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1.
Elagolix Alone or With Add-Back Therapy in Women With Heavy Menstrual Bleeding and Uterine Leiomyomas: A Randomized Controlled Trial.
Carr, BR, Stewart, EA, Archer, DF, Al-Hendy, A, Bradley, L, Watts, NB, Diamond, MP, Gao, J, Owens, CD, Chwalisz, K, et al
Obstetrics and gynecology. 2018;(5):1252-1264
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Abstract
OBJECTIVE To evaluate elagolix, an oral gonadotropin-releasing hormone receptor antagonist, alone or with add-back therapy, in premenopausal women with heavy menstrual bleeding (greater than 80 mL per month) associated with uterine leiomyomas. METHODS This double-blind, randomized, placebo-controlled, parallel-group study evaluated efficacy and safety of elagolix in cohorts 1 (300 mg twice daily) and 2 (600 mg daily) with four arms per cohort: placebo, elagolix alone, elagolix with 0.5 mg estradiol/0.1 norethindrone acetate, and elagolix with 1.0 mg estradiol/0.5 mg norethindrone acetate. A sample size of 65 per group was planned to compare elagolix with add-back to placebo on the primary end point: the percentage of women who had less than 80 mL menstrual blood loss and 50% or greater reduction in menstrual blood loss from baseline to the last 28 days of treatment. Safety assessments included changes in bone mineral density. RESULTS From April 8, 2013, to December 8, 2015, 571 women were enrolled, 567 were randomized and treated (cohort 1=259; cohort 2=308), and 80% and 75% completed treatment, respectively. Participants had a mean±SD age of 43±5 years (cohort 2, 42±5 years), and 70% were black (cohort 2, 74%). Primary end point responder rates in cohort 1 (cohort 2) were 92% (90%) for elagolix alone, 85% (73%) for elagolix with 0.5 mg estradiol/0.1 mg norethindrone acetate, 79% (82%) for elagolix with 1.0 mg estradiol/0.5 mg norethindrone acetate, and 27% (32%) for placebo (all P<.001 vs placebo). Elagolix groups had significant decreases compared with placebo in lumbar spine bone mineral density, which was attenuated by adding 1.0 mg estradiol/0.5 mg norethindrone acetate. CONCLUSION Elagolix with and without add-back significantly reduced menstrual blood loss in women with uterine leiomyomas. Add-back therapy reduced hypoestrogenic effects on bone mineral density. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, NCT01817530; EU Clinical Trial Register, 2013-000082-37.
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Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts.
Mahemuti, L, Chen, Q, Coughlan, MC, Qiao, C, Chepelev, NL, Florian, M, Dong, D, Woodworth, RG, Yan, J, Cao, XL, et al
Archives of toxicology. 2018;(4):1453-1469
Abstract
Experimental and/or epidemiological studies suggest that prenatal exposure to bisphenol A (BPA) may delay fetal lung development and maturation and increase the susceptibility to childhood respiratory disease. However, the underlying mechanisms remain to be elucidated. In our previous study with cultured human fetal lung fibroblasts (HFLF), we demonstrated that 24-h exposure to 1 and 100 µM BPA increased GPR30 protein in the nuclear fraction. Exposure to 100 μM BPA had no effects on cell viability, but increased cytoplasmic expression of ERβ and release of GDF-15, as well as decreased release of IL-6, ET-1, and IP-10 through suppression of NFκB phosphorylation. By performing global gene expression and pathway analysis in this study, we identified molecular pathways, gene networks, and key molecules that were affected by 100, but not 0.01 and 1 µM BPA in HFLF. Using multiple genomic and proteomic tools, we confirmed these changes at both gene and protein levels. Our data suggest that 100 μM BPA increased CYP1B1 and HSD17B14 gene and protein expression and release of endogenous estradiol, which was associated with increased ROS production and DNA double-strand breaks, upregulation of genes and/or proteins in steroid synthesis and metabolism, and activation of Nrf2-regulated stress response pathways. In addition, BPA activated ATM-p53 signaling pathway, resulting in increased cell cycle arrest at G1 phase, senescence and autophagy, and decreased cell proliferation in HFLF. The results suggest that prenatal exposure to BPA at certain concentrations may affect fetal lung development and maturation, and thereby affecting susceptibility to childhood respiratory diseases.
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Fabrication of Stabilized Fe⁻Mn Binary Oxide Nanoparticles: Effective Adsorption of 17β-Estradiol and Influencing Factors.
Ning, Q, Yin, Z, Liu, Y, Tan, X, Zeng, G, Jiang, L, Liu, S, Tian, S, Liu, N, Wang, X
International journal of environmental research and public health. 2018;(10)
Abstract
Fe⁻Mn binary oxide nanoparticles (FMBON) were reported to be high performance as adsorbent for pollutants removal from aqueous solution. However, there are still limitations in practice application due to the FMBON tend to aggregate into the micro millimeter level. In order to avoid the agglomeration of nanoparticles, this work synthesized the stabilized Fe⁻Mn binary oxide nanoparticles (CMC-FMBON) by using water-soluble carboxymethyl celluloses (CMC) as the stabilizer. The characteristics of CMC-FMBON and FMBON were measured by using Transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, and Zeta potential. This work systematically investigated the adsorption capacity of CMC-FMBON for 17β-estradiol (E2) and the influences of external environmental factors on E2 removal. The results indicated that CMC-FMBON had much smaller particles, wider dispersion and larger surface area than the FMBON. CMC-FMBON showed better adsorption performance for E2 than FMBON with the maximum adsorption capacity of CMC-FMBON and FMBON were 124.10 and 98.14 mg/g at 298 K, respectively. The experimental data can be well fitted by the model of pseudo-second-order and Langmuir model. The E2 removal by CMC-FMBON was obviously dependent on pH with the maximum adsorption occurring when the pH was acidic. The removal capacity of CMC-FMBON increased when enhancing ionic strength in solution. Background electrolytes promoted slightly E2 adsorption process whereas the presence of humic acid inhibited the E2 removal. π-π interactions, hydrogen bonds, and oxidation might be responsible for E2 removal. This research suggested that the CMC-FMBON has been considered to be a cost-efficient adsorbent for removing E2 from water.
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SLCO1B1 genetic variation and hormone therapy in menopausal women.
Moyer, AM, de Andrade, M, Faubion, SS, Kapoor, E, Dudenkov, T, Weinshilboum, RM, Miller, VM
Menopause (New York, N.Y.). 2018;(8):877-882
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Abstract
OBJECTIVE Response to menopausal hormone therapy (MHT) shows individual variation. SLCO1B1 encodes the OATP1B1 transporter expressed in the liver that transports many endogenous substances, including estrone sulfate, from the blood into hepatocytes. This study evaluated the relationship between genetic variation in SLCO1B1 and response to MHT in women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS) at Mayo Clinic, Rochester, MN. METHODS KEEPS participants were randomized to oral conjugated equine estrogen (n = 33, oCEE), transdermal 17β-estradiol (n = 33, tE2), or placebo (n = 34) for 48 months. Menopausal symptoms (hot flashes, night sweats, insomnia, palpitations) were self-reported before treatment and at 48 months. Estrone (E1), E2, and sulfated conjugates (E1S, E2S) were measured using high-performance liquid chromatography-tandem mass spectrometry. SLCO1B1 rs4149056 (c.521T>C, p.Val174Ala) was genotyped using a TaqMan assay. RESULTS After adjusting for treatment, there was a significant association between the SLCO1B1 rs4149056 TT genotype (encoding normal function transporter) and lower E1S, E1S/E1, and E2S (P = 0.032, 0.010, and 0.008, respectively) compared with women who were heterozygous (TC) or homozygous (CC) for the reduced function allele. The interactions between genotype, treatment, and E2S concentration were stronger in women assigned to tE2 (P = 0.013) than the women taking oCEE (P = 0.056). Among women assigned to active treatment, women with the CT genotype showed a significantly greater decrease in night sweats (P = 0.041) than those with the TT genotype. CONCLUSIONS Individual variation in sulfated estrogens is explained, in part, by genetic variation in SLCO1B1. Bioavailability of sulfated estrogens may contribute to relief of night sweats.
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Adipocytes ESR1 Expression, Body Fat and Response to Testosterone Therapy in Hypogonadal Men Vary According to Estradiol Levels.
Colleluori, G, Aguirre, LE, Qualls, C, Chen, R, Napoli, N, Villareal, DT, Armamento-Villareal, R
Nutrients. 2018;(9)
Abstract
UNLABELLED Estradiol (E2), mainly produced from Testosterone (T) in men, promotes visceral lipolysis. However, high visceral fat and hyperestrogenemia are features of obese hypogonadal (HG) men. Our study objectives are to evaluate relationships between circulating E2 and: (1) fat mass; (2) Estrogen Receptor α (ESR1) expression in subcutaneous adipose tissue; (3) changes in body fat after 6 months (M) of T therapy in HG men. HYPOTHESES (1) existence of a range of circulating E2 associated with better body composition; (2) serum E2 determines tissue E2 sensitivity which affects response to T therapy. Men 40⁻74 years old, T < 300 (ng/dL), given T-cypionate for 6 months. Subjects were divided into 4-E2 categories: (1) <10.0; (2) 10.0⁻15.9; (3) 16.0⁻19.9; (4) ≥20.0 (pg/mL). Body composition (DXA), fat biopsies (liposuction), gene expression (qPCR), serum E2 and T (LC/MS), at baseline and 6 months. We enrolled 105 men; 90 completed the study. Group 2 had lower total and truncal fat mass (p < 0.01) but higher % lean mass (p < 0.001). ESR1 mRNA was the highest in group 1 (p = 0.01). At 6 months, group 1 had higher reduction in total (p = 0.03) and truncal (p = 0.01) fat. In conclusion, serum E2 = 10⁻15.9 (pg/mL) is associated with the best body composition profile in HG men; however, those with E2 < 10 (pg/mL) had the best response (greater fat loss) to T replacement possibly because of greater E2 sensitivity.
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Alcohol and oestrogen metabolites in postmenopausal women in the Women's Health Initiative Observational Study.
Playdon, MC, Coburn, SB, Moore, SC, Brinton, LA, Wentzensen, N, Anderson, G, Wallace, R, Falk, RT, Pfeiffer, R, Xu, X, et al
British journal of cancer. 2018;(3):448-457
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Abstract
BACKGROUND Alcohol consumption is associated with an increased risk of several cancers. Potential mechanisms include altered oestrogen metabolism. Parent oestrogens metabolise into alternate pathways of oestrogen metabolites that may have variable effects on cancer pathogenesis. We examined associations of alcohol consumption with circulating oestrogen/oestrogen metabolites in postmenopausal women in the Women's Health Initiative (WHI)-Observational Study (OS). METHODS We conducted a cross-sectional analysis of prediagnosis ovarian/endometrial cancer case-control data within WHI-OS (N=1864). Alcohol consumption was measured by validated food frequency questionnaire. Fasting serum parent oestrogens/oestrogen metabolites were assayed using liquid chromatography tandem mass-spectrometry. Geometric mean analyte concentrations (GM, pmol l-1) were calculated by alcohol category using inverse-probability weighted linear regression, adjusting for venepuncture age/year, race, smoking, body mass index, years since menopause, oral contraceptive duration, caffeine intake, and physical activity. RESULTS There was evidence for a positive association between alcohol consumption and oestrone, oestradiol and 2-hydroxylation oestrogen metabolite concentrations among menopausal hormone therapy (MHT) users. We observed an association between liquor consumption and parent oestrogens among non-MHT users, who consumed larger doses of liquor than MHT users. CONCLUSIONS Among postmenopausal women, the association between alcohol intake and parent oestrogen, but not oestrogen metabolite concentrations, may be influenced by MHT and type of alcohol.
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Anaerobic biodegradation of pharmaceutical compounds: New insights into the pharmaceutical-degrading bacteria.
Martins, M, Sanches, S, Pereira, IAC
Journal of hazardous materials. 2018;:289-297
Abstract
Antibiotics and hormones are among the most concerning trace contaminants in the environment. Therefore, the present work aimed to identify anaerobic microorganisms with the ability to remove pharmaceutical products (PhPs) belonging to these two classes (ciprofloxacin, 17β-estradiol and sulfamethoxazole) under different anaerobic conditions, and to elucidate the bio-removal mechanisms involved. Ciprofloxacin was efficiently biodegraded under both nitrate- and sulfate-reducing conditions reaching a PhP removal superior to 80%, whereas 17β-estradiol was only biodegraded under nitrate-reducing conditions reaching a removal of 84%. No biodegradation of sulfamethoxazole was observed. In nitrate-reducing conditions the ciprofloxacin-degrading community was composed of Comamonas, Arcobacter, Dysgonomonas, Macellibacteroides and Actinomyces, genera while Comamonas and Castellaniella were the main bacteria present in the 17β-estradiol-degrading community. In sulfate-reducing conditions the community was mainly composed by bacteria affiliated to Desulfovibrio, Enterococcus and Peptostreeptococcus. Interestingly, the PhP under study were biodegraded even in the absence of additional carbon source, with 85% of ciprofloxacin removed under sulfate-reducing conditions and 62% and 83% of ciprofloxacin and estradiol removed, respectively, under nitrate-reducing conditions. This work provides new insights into anaerobic bioremediation of PhP and novel PhP-degrading bacteria.
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A novel electrochemical sensor based on Fe3O4-doped nanoporous carbon for simultaneous determination of diethylstilbestrol and 17β-estradiol in toner.
Chen, X, Shi, Z, Hu, Y, Xiao, X, Li, G
Talanta. 2018;:81-90
Abstract
In this paper, Fe3O4-doped nanoporous carbon (Fe3O4-NC) was synthesized through the carbonization of Fe-porous coordination polymer (Fe-PCP), which are also known as metal-organic framework (MOF), and fabricated into an electrochemical sensor for simultaneous analysis of diethylstilbestrol (DES) and 17β-estradiol (E2) in toner. Fe3O4-NC was characterized by scanning electron microscope (SEM), powder X-ray diffraction (pXRD), X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, N2 adsorption-desorption and so on. It is of great practical significance to achieve the simultaneous determination of the two estrogens because estrogens are co-existing in many real samples. The simultaneous determination of two common estrogens, DES and E2, was achieved through electro-catalytically oxidization at a Fe3O4-NC modified glassy carbon electrode (Fe3O4-NC/GCE). The peak currents of DES and E2 increased linearly as their concentrations increasing from 0.01 to 12 μmol/L and from 0.01 to 20 μmol/L, with detection limits of 4.6 nmol/L and 4.9 nmol/L (S/N = 3), respectively. This work was focused on the simultaneous determination of the two estrogens in toner. Furthermore, the recoveries of DES and E2 were 91.2-110%, in actual toner samples. The experimental results manifest that the sensor with a stronger anti-interference ability can be used for the simultaneous detection of DES and E2 in the actual toner sample.
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A Double-Blind Randomized Pilot Study Evaluating the Safety and Efficacy of Topical MEP in the Facial Appearance Improvement of Estrogen Deficient Females.
Draelos, ZD
Journal of drugs in dermatology : JDD. 2018;(11):1186 - 1189
Abstract
Facial skin aging is accelerated in postmenopausal females due to decreased collagen, reduced hydration, and loss of skin elasticity constituting the characteristics of estrogen deficient skin (EDS). The presence of estrogen receptors on dermal fibroblasts and epidermal keratinocytes confirms the role of estrogen in skin health. This research examined the efficacy and tolerability of topical methyl estradiolpropanoate (MEP) as an anti-aging cosmeceutical with estrogen like cutaneous effects in postmenopausal women who had never taken hormone replacement therapy (HRT). MEP was applied to the face twice daily for 14 weeks but was metabolized in the skin to an inactive compound avoiding estrogen side effects, as demonstrated by the safety study. The efficacy study investigator noted MEP induced statistically significant improvement from baseline at week 14 in dryness (P<0.001), laxity (P=0.001), atrophy (P=0.003), and dullness (P<0.001) as compared to vehicle. Four of nine subjects in the biopsy sub study demonstrated an increase in fibroblasts estrogen receptor staining. The novel concept of a safe and efficacious soft estrogen facial cosmeceutical may provide appearance benefits for postmenopausal women.
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Kinetics and mechanism of 17β-estradiol chlorination in a pilot-scale water distribution systems.
Li, C, Dong, F, Crittenden, JC, Luo, F, Chen, X, Zhao, T
Chemosphere. 2017;:73-79
Abstract
The kinetics and mechanisms of 17β-estradiol (E2) chlorination in water distribution systems (WDS) were studied. We examined the impacts of different factors, including pH, temperature, humic acid concentration and type, and flow velocity. The experimental results showed that the rate constants in beaker tests and WDS were described by a pseudo-first-order model. pH had the greatest impact on E2 chlorination in the beaker tests. However, temperature had the greatest impact on E2 chlorination in WDS. Mechanistic analysis of E2 chlorination showed that chlorine attacked E2 in three stages: 1) halogenation of the aromatic ring, 2) cleavage of the benzene moiety and chlorine or bromine substitution formation, and 3) formation of trihalomethanes (THMs) and halogenated acetic acids (HAAs) from phenolic intermediates through benzene ring opening with chlorine and/or bromine substitution of hydrogen on the carbon atoms. In the third stage, the concentrations of THMs and HAAs increased rapidly.