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Aromatase Inhibitor (aromatase + inhibitor)
Kinds of Aromatase Inhibitor Selected AbstractsComparison of the Effect of the Aromatase Inhibitor, Anastrazole, to the Antioestrogen, Tamoxifen Citrate, on Canine Prostate and SemenREPRODUCTION IN DOMESTIC ANIMALS, Issue 2009G Gonzalez Contents This study compared the efficiency of the aromatase inhibitor, anastrazole, with the antioestrogenic receptor blocker, tamoxifen, on normal (NRL) and hyperplastic prostate glands. Forty healthy dogs were classified as NRL (n = 18) or abnormal (ABN) with benign prostate hyperplasia (n = 22). The dogs were randomly assigned to one of the following six groups, treated for 60 days; oral placebo for normal (NRL-PLC; n = 6) and abnormal (ABN-PLC; n = 6), oral anastrazole 0.25,1 mg/day, for normal (NRL-ANZ, n = 6) and abnormal (ABN-ANZ, n = 8) and oral tamoxifen citrate 2.5,10 mg/day for normal (NRL-TMX; n = 6) and abnormal (ABN-TMX; n = 8) dogs. The dogs were evaluated before treatment and then monthly for 4 months. At the end of the treatment, the prostatic volume decreased by 28.5 ± 4.3%, 21.6 ± 6.3% and 0.7 ± 1.0% in the ABN-TMX, ABN-ANZ and ABN-PLC (p < 0.01), respectively. From then on, prostatic volume began to increase without reaching pre-treatment values at the end of the study. In the ABN animals, there were no differences for this parameter between ANZ and TMX treatment (p > 0.1), whereas in the NRL animals ANZ produced a less pronounced decrease (p < 0.05), libido, testicular consistency and scrotal diameter decreased during treatment in the TMX group (p > 0.05). These parameters and sperm volume, count, motility and morphological abnormalities remained unaltered throughout the study in the ANZ and PLC groups (p > 0.05). There were no haematological nor biochemical side effects. Anastrazole might offer a safe and effective alternative for the medical management of dogs with benign prostatic hyperplasia. [source] Synthesis and Evaluation of a Dimer of 2-(4-Pyridylmethyl)-1-indanone as a Novel Nonsteroidal Aromatase Inhibitor.CHEMINFORM, Issue 44 2004Ranju Gupta Abstract For Abstract see ChemInform Abstract in Full Text. [source] A Roundtable Discussion of Aromatase Inhibitors as Therapy for Breast CancerTHE BREAST JOURNAL, Issue 3 2003D. Craig Allred MD Abstract: This article summarizes the conclusions of a meeting of diverse breast cancer experts who discussed issues, controversies, and new clinical trial results relevant to the use of aromatase inhibitors for treating postmenopausal women with breast cancer. The new generation of aromatase inhibitors (anastrozole, letrozole, exemestane) have largely replaced megestrol acetate as a second-line therapy in postmenopausal women with hormone-responsive advanced breast cancer. In addition, anastrozole and letrozole have been shown to be superior to tamoxifen for first-line therapy. Finally, recent results suggest that anastrozole may be superior to tamoxifen as adjuvant therapy for early stage disease in postmenopausal women with hormone-responsive disease. [source] The Effect of Aromatase Inhibitors on Bone MetabolismBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 1 2009Lars Folkestad 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 and simultaneously increases the production of antireceptive cytokines, which leads to increased osteoclastic apoptosis and increased osteoblastic activity. Aromatase inhibitors inhibit the endogenous production of oestrogen by 50,90%. Studies designed to look at the effect of aromatase inhibitors on bone mineral density have shown a significant decrease in bone mineral density of the femoral neck in the aromatase inhibitor groups compared to placebo groups. Placebo-controlled studies lack statistical power to detect changes in fracture incidence; however, aromatase inhibitors increase the incidence of fractures 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. [source] Synthesis and Evaluation of 4-Triazolylflavans as New Aromatase Inhibitors.CHEMINFORM, Issue 5 2005Samir Yahiaoui Abstract For Abstract see ChemInform Abstract in Full Text. [source] Synthesis of Aromatase Inhibitors and Dual Aromatase Steroid Sulfatase Inhibitors by Linking an Arylsulfamate Motif to 4-(4H -1,2,4-triazol-4-ylamino)benzonitrile: SAR, Crystal Structures, in,vitro and in,vivo ActivitiesCHEMMEDCHEM, Issue 11 2008Christian Bubert Dr. Abstract 4-(((4-Cyanophenyl)(4H -1,2,4-triazol-4-yl)amino)methyl)phenyl sulfamate (6,a) was the first dual aromatase,sulfatase inhibitor (DASI) reported. Several series of its derivatives with various linker systems between the steroid sulfatase (STS) and the aromatase inhibitory pharmacophores were synthesised and evaluated in JEG-3 cells. The X-ray crystal structures of the aromatase inhibitors, DASI precursors 42,d and 60, and DASI 43,h were determined. Nearly all derivatives show improved in,vitro aromatase inhibition over 6,a but decreased STS inhibition. The best aromatase inhibitor is 42,e (IC50=0.26,nM) and the best DASI is 43,e (IC50,aromatase=0.45,nM, IC50,STS=1200,nM). SAR for aromatase inhibition shows that compounds containing an alkylene- and thioether-based linker system are more potent than those that are ether-, sulfone-, or sulfonamide-based, and that the length of the linker has a limited effect on aromatase inhibition beyond two methylene units. Compounds 43,d,f were studied in,vivo (10,mg,kg,1, single, p.o.). The most potent DASI is 43,e, which inhibited PMSG-induced plasma estradiol levels by 92,% and liver STS activity by 98,% 3,h after dosing. These results further strengthen the concept of designing and developing DASIs for potential treatment of hormone-related cancers. [source] Expression of AMH, SF1, and SOX9 in gonads of genetic female chickens during sex reversal induced by an aromatase inhibitorDEVELOPMENTAL DYNAMICS, Issue 2 2001Séverine Vaillant Abstract Aromatase inhibitors administered prior to histological signs of gonadal sex differentiation can induce sex reversal of genetic female chickens. Under the effects of Fadrozole (CGS 16949A), a nonsteroidal aromatase inhibitor, the right gonad generally becomes a testis, and the left gonad a testis or an ovotestis. We have compared the expression pattern of the genes encoding AMH (the anti-Müllerian hormone), SF1 (steroidogenic factor 1), and SOX9 (a transcription factor related to SRY) in these sex-reversed gonads with that in control testes and ovaries, using in situ hybridization with riboprobes on gonadal sections. In control males, the three genes are expressed in Sertoli cells of testicular cords; however, only SOX9 is male specific, since as observed previously AMH and SF1 but not SOX9 are expressed in the control female gonads. In addition to testicular-like cords, sex-reversed gonads present many lacunae with a composite, thick and flat epithelium. We show that during embryonic and postnatal development, AMH, SF1 and SOX9 are expressed in the epithelium of testicular-like cords and in the thickened part but not in the flattened part of the epithelium of composite lacunae. AMH and SF1 but not SOX9 are expressed in follicular cells of ovotestes. Coexpression of the three genes, of which SOX9 is a specific Sertoli-cell marker, provides strong evidence for the transdifferentiation of ovarian into testicular epithelium in gonads of female chickens treated with Fadrozole. © 2001 Wiley-Liss, Inc. [source] Aromatase inhibitors in preventing breast cancer recurrenceFUTURE PRESCRIBER, Issue 1 2006Associate Director of Cancer Services, Endocrine Surgeon, Robert Carpenter Consultant Breast First page of article [source] In situ estrogen production and its regulation in human breast carcinoma: From endocrinology to intracrinologyPATHOLOGY INTERNATIONAL, Issue 11 2009Hironobu Sasano The great majority of breast carcinomas arising in postmenopausal women are estrogen dependent or positive for estrogen receptor (ER) in carcinoma cells despite markedly low plasma or circulating estrogen concentrations. In these patients, biologically active estrogens are locally produced from circulating inactive steroids including adrenal androgens in an intracrine mechanism in the breast cancer tissues and confer estrogenic activities on carcinoma cells. A series of enzymes are involved in this intra-tumoral or in situ production of estrogens in breast carcinoma tissues but aromatase, a member of the cytochrome P450 family, is a key enzyme of estrogen production through conversion from circulating adrenal androgens in estrogen-dependent postmenopausal breast cancer. It then becomes important to identify the sites of this estrogen production. There has been, however, controversy regarding intra-tumoral localization of aromatase in breast carcinoma, especially whether intra-tumoral production of estrogens through aromatase occurs in carcinoma or stromal cells. The enzyme was demonstrated to be expressed in both carcinoma and stromal cells in breast carcinoma tissues on immunohistochemistry with a well-characterized mAb 677 and combined laser capture microdissection/qualitative reverse transcriptase,polymerase chain reaction. Intra-tumoral aromatase in both of these cell types was subsequently demonstrated to be induced by carcinoma,stromal interactions associated with carcinoma invasion in breast tissue. The signals through various nuclear receptors, especially estrogen-related receptor-, in carcinoma cells and liver receptor homologue-1 in adipocytes adjacent to carcinoma invasion, in conjunction with various cytokines and/or growth factors, play pivotal roles in this induction of intra-tumoral aromatase. This increased aromatase subsequently results in increased in situ estrogen concentrations of breast cancer. Aromatase inhibitors are currently established as the gold standard for the treatment for ER-positive breast carcinoma but resistance to the therapy still remains to be solved by other modes of suppression of intra-tumoral estrogen production. [source] Aromatase inhibitors and osteoporosis: Comment on the review by Felson and CummingsARTHRITIS & RHEUMATISM, Issue 4 2006Prabha Ranganathan MD No abstract is available for this article. [source] The Effect of Aromatase Inhibitors on Bone MetabolismBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 1 2009Lars Folkestad 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 and simultaneously increases the production of antireceptive cytokines, which leads to increased osteoclastic apoptosis and increased osteoblastic activity. Aromatase inhibitors inhibit the endogenous production of oestrogen by 50,90%. Studies designed to look at the effect of aromatase inhibitors on bone mineral density have shown a significant decrease in bone mineral density of the femoral neck in the aromatase inhibitor groups compared to placebo groups. Placebo-controlled studies lack statistical power to detect changes in fracture incidence; however, aromatase inhibitors increase the incidence of fractures 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. [source] Sex-specific and left-right asymmetric expression pattern of Bmp7 in the gonad of normal and sex-reversed chicken embryosDEVELOPMENT GROWTH & DIFFERENTIATION, Issue 2 2005Anshin Hoshino A genetic switch determines whether the indifferent gonad develops into an ovary or a testis. In adult females of many avian species, the left ovary is functional while the right one regresses. In the embryo, bone morphogenetic proteins (BMP) mediate biological effects in many organ developments but their roles in avian sex determination and gonadal differentiation remains largely unknown. Here, we report the sex-specific and left-right (L-R) asymmetric expression pattern of Bmp7 in the chicken gonadogenesis. Bmp7 was L-R asymmetrically expressed at the beginning of genital ridge formation. After sexual differentiation occurred, sex-specific expression pattern of Bmp7 was observed in the ovary mesenchyme. In addition, ovary-specific Bmp7 expression was reduced in experimentally induced female-to-male reversal using the aromatase inhibitor (AI). These dynamic changes of expression pattern of Bmp7 in the gonad with or without AI treatment suggest that BMP may play roles in determination of L-R asymmetric development and sex-dependent differentiation in the avian gonadogenesis. [source] Expression of AMH, SF1, and SOX9 in gonads of genetic female chickens during sex reversal induced by an aromatase inhibitorDEVELOPMENTAL DYNAMICS, Issue 2 2001Séverine Vaillant Abstract Aromatase inhibitors administered prior to histological signs of gonadal sex differentiation can induce sex reversal of genetic female chickens. Under the effects of Fadrozole (CGS 16949A), a nonsteroidal aromatase inhibitor, the right gonad generally becomes a testis, and the left gonad a testis or an ovotestis. We have compared the expression pattern of the genes encoding AMH (the anti-Müllerian hormone), SF1 (steroidogenic factor 1), and SOX9 (a transcription factor related to SRY) in these sex-reversed gonads with that in control testes and ovaries, using in situ hybridization with riboprobes on gonadal sections. In control males, the three genes are expressed in Sertoli cells of testicular cords; however, only SOX9 is male specific, since as observed previously AMH and SF1 but not SOX9 are expressed in the control female gonads. In addition to testicular-like cords, sex-reversed gonads present many lacunae with a composite, thick and flat epithelium. We show that during embryonic and postnatal development, AMH, SF1 and SOX9 are expressed in the epithelium of testicular-like cords and in the thickened part but not in the flattened part of the epithelium of composite lacunae. AMH and SF1 but not SOX9 are expressed in follicular cells of ovotestes. Coexpression of the three genes, of which SOX9 is a specific Sertoli-cell marker, provides strong evidence for the transdifferentiation of ovarian into testicular epithelium in gonads of female chickens treated with Fadrozole. © 2001 Wiley-Liss, Inc. [source] Aromatase expression and cell proliferation following injury of the adult zebra finch hippocampusDEVELOPMENTAL NEUROBIOLOGY, Issue 14 2007R. Scott Peterson Abstract Estrogens can be neuroprotective following traumatic brain injury. Immediately after trauma to the zebra finch hippocampus, the estrogen-synthetic enzyme aromatase is rapidly upregulated in astrocytes and radial glia around the lesion site. Brain injury also induces high levels of cell proliferation. Estrogens promote neuronal differentiation, migration, and survival naturally in the avian brain. We suspect that glia are a source of estrogens promoting cell proliferation after neural injury. To explore this hypothesis, we examined the spatial and temporal relationship between glial aromatase expression and cell proliferation after neural injury in adult female zebra finches. Birds were ovariectomized and given a blank implant or one filled with estradiol; some birds were also administered an aromatase inhibitor or vehicle. All birds received penetrating injuries to the right hippocampus. Twenty-four hours after lesioning, birds were injected once with BrdU to label mitotically active cells and euthanized 2 h, 24 h, or 7 days later. The brains were processed for double-label BrdU and aromatase immunocytochemistry. Injury-induced glial aromatase expression was unaffected by survival time and aromatase inhibition. BrdU labeling was significantly reduced at 24 h by ovariectomy and by aromatase inhibition; effects were partially reversed by E2 replacement. Irrespective of ovariectomy, the densities of aromatase immunoreactive astrocytes and BrdU-labeled cells at known distances from the lesion site were highly correlated. These data suggest that injury-induced glial aromatization may influence the reorganization of injured tissue by providing a rich estrogenic environment available to influence cellular incorporation. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007. [source] Gonadal differentiation in frogs exposed to estrogenic and antiestrogenic compoundsENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 10 2003Constanze A. Mackenzie Abstract Exposure of amphibians to endocrine disrupting compounds (EDCs) may alter differentiationof gonads, especially when exposures begin during early life stages. Gonadal differentiation was observed in leopard frogs (Rana pipiens) and wood frogs (Rana sylvatica) exposed as tadpoles to estrogenic (estradiol, ethinylestradiol, nonylphenol) and antiestrogenic compounds (an aromatase inhibitor, flavone, and an antiestrogen, ICI 182780). Exposure to all compounds at ,g/L concentrations altered gonadal differentiation in some animals by inducing either complete feminization or an intersex condition, and altered testicular tubule morphology, increased germ cell maturation (vitellogenesis), and oocyte atresia. Comparisons between the two species indicate that R. pipiens are more susceptible to sex reversal and development of intersex gonads. However, R. sylvatica also showed alterations to testicular morphology, germ cell maturation, and ooctye atresia. These laboratory results indicate that amphibians could be susceptible to altered gonadal differentiation and development when exposed to estrogenic and antiestrogenic compounds in aquatic environments, such as those impacted by agricultural, industrial, and municipal runoff. [source] THE ADAPTIVE SIGNIFICANCE OF TEMPERATURE-DEPENDENT SEX DETERMINATION: EXPERIMENTAL TESTS WITH A SHORT-LIVED LIZARDEVOLUTION, Issue 10 2005Daniel A. Warner Abstract Why is the sex of many reptiles determined by the temperatures that these animals experience during embryogenesis, rather than by their genes? The Charnov-Bull model suggests that temperature-dependent sex determination (TSD) can enhance maternal fitness relative to genotypic sex determination (GSD) if offspring traits affect fitness differently for sons versus daughters and nest temperatures either determine or predict those offspring traits. Although potential pathways for such effects have attracted much speculation, empirical tests largely have been precluded by logistical constraints (i.e., long life spans and late maturation of most TSD reptiles). We experimentally tested four differential fitness models within the Charnov-Bull framework, using a short-lived, early-maturing Australian lizard (Amphibolurus muricatus) with TSD. Eggs from wild-caught females were incubated at a range of thermal regimes, and the resultant hatchlings raised in large outdoor enclosures. We applied an aromatase inhibitor to half the eggs to override thermal effects on sex determination, thus decoupling sex and incubation temperature. Based on relationships between incubation temperatures, hatching dates, morphology, growth, and survival of hatchlings in their first season, we were able to reject three of the four differential fitness models. First, matching offspring sex to egg size was not plausible because the relationship between egg (offspring) size and fitness was similar in the two sexes. Second, sex differences in optimal incubation temperatures were not evident, because (1) although incubation temperature influenced offspring phenotypes and growth, it did so in similar ways in sons versus daughters, and (2) the relationship between phenotypic traits and fitness was similar in the two sexes, at least during preadult life. We were unable to reject a fourth model, in which TSD enhances offspring fitness by generating seasonal shifts in offspring sex ratio: that is, TSD allows overproduction of daughters (the sex likely to benefit most from early hatching) early in the nesting season. In keeping with this model, hatching early in the season massively enhanced body size at the beginning of the first winter, albeit with a significant decline in probability of survival. Thus, the timing of hatching is likely to influence reproductive success in this short-lived, early maturing species; and this effect may well differ between the sexes. [source] Effects of oestrogen agonists on human dermal fibroblasts in an in vitro wounding assayEXPERIMENTAL DERMATOLOGY, Issue 11 2009Susan Stevenson Abstract:, Oestrogen and dehydroepiandrosterone (DHEA) improve wound healing, but circulating levels decline significantly with age. Recently, the selective oestrogen receptor modulators (SERMs) tamoxifen and raloxifene have been shown to improve age-associated impaired wound healing. Therefore, we have evaluated the effects of 17,-oestradiol, ER, and ER, agonists, tamoxifen, raloxifene and DHEA on human dermal fibroblasts using an in vitro wound assay. An ER, agonist, 17,-oestradiol and DHEA all significantly accelerated cell migration; the DHEA effect was blocked with an aromatase inhibitor. Tamoxifen, raloxifene and DHEA all significantly increased DNA synthesis; the DHEA stimulatory effect was reversed by an aromatase inhibitor. This study demonstrates that 17,-oestradiol, an ER, agonist, tamoxifen, raloxifene and DHEA (following conversion to oestrogen) all have significant effects on human fibroblasts, the key mesenchymal cell involved in the wound healing process. Further understanding of the mechanisms involved may have important implications for the management of age-related impaired wound healing. [source] Cholesterol-promoted synaptogenesis requires the conversion of cholesterol to estradiol in the hippocampusHIPPOCAMPUS, Issue 8 2009Lars Fester Abstract Cholesterol of glial origin promotes synaptogenesis (Mauch et al., (2001) Science 294:1354,1357). Because in the hippocampus local estradiol synthesis is essential for synaptogenesis, we addressed the question of whether cholesterol-promoted synapse formation results from the function of cholesterol as a precursor of estradiol synthesis in this brain area. To this end, we treated hippocampal cultures with cholesterol, estradiol, or with letrozole, a potent aromatase inhibitor. Cholesterol increased neuronal estradiol release into the medium, the number of spine synapses in hippocampal slice cultures, and immunoreactivity of synaptic proteins in dispersed cultures. Simultaneous application of cholesterol and letrozole or blockade of estrogen receptors by ICI 182 780 abolished cholesterol-induced synapse formation. As a further approach, we inhibited the access of cholesterol to the first enzyme of steroidogenesis by knock-down of steroidogenic acute regulatory protein, the rate-limiting step in steroidogenesis. A rescue of reduced synaptic protein expression in transfected cells was achieved by estradiol but not by cholesterol. Our data indicate that in the hippocampus cholesterol-promoted synapse formation requires the conversion of cholesterol to estradiol. © 2009 Wiley-Liss, Inc. [source] Effects of a New Selective Estrogen Receptor Modulator (MDL 103,323) on Cancellous and Cortical Bone in Ovariectomized Ewes: A Biochemical, Histomorphometric, and Densitometric StudyJOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2001Pascale Chavassieux Abstract The aims of this study performed in ewes were: (1) to confirm in this animal model the effects on bone of ovariectomy (OVX) alone or associated with Lentaron (L), a potent peripheral aromatase inhibitor, used to amplify the effects of OVX and (2) to evaluate the effects of a new selective estrogen receptor modulator (SERM; MDL 103,323) on bone remodeling. Thirty-nine old ewes were divided into five groups: sham (n = 7); OVX (n = 8); OVX + L (n = 8); OVX + L + MDL; 0.1 mg/kg per day (n = 8); and OVX + L + MDL 1 mg/kg per day (n = 8). The animals were treated for 6 months. Biochemical markers of bone turnover (urinary excretion of type 1 collagen C-telopeptide [CTX], serum osteocalcin [OC], and bone alkaline phosphatase [BAP]) were measured each month. Bone biopsy specimens were taken at the beginning and after death at the end of the experiment. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) on the lumbar spine and femur. OVX induced a significant increase in biochemical markers. This effect was the highest after 3 months for CTX (+156% vs. sham) and after 4 months for OC and BAP (+74% and +53% vs. sham, respectively). L tended to amplify the effect of OVX on OC and BAP. OVX induced significant increases in the porosity, eroded, and osteoid surfaces in cortical bone but no effect was observed in cancellous bone. MDL treatment reduced the bone turnover as assessed by bone markers, which returned to sham levels as well as histomorphometry both in cortical and in cancellous bone. Cancellous osteoid thickness decreased by 27% (p < 0.05), mineralizing perimeter by 81% (p < 0.05), and activation frequency by 84% (p < 0.02) versus OVX + L. Femoral and spinal BMD were increased by MDL and tended to return to the sham values. The effects of OVX on bone turnover were different on cortical and cancellous bone. These effects on cortical bone were reflected by changes in biochemical markers. MDL markedly reduces bone turnover and increases BMD suggesting that this new agent may prevent postmenopausal bone loss. [source] Mechanical Strain Stimulates Osteoblast Proliferation Through the Estrogen Receptor in Males as Well as FemalesJOURNAL OF BONE AND MINERAL RESEARCH, Issue 11 2000E. Damien Abstract Mechanical strain, testosterone, and estrogen all stimulate proliferation of primary cultures of male rat long bone (LOB)-derived osteoblast-like cells as determined by [3H]thymidine incorporation. The maximum proliferative effect of a single period of mechanical strain (3400 ,,, 1 Hz, and 600 cycles) is additional to that of testosterone (10,8 M) or estrogen (10,8 M). The cells' proliferative response to strain is abolished both by concentrations of tamoxifen that cause proliferation (10,8 M) and by those that have no effect (10,6 M). Strain-related proliferation also is reduced by the estrogen antagonist ICI 182,780 (10,8 M) but is unaffected by the androgen receptor antagonist hydroxyflutamide (10,7 M). Tamoxifen, ICI 182,780, and the aromatase inhibitor 4-dihydroandrostenedione, at concentrations that have no effect on basal proliferation, significantly reduce the proliferative effect of the aromatizable androgen testosterone but not that of the nonaromatizable androgen 5,-dihydrotestosterone. Hydroxyflutamide, at a concentration that has no effect on basal proliferation (10,7 M), eliminates the proliferative effect of 5,-dihydro-testosterone but had no significant effect on that caused by testosterone. Proliferation associated with strain is blocked by neutralizing antibody to insulin-like growth factor II (IGF-II) but not by antibody to IGF-I. Proliferation associated with testosterone is blocked by neutralizing antibody to IGF-I but is unaffected by antibody to IGF-II. These data suggest that in rat osteoblast-like cells from males, as from females, strain-related proliferation is mediated through the estrogen receptor (ER) in a manner that does not compete with estrogen but that can be blocked by ER modulators. Proliferation associated with testosterone appears to follow its aromatization to estrogen and is mediated through the ER, whereas proliferation associated with 5,-dihydrotestosterone is mediated by the androgen receptor. Strain-related proliferation in males, as in females, is mediated by IGF-II, whereas proliferation associated with estrogen and testosterone is mediated by IGF-I. [source] Altered gene expression in the brain and liver of female fathead minnows Pimephales promelas Rafinesque exposed to fadrozoleJOURNAL OF FISH BIOLOGY, Issue 9 2008D. L. Villeneuve The fathead minnow Pimephales promelas is a small fish species widely used for ecotoxicology research and regulatory testing in North America. This study used a 2000 gene oligonucleotide microarray to evaluate the effects of the aromatase inhibitor, fadrozole, on gene expression in the liver and brain tissue of exposed females. Reproductive measures, plasma vitellogenin and gene expression data for the brain isoform of aromatase (cytP19B), vitellogenin precursors and transferrin provided evidence supporting the efficacy of the fadrozole exposure. Unsupervised analysis of the microarray results identified 20 genes in brain and 41 in liver as significantly up-regulated and seven genes in brain and around 45 in liver as significantly down-regulated. Differentially expressed genes were associated with a broad spectrum of biological functions, many with no obvious relationship to aromatase inhibition. However, in brain, fadrozole exposure elicited significant up-regulation of several genes involved in the cholesterol synthesis, suggesting it as a potentially affected pathway. Gene ontology-based analysis of expression changes in liver suggested overall down-regulation of protein biosynthesis. While real-time polymerase chain reaction analyses supported some of the microarray responses, others could not be verified. Overall, results of this study provide a foundation for developing novel hypotheses regarding the system-wide effects of fadrozole, and other chemical stressors with similar modes of action, on fish biology. [source] Role of aromatase inhibitor in patients with poor response to clomiphene citrate needs further evaluationJOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH (ELECTRONIC), Issue 5 2007Jeevan P. Marasinghe [source] Comparison of the Effect of the Aromatase Inhibitor, Anastrazole, to the Antioestrogen, Tamoxifen Citrate, on Canine Prostate and SemenREPRODUCTION IN DOMESTIC ANIMALS, Issue 2009G Gonzalez Contents This study compared the efficiency of the aromatase inhibitor, anastrazole, with the antioestrogenic receptor blocker, tamoxifen, on normal (NRL) and hyperplastic prostate glands. Forty healthy dogs were classified as NRL (n = 18) or abnormal (ABN) with benign prostate hyperplasia (n = 22). The dogs were randomly assigned to one of the following six groups, treated for 60 days; oral placebo for normal (NRL-PLC; n = 6) and abnormal (ABN-PLC; n = 6), oral anastrazole 0.25,1 mg/day, for normal (NRL-ANZ, n = 6) and abnormal (ABN-ANZ, n = 8) and oral tamoxifen citrate 2.5,10 mg/day for normal (NRL-TMX; n = 6) and abnormal (ABN-TMX; n = 8) dogs. The dogs were evaluated before treatment and then monthly for 4 months. At the end of the treatment, the prostatic volume decreased by 28.5 ± 4.3%, 21.6 ± 6.3% and 0.7 ± 1.0% in the ABN-TMX, ABN-ANZ and ABN-PLC (p < 0.01), respectively. From then on, prostatic volume began to increase without reaching pre-treatment values at the end of the study. In the ABN animals, there were no differences for this parameter between ANZ and TMX treatment (p > 0.1), whereas in the NRL animals ANZ produced a less pronounced decrease (p < 0.05), libido, testicular consistency and scrotal diameter decreased during treatment in the TMX group (p > 0.05). These parameters and sperm volume, count, motility and morphological abnormalities remained unaltered throughout the study in the ANZ and PLC groups (p > 0.05). There were no haematological nor biochemical side effects. Anastrazole might offer a safe and effective alternative for the medical management of dogs with benign prostatic hyperplasia. [source] 6,-Methyl- B -norandrostenedioneACTA CRYSTALLOGRAPHICA SECTION C, Issue 4 2010L. C. R. Andrade The title compound, C19H26O2, a B -norandrogen with a 6,-methyl group, is a recently identified and experimentally tested potent new aromatase inhibitor. It shares structural and physicochemical similarities both with the natural substrate of the enzyme, androstenedione, and with exemestane, another potent aromatase inhibitor having a 6-methylidene group. X-ray diffraction results indicate that the B -nor molecule and exemestane have nearly the same oxygen,oxygen and methyl,methyl separations, though they have distinct configurations of the hydrophobic groups at the 6-position. These structural comparisons allow correlations to be inferred between the active site geometry of the molecules and the aromatase inhibition power of the studied compound. [source] Effects of a nonsteroidal aromatase inhibitor on gonadal differentiation of bluegill sunfish Lepomis macrochirusAQUACULTURE RESEARCH, Issue 9 2010Ze-Xia Gao Abstract In the present study, the efficacy of Letrozole, a potent nonsteroidal aromatase inhibitor (AI), on gonadal sex differentiation and sex reversal was examined in bluegill sunfish (Lepomis macrochirus). In Experiment 1, using AI diet treatments (50, 150, 250 and 500 mg kg,1) from 30 to 90 days posthatch (dph), AI interrupted ovarian cavity formation at a dose of 500 mg kg1 diet and one intersex fish was identified in this group. The proportions of males in all the treated groups were significantly higher than those in the control group. In Experiment 2, using AI immersion treatments (250, 500 and 1000 ,g L,1) during 30,50 dph, the treated groups of 500 and 1000 ,g L,1 produced significantly more males than the control and 250 ,g L,1 groups. Histological examination revealed no differences in ovary or testis tissue between control and AI-treated fish. There were no significant differences detected in body weight and length among the AI treated and control groups (P>0.05) for both experiments. The results from these two experiments suggest that inhibition of aromatase activity by AI could influence sex differentiation in bluegill sunfish. [source] Effect of age and single versus multiple dose pharmacokinetics of letrozole (Femara®) in breast cancer patientsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 5 2001Christian U. Pfister Abstract Letrozole (trademark Femara®) is a new orally active, potent and selective aromatase inhibitor for the hormonal treatment of advanced breast cancer in postmenopausal women. The pharmacokinetics of letrozole and the suppression of peripheral estrogens were studied in 28 breast cancer patients after a single dose and at steady state. The pharmacokinetics of two distinct age groups (,50, ,65, N=15 and ,70 years old, N=9) were compared. There were no significant differences in area under the curve (AUC) or terminal half-life between the two age groups neither after a single dose nor at steady state. However, when comparing steady state to single dose kinetics, half-life and AUC increased significantly by 42% (90% CI: 1.13, 1.78) and 28% (90% CI: 1.12, 1.47), respectively. This deviation from linearity was probably due to a partial saturation or auto-inhibition of the dominant metabolic clearance mechanism of letrozole. At steady state, approximately 70% of the administered dose was excreted in urine as unchanged letrozole (6.0±3.8%) or as the glucuronide of the major, pharmacologically inactive metabolite CGP44645 (64.2±22.7%). A single dose of letrozole caused suppression of serum estrogen levels close to the quantification limit of the assay. No difference between single dose suppression and suppression at steady state could be detected. Copyright © 2001 John Wiley & Sons, Ltd. [source] Effect of letrozole on urinary bladder function in the female rabbitBJU INTERNATIONAL, Issue 6 2007Wei-Yu Lin OBJECTIVE To investigate the effect of letrozole (a potent aromatase inhibitor that effectively inhibit the synthesis of oestrogen) on bladder contraction with changes in morphology and biochemistry. MATERIALS AND METHODS Sixteen female New Zealand white rabbits were separated into four equal groups; groups 1,3 were given oral letrozole for 1, 2 and 3 weeks, and group 4 was given saline and served as the control group. At the end of the medication period each rabbit was anaesthetized and the bladder muscle strips were used for contractile, histological and biochemical studies. RESULTS The concentration of serum oestrogen was significantly lower and testosterone was significantly higher in letrozole-treated rabbits than in the control group. The rabbits treated for 1 week with letrozole showed significant decreases in the contractile responses to electrical field stimulation, ATP and carbachol, but not to KCl. Contractility returned to normal in the rabbits treated for 2 and 3 weeks. Letrozole resulted in an increased volume percentage of collagens and decreased bladder compliance. The volume percentage of the smooth muscle component also changed, with a significant decrease at 1 week and then a gradual increase at 2 and 3 weeks. Contractile dysfunction was absent at 2 and 3 weeks, which was consistent with no change in sarcoplasmic reticulum Ca2+ -ATPase content or mitochondrial function. CONCLUSIONS The bladder contractility decline in the first week and was restored at 2 and 3 weeks. The present study unexpectedly showed the possibility that testosterone might be as important as oestrogen in the contractile function of the female bladder. [source] High circulating HER2 extracellular domain levels correlate with reduced efficacy of an aromatase inhibitor in hormone receptor-positive metastatic breast cancer: A confirmatory prospective studyCANCER, Issue 10 2007Ramon Colomer MD Abstract BACKGROUND. In this specifically designed, prospective study, the authors addressed the predictive value of circulating levels of the extracellular domain (ECD) of HER2 in patients with metastatic breast cancer who were treated with letrozole. METHODS. Two hundred twenty-six patients with hormone receptor-positive, metastatic breast cancer received letrozole (2.5 mg daily) until they developed either disease progression or unacceptable toxicity. Efficacy was measured primarily as the time to progression (TTP) and, secondarily, as the objective response rate (ORR) and overall survival. HER2 ECD levels were determined by using a sandwich enzyme HER2/neu immunoassay before letrozole treatment was initiated. Positive HER2 ECD status was correlated with treatment efficacy. RESULTS. Forty-two patients (19%) had elevated HER2 ECD levels, which were associated with primary tumor HER2 expression (P < .001) but not with age, performance status, location, or number of metastatic sites. The median TTP was significantly shorter among patients who had elevated HER2 ECD compared with the median TTP among patients who had normal levels (4 months vs 14 months; P = .0004), and the ORR was lower in the group with elevated HER2 ECD levels (14% vs 30%; P < .036). Overall survival was significantly shorter among patients with elevated serum HER-2 ECD (P < .0005). CONCLUSIONS. Elevated HER2 ECD concentrations predicted poorer outcomes in postmenopausal women with metastatic hormone receptor-positive breast cancer who were treated with aromatase inhibitors like letrozole. © 2007 American Cancer Society. [source] Chiral separation of N -imidazole derivatives, aromatase inhibitors, by cyclodextrin-capillary zone electrophoresis.ELECTROPHORESIS, Issue 16 2004Mechanism of enantioselective recognition Abstract Baseline separation of ten new, substituted [1-(imidazo-1-yl)-1-phenylmethyl)] benzothiazolinone and benzoxazolinone derivatives with one chiral center was achieved using cyclodextrin-capillary zone electrophoresis (CD-CZE). A method for the enantiomeric resolution of these compounds was developed using neutral CDs (native ,-, ,-, ,-CDs or ,-, ,-, ,-hydroxypropyl (HP)-CDs) as chiral selectors. Operational parameters including the nature and concentration of the chiral selectors, pH, ionic strength, organic modifiers, temperature, and applied voltage were investigated. The use of neutral CDs provides enantiomeric resolution by inclusion of compounds in the CD cavity. The HP-,-CD and HP-,-CD were found to be the most effective complexing agents and allowed efficient enantiomeric resolutions. Optimal separation of N -imidazole derivatives was obtained using 50 mM phosphate buffer at pH 2.5 containing either HP-,-CD or HP-,-CD (7.5,12.5 mM) at 25°C, with an applied field of 0.50 kV·cm,1 giving resolution factors Rs superior to 1.70 with migration times of the second enantiomer less than 13 min. The same enantiomer migration order observed for all molecules can be related to a close interaction mechanism with CDs. The influence of structural features of the solutes on Rs and tm was studied. The lipophilic character (log kw) of the solutes and the apparent and averaged association constants of inclusion complexes for four compounds with the six different CDs led us to rationalize the enantioseparation mechanisms. The conclusions were corroborated with reversed-phase high-performance liquid chromatography (HPLC) on chiral stationary phases (CSPs) based on CDs. [source] Evaluation of the methoxytriazine herbicide prometon using a short-term fathead minnow reproduction test and a suite of in vitro bioassaysENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 8 2006Daniel L. Villeneuve Abstract Prometon is one of the most consistently detected herbicides in the U.S. environment. However, no previous assessment of the potential for prometon or related methoxytriazine herbicides to act as endocrine-disrupting chemicals has been conducted. This study used an array of in vitro bioassays to assess whether prometon, atraton, terbumeton, or secbumeton might act as potent (ant)agonists of the aryl hydrocarbon, estrogen, androgen, or glucocorticoid receptors or as aromatase inhibitors or inducers in vitro. Potential effects of prometon were also evaluated using a 21-d fathead minnow reproduction assay. Concentrations of methoxytriazines, as great as 1 mg/L (4.4 ,M), did not induce significant dioxin-like responses in H4IIE-luc cells, estrogenic responses in MVLN cells, or androgen or glucocorticoid receptor,mediated responses in MDA-kb2 cells, nor did the methoxytriazines significantly affect aromatase activity in vitro. In the fathead minnow assay, exposure to 20, 200, or 1,000 ,g prometon/L significantly reduced the weight of the male fat pad (an androgen-responsive tissue) relative to body weight. Exposure to 20 ,g prometon/L significantly increased female plasma testosterone concentrations, but the effect was not observed at greater concentrations. Overall, prometon did not significantly reduce fecundity over the 21-d exposure, nor were other endpoints, including plasma vitellogenin and estradiol concentrations, brain and ovary aromatase activity, and male tubercle index, significantly affected. Evidence from our work suggests that prometon may cause subtle endocrine and/or reproductive effects in fathead minnows, but no clear mechanism of action was observed. The relevance of these effects to hazard assessment for the pesticide is uncertain. [source] | |||||||||||||||||||