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1.
Gen Comp Endocrinol ; 330: 114142, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36243057

RESUMO

This study demonstrates the utility of the analysis of fecal hormone metabolites as a reproductive management tool for captive short-beaked echidnas. Over three breeding seasons daily fecal samples were collected from female echidnas (n = 8) that were monitored continuously by video surveillance to confirm key reproductive events. Fecal progesterone metabolite concentrations were elevated above baseline values (448.0 ± 156.3 ng/g) during pregnancy and the luteal phase. However, compared to plasma progesterone the rise in fecal progesterone metabolite concentrations after copulation was delayed (3.3 ± 0.4 versus 8.3 ± 0.6 days, respectively), such that pregnancy was more reliably detected in its latter half when using fecal samples. Mating and oviposition were observed for 14 of the 19 pregnancies resulting in an estimated gestation of 16.7 ± 0.2 days (range 16.0-18.1 d). The estrogen enzyme-immunoassays tested (n = 3) in this study were not suitable for the fecal samples of the echidna. Fecal progesterone metabolites are an effective tool for confirming the timing and occurrence of estrous cycles in captive echidna colonies and can assist zookeepers in identifying possible causes of sub-optimal reproductive success without the unnecessary stress of repeated capture and anaesthesia for blood collection.


Assuntos
Monotremados , Tachyglossidae , Gravidez , Animais , Feminino , Progesterona/metabolismo , Reprodução , Fezes , Estrogênios/metabolismo
2.
Gen Comp Endocrinol ; 330: 114125, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36116484

RESUMO

In this study, we used juvenile rainbow trout to examine the direct effects of selected environmental estrogens (EE), specifically, 17 ß-estradiol (E2), ß-sitosterol (ßS), and 4-n-nonylphenol (NP), on target tissue sensitivity to insulin-like growth factor (IGF) as assessed by expression of IGF receptor type 1 (IGFR1) mRNAs and IGF-1 binding capacity, as well as on the cell signaling pathways through which EE exert their effects. E2 and NP inhibited IGFR1A and IGFR1B mRNA expression in a time- and concentration-related manner in gill and muscle; however, ßS had no effect on expression of IGFR1 mRNAs in either tissue. NP reduced 125I-IGF binding in gill and E2 and NP reduced 125I-IGF in white muscle; ßS had no effect on 125I-IGF binding in either gill or white muscle. Treatment of gill filaments with either E2 or NP rapidly deactivated (via reduced proportion of phosphorylation) JAK2, STAT5, Akt, and ERK; ßS had no effect on the activation state of any cell signaling elements tested. The effects of EE on IGFR mRNA expression in gill were estrogen receptor (ER) dependent as the inhibitory effects were rescued by the ER antagonist, ICI 182,780. All EE tested blocked growth hormone (GH)-stimulated IGFR mRNA expression in gill filaments. GH-stimulated activation of JAK2, STAT5, Akt, and ERK were blocked by E2, ßS, and NP. Lastly, E2 and NP stimulated suppressor of cytokine signaling 2 (SOCS-2) mRNA expression, an effect that also was ER dependent. These results indicate that EE directly reduce the sensitivity of peripheral tissues to IGF by reducing mRNA and functional expression of IGFRs. Such inhibitory actions of EE are mediated, at least in part, by ER-dependent mechanisms that deactivate JAK, STAT, Akt, and ERK and enhance expression of SOCS-2. These findings together with our previous results show that EE retard growth of post-embryonic rainbow trout through widespread direct effects on the GH-IGF system, specifically, by reducing tissue sensitivity to GH, inhibiting IGF production, reducing tissue sensitivity to IGF, and by deactivating post-receptor IGF cell signaling pathways.


Assuntos
Oncorhynchus mykiss , Animais , Oncorhynchus mykiss/metabolismo , Fosforilação , Fator de Transcrição STAT5/metabolismo , Fator de Transcrição STAT5/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Estrogênios/metabolismo , Hormônio do Crescimento/metabolismo , Receptores de Somatomedina/metabolismo , Transdução de Sinais , RNA Mensageiro/genética
3.
Mol Cell Endocrinol ; 559: 111783, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36198363

RESUMO

Selective serotonin reuptake inhibitors (SSRI) are the most used antidepressants. However, up to 80% of women taking SSRI suffer from sexual dysfunction. We investigated the effects of fluoxetine (Prozac®) (low and high dose, n = 6-7/group) on reproductive function and the regulation of the estrous cycle. All mice treated with high dose of fluoxetine had interruption of estrous cycles within a few days after onset of treatment. When treated for 14 days, mice in the high dose group had fewer CL, often lack of any CL, and antral follicles. Uterine expression of estrogen receptor alpha, G-protein coupled estrogen receptor, and steroidogenesis enzymes were upregulated in the high dose group. Nevertheless, decreased expression of connexin 43 and alkaline phosphatase and increased expression of insulin-like growth factor-binding protein 3 and monoamine oxidase A are consistent with decreased estrogen signaling and the decreased uterine weight. Taken together, fluoxetine modulates estrogen synthesis/signaling and dysregulates estrous cycles.


Assuntos
Ciclo Estral , Fluoxetina , Camundongos , Feminino , Animais , Fluoxetina/farmacologia , Inibidores de Captação de Serotonina/farmacologia , Antidepressivos/farmacologia , Útero/metabolismo , Estrogênios/farmacologia , Estrogênios/metabolismo
4.
Life Sci Alliance ; 6(1)2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36384894

RESUMO

The role of the alternate G protein-coupled estrogen receptor 1 (GPER1) in colorectal cancer (CRC) development and progression is unclear, not least because of conflicting clinical and experimental evidence for pro- and anti-tumorigenic activities. Here, we show that low concentrations of the estrogenic GPER1 ligands, 17ß-estradiol, bisphenol A, and diethylstilbestrol cause the generation of lagging chromosomes in normal colon and CRC cell lines, which manifest in whole chromosomal instability and aneuploidy. Mechanistically, (xeno)estrogens triggered centrosome amplification by inducing centriole overduplication that leads to transient multipolar mitotic spindles, chromosome alignment defects, and mitotic laggards. Remarkably, we could demonstrate a significant role of estrogen-activated GPER1 in centrosome amplification and increased karyotype variability. Indeed, both gene-specific knockdown and inhibition of GPER1 effectively restored normal centrosome numbers and karyotype stability in cells exposed to 17ß-estradiol, bisphenol A, or diethylstilbestrol. Thus, our results reveal a novel link between estrogen-activated GPER1 and the induction of key CRC-prone lesions, supporting a pivotal role of the alternate estrogen receptor in colon neoplastic transformation and tumor progression.


Assuntos
Centrossomo , Estrogênios , Receptores de Estrogênio , Receptores Acoplados a Proteínas G , Humanos , Centrossomo/metabolismo , Instabilidade Cromossômica/genética , Colo , Dietilestilbestrol/farmacologia , Estradiol/farmacologia , Estrogênios/farmacologia , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo
5.
J Hazard Mater ; 443(Pt A): 130174, 2023 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-36265380

RESUMO

Environmental endocrine disruptors (EEDs), a class of molecules that are widespread in our environment, may adversely affect the endocrine system. Exploring the interactions between these compounds and their potential targets is important for assessing their role in the organism. Focused on the human estrogen-related receptor γ (hERRγ) with BPA, BPB, HPTE, BPE, BP(2,2)(Et), and BP(2,2)(MeO) complexes, respectively, we groped for the mechanisms of conformational changes and interactions of hERRγ when binding to these six EEDs by combining multiple molecular dynamics (MD) simulations with energy prediction (MM-PBSA and solvated interaction energy (SIE)). Dynamics analysis results revealed these six EEDs have different effects on the internal dynamics of hERRγ, resulting in significant changes in the interaction of key residues around Leu268, Val313, Leu345, and Phe435 with EEDs, and thus affected its binding energy with these EEDs. The energy calculations further demonstrated that van der Waals interactions are critical for these EEDs binding to hERRγ. These results present detailed molecular insight into the interaction features between EEDs and hERRγ and help guide the search for safer alternatives to BPA.


Assuntos
Disruptores Endócrinos , Humanos , Disruptores Endócrinos/toxicidade , Simulação de Dinâmica Molecular , Estrogênios
6.
Chemosphere ; 310: 136917, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36272630

RESUMO

The presence of estrogenic endocrine disruptors in aquatic environments has been a concern and bioassays are recommended tools for their monitoring. However, the physicochemical properties of contaminants and the environmental matrix features may influence the resultant response. This study aimed to assess this influence on the Yeast Estrogen Screen (YES) assay. Mixtures of 17ß-estradiol (E2) and humic acid (HA) were evaluated through the Schild approach aiming to investigate the interactions between estrogens and dissolved organic matter (DOM). Moreover, environmental samples from municipal landfill leachate and wastewater treatment plant (WWTP) influents and effluents were screened for (anti)estrogenic activity at both dissolved and particulate phases. Finally, results were statistically confronted with physicochemical parameters through principal component analysis (PCA). The HA test concentrations strongly reduced the E2 response, even at low levels. Humic substances may not only reduce estrogen bioavailability, but also interfere with the assay mechanism through enzymatic inhibition thus masking the sample estrogenic potential. Landfill leachate had total E2-Eq in the range 1282-2591 ng L-1, while WWTP influent and effluent were in the range 12.1-41.4 and

Assuntos
Disruptores Endócrinos , Poluentes Químicos da Água , Poluentes Químicos da Água/análise , Matéria Orgânica Dissolvida , Estrogênios/análise , Estradiol/análise , Disruptores Endócrinos/toxicidade , Disruptores Endócrinos/análise , Estrona/análise , Antagonistas de Estrogênios/análise , Monitoramento Ambiental/métodos
7.
Food Chem ; 401: 134084, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36115225

RESUMO

Enzyme labeled competitive molecules are generally homologous with competitors in competitive broad-spectrum enzyme-linked immunosorbent assays (ELISA). It is speculated that the detectability will be improved when the competitiveness of competitive molecule is weak. Herein, common small molecule food hazard-estrogen disrupting chemicals (EDCs) were used as target model for verification. The dual-estrogen receptor (ER) and three estrogen-enzyme conjugates with various responses were used as recognizers and competitive molecules in ELISA. ELISA based on bisphenol (BPA)-horseradish peroxidase (HRP) has the highest detectability and can screen all six EDCs, in which BPA-HRP showed the weakest ER excitatory activity (Ka = 1.39 × 10-2 nmol·L-1) among three conjugates. The proposal showed good practicability with spiked recovery of 80.0-110 % for estrogens (17ß-estradiol, 17α-estradiol, BPA) in foodstuffs, and revealed biomarkers with weak competitiveness may be applied to other competitive procedures to improve detectability, and it provides sensitive pre-screening strategy for follow-up screening tool.


Assuntos
Disruptores Endócrinos , Receptores de Estrogênio , Estrogênios , Compostos Benzidrílicos , Estradiol/química , Ensaio de Imunoadsorção Enzimática/métodos , Peroxidase do Rábano Silvestre
8.
J Steroid Biochem Mol Biol ; 225: 106182, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36152789

RESUMO

Xian-Ling-Gu-Bao capsule (XLGB) is a widely prescribed traditional Chinese medicine used for the treatment of osteoporosis. However, it significantly elevates levels of serum estrogens. Here we aimed to assess the dominant contributors of sulfotransferase (SULT) enzymes to the sulfation of estrogens and identify the effective inhibitors of this pathway in XLGB. First, estrone, 17ß-estradiol, and estriol underwent sulfation in human liver S9 extracts. Phenotyping reactions and enzyme kinetics assays revealed that SULT1A1, 1A2, 1A3, 1C4, 1E1, and 2A1 all participated in estrogen sulfation, with SULT1E1 and 1A1 as the most important contributors. The incubation system for these two active enzymes were optimized with Tris-HCl buffer, DL-Dithiothreitol (DTT), MgCl2, adenosine 3'-phosphate 5'-phosphosulfate (PAPS), protein concentration, and incubation time. Then, 29 compounds in XLGB were selected to investigate their inhibitory effects and mechanisms against SULT1E1 and 1A1 through kinetic modelling. Moreover, in silico molecular docking was used to validate the obtained results. And finally, the prenylated flavonoids (isobavachin, neobavaisoflavone, etc.) from Psoralea corylifolia L., prenylated flavanols (icariside II) from Epimedium brevicornu Maxim., tanshinones (dihydrotanshinone, tanshinone II-A,) from Salvia miltiorrhiza Bge., and others (corylifol A, corylin) were identified as the most potent inhibitors of estrogen sulfation. Taken together, these findings provide insights into the understanding regioselectivity of estrogen sulfation and identify the effective components of XLGB responsible for the promotion of estrogen levels.


Assuntos
Polifenóis , Sulfotransferases , Humanos , Simulação de Acoplamento Molecular , Sulfotransferases/metabolismo , Estrogênios
9.
J Steroid Biochem Mol Biol ; 225: 106196, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36181991

RESUMO

ß-estradiol (ß-E2) and α-estradiol (α-E2) act as an endo- and an exon-estrogen in humans, respectively. There is a structural variation in C17-OH configuration of the two estrogens. UDP-glucuronosyltransferases (UGT) are responsible for termination of activities of a variety of endogenous hormones, clinical drugs, and environmental toxicants. The current study was conducted to investigate the effects of the two estrogens towards catalytic activities of UGTs. It was found that ß-E2 could decrease activities of UGT1A9, - 2B4 and - 2B7, with Ki values of a few micro-molars. ß-E2 could additionally accelerate the activity of UGT2B17 via promoting enzyme-substrate binding and increasing the turn over number. Comparatively, α-E2 displayed much stronger inhibitory potentials towards UGT2B7 and - 2B4, but showed little influence to UGT1A9 and - 2B17. The Ki values for inhibition of UGT2B7 in glucuronidation of different substrates by α-E2 were in a nanomolar range that is only about 1/100-1/50 of ß-E2. UGT2B7 structural model was fatherly constructed to explore the mechanism underlying dramatically different inhibition selectivity of the two estrogens. Compared to ß-E2, α-E2 formed more hydrophobic and hydrogen-bonded interactions with the residues in the active pocket. It is concluded that the configuration of E2-17-OH determines the inhibitory potentials towards UGTs. The results are useful in better understanding ligand selectivity of UGTs, as well as in further development of α-E2 in health protection.


Assuntos
Estradiol , Glucuronosiltransferase , Humanos , Glucuronosiltransferase/química , Glucuronosiltransferase/metabolismo , Estradiol/metabolismo , UDP-Glucuronosiltransferase 1A , Cinética , Estrogênios , Difosfato de Uridina
10.
J Steroid Biochem Mol Biol ; 225: 106203, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36228841

RESUMO

Straightforward access to steroidal selenocyanates in a single assembly step from steroids remains a significant challenge. However, the development of novel method for the synthesis of steroidal selenocyanates and further investigation of their bioactivities have largely lagged behind. In this work, selenocyano groups were directly introduced into the 17- or 21-position of pregnenolone, the 2-position of estradiol, and the 16-position of estrone. A total of 16 estrogen selenocyanate derivatives with diverse structures were synthesized, and the tumor cell lines closely related to the expression level of estrogen were used to investigate the inhibitory activity of the target products on tumor cell proliferation in vitro. The results revealed that the 17-selenocyano-substituted pregnenolone selenocyanate derivatives 1b-3b exhibit obvious inhibitory activity against the tested tumor cell lines. Additionally, the 2-selenocyano-substituted estradiol derivatives and 16-selenocyano-substituted estrone derivatives exhibit selective inhibitory on HeLa cell lines. Among them, 2-selenocyano-3-methoxyestradiol-17-benzoate (7e) displayed an IC50 value of 4.1 µM against HeLa cells and induced programmed apoptosis in HeLa cancer cells. Furthermore, compound 7e could significantly inhibit the growth of human cervical cancer xenografts in zebrafish in vivo. This approach provides new insights for future steroid antitumor drug design.


Assuntos
Antineoplásicos , Estrona , Animais , Humanos , Células HeLa , Peixe-Zebra , Linhagem Celular Tumoral , Proliferação de Células , Antineoplásicos/química , Estrogênios/farmacologia , Estradiol/farmacologia , Pregnenolona/farmacologia , Estresse Oxidativo , Ensaios de Seleção de Medicamentos Antitumorais , Relação Estrutura-Atividade
11.
Domest Anim Endocrinol ; 82: 106770, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36279747

RESUMO

Early embryos of rodent species and rabbits but also farm animals such as pigs, horses and cattle produce estrogens, which are considered important regulators of the implantation process. In cattle, the exact stage at which embryonic estrogen synthesis commences is yet unknown. However, this information is regarded as important to consider a possible role of embryonic estrogens in preimplantation development. Therefore, in this study, we first used quantitative reverse transcription PCR to examine the mRNA expression of the enzymes required for the conversion of cholesterol into free and sulfonated estrogens (CYP11A1, CYP17A1, HSD3B, CYP19A1, and SULT1E1), the cholesterol carrier protein STAR, and the estrogen receptors ESR1 and ESR2 in in vitro produced morulae and unhatched blastocysts (d 6-9). Only in the blastocysts, were the mRNAs of the entire estrogen biosynthesis chain and of both estrogen receptors clearly present, whereas mRNA specific to ESRs was already detectable in the morulae. We also examined the expression of the corresponding enzymes in blastocysts at the protein level. None of the enzymes were detectable by capillary-based western analysis. Immunofluorescence methods were established for the detection of CYP17A1, CYP19A1, and SULT1E1. CYP17A1 was observed in the inner cell mass and trophectoderm, whereas CYP19A1 and SULT1E1 were present only in trophectoderm. An attempt to detect estrogen sulfotransferase activity was unsuccessful. Despite clear evidence that some elements of the estrogen biosynthetic pathway are also present at the protein level, it remains to be clarified whether the enzyme cascade underlying estrogen production is already functional in unhatched blastocysts.


Assuntos
Vias Biossintéticas , Receptores de Estrogênio , Bovinos/genética , Animais , Suínos , Coelhos , Cavalos/genética , Blastocisto/fisiologia , Estrogênios/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Esteroides/metabolismo
12.
JAMA ; 328(17): 1740-1746, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36318127

RESUMO

Importance: Menopause is defined as the cessation of a person's menstrual cycle. It is defined retrospectively, 12 months after the final menstrual period. Perimenopause, or the menopausal transition, is the few-year time period preceding a person's final menstrual period and is characterized by increasing menstrual cycle length variability and periods of amenorrhea, and often symptoms such as vasomotor dysfunction. The prevalence and incidence of most chronic diseases (eg, cardiovascular disease, cancer, osteoporosis, and fracture) increase with age, and US persons who reach menopause are expected on average to live more than another 30 years. Objective: To update its 2017 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review to evaluate the benefits and harms of systemic (ie, oral or transdermal) hormone therapy for the prevention of chronic conditions in postmenopausal persons and whether outcomes vary by age or by timing of intervention after menopause. Population: Asymptomatic postmenopausal persons who are considering hormone therapy for the primary prevention of chronic medical conditions. Evidence Assessment: The USPSTF concludes with moderate certainty that the use of combined estrogen and progestin for the primary prevention of chronic conditions in postmenopausal persons with an intact uterus has no net benefit. The USPSTF concludes with moderate certainty that the use of estrogen alone for the primary prevention of chronic conditions in postmenopausal persons who have had a hysterectomy has no net benefit. Recommendation: The USPSTF recommends against the use of combined estrogen and progestin for the primary prevention of chronic conditions in postmenopausal persons. (D recommendation) The USPSTF recommends against the use of estrogen alone for the primary prevention of chronic conditions in postmenopausal persons who have had a hysterectomy. (D recommendation).


Assuntos
Doença Crônica , Estrogênios , Terapia de Reposição Hormonal , Hormônios , Pós-Menopausa , Progestinas , Feminino , Humanos , Doença Crônica/prevenção & controle , Estrogênios/efeitos adversos , Estrogênios/uso terapêutico , Prevenção Primária , Progestinas/efeitos adversos , Progestinas/uso terapêutico , Terapia de Reposição Hormonal/efeitos adversos , Terapia de Reposição Hormonal/métodos , Hormônios/efeitos adversos , Hormônios/uso terapêutico
13.
JAMA ; 328(17): 1747-1765, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36318128

RESUMO

Importance: It is uncertain whether hormone therapy should be used for the primary prevention of chronic conditions such as heart disease, osteoporosis, or some types of cancers. Objective: To update evidence for the US Preventive Services Task Force on the benefits and harms of hormone therapy in reducing risks for chronic conditions. Data Sources: PubMed/MEDLINE, Cochrane Library, EMBASE, and trial registries from January 1, 2016, through October 12, 2021; surveillance through July 2022. Study Selection: English-language randomized clinical trials and prospective cohort studies of fair or good quality. Data Extraction and Synthesis: Dual review of abstracts, full-text articles, and study quality; meta-analyses when at least 3 similar studies were available. Main Outcomes and Measures: Morbidity and mortality related to chronic conditions; health-related quality of life. Results: Twenty trials (N = 39 145) and 3 cohort studies (N = 1 155 410) were included. Participants using estrogen only compared with placebo had significantly lower risks for diabetes over 7.1 years (1050 vs 903 cases; 134 fewer [95% CI, 18-237]) and fractures over 7.2 years (1024 vs 1413 cases; 388 fewer [95% CI, 277-489]) per 10 000 persons. Risks per 10 000 persons were statistically significantly increased for gallbladder disease over 7.1 years (1113 vs 737 cases; 377 more [95% CI, 234-540]), stroke over 7.2 years (318 vs 239 cases; 79 more [95% CI, 15-159]), venous thromboembolism over 7.2 years (258 vs 181 cases; 77 more [95% CI, 19-153]), and urinary incontinence over 1 year (2331 vs 1446 cases; 885 more [95% CI, 659-1135]). Participants using estrogen plus progestin compared with placebo experienced significantly lower risks, per 10 000 persons, for colorectal cancer over 5.6 years (59 vs 93 cases; 34 fewer [95% CI, 9-51]), diabetes over 5.6 years (403 vs 482 cases; 78 fewer [95% CI, 15-133]), and fractures over 5 years (864 vs 1094 cases; 230 fewer [95% CI, 66-372]). Risks, per 10 000 persons, were significantly increased for invasive breast cancer (242 vs 191 cases; 51 more [95% CI, 6-106]), gallbladder disease (723 vs 463 cases; 260 more [95% CI, 169-364]), stroke (187 vs 135 cases; 52 more [95% CI, 12-104]), and venous thromboembolism (246 vs 126 cases; 120 more [95% CI, 68-185]) over 5.6 years; probable dementia (179 vs 91 cases; 88 more [95% CI, 15-212]) over 4.0 years; and urinary incontinence (1707 vs 1145 cases; 562 more [95% CI, 412-726]) over 1 year. Conclusions and Relevance: Use of hormone therapy in postmenopausal persons for the primary prevention of chronic conditions was associated with some benefits but also with an increased risk of harms.


Assuntos
Doença Crônica , Estrogênios , Terapia de Reposição Hormonal , Pós-Menopausa , Progestinas , Feminino , Humanos , Comitês Consultivos/normas , Comitês Consultivos/tendências , Doença Crônica/epidemiologia , Doença Crônica/mortalidade , Doença Crônica/prevenção & controle , Estrogênios/efeitos adversos , Estrogênios/uso terapêutico , Fraturas Ósseas/prevenção & controle , Terapia de Reposição Hormonal/efeitos adversos , Terapia de Reposição Hormonal/métodos , Hormônios/efeitos adversos , Hormônios/uso terapêutico , Prevenção Primária , Progestinas/efeitos adversos , Progestinas/uso terapêutico , Estudos Prospectivos , Qualidade de Vida , Medição de Risco , Estados Unidos , Incontinência Urinária/induzido quimicamente , Tromboembolia Venosa/induzido quimicamente
14.
Front Endocrinol (Lausanne) ; 13: 967857, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36325455

RESUMO

Turner syndrome (TS), the most common type of X chromosomal disorder, has various, clinical manifestations. Among these, primary hypogonadism, which may lead to osteoporosis, is a life-long health issue. A high prevalence of fractures associated with osteoporosis is a major problem in patients with TS, where it may be 1.4-2.2 times higher than in healthy individuals and increases with age. Among the risk factors associated with fractures in TS, hypogonadism is arguably the most important. Estrogen deficiency due to hypogonadism leads to low bone mineral density (BMD), resulting in a high prevalence of bone fractures. Estrogen replacement therapy (ERT) in patients with TS reportedly improved their BMD. However, other causes of low BMD may exist, given that this condition begins in the prepubertal period in patients with TS. Most previous studies have reported low BMD in patients with TS using dual-energy X-ray absorptiometry (DXA), but this method has some limitations. Areal BMD values assessed by DXA were influenced by bone size and short stature, resulting in an underestimation of BMD. Currently, volumetric BMD values may be accurately obtained using peripheral quantitative computed tomography (pQCT). pQCT, high-resolution pQCT, and the trabecular bone score can also be used to evaluate bone quality, including bone geometry and microarchitecture, in TS. The present review discusses the high fracture risk, role of estrogen deficiency in low BMD, advantages and disadvantages of various bone assessment methods, and characteristics of bone quality in TS.


Assuntos
Doenças Ósseas Metabólicas , Fraturas Ósseas , Hipogonadismo , Osteoporose , Síndrome de Turner , Feminino , Humanos , Síndrome de Turner/tratamento farmacológico , Densidade Óssea/fisiologia , Osteoporose/etiologia , Osteoporose/complicações , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/etiologia , Doenças Ósseas Metabólicas/tratamento farmacológico , Estrogênios/uso terapêutico , Hipogonadismo/complicações
15.
Nutrients ; 14(21)2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36364772

RESUMO

Recently, adverse events, such as irregular vaginal bleeding and menstrual disorders, associated with the use of dietary supplements containing Pueraria mirifica, have been reported in Japan. P. mirifica contains phytoestrogens, such as deoxymiroestrol and miroestrol. Therefore, we investigated the use of supplements that claim to have estrogen-like effects (i.e., estrogen-like supplements) in Japanese women aged from 15 to 69 years old in an online survey. The prevalence of estrogen-like supplement use was 5%, accounting for approximately 15% of the sample, including ex-users. The majority of the users were in their 40s and 50s, mainly using these supplements for the treatment of menopausal symptoms. In contrast, the younger generation mainly used them for beauty purposes, such as weight loss, mastogenic effects, and skin care. Many of them visited a clinic or took medicines for menstrual-related troubles. In all age groups, soybeans/isoflavones were the most commonly used, followed by equol and placenta. Participants in their teens and 20s also used P. mirifica. Among them, 16.2% had experienced adverse events, including irregular vaginal bleeding, breast swelling and pain, and heavy menstruation. In conclusion, estrogen-like supplement use is associated with adverse events; thus, it is necessary to pay attention to the use of these supplement. Furthermore, because the purpose of use differs depending on generation, caution according to each generation is necessary.


Assuntos
Estrogênios , Pueraria , Humanos , Feminino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Estrogênios/efeitos adversos , Japão/epidemiologia , Prevalência , Suplementos Nutricionais/efeitos adversos , Hemorragia Uterina
16.
Sci Rep ; 12(1): 19731, 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36396974

RESUMO

Most endometrial cancers express the hormone receptor estrogen receptor alpha (ER) and are driven by excess estrogen signaling. However, evaluation of the estrogen response in endometrial cancer cells has been limited by the availability of hormonally responsive in vitro models, with one cell line, Ishikawa, being used in most studies. Here, we describe a novel, adherent endometrioid endometrial cancer (EEC) cell line model, HCI-EC-23. We show that HCI-EC-23 retains ER expression and that ER functionally responds to estrogen induction over a range of passages. We also demonstrate that this cell line retains paradoxical activation of ER by tamoxifen, which is also observed in Ishikawa and is consistent with clinical data. The mutational landscape shows that HCI-EC-23 is mutated at many of the commonly altered genes in EEC, has relatively few copy-number alterations, and is microsatellite instable high (MSI-high). In vitro proliferation of HCI-EC-23 is strongly reduced upon combination estrogen and progesterone treatment. HCI-EC-23 exhibits strong estrogen dependence for tumor growth in vivo and tumor size is reduced by combination estrogen and progesterone treatment. Molecular characterization of estrogen induction in HCI-EC-23 revealed hundreds of estrogen-responsive genes that significantly overlapped with those regulated in Ishikawa. Analysis of ER genome binding identified similar patterns in HCI-EC-23 and Ishikawa, although ER exhibited more bound sites in Ishikawa. This study demonstrates that HCI-EC-23 is an estrogen- and progesterone-responsive cell line model that can be used to study the hormonal aspects of endometrial cancer.


Assuntos
Carcinoma Endometrioide , Neoplasias do Endométrio , Feminino , Humanos , Progesterona/farmacologia , Progesterona/uso terapêutico , Estradiol/farmacologia , Células Tumorais Cultivadas , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Estrogênios/farmacologia , Estrogênios/uso terapêutico , Carcinoma Endometrioide/tratamento farmacológico , Carcinoma Endometrioide/genética , Linhagem Celular
17.
Cell Rep ; 41(7): 111672, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36384125

RESUMO

Recent work showed that the dominant post-menopausal estrogen, estrone, cooperates with nuclear factor κB (NF-κB) to stimulate inflammation, while pre-menopausal 17ß-estradiol opposes NF-κB. Here, we show that post-menopausal estrone, but not 17ß-estradiol, activates epithelial-to-mesenchymal transition (EMT) genes to stimulate breast cancer metastasis. HSD17B14, which converts 17ß-estradiol to estrone, is higher in cancer than normal breast tissue and in metastatic than primary cancers and associates with earlier metastasis. Treatment with estrone, but not 17ß-estradiol, and HSD17B14 overexpression both stimulate an EMT, matrigel invasion, and lung, bone, and liver metastasis in estrogen-receptor-positive (ER+) breast cancer models, while HSD17B14 knockdown reverses the EMT. Estrone:ERα recruits CBP/p300 to the SNAI2 promoter to induce SNAI2 and stimulate an EMT, while 17ß-estradiol:ERα recruits co-repressors HDAC1 and NCOR1 to this site. Present work reveals novel differences in gene regulation by these estrogens and the importance of estrone to ER+ breast cancer progression. Upon loss of 17ß-estradiol at menopause, estrone-liganded ERα would promote ER+ breast cancer invasion and metastasis.


Assuntos
Neoplasias da Mama , Transição Epitelial-Mesenquimal , Estrona , Fatores de Transcrição da Família Snail , Feminino , Humanos , 17-Hidroxiesteroide Desidrogenases , Neoplasias da Mama/patologia , Estradiol/farmacologia , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Estrogênios/metabolismo , Estrona/metabolismo , NF-kappa B , Pós-Menopausa , Fatores de Transcrição da Família Snail/genética , Metástase Neoplásica
18.
BMC Cancer ; 22(1): 1189, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36401195

RESUMO

BACKGROUND: Weight gain is commonly observed during and after breast cancer treatment and is associated with poorer survival outcomes, notably in women with oestrogen-receptor positive disease. The aim of this qualitative study was to investigate the experiences and perceptions of oestrogen-receptor positive (ER +) female breast cancer patients (BCPs) regarding weight management behaviours during and after treatment. Secondly, to gain insight into the experiences of healthcare professionals (HCPs) regarding the provision of weight management advice to patients undergoing treatment. METHODS: Four focus groups involving 16 BCPs having a median (range) age of 51 (35-70 y) and three focus groups involving 21 HCPs aged 46 (29-62) were held at a university campus, local cancer support centre or clinical site. Data were analysed using Framework analysis. RESULTS: Four overarching themes (and 10 subthemes) were identified: (1) Treatment; (2) Support for lifestyle behaviour change; (3) Information availability for BCPs; (4) Knowledge of current evidence amongst HCPs. The physical and psychological consequences of treatment influenced motivation for weight management amongst BCPs. Social support for health promoting behaviours was viewed as important but was conflicting, requiring context-specific considerations. BCPs said they would have welcomed access to credible information (guided by HCPs) about the potential detrimental health effects of excess body weight and weight gain, together with advice on weight management via healthy eating and physical activity. HCPs felt that they had insufficient knowledge of public health dietary and physical activity recommendations or evidence-based interventions to confidently offer such advice. HCPs expressed concern that raising weight management issues would exacerbate distress or invoke feelings of guilt amongst BCPs, and cited time pressures on patient consultations as additional barriers to providing weight management support. CONCLUSION: The study yielded novel insights into factors influencing weight management behaviours amongst overweight ER + BCPs. The results suggest that evidence-based information and support, which addresses key physical and psychological challenges to physical activity and dietary behaviours, offers the best route to sustainable weight management in this population.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Pesquisa Qualitativa , Sobrepeso/epidemiologia , Aumento de Peso , Estrogênios/uso terapêutico
19.
Reprod Biol Endocrinol ; 20(1): 157, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36401248

RESUMO

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex reproductive disorder, that affects approximately 5-10% of women of reproductive age. The disease is complex because its evolution may be impacted by genetic, lifestyle and environmental factors. Previous studies have emphasized the important roles of estrogen receptors in the pathogenesis of PCOS. OBJECTIVE: To use whole exome sequencing (WES) to assess possible pathogenic factors in a PCOS patient who exhibited estrogen insensitivity during hormone replacement therapy (HRT) treatment. METHODS: Genome sequencing and variant filtering via WES were performed in a patient with PCOS. DNA extraction from 364 unrelated female controls without PCOS was followed by PCR amplification, Sanger sequencing and sequence alignment. Evolutionary conservation analysis, protein structural modelling and in silico prediction were applied to analyse the potential pathogenicity of the novel ESR1 mutation. RESULT(S): During the controlled ovarian hyperstimulation (COH) period of an IVF cycle, the patient experienced markedly prolonged ovarian stimulation due to a poor response to gonadotropins (Gn) and elevated serum FSH. A novel heterozygous ESR1 mutation, c.619G > A/p.A207T, leading to the replacement of a highly conserved alanine with a threonine, was identified in this patient, via WES analysis. This novel variant was not identified in 364 unrelated female controls without PCOS, or in the Exome Aggregation Consortium (ExAC) or 1000 Genome Project. CONCLUSION(S): We identified a novel heterozygous ESR1 mutation in a Han Chinese PCOS woman exhibiting clinical signs of estrogen insensitivity. This study may provide new strategies for IVF therapy, especially for patients who exhibit estrogen insensitivity during IVF cycle.


Assuntos
Síndrome do Ovário Policístico , Humanos , Feminino , Síndrome do Ovário Policístico/genética , Fertilização In Vitro , Mutação , China , Estrogênios
20.
Prog Mol Biol Transl Sci ; 193(1): 37-63, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36357079

RESUMO

Breast cancer is the most diagnosed malignancy in women worldwide and in the majority of the countries. Breast cancers are classified on the expression of estrogen and progesterone receptor expression and overexpression of human epidermal growth factor receptor 2 (HER2) as luminal, HER2+ and triple negative breast cancer. The intrinsic molecular subtypes match this classification. Cancer diagnosis and treatment cause distress. In both acute and chronic stress, the secreted catecholamines adrenaline and noradrenaline trigger the "fight-or-flight" response. This chapter focuses on the actions of the ß2 and α2 adrenergic receptors in several models of breast cancer. The actions of these receptors depend on the model used to investigate them. The ß2-adrenergic receptors seem to exert a dual action. They can directly act on the epithelial cells inhibiting cell proliferation and migration/invasion and indirectly upon the immune microenvironment. The proportion of ß2 receptors in each compartment could, therefore, lean the scale to an inhibition or to an exacerbation of tumor growth, invasion and metastasis. All the work points to a beneficial or neutral action of ß-blockers on breast cancer. With respect to α2-adrenergic receptors, the investigation performed by our group suggest that the α2B and the α2C receptors are linked to enhanced cell proliferation and tumor growth acting through both the epithelial and the stromal (fibroblastic) compartments while α2A could be beneficial for patients. Some adrenergic compounds could be repurposed for breast cancer treatment due to their very low side effects and very well-known pharmacology.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Proliferação de Células , Estrogênios/farmacologia , Norepinefrina/farmacologia , Norepinefrina/uso terapêutico , Receptores Adrenérgicos , Microambiente Tumoral
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