-
1.
Effect of estrogen-active compounds on the expression of RACK1 and immunological implications.
Buoso, E, Masi, M, Galbiati, V, Maddalon, A, Iulini, M, Kenda, M, Sollner Dolenc, M, Marinovich, M, Racchi, M, Corsini, E
Archives of toxicology. 2020;(6):2081-2095
-
-
Free full text
-
Abstract
We previously demonstrated the existence of a balance among steroid hormones, i.e. glucocorticoids and androgens, in RACK1 (receptor for activated C kinase 1) expression and innate immunity activation, which may offer the opportunity to use RACK1 expression as marker to evaluate immunotoxicity of hormone-active substances. Because of the existence of close interconnections between the different steroid hormone receptors with overlapping ligand specificities and signaling pathways, in this study, we wanted to investigate a possible effect of estrogenic active compounds, namely 17β-estradiol, diethylstilbestrol, and zearalenone, on RACK-1 expression and innate immune responses using THP-1 cells as experimental model. All compounds increased RACK1 transcriptional activity as evaluated by reporter luciferase activity, mRNA expression as assessed by real time-PCR and protein expression by western blot analysis, which paralleled an increase in LPS-induced IL-8, TNF-α production, and CD86 expression, which we previously demonstrated to be dependent on RACK1/PKCβ activation. As the induction of RACK1 expression can be blocked by the antagonist G15, induced by the agonist G1 and by the non-cell permeable 17β-estradiol conjugated with BSA, a role of GPER (previously named GPR30) activation in estrogen-induced RACK1 expression could be demonstrated. In addition, a role of androgen receptor (AR) in RACK1 transcription was also demonstrated by the ability of flutamide, a nonsteroidal antiandrogen, to completely prevent diethylstilbestrol-induced RACK1 transcriptional activity and protein expression. Altogether, our data suggest that RACK1 may represent an interesting target of steroid-active compounds, and its evaluation may offer the opportunity to screen the immunotoxic potential of hormone-active substances.
-
2.
Adsorption of 17β-estradiol from aqueous solution by raw and direct/pre/post-KOH treated lotus seedpod biochar.
Liu, N, Liu, Y, Zeng, G, Gong, J, Tan, X, JunWen, , Liu, S, Jiang, L, Li, M, Yin, Z
Journal of environmental sciences (China). 2020;:10-23
Abstract
Five biochars derived from lotus seedpod (LSP) were applied to examine and compare the adsorption capacity of 17β-estradiol (E2) from aqueous solution. The effect of KOH activation and the order of activation steps on material properties were discussed. The effect of contact time, initial concentration, pH, ionic strength and humic acid on E2 adsorption were investigated in a batch adsorption process. Experimental results demonstrated that the pseudo second-order model fitted the experimental data best and that adsorption equilibrium was reached within 20 hr. The efficiency of E2 removal increased with increasing E2 concentration and decreased with the increase of ionic strength. E2 adsorption on LSP-derived biochar (BCs) was influenced little by humic acid, and slightly affected by the solution pH when its value ranged from 4.0 to 9.0, but considerably affected at pH 10.0. Low environmental temperature is favorable for E2 adsorption. Chemisorption, π-π interactions, monolayer adsorption and electrostatic interaction are the possible adsorption mechanisms. Comparative studies indicated that KOH activation and the order of activation steps had significant impacts on the material. Post-treated biochar exhibited better adsorption capacity for E2 than direct treated, pre-treated, and raw LSP biochar. Pyrolyzed biochar at higher temperature improved E2 removal. The excellent performance of BCs in removing E2 suggested that BCs have potential in E2 treatment and that the biochar directly treated by KOH would be a good choice for the treatment of E2 in aqueous solution, with its advantages of good efficiency and simple technology.
-
3.
The effects of Elaeagnus angustifolia L. whole fruit on the sex hormone profile in menopausal women: A double-blind, randomized, placebo-controlled study.
Emaminia, F, Rezaei, A, Badehnoosh, B, Ramezani, R, Shabani, M
Journal of ethnopharmacology. 2020;:112229
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Menopause is a product of interrupted ovarian activity and decrease in its estradiol production. Herbal medicines as an alternative to hormone therapy are increasingly used by menopausal women. Elaeagnus angustifolia L. (Senjed in Persian) is a well-known herbal remedy with various therapeutic effects according to Iranian traditional medicine which is recommended to relieve the menopausal side effects. The aim of present study was to evaluate the effects of oral intake of whole fruit powder of E. angustifolia on the sex hormones profile in menopausal women. MATERIALS AND METHODS In present double-blind randomized placebo-controlled trial, 58 eligible women who were referred to Kamali Women Hospital (Karaj, Iran, 2017) were randomly assigned into herbal medicine (15 g E. angustifolia) and placebo (7.5 g cornstarch +7.5 g isomalt) groups. Initially and after 10 weeks of the treatment, serum levels of estradiol, progesterone, testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) hormones were measured. RESULTS According to between-group analyses, the changes in the studied parameters were not significant between herbal medicine and placebo groups, except for joint pain that improved significantly in herbal medicine group. However, by within-group analysis the levels of FSH and FSH to testosterone showed a significant increase, whereas the level of progesterone decreased significantly after 10 weeks of E. angustifolia consumption. CONCLUSIONS The improvement of the sex hormone profile was not in a full accordance with Iranian folklore after E. angustifolia consumption in the present menopausal participants. However, considering a strong belief on the beneficial effects of E. angustifolia in Iranian folklore, a long-term studies of larger group participants are needed to evaluate the efficacy.
-
4.
Genistein and 17β-Estradiol Protect Hepatocytes from Fatty Degeneration by Mechanisms Involving Mitochondria, Inflammasome and Kinases Activation.
Farruggio, S, Cocomazzi, G, Marotta, P, Romito, R, Surico, D, Calamita, G, Bellan, M, Pirisi, M, Grossini, E
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 2020;(3):401-416
Abstract
BACKGROUND/AIMS: Oxidative stress and mitochondria dysfunction could be involved in the onset of non-alcoholic fatty liver disease (NAFLD) and in its progression to non-alcoholic steatohepatitis (NASH). Estrogens/phytoestrogens could counteract liver fat deposition with beneficial effects against NAFLD by unclear mechanisms. We aimed to analyze the protective effects elicited by genistein/estradiol in hepatocytes cultured in NAFLD-like medium on cell viability, triglycerides accumulation, mitochondrial function and oxidative stress and the role of NLRP3 inflammasome, toll like receptors 4 (TLR4), Akt and 5' AMP-activated protein kinase (AMPK)α1/2. METHODS Human primary hepatocytes/hepatoma cell line (Huh7.5 cells) were incubated with a 2 mM mixture of oleate/palmitate in presence/absence of genistein/17β-estradiol. In some experiments, Huh7.5 cells were exposed to various inhibitors of the above pathways and estrogenic receptors (ERs) and G protein-coupled estrogen receptor (GPER) blockers, before genistein/17β-estradiol. Cell viability, mitochondrial membrane potential, reactive oxygen species and triglycerides content were examined by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT), 5,51,6,61-tetrachloro-1,11,3,31 tetraethylbenzimidazolyl carbocyanine iodide (JC-1), 2,7-dichlorodihydrofluorescein diacetate (H2DCFDA) and the Triglyceride Colorimetric Assay. The expression/activation of kinases was analyzed by means of Western blot. RESULTS Genistein/17β-estradiol protected hepatocytes against NAFLD-like medium, by preventing the loss of cell viability and mitochondrial function, triglycerides accumulation and peroxidation. The blocking of kinases, ERs and GPER was able to reduce the above effects, which were potentiated by NLRP3 inflammasome. CONCLUSION Our findings suggest novel mechanisms underlying the protective effects elicited by phytoestrogens/estrogens against NAFLD/NASH and open novel therapeutic perspectives in the management of NAFLD in postmenopausal women.
-
5.
Elagolix for Heavy Menstrual Bleeding in Women with Uterine Fibroids.
Schlaff, WD, Ackerman, RT, Al-Hendy, A, Archer, DF, Barnhart, KT, Bradley, LD, Carr, BR, Feinberg, EC, Hurtado, SM, Kim, J, et al
The New England journal of medicine. 2020;(4):328-340
Abstract
BACKGROUND Uterine fibroids are hormone-responsive neoplasms that are associated with heavy menstrual bleeding. Elagolix, an oral gonadotropin-releasing hormone antagonist resulting in rapid, reversible suppression of ovarian sex hormones, may reduce fibroid-associated bleeding. METHODS We conducted two identical, double-blind, randomized, placebo-controlled, 6-month phase 3 trials (Elaris Uterine Fibroids 1 and 2 [UF-1 and UF-2]) to evaluate the efficacy and safety of elagolix at a dose of 300 mg twice daily with hormonal "add-back" therapy (to replace reduced levels of endogenous hormones; in this case, estradiol, 1 mg, and norethindrone acetate, 0.5 mg, once daily) in women with fibroid-associated bleeding. An elagolix-alone group was included to assess the impact of add-back therapy on the hypoestrogenic effects of elagolix. The primary end point was menstrual blood loss of less than 80 ml during the final month of treatment and at least a 50% reduction in menstrual blood loss from baseline to the final month; missing data were imputed with the use of multiple imputation. RESULTS A total of 412 women in UF-1 and 378 women in UF-2 underwent randomization, received elagolix or placebo, and were included in the analyses. Criteria for the primary end point were met in 68.5% of 206 women in UF-1 and in 76.5% of 189 women in UF-2 who received elagolix plus add-back therapy, as compared with 8.7% of 102 women and 10% of 94 women, respectively, who received placebo (P<0.001 for both trials). Among the women who received elagolix alone, the primary end point was met in 84.1% of 104 women in UF-1 and in 77% of 95 women in UF-2. Hot flushes (in both trials) and metrorrhagia (in UF-1) occurred significantly more commonly with elagolix plus add-back therapy than with placebo. Hypoestrogenic effects of elagolix, especially decreases in bone mineral density, were attenuated with add-back therapy. CONCLUSIONS Elagolix with add-back therapy was effective in reducing heavy menstrual bleeding in women with uterine fibroids. (Funded by AbbVie; Elaris UF-1 and Elaris UF-2 ClinicalTrials.gov numbers, NCT02654054 and NCT02691494.).
-
6.
Exercise type and fat mass loss regulate breast cancer-related sex hormones in obese and overweight postmenopausal women.
Gonzalo-Encabo, P, Valadés, D, García-Honduvilla, N, de Cos Blanco, A, Friedenreich, CM, Pérez-López, A
European journal of applied physiology. 2020;(6):1277-1287
Abstract
PURPOSE The aim of the study was to examine the effects of a time-matched endurance versus concurrent training on circulating sex hormone levels and body composition in postmenopausal women. METHODS Thirty-five sedentary and obese postmenopausal women were recruited and randomly divided into endurance training (EN, n = 10), concurrent training (CON, n = 13), or control group (C, n = 12). Participants took part in a 12-week supervised intervention, training 3 days/week and 60 min/session. Before and after the intervention, body composition was assessed, and blood samples were obtained to evaluate estradiol, testosterone, DHEA-S, and SHBG. RESULT In response to training, a reduction in total fat mass was found (5.3%; P < 0.05), while an increase in lean body mass was observed in the CON group (1.5%; P < 0.05). There was a significant decrease in DHEA-S (- 13%), total (- 40%) and free testosterone (- 41%) in the EN group, while in the CON group, total (25%) and free testosterone (21%) increased significantly (P < 0.05). When participants were stratified according to fat mass loss (> or < 2 kg), a statistically significant increase in circulating SHBG (21%) and decrease in DHEA-S (- 13%) were found. CONCLUSION The type of exercise and exercise-induced fat mass loss seem to modify the sex hormone profile in postmenopausal women that is an established risk factor of breast cancer. Thus, this study provides additional evidences to the intricated interaction among sex hormones, adipose tissue, and muscle mass in postmenopausal women.
-
7.
Adiposity and estrogen receptor-positive, postmenopausal breast cancer risk: Quantification of the mediating effects of fasting insulin and free estradiol.
Dashti, SG, Simpson, JA, Karahalios, A, Viallon, V, Moreno-Betancur, M, Gurrin, LC, MacInnis, RJ, Lynch, BM, Baglietto, L, Morris, HA, et al
International journal of cancer. 2020;(6):1541-1552
-
-
Free full text
-
Abstract
Adiposity increases estrogen receptor (ER)-positive postmenopausal breast cancer risk. While mechanisms underlying this relationship are uncertain, dysregulated sex-steroid hormone production and insulin signaling are likely pathways. Our aim was to quantify mediating effects of fasting insulin and free estradiol in the adiposity and ER-positive postmenopausal breast cancer association. We used data from a case-cohort study of sex hormones and insulin signaling nested within the Melbourne Collaborative Cohort Study. Eligible women, at baseline, were not diagnosed with cancer, were postmenopausal, did not use hormone therapy and had no history of diabetes or diabetes medication use. Women with ER-negative disease or breast cancer diagnosis within the first follow-up year were excluded. We analyzed the study as a cumulative sampling case-control study with 149 cases and 1,029 controls. Missing values for insulin and free estradiol were multiply imputed with chained equations. Interventional direct (IDE) and indirect (IIE) effects were estimated using regression-based multiple-mediator approach. For women with body mass index (BMI) >30 kg/m2 compared to women with BMI 18.5-25 kg/m2 , the risk ratio (RR) of breast cancer was 1.75 (95% confidence interval [CI] 1.05-2.91). The estimated IDE (RR) not through the mediators was 1.03 (95% CI 0.43-2.48). Percentage mediated effect through free estradiol was 72% (IIE-RR 1.56; 95% CI 1.11-2.19). There was no evidence for an indirect effect through insulin (IIE-RR 1.12; 95% CI 0.68-1.84; 28% mediated). Our results suggest that circulating free estradiol plays an important mediating role in the adiposity-breast cancer relationship but does not explain all of the association.
-
8.
A phase 1b study evaluating the effect of elacestrant treatment on estrogen receptor availability and estradiol binding to the estrogen receptor in metastatic breast cancer lesions using 18F-FES PET/CT imaging.
Jager, A, de Vries, EGE, der Houven van Oordt, CWM, Neven, P, Venema, CM, Glaudemans, AWJM, Wang, Y, Bagley, RG, Conlan, MG, Aftimos, P
Breast cancer research : BCR. 2020;(1):97
Abstract
BACKGROUND Elacestrant is an oral selective estrogen receptor (ER) degrader. This phase 1b open-label, non-randomized study (RAD1901-106) was initiated to determine the effect of elacestrant on the availability of ER in lesions from postmenopausal women with ER+ advanced breast cancer (ABC) using 16α-18F-fluoro-17β-estradiol positron emission tomography with low-dose computed tomography (FES-PET/CT). METHODS Eligible patients were postmenopausal women with ER+, HER2- ABC; tumor progression after ≥ 6 months of 1-3 lines of endocrine treatment for ABC; and measurable or evaluable disease. Two 8-patient cohorts were enrolled: one treated with 400 mg elacestrant once daily (QD) and one treated with 200 mg elacestrant QD with dose escalation to 400 mg QD after 14 days. Elacestrant was dosed continuously until progressive disease, toxicity, or withdrawal. FES-PET/CT was performed pre-dose at baseline and 4 h post-dose on day 14. The primary endpoint was the percentage difference in FES uptake in tumor lesions (maximum 20) after 14 days of treatment compared to baseline. Overall response was investigator-assessed by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1. RESULTS Patients (n = 16; median age, 53.5 years) had ABC with a median 2.5 prior lines of endocrine therapy. Median reduction in tumor FES uptake from baseline to day 14 was 89.1% (Q1, Q3: 75.1%, 94.1%) and was similar in both cohorts (89.1% [Q1, Q3: 67.4%, 94.2%], 200/400 mg and 88.7% [Q1, Q3: 79.5%, 94.1%], 400 mg). Residual ER availability (> 25% persistence in FES uptake) on day 14 was observed in 3 patients receiving 200/400 mg (3/78, 37.5%) and 1 patient receiving 400 mg (1/8, 12.5%). The overall response rate (ORR) was 11.1% (1 partial response), and clinical benefit rate (CBR) was 30.8%. Median percentage change in FES uptake did not correlate with ORR or CBR. Adverse events occurring in > 20% of the patients were nausea (68.8%), fatigue (50.0%), dyspepsia (43.8%), vomiting (37.5%), and decreased appetite, dysphagia, and hot flush (31.3% each). Most events were grade 2 in severity. CONCLUSION Elacestrant 200 mg and 400 mg QD greatly reduced ER availability measured by FES-PET/CT. In a heavily pretreated population, elacestrant was associated with antitumor activity. TRIAL REGISTRATION ClinicalTrials.gov, NCT02650817 . Registered on 08 January 2016.
-
9.
Estradiol Valerate in COC Has More Favorable Inflammatory Profile Than Synthetic Ethinyl Estradiol: A Randomized Trial.
Kangasniemi, MH, Haverinen, A, Luiro, K, Hiltunen, JK, Komsi, EK, Arffman, RK, Heikinheimo, O, Tapanainen, JS, Piltonen, TT
The Journal of clinical endocrinology and metabolism. 2020;(7)
Abstract
CONTEXT Combined oral contraceptives (COCs) alter inflammatory status and lipid metabolism. Whether different estrogens have different effects is poorly understood. OBJECTIVE We compared the effects of COCs containing ethinyl estradiol (EE) or estradiol valerate (EV) and dienogest (DNG) with those containing DNG only on inflammation and lipid metabolism. DESIGN Randomized, controlled, open-label clinical trial. SETTING Two-center study in Helsinki and Oulu University Hospitals. PARTICIPANTS Fifty-nine healthy, young, nonsmoking women with regular menstrual cycles. Age, body mass index, and waist-to-hip ratio were comparable in all study groups at the beginning. Fifty-six women completed the study (EV + DNG, n = 20; EE + DNG, n = 19; DNG only, n = 17). INTERVENTIONS Nine-week continuous use of COCs containing either EV + DNG or EE + DNG, or DNG only as control. MAIN OUTCOME MEASURES Parameters of chronic inflammation (high-sensitivity C-reactive protein [hs-CRP], and pentraxin 3 [PTX-3]) and lipid profile (high-density lipoprotein [HDL], low-density lipoprotein [LDL], triglycerides, and total cholesterol). RESULTS Serum hs-CRP increased after 9-week use of EE + DNG (mean change ± standard deviation 1.10 ± 2.11 mg/L) compared with EV + DNG (-0.06 ± 0.97 mg/L, P = 0.001) or DNG only (0.13 ± 0.68 mg/L, P = 0.021). Also, PTX-3 increased in the EE + DNG group compared with EV + DNG and DNG-only groups (P = 0.017 and P = 0.003, respectively). In the EE + DNG group, HDL and triglycerides increased compared with other groups (HDL: EE + DNG 0.20 ± 0.24 mmol/L vs EV + DNG 0.02 ± 0.20 mmol/L [P = 0.002] vs DNG 0.02 ± 0.18 mmol/L [P = 0.002]; triglycerides: EE + DNG 0.45 ± 0.21 mmol/L vs EV + DNG 0.18 ± 0.36 mmol/L [P = 0.003] vs DNG 0.06 ± 0.18 mmol/L [P < 0.001]). CONCLUSIONS EV + DNG and DNG only had a neutral effect on inflammation and lipids, while EE + DNG increased both hs-CRP and PTX-3 levels as well as triglycerides and HDL. TRIAL REGISTRATION ClinicalTrials.gov NCT02352090.
-
10.
Elucidating Binding Sites and Affinities of ERα Agonists and Antagonists to Human Alpha-Fetoprotein by In Silico Modeling and Point Mutagenesis.
Moldogazieva, NT, Ostroverkhova, DS, Kuzmich, NN, Kadochnikov, VV, Terentiev, AA, Porozov, YB
International journal of molecular sciences. 2020;(3)
Abstract
Alpha-fetoprotein (AFP) is a major embryo- and tumor-associated protein capable of binding and transporting a variety of hydrophobic ligands, including estrogens. AFP has been shown to inhibit estrogen receptor (ER)-positive tumor growth, which can be attributed to its estrogen-binding ability. Despite AFP having long been investigated, its three-dimensional (3D) structure has not been experimentally resolved and molecular mechanisms underlying AFP-ligand interaction remains obscure. In our study, we constructed a homology-based 3D model of human AFP (HAFP) with the purpose of molecular docking of ERα ligands, three agonists (17β-estradiol, estrone and diethylstilbestrol), and three antagonists (tamoxifen, afimoxifene and endoxifen) into the obtained structure. Based on the ligand-docked scoring functions, we identified three putative estrogen- and antiestrogen-binding sites with different ligand binding affinities. Two high-affinity binding sites were located (i) in a tunnel formed within HAFP subdomains IB and IIA and (ii) on the opposite side of the molecule in a groove originating from a cavity formed between domains I and III, while (iii) the third low-affinity binding site was found at the bottom of the cavity. Here, 100 ns molecular dynamics (MD) simulation allowed us to study their geometries and showed that HAFP-estrogen interactions were caused by van der Waals forces, while both hydrophobic and electrostatic interactions were almost equally involved in HAFP-antiestrogen binding. Molecular mechanics/Generalized Born surface area (MM/GBSA) rescoring method exploited for estimation of binding free energies (ΔGbind) showed that antiestrogens have higher affinities to HAFP as compared to estrogens. We performed in silico point substitutions of amino acid residues to confirm their roles in HAFP-ligand interactions and showed that Thr132, Leu138, His170, Phe172, Ser217, Gln221, His266, His316, Lys453, and Asp478 residues, along with two disulfide bonds (Cys224-Cys270 and Cys269-Cys277), have key roles in both HAFP-estrogen and HAFP-antiestrogen binding. Data obtained in our study contribute to understanding mechanisms underlying protein-ligand interactions and anticancer therapy strategies based on ERα-binding ligands.