Submucous myomas: A new presurgical classification to evaluate the viability of hysteroscopic surgical treatment - Preliminary report

STUDY OBJECTIVE: To develop a new preoperative classification of submucous myomas for evaluating the viability and the degree of difficulty of hysteroscopic myomectomy.DESIGN: Retrospective study (Canadian Task Force classification II-3)SETTING: University teaching hospitals.PATIENTS: Fifty-five patients who underwent hysteroscopic resection of submucous myomas.INTERVENTION: the possibility of total resection of the myoma, the operating time, the fluid deficit, and the frequency of any complications were considered. The myomas were classified according to the Classification of the European Society for Gynaecological Endoscopy (ESGE) and by our group's new classification (NC), which considers not only the degree of penetration of the myoma into the myometrium, but also adds in such parameters as the distance of the base of the myoma from the uterine wall, the size of the nodule (cm), and the topography of the uterine cavity. The Fisher's exact test, the Student's t test, and the analysis of variance test were used in the statistical analysis. A p value less than .05 in the two-tailed test was considered significant.MEASUREMENTS AND MAIN RESULTS: In 57 myomas, hysteroscopic surgery was considered complete. There was no significant difference among the three ESGE levels (0, 1, and 2). Using the NC, the difference between the numbers of complete surgeries was significant (p < .001) for the two levels (groups I and H). The difference between the operating times was significant for the two classifications. With respect to the fluid deficit, only the NC showed significant differences between the levels (p = .02).CONCLUSIONS: We believe that the NC gives more clues as to the difficulties of a hysteroscopic myomectomy than the standard ESGE classification. It should be stressed that the number of hysteroscopic myomectomies used in this analysis was low, and it would be interesting to evaluate the performance of the classification in a larger number of patients. (c) 2005 AAGL. All rights reserved.

Miomas submucosos: classificação pré-operatória para avaliação da viabilidade da cirurgia histeroscópica

OBJETIVO: desenvolver uma nova classificação pré-operatória dos miomas submucosos para avaliação da viabilidade e do grau de dificuldade da miomectomia histeroscópica. MÉTODOS: conduzimos um estudo onde quarenta e quatro pacientes foram submetidas a ressecção histeroscópica de 51 miomas submucosos. Foram considerados a possibilidade da ressecção total do mioma, o tempo cirúrgico, o balanço hídrico e a incidência de complicações. Os miomas foram classificados pela classificação da sociedade Européia de Cirurgia Endoscópica (CSECE) e pela Classificação Proposta (CP) pelo nosso grupo, que, além do grau de penetração do mioma no miométrio, adiciona como parâmetros a extensão da base do mioma em relação à parede do útero, o tamanho do nódulo em centímetros e a topografia na cavidade uterina. Para análise estatística foram usados o teste de Fisher, o teste t de Student e a análise de variância. Foi considerado estatisticamente significativo quando o valor de p-valor foi menor que 0,05 no teste bicaudal. RESULTADOS: em 47 miomas a cirurgia histeroscópica foi considerada completa. Não houve diferença significativa entre os três níveis (0, 1 e 2) da CSECE. Pela CP, a diferença quanto ao número de cirurgias completas foi significativa (p=0,001) entre os dois níveis (grupos I e II). A diferença da duração da cirurgia quando se compara as duas classificações foi significativa. em relação ao balanço hídrico, apenas a CP mostrou diferenças entre os níveis (p=0,02). CONCLUSÕES: a CP inclui mais dados sinalizadores das dificuldades da miomectomia histeroscópica do que a CSECE, atualmente em uso. Deve ser enfatizado que o número de miomectomias histeroscópicas usado para essa análise foi modesto, sendo interessante a avaliação do desempenho dessa classificação em séries maiores de casos.

Role of TGF-beta beta and BMP7 in the pathogenesis of oral submucous fibrosis

To understand the molecular pathogenesis of oral submucous fibrosis (OSF), which is a chronic inflammatory disease, gene expression profiling was performed in 10 OSF tissues against 8 pooled normal tissues using oligonucleotide arrays. Microarray results revealed differential expression of 5288 genes (P < a parts per thousand currency sign 0.05 and fold change >= a parts per thousand yen 1.5). Among these, 2884 are upregulated and 2404 are downregulated. Validation employing quantitative real-time PCR and immunohistochemistry confirmed upregulation of transforming growth factor-beta beta 1 (TGF-beta beta 1), TGFBIp, THBS1, SPP1, and TIG1 and downregulation of bone morphogenic protein 7 (BMP7) in OSF tissues. Furthermore, activation of TGF-beta beta pathway was evident in OSF as demonstrated by pSMAD2 strong immunoreactivity. Treatment of keratinocytes and oral fibroblasts by TGF-beta beta confirmed the regulation of few genes identified in microarray including upregulation of connective tissue growth factor, TGM2, THBS1, and downregulation of BMP7, which is a known negative modulator of fibrosis. Taken together, these data suggest activation of TGF-beta beta signaling and suppression of BMP7 expression in the manifestation of OSF.

Activation of TGF-beta Pathway by Areca Nut Constituents: A Possible Cause of Oral Submucous Fibrosis

Oral submucous fibrosis (OSF) is a chronic inflammatory disease characterized by the accumulation of excess collagen, and areca nut chewing has been proposed as an important etiological factor for disease manifestation. Activation of transforming growth factor-beta signaling has been postulated as the main causative event for increased collagen production in OSF. Oral epithelium plays important roles in OSF, and arecoline has been shown to induce TGF-beta in epithelial cells. In an attempt to understand the role of areca nut constituents in the manifestation of OSF, we studied the global gene expression profile in epithelial cells (HaCaT) following treatment with areca nut water extract or TGF-beta. Interestingly, 64% of the differentially regulated genes by areca nut water extract matches with the TGF-beta induced gene expression profile. Out of these, expression of 57% of genes was compromised in the presence of ALK5 (T beta RI) inhibitor and 7% were independently induced by areca nut, highlighting the importance of TGF-beta in areca nut actions. Areca nut water extract treatment induced p-SMAD2 and TGF-beta downstream targets in HaCaT cells but not in human gingival fibroblast cells (hGF), suggesting epithelial cells could be the source of TGF-beta in promoting OSF. Water extract of areca nut consists of polyphenols and alkaloids. Both polyphenol and alkaloid fractions of areca nut were able to induce TGF-beta signaling and its downstream targets. Also, SMAD-2 was phosphorylated following treatment of HaCaT cells by Catechin, Tannin and alkaloids namely Arecoline, Arecaidine and Guvacine. Moreover, both polyphenols and alkaloids induced TGF-beta 2 and THBS1 (activator of latent TGF-beta) in HaCaT cells suggesting areca nut mediated activation of p-SMAD2 involves up-regulation and activation of TGF-beta. These data suggest a major causative role for TGF-beta that is induced by areca nut in OSF progression.

Role of Areca Nut Induced TGF-beta and Epithelial-Mesenchymal Interaction in the Pathogenesis of Oral Submucous Fibrosis

Areca nut consumption has been implicated in the progression of Oral Submucous fibrosis (OSF); an inflammatory precancerous fibrotic condition. Our previous studies have demonstrated the activation of TGF-beta signaling in epithelial cells by areca nut components and also propose a role for epithelial expressed TGF-beta in the pathogenesis of OSF. Although the importance of epithelial cells in the manifestation of OSF has been proposed, the actual effectors are fibroblast cells. However, the role of areca nut and TGF-beta in the context of fibroblast response has not been elucidated. Therefore, to understand their role in the context of fibroblast response in OSF pathogenesis, human gingival fibroblasts (hGF) were treated with areca nut and/or TGF-beta followed by transcriptome profiling. The gene expression profile obtained was compared with the previously published transcriptome profiles of OSF tissues and areca nut treated epithelial cells. The analysis revealed regulation of 4666 and 1214 genes by areca nut and TGF-beta treatment respectively. The expression of 413 genes in hGF cells was potentiated by areca nut and TGF-beta together. Further, the differentially expressed genes of OSF tissues compared to normal tissues overlapped significantly with areca nut and TGF-beta induced genes in epithelial and hGF cells. Several positively enriched pathways were found to be common between OSF tissues and areca nut + TGF-beta treated hGF cells. In concordance, areca nut along with TGF-beta enhanced fibroblast activation as demonstrated by potentiation of alpha SMA, gamma SMA and collagen gel contraction by hGF cells. Furthermore, TGF-beta secreted by areca nut treated epithelial cells influenced fibroblast activation and other genes implicated in fibrosis. These data establish a role for areca nut influenced epithelial cells in OSF progression by activation of fibroblasts and emphasizes the importance of epithelial-mesenchymal interaction in OSF.

Epithelial atrophy in oral submucous fibrosis is mediated by copper (II) and arecoline of areca nut

Exposure of oral cavity to areca nut is associated with several pathological conditions including oral submucous fibrosis (OSF). Histopathologically OSF is characterized by epithelial atrophy, chronic inflammation, juxtaepithelial hyalinization, leading to fibrosis of submucosal tissue and affects 0.5% of the population in the Indian subcontinent. As the molecular mechanisms leading to atrophied epithelium and fibrosis are poorly understood, we studied areca nut actions on human keratinocyte and gingival fibroblast cells. Areca nut water extract (ANW) was cytotoxic to epithelial cells and had a pro-proliferative effect on fibroblasts. This opposite effect of ANW on epithelial and fibroblast cells was intriguing but reflects the OSF histopathology such as epithelial atrophy and proliferation of fibroblasts. We demonstrate that the pro-proliferative effects of ANW on fibroblasts are dependent on insulin-like growth factor signalling while the cytotoxic effects on keratinocytes are dependent on the generation of reactive oxygen species. Treatment of keratinocytes with arecoline which is a component of ANW along with copper resulted in enhanced cytotoxicity which becomes comparable to IC50 of ANW. Furthermore, studies using cyclic voltammetry, mass spectrometry and plasmid cleavage assay suggested that the presence of arecoline increases oxidation reduction potential of copper leading to enhanced cleavage of DNA which could generate an apoptotic response. Terminal deoxynucleotidyl transferase dUTP Nick End Labeling assay and Ki-67 index of OSF tissue sections suggested epithelial apoptosis, which could be responsible for the atrophy of OSF epithelium.

Submucous fibroids classification - STEP-W classification

Objective: To develop a new submucous fibroids classification for evaluating the viability and the degree of difficulty and complexity of a hysteroscopic myomectomy.Methods: We have included more four parameters in addition to penetration the fibroid into the myometrium. The extra-parameters were: size of the fibroid, it topography, it extension of the base in relation the wall was set and the wall it was set. The fibroids were classified according to the Classification of the European Society for Gynaecological Endoscopy (ESGE) and to the new classification (STEP-W) in patients who were submitted to hysteroscopic resection of submucous fibroids. The possibility of total resection of the fibroid, the operating time, the fluid deficit and the frequency of any complications were considered. The Fisher test, the Student t test and the analysis of variance test were used in the statistical analyses. It was considered statistically significant when the p-value was less than 0.05 in the two-tailed test.Results: In group which the hysteroscopic surgery was considered complete there was no significant difference between the three ESGE levels (0, 1 and 2). Using the STEP-W, the difference between the numbers of complete surgeries was significant (p < 0.001) for the two levels (groups I and II). The difference between the operating times was significant for the two classifications. In relation to the fluid deficit, only the STEP-W showed significant differences between the levels (p=0.02).Conclusions: It seems to us that the new classification (STEP-W) gives more clues to the difficulties of a hysteroscopic myornectomy than the standard classification (ESGE).

Hysteroscopic myomectomy in a submucous fibroid 3 mm from the serosa: A case report - Case report from the endoscopy service of Ginendo-RJ

This is a case report of a 39-year-old black woman, nulliparous, married who presented a heavy menstrual flow with clots and dysmenorrhea. Gynaecological examination of the uterus revealed RVF, mobility, no pain, slight enlargement, and right displacement. Magnetic resonance imaging (MRI) of the pelvis showed a 40 mm submucous fibroid with intramural component less than 50%, type 1, with a 3 mm distance from serosa. In an office hysteroscopy, it was noted a 40 mm submucous fibroid with an intramural component with less than 50%, type 1, classified in STEP-W submucous fibroids classification as a Score 6, Group II. The patient was submitted to partial hysteroscopic myomectomy, removing 60% of the fibroid volume in a 48.75-minute surgery. GnRH analogue was indicated for 3 months before another intervention. In the second evaluation MRI revealed a 22 mm-fibroid with intramural component more than 50%, type 2, with a 7 mm distance from serosa. Hysteroscopy found a 20 mm submucous fibroid, with intramural component more than 50%, type 2, Score 4, Group I on STEP-W classification. The patient was submitted to a second hysteroscopic myomectomy with complete removal and 10.5 minutes operating time, without complications. © 2006 Springer-Verlag.

Hysteroscopic myomectomy in a submucous fibroid near from tubal ostia and 5 mm from the serosa: A case report from the Endoscopy Service of Ginendo-RJ

This is a case report of a 27-year-old white woman, nuliparous, single, who presented a heavy menstrual flow with clots, dysmenorrhoea and anaemia. Gynaecological examination of the uterus revealed anteverted position, mobility, no pain, slight enlargement and right displacement. Magnetic resonance imaging of the pelvis showed a 29-mm submucous fibroid with intramural component more than 50%, type 2, in the posterior wall, with a 5-mm distance from serosa. In office hysteroscopy, a 30-mm submucous fibroid with an intramural component with more than 50%, type 2, near around 5 mm from left tubal ostia, classified in STEP-W submucous fibroids classification as score 6, group II, was noted. GnRH analogue was indicated for 3 months before intervention to treat anaemia. The patient was submitted to hysteroscopic myomectomy with direct mobilisation technique, with the fibroid completely removed without complications in a surgery which lasted for 52 min and 20 s. © 2008 Springer-Verlag.

A systematic review of medical interventions for oral submucous fibrosis and future research opportunities

Oral Diseases (2011) 17 (Suppl. 1), 42-57 Oral submucous fibrosis (OSF) is a chronic, insidious disease caused by areca nut use, and is associated with both significant morbidity (including pain and reduced oral opening) and an increased risk for malignancy. This systematic review explored and updated the current medical (i.e., non-surgical) interventions available for the management of OSF. Of the 27 published medical interventions, there were four randomized controlled trials. The overall quality of these randomized controlled studies was assessed using the GRADE approach and significant limitations that challenged the conclusions were found. However, this review was valuable in terms of identifying opportunities to provide recommendations for future research, in terms of the populations to research, the types of interventions needed, the types of outcomes to be measured, the study designs needed, and the infrastructure required to conduct studies. The next step is to initiate a pathway for a low-cost research plan leading to the development of a brief protocol for future clinical trials in this field, with an emphasis on conducting studies in regions of the world where OSF is prevalent.

Transglutaminase-2 Regulation by Arecoline in Gingival Fibroblasts

Transglutaminase-2 (TGM-2) stabilizes extracellular matrix (ECM) proteins by cross-linking and has been implicated in several fibrotic disorders. Arecoline present in betel quid has been proposed as one of the causative factors for oral submucous fibrosis (OSMF). Hence, we hypothesize that arecoline may regulate TGM-2 and may have a role in the pathogenesis of OSMF. The expression of TGM-2 was studied in OSMF tissues by real-time RT-PCR analysis, and significant overexpression was observed in most OSMF tissues (P = 0.0112) compared with normal tissues. Arecoline induced TGM-2 mRNA and protein expression as well as TGM-2 activity in human gingival fibroblast cells. The addition of methocramine hemihydrate (M-2 muscarinic acetylcholine receptor selective antagonist) or 8'-bromo-cAMP abolished arecoline-mediated TGM-2 induction, suggesting a role for M-2 muscarinic acid receptor and a repressor role for cAMP. Our study provides evidence for TGM-2 overexpression in OSMF and its regulation by arecoline in oral fibroblasts.

Mitochondrial Malfunction in Tumor Formation and Neuromuscular Diseases : Consequences of defects in fumarate hydratase and in the respiratory chain

The mitochondrion is an organelle of outmost importance, and the mitochondrial network performs an array of functions that go well beyond ATP synthesis. Defects in mitochondrial performance lead to diseases, often affecting nervous system and muscle. Although many of these mitochondrial diseases have been linked to defects in specific genes, the molecular mechanisms underlying the pathologies remain unclear. The work in this thesis aims to determine how defects in mitochondria are communicated within - and interpreted by - the cells, and how this contributes to disease phenotypes. Fumarate hydratase (FH) is an enzyme of the citrate cycle. Recessive defects in FH lead to infantile mitochondrial encephalopathies, while dominant mutations predispose to tumor formation. Defects in succinate dehydrogenase (SDH), the enzyme that precedes FH in the citrate cycle, have also been described. Mutations in SDH subunits SDHB, SDHC and SDHD are associated with tumor predisposition, while mutations in SDHA lead to a characteristic mitochondrial encephalopathy of childhood. Thus, the citrate cycle, via FH and SDH, seems to have essential roles in mitochondrial function, as well as in the regulation of processes such as cell proliferation, differentiation or death. Tumor predisposition is not a typical feature of mitochondrial energy deficiency diseases. However, defects in citrate cycle enzymes also affect mitochondrial energy metabolism. It is therefore necessary to distinguish what is specific for defects in citrate cycle, and thus possibly associated with the tumor phenotype, from the generic consequences of defects in mitochondrial aerobic metabolism. We used primary fibroblasts from patients with recessive FH defects to study the cellular consequences of FH-deficiency (FH-). Similarly to the tumors observed in FH- patients, these fibroblasts have very low FH activity. The use of primary cells has the advantage that they are diploid, in contrast with the aneuploid tumor cells, thereby enabling the study of the early consequences of FH- in diploid background, before tumorigenesis and aneuploidy. To distinguish the specific consequences of FH- from typical consequences of defects in mitochondrial aerobic metabolism, we used primary fibroblasts from patients with MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) and from patients with NARP (neuropathy, ataxia and retinitis pigmentosa). These diseases also affect mitochondrial aerobic metabolism but are not known to predispose to tumor formation. To study in vivo the systemic consequences of defects in mitochondrial aerobic metabolism, we used a transgenic mouse model of late-onset mitochondrial myopathy. The mouse contains a transgene with an in-frame duplication of a segment of Twinkle, the mitochondrial replicative helicase, whose defects underlie the human disease progressive external ophthalmoplegia. This mouse model replicates the phenotype in the patients, particularly neuronal degeneration, mitochondrial myopathy, and subtle decrease of respiratory chain activity associated with mtDNA deletions. Due to the accumulation of mtDNA deletions, the mouse was named deletor. We first studied the consequences of FH- and of respiratory chain defects for energy metabolism in primary fibroblasts. To further characterize the effects of FH- and respiratory chain malfunction in primary fibroblasts at transcriptional level, we used expression microarrays. In order to understand the in vivo consequences of respiratory chain defects in vivo, we also studied the transcriptional consequences of Twinkle defects in deletor mice skeletal muscle, cerebellum and hippocampus. Fumarate accumulated in the FH- homozygous cells, but not in the compound heterozygous lines. However, virtually all FH- lines lacked cytoplasmic FH. Induction of glycolysis was common to FH-, MELAS and NARP fibroblasts. In deletor muscle glycolysis seemed to be upregulated. This was in contrast with deletor cerebellum and hippocampus, where mitochondrial biogenesis was in progress. Despite sharing a glycolytic pattern in energy metabolism, FH- and respiratory chain defects led to opposite consequences in redox environment. FH- was associated with reduced redox environment, while MELAS and NARP displayed evidences of oxidative stress. The deletor cerebellum had transcriptional induction of antioxidant defenses, suggesting increased production of reactive oxygen species. Since the fibroblasts do not represent the tissues where the tumors appear in FH- patients, we compared the fibroblast array data with the data from FH- leiomyomas and normal myometrium. This allowed the determination of the pathways and networks affected by FH-deficiency in primary cells that are also relevant for myoma formation. A key pathway regulating smooth muscle differentiation, SRF (serum response factor)-FOS-JUNB, was found to be downregulated in FH- cells and in myomas. While in the deletor mouse many pathways were affected in a tissue-specific basis, like FGF21 induction in the deletor muscle, others were systemic, such as the downregulation of ALAS2-linked heme synthesis in all deletor tissues analyzed. However, interestingly, even a tissue-specific response of FGF21 excretion could elicit a global starvation response. The work presented in this thesis has contributed to a better understanding of mitochondrial stress signalling and of pathways interpreting and transducing it to human pathology.

Regulation of oxidative-stress responsive genes by arecoline in human keratinocytes

Background and Objective: Arecoline, an arecanut alkaloid present in the saliva of betel quid chewers, has been implicated in the pathogenesis of a variety of inflammatory oral diseases, including oral submucous fibrosis and periodontitis. To understand the molecular b asis of arecoline action in epithelial changes associated with these diseases, we investigated the effects of arecoline on human keratinocytes with respect to cell growth regulation and the expression of stress-responsive genes.Material and Methods:Human keratinocyte cells (of the HaCaT cell line) were treated with arecoline, following which cell viability was assessed using the Trypan Blue dye-exclusion assay, cell growth and proliferation were analyzed using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) and 5-bromo-2-deoxyuridine incorporation assays, cell cycle arrest and generation of reactive oxygen species were examined using flow cytometry, and gene expression changes were investigated using the reverse transcription-polymerase chain reaction technique. The role of oxidative stress, muscarinic acetylcholine receptor and mitogen-activated protein kinase (MAPK) pathways were studied using specific inhibitors. Western blot analysis was performed to study p38 MAPK activation.Results:Arecoline induced the generation of reactive oxygen species and cell cycle arrest at the G1/G0 phase in HaCaT cells without affecting the expression of p21/Cip1. Arecoline-induced epithelial cell death at higher concentrations was caused by oxidative trauma without eliciting apoptosis. Sublethal concentrations of arecoline upregulated the expression of the following stress-responsive genes: heme oxygenase-1; ferritin light chain; glucose-6-phosphate dehydrogenase; glutamate-cysteine ligase catalytic subunit; and glutathione reductase.Additionally, there was a dose-dependent induction of interleukin-1alfa mRNA by arecoline via oxidative stress and p38 MAPK activation. Conclusion:our data highlight the role of oxidative stress in arecoline-mediated cell death, gene regulation and inflammatory processes in human keratinocytes.

Regulation of extracellular matrix genes by arecoline in primary gingival fibroblasts requires epithelial factors

Background and Objective: Oral submucous fibrosis, a disease of collagen disorder, has been attributed to arecoline present in the saliva of betel quid chewers. However, the molecular basis of the action of arecoline in the pathogenesis of oral submucous fibrosis is poorly understood. The basic aim of our study was to elucidate the mechanism underlying the action of arecoline on the expression of genes in oral fibroblasts. Material and Methods: Human keratinocytes (HaCaT cells) and primary human gingival fibroblasts were treated with arecoline in combination with various pathway inhibitors, and the expression of transforming growth factor-beta isoform genes and of collagen isoforms was assessed using reverse transcription polymerase chain reaction analysis. Results: We observed the induction of transforming growth factor-beta2 by arecoline in HaCaT cells and this induction was found to be caused by activation of the M-3 muscarinic acid receptor via the induction of calcium and the protein kinase C pathway. Most importantly, we showed that transforming growth factor-beta2 was significantly overexpressed in oral submucous fibrosis tissues (p = 0.008), with a median of 2.13 (n = 21) compared with 0.75 (n = 18) in normal buccal mucosal tissues. Furthermore, arecoline down-regulated the expression of collagens 1A1 and 3A1 in human primary gingival fibroblasts; however these collagens were induced by arecoline in the presence of spent medium of cultured human keratinocytes. Treatment with a transforming growth factor-beta blocker, transforming growth factor-beta1 latency-associated peptide, reversed this up-regulation of collagen, suggesting a role for profibrotic cytokines, such as transforming growth factor-beta, in the induction of collagens. Conclusion: Taken together, our data highlight the importance of arecoline-induced epithelial changes in the pathogenesis of oral submucous fibrosis.

Influência da posição sócio-econômica ao longo da vida nas desigualdades de cor/raça na ocorrência de miomas uterinos: Estudo Pró-Saúde

Os miomas uterinos (MU) são considerados os tumores mais comuns do sistema reprodutor feminino. Estudos norte-americanos demonstram que mulheres negras são mais acometidas pelos MU que as de outros grupos étnico-raciais. No entanto, as causas da desigualdade racial na ocorrência dos tumores permanecem desconhecidas e possíveis mecanismos são pouco explorados na literatura. Em outra direção, devido às características dos MU (crescimento lento e longo período de latência) parte considerável dos estudos epidemiológicos utilizam um delineamento transversal, o que pode gerar problemas metodológicos, como os relacionados à utilização da idade coletada transversalmente (posteriormente a ocorrência dos MU) como proxy da idade do surgimento dos tumores. Assim, este trabalho de tese foi dividido em três partes, como se segue. A primeira, com características descritivas, teve por objetivo estimar a ocorrência de MU autorelatados segundo categorias demográficas e sócio-econômicas na população de estudo (compôs o artigo 1). A segunda, com componente analítico, propôs-se a avaliar o papel da PSE ao longo da vida como mediadora do efeito da cor/raça na ocorrência de MU auto-relatados (compôs o artigo 2). A terceira, com caráter metodológico, teve por objetivo comparar medidas de associação, entre variáveis aferidas transversalmente, em análises que incluem a co-variável idade no momento da coleta de dados e análises que consideram a idade ao diagnóstico dos MU (compôs o artigo 3). Para tanto, foram analisados dados transversais da população feminina participante das duas etapas da linha de base do Estudo Pró-Saúde, referentes à história auto-relatada de diagnóstico médico de MU e ainda a características sócio-demográficas, da vida reprodutiva e de acesso a serviços de saúde. Os resultados evidenciaram o aumento de ocorrência de MU em mulheres de maior idade e com a cor da pele mais escura (artigo 1); que a PSE ao longo da vida não medeia as associações entre cor/raça e MU (artigo 2); e que apesar das diferenças de pequena magnitude, a idade referida no momento da coleta de dados parece ser menos indicada para fins de especificação dos modelos analíticos do que a idade ao diagnóstico dos MU(artigo 3).