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1.
Zhonghua Zhong Liu Za Zhi ; 42(3): 192-196, 2020 Mar 23.
Artigo em Chinês | MEDLINE | ID: mdl-32252196

RESUMO

Luminal breast cancer is the most common subtype of breast cancer, representing more than 60% of all breast cancers. Endocrine resistance and late recurrence are two challenges in the treatment of luminal breast cancer. To overcome endocrine resistance in multiple levels, high-dose-fulvestrant can inhibit estrogen-receptor (ER)-dependent pathways, while targeted drugs can block ER-independent pathways.To reduce the risk of late recurrence in luminal breast cancer, recurrence prediction model should be formed. For patients with high risk of late recurrence, extended endocrine therapy, combination of ovarian function suppression (OFS) or vascular endothelial growth factor (VEGF) inhibitor could be utilized. Based on the challenges of the treatment, scientific research achievements can be used in clinical practice, and finally optimize the clinical treatment strategy.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Moduladores de Receptor Estrogênico/uso terapêutico , Fulvestranto/uso terapêutico , Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/imunologia , Humanos , Recidiva Local de Neoplasia , Receptores Estrogênicos/metabolismo , Fator A de Crescimento do Endotélio Vascular
2.
Cell Mol Life Sci ; 77(4): 559-572, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31471681

RESUMO

Endocrine therapy represents a mainstay adjuvant treatment of estrogen receptor-positive (ER+) breast cancer in clinical practice with an overall survival (OS) benefit. However, the emergence of resistance is inevitable over time and is present in one-third of the ER+ breast tumors. Several mechanisms of endocrine resistance in ER+/HER2- advanced breast cancers, through ERα itself, receptor tyrosine signaling, or cell cycle pathway, have been identified to be pivotal in endocrine therapy. The epigenetic alterations also contribute to ensuring tumor cells' escape from endocrine therapies. The strategy of combined hormone therapy with targeted pharmaceutical compounds has shown an improvement of progression-free survival or OS in clinical practice, including three different classes of drugs: CDK4/6 inhibitors, selective inhibitor of PI3Kα and mTOR inhibitors. Many therapeutic targets of cell cycle pathway and cell signaling and their combination strategies have recently entered clinical trials. This review focuses on Cyclin D-CDK4/6-RB axis, PI3K pathway and HDACs. Additionally, genomic evolution is complex in tumors exposed to hormonal therapy. We highlight the genomic alterations present in ESR1 and PIK3CA genes to elucidate adaptive mechanisms of endocrine resistance, and discuss how these mutations may inform novel combinations to improve clinical outcomes in the future.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Moduladores de Receptor Estrogênico/farmacologia , Receptor alfa de Estrogênio/metabolismo , Receptor ErbB-2/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Ciclina D/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Moduladores de Receptor Estrogênico/uso terapêutico , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Mutação/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Receptor ErbB-2/genética , Transdução de Sinais/efeitos dos fármacos
3.
Zhonghua Fu Chan Ke Za Zhi ; 54(12): 848-853, 2019 Dec 25.
Artigo em Chinês | MEDLINE | ID: mdl-31874475

RESUMO

Objective: To study influencing factors which cause the endometrial diseases in patients with breast cancer after operation. Methods: A retrospective study was performed on 212 breast cancer post-operation patients with endometrial diseases between June 2006 and January 2018 in Women's Hospital School of Medicine Zhejiang University to analyse the factors which influenced the endometrial diseases. Results: The abnormal uterine bleeding and endometrial thickness were related to the severity of endometrial disease in patients with breast cancer, and they were independent risk factors for breast cancer patients to have endometrial cancer (P<0.05) . When the diagnostic cut off value of endometrial thickness was ≥0.49 cm, the sensitivity and specificity to endometrial cancer were 78% and 25%, respectively. The average endometrial thickness was (0.56±0.39) cm in patients who were treated by selective estrogen receptor modulator (SERM) after gynecological surgery, which was significantly thicker than that of aromatase inhibitor (AI) group [ (0.33±0.23) cm] and no treatment group [ (0.44±0.28) cm, P<0.05]. The endometrial disease recurrent rate and reoperation rate in SERM group were (26.2%, 14.3%) slightly higher than that of AI group (9.5%, 4.8%) and no treatment group (21.6%, 4.9%), but there were not significant differences (all P>0.05). Conclusions: The clinical symptom of abnormal uterine bleeding and thickening endometrium are risk factors for breast cancer patients to have endometrial cancer. The endometrial thickness has high predictive value for breast cancer patients to diagnose endometrial cancer. The SERM treatment increases the endometrial thickness, recurrent rate and reoperation rate in post-operation patients.


Assuntos
Antineoplásicos Hormonais/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Hiperplasia Endometrial/induzido quimicamente , Neoplasias do Endométrio/induzido quimicamente , Endométrio/efeitos dos fármacos , Moduladores de Receptor Estrogênico/efeitos adversos , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Hemorragia Uterina/etiologia , Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Terapia Combinada , Hiperplasia Endometrial/epidemiologia , Hiperplasia Endometrial/patologia , Neoplasias do Endométrio/epidemiologia , Neoplasias do Endométrio/patologia , Endométrio/patologia , Moduladores de Receptor Estrogênico/uso terapêutico , Feminino , Humanos , Estudos Retrospectivos , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Índice de Gravidade de Doença , Ultrassonografia
4.
Cas Lek Cesk ; 158(3-4): 107-111, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31416316

RESUMO

Tibolon is the only therapeutic approach to climacteric symptoms, prevention of osteoporosis and urogenital atrophy with the same efficacy as hormone replacement therapy. Tibolon has more positive effects on sexuality and mood changes in menopausal women. It decreases the mammographic density. Its safety for breast cancer is the same as for only estrogen therapy and better than for estrogen-gestagen therapy. Tibolon is the first choice for postmenopausal women with mood and sexuality disorders, women with mastodynia and high mammographic density.


Assuntos
Moduladores de Receptor Estrogênico , Norpregnenos , Osteoporose , Neoplasias da Mama/induzido quimicamente , Clima , Moduladores de Receptor Estrogênico/efeitos adversos , Moduladores de Receptor Estrogênico/uso terapêutico , Estrogênios , Feminino , Humanos , Menopausa , Norpregnenos/efeitos adversos , Norpregnenos/uso terapêutico , Osteoporose/prevenção & controle , Progestinas
5.
Mol Oncol ; 13(8): 1778-1794, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31180176

RESUMO

Estrogens have been shown to elicit anticancer effects against estrogen receptor α (ER)-positive breast cancer. We sought to determine the mechanism underlying the therapeutic response. Response to 17ß-estradiol was assessed in ER+ breast cancer models with resistance to estrogen deprivation: WHIM16 patient-derived xenografts, C7-2-HI and C4-HI murine mammary adenocarcinomas, and long-term estrogen-deprived MCF-7 cells. As another means to reactivate ER, the anti-estrogen fulvestrant was withdrawn from fulvestrant-resistant MCF-7 cells. Transcriptional, growth, apoptosis, and molecular alterations in response to ER reactivation were measured. 17ß-estradiol treatment and fulvestrant withdrawal induced transcriptional activation of ER, and cells adapted to estrogen deprivation or fulvestrant were hypersensitive to 17ß-estradiol. ER transcriptional response was followed by an unfolded protein response and apoptosis. Such apoptosis was dependent upon the unfolded protein response, p53, and JNK signaling. Anticancer effects were most pronounced in models exhibiting genomic amplification of the gene encoding ER (ESR1), suggesting that engagement of ER at high levels is cytotoxic. These data indicate that long-term adaptation to estrogen deprivation or ER inhibition alters sensitivity to ER reactivation. In such adapted cells, 17ß-estradiol treatment and anti-estrogen withdrawal hyperactivate ER, which drives an unfolded protein response and subsequent growth inhibition and apoptosis. 17ß-estradiol treatment should be considered as a therapeutic option for anti-estrogen-resistant disease, particularly in patients with tumors harboring ESR1 amplification or ER overexpression. Furthermore, therapeutic strategies that enhance an unfolded protein response may increase the therapeutic effects of ER reactivation.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Estrogênios/uso terapêutico , Receptores Estrogênicos/metabolismo , Resposta a Proteínas não Dobradas , Animais , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Morte Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Moduladores de Receptor Estrogênico/farmacologia , Moduladores de Receptor Estrogênico/uso terapêutico , Estrogênios/farmacologia , Feminino , Fulvestranto/farmacologia , Fulvestranto/uso terapêutico , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Células MCF-7 , Camundongos , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Ativação Transcricional/efeitos dos fármacos , Ativação Transcricional/genética , Transcriptoma/genética , Proteína Supressora de Tumor p53/metabolismo , Resposta a Proteínas não Dobradas/efeitos dos fármacos
6.
Proc Natl Acad Sci U S A ; 116(25): 12452-12461, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31152137

RESUMO

Tumor hypoxia is associated with poor patient outcomes in estrogen receptor-α-positive (ERα+) breast cancer. Hypoxia is known to affect tumor growth by reprogramming metabolism and regulating amino acid (AA) uptake. Here, we show that the glutamine transporter, SNAT2, is the AA transporter most frequently induced by hypoxia in breast cancer, and is regulated by hypoxia both in vitro and in vivo in xenografts. SNAT2 induction in MCF7 cells was also regulated by ERα, but it became predominantly a hypoxia-inducible factor 1α (HIF-1α)-dependent gene under hypoxia. Relevant to this, binding sites for both HIF-1α and ERα overlap in SNAT2's cis-regulatory elements. In addition, the down-regulation of SNAT2 by the ER antagonist fulvestrant was reverted in hypoxia. Overexpression of SNAT2 in vitro to recapitulate the levels induced by hypoxia caused enhanced growth, particularly after ERα inhibition, in hypoxia, or when glutamine levels were low. SNAT2 up-regulation in vivo caused complete resistance to antiestrogen and, partially, anti-VEGF therapies. Finally, high SNAT2 expression levels correlated with hypoxia profiles and worse outcome in patients given antiestrogen therapies. Our findings show a switch in the regulation of SNAT2 between ERα and HIF-1α, leading to endocrine resistance in hypoxia. Development of drugs targeting SNAT2 may be of value for a subset of hormone-resistant breast cancer.


Assuntos
Sistema A de Transporte de Aminoácidos/metabolismo , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/patologia , Hipóxia Celular , Resistencia a Medicamentos Antineoplásicos , Moduladores de Receptor Estrogênico/uso terapêutico , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Receptor alfa de Estrogênio/metabolismo , Feminino , Xenoenxertos , Humanos , Camundongos , Microambiente Tumoral
7.
Int J Mol Sci ; 20(10)2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31137666

RESUMO

Osteoporosis is an unavoidable public health problem in an aging or aged society. Anti-resorptive agents (calcitonin, estrogen, and selective estrogen-receptor modulators, bisphosphonates, anti-receptor activator of nuclear factor κB ligand antibody along with calcium and vitamin D supplementations) and anabolic agents (parathyroid hormone and related peptide analogs, sclerostin inhibitors) have major roles in current treatment regimens and are used alone or in combination based on the pathological condition. Recent advancements in the molecular understanding of bone metabolism and in bioengineering will open the door to future treatment paradigms for osteoporosis, including antibody agents, stem cells, and gene therapies. This review provides an overview of the molecular mechanisms, clinical evidence, and potential adverse effects of drugs that are currently used or under development for the treatment of osteoporosis to aid clinicians in deciding how to select the best treatment option.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Moduladores de Receptor Estrogênico/uso terapêutico , Osteoporose/tratamento farmacológico , Animais , Difosfonatos/uso terapêutico , Humanos , Osteoporose/metabolismo , Osteoporose/terapia , Transplante de Células-Tronco/métodos , Vitamina D/uso terapêutico
9.
J Clin Endocrinol Metab ; 104(5): 1595-1622, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30907953

RESUMO

OBJECTIVE: The objective is to formulate clinical practice guidelines for the pharmacological management of osteoporosis in postmenopausal women. CONCLUSIONS: Evidence from clinical trials and insights from clinical experience with pharmacologic therapies for osteoporosis were critically evaluated in formulating this guideline for the management of postmenopausal osteoporosis. Patient preferences, data on adherence and persistence, and risks and benefits from the patient and provider perspectives were also considered in writing committee deliberations. A consensus by the Writing Committee members was achieved for four management principles: (i) The risk of future fractures in postmenopausal women should be determined using country-specific assessment tools to guide decision-making. (ii) Patient preferences should be incorporated into treatment planning. (iii) Nutritional and lifestyle interventions and fall prevention should accompany all pharmacologic regimens to reduce fracture risk. (iv) Multiple pharmacologic therapies are capable of reducing fracture rates in postmenopausal women at risk with acceptable risk-benefit and safety profiles.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Denosumab/uso terapêutico , Difosfonatos/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Fraturas por Osteoporose/prevenção & controle , Absorciometria de Fóton , Acidentes por Quedas/prevenção & controle , Calcitonina/uso terapêutico , Cálcio/uso terapêutico , Tomada de Decisão Clínica , Moduladores de Receptor Estrogênico/uso terapêutico , Terapia de Reposição de Estrogênios , Feminino , Humanos , Norpregnenos/uso terapêutico , Osteoporose Pós-Menopausa/diagnóstico por imagem , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Preferência do Paciente , Cloridrato de Raloxifeno/uso terapêutico , Medição de Risco , Comportamento de Redução do Risco , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Teriparatida/uso terapêutico , Vitamina D/uso terapêutico
10.
J Clin Endocrinol Metab ; 104(5): 1623-1630, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30907957

RESUMO

BACKGROUND: Osteoporosis and osteopenia are associated with increased fracture incidence in postmenopausal women. We aimed to determine the comparative effectiveness of various available pharmacological therapies. METHODS: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ISI Web of Science, and Scopus for randomized controlled trials that enrolled postmenopausal women with primary osteoporosis and evaluated the risk of hip, vertebral, or nonvertebral fractures. A network meta-analysis was conducted using the multivariate random effects method. RESULTS: We included 107 trials (193,987 postmenopausal women; mean age, 66 years; 55% white; median follow-up, 28 months). A significant reduction in hip fractures was observed with romosozumab, alendronate, zoledronate, risedronate, denosumab, estrogen with progesterone, and calcium in combination with vitamin D. A significant reduction in nonvertebral fractures was observed with abaloparatide, romosozumab, denosumab, teriparatide, alendronate, risedronate, zoledronate, lasofoxifene, tibolone, estrogen with progesterone, and vitamin D. A significant reduction in vertebral fractures was observed with abaloparatide, teriparatide, parathyroid hormone 1-84, romosozumab, strontium ranelate, denosumab, zoledronate, risedronate, alendronate, ibandronate, raloxifene, bazedoxifene, lasofoxifene, estrogen with progesterone, tibolone, and calcitonin. Teriparatide, abaloparatide, denosumab, and romosozumab were associated with the highest relative risk reductions, whereas ibandronate and selective estrogen receptor modulators had lower efficacy. The evidence for the treatment of fractures with vitamin D and calcium remains limited despite numerous large trials. CONCLUSIONS: This network meta-analysis provides comparative effective estimates for the various available treatments to reduce the risk of fragility fractures in postmenopausal women.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Fraturas do Quadril/prevenção & controle , Osteoporose Pós-Menopausa/tratamento farmacológico , Fraturas por Osteoporose/prevenção & controle , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Fraturas da Coluna Vertebral/prevenção & controle , Doenças Ósseas Metabólicas/tratamento farmacológico , Calcitonina/uso terapêutico , Moduladores de Receptor Estrogênico/uso terapêutico , Terapia de Reposição de Estrogênios , Feminino , Humanos , Metanálise em Rede , Norpregnenos/uso terapêutico , Pós-Menopausa , Vitamina D/uso terapêutico
11.
Expert Opin Biol Ther ; 19(4): 343-360, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30763525

RESUMO

INTRODUCTION: Endometriosis is a chronic benign estrogen-dependent disease characterized by the presence of endometriotic glands and stroma outside the uterine cavity. Although combined hormonal contraceptives and progestins, currently available first-line treatments for endometriosis, are efficacious and well tolerated for treating disease-related pain, some women experience partial or no improvement of pain or its recurrence is frequent after discontinuation of the therapies. For these reasons, new drugs are under investigation for the treatment of endometriosis. AREAS COVERED: This review aims to give to the reader a complete and updated overview of hormonal and biological therapies for the treatment of endometriosis, underlining the latest developments in this field of research. EXPERT OPINION: Among the new drugs investigated, late clinical trials on gonadotropin-releasing hormone (GnRH) antagonists and aromatase inhibitors (AIs) have demonstrated the most promising results. For this reason, elagolix, a new GnRH-antagonist, recently received the approval by the Food and Drug Administration (FDA) for treating pain associated to endometriosis. Other drugs with innovative targets have been identified, but the majority of these compounds have only been evaluated in pre-clinical studies or early clinical trials. Thus, a further extensive clinical research is necessary to better elucidate their pharmacologic characteristics, their efficacy, and safety for the treatment of this benign chronic disease.


Assuntos
Produtos Biológicos/uso terapêutico , Endometriose/tratamento farmacológico , Antagonistas de Hormônios/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Ensaios Clínicos como Assunto , Endometriose/patologia , Moduladores de Receptor Estrogênico/uso terapêutico , Feminino , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Humanos , Progestinas/uso terapêutico
12.
Blood Coagul Fibrinolysis ; 30(1): 17-23, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30507711

RESUMO

: Postmenopausal hormone therapy increases the risk of venous thrombosis. Sex hormone binding globulin (SHBG) is a suggested marker of 'total estrogenicity'. The study objective was to evaluate the impact of hormone therapy on SHBG and the association with coagulation variables. The study populations comprised 202 healthy postmenopausal women randomized to treatment with low-dose or conventional-dose hormone therapy, tibolone or raloxifene (RET-study) and 140 women with a history of venous thrombosis randomized to conventional-dose hormone therapy or placebo (EVTET-study). SHBG was determined in serum collected at baseline and after 12 weeks. In healthy women, conventional-dose hormone therapy increased SHBG with mean 9.7 (95% confidence interval 4.8-14.5) nmol/l, low-dose hormone therapy by mean 5.9 (0.4-11.5) nmol/l, raloxifene by mean 7.2 (3.9-10.4) nmol/l, while tibolone reduced SHBG with mean -25.1 (-29.9 to -20.4) nmol/l. SHBG correlated with protein S, tissue factor pathway inhibitor (TFPI) and protein C at baseline, and with protein S and TFPI after 12 weeks, but the change in SHBG from baseline to 12 weeks was only associated with the change in activated protein C (APC) resistance. In women with a history of venous thrombosis, the mean increase in SHBG was 13.6 (8.4-18.9) nmol/l in the conventional-dose hormone therapy group, with no change in the placebo group. Baseline SHBG was higher among women who developed recurrent venous thrombosis on conventional-dose hormone therapy. SHBG correlated with several coagulation inhibitors, but the change in SHBG induced by postmenopausal hormone therapy was only associated with the change in APC resistance.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Terapia de Reposição de Estrogênios/métodos , Globulina de Ligação a Hormônio Sexual/efeitos dos fármacos , Trombose Venosa/tratamento farmacológico , Resistência à Proteína C Ativada/sangue , Moduladores de Receptor Estrogênico/farmacologia , Moduladores de Receptor Estrogênico/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Norpregnenos , Pós-Menopausa/sangue , Cloridrato de Raloxifeno , Globulina de Ligação a Hormônio Sexual/análise
13.
Rev. chil. endocrinol. diabetes ; 12(1): 26-28, 2019. ilus
Artigo em Espanhol | LILACS | ID: biblio-982035

RESUMO

La definición de sangrado ginecológico anormal durante terapia hormonal de la menopausia es aquel sangrado no programado durante el uso de la terapia. Este artículo es un pauteo que describe: 1) cuándo diagnosticar unsangrado anormal, ya que difiere según el tipo de esquema hormonal utilizado; 2) eldiagnóstico diferencial del origen del sangrado anormal; 3) los métodos de evaluación para diagnosticar el origen del sangrado. Se destacan los aspectos principales para el diagnóstico diferencial entre patología orgánica versus disrupción endometrial debida al tratamiento hormonal. Además, se describen los ajustes posibles para resolver el sangrado cuando éste se debe a disrupción del endometrio.


Abnormal bleeding related to menopausal hormone therapy is defined as unscheduled bleeding during the use of the therapy. This article outlines when to diagnose an abnormal bleeding -as this differs according to the type of hormonal scheme used-, the differential diagnosis of the origin of abnormal bleeding, and the methods of evaluation to assess the origin of the bleeding. The main aspects are highlighted on the differentiation of organic pathology versus disruption of the endometrium due to treatment. Also, treatment adjustments to resolve bleeding when it is due to disruption of the endometrium are outlined.


Assuntos
Humanos , Feminino , Hemorragia Uterina/etiologia , Menopausa , Terapia de Reposição de Estrogênios/efeitos adversos , Moduladores de Receptor Estrogênico/efeitos adversos , Norpregnenos/efeitos adversos , Pólipos/complicações , Pólipos/diagnóstico , Neoplasias do Endométrio/complicações , Neoplasias do Endométrio/diagnóstico , Moduladores de Receptor Estrogênico/uso terapêutico , Diagnóstico Diferencial , Hiperplasia Endometrial/complicações , Hiperplasia Endometrial/diagnóstico , Endométrio/diagnóstico por imagem , Metrorragia/etiologia , Norpregnenos/uso terapêutico
16.
Toxicol Appl Pharmacol ; 355: 226-237, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30017638

RESUMO

It has been reported that endogenous or exogenous estrogens can affect the immune system, resulting in immune disorders; however, their direct involvement in such conditions remains to be demonstrated. The purpose of this study was to investigate whether estrogen receptors (ER) are directly implicated in pro-pruritic and pro-inflammatory reactions in cutaneous allergy. Initially, enhancement of the pro-inflammatory response by several ER agonists [methoxychlor (MXC), ß-estradiol (E2), propylpyrazoletriol (PPT; an ERα agonist), and diarylpropionitrile (DPN; an ERß agonist)] was examined in vivo using a male BALB/c mouse model of allergic dermatitis induced by toluene-2,4-diisocyanate administration. The ear swelling response, itch response, and local cytokine secretion were measured. Subsequently, the mechanism underlying the development of such allergic reactions was analyzed in vitro using human epidermal keratinocytes, murine bone marrow-derived dendritic cells (mBMDCs), and the mixed leucocyte reaction assay. Activated cells were exposed to each ER agonist for 24 h, and cytokine secretion and cell proliferation were measured. Our in vivo experiments indicated significant upregulation of pro-inflammatory and pro-pruritic responses in the E2-, MXC-, and PPT-treated groups compared to the control group; however, no change was observed in the DPN-treated group. Levels of cytokines expressed by keratinocytes, such as TSLP and IL-33, were particularly increased by exposure to E2, MXC, or PPT. These in vivo results were confirmed in vitro in keratinocytes, but not mBMDCs or T cells. Our findings imply that ERα is involved in pro-inflammatory and pro-pruritic responses in cutaneous allergy through activation of keratinocytes.


Assuntos
Dermatite Alérgica de Contato/tratamento farmacológico , Moduladores de Receptor Estrogênico/uso terapêutico , Receptor alfa de Estrogênio/efeitos dos fármacos , Inflamação/tratamento farmacológico , Prurido/tratamento farmacológico , Animais , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Células Dendríticas , Dermatite Alérgica de Contato/patologia , Orelha Externa/patologia , Feminino , Humanos , Inflamação/patologia , Queratinócitos/metabolismo , Teste de Cultura Mista de Linfócitos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Prurido/patologia
17.
J Affect Disord ; 236: 88-92, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29723767

RESUMO

BACKGROUND: Many women with no past psychiatric history experience severe mood symptoms for the first time in their life during the menopausal transition, with debilitating long-term consequences. Women with a history of depression can experience a relapse or worsening of symptoms during the menopause transition. Traditional antidepressants, SSRIs or SNRIs, are commonly prescribed as the first line response. However, such treatment has shown only small improvements with side effects. Hormone therapies directly targeting the perimenopausal fluctuations in reproductive hormonal systems such as tibolone, have significant potential to treat perimenopausal depression. Our study investigated the use of adjunctive tibolone, selective tissue estrogenic activity regulator, to treat de-novo or relapsing depression occurring during the menopause transition period. METHODS: Women who were going through the menopause transition with depressive symptoms were invited to participate in a double-blind, 12 week randomized control trial with two arms: tibolone (2.5 mg oral/day) or oral placebo (NCT01470092). Forty-four women met inclusion/exclusion criteria; 22 were randomized to tibolone and 22 were randomized to oral placebo. Symptoms were measured with the 'Montgomery- Asberg depression rating scale' (MADRS) as the primary outcome measure. Latent growth curve analysis was used to assess the MADRS scores change over time. RESULTS: Participants in the tibolone group demonstrated a significant improvement in depression scores, as compared to the placebo group, without any significant side effects. LIMITATIONS: This trial only monitored tibolone's effects over 12 weeks. Future research should be conducted over an extended timeframe and explore whether the benefits of tibolone extend to other symptoms of perimenopausal depression. CONCLUSIONS: The use of hormone therapies such as tibolone provide exciting innovations for the treatment of depression during the menopause transition.


Assuntos
Depressão/tratamento farmacológico , Moduladores de Receptor Estrogênico/uso terapêutico , Menopausa/efeitos dos fármacos , Norpregnenos/uso terapêutico , Administração Oral , Adulto , Afeto/fisiologia , Antidepressivos/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Menopausa/psicologia , Pessoa de Meia-Idade , Resultado do Tratamento
18.
Proc Natl Acad Sci U S A ; 115(16): E3673-E3681, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29592953

RESUMO

Metastases constitute the greatest causes of deaths from cancer. However, no effective therapeutic options currently exist for cancer patients with metastasis. Estrogen receptor ß (ERß), as a member of the nuclear receptor superfamily, shows potent tumor-suppressive activities in many cancers. To investigate whether modulation of ERß could serve as a therapeutic strategy for cancer metastasis, we examined whether the selective ERß agonist LY500307 could suppress lung metastasis of triple-negative breast cancer (TNBC) and melanoma. Mechanistically, while we observed that LY500307 potently induced cell death of cancer cells metastasized to lung in vivo, it does not mediate apoptosis of cancer cells in vitro, indicating that the cell death-inducing effects of LY500307 might be mediated by the tumor microenvironment. Pathological examination combined with flow cytometry assays indicated that LY500307 treatment induced significant infiltration of neutrophils in the metastatic niche. Functional experiments demonstrated that LY500307-treated cancer cells show chemotactic effects for neutrophils and that in vivo neutrophil depletion by Ly6G antibody administration could reverse the effects of LY500307-mediated metastasis suppression. RNA sequencing analysis showed that LY500307 could induce up-regulation of IL-1ß in TNBC and melanoma cells, which further triggered antitumor neutrophil chemotaxis. However, the therapeutic effects of LY500307 treatment for suppression of lung metastasis was attenuated in IL1B-/- murine models, due to failure to induce antitumor neutrophil infiltration in the metastatic niche. Collectively, our study demonstrated that pharmacological activation of ERß could augment innate immunity to suppress cancer metastatic colonization to lung, thus providing alternative therapeutic options for cancer patients with metastasis.


Assuntos
Antineoplásicos/farmacologia , Benzopiranos/farmacologia , Moduladores de Receptor Estrogênico/farmacologia , Receptor beta de Estrogênio/agonistas , Imunidade Inata/efeitos dos fármacos , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/patologia , Melanoma Experimental/secundário , Infiltração de Neutrófilos/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/terapia , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Benzopiranos/uso terapêutico , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Moduladores de Receptor Estrogênico/uso terapêutico , Estrogênios , Feminino , Interleucina-1beta/deficiência , Interleucina-1beta/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/terapia , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Hormônio-Dependentes/imunologia , Neoplasias Hormônio-Dependentes/secundário , Neoplasias Hormônio-Dependentes/terapia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Organismos Livres de Patógenos Específicos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
19.
Molecules ; 23(2)2018 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-29415446

RESUMO

The objective of this article is to review the basis supporting the usefulness of melatonin as an adjuvant therapy for breast cancer (BC) prevention in several groups of individuals at high risk for this disease. Melatonin, as a result of its antiestrogenic and antioxidant properties, as well as its ability to improve the efficacy and reduce the side effects of conventional antiestrogens, could safely be associated with the antiestrogenic drugs presently in use. In individuals at risk of BC due to night shift work, the light-induced inhibition of melatonin secretion, with the consequent loss of its antiestrogenic effects, would be countered by administering this neurohormone. BC risk from exposure to metalloestrogens, such as cadmium, could be treated with melatonin supplements to individuals at risk of BC due to exposure to this xenoestrogen. The BC risk related to obesity may be reduced by melatonin which decrease body fat mass, inhibits the enhanced aromatase expression in obese women, increases adiponectin secretion, counteracts the oncogenic effects of elevated concentrations of leptin; and decreases blood glucose levels and insulin resistance. Despite compelling experimental evidence of melatonin's oncostatic actions being susceptible to lowering BC risk, there is still a paucity of clinical trials focused on this subject.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/prevenção & controle , Melatonina/metabolismo , Animais , Neoplasias da Mama/etiologia , Meio Ambiente , Moduladores de Receptor Estrogênico/farmacologia , Moduladores de Receptor Estrogênico/uso terapêutico , Feminino , Humanos , Melatonina/farmacologia , Melatonina/uso terapêutico , Obesidade/complicações , Obesidade/metabolismo , Risco
20.
J Bone Miner Res ; 33(4): 634-642, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29318649

RESUMO

Few pooled analyses of antiresorptive (AR) treatment trials relate short-term changes in bone turnover markers (BTMs) to subsequent fracture reduction. Such information would be useful to assess new ARs or novel dosing regimens. In the Foundation for the National Institutes of Health (FNIH) Bone Quality project, we analyzed individual-level data from 28,000 participants enrolled in 11 bisphosphonate (BP) and three selective estrogen receptor modulator (SERM) placebo-controlled fracture endpoint trials. Using BTM results for two bone formation markers (bone-specific alkaline phosphatase [bone ALP] and pro-collagen I N-propeptide [PINP]) and two bone resorption markers (N-terminal and C-terminal telopeptide of type I collagen) and incident fracture outcome data, we performed a meta-regression relating the mean net effect of treatment on change in bone turnover (active minus placebo % difference after 3 to 12 months) to the log of study-wide fracture risk reduction, and used linear regression to plot the best fitting line. Separate analyses were performed for incident morphometric vertebral, nonvertebral, and hip fractures over 1 to 4 years of follow-up. Change in bone ALP and PINP were available for over 16,000 and 10,000 participants, respectively. For vertebral fracture, the results showed a strong relationship between treatment-related bone ALP or PINP changes and vertebral fracture risk reduction (r2 = 0.82 [p < 0.001] and r2 = 0.75 [p = 0.011], respectively) Relationships were weaker and no longer statistically significant for nonvertebral (r2 = 0.33 [p = 0.053] and r2 = 0.53 [p = 0.065], respectively) and hip fracture (r2 = 0.17 [p = 0.24] and r2 = 0.43 [p = 0.11], respectively) outcomes. Analyses limited to BP trials gave similar results. For all fracture types, relationships were weaker and nonsignificant for bone resorption markers. We conclude that short-term AR treatment-related changes in bone ALP and PINP strongly predict vertebral fracture treatment efficacy, but not nonvertebral or hip fracture treatment efficacy. Change in bone formation markers might be useful to predict the anti-vertebral fracture efficacy of new AR compounds or novel dosing regiments with approved AR drugs. © 2017 American Society for Bone and Mineral Research.


Assuntos
Fosfatase Alcalina/sangue , Remodelação Óssea/efeitos dos fármacos , Reabsorção Óssea , Difosfonatos/uso terapêutico , Moduladores de Receptor Estrogênico/uso terapêutico , Fragmentos de Peptídeos/sangue , Pró-Colágeno/sangue , Biomarcadores/sangue , Reabsorção Óssea/sangue , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/epidemiologia , Feminino , Fraturas Ósseas/sangue , Fraturas Ósseas/tratamento farmacológico , Fraturas Ósseas/epidemiologia , Humanos , Incidência , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco
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