Thesis (Ph.D. in Molecular Biology) -- University of Colorado at Denver and Health Sciences Center, 2005. / Typescript. Includes bibliographical references (leaves 89-109 and 224-228).

München, Techn. Univ., Diss., 2004.

The aryl hydrocarbon receptor (AhR) has been reported to interact with multiple signaling pathways during prostate development including the androgen receptor. AhR was overexpressed in LNCaP using PLNCX2 retrovirus vector containing AhR cDNA to determine if ectopic overexpression induces castrate resistant phenotype. The highly overexpressed AhR clone illustrated further increase in transcriptional and promotor activity for AhR and AR compared to the moderately overexpressed AhR clone and control. Western blot analysis showed more AhR, AR, cSrc, and pSrc protein expression in clones. AhR overexpression was found to induce several biological properties such as migration, invasion, proliferation, and promotion of G1 to S phase during the cell cycle. Bicalutamide treatment had no effect on AR transcriptional activity in either clone, proving resistance to anti-androgen therapy. Our results confirm that overexpression of AhR induces constitutive activity and stimulates androgen receptor signaling. This suggests a role for AhR in the development of CRPC.

Master of Science / Department of Kinesiology / Carl Ade / Background: Androgen Deprivation Therapy (ADT) is a commonly used treatment for prostate cancer with controversy currently surrounding its association with long-term cardiovascular disease risk. Therefore, the aim of the current investigation was to non-invasively measure left ventricular mechanics at rest and during submaximal exercise in human prostate cancer survivors with and without a history of ADT. Methods: Eighteen prostate cancer survivors, 9 with a history of ADT and 9 matched (1:1) non-ADT controls, completed the protocol. Standard and tissue Doppler echocardiography were used to evaluate left ventricular systolic and diastolic function at rest and during submaximal cycling exercise. Results: At rest, there were no differences between groups. Ejection fraction was not different between groups at rest or during exercise (rest p=0.7; exercise p=0.8). During exercise, systolic left ventricular longitudinal strain and strain rate failed to increase in the ADT group (p=0.4; p=0.07), but significantly increased in the non-ADT group (p=0.03; p=0.02). During exercise, systolic strain was significantly different between groups (p=0.02). Diastolic longitudinal strain increased with exercise in both groups (p=0.003; p=0.003). In the ADT group during exercise, mitral valve deceleration time was not significantly different from rest (p=0.8) and was slower compared to non-ADT (p=0.03). Conclusion: In prostate cancer survivors with a history of ADT, there are significant abnormalities of left ventricular systolic function that become apparent with exercise. These findings may hold significant value beyond the standard resting characterization of ventricular function, in particular as part of a risk-stratification strategy.

INTRODUÇÃO: Carcinomas de mama triplo-negativos (CMTN) constituem um grupo de tumores heterogêneos caracterizados por sobrevida pobre dos pacientes e falta de terapia-alvo. Receptor andrógeno (AR) tem sido descrito no CMTN, mas o impacto prognóstico da expressão nesse subgrupo não está bem claro. OBJETIVO: Investigar a associação do status de expressão AR analisado por imunohistoquímica em casos de CMTN com parâmetros clínicos (idade, sobrevida) e variáveis patológicas (tamanho do tumor, grau do tumor). MÉTODOS: Foram analisados 62 CMTN por imuno-histoquímica automatizada para receptor andrógeno. A imuno-histoquímica foi avaliada por dois diferentes patologistas e a expressão do biomarcador foi avaliada por H-Score (intensidade mais percentagem de coloração). Kaplan-Meyer foi o método usado para avaliar a sobrevida global, tendo as diferenças nas distribuições sido avaliadas com base na expressão do marcador. RESULTADOS: 26% dos CMTNs foram AR positivos (n = 16) e 74% AR negativos (n = 46). Todos os casos de AR positivos ocorreram em mulheres ≥ 40 anos enquanto 13% dos casos de AR negativos foram vistos em mulheres ≤ 40 anos. 93% (52/56) de todos os CMTNs foram carcinoma ductal invasivo do tipo não especial (ICNST) e 93% (14/15) de AR positivos dos casos de ICNST. O tamanho do tumor variou de 2 a 4,9 cm na maioria dos cânceres AR positivos (n = 8/13; 62%). 60% (n = 9/15) dos casos de AR positivos mostraram grau histológico 3 seguidos de 27% de tumores de grau 2. Não se observou diferença entre pacientes AR positivos e AR negativos quando comparados por idade, tamanho do tumor, grau do tumor e tipo do tumor (p > 0,17). A positividade imuno-histoquímica para ARs também não foi associada com melhor sobrevida (p = 0,737; n = 51) ou sobrevida livre da doença (p = 0,552; n = 45) em CMTNs. CONCLUSÃO: Sob o ponto de vista do prognóstico, a imunorreatividade do AR tem sido associada com melhor sobrevida das pacientes. Esse resultado não foi confirmado na presente série. Isso poderia estar relacionado com o pequeno tamanho amostral ou com uma baixa prevalência de casos de AR positivos especificamente nesse subtipo de câncer de mama. Estudos realizados com maiores amostras são necessários para investigar esse biomarcador em CMTNs. / INTRODUCTION: Triple negative breast carcinomas (TNBC) are a heterogeneous group of tumors characterized by poor patient survival and lack of targeted therapies. Androgen receptor (AR) has been described in TNBC but the prognostic impact of the expression in this subgroup of tumors is not clear. OBJECTIVE: To investigate the association of AR expression status by immunohistochemistry in TNBC cases with clinical (age, survival) and pathological variables (tumor size, tumor grade). METHODS: 62 TNBC were analyzed by automated immunohistochemistry for androgen receptor. Immunohistochemistry was scored by two investigators and biomarker expression was assessed by H-Score (intensity plus the percentage of staining). Kaplan-Meier was used to evaluate overall survival, where differences in distributions were evaluated based on marker expression. RESULTS: 26% of TNBC were AR-positive (n = 16) and 74% AR negative (n = 46). All AR-positive cases occurred in women ≥ 40 years, while 13% of AR-negative cases were seen in women ≤ 40 years. 93% (52/56) of all TNBC were infiltrating ductal carcinomas of no special type (ICNST) and 14/15 (93%) of AR-positive cases were ICNST. Tumor size varied from 2-4.9 cm in the majority of AR-positive cancers (n = 8/13; 62%). 60% (n = 9/15) of AR-positive cases showed histological grade 3 tumors, followed by 27% of grade 2 tumors. No differences were observed between AR-positive and AR-negative patients when compared for age, tumor size, tumor grade and tumor type (all p > 0.17). AR immunohistochemical positivity was also not associated with better overall survival (p = 0.737, n = 51) or disease-free survival (p = 0.552; n = 45) in TNBCs. CONCLUSION: From the prognostic point of view, AR immunoreactivity has been associated with better overall patient survival. Unfortunately, this result could not be confirmed in our series. This could be related to the relatively small series of analyzed samples and to the low prevalence of AR-positive cases in this specific breast cancer subtype. Further studies with bigger samples are needed to investigate this biomarker in TNBC.

Androgens are well documented as important regulators of male health, primarily in the maintenance and development of male sexual characteristics. However, a decline in circulating androgens has also been associated with co-morbidities such as obesity, cardiac disease and metabolic syndrome. Previous research has focussed upon the body wide impact of adrenal androgens, however whilst androgen receptor (AR) is abundantly expressed in the adrenal cortex of both rodents and humans, surprisingly little is known about androgen action on the adrenal cortex itself. This gap in our understanding is at least in part due to the perceived lack of suitable animal models. Rodents have largely been overlooked as a model system as their adrenals are unable to produce androgens due to lack of 17α Hydroxylase and 17, 20 lyse activity and they therefore do not have a zona reticularis. However, historical studies using castrated mice showed that removal of androgens leads to the redevelopment of an additional cortex zone known as the transient X-zone. The foetal adrenal is thought to give rise the adult adrenal cortex in human and rodents. These foetal cells are maintained for a period postnatally and regress differently depending on species and sex. In the human this zone is known as the ‘foetal zone’, and the rodent homologue termed the ‘X-zone’. The mechanisms underpinning the regression of the X-zone and its purpose and maintenance postnatally still aren’t clearly understood. To provide a comprehensive overview of androgen signalling in the adrenal cortex, multiple mouse models were utilised. First, Cre/loxP technology was used to ablate AR specifically from the adrenal cortex. Further androgen manipulation was achieved through castration (removal of androgens) and human chorionic gonadotropin (hCG) treatment (increased androgens). The initial study investigates the impacts on the male mouse adrenal. Histology analysis revealed the presence of an X-zone in all experimental cohorts following loss of AR or circulating androgens, confirmed by 20- α-hydroxysteroid dehydrogenase (20 alpha-HSD) expression. These data demonstrate that androgens signalling via AR is required for X-zone regression during puberty. However, interrogation of morphology of hCG treated cohorts revealed no phenotypic changes compared to controls, this demonstrates that hyper stimulation with androgens does not negatively impact the adrenal cortex or influence X-zone morphology. Differences in X-zone morphology and 20 alpha-HSD localization prompted cortex measurements which revealed significant differences in X-zone depth and cell density depending on ablation of AR, circulating androgens or both. This suggests that androgens and androgen receptor are working together and also independently to regulate the adrenal cortex. This result was strengthened through analysis of steroid enzyme genes and cortex markers, which revealed that normal AKR1B7 expression was absent following loss of androgens but not androgen receptor. A final part of this study examined the impacts long term androgen receptor ablation and long term castration in ageing animals. A final part of this study examined the impacts long term androgen receptor ablation and long term castration in ageing animals. These results demonstrate that following prolonged loss of androgens that there is no major disruption to the adrenal cortex. Morphology analysis and X-zone measurements revealed that X-zone regression was occurring in mice with long term castration, characterized by a reduction in size and pockets of vacuolization throughout the X-zone. This phenotype is also observed in ageing females with X-zone regression via vacuolization. These data suggest that following prolonged loss of androgens, the male adrenal is feminized and behaves as such. In contrast, AR ablation only, results in an enlarged adrenal with large spindle cell lesions and X-zone expansion confirmed by X-zone measurements. Initial experiments have demonstrated that androgens can work independently of AR to regulate the adrenal cortex. Together these data suggests that AR is required to control the appropriate action of circulating androgens in the adrenal cortex, with loss of AR resulting in off target signalling from circulating androgens in the adrenal leading to spindle cell hyperplasia, X-zone expansion and X-zone mislocation. A second set of studies were carried out to determine the role of androgen signalling in the female adrenal, specifically, if loss of AR leads to the absence of normal X-zone regression during pregnancy. To answer this question the same selective AR ablation model was used. Analysis of litters comparing observed and expected genetic distribution revealed significantly fewer females being born carrying complete ablation of adrenal AR. Morphology analysis of these mice revealed severe cortex disruption and spindle cell hyperplasia similar to that observed in mutant males. Investigation of adrenals following pregnancy revealed that X-zone regression still occurred despite loss of AR. This result shows that X-zone regression in the female is under different regulation compared to male adrenal and occurs via an androgen-independent signalling mechanism. However, loss of AR still leads to anatomical dysregulation of the adrenal cortex. AR ablation revealed changes in glucocorticoid receptor (GR) expression in the adrenal cortex. To dissect this relationship further a final study was conducted, attempting to ablate GR from the adrenal cortex also using the Cyp11a1 Cre. Initial observations of these mice revealed excessive hair loss through barbering, curved spines and stressed behaviour when monitored in the cage under normal conditions. Immunohistochemistry was used to confirm GR ablation in the adrenal cortex, however, to our surprise, GR expressing cells were not steroidogenic and thus were not targeted by the Cre recombinase. Despite no GR ablation in the adrenal, morphology analysis revealed severe disruption to the adrenal cortex. The Cyp11a1 Cre not only targets the adrenal but is expressed in the hindbrain. To determine if GR ablation in the hindbrain explains the phenotype, we next used PCR analysis interrogating hindbrain genomic DNA to determine if there was recombination of GR. Results confirmed GR recombination in the hindbrain. Due to the observation of stressed behaviour and adrenal cortex disruption, we wanted to determine if this was a result of hyperactivity of the adrenal cortex. Serum corticosterone was analysed and was elevated in these animals. These data revealed that GR ablation in the hindbrain results in adrenal cortex disruption and an elevated stress response, potentially highlighting a new model to investigate stress disorders and their impact on the hypothalamic-pituitary-adrenal axis. Together this data defines new roles for AR signalling in the adrenal cortex and the role of the hindbrain GR signalling in regulating adrenal morphology and function.

INTRODUÇÃO: Carcinomas de mama triplo-negativos (CMTN) constituem um grupo de tumores heterogêneos caracterizados por sobrevida pobre dos pacientes e falta de terapia-alvo. Receptor andrógeno (AR) tem sido descrito no CMTN, mas o impacto prognóstico da expressão nesse subgrupo não está bem claro. OBJETIVO: Investigar a associação do status de expressão AR analisado por imunohistoquímica em casos de CMTN com parâmetros clínicos (idade, sobrevida) e variáveis patológicas (tamanho do tumor, grau do tumor). MÉTODOS: Foram analisados 62 CMTN por imuno-histoquímica automatizada para receptor andrógeno. A imuno-histoquímica foi avaliada por dois diferentes patologistas e a expressão do biomarcador foi avaliada por H-Score (intensidade mais percentagem de coloração). Kaplan-Meyer foi o método usado para avaliar a sobrevida global, tendo as diferenças nas distribuições sido avaliadas com base na expressão do marcador. RESULTADOS: 26% dos CMTNs foram AR positivos (n = 16) e 74% AR negativos (n = 46). Todos os casos de AR positivos ocorreram em mulheres ≥ 40 anos enquanto 13% dos casos de AR negativos foram vistos em mulheres ≤ 40 anos. 93% (52/56) de todos os CMTNs foram carcinoma ductal invasivo do tipo não especial (ICNST) e 93% (14/15) de AR positivos dos casos de ICNST. O tamanho do tumor variou de 2 a 4,9 cm na maioria dos cânceres AR positivos (n = 8/13; 62%). 60% (n = 9/15) dos casos de AR positivos mostraram grau histológico 3 seguidos de 27% de tumores de grau 2. Não se observou diferença entre pacientes AR positivos e AR negativos quando comparados por idade, tamanho do tumor, grau do tumor e tipo do tumor (p > 0,17). A positividade imuno-histoquímica para ARs também não foi associada com melhor sobrevida (p = 0,737; n = 51) ou sobrevida livre da doença (p = 0,552; n = 45) em CMTNs. CONCLUSÃO: Sob o ponto de vista do prognóstico, a imunorreatividade do AR tem sido associada com melhor sobrevida das pacientes. Esse resultado não foi confirmado na presente série. Isso poderia estar relacionado com o pequeno tamanho amostral ou com uma baixa prevalência de casos de AR positivos especificamente nesse subtipo de câncer de mama. Estudos realizados com maiores amostras são necessários para investigar esse biomarcador em CMTNs. / INTRODUCTION: Triple negative breast carcinomas (TNBC) are a heterogeneous group of tumors characterized by poor patient survival and lack of targeted therapies. Androgen receptor (AR) has been described in TNBC but the prognostic impact of the expression in this subgroup of tumors is not clear. OBJECTIVE: To investigate the association of AR expression status by immunohistochemistry in TNBC cases with clinical (age, survival) and pathological variables (tumor size, tumor grade). METHODS: 62 TNBC were analyzed by automated immunohistochemistry for androgen receptor. Immunohistochemistry was scored by two investigators and biomarker expression was assessed by H-Score (intensity plus the percentage of staining). Kaplan-Meier was used to evaluate overall survival, where differences in distributions were evaluated based on marker expression. RESULTS: 26% of TNBC were AR-positive (n = 16) and 74% AR negative (n = 46). All AR-positive cases occurred in women ≥ 40 years, while 13% of AR-negative cases were seen in women ≤ 40 years. 93% (52/56) of all TNBC were infiltrating ductal carcinomas of no special type (ICNST) and 14/15 (93%) of AR-positive cases were ICNST. Tumor size varied from 2-4.9 cm in the majority of AR-positive cancers (n = 8/13; 62%). 60% (n = 9/15) of AR-positive cases showed histological grade 3 tumors, followed by 27% of grade 2 tumors. No differences were observed between AR-positive and AR-negative patients when compared for age, tumor size, tumor grade and tumor type (all p > 0.17). AR immunohistochemical positivity was also not associated with better overall survival (p = 0.737, n = 51) or disease-free survival (p = 0.552; n = 45) in TNBCs. CONCLUSION: From the prognostic point of view, AR immunoreactivity has been associated with better overall patient survival. Unfortunately, this result could not be confirmed in our series. This could be related to the relatively small series of analyzed samples and to the low prevalence of AR-positive cases in this specific breast cancer subtype. Further studies with bigger samples are needed to investigate this biomarker in TNBC.

Orientador: Hernandes Faustino de Carvalho / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-10T10:22:10Z (GMT). No. of bitstreams: 1 Victorio_SheilaCristinadaSilva_M.pdf: 1499738 bytes, checksum: 1208b4b617e591a974a869b7fa20a388 (MD5) Previous issue date: 2007 / Resumo: O crescimento e função prostática dependem da estimulação androgênica e interação epitélio-estroma. Além dos andrógenos, outros fatores interagem com a próstata e são igualmente importantes para sua fisiologia. Sabe-se que os estrógenos exercem um importante papel no desenvolvimento prostático e que, combinados com andrógenos, podem contribuir para o aparecimento de patologias. A insulina é outro hormônio que afeta a atividade destes hormônios sexuais nos tecidos, inclusive na próstata. Os níveis séricos de esteróides sexuais estão intimamente relacionados com a sensibilidade a insulina, embora esta relação ainda seja pouco esclarecida. No estroma prostático, as células musculares lisas são o tipo celular predominante, influenciando a atividade do epitélio por mecanismos parácrinos e modificando a matriz extracelular em situações de remodelação, como no crescimento, na regressão e na invasão tumoral. Sabe-se que estas células apresentam receptores de andrógeno (AR) e que respondem à privação androgênica, alterando sua morfologia. O presente estudo buscou verificar a influência da testosterona, estradiol e insulina sobre a expressão e localização do AR em células musculares lisas da próstata ventral de ratos Wistar cultivadas in vitro. Os resultados mostraram que o estradiol causou alterações nos níveis protéicos, os níveis de RNAm do AR foram pouco afetados e a localização do AR foi predominantemente nuclear independente da dose de estradiol. Os tratamentos feitos com insulina mostraram que a sua presença causou uma queda da expressão da proteína e uma localização predominante nuclear do AR na situação em que os dois hormônios, insulina e testosterona, foram administrados juntamente. Os resultados permitem sugerir que a expressão do AR pode ser modulada por outros fatores como estrógeno e insulina / Abstract: The prostate function and growth depends on the androgenic stimulation and epitheliumstroma interaction. Besides androgens, other factors interact with the prostate and are also important for its physiology. It is known that estrogens exert an important role in prostate development, and combined with androgens they can contribute for the appearance of pathologies. The insulin is another hormone that interacts with these sexual hormones in tissues, and also in the prostate. The serum levels of sexual steroids are closely related with the sensitivity to the insulin, even though this relation is not yet clear. In prostatic stroma, smooth muscle cells are the predominant cell type. They influence the activity of the epithelium through paracrine mechanisms and modify the extracellular matrix in remodeling situations, such as gland growth and regression, and during tumor invasion. It is known that these cells express androgen receptor (AR) and respond to androgen deprivation by modifying its phenotype. The present study was undertaken to verify the influence of testosterone, estradiol and insulin on the expression and localization of the AR in the smooth muscle cells from the Wistar rat ventral prostate cultured in vitro. The results showed that estradiol caused alterations in the AR protein levels, the mRNA level was less affected and AR localization was predominantly nuclear irrespective of the estradiol dose. Insulin treatments caused a decrease in the expression of the protein and a predominant nuclear localization of AR in the presence of testosterone. The results suggest that AR expression and regulation might be modulated by others factors such as estrogen and insulin / Mestrado / Biologia Celular / Mestre em Biologia Celular e Estrutural

INTRODUÇÃO: Carcinomas de mama triplo-negativos (CMTN) constituem um grupo de tumores heterogêneos caracterizados por sobrevida pobre dos pacientes e falta de terapia-alvo. Receptor andrógeno (AR) tem sido descrito no CMTN, mas o impacto prognóstico da expressão nesse subgrupo não está bem claro. OBJETIVO: Investigar a associação do status de expressão AR analisado por imunohistoquímica em casos de CMTN com parâmetros clínicos (idade, sobrevida) e variáveis patológicas (tamanho do tumor, grau do tumor). MÉTODOS: Foram analisados 62 CMTN por imuno-histoquímica automatizada para receptor andrógeno. A imuno-histoquímica foi avaliada por dois diferentes patologistas e a expressão do biomarcador foi avaliada por H-Score (intensidade mais percentagem de coloração). Kaplan-Meyer foi o método usado para avaliar a sobrevida global, tendo as diferenças nas distribuições sido avaliadas com base na expressão do marcador. RESULTADOS: 26% dos CMTNs foram AR positivos (n = 16) e 74% AR negativos (n = 46). Todos os casos de AR positivos ocorreram em mulheres ≥ 40 anos enquanto 13% dos casos de AR negativos foram vistos em mulheres ≤ 40 anos. 93% (52/56) de todos os CMTNs foram carcinoma ductal invasivo do tipo não especial (ICNST) e 93% (14/15) de AR positivos dos casos de ICNST. O tamanho do tumor variou de 2 a 4,9 cm na maioria dos cânceres AR positivos (n = 8/13; 62%). 60% (n = 9/15) dos casos de AR positivos mostraram grau histológico 3 seguidos de 27% de tumores de grau 2. Não se observou diferença entre pacientes AR positivos e AR negativos quando comparados por idade, tamanho do tumor, grau do tumor e tipo do tumor (p > 0,17). A positividade imuno-histoquímica para ARs também não foi associada com melhor sobrevida (p = 0,737; n = 51) ou sobrevida livre da doença (p = 0,552; n = 45) em CMTNs. CONCLUSÃO: Sob o ponto de vista do prognóstico, a imunorreatividade do AR tem sido associada com melhor sobrevida das pacientes. Esse resultado não foi confirmado na presente série. Isso poderia estar relacionado com o pequeno tamanho amostral ou com uma baixa prevalência de casos de AR positivos especificamente nesse subtipo de câncer de mama. Estudos realizados com maiores amostras são necessários para investigar esse biomarcador em CMTNs. / INTRODUCTION: Triple negative breast carcinomas (TNBC) are a heterogeneous group of tumors characterized by poor patient survival and lack of targeted therapies. Androgen receptor (AR) has been described in TNBC but the prognostic impact of the expression in this subgroup of tumors is not clear. OBJECTIVE: To investigate the association of AR expression status by immunohistochemistry in TNBC cases with clinical (age, survival) and pathological variables (tumor size, tumor grade). METHODS: 62 TNBC were analyzed by automated immunohistochemistry for androgen receptor. Immunohistochemistry was scored by two investigators and biomarker expression was assessed by H-Score (intensity plus the percentage of staining). Kaplan-Meier was used to evaluate overall survival, where differences in distributions were evaluated based on marker expression. RESULTS: 26% of TNBC were AR-positive (n = 16) and 74% AR negative (n = 46). All AR-positive cases occurred in women ≥ 40 years, while 13% of AR-negative cases were seen in women ≤ 40 years. 93% (52/56) of all TNBC were infiltrating ductal carcinomas of no special type (ICNST) and 14/15 (93%) of AR-positive cases were ICNST. Tumor size varied from 2-4.9 cm in the majority of AR-positive cancers (n = 8/13; 62%). 60% (n = 9/15) of AR-positive cases showed histological grade 3 tumors, followed by 27% of grade 2 tumors. No differences were observed between AR-positive and AR-negative patients when compared for age, tumor size, tumor grade and tumor type (all p > 0.17). AR immunohistochemical positivity was also not associated with better overall survival (p = 0.737, n = 51) or disease-free survival (p = 0.552; n = 45) in TNBCs. CONCLUSION: From the prognostic point of view, AR immunoreactivity has been associated with better overall patient survival. Unfortunately, this result could not be confirmed in our series. This could be related to the relatively small series of analyzed samples and to the low prevalence of AR-positive cases in this specific breast cancer subtype. Further studies with bigger samples are needed to investigate this biomarker in TNBC.

Orientador: Aparecida Machado de Moraes / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-13T11:25:06Z (GMT). No. of bitstreams: 1 Cordeiro_RaquelCristinaTancsik_D.pdf: 1883576 bytes, checksum: c00bc86b625d6d904784f53f3f6041e6 (MD5) Previous issue date: 2009 / Resumo: A estria atrófica cutânea ou striae distensae (SD) é uma afecção muito comum, sendo causa freqüente de procura por consultas dermatológicas. Ainda que não representem qualquer risco à saúde física, produzem impacto emocional e induzem busca por tratamentos trabalhosos, caros e dolorosos e, com freqüência, inadequados. Além disso, o surgimento de striae distensae pode refletir alteração do tecido conjuntivo e indicar condições patológicas locais e sistêmicas. Alguns autores descrevem as estrias cutâneas como uma condição de estiramento ou distensão da pele, com perda ou ruptura das fibras elásticas na região acometida. Entretanto, vários autores observam que as estrias não surgem com frequência sobre a pele acima de tumores abdominais, ascites, hemorragias extensas ou grandes hérnias. Atualmente admite-se que sua etiopatogenia é multifatorial, englobando aspectos mecânicos, bioquímicos e genéticos. No entanto, considerando-se a multiplicidade de fatores envolvidos, a literatura é divergente e inconclusiva. Portanto, através do estudo de fatores clínicos associados às SD e dos receptores hormonais (estrógeno, andrógeno e glicocorticóide), pretendeu-se entender melhor a participação dos hormônios na fisiopatogênese das estrias. Para o estudo clínico foram selecionados pacientes com queixa de estrias cutâneas e a comparação foi feita com grupo controle de número semelhante, atendido aleatoriamente por outras queixas no Ambulatório Geral de Dermatologia do HC, FCM/UNICAMP. O estudo da expressão dos receptores hormonais foi realizado por Western blot em oito amostras de pele de estrias recentes, com menos de um ano de evolução, comparando com a avaliação de pele sem lesão de região palpebral de oito pacientes que se submenteram a blefaroplastia. Observou-se que fatores como adolescência, gestação e obesidade estão significativamente relacionados ao surgimento das SD. Constatou-se ainda que a idade materna jovem e o ganho ponderal durante a gestação são importantes fatores associados ao desenvolvimento das lesões. Além disso, a localização das lesões correlaciona-se ao fator causador das estrias. Em relação ao estudo dos receptores hormonais, observou-se que na SD recentes há duas vezes mais expressão de receptores de estrógeno e 1,7 vezes mais expressão receptores de andrógeno e glicocorticóide. Alguns autores interpretam SD como cicatrizes. Após influência hormonal, haveria uma reação inflamatória inicial que determinaria a destruição de fibras elásticas e colágenas. O processo seria seguido de regeneração das fibras, um fenômeno de remodelação dinâmica,ou seja, um balanço entre síntese de colágeno e sua quebra, o qual reestrutura o tecido para acomodar as forças que agem sobre ele, resultando na formação das SD. O balanço entre a expressão de receptores de estrógeno, andrógeno e glicocorticóide poderia induzir as modificações específicas da matriz extracelular, o que levaria a esse fenômeno de remodelação. Em concordância com outros estudos, observamos que as estrias surgem em situação de grande modificação sistêmica, como adolescência e gestação. Através das observações morfológicas e moleculares, nota-se que as SD estão correlacionadas com intensas alterações do tecido conectivo. Os resultados mostram-se relevantes e representam mais um passo na compreensão do mecanismo fisiopatológico da estrias cutâneas e abrem espaço para novas linhas de pesquisa, relacionadas às SD e a outras alterações do tecido conectivo. / Abstract: Stretch marks or striae distensae (SD) are a very common condition which often results in persons searching dermatological treatment. While not presenting any risk to one's physical health, the emotional impact often induces those so affected to demand medical treatments, which are often laborious, expensive and painful, and frequently ineffective. Beyond this, the appearance of SD may indicate other alterations in conjunctive tissues, including both local and systemic pathologies. Some authors described cutaneous strias as a condition of stretching or distension of the skin which results in the loss or rupture of elastic fibers in the affected areas. However, many authors have also observed that SD do not occur frequently associated with abdominal tumors, ascites, extensive hemorrhages or large hernias. Current medical opinion is that its etiopathogenesis is multifactored, englobing mechanical, biochemical and genetic aspects. Nevertheless, in view of the multiplicity of the factors involved, the literature is divergent and inconclusive. This study was proposed to look for better understanding of the role played by hormones in the physiopathology of SD studying clinical factors associated with SD and hormone receptors (estrogen, androgen and glycocorticoid). Patients complaining of SD were selected for inclusion in this clinical study, and comparisons were made with a control group of a similar number of persons who had been treated for other medical conditions at the General Ambulatory Dermatology Care Facility at HC, FCM/UNICAMP. The expression of hormone receptors was undertaken of the Western Blot testing of recent skin striations, in comparison with lesion-free skin taken from the eyelids of patients who had undergone blepharoplasty. The study revealed that factors such as adolescence, pregnancy and obesity are significantly related to the appearance of SD. It was further established that age (the younger the gravid, the greater the possibility of SD) and significant weight gain during pregnancy are important factors associated with the development of SD lesions. In addition, there was a positive correlation with the location of the lesions. In relation to the study of hormone receptors, it was observed that recently-formed SD have two times more expression of estrogen receptors, and 1,7 times more expression of androgen and glycocorticoid receptors. Some authors classify SD as scars. Under hormonal influence, there is an initial inflammatory reaction which results in the destruction of elastic fibers and collagens. This is followed by the regeneration of the destroyed fibers, a phenomenon of dynamic remodeling, a balance between the synthesis and destruction of collagens, which restructures the tissue in order to accommodate the forces acting upon it, resulting in the formation of SD. The balance between the expression of estrogen, androgen and glycocorticoid may elicit the specific modifications of the extracellular matrix which leads to the phenomenon of remodalation. In agreement with other studies, we observed that the strias arise under conditions of significant system modification, such as adolescence and pregnancy. The observation of morphological and molecular changes showed that there is a correlation between SD and with intense alterations in connective tissue. The results of this study are relevant and represent an important step in the understanding of physiopathological mechanisms in stretch marks, opening new horizons for new directions in research of SD and other alterations in connective tissues as well. / Doutorado / Clinica Medica / Doutor em Clínica Médica