Role of immune and angiogenic markers in the pathology of endometriosis

Background: Endometriosis is an estrogen-dependent, pro-inflammatory, pro-angiogenic condition that affects 5 to 10% of women of reproductive age. Its defining feature is the presence of endometrium-like tissue in sites outside the uterine cavity, primarily on the pelvic peritoneum and ovaries. The main clinical features are chronic pain, pain during intercourse and infertility. In patients with endometriosis, inflammatory and immune responses, angiogenesis and apoptosis are altered in favour of the survival and replenishment of endometriotic tissue. These basic pathological processes depend on the excessive formation of estrogen and prostaglandins. Recently, new cellular and molecular mechanisms for the resolution of inflammation have been discovered, revealing key roles for lipid mediators such as lipoxins, resolvins and protectins. It is possible that disequilibrium in the expression of these molecules exists in endometriosis. Objective: To compare the expression of two proteins involved in the synthe sis and in the function of lipid mediators; the Arachidonate 15-lipoxygenase (ALOXI5), implicated in the synthesis of lipoxins A4 and B4 and the Formyl peptide receptor 1 (FPRLI), the specific receptor for Lipoxin A4 and B4, between women who suffer from endometriosis and a control group. We wish to demonstrate the cellular localisation of these two molecules and to investigate if their expression is alteted in this pathology. Methods and Materials Using immunohistochemistry we will compare ALOXI5 and FPRLI staining, in endometrium, normal peritoneum and endometriotic lesions. The samples are being collected in the department of Gynaecology and Obstetrics at the Centre Hospitalier Universitaire Lausanne (CHUV). Women attending the department for laparoscopic investigation of pain/infertility, suspected endometriosis or for a hysterectomy, are invited to participate. Approval of the ethics committee (Commission d'Ethique de la recherché clinique) was obtained in March 2009. Clinical samples will only be obtained from subjects having consented. Expected results and interpretation: No published studies investigating the expression of these two molecules in endometriotic lesions exist. A better understanding of the mechanisms underlying this disease will result in the development of new medical therapies and new diagnostic tests, with the aim of ameliorating the quality of life of endometriosis patients.

Role of human hydroxysteroid (17beta) dehydrogenase type 1 (HSD17B1) in steroid-dependent diseases in females –novel indications for HSD17B1 inhibitors. Phenotypic analysis of transgenic mice overexpressing human HSD17B1.

Hormone-dependent diseases, e.g. cancers, rank high in mortality in the modern world, and thus, there is an urgent need for new drugs to treat these diseases. Although the diseases are clearly hormone-dependent, changes in circulating hormone concentrations do not explain all the pathological processes observed in the diseased tissues. A more inclusive explanation is provided by intracrinology – a regulation of hormone concentrations at the target tissue level. This is mediated by the expression of a pattern of steroid-activating and -inactivating enzymes in steroid target tissues, thus enabling a concentration gradient between the blood circulation and the tissue. Hydroxysteroid (17beta) dehydrogenases (HSD17Bs) form a family of enzymes that catalyze the conversion between low active 17-ketosteroids and highly active 17beta-hydroxysteroids. HSD17B1 converts low active estrogen (E1) to highly active estradiol (E2) with high catalytic efficiency, and altered HSD17B1 expression has been associated with several hormone-dependent diseases, including breast cancer, endometriosis, endometrial hyperplasia and cancer, and ovarian epithelial cancer. Because of its putative role in E2 biosynthesis in ovaries and peripheral target tissues, HSD17B1 is considered to be a promising drug target for estrogen-dependent diseases. A few studies have indicated that the enzyme also has androgenic activity, but they have been ignored. In the present study, transgenic mice overexpressing human HSD17B1 (HSD17B1TG mice) were used to study the effects of the enzyme in vivo. Firstly, the substrate specificity of human HSD17B1 was determined in vivo. The results indicated that human HSD17B1 has significant androgenic activity in female mice in vivo, which resulted in increased fetal testosterone concentration and female disorder of sexual development appearing as masculinized phenotype (increased anogenital distance, lack of nipples, lack of vaginal opening, combination of vagina with urethra, enlarged Wolffian duct remnants in the mesovarium and enlarged female prostate). Fetal androgen exposure has been linked to polycystic ovary syndrome (PCOS) and metabolic syndrome during adulthood in experimental animals and humans, but the genes involved in PCOS are largely unknown. A putative mechanism to accumulate androgens during fetal life by HSD17B1 overexpression was shown in the present study. Furthermore, as a result of prenatal androgen exposure locally in the ovaries, HSD17B1TG females developed ovarian benign serous cystadenomas in adulthood. These benign lesions are precursors of low-grade ovarian serous tumors. Ovarian cancer ranks fifth in mortality of all female cancers in Finland, and most of the ovarian cancers arise from the surface epithelium. The formation of the lesions was prevented by prenatal antiandrogen treatment and by transplanting wild type (WT) ovaries prepubertally into HSD17B1TG females. The results obtained in our non-clinical TG mouse model, together with a literature analysis, suggest that HSD17B1 has a role in ovarian epithelial carcinogenesis, and especially in the development of serous tumors. The role of androgens in ovarian carcinogenesis is considered controversial, but the present study provides further evidence for the androgen hypothesis. Moreover, it directly links HSD17B1-induced prenatal androgen exposure to ovarian epithelial carcinogenesis in mice. As expected, significant estrogenic activity was also detected for human HSD17B1. HSD17B1TG mice had enhanced peripheral conversion of E1 to E2 in a variety of target tissues, including the uterus. Furthermore, this activity was significantly decreased by treatments with specific HSD17B1 inhibitors. As a result, several estrogen-dependent disorders were found in HSD17B1TG females. Here we report that HSD17B1TG mice invariably developed endometrial hyperplasia and failed to ovulate in adulthood. As in humans, endometrial hyperplasia in HSD17B1TG females was reversible upon ovulation induction, triggering a rise in circulating progesterone levels, and in response to exogenous progestins. Remarkably, treatment with a HSD17B1 inhibitor failed to restore ovulation, yet completely reversed the hyperplastic morphology of epithelial cells in the glandular compartment. We also demonstrate that HSD17B1 is expressed in normal human endometrium, hyperplasia, and cancer. Collectively, our non-clinical data and literature analysis suggest that HSD17B1 inhibition could be one of several possible approaches to decrease endometrial estrogen production in endometrial hyperplasia and cancer. HSD17B1 expression has been found in bones of humans and rats. The non-clinical data in the present study suggest that human HSD17B1 is likely to have an important role in the regulation of bone formation, strength and length during reproductive years in female mice. Bone density in HSD17B1TG females was highly increased in femurs, but in lesser amounts also in tibias. Especially the tibia growth plate, but not other regions of bone, was susceptible to respond to HSD17B1 inhibition by increasing bone length, whereas the inhibitors did not affect bone density. Therefore, HSD17B1 inhibitors could be safer than aromatase inhibitors in regard to bone in the treatment of breast cancer and endometriosis. Furthermore, diseases related to improper growth, are a promising new indication for HSD17B1 inhibitors.

Can endometrial arylsulfatase A activity predict the onset of endometrial polyps over the years?

PURPOSE: To assess if arylsulfatase A activity (ASA) and sulfatide (SL) concentration in the human endometrium can be predictive of the development of endometrial polyps over the years, since ASA activity reflects the endometrial sensitivity to hormones. METHODS: ASA activity and SL concentration were determined by biochemical procedures on endometrial samples collected between 1990 and 1994 in non-menopausal women. These women underwent a new endometrial sampling following the clinical indication some years after the first endometrial sampling. The histological assessment of the second endometrial specimens found four patients with normal endometrial pattern and 10 patients with one or more endometrial polyps. ASA activity/years elapsed and SL concentration/years elapsed were compared using two tailed Mann-Whitney test for unpaired data between patients with normal pattern and patients with endometrial polyps. RESULTS: Median ASA activities were 2.62 (normal pattern) versus 1.85 (endometrial polyps) nmol hydrolized substrate/min. Median activity/years elapsed is higher in patients with second endometrial sample presenting normal pattern (p=0.006) and median SL concentration/years elapsed does not differ significantly among groups, even if median SL concentration seems to be higher in patients who subsequently developed polyps (1031 µg/g of fresh tissue versus 341,5 µg/g of fresh tissue). CONCLUSIONS: ASA activity can predict the onset of endometrial polyps over the years.

Accuracy of sonography and hysteroscopy in the diagnosis of premalignant and malignant polyps in postmenopausal women

PURPOSE: To evaluate the accuracy of sonographic endometrial thickness and hysteroscopic characteristics in predicting malignancy in postmenopausal women undergoing surgical resection of endometrial polyps. METHODS: Five hundred twenty-one (521) postmenopausal women undergoing hysteroscopic resection of endometrial polyps between January 1998 and December 2008 were studied. For each value of sonographic endometrial thickness and polyp size on hysteroscopy, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated in relation to the histologic diagnosis of malignancy. The best values of sensitivity and specificity for the diagnosis of malignancy were determined by the Receiver Operating Characteristic (ROC) curve. RESULTS: Histologic diagnosis identified the presence of premalignancy or malignancy in 4.1% of cases. Sonographic measurement revealed a greater endometrial thickness in cases of malignant polyps when compared to benign and premalignant polyps. On surgical hysteroscopy, malignant endometrial polyps were also larger. An endometrial thickness of 13 mm showed a sensitivity of 69.6%, specificity of 68.5%, PPV of 9.3%, and NPV of 98% in predicting malignancy in endometrial polyps. Polyp measurement by hysteroscopy showed that for polyps 30 mm in size, the sensitivity was 47.8%, specificity was 66.1%, PPV was 6.1%, and NPV was 96.5% for predicting cancer. CONCLUSIONS: Sonographic endometrial thickness showed a higher level of accuracy than hysteroscopic measurement in predicting malignancy in endometrial polyps. Despite this, both techniques showed low accuracy for predicting malignancy in endometrial polyps in postmenopausal women. In suspected cases, histologic evaluation is necessary to exclude malignancy.

Immunohistochemical detection of Tritrichomonas foetus in experimentally infected mice

The need to intensify knowledge of the pathogenesis of bovine genital trichomoniasis (BGT) led to the use of alternative animal models such as the mouse. Nevertheless, it is necessary to elucidate the dynamics of the infection in this animal species, evaluating different stages of the colonization and evolution of the pathological alterations. The immunohistochemistry (IHC) offers advantages over the routine histopathological staining techniques for the detection of the protozoan in tissues, cellular detritus and inside the macrophages. The goal of the present study was to demonstrate the presence of Tritrichomonas foetus in the reproductive tract of infected mice using an IHC technique. Female BALB/c mice were infected with a suspension of T. foetus by intravaginal route, in the estrum phase, detected by exfoliative vaginal cytology. After 10 weeks, the animals were sacrificed; uterus and vagina were fixed and histologically processed. Some slides were stained with HE. The rest of the slides were processed for IHC. An immunoadsorbed polyclonal serum against T. foetus was used. The avidine-biotine technique (HistoMouse, Zymed™) was employed. The histopathological studies showed a dilation of the uterine glands, presence of macrophages in the lumen of the organ and inner part of the endometrial glands. No T. foetus was identified using this method. The IHQ allowed additionally the identification of the protozoan in the endometrium, endometrial glands, uterine lumen and inside neutrophils and macrophages. The cytological studies stained with IHC showed either isolated T. foetus adhered to epithelial cells or inside macrophages. This technique proves to be a useful tool for the study of the pathogenesis of bovine genital trichomoniasis (BGT) in an experimental model.

Morphological and morphometric evaluation of prepubertal gilt ovaries, uterine tubes and uterus at different oestrus cycle stages

Studies are performed in developing techniques/procedures that provide greater reproductive performance in farm animals, including pigs. In this sense, the study of gilts reproductive organs at different oestrus cycle stages for assessing the presence of abnormalities and/or other parameters that may affect the future animal fertility is important. In order to evaluate the morphological, morphometric and histomorphometric features of ovaries, uterus and uterine tubes (UTs) characteristics of prepubertal gilts at different oestrus cycle stages, reproductive tracts from 48 animals immediately after slaughter were obtained. After, the structures were dissected and removed, and the ovaries were used for classification of oestrus cycle stage of each gilt in follicular phase (FP) and luteal phase (FL). Then, morphometric evaluations of ovaries, UTs, uterine horns and uterine body were performed. Besides that, medial segments of UTs and uterus were fixed in Bouin solution, processed and included in paraffin, when histological sections of 5.0 micrometers (µm) were obtained and stained with Hematoxylin and Eosin. Histomorphometric analyzes using image capture system and specific software were performed. Afterwards, data were submitted to Student's t test for assessment the statistical differences (P<0.05) between the two different oestrus cycle stages (FP × LP) and between the placement of reproductive structures (right × left antimer). Among the gilts evaluated, 35 were in the FP and 13 in LP. There was no difference (P>0.05) between morphometric parameters of ovaries, UTs and uterus of gilts in FP and LP. Likewise, in respect to the placement of reproductive structures, both in the oestrus cycle stages, as in the general average, there was no difference (P>0.05). Regarding the histomorphometric variables, gilts classified in FP presented a higher (P<0.05) height of glandular and UT epithelium compared to animals in LP. On the other hand, the diameter of endometrial glands was higher (P<0.05) in gilts at LP compared to FP. Furthermore, gilts in LP presented a higher (P<0.05) proportion of endometrium occupied by glands, whereas animals in FP had a higher (P<0.05) proportion of connective tissue and blood vessels. In conclusion, in prepubertal gilts, the histomorphometric parameters as endometrial glands diameter, the height of glandular epithelium and of UT epithelium and the proportion of endometrium occupied by connective tissue, besides the glands and blood vessels varies through the oestrus cycle, possibly under the influence of ovarian steroids.

Distribution of versican and hyaluronan in the mouse uterus during decidualization

Preparation for embryo implantation requires extensive adaptation of the uterine microenvironment. This process consists of cell proliferation and cell differentiation resulting in the transformation of endometrial fibroblasts into a new type of cell called decidual cell. In the present study, we followed the space-time distribution of versican and hyaluronan (HA) in different tissues of the uterus before and after embryo implantation. Fragments of mouse uteri obtained on the fourth, fifth, sixth and seventh days of pregnancy were fixed in Methacarn, embedded in Paraplast and cut into 5-µm thick sections. HA was detected using a biotinylated fragment of the proteoglycan aggrecan, which binds to this glycosaminoglycan with high affinity and specificity. Versican was detected by a polyclonal antibody. Both reactions were developed by peroxidase methods. Before embryo implantation, both HA and versican were present in the endometrial stroma. However, after embryo implantation, HA disappeared from the decidual region immediately surrounding the implantation chamber, whereas versican accumulated in the same region. The differences observed in the expression of HA and versican suggest that both molecules may participate in the process of endometrial decidualization and/or embryo implantation.

Genomic alterations detected by comparative genomic hybridization in ovarian endometriomas

Endometriosis is a complex and multifactorial disease. Chromosomal imbalance screening in endometriotic tissue can be used to detect hot-spot regions in the search for a possible genetic marker for endometriosis. The objective of the present study was to detect chromosomal imbalances by comparative genomic hybridization (CGH) in ectopic tissue samples from ovarian endometriomas and eutopic tissue from the same patients. We evaluated 10 ovarian endometriotic tissues and 10 eutopic endometrial tissues by metaphase CGH. CGH was prepared with normal and test DNA enzymatically digested, ligated to adaptors and amplified by PCR. A second PCR was performed for DNA labeling. Equal amounts of both normal and test-labeled DNA were hybridized in human normal metaphases. The Isis FISH Imaging System V 5.0 software was used for chromosome analysis. In both eutopic and ectopic groups, 4/10 samples presented chromosomal alterations, mainly chromosomal gains. CGH identified 11q12.3-q13.1, 17p11.1-p12, 17q25.3-qter, and 19p as critical regions. Genomic imbalances in 11q, 17p, 17q, and 19p were detected in normal eutopic and/or ectopic endometrium from women with ovarian endometriosis. These regions contain genes such as POLR2G, MXRA7 and UBA52 involved in biological processes that may lead to the establishment and maintenance of endometriotic implants. This genomic imbalance may affect genes in which dysregulation impacts both eutopic and ectopic endometrium.

Gene expression of estrogen and oxytocin receptors in the uterus of pregnant and parturient bitches

In the canine species, the precise mechanisms of pregnancy maintenance and the initiation of parturition are not completely understood. The expression of genes encoding the receptors for estrogen (ERα mRNA) and oxytocin (OTR mRNA) was studied in the endometrium and myometrium during pregnancy and parturition in dogs. Real-time PCR was performed to quantify the levels of ERα mRNA and OTR mRNA in the uterus of bitches during early (up to 20 days of gestation), mid (20 to 40 days) and late pregnancy (41 to 60 days), and parturition (first stage of labor). All tissues expressed ERα and OTR mRNA, and are thus possibly able to respond to eventual estrogen and oxytocin hormonal stimuli. No statistically significant differences in the expression of ERα mRNA were verified in the endometrium and myometrium throughout pregnancy and parturition, but expression of OTR mRNA increased at both parturition and late pregnancy. We concluded that the increase of endometrial and myometrial OTR mRNA expression in dogs is not an event dependent on estrogenic stimulation. Moreover, the contractility response of the canine uterus to oxytocin begins during pregnancy and maintains myometrial activity. The expression of OTR mRNA in canine uterine tissues varied over time, which supports an interpretation that the sensitivity and response to hormone therapy varies during the course of pregnancy and labor. Further studies are needed to elucidate the factors underlying the synthesis of uterine oxytocin receptors and the possible role of ERβ rather than ERα in the uterine tissues during pregnancy and parturition in dogs.

Conceptus-mediated endometrial vascular changes during early pregnancy in mares: an anatomic, histomorphometric, and vascular endothelial growth factor receptor system immunolocalization and gene expression study

This work examined how the conceptus modulates endometrial tissue remodeling and vascular development prior to implantation in mares. A macroscopic uterine examination was completed at day 21 of pregnancy. In situ morphology revealed that the endometrium involved in encroachment is restricted to the dorsal endometrium immediately overlying the yolk sac. The amount of stromal area occupied by blood vessels and the number of endometrial glands were increased during early pregnancy. Endometrial histomorphometry as well as the endometrial mRNA abundance and immunolocalization of VEGF, VEGFR1, VEGFR2, and Ki-67 was completed at days 14 and 21 of pregnancy, at day 10 of the estrous cycle, and during estrus. No obvious differences in VEGF and VEGFR1 protein localization were detected between pregnant and cycling mares but differential staining pattern for VEGFR2 and Ki-67 was observed. VEGFR2 localized to luminal and glandular epithelium of pregnant mares, while luminal epithelium was negative in cycling mares. Ki-67 staining was weak during the luteal phase but exhibited prominent luminal epithelium staining during estrus. In pregnant mares, all endometrial layers were Ki-67 positive. Quantitative RT-PCR revealed a greater abundance of VEGF mRNA during pregnancy. VEGFR2 transcript abundance was greatest in pregnant mares on day 21. This study supports the concept that the conceptus plays an active role in directing vasculogenesis within the uterus and thereby establishing hemotrophic nutrition that supports pregnancy after implantation. Reproduction (2011) 142 593-603

The Estrous Cycle Modulates Small Leucine-Rich Proteoglycans Expression in Mouse Uterine Tissues

In the pregnant mouse uterus, small leucine-rich proteoglycans (SLRPs) are drastically remodeled within a few hours after fertilization, suggesting that ovarian hormone levels modulate their synthesis and degradation. In this study, we followed by immunoperoxidase approach, the presence of four members of the SLRP family (decorin, lumican, biglycan, and fibromodulin) in the uterine tissues along the estrous cycle of the mouse. All molecules except fibromodulin, which predominates in the myometrium, showed a striking modulation in their distribution in the endometrial stroma, following the rise in the level of estrogen. Moreover, notable differences in the distribution of SLRPs were observed between superficial and deep stroma, as well as between the internal and external layers of the myometrium. Only biglycan and fibromodulin were expressed in the luminal and glandular epithelia. All four SLRPs were found in cytoplasmic granules of mononucleated cells. The pattern of distribution of the immunoreaction for these molecules in the uterine tissues was found to be estrous cycle-stage dependent, suggesting that these molecules undergo ovarian hormonal control and probably participate in the preparation of the uterus for decidualization and embryo implantation. In addition, this and previous results from our laboratory suggest the existence of two subpopulations of endometrial fibroblasts that may be related to the centrifugal development of the decidua. Anat Rec, 292:138-153, 2009. (c) 2008 Wiley-Liss, Inc.

Cariometria digital em adenocarcinoma de pâncreas

O adenocarcinoma de pâncreas continua sendo uma doença com alta mortalidade apesar dos avanços na ciência e na tecnologia. O diagnóstico é tardio, na maior parte dos casos, impossibilitando uma abordagem com fins curativos. Os estudos em busca de um método para o diagnóstico precoce ou mesmo um tratamento eficaz, até o momento, não revelaram mudanças significativas. Atualmente, pesquisas em biologia molecular apontando alterações em determinados genes nos tumores de pâncreas parecem ser promissoras. Neste sentido, porém seguindo uma outra linha de pesquisa, o estudo atual que objetiva a determinação das características nucleares das células neoplásicas através da cariometria por análise digital, constitui um passo inicial para futuras especulações. Recentemente, estudos em outros tecidos como o prostático, o mamário e o endométrio vêm demonstrando existir eficácia na diferenciação entre seus tecidos normais e neoplásicos e também uma forte relação entre as alterações encontradas na cromatina de seus núcleos celulares e a agressividade de seus respectivos tumores. Utilizando-se tecido pancreático estocado em parafina por até onze anos no laboratório de Patologia do Hospital de Clínicas de Porto Alegre (HCPA), foram determinadas as características nucleares em mil e trezentos núcleos de células ductais de adenocarcinoma de pâncreas e de tecido pancreático normal. Noventa e três características da cromatina foram estudadas por análise digital. Onze características apresentaram valores diferentes entre os dois grupos e estas diferenças foram estatisticamente significativas. A média para o valor da ÁREA nuclear nos tumores foi de 977.78 e de 336.60, no tecido normal; a da RLM278 foi de 353.23 e 97.07; a da RLM266 de 99.32 e 28.06; a do PERIM de 125.58 e 65.05; a do ROUND de 1.37 e 1.04; a da IOD de 123.49 e 107.97; a da FRACDIM de 1.22 e 1.05; a da DENSMIN de 0.01 e 0.14; a da DENSMAX de 0.53 e 0.62; a da DENSSD 0.25 e 0.10 e a da DENS20P de 0.49 e 0.33, respectivamente para os núcleos dos tumores e para os do tecido normal. Sete destas características serviram como marcadores ideais de neoplasia. Estes achados permitiram a criação de uma assinatura digital específica para cada um dos dois tipos de tecido estudado.

Expressão gênica de bcl2, receptor de estradiol e receptores de progesterona A e B em endométrio eutópico e ectópico de pacientes inférteis sem e com endometriose

A endometriose caracteriza-se pela presença de tecido endometriótico – glândulas e estroma – fora da cavidade uterina. A doença acomete superfícies peritoniais da pélvis, ovários e septo rectovaginal, sendo mais comum a endometriose pélvica. Embora os dados sobre a prevalência exata de endometriose sejam incertos, as evidências indicam uma prevalência em torno de 5 a 10% das mulheres em idade reprodutiva. Dor, dismenorréia, dispareunia e infertilidade são sintomas freqüentes da doença. Além de apresentar dependência aos hormônios sexuais, a endometriose está associada a um conjunto de desordens de diferentes etiologias, sendo considerada uma doença multifatorial de caráter genético e imune. Neste sentido, a carência de respostas imunológicas adequadas, aliada a um provável desequilíbrio entre os processos de proliferação e apoptose celular, pode ter um papel importante na instalação e manutenção das lesões endometrióticas. O objetivo deste trabalho foi caracterizar a expressão de genes relacionados aos processos de proliferação e diferenciação celular em implantes endometrióticos e endométrio eutópico de mulheres inférteis sem e com endometriose, através da análise semiquantitativa por RT-PCR. Foram estudadas 34 pacientes consultando por infertilidade e submetidas à laparoscopia diagnóstica. Quinze pacientes (31,7 ± 1,5 anos) apresentavam endometriose e 19 (32,9 ± 0,9 anos) foram consideradas controles inférteis sem endometriose. Os dois grupos apresentaram IMC e SHBG similares. As biópsias de endométrio foram realizadas, em fase folicular, nas pacientes do grupo controle (C) e nas pacientes com endometriose (endométrio eutópico (EUT) e ectópico (ECT)). A presença do mRNA para os receptores de estrogênio e progesterona detectada nos 3 grupos estudados, sustenta a existência de sensibilidade tecidual local aos hormônios sexuais. Nas condições experimentais do presente estudo não foi observada diferença estatística na expressão gênica de bcl2 entre os grupos. A expressão do gene do ER endometrial também foi similar entre os grupos controle, eutópico e ectópico. Contudo, o endométrio ectópico apresentou níveis de mRNA mais elevados para PR-A (0,84  0,02 UA) em relação aos grupos controle e eutópico (0,60  0,04 UA e 0,63  0,04 UA; p < 0,05). A expressão gênica do PR-B não foi estatisticamente diferente entre os grupos do presente trabalho. Porém, houve forte correlação negativa entre a expressão dos genes bcl2 e PR-B nas amostras de endométrio sem e com endometriose (r = - 0,795 e p = 0,018), sugerindo que um papel anti-proliferativo do PR-B possa ser operativo neste modelo de estudo.

Raloxifene therapy does not affect uterine blood flow in postmenopausal women: a transvaginal Doppler study

AZEVEDO, George Dantas de et al. Raloxifene therapy does not affect uterine blood flow in postmenopausal women: a transvaginal Doppler study. Maturitas, Amsterdam, v.47, n.3, p.195-200, 2004

Efeitos dos esteroides anabólicos androgênicos sobre o útero e parâmetros reprodutivos de ratas adultas

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)