Dissertations / Theses on the topic 'Endometriosis'

Endometriosis is an inflammatory condition in which the immune system is thought to play a fundamental role in establishment and progression. Within peritoneal endometriotic lesions there is evidence of increased immune cell recruitment and activation. However, it is still unclear how the immune environment relates to peritoneal endometriotic lesion development. Therefore, the main aim of this project was to investigate peritoneal endometriotic lesion development by characterising the immune environment by macroscopic appearance (red, black and white scarred). Peritoneal endometriotic lesions were prospectively collected and immunohistochemically stained to identify T cells, B cells, macrophages and dendritic cells. Immune cells were present in both the endometriotic stroma and lesion-surrounding tissue. Additionally, there were some differences in immune cell population densities between stroma and surrounding tissue. Also a number of correlations were found between the densities of different immune cell populations in both tissue types, indicating relationships and interactions between cell types. The density of immune cells in and around peritoneal endometriotic lesions was not correlated with lesion appearance. The recruitment of immune cells to tissue within and around peritoneal endometriotic lesions is likely an attempt to attack the lesion. However, products released by these cells may in fact promote processes such as angiogenesis and fibrosis and thereby lesion growth and persistence. The findings from this thesis have implications for understanding of endometriosis pathogenesis, and also potentially for development of novel treatment approaches.

Lo scopo del seguente lavoro è di analizzare il profilo di attivazione dei geni legati al pathway dell’Unfolded Protein Response (UPR) nel carcinoma endometrioide dell’ovaio e di valutare il suo possibile coinvolgimento nella trasformazione neoplastica dell’endometriosi. Lo studio è stato eseguito utilizzando diversi campioni istologici: carcinoma endometrioide dell’ovaio, tessuto ovarico sano, cisti endometriosica, endometrio eutopico provenienti da pazienti con endometriosi e da pazienti con endometrio sano. Da tutti i campioni è stato estratto l’RNA e sintetizzato il cDNA utilizzando la trascrizione inversa. Il cDNA è stato utilizzato per i saggi di espressione quantitativa dei geni, tramite Real Time PCR, con analisi dei geni appartenenti al pathway dell’UPR. I campioni sono stati divisi in tre gruppi: patienti con endometriosi (n=6), pazienti sane (n=6) e pazienti con carcinoma endometrioide dell’ovaio (n=6). L’analisi statistica effettuata è il t-test, con analisi delle differenze statistiche tra i dati provenienti da pazienti sane (CTRL) e pazienti affette da endometriosi (Ectopic e Eutopic) e pazienti affette da carcinoma endometrioide dell’ovaio (CA). Abbiamo in primo luogo analizzato la differente espressione del pathway dell’UPR nel carcinoma endometrioide dell’ovaio, comparandolo al tessuto ovarico sano e abbiamo dimostrato un’alterata espressione dei geni dell’UPR nelle pazienti tumorali. In secondo luogo, abbiamo analizzato l’espressione genica dell’UPR nel carcionma endometrioide ovarico, comparandola all’endometrio sano di pazienti sane e di pazienti affette da endometriosi. Il nostro studio mostra una graduale riduzione dell’espressione del gene XBP1 nell’endometriosi, caratterizzata da intensa infiammazione e nel carcinoma endometrioide dell’ovaio, valorizzando l’ipotesi che XBP1 possa rappresentare un marker di trasformazione neoplastica. In conclusione XBP1 ha un’alta espressione nell’endometrio sano, un tessuto costitutivamente secretivo, e poi gradualmente riduce la sua espressione nell’endometriosi e, in maniera più accentuata, nel carcinoma ovarico. Comprendere questi meccanismi potrebbe rappresentare uno step importante per una migliore definizione della patogenesi tumorale e per lo sviluppo in futuro di terapie geniche mirate.
The present study aims to analyze the activation profile of Unfolded Protein Response (UPR) related genes in endometriod ovarian carcinoma and to assess its possible involvement in the neoplastic transformation from endometriosis. The study was performed using different histological samples: endometrioid carcinoma of the ovary, healthy ovary, endometriosis cysts, eutopic endometrium from patients with endometriosis and healthy endometrium. From all the samples RNA was extracted and cDNA synthesis was performed by reverse transcription. cDNA was used for quantitative gene expression assays, made by Real Time PCR, analyzing genes belonging to the UPR pathway. Samples were divided into three groups: patients with endometriosis (n = 6), healthy patients (n = 6) patients with ovarian endometrioid carcinoma (n = 6). Statistical analysis performed was a t - test, testing the statistical differences, between data means from healthy patients (CTRL) and groups of patients with endometriosis (Ectopic and Eutopic) and patient with endometrioid carcinoma of the ovary (CA). We started analyzing the different expression of UPR pathway in endometrioid ovarian carcinoma compared to healthy ovary and we demonstrated an altered UPR gene expression in patients affected by endometrioid ovarian carcinoma, compared to healthy ovary. As a second step, we decided to analyze the UPR pathway genetic expression in the endometrioid ovarian carcinoma compared to the endometrium of healthy patients and of endometriosis patients. Our study shows a gradual reduction of XBP1 expression in endometriosis, characterized by intense inflammation, and endometrioid ovarian carcinoma, thus strengthening the hypothesis of XBP1 as a marker of neoplastic transformation. Conclusively XBP1s has a high basic expression in healthy endometrium, being a secretive tissue, then gradually decreases in endometriosis and to a higher degree, in ovarian carcinoma. Understanding these mechanisms could represent an important step, for a better definition of cancer pathogenesis, and also in the future, for the development of customized therapies.

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Fundação para o Desenvolvimento Médico e Hospitalar (Famesp)
As dosagens da leptina, da interleucina-6 (IL-6) e do fator de necrose tumoral alfa (TNF-a) foram avaliadas no diagnóstico da endometriose peritoneal mínima e leve (estádios I e 11 - American Society for Reproductive Medicine). Participaram, deste estudo prospectivo e casocontrole, 29 mulheres, em idade reprodutiva, submetidas a videolaparoscopia. O grupo de estudo foi composto por 15 pacientes em investigação de esterilidade conjugal ou dor pélvica crônica (grupo E) e o grupo controle por 14 mulheres assintomáticas encaminhadas para realização de ligadura tubária (grupo C). Foram coletadas amostras de sangue periférico e líquido peritoneal para a dosagem laboratorial das citocinas determinadas por meio de testes ELlSA. No soro, não se observou diferenças significantes nas amostras de leptina, de IL-6 e do TNF-Q entre os grupos estudados (p>O,05). No líquido peritoneal, houve diferenças significantes nas dosagens da leptina e do TNF-Q entre os grupos estudados (pO,05). No líquido peritoneal, há evidências da possibilidade da utilização da leptina e do TNF-Q no diagnóstico da endometriose mínima ou leve, na amostra estudada.
The levels of leptin, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-o) were evaluated as a diagnostic tool for minimal and mild peritoneal endometriosis (stages I and II - American Society for Reproductive Medicine). lhe subjects of this prospective, case-control study were 29 women of reproductive age, who underwent laparoscopy. Subjects of the study-group were 15 women under investigation of infertility or chronic pelvic pain (E-group) and controls were patients with no symptoms in which tubal ligation would be performed (C-group). In ali these patients were collected samples of peripheral blood and peritoneal f1uid, in order to determine cytokine levels employing ELlSA tests. There were no statistical differences of the sera on the studied groups concerning the levels of leptin, IL-6 and TNF-o (p> 0.05). There were statistical differences in the peritoneal fluid of the studied groups, concerning the levels of leptin and TNF-o (p< 0.05) but not for IL-6 (p> 0.05). There is an evidence of using leptin and TNF-o in the peritoneal f1uid as a diagnostic tool for minimal and mild endometriosis.

Endometriosis is a common, benign, oestrogen-dependent, gynaecological disorder that occurs in women in their reproductive years. Although it has been studied for many years, the aetiology and pathophysiology of endometriosis are still unclear. Accumulated evidence indicates that endometriosis has a heritable component. Recently, the International Endogene Study (IES) identified two significant linkage regions on chromosomes 7 and 10. The signal on chromosome 7 may be caused by a rare variant, with near-Mendelian inheritance, present in a subset of families. This thesis comprises follow-up studies aimed at: 1) narrowing down the linkage region on chromosome 7 through fine mapping and haplotype analyses; 2) screening candidate genes for mutations potentially responsible for the susceptibility to endometriosis through sequencing, and 3) conducting linkage analyses in two orthologous regions in a large, complex pedigree of rhesus monkeys with spontaneous disease. Firstly, linkage and haplotype analyses were conducted on 32 extended families, which contributed most to the linkage signal, from the Oxford dataset. Haplotype analyses narrowed down the linkage region to an area surrounding a single marker (D7S2251), containing 10 genes, although this result was dependent on a critical recombination in a single family. Secondly, fine mapping and haplotype analyses conducted to narrow an 11Mb region originally identified in the analysis of the combined IES dataset, identified a 1Mb region, comprising 5 genes, based on the haplotype segments shared between the affected members. The exons and part of the 5' untranslated regions ofINHBA, SFRP4 and HOXAlO were screened by TOCE and/or PCR-sequencing in affected members of the 32 Oxford families. Although some variants were identified, none of them were sufficiently frequent among cases to be responsible for the linkage signal in this group of women. Analyses were conducted in a 6-generational pedigree of 894 rhesus macaques residing at the Wisconsin National Primate Research Center, USA. Novel protocols were developed to extract DNA from paraffin-embedded tissues. Linkage analysis, conducted using Merlin and SimWalk2 on smaller sub-pedigrees, showed some evidence for linkage in both regions, particularly on chromosome 7, although results were not significant. The position of the linkage signals was close (2Mb and 500 kb) to the corresponding positions where the linkage signals had been found in humans. These results indicate that susceptibility genes to endometriosis might be located within the two regions. Possible studies following on from this thesis will include screening of more candidate genes in the linkage regions, re-sequencing of the linkage regions in humans, and performing a genome wide linkage analysis in the rhesus monkey model. Further investigations of biological pathways involved in endometriosis will lead to a better understanding of the aetiology of the disease, new treatments and improved patient quality of life.

Endometriosis is an estrogen-dependent gynecological condition characterized by the presence and growth of ectopic endometrial tissue, often associated with inflammation, severe and chronic pain, and infertility. Lesions are categorized as superficial peritoneal lesions, endometriomas, or deep infiltrating nodules, with high degree of individual variability in lesion color, size, and morphology. Numerous factors involved in this disease, including inflammation, angiogenesis, cytokine/chemokine expression, and endocrine alterations such as steroid and steroid receptor expression. When endometrial-like glands and stroma infiltrate the bowel wall, reaching at least the subserous fat tissue or the adjacent subserous plexus, the condition is diagnosed as intestinal endometriosis. Matherial and methods The aim of this study is to analyze the bowel comorbidities of the endometriosis. In particular, the frequency of endometriosis in young women with abdominal pain and to evaluate the most feared complication after surgery. In the first time, we consider the young fertile age women with right iliac fossa (RIF) pain . This is one of the most common complaint in those presenting at the emergency department and requiring acute care. A group of fertile age women (18-45 years) undergoing emergency surgery for acute RIF pain According to the intraoperative and pathology findings, patients were subdivided into 2 groups: group A was composed by those with histological diagnosis of endometriosis, whereas group B identified the controls. During the surgery, peritoneal samples were taken and analized. The present study showed that in women undergoing appendectomy for a RIF pain, superficial peritoneal endometriosis (SUP) is an incidental diagnosis in 23% of cases. In the second time, we consider the bowel endometriosis. When endometriosis infiltrate the bowel wall, reaching at least the subserous fat tissue or the adjacent subserous plexus, the condition is diagnosed as intestinal endometriosis Medical treatments include nonsteroidal anti-inflammatory drugs, oral contraceptives, progesterone, and gonadotropin-releasing hormone. Instead, surgical treatment includes shaving or resection. We performed this study with the aim of identifying the number of leaks in colonic resections for deep endometriosis. Conclusions Endometriosis is a very common condition in fertile young women. Knowing the degree of infiltration and deciding on the best treatment strategy should not be undervalued.

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
A endometriose constitui uma doença de etiologia incerta, caracterizada pela presença de tecido endometriótico fora da cavidade uterina. E uma causa comum de morbidade, atingindo 5 a 10% das mulheres em idade reprodutiva. A metilção anormal na região promotora de genes especificos e os niveis de expressão alterados das DNA metiltransferases (DNMTs) compoem 0 conjunto de evidencias recentes indicando a endometriose como uma doença epigenetica. 0 presente estudo propos a investigaçao do perfil diferencial de metilaçao do DNA na endometriose, utilizando uma abordagem genomica de alta resoluçao baseada na metodologia de microarrays. Para isso, foram coletadas amostras pareadas de endometrio eutópico e de endometriose intestinal profunda de 18 pacientes. Foram selecionadas dez amostras pareadas para a hibridação do DNA: cinco casos foram submetidos ao enriquecimento das sequencias não metiladas (digerido com a enzima de restrição dependente de metilação McrBC ) e nove ao enriquecimento das sequencias metiladas (digerido com 0 coquetel de enzimas sensiveis a metilação do DNA Acil, HinP11, HpyCH41Ve Hpall). Os ensaios foram realizados em duplicatas totalizando 28 hibridações independentes na plataforma disponivel comercialmente Human CpG Island ChIP-on-Chip Set 244K (Agilent Technologies). Este protocolo foi previamente padronizada utilizando-se 0 DNA das linhagens derivadas de carcinomas de c610n HCT116 e DKO (celulas HCT116 duplo knockout para as DNMT1 e DNMT3b) usando marcação reversa (dye swap). Os dados foram avaliados nos software Agilent Technologies Genomic Workbench (DNA Analytics 5.0) e GeneSpring 7.3 (Agilent Technologies). Estre os 925 genes que apresentaram metila9ao diferencial, 55 foram recorrentes em dois ou mais casos. Varios destes genes mostram-se interessantes por exercerem funções relacionadas a fatores de transcrição (MSX1, EMX2, HOXB13, HOXD8 e HOXD9)...
Endometriosis is a disease of unknown etiology characterized by the presence of endometrial tissue outside the uterine cavity. It is a common cause of morbidity, affecting 5-10% of women in reproductive ages. The aberrant methylation in the promoter region of specific genes and the higher expression levels of DNA methyltransferases (DNMTs) in comparison with normal endometrium have been reported as evidences indicating that endometriosis is an epigenetic disease. The present study investigated the differential profile of DNA methylation in endometriosis using a high-resolution microarray-based assay. There were collected paired samples of eutopic endometrium and deep intestinal endometriosis from 18 patients and, subsequently, it was selected ten pairs to the DNA hybridization: five matched samples were submitted to the enrichment of unmethylated sequences (digested with the methylation-dependent restriction enzyme McrBG) and ten to the enrichment of methylated sequences (digested with the cocktail of enzymes sensitive to DNA methylation AGII, HinP1/, HpyGH4/V and Hpa/I). The assays were performed in duplicates totalizing 28 independent hybridizations in the commercially available platform Human CpG Island ChIP-on-Chip Set 244K (Agilent Technologies). The protocol was previously standardized using the DNA from the colon carcinomas cell lines HCT116 and DKO (HCT116 cells double-knockout for DNMT1 and DNMT3b) using reverse labeling (dye swap). The data were evaluated using the software Genomic Workbench (DNA Analytics 5.0) and GeneSpring 7.3. Among the 925 genes showing differential methylation, 55 genes were detected in at least two cases. Several of these gene could be considered good candidates to molecular biomarkers of endometriosis since that they act as transcription factors (MSX1, EMX2, HOXB13, HOXDB e HOXD9) , chromatin remodeling (MAD1L 1, WDR5 e BGOR)... (Complete abstract click electronic access below)

Orientador: Rogério Dias
Banca: Jorge Nahás
Banca: Waldir Pereira Modotte
Banca: Reginaldo Guedes Coelho Lopes
Banca: Ilza Maria Urbano Monteiro
Resumo: As dosagens da leptina, da interleucina-6 (IL-6) e do fator de necrose tumoral alfa (TNF-a) foram avaliadas no diagnóstico da endometriose peritoneal mínima e leve (estádios I e 11 - American Society for Reproductive Medicine). Participaram, deste estudo prospectivo e casocontrole, 29 mulheres, em idade reprodutiva, submetidas a videolaparoscopia. O grupo de estudo foi composto por 15 pacientes em investigação de esterilidade conjugal ou dor pélvica crônica (grupo E) e o grupo controle por 14 mulheres assintomáticas encaminhadas para realização de ligadura tubária (grupo C). Foram coletadas amostras de sangue periférico e líquido peritoneal para a dosagem laboratorial das citocinas determinadas por meio de testes ELlSA. No soro, não se observou diferenças significantes nas amostras de leptina, de IL-6 e do TNF-Q entre os grupos estudados (p>O,05). No líquido peritoneal, houve diferenças significantes nas dosagens da leptina e do TNF-Q entre os grupos estudados (pO,05). No líquido peritoneal, há evidências da possibilidade da utilização da leptina e do TNF-Q no diagnóstico da endometriose mínima ou leve, na amostra estudada.
Abstract: The levels of leptin, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-o) were evaluated as a diagnostic tool for minimal and mild peritoneal endometriosis (stages I and II - American Society for Reproductive Medicine). lhe subjects of this prospective, case-control study were 29 women of reproductive age, who underwent laparoscopy. Subjects of the study-group were 15 women under investigation of infertility or chronic pelvic pain (E-group) and controls were patients with no symptoms in which tubal ligation would be performed (C-group). In ali these patients were collected samples of peripheral blood and peritoneal f1uid, in order to determine cytokine levels employing ELlSA tests. There were no statistical differences of the sera on the studied groups concerning the levels of leptin, IL-6 and TNF-o (p> 0.05). There were statistical differences in the peritoneal fluid of the studied groups, concerning the levels of leptin and TNF-o (p< 0.05) but not for IL-6 (p> 0.05). There is an evidence of using leptin and TNF-o in the peritoneal f1uid as a diagnostic tool for minimal and mild endometriosis.
Doutor

Bakgrund: Endometrios är en kronisk inflammatorisk sjukdom som uppskattas drabba 10 procent av alla personer med livmoder i fertil ålder. Sjukdomen har setts påverka flera aspekter i livet och kan orsaka stort lidande hos individen. Syfte: Syftet med denna litteraturöversikt var att undersöka hur personer med endometrios upplever att olika aspekter livskvaliteten påverkas av sjukdomen. Metod: Litteraturöversikten baserades på vetenskapliga artiklar publicerade i databaserna PubMed och CINAHL. Efter kvalitetsgranskning av 23 artiklar återstod 17, varav två kvalitativa och 15 kvantitativa. Resultaten från de inkluderade studierna gick sedan igenom och delades upp under rubriker utifrån de aspekter av livskvalitet som framkom. Huvudresultat: Endometrios visades ha en negativ påverkan på de drabbades liv och vardag. Kvinnor med endometrios skattade signifikant lägre generell livskvalitet och hälsorelaterad livskvalitet än kvinnor utan sjukdomen. De vanligast förekommande symtomen var olika typer av smärta vilka sågs ha en signifikant negativ påverkan på livskvaliteten och det dagliga livet, som nedsatt produktivitet inom arbete och utbildning. Endometrios innebar även psykiska begränsningar i form av antingen minskat generellt välmående eller sämre emotionell funktion. Gällande socialt nätverk visade flera studier att kvinnor med endometrios upplevde en negativ påverkan på relationer och/eller deras sociala liv. Normalisering och okunskap kunde bidra till försening i diagnos och påverkan på livskvalitet. Även vårdpersonalens kunskap inom ämnet ansågs vara otillräcklig i många fall. Slutsats: Kvinnor med endometrios hade lägre livskvalitet än kvinnor utan sjukdomen. Vidare forskning kring sjukdomen kan förbättra behandling och påskynda diagnostisering, vilket kan påverka den fysiska, psykiska och sociala funktionen hos individen. Detta kan minska kostnaderna vid såväl sjukskrivning som lägre arbetsproduktivitet samt frekventa vårdbesök relaterade till feldiagnostisering och vårdfördröjning.
Background: Endometriosis is a chronic inflammatory disease estimated to occur in 10 percent of the population with uterus of reproductive age. The disease has been observed to affect many aspects of life and causing great suffering for the individual. Aim: The aim of this literature review is to examine how people with endometriosis are experiencing how different aspects of quality of life is affected by the disease. Method: The literature review was based on scientific articles published in PubMed and CINAHL. After examining the quality of 23 articles 17 remained, including two qualitative and 15 quantitative studies. The results of the included studies were broken down and assorted into subgroups depending on which aspects of quality of life mentioned. Main Results: The result showed that endometriosis had a negative impact on the daily lives of those suffering of the disease. Women with endometriosis stated significantly lower overall quality of life and health-related quality of life than women without the disease. The most commonly reported symptoms were different types of pain which had a significant negative impact on quality of life and daily life, such as reduced work and education productivity. Endometriosis could also lead to mental limitations as decreased general wellbeing or emotional function. Regarding the social aspects, multiple studies showed that women with endometriosis experienced that the disease had a negative influence on relationships and/or their social life. Normalization and insufficient knowledge about the disease could contribute to delay in diagnosis and impact the quality of life. The knowledge of health care personnel was also seen inadequate in many cases. Conclusion: Women with endometriosis had lower quality of life than women without the disease. Further research could improve treatment and speed up diagnosis, affecting the physical, psychological and social functioning of the individual. This could reduce the costs from both sick leave and decreased work productivity as well as frequent health care visits related to misdiagnosis and delay of treatment.

Bakgrund: I Sverige lider ca 5 – 15 % av fertila kvinnor i åldern 30 – 40 år av endometrios. Det kan ta upp till 10 år innan den korrekta diagnosen ställs. Många kvinnor lider av bland annat stark smärta, smärtor vid ägglossning och djupa samlagssmärtor. Det finns endast behandling som kan lindra kvinnornas symtom. Behandlingen medför stora sjukvårdskostnader som påverkar samhällets ekonomi. Syfte: Syftet var att belysa kvinnors upplevelser av att leva med endometrios. Metod: Litteraturöversikten har genomförts av resultatet från 10 vetenskapliga kvalitativa artiklar som hämtats från databasen Cinahl Complete och Medline. Resultat: Ur resultatet framkom två huvudteman. (1) Leva med långvarig smärta med undertemat; Påverkan på det sexuella livet, Oro kring fertilitet och Hur smärtan påverkade kvinnornas arbetssituation. (2) Möten med vården med undertemat; Vårdens olika värderingar och Att vara sin egen expert. Slutsats: Resultatet av den här litteraturöversikten visar att endometrios är en diagnos där det saknas kunskap och utbildning från vårdens håll och där kvinnor lider både fysiskt och psykiskt, vilket påverkar deras liv i stor utsträckning. Sjukvården måste ta kvinnor som söker vård på allvar och kunskapen måste ökas för samtliga vårdkategorier för att kunna bygga en relation samt hjälpa dem till ett värdigt liv.

Bakgrund: I Sverige lider ca 5 – 15 % av fertila kvinnor i åldern 30 – 40 år av endometrios. Det kan ta upp till 10 år innan den korrekta diagnosen ställs. Många kvinnor lider av bland annat stark smärta, smärtor vid ägglossning och djupa samlagssmärtor. Det finns endast behandling som kan lindra kvinnornas symtom. Behandlingen medför stora sjukvårdskostnader som påverkar samhällets ekonomi. Syfte: Syftet var att belysa kvinnors upplevelser av att leva med endometrios. Metod: Litteraturöversikten har genomförts av resultatet från 10 vetenskapliga kvalitativa artiklar som hämtats från databasen Cinahl Complete och Medline. Resultat: Ur resultatet framkom två huvudteman. (1) Leva med långvarig smärta med undertemat; Påverkan på det sexuella livet, Oro kring fertilitet och Hur smärtan påverkade kvinnornas arbetssituation. (2) Möten med vården med undertemat; Vårdens olika värderingar och Att vara sin egen expert. Slutsats: Resultatet av den här litteraturöversikten visar att endometrios är en diagnos där det saknas kunskap och utbildning från vårdens håll och där kvinnor lider både fysiskt och psykiskt, vilket påverkar deras liv i stor utsträckning. Sjukvården måste ta kvinnor som söker vård på allvar och kunskapen måste ökas för samtliga vårdkategorier för att kunna bygga en relation samt hjälpa dem till ett värdigt liv.

Endometriosis is a disease that is historically known to present in many guises. Since 13th century it has been metaphorically regarded as an animalistic womb causing female hysteria. Albeit widely researched, significant controversies that surround the disease remain unsolved, from the clinical presentations, diagnosis, right through to its management strategies. Despite the rapid advancement of technology in modern medicine, the ideal diagnostic and investigative tool of the disease remains elusive, and hence the management of the disease remains a challenge to clinicians. Whilst it is long known that endometriosis is detrimental to fertility, it is unclear if Assisted Reproductive Technology (ART) obliterates that risk. This thesis aims to investigate the impact of different stages and types of endometriosis on ART outcomes, and how various surgical interventions influence the reproductive outcomes. The thesis will also focus on answering two important questions in endometriosis research, that of whether and how endometriosis impacts on 1) the developing oocytes and embryo, and 2) the endometrium. The thesis begins with the introduction of two robust systematic reviews and meta-analyses, which concluded that women with endometriosis had a lower pregnancy rate and fewer oocytes retrieved during ART. Worse reproductive outcomes were found in those with more severe disease. Surgical treatment, which traditionally is thought to be beneficial, was found to result similar reproductive outcome in diseased and controls, and possibly more harm. Gathering evidence retrospectively from the IVF databases supported the former conclusion that women with endometriosis undertaking ART had lower number of oocytes collected from matured follicles, and further investigation into the laboratory details showed that women with endometriosis had a higher proportion of early embryo arrest. A mouse oocyte model was then utilised to explore the influence of follicular fluid of women with endometriosis on oocyte development. The study found that follicular fluid retrieved from women with endometriosis results in the activation of DNA damage response pathway, which in turn prevented normal oocyte maturation. These effects were found reversed by the agent resveratrol. The thesis concludes with a biomarker discovery study on the endometrium of women with endometriosis compared to controls using a highly sensitive and specific state of the art proteomics analysis method (liquid chromatography mass spectrometry with isobaric tag for relative and absolute quantitation (LCMS/MS iTRAQ®) which uncovered unique proteins not yet described in the literature. Endometriosis is a disease that is detrimental to the reproductive outcomes of those undergoing ART. Its influence on reproduction is complex, but it is now clear that its impact on reproduction does not stop at the traditionally viewed anatomical distortion with resultant subfertility; but have far reaching consequences including that of defective oocyte and embryo development, with a differential impact on the endometrial proteome. The solution to this challenging disease partly lies in the early diagnosis and treatment of the condition; as such not withstanding pitfalls and fallacies surrounding biomarker discovery research, the ultimate validation of a diagnostic panel of biomarkers for the non-invasive diagnosis of endometriosis is now urgently needed.

Bakgrund: Endometrios är en kronisk sjukdom som drabbar 10% av alla kvinnor i världen.Sjukdomen är ett problem som berör många kvinnor i samhället. Detta bör belysas i störreutsträckning än det gör idag då många läkare inte tar sjukdomen och kvinnornas symtom påallvar. Detta leder till lidande hos kvinnor och lång tid innan diagnostisering sker. Ofta fårkvinnor höra att smärtan är normal, vilket kan leda till förtvivlan och isolering från vänneroch familj.Syfte: Syftet med denna litteraturstudie var att beskriva hanteringsstrategier hos kvinnor somlever med endometrios.Metod: En litteraturstudie med kvalitativ ansats. Metodlitteraturen som använts är Polit ochBeck. Studien har analyserats enligt Graneheim och Lundmans kvalitativa innehållsanalysoch databassökningar utfördes i Cinahl, Pubmed och Psycinfo.Resultat: Resultatet mynnade ut i fyra huvudteman initiering av livsstilsförändringar, behovav alternativa behandlingar, sökande efter kunskap, noncompliance och tre subtemakostomläggningar, ökad fysisk aktivitet, strategiska verktyg.Konklusion: Endometrios påverkar många faktorer i det dagliga livet för kvinnor som levermed sjukdomen. Det kan handla om hantering av smärta, relationer, arbete och utbildning.Dessa kvinnor utvecklar hanteringsstrategier för att lindra symtom av smärta och för attförbättra livskvaliteten. Dessa strategier handlar om ändrade motionsvanor, kost, kunskap ochatt själv ta kontroll. Målet för många kvinnor är att uppnå smärtfrihet samtidigt som önskanom att minska användning av läkemedel önskas. Hanteringsstrategierna upplevs av de flestakvinnor som positiva och bidrar till en ökad livskvalitet. Mer kunskap kan behövas om vilkahanteringsstrategier som används, för att kunna stödja och behandla kvinnor på ett bättre sättinom hälso- och sjukvården.
Background: Endometriosis is a chronic disease that affect 10% of all women of the world.Endometriosis is a problem which affects many women in society. This should be noted to agreater extent than today because many doctors don’t take the disease or the womenssymtoms seriously. This leads to a suffering for women and it takes long time beforediagnosis. Women often hear that the pain is normal which leads to dispair and isolation.Aim: The aim of the study was to describe management strategies among women that liveswith endometriosis.Method: A qualitative literature review. The literature that was used for the method was Politand Beck. Graneheim and Lundman’s qualitative contentanalysis was used for the analysis.Cinahl, pubmed and Psycinfo was used for retrieve material.Results: The result showed four main themes, these were initiation of lifestyle changes, needfor alternative treatments, searching for knowledge, noncompliance and three subthemeswere also identified change of diet, increased physical activity, strategic tools.Conclusion: Endometriosis affects many factors in the daily life of women living with thedisease. It can be about managing pain, relationships, work and education. These womendevelop management strategies to relieve symtoms of pain and to improve quality of life.These strategies is about change exercise patterns, diet, knowledge and taking control. Theaim for many women is to achieve painlessness with less painkillers at the same time. Themanagement strategies have a positive impact for most of the women and contributes tobetter life quality. If more knowledge is revealed about management strategies used, thenbetter support and treatment could be possible in healthcare.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior
Endometriose à uma doenÃa caracterizada pela presenÃa de glÃndulas e estroma endometriais for a da cavidade uterina e do miomÃtrio. Clinicamente pode causar tumores, dor (dor pÃlvica crÃnica, dispareunia e dismenorrÃia) e infertilidade. EvidÃncias correntes indicam que as cÃlulas endometriais ectÃpicas durante a menstruaÃÃo (menstruaÃÃo retrÃgrada) jogadas a cavidade peritoneal em mulheres com endometriose, implantam e proliferam ectÃpicamente no peritÃnio e em outros ÃrgÃos, uma aÃÃo que està associada com a mobilizaÃÃo de cÃlulas do sistema imune para a cavidade peritoneal e com uma profunda resposta imune e local. Um aumento na quantidade do lÃquido peritoneal à um achado caracterÃstico na endometriose e està associado com a presenÃa aumentada de cÃlulas imunes como os macrÃfagos assim como um sem numero de substancias solÃveis derivadas daqueles macrÃfagos como prostaglandinas, interleucinas, TNF, fatores de crescimento e espÃcies reativas de oxigÃnio. à provÃvel por isso que novas medicaÃÃes para essa doenÃa evoluam no futuro prÃximo, para isso devem-se elucidar os mecanismos de todas essas substÃncias na patogÃnese da endometriose. Os objetivos desse trabalho sÃo verificar: (i) os efeitos de drogas inibidoras seletivas da enzima ciclooxigenase tipo 1 (COX-1) responsÃvel pelos eventos fisiolÃgicos do organismo e pela induzida COX-2, envolvida nos processos inflamatÃrios; (ii) os efeitos do L-NAME, um antagonista competitivo do Ãxido nÃtrico assim como a atividade da NO-sintase avaliada pelo ensaio da citrulina marcada (3H-labelled citrulline from labelled L-arginine) e (iii) os efeitos da drogas moduladoras de TNF-alfa (Talidomida e pentoxifilina) sobre o desenvolvimento da endometriose experimental e suas repercussÃes sobre a dor e a fertilidade em ratas. Endometriose experimental foi desenvolvida em ratas Wistar e os animais foram divididos em grupos testes. O tratamento foi dado do 5o ao 15o dia da induÃÃo da endometriose para verificar os efeitos sobre o crescimento dos endometriomas avaliados pelo peso Ãmido e histopatologia e agudamente 30 minutos antes do estÃmulo nociceptivo para avaliar a dor (contorÃÃes abdominais) e a fertilidade investigada pela percentagem de ratas grÃvidas e pelo numero de embriÃes por corno uterino. Aspirina (30mg/kg - um inibidor de seletividade intermediÃria entre as COXs); piroxicam (1mg/kg) e indometacina (2mg/kg), um inibidor seletivo especÃfico da COX-1 e nabumetona (5 e 15mg/kg) e meloxicam (0,4mg/kg) inibidor seletivo relativo da COX-2 foram usados por via oral. Todos os tratamentos realizados diminuÃram significativamente a dor quando avaliadas pelo teste de contorÃÃes. A mÃdia dos pesos Ãmidos dos endometriomas (g%) sÃo mostrados (Controle endometriose: 0,595Â0,085; Aspirina: 0,122Â0,019; piroxicam: 0,766Â0,35; indometacina: 2,05Â0,96 e para Nabumetona 5mg: 0,52 0,032; Nabumetona 15mg: 0,135Â0,03 e meloxicam: 0,387Â0,04). Com relaÃÃo à fertilidade, a percentagem de ratas grÃvidas foi: Controle endometriose, 40%; controle intacto, 100%; Falso-operado, 100%; Indometacina, Zero%; meloxicam, 60%; Aspirina, 60% e Nabumetona 5 e 15, 50 e 58% respectivamente. Os tratamentos com Aspirina e Nabumetona diminuÃram significativamente o desenvolvimento dos endometriomas assim como contribuÃram para o alivio da dor e incrementaram a fertilidade. Estes resultados sugerem o papel da COX-1 e -2 na fisiopatologia da dor relacionada a endometriose assim como a infertilidade e o crescimento dos endometriomas. A atividade da sintase de Ãxido nÃtrico realizada atravÃs da citrulina marcada dada em pmol de citrullina/mgxproteÃna/min à expressa nos endometriomas. A iNOS no 5o dia: 1,94+0,5; 10o dia: 2,46Â0,2 e no dia 15: 1,17Â0,3 assim como com a cNOS que diminui de forma tempo-dependente (5 dia: 2,48Â0,7; 10 dia: 1,8Â0,19; e dia 15: 0,78Â0,3). Essa diminuiÃÃo da atividade da cNOS à provavelmente devida a descamaÃÃo endometrial que ocorre normalmente com a evoluÃÃo da doenÃa assim como devida a fibrose que circunda os endometriomas e o aumento da iNOS pelo processo inflamatÃrio peritoneal encontrado na endometriose. O uso do L-NAME tambÃm fez diminuir os pesos Ãmidos dos endometriomas assim como melhorou a fertilidade e aliviou a dor de forma dose-dependente. A Pentoxifilina (30mg/Kg/day) administrada entre o 5 e o 14 dia da induÃÃo da endometriose foi efetiva na diminuiÃÃo da expressÃo da sintase de Ãxido nÃtrico, ambas constitutiva como induzida. Os resultados desse estudo sugerem o envolvimento do Ãxido nÃtrico no desenvolvimento da endometriose experimental assim como nas suas repercussÃes: dor e infertilidade. Os nÃveis peritoneais de TNF-alfa em ratas intactas foram de 28,95Â1,18ng/ml. Os nÃveis de TNF-alfa aumentaram no lÃquido peritoneal de ratas endometriÃticas de forma tempo dependente. Drogas que modulam o TNF foram efetivas em reduzir o crescimento de endometriomas experimentais: Controle: 0,595Â0,085g%; pentoxifilina (30 mg/Kg): 0,06Â0,008g%; talidomida (5mg/Kg): 0,20Â0,049g% e dexametasona (0,2mg/Kg): 0,145Â0,02g%. Essas drogas tambÃm aliviaram a dor e incrementaram a fertilidade. Esses resultados sugerem o envolvimento do TNF na fisiopatologia da endometriose.
Endometriosis is a disease characterized by the presence of endometrial glands and stroma out of the uterine cavity and of the myometrium. It may cause tumor, pain (chronic pelvic pain, dyspareunia and dysmenorrhea) and infertility. Currently available evidence indicates that endometrial cells misplaced during menses into the peritoneal cavity in women with endometriosis, implant and proliferate in the ectopic locations, an action that is associated with mobilization of the immune cells into the peritoneal cavity and a profound local and systemic immune response. An increase in the amount of peritoneal fluid is a characteristic finding in endometriosis and associated with improved presence of immune cells like macrophages as well as a wide range of soluble substances derived from those macrophages like prostaglandins, interleukins, TNF, growth factors and reactive oxygen species. It is likely the role of medication for this disease will expand in the future. Also the mechanisms of all these substances must be elucidated in the pathogenesis of endometriosis. The purpose of this study is to verify: (i) the drugs effects that selectively inhibits one of the enzymes ciclooxigenase type 1 (COX-1) responsible for the physiologic events of the organism and the induced COX-2, involved in the inflammatory process; (ii) the effects of L-NAME, a competitive antagonist of nitric oxide as well as NO synthase actvity assayed by 3H-labelled citrulline from labelled L-arginine and (iii) the effects of TNF-alfa modulating drugs (Thalidomide and pentoxifilline) on the development of experimental endometriosis and on its related pain and infertility in female rats. Experimental endometriosis was developed in female Wistar rats and the animals were divided into tests groups. The treatment was given from the 5th to the 14th day of endometriosis induction to verify the effects on growth of endometriomas evaluated by its wet weight and histopathology and acutely 30 minutes before the nociceptive stimulus in order to evaluating pain (writhing test) and fertility was assessed through the percentage of pregnant rats. Aspirin (30mg/kg - an inhibitor of intermediate selectivity among COXs); piroxicam (1mg/kg) and indomethacin (2mg/kg), specific selective inhibitors of COX-1 and nabumetone (5 and 15mg/kg) and meloxicam (0.4mg/kg) relative selective inhibitors against COX-2 were used per os. All the accomplished treatments decreased significantly the pain as evaluated by the writhing test. The mean wet weights of the endometriomas (g%) were as shown [Endo control: 0.595 Â 0.085; Aspirin: 0.122 Â 0.019; piroxicam: 0.766 Â 0.35; indomethacin: 2.058 Â 0.96 and for Nabumetone 5mg: 0.252 Â 0.032; Nabumetone 15mg: 0.135 Â 0.03 and meloxicam: 0.387 Â 0.04]. As to fertility, the percentage of pregnant animals were as follows: Endo control, 40%; intact control, 100%; Sham operated, 100%; Indomethacin, Zero%; meloxicam, 60%; Aspirin, 60% and Nabumetone 5 and 15, 50 e 58% respectively. The treatments with Aspirin and Nabumetone had decreased the development of the endometriomas significantly as well as contributed to the relief of the pain and increasing fertility. These results suggest the role of COX-1 and -2 in the pathophysiology of endometriosis related pain, fertility and on its growth. NO synthase actvity assayed by 3H-labelled citrulline from labelled L-arginine. The nitric oxide synthase was expressed as pmol of citrulline/mg protein/min. The endometriomas expressed iNOS at the: 5th day: 1.94 + 0.5; 10th day: 2.46 Â 0.2 and day 15: 1.17 Â 0.3 as well as cNOS that decreased in a time-dependent way (5th day: 2.48 Â 0.7; 10th day: 1.8 Â 0.19; and day 15: 0.78 Â 0.3). This decreasing activity of cNOS was probably found by the endometrial shedding that occurs normally in the course of this disease as well as by the fibrosis that surrounds the endometriomas and the increasing iNOS by the inflammatory peritoneal and tissue reaction that is frequently found in endometriosis. The use of L-NAME also decreased the wet weight of endometriomas as well as ameliorates the pain and fertility in a dose dependent fashion. Pentoxifylline (30mg/Kg/day) administered subcutaneously for 10 consecutive days during the established phase of endometriosis (days 5-14 post induction) was effective in decreasing the expression of nitric oxide synthase, both induced and constitutive. The results of the present study as those previously shown suggest the involvement of nitric oxide in the development of experimental endometriosis. TNF-alfa modulating drugs proved to reduce the mean weights of endometrial implants, obtained at day 15 of endometriosis induction with pentoxifylline (30 mg/Kg), thalidomide (5mg/Kg) and dexamethasone (0.2mg/Kg) treated rats (control: 0.595 Â 0.085g%; pentoxifylline: 0.06 Â 0.008g%; thalidomide: 0.206 Â 0.049g% and dexamethasone: 0.145 Â 0.02g%). The results of the present study suggest the involvement of TNF-alfa in the pathophysiology of experimental endometriosis. The peritoneal levels of TNF-alfa evaluated in intact rats showed 28.95 Â 1.18ng of TNF-alfa/ml. The levels of TNF-alfa increased in the peritoneal fluid in a time dependent way after the peritoneal implant (endometriotic rat). These drugs also attenuated pain and increased fertility.

Orientador: Cláudia Aparecida Rainho
Banca: Maria Claudia Moura Campos
Banca: Ester Silveira Ramos
Resumo: A endometriose constitui uma doença de etiologia incerta, caracterizada pela presença de tecido endometriótico fora da cavidade uterina. E uma causa comum de morbidade, atingindo 5 a 10% das mulheres em idade reprodutiva. A metilção anormal na região promotora de genes especificos e os niveis de expressão alterados das DNA metiltransferases (DNMTs) compoem 0 conjunto de evidencias recentes indicando a endometriose como uma doença epigenetica. 0 presente estudo propos a investigaçao do perfil diferencial de metilaçao do DNA na endometriose, utilizando uma abordagem genomica de alta resoluçao baseada na metodologia de microarrays. Para isso, foram coletadas amostras pareadas de endometrio eutópico e de endometriose intestinal profunda de 18 pacientes. Foram selecionadas dez amostras pareadas para a hibridação do DNA: cinco casos foram submetidos ao enriquecimento das sequencias não metiladas (digerido com a enzima de restrição dependente de metilação McrBC ) e nove ao enriquecimento das sequencias metiladas (digerido com 0 coquetel de enzimas sensiveis a metilação do DNA Acil, HinP11, HpyCH41Ve Hpall). Os ensaios foram realizados em duplicatas totalizando 28 hibridações independentes na plataforma disponivel comercialmente Human CpG Island ChIP-on-Chip Set 244K (Agilent Technologies). Este protocolo foi previamente padronizada utilizando-se 0 DNA das linhagens derivadas de carcinomas de c610n HCT116 e DKO (celulas HCT116 duplo knockout para as DNMT1 e DNMT3b) usando marcação reversa (dye swap). Os dados foram avaliados nos software Agilent Technologies Genomic Workbench (DNA Analytics 5.0) e GeneSpring 7.3 (Agilent Technologies). Estre os 925 genes que apresentaram metila9ao diferencial, 55 foram recorrentes em dois ou mais casos. Varios destes genes mostram-se interessantes por exercerem funções relacionadas a fatores de transcrição (MSX1, EMX2, HOXB13, HOXD8 e HOXD9)... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Endometriosis is a disease of unknown etiology characterized by the presence of endometrial tissue outside the uterine cavity. It is a common cause of morbidity, affecting 5-10% of women in reproductive ages. The aberrant methylation in the promoter region of specific genes and the higher expression levels of DNA methyltransferases (DNMTs) in comparison with normal endometrium have been reported as evidences indicating that endometriosis is an epigenetic disease. The present study investigated the differential profile of DNA methylation in endometriosis using a high-resolution microarray-based assay. There were collected paired samples of eutopic endometrium and deep intestinal endometriosis from 18 patients and, subsequently, it was selected ten pairs to the DNA hybridization: five matched samples were submitted to the enrichment of unmethylated sequences (digested with the methylation-dependent restriction enzyme McrBG) and ten to the enrichment of methylated sequences (digested with the cocktail of enzymes sensitive to DNA methylation AGII, HinP1/, HpyGH4/V and Hpa/I). The assays were performed in duplicates totalizing 28 independent hybridizations in the commercially available platform Human CpG Island ChIP-on-Chip Set 244K (Agilent Technologies). The protocol was previously standardized using the DNA from the colon carcinomas cell lines HCT116 and DKO (HCT116 cells double-knockout for DNMT1 and DNMT3b) using reverse labeling (dye swap). The data were evaluated using the software Genomic Workbench (DNA Analytics 5.0) and GeneSpring 7.3. Among the 925 genes showing differential methylation, 55 genes were detected in at least two cases. Several of these gene could be considered good candidates to molecular biomarkers of endometriosis since that they act as transcription factors (MSX1, EMX2, HOXB13, HOXDB e HOXD9) , chromatin remodeling (MAD1L 1, WDR5 e BGOR)... (Complete abstract click electronic access below)
Mestre

Introdução: Endometriose é uma doença benigna que afeta mulheres em idade fértil. Tem caráter multifatorial estrogenodependente associado à resposta inflamatória generalizada na cavidade peritoneal e sendo a causa mais comum de dor pélvica crônica. Objetivos: O estudo comparou o efeito da melatonina (10 mg/dia) com placebo na dor e níveis séricos do Brainderived neurotrophic factor (BDNF) de pacientes com endometriose. Métodos: Foi realizado um ensaio clínico randomizado, duplo-cego, em paralelo, controlado com placebo. Foram incluídas mulheres com idade entre 24 e 52 anos com diagnóstico de endometriose por laparoscopia selecionadas a partir da agenda diária de consultas do ambulatório de Ginecologia e por chamamento na mídia local, no período de setembro de 2010 a abril de 2012. Foram utilizados questionários para avaliar a frequência e a intensidade da dor (na relação sexual, na micção e no trabalho), sintomas depressivos, nível de pensamento catastrófico e o Structured Clinical Interview for DSM-IV (SCID) para diagnósticos psiquiátricos.Resultados: Na analise por intenção de tratar a média de dor no período menstrual foi de 4,8 cm ± 0,15 no grupo que recebeu melatonina (n=20) e de 6,9 cm ± 0,13 no grupo placebo (n=20), com diferença média (ajustada para o efeito de cada paciente) de 2,147 cm na escala análogo visual de dor (EAV) (IC 95%; 1,767 a 2,527; p<0,001). Também houve diferença entre as médias de dor ao urinar (diferença média=0,660; IC 95%; 0,348 a 0,971; p<0,001) e dor ao evacuar (diferença média=0,515; IC 95%; 0,180 a 0,849; p=0,003). Pacientes que receberam melatonina tiveram redução nos níveis séricos de BDNF. Conclusões: O uso da melatonina foi associado à redução da dor mesmo fora do período menstrual em pacientes com endometriose. O tratamento também reduziu os níveis de BDNF, sugerindo mudança em sistemas moduladores de dor. Tais achados sugerem que a melatonina é eficaz no tratamento da endometriose.
Background: Endometriosis is a benign condition that affects women in childbearing age. It is a estrogen-dependent disease, multifactorial, associated with a generalized inflammatory response in the peritoneal cavity, being the most common cause of chronic pelvic pain. Objective: This study have compared the effect of melatonin 10 mg / day with placebo in pain and in serum levels of brain-derived neurotrophic factor (BDNF) in patients with endometriosis. Methods: We conducted a randomized, double-blind, parallel, placebocontrolled trial. We included women at aged between 24 and 52 years with the diagnosis of endometriosis by laparoscopy selected from the daily schedule of consultations of the Gynecology outpatient clinic and by calling the local media, for the period September 2010 to April 2012. Questionnaires were used to evaluate the frequency and intensity of pain (during intercourse, urination and work), depressive symptoms, level of catastrophic thinking and the Structured Clinical Interview for DSM-IV (SCID) for psychiatric diagnoses. Results: In the analysis by intention to treat, the mean pain during menstruation was 4.8 ± 0.15 cm in the group receiving Melatonin (n = 20) and 6.9 ± 0.13 cm in the group placebo (n = 20), with mean difference (adjusted for the effect of each patient) of 2.147 cm in VAS (95% CI 1.767 to 2.527, p <0.001). There were also differences between the means of pain when urinating (mean difference = 0.660 95% CI 0.348 to 0.971, p <0.001), and pain when defecating (mean difference = 0.515 95% CI 0.180 to 0.849, p = 0.003). Patients who received melatonin had reduced serum levels of BDNF. Conclusion: The use of melatonin was associated with reduced pain even outside the menstrual period in women with endometriosis. The treatment also reduced levels of BDNF, suggesting change in pain modulatory systems. These findings suggest that melatonin is effective in the treatment of endometriosis.

Resveratrol, um fitoestrógeno natural tem sido visto como um opção potencial de tratamento para mulheres com endometriose, porém nenhum estudo clínico adequado foi realizado. Objetivo: Em comparação com placebo, o resveratrol (40mg/dia) reduz níveis de dor após 42 dias de uso em mulheres com endometriose usando pílula anticoncepcional monofásica (PAM). Delineamento do estudo: Neste estudo clínico randomizado, duplo-cego, controlado com placebo clínico, as mulheres com endometriose foram randomizados para receber PAM por 42 dias, para ser tomado com 42 cápsulas idênticas contendo 40 mg de resveratrol ou placebo em frascos codificados Os escores médios de dor foram medidos utilizando uma escala visual analógica (EVA) nos dias 0, 7, 21 e 42. Resultados: Este estudo decorreu entre Junho e Setembro de 2015 envolvendo 44 pacientes. Um software foi utilizado para a geração da sequência da randomização. Foram utilizados envelopes opacos selados e codificados para o cegamento. O tamanho da amostra foi calculada para ter uma chance de 95% de detectar, como significativa ao nível de 1%, uma redução de 90% em comparação com placebo e resveratrol em uma escala de 0 a 10 dor. Uma redução significativa nos níveis de dor foi encontrada entre o dia 0 e o dia 42, no grupo placebo (P = 0.02- de Equações estimação generalizada - GEE) e no grupo de resveratrol (P = 0,003 -GEE). (95% IC) Os escores médios de dor no dia 0 foram de 5,4 (4,2-6,6) no placebo e 5,7 (4,8-6,6) no grupo de resveratrol. Após 42 dias de tratamento, os valores de dor mediana foram [3,5 (2,2-4,9); n = 22] e [2,9 (1,8 a 4); n = 22] em relação ao placebo e resveratrol, respectivamente (p = 0,8 - GEE); diferença média entre os grupos (95% CI) foi de 0,75 (-1,6 a 2,3). Conclusão: Em mulheres com endometriose fazendo uso de pílula anticoncepcional monofásica, os escores de dor após 42 dias de utilização diária de 40 mg de resveratrol não foram significativamente diferentes do placebo.
Background: Resveratrol, a natural phytoestrogen, has been suggested as a possible treatment option for women with endometriosis, but there are no proper randomized clinical trial. Objective : Compared to placebo, does resveratrol (40 mg/day) reduce pain scores after 42 days of use in women with endometriosis using monophasic contraceptive pill (COC). Study Design: In this randomized double-blinded, placebo controlled clinical trial, women with endometriosis were randomized to receive COC for 42 days, to be taken with 42 identical capsules containing 40 mg of resveratrol or placebo in coded bottles. Median pain scores measured with an analog visual scale (AVS) on day 42 was the primary outcome. Results: This trial took place between June and September 2015 and enrolled 44 subjects. A software generated the randomization sequence. Allocation sequence was concealed in coded sequenced opaque sealed envelopes. Sample size was calculated to have a 95% chance of detecting, as significant at the 1% level, a 90% reduction comparing placebo and resveratrol in a 0 to 10 pain scale. A significant reduction in pain levels was found between day 0 and day 42, in placebo ( P =0.02- Generalized Estimating Equations - GEE) and in the resveratrol group ( P =0.003 -GEE). Mean (95%CI) pain scores at day 0 were 5.4 (4.2 to 6.6) in placebo and 5.7(4.8 to 6.6) in resveratrol groups. After 42 days of treatment, median pain values were [3.5 (2.2 to 4.9); n=22] and [2.9 (1.8 to 4); n=22] in the placebo and in the resveratrol groups, respectively ( P =0.8 - GEE); median difference between groups (95%CI) was 0.75 ( -1.6 to 2.3). Conclusion : In women with endometriosis in use of monophasic contraceptive pill, pain scores after 42 days of daily use of 40 mg of resveratrol are not significantly different from placebo.

Bakgrund: Endometrios är en kronisk gynekologisk sjukdom som drabbar mellan 5-10% av alla kvinnor i fertil ålder. Det finns okunskap inom området hos både vårdgivare och allmänheten. Syfte: Syftet med litteraturstudien var att beskriva kvinnors erfarenheter av att leva med endometrios.                                         Metod: Via databaserna CINAHL, PubMed och EBSCO valdes nio kvalitativa studier ut. Resultaten har kvalitetsgranskats, analyserats och sammanställts. Resultat: Litteraturstudien visade att leva med endometrios innebar negativ påverkan på kvinnors fysiska, psykiska och emotionella hälsa. Tre huvudkategorier ”Att hantera sin vardag”, ”Att möta hälso- och sjukvården” och ”Att oroa sig för framtiden” sammanfattade olika aspekter av kvinnornas upplevelser. Socialt liv och relationer påverkades av sjukdomen till följd av mycket smärta. Tillståndet togs inte heller på allvar vid kontakter med hälso-och sjukvården vilket medförde att de drabbade inte fick den vård eller behandling som behövdes. Konklusion: Att leva med endometrios innebär en stor påfrestning för de drabbade. Kvinnorna är i behov av mer stöd och information från vården och det är viktigt att sjuksköterskan har den kunskap som behövs för att känna igen sjukdomen.
Background: Endometriosis is a chronic gynecological disease that affects 5-10% of all women of reproductive age. There is ignorance in public and in health care concerning this disease. Aim: The aim of this study was to describe women’s experiences of living with endometriosis. Method: Nine qualitative studies were selected through the databases CINAHL, PubMed and EBSCO. The results have been quality reviewed, analyzed and compiled. Results: The literature review showed that living with endometriosis meant negative impact on women's physical, mental and emotional health. Three main categories of "Coping with everyday life ", "Meeting the health service " and " Worry about the future," summarized the various aspects of women's experiences. Social life and relationships were affected by the disease as a result of a lot of pain. The health care didn’t take the illness seriously, which meant that the women did not get the care or treatment needed. Conclusion: Living with endometriosis results in great emotional distress in those affected. These women are in need of more support and information from health care providers. It is important that nurses have the knowledge needed to identify the disease.

Endometriosis is a disease that affects almost 10% of reproductive-age women, where 50 % of these women have pelvic pain with sexual intercourse. Deep endometriosis is defined as an endometriotic lesion penetrating to a depth of 5 mm or more, and is characterized by both fibrosis (forming nodules) and invasion (into structures such as the colon). Other groups have found that increased plasminogen activator inhibitor-1 (PAI-1) or (SERPINE1) expression was associated with fibrosis and tumor invasion. In addition, a previous study found that the SERPINE1 4G allele (and thus increased gene expression) was associated with increased pain in women with endometriosis, and other work suggested that SERPINE1 may be implicated in local neurogenesis. The objective of this thesis is to determine whether PAI-1 expression is associated with a) deep infiltrating endometriosis; and b) deep dyspareunia. We propose that increased PAI-1 expression will be associated with deep infiltrating endometriosis, and increased pain in endometriosis via an increase in local nerve fibers. We utilized immunohistochemical analysis using a validated PAI-1 antibody. In the first cohort, we examined PAI-1 expression in deep infiltrating endometriosis and compared to endometrioma, superficial endometriosis, and eutopic endometrium. In the second cohort, we examined PAI-1 expression in cul-de-sac endometriosis from women with or without deep dyspareunia. We found higher expression of PAI-1 in deep infiltrating endometriosis (n = 10) compared to superficial endometriosis (n = 10) (p = 0.031) and eutopic endometrium (n = 10) (p = 0.002). In the second cohort, we found lower expression of PAI-1 in women with more severe deep dyspareunia (r = - 0.352, n =35, p = 0.038). However, there was no association between PAI-1 expression and local nerve bundle density. In conclusion, we observed higher PAI-1 expression in deep infiltrating endometriosis, but lower PAI-1 expression in endometriosis from women with deep dyspareunia. Further research is needed to clarify the complexities of PAI-1 expression in endometriosis.
Medicine, Faculty of
Graduate

The nude mouse model of endometriosis was used to study the longitudinal integration of human endometrium at an ectopic site. Histological, morphometric and immunohistochemical techniques were used to investigate nude mouse lesion development. Seven days after endometrial implantation, central necrosis and glandular degeneration were invariably seen in nude mouse lesions. By day 14, tissue remodelling had occurred and a novel vasculature was apparent. Affymetrix microarray GeneChips were used to ascertain the peritoneal transcriptome of nude mouse lesions. mRNA sequences not previously associated with endometriotic lesion development were detected, including some linked to osteoblast activity. techniques to verify the murine origin of these transcripts were developed. A selective cyclooxygenase-2 (COX-2) inhibitor and anti-angiogenic agents were tested in the nude mouse model of endometriosis. COX-2 can modulate inflammation, angiogenesis and cellular proliferation, which were observed in developing nude mouse lesions. However, the quantity and volume of lesions remained unaltered in mice treated with a COX-2 inhibitor. In contrast, when agents that inhibited vascular endothelial growth factor were administered to nude mice, the number of lesions was reduced. This thesis provides the first comprehensive description of the cellular and molecular events that occur during endometriosis-like lesion development. Disruption of only one aspect of this process (neovascularisation) revealed the therapeutic potential of anti-angiogenic agents in endometriotic disease. Many other transcripts and cells were identified that may be critical to nude mouse lesion establishment. Future research directed towards functional suppression of these factors may inhibit endometriotic lesions and increase treatment options for women with endometriosis.

This PhD project advances our understanding of the relationship between endometriosis and its common comorbid disorders with a focus on asthma, depression, and migraine. Appropriate sets of well-regarded statistical genetic approaches were utilised in the analysis of world-leading genetic data. Findings confirm a comorbid association between endometriosis and each of asthma, depression, and migraine, largely due to shared genetics and biological mechanisms. Causality assessment suggests a potential causal relationship between endometriosis and depression. Further analyses implicate causal links between each of endometriosis and depression and at least one abnormal condition of gastric mucosa—gastritis and gastroesophageal reflux disease.

PEREIRA, Francisco Edson Ximenes Gomes. Desenvolvimento e validação de um modelo de endometriose subcutânea em ratas para estudo de prováveis mecanismos fisiopatológicos e do efeito de drogas. 2013. 78 f. Dissertação (Mestrado em Cirurgia) - Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, 2013.
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Endometriosis is defined as the presence of endometrial tissue (gland and stroma) outside the uterus. The objective of this study was to design a model of subcutaneous endometriosis in rats for the evaluation of the effect of drugs and the pathophysiology of endometriosis. Initially, female Wistar rats (Rattus norvergicus) were implanted subcutaneously with 4x4 mm uterine fragments to evaluate endometrioma growth after 1, 7, 14 and 21 days. Endometrial tissue implants were confirmed by histological analysis. The greatest relative weight gain was observed on the 14th day (wet weight 29.17 ± 6.79 mg%; dry weight 5.36 ± 0.97 mg%). Subsequently, animals were assigned to treatment groups and given either estradiol (2.5 mg/kg, 5 mg/kg, 10 mg/kg sc), medroxyprogesterone acetate (0.5 mg/kg, 2 mg/kg, 5 mg/kg sc), triptorelin pamoate (0.18 mg/kg, 0.56 mg/kg sc) and acetylsalicylic acid (3 mg/kg gavage) on the fifth day following implantation. Wet and dry relative weight of the endometrioma were used as a indicator of growth for model of endometriosis. In the group treated with estradiol, the average wet weight and dry weight on the 14 th day following implantation was 36.62 ± 4.97 mg% and 3.97 ± 1 mg% (2.5 mg), 56.37 ± 20.19 mg% and 9.11 ± 3.85 mg% (5 mg), and 173.89 ± 69.53 mg% and 27.67 ± 10.27 mg% (10 mg), respectively. In the group treated with medroxyprogesterone acetate, the corresponding figures were 13.58 ± 2.53 mg% and 2.67 ± 0.5 mg% (0.5 mg), 14.29 ± 2.07 mg% and 3.71 ± 1.31 mg% (2 mg), and 15.33 ± 7.08 mg% and 2.68 ± 1.44 mg% (5 mg). In the group treated with triptorelin pamoate, the corresponding figures were 20.04 ± 4.02 mg% and 5.21 ± 1.54 mg% (0.18 mg), and 10.86 ± 1.88 mg% and 1.89 ± 0.29 mg% (0.56 mg). In the group treated with 3 mg acetylsalicylic acid, the corresponding figures were 12.81 ± 2.04 mg% and 2.09 ± 0.4 mg%. In the estradiol group, growth gain was dose-dependent: animals receiving 10 mg differed significantly from animals receiving lower doses and from untreated animals (p<0.0001). In conclusion, the model was found to be reproducible and easy to use.
A endometriose é definida como a presença de tecido endometrial (glândula e estroma) fora do útero (mais precisamente revestimento endometrial). O objetivo foi desenvolver e validar um modelo de endometriose subcutânea em ratas para estudo de prováveis mecanismos fisiopatológicos e do efeito de drogas. Inicialmente, as ratas (Rattus norvergicus, linhagem Wistar) foram implantadas subcutaneamente com fragmentos uterinos 4x4 mm para avaliar o crescimento de endometrioma após 1, 7, 14 e 21dias. Implantes de tecido endometrial foram confirmados por análise histológica. O maior ganho de peso relativo do endometrioma foi observado no dia 14 (peso úmido relativo 29,1 ± 6,79 mg%, peso seco relativo 5,36 ± 0,97 mg%). Posteriormente, os animais foram divididos em grupos e receberam estradiol (2,5 mg/kg, 5 mg/kg, 10 mg/kg sc), acetato de medroxiprogesterona (0,5 mg/kg, 2 mg/kg, 5 mg/kg sc), pamoato de triptorrelina (0,18 mg/kg, 0,56 mg/kg sc) e ácido acetilsalicílico (3 mg/kg gavagem) no quinto dia após a implantação. Peso úmido relativo e seco relativo do endometrioma foram usados como um indicador de crescimento para o modelo de endometriose. No grupo tratado com estradiol, o peso úmido relativo médio e peso seco relativo médio no dia 14 após a implantação foi de 36,62 ± 4,97 mg% e 3,97 ± 1mg % (2,5 mg/kg), 56,37 ± 20,19 mg% e 9,11 ± 3,85 mg% (5 mg/kg), 173,89 ± 69,53 mg% e 27,67 ± 10,27 mg% (10 mg/kg), respectivamente. No grupo tratado com acetato de medroxiprogesterona, os valores correspondentes foram 13,58 ± 2,53 mg% e 2,67 ± 0,5 mg% (0,5 mg/kg), 14,29 ± 2,07 mg% e 3,71 ± 1,31 mg% (2 mg/kg), e 15,33 ± 7,08 mg% e 2,68 ± 1,44 mg% (5 mg/kg). No grupo tratado com pamoato de triptorrelina, os valores correspondentes foram 20,04 ± 4,02 mg% e 5,21 ± 1,54 m% (0,18 mg/kg), e 10,86 ± 1,88 mg% e 1,89 ± 0,29 mg% (0,56 mg/kg). No grupo tratado com ácido acetilsalicílico 3 mg/kg, os valores correspondentes foram 12,81 ± 2,04 mg% e 2,09 ± 0,4 mg%. No grupo de estradiol, o ganho de crescimento foi dependente da dose: os animais que receberam 10 mg/kg diferiram significativamente dos animais que receberam doses mais baixas e a partir de animais não tratados (p < 0,0001). Em conclusão, o modelo mostrou ser reprodutível e fácil de usar.

Bakgrund: Endometrios är en vanligt förekommande gynekologisk sjukdom som ofta förorsakar lidande. Trots det får drabbade kvinnor ofta vänta länge på diagnos, rätt vård och behandling. Sjukdomen har en komplex sjukdomsbild som skiljer sig åt och på olika sätt påverkar kvinnornas liv. Syfte: Syftet var att beskriva kvinnors upplevelse av att leva med endometrios utifrån sjukdomslidande, vårdlidande och livslidande. Metod: Allmän litteraturöversikt där tio vetenskapliga artiklar analyserades med Katie Erikssons teorier om sjukdomslidande, vårdlidande och livslidande som bedömningsgrund. Resultat: Endometrios påverkade kvinnornas liv på flera sätt. Kvinnorna led ofta av intensiv smärta samt andra symtom och tecken vilka ofta bagatelliserades av vårdgivare som många gånger ansåg att kvinnornas symtom var inbillade eller av psykosomatisk karaktär. Vidare påverkade sjukdomen kvinnornas relationer och sociala liv då de inte sällan bemöttes med misstro från sin omgivning Slutsats: Vårdgivare behöver mer kunskap om endometrios och dess sjukdomsbild för att förhindra att kvinnornas symtom blir trivialiserade och negligerade. Bemötandet av kvinnorna behöver förbättras och generera i tidigare diagnostisering och behandling. Ett emotionellt stöd från både omgivning och vårdgivare är en viktig faktor för att bekräfta kvinnorna och deras upplevelser av sjukdomen. Klinisk betydelse: Det är av klinisk betydelse att vårdgivare har förståelse för kvinnors upplevelse av att leva med endometrios för att omvårdnaden ska kunna formas ur ett helhetsperspektiv. En ökad förståelse kan leda till ett bättre bemötande och kan således resultera i att kvinnorna får bättre stöd samt tidigare diagnostisering och behandling.
Background: Endometriosis is a common gynecological disease which in many cases can cause a great deal of suffering. Despite this fact many women have to wait a long time to get a proper diagnosis, the right medical care and treatment. The disease has a complex clinical picture that differs and which in many different ways have an impact on women’s lives. Aim: The aim was to describe women’s experiences living with endometriosis by looking at how women suffer due to the disease, from the points of disease-suffering, care-suffering and life-suffering. Method: General literature review where ten scientific articles were analysed based on the theory on suffering by Katie Eriksson as a criterion of the categories, disease-suffering, caresuffering and life-suffering. Result: Endometriosis impacted women’s lives in many different aspects. Women often suffered from intense pain and other symptoms and signs, which were often dismissed by caregivers. The disease also impacted women’s relationships as well as their social life in the sense that they often were treated with distrust from immediate surroundings. Conclusion: Caregivers need to have a deeper knowledge and understanding of endometriosis and its clinical picture to prevent women’s symptoms from being trivialized and neglected. The caregivers’ attitudes in the encounter with women have to be better and generate an earlier diagnosis and treatment. Emotional support from both caregivers and their immediate surroundings is important to substantiate women and their experiences of the disease. Clinical importance: It is of clinical significance that caregivers have an understanding for women’s experience of living with endometriosis. This in order for the care to be given from a broader perspective looking at the women’s life situation.

Bakgrund: Endometrios är en gynekologisk sjukdom som drabbar ett stort antal kvinnori hela världen. Ofta bemöts dessa kvinnor av kunskapsbrist, misstro och normaliserande attityder som förorsakar försening av diagnos, vård och behandling som skapar onödigt lidande för dessa kvinnor. Sjuksköterskor har en viktig funktion i bemötandet av dessa kvinnor genom att stödja kvinnan, skapa en god allians och ge relevant information. Syfte: Syftet med studien var att beskriva kvinnors upplevelser av livskvalitet vid endometrios samt att granska och beskriva de inkluderade artiklarnas datainsamlingsmetoder. Metod: Litteraturstudien har en deskriptiv design. Data insamlades via databaserna Medline/PubMed samt Cinahl och tolv artiklar återfanns, samtliga med kvalitativ ansats och ligger till grund för resultatet i studien. Resultat: Endometrios medför en kraftigt nedsatt livskvalitet som inverkar på deras parrelation samt sociala liv såsom arbete, skola och fritidsintressen. Kunskapsbrist inom vården leder till normalisering och fördröjd diagnos som skapar onödigt lidande för dessa kvinnor. Många av kvinnorna skapade egna strategier för att hantera sina symtom i  vardagen. Samtliga tolv artiklar med deskriptiv design, har samlat in data genom att intervjua kvinnorna om deras erfarenheter av att leva med endometrios. Slutsats: Endometrios påverkar markant kvinnornas vardag och samtliga relationer på ett negativt sätt. De påverkas både fysiskt, psykiskt och socialt vilket leder till att de får sin livskvalitet kraftigt sänkt. Med ökade kunskaper inom området kan stora ekonomiska besparingar göras om diagnos ställs i ett tidigare skede. Kvinnornas lidande skulle minska och deras livskvalitet öka avsevärt.
Background: Endometriosis is a gynaecological disease that affects a large number of women throughout the world. These women are often treated by the lack of knowledge, distrust and normalizing attitudes. That causes delay in diagnosis care and treatment, which creates unnecessary suffering. Nurses have an important function in the treatment of these women by supporting the woman, create a good alliance and provide relevant information. Aim: The aim of the study was to describe women's experiences of quality of life in endometriosis and to examine and describe the articles included data collection methods. Method: Literature study has a descriptive design. Data were collected through Medline / PubMed and CINAHL and twelve articles were found, all with qualitative approach. These articles were the basis for this study. Results: Endometriosis results in a greatly reduced quality of life that affects their partner, relationship and social life, such as work, school and hobbies. A lack of knowledge in health-care leads to normalization and delayed diagnosis that creates unnecessary suffering for these women. Many of the women created their own strategies to deal with their symptoms in daily life. All twelve articles with descriptive design have collected data by interviewing women about their experiences of living with endometriosis. Conclusion: Endometriosis affects significantly the women's daily lives, and all the relationships, in a negative way. Their health is affected physically, psychologically and socially with the result that they get their quality of life greatly reduced. Significant financial savings can be made by increased knowledge in the field and diagnosis at an earlier stage. Suffering from Endometriosis would be reduced, and the quality of life for those women’s will significantly increase.

Background: Endometriosis is a chronic disease affecting about 176 million fertile women worldwide. Severe menstrual pain and pain during intercourse are the primary symptoms that characterizes the disease. It often takes a long time to get the diagnosis, the nurse should be responsive and identify the patient's needs. Aim: The aim of this literature study was to describe women's experiences of living with endometriosis and the included articles data collection methods. Method: Literature study with descriptive design. Data were collected through the databases PubMed and Cinahl, the result is built on eleven scholarly articles with qualitative and mixed designs. Main Results: The woman who lives with endometriosis experiences severe pain at different time at the menstrual cycle. The diagnosis could take up to several years for some women to receive, where a common occurrence for most of them were mistrust and normalization of the symptoms from the healthcare. Endometriosis has a major impact on women's everyday life where they are both mentally and socially affected by the disease. Most of the women used their own self-strategies as dietary changes to prevent the symptoms. The eleven scholarly articles in this study used different interview methods to collect the data. Conclusion: Endometriosis has a major negative impact on women's everyday life and relationships, the disease causes infertility and social constraints. Increased knowledge in society and in health care can contribute to reduced suffering in these women.

Endometriosis is associated with locally dysregulated immune responses and increased lymphangiogenesis. This study aimed to examine endometrial-like cells and immune cell populations in uterine-draining iliac lymph nodes throughout the menstrual cycle and lymph nodes associated with deep infiltrating endometriotic lesions of the bowel. Paraffin-embedded uterine-draining iliac lymph nodes (endometriosis = 6, control = 9) and deep infiltrating bowel endometriotic lesion-associated nodes (n = 12) were immunohistochemically stained for endometrial-like cells and a range of immune cells. In uterine-draining iliac nodes, DC-Sign+ cell numbers and CD4 antigen expression peaked during menstruation, and CD20 antigen expression significantly decreased between the proliferative and secretory phases. In deep infiltrating bowel endometriosis associated nodes, CD10+ endometrial-like cells were decreased compared to iliac nodes; CD4+ numbers, and CD4 and FoxP3 antigen expression were increased but DC-Lamp+, CD20+ and CD57+ numbers and DC-Lamp, CD79 and CD57 antigen expression were decreased. The presence of endometrial-like cells and dysregulated immune cell environment in pelvic lymph nodes indicate an important role for the lymphatic system in endometriosis. This study provides new evidence for lymphatic and immune system involvement in the development and progression of endometriosis, which may open up new venues for exploring lymphatic-based therapeutic approaches.

Endometriosis is a chronic inflammatory disease that affects 1 in 10 women of childbearing age. It is characterized by the growth of endometrium in extrauterine locations and is associated with chronic pelvic pain, infertility, emotional distress and loss of working ability. Current clinical management provides unsatisfactory outcomes. Thus, the development of more effective therapeutic strategies is still an unmet clinical need, and their development relies on the establishment of animal models that recapitulate the features of endometriosis. The present Thesis has characterized a surgical model of endometriosis that shows nociceptive, affective-like behaviors and impaired cognition, reproducing the symptoms observed in endometriosis patients. In this model of endometriosis, natural cannabinoids alleviate nociceptive behaviors, restore cognitive function and inhibit the development of endometriotic growths. A kappa opioid receptor agonist also shows pain-relieving properties in this model, although affective and cognitive disturbances persist regardless of the pain alleviation. A minimally invasive model of endometriosis that also mimics the symptoms of human endometriosis revealed that minimal endometriosis leads to neuroinflammation in the central nervous system.
La endometriosis es una enfermedad inflamatoria crónica que afecta a 1 de cada 10 mujeres en edad fértil. Se caracteriza por el crecimiento de tejido endometrial fuera del útero y se asocia con dolor pélvico crónico, infertilidad, alteraciones emocionales y disminución de la capacidad de trabajo. Los tratamientos actuales proporcionan resultados insatisfactorios. Por lo tanto, se necesitan estrategias terapéuticas más eficaces y su desarrollo depende de la disponibilidad de modelos animales que recapitulen las características de esta enfermedad. La presente Tesis ha caracterizado un modelo quirúrgico de endometriosis que muestra alteraciones nociceptivas, afectivas y cognitivas, reproduciendo los síntomas de la endometriosis. En este modelo, el tratamiento con fitocannabinoides alivia las manifestaciones nociceptivas, restaura la función cognitiva e inhibe el desarrollo del tejido endometrial ectópico. El tratamiento con un agonista del receptor opioide kappa también reduce las manifestaciones nociceptivas de este modelo, aunque no modifica las alteraciones afectivas y cognitivas. Se ha utilizado un modelo mínimamente invasivo, que también reproduce los síntomas de la endometriosis, para explorar los cambios neuroinflamatorios inducidos por la presencia de células endometriales ectópicas. En este modelo, la endometriosis mínima-leve provoca neuroinflamación en el sistema nervioso central.

Endometriosis is a common chronic gynaecological condition within women of reproductive age. Section A: A literature review was conducted to evaluate the prevalence of depression in women with endometriosis and explain the development of depression using a diathesis-stress framework. A systematic search revealed twenty-one relevant studies. The evidence suggested that depression was more prevalent within women with endometriosis than women in the general population. The effects of chronic pelvic pain, dyspareunia, infertility and the psychosocial implications associated with these stressors were suggested to be involved in the development of depression in women with endometriosis, mediated by cognitive diatheses such as illness representations, perceived control, perceived self efficacy and coping style. In conclusion, the literature supported the application of the diathesis-stress model to explain the development of depression in women with endometriosis. Section B: The research study investigated whether endometriosis affected womanhood through the qualitative exploration of identity as a woman, wellbeing, sexuality, fertility and relationships. Seven women with a laparoscopic diagnosis of endometriosis were interviewed. Four master themes were elicited from the data using Interpretative Phenomenology Analysis that represented women’s experiences of endometriosis and its effect on womanhood, motherhood and emotional wellbeing. Womanhood remained relatively intact, although at times it affected identity as a woman, sexuality and self-esteem. The endometriosis journey was fluctuating and unpredictable, yet, women with endometriosis were able to regain control and normality, adjusting to the condition. The need for the availability of professional emotional support for women with endometriosis was highlighted. Section C: The critique of research outlined my experiences and reflections of conducting research. It described the origin and development of the study, as well as the challenges met and learning points gained along the way. Furthermore, it detailed a critique of myself as a researcher and reflected on the personal impact of research on the self.

Endometriosis is a puzzling condition responsible for considerable morbidity. The literature is characterised by a large number of reports but there is surprisingly little agreement on the aetiology and pathophysiology. In particular the relationship between mild endometriosis and subfecundity is uncertain. The aim of the studies described in this thesis was to document the incidence, and symptomatology of endometriosis in the fertile and infertile population, to study the natural history of endometriosis in infertile women and to study folliculogenesis, fertilisation and pathophysiology of periovulatory events in spontaneous menstrual cycles. The relevant literature has been extensively reviewed in the first chapter. By using diagnostic laparoscopy, a large group of fertile and infertile women in the premenopausal age group were studied to document the incidence of endometriosis. Endometriosis was more common in the infertile women. Prolonged usage of combined oral contraceptive pill might have a protective effect against the development of endometriosis. A questionnaire based study of menstrual symptomatology concluded that deep dyspareunia was equally frequent among women harbouring pelvic pathology whether endometriotic or post infective in origin, but congestive dysmenorrhoea was more prevalent among women having mild endometriosis. The study of the natural history of endometriosis suggested that among susceptible women the disease will progress despite treatment with danazol or with diathermy ablation but disease progression was much worse if patients were left untreated. A group of 21 women with primary infertility of more than 3 years duration were extensively studied over two consecutive cycles to study folliculogenesis. The majority of these patients had normal follicular development, and had sonographic evidence of ovulation followed by a normal luteal phase. Furthermore no abnormalities of oocyte maturity and fertilisation were noted in the spontaneous cycles studied. Similarly the endocrine milieu provided by follicular and peritoneal fluids was comparable to a control group. The subfecundity in patients with endometriosis remain essentially unexplained.

Introducción La distancia anogenital (DAG) es un marcador de desarrollo genital que presenta dimorfismo sexual en mamíferos placentarios. Estudios en modelos animales han demostrado que la DAG se determina en útero y persiste durante la vida, La exposición prenatal a elevados niveles de andrógenos, da como resultado una DAG más larga (Mendiola 2011). La DAG predice alteraciones de la función reproductiva así, una DAG más corta en varones se asocia con una peor calidad seminal mientras que en mujeres se hay una asociación positiva entre la DAG y el número de folículos ováricos y mayores concentraciones de testosterona sérica (Mira Escolano 2014). Los estrógenos se han propuesto como uno de los factores más importantes en la patogenia de la endometriosis (Ferrerro et al 2014). La terapia antiestrogenica mejora los síntomas por su efecto directo sobre las lesiones endometriósicas y el indirecto sobre el sistema inmune. La endometriosis es una enfermedad estrógeno-dependiente de probable etiología intrauterina, ( Shah 2013 ). Upson (2015) muestra que los fetos prematuros, presentan mayor riesgo de padecer endometriosis por falta del estrógeno placentario producido en las gestaciones a término, imposibilitando el freno del eje hipotalamohipofisario. La endometriosis es una de las causas de esterilidad. La hormona antimülleriana (AMH) parece ser el marcador biológico actualmente más aceptado como predictor de reserva ovárica. Hipótesis Las mujeres con endometriosis presentan DAG acortada Las mujeres con endometriosis profunda presentan DAG más acortada. Las mujeres con endometriosis y con la DAG acortada tinen una AMH menor Material y Métodos Estudio de casos y controles con casos de endometriosis de la consulta de Ginecología del Hospital Clínico Universitario Virgen de la Arrixaca. Se analizó la hormona antimüleriana. Se obtuvieron mediciones de dos variantes de distancia anogenital : DAGAC: desde superficie anterior al clítoris hasta el borde superior del ano y DAGAH: desde inicio horquilla vulvar posterior al borde superior del ano. Resultados La DAGAH en los casos con endometriosis fue significativamente más corta (P-valor < 0,001) que en los controles. El valor medio de la Hormona Antimülleriana(AMH) fue 1,8 (DE: 2,2) menor en el grupo de los casos de endometriosis, frente a un 3,3 (DE: 2,0) en el grupo control, siendo estas diferencias estadísticamente significativas entre ambos grupos (P-valor < 0’001). Se calculó la Odds Ratio con las medidas de la DAG divididas alrededor de la mediana comparando el subgrupo de endometriosis profunda con los controles. También se encontró una diferencia estadísticamente significativa con una OR de 12,9 (IC 95%: 4,1-40,9) (p<0001) en la categoría de DAGAH más corta, incrementándose los valores de la OR a 95,7 (IC95%= 5.5-1,668) en los análisis ajustados por edad y partos. Finalmente se calculó la OR para casos de endometriosis no operadas y controles en relación con los niveles sericos de AMH observándose tras ajustar por edad y partos que son mucho menores en mujeres con endometriosis no operada que en el grupo control. Discusión Siendo la endometriosis una enfermedad estrógeno-dependiente de probable etiología intrauterina y la DAG una marcador del ambiente estrogénico intrauterino que se mantiene en la edad adulta y relacionado con la fertilidad del individuo, nos parece que puede tratarse de un nuevo biomarcador clínico accesible , fácilmente reproductible y barato. La DAG podría predecir casos de endometriosis, antes de su manifestación clínica. Podría ser especialmente útil en la endometriosis profunda para intensificar los controles e intentar tratarlas para evitar la progresión de la enfermedad. La DAG también supone un marcador de la reserva ovárica disminuida, lo que serviría para orientar a las pacientes sobre las posibles dificultades en su fertilidad.
Introduction The anogenital distance (DAG) is a marker of dimorphic genital development in placental mammals. Studies in animal models have shown that DAG is determined in utero and persists throughout life. Prenatal exposure to high levels of androgens, results in a longer DAG (Mendiola 2011). The DAG predicts changes in reproductive function, for example a shorter DAG in men is associated with poorer semen quality while in women there is a positive association between the DAG and the number of ovarian follicles and higher concentrations of serum testosterone levels (Mira Escolano 2014). Estrogens have been proposed as one of the most important factors in the pathogenesis of endometriosis (Ferrerro et al 2014). The antiestrogen therapy improves symptoms because of its direct effect on endometriotic lesions and indirectly due to the action on the immune system. Endometriosis is an estrogen-dependent disease, which may likely have an intrauterine etiology (Shah 2013). Upson (2015) shows that premature fetuses have a higher risk of endometriosis due to lack of estrogen, produced in the placental gestation to term, making it impossible to brake hypothalamo-hypophyseal-axis. Endometriosis is a cause of infertility. Anti-Mullerian hormone (AMH) appears to be the current biological marker accepted as a predictor of ovarian reserve. Hypothesis Women with endometriosis have shortened DAG Women with endometriosis have more profound shortened DAG. Women with endometriosis and the DAG shortened have lower AMH Material and methods Case-control study with cases of endometriosis of the department of Gynecology of the University Hospital Virgen de la Arrixaca. The AMH was analyzed. For each subject, AGD was measured in two ways. First DAGAC: was measured from the anterior clitoral surface to the upperof the anus and Second, AGDAH was measured from the posterior fourchette to the upperof the anus. Results The DAGAH in patients with endometriosis was significantly shorter (P-value <0.001) than in controls. The average value of AMH was 1.8 (SD 2.2) lower in the cases of endometriosis, to 3.3 (SD 2.0) in the control group, being these differences statistically significant between groups (P-value <0.001). Odds ratios were calculated using measurements of the DAG divided around the median and comparing the subgroup of deep endometriosis with controls. A statistically significant difference with an OR of 12.9 (95% CI 4.1 to 40.9) was also found (p <0001) in the category of shorter DAGAH, increasing the values of the OR to 95.7 (95% CI = 5.5-1,668) in analyzes adjusted for age and childbirth of the patients. Finally, the relation of serum AMH levels observed in controls and in cases of endometriosis that were not operated was analyzed and the OR was calculated after adjusting for age and births, and they were much lower in women with endometriosis which were not operated than in the control group. Discussion Endometriosis being an easily reproducible estrogen-dependent disease with a a probable intrauterine etiology and DAG one marker of estrogenic intrauterine environment which is maintained in adulthood and is related to fertility, we think it may be a new accessible and cheap clinical biomarker. The DAG could predict cases of endometriosis before clinical manifestation. It could be especially useful in deep endometriosis to increase control and to try to prevent disease progression. The DAG is also a marker of diminished ovarian reserve, which would be useful to guide patients on the possible difficulties in their fertility.

Endometriosis is a chronic gynecological disorder, defined by the presence of endometrial tissue outside the uterine cavity, which undergoes the same cyclic changes of eutopic endometrium. The prevalence of the disease can reach about 10% of reproductive-age women, who present with chronic pelvic pain and/or infertility, leading to negative physical and psychological impact in patient’s lives. The pathogenesis involves several hormonal, inflammatory, immune, genetic, and epigenetic mechanisms, which may play a role in the establishment and progression of endometriotic lesions and their clinical manifestations. In the last years, a possible link between high levels of chronic stress and endometriosis has been hypothesized. Clinical evidence shows that patients with endometriosis report higher levels of perceived stress, anxiety, and depression than healthy women. Stress levels are positively correlated to the severity of the disease and pain intensity. Women with endometriosis, in fact, report impaired quality of life and they are more likely to be affected also by systemic and gynecological comorbidities, contributing to stress in a vicious circle. A high prevalence of immune, inflammatory, allergic and mental health diseases has been found and a strict link with adenomyosis has been shown. Moreover, experimental studies have shown that previous exposure to repeated and excessive stress accelerates the development and increases the severity of endometriosis in animal models and early life stressor contribute to the development of the disease in adult life. However, it is still debatable whether endometriosis is a cause and/or a consequence of stress and which mechanisms explain this relationship. An adequate management of endometriosis contribute to improve quality of life, reducing stress levels. It has been shown that among women surgically treated, those with worse quality of life had first surgery at a younger age, more symptoms recurrence and more reoperations. Thus, first endometriosis surgery at a later age is an independent predictor of better health condition. Furthermore, patients experiencing repetitive surgery for endometriosis recurrences have lower physical and mental scores than patients receiving a single surgical treatment. Women undergoing hormonal treatment both before and after surgery have a lower rate of recurrence and an improvement of clinical presentation, in terms of pain symptoms. Thus, hormonal treatments represent a valid cornerstone of endometriosis management and may be useful as a first-line therapeutic approach, in order to postpone surgery, and after surgery itself to reduce the risk of recurrence. The gold standard for modern endometriosis management is the individualized approach, aiming to reduce perceived stress, stress-related comorbidities and to improve quality of life.

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
O objetivo do presente estudo foi estimar os efeitos da injeção local da solução de ácido acetilsalicílico a 20% em implantes de endométrio autólogo intraperitoneal. Foram utilizadas 30 coelhas adultas dividas em 3 grupos de 10 coelhas, com indução da endometriose peritoneal. Após 20 dias da indução da endometriose as coelhas foram randomizadas e de acordo com os grupos receberam os determinados tratamentos: solução fisiológica 0,9% por 20 dias (grupo 1, controle), solução bicarbonatada de ácido acetilsalicílico 20% durante 10 dias (grupo 2, tratamento) e solução bicarbonatada de ácido acetilsalicílico 20% durante 20 dias (grupo 3, tratamento). Os focos de endometriose foram removidos e preparados em lâminas para análise histológica. Foi utilizado um programa de computador para análise das lâminas e aferição da área total de endometriose remanescente. A área do grupo 2 (tratamento 10 dias) foi significativamente menor que a área de endometriose no grupo 1 (controle) e no grupo 3 (tratamento 20 dias), a área não foi aferida por não ter restado endometriose remanescente em nenhuma das 10 lâminas. O tratamento com ácido acetilsalicílico em um período de 20 dias destrói toda a área de endometrios...
The objective of the present study was to estimate the effects of local injection of acetylsalicylic acid solution into intraperitoneal implants of autologous endometrium. The 30 adult female rabbits utilized were divided into 3 groups of 10 each, in which peritoneal endometriosis was induced. Twenty days after endometriosis induction the rabbits were randomized and according to group received the following treatments: physiological solution 0.9% for 20 days (Group 1, control), bicarbonate solution of acetylsalicylic acid 20% for 10 days (Group 2, treatment) and bicarbonate solution of acetylsalicylic acid 20% for 20 days (Group 3, treatment). The endometriosis foci were removed and prepared on slides for histological analysis. A computer program was utilized to analyze the slides and measure the total area of remaining endometriosis. Group 2 (10- day treatment) presented a significantly smaller endometriosis area than Group 1 (control) and Group 3 (20-day treatment); the area was not measured on account of lack of endometriosis residue in any of the 10 slides. The 20-day treatment with acetylsalicylic acid destroys the entire endometriosis area... (Complete abstract, click electronic access below)

Orientadores: Carlos Alberto Petta, Denise Engelbrecht Zantut-Wittmann
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: O objetivo deste estudo de corte transversal foi comparar a prevalência de doença tiroideana auto-imune e disfunção tiroideana entre mulheres portadoras de endometriose e um grupo de controle. Foram avaliadas 148 mulheres, com diagnóstico cirúrgico de endometriose, acompanhadas no Ambulatório de Endometriose do Centro de Atenção Integral à Saúde da Mulher da Universidade Estadual de Campinas, no período de dezembro de 2005 a abril de 2006, e comparadas a 158 mulheres atendidas no Ambulatório de Planejamento Familar da mesma intituição e no mesmo período. As pacientes foram entrevistadas durante uma de suas consultas nos respectivos Ambulatórios. Foram avaliadas: i) a função tiroideana através das dosagens dos hormônios Tiroestimulante e Tiroxina livre, e ii) a presença de doença tiroideana auto-imune através dos anticorpos anti-tiroglobulina e anti-tiroperoxidase. A associação entre as variáveis independentes, o grupo de estudo e as doenças tiroidianas foi avaliada através dos testes qui-quadrado e exato de Fisher, teste de Mann-Whitney e cálculo de odds ratio com seu respectivo intervalo de confiança 95%. A prevalência de hipotiroidismo foi de 12,2% (18 mulheres) no grupo com endometriose e 7,8% (12 mulheres) no grupo de controle (OR 1,49; IC 95%, 0,69 ¿ 3,2). A prevalência de hipotiroidismo auto-imune foi de 6,0% (9/148) e 5,0% (8/158), nos dois grupos, respectivamente (p <0,005). Identificamos 4,0% (6 mulheres) de hipotiroidismo instalado entre as mulheres com endometriose e 3,2% (5 casos) nas mulheres do grupo de controle. A prevalência de doença tiroidiana auto-imune foi de 8,8% (13/148 mulheres) entre as mulheres com endometriose e 15,8% (25/158) entre as mulheres no grupo de controle (OR 0,52; IC 95%, 0,25 ¿ 1,06). Em conclusão, os resultados obtidos neste estudo não sustentam a hipótese de que mullheres com endometriose apresentam maior prevalência de disfunção tiroidiana ou doença tiroidiana autoimune. Assim, entendemos não haver necessidade de rastreamento diferenciado para hipotiroidismo ou para disfunção tiroidiana nas mulheres com endometriose
Abstract: The objective of this cross sectional study was to compare the prevalence of autoimmune thyroid disease and thyroid dysfunction between women with endometriosis and a control group. One hundred forty eight women with surgically confirmed endometriosis attended at the endometriosis outpatient clinic at the Department of Obstetrics and Gynaecology, School of Medicine, Universidade Estadual de Campinas (Unicamp) were evaluated from December 2005 to April 2006 and compared to 158 women from the family planning outpatient clinic at the same institution, during the same time period. All patients were interviewed in one of their regular visit. Thyroid function and autoimmunity were evaluated by measuring serum level of thyroid stimulating hormone, free thyroxin and the antibodies antithyroperoxidase and antithyroglobulin. The association of independent variables and the study group with thyroid disorder and with thyroid dysfunction was assessed by X2 test and Fisher test. Prevalence of thyroid disorders and thyroid dysfuncion among women with endometriosis were calculated and compared with the control group using Mann-Whitney test and the odds ratio was calculated with the 95% confidence interval. The prevalence of hypothyroidism was 12.2 % (18 women) among women with endometriosis and 7.8% (12 women) in the control group (OR 1.49; CI 95%, 0.69 ¿ 3.23). The prevalence of autoimmune hypothyroidism was 6% (9/148) and 5% (8/158) in both groups, respectively. We identified 4% (6 women) with overt hypothyroidism in the group of women with endometriosis and 3.2% (5 cases) among women from the control group. The prevalence of autoimmune thyroid disease was 8.8 % (13 women) among women with endometriosis and 15.8% (25 women) in the control group (OR 0.52; CI 95%, 0.25 ¿ 1.06). Our data do not support the hypotesis that women with endometriosis present a higher prevalence of autoimmune thyroid disease or thyroid dysfuction. Therefore, we believe there is no need for a specific screening of thyroid diseases among women with endometriosis
Doutorado
Tocoginecologia
Doutor em Tocoginecologia

Orientador: Rogério Saad-Hossne
Banca: José Luis Chiaradia Gabriel
Banca: Juan Llanos
Resumo: O objetivo do presente estudo foi estimar os efeitos da injeção local da solução de ácido acetilsalicílico a 20% em implantes de endométrio autólogo intraperitoneal. Foram utilizadas 30 coelhas adultas dividas em 3 grupos de 10 coelhas, com indução da endometriose peritoneal. Após 20 dias da indução da endometriose as coelhas foram randomizadas e de acordo com os grupos receberam os determinados tratamentos: solução fisiológica 0,9% por 20 dias (grupo 1, controle), solução bicarbonatada de ácido acetilsalicílico 20% durante 10 dias (grupo 2, tratamento) e solução bicarbonatada de ácido acetilsalicílico 20% durante 20 dias (grupo 3, tratamento). Os focos de endometriose foram removidos e preparados em lâminas para análise histológica. Foi utilizado um programa de computador para análise das lâminas e aferição da área total de endometriose remanescente. A área do grupo 2 (tratamento 10 dias) foi significativamente menor que a área de endometriose no grupo 1 (controle) e no grupo 3 (tratamento 20 dias), a área não foi aferida por não ter restado endometriose remanescente em nenhuma das 10 lâminas. O tratamento com ácido acetilsalicílico em um período de 20 dias destrói toda a área de endometrios... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: The objective of the present study was to estimate the effects of local injection of acetylsalicylic acid solution into intraperitoneal implants of autologous endometrium. The 30 adult female rabbits utilized were divided into 3 groups of 10 each, in which peritoneal endometriosis was induced. Twenty days after endometriosis induction the rabbits were randomized and according to group received the following treatments: physiological solution 0.9% for 20 days (Group 1, control), bicarbonate solution of acetylsalicylic acid 20% for 10 days (Group 2, treatment) and bicarbonate solution of acetylsalicylic acid 20% for 20 days (Group 3, treatment). The endometriosis foci were removed and prepared on slides for histological analysis. A computer program was utilized to analyze the slides and measure the total area of remaining endometriosis. Group 2 (10- day treatment) presented a significantly smaller endometriosis area than Group 1 (control) and Group 3 (20-day treatment); the area was not measured on account of lack of endometriosis residue in any of the 10 slides. The 20-day treatment with acetylsalicylic acid destroys the entire endometriosis area... (Complete abstract, click electronic access below)
Mestre

p. 1-78
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A expressão de aromatase no endométrio eutópico é desencadeada pela constante exposição a mediadores inflamatórios, que são produzidos durante o período menstrual e proliferativo do ciclo menstrual. A presença de aromatase nas células endometriais é um dos fatores desencadeantes de endometriose na cavidade peritonial, miomas submucosos e intra-murais, pólipos endometriais e adenomiose. Diante disso, esta tese tem como objetivo investigar os efeitos da expressão de aromatase no endométrio, compreendendo a ação desta e como se evitar o desenvolvimento das patologias endometriais. Para isso, foram analisados resultados de biopsias de pacientes submetidas à histerectomia e laparoscopia, no período de janeiro de 2007 a março de 2009 de dois centros de tratamento da cidade de Salvador- Bahia, as quais apresentavam algumas das patologias citadas, seguindo os critérios da American Sciety of Reproductive Medicine. Por fim concluiu-se que a diminuição da expressão de aromatase induzida por progestínicos foi acompanhada por uma redução na expressão de enzimas como ciclooxigenase-2 (Cox-2) ou de fatores angiogênicos como VEGF no endométrio. A inflamação no endométrio também foi reduzida pela progesterona ou por progestínicos e este mecanismo envolveu a inibição da ativação do NF-kappa B. Estes achados sustentam a hipótese do papel que teriam os progestínicos como agentes anti-aromatase e anti-inflamatórios no manejo atual da endometriose e de outras patologias ginecológicas. E que o uso contínuo de contraceptivos orais combinados contendo gestodeno ou o uso de sistemas intra-uterinos liberadores de levonorgetsrel são efetivos na prevenção tanto da recorrência de endometriose, quanto da menorragia associada a miomas.
Salvador

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Universidade Federal Fluminense. Hospital Universitário Antonio Pedro. Centro de Ciências Médicas
A endometriose é definida pela presença de tecido endometrial (glândula e/ou estroma) fora da cavidade uterina, a patologia afeta 10-15% das mulheres em idade reprodutiva, além disso, os sintomas álgicos da doença implicam em impactos econômicos e sociais. A doença apresenta diagnóstico tardio e sua etiologia ainda não foi completamente elucidada, porém, sabe-se que a endometriose possui caráter poligênico e multifatorial. O objetivo do estudo foi avaliar se os polimorfismos no gene HSD17β1 (rs605059), envolvido na síntese de estrogênio, e nos genes MMP2 (rs243865) e MMP9 (rs17576), que atuam no remodelamento da matriz extracelular, estão associados com a endometriose quanto ao risco e o grau de severidade da doença. O estudo do tipo caso-controle foi composto por 231 mulheres, sendo 97 casos e 134 controles. Todas as pacientes do grupo caso possuíam diagnóstico histopatológico para a endometriose. O DNA genômico foi extraído a partir de saliva, e o polimorfismo no gene HSD17β1 foi detectado pela técnica de PCR- Nested seguido de digestão do produto de PCR pela enzima BstUI, os genes MMP2 e MMP9 foram genotipados pela técnica de PCR em Tempo Real. Não foi encontrada diferença estatisticamente significante entre as distribuições genotípicas e alélicas dos genes analisados entre os grupos estudados (p>0,05). Do mesmo modo não foi observada diferença significativa na frequência dos genótipos e alelos entre os diferentes estágios da doença (p>0,05). Os resultados do presente estudo sugerem que os polimorfismos nos genes HSD17β1 (rs605059), MMP2 (rs243865) e MMP9 (rs17576), não estão associado com a endometriose em pacientes brasileiras, mesmo quando avaliado as relações entre graus de severidade variados
Endometriosis is defined by the presence of endometrial tissue (glands and / or stroma) outside the uterine cavity, this condition affects 10-15% of women of reproductive age, in addition, the pain symptoms of the disease involves economic and social impacts. The disease presents late diagnosis and its etiology has not been fully elucidated, but it is known that endometriosis has multifactorial and polygenic character. The aim of the study was to assess whether the polymorphisms in the HSD17β1 (rs605059), involved in estrogen synthesis, and MMP2 genes (rs243865) and MMP9 (rs17576), which act in extracellular matrix remodeling are associated with endometriosis as the risk and severity of the disease. The case-control study consisted of 231 women, with 97 cases and 134 controls. All patients in the case group had histopathological diagnosis for endometriosis. Genomic DNA was extracted from saliva, and HSD17β1 gene polymorphism was detected by Nested-PCR followed by digestion of the PCR product by the enzyme BstUI, MMP2 and MMP9 genes were genotyped by Real Time-PCR. There was no statistically significant difference between the genotypic and allelic distributions of genes analyzed between groups (p> .05). Similarly there was no significant difference in the frequency of genotypes and alleles between different stages of the disease (p> .05). The results of this study suggest that polymorphisms in genes HSD17β1 (rs605059), MMP2 (rs243865) and MMP9 (rs17576), are not associated with endometriosis in Brazilian patients, even when the relations between different degrees of severity were evaluated