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

Cancer.gov

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. |

Role of P-450 aromatase in sex determination of the diamondback terrapin, Malaclemys terrapin.

PubMed

Jeyasuria, P; Roosenburg, W M; Place, A R

1994-09-15

Sex determination in the diamondback terrapin, Malaclemys terrapin, is temperature-dependent. Eggs incubated at 31 degrees C, and above, hatch in approximately 45 days as females. Eggs incubated below 27 degrees C hatch in about 60 days as males. Sex is not reversible after hatching. Nest temperatures in the wild can be as low as 20 degrees C and as high as 37 degrees C with as much as a 10 degrees C diel cycle. The shortest incubation time measured in nature was 56 days and the longest approaching 120 days. Nests in our study site produced predominantly (> 95%) male hatchlings. Treatment of developing embryos with estrogen produces females at male producing temperatures while treatment with fadrozole (a nonsteroidal aromatase inhibitor) induces partial male-like gonads. Treatment with a steroidal aromatase inhibitor (4-hydroxyandrostenedione, 4-OHA) had no effect on sex determination. Both fadrozole and 4-OHA are potent competitive inhibitors (Ki approximately 40-50 nM) for terrapin in vitro aromatase activity. These findings are consistent with aromatase expression being a key step in sex determination of terrapins. We have cloned a partial single copy P-450 aromatase from the terrapin using a cDNA library constructed from ovarian mRNA. This partial clone is highly homologous to other vertebrate aromatases.

Mechanism-based Categorization of Aromatase Inhibitors: A Potential Discovery and Screening Tool

EPA Science Inventory

Cytochrome P450 aromatase is a key steroidogenic enzyme that converts androgens to estrogens in vertebrates. There is much interest in aromatase inhibitors (AIs) because a number of environmental contaminants can act as AIs, thereby disrupting endocrine function in humans and wil...

Dry eye syndrome in aromatase inhibitor users.

PubMed

Turaka, Kiran; Nottage, Jennifer M; Hammersmith, Kristin M; Nagra, Parveen K; Rapuano, Christopher J

2013-04-01

Aromatase inhibitors are frequently used as an adjuvant therapy in the treatment of breast cancer. We observed that several patients taking aromatase inhibitors presented with severe dry eye symptoms, and we investigated whether there is a relationship between aromatase inhibitors and dry eyes in these patients. Retrospective chart review. Forty-one women. A computerized search of health records was performed to identify patients using anastrazole, letrozole and exemestane seen by the Cornea Service from August 2008 to March 2011. The results were compared with age-matched controls. Ocular surface changes among aromatase inhibitors users. Of the 41 women, 39 were Caucasians. Thirty-nine patients had breast cancer (95%), one patient had ovarian cancer (2.5%) and one had an unknown primary cancer. Mean age was 68 ± 11.3 years (range 47-95). Most common presenting symptoms were blurred vision in 28 (68%) patients, irritation/foreign body sensation in 12 (29%) patients, redness in 9 (22%) patients, tearing in 6 (22%) patients and photosensitivity in 2 (5%) patients. Mean Schirmer's test measurement was 11 ± 5.8 mm (range 0.5-20 mm). Blepharitis was noted in 68 of 82 eyes (73%), decreased or poor tear function in 24 eyes (29%), conjunctival injection in 18 eyes (22%) and superficial punctate keratitis in 12 eyes (29%). Among an age-matched population (45-95 years), dry eye syndrome was found in only 9.5% of patients. Because the prevalence of ocular surface disease signs and symptoms appears to be higher in study group than control patients, aromatase inhibitors might be a contributing factor to the dry eye symptoms. © 2012 The Authors. Clinical and Experimental Ophthalmology © 2012 Royal Australian and New Zealand College of Ophthalmologists.

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

PubMed Central

Kümler, Iben; Knoop, Ann S; Jessing, Christina A R; Ejlertsen, Bent; Nielsen, Dorte L

2016-01-01

Background Endocrine therapy constitutes a central modality in the treatment of oestrogen receptor (ER)-positive advanced breast cancer. Purpose To evaluate the evidence for endocrine treatment in postmenopausal patients with advanced breast cancer focusing on the aromatase inhibitors, letrozole, anastrozole, exemestane and fulvestrant. Methods A review was carried out using PubMed. Randomised phase II and III trials reporting on ≥100 patients were included. Results 35 trials met the inclusion criteria. If not used in the adjuvant setting, a non-steroid aromatase inhibitor was the optimal first-line option. In general, the efficacy of the different aromatase inhibitors and fulvestrant was similar in tamoxifen-refractory patients. A randomised phase II trial of palbociclib plus letrozole versus letrozole alone showed significantly increased progression-free survival (PFS) when compared with endocrine therapy alone in the first-line setting (20.2 vs 10.2 months). Furthermore, the addition of everolimus to exemestane in the Breast Cancer Trials of OraL EveROlimus-2 (BOLERO-2) study resulted in an extension of median PFS by 4.5 months after recurrence/progression on a non-steroid aromatase inhibitor. However, overall survival was not significantly increased. Conclusion Conventional treatment with an aromatase inhibitor or fulvestrant may be an adequate treatment option for most patients with hormone receptor-positive advanced breast cancer. Mammalian target of rapamycin (mTOR) inhibition and cyclin-dependent kinase 4/6 (CDK4/6) inhibition might represent substantial advances for selected patients in some specific settings. However, there is an urgent need for prospective biomarker-driven trials to identify patients for whom these treatments are cost-effective. PMID:27843622

EVALUATION OF THE AROMATASE INHIBITOR FADROZOLE IN A SHORT-TERM REPRODUCTION ASSAY WITH THE FATHEAD MINNOW (PIMEPHALES PROMELAS)

EPA Science Inventory

Cytochrome P450 aromatase is a key enzyme in vertebrate steroidogenesis, catalyzing the conversion of C19 androgens to C18 estrogens such a B-estradiol (E2). The objective of this study was to assess effects of the CYP inhibitor fadrozole on fathead minnow reproductive endocrinol...

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

EPA Science Inventory

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

Comparing exercise responses to aerobic plus resistance training between postmenopausal breast cancer survivors undergoing aromatase inhibitor therapy and healthy women.

PubMed

Paulo, Thais R S de; Winters-Stone, Kerri M; Viezel, Juliana; Rossi, Fabricio E; Aro, Bruna L; Trindade, Ana Carolina A C; Codogno, Jamile S; Freitas Junior, Ismael F

2018-04-12

The aim of this study was to explore whether postmenopausal breast cancer survivors undergoing aromatase inhibitor therapy differ from healthy postmenopausal women in their response to the same aerobic + resistance training. The participants were separated into two groups: postmenopausal breast cancer survivors undergoing aromatase inhibitor therapy for an average of 20 months (18 women) and healthy postmenopausal women (24 women). We assessed aerobic capacity (predicted maximum oxygen uptake (VO 2 max) and maximum running velocity test (Vmax)) through a walking test, upper and lower body muscle strength using an estimated one-repetition maximum test, and body composition by dual-energy X-ray absorptiometry at baseline and at three, six, and nine months, respectively. The exercise program was performed three times/week over nine months and consisted of 40 min of machine-based strength training (seated cable row, bench press, leg extension, leg press, and leg curl, as well as bridge, abdominal, and standard plank exercises) followed by 30 min of treadmill walking. Analysis of variance (ANOVA) with repeated measures was used to compare the groups over time. Postmenopausal breast cancer survivors undergoing aromatase inhibitor therapy and healthy postmenopausal women presented similar improvements in estimated lower body strength, predicted VO 2max and V max , and body fat mass. For maximal upper body strength, there was a significant group x time interaction after six months of training (p = 0.01). The healthy postmenopausal women presented a significant increase in upper body strength after six months, while postmenopausal breast cancer survivors undergoing aromatase inhibitor therapy demonstrated an improvement only at nine months of training. The breast cancer survivors undergoing aromatase inhibitor therapy presented increased lean mass while healthy postmenopausal women maintained values over time (Breast cancer: 33.7 ± 3.9(Pre) vs. 34.1 ± 3.4 kg (Post) and healthy women: 36.4 ± 5.1 (Pre) vs. 36.4 ± 5.0 kg (Post), p = 0.004). Our findings suggest that postmenopausal women undergoing aromatase inhibitor therapy for breast cancer demonstrated adaptations and similar trainability to the same regimen of resistance + aerobic training as healthy postmenopausal women. Implications for Rehabilitation Combined exercise program (aerobic plus resistance) is an important non-pharmacological strategies to improve strength, aerobic capacity, and body composition in breast cancer survivors undergoing aromatase inhibitor therapy. Furthermore, it is important to highlight that the time of intervention seems to influence the upper body strength response in this population. This study showed that trainers and other specialists do not need to modify the prescription of exercise related to healthy women, since the combined exercise program induced similar benefits in strength, aerobic capacity, and body composition in postmenopausal breast cancer survivors undergoing aromatase inhibitor therapy and healthy postmenopausal women.

Leptin induces CREB-dependent aromatase activation through COX-2 expression in breast cancer cells.

PubMed

Kim, Hyung Gyun; Jin, Sun Woo; Kim, Yong An; Khanal, Tilak; Lee, Gi Ho; Kim, Se Jong; Rhee, Sang Dal; Chung, Young Chul; Hwang, Young Jung; Jeong, Tae Cheon; Jeong, Hye Gwang

2017-08-01

Leptin plays a key role in the control of adipocyte formation, as well as in the associated regulation of energy intake and expenditure. The goal of this study was to determine if leptin-induced aromatase enhances estrogen production and induces tumor cell growth stimulation. To this end, breast cancer cells were incubated with leptin in the absence or presence of inhibitor pretreatment, and changes in aromatase and cyclooxygenase-2 (COX-2) expression were evaluated at the mRNA and protein levels. Transient transfection assays were performed to examine the aromatase and COX-2 gene promoter activities and immunoblot analysis was used to examine protein expression. Leptin induced aromatase expression, estradiol production, and promoter activity in breast cancer cells. Protein levels of phospho-STAT3, PKA, Akt, ERK, and JNK were increased by leptin. Leptin also significantly increased cAMP levels, cAMP response element (CRE) activation, and CREB phosphorylation. In addition, leptin induced COX-2 expression, promoter activity, and increased the production of prostaglandin E 2 . Finally, a COX-2 inhibitor and aromatase inhibitor suppressed leptin-induced cell proliferation in MCF-7 breast cancer cells. Together, our data show that leptin increased aromatase expression in breast cancer cells, which was correlated with COX-2 upregulation, mediated through CRE activation and cooperation among multiple signaling pathways. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

PubMed

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.

Studies on non-steroidal inhibitors of aromatase enzyme; 4-(aryl/heteroaryl)-2-(pyrimidin-2-yl)thiazole derivatives.

PubMed

Sahin, Zafer; Ertas, Merve; Berk, Barkın; Biltekin, Sevde Nur; Yurttas, Leyla; Demirayak, Seref

2018-05-01

Steroidal and non-steroidal aromatase inhibitors target the suppression of estrogen biosynthesis in the treatment of breast cancer. Researchers have increasingly focused on developing non-steroidal derivatives for their potential clinical use avoiding steroidal side-effects. Non-steroidal derivatives generally have planar aromatic structures attached to the azole ring system. One part of this ring system comprises functional groups that inhibit aromatization through the coordination of the haem group of the aromatase enzyme. Replacement of the triazole ring system and development of aromatic/cyclic structures of the side chain can increase selectivity over aromatase enzyme inhibition. In this study, 4-(aryl/heteroaryl)-2-(pyrimidin-2-yl)thiazole derivatives were synthesized and physical analyses and structural determination studies were performed. The IC 50 values were determined by a fluorescence-based aromatase inhibition assay and compound 1 (4-(2-hydroxyphenyl)-2-(pyrimidine-2-yl)thiazole) were found potent inhibitor of enzyme (IC 50 :0.42 nM). Then, their antiproliferative activity over MCF-7 and HEK-293 cell lines was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Compounds 1, 7, 8, 13, 15, 18, 21 were active against MCF-7 breast cancer cells. Lastly, a series of docking experiments were undertaken to analyze the crystal structure of human placental aromatase and identify the possible interactions between the most active structure and the active site. Copyright © 2018 Elsevier Ltd. All rights reserved.

Potential use of COX-2–aromatase inhibitor combinations in breast cancer

PubMed Central

Bundred, N J; Barnes, N L P

2005-01-01

Cyclooxygenase-2 (COX-2) is overexpressed in several epithelial tumours, including breast cancer. Cyclooxygenase-2-positive tumours tend to be larger, higher grade, node-positive and HER-2/neu-positive. High COX-2 expression is associated with poor prognosis. Cyclooxygenase-2 inhibition reduces the incidence of tumours in animal models, inhibits the development of invasive cancer in colorectal cancer and reduces the frequency of polyps in familial adenomatous polyposis (FAP). These effects may be as a result of increased apoptosis, reduced angiogenesis and/or proliferation. Studies of COX-2 inhibitors in breast cancer are underway both alone and in combination with other agents. There is evidence to suggest that combining COX-2 inhibitors with aromatase inhibitors, growth factor receptor blockers, or chemo- or radiotherapy may be particularly effective. Preliminary results from combination therapy with celecoxib and exemestane in postmenopausal women with advanced breast cancer showed that the combination increased the time to recurrence. Up to 80% of ductal carcinomas in situ (DCISs) express COX-2, therefore COX-2 inhibition may be of particular use in this situation. Cyclooxygenase-2 expression correlates strongly with expression of HER-2/neu. As aromatase inhibitors appear particularly effective in patients with HER-2/neu-positive tumours, the combination of aromatase inhibitors and COX-2 inhibitors may be particularly useful in both DCIS and invasive cancer. PMID:16100520

IGF-I stimulates ERβ and aromatase expression via IGF1R/PI3K/AKT-mediated transcriptional activation in endometriosis.

PubMed

Zhou, Yan; Zeng, Cheng; Li, Xin; Wu, Pei-Li; Yin, Ling; Yu, Xiao-Lan; Zhou, Ying-Fang; Xue, Qing

2016-08-01

Estrogen receptor beta (ERβ, encoded by ESR2 gene) and cytochrome P450 aromatase (encoded by CYP19A1 gene) play critical roles in endometriosis, and the levels of insulin-like growth factor-I (IGF-I) in the peritoneal fluid are significantly higher in patients with endometriosis compared with those in normal women. However, the effects and mechanisms of IGF-I on ERβ and aromatase expression remain to be fully elucidated. In this study, human endometriotic stromal cells (ESCs) and endometrial cells (EMs) derived from ovarian endometriomas and eutopic endometrial tissues. ESCs were cultured with IGF-I, signal pathway inhibitors, and siRNAs. ERβ and aromatase expression were measured by real-time PCR and Western, respectively. The binding of c-Jun and CREB to the ESR2 and CYP19A1 promoters was assessed by chromatin immunoprecipitation assay. Animal experiments were performed in a xenograft mouse model. Levels of IGF-I mRNA in ESCs were markedly higher than those in EMs. IGF-I upregulated ERβ and aromatase expression in ESCs after stimulation of the IGF1R/PI3K/AKT pathway. Following IGF-I treatment, a marked increase in c-Jun and CREB phosphorylation occurred, enhancing binding to the ESR2 and CYP19A1 promoters. An IGF1R inhibitor in vivo reduced IGF-I-induced endometriosis graft growth and ERβ and aromatase expression. In conclusion, this is the first report to describe a mechanistic analysis of ERβ and aromatase expression regulated by IGF-I in ESCs. Moreover, an IGF1R inhibitor impeded ectopic lesion growth in nude mice. These findings suggest that an inhibitor of IGF1R might have therapeutic potential as an antiendometriotic drug. Level of IGF-I mRNA in ESCs is markedly higher than that in EMs. IGF-I up-regulates ERβ and aromatase expression via IGF1R/PI3K/AKT pathway. C-Jun and CREB are recruited to ESR2 or CYP19A1 promoter by IGF-I stimulation. IGF-1R inhibitors in vivo impede the growth of ectopic lesions in nude mice.

Functional activation of the estrogen receptor-α and aromatase by the HDAC inhibitor, entinostat, sensitizes of ER-negative tumors to letrozole

PubMed Central

Sabnis, Gauri J; Goloubeva, Olga; Chumsri, Saranya; Nguyen, Nguyen; Sukumar, Saraswati; Brodie, Angela MH

2011-01-01

Approximately 25% of breast cancers do not express the estrogen receptor (ERα) and consequently do not respond to endocrine therapy. In these tumors, ERα repression is often due to epigenetic modifications such as methylation and histone deacetylation. For this reason, we investigated the ability of the histone deacetylase inhibitor entinostat (ENT) to trigger re-expression of ERα and aromatase in breast cancer cells, with the notion that this treatment would restore sensitivity to the aromatase inhibitor letrozole. ENT treatment of tumor cells increased expression of ERα and aromatase along with the enzymatic activity of aromatase, in a dose-dependent manner both in vitro and in vivo. Notably, ERα and aromatase upregulation resulted in sensitization of breast cancer cells to estrogen and letrozole. Tumor growth rate was significantly lower in tumor xenografts following treatment with ENT alone and in combination with letrozole compared to control tumors (p >0.001). ENT plus letrozole also prevented lung colonization and growth of tumor cells with a significant reduction (p>0.03) in both visible and microscopic foci. Our results demonstrate that ENT treatment can be used to restore the letrozole responsiveness of ER-negative tumors. More generally, they provide a strong rationale for immediate clinical evaluation of combinations of histone deacetylase and aromatase inhibitors to treat ER-negative and endocrine-resistant breast cancers. PMID:21245100

Aromatase inhibitors in human lung cancer therapy.

PubMed

Weinberg, Olga K; Marquez-Garban, Diana C; Fishbein, Michael C; Goodglick, Lee; Garban, Hermes J; Dubinett, Steven M; Pietras, Richard J

2005-12-15

Lung cancer is the most common cancer in the world. It is a highly lethal disease in women and men, and new treatments are urgently needed. Previous studies implicated a role of estrogens and estrogen receptors in lung cancer progression, and this steroidal growth-stimulatory pathway may be promoted by tumor expression and activity of aromatase, an estrogen synthase. We found expression of aromatase transcripts and protein in human non-small cell lung cancer (NSCLC) cells using reverse transcription-PCR and Western immunoblots, respectively. Aromatase staining by immunohistochemistry was detected in 86% of archival NSCLC tumor specimens from the clinic. Further, biological activity of aromatase was determined in NSCLC tumors using radiolabeled substrate assays as well as measure of estradiol product using ELISA. Significant activity of aromatase occurred in human NSCLC tumors, with enhanced levels in tumor cells compared with that in nearby normal cells. Lung tumor aromatase activity was inhibited by anastrozole, an aromatase inhibitor, and treatment of tumor cells in vitro with anastrozole led to significant suppression of tumor cell growth. Similarly, among ovariectomized nude mice with A549 lung tumor xenografts, administration of anastrozole by p.o. gavage for 21 days elicited pronounced inhibition of tumor growth in vivo. These findings show that aromatase is present and biologically active in human NSCLCs and that tumor growth can be down-regulated by specific inhibition of aromatase. This work may lead to development of new treatment options for patients afflicted with NSCLC.

Combining Src inhibitors and aromatase inhibitors: a novel strategy for overcoming endocrine resistance and bone loss.

PubMed

Hiscox, Stephen; Barrett-Lee, Peter; Borley, Annabel C; Nicholson, Robert I

2010-08-01

Aromatase inhibitors have largely replaced tamoxifen as the first-line treatment for postmenopausal women with metastatic, hormone receptor-positive (HR+) breast cancer. However, many patients develop clinical resistance with prolonged treatment, and oestrogen deprivation following aromatase inhibition can result in loss of bone mineral density. Furthermore, most patients with metastatic breast cancer develop bone metastases, and the resulting adverse skeletal-related events are a significant cause of patient morbidity. Src, a non-receptor tyrosine kinase, is a component of signalling pathways that regulate breast cancer cell proliferation, invasion and metastasis as well as osteoclast-mediated bone turnover. Preclinical evidence also suggests a role for Src in acquired endocrine resistance. As such, Src inhibition represents a logical strategy for the treatment of metastatic breast cancer. In vitro, combination therapy with Src inhibitors and endocrine agents, including aromatase inhibitors, has been shown to inhibit the proliferation and metastasis of both endocrine-responsive and endocrine-resistant breast cancer cell lines more effectively than either of the therapy alone. Src inhibition has also been shown to suppress osteoclast formation and activity. Combination therapy with aromatase inhibitors and Src inhibitors therefore represents a novel approach through which the development of both acquired resistance and bone pathology could be delayed. Data from clinical trials utilising such combinations will reveal if this strategy has the potential to improve patient outcomes. Copyright 2010 Elsevier Ltd. All rights reserved.

The Breast International Group 1-98 trial: big results for women with hormone-sensitive early breast cancer.

PubMed

Monnier, Alain M

2007-05-01

As there is a risk for relapse in early breast cancer, especially at 1-3 years post surgery, the need for adjuvant therapy is clear. In terms of disease-free survival, aromatase inhibitors have emerged as superior to tamoxifen for the adjuvant treatment of hormone-sensitive breast cancer in several Phase III clinical trials. Of these trials, the Breast International Group (BIG) 1-98 trial stands out as unique in design, as it is the only trial to address whether an aromatase inhibitor is more effective as initial adjuvant therapy or as sequential therapy with an aromatase inhibitor and tamoxifen in either order and in rigor of end points and safety evaluations. When compared with tamoxifen, letrozole has been shown to significantly reduce recurrence risk in the overall population by 19% and also significantly reduced recurrence risk in the patient subgroups at increased risk: node-positive and previously chemotherapy-treated patients. Letrozole is the only aromatase inhibitor to demonstrate a significant 27% reduction in the risk of distant metastases (p = 0.001) in the clinically relevant, hormone receptor-positive population in the initial adjuvant setting. Recent results also suggest that letrozole in particular reduces the risk of distant metastases early on after initial surgery for breast cancer. This is important, as early distant metastatic events compose the majority of early recurrences and are a well-recognized predictor of breast cancer death. Letrozole has been found to be well tolerated in the initial adjuvant treatment setting, and these data have been confirmed by long-term safety data from the monotherapy analysis in the BIG 1-98 study. Thus far, the results from the BIG 1-98 trial provide clear support for the use of letrozole in the initial adjuvant treatment of breast cancer. Future studies will provide the definitive answer to questions of which initial adjuvant therapy is superior (i.e., anastrozole or letrozole) and information as to the optimal treatment strategy (i.e., initial adjuvant aromatase inhibitor therapy or sequential adjuvant aromatase inhibitor therapy).

Inhibition of estrogen biosynthesis with a potent aromatase inhibitor increases predicted adult height in boys with idiopathic short stature: a randomized controlled trial.

PubMed

Hero, Matti; Norjavaara, Ensio; Dunkel, Leo

2005-12-01

In males as well as in females, estrogen is an essential regulator of bone maturation, growth plate fusion, and cessation of longitudinal growth. Therefore, an increase in predicted adult height (PAH) may be achieved in short boys by blocking estrogen biosynthesis. We tested the hypothesis that a decrease in the rate of bone maturation and an increase in PAH can be achieved in boys with idiopathic short stature (ISS) by the method of blocking estrogen biosynthesis with an aromatase inhibitor. Secondarily, we investigated the effects of aromatase inhibition on bone mineralization. This was a prospective, double-blind, randomized, placebo (Pl)-controlled clinical study. The study was performed at a university hospital out-patient clinic. Thirty-one boys, aged 9.0-14.5 yr, with ISS were studied. The boys were treated with the aromatase inhibitor letrozole (Lz; 2.5 mg/d) or Pl for 2 yr. The main outcome measure was the change in PAH after 24 months of treatment. PAH increased by 5.9 cm (P < 0.0001), and height SD score for bone age increased by 0.7 SD score (P < 0.0001) in the Lz-treated boys, whereas no changes occurred in the respective measures in Pl-treated boys. Areal bone mineral density of the lumbar spine and femoral neck, assessed by dual-energy x-ray absorptiometry, increased in a similar fashion in both groups during the treatment, whereas bone mineral apparent density increased only in those taking Lz (median increase, 4.3%; P = 0.009). Treatment with the aromatase inhibitor Lz delays bone maturation and improves PAH in boys with ISS. No adverse effects on bone mineralization were evident after 2 yr of treatment.

Molecular Action and Clinical Relevance of Aromatase Inhibitors.

PubMed

Murphy

1998-01-01

BREAST CANCER: HIGH PREVALENCE AND RISING INCIDENCE: Breast cancer is the most common form of cancer among women in Europe, North and South America and Australasia; approximately 1 in 10 women in Western countries will develop breast cancer during their lifetime. It is estimated that the disease will affect five million women worldwide over the next decade, and the incidence of breast cancer is increasing on average by about 1% per year in industrialized countries and at a greater rate in developing countries. COMPLEX ETIOLOGY: Although the specific etiology of breast cancer remains unknown, a number of factors are recognized which increase a woman's risk of developing the disease. Genetic predisposition, or family history of breast cancer, is known to be responsible for 5% of all cases. However, the variation in incidence throughout populations, and changes relating to population migration and adoption of altered lifestyles, all point to the critical importance of nongenetic determinants. Such factors include early menarche, late menopause, late age at birth of first child or nulliparity, a history of benign breast disease, and diet. There is also evidence that hormones play a major role in the etiology of breast cancer, with the risk of developing malignancies related to the cumulative exposure of the breast to estrogen and progesterone, which stimulate the growth of tumor cells. TREATMENT FOR EARLY BREAST CANCER: SURGERY -/+ ADJUVANT THERAPY: At the time of diagnosis, approximately 50% of patients will be diagnosed with early breast cancer. This proportion is increasing as a consequence of the introduction of early detection programs. Surgery remains the primary treatment for early breast cancer, and the frequency of radical mastectomy has been replaced by breast conserving surgery. After surgery, other therapeutic modalities such as radiation, chemotherapy or endocrine therapy may be given in the adjuvant setting. Surgical cure rates vary for patients with early breast cancer; the US figure is approximately 40%, and there are no definitive means to predict those who will be cured and those who will have recurrent disease. As a result, following primary surgical treatment, adjuvant therapy is usually recommended to destroy any remaining cancer cells at the primary site, to control micrometastases and to prolong disease-free survival, with the ultimate aim of providing an overall survival benefit. Upon disease recurrence in the remaining 60% of patients, endocrine therapy and chemotherapy represent the two general classes of treatment. One of the principle decisions to be taken in advanced breast cancer is which therapy to select in order to maximize patient benefit. The choice is largely dependent upon prognostic factors and whether the patient is pre- or postmenopausal. ENDOCRINE THERAPY OR CHEMOTHERAPY IN ADVANCED BREAST CANCER: Unlike chemotherapy, endocrine therapy is not cytotoxic and is therefore better tolerated by the patient. A recent study comparing therapy for prognostically different groups showed that patients benefiting most from the use of sequential endocrine agents are those regarded as low risk. The preferred sequence of treatment has been suggested to be tamoxifen followed by selective aromatase inhibitor and then a progestin. ENDOCRINES AND ENZYMES OFFER NEW TREATMENTS FOR ADVANCED BREAST CANCER: ESTROGEN-DRIVEN BREAST CANCER: Since 1896, when Sir George Beatson demonstrated that ovariectomy induced regression of mammary tumors in women, the aim of endocrine breast cancer therapy has been to selectively deprive the body of estrogen. Ovariectomy accomplished this by removing the gland that is the predominant source of estrogens in premenopausal women. Since the avoidance of such surgery is preferable, emphasis is devoted to the pharmacological inhibitors of estrogen production. ENDOCRINE PATHWAY REVEALS "ACHILLES' HEEL": Like other steroid hormones, the two circulating estrogens-estrone and estradiol-are produced from cholesterol. Inhibiting the enzymes that are involved at earlier steps in the branching pathway of steroidogenesis could have an undesirable impact on the production of other physiologically important hormones such as aldosterone and cortisol. Since aromatase catalyzes the last step in estrogen production, it makes an ideal target for the development of selective and potent inhibitors (Fig. 1). STRUCTURE OF AROMATASE REVEALS SECRETS OF SELECTIVE INHIBITION: Aromatase is a cytochrome P450 enzyme, with both an iron-containing and a steroid-binding site. The substrate, androstenedione, sits in the enzyme's steroid-binding site, that site which otherwise catalyzes the formation of estrogen. From this structural relationship, there are, therefore, two reasonable ways to inhibit aromatase: * by occupying the steroid-binding site of the enzyme with a compound such as formestane (Lentaron®), or * by binding the iron with nitrogen-containing compounds such as aminoglutethimide (Orimeten®), the oldest aromatase inhibitor. AROMATASE INHIBITORS: STEROIDAL AND NON-STEROIDAL: Formestane (Lentaron®) is the only commercially available steroidal compound which inhibits aromatase and must be administered parenterally. Other new aromatase inhibitors such as fadrozole (Afema®) and letrozole (Femara®) are orally active nitrogen-containing compounds that bind the heme iron of aromatase. AMINOGLUTETHIMIDE VERSUS LETROZOLE: OLD VERSUS NEW: Although aminoglutethimide has long been used to treat advanced breast cancer, its aromatase inhibition is not selective. Consequently, aminoglutethimide also binds to and thereby inhibits several other cytochrome P450 enzymes in the steroidogenesis pathway. An ideal aromatase inhibitor would fit the catalytic site of aromatase optimally and would thus interact only with aromatase. The affinity of letrozole (Femara®) for the heme group of aromatase makes it a selective and potent inhibitor (Fig. 2). In fact, studies show that Femara® has little effect on the other adrenal steroids, and is the most selective aromatase inhibitor available today.

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

PubMed Central

Numazawa, M; Yoshimura, A; Oshibe, M

1998-01-01

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

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Biegon, A.; Biegon, A.; Kim, S.W.

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-minmore » 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.« less

Aromatase inhibition by synthetic lactones and flavonoids in human placental microsomes and breast fibroblasts - A comparative study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meeuwen, J.A. van; Nijmeijer, S.; Mutarapat, T.

2008-05-01

Interference of exogenous chemicals with the aromatase enzyme can be useful as a tool to identify chemicals that could act either chemopreventive for hormone-dependent cancer or adverse endocrine disruptive. Aromatase is the key enzyme in the biosynthesis of steroids, as it converts androgens to estrogens. Certain flavonoids, plant derived chemicals, are known catalytic aromatase inhibitors. Various systems are in use to test aromatase inhibitory properties of compounds. Commonly used are microsomes derived from ovary or placental tissue characterized by high aromatase activity. To a lesser extent whole cell systems are used and specifically cell systems that are potential target tissuemore » in breast cancer development. In this study aromatase inhibitory properties of fadrozole, 8-prenylnaringenin and a synthetic lactone (TM-7) were determined in human placental microsomes and in human primary breast fibroblasts. In addition, apigenin, chrysin, naringenin and two synthetic lactones (TM-8 and TM-9) were tested in human microsomes only. Comparison of the aromatase inhibitory potencies of these compounds between the two test systems showed that the measurement of aromatase inhibition in human placental microsomes is a good predictor of aromatase inhibition in human breast fibroblasts.« less

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

PubMed Central

2017-01-01

Cytochrome P450 aromatase (CYP19A1) plays a key role in the development of estrogen dependent breast cancer, and aromatase inhibitors have been at the front line of treatment for the past three decades. The development of potent, selective and safer inhibitors is ongoing with in silico screening methods playing a more prominent role in the search for promising lead compounds in bioactivity-relevant chemical space. Here we present a set of comprehensive binding affinity prediction models for CYP19A1 using our automated Linear Interaction Energy (LIE) based workflow on a set of 132 putative and structurally diverse aromatase inhibitors obtained from a typical industrial screening study. We extended the workflow with machine learning methods to automatically cluster training and test compounds in order to maximize the number of explained compounds in one or more predictive LIE models. The method uses protein–ligand interaction profiles obtained from Molecular Dynamics (MD) trajectories to help model search and define the applicability domain of the resolved models. Our method was successful in accounting for 86% of the data set in 3 robust models that show high correlation between calculated and observed values for ligand-binding free energies (RMSE < 2.5 kJ mol–1), with good cross-validation statistics. PMID:28776988

Efficacy and mechanism of action of Proellex, an antiprogestin in aromatase overexpressing and Letrozole resistant T47D breast cancer cells.

PubMed

Gupta, Akash; Mehta, Rajeshwari; Alimirah, Fatouma; Peng, Xinjian; Murillo, Genoveva; Wiehle, Ronald; Mehta, Rajendra G

2013-01-01

Aromatase inhibitors (AI) are considered as a first line therapy for ER+PR+ breast cancers. However, many patients acquire resistance to AI. In this study, we determined the response of antiprogestin CDB-4124 (Proellex) on the aromatase overexpressing and Letrozole resistant cell lines and also studies its mechanism of action in inhibition of breast cancer cell proliferation. For these studies we generated aromatase overexpressing T47D (T47Darom) and respective control (T47Dcon) breast cancer cell lines by stable transfection with plasmid containing CYP19A1 gene, or empty vector respectively. Letrozole resistant cell line (T47DaromLR) was generated by incubating T47Darom for 75 weeks in the presence of 10 μM Letrozole. Cell proliferation was determined by MTT or crystal violet assays. Gene expressions were quantified by QRT-PCR whereas proteins were identified by western blot analyses, flow cytometry and immunofluorescence staining. Aromatase activity was determined by estradiol ELISA. The effects of Proellex on the anchorage independent growth were measured by soft agar colony formation. Statistical differences between the various groups were determined by Student's 't' test or ANOVA followed by Bonferroni's post hoc test. Results showed that T47Darom and T47DaromLR cell lines had significantly higher aromatase expression (mRNA; 80-90 fold and protein) and as a result exhibited increased aromatization of testosterone to estradiol as compared to T47Dcon. Both these cell lines showed enhanced growth in the presence of Testosterone (50-60%). In T47DaromLR cells increased PR-B and EGFR expression as compared to T47Dcon cells was observed. Proellex and other known aromatase inhibitors (Letrozole, Anastrozole, and Exemestane) inhibited testosterone induced cell proliferation and anchorage independent growth of T47Darom cells. Cell growth inhibition was significantly greater when cells were treated with Proellex alone or in combination with other AIs as compared to AIs alone. Proellex inhibited mRNA and protein levels of PR-B, reduced PRB/p300 complex formation in the nuclei and significantly reduced EGFR expression in T47Darom cells. Our results in the present study indicate that antiproliferative effect of Proellex is probably due to PR-B/EGFR modulation in ER+PR+, aromatase expressing cells. Overall these results suggest that antiprogestin, Proellex can be developed as a possible treatment strategy for aromatase overexpressing ER+/PR+ breast cancer patients as well as for aromatase inhibitor resistant breast cancer patients. Copyright © 2012 Elsevier Ltd. All rights reserved.

Assessing differences in sensitivity to aromatase inhibitors among freshwater fish species

EPA Science Inventory

There is significant concern regarding potential impairment of fish reproduction associated with exposure to endocrine disrupting chemicals (EDCs). Aromatase is a steroidogenic enzyme involved in the conversion of androgens to estrogens. Inhibition of aromatase activity by exposu...

Assessment of differences in sensitivity to aromatase inhibitors among freshwater fish species

EPA Science Inventory

There is significant concern regarding potential impairment of fish reproduction associated with exposure to endocrine disrupting chemicals (EDCs). Aromatase is a steroidogenic enzyme involved in the conversion of androgens to estrogens. Inhibition of aromatase can reduce levels ...

Aromatase Inhibition in a Transcriptional Network Context

EPA Science Inventory

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 minnow ovaries (FHM, Pimephales promelas) to a model aromatase inhibitor, fadrozole, using a transcriptional ne...

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Biegon, A.; Biegon, A.; Kim, S.-W.

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 largestmore » 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.« less

ALTERATIONS IN THE TRANSCRIPTOME AND PROTEOME OF ZEBRAFISH (DANIO RERIO) EXPOSED TO FADROZOLE, A MODEL AROMATASE INHIBITOR

EPA Science Inventory

Fadrozole is a reversible, competitive inhibitor of aromatase activity and therefore an endocrine-disrupting compound (EDC) that disrupts steroidogenesis by inhibiting the conversion of testosterone to 172-estradiol. While fadrozole is a therapeutic drug with generally no enviro...

Defining the Biological Domain of Applicability of Adverse Outcome Pathways Across Diverse Species: The Estrogen Receptor/Aromatase Case Study

EPA Science Inventory

Aromatase inhibitors (e.g. fadrozole, prochloraz) and estrogen receptor antagonists (e.g. tamoxifen) reduce the circulating concentration of 17β-estradiol, leading to reproductive dysfunction in affected organisms. While these toxic effects are well-characterized in fish and...

Direct Effects, Compensation, and Recovery in Female Fathead Minnows Exposed to the Aromatase Inhibitor Fadrozole

EPA Science Inventory

A variety of chemicals present in the environment have the potential to inhibit aromatase, an enzyme critical to estrogen synthesis. The objective of this study was to provide a detailed characterization of the molecular and biochemical responses of female fathead minnows to a m...

High-Throughput Analysis of Ovarian Cycle Disruption by Mixtures of Aromatase Inhibitors

PubMed Central

Golbamaki-Bakhtyari, Nazanin; Kovarich, Simona; Tebby, Cleo; Gabb, Henry A.; Lemazurier, Emmanuel

2017-01-01

Background: Combining computational toxicology with ExpoCast exposure estimates and ToxCast™ assay data gives us access to predictions of human health risks stemming from exposures to chemical mixtures. Objectives: We explored, through mathematical modeling and simulations, the size of potential effects of random mixtures of aromatase inhibitors on the dynamics of women's menstrual cycles. Methods: We simulated random exposures to millions of potential mixtures of 86 aromatase inhibitors. A pharmacokinetic model of intake and disposition of the chemicals predicted their internal concentration as a function of time (up to 2 y). A ToxCast™ aromatase assay provided concentration–inhibition relationships for each chemical. The resulting total aromatase inhibition was input to a mathematical model of the hormonal hypothalamus–pituitary–ovarian control of ovulation in women. Results: Above 10% inhibition of estradiol synthesis by aromatase inhibitors, noticeable (eventually reversible) effects on ovulation were predicted. Exposures to individual chemicals never led to such effects. In our best estimate, ∼10% of the combined exposures simulated had mild to catastrophic impacts on ovulation. A lower bound on that figure, obtained using an optimistic exposure scenario, was 0.3%. Conclusions: These results demonstrate the possibility to predict large-scale mixture effects for endocrine disrupters with a predictive toxicology approach that is suitable for high-throughput ranking and risk assessment. The size of the effects predicted is consistent with an increased risk of infertility in women from everyday exposures to our chemical environment. https://doi.org/10.1289/EHP742 PMID:28886606

A randomized, controlled clinical trial comparing the effects of aromatase inhibitor (letrozole) and gonadotropin-releasing hormone agonist (triptorelin) on uterine leiomyoma volume and hormonal status.

PubMed

Parsanezhad, Mohammad Ebrahim; Azmoon, Mina; Alborzi, Saeed; Rajaeefard, Abdoreza; Zarei, Afsun; Kazerooni, Talieh; Frank, Vivian; Schmidt, Ernst Hienrich

2010-01-01

To examine and compare the efficacy and safety of GnRH agonist (GnRHa) vs. aromatase inhibitor in premenopausal women with leiomyomas. Multicenter, randomized, controlled clinical trial. University hospitals. A total of 70 subjects with a single uterine myoma measuring >or=5 cm. Subjects were randomized into two groups with use of a random table. They were treated with aromatase inhibitor (group A) or GnRHa (group B). Group A received letrozole (2.5 mg/d) for 12 weeks. Group B received triptorelin (3.75 mg/mo) for 12 weeks. Measurement of myoma volume and E(2), FSH, LH, and T levels. Total myoma volume decreased by 45.6% in group A and 33.2% in group B. Reductions in myoma volume in the two groups were statistically significant. There was no significant change in hormonal milieu in group A. The serum level of hormones significantly decreased in group B by the 12th week of treatment. Uterine myoma volume was successfully reduced by use of an aromatase inhibitor. Rapid onset of action and avoidance of initial gonadotropin flare with an aromatase inhibitor may be advantageous for short-term management of women with myomas of any size who are to be managed transiently and who wish to avoid surgical intervention, specifically women with unexplained infertility having uterine myoma. Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Regulation of aromatase activity in bone-derived cells: possible role of mitogen-activated protein kinase.

PubMed

Shozu, M; Sumitani, H; Murakami, K; Segawa, T; Yang, H J; Inoue, M

2001-12-01

Fetal human osteoblast-like cells and the THP-1 cell line that differentiates into macrophage/osteoblast-like cells in the presence of Vitamin D3 and which possesses high aromatase activity, constitute a useful model with which to study the regulation of aromatase in bone. We showed that dexamethasone (DEX)-induced aromatase activity in the THP-1 cell line is completely suppressed by forskolin and by dibutyryl cAMP. We therefore investigated the contribution of mitogen-activated protein kinase (MAPK) to the regulation of aromatase, because cAMP inhibits MAPK in many cells. We examined the role of MAPK on aromatase activity using PD98059, a selective inhibitor of MEK-1. PD98059 (100 microM) reduced DEX+interleukin (IL)-1beta-induced aromatase activity in human osteoblast-like cells by more than 90%, whereas 50% of the aromatase mRNA concentration was retained compared with the control incubated with DEX+IL-1beta. PD98059 (50 microM) reduced the activity of aromatase in THP-1 cells by 80% without significantly affecting the mRNA level. These results indicated that MAPK plays an important role in aromatase activation at the post-transcriptional level.

Vaginal Gene Expression During Treatment With Aromatase Inhibitors.

PubMed

Kallak, Theodora Kunovac; Baumgart, Juliane; Nilsson, Kerstin; Åkerud, Helena; Poromaa, Inger Sundström; Stavreus-Evers, Anneli

2015-12-01

Aromatase inhibitor (AI) treatment suppresses estrogen biosynthesis and causes genitourinary symptoms of menopause such as vaginal symptoms, ultimately affecting the quality of life for many postmenopausal women with breast cancer. Thus, the aim of this study was to examine vaginal gene expression in women during treatment with AIs compared with estrogen-treated women. The secondary aim was to study the presence and localization of vaginal aromatase. Vaginal biopsies were collected from postmenopausal women treated with AIs and from age-matched control women treated with vaginal estrogen therapy. Differential gene expression was studied with the Affymetrix Gene Chip Gene 1.0 ST Array (Affymetrix Inc, Santa Clara, CA) system, Ingenuity pathway analysis, quantitative real-time polymerase chain reaction, and immunohistochemistry. The expression of 279 genes differed between the 2 groups; AI-treated women had low expression of genes involved in cell differentiation, proliferation, and cell adhesion. Some differentially expressed genes were found to interact indirectly with the estrogen receptor alpha. In addition, aromatase protein staining was evident in the basal and the intermediate vaginal epithelium layers, and also in stromal cells with a slightly stronger staining intensity found in AI-treated women. In this study, we demonstrated that genes involved in cell differentiation, proliferation, and cell adhesion are differentially expressed in AI-treated women. The expression of vaginal aromatase suggests that this could be the result of local and systemic inhibition of aromatase. Our results emphasize the role of estrogen for vaginal cell differentiation and proliferation and future drug candidates should be aimed at improving cell differentiation and proliferation. Copyright © 2015 Elsevier Inc. All rights reserved.

Prenatal administration of letrozole reduces SDN and SCN volume and cell number independent of partner preference in the male rat.

PubMed

Olvera-Hernández, Sandra; Tapia-Rodríguez, Miguel; Swaab, Dick F; Fernández-Guasti, Alonso

2017-03-15

During development, the exposure to testosterone, and its conversion to estradiol by an enzyme complex termed aromatase, appears to be essential in adult male rats for the expression of typical male sexual behavior and female-sex preference. Some hypothalamic areas are the supposed neural bases of sexual preference/orientation; for example, male-oriented rams have a reduced volume of the sexually dimorphic nucleus (oSDN), while in homosexual men this nucleus does not differ from that of heterosexual men. In contrast, homosexual men showed a larger number of vasopressinergic cells in the suprachiasmatic nucleus (SCN). Interestingly, male rats perinatally treated with an aromatase inhibitor, 1,4,6-androstatriene-3,17-dione (ATD), also showed bisexual preference and an increased number of vasopressinergic neurons in the SCN. However, this steroidal aromatase inhibitor has affinity for all three steroid receptors. Recently, we reported that the prenatal administration of the selective aromatase inhibitor, letrozole, produced a subpopulation of males with same-sex preference. The aim of this study was to compare the volume and number of cells of the SDN and SCN (the latter nucleus was immunohistochemically stained for vasopressin) between males treated with letrozole with same-sex preference, males treated with letrozole with female preference and control males with female preference. Results showed that all males prenatally treated with letrozole have a reduced volume and estimated cell number in the SDN and SCN, independent of their partner preference. These results indicate that the changes in these brain areas are not related to sexual preference, but rather to the effects of letrozole. The divergent results may be explained by species differences as well as by the critical windows during which the aromatase inhibitor was administered. Copyright © 2017 Elsevier Inc. All rights reserved.

Altered Gene Expression in the Brain and Ovaries of Zebrafish Exposed to the Aromatase Inhibitor Fadrosole: Microarray Analysis for Hypothesis Generation

EPA Science Inventory

A part of an overall program of research aimed at examining system-wide responses of the hypothalamic-pituitary-gonadal axis in fish to endocrine active chemicals acting through a variety of modes of action, we exposed zebrafish (Danio rerio) to the aromatase inhibitor fadrozole ...

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)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guo, Jiajia; Yuan, Yun; School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang

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 levelsmore » 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 aromatase transcription without affecting its catalytic activity. • They decreased the transcription or protein expression of CREB. • They inhibited p38 MAPK to exert their inhibitory effects on aromatase expression.« less

New endocrine therapies for breast cancer.

PubMed

Howell, A; Downey, S; Anderson, E

1996-04-01

How do the new endocrine therapies stand up to the aims of modern endocrine therapy outlined in Table 1? We wish to see increased efficacy, decreased toxicity and improved general health in women taking a new agent. None of the new non-steroidal anti-oestrogens have shown unequivocal evidence of improved efficacy in the clinic to mirror their improved profiles over tamoxifen in preclinical studies. We know that toremifene is equivalent to tamoxifen, but we do not have any phase III data from the other four compounds in development. The specific steroidal antioestrogen, ICI 182,780, looks very promising, but is early in its developmental programme. The new aromatase inhibitors are likely to prove equal to tamoxifen or progestagens, but it is disappointing that improved oestrogen suppression has not led, to date, to improved efficacy. No comment can be made about adjuvant or preventative therapy for any of the new agents, although trials are planned for the new aromatase inhibitors in this clinical situation. Currently, the antiprogestins are disappointing and we will need to wait a considerable time for new agents in preclinical testing to reach the clinic. Many of the new agents are associated with decreased toxicity. It is likely that the NSAEs will be equitoxic with tamoxifen. The steroidal antioestrogen looks particularly non-toxic as do the new aromatase inhibitors, and thus we have an advance in terms of reduced toxicity. The effects of the new agents on the uterus, lipids and bone are in the early stages of testing. Raloxifene, ICI 182,780 and the new aromatase inhibitors are expected to have no proliferative effects on the endometrium, but only the new NSAEs are expected to have beneficial cardiovascular and skeletal effects. If the steroidal anti-oestrogens and new aromatase inhibitors become adjuvant therapies of choice, other agents to prevent osteoporosis and cardiovascular events may also have to be administered.

Altered Gene Expression in the Brain and Ovaries of Zebrafish Exposed to the Aromatase Inhibitor Fadrozole: Microarray analysis and Hypothesis Generation

EPA Science Inventory

As part of a research effort examining system-wide responses of the hypothalamic-pituitary-gonadal (HPG) axis in fish to endocrine active chemicals (EACs) with different modes of action, we exposed zebrafish (Danio rerio) to 25 or 100 ìg/L of the aromatase inhibitor fadrozole for...

Anti-GD2-ch14.18/CHO coated nanoparticles mediate glioblastoma (GBM)-specific delivery of the aromatase inhibitor, Letrozole, reducing proliferation, migration and chemoresistance in patient-derived GBM tumor cells.

PubMed

Tivnan, Amanda; Heilinger, Tatjana; Ramsey, Joanne M; O'Connor, Gemma; Pokorny, Jenny L; Sarkaria, Jann N; Stringer, Brett W; Day, Bryan W; Boyd, Andrew W; Kim, Ella L; Lode, Holger N; Cryan, Sally-Ann; Prehn, Jochen H M

2017-03-07

Aromatase is a critical enzyme in the irreversible conversion of androgens to oestrogens, with inhibition used clinically in hormone-dependent malignancies. We tested the hypothesis that targeted aromatase inhibition in an aggressive brain cancer called glioblastoma (GBM) may represent a new treatment strategy. In this study, aromatase inhibition was achieved using third generation inhibitor, Letrozole, encapsulated within the core of biodegradable poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs). PLGA-NPs were conjugated to human/mouse chimeric anti-GD2 antibody ch14.18/CHO, enabling specific targeting of GD2-positive GBM cells. Treatment of primary and recurrent patient-derived GBM cells with free-Letrozole (0.1 μM) led to significant decrease in cell proliferation and migration; in addition to reduced spheroid formation. Anti-GD2-ch14.18/CHO-NPs displayed specific targeting of GBM cells in colorectal-glioblastoma co-culture, with subsequent reduction in GBM cell numbers when treated with anti-GD2-ch14.18-PLGA-Let-NPs in combination with temozolomide. As miR-191 is an estrogen responsive microRNA, its expression, fluctuation and role in Letrozole treated GBM cells was evaluated, where treatment with premiR-191 was capable of rescuing the reduced proliferative phenotype induced by aromatase inhibitor. The repurposing and targeted delivery of Letrozole for the treatment of GBM, with the potential role of miR-191 identified, provides novel avenues for target assessment in this aggressive brain cancer.

Anti-GD2-ch14.18/CHO coated nanoparticles mediate glioblastoma (GBM)-specific delivery of the aromatase inhibitor, Letrozole, reducing proliferation, migration and chemoresistance in patient-derived GBM tumor cells

PubMed Central

Tivnan, Amanda; Heilinger, Tatjana; Ramsey, Joanne M; O’Connor, Gemma; Pokorny, Jenny L; Sarkaria, Jann N; Stringer, Brett W; Day, Bryan W; Boyd, Andrew W; Kim, Ella L; Lode, Holger N; Cryan, Sally-Ann; Prehn, Jochen H.M

2017-01-01

Aromatase is a critical enzyme in the irreversible conversion of androgens to oestrogens, with inhibition used clinically in hormone-dependent malignancies. We tested the hypothesis that targeted aromatase inhibition in an aggressive brain cancer called glioblastoma (GBM) may represent a new treatment strategy. In this study, aromatase inhibition was achieved using third generation inhibitor, Letrozole, encapsulated within the core of biodegradable poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs). PLGA-NPs were conjugated to human/mouse chimeric anti-GD2 antibody ch14.18/CHO, enabling specific targeting of GD2-positive GBM cells. Treatment of primary and recurrent patient-derived GBM cells with free-Letrozole (0.1 μM) led to significant decrease in cell proliferation and migration; in addition to reduced spheroid formation. Anti-GD2-ch14.18/CHO-NPs displayed specific targeting of GBM cells in colorectal-glioblastoma co-culture, with subsequent reduction in GBM cell numbers when treated with anti-GD2-ch14.18-PLGA-Let-NPs in combination with temozolomide. As miR-191 is an estrogen responsive microRNA, its expression, fluctuation and role in Letrozole treated GBM cells was evaluated, where treatment with premiR-191 was capable of rescuing the reduced proliferative phenotype induced by aromatase inhibitor. The repurposing and targeted delivery of Letrozole for the treatment of GBM, with the potential role of miR-191 identified, provides novel avenues for target assessment in this aggressive brain cancer. PMID:28178667

Natural Products as Aromatase Inhibitors

PubMed Central

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

2010-01-01

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 purposes (e.g., botanical dietary supplements) may also afford AIs with reduced side effects. A thorough review of the literature regarding natural product extracts and secondary metabolites of plant, microbial, and marine origin that have been shown to exhibit aromatase inhibitory activity is presented herein. PMID:18690828

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Biegon, Anat; Fowler, Joanna S.; Alexoff, David L.

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

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

DOE PAGES

Biegon, Anat; Fowler, Joanna S.; Alexoff, David L.; ...

2015-02-19

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

Targeting the receptor tyrosine kinase RET in combination with aromatase inhibitors in ER positive breast cancer xenografts.

PubMed

Andreucci, Elena; Francica, Paola; Fearns, Antony; Martin, Lesley-Ann; Chiarugi, Paola; Isacke, Clare M; Morandi, Andrea

2016-12-06

The majority of breast cancers are estrogen receptor positive (ER+). Blockade of estrogen biosynthesis by aromatase inhibitors (AIs) is the first-line endocrine therapy for post-menopausal women with ER+ breast cancers. However, AI resistance remains a major challenge. We have demonstrated previously that increased GDNF/RET signaling in ER+ breast cancers promotes AI resistance. Here we investigated the efficacy of different small molecule RET kinase inhibitors, sunitinib, cabozantinib, NVP-BBT594 and NVP-AST487, and the potential of combining a RET inhibitor with the AI letrozole in ER+ breast cancers. The most effective inhibitor identified, NVP-AST487, suppressed GDNF-stimulated RET downstream signaling and 3D tumor spheroid growth. Ovariectomized mice were inoculated with ER+ aromatase-overexpressing MCF7-AROM1 cells and treated with letrozole, NVP-AST487 or the two drugs in combination. Surprisingly, the three treatment regimens showed similar efficacy in impairing MCF7-AROM1 tumor growth in vivo. However in vitro, NVP-AST487 was superior to letrozole in inhibiting the GDNF-induced motility and tumor spheroid growth of MCF7-AROM1 cells and required in combination with letrozole to inhibit GDNF-induced motility in BT474-AROM3 aromatase expressing cells. These data indicate that inhibiting RET is as effective as the current therapeutic regimen of AI therapy but that a combination treatment may delay cancer cell dissemination and metastasis.

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

PubMed

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

2017-08-01

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

Prevention of ER-Negative Breast Cancer

PubMed Central

Li, Yuxin

2014-01-01

The successful demonstration that the selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene reduce the risk of breast cancer has stimulated great interest in using drugs to prevent breast cancer in high-risk women. In addition, recent results from breast cancer treatment trials suggest that aromatase inhibitors may be even more effective at preventing breast cancer than are SERMs. However, while SERMs and aromatase inhibitors do prevent the development of many estrogen-receptor (ER)-positive breast cancers, these drugs do not prevent the development of ER-negative breast cancer. Thus, there is an urgent need to identify agents that can prevent ER-negative breast cancer. We have studied the cancer preventative activity of several classes of drugs for their ability to prevent ER-negative breast cancer in preclinical models. Results from these studies demonstrate that rexinoids (analogs of retinoids that bind and activate RXR receptors), tyrosine kinase inhibitors (such as EGFR inhibitors and dual kinase inhibitors that block EGFR and HER2/neu signaling), and cyclo-oxygenase 2 (COX-2) inhibitors all prevent ER-negative breast cancer in transgenic mice that develop ER-negative breast cancer. Other promising agents now under investigation include vitamin D and vitamin D analogs, drugs that activate PPAR-gamma nuclear receptors, and statins. Many of these agents are now being tested in early phase cancer prevention clinical trials to determine whether they will show activity in breast tissue and whether they are safe for use in high-risk women without breast cancer. The current status of these studies will be reviewed. It is anticipated that in the future, drugs that effectively prevent ER-negative breast cancer will be used in combination with hormonal agents such SERMs or aromatase inhibitors to prevent all forms of breast cancer. PMID:19213564

Long-Term Outcome of Aromatase Inhibitor Therapy With Letrozole in Patients With Advanced Low-Grade Endometrial Stromal Sarcoma.

PubMed

Yamaguchi, Munekage; Erdenebaatar, Chimeddulam; Saito, Fumitaka; Motohara, Takeshi; Miyahara, Yo; Tashiro, Hironori; Katabuchi, Hidetaka

2015-11-01

There has been no consensus on the indications for the treatment of advanced low-grade endometrial stromal sarcoma (LGESS), and the possible effects of hormonal treatment including progestins and aromatase inhibitors have been reported. The aim of this study was to investigate the efficacy of aromatase inhibitor therapy with letrozole for patients with residual or recurrent LGESS. We retrospectively reviewed the clinical response of patients with advanced LGESS who had been treated with letrozole. We also analyzed the adverse effects after the administration of letrozole. The expression levels of estrogen receptor and aromatase in the tumors were immunohistochemically examined. In 5 patients who had been treated for unresectable LGESS lesions after initial or repeat surgical procedures, residual lesions in 3 patients and recurrence lesions in 2 patients were the indications for hormonal therapy with letrozole. The median duration of letrozole exposure at retrospective analysis was 53 (10-96) months. The clinical outcomes were classified as complete response in 2 patients, partial response in 1 patient, and stable disease in 2 patients. Myalgias, hot flashes, and arthralgias were not observed during the follow-up period in any patients. The median serum levels of estradiol were <5.0 (cutoff value, <0.5-11.8) pg/mL. The median age-matched bone mineral densities were 92% (79%-123%). The LGESS tissues in all 5 patients were positive for estrogen receptor and aromatase expression. Letrozole as well as progestins could be the first choice of treatment for patients with recurrent or residual LGESS, which is difficult to resect surgically because of its efficacy and minimal adverse effects.

Prevention and treatment of breast cancer by suppressing aromatase activity and expression.

PubMed

Chen, Shiuan; Zhou, Dujin; Okubo, Tomoharu; Kao, Yeh-Chih; Eng, Elizabeth T; Grube, Baiba; Kwon, Annette; Yang, Chun; Yu, Bin

2002-06-01

Estrogen promotes the proliferation of breast cancer cells. Aromatase is the enzyme that converts androgen to estrogen. In tumors, expression of aromatase is upregulated compared to that of surrounding noncancerous tissue. Tumor aromatase is thought to stimulate breast cancer growth in both an autocrine and a paracrine manner. A treatment strategy for breast cancer is to abolish in situ estrogen formation with aromatase inhibitors. In addition, aromatase suppression in postmenapausal women is being evaluated as a potential chemopreventive modality against breast cancer. One area of aromatase research in this laboratory is the identification of foods and dietary compounds that can suppress aromatase activity. In vitro and in vivo studies have found that grapes and mushrooms contain chemicals that can inhibit aromatase. Therefore, a diet that includes grapes and mushrooms would be considered preventative against breast cancer. Another area of our aromatase research is the elucidation of the regulatory mechanism of aromatase expression in breast cancer tissue. Increased aromatase expression in breast tumors is attributed to changes in the transcriptional control of aromatase expression. Whereas promoter I.4 is the main promoter that controls aromatase expression in noncancerous breast tissue, promoters II and I.3 are the dominant promoters that drive aromatase expression in breast cancer tissue. Our recent gene regulation studies revealed that in cancerous versus normal tissue, several positive regulatory proteins (e.g., nuclear receptors and CREB1) are present at higher levels and several negative regulatory proteins (e.g., snail and slug proteins) are present at lower levels. This may explain why the activity of promoters II and I.3 is upregulated in cancerous tissue. In addition, our in vitro transcription/translation analysis using plasmids containing T7 promoter and the human snail gene as a reporter capped with different untranslated exon Is revealed that exon PII-containing transcripts were translated more effectively than were exon I.3-containing transcripts. An understanding of the molecular mechanisms of aromatase expression between noncancerous and cancerous breast tissue, at both transcriptional and translational levels, may help in the design of a therapy based on suppressing aromatase expression in breast cancer tissue.

Exogenous application of estradiol to eggs unexpectedly induces male development in two turtle species with temperature-dependent sex determination.

PubMed

Warner, Daniel A; Addis, Elizabeth; Du, Wei-guo; Wibbels, Thane; Janzen, Fredric J

2014-09-15

Steroid hormones affect sex determination in a variety of vertebrates. The feminizing effects of exposure to estradiol and the masculinizing effects of aromatase inhibition during development are well established in a broad range of vertebrate taxa, but paradoxical findings are occasionally reported. Four independent experiments were conducted on two turtle species with temperature-dependent sex determination (Chrysemys picta and Chelydra serpentina) to quantify the effects of egg incubation temperature, estradiol, and an aromatase inhibitor on offspring sex ratios. As expected, the warmer incubation temperatures induced female development and the cooler temperatures produced primarily males. However, application of an aromatase inhibitor had no effect on offspring sex ratios, and exogenous applications of estradiol to eggs produced male offspring across all incubation temperatures. These unexpected results were remarkably consistent across all four experiments and both study species. Elevated concentrations of estradiol could interact with androgen receptors or inhibit aromatase expression, which might result in relatively high testosterone concentrations that lead to testis development. These findings add to a short list of studies that report paradoxical effects of steroid hormones, which addresses the need for a more comprehensive understanding of the role of sex steroids in sexual development. Copyright © 2014 Elsevier Inc. All rights reserved.

Investigating the Regulation and Potential Role of Nonhypoxic Hypoxia Inducible Factor 1 (HIF 1) in Aromatase Inhibitor Resistant Breast Cancer

DTIC Science & Technology

2015-12-01

resistance include: 1) cancer stem cell maintenance markers (Oct-4, kit ligand, JARID1B); 2) epithelial- mesenchymal -transition (EMT) markers (Snail...target proteins, such as BCRP andvimentin. BCRP and vimentin contribute to letrozole resistance through their effects on maintaining cacer stem cell ...treatment of acquired AI resistance. 15. SUBJECT TERMS Breast cancer, aromatase inhibitors (ex. letrozole), drug resistance, cancer stem cells ,nonhypoxic

Structural basis for androgen specificity and oestrogen synthesis in human aromatase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ghosh, Debashis; Griswold, Jennifer; Erman, Mary

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 hallmarkmore » 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.« less

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

EPA Science Inventory

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...

Intratumoral concentration of estrogens and clinicopathological changes in ductal carcinoma in situ following aromatase inhibitor letrozole treatment

PubMed Central

Takagi, K; Ishida, T; Miki, Y; Hirakawa, H; Kakugawa, Y; Amano, G; Ebata, A; Mori, N; Nakamura, Y; Watanabe, M; Amari, M; Ohuchi, N; Sasano, H; Suzuki, T

2013-01-01

Background: Estrogens have important roles in ductal carcinoma in situ (DCIS) of the breast. However, the significance of presurgical aromatase inhibitor treatment remains unclear. Therefore, we examined intratumoral concentration of estrogens and changes of clinicopathological factors in DCIS after letrozole treatment. Methods: Ten cases of postmenopausal oestrogen receptor (ER)-positive DCIS were examined. They received oral letrozole before the surgery, and the tumour size was evaluated by ultrasonography. Surgical specimens and corresponding biopsy samples were used for immunohistochemistry. Snap-frozen specimens were also available in a subset of cases, and used for hormone assays and microarray analysis. Results: Intratumoral oestrogen levels were significantly lower in DCIS treated with letrozole compared with that in those without the therapy. A great majority of oestrogen-induced genes showed low expression levels in DCIS treated with letrozole by microarray analysis. Moreover, letrozole treatment reduced the greatest dimension of DCIS, and significantly decreased Ki-67 and progesterone receptor immunoreactivity in DCIS tissues. Conclusion: These results suggest that estrogens are mainly produced by aromatase in DCIS tissues, and aromatase inhibitors potently inhibit oestrogen actions in postmenopausal ER-positive DCIS through rapid deprivation of intratumoral estrogens. PMID:23756858

Methadone: A Substrate and Mechanism-Based Inhibitor of CYP19 (Aromatase)

PubMed Central

Bies, Robert; Kamden, Landry K.; Desta, Zeruesenay; Flockhart, David A.

2010-01-01

The peripheral conversion of testosterone to estradiol by aromatase is the primary source of endogenous estrogen in postmenopausal women. Studies indicating that placental aromatase is able to metabolize methadone to its primary metabolite, 2-ethylidene-1, 5-dimethyl-3, 3-diphenylpyrrolidin (EDDP), led us to test the hypothesis that methadone is able to act as an inhibitor of aromatase. Using recombinant human CYP19, we examined the ability of methadone to bring about either reversible or mechanism-based inhibition of the conversion of testosterone to estradiol. To test for reversible inhibition, racemic methadone or its metabolite EDDP or 2-ethyl-5-methyl-3, 3-diphenylpyrroline (EMDP) was incubated for 30 min with testosterone at the Km (4 μM). To test for mechanism-based inhibition, microsomal preincubations were performed for up to 30 min using racemic methadone (1–1000 μM), R- or S-methadone (0.5–500 μM), or EDDP or EMDP (10 and 100 μM) followed by incubation with testosterone at a Vmax concentration (50 μM). Racemic methadone, EDDP, and EMDP did not act as competitive inhibitors of CYP19. Preincubation of methadone, EDDP, or EMDP with CYP19 resulted in time- and concentration-dependent inhibition, indicating a mechanism-based reaction that destroys CYP19 activity. The KI and kinact values for racemic methadone were calculated to be 40.6 ± 2.8 μM and 0.061 ± 0.001 min−1, respectively. No stereoselectivity was observed. Methadone is metabolized by CYP19 and may act as a potent inhibitor of CYP19 in vivo. These findings may contribute to variability in methadone clearance, to drug-drug interactions, and to side effects observed in individual patients. PMID:20410453

Acute inhibition of neurosteroid estrogen synthesis suppresses status epilepticus in an animal model

PubMed Central

Sato, Satoru M; Woolley, Catherine S

2016-01-01

Status epilepticus (SE) is a common neurological emergency for which new treatments are needed. In vitro studies suggest a novel approach to controlling seizures in SE: acute inhibition of estrogen synthesis in the brain. Here, we show in rats that systemic administration of an aromatase (estrogen synthase) inhibitor after seizure onset strongly suppresses both electrographic and behavioral seizures induced by kainic acid (KA). We found that KA-induced SE stimulates synthesis of estradiol (E2) in the hippocampus, a brain region commonly involved in seizures and where E2 is known to acutely promote neural activity. Hippocampal E2 levels were higher in rats experiencing more severe seizures. Consistent with a seizure-promoting effect of hippocampal estrogen synthesis, intra-hippocampal aromatase inhibition also suppressed seizures. These results reveal neurosteroid estrogen synthesis as a previously unknown factor in the escalation of seizures and suggest that acute administration of aromatase inhibitors may be an effective treatment for SE. DOI: http://dx.doi.org/10.7554/eLife.12917.001 PMID:27083045

Sex Amphibian, Xenopus tropicalis, following Larval Exposure to an Aromatase Inhibitor

EPA Science Inventory

Aromatase is a steroidogenic enzyme that catalyzes the conversion of androgens to estrogens in vertebrates. Modulation of this enzyme’s activity by xenobiotic exposure has been shown to adversely affect gonadal differentiation in a number of diverse species. We hypothesized tha...

Transferrin-conjugated lipid-coated PLGA nanoparticles for targeted delivery of aromatase inhibitor 7alpha-APTADD to breast cancer cells.

PubMed

Zheng, Yu; Yu, Bo; Weecharangsan, Wanlop; Piao, Longzhu; Darby, Michael; Mao, Yicheng; Koynova, Rumiana; Yang, Xiaojuan; Li, Hong; Xu, Songlin; Lee, L James; Sugimoto, Yasuro; Brueggemeier, Robert W; Lee, Robert J

2010-05-10

Transferrin (Tf)-conjugated lipid-coated poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles carrying the aromatase inhibitor, 7alpha-(4'-amino)phenylthio-1,4-androstadiene-3,17-dione (7alpha-APTADD), were synthesized by a solvent injection method. Formulation parameters including PLGA-to-lipid, egg PC-to-TPGS, and drug-to-PLGA ratios and aqueous-to-organic phase ratio at the point of synthesis were optimized to obtain nanoparticles with desired sizes and drug loading efficiency. The optimal formulation had a drug loading efficiency of 36.3+/-3.4%, mean diameter of 170.3+/-7.6nm and zeta potential of -18.9+/-1.5mV. The aromatase inhibition activity of the nanoparticles was evaluated in SKBR-3 breast cancer cells. IC(50) value of the Tf-nanoparticles was ranging from 0.77 to 1.21nM, and IC(50) value of the nanoparticles was ranging from 1.90 to 3.41nM (n=3). The former is significantly lower than the latter (p<0.05). These results suggested that the aromatase inhibition activity of the Tf-nanoparticles was enhanced relative to that of the non-targeted nanoparticles, which was attributable to Tf receptor (TfR) mediated uptake. In conclusion, Tf-conjugated lipid-coated PLGA nanoparticles are potential vehicles for improving the efficiency and specificity of therapeutic delivery of aromatase inhibitors. Copyright 2010 Elsevier B.V. All rights reserved.

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

PubMed Central

2016-01-01

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

Inference of a Transcriptional Network Involved in Chemical Inhibition of Estrogen Synthesis in Fathead Minnow

EPA Science Inventory

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...

A qualitative systematic review of the evidence base for non-cross-resistance between steroidal and non-steroidal aromatase inhibitors in metastatic breast cancer.

PubMed

Beresford, M; Tumur, I; Chakrabarti, J; Barden, J; Rao, N; Makris, A

2011-04-01

The most effective sequence of tamoxifen and both steroidal (SAIs) and non-steroidal aromatase inhibitors (NSAIs) has been extensively studied in the adjuvant setting. However, treatments for women who have failed initial aromatase inhibitor therapy in the metastatic setting have received relatively little attention. A systematic review was undertaken to assess the use of SAIs and NSAIs in metastatic breast cancer. Medline, Embase and the Cochrane library were searched using free text and MeSH terms. Studies assessing the cross-resistance, efficacy and safety of SAIs and NSAIs for postmenopausal women with advanced metastatic breast cancer confirmed by histology/cytology were included. Patients had progressed/relapsed from previous adjuvant, first- or second-line aromatase inhibitor treatment and had undergone treatment with at least two regimens consisting of aminoglutethimide, anastrozole, letrozole and/or exemestane. Nine studies reported results for patients treated with an SAI after treatment failure with an NSAI. For SAI after NSAI, clinical benefit was the most frequently reported outcome. The clinical benefit for exemestane (SAI) after any NSAI failure or before treatment ranged from 12% (complete response not recorded, partial response 2%, stable disease 10%) to 55% (complete response 6%, partial response 13%, stable disease 35%) Survival outcomes were infrequently reported; four studies reported disease progression. The time to progression ranged from 3.7 to 5.2 months. Only one study reported a median overall survival with exemestane at 15.2 months. Only one study reported information for an NSAI after SAI and an NSAI followed by another NSAI. This review suggests that switching from an NSAI to an SAI is a reasonable option. This would be particularly important for patients who would probably respond to further endocrine manoeuvres; strongly oestrogen receptor-positive disease, non-visceral disease, a good prior response or a long duration of response. Further research to optimise the sequence of endocrine therapies in metastatic breast cancer is needed. Copyright © 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

The role of aromatase inhibitors in ameliorating deleterious effects of ovarian stimulation on outcome of infertility treatment

PubMed Central

Mitwally, Mohamed FM; Casper, Robert F; Diamond, Michael P

2005-01-01

Clinical utilization of ovulation stimulation to facilitate the ability of a couple to conceive has not only provided a valuable therapeutic approach, but has also yielded extensive information on the physiology of ovarian follicular recruitment, endometrial receptivity and early embryo competency. One of the consequences of the use of fertility enhancing agents for ovarian stimulation has been the creation of a hyperestrogenic state, which may influence each of these parameters. Use of aromatase inhibitors reduces hyperestrogenism inevitably attained during ovarian stimulation. In addition, the adjunct use of aromatase inhibitors during ovarian stimulation reduces amount of gonadotropins required for optimum stimulation. The unique approach of reducing hyperestrogenism, as well as lowering amount of gonadotropins without affecting the number of mature ovarian follicles is an exciting strategy that could result in improvement in the treatment outcome by ameliorating the deleterious effects of the ovarian stimulation on follicular development, endometrial receptivity, as well as oocyte and embryo quality. PMID:16202169

Caught in a Network: Recovery from Aromatase Inhibition

EPA Science Inventory

Fadrozole is an inhibitor of aromatase, an enzyme critical to estrogen synthesis. We exposed female fathead minnows (Pimephales promelas, FHM) to 0 or 30 ug/L fadrozole for 8 days, and fish were then held in clean water for 8 extra days. We analyzed ex vivo steroid production, pl...

Coadministrating luteolin minimizes the side effects of the aromatase inhibitor letrozole.

PubMed

Li, Fengjuan; Wong, Tsz Yan; Lin, Shu-mei; Chow, Simon; Cheung, Wing-hoi; Chan, Franky L; Chen, Shiuan; Leung, Lai K

2014-11-01

Aromatase inhibitors (AIs) have been used as adjuvant therapeutic agents for breast cancer. Their adverse side effect on blood lipid is well documented. Some natural compounds have been shown to be potential AIs. In the present study, we compared the efficacy of the flavonoid luteolin to the clinically approved AI letrozole (Femara; Novartis Pharmaceuticals, East Hanover, NJ) in a cell and a mouse model. In the in vitro experimental results for aromatase inhibition, the Ki values of luteolin and letrozole were estimated to be 2.44 µM and 0.41 nM, respectively. Both letrozole and luteolin appeared to be competitive inhibitors. Subsequently, an animal model was used for the comparison. Aromatase-expressing MCF-7 cells were transplanted into ovariectomized athymic mice. Luteolin was given by mouth at 5, 20, and 50 mg/kg, whereas letrozole was administered by intravenous injection. Similar to letrozole, luteolin administration reduced plasma estrogen concentrations and suppressed the xenograft proliferation. The regulation of cell cycle and apoptotic proteins-such as a decrease in the expression of Bcl-xL, cyclin-A/D1/E, CDK2/4, and increase in that of Bax-was about the same in both treatments. The most significant disparity was on blood lipids. In contrast to letrozole, luteolin increased fasting plasma high-density lipoprotein concentrations and produced a desirable blood lipid profile. These results suggested that the flavonoid could be a coadjuvant therapeutic agent without impairing the action of AIs. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Insulin-like growth factor I enhances the expression of aromatase P450 by inhibiting autophagy.

PubMed

Zhang, Bo; Shozu, Makio; Okada, Masahiko; Ishikawa, Hiroshi; Kasai, Tadayuki; Murakami, Kouich; Nomura, Kazuhito; Harada, Nobuhiro; Inoue, Masaki

2010-10-01

Aromatase, a key enzyme of estrogen biosynthesis, is transcriptionally regulated by many growth factors. IGF-I enhances aromatase activity in a variety of cells, but the mechanism of action has not been determined. We herein report our finding of a novel mechanism of action for IGF-I. IGF-I enhanced the dexamethasone (DEX)-induced aromatase activity by 30% in serum-starved THP-1 cells. The increase was associated with a corresponding increase in the level of aromatase protein but not with any change in the mRNA level. Metabolic labeling experiments revealed that IGF-I inhibited the degradation of aromatase. We identified pepstatin A as the most effective inhibitor of aromatase degradation by in vitro assay. Using a nontoxic concentration of pepstatin A, we examined IGF-I's action on aromatase distribution in microsomes and lysosomes. In the presence of pepstatin A, DEX caused an increase in the amount of aromatase in both microsomes and lysosomes, and IGF-I attenuated the DEX-induced accumulation of aromatase in lysosomes and, conversely, enhanced its accumulation in the microsomes. The addition of serum abolished the IGF-I-induced changes. The transport from microsome to lysosome was fluorescently traced in cells using a recombinant aromatase. IGF-I selectively reduced the aromatase signal in the lysosomes. Finally, we observed that IGF-I enhanced the aromatase activity by 50% as early as 1 h after treatment; furthermore, rapamycin, an enhancer of autophagy, completely negated the effect of IGF-I on the enzyme. These results indicate that IGF-I enhances aromatase by the inhibition of autophagy.

AROMATASE-B (CYP 19B) EXPRESSION IN FATHEAD MINNOWS (PIMEPHALES PROMELAS) EXPOSED TO PERFLUOROOCTANE (PFOS) AND THE AROMATASE INHIBITOR FADROZOLE

EPA Science Inventory

Perfluorooctane sulfonate (PFOS) is a fluorinated organic contaminant that is globally distributed in both humans and wildlife. PFOS belongs to a family of perfluorinated sulfonates that are highly persistent in the environment and have been commercially produced for over 40 year...

Aromatase inhibitors: the next generation of therapeutics for endometriosis?

PubMed

Attar, Erkut; Bulun, Serdar E

2006-05-01

To review the role of aromatase inhibitors (AIs) in the treatment of endometriosis. Endometriosis is a common estrogen-dependent disorder that can result in substantial morbidity, including pelvic pain, multiple operations, and infertility. Approximately only half of women with endometriosis get pain relief from existing medical or surgical treatments. Medical treatments usually are directed at inhibiting estrogen action or its production from the ovaries and do not address local estrogen biosynthesis by the aromatase enzyme in endometriotic lesions. A single gene encodes aromatase, which is the final enzyme in the estrogen biosynthesis pathway, and its inhibition effectively eliminates estrogen production. The recently introduced highly specific AIs have successfully treated pelvic pain and significantly reduced the lesion size. In premenopausal women, an AI alone may induce ovarian folliculogenesis, and thus AIs are combined with a progestin, a combination oral contraceptive, or a GnRH analogue. The side-effect profile of AIs administered in combination with an oral contraceptive or a progestin is remarkably benign. We review herein the published clinical evidence for the use of AIs in the treatment of endometriosis.

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

PubMed Central

2009-01-01

Background New, third-generation aromatase inhibitors (AIs) have proven comparable or superior to the anti-estrogen tamoxifen for treatment of estrogen receptor (ER) and/or progesterone receptor (PR) positive breast cancer. AIs suppress total body and intratumoral estrogen levels. It is unclear 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 in the synthesis of aromatase, has been suggested as a surrogate marker for aromatase expression. Methods Primary tumor material was retrospectively collected from 88 patients who participated in a randomized clinical trial comparing the AI letrozole to the anti-estrogen tamoxifen for first-line treatment 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 Wilcoxon analysis and the Cox-analysis were performed to evaluate time to progression (TTP) in relation to marker expression. Results Aromatase expression was associated with ER, but not with PR or COX-2 expression in carcinoma cells. Measurements of aromatase in WS were not comparable to results from 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 expression in carcinoma cells to be a surrogate marker for aromatase. In situ aromatase expression in tumor cells is associated with ER expression and may thus point towards good prognosis. Aromatase expression in cancer cells is not predictive of response to endocrine therapy, indicating that in situ estrogen synthesis may not be the major source of intratumoral estrogen. However, aromatase expression in combination with high PR expression may select letrozole treated patients with longer TTP. Trial registration Sub-study of trial P025 for advanced breast cancer. PMID:19531212

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

PubMed Central

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

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

PubMed

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. Copyright © 2015 Elsevier Ltd. All rights reserved.

Are We Ready to Use ESR1 Mutations in Clinical Practice?

PubMed

Jeselsohn, Rinath

2017-10-01

The recurrent ligand-binding domain ESR1 mutations are an important mechanism of endocrine resistance in estrogen receptor-positive (ER+) metastatic breast cancer. These mutations evolve under the selective pressure of endocrine treatments and are rarely found in treatment-naïve ER+ breast cancers. Preclinical studies showed that these mutations lead to ligand-independent activity facilitating resistance to aromatase inhibitors and relative resistance to tamoxifen and fulvestrant. Retrospective analyses of ESR1 mutations in baseline plasma circulating tumor DNA from clinical trials suggest that these mutations are prognostic of poor overall survival and predictive of resistance to aromatase inhibitors in metastatic disease. Larger datasets and prospective studies to confirm these results are lacking. In addition, response to other standard treatments for metastatic breast cancer in the presence of the ESR1 mutations is unknown, and studies to determine the optimal treatment combinations for patients with ESR1 mutations are also needed.

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

PubMed Central

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 aromatase, it may be useful in measuring letrozole distribution and pharmacokinetics in brain and peripheral organs. PMID:19217534

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

PubMed

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

2009-02-01

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

Tolerance of adjuvant letrozole outside of clinical trials.

PubMed

Fontaine, C; Meulemans, A; Huizing, M; Collen, C; Kaufman, L; De Mey, J; Bourgain, C; Verfaillie, G; Lamote, J; Sacre, R; Schallier, D; Neyns, B; Vermorken, J; De Grève, J

2008-08-01

Recently aromatase inhibitors have become a standard care as an adjuvant treatment for many postmenopausal patients with hormone receptor positive early breast cancer. Adjuvant letrozole was made available either immediately postoperative, after 2-3 years of tamoxifen, or as an extended treatment after 5 years of tamoxifen. Between October 2003 and October 2005, we analyzed the subjective tolerance in 185 postoperative early breast cancer patients receiving letrozole outside of a clinical trial. The most prominent toxicity was musculoskeletal pain. In addition hot flushes, increased fatigue, nausea, vomiting, anorexia, mood disturbances, vaginal dryness, hair loss and rash were also recorded. In contrast to the prospective randomized clinical trials, a high drop-out rate of 20% was documented, mainly due to aromatase inhibitor-associated arthralgia syndrome interfering significantly with the daily life of our patients. Although adjuvant aromatase inhibitors have proven to be generally superior to tamoxifen in the adjuvant setting, it is important to focus attention on the tolerance during the adjuvant therapy and to balance this against the potential benefit in individual patients. Alternative options including switching to tamoxifen remain available.

Blockade of oestrogen biosynthesis in peripubertal boys: effects on lipid metabolism, insulin sensitivity, and body composition.

PubMed

Hero, Matti; Ankarberg-Lindgren, Carina; Taskinen, Marja-Riitta; Dunkel, Leo

2006-09-01

In males, the pubertal increase in sex hormone production has been associated with proatherogenic changes in lipid and carbohydrate metabolism. Aromatase inhibitors, a novel treatment modality for some growth disorders, may significantly influence these risk factors for cardiovascular disease by suppressing oestrogen biosynthesis and stimulating gonadal androgen production. In the current study, we explored the effects of aromatase inhibition on lipid metabolism, insulin sensitivity, body composition and serum adiponectin in peripubertal boys. Prospective, double-blind, randomised, placebo-controlled clinical study. Thirty-one boys, aged 9.0-14.5 years, with idiopathic short stature were treated with the aromatase inhibitor letrozole (2.5 mg/day) or placebo for 2 years. During the treatment, the concentrations of sex hormones, IGF-I, lipids, lipoproteins and adiponectin were followed-up. The percentage of fat mass (FM) was assessed by skinfold measurements and insulin resistance by homeostasis model assessment (HOMA) index. In pubertal boys, who received letrozole, high-density lipoprotein cholesterol (HDL-C) decreased by 0.47 mmol/l (P<0.01) during the study. Simultaneously, their percentage of FM decreased from 17.0 to 10.5 (P<0.001), in an inverse relationship with serum testosterone. The concentrations of low-density lipoprotein cholesterol, triglycerides and HOMA index remained at pretreatment level in both groups. Serum adiponectin decreased similarly in letrozole- and placebo-treated pubertal boys (2.9 and 3.3 mg/l respectively). In males, aromatase inhibition reduces HDL-C and decreases relative FM after the start of puberty. The treatment does not adversely affect insulin sensitivity in lean subjects.

Nandrolone and stanozolol induce Leydig cell tumor proliferation through an estrogen-dependent mechanism involving IGF-I system.

PubMed

Chimento, Adele; Sirianni, Rosa; Zolea, Fabiana; De Luca, Arianna; Lanzino, Marilena; Catalano, Stefania; Andò, Sebastiano; Pezzi, Vincenzo

2012-05-01

Several substances such as anabolic androgenic steroids (AAS), peptide hormones like insulin-like growth factor-I (IGF-I), aromatase inhibitors and estrogen antagonists are offered via the Internet, and are assumed without considering the potential deleterious effects that can be caused by their administration. In this study we aimed to determine if nandrolone and stanozolol, two commonly used AAS, could have an effect on Leydig cell tumor proliferation and if their effects could be potentiated by the concomitant use of IGF-I. Using a rat Leydig tumor cell line, R2C cells, as experimental model we found that nandrolone and stanozolol caused a dose-dependent induction of aromatase expression and estradiol (E2) production. When used in combination with IGF-I they were more effective than single molecules in inducing aromatase expression. AAS exhibited estrogenic activity and induced rapid estrogen receptor (ER)-dependent pathways involving IGF1R, AKT, and ERK1/2 phosphorylation. Inhibitors for these kinases decreased AAS-dependent aromatase expression. Up-regulated aromatase levels and related E2 production increased cell proliferation as a consequence of increased cyclin E expression. The observation that ER antagonist ICI182,780 was also able to significantly reduce ASS- and AAS + IGF-induced cell proliferation, confirmed a role for estrogens in AAS-dependent proliferative effects. Taken together these data clearly indicate that the use of high doses of AAS, as it occurs in doping practice, enhances Leydig cell proliferation, increasing the risk of tumor development. This risk is higher when AAS are used in association with IGF-I. To our knowledge this is the first report directly associating AAS and testicular cancer. Copyright © 2011 Wiley Periodicals, Inc.

Mechanisms of Aromatase Inhibitor-induced Musculoskeletal Symptoms

DTIC Science & Technology

2012-07-01

through the TRPV1 cation channel, an important chemical and thermal nociceptive transducer (15). In addition to steroids supplied by circulation in...identify whether aromatase expression co-localizes with functional neuronal populations, such as TRPV1 or CGRP expressing sensory neurons...to augment neuropeptide release from cultured sensory neurons evoked by the inflammatory mediator bradykinin and TRPV1 -selective agonist capsaicin (17

Synthesis and evaluation of a dimer of 2-(4-pyridylmethyl)-1-indanone as a novel nonsteroidal aromatase inhibitor.

PubMed

Gupta, Ranju; Jindal, Dharam Paul; Jit, Birinder; Narang, Gaurav; Palusczak, Anja; Hartmann, Rolf W

2004-07-01

A novel dimer of 2-(4-pyridylmethyl)-1-indanone (2) was obtained while carrying out aldol condensation of 1-indanone with pyridine-4-carboxaldehyde in potassium hydroxide. The structure of dimer 3 has been established using various spectral techniques and was screened for its ability to inhibit the cytochrome P(450) enzyme aromatase. The dimer showed strong inhibition of human placental aromatase and was found 3 times more potent (RP = 3, IC(50) = 10.2 microM) as compared to aminoglutethimide (RP = 1, IC(50) = 18.5 microM.

Pyridine-substituted thiazolylphenol derivatives: Synthesis, modeling studies, aromatase inhibition, and antiproliferative activity evaluation.

PubMed

Ertas, Merve; Sahin, Zafer; Berk, Barkin; Yurttas, Leyla; Biltekin, Sevde N; Demirayak, Seref

2018-04-01

Drugs used in breast cancer treatments target the suppression of estrogen biosynthesis. During this suppression, the main goal is to inhibit the aromatase enzyme that is responsible for the cyclization and structuring of estrogens either with steroid or non-steroidal-type inhibitors. Non-steroidal derivatives generally have a planar aromatic structure attached to the triazole ring system in their structures, which inhibits hydroxylation reactions during aromatization by coordinating the heme group. Bioisosteric replacement of the triazole ring system and development of aromatic/cyclic structures of the side chain can increase the selectivity for aromatase enzyme inhibition. In this study, pyridine-substituted thiazolylphenol derivatives, which are non-steroidal triazole bioisosteres, were synthesized using the Hantzsch method, and physical analysis and structural determination studies were performed. The IC 50 values of the compounds were determined by a fluorescence-based aromatase inhibition assay. Then, their antiproliferative activities on the MCF7 and HEK 293 cell lines were evaluated with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Furthermore, the crystal structure of human placental aromatase was subjected to a series of docking experiments to identify the possible interactions between the most active structure and the active site. Lastly, an in silico technique was performed to analyze and predict the drug-likeness, molecular and ADME properties of the synthesized molecules. © 2018 Deutsche Pharmazeutische Gesellschaft.

Adjuvant anastrozole versus exemestane versus letrozole, upfront or after 2 years of tamoxifen, in endocrine-sensitive breast cancer (FATA-GIM3): a randomised, phase 3 trial.

PubMed

De Placido, Sabino; Gallo, Ciro; De Laurentiis, Michelino; Bisagni, Giancarlo; Arpino, Grazia; Sarobba, Maria Giuseppa; Riccardi, Ferdinando; Russo, Antonio; Del Mastro, Lucia; Cogoni, Alessio Aligi; Cognetti, Francesco; Gori, Stefania; Foglietta, Jennifer; Frassoldati, Antonio; Amoroso, Domenico; Laudadio, Lucio; Moscetti, Luca; Montemurro, Filippo; Verusio, Claudio; Bernardo, Antonio; Lorusso, Vito; Gravina, Adriano; Moretti, Gabriella; Lauria, Rossella; Lai, Antonella; Mocerino, Carmela; Rizzo, Sergio; Nuzzo, Francesco; Carlini, Paolo; Perrone, Francesco

2018-04-01

Uncertainty exists about the optimal schedule of adjuvant treatment of breast cancer with aromatase inhibitors and, to our knowledge, no trial has directly compared the three aromatase inhibitors anastrozole, exemestane, and letrozole. We investigated the schedule and type of aromatase inhibitors to be used as adjuvant treatment for hormone receptor-positive early breast cancer. FATA-GIM3 is a multicentre, open-label, randomised, phase 3 trial of six different treatments in postmenopausal women with hormone receptor-positive early breast cancer. Eligible patients had histologically confirmed invasive hormone receptor-positive breast cancer that had been completely removed by surgery, any pathological tumour size, and axillary nodal status. Key exclusion criteria were hormone replacement therapy, recurrent or metastatic disease, previous treatment with tamoxifen, and another malignancy in the previous 10 years. Patients were randomly assigned in an equal ratio to one of six treatment groups: oral anastrozole (1 mg per day), exemestane (25 mg per day), or letrozole (2·5 mg per day) tablets upfront for 5 years (upfront strategy) or oral tamoxifen (20 mg per day) for 2 years followed by oral administration of one of the three aromatase inhibitors for 3 years (switch strategy). Randomisation was done by a computerised minimisation procedure stratified for oestrogen receptor, progesterone receptor, and HER2 status; previous chemotherapy; and pathological nodal status. Neither the patients nor the physicians were masked to treatment allocation. The primary endpoint was disease-free survival. The minimum cutoff to declare superiority of the upfront strategy over the switch strategy was assumed to be a 2% difference in disease-free survival at 5 years. Primary efficacy analyses were done by intention to treat; safety analyses included all patients for whom at least one safety case report form had been completed. Follow-up is ongoing. This trial is registered with the European Clinical Trials Database, number 2006-004018-42, and ClinicalTrials.gov, number NCT00541086. Between March 9, 2007, and July 31, 2012, 3697 patients were enrolled into the study. After a median follow-up of 60 months (IQR 46-72), 401 disease-free survival events were reported, including 211 (11%) of 1850 patients allocated to the switch strategy and 190 (10%) of 1847 patients allocated to upfront treatment. 5-year disease-free survival was 88·5% (95% CI 86·7-90·0) with the switch strategy and 89·8% (88·2-91·2) with upfront treatment (hazard ratio 0·89, 95% CI 0·73-1·08; p=0·23). 5-year disease-free survival was 90·0% (95% CI 87·9-91·7) with anastrozole (124 events), 88·0% (85·8-89·9) with exemestane (148 events), and 89·4% (87·3 to 91·1) with letrozole (129 events; p=0·24). No unexpected serious adverse reactions or treatment-related deaths occurred. Musculoskeletal side-effects were the most frequent grade 3-4 events, reported in 130 (7%) of 1761 patients who received the switch strategy and 128 (7%) of 1766 patients who received upfront treatment. Grade 1 musculoskeletal events were more frequent with the upfront schedule than with the switch schedule (924 [52%] of 1766 patients vs 745 [42%] of 1761 patients). All other grade 3-4 adverse events occurred in less than 2% of patients in either group. 5 years of treatment with aromatase inhibitors was not superior to 2 years of tamoxifen followed by 3 years of aromatase inhibitors. None of the three aromatase inhibitors was superior to the others in terms of efficacy. Therefore, patient preference, tolerability, and financial constraints should be considered when deciding the optimal treatment approach in this setting. Italian Drug Agency. Copyright © 2018 Elsevier Ltd. All rights reserved.

Sulfonanilide Derivatives in Identifying Novel Aromatase Inhibitors by Applying Docking, Virtual Screening, and MD Simulations Studies

PubMed Central

Son, Minky; Park, Chanin; Kim, Hyong-Ha; Suh, Jung-Keun

2017-01-01

Breast cancer is one of the leading causes of death noticed in women across the world. Of late the most successful treatments rendered are the use of aromatase inhibitors (AIs). In the current study, a two-way approach for the identification of novel leads has been adapted. 81 chemical compounds were assessed to understand their potentiality against aromatase along with the four known drugs. Docking was performed employing the CDOCKER protocol available on the Discovery Studio (DS v4.5). Exemestane has displayed a higher dock score among the known drug candidates and is labeled as reference. Out of 81 ligands 14 have exhibited higher dock scores than the reference. In the second approach, these 14 compounds were utilized for the generation of the pharmacophore. The validated four-featured pharmacophore was then allowed to screen Chembridge database and the potential Hits were obtained after subjecting them to Lipinski's rule of five and the ADMET properties. Subsequently, the acquired 3,050 Hits were escalated to molecular docking utilizing GOLD v5.0. Finally, the obtained Hits were consequently represented to be ideal lead candidates that were escalated to the MD simulations and binding free energy calculations. Additionally, the gene-disease association was performed to delineate the associated disease caused by CYP19A1. PMID:29312992

Sulfonanilide Derivatives in Identifying Novel Aromatase Inhibitors by Applying Docking, Virtual Screening, and MD Simulations Studies.

PubMed

Rampogu, Shailima; Son, Minky; Park, Chanin; Kim, Hyong-Ha; Suh, Jung-Keun; Lee, Keun Woo

2017-01-01

Breast cancer is one of the leading causes of death noticed in women across the world. Of late the most successful treatments rendered are the use of aromatase inhibitors (AIs). In the current study, a two-way approach for the identification of novel leads has been adapted. 81 chemical compounds were assessed to understand their potentiality against aromatase along with the four known drugs. Docking was performed employing the CDOCKER protocol available on the Discovery Studio (DS v4.5). Exemestane has displayed a higher dock score among the known drug candidates and is labeled as reference. Out of 81 ligands 14 have exhibited higher dock scores than the reference. In the second approach, these 14 compounds were utilized for the generation of the pharmacophore. The validated four-featured pharmacophore was then allowed to screen Chembridge database and the potential Hits were obtained after subjecting them to Lipinski's rule of five and the ADMET properties. Subsequently, the acquired 3,050 Hits were escalated to molecular docking utilizing GOLD v5.0. Finally, the obtained Hits were consequently represented to be ideal lead candidates that were escalated to the MD simulations and binding free energy calculations. Additionally, the gene-disease association was performed to delineate the associated disease caused by CYP19A1.

Short report: Monitoring ESR1 mutations by circulating tumor DNA in aromatase inhibitor resistant metastatic breast cancer.

PubMed

Sefrioui, David; Perdrix, Anne; Sarafan-Vasseur, Nasrin; Dolfus, Claire; Dujon, Antoine; Picquenot, Jean-Michel; Delacour, Julien; Cornic, Marie; Bohers, Elodie; Leheurteur, Marianne; Rigal, Olivier; Tennevet, Isabelle; Thery, Jean-Christophe; Alexandru, Cristina; Guillemet, Cécile; Moldovan, Cristian; Veyret, Corinne; Frebourg, Thierry; Di Fiore, Frédéric; Clatot, Florian

2015-11-15

Acquired estrogen receptor gene (ESR1) mutations have been recently reported as a marker of resistance to aromatase inhibitors in hormone receptor positive metastatic breast cancer. We retrospectively considered seven patients treated for metastatic breast cancer with available samples from the primary tumor before any treatment, cryopreserved metastasis removed during progression and concomitant plasmas. All these seven patients were in disease progression after previous exposure to aromatase inhibitors for at least 6 months, and were assessed for ESR1 mutations detection in tumor and circulating DNA. For these patients, Sanger sequencing identified four metastases with clear ESR1 mutation and one possible, whereas digital PCR identified six mutated metastases. Then, under blind conditions and using digital PCR, corresponding circulating ESR1 mutations were successfully detected in four of these six metastatic breast cancer patients. Moreover, in two patients with serial blood samples following treatments exposure, the monitoring of circulating ESR1 mutations clearly predicted disease evolution. In the context of high interest for ESR1 mutations, our results highlight that these acquired recurrent mutations may be tracked in circulating tumor DNA and may be of clinical relevance for metastatic breast cancer patient monitoring. © 2015 UICC.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Duursen, Majorie B.M. van, E-mail: M.vanDuursen@uu.nl; Smeets, Evelien E.J.W.; Rijk, Jeroen C.W.

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 adrenocorticocarcinomamore » 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 cancer model. • Letrozole or tamoxifen treatment is used to inhibit ER-dependent breast tumor growth. • Phytoestrogens induce in vitro tumor cell growth, even in combination with LET or TAM. • Use of phytoestrogens during breast cancer treatment should better be avoided.« less

Randomized Phase II, Double-Blind, Placebo-Controlled Study of Exemestane With or Without Entinostat in Postmenopausal Women With Locally Recurrent or Metastatic Estrogen Receptor-Positive Breast Cancer Progressing on Treatment With a Nonsteroidal Aromatase Inhibitor

PubMed Central

Yardley, Denise A.; Ismail-Khan, Roohi R.; Melichar, Bohuslav; Lichinitser, Mikhail; Munster, Pamela N.; Klein, Pamela M.; Cruickshank, Scott; Miller, Kathy D.; Lee, Min J.; Trepel, Jane B

2013-01-01

Purpose Entinostat is an oral isoform selective histone deacetylase inhibitor that targets resistance to hormonal therapies in estrogen receptor–positive (ER+) breast cancer. This randomized, placebo-controlled, phase II study evaluated entinostat combined with the aromatase inhibitor exemestane versus exemestane alone. Patients and Methods Postmenopausal women with ER+ advanced breast cancer progressing on a nonsteroidal aromatase inhibitor were randomly assigned to exemestane 25 mg daily plus entinostat 5 mg once per week (EE) or exemestane plus placebo (EP). The primary end point was progression-free survival (PFS). Blood was collected in a subset of patients for evaluation of protein lysine acetylation as a biomarker of entinostat activity. Results One hundred thirty patients were randomly assigned (EE group, n = 64; EP group, n = 66). Based on intent-to-treat analysis, treatment with EE improved median PFS to 4.3 months versus 2.3 months with EP (hazard ratio [HR], 0.73; 95% CI, 0.50 to 1.07; one-sided P = .055; two-sided P = .11 [predefined significance level of .10, one-sided]). Median overall survival was an exploratory end point and improved to 28.1 months with EE versus 19.8 months with EP (HR, 0.59; 95% CI, 0.36 to 0.97; P = .036). Fatigue and neutropenia were the most frequent grade 3/4 toxicities. Treatment discontinuation because of adverse events was higher in the EE group versus the EP group (11% v 2%). Protein lysine hyperacetylation in the EE biomarker subset was associated with prolonged PFS. Conclusion Entinostat added to exemestane is generally well tolerated and demonstrated activity in patients with ER+ advanced breast cancer in this signal-finding phase II study. Acetylation changes may provide an opportunity to maximize clinical benefit with entinostat. Plans for a confirmatory study are underway. PMID:23650416

Femara® and the future: tailoring treatment and combination therapies with Femara

PubMed Central

Ma, Cynthia

2007-01-01

Long-term estrogen deprivation treatment for breast cancer can, in some patients, lead to the activation of alternate cellular pathways, resulting in the re-emergence of the disease. This is a distressing scenario for oncologists and patients, but recent intensive molecular and biochemical studies are beginning to unravel these pathways, revealing opportunities for new targeted treatments. Far from making present therapies redundant, these new discoveries open the door to novel combination therapies that promise to provide enhanced efficacy or overcome treatment resistance. Letrozole, one of the most potent aromatase inhibitors, is the ideal candidate for combination therapy; indeed, it is one of the most intensively studied aromatase inhibitors in the evolving combinatorial setting. Complementary to the use of combination therapy is the development of molecular tools to identify patients who will benefit the most from these new treatments. Microarray gene profiling studies, designed to detect letrozole-responsive targets, are currently under way to understand how the use of the drug can be tailored more efficiently to specific patient needs. PMID:17912640

Side effects of anastrozole in the experimental pre-menopausal mammary carcinogenesis.

PubMed

Sadlonova, V; Kubatka, P; Kajo, K; Ostatnikova, D; Nosalova, G; Adamicova, K; Sadlonova, J

2009-01-01

The aim of this study was to assess side effects of aromatase inhibitor anastrozole in the prevention of N-methyl-N-nitrosourea - induced pre-menopausal mammary carcinogenesis in female Sprague-Dawley rats. This model mimicked situation in healthy, but from the point of view of the development of breast cancer, high-risk pre-menopausal women.

Aromatase inhibitor anastrozole was used as a chemopreventive agent taken by the animals in the food during the whole period of time of the experiment. Group 1 - the control group had taken food without anastrozole, the groups 2 and 3 with anastrozole in various concentrations - 0.05 mg/1 kg of food (ANA 0.05) and 0.5 mg/1 kg of food (ANA 0.5).

In anastrozole-treated animals in comparison with untreated animals, macroscopic changes of uterus and vagina were not found. The values of absolute and relative wet weight of uterus and vagina in the groups ANA 0.05 and ANA 0.5 were comparable with the control. Histological examination did not show atrophic changes in endometrium of uterus and in epithelium of vagina in anastrozole-treated animals. In the group ANA 0.5 myometrium was significantly grosser than in the group ANA 0.05 (P<0.05). Anastrozole neither affects parameters of plasma lipid metabolism (triacylglycerols, total cholesterol, low - density lipoprotein cholesterol and high - density lipoprotein cholesterol) nor serum levels of sex hormones (estradiol, testosterone, dehydroepiandrosterone). Compact bone thickness in the groups with anastrozole was significantly increased in comparison with untreated animals (P<0.001). A significant increase in body weight was found in the group ANA 0.5 compared with the control group (P<0.01). The significant increase in body weight gain was not attended by the significant increase in food intake.

The side effects of aromatase inhibitor anastrozole in the prevention of N-methyl-N-nitrosourea - induced pre-menopausal mammary carcinogenesis in female Sprague-Dawley rats on myometrium, compact bone thickness and body weight gain were observed.

Quantitative Adverse Outcome Pathways and Their ...

EPA Pesticide Factsheets

A quantitative adverse outcome pathway (qAOP) consists of one or more biologically based, computational models describing key event relationships linking a molecular initiating event (MIE) to an adverse outcome. A qAOP provides quantitative, dose–response, and time-course predictions that can support regulatory decision-making. Herein we describe several facets of qAOPs, including (a) motivation for development, (b) technical considerations, (c) evaluation of confidence, and (d) potential applications. The qAOP used as an illustrative example for these points describes the linkage between inhibition of cytochrome P450 19A aromatase (the MIE) and population-level decreases in the fathead minnow (FHM; Pimephales promelas). The qAOP consists of three linked computational models for the following: (a) the hypothalamic-pitutitary-gonadal axis in female FHMs, where aromatase inhibition decreases the conversion of testosterone to 17β-estradiol (E2), thereby reducing E2-dependent vitellogenin (VTG; egg yolk protein precursor) synthesis, (b) VTG-dependent egg development and spawning (fecundity), and (c) fecundity-dependent population trajectory. While development of the example qAOP was based on experiments with FHMs exposed to the aromatase inhibitor fadrozole, we also show how a toxic equivalence (TEQ) calculation allows use of the qAOP to predict effects of another, untested aromatase inhibitor, iprodione. While qAOP development can be resource-intensive, the quan

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

NASA Astrophysics Data System (ADS)

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.

A Study to Evaluate Genetic Predictors of Aromatase Inhibitor Musculoskeletal Symptoms (AIMSS)

ClinicalTrials.gov

2015-05-07

Estrogen Receptor-positive Breast Cancer; Musculoskeletal Complications; Progesterone Receptor-positive Breast Cancer; Recurrent Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

Acupuncture Reduces Breast Cancer Joint Pain | Division of Cancer Prevention

Cancer.gov

In the largest, most rigorous study of its kind, acupuncture was found to significantly reduce the debilitating joint pain experienced by tens of thousands of women each year while being treated for early stage breast cancer with aromatase inhibitors (AIs). |

GP88 (PC-Cell Derived Growth Factor, progranulin) stimulates proliferation and confers letrozole resistance to aromatase overexpressing breast cancer cells

PubMed Central

2011-01-01

Background Aromatase inhibitors (AI) that inhibit breast cancer cell growth by blocking estrogen synthesis have become the treatment of choice for post-menopausal women with estrogen receptor positive (ER+) breast cancer. However, some patients display de novo or acquired resistance to AI. Interactions between estrogen and growth factor signaling pathways have been identified in estrogen-responsive cells as one possible reason for acquisition of resistance. Our laboratory has characterized an autocrine growth factor overexpressed in invasive ductal carcinoma named PC-Cell Derived Growth Factor (GP88), also known as progranulin. In the present study, we investigated the role GP88 on the acquisition of resistance to letrozole in ER+ breast cancer cells Methods We used two aromatase overexpressing human breast cancer cell lines MCF-7-CA cells and AC1 cells and their letrozole resistant counterparts as study models. Effect of stimulating or inhibiting GP88 expression on proliferation, anchorage-independent growth, survival and letrozole responsiveness was examined. Results GP88 induced cell proliferation and conferred letrozole resistance in a time- and dose-dependent fashion. Conversely, naturally letrozole resistant breast cancer cells displayed a 10-fold increase in GP88 expression when compared to letrozole sensitive cells. GP88 overexpression, or exogenous addition blocked the inhibitory effect of letrozole on proliferation, and stimulated survival and soft agar colony formation. In letrozole resistant cells, silencing GP88 by siRNA inhibited cell proliferation and restored their sensitivity to letrozole. Conclusion Our findings provide information on the role of an alternate growth and survival factor on the acquisition of aromatase inhibitor resistance in ER+ breast cancer. PMID:21658239

Higher than expected estradiol levels in aromatase inhibitor-treated, postmenopausal breast cancer patients.

PubMed

Kunovac Kallak, T; Baumgart, J; Stavreus Evers, A; Sundström Poromaa, I; Moby, L; Kask, K; Norjavaara, E; Kushnir, M M; Bergquist, J; Nilsson, K

2012-10-01

Vaginal estradiol is considered contraindicated in aromatase inhibitor (AI)-treated patients because of the risk of elevated estrogen levels. This leaves limited treatment options for patients experiencing gynecological symptoms. However, in clinical practice, no precise estimation has been performed of circulating estrogens and aromatase index in postmenopausal breast cancer patients on long-lasting AI or tamoxifen treatment. Steroid hormones were measured using liquid chromatography tandem mass spectrometry (LC-MS/MS) and extraction radioimmunoassay (RIA). Postmenopausal AI-treated patients (n =33) were compared with tamoxifen-treated patients (n =34) and controls without vaginal treatment (n =56), with vaginal estradiol (n =25), or with estriol (n =11) treatment. By use of LC-MS/MS, median (range) estradiol plasma concentrations were 16.7 (2.4-162.6), 31.0 (13.4-77.1), 27.2 (7.8-115.8) and 33.3 (20.3-340.1) pmol/l in AI-treated breast cancer patients, tamoxifen-treated breast cancer patients, postmenopausal controls and postmenopausal controls on vaginal estradiol, respectively. The AI-treated group and subgroups had significantly lower estradiol and estrone concentrations than all other groups (p <0.05). There was extensive interindividual variation in estradiol concentration within the AI-treated group, measured using both LC-MS/MS (2.3-182.0 pmol/l) and extraction RIA (2.4-162.6 pmol/l). The AI-treated group had lower aromatase index compared to all other groups (p <0.05-0.001). Circulating estrogen levels may have been underestimated in previous longitudinal studies of AI-treated breast cancer patients. Additional studies are required to further evaluate the role of circulating estrogens in breast cancer patients suffering from gynecological symptoms.

Nordic Walking as an Exercise Intervention to Reduce Pain in Women With Aromatase Inhibitor-Associated Arthralgia: A Feasibility Study.

PubMed

Fields, Jo; Richardson, Alison; Hopkinson, Jane; Fenlon, Deborah

2016-10-01

Women taking aromatase inhibitors as treatment for breast cancer commonly experience joint pain and stiffness (aromatase inhibitor-associated arthralgia [AIAA]), which can cause problems with adherence. There is evidence that exercise might be helpful, and Nordic walking could reduce joint pain compared to normal walking. To determine the feasibility of a trial of Nordic walking as an exercise intervention for women with AIAA. A feasibility study was carried out in a sample of women with AIAA using a randomized control design. Women were randomized to exercise (six-week supervised group Nordic walking training once per week with an increasing independent element, followed by six weeks 4 × 30 minutes/week independent Nordic walking); or enhanced usual care. Data were collected on recruitment, retention, exercise adherence, safety, and acceptability. The Brief Pain Inventory, GP Physical Activity Questionnaire, and biopsychosocial measures were completed at baseline, six and 12 weeks. Forty of 159 eligible women were recruited and attrition was 10%. There was no increased lymphedema and no long-term or serious injury. Adherence was >90% for weekly supervised group Nordic walking, and during independent Nordic walking, >80% women managed one to two Nordic walking sessions per week. From baseline to study end point, overall activity levels increased and pain reduced in both the intervention and control groups. Our findings indicate that women with AIAA are prepared to take up Nordic walking, complete a six-week supervised course and maintain increased activity levels over a 12-week period with no adverse effects. Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Aromatase inhibition by letrozole attenuates kainic acid-induced seizures but not neurotoxicity in mice.

PubMed

Iqbal, Ramsha; Jain, Gaurav K; Siraj, Fouzia; Vohora, Divya

2018-07-01

Evidence shows neurosteroids play a key role in regulating epileptogenesis. Neurosteroids such as testosterone modulate seizure susceptibility through its transformation to metabolites which show proconvulsant and anticonvulsant effects, respectively. Reduction of testosterone by aromatase generates proconvulsant 17-β estradiol. Alternatively, testosterone is metabolized into 5α-dihydrotestosterone (5α-DHT) by 5α-reductase, which is then reduced by 3α-hydroxysteroid oxidoreductase enzyme (3α-HSOR) to form anticonvulsant metabolite 3α-androstanediol (3α-Diol), a potent GABA A receptor modulating neurosteroid. The present study evaluated whether inhibition of aromatase inhibitor letrozole protects against seizures and neuronal degeneration induced by kainic acid (KA) (10 mg/kg, i.p.) in Swiss albino mice. Letrozole (1 mg/kg, i.p.) administered one hour prior to KA significantly increased the onset time of seizures and reduced the% incidence of seizures. Pretreatment with finasteride, a selective inhibitor of 5α-reductase and indomethacin, a selective inhibitor of 3α-hydroxysteroid oxidoreductase enzyme (3α-HSOR), reversed the protective effects of letrozole in KA-induced seizures in mice. Microscopic examination using cresyl violet staining revealed that letrozole did not modify KA-induced neurotoxicity in the CA1, CA3 and DG region of the hippocampus. Letrozole treatment resulted in the reduced levels of 17-β estradiol and elevated the levels of 5α-dihydrotestosterone (DHT) and 3α-Diol in the hippocampus. Finasteride and indomethacin attenuated letrozole-induced elevations of 5α-DHT and 3α-Diol. Our results indicate the potential anticonvulsant effects of letrozole against KA-induced seizures in mice that might be mediated by inhibiting aromatization of testosterone to 17β-estradiol, a proconvulsant hormone and by redirecting the synthesis to anticonvulsant metabolites, 5α-DHT and 3α-Diol. Acute aromatase inhibition, thus, might be used as an adjuvant in the treatment of status epilepticus and can be pursued further. Copyright © 2018 Elsevier B.V. All rights reserved.

Aromatase inhibitor regulates let-7 expression and let-7f induced cell migration in endometrial cells from women with endometriosis

PubMed Central

Cho, SiHyun; Mutlu, Levent; Zhou, Yuping; Taylor, Hugh S.

2018-01-01

Objectives To evaluate associations between aromatase inhibitor (AI) treatment and let-7 family microRNA expression in endometriosis. Design In vitro study using Ishikawa cells and human endometrial stromal cells (HESC) obtained from patients with endometriosis Setting University research center. Patients Women undergoing laparoscopic surgery for endometriosis Interventions HESCs and Ishikawa cells treated with various letrozol concentrations and transfected with a mimic of let-7 subtypes of interest Main Outcome Measures microRNAs let7a-f and aromatase expression were evaluated. Migration potential after transfection with a let-7f mimic were analyzed. Results After letrozole treatment for 48 hours, all let-7 subtypes showed a trend toward increased expression in a dose dependent manner in Ishikawa cells, and significant differences were found in let-7b and let-7f between controls and the 20 μmol/L treated groups. Further, let-7f showed significant differences between control and 1.0 μmol/L treatment group, a typical therapeutic level, in HESCs. Transfection of a let-7f mimic decreased aromatase expression in both Ishikawa cells and HESC, and led to a significant decrease in number of migrating cells in both cell types. Conclusions AI treatment significantly increased expression of let-7f in Ishikawa cells and HESCs from patient with endometriosis; increased lef-7f expression effectively reduced the migration of endometrial cells. Modulation of miRNAs involved in the pathogenesis of endometriosis may have therapeutic potential for endometriosis. PMID:27320036

Abemaciclib gets new approval for breast cancer

Cancer.gov

DA has approved the CDK4/6 inhibitor abemaciclib (Verzenio) as a first-line treatment in some women with advanced or metastatic breast cancer. Under the approval, it must be used in combination with an aromatase inhibitor, as this Cancer Currents blog post explains.

Serum leptin level and waist-to-hip ratio (WHR) predict the overall survival of metastatic breast cancer (MBC) patients treated with aromatase inhibitors (AIs).

PubMed

Artac, Mehmet; Bozcuk, Hakan; Kiyici, Aysel; Eren, Orhan Onder; Boruban, Melih Cem; Ozdogan, Mustafa

2013-04-01

Our objective was to determine whether serum leptin levels and obesity-related factors could affect outcome for metastatic breast cancer (MBC) patients treated with aromatase inhibitors (AIs). Sixty MBC patients treated with first line hormonal therapy were enrolled in this study. Median age was 51 years (range 28-75). Median leptin level was 19400 pg/ml (1970-91900) and estradiol level 29.6 pg/ml (4.0-181.9). Factors associated with overall survival in univariate analysis were age and waist-to-hip ratio (WHR), whereas only WHR retained significance in the multivariate analysis. However, no factor was associated with progression-free survival. However, WHR was found to be a significant prognostic marker only if the leptin level was ≥19400 pg/ml (HR = 0.38; 95% CI: 0.16-0.91). This study suggests that serum leptin levels and WHR together may serve as potential prognostic markers in MBC patients treated with AIs.

Adult height in patients with familial male-limited precocious puberty and the role of an aromatase inhibitor in patient management.

PubMed

Lane, Laura C; Flowers, Josephine; Johnstone, Helen; Cheetham, Tim

2018-04-25

There is little adult height data in patients with familial male-limited precocious puberty (FMPP) and no management consensus. We assessed the treatment and adult height in local patients with FMPP and those reported in the literature. Growth data were obtained on four local patients with FMPP and a search performed to obtain management details and adult height data on cases in the literature. UK (90) population standards were used to calculate standard deviation scores (SDS). Adult height data were available on 25 men with FMPP of whom 21 were treated. Median adult height SDS of patients was -1.5 SD with a mid-parental target of -0.6 SD (p=0.1). Eight patients (32%) had an adult height above the mid-parental target and seven patients (28%) had a height >2 SD below the mean. The median height SD was -0.03 in untreated patients and +0.5 SD in those receiving an aromatase inhibitor. There was no relationship between height and age at presentation. Aromatase inhibitor therapy is associated with a positive height outcome in FMPP but the outcome with and without intervention is unpredictable. Clinicians need to be cautious when counselling families about the potential height outcome in FMPP.

Aromatase Inhibitors and Bone Loss

PubMed Central

PEREZ, EDITH A.; M., Serene; Durling, Frances C.; WEILBAECHER, KATHERINE

2009-01-01

The aromatase inhibitors (AIs) anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are significantly more effective than the selective estrogen-receptor modulator (SERM) tamoxifen in preventing recurrence in estrogen receptor–positive early breast cancer. Aromatase inhibitors are likely to replace SERMs as first-line adjuvant therapy for many patients. However, AIs are associated with significantly more osteoporotic fractures and greater bone mineral loss. As antiresorptive agents, oral and intravenous bisphosphonates such as alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), pamidronate (Aredia), and zoledronic acid (Zometa) have efficacy in preventing postmenopausal osteoporosis, cancer treatment–related bone loss, or skeletal complications of metastatic disease. Clinical practice guidelines recommend baseline and annual follow-up bone density monitoring for all patients initiating AI therapy. Bisphosphonate therapy should be prescribed for patients with osteoporosis (T score < −2.5) and considered on an individual basis for those with osteopenia (T score < −1). Modifiable lifestyle behaviors including adequate calcium and vitamin D intake, weight-bearing exercise, and smoking cessation should be addressed. Adverse events associated with bisphosphonates include gastrointestinal toxicity, renal toxicity, and osteonecrosis of the jaw. These safety concerns should be balanced with the potential of bisphosphonates to minimize or prevent the debilitating effects of AI-associated bone loss in patients with early, hormone receptor–positive breast cancer. PMID:16986348

Comparison of pharmacokinetics of newly discovered aromatase inhibitors by a cassette microdosing approach in healthy Japanese subjects.

PubMed

Kusuhara, Hiroyuki; Takashima, Tadayuki; Fujii, Hisako; Takashima, Tsutomu; Tanaka, Masaaki; Ishii, Akira; Tazawa, Shusaku; Takahashi, Kazuhiro; Takahashi, Kayo; Tokai, Hidekichi; Yano, Tsuneo; Kataoka, Makoto; Inano, Akihiro; Yoshida, Suguru; Hosoya, Takamitsu; Sugiyama, Yuichi; Yamashita, Shinji; Hojo, Taisuke; Watanabe, Yasuyoshi

2017-12-01

The aim of the present study is to investigate the pharmacokinetics of our newly developed aromatase inhibitors (cetrozole and TMD-322) in healthy subjects by a cassette microdose strategy. A cocktail of cetrozole and TMD-322 was administered intravenously or orally (1.98 μg for each drug) to six healthy volunteers in a crossover fashion. Anastrozole (1.98 μg) was also included in the oral cocktail. Total body clearance and bioavailability were 12.1 ± 7.1 mL/min/kg and 34.9 ± 32.3% for cetrozole, and 16.8 ± 3.5 mL/min/kg and 18.4 ± 12.2% for TMD-322, respectively. The area under the plasma concentration-time curves of cetrozole and TMD-322 after oral administration was markedly lower than that of anastrozole because of their high hepatic clearance. Two subjects out of six exhibited 4- and 17-fold larger exposure of cetrozole than the others following intravenous and oral administration, respectively. Such variation was not observed for TMD-322 and anastrozole. Extensive metabolism of cetrozole and TMD-322 was observed in the CYP2C19 expression system among the test CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). We report the first clinical investigation of our aromatase inhibitors by a cassette microdose strategy in healthy Japanese subjects. This strategy offers an optional approach for candidate selection as a phase zero study in drug development. Copyright © 2017. Published by Elsevier Ltd.

PUTATIVE ADVERSE OUTCOME PATHWAY FOR INHIBITON ...

EPA Pesticide Factsheets

The adverse outcome pathway (AOP) provides a framework for organizing knowledge to define links between a molecular initiating event (MIE) and an adverse outcome (AO) occurring at a higher level of biological organization, such as the individual or population. The AOP framework proceeds from a general (e.g., not chemical specific) molecular mode of action, designated as a MIE, through stepwise changes in biological status, defined as key events (KEs), to a final AO that can be used in risk assessment. Because aromatase-inhibiting pharmaceuticals are widely used to treat breast cancer patients, we explored the unintended consequences that might occur in fish exposed to these chemicals through wastewater discharge into the aquatic environment. Unlike mammals, fish have two isoforms of aromatase, one that predominates in the ovary (cyp19a1a) and a second (cyp19a1b) that prevails in the brain. Aromatase activity in fish brain can be 100 to 1000 times that in mammals and is associated with reproduction. We have developed a putative AOP for inhibition of brain aromatase in fish leading to reproductive dysfunction based on review of relevant literature and reproductive experiments with the marine fish cunner (Tautogolabrus adspersus) exposed to aromatase-inhibiting pharmaceuticals in the laboratory. The first KE in this AOP is a decrease in brain aromatase activity due to exposure to an aromatase inhibitor. KEs then progress through subsequent steps including decreas

A Novel Method for Assessing Sex-Specific and Genotype-Specific Response to Injury in Astrocyte Culture

PubMed Central

Liu, Mingyue; Oyarzabal, Esteban; Yang, Rui; Murphy, Stephanie J; Hurn, Patricia D.

2008-01-01

Female astrocytes sustain less cell death from oxygen-glucose deprivation (OGD) than male astrocytes. Arimidex, an aromatase inhibitor, abolishes these sex differences. To verify sex-dependent differences in P450 aromatase function in astrocyte cell death following OGD, we developed a novel method that uses sex-specific and genotype-specific single pup primary astrocyte cultures from wild-type (WT) and aromatase-knockout (ArKO) mice. After determining sex by external and internal examination as well as PCR and genotype by PCR amplification of tail cDNA, we established cultures from 1−3 day-old male and female, WT and ArKO mice pups and grew them to confluence in estrogen-free media. Cell death was measured by lactate dehydrogenase (LDH) assay. Our study shows that, while WT female astrocytes are more resistant to OGD than WT male cells, sex differences disappear in ArKO cells. Cell death is significantly increased in ArKO compared to WT in female astrocytes but not male cells. Therefore, P450 aromatase appears to be essential in endogenous neuroprotection in females, and this finding may have clinical implications. This innovative technique may also be applied to other in vitro studies of sex-related functional differences. PMID:18436308

Letrozole: a review of its use in the treatment of postmenopausal women with hormone-responsive early breast cancer.

PubMed

Keating, Gillian M

2009-08-20

Letrozole (Femara) is a third-generation, nonsteroidal aromatase inhibitor. Adjuvant therapy with letrozole is more effective than tamoxifen in postmenopausal women with hormone-responsive early breast cancer, and extended adjuvant therapy with letrozole after the completion of adjuvant tamoxifen therapy is more effective than placebo in this patient population; letrozole is generally well tolerated. Ongoing trials will help answer outstanding questions regarding the optimal duration of letrozole therapy in early breast cancer and its efficacy compared with other third-generation aromatase inhibitors such as anastrozole. In the meantime, letrozole should be considered a valuable option in the treatment of postmenopausal women with hormone-responsive early breast cancer, both as adjuvant and extended adjuvant therapy.

Zoledronic Acid Inhibits Aromatase Activity and Phosphorylation: Potential Mechanism for Additive Zoledronic Acid and Letrozole Drug Interaction

PubMed Central

Schech, Amanda J.; Nemieboka, Brandon E.; Brodie, Angela H.

2012-01-01

Zoledronic acid (ZA), a bisphosphonate originally indicated for use in osteoporosis, has been reported to exert a direct effect on breast cancer cells, although the mechanism of this effect is currently unknown. Data from the ABCSG-12 and ZO-FAST clinical trials suggest that treatment with the combination of ZA and aromatase inhibitors (AI) result in increased disease free survival in breast cancer patients over AI alone. To determine whether the mechanism of this combination involved inhibition of aromatase, AC-1 cells (MCF-7 human breast cancer cells transfected with an aromatase construct) were treated simultaneously with combinations of ZA and AI letrozole for 72 hours. This combination significantly increased inhibition of aromatase activity of AC-1 cells by compared to letrozole alone. Combination treatment of 1nM letrozole and 1μM and 10μM zoledronic acid resulted in an additive drug interaction on inhibiting cell viability, as measured by MTT assay. Treatment with ZA was found to inhibit phosphorylation of aromatase on serine 473. Zoledronic acid was also shown to be more effective in inhibiting cell viability in aromatase transfected AC-1 cells when compared to inhibition of cell viability observed in non-transfected MCF-7. Estradiol was able to partially rescue the effect of 1μM and 10μM ZA on cell viability following treatment for 72 hours, as shown by a shift to the right in the estradiol dose response curve. In conclusion, these results indicate that the combination of ZA and letrozole results in an additive inhibition of cell viability. Furthermore, ZA alone can inhibit aromatase activity through inhibition of serine phosphorylation events important for aromatase enzymatic activity and contributes to inhibition of cell viability. PMID:22659283

Cell-Based High-Throughput Screening for Aromatase Inhibitors in the Tox21 10K Library.

PubMed

Chen, Shiuan; Hsieh, Jui-Hua; Huang, Ruili; Sakamuru, Srilatha; Hsin, Li-Yu; Xia, Menghang; Shockley, Keith R; Auerbach, Scott; Kanaya, Noriko; Lu, Hannah; Svoboda, Daniel; Witt, Kristine L; Merrick, B Alex; Teng, Christina T; Tice, Raymond R

2015-10-01

Multiple mechanisms exist for endocrine disruption; one nonreceptor-mediated mechanism is via effects on aromatase, an enzyme critical for maintaining the normal in vivo balance of androgens and estrogens. We adapted the AroER tri-screen 96-well assay to 1536-well format to identify potential aromatase inhibitors (AIs) in the U.S. Tox21 10K compound library. In this assay, screening with compound alone identifies estrogen receptor alpha (ERα) agonists, screening in the presence of testosterone (T) identifies AIs and/or ERα antagonists, and screening in the presence of 17β-estradiol (E2) identifies ERα antagonists. Screening the Tox-21 library in the presence of T resulted in finding 302 potential AIs. These compounds, along with 31 known AI actives and inactives, were rescreened using all 3 assay formats. Of the 333 compounds tested, 113 (34%; 63 actives, 50 marginal actives) were considered to be potential AIs independent of cytotoxicity and ER antagonism activity. Structure-activity analysis suggested the presence of both conventional (eg, 1, 2, 4, - triazole class) and novel AI structures. Due to their novel structures, 14 of the 63 potential AI actives, including both drugs and fungicides, were selected for confirmation in the biochemical tritiated water-release aromatase assay. Ten compounds were active in the assay; the remaining 4 were only active in high-throughput screen assay, but with low efficacy. To further characterize these 10 novel AIs, we investigated their binding characteristics. The AroER tri-screen, in high-throughput format, accurately and efficiently identified chemicals in a large and diverse chemical library that selectively interact with aromatase. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Cell-Based High-Throughput Screening for Aromatase Inhibitors in the Tox21 10K Library

PubMed Central

Chen, Shiuan; Hsieh, Jui-Hua; Huang, Ruili; Sakamuru, Srilatha; Hsin, Li-Yu; Xia, Menghang; Shockley, Keith R.; Auerbach, Scott; Kanaya, Noriko; Lu, Hannah; Svoboda, Daniel; Witt, Kristine L.; Merrick, B. Alex; Teng, Christina T.; Tice, Raymond R.

2015-01-01

Multiple mechanisms exist for endocrine disruption; one nonreceptor-mediated mechanism is via effects on aromatase, an enzyme critical for maintaining the normal in vivo balance of androgens and estrogens. We adapted the AroER tri-screen 96-well assay to 1536-well format to identify potential aromatase inhibitors (AIs) in the U.S. Tox21 10K compound library. In this assay, screening with compound alone identifies estrogen receptor alpha (ERα) agonists, screening in the presence of testosterone (T) identifies AIs and/or ERα antagonists, and screening in the presence of 17β-estradiol (E2) identifies ERα antagonists. Screening the Tox-21 library in the presence of T resulted in finding 302 potential AIs. These compounds, along with 31 known AI actives and inactives, were rescreened using all 3 assay formats. Of the 333 compounds tested, 113 (34%; 63 actives, 50 marginal actives) were considered to be potential AIs independent of cytotoxicity and ER antagonism activity. Structure-activity analysis suggested the presence of both conventional (eg, 1, 2, 4, - triazole class) and novel AI structures. Due to their novel structures, 14 of the 63 potential AI actives, including both drugs and fungicides, were selected for confirmation in the biochemical tritiated water-release aromatase assay. Ten compounds were active in the assay; the remaining 4 were only active in high-throughput screen assay, but with low efficacy. To further characterize these 10 novel AIs, we investigated their binding characteristics. The AroER tri-screen, in high-throughput format, accurately and efficiently identified chemicals in a large and diverse chemical library that selectively interact with aromatase. PMID:26141389

Novel Strategies for the Treatment of Estrogen Receptor-Negative Breast Cancer

DTIC Science & Technology

2009-04-01

and aromatase inhibitors reduce ER-positive breast cancer recurrence by approximately 50% (2,3). These agents, however, are not effective in... inhibitors that can interrupt this mitogenic signaling, preventing and treating these cancers. Currently the mechanisms governing ER-negative breast...or invasion. 3.2) Use existing small molecule inhibitors of the identified signaling molecules to block the activity of these proteins and assay for

Epigenetic activation of the prostaglandin receptor EP4 promotes resistance to endocrine therapy for breast cancer

PubMed Central

Hiken, Jeffrey F.; McDonald, James I.; Decker, Keith F.; Sanchez, Cesar; Hoog, Jeremy; VanderKraats, Nathan D.; Jung, Kyle L.; Akinhanmi, Margaret; Rois, Lisa E.; Ellis, Matthew J.; Edwards, John R.

2016-01-01

Approximately 75% of breast cancers express estrogen receptor α (ERα) and depend on estrogen signals for continued growth. Aromatase inhibitors (AIs) prevent estrogen production and inhibit estrogen receptor signaling, resulting in decreased cancer recurrence and mortality. Advanced tumors treated with AIs almost always develop resistance to these drugs via the up-regulation of alternative growth signals. The mechanisms that drive this resistance—especially epigenetic events that alter gene expression—are however not well understood. Genome-wide DNA methylation and expression analysis of cell line models of acquired aromatase inhibitor resistance indicated that prostaglandin E2 receptor 4 (PTGER4) is up-regulated after demethylation in resistant cells. Knockdown and inhibitor studies demonstrate that PTGER4 is essential for estrogen independent growth. Our exploratory analysis of downstream signaling indicates that PTGER4 likely promotes AI resistance via ligand independent activation of the ERα-cofactor CARM1. We believe that we have discovered a novel epigenetic mechanism for altering cell signaling and acquiring endocrine therapy resistance. Our findings indicate that PTGER4 is a potential drug target in AI resistant cancers. Additionally, the epigenetic component of PTGER4 regulation suggests that further study of PTGER4 may yield valuable insights into how DNA methylation-targeted diagnoses and treatments can improve AI resistant breast cancer treatment. PMID:27869171

Evaluation of the Methoxytriazine Herbicide Prometon Using a Short-term Fathead Minnow Reproduction Test and a Suite of in vitro Bioassays

EPA Science Inventory

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 and whether they might act as aromatase inhibitors or inducers ...

Breast Cancer Prevention

MedlinePlus

... estrogen-only hormone therapy after hysterectomy, selective estrogen receptor modulators, or aromatase inhibitors and inactivators Estrogen-only ... who take estrogen after a hysterectomy. Selective estrogen receptor modulators Tamoxifen and raloxifene belong to the family ...

Quantum mechanical/molecular mechanical and docking study of the novel analogues based on hybridization of common pharmacophores as potential anti-breast cancer agents

PubMed Central

Asadi, Parvin; Khodarahmi, Ghadamali; Farrokhpour, Hossein; Hassanzadeh, Farshid; Saghaei, Lotfollah

2017-01-01

In an attempt to identify some new potential leads as anti-breast cancer agents, novel hybrid compounds were designed by molecular hybridization approach. These derivatives were structurally derived from hybrid benzofuran–imidazole and quinazolinone derivatives, which had shown good cytotoxicity against the breast cancer cell line (MCF-7). Since aromatase enzyme (CYP19) is highly expressed in the MCF-7 cell line, the binding of these novel hybrid compounds to aromatase was investigated using the docking method. In this study, due to the positive charge on the imidazole ring of the designed ligands and also, the presence of heme iron in the active site of the enzyme, it was decided to optimize the ligand inside the protein to obtain more realistic atomic charges for it. Quantum mechanical/molecular mechanical (QM/MM) method was used to obtain more accurate atomic charges of ligand for docking calculations by considering the polarization effects of CYP19 on ligands. It was observed that the refitted charge improved the binding energy of the docked compounds. Also, the results showed that these novel hybrid compounds were adopted properly within the aromatase binding site, thereby suggesting that they could be potential inhibitors of aromatase. The main binding modes in these complexes were through hydrophobic and H bond interactions showing agreement with the basic physicochemical features of known anti aromatase compounds. Finally, the complex structures obtained from the docking study were used for single point QM/MM calculations to obtain more accurate electronic interaction energy, considering the electronic polarization of the ligand by its protein environment. PMID:28626481

A Systematic Review and Methodological Evaluation of Published Cost-Effectiveness Analyses of Aromatase Inhibitors versus Tamoxifen in Early Stage Breast Cancer

PubMed Central

John-Baptiste, Ava A.; Wu, Wei; Rochon, Paula; Anderson, Geoffrey M.; Bell, Chaim M.

2013-01-01

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. Results of these CEA analyses may be suboptimal for guiding policy. PMID:23671612

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

PubMed

John-Baptiste, Ava A; Wu, Wei; Rochon, Paula; Anderson, Geoffrey M; Bell, Chaim M

2013-01-01

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. 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. 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. 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. Results of these CEA analyses may be suboptimal for guiding policy.

Proteomic Signatures of Acquired Letrozole Resistance in Breast Cancer: Suppressed Estrogen Signaling and Increased Cell Motility and Invasiveness*

PubMed Central

Tilghman, Syreeta L.; Townley, Ian; Zhong, Qiu; Carriere, Patrick P.; Zou, Jin; Llopis, Shawn D.; Preyan, Lynez C.; Williams, Christopher C.; Skripnikova, Elena; Bratton, Melyssa R.; Zhang, Qiang; Wang, Guangdi

2013-01-01

Aromatase inhibitors, such as letrozole, have become the first-line treatment for postmenopausal women with estrogen-dependent breast cancer. However, acquired resistance remains a major clinical obstacle. Previous studies demonstrated constitutive activation of the MAPK signaling, overexpression of HER2, and down-regulation of aromatase and ERα in letrozole-resistant breast cancer cells. Given the complex signaling network involved in letrozole-refractory breast cancer and the lack of effective treatment for hormone resistance, further investigation of aromatase inhibitor resistance by a novel systems biology approach may reveal previously unconsidered molecular changes that could be utilized as therapeutic targets. This study was undertaken to characterize for the first time global proteomic alterations occurring in a letrozole-resistant cell line. A quantitative proteomic analysis of the whole cell lysates of LTLT-Ca (resistant) versus AC-1 cells (sensitive) was performed to identify significant protein expression changes. A total of 1743 proteins were identified and quantified, of which 411 were significantly up-regulated and 452 significantly down-regulated (p < 0.05, fold change > 1.20). Bioinformatics analysis revealed that acquired letrozole resistance is associated with a hormone-independent, more aggressive phenotype. LTLT-Ca cells exhibited 84% and 138% increase in migration and invasion compared with the control cells. The ROCK inhibitor partially abrogated the enhanced migration and invasion of the letrozole-resistant cells. Flow cytometric analyses also demonstrated an increase in vimentin and twist expression in letrozole-resistance cells, suggesting an onset of epithelial to mesenchymal transition (EMT). Moreover, targeted gene expression arrays confirmed a 28-fold and sixfold up-regulation of EGFR and HER2, respectively, whereas ERα and pS2 were dramatically reduced by 28-fold and 1100-fold, respectively. Taken together, our study revealed global proteomic signatures of a letrozole-resistant cell line associated with hormone independence, enhanced cell motility, EMT and the potential values of several altered proteins as novel prognostic markers or therapeutic targets for letrozole resistant breast cancer. PMID:23704778

Use of MR-based trabecular bone microstructure analysis at the distal radius for osteoporosis diagnostics: a study in post-menopausal women with breast cancer and treated with aromatase inhibitor.

PubMed

Baum, Thomas; Karampinos, Dimitrios C; Seifert-Klauss, Vanadin; Pencheva, Tsvetelina D; Jungmann, Pia M; Rummeny, Ernst J; Müller, Dirk; Bauer, Jan S

2016-01-01

Treatment with aromatase inhibitor (AI) is recommended for post-menopausal women with hormone-receptor positive breast cancer. However, AI therapy is known to induce bone loss leading to osteoporosis with an increased risk for fragility fractures. The purpose of this study was to investigate whether changes of magnetic resonance (MR)-based trabecular bone microstructure parameters as advanced imaging biomarker can already be detected in subjects with AI intake but still without evidence for osteoporosis according to dual energy X-ray absorptiometry (DXA)-based bone mineral density (BMD) measurements as current clinical gold standard. Twenty-one postmenopausal women (62±6 years of age) with hormone-receptor positive breast cancer, ongoing treatment with aromatase inhibitor for 23±15 months, and no evidence for osteoporosis (current DXA T-score greater than -2.5) were recruited for this study. Eight young, healthy women (24±2 years of age) were included as controls. All subjects underwent 3 Tesla magnetic resonance imaging (MRI) of the distal radius to assess the trabecular bone microstructure. Trabecular bone microstructure parameters were not significantly (p>0.05) different between subjects with AI intake and controls, including apparent bone fraction (0.42±0.03 vs. 0.42±0.05), trabecular number (1.95±0.10 mm(-1) vs 1.89±0.15 mm(-1)), trabecular separation (0.30±0.03 mm vs 0.31±0.06 mm), trabecular thickness (0.21±0.01 mm vs 0.22±0.02 mm), and fractal dimension (1.70±0.02 vs. 1.70±0.03). These findings suggest that the initial deterioration of trabecular bone microstructure as measured by MRI and BMD loss as measured by DXA occur not sequentially but rather simultaneously. Thus, the use of MR-based trabecular bone microstructure assessment is limited as early diagnostic biomarker in this clinical setting.

Aromatase inhibitory activity of 1,4-naphthoquinone derivatives and QSAR study

PubMed Central

Prachayasittikul, Veda; Pingaew, Ratchanok; Worachartcheewan, Apilak; Sitthimonchai, Somkid; Nantasenamat, Chanin; Prachayasittikul, Supaluk; Ruchirawat, Somsak; Prachayasittikul, Virapong

2017-01-01

A series of 2-amino(chloro)-3-chloro-1,4-naphthoquinone derivatives (1-11) were investigated for their aromatase inhibitory activities. 1,4-Naphthoquinones 1 and 4 were found to be the most potent compounds affording IC50 values 5.2 times lower than the reference drug, ketoconazole. A quantitative structure-activity relationship (QSAR) model provided good predictive performance (R2CV = 0.9783 and RMSECV = 0.0748) and indicated mass (Mor04m and H8m), electronegativity (Mor08e), van der Waals volume (G1v) and structural information content index (SIC2) descriptors as key descriptors governing the activity. To investigate the effects of structural modifications on aromatase inhibitory activity, the model was employed to predict the activities of an additional set of 39 structurally modified compounds constructed in silico. The prediction suggested that the 2,3-disubstitution of 1,4-naphthoquinone ring with halogen atoms (i.e., Br, I and F) is the most effective modification for potent activity (1a, 1b and 1c). Importantly, compound 1b was predicted to be more potent than its parent compound 1 (11.90-fold) and the reference drug, letrozole (1.03-fold). The study suggests the 1,4-naphthoquinone derivatives as promising compounds to be further developed as a novel class of aromatase inhibitors. PMID:28827987

Drug Reduces Cancer Treatment-Related Joint Pain

Cancer.gov

A Cancer Currents blog post about a clinical trial demonstrating that duloxetine (Cymbalta®) may reduce joint pain caused by aromatase inhibitors in women being treated for early-stage breast cancer.

Rapid decreases in preoptic aromatase activity and brain monoamine concentrations after engaging in male sexual behavior

PubMed Central

Cornil, C. A.; Dalla, C.; Papadopoulou-Daifoti, Z.; Baillien, M.; Dejace, C.; Ball, G.F.; Balthazart, J.

2014-01-01

In Japanese quail as in rats, the expression of male sexual behavior over relatively long time periods (days to weeks) is dependent on the local production of estradiol in the preoptic area via the aromatization of testosterone. On a short-term basis (minutes to hours), central actions of dopamine as well as locally produced estrogens modulate behavioral expression. In rats, a view of and sexual interaction with a female increases dopamine release in the preoptic area. In quail, in vitro brain aromatase activity is rapidly modulated by calcium-dependent phosphorylations that are likely to occur in vivo as a result of changes in neurotransmitter activity. Furthermore, an acute estradiol injection rapidly stimulates copulation in quail, while a single injection of the aromatase inhibitor Vorozole™ rapidly inhibits this behavior. We hypothesized that brain aromatase and dopaminergic activities are regulated in quail in association with the expression of male sexual behavior. Visual access as well as sexual interactions with a female produced a significant decrease in brain aromatase activity that was maximal after 5 min. This expression of sexual behavior also resulted in a significant decrease in dopaminergic as well as serotonergic activity after 1 min, which returned to basal levels after 5 min. These results demonstrate for the first time that aromatase activity is rapidly modulated in vivo in parallel with changes in dopamine activity. Sexual interactions with the female decreased aromatase and dopamine activity. These data challenges established views about the causal relationships among dopamine, estrogen action and male sexual behavior. PMID:15932925

Extended Adjuvant Therapy for Breast Cancer

Cancer.gov

An NCI Cancer Currents blog on findings from a recent clinical trial which showed that extending adjuvant therapy with an aromatase inhibitor can have important benefits for some women with early-stage cancer.

Treatment options in HR⁺/HER2⁻ advanced breast cancer patients pretreated with nonsteroidal aromatase inhibitors: what does current evidence tell us?

PubMed

De Placido, Sabino; Pronzato, Paolo

2015-01-01

Many postmenopausal women with advanced or metastatic breast cancer (BC) receive nonsteroidal aromatase inhibitors (NSAIs). Virtually all of them experience progression, but may still gain benefit from a different endocrine or targeted agent. We indirectly compare the results of trials on endocrine or targeted treatment in HR(+)/HER2(-) mBC patients who progressed after a prior NSAI therapy. Although with the limitations of any indirect comparison, evidence suggests that only the combination of everolimus and exemestane is associated with a prolonged progression-free survival and a more evident clinical benefit than its comparators. We speculate that prior NSAI therapy can 'per se' individuate patients eligible to everolimus. More robust data from head-to-head trials will provide more grounded evidence on this issue.

Zoledronic Acid in Aromatase Inhibitor Induced Musculoskeletal Symptoms

ClinicalTrials.gov

2017-10-05

Ductal Carcinoma in Situ; Estrogen Receptor-positive Breast Cancer; Progesterone Receptor-positive Breast Cancer; Stage I Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

Use of mTOR inhibitors in the treatment of breast cancer: an evaluation of factors that influence patient outcomes

PubMed Central

Jerusalem, Guy; Rorive, Andree; Collignon, Joelle

2014-01-01

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 impossible to select patients not benefiting from addition of everolimus to exemestane. Side effects and impact on quality of life are other important issues discussed in this review. Second-generation mTOR inhibitors and dual mTOR-phosphatidylinositol-3-kinase inhibitors are currently being evaluated in clinical trials. PMID:24833916

Predicting Adherence to Aromatase Inhibitor Therapy among Breast Cancer Survivors: An Application of the Protection Motivation Theory

PubMed Central

Karmakar, Monita; Pinto, Sharrel L; Jordan, Timothy R; Mohamed, Iman; Holiday-Goodman, Monica

2017-01-01

The purpose of this observational study was to determine if the Protection Motivation Theory could predict and explain adherence to aromatase inhibitor (AI) therapy among breast cancer survivors. Purposive sampling was used to identify 288 survivors who had been prescribed AI therapy. A valid and reliable survey was mailed to survivors. A total of 145 survivors completed the survey. The Morisky scale was used to measure adherence to AI. The survivors reported a mean score of 6.84 (±0.66) on the scale. Nearly 4 in 10 survivors (38%) were non-adherent. Adherence differed by age, marital status, insurance status, income, and presence of co-morbid conditions. Self-efficacy (r=0.485), protection motivation (r=0.310), and Response Efficacy (r=0.206) were positively and significantly correlated with adherence. Response Cost (r=-0.235) was negatively correlated with adherence. The coping appraisal constructs were statistically significant predictors medication adherence (β=0.437) with self-efficacy being the strongest significant predictor of adherence (β = 0.429). PMID:28469437

Predicting Adherence to Aromatase Inhibitor Therapy among Breast Cancer Survivors: An Application of the Protection Motivation Theory.

PubMed

Karmakar, Monita; Pinto, Sharrel L; Jordan, Timothy R; Mohamed, Iman; Holiday-Goodman, Monica

2017-01-01

The purpose of this observational study was to determine if the Protection Motivation Theory could predict and explain adherence to aromatase inhibitor (AI) therapy among breast cancer survivors. Purposive sampling was used to identify 288 survivors who had been prescribed AI therapy. A valid and reliable survey was mailed to survivors. A total of 145 survivors completed the survey. The Morisky scale was used to measure adherence to AI. The survivors reported a mean score of 6.84 (±0.66) on the scale. Nearly 4 in 10 survivors (38%) were non-adherent. Adherence differed by age, marital status, insurance status, income, and presence of co-morbid conditions. Self-efficacy (r=0.485), protection motivation (r=0.310), and Response Efficacy (r=0.206) were positively and significantly correlated with adherence. Response Cost (r=-0.235) was negatively correlated with adherence. The coping appraisal constructs were statistically significant predictors medication adherence (β=0.437) with self-efficacy being the strongest significant predictor of adherence (β = 0.429).

SGK3 sustains ERα signaling and drives acquired aromatase inhibitor resistance through maintaining endoplasmic reticulum homeostasis.

PubMed

Wang, Yuanzhong; Zhou, Dujin; Phung, Sheryl; Warden, Charles; Rashid, Rumana; Chan, Nymph; Chen, Shiuan

2017-02-21

Many estrogen receptor alpha (ERα)-positive breast cancers initially respond to aromatase inhibitors (AIs), but eventually acquire resistance. Here, we report that serum- and glucocorticoid-inducible kinase 3 (SGK3), a kinase transcriptionally regulated by ERα in breast cancer, sustains ERα signaling and drives acquired AI resistance. SGK3 is up-regulated and essential for endoplasmic reticulum (EnR) homeostasis through preserving sarcoplasmic/EnR calcium ATPase 2b (SERCA2b) function in AI-resistant cells. We have further found that EnR stress response down-regulates ERα expression through the protein kinase RNA-like EnR kinase (PERK) arm, and SGK3 retains ERα expression and signaling by preventing excessive EnR stress. Our study reveals regulation of ERα expression mediated by the EnR stress response and the feed-forward regulation between SGK3 and ERα in breast cancer. Given SGK3 inhibition reduces AI-resistant cell survival by eliciting excessive EnR stress and also depletes ERα expression/function, we propose SGK3 inhibition as a potential effective treatment of acquired AI-resistant breast cancer.

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

PubMed Central

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

Ovulation induction in polycystic ovary syndrome.

PubMed

Tanbo, Tom; Mellembakken, Jan; Bjercke, Sverre; Ring, Eva; Åbyholm, Thomas; Fedorcsak, Peter

2018-06-11

The objective of this narrative review is to suggest a rational order of treatment choices in anovulatory women with polycystic ovary syndrome (PCOS), for whom a multitude of treatment options exist. In obese/overweight PCOS patients the importance of weight reduction should be stressed. Inositol, a dietary supplement with a documented effect on ovulation and without side effects in the doses recommended, may be suggested. Additional first line medical alternatives include insulin sensitizers, selective estrogen receptor modulators and aromatase inhibitors. Of these, the aromatase inhibitor letrozole and the combination of clomiphene citrate and metformin have the highest rates of ovulation and live birth. Second line treatments are ovarian electrocautery and low-dose follicle stimulating hormone stimulation. Controlled ovarian stimulation with in vitro fertilization, should be considered the last option since it carries a significant risk of ovarian hyperstimulation syndrome in patients with PCOS. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

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

PubMed

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

2013-12-01

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

Exemestane Reduces Breast Cancer Risk in High-Risk Postmenopausal Women

Cancer.gov

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.

Localization of the aromatase enzyme expression in the human pituitary gland and its effect on growth hormone, prolactin, and thyroid stimulating hormone axis.

PubMed

Caglar, Asli Sezgin; Kapucu, Aysegul; Dar, Kadriye Akgun; Ozkaya, Hande Mefkure; Caglar, Erkan; Ince, Haluk; Kadioglu, Pinar

2015-08-01

The aim of this study is to evaluate aromatase expression in prolactin (PRL), thyroid stimulating hormone (TSH), and growth hormone (GH) secreting cells. Nontumoral human pituitary specimens were obtained from autopsy samples. Aromatase co-expression was determined by double immunohistochemical staining and assessed using H scores. H scores for GH-aromatase co-expression (GH-aromatase), TSH-aromatase co-expression (TSH-aromatase), and PRL-aromatase co-expression (PRL-aromatase) were 83.1 ± 13.1, 95.6 ± 16.1, and 83.7 ± 14.5, respectively. TSH producing cells exhibited the highest H score for co-expression of aromatase (p < 0.001). There was no gender difference in terms of H scores for aromatase expression and double immunohistochemical staining results (p > 0.05 for all). There was a negative correlation between the H scores for aromatase and PRL-aromatase, GH-aromatase and TSH-aromatase, respectively (r = -0.592, p < 0.001; r = -0.593, p < 0.001; r = -0.650, p < 0.001, respectively). Also, H scores for aromatase co-expression of each hormone were negatively correlated with the H scores for the corresponding hormone (r = -0.503, p < 0.001 for PRL-aromatase and PRL; r = -0.470, p < 0.001 for GH-aromatase, and GH; r = -0.641, p < 0.001 for TSH-aromatase and TSH). H scores for mean aromatase, GH-aromatase, TSH-aromatase were invariant of age (p > 0.05 for all). Age was negatively correlated with PRL-aromatase H score (r = -0.373, p = 0.008). Our study demonstrated significant aromatase co-expression in PRL, GH, and TSH secreting cells of the human anterior pituitary gland. The mutual paracrinal regulation between aromatase and three adenohypophyseal hormones indicates that aromatase may have a regulatory role on the synthesis and secretion of these hormones.

Complementary or Alternative Medicine as Possible Determinant of Decreased Persistence to Aromatase Inhibitor Therapy among Older Women with Non-Metastatic Breast Cancer

PubMed Central

Huiart, Laetitia; Bouhnik, Anne-Deborah; Rey, Dominique; Rousseau, Frédérique; Retornaz, Frédérique; Meresse, Mégane; Bendiane, Marc Karim; Viens, Patrice; Giorgi, Roch

2013-01-01

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. PMID:24367488

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

PubMed

Huiart, Laetitia; Bouhnik, Anne-Deborah; Rey, Dominique; Rousseau, Frédérique; Retornaz, Frédérique; Meresse, Mégane; Bendiane, Marc Karim; Viens, Patrice; Giorgi, Roch

2013-01-01

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. 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. 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. 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.

Review: aromatase inhibitors for ovulation induction.

PubMed

Casper, Robert F; Mitwally, Mohamed F M

2006-03-01

For the last 40 yr, the first line of treatment for anovulation in infertile women has been clomiphene citrate (CC). CC is a safe, effective oral agent but is known to have relatively common antiestrogenic endometrial and cervical mucous side effects that could prevent pregnancy in the face of successful ovulation. In addition, there is a significant risk of multiple pregnancy with CC, compared with natural cycles. Because of these problems, we proposed the concept of aromatase inhibition as a new method of ovulation induction that could avoid many of the adverse effects of CC. The objective of this review was to describe the different physiological mechanisms of action for CC and aromatase inhibitors (AIs) and compare studies of efficacy for both agents for ovulation induction. We conducted a systematic review of all the published studies, both controlled and noncontrolled, comparing CC and AI treatment, either alone or in combination with gonadotropins, for ovulation induction or augmentation, identified through the Entrez-PubMed search engine. Because of the recent acceptance of the concept of using AIs for ovulation induction, few controlled studies were identified, and the rest of the studies were pilot or preliminary comparisons. Based on these studies, it appears that AIs are as effective as CC in inducing ovulation, are devoid of any antiestrogenic side effects, result in lower serum estrogen concentrations, and are associated with good pregnancy rates with a lower incidence of multiple pregnancy than CC. When combined with gonadotropins for assisted reproductive technologies, AIs reduce the dose of FSH required for optimal follicle recruitment and improve the response to FSH in poor responders. Preliminary evidence suggests that AIs may replace CC in the future because of similar efficacy with a reduced side effect profile. Although worldwide experience with AIs for ovulation induction is increasing, at present, definitive studies in the form of randomized controlled trials comparing CC with AIs are lacking.

[The drug of the month: everolimus (Afinitor) for the treatment of metastatic breast cancer].

PubMed

Jerusalem, G; Rorive, A; Collignon, J

2014-09-01

Sequential endocrine treatments are recommended for estrogen receptor (ER) positive human epidermal growth factor receptor 2 (HER 2) negative metastatic breast cancers except in the case of symptomatic visceral disease. However, patients who suffer from disease progression while receiving a non-steroidal aromatase inhibitor (NSAI) have a very poor prognosis with standard endocrine therapy alone. Recently, based onthe results of the BOLERO 2 trial, the mammalian target of rapamycin (mTOR) inhibitor everolimus, combined with exemestane, a steroidal aromatase inhibitor, has been approved in Europe and the US for patients suffering from ER positive HER2 negative advanced breast cancer previously treated by a NSAI. The median progression-free survival (PFS) increased from 3.2 to 7.8 months in patients receiving everolimus and exemestane compared to placebo and exemestane. The magnitude of benefit was consistent in all pre-specified subgroups. Side effects were manageable and the quality of life was at least maintained. Everolimus has also beenrecently studied in HER2 positive locally advanced or metastatic disease in heavily pretreated patients (BOLERO 3 trial). This trial met its primary endpoint. The median PFS was increased in patients receiving trastuzumab, vinorelbine and everolimus compared to patients receiving trastuzumab, vinorelbine and placebo. We review pharmacological data and side effects of the drug. We also review the most important clinical trials leading to reimbursement of everolimus in metastatic breast cancer.

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

PubMed

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. Copyright © 2015 Elsevier B.V. All rights reserved.

Expression and regulation of estrogen-converting enzymes in ectopic human endometrial tissue.

PubMed

Fechner, Sabine; Husen, Bettina; Thole, Hubert; Schmidt, Markus; Gashaw, Isabella; Kimmig, Rainer; Winterhager, Elke; Grümmer, Ruth

2007-10-01

To investigate the regulation of estrogen-converting enzymes in human ectopic endometrial tissue. Animal study. Academic medical center. Sixty female nude mice with implanted human endometrial tissue. Twenty-two premenopausal women undergoing endometrial biopsy or hysterectomy. Human endometrial tissue was implanted into the peritoneal cavity of nude mice, and the effect of therapeutic drugs on transcription of steroid receptors and estrogen-converting enzymes was analyzed. Transcript levels of steroid hormone receptors, 17beta-hydroxysteroid dehydrogenase type 1 and 2, aromatase, and steroid sulfatase as well as proliferation rate were analyzed in the human ectopic endometrial tissue. Steroid receptors and estrogen-converting enzymes were expressed in the ectopic human endometrial fragments. Application of medroxyprogesterone acetate, dydrogesterone, danazol, and the aromatase inhibitor finrozole significantly inhibited aromatase transcription. In addition, danazol caused a significant decrease in transcription of steroid sulfatase, and finrozole, of 17beta-hydroxysteroid dehydrogenase type 1 in parallel to a decrease in proliferation rate in the ectopic human endometrial tissue. Pharmacological regulation of transcription of estrogen-converting enzymes in human endometrium cultured in nude mice may help to develop new therapeutic concepts based on local regulation of estrogen metabolism in endometriosis.

The discovery and mechanism of action of letrozole

PubMed Central

2007-01-01

Because estrogen contributes to the promotion and progression of breast cancer, a greater understanding of the role of estrogen in breast cancer has led to therapeutic strategies targeting estrogen synthesis, the estrogen receptor, and intracellular signaling pathways. The enzyme aromatase catalyses the final step in estrogen biosynthesis and was identified as an attractive target for selective inhibition. Modern third-generation aromatase inhibitors (AIs) effectively block the production of estrogen without exerting effects on other steroidogenic pathways. The discovery of letrozole (Femara®) achieved the goal of discovering a highly potent and totally selective AI. Letrozole has greater potency than other AIs, including anastrozole, exemestane, formestane, and aminoglutethimide. Moreover, letrozole produces near complete inhibition of aromatase in peripheral tissues and is associated with greater suppression of estrogen than is achieved with other AIs. The potent anti-tumor effects of letrozole were demonstrated in several animal models. Studies with MCF-7Ca xenografts successfully predicted that letrozole would be clinically superior to the previous gold standard tamoxifen and also indicated that it may be more effective than other AIs. An extensive program of randomized clinical trials has demonstrated the clinical benefits of letrozole across the spectrum of hormone-responsive breast cancer in postmenopausal women. PMID:17912633

Glyceollin I reverses epithelial to mesenchymal transition in letrozole resistance

USDA-ARS?s Scientific Manuscript database

Although aromatase inhibitors, such as letrozole; are standard endocrine therapy for postmenopausal women with early stage metastatic estrogen-dependent breast cancer, the major limitation in managing this disease is the development of drug resistance; therefore, a better understanding of this proce...

Clinical Use of Aromatase Inhibitors in Adult Males.

PubMed

Tan, Ronny B W; Guay, Andre T; Hellstrom, Wayne J G

2014-04-01

There is a growing interest in the treatment of late-onset hypogonadism, another name for the study of testosterone deficiency in an older age group. Initial attempts at testosterone replacement have also brought attention to the possible adverse effects on the patients' cardiovascular risk factors and their prostate health. The "female" hormone estradiol is no longer considered as the feminizing hormone, as it has been identified to have an effect on the sexual and general well-being of adult males. Urologists and endocrinologists alike have started to pay attention to the serum T/E 2 (testosterone : estradiol) ratio that appears to be more important than the respective individual hormonal levels. Therein lies the possible role of aromatase inhibitors (AIs) in restoring the normal balance of serum testosterone and estradiol levels for the adequate treatment of late-onset hypogonadism, while limiting the potential adverse effects. Currently, other established clinical indications of AIs include the treatment of breast cancer in female patients and developmental growth problems in pediatric patients. This review evaluates the role of AIs as a treatment option for late-onset hypogonadism and the evidence for its other clinical uses in men, including its possible adverse effects. A literature review was performed with regards to the use of aromatase inhibitors in adult males, the role of estrogens in adult males, as well as adverse effect of AIs on bone health in adult males. To evaluate the evidence for the use of AIs in adult males to treat late-onset hypogonadism, obesity-related hypogonadotropic hypogonadism, gynecomastia, and male subfertility. To evaluate the evidence for the possible adverse effects on the bone health of adult males with the use of AIs. Currently there is no literature to recommend the use of AIs in adult males to treat late-onset hypogonadism, obesity-related hypogonadotropic hypogonadism, gynecomastia, or male subfertility, although some positive effects have been reported. The adverse effects on bone health seen in females treated with AIs are not seen in males. With the better understanding of the T/E 2 ratio in adult males, the lack of scientific data to show that bone health is adversely affected by AI usage in adult males, the positive effects of AIs on the treatment of conditions like late-onset hypogonadism and male subfertility encourages conducting large-scale, multicenter, randomized controlled trials for the clinical use of AIs in adult males. Tan RBW, Guay AT, and Hellstrom WJG. Clinical use of aromatase inhibitors in adult males. Sex Med Rev 2014;2:79-90. Copyright © 2014 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

The effect of grape seed extract on estrogen levels of postmenopausal women: a pilot study.

PubMed

Wahner-Roedler, Dietlind L; Bauer, Brent A; Loehrer, Laura L; Cha, Stephen S; Hoskin, Tanya L; Olson, Janet E

2014-06-01

The role of estrogens in breast cancer (BC) development is widely accepted, leading to the development of selective estrogen receptor modulators and aromatase inhibitors for BC treatment and prevention. However, because of potential adverse effects, healthy women with high risk of BC are hesitant to take them. Preliminary evidence from animal studies shows that grapes may have an aromatase-inhibiting effect, decreasing estrogen synthesis and increasing androgen precursors. We conducted a randomized, double-blind, dose-finding early-phase trial on the effect of grape seed extract (GSE) on estrogen levels. Postmenopausal women who met study inclusion criteria (N = 46) were randomly assigned to daily GSE at a dose of 200, 400, 600, or 800 mg for 12 weeks. Primary outcome was change in plasma levels of estrogen conjugates from baseline to 12 weeks posttreatment. Thirty-nine participants (84.8%) completed the study. GSE in the 4 daily doses did not significantly decrease estrogen or increase androgen precursors.

Estrogen and androgen-converting enzymes 17β-hydroxysteroid dehydrogenase and their involvement in cancer: with a special focus on 17β-hydroxysteroid dehydrogenase type 1, 2, and breast cancer

PubMed Central

Hilborn, Erik; Stål, Olle; Jansson, Agneta

2017-01-01

Sex steroid hormones such as estrogens and androgens are involved in the development and differentiation of the breast tissue. The activity and concentration of sex steroids is determined by the availability from the circulation, and on local conversion. This conversion is primarily mediated by aromatase, steroid sulfatase, and 17β-hydroxysteroid dehydrogenases. In postmenopausal women, this is the primary source of estrogens in the breast. Up to 70-80% of all breast cancers express the estrogen receptor-α, responsible for promoting the growth of the tissue. Further, 60-80% express the androgen receptor, which has been shown to have tissue protective effects in estrogen receptor positive breast cancer, and a more ambiguous response in estrogen receptor negative breast cancers. In this review, we summarize the function and clinical relevance in cancer for 17β-hydroxysteroid dehydrogenases 1, which facilitates the reduction of estrone to estradiol, dehydroepiandrosterone to androstendiol and dihydrotestosterone to 3α- and 3β-diol as well as 17β-hydroxysteroid dehydrogenases 2 which mediates the oxidation of estradiol to estrone, testosterone to androstenedione and androstendiol to dehydroepiandrosterone. The expression of 17β-hydroxysteroid dehydrogenases 1 and 2 alone and in combination has been shown to predict patient outcome, and inhibition of 17β-hydroxysteroid dehydrogenases 1 has been proposed to be a prime candidate for inhibition in patients who develop aromatase inhibitor resistance or in combination with aromatase inhibitors as a first line treatment. Here we review the status of inhibitors against 17β-hydroxysteroid dehydrogenases 1. In addition, we review the involvement of 17β-hydroxysteroid dehydrogenases 4, 5, 7, and 14 in breast cancer. PMID:28430630

Estrogen and androgen-converting enzymes 17β-hydroxysteroid dehydrogenase and their involvement in cancer: with a special focus on 17β-hydroxysteroid dehydrogenase type 1, 2, and breast cancer.

PubMed

Hilborn, Erik; Stål, Olle; Jansson, Agneta

2017-05-02

Sex steroid hormones such as estrogens and androgens are involved in the development and differentiation of the breast tissue. The activity and concentration of sex steroids is determined by the availability from the circulation, and on local conversion. This conversion is primarily mediated by aromatase, steroid sulfatase, and 17β-hydroxysteroid dehydrogenases. In postmenopausal women, this is the primary source of estrogens in the breast. Up to 70-80% of all breast cancers express the estrogen receptor-α, responsible for promoting the growth of the tissue. Further, 60-80% express the androgen receptor, which has been shown to have tissue protective effects in estrogen receptor positive breast cancer, and a more ambiguous response in estrogen receptor negative breast cancers. In this review, we summarize the function and clinical relevance in cancer for 17β-hydroxysteroid dehydrogenases 1, which facilitates the reduction of estrone to estradiol, dehydroepiandrosterone to androstendiol and dihydrotestosterone to 3α- and 3β-diol as well as 17β-hydroxysteroid dehydrogenases 2 which mediates the oxidation of estradiol to estrone, testosterone to androstenedione and androstendiol to dehydroepiandrosterone. The expression of 17β-hydroxysteroid dehydrogenases 1 and 2 alone and in combination has been shown to predict patient outcome, and inhibition of 17β-hydroxysteroid dehydrogenases 1 has been proposed to be a prime candidate for inhibition in patients who develop aromatase inhibitor resistance or in combination with aromatase inhibitors as a first line treatment. Here we review the status of inhibitors against 17β-hydroxysteroid dehydrogenases 1. In addition, we review the involvement of 17β-hydroxysteroid dehydrogenases 4, 5, 7, and 14 in breast cancer.

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

PubMed

Alviggi, C; Marci, R; Vallone, R; Conforti, A; Di Rella, F; Strina, I; Picarelli, S; De Rosa, P; De Laurentiis, M; Yding Andersen, C; De Placido, G

2017-07-01

To evaluate the hormonal profile in three breast cancer patients who underwent controlled ovarian stimulation in the presence of the aromatase inhibitor letrozole. In IVF University referral center, a case series of three breast cancer patients who underwent controlled ovarian stimulation (COS) with recombinant FSH and letrozole were investigated. Ovulation was induced with hCG (case No. 1) or with GnRH agonist (case No. 2-3). The primary outcome of our study was the detection of progesterone levels in the luteal phase. Very high progesterone values (mean 186.6 ± 43.6 ng/mL) during the luteal phase were recorded in all three cases. High progesterone levels can be related to the use of letrozole independently of the most commonly used trigger regimen. Although progesterone has long been considered a protective factor against breast cancer, several studies have demonstrated that progesterone could expand a transformation-sensitive stem cell population in the mammary glands. The estrogen negative feedback effect on the hypothalamus-pituitary axis and the disruption of steroid biosynthesis and could represent an intriguing reason behind this phenomenon. Our results highlight the need to evaluate further the increase in progesterone levels in the luteal phase in women with breast cancer undergoing COS with letrozole.

Distribution of aromatase and sex steroid receptors in the baculum during the rat life cycle: effects of estrogen during the early development of the baculum.

PubMed

Yonezawa, Tomohiro; Higashi, Mayuko; Yoshioka, Kazuki; Mutoh, Ken-ichiro

2011-07-01

The baculum, also called os penis, plays an important role during copulation. However, the hormonal regulation of its development remains to be elucidated. To determine the direct involvement of sex steroids in the development of the baculum of rats, the distributions of androgen receptors (ARs), aromatase, and estrogen receptor alpha (ESR1) were observed immunohistochemically. On Postnatal Day 1, the rudiment of the baculum expressed ARs, aromatase, and ESR1. In the proximal segment of the baculum of neonatal rats, ARs were expressed in the parosteal layer but not in the periosteum or osteoblasts. Aromatase was expressed from the parosteal layer to the endosteum, particularly in the inner osteogenic layer. ESR1 was also abundantly expressed in almost all cells from the parosteal layer to the endosteum. ARs, aromatase, and ESR1 were all abundantly expressed during the neonatal period in the hyaline cartilage of the proximal segment and in fibrocartilage of the distal segment of the baculum. Expression in all the tissues was attenuated in an age-dependent manner and became quite weak at puberty. To determine the effect of estrogen on the growth of the baculum, the aromatase inhibitor 1,4,6-androstatrien-3,17-dione (ATD) was subcutaneously injected daily into pregnant rats from Days 19 to 23 of gestation and into pups on postnatal Days 1, 3, 5, 7, and 9. On Day 10, the length of the baculum in the ATD-treated rats was significantly shorter than that in the controls, although the body weight did not change. These findings suggest that not only androgen but also locally aromatized estrogen is involved in the early growth and development of the baculum.

Preclinical Pharmacological Evaluation of Letrozole as a Novel Treatment for Gliomas

PubMed Central

Dave, Nimita; Chow, Lionel M.L.; Gudelsky, Gary A.; LaSance, Kathleen; Qi, Xiaoyang; Desai, Pankaj B.

2015-01-01

We present data that letrozole, an extensively used aromatase inhibitor in the treatment of estrogen receptor-positive breast tumors in postmenopausal women, may be potentially used in the treatment of glioblastomas. First, we measured the in vitro cytotoxicity of letrozole and aromatase (CYP19A1) expression and activity in human LN229, T98G, U373MG, U251MG, and U87MG, and rat C6 glioma cell lines. Estrogen receptor (ER)positive MCF-7 and ER-negative MDA-MB-231 cells served as controls. Cytotoxicity was determined employing the MTT assay, and aromatase activity using an immunoassay that measures the conversion of testosterone to estrogen. Second, in vivo activity of letrozole was assessed in Sprague-Dawley rats orthotopically implanted with C6 gliomas. The changes in tumor volume with letrozole treatment (4 mg/kg/day) were assessed employing μPET/CT imaging, employing [18F]-fluorodeoxyglucose (F18-FDG) as the radiotracer. Brain tissues were collected for histologic evaluations. All glioma cell lines included here expressed CYP19A1 and letrozole exerted considerable cytotoxicity and decrease in aromatase activity against these cells (IC50, 0.1–3.5 μmol/L). Imaging analysis employing F18-FDG μPET/CT demonstrated a marked reduction of active tumor volume (>75%) after 8 days of letrozole treatment. Immunohistochemical analysis revealed marked reduction in aromatase expression in tumoral regions of the brain after letrozole treatment. Thus, employing multifaceted tools, we demonstrate that aromatase may be a novel target for the treatment of gliomas and that letrozole, an FDA-approved drug with an outstanding record of safety may be repurposed for the treatment of such primary brain tumors, which currently have few therapeutic options. PMID:25695958

Preclinical pharmacological evaluation of letrozole as a novel treatment for gliomas.

PubMed

Dave, Nimita; Chow, Lionel M L; Gudelsky, Gary A; LaSance, Kathleen; Qi, Xiaoyang; Desai, Pankaj B

2015-04-01

We present data that letrozole, an extensively used aromatase inhibitor in the treatment of estrogen receptor-positive breast tumors in postmenopausal women, may be potentially used in the treatment of glioblastomas. First, we measured the in vitro cytotoxicity of letrozole and aromatase (CYP19A1) expression and activity in human LN229, T98G, U373MG, U251MG, and U87MG, and rat C6 glioma cell lines. Estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 cells served as controls. Cytotoxicity was determined employing the MTT assay, and aromatase activity using an immunoassay that measures the conversion of testosterone to estrogen. Second, in vivo activity of letrozole was assessed in Sprague-Dawley rats orthotopically implanted with C6 gliomas. The changes in tumor volume with letrozole treatment (4 mg/kg/day) were assessed employing μPET/CT imaging, employing [(18)F]-fluorodeoxyglucose (F18-FDG) as the radiotracer. Brain tissues were collected for histologic evaluations. All glioma cell lines included here expressed CYP19A1 and letrozole exerted considerable cytotoxicity and decrease in aromatase activity against these cells (IC50, 0.1-3.5 μmol/L). Imaging analysis employing F18-FDG μPET/CT demonstrated a marked reduction of active tumor volume (>75%) after 8 days of letrozole treatment. Immunohistochemical analysis revealed marked reduction in aromatase expression in tumoral regions of the brain after letrozole treatment. Thus, employing multifaceted tools, we demonstrate that aromatase may be a novel target for the treatment of gliomas and that letrozole, an FDA-approved drug with an outstanding record of safety may be repurposed for the treatment of such primary brain tumors, which currently have few therapeutic options. ©2015 American Association for Cancer Research.

Testing quantitative adverse outcome pathway predictions using aromatase inhibitors in female fathead minnows

EPA Science Inventory

To become more efficient and cost effective regulatory toxicology is increasingly averting from whole animal testing toward collecting data at lower levels of biological organization, through such means as in vitro high throughput screening (HTS) assays. When anchored to relevant...

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

EPA Science Inventory

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...

Adaptation of an Evidence-Based Arthritis Program for Breast Cancer Survivors on Aromatase Inhibitor Therapy Who Experience Joint Pain

PubMed Central

Callahan, Leigh F.; Rini, Christine; Altpeter, Mary; Hackney, Betsy; Schecher, Arielle; Wilson, Anne; Muss, Hyman B.

2015-01-01

Adding aromatase inhibitors (AIs) to adjuvant treatment of postmenopausal women with hormone-receptor–positive breast cancer significantly reduces cancer recurrence. A common side effect of AIs is noninflammatory joint pain and stiffness (arthralgia) similar to arthritis symptoms. An evidence-based walking program developed by the Arthritis Foundation — Walk With Ease (WWE) — reduces arthritis-related joint symptoms. We hypothesized that WWE may also reduce AI-associated arthralgia. However, the potential for different barriers and facilitators to physical activity for these 2 patient populations suggested a need to adapt WWE before testing it with breast cancer survivors. We conducted qualitative research with 46 breast cancer survivors to explore program modification and inform the development of materials for an adapted program (Walk With Ease-Breast Cancer). Our process parallels the National Cancer Institute’s Research-Tested Intervention Programs (RTIPs) guidelines for adapting evidence-based programs for cancer populations. Findings resulted in a customized 8-page brochure to supplement existing WWE materials. PMID:26068412

Aromatase inhibitor letrozole downregulates steroid receptor coactivator-1 in specific brain regions that primarily related to memory, neuroendocrine and integration.

PubMed

Bian, Chen; Zhao, Yangang; Guo, Qiang; Xiong, Ying; Cai, Wenqin; Zhang, Jiqiang

2014-05-01

As one of the third generation of aromatase inhibitors, letrozole is a favored drug for the treatment of hormone receptor-positive breast cancer with some adverse effects on the nervous system, but the knowledge is limited and the results are controversial, the mechanism underlying its central action is also unclear. Accumulated evidences have demonstrated that estrogens derived from androgens by aromatase play profound roles in the brain through their receptors, which needs coactivator for the transcription regulation, among which steroid receptor coactivator-1 (SRC-1) has been shown to be multifunctional potentials in the brain, but whether it is regulated by letrozole is currently unknown. In this study, we examined letrozole regulation on SRC-1 expression in adult mice brain using immunohistochemistry. The results showed that letrozole induced dramatic decrease of SRC-1 in the medial septal, hippocampus, medial habenular nucleus, arcuate hypothalamic nucleus and superior colliculus (p<0.01). Significant decrease was detected in the dorsal lateral septal nucleus, bed nucleus of stria terminalis, ventral taenia tecta, dorsomedial and ventromedial hypothalamic nuclei, dorsomedial periaqueductal gray, superior paraolivary nucleus and pontine nucleus (p<0.05). In the hippocampus, levels of estradiol content, androgen receptor, estrogen receptor α and β also decreased significantly after letrozole injection. The above results demonstrated letrozole downregulation of SRC-1 in specific regions that are primarily related to learning and memory, cognition and mood, neuroendocrine as well as information integration, indicating that SRC-1 may be one important downstream central target of letrozole. Furthermore, these potential central adverse effects of letrozole should be taken into serious considerations. Copyright © 2014 Elsevier Ltd. All rights reserved.

Use of Aromatase Inhibitors in Large Cell Calcifying Sertoli Cell Tumors: Effects on Gynecomastia, Growth Velocity, and Bone Age

PubMed Central

Crocker, Melissa K.; Gourgari, Evgenia; Stratakis, Constantine A.

2014-01-01

Context: Large cell calcifying Sertoli cell tumors (LCCSCT) present in isolation or, especially in children, in association with Carney Complex (CNC) or Peutz-Jeghers Syndrome (PJS). These tumors overexpress aromatase (CYP19A1), which leads to increased conversion of delta-4-androstenedione to estrone and testosterone to estradiol. Prepubertal boys may present with growth acceleration, advanced bone age, and gynecomastia. Objective: To investigate the outcomes of aromatase inhibitor therapy (AIT) in prepubertal boys with LCCSCTs. Design: Case series of a very rare tumor and chart review of cases treated at other institutions. Setting: Tertiary care and referral center. Patients: Six boys, five with PJS and one with CNC, were referred to the National Institutes of Health for treatment of LCCSCT. All patients had gynecomastia, testicular enlargement, and advanced bone ages, and were being treated by their referring physicians with AIT. Interventions: Patients were treated for a total of 6–60 months on AIT. Main Outcome Measures: Height, breast tissue mass, and testicular size were all followed; physical examination, scrotal ultrasounds, and bone ages were obtained, and hormonal concentrations and tumor markers were measured. Results: Tumor markers were negative. All patients had decreases in breast tissue while on therapy. Height percentiles declined, and predicted adult height moved closer to midparental height as bone age advancement slowed. Testicular enlargement stabilized until entry into central puberty. Only one patient required unilateral orchiectomy. Conclusions: Patients with LCCSCT benefit from AIT with reduction and/or elimination of gynecomastia and slowing of linear growth and bone age advancement. Further study of long-term outcomes and safety monitoring are needed but these preliminary data suggest that mammoplasty and/or orchiectomy may be foregone in light of the availability of medical therapy. PMID:25226294

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.

PubMed

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.

Artificial masculinization in tilapia involves androgen receptor activation.

PubMed

Golan, Matan; Levavi-Sivan, Berta

2014-10-01

Estrogens have a pivotal role in natural female sexual differentiation of tilapia while lack of steroids results in testicular development. Despite the fact that androgens do not participate in natural sex differentiation, synthetic androgens, mainly 17-α-methyltestosterone (MT) are effective in the production of all-male fish in aquaculture. The sex inversion potency of synthetic androgens may arise from their androgenic activity or else as inhibitors of aromatase activity. The current study is an attempt to differentiate between the two alleged activities in order to evaluate their contribution to the sex inversion process and aid the search for novel sex inversion agents. In the present study, MT inhibited aromatase activity, when applied in vitro as did the non-aromatizable androgen dihydrotestosterone (DHT). In comparison, exposure to fadrozole, a specific aromatase inhibitor, was considerably more effective. Androgenic activity of MT was evaluated by exposure of Sciaenochromis fryeri fry to the substance and testing for the appearance of blue color. Flutamide, an androgen antagonist, administered concomitantly with MT, reduced the appearance of the blue color and the sex inversion potency of MT in a dose-dependent manner. In tilapia, administration of MT, fadrozole or DHT resulted in efficient sex inversion while flutamide reduced the sex inversion potency of all three compounds. In the case of MT and DHT the decrease in sex inversion efficiency caused by flutamide is most likely due to the direct blocking of the androgen binding to its cognate receptor. The negative effect of flutamide on the efficiency of the fadrozole treatment may indicate that the masculinizing activity of fadrozole may be attributed to excess, un-aromatized, androgens accumulated in the differentiating gonad. The present study shows that when androgen receptors are blocked, there is a reduction in the efficiency of sex inversion treatments. Our results suggest that in contrast to natural sex differentiation, during sex inversion treatments, androgens, either endogenous or exogenous, participate in inducing testicular differentiation. Copyright © 2014 Elsevier Inc. All rights reserved.

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

PubMed Central

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

2007-01-01

Treatment with aromatase inhibitors for postmenopausal women with breast cancer has been shown to reduce or obviate invasive procedures such as hysteroscopy or curettage associated with tamoxifen-induced endometrial abnormalities. The side effect of upfront aromatase inhibitors, diminished estrogen synthesis, is similar to that seen with the natural events of aging. The consequences often include vasomotor symptoms (hot flushes) and vaginal dryness and atrophy, which in turn may result in cystitis and vaginitis. Not surprisingly, painful intercourse (dyspareunia) and loss of sexual interest (decreased libido) frequently occur as well. Various interventions, both non-hormonal and hormonal, are currently available to manage these problems. The purpose of the present review is to provide the practitioner with a wide array of management options to assist in treating the sexual consequences of aromatase inhibitors. The suggestions in this review are based on recent literature and on the recommendations set forth both by the North American Menopause Association and in the clinical practice guidelines of the Society of Gynaecologists and Obstetricians of Canada. The complexity of female sexual dysfunction necessitates a biopsychosocial approach to assessment and management alike, with interventions ranging from education and lifestyle changes to sexual counselling, pelvic floor therapies, sexual aids, medications, and dietary supplements—all of which have been reported to have a variable, but often successful, effect on symptom amelioration. Although the use of specific hormone replacement—most commonly local estrogen, and less commonly, systemic estrogen with or without an androgen, progesterone, or the additional of an androgen in an estrogenized woman (or a combination)—may be highly effective, the concern remains that in patients with estrogen-dependent breast cancer, including those receiving anti-estrogenic adjuvant therapies, the use of these hormones may be attended with potential risk. Therefore, non-hormonal alternatives should in all cases be initially tried with the expectation that symptomatic relief can often be achieved. First-line therapy for urogenital symptoms, notably vaginal dryness and dyspareunia, should be the non-hormonal group of preparations such as moisturizers and precoital vaginal lubricants. In patients with estrogen-dependent breast cancer (notably those receiving anti-estrogenic adjuvant therapies) and severely symptomatic vaginal atrophy that fails to respond to non-hormonal options, menopausal hormone replacement or prescription vaginal estrogen therapy may considered. Systemic estrogen may be associated with risk and thus is best avoided. Judicious use of hormones may be appropriate in the well-informed patient who gives informed consent, but given the potential risk, these agents should be prescribed only after mutual agreement of the patient and her oncologist. PMID:18087605

The Effect of COX-2 Inhibitors on the Aromatase Gene (CYP19) Expression in Human Breast Cancer

DTIC Science & Technology

2006-12-01

drug is it is associated with less side effects than non - steroidal inflammatory drugs ( NSAIDs ), particularly gastroduodenal ulcers. Randomized...Nested case-control study of effects of non - steroidal anti - inflammatory drugs on breast cancer risk and stage. B J Cancer 2000;83:112-120. 18...another non - steroidal anti - inflammatory ; 1 was determined to need neoadjuvant chemotherapy; 1 had a benign core biopsy, and 2

Letrozole regulates actin cytoskeleton polymerization dynamics in a SRC-1 dependent manner in the hippocampus of mice.

PubMed

Zhao, Yangang; Yu, Yanlan; Zhang, Yuanyuan; He, Li; Qiu, Linli; Zhao, Jikai; Liu, Mengying; Zhang, Jiqiang

2017-03-01

In the hippocampus, local estrogens (E 2 ) derived from testosterone that is catalyzed by aromatase play important roles in the regulation of hippocampal neural plasticity, but the underlying mechanisms remain unclear. The actin cytoskeleton contributes greatly to hippocampal synaptic plasticity; however, whether it is regulated by local E 2 and the related mechanisms remain to be elucidated. In this study, we first examined the postnatal developmental profiles of hippocampal aromatase and specific proteins responsible for actin cytoskeleton dynamics. Then we used aromatase inhibitor letrozole (LET) to block local E 2 synthesis and examined the changes of these proteins and steroid receptor coactivator-1 (SRC-1), the predominant coactivator for steroid nuclear receptors. Finally, SRC-1 specific RNA interference was used to examine the effects of SRC-1 on the expression of these actin remodeling proteins. The results showed a V-type profile for aromatase and increased profiles for actin cytoskeleton proteins in both male and female hippocampus without obvious sex differences. LET treatment dramatically decreased the F-actin/G-actin ratio, the expression of Rictor, phospho-AKT (ser473), Profilin-1, phospho-Cofilin (Ser3), and SRC-1 in a dose-dependent manner. In vitro studies demonstrated that LET induced downregulation of these proteins could be reversed by E 2 , and E 2 induced increase of these proteins were significantly suppressed by SRC-1 shRNA interference. These results for the first time clearly demonstrated that local E 2 inhibition could induce aberrant actin polymerization; they also showed an important role of SRC-1 in the mediation of local E 2 action on hippocampal synaptic plasticity by regulation of actin cytoskeleton dynamics. Copyright © 2016 Elsevier Ltd. All rights reserved.

Quantitative AOP-based predictions for two aromatase inhibitors evaluating the influence of bioaccumulation on prediction accuracy

EPA Science Inventory

The adverse outcome pathway (AOP) framework can be used to support the use of mechanistic toxicology data as a basis for risk assessment. For certain risk contexts this includes defining, quantitative linkages between the molecular initiating event (MIE) and subsequent key events...

Develop cost effective field monitoring and laboratory methods to measure groups of contaminants of emerging concern and/or legacy chemicals and pathogens

EPA Science Inventory

Analytical chemistry methods were developed to quantify numerous emerging contaminants (ECs), such as pharmaceuticals (i.e., tamoxifen, tamoxifen metabolites, aromatase inhibitors, antibiotics, illicit drugs, over-the-counter drugs) in aqueous samples (wastewater, surface waters)...

MECHANISMS OF IMPOSEX INDUCTION IN THE MUD SNAIL, ILYANASSA OBSOLETA: TBT AS A NEUROTOXIN AND AROMATASE INHIBITOR. (R827401)

EPA Science Inventory

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...

Adaptive Response in Female Fathead Minnows Exposed to an Aromatase Inhibitor: Computational Modeling of the Hypothalamic-Pituitary-Gonadal Axis

EPA Science Inventory

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

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

EPA Science Inventory

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...

Early life exposure to environmental levels of the aromatase inhibitor tributyltin causes masculinisation and irreversible sperm damage in zebrafish (Danio rerio).

PubMed

McAllister, Brian G; Kime, David E

2003-11-19

To determine whether early life exposure to tributyltin (TBT), an aromatase inhibitor, impaired reproductive function in fish, Danio rerio were exposed to environmentally realistic levels (0.01-100 ng l(-1)) of TBT from 0 to 30, 30 to 60, and 0 to 70 days post-hatch, and the sex ratio and sperm motility of the adults examined 3-5 months after cessation of exposure. Fish exposed for 70 days to 0.1 ng l(-1) of TBT, a concentration presently below the detection limit in water, showed a male biased population which produced a high incidence of sperm lacking flagella. At 1 ng l(-1), the motility of sperm was significantly lower than that of control fish, while at 10 ng l(-1), all sperm lacked flagella and, at 100 ng l(-1), milt volume had increased. The effect of exposure on sex ratio was similar after exposure from 0 to 70 and 0 to 30 days, but even 100 ng l(-1) gave only 65% males after exposure from 30 to 60 days. Effects on sperm motility and morphology and on milt volume were less pronounced after 30 day than 70 day exposure. Our data suggest that screening for aromatase inhibiting activity and assessment of its risks in early life to human and wildlife fertility needs to be urgently addressed, and that the reproductive toxicity of TBT may presently be underestimated.

TBT-induced imposex in marine neogastropods is mediated by an increasing androgen level

NASA Astrophysics Data System (ADS)

Bettin, C.; Oehlmann, J.; Stroben, E.

1996-09-01

Tributyltin (TBT) exposure at different concentrations (5, 60, and 100 ng TBT as Sn/l) induces a concentration- and time-dependent imposex (=pseudohermaphroditism) development in female Nucella lapillus and Hinia reticulata. In both species the average imposex stage, termed as vas deferens sequence (VDS) index, and the average female penis length increases with increasing TBT concentration and duration of TBT exposure. Testosterone added at a concentration of 500 ng/l induces a faster and more intensive imposex development compared to that induced by the TBT concentrations used in the present experiments. Radioimmunological determination of endogenous steroid content reveals increasing testosterone titres in female gastropods exposed to TBT which correlate with the TBT concentration used and the duration of the experiment. The most marked and highest increase of the endogenous testosterone level is exhibited by females, of both species exposed to testosterone. Simulataneous exposure to TBT and to the antiandrogen cyproterone acetate which suppresses imposex development completely in N. lapillus and reduces imposex development strongly in H. reticulata proves that the imposex-inducing effects of TBT are mediated by an increasing androgen level and are not caused directly by the organotin compound itself. Further-more, TBT-induced imposex development can be suppressed in both snails by adding estrogens to the aqueous medium. These observations suggest that TBT causes an inhibition of the cytochrome P-450 dependent aromatase system which catalyses the aromatization of androgens to estrogens. The increase of the androgen content or the shift of the androgen-estrogen balance in favour of androgens induces the development of pseudohermaphroditism in marine prosobranchs. Artificial inhibition of the cytochrome P-450 dependent aromatase system using SH 489 (1-methyl-1,4-androstadiene-3,17-dione) as a steroidal aromatase inhibitor and flavone as a nonsteroidal aromatase inhibitor induces imposex development in N. lapillus as well as in H. reticulata.

Rapid decreases in preoptic aromatase activity and brain monoamine concentrations after engaging in male sexual behavior.

PubMed

Cornil, C A; Dalla, C; Papadopoulou-Daifoti, Z; Baillien, M; Dejace, C; Ball, G F; Balthazart, J

2005-09-01

In Japanese quail, as in rats, the expression of male sexual behavior over relatively long time periods (days to weeks) is dependent on the local production of estradiol in the preoptic area via the aromatization of testosterone. On a short-term basis (minutes to hours), central actions of dopamine as well as locally produced estrogens modulate behavioral expression. In rats, a view of and sexual interaction with a female increase dopamine release in the preoptic area. In quail, in vitro brain aromatase activity (AA) is rapidly modulated by calcium-dependent phosphorylations that are likely to occur in vivo as a result of changes in neurotransmitter activity. Furthermore, an acute estradiol injection rapidly stimulates copulation in quail, whereas a single injection of the aromatase inhibitor vorozole rapidly inhibits this behavior. We hypothesized that brain aromatase and dopaminergic activities are regulated in quail in association with the expression of male sexual behavior. Visual access as well as sexual interactions with a female produced a significant decrease in brain AA, which was maximal after 5 min. This expression of sexual behavior also resulted in a significant decrease in dopaminergic as well as serotonergic activity after 1 min, which returned to basal levels after 5 min. These results demonstrate for the first time that AA is rapidly modulated in vivo in parallel with changes in dopamine activity. Sexual interactions with the female decreased aromatase and dopamine activities. These data challenge established views about the causal relationships among dopamine, estrogen action, and male sexual behavior.

Inhibitory effect of luteolin on estrogen biosynthesis in human ovarian granulosa cells by suppression of aromatase (CYP19).

PubMed

Lu, Dan-feng; Yang, Li-juan; Wang, Fei; Zhang, Guo-lin

2012-08-29

Inhibition of aromatase, the key enzyme in estrogen biosynthesis, is an important strategy in the treatment of breast cancer. Several dietary flavonoids show aromatase inhibitory activity, but their tissue specificity and mechanism remain unclear. This study found that the dietary flavonoid luteolin potently inhibited estrogen biosynthesis in a dose- and time-dependent manner in KGN cells derived from human ovarian granulosa cells, the major source of estrogens in premenopausal women. Luteolin decreased aromatase mRNA and protein expression in KGN cells. Luteolin also promoted aromatase protein degradation and inhibited estrogen biosynthesis in aromatase-expressing HEK293A cells, but had no effect on recombinant expressed aromatase. Estrogen biosynthesis in KGN cells was inhibited with differing potencies by extracts of onion and bird chili and by four other dietary flavonoids: kaempferol, quercetin, myricetin, and isorhamnetin. The present study suggests that luteolin inhibits estrogen biosynthesis by decreasing aromatase expression and destabilizing aromatase protein, and it warrants further investigation as a potential treatment for estrogen-dependent cancers.

Cost utility and budget impact of third-generation aromatase inhibitors for advanced breast cancer: a literature-based model analysis of costs in the Italian National Health Service.

PubMed

Marchetti, Monia; Caruggi, Mauro; Colombo, Giorgio

2004-09-01

Third-generation aromatase inhibitors are effective alternatives to tamoxifen in patients with advanced breast cancer. However, their acquisition costs might burden fixed-budget health care systems. This study is a decision analysis of the clinical and economic consequences of alternative first-line hormone therapies for postmenopausal women with estrogen receptor-positive metastatic breast cancer in a real-life Italian health care setting. A Markov model was developed to describe disease evolution according to data from previously published, randomized clinical trials. The costs incurred by a local community hospital in the Italian National Health Service were considered (year-2003 values). Clinical data were taken from previously published trials. A 3% discount rate was applied to both resources and life-years gained. Based on model estimates, mean survival times with the third-generation aromatase inhibitors anastrozole and letrozole were 30.72 and 30.64 months, respectively, as opposed to 27.28 months with tamoxifen. Mean survival times after adjustment for quality of life were 18.84 and 18.78 months with anastrozole and letrozole, respectively, and 16.14 months with tamoxifen. Baseline analysis produced incremental cost-effectiveness ratios per quality-adjusted life-year gained of 10,795 Euro (95% CI, 7737 Euro-12,899 Euro) and 16,886 Euro (95% CI, 9117 Euro-15,465 Euro) for anastrozole and letrozole, respectively, compared with tamoxifen. The observed difference between the 2 cost-utility ratios may have been mainly due to the higher acquisition costs of letrozole compared with anastrozole. Despite similar incremental cost-effectiveness ratios, anastrozole and letrozole might increase the budget for advanced breast cancer care by 12% and 18%, respectively, based on the year-2003 Italian market prices of the 2 drugs. In this cost-effectiveness analysis using previously published clinical data and year-2003 cost data from a community hospital in the Italian National Health Service, anastrozole and letrozole were both cost-effective alternatives to tamoxifen for first-line therapy of postmenopausal women with advanced estrogen receptor-positive breast cancer.

Randomized controlled trial of toremifene 120 mg compared with exemestane 25 mg after prior treatment with a non-steroidal aromatase inhibitor in postmenopausal women with hormone receptor-positive metastatic breast cancer.

PubMed

Yamamoto, Yutaka; Ishikawa, Takashi; Hozumi, Yasuo; Ikeda, Masahiko; Iwata, Hiroji; Yamashita, Hiroko; Toyama, Tatsuya; Chishima, Takashi; Saji, Shigehira; Yamamoto-Ibusuki, Mutsuko; Iwase, Hirotaka

2013-05-16

After the failure of a non-steroidal aromatase inhibitor (nsAI) for postmenopausal patients with metastatic breast cancer (mBC), it is unclear which of various kinds of endocrine therapy is the most appropriate. A randomized controlled trial was performed to compare the efficacy and safety of daily toremifene 120 mg (TOR120), a selective estrogen receptor modulator, and exemestane 25 mg (EXE), a steroidal aromatase inhibitor. The primary end point was the clinical benefit rate (CBR). The secondary end points were objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicity. Initially, a total of 91 women was registered in the study and randomly assigned to either TOR120 (n = 46) or EXE (n = 45) from October 2008 to November 2011. Three of the 46 patients in the TOR120 arm were not received treatment, 2 patients having withdrawn from the trial by their preference and one having been dropped due to administration of another SERM. When analyzed after a median observation period of 16.9 months, the intention-to-treat analysis showed that there were no statistical difference between TOR120 (N = 46) and EXE (n = 45) in terms of CBR (41.3% vs. 26.7%; P = 0.14), ORR (10.8% vs. 2.2%; P = 0.083), and OS (Hazard ratio, 0.60; P = 0.22). The PFS of TOR120 was longer than that of EXE, the difference being statistically significant (Hazard ratio, 0.61, P = 0.045). The results in treatment-received cohort (N = 88) were similar to those in ITT cohort. Both treatments were well-tolerated with no severe adverse events, although the treatment of 3 of 43 women administered TOR120 was stopped after a few days because of nausea, general fatigue, hot flush and night sweating. TOR120, as a subsequent endocrine therapy for mBC patients who failed non-steroidal AI treatment, could potentially be more beneficial than EXE. UMIN000001841.

Randomized controlled trial of toremifene 120 mg compared with exemestane 25 mg after prior treatment with a non-steroidal aromatase inhibitor in postmenopausal women with hormone receptor-positive metastatic breast cancer

PubMed Central

2013-01-01

Background After the failure of a non-steroidal aromatase inhibitor (nsAI) for postmenopausal patients with metastatic breast cancer (mBC), it is unclear which of various kinds of endocrine therapy is the most appropriate. A randomized controlled trial was performed to compare the efficacy and safety of daily toremifene 120 mg (TOR120), a selective estrogen receptor modulator, and exemestane 25 mg (EXE), a steroidal aromatase inhibitor. The primary end point was the clinical benefit rate (CBR). The secondary end points were objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicity. Methods Initially, a total of 91 women was registered in the study and randomly assigned to either TOR120 (n = 46) or EXE (n = 45) from October 2008 to November 2011. Three of the 46 patients in the TOR120 arm were not received treatment, 2 patients having withdrawn from the trial by their preference and one having been dropped due to administration of another SERM. Results When analyzed after a median observation period of 16.9 months, the intention-to-treat analysis showed that there were no statistical difference between TOR120 (N = 46) and EXE (n = 45) in terms of CBR (41.3% vs. 26.7%; P = 0.14), ORR (10.8% vs. 2.2%; P = 0.083), and OS (Hazard ratio, 0.60; P = 0.22). The PFS of TOR120 was longer than that of EXE, the difference being statistically significant (Hazard ratio, 0.61, P = 0.045). The results in treatment-received cohort (N = 88) were similar to those in ITT cohort. Both treatments were well-tolerated with no severe adverse events, although the treatment of 3 of 43 women administered TOR120 was stopped after a few days because of nausea, general fatigue, hot flush and night sweating. Conclusions TOR120, as a subsequent endocrine therapy for mBC patients who failed non-steroidal AI treatment, could potentially be more beneficial than EXE. Trial registration number UMIN000001841 PMID:23679192

A Pilot Study of Website Information Regarding Aromatase Inhibitors: Dietary Supplement Interactions

PubMed Central

McDermott, Cara L.; Hsieh, Angela A.; Sweet, Erin S.; Tippens, Kimberly M.

2011-01-01

Abstract Objectives Patients who have hormone receptor–positive breast cancer and who are taking aromatase inhibitors (AIs) should understand the benefits and risks of concomitant dietary supplement (DS) use. The International Society for Integrative Oncology (SIO) encourages patients to discuss DS use with their health care practitioners. The objective was to conduct a pilot study rating Internet websites from the perspective of health care practitioners for information about AI–DS interactions. Design Five (5) Internet websites suggested by SIO were evaluated using the DISCERN instrument rating tool. The available AI–DS information on these websites was rated by 4 evaluators: 2 naturopathic doctors, 1 oncology pharmacy resident, and a pharmacy student. Results The overall rankings ranged from 1.6 to 3.9, with considerable variability in the type of information available from the websites. The interevaluator rankings of the websites ranged from 0.44 to 0.89. The evaluators consistently found the most reliable, unbiased, and comprehensive information on AI–DS interactions at the Natural Medicines Comprehensive Database and Memorial Sloan-Kettering Cancer Center websites. However, more than one database was needed for provision of optimal patient information on AI–DS interactions. Conclusions In order to effectively advise patients regarding AI–DS interactions, more than one website should be evaluated to assess the potential efficacy and safety of DS in women whose breast cancer is being treated with an AI. PMID:22087614

Identification of endocrine disrupting chemicals acting on human aromatase.

PubMed

Baravalle, Roberta; Ciaramella, Alberto; Baj, Francesca; Di Nardo, Giovanna; Gilardi, Gianfranco

2018-01-01

Human aromatase is the cytochrome P450 catalysing the conversion of androgens into estrogens playing a key role in the endocrine system. Due to this role, it is likely to be a target of the so-called endocrine disrupting chemicals, a series of compounds able to interfere with the hormone system with toxic effects. If on one side the toxicity of some compounds such as bisphenol A is well known, on the other side the toxic concentrations of such compounds as well as the effect of the many other molecules that are in contact with us in everyday life still need a deep investigation. The availability of biological assays able to detect the interaction of chemicals with key molecular targets of the endocrine system represents a possible solution to identify potential endocrine disrupting chemicals. Here the so-called alkali assay previously developed in our laboratory is applied to test the effect of different compounds on the activity of human aromatase. The assay is based on the detection of the alkali product that forms upon strong alkali treatment of the NADP + released upon enzyme turnover. Here it is applied on human aromatase and validated using anastrozole and sildenafil as known aromatase inhibitors. Out of the small library of compounds tested, resveratrol and ketoconazole resulted to inhibit aromatase activity, while bisphenol A and nicotine were found to exert an inhibitory effect at relatively high concentrations (100μM), and other molecules such as lindane and four plasticizers did not show any significant effect. These data are confirmed by quantification of the product estrone in the same reaction mixtures through ELISA. Overall, the results show that the alkali assay is suitable to screen for molecules that interfere with aromatase activity. As a consequence it can also be applied to other molecular targets of EDCs that use NAD(P)H for catalysis in a high throughput format for the fast screening of many different compounds as endocrine disrupting chemicals. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone. Copyright © 2017 Elsevier B.V. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

kil K. E.; Biegon A.; Kil, K.-E.

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

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

PubMed

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.

Inhibition of Estradiol Synthesis Impairs Fear Extinction in Male Rats

ERIC Educational Resources Information Center

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,…

Hormonal Resistance And Metastasis ER-Coregulartor-Src Signaling Targeted Therapy

DTIC Science & Technology

2011-09-01

with STAT3 and cross-talk between ER~ and STAT3 play an important role in leptin -in- duced STAT3 activation’’ The II.Kl axis is the major signaling...cancer. These patients could be treated with an aromatase inhibitor (Letrozole) that ablates peripheral estrogen synthesis and ER degraders /signaling

Computational Modeling of Hypothalamic-Pituitary-Gonadal Axis to Predict Adaptive Responses in Female Fathead Minnows Exposed to an Aromatase Inhibitor

EPA Science Inventory

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

Aromatase Blockade Is Associated With Increased Mortality in Acute Illness in Male Mice.

PubMed

Connerney, Jeannette J; Spratt, Daniel I

2017-09-01

The increase in circulating estrogen levels with acute illness in humans is accompanied by increased aromatase expression in adipose tissue and increased peripheral aromatization of estrogens to androgens. Animal studies indicate that estrogen may be beneficial in acute illness. We hypothesized that blockade of aromatase in acute illness would decrease survival. Prospective sham controlled. Maine Medical Center Research Institute animal facility. Six- to 8-week-old male black 6 mice. Mice underwent cecal ligation and puncture (CLP) to induce acute illness and were administered letrozole to block aromatase or saline. Mice undergoing sham surgery with or without letrozole served as controls. Adipose and cardiovascular tissue was harvested for preliminary evaluation of aromatase expression. Survival was the main outcome measurement. Evidence for aromatase expression in tissue samples was assessed using western blot and/or immunohistochemistry. With aromatase blockade, survival in CLP mice was decreased ( P = 0.04). The presence of aromatase in adipose tissue was observed by western blot in CLP but not control mice. Similarly, the presence of aromatase was observed in cardiac tissue of CLP but not in control mice. The decreased survival during sepsis with aromatase blockade suggests that this response to acute illness may be important both physiologically and clinically. The preliminary observation of aromatase expression in adipose and cardiovascular tissue during acute illness in this mouse model indicates that this model has parallels to human physiology and may be useful for further studying the aromatase response to acute illness.

Histological and transcriptomic effects of 17α-methyltestosterone on zebrafish gonad development.

PubMed

Lee, Stephanie Ling Jie; Horsfield, Julia A; Black, Michael A; Rutherford, Kim; Fisher, Amanda; Gemmell, Neil J

2017-07-24

Sex hormones play important roles in teleost ovarian and testicular development. In zebrafish, ovarian differentiation appears to be dictated by an oocyte-derived signal via Cyp19a1a aromatase-mediated estrogen production. Androgens and aromatase inhibitors can induce female-to-male sex reversal, however, the mechanisms underlying gonadal masculinisation are poorly understood. We used histological analyses together with RNA sequencing to characterise zebrafish gonadal transcriptomes and investigate the effects of 17α-methyltestosterone on gonadal differentiation. At a morphological level, 17α-methyltestosterone (MT) masculinised gonads and accelerated spermatogenesis, and these changes were paralleled in masculinisation and de-feminisation of gonadal transcriptomes. MT treatment upregulated expression of genes involved in male sex determination and differentiation (amh, dmrt1, gsdf and wt1a) and those involved in 11-oxygenated androgen production (cyp11c1 and hsd11b2). It also repressed expression of ovarian development and folliculogenesis genes (bmp15, gdf9, figla, zp2.1 and zp3b). Furthermore, MT treatment altered epigenetic modification of histones in zebrafish gonads. Contrary to expectations, higher levels of cyp19a1a or foxl2 expression in control ovaries compared to MT-treated testes and control testes were not statistically significant during early gonad development (40 dpf). Our study suggests that both androgen production and aromatase inhibition are important for androgen-induced gonadal masculinisation and natural testicular differentiation in zebrafish.

Mechanism of Action of a Novel Analog of Vitamin D3, 1alpha-hydroxy-24-ethyl Cholecalciferol (D5), in Normal and Transformed Human Breast Epithelial Cells

DTIC Science & Technology

2003-05-01

retinoids, deltanoids (vitamin D derivatives), phytoestrogens, flavonoids , and aromatase inhibitors among others (Kelloffet al, 1996). On a global basis...Dietetics, University of Illinois at Chicago, Chicago. Responsibilities included development and validation of MDA-TBA assay by HPLC with fluorometric

Investigating the Regulation and Potential Role of Nonhypoxic Hypoxia-Inducible Factor 1 (HIF-1) in Aromatase Inhibitor Resistant Breast Cancer

DTIC Science & Technology

2013-10-01

hypoxia responsive element ( HRE ) to which HIF-1 binds in order to regulate vimentin gene expresson has not been identified. We have currently, analyzed...the vimentin promoter and have identified 2 potential HRE sites, based on sequence (Figure 5). Primers have been designed and ordered, and

RELATIONSHIP BETWEEN BRAIN AND OVARY AROMATASE ACTIVITY AND ISOFORM-SPECIFIC AROMATASE MRNA EXPRESSION IN THE FATHEAD MINNOW (PIMEPHALES PROMELAS)

EPA Science Inventory

There is growing evidence that some chemicals present in the environment have the capacity to inhibit, or potentially induce, aromatase activity. This study compared aromatase activities and isoform-specific mRNA expression in brain and ovary tissue from non-exposed fathead min...

RELATIONSHIP BETWEEN BRAIN AND OVARY AROMATASE ACTIVITY AND ISOFORM-SPECIFIC AROMATASE MRNA EXPRESSION IN THE FATHEAD MINNOW (PIMEPHALES PROMELAS) - JOURNAL ARTICLE

EPA Science Inventory

There is growing evidence that some chemicals present in the environment have the capacity to inhibit, or potentially induce, aromatase activity. This study compared aromatase activities and isoform-specific mRNA expression in brain and ovary tissue from non-exposed fathead minn...

Linking the response of endocrine regulated genes to adverse effects on sex differentiation improves comprehension of aromatase inhibition in a Fish Sexual Development Test.

PubMed

Muth-Köhne, Elke; Westphal-Settele, Kathi; Brückner, Jasmin; Konradi, Sabine; Schiller, Viktoria; Schäfers, Christoph; Teigeler, Matthias; Fenske, Martina

2016-07-01

The Fish Sexual Development Test (FSDT) is a non-reproductive test to assess adverse effects of endocrine disrupting chemicals. With the present study it was intended to evaluate whether gene expression endpoints would serve as predictive markers of endocrine disruption in a FSDT. For proof-of-concept, a FSDT according to the OECD TG 234 was conducted with the non-steroidal aromatase inhibitor fadrozole (test concentrations: 10μg/L, 32μg/L, 100μg/L) using zebrafish (Danio rerio). Gene expression analyses using quantitative RT-PCR were included at 48h, 96h, 28days and 63days post fertilization (hpf, dpf). The selection of genes aimed at finding molecular endpoints which could be directly linked to the adverse apical effects of aromatase inhibition. The most prominent effects of fadrozole exposure on the sexual development of zebrafish were a complete sex ratio shift towards males and an acceleration of gonad maturation already at low fadrozole concentrations (10μg/L). Due to the specific inhibition of the aromatase enzyme (Cyp19) by fadrozole and thus, the conversion of C19-androgens to C18-estrogens, the steroid hormone balance controlling the sex ratio of zebrafish was altered. The resulting key event is the regulation of directly estrogen-responsive genes. Subsequently, gene expression of vitellogenin 1 (vtg1) and of the aromatase cyp19a1b isoform (cyp19a1b), were down-regulated upon fadrozole treatment compared to controls. For example, mRNA levels of vtg1 were down-regulated compared to the controls as early as 48 hpf and 96 hpf. Further regulated genes cumulated in pathways suggested to be controlled by endocrine mechanisms, like the steroid and terpenoid synthesis pathway (e.g. mevalonate (diphospho) decarboxylase (mvd), lanosterol synthase (2,3-oxidosqualene-lanosterol cyclase; lss), methylsterol monooxygenase 1 (sc4mol)) and in lipid transport/metabolic processes (steroidogenic acute regulatory protein (star), apolipoprotein Eb (apoEb)). Taken together, this study demonstrated that the existing Adverse Outcome Pathway (AOP) for aromatase inhibition in fish can be translated to the life-stage of sexual differentiation. We were further able to identify MoA-specific marker gene expression which can be instrumental in defining new measurable key events (KE) of existing or new AOPs related to endocrine disruption. Copyright © 2016 The Author(s). Published by Elsevier B.V. All rights reserved.

Opposite-directional sex change in functional female protandrous anemonefish, Amphiprion clarkii: effect of aromatase inhibitor on the ovarian tissue.

PubMed

Nakamura, Masaru; Miura, Saori; Nozu, Ryo; Kobayashi, Yasuhisa

2015-01-01

The anemonefish, Amphiprion clarkii, is a protandrous hermaphrodite. Under appropriate social conditions, male fish can become female. Previous studies indicated that estrogens are important regulators of sex change in this fish. However, the mechanism of sexual plasticity in the gonad of this fish is still unknown. To elucidate the mechanisms underlying the sexual plasticity in the ovary of female anemonefish, an aromatase inhibitor (AI, 500 μg/g diet) was administered to the functional female fish for 80 days. The levels of estradiol-17β (E2) in the fish treated with AI were significantly lower than those in the control group. Three out of five fish had ambisexual gonads with active spermatogenic germ cells in the ovarian tissue. However, female fish in the AI-treated group prior to treatment and those in the control group displayed no testicular characteristics in their developed ovaries. This result strongly suggests that germ cells with bipotentiality or spermatogonial cells remain in the functional ovaries of anemonefish following sex change from functional males to functional females. There is a possibility that estrogen depletion due to AI treatment might have caused the opposite-directional sex change from functional female to male in the anemonefish. The anemonefish keeps their high sexual bipotential in the ovary after sex change.

Letrozole in advanced breast cancer: the PO25 trial

PubMed Central

2007-01-01

Tamoxifen has been a standard first-line endocrine therapy for post-menopausal women with hormone-responsive advanced breast cancer, but more than half of patients fail to respond and time to progression is less than 12 months in responders. The third-generation aromatase inhibitors were developed to provide more effective alternatives to tamoxifen. In the Femara Study PO25, post-menopausal women with advanced breast cancer were randomized to receive letrozole 2.5 mg (n = 453) or tamoxifen 20 mg (n = 454) given orally daily until progressive disease occurred. Patients were permitted to cross over to the other treatment at progression. In the primary efficacy analysis, median time to progression (TTP) was significantly longer with letrozole than with tamoxifen (9.4 months vs. 6.0 months, respectively; P < 0.0001). The objective response rate (ORR) was significantly higher for letrozole than for tamoxifen (32% vs. 21%; P = 0.0002). Prospectively planned analyses of the intent-to-treat population showed that letrozole significantly improved overall survival (OS) compared with tamoxifen over the first 24 months of the trial. An exploratory analysis of patients, who did not cross over, indicated a median OS benefit of 14 months for letrozole compared with tamoxifen. Letrozole is the only third-generation aromatase inhibitor that has demonstrated significant improvements in ORR, TTP, and early OS. PMID:17333340

Effect of rejuvenation hormones on spermatogenesis.

PubMed

Moss, Jared L; Crosnoe, Lindsey E; Kim, Edward D

2013-06-01

To review the current literature for the effect of hormones used in rejuvenation clinics on the maintenance of spermatogenesis. Review of published literature. Not applicable. Men who have undergone exogenous testosterone (T) and/or anabolic androgenic steroid (AAS) therapies. None. Semen analysis, pregnancy outcomes, and time to recovery of spermatogenesis. Exogenous testosterone and anabolic androgenic steroids suppress intratesticular testosterone production, which may lead to azoospermia or severe oligozoospermia. Therapies that protect spermatogenesis involve human chorionic gonadotropin (hCG) therapy and selective estrogen receptor modulators (SERMs). The studies examining the effect of human growth hormone (HGH) on infertile men are uncontrolled and unconvincing, but they do not appear to negatively impact spermatogenesis. At present, routine use of aromatase inhibitors is not recommended based on a lack of long-term data. The use of hormones for rejuvenation is increasing with the aging of the Baby Boomer population. Men desiring children at a later age may be unaware of the side-effect profile of hormones used at rejuvenation centers. Testosterone and anabolic androgenic steroids have well-established detrimental effects on spermatogenesis, but recovery may be possible with cessation. Clomiphene citrate, human growth hormone (HGH)/insulin-like growth factor-1 (IGF-1), human chorionic gonadotropin (hCG), and aromatase inhibitors do not appear to have significant negative effects on sperm production, but quality data are lacking. Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

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

USGS Publications Warehouse

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

2009-01-01

Cliff swallows (Petrochelidon pyrrhonota) and cave swallows (P. fulva) were sampled during the breeding season at several locations in the Rio Grande, Texas, to evaluate the potential effects of environmental contaminants on P450 aromatase activity in brain and gonads and DNA damage in blood cells. The tritiated water-release aromatase assay was used to measure aromatase activity and flow cytometry was used to measure DNA damage in nucleated blood cells. There were no significant differences in brain and gonadal aromatase activities or in estimates of DNA damage (HPCV values) among cave swallow colonies from the Lower Rio Grande Valley (LRGV) and Somerville. However, both brain and gonadal aromatase activities were significantly higher (P < 0.05) in male cliff swallows from Laredo than in those from Somerville. Also, DNA damage estimates were significantly higher (P < 0.05) in cliff swallows (males and females combined) from Laredo than in those from Somerville. Contaminants of current high use in the LRGV, such as atrazine, and some of the highly persistent organochlorines, such as toxaphene and DDE, could be potentially associated with modulation of aromatase activity in avian tissues. Previous studies have indicated possible DNA damage in cliff swallows. We did not observe any differences in aromatase activity or DNA damage in cave swallows that could be associated with contaminant exposure. Also, the differences in aromatase activity and DNA damage between male cliff swallows from Laredo and Somerville could not be explained by contaminants measured at each site in previous studies. Our study provides baseline information on brain and gonadal aromatase activity in swallows that could be useful in future studies. ?? 2008 Springer Science+Business Media, LLC.

The efficacy of bisphosphonates in preventing aromatase inhibitor induced bone loss for postmenopausal women with early breast cancer: a systematic review and meta-analysis.

PubMed

Anagha, Pooleriveetil Padikkal; Sen, Suchandra

2014-01-01

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.

A Pilot Study Comparing the Effect of Flaxseed, Aromatase Inhibitor, and the Combination on Breast Tumor Biomarkers

PubMed Central

McCann, Susan E.; Edge, Stephen B.; Hicks, David G.; Thompson, Lilian U.; Morrison, Carl D.; Fetterly, Gerald; Andrews, Christopher; Clark, Kim; Wilton, John; Kulkarni, Swati

2014-01-01

Use of complementary approaches is common among breast cancer survivors. Potential interactions between aromatase inhibitors (AI) and high phytoestrogen foods, such as flaxseed (FS) are not often described. We conducted a pilot 2×2 factorial, randomized intervention study between tumor biopsy and resection, in 24 postmenopausal women with estrogen receptor positive (ER+) breast cancer, to assess the effects of flaxseed and anastrozole, and possible interactions between them, on serum steroid hormone and tumor-related characteristics associated with long-term survival (Roswell Park Cancer Institute, 2007–2010). The effect of each treatment vs placebo on outcomes was determined by linear regression adjusting for pre-treatment measure, stage, and grade. Although not statistically significant, mean ERβ expression was approximately 40% lower from pre- to post-intervention in the FS+AI group only. We observed a statistically significant negative association (β±SE −0.3±0.1; p=0.03) for androstenedione in the FS+AI group vs placebo and for DHEA with AI treatment (β±SE −1.6±0.6; p=0.009). Enterolactone excretion was much lower in the FS+AI group compared to the FS group. Our results do not support strong effects of flaxseed on AI activity for selected breast tumor characteristics or serum steroid hormone levels, but suggest AI therapy might reduce the production of circulating mammalian lignans from flaxseed. PMID:24669750

Of mice and men: the evolving phenotype of aromatase deficiency.

PubMed

Jones, Margaret E E; Boon, Wah Chin; Proietto, Joseph; Simpson, Evan R

2006-03-01

We are rapidly becoming aware of the importance of estrogen in maintaining virtually all facets of male health. In order for estrogens to be synthesized endogenously, the enzyme responsible for their synthesis from androgens, aromatase, must be functional. The seven known men in whom aromatase is nonfunctional all have a mutation in either exon V or IX of the CYP19 gene, which encodes aromatase. Collectively, these men are reported to have undetectable estrogen; normal to high levels of testosterone and gonadotropins; tall stature with delayed skeletal maturation and epiphyseal closure; osteoporosis; impaired lipid and insulin metabolism; and impaired reproductive function. The aromatase knockout mouse presents with a phenotype that is similar in many aspects and provides a valuable tool with which to examine and manipulate the actions of estrogen. By studying the naturally occurring aromatase-deficient humans, together with studies of the aromatase-knockout mouse, we are expanding our understanding of the essential role of estrogen in male physiology.

Vaginal Testosterone for Management of Aromatase Inhibitor-Related Sexual Dysfunction: An Integrative Review.

PubMed

Lemke, Emily A; Madsen, Lydia T; Dains, Joyce E

2017-05-01

Women taking aromatase inhibitors (AIs) as part of the management of hormone receptor-positive breast cancer experience more symptoms of sexual dysfunction, including vaginal atrophy, as opposed to postmenopausal women and women treated with tamoxifen (Nolvadex®). Vaginal testosterone could be an alternative to estrogen, which is contraindicated in this population.
. A systematic review was completed by searching PubMed and Scopus databases.
. 64 search results were reduced to a final sample of 3 articles after applying inclusion and exclusion criteria.
. Published results suggest that vaginally applied testosterone doses of 150 mcg and 300 mcg improve symptoms of sexual dysfunction in women taking AIs. Minimal side effects are observed, and estradiol levels are not affected by vaginally applied testosterone. Additional research is needed to evaluate vaginal testosterone in women taking AIs.
. Vaginal testosterone shows preliminary promise as an option to manage sexual side effects of AI therapy in postmenopausal cancer survivors; however, available data are too limited to draw practice-changing conclusions.
. Large-scale randomized, controlled trials need to be completed to evaluate the efficacy and safety of vaginal testosterone in women taking AIs.

Update on breast cancer risk prediction and prevention.

PubMed

Sestak, Ivana; Cuzick, Jack

2015-02-01

Breast cancer is the most common cancer in women worldwide. This review will focus on current prevention strategies for women at high risk. The identification of women who are at high risk of developing breast cancer is key to breast cancer prevention. Recent findings have shown that the inclusion of breast density and a panel of low-penetrance genetic polymorphisms can improve risk estimation compared with previous models. Preventive therapy with aromatase inhibitors has produced large reductions in breast cancer incidence in postmenopausal women. Tamoxifen confers long-term protection and is the only proven preventive treatment for premenopausal women. Several other agents, including metformin, bisphosphonates, aspirin and statins, have been found to be effective in nonrandomized settings. There are many options for the prevention of oestrogen-positive breast cancer, in postmenopausal women who can be given a selective oestrogen receptor modulator or an aromatase inhibitor. It still remains unclear how to prevent oestrogen-negative breast cancer, which occurs more often in premenopausal women. Identification of women at high risk of the disease is crucial, and the inclusion of breast density and a panel of genetic polymorphisms, which individually have low penetrance, can improve risk assessment.

Adjuvant Endocrine Therapy in Breast Cancer: Evolving Paradigms in Premenopausal Women.

PubMed

Rossi, Lorenzo; Pagani, Olivia

2017-05-01

In the last few years, new adjuvant endocrine treatment options have become available in young women with early breast cancer, such as the addition of ovarian function suppression to tamoxifen or aromatase inhibitors. Treatment duration has been also adapted in the latest guidelines based on the individual risk of recurrence. The oncologist is therefore challenged to precisely assess the risk of recurrence according to currently available predictive and prognostic factors in order to offer the most appropriate therapeutic option to the individual patient, considering also potential side effects, quality of life, pregnancy planning and patients' preferences. The adjuvant treatment planning should always be discussed and agreed in a multidisciplinary context. Tamoxifen remains the standard of care in low-risk patients or in case of intolerance to combined treatment with pharmacological ovarian function suppression or aromatase inhibitors. Combination treatment is indicated in intermediate high-risk disease. The patient should always be considered an active partner in the treatment decision process, to improve treatment motivation and adherence. Finally, the therapeutic choice should take into account drug availability and pharmacoeconomic issues, which unfortunately may prevent, in many low-income countries, the provision of such effective treatments.

Evaluation of Therapy Management and Patient Compliance in Postmenopausal Patients with Hormone Receptor-positive Breast Cancer Receiving Letrozole Treatment: The EvaluateTM Study

PubMed Central

Fasching, P. A.; Fehm, T.; Kellner, S.; de Waal, J.; Rezai, M.; Baier, B.; Baake, G.; Kolberg, H.-C.; Guggenberger, M.; Warm, M.; Harbeck, N.; Würstlein, R.; Deuker, J.-U.; Dall, P.; Richter, B.; Wachsmann, G.; Brucker, C.; Siebers, J. W.; Fersis, N.; Kuhn, T.; Wolf, C.; Vollert, H.-W.; Breitbach, G.-P.; Janni, W.; Landthaler, R.; Kohls, A.; Rezek, D.; Noesslet, T.; Fischer, G.; Henschen, S.; Praetz, T.; Heyl, V.; Kühn, T.; Krauß, T.; Thomssen, C.; Kümmel, S.; Hohn, A.; Tesch, H.; Mundhenke, C.; Hein, A.; Rauh, C.; Bayer, C. M.; Jacob, A.; Schmidt, K.; Belleville, E.; Hadji, P.; Wallwiener, D.; Grischke, E.-M.; Beckmann, M. W.; Brucker, S. Y.

2014-01-01

Introduction: The EvaluateTM study (Evaluation of therapy management and patient compliance in postmenopausal hormone receptor-positive breast cancer patients receiving letrozole treatment) is a prospective, non-interventional study for the assessment of therapy management and compliance in the routine care of postmenopausal women with invasive hormone receptor-positive breast cancer receiving letrozole. The parameters for inclusion in the study are presented and discussed here. Material and Methods: Between January 2008 and December 2009 a total of 5045 patients in 310 study centers were recruited to the EvaluateTM study. Inclusion criteria were hormone receptor-positive breast cancer and adjuvant treatment or metastasis. 373 patients were excluded from the analysis for various reasons. Results: A total of 4420 patients receiving adjuvant treatment and 252 patients with metastasis receiving palliative treatment were included in the study. For 4181 patients receiving adjuvant treatment, treatment with the aromatase inhibitor letrozole commenced immediately after surgery (upfront). Two hundred patients had initially received tamoxifen and started aromatase inhibitor treatment with letrozole at 1–5 years after diagnosis (switch), und 39 patients only commenced letrozole treatment 5–10 years after diagnosis (extended endocrine therapy). Patient and tumor characteristics were within expected ranges, as were comorbidities and concurrent medication. Conclusion: The data from the EvaluateTM study will offer a good overview of therapy management in the routine care of postmenopausal women with hormone receptor-positive breast cancer. Planned analyses will look at therapy compliance and patient satisfaction with how information is conveyed and the contents of the conveyed information. PMID:25568468

MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer.

PubMed

Goetz, Matthew P; Toi, Masakazu; Campone, Mario; Sohn, Joohyuk; Paluch-Shimon, Shani; Huober, Jens; Park, In Hae; Trédan, Olivier; Chen, Shin-Cheh; Manso, Luis; Freedman, Orit C; Garnica Jaliffe, Georgina; Forrester, Tammy; Frenzel, Martin; Barriga, Susana; Smith, Ian C; Bourayou, Nawel; Di Leo, Angelo

2017-11-10

Purpose Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, demonstrated efficacy as monotherapy and in combination with fulvestrant in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer previously treated with endocrine therapy. Methods MONARCH 3 is a double-blind, randomized phase III study of abemaciclib or placebo plus a nonsteroidal aromatase inhibitor in 493 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had no prior systemic therapy in the advanced setting. Patients received abemaciclib or placebo (150 mg twice daily continuous schedule) plus either 1 mg anastrozole or 2.5 mg letrozole, daily. The primary objective was investigator-assessed progression-free survival. Secondary objectives included response evaluation and safety. A planned interim analysis occurred after 189 events. Results Median progression-free survival was significantly prolonged in the abemaciclib arm (hazard ratio, 0.54; 95% CI, 0.41 to 0.72; P = .000021; median: not reached in the abemaciclib arm, 14.7 months in the placebo arm). In patients with measurable disease, the objective response rate was 59% in the abemaciclib arm and 44% in the placebo arm ( P = .004). In the abemaciclib arm, diarrhea was the most frequent adverse effect (81.3%) but was mainly grade 1 (44.6%). Comparing abemaciclib and placebo, the most frequent grade 3 or 4 adverse events were neutropenia (21.1% v 1.2%), diarrhea (9.5% v 1.2%), and leukopenia (7.6% v 0.6%). Conclusion Abemaciclib plus a nonsteroidal aromatase inhibitor was effective as initial therapy, significantly improving progression-free survival and objective response rate and demonstrating a tolerable safety profile in women with HR-positive, HER2-negative advanced breast cancer.

Modelling inhibition of avian aromatase by azole pesticides.

PubMed

Saxena, A K; Devillers, J; Bhunia, S S; Bro, E

2015-01-01

The potential effects of pesticides and their metabolites on the endocrine system are of major concern to wildlife and human health. In this context, the azole pesticides have earned special attention due to their cytochrome P450 aromatase inhibition potential. Cytochrome P450 aromatase (CYP19) catalyses the conversion of androstenedione and testosterone into oestrone and oestradiol, respectively. Thus, aromatase modulates the oestrogenic balance essential not only for females, but also for male physiology, including gonadal function. Its inhibition affects reproductive organs, fertility and sexual behaviour in humans and wildlife species. Several studies have shown that azole pesticides are able to inhibit human and fish aromatases but the information on birds is lacking. Consequently, it appeared to be of interest to estimate the aromatase inhibition of azoles in three different avian species, namely Gallus gallus, Coturnix coturnix japonica and Taeniopygia guttata. In the absence of the crystal structure of the aromatase enzyme in these bird species, homology models for the individual avian species were constructed using the crystal structure of human aromatase (hAr) (pdb: 3EQM) that showed high sequence similarity for G. gallus (82.0%), T. guttata (81.9%) and C. japonica (81.2%). A homology model with Oncorhynchus mykiss (81.9%) was also designed for comparison purpose. The homology-modelled aromatase for each avian and fish species and crystal structure of human aromatase were selected for docking 46 structurally diverse azoles and related compounds. We showed that the docking behaviour of the chemicals on the different aromatases was broadly the same. We also demonstrated that there was an acceptable level of correlation between the binding score values and the available aromatase inhibition data. This means that the homology models derived on bird and fish species can be used to approximate the potential inhibitory effects of azoles on their aromatase.

Bone health and adherence to vitamin D and calcium therapy in early breast cancer patients on endocrine therapy with aromatase inhibitors.

PubMed

Bošković, Lidija; Gašparić, Maja; Petković, Marija; Gugić, Damir; Lovasić, Ingrid Belac; Soldić, Željko; Miše, Branka Petrić; Dabelić, Nina; Vazdar, Ljubica; Vrdoljak, Eduard

2017-02-01

Randomized trials involving aromatase inhibitors (AIs) in the adjuvant treatment of breast cancer patients have reported increased osteoporosis risk. Bone loss can be reduced with appropriate life style, vitamin D and calcium supplements, and with bisphosphonate therapy. The aim of this analysis was to investigate adherence to vitamin D and calcium in postmenopausal breast cancer patients receiving adjuvant non-steroidal AIs, and oncologists' adherence to the bone health guidelines. This prospective study included 438 newly diagnosed patients and those who have already been receiving non-steroidal AIs for up to 3.5 years. Median endocrine therapy duration before recruitment in the study was 10.5 months (interquartile 4.8-26.6). Densitometry was performed on 142 patients (32.4%) before initiation of endocrine therapy, and on additional 38 (8.6%) patients at second study visit. Densitometry was not performed on 258 (59%) patients. Vitamin D and calcium were prescribed to 329/438 (75.1%) patients at some point during the study. Patients who took more than 80% of the prescribed dose were considered adherent. Self-reported adherence was 88.4%. Osteoporosis was diagnosed in 24 patients (5.5%) of the total study population, bearing in mind that 258/438 (59%) patients did not have densitometry. Bisphosphonates were prescribed to 54/438 (12.3%) patients, whilst only 19 (35.2%) of those had osteoporosis. In this analysis, lack of oncologists' adherence to the bone health guidelines was observed. In addition, a significant proportion of the patients did not adhere to the vitamin D and calcium. Copyright © 2016 Elsevier Ltd. All rights reserved.

Subcutaneous testosterone-letrozole therapy before and concurrent with neoadjuvant breast chemotherapy: clinical response and therapeutic implications.

PubMed

Glaser, Rebecca L; York, Anne E; Dimitrakakis, Constantine

2017-07-01

Hormone receptor-positive breast cancers respond favorably to subcutaneous testosterone combined with an aromatase inhibitor. However, the effect of testosterone combined with an aromatase inhibitor on tumor response to chemotherapy was unknown. This study investigated the effect of testosterone-letrozole implants on breast cancer tumor response before and during neoadjuvant chemotherapy. A 51-year-old woman on testosterone replacement therapy was diagnosed with hormone receptor-positive invasive breast cancer. Six weeks before starting neoadjuvant chemotherapy, the patient was treated with subcutaneous testosterone-letrozole implants and instructed to follow a low-glycemic diet. Clinical status was followed. Tumor response to "testosterone-letrozole" and subsequently, "testosterone-letrozole with chemotherapy" was monitored using serial ultrasounds and calculating tumor volume. Response to therapy was determined by change in tumor volume. Cost of therapy was evaluated. There was a 43% reduction in tumor volume 41 days after the insertion of testosterone-letrozole implants, before starting chemotherapy. After the initiation of concurrent chemotherapy, the tumor responded at an increased rate, resulting in a complete pathologic response. Chemotherapy was tolerated. Blood counts and weight remained stable. There were no neurologic or cardiac complications from the chemotherapy. Cost of therapy is reported. Subcutaneous testosterone-letrozole was an effective treatment for this patient's breast cancer and did not interfere with chemotherapy. This novel combination implant has the potential to prevent side effects from chemotherapy, improve quality of life, and warrants further investigation.

Menopausal-type symptoms among breast cancer patients on aromatase inhibitor therapy.

PubMed

Gallicchio, L; MacDonald, R; Wood, B; Rushovich, E; Helzlsouer, K J

2012-08-01

To examine self-reported menopausal-type symptoms among breast cancer patients on aromatase inhibitors (AIs) compared to women of the same age who had not been diagnosed with cancer, and to determine whether the percentage of breast cancer patients experiencing these symptoms changed over the first 6 months of AI treatment. Data from a 6-month cohort study of 100 breast cancer patients initiating AI therapy and of 200 women of a similar age without a history of cancer were analyzed. At baseline (prior to the initiation of AI therapy among the breast cancer patients), 3 months, and 6 months, a comprehensive questionnaire was administered to participants that ascertained data on the experiencing of specific menopausal-type symptoms. The data showed statistically significant increases in the prevalence of certain symptoms from baseline to either follow-up point among the breast cancer patients; these symptoms included hot flushes, night sweats, pain during intercourse, hair loss, forgetfulness, depression, difficulty falling asleep, and interrupted sleep. Additionally, breast cancer patients were more likely than the women in the comparison group to report the new onset of many of these same symptoms during the follow-up time period. Because bothersome symptoms and side-effects are a major reason for discontinuation and non-adherence to treatment, symptoms should be monitored and addressed by oncologists so that the breast cancer patient can maintain her quality of life and remain adherent to the treatment schedule.

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

PubMed Central

2009-01-01

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. PMID:19909552

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

PubMed

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

2015-07-01

Aromatase inhibitor (AI) use results in low estrogen levels, which in turn affect bone mineral density (BMD). Periodontitis, alveolar bone loss, and tooth loss are associated with low BMD. The goal of this study is to assess the prevalence of periodontitis and perceived oral health and evaluate salivary biomarkers in postmenopausal women who are survivors of early-stage (I to IIIA) breast cancer (BCa) and receive adjuvant AI therapy. Participants included 58 postmenopausal women: 29 with BCa on AIs and 29 controls without BCa diagnoses. Baseline periodontal status was assessed with: 1) periodontal probing depth (PD); 2) bleeding on probing (BOP); and 3) attachment loss (AL). Demographic and dental utilization information was gathered by questionnaire. Linear regression modeling was used to analyze the outcomes. No differences were found in mean PD or number of teeth. The AI group had significantly more sites with BOP (27.8 versus 16.7; P = 0.02), higher worst-site AL (5.2 versus 4.0 mm; P <0.01), and more sites with dental calculus (18.2 versus 6.4; P <0.001) than controls. Linear regression adjusted for income, tobacco use, dental insurance, and previous radiation and chemotherapy exposure demonstrated that AI use increased AL by >2 mm (95% confidence interval, 0.46 to 3.92). Median salivary osteocalcin and tumor necrosis factor-α levels were significantly higher in the AI group than the control group. This first investigation of the periodontal status of women initiating adjuvant AI therapy identifies this population as having an increased risk for periodontitis.

Joint symptoms associated with anastrozole and letrozole in patients with breast cancer: a retrospective comparative study.

PubMed

Morimoto, Yoshihito; Sarumaru, Shuhei; Oshima, Yuko; Tsuruta, Chiho; Watanabe, Kazuhiro

2017-01-01

Joint symptoms are a common side effect of aromatase inhibitors. However, it is not known if the risk of these symptoms varies between the members of this drug class. The aim of this study was to compare the frequency of joint symptoms associated with anastrozole and that associated with letrozole. We retrospectively reviewed patients with breast cancer who were treated with anastrozole or letrozole at Tsukiji Breast Clinic, Japan, between April 2008 and July 2014. Joint symptoms were deemed to include both joint pain and painless joint symptoms. The time to onset of joint symptoms in the anastrozole group was compared with that in the letrozole group using Kaplan-Meier curves and the log-rank test. Of 141 patients identified to have received aromatase inhibitors, 70 had been treated with anastrozole and 71 with letrozole. Joint symptoms occurred in 60.3% of the 141 patients (60.0% in the anastrozole group and 60.6% in the letrozole group; p  = 1). Median time to appearance of joint symptoms was 583 days, with no significant difference between the anastrozole and letrozole groups ( p  = 0.962). There was no significant difference in time to onset of joint pain ( p  = 0.139); however, time to onset of painless joint symptoms was significantly shorter in the anastrozole group ( p  = 0.022). The sites at which joint symptoms occurred were similar in the two groups. The results of this study indicate that there is no difference in the pattern of occurrence of joint symptoms caused by anastrozole and those caused by letrozole. Trial registration was not required for this study because of its retrospective nature and lack of intervention.

HDAC inhibitor entinostat restores responsiveness of letrozole resistant MCF-7Ca xenografts to AIs through modulation of Her-2

PubMed Central

Sabnis, Gauri J.; Goloubeva, Olga G.; Kazi, Armina A.; Shah, Preeti; Brodie, Angela H.

2013-01-01

We previously showed that in innately resistant tumors, silencing of the estrogen receptor (ER) could be reversed by treatment with a histone deacetylase (HDAC) inhibitor entinostat (ENT). Tumors were then responsive to aromatase inhibitor (AIs) letrozole. Here, we investigated whether ER in the acquired letrozole resistant tumors could be restored with ENT. Ovariectomized athymic mice were inoculated with MCF-7Ca cells, supplemented with androstenedione (Δ4A), the aromatizable substrate. When the tumors reached ~300mm3, the mice were treated with letrozole. After initial response to letrozole, the tumors eventually became resistant (doubled their initial volume). The mice then were grouped to receive letrozole, exemestane (250μg/day), ENT (50μg/day) or the combination of ENT with letrozole or exemestane for 26 weeks. The growth rates of tumors of mice treated with the combination of ENT with letrozole or exemestane were significantly slower than with the single agent (p<0.05). Analysis of the letrozole resistant tumors showed ENT increased ERα expression and aromatase activity but downregulated Her-2, p-Her-2, p-MAPK and p-Akt. However, the mechanism of action of ENT in reversing acquired resistance did not involve epigenetic silencing, but rather included post-translational as well as transcriptional modulation of Her-2. ENT treatment reduced the association of the Her-2 protein with HSP-90, possibly by reducing the stability of Her-2 protein. In addition, ENT also reduced Her-2 mRNA levels and its stability. Our results suggest that the HDAC inhibitor may reverse letrozole resistance in cells and tumors by modulating Her-2 expression and activity. PMID:24092810

Aromatase inhibitors for subfertile women with polycystic ovary syndrome.

PubMed

Franik, Sebastian; Kremer, Jan A M; Nelen, Willianne L D M; Farquhar, Cindy

2014-02-24

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 treatment clomiphene citrate (CC). To evaluate the effectiveness and safety of aromatase inhibitors for subfertile women with anovulatory PCOS. We searched the following sources from inception to 24/10/2013 to identify relevant randomised controlled trials (RCTs): the Menstrual Disorders and Subfertility Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, PsycINFO, Pubmed, LILACS, Web of Knowledge, the World Health Organisation (WHO) clinical trials register and Clinicaltrials.gov. Furthermore, we manually searched the references of relevant articles.The search was not restricted by language or publication status. We included all RCTs of aromatase inhibitors used alone or with other medical therapies for ovulation induction in women of reproductive age with anovulatory PCOS. Two review authors independently selected trials, extracted the data and assessed trial quality. Studies were pooled where appropriate using a fixed effect model to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs) for most outcomes and risk differences (RDs) for ovarian hyperstimulation syndrome (OHSS). The primary outcomes were live birth and OHSS. Secondary outcomes were pregnancy, miscarriage and multiple pregnancy. The quality of the evidence for each comparison was assessed using GRADE methods. We included 26 RCTs (5560 women). In all studies the aromatase inhibitor was letrozole. Live birth (12 RCTs) One RCT compared letrozole with placebo in women who were clomiphene resistant and the results were inconclusive (OR 3.17, 95% CI 0.12 to 83.17, n=36)Nine RCTs compared letrozole with clomiphene citrate (with or without adjuncts) followed by timed intercourse. The birth rate was higher in the letrozole group (OR 1.63, 95% CI 1.31 to 2.03, n=1783, I²=3%)Two RCTs compared letrozole with laparoscopic ovarian drilling. There was no evidence of a difference between the groups in live birth rate (OR 1.19, 95% CI 0.76 to 1.86, n=407, I²=0%) OHSS (16 RCTs) There was no evidence of a difference in OHSS rates when letrozole was compared with placebo (one RCT, n=36), clomiphene citrate (with or without adjuncts) followed by timed intercourse (nine RCTs, n=2179), clomiphene citrate (with or without adjuncts) followed by intrauterine insemination (IUI) (two RCTs, n=1494), laparoscopic ovarian drilling (one RCT, n=260) or anastrozole (one RCT, n=220). Events were absent or very rare, and no study had more than 2 cases of OHSS. Clinical pregnancy (25 RCTs) One RCT compared letrozole versus placebo in women who were clomiphene resistant and the results were inconclusive (OR 3.17, 95% CI 0.12 to 83.17, n=36)Fourteen RCTs compared letrozole versus clomiphene citrate (with or without adjuncts) followed by timed intercourse. The pregnancy rate was higher in the letrozole group (OR 1.32, 95% CI 1.09 to 1.60, n=2066, I²=25%)Three RCTs compared letrozole versus clomiphene citrate (with or without adjuncts) followed by IUI. The pregnancy rate was higher in the letrozole group (OR 1.71, 95% CI 1.30 to 2.25, n=1597)Three RCTs compared letrozole versus laparoscopic ovarian drilling. There was no evidence of a difference in the clinical pregnancy rate (OR 1.14, 95% CI 0.80 to 1.65, n=553, I²=0%)Two RCTs compared letrozole versus anastrozole, one RCT compared a five day versus a 10 day administration protocol for letrozole and another RCT compared 5 mg of letrozole versus 7.5 mg of letrozole. There was no evidence of a difference in the clinical pregnancy rate in these comparisons.The quality of the evidence was rated as low for live birth and pregnancy outcomes. The reasons for downgrading the evidence were poor reporting of study methods, possible publication bias and the tendency for studies that reported live birth to report higher clinical pregnancy rates in the letrozole group than studies that failed to report live birth (suggesting that results might be somewhat less favourable to letrozole if all studies reported live birth). Letrozole appears to improve live birth and pregnancy rates in subfertile women with anovulatory PCOS, compared to clomiphene citrate. The quality of this evidence is low and findings should be regarded with some caution. There appears to be no difference in effectiveness between letrozole and laparoscopic ovarian drilling, though there were few relevant studies. OHSS was a very rare event, with no occurrences in most studies.

Inhibition of Aromatase Induces Partial Sex Change in a Cichlid Fish: Distinct Functions for Sex Steroids in Brains and Gonads.

PubMed

Göppert, Carolin; Harris, Rayna M; Theis, Anya; Boila, Anna; Hohl, Simon; Rüegg, Attila; Hofmann, Hans A; Salzburger, Walter; Böhne, Astrid

2016-01-01

Sex steroids are major drivers of sexual development and also responsible for the maintenance of the established gender. Especially fishes exhibit great plasticity and less conservation in sex determination and sexual development compared to other vertebrate groups. In addition, fishes have a constant sex steroid production throughout their entire lifespan, which makes them particularly susceptible to interferences with the endogenous sex steroid system. This susceptibility has recently been used to show that inhibition of the key enzyme of estrogen synthesis, aromatase Cyp19a1, can induce functional sex reversal even in adult fish. Here, we investigated the impact of the aromatase inhibitor (AI) fadrozole in adult females of the East African cichlid fish Astatotilapia burtoni. Using gene expression, phenotypic measurements, behavioral experiments, and hormone measurements, we assessed if females treated with fadrozole develop a male-like phenotype. We found that AI treatment has a different effect on gene expression in the gonad compared to the brain, the 2 tissues mostly implicated in sexual development. In contrast to observations in other gonochoristic species, A. burtoni ovaries cannot be transformed into functional testis by AI. However, rapid changes towards a male-like phenotype can be induced with AI in coloration, hormone levels, and behavior. © 2016 S. Karger AG, Basel.

Regulation of aromatase expression in the anterior amygdala of the developing mouse brain depends on ERβ and sex chromosome complement.

PubMed

Cisternas, Carla Daniela; Cabrera Zapata, Lucas Ezequiel; Arevalo, María Angeles; Garcia-Segura, Luis Miguel; Cambiasso, María Julia

2017-07-13

During development sex differences in aromatase expression in limbic regions of mouse brain depend on sex chromosome factors. Genes on the sex chromosomes may affect the hormonal regulation of aromatase expression and this study was undertaken to explore that possibility. Male E15 anterior amygdala neuronal cultures expressed higher levels of aromatase (mRNA and protein) than female cultures. Furthermore, treatment with oestradiol (E2) or dihydrotestosterone (DHT) increased Cyp19a1 expression and aromatase protein levels only in female neuronal cultures. The effect of E2 on aromatase expression was not imitated by oestrogen receptor (ER) α agonist PPT or the GPER agonist G1, but it was fully reproduced by DPN, a specific ligand of ERβ. By contrast, the effect of DHT on aromatase expression was not blocked by the anti-androgen flutamide, but completely abrogated by the ERβ antagonist PHTPP. Experiments using the four core genotype model showed a sex chromosome effect in ERβ expression (XY > XX) and regulation by E2 or DHT (only XX respond) in amygdala neurons. In conclusion, sex chromosome complement governs the hormonal regulation of aromatase expression through activation of ERβ in developing mouse brain.

Tamoxifen and Aromatase Inhibitors: Cognitive Function in Occupationally Active Breast Cancer Survivors

DTIC Science & Technology

2010-05-04

assessments of cognitive function and sedation in patients with cancer pain admitted to a palliative care unit. Palliative Medicine, 16 (6), 513-9. 71...interventions. Palliative & Supportive Care, 5(3), 273-280. 72 Noblett, K.L., & Swain, R.A. (2003). Pretraining enhances recovery from visuospatial...Self-reported cognitive problems in women receiving adjuvant endocrine therapy for breast cancer. Eurpoean Journal of Oncology Nursing , 11(1), 6

Hormonal Resistance and Metastasis: ER-coregulator-Src Targeted Therapy

DTIC Science & Technology

2009-09-01

monoamine oxidase inhibitor that blocks LSD1 activity [50] and is approved by FDA for treatment of moderate to severe hypertension. Pargyline is...Research Institute, Princeton, NJ Estrogen receptor (ER) is implicated in breast cancer progression and the majority of the human breast cancers...II. Analysis of PELP1 driven mammary tumors in xenograft as well as in transgenic mouse models revealed increased aromatase expression. PELP1

A comparison of the effect of short-term aromatase inhibitor (letrozole) and GnRH agonist (triptorelin) versus case control on pregnancy rate and symptom and sign recurrence after laparoscopic treatment of endometriosis.

PubMed

Alborzi, Saeed; Hamedi, Bahareh; Omidvar, Azizeh; Dehbashi, Sedigheh; Alborzi, Soroosh; Alborzi, Mehrnoosh

2011-07-01

To compare the role of an aromatase inhibitor (letrozole) with a GnRH agonist (triptorelin) versus case control on the pregnancy rate and recurrence of symptoms and signs in patients with endometriosis. In a prospective randomized clinical trial, after treatment of 144 infertile women in their reproductive age by laparoscopy (whose endometriosis was confirmed by prior laparoscopy), they were divided into 3 groups: group 1 (47 cases) who received letrozole for 2 months, group 2 (40 patients) who were prescribed triptorelin for 2 months and group 3 who were 57 patients in the control group and did not receive any medication. We followed up each group at least for 12 months after their restoration of regular cycle. Pregnancy rate was 23.4% in group 1, 27.5% in group 2, and 28.1% in group 3. The results did not show significant differences among the 3 groups. Recurrence rate of endometriosis was 6.4% in group 1, 5% group 2 and 5.3% in group 3, which was not statistically significantly different as well. Pregnancy rate and endometriosis recurrence rate are comparable among the 3 groups.

Methodological issues in evaluating cost effectiveness of adjuvant aromatase inhibitors in early breast cancer: a need for improved modelling to aid decision making.

PubMed

Annemans, Lieven

2008-01-01

The optimal adjuvant hormonal strategy in post-menopausal women with early breast cancer is a subject of ongoing debate. Aromatase inhibitors (AIs) have been successfully evaluated in clinical trials that have compared them with a standard treatment of 5 years of tamoxifen. However, several options are available in terms of treatment schedule and selected drug. Systematic reviews of clinical trials and health economic evaluations attempt to contribute to the debate. The objective of this paper is to provide a critical review of existing health economic evaluations with a focus on those parameters and assumptions with the largest impact on final outcomes.A wide range of different inputs and assumptions exist, which make a comparison of results difficult, if not impossible. In particular, the modelling of recurrence rates over longer time horizons than those observed in clinical trials, a cornerstone of health economic modelling, is subject to quite different approaches. The practice of indirect comparison of different AIs without sufficiently acknowledging population differences is also bothersome. A list of key features (related to time horizon, clinical data input, patient subtypes, budget impact and model calibration) that an ideal model should have in order to better assist decision makers in this field is proposed.

Randomized placebo-controlled pilot trial of omega 3 fatty acids for prevention of aromatase inhibitor-induced musculoskeletal pain.

PubMed

Lustberg, Maryam B; Orchard, Tonya S; Reinbolt, Raquel; Andridge, Rebecca; Pan, Xueliang; Belury, Martha; Cole, Rachel; Logan, Amanda; Layman, Rachel; Ramaswamy, Bhuvaneswari; Wesolowski, Robert; Berger, Michael; Patterson, Elaine; Loprinzi, Charles; Shapiro, Charles L; Yee, Lisa

2018-02-01

Aromatase inhibitor (AI)-induced joint symptoms negatively impact drug adherence and quality of life in breast cancer survivors. Mechanisms underlying symptoms may include inflammation. It is hypothesized that n - 3 polyunsaturated fatty acids (PUFAs) have anti-inflammatory properties and may reduce symptoms. We conducted a randomized, double-blind, placebo-controlled study comparing 4.3 g/day n - 3 PUFA supplements vs placebo for 24 weeks in postmenopausal breast cancer patients starting adjuvant AIs. Primary endpoints were adherence and tolerability; secondary outcomes included inflammatory cytokines and symptoms assessed by the Brief Pain Inventory short form (BPI-SF) and Functional Assessment of Cancer Treatment-Endocrine Symptoms (FACT-ES) at 0, 12, and 24 weeks. Forty-four women were randomized, of which 35 completed the study. Adherence was ≥ 88% based on these 35 patients with pill counts as well as change in red blood cell (RBC) n - 3 PUFAs. Common toxicities included grade 1 flatulence (55% of both groups) and belching (45% of n - 3 group). Mean pain severity scores (BPI-SF) did not change significantly by time or treatment arm. Quality of life, based on FACT-ES scores, significantly decreased within placebo (p = 0.04), but not the n - 3 group (p = 0.58), with a trend toward between-group differences (p = 0.06) at 12 weeks, but no significant differences at 24 weeks. RBC n - 3 levels were strongly positively correlated with FACT-ES at 12 weeks, but attenuated at 24 weeks. High-dose n - 3 PUFA supplementation is feasible and well tolerated when administered with AIs. Additional studies are needed to evaluate efficacy in prevention of joint symptoms.

Pilot study of acupuncture for the treatment of joint symptoms related to adjuvant aromatase inhibitor therapy in postmenopausal breast cancer patients.

PubMed

Crew, Katherine D; Capodice, Jillian L; Greenlee, Heather; Apollo, Arlyn; Jacobson, Judith S; Raptis, George; Blozie, Kimberly; Sierra, Alex; Hershman, Dawn L

2007-12-01

Aromatase inhibitors (AIs) have become the standard of care for the adjuvant treatment of postmenopausal, hormone-sensitive breast cancer. However, patients receiving AIs may experience joint symptoms, which may lead to early discontinuation of this effective therapy. We hypothesize that acupuncture is a safe and effective treatment for AI-induced arthralgias. Postmenopausal women with early-stage breast cancer who had self-reported musculoskeletal pain related to adjuvant AI therapy were randomized in a crossover study to receive acupuncture twice weekly for 6 weeks followed by observation or vice-versa. The intervention included full body and auricular acupuncture, and a joint-specific point prescription. Outcome measures included the Brief Pain Inventory-Short Form (BPI-SF), Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index, the Functional Assessment of Cancer Therapy-General (FACT-G) quality of life measure, and serum levels of inflammatory markers, IL-1 beta and TNF-alpha. Twenty-one women were enrolled and two discontinued early. From baseline to the end of treatment, patients reported improvement in the mean BPI-SF worst pain scores (5.3 to 3.3, p = 0.01), pain severity (3.7 to 2.5, p = 0.02), and pain-related functional interference (3.1 to 1.7, p = 0.02), as well as the WOMAC function subscale and FACT-G physical well-being (p = 0.02 and 0.04, respectively). No adverse events were reported. In this pilot study, acupuncture reduced AI-related joint symptoms and improved functional ability and was well-tolerated. Musculoskeletal side effects are common among breast cancer survivors on adjuvant AI therapy, therefore, effective treatments are needed for symptom relief and to improve adherence to these life-saving medications.

Treatment of Intravenous Leiomyomatosis with Cardiac Extension following Incomplete Resection.

PubMed

Doyle, Mathew P; Li, Annette; Villanueva, Claudia I; Peeceeyen, Sheen C S; Cooper, Michael G; Hanel, Kevin C; Fermanis, Gary G; Robertson, Greg

2015-01-01

Aim. Intravenous leiomyomatosis (IVL) with cardiac extension (CE) is a rare variant of benign uterine leiomyoma. Incomplete resection has a recurrence rate of over 30%. Different hormonal treatments have been described following incomplete resection; however no standard therapy currently exists. We review the literature for medical treatments options following incomplete resection of IVL with CE. Methods. Electronic databases were searched for all studies reporting IVL with CE. These studies were then searched for reports of patients with inoperable or incomplete resection and any further medical treatments. Our database was searched for patients with medical therapy following incomplete resection of IVL with CE and their results were included. Results. All studies were either case reports or case series. Five literature reviews confirm that surgery is the only treatment to achieve cure. The uses of progesterone, estrogen modulation, gonadotropin-releasing hormone antagonism, and aromatase inhibition have been described following incomplete resection. Currently no studies have reviewed the outcomes of these treatments. Conclusions. Complete surgical resection is the only means of cure for IVL with CE, while multiple hormonal therapies have been used with varying results following incomplete resection. Aromatase inhibitors are the only reported treatment to prevent tumor progression or recurrence in patients with incompletely resected IVL with CE.

Treatment of Intravenous Leiomyomatosis with Cardiac Extension following Incomplete Resection

PubMed Central

Doyle, Mathew P.; Li, Annette; Villanueva, Claudia I.; Peeceeyen, Sheen C. S.; Cooper, Michael G.; Hanel, Kevin C.; Fermanis, Gary G.; Robertson, Greg

2015-01-01

Aim. Intravenous leiomyomatosis (IVL) with cardiac extension (CE) is a rare variant of benign uterine leiomyoma. Incomplete resection has a recurrence rate of over 30%. Different hormonal treatments have been described following incomplete resection; however no standard therapy currently exists. We review the literature for medical treatments options following incomplete resection of IVL with CE. Methods. Electronic databases were searched for all studies reporting IVL with CE. These studies were then searched for reports of patients with inoperable or incomplete resection and any further medical treatments. Our database was searched for patients with medical therapy following incomplete resection of IVL with CE and their results were included. Results. All studies were either case reports or case series. Five literature reviews confirm that surgery is the only treatment to achieve cure. The uses of progesterone, estrogen modulation, gonadotropin-releasing hormone antagonism, and aromatase inhibition have been described following incomplete resection. Currently no studies have reviewed the outcomes of these treatments. Conclusions. Complete surgical resection is the only means of cure for IVL with CE, while multiple hormonal therapies have been used with varying results following incomplete resection. Aromatase inhibitors are the only reported treatment to prevent tumor progression or recurrence in patients with incompletely resected IVL with CE. PMID:26783463

Aromatase activity modulation by lindane and bisphenol-A in human placental JEG-3 and transfected kidney E293 cells.

PubMed

Nativelle-Serpentini, C; Richard, S; Séralini, G-E; Sourdaine, P

2003-08-01

Aromatase is the cytochrome P-450 involved in converting androgens to estrogens. The cytochrome P-450 family plays a central role in the oxidative metabolism of compounds including environmental pollutants. Since lindane and bisphenol-A (BPA) are two well-characterized endocrine disruptors that have been detected in animals and humans, it was important to learn whether they could affect aromatase activity and consequently estrogen biosynthesis. The present study investigates the effects of BPA and lindane on cytotoxicity, aromatase activity and mRNA levels in human placental JEG-3 cells and transfected human embryonal kidney 293 cells. Both cell lines were exposed to increasing concentrations of lindane (25, 50 and 75 microM) and bisphenol-A (25, 50 and 100 microM) over different time periods (10 min-18 h). As a result, none of these concentrations showed cytotoxicity. After short pre-incubation times (10 min-6 h), aromatase activity was enhanced by both compounds. Longer time incubation (18 h), however, produced dose-related inhibition. Lindane and BPA had no significant effects on CYP19 mRNA levels. Therefore, lindane and BPA modulate aromatase activity suggesting an interaction with the cytochrome P-450 aromatase. This study highlights the endocrine-modulating properties of lindane and bisphenol-A.

REPRODUCTION AND AROMATASE ACTIVITY IN THE MARINE FISH CUNNER (TAUTOGOLABROUS ADSPERSUS) EXPOSED TO ATRAZINE AND OCTYLPHENOL IN THE LABORATORY

EPA Science Inventory

This study was conducted to test the hypothesis that reproduction in fish is altered by exposure to endocrine-disrupting chemicals (EDCs) that modify aromatase activity. Aromatase, a product of the CYP19 gene, is the enzyme that catalyzes the conversion of the androgens androst...

Sex-dependent effects of letrozole on anxiety in middle-aged rats.

PubMed

Borbélyová, Veronika; Domonkos, Emese; Csongová, Melinda; Kačmárová, Mária; Ostatníková, Daniela; Celec, Peter; Hodosy, Július

2017-12-01

Aromatase catalyzes the conversion of testosterone to estradiol and is involved in the physiological effects of sex hormones on brain function. Animal experiments have shown that the aromatase inhibitor, letrozole, can induce anxiety in young ovariectomized females that are used as a model of aging. Whether or not these effects would be similar in intact middle-aged animals is unknown. The aim of our study was to analyze the effects of letrozole on anxiety in middle-aged rats of both sexes. Fifteen month old male and female rats were treated daily with either letrozole or vehicle for 2 weeks. The elevated plus maze was used to test anxiety-like behaviour. Sex differences were found not only in plasma concentrations of testosterone but also in the effects of letrozole treatment on plasma testosterone (P<.05). The interaction between sex and treatment was also proven in locomotor activity (P<.05) and time spent in the open arms of the elevated plus maze (P<.05). Letrozole-treated male rats spent 95% less time in the open arms of the elevated plus maze than the control rats did (P<.05) suggesting an anxiogenic effect of aromatase inhibition. This difference was not found between letrozole-treated and vehicle-treated females. In contrast to previous experiments on young animals, letrozole seems to induce anxiety in male but not in female middle-aged rats. This sex-specific effect might be related to sex differences of oestrogen and androgen signalling in aging brains. These results should be taken into account in clinical applications of letrozole, especially in men. © 2017 John Wiley & Sons Australia, Ltd.

Cost effectiveness of letrozole versus anastrozole in postmenopausal women with HR+ early-stage breast cancer.

PubMed

Lipsitz, Michael; Delea, Thomas E; Guo, Amy

2010-10-01

The Breast International Group (BIG) 1-98 and Arimidex, Tamoxifen Alone or in Combination (ATAC) trials demonstrated that, in postmenopausal women with hormone receptor positive (HR+) early-stage breast cancer, 5 years of initial adjuvant endocrine therapy with letrozole or anastrozole is superior to tamoxifen. With expected generic availability of anastrozole in July 2010 and letrozole in June 2011, there may be financial pressures prior to letrozole's generic availability to start treatment-naïve patients on anastrozole vs. letrozole or to switch patients already receiving letrozole to anastrozole. A Markov model was used to estimate cost per quality-adjusted life-year (QALY) gained with letrozole vs. anastrozole from the US healthcare system perspective. Cost effectiveness was examined separately in treatment-naïve patients and in patients already receiving letrozole. For the latter, cost effectiveness of continued letrozole vs. therapeutic substitution (TS) to generic anastrozole was evaluated separately in cohorts defined on years of endocrine therapy remaining. TS to generic anastrozole was assumed to result in an additional 5% of patients discontinuing endocrine therapy. Probabilities of distant recurrence and death were taken from reports of BIG 1-98, ATAC, the Early Breast Cancer Trialists' Collaborative Group meta-analysis of tamoxifen, and other published sources. Carry-over effects of aromatase inhibitors were assumed to be proportional to treatment duration. Costs of aromatase inhibitors were assumed to decline by 75% with generic availability. In treatment-naïve patients, total expected lifetime costs are $3916 greater with letrozole vs. anastrozole. However, initiation of treatment with letrozole results in a gain of 0.15 QALYs. Cost per QALY gained with letrozole vs. anastrozole is $25,846. In patients already receiving letrozole, the increase in total expected lifetime costs with continued letrozole vs. TS to anastrozole is between $4200 and $4500 in all cohorts. QALYs gained with letrozole range from 0.21 in those with 4 years of endocrine therapy remaining to 0.13 in those with 1 year of therapy remaining. Cost per QALY gained ranges from $20,276 to $34,356. For postmenopausal women with HR+ early-stage breast cancer, letrozole is more likely to be cost effective vs. anastrozole in treatment-naïve patients and in patients already receiving letrozole. Limitations of the study include a lack of direct evidence comparing letrozole and anastrozole and lack of data on rates of discontinuation due to therapeutic substitution with aromatase inhibitors.

[Pharmacogenic osteoporosis beyond cortisone. Proton pump inhibitors, glitazones and diuretics].

PubMed

Kann, P H; Hadji, P; Bergmann, R S

2014-05-01

[corrected] There are many drugs which can cause osteoporosis or at least favor its initiation. The effect of hormones and drugs with antihormonal activity, such as glucocorticoids and aromatase inhibitors, on initiation of osteoporosis is well known. In addition, proton pump inhibitors, glitazones and diuretics also influence the formation of osteoporosis. The results of currently available studies on the correlation between proton pump inhibitors, glitazones and diuretics on formation of osteoporosis were evaluated and summarized. Proton pump inhibitors and glitazones increase the risk for osteoporotic fractures. Loop diuretics may slightly increase fracture risk, whereas thiazides were shown to be osteoprotective by reducing fracture probability on a relevant scale. Proton pump inhibitors should not be prescribed without serious consideration and then only as long as necessary. Alternatively, the administration of the less effective H2 antagonists should be considered when possible due to the reduction of acid secretion. Because the long-term intake of thiazides is associated with a clinically relevant reduction in the risk of fractures and they are economic and well-tolerated, prescription can be thoroughly recommended within the framework of differential diagnostic considerations in an appropriate clinical context. The briefly increased risk of falling immediately after starting diuretic therapy is the only point which needs to be considered.

GDNF-RET signaling in ER-positive breast cancers is a key determinant of response and resistance to aromatase inhibitors

PubMed Central

Morandi, Andrea; Martin, Lesley-Ann; Gao, Qiong; Pancholi, Sunil; Mackay, Alan; Robertson, David; Zvelebil, Marketa; Dowsett, Mitch; Plaza-Menacho, Ivan; Isacke, Clare M.

2013-01-01

Most breast cancers at diagnosis are estrogen receptor (ER)-positive and depend on estrogen for growth and survival. Blocking estrogen biosynthesis by aromatase inhibitors (AI) has therefore become a first-line endocrine therapy for post-menopausal women with ER-positive breast cancers. Despite providing substantial improvements in patient outcome, AI resistance remains a major clinical challenge. The receptor tyrosine kinase RET and its co-receptor GFRα1 are upregulated in a subset of ER-positive breast cancers, and the RET ligand, glial-derived neurotrophic factor (GDNF) is upregulated by inflammatory cytokines. Here we report the findings of a multidisciplinary strategy to address the impact of GDNF-RET signaling in the response to AI treatment. In breast cancer cells in 2D and 3D culture, GDNF-mediated RET signaling is enhanced in a model of AI resistance. Further, GDNF-RET signaling promoted the survival of AI-resistant cells and elicited resistance in AI-sensitive cells. Both these effects were selectively reverted by the RET kinase inhibitor NVP-BBT594. Gene expression profiling in ER-positive cancers defined a proliferation-independent GDNF-response signature that prognosed poor patient outcome and, more importantly, predicted poor response to AI treatment with the development of resistance. We validated these findings by demonstrating increased RET protein expression levels in an independent cohort of AI-resistant patient specimens. Together, our results establish GDNF-RET signaling as a rational therapeutic target to combat or delay the onset of AI resistance in breast cancer. PMID:23650283

Vitamin D threshold to prevent aromatase inhibitor-related bone loss: the B-ABLE prospective cohort study.

PubMed

Prieto-Alhambra, Daniel; Servitja, Sonia; Javaid, M Kassim; Garrigós, Laia; Arden, Nigel K; Cooper, Cyrus; Albanell, Joan; Tusquets, Ignasi; Diez-Perez, Adolfo; Nogues, Xavier

2012-06-01

Aromatase inhibitor (AI)-related bone loss is associated with increased fracture rates. Vitamin D might play a role in minimising this effect. We hypothesised that 25-hydroxy-vitamin D concentrations [25(OH)D] after 3 months supplementation might relate to bone loss after 1 year on AI therapy. We conducted a prospective cohort study from January 2006 to December 2011 of a consecutive sample of women initiating AI for early breast cancer who were ineligible for bisphosphonate therapy and stayed on treatment for 1 year (N = 232). Serum 25(OH)D was measured at baseline and 3 months, and lumbar spine (LS) bone mineral density at baseline and 1 year. Subjects were supplemented with daily calcium (1 g) and vitamin D(3) (800 IU) and additional oral 16,000 IU every 2 weeks if baseline 25(OH)D was <30 ng/ml. Linear regression models were fitted to adjust for potential confounders. After 1 year on AI therapy, 232 participants experienced a significant 1.68 % [95 % CI 1.15-2.20 %] bone loss at LS (0.017 g/cm(2) [0.012-0.024], P < 0.0001). Higher 25(OH)D at 3 months protected against LS bone loss (-0.5 % per 10 ng/ml [95 % CI -0.7 to -0.3 %], adjusted P = 0.0001), and those who reached levels ≥40 ng/ml had reduced bone loss by 1.70 % [95 % CI 0.4-3.0 %; adjusted P = 0.005] compared to those with low 25(OH)D levels (<30 ng/ml). We conclude that improved vitamin D status using supplementation is associated with attenuation of AI-associated bone loss. For this population, the current Institute of Medicine target recommendation of 20 ng/ml might be too low to ensure good bone health.

Personalized prevention in high risk individuals: Managing hormones and beyond.

PubMed

Evans, D Gareth; Howell, Sacha J; Howell, Anthony

2018-06-01

Increasing numbers of women are being identified at 'high-risk' of breast cancer, defined by The National Institute of Health and Care Excellence (NICE) as a 10-year risk of ≥8%. Classically women have been so identified through family history based risk algorithms or genetic testing of high-risk genes. Recent research has shown that assessment of mammographic density and single nucleotide polymorphisms (SNPs), when combined with established risk factors, trebles the number of women reaching the high risk threshold. The options for risk reduction in such women include endocrine chemoprevention with the selective estrogen receptor modulators tamoxifen and raloxifene or the aromatase inhibitors anastrozole or exemestane. NICE recommends offering anastrozole to postmenopausal women at high-risk of breast cancer as cost effectiveness analysis showed this to be cost saving to the National Health Service. Overall uptake to chemoprevention has been disappointingly low but this may improve with the improved efficacy of aromatase inhibitors, particularly the lack of toxicity to the endometrium and thrombogenic risks. Novel approaches to chemoprevention under investigation include lower dose and topical tamoxifen, denosumab, anti-progestins and metformin. Although oophorectomy is usually only recommended to women at increased risk of ovarian cancer it has been shown in numerous studies to reduce breast cancer risks in the general population and in those with mutations in BRCA1/2. However, recent evidence from studies that have confined analysis to true prospective follow up have cast doubt on the efficacy of oophorectomy to reduce breast cancer risk in BRCA1 mutation carriers, at least in the short-term. Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.

Perinatal administration of aromatase inhibitors in rodents as animal models of human male homosexuality: similarities and differences.

PubMed

Olvera-Hernández, Sandra; Fernández-Guasti, Alonso

2015-01-01

In this chapter we briefly review the evidence supporting the existence of biological influences on sexual orientation. We focus on basic research studies that have affected the estrogen synthesis during the critical periods of brain sexual differentiation in male rat offspring with the use of aromatase inhibitors, such as 1,4,6-androstatriene-3,17 (ATD) and letrozole. The results after prenatal and/or postnatal treatment with ATD reveal that these animals, when adults, show female sexual responses, such as lordosis or proceptive behaviors, but retain their ability to display male sexual activity with a receptive female. Interestingly, the preference and sexual behavior of these rats vary depending upon the circadian rhythm.Recently, we have established that the treatment with low doses of letrozole during the second half of pregnancy produces male rat offspring, that when adults spend more time in the company of a sexually active male than with a receptive female in a preference test. In addition, they display female sexual behavior when forced to interact with a sexually experienced male and some typical male sexual behavior when faced with a sexually receptive female. Interestingly, these males displayed both sexual behavior patterns spontaneously, i.e., in absence of exogenous steroid hormone treatment. Most of these features correspond with those found in human male homosexuals; however, the "bisexual" behavior shown by the letrozole-treated rats may be related to a particular human population. All these data, taken together, permit to propose letrozole prenatal treatment as a suitable animal model to study human male homosexuality and reinforce the hypothesis that human sexual orientation is underlied by changes in the endocrine milieu during early development.

Survival benefit of tamoxifen and aromatase inhibitor in male and female breast cancer.

PubMed

Eggemann, Holm; Altmann, Udo; Costa, Serban-Dan; Ignatov, Atanas

2018-02-01

Our goal was to compare the survival advantage of tamoxifen (TAM) and aromatase inhibitor (AI) in female (FBC) and male breast cancer (MBC). We performed a retrospective study of 2785 FBC and 257 MBC patients treated with hormonal therapy. The median follow-up was 106 months (range 3-151 months) and 42 months (range 2-115 months) for FBC and MBC, respectively. The patients were divided into two groups according to the hormonal therapy used: TAM-treated and AI-treated. MBC was characterized by older age, advanced tumor stage, and higher rate of lymph node metastases, in comparison with FBC. Matching analysis was performed using six prognostic criteria: patient age, tumor stage, tumor grade, lymph node status, human epidermal growth factor receptor (HER2) status, and administration of chemotherapy. The female and male patients were matched 2:1. In this analysis, 316 women and 158 men treated with TAM, and 60 women and 30 men treated with AI, were included. The overall survival (OS) was estimated by the Kaplan-Meier method and was compared between FBC and MBC. TAM-treated FBC and MBC patients had similar 5-year OS, 85.1 and 89.2%, respectively (p = 0.972). Notably, FBC patients treated with AI had significantly greater 5-year OS (85.0%) in comparison with AI-treated MBC patients (5-year OS of 73.3%; p = 0.028). The OS of TAM-treated patients with MBC was similar to the OS of TAM-treated FBC patients, whereas AI treatment is associated with poorer survival of MBC patients.

Down-regulation of heat-shock protein 70 (HSP-70) correlated with responsiveness to neoadjuvant aromatase inhibitor therapy in breast cancer patients.

PubMed

Yiu, Christopher C P; Chanplakorn, Niramol; Chan, Monica S M; Loo, Wings T Y; Chow, Louis W C; Toi, Masakazu; Sasano, Hironobu

2010-09-01

Aromatase inhibitor (AI) has been established as an effective endocrine therapy in estrogen receptor (ER)-positive postmenopausal breast cancer patients. Our recent proteomic analysis demonstrated that ten proteins were significantly altered in their expression levels before and after the therapy in the patients receiving neoadjuvant AI. Among these newly identified proteins, heat-shock protein 70 (HSP-70) was the most significantly correlated with both clinical and pathological responses. Therefore, in this study, we further evaluated the significance of this HSP-70 alteration using immunohistochemistry. A total of 32 patients treated with neoadjuvant exemestane or letrozole in whom pre- and post-treatment tumor tissues were available were included. Immunohistochemical evaluation of ER, progesterone receptor (PgR), Her-2, Ki-67 and HSP-70 was performed. Results obtained were compared to both clinical and biological responses of the patients. The majority of the patients responded to treatment (16 patients with partial response, 14 with stable disease and 2 with progressive disease). The means of ER, Ki-67 and HSP-70 were significantly different between treatment responders and non-responders. Decrement of HSP-70 and Ki-67 after AI treatment and pretreatment Ki-67 labeling index of >10% tumor cells were significantly associated with clinical responsiveness to AI treatment (p<0.0001). There was a significant positive correlation between changes of HSP-70 and Ki-67 before and after the therapy. Decrement of HSP-70 in breast carcinoma cells plays important roles in therapeutic mechanisms of AIs through suppressing tumor cell proliferation in breast cancer patients.

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

PubMed

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. © 2015 Marine Biological Laboratory.

Endometrial seedlings. A survival instinct? Immunomodulation and its role in the pathophysiology of endometriosis.

PubMed

Portelli, M; Pollacco, J; Sacco, K; Schembri-Wismayer, P; Calleja-Agius, J

2011-12-01

Endometriosis occurs when ectopic cells from the endometrium implant within the peritoneum. It is considered as a disease of multifactorial aetiology and affects 7-10% of women of reproductive age worldwide. In endometriosis, the immune system is thought to be dysfunctional and various studies have shown cytokine imbalance. Commonly upregulated cytokines include Tumour necrosis factor-alpha, interferon gamma and interleukin-10. Through analysis of the molecular makeup of the peritoneal fluid, a change is shown to occur, conferring resistance from macrophages and lymphocytes to endometrial cells. This is possibly due to a reduced Inter-cellular adhesion molecule-1 synthesis. Survival of ectopic endometrial cells also arises through the expression of human leukocyte antigens. Apart from the survival of ectopic/eutopic cells in endometriosis, there is marked cellular proliferation, which has also been attributed to a change in the expression of proteins such as Bcl-2-Associated X protein, B-cell lymphoma-2 protein, transforming growth factor-beta and the enzyme aromatase. Danazol and aromatase inhibitors modulate the immune system, thus allowing partial restoration of cytokine levels. Pharmacogenomics may be the way forward in developing novel treatment modalities for endometriosis.

Tall stature without growth hormone: four male patients with aromatase deficiency.

PubMed

Rochira, Vincenzo; Zirilli, Lucia; Maffei, Laura; Premrou, Valeria; Aranda, Claudio; Baldi, Matteo; Ghigo, Ezio; Aimaretti, Gianluca; Carani, Cesare; Lanfranco, Fabio

2010-04-01

From preliminary observations, GH-IGF-I seems to be compromised in men with aromatase deficiency. The GH deficiency (GHD) coexists paradoxically with tall stature, raising the question whether or not a true GHD is part of this rare syndrome. To evaluate the GH secretion in aromatase-deficient men, their GH response to the GHRH plus arginine (GHRH-ARG) test was compared with that of normal subjects. The effect of estrogen replacement treatment on the GH-IGF-I axis in aromatase-deficient men was evaluated before and during therapy. A case-control study was conducted. Four adult men with aromatase deficiency were compared with 12 normal subjects. We measured the GH response to GHRH-ARG in aromatase-deficient men (at baseline and during estrogen treatment) and in normal subjects. Basal serum IGF-I was measured in both patients and controls. The response of GH to GHRH-ARG was severely impaired in men with aromatase deficiency and resulted in significantly lower (P < 0.001) levels than in normal subjects. Although normal, serum IGF-I levels were also significantly lower (P < 0.001) than in normal subjects. Both GH peak and IGF-I concentrations were not modified by estrogen therapy in men with aromatase deficiency. In aromatase-deficient men, GH response to potent provocative stimuli is impaired and is not restored by exogenous estrogens. Furthermore, a tall stature may be reached, notwithstanding the coexistence of GHD, if a prolonged time for growth is available due to a delay in bone maturation, and other growth factors different from GH (mainly insulin) promote growth.

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

USGS Publications Warehouse

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.

Skeletal effects of estrogen deficiency as induced by an aromatase inhibitor in an aged male rat model.

PubMed

Vanderschueren, D; Boonen, S; Ederveen, A G; de Coster, R; Van Herck, E; Moermans, K; Vandenput, L; Verstuyf, A; Bouillon, R

2000-11-01

Aromatization of androgens into estrogens may be important for maintenance of the male skeleton. To address this hypothesis, we evaluated the skeletal effects of selective estrogen deficiency as induced by the aromatase inhibitor vorozole (Vor), with or without 17beta-estradiol (E(2)) administration (1.35 microg/day), in aged (12-month-old) male rats. A baseline group was killed at the start of the experiment (Base). The control group (Control), the group treated with vorozole alone (Vor), the group treated with E(2) alone (E(2)), or the group with a combination of both (Vor + E(2)) were killed 15 weeks later. Vorozole significantly increased serum testosterone (T) and reduced serum E(2) compared with Control. Body weight gain and serum insulin-like growth factor-I (IGF-I) were also lower in Vor, whereas significant weight loss and decrease of serum IGF-I occurred as a result of E(2) administration. Bone formation as assessed by serum osteocalcin was unaffected but osteoid surface in the proximal metaphysis of the tibia was increased in Vor-treated rats. Bone resorption as evaluated by urinary deoxypyridinoline excretion was increased in Vor. Biochemical parameters of bone turnover were reduced significantly in all E(2) treated rats. Premature closure of the growth plates and decreased osteoid and mineralizing surfaces were also observed in E(2) and Vor + E(2). Apparent bone density of lumbar vertebrae and femur, as measured by dual-energy X-ray absorptiometry (DXA), was significantly reduced in Vor. Vorozole decreased femoral bone density mainly in the distal femur (trabecular and cortical region). This decrease of bone density was not present in E(2) and Vor + E(2). Similar findings were observed when bone density was assessed by peripheral quantitative computed tomography (pQCT); that is, trabecular density of the distal femur, the proximal tibia, and the distal lumbar vertebra were all lower in Vor. This decrease in density was not observed in all E(2)-treated animals. In conclusion, administration of the aromatase inhibitor, vorozole, to aged male rats induces net trabecular bone loss in both the appendicular and axial skeleton, despite a concomitant increase in serum testosterone. E(2) administration is able to prevent this trabecular bone loss in vorozole-treated animals.

Significance of Ovarian Function Suppression in Endocrine Therapy for Breast Cancer in Pre-Menopausal Women

PubMed Central

Scharl, A.; Salterberg, A.

2016-01-01

Ovarian function suppression (OFS) for treating breast cancer in pre-menopausal women was introduced for the first time in the late 19th century as bilateral oophorectomy. It was not until the 1960s that the oestrogen receptor was identified and a test for detecting endocrine sensitivity of the breast cancer was developed. A weakness of early trials on OFS for breast cancer treatment is therefore their failure to take receptor sensitivity into account when selecting participants. A meta-analysis performed in the early 1990s first proved that adjuvant OFS significantly improved the cure rate of oestrogen receptor-positive breast cancer in pre-menopausal women regardless of whether it was carried out through oophorectomy, radiation-induced ablation or drug therapy. In the 1970s, tamoxifen was synthesized. It became one of the most important cancer drugs and today constitutes the gold standard for endocrine adjuvant therapy. Taking tamoxifen for a five-year period lowers mortality by 30 % over 15 years. Ten years of tamoxifen therapy reduces mortality even further, with increased side effects, however. Research over the past ten years has proven that for post-menopausal women, aromatase inhibitors have benefits over tamoxifen. Current trial results have rekindled the debate about the combination of OFS with tamoxifen or with aromatase inhibitors for adjuvant breast cancer treatment of pre-menopausal women. These trials have reported an improvement in disease-free survival in patients with a high risk of recurrence when they are treated with a combination of OFS plus tamoxifen or aromatase inhibitors, especially in women younger than 35. However, combination therapy causes significantly more side effects, which could negatively impact compliance. Endocrine treatments administered over a period of many years show waning compliance, which tends to be only around 50 % after five years. Inadequate compliance compromises efficacy and increases the risk of mortality. For this reason, when indicating and supporting endocrine adjuvant therapy, physicians must ensure that compliance will be good. To prevent recurrence in the long run, it is much more effective to prescribe a somewhat less effective therapy that will actually be carried out than to prescribe one that is theoretically more effective, but is not adhered to consistently. PMID:27239060

Randomized Controlled Trial of a Home‐Based Walking Program to Reduce Moderate to Severe Aromatase Inhibitor‐Associated Arthralgia in Breast Cancer Survivors

PubMed Central

Callahan, Leigh F.; Cleveland, Rebecca J.; Arbeeva, Liubov L.; Hackney, Betsy S.; Muss, Hyman B.

2017-01-01

Abstract Background. In postmenopausal women diagnosed with breast cancer (BC), most BC tumors are hormone receptor positive and guidelines recommend adjuvant endocrine therapy that includes an aromatase inhibitor (AI). This study investigates the impact of a 6‐week, home‐based, self‐directed walking program on the commonly reported side effect of AI‐associated arthralgia (AIAA). Materials and Methods. In this phase II trial, consented BC patients were randomized to walking Intervention (n = 31) or Wait List Control (WLC; n = 31). Eligibility criteria included: stage 0–III BC, on AI for at least 4 weeks, ≥3 on a 5‐point scale inquiring about joint symptom intensity “at its worst,” and exercising ≤150 minutes per week. Outcomes were self‐reported joint symptoms and psychosocial measures. Analyses comparing Intervention and WLC groups were conducted on an intention‐to‐treat basis to assess intervention impact at 6 weeks (postintervention) and at 6‐months follow‐up. Adjusted means were calculated to assess differences in two groups. Results. In our final sample (n = 62), mean age was 64 years, 74% were white, and 63% had a body mass index of 30 or higher. At postintervention, Intervention group participants reported significantly increased walking minutes per week, reduced stiffness, less difficulty with activities of daily living (ADL), and less perceived helplessness in managing joint symptoms. At 6‐months follow‐up (postwalking period in both Intervention and WLC), walking minutes per week had decreased significantly; however, improvements in stiffness and difficulty with ADLs were maintained. Conclusion. This study adds to the growing evidence base suggesting exercise as a safe alternative or adjunct to medications for the management of AIAA. Implications for Practice. Breast cancer survivors whose adjuvant endocrine treatment includes an aromatase inhibitor (AI) often experience the side effect of AI‐associated arthralgia (AIAA). This study investigates the impact of a 6‐week, home‐based, self‐directed walking program in the management of AIAA. Compared with Wait List Control, women in the Intervention group reported significantly increased walking minutes per week, reduced stiffness, less difficulty with activities of daily living, and less perceived helplessness in managing joint symptoms. This study adds to the growing evidence base suggesting exercise as a safe alternative or adjunct to medications for the management of AIAA. PMID:28698390

Hypogonadism in a male-to-female transsexual with super obesity.

PubMed

Ayanian, S; Irwig, M S

2013-08-01

The global obesity epidemic is having a profound impact on the health of populations. From a reproductive standpoint, obesity has been associated with infertility and hypogonadism. We present the case of a 29-year-old male-to-female transsexual with super obesity (body mass index >50) who was found to have profound hypogonadism with total and free testosterone levels in the normal female reference range. There is virtually no literature on the hormonal sequelae of obesity in transsexual people. The patient was prescribed an aromatase inhibitor, letrozole 2.5 mg twice daily for 2 weeks, to determine the role of oestrogen in the hypogonadism. The aromatase inhibitor reduced the serum oestradiol concentration from 125 to 6.9 pm. There were dramatic corresponding rises in total testosterone (2.8 to 10.7 nm), luteinising hormone (4.1 to 20.5 mIU ml(-1) ) and follicle stimulating hormone (1.8 to 15.3 mIU ml(-1) ). This diagnostic test demonstrated the important role of oestrogen in mediating the hypogonadism. After the testing, the patient was started on oestrogen therapy after a careful discussion of the benefits versus risks of oestrogen therapy. We anticipate that similar cases of hypogonadism in male-to-female transsexuals will likely become more common in an era of increased obesity rates. © 2012 Blackwell Verlag GmbH.

Supportive care of women with breast cancer: key concerns and practical solutions.

PubMed

Zdenkowski, Nicholas; Tesson, Stephanie; Lombard, Janine; Lovell, Melanie; Hayes, Sandra; Francis, Prudence A; Dhillon, Haryana M; Boyle, Frances M

2016-11-21

Patients diagnosed with breast cancer may have supportive care needs for many years after diagnosis. High quality multidisciplinary care can help address these needs and reduce the physical and psychological effects of breast cancer and its treatment. Ovarian suppression and extended endocrine therapy benefits are associated with vasomotor, musculoskeletal, sexual and bone density-related side effects. Aromatase inhibitor musculoskeletal syndrome is a common reason for treatment discontinuation. Treatment strategies include education, exercise, simple analgesia and a change to tamoxifen or another aromatase inhibitor. Chemotherapy-induced alopecia may be a constant reminder of breast cancer to the patient, family, friends, acquaintances and even strangers. Alopecia can be prevented in some patients using scalp-cooling technology applied at the time of chemotherapy infusion. The adverse impact of breast cancer diagnosis and treatment on sexual wellbeing is under-reported. Identification of physical and psychological impacts is needed for implementation of treatment strategies. Fear of cancer recurrence reduces quality of life and increases distress, with subsequent impact on role functioning. Identification and multidisciplinary management are key, with referral to psychosocial services recommended where indicated. The benefits of exercise include reduced fatigue, better mental health and reduced musculoskeletal symptoms, and may also include reduced incidence of breast cancer recurrence. Identification and management of unmet supportive care needs are key aspects of breast cancer care, to maximise quality of life and minimise breast cancer recurrence.

Evaluation of the methoxytriazine herbicide prometon using a short-term fathead minnow reproduction test and a suite of in vitro bioassays.

PubMed

Villeneuve, Daniel L; Murphy, Margaret B; Kahl, Michael D; Jensen, Kathleen M; Butterworth, Brian C; Makynen, Elizabeth A; Durhan, Elizabeth J; Linnum, Ann; Leino, Richard L; Curtis, Lawrence R; Giesy, John P; Ankley, Gerald T

2006-08-01

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 microM), 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 microg prometon/L significantly reduced the weight of the male fat pad (an androgen-responsive tissue) relative to body weight. Exposure to 20 microg 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.

A randomized phase II trial of ridaforolimus, dalotuzumab, and exemestane compared with ridaforolimus and exemestane in patients with advanced breast cancer.

PubMed

Rugo, Hope S; Trédan, Olivier; Ro, Jungsil; Morales, Serafin M; Campone, Mario; Musolino, Antonino; Afonso, Noémia; Ferreira, Marta; Park, Kyong Hwa; Cortes, Javier; Tan, Antoinette R; Blum, Joanne L; Eaton, Lamar; Gause, Christine K; Wang, Zhen; Im, Ellie; Mauro, David J; Jones, Mary Beth; Denker, Andrew; Baselga, José

2017-10-01

To evaluate whether adding humanized monoclonal insulin growth factor-1 receptor (IGF-1R) antibody (dalotuzumab) to mammalian target of rapamycin (mTOR) inhibitor (ridaforolimus) plus aromatase inhibitor (exemestane) improves outcomes in patients with estrogen receptor (ER)-positive advanced/metastatic breast cancer. This randomized, open-label, phase II trial enrolled 80 postmenopausal women with high-proliferation (Ki67 index staining ≥15%), ER-positive breast cancer that progressed after a non-steroidal aromatase inhibitor (NCT01605396). Randomly assigned patients were given oral ridaforolimus 10 mg QD 5 ×/week, intravenous dalotuzumab 10 mg/kg/week, and oral exemestane 25 mg/day (R/D/E, n = 40), or ridaforolimus 30 mg QD 5 ×/week and exemestane 25 mg/day (R/E; n = 40). Primary end point was progression-free survival (PFS). Median PFS was 23.3 weeks for R/D/E versus 31.9 weeks for R/E (hazard ratio 1.18; 80% CI 0.81-1.72; P = 0.565). Grade 3-5 adverse events were reported in 67.5% of patients in the R/E arm and 59.0% in the R/D/E arm. Stomatitis (95.0 vs. 76.9%; P = 0.021) and pneumonitis (22.5 vs. 5.1%; P = 0.027) occurred more frequently in the R/E than the R/D/E arm; hyperglycemia (27.5 vs. 28.2%) occurred at a similar rate. R/D/E did not improve PFS compared with R/E. Because the PFS reported for R/E was similar to that reported for everolimus plus exemestane in patients with advanced breast cancer, it is possible that lower-dose ridaforolimus in the R/D/E arm (from overlapping toxicities with IGF1R inhibitor) contributed to lack of improved PFS.

BRCA1/BARD1 Complex Interacts with Steroidogenic Factor 1----a Potential Mechanism for Regulation of Aromatase Expression by BRCA1

PubMed Central

Lu, Yunzhe; Kang, Tao; Hu, Yanfen

2010-01-01

Germline mutations in BRCA1 predispose women to early onset of breast and ovarian cancers. Findings from previous studies support the notion that the tissue- and gender-specific tumor suppression function of BRCA1 is associated with its role in negative regulation of aromatase expression, the rate-limiting step in estrogen biosynthesis. The molecular mechanism of BRCA1 in regulating aromatase promoter activity remains to be elucidated. In this study, we demonstrate that, in an ovarian granulosa cell line KGN, steroidogenic factor 1 (SF-1) is required for aromatase PII promoter basal activity as well as the elevated aromatase expression mediated by BRCA1 knockdown. Furthermore, BRCA1 in KGN cells exists mainly as a heterodimer with BARD1. We provide evidence that the BRCA1/BARD1 complex interacts with SF-1 both in vivo and in vitro. However, the intrinsic ubiquitin E3 ligase activity of BRCA1/BARD1 does not appear to contribute to ubiquitynation of SF-1. We propose that the interaction between SF-1 and BRCA1/BARD1 may recruit BRCA1/BARD1 complex to the aromatase PII promoter for BRCA1/BARD1-mediate transcriptional repression. PMID:21087664

Steroids, aromatase and sex differentiation of the newt Pleurodeles waltl.

PubMed

Kuntz, S; Chardard, D; Chesnel, A; Grillier-Vuissoz, I; Flament, S

2003-01-01

In the newt Pleurodeles waltl, genetic sex determination obeys female heterogamety (female ZW, male ZZ). In this species as in most of non-mammalian vertebrates, steroid hormones play a key role in sexual differentiation of gonads. In that context, male to female sex reversal can be obtained by treatment of ZZ larvae with estradiol. Male to female sex reversal has also been observed following treatment of ZZ larvae with testosterone, a phenomenon that was called the "paradoxical effect". Female to male sex reversal occurs when ZW larvae are reared at 32 degrees C during a thermosensitive period (TSP) that takes place from stage 42 to stage 54 of development. Since steroids play an important part in sex differentiation, we focussed our studies on the estrogen-producing enzyme aromatase during normal sex differentiation as well as in experimentally induced sex reversal situations. Our results based on treatment with non-aromatizable androgens, aromatase activity measurements and aromatase expression studies demonstrate that aromatase (i) is differentially active in ZZ and ZW larvae, (ii) is involved in the paradoxical effect and (iii) might be a target of temperature. Thus, the gene encoding aromatase might be one of the master genes in the process leading to the differentiation of the gonad in Pleurodeles waltl. Copyright 2003 S. Karger AG, Basel

Aromatase inhibitors decrease radiation-induced lung fibrosis: Results of an experimental study.

PubMed

Altinok, A Y; Yildirim, S; Altug, T; Sut, N; Ober, A; Ozsahin, E M; Azria, D; Bese, N S

2016-08-01

In experimental and clinical trials, tamoxifen (TAM) has been shown to increase radiation-induced lung fibrosis (RILF). Furthermore, aromatase inhibitors (AI) have been shown to be superior to TAM in the adjuvant setting and preclinical data suggest that letrozole (LET) sensitizes breast cancer cells to ionizing radiation in other studies. In this experimental study, we evaluated whether AI have any impact on the development of RILF in rats. 60 female wistar- albino rats were divided into 6 groups: Control (group A), RT alone (group B), RT + TAM (group C), RT + anastrozole (ANA group D), RT + LET (group E), and RT + exemestane (EXE, group F). RT consisted of 30 Gy in 10 fractions to both lungs with an anterior field at 2 cm depth. Equivalent doses for 60 kg adult dose per day of TAM, ANA, LET, and EXE were calculated according to the mean weight of rats and orally administrated with a feeding tube. Percentage of lung with fibrosis was quantified with image analysis of histological sections of the lung. The mean score values were calculated for each group. the significance of the differences among groups were calculated using one way ANOVA test and Tukey HSD post-hoc test. Mean values of fibrosis were 1.7, 5.9, 6.7, 2.5, 2 and 2.2 for groups A, B, C, D, E, and F, respectively (p = 0.000). TAM increased RT-induced lung fibrosis but without statistical significance. Groups treated with RT + AI showed significantly less lung fibrosis than groups treated with RT alone or RT + TAM (p = 0.000). RT + AI groups showed nearly similar RT-induced lung fibrosis than control group. In this study, we found that AI decreased RT-induced lung fibrosis to the control group level suggesting protective effect. Copyright © 2016 Elsevier Ltd. All rights reserved.

Investigating the Regulation and Potential Role of Nonhypoxic Hypoxia-Inducible Factor 1 (HIF-1) in Aromatase Inhibitor Resistant Breast Cancer

DTIC Science & Technology

2012-10-01

digestion , prior to analysis of HIF-1 protein by western blot apaparatus. Representative blots are shown. Figure 3. The effects of cell density...mouse xenograft tumors treated for 56 weeks with letrozole, and maintained in phenol red-free (PRF) modified IMEM (Invitrogen) supplemented with 5...conditions for 2–3 days prior to cytospinning. Pelleted cells were fixed with 4 % para- formaldehyde and incubated with OCT4 antibody (Santa Cruz

Drug-induced gynecomastia.

PubMed

Eckman, Ari; Dobs, Adrian

2008-11-01

Gynecomastia is caused by drugs in 10 - 25% of all cases. The pathophysiologic mechanism for some drugs includes exogenous estrogens exposure, medications that cause hypogonadism, anti-androgenic effects and hyperprolactinemia. This manuscript reviews common examples of drug-induced gynecomastia, discussing the mechanisms and possible treatments. Discontinuing the medication is always the best choice; however, if this is not possible, then testosterone replacement therapy may be needed for hypogonadism. When a man is euogonadal, a trial of the anti-estrogen, tamoxifen or an aromatase inhibitor may be an option.

Acupuncture does not ameliorate metabolic disturbances in the P450 aromatase inhibitor-induced rat model of polycystic ovary syndrome.

PubMed

Maliqueo, Manuel; Benrick, Anna; Marcondes, Rodrigo Rodrigues; Johansson, Julia; Sun, Miao; Stener-Victorin, Elisabet

2017-01-01

What is the central question of this study? The effectiveness of low-frequency electroacupuncture in the treatment of metabolic disorders associated with polycystic ovary syndrome (PCOS), an endocrine-metabolic disorder characterized by an imbalance in sex steroid production, is controversial. What is the main finding and its importance? In a rat model of PCOS induced by the inhibition of P450 aromatase, low-frequency electroacupuncture increased low-density lipoprotein-cholesterol but did not improve the insulin resistance or the adipose tissue dysfunction, suggesting that a balance of sex steroids is needed to restore the metabolic function in this rat model of PCOS. Low-frequency electroacupuncture restores sex steroid synthesis and sympathetic activity in women with polycystic ovary syndrome, which may ameliorate its metabolic disturbances, probably by modulating sympathetic nerve activity or sex steroid synthesis. We investigated whether low-frequency electroacupuncture regulates the metabolic function to the same extent as treatment with estradiol or β-adrenergic blocking in a rat model of polycystic ovary syndrome induced by a P450 aromatase inhibitor (letrozole). Letrozole (200 μg day -1 ) or placebo pellets were implanted in prepubertal Wistar rats. Six weeks thereafter, rats were treated for 5-6 weeks with the following: low-frequency electroacupuncture (5 days per week); a β-adrenergic blocker (propranolol hydrochloride, 0.1 mg kg -1 , 5 days per week); or 17β-estradiol (2.0 μg) every fourth day. Body weight development, body composition, locomotor activity, insulin sensitivity, tissue-specific glucose uptake, lipid profile, adipocyte size, serum concentrations of adiponectin and insulin, and gene expression in inguinal fat were measured. All treatments increased circulating levels of low-density lipoprotein-cholesterol. Estradiol treatment restored locomotor activity and increased insulin sensitivity but did not modify the glucose uptake in muscle and fat. An upregulation of genes related to insulin sensitivity and downregulation of genes related to adipogenesis were observed in subcutaneous adipose tissue from rats exposed to letrozole. Only estradiol treatment normalized the expression of these genes. In conclusion, low-frequency electroacupuncture increased low-density lipoprotein-cholesterol without affecting insulin sensitivity or adipose tissue function, which could suggest effects on hepatic lipid regulation, probably mediated by the action of estradiol or the β-adrenergic pathway. © 2016 The Authors. Experimental Physiology © 2016 The Physiological Society.

Kinetics, prognostic and predictive values of ESR1 circulating mutations in metastatic breast cancer patients progressing on aromatase inhibitor

PubMed Central

Clatot, Florian; Perdrix, Anne; Augusto, Laetitia; Beaussire, Ludivine; Delacour, Julien; Calbrix, Céline; Sefrioui, David; Viailly, Pierre-Julien; Bubenheim, Michael; Moldovan, Cristian; Alexandru, Cristina; Tennevet, Isabelle; Rigal, Olivier; Guillemet, Cécile; Leheurteur, Marianne; Gouérant, Sophie; Petrau, Camille; Théry, Jean-Christophe; Picquenot, Jean-Michel; Veyret, Corinne; Frébourg, Thierry; Jardin, Fabrice

2016-01-01

Purpose To assess the prognostic and predictive value of circulating ESR1 mutation and its kinetics before and after progression on aromatase inhibitor (AI) treatment. Patients and methods ESR1 circulating D538G and Y537S/N/C mutations were retrospectively analyzed by digital droplet PCR after first-line AI failure in patients treated consecutively from 2010 to 2012 for hormone receptor-positive metastatic breast cancer. Progression-free survival (PFS) and overall survival (OS) were analyzed according to circulating mutational status and subsequent lines of treatment. The kinetics of ESR1 mutation before (3 and 6 months) and after (3 months) AI progression were determined in the available archive plasmas. Results Circulating ESR1 mutations were found at AI progression in 44/144 patients included (30.6%). Median follow-up from AI initiation was 40 months (range 4-94). The median OS was decreased in patients with circulating ESR1 mutation than in patients without mutation (15.5 versus 23.8 months, P=0.0006). The median PFS was also significantly decreased in patients with ESR1 mutation than in patients without mutation (5.9 vs 7 months, P=0.002). After AI failure, there was no difference in outcome for patients receiving chemotherapy (n = 58) versus non-AI endocrine therapy (n=51) in patients with and without ESR1 mutation. ESR1 circulating mutations were detectable in 75% of all cases before AI progression, whereas the kinetics 3 months after progression did not correlate with outcome. Conclusion ESR1 circulating mutations are independent risk factors for poor outcome after AI failure, and are frequently detectable before clinical progression. Interventional studies based on ESR1 circulating status are warranted. PMID:27801670

Estrogen receptor (ESR1) mutation in bone metastases from breast cancer.

PubMed

Bartels, Stephan; Christgen, Matthias; Luft, Angelina; Persing, Sascha; Jödecke, Kai; Lehmann, Ulrich; Kreipe, Hans

2018-01-01

Activating mutations of estrogen receptor α gene (ESR1) in breast cancer can cause endocrine resistance of metastatic tumor cells. The skeleton belongs to the metastatic sides frequently affected by breast cancer. The prevalence of ESR1 mutation in bone metastasis and the corresponding phenotype are not known. In this study bone metastases from breast cancer (n=231) were analyzed for ESR1 mutation. In 27 patients (12%) (median age 73 years, range: 55-82 years) activating mutations of ESR1 were detected. The most frequent mutation was p.D538G (53%), no mutations in exon 4 (K303) or 7 (S463) were found. Lobular breast cancer was present in 52% of mutated cases (n=14) and in 49% of all samples (n=231), respectively. Mutated cancers constantly displayed strong estrogen receptor expression. Progesterone receptor was positive in 78% of the mutated cases (n=21). From 194 estrogen receptor-positive samples, 14% had ESR1 mutated. Except for one mutated case, no concurrent HER2 overexpression was noted. Metastatic breast cancer with activating mutations of ESR1 had a higher Ki67 labeling index than primary luminal cancers (median 30%, ranging from 5 to 60% with 85% of cases revealing ≥20% Ki67-positive cells). From those patients from whom information on endocrine therapy was available (n=7), two had received tamoxifen only, 4 tamoxifen followed by aromatase inhibitors and one patient had been treated with aromatase inhibitors only. We conclude that ESR1 mutation is associated with estrogen receptor expression and high proliferative activity and affects about 14% of estrogen receptor-positive bone metastases from breast cancer.

Kinetics, prognostic and predictive values of ESR1 circulating mutations in metastatic breast cancer patients progressing on aromatase inhibitor.

PubMed

Clatot, Florian; Perdrix, Anne; Augusto, Laetitia; Beaussire, Ludivine; Delacour, Julien; Calbrix, Céline; Sefrioui, David; Viailly, Pierre-Julien; Bubenheim, Michael; Moldovan, Cristian; Alexandru, Cristina; Tennevet, Isabelle; Rigal, Olivier; Guillemet, Cécile; Leheurteur, Marianne; Gouérant, Sophie; Petrau, Camille; Théry, Jean-Christophe; Picquenot, Jean-Michel; Veyret, Corinne; Frébourg, Thierry; Jardin, Fabrice; Sarafan-Vasseur, Nasrin; Di Fiore, Frédéric

2016-11-15

To assess the prognostic and predictive value of circulating ESR1 mutation and its kinetics before and after progression on aromatase inhibitor (AI) treatment. ESR1 circulating D538G and Y537S/N/C mutations were retrospectively analyzed by digital droplet PCR after first-line AI failure in patients treated consecutively from 2010 to 2012 for hormone receptor-positive metastatic breast cancer. Progression-free survival (PFS) and overall survival (OS) were analyzed according to circulating mutational status and subsequent lines of treatment. The kinetics of ESR1 mutation before (3 and 6 months) and after (3 months) AI progression were determined in the available archive plasmas. Circulating ESR1 mutations were found at AI progression in 44/144 patients included (30.6%). Median follow-up from AI initiation was 40 months (range 4-94). The median OS was decreased in patients with circulating ESR1 mutation than in patients without mutation (15.5 versus 23.8 months, P=0.0006). The median PFS was also significantly decreased in patients with ESR1 mutation than in patients without mutation (5.9 vs 7 months, P=0.002). After AI failure, there was no difference in outcome for patients receiving chemotherapy (n = 58) versus non-AI endocrine therapy (n=51) in patients with and without ESR1 mutation. ESR1 circulating mutations were detectable in 75% of all cases before AI progression, whereas the kinetics 3 months after progression did not correlate with outcome. ESR1 circulating mutations are independent risk factors for poor outcome after AI failure, and are frequently detectable before clinical progression. Interventional studies based on ESR1 circulating status are warranted.

A nude mouse model of obesity to study the mechanisms of resistance to aromatase inhibitors.

PubMed

Schech, Amanda; Yu, Stephen; Goloubeva, Olga; McLenithan, John; Sabnis, Gauri

2015-08-01

Obesity is a risk factor for breast cancer progression. Breast cancer patients who are overweight or obese or have excess abdominal fat have an increased risk of local or distant recurrence and cancer-related death. Hormone depletion therapies can also cause weight gain, exacerbating the risk for these patients. To understand the effect of obesity on hormone-dependent human breast cancer tumors, we fed ovariectomized athymic nude mice a diet containing 45% kcal fat and 17% kcal sucrose (high fat sucrose diet (HFSD)), 10% kcal fat (low fat diet (LFD)), or a standard chow diet (chow). The mice fed the HFSD developed metabolic abnormalities consistent with the development of obesity such as weight gain, high fasting blood glucose, and impaired glucose tolerance. These mice also developed hyperinsulinemia and insulin resistance. The obese mice also had a higher tumor growth rate compared to the lean mice. Furthermore, the obese mice showed a significantly reduced responsiveness to letrozole. To understand the role of obesity in this reduced responsiveness, we examined the effect of insulin on the growth of MCF-7Ca cells in response to estrogen or letrozole. The presence of insulin rendered MCF-7Ca cells less responsive to estrogen and letrozole. Exogenous insulin treatment of MCF-7Ca cells also resulted in increased p-Akt as well as ligand-independent phosphorylation of ERα. These findings suggest that diet-induced obesity may result in reduced responsiveness of tumors to letrozole due to the development of hyperinsulinemia. We conclude that obesity influences the response and resistance of breast cancer tumors to aromatase inhibitor treatment. © 2015 Society for Endocrinology.

Electroacupuncture for fatigue, sleep, and psychological distress in breast cancer patients with aromatase inhibitor-related arthralgia: a randomized trial.

PubMed

Mao, Jun J; Farrar, John T; Bruner, Deborah; Zee, Jarcy; Bowman, Marjorie; Seluzicki, Christina; DeMichele, Angela; Xie, Sharon X

2014-12-01

Although fatigue, sleep disturbance, depression, and anxiety are associated with pain in breast cancer patients, it is unknown whether acupuncture can decrease these comorbid symptoms in cancer patients with pain. The objective of this study was to evaluate the effect of electroacupuncture (EA) on fatigue, sleep, and psychological distress in breast cancer survivors who experience joint pain related to aromatase inhibitors (AIs). The authors performed a randomized controlled trial of an 8-week course of EA compared with a waitlist control (WLC) group and a sham acupuncture (SA) group in postmenopausal women with breast cancer who self-reported joint pain attributable to AIs. Fatigue, sleep disturbance, anxiety, and depression were measured using the Brief Fatigue Inventory (BFI), the Pittsburgh Sleep Quality Index (PSQI), and the Hospital Anxiety and Depression Scale (HADS). The effects of EA and SA versus WLC on these outcomes were evaluated using mixed-effects models. Of the 67 randomly assigned patients, baseline pain interference was associated with fatigue (Pearson correlation coefficient [r]=0.75; P < .001), sleep disturbance (r=0.38; P=.0026), and depression (r=0.58; P < .001). Compared with the WLC condition, EA produced significant improvements in fatigue (P=.0095), anxiety (P=.044), and depression (P=.015) and a nonsignificant improvement in sleep disturbance (P=.058) during the 12-week intervention and follow-up period. In contrast, SA did not produce significant reductions in fatigue or anxiety symptoms but did produce a significant improvement in depression compared with the WLC condition (P=.0088). Compared with usual care, EA produced significant improvements in fatigue, anxiety, and depression; whereas SA improved only depression in women experiencing AI-related arthralgia. © 2014 American Cancer Society.

Altered gene expression in the brain and ovaries of zebrafish (Danio rerio) exposed to the aromatase inhibitor fadrozole: microarray analysis and hypothesis generation.

PubMed

Villeneuve, L; Wang, Rong-Lin; Bencic, David C; Biales, Adam D; Martinović, Dalma; Lazorchak, James M; Toth, Gregory; Ankley, Gerald T

2009-08-01

As part of a research effort examining system-wide responses of the hypothalamic-pituitary-gonadal (HPG) axis in fish to endocrine-active chemicals (EACs) with different modes of action, zebrafish (Danio rerio) were exposed to 25 or 100 microg/L of the aromatase inhibitor fadrozole for 24, 48, or 96 h. Global transcriptional response in brain and ovarian tissue of fish exposed to 25 microg/L of fadrozole was compared to that in control fish using a commercially available, 22,000-gene oligonucleotide microarray. Transcripts altered in brain were functionally linked to differentiation, development, DNA replication, and cell cycle. Additionally, multiple genes associated with the one-carbon pool by folate pathway (KEGG 00670) were significantly up-regulated. Transcripts altered in ovary were functionally linked to cell-cell adhesion, extracellular matrix, vasculogenesis, and development. Promoter motif analysis identified GATA-binding factor 2, Ikaros 2, alcohol dehydrogenase gene regulator 1, myoblast-determining factor, and several heat shock factors as being associated with coexpressed gene clusters that were differentially expressed following exposure to fadrozole. Based on the transcriptional changes observed, it was hypothesized that fadrozole elicits neurodegenerative stress in brain tissue and that fish cope with this stress through proliferation of radial glial cells. Additionally, it was hypothesized that changes of gene expression in the ovary of fadrozole-exposed zebrafish reflect disruption of oocyte maturation and ovulation because of impaired vitellogenesis. These hypotheses and others derived from the microarray results provide a foundation for future studies aimed at understanding responses of the HPG axis to EACs and other chemical stressors.

Sexuality and quality of life in women with a prior diagnosis of breast cancer after risk-reducing salpingo-oophorectomy.

PubMed

Tucker, Paige E; Saunders, Christobel; Bulsara, Max K; Tan, Jason Jit-Sun; Salfinger, Stuart G; Green, Helena; Cohen, Paul A

2016-12-01

To investigate the prevalence of sexual dysfunction in women with a history of breast cancer following risk-reducing salpingo-oophorectomy (RRSO). A secondary objective was to examine the effect of a prior diagnosis of breast cancer, and other factors, on sexuality and quality of life (QoL) outcomes. Cross-sectional study of 119 women who underwent RRSO between 2009 and 2014. Data were collected via a questionnaire comprising demographic information and validated measures of sexual function, sexual distress, relationship satisfaction, body image, psychological stress, menopause symptoms and general quality of life. Sixty out of 119 participants who underwent RRSO had a history of breast cancer. Eighty percent of women with breast cancer had female sexual dysfunction (FSD) and 82% had hypoactive sexual desire disorder (HSDD) after RRSO. Bilateral mastectomy was associated with higher rates of HSDD (p = 0.028) and higher body image self-consciousness (BISC) during sexual activity (p = 0.011). Breast reconstruction was associated with higher relationship satisfaction (RAS) scores (p = 0.004). Compared to Tamoxifen, aromatase inhibitors (AI) were significantly associated with reduced lubrication (p = 0.041), arousal (p = 0.004), orgasm (p = 0.002) and greater dyspareunia (p = 0.027). Prior diagnosis of breast cancer was not associated with the prevalence of FSD (p = 0.532). High rates of FSD and HSDD occur in women with breast cancer following RRSO. Low relationship satisfaction, bodily pain, bilateral mastectomy and the use of aromatase inhibitors were associated with poorer sexual function. Women had similar sexual outcomes and QoL after RRSO, regardless of breast cancer history. Copyright © 2016 Elsevier Ltd. All rights reserved.

Quality of Life From Canadian Cancer Trials Group MA.17R: A Randomized Trial of Extending Adjuvant Letrozole to 10 Years.

PubMed

Lemieux, Julie; Brundage, Michael D; Parulekar, Wendy R; Goss, Paul E; Ingle, James N; Pritchard, Kathleen I; Celano, Paul; Muss, Hyman; Gralow, Julie; Strasser-Weippl, Kathrin; Whelan, Kate; Tu, Dongsheng; Whelan, Timothy J

2018-02-20

Purpose MA.17R was a Canadian Cancer Trials Group-led phase III randomized controlled trial comparing letrozole to placebo after 5 years of aromatase inhibitor as adjuvant therapy for hormone receptor-positive breast cancer. Quality of life (QOL) was a secondary outcome measure of the study, and here, we report the results of these analyses. Methods QOL was measured using the Short Form-36 (SF-36; two summary scores and eight domains) and menopause-specific QOL (MENQOL; four symptom domains) at baseline and every 12 months up to 60 months. QOL assessment was mandatory for Canadian Cancer Trials Group centers but optional for centers in other groups. Mean change scores from baseline were calculated. Results One thousand nine hundred eighteen women were randomly assigned, and 1,428 women completed the baseline QOL assessment. Compliance with QOL measures was > 85%. Baseline summary scores for the SF-36 physical component summary (47.5 for letrozole and 47.9 for placebo) and mental component summary (55.5 for letrozole and 54.8 for placebo) were close to the population norms of 50. No differences were seen between groups in mean change scores for the SF-36 physical and mental component summaries and the other eight QOL domains except for the role-physical subscale. No difference was found in any of the four domains of the MENQOL Conclusion No clinically significant differences were seen in overall QOL measured by the SF-36 summary measures and MENQOL between the letrozole and placebo groups. The data indicate that continuation of aromatase inhibitor therapy after 5 years of prior treatment in the trial population was not associated with a deterioration of overall QOL.

Quality of Life From Canadian Cancer Trials Group MA.17R: A Randomized Trial of Extending Adjuvant Letrozole to 10 Years

PubMed Central

Brundage, Michael D.; Parulekar, Wendy R.; Goss, Paul E.; Ingle, James N.; Pritchard, Kathleen I.; Celano, Paul; Muss, Hyman; Gralow, Julie; Strasser-Weippl, Kathrin; Whelan, Kate; Tu, Dongsheng; Whelan, Timothy J.

2018-01-01

Purpose MA.17R was a Canadian Cancer Trials Group–led phase III randomized controlled trial comparing letrozole to placebo after 5 years of aromatase inhibitor as adjuvant therapy for hormone receptor–positive breast cancer. Quality of life (QOL) was a secondary outcome measure of the study, and here, we report the results of these analyses. Methods QOL was measured using the Short Form-36 (SF-36; two summary scores and eight domains) and menopause-specific QOL (MENQOL; four symptom domains) at baseline and every 12 months up to 60 months. QOL assessment was mandatory for Canadian Cancer Trials Group centers but optional for centers in other groups. Mean change scores from baseline were calculated. Results One thousand nine hundred eighteen women were randomly assigned, and 1,428 women completed the baseline QOL assessment. Compliance with QOL measures was > 85%. Baseline summary scores for the SF-36 physical component summary (47.5 for letrozole and 47.9 for placebo) and mental component summary (55.5 for letrozole and 54.8 for placebo) were close to the population norms of 50. No differences were seen between groups in mean change scores for the SF-36 physical and mental component summaries and the other eight QOL domains except for the role-physical subscale. No difference was found in any of the four domains of the MENQOL Conclusion No clinically significant differences were seen in overall QOL measured by the SF-36 summary measures and MENQOL between the letrozole and placebo groups. The data indicate that continuation of aromatase inhibitor therapy after 5 years of prior treatment in the trial population was not associated with a deterioration of overall QOL. PMID:29328860

Aromatase inhibitors associated musculoskeletal disorders and bone fractures in postmenopausal breast cancer patients: a result from Chinese population.

PubMed

Xu, Lu; Wang, Jue; Xue, Dan-Dan; He, Wei

2014-09-01

As the prognosis of early breast cancer patients improves, the long-term safety of aromatase inhibitors (AIs) is increasingly important. In the present study, we retrospectively investigated the incidences of musculoskeletal disorders (MSDs) and bone fractures in a cohort of Chinese postmenopausal patients with breast cancer. Data of postmenopausal patients with breast cancer were collected. Among which, 70 patients received AIs therapy (median follow-up of 32.5 months), 52 patients received tamoxifen (TAM), and 89 patients received no endocrine therapy (NE). Baseline characteristics, incidence of MSDs and bone fractures were analyzed and compared. When compared with NE group (40.4 %, 36/89), more patients in AIs group developed MSDs (72.9 %, 51/70, adjusted odds ratio (AOR) = 3.30, 95 % confidence interval (CI) = 1.59-6.88, P = 0.001). But no difference was found between TAM group (36.5 %, 19/52, AOR = 0.70, 95 % CI = 0.32-1.52, P = 0.372) and NE group. About 39.7 months after initial AIs therapy, nine patients in AI group developed bone fractures in different sites, and the bone fracture rate was significantly increased (12.9 %, 9/70, adjusted hazard ratio (AHR) = 20.08, 95 % CI = 1.72-234.08, P = 0.017) in comparison with NE group (1.1 %, 1/89). Moreover, the bone fracture rate of TAM group was not different from NE group (1.9 %, 1/52, AHR = 2.64, 95 % CI = 0.14-48.73, P = 0.513). AIs therapy may induce increased rates of MSDs and bone fractures in Chinese population of postmenopausal breast cancer patients, whereas TAM therapy did not help reduce the incidences of MSDs and bone fractures.

Male rats with same-sex preference show higher immobility in the forced swim test, but similar effects of fluoxetine and desipramine than males that prefer females.

PubMed

Hernández, Alejandra; Fernández-Guasti, Alonso

2018-05-25

Sex preference in male rats is partly determined by the organizational action of estradiol. Thus, several paradigms have used aromatase inhibitors to manipulate sex preference. We recently showed that a subpopulation of male rats prenatally treated with letrozole (0.56 μg/kg, G10-G22), a non-steroidal third generation aromatase inhibitor, had same sex preference, female sexual behavior (including lordosis and proceptivity) and penile erections when exposed to other males. These males, in addition, displayed high levels of experimental anxiety in the plus maze test and were insensitive to the anxiogenic-like acute effect of FLX (10 mg/kg). The two main purposes of the present work were: a) to study the behavioral profile of males displaying same sex preference in the forced swim test (FST), and b) to analyze if the antidepressant-like effect of the subchronic treatment with FLX (10 mg/kg, 3 times) or desipramine (DMI, 10 mg/kg, 3 times) vary according to sex preference. Males treated prenatally with letrozole with same-sex preference showed more immobility and less active behaviors (swimming and climbing) in the FST than males with female preference. Subchronic treatment with FLX and DMI reduced immobility when compared to saline controls, while FLX increased swimming and DMI increased climbing behavior. Treatments were equally effective in males with preference for other males and those that preferred females. These results indicate that an association exists between prenatal letrozole treatment, same sex preference and immobility in the FST. Copyright © 2017. Published by Elsevier Inc.

Red Versus White Wine as a Nutritional Aromatase Inhibitor in Premenopausal Women: A Pilot Study

PubMed Central

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

2012-01-01

Abstract Background An increased risk of breast cancer is associated with alcohol consumption; however, it is controversial whether red wine increases this risk. Aromatase inhibitors (AIs) prevent the conversion of androgens to estrogen and occur naturally in grapes, grape juice, and red, but not white wine. We tested whether red wine is a nutritional AI in premenopausal women. Methods In a cross-over design, 36 women (mean age [SD], 36 [8] years) were assigned to 8 ounces (237 mL) of red wine daily then white wine for 1 month each, or the reverse. Blood was collected twice during the menstrual cycle for measurement of estradiol (E2), estrone (E1), androstenedione (A), total and free testosterone (T), sex hormone binding globulin (SHBG), luteinizing hormone (LH), and follicle stimulating hormone (FSH). Results Red wine demonstrated higher free T vs. white wine (mean difference 0.64 pg/mL [0.2 SE], p=0.009) and lower SHBG (mean difference −5.0 nmol/L [1.9 SE], p=0.007). E2 levels were lower in red vs. white wine but not statistically significant. LH was significantly higher in red vs. white wine (mean difference 2.3 mIU/mL [1.3 SE], p=0.027); however, FSH was not. Conclusion Red wine is associated with significantly higher free T and lower SHBG levels, as well as a significant higher LH level vs. white wine in healthy premenopausal women. These data suggest that red wine is a nutritional AI and may explain the observation that red wine does not appear to increase breast cancer risk. PMID:22150098

Activity of megestrol acetate in postmenopausal women with advanced breast cancer after nonsteroidal aromatase inhibitor failure: a phase II trial.

PubMed

Bines, J; Dienstmann, R; Obadia, R M; Branco, L G P; Quintella, D C; Castro, T M; Camacho, P G; Soares, F A; Costa, M E F

2014-04-01

As novel treatments carry substantial price tags and are mostly cost-prohibitive in low- and middle-income countries, there is an urgent need to develop alternatives, such as off-patent drugs. Megestrol acetate (MA) has a longstanding history in the treatment of breast cancer, but recently it is being used less often due to the advent of newer agents. This two-stage phase II trial evaluated the antitumor activity and toxicity of MA in postmenopausal women with hormone-sensitive advanced breast cancer who had experienced disease progression on a third-generation nonsteroidal aromatase inhibitor (NSAI). Eligible patients had metastatic breast cancer treated with a NSAI with at least 6-month progression-free survival (PFS), or relapse after ≥1 year on adjuvant NSAI. Patients received MA at a single daily oral dose of 160 mg. Primary end point was clinical benefit rate (CBR). Forty-eight patients were enrolled. The CBR was 40% [95% confidence interval (CI) 25% to 55%], and the median duration of clinical benefit was 10.0 (95% CI 8.0-14.2) months. The median PFS was 3.9 (95% CI 3.0-4.8) months. The most common grade 3 adverse events were anemia (2%), dyspnea (2%), fatigue (2%), musculoskeletal pain (4%), deep vein thrombosis (10%), and weight gain (2%). This is the first study to prospectively evaluate the efficacy and safety of MA in postmenopausal women with hormone-sensitive disease progressing on a NSAI. MA has demonstrated activity and acceptable tolerability in this setting, and therefore remains a reasonable treatment option in a cost-sensitive environment. These results also provide the background for further evaluation of progestins in the treatment of breast cancer. local trial number, related to the approval by the IRB: CEP 108/06.

Efficacy of exemestane after nonsteroidal aromatase inhibitor use in metastatic breast cancer patients.

PubMed

Kim, Sun Hye; Park, In Hae; Lee, Hyewon; Lee, Keun Seok; Nam, Byung-Ho; Ro, Jungsil

2012-01-01

Previous studies have suggested a lack of complete cross-resistance between steroidal (exemestane) and non-steroidal aromatase inhibitors (nSAI). Eighty-eight metastatic breast cancer (MBC) patients who received 25 mg of exemestane orally once a day at the National Cancer Center, Korea, between 2003 and 2009, were reviewed retrospectively. All patients had received nSAI for metastatic disease prior to exemestane therapy. The median age was 52 years (range, 33-79), and 13 (14.8%) patients were premenopausal who concomitantly received GnRH agonist. Exemestane was given as a second- (80.7%) or third-line (19.3%) hormone therapy. The clinical benefit (CB) rate (complete response + partial response + stable disease ≥ 24 weeks) was 30.7%, with a median CB duration of 10.0 months (range, 6.3-78.7). The median progression-free survival (PFS) was 3.0 months (95% confidence interval [CI], 1.99-4.01) and the overall survival (OS) 21.5 months (95% CI, 17.96-25.04), with a median follow-up of 50.3 months. Patients who achieved CB had longer OS than those patients who did not (29.6 vs 17.9 months; P = 0.002). On univariate analysis of predictive factors, patients who had achieved CB from previous nSAI tended to show lower CB rate (24.6% vs 44.4%, respectively; P = 0.063) and shorter PFS (2.8 vs 4.8 months, respectively; p = 0.233) than patients who had not. Achieving CB from previous nSAI became independent predictive factor for CBR to exemestane on multivariable analysis (Odds ratio = 2.852, P = 0.040). Exemestane after nSAI failure was effective in prolonging CB duration. The drug's efficacy seemed to be inferior in patients who had benefit from previous nSAI use.

Aromatase Inhibitor-Associated Bone Fractures: A Case-Cohort GWAS and Functional Genomics

PubMed Central

Liu, Mohan; Goss, Paul E.; Ingle, James N.; Kubo, Michiaki; Furukawa, Yoichi; Batzler, Anthony; Jenkins, Gregory D.; Carlson, Erin E.; Nakamura, Yusuke; Schaid, Daniel J.; Chapman, Judy-Anne W.; Shepherd, Lois E.; Ellis, Matthew J.; Khosla, Sundeep; Wang, Liewei

2014-01-01

Bone fractures are a major consequence of osteoporosis. There is a direct relationship between serum estrogen concentrations and osteoporosis risk. Aromatase inhibitors (AIs) greatly decrease serum estrogen levels in postmenopausal women, and increased incidence of fractures is a side effect of AI therapy. We performed a discovery case-cohort genome-wide association study (GWAS) using samples from 1071 patients, 231 cases and 840 controls, enrolled in the MA.27 breast cancer AI trial to identify genetic factors involved in AI-related fractures, followed by functional genomic validation. Association analyses identified 20 GWAS single nucleotide polymorphism (SNP) signals with P < 5E-06. After removal of signals in gene deserts and those composed entirely of imputed SNPs, we applied a functional validation “decision cascade” that resulted in validation of the CTSZ-SLMO2-ATP5E, TRAM2-TMEM14A, and MAP4K4 genes. These genes all displayed estradiol (E2)-dependent induction in human fetal osteoblasts transfected with estrogen receptor-α, and their knockdown altered the expression of known osteoporosis-related genes. These same genes also displayed SNP-dependent variation in E2 induction that paralleled the SNP-dependent induction of known osteoporosis genes, such as osteoprotegerin. In summary, our case-cohort GWAS identified SNPs in or near CTSZ-SLMO2-ATP5E, TRAM2-TMEM14A, and MAP4K4 that were associated with risk for bone fracture in estrogen receptor-positive breast cancer patients treated with AIs. These genes displayed E2-dependent induction, their knockdown altered the expression of genes related to osteoporosis, and they displayed SNP genotype-dependent variation in E2 induction. These observations may lead to the identification of novel mechanisms associated with fracture risk in postmenopausal women treated with AIs. PMID:25148458

Effects of incubation temperature and estrogen exposure on aromatase activity in the brain and gonads of embryonic alligators.

PubMed Central

Milnes, Matthew R; Roberts, Robert N; Guillette, Louis J

2002-01-01

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 differentiation of species that exhibit temperature-dependent sex determination (TSD). During the temperature-sensitive period (TSP) of sex determination, we compared aromatase activity in the brain and gonads of putative male and female alligator embryos to determine if aromatase activity in the embryonic brain could provide the hormonal environment necessary for ovarian development in a TSD species. In addition, we assessed the pattern of aromatase activity in the brain and gonads of embryos treated with estradiol-17beta (E(2)) and incubated at male-producing temperatures to compare enzyme activity in E(2) sex-reversed females to control males and females. This has particular significance regarding wildlife species living in areas contaminated with suspected environmental estrogens. Gonadal aromatase activity remained low during the early stages of the TSP in both sexes and increased late in the TSP only in females. Aromatase activity in the brain increased prior to gonadal differentiation in both sexes. These results suggest that aromatase activity in the brain is not directly responsible for mediating differentiation of the gonad. E(2) exposure at male-producing temperatures resulted in sex-reversed females that had intermediate gonad function and masculinized brain activity. This study indicates the need to examine multiple end points and to determine the persistence of developmental alterations in contaminant-exposed wildlife populations. PMID:12060834

Genome-Wide Associations and Functional Genomic Studies of Musculoskeletal Adverse Events in Women Receiving Aromatase Inhibitors

PubMed Central

Ingle, James N.; Schaid, Daniel J.; Goss, Paul E.; Liu, Mohan; Mushiroda, Taisei; Chapman, Judy-Anne W.; Kubo, Michiaki; Jenkins, Gregory D.; Batzler, Anthony; Shepherd, Lois; Pater, Joseph; Wang, Liewei; Ellis, Matthew J.; Stearns, Vered; Rohrer, Daniel C.; Goetz, Matthew P.; Pritchard, Kathleen I.; Flockhart, David A.; Nakamura, Yusuke; Weinshilboum, Richard M.

2010-01-01

Purpose We performed a case-control genome-wide association study (GWAS) to identify single nucleotide polymorphisms (SNPs) associated with musculoskeletal adverse events (MS-AEs) in women treated with aromatase inhibitors (AIs) for early breast cancer. Patients and Methods A nested case-control design was used to select patients enrolled onto the MA.27 phase III trial comparing anastrozole with exemestane. Cases were matched to two controls and were defined as patients with grade 3 or 4 MS-AEs (according to the National Cancer Institute's Common Terminology Criteria for Adverse Events v3.0) or those who discontinued treatment for any grade of MS-AE within the first 2 years. Genotyping was performed with the Illumina Human610-Quad BeadChip. Results The GWAS included 293 cases and 585 controls. A total of 551,358 SNPs were analyzed, followed by imputation and fine mapping of a region of interest on chromosome 14. Four SNPs on chromosome 14 had the lowest P values (2.23E-06 to 6.67E-07). T-cell leukemia 1A (TCL1A) was the gene closest (926-7000 bp) to the four SNPs. Functional genomic studies revealed that one of these SNPs (rs11849538) created an estrogen response element and that TCL1A expression was estrogen dependent, was associated with the variant SNP genotypes in estradiol-treated lymphoblastoid cells transfected with estrogen receptor alpha and was directly related to interleukin 17 receptor A (IL17RA) expression. Conclusion This GWAS identified SNPs associated with MS-AEs in women treated with AIs and with a gene (TCL1A) which, in turn, was related to a cytokine (IL17). These findings provide a focus for further research to identify patients at risk for MS-AEs and to explore the mechanisms for these adverse events. PMID:20876420

Circulating ESR1 mutations at the end of aromatase inhibitor adjuvant treatment and after relapse in breast cancer patients.

PubMed

Allouchery, Violette; Beaussire, Ludivine; Perdrix, Anne; Sefrioui, David; Augusto, Laetitia; Guillemet, Cécile; Sarafan-Vasseur, Nasrin; Di Fiore, Frédéric; Clatot, Florian

2018-05-16

Detection of circulating ESR1 mutations is associated with acquired resistance to aromatase inhibitor (AI) in metastatic breast cancer. Until now, the presence of circulating ESR1 mutations at the end of adjuvant treatment by AI in early breast cancer had never been clearly established. In this context, the aim of the present study was to evaluate the circulating ESR1 mutation frequency at the end of adjuvant treatment and after relapse. This monocentric retrospective study was based on available stored plasmas and included all early breast cancer patients who completed at least 2 years of AI adjuvant treatment and experienced a documented relapse after the end of their treatment. Circulating ESR1 mutations (D538G, Y537S/N/C) were assessed by droplet digital PCR in plasma samples taken at the end of adjuvant treatment, at time of relapse and at time of progression under first line metastatic treatment. A total of 42 patients were included, with a median adjuvant AI exposure of 60 months (range 41-85). No circulating ESR1 mutation was detectable at the end of AI adjuvant therapy. At first relapse, 5.3% of the patients (2/38) had a detectable circulating ESR1 mutation. At time of progression on first-line metastatic treatment, 33% of the patients (7/21) under AI had a detectable circulating ESR1 mutation compared to none of the patients under chemotherapy (0/10). The two patients with a detectable ESR1 mutation at relapse were treated by AI and had an increase of their variant allele fraction at time of progression on first-line metastatic treatment. Circulating ESR1 mutation detection at the end of AI-based adjuvant treatment is not clinically useful. Circulating ESR1 mutation could be assessed as soon as first relapse to guide interventional studies.

Serum insulin-like factor 3 levels during puberty in healthy boys and boys with Klinefelter syndrome.

PubMed

Wikström, Anne M; Bay, Katrine; Hero, Matti; Andersson, Anna-Maria; Dunkel, Leo

2006-11-01

Levels of the Leydig cell-specific hormone insulin-like factor 3 (INSL3) are incompletely characterized in boys during pubertal development. The objective of the study was to characterize changes in INSL3 levels during spontaneous puberty in healthy boys, boys with aromatase inhibitor-induced hypergonadotropic hyperandrogenism, and boys with Leydig cell dysfunction. This was a prospective clinical study. The study was conducted at a university hospital pediatric endocrinology outpatient clinic. Patients included 30 healthy boys with idiopathic short stature (ISS) aged 9.0-14.5 yr and 14 boys with Klinefelter syndrome (KS) aged 10-13.9 yr. In ISS boys, intervention included aromatase inhibitor letrozole or placebo for 24 months. Serum INSL3 levels in relation to bone age, Tanner pubertal stages, and LH and testosterone levels were measured. Onset of puberty was associated with a significant increase in INSL3 levels from 0.06 +/- 0.01 ng/ml at Tanner G1 to 0.32 +/- 0.16 ng/ml at G2 (P < 0.0001). Adult INSL3 levels (> or = 0.55 ng/ml) were attained at bone age 13-14 yr. ISS boys with letrozole-induced hypergonadotropic hyperandrogenism had, after 12 months of therapy, higher INSL3 levels than did placebo treated (0.85 +/- 0.54 vs. 0.26 +/- 0.17 ng/ml, P < 0.01). In KS boys during spontaneous puberty, after an initial increase similar to that in healthy boys, INSL3 concentrations leveled off despite hyperstimulation by LH. Positive correlations occurred between serum INSL3 and LH and between INSL3 and testosterone levels in all three groups (P < 0.0001). In boys, the Leydig cell-specific hormone INSL3 may serve as a new marker for onset and progression of puberty. Pubertal increase in INSL3 levels seems to depend on LH. In KS subjects, INSL3 concentrations indicate Leydig cell dysfunction from midpuberty onward.

Inhibition and induction of aromatase (CYP19) activity by brominated flame retardants in H295R human adrenocortical carcinoma cells.

PubMed

Cantón, Rocío F; Sanderson, J Thomas; Letcher, Robert J; Bergman, Ake; van den Berg, Martin

2005-12-01

Brominated flame retardants (BFRs) are persistent and ubiquitous chemicals in the environment, and they are found at increasing levels in tissues of wildlife and humans. Previous in vitro studies with the BFR class of polybrominated diphenyl ethers (BDEs) have shown endocrine-disrupting properties. Our study assessed the potential effects of nineteen BDEs, five hydroxylated BDEs (OH-BDEs), one methoxylated BDE (CH(3)O-BDE), tetrabromobisphenol-A (TBBPA), its dibromopropane ether derivative (TBBPA-DBPE), and the brominated phenols/anisols 2,4,6-tribromophenol (TBP), 4-bromophenol (4BP) and 2,4,6-tribromoanisole (TBA) on the catalytic activity of the steroidogenic enzyme aromatase (CYP19) in H295R human adrenocortical carcinoma cells. Effects were studied in the concentration range from 0.5 to 7.5 microM; exposures were for 24 h. Both 6-OH-BDE47 and 6-OH-BDE99 showed an inhibitory effect on aromatase activity at concentrations >2.5 microM and >5 microM, respectively. However, 6-OH-BDE47 also caused a statistically significant increase in cytotoxicity (based on mitochondrial MTT reduction and lactate dehydrogenase-leakage [LDH]) at concentrations >2.5 microM that could explain in part the apparent inhibitory effect on aromatase activity. Compared to 6-OH-BDE47, the methoxy analog (6-CH(3)O-BDE47) did not elicit a cytotoxic effect, whereas significant inhibition of aromatase remained. TBP caused a concentration-dependent induction of aromatase activity between 0.5 and 7.5 microM (with a maximum of 3.8-fold induction at 7.5 microM). This induction was not observed when a OH- group replaced the CH(3)O- group or when bromine atoms adjacent to this OH- group were absent. These in vitro results provide a basis for studies of more detailed structure-activity relationships between these brominated compounds and the modulation of aromatase activity.

Memory and Spatial Cognition in Breast Cancer Patients Undergoing Adjuvant Endocrine Therapy

PubMed Central

Berndt, Ute; Leplow, Bernd; Schoenfeld, Robby; Lantzsch, Tilmann; Grosse, Regina; Thomssen, Christoph

2016-01-01

Introduction It is generally accepted that estrogens play a protective role in cognitive function. Therefore, it can be expected that subtotal estrogen deprivation following aromatase inhibition will alter cognitive performance. Methods In a cross-sectional study we investigated 80 postmenopausal women with breast cancer. Memory and spatial cognition were compared across 4 treatment groups: tamoxifen only (TAM, n = 22), aromatase inhibitor only (AI, n = 22), TAM followed by AI (‘SWITCH group’, n = 15), and patients with local therapy (LT) only (surgery and radiation, n = 21). Duration of the 2 endocrine monotherapy arms prior to the assessment ranged from 1 to 3 years. The ‘SWITCH group’ received 2-3 years TAM followed by at least 1 year and at most 3 years of AI. Memory and spatial cognition were investigated as planned comparisons. Investigations of processing speed, attention, executive function, visuoconstruction and self-perception of memory were exploratory. Results With regard to general memory, AI patients performed significantly worse than the LT group (p = 0.013). Significant differences in verbal memory did not remain significant after p-value correction for multiple testing. We found no significant differences concerning spatial cognition between the groups. Conclusion AI treatment alone significantly impairs general memory compared to the LT group. PMID:27721710

Possible role of the aromatase-independent steroid metabolism pathways in hormone responsive primary breast cancers.

PubMed

Hanamura, Toru; Niwa, Toshifumi; Gohno, Tatsuyuki; Kurosumi, Masafumi; Takei, Hiroyuki; Yamaguchi, Yuri; Ito, Ken-ichi; Hayashi, Shin-ichi

2014-01-01

Aromatase inhibitors (AIs) exert antiproliferative effects by reducing local estrogen production from androgens in postmenopausal women with hormone-responsive breast cancer. Previous reports have shown that androgen metabolites generated by the aromatase-independent enzymes, 5α-androstane-3β, 17β-diol (3β-diol), androst-5-ene-3β, and 17β-diol (A-diol), also activate estrogen receptor (ER) α. Estradiol (E2) can also reportedly be generated from estrone sulfate (E1S) pooled in the plasma. Estrogenic steroid-producing aromatase-independent pathways have thus been proposed as a mechanism of AI resistance. However, it is unclear whether these pathways are functional in clinical breast cancer. To investigate this issue, we assessed the transcriptional activities of ER in 45 ER-positive human breast cancers using the adenovirus estrogen-response element-green fluorescent protein assay and mRNA expression levels of the ER target gene, progesterone receptor, as indicators of ex vivo and in vivo ER activity, respectively. We also determined mRNA expression levels of 5α-reductase type 1 (SRD5A1) and 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD type 1; HSD3B1), which produce 3β-diol from androgens, and of steroid sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD type 1; HSD17B1), which produce E2 or A-diol from E1S or dehydroepiandrosterone sulfate. SRD5A1 and HSD3B1 expression levels were positively correlated with ex vivo and in vivo ER activities. STS and HSD17B1 expression levels were positively correlated with in vivo ER activity alone. Elevated expression levels of these steroid-metabolizing enzymes in association with high in vivo ER activity were particularly notable in postmenopausal patients. Analysis of the expression levels of steroid-metabolizing enzymes revealed positive correlations between SRD5A1 and HSD3B1, and STS and HSD17B1. These findings suggest that the SRD5A1-HSD3B1 as well as the STS-HSD17B pathways, could contributes to ER activation, especially postmenopause. These pathways might function as an alternative estrogenic steroid-producing, aromatase-independent pathways.

Differential Regulation of Aromatase Isoforms and Tissue Responses to Environmental Chemicals in Fish

EPA Science Inventory

As in mammals, aromatase plays a basic role in fish reproduction. Unlike most mammals, with only one form of aromatase, fish have two distinct forms. One isoform, P450aromA, predominates in ovaries. Ovarian aromatase activity controls circulating levels of estrogens and is critic...

The comparision of effect of microdose GnRH-a flare-up, GnRH antagonist/aromatase inhibitor letrozole and GnRH antagonist/clomiphene citrate protocols on IVF outcomes in poor responder patients.

PubMed

Ozcan Cenksoy, Pinar; Ficicioglu, Cem; Kizilkale, Ozge; Suhha Bostanci, Mehmet; Bakacak, Murat; Yesiladali, Mert; Kaspar, Cigdem

2014-07-01

To compare the effects of microdose GnRH-a flare-up, GnRH antagonist/aromatase inhibitor letrozole and GnRH antagonist/clomiphene citrate protocols on IVF outcomes in poor responder patients. Of 225 patients, 83 patients were in microdose flare-up group (Group 1), 70 patients were in GnRH antagonist/letrozole group (Group 2) and 72 patients were in GnRH antagonist/clomiphene citrate group (Group 3). Demographic and endocrine characteristics, the total number of oocytes retrieved, cancellation rate and clinical pregnancy rate were collected Results: Total dosage of gonadotropins (p=0.002) and serum E2 levels on the day of hCG administration (p=0.010) were significantly higher and duration of stimulations (p=0.03) was significantly longer in group 1. The number of oocytes retrieved was significantly greater in group 1 and 2 when compare to those of group 3 (p=0,000). There was a trend towards increasing cycle cancellation rates with GnRH antagonist/clomiphene citrate and GnRH antagonist/letrozole. Our finding suggest that the results of microdose flare-up protocol are better than other two used treatment protocols, in terms of maximum estradiol levels, number of mature oocytes retrieved, and cancellation rate and it still seems to be superior the ovarian stimulation regime for the poor responder patients.

Estrogenic encounters: How interactions between aromatase and the environment modulate aggression

PubMed Central

Trainor, Brian C.; Kyomen, Helen H.; Marler, Catherine A.

2007-01-01

Initial investigations into the mechanistic basis of aggression focused on the role of testosterone (T) and a variety of studies on non-human animals found that elevated T levels promote aggression. However, many correlational studies have not detected a significant association between aggression and peripheral T levels. One reason for this inconsistency may be due to differential metabolism of T within the brain, in particular, the conversion of T to estrogen by aromatase. Thus, differences in aromatase enzyme activity, estrogen receptor expression, and related cofactors may have important effects on how steroids affect aggressive behavior. Hormone manipulation studies conducted in a wide variety of species indicate that estrogens modulate aggression. There is also growing evidence that social experience has important effects on the production of estrogen within the brain, and some cases can not be explained by androgenic regulation of aromatase. Such changes in central aromatase activity may play an important role in determining how social experiences affect the probability of whether an individual engages in aggressive behavior. Although studies have been conducted in many taxa, there has been relatively little integration between literatures examining aggression in different species. In this review, we compare and contrast studies examining aggression in birds, mammals, and humans. By taking an integrative approach to our review, we consider mechanisms that could explain species differences in how estrogen modulates aggression. PMID:16376420

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

PubMed

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

2014-09-01

Dienogest is a novel progestin that is highly selective for progesterone receptors and inhibits endometriosis. However, it remains unknown how the administration of dienogest to patients with endometriosis impacts on their lesion tissues. The aim of this study was to evaluate the in vivo effect of dienogest on endometriosis tissue. We collected endometrioma tissues from patients treated with dienogest (N = 7) or not treated (N = 11, controls). Cell proliferation, aromatase expression and blood vessel density were evaluated by staining for Ki67, aromatase and the von Willebrand factor, respectively. Apoptosis was detected using the TUNEL assay. The proportion of Ki67 and aromatase positive epithelial cells was significantly lower in the dienogest group than in controls (p < 0.05, respectively). The number of TUNEL positive cells was significantly higher in the dienogest group (p < 0.05). The density of blood vessels in endometrioma was marginally lower in the dienogest group compared with controls (p = 0.20). Our study demonstrates that endometrioma taken from patients treated with dienogest show remarkable histological features such as reduction of proliferation, aromatase expression and angiogenesis, and increase of apoptosis. This study clarified the impact of dienogest on local histological events that explain its therapeutic effect on endometriosis.

Potential role for mammalian target of rapamycin inhibitors as first-line therapy in hormone receptor–positive advanced breast cancer

PubMed Central

Beck, J Thaddeus

2015-01-01

Despite advances in cytotoxic chemotherapy and targeted therapies, 5-year survival rates remain low for patients with advanced breast cancer at diagnosis. This highlights the limited effectiveness of current treatment options. An improved understanding of cellular functions associated with the development and progression of breast cancer has resulted in the creation of a number of novel targeted molecular therapies. However, more work is needed to improve outcomes, particularly in the first-line recurrent or metastatic hormone receptor–positive breast cancer setting. The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) pathway is a major intracellular signaling pathway that is often upregulated in breast cancer, and overactivation of this pathway has been associated with primary or developed resistance to endocrine treatment. Clinical data from the Phase III Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2) study of the mTOR inhibitor everolimus combined with exemestane in hormone receptor–positive advanced breast cancer were very promising, highlighting the potential role of mTOR inhibitors in combination with endocrine therapies as a first-line treatment option for these patients. It is hoped that the use of mTOR inhibitors combined with current standard-of-care endocrine therapies, such as aromatase inhibitors, in the first-line advanced breast cancer setting may result in greater antitumor effects and also delay or reverse treatment resistance. PMID:26675495

[Everolimus plus exemestane in postmenopausal patients with estrogen-receptor-positive advanced breast cancer - Japanese subgroup analysis of BOLERO -2].

PubMed

Ito, Yoshinori; Masuda, Norikazu; Iwata, Hiroji; Mukai, Hirofumi; Horiguchi, Jun; Tokuda, Yutaka; Kuroi, Katsumasa; Mori, Asuka; Ohno, Nobutsugu; Noguchi, Shinzaburo

2015-01-01

In a phase 3, double-blind, randomized, international study (the BOLERO-2), the addition of mTOR inhibitor everolimus to exemestane was evaluated in postmenopausal women with estrogen-receptor-positive (ER⁺) advanced/recurrent breast cancer that was refractory to any nonsteroidal aromatase inhibitor (NSAI). This report presents the safety and updated (18- month) efficacy results from the Japanese subset (n=106) of BOLERO-2. After a median follow-up of 18 months, the median progression-free survival time was 8.5 months with everolimus plus exemestane compared to 4.2 months with placebo plus exemestane. The most common adverse events (AEs) with everolimus plus exemestane were stomatitis, rash, dysgeusia, and non-infectious lung disease. The AEs reported with the combination therapy were mostly of grade 1 or 2 and manageable with appropriate intervention. In conclusion, this combination could be a useful addition to the armamentarium of treatments for Japanese postmenopausal women with ER⁺ advanced/recurrent breast cancer progressing on NSAIs.

Estrogen biosynthesis in THP1 cells is regulated by promoter switching of the aromatase (CYP19) gene.

PubMed

Shozu, M; Zhao, Y; Simpson, E R

1997-12-01

The expression of aromatase, the enzyme responsible for estrogen biosynthesis, has been studied in THP-1 cells of human mononuclear leukemic origin, which exhibit high rates of aromatase activity. These cells have the capacity to differentiate in the presence of vitamin D into cells with osteoclast-like properties. Differentiated cells displayed higher rates of aromatase than undifferentiated cells, and, in both cases, activity was stimulated 10- to 20-fold by dexamethasone. Phorbol esters also increased aromatase activity, but the effect was the same in differentiated as in undifferentiated cells. In a similar fashion to adipose stromal cells, serum potentiated the response to dexamethasone but had no effect on phorbol ester-stimulated activity. By contrast to its action in adipose stromal cells, (Bu)2cAMP markedly inhibited aromatase activity of THP-1 cells, as did factors whose actions are mediated by cAMP, such as PTH and PTH-related peptide. This was true of control cells, as well as of dexamethasone- and phorbol ester-stimulated cells. Previously we have shown that type 1 cytokines as well as tumor necrosis factor-alpha stimulate aromatase activity of adipose stromal cells in the presence of dexamethasone. By contrast, interleukin-6, interleukin-11, and leukemia-inhibitory factor had no effect on aromatase activity of THP-1 cells, whereas tumor necrosis factor-alpha, oncostatin M, and platelet-derived growth factor were slightly inhibitory of aromatase activity. Exon-specific Southern analysis of rapid amplification of cDNA ends-amplified transcripts was employed to examine the distribution of the various 5'-termini of aromatase transcripts. In the control group, most of the clones contained transcripts specific for the proximal promoter II, whereas in dexamethasone-treated cells, most transcripts contained exon I.4. In the phorbol ester-treated cells, a broader spectrum of transcripts was present, with equal proportions of I.4, II, and I.3-containing clones. Additionally, one clone containing a new sequence, exon I.6, was found. This was shown to be located about 1 kb upstream of exon II. By contrast, all clones from cells treated with (Bu)2cAMP contained promoter II-specific sequences. In addition to these transcripts, two clones in the library from the dexamethasone-treated cells contained the sequence previously defined as the brain-specific sequence, 1f. In one of these, the 1f sequence was fused downstream of exon I.4, indicative that its expression likely employed promoter I.4. These results point to similarities and important differences between aromatase expression in THP-1 cells and other cells such as adipose stromal cells, indicative of unique regulatory pathways governing aromatase expression in these cells.

Incidence and management of arthralgias in breast cancer patients treated with aromatase inhibitors in an outpatient oncology clinic.

PubMed

Menas, Pamela; Merkel, Douglas; Hui, Wendy; Lawton, Jessica; Harper, Abigail; Carro, George

2012-12-01

Aromatase inhibitors (AIs) are routinely used as first-line adjuvant treatment of breast cancer in postmenopausal women with hormone receptor positive tumors. The current recommended length of treatment with an AI is 5 years. Arthralgias have been frequently cited as the primary reason for discontinuation of AI therapy. Various treatment strategies are proposed in literature, but a standardized treatment algorithm has not been established. The initial purpose of this study was to describe the incidence and management of AI-induced arthralgias in patients treated at Kellogg Cancer Center (KCC). Further evaluation led to the development and the implementation of a treatment algorithm and electronic medical record (EMR) documentation tools. The retrospective chart review included 206 adult patients with hormone receptor positive breast cancer who were receiving adjuvant therapy with an AI. A multidisciplinary treatment team consisting of pharmacists, collaborative practice nurses, and physicians met to develop a standardized treatment algorithm and corresponding EMR documentation tool. The treatment algorithm and documentation tool were developed after the study to better monitor and proactively treat patients with AI-induced arthralgias. RESULTS/ CONCLUSIONS: The overall incidence of arthralgias at KCC was 48% (n = 98/206). Of these patients, 32% were documented as having arthralgias within the first 6 months of therapy initiation. Patients who reported AI-induced arthralgias were younger than patients who did not report AI-induced arthralgias (61 vs. 65 years, p = 0.002). There was no statistical difference in the incidence of arthralgias in patients with a history of chemotherapy (including taxane therapy) compared to those who did not receive chemotherapy (p = 0.352). Of patients presenting with AI-induced arthralgias, 41% did not have physician-managed treatment documented in the EMR. A standardized treatment algorithm and electronic chart documentation tools were then developed by the multidisciplinary team.

Single or Multiple Access Channels to the CYP450s Active Site? An Answer from Free Energy Simulations of the Human Aromatase Enzyme.

PubMed

Magistrato, Alessandra; Sgrignani, Jacopo; Krause, Rolf; Cavalli, Andrea

2017-05-04

Cytochromes P450 (CYP450s), in particular, CYP19A1 and CYP17A1, are key clinical targets of breast and prostate anticancer therapies, critical players in drug metabolism, and their overexpression in tumors is associated with drug resistance. In these enzymes, ligand (substrates, drugs) metabolism occurs in deeply buried active sites accessible only via several grueling channels, whose exact biological role remains unclear. Gaining direct insights on the mechanism by which ligands travel in and out is becoming increasingly important given that channels are involved in the modulation of binding/dissociation kinetics and the specificity of ligands toward a CYP450. This has profound implications for enzymatic efficiency and drug efficacy/toxicity. Here, by applying free energy methods, for a cumulative simulation time of 20 μs, we provide detailed atomistic characterization and free energy profiles of the entry/exit routes preferentially followed by a substrate (androstenedione) and a last-generation inhibitor (letrozole) to/from the catalytic site of CYP19A1 (the human aromatase (HA) enzyme), a key clinical target against breast cancer, studied here as prototypical CYP450. Despite the remarkably different size/shape/hydrophobicity of the ligands, two channels appear accessible to their entrance, while only one exit route appears to be preferential. Our study shows that the preferential paths may be conserved among different CYP450s. Moreover, our results highlight that, at least in the case of HA, ligand channeling is associated with large enzyme structural rearrangements. A wise choice of the computational method and very long simulations are, thus, required to obtain fully converged quantitative free energy profiles, which might be used to design novel biocatalysts or next-generation cytochrome inhibitors with an in silico tuned K m .

Ultra-low-dose estriol and Lactobacillus acidophilus vaginal tablets (Gynoflor(®)) for vaginal atrophy in postmenopausal breast cancer patients on aromatase inhibitors: pharmacokinetic, safety, and efficacy phase I clinical study.

PubMed

Donders, Gilbert; Neven, Patrick; Moegele, Maximilian; Lintermans, Anneleen; Bellen, Gert; Prasauskas, Valdas; Grob, Philipp; Ortmann, Olaf; Buchholz, Stefan

2014-06-01

Phase I pharmacokinetic (PK) study assessed circulating estrogens in breast cancer (BC) patients on a non-steroidal aromatase inhibitor (NSAI) with vaginal atrophy using vaginal ultra-low-dose 0.03 mg estriol (E3) and Lactobacillus combination vaginal tablets (Gynoflor(®)). 16 women on NSAI with severe vaginal atrophy applied a daily vaginal tablet of Gynoflor(®) for 28 days followed by a maintenance therapy of 3 tablets weekly for 8 weeks. Primary outcomes were serum concentrations and PK of E3, estradiol (E2), and estrone (E1) using highly sensitive gas chromatography-mass spectrometry. Secondary outcomes were clinical measures for efficacy and side effects; microscopic changes in vaginal epithelium and microflora; and changes in serum FSH, LH, and sex hormone-binding globulin. Compared with baseline, serum E1 and E2 did not increase in any of the women at any time following vaginal application. Serum E3 transiently increased after the first application in 15 of 16 women, with a maximum of 168 pg/ml 2-3 h post-insertion. After 4 weeks, serum E3 was slightly increased in 8 women with a maximum of 44 pg/ml. The vaginal atrophy resolved or improved in all women. The product was well tolerated, and discontinuation of therapy was not observed. The low-dose 0.03 mg E3 and Lactobacillus acidophilus vaginal tablets application in postmenopausal BC patients during AI treatment suffering from vaginal atrophy lead to small and transient increases in serum E3, but not E1 or E2, and therefore can be considered as safe and efficacious for treatment of atrophic vaginitis in BC patients taking NSAIs.

Survivorship, Version 2.2017

PubMed Central

Denlinger, Crystal S.; Sanft, Tara; Baker, K. Scott; Baxi, Shrujal; Broderick, Gregory; Demark-Wahnefried, Wendy; Friedman, Debra L.; Goldman, Mindy; Hudson, Melissa; Khakpour, Nazanin; King, Allison; Koura, Divya; Kvale, Elizabeth; Lally, Robin M.; Langbaum, Terry S.; Melisko, Michelle; Montoya, Jose G.; Mooney, Kathi; Moslehi, Javid J.; O’Connor, Tracey; Overholser, Linda; Paskett, Electra D.; Peppercorn, Jeffrey; Rodriguez, M. Alma; Ruddy, Kathryn J.; Silverman, Paula; Smith, Sophia; Syrjala, Karen L.; Tevaarwerk, Amye; Urba, Susan G.; Wakabayashi, Mark T.; Zee, Phyllis; Freedman-Cass, Deborah A.; McMillian, Nicole R.

2018-01-01

Many cancer survivors experience menopausal symptoms, including female survivors taking aromatase inhibitors or with a history of oophorectomy or chemotherapy, and male survivors who received or are receiving androgen-ablative therapies. Sexual dysfunction is also common in cancer survivors. Sexual dysfunction and menopause-related symptoms can increase distress and have a significant negative impact on quality of life. This portion of the NCCN Guidelines for Survivorship provide recommendations for screening, evaluation, and treatment of sexual dysfunction and menopausal symptoms to help healthcare professionals who work with survivors of adult-onset cancer in the posttreatment period. PMID:28874599

Medical management of male infertility in the absence of a specific etiology.

PubMed

Gudeloglu, Ahmet; Brahmbhatt, Jamin V; Parekattil, Sijo J

2014-07-01

Idiopathic male infertility can be diagnosis in approximately one-third of infertile males. The empirical medical treatment with or without assisted reproductive techniques appears common in male infertility practice. This type of management can be classified as hormonal treatment including gonadotropins, antiestrogens, and aromatase inhibitors and support with antioxidant supplements such as carnitine, lycopene, glutathione, and vitamin E. This review investigates the evidence of commonly used empirical medical management of male infertility when there is no demonstrable diagnosis. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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

PubMed

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

2017-06-01

Des-acyl ghrelin is the unacylated form of the well-characterized appetite-stimulating hormone ghrelin. It affects a number of physiological processes, including increasing adipose lipid accumulation and inhibiting adipose tissue inflammation. Breast adipose tissue inflammation in obesity is associated with an increase in the expression of the estrogen biosynthetic enzyme, aromatase, and is hypothesized to create a hormonal milieu conducive to tumor growth. We previously reported that des-acyl ghrelin inhibits the expression and activity of aromatase in isolated human adipose stromal cells (ASCs), the main site of aromatase expression in the adipose tissue. The current study aimed to examine the effect of des-acyl ghrelin on the capacity of mouse macrophages (RAW264.7 cells) and human adipose tissue macrophages (ATMs) to stimulate aromatase expression in primary human breast ASCs. RAW264.7 cells were treated with 0, 10 and 100pM des-acyl ghrelin following activation with phorbol 12-myristate 13-acetate, and cells and conditioned media were collected after 6 and 24h. The effect of des-acyl ghrelin on macrophage polarization was examined by assessing mRNA expression of pro-inflammatory M1-specific marker Cd11c and anti-inflammatory M2-specific marker Cd206, as well as expression of Tnf and Ptgs2, known mediators of the macrophage-dependent stimulation of aromatase. TNF protein in conditioned media was assessed by ELISA. The effect of RAW264.7 and ATM-conditioned media on aromatase expression in ASCs was assessed after 6h. Results demonstrate des-acyl ghrelin significantly increases the expression of Cd206 and suppresses the expression of Cd11c, Tnf and Ptgs2 in activated RAW264.7 cells. Treatment of RAW264.7 and ATMs with des-acyl ghrelin also significantly reduces the capacity of these cells to stimulate aromatase transcript expression in human breast ASCs. Overall, these findings suggest that in addition to direct effects on aromatase in ASCs, des-acyl ghrelin also has the capacity to inhibit the macrophage-dependent induction of aromatase, and provides a novel mechanism for potential effects of des-acyl ghrelin to break the linkage between obesity and breast cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

PubMed

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

2014-01-01

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

Fish with thermolabile sex determination (TSD) as models to study brain sex differentiation.

PubMed

Blázquez, Mercedes; Somoza, Gustavo M

2010-05-01

As fish are ectothermic animals, water temperature can affect their basic biological processes such as larval development, growth and reproduction. Similar to reptiles, the incubation temperature during early phases of development is capable to modify sex ratios in a large number of fish species. This phenomenon, known as thermolabile sex determination (TSD) was first reported in Menidia menidia, a species belonging to the family Atherinopsidae. Since then, an increasing number of fish have also been found to exhibit TSD. Traditionally, likewise in reptiles, several TSD patterns have been described in fish, however it has been recently postulated that only one, females at low temperatures and males at high temperatures, may represent the "real" or "true" TSD. Many studies regarding the influence of temperature on the final sex ratios have been focused on the expression and activity of gonadal aromatase, the enzyme involved in the conversion of androgens into estrogens and encoded by the cyp19a1a gene. In this regard, teleost fish, may be due to a whole genome duplication event, produce another aromatase enzyme, commonly named brain aromatase, encoded by the cyp19a1b gene. Contrary to what has been described in other vertebrates, fish exhibit very high levels of aromatase activity in the brain and therefore they synthesize high amounts of neuroestrogens. However, its biological significance is still not understood. In addition, the mechanism whereby temperature can induce the development of a testis or an ovary still remains elusive. In this context the present review is aimed to discuss several theories about the possible role of brain aromatase using fish as models. The relevance of brain aromatase and therefore of neuroestrogens as the possible cue for gonadal differentiation is raised. In addition, the possible role of brain aromatase as the way to keep the high levels of neurogenesis in fish is also considered. Several key examples of how teleosts and aromatase regulation can offer more insight into basic mechanisms of TSD are also reviewed. Copyright 2009 Elsevier Inc. All rights reserved.

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

PubMed

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

2018-02-12

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

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

PubMed Central

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

2016-01-01

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

Intracrine sex steroid synthesis and signaling in human epidermal keratinocytes and dermal fibroblasts.

PubMed

Pomari, Elena; Dalla Valle, Luisa; Pertile, Paolo; Colombo, Lorenzo; Thornton, M Julie

2015-02-01

Peripheral intracrine sex steroid synthesis from adrenal precursors dehydroepiandrosterone (DHEA) and DHEA-sulfate has evolved in humans. We sought to establish if there are differences in intracrine, paracrine, and endocrine regulation of sex steroids by primary cultures of human skin epidermal keratinocytes and dermal fibroblasts. Microarray analysis identified multifunctional genes modulated by steroids, quantitative RT-PCR (qRT-PCR) mRNA expression, enzymatic assay aromatase activity, scratch assay cell migration, immunocytochemistry α-smooth muscle actin (α-SMA), and collagen gel fibroblast contraction. All steroidogenic components were present, although only keratinocytes expressed the organic anion organic anion transporter protein (OATP) 2B1 transporter. Both expressed the G-protein-coupled estrogen receptor (GPER1). Steroids modulated multifunctional genes, up-regulating genes important in repair and aging [angiopoietin-like 4 (ANGPTL4), chemokine (C-X-C motif) ligand 1 (CXCL1), lamin B1 (LMNB1), and thioredoxin interacting protein (TXNIP)]. DHEA-sulfate (DHEA-S), DHEA, and 17β-estradiol stimulated keratinocyte and fibroblast migration at early (4 h) and late (24-48 h) time points, suggesting involvement of genomic and nongenomic signaling. Migration was blocked by aromatase and steroid sulfatase (STS) inhibitors confirming intracrine synthesis to estrogen. Testosterone had little effect, implying it is not an intermediate. Steroids stimulated fibroblast contraction but not α-SMA expression. Mechanical wounding reduced fibroblast aromatase activity but increased keratinocyte activity, amplifying the bioavailability of intracellular estrogen. Cultured fibroblasts and keratinocytes provide a biologically relevant model system to investigate the complex pathways of sex steroid intracrinology in human skin. © FASEB.

Perfluorinated chemicals: differential toxicity, inhibition of aromatase activity and alteration of cellular lipids in human placental cells.

PubMed

Gorrochategui, Eva; Pérez-Albaladejo, Elisabet; Casas, Josefina; Lacorte, Sílvia; Porte, Cinta

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. Copyright © 2014 Elsevier Inc. All rights reserved.

[New medical treatments for painful endometriosis: CNGOF-HAS Endometriosis Guidelines].

PubMed

Legendre, G; Delbos, L; Hudon, E; Chabbert-Buffet, N; Geoffron, S; Sauvan, M; Fernandez, H; Bouet, P-E; Descamps, P

2018-03-01

The objective of this work is to evaluate the place of new treatments in the management of endometriosis outside the context of infertility. A review of the literature was conducted by consulting Medline data until July 2017. Dienogest is effective compared to placebo in short term (NP2) and long term (NP4) for the treatment of painful endometriosis. In comparison with GnRH agonists, dienogest is also effective in terms of decreased pain and improved quality of life in non-operated patients (NP2) as well as for recurrence of lesions and symptomatology postoperatively (NP2). Data on GnRH antagonists, selective progesterone receptor modulators as well as selective inhibitors (anti-TNF-α, matrix metalloprotease inhibitors, angiogenesis growth factor inhibitors) are insufficient to provide evidence of interest in clinical practice for the management of painful endometriosis (NP3). Dienogest is recommended as second-line therapy for the management of painful endometriosis (Grade B). Because of lack of evidence, aromatase inhibitors, elagolix, SERM, SPRM and anti-TNF-α are not recommended for the management of painful endometriosis (Grade C). Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant

PubMed Central

Spoerke, Jill M.; Gendreau, Steven; Walter, Kimberly; Qiu, Jiaheng; Wilson, Timothy R.; Savage, Heidi; Aimi, Junko; Derynck, Mika K.; Chen, Meng; Chan, Iris T.; Amler, Lukas C.; Hampton, Garret M.; Johnston, Stephen; Krop, Ian; Schmid, Peter; Lackner, Mark R.

2016-01-01

Mutations in ESR1 have been associated with resistance to aromatase inhibitor (AI) therapy in patients with ER+ metastatic breast cancer. Little is known of the impact of these mutations in patients receiving selective oestrogen receptor degrader (SERD) therapy. In this study, hotspot mutations in ESR1 and PIK3CA from ctDNA were assayed in clinical trial samples from ER+ metastatic breast cancer patients randomized either to the SERD fulvestrant or fulvestrant plus a pan-PI3K inhibitor. ESR1 mutations are present in 37% of baseline samples and are enriched in patients with luminal A and PIK3CA-mutated tumours. ESR1 mutations are often polyclonal and longitudinal analysis shows distinct clones exhibiting divergent behaviour over time. ESR1 mutation allele frequency does not show a consistent pattern of increases during fulvestrant treatment, and progression-free survival is not different in patients with ESR1 mutations compared with wild-type patients. ESR1 mutations are not associated with clinical resistance to fulvestrant in this study. PMID:27174596

Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant.

PubMed

Spoerke, Jill M; Gendreau, Steven; Walter, Kimberly; Qiu, Jiaheng; Wilson, Timothy R; Savage, Heidi; Aimi, Junko; Derynck, Mika K; Chen, Meng; Chan, Iris T; Amler, Lukas C; Hampton, Garret M; Johnston, Stephen; Krop, Ian; Schmid, Peter; Lackner, Mark R

2016-05-13

Mutations in ESR1 have been associated with resistance to aromatase inhibitor (AI) therapy in patients with ER+ metastatic breast cancer. Little is known of the impact of these mutations in patients receiving selective oestrogen receptor degrader (SERD) therapy. In this study, hotspot mutations in ESR1 and PIK3CA from ctDNA were assayed in clinical trial samples from ER+ metastatic breast cancer patients randomized either to the SERD fulvestrant or fulvestrant plus a pan-PI3K inhibitor. ESR1 mutations are present in 37% of baseline samples and are enriched in patients with luminal A and PIK3CA-mutated tumours. ESR1 mutations are often polyclonal and longitudinal analysis shows distinct clones exhibiting divergent behaviour over time. ESR1 mutation allele frequency does not show a consistent pattern of increases during fulvestrant treatment, and progression-free survival is not different in patients with ESR1 mutations compared with wild-type patients. ESR1 mutations are not associated with clinical resistance to fulvestrant in this study.

Chemopreventive agents alters global gene expression pattern: predicting their mode of action and targets.

PubMed

Narayanan, Bhagavathi A

2006-12-01

Chemoprevention has the potential to be a major component of colon, breast, prostate and lung cancer control. Epidemiological, experimental, and clinical studies provide evidence that antioxidants, anti-inflammatory agents, n-3 polyunsaturated fatty acids and several other phytochemicals possess unique modes of action against cancer growth. However, the mode of action of several of these agents at the gene transcription level is not completely understood. Completion of the human genome sequence and the advent of DNA microarrays using cDNAs enhanced the detection and identification of hundreds of differentially expressed genes in response to anticancer drugs or chemopreventive agents. In this review, we are presenting an extensive analysis of the key findings from studies using potential chemopreventive agents on global gene expression patterns, which lead to the identification of cancer drug targets. The summary of the study reports discussed in this review explains the extent of gene alterations mediated by more than 20 compounds including antioxidants, fatty acids, NSAIDs, phytochemicals, retinoids, selenium, vitamins, aromatase inhibitor, lovastatin, oltipraz, salvicine, and zinc. The findings from these studies further reveal the utility of DNA microarray in characterizing and quantifying the differentially expressed genes that are possibly reprogrammed by the above agents against colon, breast, prostate, lung, liver, pancreatic and other cancer types. Phenolic antioxidant resveratrol found in berries and grapes inhibits the formation of prostate tumors by acting on the regulatory genes such as p53 while activating a cascade of genes involved in cell cycle and apoptosis including p300, Apaf-1, cdk inhibitor p21, p57 (KIP2), p53 induced Pig 7, Pig 8, Pig 10, cyclin D, DNA fragmentation factor 45. The group of genes significantly altered by selenium includes cyclin D1, cdk5, cdk4, cdk2, cdc25A and GADD 153. Vitamine D shows impact on p21(Waf1/Cip1) p27 cyclin B and cyclin A1. Genomic expression profile with vitamin D indicated differential expression of gene targets such as c-JUN, JUNB, JUND, FREAC-1/FoxF1, ZNF-44/KOX7, plectin, filamin, and keratin-13, involved in antiproliferative, differentiation pathways. The agent UBEIL has a remarkable effect on cyclin D1. Curcumin mediated NrF2 pathway significantly altered p21(Waf1/Cip1) levels. Aromatase inhibitors affected the expression of cyclin D1. Interestingly, few dietary compounds listed in this review also have effect on APC, cdk inhibitors p21(Waf1/Cip1) and p27. Tea polyphenol EGCG has a significant effect on TGF-beta expression, while several other earlier studies have shown its effect on cell cycle regulatory proteins. This review article reveals potential chemoprevention drug targets, which are mainly centered on cell cycle regulatory pathway genes in cancer.

Analysis of the complex formation, interaction and electron transfer pathway between the "open" conformation of NADPH-cytochrome P450 reductase and aromatase.

PubMed

Dai, Yuejie; Zhen, Jing; Zhang, Xiuli; Zhong, Yonghui; Liu, Shaodan; Sun, Ziyue; Guo, Yue; Wu, Qingli

2015-09-01

The complex structure of human aromatase (CYP19) and the open form of ΔTGEE mutant NADPH-cytochrome P450 reductase (mCPR) was constructed using template-based protein alignment method. Dynamic simulation of formed complex was performed on NAMD 2.9, in which CHARMm all 27_prot_lipid_na force field and an explicit TIP3P water solvent model were applied. The result showed mCPR in its open conformation could steadily combine with aromatase from the proximal face. Data analysis indicates hydrogen bonds and four salt bridges on the binding surface enhance the interaction between the two protein molecules. Amino acid, Lys108 plays a key role in aromatase activity through the formation of a salt bridge with Asp147 and two hydrogen bonds with Asp147 and Gln150 in mCPR. The optimal pathway for the first electron transfer from CPR to aromatase was revealed and calculated using HARLEM software. The rates for solvent mediated and non-solvent mediated electron transfer from FMNH2 to heme were determined as 1.04×10(6)s(-)(1) and 4.86×10(5)s(-)(1) respectively, which indicates the solvent water can facilitate the electron transfer from FMNH2 to heme. This study presents a novel strategy for the study of the protein-protein interactions based on the template-based protein alignment, which may help new aromtase development targeting the electron transfer between mCPR and aromatase. Copyright © 2015 Elsevier Inc. All rights reserved.

Red wine interferes with oestrogen signalling in rat hippocampus.

PubMed

Monteiro, Rosário; Faria, Ana; Mateus, Nuno; Calhau, Conceição; Azevedo, Isabel

2008-07-01

Oestrogens have neuroprotective properties, resulting in memory and learning preservation. Red wine (RW) has been linked to neuroprotection, but mechanisms are largely unknown. The aim of this work was to test the effect of RW or 13% ethanol solution consumption on the expression of aromatase and estrogen receptors (ER) in the rat hippocampus. Beverages were supplied to male Wistar rats and after 8 weeks of treatment animals were euthanised, hippocampus was removed, aromatase expression assessed by western blotting and aromatase and ER transcription determined by RT-PCR. The effects of treatments on hippocampal aromatase activity were also determined, as well as the effect of several red wine polyphenols in hippocampal homogenates from untreated animals. Aromatase transcription was increased by ethanol (to 158+/-7%) but only significantly by RW (to 180+/-9%). No difference was found in ERalpha expression among groups, whereas RW significantly decreased ERbeta expression (to 63+/-10%). Resveratrol, quercetin, myricetin and kaempferol had no effect on aromatase activity and catechin (300 microM), epicatechin (200 microM), procyanidin extract (200 mg/L) and fractioned procyanidins (FI and FII; 200 mg/L) significantly decreased aromatase activity. The contribution of procyanidins in wine to the effect observed in aromatase was investigated in animals treated for the same period with these compounds (200 mg/L), although no effect was seen in aromatase activity, mRNA or protein levels, meaning that this group of compounds had little contribution, if any, to the effects observed. Nevertheless, the increase in aromatase expression induced by RW may corroborate the neuroprotective ability attributed to this beverage. Alterations in the relative abundance of ER expression may also play an important role in the protection.

Epigenetic Control of Gonadal Aromatase (cyp19a1) in Temperature-Dependent Sex Determination of Red-Eared Slider Turtles

PubMed Central

Matsumoto, Yuiko; Buemio, Alvin; Chu, Randy; Vafaee, Mozhgon; Crews, David

2013-01-01

In the red-eared slider turtle (Trachemys scripta), a species with temperature-dependent sex determination (TSD), the expression of the aromatase gene during gonad development is strictly limited to the female-producing temperature. The underlying mechanism remains unknown. In this study, we identified the upstream 5′-flanking region of the aromatase gene, gonad-specific promoter, and the temperature-dependent DNA methylation signatures during gonad development in the red-eared slider turtle. The 5′-flanking region of the slider aromatase exhibited sequence similarities to the aromatase genes of the American alligator, chicken, quail, and zebra finch. A putative TATA box was located 31 bp upstream of the gonad-specific transcription start site. DNA methylation at the CpG sites between the putative binding sites of the fork head domain factor (FOX) and vertebrate steroidogenic factor 1 (SF1) and adjacent TATA box in the promoter region were significantly lower in embryonic gonads at the female-producing temperature compared the male-producing temperature. A shift from male- to female-, but not from female- to male-, producing temperature changed the level of DNA methylation in gonads. Taken together these results indicate that the temperature, particularly female-producing temperature, allows demethylation at the specific CpG sites of the promoter region which leads the temperature-specific expression of aromatase during gonad development. PMID:23762231

Genetics Home Reference: aromatase excess syndrome

MedlinePlus

... Males with aromatase excess syndrome experience breast enlargement (gynecomastia) in late childhood or adolescence. The bones of ... of androgens to estrogen are responsible for the gynecomastia and limited bone growth characteristic of aromatase excess ...

Effect of mono-(2-ethylhexyl) phthalate on steroid production of human granulosa cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Reinsberg, Jochen; Wegener-Toper, Petra; Ven, Katrin van der

2009-08-15

The phthalate ester mono-(2-ethylhexyl) phthalate (MEHP) is the active metabolite of di-(2-ethylhexyl) phthalate, a high-production-volume chemical used as a plasticizer and solvent in numerous consumer products. MEHP has been demonstrated to be a reproductive toxicant in rodents decreasing estradiol and progesterone production in preovulatory granulosa cells. In the present study, we examined the effect of MEHP on steroid production of human granulosa-lutein (GL) cells. Human GL cells collected from women undergoing in vitro fertilization were cultured in medium containing FSH, hCG and 8-Br-cAMP, respectively, together with various concentrations of MEHP (0-500 {mu}mol L{sup -1}). After incubation for 48 h estradiolmore » and progesterone were assayed in the spent culture medium. Furthermore, aromatase activity and mRNA levels of GL cells were determined. Basal as well as FSH-, hCG- and 8-Br-cAMP-stimulated estradiol production of GL cells was suppressed by MEHP in a dose-dependent manner (IC{sub 50} = 105 {mu}mol L{sup -1}, 138 {mu}mol L{sup -1}, 49 {mu}mol L{sup -1} and 78 {mu}mol L{sup -1}). Furthermore aromatase activity and mRNA levels were reduced in GL cells cultured with MEHP. In contrast, MEHP did not alter the production of progesterone up to a concentration of 167 {mu}mol L{sup -1}. The present data indicate that MEHP is a specific inhibitor of estradiol production in human GL cells with a post-cAMP site of action. The inhibition of estradiol production obviously results from a reduction of aromatase activity on the transcript level. As the in vitro effective doses of MEHP are within the range of real environmental exposure levels an inhibitory effect on estrogen production in vivo seems to be possi0009b.« less

Efficacy of Exemestane in Korean Patients with Metastatic Breast Cancer after Failure of Nonsteroidal Aromatase Inhibitors

PubMed Central

Lee, June Koo; Lee, Daewon; Kim, Ji-Yeon; Lim, Yoojoo; Lee, Eunyoung; Moon, Hyeong-Gon; Kim, Tae-Yong; Han, Sae-Won; Oh, Do-Youn; Lee, Se-Hoon; Han, Wonshik; Kim, Dong-Wan; Kim, Tae-You; Noh, Dong-Young

2013-01-01

Purpose Exemestane has shown good efficacy and tolerability in postmenopausal women with hormone receptor-positive metastatic breast cancer. However, clinical outcomes in Korean patients have not yet been reported. Methods Data on 112 postmenopausal women with metastatic breast cancer were obtained retrospectively. Clinicopathological characteristics and treatment history were extracted from medical records. All patients received 25 mg exemestane daily until objective disease progression. Progression-free survival (PFS) was the primary endpoint, and secondary endpoints were overall survival (OS), objective response rate (ORR), and clinical benefit rate (CBR=complete response+partial response+stable disease for 6 months). Results The median age of the subjects was 55 years (range, 28-76 years). Exemestane treatment resulted in a median PFS of 5.7 months (95% confidence interval [CI], 4.4-7.0 months) and median OS of 21.9 months (95% CI, 13.6-30.3 months). ORR was 6.4% and CBR was 46.4% for the 110 patients with evaluable lesions. Symptomatic visceral disease was independently associated with shorter PFS (hazard ratio, 3.611; 95% CI, 1.904-6.848; p<0.001), compared with bone-dominant disease in a multivariate analysis of PFS after adjusting for age, hormone receptor, human epidermal growth factor receptor 2, Ki-67 status, dominant metastasis site, and sensitivity to nonsteroidal aromatase inhibitor (AI) treatment. Sensitivity to previous nonsteroidal AI treatment was not associated with PFS, suggesting no cross-resistance between exemestane and nonsteroidal AIs. Conclusion Exemestane was effective in postmenopausal Korean women with hormone receptor-positive metastatic breast cancer who failed previous nonsteroidal AI treatment. PMID:23593084

Association between self-report adherence measures and oestrogen suppression among breast cancer survivors on aromatase inhibitors.

PubMed

Brier, Moriah J; Chambless, Dianne; Gross, Robert; Su, H Irene; DeMichele, Angela; Mao, Jun J

2015-09-01

Poor adherence to oral adjuvant hormonal therapy for breast cancer is a common problem, but little is known about the relationship between self-report adherence measures and hormonal suppression. We evaluated the relationship of three self-report measures of medication adherence and oestrogen among patients on aromatase inhibitors (AIs). We recruited 235 women with breast cancer who were prescribed AI therapy. Participants self-reported AI adherence by completing the following: (1) a single item asking whether they took an AI in the last month, (2) a modified Morisky Medication Adherence Scale-8 (MMAS-8) and (3) the Visual Analog Scale (VAS). Serum estrone and estradiol were analysed using organic solvent extraction and Celite column partition chromatography, followed by radioimmunoassay. Ten percent of participants reported they had not taken an AI in the last month and among this group, median estrone (33.2 pg/ml [interquartile range (IQR)=22.3]) and estradiol levels (7.2 pg/mL [IQR=3.3]) were significantly higher than those in participants who reported AI use (median estrone=11.5 pg/mL [IQR=4.9]; median estradiol=3.4 pg/mL [IQR=2.1]; p<0.001). This relationship held when controlling for race and AI drug type. A single-item monthly-recall adherence measure for AIs was associated with oestrogen serum levels. This suggests that patient-reported monthly adherence may be a useful measure to identify early non-adherence behaviour and guide interventions to improve patient adherence to hormonal treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cost-effectiveness of dual-energy X-ray absorptiometry plus antiresorptive treatment in Australian women with breast cancer who receive aromatase inhibitors.

PubMed

Sowa, P Marcin; Downes, Martin J; Gordon, Louisa G

2017-03-01

Postmenopausal women with breast cancer on aromatase inhibitor (AI) treatment are at increased risk of bone mineral density loss, which may lead to minimal trauma fractures. We examined the cost-effectiveness of dual energy X-ray absorptiometry (DXA) with antiresorptive (AR) therapy compared with fracture risk assessment, lifestyle advice, and vitamin supplementation. We used a hypothetical Markov cohort model of lifetime duration for 60-year-old women with early stage breast cancer receiving AIs. The data to inform the model came from medical literature, epidemiological reports, and costing data sets. Two eligibility scenarios for AR therapy were considered: (A) osteoporosis and (B) osteopenia or osteoporosis. The main outcomes were incremental cost per quality-adjusted life years gained and cumulative fractures per 1000 women, calculated relative to the comparator. Key aspects of the model were explored in sensitivity analyses. Due to relatively low effectiveness gains, the outcomes were primarily driven by the costs. The incremental cost per quality-adjusted life year gained was A$47,556 and A$253,000 for scenarios A and B, respectively. The numbers of fractures avoided were 56 and 77 per 1000 women, respectively. The results were most sensitive to the initial probability of osteoporosis, baseline risk of fracture, and cohort starting age. Compared with risk assessment and lifestyle advice only, a DXA scan followed by an AR treatment is potentially cost-effective for women aged 60 and over undergoing AI therapy for early breast cancer. However, the number of fractures averted through this intervention is small.

Isolation of chicken homolog of the FOXL2 gene and comparison of its expression patterns with those of aromatase during ovarian development.

PubMed

Govoroun, Marina S; Pannetier, Maëlle; Pailhoux, Eric; Cocquet, Julie; Brillard, Jean-Pierre; Couty, Isabelle; Batellier, Florence; Cotinot, Corinne

2004-12-01

Mutations in the forkhead transcription factor gene FOXL2 are involved in ovarian failure, which occurs in human BPES syndrome. This syndrome presents a sexually dimorphic expression, specific to the ovary in several vertebrates. We cloned the open reading frame of chicken FOXL2 (cFoxL2) and studied cFoxL2 expression in developing gonads and during adulthood to examine the role of FOXL2 in ovarian differentiation and function in birds. The spatial and temporal dynamics of cFoxL2 and aromatase expression were analyzed in parallel by using real-time quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry in attempt to investigate the possible role of cFoxL2 in the regulation of aromatase. The expression patterns of cFoxL2 and aromatase transcripts were highly correlated during the sex-differentiation period (4.7-12.7 days of incubation). Aromatase and cFoxL2 proteins were colocalized in the medullar part of female gonads on embryonic day 14. Fourteen days after hatching, cFoxL2 protein was mainly detected in granulosa cells of developing follicles. In adult ovary follicular envelopes, apart from granulosa cells, cFoxL2 transcript and protein were detected at lower levels in theca cells where aromatase was present. A high level of cFoxL2 transcription was also observed in maturing and ovulated oocytes. Our results confirm that FoxL2 is an early regulator of ovarian development in birds and may be involved in aromatase transcription regulation. Copyright (c) 2004 Wiley-Liss, Inc.

A peptide derived from alpha-fetoprotein inhibits the proliferation induced by estradiol in mammary tumor cells in culture.

PubMed

Sierralta, Walter D; Epuñan, Maria J; Reyes, José M; Valladares, Luis E; Andersen, Thomas T; Bennett, James A; Jacobson, Herbert I; Pino, Ana M

2008-01-01

This study was aimed to obtain additional information on the activity of a cyclized 9-amino acid peptide (cP) containing the active site of alpha fetoprotein, which inhibits the estrogen-stimulated proliferation of tumor cells in culture and of xenografts in immunodeficient mice. Breast cancer cells cultured in the presence of 2 nM estradiol were exposed to cP for different periods and their proliferation, estradiol binding parameters, clustering tendency and expression of E-cadherin and p21Cip1 were analyzed by biochemical and cell biology methods. The proliferation of MCF7 cells was significantly decreased by the addition of 2 microg/ml cP to the medium. cP did not increase cell death rate nor alter the number of binding sites for estradiol nor the endogenous aromatase activity of MCF7 cells. cP also decreased the proliferation of estrogen-dependent ZR75-1 cells but had no effect on estrogen-independent MDA-MB-231 cells. An increased nuclear p21Cip1 expression detected after cP treatment suggests that cP slows MCF7 cell proliferation via this regulator. We propose that cP could represent a novel breast cancer therapeutic agent whose mechanism of action is different from that of tamoxifen or of inhibitors of aromatase.

Sex steroid receptors in male human bladder: expression and biological function.

PubMed

Chavalmane, Aravinda K; Comeglio, Paolo; Morelli, Annamaria; Filippi, Sandra; Fibbi, Benedetta; Vignozzi, Linda; Sarchielli, Erica; Marchetta, Matilde; Failli, Paola; Sandner, Peter; Saad, Farid; Gacci, Mauro; Vannelli, Gabriella B; Maggi, Mario

2010-08-01

In male, lower urinary tract symptoms (LUTS) have been associated, beside benign prostatic hyperplasia, to some unexpected comorbidities (hypogonadism, obesity, metabolic syndrome), which are essentially characterized by an unbalance between circulating androgens/estrogens. Within the bladder, LUTS are linked to RhoA/Rho-kinase (ROCK) pathway overactivity. To investigate the effects of changing sex steroids on bladder smooth muscle. ER α, ER β, GPR30/GPER1 and aromatase mRNA expression was analyzed in male genitourinary tract tissues, and cells isolated from bladder, prostate, and urethra. Estrogen and G1 effect on RhoA/ROCK signaling output like cell migration, gene expression, and cytoskeletal remodeling, and [Ca(2+) ](i) was also studied in hB cells. Contractile studies on bladder strips from castrated male rats supplemented with estradiol and testosterone was also performed. The effects of classical (ER α, ER β) and nonclassical (GPR30/GPER1) estrogen receptor ligands (17 β-estradiol and G1, respectively) and androgens on RhoA/ROCK-.mediated cell functions were studied in hB cells. Contractility studies were also performed in bladder strips from castrated male rats supplemented with testosterone or estradiol. Aromatase and sex steroid receptors, including GPR30, were expressed in human bladder and mediates several biological functions. Both 17 β-estradiol and G1 activated calcium transients and induced RhoA/ROCK signaling (cell migration, cytoskeleton remodeling and smooth muscle gene expression). RhoA/ROCK inhibitors blunted these effects. Estrogen-, but not androgen-supplementation to castrated rats increased sensitivity to the ROCK inhibitor, Y-27632 in isolated bladder strips. In hB cells, testosterone elicited effects similar to estrogen, which were abrogated by blocking its aromatization through letrozole. Our data indicate for the first time that estrogen-more than androgen-receptors up-regulate RhoA/ROCK signaling. Since an altered estrogen/androgen ratio characterizes conditions, such as aging, obesity and metabolic syndrome, often associated to LUTS, we speculate that a relative hyperestrogenism may induce bladder overactivity through the up-regulation of RhoA/ROCK pathway. © 2010 International Society for Sexual Medicine.

Differential responsiveness of luteinized human granulosa cells to gonadotropins and insulin-like growth factor I for induction of aromatase activity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Christman, G.M.; Randolph, J.F. Jr.; Peegel, H.

1991-06-01

The objective of this study was to examine the in vitro responsiveness of cultured luteinized human granulosa cells over time to insulin-like growth factor 1 (IGF-1), human follicle-stimulating hormone (FSH), and human chorionic gonadotropin (hCG) for the induction of aromatase activity. Granulosa cells were retrieved from preovulatory follicles in patients undergoing in vitro fertilization. Cells were cultured for a period of 72 hours or 10 days. The ability of hCG, human FSH, and/or IGF-I to induce aromatase activity was assayed by the stereospecific release of tritium from (1B-3H)androstenedione. Short-term cultures (72 hours) demonstrated a marked rise in aromatase activity inmore » 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.« less

A game of two? Gene expression analysis of brain (cyp19a1b) and gonadal (cyp19a1a) aromatase in females of a Neotropical cichlid fish through the parental care period and removal of the offspring.

PubMed

Ramallo, Martín R; Honji, Renato M; Birba, Agustina; Morandini, Leonel; Varela, María L; Genovese, Griselda; Moreira, Renata G; Somoza, Gustavo M; Pandolfi, Matías

2017-10-01

For many species parental behavior is essential for the survival of the offspring. While the ultimate causes of teleost parental behavior have been widely studied, comparatively little is known about its proximate causes. The aim of this study was to analyze the yet unexplored, potential dual role of brain and gonadal aromatases, the enzymes responsible for the conversion of androgens to estrogens in the brains and gonads of teleosts, respectively, on the different stages of the maternal care period of the biparental cichlid Cichlasoma dimerus, locally known as chanchita. By immunohistochemistry we analyzed the neural distribution of brain aromatase and observed it exclusively within the forebrain, including areas involved in the regulation of parental behavior. We next analyzed the gene expression of brain aromatase in the brain, and gonadal aromatase in the ovary, of female chanchitas through the parental care period. To further characterize the physiological environment associated to maternal care, we also evaluated sex steroid levels (17β-estradiol, testosterone and 11-ketotestoterone) and ovarian follicle percentage. The onset of parental behavior specifically downregulated sex steroids synthesis and the rate of ovarian maturation, as denoted by a more than 10-fold decrease in steroid levels and delayed detection of mature follicles in females with offspring, compared to females which eggs were removed. Gene expression levels of both aromatases were independent of maternal care at the evaluated time points, even though they varied during the parental care period. Copyright © 2017 Elsevier Inc. All rights reserved.

Gonadal expression of Sf1 and aromatase during sex determination in the red-eared slider turtle (Trachemys scripta), a reptile with temperature-dependent sex determination.

PubMed

Ramsey, Mary; Shoemaker, Christina; Crews, David

2007-12-01

Many egg-laying reptiles have temperature-dependent sex determination (TSD), where the offspring sex is determined by incubation temperature during a temperature-sensitive period (TSP) in the middle third of development. The underlying mechanism transducing a temperature cue into an ovary or testis is unknown, but it is known that steroid hormones play an important role. During the TSP, exogenous application of estrogen can override a temperature cue and produce females, while blocking the activity of aromatase (Cyp19a1), the enzyme that converts testosterone to estradiol, produces males from a female-biased temperature. The production of estrogen is a key step in ovarian differentiation for many vertebrates, including TSD reptiles, and temperature-based differences in aromatase expression during the TSP may be a critical step in ovarian determination. Steroidogenic factor-1 (Sf1) is a key gene in vertebrate sex determination and regulates many steroidogenic enzymes, including aromatase. We find that Sf1 and aromatase are differentially expressed during sex determination in the red-eared slider turtle, Trachemys scripta elegans. Sf1 is expressed at higher levels during testis development while aromatase expression increases during ovary determination. We also assayed Sf1 and aromatase response to sex-reversing treatments via temperature or the modulation of estrogen availability. Sf1 expression was redirected to low-level female-specific patterns with feminizing temperature shift or exogenous estradiol application and redirected to more intense male-specific patterns with male-producing temperature shift or inhibition of aromatase activity. Conversely, aromatase expression was redirected to more intense female-specific patterns with female-producing treatment and redirected toward diffuse low-level male-specific patterns with masculinizing sex reversal. Our data do not lend support to a role for Sf1 in the regulation of aromatase expression during slider turtle sex determination, but do support a critical role for estrogen in ovarian development.

Marked increase of final height by long-term aromatase inhibition in a boy with idiopathic short stature.

PubMed

Krebs, Andreas; Moske-Eick, Olaf; Doerfer, Jürgen; Roemer-Pergher, Cordula; van der Werf-Grohmann, Natascha; Schwab, Karl Otfried

2012-01-01

Growth hormone (GH) is the most frequently used treatment in children with idiopathic short stature (ISS). Aromatase inhibitor (AI) therapy is still in an experimental state, and both final height (FH) and long-term efficacy data in ISS have not been published. We present a 14.5-year-old boy with ISS and a height of 142.7 cm [standard deviation score (SDS) -2.79]. Based on the baseline bone age (BA) of 13.5-14 years, his predicted adult height (PAH) by Bayley/Pinneau was 154 cm (SDS -3.77)-158.2 (SDS -3.15). After a 5-year letrozole monotherapy, FH was 169 cm (SDS -1.57) showing a height difference between PAH and FH from 10.8 to 15 cm. No permanent side effects of the medication have been observed. Both a transient occurrence and a spontaneous recovery of decreased bone mineral apparent density were seen, verified by dual-energy X-ray absorptiometry. Spinal magnetic resonance imaging revealed no vertebral abnormalities. All therapy might be an effective and low-cost alternative to the use of GH. Further controlled trials should prove efficacy and safety of long-term AI therapy in boys with ISS.

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

PubMed

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

2016-01-05

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. On the basis of this targeted metabolomic approach, the administration of 6-OXO and ATD could be detected for much longer relative to that of the conventional direct detection approach.

Different patterns in the risk of newly developed fatty liver and lipid changes with tamoxifen versus aromatase inhibitors in postmenopausal women with early breast cancer: A propensity score-matched cohort study.

PubMed

Hong, Namki; Yoon, Han Gyul; Seo, Da Hea; Park, Seho; Kim, Seung Il; Sohn, Joo Hyuk; Rhee, Yumie

2017-09-01

Management of metabolic complications of long-term adjuvant endocrine therapy in early breast cancer remained an unmet need. We aimed to compare the effects of tamoxifen (TMX) and aromatase inhibitors (AIs) on the risk of fatty liver in conjunction with longitudinal changes in the serum lipid parameters. Among 1203 subjects who were taking adjuvant TMX or AI (anastrozole or letrozole) without fatty liver at baseline, those taking TMX or AI were 1:1 matched on the propensity score. The primary outcome was newly developed fatty liver detected on annual liver ultrasonography. Among 328 matched subjects (mean age 53.5 years, body mass index 22.9 kg/m 2 ), 62 cases of fatty liver in the TMX group and 41 cases in the AI group were detected in a total of 987.4 person-years. The incidence rate of fatty liver was higher in the TMX group than in the AI group (128.7 versus 81.1 per 1000 person-years, P = 0.021), particularly within the first 2 years of therapy. TMX was associated with an increased 5-year risk of newly developed fatty liver (adjusted hazard ratio 1.61, P = 0.030) compared with AI independent of obesity and cholesterol level. Subjects who developed fatty liver had higher triglycerides (TGs) and lower high-density lipoprotein cholesterol (HDL-C) level at baseline than those without, which was sustained during follow-up despite the serum cholesterol-lowering effect of TMX. TMX independently increased the 5-year risk of newly developed fatty liver compared with AI in postmenopausal women with early breast cancer. Our findings suggest the need for considering the risk of fatty liver as a different adverse event profile between AI and TMX, particularly in patients with obesity, high TGs and low HDL-C. Copyright © 2017 Elsevier Ltd. All rights reserved.

Breast Cancer Chemoprevention: A Network Meta-Analysis of Randomized Controlled Trials.

PubMed

Mocellin, Simone; Pilati, Pierluigi; Briarava, Marta; Nitti, Donato

2016-02-01

Several agents have been advocated for breast cancer primary prevention. However, few of them appear effective, the associated severe adverse effects limiting their uptake. We performed a comprehensive search for randomized controlled trials (RCTs) reporting on the ability of chemoprevention agents (CPAs) to reduce the incidence of primary breast carcinoma. Using network meta-analysis, we ranked CPAs based simultaneously on efficacy and acceptability (an inverse measure of toxicity). All statistical tests were two-sided. We found 48 eligible RCTs, enrolling 271 161 women randomly assigned to receive either placebo or one of 21 CPAs. Aromatase inhibitors (anastrozole and exemestane, considered a single CPA class because of the lack of between-study heterogeneity; relative risk [RR] = 0.468, 95% confidence interval [CI] = 0.346 to 0.634), arzoxifene (RR = 0.415, 95% CI = 0.253 to 0.682), lasofoxifene (RR = 0.208, 95% CI = 0.079 to 0.544), raloxifene (RR = 0.572, 95% CI = 0.372 to 0.881), tamoxifen (RR = 0.708, 95% CI = 0.595 to 0.842), and tibolone (RR = 0.317, 95% CI = 0.127 to 0.792) were statistically significantly associated with a therapeutic effect, which was restricted to estrogen receptor-positive tumors of postmenopausal women (except for tamoxifen, which is active also during premenopause). Network meta-analysis ranking showed that the new selective estrogen receptor modulators (SERMs) arzoxifene, lasofoxifene, and raloxifene have the best benefit-risk ratio. Aromatase inhibitors and tamoxifen ranked second and third, respectively. These results provide physicians and health care regulatory agencies with RCT-based evidence on efficacy and acceptability of currently available breast cancer CPAs; at the same time, we pinpoint how much work still remains to be done before pharmacological primary prevention becomes a routine option to reduce the burden of this disease. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Synaptic long-term potentiation and depression in the rat medial vestibular nuclei depend on neural activation of estrogenic and androgenic signals.

PubMed

Scarduzio, Mariangela; Panichi, Roberto; Pettorossi, Vito Enrico; Grassi, Silvarosa

2013-01-01

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.

Optimal prophylactic and definitive therapy for bicalutamide-induced gynecomastia: results of a meta-analysis

PubMed Central

Tunio, M.A.; Al-Asiri, M.; Al-Amro, A.; Bayoumi, Y.; Fareed, M.

2012-01-01

Objective Bicalutamide is approved as an adjuvant to primary treatments (radical prostatectomy or radiotherapy) or as monotherapy in men with locally advanced, nonmetastatic prostate cancer (pca). However, this treatment induces gynecomastia in most patients, which often results in treatment discontinuation. Optimal therapy for these breast events is not known so far. We undertook a meta-analysis to assess the efficacy of various treatment options for bicalutamide-induced gynecomastia. Methods The medline, cancerlit, and Cochrane library databases were searched and the Google search engine was used to identify prospective and retrospective controlled studies published in English from January 2000 to December 2010 comparing prophylactic or curative treatment options with a control group (no treatment) for pca patients who developed bicalutamide-induced gynecomastia. Radiotherapy-induced cardiotoxicity was also evaluated. Results The search identified nine controlled trials with a total patient population of 1573. Pooled results from prophylactic trials showed a significant reduction of gynecomastia in pca patients treated with prophylactic tamoxifen 20 mg daily (odds ratio: 0.06; 95% confidence interval: 0.05 to 0.09; p = 0.09), and pooled results from treatment trials showed a significant response of gynecomastia to definitive radiotherapy (odds ratio: 0.06; 95% confidence interval: 0.01 to 0.24; p < 0.0001). Aromatase inhibitors and weekly tamoxifen were not found to be effective as prophylactic and curative options. For the radiotherapy, skin-to-heart distance was found to be an important risk factor for cardiotoxicity (p = 0.006). A funnel plot of the meta-analysis showed significant heterogeneity (Egger test p < 0.00001) because of low sample size. Conclusions Our meta-analysis suggests using prophylactic tamoxifen 20 mg daily as the first-line preventive measure and radiotherapy as the first-line treatment option for bicalutamide-induced gynecomastia. Aromatase inhibitors and weekly tamoxifen are not recommended. PMID:22876157

Hippocampal Aromatization Modulates Spatial Memory and Characteristics of the Synaptic Membrane in the Male Zebra Finch

PubMed Central

Makeyeva, Yekaterina V.; Paitel, Elizabeth R.; Pedersen, Alyssa L.; Hon, Angel T.; Gunderson, Jordan A.; Saldanha, Colin J.

2017-01-01

The estrogen-synthesizing enzyme aromatase is abundant at the synapse in the zebra finch hippocampus (HP), and its inhibition impairs spatial memory function. To more fully test the role of local estradiol (E2) synthesis in memory, the HP of adult male zebra finches was exposed to either control pellets or those containing the aromatase inhibitor 1,4,6-androstatriene-3,17-dione (ATD), ATD and E2, ATD and the G protein-coupled estrogen receptor (GPER) agonist G1, or the antagonist G15 alone. Birds were tested for spatial memory acquisition and performance, and HP levels of the postsynaptic protein PSD95 were measured. ATD-treated birds took longer to reach criterion than control birds, whereas acquisition in ATD+E2 and ATD+G1 birds was indistinguishable from control and ATD treatments. Interestingly, all G15 birds failed to acquire the task. Following a retention interval, ATD birds took the longest to reach the (formerly) baited cup and made the most mistakes. ATD+E2 animals displayed the lowest retention latencies and made fewer mistakes than ATD-treated birds, and ATD+G1 birds did not significantly differ from controls in retention latencies. The amount of PSD95 in the HP was lowest in ATD-treated animals compared with birds with silicone-only–implanted craniotomies, ATD+E2, and ATD+G1 birds, who did not differ in this expression. Thus, spatial memory acquisition and performance appear aromatase and E2 dependent, an effect more reliably revealed after consolidation and/or recall compared to acquisition. E2 may exert this effect via GPERs, resulting in an increase in PSD95 levels that may modify receptor activity or intracellular signaling pathways to increase synaptic strength. PMID:28324066

Hippocampal Aromatization Modulates Spatial Memory and Characteristics of the Synaptic Membrane in the Male Zebra Finch.

PubMed

Bailey, David J; Makeyeva, Yekaterina V; Paitel, Elizabeth R; Pedersen, Alyssa L; Hon, Angel T; Gunderson, Jordan A; Saldanha, Colin J

2017-04-01

The estrogen-synthesizing enzyme aromatase is abundant at the synapse in the zebra finch hippocampus (HP), and its inhibition impairs spatial memory function. To more fully test the role of local estradiol (E2) synthesis in memory, the HP of adult male zebra finches was exposed to either control pellets or those containing the aromatase inhibitor 1,4,6-androstatriene-3,17-dione (ATD), ATD and E2, ATD and the G protein-coupled estrogen receptor (GPER) agonist G1, or the antagonist G15 alone. Birds were tested for spatial memory acquisition and performance, and HP levels of the postsynaptic protein PSD95 were measured. ATD-treated birds took longer to reach criterion than control birds, whereas acquisition in ATD+E2 and ATD+G1 birds was indistinguishable from control and ATD treatments. Interestingly, all G15 birds failed to acquire the task. Following a retention interval, ATD birds took the longest to reach the (formerly) baited cup and made the most mistakes. ATD+E2 animals displayed the lowest retention latencies and made fewer mistakes than ATD-treated birds, and ATD+G1 birds did not significantly differ from controls in retention latencies. The amount of PSD95 in the HP was lowest in ATD-treated animals compared with birds with silicone-only-implanted craniotomies, ATD+E2, and ATD+G1 birds, who did not differ in this expression. Thus, spatial memory acquisition and performance appear aromatase and E2 dependent, an effect more reliably revealed after consolidation and/or recall compared to acquisition. E2 may exert this effect via GPERs, resulting in an increase in PSD95 levels that may modify receptor activity or intracellular signaling pathways to increase synaptic strength. Copyright © 2017 Endocrine Society.

Tadalafil modulates aromatase activity and androgen receptor expression in a human osteoblastic cell in vitro model.

PubMed

Aversa, A; Fittipaldi, S; Bimonte, V M; Wannenes, F; Papa, V; Francomano, D; Greco, E A; Lenzi, A; Migliaccio, S

2016-02-01

Phosphodiesterase type-5 inhibitor (PDE5i) tadalafil administration in men with erectile dysfunction is associated with increased testosterone/estradiol ratio, leading to hypothesize a potential increased effect of androgen action on target tissues. We aimed to characterize, in a cellular model system in vitro, the potential modulation of aromatase and sex steroid hormone receptors upon exposure to tadalafil (TAD). Human osteoblast-like cells SAOS-2 were chosen as an in vitro model system since osteoblasts are target of steroid hormones. Cells were tested for viability upon TAD exposure, which increased cell proliferation. Then, cells were treated with/without TAD for several times to evaluate potential modulation in PDE5, aromatase (ARO), androgen (AR) and estrogen (ER) receptor expression. Osteoblasts express significant levels of both PDE5 mRNA and protein. Exposure of cells to increasing concentrations of TAD (10(-8)-10(-7) M) decreased PDE5 mRNA and protein expression. Also, TAD inhibited ARO mRNA and protein expression leading to an increase in testosterone levels in the supernatants. Interestingly, TAD increased total AR mRNA and protein expression and decreased ERα, with an increased ratio of AR/ER, suggesting preferential androgenic vs estrogenic pathway activation. Our results demonstrate for the first time that TAD decreases ARO expression and increases AR protein expression in human SAOS-2, strongly suggesting a new control of steroid hormones pathway by PDE5i. These findings might represent the first evidence of translational actions of PDE5i on AR, which leads to hypothesize a growing relevance of this molecule in men with prostate cancer long-term treated with TAD for sexual rehabilitation.

A Critical Period in Purkinje Cell Development Is Mediated by Local Estradiol Synthesis, Disrupted by Inflammation, and Has Enduring Consequences Only for Males.

PubMed

Hoffman, Jessica F; Wright, Christopher L; McCarthy, Margaret M

2016-09-28

Identifying and understanding critical periods in brain development is essential to decoding the long-term impact of widespread, poorly defined, and frequently occurring insults such as inflammation. Using the laboratory rat Rattus norvegicus, we have discovered a narrowly constrained critical period in Purkinje neuron development subject to dysregulation by inflammation. The onset and offset of heightened vulnerability are attributed to a tightly orchestrated gene expression profile present only during the second postnatal week and not the first or third weeks. Genes expressed during this time code for enzymes and receptors which are critical not only for prostaglandin production and activity but also for estradiol production via the aromatase enzyme and estradiol action via the α isoform of the estrogen receptor. The two synthetic pathways are connected by prostaglandin E2 (PGE2) activation of the aromatase enzyme, as we reported previously (Dean et al., 2012b) and confirm here. Dysregulation of the PGE2-estradiol pathway during the second week by treatment with PGE2 or lipopolysaccharides produces enduring consequences as a result of reduced growth of Purkinje dendritic trees and impaired juvenile social play behavior, but only in males. The deleterious consequences of inflammation locally in the cerebellum are prevented by peripheral treatment with the cyclooxygenase inhibitor nimesulide or the aromatase inhibitor formestane. These findings highlight a novel regulatory pathway that creates a critical period in brain development vulnerable to dysregulation by inflammation. The cerebellum is increasingly appreciated for its role in social, emotional, and cognitive behaviors. It is consistently and severely affected in neuropsychiatric disorders originating during development, such as autism spectrum disorder and schizophrenia. We have identified a critical period in rat development during the second week of life that is dysregulated by inflammatory insults. An intrinsic program of gene expression determines the critical period. The enduring consequences of inflammation during the second postnatal week are stunted dendrites of the cerebellum's principal neurons, Purkinje cells, and impairments in later social behavior. These changes are not evident if inflammation occurs during the first or third week, highlighting the importance of fine-grained analyses of developmental processes and the factors that influence them. Copyright © 2016 the authors 0270-6474/16/3610039-11$15.00/0.

Effect of aromatase inhibitor letrozole on the proliferation of spermatogonia by regulating the MAPK pathway.

PubMed

Wang, Shunde; Wang, Shuhong; Li, Hang; Li, Xiaoxia; Xie, Menglin; Wen, Jiayu; Li, Meicai; Long, Tengbo

2018-06-01

The molecular mechanism of the aromatase inhibitor letrozole was investigated. It promotes the proliferation of spermatogonia by regulating the mitogen-activated protein kinase (MAPK) pathway. Six different concentrations were selected for letrozole in order to incubate mouse spermatogonia [GC-1 spermatogonia (spg)] for 24, 48 and 72 h, respectively. Cell Counting Kit-8 (CCK-8) was used to observe the effect of letrozole on the proliferation of GC-1 spg cells, and the effect was further verified by cell plate clone formation assay. Reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis were used to detect the effects of letrozole on MAPK signaling pathways [Ras/extracellular signal-regulated kinase 1 (ERK1)/c-Myc], proliferation indexes [Ki-67 and proliferating cell nuclear antigen (PCNA)]. Bromodeoxyuridine (BrdU) staining was used to study the effects of letrozole and MAPK signaling pathways on cell proliferation. The results of CCK-8 showed that the proliferation rate of GC-1 spg cells was improved. Study results also revealed a significant increase in letrozole concentration along with the time of action. The results of plate clone formation assay further indicated that letrozole could significantly promote the proliferation capacity of GC-1 spg cells (p<0.05). The results of RT-PCR and western blot analysis confirmed letrozole significantly activated the expression of Ras/ERK1/c-Myc in the classical MAPK pathway. A significant increase was noted in the protein levels of Ki-67 and PCNA (p<0.05). By contrast, inhibition of the MAPK pathway resulted in a significant decrease in the levels of the above indexes (p<0.05). The number of BrdU cells in the letrozole group was also higher than that of the control group, while the number of BrdU-stained cells in the letrozole + MAPK inhibition group showed a significant decrease in comparison to the letrozole group. In conclusion, letrozole activated the MAPK signaling pathway and promoted the proliferation of mouse spermatogonia GC-1 spg cells. The present study provides a theoretical basis for the clinical application of letrozole.

Idiopathic hirsutism: local and peripheral expression of aromatase (CYP19A) and 5α-reductase genes (SRD5A1 and SRD5A2).

PubMed

Caglayan, A Okay; Dundar, Munis; Tanriverdi, Fatih; Baysal, Nuran A; Unluhizarci, Kursad; Ozkul, Yusuf; Borlu, Murat; Batukan, Cem; Kelestimur, Fahrettin

2011-08-01

To evaluate idiopathic hirsutism etiology via molecular studies testing peripheral and local aromatase and 5α-reductase expression. Assessment of the expression of messenger RNA (mRNA) for type 1 and 2,5α-reductase isoenzyme gene (SDR5A1, SDR5A2) and aromatase (CYP19A) in dermal papillae cells and peripheral blood mononuclear cells. University hospital. 28 untreated idiopathic hirsute patients and 20 healthy women (controls). Human skin biopsies and peripheral venous blood. SDR5A1, SDR5A2, CYP19A gene expression in skin biopsies and peripheral blood. A statistically significant reduction of SRD5A1, SRD5A2, and CYP19A gene expression was found in the dermal papillae cells and peripheral blood mononuclear cell between the study and control group. Further study, including protein expression and enzyme activity assays, are warranted to characterize the paradoxically low gene expression levels of local 5α-reductase and aromatase in women with idiopathic hirsutism. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Pharmacokinetics, pharmacodynamics, safety and tolerability of an intravaginal ring releasing anastrozole and levonorgestrel in healthy premenopausal women: a Phase 1 randomized controlled trial.

PubMed

Schultze-Mosgau, M-H; Waellnitz, K; Nave, R; Klein, S; Kraetzschmar, J; Rautenberg, T; Schmitz, H; Rohde, B

2016-08-01

What are suitable doses of the aromatase inhibitor anastrozole (ATZ) and the progestin levonorgestrel (LNG), when delivered to the systemic circulation by an intravaginal ring (IVR), for further clinical development as a potential new therapy for the treatment of endometriosis? Anticipated targets for pharmacokinetics, pharmacodynamics and safety/tolerability were achieved for both drug components of the IVR at the doses investigated, supporting selection of the doses to be investigated in Phase 2 studies. Aromatase is a key enzyme in the biosynthesis of estrogens and is known to increase local levels of estradiol (E2) at extragonadal sites. Up-regulation of aromatase expression has been demonstrated in endometriotic lesions and the use of oral aromatase inhibitors has been shown to reduce endometriosis-associated pelvic pain in small-scale clinical trials. This Phase 1, randomized, multicentre, parallel-group, three-arm, open-label study assessed the pharmacokinetics, pharmacodynamics, safety and tolerability of various IVRs intended for systemic drug delivery. After screening, healthy, ovulating women aged 18-35 years were randomized to use IVRs releasing one of the three ATZ/LNG dose combinations (in vitro nominal daily drug release rates on Day 29: ATZ/LNG 500 µg/20 µg [low dose], ATZ/LNG 1000 µg/30 µg [mid dose] or ATZ/LNG 1500 µg/40 µg [high dose]) for two consecutive 28-day wearing periods without a treatment break. Sixty women were included in the per protocol set. The primary variables were plasma concentrations of ATZ and LNG at the end of each treatment period and the mean size of largest follicle-like structures (FLSs) over 56 days. Serum concentrations of several hormones were also evaluated, with emphasis on E2 levels. At the end of the first treatment period, geometric mean plasma concentrations of LNG and ATZ, respectively, were 0.228 and 12.5 µg/l for the low dose, 0.269 and 19.8 µg/l for the mid dose and 0.384 and 37.3 µg/l for the high dose; results were similar at the end of the second treatment period. Over the entire treatment period, mean FLS sizes were higher in all three treatment groups than during the pretreatment cycle; more women in the mid- and high-dose groups had FLSs of at least 30 mm (32-45%) than those in the low-dose group (14-24%). Changes in the mean size of FLSs were similar to those reported for low-dose progestin-only oral contraceptives and generally resolved during the 2-month treatment period. Serum E2 levels were decreased, but only one woman in each of the mid- and high-dose groups, and no woman in the low-dose group, had a serum E2 level below 20 pg/ml in both cycles. All ATZ and LNG combinations showed good tolerability. This was an exploratory study; no formal power calculation was performed. The results of this first-in-human study of the ATZ/LNG IVR facilitated the selection of ATZ and LNG doses to be investigated in the Phase 2 studies of patients with endometriosis. The study was funded by Bayer Pharma AG. T.R. is an employee of DINOX GmbH, which received funding from Bayer Pharma AG to perform this study. M.-H.S.-M., K.W., R.N., S.K., J.K., H.S. and B.R. are or have been employees of Bayer Pharma AG. H.S. is a named inventor on EP 2 552 404 B1, a patent application relating to this work. EudraCT number: 2011-005620-18. 16 November 2011. 14 March 2012. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rivest, Patricia, E-mail: patricia.rivest@iaf.inrs.ca; Devine, Patrick J., E-mail: patrick.devine@iaf.inrs.ca; Sanderson, J. Thomas, E-mail: thomas.sanderson@iaf.inrs.c

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 expressionmore » 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 environmental contaminants.« less

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

EPA Science Inventory

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

Safety, Efficacy, and Patient Acceptability of Everolimus in the Treatment of Breast Cancer.

PubMed

Lousberg, Laurence; Jerusalem, Guy

2016-01-01

Everolimus combined with exemestane is an important treatment option for patients suffering from estrogen receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer (ABC) who have been previously treated with a nonsteroidal aromatase inhibitor (NSAI). After presentation of phase III registration trial BOLERO-2, several phase IIIb trials have been started to evaluate this regimen in a more real-world setting. Here, we review the efficacy and safety data published or presented at selected international meetings. These studies confirmed the outcome observed in the BOLERO-2 trial. Patient acceptance rate is also discussed by focusing on the permanent everolimus discontinuation rate in these trials. Factors influencing the safety profile are also reported, including the impact of age. The optimal sequence of combined therapy approaches associating targeted and endocrine therapy (ET) has yet to be determined as new treatment options such as cyclin-dependent kinase inhibitors become available. However, everolimus-exemestane remains an important treatment option with a major impact on progression-free survival (PFS) and an acceptable safety profile.

Safety, Efficacy, and Patient Acceptability of Everolimus in the Treatment of Breast Cancer

PubMed Central

Lousberg, Laurence; Jerusalem, Guy

2016-01-01

Everolimus combined with exemestane is an important treatment option for patients suffering from estrogen receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer (ABC) who have been previously treated with a nonsteroidal aromatase inhibitor (NSAI). After presentation of phase III registration trial BOLERO-2, several phase IIIb trials have been started to evaluate this regimen in a more real-world setting. Here, we review the efficacy and safety data published or presented at selected international meetings. These studies confirmed the outcome observed in the BOLERO-2 trial. Patient acceptance rate is also discussed by focusing on the permanent everolimus discontinuation rate in these trials. Factors influencing the safety profile are also reported, including the impact of age. The optimal sequence of combined therapy approaches associating targeted and endocrine therapy (ET) has yet to be determined as new treatment options such as cyclin-dependent kinase inhibitors become available. However, everolimus–exemestane remains an important treatment option with a major impact on progression-free survival (PFS) and an acceptable safety profile. PMID:28096680

Ovulation induction in women with polycystic ovary syndrome: an update.

PubMed

Bhagavath, Balasubramanian; Carson, Sandra A

2012-03-01

Infertility is frequently caused by anovulation. The affected women present with irregular menstrual cycles and the most common diagnosis is polycystic ovary syndrome. Ovulation induction is commonly used to treat these women. Clomiphene citrate (a selective estrogen receptor modulator or SERM) remains the most used medication for treating this condition. Alternatives that have been used include other SERMs such as tamoxifen, aromatase inhibitors, insulin sensitizing agents, and ovarian drilling. Evidence for and against the effectiveness of these agents has fluctuated over the last decade. Controversies surrounding the use of ovulation induction such as development of functional cysts, high-order multiple births, and development of ovarian cancer have been further studied and some controversies have almost been laid to rest in the last decade. Copyright © 2012 Mosby, Inc. All rights reserved.

Endocrine therapy for breast cancer prevention in high-risk women: clinical and economic considerations.

PubMed

Groom, Amy G; Younis, Tallal

2016-01-01

The global burden of breast cancer highlights the need for primary prevention strategies that demonstrate both favorable clinical benefit/risk profile and good value for money. Endocrine therapy with selective estrogen-receptor modulators (SERMs) or aromatase inhibitors (AIs) has been associated with a favorable clinical benefit/risk profile in the prevention of breast cancer in women at high risk of developing the disease. The available endocrine therapy strategies differ in terms of their relative reductions of breast cancer risk, potential side effects, and upfront drug acquisition costs, among others. This review highlights the clinical trials of SERMs and AIs for the primary prevention of breast cancer, and the cost-effectiveness /cost-utility studies that have examined their "value for money" in various health care jurisdictions.

Inhibition of drug metabolizing cytochrome P450s by the aromatase inhibitor drug letrozole and its major oxidative metabolite 4,4′-methanol-bisbenzonitrile in vitro

PubMed Central

Jeong, Seongwook; Woo, Margaret M.; Flockhart, David A.

2009-01-01

Purpose To determine the inhibitory potency of letrozole and its main human metabolite, 4,4′-methanol-bisbenzonitrilee, on the activities of eight cytochrome P450 (CYP) enzymes. Methods Letrozole and its metabolite were incubated with human liver microsomes (HLMs) (or expressed CYP isoforms) and NADPH in the absence (control) and presence of the test inhibitor. Results Letrozole was a potent competitive inhibitor of CYP2A6 (Ki 4.6 ± 0.05 μM and 5.0 ± 2.4 μM in HLMs and CYP2A6, respectively) and a weak inhibitor of CYP2C19 (Ki 42.2 μM in HLMs and 33.3 μM in CYP2C19), while its metabolite showed moderate inhibition of CYP2C19 and CYP2B6. Letrozole or its metabolite had negligible effect on other CYPs. Conclusions Based on the in vitro Ki values, letrozole is predicted to be a weak inhibitor of CYP2A6 in vivo. Letrozole and its major human metabolite show inhibitory activity towards other CYPs, but clinically relevant drug interactions seem less likely as the Ki values are above the therapeutic plasma concentrations of letrozole. PMID:19198839

Melasma treatment: A novel approach using a topical agent that contains an anti-estrogen and a vascular endothelial growth factor inhibitor.

PubMed

Cohen, Philip R

2017-04-01

Melasma is an acquired disorder of pigmentation that presents with asymptomatic symmetric darkening of the face. The pathogenesis of this condition is multifactorial and influenced by several factors including female sex hormones, genetic predisposition and ultraviolet light exposure. The management of melasma is usually directed at more than one of the causative etiologic factors and often incorporates a combination of topical agents, with or without the addition of physical modalities. Estrogen and angiogenesis are significant factors in the etiology of melasma. A useful addition to the therapeutic armentarium for treating melasma would include a topical agent that could effect both of these causative factors. Specifically, a topical preparation consisting of an anti-estrogen and a vascular endothelial growth factor inhibitor would accomplish this goal. Suitable candidates that target estrogen receptors and vascular endothelial growth factor are currently used in medical oncology as systemic antineoplastic agents. The anti-estrogen could be either a selective estrogen receptor modulator (such as tamoxifen or raloxifene) or an aromatase inhibitor (such as anastrozole or letrozole or exemestane). The vascular endothelial growth factor inhibitor would be bevacizumab. In conclusion, a novel-topically administered-therapy for melasma would combine an anti-estrogen and a vascular endothelial growth factor inhibitor. Copyright © 2017 Elsevier Ltd. All rights reserved.

Inhibitors of steroidal cytochrome p450 enzymes as targets for drug development.

PubMed

Baston, Eckhard; Leroux, Frédéric R

2007-01-01

Cytochrome P450's are enzymes which catalyze a large number of biological reactions, for example hydroxylation, N-, O-, S- dealkylation, epoxidation or desamination. Their substrates include fatty acids, steroids or prostaglandins. In addition, a high number of various xenobiotics are metabolized by these enzymes. The enzyme 17alpha-hydroxylase-C17,20-lyase (P450(17), CYP 17, androgen synthase), a cytochrome P450 monooxygenase, is the key enzyme for androgen biosynthesis. It catalyzes the last step of the androgen biosynthesis in the testes and adrenal glands and produces androstenedione and dehydroepiandrosterone from progesterone and pregnenolone. The microsomal enzyme aromatase (CYP19) transforms these androgens to estrone and estradiol. Estrogens stimulate tumor growth in hormone dependent breast cancer. In addition, about 80 percent of prostate cancers are androgen dependent. Selective inhibitors of these enzymes are thus important alternatives to treatment options like antiandrogens or antiestrogens. The present article deals with recent patents (focus on publications from 2000 - 2006) concerning P450 inhibitor design where steroidal substrates are involved. In this context a special focus is provided for CYP17 and CYP19. Mechanisms of action will also be discussed. Inhibitors of CYP11B2 (aldosterone synthase) will also be dealt with.

Computational Modeling to Evaluate Alternative Hypotheses for the Linkage of Aromatase Inhibition to Vitellogenin Levels in Fathead Minnows

EPA Science Inventory

Aromatase converts testosterone to estradiol (E2). In fish, E2 concentrations control hepatic synthesis of the glycolipoprotein vitellogenin (VTG), an egg yolk precursor protein essential to oocyte development and larval survival. Fathead minnows were exposed to the aromatase in...

Aromatase in the brain: not just for reproduction anymore.

PubMed

Garcia-Segura, L M

2008-06-01

Aromatase, the enzyme that synthesises oestrogens from androgen precursors, is expressed in the brain, where it has been classically associated with the regulation of neuroendocrine events and behaviours linked with reproduction. Recent findings, however, have revealed new unexpected roles for brain aromatase, indicating that the enzyme regulates synaptic activity, synaptic plasticity, neurogenesis and the response of neural tissue to injury, and may contribute to control nonreproductive behaviours, mood and cognition. Therefore, the function of brain aromatase is not restricted to the regulation of reproduction as previously thought.

Brain aromatase: roles in reproduction and neuroprotection.

PubMed

Roselli, Charles F

2007-01-01

It is well established that aromatization constitutes an essential part of testosterone's signaling pathway in brain and that estrogen metabolites, often together with testosterone, organize and activate masculine neural circuits. This paper summarizes the current understanding regarding the distribution, regulation and function of brain aromatase in mammals. Data from our laboratory are presented that highlight the important function of aromatase in the regulation of androgen feedback sensitivity in non-human primates and the possible role that aromatase plays in determining the brain structure and sexual partner preferences of rams. In addition, new data is presented indicating that the capacity for aromatization in cortical astrocytes is associated with cell survival and may be important for neuroprotection. It is anticipated that a better appreciation of the physiological and pathophysiological functions of aromatase will lead to important clinical insights.

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

PubMed

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. Copyright © 2015 John Wiley & Sons, Ltd.

Quantitative (q)AOP for aromatase inhibition as case study to advance qAOP development practices

EPA Science Inventory

Here we describe how “read across” of a quantitative adverse outcome pathway (qAOP) developed with data for one chemical can be used to screen impacts of other chemicals. We developed a qAOP starting with inhibition of CYP19A (aromatase) in fathead minnows (FHM) as th...

[New approaches in the treatment of short stature].

PubMed

Zung, Amnon; Zadik, Zvi

2002-12-01

Over the past years, the efforts to improve the final height of children with short stature has yielded new modalities of therapy. New types of injection devices, mainly ready-to-use injection pens with multi-dose vials of reconstituted growth hormone (GH), have made the treatment technically easier and less stressful for the patients. A new type of slow-release GH injected once or twice a month has recently been studied. In addition, several types of synthetic GH-secretagogues were examined, with the advantage of being introduced by the oral or nasal route. The recognition of the pivotal role of estrogens in skeletal maturation and subsequent growth arrest, was the basis for the use of aromatase inhibitor in a pioneering study, with promising results. We have concluded the review with an update on the benefit of GH therapy in children with normal short stature, based on 12 studies that provided data on the final height of these children.

Inhibition of hippocampal aromatization impairs spatial memory performance in a male songbird.

PubMed

Bailey, David J; Ma, Chunqi; Soma, Kiran K; Saldanha, Colin J

2013-12-01

Recent studies have revealed the presence and regulation of aromatase at the vertebrate synapse, and identified a critical role played by presynaptic estradiol synthesis in the electrophysiological response to auditory and other social cues. However, if and how synaptic aromatization affects behavior remains to be directly tested. We have exploited 3 characteristics of the zebra finch hippocampus (HP) to test the role of synaptocrine estradiol provision on spatial memory function. Although the zebra finch HP contains abundant aromatase transcripts and enzyme activity, immunocytochemical studies reveal widespread pre- and postsynaptic, but sparse to undetectable somal, localization of this enzyme. Further, the superficial location of the avian HP makes possible the more exclusive manipulation of its neurochemical characteristics without perturbation of the neuropil and the resultant induction of astroglial aromatase. Last, as in other vertebrates, the HP is critical for spatial memory performance in this species. Here we report that local inhibition of hippocampal aromatization impairs spatial memory performance in an ecologically valid food-finding task. Local aromatase inhibition also resulted in lower levels of estradiol in the HP, but not in adjacent brain areas, and was achieved without the induction of astroglial aromatase. The observed decrement in acquisition and subsequent memory performance as a consequence of lowered aromatization was similar to that achieved by lesioning this locus. Thus, hippocampal aromatization, much of which is achieved at the synapse in this species, is critical for spatial memory performance.

Effects of transdermal testosterone gel or an aromatase inhibitor on serum concentration and pulsatility of growth hormone in older men with age-related low testosterone.

PubMed

Dias, Jenny Pena; Veldhuis, Johannes D; Carlson, Olga; Shardell, Michelle; Chia, Chee W; Melvin, Denise; Egan, Josephine M; Basaria, Shehzad

2017-04-01

Growth hormone is the major regulator of growth and body composition. Pulsatile GH secretion declines exponentially with age. Testosterone replacement is being increasingly offered to older men with age-related low testosterone. Testosterone administration has been shown to stimulate GH secretion. However, little is known about the effect of testosterone aromatization to estradiol on GH pulsatility and its impact on IGF-1 in older men. This randomized controlled proof-of-concept trial investigated the relative effects of testosterone and estradiol on GH pulsatility and IGF-1 in older men with low testosterone. Thirty-seven men, ≥65years with total testosterone <350ng/dL were randomized to 5g transdermal testosterone gel (TT), 1mg oral aromatase inhibitor (AI) or placebo daily for 12months. Primary outcome was deconvolution and approximate entropy analyses of pulsatile including basal and entropic modes of secretion performed at baseline and 3months. Secondary outcomes included IGF-1 evaluated at baseline, 3 and 6months. At 3months, mean GH and in IGF-1 were similar between the three groups. At 6months, IGF-1 significantly increased by Δ 15.3±10.3ng/ml in the TT-group compared to placebo (P=0.03). Both intervention groups significantly increased GH pulse frequency (TT-group, P=0.04; AI-group, P=0.05) compared to placebo. The GH secretory-burst mode (duration) significantly decreased in the TT-group (P=0.0018) compared to placebo while it remained unchanged in the AI-group (P=0.059). In older men, testosterone increases GH pulse frequency while the aromatization to estradiol is involved in the rise of IGF-1 levels. Copyright © 2017 Elsevier Inc. All rights reserved.

Involvement of pituitary gonadotropins, gonadal steroids and breeding season in sex change of protogynous dusky grouper, Epinephelus marginatus (Teleostei: Serranidae), induced by a non-steroidal aromatase inhibitor.

PubMed

Garcia, Carlos Eduardo de O; Araújo, Bruno C; Mello, Paulo H; Narcizo, Amanda de M; Rodrigues-Filho, Jandyr A; Medrado, Andreone T; Zampieri, Ricardo A; Floeter-Winter, Lucile M; Moreira, Renata Guimarães

2013-10-01

Two experiments were performed using the aromatase inhibitor (AI) letrozole (100mg/kg) to promote sex change, from female-to-male, in protogynous dusky grouper. One experiment was performed during the breeding season (spring) and the other at the end of the breeding season (summer). During the spring, AI promoted sex change after 9 weeks and the sperm produced was able to fertilize grouper oocytes. During the summer, the sex change was incomplete; intersex individuals were present and sperm was not released by any of the animals. Sex changed gonads had a lamellar architecture; cysts of spermatocytes and spermatozoa in the lumen of the germinal compartment. In the spring, after 4 weeks, 11ketotestosterone (11KT) levels were higher in the AI than in control fish, and after 9 weeks, coincident with semen release, testosterone levels increased in the AI group, while 11KT returned to the initial levels. Estradiol (E2) levels remained unchanged during the experimental period. Instead of decreasing throughout the period, as in control group, 17 α-OH progesterone levels did not change in the AI-treated fish, resulting in higher values after 9 weeks when compared with control fish. fshβ and lhβ gene expression in the AI animals were lower compared with control fish after 9 weeks. The use of AI was effective to obtain functional males during the breeding season. The increase in androgens, modulated by gonadotropins, triggered the sex change, enabling the development of male germ cells, whereas a decrease in E2 levels was not required to change sex in dusky grouper. Copyright © 2013 Elsevier Inc. All rights reserved.

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.

PubMed

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.

Treatment-associated musculoskeletal and vasomotor symptoms and relapse-free survival in the NCIC CTG MA.27 adjuvant breast cancer aromatase inhibitor trial.

PubMed

Stearns, Vered; Chapman, Judith-Anne W; Ma, Cynthia X; Ellis, Matthew J; Ingle, James N; Pritchard, Kathleen I; Budd, G Thomas; Rabaglio, Manuela; Sledge, George W; Le Maitre, Aurélie; Kundapur, Jessica; Liedke, Pedro E R; Shepherd, Lois E; Goss, Paul E

2015-01-20

Treatment-emergent symptoms with adjuvant tamoxifen and aromatase inhibitors (AIs) have been associated with superior recurrence-free survival (RFS). We hypothesized that MA.27 anastrozole- or exemestane-treated patients with new or worsening vasomotor and/or joint symptoms would have improved RFS. MA.27 randomly assigned 7,576 postmenopausal women with breast cancer to 5 years of anastrozole or exemestane. Patient-reported symptoms were collected using the Common Terminology Criteria for Adverse Events version 3.0 at protocol-specified baseline and 6- and 12-month clinical visits. Symptoms were considered present with either vasomotor and/or joint complaints. Associations between symptoms and baseline patient characteristics were examined with χ(2) and Fisher's exact tests. Subsequent effects of new or worsening symptoms on RFS were examined with landmark analyses and stratified univariable and multivariable Cox models. We examined the effects of 3-month symptoms arising from unplanned clinic visits as a result of severe toxicity. Patients were assessable if eligible for the MA.27 trial, received some trial therapy, and had no disease recurrence at the end of a symptom assessment period; 96% of patients (n = 7,306 patients) were included at 6 months, and 96% (n = 7,246) were included at 12 months. Thirty-four percent of patients had baseline symptoms. For patients without baseline symptoms, 25% and 52% had new symptoms by 6 and 12 months, respectively. Neither treatment-emergent nor baseline symptoms significantly impacted RFS (P > .10) in patients with or without baseline symptoms. In MA.27, anastrozole or exemestane treatment-emergent symptoms were not associated with improved RFS. Women should be supported through treatment and encouraged to remain on their AI regardless of their symptoms. © 2014 by American Society of Clinical Oncology.

Aromatase inhibitors augment nociceptive behaviors in rats and enhance the excitability of sensory neurons

PubMed Central

Robarge, Jason D.; Duarte, Djane B.; Shariati, Behzad; Wang, Ruizhong; Flockhart, David A.; Vasko, Michael R.

2016-01-01

Although aromatase inhibitors (AIs) are commonly used therapies for breast cancer, their use is limited because they produce arthralgia in a large number of patients. To determine whether AIs produce hypersensitivity in animal models of pain, we examined the effects of the AI, letrozole, on mechanical, thermal, and chemical sensitivity in rats. In ovariectomized (OVX) rats, administering a single dose of 1 or 5 mg/kg letrozole significantly reduced mechanical paw withdrawal thresholds, without altering thermal sensitivity. Repeated injection of 5 mg/kg letrozole in male rats produced mechanical, but not thermal, hypersensitivity that extinguished when drug dosing was stopped. A single dose of 5 mg/kg letrozole or daily dosing of letrozole or exemestane in male rats also augmented flinching behavior induced by intraplantar injection of 1000 nmol of adenosine 5′-triphosphate (ATP). To determine whether sensitization of sensory neurons contributed to AI-induced hypersensitivity, we evaluated the excitability of neurons isolated from dorsal root ganglia of male rats chronically treated with letrozole. Both small and medium-diameter sensory neurons isolated from letrozole-treated rats were more excitable, as reflected by increased action potential firing in response to a ramp of depolarizing current, a lower resting membrane potential, and a lower rheobase. However, systemic letrozole treatment did not augment the stimulus-evoked release of the neuropeptide calcitonin gene-related peptide (CGRP) from spinal cord slices, suggesting that the enhanced nociceptive responses were not secondary to an increase in peptide release from sensory endings in the spinal cord. These results provide the first evidence that AIs modulate the excitability of sensory neurons, which may be a primary mechanism for the effect of these drugs to augment pain behaviors in rats. PMID:27072527

Effects of letrozole on breast cancer micro-metastatic tumor growth in bone and lung in mice inoculated with murine 4T1 cells.

PubMed

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.

Randomized, Blinded Trial of Vitamin D3 for Treating Aromatase Inhibitor-Associated Musculoskeletal Symptoms (AIMSS)

PubMed Central

Shapiro, Alice C.; Adlis, Susan A.; Robien, Kim; Kirstein, Mark N.; Liang, Shuang; Richter, Sara A.; Lerner, Rachel E.

2017-01-01

Purpose To evaluate the efficacy and safety of vitamin D3 at 4,000 IU/day as a treatment option for aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) when compared with the usual care dose of 600 IU D3. Methods Single site randomized, double-blind, phase 3 clinical trial in women with AIMSS comparing change in symptoms, reproductive hormones and AI pharmacokinetics. Postmenopausal women ≥18 years with stage I-IIIA breast cancer, taking AI and experiencing AIMSS (Breast Cancer Prevention Trial Symptom Scale-Musculoskeletal Subscale ≥1.5 (BCPT-MS)) were admitted. Following randomization, 116 patients had a run-in period of 1 month on 600 IU D3, then began the randomized assignment to either 600 IU D3 (n=56) or 4,000 IU D3 (n=57) daily for 6 months. The primary endpoint was change in AIMSS from baseline (after 1 month run-in) on the BCPT-MS (general musculoskeletal pain; joint pain; muscle stiffness; range for each question: 0=not at all to 4=extremely). Results Groups had no statistically significant differences demographically or clinically. There were no discernable differences between the randomly allocated treatment groups at 6 months in measures of AIMSS, pharmacokinetics of anastrozole and letrozole, serum levels of reproductive hormones, or adverse events. Conclusions We found no significant changes in AIMSS measures between women who took 4000 IU D3 daily compared with 600 IU D3. The 4000 IU D3 did not adversely affect reproductive hormone levels or the steady state pharmacokinetics of anastrozole or letrozole. In both groups, serum 25(OH)D remained in the recommended range for bone health (≥30 ng/mL) and safety (<50 ng/mL). PMID:26868123

Endocrine therapy for postmenopausal women with hormone receptor-positive her2-negative advanced breast cancer after progression or recurrence on nonsteroidal aromatase inhibitor therapy: a Canadian consensus statement.

PubMed

Pritchard, K I; Gelmon, K A; Rayson, D; Provencher, L; Webster, M; McLeod, D; Verma, S

2013-02-01

Approximately 22,700 Canadian women were expected to be diagnosed with breast cancer in 2012. Despite improvements in screening and adjuvant treatment options, a substantial number of postmenopausal women with hormone receptor positive (hr+) breast cancer will continue to develop metastatic disease during or after adjuvant endocrine therapy. Guidance on the selection of endocrine therapy for patients with hr+ disease that is negative for the human epidermal growth factor receptor 2 (her2-) and that has relapsed or progressed on earlier nonsteroidal aromatase inhibitor (nsai) therapy is of increasing clinical importance. Exemestane, fulvestrant, and tamoxifen are approved therapeutic options in this context. Four phase iii trials involving 2876 patients-efect, sofea, confirm, and bolero-2-have assessed the efficacy of various treatment options in this clinical setting. Data from those trials suggest that standard-dose fulvestrant (250 mg monthly) and exemestane are of comparable efficacy, that doubling the dose of fulvestrant from 250 mg to 500 mg monthly results in a 15% reduction in the risk of progression, and that adding everolimus to exemestane (compared with exemestane alone) results in a 57% reduction in the risk of progression, albeit with increased toxicity. Multiple treatment options are now available to women with hr+ her2- advanced breast cancer recurring or progressing on earlier nsai therapy, although current clinical trial data suggest more robust clinical efficacy with everolimus plus exemestane. Consideration should be given to the patient's age, functional status, and comorbidities during selection of an endocrine therapy, and use of a proactive everolimus safety management strategy is encouraged.

Endocrine therapy for postmenopausal women with hormone receptor–positive her2–negative advanced breast cancer after progression or recurrence on nonsteroidal aromatase inhibitor therapy: a Canadian consensus statement

PubMed Central

Pritchard, K.I.; Gelmon, K.A.; Rayson, D.; Provencher, L.; Webster, M.; McLeod, D.; Verma, S.

2013-01-01

Approximately 22,700 Canadian women were expected to be diagnosed with breast cancer in 2012. Despite improvements in screening and adjuvant treatment options, a substantial number of postmenopausal women with hormone receptor positive (hr+) breast cancer will continue to develop metastatic disease during or after adjuvant endocrine therapy. Guidance on the selection of endocrine therapy for patients with hr+ disease that is negative for the human epidermal growth factor receptor 2 (her2–) and that has relapsed or progressed on earlier nonsteroidal aromatase inhibitor (nsai) therapy is of increasing clinical importance. Exemestane, fulvestrant, and tamoxifen are approved therapeutic options in this context. Four phase iii trials involving 2876 patients—efect, sofea, confirm, and bolero-2—have assessed the efficacy of various treatment options in this clinical setting. Data from those trials suggest that standard-dose fulvestrant (250 mg monthly) and exemestane are of comparable efficacy, that doubling the dose of fulvestrant from 250 mg to 500 mg monthly results in a 15% reduction in the risk of progression, and that adding everolimus to exemestane (compared with exemestane alone) results in a 57% reduction in the risk of progression, albeit with increased toxicity. Multiple treatment options are now available to women with hr+ her2– advanced breast cancer recurring or progressing on earlier nsai therapy, although current clinical trial data suggest more robust clinical efficacy with everolimus plus exemestane. Consideration should be given to the patient’s age, functional status, and comorbidities during selection of an endocrine therapy, and use of a proactive everolimus safety management strategy is encouraged. PMID:23443928

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

PubMed Central

Sun, Zhuoxin; Smith, Ian; Price, Karen N.; Thürlimann, Beat; Ejlertsen, Bent; Bonnefoi, Hervé; Regan, Meredith M.; Goldhirsch, Aron; Coates, Alan S.

2016-01-01

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. PMID:21892704

Impact of an osteoporosis specialized unit on bone health in breast cancer survivals treated with aromatase inhibitors.

PubMed

Martínez, Purificación; Galve, Elena; Arrazubi, Virginia; Sala, M Ángeles; Fernández, Seila; Pérez, Clara E; Arango, Juan F; Torre, Iñaki

2017-10-11

Considering the increased fracture risk in early breast cancer patients treated with aromatase inhibitors (AI), we assessed the impact of a preventive intervention conducted by a specialized osteoporosis unit on bone health at AI treatment start. Retrospective cohort of postmenopausal women who started treatment with AI after breast cancer surgical/chemotherapy treatment and were referred to the osteoporosis unit for a comprehensive assessment of bone health. Bone densitometry and fracture screening by plain X-ray were performed at the baseline visit and once a year for 5 years. The final record included 130 patients. At AI treatment start, 49% had at least one high-risk factor for fractures, 55% had osteopenia, and 39% osteoporosis. Based on the baseline assessment, 79% of patients initiated treatment with bisphosphonates, 88% with calcium, and 79% with vitamin D. After a median of 65 (50-77) months, 4% developed osteopenia or osteoporosis, and 14% improved their densitometric diagnosis. Fifteen fractures were recorded in 11 (8.5%) patients, all of them receiving preventive treatment (10 with bisphosphonates). During the follow-up period, patients with one or more high-risk factors for fracture showed a greater frequency of fractures (15% vs. 3%) and experienced the first fracture earlier than those without high-risk factors (mean of 99 and 102 months, respectively; P=0.023). The preventive intervention of a specialized unit at the start of AI treatment in breast cancer survivors allows the identification of patients with high fracture risk and may contribute to preventing bone events in these patients. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Potential utility of natural products as regulators of breast cancer-assoicated aromatase promoters

USDA-ARS?s Scientific Manuscript database

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 i...

Tissue Physiology and Pathology of Aromatase

PubMed Central

Stocco, Carlos

2011-01-01

Summary Aromatase is expressed in multiple tissues, indicating a crucial role for locally produced oestrogens in the differentiation, regulation and normal function of several organs and processes. This review is an overview of the role of aromatase in different tissues under normal physiological conditions and its contribution to the development of some oestrogen-related pathologies. PMID:22108547

Integrated approach to explore the mechanisms of aromatase inhibition and recovery in fathead minnows (Pimephales promelas)

EPA Science Inventory

Aromatase, a member of the cytochrome P450 superfamily, is a key enzyme in estradiol synthesis that catalyzes the aromatization of androgens into estrogens in ovaries. Here, we used an integrated approach to assess the mechanistic basis of the direct effects of aromatase inhibiti...

The place of targeted therapies in the management of non-small cell bronchial carcinoma. Molecular markers as predictors of tumor response and survival in lung cancer.

PubMed

Rosell, R; Moran, T; Fernanda Salazar, M; Mendez, P; De Aguirre, I; Ramirez, J-L; Isla, D; Cobo, M; Camps, C; Lopez-Vivanco, G; Alberola, V; Taron, M

2006-11-01

This review highlights the numerous molecular biology findings in the field of lung cancer with potential therapeutic impact in both the near and distant future. Abundant pre-clinical and clinical data indicate that BRCA1 mRNA expression is a differential modulator of chemotherapy sensitivity. Low levels predict cisplatin sensitivity and antimicrotubule drug resistance, and the opposite occurs with high levels. The main core of recent research has centered on epidermal growth factor receptor (EGFR) mutations and gene copy numbers. For the first time, EGFR mutations have been shown to predict dramatic responses in metastatic lung adenocarcinomas, with a threefold increase in time to progression and survival in patients receiving EGFR tyrosine-kinase inhibitors. Evidence has also been accumulated on the crosstalk between estrogen and EGFR receptor pathways, paving the way for clinical trials of EGFR tyrosine-kinase inhibitors plus aromatase inhibitors. Understanding the relevance of these findings can help to change the clinical practice in oncology towards customizing chemotherapy and targeted therapies, leading to improvement both in survival and in cost-effectiveness.

Design, conduct, and analyses of Breast International Group (BIG) 1-98: a randomized, double-blind, phase-III study comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive, early breast cancer.

PubMed

Giobbie-Hurder, Anita; Price, Karen N; Gelber, Richard D

2009-06-01

Aromatase inhibitors provide superior disease control when compared with tamoxifen as adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer. To present the design, history, and analytic challenges of the Breast International Group (BIG) 1-98 trial: an international, multicenter, randomized, double-blind, phase-III study comparing the aromatase inhibitor letrozole with tamoxifen in this clinical setting. From 1998-2003, BIG 1-98 enrolled 8028 women to receive monotherapy with either tamoxifen or letrozole for 5 years, or sequential therapy of 2 years of one agent followed by 3 years of the other. Randomization to one of four treatment groups permitted two complementary analyses to be conducted several years apart. The first, reported in 2005, provided a head-to-head comparison of letrozole versus tamoxifen. Statistical power was increased by an enriched design, which included patients who were assigned sequential treatments until the time of the treatment switch. The second, reported in late 2008, used a conditional landmark approach to test the hypothesis that switching endocrine agents at approximately 2 years from randomization for patients who are disease-free is superior to continuing with the original agent. The 2005 analysis showed the superiority of letrozole compared with tamoxifen. The patients who were assigned tamoxifen alone were unblinded and offered the opportunity to switch to letrozole. Results from other trials increased the clinical relevance about whether or not to start treatment with letrozole or tamoxifen, and analysis plans were expanded to evaluate sequential versus single-agent strategies from randomization. Due to the unblinding of patients assigned tamoxifen alone, analysis of updated data will require ascertainment of the influence of selective crossover from tamoxifen to letrozole. BIG 1-98 is an example of an enriched design, involving complementary analyses addressing different questions several years apart, and subject to evolving analytic plans influenced by new data that emerge over time.

Letrozole and norethisterone acetate versus letrozole and triptorelin in the treatment of endometriosis related pain symptoms: a randomized controlled trial

PubMed Central

2011-01-01

Background When aromatase inhibitors are used to treat premenopausal women with endometriosis, additional drugs should be used to effectively down-regulate gonadal estrogen biosynthesis. This randomized prospective open-label study compared the efficacy in treating pain symptoms and the tolerability of letrozole combined with either norethisterone acetate or triptorelin. Methods Women with pain symptoms caused by rectovaginal endometriosis were treated with letrozole (2.5 mg/day) and were randomized to also receive either oral norethisterone acetate (2.5 mg/day; group N) or intramuscular injection of triptorelin (11.25 mg every 3 months; group T). The scheduled length of treatment was 6 months. A visual analogue scale and a multidimensional categorical rating scale were used to assess the severity of pain symptoms. The volume of the endometriotic nodules was estimated by ultrasonography using virtual organ computer-aided analysis. Adverse effects of treatment were recorded. Results A total of 35 women were randomized between the two treatment protocols. Significantly more patients in group N rated their treatment as satisfactory or very satisfactory (64.7%) as compared to group T (22.2%; p = 0.028). The intensity of both non-menstrual pelvic pain and deep dyspareunia significantly decreased during treatment in both study groups, though no statistically meaningful difference between the two groups was apparent. Reduction in the volume of endometriotic nodules was significantly greater in group T than in group N. Interruption of treatment due to adverse effects significantly differed between the groups, with 8 women in group T (44.4%) and 1 woman in group N (5.9%) interrupting treatment (p = 0.018). Similarly, 14 women included in group T (77.8%) and 6 women included in group N (35.3%) experienced adverse effects of treatment (p = 0.018). During treatment, mineral bone density significantly decreased in group T but not in group N. Conclusions Aromatase inhibitors reduce the intensity of endometriosis-related pain symptoms. Combining letrozole with oral norethisterone acetate was associated with a lower incidence of adverse effects and a lower discontinuation rate than combining letrozole with triptorelin. PMID:21693037

Letrozole and norethisterone acetate versus letrozole and triptorelin in the treatment of endometriosis related pain symptoms: a randomized controlled trial.

PubMed

Ferrero, Simone; Venturini, Pier L; Gillott, David J; Remorgida, Valentino

2011-06-21

When aromatase inhibitors are used to treat premenopausal women with endometriosis, additional drugs should be used to effectively down-regulate gonadal estrogen biosynthesis. This randomized prospective open-label study compared the efficacy in treating pain symptoms and the tolerability of letrozole combined with either norethisterone acetate or triptorelin. Women with pain symptoms caused by rectovaginal endometriosis were treated with letrozole (2.5 mg/day) and were randomized to also receive either oral norethisterone acetate (2.5 mg/day; group N) or intramuscular injection of triptorelin (11.25 mg every 3 months; group T). The scheduled length of treatment was 6 months. A visual analogue scale and a multidimensional categorical rating scale were used to assess the severity of pain symptoms. The volume of the endometriotic nodules was estimated by ultrasonography using virtual organ computer-aided analysis. Adverse effects of treatment were recorded. A total of 35 women were randomized between the two treatment protocols. Significantly more patients in group N rated their treatment as satisfactory or very satisfactory (64.7%) as compared to group T (22.2%; p=0.028). The intensity of both non-menstrual pelvic pain and deep dyspareunia significantly decreased during treatment in both study groups, though no statistically meaningful difference between the two groups was apparent. Reduction in the volume of endometriotic nodules was significantly greater in group T than in group N. Interruption of treatment due to adverse effects significantly differed between the groups, with 8 women in group T (44.4%) and 1 woman in group N (5.9%) interrupting treatment (p=0.018). Similarly, 14 women included in group T (77.8%) and 6 women included in group N (35.3%) experienced adverse effects of treatment (p=0.018). During treatment, mineral bone density significantly decreased in group T but not in group N. Aromatase inhibitors reduce the intensity of endometriosis-related pain symptoms. Combining letrozole with oral norethisterone acetate was associated with a lower incidence of adverse effects and a lower discontinuation rate than combining letrozole with triptorelin.

Androgen Triggers the Pro-Migratory CXCL12/CXCR4 Axis in AR-Positive Breast Cancer Cell Lines: Underlying Mechanism and Possible Implications for the Use of Aromatase Inhibitors in Breast Cancer.

PubMed

Azariadis, Kalliopi; Kiagiadaki, Fotini; Pelekanou, Vasiliki; Bempi, Vasiliki; Alexakis, Kostas; Kampa, Marilena; Tsapis, Andreas; Castanas, Elias; Notas, George

2017-01-01

Reports regarding the role of androgen in breast cancer (BC) are conflicting. Some studies suggest that androgen could lead to undesirable responses in the presence of certain BC tumor characteristics. We have shown that androgen induces C-X-C motif chemokine 12 (CXCL12) in BC cell lines. Our aim was to identify the mechanisms regulating the phenotypic effects of androgen-induced CXCL12 on Androgen Receptor (AR) positive BC cell lines. We analyzed the expression of CXCL12 and its receptors with qPCR and ELISA and the role of Nuclear Receptor Coactivator 1 (NCOA1) in this effect. AR effects on the CXCL12 promoter was studied via Chromatin-immunoprecipitation. We also analyzed publically available data from The Cancer Genome Atlas to verify AR-CXCL12 interactions and to identify the effect or Aromatase Inhibitors (AI) therapy on CXCL12 expression and disease progression in AR positive cases. CXCL12 induction occurs only in AR-positive BC cell lines, possibly via an Androgen Response Element, upstream of the CXCL12 promoter. The steroid receptor co-regulator NCOA1 is critical for this effect. Androgen only induced the motility of p53-mutant BC cells T47D cells via upregulation of CXCR4 expression while they had no effect on wild-type p53 MCF-7 cells. Loss of CXCR4 expression and depletion of CXCL12 abolished the effect of androgen in T47D cells while inhibition of p53 expression in MCF-7 cells made them responsive to androgen and increased their motility in the presence to androgen. Patients with estrogen receptor positive (ER+)/AR+ BC treated with AIs were at increased risk of disease progression compared to ER+/AR+ non-AI treated and ER+/AR- AI treated cases. AIs may lead to unfavorable responses in some ER/AR positive BC cases, especially in patients with AR+, p53 mutant tumors. © 2017 The Author(s). Published by S. Karger AG, Basel.

Is there a role for estrogen activity assays? Recombinant cell bioassay for estrogen: Development and applications.

PubMed

Klein, Karen Oerter

2015-07-01

There are many questions which cannot be answered without a very sensitive estradiol assay. A recombinant cell bioassay (RCBA) for estradiol was developed in 1994. The sensitivity of the bioassay is 0.02-0.2 pg/ml (0.07-0.7 pmol/L), more than 20 times more sensitive than commercial RIAs and 10 times more sensitive than newer mass spectrometry assays. The RCBA for estradiol opened the door to study low levels of estradiol equivalents (EE) across the physiological spectrum of life from prepubertal children through menopause and across the spectrum from normal physiology, in boys as well as girls, to pathology, including: premature thelarche; estradiol suppression in children treated with GnRH analogues for precocious puberty; aromatase inhibition in boys with growth hormone deficiency; the differences between oral and transdermal routes of estrogen administration in girls with Turner's syndrome; women with breast cancer treated with aromatase inhibitors; and women with urogenital atrophy treated with low dose vaginal estrogen. A bioassay also allows study of endocrine disruptors, like phytoestrogens and other environmental compounds, which are relevant to public health and alternative medicine options. This paper reviews the assay and the last 20 years of applications. A bioassay for estrogen has a role because measuring biological effect is theoretically useful, increasing the understanding of physiology in addition to biochemical levels, giving different information than other assays, and opening the door to measure very low levels of estrogen activity in both humans and the environment. Copyright © 2014 Elsevier Inc. All rights reserved.

Inhibition of local estrogen synthesis in the hippocampus impairs hippocampal memory consolidation in ovariectomized female mice

PubMed Central

Tuscher, Jennifer J.; Szinte, Julia S.; Starrett, Joseph R.; Krentzel, Amanda A.; Fortress, Ashley M.; Remage-Healey, Luke; Frick, Karyn M.

2016-01-01

The potent estrogen 17β-Estradiol (E2) plays a critical role in mediating hippocampal function, yet the precise mechanisms through which E2 enhances hippocampal memory remain unclear. In young adult female rodents, the beneficial effects of E2 on memory are generally attributed to ovarian-synthesized E2. However, E2 is also synthesized in the adult brain in numerous species, where it regulates synaptic plasticity and is synthesized in response to experiences such as exposure to females or conspecific song. Although de novo E2 synthesis has been demonstrated in rodent hippocampal cultures, little is known about the functional role of local E2 synthesis in mediating hippocampal memory function. Therefore, the present study examined the role of hippocampal E2 synthesis in hippocampal memory consolidation. Using bilateral dorsal hippocampal infusions of the aromatase inhibitor letrozole, we first found that blockade of dorsal hippocampal E2 synthesis impaired hippocampal memory consolidation. We next found that elevated levels of E2 in dorsal hippocampus observed 30 min after object training were blocked by dorsal hippocampal infusion of letrozole, suggesting that behavioral experience increases acute and local E2 synthesis. Finally, aromatase inhibition did not prevent exogenous E2 from enhancing hippocampal memory consolidation, indicating that hippocampal E2 synthesis is not necessary for exogenous E2 to enhance hippocampal memory. Combined, these data are consistent with the hypothesis that hippocampally-synthesized E2 is necessary for hippocampus-dependent memory consolidation in rodents. PMID:27178577

Design, Synthesis and Biological Evaluation of4-(Imidazolylmethyl)-2-(4-methylsulfonyl phenyl)-Quinoline Derivatives as Selective COX-2 Inhibitors and In-vitro Anti-breast Cancer Agents

PubMed Central

Ghodsi, Razieh; Azizi, Ebrahim; Zarghi, Afshin

2016-01-01

A new group of 4-(Imidazolylmethyl)quinoline derivatives possessing a methylsulfonyl COX-2 pharmacophore at the para position of the C-2 phenyl ring were designed and synthesized as selective COX-2 inhibitors and in-vitroanti breast cancer agents. In-vitro COX-1 and COX-2 inhibition studies showed that all the compounds were potent and selective inhibitors of the COX-2 isozyme with IC50 values in the potent range 0.063-0.090 µM, and COX-2 selectivity indexes in the 179.9 to 547.6 range. Molecular modeling studies indicated that the methylsulfonyl substituent can be inserted into the secondary pocket of COX-2 active site for interactions with Arg513. Cytotoxicity of quinolines 9a-e against human breast cancer MCF-7 and T47D cell lines were also evaluated. All the compounds 9a-e were more cytotoxic against MCF-7 cells in comparison with those of T47D which express aromatase mRNA less than MCF-7 cells.The data showed that the increase of lipophilic properties of substituents on the C-7 and C-8 quinoline ring increased their cytotoxicity on MCF-7cells andCOX-2 inhibitory activity. Among the quinolines 9a-e, 4-((1H-Imidazol-1-yl)methyl) 7,8,9,10-tetrahydro-2-(4-methylsulfonylphenyl)-benzo[h]quinoline (9d)was identified as the most potent andselective COX-2inhibitor as well as the most cytotoxic agent against MCF-7 cells. PMID:27610157

Aromatase Activity in Sheepshead Minnow (Cyprinodon variegatus), Exposed to 17B-Trenbolone or 17B-estradiol in a Tier II Two-Generation Test

EPA Science Inventory

We tested the hypothesis that endocrine disrupting chemicals (EDCs) that alter fish reproduction will also modulate activity of the steroidogenic enzyme aromatase. There are two distinct isozymes of aromatase that have been characterized in fish, one predominating in brains and a...

Estrogen Receptor-Related Receptor α Mediates Up-Regulation of Aromatase Expression by Prostaglandin E2 in Prostate Stromal Cells

PubMed Central

Miao, Lin; Shi, Jiandang; Wang, Chun-Yu; Zhu, Yan; Du, Xiaoling; Jiao, Hongli; Mo, Zengnan; Klocker, Helmut; Lee, Chung; Zhang, Ju

2010-01-01

Estrogen receptor-related receptor α (ERRα) is an orphan member of the nuclear receptor superfamily of transcription factors. ERRα is highly expressed in the prostate, especially in prostate stromal cells. However, little is known about the regulation and function of ERRα, which may contribute to the progression of prostatic diseases. We previously found that prostaglandin E2 (PGE2) up-regulated the expression of aromatase in prostate stromal cells. Here we show that PGE2 also up-regulates the expression of ERRα, which, as a transcription factor, further mediates the regulatory effects of PGE2 on the expression of aromatase. ERRα expression was up-regulated by PGE2 in prostate stromal cell line WPMY-1, which was mediated mainly through the protein kinase A signaling pathway by PGE2 receptor EP2. Suppression of ERRα activity by chlordane (an antagonist of ERRα) or small interfering RNA knockdown of ERRα blocked the increase of expression and promoter activity of aromatase induced by PGE2. Overexpression of ERRα significantly increased aromatase expression and promoter activity, which were further augmented by PGE2. Chromatin immunoprecipitation assay demonstrated that ERRα directly bound to the aromatase promoter in vivo, and PGE2 enhanced the recruitment of ERRα and promoted transcriptional regulatory effects on aromatase expression in WPMY-1. 17β-Estradiol concentration in WPMY-1 medium was up-regulated by ERRα expression, and that was further increased by PGE2. Our results provided evidence that ERRα contributed to local estrogen production by up-regulating aromatase expression in response to PGE2 and provided further insights into the potential role of ERRα in estrogen-related prostatic diseases. PMID:20351196

Indirect androgen doping by oestrogen blockade in sports

PubMed Central

Handelsman, D J

2008-01-01

Androgens can increase muscular mass and strength and remain the most frequently abused and widely available drugs used in sports doping. Banning the administration of natural or synthetic androgens has led to a variety of strategies to circumvent the ban of the most effective ergogenic agents for power sports. Among these, a variety of indirect androgen doping strategies aiming to produce a sustained rise in endogenous testosterone have been utilized. These include oestrogen blockade by drugs that act as oestrogen receptor antagonists (antioestrogen) or aromatase inhibitors. The physiological and pharmacological basis for the effects of oestrogen blockade in men, but not women, are reviewed. PMID:18500381

Chapter 4- Fertility preservation in women with breast cancer

PubMed Central

Rodriguez-Wallberg, Kenny A.; Oktay, Kutluk

2010-01-01

Fertility preservation is an important issue for young women diagnosed with breast cancer. The most well-established options for fertility preservation in cancer patients, embryo and oocyte cryopreservation, have not been traditionally offered to breast cancer patients as estradiol rise during standard stimulation protocols may not be safe for those patients. Potentially safer stimulation protocols using tamoxifen and aromatase inhibitors induce lower levels of estradiol while similar results in terms of number of oocyte and embryo obtained to standard protocols. Cryopreservation of immature oocytes and ovarian cortical tissue, both still experimental methods, are also fertility preservation options for breast cancer patients. PMID:21048442

Primary breast cancer of the vulva: a case report.

PubMed

Diniz da Costa, Ana Teresa Minhoto; Coelho, Ana Maria; Lourenço, Alexandre Valentim; Bernardino, Margarida; Ribeirinho, Ana Luisa; Jorge, Carlos Calhaz

2012-04-01

The occurrence of primary breast cancer of the vulva is extremely rare (24 cases described in the English-language literature). We report a case of a primary breast carcinoma of the vulva. An 82-year-old woman presented with a nodule of the left labia minor, which was excised. The histologic examination revealed the presence of adenocarcinoma of mammary origin, positive for common breast markers and for estrogen and progesterone receptors. The study for orthotopic breast carcinoma was negative, as well as the study for metastatic disease. The diagnosis of primary breast carcinoma was established. Our patient was then submitted to pelvic and inguinal radiotherapy as well as an aromatase inhibitor (letrozole), and she remained completely asymptomatic. Because of the rarity of this condition, guidelines for therapy are unavailable. The management suggested in the literature is that of primary orthotopic breast neoplasm of a similar stage.

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

PubMed

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

2017-12-15

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

Effect of Letrozole, a selective aromatase inhibitor, on testicular activities in adult mice: Both in vivo and in vitro study.

PubMed

Verma, Rachna; Krishna, Amitabh

2017-01-15

The aim of present study was to evaluate the significance of estradiol (E2) in testicular activities and to find out the mechanism by which E2 regulates spermatogenesis in mice. To achieve this, both in vivo and in vitro effect of Letrozole on testis of adult mice was investigated. Letrozole-induced changes in testicular histology, cell proliferation (proliferating cell nuclear antigen; PCNA), cell survival (B cell lymphoma factor-2; Bcl2), apoptotic (cysteine-aspartic proteases; caspase-3), steroidogenic (side chain cleavage; SCC, 3β-hydroxy steroid dehydrogenase enzyme; 3β HSD, steroidogenic acute regulatory protein; StAR, aromatase and luteinizing hormone receptor; LH-R) markers, glucose level, and rate of expression of glucose transporter (GLUT) 8 and insulin receptor (IR) proteins in the testis along with changes in serum E2 and testosterone (T) levels were evaluated. Letrozole acts on testis and caused significant decrease in E2 synthesis, but increase in testosterone level and showed regressive changes in the spermatogenesis. Letrozole-induced changes in various testicular markers were compared with the changes in serum E2 level. The correlation study showed that decreased circulating E2 level may be responsible for decreased insulin receptor (IR) level in the testis. The decreased effects of insulin inhibited the glucose transport in the testis by suppressing GLUT8. The decreased level of testicular glucose may produce less lactate as energy support to developing germ cells consequently resulting in decreased cell proliferation and cell survival, but increased apoptosis. Thus, Letrozole suppresses spermatogenesis by reducing insulin sensitivity and glucose transport in the testis, but significantly increased testosterone level by promoting gonadotrophin release by decreased E2. Copyright © 2016 Elsevier Inc. All rights reserved.

Aromatase mRNA in the brain of adult green anole lizards: effects of sex and season.

PubMed

Cohen, R E; Wade, J

2011-03-01

Neural testosterone metabolism, particularly the synthesis of oestradiol (E(2)) via the aromatase enzyme, is important for sexual behaviours in many vertebrates. In green anole lizards, E(2) metabolised from testosterone facilitates female receptivity and increases sexual motivation in males. Testosterone treatment increases aromatase activity in the whole brain homogenates of gonadectomised male, but not female, anoles, which is an effect limited to the breeding season (BS). To investigate the potential for local effects of this enzyme in reproductive behaviour, we used in situ hybridisation for aromatase mRNA to examine expression during the BS and nonbreeding season (NBS) in areas of the brain that control male sexual behaviours [preoptic area (POA) and amygdala (AMY)], as well as one regulating female reproductive behaviours ventromedial hypothalamus (VMH). Males had a greater total number of aromatase-expressing cells in the POA than females, and the density of aromatase-expressing cells (number per unit volume) was greater in the VMH and AMY of females. This density was also higher during the BS than NBS in the POA. Expression of aromatase in the AMY appeared to be lateralised because trends were detected for the left side to have more total cells and more cells per unit volume than the right. These results suggest that, similar to other vertebrates, regional aromatisation of testosterone may be important for the control of sex-specific reproductive behaviours. © 2011 The Authors. Journal of Neuroendocrinology © 2011 Blackwell Publishing Ltd.

Medical Treatments for Endometriosis-Associated Pelvic Pain

PubMed Central

Luppi, Stefania; Ricci, Giuseppe

2014-01-01

The main sequelae of endometriosis are represented by infertility and chronic pelvic pain. Chronic pelvic pain causes disability and distress with a very high economic impact. In the last decades, an impressive amount of pharmacological agents have been tested for the treatment of endometriosis-associated pelvic pain. However, only a few of these have been introduced into clinical practice. Following the results of the controlled studies available, to date, the first-line treatment for endometriosis associated pain is still represented by oral contraceptives used continuously. Progestins represent an acceptable alternative. In women with rectovaginal lesions or colorectal endometriosis, norethisterone acetate at low dosage should be preferred. GnRH analogues may be used as second-line treatment, but significant side effects should be taken into account. Nonsteroidal anti-inflammatory drugs are widely used, but there is inconclusive evidence for their efficacy in relieving endometriosis-associated pelvic pain. Other agents such as GnRH antagonist, aromatase inhibitors, immunomodulators, selective progesterone receptor modulators, and histone deacetylase inhibitors seem to be very promising, but there is not enough evidence to support their introduction into routine clinical practice. Some other agents, such as peroxisome proliferator activated receptors-γ ligands, antiangiogenic agents, and melatonin have been proven to be efficacious in animal studies, but they have not yet been tested in clinical studies. PMID:25165691

Merlin, the product of NF2 gene, is associated with aromatase expression and estrogen formation in human liver tissues and liver cancer cells.

PubMed

Cocciadiferro, Letizia; Miceli, Vitale; Granata, Orazia M; Carruba, Giuseppe

2017-09-01

The product of neurofibromatosis type 2 (NF2) gene, also known as Merlin/neurofibromin 2, homeostatically regulates liver stem cells by controlling abundance and signaling of epidermal growth factor receptor (EGFR), with a mechanism independent of the Hippo pathway. We have reported that locally elevated estrogen formation, driven by abnormally high expression and function of aromatase, may be implicated in development and progression of human hepatocellular carcinoma (HCC) through activation of a rapid signaling pathway mediated by amphiregulin (AREG) and EGFR. We have recently presented a model by which the aromatase-estrogen-amphiregulin-EGFR axis is activated in response to tissue injury and/or inflammatory disease, with its alteration eventually leading to development of major human tumors (liver, breast, prostate) and other chronic diseases (diabetes, obesity, Alzheimer's and heart disease). In this study, we investigated NF2 expression in liver cancer cells and tissues in relation to aromatase expression/function, estrogen receptor (ER) status and amphiregulin. Our data indicate that NF2 expression is associated with aromatase and AREG expression, being elevated in HCC tissues and HepG2 cells, intermediate in cirrhotic tissues and Huh7 cells, and lower in nontumoral liver and HA22T cells. In addition, NF2 expression is inversely related to wild type hERα66 and proportional to the expression of the membrane-associated hERα36 splice variant, as measured by exon-specific RT-PCR analysis, both in vivo and in vitro. Furthermore, incubation with estradiol induced a significant decrease of NF2 expression in both HA22T and Huh7 cells (over 54% and 22%, respectively), while no change could be observed in HepG2 cells, this effect being inversely related to aromatase expression and activity in HCC cell lines. Based on the above combined evidence, we hypothesize that NF2 behaves as a protein sensing tissue damage and aromatase-driven local estrogen formation, eventually leading to regulation of stem cells differentiation and tissue repair. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

PubMed

Franik, Sebastian; Eltrop, Stephanie M; Kremer, Jan Am; Kiesel, Ludwig; Farquhar, Cindy

2018-05-24

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 class of drugs that were introduced for ovulation induction in 2001. Since about 2001 clinical trials have reached differing conclusions as to whether the AI letrozole is at least as effective as the first-line treatment clomiphene citrate (CC). To evaluate the effectiveness and safety of aromatase inhibitors for subfertile women with anovulatory PCOS for ovulation induction followed by timed intercourse or intrauterine insemination (IUI). We searched the following sources from inception to November 2017 to identify relevant randomised controlled trials (RCTs): the Cochrane Gynaecology and Fertility Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO, Pubmed, LILACS, Web of Knowledge, the World Health Organization (WHO) clinical trials register and Clinicaltrials.gov. We also searched the references of relevant articles. We did not restrict the searches by language or publication status. We included all RCTs of AIs used alone or with other medical therapies for ovulation induction in women of reproductive age with anovulatory PCOS. Two review authors independently selected trials, extracted the data and assessed risks of bias. We pooled studies where appropriate using a fixed-effect model to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for most outcomes, and risk differences (RDs) for ovarian hyperstimulation syndrome (OHSS). The primary outcomes were live birth and OHSS. Secondary outcomes were clinical pregnancy, miscarriage and multiple pregnancy. We assessed the quality of the evidence for each comparison using GRADE methods. This is a substantive update of a previous review. We identified 16 additional studies for the 2018 update. We include 42 RCTs (7935 women). The aromatase inhibitor letrozole was used in all studies.Letrozole compared to clomiphene citrate (CC) with or without adjuncts followed by timed intercourseLive birth rates were higher with letrozole (with or without adjuncts) compared to clomiphene citrate (with our without adjuncts) followed by timed intercourse (OR 1.68, 95% CI 1.42 to 1.99; 2954 participants; 13 studies; I 2 = 0%; number needed to treat for an additional beneficial outcome (NNTB) = 10; moderate-quality evidence). There is high-quality evidence that OHSS rates are similar with letrozole or clomiphene citrate (0.5% in both arms: risk difference (RD) -0.00, 95% CI -0.01 to 0.00; 2536 participants; 12 studies; I 2 = 0%; high-quality evidence). There is evidence for a higher pregnancy rate in favour of letrozole (OR 1.56, 95% CI 1.37 to 1.78; 4629 participants; 25 studies; I 2 = 1%; NNTB = 10; moderate-quality evidence). There is little or no difference between treatment groups in the rate of miscarriage by pregnancy (20% with CC versus 19% with letrozole; OR 0.94, 95% CI 0.70 to 1.26; 1210 participants; 18 studies; I 2 = 0%; high-quality evidence) and multiple pregnancy rate (1.7% with CC versus 1.3% with letrozole; OR 0.69, 95% CI 0.41 to 1.16; 3579 participants; 17 studies; I 2 = 0%; high-quality evidence). However, a funnel plot showed mild asymmetry, indicating that some studies in favour of clomiphene might be missing.Letrozole compared to laparoscopic ovarian drillingThere is low-quality evidence that live birth rates are similar with letrozole or laparoscopic ovarian drilling (OR 1.38, 95% CI 0.95 to 2.02; 548 participants; 3 studies; I 2 = 23%; low-quality evidence). There is insufficient evidence for a difference in OHSS rates (RD 0.00, 95% CI -0.01 to 0.01; 260 participants; 1 study; low-quality evidence). There is low-quality evidence that pregnancy rates are similar (OR 1.28, 95% CI 0.94 to 1.74; 774 participants; 5 studies; I 2 = 0%; moderate-quality evidence). There is insufficient evidence for a difference in miscarriage rate by pregnancy (OR 0.66, 95% CI 0.30 to 1.43; 240 participants; 5 studies; I 2 = 0%; moderate-quality evidence), or multiple pregnancies (OR 3.00, 95% CI 0.12 to 74.90; 548 participants; 3 studies; I 2 = 0%; low-quality evidence).Additional comparisons were made for Letrozole versus placebo, Selective oestrogen receptor modulators (SERMS) followed by intrauterine insemination (IUI), follicle stimulating hormone (FSH), Anastrozole, as well as dosage and administration protocols. There is insufficient evidence for a difference in either group of treatment due to a limited number of studies. Hence more research is necessary. Letrozole appears to improve live birth and pregnancy rates in subfertile women with anovulatory polycystic ovary syndrome, compared to clomiphene citrate. There is high-quality evidence that OHSS rates are similar with letrozole or clomiphene citrate. There is high-quality evidence of no difference in miscarriage rates or multiple pregnancy rates. There is low-quality evidence of no difference in live birth and pregnancy rates between letrozole and laparoscopic ovarian drilling, although there were few relevant studies. For the 2018 update, we added good-quality trials, upgrading the quality of the evidence.

(Anti)estrogenic effects of phytochemicals on human primary mammary fibroblasts, MCF-7 cells and their co-culture

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meeuwen, J.A. van; Korthagen, N.; Jong, P.C. de

In the public opinion, phytochemicals (PCs) present in the human diet are often considered beneficial (e.g. by preventing breast cancer). Two possible mechanisms that could modulate tumor growth are via interaction with the estrogen receptor (ER) and inhibition of aromatase (CYP19). Multiple in vitro studies confirmed that these compounds act estrogenic, thus potentially induce tumor growth, as well as aromatase inhibitory, thus potentially reduce tumor growth. It is thought that in the in vivo situation breast epithelial (tumor) cells communicate with surrounding connective tissue by means of cytokines, prostaglandins and estradiol forming a complex feedback mechanism. Recently our laboratory developedmore » an in vitro co-culture model of healthy mammary fibroblasts and MCF-7 cells that (at least partly) simulated this feedback mechanism (M. Heneweer et al., TAAP vol. 202(1): 50-58, 2005). In the present study biochanin A, chrysin, naringenin, apigenin, genistein and quercetin were studied for their estrogenic properties (cell proliferation, pS2 mRNA) and aromatase inhibition in MCF-7 breast tumor cells, healthy mammary fibroblasts and their co-culture. The proliferative potency of these compounds in the MCF-7 cells derived from their EC{sub 50}s decreased in the following order: estadiol (4*10{sup -3} nM) > biochanin A (9 nM) > genistein (32 nM) > testosterone (46 nM) > naringenin (287 nM) > apigenin (440 nM) > chrysin (4 {mu}M). The potency to inhibit aromatase derived from their IC{sub 50}s decreased in the following order: chrysin (1.5 {mu}M) > naringenin (2.2 {mu}M) > genistein (3.6 {mu}M) > apigenin (4.1 {mu}M) > biochanin A (25 {mu}M) > quercetin (30 {mu}M). The results of these studies show that these PCs can induce cell proliferation or inhibit aromatase in the same concentration range (1-10 {mu}M). Results from co-cultures did not elucidate the dominant effect of these compounds. MCF-7 cell proliferation occurs at concentrations that are not uncommon in blood of individuals using food supplements. Results also indicate that estrogenicity of these PCs is quantitatively more sensitive than aromatase inhibition. It is suggested that perhaps a more cautionary approach should be taken for these PCs before taken as food supplements.« less

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Canton, Rocio F.; Scholten, Deborah E.A.; Marsh, Goeran

2008-02-15

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 adrenocorticalmore » 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 IC{sub 50} 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 K{sub i}/K{sub i}' of 7.68/0,02 {mu}M and 5.01/0.04 {mu}M 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 OH-PBDEs have the potential to disturb steroidogenesis and indicate a potential mechanism of action of these brominated flame retardant derivatives as endocrine disruptors in humans and wildlife.« less

CoMFA, LeapFrog and blind docking studies on sulfonanilide derivatives acting as selective aromatase expression regulators.

PubMed

Gueto, Carlos; Torres, Juan; Vivas-Reyes, Ricardo

2009-09-01

Aromatase, the enzyme responsible for estrogen biosynthesis, is an attractive target in the treatment of hormone-dependent breast cancer. In this manuscript, the structure-based drug design approach of sulfonanilide analogues as potential selective aromatase expression regulators (SAERs) is described. Receptor-independent CoMFA (Comparative Molecular Field Analysis) maps were employed for generating a pseudocavity for LeapFrog calculation. A robust model, using 45 and 10 molecules in the training and test sets, respectively, was developed producing statistically significant results with cross-validated and conventional correlation coefficients of 0.656 and 0.956, respectively. This model was used to predict the activity of newly proposed molecules as SAERs candidates being two magnitude orders more potent than the previously reported compounds. Also in the present study, the computational blind docking method using eHiTS is tested on molecules study group and COX-2 enzyme. Future perspectives of the method in the screening of SAERs candidates with no COX-2 inhibitory activity are discussed.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gorrochategui, Eva; Pérez-Albaladejo, Elisabet; Casas, Josefina

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 evidencesmore » 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 lipidome.« less

Steroid receptor coactivator-1 mediates letrozole induced downregulation of postsynaptic protein PSD-95 in the hippocampus of adult female rats.

PubMed

Liu, Mengying; Huangfu, Xuhong; Zhao, Yangang; Zhang, Dongmei; Zhang, Jiqiang

2015-11-01

Hippocampus local estrogen which is converted from androgen that catalyzed by aromatase has been shown to play important roles in the regulation of learning and memory as well as cognition through action on synaptic plasticity, but the underlying mechanisms are poorly understood. Steroid receptor coactivator-1 (SRC-1) is one of the coactivators of steroid nuclear receptors; it is widely distributed in brain areas that related to learning and memory, reproductive regulation, sensory and motor information integration. Previous studies have revealed high levels of SRC-1 immunoreactivities in the hippocampus; it is closely related to the levels of synaptic proteins such as PSD-95 under normal development or gonadectomy, but its exact roles in the regulation of these proteins remains unclear. In this study, we used aromatase inhibitor letrozole in vivo and SRC-1 RNA interference in vitro to investigate whether SRC-1 mediated endogenous estrogen regulation of hippocampal PSD-95. The results revealed that letrozole injection synchronously decreased hippocampal SRC-1 and PSD-95 in a dose-dependant manner. Furthermore, when SRC-1 specific shRNA pool was applied to block the expression of SRC-1 in the primary hippocampal neuron culture, both immunocytochemistry and Western blot revealed that levels of PSD-95 were also decreased significantly. Taking together, these results provided the first evidence that SRC-1 mediated endogenous estrogen regulation of hippocampal synaptic plasticity by targeting the expression of synaptic protein PSD-95. Additionally, since letrozole is frequently used to treat estrogen-sensitive breast cancer, the above results also indicate its potential side effects in clinical administration. Copyright © 2015 Elsevier Ltd. All rights reserved.

Ki67 Proliferation Index as a Tool for Chemotherapy Decisions During and After Neoadjuvant Aromatase Inhibitor Treatment of Breast Cancer: Results From the American College of Surgeons Oncology Group Z1031 Trial (Alliance).

PubMed

Ellis, Matthew J; Suman, Vera J; Hoog, Jeremy; Goncalves, Rodrigo; Sanati, Souzan; Creighton, Chad J; DeSchryver, Katherine; Crouch, Erika; Brink, Amy; Watson, Mark; Luo, Jingqin; Tao, Yu; Barnes, Michael; Dowsett, Mitchell; Budd, G Thomas; Winer, Eric; Silverman, Paula; Esserman, Laura; Carey, Lisa; Ma, Cynthia X; Unzeitig, Gary; Pluard, Timothy; Whitworth, Pat; Babiera, Gildy; Guenther, J Michael; Dayao, Zoneddy; Ota, David; Leitch, Marilyn; Olson, John A; Allred, D Craig; Hunt, Kelly

2017-04-01

Purpose To determine the pathologic complete response (pCR) rate in estrogen receptor (ER) -positive primary breast cancer triaged to chemotherapy when the protein encoded by the MKI67 gene (Ki67) level was > 10% after 2 to 4 weeks of neoadjuvant aromatase inhibitor (AI) therapy. A second objective was to examine risk of relapse using the Ki67-based Preoperative Endocrine Prognostic Index (PEPI). Methods The American College of Surgeons Oncology Group (ACOSOG) Z1031A trial enrolled postmenopausal women with stage II or III ER-positive (Allred score, 6 to 8) breast cancer whose treatment was randomly assigned to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For the trial ACOSOG Z1031B, the protocol was amended to include a tumor Ki67 determination after 2 to 4 weeks of AI. If the Ki67 was > 10%, patients were switched to neoadjuvant chemotherapy. A pCR rate of > 20% was the predefined efficacy threshold. In patients who completed neoadjuvant AI, stratified Cox modeling was used to assess whether time to recurrence differed by PEPI = 0 score (T1 or T2, N0, Ki67 < 2.7%, ER Allred > 2) versus PEPI > 0 disease. Results Only two of the 35 patients in ACOSOG Z1031B who were switched to neoadjuvant chemotherapy experienced a pCR (5.7%; 95% CI, 0.7% to 19.1%). After 5.5 years of median follow-up, four (3.7%) of the 109 patients with a PEPI = 0 score relapsed versus 49 (14.4%) of 341 of patients with PEPI > 0 (recurrence hazard ratio [PEPI = 0 v PEPI > 0], 0.27; P = .014; 95% CI, 0.092 to 0.764). Conclusion Chemotherapy efficacy was lower than expected in ER-positive tumors exhibiting AI-resistant proliferation. The optimal therapy for these patients should be further investigated. For patients with PEPI = 0 disease, the relapse risk over 5 years was only 3.6% without chemotherapy, supporting the study of adjuvant endocrine monotherapy in this group. These Ki67 and PEPI triage approaches are being definitively studied in the ALTERNATE trial (Alternate Approaches for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer Neoadjuvant Treatment in Postmenopausal Women: A Phase III Study; clinical trial information: NCT01953588).

Analysis of Obesity-Related Factors and their Association with Aromatase Expression in Canine Malignant Mammary Tumours.

PubMed

Shin, J-I; Lim, H-Y; Kim, H-W; Seung, B-J; Ju, J-H; Sur, J-H

2016-07-01

This study was designed to investigate the role of obesity in canine malignant mammary tumours (CMMTs), by assessing aromatase expression and the regulatory roles of immune mediators such as cyclo-oxygenase-2 (COX2), prostaglandin E2 (PGE2), nuclear factor kappa beta (NF-κB), hypoxia inducible factor-1α (HIF-1α) and adipokines (i.e. leptin) in lean, optimal body weight, overweight and obese animals. Clinicopathological data, including the breed, body weight, body condition score and age and neutering status, were collected, together with histopathological characteristics (i.e. histological types, grading and lymphatic invasion). To determine the expression of each factor, immunohistochemistry was conducted with 60 samples of malignant CMMTs. CMMTs from overweight and obese animals had significantly elevated levels of PGE2, and aromatase expression correlated significantly with PGE2, NF-κB and leptin expression. However, no significant difference was observed in terms of histopathological characteristics. The results suggest that PGE2, a known obesity-related immune mediator, could be upregulated in CMMTs from overweight and obese animals. In addition, PGE2, NF-κB and leptin influenced the expression of aromatase, as observed in women. Copyright © 2016 Elsevier Ltd. All rights reserved.

A qualitative exploration of the impact of yoga on breast cancer survivors with aromatase inhibitor-associated arthralgias.

PubMed

Galantino, Mary Lou; Greene, Laurie; Archetto, Benjamin; Baumgartner, Melissa; Hassall, Paula; Murphy, Joanna Kluz; Umstetter, Jamie; Desai, Krupali

2012-01-01

Arthralgia affects postmenopausal breast cancer survivors (BCS) receiving aromatase inhibitors (AI), which may result in reduced function and long-term well-being. This is an exploratory, qualitative investigation of BCS who participated in a yoga-based program to understand impact on joint pain and various aspects of quality of life (QOL) through a yoga program. Social cognitive theory was used and provided the foundation for developing a yoga intervention through sources of efficacy information: (1) performance accomplishment, (2) structured experience, (3) verbal support from instructor and group, and (4) physical feedback. Ten postmenopausal women with stage I-III breast cancer and AI associated arthralgia (AIAA) received yoga twice a week for eight weeks for 90 minutes and were instructed to continue in a home-based yoga program. We used social cognitive theory (SCT) to structure a yoga intervention as an ongoing physical activity to manage joint pain and function. Participants completed journal reflections on their experience and received weekly phone calls. Data was collected and analyzed using qualitative methods. Member checks were completed and emergent themes were explored and agreed upon by the research team to ensure reliability and validity of data. Several emergent themes were discovered: Empowerment: Importance of Camaraderie, Community, and Sharing; Pain Relief; Increased Physical Fitness (Energy, Flexibility, and Function); Relieved Stress/Anxiety and Transferability of Yoga through Breathing. These themes were identified through instructor observation, participant observation, and weekly phone call documentation. Participants experienced an eight-week yoga intervention as an effective physical activity and support group that fostered various improvements in quality of life (QOL) and reduction in AIAA. Participants were highly motivated to improve physical fitness levels and reduce pain. This study revealed benefits from alternative forms of exercise such as yoga to provide a structure, which is transferable in other situations. Information, structured physical guidance in yoga postures, support, and feedback are necessary to foster physical activity for BCS experiencing pain. Results of this qualitative analysis indicate that interventions to support BCS with AIAA are warranted. Yoga appears to positively impact these side effects of hormonal therapies. Additional research would aid in the development of other interventions. Published by Elsevier Inc.

Synaptic Long-Term Potentiation and Depression in the Rat Medial Vestibular Nuclei Depend on Neural Activation of Estrogenic and Androgenic Signals

PubMed Central

Scarduzio, Mariangela; Panichi, Roberto; Pettorossi, Vito Enrico; Grassi, Silvarosa

2013-01-01

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. PMID:24265837

The Paradox of Oestradiol-Induced Breast Cancer Cell Growth and Apoptosis.

PubMed

Maximov, Philipp Y; Lewis-Wambi, Joan S; Jordan, V Craig

2009-05-01

High dose oestrogen therapy was used as a treatment for postmenopausal patients with breast cancer from the 1950s until the introduction of the safer antioestrogen, tamoxifen in the 1970s. The anti-tumour mechanism of high dose oestrogen therapy remained unknown. There was no enthusiasm to study these signal transduction pathways as oestrogen therapy has almost completely been eliminated from the treatment paradigm. Current use of tamoxifen and the aromatase inhibitors seek to create oestrogen deprivation that prevents the growth of oestrogen stimulated oestrogen receptor (ER) positive breast cancer cells. However, acquired resistance to antihormonal therapy does occur, but it is through investigation of laboratory models that a vulnerability of the cancer cell has been discovered and is being investigated to provide new opportunities in therapy with the potential for discovering new cancer-specific apoptotic drugs. Laboratory models of resistance to raloxifene and tamoxifen, the selective oestrogen receptor modulators (SERMs) and aromatase inhibitors demonstrate an evolution of drug resistance so that after many years of oestrogen deprivation, the ER positive cancer cell reconfigures the survival signal transduction pathways so oestrogen now becomes an apoptotic trigger rather than a survival signal. Current efforts are evaluating the mechanisms of oestrogen-induced apoptosis and how this new biology of oestrogen action can be amplified and enhanced, thereby increasing the value of this therapeutic opportunity for the treatment of breast cancer. Several synergistic approaches to therapeutic enhancement are being advanced which involve drug combinations to impair survival signaling with the use of specific agents and to impair bcl-2 that protects the cancer cell from apoptosis. We highlight the historical understanding of oestrogen's role in cell survival and death and specifically illustrate the progress that has been made in the last five years to understand the mechanisms of oestrogen-induced apoptosis. There are opportunities to harness knowledge from this new signal transduction pathway to discover the precise mechanism of this oestrogen-induced apoptotic trigger. Indeed, the new biology of oestrogen action also has significance for understanding the physiology of bone remodeling. Thus, the pathway has a broad appeal in both physiology and cancer research.

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

PubMed

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 < 0.05), and the gene expression alterations were confirmed using qRT-PCR. Ten of these 26 genes could be linked in a network associated with cellular 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.

Epigenetic activation of the prostaglandin receptor EP4 promotes resistance to endocrine therapy for breast cancer.

PubMed

Hiken, J F; McDonald, J I; Decker, K F; Sanchez, C; Hoog, J; VanderKraats, N D; Jung, K L; Akinhanmi, M; Rois, L E; Ellis, M J; Edwards, J R

2017-04-20

Approximately 75% of breast cancers express estrogen receptor α (ERα) and depend on estrogen signals for continued growth. Aromatase inhibitors (AIs) prevent estrogen production and inhibit ER signaling, resulting in decreased cancer recurrence and mortality. Advanced tumors treated with AIs almost always develop resistance to these drugs via the upregulation of alternative growth signals. The mechanisms that drive this resistance-especially epigenetic events that alter gene expression-are, however, not well understood. Genome-wide DNA methylation and expression analysis of cell line models of acquired AI resistance indicated that prostaglandin E 2 receptor 4 (PTGER4) is upregulated after demethylation in resistant cells. Knockdown and inhibitor studies demonstrate that PTGER4 is essential for estrogen-independent growth. Our exploratory analysis of downstream signaling indicates that PTGER4 likely promotes AI resistance via ligand-independent activation of the ERα-cofactor CARM1. We believe that we have discovered a novel epigenetic mechanism for altering cell signaling and acquiring endocrine therapy resistance. Our findings indicate that PTGER4 is a potential drug target in AI-resistant cancers. In addition, the epigenetic component of PTGER4 regulation suggests that further study of PTGER4 may yield valuable insights into how DNA methylation-targeted diagnoses and treatments can improve AI-resistant breast cancer treatment.

NLRP3 in Somatic Non-Immune Cells of Rodent and Primate Testes.

PubMed

Walenta, Lena; Schmid, Nina; Schwarzer, J U; Köhn, Frank-Michael; Urbanski, Henryk; Behr, Ruediger; Strauss, Leena; Poutanen, Matti; Mayerhofer, Artur

2018-06-15

NLRP3 is part of the NLRP3 inflammasome and a global sensor of cellular damage. It was recently discovered in rodent Sertoli cells. We investigated NLRP3 in mouse, human and non-human primate (marmoset and rhesus macaque) testes, employing immunohistochemistry. Sertoli cells of all species expressed NLRP3, and the expression preceded puberty. In addition, peritubular cells of the adult human testes expressed NLRP3. NLRP3 and associated genes (ASC, CASP1, IL1B) were also found in isolated human testicular peritubular cells (HTPCs) and the mouse Sertoli cell line TM4. Male infertility due to impairments of spermatogenesis may be related to sterile inflammatory events. We observed that the expression of NLRP3 was altered in the testes of patients suffering from mixed atrophy syndrome, in which tubules with impairments of spermatogenesis showed prominent NLRP3 staining. In order to explore a possible role of NLRP3 in male infertility, associated with sterile testicular inflammation, we studied a mouse model of male infertility. These human aromatase expressing transgenic mice (AROM+) develop testicular inflammation and impaired spermatogenesis during aging, and the present data show that this is associated with strikingly elevated Nlrp3 expression in the testes compared to wild type controls. Interference by aromatase inhibitor treatment significantly reduced increased Nlrp3 levels. Thus, throughout species NLRP3 is expressed by somatic cells of the testis, which are involved in testicular immune surveillance. We conclude that NLRP3 may be a novel player in testicular immune regulation. .

Inhibition of local estrogen synthesis in the hippocampus impairs hippocampal memory consolidation in ovariectomized female mice.

PubMed

Tuscher, Jennifer J; Szinte, Julia S; Starrett, Joseph R; Krentzel, Amanda A; Fortress, Ashley M; Remage-Healey, Luke; Frick, Karyn M

2016-07-01

The potent estrogen 17β-Estradiol (E2) plays a critical role in mediating hippocampal function, yet the precise mechanisms through which E2 enhances hippocampal memory remain unclear. In young adult female rodents, the beneficial effects of E2 on memory are generally attributed to ovarian-synthesized E2. However, E2 is also synthesized in the adult brain in numerous species, where it regulates synaptic plasticity and is synthesized in response to experiences such as exposure to females or conspecific song. Although de novo E2 synthesis has been demonstrated in rodent hippocampal cultures, little is known about the functional role of local E2 synthesis in mediating hippocampal memory function. Therefore, the present study examined the role of hippocampal E2 synthesis in hippocampal memory consolidation. Using bilateral dorsal hippocampal infusions of the aromatase inhibitor letrozole, we first found that blockade of dorsal hippocampal E2 synthesis impaired hippocampal memory consolidation. We next found that elevated levels of E2 in the dorsal hippocampus observed 30min after object training were blocked by dorsal hippocampal infusion of letrozole, suggesting that behavioral experience increases acute and local E2 synthesis. Finally, aromatase inhibition did not prevent exogenous E2 from enhancing hippocampal memory consolidation, indicating that hippocampal E2 synthesis is not necessary for exogenous E2 to enhance hippocampal memory. Combined, these data are consistent with the hypothesis that hippocampally-synthesized E2 is necessary for hippocampus-dependent memory consolidation in rodents. Copyright © 2016 Elsevier Inc. All rights reserved.

From molecule to behavior: Brain aromatase (cyp19a1b) characterization, expression analysis and its relation with social status and male agonistic behavior in a Neotropical cichlid fish.

PubMed

Ramallo, Martín R; Morandini, Leonel; Birba, Agustina; Somoza, Gustavo M; Pandolfi, Matías

2017-03-01

The enzyme aromatase, responsible for the conversion of C19 androgens to C18 estrogens, exists as two paralogue copies in teleost fish: Cyp19a1a mostly expressed in the gonads, referred as gonadal aromatase, and Cyp19a1b, mostly expressed in the brain, accordingly known as brain aromatase. The neural localization of Cyp19a1b is greatly contained within the social behavior network and mesolimbic reward system in fish, suggesting a strong role of estrogen synthesis in the regulation of social behavior. In this work we aimed to analyze the variation in cyp19a1b expression in brain and pituitary of males of a highly social cichlid, Cichlasoma dimerus (locally known as chanchita), and its relation with inter-individual variability in agonistic behavior in a communal social environment. We first characterized chanchita's cyp19a1b mRNA and deduced amino acid sequence, which showed a high degree of conservation when compared to other teleost brain aromatase sequences, and its tissue expression patterns. Within the brain, Cyp19a1b was solely detected at putative radial glial cells of the forebrain, close to the brain ventricles. We then studied the relative expression levels of cyp19a1b by Real Time PCR in the brain and pituitary of males of different social status, territorial vs. non-territorial, and its relationship with an index of agonistic behavior. We found that even though, brain aromatase expression did not differ between types of males, pituitary cyp19a1b expression levels positively correlated with the index of agonistic behavior. This suggests a novel role of the pituitary in the regulation of social behavior by local estrogen synthesis. Copyright © 2017 Elsevier Inc. All rights reserved.

Ovulation induction in women with polycystic ovary syndrome.

PubMed

Perales-Puchalt, Alfredo; Legro, Richard S

2013-08-01

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. There are multiple ways to induce ovulation in PCOS patients, which will eventually provide a successful live birth. Each of these treatments varies in aggressiveness and effectiveness. Ranging from lifestyle modifications, through insulin-sensitizing agents, selective estrogen receptor modulators, aromatase inhibitors, gonadotropins, to laparoscopic ovarian drilling and assisted reproductive techniques, each method achieves ovulation induction through different mechanisms of action. This review provides a description and specific characteristics of the different methods used for ovulation induction which can help to design a personalized approach to each PCOS patient, and a general stepwise approach to ovulation induction in these patients. Copyright © 2013 Elsevier Inc. All rights reserved.

Novel Therapy for Male Hypogonadism.

PubMed

Carrasquillo, Robert; Chu, Kevin; Ramasamy, Ranjith

2018-06-09

Hypogonadism and the treatment of low testosterone is increasingly a subject of medical inquiry and controversy. The few treatments that are FDA-approved such as testosterone topicals, injections, and pellets create significant demand from patients for treatments with more convenient means of administration, fewer adverse effects, and the ability to maintain male fertility. Off-label drugs are in abundant use for low testosterone, including selective estrogen receptor modulators, gonadotropins, and aromatase inhibitors. In this review, we summarize the evidence in support of commonly used treatments for male hypogonadism, as well as discuss recent updates in the development of novel therapeutics. New therapies include nasal testosterone, new oral testosterone formulations, anabolic-androgenic steroids, and selective androgen receptor modulators.

Design and synthesis of functionalized piperazin-1yl-(E)-stilbenes as inhibitors of 17α-hydroxylase-C17,20-lyase (Cyp17).

PubMed

Blass, Benjamin E; Iyer, Pravin; Abou-Gharbia, Magid; Childers, Wayne E; Gordon, John C; Ramanjulu, Mercy; Morton, George; Arumugam, Premkumar; Boruwa, Joshodeep; Ellingboe, John; Mitra, Sayan; Reddy Nimmareddy, Rajashekar; Paliwal, Shalini; Rajasekhar, Jamallamudi; Shivakumar, Savithiri; Srivastava, Pratima; Tangirala, Raghuram S; Venkataramanaiah, Konda; Bobbala, Ramreddy; Yanamandra, Mahesh; Krishnakanth Reddy, L

2018-07-15

The synthesis of steroid hormones is critical to human physiology and improper regulation of either the synthesis of these key molecules or activation of the associated receptors can lead to disease states. This has led to intense interest in developing compounds capable of modulating the synthesis of steroid hormones. Compounds capable of inhibiting Cyp19 (Aromatase), a key enzyme in the synthesis of estrogens, have been successfully employed as breast cancer therapies, while inhibitors of Cyp17 (17α-hydroxylase-17,20-lyase), a key enzyme in the synthesis of glucocorticoids, mineralocorticoids and steroidal sex hormones, are a key component of prostate cancer therapy. Inhibition of CYP17 has also been suggested as a possible target for the treatment of Cushing Syndrome and Metabolic Syndrome. We have identified two novel series of stilbene based CYP17 inhibitors and demonstrated that exemplary compounds in these series have pharmacokinetic properties consistent with orally delivered drugs. These findings suggest that compounds in these classes may be useful for the treatment of diseases and conditions associated with improper regulation of glucocorticoids synthesis and glucocorticoids receptor activation. Copyright © 2018. Published by Elsevier Ltd.

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

PubMed

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

2017-10-01

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

Impact of mutational profiles on response of primary oestrogen receptor-positive breast cancers to oestrogen deprivation.

PubMed

Gellert, Pascal; Segal, Corrinne V; Gao, Qiong; López-Knowles, Elena; Martin, Lesley-Ann; Dodson, Andrew; Li, Tiandao; Miller, Christopher A; Lu, Charles; Mardis, Elaine R; Gillman, Alexa; Morden, James; Graf, Manuela; Sidhu, Kally; Evans, Abigail; Shere, Michael; Holcombe, Christopher; McIntosh, Stuart A; Bundred, Nigel; Skene, Anthony; Maxwell, William; Robertson, John; Bliss, Judith M; Smith, Ian; Dowsett, Mitch

2016-11-09

Pre-surgical studies allow study of the relationship between mutations and response of oestrogen receptor-positive (ER+) breast cancer to aromatase inhibitors (AIs) but have been limited to small biopsies. Here in phase I of this study, we perform exome sequencing on baseline, surgical core-cuts and blood from 60 patients (40 AI treated, 20 controls). In poor responders (based on Ki67 change), we find significantly more somatic mutations than good responders. Subclones exclusive to baseline or surgical cores occur in ∼30% of tumours. In phase II, we combine targeted sequencing on another 28 treated patients with phase I. We find six genes frequently mutated: PIK3CA, TP53, CDH1, MLL3, ABCA13 and FLG with 71% concordance between paired cores. TP53 mutations are associated with poor response. We conclude that multiple biopsies are essential for confident mutational profiling of ER+ breast cancer and TP53 mutations are associated with resistance to oestrogen deprivation therapy.

The sex-specific associations of the aromatase gene with Alzheimer's disease and its interaction with IL10 in the Epistasis Project.

PubMed

Medway, Christopher; Combarros, Onofre; Cortina-Borja, Mario; Butler, Helen T; Ibrahim-Verbaas, Carla A; de Bruijn, Renée F A G; Koudstaal, Peter J; van Duijn, Cornelia M; Ikram, M Arfan; Mateo, Ignacio; Sánchez-Juan, Pascual; Lehmann, Michael G; Heun, Reinhard; Kölsch, Heike; Deloukas, Panos; Hammond, Naomi; Coto, Eliecer; Alvarez, Victoria; Kehoe, Patrick G; Barber, Rachel; Wilcock, Gordon K; Brown, Kristelle; Belbin, Olivia; Warden, Donald R; Smith, A David; Morgan, Kevin; Lehmann, Donald J

2014-02-01

Epistasis between interleukin-10 (IL10) and aromatase gene polymorphisms has previously been reported to modify the risk of Alzheimer's disease (AD). However, although the main effects of aromatase variants suggest a sex-specific effect in AD, there has been insufficient power to detect sex-specific epistasis between these genes to date. Here we used the cohort of 1757 AD patients and 6294 controls in the Epistasis Project. We replicated the previously reported main effects of aromatase polymorphisms in AD risk in women, for example, adjusted odds ratio of disease for rs1065778 GG=1.22 (95% confidence interval: 1.01-1.48, P=0.03). We also confirmed a reported epistatic interaction between IL10 rs1800896 and aromatase (CYP19A1) rs1062033, again only in women: adjusted synergy factor=1.94 (1.16-3.25, 0.01). Aromatase, a rate-limiting enzyme in the synthesis of estrogens, is expressed in AD-relevant brain regions ,and is downregulated during the disease. IL-10 is an anti-inflammatory cytokine. Given that estrogens have neuroprotective and anti-inflammatory activities and regulate microglial cytokine production, epistasis is biologically plausible. Diminishing serum estrogen in postmenopausal women, coupled with suboptimal brain estrogen synthesis, may contribute to the inflammatory state, that is a pathological hallmark of AD.

Management strategies for ovulation induction in women with polycystic ovary syndrome and known clomifene citrate resistance.

PubMed

Palomba, Stefano; Falbo, Angela; Zullo, Fulvio

2009-12-01

Clomifene citrate is the first and the most used agent for inducing ovulation in patients affected by polycystic ovary syndrome (PCOS). About 60-85% of PCOS women ovulated under clomifene citrate, whereas the others were defined clomifene citrate-resistant. The purpose of the current review will be to describe treatment strategies to induce ovulation in infertile PCOS patients with clomifene citrate resistance. Clomifene citrate and metformin association are a valid option for inducing ovulation in clomifene citrate-resistant PCOS patients. Surgical ovulation induction by laparoscopic ovarian drilling should be reserved to well selected cases. Excellent preliminary results are obtained using new drug formulations, such as aromatase inhibitors. In clomifene citrate-resistant PCOS patients, clomifene citrate and metformin combination and laparoscopic ovarian drilling, in selected cases, should be considered before gonadotropin administration. The efficacy of the other treatments must be confirmed in future well designed studies.

Effects of femara and tamoxifen on proliferation of FM3A cells in culture.

PubMed

Topcul, Mehmet; Topcul, Funda; Cetin, Idil

2013-01-01

In this study, antiproliferative effects of the selective estrogen receptor modulator Tamoxifen and the aromatase inhibitor letrozole (Femara) were evaluated and compared using the FM3A cell line, originating from a C3H mouse mammary carcinoma and positive in terms of estrogen receptor (ER) expression. Cell kinetic parameters including labelling index, mitotic index and labelling index were assessed after exposure of the. FM3A cell line to 0.001μg/ml of Tamoxifen and 0.25μg/ml of Femara for 4, 8, 16 and 32 h for all parameters. The results showed that cell growth was inhibited by both agents. There was a significant decrease in labelling index and mitotic index and significant increase in apoptotic index for all experimental groups. The differences between control and all experimental groups were statistically significant (p<0.001) for all applications.

Chemotherapy-Induced Amenorrhea – An Update

PubMed Central

Liedtke, C.; Kiesel, L.

2012-01-01

Because of the heterogeneity in the definition of chemotherapy-induced amenorrhea (CIA) there are distinct differences in the literature with regard to its incidence as well as its dependence on various influencing factors. The occurrence of CIA varies greatly depending on the applied chemotherapy. The pathogenesis of CIA is especially based on a reduction of ovarian reserves. Various sonographic and biochemical factors can be used to exclude or confirm CIA. This is particularly important when an endocrine therapy with tamoxifen is not possible and the use of aromatase inhibitors is under consideration. CIA and especially the frequently thereby resulting early menopause can lead to pronounced restrictions in the quality of life of the affected patients, not least due to the resulting infertility. On the other hand, various studies have shown that CIA may have a positive prognostic significance. Thus, the identification of measures to prevent CIA (for example, through the use of GnRH analogues) is of particular importance. PMID:26640289

Review: neuroestrogen regulation of socio-sexual behavior of males.

PubMed

Ubuka, Takayoshi; Tsutsui, Kazuyoshi

2014-01-01

It is thought that estrogen (neuroestrogen) synthesized by the action of aromatase in the brain from testosterone activates male socio-sexual behaviors, such as aggression and sexual behavior in birds. We recently found that gonadotropin-inhibitory hormone (GnIH), a hypothalamic neuropeptide, inhibits socio-sexual behaviors of male quail by directly activating aromatase and increasing neuroestrogen synthesis in the preoptic area (POA). The POA is thought to be the most critical site of aromatization and neuroestrogen action for the regulation of socio-sexual behavior of male birds. We concluded that GnIH inhibits socio-sexual behaviors of male quail by increasing neuroestrogen concentration beyond its optimal concentration in the brain for expression of socio-sexual behavior. On the other hand, it has been reported that dopamine and glutamate, which stimulate male socio-sexual behavior in birds and mammals, inhibit the activity of aromatase in the POA. Multiple studies also report that the activity of aromatase or neuroestrogen is negatively correlated with changes in male socio-sexual behavior in fish, birds, and mammals including humans. Here, we review previous studies that investigated the role of neuroestrogen in the regulation of male socio-sexual behavior and reconsider the hypothesis that neuroestrogen activates male socio-sexual behavior in vertebrates. It is considered that basal concentration of neuroestrogen is required for the maintenance of male socio-sexual behavior but higher concentration of neuroestrogen may inhibit male socio-sexual behavior.

Review: neuroestrogen regulation of socio-sexual behavior of males

PubMed Central

Ubuka, Takayoshi; Tsutsui, Kazuyoshi

2014-01-01

It is thought that estrogen (neuroestrogen) synthesized by the action of aromatase in the brain from testosterone activates male socio-sexual behaviors, such as aggression and sexual behavior in birds. We recently found that gonadotropin-inhibitory hormone (GnIH), a hypothalamic neuropeptide, inhibits socio-sexual behaviors of male quail by directly activating aromatase and increasing neuroestrogen synthesis in the preoptic area (POA). The POA is thought to be the most critical site of aromatization and neuroestrogen action for the regulation of socio-sexual behavior of male birds. We concluded that GnIH inhibits socio-sexual behaviors of male quail by increasing neuroestrogen concentration beyond its optimal concentration in the brain for expression of socio-sexual behavior. On the other hand, it has been reported that dopamine and glutamate, which stimulate male socio-sexual behavior in birds and mammals, inhibit the activity of aromatase in the POA. Multiple studies also report that the activity of aromatase or neuroestrogen is negatively correlated with changes in male socio-sexual behavior in fish, birds, and mammals including humans. Here, we review previous studies that investigated the role of neuroestrogen in the regulation of male socio-sexual behavior and reconsider the hypothesis that neuroestrogen activates male socio-sexual behavior in vertebrates. It is considered that basal concentration of neuroestrogen is required for the maintenance of male socio-sexual behavior but higher concentration of neuroestrogen may inhibit male socio-sexual behavior. PMID:25352775

Benomyl induction of brain aromatase and toxic effects in the zebrafish embryo.

PubMed

Kim, Dong-Jae; Seok, Seung-Hyeok; Baek, Min-Won; Lee, Hui-Young; Na, Yi-Rang; Park, Sung-Hoon; Lee, Hyun-Kyoung; Dutta, Noton Kumar; Kawakami, Koichi; Park, Jae-Hak

2009-05-01

Benomyl is a benzimidazole fungicide that has been widely used on a variety of food crops and ornamental plants. It is known to cause adverse effects on reproductive systems, including decreased testicular and epididymal weights and reduced epididymal sperm counts and fertility. The brain aromatase gene is up-regulated by estrogens and estrogen mimics and considered a target gene to screen estrogen mimics. This study was designed to test the estrogenic potential and toxic effects of benomyl in the zebrafish system, and validated this system as a model that may correspond to the effect of benomyl in rodents. Concentrations of 20 x 10(-6), 40 x 10(-6) and 80 x 10(-6) M of benomyl-treated embryos showed decreased survival, hatching and heart rates, and increased incidence of malformations, such as pericardial edema, spinal lordosis, elongated heart, head edema, eye lens protrusion and caudal fin disappearance. Benomyl induced enhanced green fluorescent protein (EGFP) expression in the mediobasal hypothalamus (MBH) in transient zebrafish embryos with a brain aromatase-based reporter gene. In this study, we determined that benomyl has estrogenic potential based on zebrafish brain aromatase gene induction, and that benomyl is toxic at 20 x 10(-6) M concentration and higher. These results demonstrate the usefulness of zebrafish embryos as an in vivo system to examine the estrogenic and developmental toxic potential of unknown compounds.

Genetics Home Reference: aromatase deficiency

MedlinePlus

... to impaired female sexual development, unusual bone growth, insulin resistance, and other signs and symptoms of aromatase deficiency . In women who are pregnant with an affected fetus, excess androgens in the ...

Bisphosphonates as adjuvant therapy for breast cancer.

PubMed

Burkinshaw, Roger; Coleman, Robert

2006-01-01

Great strides have been made over the last 20 years in the treatment of breast cancer and despite an increasing incidence, the number of deaths has fallen sharply since the late 1980s. The advent of new therapies, including taxanes and aromatase inhibitors, and exciting results announced recently using trastuzumab in the adjuvant treatment of HER2-positive patients should decrease this even further. However, although most patients present with disease that appears to be localized to the breast, a significant proportion of women will eventually develop metastatic breast cancer. Therefore, the detection and treatment of micrometastatic disease represents perhaps the most important remaining challenge in breast cancer management, and is the focus of extensive ongoing research. Bone is the most frequent site of distant relapse, accounting for approximately 40% of all first recurrences. In addition to the well recognized release of bone cell-activating factors from the tumor, it is now appreciated that the release of bone-derived growth factors and cytokines from resorbing bone can attract cancer cells to the bone surface and facilitate their growth and proliferation. Bisphosphonates are potent inhibitors of bone osteolysis and the inhibition of bone resorption could therefore have an effect on the development and progression of metastatic bone disease. They could represent an adjuvant therapeutic strategy of potential importance. Clinical trial results with the early bisphosphonate, clodronate, have proved inconclusive. A large, randomized, controlled trial has recently completed accrual and should provide the definitive answer to the question of the role of clodronate in this setting. More potent second- and third-generation bisphosphonates have also shown enhanced antitumor effects in preclinical evaluation and further studies are required to determine whether this antitumor potential of bisphosphonates translates to the clinical setting. Adjuvant bisphosphonates are, therefore, currently only recommended in the research setting and clinical trials evaluating the adjuvant use of these newer compounds are currently recruiting or being established. This article will review in more detail the rationale for the adjuvant use of bisphosphonates, the results of early trials, the progress of the later trials and the potential future role of bisphosphonates in the adjuvant treatment of breast cancer. In addition, it is increasingly acknowledged that many cancer treatments have detrimental effects on bone and can increase the risk of fracture. The increasing use of aromatase inhibitors, in particular, will become a major cause of treatment-induced bone loss. This bone loss can be prevented with bisphosphonate treatment and this will also be discussed.

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

PubMed Central

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

2015-01-01

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

Endometriosis: alternative methods of medical treatment

PubMed Central

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

Neural 17β-estradiol facilitates long-term potentiation in the hippocampal CA1 region.

PubMed

Grassi, S; Tozzi, A; Costa, C; Tantucci, M; Colcelli, E; Scarduzio, M; Calabresi, P; Pettorossi, V E

2011-09-29

In the hippocampal formation many neuromodulators are possibly implied in the synaptic plasticity such as the long-term potentiation (LTP) induced by high-frequency stimulation (HFS) of afferent fibers. We investigated the involvement of locally synthesized neural 17β-estradiol (nE(2)) in the induction of HFS-LTP in hippocampal slices from male rats by stimulating the Schaffer collateral fibers and recording the evoked field excitatory postsynaptic potential (fEPSP) in the CA1 region. We demonstrated that either the blockade of nE(2) synthesis by the aromatase inhibitor letrozole, or the antagonism of E(2) receptors (ERs) by ICI 182,780 did not prevent the induction of HFS-LTP, but reduced its amplitude by ∼60%, without influencing its maintenance. Moreover, letrozole and ICI 182,780 did not affect the first short-term post-tetanic component of LTP and the paired-pulse facilitation (PPF). These findings demonstrate that nE(2) plays an important role in the induction phase of HFS-dependent LTP. Since the basal responses were not affected by the blocking agents, we suggest that the synthesis of nE(2) is induced or enhanced by HFS through aromatase activation. In this context, the local production of nE(2) seems to be a very effective mechanism to modulate the amplitude of LTP. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Sex, estradiol, and spatial memory in a food-caching corvid.

PubMed

Rensel, Michelle A; Ellis, Jesse M S; Harvey, Brigit; Schlinger, Barney A

2015-09-01

Estrogens significantly impact spatial memory function in mammalian species. Songbirds express the estrogen synthetic enzyme aromatase at relatively high levels in the hippocampus and there is evidence from zebra finches that estrogens facilitate performance on spatial learning and/or memory tasks. It is unknown, however, whether estrogens influence hippocampal function in songbirds that naturally exhibit memory-intensive behaviors, such as cache recovery observed in many corvid species. To address this question, we examined the impact of estradiol on spatial memory in non-breeding Western scrub-jays, a species that routinely participates in food caching and retrieval in nature and in captivity. We also asked if there were sex differences in performance or responses to estradiol. Utilizing a combination of an aromatase inhibitor, fadrozole, with estradiol implants, we found that while overall cache recovery rates were unaffected by estradiol, several other indices of spatial memory, including searching efficiency and efficiency to retrieve the first item, were impaired in the presence of estradiol. In addition, males and females differed in some performance measures, although these differences appeared to be a consequence of the nature of the task as neither sex consistently out-performed the other. Overall, our data suggest that a sustained estradiol elevation in a food-caching bird impairs some, but not all, aspects of spatial memory on an innate behavioral task, at times in a sex-specific manner. Copyright © 2015 Elsevier Inc. All rights reserved.

SEX, ESTRADIOL, AND SPATIAL MEMORY IN A FOOD-CACHING CORVID

PubMed Central

Rensel, Michelle A.; Ellis, Jesse M.S.; Harvey, Brigit; Schlinger, Barney A.

2015-01-01

Estrogens significantly impact spatial memory function in mammalian species. Songbirds express the estrogen synthetic enzyme aromatase at relatively high levels in the hippocampus and there is evidence from zebra finches that estrogens facilitate performance on spatial learning and/or memory tasks. It is unknown, however, whether estrogens influence hippocampal function in songbirds that naturally exhibit memory-intensive behaviors, such as cache recovery observed in many corvid species. To address this question, we examined the impact of estradiol on spatial memory in non-breeding Western scrub-jays, a species that routinely participates in food caching and retrieval in nature and in captivity. We also asked if there were sex differences in performance or responses to estradiol. Utilizing a combination of an aromatase inhibitor, fadrozole, with estradiol implants, we found that while overall cache recovery rates were unaffected by estradiol, several other indices of spatial memory, including searching efficiency and efficiency to retrieve the first item, were impaired in the presence of estradiol. In addition, males and females differed in some performance measures, although these differences appeared to be a consequence of the nature of the task as neither sex consistently out-performed the other. Overall, our data suggest that a sustained estradiol elevation in a food-caching bird impairs some, but not all, aspects of spatial memory on an innate behavioral task, at times in a sex-specific manner. PMID:26232613

Adjuvant Exemestane with Ovarian Suppression in Premenopausal Breast Cancer

PubMed Central

Pagani, Olivia; Regan, Meredith M.; Walley, Barbara A.; Fleming, Gini F.; Colleoni, Marco; Láng, István; Gomez, Henry L.; Tondini, Carlo; Burstein, Harold J.; Perez, Edith A.; Ciruelos, Eva; Stearns, Vered; Bonnefoi, Hervé R.; Martino, Silvana; Geyer, Charles E.; Pinotti, Graziella; Puglisi, Fabio; Crivellari, Diana; Ruhstaller, Thomas; Winer, Eric P.; Rabaglio-Poretti, Manuela; Maibach, Rudolf; Ruepp, Barbara; Giobbie-Hurder, Anita; Price, Karen N.; Bernhard, Jürg; Luo, Weixiu; Ribi, Karin; Viale, Giuseppe; Coates, Alan S.; Gelber, Richard D.; Goldhirsch, Aron; Francis, Prudence A.

2014-01-01

BACKGROUND Adjuvant therapy with an aromatase inhibitor improves outcomes, as compared with tamoxifen, in postmenopausal women with hormone-receptor–positive breast cancer. METHODS In two phase 3 trials, we randomly assigned premenopausal women with hormone-receptor–positive early breast cancer to the aromatase inhibitor exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 years. Suppression of ovarian estrogen production was achieved with the use of the gonadotropin-releasing-hormone agonist triptorelin, oophorectomy, or ovarian irradiation. The primary analysis combined data from 4690 patients in the two trials. RESULTS After a median follow-up of 68 months, disease-free survival at 5 years was 91.1% in the exemestane–ovarian suppression group and 87.3% in the tamoxifen–ovarian suppression group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.72; 95% confidence interval [CI], 0.60 to 0.85; P<0.001). The rate of freedom from breast cancer at 5 years was 92.8% in the exemestane–ovarian suppression group, as compared with 88.8% in the tamoxifen–ovarian suppression group (hazard ratio for recurrence, 0.66; 95% CI, 0.55 to 0.80; P<0.001). With 194 deaths (4.1% of the patients), overall survival did not differ significantly between the two groups (hazard ratio for death in the exemestane–ovarian suppression group, 1.14; 95% CI, 0.86 to 1.51; P = 0.37). Selected adverse events of grade 3 or 4 were reported for 30.6% of the patients in the exemestane–ovarian suppression group and 29.4% of those in the tamoxifen–ovarian suppression group, with profiles similar to those for postmenopausal women. CONCLUSIONS In premenopausal women with hormone-receptor–positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence. (Funded by Pfizer and others; TEXT and SOFT ClinicalTrials.gov numbers, NCT00066703 and NCT00066690, respectively.) PMID:24881463

Adjuvant endocrine therapy for premenopausal women with hormone-responsive breast cancer.

PubMed

Mathew, Aju; Davidson, Nancy E

2015-11-01

Multiple strategies for endocrine treatment of premenopausal women with hormone-responsive breast cancer have been assessed and results have been presented over the last two years. These include tamoxifen for 5-10 years (ATLAS and aTTom), tamoxifen for 5 years followed by aromatase inhibitor (AI) for 5 years for women who have become postmenopausal (MA-17); ovarian ablation (OA) by surgery (EBCTCG overview); ovarian function suppression (OFS) by LHRH agonist (LHRH agonist meta-analysis); or combinations of approaches including OFS plus tamoxifen or AI (SOFT, TEXT, ABCSG 12 and E3193). Many of these trials have taken place in the backdrop of (neo)adjuvant chemotherapy which can confound interpretation because such therapy can suppress ovarian function either transiently or permanently. Nonetheless these trials suggest in aggregate that 10 years of tamoxifen are better than 5 years and that a program of extended adjuvant therapy of tamoxifen for 5 years followed by aromatase inhibitor for 5 years is effective for suitable candidates. The SOFT and E3193 trials do not show a major advantage for use of OFS + tamoxifen compared to tamoxifen alone. The joint SOFT/TEXT analysis and ABCGS12 trials both suggest that outcomes can be excellent with the use of combined endocrine therapy alone in properly selected patients but give conflicting results with regard to potential benefits for OFS + AI compared with OFS + tamoxifen. Further work will be needed to ascertain long-term outcomes, identify factors that predict who will benefit from extended adjuvant endocrine therapy, and assess role of OFS by medical or surgical means. It is clear, however, that endocrine therapy is a critical part of the adjuvant regimen for most premenopausal women with hormone-responsive breast cancer, and a subset of these women with luminal A-type tumors can be safely treated with endocrine therapy alone. Copyright © 2015 Elsevier Ltd. All rights reserved.

Adjuvant exemestane with ovarian suppression in premenopausal breast cancer.

PubMed

Pagani, Olivia; Regan, Meredith M; Walley, Barbara A; Fleming, Gini F; Colleoni, Marco; Láng, István; Gomez, Henry L; Tondini, Carlo; Burstein, Harold J; Perez, Edith A; Ciruelos, Eva; Stearns, Vered; Bonnefoi, Hervé R; Martino, Silvana; Geyer, Charles E; Pinotti, Graziella; Puglisi, Fabio; Crivellari, Diana; Ruhstaller, Thomas; Winer, Eric P; Rabaglio-Poretti, Manuela; Maibach, Rudolf; Ruepp, Barbara; Giobbie-Hurder, Anita; Price, Karen N; Bernhard, Jürg; Luo, Weixiu; Ribi, Karin; Viale, Giuseppe; Coates, Alan S; Gelber, Richard D; Goldhirsch, Aron; Francis, Prudence A

2014-07-10

Adjuvant therapy with an aromatase inhibitor improves outcomes, as compared with tamoxifen, in postmenopausal women with hormone-receptor-positive breast cancer. In two phase 3 trials, we randomly assigned premenopausal women with hormone-receptor-positive early breast cancer to the aromatase inhibitor exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 years. Suppression of ovarian estrogen production was achieved with the use of the gonadotropin-releasing-hormone agonist triptorelin, oophorectomy, or ovarian irradiation. The primary analysis combined data from 4690 patients in the two trials. After a median follow-up of 68 months, disease-free survival at 5 years was 91.1% in the exemestane-ovarian suppression group and 87.3% in the tamoxifen-ovarian suppression group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.72; 95% confidence interval [CI], 0.60 to 0.85; P<0.001). The rate of freedom from breast cancer at 5 years was 92.8% in the exemestane-ovarian suppression group, as compared with 88.8% in the tamoxifen-ovarian suppression group (hazard ratio for recurrence, 0.66; 95% CI, 0.55 to 0.80; P<0.001). With 194 deaths (4.1% of the patients), overall survival did not differ significantly between the two groups (hazard ratio for death in the exemestane-ovarian suppression group, 1.14; 95% CI, 0.86 to 1.51; P=0.37). Selected adverse events of grade 3 or 4 were reported for 30.6% of the patients in the exemestane-ovarian suppression group and 29.4% of those in the tamoxifen-ovarian suppression group, with profiles similar to those for postmenopausal women. In premenopausal women with hormone-receptor-positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence. (Funded by Pfizer and others; TEXT and SOFT ClinicalTrials.gov numbers, NCT00066703 and NCT00066690, respectively.).

Randomized Trial of Aromatase Inhibitors, Growth Hormone, or Combination in Pubertal Boys with Idiopathic, Short Stature.

PubMed

Mauras, Nelly; Ross, Judith L; Gagliardi, Priscila; Yu, Y Miles; Hossain, Jobayer; Permuy, Joseph; Damaso, Ligeia; Merinbaum, Debbie; Singh, Ravinder J; Gaete, Ximena; Mericq, Veronica

2016-12-01

Growth of short children in puberty is limited by the effect of estrogen on epiphyseal fusion. To compare: 1) the efficacy and safety of aromatase inhibitors (AIs) vs GH vs AI/GH on increasing adult height potential in pubertal boys with severe idiopathic short stature (ISS); and 2) differences in body composition among groups. Randomized three-arm open-label comparator. Outpatient clinical research. Seventy-six pubertal boys [mean (SE) age, 14.1 (0.1) years] with ISS [height SD score (SDS), -2.3 (0.0)]. Daily AIs (anastrozole or letrozole), GH, or AI/GH for 24-36 months. Anthropometry, bone ages, dual x-ray absorptiometry, spine x-rays, hormones, safety labs. Height gain [mean (SE)] at 24 months was: AI, +14.0 (0.8) cm; GH, +17.1 (0.9) cm; AI/GH, +18.9 (0.8) cm (P < .0006, analysis of covariance). Height SDS was: AI, -1.73 (0.12); GH, -1.43 (0.14); AI/GH, -1.25 (0.12) (P < .0012). Those treated through 36 months grew more. Regardless of treatment duration, height SDS at near-final height [n = 71; age, 17.4 (0.2) years; bone age, 15.3 (0.1) years; height achieved, ∼97.6%] was: AI, -1.4 (0.1); GH, -1.4 (0.2); AI/GH, -1.0 (0.1) (P = .06). Absolute height change was: AI, +18.2 (1.6) cm; GH, +20.6 (1.5) cm; AI/GH, +22.5 (1.4) cm (P = .01) (expected height gain at -2.0 height SDS, +13.0 cm). AI/GH had higher fat free mass accrual. Measures of bone health, safety labs, and adverse events were similar in all groups. Letrozole caused higher T and lower estradiol than anastrozole. Combination therapy with AI/GH increases height potential in pubertal boys with ISS more than GH and AI alone treated for 24-36 months with a strong safety profile.

Leptin stimulates aromatase in the growth plate: limiting catch-up growth efficiency.

PubMed

Masarwi, Majdi; Shamir, Raanan; Phillip, Moshe; Gat-Yablonski, Galia

2018-06-01

Catch-up growth (CUG) in childhood is defined as periods of growth acceleration, after the resolution of growth attenuation causes, bringing the children back to their original growth trajectory. Sometimes, however, CUG is incomplete, leading to permanent growth deficit and short stature. The aim of this study was to investigate the mechanisms that limit nutritional-CUG. Specifically, we focused on the crosstalk between leptin, increased by re-feeding, and sex hormones, which increase with age. In vivo studies were performed in young male Sprague Dawley rats fed ad libitum or subjected to 10/36 days of 40% food restriction followed by 90-120 days of re-feeding. In vitro studies were performed on ATDC5 cells. Analyses of mRNA and protein levels were done using qPCR and Western blot, respectively. CUG was complete in body weight and humerus length in animals that were food-restricted for 10 days but not for those food-restricted for 36 days. In vitro studies showed that leptin significantly increased aromatase gene expression and protein level as well as the expression of estrogen and leptin receptors in a dose- and time-dependent manner. The effect of leptin on aromatase was direct and was mediated through the MAPK/Erk, STAT3 and PI3K pathways. The crosstalk between leptin and aromatase in the growth plate suggests that re-feeding during puberty may lead to increased estrogen level and activity, and consequently, irreversible premature epiphyseal growth plate closure. These results may have important implications for the development of novel treatment strategies for short stature in children. © 2018 Society for Endocrinology.

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.

PubMed

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 < 0.001). Whereas BV was a rare event, AV was frequent and substantially improved during 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.

Cardiovascular Disease After Aromatase Inhibitor Use.

PubMed

Haque, Reina; Shi, Jiaxiao; Schottinger, Joanne E; Chung, Joanie; Avila, Chantal; Amundsen, Britta; Xu, Xiaoqing; Barac, Ana; Chlebowski, Rowan T

2016-12-01

Cardiovascular disease (CVD) is an important cause of death in older patients with breast cancer. However, limited information exists on the long-term effect of aromatase inhibitor (AI) use on CVD risk in breast cancer survivors. To this point, no other population-based studies have been able to adjust for CVD risk factors or cardiovascular medications. To determine the long-term influence of adjuvant endocrine therapies on CVD in a cohort of postmenopausal breast cancer survivors in analyses that accounted for major CVD risk factors, medication use, chemotherapy, and radiotherapy. A retrospective cohort of postmenopausal women with breast cancer diagnosed from January 1, 1991, to December 31, 2010, and followed up through December 31, 2011 (maximum, 21 years [72 886 person-years]), was evaluated using records from a managed care organization with nearly 20 community hospitals in California. A total of 13 273 postmenopausal women with hormone receptor-positive breast cancer without prior CVD were included. Cardiovascular disease incidence was compared across endocrine therapy categories. Information on demographics, comorbidity, medication, use, and CVD risk was captured from electronic health records. Multivariate Cox proportional hazards models using time-dependent endocrine drug use variables and propensity scores were conducted. Data analysis was conducted from September 15, 2014, to February 1, 2016. Women were grouped by endocrine therapy status (tamoxifen citrate only, AI only, both, or neither). Person-year rates of CVD for each therapy group. During 72 886 person-years in 13 273 women (mean [SD] age, 66.8 [8.1] years) with follow-up through 2011, we observed 3711 CVD events. In multivariable analyses (reported as hazard ratio [95% CI]), AI-only users had a similar risk of cardiac ischemia (myocardial infarction and angina) (adjusted, 0.97 [0.78-1.22]) and stroke (adjusted, 0.97 [0.70-1.33]) as tamoxifen-only users (reference). However, we found an increased risk of other CVD (dysrhythmia, valvular dysfunction, and pericarditis) (adjusted, 1.29 [1.11-1.50]) in women who used AIs only or sequentially after tamoxifen (1.26 [1.09-1.45]) vs tamoxifen (reference) as well nonhormone users (1.18 [1.02-1.35]). The risk of the most serious cardiovascular events (cardiac ischemia or stroke) was not elevated in AI-only users compared with tamoxifen users. The finding that other CVD events combined were greater in AI users requires further study.

Behavioral Analysis of Genetically Modified Mice Indicates Essential Roles of Neurosteroidal Estrogen

PubMed Central

Honda, Shin-Ichiro; Wakatsuki, Toru; Harada, Nobuhiro

2011-01-01

Aromatase in the mouse brain is expressed only in the nerve cells of specific brain regions with a transient peak during the neonatal period when sexual behaviors become organized. The aromatase-knockout (ArKO) mouse, generated to shed light on the physiological functions of estrogen in the brain, exhibited various abnormal behaviors, concomitant with undetectable estrogen and increased androgen in the blood. To further elucidate the effects of neurosteroidal estrogens on behavioral phenotypes, we first prepared an brain-specific aromatase transgenic (bsArTG) mouse by introduction of a human aromatase transgene controlled under a −6.5 kb upstream region of the brain-specific promoter of the mouse aromatase gene into fertilized mouse eggs, because the −6.5 kb promoter region was previously shown to contain the minimal essential element responsible for brain-specific spatiotemporal expression. Then, an ArKO mouse expressing the human aromatase only in the brain was generated by crossing the bsArTG mouse with the ArKO mouse. The resulting mice (ArKO/bsArTG mice) nearly recovered from abnormal sexual, aggressive, and locomotive (exploratory) behaviors, in spite of having almost the same serum levels of estrogen and androgen as the adult ArKO mouse. These results suggest that estrogens locally synthesized in the specific neurons of the perinatal mouse brain directly act on the neurons and play crucial roles in the organization of neuronal networks participating in the control of sexual, aggressive, and locomotive (exploratory) behaviors. PMID:22654807

Aromatase and estrogen receptors in male reproduction.

PubMed

Carreau, Serge; Delalande, Christelle; Silandre, Dorothée; Bourguiba, Sonia; Lambard, Sophie

2006-02-26

Aromatase is a terminal enzyme which transforms irreversibly androgens into estrogens and it is present in the endoplasmic reticulum of numerous tissues. We have demonstrated that mature rat germ cells express a functional aromatase with a production of estrogens equivalent to that of Leydig cells. In humans in addition to Leydig cells, we have shown the presence of aromatase in ejaculated spermatozoa and in immature germ cells. In most tissues, high affinity estrogen receptors, ERalpha and/or ERbeta, mediate the role of estrogens. Indeed, in human spermatozoa, we have successfully amplified ERbeta mRNA but the protein was not detectable. Using ERalpha antibody we have detected two proteins in human immature germ cells: one at the expected size 66 kDa and another at 46 kDa likely corresponding to the ERalpha isoform lacking exon 1. In spermatozoa only the 46 kDa isoform was present, and we suggest that it may be located on the membrane. In addition, in men genetically deficient in aromatase, it is reported that alterations of spermatogenesis occur both in terms of the number and motility of spermatozoa. All together, these observations suggest that endogenous estrogens are important in male reproduction.

Social factors and aromatase gene expression during adult male-to-female sex change in captive leopard grouper Mycteroperca rosacea.

PubMed

Romo-Mendoza, Daniel; Campos-Ramos, Rafael; Vázquez-Islas, Grecia; Burgos-Aceves, Mario A; Esquivel-Gutiérrez, Edgar R; Guerrero-Tortolero, Danitzia A

2018-01-25

Social factors and aromatase gene expression in the leopard grouper Mycteroperca rosacea was studied when captive fish were separated by sex during the reproductive (April-June) and post-reproductive (July-September) seasons. Monosex females, monosex males, and mixed-sex, held in social sextet units were analyzed for sex steroids throughout confinement. At the end of the experiment, the gonad-sex was defined by histology, and gonad and brain aromatase gene expressions were quantified. Only males held in the monosex social units changed sex. Histology showed one male remained unchanged, six were found in a transitional sexual stage, in which two had intersex-predominantly-testes, and four had a more defined intersex ovo-testes pattern, and 11 were immature de novo females (neofemales). Neofemales and most intersex fish did not survive. In spring, 11-ketosterone showed a specific male profile, which suggests that male-to-female sex change was not triggered during the reproductive season. The low steroid levels in summer made it impossible to associate the sex change to a gonad hormonal shift; in September, gonad aromatase gene expression was not significantly different among groups. However, brain aromatase expression in intersex fish was significantly higher than monosex females, mixed-sex females, and neofemale groups. These results suggest that in the absence of female hormonal compounds, and at a time when male gonad steroidogenesis was diminished, the brain mediated male-to-male social-behavioral interactions, including stress, by increasing aromatization, resulting in derived intersex-male, which triggered more aromatization, followed by a sex change. Copyright © 2018 Elsevier Inc. All rights reserved.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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 luciferasemore » 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. - Highlights: • Currently used pesticides possess endocrine-disrupting (ED) potential in vitro. • ED effects can be mediated via sex hormone receptors and/or the aromatase enzyme. • Additive mixture effects on androgen receptor transactivity were observed.« less

Effects of chloro-s-triazine herbicides and metabolites on aromatase activity in various human cell lines and on vitellogenin production in male carp hepatocytes.

PubMed Central

Sanderson, J T; Letcher, R J; Heneweer, M; Giesy, J P; van den Berg, M

2001-01-01

We investigated a potential mechanism for the estrogenic properties of three chloro-s-triazine herbicides and six metabolites in vitro in several cell systems. We determined effects on human aromatase (CYP19), the enzyme that converts androgens to estrogens, in H295R (adrenocortical carcinoma), JEG-3 (placental choriocarcinoma), and MCF-7 (breast cancer) cells; we determined effects on estrogen receptor-mediated induction of vitellogenin in primary hepatocyte cultures of adult male carp (Cyprinus carpio). In addition to atrazine, simazine, and propazine, two metabolites--atrazine-desethyl and atrazine-desisopropyl--induced aromatase activity in H295R cells concentration-dependently (0.3-30 microM) and with potencies similar to those of the parent triazines. After a 24-hr exposure to 30 microM of the triazines, an apparent maximum induction of about 2- to 2.5-fold was achieved. The induction responses were confirmed by similar increases in CYP19 mRNA levels, determined by reverse-transcriptase polymerase chain reaction. In JEG-3 cells, where basal aromatase expression is about 15-fold greater than in H295R cells, the induction responses were similar but less pronounced; aromatase expression in MCF-7 cells was neither detectable nor inducible under our culture conditions. The fully dealkylated metabolite atrazine-desethyl-desisopropyl and the three hydroxylated metabolites (2-OH-atrazine-desethyl, -desisopropyl, and -desethyl-desisopropyl) did not induce aromatase activity. None of the triazine herbicides nor their metabolites induced vitellogenin production in male carp hepatocytes; nor did they antagonize the induction of vitellogenin by 100 nM (EC(50) 17beta-estradiol. These findings together with other reports indicate that the estrogenic effects associated with the triazine herbicides in vivo are not estrogen receptor-mediated, but may be explained partly by their ability to induce aromatase in vitro. PMID:11675267

Aromatase expression in a human osteoblastic cell line increases in response to prostaglandin E(2) in a dexamethasone-dependent fashion.

PubMed

Watanabe, M; Noda, M; Nakajin, S

2007-09-01

Recent progress supports the importance of local estrogen secretion in human bone tissue to increase and maintain bone-mineral density. In a previous report, we found that forskolin (FSK) synergistically induces aromatase (CYP19: a rate-limiting enzyme for estrogen synthesis) expression in dexamethasone (Dex) dependent manner in a human osteoblastic cell line, SV-HFO [Watanabe M, Ohno S, Nakajin S. Forskolin and dexamethasone synergistically induce aromatase (CYP19) expression in the human osteoblastic cell line SV-HFO. Eur J Endocrinol 2005;152:619-24]. In this report, we investigated whether prostaglandin (PG) E(2) induces estrogen production, in other words, if PGE(2) exerts the same effect as FSK because PGE(2) is the major prostanoid in the bone and is one of the key molecules in the osteoblast. We found PGE(2) up-regulates aromatase activity synergistically, but this up-regulation depends on Dex. CYP19 gene expression was also increased synergistically by Dex and PGE(2). Promoter I.4 was activated synergistically by PGE(2) and Dex. PGE(2) receptor, EP(1), EP(2) and EP(4) were involved in the up-regulation of aromatase activity in response to PGE(2) in a Dex-dependent manner. The cAMP-PKA pathway and Ca(2+) signaling pathway were involved in the up-regulation of aromatase activity in response to PGE(2). Furthermore, glucocorticoid response element on promoter I.4 sequence was an essential minimum requirement for its activity and synergism of PGE(2) and Dex. These findings are the first report on osteoblastic cell line which uses predominantly promoter I.4 to drive aromatase expression. These findings also suggest that endogenous PGE(2) produced in bone mainly may synergistically support local estrogen production in osteoblastic cells in the presence of glucocorticoid.

Coexistence of breast cancer metastases and tuberculosis in axillary lymph nodes--a rare association and review of the literature.

PubMed

Salemis, Nikolaos S; Razou, Anna

2010-05-01

The coexistence of metastatic breast cancer and tuberculosis in axillary lymph nodes is very rare. We present the case of a 57-year-old woman with multifocal invasive ductal breast carcinoma in whom the resected axillary nodes were found to harbor both metastatic cancer and tuberculous lymphadenitis. Thorough investigation revealed no evidence of primary tuberculosis elsewhere. A quantiFERON TB-Gold test was positive, indicating latent tuberculosis. The patient was treated with adjuvant chemotherapy antituberculous therapy, radiation and hormonal therapy with aromatase inhibitors. We conclude the possibility of coexistent latent tuberculosis should be kept in mind when granulomatous lesions are identified in axillary lymph nodes with metastatic breast cancer, especially in patients from endemic regions.

Anovulation and ovulation induction

PubMed Central

Katsikis, I; Kita, M; Karkanaki, A; Prapas, N; Panidis, D

2006-01-01

Conventional treatment of normogonadotropic anovulatory infertility is ovulation induction using the antiestrogen clomiphene citrate, followed by follicle-stimulating hormone. Multiple follicle development, associated with ovarian hyperstimulation, and multiple pregnancy remain the major complications. Cumulative singleton and multiple pregnancy rate data after different induction treatments are needed. Newer ovulation induction interventions, such as insulin-sensitizing drugs, aromatase inhibitors and laparoscopic ovarian electrocoagulation, should be compared with conventional treatments. Ovulation induction efficiency might improve if patient subgroups with altered chances for success or complications with new or conventional techniques could be identified, using multivariate prediction models based on initial screening characteristics. This would make ovulation induction more cost-effective, safe and convenient, enabling doctors to advise patients on the most effective and patient-tailored treatment strategy. PMID:20351807

Improving Adherence to Endocrine Therapy in Women With HR-Positive Breast Cancer.

PubMed

Brockway, Julia P; Shapiro, Charles L

2018-05-15

Aromatase inhibitors (AIs) are the standard treatment for postmenopausal women with hormone receptor-positive breast cancers. One of the most common side effects of AIs is joint pain; it is also the most frequently cited reason for nonadherence and discontinuation before completion of the prescribed treatment course. Nonadherence and, in particular, discontinuation, can lead to increased rates of breast cancer mortality. The prevalence of AI-induced arthralgias is about 50%, and there are several interventions, including switching to a different AI, that can increase adherence. The healthcare professional plays a part in fostering adherence by communicating the side effects of AIs to patients before the initiation of treatment, as well as explaining the strategies for addressing these side effects, should they occur.

Tributyltin or triphenyltin inhibits aromatase activity in the human granulosa-like tumor cell line KGN.

PubMed

Saitoh, M; Yanase, T; Morinaga, H; Tanabe, M; Mu, Y M; Nishi, Y; Nomura, M; Okabe, T; Goto, K; Takayanagi, R; Nawata, H

2001-11-23

The superimposition of male sex organs (penis and vas deferens) in a female gastropod, called imposex, is widely attributed to the exposure to tributyltin (TBT) compounds, used world-wide in antifouling paints for ships. It has been hypothesized that the TBT-induced imposex is mediated by an increasing androgen level relative to the estrogen level, namely a decreased conversion of androgens to estrogens (i.e., aromatization). In the present study, we tested this hypothesis by examining the effects of TBT or triphenyltin (TPT) on the aromatase activity in a cultured human granulosa-like tumor cell line, KGN, which was recently established by our group. Treatment with more than 1000 ng/ml TBT compounds was very toxic to the cells and caused immediate cell death within 24 h, while 200 ng/ml was found to cause apoptosis of the cells. Treatment of the KGN cells for more than 48 h with 20 ng/ml TBT or TPT, which is a concentration level reported to cause imposex in marine species, did not affect cell proliferation but significantly suppressed the aromatase activity determined by a [(3)H]H(2)O release assay. Treatment with 20 ng/ml TBT compounds for 7 days also resulted in a reduction of the E2 production from Delta 4-androstenedione stimulated by db-cAMP. The changes in the aromatase activity by TBT compounds were associated with comparable changes in P450arom mRNA assessed by RT-PCR. The luciferase activity of the P450arom promoter II (1 kb) decreased after the addition of 20 ng/ml TBT compounds in transfected KGN cells either in a basic state or in states stimulated by db-cAMP. The Ad4BP-dependent increase in the luciferase activity of P450arom promoter II was also downregulated by such treatments. These results indicate that TBT compounds inhibited the aromatase activity and also decreased the P450arom mRNA level at the transcriptional level in KGN cells. The direct inhibitory effect of TBT compounds on the aromatase activity may therefore partly explain the induction of imposex by these compounds in female species. Copyright 2001 Academic Press.

Dysregulated Estrogen Receptor Signaling in the Hypothalamic-Pituitary-Ovarian Axis Leads to Ovarian Epithelial Tumorigenesis in Mice

PubMed Central

Laws, Mary J.; Kannan, Athilakshmi; Pawar, Sandeep; Haschek, Wanda M.; Bagchi, Milan K.; Bagchi, Indrani C.

2014-01-01

The etiology of ovarian epithelial cancer is poorly understood, mainly due to the lack of an appropriate experimental model for studying the onset and progression of this disease. We have created a mutant mouse model in which aberrant estrogen receptor alpha (ERα) signaling in the hypothalamic-pituitary-ovarian axis leads to ovarian epithelial tumorigenesis. In these mice, termed ERαd/d, the ERα gene was conditionally deleted in the anterior pituitary, but remained intact in the hypothalamus and the ovary. The loss of negative-feedback regulation by estrogen (E) at the level of the pituitary led to increased production of luteinizing hormone (LH) by this tissue. Hyperstimulation of the ovarian cells by LH resulted in elevated steroidogenesis, producing high circulating levels of steroid hormones, including E. The ERαd/d mice exhibited formation of palpable ovarian epithelial tumors starting at 5 months of age with 100% penetrance. By 15 months of age, 80% of ERαd/d mice die. Besides proliferating epithelial cells, these tumors also contained an expanded population of luteinized stromal cells, which acquire the ability to express P450 aromatase and synthesize E locally. In response to the elevated levels of E, the ERα signaling was accentuated in the ovarian epithelial cells of ERαd/d mice, triggering increased ERα-dependent gene expression, abnormal cell proliferation, and tumorigenesis. Consistent with these findings, treatment of ERαd/d mice with letrozole, an aromatase inhibitor, markedly reduced circulating E and ovarian tumor volume. We have, therefore, developed a unique animal model, which serves as a useful tool for exploring the involvement of E-dependent signaling pathways in ovarian epithelial tumorigenesis. PMID:24603706

Sex Reversal and Comparative Data Undermine the W Chromosome and Support Z-linked DMRT1 as the Regulator of Gonadal Sex Differentiation in Birds.

PubMed

Hirst, Claire E; Major, Andrew T; Ayers, Katie L; Brown, Rosie J; Mariette, Mylene; Sackton, Timothy B; Smith, Craig A

2017-09-01

The exact genetic mechanism regulating avian gonadal sex differentiation has not been completely resolved. The most likely scenario involves a dosage mechanism, whereby the Z-linked DMRT1 gene triggers testis development. However, the possibility still exists that the female-specific W chromosome may harbor an ovarian determining factor. In this study, we provide evidence that the universal gene regulating gonadal sex differentiation in birds is Z-linked DMRT1 and not a W-linked (ovarian) factor. Three candidate W-linked ovarian determinants are HINTW, female-expressed transcript 1 (FET1), and female-associated factor (FAF). To test the association of these genes with ovarian differentiation in the chicken, we examined their expression following experimentally induced female-to-male sex reversal using the aromatase inhibitor fadrozole (FAD). Administration of FAD on day 3 of embryogenesis induced a significant loss of aromatase enzyme activity in female gonads and masculinization. However, expression levels of HINTW, FAF, and FET1 were unaltered after experimental masculinization. Furthermore, comparative analysis showed that FAF and FET1 expression could not be detected in zebra finch gonads. Additionally, an antibody raised against the predicted HINTW protein failed to detect it endogenously. These data do not support a universal role for these genes or for the W sex chromosome in ovarian development in birds. We found that DMRT1 (but not the recently identified Z-linked HEMGN gene) is male upregulated in embryonic zebra finch and emu gonads, as in the chicken. As chicken, zebra finch, and emu exemplify the major evolutionary clades of birds, we propose that Z-linked DMRT1, and not the W sex chromosome, regulates gonadal sex differentiation in birds. Copyright © 2017 Endocrine Society.

Cytotoxic effects and aromatase inhibition by xenobiotic endocrine disrupters alone and in combination.

PubMed

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

2007-07-15

Xenobiotics may cause long-term adverse effects in humans, especially at the embryonic level, raising questions about their levels of exposure, combined effects, and crucial endpoints. We are interested in the possible interactions between xenobiotic endocrine disrupters, cellular viability and androgen metabolism. Accordingly, we tested aroclor 1254 (A1254), atrazine (AZ), o,p'-DDT, vinclozolin (VZ), p,p'-DDE, bisphenol A (BPA), chlordecone (CD), nonylphenol (NP), tributylin oxide (TBTO), and diethylstilbestrol (DES) for cellular toxicity against human embryonic 293 cells, and activity against cellular aromatase, but also on placental microsomes and on the purified equine enzyme. Cellular viability was affected in 24 h by all the xenobiotics with a threshold at 50 microM (except for TBTO and DES, 10 microM threshold), and aromatase was inhibited at non-toxic doses. In combination synergism was observed reducing the threshold values of toxicity to 4-10 microM, and aromatase activity by 50% in some cases. In placental microsomes the most active xenobiotics rapidly inhibited microsomal aromatase in a manner independent of NADPH metabolism. Prolonged exposures to low doses in cells generally amplified by 50 times aromatase inhibition. These xenobiotics may act by inhibition of the active site or by allosteric effects on the enzyme. Bioaccumulation is a feature of some xenobiotics, especially chlordecone, DDT and DDE, and low level chronic exposures can also affect cell signaling mechanisms. This new information about the mechanism of action of these xenobiotics will assist in improved molecular design with a view to providing safer compounds for use in the (human) environment.

ASCO 2016: highlights in breast cancer.

PubMed

Bartsch, Rupert; Bergen, Elisabeth

2016-01-01

At the 2016 ASCO Annual Meeting, several pertinent studies in the field of breast cancer were presented. MA17.R was the first randomized phase III trial to evaluate the prolongation of adjuvant aromatase-inhibitor (AI) therapy from 5 to 10 years; while a significant reduction of disease-free survival events was observed in the extended treatment group, the absolute difference was relatively small and longer endocrine therapy resulted in a higher fracture rate. A combined analysis of three North American trials emphasized the superiority of anthracycline containing adjuvant chemotherapy regimens compared with docetaxel/cyclophosphamide (TC), while the PANTHER trial investigated dose-dense tailored adjuvant treatment. In metastatic breast cancer, the main interest was on cyclin-dependent kinase (CDK) 4/6 inhibitors. In PALOMA-2, the addition of palbociclib to letrozole prolonged progression-free survival (PFS) from 14.5 to 24.8 months resulting in the longest PFS data ever reported in the first-line setting. A subgroup analysis of premenopausal patients accrued to PALOMA-3 indicated that in this patient subset, ovarian function suppression plus fulvestrant and palbociclib yielded results comparable to the postmenopausal population. ESR1 mutations were another focus of interest as these activating mutations in the gene coding for the estrogen receptor alpha apparently evolve under the selection pressure of AI therapy.

AR Expression in Breast Cancer CTCs Associates with Bone Metastases.

PubMed

Aceto, Nicola; Bardia, Aditya; Wittner, Ben S; Donaldson, Maria C; O'Keefe, Ryan; Engstrom, Amanda; Bersani, Francesca; Zheng, Yu; Comaills, Valentine; Niederhoffer, Kira; Zhu, Huili; Mackenzie, Olivia; Shioda, Toshi; Sgroi, Dennis; Kapur, Ravi; Ting, David T; Moy, Beverly; Ramaswamy, Sridhar; Toner, Mehmet; Haber, Daniel A; Maheswaran, Shyamala

2018-04-01

Molecular drivers underlying bone metastases in human cancer are not well understood, in part due to constraints in bone tissue sampling. Here, RNA sequencing was performed of circulating tumor cells (CTC) isolated from blood samples of women with metastatic estrogen receptor (ER) + breast cancer, comparing cases with progression in bone versus visceral organs. Among the activated cellular pathways in CTCs from bone-predominant breast cancer is androgen receptor (AR) signaling. AR gene expression is evident, as is its constitutively active splice variant AR-v7. AR expression within CTCs is correlated with the duration of treatment with aromatase inhibitors, suggesting that it contributes to acquired resistance to endocrine therapy. In an established breast cancer xenograft model, a bone-tropic derivative displays increased AR expression, whose genetic or pharmacologic suppression reduces metastases to bone but not to lungs. Together, these observations identify AR signaling in CTCs from women with bone-predominant ER + breast cancer, and provide a rationale for testing androgen inhibitors in this subset of patients. Implications: This study highlights a role for the AR in breast cancer bone metastasis, and suggests that therapeutic targeting of the AR may benefit patients with metastatic breast cancer. Mol Cancer Res; 16(4); 720-7. ©2018 AACR . ©2018 American Association for Cancer Research.

The selective estrogen enzyme modulators in breast cancer: a review.

PubMed

Pasqualini, Jorge R

2004-06-07

It is well established that increased exposure to estradiol (E(2)) is an important risk factor for the genesis and evolution of breast tumors, most of which (approximately 95-97%) in their early stage are estrogen-sensitive. However, two thirds of breast cancers occur during the postmenopausal period when the ovaries have ceased to be functional. Despite the low levels of circulating estrogens, the tissular concentrations of these hormones are significantly higher than those found in the plasma or in the area of the breast considered as normal tissue, suggesting a specific tumoral biosynthesis and accumulation of these hormones. Several factors could be implicated in this process, including higher uptake of steroids from plasma and local formation of the potent E(2) by the breast cancer tissue itself. This information extends the concept of 'intracrinology' where a hormone can have its biological response in the same organ where it is produced. There is substantial information that mammary cancer tissue contains all the enzymes responsible for the local biosynthesis of E(2) from circulating precursors. Two principal pathways are implicated in the last steps of E(2) formation in breast cancer tissues: the 'aromatase pathway' which transforms androgens into estrogens, and the 'sulfatase pathway' which converts estrone sulfate (E(1)S) into E(1) by the estrone-sulfatase. The final step of steroidogenesis is the conversion of the weak E(1) to the potent biologically active E(2) by the action of a reductive 17beta-hydroxysteroid dehydrogenase type 1 activity (17beta-HSD-1). Quantitative evaluation indicates that in human breast tumor E(1)S 'via sulfatase' is a much more likely precursor for E(2) than is androgens 'via aromatase'. Human breast cancer tissue contains all the enzymes (estrone sulfatase, 17beta-hydroxysteroid dehydrogenase, aromatase) involved in the last steps of E(2) biosynthesis. This tissue also contains sulfotransferase for the formation of the biologically inactive estrogen sulfates. In recent years, it was demonstrated that various progestins (promegestone, nomegestrol acetate, medrogestone, dydrogesterone, norelgestromin), tibolone and its metabolites, as well as other steroidal (e.g. sulfamates) and non-steroidal compounds, are potent sulfatase inhibitors. Various progestins can also block 17beta-hydroxysteroid dehydrogenase activities. In other studies, it was shown that medrogestone, nomegestrol acetate, promegestone or tibolone can stimulate the sulfotransferase activity for the local production of estrogen sulfates. All these data, in addition to numerous agents which can block the aromatase action, lead to the new concept of 'Selective Estrogen Enzyme Modulators' (SEEM) which can largely apply to breast cancer tissue. The exploration of various progestins and other active agents in trials with breast cancer patients, showing an inhibitory effect on sulfatase and 17beta-hydroxysteroid dehydrogenase, or a stimulatory effect on sulfotransferase and consequently on the levels of tissular levels of E(2), will provide a new possibility in the treatment of this disease.

Nimesulide, a COX-2 inhibitor, does not reduce lesion size or number in a nude mouse model of endometriosis.

PubMed

Hull, M L; Prentice, A; Wang, D Y; Butt, R P; Phillips, S C; Smith, S K; Charnock-Jones, D S

2005-02-01

Women with endometriosis have elevated levels of cyclooxygenase-2 (COX-2) in peritoneal macrophages and endometriotic tissue. Inhibition of COX-2 has been shown to reduce inflammation, angiogenesis and cellular proliferation. It may also downregulate aromatase activity in ectopic endometrial lesions. Ectopic endometrial establishment and growth are therefore likely to be suppressed in the presence of COX-2 inhibitors. We hypothesized that COX-2 inhibition would reduce the size and number of ectopic human endometrial lesions in a nude mouse model of endometriosis. The selective COX-2 inhibitor, nimesulide, was administered to estrogen-supplemented nude mice implanted with human endometrial tissue. Ten days after implantation, the number and size of ectopic endometrial lesions were evaluated and compared with lesions from a control group. Immunohistochemical assessment of vascular development and macrophage and myofibroblast infiltration in control and treated lesions was performed. There was no difference in the number or size of ectopic endometrial lesions in control and nimesulide-treated nude mice. Nimesulide did not induce a visually identifiable difference in blood vessel development or macrophage or myofibroblast infiltration in nude mouse explants. The hypothesized biological properties of COX-2 inhibition did not influence lesion number or size in the nude mouse model of endometriosis.

Palbociclib: A Review in HR-Positive, HER2-Negative, Advanced or Metastatic Breast Cancer.

PubMed

Kim, Esther S; Scott, Lesley J

2017-06-01

Oral palbociclib (Ibrance®) is a first-in-class, highly selective inhibitor of cyclin-dependent kinases 4 and 6 (i.e. a CDK4/6 inhibitor). It is indicated for the treatment of women with HR-positive, HER2-negative advanced or metastatic breast cancer, in combination with an aromatase inhibitor as initial endocrine-based therapy, and in combination with fulvestrant (with or without a luteinizing hormone-releasing hormone agonist) in those previously treated with endocrine therapy. In clinical trials, palbociclib in combination with letrozole as initial endocrine-based therapy in postmenopausal women (PALOMA-1 and PALOMA-2), or in combination with fulvestrant in pre-, peri-, or postmenopausal women with disease progression after endocrine therapy (PALOMA-3), significantly prolonged progression-free survival (PFS) and improved clinical benefit response (CBR) rates. Neutropenia was the most commonly reported any-grade and grade ≥ 3 adverse event. It was infrequently associated with febrile neutropenia (<2%) and generally manageable with a palbociclib dose delay, interruption or reduction, without the routine use of growth factors, and without affecting efficacy. In conclusion, oral palbociclib combination therapy is a valuable emerging option for use in patients with HR-positive, HER2-negative advanced or metastatic breast cancer.

Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: ALTERNATIVE.

PubMed

Johnston, Stephen R D; Hegg, Roberto; Im, Seock-Ah; Park, In Hae; Burdaeva, Olga; Kurteva, Galina; Press, Michael F; Tjulandin, Sergei; Iwata, Hiroji; Simon, Sergio D; Kenny, Sarah; Sarp, Severine; Izquierdo, Miguel A; Williams, Lisa S; Gradishar, William J

2018-03-10

Purpose Human epidermal growth factor receptor 2 (HER2) targeting plus endocrine therapy (ET) improved clinical benefit in HER2-positive, hormone receptor (HR)-positive metastatic breast cancer (MBC) versus ET alone. Dual HER2 blockade enhances clinical benefit versus single HER2 blockade. The ALTERNATIVE study evaluated the efficacy and safety of dual HER2 blockade plus aromatase inhibitor (AI) in postmenopausal women with HER2-positive/HR-positive MBC who received prior ET and prior neo(adjuvant)/first-line trastuzumab (TRAS) plus chemotherapy. Methods Patients were randomly assigned (1:1:1) to receive lapatinib (LAP) + TRAS + AI, TRAS + AI, or LAP + AI. Patients for whom chemotherapy was intended were excluded. The primary end point was progression-free survival (PFS; investigator assessed) with LAP + TRAS + AI versus TRAS + AI. Secondary end points were PFS (comparison of other arms), overall survival, overall response rate, clinical benefit rate, and safety. Results Three hundred fifty-five patients were included in this analysis: LAP + TRAS + AI (n = 120), TRAS + AI (n = 117), and LAP + AI (n = 118). Baseline characteristics were balanced. The study met its primary end point; superior PFS was observed with LAP + TRAS + AI versus TRAS + AI (median PFS, 11 v 5.7 months; hazard ratio, 0.62; 95% CI, 0.45 to 0.88; P = .0064). Consistent PFS benefit was observed in predefined subgroups. Overall response rate, clinical benefit rate, and overall survival also favored LAP + TRAS + AI. The median PFS with LAP + AI versus TRAS + AI was 8.3 versus 5.7 months (hazard ratio, 0.71; 95% CI, 0.51 to 0.98; P = .0361). Common adverse events (AEs; ≥ 15%) with LAP + TRAS + AI, TRAS + AI, and LAP + AI were diarrhea (69%, 9%, and 51%, respectively), rash (36%, 2%, and 28%, respectively), nausea (22%, 9%, and 22%, respectively), and paronychia (30%, 0%, and 15%, respectively), mostly grade 1 or 2. Serious AEs were reported similarly across the three groups, and AEs leading to discontinuation were lower with LAP + TRAS + AI. Conclusion Dual HER2 blockade with LAP + TRAS + AI showed superior PFS benefit versus TRAS + AI in patients with HER2-positive/HR-positive MBC. This combination offers an effective and safe chemotherapy-sparing alternative treatment regimen for this patient population.

Ki67 Proliferation Index as a Tool for Chemotherapy Decisions During and After Neoadjuvant Aromatase Inhibitor Treatment of Breast Cancer: Results From the American College of Surgeons Oncology Group Z1031 Trial (Alliance)

PubMed Central

Ellis, Matthew J.; Suman, Vera J.; Hoog, Jeremy; Goncalves, Rodrigo; Sanati, Souzan; Creighton, Chad J.; DeSchryver, Katherine; Crouch, Erika; Brink, Amy; Watson, Mark; Luo, Jingqin; Tao, Yu; Barnes, Michael; Dowsett, Mitchell; Budd, G. Thomas; Winer, Eric; Silverman, Paula; Esserman, Laura; Carey, Lisa; Ma, Cynthia X.; Unzeitig, Gary; Pluard, Timothy; Whitworth, Pat; Babiera, Gildy; Guenther, J. Michael; Dayao, Zoneddy; Ota, David; Leitch, Marilyn; Olson, John A.; Allred, D. Craig; Hunt, Kelly

2017-01-01

Purpose To determine the pathologic complete response (pCR) rate in estrogen receptor (ER) –positive primary breast cancer triaged to chemotherapy when the protein encoded by the MKI67 gene (Ki67) level was > 10% after 2 to 4 weeks of neoadjuvant aromatase inhibitor (AI) therapy. A second objective was to examine risk of relapse using the Ki67-based Preoperative Endocrine Prognostic Index (PEPI). Methods The American College of Surgeons Oncology Group (ACOSOG) Z1031A trial enrolled postmenopausal women with stage II or III ER-positive (Allred score, 6 to 8) breast cancer whose treatment was randomly assigned to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For the trial ACOSOG Z1031B, the protocol was amended to include a tumor Ki67 determination after 2 to 4 weeks of AI. If the Ki67 was > 10%, patients were switched to neoadjuvant chemotherapy. A pCR rate of > 20% was the predefined efficacy threshold. In patients who completed neoadjuvant AI, stratified Cox modeling was used to assess whether time to recurrence differed by PEPI = 0 score (T1 or T2, N0, Ki67 < 2.7%, ER Allred > 2) versus PEPI > 0 disease. Results Only two of the 35 patients in ACOSOG Z1031B who were switched to neoadjuvant chemotherapy experienced a pCR (5.7%; 95% CI, 0.7% to 19.1%). After 5.5 years of median follow-up, four (3.7%) of the 109 patients with a PEPI = 0 score relapsed versus 49 (14.4%) of 341 of patients with PEPI > 0 (recurrence hazard ratio [PEPI = 0 v PEPI > 0], 0.27; P = .014; 95% CI, 0.092 to 0.764). Conclusion Chemotherapy efficacy was lower than expected in ER-positive tumors exhibiting AI-resistant proliferation. The optimal therapy for these patients should be further investigated. For patients with PEPI = 0 disease, the relapse risk over 5 years was only 3.6% without chemotherapy, supporting the study of adjuvant endocrine monotherapy in this group. These Ki67 and PEPI triage approaches are being definitively studied in the ALTERNATE trial (Alternate Approaches for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer Neoadjuvant Treatment in Postmenopausal Women: A Phase III Study; clinical trial information: NCT01953588). PMID:28045625

A Quantative Adverse Outcome Pathway Linking Aromatase Inhibition in Fathead Minnows with Population Dynamics

EPA Science Inventory

A Quantitative Adverse Outcome Pathway Linking Aromatase Inhibition in Fathead Minnows with Population DynamicsAn adverse outcome pathway (AOP) is a qualitative description linking a molecular initiating event (MIE) with measureable key events leading to an adverse outcome (AO). ...

AOP description: Aromatase inhibition leading to reproductive dysfunction (in fish)

EPA Science Inventory

This adverse outcome pathway details the linkage between inhibition of gonadal aromatase activity in females and the adverse effect of reduced cumulative fecundity in repeat-spawning fish species. Cumulative fecundity is the most apical endpoint considered in the OECD 229 Fish Sh...

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

EPA Science Inventory

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...

Evolutionary origins of the estrogen signaling system: insights from amphioxus

PubMed Central

Tarrant, AM; Novillo, A; Yacci, P; Ciaccia, L; Vajda, S; Chuang, G-Y; Kozakov, D; Greytak, SR; Sawyer, S; Hoover, C; Cotter, K

2011-01-01

Classically, the estrogen signaling system has two core components: cytochrome P450 aromatase (CYP19), the enzyme complex that catalyzes the rate limiting step in estrogen biosynthesis; and estrogen receptors (ERs), ligand activated transcription factors that interact with the regulatory region of target genes to mediate the biological effects of estrogen. While the importance of estrogens for regulation of reproduction, development and physiology has been well-documented in gnathostome vertebrates, the evolutionary origins of estrogen as a hormone are still unclear. As invertebrates within the phylum Chordata, cephalochordates (e.g. the amphioxus of the genus Branchiostoma) are among the closest invertebrate relatives of the vertebrates and can provide critical insight into the evolution of vertebrate-specific molecules and pathways. To address this question, this paper briefly reviews relevant earlier studies that help to illuminate the history of the aromatase and ER genes, with a particular emphasis on insights from amphioxus and other invertebrates. We then present new analyses of amphioxus aromatase and ER sequence and function, including an in silico model of the amphioxus aromatase protein, and CYP19 gene analysis. CYP19 shares a conserved gene structure with vertebrates (9 coding exons) and moderate sequence conservation (40% amino acid identity with human CYP19). Modeling of the amphioxus aromatase substrate binding site and simulated docking of androstenedione in comparison to the human aromatase shows that the substrate binding site is conserved and predicts that androstenedione could be a substrate for amphioxus CYP19. The amphioxus ER is structurally similar to vertebrate ERs, but differs in sequence and key residues of the ligand binding domain. Consistent with results from other laboratories, amphioxus ER did not bind radiolabeled estradiol, nor did it modulate gene expression on anestrogen-responsive element (ERE) in the presence of estradiol, 4-hydroxytamoxifen, diethylstilbestrol, bisphenol A or genistein. Interestingly, it has been shown that a related gene, the amphioxus “steroid receptor” (SR), can be activated by estrogens and that amphioxus ER can repress this activation. CYP19, ER and SR are all primarily expressed in gonadal tissue, suggesting an ancient paracrine/autocrinesignaling role, but it is not yet known how their expression is regulated and, if estrogen is actually synthesized in amphioxus, whether it has a role in mediating any biological effects. Functional studies are clearly needed to link emerging bioinformatics and in vitro molecular biology results with organismal physiology to develop an understanding of the evolution of estrogen signaling. PMID:21514383

Oestrogens and spermatogenesis

PubMed Central

Carreau, Serge; Hess, Rex A.

2010-01-01

The role of oestrogens in male reproductive tract physiology has for a long time been a subject of debate. The testis produces significant amounts of oestrogenic hormones, via aromatase, and oestrogen receptors (ERs)α (ESR1) and ERβ (ESR2) are selectively expressed in cells of the testis as well as the epididymal epithelium, depending upon species. This review summarizes the current knowledge concerning the presence and activity of aromatase and ERs in testis and sperm and the potential roles that oestrogens may have in mammalian spermatogenesis. Data show that physiology of the male gonad is in part under the control of a balance of androgens and oestrogens, with aromatase serving as a modulator. PMID:20403867

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

EPA Science Inventory

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...

Endocrine therapy toxicity: management options.

PubMed

Henry, N Lynn

2014-01-01

Treatment with adjuvant endocrine therapy, including tamoxifen and the aromatase inhibitors, has resulted in notable improvements in disease-free and overall survival for patients with hormone receptor-positive breast cancer. Despite their proven benefit, however, adherence to and persistence with the medications is poor in part because of bothersome side effects that can negatively affect quality of life. Retrospective analyses have identified possible predictors of development of toxicity. Reports have also suggested that development of toxicity may be a biomarker of better response to therapy. In addition, there has been considerable research investment into the management of these side effects, which may lead to improved adherence and persistence with therapy. However, although notable advances have been made, much more remains to be done to provide patients with truly personalized therapy for hormone receptor-positive breast cancer.

Differentiating the Causes of Spontaneous Rib Fracture After Breast Cancer.

PubMed

Harris, Susan R

2016-12-01

Spontaneous rib fracture after treatment for primary breast cancer is not uncommon. Although metastatic disease accounts for about 30% of spontaneous rib fractures and should constitute the first line of diagnostic investigation, other possible contributors include primary osteoporosis or secondary osteoporosis resulting from cancer treatments. Chemotherapy-induced menopause, aromatase inhibitors, radiation therapy, and long-term bisphosphonate use can all contribute to bone fragility, including spontaneous rib fractures in the latter 3. Drawing on recent breast cancer practice guidelines as well as population-based studies of fracture risk for women with a history of breast cancer and systematic reviews, this Perspective will provide an update on recent developments in understanding how to differentiate the possible reasons for non-traumatic rib fracture in women treated for breast cancer. In addition to describing the various possible causes of spontaneous rib fracture, the recommended medical and imaging procedures for differentiating among the potential causes will be presented. Copyright © 2016 Elsevier Inc. All rights reserved.

What is the current status of ovarian suppression/ablation in women with premenopausal early-stage breast cancer?

PubMed

Higgins, Michaela J; Davidson, Nancy E

2009-01-01

The role of ovarian suppression/ablation (OS/OA) in premenopausal women with hormone receptor-positive breast cancer has been evolving for more than a century. It is clear that OS/OA is an effective adjuvant therapy for these women, but despite numerous studies enrolling thousands of women, many unanswered questions remain. In particular, a major question is whether additional benefit is gained with combination treatment comprising luteinizing hormone-releasing hormone (LH-RH) agonists and tamoxifen over tamoxifen alone. Ongoing trials also are assessing the coupling of aromatase inhibitors (traditionally contraindicated in these patients because of paradoxic stimulation of estrogen production) and LH-RH agonists. Any potential disease-free or overall survival advantage of combination treatment must be balanced against a possible increase in adverse effects and impairment of quality of life. This review focuses on new data on how to incorporate OS/OA into the rational treatment of this challenging patient population.

Hypothesis testing with computational modeling: linking aromatase inhibition with plasma vitellogenin dynamics in fathead minnows

EPA Science Inventory

Fadrozole inhibits aromatase (CYP19A), a key enzyme that converts testosterone to estradiol (E2). In fish, E2 concentrations control hepatic synthesis ofthe glycolipoprotein vitellogenin (VTG), an egg yolk precursor protein essential to oocyte development and larval survival. Whe...

Gonadal expression of aromatase and estrogen receptor alpha genes in two races of Tunisian mice and their hypofertile hybrids.

PubMed

Saïd, Lamia; Delalande, Christelle; Britton-Davidian, Janice; Saïd, Khaled; Saad, Ali; Carreau, Serge

2007-07-01

House mice (Mus musculus domesticus) in Tunisia consists of two races, one carries the 40-acrocentric standard karyotypes and the other one is a robertsonian race (2n=22) homozygous for nine centric fusions (Rb). The F1 hybrids between the two chromosomal races showed a significant decrease in reproductive success and litter size. Such results can be related to the formation of meiotic trivalent in the hybrids leading to the production of viable aneuploid gametes and post-zygotic elimination of embryos due to chromosomal non disjunction events at meiosis. Moreover, testicular histology of F1 and backcross males showed in some cases a breakdown in spermatogenesis. In both females and males, androgens but also estrogens play an important role in gametogenesis. In this study, we have studied aromatase and estrogen receptor alpha (ERalpha) gene expression in the gonads of the two parental races and their chromosomal hybrids. The results showed that aromatase and ERalpha mRNAs are expressed in hybrid males of inter-racial crosses (female22Rb x male40Std and female40Std x male22Rb) and in hybrid females of inter-racial crosses (female22Rb x male40Std) as in the two parental races. However, in hybrid females of inter-racial crosses (female40Std x male22Rb) the amount of aromatase transcripts decreased sharply suggesting that this gene is involved in the breakdown of hybrid fertility in females, but not in males. However, in hybrid males, a putative post-translational modification of this enzyme, in terms of activity, should be verified.

Randomized Trial of Aromatase Inhibitors, Growth Hormone, or Combination in Pubertal Boys with Idiopathic, Short Stature

PubMed Central

Ross, Judith L.; Gagliardi, Priscila; Yu, Y. Miles; Hossain, Jobayer; Permuy, Joseph; Damaso, Ligeia; Merinbaum, Debbie; Singh, Ravinder J.; Gaete, Ximena; Mericq, Veronica

2016-01-01

Context: Growth of short children in puberty is limited by the effect of estrogen on epiphyseal fusion. Objectives: To compare: 1) the efficacy and safety of aromatase inhibitors (AIs) vs GH vs AI/GH on increasing adult height potential in pubertal boys with severe idiopathic short stature (ISS); and 2) differences in body composition among groups. Design: Randomized three-arm open-label comparator. Setting: Outpatient clinical research. Patients: Seventy-six pubertal boys [mean (SE) age, 14.1 (0.1) years] with ISS [height SD score (SDS), −2.3 (0.0)]. Intervention: Daily AIs (anastrozole or letrozole), GH, or AI/GH for 24–36 months. Outcomes: Anthropometry, bone ages, dual x-ray absorptiometry, spine x-rays, hormones, safety labs. Results: Height gain [mean (SE)] at 24 months was: AI, +14.0 (0.8) cm; GH, +17.1 (0.9) cm; AI/GH, +18.9 (0.8) cm (P < .0006, analysis of covariance). Height SDS was: AI, −1.73 (0.12); GH, −1.43 (0.14); AI/GH, −1.25 (0.12) (P < .0012). Those treated through 36 months grew more. Regardless of treatment duration, height SDS at near-final height [n = 71; age, 17.4 (0.2) years; bone age, 15.3 (0.1) years; height achieved, ∼97.6%] was: AI, −1.4 (0.1); GH, −1.4 (0.2); AI/GH, −1.0 (0.1) (P = .06). Absolute height change was: AI, +18.2 (1.6) cm; GH, +20.6 (1.5) cm; AI/GH, +22.5 (1.4) cm (P = .01) (expected height gain at −2.0 height SDS, +13.0 cm). AI/GH had higher fat free mass accrual. Measures of bone health, safety labs, and adverse events were similar in all groups. Letrozole caused higher T and lower estradiol than anastrozole. Conclusions: Combination therapy with AI/GH increases height potential in pubertal boys with ISS more than GH and AI alone treated for 24–36 months with a strong safety profile. PMID:27710241

Combined metformin-clomiphene in clomiphene-resistant polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials.

PubMed

Abu Hashim, Hatem; Foda, Osama; Ghayaty, Essam

2015-09-01

Our objective was to compare the effectiveness of metformin plus clomiphene citrate vs. gonadotrophins, laparoscopic ovarian diathermy, aromatase inhibitors, N-acetyl-cysteine and other insulin sensitizers+clomiphene for improving fertility outcomes in women with clomiphene-resistant polycystic ovary syndrome. PubMed, SCOPUS and CENTRAL databases were searched until April 2014 with the key words: PCOS, polycystic ovary syndrome, metformin, clomiphene citrate, ovulation induction and pregnancy. The search was limited to articles conducted with humans and published in English. The PRISMA statement was followed. Twelve randomized controlled trials (n = 1411 women) were included. Ovulation and clinical pregnancy rates per woman randomized. Compared with gonadotrophins, the metformin+clomiphene combination resulted in significantly fewer ovulations (odds ratio 0.25; 95% confidence interval 0.15-0.41; p < 0.00001, 3 trials, I(2) = 85%, n = 323) and pregnancies (odds ratio 0.45; 95% confidence interval 0.27-0.75; p = 0.002, 3 trials, I(2) = 0%, n = 323). No significant differences were found when metformin+clomiphene was compared with laparoscopic ovarian diathermy (odds ratio 0.88; 95% confidence interval 0.53-1.47; p = 0.62, 1 trial, n = 282; odds ratio 0.96; 95% confidence interval 0.60-1.54; p = 0.88, 2 trials, I(2) = 0%, n = 332, for ovulation and pregnancy rates, respectively). Likewise, no differences were observed in comparison with aromatase inhibitors (odds ratio 0.88; 95% confidence interval 0.58-1.34; p = 0.55, 3 trials, I(2) = 3%, n = 409; odds ratio 0.85; 95% confidence interval 0.53-1.36; p = 0.50, 2 trials, n = 309, for ovulation and pregnancy rates, respectively). There is evidence for the superiority of gonadotrophins, but the metformin+clomiphene combination is mainly relevant for clomiphene-resistant polycystic ovary syndrome patients and, if not effective, a next step could be gonadotrophins. More attempts with metformin+clomiphene are only relevant if there is limited access to gonadotrophins. © 2015 Nordic Federation of Societies of Obstetrics and Gynecology.

Prevalence of ESR1 Mutations in Cell-Free DNA and Outcomes in Metastatic Breast Cancer: A Secondary Analysis of the BOLERO-2 Clinical Trial.

PubMed

Chandarlapaty, Sarat; Chen, David; He, Wei; Sung, Patricia; Samoila, Aliaksandra; You, Daoqi; Bhatt, Trusha; Patel, Parul; Voi, Maurizio; Gnant, Michael; Hortobagyi, Gabriel; Baselga, José; Moynahan, Mary Ellen

2016-10-01

Estrogen receptor α (ESR1) mutations found in metastatic breast cancer (MBC) promote ligand-independent receptor activation and resistance to estrogen-deprivation therapy in laboratory models. The prevalence of these mutations and their potential impact on clinical outcomes has not been established. To determine the prevalence of ESR1 mutations (Y537S and D538G) in estrogen receptor (ER)-positive MBC and determine whether mutation is associated with inferior outcomes. From December 16, 2014, to August 26, 2015, we analyzed cell-free DNA (cfDNA) from baseline plasma samples from participants in the BOLERO-2 double-blind phase 3 study that randomized patients from 189 centers in 24 countries with MBC to exemestane plus placebo or exemestane plus everolimus. The study enrolled postmenopausal women with a diagnosis of MBC and prior exposure to an aromatase inhibitor. Baseline plasma samples were available from 541 of 724 patients (74.7%). We assessed the effect of mutation on overall survival of the population and the effect of mutation on progression-free survival (PFS) by treatment arm. Patients were randomized to treatment with exemestane (25 mg oral daily) together with everolimus (10 mg oral daily) or with placebo. The 2 most frequent mutations in ESR1 (Y537S and D538G) were analyzed from cfDNA using droplet digital polymerase chain reaction and samples scored as wild-type, D538G, Y537S, or double mutant. Cox-proportional hazards model was used to assess PFS in patient subgroups defined by mutations, and the effect of each mutation on overall survival. Of 541 evaluable patients, 156 (28.8%) had ESR1 mutation D538G (21.1%) and/or Y537S (13.3%), and 30 had both. These mutations were associated with shorter overall survival (wild-type, 32.1 months [95% CI, 28.09-36.40 months]; D538G, 25.99 months [95% CI, 19.19-32.36 months]; Y537S, 19.98 months [13.01-29.31 months]; both mutations, 15.15 months [95% CI, 10.87-27.43 months]). The D538G group (hazard ratio, 0.34 [95% CI, 0.02-0.57]) derived a similar PFS benefit as wild type from addition of everolimus to exemestane. ESR1 mutations are prevalent in ER-positive aromatase inhibitor-treated MBC. Both Y537S and D538G mutations are associated with more aggressive disease biology. clinicaltrials.gov Identifier: NCT00863655.

Physicians’ influence on breast cancer patient compliance

PubMed Central

Kostev, Karel; Waehlert, Lilia; Jockwig, Achim; Jockwig, Barbara; Hadji, Peyman

2014-01-01

In recent years there have been major advances in the treatment of breast cancer. However, taking the prescribed medication for a sufficient period of time is crucial to the success of any therapy. Thus far, no database-based studies have been published in German-speaking countries empirically examining the influence of the physician on the compliance of patients. The aim of this study is to investigate, quantify, and critically discuss the effect treating physicians have on the compliance of their breast cancer patients. Patients with a confirmed breast cancer diagnosis who started therapy (tamoxifen or aromatase inhibitors) between January 2001 and December 2011 were selected from the representative IMS Disease Analyzer database and analyzed with regard to their compliance. Practices were grouped into two categories concerning the compliance of all treated patients. A regression model showed that a breast cancer patient who is treated in a practice with a trend toward poor compliance has a nearly 60% higher risk for treatment discontinuation than would be the case in a practice with good compliance. It shows how important it is to motivate physicians to strive toward good compliance rates. PMID:24454275

Computational modeling of dynamic alteration of plasma vitellogenin in response to aromatase CYP19 inhibition in fathead minnows

EPA Science Inventory

In vertebrates, conversion of testosterone into 17β-estradiol (E2) is catalyzed by cytochrome P450 (CYP) 19A aromatase. An important role of E2 in oviparous vertebrates such as fish is stimulation of hepatic synthesis of the glycolipoprotein vitellogenin (VTG), an egg yolk precur...

The Anxiolytic and Antidepressant-like Effects of Testosterone and Estrogen in Gonadectomized Male Rats

PubMed Central

Carrier, Nicole; Saland, Samantha K.; Duclot, Florian; He, Huan; Mercer, Roger; Kabbaj, Mohamed

2015-01-01

Background While the influence of testosterone levels on vulnerability to affective disorders is not straightforward, research suggests this hormone may confer some degree of resiliency in men. We recently demonstrated a role for the dentate gyrus in mediating testosterone’s protective effects on depressive-like behavior in gonadectomized male rats. Here, testosterone may exert its effects through androgen receptor-mediated mechanisms or via local aromatization to estradiol. Methods Gonadectomized male rats were implanted with a placebo, testosterone, or estradiol pellet, and subsequent protective anxiolytic- and antidepressant-like effects of testosterone and its aromatized metabolite, estradiol, were then investigated in the open field and sucrose preference tests, respectively. Moreover, their influence on gene expression in the hippocampus was analyzed by genome-wide cDNA microarray analysis. Finally, the contribution of testosterone’s aromatization within the dentate gyrus was assessed by local infusion of the aromatase inhibitor, fadrozole, whose efficacy was confirmed by LC-MS/MS. Results Both hormones had antidepressant-like effects associated with a substantial overlap in transcriptional regulation, particularly in synaptic plasticity- and mitogen-activated protein kinase pathway-related genes. Further, chronic aromatase inhibition within the dentate gyrus blocked the protective effects of testosterone. Conclusions Both testosterone and estradiol exhibit anxiolytic- and antidepressant-like effects in gonadectomized male rats, while similarly regulating critical mediators of these behaviors, suggesting common underlying mechanisms. Accordingly, we demonstrated that testosterone’s protective effects are mediated, in part, by its aromatization in the dentate gyrus. These findings thus provide further insight into a role for estradiol in mediating the protective anxiolytic- and antidepressant-like effects of testosterone. PMID:25683735

The turnover of estrogen receptor α by the selective estrogen receptor degrader (SERD) fulvestrant is a saturable process that is not required for antagonist efficacy

PubMed Central

Wardell, Suzanne E.; Marks, Jeffrey R.; McDonnell, Donald P.

2011-01-01

It has become apparent of late that even in tamoxifen and/or aromatase resistant breast cancers, ERα remains a bona fide therapeutic target. Not surprisingly, therefore, there has been considerable interest in developing Selective ER Degraders (SERDs), compounds that target the receptor for degradation. Currently, ICI 182,780 (ICI, fulvestrant) is the only SERD approved for the treatment of breast cancer. However, the poor pharmaceutical properties of this injectable drug and its lack of superiority over second line aromatase inhibitors in late stage breast cancer have negatively impacted its clinical use. These findings have provided the impetus to develop second generation, orally bioavailable SERDs with which quantitative turnover of ERα in tumors can be achieved. Interestingly however, the contribution of SERD activity to fulvestrant efficacy is unclear, making it difficult to define the characteristics desired of the next generation of ER antagonists. It is of significance therefore, that we have determined that the antagonist activity of ICI and its ability to induce ERα degradation are not coupled processes. Specifically, our results indicate that it is the ability of ICI to interact with ERα and to (a) competitively displace estradiol and (b) induce a conformational change in ER incompatible with transcriptional activation that are likely to be the most important pharmacological characteristics of this drug. Collectively, these data argue for a renewed emphasis on the development of high affinity, orally bioavailable pure antagonists and suggest that SERD activity though proven effective may not be required for ERα antagonism in breast cancer. PMID:21501600

Treatment with Ruta graveolens 5CH and Rhus toxicodendron 9CH may reduce joint pain and stiffness linked to aromatase inhibitors in women with early breast cancer: results of a pilot observational study.

PubMed

Karp, Jean-Claude; Sanchez, Carole; Guilbert, Philippe; Mina, William; Demonceaux, Antoine; Curé, Hervé

2016-11-01

To determine the possible effect of two homeopathic medicines, Ruta graveolens 5CH and Rhus toxicodendron 9CH, in the prevention of aromatase inhibitor (AI) associated joint pain and/or stiffness in women with early, hormone-receptor positive, breast cancer. This prospective, unrandomized observational study was carried out between April and October 2014. Women were recruited in two groups, according to which of the two study centres they attended: one receiving homeopathy in addition to standard treatment (group H) and a control group, receiving standard treatment (group C). All women were treated with an AI. In addition, women in group H also took Ruta graveolens 5CH and Rhus toxicodendron 9CH (5 granules, twice a day) up to 7 days before starting AI treatment. The homeopathic medicines were continued for 3 months. Demographic and clinical data were recorded using a self-assessment questionnaire at inclusion (T0) and 3 months (T3). Primary evaluation criteria were the evolution of scores for joint pain and stiffness, the impact of pain on sleep and analgesic consumption in the two groups after 3 months of treatment. Forty patients (mean age 64.9±8.1 years) were recruited, 20 in each group. Two-thirds of the patients had joint pain before starting AI treatment. There was a significant difference in the evolution of mean composite pain score between T0 and T3 in the two groups (-1.3 in group H vs. +3.4 in group C; p=0.0001). The individual components of the pain score (frequency, intensity and number of sites of pain) also decreased significantly in group H. Nine patients in group C (45%) vs. 1 (5%) in group H increased their analgesic consumption between T0 and T3 (p=0.0076). After 3 months of treatment, joint pain had a worse impact on sleep in patients in group C (35% vs. 0% of patients; p=0.0083). The differences observed in the evolution of morning and daytime stiffness between the two groups were smaller (p=0.053 and p=0.33, respectively), with the exception of time necessary for the disappearance of morning stiffness which was greater in group C (37.7±23.0 vs. 17.9±20.1 min; p=0.0173). These preliminary results suggest that treatment with Ruta graveolens 5CH and Rhus toxicodendron 9CH may decrease joint pain/stiffness in breast cancer patients treated with AIs. A larger-scale randomized study is required to confirm these results. Copyright © 2016 The Faculty of Homeopathy. Published by Elsevier Ltd. All rights reserved.

Management of bone disease in women after breast cancer.

PubMed

Milat, F; Vincent, A J

2015-01-01

Breast cancer and osteoporosis are common conditions affecting women, particularly following menopause. With increasing breast cancer incidence, effects of therapies and decreasing mortality, issues relating to the preservation of bone health with breast cancer therapy have become a priority. Contributing factors to bone loss and fractures in women with breast cancer include tumor effects, estrogen deprivation secondary to breast cancer therapies (chemotherapy, ovarian ablation or aromatase inhibitors), natural menopause and secondary causes of bone loss, typically from concurrently prescribed medications. Management of osteoporosis and other survivorship care is complex, and a multi-disciplinary approach is recommended with assessment of risk factors for bone loss, optimization of bone health through lifestyle approaches and pharmacological interventions based on evidence-based algorithms. This review examines the pathophysiology of bone loss and gives guidelines for the management of bone disease in women with breast cancer.

Real-world effectiveness of everolimus-based therapy versus fulvestrant monotherapy in HR(+)/HER2(-) metastatic breast cancer.

PubMed

Hao, Yanni; Lin, Peggy L; Xie, Jipan; Li, Nanxin; Koo, Valerie; Ohashi, Erika; Wu, Eric Q; Rogerio, Jaqueline

2015-08-01

Assessing real-world effectiveness of everolimus-based therapy (EVE) versus fulvestrant monotherapy (FUL) among postmenopausal women with hormone receptor-positive (HR(+))/HER2(-) metastatic breast cancer (mBC) after progression on nonsteroidal aromatase inhibitor (NSAI). Medical charts of community-based patients who received EVE or FUL for mBC after NSAI were examined. Progression-free survival (PFS), time on treatment and time to chemotherapy were compared using Kaplan-Meier curves and Cox proportional hazards models adjusting for line of therapy and patient characteristics. 192 patients received EVE and 156 FUL. After adjusting for patient characteristics, EVE was associated with significantly longer PFS than FUL (hazard ratio: 0.71; p = 0.045). EVE was associated with better PFS than FUL among NSAI-refractory postmenopausal HR(+)/HER2(-) mBC patients.

[Anabolic steroid induced hypogonadism in men: overview and case report].

PubMed

Stárka, Luboslav; Dušková, Michaela; Kolátorová, Lucie; Lapčík, Oldřich

An important potential consequence of the anabolic steroid misuse is hypogonadotropic hypogonadism due to the inhibition of pituitary secretion of gonadotropins. By the symptoms as testicular atrophy, spermatogenic and fertility disturbances or dysfunction in sexual life, the anabolic steroids induced hypogonadism (ASIH) could be differentiated from organic hypogonadotropic hypogonadism only with difficulty unless the misuse is reported by the user. When diagnosed, the crucial step in the therapy is the stop of anabolic use. Convalescence lasts usually several months or even more than one year. First could be seen the retreat of testicular atrophy followed by the rearrangement of spermatogenesis. The users mainly well informed from internet use for amelioration of the symptoms injections of human choriogonadotropin (hCG), selective estrogen receptor modulators (SERM) or aromatase inhibitors.Key words: anabolic steroids - doping - hypogonadotropic hypogonadism - side effects.

The Impact of Endocrine Therapy on Cognitive Functions of Breast Cancer Patients: A Systematic Review.

PubMed

Bakoyiannis, Ioannis; Tsigka, Eleousa-Alexandra; Perrea, Despina; Pergialiotis, Vasilios

2016-02-01

The purpose of the present review was to study the impact of endocrine therapy (ET) on the cognitive outcomes of breast cancer patients. We systematically searched the literature using the MEDLINE (1966-2015), Scopus (2004-2015), ClinicalTrials.gov (2008-2015) and Cochrane Central Register (CENTRAL) databases, as well as the references of the electronically retrieved articles. Twelve studies were included in the present systematic review, which assessed the cognitive function of 2756 patients. Among these patients, 2381 received ET, whereas the remaining 375 served as controls (placebo or no therapy). The majority of patients were postmenopausal, and the minimum follow-up period was 3 months and the maximum 2 years. Treatment with ET seems to be accompanied by altered cognitive abilities, including verbal memory, verbal fluency, motor speed, attention and working memory. Tamoxifen seems to be related to decreased cognitive performances compared with treatment with an aromatase inhibitor. ET among breast cancer patients seems to negatively alter the cognitive outcomes of breast cancer patients. However, the methodological heterogeneity of the included studies, as well as the relatively small follow-up period, render imperative the conduct of further studies in the field.

Localization and Divergent Profiles of Estrogen Receptors and Aromatase in the Vocal and Auditory Networks of a Fish with Alternative Mating Tactics

PubMed Central

Fergus, Daniel J.; Bass, Andrew H.

2013-01-01

Estrogens play a salient role in the development and maintenance of both male and female nervous systems and behaviors. The plainfin midshipman (Porichthys notatus), a teleost fish, has two male reproductive morphs that follow alternative mating tactics and diverge in multiple somatic, hormonal and neural traits, including the central control of morph-specific vocal behaviors. After we identified duplicate estrogen receptors (ERβ1 and ERβ2) in midshipman, we developed antibodies to localize protein expression in the central vocal-acoustic networks and saccule, the auditory division of the inner ear. As in other teleost species, ERβ1 and ERβ2 were robustly expressed in the telencephalon and hypothalamus in vocal-acoustic and other brain regions shown previously to exhibit strong expression of ERα and aromatase (estrogen synthetase, CYP19) in midshipman. Like aromatase, ERβ1 label co-localized with glial fibrillary acidic protein (GFAP) in telencephalic radial glial cells. Quantitative PCR revealed similar patterns of transcript abundance across reproductive morphs for ERβ1, ERβ2, ERα and aromatase in the forebrain and saccule. In contrast, transcript abundance for ERs and aromatase varied significantly between morphs in and around the sexually polymorphic vocal motor nucleus (VMN). Together, the results suggest that VMN is the major estrogen target within the estrogen-sensitive hindbrain vocal network that directly determines the duration, frequency and amplitude of morph-specific vocalizations. Comparable regional differences in steroid receptor abundances likely regulate morph-specific behaviors in males and females of other species exhibiting alternative reproductive tactics. PMID:23460422

Interactions between aromatase (estrogen synthase) and dopamine in the control of male sexual behavior in quail.

PubMed

Balthazart, Jacques; Baillien, Michelle; Ball, Gregory F

2002-05-01

In male quail, like in other vertebrates including rodents, testosterone acting especially through its estrogenic metabolites is necessary for the activation of male sexual behavior. Also, the administration of dopamine agonists and antagonists profoundly influences male sexual behavior. How the steroid-sensitive neural network and dopamine interact physiologically, remains largely unknown. It is often implicitly assumed that testosterone or its metabolite estradiol, stimulates male sexual behavior via the modification of dopaminergic transmission. We have now identified in quail two possible ways in which dopamine could potentially affect sexual behavior by modulating the aromatization of testosterone into an estrogen. One is a long-acting mechanism that presumably involves the modification of dopaminergic transmission followed by the alteration of the genomic expression of aromatase. The other is a more rapid mechanism that does not appear to be dopamine receptor-mediated and may involve a direct interaction of dopamine with aromatase (possibly via substrate competition). We review here the experimental data supporting the existence of these controls of aromatase activity by dopamine and discuss the possible contribution of these controls to the activation of male sexual behavior.

Dimethandrolone (7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone are not converted to aromatic A-ring products in the presence of recombinant human aromatase☆

PubMed Central

Attardi, Barbara J.; Pham, Trung C.; Radler, Lisa M.; Burgenson, Janet; Hild, Sheri A.; Reel, Jerry R.

2008-01-01

Dimethandrolone undecanoate (DMAU: 7α,11β-dimethyl-19-nortestosterone 17β-undecanoate) is a potent orally active androgen in development for hormonal therapy in men. Cleavage of the 17β-ester bond by esterases in vivo leads to liberation of the biologically active androgen, dimethandrolone (DMA), a 19-norandrogen. For hormone replacement in men, administration of C19 androgens such as testosterone (T) may lead to elevations in circulating levels of estrogens due to aromatization. As several reports have suggested that certain 19-norandrogens may serve as substrates for the aromatase enzyme and are converted to the corresponding aromatic A-ring products, it was important to investigate whether DMA, the related compound, 11β-methyl-19-nortestosterone (11β-MNT), also being tested for hormonal therapy in men, and other 19-norandrogens can be converted to aromatic A-ring products by human aromatase. The hypothetical aromatic A-ring product corresponding to each substrate was obtained by chemical synthesis. These estrogens bound with high affinity to purified recombinant human estrogen receptors (ER) α and β in competitive binding assays (IC50's: 5−12 × 10−9 M) and stimulated transcription of 3XERE-luciferase in T47Dco human breast cancer cells with a potency equal to or greater than that of estradiol (E2) (EC50's: 10−12 to 10−11 M). C19 androgens (T, 17α-methyltestosterone (17α-MT), androstenedione (AD), and 16α-hydroxyandrostenedione (16α-OHAD)), 19-norandrogens (DMA, 11β-MNT, 19-nortestosterone (19-NT), and 7α-methyl-19-nortestosterone (MENT)) or the structurally similar 19-norprogestin, norethindrone (NET) were incubated at 50 μM with recombinant human aromatase for 10−180 min at 37 °C. The reactions were terminated by extraction with acetonitrile and centrifugation, and substrate and potential product were separated by HPLC. Retention times were monitored by UV absorption, and UV peaks were quantified using standard curves. Aromatization of the positive controls, T, AD, and 16α-OHAD was linear for 40−60 min, and conversion of T or AD was complete by 120 min. The nonsteroidal aromatase inhibitor, letrozole, demonstrated concentration-dependent suppression of T aromatization. Under the same conditions, there was no detectable conversion of DMA, 11β-MNT, or NET to their respective hypothetical aromatic A-ring products during incubation times up to 180 min. Aromatization of MENT and 19-NT proceeded slowly and was limited. Collectively, these data support the notion that in the absence of the C19-methyl group, which is the site of attack by oxygen, aromatization of androgenic substrates proceeds slowly or not at all and that this reaction is impeded by the presence of a methyl group at the 11β position. PMID:18555683

TGF-beta1 stimulates expression of the aromatase (CYP19) gene in human osteoblast-like cells and THP-1 cells.

PubMed

Shozu, M; Zhao, Y; Simpson, E R

2000-02-25

Recent evidence has shown that bone is not only a target of estrogen action but also a source of local estrogen production. Bone cells such as osteoblasts express aromatase (P450arom) and the expression of P450arom in osteoblasts is positively regulated in a tissue specific fashion, as in the case of other tissues which express P450arom. To clarify the physiological factors regulating expression of P450arom in bone, we tested TGF-beta1 using osteoblast-like cells obtained from human fetuses as well as THP-1 cells. TGF-beta1 increased IL-1beta+DEX- induced aromatase activity in osteoblast-like cells, while it inhibited activity in skin fibroblasts. Similar enhancement of aromatase activity by TGF-beta1 was found in DEX-stimulated THP-1 cells and this cell line was used for further experiments. In THP-1 cells, TGF-beta1 enhanced DEX-induced aromatase activity almost linearly by 12 h and thereafter. Increased levels of P450arom transcripts were also demonstrated by RT-PCR at 3 h of TGF-beta1 treatment and thereafter. Cyclohexamide abolished enhancement of activity but did not inhibit the accumulation of P450arom transcripts induced by TGF-beta1. Increase in P450arom expression by TGF-beta1 was attributable to expression driven by promoter I.4. TGF-beta1 did not change the half life of P450arom transcripts. To identify the cis-acting elements responsible for TGF-beta1 action on aromatase expression, transient transfection assays were performed using a series of deletion constructs for promoter I.4 (P450-I.4/Luc). Two constructs (-410/+14 and-340/+14) that contain a functional glucocorticoid response element (GRE) and downstream sequence showed significant increase of luciferase activity in response to TGF-beta1. Deletion and mutation of the GRE in P450-I.4/Luc (-340/+14) abolished the TGF-beta1. The luciferase activity of a (GRE)(1)-SV40/Luc construct was also stimulated by TGF-beta1. These results indicate that TGF-beta1 increases the expression of P450arom at the level of transcription through promoter I.4, at least in part via an enhancement of transactivation activity of the GR in THP-1 cells. TGF-beta1 is suggested to be one of the physiological up-regulatory factors of bone aromatase.

Development of a Novel Tissue Specific Aromatase Activity Regulation Therapeutic Method

DTIC Science & Technology

2009-09-01

Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Estrogen is essential for normal growth and development of the female ...the ovaries and other tissues of the body using an enzyme called aromatase. Once women have reached menopause, the ovaries no longer produce estrogen...Introduction Estrogen is essential for normal growth and development of the female reproductive system, including breast tissue, and lifetime

Expression and regulation of aromatase and 17 beta-hydroxysteroid dehydrogenase type 4 in human THP 1 leukemia cells.

PubMed

Jakob, F; Homann, D; Adamski, J

1995-12-01

Estradiol is active in proliferation and differentiation of sex-related tissues like ovary and breast. Glandular steroid metabolism was for a long time believed to dominate the estrogenic milieu around any cell of the organism. Recent reports verified the expression of estrogen receptors in "non-target" tissues as well as the extraglandular expression of steroid metabolizing enzymes. Extraglandular steroid metabolism proved to be important in the brain, skin and in stromal cells of hormone responsive tumors. Aromatase converts testosterone into estradiol and androstenedione into estrone, thereby activating estrogen precursors. The group of 17 beta-hydroxysteroid dehydrogenases catalyzes the oxidation and/or reduction of the forementioned compounds, e.g. estradiol/estrone, thereby either activating or inactivating estradiol. Aromatase is expressed and regulated in the human THP 1 myeloid leukemia cell line after vitamin D/GMCSF-propagated differentiation. Aromatase expression is stimulated by dexamethasone, phorbolesters and granulocyte/macrophage stimulating factor (GMCSF). Exons I.2 and I.4 are expressed in PMA-stimulated cells only, exon I.3 in both PMA- and dexamethasone-stimulated cells. Vitamin D-differentiated THP 1 cells produce a net excess of estradiol in culture supernatants, if testosterone is given as aromatase substrate. In contrast, the 17 beta-hydroxysteroid dehydrogenase type 4 (17 beta-HSD 4) is abundantly expressed in unstimulated THP 1 cells and is further stimulated by glucocorticoids (2-fold). The expression is unchanged after vitamin D/GMCSF-propagated differentiation. 17 beta-HSD 4 expression is not altered by phorbolester treatment in undifferentiated cells but is abolished after vitamin D-propagated differentiation along with downregulation of beta-actin. Protein kinase C activation therefore appears to dissociate the expression of aromatase and 17 beta-HSD 4 in this differentiation stage along the monocyte/phagocyte pathway of THP 1 myeloid cells. The expression of steroid metabolizing enzymes in myeloid cells is able to create a microenvironment which is uncoupled from dominating systemic estrogens. These findings may be relevant in the autocrine, paracrine or iuxtacrine cellular crosstalk of myeloid cells in their respective states of terminal differentiation, e.g. in bone metabolism and inflammation.

Sex steroid-related genes and male-to-female transsexualism.

PubMed

Henningsson, Susanne; Westberg, Lars; Nilsson, Staffan; Lundström, Bengt; Ekselius, Lisa; Bodlund, Owe; Lindström, Eva; Hellstrand, Monika; Rosmond, Roland; Eriksson, Elias; Landén, Mikael

2005-08-01

Transsexualism is characterised by lifelong discomfort with the assigned sex and a strong identification with the opposite sex. The cause of transsexualism is unknown, but it has been suggested that an aberration in the early sexual differentiation of various brain structures may be involved. Animal experiments have revealed that the sexual differentiation of the brain is mainly due to an influence of testosterone, acting both via androgen receptors (ARs) and--after aromatase-catalyzed conversion to estradiol--via estrogen receptors (ERs). The present study examined the possible importance of three polymorphisms and their pairwise interactions for the development of male-to-female transsexualism: a CAG repeat sequence in the first exon of the AR gene, a tetra nucleotide repeat polymorphism in intron 4 of the aromatase gene, and a CA repeat polymorphism in intron 5 of the ERbeta gene. Subjects were 29 Caucasian male-to-female transsexuals and 229 healthy male controls. Transsexuals differed from controls with respect to the mean length of the ERbeta repeat polymorphism, but not with respect to the length of the other two studied polymorphisms. However, binary logistic regression analysis revealed significant partial effects for all three polymorphisms, as well as for the interaction between the AR and aromatase gene polymorphisms, on the risk of developing transsexualism. Given the small number of transsexuals in the study, the results should be interpreted with the utmost caution. Further study of the putative role of these and other sex steroid-related genes for the development of transsexualism may, however, be worthwhile.

In vitro and in vivo metabolic investigation of the Palbociclib by UHPLC-Q-TOF/MS/MS and in silico toxicity studies of its metabolites.

PubMed

Chavan, Balasaheb B; Tiwari, Shristy; G, Shankar; Nimbalkar, Rakesh D; Garg, Prabha; R, Srinivas; Talluri, M V N Kumar

2018-05-14

Palbociclib (PAB) is a CDK4/6 inhibitor and U. S Food and Drug Administration (FDA) granted regular approval for the treatment of hormone receptor (HR) positive, metastatic breast cancer in combination with an aromatase inhibitor in postmenopausal women. Metabolite identification is a crucial aspect during drug discovery and development as the drug metabolites may be pharmacologically active or possess toxicological activity. As there are no reports on the metabolism studies of the PAB, the present study focused on investigation of the in vitro and in vivo metabolic fate of the drug. The in vitro metabolism studies were carried out by using microsomes (HLM and RLM) and S9 fractions (Human and rat). The in vivo metabolism of the drug was studied by administration of the PAB orally to the Sprague-Dawley rats followed by analysis of urine, faeces and plasma samples. The sample preparation includes simple protein precipitation (PP) followed by solid phase extraction (SPE). The extracted samples were analyzed by ultrahigh-performance liquid chromatography-quadruple time-of-flight tandem mass spectrometry (UHPLC/Q-TOF/MS/MS). A total of 14 metabolites were detected in in vivo matrices. The PAB was metabolized via hydroxylation, oxidation, sulphation, N-dealkylation, acetylation and carbonylation pathways. A few of the metabolites were also detected in in vitro samples. Metabolite identification and characterization were performed by using UHPLC/Q-TOF/MS/MS in combination with HRMS data. To identify the toxicity potential of these metabolites, in silico toxicity assessment was carried out using TOPKAT and DEREK softwares. Copyright © 2018. Published by Elsevier B.V.

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

PubMed

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

2018-03-01

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

The planetary biology of cytochrome P450 aromatases.

PubMed

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

2004-08-17

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

Prenatal programming of sexual partner preference: the ram model.

PubMed

Roselli, C E; Stormshak, F

2009-03-01

In our laboratory, the domestic ram is used as an experimental model to study the early programming of neural mechanisms underlying same-sex partner preference. This interest developed from the observation that approximately 8% of domestic rams are sexually attracted to other rams (male-oriented) in contrast to the majority of rams that are attracted to oestrous ewes (female-oriented). One prominent feature of sexual differentiation in many species is the presence of a sexually dimorphic nucleus (SDN) in the preoptic/anterior hypothalamus that is larger in males than in females. Lesion studies in rats and ferrets implicate the SDN in the expression of sexual preferences. We discovered an ovine SDN (oSDN) in the preoptic/anterior hypothalamus that is smaller in male- than in female-oriented rams and similar in size to the oSDN of ewes. Neurones of the oSDN show abundant aromatase expression that is also reduced in male-oriented compared to female-oriented rams. This observation suggests that sexual partner preferences are neurologically hard-wired and could be influenced by hormones. Aromatase-containing neurones constitute a nascent oSDN as early as day 60 of gestation, which becomes sexually dimorphic by day 135 of gestation when it is two-fold larger in males than in females. Exposure of fetal female lambs to exogenous testosterone from days 30-90 of gestation resulted in a masculinised oSDN. These data demonstrate that the oSDN develops prenatally and may influence adult sexual preferences. Surprisingly, inhibition of aromatase activity in the brain of ram foetuses during the critical period did not interfere with defeminisation of adult sexual partner preference or oSDN volume. These results fail to support an essential role for neural aromatase in the sexual differentiation of sheep brain and behaviour. Thus, we propose that oSDN morphology and male-typical partner preferences may instead be programmed through an androgen receptor mechanism not involving aromatisation.

SDN-POA volume, sexual behavior, and partner preference of male rats affected by perinatal treatment with ATD.

PubMed

Houtsmuller, E J; Brand, T; de Jonge, F H; Joosten, R N; van de Poll, N E; Slob, A K

1994-09-01

The present study investigated 1) the importance of the aromatization process during the perinatal period for the development of the sexually dimorphic nucleus in the preoptic area of the hypothalamus (SDN-POA) of male rats, and 2) the relationship between SDN-POA volume and parameters of masculinization in male rats that were treated perinatally with the aromatase-inhibitor ATD. Males were treated with ATD either prenatally or pre- and neonatally, or with the vehicle. Masculine sexual behavior and partner preference were investigated in adulthood. Thereafter, animals were sacrificed and SDN-POA volume was measured. The SDN-POA volume was reduced in both the prenatally and the pre- and neonatally treated group, with a larger reduction in the latter than in the former group. Combined pre- and neonatal ATD treatment resulted in reduced frequency of mounts, intromissions, and ejaculations, as well as a reduced preference for a female over a male. The SDN-POA size was significantly and positively correlated with frequency of masculine sexual behavior, as well as preference for a female over a male.

Fluoxetine and its active metabolite norfluoxetine disrupt estrogen synthesis in a co-culture model of the feto-placental unit.

PubMed

Hudon Thibeault, Andrée-Anne; Laurent, Laetitia; Vo Duy, Sung; Sauvé, Sébastien; Caron, Patrick; Guillemette, Chantal; Sanderson, J Thomas; Vaillancourt, Cathy

2017-02-15

The effects of fluoxetine, one of the most prescribed selective serotonin-reuptake inhibitors (SSRIs) during pregnancy, and its active metabolite norfluoxetine were studied on placental aromatase (CYP19) and feto-placental steroidogenesis. Fluoxetine did not alter estrogen secretion in co-culture of fetal-like adrenocortical (H295R) and trophoblast-like (BeWo) cells used as a model of the feto-placental unit, although it induced CYP19 activity, apparently mediated by the serotonin (5-HT) 2A receptor/PKC signaling pathway. Norfluoxetine decreased estrogen secretion in the feto-placental co-culture and competitively inhibited catalytic CYP19 activity in BeWo cells. Decreased serotonin transporter (SERT) activity in the co-culture was comparable to 17β-estradiol treatment of BeWo cells. This work shows that the complex interaction of fluoxetine and norfluoxetine with placental estrogen production, involves 5-HT-dependent and -independent mechanisms. Considering the crucial role of estrogens during pregnancy, our results raise concern about the impact of SSRI treatment on placental function and fetal health. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Estrogen receptor agonists/antagonists in breast cancer therapy: A critical review.

PubMed

Jameera Begam, A; Jubie, S; Nanjan, M J

2017-04-01

Estrogens display intriguing tissue selective action that is of great biomedical importance in the development of optimal therapeutics for the prevention and treatment of breast cancer. There are also strong evidences to show that both endogenous and exogenous estrogens are involved in the pathogenesis of breast cancer. Tamoxifen has been the only drug of choice for more than 30years to treat patients with estrogen related (ER) positive breast tumors. There is a need therefore, for identifying newer, potential and novel candidates for breast cancer. Keeping this in view, the present review focuses on selective estrogen receptor modulators and estrogen antagonists such as sulfatase and aromatase inhibitors involved in breast cancer therapy. A succinct and critical overview of the structure of estrogen receptors, their signaling and involvement in breast carcinogenesis are herein described. Copyright © 2017 Elsevier Inc. All rights reserved.

Ovulation induction in normogonadotropic anovulation (PCOS).

PubMed

van Santbrink, Evert J P; Fauser, Bart C J M

2006-06-01

Treatment of normogonadotropic anovulatory infertility (World Health Organization class 2, or WHO2) is by induction of ovulation using clomiphene citrate (CC), followed by follicle-stimulating hormone (FSH) in cases of treatment failure. Not all patients will become ovulatory or will conceive with this treatment. Others, exhibiting multifollicular instead of monofollicular development, may encounter complications such as ovarian hyperstimulation and multiple pregnancy. Recently introduced alternative treatment interventions-such as insulin-sensitizing drugs, aromatase inhibitors, or laparoscopic electrocautery of the ovaries-may offer the possibility of improving the efficacy of the classical ovulation induction algorithm. Based on initial patient characteristics, it may be possible to identify specific patient subgroups with altered chances of success or complications while using one of these interventions. Regarding CC and FSH ovulation induction, this has been performed using multivariate prediction models. This approach may enable us to improve safety, cost-effectiveness, and patient convenience in future ovulation induction.

Ovulation induction: a mini review.

PubMed

Messinis, Ioannis E

2005-10-01

Ovulation induction is the method for treating anovulatory infertility. For patients with hypogonadotrophic hypogonadism, the treatment involves administration of both FSH and LH, while HCG is injected for follicle rupture. Pulsatile GnRH has the same effectiveness as gonadotrophins and the advantage of the low multiple pregnancy rate. In polycystic ovary syndrome (PCOS), the first treatment choice is clomiphene citrate. With this drug, in properly selected patients, the cumulative pregnancy rate approaches that of normal women. Low-dose protocols of FSH are the second line of treatment, effective in inducing monofollicular development. Laparoscopic ovarian drilling can be an alternative but not as a first choice treatment in clomiphene-resistant patients. Other treatments, such as pulsatile GnRH and GnRH agonists, are hardly used today in PCOS. However, in obese women with PCOS, weight loss and exercise should be recommended as the first line of therapy. Newer agents including aromatase inhibitors and insulin sensitizers, although promising, need further evaluation.

[Benign metastasizing leiomyoma: An unusual cause of aggressive femoral bone tumor].

PubMed

Alexandre, L; Taillieu, F; Arlet, J-B; Passeron, A; Michon, A; Bats, A-S; Pouchot, J; Ranque, B

2018-06-01

Benign metastasizing leiomyoma (BML) is a rare condition characterized by histologically benign "metastatic" smooth muscle tumors, which can affect women with history of uterine surgery. We report the case of a patient with bone metastases of BML. A 78-year-old woman who had undergone uterine surgery six years before hospital admission, was diagnosed with large pulmonary and pleural metastases that necessitated surgical removal. Pathological examination allowed the diagnosis of BML with positive staining for estrogen and progesterone receptors. Three years later, a BML metastasis in the right femoral diaphysis was unexpectedly discovered and treated by osteosynthesis because of a high risk of fracture. Despite an aromatase-inhibitor treatment, new lungs lesions appeared in the next few months. BML is a potential cause of aggressive, although histologically benign, bone tumor in women with a history of uterine surgery. Copyright © 2018. Published by Elsevier SAS.

The Cytochrome P450 Enzyme Responsible for the Production of (Z)-Norendoxifen in vitro.

PubMed

Ma, Jianli; Chu, Zhong; Lu, Jessica Bo Li; Liu, Jinzhong; Zhang, Qingyuan; Liu, Zhaoliang; Tang, Dabei

2018-01-01

Norendoxifen, an active metabolite of tamoxifen, is a potent aromatase inhibitor. Little information is available regarding production of norendoxifen in vitro. Here, we conducted a series of kinetic and inhibition studies in human liver microsomes (HLMs) and expressed P450s to study the metabolic disposition of norendoxifen. To validate that norendoxifen was the metabolite of endoxifen, metabolites in HLMs incubates of endoxifen were measured using a HPLC/MS/MS method. To further probe the specific isoforms involved in the metabolic route, endoxifen was incubated with recombinant P450s (CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, 3A5 and CYP4A11). Formation rates of norendoxifen were evaluated in the absence and presence of P450 isoform specific inhibitors using HLMs. The peak of norendoxifen was found in the incubations consisting of endoxifen, HLMs, and cofactors. The retention times of norendoxifen, endoxifen, and the internal standard (diphenhydramine) were 7.81, 7.97, and 5.86 min, respectively. The K m (app) and V max (app) values of norendoxifen formation from endoxifen in HLM was 47.8 μm and 35.39 pmol min -1 mg -1 . The apparent hepatic intrinsic clearances of norendoxifen formation were 0.74 μl mg -1 min. CYP3A5 and CYP2D6 were the major enzymes capable of norendoxifen formation from endoxifen with the rates of 0.26 and 0.86 pmol pmol -1 P450 × min. CYP1A2, 3A2, 2C9, and 2C19 also contributed to norendoxifen formation, but the contributions were at least 6-fold lower. One micromolar ketoconazole (CYP3A inhibitor) showed an inhibitory effect on the rates of norendoxifen formation by 45%, but 1 μm quinidine (CYP2D6 inhibitor) does not show any inhibitory effect. Norendoxifen, metabolism from endoxifen by multiple P450s that including CYP3A5. © 2018 Wiley-VHCA AG, Zurich, Switzerland.

Characterization of a cis-acting element involved in cell-specific expression of the zebrafish brain aromatase gene.

PubMed

Le Page, Yann; Menuet, Arnaud; Kah, Olivier; Pakdel, Farzad

2008-10-01

The cytochrome P450 Aromatase is the key enzyme catalyzing the conversion of androgens into estrogens. In zebrafish, the brain aromatase is encoded by cyp19b. Expression of cyp19b is restricted to radial glial cells bordering forebrain ventricles and is strongly stimulated by estrogens during development. At the promoter level, we have previously shown that an estrogen responsive element (ERE) is required for induction by estrogens. Here, we investigated the role of ERE flanking regions in the control of cell-specific expression. First, we show that a 20 bp length motif, named G x RE (glial x responsive element), acts in synergy with the ERE to mediate the estrogenic induction specifically in glial cells. Second, we demonstrate that, in vitro, this sequence binds factors exclusively present in glial or neuro-glial cells and is able to confer a glial specificity to an artificial estrogen-dependent gene. Taken together, these results contribute to the understanding of the molecular mechanisms allowing cyp19b regulation by estrogens and allowed to identify a promoter sequence involved in the strong estrogen inducibility of cyp19b which is specific for glial cells. The exceptional aromatase activity measured in the brain of teleost fish could rely on such mechanisms.

Targeted Therapy for Breast Cancer Prevention

PubMed Central

den Hollander, Petra; Savage, Michelle I.; Brown, Powel H.

2013-01-01

With a better understanding of the etiology of breast cancer, molecularly targeted drugs have been developed and are being testing for the treatment and prevention of breast cancer. Targeted drugs that inhibit the estrogen receptor (ER) or estrogen-activated pathways include the selective ER modulators (tamoxifen, raloxifene, and lasofoxifene) and aromatase inhibitors (AIs) (anastrozole, letrozole, and exemestane) have been tested in preclinical and clinical studies. Tamoxifen and raloxifene have been shown to reduce the risk of breast cancer and promising results of AIs in breast cancer trials, suggest that AIs might be even more effective in the prevention of ER-positive breast cancer. However, these agents only prevent ER-positive breast cancer. Therefore, current research is focused on identifying preventive therapies for other forms of breast cancer such as human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer (TNBC, breast cancer that does express ER, progesterone receptor, or HER2). HER2-positive breast cancers are currently treated with anti-HER2 therapies including trastuzumab and lapatinib, and preclinical and clinical studies are now being conducted to test these drugs for the prevention of HER2-positive breast cancers. Several promising agents currently being tested in cancer prevention trials for the prevention of TNBC include poly(ADP-ribose) polymerase inhibitors, vitamin D, and rexinoids, both of which activate nuclear hormone receptors (the vitamin D and retinoid X receptors). This review discusses currently used breast cancer preventive drugs, and describes the progress of research striving to identify and develop more effective preventive agents for all forms of breast cancer. PMID:24069582

A Review of Fulvestrant in Breast Cancer.

PubMed

Nathan, Mark R; Schmid, Peter

2017-01-01

Fulvestrant is a selective estrogen receptor degrader that binds, blocks and degrades the estrogen receptor (ER), leading to complete inhibition of estrogen signaling through the ER. This review article further explains the mechanism of action of the drug and goes on to review the trials carried out to optimize its dosing. Multiple trials have been undertaken to compare fulvestrant with other endocrine treatments, and results have shown it to have similar efficacy to anastrozole, tamoxifen and exemestane at 250 mg every 28 days. However, when given at 500 mg every 28 days, with an extra loading dose on day 14, it has demonstrated an improved progression-free survival (PFS) compared to anastrozole. We look at how fulvestrant has been used in combination with CDK4/6 inhibitors such as palbociclib (PALOMA-3) and ribociclib (MONALEESA-3) and drugs targeting the PI3K/AKT/mTOR pathway such as pictilisib (FERGI) and buparlisib (BELLE-2 and BELLE-3). We then go on to describe a selection of the ongoing clinical trials looking at combination therapy involving fulvestrant. Finally, we review the effect of fulvestrant in patients who have developed resistance to aromatase inhibitors via ESR1 mutation, where it has been shown to offer a PFS benefit that is further improved by the addition of the CDK4/6 inhibitor palbociclib. Whilst fulvestrant is clearly an effective drug as monotherapy, we believe that its role in the treatment of ER-positive breast cancer may be best reserved for combination therapy, and whilst there are multiple trials currently in progress, it would appear that the combination with CDK4/6 inhibitors would offer the greatest promise in terms of balancing benefit with toxicity.

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

PubMed

Ohe, E

1994-03-01

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

Relevance of anti-inflammatory and antioxidant activities of exemestane and synergism with sulforaphane for disease prevention

PubMed Central

Liu, Hua; Talalay, Paul

2013-01-01

Exemestane (6-methyleneandrosta-1,4-diene-3,17-dione) is a synthetic steroidal inhibitor of the aromatase reaction that catalyzes the terminal and rate-limiting step of the biosynthesis of estrogens. It is active clinically in preventing, delaying progression of, and treating mammary cancers, many of which are estrogen receptor-positive. A striking feature of the structure of exemestane is an extended system of conjugated Michael reaction functions, which is also characteristic of inducers of a broad network of chemoprotective genes regulated by the Keap1 (Kelch-like ECA-associated protein)/Nrf2 (nuclear factor E2-related factor 2)/ARE (antioxidant response element) signaling system. These genes are largely involved in xenobiotic metabolism and antioxidative and anti-inflammatory protection, as well as the synthesis and reduction of glutathione. We show here that exemestane transcriptionally activates NAD(P)H:quinone oxidoreductase 1 (NQO1) and heme oxygenase 1 (HO-1), typical chemoprotective gene products, in a wide variety of mouse, rat, and human cells. It protects several cell lines against oxidative toxicity of tert-butyl hydroperoxide and 4-hydroxynonenal, against free radical damage arising from hypoxia–reoxygenation, and against UVA radiation damage. Exemestane also inhibits the inflammatory increases in inducible nitric oxide synthase (iNOS) in mouse macrophages exposed to LPS (lipopolysaccharide), thereby resembling the isothiocyanate sulforaphane derived from broccoli. Remarkably, combinations of exemestane and sulforaphane act highly synergistically, and this property is also displayed by several other phytochemicals. Thus, exemestane has a wide range of previously unrecognized protective activities, probably unrelated to aromatase inhibition. Its potential for reducing the risk, not only of breast cancer, but also of other chronic diseases that arise from inflammation, oxidative stress, and DNA-damaging electrophiles, requires exploration, particularly in view of the synergism with other phytochemicals. PMID:24191056

Relevance of anti-inflammatory and antioxidant activities of exemestane and synergism with sulforaphane for disease prevention.

PubMed

Liu, Hua; Talalay, Paul

2013-11-19

Exemestane (6-methyleneandrosta-1,4-diene-3,17-dione) is a synthetic steroidal inhibitor of the aromatase reaction that catalyzes the terminal and rate-limiting step of the biosynthesis of estrogens. It is active clinically in preventing, delaying progression of, and treating mammary cancers, many of which are estrogen receptor-positive. A striking feature of the structure of exemestane is an extended system of conjugated Michael reaction functions, which is also characteristic of inducers of a broad network of chemoprotective genes regulated by the Keap1 (Kelch-like ECA-associated protein)/Nrf2 (nuclear factor E2-related factor 2)/ARE (antioxidant response element) signaling system. These genes are largely involved in xenobiotic metabolism and antioxidative and anti-inflammatory protection, as well as the synthesis and reduction of glutathione. We show here that exemestane transcriptionally activates NAD(P)H:quinone oxidoreductase 1 (NQO1) and heme oxygenase 1 (HO-1), typical chemoprotective gene products, in a wide variety of mouse, rat, and human cells. It protects several cell lines against oxidative toxicity of tert-butyl hydroperoxide and 4-hydroxynonenal, against free radical damage arising from hypoxia-reoxygenation, and against UVA radiation damage. Exemestane also inhibits the inflammatory increases in inducible nitric oxide synthase (iNOS) in mouse macrophages exposed to LPS (lipopolysaccharide), thereby resembling the isothiocyanate sulforaphane derived from broccoli. Remarkably, combinations of exemestane and sulforaphane act highly synergistically, and this property is also displayed by several other phytochemicals. Thus, exemestane has a wide range of previously unrecognized protective activities, probably unrelated to aromatase inhibition. Its potential for reducing the risk, not only of breast cancer, but also of other chronic diseases that arise from inflammation, oxidative stress, and DNA-damaging electrophiles, requires exploration, particularly in view of the synergism with other phytochemicals.

Opposite effects of dihydrotestosterone and estradiol on apoptosis in the anterior pituitary gland from male rats.

PubMed

Magri, María Laura; Gottardo, María Florencia; Zárate, Sandra; Eijo, Guadalupe; Ferraris, Jimena; Jaita, Gabriela; Ayala, Mariela Moreno; Candolfi, Marianela; Pisera, Daniel; Seilicovich, Adriana

2016-03-01

Hormones locally synthesized in the anterior pituitary gland are involved in regulation of pituitary cell renewal. In the pituitary, testosterone (T) may exert its actions per se or by conversion to dihydrotestosterone (DHT) or 17β-estradiol (E2) by 5α-reductase and aromatase activity, which are expressed in this gland. Previous reports from our laboratory showed that estrogens modulate apoptosis of lactotropes and somatotropes from female rats. Now, we examined the in vitro and in vivo effects of gonadal steroids on apoptosis of anterior pituitary cells from adult male rats. T in vitro did not modify apoptosis in anterior pituitary cells from gonadectomized (GNX) male rats. DHT, a non-aromatizable androgen, exerted direct antiapoptotic action on total anterior pituitary cells and folliculo-stellate cells, but not on lactotropes, somatotropes, or gonadotropes. On the contrary, E2 exerted a rapid apoptotic effect on total cells as well as on lactotropes and somatotropes. Incubation of anterior pituitary cells with T in presence of Finasteride, an inhibitor of 5α-reductase, increased the percentage of TUNEL-positive cells. In vivo administration of DHT to GNX rats reduced apoptosis in the anterior pituitary whereas E2 exerted proapoptotic action and reduced cells in G2/M-phase of the cell cycle. In summary, our results indicate that DHT and E2 have opposite effects on apoptosis in the anterior pituitary gland suggesting that local metabolization of T to these steroids could be involved in pituitary cell turnover in males. Changes in expression and/or activity of 5α-reductase and aromatase may play a role in the development of anterior pituitary tumors.

Metabolism of androsta-1,4,6-triene-3,17-dione and detection by gas chromatography/mass spectrometry in doping control.

PubMed

Parr, Maria K; Fusshöller, Gregor; Schlörer, Nils; Opfermann, Georg; Piper, Thomas; Rodchenkov, Grigory; Schänzer, Wilhelm

2009-01-01

The urinary metabolism of the irreversible aromatase inhibitor androsta-1,4,6-triene-3,17-dione was investigated. It is mainly excreted unchanged and as its 17beta-hydroxy analogue. For confirmation, 17beta-hydroxyandrosta-1,4,6-trien-3-one was synthesized and characterized by nuclear magnetic resonance (NMR) in addition to the parent compound. In addition, several reduced metabolites were detected in the post-administration urines, namely 17beta-hydroxyandrosta-1,4-dien-3-one (boldenone), 17beta-hydroxy-5beta-androst-1-en-3-one (boldenone metabolite), 17beta-hydroxyandrosta-4,6-dien-3-one, and androsta-4,6-diene-3,17-dione. The identification was performed by comparison of the metabolites with reference material utilizing gas chromatography/mass spectrometry (GC/MS) of the underivatized compounds and GC/MS and GC/tandem mass spectrometry (MS/MS) of their trimethylsilyl (TMS) derivatives. Alterations in the steroid profile were also observed, most obviously in the androsterone/testosterone ratio. Even if not explicitly listed, androsta-1,4,6-triene-3,17-dione is classified as a prohibited substance in sports by the World Anti-Doping Agency (WADA) due to its aromatase-inhibiting properties. In 2006 three samples from human routine sports doping control tested positive for metabolites of androsta-1,4,6-triene-3,17-dione. The samples were initially found suspicious for the boldenone metabolite 17beta-hydroxy-5beta-androst-1-en-3-one. Since metabolites of androst-4-ene-3,6,17-trione were also present in the urine samples, it is presumed that these findings were due to the administration of a product like 'Novedex Xtreme', which could be easily obtained from the sport supplement market. Copyright (c) 2008 John Wiley & Sons, Ltd.

American Society of Clinical Oncology Clinical Practice Guideline Update on the Use of Pharmacologic Interventions Including Tamoxifen, Raloxifene, and Aromatase Inhibition for Breast Cancer Risk Reduction

PubMed Central

Visvanathan, Kala; Chlebowski, Rowan T.; Hurley, Patricia; Col, Nananda F.; Ropka, Mary; Collyar, Deborah; Morrow, Monica; Runowicz, Carolyn; Pritchard, Kathleen I.; Hagerty, Karen; Arun, Banu; Garber, Judy; Vogel, Victor G.; Wade, James L.; Brown, Powel; Cuzick, Jack; Kramer, Barnett S.; Lippman, Scott M.

2009-01-01

Purpose To update the 2002 American Society of Clinical Oncology guideline on pharmacologic interventions for breast cancer (BC) risk reduction. Methods A literature search identified relevant randomized trials published since 2002. Primary outcome of interest was BC incidence (invasive and noninvasive). Secondary outcomes included BC mortality, adverse events, and net health benefits. An expert panel reviewed the literature and developed updated consensus guidelines. Results Seventeen articles met inclusion criteria. In premenopausal women, tamoxifen for 5 years reduces the risk of BC for at least 10 years, particularly estrogen receptor (ER) –positive invasive tumors. Women ≤ 50 years of age experience fewer serious side effects. Vascular and vasomotor events do not persist post-treatment across all ages. In postmenopausal women, raloxifene and tamoxifen reduce the risk of ER-positive invasive BC with equal efficacy. Raloxifene is associated with a lower risk of thromboembolic disease, benign uterine conditions, and cataracts than tamoxifen in postmenopausal women. No evidence exists establishing whether a reduction in BC risk from either agent translates into reduced BC mortality. Recommendations In women at increased risk for BC, tamoxifen (20 mg/d for 5 years) may be offered to reduce the risk of invasive ER-positive BC, with benefits for at least 10 years. In postmenopausal women, raloxifene (60 mg/d for 5 years) may also be considered. Use of aromatase inhibitors, fenretinide, or other selective estrogen receptor modulators to lower BC risk is not recommended outside of a clinical trial. Discussion of risks and benefits of preventive agents by health providers is critical to patient decision making. PMID:19470930

Increase of antitumor activity of cisplatin using agonist of gonadotropin-realising hormone and inhibitor of aromatase on the model of ascites ovarian tumor.

PubMed

Tkalia, I G; Vorobyova, L I; Grabovoy, A N; Svintsitsky, V S; Tarasova, T O; Lukyanova, N Y; Todor, I N; Chekhun, V F

2014-09-01

To study antitumor activity of triptorelin - agonist of gonadotropin-releasing hormone and exemestane - inhibitor of aromatase in monotherapy and in combination with cisplatin on the model of receptor-positive for estrogens and progesterone malignant ascites transplantable ovarian tumor (TOT), to assess therapeutic pathomorphosis and level of VEGF expression in tumor cells using diffe-rent combinations of cytostatics and hormonal drugs. 72 female Wistar rats, which underwent intraperitoneal transplantation of ascitic TOT, by 5·10(6) cells per animal, have been involved in the study. Rats were divided into 8 groups, 9 rats in each group. Histological study with assessment of therapeutic pathomorphosis in TOT and immunohistochemical study has been carried out. Survival of animals in the studied groups has been evaluated. Among animals treated in regimen of monotherapy, the most pronounced antiangiogenic activity in TOT has been observed on application of hormonal drugs (triptorelin - 39.4 ± 1.9 and exemestane - 33.9 ± 1.4%; р = 0.003), the highest grade of treatment pathomorphosis in TOT has been observed at treatment with cisplatin (11.7%; р = 0.001). Combination of triptorelin and exemestane has amplified antiangiogenic activity in TOT (12.2 ± 0.9%; р = 0.001), but has not significantly changed rates of pathomorphosis (22.1 ± 0.4%; р=0.005) and survival of animals (32.2%; р = 0.007) as compared with the same rates in rats treated with hormonal drugs in monotherapy. Significant correlation between VEGF expression and pathomorphosis has been established (relative part of viable tumor tissue (RPVTT)) in TOT (r = 0.712; р = 0.001), as well as between RPVTT and life-span of animals (r = -0.320; р = 0.007). However, lack of correlation between VEGF expression in cells of TOT and survival of rats has been determined (r = -0.194; р = 0.11). Combination of cytostatic agent with triptorelin or exemestane has demonstrated significantly high rates of therapeutic pathomorphosis (10.1 ± 0.1% and 16.2 ± 0.3%, respectively) and antiangiogenic activity in TOT (21.4 ± 1.4% and 15.0 ± 1.3%, respectively) as well as the highest survival of animals (100.0%, increase of life-span (ILS) = 231.9% and 85.7%, ILS = 205.8%, respectively) as compared with the same one in rats treated in regimen of monotherapy with cisplatin, triptorelin, exemestane or by combination of hormonal drugs. Among animals treated by combination of cytostatic drug with triptorelin, two were cured, and among rats, which received cisplatin and exemestane, one animal was cured. Triptorelin and exemestane increase antitumor activity of cisplatin in respect to the malignant ascitic TOT and significantly increase survival of animals, especially when triptorelin and cisplatin are used in combination.

Breast Cancer and Estrogen Biosynthesis in Adipose Tissue

DTIC Science & Technology

1998-10-01

transferred to a nitrocellulose mem - brane. The transferred proteins were subjected to a denaturation/rena- turation process and hybridized to the 32P...aromatase expression in adipose tissue has been recently observed to be regulated by mem - bers of the interleukin-6 (IL-6) cytokine family. Based on...shown in human adipose stromal cells that the stimulatory effects of serum on aromatase expression can be mimicked by mem - bers of the interleukin-6

Local effect of bisphenol A on the estradiol synthesis of ovarian granulosa cells from PCOS.

PubMed

Wang, Yuan; Zhu, Qinling; Dang, Xuan; He, Yaqiong; Li, Xiaoxue; Sun, Yun

2017-01-01

Close relationship between polycystic ovary syndrome (PCOS) and bisphenol A (BPA) has drawn much attention in recent years, while the underlying mechanisms are poorly understood. In our study, we aim to detect BPA concentration in the follicular fluid and investigate its effect on estradiol synthesis in human granulosa cells from PCOS and non-PCOS patients. Follicular fluid and granulosa cells were collected from women who underwent controlled ovarian stimulation for in vitro fertilization or intracytoplasmic sperm injection. BPA concentration in the follicular fluid from PCOS patients (440.50 ± 63.70 pg/ml) was significantly higher than that from non-PCOS patients (338.00 ± 57.88 pg/ml). Expression of aromatase and estradiol synthesis in cultured granulosa cells was examined after treatment with BPA from 0.01 to 1 μM for 24 h. Expression of aromatase and estradiol synthesis was downregulated by BPA in a dose-dependent manner in PCOS, but no effect was observed in granulosa cells from non-PCOS patients. These findings provide evidence that increased BPA concentration in the follicular fluid of PCOS patients may play an important role in its pathogenesis by attenuating the expression of aromatase in granulosa cells.

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

PubMed Central

Atta, Mustafa S.; Almadaly, Essam A.; El-Far, Ali H.; Saleh, Rasha M.; Assar, Doaa H.; Al Jaouni, Soad K.; Mousa, Shaker A.

2017-01-01

Antioxidants have valuable effects on the process of spermatogenesis, particularly with diabetes mellitus (DM). Therefore, the present study investigated the impact and the intracellular mechanisms by which thymoquinone (TQ) works against diabetes-induced testicular deteriorations in rats. Wistar male rats (n = 60) were randomly allocated into four groups; Control, Diabetic (streptozotocin (STZ)-treated rats where diabetes was induced by intraperitoneal injection of STZ, 65 mg/kg), Diabetic + TQ (diabetic rats treated with TQ (50 mg/kg) orally once daily), and TQ (non-diabetic rats treated with TQ) for 12 weeks. Results revealed that TQ significantly improved the sperm parameters with a reduction in nitric oxide (NO) and malondialdehyde (MDA) levels in testicular tissue. Also, it increased testicular reduced glutathione (GSH) levels and superoxide dismutase (SOD) activity. Interestingly, TQ induced downregulation of testicular inducible nitric oxide synthase (iNOS) and nuclear factor kappa-B (NF-κB) and significantly upregulated the aromatase protein expression levels in testicles in comparison with the diabetic rats. In conclusion, TQ treatment exerted a protective effect against reproductive dysfunction induced by diabetes not only through its powerful antioxidant and hypoglycemic effects but also through its downregulation of testicular iNOS and NF-κB along with upregulation of aromatase expression levels in diabetic rats. PMID:28448463

The compounds from the hollyhock extract (Althaea rosea Cav. var. nigra) affect the aromatization in rat testicular cells in vivo and in vitro.

PubMed

Papiez, Monika; Gancarczyk, Monika; Bilińska, Barbara

2002-01-01

Among medicinal plants, extract from the hollyhock flowers is a source of antocyanides and flavonoids. The latter compounds belong, among others, to phytoestrogens (plant-derived dietary estrogens). The important role of estrogens in the testis is now well documented, and phytoestrogens, which may act as estrogen agonists or estrogen antagonists can also alter the reproductive function of the male. The aim of this study was to show whether the exposure of male rats to the aqueous hollyhock extract could affect the process of aromatization in their testes and in cultured Leydig cells. This was investigated by immunocytochemistry and radioimmunological assays. Immunoreactivities for aromatase and estrogen receptor beta were weaker both in testicular sections and cultured Leydig cells after hollyhock extract administration when compared to the controls, while the intensity of immunoreaction for estrogen receptor alpha remained unchanged. A lower level of estradiol secreted by cultured Leydig cells from the experimental group positively correlated with a direct inhibition of aromatase activity. Additionally, a quantitative analysis of flavonoid fraction from the hollyhock extract revealed the presence of quercetin and kaempferol. It seems that a weak antiestrogenic activity of flavonoid compounds present in the hollyhock extract is mediated through aromatase and estrogen receptor beta rather than by estrogen receptor alpha.