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Carvalhosa, Artur Aburad de. ""Pesquisa dos receptores de estrógeno (RE) e do receptor da progesterona (RP) in vivo e verificação da influência destes hormônios in vitro em duas linhagens de adenomas pelomórficos"." Universidade de São Paulo, 2001. http://www.teses.usp.br/teses/disponiveis/23/23141/tde-02042004-115521/.
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RESUMO A similaridade entre o tecido da mama e o da glândula salivar está bem estabelecida. A porção das estruturas acinares e ductais destes órgãos são basicamente semelhantes. Estes aspectos, associados ao fato de que uma coexistência de carcinomas da mama e de glândula salivar, têm sido relatados em uma incidência maior do que a esperada. Guiaram estudos tentando determinar a importância dos receptores de estrógeno e progesterona em adenomas pleomórficos (AP). A neoplasia é mais freqüente nas glândulas salivares e exibe uma predileção para o sexo feminino. Recentemente a presença do receptor de estrógeno (RE) e do receptor de progesterona (RP) tem sido investigada no AP, entre outras neoplasias de glândula salivar, questionando-se a possibilidade da existência da dependência hormonal. A expressão dos receptores hormonais nos carcinomas de mama é importante para determinar o prognóstico e a probabilidade de responder à manipulação hormonal. Neoplasias que apresentam positividade para ambos os receptores, estrógeno e progesterona, exibem maior probabilidade de resposta à terapia anti-estrogênica do que as neoplasias que são negativas para estes receptores. Baseando-se na literatura científica pertinente, o presente trabalho se propõe a investigar a presença da proteína RE e da proteína RP em APs humanos, relacionando-os com a proliferação de linhagens celulares sob a influência destes hormônios. A técnica utilizada foi a imuno-histoquímica para a pesquisa dos RE e RP em 10 APs emblocados em parafina pertencentes ao arquivo do Serviço de Patologia Cirúrgica da FOUSP, e de duas linhagens de APs estabelecidas no mesmo serviço: uma derivada de um paciente do sexo masculino e a outra de um paciente do sexo feminino. No meio de cultivo onde subculturas destas células proliferavam foram diluídos 17-b-estradiol e progesterona. Através de contagens destas células em períodos pré-determinados (24 horas, 48 horas e 72 horas), pretendeu-se verificar a influência dos respectivos hormônios na multiplicação celular. Como controle positivo utilizou-se uma linhagem denominada T-47D, que foi largamente estudada na literatura. A T-47D é derivada de um carcinoma metastático de mama, reconhecidamente hormônio dependente. E como controle negativo, utilizou-se de uma linhagem de carcinoma epidermóide, denominada HN30. Encontrou-se positividade para o RE em 7 de 10 APs estudados (4 em homens e 3 em mulheres) e positividade para o RP em 8 Aps estudados (4 em mulheres e 4 em homens). Pela análise estatística, constatou-se que existe uma diferença significativa no índice proliferativo entre o controle e as células submetidas à ação do 17-b-estradiol e da progesterona. Para a linhagem derivada do paciente do sexo masculino houve diferença entre o controle e as células expostas ao 17-b-estradiol e a progesterona somente nas últimas 72 horas. Para a linhagem derivada do sexo feminino constatou-se uma diferença significativa entre o controle e as células sob a influência da progesterona, a partir de 48 horas de proliferação celular. A diferença significativa entre o controle e as células sob a ação do 17-b-estradiol ocorreu somente a partir das 72 horas, sugerindo que o AP poderia ser uma neoplasia influenciada pela ação hormonal.SUMARY It is well established the similarity between mammary and salivary glands especially between the acinic and ductile structures. These aspects, associated to the fact of coexistence of breast carcinomas and of salivary gland tumors been described, leaded studies in attempt to determine the importance of the ERs and Pr in pleomorphic adenomas (PA), the most frequent salivary gland tumor and with predilection for the females. Lately, the presence of ERs and of the PRs has been investigated in PA and other salivary gland tumors pointing out their hormonal dependency. The expression of hormone receptors in breast carcinomas is crucial to determine a presence for both receptors. These tumors exhibit better response to anti-estrogenic therapy than the negative ones. Basing on the pertinent scientific literature, the present study proposes to investigate the presence of the RE and of the RP in humans PA and connecting them with cellular proliferation in vitro, under the influence of these hormones. Immunohistochemistry technique was used for the detection of RE and RP in paraffin embedded 10 PAs from the files of the Department of Oral Pathology, School of Dentistry, University of São Paulo, and two PA cell lines one from a male patient and other female. The culture midia was supplied with, 17-b-estradiol and progesterone. A growth curve was performed (24 hours, 48 hours and 72 hours) to verify the influence of the respective hormones in the cellular proliferation. As a positive control T-47-D cells derived from a hormone dependent metastatic breast carcinoma were used, and as negative control HN30 cells, derived from a tongue squamous cell carcinoma. 7 of 10 PAs were positive (4 in men and 3 in women) for RP and 8 of 8 PAs (4 in women and 4 in men) for RE. The statistical analysis verified a significant difference in the proliferative index between the control cells and the ones submitted to the action of the 17-b-estradiol and of the progesterone: for male derived lineage a difference was only observed in the last 72 hours. In the other hand, for the female derived lineage a significant difference was verified starting from 48 hours, suggesting that PA can be influenced by hormonal action.
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Szymanski, de Toledo Maria Carolina 1982. "Expressão dos receptores de estrógeno, progesterona, andrógeno e HER2 no câncer epitelial de ovário : Expression of estrogen, progesterone, androgen and HER2 receptors in the epithelial ovarian cancer." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310530.
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Orientadores: Luis Otávio Zanatta Sarian, Sophie Françoise Mauricette DerchainDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
Made available in DSpace on 2018-11-07T13:36:45Z (GMT). No. of bitstreams: 1 Toledo_MariaCarolinaSzymanski_M.pdf: 838964 bytes, checksum: 3c546db1a656989db9f433b93287b2d2 (MD5) Previous issue date: 2012
Resumo: Introdução: o câncer de ovário é comumente diagnosticado em estágios avançados, sendo atualmente a neoplasia ginecológica de maior letalidade. As pesquisas têm direcionado esforços na tentativa de descobrir novos fatores prognósticos e métodos terapêuticos. Muitos trabalhos estudam a expressão dos receptores de esteróides (dentre eles, estrógeno (RE), progesterona (RP) e andrógeno (RA)) e HER2 (receptor estimulador de crescimento epitelial - subtipo 2) como fatores prognósticos e associados à resposta terapêutica, apresentando; entretanto, resultados conflitantes. Até onde conhecemos, não há estudos desta natureza no Brasil. Objetivo: Correlacionar à expressão dos RE, RP, RA e HER2 aos fatores clínico patológicos, ao intervalo livre de doença e à sobrevida nos cânceres epiteliais de ovário. Material e métodos: Este é um estudo observacional de coorte retrospectiva. Foram incluídas 152 mulheres com tumores epiteliais malignos, selecionados através dos prontuários no período de 1993 a 2008, no Centro de Atenção Integral à Saúde da Mulher (CAISM) da Universidade Estadual de Campinas - UNICAMP, São Paulo, Brasil. A avaliação da expressão dos RE [subtipos alfa (RE?) e beta (RE?)], RP, RA e HER2 foram realizadas por imunoistoquímica através da construção de microarranjos de tecidos (TMA). Inicialmente, foi realizada análise uni variada da expressão dos receptores acima quanto à idade, estado menopausal, índice de massa corpórea (IMC), tipo histológico, grau histológico, estadiamento inicial de acordo com a classificação proposta pela FIGO e presença de doença residual pós-tratamento cirúrgico. Em seguida, as pacientes foram divididas em dois grupos: ausência da expressão de RE?, RP e HER2 (triplo negativo) e positividade para pelo menos um desses receptores (não triplo negativo); e, avaliadas em relação aos critérios clínicos e epidemiológicos acima. Foram, então, realizadas análises multivariadas dos padrões de expressão de RE ? e ?, RP, RA, HER2 e triplo negativo em relação a estes mesmos critérios. Por fim, análise de sobrevida multivariada foi realizada utilizando-se todos os padrões de expressão e os fatores clínicos epidemiológicos estudados. Resultados: Nas análises multivariadas, mostraram-se significativas as seguintes associações: do receptor de estrógeno alfa (ER?) com tumores de grau histológico menos diferenciado (p=0.01); do receptor de progesterona (RP) à obesidade (p= 0.01); do receptor de andrógeno (RA) com tumores do subtipo seroso (p= 0.01); do receptor de HER2 com tumores dos graus histológicos II-III (p=0.02); do subgrupo triplo negativo com tumores de grau histológico menos diferenciado (II-III) (p<0.01). Não houve associação do RE? com nenhum dos fatores estudados. Quanto à análise multivariada de sobrevida livre de doença e sobrevida global; dentre os padrões de expressão de receptores, apenas o RE? esteve associado com melhor sobrevida livre de doença (RR=0.39; 95%CI 0.17 -0.90). Conclusões: A expressão do RE? esteve mais significativamente associada a fatores clínicos de pior prognóstico. O RP esteve associado à obesidade. O RA esteve significativamente mais presente nos tumores serosos. A expressão do HER2 e a presença de tumores triplo negativo foram maiores em tumores menos diferenciados. Paradoxalmente; o RE? foi o único receptor a apresentar associação com maior sobrevida livre de doença apesar de sua relação significativa com fatores reconhecidos de pior evolução clínica. Não houve diferença estatística significativa na análise multivariada de sobrevida total e sobrevida livre de doença quanto ao grupo de tumores triplo negativo
Abstract: Introduction: Ovarian cancer is commonly diagnosed in advanced stages and currently is the most lethal gynecological malignancy. Surveys have focused efforts in an attempt to discover new prognostic and therapeutic methods. A plenty of studies investigates the expression of steroid receptors (among them, estrogen (ER), progesterone (PR) and androgen AR)) and HER2 (epidermal growth receptor stimulator - subtype 2) as prognostic factors and associated to therapeutic response, presenting, however, conflicting results. As far as we know, there are no studies of this nature in Brazil. Objective: The aim of this study was to correlate the expression of ER (subtypes ? (ER ?) and ? (ER ?), PR, AR and HER2 to clinical pathological factors, the disease-free survival and overall survival of epithelial ovarian cancers. Methods: This is a retrospective observational cohort study. The study included 152 women with malignant epithelial tumors, selected through the records from 1993 to 2008, in the Centro de Atenção Integral à Saúde da Mulher (CAISM) at the State University of Campinas - UNICAMP, São Paulo, Brazil. The expression of ER (? and ?), PR, AR and HER2 was evaluated by immuno histochemistry through tissue microarray (TMA) technique. Initially, univariate analyses were performed, evaluating the expression of each receptor mentioned above to age, menopausal status, body mass index (BMI), histological type, histological grade, initial staging as preconized by FIGO staging of ovarian tumors and presence of residual disease after surgical treatment. Then, the patients were divided into two groups: absence of the expression of ER?, PR and HER2 (triple negative) and positive for at least one of these receptors (not triple negative), and evaluated in relation to the clinical and epidemiological criteria mentioned above. Multivariate analyzes were performed with ER ?, ER?, PR, AR, HER2 and triple negative towards these same criteria. At last, multivariate survival analyses were conducted using all the patterns of receptors' expression, epidemiological and clinical factors studied. Results: In multivariate analyzes, there were the following significant associations: of the estrogen receptor alpha (ER?) with less differentiated histological grade tumors (p = 0.01); of the progesterone receptor (PR) to obesity (p = 0.01); of the androgen receptor (AR) with the serous tumors (p = 0.01); of the HER2 receptor with tumors of histological grades II-III ( p = 0.02); of the triple negative subgroup with less differentiated histological grade tumors (II-III) (p <0.01). There was no association of the ER? with any of the factors studied. In the multivariate analysis of disease-free survival and overall survival; considering the patterns of receptors' expression, only the ER? expression was associated with better disease-free survival (RR= 0.39, 95% CI 0.17 to 0.90). Conclusions: The expression of ER? was more significantly associated with clinical factors of poor prognosis. The PR was associated with obesity. The AR was significantly more prevalent in serous tumors. The HER2 expression and the presence of triple negative epithelial ovarian cancer tumors were higher in less differentiated tumors. Paradoxically, the ER? was the only receptor which showed association with better disease-free survival despite its significant relationship with recognized factors of worse clinical outcome. There was no statistically significant difference in multivariate analysis of overall survival and disease-free survival regarding to the triple negative group
Mestrado
Oncologia Ginecológica e Mamária
Mestra em Ciências da Saúde
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Tran, Thuyet Van. "Modulation of folate receptor-[alpha] by glucocorticoid receptor and progesterone receptor." Connect to full-text via OhioLINK ETD Center, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=mco1104777244.
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Thesis (Ph. D.)--Medical College of Ohio, 2004."In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Medical Sciences." Major advisor: Manohar Ratnam. Includes abstract. Document formatted into pages: iii, 293 p. Title from title page of PDF document. Includes bibliographical references (p. 175-281).
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Tran, Thuyet Van. "Modulation of Folate Receptor-alpha by Glucocorticoid Receptor and Progesterone Receptor." University of Toledo Health Science Campus / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=mco1104777244.
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Yu, Yue. "The progesterone receptors in human prostate." Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/46509.
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The prostate composes of epithelium and stroma, both of which are kept in balance to maintain normal prostate function. The balance between epithelium and stroma can be disrupted by the abnormal growth of stromal cells which results in prostate diseases such as benign prostatic hyperplasia. The epithelial-stromal interaction plays important roles not only in normal prostate homeostasis maintaining but also in prostate cancer development and progression. In prostate tumor, cancer associated fibroblasts enhance the secretions of cytokines and growth factors to favor cancer cells growth and metastasis. Androgen receptors are reported to regulate the development and maintenance the function of prostate. Progesterone receptor (PR) which belongs to the same steroid hormone receptor family as androgen receptors are little known in prostate. PR was reported to express in prostate, but there is no clear conclusion about the localization and function of PR in human prostate.
The objective of this thesis is to investigate the expression and function of PR in human prostate. Two PR isoforms, PRA and PRB, are detected in subsets of the human prostate stromal cells by applying immunohistochemistry assays. Both PR isoforms express specifically in human prostate stromal fibroblasts and smooth muscle cells. Both PRA and PRB are demonstrated to play an inhibitory role in prostate stromal cell proliferation. PR suppresses the expression of cyclin A, cyclinB and cdc25c to delay cell cycle. PRA and PRB are demonstrated to regulate different transcriptomes by gene microarray assay. Immunohistochemistry assays were applied to human prostate cancer tissue biopsies, and PR levels are detected to decrease in the cancer associated stroma compared to the paired normal stroma. The conditioned media from PR positive stromal cell inhibit PC-3 and C4-2B cell motility through down-regulating the secretion of stromal cell derived factor 1 and interleukin 6. We conclude that PRA and PRB express in prostate stromal cells and inhibit the stromal cells proliferation. Decreased expression of PR in cancer associated stroma contributes to prostate tumor progression.
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Stavréus-Evers, Anneli. "Implantation : morphological and biochemical characterization of the receptive human endometrium /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-313-9.
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Hild-Petito, Sheri Ann. "Distribution of estrogen and progesterone receptors in the primate ovary, with emphasis on subpopulations of cells within the corpus luteum." Diss., The University of Arizona, 1988. http://hdl.handle.net/10150/184485.
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Both estradiol and progeterone are proposed autocrine or paracrine regulators of ovarian function in primate species. However, specific receptors for these steroids have not been localized to individual compartments of the primate ovary. Using immunocytochemical techniques, estradiol receptors were detected in the germinal epithelium, but not other structures, of ovaries obtained from rhesus or cynomolgus monkeys during the follicular and luteal phases of the menstrual cycle. In contrast, progesterone receptors were present in stromal and interstitial tissue, the thecal layers of healthy and atretic follicles, as well as the functional corpus luteum. These results are consistent with the concept of a receptor-mediated role for progesterone, but not estrogen, within the predominant gametogenic and endocrine structures, e.g., the follicle and corpus luteum, of the primate ovary. The recent discovery of distinct cell types in the corpus luteum of domestic ungulates has revised concepts on the control of luteal function in these species. Studies were designed to test the hypothesis that the primate corpus luteum consists of cell subpopulations that differ in physical characteristics, function and regulation. Cells enzymatically-dispersed from the monkey corpus luteum at mid-luteal phase of the menstrual cycle differed in size (diameter) and the presence of the steroidogenic enzyme, 3β-hydroxysteroid dehydrogenase (3β-HSD). Analysis of dispersed cells for forward and 90° light scatter properties by flow cytometry revealed two distinct continua (Cα and Cβ). These continua were isolated using the sorting capabilities of the flow cytometer. Cα contained single cells of ≤ 15 μm and cell clusters; the cells were typically 3β-HSD-negative nonsteroidogenic. Cβ consisted of single cells that increased in size up to 40 μm and were 3β-HSD-positive. Cβ was divided into two regions (R₁ and R₃) and the cells isolated. R₁ cells were ≤ 15 μm whereas R₃ cells were ≥ 20 μm. Basal progesterone and estrogen production by R₃ cells was greater than that produced by R₁ cells (as determined by radioimmunoassay of the incubation media). Relative stimulation of progesterone production by hCG, cAMP or PGE₂ was not different between R₁ and R₃ luteal cells. These results support the hypothesis that the primate corpus luteum consists of distinct cell subpopulations which differ in size and steroidogenic capacity. However, the cell types which secrete progesterone are typically responsive to gonadotropin and PGE₂, possibly via a cAMP-mediated pathway.
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Zhu, Xiaoyan. "Progesterone in Stroke Cerebroprotection : Metabolites, Target Cells, and Role of Neural Progesterone Receptors (PR)." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS449.
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L’accident vasculaire cérébral (AVC) déclenche une cascade de changements qui conduisent à la mort cellulaire mais aussi des processus endogènes de protection en réponse à l'ischémie. La compréhension de ces processus est très importante pour le développement d’agents neuro-protecteurs potentiels qui peuvent être seulement des amplificateurs des processus endogènes. Le traitement par la progestérone est neuro-protecteur dans des modèles expérimentaux d’occlusion de l'artère cérébrale moyenne (MCAO). Cependant, des niveaux endogènes significatifs de progestérone sont mesurables dans le cerveau de souris mâles et femelles.Le but de notre travail était d'étudier: 1) les effets de l’ischémie sur les niveaux endogènes des stéroïdes et le rôle des récepteurs de la progestérone (PR) à la phase aiguë après ischémie chez les souris jeunes adultes et âgées des deux sexes; 2) la base cellulaire de la neuroprotection par la progestérone après ischémie et le rôle de PR neural. Nous avons utilisé un modèle d’ischémie expérimentale (MCAO); une lignée transgénique de souris (PRNesCre) dans laquelle l’expression de PR a été sélectivement invalidée dans les cellules neurales; la chromatographie en phase gazeuse-spectrométrie de masse en tandem (GC-MS/MS); et des analyses histologiques, comportementales, et d’immunofluorescence.Dans la première partie, nous avons montré que dans le cerveau de souris mâles la progestérone est principalement convertie en 5a-dihydroprogestérone (5a-DHP), qui est un agoniste naturel de PR. Après MCAO, les niveaux de progestérone et de 5a-DHP cérébrales augment chez les mâles, mais pas chez les femelles. En revanche, les femelles peuvent utiliser l’inter-conversion de la 20a-dihydroprogestérone et de la progestérone pour réguler la disponibilité des pregnanes actifs au niveau de PR. De plus, les souris PRNesCre, mâles et femelles jeunes adultes et âgées, ont des infarctus plus grands et des déficits sensori-moteurs plus importants ainsi qu’une diminution de la densité des neurones et de la microglie activée comparativement aux souris témoins PRloxP/loxP. En outre, nos résultats ont révélé des différences liées au sexe chez les souris jeunes, mais pas chez les souris âgées. Dans la deuxième partie de l'étude, nous avons montré que, chez les souris mâles PRloxP/loxP, le traitement par la progestérone améliore la récupération fonctionnelle et réduit le volume de l'infarctus. Dans le péri-infarctus, la progestérone augmente la densité des neurones, des oligodendrocytes et de leurs précurseurs, et diminue la densité des astrocytes et de la microglie activée, et l'expression de l’aquaporine 4. Ces effets de la progestérone n’ont pas été observés chez les souris PRNesCre.Nos résultats montrent 1) l'importance des pregnanes endogènes et du PR neural pour la protection cérébrale à la phase aiguë précoce après une ischémie; 2) que le traitement par la progestérone chez les souris mâles après ischémie a des effets neuro-protecteurs, pro-myélinisants et anti-inflammatoires et que PR neural est requis pour la médiation de ces effets. Ces données suggèrent fortement que les ligands de PR ou des agents ciblant leur signalisation en aval pourraient être développés pour la neuro-protection après un AVCIschemic stroke initiates a cascade of changes that lead to cell death and also coordinates endogenous processes that counteract the nocuous consequences of ischemia. Understanding these processes is very important for the development of potential neuroprotectants which can be just boosters of endogenous processes. Treatment with exogenous progesterone is neuroprotective after middle cerebral artery occlusion (MCAO). However, the male and female brains contain significant amounts of endogenous progesterone.The aim of our work was to study: 1) the effects of MCAO on the endogenous levels of steroids and the role of neural progesterone receptors (PR) at the acute phase after stoke in young and aging mice of both sexes; 2) the cellular basis of the neuroprotection by progesterone following stroke and the role of neural PR. We used an in vivo model of MCAO; a transgenic mice line (PRNesCre) selectively lacking the expression of PR in neural cells; gas chromatography-tandem mass spectrometry (GC-MS/MS); and histological, behavioral, and immunofluorescence analyses.In the first part of the study, we showed that in the male mouse brain, progesterone is mainly converted to 5a-dihydroprogesterone (5a-DHP), which is a natural PR agonist ligand. After MCAO, brain levels of progesterone and 5a-DHP are rapidly upregulated in males but not in females. In contrast, females may use the interconversion of 20a-dihydroprogesterone and progesterone for regulating the availability of PR-active pregnanes. Moreover, young and aging male and female PRNesCre mice exhibited increased infarcts, severe sensorimotor deficits, and decreased densities of neurons and microglia comparatively to age-matched control mice PRloxP/loxP. In addition, our results revealed sex differences in stroke outcomes in young but not in aging mice. In the second part of the study, we showed that, in male PRloxP/loxP mice, progesterone improved sensorimotor outcomes and reduced infarct volumes. In the peri-infarct, progesterone increased the densities of neurons, oligodendrocytes and their precursors, decreased the densities of activated astrocytes and microglia, and the expression of the aquaporin 4. These beneficial effects of progesterone were not observed in PRNesCre mice.Our findings 1) uncover the importance of endogenous pregnanes and neural PR for the cerebroprotection at the early acute phase after stroke; 2) show that progesterone treatment in male mice has neuro-protectant, pro-myelinating and anti-inflammatory effects after MCAO and that neural PR is required for the mediation of these effects. These data strongly suggest that ligands of PR or agents targeting their downstream signaling could be developed for neuroprotection after stroke
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Khan, Junaid Ali. "Progesterone Receptor Isoforms : functional Selectivity and Pharmacological Targeting." Phd thesis, Université Paris Sud - Paris XI, 2011. http://tel.archives-ouvertes.fr/tel-00769945.
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Progesterone receptor (PR) is an essential pharmacological target for contraception, female reproductive disorders as well as for hormone-dependent breast and uterine cancers. Human PR is expressed as two major isoforms PRA and PRB which behave as distinct transcriptional factors. PRA vs PRB expression is often altered under pathological conditions notably breast cancer through unknown mechanisms. In this thesis we demonstrate that down-regulations of PRB and PRA proteins are negatively controlled by key phosphorylation events involving distinct MAP kinase signaling. PRA is selectively stabilized by p38 MAPK whereas p42/44 MAPK specifically controls PRB stability leading to unbalanced PRA/PRB ratios in a ligand sensitive manner. In cancer cells, elevated extracellular stimuli such as epidermal growth factors or pro-inflammatory cytokines that preferentially activate p42/44 or p38 MAPK respectively may result in opposite variations in PRA/PRB expression ratio. These results may explain altered PRA/PRB ratios often associated with breast tumors. To get a mechanistic understanding of how varied PRA/PRB ratio contributes in cell signaling, we generated an original bi-inducible PR-isoform cell model allowing selective, reversible and dose-dependent expression of PRA and/or PRB, enabling fine-tune adjustment of PRA/PRB ratio in the same cells. Using this cell-based system, we undertook genome-wide transcriptomic studies to investigate transcriptional regulation driven by unliganded and liganded PR isoforms. We report that several aspects of PR signaling such as target gene selection/transcriptional regulation, cross-talk with growth factors and antiproliferative efficacy of antiprogestin are highly dependent upon variation in PRA/PRB ratio. A new potential therapeutic strategy in PR-dependent pathological conditions may rely on the use of PR antagonists. Most of the currently available antiprogestins such as mifepristone present partial agonist activity and are not selective to PR leading to undesirable side effects. Therefore, in a collaborative project we have synthesized and characterized several new PR antagonist compounds named as APRn. Structure-activity relationship studies allowed identification of the key substitutions in steroidal skeleton responsible for agonist/antagonist character of these molecules. Several selected APRn lack partial agonist effect, are PR specific and inhibit PR transcriptional properties through a new passive mechanism of action i.e. impaired recruitment of transcriptional coregulators. Such PR selective antagonists devoid of partial agonist character might provide important therapeutic perspectives for various reproductive tract abnormalities and hormone-dependent uterine and breast cancers. Altogehter, our results provide mechanistic insights into the functional selectivity of PR isoforms and their pharmacological targeting by the use of PR antagonists.
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Bolden-Tiller, Olga U. "Characterization of progesterone receptor in bovine corpora lutea /." free to MU campus, to others for purchase, 2002. http://wwwlib.umi.com/cr/mo/fullcit?p3074376.
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Wilson, Rachel Abigail. "REGULATION OF PHOSPHORYLATED PROGESTERONE RECEPTOR-A IN UTERINE MYOMETRIAL CELLS." Case Western Reserve University School of Graduate Studies / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case160795772020875.
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Hampton, Kaia K. "THE ROLE OF PROGESTERONE RECEPTOR MEMBRANE COMPONENT 1 IN RECEPTOR TRAFFICKING AND DISEASE." UKnowledge, 2017. https://uknowledge.uky.edu/pharmacol_etds/21.
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The progesterone receptor membrane component 1 (PGRMC1) is a multifunctional protein with a heme-binding domain that promotes cellular signaling via receptor trafficking, and is essential for some elements of tumor growth and metastasis. PGRMC1 is upregulated in breast, colon, lung and thyroid tumors. We expanded the analysis of PGRMC1 in the clinical setting, and report the first analysis of PGRMC1 in human oral cavity and ovarian tumors and found PGRMC1 to correlate with lung and ovarian cancer patient survival. Furthermore, we discovered a specific role for PGRMC1 in cancer stem cell viability. PGRMC1 directly associates with the epidermal growth factor (EGFR) in cancer cells, and we reviewed multiple signaling-associated pathways that are important in trafficking wild-type and mutant EGFR. To better understand the potential of PGRMC1 in receptor tyrosine kinase trafficking, we extended our research to the insulin receptor (IR). Changes in insulin signaling have been linked to multiple diseases, because IR plays a key role in glucose metabolism, cellular survival and proliferation. We found PGRMC1 to co-precipitate with IR in cancer cells and in an adipose model system. PGRMC1 increased IR plasma membrane levels in multiple cancer cell lines, and was also found to increase plasma membrane levels of two glucose transporters. Treatment with a PGRMC1 ligand significantly increased IR levels in human adipocytes. Moreover, we demonstrate that both insulin binding and glucose uptake are dependent on PGRMC1.
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Gray, Phillip Neal. "Characterization of the membrane associated progesterone receptor (MAPR) homologues in Saccharomyces cervisiae and Arabidopsis thaliana." Diss., Georgia Institute of Technology, 2001. http://hdl.handle.net/1853/25589.
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Gonçalves, José Sergio de Arruda. "Análise da expressão gênica diferencial dos receptores de estrógeno (erα e erβ) e progesterona (pr) em oócitos e células do cumulus nas diferentes fases do ciclo estral em cães." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/10/10131/tde-13122007-150929/.
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O objetivo do presente estudo foi analisar a expressão gênica dos receptores de estrógeno (ERα e ERβ) e progesterona (PR) em oócitos e células do cumulus de cadelas nas diferentes fases do ciclo estral. Ovários de cadelas previamente avaliadas e submetidas à ovário-histerectomia foram fatiados, sob refrigeração, em PBS com 10% de SFB. No momento imediatamente pré-cirúrgico foi colhido sangue da cadela, que foi submetido posteriormente à dosagem de estradiol e progesterona. As cadelas foram agrupadas nas diferentes fases do ciclo estral de acordo com a avaliação prévia por colpocitologia, colposcopia e dosagem sérica de progesterona. Os oócitos recuperados após o fatiamento foram denudados mecanicamente. Oócitos e células do cumulus foram criopreservados separadamente e posteriormente foram submetidas a PCR em tempo real para quantificação relativa dos genes de interesse. A expressão gênica de ERα, ERβ e PR em oócitos e células do cumulus não foi diferente nas fases do ciclo estral. Foi possível, pela primeira vez, relatar a presença de ERα e ERβ em oócitos de cadelas.The objective of the present study was to analyze the gene expression of estrogen (ERα and ERβ) and progesterone (PR) receptors in oocytes and cumulus cells on different phases of the estrous cycle in dogs. Ovaries from selected bitches were recovered after ovary-hysterectomy and sliced at low temperatures in PBS supplemented with 10% FCS. Immediately after surgery, blood samples were harvested for measurement of estrogen and progesterone serum concentration. Bitches were grouped within different phases of the estrous cycles, according to previous evaluation of colpocytology, colposcopy and serum progesterone levels. Oocytes recovered after slicing were mechanically denuded. Isolated oocytes and cumulus cells were cryopreserved and submitted to RT-PCR followed by a real time PCR for relative quantification of gene expression. Gene expression of ERα, ERβ and PR in oocytes and cumulus cells was not different among phases of the estrous cycles. For the first time it was possible to demonstrate ERα and ERβ in dog oocytes.
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Roemer, Sarah Clark. "Structural and functional analysis of progesterone receptor-DNA interaction /." Connect to full text via ProQuest. IP filtered, 2005.
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Thesis (Ph.D. in Molecular Biology) -- University of Colorado at Denver and Health Sciences Center, 2005.Typescript. Includes bibliographical references (leaves 165-185). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;
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Birzniece, Vita. "Neuroactive steroids and rat CNS." Doctoral thesis, Umeå : Univ, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-296.
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Oudanonh, Thiphavone. "Progesterone receptor, obesity and prognosis in women diagnosed with estrogen receptor positive breast cancer." Master's thesis, Université Laval, 2020. http://hdl.handle.net/20.500.11794/67944.
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INTRODUCTION: Le pronostic du cancer du sein (CS) est délétère pour les femmes obèses comparé à celles de poids normal et pourrait dépendre du statut du récepteur de la progestérone (PR). L’objectif était d’examiner si l’association entre l’obésité et la mortalité varie selon le statut de PR chez les femmes avec un CS positif pour le récepteur d’estrogène (ER+). MÉTHODOLOGIE: Les 3747 femmes diagnostiquées au Centre des Maladies du Sein d’un CS ER+ non métastatique entre 1995 et 2010 étaient catégorisées selon l’indice de masse corporelle (IMC) (<18,5; 18,5-24,9; 25,0-29,9; ≥30,0 kg/m²) et le statut de PR (PR–; PR+). Les risques instantanés (HR) de mortalité globale et spécifique au CS et leur 95% intervalle de confiance (IC) étaient estimés par des modèles de Cox multivariés. L’effet modifiant de PR était évalué sur les échelles additive et multiplicative. RÉSULTATS: Après un suivi médian de 5,9 années, le risque de mortalité globale pour les femmes avec une tumeur PR– augmentait en moyenne par 2,76 (95%IC:1,40-4,91) pour celles de faible poids, 2,02 (95%IC:1,43-2,81) pour celles en surpoids et 2,51 (95%IC:1,67-3,65) pour celles obèses, comparé aux femmes de poids normal avec une tumeur PR+. Des augmentations similaires étaient observées pour la mortalité spécifique au CS. Les risques de mortalité étaient similaires pour les femmes avec une tumeur PR+, peu importe leur IMC. Le risque de mortalité globale était modifié positivement par le statut de PR sur l’échelle additive chez les femmes en surpoids et obèses, tandis que la mortalité spécifique au CS était modifiée positivement chez les femmes de faible poids. Des observations similaires ont été trouvées sur l’échelle multiplicative. CONCLUSION: Notre étude suggère que le risque de décès plus élevé chez les femmes de faible poids, en surpoids et obèses avec un CS ER+ pourrait être lié au statut de PR.INTRODUCTION: Studies have shown that prognosis for breast cancer (BC) was worse for obese than normal weight women. This differential survival might depend on the progesterone receptor (PR) status of the tumor. Our objective was to examine whether the association between obesity and mortality varies by PR status among women with estrogen receptor positive (ER+) BC. METHODS: The 3747 women diagnosed at the Center of Breast Diseases with non metastatic invasive ER+ BC between 1995 and 2010 were included in the analyses, and classified according to the body mass index (BMI) (<18.5, 18.5-24.9, 25.0-29.9, ≥30.0 kg/m²) and tumor PR status (PR–, PR+). Hazard ratios (HR) for all-cause and BC-specific mortalities, and 95% confidence interval (95%CI) were estimated from multivariable Cox proportional hazards models. Effect modification was evaluated on the additive and multiplicative scales using relative excess risk due to interaction (RERI) and ratio of HR, respectively. RESULTS: After a median follow-up of 5.9 years, the risk of all-cause mortality was increased on average by 2.76 (95%CI: 1.40-4.91) for underweight women with PR– tumors, by 2.02 (95%CI: 1.43-2.81) for overweight women with PR– tumors and by 2.51 (95%CI:1.67-3.65) for obese women with PR– tumors compared to women with normal weight and PR+ tumors. Similar increased risks were observed for BC-specific mortality. Conversely, risks of mortality were similar for women with PR+ tumors, regardless of BMI. All-cause mortality was modified by PR status on the additive scale for overweight (RERI=0.85,95%CI: 0.18-1.52) and obese women (RERI=1.28, 95%CI: 0.31-2.25), whereas BC-specific mortality was modified for underweight women (RERI=3.57, 95%CI: 0.25-6.88). Similar observations were found on the multiplicative scale. CONCLUSION: Our study suggests that the higher risk of dying observed among underweight, overweight and obese women with ER+ BC could be related to the PR status of the tumor.
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Fochi, Ricardo Alexandre 1982. "Influência da progesterona sobre a próstata do gerbilo (Meriones unguiculatus) = interações com o estrógeno e com a testosterona = Progesterone influence on gerbil (Meriones unguiculatus) prostat e: interactions with estrogen and testosterone." [s.n.], 2013. http://repositorio.unicamp.br/jspui/handle/REPOSIP/317913.
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Orientador: Sebastião Roberto TabogaTese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: A próstata, glândula do sistema genital que tem origem embrionária a partir do seio urogenital, não é exclusiva do sistema reprodutor masculino, sendo também encontrada em fêmeas de vários mamíferos, incluindo humanos e roedores. No macho ela pode apresentar-se altamente desenvolvida em razão da maior quantidade do hormônio testosterona, e, apesar de pouco desenvolvida em fêmeas, devido à baixa quantidade desse mesmo tipo hormonal, é uma glândula funcional. Em fêmeas adultas de gerbilos, a próstata possui uma localização parauretral, exibindo íntimo contato com a parede proximal e medial da uretra, a qual é homóloga a próstata ventral de roedores machos. Embora se conheça a influência da progesterona na fisiologia do sistema reprodutor feminino e masculino, poucos estudos exploram a sua influência, especificamente, sobre a glândula prostática. Desta forma, este trabalho avaliou os aspectos morfofuncionais da glândula prostática masculina e feminina, resultantes da influência da progesterona, e de suas interações com o estradiol e a testosterona. Para isso, gerbilos machos e fêmeas foram castrados cirurgicamente no início do período puberal, aos 45 dias de idade. Ao completarem 90 dias de idade, os gerbilos receberam doses subcutâneas de progesterona ou desse somado a estradiol e testosterona, durante 14 dias. Nos animais castrados de ambos os sexos a próstata mostrou uma morfologia regredida, com uma redução significativa na sua capacidade de secreção, da quantidade de células receptoras de androgênio (AR) e receptoras de estrógeno ? (ER?), porém sem alterar a marcação para receptor de estrógeno ? (ER?). Dessa forma, a castração cirúrgica foi bastante importante, uma vez que permitiu mimetizar de forma satisfatória um ambiente prostático com baixos níveis hormonais. Nos dois sexos, a administração de progesterona isoladamente conseguiu reverter alguns desses efeitos, com uma melhora considerável no padrão secretório da glândula, porém estruturalmente essas mudanças ocorreram de forma moderada. Nesses animais, foi observado um aumento expressivo dos ERs ? e ?, além da presença de células receptoras de progesterona (PR). Em relação aos ARs foi evidenciado que a progesterona pode apresentar características indutoras ou inibitórias dependendo da sua concentração. O tratamento, simultâneo com a progesterona, de estradiol e testosterona desencadeou uma reestruturação glandular mais intensa nos machos e fêmeas, resultando em hipertrofia e hiperplasia do epitélio e do estroma glandular, recuperação do padrão de secreção e amplitude alveolar. Essas características, no entanto, foram acompanhadas pelo surgimento de lesões prostáticas como neoplasias intraepiteliais e o surgimento de debris celulares. A interação da progesterona com o estradiol também regulou positivamente os AR, ER? e ER?, porém não apresentou qualquer efeito sobre os PRs quando comparado aos animais tratados somente com progesterona. Em adição, nesses animais houve um aumento acentuado da proliferação celular, o qual foi contrabalanceado pelo aumento também do índice de morte celular. Nos animais tratados com progesterona e testosterona, a próstata também se desenvolveu e mostrou um aumento das células AR-positivas e do índice apoptótico, havendo, entretanto uma redução dos ER?, ER? e PR. Dessa forma, é razoável concluir que a próstata feminina e masculina comporta-se de forma bastante semelhante frente à ação dos hormônios progesterona, estradiol e testosterona. Ademais, embora a progesterona apresente efeitos estruturais razoáveis na glândula prostática, a sua interação com o estrógeno e a testosterona é capaz de promover uma intensificação desses efeitos, sem recriar, porém um ambiente homeostático semelhante aos dos animais intactos. A progesterona também mostrou ser um fator regulador em potencial da atividade proliferativa e apoptótica prostática, opondo-se aos efeitos da testosterona e do estradiol. Outro fator importante é a descoberta de que a progesterona pode induzir ou inibir a presença de células AR-positivas na glândula, e que esse dualismo funcional é resultado do efeito dose-dependente desse hormônio sobre a próstata
Abstract: The prostate is a gland of reproductive system that arises from the urogenital sinus, being located around the urethra below the bladder. The existence of this gland is not exclusive of the male reproductive system, being found in females of various species, including rodents and humans. In the male, it can be highly developed due to the increased amount of the testosterone, and although poorly developed in females, due to the low quantity of this hormone, it is a functional gland. The prostate of female gerbils has a paraurethral location, showing a closer contact with the proximal and medial urethra wall, being homologous to the ventral prostate of male rats. This study evaluates the morphofunctional aspects of the prostate gland in males and females, regarding the influence of progesterone, and their interactions with estradiol and testosterone. For this, male and female gerbils were surgically castrated in early pubertal period, at 45 days of age. At 90 days of age, the gerbils received subcutaneous doses of progesterone alone or associated to testosterone or estradiol during 14 days. In castrated animals of both sexes, prostate showed a regressed morphology, with a significant reduction in its secretion capacity, the amount of androgen receptor cells (AR) and estrogen receptor ? (ER?), but without changing the labeling for estrogen receptor ? (ER?). Thereby, surgical castration was very important, since it allowed mimetize a prostatic environment with low hormone levels. In both sexes, the administration of progesterone alone could reverse some of these effects with a considerable secretion improvement, but structurally these changes occurred in a moderate way. In these animals, we observed a significant increase of ER ? and ?, besides the presence of progesterone receptor (PR) cells. Regarding ARs, it was shown that progesterone can have inductor or inhibitory characteristics depending on its concentration. The treatment with progesterone plus estradiol and progesterone plus testosterone triggered a more intense prostate restructuration in male and female, resulting however in a hypertrophy and hyperplasia of the glandular epithelium and stroma, besides recovery of the alveoli amplitude and pattern of cellular secretion. These characteristics, however, were followed by the development of prostatic lesions like intraepithelial neoplasia and cellular desquamation. The progesterone and estradiol interaction also upregulated the AR, ER? and ER?, however had no effect on the PRs when compared to the animals treated with progesterone alone. In addition, in these animals there was a marked increase in cellular proliferation, which was counterbalanced by increased cell death. In animals of either sex treated with progesterone and testosterone, the prostate also became developed and showed an increase of AR-positive cells and apoptotic index, although there was a reduction of ER?, ER? and PR. Thus, it is reasonable to conclude that the female and male prostate behaves similarly after the progesterone, estradiol and testosterone administration. Moreover, although the progesterone has reasonable structural effects on the prostate gland, its interaction with estrogen and testosterone can intensificate these effects, but do not recover a homeostatic environment similar to that of intact animals. The progesterone also proved to be a potential regulatory factor of the proliferative and apoptotic activity, opposing the effects of testosterone and estradiol. Another important finding is that progesterone can induce or inhibit the presence of ARpositive cells in the gland, and this functional dualism is the result of dose-dependent effect of this hormone on the prostate
Doutorado
Biologia Celular
Doutor em Biologia Celular e Estrutural
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Manolitsas, Tom. "An investigation of tumour suppressor genes on chromosome 11 in ovarian cancer." Thesis, University of Southampton, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299413.
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Siauw, Michael. "The effects of progesterone on muscarinic receptors in the heart." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/mq24914.pdf.
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Habbal, Karim. "Anatomical Localization of Membrane Progesterone Receptors in Brainstem Respiratory Areas." Thesis, Université Laval, 2012. http://www.theses.ulaval.ca/2012/29227/29227.pdf.
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La progestérone est un stimulant respiratoire, mais l’implication des différents types de récepteurs de progesterone dans ces effets n’est pas connue. La progesterone possède 2 types de récepteurs: des récepteurs nucléaires (nPR) et des récepteurs membranaires (mPR). nPR est exprimé dans le noyau du tractus solitatrius (NTS), un des noyaux du tronc cérébral impliquées dans le contrôle respiratoire. En revanche on ne sait pas si les mPR sont exprimés dans ce noyaux. Nous avons effectués des marquages immunohistochimiques sur des coupes de tronc cérébral de souris adultes (mâles). Une coloration dense a été trouvé pour les récepteurs mPRα et mPRβ dans les NTS caudal et rostral, le noyau vague et le noyau hypoglosse. mPRα est exprimé dans les corps cellulaires, tandis que mPRβ se trouve dans les fibres neuronales. Des experiences de double marquage en immunofluorescence montrent une co-localisation de mPRα et mPRβ dans des neurones exprimant la tyrosine hydroxylase, enzyme de synthèse des catécholamines dans le NTS. De plus, la 3β-hydroxystéroïde déshydrogénase, impliquée dans la synthèse de progestérone, est également exprimé dans le NTS. Ces résultats suggèrent que mPRα et mPRβ peuvent jouer un rôle dans le contrôle respiratoire et que la synthèse de progestérone locale peut moduler la fonction respiratoire.Progesterone is a potent respiratory stimulant, but the implication of progesterone receptor subtypes on this effect are not known. Progesterone has two main types of receptors, the "classical" nuclear receptor, and the recently identified membrane progesterone receptors. While it has been shown that the nuclear progesterone receptor is expressed in the nucleus tractus solitatrius, a brainstem nuclei involved in respiratory control, much less is known relatively to the expression of membrane progesterone receptors in this area. Accordingly, we used immunohistochemistry to determine the localization of membrane progesterone receptors (mPR) in respiratory-related areas in the brainstem of adult male mice. Serial slices were incubated with antibodies against alpha and beta mPR (mPRα and mPRβ). A prominent staining for mPRα, and mPRβ appeared in caudal and rostral parts of the nucleus tractus solitarius (NTS), X and XII nuclei, but while mPRα stained cell bodies, mPRβ stained fibers. With double fluorescence labeling and confocal microscopy we showed that mPRα is co-localized in catecholaminergic neurons (TH+) in NTS. mPRβ is expressed in TH+ fibers in these regions. Furthermore, 3β- hydroxysteroid dehydrogenase (3β-HSD), which is involved in progesterone synthesis, was also densily expressed in these regions. These results suggest that mPRα and mPRβ may play a role in respiratory control, and that local progesterone synthesis may modulate respiratory function.
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Choi, Hosoon. "mPR (membrane associated progesterone receptor) homologues in plants and mammals." Diss., Georgia Institute of Technology, 2000. http://hdl.handle.net/1853/25372.
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Rung, Emilia. "Progesterone receptor-mediated effects on apoptosis in periovulatory granulosa cells /." Göteborg : Institute of Neuroscience and Physiology, The Sahlgrenska Academy at Göteborg University, 2006. http://hdl.handle.net/2077/771.
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Tanja, Lakić. "Klinička vrednost određivanja Ki-67 proliferativnog indeksa u karcinomima dojke sa pozitivnim hormonskim receptorima." Phd thesis, Univerzitet u Novom Sadu, Medicinski fakultet u Novom Sadu, 2018. https://www.cris.uns.ac.rs/record.jsf?recordId=107631&source=NDLTD&language=en.
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Uvod: Karcinom dojke je heterogena bolest koju karakterišu različita morfologija, imunohisto-hemijski profil, klinički tok i terapijski odgovor. Ki-67 proliferativni indeks je jedan od markera sa prognostičkim i prediktivnim značajem, čije metodološko određivanje i analiza još uvek nisu standardizovani. Cilj: Utvrditi graničnu (“cut-off”) prognostičku vrednost Ki-67 indeksa, kao i povezanost vrednosti Ki-67 u ranom luminalnom karcinomu dojke sa prognostičkim i prediktivnim parametrima karcinoma dojke, kao što su životna dob bolesnica, veličina tumora, histološki gradus (HG) i nivo tumorske ekspresije receptora estrogena (ER) i progesterona (PR). Takođe, cilj istraživanja je i utvrđivanje značajnosti razlike u vrednosti Ki-67 proliferativnog indeksa u odnosu na pojavu lokalnog recidiva, udaljenih metastaza i dužinu preživljavanja u toku petogodišnjeg perioda praćenja pacijentkinja. Metode: Retrospektivno je analizirano 120 patohistoloških izveštaja bolesnica kojima je u periodu od 01.01.2009. godine do 31.12.2011. godine na Institutu za onkologiju Vojvodine imunohistohemijskom analizom dokazan luminalni karcinom dojke (pozitivan ER i PR, negativan HER2), bez metastaza u aksilarnim limfnim čvorovima. Rezultati: Metodama deskriptivne statistike prosečna starost pacijentkinja je iznosila 57,42±10,17 godina; prosečna veličina tumora 17,98±6,97mm; recidiv je registrovan kod 8 (6,7%) pacijentkinja uz prosečan vremenski period do pojave recidiva od 49±20,23 meseci. Vrednost “cut off” indeksa Ki-67 od prognostičkog značaja za vremenski period bez recidiva je iznosio 20,75%. Nije dokazana signifikantna veza između vrednosti Ki-67 i godina starosti pacijentkinja (p=0,401, odnosno p=0,293), kao i jačine ekspresije ER (p=1,00, p=0,957) i PR (p=0,273, p=0,189). Ustanovljena je signifikantna povezanost Ki-67 postoji sa veličinom (p=0,035, p=0,20) i HG tumora (p=0,041, p=0,20). Prosečan period praćenja bolesnica iznosio je 72,92±8,38 meseci; nije registrovana pojava udaljenih metastaza, kao ni smrtni ishod. U odnosu na pojavu lokalnog recidiva, Kaplan-Majerovom analizom i Koksovom regresionom analizom proliferativni indeks Ki-67 se pokazao kao signifikantan prediktor za procenu ponovnog javljanja bolesti, lokalnog recidiva (Log rank (df = 1) = 2,73; p=0,045). Takođe je ustanovljeno da je statistički značajan prediktor za procenu recidiva bolesti i starosna dob bolesnica (Log rank (df = 1) = 6,885; p=0,009). Intenzitet pozitivnosti ER i PR, veličina tumora i histološki gradus se nisu pokazali kao prediktori za pojavu recidiva luminalnih karcinoma dojke (p > 0,05). Zaključak: Zbog heterogene prirode oboljenja, korišćenjem standardnih histopatoloških faktora i biomarkera teško je predvideti tok i ishod karcinoma dojke. Ki-67 je proliferativni marker, čija visoka vrednost korelira sa faktorima loše prognoze.Introduction: Breast cancer is a heterogeneous disease characterized by different morphology, immunohistochemical profile, clinical course and response to applied therapy. Ki-67 proliferative index is one of the prognostic and predictive factors, whose methodological determination and analysis are still unstandardized. Objective: Determination of cut-off value for Ki-67 index, its corelation in luminal breast carcinoma with patient's age, tumor size, histological grade (HG) and expression of estrogen (ER) and progesterone (PR). Also, the aim of the study was to determine the significance of the difference in the value of the Ki-67 proliferative index in relation to the occurrence of local relapse, distant metastases and survival rates during the five-year follow-up period of the patient. Methods: Retrospectively, we analysed 120 pathohistological reports of patients who were treated in the period from 01.01.2009 until 31.12.2011 at the Oncology Institute of Vojvodina, and to whom immunohistochemically was proven luminal breast cancer (positive ER and PR, negative HER2), without axillary lymph node metastases. Results: The average patient’s age was 57.42±10.17 years; average tumor size 17.98±6.97mm; recurrence was registered in 8 (6.7%) patients with average recurrence time of 49±20.23 months. "Cut off" Ki-67 value of prognostic significance for period without recurrence was 20.75%. Test didn’t show significant relationship between Ki-67 and patient’s age (p=0.401 and p=0.293), as well as the strength of expression ER (p=1.00, p=0.957) and PR (p=0.273, p=0.189). Significant correlation was present for Ki-67 with size (p=0.035, p=0.20) and tumor’s HG (p=0.041, p=0.20). The average follow-up period for patients was 72.92±8.38 months; there was no registered occurrence of distant metastases or fatal outcome. In relation to the occurrence of local relapse, Kaplan-Meier analysis and Cox regression analysis, the proliferative index Ki-67 proved to be a significant predictor for the assessment of recurrence of the disease, local relapse (Log rank (df = 1) = 2.73; p = 0.045). Also, it was founded that a statistically significant predictor for assessing the recurrence of the disease is the age of the patients (Log rank (df = 1) = 6.885; p = 0.009). The intensity of ER and PR expression, tumor size and histological grade have not been shown to be predictors of the recurrence of luminal breast carcinoma (p> 0.05). Conclusion: Breast carcinoma is heterogeneous disease, so it is difficult to predict its course and outcome using standard histopathological factors and biomarkers. Ki-67 is proliferative marker whose high value correlates with factors of bad prognosis.
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Bayaa, Mustafa. "Cloning and characterization of Xenopus laevis insulin receptor substrate (xIRS-u) and progesterone receptor (xPR)." Thesis, University of Ottawa (Canada), 2001. http://hdl.handle.net/10393/9222.
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Xenopus laevis oocytes are physiologically arrested at G2 of meiosis I. Resumption of meiosis, or oocyte maturation, is triggered in vivo by progesterone, and in vitro by many hormones, such as insulin. Downstream of IGF-1 receptor activation is the activity of docking proteins such as xIRS-1 and xIRS-u. Sequence analysis suggested that xIRS-u was a novel member of the IRS family rather than a Xenopus homolog of an existing member. The cloned xIRS-u cDNA contains an amino-terminal pleckstrin homology (PH) domain and phosphotyrosine-binding (PTB) domain. The carboxy terminus of xIRS-u contains several potential Src homology 2 (SH2)-binding sites, five such sites are potential binding sites for phosphatidylinositol 3-kinase (YM/LXM). It also contains a putative binding site for Grb2 (YINID). The injection of xIRS-u mRNA accelerated insulin-induced MAP kinase activation and oocyte maturation. An amino-terminal deletion of the PH domain reduced the ability of xIRS-u to potentiate insulin signaling. (Abstract shortened by UMI.)
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Cintra, Jane Rocha Duarte. "Sobrevida e fatores associados em pacientes com câncer de mama, com diagnóstico entre 2003 e 2005 no munícipio de Juiz de Fora – Minas Gerais." Universidade Federal de Juiz de Fora, 2012. https://repositorio.ufjf.br/jspui/handle/ufjf/1747.
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Objetivo: Analisar as taxas de sobrevida de cinco anos e os principais fatores associados ao perfil imunohistoquímico, em mulheres com câncer de mama. Métodos: A população foi composta a partir de coorte hospitalar formada por mulheres com diagnóstico de câncer de mama efetuado entre 2003 e 2005 (n=563) e atendidas em centro de referência em assistência oncológica de Juiz de Fora/MG. A data do diagnóstico histopatológico da doença foi considerada como início do tempo de sobrevida e a data do óbito pela doença foi considerada como o evento adverso. Foram censuradas as mulheres que permaneceram vivas até dezembro de 2010, data final do seguimento. Para aquelas que interromperam o seguimento, a data da censura foi referente ao último acompanhamento no registro médico. As curvas de sobrevida foram estimadas pelo método de Kaplan-Meier e o modelo de riscos proporcionais de Cox foi utilizado para a avaliação prognóstica. Resultados: A idade média das pacientes foi de 58,1 anos, sendo a maioria das pacientes (81,1%) da raça branca e pós-menopausa (66,8%). Os estádios clínicos predominantes foram o II (36,7%) e III (25,3%). Os subtipos mais frequentes foram os luminais A (n=295 casos – 52,4%) e os casos com perfil desconhecido (n=107 - 19%). A função de sobrevida específica para o câncer de mama, no período de cinco anos, foi de 79,9%. Entre as principais características associadas com uma melhor sobrevida não ajustada, na população de estudo, destacaram-se: subtipos imunohistoquímicos luminais (A e B) (p<0,0001), raça branca (p<0,0001), tamanho do tumor ≤ 2,0cm (p<0,0001), ausência de comprometimento linfonodal (p<0,0001), estádios mais precoces da doença (p<0,0001), realização de tratamento sistêmico (p=0,01) e uso de hormonioterapia (p<0,0001). Os principais fatores prognósticos associados à pior sobrevida foram: subtipos triplo negativo (p<0,001), HER2 superexpresso (p=0,01) e perfil imunohistoquímico desconhecido (p=0,01); raça não branca (p=0,02); doença avançada (estágio III e IV – p<0,001); tratamento sistêmico não realizado (p=0,009) e não utilização de quimioterapia de 1ª linha (p=0,09). Conclusão: Esta pesquisa possibilitou uma melhor caracterização do perfil imunohistoquímico e da sobrevida de pacientes com câncer de mama.
Purpose: Analyze the 5-year breast cancer specific-survival rate and according to the immunohistochemical profile of women diagnosed with breast cancer. Methods: The population was composed from a hospital-based cohort of all women diagnosed with breast cancer between 2003 and 2005 (n= 563), and treated at cancer care reference center in the city of Juiz de Fora/MG, Brazil. Survival time was counted from the date of the histopathological diagnosis and the date of death due to breast cancer was considered the adverse event. Women alive until December 2010, the final date of the follow-up, were censored. For those who interrupt treatment, censor date was the last follow-up in the medical records. Kaplan-Meier survival curves were estimated, and multivariate analysis was performed by the Cox proporciona hazard model. Results: Mean age was 58,05 years, and the majority were white skin color (81,1%) and postmenopausal (66,8%). Clinical Stages II (36,7%) and III (25,3%) predominated. The most common subtypes were luminal A (n= 295 cases – 52,4%) and cases with unknown profile (n= 107 – 19%) Breast cancer specific five-year survival rate was 79,93%. A better unadjusted survival was observed among women with disease diagnostic, immunohistochemical subtypes luminal A and B (p<0,0001), white skin color (p<0,0001), with tumor size ≤ 2.0cm (p<0,0001), without lymph node involvement (p<0,0001), in a less advanced disease stage (p<0,001), and of systemic treatment (p=0,01), and who used hormone therapy (p<0.0001). The main prognostic factors associated with poor survival were: subtypes triple negative (p<0.001), HER2 overexpression (p=0.01) and immunohistochemical profile unknown (p=0.01), no white race (p=0.02), advanced disease (stage III and IV – p<0.001), no realization of systemic treatment (p=0.009) and no use of first line chemotherapy (p=0.09). Conclusion: This research allowed identification of the profile and disease survival of breast cancer patients, according to imunohistochemical profile.
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Suzuki, Reiko. "Hormone-related dietary factors and estrogen/progesterone-receptor defined postmenopausal breast cancer /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7357-005-2/.
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Haglund, Elizabeth. "Mechanism of action of two progesterone receptor modulators PRA-348 and PRA-920 /." Click here for download, 2009. http://proquest.umi.com.ps2.villanova.edu/pqdweb?did=1889024471&sid=1&Fmt=2&clientId=3260&RQT=309&VName=PQD.
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Fritsch, Samuel. "Efeito da administração de diferentes doses de estradiol seguido de progesterona sobre a expressão de receptores endometriais de estrógeno e progesterona em éguas receptoras acíclicas." Botucatu, 2016. http://hdl.handle.net/11449/140280.
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Orientador: Cezinande de MeiraResumo: Diferentes tratamentos hormonais com a utilização de estrógenos e progestágenos são comumente utilizados para aumentar a oferta de receptoras nos programas de TE. Porém, pouco se sabe sobre a ação destes hormônios na expressão gênica e proteica dos receptores endometriais de estrógeno e progesterona em éguas acíclicas. O presente estudo teve como objetivo avaliar os efeitos de três tratamentos hormonais utilizados durante a preparação de éguas acíclicas sobre o edema, tônus uterino e expressão gênica e proteica de receptores de estrógeno e progesterona endometriais. Éguas em anestro foram divididas em três grupos: Dose Total 10 mg BE+P4, (n=7), Dose Total 5 mg BE+P4 (n=7), Priming Hormonal (n=7) e comparadas com o grupo de éguas cíclicas (n=7). Foram avaliados: a expressão proteica e gênica relativa dos transcritos para os receptores de estrógeno e progesterona presentes no endométrio por meio das técnicas de imunohistoquímica e RT-qPCR; e as características morfológicas do útero por palpação retal e ultrassonografia em modo B. Os tratamentos hormonais utilizados no presente estudo foram eficazes em promover edema e tônus uterinos semelhante ao que ocorre em éguas cíclicas. Adicionalmente, o grupo Priming Hormonal demonstrou induzir características uterinas similares as observadas nos grupos 5 mg BE+P4 e no grupo controle, após 14 dias de intervalo. O tratamento hormonal com dose total de 10 mg de BE+P4 LA utilizando para o preparo de éguas acíclicas, demonstrou ser similar ... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Different hormonal treatments with the use of estrogen and progestogen are commonly used to increase the supply of receiving the TE programs. However, little is known about the effect of these hormones on gene and protein expression of endometrial receptors for estrogen and progesterone in non-cyclic mares. This study aimed to evaluate the effects of three hormonal treatments used for the preparation of non-cyclic mares on the edema and uterine tone and gene and protein expression of estrogen and endometrial progesterone receptors. Mares anestrus were divided into three groups: total dose 10 mg EB + P4 (n = 7) total dose 5 mg EB + P4 (n = 7) Hormonal Priming (n = 7) and compared with the group of cyclic mares (n = 7). Were evaluated: protein expression and gene transcripts related to the estrogen and progesterone receptors present in the endometrium by the techniques of immunohistochemistry and RT-qPCR; and the morphological characteristics of the uterus by rectal palpation and ultrasound in B mode. Hormonal treatments used in this study were effective in promoting edema and uterine tone similar to what occurs in cyclic mares. Additionally, the Hormonal Priming group demonstrated induce uterine similar characteristics observed in the groups 5 mg EB + P4 and control group, after 14 days apart. Hormonal treatment with a total dose of 10 mg EB + P4 LA using for the preparation of non-cyclic mares, was shown to be similar in tone and uterine edema, protein expression and relative... (Complete abstract click electronic access below)
Mestre
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Sousa, Juarez Antônio de [UNIFESP]. "Estudo da Imunorreação do Anticorpo Monoclonal Ki-67 (MIB-1) e dos Receptores de Estrogênio e Progesterona no Carcinoma de Mama de Mulheres Tratadas com Tamoxifeno em Baixa Dosagem." Universidade Federal de São Paulo (UNIFESP), 2006. http://repositorio.unifesp.br/handle/11600/9523.
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Previous issue date: 2006-12-31O carcinoma da mama é a neoplasia maligna mais freqüente entre as mulheres com grande impacto na mortalidade. Os estudos de quimioprevenção primária com tamoxifeno têm gerado boas expectativas e consideradas taxas de sucesso. Doses menores do tamoxifeno apresentam eficácia semelhante à dose padrão, com redução de custos e efeitos adversos. Estudou-se a imunorreação do anticorpo monoclonal Ki-67 (MIB-1) e a positividade dos receptores de estrogênio (1D5) e progesterona (PgR 636) no carcinoma de mama de mulheres tratadas com 10 mg de tamoxifeno por um período de 14 dias. Realizou-se estudo prospectivo, randomizado, com 38 mulheres, divididas em dois grupos: Grupo A: N = 20 (Grupo controle - sem medicação) e Grupo B: N = 18 (tamoxifeno 10 mg/dia por 14 dias). Todas as pacientes assinaram termo de consentimento previamente aprovado pelas duas instituições (Universidade Federal de São Paulo – Escola Paulista de Medicina e Hospital Materno Infantil de Goiânia-GO). A seguir foram submetidas à biópsia incisional e, após 14 dias, foi obtida nova amostra do tecido tumoral durante o tratamento cirúrgico definitivo. A positividade foi avaliada quantitativamente, contando-se no mínimo 1.000 células para cada lâmina. Para a análise estatística dos dados, foi utilizado o teste não paramétrico de Wilcoxon, fixandose α em 5%. Os dois grupos (A e B) foram considerados homogêneos em relação às variáveis de controle. No grupo A (controle) não houve redução estatisticamente significativa da positividade do Ki-67 (MIB-1) (p=0,627), e dos receptores de estrogênio (1D5) (p=0,296) e progesterona (PgR 636) (p=0,381). No grupo B (tamoxifeno 10 mg/dia) a porcentagem média de núcleos corados pelo Ki-67 (MIB-1) foi 24,7% antes e 10,4% após. Para o receptor de estrogênio (1D5), 59,5% antes e 25,9% após e para o receptor de progesterona (PgR 636), 59,3% e 29,6%, respectivamente. Houve redução significativa para os três marcadores (p<0,001). O tamoxifeno reduziu significativamente a positividade do anticorpo monoclonal Ki-67 (MIB-1), receptor de estrogênio (1D5) e receptor de progesterona (PgR 636) no epitélio mamário de pacientes com carcinoma, tratadas com tamoxifeno na dose de 10 mg por 14 dias.
Breast carcinoma is the most common malignancy among women, and it has a major impact on mortality. Studies of primary chemoprevention with tamoxifen have generated high expectations and considerable success rates. The efficacy of lower doses of tamoxifen is similar to that seen with the standard dose of the drug, and there is a reduction in medical care costs and adverse effects. The immune reaction to monoclonal antibody Ki-67 (MIB-1) and the expression of estrogen receptors (1D5) and progesterone receptors (PgR 636) in breast carcinoma were studied in patients treated with 10 mg of tamoxifen for a period of 14 days. A prospective randomized clinical trial was conducted with 38 patients divided into two groups: Group A: N = 20 (control group–without medication) and Group B: N = 18 (tamoxifen/10 mg/day for 14 days). All patients signed an informed consent term previously approved by both institutions (UNIFESP-EPM and Hospital Materno Infantil, Goiânia-GO). Patients underwent incisional biopsy before treatment and 14 days later a sample of tumor tissue was obtained during surgical treatment. Positivity was quantitatively assessed, counting at least 1.000 cells per slide. For statistical data analysis, a Wilcoxon non-parametric test was used, and α was set at 5%. Both groups (A and B) were considered homogeneous regarding control variables. In Group A (control), there was no statistically significant reduction in Ki-67 (MIB-1) (p=0.627), estrogen receptor (1D5) (p=0.296) and progesterone receptor positivity (PgR 636) (p=0.381). In Group B (tamoxifen 10 mg/day), the mean percentage of nuclei stained by Ki- 67 (MIB-1) was 24.7% before and 10.4% after tamoxifen treatment. Mean percentage of nuclei stained by estrogen receptor (1D5) was 59.5% before and 25.9% after tamoxifen treatment. Mean percentage of nuclei stained by progesterone receptor (PgR 636), was 59.3 before and 29.6% after tamoxifen treatment. A statistically significant reduction was found with the three markers (p<0.001). Tamoxifen significantly reduced monoclonal antibody Ki-67 (MIB-1), estrogen receptor (1D5) and progesterone receptor positivity (PgR 636) in the breast epithelium of patients with carcinoma, treated with a 10 mg dose of tamoxifen for 14 days.
TEDE
BV UNIFESP: Teses e dissertações
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Clarkson, Alison Marie. "Maternal recognition of pregnancy and steroid receptors in ovine endometrium." Thesis, University of Nottingham, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267152.
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Dhananjayan, Sarath Chandran. "Receptor Selective Coactivators: Characterization of a Novel Protein-Protein Interaction Module in Steroid Hormone Receptor Signaling." Scholarly Repository, 2008. http://scholarlyrepository.miami.edu/oa_dissertations/67.
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WW-domain binding protein-2 (WBP-2) was cloned as an E6-associated protein (E6-AP) interacting protein and its role in steroid hormone receptor (SHR) function was investigated. We show that WBP-2 differs from other SHR coactivators, as it specifically enhanced the transactivation functions of progesterone receptor (PR) and estrogen receptor (ER alpha), whereas it had no significant effect on the androgen receptor, glucocorticoid receptor or the activation functions of p53 or VP-16. We also demonstrated that, like other well characterized coactivators, WBP-2 contains an intrinsic activation domain. Depletion of endogenous WBP-2 with small interfering RNAs indicated that normal physiological protein level of WBP-2 was required for the proper functioning of ER alpha and PR. Moreover, chromatin immunoprecipitation (ChIP) assays demonstrate the hormone-dependent recruitment of WBP-2 onto an estrogen-responsive promoter. As we initially identified WBP-2 as an E6-AP interacting protein, we investigated whether WBP-2 and E6-AP function in concert. Our data shows that WBP-2 and E6-AP each enhance PR function and when co-expressed they additively enhance the transactivation functions of PR. However, WBP-2 was also able to enhance the transactivation functions of ER alpha and PR in mouse embryonic fibroblast cells generated from E6-AP knockout mice lines, suggesting that the coactivation functions of WBP-2 was not dependent on E6-AP. The further elucidate the molecular mechanism of action of WBP-2; we dissected the functional importance of the polyproline (PY) motifs contained within the WBP-2 protein. Mutational analysis suggests that one of three PY motifs, PY3 of WBP-2 was essential for its coactivation and intrinsic activation functions. In this study, we also demonstrate that the WBP-2 binding protein, Yes-kinase associated protein 1 (YAP1) acts as a secondary coactivator of ER alpha and PR. However, the coactivation function of YAP1 is revealed only in the presence of wild-type WBP-2 and not with the PY motif 3 mutant WBP-2. This is consistent with our observations that, unlike the wild-type WBP-2, the PY motif 3 mutant WBP-2 does not interact with YAP1. Our quantitative reChIP assays demonstrates an estrogen-dependent recruitment and association of ER alpha with both WBP-2 and YAP1. The hormone-dependent recruitment of YAP1 to ER alpha responsive promoter is dependent on the physiological expression levels of WBP-2. This is consistent with, our observation that the coactivation functions of YAP1 is dependent on WBP-2, and is also in agreement with other known secondary coactivators that get recruited to SHR responsive promoter via their interaction with primary coactivators. Surprisingly, the association of WBP-2 with ER alpha and its recruitment to the ER alpha target promoter was abrogated by YAP1 knock-down, suggesting that WBP-2 and YAP1 may stabilize each other at the promoter, and consequently, are functionally interdependent. Taken together our data establish the role of WBP-2 and YAP1 as selective coactivators for ER alpha and PR transactivation pathways.
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Wludarski, Sheila Cristina Lordelo. "Comparação dos resultados de marcadores prognósticos e preditivos (HER2 e receptores de estrógeno e progesterona) para carcinoma de mama entre laboratórios locais e de referência no Brasil." Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/5/5144/tde-01022011-161711/.
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O câncer de mama corresponde a aproximadamente um quarto das neoplasias malignas em mulheres. A incidência do câncer de mama no Brasil é de cerca de 50.000 novos casos por ano, sendo considerado importante problema de saúde pública. HER2 e receptores hormonais (receptores de estrógeno e progesterona) são considerados os mais importantes marcadores prognósticos e preditivos em carcinoma de mama. A amplificação do gene HER2 ou a superexpressão da proteína HER2, que ocorre em cerca de 20 porcento dos carcinomas de mama, está associada a curso clínico mais agressivo e determina elegibilidade para terapia específica anti-HER2 com trastuzumabe. A terapia hormonal reduz em mais de 50 porcento o risco relativo de recorrência da doença em pacientes com tumores sensíveis a esse tratamento. Os testes de HER2 e receptores hormonais são partes essenciais da avaliação clínica das pacientes com carcinoma de mama; resultados precisos são fundamentais na identificação de pacientes que podem ser beneficiadas por terapias específicas. O presente estudo investigou a concordância nos resultados dos testes de HER2 e receptores hormonais determinados por imuno-histoquímica em 500 carcinomas invasivos de mama entre um laboratório referência e laboratórios locais de todas as regiões geográficas do Brasil. Os resultados demonstram baixa concordância geral (171/500 casos, 34,2 porcento) em relação aos resultados do teste de HER2 entre laboratórios locais e referência, o que pode estar relacionado ao baixo volume de testes de HER2 realizados, inexperiência com o sistema de escores de HER2 e/ou questões técnicas relacionadas à imuno-histoquímica nos laboratórios locais. A concordância nos resultados do teste de receptores de estrógeno e progesterona foi de 89,4 porcento (447/500 casos) e de 85,0 porcento (425/500 casos), respectivamente, entre laboratórios locais e referência. Padronização dos testes de HER2 e receptores hormonais com medidas de controle de qualidade rigorosas por laboratórios locais é fortemente recomendada para se evitar o tratamento inadequado de pacientes com câncer de mamaBreast cancer accounts for approximately one quarter of all cancers in females. The incidence of breast cancer in Brazil is about 50,000 new cases per year, and it is considered an important public health problem. HER2 and hormone receptors (estrogen and progesterone receptors) are considered the main prognostic and predictive markers for breast carcinoma. HER2 gene amplification or HER2 protein overexpression, detected in about 20 percent of breast carcinomas, predicts a more aggressive clinical course and determines eligibility for targeted therapy with trastuzumab. Hormonal therapy reduces the relative risk of recurrence by more than 50% in breast cancer patients with hormone-sensitive tumors. HER2 and hormone receptors testing has become an essential part of the clinical evaluation of all breast carcinoma patients, and accurate results are critical in identifying patients who may benefit from targeted therapy. The present study investigated the concordance in the results of HER2 and hormone receptors immunohistochemistry assays performed in 500 invasive breast carcinomas between a reference laboratory and local laboratories from all geographic regions of Brazil. Our results showed an overall poor concordance (171/500 cases, 34.2 percent) regarding HER2 results between local and reference laboratories, which may be related to the low-volume load of HER2 assays, inexperience with HER2 scoring system, and/or technical issues related to immunohistochemistry in local laboratories. The concordance of estrogen and progesterone receptors results was 89.4 percent (447/500 cases) and 85.0 percent (425/500 cases), respectively, between local and reference laboratories. Standardization of HER2 and hormone receptors testing with rigorous quality control measures by local laboratories is highly recommended in order to avoid erroneous treatment of breast cancer patients
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Carranza, Neira Julia Alejandra, Subauste Roxana Sofía Díaz, and Tupayachi Silvana Patricia Roig. "Quimioterapia adyuvante asociada a hormonoterapia en mujeres postmenopáusicas con cáncer de mama subtipo Luminal A en estadio temprano: análisis comparativo de la supervivencia global." Bachelor's thesis, Universidad Peruana de Ciencias Aplicadas (UPC), 2015. http://hdl.handle.net/10757/621762.
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Purpose: to evaluate if there is a difference between adjuvant chemo-endocrine therapy (QHT) and hormone therapy (HT) alone in ten years overall survival (OS) in post-menopausal women with early stage luminal A breast cancer
Methods: A non concurrent cohort study was conducted in a cancer treatment center in Peru, we measured demographic and clinical-pathologic anatomy variables. Log-rank test and a Kaplan-Meier (KM) curve were performed to evaluate ten years OS. Cox regression analysis was used and hazard ratio were reported with confidence intervals 95% (95%CI) for crude and adjusted by the significant variables in the bivariate analysis. The fullfilment of hazard proportionality was evaluated by Schoenfeld residuals method and graphic method.
Results: 65 patients received adjuvant chemo-endocrine therapy and 140 only received hormone therapy. Ten years OS was 77% for QHT and 84% for HT, this difference was not significant when using KM and log-rank; age at diagnosis (p=0,01), clinical status (p=0,02), tumor size (p=0,04), positive estrogen receptor (p=0,03), node status (p=0,012) and type of surgery (p=0,03) were statistically significant when compare with OS. When proportional hazards assumption was evaluated (SPH), only the period of time after two years of following was satisfied, cox models were created for this period of time. Crude HR for ten years OS was 1,48 (CI95%:0,65-3,39). First model adjusted HR was 1,83 (CI95%:0,64-5,30) and second model adjusted HR was 1,77 (CI95%:0,64-4,90).
Conclusions: There was no significant difference in ten years OS between both courses of treatment evaluated in post-menopausal women with luminal A breast cancer.Objetivo: evaluar si existe diferencia en la supervivencia global (SG) a diez años entre la quimioterapia adyuvante asociada a hormonoterapia (QHT) frente a la hormonoterapia sola en mujeres posmenopáusicas diagnosticadas con cáncer de mama luminal A (CMLA) en estadio temprano. Métodos: se realizó un estudio cohortes no concurrente en un centro de atención oncológica en Perú. Se incluyeron variables demográficas y clínico-patológicas. Para comparar la SG se utilizó la curva de Kaplan-Meier (KM), test de log-Rank y la regresión de Cox para estimar el Hazard Ratio (HR) con intervalos de confianza 95% (IC95%) tanto crudos como ajustados por las variables asociadas durante el análisis bivariado. Se evaluó el cumplimiento del supuesto de proporcionalidad de hazard (SPH) con el método de residuos de Schoenfeld y método gráfico. Resultados: 65 pacientes recibieron QHT y 140 sólo hormonoterapia. La SG a los diez años fue 77% y 84% para QHT y HT respectivamente, esta diferencia no fue significativa al utilizar KM y test de log-Rank; no obstante la edad (p=0,01), estadio clínico (p=0,02), tamaño tumoral (p=0,04), receptor estrogénico positivo (p=0,03), número de ganglios (p=0,012) y tipo de cirugía (p=0,03) resultaron asociadas significativamente a la supervivencia global a los diez años. Cuando se evaluó el SPH se evidenció que sólo se cumplía tras los dos años de seguimiento, por lo que se generaron modelos de Cox en éste periodo. El HR crudo a los diez años fue de 1,48 (IC95%: 0,65-3,39). En el modelo ajustado uno se observó un HR de 1,83 (IC95%: 0,64-5,30) y para el segundo modelo ajustado un HR de 1,77 (IC 95%: 0,64-4,90). Conclusiones: no se encontró diferencia significativa en la SG a los diez años entre los esquemas terapéuticos evaluados en mujeres posmenopáusicas con CMLA.
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Mathew, Daniel J. Lucy Matthew C. Geisert Rodney D. "Effect of RU486, a progesterone antagonist, on uterine progesterone receptor, embryonic development and ovarian function during early pregnancy in pigs." Diss., Columbia, Mo. : University of Missouri--Columbia, 2009. http://hdl.handle.net/10355/5371.
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The entire thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file; a non-technical public abstract appears in the public.pdf file. Title from PDF of title page (University of Missouri--Columbia, viewed on December 29, 2009). Thesis advisor: Dr. Matthew C. Lucy and Rodney D. Geisert. Vita. Includes bibliographical references.
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Zachariades, Ellen Barbara. "Progesterone receptors in the human placenta : expression, signalling characteristics and functional relevance." Thesis, Brunel University, 2011. http://bura.brunel.ac.uk/handle/2438/6417.
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The human placenta is a transient life sustaining organ which is responsible for mediating all the physiological exchanges between the mother and the fetus. The steroid hormone progesterone, often referred to as the hormone of pregnancy, is critical for the establishment and for maintaining the pregnancy. During the gestation period the human placenta produces progesterone which via interacting with the progesterone receptors exerts its many effects. Specific intracellular progesterone receptors (PRs) have been reported to mediate the genomic signalling of progesterone whereas recently two novel receptor families which are phylogenetically distinct to the nuclear receptor superfamily have been characterised, and shown to mediate progesterone’s non genomic actions. These are the multiple membrane progestin receptors (mPRα, mPRβ, and mPRγ) and progesterone membrane receptor component 1 (PGMRC-1). The rapid progesterone actions mediated via these non-classical progesterone receptors have received attention with main focus on their reproductive functions. Our aim is to elucidate the expression of the receptors in the human placenta, further understand the signalling pathways via which progesterone mediates its effects and lastly examine the functional relevance of these receptors in this organ. Choriocarcinoma cell lines are used frequently as placental models for investigations of steroid hormone actions, but until now little is known about the expression of progesterone receptors (PRs) in these cell lines. Quantitative RT-PCR revealed that in fully syncytialized BeWo cells (treated with 50 µM forskolin for 72 h) there was a significant down-regulation of mPRα and up-regulation of mPRβ and of the PGRMC1 when compared with non-syncytialized BeWo cells. Expression of all the mPR and PGRMC1 mRNAs was significantly lower in JEG-3 cells compared to non-syncytialized BeWo cells. Expression of PR-B was unaltered between the two BeWo states but was significantly higher in JEG-3 cells. Immunofluorescence analysis revealed that mPR proteins are differentially expressed in these choriocarcinoma cell lines as well as in the human placenta. The functionality of mPRs was investigated in vitro, using BeWo and JEG-3 cells that were treated with Org OD-02 (a specific mPR agonist), progesterone (P4) and R5020 (a specific nuclear PR agonist) in the presence or absence of the pro-inflammatory cytokine inteleukin-1β (IL-1β) at a concentration of 10ng/μl. The effect was more exacerbated in JEG-3 cells, where IL-1β induced 40% cell death when compared to BeWo cells that reached a modest but significant 15% cell death. When JEG-3 cells were treated with IL-1β and progesterone, there was a significant decrease in cell death at concentrations of 100nM and 1000nM. When cells were treated with 1000nM progesterone, IL-1β’s effect was completely abolished. Progesterone was also able to induce phosphorylation of ERK1/2 in these cells. Pretreatment of JEG-3 cells with a specific MAPK inhibitor (UO126) inhibited substantially the progesterone’s proliferative effect. Moreover, using the specific mPR agonist Org OD 02-0, we have shown that that the progestin antagonism of apoptotic effects of IL-1β on BeWo cells is mediated through mPRs. Quantitative PCR in clinical samples revealed a 2.8 fold decrease of mPRβ in labouring comparing to non-labouring tissues and 4.6 fold higher levels of mPRγ in preterm mPRγ compared to term placentas. The ratio of mPRα to PR-B was increased in term compared to preterm samples, whereas it was decreased in labour compared to non-labour placentas. There was also a high correlation between mPRα and PGRMC1 expression irrespective of pathologies. This study addressed many fundamental questions regarding how progestins exert their effect at placental level. It is evident that there is a higher order of complexity and changes in the ratios of placental progesterone receptors rather than individual fluctuations might affect subsequent signalling events.
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Font, Mateu Jofre 1977. "Dynamics of progesterone receptor interactors in breast cancer cells upon hormone exposure." Doctoral thesis, Universitat Pompeu Fabra, 2016. http://hdl.handle.net/10803/511363.
Full textAbstract:
El receptor de la progesterona és un regulador clau per la proliferació de les cèl·lules de càncer de mama dependents d’hormona. El mecanisme d’acció del PR ha tingut un paper important en la resolució del mecanisme molecular d’activació de la transcripció. No obstant això, no hi ha hagut un estudi a fons de les seves interaccions en resposta a hormona. En aquest treball s'han identificat per RIME (immunoprecipitació ràpida per l'espectrometria de masses de proteïnes endògenes) 315 interactors d’alta confiança del PR en cèl·lules de càncer de mama exposades a la potent agonista de la progesterona R5020 durant 0, 1, 5, 15, 30 i 60 minuts. Hem identificat 20 interactors coneguts del PR i 295 de nous. Els interactors del PR trobats formen 4 grups dinàmics; El grup basal, 66 proteïnes presents en nivells similars en tots els temps; grup 1, 41 proteïnes que disminueixen la seva interacció després de l'hormona; grup 2, 115 proteïnes que augmenten la seva interacció ràpidament després de l'hormona; i el grup 3, 91 proteïnes que tenen un augment de la seva interacció constant amb el temps. Els interactors del PR formen complexes funcionals que intervenen en la regulació transcripcional, remodelació de la cromatina, el processament del ARNm, reparació de l’ADN danyat, la degradació proteosomal, proteïnes estabilitzadores i proteïnes de l’estructura nuclear. L'exposició de cèl·lules a l’antagonista parcial de la progesterona RU486 manté la majoria dels interactors del PR, però perd els relacionats amb la regulació de la transcripció. Aquest estudi estableix les bases per a l'anàlisi de les noves funcions dels receptors de progesterona en cèl·lules de càncer de mama.Progesterone receptor is a key regulatory element in hormone-dependent breast cancer cells proliferation. The mechanism of action of PR has played an important role in solving the molecular mechanism of transcription regulation. However, it has not been a thorough study of its interactors in response to hormone. In this work we have identified by RIME (Rapid Immunoprecipitation Mass spectrometry of Endogenous proteins) 315 high confidence PR interactors in breast cancer cells exposed to the potent progesterone agonist R5020 for 0, 1, 5, 15, 30 and 60 minutes. We have identified 20 known PR interactors and 295 new ones. The found PR interactors form 4 dynamic clusters; Basal cluster, 66 proteins present at similar level at all time points; Cluster 1, 41 proteins decreasing their interaction after hormone; cluster 2, 115 proteins increasing their interaction rapidly after hormone; and cluster 3, 93 proteins increasing their interaction steadily over time. PR interactors form functional complexes involved in transcriptional regulation, chromatin remodelling, mRNA processing, DNA damage repair, proteosomal degradation, protein stability and nuclear structural proteins. Exposure of cells to progesterone partial antagonist RU486 maintain the majority of PR interactors, but loses the interactors related to transcription regulation. This study set the bases for analyses of new functions of progesterone receptor in breast cancer cells.
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An, Beum-Soo. "Cross-talk between gonadotropin-releasing hormones and progesterone receptor in neuroendocrine cells." Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/30705.
Full textAbstract:
Hypothalamic gonadotropin-releasing hormone (GnRH) is a decapeptide that plays a
pivotal role in mammalian reproduction. It is hypothesized that progesterone (P4) may regulate
GnRH I, GnRH II (a second form of GnRH) and GnRH I receptor (GnRH I R) at the
transcriptional level. Alternatively, GnRHs may stimulate transactivation of the progesterone
receptor (PR), thereby, modulating gonadotropin subunit gene expression. Treatment of human
neuronal cells with P4 suppressed GnRH I R promoter activity. This P4-stimulated inhibition
was enhanced when PR A was over-expressed. With respect to the two GnRHs, P4 increased
GnRH I mRNA levels, but did not significantly affect GnRH II gene expression.
Regulation of gonadotropin production involves interplay between steroids and neuropeptides,
thus we have examined the effects of GnRHs on PR activation in pituitary cells.
Treatment with GnRHs increased a progesterone response element (PRE)-luciferase reporter gene
activity. PR was phosphorylated at Ser294 and translocated into nucleus after GnRH treatment in
the absence of P4. Interactions between the PR and several coactivators were examined, and
treatment with GnRHs specifically induced PR: Steroid Receptor Coactivator-3 (SRC-3)
interaction. In chromatin immunoprecipitation assays, recruitment of PR and SRC-3 to the PRE
reporter gene was also increased by GnRHs. The knockdown of GnRH I R and SRC-3 levels by
siRNA treatment reduced GnRH-induced PR transactivation. Gonadotropin subunit gene
expression was evaluated following treatment with GnRHs, and common α-subunit and FSHβ
transcription were upregulated by GnRHs. We used siRNA for PR to examine the involvement of
PR in GnRH I-induced FSHβ gene expression. The effect of GnRH I on FSHβ, but not α -subunit
gene expression was reduced when siRNA targeting PR was introduced.
In summary, these results indicate that P4 is a potent regulator of GnRH I R and GnRH I at the transcriptional level, and this distinct effect of P4 on the GnRH system may be derived from the
differential action of PR A or PR B . Conversely, GnRHs can activate PR-mediated transcription in
the absence of P4, and this ligand-independent mechanism of PR additionally regulates FSHβ
subunit gene expression.Medicine, Faculty of
Obstetrics and Gynaecology, Department of
Graduate
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Lundström, Eva. "Mammographic breast density and postmenopausal hormone therapy /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-581-X/.
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Oliveira, Nayara Pestana de. "Efeitos da terapia estrogênica sobre a neuroquímica de fêmeas em modelo animal de perimenopausa (rata) induzida pelo 4-diepóxido de vinilciclohexano." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/17/17134/tde-23072018-104343/.
Full textAbstract:
A perimenopausa representa a transição da vida reprodutiva para não reprodutiva. É geralmente caracterizada por alterações neuroendócrinas, metabólicas e comportamentais, um possível resultado da depleção folicular ovariana e consequente redução do número de folículos ovarianos. É o período em que as mulheres podem apresentar maior susceptibilidade a manifestar transtornos afetivos e de ansiedade. A exposição de roedores ao resíduo químico 4-diepóxido de vinilciclohexeno (VCD) é um modelo bem estabelecido para estudos sobre perimenopausa, pois o VCD acelera o processo natural de atresia folicular. Embora as concentrações plasmáticas de estradiol estejam normais ou elevadas durante a perimenopausa, a terapia com estradiol pode ser benéfica para mulheres sintomáticas na perimenopausa. Portanto, o objetivo do presente trabalho foi investigar se a depleção folicular gradativa acelerada pelo VCD resulta em alterações na neuroquímica de ratas fêmeas em núcleos cerebrais que controlam o humor, além de avaliar se o estradiol seria capaz de reverter as possíveis alterações. Ratas da linhagem Wistar (28 dias pós-natal) receberam diariamente, durante 15 dias consecutivos, injeções subcutâneas de VCD (160 mg / kg) ou óleo de milho (O). Aproximadamente 55 dias após a primeira injeção, cápsulas de silastic contendo 17?-estradiol (E) ou O foram inseridas subcutaneamente (Grupos O+O; VCD+O; VCD+E). Cerca de 21 dias após o implante das cápsulas, as ratas dos grupos O+O e VCD+O foram decapitadas na manhã do diestro, enquanto que as do grupo VCD+E foram decapitadas exatamente 21 dias após o implante das cápsulas contendo estradiol, entre 0900 h e 1100 h. O sangue foi colhido para avaliação das concentrações plasmáticas de estradiol e progesterona por radioimunoensaio (RIE). Os cérebros foram removidos para microdissecção do hipocampo, amígdala, Locus coeruleus (LC) e Núcleo Dorsal da Rafe (NDR), para posterior análise dos níveis de RNAm para os receptores de progesterona (PR) e estradiol do tipo beta (ER?) por meio de RT/PCR. Este experimento foi replicado para remoção do hipocampo e amígdala para dosagem dos conteúdos de noradrenalina (NA) e serotonina (5-HT) por meio de cromatografia líquida de alta performance, seguida de detecção eletroquímica (HPLC/ED). Outro conjunto de ratas submetidas às mesmas condições10 experimentais foi perfundido para imunohistoquímica para TPH no NDR e TH no LC. Como esperado, na periestropausa (grupo VCD+O) as concentrações plasmáticas de estradiol não foram diferentes daquelas das ratas controles (O+O). As concentrações plasmáticas de progesterona na periestropausa foram menores que as do grupo controle, o que foi revertido pelo estradiol. No LC, a expressão de PR na periestropausa foi igual à das ratas controles, enquanto a expressão do ER? foi menor; a terapia com estradiol não modificou a expressão de nenhum destes receptores. A densidade de neurônios noradrenérgicos (TH+) no LC não foi alterada nem pela depleção folicular nem pela terapia estrogênica. Na periestropausa, o conteúdo de NA foi menor na amígdala, mas não no hipocampo, e o estradiol não alterou este conteúdo em nenhuma das áreas. No NDR, a expressão de PR e de ER? nas ratas na periestropausa foi menor que nas ratas controles; o estradiol preveniu o declínio da expressão de ER?, mas não de PR. O NDR foi analisado separadamente por toda a extensão rostro-caudal em 3 níveis anatômicos: rostral, médio e caudal, cada um dividido em 3 sub-regiões: lateral, dorsal e ventral. O número de neurônios serotonérgicos (TPH+) no NDR foi menor na periestropausa, e o estradiol foi capaz de reverter esse efeito, atuando principalmente na região caudal. A expressão gênica de PR não foi alterada nem pela depleção folicular nem pela terapia estrogênica tanto na amígdala como no hipocampo. A expressão de ER? também não foi diferente na periestropausa, quando comparada ao grupo controle, mas o estradiol aumentou esta expressão no hipocampo. Tanto na amígdala como no hipocampo houve redução no conteúdo de 5-HT na periestropausa e estradiol foi capaz de reestabelecer os níveis deste neurotransmissor aos valores controles apenas no hipocampo. Estes dados elucidam, pelo menos em parte os mecanismos do efeito positivo da terapia estrogênica nos sintomas de mulheres normoestrogênicas na perimenopausa. Estes efeitos parecem não envolver de forma importante o sistema noradrenérgico central, mas resultar do aumento da biossíntese de progesterona periférica em associação com a regulação positiva de ER? no NDR e hipocampo, que parece potencializar a via serotonérgica NDR/HPC. Portanto, o desenvolvimento de novas terapias que ativem os ER? pode ser uma alternativa para obter os efeitos positivos da ação do estradiol, eliminando os efeitos colaterais das terapias de estradiol que normalmente resultam da ativação do ER?.Perimenopause represents the transition from reproductive to non-reproductive life. It is usually characterized by neuroendocrine, metabolic and behavioural changes, which result from a follicular depletion and reduced number of ovarian follicles. During this period, women are more likely to express mood disorders and anxiety. The exposure of animals to diepoxide 4-vinylcyclohexene (VCD) is a well-established experimental model for perimenopause studies, as VCD induces loss of ovarian small follicles (primary and primordial) in mice and rats by accelerating the natural process of atresia. Although estrogens levels are normal or even high during perimenopause, estrogen therapy can be beneficial for symptomatic perimenopausal women. The aim of this study was to investigate whether gradual follicular depletion induced by VCD results in changes in the neurochemistry of female rats in brain nuclei that control mood and the role of estradiol on these changes. Female rats (28 days) were daily injected with VCD or corn oil (O) for 15 days. Around 55 days after the first injection, pellets of 17?-estradiol (E) or O were inserted s.c (Groups O+O; VCD+O; VCD+E). Around 21 days after, rats O+O and VCD+O were decapitated between 0900 h and 1100 of diestrus while rats VCD+E were decapitated exactly 21 days after the onset of E therapy. Another set of rats followed the same experimental design and were perfused for TH and TPH immunohistochemistry in Locus coeruleus (LC) and Dorsal Raphe Nuclei (DRN), respectively. Blood was collected for estradiol and progesterone measurement by radioimmunoassay (RIA). The brains were removed from decapitated rats to punch out LC, DRN, hippocampus and amygdala to analyse the expression of mRNA for ER? and PR by RT/PCR. This experiment was replicated to punch out the hippocampus and amygdala for the determination of noradrenaline (NE) and serotonin (5-HT) contents by High Performance Liquid Chromatography, followed by Electrochemical Detection (HPLC/ED). As expected, plasma concentrations of estradiol were not different from those of control rats (O + O). Plasma concentrations of progesterone in the periestropause were lower than those in the control group, which was reversed by estradiol. In the LC, the PR expression in the periestropause was similar to that of the control rats, whereas the ER? expression was lower; estradiol therapy did not modify the expression of any of these receptors. The12 density of noradrenergic (TH +) neurons in LC was not altered by either follicular depletion or estrogen therapy. In periestropause, NA content was lower in the amygdala, but not in the hippocampus, and estradiol did not alter this content in any of the areas. In NDR, the expression of PR and ER? in periestropausal rats was lower than in controls; estradiol prevented the decrease of ER? expression, but not PR. The NDR was analyzed separately for the entire rostrocaudal axis in three anatomical levels: rostral, middle and caudal, each divided into three sub-regions: lateral, dorsal and ventral. The number of serotonergic neurons (TPH +) in NDR was lower in the periestropause, and estradiol was able to reverse this effect, acting mainly in the caudal region. PR gene expression was not altered by either follicular depletion or estrogen therapy in either the amygdala or the hippocampus. ER? expression was also no different in periestropause compared to the control group, but estradiol increased this expression in the hippocampus. Both in the amygdala and in the hippocampus there was a reduction in 5-HT content in the periestropause, and estradiol was able to reestablish the levels of this neurotransmitter at the control values only in the hippocampus. These data elucidate, at least in part, the mechanisms of the positive effect of estrogen therapy on the symptoms of normoestrogenic women in perimenopause. These effects do not appear to significantly involve the central noradrenergic system but result from increased peripheral progesterone biosynthesis in association with positive regulation of ER? in the NDR and hippocampus, which appears to potentiate the serotonergic NDR/HPC pathway. Therefore, the development of new therapies that activate ER? may be an alternative to obtain the positive effects of the estradiol action, eliminating the side effects of the estradiol therapies that normally result from the activation of ER?.
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Martins, Mayane Emanuela Melo Lopes. "Immunohistochemical evaluation ESTROGEN RECEPTORS ΑLFA EXPRESSION AND PROGESTERONE in differentiated thyroid cancer." Universidade Federal do CearÃ, 2015. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=16565.
Full textAbstract:
Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgicoWith the use of sensitive imaging methods, there is an increase in thyroid nodules diagnosed. Even the CDT (differentiated thyroid cancer) being proportionately rare, its incidence is increasing, especially small tumors whose clinical outcome is uncertain. It is observed that in clinical practice most patients with CDT develops well when properly treated, mortality rates similar to the general population. On the other hand, a non-negligible percentage has relapses and some eventually not respond to conventional therapies, and died. It can be seen that with the need to identify markers that can predict the behavior of tumors, mainly due to the variable clinical disease progression. With these data, some researchers in search of these markers, are studying a possible relationship of hormonal and reproductive factors in the evolution of CDT. This study analyzes the immunoreactivity of α estrogen receptor (ERα) and progesterone receptor (PR), correlating it with clinical features in 80 female and male patients with papillary thyroid cancer (PDT) and follicular thyroid cancer (FDT ) with materials related to thyroidectomy pieces performed at the University Hospital Walter CantÃdio (HUWC) in the period from 2010 to 2014. There was a predominance of female patients (87.5%), older than or equal to 40 years (68.57%), average age 49.12, tumor size> 1 cm (69.04%), papillary histological type (95.24%), with location in one wolf, not multicenter, (61.90 %), lack of angiolymphatic invasion (67.85%), absence of invasion of the capsule (75%) without Hashimoto\'s thyroiditis (73.80%). In adjacent normal tissues it was observed that ER expression (77.77%) is greater than the PR expression (47.05%). In tumors observed the opposite, ERα (43.75%) and PR (47.5%) with a higher PR expression, these data were correlated with the clinical characteristics of tumors, such as gender, tumor size, age the diagnosis, capsular invasion, lymphatic invasion, Hashimoto\'s thyroiditis, tumor location, histological type and variants.
Com o uso de mÃtodos sensÃveis de imagem, observa-se um aumento nos nÃdulos tireoidianos diagnosticados. Mesmo o CDT (cÃncer diferenciado de tireÃide) sendo proporcionalmente raro, sua incidÃncia vem aumentando, especialmente de tumores pequenos, cuja evoluÃÃo clÃnica à incerta. Observa-se na prÃtica clÃnica que a maioria dos pacientes com CDT evolui bem quando adequadamente tratada, com Ãndices de mortalidade similares à populaÃÃo geral. Por outro lado, um percentual nÃo desprezÃvel apresenta recidivas e alguns eventualmente nÃo respondem Ãs terapias convencionais, evoluindo para Ãbito. Percebe-se com isso a necessidade de identificaÃÃo de marcadores que possam predizer o comportamento dos tumores devido, sobretudo, à variabilidade na progressÃo clÃnica da doenÃa. Com esses dados, alguns pesquisadores, em busca desses marcadores, estÃo estudando uma possÃvel relaÃÃo de fatores hormonais e reprodutivos na evoluÃÃo do CDT. No presente estudo analisamos a imunoexpressÃo do receptor de estrogÃnio α (ERα) e receptor de progesterona (PR), correlacionando-a com caracterÃsticas clÃnicas, em 80 pacientes femininos e masculinos com cÃncer papilÃfero de tireÃide (PDT) e cÃncer folicular de tireÃide (FDT), utilizando material referente a peÃas de tireoidectomia realizadas no Hospital UniversitÃrio Walter CantÃdio (HUWC), no perÃodo de 2010 a 2014. Observou-se o predomÃnio de pacientes do sexo feminino (87,5%), com idade superior ou igual a 40 anos (68,57%), mÃdia de idade 49,12, tumor com dimensÃo >1cm (69,04%), tipo histolÃgico papilÃfero (95,24%), com localizaÃÃo em Ãnico lobo, nÃo multicÃntrico, (61,90%), ausÃncia de invasÃo angiolinfÃtica (67,85%), ausÃncia de invasÃo da cÃpsula (75%), sem Tireoidite de Hashimoto (73,80%). Em tecidos normais adjacentes observou-se que a expressÃo de RE (77,77%) à maior que a expressÃo de RP (47,05%). Em tumores observou-se o contrÃrio, ERα (43,75%) e PR (47,5%) sendo maior a expressÃo de RP, esses dados foram correlacionados com as caracterÃsticas clÃnicas dos tumores, como: sexo, tamanho do tumor, idade ao diagnÃstico, invasÃo capsular, invasÃo linfÃtica, tireoidite de Hashimoto, localizaÃÃo do tumor, tipo histolÃgico e variantes.
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Banna, Christopher David. "Characterization of DAP1/YPL170W: the Saccharomyces cerevisiae Membrane Associated Progesterone Receptor (MAPR)Homologue." Diss., Georgia Institute of Technology, 2005. http://hdl.handle.net/1853/6826.
Full textAbstract:
Characterization of DAP1/YPL170W: the Saccharomyces cerevisiae Membrane Associated Progesterone Receptor (MAPR) Homologue
Christopher D. Banna
135 pages
Directed by Dr. Jung H. Choi
MAPRs (Membrane Associated Progesterone Receptors) from several sources have been isolated, studied and minimally characterized in mammalian systems, yet the specific role of this protein family has not been fully determined. Early worked characterized this protein family as a type of steroid binding protein, unrelated to the classical nuclear receptors, and linked this family to non-genomic cellular responses. The MAPR homologues as a group have been suggested to play widely varying roles from axon guidance and neuronal formation, to steroid hydroxylation, to influencing reproductive behavior. Their specific role has not yet been clearly demonstrated in any organism. There is some debate as to whether MAPRs do indeed bind steroid compounds, but there is clear evidence this family of proteins is involved in steroid perception. Recent work has begun to link a specific member of the MAPR family, IZAg from rat, to steroid metabolism/production, specifically, in the hydroxylation step of glucocorticoid production from progesterone. In the yeast Saccharomyces cerevisiae, the MAPR homologue is DAP1. Preliminary work on haploid strains demonstrated several phenotypes associated with the DAP1 deletion mutant, most notably an altered sterol profile. Previous characterization of diploid homozygous mutant strain has shown a differential sensitivity to alcohol, an altered sterol profile, and a strong yeast two-hybrid interaction with Ypr118wp; methylthioribose-1-phosphate isomerase. Work in this study link the localization of Dap1p to lipid particles and on the ER, both sites of sterol synthesis. The sterol profiles of the control strain and the dap1Ġdeletion mutant strain were examined in detail. The most notable difference was the presence of an additional sterol compound associated with the deletion mutant strain. The structure of this compound does not correspond to normal sterols in the ergosterol biosynthetic pathway, but does correspond to structure of sterols in so-called alternate aberrant sterol pathways. The data presented in this study demonstrates that Dap1p was involved in sterol processing, although its specific role is unknown. Two possible scenarios are proposed; one where Dap1p is involved in regulating the flux of sterols from one internal membrane to another, and another where Dap1p is involved in aberrant sterol pathways.
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Acino, Erin Reese. "Transcriptional Regulation of the Mouse FKBP5 Gene by Progesterone and Glucocorticoid Receptor Binding." Thesis, The University of Arizona, 2010. http://hdl.handle.net/10150/146207.
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Steroid hormone receptors bind to DNA and interact with transcription-regulating proteins to affect a change in gene expression levels. However, questions remain about their choice of binding sites in vivo and their cooperation with other transcription factors. This experiment uses chromatin immuno-precipitation (ChIP) to attempt to identify progesterone and glucocorticoid receptor binding sites in the mouse FKBP5 gene. However, no sites were identified due to poor-quality sheared chromatin. Use of a circulating water bath to maintain low temperatures during sonication could improve consistency in future experiments, and more cellular material could increase the likelihood of successful immuno-precipitations.
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Carmo, Patrícia Oliveira. "Sobrevida de mulheres com câncer de mama subtipo luminal assistidas em Juiz de Fora, Minas Gerais, Brasil." Universidade Federal de Juiz de Fora, 2015. https://repositorio.ufjf.br/jspui/handle/ufjf/374.
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Em geral, o câncer de mama subtipo luminal exibe melhor prognóstico em relação aos outros subtipos tumorais. No entanto, a doença nesta condição pode assumir uma evolução desfavorável em algumas circunstâncias, o que sinaliza para a necessidade de melhor entendimento sobre o comportamento deste subtipo tumoral. O presente estudo teve por objetivo estimar a sobrevida livre de doença de mulheres em cinco anos com câncer de mama subtipo luminal e avaliar as variáveis prognósticas, clínicas, sociodemográficas, histopatológicas, relacionadas à utilização dos serviços de saúde e ao tratamento visando conhecer o impacto destas e sua implicação na recorrência e sobrevida da população estudada. Os dados foram obtidos a partir de uma coorte de base hospitalar, composta por 331 mulheres diagnosticadas com a doença no período entre 2003 e 2005, com perfil imunohistoquímico compatível com tumor luminal, não metastático (estadios I, II e III), atendidas em hospital referência em Oncologia no Município de Juiz de Fora – MG. A sobrevida livre de doença em cinco anos foi de 79,5% (IC95%: 74,6-83,6). Na análise univariada, observou-se associação da recorrência do tumor com o tipo de serviço de saúde, estadiamento, tamanho tumoral, comprometimento linfonodal e número de linfonodos comprometidos, quimioterapia e hormonioterapia (p<0,05), sendo verificada menor recorrência para as mulheres que frequentaram o serviço privado, que apresentaram doença inicial, menor tamanho tumoral e ausência de comprometimento linfonodal axilar e que foram submetidas a hormonioterapia. No modelo multivariado, permaneceram gravidade da doença e hormonioterapia como os fatores prognósticos mais importantes. As técnicas de biologia molecular representam o futuro do tratamento do câncer e também para os tumores luminais. Deve-se garantir o acesso ao tratamento hormonal quando indicado e os estágios avançados devem ser objeto de abordagem terapêutica mais ampliada.
Luminal breast cancer usually has a better prognosis in relation to other tumoral subtypes. Nonetheless, the illness in this point can evolve unfavorably in some circumstances what signals the need for a better understanding about this tumoral subtype behavior. The present study aimed at estimating the diseasefree survival of women with luminal breast cancer in five years. In this study, many variables have been evaluated, including prognostic, clinic, sociodemographic, histopathological and related to the use of public health services and treatment, aiming to get to know their impact and implications on recurrence and survival among the population of the study. The database was a hospital based cohort study, composed of 331 women diagnosed with the disease between 2003 and 2005, with immunohistochemical profile compatible with luminal breast cancer, non-metastatic (stages I, II or III), treated in a hospital seen as a reference for cancer care in Juiz de Fora, MG. The study showed a disease-free survival of 79.5% (IC95%: 74.6-83.6) in five years. The univariate analysis has shown an association of tumor recurrence with the type of health care, staging, tumor size, lymph node involvement and their number, chemotherapy and hormonal therapy (p<0.05) and it has indicated better survival rates among women who used private health care, who are in an initial stage, with smaller tumors, no axillary involvement and who used hormonal therapy. In the multivariate model, there remained gravity of the illness and the use of hormonal therapy as the most important prognostic factors. Molecular biology techniques represent the future for cancer treatment and also for luminal tumors. Access to hormonal therapy should be granted whenever prescribed and advanced stages must receive an amplified range of therapeutic approach.
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Bick, Alexis J. "Cross talk between the glucocorticoid receptor and the progesterone receptor in modulation of progestin responses and HIV-1 infection." Thesis, University of Cape Town, 2018. http://hdl.handle.net/11427/28403.
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Current epidemiological data showing that the use of the injectable contraceptive progestin Depotmedroxyprogesterone acetate (DMPA) is associated with increased HIV-1 acquisition is controversial. However, animal and ex vivo data reveal plausible biological mechanisms whereby MPA may increase HIV-1 acquisition. Relatively high levels of endogenous progesterone (P4) found in the luteal phase of the menstrual cycle have also been linked to increased HIV-1 acquisition in animal, clinical and ex vivo models. One of the central hypotheses of the present study was that the mechanism of MPA-induced increase in HIV-1 infection occurs via a different mechanism to that of the luteal phase. Furthermore, MPA has been shown to activate both the glucocorticoid receptor (GR) and its target, the progesterone receptor (PR) isoform B (PR-B), which are both transcription factors and regulate genes involved in immune function. Both the GR and PR are expressed in the cervix, the primary site of heterosexual HIV-1 infection. PR is regulated by endogenous estrogen (E2), of which the concentrations fluctuate throughout the menstrual cycle, and GR expression also varies in response to stress hormones, leading to conditions of varied relative levels of GR/PR. The immune-related consequences of changing the relative levels of GR and PR-B are not well understood. Therefore another hypothesis of this study was that changing the relative levels of GR/PR-B modulates HIV-1 infection and immunomodulatory gene expression in response to the GR/PR agonist, MPA. Since GR and PR-B recognize similar DNA target sequences and may regulate the same genes at the same time, the final hypothesis of the present study was that GR and PR-B reciprocally modulate each other’s activity, through possible association. To investigate the effects of exogenous hormones on HIV-1 infection and mechanisms thereof, peripheral blood mononuclear cells (PBMCs) and TZM-bl cervical cells were used as model systems for HIV-1 infection. These cells were stimulated with P4 and E2 at concentrations mimicking the menstrual cycle phases or with levels of MPA at the upper range of peak serum levels detected in DMPA users. Cells were infected with the R-tropic HIV-1 infectious molecular clone, HIV-1Bal_Renilla and luciferase assays were used to measure HIV-1 infection. Levels of HIV-1 CD4 receptor and CCR5 co-receptor protein or mRNA were measured by flow cytometry or qPCR, respectively, while activation of CD4+ T cells using the activation marker CD69 was measured by flow cytometry in PBMCs. To investigate the effects of changing GR/PR-B levels on HIV-1 infection and immune gene regulation, GR/PR levels were altered in End1/E6E7 immortalized endocervical and HeLa/TZM-bl cervical carcinoma cells by GR siRNA knockdown with or without the simultaneous over-expression of PR-B, and cells were stimulated with MPA or the GR agonist Dexamethasone. mRNA expression iii of key immunomodulatory genes in End1/E6E7 and HeLa cells was measured by qPCR. The modulation of GR activity by PR-B was assessed by promoter-reporter assay in COS1 and U2OS cells over-expressing GR and PR and stimulated with GR- and/or PR-specific ligands. Association of GR and PR-B was measured by co-immunoprecipitation in COS1 and MCF-7 cells, while co-localization of GR and PR-B was measured by confocal microscopy and super-resolution structured illumination microscopy in COS1 cells. MPA significantly increased HIV-1 infection in both PBMCs and TZM-bl cells, while luteal phase hormones did so to a lesser extent. However, MPA but not luteal phase hormones increased the ratio of CD4+/CD8+ T cells in PBMCs. MPA but not luteal phase hormones also increased CCR5 protein expression on CD4+ T cells in PBMCs and total CCR5 mRNA expression in TZM-bl cells. In addition, MPA but not luteal phase hormones increased activation of CD4+ T cells in PBMCs. Using a GR antagonist or GR siRNA, it was shown that the GR but not PR-B is required for MPA-, but not luteal phase hormone-induced increased HIV-1 infection in PBMCs and TZM-bls. The presence of PR-B altered the anti-inflammatory, GR-mediated regulation of some key immunomodulatory genes, including GILZ and IL-6, in End1/E6E7 and HeLa cells in response to MPA. In general, basal (unliganded) expression of immunomodulatory genes exhibited a pro-inflammatory profile in the presence of PR-B. Co-immunoprecipitation assays showed that GR and PR-B appeared to associate. Confocal microscopy suggested GR and PR co-localized in the nucleus in response to GR- and/or PRspecific ligands, while super-resolution microscopy showed that co-localization occurred in select regions within the nucleus. Taken together, MPA increases HIV-1 infection in a manner different from that of luteal phase hormones, most likely involving increased CD4+ T cell frequency (CD4+/CD8+ ratio), activation and increased expression of CCR5 on CD4+ T cells, and requiring the GR. Furthermore, PR-B modulates GR-mediated immune function gene regulation, via potential association and region-specific nuclear co-localization. This suggests that the relative levels of GR/PR may play an important role in determining the inflammatory and immune responses and HIV-1 infection in HIV-1 target cells, both in DMPA users and women not using hormonal contraception.
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Banerjee, Ananya. "Differential Regulation of Glucocorticoid and Progesterone Receptor Subcellular Localization by Tetratricopeptide Repeat Domain Proteins." University of Toledo Health Science Campus / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=mco1177535048.
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Al, Ramadan Saeed Yaseen. "Analysis of some novel uterine extracellular matrix proteins and a growth factor." [College Station, Tex. : Texas A&M University, 2007. http://hdl.handle.net/1969.1/ETD-TAMU-1383.
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Bergeron, Christine. "Immunocytochemical localization of estrogen and progesterone receptors in normal, hyperplastic and neoplastic human endometria." Thesis, McGill University, 1989. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=75995.
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Estrogen and progesterone receptors were localized in fresh frozen sections of human endometrial tissues, in both health and disease, using the ER-ICA kit and a mouse monoclonal antiprogesterone receptor antibody ($ alpha$PR6), respectively. Estrogen and progesterone receptors were detected exclusively in the nuclei of epithelial and stromal cells of the endometrium. Their highest levels in both components were found during the late proliferative phase of the normal menstrual cycle. Estrogen receptors decreased faster in the stroma than in the epithelium throughout the post ovulatory phase, whereas progesterone receptors decreased more rapidly in the epithelium during the mid and late secretory phases. Estrogen and progesterone receptor levels were high in the epithelium of hyperplasia without cytologic atypia. They were low in the epithelium of endometrial intraepithelial neoplasia (hyperplasia with cytologic atypia) and the majority of invasive carcinomas. The stroma contained relatively high estrogen and progesterone receptors levels, irrespective of whether the epithelium was hyperplastic or neoplastic.
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Poppe, Ana Carolina Machado. "Avaliação de marcadores relacionados à transição epitélio-mesênquima na endometriose pélvica." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/5/5139/tde-20022014-092016/.
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Introdução: A endometriose é uma doença ginecológica comum caracterizada pela presença de estroma e/ou glândula endometrial fora da cavidade uterina, e que não possui sua etiopatogenia bem estabelecida. A transição epitélio-mesênquima (TEM) é um processo que consiste em uma série de mudanças no fenótipo de células epiteliais que fazem com que estas células assumam características de células mesenquimais. Assim como observado na TEM, as células endometriais no contexto da endometriose apresentam capacidade migratória, invasibilidade e elevada resistência à apoptose. As moléculas de adesão têm adquirido crescente relevância na TEM, pois relacionam-se à perda de adesão célula-célula com o aumento da invasão e metástase. O objetivo deste estudo foi investigar a expressão de marcadores relacionados com a TEM na endometriose superficial, ovariana e profunda. Pacientes e Métodos: Foram selecionadas 103 mulheres que preenchiam os critérios de inclusão estabelecidos, constituindo 2 grupos de estudo independentes entre si: 18 mulheres com endometriose peritoneal, ovariana e profunda concomitantes; 85 mulheres com endometriose ovariana e/ou profunda, dividido em 44 mulheres com endometriose ovariana e 41 com endometriose intestinal. Através de reações de imunoistoquímica, a expressão proteica dos marcadores e-caderina, n-caderina, betacatenina, receptor de estrogênio e receptor de progesterona foram avaliados nos tecidos de interesse em cada grupo de estudo. Além dos locais de doença, as mulheres foram avaliadas quanto à relação com a fase do ciclo e à classificação histológica da doença. Resultados: As lesões de endometriose de ovário mostraram uma menor expressão de n-caderina em comparação às lesões de intestino e peritônio (p=0,032). O receptor de estrogênio e receptor de progesterona se mostraram significativamente menos expressos no componente epitelial da doença de ovário do que no epitélio da endometriose de peritônio e intestino (p=0,002; p=0,48). A expressão da n-caderina apresentou uma correlação direta com a expressão do receptor de estrogênio no estroma da endometriose de intestino (p=0,036). Conclusão: Estes resultados sugerem que a transição epitélio-mesênquima esteja envolvida na etiopatogenia da endometriose, demonstrando que a doença de ovário se comporta de maneira diferente da doença superficial e da doença infiltrativa profunda, sendo a n-caderina um importante fator envolvido neste processo possivelmente influenciada pela ação do estrogênioBackground: Endometriosis is a common gynecological disease defined as the presence of ectopic endometrial glands and stroma outside the uterine cavity, and its pathogenesis is not well established. The epithelial to mesenchymal transition (EMT) is a process consisting of a series of changes in the phenotype of epithelial cells that make these cells assume the characteristics of mesenchymal cells. As observed in the EMT, endometrial cells in the context of endometriosis have the capacity of migration, invasiveness and high resistance to apoptosis. . The adhesion molecules have become progressively relevant in EMT, in view of the cell-to-cell adhesion loss, with increased invasion and metastasis. The goal of this study was to investigate the expression of markers related to EMT in superficial, ovarian and deep endometriosis. Patients and Methods: 103 women were selected who met the inclusion criteria, constituting two independent study groups: 18 women with peritoneal, ovarian and deep concomitant endometriosis, 85 women with ovarian and / or deep endometriosis, divided in 44 women with ovarian endometriosis and 41 with intestinal endometriosis. Through immunohistochemical reactions, the protein expression of e-cadherin, ncadherin, beta-catenin, estrogen receptor and progesterone receptor markers were evaluated in tissues of interest in each study group. In addition to the sites of the disease, menstrual phase and histological classification (well-differentiated, undifferentiated, mixed pattern and stromal) of the disease were recorded. Results: The ovarian endometrisis showed less n-cadherin marker than lesions of the peritoneum and bowel (p=0,032). Ovarian endometriosis also showed markedly decreased expression of estrogen and progesterone receptors in epithelial cells, compared with peritoneal and deep endometriosis (p=0,002; p=0,48). The expression of N-cadherin showed a direct correlation with estrogen receptor expression in the stroma of bowel endometriosis (p = 0.036). Conclusion: These results suggest that epithelial to mesenchymal transition involved in the pathogenesis of endometriosis, demonstrating that the ovary disease behaves differently disease than peritoneal and deep disease, so that the n-cadherin is an important factor involved in this process, possibly influenced by the action of estrogen
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Whitaker, Lucy Harriet Ravenscroft. "Effect of administration of selective progesterone receptor modulators (SPRMs) on uterine and endometrial morphology." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/28974.
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Introduction: The human menstrual cycle is regulated by sex-steroid hormones, including oestrogen (E), progesterone (P4) and androgens which act by ligand binding to their cognate receptors. Perturbation of the complex series of events governing the menstrual cycle may lead to heavy menstrual bleeding (HMB). This is a common debilitating condition and often associated with uterine fibroids. There remains an unmet need for effective, long-term medical treatment so women avoid surgery and preserve their fertility. Selective progesterone receptor modulators (SPRMs, e.g. ulipristal acetate, UPA) are synthetic ligands that bind the progesterone receptor (PR). Many SPRMs have been developed but only mifepristone (for the management of unwanted pregnancy) and UPA are in current clinical use. UPA is licensed for the intermittent treatment of symptomatic fibroids. SPRMs have potential utility for treatment of HMB as administration rapidly induces amenorrhoea but the mechanisms by which this is achieved are unknown. SPRM administration results in unique endometrial morphological changes (progesterone receptor modulator-associated endometrial changes; PAEC). Despite endometrial unopposed estradiol exposure these morphological changes do not appear to be associated with malignancy or pre-malignancy risk. Indeed endometrial cell proliferation appears reduced despite relative progesterone-antagonism. Based upon findings with other SPRMs it was hypothesised that: (i) administration of UPA would have an endometrial specific effect upon the reproductive tract, with regard to alteration in morphology, localisation of sex steroid receptors (SSR) and cell proliferation.; (ii) administration of UPA would impact upon progesterone-regulated (Pregulated) genes in the endometrium. Methods: The data presented within this thesis are derived from biopsies obtained at hysterectomy from the endometrium, fallopian tubes and cervices of women with symptomatic fibroids administered UPA for 8-15 weeks. Samples were obtained for histological assessment, immunohistochemistry and RNA extraction for subsequent quantitative RT-qPCR of sex-steroid receptors (SSR) and proliferation markers. In addition key P-regulated genes within the endometrium were investigated by RT-qPCR and selected protein expression. To further interrogate the anti-proliferative effect, RNA was extracted from “paired” endometrial biopsies from the same woman in the proliferative phase of the menstrual cycle and following subsequent treatment with UPA for at least eight weeks and microarray gene analyses undertaken. Results: Morphological alteration of the endometrium with UPA administration was consistent with previously published data, but with a higher prevalence than previously described. There was a striking alteration in expression and localization of SSRs, particularly PR and androgen receptor (AR), and alteration of many P-regulated genes, consistent with UPA acting with low progesteroneagonism within the endometrium. There was no alteration of SSR expression within the cervix and proliferation was unchanged. Fallopian tube morphology and SSR expression was consistent with proliferative phase but cell proliferation was reduced following UPA administration, consistent with secretory phase levels. Microarray analyses identified multiple transcripts altered relative to proliferative phase, with GREM2 the most significantly down-regulated gene and MUC1 one of the most significantly upregulated genes. Consistent with low levels of mitotic figures and cell proliferation, the most down regulated KEGG pathway was the cell cycle. Multiple elements within this were subsequently validated (RT-qPCR) and included key regulators of all elements of the mitotic cell cycle, many of which were novel to those previously described following administration of another SPRM, mifepristone. In summary the novel data presented in this thesis considerably extend the data available to date concerning the actions of the SPRM, UPA, on the female reproductive tract, and increases knowledge regarding a compound with promising utility for the management of the debilitating complaint of HMB.