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1.
Eur J Endocrinol ; 183(4): 439-452, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32698159

RESUMO

Objective: Combining conjugated estrogens (CE) with the selective estrogen receptor modulator bazedoxifene (BZA) is a novel, orally administered menopausal therapy. We investigated the effect of CE/BZA on insulin sensitivity, energy metabolism, and serum metabolome in postmenopausal women with obesity. Design: Randomized, double-blind, crossover pilot trial with washout was conducted at Pennington Biomedical Research Center. Eight postmenopausal women (age 50-60 years, BMI 30-40 kg/m2) were randomized to 8 weeks CE/BZA or placebo. Primary outcome was insulin sensitivity (hyperinsulinemic-euglycemic clamp). Secondary outcomes included body composition (DXA); resting metabolic rate (RMR); substrate oxidation (indirect calorimetry); ectopic lipids (1H-MRS); fat cell size, adipose and skeletal muscle gene expression (biopsies); serum inflammatory markers; and serum metabolome (LC/MS). Results: CE/BZA treatment produced no detectable effect on insulin sensitivity, body composition, ectopic fat, fat cell size, or substrate oxidation, but resulted in a non-significant increase in RMR (basal: P = 0.06; high-dose clamp: P = 0.08) compared to placebo. CE/BZA increased serum high-density lipoprotein (HDL)-cholesterol. CE/BZA also increased serum diacylglycerol (DAG) and triacylglycerol (TAG) species containing long-chain saturated, mono- and polyunsaturated fatty acids (FAs) and decreased long-chain acylcarnitines, possibly reflecting increased hepatic de novo FA synthesis and esterification into TAGs for export into very low-density lipoproteins, as well as decreased FA oxidation, respectively (P < 0.05). CE/BZA increased serum phosphatidylcholines, phosphatidylethanolamines, ceramides, and sphingomyelins, possibly reflecting the increase in serum lipoproteins (P < 0.05). Conclusions: A short treatment of obese postmenopausal women with CE/BZA does not alter insulin action or ectopic fat but increases serum markers of hepatic de novo lipogenesis and TAG production.


Assuntos
Metabolismo dos Carboidratos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Estrogênios Conjugados (USP)/farmacologia , Glucose/metabolismo , Indóis/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Obesidade/metabolismo , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Estudos Cross-Over , Método Duplo-Cego , Estrogênios Conjugados (USP)/uso terapêutico , Feminino , Humanos , Indóis/uso terapêutico , Pessoa de Meia-Idade , Obesidade/tratamento farmacológico , Projetos Piloto , Pós-Menopausa/efeitos dos fármacos , Pós-Menopausa/metabolismo
2.
JAMA ; 324(4): 369-380, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32721007

RESUMO

Importance: The influence of menopausal hormone therapy on breast cancer remains unsettled with discordant findings from observational studies and randomized clinical trials. Objective: To assess the association of prior randomized use of estrogen plus progestin or prior randomized use of estrogen alone with breast cancer incidence and mortality in the Women's Health Initiative clinical trials. Design, Setting, and Participants: Long-term follow-up of 2 placebo-controlled randomized clinical trials that involved 27 347 postmenopausal women aged 50 through 79 years with no prior breast cancer and negative baseline screening mammogram. Women were enrolled at 40 US centers from 1993 to 1998 with follow-up through December 31, 2017. Interventions: In the trial involving 16 608 women with a uterus, 8506 were randomized to receive 0.625 mg/d of conjugated equine estrogen (CEE) plus 2.5 mg/d of medroxyprogesterone acetate (MPA) and 8102, placebo. In the trial involving 10 739 women with prior hysterectomy, 5310 were randomized to receive 0.625 mg/d of CEE alone and 5429, placebo. The CEE-plus-MPA trial was stopped in 2002 after 5.6 years' median intervention duration, and the CEE-only trial was stopped in 2004 after 7.2 years' median intervention duration. Main Outcomes and Measures: The primary outcome was breast cancer incidence (protocol prespecified primary monitoring outcome for harm) and secondary outcomes were deaths from breast cancer and deaths after breast cancer. Results: Among 27 347 postmenopausal women who were randomized in both trials (baseline mean [SD] age, 63.4 years [7.2 years]), after more than 20 years of median cumulative follow-up, mortality information was available for more than 98%. CEE alone compared with placebo among 10 739 women with a prior hysterectomy was associated with statistically significantly lower breast cancer incidence with 238 cases (annualized rate, 0.30%) vs 296 cases (annualized rate, 0.37%; hazard ratio [HR], 0.78; 95% CI, 0.65-0.93; P = .005) and was associated with statistically significantly lower breast cancer mortality with 30 deaths (annualized mortality rate, 0.031%) vs 46 deaths (annualized mortality rate, 0.046%; HR, 0.60; 95% CI, 0.37-0.97; P = .04). In contrast, CEE plus MPA compared with placebo among 16 608 women with a uterus was associated with statistically significantly higher breast cancer incidence with 584 cases (annualized rate, 0.45%) vs 447 cases (annualized rate, 0.36%; HR, 1.28; 95% CI, 1.13-1.45; P < .001) and no significant difference in breast cancer mortality with 71 deaths (annualized mortality rate, 0.045%) vs 53 deaths (annualized mortality rate, 0.035%; HR, 1.35; 95% CI, 0.94-1.95; P= .11). Conclusions and Relevance: In this long-term follow-up study of 2 randomized trials, prior randomized use of CEE alone, compared with placebo, among women who had a previous hysterectomy, was significantly associated with lower breast cancer incidence and lower breast cancer mortality, whereas prior randomized use of CEE plus MPA, compared with placebo, among women who had an intact uterus, was significantly associated with a higher breast cancer incidence but no significant difference in breast cancer mortality.


Assuntos
Neoplasias da Mama/epidemiologia , Estrogênios Conjugados (USP)/efeitos adversos , Terapia de Reposição Hormonal/efeitos adversos , Histerectomia , Acetato de Medroxiprogesterona/efeitos adversos , Idoso , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/mortalidade , Neoplasias da Mama/prevenção & controle , Estrogênios Conjugados (USP)/uso terapêutico , Feminino , Seguimentos , Humanos , Histerectomia/efeitos adversos , Incidência , Acetato de Medroxiprogesterona/uso terapêutico , Pessoa de Meia-Idade , Pós-Menopausa , Risco
3.
J Pharm Pharm Sci ; 23(1): 75-85, 2020.
Artigo em Inglês | MEDLINE | ID: covidwho-196744

RESUMO

The presented work summarizes the results of studies underlining the crucial role of estrogen receptor (ER) signaling in both innate and adaptive immune responses as well as in tissue repairing processes during respiratory virus infection. Experimental studies justify that among respiratory virus infected mice, a weaker ER signaling leads to increased morbidity and mortality in both males and females. In animal experiments, estrogen treatment silences the inflammatory reactions and decreases virus titers leading to improved survival rate; it seems to be an ideal prevention and therapy against COVID-19. We should overcome the widespread reluctance to estrogen therapy as we have a unique estrogen formula; conjugated estrogens, or conjugated equine estrogens available under the brand name of Premarin deriving from natural sources. Premarin can exert similar ER upregulative and gene repairing power like endogenous estrogen without any risk for adverse reactions. Premarin is capable of stopping the COVID-19 pandemic.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Estrogênios/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Receptores Estrogênicos/fisiologia , Imunidade Adaptativa , Fatores Etários , Animais , Betacoronavirus , Comorbidade , Infecções por Coronavirus/mortalidade , Estrogênios Conjugados (USP)/uso terapêutico , Feminino , Humanos , Imunidade Inata , Inflamação/tratamento farmacológico , Masculino , Camundongos , Pandemias , Pneumonia Viral/mortalidade , Fatores Sexuais , Transdução de Sinais , Regulação para Cima/efeitos dos fármacos
4.
J Pharm Pharm Sci ; 23(1): 75-85, 2020.
Artigo em Inglês | MEDLINE | ID: covidwho-118968

RESUMO

The presented work summarizes the results of studies underlining the crucial role of estrogen receptor (ER) signaling in both innate and adaptive immune responses as well as in tissue repairing processes during respiratory virus infection. Experimental studies justify that among respiratory virus infected mice, a weaker ER signaling leads to increased morbidity and mortality in both males and females. In animal experiments, estrogen treatment silences the inflammatory reactions and decreases virus titers leading to improved survival rate; it seems to be an ideal prevention and therapy against COVID-19. We should overcome the widespread reluctance to estrogen therapy as we have a unique estrogen formula; conjugated estrogens, or conjugated equine estrogens available under the brand name of Premarin deriving from natural sources. Premarin can exert similar ER upregulative and gene repairing power like endogenous estrogen without any risk for adverse reactions. Premarin is capable of stopping the COVID-19 pandemic.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Estrogênios/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Receptores Estrogênicos/fisiologia , Imunidade Adaptativa , Fatores Etários , Animais , Betacoronavirus , Comorbidade , Infecções por Coronavirus/mortalidade , Estrogênios Conjugados (USP)/uso terapêutico , Feminino , Humanos , Imunidade Inata , Inflamação/tratamento farmacológico , Masculino , Camundongos , Pandemias , Pneumonia Viral/mortalidade , Fatores Sexuais , Transdução de Sinais , Regulação para Cima/efeitos dos fármacos
5.
J Pharm Pharm Sci ; 23(1): 75-85, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32324533

RESUMO

The presented work summarizes the results of studies underlining the crucial role of estrogen receptor (ER) signaling in both innate and adaptive immune responses as well as in tissue repairing processes during respiratory virus infection. Experimental studies justify that among respiratory virus infected mice, a weaker ER signaling leads to increased morbidity and mortality in both males and females. In animal experiments, estrogen treatment silences the inflammatory reactions and decreases virus titers leading to improved survival rate; it seems to be an ideal prevention and therapy against COVID-19. We should overcome the widespread reluctance to estrogen therapy as we have a unique estrogen formula; conjugated estrogens, or conjugated equine estrogens available under the brand name of Premarin deriving from natural sources. Premarin can exert similar ER upregulative and gene repairing power like endogenous estrogen without any risk for adverse reactions. Premarin is capable of stopping the COVID-19 pandemic.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Estrogênios/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Receptores Estrogênicos/fisiologia , Imunidade Adaptativa , Fatores Etários , Animais , Betacoronavirus , Comorbidade , Infecções por Coronavirus/mortalidade , Estrogênios Conjugados (USP)/uso terapêutico , Feminino , Humanos , Imunidade Inata , Inflamação/tratamento farmacológico , Masculino , Camundongos , Pandemias , Pneumonia Viral/mortalidade , Fatores Sexuais , Transdução de Sinais , Regulação para Cima/efeitos dos fármacos
6.
Environ Pollut ; 256: 113384, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31677876

RESUMO

Although livestock manure, such as from swine (Sus scrofa domestica), have high capacity to introduce endocrine-disrupting free estrogens into the environment, the frequency of estrogen detections from reconnaissance studies suggest that these compounds are ubiquitous in the environment, perhaps resulting from historic manure inputs (e.g. cattle grazing residues, undocumented historic manure applications) or uncontrolled natural sources. Compared to free estrogens, conjugates of estrogens are innocuous but have greater mobility in the environment. Estrogen conjugates can also hydrolyze to re-form the potent free estrogens. The objective of this study was to identify the transport of free and conjugated estrogens to subsurface tile drains and groundwater beneath fields treated with swine manure slurry. Three field treatments were established, two receiving swine lagoon manure slurry and one with none. Manure slurry was injected into soils at a shallow depth (∼8 cm) and water samples from tile drains and shallow wells were sampled periodically for three years. Glucuronide and sulfate conjugates of 17ß-estradiol (E2) and estrone (E1) were the only estrogen compounds detected in the tile drains (total detects = 31; 5% detection frequency; conc. range = 3.9-23.1 ng L-1), indicating the important role conjugates played in the mobility of estrogens. Free estrogens and estrogen conjugates were more frequently detected in the wells compared to the tile drains (total detects = 70; 11% detection frequency; conc. range = 4.0-1.6 × 103 ng L-1). No correlations were found between estrogen compound detections and dissolved or colloidal organic carbon (OC) fractions or other water quality parameters. Estrogenic compounds were detected beneath both manure treated and non-treated plots; furthermore, the total potential estrogenic equivalents (i.e. estrogenicity of hydrolyzed conjugates + free estrogens) were similar between treated and non-treated plots.


Assuntos
Disruptores Endócrinos/análise , Estrogênios Conjugados (USP)/análise , Estrogênios/análise , Água Subterrânea/química , Esterco/análise , Águas Residuárias/química , Animais , Bioensaio , Bovinos , Estradiol/análise , Estrona/análise , Gado , Solo/química , Suínos
7.
Medicina (Kaunas) ; 55(9)2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31500261

RESUMO

Hormone replacement therapy (HRT) remains the most effective treatment for menopausal symptoms and has been shown to prevent bone loss and fracture. The progestogen is added to provide endometrial protection in women with an intact uterus. After the publication of the initial WHI (Women's Health Initiative) results in 2002 reporting an overall increased risk of breast cancer, many women discontinued HRT. Despite the re-analysis of the results by subgroups of patients and updates with extended follow-up, much controversy remains, which we will analyze later in the text. Different types of estrogen or progestogen, as well as different formulations, doses, and durations, may play a role in HRT's effects on breast tissue. Evidence states that conjugated equine estrogen (CEE), compared to estro-progestin therapy, shows a better profile risk (HR 0.79, CI 0.65-0.97) and that, among different type of progestins, those structurally related to testosterone show a higher risk (RR 3.35, CI 1.07-10.4). Chronic unopposed endometrial exposure to estrogen increases the risk of endometrial hyperplasia and cancer, whereas the association with progestins, especially in continuous combined regimen, seems to reduce the risk (RR 0.71, CI 0.56-0.90). HRT was also associated with a protective effect on colon cancer risk (HR 0.61, CI 0.42-0.87). Data about ovarian and cervical cancer are still controversial.


Assuntos
Neoplasias dos Genitais Femininos/prevenção & controle , Terapia de Reposição Hormonal/normas , Estrogênios Conjugados (USP)/farmacologia , Estrogênios Conjugados (USP)/normas , Estrogênios Conjugados (USP)/uso terapêutico , Feminino , Neoplasias dos Genitais Femininos/fisiopatologia , Terapia de Reposição Hormonal/métodos , Terapia de Reposição Hormonal/estatística & dados numéricos , Humanos
8.
J Biol Chem ; 294(32): 12112-12121, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31217279

RESUMO

Conjugated equine estrogens (CEEs), whose brand name is Premarin, are widely used as a hormone-replacement therapy (HRT) drug to manage postmenopausal symptoms in women. Extracted from pregnant mare urine, CEEs are composed of nearly a dozen estrogens existing in an inactive sulfated form. To determine whether the hepatic steroid sulfatase (STS) is a key contributor to the efficacy of CEEs in HRT, we performed estrogen-responsive element (ERE) reporter gene assay, real-time PCR, and UPLC-MS/MS to assess the STS-dependent and inflammation-responsive estrogenic activity of CEEs in HepG2 cells and human primary hepatocytes. Using liver-specific STS-expressing transgenic mice, we also evaluated the effect of STS on the estrogenic activity of CEEs in vivo We observed that CEEs induce activity of the ERE reporter gene in an STS-dependent manner and that genetic or pharmacological inhibition of STS attenuates CEE estrogenic activity. In hepatocytes, inflammation enhanced CEE estrogenic activity by inducing STS gene expression. The inflammation-responsive estrogenic activity of CEEs, in turn, attenuated inflammation through the anti-inflammatory activity of the active estrogens. In vivo, transgenic mice with liver-specific STS expression exhibited markedly increased sensitivity to CEE-induced estrogenic activity in the uterus resulting from increased levels of liver-derived and circulating estrogens. Our results reveal a critical role of hepatic STS in mediating the hormone-replacing activity of CEEs. We propose that caution needs to be applied when Premarin is used in patients with chronic inflammatory liver diseases because such patients may have heightened sensitivity to CEEs due to the inflammatory induction of STS activity.


Assuntos
Estrogênios Conjugados (USP)/metabolismo , Esteril-Sulfatase/metabolismo , Animais , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Estrogênios Conjugados (USP)/análise , Estrogênios Conjugados (USP)/farmacologia , Feminino , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Cavalos , Humanos , Inflamação/metabolismo , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Esteril-Sulfatase/antagonistas & inibidores , Esteril-Sulfatase/genética , Espectrometria de Massas em Tandem , Útero/efeitos dos fármacos , Útero/metabolismo , Útero/patologia
9.
Gac Med Mex ; 155(2): 199-201, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31056600

RESUMO

Introduction: Conjugated estrogens, when used by the vaginal route for the relief of vaginal dryness and atrophy, can produce endometrial changes. Objective: To know the effect of vaginal conjugated estrogens application frequency on endometrial thickness in postmenopausal women. Method: Seventy postmenopausal women with vaginal dryness who received conjugated estrogen cream (0.625 mg/1 g) for 12 weeks were studied. The women were divided according to application frequency as follows: group 1, twice-weekly (n = 35), and group 2, thrice-weekly (n = 35). At baseline and at end-of-treatment, vaginal cytology was examined to determine the estrogenic value, and an endovaginal ultrasound was performed to measure endometrial thickness. The comparison between groups was carried out with Mann Whitney's U-test, and the comparison between baseline and post-treatment values, with Wilcoxon's test. Results: Of 70 recruited women, only 38 were studied, 19 in each group, paired by baseline estrogenic value. No difference was found between groups, neither at baseline nor after treatment, in the maturation index, estrogenic value or endometrial thickness. Conclusion: There were no differences in endometrial thickness between the conjugate estrogen cream different application frequencies.


Assuntos
Estrogênios Conjugados (USP)/administração & dosagem , Pós-Menopausa , Vagina/efeitos dos fármacos , Administração Intravaginal , Idoso , Atrofia/tratamento farmacológico , Atrofia/etiologia , Esquema de Medicação , Endométrio/diagnóstico por imagem , Feminino , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Estudos Prospectivos , Estatísticas não Paramétricas , Resultado do Tratamento , Ultrassonografia , Vagina/diagnóstico por imagem
10.
Artigo em Inglês | MEDLINE | ID: mdl-31035709

RESUMO

Zearalenone (ZEA) is a non-steroidal estrogen mycotoxin produced by several Gibberella and Fusarium species. Accumulating evidence has indicated that ZEA strongly stimulates cell proliferation. However the detailed molecular and cellular mechanisms of ZEA-mediated induction of cell proliferation have not yet been completely explained. The aim of this study was to detect the role of miRNAs in ZEA-mediated induction of cell proliferation. The effects of ZEA on cell proliferation were assessed using a cell counting kit assay and xCELLigence system. Micro-RNA sequencing was performed after treatment of TM3 cells with ZEA (0.01 µmol/L) for different time periods (0, 2, 6 and 18 h). Cell function and pathway analysis of the miRNA target genes were performed by Ingenuity Pathway Analysis (IPA). We found that ZEA promotes TM3 cell proliferation at low concentrations. miRNA sequenceing revealed 66 differentially expressed miRNAs in ZEA-treated cells in comparison to the untreated control ( p < 0.05). The miRNA sequencing indicated that compared to control group, there were 66 miRNAs significant change (p < 0.05) in ZEA-treated groups. IPA analysis showed that the predicated miRNAs target gene involved in cell Bio-functions including cell cycle, growth and proliferation, and in signaling pathways including MAPK and RAS-RAF-MEK-ERK pathways. Results from flow cytometry and Western Blot analysis validated the predictions that ZEA can affect cell cycle, and the MAPK signaling pathway. Taking these together, the cell proliferation induced ZEA is regulated by miRNAs. The results shed light on the molecular and cellular mechanisms for the mediation of ZEA to induce proliferation.


Assuntos
Proliferação de Células/efeitos dos fármacos , MicroRNAs/metabolismo , Zearalenona/toxicidade , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Estrogênios Conjugados (USP) , Regulação da Expressão Gênica/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , MicroRNAs/genética , Transdução de Sinais/efeitos dos fármacos
11.
Cancer Radiother ; 23(2): 151-160, 2019 Apr.
Artigo em Francês | MEDLINE | ID: mdl-30898418

RESUMO

Abdominal and pelvic irradiations play a major place in the management of patients with cancer and present a risk of acute and late side effects. Radiation-induced lesions can affect kidney or urological structures. These side effects can have an impact in the quality of life of patients. The aim of this article is to describe the physiopathology, the symptomatology, and the principles of management of radiation-induced nephropathy, uretheritis, cystitis, and urethritis.


Assuntos
Radioterapia/efeitos adversos , Doenças Urológicas/etiologia , Doenças Urológicas/terapia , Antioxidantes/uso terapêutico , Estrogênios Conjugados (USP)/administração & dosagem , Humanos , Fatores Imunológicos/administração & dosagem , Terapia a Laser , Mioblastos/transplante , Neoplasias/radioterapia , Polidesoxirribonucleotídeos/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/administração & dosagem
12.
Climacteric ; 22(2): 140-147, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30895900

RESUMO

Selective estrogen receptor modulators (SERMs) are synthetic non-steroidal agents which have variable estrogen agonist and antagonist activities in different target tissues. Tamoxifen is an anti-estrogen in the breast used for treatment and prevention of breast cancer, with estrogen agonist activity in the uterus. Raloxifene prevents and treats osteoporosis and prevents breast cancer, and can be safely combined with vaginal but not systemic estrogen. The tissue selective estrogen complex combines conjugated equine estrogens (CEE) with the SERM bazedoxifene (BZA). The five Selective Estrogen Menopause and Response to Therapy studies, with up to 2 years of data, demonstrated that CEE/BZA 0.45 mg/BZA 20 mg improved vasomotor symptoms and vulvovaginal atrophy, prevented bone loss, and was neutral on breast tenderness, breast density, with breast cancer incidence similar to placebo. Protection against estrogen-induced endometrial hyperplasia and cancer was found, with similar amenorrhea rates to placebo. Ospemifene is approved to treat dyspareunia, with potential benefits on bone and the breast, while lasofoxifene is being developed to treat resistant estrogen receptor-positive breast cancer in women. Estetrol is an estrogen synthesized exclusively during pregnancy by the human fetal liver and initially considered a weak estrogen, but it appears to have dual weak estrogenic/anti-estrogenic features.


Assuntos
Pós-Menopausa , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Adulto , Idoso , Atrofia/prevenção & controle , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/prevenção & controle , Estrogênios Conjugados (USP)/administração & dosagem , Estrogênios Conjugados (USP)/efeitos adversos , Feminino , Doenças Urogenitais Femininas/tratamento farmacológico , Fogachos/tratamento farmacológico , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/tratamento farmacológico , Cloridrato de Raloxifeno/uso terapêutico , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Tamoxifeno/uso terapêutico , Vagina/efeitos dos fármacos , Vagina/patologia
13.
Menopause ; 26(7): 800-807, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30889085

RESUMO

OBJECTIVE: The aim of the study was to systematically review studies that evaluated endometrial hyperplasia or cancer incidence with unopposed vaginal estrogens. METHODS: PubMed and EMBASE were searched from inception to August 2017 for relevant articles and abstracts. Bibliographies of review articles and abstracts of major women's health medical meetings were examined. Eligible studies (independently reviewed by 4 authors) had to report menopausal vaginal estrogen use and endometrial histology, or incidence of endometrial hyperplasia or cancer. RESULTS: Of 5,593 abstracts from the literature search and 47 articles from other sources, 36 articles and 2 abstracts were eligible, describing 20 randomized controlled studies, 8 interventional studies, and 10 observational studies. Collectively, the studies did not support an increased risk of endometrial hyperplasia or cancer with low-dose vaginal estrogens. Rates of endometrial cancer and hyperplasia were 0.03% and 0.4%, respectively, from 20 randomized controlled trials (2,983 women) of vaginal estrogens. Overall, reports of endometrial hyperplasia were observed with various doses and durations and appeared sporadic (except 1.25 mg conjugated equine estrogens), consistent with endometrial hyperplasia rates in the general population. A Denmark registry study was an exception and may be of limited applicability to the United States. The Women's Health Initiative Observational Study showed no association (1.3 cases/1,000 women-years with vaginal estrogens versus 1.0/1,000 women-years for nonuse). CONCLUSION: This systematic review supports the use of low-dose vaginal estrogens for treating vulvar and vaginal atrophy in menopausal women without a concomitant progestogen. This review does not support increased endometrial hyperplasia or cancer risk with low-dose, unopposed vaginal estrogens; however, longer-term, real-world data are needed.


Assuntos
Hiperplasia Endometrial/epidemiologia , Estrogênios/administração & dosagem , Estrogênios/efeitos adversos , Medicina Baseada em Evidências , Menopausa , Administração Intravaginal , Relação Dose-Resposta a Droga , Estrogênios Conjugados (USP)/administração & dosagem , Feminino , Humanos , Estudos Observacionais como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Estados Unidos/epidemiologia , Saúde da Mulher
14.
Environ Sci Pollut Res Int ; 26(10): 9443-9468, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30758794

RESUMO

Natural steroid estrogens (NSEs), including free estrogens (FEs) and conjugated estrogens (CEs), are of emerging concern globally among public and scientific community due to their recognized adverse effects on human and wildlife endocrine systems in recent years. In this review, the properties, occurrence, sorption process, and transformation pathways of NSEs are clarified in the environment. The work comprehensively summarizes the occurrence of both free and conjugated estrogens in different natural and built environments (e.g., river, WWTPs, CAFOs, soil, and sediment). The sorption process of NSEs can be impacted by organic compounds, colloids, composition of clay minerals, specific surface area (SSA), cation exchange capacity (CEC), and pH value. The degradation and transformation of free and conjugated estrogens in the environment primarily involves oxidation, reduction, deconjugation, and esterification reactions. Elaboration about the major, subordinate, and minor transformation pathways of both biotic and abiotic processes among NSEs is highlighted. The moiety types and binding sites also would affect deconjugation degree and preferential transformation pathways of CEs. Notably, some intermediate products of NSEs still remain estrogenic potency during transformation process; the elimination of total estrogenic activity needs to be addressed in further studies. The in-depth researches regarding the behavior of both free and conjugated estrogens are further required to tackle their contamination problem in the ecosystem. Graphical abstract ᅟ.


Assuntos
Poluentes Ambientais/análise , Estrona/análise , Sistema Endócrino/metabolismo , Poluentes Ambientais/química , Congêneres do Estradiol , Estrogênios/metabolismo , Estrogênios Conjugados (USP) , Estrona/química , Humanos , Compostos Orgânicos , Rios , Solo
15.
Med Sci Monit ; 25: 819-826, 2019 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-30690446

RESUMO

BACKGROUND This study was designed to explore the effect of menopausal hormone therapy (MHT) on bone mineral density (BMD) in Chinese women. MATERIAL AND METHODS This was a prospective, open-label, randomized-controlled clinical trial. We randomly assigned 123 postmenopausal women to 3 groups: group A received 0.625 mg conjugated equine estrogen (CEE) plus 100 mg micronized progesterone (MP), group B received 0.3 mg CEE daily plus 100 mg MP, and group C received 0.625 mg CEE daily plus 10 mg dydrogesterone (DHG). All subjects received a 2-year intervention and drugs were given in a continuous sequential pattern. RESULTS Ninety-six patients were followed up. At 1 year, groups A and B gained 2.31% and 1.95% BMD, respectively (P<0.01); at 2 years, groups B and C gained 2.37% and 4.15% BMD (P<0.01) respectively. At 2 years, group A gained 3.28% BMD in the femoral neck and 3.77% BMD in Ward's triangle (P<0.05). At 1 year, group B lost 2.14% BMD in the trochanter and 1.20% BMD in the total hip (P<0.05); at 2 years, group B lost 1.51% BMD in the total hip (P<0.01). ALP, Ca, P, and Ca/Cr levels were all decreased in the 3 groups (P<0.05). The changes in Cr level at 1 and 2 years were not significant when compared with baseline in all groups (P>0.05). CONCLUSIONS Both lower-dose and standard-dose CEE increased lumbar BMD, sustain femoral neck BMD, and Ward's triangle BMD, while there was a reduced bone turnover rate. Standard-dose CEE combined with MP can increase BMD at these 2 sites. CEE combined with MP is recommended because it has better clinical benefits.


Assuntos
Densidade Óssea/efeitos dos fármacos , Osteoporose Pós-Menopausa/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , China , Didrogesterona/farmacologia , Estrogênios/farmacologia , Estrogênios Conjugados (USP)/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Pós-Menopausa , Progesterona/farmacologia , Estudos Prospectivos
16.
Cochrane Database Syst Rev ; 1: CD005431, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30640411

RESUMO

BACKGROUND: Traumatic hyphema is the entry of blood into the anterior chamber (the space between the cornea and iris) subsequent to a blow or a projectile striking the eye. Hyphema uncommonly causes permanent loss of vision. Associated trauma (e.g. corneal staining, traumatic cataract, angle recession glaucoma, optic atrophy, etc.) may seriously affect vision. Such complications can lead to permanent impairment of vision. People with sickle cell trait/disease may be particularly susceptible to increases of elevated intraocular pressure. If rebleeding occurs, the rates and severity of complications increase. OBJECTIVES: To assess the effectiveness of various medical interventions in the management of traumatic hyphema. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2018, Issue 6); MEDLINE Ovid; Embase.com; PubMed (1948 to June 2018); the ISRCTN registry; ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). The date of the search was 28 June 2018. SELECTION CRITERIA: Two review authors independently assessed the titles and abstracts of all reports identified by the electronic and manual searches. In this review, we included randomized and quasi-randomized trials that compared various medical (non-surgical) interventions versus other medical intervention or control groups for the treatment of traumatic hyphema following closed-globe trauma. We applied no restrictions regarding age, gender, severity of the closed-globe trauma, or level of visual acuity at the time of enrollment. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted the data for the primary outcomes, visual acuity and time to resolution of primary hemorrhage, and secondary outcomes including: secondary hemorrhage and time to rebleed; risk of corneal blood staining, glaucoma or elevated intraocular pressure, optic atrophy, or peripheral anterior synechiae; adverse events; and duration of hospitalization. We entered and analyzed data using Review Manager 5. We performed meta-analyses using a fixed-effect model and reported dichotomous outcomes as risk ratios (RR) and continuous outcomes as mean differences (MD). MAIN RESULTS: We included 20 randomized and seven quasi-randomized studies with a total of 2643 participants. Interventions included antifibrinolytic agents (systemic and topical aminocaproic acid, tranexamic acid, and aminomethylbenzoic acid), corticosteroids (systemic and topical), cycloplegics, miotics, aspirin, conjugated estrogens, traditional Chinese medicine, monocular versus bilateral patching, elevation of the head, and bed rest.We found no evidence of an effect on visual acuity for any intervention, whether measured within two weeks (short term) or for longer periods. In a meta-analysis of two trials, we found no evidence of an effect of aminocaproic acid on long-term visual acuity (RR 1.03, 95% confidence interval (CI) 0.82 to 1.29) or final visual acuity measured up to three years after the hyphema (RR 1.05, 95% CI 0.93 to 1.18). Eight trials evaluated the effects of various interventions on short-term visual acuity; none of these interventions was measured in more than one trial. No intervention showed a statistically significant effect (RRs ranged from 0.75 to 1.10). Similarly, visual acuity measured for longer periods in four trials evaluating different interventions was also not statistically significant (RRs ranged from 0.82 to 1.02). The evidence supporting these findings was of low or very low certainty.Systemic aminocaproic acid reduced the rate of recurrent hemorrhage (RR 0.28, 95% CI 0.13 to 0.60) as assessed in six trials with 330 participants. A sensitivity analysis omitting two studies not using an intention-to-treat analysis reduced the strength of the evidence (RR 0.43, 95% CI 0.17 to 1.08). We obtained similar results for topical aminocaproic acid (RR 0.48, 95% CI 0.20 to 1.10) in two studies with 121 participants. We assessed the certainty of these findings as low and very low, respectively. Systemic tranexamic acid had a significant effect in reducing the rate of secondary hemorrhage (RR 0.31, 95% CI 0.17 to 0.55) in five trials with 578 participants, as did aminomethylbenzoic acid as reported in one study (RR 0.10, 95% CI 0.02 to 0.41). The evidence to support an associated reduction in the risk of complications from secondary hemorrhage (i.e. corneal blood staining, peripheral anterior synechiae, elevated intraocular pressure, and development of optic atrophy) by antifibrinolytics was limited by the small number of these events. Use of aminocaproic acid was associated with increased nausea, vomiting, and other adverse events compared with placebo. We found no evidence of an effect in the number of adverse events with the use of systemic versus topical aminocaproic acid or with standard versus lower drug dose. The number of days for the primary hyphema to resolve appeared to be longer with the use of systemic aminocaproic acid compared with no use, but this outcome was not altered by any other intervention.The available evidence on usage of systemic or topical corticosteroids, cycloplegics, or aspirin in traumatic hyphema was limited due to the small numbers of participants and events in the trials.We found no evidence of an effect between a single versus binocular patch or ambulation versus complete bed rest on the risk of secondary hemorrhage or time to rebleed. AUTHORS' CONCLUSIONS: We found no evidence of an effect on visual acuity by any of the interventions evaluated in this review. Although evidence was limited, it appears that people with traumatic hyphema who receive aminocaproic acid or tranexamic acid are less likely to experience secondary hemorrhaging. However, hyphema took longer clear in people treated with systemic aminocaproic acid.There is no good evidence to support the use of antifibrinolytic agents in the management of traumatic hyphema other than possibly to reduce the rate of secondary hemorrhage. Similarly, there is no evidence to support the use of corticosteroids, cycloplegics, or non-drug interventions (such as binocular patching, bed rest, or head elevation) in the management of traumatic hyphema. As these multiple interventions are rarely used in isolation, further research to assess the additive effect of these interventions might be of value.


Assuntos
Traumatismos Oculares/complicações , Hifema/terapia , Ferimentos não Penetrantes/complicações , Corticosteroides/uso terapêutico , Ácido Aminocaproico/uso terapêutico , Antifibrinolíticos/uso terapêutico , Aspirina/uso terapêutico , Bandagens , Repouso em Cama , Criança , Estrogênios Conjugados (USP)/uso terapêutico , Humanos , Hifema/etiologia , Midriáticos/uso terapêutico , Posicionamento do Paciente/métodos , Inibidores da Agregação de Plaquetas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Ácido Tranexâmico/uso terapêutico , Acuidade Visual
17.
Gynecol Endocrinol ; 35(5): 390-394, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30668182

RESUMO

Bazedoxifene (BZA) paired with conjugated estrogens (CE) is the first tissue selective estrogen receptor complex (TSEC) approved by the United States Food and Drug Administration for the treatment of menopausal symptoms. Clinical trials in menopausal women and in premenopausal murine models of endometriosis have demonstrated safety and efficacy, however, the impact of BZA/CE on premenopausal women is not known. Here we report a case series study in premenopausal women assessing effects of BZA/CE on reproductive hormones, and uterine/ovarian ultrasonographic appearance. After one monitoring cycle, five subjects underwent daily administration of BZA/CE (20 mg/0.45 mg) for 12 weeks, and were followed for 4 weeks after treatment. Uterine/ovarian morphology was assessed with ultrasound, and endocrinologic function with ovulation prediction kits and serum assessment of reproductive hormones throughout the menstrual cycle. All subjects demonstrated an LH surge on the medication; interestingly there was a significant decrease in luteinizing hormone level during treatment compared to posttreatment values. BZA/CE was well-tolerated in premenopausal women and did not induce clinically relevant reproductive hormone changes, endometrial alterations, or abnormal ovarian folliculogenesis.


Assuntos
Estrogênios Conjugados (USP)/farmacologia , Indóis/farmacologia , Ovário/efeitos dos fármacos , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Útero/efeitos dos fármacos , Adulto , Feminino , Humanos , Ovário/diagnóstico por imagem , Pré-Menopausa , Estudos Prospectivos , Ultrassonografia , Útero/diagnóstico por imagem
18.
Climacteric ; 22(2): 182-189, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30661405

RESUMO

OBJECTIVE: Women who are currently using menopausal hormone therapy (MHT) have higher cerebrovascular reactivity when compared with postmenopausal women who are not taking MHT; however, the effect of cessation of MHT on cerebrovascular reactivity is not known. Given that MHT can have structural and activational effects on vascular function, this study was performed to characterize cerebrovascular reactivity following cessation of MHT in women at low risk for cerebrovascular disease. METHODS: Cerebrovascular reactivity was measured in a subset of women from the Kronos Early Estrogen Prevention Study (KEEPS) 3 years after cessation of the study drug (oral conjugated equine estrogen, transdermal 17ß-estradiol, or placebo [PLA]). RESULTS: Age, body mass index, and blood pressure were comparable among groups. At rest, the middle cerebral artery velocity (MCAv), cerebrovascular conductance index, mean arterial pressure, and cerebral pulsatility index did not differ among groups. Slope-based summary measures of cerebrovascular reactivity did not differ significantly among groups. However, utilizing repeated-measures modeling, there was a significant upward shift in MCAv responses (p = 0.029) in the combined MHT group compared with the PLA group. CONCLUSION: MHT has a marginal sustained effect on cerebrovascular reactivity when measured 3 years after cessation of hormone treatment.


Assuntos
Encéfalo/irrigação sanguínea , Terapia de Reposição de Estrogênios/efeitos adversos , Menopausa , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Pressão Sanguínea , Dióxido de Carbono/administração & dosagem , Artérias Cerebrais/fisiologia , Circulação Cerebrovascular/efeitos dos fármacos , Circulação Cerebrovascular/fisiologia , Transtornos Cerebrovasculares , Estradiol/administração & dosagem , Estrogênios/administração & dosagem , Estrogênios Conjugados (USP)/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Placebos , Fluxo Pulsátil/efeitos dos fármacos
19.
PLoS One ; 14(1): e0211462, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30699196

RESUMO

The adhesion of monocytes to endothelial cells, which is mediated by adhesion molecules, plays a crucial role in the onset of atherosclerosis. Conjugated equine estrogen, which is widely used for estrogen-replacement therapy, contains both estrone sulfate and various nonhuman estrogens, including equilin. To investigate the association between various estrogen types and atherosclerosis risk, we examined their effect on adhesion-molecule expression in human umbilical vein endothelial cells (HUVECs). In estrogen-treated HUVECs, the mRNA and protein expression levels of adhesion molecules were quantified by real-time polymerase chain reaction and enzyme immunoassay. Additionally, a flow-chamber system was used to assess the effects of estrogens on the adherence of U937 monocytoid cells to HUVECs. Equilin, but not 17ß-estradiol (E2) or other types of estrogen, significantly increased the mRNA (P < 0.01) and protein (P < 0.05) expression of the adhesion molecules E-selectin and intercellular adhesion molecule-1 as compared with levels in controls. Equilin treatment increased the adherence of U937 monocytoid cells to HUVECs relative to the that in the control (P < 0.05), decreased estrogen receptor (ER)ß expression, and increased the expression of proteins involved in nuclear factor kappa-B (NF-κB) activation relative to levels in controls. Furthermore, the accumulation of NF-κB subunit p65 in HUVEC nuclei was promoted by equilin treatment. By contrast, E2 treatment neither increased the number of adhered monocytoid cells to HUVECs nor altered the expression of ERß or NF-κB-activating proteins. Our findings suggest that in terms of the adhesion of monocytes at the onset of atherosclerosis, E2 may be preferable for estrogen-replacement therapy. Further studies comparing equilin treatment with that of E2 are needed to investigate their differential impacts on atherosclerosis.


Assuntos
Moléculas de Adesão Celular/metabolismo , Adesão Celular , Equilina/farmacologia , Estrogênios Conjugados (USP)/farmacologia , Células Endoteliais da Veia Umbilical Humana/fisiologia , Monócitos/fisiologia , Animais , Células Cultivadas , Cavalos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Monócitos/efeitos dos fármacos , Transdução de Sinais
20.
Gynecol Endocrinol ; 35(2): 165-169, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30449208

RESUMO

The aim of the study is to compare the bone sparing effect of half-dose with standard-dose conjugated equine estrogen (CEE) combined with progestin. A total of 123 participants were administrated with 0.625 mg of CEE and 100 mg of micronized progesterone (MP) in group A, 0.3 mg of CEE and 100 mg of MP in group B, 0.625 mg of CEE and 10 mg of dydrogesterone (DDG) in group C for one year. Percent changes from baseline in BMD at lumbar spine and fracture rate were primary outcomes. Secondary endpoints included changes of BMD at femoral neck, total hip and arm, bone markers (alkaline phosphatase, calcium and phosphorus), serum alanine aminotransferase (ALT) and endometrial thickness. No fractures occurred during the treatment. Standard dose of CEE leads to significant changes in lumbar spine and arm. The 3.78% growth of BMD at femoral neck in group C marked a statistically difference. There was no statistically remarkable bone loss at hip in all three groups. Bone turnover markers and ALT significantly decreased from basic values. Endometrium thickened more with traditional dose of CEE. Both the half and standard dose CEE are effective in BMD preservation among early menopausal women with subtle side effects. Low-dose estrogen is less efficacious than traditional one.


Assuntos
Didrogesterona/uso terapêutico , Estrogênios Conjugados (USP)/administração & dosagem , Estrogênios/administração & dosagem , Fraturas Ósseas/epidemiologia , Osteoporose Pós-Menopausa/prevenção & controle , Progestinas/uso terapêutico , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Densidade Óssea , Cálcio/sangue , Quimioterapia Combinada , Endométrio/patologia , Feminino , Colo do Fêmur/diagnóstico por imagem , Humanos , Vértebras Lombares/diagnóstico por imagem , Pessoa de Meia-Idade , Tamanho do Órgão , Osteoporose Pós-Menopausa/sangue , Osteoporose Pós-Menopausa/diagnóstico por imagem , Osteoporose Pós-Menopausa/tratamento farmacológico , Fósforo/sangue
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