Increased Aromatase Activity Research Articles

Tackling the adverse health effects of excess body fat in breast cancer: where does physical activity fit in?

Weight gain is commonly observed during and after breast cancer treatment due to chemotherapy and endocrine therapies, induced menopause, changes in metabolism and food intake and decreased physical activity. Systematic reviews show that women who are overweight or obese at diagnosis, and those who gain weight, have poorer breast cancer survival outcomes than women of a healthy weight, irrespective of menopausal status. Excess body weight after breast cancer also increases the risk of type 2 diabetes mellitus and CVD. The adverse impact of excess body weight on survival outcomes is clearly shown for women with oestrogen receptor-positive (ER+) breast cancer, which accounts for 70 % of all breast cancer cases. Higher body fat is thought to increase the risk of ER+ recurrence because of increased aromatase activity. However, this could be compounded by other risk factors, including abnormal insulin and adipokine metabolism, impaired anti-tumour immunity and chronic low-grade systemic inflammation. Observational evidence linking poorer survival outcomes with excess body fat and low physical activity in women recovering from early-stage curative-intent breast cancer treatment is reviewed, before reflecting on the proposed biological mechanisms. The issues and sensitivities surrounding exercise participation amongst overweight breast cancer patients is also discussed, before providing an overview of the co-design process involved in development of an intervention (support programme) with appropriate content, structure and delivery model to address the weight management challenges faced by overweight ER+ breast cancer patients.

The role of fat distribution and inflammation in the origin of endometrial cancer, study protocol of the ENDOCRINE study.

Obesity is a growing problem worldwide, especially in countries with improved socioeconomic circumstances. Also, in the Netherlands the incidence of overweight and obesity is rising. There is increasing evidence on the association between obesity and tumorigenesis. Of all cancer types, endometrial cancer (EC) has the strongest positive correlation with obesity. Obesity is generally defined as a body mass index (BMI) >30, yet does not cover the differences in fat distribution in visceral and subcutaneous compartments. Visceral fat is assumed to be relatively more metabolically active and likely negative prognostic biomarker in non-endometrioid EC. Whereas subcutaneous fat is mainly responsible for oestrogen production through increased aromatase activity. The aim of this study is to compare hormone levels and inflammatory markers after bilateral salpingo-oophorectomy (BSO) in obese and non-obese patients. Secondary objectives are to compare the effect of fat distribution and diagnosis (benign vs. EC) on the observed changes in hormone levels and inflammatory markers, and to compare the effect of BSO on menopausal complaints. Prospective multicentre observational cohort study. A total of 160 patients will be included, of which 80 patients with a normal BMI (18-25 kg/m2) and 80 patients with an obese BMI >32-35 kg/m2. Preoperative abdominal CT will be performed and fasting venous blood samples are obtained for hormone levels and inflammation markers analysis. During surgery, adipose tissue biopsies of subcutaneous and visceral (omental and intestinal epiploic fat) compartments will be collected and stored fresh frozen. In addition a fasting blood draw six weeks after surgery will be obtained. All subjects will fill in two questionnaires before surgery and one after surgery. We hypothesize that BMI, the type of fat distribution, and possibly the underlying pathology significantly influence in hormone levels, and systemic inflammation changes after BSO. Previous studies have found several clues for a relationship between obesity and endometrial cancer. We expect that our study will contribute to pinpoint the exact differences between 'healthy obesity' and 'unhealthy obesity' and will help to identify patients that are more at risk of developing cancer (or possibly suffer from other related problems such as cardiovascular problems e.g.).

The role of leptin and low testosterone in obesity.

Obesity is a medical condition associated with metabolic disorders and low-grade systemic inflammation. Another characterizing feature of obesity is high circulating levels of leptin (a hormone predominantly made by adipose cells and enterocytes in the small intestine that helps to regulate energy balance), a phenomenon termed hyperleptinemia. Hyperleptinemia is associated with both low-grade systemic inflammation and metabolic dysfunction in obese human beings. Moreover, obesity is associated with low testosterone in men, which correlates with high body fat. The association between leptin and low testosterone could potentially be explained via the imbalanced leptin levels that results in higher estrogen levels, which further increases the aromatase activity. The increase in aromatase activity in turn reciprocally inhibits the testosterone levels and hypothalamic pituitary gonadal axis. Novel strategies are being used to treat obesity, including leptin and testosterone therapy. However, the efficacy and adverse effects of these strategies need further validation through preclinical and clinical studies. Additionally, further studies are needed to establish the molecular mechanism behind leptin-modulated changes to testosterone in obese men. This review summarizes the available literature on the role of leptin and low testosterone during obesity.

Sex hormones and adaptive potential of the circulatory system in men of the European and Asian North

The article presents the results that reveal the features of the state of the hypothalamic-pituitary-gonadal axis and the level of dopamine in apparently healthy men with different adaptive potential of the circulatory system, taking into account age and territory of residence. Material and methods. The study involved 155 men (90 residents of the European North (Arkhangelsk Oblast) and 65 residents of the Asian North (Yamalo-Nenets Autonomous Okrug)) aged 22–59 years. Serum hormone levels of the hypothalamic-pituitary- gonadal axis were determined by enzyme immunoassay and radioimmunoassay in vitro analysis. The adaptive potential was calculated according to R.M. Baevsky. Results and its discussion. The functional tension of the mechanisms of adaptation of the circulatory system in men of the European North and unsatisfactory adaptation in men of the Asian North were revealed. In the studied regions of the North, there are no people with good and satisfactory adaptation, and the group of people with a breakdown in adaptation was identified only in the Asian North in men aged 45–59 years, which allows us to classify these subjects as a risk group for developing cardiovascular diseases. In men of the European North, the unsatisfactory adaptation was combined with an increase in the levels of prolactin (at the age of 22–44 years) and follitropin (at the age of 45–59 years) and a decrease in the level of sex hormone-binding globulin (at the age of 22–44 years). A decrease in the levels of total and free testosterone can be attributed to the key markers of failure of adaptation in men of the Asian North aged of 45–59 years. When analyzing the data of the entire surveyed population of men aged 22–59 years, an increase in aromatase activity was noted against the background of a decrease in testosterone levels in men of the European North with the 4th degree of adaptive potential and in men of the Asian North with the 5th degree of adaptive potential, which can be considered as a compensatory reaction to preserve the function of the cardiovascular system.

P–569 Woman with CYP19A1 TC/CC genotype have increased susceptibility to infertility development, independently of the cause

Abstract Study question Is TC/CC genotype of codon 39 at CYP19A1 gene associated with the development of female infertility? Summary answer Yes, CYP19A1 codon 39 TC/CC genotype is associated with increased susceptibility to infertility development in women, regardless of associated cause. What is known already Aromatase protein is responsible for the aromatization of androgens into estrogens. This protein that catalyzes the final step in biosynthesis of estrogens is encoded by the gene CYP19A1. The CYP19A1 gene is located on chromosome 15q21.1. It is a member of the cytochrome P450 superfamily which are monooxygenases that catalyze many reactions involved in steroidogenesis. TC/CC genotype of codon 39 at CYP19A1 gene results in an increase of aromatase activity and thus affect the hormone levels which can lead to the development of various diseases, including infertility. Study design, size, duration A case-control study was designed to investigate the association of CYP19A1 gene polymorphism with female infertility. Case subjects, 201 women with infertility established as women under 39 years of age, that failed to establish a clinical pregnancy after 12 months of regular, unprotected sexual intercourse. 161 fertile female controls, with no previous history of infertility, no previous history of gynecological pathologies compatible with infertility, and no history of IVF treatments, were selected. Participants/materials, setting, methods Blood was collected by venous puncture and genomic DNA was extracted. CYP19A1 genotyping was performed by polymerase chain reaction-based methods with confronting two-pair primers. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by unconditional logistic regression. Main results and the role of chance Significant statistical association of the TC/CC genotype combined with endometriosis risk was found, with reference to TT genotype (OR 4.554; 95% CI 2.209–9.386; p < 0.001). We also found an increased risk of developing polycystic ovary syndrome (PCOS) associated with TC/CC genotype (OR 5.317; 95% CI 2.767–10.215; p < 0.001). We also observed an increased prevalence of premature ovarian failure associated with TC/CC genotype (OR 3.376; 95% CI 1.672–6.815; p = 0.001) and verified an increased prevalence of tubal pathology in carriers of TC/CC genotype (OR 3.231; 95% CI 1.653–6.314; p = 0.001). Finally, a strong association of TC/CC genotype with female infertility, regardless of the cause was found (OR 4.232; 95% CI 2.710–6.609; p < 0.001). In conclusion, TC/CC genotype is associated with increased susceptibility to infertility development in women. Limitations, reasons for caution The sample size may eventually be considered small, despite the strong significance found. Wider implications of the findings: There are not many studies in this area and the few existing exhibit disparate results. The association of TC/CC genotype with endometriosis was observed in a few studies, but some disagree. This difference could be attributed to the notable heterogeneity across the different studies. Trial registration number Not applicable

Crown-Like Structures in Breast Adipose Tissue: Early Evidence and Current Issues in Breast Cancer.

Simple SummaryObesity increases the risk of postmenopausal, hormone receptor-positive breast cancer and has been linked to a higher risk of recurrence and mortality. During obesity, adipose tissue can become dysfunctional, resulting in chronic low-grade inflammation. Crown-like structures in breast adipose tissue (CLS-B), composed of macrophages surrounding dead or dying adipocytes in a crown-like pattern, are a new histologic marker of local inflammation. In this review, we aim to evaluate the early evidence of CLS-B in breast cancer. There is consistent evidence that CLS-B are more frequently detected among obese compared to non-obese breast cancer patients. Additionally, several studies have found that CLS-B presence is associated with metabolic and inflammatory factors that contribute to breast cancer development and progression. However, more studies are needed to understand the potential clinical utility of CLS-B as a marker of breast cancer risk or prognosis.Obesity is an established risk factor for postmenopausal breast cancer and has been linked to worse breast cancer prognosis, most clearly for hormone receptor-positive breast cancers. The underlying mechanisms of the obesity–breast cancer association are not fully understood, but growing evidence points to the breast adipose tissue microenvironment playing an important role. Obesity-induced adipose tissue dysfunction can result in a chronic state of low-grade inflammation. Crown-like structures of the breast (CLS-B) were recently identified as a histologic marker of local inflammation. In this review, we evaluate the early evidence of CLS-B in breast cancer. Data from preclinical and clinical studies show that these inflammatory lesions within the breast are associated with local NF-κB activation, increased aromatase activity, and elevation of pro-inflammatory mediators (TNFα, IL-1β, IL-6, and COX-2-derived PGE2)—factors involved in multiple pathways of breast cancer development and progression. There is also substantial evidence from epidemiologic studies that CLS-B are associated with greater adiposity among breast cancer patients. However, there is insufficient evidence that CLS-B impact breast cancer risk or prognosis. Comparisons across studies of prognosis were complicated by differences in CLS-B evaluation and deficiencies in study design, which future studies should take into consideration. Breast adipose tissue inflammation provides a plausible explanation for the obesity–breast cancer association, but further study is needed to establish its role and whether markers such as CLS-B are clinically useful.

Abstract PS8-10: Inhibition of estrogen biosynthesis by hops, licorice species, and their bioactive compounds

Abstract Introduction: Breast cancer risk continues to rise following menopause, despite the cessation of ovarian estrogen synthesis. Pathways involving increased aromatase activity and inflammation in the breast microenvironment are implicated. Their concerted disruption could be protective against breast cancer. Popular botanicals for menopausal health, such as hops (Humulus lupulus), three licorice species (Glycyrrhiza glabra, Glycyrrhiza inflata, Glycyrrhiza uralensis) extracts, and their bioactive compounds have shown estrogenic and chemopreventive properties in vitro and in vivo. Their effects on aromatase expression and activity, and on inflammatory responses in the breast are not well characterized.Methods: Inhibition of aromatase activity by hops extract, its compounds (8-prenylnaringenin, 6-prenylnaringenin, and xanthohumol); three licorice extracts, and their bioactive compounds, (liquiritigenin, isoliquiritigenin, 8-prenylapigenin, and licochalcone A) were evaluated fluorometrically, using aromatase supersomes. Computational docking was performed to assess the binding of the bioactive compounds to the binding pocket of aromatase crystal structure compared to the known aromatase inhibitors, letrozole (non-steroidal) and exemestane (steroidal). Using qPCR, the effect of treatments on aromatase mRNA expression in breast microstructures of menopausal women was evaluated. The effects of hops and licorice on transactivation of NF-kB in MCF-7 breast cancer cells were studied, using a luciferase assay.Results: Among the extracts, one of the licorice species, Glycyrrhiza inflata showed the highest aromatase inhibitory potency (IC50 ≈ 1 µg/mL). Among the compounds, the phytoestrogens 8-prenylnaringenin (IC50 = 50 nM or 17 ng/mL) from hops, liquiritigenin (400 nM or 0.1 µg/mL), and 8-prenylapigenin (IC50 ≈ 590 nM or 0.2 µg/mL) from licorice exhibited the highest potency. Computational docking suggested that these phytoestrogens bind to the aromatase binding pocket like the aromatase inhibitor, letrozole. This effect was not observed with non-estrogenic bioactive compounds including 6-prenylnaringenin and xanthohumol from hops as well as isoliquiritigenin and licochalcone A from licorice. Hops and 8-prenylnaringenin reduced aromatase expression in breast microstructures by 60% (P < 0.05). Moreover, hops and licorice extracts suppressed NF-kB-luciferase activity by 70% in MCF-7 cells (P< 0.01). Conclusions: Hops, licorice species, and their phytoestrogens inhibit aromatase activity and expression. The extracts suppress NF-kB transactivation in MCF-7 cells, suggesting inhibition of inflammatory response. Further studies will better elucidate the potential of these popular botanicals and their bioactive compounds for preventing breast cancer in menopausal women. Citation Format: Atieh Hajirahimkhan, Caitlin Howell, Tareisha Dunlap, Shao-Nong Chen, Susan E. Clare, Guido F. Pauli, Judy L. Bolton, Birgit M. Dietz, Seema A. Khan. Inhibition of estrogen biosynthesis by hops, licorice species, and their bioactive compounds [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-10.

Endocrineand follicular studies in Meishan pig

The enhanced early embryonic survival in Chinese Meishan compared with Large- White gilts may be due, in part, to differences in ovarian and endocrine function, particularly during the periovulatory period. The overall patterns of oestradiol, LH and FSH secretion were not different between Meishan and Large-White hybrid controls during this period, although circulating inhibin concentrations were higher in Meishan gilts. Thus, there appeared to be a decreased sensitivity to inhibin feedback on FSH secretion in Meishan gilts. Behavioural oestrus was exhibited earlier relative to the LH surge in Meishan gilts than in Large-White hybrid gilts, but the time interval from the oestradiol peak until the LH surge was similar in both breeds. This finding suggests that Meishan gilts are more sensitive in terms of initiating a behavioural response, but not in terms of positive feedback. Although preovulatory follicular characteristics were as variable in Meishan as in Large-White hybrid gilts, follicles from Meishan gilts were smaller, but contained a higher concentration of oestradiol in the follicular fluid. This was probably due to increased aromatase activity in both granulosa and theca cells of Meishan follicles. The enhanced maturation of the intrafollicular environment in Meishan gilts was reflected in the oocyte population which was at a more advanced stage of development in the period preceding ovulation. In addition to decreasing the time between onset of oestrus and ovulation, advancing the LH surge to coincide with onset of oestrus (via hCG administration) decreased embryo survival at day 30 of gestation. It is concluded that both endocrine and follicular mechanisms have a role in ensuring the prolificacy in the Meishan breed.

Regulation of Inflammation Pathways and Inflammasome by Sex Steroid Hormones in Endometriosis.

Endometriosis is a gynecological disorder characterized by the growth of endometrial tissue (glands and stroma) outside the uterus, mainly in the peritoneal cavity, ovaries, and intestines. This condition shows estrogen dependency and progesterone resistance, and it has been associated with chronic inflammation, severe pain, and infertility, which negatively affect the quality of life in reproductive women. The molecular mechanisms involved in the pathogenesis of endometriosis are not completely understood; however, inflammation plays a key role in the pathophysiology of the disease, mainly by altering the function of immune cells (macrophages, natural killer, and T cells) and increasing levels of pro-inflammatory mediators in the peritoneal cavity, endometrium, and blood. These immune alterations inhibit apoptotic pathways and promote adhesion and proliferation of endometriotic cells, as well as angiogenesis and neurogenesis in endometriotic lesions. It has been demonstrated that hormonal alterations in endometriosis are related to the inflammatory unbalance in this disease. Particularly, steroid hormones (mainly estradiol) promote the expression and release of pro-inflammatory factors. Excessive inflammation in endometriosis contributes to changes of hormonal regulation by modulating sex steroid receptors expression and increasing aromatase activity. In addition, dysregulation of the inflammasome pathway, mediated by an alteration of cellular responses to steroid hormones, participates in disease progression through preventing cell death, promoting adhesion, invasion, and cell proliferation. Furthermore, inflammation is involved in endometriosis-associated infertility, which alters endometrium receptivity by impairing biochemical responses and decidualization. The purpose of this review is to present current research about the role of inflammasome in the pathogenesis of endometriosis as well as the molecular role of sex hormones in the inflammatory responses in endometriosis.

PO-01-012 Tadalafil modulates aromatase and androgem receptor expression in human prostatic adenocarcinoma cells in vitro

Our previous data suggest that Tadalafil (TAD), a phosphodiesterase type-5 inhibitor, has a direct effect on aromatase (ARO) expression and function in human visceral adipocytes; it also accelerates myogenic differentiation and induces higher expression of the androgen receptor (AR) in murine C2C12 muscle cells. In human osteoblastic cells in vitro, TAD modulates expression of ARO, and increases androgen receptor (AR) protein expression. We herein evaluated the potential modulation of ARO and sex steroid hormone receptors by TAD in prostate adenocarcinoma cells (LNCaP), a cellular in vitro model system of androgen-sensitive human adenocarcinoma. First series of experiments were performed to test LNCaP viability upon TAD exposure. Then, cells were treated with/without TAD 10-6M for several interval times to evaluate potential modulation of ARO, AR and estrogen receptor β (ERβ) expression. After 24 hs exposure to TAD, cells increases ARO mRNA expression level (p<0.05) and, as expected, an increase of ARO protein expression (p<0.01) after 48 hours occurred. Moreover, TAD exposure induced and increase of total AR protein expression (p<0.05) after 24 hours and there was an increased trend of ERβ mRNA expression level with maximal effects after 24 hours. Furthermore, there was an increased ratio of estradiol/testosterone levels in LNCaP in the supernatants, suggesting an increase in ARO activity after 48 hours.

Low-dose environmental endocrine disruptors, increase aromatase activity, estradiol biosynthesis and cell proliferation in human breast cells

BackgroundPhenolic endocrine-disrupting compounds (EDCs) have long been suspected of increasing human breast cancer risk, via aromatase up-regulation; however, the metabolic effects upon aromatase in human breast cells exposed to environmentally relevant concentrations of phenolic compounds, have not been addressed. ObjectivesTo examine the mechanistic responses of aromatase CYP19A1 mRNA, aromatase activity, estradiol biosynthesis and cellular proliferation, in three human breast cell lines, exposed to seven phenolic compounds, at environmentally relevant concentrations. MethodsMCF-7 and ZR-75-1 breast cancer cells, and HMF3A breast fibroblasts were treated with specific concentrations of p,p’-DDT, methoxychlor, benzophenone-2, bisphenol A, bisphenol S, 4-phenylphenol and n-butylparaben, with and without the presence of aromatase inhibitors and estrogen receptor inhibitors. ResultsAll test EDCs up-regulated aromatase mRNA, increased aromatase activity, significantly increased the aromatase-induced biosynthesis of the breast carcinogen 17β-estradiol, and increased ERα-positive breast cell proliferation. ConclusionInadvertent exposures to ‘phenolic’ EDCs, increase estradiol biosynthesis, and estrogen-sensitive breast cancer proliferation.

Assessing the impact of waste water effluents on native fish species from a semi-arid region, NE Spain

Mediterranean rivers are strongly affected by pollution and water scarcity. Over the summer period, urban and industrial effluents arrive into the rivers with little dilution. In order to assess the water quality, two native fish species, Barbus meridionalis and Squalius laietanus, were collected from six sites along the Ripoll River (Spain). PAH metabolites, alkylphenols (nonylphenol and octylphenol) and the musk galaxolide levels were determined in bile. 7-Ethoxyresorufin-O-deethylase (EROD) and 7-benzyloxy-4-trifluoromethyl-coumarin O-debenzyloxylase (BFCOD) were measured as metabolic biomarkers, and the activity of CYP19 aromatase was determined in the ovaries of B. meridionalis as a biomarker of endocrine disruption. The analysis of bile indicated that fish from the lower course of the river were highly exposed to different pollutants. Accordingly, a significant induction of EROD (9 to 10-fold) and BFCOD (3 to 5-fold) activities were detected in both fish species together with an increased aromatase activity in females of B. meridionalis from the most polluted sites. Considering that sewage treatment plant (STP) effluents are essential for maintaining environmental flows in small Mediterranean rivers, this study highlights the need to improve the efficiency of STPs to protect fish health.

Disruption of oocyte maturation by selected environmental chemicals in zebrafish

Oocyte maturation can be a target of endocrine disruption by environmental chemicals capable of acting as hormone mimics, receptor blockers, and/or enzyme inhibitors. Six environmental chemicals (genistein, endosulfan, malathion, iprodione, carbaryl, and glyphosate) were selected to determine their ability to interfere with oocyte maturation in zebrafish. The translucent oocytes undergoing germinal vesicle (nucleus) breakdown (GVBD) were counted and expressed as a ratio of oocytes undergoing GVBD and total oocytes exposed. The GVBD increased significantly in oocytes exposed to 10 IU/ml to 100 IU/ml human chorionic gonadotropin (hCG). The lowest effective concentration of genistein that inhibited hCG-induced GVBD was 30 μM, while endosulfan inhibited it at 0.03 μM concentration. In addition, malathion inhibited hCG-induced GVBD at the lowest concentration of 60 μM. These inhibitory effects were likely due to the chemicals acting as estrogen mimics, induction of estrogen receptors, or increase in aromatase activity resulting in enhanced estrogen action. Fungicide iprodione, possibly acting as a progestin mimic, promoted hCG-induced GVBD at the lowest concentration of 20 μM, while the weed killer glyphosate inhibited hCG-induced GVBD starting at the 50 μM concentration. These results demonstrate the feasibility of using fully grown zebrafish oocytes arrested at the prophase I stage in an in vitro incubation system to evaluate the effects of a variety of environmental chemicals on oocyte maturation.

The effect of third-generation aromatase inhibitors on aromatase avtivity in visceral adipose tissue

Pathogenesis and clinical manifestations of metabolic syndrome (and other conditions characterized by the growth of fat mass and decreased adiponectin content) is associated with an imbalance of sex hormones, which develops under the influence of increased aromatase activity in adipose tissue. Drugs of the aromatase inhibitors therapeutic group are able to suppress the course of the aromatase reaction in the central and peripheral organs and tissues. The aim of our study was to establish the relationship between levels of serum adiponectin and adipose tissue aromatase avtivity in Syrian hamsters of different ages and gender with experimental metabolic syndrome and study the effect of aromatase inhibitors on these indicators. Experimental metabolic syndrome in animals was induced by a high-fat and fructose diet. The drugs were administered during the 21-st day in doses of 3.086 (exemestane), 0.309 (letrozole) and 0.126 mg/kg (anastrozole). The aromatase activity of the visceral adipose tissue was determined by the modified kinetic method based on the amount of the reaction product estradiol converted from testosterone. The content of estradiol in adipose tissue homogenate and serum adiponectin levels were measured by the immune enzyme method. The results showed a high inverse correlation between serum adiponectin and adipose tissue aromatase activity in hamsters. Aromatase inhibitors caused a decrease in the adipose tissue aromatase activity and increase in serum adiponectin levels. Letrazol demonstrated the greatest effect, it reduced aromatase activity in adipose tissue by 72–84% and increased serum adiponectin content by 1.6–1.8 times. At the same time, intra-group correlation of the studied parameters was significant. The results show the relationship between adiponectin level and adipose tissue aromatase activity and ability to change these rates by the way of aromatase inhibitors, which may be useful in clinical practice. Third-generation aromatase inhibitors are promising drugs for metabolic syndrome treatment and require further study in clinical trials.

Abstract SY01-01: Endocrine resistance in metastatic breast cancer: Mechanisms and new therapeutic strategies

Abstract SY01-01: Endocrine resistance in metastatic breast cancer: Mechanisms and new therapeutic strategies

MP07-03 ANASTRAZOLE IS AN EFFECTIVE TREATMENT FOR INFERTILE MEN WITH HYPERESTROGENEMIA

You have accessJournal of UrologyInfertility: Therapy II1 Apr 2018MP07-03 ANASTRAZOLE IS AN EFFECTIVE TREATMENT FOR INFERTILE MEN WITH HYPERESTROGENEMIA Andrew Radtke, Dane Johnson, Luriel Smith-Harrison, and Jay Sandlow Andrew RadtkeAndrew Radtke More articles by this author , Dane JohnsonDane Johnson More articles by this author , Luriel Smith-HarrisonLuriel Smith-Harrison More articles by this author , and Jay SandlowJay Sandlow More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.3066AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Male infertility has multiple etiologies, many of which are treatable. Recent reports have demonstrated the deleterious impact of obesity on male fertility. Obese men often experience hypogonadism, typically secondary to hyperestrogenemia. This is presumably due to increased aromatase activity in body fat, resulting in impaired hormone and sperm production. The aim of this study is to investigate the effect of anastrazole on semen profiles in infertile men with hyperestrogenemia. METHODS Following IRB approval, we retrospectively evaluated all patients seen at a single academic Reproductive Medicine Center from January 2011 to June 2016 for infertility related to hyperestrogenemia. Patients included in this study demonstrated either true (Estradiol >42pg/mL) or relative (defined as Testosterone: Estradiol ratios <10) hyperestrogenemia, with at least 1 abnormal semen analysis, and subsequently underwent treatment with anastrazole 1 mg 3 times/week. Any patients with palpable varicoceles, hypergonadotrophic hypogonadism, or those receiving any additional hormonally active pharmaceuticals were excluded. Patient characteristics included testicular volume, BMI, as well as their hormonal evaluation, which included serum Follicle-Stimulating Hormone (FSH), Luteinizing Hormone (LH), total Testosterone (T) and Estradiol (E2) levels. Semen parameters were compared pre-and post-treatment. RESULTS Seventy-two patients fit inclusion criteria and received anastrazole for either true or relative hyperestrogenemia. 23 patients had adequate post treatment follow up for evaluation. Following initiation of anastrazole therapy, average T, T:E2 ratios, total sperm count, and total progressively motile sperm count all significantly increased. Thirteen patients (56%) experienced a >50% increase in total progressively motile sperm counts (p=0.02). CONCLUSIONS Anastrazole therapy can significantly improve semen quality in infertile men with hyperestrogenemia. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e88 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Andrew Radtke More articles by this author Dane Johnson More articles by this author Luriel Smith-Harrison More articles by this author Jay Sandlow More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Aromatase inhibitors effect on the total protein content of visceral adipose tissue in hamsters with metabolic syndrome

Topicality. Recently, more attention has been paid to the role of the peripheral aromatase reaction enhancement in pathogenesis of obesity and metabolic syndrome. About 39 % of men and 40 % of women over 18 around the world are overweight (BMI > 25) and in almost all cases they have an imbalance of sex hormones, which is caused by increased aromatase activity of adipose tissue. Aim . To study the effect of aromatase inhibitors on the parameters of total body weight, protein content in adipose tissue and their correlation in hamsters with experimental metabolic syndrome. Materials and method s. Protein content in the visceral adipose tissue homogenate was detected by the Lowry method in the Hartree modification. Statistical processing of the results was carried out by variational statistics methods using nonparametric methods of analysis, the interrelations between the signs were determined by the Pearson linear correlation coefficient. Results and discussion . The most effective drug from the group of aromatase inhibitors which reduced hypertrophic growth of adipose tissue in all animals both sexes and ages was letrozole. Anastrozole and exemestane showed less efficacy, and had a better effect on young animals. Conclusions . The letrozole administration at a dose of 0.309 mg/kg resulted in a significant decrease in the average body weight by 24-35 % and a corresponding increase in protein content of visceral adipose tissue by 12-46 % with a high correlation coefficient.

Methylation dictates PI.f-specific CYP19 transcription in human glial cells

CYP19 is the single copy gene encoding for the estrogen synthetic enzyme aromatase. Alternate splicing of the promoter is the regulatory mechanism of this gene. In the brain, estrogen is synthesized in neuronal and glial cells and the gene is mainly regulated by the alternate promoter PI.f. The hormone produced in this vicinity has been associated with maintaining normal brain functions. Previously, epigenetic regulation has been shown in the promoters PII and I.3 of CYP19 in adipocytes. In the present study, the methylation of PI.f in CYP19 was examined in glial cells. Treatment of the hypomethylating agent 5-aza-2′deoxycytidine increased CYP19 mRNA species in U87 MG cells while little changes were observed in the other glia cell lines. As PI.f is also chiefly used in T98G cells with high expression of CYP19, the methylation statuses of the promoter in these two cell models were compared. Our results showed that treating U87 MG cells with 10 μM 5-aza-2′deoxycytidine significantly induced a ∼10-fold increase in CYP19 transcription and ∼80% increase in aromatase activity. In contrast, the same treatment did not change either endpoint in T98G cells. Further investigation illustrated the CpGs in PI.f were differentially methylated in the two cell lines; 63% and 37% of the 14 CpG sites were methylated in U87 MG and T98G cells respectively. In conclusion, this study illustrated that the brain-specific PI.f derived CYP19 expression can be regulated by DNA methylation.

Premenapozal Kadınlarda Myoma Uteri Gelişimi Üzerine Visseral/Trunkal Yağ Oranının ve İnsülin Direncinin Etkisinin Değerlendirilmesi

Objectives: Within the scope of this study, we aimed to analyze the effect of visceral and truncal fat rate and insulin resistance on myoma uteri progression in premenopausal women. Materials and Methods: 100 patients, who have been applied to the gynecology department with myoma diagnosis and 50 control patients who had no myomas and had similar properties with the patient group were included in the study. Anthropometric measures, pre-prandial serum glucose, HbA1c, insulin, LDL-cholesterol, triglyceride, HDL-cholesterol and total cholesterol levels were studied. All statistical analyses were performed with SPSS 16.0 statistical soft-ware and a level of p < 0.05 is accepted statistically significant. Results: Truncal fat rate of the patient group is found higher than the control group (p=0.014). Mean HbA1c was higher and statistically significant (p< 0.001) in the patient group. Mean HDL-C was found significantly lower in the patient group (p= 0.001). Conclusion: In our study, higher levels of truncal fat rate in the patient group can be inferred to the production of estrogen in truncal fat tissue due to increased aromatase activity and thus myoma frequency was increased. We have also determined in this study that higher HbA1c levels in patient group caused an increase in the risk of myoma up to 3.5 times. Normal values of HOMA-IR suggest that insulin resistance is not a risk factor for the development of myoma. It is believed that there is a negative correlation between hyperlipidemia and myoma.

Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ERα metastatic breast cancer.

Tumor evolution is shaped by many variables, potentially involving external selective pressures induced by therapies1. After surgery, estrogen receptor (ERα) positive breast cancer (BCa) patients are treated with adjuvant endocrine therapy2 including selective estrogen receptor modulators (SERMs) and/or aromatase inhibitors (AIs)3. However, over 20% of patients relapse within 10 years and eventually progress to incurable metastatic disease4. Here we demonstrate that the choice of therapy has a fundamental influence on the genetic landscape of relapsed diseases: in this study, 21.5% of AI-treated, relapsed patients had acquired CYP19A1 gene (aromatase) amplification (CYP19A1amp). Relapsed patients also developed numerous mutations targeting key breast cancer genes including ESR1 and CYP19A1. Strikingly, CYP19A1amp cells also emerge in vitro but only in AI resistant models. CYP19A1 amplification causes increased aromatase activity and estrogen-independent ERα binding to target genes resulting in CYP19A1amp cells displaying decreased sensitivity to AI treatment. Collectively these data suggest that AI treatment itself selects for acquired CYP19A1 amplification and promotes local autocrine estrogen signalling in AI resistant metastatic patients.