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1.
Biochim Biophys Acta Rev Cancer ; 1873(1): 188339, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31917206

RESUMO

Increasing emphasis has been given to prevention as a feasible approach to reduce the cancer burden. However, for its clinical success, further advances are required to identify effective chemopreventive agents. This review affords a critical and up-to-date discussion of issues related to cancer prevention, including an in-depth knowledge on BRCA1 and p53 tumor suppressor proteins as key molecular players. Indeed, it compiles the most recent advances on the topic, highlighting the unique potential of BRCA1 and p53 germline mutations as molecular biomarkers for risk assessment and targets for chemoprevention. Relevant evidences are herein provided supporting the effectiveness of distinct pharmacological agents in cancer prevention, by targeting BRCA1 and p53. Moreover, the rationale for using germline mutant BRCA1- or p53-related cancer syndromes as model systems to investigate effective chemopreventive agents is also addressed. Altogether, this work provides an innovative conception about the dependence on p53 and BRCA1 co-inactivation in tumor formation and development, emphasizing the relationship between these two proteins as an encouraging direction for future personalized pharmacological interventions in cancer prevention.


Assuntos
Proteína BRCA1/genética , Quimioprevenção/métodos , Mutação em Linhagem Germinativa , Neoplasias Ovarianas/prevenção & controle , Tamoxifeno/uso terapêutico , Proteína Supressora de Tumor p53/genética , Proteína BRCA1/metabolismo , Feminino , Humanos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Proteína Supressora de Tumor p53/metabolismo
2.
Pediatrics ; 145(2)2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31974217

RESUMO

Many transgender and gender-diverse people have a gender identity that does not conform to the binary categories of male or female; they have a nonbinary gender. Some nonbinary individuals are most comfortable with an androgynous gender expression. For those who have not yet fully progressed through puberty, puberty suppression with gonadotrophin-releasing hormone agonists can support an androgynous appearance. Although such treatment is shown to ameliorate the gender dysphoria and serious mental health issues commonly seen in transgender and gender-diverse young people, long-term use of puberty-suppressing medications carries physical health risks and raises various ethical dilemmas. In this Ethics Rounds, we analyze a case that raised issues about prolonged pubertal suppression for a patient with a nonbinary gender.


Assuntos
Disforia de Gênero/tratamento farmacológico , Consentimento Informado por Menores/ética , Consentimento dos Pais/ética , Puberdade/efeitos dos fármacos , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Minorias Sexuais e de Gênero/psicologia , Adolescente , Ansiedade/tratamento farmacológico , Temas Bioéticos , Densidade Óssea/efeitos dos fármacos , Tomada de Decisão Clínica/ética , Esquema de Medicação , Ética Médica , Disforia de Gênero/psicologia , Fraturas do Quadril/etiologia , Humanos , Autonomia Pessoal
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
5.
JAMA ; 322(9): 868-886, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31479143

RESUMO

Importance: Medications to reduce risk of breast cancer are effective for women at increased risk but also cause adverse effects. Objective: To update the 2013 US Preventive Services Task Force systematic review on medications to reduce risk of primary (first diagnosis) invasive breast cancer in women. Data Sources: Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, EMBASE, and MEDLINE (January 1, 2013, to February 1, 2019); manual review of reference lists. Study Selection: Discriminatory accuracy studies of breast cancer risk assessment methods; randomized clinical trials of tamoxifen, raloxifene, and aromatase inhibitors for primary breast cancer prevention; studies of medication adverse effects. Data Extraction and Synthesis: Investigators abstracted data on methods, participant characteristics, eligibility criteria, outcome ascertainment, and follow-up. Results of individual trials were combined by using a profile likelihood random-effects model. Main Outcomes and Measures: Probability of breast cancer in individuals (area under the receiver operating characteristic curve [AUC]); incidence of breast cancer, fractures, thromboembolic events, coronary heart disease events, stroke, endometrial cancer, and cataracts; and mortality. Results: A total of 46 studies (82 articles [>5 million participants]) were included. Eighteen risk assessment methods in 25 studies reported low accuracy in predicting the probability of breast cancer in individuals (AUC, 0.55-0.65). In placebo-controlled trials, tamoxifen (risk ratio [RR], 0.69 [95% CI, 0.59-0.84]; 4 trials [n = 28 421]), raloxifene (RR, 0.44 [95% CI, 0.24-0.80]; 2 trials [n = 17 806]), and the aromatase inhibitors exemestane and anastrozole (RR, 0.45 [95% CI, 0.26-0.70]; 2 trials [n = 8424]) were associated with a lower incidence of invasive breast cancer. Risk for invasive breast cancer was higher for raloxifene than tamoxifen in 1 trial after long-term follow-up (RR, 1.24 [95% CI, 1.05-1.47]; n = 19 747). Raloxifene was associated with lower risk for vertebral fractures (RR, 0.61 [95% CI, 0.53-0.73]; 2 trials [n = 16 929]) and tamoxifen was associated with lower risk for nonvertebral fractures (RR, 0.66 [95% CI, 0.45-0.98]; 1 trial [n = 13 388]) compared with placebo. Tamoxifen and raloxifene were associated with increased thromboembolic events compared with placebo; tamoxifen was associated with more events than raloxifene. Tamoxifen was associated with higher risk of endometrial cancer and cataracts compared with placebo. Symptomatic effects (eg, vasomotor, musculoskeletal) varied by medication. Conclusions and Relevance: Tamoxifen, raloxifene, and aromatase inhibitors were associated with lower risk of primary invasive breast cancer in women but also were associated with adverse effects that differed between medications. Risk stratification methods to identify patients with increased breast cancer risk demonstrated low accuracy.


Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/prevenção & controle , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Tamoxifeno/uso terapêutico , Adulto , Área Sob a Curva , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/genética , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Mutação , Guias de Prática Clínica como Assunto , Cloridrato de Raloxifeno/efeitos adversos , Cloridrato de Raloxifeno/uso terapêutico , Medição de Risco/métodos , Fatores de Risco , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Tamoxifeno/efeitos adversos
6.
JAMA ; 322(9): 857-867, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31479144

RESUMO

Importance: Breast cancer is the most common nonskin cancer among women in the United States and the second leading cause of cancer death. The median age at diagnosis is 62 years, and an estimated 1 in 8 women will develop breast cancer at some point in their lifetime. African American women are more likely to die of breast cancer compared with women of other races. Objective: To update the 2013 US Preventive Services Task Force (USPSTF) recommendation on medications for risk reduction of primary breast cancer. Evidence Review: The USPSTF reviewed evidence on the accuracy of risk assessment methods to identify women who could benefit from risk-reducing medications for breast cancer, as well as evidence on the effectiveness, adverse effects, and subgroup variations of these medications. The USPSTF reviewed evidence from randomized trials, observational studies, and diagnostic accuracy studies of risk stratification models in women without preexisting breast cancer or ductal carcinoma in situ. Findings: The USPSTF found convincing evidence that risk assessment tools can predict the number of cases of breast cancer expected to develop in a population. However, these risk assessment tools perform modestly at best in discriminating between individual women who will or will not develop breast cancer. The USPSTF found convincing evidence that risk-reducing medications (tamoxifen, raloxifene, or aromatase inhibitors) provide at least a moderate benefit in reducing risk for invasive estrogen receptor-positive breast cancer in postmenopausal women at increased risk for breast cancer. The USPSTF found that the benefits of taking tamoxifen, raloxifene, and aromatase inhibitors to reduce risk for breast cancer are no greater than small in women not at increased risk for the disease. The USPSTF found convincing evidence that tamoxifen and raloxifene and adequate evidence that aromatase inhibitors are associated with small to moderate harms. Overall, the USPSTF determined that the net benefit of taking medications to reduce risk of breast cancer is larger in women who have a greater risk for developing breast cancer. Conclusions and Recommendation: The USPSTF recommends that clinicians offer to prescribe risk-reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors, to women who are at increased risk for breast cancer and at low risk for adverse medication effects. (B recommendation) The USPSTF recommends against the routine use of risk-reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors, in women who are not at increased risk for breast cancer. (D recommendation) This recommendation applies to asymptomatic women 35 years and older, including women with previous benign breast lesions on biopsy (such as atypical ductal or lobular hyperplasia and lobular carcinoma in situ). This recommendation does not apply to women who have a current or previous diagnosis of breast cancer or ductal carcinoma in situ.


Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/prevenção & controle , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Tamoxifeno/uso terapêutico , Adulto , Neoplasias da Mama/genética , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Pessoa de Meia-Idade , Mutação , Cloridrato de Raloxifeno/uso terapêutico , Medição de Risco/métodos , Fatores de Risco
7.
Int J Mol Sci ; 20(12)2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31226730

RESUMO

Estrogen-receptor-mediated signaling has been suggested to decrease the inflammatory response in monocyte macrophages. Previously, we showed that a novel selective estrogen receptor modulator (SERM2) promotes anti-inflammatory phenotype of monocytes in vitro. In this study, we demonstrate the potential of SERM2 in amelioration of colitis. We utilized a dextran sodium sulfate (DSS)-induced colitis model in FVB/n mice to demonstrate the effects of orally administered SERM2 on the clinical status of the mice and the histopathological changes in the colon, as well as proportion of Mrc-1 positive macrophages. SERM2 nuclear receptor affinities were measured by radioligand binding assays. Orally administered, this compound significantly alleviated DSS-induced colitis in male mice and induced local estrogen receptor activation in the inflamed colon, as well as promoting anti-inflammatory cytokine expression and infiltration of anti-inflammatory monocytes. We show that this novel drug candidate has an affinity to estrogen receptors α and ß and progesterone receptors, but not to glucocorticoid receptor, thus expressing unique binding properties compared to other sex steroid receptor ligands. These results indicate that novel drug candidates to alleviate inflammatory conditions of the colon could be found among sex steroid receptor activating compounds.


Assuntos
Colite/tratamento farmacológico , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Animais , Colite/induzido quimicamente , Colite/patologia , Colo/efeitos dos fármacos , Colo/patologia , Citocinas/análise , Sulfato de Dextrana , Modelos Animais de Doenças , Masculino , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/patologia
8.
Breast Cancer ; 26(6): 766-775, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31172425

RESUMO

BACKGROUND: Icariin is a major component isolated from Epimedium brevicornum Maxim and has been reported to exhibit anti-tumor activity. However, whether icariin could reverse the acquired drug resistance in breast cancer remains largely unclear. Therefore, this study was designed to explore the antitumor effects of icariin and its underlying mechanisms in a tamoxifen-resistant breast cancer cell line MCF-7/TAM. METHODS: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Lactate dehydrogenase (LDH) assay were performed to determine the effects of icariin on cell viability and cell death. Cell cycle progression and apoptosis were detected by flow cytometry analysis. Transmission electron microscopy (TEM) assay was utilized to observe cell autophagy. The downstream protein levels were measured using western blotting. RESULTS: Here, we observed that icariin treatment not only inhibited the growth of MCF-7 but also has a potential function to overcome tamoxifen resistance in MCF-7/TAM. Moreover, icariin significantly induced cell cycle G0/G1 phase arrest and apoptosis, as well as suppressed autophagy. At molecular levels, icariin treatment remarkably down-regulated the expression levels of CDK2, CDK4, Cyclin D1, Bcl-2, LC3-1, LC3-II, AGT5, Beclin-1, but upregulated the expression levels of caspase-3, PARP and p62. Most importantly, we found inhibition of autophagy via 3-MA treatment could significantly enhance the effects of icariin on cell viability and apoptosis. Enhanced autophagy via autophagy related 5 (ATG5) overexpression could partially reverse the effects of icariin on cell viability and apoptosis. CONCLUSION: These results revealed that icariin might potentially be useful as an adjuvant agent in cancer chemotherapy to enhance the effect of tamoxifen through suppression of autophagy in vitro and provide insight into the therapeutic potential of icariin for the treatment of chemo-resistant breast cancer.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Flavonoides/farmacologia , Extratos Vegetais/farmacologia , Tamoxifeno/efeitos adversos , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Neoplasias da Mama/tratamento farmacológico , Caspase 3/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Epimedium/química , Feminino , Humanos , Células MCF-7 , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Tamoxifeno/uso terapêutico , Transfecção
9.
Expert Opin Pharmacother ; 20(10): 1201-1210, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31091133

RESUMO

Introduction: Bazedoxifene (BZD) is a third-generation selective estrogen receptor modulator approved for the treatment of postmenopausal osteoporosis with additional favorable effects in lipids, uterine and breast tissue. Areas covered: In this review, the authors outline clinical data regarding the efficacy, safety, and tolerability of continuous BZD administration up to seven years in randomized, placebo-controlled, phase III clinical trials. Long-term treatment with BZD for postmenopausal osteoporosis is generally safe and well tolerated. BZD achieves small but significant increases in the bone mineral density of the lumbar spine but not the total hip. In addition, BZD reduces significantly the risk of vertebral fractures but not of non-vertebral and hip fractures, with the exception of high fracture risk postmenopausal women in whom BZD significantly reduces non-vertebral fractures. Expert opinion: BZD does not seem to offer significant advantages over the other available antiresorptive agents. However, considering the need for long-term management of osteoporosis, BZD may have a place in the long-term therapeutic planning of the disease.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Indóis/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Densidade Óssea/efeitos dos fármacos , Feminino , Humanos , Osteoporose/tratamento farmacológico , Fraturas por Osteoporose/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Fraturas da Coluna Vertebral/prevenção & controle
10.
Eur J Med Chem ; 177: 116-143, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31129450

RESUMO

Breast cancer, a most common malignancy in women, was known to be associated with steroid hormone estrogen. The discovery of estrogen receptor (ER) gave us not only a powerful predictive and prognostic marker, but also an efficient target for the treatment of hormone-dependent breast cancer with various estrogen ligands. ER consists of two subtypes i.e. ERα and ERß, that are mostly G-protein-coupled receptors and activated by estrogen, specially 17ß-estradiol. The activation is followed by translocation into the nucleus and binding with DNA to modulate activities of different genes. ERs can manage synthesis of RNA through genomic actions without directly binding to DNA. Receptors are tethered by protein-protein interactions to a transcription factor complex to communicate with DNA. Estrogens also exhibit nongenomic actions, a characteristic feature of steroid hormones, which are so rapid to be considered by the activation of RNA and translation. These are habitually related to stimulation of different protein kinase cascades. Majority of post-menopausal breast cancer is estrogen dependent, mostly potent biological estrogen (E2) for continuous growth and proliferation. Estrogen helps in regulating the differentiation and proliferation of normal breast epithelial cells. In this review we have investigated the important role of ER in development and progression of breast cancer, which is complicated by receptor's interaction with co-regulatory proteins, cross-talk with other signal transduction pathways and development of treatment strategies viz. selective estrogen receptor modulators (SERMs), selective estrogen receptor down regulators (SERDs), aromatase and sulphatase inhibitors.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Antagonistas de Estrogênios/uso terapêutico , Estrogênios/uso terapêutico , Receptores Estrogênicos/metabolismo , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Inibidores da Aromatase/química , Inibidores da Aromatase/farmacologia , Inibidores da Aromatase/uso terapêutico , Linhagem Celular Tumoral , Antagonistas de Estrogênios/química , Antagonistas de Estrogênios/farmacologia , Estrogênios/química , Estrogênios/farmacologia , Feminino , Humanos , Ligantes , Homens , Estrutura Molecular , Moduladores Seletivos de Receptor Estrogênico/química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Transdução de Sinais/fisiologia , Sulfatases/antagonistas & inibidores
11.
Expert Opin Pharmacother ; 20(12): 1517-1525, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31120775

RESUMO

Background: Selective estrogen receptor modulators (SERMs) represent a poorly investigated class of drugs for the treatment of male infertility. The aim of this study was to assess the effects of SERMs on conventional sperm parameters, serum gonadotropin and testosterone levels, and pregnancy rate in patients with idiopathic infertility. Methods: The authors performed a comprehensive systematic review with meta-analysis of all available controlled and not-controlled studies of the literature reporting sperm conventional parameters, gonadotropin and testosterone levels, and/or the pregnancy rate following SERM administration in normogonadotropic patients with idiopathic oligozoospermia. Results: From the 418 papers retrieved, 16 controlled and not-controlled trials were lastly included. SERM administration increased significantly sperm concentration, total sperm count, and serum luteinizing hormone, follicle-stimulating hormone, and total testosterone levels compared with baseline values. In contrast, SERMs did not have any significant effect on sperm concentration and progressive and total motility, but improved total sperm count, sperm morphology, and increased the pregnancy rate compared to the control group, which included studies done with placebo or other treatments. Conclusions: The results of this meta-analysis suggest that SERMs may be effective in the treatment of infertile patients with idiopathic infertility. However, the paucity of data does not allow to draw a definitive conclusion.


Assuntos
Infertilidade Masculina/tratamento farmacológico , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Antagonistas de Estrogênios/uso terapêutico , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Infertilidade Masculina/epidemiologia , Hormônio Luteinizante/sangue , Masculino , Oligospermia/tratamento farmacológico , Oligospermia/epidemiologia , Gravidez , Taxa de Gravidez , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Contagem de Espermatozoides , Testosterona/sangue , Resultado do Tratamento
12.
Eur J Obstet Gynecol Reprod Biol ; 238: 104-109, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31128532

RESUMO

OBJECTIVE: To determine the effect of a 3-month course of clomiphene citrate (CC) on plasma testosterone (T) level and on semen parameters in 18 infertile men with low T level and normal or low gonadotropines level. STUDY DESIGN: A retrospective study was conducted by reviewing the medical records of men referred to a university fertility medicine unit for infertility management between January 2010 and March 2015. Men treated with CC for at least 3 months were included if they presented with: RESULTS: 18 patients met the inclusion criteria. CC was prescribed for 3 months at the dose of 50 mg every 48 h. Plasma T level was assessed at baseline and after 1 month of CC administration. Semen parameters were assessed at baseline and after 3 months of CC administration. The median pre-treatment T level was 9.1 nmol/l; after 1 month of CC treatment the median post-treatment T level increased to 20.2 nmol/l (p = <0.001). Median baseline sperm concentration was 7 millions/ml with a median progressive motility of 18%. After 3 months of CC, the median post-treatment sperm concentration was 17.5 millions/ml (p = 0.024) and the median post-treatment progressive sperm motility was 18% (p = 0.40). Three natural pregnancies occurred during the treatment period. CONCLUSION: CC is an effective and inexpensive treatment to increase plasma T level in infertile men with low T level and normal or low gonadotropines level. Our study suggests that CC could increase sperm concentration even in oligospermic infertile men, without, however, a significant effect on progressive sperm motility. More powered randomized controlled trials are needed to definitively assess CC effect on sperm parameters and on natural pregnancy rates.


Assuntos
Clomifeno/uso terapêutico , Gonadotropinas/sangue , Infertilidade Masculina/tratamento farmacológico , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Testosterona/sangue , Adulto , Humanos , Infertilidade Masculina/sangue , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise do Sêmen , Adulto Jovem
13.
Cochrane Database Syst Rev ; 4: CD012191, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31032883

RESUMO

BACKGROUND: Breast cancer is the most frequently occurring malignancy and the second cause of death for cancer in women. Cancer prevention agents (CPAs) are a promising approach to reduce the burden of breast cancer. Currently, two main types of CPAs are available: selective estrogen receptor modulators (SERMs, such as tamoxifen and raloxifene) and aromatase inhibitors (AIs, such as exemestane and anastrozole). OBJECTIVES: To assess the efficacy and acceptability of single CPAs for the prevention of primary breast cancer, in unaffected women, at an above-average risk of developing breast cancer.Using a network meta-analysis, to rank single CPAs, based on their efficacy and acceptability (an endpoint that is defined as the inverse of CPA-related toxicity). SEARCH METHODS: We searched the Cochrane Breast Cancer Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP), and ClinicalTrials.gov on 17 August 2018. We handsearched reference lists to identify additional relevant studies. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that enrolled women without a personal history of breast cancer but with an above-average risk of developing a tumor. Women had to be treated with a CPA and followed up to record the occurrence of breast cancer and adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and conducted risk of bias assessments of the included studies, and assessed the certainty of the evidence using GRADE. Outcome data included incidence of breast carcinoma (both invasive and in situ carcinoma) and adverse events (both overall and severe toxicity). We performed a conventional meta-analysis (for direct comparisons of a single CPA with placebo or a different CPA) and network meta-analysis (for indirect comparisons). MAIN RESULTS: We included six studies enrolling 50,927 women randomized to receive one CPA (SERMs: tamoxifen or raloxifene, or AIs: exemestane or anastrozole) or placebo. Three studies compared tamoxifen and placebo, two studies compared AIs (exemestane or anastrozole) versus placebo, and one study compared tamoxifen versus raloxifene. The risk of bias was low for all RCTs.For the tamoxifen versus placebo comparison, tamoxifen likely resulted in a lower risk of developing breast cancer compared to placebo (risk ratio (RR) 0.68, 95% confidence interval (CI) 0.62 to 0.76; 3 studies, 22,832 women; moderate-certainty evidence). In terms of adverse events, tamoxifen likely increased the risk of severe toxicity compared to placebo (RR 1.28, 95% CI 1.12 to 1.47; 2 studies, 20,361 women; moderate-certainty evidence). In particular, women randomized to receive tamoxifen experienced a higher incidence of both endometrial carcinoma (RR 2.26, 95% CI 1.52 to 3.38; high-certainty evidence) and thromboembolism (RR 2.10, 95% CI 1.14 to 3.89; high-certainty evidence) compared to women who received placebo.For the AIs versus placebo comparison, AIs (exemestane or anastrozole) reduced the risk of breast cancer by 53% (RR 0.47, 95% CI 0.35 to 0.63; 2 studies, 8424 women; high-certainty evidence). In terms of adverse events, AIs increased the risk of severe toxicity by 18% (RR 1.18, 95% CI 1.09 to 1.28; 2 studies, 8352 women; high-certainty evidence). These differences were sustained especially by endocrine (e.g. hot flashes), gastrointestinal (e.g. diarrhea), and musculoskeletal (e.g. arthralgia) adverse events, while there were no differences in endometrial cancer or thromboembolism rates between AIs and placebo.For the tamoxifen versus raloxifene comparison, raloxifene probably performed worse than tamoxifen in terms of breast cancer incidence reduction (RR 1.25, 95% CI 1.09 to 1.43; 1 study, 19,490 women; moderate-certainty evidence), but its use was associated with lower toxicity rates (RR 0.87, 95% CI 0.80 to 0.95; 1 study, 19,490 women; moderate-certainty evidence), particularly relating to incidence of endometrial cancer and thromboembolism.An indirect comparison of treatment effects allowed us to compare the SERMs and AIs in this review. In terms of efficacy, AIs (exemestane or anastrozole) may have reduced breast cancer incidence slightly compared to tamoxifen (RR 0.67, 95% CI 0.46 to 0.98; 5 RCTs, 31,256 women); however, the certainty of evidence was low. A lack of model convergence did not allow us to analyze toxicity data. AUTHORS' CONCLUSIONS: For women with an above-average risk of developing breast cancer, CPAs can reduce the incidence of this disease. AIs appear to be more effective than SERMs (tamoxifen) in reducing the risk of developing breast cancer. AIs are not associated with an increased risk of endometrial cancer and thromboembolic events. However, long-term data on toxicities from tamoxifen are available while the follow-up toxicity data on unaffected women taking AIs is relatively short. Additional data from direct comparisons are needed to fully address the issues of breast cancer prevention by risk-reducing medications, with special regards to acceptability (i.e. the benefit/harm ratio).


Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Feminino , Humanos , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto
14.
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
15.
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
16.
Front Neuroendocrinol ; 53: 100743, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30922675

RESUMO

More than thirty years have passed since sex and gender differences were noted in the age of onset, course and outcomes for schizophrenia. The 'estrogen hypothesis" was coined in the 1990's to describe neuroprotective effects of estrogen. Intervention studies in schizophrenia patients with estradiol and selective estrogen receptor modulators (SERMs) are promising but psychiatrists and other health practitioners do not generally take up this useful adjunctive treatment for their female patients with schizophrenia. The reasons for this are manifold, but overall a cultural shift in the practice of psychiatry is needed to recognise the specific needs of women with schizophrenia and tailor treatments, such as hormone adjuncts to improve the outcomes for this significant population. The two main aims of this article are to review the evidence and theory of estrogen treatments in schizophrenia and to recommend translation of adjunctive estrogen treatment into clinical practice for women with schizophrenia.


Assuntos
Estradiol/uso terapêutico , Estrogênios/uso terapêutico , Esquizofrenia/tratamento farmacológico , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Animais , Humanos , Fatores Sexuais , Resultado do Tratamento
17.
Ann Surg Oncol ; 26(7): 1981-1990, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30911948

RESUMO

BACKGROUND: The discovery of nonsteroidal antiestrogens created a new group of medicines looking for an application; however, at the time, cytotoxic chemotherapy was the modality of choice to treat all cancers. Antiestrogens were orphan drugs until 1971, with the passing of the National Cancer Act. This enabled laboratory innovations to aid patient care. METHODS: This article traces the strategic application of tamoxifen to treat breast cancer by targeting the estrogen receptor (ER), deploying long-term adjuvant tamoxifen therapy, and becoming the first chemopreventive for any cancer. Laboratory discoveries from the University of Wisconsin Comprehensive Cancer Center (UWCCC) are described that address a broad range of biological issues with tamoxifen. These translated to improvements in clinical care. RESULTS: Tamoxifen was studied extensively at UWCCC in the 1980s for the development of acquired resistance to long-term therapy. Additionally, the long-term metabolism of tamoxifen and regulation of growth factors were also studied. A concern with tamoxifen use for chemoprevention was that an antiestrogen would increase bone loss and atherosclerosis. Laboratory studies with tamoxifen and keoxifene (subsequently named raloxifene) demonstrated that 'nonsteroidal antiestrogens' maintained bone density, and this translated into successful clinical trials with tamoxifen at UWCCC. However, tamoxifen also increased endometrial cancer growth; this discovery in the laboratory translated into changes in clinical care. Selective estrogen receptor modulators (SERMs) were born at UWCCC. CONCLUSIONS: There are now five US FDA-approved SERMs, all with discovery origins at UWCCC. Women's health was revolutionized as SERMs have the ability to treat multiple diseases by switching target sites around a woman's body on or off.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Receptores Estrogênicos/metabolismo , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , American Cancer Society , Feminino , Humanos
19.
Support Care Cancer ; 27(10): 3813-3822, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30729298

RESUMO

PURPOSE: To clarify the profile of adverse events from endocrine therapies in older patients. METHODS: We surveyed 15 subjective symptoms including hot flashes, sweating, knuckle stiffness, knee/shoulder joint pain, limb numbness, lethargy, forgetfulness, depressive state, irritated state, genital bleeding, leukorrhea increase, vaginal dryness, bone fracture, and weight gain by a questionnaire among 2044 patients over 55 years old (total number of answered sheets, 8875) and compared the results according to age (56-69 years old vs. ≥ 70 years old) and type of therapy (aromatase inhibitors (AIs) vs. selective estrogen receptor modulators (SERMs)). Among patients 56-69 years old, 6093 and 314 responses were from patients treated with AIs (1477 patients) and SERMs (123 patients), respectively, and 2292 and 176 responses were from those ≥ 70 years old treated with AIs (581 patients) and SERMs (51 patients), respectively. RESULTS: In patients ≥ 70 years old, sweating, knuckle stiffness, knee/shoulder joint pain, limb numbness, and lethargy were significantly more frequent/severe with AIs than with SERMs. In those aged 56-69, knuckle stiffness and vaginal dryness were significantly more frequent with AIs than with SERMs, but the opposite occurred for hot flashes, leukorrhea increase, genital bleeding, and weight gain. CONCLUSIONS: Among patients ≥ 70 years old, many symptoms were significantly more frequent/severe with AIs than with SERMs, compared with those aged 56-69, which suggests a difference in the profile of adverse events according to the type of endocrine therapy and the patient's age. It is important to consider the benefits and risks of each treatment to optimize endocrine therapy for older patients.


Assuntos
Antineoplásicos Hormonais/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Tamoxifeno/efeitos adversos , Fatores Etários , Idoso , Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Artralgia/induzido quimicamente , Neoplasias da Mama/tratamento farmacológico , Feminino , Fraturas Ósseas/prevenção & controle , Fogachos/induzido quimicamente , Humanos , Pessoa de Meia-Idade , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Inquéritos e Questionários , Sudorese/efeitos dos fármacos , Tamoxifeno/uso terapêutico
20.
J Exp Clin Cancer Res ; 38(1): 63, 2019 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-30736824

RESUMO

BACKGROUND: Interleukin-11 (IL-11), a dominant IL-6 family cytokine, is involved in tumorigenesis, tumor progression and differentiation in colon cancer cells. IL-11 signaling has been recently identified as a potential therapeutic target in colon cancer. Bazedoxifene, a third- generation selective estrogen modulator approved by the Food and Drug Administration (FDA), is a novel inhibitor of IL-11/GP130 signaling discovered by docking modeling. METHODS: In this study, the inhibition efficacy of bazedoxifene in colon cancer cells and its potential mechanism were investigated in vitro and in vivo by using MTT cell viability assay, BrdU cell proliferation assay, colony formation assay, wound-healing/cell migration assay, immunofluorescence, western blot assay and the mouse xenograft tumor model. RESULTS: Bazedoxifene inhibits phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) and its nuclear translocation induced by IL-11 in colon cancer cells. It also inhibits p-STAT3 induced by IL-6 and IL-11 but not by OSM or STAT1 phosphorylation induced by INF-γ in human colon cancer cells. In addition, bazedoxifene can significantly inhibit phosphorylation of AKT and STAT3 downstream targets. Furthermore, bazedoxifene alone or together with oxaliplatin can significantly induce apoptosis, inhibit cell viability, cell colony formation and cell migration in colon cancer cells. Knock-down of IL-11R can reduce the sensitivity of colon cancer cells to bazedoxifene. IL-11 can reduce the efficacy of oxaliplatin-mediated inhibition of cell viability. Consistent with in vitro findings, bazedoxifene alone also attenuated HCT-15 xenograft tumor burden and reduced p-STAT3, p-AKT and p-ERK in vivo. Its combination with oxaliplatin attenuated DLD-1 xenograft tumor burden and reduced p-STAT3 in vivo. CONCLUSIONS: Taken together, these results support bazedoxifene as a novel and effective therapeutic agent targeting IL-11/GP130 signaling for human colorectal cancer therapy.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Receptor gp130 de Citocina/metabolismo , Indóis/uso terapêutico , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Linhagem Celular Tumoral , Humanos , Indóis/farmacologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Transfecção
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