by Yu Hon Ming. / Thesis (M.Sc.)--Chinese University of Hong Kong, 1996. / Includes bibliographical references (leaves 70-74). / Abstract --- p.ii / Acknowledgements --- p.v / Abbreviations --- p.vi / List of tables and figures --- p.viii / Chapter Chapter I. --- Introduction / Chapter 1. --- Background --- p.1 / Chapter 2. --- Physiology of prostate --- p.3 / Chapter 2.1. --- Prostate --- p.3 / Chapter 2.2. --- Embryonic development of prostate --- p.3 / Chapter 2.3. --- Anatomy of prostate --- p.5 / Chapter 2.4. --- The role of steroids in the growth of prostate --- p.7 / Chapter 2.4.1. --- T --- p.7 / Chapter 2.4.2. --- DHT --- p.8 / Chapter 2.5. --- 5α-reductase --- p.10 / Chapter 3. --- Pathophysiology of BPH --- p.11 / Chapter 3.1. --- Anatomic progression of BPH --- p.11 / Chapter 3.2. --- Epidemiology of BPH --- p.11 / Chapter 3.3. --- Pathogenesis of BPH --- p.12 / Chapter 3.4. --- Clinical manifestations of BPH --- p.13 / Chapter 3.5. --- Diagnosis of BPH --- p.14 / Chapter 4. --- Treatment of BPH --- p.15 / Chapter 4.1. --- a-adrenergic antagonist --- p.16 / Chapter 4.2. --- DHT hypothesis --- p.16 / Chapter 4.3. --- 5α-reductase inhibitor --- p.17 / Chapter 5. --- Radioimmunoassay of DHT --- p.21 / Chapter 6. --- Objectives --- p.22 / Chapter Chapter II. --- Materials and methods --- p.23 / Chapter 1. --- Materials and methods for development of specific RIA for serum DHT --- p.23 / Chapter 1.1. --- Materials --- p.23 / Chapter 1.2. --- Methods --- p.23 / Chapter 1.2.1. --- Antiserum for DHT-RIA --- p.23 / Chapter 1.2.1.1. --- Optimal antibody titre and dilution curve for DHT-RIA --- p.24 / Chapter 1.2.1.2. --- Cross-reactivity with related steroids --- p.25 / Chapter 1.2.2. --- KMnO4 treatment of T antiserum for DHT-RIA --- p.26 / Chapter 1.2.2.1. --- Optimization of KMnO4 treatment --- p.26 / Chapter 1.2.2.2. --- Upper limit of oxidizing power of 0.5% KMnO4 --- p.27 / Chapter 1.2.2.3. --- Efficiency and background effect of 0.5% KMnO4 oxidation on DHT-RIA --- p.28 / Chapter 1.2.3. --- Characteristic of DHT-RIA --- p.29 / Chapter 1.2.3.1. --- Standard preparation --- p.29 / Chapter 1.2.3.2. --- Blank preparation --- p.30 / Chapter 1.2.3.3. --- Control preparation --- p.31 / Chapter 1.2.3.4. --- Sample preparation --- p.31 / Chapter 1.2.3.5. --- Dextran-coated charcoal --- p.31 / Chapter 1.2.3.6. --- DHT-RIA procedure --- p.32 / Chapter 1.2.3.7. --- Sensitivity test for DHT-RIA --- p.33 / Chapter 1.2.3.8. --- Linearity test for DHT-RIA --- p.33 / Chapter 1.2.3.9. --- Recovery test for DHT-RIA --- p.34 / Chapter 1.2.3.10. --- Precision test for DHT-RIA --- p.34 / Chapter 2. --- Materials and methods for establishing reference range of DHT in Chinese males and females --- p.35 / Chapter 2.1. --- Samples --- p.35 / Chapter 2.2. --- Methods --- p.35 / Chapter 2.2.1. --- DHT determination --- p.35 / Chapter 2.2.2. --- T determination --- p.36 / Chapter 2.2.3. --- Cholesterol determination --- p.37 / Chapter 3. --- Materials and methods for a small clinical trial on the usefulness of 5α-reductase inhibitor (finasteride) in the treatment of BPH --- p.38 / Chapter 3.1. --- Samples --- p.38 / Chapter 3.2. --- Methods --- p.38 / Chapter 4. --- Statistical analysis --- p.39 / Chapter Chapter III. --- Result --- p.40 / Chapter 1. --- DHT-RIA --- p.40 / Chapter 1.1. --- Antiserum for DHT-RIA / Chapter 1.1.1. --- Optimal antibody titre for DHT-RIA --- p.40 / Chapter 1.1.2. --- Cross reactivity with related steroids --- p.42 / Chapter 1.2. --- KMnO4 treatment of T antiserum for DHT-RIA --- p.43 / Chapter 1.2.1. --- Optimization of KMnO4 treatment --- p.43 / Chapter 1.2.2. --- Upper limit of oxidizing power of 0.5% KMnO4 --- p.44 / Chapter 1.2.3. --- Efficiency and background effect of 0.5% KMnO4 treatment on DHT-RIA --- p.45 / Chapter 1.3. --- Characterization of the DHT-RIA --- p.47 / Chapter 2. --- Reference range for DHT in Chinese males and females --- p.51 / Chapter 2.1. --- Reference range of DHT in three different study groups --- p.51 / Chapter 2.2. --- Ratio of DHT/T in Chinese males and Caucasian males --- p.52 / Chapter 2.3. --- Correlation studies --- p.53 / Chapter 3. --- Results of small clinical trial --- p.54 / Chapter 3.1. --- Mean serum analyte changes during the course --- p.54 / Chapter 3.2. --- Changes in analyte concentrations during the course --- p.56 / Chapter 3.3. --- Difference in mean serum analytes between BPH males predose level and normal males with and without age matching --- p.57 / Chapter 3.4. --- "The response, percentage change of DHT and DHT/T ratio of individual patient during the course of study" --- p.58 / Chapter Chapter IV. --- Discussion --- p.59 / Chapter 1. --- Radioimmunoassay for DHT --- p.59 / Chapter 2 . --- Establishment of DHT reference range in Chinese males and females --- p.62 / Chapter 3. --- The usefulness of 5a reductase inhibitor in the treatment of BPH --- p.65 / Chapter Chapter V. --- Conclusion --- p.69 / References --- p.70

Orientadores: Luis Antonio Violin Dias Pereira, Suzana de Fatima Paccola Mesquita / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-20T22:34:25Z (GMT). No. of bitstreams: 1 Garcia_PatrickVianna_D.pdf: 2682268 bytes, checksum: c80303a2f196fc3cdb21e73865600ba4 (MD5) Previous issue date: 2012 / Resumo: Durante o processo de maturação epididimária, proteínas secretadas pelo epidídimo interagem com os espermatozoides modificando-os funcionalmente. Cerca de 75% das proteínas que participam da maturação epididimária são secretadas pelas células epiteliais do segmento inicial e cabeça do epidídimo e 48% destas proteínas tem a síntese dependente de dihidrotestosterona (DHT), a qual é sintetizada a partir da testosterona pela ação da enzima 5 ? redutase. A DHT é de extrema importância para a fisiologia do sistema reprodutor masculino. Níveis elevados de DHT na vida adulta podem predispor a vários distúrbios, tais como a alopecia androgênica. Com o intuito de se minimizar os efeitos da DHT, a finasterida foi o primeiro inibidor da 5 ? redutase que recebeu aprovação clínica para o tratamento desses distúrbios.Um público cada vez mais jovem utiliza a finasterida como um método preventivo e paliativo contra a alopecia androgênica, com isso, estudos dos efeitos da finasterida no sistema reprodutor masculino são de grande interesse clínico. O ojetivo desse estudo foi avaliar as possíveis alterações no segmento da cabeça do epidídidmo e na qualidade espermática em animais submetidos ao tratamento agudo (15 dias), crônico (56 dias) e animais que tiveram o tratamento (agudo e crônico) interrompido por um período de 30 dias. Na administração aguda (15 dias) de finasterida em ratos observou-se algumas alterações na integridade da membrana plasmática do espermatozoide. A administração crônica (56 dias) de finasterida em ratos leva a alterações no epidídimo, tais como: redução do peso, alterações morfométricas-estereológicas, diminuição do tempo de trânsito do espermatozoide, redução da motilidade, alterações na integridade da membrana do espermatozóide e redução nos parâmetros de fertilidade desses animais. Mesmo com a interrupção do tratamento com finasterida (por 30 dias) a qualidade do espermatozóide continua comprometida. Dessa forma, estudos adicionais devem ser realizados para complementar o conhecimento existente sobre a fisiologia do epidídimo após a depleção DHT, sobre o tempo que necessário para a recuperação dos parâmetros de fertilidade após a interrupção do tratamento com finasterida, e se estes parâmetros podem ser totalmente recuperados / Abstract: During epididymal maturation, proteins secreted by epididymis functionally interact with the spermatozoa modifying it. About 75% of the proteins that participate in the epididymal maturation are secreted by the epithelial cells of the initial segment and caput of the epididymis and 48% of the synthesis is dependent on dihydrotestosterone (DHT), which is synthesized from testosterone by the action of the enzyme 5 ? reductase.The DHT is extremely important for the physiology of the male reproductive system. High levels of DHT in adulthood may predispose to various disorders such as androgenic alopecia. In order to minimize the effects of DHT, medications were produced with the purpose of inhibit the action of 5 ?-reductase and among those medications the finasteride was the first 5 ? reductase inhibitor that received clinical approval for the treatment of these disorders. A public increasingly young uses finasteride as a preventive and palliative method and against androgenic alopecia, in this way; studies of the effects of finasteride in the male reproductive system are of clinical and commercial interest. The aim of this study was to evaluate the possible alterations in the caput epididymis and sperm quality in animals submitted to acute (15 days) and chronic (56 days) treatment and animals with 30 days post- treatment. Acute administration of finasteride in rats (15 days) was observed reduction in sperm membrane integrity. Chronic administration of finasteride in rats (56 days), leads to changes in the epididymis, such as weight reduction, morphometric-stereological changes, decreased transit time of sperm, motility of the sperm membrane integrity and consequently in fertility parameters of these animals. Even with the interruption of treatment with finasteride (30 days) sperm quality remains committed. Thus, further studies should be performed to complement the existing knowledge on the physiology of the epididymis after DHT depletion, on the time that is needed for the recovery of fertility parameters after interruption of finasteride treatment, and if it these parameters can be fully recovered / Doutorado / Histologia / Doutor em Biologia Celular e Estrutural

Master of Science / Department of Human Nutrition / Brian Lindshield / 5α-reductase 1 (5αR1) and 5α-reductase 2 (5αR2) convert testosterone into the more potent androgen, dihydrotestosterone (DHT), that is responsible for regulating prostate growth and proliferation. 5αR2 is the main isoenzyme in normal prostate tissue, however prostate tumors have increased 5αR1 and decreased or unchanged 5αR2 expression. Previously, finasteride (5αR2 inhibitor) treatment begun 3 weeks after tumor implantation had no effect on Dunning R3327-H rat prostate tumor growth. We believe the tumor compensated for finasteride treatment by increasing tumor 5αR1 activity to produce dihydrotestosterone to stimulate its growth. We hypothesize that finasteride treatment would not significantly alter tumor growth even if begun before tumor implantation, while dutasteride (dual 5αR1 & 5αR2 inhibitor) treatment would decrease tumor growth regardless if treatment is begun before or after tumor implantation. Sixty, 8-week old male nude mice were randomized to Control, Pre-Finasteride, Post-Finasteride, Pre-Dutasteride and Post-Dutasteride diet groups (all diets contained 83.3 mg drug/kg diet). Pre groups began their treatment diets 1-2 weeks prior to tumor implantation, while post groups began their treatment diets 3 weeks after tumor implantation. Tumors were implanted by subcutaneous injection of 1 x 10⁵ WPE1-NA22 human prostate cancer cells in Matrigel™ and allowed to grow for 22 weeks. Tumor areas, body weights, and feed intakes were measured weekly. At study conclusion, prostate and seminal vesicle weights were significantly decreased in all treatment groups versus the control. Dutasteride intake also significantly reduced seminal vesicle weights compared to finasteride intake. There were no significant differences in final tumor areas or tumor weights between groups, likely due to poor tumor growth. In follow-up studies, proliferation of WPE1-NA22 prostate cancer cells, and its parent line RWPE-1 prostate epithelial cells, were unaltered by treatment with testosterone, DHT, or the synthetic androgen mibolerone, suggesting that these cell lines are not androgen-sensitive. Thus, the lack of response to androgen treatment by WPE1-NA22 prostate cancer cells may explain the inadequate tumor growth observed.

Resumo: A Síndrome da Dor Pélvica Crônica (SDPC) é uma nova categoria na classificação atual das prostatites. A causa da SDPC é desconhecida, a teoria mais aceita é o refluxo intraprostático. Não há estudo que comprove qual o melhor tratamento. A finasterida, uma das drogas utilizadas para o tratamento, é um antiandrogênio que bloqueia a enzima 5-alfa redutase, diminuindo o tamanho da próstata. A finasterida agiria na SDPC reduzindo o tecido glandular prostático, diminuindo a tensão intraprostática e conseqüentemente o refluxo intraprostático. Avaliar a efetividade e a segurança da finasterida no tratamento da SDPC. Uma revisão sistemática de ensaios clínicos aleatorizados foi realizada, sem restrições de língua, datas ou outras considerações. As fontes de informação utilizadas foram Medline, Registro de Ensaios Controlados da Cochrane, Embase, Lilacs e SciELO. Contato com autores de artigos, laboratórios que comercializam finasterida e revistas médicas em geral e específicas. Foram incluídos pacientes com diagnóstico da SDPC tipo IIIA e/ou IIIB, participantes de estudos em que foi comparado o uso da finasterida com placebo ou outro tipo de tratamento. Os desfechos clínicos avaliados foram os questionários dos sintomas prostáticos, exames para avaliar a melhora bioquímica ou variável fisiológica e eventos adversos. A coleta de dados e análise foram realizadas por dois revisores que inspecionaram as referências encontradas independentemente pela estratégia de busca e aplicaram os critérios de inclusão nos estudos selecionados usando os critérios de qualidade metodológica descritos no Cochrane handbook. A escala de Jadad e Schutz também foram usadas. Os dados dos estudos elegíveis foram sumarizados em metanálise. A análise estatística foi realizada utilizando o ...(Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Chronic Pelvic Pain Syndrome (CPPS) is a new category in the current classification of prostatitis. The cause of CPPS is unknown; the most accepted theory is intraprostatic ductal reflux. The best treatment is not known. Finasteride, a specific type II 5a-reductase inhibitor, decreases the size of the prostate. A potential mechanism of action for finasteride is the reduction of the intraprostatic tension due to the glandular shrinkage, decreasing the intraprostatic ductal reflux. To assess the effectiveness and harms of finasteride in the treatment of CPPS. A systematic review of randomized controlled trials was performed, with no restrictions on language, dates or other considerations. The information sources used were Medline, the Cochrane Central Register of Controlled Trials, Embase, Lilacs and SciELO; contact authors of articles, laboratories that work with finasteride and general and specific medical magazines. It included participants with a diagnosis of CPPS type IIIA and/or IIIB taking part of studies comparing the use of finasteride to placebo or another type of treatment. The clinical outcomes evaluated were the questionnaires of prostatic symptoms, improvement in biochemical or physiologic variables and adverse events. The collecting data and analysis were performed by two reviewers that checked the found references independently by the search strategy, and applied the inclusion criteria in the selected studies using the criteria of methodological quality described on Cochrane Handbook. The Jadad and the Schutz scales were also used. After finding all eligible studies, the data were summarized in meta-analysis. The statistical analysis was undertaken using the MetaView statistical program within Review Manager software of the Cochrane Collaboration. Three studies with 181 patients were included. The length ...(Complete abstract click electronic access below) / Orientador: Antônio José Maria Catâneo / Coorientador: Paulo Eduardo de Oliveira Carvalho / Banca: Tânia Ruiz / Banca: Bernardo Garcia de Oliveira Soares / Mestre

A hiperplasia prostática benigna (HPB) é a doença de maior incidência em cães senis. Assim, a caracterização da patogênese da doença é de suma importância, tal como a avaliação de animais submetidos a tratamento clínico ou cirúrgico (terapia com finasterida e orquiectomia). Neste contexto, o objetivo dessa pesquisa foi caracterizar as alterações seminais, hormonais e hemodinâmicas da próstata e testículos de cães com HPB, submetidos a diferentes tratamentos. Assim, foram utilizados 25 cães entre doentes e hígidos e empregados as seguintes ferramentas experimentais: ultrassonografia Doppler com o intuito de caracterizar mudanças hemodinâmicas da próstata e testículos, imunohistoquímica e PCR para a expressão do fator VEGF na próstata, avaliação morfohistológica dos testículos, dosagem hormonal (testosterona, estrógeno e di-hidrotestosterona), análise andrológica, seminal e do estresse oxidativo e enzimas antioxidantes. Foi possível observar redução do escore de vascularização prostático (Doppler Colorido) em animais tratados com finasterida ou orquiectomizados, além de redução do volume prostático. O tratamento com finasterida reduziu a imunomarcação para o VEGF na próstata, porém a orquiectomia também inibiu a expressão gênica do VEGF. A finasterida, ainda, reduziu os níveis séricos de di-hidrotestosterona, não causando impactos significativos na qualidade seminal. Já a HPB promoveu alterações significativas na concentração de testosterona e na qualidade seminal (baixa concentração espermática, alteração da cinética espermática e altos índices de fragmentação de DNA espermático). Em conclusão, a atividade prostática do VEGF é dependente da ocorrência de HPB e dos diferentes tratamentos empregados, promovendo diferenças na vascularização e volume prostático. Ademais, cães com HPB possuem alterações no perfil hormonal e na espermatogênese, porém o período de tratamento com finasterida (2 meses) favorece a recuperação da doença, auxiliando em novas abordagens de diagnóstico e prognóstico da hiperplasia prostática benigna em cães. / Benign prostatic hyperplasia (BPH) is the disease of highest incidence in senile dogs. Thus, it is essential to characterize the pathogenesis of the disease, including the evaluation of animals submitted to clinical or surgical treatment (finasteride therapy and orchiectomy). In this context, the aim of this study was to characterize BPH changes of dogs submitted to different treatments. Therefore, a total of 25 dogs were used (BPH and healthy), applying distinct experimental tools: Doppler ultrasonography to characterize prostatic and testicular hemodynamic changes involved, immunohistochemistry and PCR for the expression of prostatic VEGF factor, testicular morphohistologic analysis, hormonal assay (testosterone, estrogen and dihydrotestosterone), breeding soundness examination, seminal analysis and oxidative stress and antioxidant enzymes evaluation of the prostatic fluid. It was possible to observe a reduction in prostatic vascularization score (by Color Doppler) in finasteride treated and orchiectomized animals, with an additional reduction of the prostatic volume. Finasteride treatment reduced VEGF expression by immunohistochemistry, however, orchiectomy also reduced VEGF gene expression. In addition, finasteride treatment reduced dihydrotestosterone concentration, without significant impact to seminal quality. On the other hand, BPH promoted significant changes in testosterone concentration and seminal quality, such as poor sperm concentration, changes in the sperm kinetics and high rates of sperm DNA fragmentation. In conclusion, prostatic VEGF activity in dogs is dependent on the occurrence of BPH and different therapies, promoting also differences in prostatic vascularization and volume. Furthermore, dogs with BPH had hormonal and spermatogenesis changes, however, the short course of finasteride treatment (2 months) was able to favor the disease overcome, favoring the application of new approaches to HPB diagnosis and prognosis in dogs.

A hiperplasia prostática benigna (HPB) é a doença de maior incidência em cães senis. Assim, a caracterização da patogênese da doença é de suma importância, tal como a avaliação de animais submetidos a tratamento clínico ou cirúrgico (terapia com finasterida e orquiectomia). Neste contexto, o objetivo dessa pesquisa foi caracterizar as alterações seminais, hormonais e hemodinâmicas da próstata e testículos de cães com HPB, submetidos a diferentes tratamentos. Assim, foram utilizados 25 cães entre doentes e hígidos e empregados as seguintes ferramentas experimentais: ultrassonografia Doppler com o intuito de caracterizar mudanças hemodinâmicas da próstata e testículos, imunohistoquímica e PCR para a expressão do fator VEGF na próstata, avaliação morfohistológica dos testículos, dosagem hormonal (testosterona, estrógeno e di-hidrotestosterona), análise andrológica, seminal e do estresse oxidativo e enzimas antioxidantes. Foi possível observar redução do escore de vascularização prostático (Doppler Colorido) em animais tratados com finasterida ou orquiectomizados, além de redução do volume prostático. O tratamento com finasterida reduziu a imunomarcação para o VEGF na próstata, porém a orquiectomia também inibiu a expressão gênica do VEGF. A finasterida, ainda, reduziu os níveis séricos de di-hidrotestosterona, não causando impactos significativos na qualidade seminal. Já a HPB promoveu alterações significativas na concentração de testosterona e na qualidade seminal (baixa concentração espermática, alteração da cinética espermática e altos índices de fragmentação de DNA espermático). Em conclusão, a atividade prostática do VEGF é dependente da ocorrência de HPB e dos diferentes tratamentos empregados, promovendo diferenças na vascularização e volume prostático. Ademais, cães com HPB possuem alterações no perfil hormonal e na espermatogênese, porém o período de tratamento com finasterida (2 meses) favorece a recuperação da doença, auxiliando em novas abordagens de diagnóstico e prognóstico da hiperplasia prostática benigna em cães. / Benign prostatic hyperplasia (BPH) is the disease of highest incidence in senile dogs. Thus, it is essential to characterize the pathogenesis of the disease, including the evaluation of animals submitted to clinical or surgical treatment (finasteride therapy and orchiectomy). In this context, the aim of this study was to characterize BPH changes of dogs submitted to different treatments. Therefore, a total of 25 dogs were used (BPH and healthy), applying distinct experimental tools: Doppler ultrasonography to characterize prostatic and testicular hemodynamic changes involved, immunohistochemistry and PCR for the expression of prostatic VEGF factor, testicular morphohistologic analysis, hormonal assay (testosterone, estrogen and dihydrotestosterone), breeding soundness examination, seminal analysis and oxidative stress and antioxidant enzymes evaluation of the prostatic fluid. It was possible to observe a reduction in prostatic vascularization score (by Color Doppler) in finasteride treated and orchiectomized animals, with an additional reduction of the prostatic volume. Finasteride treatment reduced VEGF expression by immunohistochemistry, however, orchiectomy also reduced VEGF gene expression. In addition, finasteride treatment reduced dihydrotestosterone concentration, without significant impact to seminal quality. On the other hand, BPH promoted significant changes in testosterone concentration and seminal quality, such as poor sperm concentration, changes in the sperm kinetics and high rates of sperm DNA fragmentation. In conclusion, prostatic VEGF activity in dogs is dependent on the occurrence of BPH and different therapies, promoting also differences in prostatic vascularization and volume. Furthermore, dogs with BPH had hormonal and spermatogenesis changes, however, the short course of finasteride treatment (2 months) was able to favor the disease overcome, favoring the application of new approaches to HPB diagnosis and prognosis in dogs.

Made available in DSpace on 2014-06-11T19:25:19Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-05-09Bitstream added on 2014-06-13T18:53:13Z : No. of bitstreams: 1 chambo_rc_me_botfm.pdf: 605131 bytes, checksum: 81f0a6d5dda1782f51f5b580a20f8761 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A Síndrome da Dor Pélvica Crônica (SDPC) é uma nova categoria na classificação atual das prostatites. A causa da SDPC é desconhecida, a teoria mais aceita é o refluxo intraprostático. Não há estudo que comprove qual o melhor tratamento. A finasterida, uma das drogas utilizadas para o tratamento, é um antiandrogênio que bloqueia a enzima 5-alfa redutase, diminuindo o tamanho da próstata. A finasterida agiria na SDPC reduzindo o tecido glandular prostático, diminuindo a tensão intraprostática e conseqüentemente o refluxo intraprostático. Avaliar a efetividade e a segurança da finasterida no tratamento da SDPC. Uma revisão sistemática de ensaios clínicos aleatorizados foi realizada, sem restrições de língua, datas ou outras considerações. As fontes de informação utilizadas foram Medline, Registro de Ensaios Controlados da Cochrane, Embase, Lilacs e SciELO. Contato com autores de artigos, laboratórios que comercializam finasterida e revistas médicas em geral e específicas. Foram incluídos pacientes com diagnóstico da SDPC tipo IIIA e/ou IIIB, participantes de estudos em que foi comparado o uso da finasterida com placebo ou outro tipo de tratamento. Os desfechos clínicos avaliados foram os questionários dos sintomas prostáticos, exames para avaliar a melhora bioquímica ou variável fisiológica e eventos adversos. A coleta de dados e análise foram realizadas por dois revisores que inspecionaram as referências encontradas independentemente pela estratégia de busca e aplicaram os critérios de inclusão nos estudos selecionados usando os critérios de qualidade metodológica descritos no Cochrane handbook. A escala de Jadad e Schutz também foram usadas. Os dados dos estudos elegíveis foram sumarizados em metanálise. A análise estatística foi realizada utilizando o... / Chronic Pelvic Pain Syndrome (CPPS) is a new category in the current classification of prostatitis. The cause of CPPS is unknown; the most accepted theory is intraprostatic ductal reflux. The best treatment is not known. Finasteride, a specific type II 5a-reductase inhibitor, decreases the size of the prostate. A potential mechanism of action for finasteride is the reduction of the intraprostatic tension due to the glandular shrinkage, decreasing the intraprostatic ductal reflux. To assess the effectiveness and harms of finasteride in the treatment of CPPS. A systematic review of randomized controlled trials was performed, with no restrictions on language, dates or other considerations. The information sources used were Medline, the Cochrane Central Register of Controlled Trials, Embase, Lilacs and SciELO; contact authors of articles, laboratories that work with finasteride and general and specific medical magazines. It included participants with a diagnosis of CPPS type IIIA and/or IIIB taking part of studies comparing the use of finasteride to placebo or another type of treatment. The clinical outcomes evaluated were the questionnaires of prostatic symptoms, improvement in biochemical or physiologic variables and adverse events. The collecting data and analysis were performed by two reviewers that checked the found references independently by the search strategy, and applied the inclusion criteria in the selected studies using the criteria of methodological quality described on Cochrane Handbook. The Jadad and the Schutz scales were also used. After finding all eligible studies, the data were summarized in meta-analysis. The statistical analysis was undertaken using the MetaView statistical program within Review Manager software of the Cochrane Collaboration. Three studies with 181 patients were included. The length ...(Complete abstract click electronic access below)

Orientador: Sérgio Luis Felisbino / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-16T21:10:50Z (GMT). No. of bitstreams: 1 Delella_FlaviaKarina_D.pdf: 4450656 bytes, checksum: dade120d2d2bab0a5a25ef2c13d30269 (MD5) Previous issue date: 2010 / Resumo: A finasterida e a doxazosina são drogas usadas no tratamento da hiperplasia prostática benigna (HPB) e, mais recentemente, estão sendo também usadas na quimioprevenção do câncer de próstata (CaP), principalmente devido aos seus efeitos na indução de apoptose das células epiteliais prostáticas. Entretanto, pouca atenção tem sido dispensada aos efeitos destes fármacos sobre o estroma glandular. Assim, o objetivo deste estudo foi analisar os efeitos da finasterida e da doxazosina no arranjo estromal e em componentes específicos, como o colágeno do tipo I, colágeno do tipo III e o TGF-Beta 1. Para isso, foram empregadas técnicas morfológicas, bioquímicas e moleculares. O tratamento com finasterida promoveu apoptose epitelial, alterações na membrana basal epitelial e na membrana basal das células musculares lisas, além da diminuição na expressão dos colágenos I e III. O bloqueio ?-adrenérgico com doxazosina aumentou a quantidade de fibras do sistema elástico, promoveu apoptose nas células epiteliais, além de alterar a expressão dos colágenos I e III. Os dois fármacos influenciaram o aumento da expressão do TGF-Beta 1, que parece estar mais relacionado com o evento da apoptose no tratamento com a finasterida e com as alterações das fibras colágenas e a ativação de fibroblastos no tratamento com a doxazosina. Conclui-se que as alterações estromais pós tratamento com finasterida e doxazosina podem contribuir para a regressão prostática esperada no tratamento da HPB e na ruptura de eventos parácrinos responsáveis pela evolução tumoral no CaP / Abstract: Finasteride and doxazosin are drugs used in the benign prostatic hyperplasia (BPH) treatment and, more recently, they're have been used in the prostate cancer (PCa) chemoprevention, mainly because their apoptotic effect in the prostatic epithelial cells. However, few attentions have been given to the effects of these drugs in the glandular stroma. Thus, the objective of this study was to analyze the effects of the finasteride or doxazosin treatment on stroma arrangement and on specific components, like collagen type I, collagen type III and TGF-Beta 1. For this aim, we have used morphological, biochemical and molecular approaches. Finasteride treatment provoked epithelial apoptosis, epithelial basal membrane and smooth muscle cells basal membrane alterations, besides decrease the type I and type III collagen fibers expression. The alpha-adrenergic blockade increased the elastic fibers system, promoted apoptosis in epithelial cells, as well altered the type I and type III collagen fibers expression. Both drugs influenced the TGF-Beta 1 up-regulation that show to be related with apoptosis in finasteride treatment and with collagen fibers alterations and fibroblasts activation in doxazosin treatment. In conclusion, the stromal alterations promoted by finasteride and doxazosin treatments can contribute to the prostate regression expected in the BPH treatment and to the rupture of paracrine events responsible by tumoral evolution in the PCa / Doutorado / Biologia Celular / Doutor em Biologia Celular e Estrutural

Orientador: Sergio Luis Felisbino / Tese (doutorado) - Universidade Estadual de Campinas, Insituto de Biologia / Made available in DSpace on 2018-08-13T04:30:25Z (GMT). No. of bitstreams: 1 JustulinJunior_LuisAntonio_D.pdf: 17091914 bytes, checksum: 15d52dabcde65a4f842895fd71f92ccd (MD5) Previous issue date: 2008 / Resumo: Finasterida (Fin), um inibidor da enzima 5a-redutase do tipo II e a Doxazosina (Dox), um inibidor do receptor a1-adrenérgico, tem sido amplamente utilizados no tratamento dos sintomas da Hiperplasia Prostática Benigna (HPB). Recentemente, dados clínicos demonstraram que a combinação destas drogas foi mais efetiva em prevenir o desenvolvimento de retenção urinária aguda. Além disso, tem sido demonstrado que tanto as drogas isoladas, como em associação também podem ser utilizadas na prevenção e tratamento do câncer de próstata, devido ao seu potencial de induzir apoptose em células epiteliais normais e tumorais. Apesar disso, pouco se conhece sobre os efeitos da Fin e da Dox administradas isoladas ou em associação sobre a morfofisiologia prostática, incluindo proliferação, morte celular, e indução de remodelação da matriz extracelular pelas metaloproteinases de matriz. Ratos wistar machos adultos (13 semanas) foram tratados com Dox (25mg/kg/dia) ou com a combinação de Fin+Dox (25mg/kg/dia). Após a eutanásia, os lobos prostáticos (ventral, dorsolateral e anterior) foram retirados, pesados e imersos em fixador para análises morfológicas ou congelados em nitrogênio líquido para posterior análises bioquímicas. Os resultados morfológicos e estereológicos demonstraram que o tratamento com a Dox isoladamente por 3 dias resultou em aumento do peso da próstata ventral, com acúmulo de secreção na luz glandular. Os pesos absoluto e relativo das próstatas dorsolateral e anterior não sofreram alteração neste período de tratamento. Entretanto, após 30 dias de tratamento, observou-se uma redução de aproximadamente 20% nos pesos absoluto e relativo de todos os lobos prostáticos e um aumento do volume glandular ocupado pelo colágeno no estroma nos três lobos prostáticos. O tratamento com doxazosina também reduziu o índice de proliferação celular e aumentou o índice apoptótico em todos os períodos analisados. A próstata ventral de ratos tratados com a combinação de Fin+Dox apresentou perda de peso após 30 dias de tratamento. Nos dois períodos de tratamento ocorreu diminuição do índice de proliferação celular, aumento de apoptose e do volume estromal de colágeno, mais evidentes quando comparados ao tratamento com as drogas isoladas. O tratamento combinado também provocou aumento da imunomarcação para o TGF-ß1 demonstrado por imunohistoquímica, principalmente no epitélio. A expressão dos RNAms para MMP-2, TIMPs-1 and - 2 dimunuiu após 30 dias de tratamento, enquanto o RNAm para a MMP-9 não foi detectado em nenhum grupo experimental. O tratamento com Fin+Dox por 30 dias promoveu uma diminuição na atividade gelatinolítica da MMP-2 e um aumento na atividade da MMP-9. Em conjunto, os resultados deste estudo demonstram que tanto o tratamento com doxazosina quanto o tratamento combinado de Fin+Dox induzem grandes alterações glandulares que levam a atrofia prostática, sendo ainda mais significativa com o tratamento combinado, possivelmente pela ação complementar destas duas drogas sobre o parênquima e o estroma glandulares. Nesta atrofia, a MMP-9 e o TGF-ß 1parecem desempenhar um papel importante. Desta forma, nossos resultados auxiliam o entendimento dos dados clínicos, demonstrando que a combinação dos dois fármacos pode ser mais eficaz no tratamento da HPB. / Abstract: Finasteride (Fin), an inhibitor of type II 5-a reductase, and Doxazosin (Dox), an a1- adrenergic blocker, have been widely used in treatment of Benign Prostate Hyperplasia (BPH) symptoms. Recently, clinical data have demonstrated that the combined therapy with Fin+Dox reduced the long-term risk of acute urinary retention and the need for invasive therapies than either drug alone. Moreover, both drugs, alone or in combination have been suggested to be effective in the treatment of prostate cancer by inducing apoptosis in normal and tumoral cells. However, little is known about the effects of these drugs administrated alone or their combination on prostate tissue morphohysiology, including prostate morphology, cell proliferation, apoptosis and matrix metalloproteinases activities. Male adult Wistar rats (13 weeks old) were treated with doxazosin (25mg/kg/day) or with finasteride (25mg/kg/day) or with the combination of both drugs. The ventral (VP), dorsolateral (DLP) and anterior prostate (AP) were excised and processed for histochemical, morphometric and biochemical analysis. The results of morphological and stereological analyses demonstrate that Dox treatment for 3 day resulted in an increased in ventral prostate absolute and relative weight with secretion accumulation. The weight of dorsolateral and anterior prostate did not change in this period of treatment. However, after 30 days, the prostate exhibited an absolute and relative weight reduction of about 20% and an increase in collagen volume fraction in the stromal space in the three prostatic lobes. Dox also reduced epithelial cell proliferation and increased apoptosis in the three prostatic lobes in all periods of tretament. Rat VP treated with Fin+Dox also presented a reduction in absolute and relative weight, decrease in epithelial cell proliferation, increase in apoptosis and collagen volume fraction in the stroma in all periods analyzed, more than Dox alone. Fin+Dox treatment also increased the TGF-ß 1 immunoreaction in the epithelium and in the stroma of VP. The mRNA for MMP-2, TIMPs-1 and - 2 expression after 30 days of treatment were decreased. The mRNA for MMP-9 was not detected in any groups analyzed. Fin+Dox treatment for 30 days promoted a decrease in gelatinolitic activity of MMP-2 and an increase in MMP-9. Take together, these results demonstrated that both Dox alone or in combination with Fin induced changes in glandular histoarchitecture, leading to a prostate atrophy, being the combined treatment more effective in inducing glandular atrophy, possibly to the complementary action of the Fin and Dox on prostate parenchyma and stroma, respectively. In this process, the MMP-9 and TGF-ß1 appear to participate effectively. Our results contribute to a better understanding of the clinical data, demonstrating that the combined treatment can be more effective in the BPH treatment. / Doutorado / Biologia Celular / Doutor em Biologia Celular e Estrutural

Doctor of Philosophy / Department of Human Nutrition / Brian L. Lindshield / The growth-inhibitory effect of saw palmetto supplements (SPS) with high long-chain fatty acids (FA)-low phytosterols (HLLP), high long-chain FA-high phytosterols (HLHP), and high medium-chain FA-low phytosterols (HMLP) was determined using androgen-sensitive LNCaP prostate cancer (PCa) cells and Syrian hamster flank organs. In vitro, all three SPS at high concentrations significantly decreased dihydrotestosterone-stimulated LNCaP cell number. HMLP and HLLP at high concentrations significantly decreased, but HLHP which significantly increased testosterone-stimulated LNCaP cell number. In Syrian hamsters, all three SPS treatments caused notable, but nonsignificant reduction in the difference between the left and right flank organ growth in the testosterone-, but not dihydrotestosterone-treated SPS groups. Results suggest SPS might be a mild 5-alpha-reductase (5-alpha-R) inhibitor. The pharmaceuticals finasteride inhibits 5-alpha-R2, and dutasteride inhibits 5-alpha-R1 and 5-alpha-R2 isoenzymes. Because finasteride inhibits only 5-alpha-R2, we hypothesized that it would not be as efficacious in preventing PCa development and/or progression in TRAMP mice as dutasteride. Six-week-old C57BL/6 TRAMP x FVB male mice were randomized to control, pre- and post- finasteride and dutasteride diet groups that began at 6 and 12 weeks of age, respectively, and terminated at 20 weeks of age. Pre and post groups received drugs before and after mice were expected to develop PCa, respectively. Post-Dutasteride treatment was significantly more effective than Pre-Dutasteride; and dutasteride treatments significantly more effective than finasteride treatments in decreasing prostatic intraepithelial neoplasia progression and PCa development. The finasteride groups and the Pre-Dutasteride group had significantly increased incidence of poorly differentiated PCa versus control. Androgen receptor and Ki-67 protein, DNA fragmentation from apoptosis, 5-alpha-R1 and 5-alpha-R2 mRNA levels were determined in mice with genitourinary weight less than 1 gram and greater than 1 gram to elucidate the discordant response in Pre-Dutasteride and finasteride groups, and Post-Dutasteride’s efficacy. Results suggest the difference in genitourinary weights is influenced more by proliferation, rather than androgen receptor and apoptosis in tumor. Mice age may not be significantly important in regulating proliferation, androgen receptor and apoptosis to promote tumor growth. In conclusion, the results with 5-alpha-reductase inhibitors may support the therapeutic use of dutasteride, but not finasteride, or saw palmetto supplements.