and aromatase-dependent AR co-localized in neurons in the POA. Aromatase-independent PR may increase in the male POA in response to visual cues provided by a partner. Aromatase-dependent PR in the POM, and basal

  13. Evaluation of a bioluminescent mouse model expressing aromatase PII-promoter-controlled luciferase as a tool for the study of endocrine disrupting chemicals

    International Nuclear Information System (INIS)

    Dysfunction of the enzyme aromatase (CYP19) is associated with endocrine pathologies such as osteoporosis, impaired fertility and development of hormone-dependent cancers. Certain endocrine disrupting chemicals affect aromatase expression and activity in vitro, but little is known about their ability to do so in vivo. We evaluated a bioluminescent mouse model (LPTA (registered) )CD-1-Tg(Cyp19-luc)-Xen) expressing luciferase under control of the gonadal aromatase pII promoter as an in vivo screening tool for chemicals that may affect aromatase expression. We studied the effects of forskolin, pregnant mare serum gonadotropin and atrazine in this model (atrazine was previously shown to induced pII-promoter-driven aromatase expression in H295R human adrenocortical carcinoma cells). About 2-4 out of every group of 10 male or female Cyp19-luc mice injected i.p. with 10 mg/kg forskolin had increased gonadal bioluminescence after 3-5 days compared to controls; the others appeared non-responsive. Similarly, about 4 per group of 9 individual females injected with pregnant mare serum gonadotropin had increased ovarian bioluminescence after 24 h. There was a statistically significant correlation between ovarian bioluminescence and plasma estradiol concentrations (n = 14; p = 0.022). Males exposed to a single dose of 100 mg/kg or males and females exposed to 5 daily injections of 30 mg/kg atrazine showed no change in gonadal bioluminescence over a 7 day period, but a significant interaction was found between atrazine (100 mg/kg) and time in female mice (p < 0.05; two-way ANOVA). Ex vivo luciferase activity in dissected organs was increased by forskolin in testis, epididymis and ovaries. Atrazine (30 mg/kg/day) increased (30%) luciferase activity significantly in epididymis only. In conclusion, certain individual Cyp19-luc mice are highly responsive to aromatase inducers, suggesting this model, with further optimization, may have potential as an in vivo screening tool for

  14. Effect of butyrate on aromatase cytochrome P450 levels in HT29, DLD-1 and LoVo colon cancer cells.

    Science.gov (United States)

    Rawłuszko, Agnieszka Anna; Sławek, Sylwia; Gollogly, Armin; Szkudelska, Katarzyna; Jagodziński, Paweł Piotr

    2012-03-01

    Epidemiological studies suggest that colonic production of butyrate and estrogen may be involved in human susceptibility to colorectal cancer (CRC). Estrone (E1) can be produced by the aromatase pathway during the conversion of androstenedione (A) to E1. Therefore, we studied the effect of sodium butyrate (NaBu) on the CYP19A1 transcript and protein levels and on the conversion of A to E1 in HT29, DLD-1 and LoVo CRC cells. We found that NaBu significantly downregulated CYP19A1 transcript and protein levels, a phenomenon that was associated with reduced conversion of A to E1 in HT29, DLD-1 and LoVo cells. Our studies demonstrated that, although butyrate exhibited a protective role in CRC development, this compound may reduce aromatase activity and the production of E1 in colon cancer cells.

  15. Immunolocalization of aromatase, estrogen and estrogen receptor α and β in the epithelium of digestive tract and enteric neurons of amphioxus (Branchiostoma belcheri )

    Institute of Scientific and Technical Information of China (English)

    FANG Yongqiang; WENG Youzhu; YE Rongzhong; LIU Lili

    2005-01-01

    Immunohistochemical localization of aromatase, estrogen and estrogen receptor in the digestive tract and enteric neurons of amphioxus is investigated. It was found that immunoreactive proteins of aromatase, estrogen and ER-α and β are expressed in hepatic diverticulum, epithelial cells of anterior and posterior region of midgut, as well as in enteric neurons, while hindgut showed immunonegative. The results suggest that digestive tract of amphioxus may be able to synthesize estrogen and possess endocrine function, like rat gastric epithelium and enteric neurons in mammals. The present study provides authentic morphological evidence for explaining the action mechanism of estrogen in regulating the digestive function of gut and the functional evolution of estrogen, which has important theoretical significance in amphioxus.

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

    Science.gov (United States)

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

    2014-10-01

    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 Modulators (SEEMs e.g. letrozole). Among various naturally occurring, biologically active compounds, resveratrol and melatonin have been suggested to act as aromatase inhibitors, which make them potential candidates in hormonal treatment of breast cancer. Here we used a co-culture model in which we previously demonstrated that primary human breast adipose fibroblasts (BAFs) can convert testosterone to estradiol, which subsequently results in estrogen receptor-mediated breast cancer T47D cell proliferation. In the presence of testosterone in this model, we examined the effect of letrozole, resveratrol and melatonin on cell proliferation, estradiol (E2) production and gene expression of CYP19A1, pS2 and Ki-67. Both melatonin and resveratrol were found to be aromatase inhibitors in this co-culture system, albeit at different concentrations. Our co-culture model did not provide any indications that melatonin is also a selective estrogen receptor modulator. In the T47D-BAF co-culture, a melatonin concentration of 20 nM and resveratrol concentration of 20 μM have an aromatase inhibitory effect as potent as 20 nM letrozole, which is a clinically used anti-aromatase drug in breast cancer treatment. The SEEM mechanism of action of especially melatonin clearly offers potential advantages for breast cancer treatment. PMID:24929094

  17. Disruptions in aromatase expression in the brain, reproductive behavior, and secondary sexual characteristics in male guppies (Poecilia reticulata) induced by tributyltin.

    Science.gov (United States)

    Tian, Hua; Wu, Peng; Wang, Wei; Ru, Shaoguo

    2015-05-01

    Although bioaccumulation of tributyltin (TBT) in fish has been confirmed, information on possible effects of TBT on reproductive system of fish is still relatively scarce, particularly at environmentally relevant levels. To evaluate the adverse effects and intrinsic toxicological properties of TBT in male fish, we studied aromatase gene expression in the brain, sex steroid contents, primary and secondary sexual characteristics, and reproductive behavior in male guppies (Poecilia reticulata) exposed to tributyltin chloride at the nominal concentrations of 5, 50, and 500 ng/L for 28 days in a semi-static exposure system. Radioimmunoassay demonstrated that treatment with 50 ng/L TBT caused an increase in systemic levels of testosterone of male guppies. Gonopodial index, which showed a positive correlation with testosterone levels, was elevated in the 5 ng/L and 50 ng/L TBT treated groups. Real-time PCR revealed that TBT exposure had inhibiting effects on expression of two isoforms of guppy aromatase in the brain, and these changes at the molecular levels were associated with a disturbance of reproductive behavior of the individuals, as measured by decreases in frequencies of posturing, sigmoid display, and chase activities when males were paired with females. This study provides the first evidence that TBT can cause abnormalities of secondary sexual characteristics in teleosts and that suppression of reproductive behavior in teleosts by TBT is due to its endocrine-disrupting action as an aromatase inhibitor targeting the nervous system.

  18. 芳香化酶抑制剂在男性中的应用%Application of Aromatase Inhibitors in Male Patients

    Institute of Scientific and Technical Information of China (English)

    茅江峰; 伍学焱

    2016-01-01

    芳香化酶抑制剂(Aromatase Inhibitor,AI)能抑制睾酮向雌二醇的转化,从而减少雌激素对下丘脑和垂体的负反馈抑制作用,促进垂体分泌促性腺激素。对男性部分性低促性腺激素性性腺功能减退症、男性身材矮小、肥胖相关性性腺功能减退症以及少精症,都具有一定的治疗作用。%Aromatase inhibitors (Aromatase Inhibitor, AI) can inhibit the conversion of testosterone to estradiol, thus reducing the feedback inhibition of estrogen to the hypothalamus and pituitary gland, promote the secretion of pituitary gonadotropins. And it is useful for the treatment of male sexual lower gonadotropin induced gonad hypofunction, men short stature, obesity relevance gonad hypofunction and oligospermia.

  19. Sex change in the protandrous black porgy, Acanthopagrus schlegeli: a review in gonadal development, estradiol, estrogen receptor, aromatase activity and gonadotropin.

    Science.gov (United States)

    Lee, Y H; Du, J L; Yueh, W S; Lin, B Y; Huang, J D; Lee, C Y; Lee, M F; Lau, E L; Lee, F Y; Morrey, C; Nagahama, Y; Chang, C F

    2001-12-01

    Black porgy, Acanthopagrus schlegeli Bleeker, a marine protandrous hermaphrodite, is functional male for the first two years of life but begins to sexually change to female after the third year. Testicular tissue and ovarian tissue was separated by connective tissue in the bisexual gonad. This sex pattern provides a very good model to study the endocrine mechanism of sex change in fish. The annual profiles of plasma estradiol, vitellogenin and 11-ketotestosterone concentrations in males were significantly different from those in the three-year-old females. Significantly high levels of plasma estradiol during the prespawning/spawning season and low levels of plasma 11-ketotestosterone during the spawning season were observed in the inversing females. No difference of plasma testosterone levels was observed in males and females. Oral administration of estradiol stimulated high levels of gonadal aromatase activity, plasma gonadotropin II levels and sex change in the two-year-old fish. Exogenous estradiol administered for 5-6 months induced a reversible sex change in one- and two-year-old fish. The sensitive period for estradiol treatment of sex change is from early prespawning to spawning season. Implantation with testosterone for more than a year could not block the natural sex change in three-year-old fish. Exogenous aromatase inhibitors (1,4,6-androstatriene-3,17-dione or fadrozole) suppressed aromatase activity in the brain. Oral administration with aromatase inhibitors for a year further inhibited the natural sex change in three-year-old black porgy and all fish became functional male with spermiation. Estrogen receptor alpha gene in the ovarian tissue of bisexual gonad is significantly less expressed than that in the vitellogenic ovary of female on the basis of reverse-transcription polymerase-chain reaction. There was no difference in the annual profiles of the plasma gonadotropin II levels in the males and natural inversing females. Plasma gonadotropin II

  20. Profile of Steroid Receptors and Increased Aromatase Immunoexpression in Canine Inflammatory Mammary Cancer as a Potential Therapeutic Target.

    Science.gov (United States)

    De Andrés, P J; Cáceres, S; Clemente, M; Pérez-Alenza, M D; Illera, J C; Peña, L

    2016-04-01

    Canine inflammatory mammary cancer (IMC) has been proposed as a model for the study of human inflammatory breast cancer (IBC). The aims of this study were to compare the immunohistochemical expression of aromatase (Arom) and several hormone receptors [estrogen receptor α (ERα), estrogen receptor β (ERβ), progesterone receptor (PR) and androgen receptor (AR)], in 21 IMC cases vs 19 non-IMC; and to study the possible effect of letrozole on canine IMC and human inflammatory breast cancer (IBC) in vitro using IPC-366 and SUM-149 cell lines. Significant elevations of the means of Arom Total Score (TS), ERβ TS and PR TS were found in the IMC group (p = 0.025, p = 0.038 and p = 0.037, respectively). Secondary IMC tumours expressed higher levels of Arom than primary IMC (p = 0.029). Non-IMC PR- tumours contained higher levels of Arom than non-IMC PR+ tumours (p = 0.007). After the addition of letrozole, the number of IMC and IBC cells dropped drastically. The overexpression of Arom found and the results obtained in vitro further support canine IMC as a model for the study of IBC and future approaches to the treatment of dogs with mammary cancer, and especially IMC, using Arom inhibitors. PMID:26899138

  1. Kinetic analysis of the three-step steroid aromatase reaction of human cytochrome P450 19A1.

    Science.gov (United States)

    Sohl, Christal D; Guengerich, F Peter

    2010-06-01

    Cytochrome P450 19A1 (P450 19A1), the aromatase, catalyzes the conversion of androgens to estrogens through a sequential three-step reaction, generating 19-hydroxy and 19-aldehyde intermediates en route to the product estrogen. A procedure for the heterologous expression and purification of P450 19A1 in Escherichia coli was developed (k(cat) of 0.06 s(-1) for the conversion of androstenedione to estrone). Binding of the substrate and intermediates show low micromolar dissociation constants and are at least two-step processes. Rates of reduction of the iron were fast in the presence of substrate, either intermediate, or product. P450 19A1 is a distributive rather than a processive enzyme, with the sequential reaction allowing free dissociation of the intermediates as revealed by pulse-chase experiments. Conversion of androstenedione to estrone (under single turnover conditions) generated a progress curve showing changes in the concentrations of the substrate, intermediates, and product. A minimal kinetic model containing the individual rate constants for the steps in P450 19A1 catalysis was developed to globally fit the time course of the overall reaction, the dissociation constants, the two-step ligand binding, the distributive character, the iron-reduction rates, and the steady-state conversion of the 19-hydroxy androstenedione and 19-aldehyde androstenedione intermediates to estrone. PMID:20385561

  2. Profile of Steroid Receptors and Increased Aromatase Immunoexpression in Canine Inflammatory Mammary Cancer as a Potential Therapeutic Target.

    Science.gov (United States)

    De Andrés, P J; Cáceres, S; Clemente, M; Pérez-Alenza, M D; Illera, J C; Peña, L

    2016-04-01

    Canine inflammatory mammary cancer (IMC) has been proposed as a model for the study of human inflammatory breast cancer (IBC). The aims of this study were to compare the immunohistochemical expression of aromatase (Arom) and several hormone receptors [estrogen receptor α (ERα), estrogen receptor β (ERβ), progesterone receptor (PR) and androgen receptor (AR)], in 21 IMC cases vs 19 non-IMC; and to study the possible effect of letrozole on canine IMC and human inflammatory breast cancer (IBC) in vitro using IPC-366 and SUM-149 cell lines. Significant elevations of the means of Arom Total Score (TS), ERβ TS and PR TS were found in the IMC group (p = 0.025, p = 0.038 and p = 0.037, respectively). Secondary IMC tumours expressed higher levels of Arom than primary IMC (p = 0.029). Non-IMC PR- tumours contained higher levels of Arom than non-IMC PR+ tumours (p = 0.007). After the addition of letrozole, the number of IMC and IBC cells dropped drastically. The overexpression of Arom found and the results obtained in vitro further support canine IMC as a model for the study of IBC and future approaches to the treatment of dogs with mammary cancer, and especially IMC, using Arom inhibitors.

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

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    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.

  4. Effects of butachlor on estrogen receptor, vitellogenin and P450 aromatase gene expression in the early life stage of zebrafish.

    Science.gov (United States)

    Chang, Juhua; Gui, Wenjun; Wang, Minghua; Zhu, Guonian

    2012-01-01

    Butachlor has adverse effects on fecundity and disrupts sex hormone homeostasis in adult zebrafish, but the underlying molecular mechanisms are still unclear. In the present study, zebrafish (Danio rerio) embryos were exposed to various concentrations of butachlor from 2 h post-fertilization (hpf) to 30 days post-fertilization (dpf). The transcription of genes involved estrogen receptors (ERα, ERβ1 and ERβ2), vitellogenins (VTG I and II), and cytochrome P450 aromatase (CYP19a) was analyzed by real-time quantitative PCR. The results showed that there was no significant alteration in the expression of VTGI, ERα, ERβ1, ERβ2 and CYP19a after 30 days of butachlor exposure, whereas the transcription of VTG II gene was significantly up-regulated in zebrafish exposed to 100 μg/L butachlor. It is suggested that butachlor may be a weak estrogen, and more endpoints need to be investigated to assess the effects of butachlor on the hypothalamus-pituitary-gonadal axis of zebrafish.

  5. Nuclear receptor co-activators and HER-2/neu are upregulated in breast cancer patients during neo-adjuvant treatment with aromatase inhibitors

    Science.gov (United States)

    Flågeng, M Hauglid; Haugan Moi, L L; Dixon, J M; Geisler, J; Lien, E A; Miller, W R; Lønning, P E; Mellgren, G

    2009-01-01

    Background: Acquired resistance to endocrine therapy in breast cancer is poorly understood. Characterisation of the molecular response to aromatase inhibitors in breast cancer tissue may provide important information regarding development of oestrogen hypersensitivity. Methods: We examined the expression levels of nuclear receptor co-regulators, the orphan nuclear receptor liver receptor homologue-1 and HER-2/neu growth factor receptor using real-time RT-PCR before and after 13–16 weeks of primary medical treatment with the aromatase inhibitors anastrozole or letrozole. Results: mRNA expression of the steroid receptor co-activator 1 (SRC-1) and peroxisome-proliferator-activated receptor γ co-activator-1α (PGC-1α) was correlated (P=0.002), and both co-activators increased during treatment in the patient group as a whole (P=0.008 and P=0.032, respectively), as well as in the subgroup of patients achieving an objective treatment response (P=0.002 and P=0.006). Although we recorded no significant change in SRC-3/amplified in breast cancer 1 level, the expression correlated positively to the change of SRC-1 (P=0.002). Notably, we recorded an increase in HER-2/neu levels during therapy in the total patient group (18 out of 26; P=0.016), but in particular among responders (15 out of 21; P=0.008). Conclusion: Our results show an upregulation of co-activator mRNA and HER-2/neu during treatment with aromatase inhibitors. These mechanisms may represent an early adaption of the breast cancer cells to oestrogen deprivation in vivo. PMID:19755984

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

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    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.

  7. DNA Methylation of the Gonadal Aromatase (cyp19a) Promoter Is Involved in Temperature-Dependent Sex Ratio Shifts in the European Sea Bass

    Science.gov (United States)

    Navarro-Martín, Laia; Viñas, Jordi; Ribas, Laia; Díaz, Noelia; Gutiérrez, Arantxa; Di Croce, Luciano; Piferrer, Francesc

    2011-01-01

    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. PMID:22242011

  8. Effects of phenol on ovarian P450arom gene expression and aromatase activity in vivo and antioxidant metabolism in common carp Cyprinus carpio.

    Science.gov (United States)

    Das, Sumana; Majumder, Suravi; Gupta, Shreyasi; Dutta, Sharmistha; Mukherjee, Dilip

    2016-02-01

    Ovarian cyp19a mRNA expression and P450 aromatase activity were measured in vivo in common carp Cyprinus carpio exposed to phenol for 96 h. Production of reactive oxygen species (ROS) and parameters of antioxidant defense system in serum ovary and liver of this fish after long-term phenol exposure were also studied. In vivo exposure of fish to sublethal dose of phenol for 96 h caused marked attenuation of ovarian cyp19a1a gene expression and P450 aromatase activity. Production of ROS like hydrogen peroxide and hydroxyl radicals in serum, liver and ovary in fish exposed to phenol for 15 days elevated significantly from day 1 to day 7 with no further significant increase thereafter compared to their respective control values. Total superoxide dismutase (SOD) and catalase activities in serum and ovary decreased gradually and significantly from day 1 to day 4, which then increased significantly for the rest of the exposure days. Liver SOD activity seemed to be distinctly responsive to phenol. SOD activity in liver of phenol-exposed fish started to increase gradually from day 1 to 4 with no further increase thereafter. Catalase activities in all the tissues showed significant inhibition up to day 4 which then increased gradually and significantly up to day 15 of phenol exposure compared to their respective control values. From our results, it appears that sublethal dose of phenol has the endocrine disruptive potential and effect is mediated via inhibition of ovarian P450arom gene expression and aromatase activity in vivo. Sublethal dose of phenol also caused oxidative stress, and antioxidant systems are very much effective to prevent the damages caused by the generation of ROS.

  9. Cyclin A1 and P450 Aromatase Promote Metastatic Homing and Growth of Stem-like Prostate Cancer Cells in the Bone Marrow.

    Science.gov (United States)

    Miftakhova, Regina; Hedblom, Andreas; Semenas, Julius; Robinson, Brian; Simoulis, Athanasios; Malm, Johan; Rizvanov, Albert; Heery, David M; Mongan, Nigel P; Maitland, Norman J; Allegrucci, Cinzia; Persson, Jenny L

    2016-04-15

    Bone metastasis is a leading cause of morbidity and mortality in prostate cancer. While cancer stem-like cells have been implicated as a cell of origin for prostate cancer metastasis, the pathways that enable metastatic development at distal sites remain largely unknown. In this study, we illuminate pathways relevant to bone metastasis in this disease. We observed that cyclin A1 (CCNA1) protein expression was relatively higher in prostate cancer metastatic lesions in lymph node, lung, and bone/bone marrow. In both primary and metastatic tissues, cyclin A1 expression was also correlated with aromatase (CYP19A1), a key enzyme that directly regulates the local balance of androgens to estrogens. Cyclin A1 overexpression in the stem-like ALDH(high) subpopulation of PC3M cells, one model of prostate cancer, enabled bone marrow integration and metastatic growth. Further, cells obtained from bone marrow metastatic lesions displayed self-renewal capability in colony-forming assays. In the bone marrow, cyclin A1 and aromatase enhanced local bone marrow-releasing factors, including androgen receptor, estrogen and matrix metalloproteinase MMP9 and promoted the metastatic growth of prostate cancer cells. Moreover, ALDH(high) tumor cells expressing elevated levels of aromatase stimulated tumor/host estrogen production and acquired a growth advantage in the presence of host bone marrow cells. Overall, these findings suggest that local production of steroids and MMPs in the bone marrow may provide a suitable microenvironment for ALDH(high) prostate cancer cells to establish metastatic growths, offering new approaches to therapeutically target bone metastases. Cancer Res; 76(8); 2453-64. ©2016 AACR. PMID:26921336

  10. 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

  11. Gene expression alterations associated with outcome in aromatase inhibitor-treated ER+ early-stage breast cancer patients.

    Science.gov (United States)

    Thomsen, Karina G; Lyng, Maria B; Elias, Daniel; Vever, Henriette; Knoop, Ann S; Lykkesfeldt, Anne E; Lænkholm, Anne-Vibeke; Ditzel, Henrik J

    2015-12-01

    Aromatase inhibitors (AI), either alone or together with chemotherapy, have become the standard adjuvant treatment for postmenopausal, estrogen receptor-positive (ER+) breast cancer. Although AIs improve overall survival, resistance is still a major clinical problem, thus additional biomarkers predictive of outcome of ER+ breast cancer patients treated with AIs are needed. Global gene expression analysis was performed on ER+ primary breast cancers from patients treated with adjuvant AI monotherapy; half experienced recurrence (median follow-up 6.7 years). Gene expression alterations were validated by qRT-PCR, and functional studies evaluating the effect of siRNA-mediated gene knockdown on cell growth were performed. Twenty-six genes, including TFF3, DACH1, RGS5, and GHR, were shown to exhibit altered expression in tumors from patients with recurrence versus non-recurrent (fold change ≥1.5, p proliferation, growth, and development. TFF3, which encodes for trefoil factor 3 and is an estrogen-responsive oncogene shown to play a functional role in tamoxifen resistance and metastasis of ER+ breast cancer, was also shown to be upregulated in an AI-resistant cell line model, and reduction of TFF3 levels using TFF3-specific siRNAs decreased the growth of both the AI-resistant and -sensitive parental cell lines. Moreover, overexpression of TFF3 in parental AI-sensitive MCF-7/S0.5 cells resulted in reduced sensitivity to the AI exemestane, whereas TFF3 overexpression had no effect on growth in the absence of exemestane, indicating that TFF3 mediates growth and survival signals that abrogate the growth inhibitory effect of exemestane. We identified a panel of 26 genes exhibiting altered expression associated with disease recurrence in patients treated with adjuvant AI monotherapy, including TFF3, which was shown to exhibit a growth- and survival-promoting effect in the context of AI treatment.

  12. Targeted Metabolomics Approach To Detect the Misuse of Steroidal Aromatase Inhibitors in Equine Sports by Biomarker Profiling.

    Science.gov (United States)

    Chan, George Ho Man; Ho, Emmie Ngai Man; Leung, David Kwan Kon; Wong, Kin Sing; Wan, Terence See Ming

    2016-01-01

    The use of anabolic androgenic steroids (AAS) is prohibited in both human and equine sports. The conventional approach in doping control testing for AAS (as well as other prohibited substances) is accomplished by the direct detection of target AAS or their characteristic metabolites in biological samples using hyphenated techniques such as gas chromatography or liquid chromatography coupled with mass spectrometry. Such an approach, however, falls short when dealing with unknown designer steroids where reference materials and their pharmacokinetics are not available. In addition, AASs with fast elimination times render the direct detection approach ineffective as the detection window is short. A targeted metabolomics approach is a plausible alternative to the conventional direct detection approach for controlling the misuse of AAS in sports. Because the administration of AAS of the same class may trigger similar physiological responses or effects in the body, it may be possible to detect such administrations by monitoring changes in the endogenous steroidal expression profile. This study attempts to evaluate the viability of using the targeted metabolomics approach to detect the administration of steroidal aromatase inhibitors, namely androst-4-ene-3,6,17-trione (6-OXO) and androsta-1,4,6-triene-3,17-dione (ATD), in horses. Total (free and conjugated) urinary concentrations of 31 endogenous steroids were determined by gas chromatography-tandem mass spectrometry for a group of 2 resting and 2 in-training thoroughbred geldings treated with either 6-OXO or ATD. Similar data were also obtained from a control (untreated) group of in-training thoroughbred geldings (n = 28). Statistical processing and chemometric procedures using principle component analysis and orthogonal projection to latent structures-discriminant analysis (OPLS-DA) have highlighted 7 potential biomarkers that could be used to differentiate urine samples obtained from the control and the treated groups

  13. Expression Patterns of Cytochrome P450 Aromatase Genes During Ovary Development and Their Responses to Temperature Stress in Female Yellow Catfish (Pelteobagrus fulvidraco)

    Institute of Scientific and Technical Information of China (English)

    LIU Miao; QI Baoxia; WEN Haishen; HE Feng; LI Jifang; SHI Dan; HU Jian; ZHANG Yuanqing; MA Ruiqin; MU Weijie

    2011-01-01

    Cytochrome P450 aromatase (P450arom) plays a pivotal role in ovary development.In this study,we used semi-quantitative reverse transcription PCR (RT-PCR) to analyze spatiotemporal expressions of two P450arom genes (CYP1gA and CYP19B)and their responses to temperature stress in female yellow catfish (Pelteobagrusfulvidraco).Tissue distribution pattern of CYP19showed that CYP19B was abundantly expressed in fish brain and ovary (brain>ovary),but weakly in intestines,whereas CYP19Awas exclusively expressed in ovary.Semi-quantitative RT-PCR analyses showed high transcript abundance of both CYP19A and CYP19B in the ovarian reproductive cycle,corresponding with serum estradiol-17β (E2) levels.Increases in aromatases,serum E2 and testosterone (T) levels in fish exposed to higher temperature indicated stimulation of ovarian maturation and recrudescence by heat stress in stages Ⅱ and V during the ovarian cycle,whereas associated decreases in stage III suggested vitellogenesis inhibition by heat stress.Gene expression of CYP19 was closely related to levels of serum E2.Results demonstrated CYP19 played a crucial role in the reproductive cycle of female yellow catfish.Different temperature stress affected CYP19 gene expression in the fish ovarian reproductive cycle.Associated P450arom genes could be useful for studying physiological aspects of yellow catfish.

  14. QUALITY OF LIFE OF WOMEN RECIEVING ADJUVANT HORMONAL TREATMENT FOR BREAST CANCER – A RANDOMIZED TRIAL COMPARING TAMOXIFEN WITH AROMATASE INHIBITORS

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    C. Volovat

    2011-05-01

    Full Text Available Purpose: The assessment and comparison of the quality of life in women with early stages breast cancer receiving Tamoxifen versus aromatase inhibitors (AINs. Methods: There were selected 223 patients treated at Center of Medical Oncology Iasi, with early stages breast cancer. The patients were divided in two groups: 115 patients receiving Tamoxifen and 107 patients receiving aromatase inhibitors. From the patients receiving AINs, 33 of patients have received Exemestane, 60 patients Letrozole and 14 patients Anastrazole. The patients have completed an EORTC C30 and EORTC BR23 questionnaire at the beginning of the treatment (after one month and after 2 years of treatment. There was calculated the difference related with global status, functional scales, emotional scales, cognitive scales and symptom scales. Results: Statistic results show a better quality of life for Anastrazole vs. Letrozole and for AINs vs. Tamoxifen group, mainly on physical scales both after 2 months and after 2 years of treatment. In the same time, the physical scales were with better results after 1 month of treatment vs. 2 years of treatment. Conclusions: Following the hormonal treatment period, there is a mild worsening of quality of life for Tamoxifen and AINs too. In the same time, the quality of life is better in the group with AINs treatment comparative with the Tamoxifen treatment.

  15. Effect of Yikun Neiyi Wan on the Expression of Aromatase P450,COX-2, and ER Related Receptor in Endometrial Cells in Vitro from Patients with Endometriosis

    Institute of Scientific and Technical Information of China (English)

    WANG Qing; ZHAO Hong; XIANG Qing; JU Hai; HAN Shu-min; WANG Ling-yan; XU Bo

    2009-01-01

    Objective: To investigate the effect of Yikun Neiyi Wan (益坤内异丸 YKNYW) and gestrinone on the expression of aromatase P450 (P450arom), cyclo-oxygenase-2 (COX-2) and estrogen receptor (ER) in isolated ectopic and normal endometrial stroma cells in vitro. Methods: Digestion and serial filtration were used to isolate and culture the ectopic and eutopic endometrial cells from patients with chocolate cyst in virto. Transformation of the cell morphology was observed in a inverted microscope. The effect of YKNYW on the expression of aromatase P450, cyclo-oxygenase-2, estrogen receptor in cultured endometriosis cells were detected by immunohistochemical method. Results: The expression levels of P450arom, COX-2 in glandular epithelium cells in vitro were decreased significantly by YKNYW compared with gestrinone (P<0.05). ER expression in mesenchymal cells of endometriosis was increased by YKNYW in the large and medium dosage groups compared with gestrinone. Conclusion: The mechanism by which YKNYW alleviates endometriosis pain is possibly related to the decrease in ectopic endometrial P450 arom and COX-2 expression in glandular epithelium, contrary to gestrinone, and the increase in ER expression in mesenchymalis, consistent with gestrione in patients with endometriosis.

  16. Targeted Metabolomics Approach To Detect the Misuse of Steroidal Aromatase Inhibitors in Equine Sports by Biomarker Profiling.

    Science.gov (United States)

    Chan, George Ho Man; Ho, Emmie Ngai Man; Leung, David Kwan Kon; Wong, Kin Sing; Wan, Terence See Ming

    2016-01-01

    The use of anabolic androgenic steroids (AAS) is prohibited in both human and equine sports. The conventional approach in doping control testing for AAS (as well as other prohibited substances) is accomplished by the direct detection of target AAS or their characteristic metabolites in biological samples using hyphenated techniques such as gas chromatography or liquid chromatography coupled with mass spectrometry. Such an approach, however, falls short when dealing with unknown designer steroids where reference materials and their pharmacokinetics are not available. In addition, AASs with fast elimination times render the direct detection approach ineffective as the detection window is short. A targeted metabolomics approach is a plausible alternative to the conventional direct detection approach for controlling the misuse of AAS in sports. Because the administration of AAS of the same class may trigger similar physiological responses or effects in the body, it may be possible to detect such administrations by monitoring changes in the endogenous steroidal expression profile. This study attempts to evaluate the viability of using the targeted metabolomics approach to detect the administration of steroidal aromatase inhibitors, namely androst-4-ene-3,6,17-trione (6-OXO) and androsta-1,4,6-triene-3,17-dione (ATD), in horses. Total (free and conjugated) urinary concentrations of 31 endogenous steroids were determined by gas chromatography-tandem mass spectrometry for a group of 2 resting and 2 in-training thoroughbred geldings treated with either 6-OXO or ATD. Similar data were also obtained from a control (untreated) group of in-training thoroughbred geldings (n = 28). Statistical processing and chemometric procedures using principle component analysis and orthogonal projection to latent structures-discriminant analysis (OPLS-DA) have highlighted 7 potential biomarkers that could be used to differentiate urine samples obtained from the control and the treated groups

  17. Sex differences, developmental changes, response to injury and cAMP regulation of the mRNA levels of steroidogenic acute regulatory protein, cytochrome p450scc, and aromatase in the olivocerebellar system.

    Science.gov (United States)

    Lavaque, Esteban; Mayen, Aurora; Azcoitia, Iñigo; Tena-Sempere, Manuel; Garcia-Segura, Luis M

    2006-02-15

    Compelling evidence has now demonstrated direct biological actions of sex steroids at the cerebellum. Likewise, the expression of key steroidogenic factors, such as the steroidogenic acute regulatory protein (StAR), cytochrome P450 side chain cleavage (P450scc), and aromatase, at this neural site has been reported. Little is known, however, about the regulation of their genes in the cerebellum. Assessment of StAR, P450scc, and aromatase mRNAs in the cerebellum of male and female rats revealed that the expression of these genes is developmentally regulated, with the highest levels at early postnatal ages in both sexes and with significantly higher mRNA levels in postnatal males. Expression of these genes in the female remained unaltered after perinatal androgenization and along the estrous cycle. In contrast, damage of cerebellar afferent neurons of the inferior olivary nucleus evoked a significant increase in StAR, P450scc, and aromatase mRNA levels at this site, as well as a transient elevation in StAR mRNA at the cerebellum. Finally, enhancement of cAMP levels in cultured cerebellar neurons induced a significant increase in StAR and aromatase mRNA levels. In summary, we present herein novel evidence for the developmentally regulated and partially sexually dimorphic pattern of expression of StAR, P450scc, and aromatase genes in the rat cerebellum. These observations, together with the finding that the mRNA levels of these steroidogenic molecules are sensitive to injury and are regulated by intracellular cAMP, strongly suggest that local steroidogenesis is likely to play an important role during development and adaptation to neurodegenerative processes in the olivocerebellar system. PMID:16329132

  18. Paradoxal metabolic flare detected by 18F-fluorodeoxyglucose positron emission tomography in a patient with metastatic breast cancer treated with aromatase inhibitor and biphosphonate

    International Nuclear Information System (INIS)

    Patients with estrogen-receptor-positive advanced breast cancer are treated with endocrine therapy. The majority of breast cancer localizations show 18F-fluorodeoxyglucose (FDG) uptake at positron emission tomography (PET) examination. In these patients, the metabolic flare after therapy is common and was proposed as an index of therapy efficacy. Nevertheless, prolonged persistence of flare can lead to misinterpretation. We describe a case of a patient with invasive ductal breast cancer with bone metastases at bone scintigraphy and FDG PET scan and with expression of estrogen receptors. Initially, the patient underwent endocrine therapy in addition to a biphosfonate. Owing to progression observed in a bone scan, Tamoxifen was substituted with aromatase inhibitors. Successive bone scan examinations showed stabilization with a marked clinical improvement. A second FDG PET was performed 28 months after the first examination and showed a metabolic flare phenomenon with concomitant partial calcification of osteolitic lesions. This is an unusual case of prolonged metabolic flare

  19. A systematic review and methodological evaluation of published cost-effectiveness analyses of aromatase inhibitors versus tamoxifen in early stage breast cancer.

    Directory of Open Access Journals (Sweden)

    Ava A John-Baptiste

    Full Text Available BACKGROUND: A key priority in developing policies for providing affordable cancer care is measuring the value for money of new therapies using cost-effectiveness analyses (CEAs. For CEA to be useful it should focus on relevant outcomes and include thorough investigation of uncertainty. Randomized controlled trials (RCTs of five years of aromatase inhibitors (AI versus five years of tamoxifen in the treatment of post-menopausal women with early stage breast cancer, show benefit of AI in terms of disease free survival (DFS but not overall survival (OS and indicate higher risk of fracture with AI. Policy-relevant CEA of AI versus tamoxifen should focus on OS and include analysis of uncertainty over key assumptions. METHODS: We conducted a systematic review of published CEAs comparing an AI to tamoxifen. We searched Ovid MEDLINE, EMBASE, PsychINFO, and the Cochrane Database of Systematic Reviews without language restrictions. We selected CEAs with outcomes expressed as cost per life year or cost per quality adjusted life year (QALY. We assessed quality using the Neumann checklist. Using structured forms two abstractors collected descriptive information, sources of data, baseline assumptions on effectiveness and adverse events, and recorded approaches to assessing parameter uncertainty, methodological uncertainty, and structural uncertainty. RESULTS: We identified 1,622 citations and 18 studies met inclusion criteria. All CE estimates assumed a survival benefit for aromatase inhibitors. Twelve studies performed sensitivity analysis on the risk of adverse events and 7 assumed no additional mortality risk with any adverse event. Sub-group analysis was limited; 6 studies examined older women, 2 examined women with low recurrence risk, and 1 examined women with multiple comorbidities. CONCLUSION: Published CEAs comparing AIs to tamoxifen assumed an OS benefit though none has been shown in RCTs, leading to an overestimate of the cost-effectiveness of AIs

  20. Germline variants in the CYP19A1 gene are related to specific adverse events in aromatase inhibitor users: a substudy of Dutch patients in the TEAM trial.

    Science.gov (United States)

    Fontein, Duveken B Y; Houtsma, Daniel; Nortier, Johan W R; Baak-Pablo, Renee F; Kranenbarg, Elma Meershoek-Klein; van der Straaten, Tahar R J H M; Putter, Hein; Seynaeve, Caroline; Gelderblom, Hans; van de Velde, Cornelis J H; Guchelaar, Henk-Jan

    2014-04-01

    Musculoskeletal adverse events (MSAEs) and vasomotor symptoms (VMSs) are known side-effects of aromatase inhibitors, and may be related to genetic variations of the aromatase gene (CYP19A1). We investigated the relationship between these specific AEs and single nucleotide polymorphisms (SNPs) in the CYP19A1 gene in postmenopausal, hormone receptor-positive early breast cancer (BC) patients treated with adjuvant exemestane for 5 years. Dutch patients who were randomized to receive 5 years of exemestane in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial were included. A tagging-SNP approach was performed, covering 80 % of variations of the CYP19A1 gene with 30 SNPs. Logistic regression analyses were used to assess the risk of reporting VMSs or MSAEs in relation to genotypes within selected SNPs. Of 737 included patients, 281 patients reported at least one MSAE (n = 210) or VMS (n = 163). Homozygous AA genotype of rs934635 was associated with a significantly higher odds of MSAEs (multivariate odds ratio (OR) 4.66, p = 0.008) and VMSs (multivariate OR 2.78, p = 0.044). Regarding both rs1694189 and rs7176005, the homozygous variant genotypes (TT) were associated with a higher odds of VMSs, but not MSAEs (OR 1.758, p = 0.025 and OR 6.361, p = 0.021, respectively). Our exploratory analysis demonstrated that some CYP19A1 gene variations may be associated with MSAEs and/or VMSs. Specifically, patients with the homozygous variant rs934635 genotype reported more MSAEs and VMSs. Although further confirmatory studies are warranted, genomic profiling can help identify patients at an increased risk of reporting these specific AEs, potentiating further personalized BC treatment. PMID:24590773

  1. Plasma concentrations of estradiol and testosterone, gonadal aromatase activity and ultrastructure of the testis in Xenopus laevis exposed to estradiol or atrazine

    International Nuclear Information System (INIS)

    The ultrastructure of testicular cells of adult male African clawed frogs (Xenopus laevis) exposed to either estradiol (0.1 μg/L) or 2-chloro-4-ethylamino-6-isopropyl-amino-s-triazine (atrazine; 10 or 100 μg/L) was examined by electron microscopy and compared to plasma concentrations of the steroid hormones, testosterone (T) and estradiol (E2), testicular aromatase activity and gonad growth expressed as the gonado-somatic index (GSI). Exposure to E2 caused significant changes both at the sub-cellular and biochemical levels. Exposure to E2 resulted in significantly fewer sperm cells, inhibition of meiotic division of germ cells, more lipid droplets that are storage compartments for the sex steroid hormone precursor cholesterol, and lesser plasma T concentrations. Although not statistically significant, frogs exposed to E2 had slightly smaller GSI values. These results may be indicative of an inhibition of gonad growth and disrupted germ cell development by E2. Concentrations of E2 in plasma were greater in frogs exposed to E2 in water. Exposure to neither concentration of atrazine caused effects on germ cell development, testicular aromatase activity or plasma hormone concentrations. These results suggest that atrazine does not affect testicular function. In contrast, exposure of male X. laevis to E2 led to sub-cellular events that are indicative of disruption of testicular development, and demasculinization processes (decrease of androgen hormone titers). These results indicate that atrazine does not cause responses that are similar to those caused by exposure to E2

  2. Complementary or alternative medicine as possible determinant of decreased persistence to aromatase inhibitor therapy among older women with non-metastatic breast cancer.

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    Laetitia Huiart

    Full Text Available PURPOSE: Aromatase inhibitor therapy (AI significantly improves survival in breast cancer patients. Little is known about adherence and persistence to aromatase inhibitors and about the causes of treatment discontinuation among older women. METHODS: We constituted a cohort of women over 65 receiving a first AI therapy for breast cancer between 2006 and 2008, and followed them until June 2011. Women were selected in the population-based French National Health Insurance databases, and data was collected on the basis of pharmacy refills, medical records and face-to-face interviews. Non-persistence to treatment was defined as the first treatment discontinuation lasting more than 3 consecutive months. Time to treatment discontinuation was studied using survival analysis techniques. RESULTS: Overall among the 382 selected women, non-persistence to treatment went from 8.7% (95%CI: 6.2-12.1 at 1 year, to 15.6% (95%CI: 12.2-19.8 at 2 years, 20.8% (95%CI: 16.7-25.6 at 3 years, and 24.7% (95%CI: 19.5-31.0 at 4 years. In the multivariate analysis on a sub-sample of 233 women with available data, women using complementary or alternative medicine (CAM (HR = 3.2; 95%CI: 1.5-6.9 or suffering from comorbidities (HR = 2.2; 95%CI: 1.0-4.8 were more likely to discontinue their treatment, whereas women with polypharmacy (HR = 0.4; 95%CI: 0.2-0.91 were less likely to discontinue. In addition, 13% of the women with positive hormonal receptor status did not fill any prescription for anti-hormonal therapy. CONCLUSION: AI therapy is discontinued prematurely in a substantial portion of older patients. Some patients may use CAM not as a complementary treatment, but as an alternative to conventional medicine. Improving patient-physician communication on the use of CAM may improve hormonal therapy adherence.

  3. A polymorphism at the 3'-UTR region of the aromatase gene defines a subgroup of postmenopausal breast cancer patients with poor response to neoadjuvant letrozole

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    Albaladejo Carlos

    2010-02-01

    Full Text Available Abstract Background Aromatase (CYP19A1 regulates estrogen biosynthesis. Polymorphisms in CYP19A1 have been related to the pathogenesis of breast cancer (BC. Inhibition of aromatase with letrozole constitutes the best option for treating estrogen-dependent BC in postmenopausal women. We evaluate a series of polymorphisms of CYP19A1 and their effect on response to neoadjuvant letrozole in early BC. Methods We analyzed 95 consecutive postmenopausal women with stage II-III ER/PgR [+] BC treated with neoadjuvant letrozole. Response to treatment was measured by radiology at 4th month by World Health Organization (WHO criteria. Three polymorphisms of CYP19A1, one in exon 7 (rs700519 and two in the 3'-UTR region (rs10046 and rs4646 were evaluated on DNA obtained from peripheral blood. Results Thirty-five women (36.8% achieved a radiological response to letrozole. The histopathological and immunohistochemical parameters, including hormonal receptor status, were not associated with the response to letrozole. Only the genetic variants (AC/AA of the rs4646 polymorphism were associated with poor response to letrozole (p = 0.03. Eighteen patients (18.9% reported a progression of the disease. Those patients carrying the genetic variants (AC/AA of rs4646 presented a lower progression-free survival than the patients homozygous for the reference variant (p = 0.0686. This effect was especially significant in the group of elderly patients not operated after letrozole induction (p = 0.009. Conclusions Our study reveals that the rs4646 polymorphism identifies a subgroup of stage II-III ER/PgR [+] BC patients with poor response to neoadjuvant letrozole and poor prognosis. Testing for the rs4646 polymorphism could be a useful tool in order to orientate the treatment in elderly BC patients.

  4. Inhibition of human CYP19 by azoles used as antifungal agents and aromatase inhibitors, using a new LC-MS/MS method for the analysis of estradiol product formation

    International Nuclear Information System (INIS)

    Azoles are used as fungicides in agriculture or antifungal drugs in medicine. Their therapeutic activity is based on the inhibition of fungal lanosterol-14α-demethylase (CYP51). Azoles are also used for the treatment of estrogen-dependent diseases, e.g. in breast cancer therapy. Inhibition of CYP19 (aromatase) is the working principle for tumor therapy, but is an unwanted side effect of azoles used as fungicides or antifungal drugs. The inhibition of recombinant human CYP19 by 21 azoles in use for the three different purposes was investigated using the natural substrate testosterone. Estradiol product formation was measured by a newly developed and fully validated analytical method based on liquid chromatography-tandem mass spectrometry utilizing photospray ionization (APPI). Potency of enzyme inhibition was expressed in terms of IC5 concentrations. The two cytostatic drugs fadrozole and letrozole were the most potent inhibitors. However, azoles used as fungicides, e.g. prochloraz, or as antifungal drugs, e.g. bifonazole, were almost as potent inhibitors of aromatase as the drugs used in tumor therapy. Comparison of plasma concentrations that may be reached in antifungal therapy do not allow for large safety factors for bifonazole and miconazole. The IC5 values were compared to data obtained with other substrates, such as the pseudo-substrate dibenzylfluorescein (DBF). A high correlation was found, indicating that the fluorescence assay with DBF can well be used for potency ranking and screening of chemicals for aromatase inhibition. The data for antifungal drugs show that side effects on steroid hormone synthesis in humans due to inhibition of aromatase should be considered

  5. Estrogen receptor and aromatase expression in gingival carcinoma tissue%雌激素受体及芳香化酶在牙龈癌组织中的表达和意义

    Institute of Scientific and Technical Information of China (English)

    王秋锐; 杨健; 赵华平; 张英怀

    2015-01-01

    AIM:To investigate the expression of estrogen receptor (ER)and aromatase in gingival carcino-ma.METHODS:ER and aromatase were detected by immunohistochemical staining SP method in gingival carcinoma (n=28)and normal gingival tissues(n=15).RESULTS:Positive expression rates of ER and aromatase expression in gingival carcinoma were 50.00% and 42.86% ,in normal gingival tissues were 13.33% and 6.67%,respectively (P<0.05).No significant correlation was found between ER and aromatase in gingival carcinoma.CONCLUSION:Estrogen metablism might be related to gingival carcinoma.Aromatase is not the exclusive reason of the high positive rate of ER.%目的:观察牙龈癌中雌激素受体(ER)与芳香化酶的表达情况,探讨局部雌激素及芳香化酶在牙龈癌中的作用与关系。方法:免疫组化过氧化物酶标记的链酶卵白素法测定雌激素受体及芳香化酶在牙龈癌中的表达。结果:牙龈癌组雌激素受体及芳香化酶的表达阳性率分别为50%和42.86%,正常对照组分别为13.33%和6.67%(P<0.05);牙龈癌中雌激素受体与芳香化酶之间未见明显相关性。结论:牙龈癌有一定的雌激素依赖性;芳香化酶在牙龈癌组织中表达升高,但芳香化酶并不是影响局部雌激素受体升高的唯一因素。

  6. The Efficacy of Bisphosphonates in Preventing Aromatase Inhibitor Induced Bone Loss for Postmenopausal Women with Early Breast Cancer: A Systematic Review and Meta-Analysis

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    Pooleriveetil Padikkal Anagha

    2014-01-01

    Full Text Available Objectives. We aim to determine the efficacy of bisphosphonates in preventing aromatase inhibitor induced bone loss (AIBL in postmenopausal women with early breast cancer. The secondary objective was to determine the safety of bisphosphonates. Materials and Methods. We searched electronic databases in a time period of 1995 January to 2013 June. Random effects meta-analytical models were used; between study heterogeneity and publication bias was assessed. Results. A total of six eligible studies reported the BMD T score of LS at 12 months and from that 3 trials of Zoledronic acid compared the change in BMD in immediate ZOL versus delayed ZOL done with subgroups like patients with normal BMD at baseline (OR = 5.402, 95% CI = 1.329–21.959, P value = 0.018 and osteopenic BMD at baseline (OR = 4.008, 95% CI = 2.249–7.143, P value = 0.0002. Both had a significant decrease in BMD that favoured the delayed ZOL; 3 trials of risedronate and ibandronate also had a significant decrease in BMD in AIs alone group. Immediate ZOL versus delayed ZOL also showed increased risk of getting an ADR in immediate group. Conclusion. Third generation bisphosphonates has an effect on BMD of patients who are on treatment of AIs in breast cancer. Furthermore, the patients treated with immediate ZOL had a significantly high risk of musculoskeletal ADR’s than patients with delayed ZOL.

  7. 芳香化酶抑制剂致骨质疏松研究进展%Research of aromatase inhibitor induced osteoporosis

    Institute of Scientific and Technical Information of China (English)

    马翠翠

    2008-01-01

    Breast cancer patients treated by aromatase inhibitor(AI) may cause ovarian failure, resulting in decreased hormone levels. Then bone loss increases, which may result in thinning bone and osteoporosis. In clinic, attention should be given and appropriate means must be chosen to prevent and treat this disease. Calcium + vitamin D, diphosphonate, selective estrogen receptor modulator, Chinese medicine are recommen-ded to reduce the incidence of esteoporosis.%乳腺癌患者服用芳香化酶抑制剂(AI)使得卵巢功能缺失导致体内雌激素水平下降,从而加速骨代谢发生骨质疏松.在临床中应给予重视并根据具体情况选择适当防治手段.推荐使用钙剂+维生素D、双膦酸盐、选择性雌激素受体调节剂、中药等药物治疗,减少骨质疏松的发病率.

  8. Chronic green tea consumption decreases body mass, induces aromatase expression, and changes proliferation and apoptosis in adult male rat adipose tissue.

    Science.gov (United States)

    Monteiro, Rosário; Assunção, Marco; Andrade, José P; Neves, Delminda; Calhau, Conceição; Azevedo, Isabel

    2008-11-01

    Green tea (GT) and its components have been shown to possess antiobesity properties and the corresponding mechanisms of action are being investigated, given the epidemic proportions of obesity incidence. In the current work, we used 12-mo-old male Wistar rats to test the effect of 6 mo of treatment with GT as the sole drinking beverage (52.8 +/- 6.4 mL/d) on adipose tissue (AT). AT aromatase expression was determined by Western blotting, plasma concentrations of 17beta-estradiol and testosterone were determined by RIA, and adipocyte size determined by measuring diameter in tissue sections. Proliferation and apoptosis were also assessed by Ki67 immunostaining and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling, respectively. Evaluations were made in subcutaneous (sc) AT and visceral (v) AT. Body weight increased over time in both groups (P rats had a higher percentage of proliferating cells (204.1 +/- 19.5% of control in scAT, P adipocytes (78.3 +/- 1.7% of control in scAT, P < 0.001, and 87.9 +/- 3.2% of control in vAT, P < 0.05). GT also increased the number of apoptotic cells in vAT (320.4 +/- 21.9% of control; P < 0.001). These results suggest new mechanisms for GT on body weight and highlight its potential benefit to prevent or treat obesity and the metabolic syndrome. PMID:18936213

  9. Testosterone treatment increases androgen receptor and aromatase gene expression in myotubes from patients with PCOS and controls, but does not induce insulin resistance

    DEFF Research Database (Denmark)

    Eriksen, Mette Brandt; Glintborg, Dorte; Nielsen, Michael Friberg Bruun;

    2014-01-01

    Polycystic ovary syndrome (PCOS) is associated with insulin resistance and increased risk of type 2 diabetes. Skeletal muscle is the major site of insulin mediated glucose disposal and the skeletal muscle tissue is capable to synthesize, convert and degrade androgens. Insulin sensitivity is conse......Polycystic ovary syndrome (PCOS) is associated with insulin resistance and increased risk of type 2 diabetes. Skeletal muscle is the major site of insulin mediated glucose disposal and the skeletal muscle tissue is capable to synthesize, convert and degrade androgens. Insulin sensitivity...... is conserved in cultured myotubes (in vitro) from patients with PCOS, but the effect of testosterone on this insulin sensitivity is unknown. We investigated the effect of 7days testosterone treatment (100nmol/l) on glucose transport and gene expression levels of hormone receptors and enzymes involved...... in the synthesis and conversion of testosterone (HSD17B1, HSD17B2, CYP19A1, SRD5A1-2, AR, ER-α, HSD17B6 and AKR1-3) in myotubes from ten patients with PCOS and ten matched controls. Testosterone treatment significantly increased aromatase and androgen receptor gene expression levels in patients and controls...

  10. Serum estradiol should be monitored not only during the peri-menopausal period but also the post-menopausal period at the time of aromatase inhibitor administration

    Directory of Open Access Journals (Sweden)

    Zembutsu Hitoshi

    2009-11-01

    Full Text Available Abstract Background Aromatase inhibitor (AI therapy is being extensively used as postoperative adjuvant therapy in patients with hormone receptor-positive postmenopausal breast cancer. On the other hand, it has been reported that ovarian function was restored when AI was administered to patients who had undergone chemical menopause with chemotherapy or tamoxifen. However, there have been no reports of comprehensive monitoring of estradiol (E2 in breast cancer patients with ordinary menopause who were being administered AI. Patients and Methods Beginning in March 2008, regular monitoring of the serum levels of E2, luteinizing hormone (LH and follicle-stimulating hormone (FSH was performed for 66 postmenopausal breast cancer patients who had been started on AI therapy. For this study, we chose anastrozole as the AI. The assays of those hormones were outsourced to a commercial clinical laboratory. Results In 4 of the 66 patients the serum E2 level was decreased at 3 months but had then increased at 6 months, while in 2 other patients E2 was decreased at both 3 and 6 months but had increased at 9 months. Conclusion The results indicate that, in some breast cancer patients with ordinary menopause, E2 rebounds following AI therapy. In the future, E2 monitoring should be performed for a larger number of patients being administered AI therapy. Trial registration Our trial registration number is 19-11-1211.

  11. 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.

  12. miR-155 Drives Metabolic Reprogramming of ER+ Breast Cancer Cells Following Long-Term Estrogen Deprivation and Predicts Clinical Response to Aromatase Inhibitors.

    Science.gov (United States)

    Bacci, Marina; Giannoni, Elisa; Fearns, Antony; Ribas, Ricardo; Gao, Qiong; Taddei, Maria Letizia; Pintus, Gianfranco; Dowsett, Mitch; Isacke, Clare M; Martin, Lesley-Ann; Chiarugi, Paola; Morandi, Andrea

    2016-03-15

    Aromatase inhibitors (AI) have become the first-line endocrine treatment of choice for postmenopausal estrogen receptor-positive (ER(+)) breast cancer patients, but resistance remains a major challenge. Metabolic reprogramming is a hallmark of cancer and may contribute to drug resistance. Here, we investigated the link between altered breast cancer metabolism and AI resistance using AI-resistant and sensitive breast cancer cells, patient tumor samples, and AI-sensitive human xenografts. We found that long-term estrogen deprivation (LTED), a model of AI resistance, was associated with increased glycolysis dependency. Targeting the glycolysis-priming enzyme hexokinase-2 (HK2) in combination with the AI, letrozole, synergistically reduced cell viability in AI-sensitive models. Conversely, MCF7-LTED cells, which displayed a high degree of metabolic plasticity, switched to oxidative phosphorylation when glycolysis was impaired. This effect was ER dependent as breast cancer cells with undetectable levels of ER failed to exhibit metabolic plasticity. MCF7-LTED cells were also more motile than their parental counterparts and assumed amoeboid-like invasive abilities upon glycolysis inhibition with 2-deoxyglucose (2-DG). Mechanistic investigations further revealed an important role for miR-155 in metabolic reprogramming. Suppression of miR-155 resulted in sensitization of MCF7-LTED cells to metformin treatment and impairment of 2-DG-induced motility. Notably, high baseline miR-155 expression correlated with poor response to AI therapy in a cohort of ER(+) breast cancers treated with neoadjuvant anastrozole. These findings suggest that miR-155 represents a biomarker potentially capable of identifying the subset of breast cancers most likely to adapt to and relapse on AI therapy. PMID:26795347

  13. Between-female variation in house sparrow yolk testosterone concentration is negatively associated with CYP19A1 (aromatase) mRNA expression in ovarian follicles.

    Science.gov (United States)

    Egbert, Jeremy R; Jackson, Melissa F; Rodgers, Buel D; Schwabl, Hubert

    2013-03-01

    Maternally-derived yolk androgens influence the development and long-term phenotype of offspring in oviparous species. Between-female variation in the amounts of these yolk androgens has been associated with a number of social and environmental factors, suggesting that the variation is adaptive, but the mechanisms behind it are unknown. Using two different approaches, we tested the hypothesis that variation in yolk androgen levels across individuals is associated with variation in their capacity to synthesize androgens. First, we injected female house sparrows with exogenous gonadotropin-releasing hormone (GnRH) to maximally stimulate ovarian steroidogenesis. Second, we collected pre-ovulatory follicle tissue and quantified the mRNA expression of four key enzymes of the steroid synthesis pathway: steroidogenic acute regulatory protein (StAR), cytochrome P450-side chain cleavage enzyme (CYP11A1), 17β-hydroxysteroid dehydrogenase (HSD17B1), and aromatase (CYP19A1). Thirty minutes after GnRH injection, androgen concentrations in both the plasma and in the yolks of pre-ovulatory follicles were significantly elevated compared to controls. However, this measure of steroidogenic capacity did not explain variation in yolk testosterone levels, although physiological differences between house sparrows and more widely studied poultry models were revealed by this approach. Steroidogenic enzyme mRNA levels were detectable in all samples and were significantly lower in the most mature pre-ovulatory follicles. Of the four measured genes, CYP19A1 expression exhibited a significant negative relationship with yolk testosterone concentrations in laid eggs, revealing a key mechanism for between-female variation in yolk testosterone. Furthermore, this suggests that any factors which alter the expression of CYP19A1 within an individual female could have dramatic effects on offspring phenotype. PMID:23247271

  14. Effects of 17α-Methyltestosterone and Aromatase Inhibitor Letrozole on Sex Reversal, Gonadal Structure, and Growth in Yellow Catfish Pelteobagrus fulvidraco.

    Science.gov (United States)

    Shen, Zhi-Gang; Fan, Qi-Xue; Yang, Wei; Zhang, Yun-Long; Wang, Han-Ping

    2015-04-01

    Monosex populations are in demand in many fish species with sexual dimorphism, e.g., better growth performance, higher gonad value, superior ornamental value. From the point of view of research, a monosex population is one of the best materials for investigating sex-determining mechanisms, sex differentiation, and sex-linked markers. Sex reversal of females (phenotypic reversal from XX female to XX male) is the first step in all-female production in species with an XX/XY system for sex determination. In the present study, masculinization of yellow catfish, a species with XX/XY sex determination, was investigated by oral administration of various doses of 17α-methyltestosterone (MT) or an aromatase inhibitor (AI) letrozole (LZ); effects on survival, growth performance, sex ratio, and changes in gonadal structure were evaluated. Three doses (20, 50, and 100 mg kg(-1) diet) of oral MT or LZ were administered to fry from 10 days post-hatching (DPH) to 59 DPH. Oral administration of MT at all doses did not significantly change the ratio of males (45.8%, 33.3%, and 50.0% respectively) compared to the control group (37.5%), while yielding intersex fish at all doses (4.2% to 8.3%). Oral administration of LZ produced a significantly higher proportion of males in all doses (75.5%, 83.3%, and 75.0%, respectively). Additionally, the lowest dose of LZ improved the growth of treated fish compared to the control, and all doses of LZ enhanced spermatogenesis in treated males. PMID:25920714

  15. Increase in in utero exposure to a migrant, 4,4'-butylidenebis(6-t-butyl-m-cresol), from nitrile-butadiene rubber gloves on brain aromatase activity in male rats.

    Science.gov (United States)

    Satoh, Kanako; Nonaka, Ryouichi; Nakae, Dai; Ogata, Akio

    2010-01-01

    4,4'-Butylidenebis(6-t-butyl-m-cresol) (BBBC) can be eluted from disposable gloves made of nitrile-butadiene rubber and possibly also detected in food. It has been reported that BBBC is an androgen and estrogen antagonist in vitro. Previously, BBBC (1.0 mg/kg body weight (bw)/d) was subcutaneously administered to pregnant rats from gestation days 11 through 18, and the effects on male offspring (postnatal day 102) were examined. Altered levels and turnover of the monoamines dopamine, serotonin, and noradrenalin as well as their metabolites were detected. This report measured the level of serum testosterone following prenatal exposure to BBBC (0.1, 1.0, 10 mg/kg bw/d) in male rats, and measured aromatase activity of the hypothalamus-preoptic area with a close connection to the sexual differentiation and sexual behavior of BBBC-treated rat brains. The serum testosterone level rose depending on exposure, and aromatase activity of the basomedial nucleus of amygdale region was increased in the BBBC-treated group compared with the control. These results suggested that prenatal exposure to BBBC affects the central nervous system of male rat offspring, and BBBC may be an endocrine disrupting-chemical during the fetal period, and might influence the functional development of the brain.

  16. 血清CA125联合子宫内膜芳香化酶检测诊断子宫内膜异位症%Diagnostic value of serum CA125 level and endometrial aromatase detection to endometriosis

    Institute of Scientific and Technical Information of China (English)

    邹华兰; 洛若愚; 熊霞鹂

    2011-01-01

    目的:探讨血清CA125、子宫内膜芳香化酶检测诊断子宫内膜异住症(endometriosis,EMs)的价值,方法:经腹腔镜或开腹手术确诊的EMs患者40例(EMs组),因盆腔炎行腹腔镜手术且排除EMs的患者20例(对照组),术前均抽血检测血清CA125水平,术中取其子宫内膜,采用免疫组织化学法检测芳香化酶的表达情况,并进行比较.结果:EMs组血清CA125水平高于对照组(P0.05).以血清CAl25≥35 μ/mL为临界值,诊断EMs的敏感性为55.0%,特异性为80.O%;免疫组织化学检测子宫内膜芳香化酶诊断EMs的敏感性为92.5%.特异性为90.0%;2种方法联合检测诊断EMs的敏感性95.0%,特异性70.5%.结论:血清CA125联合子宫内膜芳香化酶检测可提高EMs的早期诊断率和诊断准确性.%Objective To explore the value of serum CA125 level and endometrial aromatase detection to the diagnosis of endometriosis. Methods Forty patients with endometriosis diagnosed by laparoscopy or laparotomy (endometriosis group) and 20 patients receiving laparoscopy due to pelvic inflammatory disease(control group) were detected the serum CA125 level before operation. The expression of aromatase protein was detected with immunohistochemistry. The results were compared between two groups. Results Serum CA125 level was higher in endometriosis group than that in control group(P<0.05), and was higher in Ⅲ to Ⅳ stage of endometriosis than that in Ⅰ to Ⅱ stage (P<0.05). Aromatase expression of eutopic endometrium was higher in endometriosis group than that in control group(P<0.05), and showed no significant difference between Ⅲ to Ⅳ stage and Ⅰ to Ⅱ stages(P>0.05). As the cut-off of serum CA125≥35 u/mL, the sensitivity for endometriosis was 55.0% and the specificity was 80.0%. The diagnostic sensitivity of endometrial aromatase expression detected with immunohistochemistry was 92.5 % and the specificity was 90.0 %. The sensitivity of the combined methods for

  17. Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): a phase II, double-blind, placebo-controlled, randomized trial.

    Science.gov (United States)

    Rastelli, Antonella L; Taylor, Marie E; Gao, Feng; Armamento-Villareal, Reina; Jamalabadi-Majidi, Shohreh; Napoli, Nicola; Ellis, Matthew J

    2011-08-01

    A double-blind placebo-controlled randomized phase II trial was performed to determine whether High Dose Vitamin D2 supplementation (HDD) in women receiving adjuvant anastrozole improves aromatase inhibitor-induced musculoskeletal symptoms (AIMSS) and bone loss. Patients with early breast cancer and AIMSS were stratified according to their baseline 25-hydroxy vitamin D (25OHD) level. Stratum A (20-29 ng/ml) received either HDD 50,000 IU capsules weekly for 8 weeks then monthly for 4 months or placebo. Stratum B (10-19 ng/ml) received either HDD for 16 weeks and then monthly for 2 months, or placebo. AIMSS was assessed by the Brief Pain Inventory-Short Form (BPI-SF), the Fibromyalgia Impact Questionnaire (FIQ), and the Health Assessment Questionnaire-Disability Index (HAQ-DI) at baseline, 2, 4, and 6 months. Bone Mineral Density (BMD) was measured at baseline and at 6 months. The primary endpoint of the study was the change-from-baseline musculoskeletal pain. The secondary endpoint was the percent change in BMD at 6 months. Sixty women were enrolled. Baseline characteristics were comparable between the groups. At 2 months, FIQ pain (P = 0.0045), BPI worst-pain (P = 0.04), BPI average-pain (P = 0.0067), BPI pain-severity (P = 0.04), and BPI interference (P = 0.034) scores were better in the HDD than placebo group. The positive effect of HDD on AIMSS was stronger across all time points in Stratum B than Stratum A (FIQ pain, P = 0.04; BPI average, P = 0.03; BPI severity, P = 0.03; BPI interference, P = 0.04). BMD at the femoral neck decreased in the placebo and did not change in the HDD group (P = 0.06). Weekly HDD improves AIMSS and may have a positive effect on bone health. Vitamin D supplementation strategies for breast cancer patients on AI should be further investigated. PMID:21691817

  18. 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)

    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

  19. Effect of ultra-low-dose estriol and lactobacilli vaginal tablets (Gynoflor®) on inflammatory and infectious markers of the vaginal ecosystem in postmenopausal women with breast cancer on aromatase inhibitors.

    Science.gov (United States)

    Donders, G; Bellen, G; Neven, P; Grob, P; Prasauskas, V; Buchholz, S; Ortmann, O

    2015-10-01

    This study was a detailed microscopic analysis of the changes of vaginal microflora characteristics after application of 0.03 mg estriol-lactobacilli combination on the vaginal ecosystem in postmenopausal breast cancer (BC) survivors on aromatase inhibitors (AI) with severe atrophic vaginitis. A total of 16 BC women on AI applied daily one vaginal tablet of Gynoflor® for 28 days followed by a maintenance therapy of three tablets weekly for 8 weeks. During four follow up visits a smear from the upper lateral vaginal wall was analysed by phase contrast microscopy at 400 times magnification in order to classify the lactobacillary grades(LBG), bacterial vaginosis (BV), aerobic vaginitis (AV), vulvovaginal candidosis (VVC), proportional number of leukocytes and evidence of parabasal cells and epitheliolysis. LBG improved from 81% LBG-III at entry to 88% LBG-I&IIa after 2 weeks of initial therapy, which further improved upon follow up (p lactobacilli results in rapid and enduring improvement of all markers of the vaginal microflora and epithelial vaginal cell quality in women with breast cancer on AI with dyspareunia. Candida may develop soon after its use, but rapidly disappears again upon their prolonged use. Due to its excellent safety profiles and clinical efficacy we recommend this product as first choice in women on AI with severe dyspareunia.

  20. Localization of aromatase in the nervous system, Hatschek's pit and gonad of amphioxus by in situ hybridization and immunocytochemistry%芳香化酶在文昌鱼神经系统、哈氏窝和性腺特异性定位:原位杂交和免疫细胞化学研究

    Institute of Scientific and Technical Information of China (English)

    方永强; 翁幼竹; 黄威权; 孙岚

    2003-01-01

    芳香化酶活性发现在脊椎动物脑、脑垂体和性腺中,但在文昌鱼脑和哈氏窝的组织特异性定位尚无可利用资料.本文用免疫细胞化学和原位杂交技术,首次发现芳香化酶活性组织特异性定位在幼年和性腺发育不同时期雌、雄文昌鱼神经系统(脑和脊髓)、轮器、哈氏窝和性腺中.芳香化酶蛋白和转录物在前脑、中脑、脊髓、轮器和哈氏窝十分丰富,而后脑、早期卵巢和精巢不够丰富;没有芳香化酶表达的部位是哈氏窝另两种细胞(不规则形细胞和带纤毛粘液细胞)以及成熟卵巢和精巢;芳香化酶免疫活性物质分布在胞质,核为阴性.芳香化酶在文昌鱼神经系统、哈氏窝和性腺的分布模式与低等脊椎动物中的分布模式极为类似,尤其是芳香化酶在脑内调节哈氏窝分泌活动的神经内分泌中枢表达,并形成类似脊椎动物的文昌鱼原始的脑-芳香化酶调节系统.这些结果有力地证明,文昌鱼脑和哈氏窝高水平的芳香化酶活性像在其它脊椎动物中一样,对局部介导睾酮芳香化起着关键作用,同时还可能影响脑-芳香化酶系统参与调节哈氏窝的分泌活动[动物学报49(6):800~806,2003].%Aromatase activity has been found in the brain and pituitary as well as gonads of vertebrates, but no information is available on the specific localization in the brain and Hatschek's pit (primitive pituitary) of amphioxus (Branchios-toma belcheri). Using immunocytochemistry and in situ hybridization, we studied definitive tissue specific localization of aromatase in the nervous system (brain and spinal cord), wheel organ, Hatschek's pit and gonads at young and adult female and male amphioxus at different stages of gonadal development. Aromatase protein and its mRNA were abundant in the forebrain, midbrain, spinal cord, wheel organ and Hatschek's pit, but not abundant in the hindbrain or early ovary and testis. No aromatase expression

  1. Effect of ultra-low-dose estriol and lactobacilli vaginal tablets (Gynoflor®) on inflammatory and infectious markers of the vaginal ecosystem in postmenopausal women with breast cancer on aromatase inhibitors.

    Science.gov (United States)

    Donders, G; Bellen, G; Neven, P; Grob, P; Prasauskas, V; Buchholz, S; Ortmann, O

    2015-10-01

    This study was a detailed microscopic analysis of the changes of vaginal microflora characteristics after application of 0.03 mg estriol-lactobacilli combination on the vaginal ecosystem in postmenopausal breast cancer (BC) survivors on aromatase inhibitors (AI) with severe atrophic vaginitis. A total of 16 BC women on AI applied daily one vaginal tablet of Gynoflor® for 28 days followed by a maintenance therapy of three tablets weekly for 8 weeks. During four follow up visits a smear from the upper lateral vaginal wall was analysed by phase contrast microscopy at 400 times magnification in order to classify the lactobacillary grades(LBG), bacterial vaginosis (BV), aerobic vaginitis (AV), vulvovaginal candidosis (VVC), proportional number of leukocytes and evidence of parabasal cells and epitheliolysis. LBG improved from 81% LBG-III at entry to 88% LBG-I&IIa after 2 weeks of initial therapy, which further improved upon follow up (p treatment (p < 0.01). While at entry most patients had moderate or severe AV, after maintenance therapy no patient except one had AV. The number of leukocytes dropped dramatically from a score of 1.78 ± 0.70 to 1.06 ± 0.25 which was consistent till the end of the study (p < 0.01). Parabasal cells dropped from a score of 3.4 ± 0.64 at entry to 1.3 ± 0.60 at the final visit (p trend < 0.01). Starting from a low rate of Candida colonisation of 2/14 (14%), a sudden rise to 7/16 (44%) occurred after 2 weeks, to return back to base levels at subsequent visits. The vaginal use of ultra-low dose estriol and lactobacilli results in rapid and enduring improvement of all markers of the vaginal microflora and epithelial vaginal cell quality in women with breast cancer on AI with dyspareunia. Candida may develop soon after its use, but rapidly disappears again upon their prolonged use. Due to its excellent safety profiles and clinical efficacy we recommend this product as first choice in women on AI with severe dyspareunia. PMID:26223323

  2. Aromatase inhibitors in the treatment of endometriosis

    OpenAIRE

    Słopień, Radosław; Męczekalski, Błażej

    2016-01-01

    Endometriosis is a chronic inflammatory condition in which foci of endometrial tissue grow outside of the uterine cavity. Endometriosis was estimated to affect 176 million women of childbearing potential all over the world in 2010. The presence of extrauterine endometrial tissue is associated with pain and infertility. Typical symptoms of endometriosis include dysmenorrhoea, dyspareunia, heavy menstrual periods (menorrhagia), pelvic pain that is not related to menstrual cycles, dysuria, and c...

  3. Aromatase Inhibitors for IVF Poor Responders

    Institute of Scientific and Technical Information of China (English)

    R.B. Quintero; L.C Giudice; L.M. Westphal

    2006-01-01

    Objective To evaluate whether letrozole enhanced follicular recruitment, embryo numbers, and pregnancy rates in poor responders undergoing IVF.Methods We reviewed all IVF cycles between January 2002 and September 2003 using letrozole at Stanford University Medical Center. The entry criteria were the requirement of at least 450 IU/d of injectable gonadotropins in a prior failed cycle,which was used as a control.Results A total of 27 charts were reviewed revealing information on 54 cycles. The number of oocytes retrieved, fertilization embryo quality and embryos transferred yielded no statistical significance, although there appeared to be a trend toward higher numbers of each in the letrozole group. The clinical pregnancy rate was 9/27 (33.3%, P<0. 001)with a viable pregnancy rate of 7/27 (25.9%, P=0.002) in the letrozole cycle.Conclusion Our study is one of the first to evaluate letrozole with in vitro fertilization.Although this study showed no difference in number of oocytes or embryos, 25.9% of these "poor responding" patients achieved a pregnancy after a failed cycle at our center.

  4. Aromatase inhibitors in stimulated IVF cycles

    DEFF Research Database (Denmark)

    Papanikolaou, Evangelos G; Polyzos, Nikolaos P; Al Humaidan, Peter Samir Heskjær;

    2011-01-01

    are available regarding their efficacy in IVF stimulated cycles. Current available evidence support that letrozole may have a promising role in stimulated IVF cycles, either when administered during the follicular phase for ovarian stimulation. Especially for women with poor ovarian response, letrozole appears...... to test in the future how it may perform when used in GnRH agonist cycles. Finally administration of letrozole during luteal phase in IVF cycles offers another treatment modality for patients at high risk for OHSS taking into account that it drastically reduces estradiol levels....

  5. Aromatase inhibitors in adjuvant endocrine treatment of breast cancer: ending the debate of sequence or upfront?——interpretation of BIG 1-98 clinical trial%乳腺癌芳香化酶抑制剂辅助内分泌治疗:序贯或初始应用争论的结束?——解读BIG 1-98临床试验

    Institute of Scientific and Technical Information of China (English)

    陈小松; 沈坤炜

    2010-01-01

    The third generation of aromatase inhibitors (AI) play an important role in the adjuvant treatment of hormonal positive postmenopausal breast cancer. Compared with tamoxifen, either upfront or sequential using of Al can both significantly improve the outcome of breast cancer patients. However, there is a continuous debate of sequence or upfront usage of Al in clinical applications. With the publication result of BIG 1-98 clinical trial and interpretation of the data, we can further recognize and optimize the usage of Al in breast cancer treatment.%第三代芳香化酶抑制剂(aromatase inhibitors,AI)在绝经后激素受体阳性乳腺癌辅助治疗中占据着重要的地位.与他莫昔芬相比,初始或序贯应用AI均可显著提高乳腺癌患者的预后,但在临床实践中,具体是选择初始还是序贯应用AI一直存在争议.随着BIG 1-98临床试验结果的公布及对其数据的解读,可进一步认识并优化AI在乳腺癌临床上的应用.

  6. The osteoporosis knowledge and self-efficacy investigation in patients of breast cancer treated with aromatase inhibitors%乳腺癌芳香化酶抑制剂治疗患者骨质疏松知识掌握情况与自我效能水平的调查

    Institute of Scientific and Technical Information of China (English)

    倪建芬; 方群英; 吴怡; 张永芳; 蒋春儿; 江子芳

    2015-01-01

    Objective To investigate the mastering of osteoporosis knowledge and the level of self-efficacy in patients treated with aromatase inhibitors and to provide references for further preventive interventions. Methods A total of seventy five patients with breast cancer treated with aromatase inhibitors were recruited from Zhejiang Cancer Hospital using convenience sampling method. They were investigated with osteoporosis knowledge test ( OKT ) and osteoporosis self-efficacy scale ( OSES ) . Results The total score of osteoporosis knowledge was 51. 90, in which the score of risk factors of osteoporosis, exercise and calcium intake were 55. 75,50. 67 and 47. 67, respectively. The correct rate of osteoporosis knowledge was statistically different in people with different educational level and approach of health education (P<0. 05). The total score of self-efficacy and factor scores of exercise and calcium intake were (59. 80 ± 19. 88),(60. 25 ± 21. 99),(59. 35 ± 17. 76)respectively. Conclusions It is suggested to strengthen osteoporosis related health education for patients with breast cancer, and to increase their health information and beliefs, and help them to formulate health behaviors to prevent osteoporosis.%目的:探讨乳腺癌芳香化酶抑制剂治疗患者的骨质疏松知识掌握情况和自我效能的水平,为进一步预防干预提供依据。方法应用便利抽样的方法,于2014年1—6月在浙江省肿瘤医院选取符合标准的75例患者,采用骨质疏松知识问卷、骨质疏松自我效能问卷进行调查。结果75例芳香化酶抑制剂治疗的乳腺癌患者骨质疏松知识总标准分为51.90分,其中,危险因素、运动量表和钙量表的标准分分别为55.75,50.67,47.67分。不同文化程度、健康教育接受情况患者骨质疏松知识正确率差异有统计学意义(P<0.05)。75例乳腺癌患者骨质疏松自我效能总量表、运动分量表和钙摄入分量表的平均得分分别为(59.80±19

  7. 芳香化酶抑制剂对暗纹东方鲀CYP19A、DMRT1基因表达及性腺分化的影响%Effect of aromatase inhibitor on expression of CYP19A, DMRT1, and gonadal sex differentiation in Takifugu obscures

    Institute of Scientific and Technical Information of China (English)

    黄波; 杨小玉; 戴奇; 汪奇; 云丹; 周忠良

    2013-01-01

      采用组织学和分子生物学方法,研究了投喂芳香化酶抑制剂来曲唑(LE)后暗纹东方(Takifugu obscures)初鲀孵仔鱼CYP19A、DMRT1基因表达以及性腺的组织学变化,以期进一步了解P450芳香化酶(P450arom)在鱼类早期性别分化过程中的作用.RT-PCR 结果显示,对照组样品 CYP19A 和 DMRT1表达显示性二态,雌性表达 CYP19A基因,雄性表达 DMRT1基因.LE 处理组在性别分化期间,雄性样品单一表达 DMRT1,雌性样品则同时表达CYP19A 和 DMRT1.qRT-PCR 结果显示: LE 处理组雌性仔鱼 CYP19A 基因表达被显著抑;虽然在仔鱼出膜后22 d(dph)的表达水平高于9 dph,但仅为同日对照组的2.11%.LE处理组雌性样品22 dph时DMRT1基因表达量上调,至150 dph时达对照组雄性水平.55 dph的性腺组织学结果表明, LE处理可导致暗纹东方稚鱼原始卵巢退化,并鲀向功能性精巢发育.150 dph的LE处理组性腺均为精巢,并与对照组精巢发育同步.结论认为,暗纹东方性腺鲀分化期间P450arom是卵巢形成和维持发育所必须的,抑制P450arom活性可导致雌性暗纹东方发生雄性化逆转.鲀%As in all other lower vertebrates, sex differentiation in fish is susceptible to environmental and steroi-dogenic stimulation or inhibition. Alteration of the sex differentiation process is possible in many fishes through the manipulation of the environment and steroid function. Some chemicals, which have androgenic or estrogenic function, are known to alter the gonadal sex in fish from female to male or vice versa if administered during the period of gonadal sex differentiation. Other than direct androgenic or estrogenic effects, there are chemicals which are capable of disrupting the enzymatic pathway of natural androgenic-estrogenic balance in fish. Among the non-steroidal aromatase inhibitors (AI), letrozole is typically used as an effective human drug in the treatment of estrogen-dependent disease, including breast

  8. 他莫昔芬治疗芳香化酶抑制剂耐药的激素受体阳性绝经后转移性乳腺癌患者的临床研究%Clinical observation of tamoxifen in hormone receptor - positive postmenopausal patients with metastatic breast cancer failing to Aromatase inhibitors

    Institute of Scientific and Technical Information of China (English)

    童刚领; 李柱; 农巧红; 何艳玲; 申东兰; 王树滨

    2015-01-01

    Objective:To investigate the curative effect and safety of tamoxifen in hormone receptor - positive (HR + )postmenopausal patients with metastatic breast cancer(MBC)failing to Aromatase inhibitors(AIs). Meth-ods:Retrospectively analyzed clinical data of 30 patients with HR + postmenopausal MBC treated with tamoxifen after AIs resistance. The endpoints were response rate(RR),clinical benefit rate(CBR),time of tumor progression(TTP) and safety. Results:In 30 patients,the patients who acquired CR,PR and SD were 1,9 and 15. The RR and CBR were 33. 3% and 50% . The median TTP was 6. 1 months. The RR and CBR in 23 cases with bone and/ or soft tissue me-tastasis and 7 cases of liver and/ or pulmonary metastasis were 34. 8% ,52. 2% and 28. 6% ,42. 8% . The median TTP were 7. 3 and 4. 8 months in two groups(P = 0. 019). The most common adverse reactions were hot flashes,vaginal dryness,vaginal discharge,vaginal bleeding,nausea,vomiting,diarrhea and so on. Most side effects were grade Ⅰ orⅡ on the WHO scale. Conclusion:Treatment with tamoxifen in AIs resistant HR + postmenopausal patients with MBC is safe and effective,can improve prognosis of patients.%目的:探讨他莫昔芬治疗芳香化酶抑制剂(AIs)耐药的激素受体阳性(HR +)绝经后转移性乳腺癌(MBC)患者的疗效和安全性。方法:回顾性分析他莫昔芬治疗 AIs 耐药的30例 HR +绝经后 MBC 患者的临床资料,观察终点为缓解率(RR)、临床获益率(CBR)、疾病进展时间(TTP)和安全性。结果:30例患者中,CR 1例,PR 9例,SD 15例,RR 为33.3%,CBR 为50%,中位 TTP 6.1个月。23例骨和/或软组织转移患者中,RR为34.8%,CBR 为52.2%,中位 TTP 7.3 个月;7例肝脏和/或肺部转移患者中,RR 为28.6%,CBR 为42.8%,中位 TTP 4.8 个月(P =0.019)。不良反应多为面部潮红、阴道干燥、白带增多、阴道出血、恶心、呕吐、腹泻等,均为 I、II 级

  9. Histological Analysis and Aromatase Gene Expression in Sex Differentiation in Takifugu obscures%暗纹东方鲀(Takifugu obscurus)性别分化的组织学及芳香化酶基因表达研究

    Institute of Scientific and Technical Information of China (English)

    李延伸; 戴奇; 郭正龙; 朱永祥; 黄波; 周忠良

    2011-01-01

    采用组织切片技术和实时定量PCR(qRT-PCR)方法研究了暗纹东方鲀性别分化过程中性腺发育的组织学及芳香化酶基因CYP19A的表达变化.结果显示:孵化后11d的仔鱼切片中可看到原始生殖细胞(PGC);孵化后17d可看到隆起的性腺原基(GA);孵化后26d发育成为原始性腺(PG)并从体腔膜上游离出来.卵巢分化时间早于精巢,在孵化后35d切片中部分个体出现原始卵巢腔(Oc);雄性个体在孵化后41d观察到裂隙状输精管原基(Sd);孵化后47d原始精小叶和输精管形成.生殖细胞分化出现较晚,孵化后80d样品中,雌性出现原始的卵巢小叶(Ol),雄性精小叶向精巢内部深入并逐步增大,但未见初级卵母细胞或精母细胞.CYP19A基因的表达较早出现两性分化现象,雌性个体在孵化后16dCYP19A的mRNA表达显著上调,雄性则在孵化后66d略有上调.进一步证明雌激素在卵巢分化以及精原细胞增殖中的重要作用.%The process of gonadal differentiation and Aromatase gene CYP19A expression in Takifugu obscures was studied by histological analysis and quantitative real-time PCR(qRT-PCR).The results of histological analysis showed: primordial germ cells(PGC) was observed at 11 dah(day after hatching),and gonad anlage(GA) occurred at 17 dah;Primitive gonad(PG) freed from the coelarium was observed at 26 dah.Ovarian differentiation occurred earlier than testicular.The original ovarian cavity(Oc) appeared in some individuals at 35 dah,but primitive sperm lobule and sperm duct did not appear until 47 dah.At 80 dah,original ovarian lobules(Ol) has appeared and testicular lobules gradually increased,but the cytological differentiation did not occur.Sexually dimorphic gene expression of CYP19A was observed.Expression of CYP19A mRNA was increased significantly at 16 dah in female,and slightly up-regulated in male at 66 dah.The results support that estrogen is

  10. Patient adherence to aromatase inhibitor treatment in the adjuvant setting

    OpenAIRE

    Verma, S.; Madarnas, Y.; Sehdev, S.; Martin, G; Bajcar, J.

    2011-01-01

    Improvements in adjuvant systemic therapy and detection of early disease have resulted in a decline of breast cancer death rates across all patient age groups in Canada. Non-adherence to adjuvant hormonal therapy in the setting of early breast cancer may significantly affect patient outcome. Factors associated with medication adherence are complex and may be patient-related, therapy-related, and health care provider–related. To date, there is a gap in the literature concerning a comprehensive...

  11. Aromatase Inhibitors and Other Compounds for Lowering Breast Cancer Risk

    Science.gov (United States)

    ... Cancer? Breast Cancer Colon/Rectum Cancer Lung Cancer Prostate Cancer Skin Cancer Show All Cancer Types News and Features Cancer Glossary ACS Bookstore Cancer Information Cancer Basics Cancer Prevention & Detection Signs & Symptoms of Cancer Treatments & Side Effects ...

  12. 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, natura

  13. Comparative study on individual aromatase inhibitors on cardiovascular safety profile: misleading analysis and doubtful methodology

    OpenAIRE

    Guo WQ; Li L

    2015-01-01

    Wenqin Guo, Lang Li Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of ChinaZhao et al have presented the result of the relative cardiovascular safety profile in using anastrozole, letrozole, and exemestane to treat the postmenopausal estrogen receptor-positive breast cancer, in which fatal or nonfatal myocardial infarction is the outcome measure and ten randomized controlled trials are used as the data sources.1 We cong...

  14. Comparative study on individual aromatase inhibitors on cardiovascular safety profile: misleading analysis and doubtful methodology

    OpenAIRE

    Guo, Wenqin; Li, Lang

    2015-01-01

    Wenqin Guo, Lang Li Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of ChinaZhao et al have presented the result of the relative cardiovascular safety profile in using anastrozole, letrozole, and exemestane to treat the postmenopausal estrogen receptor-positive breast cancer, in which fatal or nonfatal myocardial infarction is the outcome measure and ten randomized controlled trials are used as the data sources.1 We ...

  15. Comparative study on individual aromatase inhibitors on cardiovascular safety profile: misleading analysis and doubtful methodology

    Directory of Open Access Journals (Sweden)

    Guo WQ

    2015-11-01

    Full Text Available Wenqin Guo, Lang Li Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of ChinaZhao et al have presented the result of the relative cardiovascular safety profile in using anastrozole, letrozole, and exemestane to treat the postmenopausal estrogen receptor-positive breast cancer, in which fatal or nonfatal myocardial infarction is the outcome measure and ten randomized controlled trials are used as the data sources.1 We congratulate and applaud their important work, but there are some issues of concern.  View original article by Zhao et al 

  16. Differential Effects of Glyphosate and Roundup on Human Placental Cells and Aromatase

    OpenAIRE

    Richard, Sophie; Moslemi, Safa; Sipahutar, Herbert; Benachour, Nora; Seralini, Gilles-Eric

    2005-01-01

    Roundup is a glyphosate-based herbicide used worldwide, including on most genetically modified plants that have been designed to tolerate it. Its residues may thus enter the food chain, and glyphosate is found as a contaminant in rivers. Some agricultural workers using glyphosate have pregnancy problems, but its mechanism of action in mammals is questioned. Here we show that glyphosate is toxic to human placental JEG3 cells within 18 hr with concentrations lower than those found with agricult...

  17. Benzo(A)pyrene Decreases Brain and Ovarian Aromatase mRNA Expression

    Science.gov (United States)

    The higher molecular weight polycyclic aromatic hydrocarbons (PAHs) such as benzo(a)pyrene (BaP) are typically associated with genotoxicity, however newer evidence suggests that these compounds may also act as endocrine system disruptors. We hypothesized that a target for reproductive or development...

  18. 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 environ

  19. A Case of Erythrocytosis in a Patient Treated with an Aromatase Inhibitor for Breast Cancer

    OpenAIRE

    Abhinav Iyengar; Dawn Sheppard

    2013-01-01

    A previously healthy 79-year-old female was referred to hematology for further evaluation of erythrocytosis. Two years earlier she had been diagnosed with ER/PR-positive ductal carcinoma of the breast and was receiving hormonal therapy with exemestane. No secondary cause of erythrocytosis was identified. Serum erythropoietin (EPO) level was normal, and molecular testing for the JAK2 V617F and exon 12 mutations was negative. A bone marrow biopsy showed a mild increase in erythropoiesis, and no...

  20. Quantitative AOP linking aromatase inhibition to impaired reproduction: A case study in predictive ecotoxicology

    Science.gov (United States)

    The adverse outcome pathway (AOP) framework is intended to help support greater use of mechanistic toxicology data as a basis for risk assessment and/or regulatory decision-making. While there have been clear advances in the ability to rapidly generate mechanistically-oriented da...

  1. Investigation of adaptive responses in fathead minnows (Pimephales promelas) exposed to the model aromatase inhibitor fadrozole

    Science.gov (United States)

    The vertebrate hypothalamic-pituitary-gonadal (HPG) axis is a highly dynamic system, which, through various feedback mechanisms, strives to maintain physiological conditions conducive to reproduction even in potentially stressful situations. The development of useful predictive m...

  2. 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. INTRODU

  3. Effects of bisphenol A and triclocarban on brain-specific expression of aromatase in early zebrafish embryos

    OpenAIRE

    Chung, Eunah; Genco, Maria C.; Megrelis, Laura; Ruderman, Joan V.

    2011-01-01

    Estrogen regulates numerous developmental and physiological processes. Most effects are mediated by estrogen receptors (ERs), which function as ligand-regulated transcription factors. Estrogen also regulates the activity of GPR30, a membrane-associated G protein-coupled receptor. Many different types of environmental contaminants can activate ERs; some can bind GPR30 as well. There is growing concern that exposure to some of these compounds, termed xenoestrogens, is interfering with the behav...

  4. Developing Predictive Approaches to Characterize Adaptive Responses of the Reproductive Endocrine Axis to Aromatase Inhibition II: Computational Modeling

    Science.gov (United States)

    ABSTRACT Exposure to endocrine disrupting chemicals can affect reproduction and development in both humans and wildlife. We developed a mechanistic mathematical model of the hypothalamic­ pituitary-gonadal (HPG) axis in female fathead minnows to predic...

  5. Developing Predictive Approaches to Characterize Adaptive Responses of the Reproductive Endocrine Axis to Aromatase Inhibition: Computational Modeling

    Science.gov (United States)

    Exposure to endocrine disrupting chemicals can affect reproduction and development in both humans and wildlife. We developed a mechanistic mathematical model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows to predict dose-response and time-course (DRTC)...

  6. Increased number of vasopressin neurons in the suprachiasmatic nucleus (SCN) of 'bisexual' adult male rats following perinatal treatment with the aromatase blocker ATD

    NARCIS (Netherlands)

    D.F. Swaab (Dick); A.K. Slob (Koos); E.J. Houtsmuller (Elisabeth Judith); T. Brand (Teus); J.N. Zhou (J.)

    1995-01-01

    textabstractIn an earlier article an enlarged subpopulation of vasopressin containing neurons was found in the suprachiasmatic nucleus (SCN) of homosexual men as compared to heterosexuals. The present study investigates the possibility that the number of vasopressin neurons in the SCN and sexual par

  7. Effects of selective serotonin reuptake inhibitors on three sex steroids in two versions of the aromatase enzyme inhibition assay and in the H295R cell assay

    DEFF Research Database (Denmark)

    Jacobsen, Naja Wessel; Hansen, Cecilie Hurup; Nellemann, Christine;

    2015-01-01

    Selective serotonin reuptake inhibitors are known to have a range of disorders that are often linked to the endocrine system e.g. hormonal imbalances, breast enlargement, sexual dysfunction, and menstrual cycle disorders. The mechanisms behind most of these disorders are not known in details...

  8. MOLECULAR CLONING AND STAGE-DEPENDENT EXPRESSION OF A CYTOCHROME P450 AROMATASE DURING SPERMATOGENESIS IN SHARK (SQUALUS ACANTHIAS) TESTIS. (R825434)

    Science.gov (United States)

    The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

  9. 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

  10. Developing predictive approaches to characterize adaptive responses of the reproductive endocrine axis to aromatase inhibition: I. Data generation in a small fish model

    Science.gov (United States)

    Adaptive or compensatory responses to chemical exposure can significantly influence in vivo concentration-duration-response relationships. The aim of this study was to provide data to support development of a computational dynamic model of the hypothalamic-pituitary-gonadal axis ...

  11. Effect of prenatal androgen receptor antagonist or aromatase inhibitor on the differentiation of neuronal Fos responses to estrous female pheromones in the rat accessory olfactory system

    OpenAIRE

    Dominguez, Emilio; Portillo, Wendy; Baum, Michael J.; Bakker, Julie; Paredes, Raul

    2002-01-01

    Many socially relevant odors are detected in rodent species by the vomeronasal organ and subsequently processed by the accessory olfactory system (AOS). We previously found that gonadectomized male and female rats treated in adulthood with testosterone propionate (TP) showed equivalent Fos responses in the AOS to odors derived from estrous females. Likewise, in contrast with numerous other mammalian species, gonadectomized female rats show surprisingly high levels of male-typical mounting beh...

  12. Adaptation, Compensation, and Recovery: Unraveling the Mechanisms through Genomics

    Science.gov (United States)

    A variety of chemicals in the environment have the potential to inhibit aromatase, an enzyme critical to estrogen synthesis. We examined the responses of female fathead minnows (Pimephales promelas) to a model aromatase inhibitor, fadrozole, using transcriptional network inferen...

  13. Molecular Characterization and Sex-Specific Tissue Expression of Estrogen Receptor Alpha (esr1), Estrogen Receptor Beta-a (esr2a) and Ovarian Aromatase (cyp19a1a) in Yellow Perch (Perca flavescens)

    Science.gov (United States)

    Yellow perch (Perca flavescens) exhibit an estrogen-stimulated sexual size dimorphism (SSD) wherein females grow faster and larger than males. To aid in the examination of this phenomenon, the cDNA sequences encoding estrogen receptor-alpha (esr1), estrogen receptor-beta-a (esr2a) and ovarian aroma...

  14. 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;

      An array of plastic components is known to possess endocrine disruption (ED) potentials. Bisphenol A (BPA) and BPA-Dimethacrylate (BPA-DM) are monomers used to high extent in the plastic industry and as dental sealants. Alkylphenols such as 4-n-nonylphenol (NP) and 4-octylphenol (OP) are widely...... used as surfactants. We have investigated the effect in vitro of these four plasticizers in four cell culture model systems.The estrogenic potencies were analyzed using the stable ERE-luciferase transfected cell line MVLN measuring the relative estrogen receptor (ER) transactivated luciferase units...... determining RLU. All four compounds elicited a response in each of the four bioassays. Thus, our in vitro data clearly indicates that the four tested plasticizers have ED potentials and that such effects can be mediated via several cellular pathway systems including the estrogen- and the androgen hormones...

  15. CYP19A1 polymorphisms and clinical outcomes in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial

    DEFF Research Database (Denmark)

    Leyland-Jones, Brian; Gray, Kathryn P; Abramovitz, Mark;

    2015-01-01

    To determine whether CYP19A1 polymorphisms are associated with abnormal activity of aromatase and with musculoskeletal and bone side effects of aromatase inhibitors. DNA was isolated from tumor specimens of 4861 postmenopausal women with hormone receptor-positive breast cancer enrolled in the BIG...

  16. Examestane in advanced or recurrent endometrial carcinoma

    DEFF Research Database (Denmark)

    Lindemann, Kristina; Malander, Susanne; Christensen, René dePont;

    2014-01-01

    We evaluated the efficacy and safety of the aromatase inhibitor exemestane in patients with advanced, persistent or recurrent endometrial carcinoma.......We evaluated the efficacy and safety of the aromatase inhibitor exemestane in patients with advanced, persistent or recurrent endometrial carcinoma....

  17. 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.

  18. Preventing Breast Cancer: Making Progress

    Science.gov (United States)

    Skip Navigation Bar Home Current Issue Past Issues Preventing Breast Cancer: Making Progress Past Issues / Fall 2006 Table of ... inhibitor, can do an even better job of preventing breast cancer than the SERMs. Aromatase inhibitors stop an enzyme ...

  19. Endocrine therapy use among elderly hormone receptor-pos...

    Data.gov (United States)

    U.S. Department of Health & Human Services — Clinical guidelines recommend that women with hormone-receptor positive breast cancer receive endocrine therapy (selective estrogen receptor modulators or aromatase...

  20. Exemestane Reduces Breast Cancer Risk in High-Risk Postmenopausal Women

    Science.gov (United States)

    Clinical trial results presented at the 2011 ASCO annual meeting showed that the aromatase inhibitor exemestane—used to treat early and advanced breast cancer—substantially reduced the risk of invasive breast cancer in high-risk postmenopausal women.

  1. Drug: D00574 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available e inhibitor Indication: Cushing's syndrome aromatase inhibitor [HSA:1588] [KO:K07434] hsa00140(1588) Steroid... D00574.gif Adrenocortical suppressant; Antineoplastic Same as: C07617 ATC code: L02BG01 Reversible aromatas

  2. Dual effects of phytoestrogens result in u-shaped dose-response curves

    DEFF Research Database (Denmark)

    Almstrup, Kristian; Fernández, Mariana F; Petersen, Jørgen H;

    2002-01-01

    Endocrine disruptors can affect the endocrine system without directly interacting with receptors, for example, by interfering with the synthesis or metabolism of steroid hormones. The aromatase that converts testosterone to 17beta-estradiol is a possible target. In this paper we describe an assay...... that simultaneously detects aromatase inhibition and estrogenicity. The principle is similar to that of other MCF-7 estrogenicity assays, but with a fixed amount of testosterone added. The endogenous aromatase activity in MCF-7 cells converts some of the testosterone to 17beta-estradiol, which is assayed...... by quantifying differences in the expression level of the estrogen-induced pS2 mRNA. Potential aromatase inhibitors can be identified by a dose-dependent reduction in the pS2 mRNA expression level after exposure to testosterone and the test compound. Using this assay, we have investigated several compounds...

  3. Expression and Significance of Aromatase in the Eutopic Endometrium of Patients and Endometriotic Lesions of Nude Mice Model in Endometriosis%子宫内膜异位症在位内膜及裸鼠模型异位病灶芳香化酶的表达及意义

    Institute of Scientific and Technical Information of China (English)

    王丹波; 任凤岩; 张淑兰; 李一宁; 牛惠彦; 陆景明

    2005-01-01

    目的:探讨芳香化酶在子宫内膜异位症(EMs)在位内膜及其裸鼠模型异位病灶中的表达意义.方法:征集EMs组及非异位症(NEMs)组各24例,应用其分泌晚期子宫内膜,建立EMs裸鼠模型,取建模后5 d、15 d、30 d裸鼠异位病灶,RT-PCR及免疫组化方法检测两组在位内膜和异位病灶芳香化酶mRNA及蛋白表达.结果:芳香化酶mRNA表达,EMs组异位病灶(0.894±0.23)表达强于在位内膜(0.685±0.15),P<0.05;阳性表达率(87.50%,83.33%)无差异.NEMs组异位病灶表达强度和阳性表达率(0.920±0.24,95.83%)均高于在位内膜(0.612±0.15,62.50%),P<0.05.两组在位内膜比较,EMs组阳性表达率高于NEMs组,P<0.05.两组异位病灶及各组不同时期异位病灶(EMs组,5 d:0.889±0.23;15 d:0.990±0.19;30 d:0.880±0.29;NEMs组,5 d:0.889±0.23;15 d:0.905±0.23;30 d:0.918±0.22)比较,芳香化酶mRNA表达无差异.芳香化酶蛋白阳性表达率,EMs组异位病灶(95.83%)与在位内膜(91.67%)比较,差异不显著.NEMs组异位病灶(95.83%)高于在位内膜(70.83%),P<0.05.EMs组在位内膜高于NEMs组,P<0.05;两组异位病灶比较,差异不显著.结论:局部雌激素合成增强在EMs发病机理中起重要作用.芳香化酶是EMs等雌激素依赖性疾病在子宫内膜特异性表达标记物.

  4. Phase 3 Trials in Breast Cancer Prevention: Focus on Estrogen-Targeting Agents, Selective Estrogen Receptor Modulators and Aromatase Inhibitors%乳腺癌预防的三期临床试验:雌激素靶向药物,选择性雌激素受体调控剂和芳香酶抑制剂

    Institute of Scientific and Technical Information of China (English)

    Barbara K.Dunn

    2013-01-01

    据估计,2008年全世界有138万新诊断的乳腺癌,占女性所有癌症的23%,是世界范围内女性中最常见的癌症.尽管早期诊断和治疗技术的进步已经降低了乳腺癌的发病率和死亡率,但乳腺癌仍然是女性中死亡率最高的癌症.因此,探索预防乳腺癌的途径和开发风险评估模型以确定最可能从预防性干预中受益的女性具有重要意义.大规模临床试验是评估乳腺癌预防药物功效的金标准,同时也是这些药物获得正式批准的基础.因此,本文重点讨论了已经进入三期临床试验或已获正式批准用于降低乳腺癌风险的药物,尤其是针对雌激素受体阳性乳腺癌的预防药物如选择性雌激素受体调控剂和芳香酶抑制剂等;此外也对乳腺癌风险评估模型进行了简单评述.

  5. Assessment of psychosocial factors and distress in women having adjuvant endocrine therapy for breast cancer: the relationship among emotional distress and patient and treatment-related factors

    OpenAIRE

    Ates, Ozturk; Soylu, Cem; Babacan, Taner; Sarici, Furkan; Kertmen, Neyran; Allen, Deborah; Sever, Ali Riza; Altundag, Kadri

    2016-01-01

    Purpose The aims of this study were to comprehensively describe the psychosocial and medical characteristics of women who initiated tamoxifen or aromatase inhibitors for breast cancer and to compare levels of emotional distress according to their medical (tumor demographics, treatment type, treatment duration) and psychosocial (self-esteem, perceived social support, sociodemographic) characteristics. Methods A total of 104 women currently receiving tamoxifen or aromatase inhibitors was recrui...

  6. Cutaneous adverse effects of hormonal adjuvant therapy for breast cancer: a case of localised urticarial vasculitis following anastrozole therapy and a review of the literature.

    Science.gov (United States)

    Bock, Vanessa L; Friedlander, Michael; Waring, Dale; Kossard, Steven; Wood, Glenda K

    2014-11-01

    Hormonal therapy with either tamoxifen or aromatase inhibitors is commonly used to treat women with breast cancer in both the adjuvant and recurrent disease setting. Cutaneous adverse reactions to these drugs have been rarely reported in the literature. We report an unusual case of urticarial vasculitis following the aromatase inhibitor anastrozole that localised to the unilateral trunk and mastectomy scar, and review the literature on the cutaneous adverse effects of hormonal therapy for breast cancer. PMID:24575835

  7. Cancer therapy disparity: unequal access to breast cancer therapeutics and drug funding in Canada

    OpenAIRE

    Verma, S.; Sehdev, S.; Joy, A.A.

    2007-01-01

    Adjuvant therapy has made a significant contribution in reducing breast cancer–specific mortality. Standard chemotherapeutics and tamoxifen have been the mainstay treatment for years, but recent clinical evidence supports the use of novel small-molecule therapy and aromatase inhibitor therapy in selected settings, challenging not only the traditional paradigm of breast cancer treatment, but also provincial funding of oncologic care across Canada. The disparity in access to aromatase inhibitor...

  8. Synergistic activity of letrozole and sorafenib on breast cancer cells

    OpenAIRE

    Bonelli, Mara A.; Fumarola, Claudia; Alfieri, Roberta R.; Monica, Silvia; Cavazzoni, Andrea; Galetti, Maricla; Gatti, Rita; Belletti, Silvana; Harris, Adrian L.; Fox, Stephen B.; Evans, Dean B.; Dowsett, Mitch; Martin, Lesley-Ann; Bottini, Alberto; Generali, Daniele

    2010-01-01

    Abstract Estrogens induce breast tumor cell proliferation by directly regulating gene expression via the estrogen receptor (ER) transcriptional activity and by affecting growth factor signaling pathways such as mitogen-activated protein kinase (MAPK) and AKT/mammalian target of rapamycin Complex1 (mTORC1) cascades. In this study we demonstrated the preclinical therapeutic efficacy of combining the aromatase inhibitor letrozole with the multi-kinase inhibitor sorafenib in aromatase-...

  9. Effects of in ovo exposure of Imazalil and Atrazine on sexual differentiation in chick gonads

    Energy Technology Data Exchange (ETDEWEB)

    Yamashita, J.; Ikeda, M. [Univ. of Shizuoka, Shizuoka (Japan); Matsushita, S.; Iwasawa, T.; Ikeya, M. [Shizuoka Swine and Poultry Experiment Station, Kikugawa (Japan)

    2004-09-15

    In contrast to mammals, the heterogametic sex (sex chromosome: ZW) in avian species is the genetic female whereas the homogametic (sex chromosome: ZZ) is the genetic male. The W chromosome positively controls early aromatase synthesis and consequently estrogen production. The presence of estrogens and their receptors plays a crucial role in female sexual differentiation. Chicken embryonic gonads are bipotential at an early stage. During development of the female, the left gonad differentiates to a single ovary/oviduct, and the right gonad regresses, developing a permanent female phenotype. This sexual differentiation occurs as a result of aromatase expression in the left gonad at day 6.5 and the production of estrogen from testosterone. In the male genotype, both gonads develop into two testes. The time- and sex-dependent expression of enzymes involved in steroidogenesis, which determine the ratio of androgens/estrogens produced by the gonads, has been extensively investigated during the last 5-6 year. These results show that the lack of estrogen synthesis in the male appears to be due to the extremely low levels of P450 aromatase expression. In female, extensive expression of the aromatase gene (around day 5-6 incubation), leading to estrogen synthesis, and specific expression of the estrogen receptor-mRNA in the left gonad result in the development of a functional left ovary. Experimental sex reversal has been performed using anti-estrogens, androgens, aromatase inhibitors and synthetic steroid. Differences between male and female gonadal differentiation and development are depended on the absence of aromatase and estrogen. On the one hand, differences between left and right ovarian development are depended on the specific expression of the estrogen receptor in the left gonad. Persistent chlorine-containing pesticide, imazalil is structurally similar to various imidazolecontaining chemicals used clinically such as the potent aromatase inhibitor, fadrozole and

  10. Effects of the Methanol Extract of Basella alba L (Basellaceae on Steroid Production in Leydig Cells

    Directory of Open Access Journals (Sweden)

    Carine Travert

    2011-01-01

    Full Text Available In this study, Leydig cells were purified from 70 day-old Sprague Dawley male rats and incubated with 10 and 100 µg/mL of methanol extract of Basella alba (MEBa for 4 hours followed by the evaluation of cell viability, steroid (testosterone and estradiol production, and the level of aromatase mRNA. Results showed that MEBa did not affect Leydig cell viability. At the concentration of 10 µg/mL, MEBa significantly stimulated testosterone and estradiol production (p < 0.01 and p < 0.03, respectively, and enhanced aromatase mRNA level (p < 0.04. These observations suggest that MEBa directly stimulated testosterone, estradiol and aromatase mRNA levels in isolated Leydig cells.

  11. Effects of the methanol extract of Basella alba L (Basellaceae) on steroid production in Leydig cells.

    Science.gov (United States)

    Nantia, Edouard Akono; Travert, Carine; Manfo, Faustin-Pascal T; Carreau, Serge; Monsees, Thomas K; Moundipa, Paul Fewou

    2011-01-01

    In this study, Leydig cells were purified from 70 day-old Sprague Dawley male rats and incubated with 10 and 100 μg/mL of methanol extract of Basella alba (MEBa) for 4 hours followed by the evaluation of cell viability, steroid (testosterone and estradiol) production, and the level of aromatase mRNA. Results showed that MEBa did not affect Leydig cell viability. At the concentration of 10 μg/mL, MEBa significantly stimulated testosterone and estradiol production (p < 0.01 and p < 0.03, respectively), and enhanced aromatase mRNA level (p < 0.04). These observations suggest that MEBa directly stimulated testosterone, estradiol and aromatase mRNA levels in isolated Leydig cells. PMID:21339992

  12. Sex-Dependent Influence of Endogenous Estrogen in Pulmonary Hypertension

    Science.gov (United States)

    Mair, Kirsty M.; Wright, Audrey F.; Duggan, Nicholas; Rowlands, David J.; Hussey, Martin J.; Roberts, Sonia; Fullerton, Josephine; Nilsen, Margaret; Loughlin, Lynn; Thomas, Matthew

    2014-01-01

    Rationale: The incidence of pulmonary arterial hypertension is greater in women, suggesting estrogens may play a role in the disease pathogenesis. Experimentally, in males, exogenously administered estrogen can protect against pulmonary hypertension (PH). However, in models that display female susceptibility, estrogens may play a causative role. Objectives: To clarify the influence of endogenous estrogen and sex in PH and assess the therapeutic potential of a clinically available aromatase inhibitor. Methods: We interrogated the effect of reduced endogenous estrogen in males and females using the aromatase inhibitor, anastrozole, in two models of PH: the hypoxic mouse and Sugen 5416/hypoxic rat. We also determined the effects of sex on pulmonary expression of aromatase in these models and in lungs from patients with pulmonary arterial hypertension. Measurements and Main Results: Anastrozole attenuated PH in both models studied, but only in females. To verify this effect was caused by reduced estrogenic activity we confirmed that in hypoxic mice inhibition of estrogen receptor α also has a therapeutic effect specifically in females. Female rodent lung displays increased aromatase and decreased bone morphogenetic protein receptor 2 and Id1 expression compared with male. Anastrozole treatment reversed the impaired bone morphogenetic protein receptor 2 pathway in females. Increased aromatase expression was also detected in female human pulmonary artery smooth muscle cells compared with male. Conclusions: The unique phenotype of female pulmonary arteries facilitates the therapeutic effects of anastrozole in experimental PH confirming a role for endogenous estrogen in the disease pathogenesis in females and suggests aromatase inhibitors may have therapeutic potential. PMID:24956156

  13. Changing Adjuvant Breast-Cancer Therapy with a Signal for Prevention.

    OpenAIRE

    Chlebowski, RT; Budoff, MJ

    2016-01-01

    Five randomized, full-scale studies have reported that 10 years of adjuvant endocrine therapy is beneficial for postmenopausal women with hormone-receptor-positive breast cancer. However, no prior study has involved more than 5 years of aromatase-inhibitor use or assessed a duration of adjuvant endocrine therapy of more than 10 years.(1) Goss and colleagues(2) now provide results from the MA.17R trial supporting the use of an aromatase inhibitor for 10 years and the use of adjuvant endocrine ...

  14. Medicinsk efterbehandling af brystkraeft. Endokrin behandling

    DEFF Research Database (Denmark)

    Mouridsen, Henning T; Andersen, Jørn

    2007-01-01

    For women with steroid receptor-positive breast cancers, endocrine therapy has proven to be a major component of adjuvant therapy reducing the risk of recurrence and death. The selective estrogen-receptor modulator (SERM) tamoxifen has been well established as safe and effective in the adjuvant...... care of both pre- and postmenopausal women. For premenopausal women, ovarian suppression is an important option to be considered. Additionally, aromatase inhibitors have recently demonstrated further benefits in postmenopausal women. The ideal sequencing of treatment with tamoxifen and/or an aromatase...

  15. Tamoxifen: the drug that came in from the cold

    OpenAIRE

    Hughes-Davies, L.; Caldas, C.; Wishart, G. C.

    2009-01-01

    Despite the perception of many oncologists that tamoxifen is an inferior drug, and should be substituted by an aromatase inhibitor in post-menopausal women, the current evidence strongly supports the view that AIs should be used 2–3 years after tamoxifen to achieve the maximal overall survival (OS) advantage.

  16. Open comparative trial of formestane versus megestrol acetate in postmenopausal patients with advanced breast cancer previously treated with tamoxifen

    NARCIS (Netherlands)

    Freue, M; Kjaer, M; Boni, C; Joliver, J; Janicke, F; Willemse, PHB; Coombes, RC; Van Belle, S; Perez-Carrion, R; Zieschang, J; de Palacios, PI; Rose, C

    2000-01-01

    The aim of the trial was to compare efficacy and safety of the aromatase inhibitor formestane (250 mg i.m. given every 2 weeks) with the progestin megestrol acetate (160 mg administered orally once daily), as second-line therapy in postmenopausal patients with advanced breast cancer previously treat

  17. Pregnancy-associated plasma protein A in human ovarian follicles and its association with intrafollicular hormone levels

    DEFF Research Database (Denmark)

    Bøtkjær, Jane Alrø; Jeppesen, Janni Vikkelsø; Wissing, Marie Louise;

    2015-01-01

    To evaluate follicular fluid (FF) levels of pregnancy-associated plasma protein A (PAPP-A) in relation to levels of intrafollicular hormones. Furthermore, immunostaining of human follicles of varying diameters was studied for PAPP-A, antimüllerian hormone (AMH), and aromatase, and the biological ...

  18. Inhibition of Estradiol Synthesis Impairs Fear Extinction in Male Rats

    Science.gov (United States)

    Graham, Bronwyn M.; Milad, Mohammed R.

    2014-01-01

    Emerging research has demonstrated that the sex hormone estradiol regulates fear extinction in female rodents and women. Estradiol may also regulate fear extinction in males, given its role in synaptic plasticity in both sexes. Here we report that inhibition of estradiol synthesis during extinction training, via the aromatase inhibitor fadrozole,…

  19. Phytoestrogens in menopausal supplements induce ER-dependent cell proliferation and overcome breast cancer treatment in an in vitro breast cancer model

    NARCIS (Netherlands)

    Duursen, van M.B.M.; Smeets, E.E.J.W.; Rijk, J.C.W.; Nijmeijer, S.M.; Berg, M.

    2013-01-01

    Breast cancer treatment by the aromatase inhibitor Letrozole (LET) or Selective Estrogen Receptor Modulator Tamoxifen (TAM) can result in the onset of menopausal symptoms. Women often try to relieve these symptoms by taking menopausal supplements containing high levels of phytoestrogens. However, li

  20. Hormonal and molecular aspects of endometrioid endometrial cancer

    NARCIS (Netherlands)

    Jongen, Vincentius Hubertus Willibrordus Maria

    2008-01-01

    This thesis concerns the expression and prognostic value of various hormones and molecular markers playing a role n endometrioid endometrial cancer. Especially we were interested in the enzyme aromatase, its expression and (prognostic) role in endometrioid endometrial cancer. Endometrial cancer is t

  1. Analyses adjusting for selective crossover show improved overall survival with adjuvant letrozole compared with tamoxifen in the BIG 1-98 study

    DEFF Research Database (Denmark)

    Colleoni, Marco; Giobbie-Hurder, Anita; Regan, Meredith M;

    2011-01-01

    Among postmenopausal women with endocrine-responsive breast cancer, the aromatase inhibitor letrozole, when compared with tamoxifen, has been shown to significantly improve disease-free survival (DFS) and time to distant recurrence (TDR). We investigated whether letrozole monotherapy prolonged ov...

  2. The effects of oestrogens on linear bone growth

    DEFF Research Database (Denmark)

    Juul, A

    2001-01-01

    boys, and non-aromatizable androgens [oxandrolone or dihydrotestosterone (DHT)] have no effect on GH secretion. Treatment with aromatase inhibitors reduces circulating IGF-I concentrations in healthy males, and reduces growth in boys with testotoxicosis. Taken together, these findings suggest...

  3. Experiment list: SRX186809 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186809 hg19 Histone H3K27me3 Breast Breast cancer NA 23961464,95.6,3.9,1109 GSM1003719: good outcome...t tumor || procedure=ChIP-seq || chip antibody=07-449 (millipore) || aromatase inhibitor treatment outcome=g

  4. Experiment list: SRX186820 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186820 hg19 Histone H3K27me3 Breast Breast cancer NA 27372177,91.7,3.1,454 GSM1003730: poor outcome... tumor || procedure=ChIP-seq || chip antibody=07-449 (millipore) || aromatase inhibitor treatment outcome=po

  5. Experiment list: SRX186823 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186823 hg19 Histone H3K27me3 Breast Breast cancer NA 21310477,97.5,3.1,350 GSM1003733: poor outcome... tumor || procedure=ChIP-seq || chip antibody=07-449 (millipore) || aromatase inhibitor treatment outcome=po

  6. Experiment list: SRX186828 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186828 hg19 Histone H3K4me3 Breast Breast cancer NA 24329817,85.2,5.1,19118 GSM1003738: poor outcome... tumor || procedure=ChIP-seq || chip antibody=ab8580 (Abcam) || aromatase inhibitor treatment outcome=poor h

  7. Experiment list: SRX186827 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186827 hg19 TFs and others ESR1 Breast Breast cancer NA 25288873,86.2,4.0,1247 GSM1003737: poor outcome...umor || procedure=ChIP-seq || chip antibody=SC-543 (Santa Cruz) || aromatase inhibitor treatment outcome=poo

  8. Experiment list: SRX186825 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186825 hg19 Histone H3K4me3 Breast Breast cancer NA 32551100,89.9,14.3,17869 GSM1003735: poor outcome...t tumor || procedure=ChIP-seq || chip antibody=ab8580 (Abcam) || aromatase inhibitor treatment outcome=poor

  9. Experiment list: SRX186806 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186806 hg19 Histone H3K27me3 Breast Breast cancer NA 19103286,92.5,3.5,938 GSM1003716: good outcome... tumor || procedure=ChIP-seq || chip antibody=07-449 (millipore) || aromatase inhibitor treatment outcome=go

  10. Experiment list: SRX186815 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186815 hg19 Histone H3K27me3 Breast Breast cancer NA 24169596,96.9,3.8,1093 GSM1003725: poor outcome...t tumor || procedure=ChIP-seq || chip antibody=07-449 (millipore) || aromatase inhibitor treatment outcome=p

  11. Experiment list: SRX186818 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186818 hg19 TFs and others ESR1 Breast Breast cancer NA 21552073,84.8,4.7,1184 GSM1003728: poor outcome...umor || procedure=ChIP-seq || chip antibody=SC-543 (Santa Cruz) || aromatase inhibitor treatment outcome=poo

  12. Experiment list: SRX186799 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186799 hg19 Histone H3K4me3 Breast Breast cancer NA 28108457,84.8,6.4,20107 GSM1003709: good outcome... tumor || procedure=ChIP-seq || chip antibody=ab8580 (Abcam) || aromatase inhibitor treatment outcome=good h

  13. Experiment list: SRX186804 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186804 hg19 TFs and others ESR1 Breast Breast cancer NA 20789758,88.0,7.4,9258 GSM1003714: good outcome...umor || procedure=ChIP-seq || chip antibody=SC-543 (Santa Cruz) || aromatase inhibitor treatment outcome=goo

  14. Experiment list: SRX186812 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186812 hg19 Histone H3K27me3 Breast Breast cancer NA 28112307,91.0,4.5,788 GSM1003722: good outcome... tumor || procedure=ChIP-seq || chip antibody=07-449 (millipore) || aromatase inhibitor treatment outcome=go

  15. Experiment list: SRX186814 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186814 hg19 Histone H3K4me3 Breast Breast cancer NA 24847783,84.2,9.3,22763 GSM1003724: poor outcome... tumor || procedure=ChIP-seq || chip antibody=ab8580 (Abcam) || aromatase inhibitor treatment outcome=poor h

  16. Experiment list: SRX186822 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186822 hg19 Histone H3K4me3 Breast Breast cancer NA 20741336,93.8,17.7,12028 GSM1003732: poor outcome...t tumor || procedure=ChIP-seq || chip antibody=ab8580 (Abcam) || aromatase inhibitor treatment outcome=poor

  17. Experiment list: SRX186829 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186829 hg19 Histone H3K27me3 Breast Breast cancer NA 23750330,97.9,3.3,975 GSM1003739: poor outcome... tumor || procedure=ChIP-seq || chip antibody=07-449 (millipore) || aromatase inhibitor treatment outcome=po

  18. Experiment list: SRX186807 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186807 hg19 TFs and others ESR1 Breast Breast cancer NA 22555195,95.0,3.8,2271 GSM1003717: good outcome...umor || procedure=ChIP-seq || chip antibody=SC-543 (Santa Cruz) || aromatase inhibitor treatment outcome=goo

  19. Experiment list: SRX186805 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186805 hg19 Histone H3K4me3 Breast Breast cancer NA 23075271,91.9,14.6,13389 GSM1003715: good outcome...t tumor || procedure=ChIP-seq || chip antibody=ab8580 (Abcam) || aromatase inhibitor treatment outcome=good

  20. Experiment list: SRX186821 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186821 hg19 TFs and others ESR1 Breast Breast cancer NA 15620215,91.6,3.5,2628 GSM1003731: poor outcome...umor || procedure=ChIP-seq || chip antibody=SC-543 (Santa Cruz) || aromatase inhibitor treatment outcome=poo

  1. Experiment list: SRX186813 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186813 hg19 TFs and others ESR1 Breast Breast cancer NA 24005555,90.5,5.3,3157 GSM1003723: poor outcome...umor || procedure=ChIP-seq || chip antibody=SC-543 (Santa Cruz) || aromatase inhibitor treatment outcome=poo

  2. Experiment list: SRX186826 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186826 hg19 Histone H3K27me3 Breast Breast cancer NA 32335775,91.4,3.5,1851 GSM1003736: poor outcome...t tumor || procedure=ChIP-seq || chip antibody=07-449 (millipore) || aromatase inhibitor treatment outcome=p

  3. Experiment list: SRX186824 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186824 hg19 TFs and others ESR1 Breast Breast cancer NA 22851650,83.0,3.9,7462 GSM1003734: poor outcome...umor || procedure=ChIP-seq || chip antibody=SC-543 (Santa Cruz) || aromatase inhibitor treatment outcome=poo

  4. Experiment list: SRX186802 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186802 hg19 Histone H3K4me3 Breast Breast cancer NA 27772208,86.6,7.5,21669 GSM1003712: good outcome... tumor || procedure=ChIP-seq || chip antibody=ab8580 (Abcam) || aromatase inhibitor treatment outcome=good h

  5. Experiment list: SRX186801 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186801 hg19 TFs and others ESR1 Breast Breast cancer NA 28745770,88.1,4.2,1477 GSM1003711: good outcome...umor || procedure=ChIP-seq || chip antibody=SC-543 (Santa Cruz) || aromatase inhibitor treatment outcome=goo

  6. Experiment list: SRX186810 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186810 hg19 TFs and others ESR1 Breast Breast cancer NA 20623693,88.8,3.9,5237 GSM1003720: good outcome...umor || procedure=ChIP-seq || chip antibody=SC-543 (Santa Cruz) || aromatase inhibitor treatment outcome=goo

  7. Experiment list: SRX186808 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186808 hg19 Histone H3K4me3 Breast Breast cancer NA 19872399,94.5,13.3,8477 GSM1003718: good outcome... tumor || procedure=ChIP-seq || chip antibody=ab8580 (Abcam) || aromatase inhibitor treatment outcome=good h

  8. Experiment list: SRX186832 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186832 hg19 Histone H3K27me3 Breast Breast cancer NA 31996441,96.9,3.4,1225 GSM1003742: poor outcome...t tumor || procedure=ChIP-seq || chip antibody=07-449 (millipore) || aromatase inhibitor treatment outcome=p

  9. Experiment list: SRX186798 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186798 hg19 TFs and others ESR1 Breast Breast cancer NA 28556249,88.7,4.2,1338 GSM1003708: good outcome...umor || procedure=ChIP-seq || chip antibody=SC-543 (Santa Cruz) || aromatase inhibitor treatment outcome=goo

  10. Experiment list: SRX186800 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186800 hg19 Histone H3K27me3 Breast Breast cancer NA 26990559,98.1,3.2,1076 GSM1003710: good outcome...t tumor || procedure=ChIP-seq || chip antibody=07-449 (millipore) || aromatase inhibitor treatment outcome=g

  11. Experiment list: SRX186803 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186803 hg19 Histone H3K27me3 Breast Breast cancer NA 22096326,97.8,3.5,909 GSM1003713: good outcome... tumor || procedure=ChIP-seq || chip antibody=07-449 (millipore) || aromatase inhibitor treatment outcome=go

  12. Experiment list: SRX186831 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186831 hg19 Histone H3K4me3 Breast Breast cancer NA 26027543,95.2,10.9,19058 GSM1003741: poor outcome...t tumor || procedure=ChIP-seq || chip antibody=ab8580 (Abcam) || aromatase inhibitor treatment outcome=poor

  13. Experiment list: SRX186819 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186819 hg19 Histone H3K4me3 Breast Breast cancer NA 27693755,94.1,14.7,20361 GSM1003729: poor outcome...t tumor || procedure=ChIP-seq || chip antibody=ab8580 (Abcam) || aromatase inhibitor treatment outcome=poor

  14. Experiment list: SRX186817 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186817 hg19 Histone H3K27me3 Breast Breast cancer NA 16423400,95.8,3.5,368 GSM1003727: poor outcome... tumor || procedure=ChIP-seq || chip antibody=07-449 (millipore) || aromatase inhibitor treatment outcome=po

  15. Experiment list: SRX186816 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186816 hg19 TFs and others ESR1 Breast Breast cancer NA 19907444,81.2,3.0,1245 GSM1003726: poor outcome...umor || procedure=ChIP-seq || chip antibody=SC-543 (Santa Cruz) || aromatase inhibitor treatment outcome=poo

  16. Experiment list: SRX186830 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186830 hg19 TFs and others ESR1 Breast Breast cancer NA 13499179,94.0,2.9,942 GSM1003740: poor outcome...mor || procedure=ChIP-seq || chip antibody=SC-543 (Santa Cruz) || aromatase inhibitor treatment outcome=poor

  17. Experiment list: SRX186811 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX186811 hg19 Histone H3K4me3 Breast Breast cancer NA 12311687,90.6,13.9,4671 GSM1003721: good outcome... tumor || procedure=ChIP-seq || chip antibody=ab8580 (Abcam) || aromatase inhibitor treatment outcome=good h

  18. Endocrine therapy for breast cancer patients in South Africa

    NARCIS (Netherlands)

    Taghipour Bazargani, Y.; De Boer, Anthonius; Leufkens, Hubertus G.M.; Mantel-Teeuwisse, Aukje K.

    2014-01-01

    Background: Endocrine therapy (tamoxifen and aromatase inhibitors (AIs)) has been shown to reduce the risk of recurrence and death in estrogen receptor positive(ER+) breast cancer patients. Objectives: The aim of this study is to assess access to these medicines by comparing the estimated number of

  19. miR-378a-3p modulates tamoxifen sensitivity in breast cancer MCF-7 cells through targeting GOLT1A

    NARCIS (Netherlands)

    Ikeda, Kazuhiro; Horie-Inoue, Kuniko; Ueno, Toshihide; Suzuki, Takashi; Sato, Wataru; Shigekawa, Takashi; Osaki, Akihiko; Saeki, Toshiaki; Berezikov, Eugene; Mano, Hiroyuki; Inoue, Satoshi

    2015-01-01

    Breast cancer is a hormone-dependent cancer and usually treated with endocrine therapy using aromatase inhibitors or anti-estrogens such as tamoxifen. A majority of breast cancer, however, will often fail to respond to endocrine therapy. In the present study, we explored miRNAs associated with endoc

  20. Disease: H00794 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available Demura M, Martin RM, Shozu M, Sebastian S, Takayama K, Hsu WT, Schultz RA, Neely K, Bryant M, Mendonca BB, H... of cryptic promoters for the CYP19 (aromatase) gene. Hum Mol Genet 16:2529-41 (2007) PMID:12736278 (description, gene) Shozu M, Seba...stian S, Takayama K, Hsu WT, Schultz RA, Neely K, Bryant

  1. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial

    DEFF Research Database (Denmark)

    Coombes, R C; Kilburn, L S; Snowdon, C F;

    2007-01-01

    BACKGROUND: Early improvements in disease-free survival have been noted when an aromatase inhibitor is given either instead of or sequentially after tamoxifen in postmenopausal women with oestrogen-receptor-positive early breast cancer. However, little information exists on the long-term effects ...

  2. Effects of Fadrozole, Ketoconazole, and 17β-trenbolone on Ex Vivo Steroidogenesis in the Fathead Minnow

    Science.gov (United States)

    A variety of endocrine-disrupting chemicals have the ability to disrupt steroidogenesis through interaction with the hypothalamic-pituitary-gonadal (HPG) axis. We examined the effects of the competitive aromatase inhibitor fadrozole (0, 3, and 30 g/L), the cytochrome P450 enzyme...

  3. 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 estrad

  4. Computational model of the fathead minnow hypothalamic-pituitary-gonadal axis: Incorporating protein synthesis in improving predictability of responses to endocrine active chemicals.

    Science.gov (United States)

    Breen, Miyuki; Villeneuve, Daniel L; Ankley, Gerald T; Bencic, David; Breen, Michael S; Watanabe, Karen H; Lloyd, Alun L; Conolly, Rory B

    2016-01-01

    There is international concern about chemicals that alter endocrine system function in humans and/or wildlife and subsequently cause adverse effects. We previously developed a mechanistic computational model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows exposed to a model aromatase inhibitor, fadrozole (FAD), to predict dose-response and time-course behaviors for apical reproductive endpoints. Initial efforts to develop a computational model describing adaptive responses to endocrine stress providing good fits to empirical plasma 17β-estradiol (E2) data in exposed fish were only partially successful, which suggests that additional regulatory biology processes need to be considered. In this study, we addressed short-comings of the previous model by incorporating additional details concerning CYP19A (aromatase) protein synthesis. Predictions based on the revised model were evaluated using plasma E2 concentrations and ovarian cytochrome P450 (CYP) 19A aromatase mRNA data from two fathead minnow time-course experiments with FAD, as well as from a third 4-day study. The extended model provides better fits to measured E2 time-course concentrations, and the model accurately predicts CYP19A mRNA fold changes and plasma E2 dose-response from the 4-d concentration-response study. This study suggests that aromatase protein synthesis is an important process in the biological system to model the effects of FAD exposure. PMID:26875912

  5. Phytoestrogens in menopausal supplements induce ER-dependent cell proliferation and overcome breast cancer treatment in an in vitro breast cancer model.

    Science.gov (United States)

    van Duursen, Majorie B M; Smeets, Evelien E J W; Rijk, Jeroen C W; Nijmeijer, Sandra M; van den Berg, Martin

    2013-06-01

    Breast cancer treatment by the aromatase inhibitor Letrozole (LET) or Selective Estrogen Receptor Modulator Tamoxifen (TAM) can result in the onset of menopausal symptoms. Women often try to relieve these symptoms by taking menopausal supplements containing high levels of phytoestrogens. However, little is known about the potential interaction between these supplements and breast cancer treatment, especially aromatase inhibitors. In this study, interaction of phytoestrogens with the estrogen receptor alpha and TAM action was determined in an ER-reporter gene assay (BG1Luc4E2 cells) and human breast epithelial tumor cells (MCF-7). Potential interactions with aromatase activity and LET were determined in human adrenocorticocarcinoma H295R cells. We also used the previously described H295R/MCF-7 co-culture model to study interactions with steroidogenesis and tumor cell proliferation. In this model, genistein (GEN), 8-prenylnaringenin (8PN) and four commercially available menopausal supplements all induced ER-dependent tumor cell proliferation, which could not be prevented by physiologically relevant LET and 4OH-TAM concentrations. Differences in relative effect potencies between the H295R/MCF-7 co-culture model and ER-activation in BG1Luc4E2 cells, were due to the effects of the phytoestrogens on steroidogenesis. All tested supplements and GEN induced aromatase activity, while 8PN was a strong aromatase inhibitor. Steroidogenic profiles upon GEN and 8PN exposure indicated a strong inhibitory effect on steroidogenesis in H295R cells and H295R/MCF-7 co-cultures. Based on our in vitro data we suggest that menopausal supplement intake during breast cancer treatment should better be avoided, at least until more certainty regarding the safety of supplemental use in breast cancer patients can be provided. PMID:23541764

  6. Dual effect of metformin on growth inhibition and oestradiol production in breast cancer cells.

    Science.gov (United States)

    Rice, S; Pellat, L; Ahmetaga, A; Bano, G; Mason, H D; Whitehead, S A

    2015-04-01

    Evidence has been accumulating for a role for metformin in reducing breast cancer risk in post-menopausal women. It inhibits growth of breast cancer cells via several mechanisms, primarily the AMPK/mTOR signalling pathway. Another possible protective mechanism may be the ability of metformin to inhibit aromatase activity. In the present study, we investigated the effects of metformin on the basal growth of MCF-7 cells, after oestradiol (E2) stimulation and after the inhibition of mTOR by rapamycin. Secondly, we investigated the effects of metformin on the activity of a number of steroidogenic enzymes and the mRNA expression of aromatase and steroid sulphatase (STS). High doses of metformin significantly inhibited both basal and oestrogen-stimulated cell division. Low-dose rapamycin (10-10 M) did not inhibit growth, but the addition of metformin induced a significant reduction in growth. High-dose rapamycin (10-8 M) inhibited growth, and this was further attenuated by the addition of metformin. Exposure to low (10-7 M) and high (10-4 M) doses of metformin for 7-10 days significantly reduced the conversion of androstenedione (ANDRO) and testosterone (TESTO) (both requiring aromatase), but not the conversion of oestrone or oestrone sulphate (ES) via 17β-hydroxysteroid dehydrogenase/sulphatase to E2. This attenuation was via a downregulation in the expression of total aromatase mRNA and promoter II, whilst the expression of sulphatase was unaffected by metformin. In conclusion, plasma levels of metformin have a dual therapeutic action, first by directly inhibiting cell proliferation which can be augmented by rapamycin analogues, and secondly, by inhibiting aromatase activity and reducing the local conversion of androgens to E2.

  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. In vitro–in vivo correlations for endocrine activity of a mixture of 5 currently used pesticides

    DEFF Research Database (Denmark)

    Taxvig, Camilla; Hadrup, Niels; Boberg, Julie;

    2013-01-01

    and increased T4 levels were seen in dams exposed to Mix 5. Neither of the two mixtures showed any effects on fetal hormone levels, but Mix 5 did caused a significant increase in aromatase mRNA levels in adrenal glands from female fetuses. Overall, aromatase induction in adrenals was found for Mix 5 both...... in vitro and in vivo. However, the hormonal responses in vitro were only partly reflected in vivo, probably due to ADME interactions, as the amniotic pesticide levels were negatively affected by the number of compounds present in the mixtures. Nonetheless, the H295R assay gives hints on interference...... with steroidogenesis, and it is suggested that one underlying mechanism for these pesticides is disturbance of steroidogenic enzymes....

  9. Evidence of altered fertility in female roach (Rutilus rutilus) from the River Seine (France).

    Science.gov (United States)

    Gerbron, M; Geraudie, P; Fernandes, D; Rotchell, J M; Porte, C; Minier, C

    2014-08-01

    A large variety of anthropogenic chemicals present in the aquatic environment have been shown to be able to alter the endocrine system of exposed organisms, potentially impacting their reproductive function. The aim of this study was to assess the effects of environmental pollution on the reproductive system of wild female roach (Rutilus rutilus) from the Seine River (Normandy, France). A suite of biomarkers of endocrine disruption including gonado-somatic index, plasmatic vitellogenin, gonadal aromatase activity and histological parameters (oocyte diameter and gonad maturation) were studied. Female fish from the polluted sites showed a number of reproductive alterations, including inhibited gonad maturation, reduced oocyte growth, reduced levels of plasmatic vitellogenin and 3-fold lower gonadal aromatase activity than females collected in the reference site. Overall, these results highlight the presence of endocrine disruption in female roach from the Seine River. PMID:24811946

  10. SNP GENOTYPING BY TAQMAN ALLELE DISCRIMINATION TECHNIQUE

    Directory of Open Access Journals (Sweden)

    Lucian Negura

    2015-07-01

    Full Text Available Breast cancer is the most frequent neoplasm in women worldwide and the principal cause of deaths by cancer, the majority being by metastatic disease. About half of breast tumors are hormone dependent, and in post-menopause women the preferred first line treatment uses third generation aromatase inhibitors. Aromatase is encoded by CYP19 gene on 15q21.1, and there is strong evidence that mutations in this gene affect its expression, with directconsequences on cancer phenotype and response to treatment. Several single nucleotide polymorphisms have beenstudied on CYP19A1 transcription variant, notably rs727479, rs10046, rs4646 and rs700518. We implemented a Taqman-based allele discrimination assay for the rapid investigation of the 4 SNPs in CYP19A1. We genotyped 22 metastaticbreast cancer patients by the technique described.

  11. Estrogen in prefrontal cortex blocks stress-induced cognitive impairments in female rats.

    Science.gov (United States)

    Yuen, Eunice Y; Wei, Jing; Yan, Zhen

    2016-06-01

    Animal and human studies have found that males and females show distinct stress responses. Recent studies suggest the contribution of estrogen in the brain to this sexual dimorphism. Repeated stress has been found to impair cognitive behaviors via suppressing glutamatergic transmission and glutamate receptor surface expression in pyramidal neurons of prefrontal cortex (PFC) in male rats. On the contrary, female rats exposed to the same stress paradigms show normal synaptic function and PFC-mediated cognition. The level of aromatase, the enzyme for the biosynthesis of estrogen, is significantly higher in the PFC of females than males. The stress-induced glutamatergic deficits and memory impairment are unmasked by blocking estrogen receptors or aromatase in females, suggesting a protective role of estrogen against the detrimental effects of repeated stress. PMID:26321384

  12. Long-term efficacy and safety of anastrozole for adjuvant treatment of early breast cancer in postmenopausal women

    Directory of Open Access Journals (Sweden)

    Sharath Gangadhara

    2009-04-01

    Full Text Available Sharath Gangadhara, Gianfilippo BertelliSouth West Wales Cancer Institute, Singleton Hospital, Swansea, UKAbstract: For more than 20 years, tamoxifen has been the gold standard for the adjuvant treatment of postmenopausal women with hormone-responsive early breast cancer. However, recent randomized trials have shown efficacy and tolerability benefits with the third-generation aromatase inhibitor anastrozole, resulting in an increased use of this agent in the adjuvant setting. Data on anastrozole’s long-term efficacy and tolerability are therefore of interest in clinical practice and will be reviewed here, especially in the light of the 100-month analysis of the ATAC (Anastrozole, Tamoxifen Alone or in Combination trial.Keywords: anastrozole, aromatase inhibitors, breast cancer, adjuvant therapy 

  13. Effects of pinostrobin on estrogen metabolism and estrogen receptor transactivation.

    Science.gov (United States)

    Le Bail, J C; Aubourg, L; Habrioux, G

    2000-08-01

    The interaction between the estrogen receptor and 5-hydroxy-7-methoxyflavanone (pinostrobin) was studied in the presence or absence of estradiol or dehydroepiandrosterone sulfate (DHEAS), respectively, using a stably transfected human breast cancer cell line (MVLN). We also evaluated its action on the proliferation in estrogen-dependent (MCF-7) human breast cancer cells in the same conditions than the estrogen receptor assay. On the other hand pinostrobin was evaluated for their effects on the human placental aromatase, 3beta-hydroxysteroid dehydrogenase Delta(4)/Delta(5) isomerase and 17beta-hydroxysteroid dehydrogenase activities. Pinostrobin did not possess antiestrogenic activity but presented anti-aromatase activity and decreased the growth of MCF-7 cells induced by DHEAS and E(2). This study provides particularly evidence of the potential biological interest of pinostrobin among the flavonoids. PMID:10840157

  14. Alopecia With Endocrine Therapies in Patients With Cancer

    OpenAIRE

    Saggar, Vishal; Wu, Shenhong; Dickler, Maura N.; Lacouture, Mario E.

    2013-01-01

    Whereas the frequency of alopecia to cytotoxic chemotherapies has been well described, the incidence of alopecia during endocrine therapies (i.e., anti-estrogens, aromatase inhibitors) has not been investigated. We performed a systematic analysis of the literature to ascertain the incidence and risk for alopecia while receiving endocrine therapies and found that alopecia is a common yet underreported adverse event of endocrine-based cancer therapies.

  15. Alcohol-related breast cancer in postmenopausal women - effect of CYP19A1, PPARG and PPARGC1A polymorphisms on female sex-hormone levels and interaction with alcohol consumption and NSAID usage in a nested case-control study and a randomised controlled trial

    OpenAIRE

    Kopp, Tine Iskov; Jensen, Ditte Marie; Ravn-Haren, Gitte; Cohen, Arieh; Sommer, Helle Mølgaard; Dragsted, Lars Ove; Tjonneland, Anne; Hougaard, David Michael; Vogel, Ulla Birgitte

    2016-01-01

    Alcohol consumption is associated with increased risk of breast cancer (BC), and the underlying mechanism is thought to be sex-hormone driven. In vitro and observational studies suggest a mechanism involving peroxisome proliferator-activated receptor gamma (PPARγ) in a complex with peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) and interaction with aromatase (encoded by CYP19A1). Use of non-steroidal anti-inflammatory drugs (NSAID) may also affect circulating sex-ho...

  16. Estrogen receptor prevents p53-dependent apoptosis in breast cancer

    OpenAIRE

    Bailey, Shannon T.; Shin, Hyunjin; Westerling, Thomas; Liu, Xiaole Shirley; Brown, Myles

    2012-01-01

    More than two-thirds of breast cancers express the estrogen receptor (ER) and depend on estrogen for growth and survival. Therapies targeting ER function, including aromatase inhibitors that block the production of estrogens and ER antagonists that alter ER transcriptional activity, play a central role in the treatment of ER+ breast cancers of all stages. In contrast to ER− breast cancers, which frequently harbor mutations in the p53 tumor suppressor, ER+ breast cancers are predominantly wild...

  17. In vitro - in vivo correlations for endocrine activity of a mixture of currently used pesticides

    Energy Technology Data Exchange (ETDEWEB)

    Taxvig, Camilla, E-mail: camta@food.dtu.dk [Division of Toxicology and Risk Assessment, National Food Institute, Technical University of Denmark, Mørkhøj Bygade 19, DK-2860 Søborg (Denmark); Hadrup, Niels; Boberg, Julie; Axelstad, Marta [Division of Toxicology and Risk Assessment, National Food Institute, Technical University of Denmark, Mørkhøj Bygade 19, DK-2860 Søborg (Denmark); Bossi, Rossana [Department of Environmental Science, Aarhus University, DK-4000 Roskilde (Denmark); Bonefeld-Jørgensen, Eva Cecilie [Department of Public Health, University of Aarhus, DK-8000 Aarhus C (Denmark); Vinggaard, Anne Marie [Division of Toxicology and Risk Assessment, National Food Institute, Technical University of Denmark, Mørkhøj Bygade 19, DK-2860 Søborg (Denmark)

    2013-11-01

    Two pesticide mixtures were investigated for potential endocrine activity. Mix 3 consisted of bitertanol, propiconazole, and cypermethrin, and Mix 5 included malathion and terbuthylazine in addition to the three pesticides in Mix 3. All five single pesticides and the two mixtures were investigated for their ability to affect steroidogenesis in vitro in H295R cells. The pesticides alone and both mixtures affected steroidogenesis with both mixtures causing increase in progesterone and decrease in testosterone. For Mix 5 an increase in estradiol was seen as well, indicating increased aromatase activity. The two mixtures were also investigated in pregnant rats dosed from gestational day 7 to 21, followed by examination of dams and fetuses. Decreased estradiol and reduced placental testosterone were seen in dams exposed to Mix 5. Also a significant increase in aromatase mRNA-levels in female adrenal glands was found for Mix5. However, either of the two mixtures showed any effects on fetal hormone levels in plasma or testis, or on anogenital distance. Overall, potential aromatase induction was found for Mix 5 both in vitro and in vivo, but not for Mix 3, an effect likely owed to terbuthylazine in Mix 5. However, the hormonal responses in vitro were only partly reflected in vivo, probably due to some toxicokinetic issues, as the pesticide levels in the amniotic fluid also were found to be negatively affected by the number of compounds present in the mixtures. Nonetheless, the H295R assay gives hints on conceivable interference with steroidogenesis, thus generating hypotheses on in vivo effects. - Highlights: • The study examines the endocrine disrupting potential of mixtures of pesticides. • All single pesticides and both mixtures affected steroidogenesis in vitro. • Potential aromatase induction was found for Mix 5 both in vitro and in vivo. • The hormonal responses in vitro were only partly reflected in vivo.

  18. Recurrent severe hyperandrogenism during pregnancy: a case report

    OpenAIRE

    Holt, H B; Medbak, S; Kirk, D.; Guirgis, R; Hughes, I.; Cummings, M H; Meeking, D R

    2005-01-01

    This report describes the case of a 28 year old woman with virilisation occurring in two successive pregnancies. Recurrent maternal virilisation is rare (seven previous reports) and this case is unique in its severity. Differential diagnoses include ovarian disease and fetal aromatase deficiency. New techniques to exclude a fetal cause were used in this case. This patient presented during the third trimester of her first pregnancy with rapid onset of hirsuitism, increased musculature, and dee...

  19. Evolution of Long-Term Adjuvant Anti-hormone Therapy: Consequences and Opportunities. The St. Gallen Prize Lecture

    OpenAIRE

    Jordan, V Craig; Obiorah, Ifeyinwa; Fan, Ping; Kim, Helen R.; Ariazi, Eric; Cunliffe, Heather; Brauch, Hiltrud

    2011-01-01

    The successful translation of the scientific principles of targeting the breast tumour oestrogen receptor (ER) with the nonsteroidal anti-oestrogen tamoxifen and using extended durations (at least 5-years) of adjuvant therapy, dramatically increased patient survivorship and significantly enhanced a drop in national mortality rates from breast cancer. The principles are the same for the validation of aromatase inhibitors to treat post-menopausal patients but tamoxifen remains a cheap, life-sav...

  20. The National Cancer Institute of Canada Clinical Trials Group MAP.3 trial: an international breast cancer prevention trial

    OpenAIRE

    Pater, J.; Richardson, H.; Johnston, D.; Goss, Paul E.

    2007-01-01

    Several large phase iii trials have demonstrated that tamoxifen—and more recently, raloxifene—can effectively reduce the incidence of invasive breast cancer by 50%. However, these selective estrogen receptor modulators can also be associated with several rare, but serious, adverse events. Recently, the third-generation aromatase inhibitors (AIS) have demonstrated excellent efficacy in adjuvant breast cancer trials, and they show particular promise in the breast cancer prevention setting. The ...

  1. In vitro - in vivo correlations for endocrine activity of a mixture of currently used pesticides

    International Nuclear Information System (INIS)

    Two pesticide mixtures were investigated for potential endocrine activity. Mix 3 consisted of bitertanol, propiconazole, and cypermethrin, and Mix 5 included malathion and terbuthylazine in addition to the three pesticides in Mix 3. All five single pesticides and the two mixtures were investigated for their ability to affect steroidogenesis in vitro in H295R cells. The pesticides alone and both mixtures affected steroidogenesis with both mixtures causing increase in progesterone and decrease in testosterone. For Mix 5 an increase in estradiol was seen as well, indicating increased aromatase activity. The two mixtures were also investigated in pregnant rats dosed from gestational day 7 to 21, followed by examination of dams and fetuses. Decreased estradiol and reduced placental testosterone were seen in dams exposed to Mix 5. Also a significant increase in aromatase mRNA-levels in female adrenal glands was found for Mix5. However, either of the two mixtures showed any effects on fetal hormone levels in plasma or testis, or on anogenital distance. Overall, potential aromatase induction was found for Mix 5 both in vitro and in vivo, but not for Mix 3, an effect likely owed to terbuthylazine in Mix 5. However, the hormonal responses in vitro were only partly reflected in vivo, probably due to some toxicokinetic issues, as the pesticide levels in the amniotic fluid also were found to be negatively affected by the number of compounds present in the mixtures. Nonetheless, the H295R assay gives hints on conceivable interference with steroidogenesis, thus generating hypotheses on in vivo effects. - Highlights: • The study examines the endocrine disrupting potential of mixtures of pesticides. • All single pesticides and both mixtures affected steroidogenesis in vitro. • Potential aromatase induction was found for Mix 5 both in vitro and in vivo. • The hormonal responses in vitro were only partly reflected in vivo

  2. A Review on Effect of Estrogen on Neural Growth and Sexual Dimorphism in the Brain

    OpenAIRE

    Robel Abay

    2015-01-01

    In addition to the usual classic views of estrogen’s actions in the brain as regulator of ovulation and reproductive behavior in the female; estrogens also play important roles in the male brain as well, where they can be generated from circulating testosterone by local aromatase enzymes or can also be synthesized de novo by neurons and glia and have profound effects on volumetric differences in different brain regions, promotion and inhibition of neurite growth, regulation of synaptic patter...

  3. Endogenous 17β-estradiol is required for activity-dependent long-term potentiation in the striatum: interaction with the dopaminergic system

    OpenAIRE

    Tozzi, Alessandro; de Iure, Antonio; Tantucci, Michela; Durante, Valentina; Quiroga-Varela, Ana; Giampà, Carmela; Di Mauro, Michela; Mazzocchetti, Petra; Costa, Cinzia; Di Filippo, Massimiliano; Grassi, Silvarosa; Pettorossi, Vito Enrico; Calabresi, Paolo

    2015-01-01

    17β-estradiol (E2), a neurosteroid synthesized by P450-aromatase (ARO), modulates various brain functions. We characterized the role of the locally synthesized E2 on striatal long-term synaptic plasticity and explored possible interactions between E2 receptors (ERs) and dopamine (DA) receptors in the dorsal striatum of adult male rats. Inhibition of E2 synthesis or antagonism of ERs prevented the induction of long-term potentiation (LTP) in both medium spiny neurons (MSNs) and cholinergic int...

  4. Endogenous 17ß-estradiol is required for activity-dependent long-term potentiation in the striatum: interaction with the dopaminergic system

    OpenAIRE

    Alessandro eTozzi; Antonio ede Iure; Michela eTantucci; Valentina eDurante; Ana eQuiroga-Varela; Carmela eGiampà; Michela eDi Mauro; Petra eMazzocchetti; Cinzia eCosta; Massimiliano eDi Filippo; Silvarosa eGrassi; Vito Enrico Pettorossi; Paolo eCalabresi

    2015-01-01

    17β-estradiol (E2), a neurosteroid synthesized by P450-aromatase (ARO), modulates various brain functions. We characterized the role of the locally synthesized E2 on striatal long-term synaptic plasticity and explored possible interactions between E2 receptors (ERs) and dopamine (DA) receptors in the dorsal striatum of adult male rats. Inhibition of E2 synthesis or antagonism of ERs prevented the induction of long-term potentiation (LTP) in both medium spiny neurons (MSNs) and cholinergic int...

  5. Hyaluronic acid-bound letrozole nanoparticles restore sensitivity to letrozole-resistant xenograft tumors in mice.

    Science.gov (United States)

    Nair, Hareesh B; Huffman, Steven; Veerapaneni, Poornachand; Kirma, Nameer B; Binkley, Peter; Perla, Rao P; Evans, Dean B; Tekmal, Rajeshwar R

    2011-05-01

    Letrozole is a potent aromatase inhibitor and superior to other defined selective estrogen receptor modulators such as tamoxifen in treating hormone-responsive postmenopausal breast cancer patients. Patients who receive this drug may become insensitive to the effects of estrogen deprivation induced by letrozole. Letrozole has known side effects on bone metabolism due to systemic ablation of estrogen production. The purpose of this study was to examine the therapeutic efficacy of hyaluronic acid-bound letrozole nanoparticles (HA-Letr-NPs) in restoring sensitivity to letrozole-resistant (LTLT-Ca) cells. To target letrozole to LTLT-Ca cells, hyaluronic acid-bound letrozole nanoparticles were prepared by nanoprecipitation using biodegradable PLGA-PEG co-polymer. Binding specificity of HA to CD44 on the cell surface was analyzed in vitro using FITC-CD44 Ab and CD44 siRNA by flow cytometry. Effects on in vitro cytotoxicity and aromatase enzymatic activity of HA-Letr-NPs were performed in MCF-7 breast cancer cells, MCF-7 cells over-expressing aromatase (MCF-7/Aro), and LTLT-Ca cells resistant to letrozole. Preclinical efficacy of HA-Letr-NPs was examined in mice using LTLT-Ca xenograft tumors. HA-Letr-NPs were restricted to a maximum size of 100 nm. The in vitro drug release assay showed that the highest released concentration of letrozole occurred after 23 hours at 37 degrees C in phosphate-buffered saline. HA-Letr-NPs on MCF-7/Aro and LTLT-Ca cells showed an IC50 of 2 microM and 5 microM, respectively. HA-Letr-NPs were more efficacious in inhibiting tumor growth, reducing in vitro cellular and in vivo tumor aromatase enzyme activity more than the corresponding Letr-NPs or letrozole. HA-Letr-NPs restored and maintained a prolonged sensitivity and targeted delivery of letrozole in letrozole-resistant tumors in vivo. PMID:21780370

  6. Endometrioza w wieku przed- i okołomenopauzalnym – jak leczyć?

    OpenAIRE

    Robert Z. Spaczyński; Agnieszka Mitkowska

    2011-01-01

    Endometriosis, i.e. extragonadal localization of endometrial stroma and glands is predominantly found inreproductive age women, however it is also diagnosed in teenagers and postmenopausal women. Prevalenceof postmenopausal endometriosis is 2-5% of all endometriosis cases, with majority found in patients usingestrogen replacement therapy (ERT). Etiopathogenesis of endometriosis after menopause is related toextragonadal aromatase activity (androstendione to estradiol conversion). The aim of en...

  7. miR-378a-3p modulates tamoxifen sensitivity in breast cancer MCF-7 cells through targeting GOLT1A

    OpenAIRE

    Kazuhiro Ikeda; Kuniko Horie-Inoue; Toshihide Ueno; Takashi Suzuki; Wataru Sato; Takashi Shigekawa; Akihiko Osaki; Toshiaki Saeki; Eugene Berezikov; Hiroyuki Mano; Satoshi Inoue

    2015-01-01

    Breast cancer is a hormone-dependent cancer and usually treated with endocrine therapy using aromatase inhibitors or anti-estrogens such as tamoxifen. A majority of breast cancer, however, will often fail to respond to endocrine therapy. In the present study, we explored miRNAs associated with endocrine therapy resistance in breast cancer. High-throughput miRNA sequencing was performed using RNAs prepared from breast cancer MCF-7 cells and their derivative clones as endocrine therapy resistan...

  8. 'New and translational perspectives of oestrogen deprivation in breast cancer'

    OpenAIRE

    Dunbier, Anita K.; Martin, Lesley-Ann; Dowsett, Mitch

    2011-01-01

    Abstract Over the last 20 years, aromatase inhibitors have been developed to become a highly effective treatment strategy for treatment of hormone receptor positive breast cancer. Despite their success, poor response and resistance limit the effectiveness of these agents in up to 50% of patients. In recent years, studies using highly sensitive hormone assays have provided insight into the source of oestrogen production for the stimulation of oestrogen receptor positive breast cance...

  9. Androgens and Bone

    OpenAIRE

    Clarke, Bart L.; Khosla, Sundeep

    2008-01-01

    Testosterone is the major gonadal sex steroid produced by the testes in men. Testosterone is also produced in smaller amounts by the ovaries in women. The adrenal glands produce the weaker androgens dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione. These androgens collectively affect skeletal homeostasis throughout life in both men and women, particularly at puberty and during adult life. Because testosterone can be metabolized to estradiol by the aromatase enzyme, ...

  10. Cancer treatment-related bone disease

    OpenAIRE

    Brown, Sue A.; Guise, Theresa A.

    2009-01-01

    Bone health may be impaired in many patients being treated for cancer. Primary tumors that reside in or form metastases to bone can result in compromised skeletal integrity. It has also been increasingly recognized that patients undergoing therapies for treatment of cancer are at higher risk of bone loss. These include androgen-deprivation therapy for prostate cancer and aromatase inhibitor therapy for breast cancer among others. Hypogonadism induced by many of these cancer treatments results...

  11. Association between urinary prostaglandin E2 metabolite and breast cancer risk: a prospective, case-cohort study of postmenopausal women

    OpenAIRE

    Kim, Sangmi; Taylor, Jack A.; Milne, Ginger L.; Sandler, Dale P.

    2013-01-01

    Overweight or obese women are at increased risk of developing and dying from breast cancer. Obesity-driven inflammation may stimulate prostaglandin E2 (PGE2)-mediated aromatase activation and estrogen biosynthesis in breast tissues. We hypothesized that increased production of PGE2 would contribute to elevated breast cancer risk in postmenopausal women. We carried out a case-cohort study with 307 incident breast cancer cases and 300 subcohort members from the Sister Study cohort. Hazard ratio...

  12. Sex-dependent influence of endogenous estrogen in pulmonary hypertension

    OpenAIRE

    Mair, Kirsty M.; Wright, Audrey F.; Duggan, Nicholas; Rowlands, David J.; Hussey, Martin J.; Roberts, Sonia; Fullerton, Josephine; Nilsen, Margaret; Loughlin, Lynn; Thomas, Matthew; MacLean, Margaret R.

    2014-01-01

    Rationale: The incidence of pulmonary arterial hypertension (PAH) is greater in women suggesting estrogens may play a role in the disease pathogenesis. Experimentally, in males exogenously administered estrogen can protect against PH; however in models that display female susceptibility estrogens may play a causative role. Objectives: To clarify the influence of endogenous estrogen and gender in PH and assess the therapeutic potential of a clinically available aromatase inhibitor. Met...

  13. A decade of letrozole: FACE

    OpenAIRE

    O’Shaughnessy, Joyce

    2007-01-01

    Third-generation nonsteroidal aromatase inhibitors (AIs), letrozole and anastrozole, are superior to tamoxifen as initial therapy for early breast cancer but have not been directly compared in a head-to-head adjuvant trial. Cumulative evidence suggests that AIs are not equivalent in terms of potency of estrogen suppression and that there may be differences in clinical efficacy. Thus, with no data from head-to-head comparisons of the AIs as adjuvant therapy yet available, the question of wheth...

  14. Effect of vitamin D supplementation on serum 25-hydroxy vitamin D levels, joint pain, and fatigue in women starting adjuvant letrozole treatment for breast cancer

    OpenAIRE

    Khan, Qamar J.; Reddy, Pavan S.; Kimler, Bruce F; Sharma, Priyanka; Baxa, Susan E.; O’Dea, Anne P.; Klemp, Jennifer R.; Fabian, Carol J.

    2009-01-01

    Vitamin D deficiency and insufficiency may contribute to musculoskeletal symptoms and bone loss observed in women taking aromatase inhibitors (AIs). This study was conducted to determine the prevalence of suboptimal vitamin D levels in women initiating adjuvant letrozole for breast cancer and to determine whether supplementation with 50,000 IU of vitamin D3 weekly could reduce musculoskeletal symptoms and fatigue in women who have suboptimal vitamin D levels. Sixty women about to begin an adj...

  15. Inhibition of estrogen biosynthesis enhances lymphoma growth in mice

    Science.gov (United States)

    Talaber, Gergely; Yakimchuk, Konstantin; Guan, Jiyu; Inzunza, Jose; Okret, Sam

    2016-01-01

    Most lymphomas show higher incidence and poorer prognosis in males compared to females. However, the endocrine contribution to this gender difference is not entirely known. Here we show that castration accelerates lymphoma growth in C57BL6 male mice grafted with murine EG7 T cell lymphoma cells. However, the androgen receptor antagonist Bicalutamide did not affect lymphoma growth, suggesting no impact of androgen receptor signaling on lymphoma progression. In contrast, inhibition of androgen-to-estrogen conversion by the aromatase inhibitor (AI) Letrozole induced faster lymphoma growth in mice, suggesting that androgens impact lymphoma growth through its conversion to estrogens. This was supported by the inability of dihydrotestosterone, which is not converted to estrogens by aromatase, to influence lymphoma growth in castrated male mice. Lymphoma growth was also stimulated in immunocompromised mice grafted with human B cell lymphoma (Granta-519) and treated with either reversible or irreversible AIs, showing that the blockage of estrogen synthesis caused enhanced growth of both murine T and human B cell lymphomas and with different AIs. Additionally, AI-treated EG7 lymphomas showed accelerated growth not only in male but also in intact female mice. Altogether, our results demonstrate that aromatase inhibition accelerates lymphoma growth but not androgens per se, highlighting a protective role of estrogens in lymphoma pathogenesis. These results also raise concern that the use of AIs in women with breast cancer might enhance lymphoma progression. PMID:26943574

  16. Action Mechanism of Ginkgo biloba Leaf Extract Intervened by Exercise Therapy in Treatment of Benign Prostate Hyperplasia

    Directory of Open Access Journals (Sweden)

    Chiung-Chi Peng

    2013-01-01

    overexpression of stromal, and epithelial growth factors associated with chronic inflammation, has become an atypical direct cause of mortality of aged male diseases. Ginkgo possesses anti-inflammatory, blood flow-enhancing, and free radical scavenging effects. Considering strenuous exercise can reduce BPH risks, we hypothesize Ginkgo + exercise (Ginkgo + Ex could be beneficial to BPH. To verify this, rat BPH model was induced by s.c. 3.5 mg testosterone (T and 0.1 mg estradiol (E2 per head per day successively for 8 weeks, using mineral oil as placebo. Cerenin® 8.33 μL/100 g was applied s.c. from the 10th to the 13th week, and simultaneously, Ex was applied (30 m/min, 3 times/week. In BPH, Ginkgo alone had no effect on T, 5α-reductase, and dihydrotestosterone (DHT, but suppressed androgen receptor (AR, aromatase, E2 and estrogen receptor (ER, and the proliferating cell nuclear antigen (PCNA; Ex alone significantly reduced T, aromatase, E2, ER, AR, and PCNA, but highly raised DHT. While Ginkgo + Ex androgenically downregulated T, aromatase, E2, and ER, but upregulated DHT, AR, and PCNA, implying Ginkgo + Ex tended to worsen BPH. Conclusively, Ginkgo or Ex alone may be more beneficial than Ginkgo + Ex for treatment of BPH.

  17. Tolerability of Therapies Recommended for the Treatment of Hormone Receptor-Positive Locally Advanced or Metastatic Breast Cancer.

    Science.gov (United States)

    Ohno, Shinji

    2016-08-01

    For women with hormone receptor-positive advanced breast cancer, endocrine therapies, including the selective estrogen receptor modulator tamoxifen, the aromatase inhibitors anastrozole, letrozole, and exemestane, and the selective estrogen receptor degrader fulvestrant, are recommended in clinical guidelines. The addition of targeted agents such as everolimus or palbociclib to aromatase inhibitors are also recommended as treatment options. Chemotherapy remains an option, although clinical guidelines have recommended these agents be reserved for patients with immediately life-threatening disease or if resistance to endocrine therapy is known or suspected. The present review has consolidated the tolerability profiles of the agents approved for use in the treatment of hormone receptor-positive advanced or metastatic breast cancer based on phase III registration trial data. Endocrine therapies are generally well tolerated, although the addition of targeted therapies to aromatase inhibitors or fulvestrant appears to increase the proportion of patients experiencing adverse events, and palbociclib and chemotherapy appear to be more closely associated with serious adverse events, including neutropenia. PMID:27151773

  18. Perbedaan β-crosslaps Serum Penderita Karsinoma Payudara Pascamenopause antara yang Diberikan Anastrozol dan Tamoksifen

    Directory of Open Access Journals (Sweden)

    Randy Sebastian

    2015-12-01

    Full Text Available Tamoxifen and inhibitor aromatases as adjuvant therapy plays an important role in postmenopausal breast cancer patients with positive estrogen receptor. Currently, inhibitor aromatases can replace tamoxifen because it has more advantages than tamoxifen. Inhibitor aromatases also have side effects which is increased bone resorption that triggers osteoporosis and fractures when compared to tamoxifen. During the process of bone resorption, bone matrix, composed of 90% type I collagen, were broken down resulting in β-crosslaps content in the blood, which is measurable. This study measured the levels of serum β-crosslaps in postmenopausal breast cancer patients who received anastrozol and tamoxifen in Dr. Hasan Sadikin General Hospital Bandung between January and July 2013. This was a cross-sectional study with comparative analytics to compare the mean levels of serum β-crosslaps in postmenopausal breast cancer patients between the two groups. There were 32 patients in this study, 16 patients in each group. The results of data processing using statistical tests at 95% confidence level revealed that there was significant differences in serum levels of β-crosslaps between the group who received anastrozol and those who received tamoxifen (p<0.05. In conclusion, the mean value of β-crosslaps serum in anastrozol group is higher than in tamoxifen group. This means that postmenopausal breast cancer patients receiving anastrozol for more than 6 months could may experienced a higher degree of bone resorption compared to those receiving tamoxifen

  19. Evidence of altered fertility in female roach (Rutilus rutilus) from the River Seine (France)

    International Nuclear Information System (INIS)

    A large variety of anthropogenic chemicals present in the aquatic environment have been shown to be able to alter the endocrine system of exposed organisms, potentially impacting their reproductive function. The aim of this study was to assess the effects of environmental pollution on the reproductive system of wild female roach (Rutilus rutilus) from the Seine River (Normandy, France). A suite of biomarkers of endocrine disruption including gonado-somatic index, plasmatic vitellogenin, gonadal aromatase activity and histological parameters (oocyte diameter and gonad maturation) were studied. Female fish from the polluted sites showed a number of reproductive alterations, including inhibited gonad maturation, reduced oocyte growth, reduced levels of plasmatic vitellogenin and 3-fold lower gonadal aromatase activity than females collected in the reference site. Overall, these results highlight the presence of endocrine disruption in female roach from the Seine River. - Highlights: • Biomarkers of endocrine disruption were studied in female roach from Seine River. • Environmental pollutant mixture impacted the reproductive function of wild female roach. • Inhibition of gonad maturation, lower VTG levels and gonadal aromatase activity were observed. - This study shows evidence of reproductive alterations in female roach (Rutilus rutilus) from the Seine River

  20. Androgenetic alopecia in women.

    Science.gov (United States)

    Price, Vera H

    2003-06-01

    Androgenetic alopecia (AGA), also known in women as female pattern hair loss, is caused by androgens in genetically susceptible women and men. The thinning begins between ages 12 and 40 years, the inheritance pattern is polygenic, and the incidence is the same as in men. In susceptible hair follicles, dihydrotestosterone binds to the androgen receptor, and the hormone-receptor complex activates the genes responsible for the gradual transformation of large terminal follicles to miniaturized follicles. Both young women and young men with AGA have higher levels of 5alpha reductase and androgen receptor in frontal hair follicles compared to occipital follicles. At the same time, young women have much higher levels of cytochrome p-450 aromatase in frontal follicles than men who have minimal aromatase, and women have even higher aromatase levels in occipital follicles. The diagnosis of AGA in women is supported by early age of onset, the pattern of increased thinning over the frontal/parietal scalp with greater density over the occipital scalp, retention of the frontal hairline, and the presence of miniaturized hairs. Most women with AGA have normal menses and pregnancies. Extensive hormonal testing is usually not needed unless symptoms and signs of androgen excess are present such as hirsutism, severe unresponsive cystic acne, virilization, or galactorrhea. Topical minoxidil solution is the only drug available for promoting hair growth in women with AGA. Efficacy has been shown in double-blind studies using hair counts and hair weight. PMID:12894991

  1. Estrogen biosynthesis in human uterine adenomyosis

    Energy Technology Data Exchange (ETDEWEB)

    Urabe, Mamoru; Yamamoto, Takara; Kitawaki, Jo; Honjo, Hideo; Okada, Hiroji (Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Kyoto (Japan))

    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-{sup 3}H)androstenedione and NADPH at 37 deg. C for 1 h. After stopping the enzymatic reaction with ethyl acetate, (4-{sup 14}C)estrone and (4-{sup 14}C)estradiol-17{beta} 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 {sup 3}H/{sup 14}C ratio of the final crystal. The value for estrone formed from androstenedione was 52-132 fmol{sup .}h{sup -1.}g{sup -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).

  2. Hypothalamic inhibition of socio-sexual behaviour by increasing neuroestrogen synthesis

    Science.gov (United States)

    Ubuka, Takayoshi; Haraguchi, Shogo; Tobari, Yasuko; Narihiro, Misato; Ishikawa, Kei; Hayashi, Takanori; Harada, Nobuhiro; Tsutsui, Kazuyoshi

    2014-01-01

    Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that inhibits gonadotropin secretion and socio-sexual behaviours. Oestrogen (neuroestrogen) synthesized in the brain from androgen by aromatase regulates male socio-sexual behaviours. Here we show that GnIH directly activates aromatase and increases neuroestrogen synthesis in the preoptic area (POA) and inhibits socio-sexual behaviours of male quail. Aromatase activity and neuroestrogen concentration in the POA are low in the morning when the birds are active, but neuroestrogen synthesis gradually increases until the evening when the birds become inactive. Centrally administered GnIH in the morning increases neuroestrogen synthesis in the POA and decreases socio-sexual behaviours. Centrally administered 17β-oestradiol at higher doses also inhibits socio-sexual behaviours in the morning. These results suggest that GnIH inhibits male socio-sexual behaviours by increasing neuroestrogen synthesis beyond its optimum concentration for the expression of socio-sexual behaviours. This is the first demonstration of any hypothalamic neuropeptide that directly regulates neuroestrogen synthesis.

  3. Phytoestrogens in menopausal supplements induce ER-dependent cell proliferation and overcome breast cancer treatment in an in vitro breast cancer model

    Energy Technology Data Exchange (ETDEWEB)

    Duursen, Majorie B.M. van, E-mail: M.vanDuursen@uu.nl [Endocrine Toxicology, Institute for Risk Assessment Sciences, Utrecht University, Yalelaan 104, PO Box 80177, 3508 TD, Utrecht (Netherlands); Smeets, Evelien E.J.W. [Endocrine Toxicology, Institute for Risk Assessment Sciences, Utrecht University, Yalelaan 104, PO Box 80177, 3508 TD, Utrecht (Netherlands); Rijk, Jeroen C.W. [RIKILT - Institute for Food Safety, Wageningen UR, P.O. Box 230, 6700 AE, Wageningen (Netherlands); Nijmeijer, Sandra M.; Berg, Martin van den [Endocrine Toxicology, Institute for Risk Assessment Sciences, Utrecht University, Yalelaan 104, PO Box 80177, 3508 TD, Utrecht (Netherlands)

    2013-06-01

    Breast cancer treatment by the aromatase inhibitor Letrozole (LET) or Selective Estrogen Receptor Modulator Tamoxifen (TAM) can result in the onset of menopausal symptoms. Women often try to relieve these symptoms by taking menopausal supplements containing high levels of phytoestrogens. However, little is known about the potential interaction between these supplements and breast cancer treatment, especially aromatase inhibitors. In this study, interaction of phytoestrogens with the estrogen receptor alpha and TAM action was determined in an ER-reporter gene assay (BG1Luc4E2 cells) and human breast epithelial tumor cells (MCF-7). Potential interactions with aromatase activity and LET were determined in human adrenocorticocarcinoma H295R cells. We also used the previously described H295R/MCF-7 co-culture model to study interactions with steroidogenesis and tumor cell proliferation. In this model, genistein (GEN), 8-prenylnaringenin (8PN) and four commercially available menopausal supplements all induced ER-dependent tumor cell proliferation, which could not be prevented by physiologically relevant LET and 4OH-TAM concentrations. Differences in relative effect potencies between the H295R/MCF-7 co-culture model and ER-activation in BG1Luc4E2 cells, were due to the effects of the phytoestrogens on steroidogenesis. All tested supplements and GEN induced aromatase activity, while 8PN was a strong aromatase inhibitor. Steroidogenic profiles upon GEN and 8PN exposure indicated a strong inhibitory effect on steroidogenesis in H295R cells and H295R/MCF-7 co-cultures. Based on our in vitro data we suggest that menopausal supplement intake during breast cancer treatment should better be avoided, at least until more certainty regarding the safety of supplemental use in breast cancer patients can be provided. - Highlights: • Supplements containing phytoestrogens are commonly used by women with breast cancer. • Phytoestrogens alter steroidogenesis in a co-culture breast

  4. Phytoestrogens in menopausal supplements induce ER-dependent cell proliferation and overcome breast cancer treatment in an in vitro breast cancer model

    International Nuclear Information System (INIS)

    Breast cancer treatment by the aromatase inhibitor Letrozole (LET) or Selective Estrogen Receptor Modulator Tamoxifen (TAM) can result in the onset of menopausal symptoms. Women often try to relieve these symptoms by taking menopausal supplements containing high levels of phytoestrogens. However, little is known about the potential interaction between these supplements and breast cancer treatment, especially aromatase inhibitors. In this study, interaction of phytoestrogens with the estrogen receptor alpha and TAM action was determined in an ER-reporter gene assay (BG1Luc4E2 cells) and human breast epithelial tumor cells (MCF-7). Potential interactions with aromatase activity and LET were determined in human adrenocorticocarcinoma H295R cells. We also used the previously described H295R/MCF-7 co-culture model to study interactions with steroidogenesis and tumor cell proliferation. In this model, genistein (GEN), 8-prenylnaringenin (8PN) and four commercially available menopausal supplements all induced ER-dependent tumor cell proliferation, which could not be prevented by physiologically relevant LET and 4OH-TAM concentrations. Differences in relative effect potencies between the H295R/MCF-7 co-culture model and ER-activation in BG1Luc4E2 cells, were due to the effects of the phytoestrogens on steroidogenesis. All tested supplements and GEN induced aromatase activity, while 8PN was a strong aromatase inhibitor. Steroidogenic profiles upon GEN and 8PN exposure indicated a strong inhibitory effect on steroidogenesis in H295R cells and H295R/MCF-7 co-cultures. Based on our in vitro data we suggest that menopausal supplement intake during breast cancer treatment should better be avoided, at least until more certainty regarding the safety of supplemental use in breast cancer patients can be provided. - Highlights: • Supplements containing phytoestrogens are commonly used by women with breast cancer. • Phytoestrogens alter steroidogenesis in a co-culture breast

  5. Chronic treatment with polychlorinated biphenyls (PCB) during pregnancy and lactation in the rat

    International Nuclear Information System (INIS)

    The gender-specific expression pattern of aromatase and 5alpha-reductases (5alpha-R) during brain development provides neurons the right amount of estradiol and DHT to induce a dimorphic organization of the structure. Polychlorinated biphenyls (PCBs) are endocrine disruptive pollutants; exposure to PCBs through placental transfer and breast-feeding may adversely affect the organizational action of sex steroid, resulting in long-term alteration of reproductive neuroendocrinology. The study was aimed at: a) evaluating the hypothalamic expression of aromatase, 5alpha-R1 and 5alpha-R2 in fetuses (GD20), infant (PN12), weaning (PN21) and young adult (PN60) male and female rats exposed to PCBs during development; b) correlating these parameters with the time of testicular descent, puberty onset, estrous cyclicity and copulatory behavior; c) evaluating possible alterations of some non reproductive behaviors (locomotion, learning and memory, depression/anxiety behavior). A reconstituted mixture of four indicator congeners (PCB 126, 138, 153 and 180) was injected subcutaneously to dams at the dose of 10 mg/kg daily from GD15 to GD19 and then twice a week till weanling. The results indicated that developmental PCB exposure produced important changes in the dimorphic hypothalamic expression of both aromatase and the 5alpha-Rs, which were still evident in adult animals. We observed that female puberty onset occurs earlier than in control animals without cycle irregularity, while testicular descent in males was delayed. A slight but significant impairment of sexual behavior and an important alteration in memory retention were also noted specifically in males. We conclude that PCBs might affect the dimorphic neuroendocrine control of reproductive system and of other neurobiological processes.

  6. Daily Rhythms of the Expression of Key Genes Involved in Steroidogenesis and Gonadal Function in Zebrafish.

    Directory of Open Access Journals (Sweden)

    Viviana Di Rosa

    Full Text Available Fish present daily and seasonal rhythms in spawning and plasmatic levels of steroids that control reproduction. However, the existence of the rhythms of expression of the genes that underlie the endocrine mechanisms responsible for processes such as steroidogenesis and reproduction in fish have still been poorly explored to date. Here we investigated the daily pattern of the expression of key genes involved in sex steroid production that ultimately set the sex ratio in fish. Adult zebrafish were maintained under a 12:12 h light-dark cycle at a constant temperature of 27°C and were sampled every 4 h during a 24-hour cycle. The expression of key genes in the gonads and brains of female and male individuals were analyzed. In gonads, the expression of aromatase (cyp19a1a, ovarian aromatase and the antimüllerian hormone (amh, testis was rhythmic, with almost opposite acrophases: ZT 5:13 h (in the light phase and ZT 15:39 h (at night, respectively. The expression of foxl2 (forkhead box L2 was also rhythmic in the ovary (acrophase located at ZT 5:02 h and the expression of dmrt1 (doublesex and mab-3-related transcription factor 1 was rhythmic in testes (acrophase at ZT 18:36 h. In the brain, cyp19a1b (brain aromatase and cyp11b (11beta-hydroxylase presented daily differences, especially in males, where the expression peaked at night. These results provide the first evidence for marked time-of-the-day-dependent differences in the expression of the genes involved in sex ratio control, which should be considered when investigating processes such as reproduction, sex differentiation and steroidogenesis in fish.

  7. Daily Rhythms of the Expression of Key Genes Involved in Steroidogenesis and Gonadal Function in Zebrafish

    Science.gov (United States)

    Di Rosa, Viviana; López-Olmeda, Jose Fernando; Burguillo, Ana; Frigato, Elena; Bertolucci, Cristiano; Piferrer, Francesc; Sánchez-Vázquez, Francisco Javier

    2016-01-01

    Fish present daily and seasonal rhythms in spawning and plasmatic levels of steroids that control reproduction. However, the existence of the rhythms of expression of the genes that underlie the endocrine mechanisms responsible for processes such as steroidogenesis and reproduction in fish have still been poorly explored to date. Here we investigated the daily pattern of the expression of key genes involved in sex steroid production that ultimately set the sex ratio in fish. Adult zebrafish were maintained under a 12:12 h light-dark cycle at a constant temperature of 27°C and were sampled every 4 h during a 24-hour cycle. The expression of key genes in the gonads and brains of female and male individuals were analyzed. In gonads, the expression of aromatase (cyp19a1a, ovarian aromatase) and the antimüllerian hormone (amh, testis) was rhythmic, with almost opposite acrophases: ZT 5:13 h (in the light phase) and ZT 15:39 h (at night), respectively. The expression of foxl2 (forkhead box L2) was also rhythmic in the ovary (acrophase located at ZT 5:02 h) and the expression of dmrt1 (doublesex and mab-3-related transcription factor 1) was rhythmic in testes (acrophase at ZT 18:36 h). In the brain, cyp19a1b (brain aromatase) and cyp11b (11beta-hydroxylase) presented daily differences, especially in males, where the expression peaked at night. These results provide the first evidence for marked time-of-the-day-dependent differences in the expression of the genes involved in sex ratio control, which should be considered when investigating processes such as reproduction, sex differentiation and steroidogenesis in fish. PMID:27322588

  8. 乳腺癌内分泌药物治疗的研究进展%Research advances in new endocrine therapy drugs of breast cancer

    Institute of Scientific and Technical Information of China (English)

    蒋维平

    2013-01-01

    Breast cancer is one of malignant tumors that seriously impact women's physical and mental health and even cause death. The traditional endocrine therapy drugs of breast cancer are estrogen receptor modulators and aromatase inhibitors that act on metabolic pathway of endogenous estrogenic steroids. The objective of the research on this class of drugs is to find new aromatase inhibitors with tissue selectivity, high efficacy and low toxic-ity. Novel steroid sulfatase inhibitors are effective hormone dependent breast cancer (HDBC) treatment drugs. Sul-famate moiety is confirmed to be the pharmacophore of these drugs. This article reviews research advances in aromatase inhibitors and steroid sulfatase inhibitors.%乳腺癌是严重影响妇女身心健康甚至危及生命的恶性肿瘤之一.传统的乳腺癌内分泌治疗药物是作用于雌激素环节的雌激素受体调节剂、芳香化酶抑制剂,但芳香化酶抑制剂的选择性较差,有中度的治疗相关毒性,如高血脂、骨丢失、肝脂肪化等,因此需要开发具有组织选择性、高效低毒的芳香化酶抑制剂.此外,新型的甾体硫酸酯酶抑制剂也已成为有效的激素依赖性乳腺癌(HDBC)治疗药物,氨基磺酸酯基团被证实是这类药物中的药效团.本文综述了芳香化酶抑制剂和硫酸酯酶抑制剂的研究进展.

  9. Non-ovarian aromatization is required to activate female sexual motivation in testosterone-treated ovariectomized quail.

    Science.gov (United States)

    de Bournonville, Catherine; Balthazart, Jacques; Ball, Gregory F; Cornil, Charlotte A

    2016-07-01

    Although aromatase is expressed in both male and female brains, its functional significance in females remains poorly understood. In female quail, sexual receptivity is activated by estrogens. However it is not known whether sexual motivation is similarly estrogen-dependent and whether estrogens locally produced in the brain contribute to these behavioral responses. Four main experiments were designed to address these questions. In Experiment 1 chronic treatment of females with the anti-estrogen tamoxifen decreased their receptivity, confirming that this response is under the control of estrogens. In Experiment 2 chronic treatment with tamoxifen significantly decreased sexual motivation as treated females no longer approached a sexual partner. In Experiment 3 (a) ovariectomy (OVX) induced a significant decrease of time spent near the male and a significantly decreased receptivity compared to gonadally intact females, (b) treatment with testosterone (OVX+T) partially restored these responses and (c) this effect of T was prevented when estradiol synthesis was inhibited by the potent aromatase inhibitor Vorozole (OVX+T+VOR). Serum estradiol concentration was significantly higher in OVX+T than in OVX or OVX+T+VOR females. Together these data demonstrate that treatment of OVX females with T increases sexual motivation and that these effects are mediated at least in part by non-gonadal aromatization of the androgen. Finally, assays of aromatase activity on brain and peripheral tissues (Experiment 4) strongly suggest that brain aromatization contributes to behavioral effects observed here following T treatment but alternative sources of estrogens (e.g. liver) should also be considered. PMID:27189762

  10. De novo synthesis of estrogen in pregnant uterus is critical for stromal decidualization and angiogenesis.

    Science.gov (United States)

    Das, Amrita; Mantena, Srinivasa Raju; Kannan, Athilakshmi; Evans, Dean B; Bagchi, Milan K; Bagchi, Indrani C

    2009-07-28

    Implantation is initiated when the embryo attaches to the uterine luminal epithelium during early pregnancy. Following this event, uterine stromal cells undergo steroid hormone-dependent transformation into morphologically and functionally distinct decidual cells in a unique process known as decidualization. An angiogenic network is also formed in the uterine stromal bed, critically supporting the early development of the embryo. The steroid-induced mechanisms that promote stromal differentiation and endothelial proliferation during decidualization are not fully understood. Although the role of ovarian progesterone as a key regulator of decidualization is well established, the requirement of ovarian estrogen (E) during this process remains unresolved. Here we show that the expression of P450 aromatase, a key enzyme that converts androgens to E, is markedly induced in mouse uterine stromal cells undergoing decidualization. The aromatase then acts in conjunction with other steroid biosynthetic enzymes present in the decidual tissue to support de novo synthesis of E. This locally produced E is able to support the advancement of the stromal differentiation program even in the absence ovarian E in an ovariectomized, progesterone-supplemented pregnant mouse model. Administration of letrozole, a specific aromatase inhibitor, to these mice blocked the stromal differentiation process. Gene expression profiling further revealed that the intrauterine E induces the expression of several stromal factors that promote neovascularization in the decidual tissue. Collectively, these studies identified the decidual uterus as a novel site of E biosynthesis and uncovered E-regulated maternal signaling pathways that critically control uterine differentiation and angiogenesis during early pregnancy. PMID:19620711

  11. Daily Rhythms of the Expression of Key Genes Involved in Steroidogenesis and Gonadal Function in Zebrafish.

    Science.gov (United States)

    Di Rosa, Viviana; López-Olmeda, Jose Fernando; Burguillo, Ana; Frigato, Elena; Bertolucci, Cristiano; Piferrer, Francesc; Sánchez-Vázquez, Francisco Javier

    2016-01-01

    Fish present daily and seasonal rhythms in spawning and plasmatic levels of steroids that control reproduction. However, the existence of the rhythms of expression of the genes that underlie the endocrine mechanisms responsible for processes such as steroidogenesis and reproduction in fish have still been poorly explored to date. Here we investigated the daily pattern of the expression of key genes involved in sex steroid production that ultimately set the sex ratio in fish. Adult zebrafish were maintained under a 12:12 h light-dark cycle at a constant temperature of 27°C and were sampled every 4 h during a 24-hour cycle. The expression of key genes in the gonads and brains of female and male individuals were analyzed. In gonads, the expression of aromatase (cyp19a1a, ovarian aromatase) and the antimüllerian hormone (amh, testis) was rhythmic, with almost opposite acrophases: ZT 5:13 h (in the light phase) and ZT 15:39 h (at night), respectively. The expression of foxl2 (forkhead box L2) was also rhythmic in the ovary (acrophase located at ZT 5:02 h) and the expression of dmrt1 (doublesex and mab-3-related transcription factor 1) was rhythmic in testes (acrophase at ZT 18:36 h). In the brain, cyp19a1b (brain aromatase) and cyp11b (11beta-hydroxylase) presented daily differences, especially in males, where the expression peaked at night. These results provide the first evidence for marked time-of-the-day-dependent differences in the expression of the genes involved in sex ratio control, which should be considered when investigating processes such as reproduction, sex differentiation and steroidogenesis in fish. PMID:27322588

  12. Molecular cloning and expression analysis of fushi tarazu factor 1 in the brain of air-breathing catfish, Clarias gariepinus.

    Directory of Open Access Journals (Sweden)

    Parikipandla Sridevi

    Full Text Available BACKGROUND: Fushi tarazu factor 1 (FTZ-F1 encodes an orphan nuclear receptor belonging to the nuclear receptor family 5A (NR5A which includes adrenal 4-binding protein or steroidogenic factor-1 (Ad4BP/SF-1 and liver receptor homologue 1 (LRH-1 and plays a pivotal role in the regulation of aromatases. METHODOLOGY/PRINCIPAL FINDINGS: Present study was aimed to understand the importance of FTZ-F1 in relation to brain aromatase (cyp19a1b during development, recrudescence and after human chorionic gonadotropin (hCG induction. Initially, we cloned FTZ-F1 from the brain of air-breathing catfish, Clarias gariepinus through degenerate primer RT-PCR and RACE. Its sequence analysis revealed high homology with other NR5A1 group members Ad4BP/SF-1 and LRH-1, and also analogous to the spatial expression pattern of the latter. In order to draw functional correlation of cyp19a1b and FTZ-F1, we analyzed the expression pattern of the latter in brain during gonadal ontogeny, which revealed early expression during gonadal differentiation. The tissue distribution both at transcript and protein levels revealed its prominent expression in brain along with liver, kidney and testis. The expression pattern of brain FTZ-F1 during reproductive cycle and after hCG induction, in vivo was analogous to that of cyp19a1b shown in our earlier study indicating its involvement in recrudescence. CONCLUSIONS/SIGNIFICANCE: Based on our previous results on cyp19a1b and the present data, it is plausible to implicate potential roles for brain FTZ-F1 in ovarian differentiation and recrudescence process probably through regulation of cyp19a1b in teleosts. Nevertheless, these interactions would require primary coordinated response from ovarian aromatase and its related transcription factors.

  13. Effects of the Methanol Extract of Basella alba L (Basellaceae) on Steroid Production in Leydig Cells

    OpenAIRE

    Carine Travert; Faustin-Pascal T. Manfo; Serge Carreau; Paul Fewou Moundipa; Monsees, Thomas K.; Edouard Akono Nantia

    2011-01-01

    In this study, Leydig cells were purified from 70 day-old Sprague Dawley male rats and incubated with 10 and 100 µg/mL of methanol extract of Basella alba (MEBa) for 4 hours followed by the evaluation of cell viability, steroid (testosterone and estradiol) production, and the level of aromatase mRNA. Results showed that MEBa did not affect Leydig cell viability. At the concentration of 10 µg/mL, MEBa significantly stimulated testosterone and estradiol production (p < 0.01 and p < 0.03, ...

  14. Quimioprevenção do câncer de mama Current status of breast cancer chemoprevention

    OpenAIRE

    Vilmar Marques de Oliveira; José Mendes Aldrighi; José Francisco Rinaldi

    2006-01-01

    Quimioprevenção é definida como o uso de agentes químicos naturais ou sintéticos para reverter, suprimir ou prevenir a progressão carcinogênica para carcinoma invasor. Os fármacos que agem como agentes quimiopreventivos contra o câncer de mama são divididos em dois grupos principais: os que previnem cânceres de mama receptor de estrogênio (RE) positivos, como os moduladores seletivos do receptor de estrogênio (SERM), inibidores de aromatase, agonistas de GnRH e fitoestrogênios; e os fármacos ...

  15. Microdissection testicular sperm extraction in patients with non-mosaic Klinefelter syndrome in programme in vitro fertilization: literature review and cases report

    Directory of Open Access Journals (Sweden)

    I. I. Vityazeva

    2014-12-01

    Full Text Available The article describes modern methods of examination, preoperative preparation and surgical treatment of infertility in men with non-mosaic form of Klinefelter syndrome (SK by microdissection method of testicular sperm retrieval. Men with SK responsive to hormonal therapy with aromatase inhibitors and human chorionic gonadotropin (НCG, have a greater chance of a favourable outcome of infertility treatment. Testicular volume, testosterone levels and test results with НCG are important prognostic factors in this group of patients. We present a clinical case of treatment of infertility in men with SK by microTESE (microdissection testicular sperm extraction.

  16. Microdissection testicular sperm extraction in patients with non-mosaic Klinefelter syndrome in programme in vitro fertilization: literature review and cases report

    Directory of Open Access Journals (Sweden)

    I. I. Vityazeva

    2014-01-01

    Full Text Available The article describes modern methods of examination, preoperative preparation and surgical treatment of infertility in men with non-mosaic form of Klinefelter syndrome (SK by microdissection method of testicular sperm retrieval. Men with SK responsive to hormonal therapy with aromatase inhibitors and human chorionic gonadotropin (НCG, have a greater chance of a favourable outcome of infertility treatment. Testicular volume, testosterone levels and test results with НCG are important prognostic factors in this group of patients. We present a clinical case of treatment of infertility in men with SK by microTESE (microdissection testicular sperm extraction.

  17. Impact of diisobutyl phthalate and other PPAR agonists on steroidogenesis and plasma insulin and leptin levels in fetal rats

    DEFF Research Database (Denmark)

    Boberg, Julie; Metzdorff, Stine Broeng; Wortziger, Rasmus Henrik Sorgenfryd;

    2008-01-01

    day (GD) 7-21 to diisobutyl phthalate (DiBP), butylparaben, perfluorooctanoate, or rosiglitazone (600, 100, 20, or 1 mg/kg bw/day, respectively). Endocrine endpoints were studied in offspring at GD 19 or 21. DiBP, butylparaben and rosiglitazone reduced plasma leptin levels in male and female offspring......, DiBP increased anogenital distance and increased ovarian aromatase mRNA levels. This study reveals new targets for phthalates and parabens in fetal male and female rats and contributes to the increasing concern about adverse effects of human exposure to these compounds. (C) 2008 Elsevier Ireland Ltd...

  18. Targeting the tumor microenvironment

    Energy Technology Data Exchange (ETDEWEB)

    Kenny, P.A.; Lee, G.Y.; Bissell, M.J.

    2006-11-07

    Despite some notable successes cancer remains, for the most part, a seemingly intractable problem. There is, however, a growing appreciation that targeting the tumor epithelium in isolation is not sufficient as there is an intricate mutually sustaining synergy between the tumor epithelial cells and their surrounding stroma. As the details of this dialogue emerge, new therapeutic targets have been proposed. The FDA has already approved drugs targeting microenvironmental components such as VEGF and aromatase and many more agents are in the pipeline. In this article, we describe some of the 'druggable' targets and processes within the tumor microenvironment and review the approaches being taken to disrupt these interactions.

  19. In vitro - in vivo correlations for endocrine activity of a mixture of currently used pesticides

    DEFF Research Database (Denmark)

    Taxvig, Camilla; Hadrup, Niels; Boberg, Julie;

    2013-01-01

    for their ability to affect steroidogenesis in vitro in H295R cells. The pesticides alone and both mixtures affected steroidogenesis with both mixtures causing increase in progesterone and decrease in testosterone. For Mix 5 an increase in estradiol was seen as well, indicating increased aromatase activity.The two......, the hormonal responses in vitro were only partly reflected in vivo, probably due to some toxicokinetic issues, as the pesticide levels in the amniotic fluid also were found to be negatively affected by the number of compounds present in the mixtures. Nonetheless, the H295R assay gives hints on conceivable...

  20. A case of recurrent organizing pneumonia after radiation therapy for postoperative breast cancer

    International Nuclear Information System (INIS)

    We report the case of a 61-year-old female patient with breast cancer who developed recurrent organizing pneumonia outside the radiation field after radiation therapy for postoperative breast cancer. The patient had received tangential radiation therapy and aromatase inhibitors for postoperative breast cancer. Chest computed tomography confirmed an irregular nodule and ground-glass opacities in the left lower lobe outside the radiation field 10 months after radiation therapy. The nodule demonstrated high uptake on 18F-fluorodeoxyglucose positron emission tomography; therefore, lung cancer could not be ruled out. We performed partial resection of the lung, and a diagnosis of organized pneumonia was made on histopathological examination of the resected specimen. Three days after surgery, a chest radiograph revealed an abnormal shadow in the right lower field. The possibility of organizing pneumonia was considered when pulmonary infiltrate did not respond to conventional antibiotic therapy and the patient recovered completely after treatment with steroids. Furthermore, chest CT performed 4 months after surgery revealed consolidation in the right lower lobe. Again, the patient recovered completely with steroid treatment, indicating the possibility of recurrent organizing pneumonia. The number of such reported cases has increased in recent years; however, the etiology remains unclear. In the case presented, aromatase inhibitor therapy combined with radiation therapy may have been the cause of the organizing pneumonia. (author)

  1. Preventative therapies for healthy women at high risk of breast cancer

    International Nuclear Information System (INIS)

    Tamoxifen has been shown to reduce the risk of developing estrogen receptor (ER)-positive breast cancer by at least 50%, in both pre- and postmenopausal women. The current challenge is to find new agents with fewer side effects and to find agents that are specifically suitable for premenopausal women with ER-negative breast cancer. Other selective estrogen receptor modulators (SERMs), such as raloxifene, arzoxifene, and lasofoxifene, have been shown to reduce the incidence of breast cancer by 50%–80%. SERMs are interesting agents for the prevention of breast cancer, but longer follow-up is needed for some of them for a complete risk–benefit profile of these drugs. Aromatase inhibitors have emerged as new drugs in the prevention setting for postmenopausal women. In the Mammary Prevention 3 (MAP3) trial, a 65% reduction in invasive breast cancer with exemestane was observed, and the Breast Cancer Intervention Study-II trial, which compared anastrozole with placebo, reported a 60% reduction in those cancers. Although SERMs and aromatase inhibitors have been proven to be excellent agents in the preventive setting specifically for postmenopausal women and ER-positive breast cancer, newer agents have to be found specifically for ER-negative breast cancers, which mostly occur in premenopausal women

  2. Ovarian and placental morphology and endocrine functions in the pregnant giraffe (Giraffa camelopardalis).

    Science.gov (United States)

    Wilsher, S; Stansfield, F; Greenwood, R E S; Trethowan, P D; Anderson, R A; Wooding, F B W; Allen, W R

    2013-06-01

    Gross, histological and immunocytochemical examinations carried out on maternal and fetal reproductive tissues from two pregnant giraffes at an estimated 8 and 13.5 months of gestation (term=15 months) revealed a typically ruminant macrocotyledonary placenta with binucleate trophoblast cells scattered sparsely in the placentome where they stained intensely with a prolactin antiserum. Binucleate cells were present in greater numbers in the intercotyledonary allantochorion where they did not stain for prolactin whereas the uninucleate trophoblast still did. A single large corpus luteum of pregnancy and several small luteinised follicles were present in the maternal ovaries while the fetal ovaries at 13.5 months gestation showed an assortment of enlarging antral follicles and partially and completely lutenised follicles, the granulosa and luteal cells of which stained positively for 3β-hydroxysteroid dehydrogenase (3β-HSD), 17,20 lyase, prolactin, progesterone receptor and androgen receptor, but negatively for aromatase. The uninucleate trophoblast of the placentome and intercotyledonary allantochorion, the epithelium of the maternal endometrial glands, the seminiferous epithelium in the fetal testis at 8 months of gestation and the zonae fasciculata and reticularis of the fetal adrenal at 13.5 months also stained positively for 3β-HSD and negatively for aromatase. Endocrinologically, it appears that the giraffe placenta is more similar to that of the sheep than the cow with a placental lactogen as the likely driver of the considerable degree of luteinisation seen in both the maternal and the fetal ovaries. PMID:23550169

  3. A role for the androgen receptor in the treatment of male breast cancer.

    Science.gov (United States)

    Zhu, Jason; Davis, Carter T; Silberman, Sandra; Spector, Neil; Zhang, Tian

    2016-02-01

    Male breast cancer (BC) is relatively rare, making up less than 1% of all breast cancer cases in the United States. Treatment guidelines for male BC are derived from studies on the treatment of female BC, and are based molecular and clinical characteristics, such as hormone receptor positivity. For female estrogen receptor positive (ER+) breast cancers, the standard of care includes three classes of endocrine therapies: selective estrogen receptor modulators, aromatase inhibitors, and pure anti-estrogens. In contrast to female ER+ breast cancers, there is less known about the optimal treatment for male ER+ BC. Furthermore, in contrast to ER, less is known about the role of the androgen receptor (AR) in male and female BC. We report here the treatment of a 28-year-old man with metastatic AR+, ER+ breast cancer otherwise refractory to chemotherapy, who has had a durable clinical response to hormonal suppression with the combination of aromatase inhibition (Letrozole) in conjunction with a GnRH agonist (Leuprolide).

  4. Kinetic analysis of [11C]vorozole binding in the human brain with positron emission tomography.

    Science.gov (United States)

    Logan, Jean; Kim, Sung Won; Pareto, Deborah; Telang, Frank; Wang, Gene-Jack; Fowler, Joanna S; Biegon, Anat

    2014-01-01

    Using positron emission tomography, we investigated the kinetics of [11C]vorozole ([11C]VOR), a radiotracer for the enzyme aromatase that catalyzes the last step in estrogen biosynthesis. Six subjects were scanned under baseline conditions followed by retest 2 weeks later. The retest was followed by a blocking study with 2.5 mg of the aromatase inhibitor letrozole. The binding potential (BP(A)ND) was estimated from a Lassen plot using the total tissue distribution volume (VT) for baseline and blocked. for the thalamus was found to be 15 times higher than that for the cerebellum. From the letrozole studies, we found that [11C]VOR exhibits a slow binding compartment (small k4) that has a nonspecific and a blockable component. Because of the sensitivity of VT to variations in k4, a common value was used for the four highest binding regions. We also considered the tissue uptake to plasma ratio for 60 to 90 minutes as an outcome measure. Using the ratio method, the difference between the highest and lowest was 2.4 compared to 3.5 for the VT. The ratio method underestimates the high regions but is less variable and may be more suitable for patient studies. Because of its kinetics and distribution, this tracer is not a candidate for a bolus infusion or reference tissue methods.

  5. Vascular endothelial growth factor A (VEGFA) modulates bovine placenta steroidogenesis in vitro.

    Science.gov (United States)

    Sousa, L M M C; Campos, D B; Fonseca, V U; Viau, P; Kfoury, J R; Oliveira, C A; Binelli, M; Buratini, J; Papa, P C

    2012-10-01

    Our objectives were to investigate the possible role of VEGFA in bovine placenta steroid synthesis and to determine whether cloned derived placental cells present similar responses as non-cloned ones. Placental cells from cloned (term) and non-cloned (days 90, 150, 210 and term) pregnancies were isolated and treated with VEGFA (50 ng/ml) for 24, 48 or 96 h. Progesterone (P(4)) and estrone sulfate (E(1)S) were assessed by RIA, while aromatase P450-positive cells were quantified using the point counting test. The percentages of steroidogenic and non-steroidogenic populations were determined by flow cytometry. VEGFA augmented or decreased P(4) and E(1)S concentrations as well as aromatase P450-positive cell density, depending on gestational age and time in culture. The percentage of steroidogenic cells was lower than that of non-steroidogenic ones for each culture time (P 0.05). VEGFA treatment altered P(4) and E(1)S levels in placental cells depending on type of gestation. These results suggest that VEGFA acts locally in the bovine placenta to modulate steroidogenesis during gestation, but in a different pattern between cloned and non-cloned derived placental cells at term. Therefore, this factor can be considered an important regulator of placental development and function.

  6. Endometriosis: alternative methods of medical treatment

    Science.gov (United States)

    Muñoz-Hernando, Leticia; Muñoz-Gonzalez, Jose L; Marqueta-Marques, Laura; Alvarez-Conejo, Carmen; Tejerizo-García, Álvaro; Lopez-Gonzalez, Gregorio; Villegas-Muñoz, Emilia; Martin-Jimenez, Angel; Jiménez-López, Jesús S

    2015-01-01

    Endometriosis is an inflammatory estrogen-dependent disease defined by the presence of endometrial glands and stroma at extrauterine sites. The main purpose of endometriosis management is alleviating pain associated to the disease. This can be achieved surgically or medically, although in most women a combination of both treatments is required. Long-term medical treatment is usually needed in most women. Unfortunately, in most cases, pain symptoms recur between 6 months and 12 months once treatment is stopped. The authors conducted a literature search for English original articles, related to new medical treatments of endometriosis in humans, including articles published in PubMed, Medline, and the Cochrane Library. Keywords included “endometriosis” matched with “medical treatment”, “new treatment”, “GnRH antagonists”, “Aromatase inhibitors”, “selective progesterone receptor modulators”, “anti-TNF α”, and “anti-angiogenic factors”. Hormonal treatments currently available are effective in the relief of pain associated to endometriosis. Among new hormonal drugs, association to aromatase inhibitors could be effective in the treatment of women who do not respond to conventional therapies. GnRH antagonists are expected to be as effective as GnRH agonists, but with easier administration (oral). There is a need to find effective treatments that do not block the ovarian function. For this purpose, antiangiogenic factors could be important components of endometriosis therapy in the future. Upcoming researches and controlled clinical trials should focus on these drugs. PMID:26089705

  7. Exemestane in early breast cancer: a review

    Directory of Open Access Journals (Sweden)

    Michael Untch

    2008-12-01

    Full Text Available Michael Untch1, Christian Jackisch21Interdisciplinary Breast Centre, Helios Klinikum Berlin-Buch, University Charité, Berlin, Germany; 2Department of Gynecology/Obstetrics, Klinikum Offenbach GmbH, Offenbach, GermanyAbstract: The adjuvant treatment of women with endocrine-sensitive early breast cancer has been dominated for the last 40 years by tamoxifen. However, the side-effects associated with this therapy have prompted a search for safer and biochemically more selective endocrine agents and led to the development of the third-generation aromatase inhibitors (AIs anastrozole, letrozole and exemestane. Promising results in advanced disease have paved the way for treating early breast cancer, and AIs are increasingly replacing tamoxifen in the adjuvant setting. Several large, randomized trials with AIs have been completed or are ongoing in women with early-stage breast cancer, documenting the significant impact that these drugs are making on the risk for recurrence of breast cancer. As a result, there is increasing and widespread use of AI therapy for the treatment of early-stage endocrine-responsive breast cancer. This review summarizes the data for exemestane in the adjuvant setting, showing that a switch to exemestane after 2 to 3 years of tamoxifen therapy is associated with a statistically significant survival benefit and is regarded as being sensitive by international and national experts.Keywords: early breast cancer, adjuvant setting, endocrine-sensitive, tamoxifen, aromatase inhibitor, exemestane, switch, IES 31, NSABP B-33, TEAM

  8. A hormonal, physical, and proteomic view of obesity-induced effects on male infertility and possible lifestyle modifications

    Institute of Scientific and Technical Information of China (English)

    Karishma Khullar; Ashok Agarwal; SS du Plessis

    2012-01-01

    The increasing incidence of obesity worldwide combined with the parallel trend of declining sperm quality has given rise to the notion that obesity and infertility are linked.While investigations of sperm quality in obese individuals have yielded inconclusive results, studies of the adverse hormonal, physical, and proteomic changes induced by obesity are more definitive.Unfavorable hormonal abnormalities reported in obese males that affect reproduction are decreased levels of testosterone, inhibinB, and ghrelin and increased levels of estrogen, leptin, and resistin.Moreover, erectile dysfunction and elevated scrotal temperatures have been associated with obesity and are important physical barriers to successful male reproduction. Recently, important advances have been made in proteomics and factors have been identified in obese individuals that may impair spermatogenesis and sperm quality.Although obesity contributes to a host of adverse effects on the reproductive system, certain lifestyle modifications can be made to alleviate such effects.Natural weight loss and surgical weight loss have demonstrated favorable results in obese patients by restoring normal hormone levels and reversing the effects of both erectile dysfunction and testicular heat stress.Pharmacological interventions have also proven to be promising in combating the effects of obesity.Particularly, aromatase inhibitors such as anastrozole, letrozole, and testolactone, have been reported to decrease the aromatase over-activity and increased estrogen levels present in obese males.An understanding of abnormalities associated with obesity and possible lifestyle modifications may help clinicians effectively guide their infertile obese male patients and increase fertility rates.

  9. Oral Drugs for Unexplained Infertility.

    Science.gov (United States)

    Allahbadia, Gautam N

    2016-02-01

    Of the infertile couples unable to conceive without any identifiable cause, 30 % are defined as having unexplained infertility. Management depends on duration of infertility and age of female partner. The treatment of unexplained infertility is empirical, and many different regimens have been used. Among these are expectant management, ovarian stimulation with clomiphene citrate, gonadotropins and aromatase inhibitors, fallopian tube sperm perfusion, tubal flushing, intrauterine insemination, gamete intrafallopian transfer, and IVF. The first approach to treatment of unexplained infertility generally is the use of drugs that stimulate oocyte production. For over four decades, the first-line treatment for ovarian stimulation in unexplained infertility has been clomiphene citrate. Multiple reports suggest that aromatase inhibitors may be effective alternative agents for ovarian stimulation in couples with unexplained infertility. Their administration is reported to be associated with monofollicular development in most cases, which may result in enhanced fertility and a reduced risk of ovarian hyperstimulation and multiple births, as compared to current standard therapies such as gonadotropin and clomiphene. Despite world evidence to the contrary, letrozole has been banned for use for infertility management in India since 2011. PMID:26924899

  10. Modulating testosterone pathway: a new strategy to tackle male skin aging?

    Directory of Open Access Journals (Sweden)

    Bernard P

    2012-09-01

    Full Text Available Philippe Bernard1, Thomas Scior2, Quoc Tuan Do11Greenpharma SAS, Orléans, France; 2Pharmacy Department, Benemerita Universidad Autonoma de Puebla, Puebla, MexicoAbstract: In men, the level of testosterone decreases with age. At the skin level, the result is observed as a decrease in density and in a lower elasticity. Identifying compounds that are able to increase the level of testosterone appears to be an attractive strategy to develop new antiaging bioactive ingredients for men. Reverse pharmacognosy was successfully applied to identify new natural compounds able to modulate testosterone levels. Among several in silico hits, honokiol was retained as a candidate as it has the greatest potential to become an active ingredient. This result was then validated in vitro on aromatase and 5-alpha-reductase type 1 and 2, which are two types of enzymes implicated in the degradation of free testosterone. Indeed, honokiol was identified as an inhibitor of aromatase, with a half-maximal inhibitory concentration (IC50 of about 50 µM. In addition, honokiol was shown to be an inhibitor of 5-alpha-reductase type 1, with an IC50 of about 75 µM. Taken together, these data indicate that honokiol modulates testosterone levels, and its structure has the potential to serve as a lead for future designs of highly selective inhibitors of 5-alpha-reductase type 1.Keywords: reverse pharmacognosy, honokiol, testosterone, man cosmetics, dermopharmacy

  11. Evidence of endocrine alteration in the red mullet, Mullus barbatus from the NW Mediterranean

    Energy Technology Data Exchange (ETDEWEB)

    Martin-Skilton, Rebeca [Department of Environmental Chemistry, IIQAB-CSIC, Jordi Girona 18, 08034 Barcelona (Spain); Lavado, Ramon [Department of Environmental Chemistry, IIQAB-CSIC, Jordi Girona 18, 08034 Barcelona (Spain); Thibaut, Remi [Department of Environmental Chemistry, IIQAB-CSIC, Jordi Girona 18, 08034 Barcelona (Spain); Minier, Christophe [Laboratoire d' Ecotoxicologie, Universite du Havre, 25 rue Philippe Lebon, B.P. 540, F-76058 Le Havre (France); Porte, Cinta [Department of Environmental Chemistry, IIQAB-CSIC, Jordi Girona 18, 08034 Barcelona (Spain)]. E-mail: cpvqam@cid.csic.es

    2006-05-15

    Red mullet (Mullus barbatus) were collected from different sampling sites (NW Mediterranean) in spring and autumn, with the aim of assessing potential alterations of the endocrine system. Alkylphenols were measured in fish bile as an indicator of estrogenic exposure. Key enzymatic activities involved in both synthesis (ovarian 17{beta}-hydroxysteroid dehydrogenases and P450 aromatase) and metabolism of steroids were assessed together with histological alterations of the gonads. During the spring sampling, delayed gamete maturation, intersexuality, fibrosis, and depressed ovarian P450 aromatase activity were observed in organisms from the most polluted sites. During the autumn sampling, those effects were less evident, indicating that fish might be more susceptible to endocrine disrupting chemicals during the reproductive period. Nonetheless, enhanced glucuronidation of testosterone and estradiol was observed. Overall, this work provides first evidences of significant alterations in the endocrine system of red mullet from highly impacted areas in the NW Mediterranean. - Red mullet may be more susceptible to endocrine disruptors during the reproductive period.

  12. Ductal Carcinoma In Situ of the Breast: A Surgical Perspective

    Directory of Open Access Journals (Sweden)

    Mohammed Badruddoja

    2012-01-01

    Full Text Available Ductal carcinoma in situ (DCIS of the breast is a heterogeneous neoplasm with invasive potential. Risk factors include age, family history, hormone replacement therapy, genetic mutation, and patient lifestyle. The incidence of DCIS has increased due to more widespread use of screening and diagnostic mammography; almost 80% of cases are diagnosed with imaging with final diagnosis established by biopsy and histological examination. There are various classification systems used for DCIS, the most recent of which is based on the presence of intraepithelial neoplasia of the ductal epithelium (DIN. A number of molecular assays are now available that can identify high-risk patients as well as help establish the prognosis of patients with diagnosed DCIS. Current surgical treatment options include total mastectomy, simple lumpectomy in very low-risk patients, and lumpectomy with radiation. Adjuvant therapy is tailored based on the molecular profile of the neoplasm and can include aromatase inhibitors, anti-estrogen, anti-progesterone (or a combination of antiestrogen and antiprogesterone, and HER2 neu suppression therapy. Chemopreventive therapies are under investigation for DCIS, as are various molecular-targeted drugs. It is anticipated that new biologic agents, when combined with hormonal agents such as SERMs and aromatase inhibitors, may one day prevent all forms of breast cancer.

  13. The effect of anastrozole on mRNA expression of oestrogen related gene in MCF-7 breast cancer cells

    Institute of Scientific and Technical Information of China (English)

    SONG Zhang-jun; WU Yi; MA Qing-yong

    2006-01-01

    Objective: To look for additional markers of molecular biology response to anastrozole, a new aromatase inhibitor, on the growth and mRNA expression level of MCF-7 cell. Methods: We investigated the effect of anastrzole on growth and gene expression in the human breast cancer cell line MCF-7and compared with the most widely used antiestrogen tamoxifen. We chose 4 genes to examine regulation of gene expression of estrogen regulated genes: PR A, PR B, ErbB-2 and cyclin D1. Results: Compared with the tamoxifen, a statistically significant growth inhibition was observed with anastrozole. The PRA,PR B and cyclin D1 mRNA level in anastrozole treated cells was sigificantly below the level in tamoxifen treated cells (P<0. 05). They had agonistic effect on ErbB gene (P>0.05). Conclusion: The third generation of aromatase inhibitors anastrozole exert more inhibit function in some expression of estrogen regulated genes than tomoxifen in MCF-7 cell line.

  14. The Interactions of Obesity, Inflammation and Insulin Resistance in Breast Cancer

    Directory of Open Access Journals (Sweden)

    David P. Rose

    2015-10-01

    Full Text Available Obese postmenopausal women have an increased breast cancer risk, the principal mechanism for which is elevated estrogen production by adipose tissue; also, regardless of menstrual status and tumor estrogen dependence, obesity is associated with biologically aggressive breast cancers. Type 2 diabetes has a complex relationship with breast cancer risk and outcome; coexisting obesity may be a major factor, but insulin itself induces adipose aromatase activity and estrogen production and also directly stimulates breast cancer cell growth and invasion. Adipose tissue inflammation occurs frequently in obesity and type 2 diabetes, and proinflammatory cytokines and prostaglandin E2 produced by cyclooxygenase-2 in the associated infiltrating macrophages also induce elevated aromatase expression. In animal models, the same proinflammatory mediators, and the chemokine monocyte chemoattractant protein-1, also stimulate tumor cell proliferation and invasion directly and promote tumor-related angiogenesis. We postulate that chronic adipose tissue inflammation, rather than body mass index-defined obesity per se, is associated with an increased risk of type 2 diabetes and postmenopausal estrogen-dependent breast cancer. Also, notably before the menopause, obesity and type 2 diabetes, or perhaps the associated inflammation, promote estrogen-independent, notably triple-negative, breast cancer development, invasion and metastasis by mechanisms that may involve macrophage-secreted cytokines, adipokines and insulin.

  15. Evidence of endocrine alteration in the red mullet, Mullus barbatus from the NW Mediterranean

    International Nuclear Information System (INIS)

    Red mullet (Mullus barbatus) were collected from different sampling sites (NW Mediterranean) in spring and autumn, with the aim of assessing potential alterations of the endocrine system. Alkylphenols were measured in fish bile as an indicator of estrogenic exposure. Key enzymatic activities involved in both synthesis (ovarian 17β-hydroxysteroid dehydrogenases and P450 aromatase) and metabolism of steroids were assessed together with histological alterations of the gonads. During the spring sampling, delayed gamete maturation, intersexuality, fibrosis, and depressed ovarian P450 aromatase activity were observed in organisms from the most polluted sites. During the autumn sampling, those effects were less evident, indicating that fish might be more susceptible to endocrine disrupting chemicals during the reproductive period. Nonetheless, enhanced glucuronidation of testosterone and estradiol was observed. Overall, this work provides first evidences of significant alterations in the endocrine system of red mullet from highly impacted areas in the NW Mediterranean. - Red mullet may be more susceptible to endocrine disruptors during the reproductive period

  16. Assessment of the environmental quality of coastal sediments by using a combination of in vitro bioassays.

    Science.gov (United States)

    Pérez-Albaladejo, Elisabet; Rizzi, Juliane; Fernandes, Denise; Lille-Langøy, Roger; Karlsen, Odd André; Goksøyr, Anders; Oros, Andra; Spagnoli, Federico; Porte, Cinta

    2016-07-15

    The environmental quality of marine sediments collected in the area of influence of the Po and Danube Rivers was assessed by using a battery of bioassays based on the use of PLHC-1 cells, zebrafish-Pxr-transfected COS-7 cells, and sea bass ovarian subcellular fractions. This allowed the determination of multiple endpoints, namely, cytotoxicity, oxidative stress, induction of CYP1A, activation of zebrafish Pxr and inhibition of ovarian aromatase. Organic extracts of sediments influenced by the Danube River and collected near harbors and urban discharges showed significant cytotoxicity, CYP1A induction and inhibition of aromatase activity. An analogous response of CYP1A induction and zfPxr activation was observed, which suggests the existence of common ligands of AhR and PXR in the sediment extracts. The study highlights the usefulness of the selected bioassays to identify those sediments that could pose a risk to aquatic organisms and that require further action in order to improve their environmental quality. PMID:27207027

  17. Application of endocrine disruptor screening program fish short-term reproduction assay: Reproduction and endocrine function in fathead minnow (Pimephales promelas) and killifish (Fundulus heteroclitus) exposed to Bermuda pond sediment.

    Science.gov (United States)

    Fort, Douglas J; Mathis, Michael; Fort, Chelsea E; Fort, Hayley M; Bacon, Jamie P

    2015-06-01

    A modified tier 1 Endocrine Disruptor Screening Program (EDSP) 21-d fish short-term reproduction assay (FSTRA) was used to evaluate the effects of sediment exposure from freshwater and brackish ponds in Bermuda on reproductive fecundity and endocrine function in fathead minnow (Pimephales promelas) and killifish (Fundulus heteroclitus). Reproductively active male and female fish were exposed to control sediment and sediment from 2 freshwater ponds (fathead minnow) and 2 marine ponds (killifish) contaminated with polyaromatic hydrocarbons and metals via flow-through exposure for 21 d. Reproductive fecundity was monitored daily. At termination, the status of the reproductive endocrine system was assessed by the gonadosomatic index, gonadal histology, plasma steroids (estrogen [E2], testosterone [T], and 11-ketotestosterone [11-KT]), steroidogenic enzymes (aromatase and combined 3β/17β -hydroxysteroid dehydrogenase [3β/17β-HSD]), and plasma vitellogenin (VTG). Decreased reproductive fecundity, lower male body weight, and altered endocrinological measures of reproductive status were observed in both species. Higher plasma T levels in female minnows and 11-KT levels in both male and female minnows and female killifish exposed to freshwater and brackish sediments, respectively. Decreased female E2 and VTG levels and gonadal cytochrome P19 (aromatase) activity were also found in sediment exposed females from both species. No effect on female 3β/17β-HSD activity was found in either species. The FSTRA provided a robust model capable of modification to evaluate reproductive effects of sediment exposure in fish. PMID:25565366

  18. Association between CYP19A1 genotype and pubertal sagittal jaw growth

    Science.gov (United States)

    He, Shushu; Hartsfield, James K.; Guo, Yujiao; Cao, Yang; Wang, Si; Chen, Song

    2016-01-01

    Introduction Sagittal jaw growth is influenced during puberty by a ratio of androgens and estrogens. The CYP19A1 (formerly CYP19) gene encodes the cytochrome P450 enzyme aromatase (estrogen synthetase), which converts testosterone to estrogen. Genetic variations including single nucleotide polymorphisms might regulate CYP19A1 gene expression or the function of the aromatase protein and thus influence sagittal jaw growth. Methods The annual sagittal jaw growth in 92 pubertal orthodontic patients was determined by using pretreatment and posttreatment cephalometric radiographs. Single nucleotide polymorphisms rs2470144 and rs2445761 were genotyped and haplotypes constructed. Associations between genotypes or haplotypes and the annual sagittal growth were estimated by using JMP (version 9.0; SAS Institute, Cary, NC). Results Two single nucleotide polymorphisms were significantly associated with average differences in annual sagittal jaw growth in boys. Haplotype analysis demonstrated that haplotypes Trs2470144Trs2445761 and Crs2470144Trs2445761 had significant effects on annual sagittal maxillary growth and on mandibular growth in boys. No association was found in girls. Conclusions A quantitative trait locus that influences male pubertal sagittal jaw growth might exist in the CYP19A1 gene, and single nucleotide polymorphisms rs2470144 and rs2445761 might be inside this quantitative trait locus or be linked to it. PMID:23116507

  19. Analysis on mechanism of outcome of residual uterine fibroid tissue after high intensity focused ultrasound ablation%探讨高强度聚焦超声消融后残余子宫肌瘤组织转归的机制

    Institute of Scientific and Technical Information of China (English)

    秦娟; 陈锦云; 王琦; 彭松; 胡亮; 刘政; 王智彪

    2012-01-01

    Objective To analyze the mechanism of outcome of residual uterine fibroid tissue after high intensity focused ultrasound (HIFU) ablation by detecting the expression of estrogen receptor (ER) and progesterone receptor (PR) as well as P450 aromatase on different sites of uterine fibroid tissue outside the ablated areas. Methods MR-guided HIFU ablation was performed on 8 uterine fibroid samples under the acoustic power of 400 W for 60 s. During ablation, temperature elevation was monitored by MR system. The experimental fibroid tissue was taken at 0. 5 (A) , 1. 0 (B) , 1. 5 cm (C) outside necrotic tissue after ablation respectively, and the controls were selected from the uterine fibroids before ablation. Immuno-histochemistry was applied to detect the expression of ER, PR and P450 aromatase, and Western-blot was applied for semi-quantitative detection of P450 aromatase protein. Results Different degrees of temperature elevation outside ablated area were shown on temperature maps. The expression of ER and PR at point A, B and C were similar to the control group. The level of P450 aromatase protein at point A, B was significantly lower than that of control group (P<0. 05) proved by immunohistochemical detection and Western-blot. Conclusion The mechanism on inhibition of residual uterine fibroids within certain range after ultrasound ablation may be related to the expression of P450 aromatase protein affected by temperature.%目的 分析超声消融对靶区外不同位点子宫肌瘤组织雌、孕激素受体以及芳香化酶的表达情况,探讨残余子宫肌瘤的转归的可能机制.方法 采用MR引导下高强度聚焦超声(HIFU)肿瘤治疗系统消融8个子宫肌瘤,声功率400 W,辐照时间60 s,以MR检测靶区外子宫肌瘤组织的升温情况.治疗前取1 cm×1 cm子宫肌瘤组织为对照组.辐照完毕后取靶区外0.5 cm、1.0 cm、1.5 cm处子宫肌瘤组织.以免疫组化法检测超声消融靶区边缘雌、孕

  20. 稀有鮈鲫脑芳香化酶cDNA片段的克隆与表达分析%CLONING AND EXPRESSIONAL ANALYSIS OF Cyp19b GENE FRAGMENT IN GOBIOCYPRIS RARUS

    Institute of Scientific and Technical Information of China (English)

    曹梦西; 杨玉慧; 江文波; 王玉凤; 胡炜; 赵浩斌

    2009-01-01

    P450 aromatase (P450arom), an enzyme catalyzing the synthesis of estrogens, is thought to play a key role in sex differentiation of neural and reproductive development in vertebrates. Most of the mammals have only one aromatase, but many teleost fish, including the zebrafish (Danio rerio) and medaka (Oryzias latipes) have two isoforms of aromatase encoded by two distinct genes, Cyp19a expressed predominantly in the ovary and Cyp19b in the brain. Gobiocypris rarus is an emerging model fish in China because of its small size, transparent embryonic biology, spawning round the year, easy breeding, short generation and sensitivity in toxicology. However, the mechanisms of sex determination and differentiation are still unclear in this fish. Aromatase as the important factor in the differentiation of sex is also unavailable, so that the exact roles of aromatase gene in neural or ovarian development in this fish are unclear. To understand the mechanisms of sex differentiation and the role of aromatase in this process, we cloned the partial sequences of Cyp19b cDNA of Gobiocypris rarus by reverse transcription-polymerase chain reaction with degenerate primers dependant on the conservative sequences of the gene in other vertebrates, and we also examined its expression pattern in the tissues of adult fish and the developmental process of embryos in this fish by gene specific primers. The partial sequence of Cyp19b of Gobiocypris rarus we cloned consisted of 1070 base pairs which encoded 357 amino acids. Structural analysis of the deduced amino acid sequence indicated that it contained three specific domains of aromatases, substrate-binding loop, distal helix I and the steroid-binding domain. Multiple alignment and phylogenetic analysis showed that this protein of Gobiocypris rarus shared 57%- 93% identities with P450arom proteins of other species and it was most similar to P450aromBs of Danio rerio, Carassius auratus and Cyprinus carpio in 91%, 92% and 93%, respectively

  1. 稀有鮈鲫脑芳香化酶cDNA片段的克隆与表达分析%CLONING AND EXPRESSIONAL ANALYSIS OF Cyp19b GENE FRAGMENT IN GOBIOCYPRIS RARUS

    Institute of Scientific and Technical Information of China (English)

    曹梦西; 杨玉慧; 江文波; 王玉凤; 胡炜; 赵浩斌

    2009-01-01

    P450 aromatase (P450arom), an enzyme catalyzing the synthesis of estrogens, is thought to play a key role in sex differentiation of neural and reproductive development in vertebrates. Most of the mammals have only one aromatase, but many teleost fish, including the zebrafish (Danio rerio) and medaka (Oryzias latipes) have two isoforms of aromatase encoded by two distinct genes, Cyp19a expressed predominantly in the ovary and Cyp19b in the brain. Gobiocypris rarus is an emerging model fish in China because of its small size, transparent embryonic biology, spawning round the year, easy breeding, short generation and sensitivity in toxicology. However, the mechanisms of sex determination and differentiation are still unclear in this fish. Aromatase as the important factor in the differentiation of sex is also unavailable, so that the exact roles of aromatase gene in neural or ovarian development in this fish are unclear. To understand the mechanisms of sex differentiation and the role of aromatase in this process, we cloned the partial sequences of Cyp19b cDNA of Gobiocypris rarus by reverse transcription-polymerase chain reaction with degenerate primers dependant on the conservative sequences of the gene in other vertebrates, and we also examined its expression pattern in the tissues of adult fish and the developmental process of embryos in this fish by gene specific primers. The partial sequence of Cyp19b of Gobiocypris rarus we cloned consisted of 1070 base pairs which encoded 357 amino acids. Structural analysis of the deduced amino acid sequence indicated that it contained three specific domains of aromatases, substrate-binding loop, distal helix I and the steroid-binding domain. Multiple alignment and phylogenetic analysis showed that this protein of Gobiocypris rarus shared 57%- 93% identities with P450arom proteins of other species and it was most similar to P450aromBs of Danio rerio, Carassius auratus and Cyprinus carpio in 91%, 92% and 93%, respectively

  2. Endometriosis: alternative methods of medical treatment

    Directory of Open Access Journals (Sweden)

    Muñoz-Hernando L

    2015-06-01

    Full Text Available Leticia Muñoz-Hernando,1 Jose L Muñoz-Gonzalez,1 Laura Marqueta-Marques,1 Carmen Alvarez-Conejo,1 Álvaro Tejerizo-García,1 Gregorio Lopez-Gonzalez,1 Emilia Villegas-Muñoz,2 Angel Martin-Jimenez,3 Jesús S Jiménez-López1 1Endometriosis Unit, Service of Obstetrics and Gynecology, Hospital Universitario 12 de Octubre, Madrid, Spain; 2Endometriosis Unit, Service of Obstetrics and Gynecology, Hospital Carlos Haya, Malaga, Spain; 3Endometriosis Unit, Service of Obstetrics and Gynecology, Hospital Son Llatzer, Palma de Mallorca, Spain Abstract: Endometriosis is an inflammatory estrogen-dependent disease defined by the presence of endometrial glands and stroma at extrauterine sites. The main purpose of endometriosis management is alleviating pain associated to the disease. This can be achieved surgically or medically, although in most women a combination of both treatments is required. Long-term medical treatment is usually needed in most women. Unfortunately, in most cases, pain symptoms recur between 6 months and 12 months once treatment is stopped. The authors conducted a literature search for English original articles, related to new medical treatments of endometriosis in humans, including articles published in PubMed, Medline, and the Cochrane Library. Keywords included “endometriosis” matched with “medical treatment”, “new treatment”, “GnRH antagonists”, “Aromatase inhibitors”, “selective progesterone receptor modulators”, “anti-TNF α”, and “antiangiogenic factors”. Hormonal treatments currently available are effective in the relief of pain associated to endometriosis. Among new hormonal drugs, association to aromatase inhibitors could be effective in the treatment of women who do not respond to conventional therapies. GnRh antagonists are expected to be as effective as GnRH agonists, but with easier administration (oral. There is a need to find effective treatments that do not block the ovarian function

  3. 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

  4. Testosterone regulation of sex steroid-related mRNAs and dopamine-related mRNAs in adolescent male rat substantia nigra

    Directory of Open Access Journals (Sweden)

    Purves-Tyson Tertia D

    2012-08-01

    Full Text Available Abstract Background Increased risk of schizophrenia in adolescent males indicates that a link between the development of dopamine-related psychopathology and testosterone-driven brain changes may exist. However, contradictions as to whether testosterone increases or decreases dopamine neurotransmission are found and most studies address this in adult animals. Testosterone-dependent actions in neurons are direct via activation of androgen receptors (AR or indirect by conversion to 17β-estradiol and activation of estrogen receptors (ER. How midbrain dopamine neurons respond to sex steroids depends on the presence of sex steroid receptor(s and the level of steroid conversion enzymes (aromatase and 5α-reductase. We investigated whether gonadectomy and sex steroid replacement could influence dopamine levels by changing tyrosine hydroxylase (TH protein and mRNA and/or dopamine breakdown enzyme mRNA levels [catechol-O-methyl transferase (COMT and monoamine oxygenase (MAO A and B] in the adolescent male rat substantia nigra. We hypothesized that adolescent testosterone would regulate sex steroid signaling through regulation of ER and AR mRNAs and through modulation of aromatase and 5α-reductase mRNA levels. Results We find ERα and AR in midbrain dopamine neurons in adolescent male rats, indicating that dopamine neurons are poised to respond to circulating sex steroids. We report that androgens (T and DHT increase TH protein and increase COMT, MAOA and MAOB mRNAs in the adolescent male rat substantia nigra. We report that all three sex steroids increase AR mRNA. Differential action on ER pathways, with ERα mRNA down-regulation and ERβ mRNA up-regulation by testosterone was found. 5α reductase-1 mRNA was increased by AR activation, and aromatase mRNA was decreased by gonadectomy. Conclusions We conclude that increased testosterone at adolescence can shift the balance of sex steroid signaling to favor androgenic responses through promoting

  5. Web Resources for Pharmacogenomics

    Directory of Open Access Journals (Sweden)

    Guoqing Zhang

    2015-02-01

    Full Text Available Pharmacogenomics is the study of the impact of genetic variations or genotypes of individuals on their drug response or drug metabolism. Compared to traditional genomics research, pharmacogenomic research is more closely related to clinical practice. Pharmacogenomic discoveries may effectively assist clinicians and healthcare providers in determining the right drugs and proper dose for each patient, which can help avoid side effects or adverse reactions, and improve the drug therapy. Currently, pharmacogenomic approaches have proven their utility when it comes to the use of cardiovascular drugs, antineoplastic drugs, aromatase inhibitors, and agents used for infectious diseases. The rapid innovation in sequencing technology and genome-wide association studies has led to the development of numerous data resources and dramatically changed the landscape of pharmacogenomic research. Here we describe some of these web resources along with their names, web links, main contents, and our ratings.

  6. A Review on Effect of Estrogen on Neural Growth and Sexual Dimorphism in the Brain

    Directory of Open Access Journals (Sweden)

    Robel Abay

    2015-10-01

    Full Text Available In addition to the usual classic views of estrogen’s actions in the brain as regulator of ovulation and reproductive behavior in the female; estrogens also play important roles in the male brain as well, where they can be generated from circulating testosterone by local aromatase enzymes or can also be synthesized de novo by neurons and glia and have profound effects on volumetric differences in different brain regions, promotion and inhibition of neurite growth, regulation of synaptic patterning, organizational and activational process of brain sex differentiation. Estrogen has opposite as well as similar effects in male and female brains. These differences include sex dimorphisms in the ability of estrogen to influence synaptic plasticity, neurotransmission, neurodegeneration, and cognition. A large part of sex differences is due to the organization of the underlying circuitry.

  7. Alternative Strategies for the Treatment of Classical Congenital Adrenal Hyperplasia: Pitfalls and Promises

    Directory of Open Access Journals (Sweden)

    Ali S. Calikoglu

    2010-01-01

    Full Text Available Despite decades of different treatment algorithms, the management of congenital adrenal hyperplasia (CAH remains clinically challenging. This is due to the inherent difficulty of suppressing adrenal androgen production using near physiological dosing of glucocorticoids (GC. As a result, alternating cycles of androgen versus GC excess can occur and may lead to short stature, obesity, virilization, and alterations in puberty. Novel therapeutic alternatives, including new and more physiological means of GC delivery, inhibitors at the level of CRH or ACTH secretion and/or action, as well as “rescue strategies”, such as GnRH analogs, anti-androgens, aromatase inhibitors, and estrogen receptor blockers, are available; many of these agents, however, still require active investigation in CAH. Bilateral adrenalectomy is effective but it is also still an experimental approach. Gene therapy and stem cells, to provide functional adrenal cortical tissue, are at preclinical stage but provide exciting avenues for a potential cure for CAH.

  8. Alternative Strategies for the Treatment of Classical Congenital Adrenal Hyperplasia: Pitfalls and Promises

    Directory of Open Access Journals (Sweden)

    Calikoglu AliS

    2010-06-01

    Full Text Available Despite decades of different treatment algorithms, the management of congenital adrenal hyperplasia (CAH remains clinically challenging. This is due to the inherent difficulty of suppressing adrenal androgen production using near physiological dosing of glucocorticoids (GC. As a result, alternating cycles of androgen versus GC excess can occur and may lead to short stature, obesity, virilization, and alterations in puberty. Novel therapeutic alternatives, including new and more physiological means of GC delivery, inhibitors at the level of CRH or ACTH secretion and/or action, as well as "rescue strategies", such as GnRH analogs, anti-androgens, aromatase inhibitors, and estrogen receptor blockers, are available; many of these agents, however, still require active investigation in CAH. Bilateral adrenalectomy is effective but it is also still an experimental approach. Gene therapy and stem cells, to provide functional adrenal cortical tissue, are at preclinical stage but provide exciting avenues for a potential cure for CAH.

  9. Web resources for pharmacogenomics.

    Science.gov (United States)

    Zhang, Guoqing; Zhang, Yunsheng; Ling, Yunchao; Jia, Jia

    2015-02-01

    Pharmacogenomics is the study of the impact of genetic variations or genotypes of individuals on their drug response or drug metabolism. Compared to traditional genomics research, pharmacogenomic research is more closely related to clinical practice. Pharmacogenomic discoveries may effectively assist clinicians and healthcare providers in determining the right drugs and proper dose for each patient, which can help avoid side effects or adverse reactions, and improve the drug therapy. Currently, pharmacogenomic approaches have proven their utility when it comes to the use of cardiovascular drugs, antineoplastic drugs, aromatase inhibitors, and agents used for infectious diseases. The rapid innovation in sequencing technology and genome-wide association studies has led to the development of numerous data resources and dramatically changed the landscape of pharmacogenomic research. Here we describe some of these web resources along with their names, web links, main contents, and our ratings.

  10. On the effects of testosterone on brain behavioral functions

    Directory of Open Access Journals (Sweden)

    Peter eCelec

    2015-02-01

    Full Text Available Testosterone influences the brain via organizational and activational effects. Numerous relevant studies on rodents and a few on humans focusing on specific behavioral and cognitive parameters have been published. The results are, unfortunately, controversial and puzzling. Dosing, timing, even the application route seem to considerably affect the outcomes. In addition, the methods used for the assessment of psychometric parameters are a bit less than ideal regarding their validity and reproducibility. Metabolism of testosterone contributes to the complexity of its actions. Reduction to dihydrotestosterone by 5-alpha reductase increases the androgen activity; conversion to estradiol by aromatase converts the androgen to estrogen activity. Recently, the non-genomic effects of testosterone on behavior bypassing the nuclear receptors have attracted the interest of researchers. This review tries to summarize the current understanding of the complexity of the effects of testosterone on brain with special focus on their role in the known sex differences.

  11. An approach to constitutional delay of growth and puberty

    Directory of Open Access Journals (Sweden)

    Ashraf T Soliman

    2012-01-01

    Full Text Available Constitutional delay of growth and puberty is a transient state of hypogonadotropic hypogonadism associated with prolongation of childhood phase of growth, delayed skeletal maturation, delayed and attenuated pubertal growth spurt, and relatively low insulin-like growth factor-1 secretion. In a considerable number of cases, the final adult height (Ht does not reach the mid-parental or the predicted adult Ht for the individual, with some degree of disproportionately short trunk. In the pre-pubertal male, testosterone (T replacement therapy can be used to induce pubertal development, accelerate growth and relieve the psychosocial complaints of the adolescents. However, some issues in the management are still unresolved. These include type, optimal timing, dose and duration of sex steroid treatment and the possible use of adjunctive or alternate therapy including: oxandrolone, aromatase inhibitors and human growth hormone.

  12. Effects of BMAL1-SIRT1-positive cycle on estrogen synthesis in human ovarian granulosa cells: an implicative role of BMAL1 in PCOS.

    Science.gov (United States)

    Zhang, Jiaou; Liu, Jiansheng; Zhu, Kai; Hong, Yan; Sun, Yun; Zhao, Xiaoming; Du, Yanzhi; Chen, Zi-Jiang

    2016-08-01

    Brain and muscle ARNT-like protein 1 (BMAL1) is necessary for fertility and has been found to be essential to follicle growth and steroidogenesis. Sirtuin1 (SIRT1) has been reported to interact with BMAL1 and function in a circadian manner. Evidence has shown that SIRT1 regulates aromatase expression in estrogen-producing cells. We aimed to ascertain if there is a relationship between polycystic ovary syndrome (PCOS) and BMAL1, and whether and how BMAL1 takes part in estrogen synthesis in human granulosa cells (hGCs). Twenty-four women diagnosed with PCOS and 24 healthy individuals undergoing assisted reproduction were studied. BMAL1 expression in their granulosa cells (GCs) was observed by quantitative real-time polymerase chain reaction (qRT-PCR). The level of expression in the PCOS group was lower than that of the group without PCOS (p PCOS. PMID:27117143

  13. The Role of Estrogen Modulators in Male Hypogonadism and Infertility.

    Science.gov (United States)

    Rambhatla, Amarnath; Mills, Jesse N; Rajfer, Jacob

    2016-01-01

    Estradiol, normally considered a female hormone, appears to play a significant role in men in a variety of physiologic functions, such as bone metabolism, cardiovascular health, and testicular function. As such, estradiol has been targeted by male reproductive and sexual medicine specialists to help treat conditions such as infertility and hypogonadism. The compounds that modulate estradiol levels in these clinical conditions are referred to as selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs). In a certain subset of infertile men, particularly those with hypogonadism, or those who have a low serum testosterone to estradiol ratio, there is some evidence suggesting that SERMs and AIs can reverse the low serum testosterone levels or the testosterone to estradiol imbalance and occasionally improve any associated infertile or subfertile state. This review focuses on the role these SERMs and AIs play in the aforementioned reproductive conditions. PMID:27601965

  14. Letrozole Induced Hypercalcemia in a Patient with Breast Cancer

    Directory of Open Access Journals (Sweden)

    Suleyman Hilmi Ipekci

    2014-01-01

    Full Text Available Hypersecretion of PTHrP is a relatively common cause of malignancy-related hypercalcemia. However, there is only one case report of letrozole induced hypercalcemia. A 52-year-old female patient was referred to our clinic because of the recent discovery of hypercalcemia (11.0 mg/dL. The patient had a history of left breast carcinoma. She had started a course of letrozole (aromatase inhibitor; 2.5 mg dose/day ten months earlier. Patient’s parathyroid hormone-related protein levels were normal and a bone scintigram revealed no evidence of skeletal metastasis. Other potential causes of high calcium levels were ruled out. We recognized that, when letrozole was taken at one dose daily (2.5 mg, she had recurrent hypercalcemia. Our experience suggests that letrozole may precipitate hypercalcemia in a patient with breast cancer.

  15. Genetic Polymorphisms Related to Testosterone Metabolism in Intellectually Gifted Boys

    Science.gov (United States)

    Celec, Peter; Tretinárová, Denisa; Minárik, Gabriel; Ficek, Andrej; Szemes, Tomáš; Lakatošová, Silvia; Schmidtová, Eva; Turňa, Ján; Kádaši, Ľudevít; Ostatníková, Daniela

    2013-01-01

    Prepubertal testosterone levels are lower in intellectually gifted boys. The aim of this pilot study was to analyze potential genetic factors related to testosterone metabolism in control and gifted boys. Intellectually gifted (IQ>130; n = 95) and control (n = 67) boys were genotyped. Polymorphisms of interests were chosen in genes including androgen and estrogen receptors, 5-alpha reductase, aromatase and sex hormone binding globulin. Significant differences between control and gifted boys in genotype distributions were found for ESR2 (rs928554) and SHBG (rs1799941). A significantly lower number of CAG repeats in the AR gene were found in gifted boys. Our results support the role of genetic factors related to testosterone metabolism in intellectual giftedness. Increased androgen signaling might explain previous results of lower testosterone levels in intellectually gifted boys and add to the understanding of variability in cognitive abilities. PMID:23382957

  16. Genetic polymorphisms related to testosterone metabolism in intellectually gifted boys.

    Science.gov (United States)

    Celec, Peter; Tretinárová, Denisa; Minárik, Gabriel; Ficek, Andrej; Szemes, Tomáš; Lakatošová, Silvia; Schmidtová, Eva; Turňa, Ján; Kádaši, Ľudevít; Ostatníková, Daniela

    2013-01-01

    Prepubertal testosterone levels are lower in intellectually gifted boys. The aim of this pilot study was to analyze potential genetic factors related to testosterone metabolism in control and gifted boys. Intellectually gifted (IQ>130; n = 95) and control (n = 67) boys were genotyped. Polymorphisms of interests were chosen in genes including androgen and estrogen receptors, 5-alpha reductase, aromatase and sex hormone binding globulin. Significant differences between control and gifted boys in genotype distributions were found for ESR2 (rs928554) and SHBG (rs1799941). A significantly lower number of CAG repeats in the AR gene were found in gifted boys. Our results support the role of genetic factors related to testosterone metabolism in intellectual giftedness. Increased androgen signaling might explain previous results of lower testosterone levels in intellectually gifted boys and add to the understanding of variability in cognitive abilities.

  17. Systemic therapy for endometrial stromal sarcomas: current treatment options.

    Science.gov (United States)

    Serkies, Krystyna; Pawłowska, Ewa; Jassem, Jacek

    2016-01-01

    Uterine endometrial stromal sarcomas including true low-grade endometrial stromal sarcoma (LG-ESS) and high-grade (HG-ESS) or undifferentiated endometrial sarcoma (UES) constitute a group of rare, aggressive malignancies. Most LG-ESSs express steroid receptors. Surgery is the principal primary therapy for endometrial stromal sarcomas and should be considered in all cases. These malignancies are relatively radio- and chemoresistant. Chemotherapy is used in recurrent and advanced HG-ESS and UES. Currently, the combination of gemcitabine and docetaxel is considered the most effective regimen, but at the expense of substantial toxicity. In steroid receptor positive advanced LG-ESS hormonal therapy, mainly with progestins, allows in some patients for a long-term survival. Aromatase inhibitors seem to be equally effective as first- and subsequent-line of treatment, and are well tolerated. The role of molecular-targeted therapies in endometrial stromal sarcomas remains to be established. PMID:27629136

  18. Future directions in cancer prevention.

    Science.gov (United States)

    Umar, Asad; Dunn, Barbara K; Greenwald, Peter

    2012-12-01

    Prevention of cancer remains the most promising strategy for reducing both its incidence and the mortality due to this disease. For more than four decades, findings from epidemiology, basic research and clinical trials have informed the development of lifestyle and medical approaches to cancer prevention. These include selective oestrogen receptor modulators and aromatase inhibitors for breast cancer, the 5-α-reductase inhibitors finasteride and dutasteride for prostate cancer, and the development of vaccines for viruses that are associated with specific cancers. Future directions include genetic, proteomic and other molecular approaches for identifying pathways that are associated with cancer initiation and development, as well as refining the search for immunologically modifiable causes of cancer. PMID:23151603

  19. 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

    2012-06-01

    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

  20. Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer

    DEFF Research Database (Denmark)

    Mouridsen, H.; Giobbie-Hurder, A.; Goldhirsch, A.;

    2009-01-01

    BACKGROUND: The aromatase inhibitor letrozole, as compared with tamoxifen, improves disease-free survival among postmenopausal women with receptor-positive early breast cancer. It is unknown whether sequential treatment with tamoxifen and letrozole is superior to letrozole therapy alone. METHODS......: In this randomized, phase 3, double-blind trial of the treatment of hormone-receptor-positive breast cancer in postmenopausal women, we randomly assigned women to receive 5 years of tamoxifen monotherapy, 5 years of letrozole monotherapy, or 2 years of treatment with one agent followed by 3 years of treatment...... with the other. We compared the sequential treatments with letrozole monotherapy among 6182 women and also report a protocol-specified updated analysis of letrozole versus tamoxifen monotherapy in 4922 women. RESULTS: At a median follow-up of 71 months after randomization, disease-free survival...

  1. Sushi Domain-Containing Protein 3: A Potential Target for Breast Cancer.

    Science.gov (United States)

    Yu, Zhenghong; Jiang, Enze; Wang, Xinxing; Shi, Yaqin; Shangguan, Anna Junjie; Zhang, Luo; Li, Jie

    2015-06-01

    Aromatase inhibitors (AIs) are the most effective endocrine treatment for estrogen receptor α-positive (ERα+) postmenopausal breast cancer. Identification of biomarkers that are able to predict AIs responsiveness of patients is a key for successful treatment. The currently used biomarkers for tamoxifen responsiveness, which including ERα as well as progesterone receptor can only predict part of the potential responders to AIs treatment. Sushi domain-containing protein 3 (SUSD3) is a potential novel biomarker of AIs responsiveness. The lack of SUSD3 expression in breast cancer tissue can be an important predictor for non-responsiveness to AI. Here we reviewed the property and function of SUSD3, its usage as a biomarker and the practicability for SUSD3 to become a target for immune therapy. We suggest this protein can be potentially measured or targeted for prevention, diagnostic, and therapeutic purposes for estrogen or progesterone-dependent disorders including breast cancer in women. PMID:25556073

  2. The role of vitamin D in breast cancer

    Directory of Open Access Journals (Sweden)

    Tu Tu Aung

    2011-12-01

    Full Text Available The biological role of vitamin D outside of calcium homeostasis is still under evaluation. The ability of vitamin D to inhibit cell proliferation and induce differentiation makes it a potential modifier of neoplastic transformation. Vitamin D affects the cell cycle, apoptosis, hormone receptors, angiogenesis, and hypoxia, all of which are related to the breast cancer growth, progression and metastasis. A large percentage of the industrial-world population is deficient in vitamin D. Epidemiological evidence suggests that vitamin D deficiency increases the risk of breast cancer. Vitamin D may have synergistic, additive, or antagonistic effects when combined with other therapeutic agents against breast cancer. Vitamin D appears to depress aromatase inhibitor by acting through cytochrome P 450. This evidence along with pre-clinical and clinical studies, justify the inclusion of vitamin D in future clinical trials related to breast cancer in order to determine its efficacy as a part of the breast cancer therapeutic armament.

  3. Tamoxifen-associated vasculitis in a breast cancer patient

    Directory of Open Access Journals (Sweden)

    Vargas-Viveros Pablo

    2007-01-01

    Full Text Available Abstract Background Estrogen plays a critical role in breast cancer. Thereafter, endocrine therapy is a standard of care in patients with breast carcinoma, expressing ER or PR. Case presentation Herein we report the case of a 53-year old patient, who developed cholestasis and vasculitis during the treatment with tamoxifen. This toxicity was reversable after the removal of the drug. Thereafter she continued adjuvant treatment for breast carcinoma with anastrazole. Since tamoxifen has been widely indicated for patients with breast carcinoma, we did a literature review, looking for other cases with this type of toxicity. Conclusion This case is the third with vasculitis informed in the literature, but the first one that additionally developed cholestasis and arthritis. Although it is rare, we discuss the indication of this drug in the actual era, where aromatase inhibitors offer a better security profile.

  4. Effects of BMAL1-SIRT1-positive cycle on estrogen synthesis in human ovarian granulosa cells: an implicative role of BMAL1 in PCOS.

    Science.gov (United States)

    Zhang, Jiaou; Liu, Jiansheng; Zhu, Kai; Hong, Yan; Sun, Yun; Zhao, Xiaoming; Du, Yanzhi; Chen, Zi-Jiang

    2016-08-01

    Brain and muscle ARNT-like protein 1 (BMAL1) is necessary for fertility and has been found to be essential to follicle growth and steroidogenesis. Sirtuin1 (SIRT1) has been reported to interact with BMAL1 and function in a circadian manner. Evidence has shown that SIRT1 regulates aromatase expression in estrogen-producing cells. We aimed to ascertain if there is a relationship between polycystic ovary syndrome (PCOS) and BMAL1, and whether and how BMAL1 takes part in estrogen synthesis in human granulosa cells (hGCs). Twenty-four women diagnosed with PCOS and 24 healthy individuals undergoing assisted reproduction were studied. BMAL1 expression in their granulosa cells (GCs) was observed by quantitative real-time polymerase chain reaction (qRT-PCR). The level of expression in the PCOS group was lower than that of the group without PCOS (p PCOS.

  5. Web Resources for Pharmacogenomics

    Institute of Scientific and Technical Information of China (English)

    Guoqing Zhang; Yunsheng Zhang; Yunchao Ling; Jia Jia

    2015-01-01

    Pharmacogenomics is the study of the impact of genetic variations or genotypes of individuals on their drug response or drug metabolism. Compared to traditional genomics research, pharmacogenomic research is more closely related to clinical practice. Pharmacogenomic discoveries may effectively assist clinicians and healthcare providers in determining the right drugs and proper dose for each patient, which can help avoid side effects or adverse reactions, and improve the drug therapy. Currently, pharmacogenomic approaches have proven their utility when it comes to the use of cardiovascular drugs, antineoplastic drugs, aromatase inhibitors, and agents used for infectious diseases. The rapid innovation in sequencing technology and genome-wide association studies has led to the development of numerous data resources and dramatically chan-ged the landscape of pharmacogenomic research. Here we describe some of these web resources along with their names, web links, main contents, and our ratings.

  6. Validity and reliability of the Patient-Reported Arthralgia Inventory: validation of a newly-developed survey instrument to measure arthralgia

    Directory of Open Access Journals (Sweden)

    Castel LD

    2015-07-01

    Full Text Available Liana D Castel,1 Kenneth A Wallston,2 Benjamin R Saville,3 JoAnn R Alvarez,3 Bradley D Shields,4 Irene D Feurer,3 David Cella5 1Meharry-Vanderbilt Alliance, Nashville, TN, USA; 2Psychology in Nursing, Vanderbilt University School of Nursing, Nashville, TN, USA; 3Surgery and Biostatistics, Vanderbilt University School of Medicine, Nashville, TN, USA; 4Medical Sciences, University of Arkansas School of Medicine, Little Rock, AR, USA; 5Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Background: There is a need for a survey instrument to measure arthralgia (joint pain that has been psychometrically validated in the context of existing reference instruments. We developed the 16-item Patient-Reported Arthralgia Inventory (PRAI to measure arthralgia severity in 16 joints, in the context of a longitudinal cohort study to assess aromatase inhibitor-associated arthralgia in breast cancer survivors and arthralgia in postmenopausal women without breast cancer. We sought to evaluate the reliability and validity of the PRAI instrument in these populations, as well as to examine the relationship of patient-reported morning stiffness and arthralgia. Methods: We administered the PRAI on paper in 294 women (94 initiating aromatase inhibitor therapy and 200 postmenopausal women without breast cancer at weeks 0, 2, 4, 6, 8, 12, 16, and 52, as well as once in 36 women who had taken but were no longer taking aromatase inhibitor therapy. Results: Cronbach's alpha was 0.9 for internal consistency of the PRAI. Intraclass correlation coefficients of test-retest reliability were in the range of 0.87–0.96 over repeated PRAI administrations; arthralgia severity was higher in the non-cancer group at baseline than at subsequent assessments. Women with joint comorbidities tended to have higher PRAI scores than those without (estimated difference in mean scores: -0.3, 95% confidence interval [CI] -0.5, -0.2; P<0.001. The PRAI was

  7. Neonatal testosterone suppresses a neuroendocrine pulse generator required for reproduction

    Science.gov (United States)

    Israel, Jean-Marc; Cabelguen, Jean-Marie; Le Masson, Gwendal; Oliet, Stéphane H.; Ciofi, Philippe

    2014-02-01

    The pituitary gland releases hormones in a pulsatile fashion guaranteeing signalling efficiency. The determinants of pulsatility are poorly circumscribed. Here we show in magnocellular hypothalamo-neurohypophyseal oxytocin (OT) neurons that the bursting activity underlying the neurohormonal pulses necessary for parturition and the milk-ejection reflex is entirely driven by a female-specific central pattern generator (CPG). Surprisingly, this CPG is active in both male and female neonates, but is inactivated in males after the first week of life. CPG activity can be restored in males by orchidectomy or silenced in females by exogenous testosterone. This steroid effect is aromatase and caspase dependent, and is mediated via oestrogen receptor-α. This indicates the apoptosis of the CPG network during hypothalamic sexual differentiation, explaining why OT neurons do not burst in adult males. This supports the view that stereotypic neuroendocrine pulsatility is governed by CPGs, some of which are subjected to gender-specific perinatal programming.

  8. 来曲唑的促排卵及胚胎毒性的研究进展%Progress in study of letrozole's ovulation induction and embryotoxicity

    Institute of Scientific and Technical Information of China (English)

    郭鹊晖; 郑志群

    2009-01-01

    芳香化酶是体内雌激素合成的关键酶,来曲唑(1etrozole,LE)是第三代芳香化酶抑制剂(aromatase inhibitors,AIs),能够特异性阻断雌激素的合成,降低机体雌激素水平,解除其对下丘脑/垂体的负反馈抑制,在卵泡早期短期使用有促排卵的作用。由于其强效且副作用小,在临床上试用于不孕症妇女的促排卵治疗已有十余年了。

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

    DEFF Research Database (Denmark)

    Baumann, Lisa; Knörr, Susanne; Keiter, Susanne;

    2014-01-01

    to examine the estrogenic effects on sexual development of zebrafish. Two exposure scenarioswere 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......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...

  10. World endocrinology news

    Directory of Open Access Journals (Sweden)

    M A Berkovskaya

    2008-03-01

    Full Text Available • Actuality of the problem of metabolic syndrome: expert opinion. • Chemerin is a novel adipokine associated with obesity and metabolic syndrome. • Brothers of women with polycystic ovary syndrome are characterised by impaired glucose tolerance, reduced insulin sensitivity and related metabolic defects. • Microvascular dysfunction: a potential pathophysiological role in the metabolic syndrome. • Cardiotrophin-1 is expressed in adipose tissue and it is UP-regulated in the metabolic syndrome. • Magnesium Intake, Metabolic Abnormalities, and Inflammation. • Red meat in the diet. • Relationships of maternal and paternal birth weights to features of the metabolic syndrome in adult offspring: an inter-generation study in South India. • The truth about milk! • Therapeutic uses of aromatase inhibitors in men. • Reduction of body weight and co-morbidities by orlistat: The XXL - Primary Health Care Trial

  11. Expression and localization of fibroblast growth factor (FGF) family in buffalo ovarian follicle during different stages of development and modulatory role of FGF2 on steroidogenesis and survival of cultured buffalo granulosa cells.

    Science.gov (United States)

    Mishra, S R; Thakur, N; Somal, A; Parmar, M S; Reshma, R; Rajesh, G; Yadav, V P; Bharti, M K; Bharati, Jaya; Paul, A; Chouhan, V S; Sharma, G T; Singh, G; Sarkar, M

    2016-10-01

    The present study investigated the expression and localization of FGF and its functional receptors in the follicle of buffalo and the treatment of FGF2 on mRNA expression of CYP19A1 (aromatase), PCNA, and BAX (BCL-2 associated X protein) in cultured buffalo granulosa cells (GCs). Follicles were classified into four groups based on size and E2 level in follicular fluid (FF): F1, 4-6mm diameter, E214mm, E2>180ng/ml. The qPCR studies revealed that the mRNA expression of FGF1, FGF2 and FGF7 were maximum (Pfamily members are expressed in a regulated manner in buffalo ovarian follicles during different stages of development where FGF2 may promote steroidogenesis and GC survival through autocrine and paracrine manner. PMID:27663377

  12. Selective androgen receptor modulators as improved androgen therapy for advanced breast cancer.

    Science.gov (United States)

    Coss, Christopher C; Jones, Amanda; Dalton, James T

    2014-11-01

    Androgens were at one time a therapeutic mainstay in the treatment of advanced breast cancer. Despite comparable efficacy, SERMs and aromatase inhibitors eventually became the therapies of choice due to in part to preferred side-effect profiles. Molecular characterization of breast tumors has revealed an abundance of androgen receptor expression but the choice of an appropriate androgen receptor ligand (agonist or antagonist) has been confounded by multiple conflicting reports concerning the role of the receptor in the disease. Modern clinical efforts have almost exclusively utilized antagonists. However, the recent clinical development of selective androgen receptor modulators with greatly improved side-effect profiles has renewed interest in androgen agonist therapy for advanced breast cancer.

  13. Deletion of P399{sub E}401 in NADPH cytochrome P450 oxidoreductase results in partial mixed oxidase deficiency

    Energy Technology Data Exchange (ETDEWEB)

    Flueck, Christa E., E-mail: christa.flueck@dkf.unibe.ch [Pediatric Endocrinology, Diabetology and Metabolism, University Children' s Hospital, Bern (Switzerland); Mallet, Delphine [Service d' Endocrinologie Moleculaire et Maladies Rares, Hospices Civils de Lyon, Bron (France); Hofer, Gaby [Pediatric Endocrinology, Diabetology and Metabolism, University Children' s Hospital, Bern (Switzerland); Samara-Boustani, Dinane [Hopital Necker-Enfants malades, Paris (France); Leger, Juliane [Hopital Robert Debre, Paris (France); Polak, Michel [Hopital Necker-Enfants malades, Paris (France); Morel, Yves [Service d' Endocrinologie Moleculaire et Maladies Rares, Hospices Civils de Lyon, Bron (France); Pandey, Amit V., E-mail: amit@pandeylab.org [Pediatric Endocrinology, Diabetology and Metabolism, University Children' s Hospital, Bern (Switzerland)

    2011-09-09

    Highlights: {yields} Mutations in human POR cause congenital adrenal hyperplasia. {yields} We are reporting a novel 3 amino acid deletion mutation in POR P399{sub E}401del. {yields} POR mutation P399{sub E}401del decreased P450 activities by 60-85%. {yields} Impairment of steroid metabolism may be caused by multiple hits. {yields} Severity of aromatase inhibition is related to degree of in utero virilization. -- Abstract: P450 oxidoreductase (POR) is the electron donor for all microsomal P450s including steroidogenic enzymes CYP17A1, CYP19A1 and CYP21A2. We found a novel POR mutation P399{sub E}401del in two unrelated Turkish patients with 46,XX disorder of sexual development. Recombinant POR proteins were produced in yeast and tested for their ability to support steroid metabolizing P450 activities. In comparison to wild-type POR, the P399{sub E}401del protein was found to decrease catalytic efficiency of 21-hydroxylation of progesterone by 68%, 17{alpha}-hydroxylation of progesterone by 76%, 17,20-lyase action on 17OH-pregnenolone by 69%, aromatization of androstenedione by 85% and cytochrome c reduction activity by 80%. Protein structure analysis of the three amino acid deletion P399{sub E}401 revealed reduced stability and flexibility of the mutant. In conclusion, P399{sub E}401del is a novel mutation in POR that provides valuable genotype-phenotype and structure-function correlation for mutations in a different region of POR compared to previous studies. Characterization of P399{sub E}401del provides further insight into specificity of different P450s for interaction with POR as well as nature of metabolic disruptions caused by more pronounced effect on specific P450s like CYP17A1 and aromatase.

  14. Current medical treatment of estrogen receptor-positive breast cancer

    Institute of Scientific and Technical Information of China (English)

    Franco; Lumachi; Davide; A; Santeufemia; Stefano; MM; Basso

    2015-01-01

    Approximately 80% of breast cancers(BC) are estrogen receptor(ER)-positive and thus endocrine therapy(ET) should be considered complementary to surgery in the majority of patients. The advantages of oophorectomy, adrenalectomy and hypophysectomy in women with advanced BC have been demonstrated many years ago, and currently ET consist of(1) ovarian function suppression(OFS), usually obtained using gonadotropinreleasing hormone agonists(Gn RHa);(2) selective estrogen receptor modulators or down-regulators(SERMs or SERDs); and(3) aromatase inhibitors(AIs), or a combination of two or more drugs. For patients aged less than 50 years and ER+ BC, there is no conclusive evidence that the combination of OFS and SERMs(i.e., tamoxifen) or chemotherapy is superior to OFS alone. Tamoxifen users exhibit a reduced risk of BC, both invasive and in situ, especially during the first 5 years of therapy, and extending the treatment to 10 years further reduced the risk of recurrences. SERDs(i.e., fulvestrant) are especially useful in the neoadjuvant treatment of advanced BC, alone or in combination with either cytotoxic agents or AIs. There are two types of AIs: type Ⅰ are permanent steroidal inhibitors of aromatase, while type Ⅱ are reversible nonsteroidal inhibitors. Several studies demonstrated the superiority of the third-generation AIs(i.e., anastrozole and letrozole) compared with tamoxifen, and adjuvant therapy with AIs reduces the recurrence risk especially in patients with advanced BC. Unfortunately, some cancers are or became ET-resistant, and thus other drugs have been suggested in combination with SERMs or AIs, including cyclin-dependent kinase 4/6 inhibitors(palbociclib) and mammalian target of rapamycin(m TOR) inhibitors, such as everolimus. Further studies are required to confirm their real usefulness.

  15. Switching to Letrozole Versus Continued Tamoxifen Therapy in Treatment of Postmenopausal Women with Early Breast Cancer

    International Nuclear Information System (INIS)

    Tamoxifen has been the mainstay of breast cancer therapy. Over time, resistance to tamoxifen may develop. The aromatase inhibitors have proven to be a powerful drug for use in hormone-sensitive early breast cancer. The switching strategy was designed to combine the apparent superior efficacy of aromatase inhibitors with tamoxifen favourable effects. Methods: This study was performed on 120 postmenopausal women with histologically confirmed, hormone receptor-positive, operable invasive breast carcinoma who remained free of disease after 2 years of adjuvant tamoxifen therapy. They were randomized to receive either letrozole 2.5 mg/day (60 patients) or to continue 20 mg/day tamoxifen for 5 years (60 patients). Results: The treatment groups were well balanced in terms of age, tumor size, nodal status, oestrogen and progesterone receptor status, and previous surgery. The disease recurred in 10 patients in the group receiving tamoxifen and 3 patients in the same group switched to letrozole. There were 8 deaths in the group receiving tamoxifen and 3 deaths in the group of patients who switched to letrozole. Disease-free survival was higher in the group of patients who switched to letrozole compared to the group of patients who received tamoxifen (p=0.04), while the overall survival was not statistically significantly different in the two groups. Letrozole was associated with a significantly lower rate of vaginal bleeding and thromboembolic events. However, bone fractures and adverse cardiovascular events were more frequent in the arm receiving letrozole than in the arm receiving tamoxifen but these differences were not statistically significant. Conclusion: Switching to letrozole after 2 years of tamoxifen may be better than continuing five years of tamoxifen therapy as regard efficacy and tolerability. Further study is recommended on a larger group of patients to verify this finding

  16. Endocrine-disrupting effects and reproductive toxicity of low dose MCLR on male frogs (Rana nigromaculata) in vivo

    International Nuclear Information System (INIS)

    Highlights: • Low-dose MCLR (1 μg/L) elicits a potential ecological effect on amphibian populations. • MCLR can induce abnormal sperm morphologies and activities on male frogs. • MCLR can induce a decrease in serum testosterone and an increase in serum estradiol of male frogs. • MCLR can increase SF-1 protein levels and decrease P450 aromatase levels in the gonads of frogs. - Abstract: Toxic cyanobacterial blooms are potential global threats to aquatic ecosystems and human health. The World Health Organization has set a provisional guideline limit of 1 μg/L microcystin-LR (MCLR) in freshwater. However, MCLR concentrations in several water bodies have exceeded this level. Despite this recommended human safety standard, MCLR-induced endocrine-disrupting effects and reproductive toxicity on male frog (Rana nigromaculata) were demonstrated in this study. Results showed that sperm motility and sperm count were significantly and negatively correlated with exposure time and concentration. By contrast, abnormal sperm rate was positively correlated with both parameters. Ultrastructural observation results revealed abnormal sperm morphologies, vacuoles in spermatogenic cells, cell dispersion, incomplete cell structures, and deformed nucleoli. These results indicated that MCLR could induce toxic effects on the reproductive system of frogs, significantly decrease testosterone content, and rapidly increase estradiol content. Prolonged exposure and increased concentration enhanced the relative expression levels of P450 aromatase and steroidogenic factor 1; thus, endocrine function in frogs was disrupted. This study is the first to demonstrate in vivo MCLR toxicity in the reproductive system of male R. nigromaculata. This study provided a scientific basis of the global decline in amphibian populations

  17. High abundance androgen receptor in goldfish brain: characteristics and seasonal changes

    International Nuclear Information System (INIS)

    Testosterone (T) exerts its actions in brain directly via androgen receptors or, after aromatization to estradiol, via estrogen receptors. Brain aromatase activity in teleost fish is 100-1000 times greater than in mammals and would be expected to significantly reduce the quantity of androgen available for receptor binding. Experiments were carried out on the goldfish Carassius auratus to determine if androgen receptors are present in teleost brain and whether their physicochemical properties reflect elevated aromatase. Cytosolic and nuclear extracts were assayed with the use of [3H]T and charcoal, Sephadex LH-20, or DNA-cellulose chromatography to separate bound and free steroids. Binding activity was saturable and had an equally high affinity for T and 5 alpha-dihydrotestosterone. Although mibolerone was a relatively weak competitor, the putative teleost androgen 11-ketotestosterone, methyltrienolone (R1881), estradiol, progesterone, and cortisol were poor ligands. Characteristics that distinguish this receptor from a steroid-binding protein in goldfish serum are the presence of binding activity in both nuclear and cytosolic extracts, a low rate of ligand-receptor dissociation, electrophoretic mobility, sedimentation properties in low vs. high salt, and tissue distribution. DNA cellulose-adhering and nonadhering forms were detected, but these did not differ in other variables measured. Although goldfish androgen receptors resembled those of mammals in all important physicochemical characteristics, they were unusually abundant compared to levels in rat brain, but comparable to levels in prostate and other male sex hormone target organs. Moreover, there were seasonal variations in total receptors, with a peak at spawning (April) 4- to 5-fold higher than values in reproductively inactive fish

  18. The advantage of letrozole over tamoxifen in the BIG 1-98 trial is consistent in younger postmenopausal women and in those with chemotherapy-induced menopause.

    Science.gov (United States)

    Chirgwin, Jacquie; Sun, Zhuoxin; Smith, Ian; Price, Karen N; Thürlimann, Beat; Ejlertsen, Bent; Bonnefoi, Hervé; Regan, Meredith M; Goldhirsch, Aron; Coates, Alan S

    2012-01-01

    Letrozole, an aromatase inhibitor, is ineffective in the presence of ovarian estrogen production. Two subpopulations of apparently postmenopausal women might derive reduced benefit from letrozole due to residual or returning ovarian activity: younger women (who have the potential for residual subclinical ovarian estrogen production), and those with chemotherapy-induced menopause who may experience return of ovarian function. In these situations tamoxifen may be preferable to an aromatase inhibitor. Among 4,922 patients allocated to the monotherapy arms (5 years of letrozole or tamoxifen) in the BIG 1-98 trial we identified two relevant subpopulations: patients with potential residual ovarian function, defined as having natural menopause, treated without adjuvant or neoadjuvant chemotherapy and age ≤ 55 years (n = 641); and those with chemotherapy-induced menopause (n = 105). Neither of the subpopulations examined showed treatment effects differing from the trial population as a whole (interaction P values are 0.23 and 0.62, respectively). Indeed, both among the 641 patients aged ≤ 55 years with natural menopause and no chemotherapy (HR 0.77 [0.51, 1.16]) and among the 105 patients with chemotherapy-induced menopause (HR 0.51 [0.19, 1.39]), the disease-free survival (DFS) point estimate favoring letrozole was marginally more beneficial than in the trial as a whole (HR 0.84 [0.74, 0.95]). Contrary to our initial concern, DFS results for young postmenopausal patients who did not receive chemotherapy and patients with chemotherapy-induced menopause parallel the letrozole benefit seen in the BIG 1-98 population as a whole. These data support the use of letrozole even in such patients.

  19. Increase in estrogen signaling in the early brain of orange-spotted grouper Epinephelus coioides: a mini-review.

    Science.gov (United States)

    Nagarajan, Ganesan; Aruna, Adimoolam; Chang, Ching-Fong

    2013-02-01

    Despite neurosteroidogenic enzymes are playing important roles in the regulation of brain development and function, the potential link between brain and gonad by the action of steroid hormones during gonadal sex differentiation is still not clear in teleosts. In this mini-review, we summarized our understanding on the early brain development related to the synthesis of neurosteroids and receptor signaling during gonadal sex differentiation in protogynous orange-spotted grouper, Epinephelus coioides (functional females for the first 6 years of life and start to sex change around the age of 7 years) and protandrous black porgy (functional males for the first 2 years of life but begin to change sex during the third year). We found a similar profile in the increased expression of brain aromatase gene (aromatatse B or cyp19a1b), aromatase activity, estradiol (E(2)), and estrogen signaling in the brain of both grouper and black porgy fish during gonadal sex differentiation. In contrast to mammals, teleost fish Cyp19a1b expressed in a unique cell type, a radial glial cell, which is acted as progenitors in the brain of developing and adult fish. In agreement with these pioneer studies, we demonstrated that the grouper cyp19a1b/Cyp19a1b was expressed in radial glial cells. Further, in vivo data in the grouper brain showed that exogenous E(2) upregulated Cyp19a1b immunoreactivity (ir) in radial glial cells. These data suggest the possible roles of Cyp19a1b and E(2) in early brain development which is presumably related to gonadal sex differentiation.

  20. Sex-specific prenatal stress effects on the rat reproductive axis and adrenal gland structure

    Science.gov (United States)

    George, Susan O; Hogg, Charis O; Lai, Yu-Ting; Brunton, Paula J

    2016-01-01

    Abstract Social stress during pregnancy has profound effects on offspring physiology. This study examined whether an ethologically relevant social stress during late pregnancy in rats alters the reproductive axis and adrenal gland structure in post-pubertal male and female offspring. Prenatally stressed (PNS) pregnant rats (n=9) were exposed to an unfamiliar lactating rat for 10 min/day from day 16 to 20 of pregnancy inclusive, whereas control pregnant rats (n=9) remained in their home cages. Gonads, adrenal glands and blood samples were obtained from one female and one male from each litter at 11 to 12-weeks of age. Anogenital distance was measured. There was no treatment effect on body, adrenal or gonad weight at 11–12 weeks. PNS did not affect the number of primordial, secondary or tertiary ovarian follicles, numbers of corpora lutea or ovarian FSH receptor expression. There was an indication that PNS females had more primary follicles and greater ovarian aromatase expression compared with control females (both P=0.09). PNS males had longer anogenital distances (0.01±0.0 cm/g vs 0.008±0.00 cm/g; P=0.007) and higher plasma FSH concentrations (0.05 ng/mL vs 0.006 ng/mL; s.e.d.=0.023; P=0.043) compared with control males. There were no treatment effects on the number of Sertoli cells or seminiferous tubules, seminiferous tubule area, plasma testosterone concentration or testis expression of aromatase, FSH receptor or androgen receptor. PNS did not affect adrenal size. These data suggest that the developing male reproductive axis is more sensitive to maternal stress and that PNS may enhance aspects of male reproductive development. PMID:27026714

  1. Estrogen-mediated mechanisms to control the growth and apoptosis of breast cancer cells: a translational research success story.

    Science.gov (United States)

    McDaniel, Russell E; Maximov, Philipp Y; Jordan, V Craig

    2013-01-01

    The treatment and prevention of solid tumors have proved to be a major challenge for medical science. The paradigms for success in the treatment of childhood leukemia, Hodgkin's disease, Burkett's lymphoma, and testicular carcinoma with cytotoxic chemotherapy did not translate to success in solid tumors--the majority of cancers that kill. In contrast, significant success has accrued for patients with breast cancer with antihormone treatments (tamoxifen or aromatase inhibitors) that are proved to enhance survivorship, and remarkably, there are now two approved prevention strategies using either tamoxifen or raloxifene. This was considered impossible 40 years ago. We describe the major clinical advances with nonsteroidal antiestrogens that evolved into selective estrogen receptor modulators (SERMs) which successfully exploited the ER target selectively inside a woman's body. The standard paradigm that estrogen stimulates breast cancer growth has been successfully exploited for over 4 decades with therapeutic strategies that block (tamoxifen, raloxifene) or reduce (aromatase inhibitors) circulating estrogens in patients to stop breast tumor growth. But this did not explain why high-dose estrogen treatment that was the standard of care to treat postmenopausal breast cancer for 3 decades before tamoxifen caused tumor regression. This paradox was resolved with the discovery that breast cancer resistance to long-term estrogen deprivation causes tumor regression with physiologic estrogen through apoptosis. The new biology of estrogen action has been utilized to explain the findings in the Women's Health Initiative that conjugated equine estrogen alone given to postmenopausal women, average age 68, will produce a reduction of breast cancer incidence and mortality compared to no treatment. Estrogen is killing nascent breast cancer cells in the ducts of healthy postmenopausal women. The modulation of the ER using multifunctional medicines called SERMs has provided not only

  2. Fluorescence in situ hybridization techniques (FISH) to detect changes in CYP19a gene expression of Japanese medaka (Oryzias latipes)

    International Nuclear Information System (INIS)

    The aim of this study was to develop a sensitive in situ hybridization methodology using fluorescence-labeled riboprobes (FISH) that allows for the evaluation of gene expression profiles simultaneously in multiple target tissues of whole fish sections of Japanese medaka (Oryzias latipes). To date FISH methods have been limited in their application due to autofluorescence of tissues, fixatives or other components of the hybridization procedure. An optimized FISH method, based on confocal fluorescence microscopy was developed to reduce the autofluorescence signal. Because of its tissue- and gender-specific expression and relevance in studies of endocrine disruption, gonadal aromatase (CYP19a) was used as a model gene. The in situ hybridization (ISH) system was validated in a test exposure with the aromatase inhibitor fadrozole. The optimized FISH method revealed tissue-specific expression of the CYP19a gene. Furthermore, the assay could differentiate the abundance of CYP19a mRNA among cell types. Expression of CYP19a was primarily associated with early stage oocytes, and expression gradually decreased with increasing maturation. No expression of CYP19a mRNA was observed in other tissues such as brain, liver, or testes. Fadrozole (100 μg/L) caused up-regulation of CYP19a expression, a trend that was confirmed by RT-PCR analysis on excised tissues. In a combination approach with gonad histology, it could be shown that the increase in CYP19a expression as measured by RT-PCR on a whole tissue basis was due to a combination of both increases in numbers of CYP19a-containing cells and an increase in the amount of CYP19a mRNA present in the cells

  3. Estrogen, SNP-Dependent Chemokine Expression and Selective Estrogen Receptor Modulator Regulation.

    Science.gov (United States)

    Ho, Ming-Fen; Bongartz, Tim; Liu, Mohan; Kalari, Krishna R; Goss, Paul E; Shepherd, Lois E; Goetz, Matthew P; Kubo, Michiaki; Ingle, James N; Wang, Liewei; Weinshilboum, Richard M

    2016-03-01

    We previously reported, on the basis of a genome-wide association study for aromatase inhibitor-induced musculoskeletal symptoms, that single-nucleotide polymorphisms (SNPs) near the T-cell leukemia/lymphoma 1A (TCL1A) gene were associated with aromatase inhibitor-induced musculoskeletal pain and with estradiol (E2)-induced TCL1A expression. Furthermore, variation in TCL1A expression influenced the downstream expression of proinflammatory cytokines and cytokine receptors. Specifically, the top hit genome-wide association study SNP, rs11849538, created a functional estrogen response element (ERE) that displayed estrogen receptor (ER) binding and increased E2 induction of TCL1A expression only for the variant SNP genotype. In the present study, we pursued mechanisms underlying the E2-SNP-dependent regulation of TCL1A expression and, in parallel, our subsequent observations that SNPs at a distance from EREs can regulate ERα binding and that ER antagonists can reverse phenotypes associated with those SNPs. Specifically, we performed a series of functional genomic studies using a large panel of lymphoblastoid cell lines with dense genomic data that demonstrated that TCL1A SNPs at a distance from EREs can modulate ERα binding and expression of TCL1A as well as the expression of downstream immune mediators. Furthermore, 4-hydroxytamoxifen or fulvestrant could reverse these SNP-genotype effects. Similar results were found for SNPs in the IL17A cytokine and CCR6 chemokine receptor genes. These observations greatly expand our previous results and support the existence of a novel molecular mechanism that contributes to the complex interplay between estrogens and immune systems. They also raise the possibility of the pharmacological manipulation of the expression of proinflammatory cytokines and chemokines in a SNP genotype-dependent fashion. PMID:26866883

  4. Atrazine reduces reproduction in Japanese medaka (Oryzias latipes).

    Science.gov (United States)

    Papoulias, Diana M; Tillitt, Donald E; Talykina, Melaniya G; Whyte, Jeffrey J; Richter, Catherine A

    2014-09-01

    Atrazine is an effective broadleaf herbicide and the second most heavily used herbicide in the United States. Effects along the hypothalamus-pituitary-gonad axis in a number of vertebrate taxa have been demonstrated. Seasonally elevated concentrations of atrazine in surface waters may adversely affect fishes, but only a few studies have examined reproductive effects of this chemical. The present study was designed to evaluate a population endpoint (egg production) in conjunction with histological (reproductive stage, gonad pathology) and biochemical (aromatase activity, sex hormone production) phenotypes associated with atrazine exposure in Japanese medaka. Adult virgin breeding groups of one male and four females were exposed to nominal concentrations of 0, 0.5, 5.0, and 50 μg/L (0, 2.3, 23.2, 231 nM) of atrazine in a flow-through diluter for 14 or 38 days. Total egg production was lower (36-42%) in all atrazine-exposed groups as compared to the controls. The decreases in cumulative egg production of atrazine-treated fish were significant by exposure day 24. Reductions in total egg production in atrazine treatment groups were most attributable to a reduced number of eggs ovulated by females in atrazine-treated tanks. Additionally, males exposed to atrazine had a greater number of abnormal germ cells. There was no effect of atrazine on gonadosomatic index, aromatase protein, or whole body 17 β-estradiol or testosterone. Our results suggest that atrazine reduces egg production through alteration of final maturation of oocytes. The reduced egg production observed in this study was very similar to our previously reported results for fathead minnow. This study provides further information with which to evaluate atrazine's risk to fish populations.

  5. Letrozole-induced functional changes in carcinoma-associated fibroblasts and their influence on breast cancer cell biology.

    Science.gov (United States)

    Li, Kaifu; Kang, Hua; Wang, Yajun; Hai, Tao; Rong, Guohua; Sun, Haichen

    2016-07-01

    Accumulating evidence suggests that carcinoma-associated fibroblasts (CAFs) influence the efficacy of endocrine therapy. Aromatase inhibitors inhibit the growth of breast tumors by inhibiting the synthesis of estrogen. However, it remains unknown whether the aromatase inhibitor letrozole has an additional impact on CAFs, which further influence the efficacy of endocrine therapy. Primary CAFs were isolated from primary estrogen receptor-positive human breast tumors. Estrogen-deprived culture medium was used to exclude the influence of steroids. In co-culture, primary cultured CAFs increased MCF7 cell adhesion, invasion, migration and proliferation, and letrozole treatment inhibited these increases, except for the increase in proliferation. In total, 258 up-regulated genes and 47 down-regulated genes with an absolute fold change >2 were identified in CAFs co-cultured with MCF7 cell after letrozole treatment. One up-regulated genes (POSTN) and seven down-regulated genes (CCL2, CCL5, CXCL1, IL-8, CXCL5, LEP and NGF) were further validated by real-time PCR. The changes in CCL2 and CXCL1 expression were further confirmed using an automated microscopic imaging-based, high content analysis platform. Although the results need further functional validation, this study is the first to describe the differential tumor-promoting phenotype of CAFs induced by letrozole and the associated gene expression alterations. Most importantly, our data revealed that down-regulation of several secreted factors (CCL2, CCL5, CXCL1 etc.) in CAFs might be partially responsible for the efficacy of letrozole.

  6. Examestane in advanced or recurrent endometrial carcinoma: a prospective phase II study by the Nordic Society of Gynecologic Oncology (NSGO)

    International Nuclear Information System (INIS)

    We evaluated the efficacy and safety of the aromatase inhibitor exemestane in patients with advanced, persistent or recurrent endometrial carcinoma. We performed an open-label one-arm, two-stage, phase II study of 25 mg of oral exemestane in 51 patients with advanced (FIGO stage III-IV) or relapsed endometrioid endometrial cancer. Patients were stratified into subsets of estrogen receptor (ER) positive and ER negative patients. Recruitment to the ER negative group was stopped prematurely after 12 patients due to slow accrual. In the ER positive patients, we observed an overall response rate of 10%, and a lack of progression after 6 months in 35% of the patients. No responses were registered in the ER negative patients, and all had progressive disease within 6 months. For the total group of patients, the median progression free survival (PFS) was 3.1 months (95% CI: 2.0-4.1). In the ER positive patients the median PFS was 3.8 months (95% CI: 0.7-6.9) and in the ER negative patients it was 2.6 months (95% CI: 2.1-3-1). In the ER positive patients the median overall survival (OS) time was 13.3 months (95% CI: 7.7-18.9), in the ER negative patients the corresponding numbers were 6.1 months (95% CI: 4.1-8.2). Treatment with exemestane was well tolerated. Treatment of estrogen positive advanced or recurrent endometrial cancer with exemestane, an aromatase inhibitor, resulted in a response rate of 10% and lack of progression after 6 months in 35% of the patients. Trial identification number (Clinical Trials.gov): http://www.clinicaltrials.gov/NCT01965080. Nordic Society of Gynecological Oncology: NSGO–EC–0302. EudraCT number: 2004-001103-35

  7. Gestational methyl donor deficiency alters key proteins involved in neurosteroidogenesis in the olfactory bulbs of newborn female rats and is associated with impaired olfactory performance.

    Science.gov (United States)

    El Hajj Chehadeh, Sarah; Pourié, Grégory; Martin, Nicolas; Alberto, Jean-Marc; Daval, Jean-Luc; Guéant, Jean-Louis; Leininger-Muller, Brigitte

    2014-03-28

    Gestational methyl donor deficiency (MDD) leads to growth retardation as well as to cognitive and motor disorders in 21-d-old rat pups. These disorders are related to impaired neurogenesis in the cerebral neurogenic areas. Olfactory bulbs (OB), the main target of neuronal progenitors originating from the subventricular zone, play a critical role during the postnatal period by allowing the pups to identify maternal odour. We hypothesised that growth retardation could result from impaired suckling due to impaired olfactory discrimination through imbalanced apoptosis/neurogenesis in the OB. Since neurosteroidogenesis modulates neurogenesis in OB, in the present study, we investigated whether altered neurosteroidogenesis could explain some these effects. Pups born to dams fed a normal diet (n 24) and a MDD diet (n 27) were subjected to olfactory tests during the lactation and weaning periods (n 24 and 20, respectively). We studied the markers of apoptosis/neurogenesis and the expression levels of the key neurosteroidogenic enzyme aromatase, the cholesterol-transfer protein StAR (steroidogenic acute regulatory protein) and the ERα oestrogen receptor and the content of oestradiol in OB. The 21-d-old MDD female pups displayed lower body weight and impaired olfactory discrimination when compared with the control pups. MDD led to greater homocysteine accumulation and more pronounced apoptosis, along with impaired cell proliferation in the OB of female pups. The expression levels of aromatase, StAR and ERα as well as the content of oestradiol were lower in the OB of the MDD female pups than in those of the control female pups. In conclusion, gestational MDD may alter olfactory discrimination performances by affecting neurogenesis, apoptosis and neurosteroidogenesis in OB in a sex-dependent manner. It may be involved in growth retardation through impaired suckling.

  8. Reproductive steroid receptors and actions in the locus coeruleus of male macaques: Part of an aggression circuit?

    Science.gov (United States)

    Bethea, Cynthia L; Belikova, Yelena; Phu, Kenny; Mammerella, Grace

    2016-11-01

    This study was initiated to determine whether the noradrenergic (NE) neurons of the locus coeruleus (LC) could mediate the stimulatory action of androgens on serotonin-related gene expression in male macaques. These experiments follow our observations that serotonin neurons lack androgen receptors (ARs), and yet respond to androgens. Male Japanese macaques (Macaca fuscata) were castrated for 5-7months and then treated for 3months with [1] placebo, [2] T (testosterone), [3] DHT (dihydrotestosterone; non-aromatizable androgen) plus ATD (steroidal aromatase inhibitor), or [4] FLUT (Flutamide; androgen antagonist) plus ATD (n=5/group). The noradrenergic (NE) innervation of the raphe was determined with immunolabeling of axons with an antibody to dopamine-β-hydroxylase (DBH). Immunolabeling of tyrosine hydroxylase (TH) dendrites and corticotropin releasing hormone (CRH) axons innervating the LC was also determined. Due to the longer treatment period employed, the expression of the cognate nuclear receptors was sought. Androgen receptor (AR), estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) immunostaining was accomplished. Quantitative image analysis was applied and immunopositive neurons or axons with boutons were measured. Double-label of NE neurons for each receptor plus TH determined whether the receptors were localized in NE neurons. Androgens with or without aromatase activity significantly stimulated DBH axon density in the raphe (ANOVA, p=0.006), and LC dendritic TH (ANOVA, p80% of LC NE neurons contained ERα or ERβ. In conclusion, the LC NE neurons may transduce the stimulatory effect of androgens on serotonin-related gene expression. Since LC NE neurons lack AR, the androgenic stimulation of dendritic TH and axonal DBH may be indirectly mediated by other neurons. Estrogen, either from metabolism of T or from de novo synthesis, appears necessary for robust CRH innervation of the LC, which differs from female macaques. PMID:27083854

  9. Cancer chemopreventive and anticancer evaluation of extracts and fractions from marine macro- and microorganisms collected from Twilight Zone waters around Guam.

    Science.gov (United States)

    Schupp, Peter J; Kohlert-Schupp, Claudia; Whitefield, Susanna; Engemann, Anna; Rohde, Sven; Hemscheidt, Thomas; Pezzuto, John M; Kondratyuk, Tamara P; Park, Eun-Jung; Marler, Laura; Rostama, Bahman; Wright, Anthony D

    2009-12-01

    The cancer chemopreventive and cytotoxic properties of 50 extracts derived from Twilight Zone (50-150 m) sponges, gorgonians and associated bacteria, together with 15 extracts from shallow water hard corals, as well as 16 fractions derived from the methanol solubles of the Twilight Zone sponge Suberea sp, were assessed in a series of bioassays. These assays included: Induction of quinone reductase (QR), inhibition of TNF-alpha activated nuclear factor kappa B (NFkappaB), inhibition of aromatase, interaction with retinoid X receptor (RXR), inhibition of nitric oxide (NO) synthase, inhibition 2,2-diphenyl-1-picrylhydrazyl radical scavenging (DPPH), and inhibition of HL-60 and MCF-7 cell proliferation. The results of these assays showed that at least 10 extracts and five fractions inhibited NFkappaB by greater than 60%, two extracts and two fractions inhibited DPPH by more than 50%, nine extracts and two fractions affected the survival of HL-60 cells, no extracts or fractions affected RXR, three extracts and six fractions affected quinone reductase (QR), three extracts and 12 fractions significantly inhibited aromatase, four extracts and five fractions inhibited nitric oxide synthase, and one extract and no fractions inhibited the growth of MCF-7 cells by more than 95%. These data revealed the tested samples to have many and varied activities, making them, as shown with the extract of the Suberea species, useful starting points for further fractionation and purification. Moreover, the large number of samples demonstrating activity in only one or sometimes two assays accentuates the potential of the Twilight Zone, as a largely unexplored habitat, for the discovery of selectively bioactive compounds. The overall high hit rate in many of the employed assays is considered to be a significant finding in terms of "normal" hit rates associated with similar samples from shallower depths.

  10. Cancer Chemopreventive and Anticancer Evaluation of Extracts and Fractions from Marine Macro- and Micro-organisms Collected from Twilight Zone Waters Around Guam[1

    Science.gov (United States)

    Schupp, Peter J.; Kohlert-Schupp, Claudia; Whitefield, Susanna; Engemann, Anna; Rohde, Sven; Hemscheidt, Thomas; Pezzuto, John M.; Kondratyuk, Tamara P.; Park, Eun-Jung; Marler, Laura; Rostama, Bahman; Wright, Anthony D.

    2010-01-01

    The cancer chemopreventive and cytotoxic properties of 50 extracts derived from Twilight Zone (50–150 m) sponges, gorgonians and associated bacteria, together with 15 extracts from shallow water hard corals, as well as 16 fractions derived from the methanol solubles of the Twilight Zone sponge Suberea sp, were assessed in a series of bioassays. These assays included: Induction of quinone reductase (QR), inhibition of TNF-α activated nuclear factor kappa B (NFκB), inhibition of aromatase, interaction with retinoid X receptor (RXR), inhibition of nitric oxide (NO) synthase, inhibition 2,2-diphenyl-1-picrylhydrazyl radical scavenging (DPPH), and inhibition of HL-60 and MCF-7 cell proliferation. The results of these assays showed that at least 10 extracts and five fractions inhibited NFκB by greater than 60%, two extracts and two fractions inhibited DPPH by more than 50%, nine extracts and two fractions affected the survival of HL-60 cells, no extracts or fractions affected RXR, three extracts and six fractions affected quinone reductase (QR), three extracts and 12 fractions significantly inhibited aromatase, four extracts and five fractions inhibited nitric oxide synthase, and one extract and no fractions inhibited the growth of MCF-7 cells by more than 95%. These data revealed the tested samples to have many and varied activities, making them, as shown with the extract of the Suberea species, useful starting points for further fractionation and purification. Moreover, the large number of samples demonstrating activity in only one or sometimes two assays accentuates the potential of the Twilight Zone, as a largely unexplored habitat, for the discovery of selectively bioactive compounds. The overall high hit rate in many of the employed assays is considered to be a significant finding in terms of “normal” hit rates associated with similar samples from shallower depths. PMID:20120114

  11. Short-term exposure to low concentrations of the synthetic androgen methyltestosterone affects vitellogenin and steroid levels in adult male zebrafish (Danio rerio).

    Science.gov (United States)

    Andersen, Lene; Goto-Kazeto, Rie; Trant, John M; Nash, Jon P; Korsgaard, Bodil; Bjerregaard, Poul

    2006-03-10

    Short-term effects of methyltestosterone (MT) on the endocrine system of adult male zebrafish (Danio rerio) were examined. Males were exposed to 0, 4.5, 6.6, 8.5, 19.8, 35.9, 62.3 ng MT/l and ethinylestradiol (EE2) (26.4 ng/l) for 7 days. Several physiological endpoints that may be affected by endocrine disrupters were analysed, specifically vitellogenin (VTG) concentration, estradiol (E2), testosterone (T), and 11-ketotestosterone (KT) content, brain aromatase activity and gene expression of CYP19A1 and CYP19A2 in the testis. Exposure to the lowest MT concentration (4.5 ng MT/l), and the EE2 increased the concentration of VTG significantly compared to solvent control group. Exposure to higher concentrations of MT did not increase VTG levels. Endogenous KT and T levels decreased significantly in a concentration-dependent manner in response to the MT exposure and the lowest effective concentrations were 6.4 and 8.5 ng MT/l, respectively. The levels of KT and T were also significantly suppressed by EE2 when compared to the solvent control group. Significant decreases in endogenous E2 levels were found in some MT groups but it was not possible to distinguish a simple concentration-response relationship. No effects of MT or EE2 on the brain aromatase activity or on testicular gene expression of CYP19A1 and CYP19A2 were detected. The results show that androgens such as MT can act as endocrine disrupters even at very low concentrations.

  12. The phytoestrogen genistein affects zebrafish development through two different pathways.

    Directory of Open Access Journals (Sweden)

    Sana Sassi-Messai

    Full Text Available BACKGROUND: Endocrine disrupting chemicals are widely distributed in the environment and derive from many different human activities or can also be natural products synthesized by plants or microorganisms. The phytoestrogen, genistein (4', 5, 7-trihydroxy-isoflavone, is a naturally occurring compound found in soy products. Genistein has been the subject of numerous studies because of its known estrogenic activity. METHODOLOGY/PRINCIPAL FINDINGS: We report that genistein exposure of zebrafish embryos induces apoptosis, mainly in the hindbrain and the anterior spinal cord. Timing experiments demonstrate that apoptosis is induced during a precise developmental window. Since adding ICI 182,780, an ER antagonist, does not rescue the genistein-induced apoptosis and since there is no synergistic effect between genistein and estradiol, we conclude that this apoptotic effect elicited by genistein is estrogen-receptors independent. However, we show in vitro, that genistein binds and activates the three zebrafish estrogen receptors ERalpha, ERbeta-A and ERbeta-B. Furthermore using transgenic ERE-Luciferase fish we show that genistein is able to activate the estrogen pathway in vivo during larval stages. Finally we show that genistein is able to induce ectopic expression of the aromatase-B gene in an ER-dependent manner in the anterior brain in pattern highly similar to the one resulting from estrogen treatment at low concentration. CONCLUSION/SIGNIFICANCE: TAKEN TOGETHER THESE RESULTS INDICATE THAT GENISTEIN ACTS THROUGH AT LEAST TWO DIFFERENT PATHWAYS IN ZEBRAFISH EMBRYOS: (i it induces apoptosis in an ER-independent manner and (ii it regulates aromatase-B expression in the brain in an ER-dependent manner. Our results thus highlight the multiplicity of possible actions of phytoestrogens, such as genistein. This suggests that the use of standardized endpoints to study the effect of a given compound, even when this compound has well known targets, may carry

  13. Dehydroepiandrosterone anti-atherogenesis effect is not via its conversion to estrogen

    Institute of Scientific and Technical Information of China (English)

    Heng-hui CHENG; Xiao-jing HU; Qiu-rong RUAN

    2009-01-01

    Aim: This study was conducted to demonstrate the anti-atherosclerotic effect of dehydroepiandrosterone (DHEA) and to investigate its possible mechanisms and whether this effect is related to its conversion to estrogen. Methods: Forty male New Zealand White rabbits aged 3 months were divided into 5 groups (n=8 per group) and fed dif-ferent diets for 10 weeks. Serum lipid levels, the area of atherosclerotic lesions and the mRNA levels of monocyte chemoat-tractant protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) in aortic lesions were measured. Then cultured vascular smooth muscle cells (VSMCs) stimulated by oxidized low density lipoprotein-cholesterol (ox-LDL) were treated by DHEA. The gene and protein expression levels of MCP-1 and VCAM-1 in VSMCs was detected. The plasmid with or with-out the gene of cytochrome P450 aromatase (CYP19) was transient transfected into cultured VSMCs respectively. Twenty hours later, the cells were stimulated with ox-LDL and DHEA. Results: DHEA could obviously decrease the area of atherosclerotic lesions and the expressions of MCP-1 and VCAM-1 in aortic lesions. But all-trans retinoic acid (atRA) which was reported would limit restenosis after balloon angioplasty had no visible synergistic effect with DHEA. DHEA could also reduce ox-LDL-induced MCP-1 and VCAM-1 expression in un-transfected or transfected VSMCs. Conclusion: The anti-atherosclerotic effect of DHEA had nothing to do with the catalysis of cytochrome P450 aromatase (CYP19), or was not related to its conversion to estrogen.

  14. Endocrine-disrupting effects and reproductive toxicity of low dose MCLR on male frogs (Rana nigromaculata) in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Jia, Xiuying; Cai, Chenchen; Wang, Jia; Gao, Nana; Zhang, Hangjun, E-mail: zhanghangjun@gmail.com

    2014-10-15

    Highlights: • Low-dose MCLR (1 μg/L) elicits a potential ecological effect on amphibian populations. • MCLR can induce abnormal sperm morphologies and activities on male frogs. • MCLR can induce a decrease in serum testosterone and an increase in serum estradiol of male frogs. • MCLR can increase SF-1 protein levels and decrease P450 aromatase levels in the gonads of frogs. - Abstract: Toxic cyanobacterial blooms are potential global threats to aquatic ecosystems and human health. The World Health Organization has set a provisional guideline limit of 1 μg/L microcystin-LR (MCLR) in freshwater. However, MCLR concentrations in several water bodies have exceeded this level. Despite this recommended human safety standard, MCLR-induced endocrine-disrupting effects and reproductive toxicity on male frog (Rana nigromaculata) were demonstrated in this study. Results showed that sperm motility and sperm count were significantly and negatively correlated with exposure time and concentration. By contrast, abnormal sperm rate was positively correlated with both parameters. Ultrastructural observation results revealed abnormal sperm morphologies, vacuoles in spermatogenic cells, cell dispersion, incomplete cell structures, and deformed nucleoli. These results indicated that MCLR could induce toxic effects on the reproductive system of frogs, significantly decrease testosterone content, and rapidly increase estradiol content. Prolonged exposure and increased concentration enhanced the relative expression levels of P450 aromatase and steroidogenic factor 1; thus, endocrine function in frogs was disrupted. This study is the first to demonstrate in vivo MCLR toxicity in the reproductive system of male R. nigromaculata. This study provided a scientific basis of the global decline in amphibian populations.

  15. Effects of letrozole on breast cancer micro-metastatic tumor growth in bone and lung in mice inoculated with murine 4T1 cells.

    Science.gov (United States)

    Wang, Wendan; Belosay, Aashvini; Yang, Xujuan; Hartman, James A; Song, Huaxin; Iwaniec, Urszula T; Turner, Russell T; Churchwell, Mona I; Doerge, Daniel R; Helferich, William G

    2016-06-01

    Breast cancer (BC) is the leading cancer in women worldwide. Metastasis occurs in stage IV BC with bone and lung being common metastatic sites. Here we evaluate the effects of the aromatase inhibitor letrozole on BC micro-metastatic tumor growth in bone and lung metastasis in intact and ovariectomized (OVX) mice with murine estrogen receptor negative (ER-) BC cells inoculated in tibia. Forty-eight BALB/c mice were randomly assigned to one of four groups: OVX, OVX + Letrozole, Intact, and Intact + Letrozole, and injected with 4T1 cells intra-tibially. Letrozole was subcutaneously injected daily for 23 days at a dose of 1.75 µg/g body weight. Tumor progression was monitored by bioluminescence imaging (BLI). Following necropsy, inoculated tibiae were scanned via µCT and bone response to tumor was scored from 0 (no ectopic mineralization/osteolysis) to 5 (extensive ectopic mineralization/osteolysis). OVX mice had higher tibial pathology scores indicative of more extensive bone destruction than intact mice, irrespective of letrozole treatment. Letrozole decreased serum estradiol levels and reduced lung surface tumor numbers in intact animals. Furthermore, mice receiving letrozole had significantly fewer tumor colonies and fewer proliferative cells in the lung than OVX and intact controls based on H&E and Ki-67 staining, respectively. In conclusion, BC-inoculated OVX animals had higher tibia pathology scores than BC-inoculated intact animals and letrozole reduced BC metastases to lungs. These findings suggest that, by lowering systemic estrogen level and/or by interacting with the host organ, the aromatase inhibitor letrozole has the potential to reduce ER- BC metastasis to lung. PMID:27209469

  16. Changes in ovarian function associated with circulating concentrations of estradiol before a GnRH-induced ovulation in beef cows.

    Science.gov (United States)

    Larimore, E L; Amundson, O L; Bridges, G A; McNeel, A K; Cushman, R A; Perry, G A

    2016-10-01

    These studies were conducted to evaluate causes for differences in circulating concentrations of estradiol before a GnRH-induced ovulation. Beef cows were synchronized by an injection of GnRH on day -7 and an injection of prostaglandin F2α (PGF2α) on day 0. In experiment 1, blood samples were collected every 3 h from PGF2α on day 0 to hour 33 after PGF2α and at slaughter (hour 36 to 42; n = 10). Cows were assigned to treatment group based on circulating concentrations of estradiol (E2): HighE2 vs LowE2. At slaughter, follicular fluid (FF) and granulosa cells were collected from the dominant follicle. In experiment 2, blood samples (n = 30) were collected every 8 h from PGF2α until the dominant follicle was aspirated via ultrasound-guided follicular aspiration to collect FF and granulosa cells (hour 38 to 46). In experiment 1, HighE2 had increased abundance of 3β-hydroxysteroid dehydrogenase, cytochrome P450 aromatase, and LHR (P ≤ 0.02), and greater concentrations of estradiol and androstenedione (P ≤ 0.02) in the FF. In experiment 2, HighE2 had increased abundance of CYP11A1, 3β-hydroxysteroid dehydrogenase, cytochrome P450 aromatase, and LHR (P ≤ 0.03) vs either LowE2 or GnRHLowE2. There was a tendency (P = 0.07) for LH pulse frequency to be increased in both the GnRHLowE2 and HighE2 compared with LowE2. HighE2 cows experienced increas in circulating concentrations of estradiol compared with LowE2. In conclusion, animals with greater concentrations of circulating estradiol before fixed-time AI experienced an upregulation of the steroidogenic pathway during the preovulatory period. PMID:27565233

  17. Effects of nonylphenol and ethinylestradiol on copper redhorse (Moxostoma hubbsi), an endangered species.

    Science.gov (United States)

    Maltais, Domynick; Roy, Robert L

    2014-10-01

    The copper redhorse, Moxostoma hubbsi, is an endangered species endemic to Quebec. The presence of contaminants, in particular endocrine disrupting chemicals (EDCs), in its habitat has been advanced as partly responsible for the reproductive difficulties encountered by the species. In the present study, immature copper redhorse were exposed to the estrogenic surfactant nonylphenol (NP; 1, 10 and 50µg/l) and the synthetic estrogen 17α-ethinylestradiol (EE2; 10ng/l) for 21 days in a flow-through system. The endpoints investigated included general health indicators (hepatosomatic index and hematocrit), thyroid hormones, sex steroids, brain aromatase activity, plasma and mucus vitellogenin (VTG), cytochrome P4501A protein expression and ethoxyresorufin-O-deethylase activity, heat shock protein 70 (HSP70) and muscle acetylcholinesterase. Exposure to 10ng EE2/l significantly increased brain aromatase activity. Exposure to 50µg NP/l resulted in a significant reduction of plasma testosterone concentrations and a significant induction of hepatic HSP70 protein expression. NP at 50µg/l also induced plasma and mucus VTG. The presence of elevated VTG levels in the surface mucus of immature copper redhorse exposed to NP, and its correlation to plasma VTG, supports the use of mucus VTG as a non-invasive biomarker to evaluate copper redhorse exposure to EDCs in the environment and contribute to restoration efforts of the species. The results of the present study indicate that exposure to high environmentally relevant concentrations of NP and EE2 can affect molecular endpoints related to reproduction in the copper redhorse. PMID:25063883

  18. Developmental alterations and endocrine-disruptive responses in farmed Nile crocodiles (Crocodylus niloticus) exposed to contaminants from the Crocodile River, South Africa.

    Science.gov (United States)

    Arukwe, Augustine; Myburgh, Jan; Langberg, Håkon A; Adeogun, Aina O; Braa, Idunn Godal; Moeder, Monika; Schlenk, Daniel; Crago, Jordan Paul; Regoli, Francesco; Botha, Christo

    2016-04-01

    In the present study, the developmental (including fertility) and endocrine-disruptive effects in relation to chemical burden in male and female Nile crocodiles (Crocodylus niloticus), from a commercial crocodile farm in the Brits district, South Africa, exposed to various anthropogenic aquatic contaminants from the natural environment was investigated. Hepatic transcript levels for vitellogenin (Vtg), zona pellucida (ZP) and ERα (also in gonads) were analyzed using real-time PCR. Plasma estradiol-17β (E2), testosterone (T) and 11-ketotestosterone (11-KT) were analyzed using enzyme immunoassay. Gonadal aromatase and hepatic testosterone metabolism (6β-hydroxylase (6β-OHase)) were analyzed using biochemical methods. Overall, there is high and abnormal number (%) of infertile and banded eggs during the studied reproductive seasons, showing up to 57 and 34% of infertile eggs in the 2009/2010 and 2013/2014 seasons, respectively. In addition, the percentage of banded eggs ranged between 10 and 19% during the period of 2009-2014 seasons. While hepatic ERα, Vtg, ZP mRNA and testosterone 6β-OHase, were equally expressed in female and male crocodiles, gonadal ERα mRNA and aromatase activity were significantly higher in females compared to male crocodiles. On the other hand, plasma T and 11-KT levels were significantly higher in males, compared to female crocodiles. Principal component analysis (PCA) produced significant grouping that revealed correlative relationships between reproductive/endocrine-disruptive variables and liver contaminant burden, that further relates to measured contaminants in the natural environment. The overall results suggest that these captive pre-slaughter farm crocodiles exhibited responses to anthropogenic aquatic contaminants with potentially relevant consequences on key reproductive and endocrine pathways and these responses may be established as relevant species endocrine disruptor biomarkers of exposure and effects in this threatened

  19. Effects of Letrozole Compared with Danazol on Patients with Confirmed Endometriosis: A Randomized Clinical Trial

    Directory of Open Access Journals (Sweden)

    Navid Koleini

    2010-01-01

    Full Text Available Background: Letrozole is an aromatase inhibitor which can decrease estrogen production inperipheral tissues and endometriosis. Danazol, as an androgen, inhibits estrogen production inovaries and recently has been introduced as an aromatase inhibitor. This study was designed tocompare the effects of Danazol with Letrozole on endometriosis symptom relief.Materials and Methods: This study was a randomized clinical trial in which 105 patients withconfirmed endometriosis were randomly assigned to one of three groups. Group 1 received Letrozoletablets (2.5 mg/day, calcium (1000 mg/day and vitamin D (800 IU/day. Group 2 received Danazoltablets (600 mg/day, calcium (1000 mg/day and vitamin D (800 IU/day. Group 3 (placebo groupwere assigned to take two calcium tablets daily (500 mg/tablet and vitamin D (800 IU/day. Pelvicpain, dysmenorrhea and dyspareunia were assessed in participants at baseline and monthly duringthe study for a total of six months. Data were analyzed via SPSS version 15 software with Freidmanand Wilcoxon tests.Results: Mean age in three groups has no significant difference. Of the 105 participants who wereenrolled in this study, 38 patients were assigned to group 1 (Letrozole group, 37 patients in group 2(Danazol group and 31 patients were placed in group 3 (placebo group. This study showed that themean scores for chronic pelvic pain, dysmenorrhea and dyspareunia for the Letrozole group wereless than the Danazol and placebo groups.Conclusion: This study showed that Letrozole can be more effective than Danazol for reducingchronic pelvic pain, dyspareunia and dysmenorrhea in patients suffering from recurrent endometriosis(Registeration Number: IRCT138812043414N1.

  20. Effects of tributyltin chloride(TBTCl) on seroid hormone and seroidogenic enzymes in Sprague-Dawley male rat

    Energy Technology Data Exchange (ETDEWEB)

    Kang, T.S.; Lee, S.J.; Shin, J.H.; Kim, T.S.; Moon, H.J.; Ki, H.Y.; Bae, H.; Han, S.Y. [Endocrine Toxicology Div., National Inst. of Toxicological Research, Korea FDA, Seoul (Korea); Dong, M.S. [Korea Univ., Seoul (Korea); Yoon, Y.D. [Hanyang Univ., Seoul (Korea)

    2004-09-15

    Tributyltin (TBT), organotin compound is used a wood preservative, a stabilizer of poly-vinyl chloride (PVC), a bactericide, a vermicide, and antifouling agent in maritime paint. TBTCl has been known to bioaccumulate through the food chain and induce imposex in female gastropods. Testosterone was synthesized from cholesterol in Leydig cell. In male rat testes, cholesterol in in the inner membrane of mitochondria is converted to prognenolone by cytochrome P450 side-chain cleavage (P450scc), and prognenolone is consequently converted to progesterone by 3{beta}-hydroxysteroid dehydrogenase (3{beta}a-HSD). Progesterone is converted to testosterone by cytochrome P450 17{alpha}-hydroxylase/C17-20 lyase (P450c17), and 17{beta}-hydroxysteroid dehydrogenase (17{beta}-HSD). Testosterone is converted to estradiol by P450 aromatase. Some studies have been reported that steroidogenic enzyme and steroid hormone were affected by TBT. In a two-generation study of tributyltin chloride, serum estradiol was decreased in F1 and F2 male rats. But serum concentration of testosterone and luteinizing hormone (LH) were not changed in F1 and F2 male rats. When pregnant rats were orally administrated by TBTCl, serum progesterone was decreased and serum estradiol was increased in female litters. Also litters were affected on development of reproductive organs and sexual of differentiation by TBTCl.3 Tributyltin increased serum progesterone in granulosa cells, but serum testosterone and estradiol were diminished.4 TBT has been known that it repressed P450 aromatase activity. In this study, we investigated effect of tributyltin chloride (TBTCl) on the mRNA expression of steroidogenic enzymes and steroid hormone in male rat.

  1. FACE: the barefaced facts of AI potency

    International Nuclear Information System (INIS)

    The use of third-generation aromatase inhibitors (AIs), such as anastrozole and letrozole, as initial adjuvant hormonal therapy in postmenopausal women (PMW) with hormone receptor-positive (HR+) breast cancer offers a significant benefit over tamoxifen for reducing recurrence risk. Clinical studies, including the Arimidex Tamoxifen Alone or in Combination (ATAC) and the Breast International Group (BIG) 1–98 trials, have proven that both anastrozole and letrozole are, respectively, superior to tamoxifen in improving disease-free survival. Although differing in design, objectives, and follow-up time, these trials offer some insight into the comparative clinical efficacy of these two nonsteroidal AIs. In particular, results from BIG 1–98 show that letrozole significantly reduces early distant metastatic (DM) events, which constitute the majority of early recurrence events. Subsequently, there is a beneficial overall survival effect emerging in the trial, whereas survival is unchanged with anastrozole after 100 months of follow-up in ATAC. Significant differences in the potency of these two drugs, vis-à-vis their degree of aromatase inhibition, have been observed in comparative trials and show that letrozole causes a more complete suppression of estrogen levels than does anastrozole. Whether this difference in potency is relevant to reductions in DM events during adjuvant therapy remains unclear. The Femara Anastrozole Clinical Evaluation trial is addressing this issue in a more unequivocal manner by comparing initial adjuvant treatment with anastrozole or letrozole in a population of breast cancer patients at high risk of recurrence: PMW with HR+ disease and axillary lymph node involvement

  2. Atrazine reduces reproduction in Japanese medaka (Oryzias latipes)

    Science.gov (United States)

    Papoulias, Diana M.; Tillitt, Donald E.; Talyknia, Melaniya G.; Whyte, Jeffrey J.; Richter, Catherine A.

    2014-01-01

    Atrazine is an effective broadleaf herbicide and the second most heavily used herbicide in the United States. Effects along the hypothalamus–pituitary–gonad axis in a number of vertebrate taxa have been demonstrated. Seasonally elevated concentrations of atrazine in surface waters may adversely affect fishes, but only a few studies have examined reproductive effects of this chemical. The present study was designed to evaluate a population endpoint (egg production) in conjunction with histological (reproductive stage, gonad pathology) and biochemical (aromatase activity, sex hormone production) phenotypes associated with atrazine exposure in Japanese medaka. Adult virgin breeding groups of one male and four females were exposed to nominal concentrations of 0, 0.5, 5.0, and 50 μg/L (0, 2.3, 23.2, 231 nM) of atrazine in a flow-through diluter for 14 or 38 days. Total egg production was lower (36–42%) in all atrazine-exposed groups as compared to the controls. The decreases in cumulative egg production of atrazine-treated fish were significant by exposure day 24. Reductions in total egg production in atrazine treatment groups were most attributable to a reduced number of eggs ovulated by females in atrazine-treated tanks. Additionally, males exposed to atrazine had a greater number of abnormal germ cells. There was no effect of atrazine on gonadosomatic index, aromatase protein, or whole body 17 β-estradiol or testosterone. Our results suggest that atrazine reduces egg production through alteration of final maturation of oocytes. The reduced egg production observed in this study was very similar to our previously reported results for fathead minnow. This study provides further information with which to evaluate atrazine's risk to fish populations.

  3. Characteristic features of ghrelin cells in the gastrointestinal tract and the regulation of stomach ghrelin expression and production

    Institute of Scientific and Technical Information of China (English)

    Zheng Zhao; Takafumi Sakai

    2008-01-01

    Ghrelin was isolated as an endogenous ligand for the GH secretagogue receptor from the rat stomach. Although physiological effects of ghrelin have been revealed by numerous studies, the regulation of stomach ghrelin remains obscure, and the factor that directly regulates ghrelin expression and production has not been identified. Here, we show some data regarding the characteristic features of ghrelin cells and the regulation of stomach ghrelin. In the gastrointestinal tract, ghrelin cells were identified as opened- and closed-type cells, and it was found that the number of ghrelin cells decreased from the stomach to the colon. The postnatal change in number of ghrelin cells in the stomach showed a sexually dimorphic pattern, indicating a role of estrogen in the regulation of stomach ghrelin. In vitro studies revealed that estrogen stimulated both ghrelin expression and production and that treatment with formestane, an aromatase (estrogen synthetase) inhibitor, decreased ghrelin expression level. On the other hand, leptin was found to inhibit both basal and estrogen-stimulated ghrelin expression. Moreover, both aromatase mRNA-expressing cells and leptin cells were found to be located close to ghrelin cells in the gastric mucosa. Furthermore, we found an inverse relationship between gastric ghrelin and leptin levels in a fasting state, and we revealed relative changes in expression of gastric ghrelin, estrogen and leptin in the postnatal rats. We propose that gastric estrogen and leptin directly regulate stomach ghrelin and that the balance control through gastric estrogen and leptin contributes to the altered ghrelin expression level in some physiological states.

  4. In vitro and in vivo models for the evaluation of new inhibitors of human steroid sulfatase, devoid of residual estrogenic activity.

    Science.gov (United States)

    Shields-Botella, J; Bonnet, P; Duc, I; Duranti, E; Meschi, S; Cardinali, S; Prouheze, P; Chaigneau, A M; Duranti, V; Gribaudo, S; Rivière, A; Mengual, L; Carniato, D; Cecchet, L; Lafay, J; Rondot, B; Sandri, J; Pascal, J C; Delansorne, R

    2003-02-01

    The goal of our research project is to develop a new class of orally active drugs, estrone sulfatase inhibitors, for the treatment of estrogen-dependent (receptor positive) breast cancer. Several compounds were synthesized and their pharmacological potencies explored. Based on encouraging preliminary results, three of them, TX 1299, TX 1492 and TX 1506 were further studied in vitro as well as in vivo. They proved to be strong inhibitors of estrone sulfatase when measured on the whole human JEG-3 choriocarcinoma and MCF-7 breast cancer cells and their IC(50)s found to be in the range of known standard inhibitors. Their residual estrogenic activity was checked as negative in the test of induction of alkaline phosphatase (APase) activity in whole human endometrial adenocarcinoma Ishikawa cells. In addition, their effect on aromatase activity in JEG-3 cells was also examined, since the goal of inhibiting both sulfatase and aromatase activities appears very attractive. However, it has been unsuccessful so far. Then, in vivo potencies of TX 1299, the lead compound in our chemical series, were evaluated in comparison with 6,6,7-COUMATE, a non-steroidal standard, in two different rat models and by oral route. First, the absence of any residual estrogenic activity for these compounds was checked in the uterotrophic model in prepubescent female rats. Second, antiuterotrophic activity in adult ovariectomized rat supplemented with estrone sulfate (E(1)S), showed that both compounds were potent inhibitors, the power of TX 1299 relative to 6,6,7-COUMATE being around 80%. This assay was combined with uterine sulfatase level determination and confirmed the complete inhibition of this enzyme within the target organ. Preliminary studies indicated that other non-steroid compounds in the Théramex series were potent in vitro and in vivo inhibitors of estrone sulfatase in rats and further studies are in progress.

  5. Short term hypothyroidism affects ovarian function in the cycling rat

    Directory of Open Access Journals (Sweden)

    Gamarra-Luques Carlos

    2010-02-01

    Full Text Available Abstract Background Rats made hypothyroid with propilthyouracil start showing abnormal cycling on the second cycle after the start of the treatment, with a high proportion of spontaneous pseudopregnancies and reduced fertility. Methods To investigate some of the mechanisms involved in these reproductive abnormalities, hypothyroidism was induced in virgin rats by propilthyouracil (0.1 g/L in the drinking water and we determined circulating hormones by radioimmunoassay and whole ovary expression of ovarian hormone receptors, growth factors and steroidogenic enzymes using semi-quantitative RT-PCR. The study was performed on days 6 to 9 of treatment, corresponding to diestrus I (at 20.00-22.00 h, diestrus II (at 20.00-22.00 h, proestrus and estrus (both at 8.00-10.00 h and 20.00-22.00 h of the second estrous cycle after beginning propilthyouracil treatment. Another group of rats was mated on day 8 and the treatment continued through the entire pregnancy to evaluate reproductive performance. Results Hypothyroidism increased circulating prolactin and estradiol on estrus 5 to 7-fold and 1.2 to 1.4-fold respectively. Growth hormone and insulin-like growth factor 1 diminished 60 and 20% respectively on proestrus morning. Hypothyroidism doubled the ovarian mRNA contents of estrogen receptor-beta on proestrus and estrus evenings, cyp19A1 aromatase mRNA on estrus evening and of growth hormone receptor on proestrus evening. Hypothyroidism did not influence ovulation rate or the number of corpora lutea at term, but a diminished number of implantation sites and pups per litter were observed (Hypothyroid: 11.7 +/- 0.8 vs. Control: 13.9 +/- 0.7. Conclusions Short term hypothyroidism alters normal hormone profile in the cycling rat increasing the expression of estrogen receptor-beta and cyp19A1 aromatase on estrus, which in turn may stimulate estradiol and prolactin secretion, favouring corpus luteum survival and the subsequent instauration of pseudopregnancy.

  6. Use of mTOR inhibitors in the treatment of breast cancer: an evaluation of factors that influence patient outcomes

    Directory of Open Access Journals (Sweden)

    Jerusalem G

    2014-04-01

    Full Text Available Guy Jerusalem, Andree Rorive, Joelle Collignon Medical Oncology, CHU Sart Tilman Liege, Domaine Universitaire du Sart Tilman, Liege, Belgium Abstract: Many systemic treatment options are available for advanced breast cancer, including endocrine therapy, chemotherapy, anti-human epidermal growth factor receptor 2 (HER2 therapy, and other targeted agents. Recently, everolimus, a mammalian target of rapamycin (mTOR inhibitor, combined with exemestane, an aromatase inhibitor, has been approved in Europe and the USA for patients suffering from estrogen receptor-positive, HER2-negative advanced breast cancer previously treated by a nonsteroidal aromatase inhibitor, based on the results of BOLERO-2 (Breast cancer trials of OraL EveROlimus. This study showed a statistically significant and clinically meaningful improvement in median progression-free survival. Results concerning the impact on overall survival are expected in the near future. This clinically oriented review focuses on the use of mTOR inhibitors in breast cancer. Results reported with first-generation mTOR inhibitors (ridaforolimus, temsirolimus, everolimus are discussed. The current and potential role of mTOR inhibitors is reported according to breast cancer subtype (estrogen receptor-positive HER2-negative, triple-negative, and HER2-positive ER-positive/negative disease. Everolimus is currently being evaluated in the adjuvant setting in high-risk estrogen receptor-positive, HER2-negative early breast cancer. Continuing mTOR inhibition or alternatively administering other drugs targeting the phosphatidylinositol-3-kinase/protein kinase B-mTOR pathway after progression on treatments including an mTOR inhibitor is under evaluation. Potential biomarkers to select patients showing a more pronounced benefit are reviewed, but we are not currently using these biomarkers in routine practice. Subgroup analysis of BOLERO 2 has shown that the benefit is consistent in all subgroups and that it is

  7. 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.

  8. Male breast cancer is not congruent with the female disease.

    Science.gov (United States)

    Fentiman, Ian S

    2016-05-01

    It has become customary to extrapolate from the results of treatment trials for female breastcancer and apply them to males with the disease. In the absence of results from national and international randomised trials for male breast cancer (MBC) this appears superficially to be an appropriate response. Closer examination of available data reveals that aspects of the aetiology and treatment of MBC do not fit the simplistic model that men usually have endocrine sensitive tumours which behave like those in postmenopausal women. Most females and males with breast cancer have none of the recognised risk factors, indicating the gaps in our knowledge of the epidemiology of this disease. Several studies have compared epidemiological risk factors for MBC and female breast cancer (FBC) but many have been blighted by small numbers. In comparison with FBC there is a larger proportion of BRCA2 tumours, (occurring in 10% of MBC), and underrepresentation of BRCA1 tumours (found in only 1%), suggesting significant differences in the genetic aetiology of MBC and FBC. Genome-wide association studies in FBC reported single nucleotide polymorphisms (SNPs) in 12 novel independent loci were consistently associated with disease but for MBC 2 SNPs had a significantly increased risk. Molecular profiles of matched cancers in males and females showed a gender-associated modulation of major processes including energy metabolism, regulation of translation, matrix remodelling and immune recruitment. Immunohistochemistry for kinase inhibitor proteins (KIPs) p27Kip1 and p21Waf1 indicate a significant difference in the immunostaining of tumours from male patients compared with females. MBC is almost always estrogen receptor positive (ER+ve) and so systemic treatment is usually endocrine. With evidence in FBC that aromatase inhibitors are more effective than tamoxifen in the postmenopausal it was seemingly logical that the same would be true for MBC. Results however suggest less efficacy with AIs

  9. Estrogen Receptor β Activation Rapidly Modulates Male Sexual Motivation through the Transactivation of Metabotropic Glutamate Receptor 1a.

    Science.gov (United States)

    Seredynski, Aurore L; Balthazart, Jacques; Ball, Gregory F; Cornil, Charlotte A

    2015-09-23

    In addition to the transcriptional activity of their liganded nuclear receptors, estrogens, such as estradiol (E2), modulate cell functions, and consequently physiology and behavior, within minutes through membrane-initiated events. The membrane-associated receptors (mERs) underlying the acute effects of estrogens on behavior have mostly been documented in females where active estrogens are thought to be of ovarian origin. We determined here, by acute intracerebroventricular injections of specific agonists and antagonists, the type(s) of mERs that modulate rapid effects of brain-derived estrogens on sexual motivation in male Japanese quail. Brain aromatase blockade acutely inhibited sexual motivation. Diarylpropionitrile (DPN), an estrogen receptor β (ERβ)-specific agonist, and to a lesser extent 17α-estradiol, possibly acting through ER-X, prevented this effect. In contrast, drugs targeting ERα (PPT and MPP), GPR30 (G1 and G15), and the Gq-mER (STX) did not affect sexual motivation. The mGluR1a antagonist LY367385 significantly inhibited sexual motivation but mGluR2/3 and mGluR5 antagonists were ineffective. LY367385 also blocked the behavioral restoration induced by E2 or DPN, providing functional evidence that ERβ interacts with metabotropic glutamate receptor 1a (mGluR1a) signaling to acutely regulate male sexual motivation. Together these results show that ERβ plays a key role in sexual behavior regulation and the recently uncovered cooperation between mERs and mGluRs is functional in males where it mediates the acute effects of estrogens produced centrally in response to social stimuli. The presence of an ER-mGluR interaction in birds suggests that this mechanism emerged relatively early in vertebrate history and is well conserved. Significance statement: The membrane-associated receptors underlying the acute effects of estrogens on behavior have mostly been documented in females, where active estrogens are thought to be of ovarian origin. Using acute

  10. Male breast cancer is not congruent with the female disease.

    Science.gov (United States)

    Fentiman, Ian S

    2016-05-01

    It has become customary to extrapolate from the results of treatment trials for female breastcancer and apply them to males with the disease. In the absence of results from national and international randomised trials for male breast cancer (MBC) this appears superficially to be an appropriate response. Closer examination of available data reveals that aspects of the aetiology and treatment of MBC do not fit the simplistic model that men usually have endocrine sensitive tumours which behave like those in postmenopausal women. Most females and males with breast cancer have none of the recognised risk factors, indicating the gaps in our knowledge of the epidemiology of this disease. Several studies have compared epidemiological risk factors for MBC and female breast cancer (FBC) but many have been blighted by small numbers. In comparison with FBC there is a larger proportion of BRCA2 tumours, (occurring in 10% of MBC), and underrepresentation of BRCA1 tumours (found in only 1%), suggesting significant differences in the genetic aetiology of MBC and FBC. Genome-wide association studies in FBC reported single nucleotide polymorphisms (SNPs) in 12 novel independent loci were consistently associated with disease but for MBC 2 SNPs had a significantly increased risk. Molecular profiles of matched cancers in males and females showed a gender-associated modulation of major processes including energy metabolism, regulation of translation, matrix remodelling and immune recruitment. Immunohistochemistry for kinase inhibitor proteins (KIPs) p27Kip1 and p21Waf1 indicate a significant difference in the immunostaining of tumours from male patients compared with females. MBC is almost always estrogen receptor positive (ER+ve) and so systemic treatment is usually endocrine. With evidence in FBC that aromatase inhibitors are more effective than tamoxifen in the postmenopausal it was seemingly logical that the same would be true for MBC. Results however suggest less efficacy with AIs

  11. The role of androgen receptor in proliferation and relative molecules expression of breast cancer cell%雄激素受体对乳腺癌细胞增殖及相关分子表达作用的研究进展∗

    Institute of Scientific and Technical Information of China (English)

    朱蔼瑜; 管晓翔

    2014-01-01

    Breast cancer is known as a hormone⁃responsive cancer. Apart from estrogen,androgen also plays a critical role in the occurrence and development of breast cancer. The binding of androgen to androgen receptor( AR) leads to the activation of AR, which interacts with molecules in the nuclear, resulting in up⁃regulation or down⁃regulation of target proteins. AR is associated with the expression of ERs, aromatase, human epidermal growth factor receptor⁃2(HER⁃2), progesterone receptor(PR) and E⁃cadherin. The resistant mechanisms of aromatase inhibitions(AIs) and selective estrogen receptor modulators(SERMs) Tamoxifen are also relevant with AR. Further investigation of AR signaling makes it possible to be an effective therapeutic target for breast cancer.%乳腺癌是激素依赖性肿瘤。除雌激素外,雄激素在乳腺癌的发生发展中也发挥重要作用。雄激素受体( AR)经雄激素作用激活,通过不同方式调控雌激素受体( ER)及芳香化酶的表达,影响人表皮生长因子受体⁃2( HER⁃2)、孕激素受体( PR)、E⁃钙黏蛋白的转录,对乳腺癌细胞的增殖既有抑制也有促进作用。 AR还与雌激素受体调节剂( SERMs)他莫昔芬及芳香化酶抑制剂( AIs)的耐药机制有关。深入研究AR调控乳腺癌分子表达的机制有助于将AR作为治疗靶点,提高乳腺癌内分泌治疗的疗效。

  12. Fertility preservation options in breast cancer patients.

    Science.gov (United States)

    Kasum, Miro; von Wolff, Michael; Franulić, Daniela; Čehić, Ermin; Klepac-Pulanić, Tajana; Orešković, Slavko; Juras, Josip

    2015-01-01

    The purpose of this review is to analyse current options for fertility preservation in young women with breast cancer (BC). Considering an increasing number of BC survivors, owing to improvements in cancer treatment and delaying of childbearing, fertility preservation appears to be an important issue. Current fertility preservation options in BC survivors range from well-established standard techniques to experimental or investigational interventions. Among the standard options, random-start ovarian stimulation protocol represents a new technique, which significantly decreases the total time of the in vitro fertilisation cycle. However, in patients with oestrogen-sensitive tumours, stimulation protocols using aromatase inhibitors are currently preferred over tamoxifen regimens. Cryopreservation of embryos and oocytes are nowadays deemed the most successful techniques for fertility preservation in BC patients. GnRH agonists during chemotherapy represent an experimental method for fertility preservation due to conflicting long-term outcome results regarding its safety and efficacy. Cryopreservation of ovarian tissue, in vitro maturation of immature oocytes and other strategies are considered experimental and should only be offered within the context of a clinical trial. An early pretreatment referral to reproductive endocrinologists and oncologists should be suggested to young BC women at risk of infertility, concerning the risks and benefits of fertility preservation options.

  13. Effective treatment protocol for poor ovarian response: A systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Yadava Bapurao Jeve

    2016-01-01

    Full Text Available Poor ovarian response represents an increasingly common problem. This systematic review was aimed to identify the most effective treatment protocol for poor response. We searched MEDLINE, EMBASE, and The Cochrane Library from 1980 to October 2015. Study quality assessment and meta-analyses were performed according to the Cochrane recommendations. We found 61 trials including 4997 cycles employing 10 management strategies. Most common strategy was the use of gonadotropin-releasing hormone antagonist (GnRHant, and was compared with GnRH agonist protocol (17 trials; n = 1696 for pituitary down-regulation which showed no significant difference in the outcome. Luteinizing hormone supplementation (eight trials, n = 847 showed no difference in the outcome. Growth hormone supplementation (seven trials; n = 251 showed significant improvement in clinical pregnancy rate (CPR and live birth rate (LBR with an odds ratio (OR of 2.13 (95% CI 1.06–4.28 and 2.96 (95% CI 1.17–7.52. Testosterone supplementation (three trials; n = 225 significantly improved CPR (OR 2.4; 95% CI 1.16–5.04 and LBR (OR 2.18; 95% CI 1.01–4.68. Aromatase inhibitors (four trials; n = 223 and dehydroepiandrosterone supplementation (two trials; n = 57 had no effect on outcome.

  14. Evaluation of Changes in Tumor Shadows and Microcalcifications on Mammography Following KORTUC II, a New Radiosensitization Treatment without any Surgical Procedure for Elderly Patients with Stage I and II Breast Cancer

    Science.gov (United States)

    Tsuzuki, Akira; Ogawa, Yasuhiro; Kubota, Kei; Tokuhiro, Shiho; Akima, Ryo; Yaogawa, Shin; Itoh, Kenji; Yamada, Yoko; Sasaki, Toshikazu; Onogawa, Masahide; Yamanishi, Tomoaki; Kariya, Shinji; Nogami, Munenobu; Nishioka, Akihito; Miyamura, Mitsuhiko

    2011-01-01

    We introduced non-surgical therapy with a novel enzyme-targeting radiosensitization treatment, Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas, Type II (KORTUC II) into early stages breast cancer treatment. The purpose of this study was to examine changes in tumor shadows and microcalcifications on mammography (MMG) following KORTUC II for elderly patients with breast cancer. We also sought to determine whether MMG was useful in evaluating the therapeutic effect of KORTUC II. In addition to MMG, positron emission tomography-computed tomography (PET-CT) was performed to detect both metastasis and local recurrence. In all 10 patients, tumor shadows on MMG completely disappeared in several months following the KORTUC II treatment. The concomitant microcalcifications also disappeared or markedly decreased in number. Disappearance of the tumors was also confirmed by the profile curve of tumor density on MMG following KORTUC II treatment; density fell and eventually approached that of the peripheral mammary tissue. These 10 patients have so far have also shown neither local recurrence nor distant metastasis on PET-CT with a mean follow-up period of approximately 27 months at the end of September, 2010. We conclude that breast-conservation treatment using KORTUC II, followed by aromatase inhibitor, is a promising therapeutic method for elderly patients with breast cancer, in terms of avoiding any surgical procedure. Moreover, MMG is considered to be useful for evaluating the efficacy of KORTUC II. PMID:24212965

  15. Evaluation of Changes in Tumor Shadows and Microcalcifications on Mammography Following KORTUC II, a New Radiosensitization Treatment without any Surgical Procedure for Elderly Patients with Stage I and II Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Tsuzuki, Akira; Ogawa, Yasuhiro, E-mail: ogaway@kochi-u.ac.jp; Kubota, Kei; Tokuhiro, Shiho; Akima, Ryo; Yaogawa, Shin; Itoh, Kenji; Yamada, Yoko; Sasaki, Toshikazu [Department of Diagnostic Radiology & Radiation Oncology, Medical school, Kochi University Nankoku, Kochi 783-8505 (Japan); Onogawa, Masahide [Department of Pharmacy, Medical School, Kochi University, Nankoku, Kochi 783-8505 (Japan); Yamanishi, Tomoaki; Kariya, Shinji; Nogami, Munenobu; Nishioka, Akihito [Department of Diagnostic Radiology & Radiation Oncology, Medical school, Kochi University Nankoku, Kochi 783-8505 (Japan); Miyamura, Mitsuhiko [Department of Pharmacy, Medical School, Kochi University, Nankoku, Kochi 783-8505 (Japan)

    2011-09-09

    We introduced non-surgical therapy with a novel enzyme-targeting radiosensitization treatment, Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas, Type II (KORTUC II) into early stages breast cancer treatment. The purpose of this study was to examine changes in tumor shadows and microcalcifications on mammography (MMG) following KORTUC II for elderly patients with breast cancer. We also sought to determine whether MMG was useful in evaluating the therapeutic effect of KORTUC II. In addition to MMG, positron emission tomography-computed tomography (PET-CT) was performed to detect both metastasis and local recurrence. In all 10 patients, tumor shadows on MMG completely disappeared in several months following the KORTUC II treatment. The concomitant microcalcifications also disappeared or markedly decreased in number. Disappearance of the tumors was also confirmed by the profile curve of tumor density on MMG following KORTUC II treatment; density fell and eventually approached that of the peripheral mammary tissue. These 10 patients have so far have also shown neither local recurrence nor distant metastasis on PET-CT with a mean follow-up period of approximately 27 months at the end of September, 2010. We conclude that breast-conservation treatment using KORTUC II, followed by aromatase inhibitor, is a promising therapeutic method for elderly patients with breast cancer, in terms of avoiding any surgical procedure. Moreover, MMG is considered to be useful for evaluating the efficacy of KORTUC II.

  16. Evaluation of Changes in Tumor Shadows and Microcalcifications on Mammography Following KORTUC II, a New Radiosensitization Treatment without any Surgical Procedure for Elderly Patients with Stage I and II Breast Cancer

    Directory of Open Access Journals (Sweden)

    Akihito Nishioka

    2011-09-01

    Full Text Available We introduced non-surgical therapy with a novel enzyme-targeting radiosensitization treatment, Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas, Type II (KORTUC II into early stages breast cancer treatment. The purpose of this study was to examine changes in tumor shadows and microcalcifications on mammography (MMG following KORTUC II for elderly patients with breast cancer. We also sought to determine whether MMG was useful in evaluating the therapeutic effect of KORTUC II. In addition to MMG, positron emission tomography-computed tomography (PET-CT was performed to detect both metastasis and local recurrence. In all 10 patients, tumor shadows on MMG completely disappeared in several months following the KORTUC II treatment. The concomitant microcalcifications also disappeared or markedly decreased in number. Disappearance of the tumors was also confirmed by the profile curve of tumor density on MMG following KORTUC II treatment; density fell and eventually approached that of the peripheral mammary tissue. These 10 patients have so far have also shown neither local recurrence nor distant metastasis on PET-CT with a mean follow-up period of approximately 27 months at the end of September, 2010. We conclude that breast-conservation treatment using KORTUC II, followed by aromatase inhibitor, is a promising therapeutic method for elderly patients with breast cancer, in terms of avoiding any surgical procedure. Moreover, MMG is considered to be useful for evaluating the efficacy of KORTUC II.

  17. Dietary withdrawal of phytoestrogens resulted in higher gene expression of 3-beta-HSD and ARO but lower 5-alpha-R-1 in male rats.

    Science.gov (United States)

    Andreoli, María F; Stoker, Cora; Rossetti, María F; Lazzarino, Gisela P; Luque, Enrique H; Ramos, Jorge G

    2016-09-01

    Removing dietary phytoestrogens causes obesity and diabetes in adult male rats. Based on the facts that hypothalamic food intake control is disrupted in phytoestrogen-deprived animals and that several steroids affect food intake, we hypothesized that phytoestrogen withdrawal alters the expression of hypothalamic steroidogenic enzymes. Male Wistar rats fed with a high-phytoestrogen diet from conception to adulthood were subjected to phytoestrogen withdrawal by feeding them a low-phytoestrogen diet or a high-phytoestrogen, high-fat diet. Withdrawal of dietary phytoestrogens increased 3β-hydroxysteroid dehydrogenase and P450 aromatase gene expression and decreased those of 5α-reductase-1. This is a direct effect of the lack of dietary phytoestrogens and not a consequence of obesity, as it was not observed in high-fat-fed rats. Phytoestrogen withdrawal and high-fat diet intake reduced hypothalamic expression of estrogen receptor (ER)α correlated with low levels of ERα-O, ERα-OS, and ERα-OT transcripts. Variations in gene expression of steroidogenic enzymes may affect the content of neurosteroids. As neurosteroids are related to food intake control, the changes observed may be a novel mechanism in the regulation of energy balance in obese phytoestrogen-deprived animals. In rats, steroidogenesis and ER signaling appear to be altered by phytoestrogen withdrawal in the rat. The ubiquity of phytoestrogens in the diet and changing intakes or withdrawal suggest that aspects of human health could be affected based on the rat and warrant further research. PMID:27632921

  18. Immunohistochemical evaluation of leiomyoma tissue and normal myometrium in patients with uter-ine leiomyoma during hypo- and hyperestrogenic conditions caused by of use of gonadotropin-releasing hormone ana-logues

    Directory of Open Access Journals (Sweden)

    Medvedev M.V.

    2012-01-01

    Full Text Available In study immunohistochemical an alysis of markers of proliferation, apoptosis, extracellular ma trix degradation, angiogenesis and steroid hormone receptors in myomatous tissue and myometrium was conducted in 62 patients with uterine leiomyomas during long-term and short-term correction of hormonal status by gosere line acetate. Studies have shown that pseudocapsule of fibroids at immunohistochemical level is unchanged myometrium. For le iomyoma tissue compared to myometrium were characteristic greater expression of steroid hormone receptors and aromatase, inhibition of apoptosis, greater expression of angiogenic factors compared to unchanged myometrium. Under the action of GnRH-a direct and medi-ated by reduction of estradiol occurred molecular changes, which cover almost all parts of th e pathogenesis of fibroids and include inhibition of expression of estrogen receptor and aromat ase synthesis, enhancing of e xpression of progesterone recep-tors, inhibition of proliferation and angi ogenesis, accelerated degradation of ECM. Under the influence of hyperestrogeny caused by flare-up effect of GnRH-a and direct peripheral effect of GnRH analogs progression of uterine leiomyoma pro-vides increased sensitivity of uterine myocyt es to ischemia. Despite the obvious role of antiapoptotic factor bcl-2 in the pathogenesis of uterine fibroids, short- and long-term hormonal treatment with GnRH-a does not lead to significant changes in its expression.

  19. Recovery of spermatogenesis following testosterone replacement therapy or anabolic-androgenic steroid use.

    Science.gov (United States)

    McBride, J Abram; Coward, Robert M

    2016-01-01

    The use of testosterone replacement therapy (TRT) for hypogonadism continues to rise, particularly in younger men who may wish to remain fertile. Concurrently, awareness of a more pervasive use of anabolic-androgenic steroids (AAS) within the general population has been appreciated. Both TRT and AAS can suppress the hypothalamic-pituitary-gonadal (HPG) axis resulting in diminution of spermatogenesis. Therefore, it is important that clinicians recognize previous TRT or AAS use in patients presenting for infertility treatment. Cessation of TRT or AAS use may result in spontaneous recovery of normal spermatogenesis in a reasonable number of patients if allowed sufficient time for recovery. However, some patients may not recover normal spermatogenesis or tolerate waiting for spontaneous recovery. In such cases, clinicians must be aware of the pathophysiologic derangements of the HPG axis related to TRT or AAS use and the pharmacologic agents available to reverse them. The available agents include injectable gonadotropins, selective estrogen receptor modulators, and aromatase inhibitors, but their off-label use is poorly described in the literature, potentially creating a knowledge gap for the clinician. Reviewing their use clinically for the treatment of hypogonadotropic hypogonadism and other HPG axis abnormalities can familiarize the clinician with the manner in which they can be used to recover spermatogenesis after TRT or AAS use. PMID:26908067

  20. [Treatment of adenomyosis (excluding pregnancy project)].

    Science.gov (United States)

    Pelage, L; Fenomanana, S; Brun, J-L; Levaillant, J-M; Fernandez, H

    2015-05-01

    In this review we aimed to update the possibilities of adenomyosis treatment in women excluding those with a desire for pregnancy. Adenomyosis is defined as the presence of endometrial tissue within the myometrium and frequently underestimated. Over the last decades, its pathophysiology has been better known. The diagnosis is essentially based on clinical symptoms like menorrhagia and dysmenorrhea. Transvaginal ultrasound and magnetic resonance imaging are the main tools of the radiologic diagnosis. However, the definitive diagnosis is histological. The most effective treatment remains hysterectomy; however it is expensive, radical and at risk of morbidity compared with medical or surgical conservative management. The literature has reported several series of patients undergoing various treatments, thus allowing different therapeutic options. The levonorgestrel-releasing intrauterine device showed its efficacy alone or in combination with hysteroscopic treatment. Oral progestins, GnRH agonists are useful at short term or in preoperative condition. Some conservative treatments like focused ultrasound therapies or uterus-sparing operative treatment stay under evaluation and seems to be effective. Embolization has been the subject of several studies and must be outlined. Furthermore, several molecules, such as modulators of progesterone receptors and the aromatase inhibitors have been recently studied and are perhaps future treatments. PMID:25899118

  1. 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.

  2. 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.

  3. Estrogen deficiency leads to telomerase inhibition,telomere shortening and reduced cell proliferation in the adrenal gland of mice

    Institute of Scientific and Technical Information of China (English)

    Sharyn Bayne; Margaret EE Jones; He Li; Alex R Pinto; Evan R Simpson; Jun-Ping Liu

    2008-01-01

    Estrogen deficiency mediates aging, but the underlying mechanism remains to be fully determined. We report here that estrogen deficiency caused by targeted disruption of aromatase in mice results in significant inhibition oftelomerase activity in the adrenal gland in vivo. Gene expression analysis showed that, in the absence of estrogen, telomerase reverse transcriptase (TERT) gene expression is reduced in association with compromised cell proliferation in the adrenal gland cortex and adrenal atrophy. Stem cells positive in c-kit are identified to populate in the parenchyma of adrenal cortex. Analysis of telomeres revealed that estrogen deficiency results in significantly shorter telomeres in the adrenal cortex than that in wild-type (WT) control mice. To further establish the causal effects of estrogen, we conducted an estrogen replacement therapy in these estrogen-deficient animals. Administration of estrogen for 3 weeks restores TERT gene expression, telomerase activity and cell proliferation in estrogen-deficient mice. Thus, our data show for the first time that estrogen deficiency causes inhibitions of TERT gene expression, telomerase activity, telomere maintenance, and cell proliferation in the adrenal gland of mice in vivo, suggesting that telomerase inhibition and telomere shortening may mediate cell proliferation arrest in the adrenal gland, thus contributing to estrogen deficiency-induced aging under physiological conditions.

  4. Isolation and characterization of new phenolic compounds with estrogen biosynthesis-inhibiting and antioxidation activities from Broussonetia papyrifera leaves.

    Directory of Open Access Journals (Sweden)

    Chunyan Yang

    Full Text Available Broussonetia papyrifera leaves (BPL as a traditional Chinese medicine are also used in livestock feed for stimulating reproduction, adipose tissue and muscle development; however, the mechanism of their action is still unknown. Through estrogen biosynthesis-guided fractionation in human ovarian granulosa-like KGN cells, five new phenolic glycosides, broussoside A-E(1-5, along with fifteen known dietary phenolic compounds, were isolated from the n-butanol extract of BPL, and their structures were elucidated on the basis of NMR spectra analysis and chemical evidence. New compounds 3, 4, 5 and the known compounds 9 and 10 were found to potently inhibit estrogen biosynthesis in KGN cells. In addition, compounds 9, 17, 18, and 20 showed strong antioxidant activity against ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid diammonium salt and DPPH (1, 1'-diphenyl -2-picryl-hydrazyl radical assays. These findings suggest that BPL may improve meat quality through the regulation of estrogen biosynthesis. Furthermore, they may be useful for the discovery of potential aromatase modulators from natural products. Finally, they could be considered as a new source for natural antioxidants.

  5. Isolation and characterization of new phenolic compounds with estrogen biosynthesis-inhibiting and antioxidation activities from Broussonetia papyrifera leaves.

    Science.gov (United States)

    Yang, Chunyan; Li, Fu; Du, Baowen; Chen, Bin; Wang, Fei; Wang, Mingkui

    2014-01-01

    Broussonetia papyrifera leaves (BPL) as a traditional Chinese medicine are also used in livestock feed for stimulating reproduction, adipose tissue and muscle development; however, the mechanism of their action is still unknown. Through estrogen biosynthesis-guided fractionation in human ovarian granulosa-like KGN cells, five new phenolic glycosides, broussoside A-E(1-5), along with fifteen known dietary phenolic compounds, were isolated from the n-butanol extract of BPL, and their structures were elucidated on the basis of NMR spectra analysis and chemical evidence. New compounds 3, 4, 5 and the known compounds 9 and 10 were found to potently inhibit estrogen biosynthesis in KGN cells. In addition, compounds 9, 17, 18, and 20 showed strong antioxidant activity against ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt) and DPPH (1, 1'-diphenyl -2-picryl-hydrazyl radical) assays. These findings suggest that BPL may improve meat quality through the regulation of estrogen biosynthesis. Furthermore, they may be useful for the discovery of potential aromatase modulators from natural products. Finally, they could be considered as a new source for natural antioxidants.

  6. Bisphenol A and ovarian steroidogenesis.

    Science.gov (United States)

    Bloom, Michael S; Mok-Lin, Evelyn; Fujimoto, Victor Y

    2016-09-15

    Bisphenol A is widely used as a component in polycarbonate plastics for food and beverage packaging, epoxy linings for canned foods, and dental sealants, among other applications. Experimental literature demonstrates BPA's affinity for estrogen receptors and downstream effects on estrogen-responsive genes. Additional data suggest that BPA reduces endogenous estrogen synthesis, likely by antagonizing ovarian enzyme activities involved in sex-steroid hormone synthesis. More specifically, evidence indicates BPA-mediated disruption of STAR, CYP450scc, and HSD-3β in theca cells and CYP450 aromatase activity in granulosa cells. Yet the results of the few human studies reported to date are equivocal. It also remains in question the extent to which BPA penetrates developing ovarian follicles. Uncertainty as to the relevance of experimental BPA doses and administration routes for common human exposure levels limits extrapolation of experimental results. To more definitively address the potential risk of BPA on human ovarian steroidogenesis, additional experimental studies using biologically active BPA doses likely to reflect those within the ovarian follicle will be necessary, as will additional prospective investigations in human populations with the use of standardized assay methodology. PMID:27543890

  7. Estrogenic Effects of Several BPA Analogs in the Developing Zebrafish Brain.

    Science.gov (United States)

    Cano-Nicolau, Joel; Vaillant, Colette; Pellegrini, Elisabeth; Charlier, Thierry D; Kah, Olivier; Coumailleau, Pascal

    2016-01-01

    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- 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. PMID:27047331

  8. Pharmacotherapy of polycystic ovary syndrome--an update.

    Science.gov (United States)

    Saha, Lekha; Kaur, Sharonjeet; Saha, Pradip Kumar

    2012-02-01

    Polycystic ovary syndrome (PCOS) is a persisting challenge to clinical and basic research scientists as none of the presently available medications have been fully able to combat these consequences. The aim of the present review is to summarize the different lines of treatment available for the different symptomologies that women with PCOS presents. In this comprehensive review, search was made for various treatment options available for PCOS by using Cochrane library, Pubmed, Medline, in addition to the relevant printed medical journals and periodicals. The search results revealed that oral contraceptives containing oestrogen and progesterone regularize the menstruation, antiandrogens like spironolactone and drosperinone have proven to be effective in hirsutism and acne, clomiphene is the gold standard for ovulation induction, but multiple pregnancies and clomiphene failure add to its limitation. Hence, aromatase inhibitors like letrozole, low-dose gondotropins, and ovarian drilling procedure have shown to be beneficial effect in clomiphene-resistant cases. Insulin sensitizers such as metformin, thiazolidinediones, and d-chiro-inositol increase insulin sensitivity and improve ovulation rate. Recently, melatonin, N-acetyl cysteine, acarbose, and statins have shown positive results in different symptomologies of PCOS. The results show that PCOS treatment constitutes varied line of treatment depending upon the clinical features with which a woman is presenting. Still, unfortunately, none of the treatments are fully able to combat the PCOS. PMID:21210850

  9. Celebrating 75 years of oestradiol.

    Science.gov (United States)

    Simpson, Evan; Santen, Richard J

    2015-12-01

    Oestrogens exert important effects on the reproductive as well as many other organ systems in both men and women. The history of the discovery of oestrogens, the mechanisms of their synthesis, and their therapeutic applications are very important components of the fabric of endocrinology. These aspects provide the rationale for highlighting several key components of this story. Two investigators, Edward Doisy and Alfred Butenandt, purified and crystalized oestrone nearly simultaneously in 1929, and Doisy later discovered oestriol and oestradiol. Butenandt won the Nobel Prize for this work and Doisy's had to await his purification of vitamin K. Early investigators quickly recognized that oestrogens must be synthesized from androgens and later investigators called this process aromatization. The aromatase enzyme was then characterized, its mechanism determined, and its structure identified after successful crystallization. With the development of knock-out methodology, the precise effects of oestrogen in males and females were defined and clinical syndromes of deficiency and excess described. Their discovery ultimately led to the development of oral contraceptives, treatment of menopausal symptoms, therapies for breast cancer, and induction of fertility, among others. The history of the use of oestrogens for postmenopausal women to relieve symptoms has been characterized by cyclic periods of enthusiasm and concern. The individuals involved in these studies, the innovative thinking required, and the detailed understanding made possible by evolving biologic and molecular techniques provide many lessons for current endocrinologists. PMID:26438567

  10. The advantage of letrozole over tamoxifen in the BIG 1-98 trial is consistent in younger postmenopausal women and in those with chemotherapy-induced menopause

    DEFF Research Database (Denmark)

    Chirgwin, Jacquie; Sun, Zhuoxin; Smith, Ian;

    2012-01-01

    Letrozole, an aromatase inhibitor, is ineffective in the presence of ovarian estrogen production. Two subpopulations of apparently postmenopausal women might derive reduced benefit from letrozole due to residual or returning ovarian activity: younger women (who have the potential for residual sub...... chemotherapy and patients with chemotherapy-induced menopause parallel the letrozole benefit seen in the BIG 1-98 population as a whole. These data support the use of letrozole even in such patients.......) in the BIG 1-98 trial we identified two relevant subpopulations: patients with potential residual ovarian function, defined as having natural menopause, treated without adjuvant or neoadjuvant chemotherapy and age ≤ 55 years (n = 641); and those with chemotherapy-induced menopause (n = 105). Neither...... with chemotherapy-induced menopause (HR 0.51 [0.19, 1.39]), the disease-free survival (DFS) point estimate favoring letrozole was marginally more beneficial than in the trial as a whole (HR 0.84 [0.74, 0.95]). Contrary to our initial concern, DFS results for young postmenopausal patients who did not receive...

  11. Efficacy of UV-C photolysis of bisphenol A on transcriptome alterations of genes in zebrafish embryos.

    Science.gov (United States)

    Saeed, Asma; Hashmi, Imran; Zare, Ava; Mehrabani-Zeinabad, Mitra; Achari, Gopal; Habibi, Hamid R

    2016-09-18

    The purpose of this study was to investigate the efficacy of UV-C direct photolysis of bisphenol A (BPA) as a remediation method of BPA contamination. We used zebrafish embryos as a model organism to test the toxicity and residual biological activity by measuring cytochrome P4501A1 (CYP1A), aromatase B (Aro B) and heat shock proteins (HSP-70) transcript levels. The mRNA levels of CYP1A gene increased about two fold while exposure of zebrafish embryos at 72 hpf resulted in significant induction (P = 0.048) of Aro B at 100 µg/L of BPA. Exposure of zebrafish embryos at 72 hpf to increasing concentrations of BPA resulted in significant induction (P = 0.0031) of HSP-70 transcript level. UV treatment of BPA resulted in a significant reduction in toxicity by reducing mortality of zebrafish embryos. The results suggest that UV-C direct photolysis may be an effective method for remediation of BPA contamination. Further studies will be necessary for better understanding of the identity and relative activity of the UV degradation by-products. PMID:27314163

  12. Significant survival improvement of patients with recurrent breast cancer in the periods 2001-2008 vs. 1992-2000

    Directory of Open Access Journals (Sweden)

    Nishimura Sumiko

    2011-03-01

    Full Text Available Abstract Background It is unclear whether individualized treatments based on biological factors have improved the prognosis of recurrent breast cancer. The purpose of this study is to evaluate the survival improvement of patients with recurrent breast cancer after the introduction of third generation aromatase inhibitors (AIs and trastuzumab. Methods A total of 407 patients who received first diagnosis of recurrent breast cancer and treatment at National Kyushu Cancer Center between 1992 and 2008 were retrospectively evaluated. As AIs and trastuzumab were approved for clinical use in Japan in 2001, the patients were divided into two time cohorts depending on whether the cancer recurred before or after 2001. Cohort A: 170 patients who were diagnosed between 1992 and 2000. Cohort B: 237 patients who were diagnosed between 2001 and 2008. Tumor characteristics, treatments, and outcome were compared. Results Fourteen percent of cohort A and 76% of cohort B received AIs and/or trastuzumab (P Conclusions The prognosis of patients with recurrent breast cancer was improved over time following the introduction of AIs and trastuzumab and the survival improvement was apparent in HR- and/or HER-2-positive tumors.

  13. Breast cancer. National Center for Radiation Therapy. Trinidad and Tobago

    International Nuclear Information System (INIS)

    Was performed a retrospective study of cases registered at the Center National Radiotherapy of Trinidad and Tobago, with histologically or cytological breast cancer in the period from January 1 to July 31, 2007. It 125 cases studied. The aim of this study was to determine the characteristics of breast cancer in these patients, the different treatments used in order to improve prevention, treatment regimens, quality of life and increase survival rates of women suffering from this disease. The risk of cancer increases with age in the age group of 50-59 years was the highest incidence of the disease, an important group of patients suffer disease after 70 years. 64% of the cases were diagnosed in stage 0-II, carcinoma in situ was diagnosed in 4% of the patients, 52.8% of cases had positive lymph nodes. Surgery and chemotherapy were treatments used, the surgery was done in 92.8% of patients, being the the most common radical surgery, chemotherapy was used in 76% of cases, doxorubicin, cyclophosphamide and taxol were the most used drugs. The hormone receptors were positive in 65% of cases and Her 2 negative in 82.02%, the third generation aromatase inhibitors were hormones most used. Our results were compared with other studies. (Author)

  14. Endometrioza w wieku przed- i okołomenopauzalnym – jak leczyć?

    Directory of Open Access Journals (Sweden)

    Robert Z. Spaczyński

    2011-08-01

    Full Text Available Endometriosis, i.e. extragonadal localization of endometrial stroma and glands is predominantly found inreproductive age women, however it is also diagnosed in teenagers and postmenopausal women. Prevalenceof postmenopausal endometriosis is 2-5% of all endometriosis cases, with majority found in patients usingestrogen replacement therapy (ERT. Etiopathogenesis of endometriosis after menopause is related toextragonadal aromatase activity (androstendione to estradiol conversion. The aim of endometriosis therapyis to relief pain. This effect can be achieved either through pharmacological or surgical treatment. Majorityof endometriosis medications relies on reduction of estradiol production. Combined hormonal contraceptivedrugs (oral, transdermal, transvaginal and gestagens constitute first-line pharmacological therapy. Second-lineconsists of GnRH analogs, intrauterine system releasing levonorgestrel, danazol, and gestrinone. Progressivelymore and more experimental treatments are applied in postmenopausal endometriosis, just to name aromataseinhibitors suppressing local estrogen production. Surgical therapy may be also considered as first-line approach.Depending on the history of illness, pain intensity, and patient expectations surgery can cover wide spectrumfrom local excision of endometriosis through interruption of neural pathways (presacral neurectomy finishingwith total hysterectomy with or without bilateral salpingoophoorectomy.

  15. Association study of the oestrogen signalling pathway genes in relation to age at natural menopause

    Indian Academy of Sciences (India)

    Li-Na He; Dong-Hai Xiong; Yong-Jun Liu; Feng Zhang; Robert R. Recker; Hong-Wen Deng

    2007-12-01

    Genetic factors play a significant role in influencing the variation of age at natural menopause (AANM). Estrogen receptor (ESR2), is an important factor in the mechanism of action of estrogen, while the aromatase gene (CYP19) and the 17-alpha-hydroxylase gene (CYP17) are involved in the biosynthesis of estrogen. We tested whether polymorphisms of ESR2, CYP19 and CYP17 genes are associated with AANM in Caucasian females. A total of 52 SNPs (17 for ESR2, 28 for CYP19, and 7 for CYP17) were successfully genotyped for 229 Caucasian women having experienced natural menopause. Comprehensive statistical analyses focusing on the association of these genes with AANM were conducted. The effects of age, height and age at menarche on AANM were adjusted when conducting association analyses. We found that six SNPs (2, 6-7, 9, 13 and 16) within ESR2 were not significantly associated with AANM after Bonferroni correction. However, two blocks of ESR2 were associated with AANM. For CYP19, two SNPs (24 and 27) were nominally associated with AANM. No significant association was observed between CYP17 and AANM. Our results suggest that genetic variation in the ESR2 and CYP19 genes may influence the variation in AANM in Caucasian women.

  16. Mugilid fish are sentinels of exposure to endocrine disrupting compounds in coastal and estuarine environments.

    Science.gov (United States)

    Ortiz-Zarragoitia, Maren; Bizarro, Cristina; Rojo-Bartolomé, Iratxe; de Cerio, Oihane Diaz; Cajaraville, Miren P; Cancio, Ibon

    2014-09-01

    Effects on fish reproduction can result from a variety of toxicity mechanisms first operating at the molecular level. Notably, the presence in the environment of some compounds termed endocrine disrupting chemicals (EDCs) can cause adverse effects on reproduction by interfering with the endocrine system. In some cases, exposure to EDCs leads to the animal feminization and male fish may develop oocytes in testis (intersex condition). Mugilid fish are well suited sentinel organisms to study the effects of reproductive EDCs in the monitoring of estuarine/marine environments. Up-regulation of aromatases and vitellogenins in males and juveniles and the presence of intersex individuals have been described in a wide array of mullet species worldwide. There is a need to develop new molecular markers to identify early feminization responses and intersex condition in fish populations, studying mechanisms that regulate gonad differentiation under exposure to xenoestrogens. Interestingly, an electrophoresis of gonad RNA, shows a strong expression of 5S rRNA in oocytes, indicating the potential of 5S rRNA and its regulating proteins to become useful molecular makers of oocyte presence in testis. Therefore, the use of these oocyte markers to sex and identify intersex mullets could constitute powerful molecular biomarkers to assess xenoestrogenicity in field conditions. PMID:25222666

  17. 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 refi ned 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 defi ciency 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 fi eld of sex steroid actions in male bone homeostasis.

  18. Androgens and estrogens in skeletal sexual dimorphism

    Directory of Open Access Journals (Sweden)

    Michaël Laurent

    2014-04-01

    Full Text Available 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 refi ned 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 defi ciency 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 fi eld of sex steroid actions in male bone homeostasis.

  19. Protective Effects of Testosterone on Presynaptic Terminals against Oligomeric β-Amyloid Peptide in Primary Culture of Hippocampal Neurons

    Directory of Open Access Journals (Sweden)

    Chi-Fai Lau

    2014-01-01

    Full Text Available Increasing lines of evidence support that testosterone may have neuroprotective effects. While observational studies reported an association between higher bioavailable testosterone or brain testosterone levels and reduced risk of Alzheimer’s disease (AD, there is limited understanding of the underlying neuroprotective mechanisms. Previous studies demonstrated that testosterone could alleviate neurotoxicity induced by β-amyloid (Aβ, but these findings mainly focused on neuronal apoptosis. Since synaptic dysfunction and degeneration are early events during the pathogenesis of AD, we aim to investigate the effects of testosterone on oligomeric Aβ-induced synaptic changes. Our data suggested that exposure of primary cultured hippocampal neurons to oligomeric Aβ could reduce the length of neurites and decrease the expression of presynaptic proteins including synaptophysin, synaptotagmin, and synapsin-1. Aβ also disrupted synaptic vesicle recycling and protein folding machinery. Testosterone preserved the integrity of neurites and the expression of presynaptic proteins. It also attenuated Aβ-induced impairment of synaptic exocytosis. By using letrozole as an aromatase antagonist, we further demonstrated that the effects of testosterone on exocytosis were unlikely to be mediated through the estrogen receptor pathway. Furthermore, we showed that testosterone could attenuate Aβ-induced reduction of HSP70, which suggests a novel mechanism that links testosterone and its protective function on Aβ-induced synaptic damage. Taken together, our data provide further evidence on the beneficial effects of testosterone, which may be useful for future drug development for AD.

  20. Should We Offer Medication to Reduce Breast Cancer Risk?: Grand Rounds Discussion From Beth Israel Deaconess Medical Center.

    Science.gov (United States)

    Burns, Risa B; Schonberg, Mara A; Tung, Nadine M; Libman, Howard

    2016-08-01

    In November 2013, the U.S. Preventive Services Task Force issued a guideline on medications for risk reduction of primary breast cancer in women. Although mammography can detect early cases, it cannot prevent development of breast cancer. Tamoxifen and raloxifene are selective estrogen receptor modulators that have been shown to reduce the risk for estrogen receptor-positive breast cancer and are approved by the U.S. Food and Drug Administration (FDA) for this indication. However, neither medication reduces the risk for estrogen receptor-negative breast cancer or all-cause mortality. The Task Force concluded that postmenopausal women with an estimated 5-year risk for breast cancer of 3% or greater will probably have more net benefit than harm and recommends that clinicians engage in shared, informed decision making about these medications. The American Society of Clinical Oncology issued a practice guideline on use of pharmacologic interventions for breast cancer in 2013. It recommends that women aged 35 years or older at increased risk, defined as a 5-year absolute risk for breast cancer of 1.66% or greater, discuss breast cancer prevention medications with their primary care practitioner. The Society includes the aromatase inhibitor exemestane in addition to tamoxifen and raloxifene as a breast cancer prevention medication, although exemestane is not FDA approved for this indication. Here, an oncologist and an internist discuss how they would balance these recommendations and what they would suggest for an individual patient. PMID:27479221

  1. Glyphosate and its formulations – Toxicity, occupational and environmental exposure

    Directory of Open Access Journals (Sweden)

    Marta Kwiatkowska

    2013-10-01

    Full Text Available Glyphosate (N-(phosphonomethylglycine is an active ingredient of the most widely used herbicide formulations in protecting agricultural and horticultural crops. Numerous results (mostly published in the years 2010-2013 concerning the action of glyphosate and its formulations in the recent decade were analyzed. Initial reports about alleged biodegradability of glyphosate in the environment turned out to be wrong. It has been shown that glyphosate remains in the soil and can reach people by spreading along with groundwater. Recent publications have shown that glyphosate is detected at low concentrations in the human blood. Publications cited in this article, which indicate a possible induction of neoplastic changes by glyphosate formulation, have raised great concern and controversy in the scientific world. Presenting adverse effects of glyphosate and its formulations we focused on the role of glyphosate formulations in hormonal disorders by impeding the expression of steroidogenic acute regulatory protein and the inhibition of aromatase activity. The impact of glyphosate on oxygen reactive species formation, changes in redox system and the effect on necrosis and apoptosis in various types of cells was shown. We also revealed that glyphosate as a phosphonate herbicide does not inhibit directly the activity of acetylcholinesterase. Based on numerous studies it was noted that commercial formulations of glyphosate exhibit higher toxicity than that of the active substance itself. The discussed problems clearly show the need to evaluate the toxicity of glyphosate and its formulations and related potential threat to humans. Med Pr 2013;64(5:717–729

  2. The role of AMH in the pathophysiology of polycystic ovarian syndrome.

    Science.gov (United States)

    Garg, Deepika; Tal, Reshef

    2016-07-01

    Polycystic ovarian syndrome (PCOS) affects 5 - 10% of reproductive age women, but its pathogenesis is still poorly understood. The aim of this review is to collate evidence and summarize our current knowledge of the role of anti-Müllerian hormone (AMH) in PCOS pathogenesis. AMH is increased and correlated with the various reproductive and metabolic/endocrine alterations in PCOS. AMH plays an inhibitory role in follicular development and recruitment, contributing to follicular arrest. AMH inhibitory action on FSH-induced aromatase production likely contributes to hyperandrogenism in PCOS, which further enhances insulin resistance in these women. Elevated serum AMH concentrations are predictive of poor response to various treatments of PCOS including weight loss, ovulation induction and laparoscopic ovarian drilling, while improvement in various clinical parameters following treatment is associated with serum AMH decline, further supporting an important role for AMH in the pathophysiology of this syndrome. This review emphasizes the need for understanding the exact mechanism of action of AMH in the pathophysiology of PCOS. This may lead to the development of new treatment modalities targeting AMH to treat PCOS, as well as help clinicians in prognostication and better tailoring existing treatments for this disease. PMID:27174394

  3. Association between Polycystic Ovary Syndrome and Gut Microbiota

    Science.gov (United States)

    Guo, Yanjie; Qi, Yane; Yang, Xuefei; Zhao, Lihui; Wen, Shu; Liu, Yinhui; Tang, Li

    2016-01-01

    Polycystic ovary syndrome (PCOS) is the most frequent endocrinopathy in women of reproductive age. It is difficult to treat PCOS because of its complex etiology and pathogenesis. Here, we characterized the roles of gut microbiota on the pathogenesis and treatments in letrozole (a nonsteroidal aromatase inhibitor) induced PCOS rat model. Changes in estrous cycles, hormonal levels, ovarian morphology and gut microbiota by PCR-DGGE and real-time PCR were determined. The results showed that PCOS rats displayed abnormal estrous cycles with increasing androgen biosynthesis and exhibited multiple large cysts with diminished granulosa layers in ovarian tissues. Meanwhile, the composition of gut microbiota in letrozole-treated rats was different from that in the controls. Lactobacillus, Ruminococcus and Clostridium were lower while Prevotella was higher in PCOS rats when compared with control rats. After treating PCOS rats with Lactobacillus and fecal microbiota transplantation (FMT) from healthy rats, it was found that the estrous cycles were improved in all 8 rats in FMT group, and in 6 of the 8 rats in Lactobacillus transplantation group with decreasing androgen biosynthesis. Their ovarian morphologies normalized. The composition of gut microbiota restored in both FMT and Lactobacillus treated groups with increasing of Lactobacillus and Clostridium, and decreasing of Prevotella. These results indicated that dysbiosis of gut microbiota was associated with the pathogenesis of PCOS. Microbiota interventions through FMT and Lactobacillus transplantation were beneficial for the treatments of PCOS rats. PMID:27093642

  4. [Natural remedies and hormone preparations--potential risk for breast cancer patients. A study surveys the use of agents which possibly counteract with the treatment].

    Science.gov (United States)

    Malekzadeh, Farnaz; Rose, Carsten; Ingvar, Christian; Jernström, Helena

    We have studied the use of complimentary alternative medicine (CAM) among 233 consecutive breast cancer patients operated on at the Lund University Hospital, Sweden between 2002 and 2004. Questionnaires were administered preoperatively (n = 233), and again 3-6 months post-operatively (n = 167) and one year after surgery (n = 88). At baseline, 14,5% used CAM, 3-6 months post-operatively 14,4% used CAM and one year after surgery 18,2% used CAM. The most common products contained omega-3, garlic, ginseng and roseroot. We identified use of 35 different types of CAM products and seven of these could potentially increase the risk of breast cancer or interact with tamoxifen or aromatase inhibitors: soy, garlic, ginko biloba, echinacea, ginseng, valerian and phytoestrogens (excluding soy). Five and a half percent of the patients used either hormone replacement therapy (HRT) or hormonal contraception at the pre-operative visit, after they had received their breast cancer diagnosis. In conclusion, it is important that doctors discuss the use of CAM and exogenous hormone therapy with their breast cancer patients given the prevalence of these drugs. PMID:16329453

  5. Impact of the Processes of Total Testicular Regression and Recrudescence on the Epididymal Physiology of the Bat Myotis nigricans (Chiroptera: Vespertilionidae.

    Directory of Open Access Journals (Sweden)

    Mateus R Beguelini

    Full Text Available Myotis nigricans is a species of vespertilionid bat, whose males show two periods of total testicular regression within the same annual reproductive cycle in the northwest São Paulo State, Brazil. Studies have demonstrated that its epididymis has an elongation of the caudal portion, which stores spermatozoa during the period of testicular regression in July, but that they had no sperm during the regression in November. Thus, the aim of this study was to analyze the impact of the total testicular regression in the epididymal morphophysiology and patterns of its hormonal regulation. The results demonstrate a continuous activity of the epididymis from the Active to the Regressing periods; a morphofunctional regression of the epididymis in the Regressed period; and a slow recrudescence process. Thus, we concluded that the processes of total testicular regression and posterior recrudescence suffered by M. nigricans also impact the physiology of the epididymis, but with a delay in epididymal response. Epididymal physiology is regulated by testosterone and estrogen, through the production and secretion of testosterone by the testes, its conduction to the epididymis (mainly through luminal fluid, conversion of testosterone to dihydrotestosterone by the 5α-reductase enzyme (mainly in epithelial cells and to estrogen by aromatase; and through the activation/deactivation of the androgen receptor and estrogen receptor α in epithelial cells, which regulate the epithelial cell morphophysiology, prevents cell death and regulates their protein expression and secretion, which ensures the maturation and storage of the spermatozoa.

  6. Altered transcription levels of endocrine associated genes in two fisheries species collected from the Great Barrier Reef catchment and lagoon.

    Science.gov (United States)

    Kroon, Frederieke J; Hook, Sharon E; Jones, Dean; Metcalfe, Suzanne; Henderson, Brent; Smith, Rachael; Warne, Michael St J; Turner, Ryan D; McKeown, Adam; Westcott, David A

    2015-03-01

    The Great Barrier Reef (GBR) is chronically exposed to agricultural run-off containing pesticides, many of which are known endocrine disrupting chemicals (EDCs). Here, we measure mRNA transcript abundance of two EDC biomarkers in wild populations of barramundi (Lates calcarifer) and coral trout (Plectropomus leopardus and Plectropomus maculatus). Transcription levels of liver vitellogenin (vtg) differed significantly in both species amongst sites with different exposures to agricultural run-off; brain aromatase (cyp19a1b) revealed some differences for barramundi only. Exposure to run-off from sugarcane that contains pesticides is a likely pathway given (i) significant associations between barramundi vtg transcription levels, catchment sugarcane land use, and river pesticide concentrations, and (ii) consistency between patterns of coral trout vtg transcription levels and pesticide distribution in the GBR lagoon. Given the potential consequences of such exposure for reproductive fitness and population dynamics, these results are cause for concern for the sustainability of fisheries resources downstream from agricultural land uses.

  7. Progress of research on drug-resistance mechanisms of endocrine therapy in breast cancer%乳腺癌内分泌治疗耐药机制研究进展

    Institute of Scientific and Technical Information of China (English)

    徐迎春; 林玉梅; 张凤春

    2006-01-01

    内分泌治疗(ednocrine therapy,ET)是乳腺癌综合治疗中的重要措施之一,选择性雌激素受体调节剂(selective estrogen receptor modulators,SERMs)、第三代芳香化酶抑制剂(aromatase inhibitors,AIs)和氟维司群是重要的内分泌治疗药物.但目前内分泌疗法面临的最大难题是原、继发耐药,其确切机制尚不清楚,近年来的研究发现,多种因素与耐药相关,如ER信号传导途径中的共激活与共抑制因子的比例,HER-2生长因子受体的高表达,各生长因子和激酶的串话调节,雌激素受体基因关键氨基酸位点的突变和多态、芳香化酶基因的突变与多态以及他莫昔芬(tamoxifen,TAM)代谢异常等.

  8. SERMs和AIs对绝经后乳腺癌患者子宫内膜的影响

    Institute of Scientific and Technical Information of China (English)

    王梅丽; 袁海英; 汪芬华

    2012-01-01

    目的 观察选择性雌激素受体调节剂(selective estrogen receptor modulators,SERMs)和芳香化酶抑制剂(aromatase inhibitors,AIs)两类药物对绝经后乳腺癌患者子宫内膜的影响.方法 采用阴道B型超声监测50例绝经后乳腺癌患者在服药0、3、6、12月时子宫内膜的变化.结果 SERMs组服药3月后子宫内膜厚度大于AIs组(P<0.05),服药6月和12月时较对照组明显增加(P<0.01).AIs组服药3月和6月时子宫内膜厚度明显小于对照组(P<0.01).结论 SERMs促进绝经后子宫内膜增生,AIs对绝经后子宫内膜增生有抑制作用;长期服用他莫昔酚需要定期监测子宫内膜.

  9. Tamoxifen-induced acute pancreatitis – a case report

    Directory of Open Access Journals (Sweden)

    Rafał Czyżykowski

    2014-03-01

    Full Text Available Tamoxifen is a selective estrogen receptor modulator used for the treatment of oestrogen/progesterone receptor positive breast cancer. It has antagonistic or agonistic activity depending on the tissue location. Generally it causes mild and reversible side effects, however more serious ones including cardiovascular and thromboembolic adverse events, uterine cancer or acute pancreatitis can also occur. Tamoxifen, like oestrogens, increases the plasma level of TG and liver secretion of VLDL. Moreover, it inhibits the key enzymes of triglyceride metabolism. In this report we present a case of a 55-year-old woman with a history of a poorly controlled hypertriglyceridaemia diagnosed with breast cancer. She was treated with surgery and adjuvant chemotherapy, radiotherapy and hormonotherapy with tamoxifen. About three months after hormonal treatment, her triglyceride level increased. Five months later she developed an acute necrotic pancreatitis that required hospitalization. Her serum samples on admission were highly lipemic. An abdominal ultrasound showed no evidence of gallstones or dilation of the bile ducts. There was no history of alcohol abuse or abdominal trauma. Tamoxifen was suspected as a trigger factor for pancreatitis. After the drug withdrawal and administration of the conservative management the patient’s medical condition improved. Due to a postmenopausal status of the patient and no harmful effect on serum lipids, an adjuvant hormonotherapy with aromatase inhibitor was started.

  10. Endogenous 17ß-estradiol is required for activity-dependent long-term potentiation in the striatum: interaction with the dopaminergic system

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    Alessandro eTozzi

    2015-05-01

    Full Text Available 17β-estradiol (E2, a neurosteroid synthesized by P450-aromatase (ARO, modulates various brain functions. We characterized the role of the locally synthesized E2 on striatal long-term synaptic plasticity and explored possible interactions between E2 receptors (ERs and dopamine (DA receptors in the dorsal striatum of adult male rats. Inhibition of E2 synthesis or antagonism of ERs prevented the induction of long-term potentiation (LTP in both medium spiny neurons (MSNs and cholinergic interneurons (ChIs. Activation of a D1-like DA receptor/cAMP/PKA-dependent pathway restored LTP. In MSNs exogenous E2 reversed the effect of ARO inhibition. Also antagonism of M1 muscarinic receptors prevented the D1-like receptor-mediated restoration of LTP confirming a role for ChIs in controlling the E2-mediated LTP of MSNs. A novel striatal interaction, occurring between ERs and D1-like receptors in both MSNs and ChIs, might be critical to regulate basal ganglia physiology and to compensate synaptic alterations in Parkinson's disease.

  11. [Modification of endocrine function of trophoblasts by thyroid hormone].

    Science.gov (United States)

    Matsuo, H; Maruo, T; Hayashi, M; Mochizuki, M

    1991-11-01

    Direct effects of L-triiodothyronine(T3) on placental endocrine function were investigated in vitro with an organ culture system for human placental tissues. Explants of trophoblastic tissues obtained from early and term placentas were cultured with or without graded doses of T3 in a serum-free condition. The addition of an optimal concentration of T3(10(-3) M T3) stimulated daily secretion of progesterone and estradiol from cultured early placental tissues by acting at the level of 3 beta-hydroxysteroid dehydrogenase and aromatase enzyme activity, together with the enhancement of hCG(alpha, beta) and hPL secretion. The addition of higher or lower concentrations of T3 gave attenuated effects and the addition of an excessive concentration of T3(10(-3) M T3) resulted in remarkable inhibition of progesterone and estradiol secretion by cultured early placental tissues. These results suggest that the optimal concentration of thyroid hormone acts as a biological amplifier of endocrine function of cultured trophoblasts obtained from early placentas. Unlike the early placental tissues, cultured term placental tissues did not respond to the addition of graded doses of T3 with increased endocrine function. Thus, the frequent occurrence of spontaneous abortion in early pregnancy during the state of hypothyroidism or hyperthyroidism may represent a direct consequence of inadequate thyroid hormone availability at the level of the trophoblast, followed by diminished endocrine function of early placental trophoblasts. PMID:1940550

  12. Isolation and biological activities of neomyrrhaol and other terpenes from the resin of Commiphora myrrha.

    Science.gov (United States)

    Su, Shu-Lan; Duan, Jin-Ao; Tang, Yu-Ping; Zhang, Xu; Yu, Li; Jiang, Feng-Rong; Zhou, Wei; Luo, Dan; Ding, An-Wei

    2009-03-01

    A new cycloartane-type triterpene named cycloartane-1alpha,2alpha,3beta,25-tetraol (neomyrrhaol) (1), along with four known terpenes, sandaracopimaric acid (2), abietic acid (3), 2-methoxy-5-acetoxyfruranogermacr-1(10)-en-6-one (4), and dehydroabietic acid (5) have been isolated from the resin of COMMIPHORA MYRRHA. Their structures were elucidated by means of 1D, 2 D NMR and HR-mass spectroscopy. Compounds 2-5 are known compounds but not previously isolated from the resin of C. MYRRHA. Compounds 4 and 5 exhibited significant aromatase inhibiting activity with IC50 values at 0.2 microM and 0.3 microM, respectively. As shown in the MTT assay, 2, 3, 4, and 5 had inhibitory effects on HUVEC growth with IC50 values of 0.122 microM (2), 0.125 microM (3), 0.069 microM (5). Compounds 1-5 did not inhibit contraction of the isolated uterine and did not protect HUVEC from damage induced by H2O2 at the tested concentration.

  13. Methoxychlor reduces estradiol levels by altering steroidogenesis and metabolism in mouse antral follicles in vitro.

    Science.gov (United States)

    Basavarajappa, Mallikarjuna S; Craig, Zelieann R; Hernández-Ochoa, Isabel; Paulose, Tessie; Leslie, Traci C; Flaws, Jodi A

    2011-06-15

    The organochlorine pesticide methoxychlor (MXC) is a known endocrine disruptor that affects adult rodent females by causing reduced fertility, persistent estrus, and ovarian atrophy. Since MXC is also known to target antral follicles, the major producer of sex steroids in the ovary, the present study was designed to test the hypothesis that MXC decreases estradiol (E₂) levels by altering steroidogenic and metabolic enzymes in the antral follicles. To test this hypothesis, antral follicles were isolated from CD-1 mouse ovaries and cultured with either dimethylsulfoxide (DMSO) or MXC. Follicle growth was measured every 24 h for 96 h. In addition, sex steroid hormone levels were measured using enzyme-linked immunosorbent assays (ELISA) and mRNA expression levels of steroidogenic enzymes as well as the E₂ metabolic enzyme Cyp1b1 were measured using qPCR. The results indicate that MXC decreased E₂, testosterone, androstenedione, and progesterone (P₄) levels compared to DMSO. In addition, MXC decreased expression of aromatase (Cyp19a1), 17β-hydroxysteroid dehydrogenase 1 (Hsd17b1), 17α-hydroxylase/17,20-lyase (Cyp17a1), 3β hydroxysteroid dehydrogenase 1 (Hsd3b1), cholesterol side-chain cleavage (Cyp11a1), steroid acute regulatory protein (Star), and increased expression of Cyp1b1 enzyme levels. Thus, these data suggest that MXC decreases steroidogenic enzyme levels, increases metabolic enzyme expression and this in turn leads to decreased sex steroid hormone levels.

  14. A computational model to predict rat ovarian steroid secretion from in vitro experiments with endocrine disruptors.

    Directory of Open Access Journals (Sweden)

    Nadia Quignot

    Full Text Available A finely tuned balance between estrogens and androgens controls reproductive functions, and the last step of steroidogenesis plays a key role in maintaining that balance. Environmental toxicants are a serious health concern, and numerous studies have been devoted to studying the effects of endocrine disrupting chemicals (EDCs. The effects of EDCs on steroidogenic enzymes may influence steroid secretion and thus lead to reproductive toxicity. To predict hormonal balance disruption on the basis of data on aromatase activity and mRNA level modulation obtained in vitro on granulosa cells, we developed a mathematical model for the last gonadal steps of the sex steroid synthesis pathway. The model can simulate the ovarian synthesis and secretion of estrone, estradiol, androstenedione, and testosterone, and their response to endocrine disruption. The model is able to predict ovarian sex steroid concentrations under normal estrous cycle in female rat, and ovarian estradiol concentrations in adult female rats exposed to atrazine, bisphenol A, metabolites of methoxychlor or vinclozolin, and letrozole.

  15. Effects of atrazine on endocrinology and physiology in juvenile barramundi, Lates calcarifer (Bloch).

    Science.gov (United States)

    Kroon, Frederieke J; Hook, Sharon E; Jones, Dean; Metcalfe, Suzanne; Osborn, Hannah L

    2014-07-01

    Exposure to certain environmental contaminants such as agricultural pesticides can alter normal endocrine and reproductive parameters in wild fish populations. Recent studies have found widespread pesticide contamination across the rivers that discharge into the Great Barrier Reef lagoon. Potential impacts on native fish species exposed to known endocrine disrupting chemicals such as atrazine, simazine, and diuron have not been assessed. In the present study, the authors examined the endocrine and physiological effects of short-term, acute exposure of environmentally relevant concentrations of analytical grade atrazine in juvenile barramundi (Lates calcarifer) in a controlled laboratory experiment. Expression of hepatic vitellogenin was not affected, supporting results of previous studies that showed that atrazine does not have a direct estrogenic effect via mediation of estrogen receptors. The lack of effect on brain cytochrome P19B (CYP19B) expression levels, combined with increases in testosterone (T) and 17β estradiol and a stable T:17β estradiol ratio, does not support the hypothesis that atrazine has an indirect estrogenic effect via modulation of aromatase expression. Gill ventilation rate, a measure of oxidative stress, did not change in contrast to other studies finding enhanced osmoregulatory disturbance and gill histopathology after atrazine exposure. To more closely reflect field conditions, the authors recommend that laboratory studies should focus more on examining the effects of commercial pesticide formulations that contain additional ingredients that have been found to be disruptive to endocrine function.

  16. Evaluation of potential mechanisms of atrazine-induced reproductive impairment in fathead minnow (Pimephales promelas) and Japanese medaka (Oryzias latipes)

    Science.gov (United States)

    Richter, Cathy; Papoulias, Diana M.; Whyte, Jeffrey J.; Tillitt, Donald E.

    2016-01-01

    Atrazine has been implicated in reproductive dysfunction of exposed organisms, and previous studies documented decreased egg production in Japanese medaka (Oryzias latipes) and fathead minnows (Pimephales promelas) during 30-d to 38-d exposures to 0.5 µg/L, 5 µg/L, and 50 µg/L atrazine. The authors evaluated possible mechanisms underlying the reduction in egg production. Gene expression in steroidogenesis pathways and the hypothalamus–pituitary–gonad axis of male and female fish was measured. Atrazine did not significantly induce gonad aromatase (cyp19a1a) expression. An atrazine-induced shift in the number of females in an active reproductive state was observed. Expression of the egg maturation genes vitellogenin 1 (vtg1) and zona pellucida glycoprotein 3.1 (zp3.1) in medaka females was correlated and had a bimodal distribution. In both species, females with low vtg1 or zp3.1 expression also had low expression of steroidogenesis genes in the gonad, estrogen receptor in the liver, and gonadotropins in the brain. In the medaka, the number of females per tank that had high expression of zp3.1 was significantly correlated with egg production per tank. The number of medaka females with low expression of zp3.1 increased significantly with atrazine exposure. Thus, the decline in egg production observed in response to atrazine exposure may be the result of a coordinated downregulation of genes required for reproduction in a subset of females.

  17. Mugilid Fish Are Sentinels of Exposure to Endocrine Disrupting Compounds in Coastal and Estuarine Environments

    Directory of Open Access Journals (Sweden)

    Maren Ortiz-Zarragoitia

    2014-09-01

    Full Text Available Effects on fish reproduction can result from a variety of toxicity mechanisms first operating at the molecular level. Notably, the presence in the environment of some compounds termed endocrine disrupting chemicals (EDCs can cause adverse effects on reproduction by interfering with the endocrine system. In some cases, exposure to EDCs leads to the animal feminization and male fish may develop oocytes in testis (intersex condition. Mugilid fish are well suited sentinel organisms to study the effects of reproductive EDCs in the monitoring of estuarine/marine environments. Up-regulation of aromatases and vitellogenins in males and juveniles and the presence of intersex individuals have been described in a wide array of mullet species worldwide. There is a need to develop new molecular markers to identify early feminization responses and intersex condition in fish populations, studying mechanisms that regulate gonad differentiation under exposure to xenoestrogens. Interestingly, an electrophoresis of gonad RNA, shows a strong expression of 5S rRNA in oocytes, indicating the potential of 5S rRNA and its regulating proteins to become useful molecular makers of oocyte presence in testis. Therefore, the use of these oocyte markers to sex and identify intersex mullets could constitute powerful molecular biomarkers to assess xenoestrogenicity in field conditions.

  18. Antiproliferative effects of anastrozole on MCF-7 human breast cancer cells in vitro are significantly enhanced by combined treatment with testosterone undecanoate.

    Science.gov (United States)

    Chen, Rong; Cui, Junwei; Wang, Qinqin; Li, Peng; Liu, Xiaoling; Hu, Hui; Wei, Wei

    2015-07-01

    The present study aimed to assess the effects of aromatase inhibitor anastrozole and testosterone undecanoate, separately and in combination, on proliferation and apoptosis in MCF-7 human breast cancer cells cultured in vitro. The effects of various concentrations of these drugs on the proliferation of MCF-7 cells were evaluated by CCK8 assay, the levels of cell apoptosis were evaluated by flow cytometry with Annexin-V/propidium iodide staining and androgen receptor (AR) protein expression was determined by western blot analysis. The results of the CCK8 assay indicated that greater antiproliferative activity was detected in the MCF-7 cells in the combined treatment groups, compared with those treated with anastrozole or testosterone undecanoate alone. Flow cytometric analysis of apoptosis revealed that treatment with a combination of the two drugs generated a higher percentage of apoptotic cells, particularly when the two drugs were applied for 48 h, compared with single drug treatment. Western blot analysis revealed a significant decrease in AR protein expression in the combined treatment groups compared with MCF7 cells treated with single drugs. The results of the present study provided evidence supporting the potential of a combination of anastrozole and testosterone undecanoate as a novel therapeutic strategy for the treatment of breast cancer. Furthermore, it was demonstrated that the antiproliferative effects of anastrozole were significantly enhanced by combined treatment with testosterone undecanoate via the AR signaling pathway. PMID:25738971

  19. Pretilachlor has the potential to induce endocrine disruption, oxidative stress, apoptosis and immunotoxicity during zebrafish embryo development.

    Science.gov (United States)

    Jiang, Jinhua; Chen, Yanhong; Yu, Ruixian; Zhao, Xueping; Wang, Qiang; Cai, Leiming

    2016-03-01

    The objectives of the present study were to investigate the toxic effects of pretilachlor on zebrafish during its embryo development. The results demonstrated that the transcription of genes involved in the hypothalamic-pituitary-gonadal/thyroid (HPG/HPT) axis was increased after exposure to 50, 100, 200 μg/L pretilachlor for 96 h, the aromatase activity, vitellogenin (VTG) and thyroid hormones T3 and T4 levels in zebrafish were also up-regulated simultaneously. Pretilachlor exposure induced a noticeable increase in ROS level, increased the transcription and level of antioxidant proteins (e.g., CAT, SOD and GPX). Moreover, the up-regulation of P53, Mdm2, Bbc3 expression and Caspase3 and Caspase9 activities in the apoptosis pathway suggested pretilachlor might trigger cell apoptosis in zebrafish. In addition, the transcription of CXCL-C1C, IL-1β and IL-8 related to the innate immunity was down-regulated after pretilachlor exposure. These data suggested that pretilachlor could simultaneously induce endocrine disruption, apoptosis, oxidative stress and immunotoxicity during zebrafish embryo development. PMID:26851375

  20. Estrogen Receptor α Regulates β-Cell Formation During Pancreas Development and Following Injury.

    Science.gov (United States)

    Yuchi, Yixing; Cai, Ying; Legein, Bart; De Groef, Sofie; Leuckx, Gunter; Coppens, Violette; Van Overmeire, Eva; Staels, Willem; De Leu, Nico; Martens, Geert; Van Ginderachter, Jo A; Heimberg, Harry; Van de Casteele, Mark

    2015-09-01

    Identifying pathways for β-cell generation is essential for cell therapy in diabetes. We investigated the potential of 17β-estradiol (E2) and estrogen receptor (ER) signaling for stimulating β-cell generation during embryonic development and in the severely injured adult pancreas. E2 concentration, ER activity, and number of ERα transcripts were enhanced in the pancreas injured by partial duct ligation (PDL) along with nuclear localization of ERα in β-cells. PDL-induced proliferation of β-cells depended on aromatase activity. The activation of Neurogenin3 (Ngn3) gene expression and β-cell growth in PDL pancreas were impaired when ERα was turned off chemically or genetically (ERα(-/-)), whereas in situ delivery of E2 promoted β-cell formation. In the embryonic pancreas, β-cell replication, number of Ngn3(+) progenitor cells, and expression of key transcription factors of the endocrine lineage were decreased by ERα inactivation. The current study reveals that E2 and ERα signaling can drive β-cell replication and formation in mouse pancreas.