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1.
Medicine (Baltimore) ; 99(25): e20590, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32569186

RESUMO

BACKGROUND: This study aims to assess the efficacy and safety of clomifene citrate (CC) for the treatment of patients with polycystic ovary syndrome (PCOS). METHODS: In this study, we will comprehensively search MEDLINE, EMBASE, The Cochrane Library, Web of Science, CINAHL, ACMD, PsycINFO, and China National Knowledge Infrastructure for original articles published from their inceptions to the January 1, 2020 without language restrictions. All studies will undergo relevance and a design selecting process. Data from qualified studies will be collected by 2 independent authors. Additionally, we will conduct a risk of bias evaluation using a Cochrane risk of bias tool. We will undertake statistical analysis utilizing RevMan 5.3 software. RESULTS: This study will summarize the up-to-date evidence to investigate the efficacy and safety of CC for the treatment of patients with PCOS. CONCLUSION: The findings of this study will provide helpful evidence of CC for the treatment of patients with PCOS, as well as may help develop treatment guidelines. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42020162818.


Assuntos
Clomifeno/administração & dosagem , Antagonistas de Estrogênios/administração & dosagem , Síndrome do Ovário Policístico/tratamento farmacológico , Clomifeno/efeitos adversos , Antagonistas de Estrogênios/efeitos adversos , Feminino , Humanos , Revisões Sistemáticas como Assunto
4.
Ren Fail ; 41(1): 507-520, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31216906

RESUMO

Menopause is an important physiological event associated with structural and functional changes in the kidneys. An animal model of bilateral ovariectomy was used to study the effects of estrogen depletion, replacement and antiestrogen on renal structure and endocrine function. Sixty female rats were divided into six groups; group I was the control group, the remaining five groups underwent ovariectomy: group II received no treatment. The other groups received estradiol in group III, tamoxifen in group IV, estradiol followed by tamoxifen in group V and tamoxifen followed by estradiol in group VI. Serum creatinine, blood urea nitrogen, and endocrine functions of kidney were measured. Tissue samples were examined both microscopically for beta estrogen receptors and ultrastructurally for cell changes. Groups II, IV & VI showed a significant increase in creatinine, blood urea nitrogen, renal malondialdehyde, renal erythropoietin, plasma renin and plasma prostaglandin E2 and a significant decrease in renal antioxidants and serum vitamin D3. Groups III &V had a significant decrease in creatinine, blood urea nitrogen, renal malondialdehyde and renal erythropoietin with an increase in renal antioxidants, plasma prostaglandin E2 and serum vitamin D3. Histopathological and ultrastructural examinations revealed atrophic tubular changes in group II. The changes were less marked in groups III &V and more extensive in groups IV & VI. Estrogen receptor beta staining showed progressively increased expression in the absence of estrogen. Structural and most endocrine functions of the kidney were significantly affected by estradiol deficiency. Estradiol replacement exhibited a protective effect on renal tissue and endocrine functions.


Assuntos
Estradiol/administração & dosagem , Terapia de Reposição de Estrogênios/métodos , Rim/metabolismo , Menopausa/efeitos dos fármacos , Animais , Antagonistas de Estrogênios/administração & dosagem , Feminino , Rim/efeitos dos fármacos , Rim/patologia , Menopausa/metabolismo , Modelos Animais , Ovariectomia/efeitos adversos , Ratos , Tamoxifeno/administração & dosagem
5.
J Perinatol ; 39(9): 1182-1189, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31217529

RESUMO

OBJECTIVE: Determine whether gestational age of 17-hydroxyprogesterone caproate (17-OHPC) initiation is associated with preterm birth (PTB) risk. STUDY DESIGN: We performed a retrospective cohort study using MarketScan® data. The primary outcome was PTB < 37 weeks. Rates of PTB were compared between medication initiation at 16-21 weeks versus 21-29 weeks. The association between compliance with weekly 17-OHPC injections and preterm birth rate was tested after adjusting for potential confounding variables. RESULT: In all 3374 pregnancies met inclusion criteria. Women with an early 17-OHPC start were less likely to deliver preterm than those with a late start (aRR 0.88; 95%CI 0.79-0.97; p = 0.02). Less compliant patients receiving <25% of recommended doses had a higher PTB rate than those receiving >85% of recommended doses (aRR 1.5; 95%CI 1.2-1.7; p < 0.01). CONCLUSION: There is an association between both early 17-OHPC initiation and compliance with reduced rates of PTB.


Assuntos
Caproato de 17 alfa-Hidroxiprogesterona/administração & dosagem , Antagonistas de Estrogênios/administração & dosagem , Adesão à Medicação , Nascimento Prematuro/prevenção & controle , Adolescente , Adulto , Esquema de Medicação , Feminino , Idade Gestacional , Humanos , Pessoa de Meia-Idade , Trabalho de Parto Prematuro/prevenção & controle , Gravidez , Segundo Trimestre da Gravidez , Terceiro Trimestre da Gravidez , Recidiva , Estudos Retrospectivos , Adulto Jovem
6.
Endocr Relat Cancer ; 26(3): 339-353, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30640711

RESUMO

Resistance to endocrine therapy remains a clinical challenge in the treatment of estrogen receptor-positive (ER+) breast cancer. We investigated if adding a traditional Asian herbal mixture consisting of 12 herbs, called Jaeumkanghwa-tang (JEKHT), to tamoxifen (TAM) therapy might prevent resistance and recurrence in the ER+ breast cancer model of 7,12-dimethylbenz[a]anthracene (DMBA)-exposed Sprague-Dawley rats. Rats were divided into four groups treated as follows: 15 mg/kg TAM administered via diet as TAM citrate (TAM only); 500 mg/kg JEKHT administered via drinking water (JEKHT only group); TAM + JEKHT and no treatment control group. The study was replicated using two different batches of JEKHT. In both studies, a significantly higher proportion of ER+ mammary tumors responded to TAM if animals also were treated with JEKHT (experiment 1: 47% vs 65%, P = 0.015; experiment 2: 43% vs 77%, P < 0.001). The risk of local recurrence also was reduced (31% vs 12%, P = 0.002). JEKHT alone was mostly ineffective. In addition, JEKHT prevented the development of premalignant endometrial lesions in TAM-treated rats (20% in TAM only vs 0% in TAM + JEKHT). Co-treatment of antiestrogen-resistant LCC9 human breast cancer cells with 1.6 mg/mL JEKHT reversed their TAM resistance in dose-response studies in vitro. Several traditional herbal medicine preparations can exhibit anti-inflammatory properties and may increase anti-tumor immune activities in the tumor microenvironment. In the tumors of rats treated with both JEKHT and TAM, expression of Il-6 (P = 0.03), Foxp3/T regulatory cell (Treg) marker (P = 0.033) and Tgfß1 that activates Tregs (P < 0.001) were significantly downregulated compared with TAM only group. These findings indicate that JEKHT may prevent TAM-induced evasion of tumor immune responses.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Antagonistas de Estrogênios/administração & dosagem , Extratos Vegetais/farmacologia , Receptores Estrogênicos/metabolismo , Tamoxifeno/administração & dosagem , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Animais , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citocinas/sangue , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Endométrio/efeitos dos fármacos , Endométrio/patologia , Feminino , Fatores de Transcrição Forkhead/genética , Humanos , Neoplasias Mamárias Experimentais , Medicina Tradicional do Leste Asiático , Recidiva Local de Neoplasia/prevenção & controle , Extratos Vegetais/administração & dosagem , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta1/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
7.
Drug Dev Ind Pharm ; 45(4): 587-602, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30633575

RESUMO

In the present work, MCM-41 and MCM-48 type of nanoparticles were successfully engineered. Effect of nanosize and amine functionalization on drug release, in vitro intestinal absorption and in vivo pharmacokinetic behavior was investigated in a comprehensive manner. The tailor-made bare and surface decorated MCM-41 and MCM-48 were synthesized and evaluated for their mesoporous skeleton, pore size, particle size, surface area, zeta potential, etc. by nitrogen sorption, DLS, TEM, etc. Incorporation of raloxifene (RLF) was affirmed using optimized immersion-solvent evaporation technique and its success confirmed by DSC, IR, and XRD analysis. TGA analysis revealed higher %grafting of amine groups on the exterior and larger RLF encapsulation into mesoporous derivate. The detailed in vitro release study revealed SGF to be the most compatible media for RLF showing an initial burst release from pristine nanoparticles and a delayed release from surface coated nanoparticles. Furthermore, release kinetics model data demonstrated Weibull and Higuchi as the best fit models for bare and amine-functionalized nanoparticles respectively. Moreover, an in vitro permeability study on Caco-2 cell line revealed higher absorption by engineered nanoparticle as compared to pure RLF and its marketed formulation. The supremacy in the in vivo pharmacokinetic parameters of RLF-41 and RLF-48 was demonstrated with 3.33 and 3.50 times enhancement in the bioavailability of RLF with respect to RLF suspension. To sum up, the results obtained were superior and promising for synthesized nanoparticles and more precisely for MCM-48 amongst them.


Assuntos
Portadores de Fármacos/química , Antagonistas de Estrogênios/farmacocinética , Cloridrato de Raloxifeno/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Células CACO-2 , Engenharia Química/métodos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Antagonistas de Estrogênios/administração & dosagem , Feminino , Humanos , Mucosa Intestinal/metabolismo , Camundongos , Nanopartículas/química , Osteoporose/tratamento farmacológico , Permeabilidade , Cloridrato de Raloxifeno/administração & dosagem , Dióxido de Silício/química
8.
Eur Arch Psychiatry Clin Neurosci ; 269(8): 941-948, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30167782

RESUMO

Accumulating evidence suggests that Specificity Protein 1 (SP1) and 4 (SP4) transcription factors are involved in the pathophysiology of schizophrenia. The therapeutic use of selective oestrogen modulators such as raloxifene added to antipsychotic drugs in the treatment of postmenopausal women with schizophrenia has been investigated in a few clinical trials, which reported an improvement in negative, positive, and general psychopathological symptoms. We aimed to investigate the possible association between peripheral SP protein levels and symptom improvement in postmenopausal women with schizophrenia treated with adjuvant raloxifene. In a subgroup of 14 postmenopausal women with schizophrenia from a 24-week, randomized, parallel, double-blind, placebo-controlled clinical trial (NCT015736370), we investigated changes in SP1 and SP4 protein levels in peripheral blood mononuclear cells. Participants were randomized to either 60 mg/day adjunctive raloxifene or placebo. Psychopathological symptoms were assessed at baseline and at week 24 with the Positive and Negative Syndrome Scale (PANSS). The expression of SP proteins was evaluated by immunoblot, and changes in PANSS scores and protein levels were compared at baseline and after 24 weeks of treatment. An improvement in symptoms was observed in the intervention group, but not in placebo group. Post-treatment protein levels of SP4, but not SP1, correlated with improvements in general and total PANSS subscales in the raloxifene intervention group. A reduction in SP4 levels was found after raloxifene treatment. These results suggest that SP4 may be involved in raloxifene symptom improvement in postmenopausal women and could be a potential candidate for future studies investigating blood-based biomarkers for raloxifene effectiveness.


Assuntos
Antipsicóticos/uso terapêutico , Antagonistas de Estrogênios/uso terapêutico , Leucócitos Mononucleares/metabolismo , Pós-Menopausa/sangue , Cloridrato de Raloxifeno/uso terapêutico , Esquizofrenia/tratamento farmacológico , Fator de Transcrição Sp1/sangue , Fator de Transcrição Sp4/sangue , Antipsicóticos/administração & dosagem , Método Duplo-Cego , Quimioterapia Combinada , Antagonistas de Estrogênios/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Cloridrato de Raloxifeno/administração & dosagem
9.
Breast Cancer Res Treat ; 174(2): 297-305, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30523459

RESUMO

PURPOSE: Approximately 70-80% of breast cancers are hormone receptor-positive (HR+). OET, including tamoxifen and aromatase inhibitors, is considered standard adjuvant therapy for HR+ breast cancer. Despite demonstrated benefits, nearly half of patients are non-adherent and over two-thirds discontinue therapy before the recommended 5 years. Our objective was to identify and summarize literature-reported barriers associated with non-adherence/non-persistence to OET among breast cancer survivors. METHODS: A PUBMED literature search was conducted using the following terms: 'breast cancer,' 'oral endocrine therapy' or 'Tamoxifen' or 'Aromatase Inhibitors,' 'adherence,' or 'barriers.' The search was restricted to past six years. The abstracts of each result were reviewed and categorized as either patient-reported or physician-reported. All patient- and physician-reported factors that affected adherence and persistence were listed and grouped together into the three main categories: Socio-demographic and medical parameters, general psychosocial parameters, and psychosocial parameters related to OET. RESULTS: A total of 320 articles were identified, of which 19 met inclusion criteria. Adverse drug reactions were the most commonly reported barrier but were generally underreported among physicians. Among patient-reported barriers, common social-demographic and medical parameters were age, comorbidity, and financial status. General psychosocial variables were lack of patient-provider communication, depressive symptoms, and lack of perceived self-efficacy. Treatment toxicity was the most commonly reported psychosocial parameter related to OET. CONCLUSION: The determinants of non-adherence and non-persistence are multi-dimensional and influenced by several factors. The three categories of adherence barriers should be evaluated and considered when designing future interventions to enhance OET adherence for a tailored approach.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Sobreviventes de Câncer/psicologia , Antagonistas de Estrogênios/administração & dosagem , Adesão à Medicação/psicologia , Idoso , Idoso de 80 Anos ou mais , Inibidores da Aromatase/administração & dosagem , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/psicologia , Antagonistas de Estrogênios/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Relações Médico-Paciente , Fatores de Risco , Padrão de Cuidado , Tamoxifeno/administração & dosagem , Tamoxifeno/uso terapêutico
10.
Clin Sci (Lond) ; 132(24): 2583-2598, 2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30545896

RESUMO

Estrogens generated within endocrine organs and the reproductive system act as ligands for at least three types of estrogen receptors. Estrogen receptors α (ERα) and ß (ERß) belong to the so-called classical family of estrogen receptors, whereas the G protein-coupled receptor GPR30, also known as GPER-1, has been described as a novel estrogen receptor sited in the cell membrane of target cells. Furthermore, these receptors are under stimulation of a family of exogenous estrogens, known as phytoestrogens, which are a diverse group of non-steroidal plant compounds derived from plant food consumed by humans and animals. Because phytoestrogens are omnipresent in our daily diet, they are becoming increasingly important in both human health and disease. Recent evidence indicates that in addition to classical estrogen receptors, phytoestrogens also activate GPER-1 a relevant observation since GPER-1 is involved in several physiopathological disorders and especially in estrogen-dependent diseases such as breast cancer.The first estrogen receptors discovered were the classical ERα and ERß, but from an evolutionary point of view G protein-coupled receptors trace their origins in history to over a billion years ago suggesting that estrogen receptors like GPER-1 may have been the targets of choice for ancient phytoestrogens and/or estrogens.This review provides a comprehensive and systematic literature search on phytoestrogens and its relationship with classical estrogen receptors and GPER-1 including its role in breast cancer, an issue still under discussion.


Assuntos
Anticarcinógenos/administração & dosagem , Neoplasias da Mama/metabolismo , Antagonistas de Estrogênios/administração & dosagem , Glândulas Mamárias Humanas/efeitos dos fármacos , Fitoestrógenos/administração & dosagem , Receptores Acoplados a Proteínas-G/agonistas , Animais , Anticarcinógenos/efeitos adversos , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/prevenção & controle , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/metabolismo , Exposição Dietética/efeitos adversos , Antagonistas de Estrogênios/efeitos adversos , Feminino , Humanos , Glândulas Mamárias Humanas/metabolismo , Glândulas Mamárias Humanas/patologia , Fitoestrógenos/efeitos adversos , Fatores de Proteção , Receptores Estrogênicos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Medição de Risco , Fatores de Risco , Transdução de Sinais/efeitos dos fármacos
11.
Int J Dev Neurosci ; 71: 146-155, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30232036

RESUMO

Prenatal and early postnatal environments can permanently influence health throughout life. Early overnutrition increases the risk to develop chronic diseases. Conversely, the intake of flavonoids and exercise practice during pregnancy seem to promote long-term benefits to offspring. We hypothesized that benefic interventions during pregnancy could protect against possible postnatal neurochemical alterations caused by overnutrition induced by reduced litter size. Female Wistar rats were divided into four groups: (1) sedentary + vehicle, (2) sedentary + naringenin, (3) swimming exercise + vehicle, and (4) swimming exercise + naringenin. One day after birth, the litter was culled to 8 pups (control) or 3 pups (overfed) per dam, yielding control and overfed subgroups for each maternal group. Serum of 21-days-old pups was collected, also the cerebellum, hippocampus, and hypothalamus were dissected. Litter size reduction increased fat mass and enhanced body weight. Maternal interventions, when isolated, caused reduced glucose serum levels in offspring nurtured in control litters. In the cerebellum, reducing the litter size decreased the activity of thioredoxin reductase, which was prevented by maternal supplementation with naringenin. Hippocampus and hypothalamus have shown altered antioxidant enzymes activities in response to litter size reduction. Interestingly, when maternal exercise and naringenin supplementation were allied, the effect disappeared, suggesting a concurrent effect of the two maternal interventions. In conclusion, exercise or naringenin supplementation during pregnancy can be important interventions for combating the increasing rates of overweight during the infancy and its related neurochemical changes, especially when applied isolated.


Assuntos
Fenômenos Fisiológicos da Nutrição Animal , Antioxidantes/farmacologia , Encéfalo/metabolismo , Tamanho da Ninhada de Vivíparos/fisiologia , Condicionamento Físico Animal/fisiologia , Desmame , Animais , Animais Recém-Nascidos , Peso Corporal/fisiologia , Antagonistas de Estrogênios/administração & dosagem , Feminino , Flavanonas/administração & dosagem , Glutationa Peroxidase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Hipernutrição/metabolismo , Oxidantes/metabolismo , Gravidez , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Natação/fisiologia
12.
BMC Cancer ; 18(1): 817, 2018 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-30103729

RESUMO

BACKGROUND: Breast cancer is the most common malignancy in women worldwide. Although the endocrine therapy that targets estrogen receptor α (ERα) signaling has been well established as an effective adjuvant treatment for patients with ERα-positive breast cancers, long-term exposure may eventually lead to the development of acquired resistance to the anti-estrogen drugs, such as fulvestrant and tamoxifen. A better understanding of the mechanisms underlying antiestrogen resistance and identification of the key molecules involved may help in overcoming antiestrogen resistance in breast cancer. METHODS: The whole-genome gene expression and DNA methylation profilings were performed using fulvestrant-resistant cell line 182R-6 and tamoxifen-resistant cell line TAMR-1 as a model system. In addition, qRT-PCR and Western blot analysis were performed to determine the levels of mRNA and protein molecules. MTT, apoptosis and cell cycle analyses were performed to examine the effect of either guanine nucleotide-binding protein beta-4 (GNB4) overexpression or knockdown on cell proliferation, apoptosis and cell cycle. RESULTS: Among 9 candidate genes, GNB4 was identified and validated by qRT-PCR as a potential target silenced by DNA methylation via DNA methyltransferase 3B (DNMT3B). We generated stable 182R-6 and TAMR-1 cell lines that are constantly expressing GNB4 and determined the effect of the ectopic GNB4 on cell proliferation, cell cycle, and apoptosis of the antiestrogen-resistant cells in response to either fulvestrant or tamoxifen. Ectopic expression of GNB4 in two antiestrogen resistant cell lines significantly promoted cell growth and shortened cell cycle in the presence of either fulvestrant or tamoxifen. The ectopic GNB4 induced apoptosis in 182R-6 cells, whereas it inhibited apoptosis in TAMR-1 cells. Many regulators controlling cell cycle and apoptosis were aberrantly expressed in two resistant cell lines in response to the enforced GNB4 expression, which may contribute to GNB4-mediated biologic and/or pathologic processes. Furthermore, knockdown of GNB4 decreased growth of both antiestrogen resistant and sensitive breast cancer cells. CONCLUSION: GNB4 is important for growth of breast cancer cells and a potential target for treatment.


Assuntos
Neoplasias da Mama/tratamento farmacológico , DNA (Citosina-5-)-Metiltransferases/genética , Subunidades beta da Proteína de Ligação ao GTP/genética , Tamoxifeno/administração & dosagem , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Metilação de DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Estradiol/administração & dosagem , Estradiol/efeitos adversos , Estradiol/análogos & derivados , Antagonistas de Estrogênios/administração & dosagem , Receptor alfa de Estrogênio/antagonistas & inibidores , Feminino , Fulvestranto , Técnicas de Silenciamento de Genes , Genoma Humano , Humanos , Células MCF-7 , Tamoxifeno/efeitos adversos
13.
Neuroimage Clin ; 20: 110-118, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30094161

RESUMO

Nearly three out of four survivors experience Cancer-Related Cognitive Impairment (CRCI) for months or years following treatment. Both clinical and animal studies point to the hippocampus as a likely brain region affected in CRCI, however no previous study has investigated the functional connectivity of the hippocampus in CRCI. We compared hippocampal connectivity in cancer survivors and healthy controls and tested the relationship between functional connectivity differences and measures of objective and subjective cognition. Exploratory analysis of inflammatory markers was conducted in a small subset of participants as well. FMRI data were acquired during a memory task from 16 breast cancer survivors and 17 controls. The NIH Toolbox was used to assess cognitive performance and Neuro-QoL was used to measure self-reported cognitive concerns. Whole-brain group-level comparisons identified clusters with different connectivity to the hippocampus in survivors versus controls during task. Average connectivity was extracted from clusters of significant difference between the groups and correlated with cognitive performance and subjective report. Survivors performed worse on a test of episodic memory and reported greater cognitive concern than controls. Exploratory analysis found higher IL6 in cancer survivors compared to controls. Cancer survivors demonstrated higher connectivity of hippocampus with left cuneus, left lingual, left precuneus, and right middle prefrontal gyrus compared with controls. In survivors, higher task-related hippocampal-cortical connectivity was related to worse subjective measures of cognitive concern. Of the four significant clusters, higher connectivity of the precuneus with hippocampus was significantly associated with worse cognitive concern in survivors. The observed greater hippocampal-cortical connectivity in survivors compared to controls is the first reported fMRI biomarker of subjective concern, and may represent a compensatory response to cancer and its treatments. This compensation could explain, in part, the subjective feelings of cognitive impairment that were reported by survivors.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Cognição/fisiologia , Antagonistas de Estrogênios/administração & dosagem , Hipocampo/diagnóstico por imagem , Rede Nervosa/diagnóstico por imagem , Autorrelato , Adulto , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante/efeitos adversos , Cognição/efeitos dos fármacos , Disfunção Cognitiva/sangue , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/diagnóstico por imagem , Estudos Transversais , Antagonistas de Estrogênios/efeitos adversos , Feminino , Hipocampo/efeitos dos fármacos , Humanos , Mediadores da Inflamação/sangue , Imagem por Ressonância Magnética/métodos , Rede Nervosa/efeitos dos fármacos , Estimulação Luminosa/métodos , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversos
14.
Eur Urol Focus ; 4(3): 321-323, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-30131284

RESUMO

The use of testosterone to treat hypogonadal symptoms has increased during the past decade. Consequently, one clinical challenge that has arisen is how to approach the young and treatment-naïve hypogonadal patient who is still within his reproductive years and may desire children in the future. Testosterone is known to suppress the hypothalamic-pituitary-gonadal axis resulting in suppressed spermatogenesis. There is a concern that, in some men, prolonged testosterone use may result in permanent spermatogenic failure. PATIENT SUMMARY: In this review, we discuss the risks and benefits of available treatment options for the young hypogonadal patient for whom future fertility is an important consideration. Fortunately, alternatives such as clomiphene citrate and human chorionic gonadotropin have been shown to increase endogenous testosterone production. However, their efficacy as treatments for hypogonadal symptoms is still under debate.


Assuntos
Clomifeno/uso terapêutico , Fertilidade/efeitos dos fármacos , Terapia de Reposição Hormonal/métodos , Hipogonadismo/tratamento farmacológico , Testosterona/uso terapêutico , Gonadotropina Coriônica/administração & dosagem , Gonadotropina Coriônica/uso terapêutico , Clomifeno/administração & dosagem , Antagonistas de Estrogênios/administração & dosagem , Antagonistas de Estrogênios/uso terapêutico , Fertilidade/fisiologia , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Masculino , Espermatogênese/efeitos dos fármacos , Testosterona/administração & dosagem
15.
BJU Int ; 122(4): 688-694, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29873446

RESUMO

OBJECTIVES: To assess the efficacy and safety of combination therapy with clomiphene citrate (CC) and anastrozole (AZ) for male hypoandrogenism. PATIENTS AND METHODS: We identified patients treated with a combination of CC + AZ in the period 2014 to 2017. Data were gathered on patient characteristics and laboratory values at baseline. Total testosterone, bioavailable testosterone, oestradiol and testosterone:oestradiol ratio were measured before combination therapy (treatment with CC only) and at CC + AZ combination therapy follow-ups. Treatment side effects were recorded; prostatic-specific antigen and haematocrit levels were measured to assess safety after 6 months. As a secondary outcome, semen characteristics were compared at baseline and after at least 3 months of combination therapy when these data were available. Data were analysed using a paired t-test and Wilcoxon's signed-rank test. RESULTS: A total of 51 men were included, with a mean age of 35.4 ± 7.4 years and a mean body mass index of 35.0 ± 8.0 kg/m2 . After CC treatment, total testosterone, bioavailable testosterone, and oestradiol levels all significantly increased. AZ was added in all patients with hyperoestrogenaemia (oestradiol >50 pg/mL) or a testosterone:oestradiol ratio <10. CC + AZ therapy maintained therapeutic total testosterone and bioavailable testosterone levels while also normalizing oestradiol levels and testosterone:oestradiol ratio. Eleven patients experienced side effects: anxiety/irritability, n = 5; decreased libido, n = 4; elevated (>54%) haematocrit, n = 2. CONCLUSION: Combination therapy with CC + AZ is an effective and safe alternative for patients with elevated oestradiol level or low testosterone:oestradiol ratio.


Assuntos
Anastrozol/administração & dosagem , Clomifeno/administração & dosagem , Antagonistas de Estrogênios/administração & dosagem , Hipogonadismo/tratamento farmacológico , Infertilidade Masculina/tratamento farmacológico , Adulto , Anastrozol/farmacologia , Clomifeno/farmacologia , Antagonistas de Estrogênios/farmacologia , Seguimentos , Humanos , Hipogonadismo/sangue , Hipogonadismo/fisiopatologia , Infertilidade Masculina/etiologia , Infertilidade Masculina/fisiopatologia , Masculino , Resultado do Tratamento
16.
J Neuroimmunol ; 321: 72-82, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29957391

RESUMO

Recent evidence suggests that clozapine and quetiapine (atypical antipsychotics), tamoxifen (selective-estrogen receptor modulator) and pioglitazone (PPARγ agonist) may improve functional recovery in multiple sclerosis (MS). We have compared the effectiveness of oral administration of these drugs, beginning at peak disease, at reducing ascending paralysis, motor deficits and demyelination in mice subjected to experimental autoimmune encephalomyelitis (EAE). Mice were immunized with an immunogenic peptide corresponding to amino acids 35-55 of the myelin oligodendrocyte glycoprotein (MOG35-55) in complete Freund's adjuvant and injected with pertussis toxin to induce EAE. Unlike clozapine, quetiapine and tamoxifen, administration of pioglitazone beginning at peak disease decreased both clinical scores and lumbar white matter loss in EAE mice. Using kinematic gait analysis, we found that pioglitazone also maintained normal movement of the hip, knee and ankle joints for at least 44 days after MOG35-55 immunization. This long-lasting preservation of hindleg joint movements was accompanied by reduced white matter loss, microglial and macrophage activation and the expression of pro-inflammatory genes in the lumbar spinal cords of EAE mice. These results support clinical findings that suggest pioglitazone may reduce the progressive loss of motor function in MS by decreasing inflammation and myelin damage.


Assuntos
Clozapina/administração & dosagem , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Pioglitazona/administração & dosagem , Fumarato de Quetiapina/administração & dosagem , Tamoxifeno/administração & dosagem , Administração Oral , Animais , Antidepressivos/administração & dosagem , Encefalomielite Autoimune Experimental/metabolismo , Antagonistas de Estrogênios/administração & dosagem , Feminino , Hipoglicemiantes/administração & dosagem , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Antagonistas da Serotonina/administração & dosagem , Resultado do Tratamento
17.
Domest Anim Endocrinol ; 65: 49-55, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29894894

RESUMO

It is established that the ovary and estrogen are essential to bovine mammary development with the onset of puberty. Recent studies have shown that ovariectomy in the very early prepubertal period, well before onset of puberty, also dramatically impairs mammary growth. Similarly, prepubertal heifers treated with the antiestrogen tamoxifen (TAM) also exhibit markedly impaired mammary growth in correspondence with reduced estrogen receptor α (ESR1) expression. Our objective was to evaluate the effect of TAM on the mammary stroma and specifically to determine if the reported decrease in mammary development was related to changes in TAM-induced alterations in the stroma surrounding the mammary parenchyma. Briefly, 16 Holstein heifers calves were randomly assigned to one of 2 treatment groups: TAM-injected or control. Calves were administered TAM (0.3 mg kg1 d1) or placebo from 28 to 120 d of age. At day 120, calves were euthanized and udders removed. Mammary tissue from near the boundary between the parenchyma and surrounding mammary fat pad was collected for histology and morphometric analysis, expression of selected extracellular matrix-related genes, and quantitation of stromal collagen deposition by study of Sirius Red-stained tissue sections imaged with polarized light. Compared with tissue from control heifers, TAM heifers frequently exhibited areas with abundant fibroblasts and mesenchymal cells especially within the intralobular stroma, as well as less complex ductal structures. Among the array of extracellular matrix-related genes tested, only a small difference (P < 0.05) in expression of laminin was found between treatments. The relative tissue area occupied by stromal tissue was not impacted by treatment. However, the deposition of collagen within the stromal tissue was more than doubled (P < 0.0001) in TAM-treated heifers. These data suggest that blocking ESR1 expression with TAM allows for excessive collagen deposition in the stroma surrounding the developing epithelial structures and that this interferes with both the degree of overall mammary parenchymal development, as well as the pattern of normal ductal morphogenesis.


Assuntos
Bovinos , Colágeno/metabolismo , Antagonistas de Estrogênios/administração & dosagem , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/crescimento & desenvolvimento , Tamoxifeno/administração & dosagem , Animais , Colágeno/análise , Receptor alfa de Estrogênio/análise , Receptor alfa de Estrogênio/antagonistas & inibidores , Feminino , Glândulas Mamárias Animais/química , Placebos , Distribuição Aleatória
18.
BJU Int ; 122(5): 889-897, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29772111

RESUMO

OBJECTIVES: To compare serum testosterone response and symptom improvement in men with hypogonadism in response to treatment with clomiphene citrate (CC), human chorionic gonadotropin (hCG), or a combination of both therapies. PATIENTS AND METHODS: A total of 282 men with hypogonadism, wishing to preserve their fertility, were randomized to one of three treatment arms: CC 50 mg (n = 95); 5000 IU hCG injections twice weekly (n = 94); or a combination of both therapies (CC + hCG; n = 94). All participants had complete medical history and had undergone thorough physical examination, including body mass index (BMI) assessment. Laboratory tests included serum total testosterone and glycated haemoglobin (HbA1c) measurements. Quantitative Androgen Deficiency in the Aging Male (qADAM) questionnaire scores were also recorded. Morning samples of total serum testosterone levels were assessed at three time points: baseline, 1 and 3 months. RESULTS: Testosterone levels increased at 1 and 3 months in all three groups. The mean baseline testosterone level was 2.31 ± 0.66 nmol/L, BMI was 30.8 ± 6.2 kg/m2 , and qADAM score was 20.5 ± 3.8. Testosterone levels increased in all groups at all time points, with a final mean value of 5.17 ± 1.77 nmol/L (223% increase) with no statistically significant difference among the groups. qADAM scores had increased in all groups at 1 month (CC group: 6.36; hCG group: 5.08; CC + hCG group: 7.26) and at 3 months (CC group: 12.73; hCG group: 11.82; CC + hCG group: 15.13) with a significant difference in intergroup analysis for the CC + hCG group compared with the other two groups (P < 0.01). CONCLUSIONS: All three treatments were equally effective in restoring testosterone levels. Single-agent CC is simple, cheap and may be used as treatment for hypogonadism when maintenance of fertility is desired. This approach seems to be as effective as either hCG alone or a combination of hCG and CC.


Assuntos
Gonadotropina Coriônica/uso terapêutico , Clomifeno/uso terapêutico , Hipogonadismo/tratamento farmacológico , Testosterona/sangue , Testosterona/deficiência , Administração Oral , Adulto , Gonadotropina Coriônica/administração & dosagem , Clomifeno/administração & dosagem , Antagonistas de Estrogênios/administração & dosagem , Antagonistas de Estrogênios/uso terapêutico , Humanos , Hipogonadismo/sangue , Infertilidade Masculina/prevenção & controle , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade
19.
J Obstet Gynaecol Res ; 44(6): 1107-1117, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29644764

RESUMO

AIM: The aim of the study was to compare simultaneously started clomiphene citrate (CC) and gonadotropins (Gn) with gonadotropins alone in conventional antagonist regimes with respect to fresh-cycle live births, cumulative live births and cost of ovarian stimulation per started cycle. METHODS: This was a single-center prospective cohort study conducted over 1 year. Women undergoing autologous in vitro fertilization (IVF) treatment in antagonist protocols and who consented to participate in the study were divided into two cohorts. The CC cohort (n = 86) received 50 mg CC for 5 days and individualized Gn daily until the hCG trigger, both starting from day 2 and antagonist daily from day 8 of menstrual cycle. The Gn-only cohort (n = 349) received individualized Gn from day 2 and the antagonist from day 7 of menstrual cycle. IVF outcomes and cost of stimulation were compared between two cohorts across expected ovarian response categories. RESULTS: The CC cohort used a mean lower dose of Gn (1741.38 ± 604.46 vs 1980.54 ± 686.42; MD = -239.16; 95%CI = -348.03 to -189.24; P = 0.003) over fewer days (8.54 ± 1.86 vs 9.25 ± 1.97; MD =-0.71;95% CI = -1.17 to -0.25; P = 0.0026) to achieve similar retrieved oocytes, (9.19 ± 5.92 vs 9.36 ± 6.96; MD = -0.17; 95%CI -1.77 to + 1.43; P = 0.83), positive bhCG rates (40% vs 29.6%, MD = 10.4%; OR = 1.65, 95%CI = 0.95-2.86; P = 0.078) and live births in fresh cycles (32.31% vs 21.30%; MD = 11.01%; OR = 1.76; 95%CI = 0.97-3.19; P = 0.06) and cumulative live births per initiated cycle (30.23% vs 20.34%; MD = 9.89%; OR = 1.697; 95%CI = 0.99-2.88; P = 0.0501). The dose lowering achieved a 28-40% reduction in the cost of stimulation, which was most noticeable in the hyper-responder category for both hMG cycles, (Rs.11 602.3 ± 3365.9 vs 19615 ± 2677.1; MD = -8012.7; %age reduction: 40.8%; P = 0.0007) and recombinant FSH cycles (Rs. 22 459.6 ± 6255.3 vs 33 022.1 ± 9891.2; MD: -10 562; %age reduction: -32%; P = 0.0001). CONCLUSION: CC started simultaneously with Gn in antagonist regimes helps lower the cost of stimulation without affecting IVF outcomes.


Assuntos
Clomifeno/farmacologia , Antagonistas de Estrogênios/farmacologia , Fertilização In Vitro/estatística & dados numéricos , Gonadotropinas/farmacologia , Nascimento Vivo/epidemiologia , Indução da Ovulação/economia , Adulto , Clomifeno/administração & dosagem , Quimioterapia Combinada , Antagonistas de Estrogênios/administração & dosagem , Feminino , Gonadotropinas/administração & dosagem , Humanos , Gravidez
20.
Expert Rev Clin Pharmacol ; 11(4): 439-458, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29505313

RESUMO

INTRODUCTION: The frequency of late-onset hypogonadism (LOH) ranges between 2 and 15%. Up to 85% of LOH is due to a functional impairment of the hypothalamus-pituitary-testicular axis, mostly secondary to metabolic conditions. Areas covered: This paper provides a comprehensive review of all the available medications for treating LOH, including antiestrogens, gonadotropins and testosterone therapy (TTh). In addition, the evidence on clinical outcomes of these treatments is provided by meta-analyzing the results from the available randomized clinical trials. Expert commentary: The present data indicate that antiestrogens are able to increase testosterone levels without changing gonadotropins or even increasing them. Therefore, they may maintain, and even to stimulate spermatogenesis. However, their efficacy in treating LOH-associated symptoms has been scarcely tested and their use in LOH is off-label. In contrast, gonadotropins are indicated for hypogonadism, in particular when fertility is required. Information on the effects of gonadotropins on LOH is scanty and the impractical administration limits their use. TTh can be administered with different modalities, making it a suitable option for LOH, when fertility is not desired. The available meta-analyses show that TTh is able to improve sexual function and body composition, with more evident results obtained with transdermal and injectable preparations.


Assuntos
Gonadotropinas/administração & dosagem , Hipogonadismo/tratamento farmacológico , Testosterona/administração & dosagem , Antagonistas de Estrogênios/administração & dosagem , Fertilidade/efeitos dos fármacos , Humanos , Hipogonadismo/fisiopatologia , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Testosterona/metabolismo
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