Tamoxifeno e Espessamento Endometrial Assintomático

Tamoxifen is a first-line agent for adjuvant treatment of estrogen-receptor positive breast cancer, and is used to reduce the risk of this condition in high-risk individuals. Retrospective studies established an association between tamoxifen use, endometrial thickness and endometrial cancer. There have been many attempts to identify an effective screening program for tamoxifen-related endometrial cancer, which have led to the use of transvaginal ultrasound and invasive procedures. The use of a 5mm endometrial cut-off in vaginal ultrasound is known to raise the number of endometrial biopsies with no gain in early cancer diagnosis. A review of the scientific literature was performed in order to establish the best available evidence for endometrial evaluation of asymptomatic breast cancer patients on tamoxifen.

Achados histeroscópicos em mulheres na pós-menopausa com diagnóstico de espessamento endometrial por ultra-sonografia transvaginal

OBJETIVO: correlacionar espessamento endometrial diagnosticado por ultra-sonografia com os achados histeroscópicos, em mulheres na pós-menopausa. MÉTODOS: foi realizado estudo transversal com avaliação histeroscópica em 121 mulheres na pós-menopausa, com diagnóstico de espessamento do endométrio por ultra-sonografia transvaginal. Das pacientes incluídas, 23 (19%) recebiam diferentes esquemas de hormonioterapia e 98 não referiam uso de reposição hormnonal.; 55 pacientes queixavam-se de sangramento por via vaginal e as restantes apresentavam-se sem esta condição. Os exames endoscópicos foram realizados ambulatorialmente, utilizando-se histeroscópio rígido de 4 mm. Para a distensão da cavidade uterina empregou-se gás carbônico (CO2). Biópsia foi praticada em todas as pacientes, com auxílio de cureta tipo Novak, de 3 mm, e o material obtido submetido a estudo histopatológico. RESULTADOS: a espessura do endométrio variou entre 6 e 38 mm, com média de 10,7 ± 5,3 mm. Os achados histeroscópicos foram: lesão polipóide, em 51 pacientes (42,1%); endométrio atrófico, em 15 (12,4%); sinéquia senil, em 15 (12,4%); espessamento focal, em 13 (10,7%); lesão cerebróide, em 6 (5,0%); endométrio proliferativo, em 5 (4,1%); muco, em 5 (4,1%); mioma, em 4 (3,3%); endométrio secretor, em 3 (2,5%); hiperplasia endometrial, em 3 (2,5%) e atrofia cística, em 1 (0,8%). Observou-se correlação entre os achados histeroscópicos e os resultados da histopatologia em 30 dos 51 casos de pólipo, em 12 dos 15 de endométrio atrófico e na totalidade dos casos sugestivos de hiperplasia endometrial e de adenocarcinoma. CONCLUSÃO: na maioria das pacientes, o exame histeroscópico revelou que não se tratava de real espessamento endometrial, mas sim de outras variedades de lesão da cavidade uterina.

Valor da ultra-sonografia na avaliação das alterações endometriais em pacientes tratadas com tamoxifeno

OBJETIVO: Avaliar as alterações endometriais por meio da ultra-sonografia transvaginal e correlacioná-las com os achados da histeroscopia e histologia, em pacientes submetidas a tratamento com tamoxifeno. MATERIAIS E MÉTODOS: No período de janeiro de 2003 a dezembro de 2005, foram incluídas pacientes com câncer de mama usuárias de tamoxifeno que apresentaram espessamento endometrial acima de 5 mm. Os achados foram correlacionados com os dados de histeroscopia e anatomopatologia. RESULTADOS: Foram selecionadas 25 pacientes com idade média de 62,6 anos. O tempo médio do diagnóstico do câncer foi de 4,3 anos e do uso de tamoxifeno, três anos. Vinte pacientes eram assintomáticas (80%) e as demais apresentaram sangramento (20%). À ultra-sonografia, 16% apresentaram espessamento endometrial entre 5 mm e 8 mm, 40% entre 9 mm e 15 mm, e 44% acima de 15 mm. Ao estudo com a histeroscopia, 40% apresentaram atrofia, 16% atrofia cística, 28% pólipos, e 16% lesão hiperplásica. O estudo anatomopatológico apresentou-se normal em 35,2% dos casos e mostrou atrofia em 5,8%, pólipo em 29,4% e hiperplasia em 11,7%. Foi observado um caso de adenocarcinoma (5,8%). CONCLUSÃO: A ultra-sonografia associada à histeroscopia apresentam-se como importantes aliados na avaliação de pacientes usuárias de tamoxifeno. A detecção de espessamento endometrial à ultra-sonografia apresenta baixa especificidade, enquanto a histeroscopia é mais acurada na detecção de pólipos, hiperplasia e alterações neoplásicas.

Avaliação da Cavidade Uterina: Estudo Comparativo entre Histerografia, Histerossonografia e Histeroscopia

Objetivo: realizar um estudo comparativo entre os métodos utilizados para avaliar a cavidade uterina por meio da análise da sensibilidade e especificidade da histerografia e da histerossonografia, comparadas com a histeroscopia (padrão ouro). Métodos: foi realizado um estudo prospectivo para a investigação da cavidade uterina com a histerografia, a histerossonografia e a histeroscopia em 18 pacientes. Todas as pacientes apresentavam suspeita de anomalias da cavidade uterina. As principais indicações para a investigação foram: distúrbios do ciclo menstrual, sangramento pós-menopausa e alterações observadas em exames ultra-sonográficos sugestivas de pólipos, miomas e/ou espessamento endometrial. Resultados: a sensibilidade da histerossonografia foi de 90% e a especificidade 87,5%, quando comparadas à histeroscopia. O valor preditivo positivo foi de 90% e o negativo 87,5%. A histerografia, por sua vez, apresentou sensibilidade de 70%, especificidade de 75%, valor preditivo positivo de 77,7% e valor preditivo negativo de 75%. Conclusão: a histerossonografia parece ser um bom método alternativo para a avaliação da cavidade uterina, identificando algumas lesões não observadas à ultra-sonografia convencional ou à histerografia, e permitindo a triagem das pacientes candidatas à realização de uma histeroscopia diagnóstica ou cirúrgica. A histerografia apresentou resultados inferiores à histerossonografia, e não parece ser de utilidade na triagem das pacientes.

A Histerossonografia na Avaliação da Cavidade Uterina em Pacientes Menopausadas

Objetivos: avaliar a acuidade diagnóstica da histerossonografia como método de avaliação da cavidade uterina em pacientes menopausadas com cavidade uterina alterada à ultra-sonografia endovaginal convencional. Métodos: este estudo consistiu na avaliação de 99 pacientes menopausadas com cavidade uterina anormal à ultra-sonografia endovaginal convencional, caracterizada por espessura endometrial maior ou igual a 5 mm em pacientes sem terapia de reposição hormonal, ou espessura endometrial maior ou igual a 8 mm em pacientes em terapia de reposição hormonal, com sangramento irregular. Estas pacientes foram submetidas à histerossonografia e após, foram obtidas amostras para avaliação histopatológica por biópsia dirigida por histeroscopia em 92 pacientes, biópsia endometrial em quatro pacientes e histerectomia em três pacientes. Os resultados da histerossonografia foram comparados com os resultados do exame histopatológico, considerado como "padrão-ouro". Resultados: houve oito casos de cavidade uterina normal e 20 casos de atrofia endometrial e a histerossonografia teve altos níveis de especificidade (97,8 e 97,5%) e baixa sensibilidade (35 e 25%). Houve altos níveis de sensibilidade (92,3 e 75,0%) e especificidade (94,1 e 97,9%) em pólipos (65 casos) e miomas submucosos (quatro casos). Houve três casos de câncer de endométrio e a histerossonografia teve sensibilidade e especificidade de 100%. Conclusões: a histerossonografia mostrou boa acuidade no diagnóstico de doenças focais (pólipos endometriais e miomas submucosos), com altos níveis de sensibilidade e especificidade. Houve três casos de câncer endometrial, e a histerossonografia diagnosticou corretamente todos eles. Mostrou também ser método acurado para excluir anormalidades endometriais. Entretanto, nos casos de espessamento endometrial difuso, a acuidade é baixa, porque endométrios atróficos ou normais freqüentemente aparecem como tendo espessamento difuso à ultra-sonografia endovaginal e à histerossonografia. A histerossonografia não teve complicações durante e após o procedimento.

Comparação entre os achados ultra-sonográficos, histeroscópicos e histopatológicos no sangramento uterino da pós-menopausa

OBJETIVOS: Determinar a associação entre os achados ultra-sonográficos, histeroscópicos e histopatológicos em mulheres com sangramento uterino na pós-menopausa. MÉTODOS: realizou-se estudo descritivo, retrospectivo, tipo transversal, incluindo 156 pacientes com sangramento uterino na pós-menopausa atendidas no Centro Diagnóstico do Instituto Materno-Infantil de Pernambuco no período de janeiro de 1995 a dezembro de 2001. Os resultados ultra-sonográficos foram classificados como anormais ou normais, de acordo com os pontos de corte de 4 e 5 mm. Determinou-se a freqüência dos principais achados histeroscópicos e histopatológicos destas mulheres, categorizados como lesões pré-malignas/malignas (hiperplasias/câncer) e lesões benignas. Determinou-se ainda a concordância entre os achados histeroscópicos e histopatológicos. RESULTADOS: a freqüência de espessamento do eco endometrial de acordo com os pontos de corte de 4 mm e 5 mm foi de 75% e de 67,3%, respectivamente. O achado histeroscópico mais freqüente foi o endométrio atrófico (37,8%), seguindo-se os pólipos endometriais (35,9%), hiperplasia do endométrio (10,9%), câncer de endométrio (10,3%), endométrio funcionante (30.2%) e outros achados (1,9%). Em relação aos achados histopatológicos, observou-se também maior freqüência do endométrio atrófico (31,4%), seguindo-se os pólipos endometriais (26,3%), material insuficiente (16,0%), câncer de endométrio (10,9%), hiperplasia (9,0%) e outros achados (6,4%). Observou-se associação estatisticamente significante entre espessamento endometrial e presença de lesões pré-malignas e malignas. Observou-se um único caso de malignidade em pacientes com ponto de corte de 5 mm, e nenhum caso foi evidenciado com o ponto de corte de 4 mm. Encontrou-se uma boa taxa de concordância entre os achados histeroscópicos e histopatológicos (kappa = 0,61). CONCLUSÕES: a freqüência de eco endometrial espessado foi de 75% e de 67,3% com os pontos de corte de 4 mm e 5 mm, respectivamente. Nenhum caso de lesão pré-maligna ou maligna foi observado quando foi adotado o ponto de corte de 4 mm. Os achados histeroscópicos e histopatológicos mais freqüentes foram o endométrio atrófico e os pólipos endometriais, observando-se boa taxa de concordância entre esses exames.

Avaliação histológica de pólipos endometriais em mulheres após a menopausa e correlação com o risco de malignização

OBJETIVOS: caracterizar histologicamente pólipos endometriais em mulheres após a menopausa e avaliar o risco de lesões hiperplásicas e neoplásicas neles contidos. MÉTODOS: análise retrospectiva de 82 casos de mulheres portadoras de histopatologia confirmatória de pólipo endometrial, submetidas à polipectomia histeroscópica devido ao diagnóstico de espessamento endometrial à ultra-sonografia transvaginal. Todos os prontuários pertinentes foram revisados para obtenção da história clínica, antecedentes, dados referentes ao exame histeroscópico e resultado final da histopatologia. RESULTADOS: das 82 mulheres avaliadas, 10,9% faziam uso de algum tipo de terapia hormonal e 28 (34,1%) queixavam-se de sangramento por via vaginal. Pólipo solitário foi encontrado em 56 mulheres (68,3%), em 19 casos (23,2%) foram encontrados dois pólipos e em 7 casos (3,6%), três ou mais pólipos. A avaliação histológica definitiva evidenciou pólipo benigno em 63 mulheres (76,8%), pólipos com hiperplasia em 17 casos (20,8%), sendo dez com hiperplasia simples sem atipias (12,2%) e sete com hiperplasia complexa sem atipias (8,6%). Em dois pólipos foi encontrada neoplasia associada (2,4%). Para a análise estatística foi empregado o teste do chi2, corrigido por Yates. Correlacionou-se a histologia dos pólipos com a presença ou não de sangramento genital (p=0,0056), o número de pólipos encontrados por mulher (p=0,921), e o tempo decorrido após a menopausa (p=0,720). CONCLUSÕES: pólipos endometriais são entidades freqüentemente encontradas após a menopausa, associando-se com baixa freqüência a hiperplasias e carcinomas endometriais e apenas o estudo histológico de todo espécime nos permite afastar malignidade.

Prevalence of endometrial cancer and hyperplasia in non-symptomatic overweight and obese women

Background: Obesity is a public health problem and it is necessary to identify if non-symptomatic obese women must be submitted to endometrial evaluation. Aims: To determine the prevalence of endometrial hyperplasia and cancer in non-symptomatic overweight or obese women. Methods: A cross-sectional study was carried out in 193 women submitted to an endometrial biopsy using a Pipelle de Cornier. The findings were classified as normal, hyperplasia or cancer, and the results were compared to body mass index (BMI; kg/m2). For the purpose of statistical analysis, women were divided into two groups: women of reproductive age and postmenopausal women, and according to BMI as overweight or obese. Results: The prevalence of endometrial cancer and hyperplasia was 1.0% and 5.8% in women of reproductive age and 3.0% and 12.1% in postmenopausal women, respectively. According to logistic regression, being in the postmenopause increased the risk of endometrial hyperplasia and cancer to 1.19 (95% confidence interval (CI): 0.36-3.90), while being postmenopausal and severely obese increased the odds ratio (OR) to 1.58 (95%CI: 0.30-8.23) and being postmenopausal and morbidly obese increased the OR to 2.72 (95%CI: 0.65-11.5). No increase in risk was found in women of reproductive age who were either overweight or obese. Discussion: Our results show that non-symptomatic, severe or morbidly obese postmenopausal women have a high risk of developing endometrial hyperplasia or cancer; however, no such risk was found for women of reproductive age.

Endometrial claudin-4 and leukemia inhibitory factor are associated with assisted reproduction outcome

Background: Claudin-4 (CLDN4) is one of several proteins that act as molecular mediators of embryo implantation. Recently, we examined immunolabeling of leukemia inhibitory factor (LIF) in the endometrial tissue of 52 IVF patients, and found that LIF staining intensity was strongly correlated with successful pregnancy initiation. In the same set of patients, we have now examined endometrial CLDN4 expression, to see how expression intensity may vary with LIF. We examined CLDN4 in the luteal phase of the menstrual cycle, immediately preceding IVF treatment. Our aim was to compare expression of LIF and CLDN4 in the luteal phase, and document these patterns as putative biomarkers for pregnancy. Methods: Endometrial tissue was collected from women undergoing IVF. Endometrial biopsies were obtained during the luteal phase preceding IVF, and were then used for tissue microarray (TMA) immunolabeling of CLDN4. Previously published LIF expression data were then combined with CLDN4 expression data, to determine CLDN4/LIF expression patterns. Associations between successful pregnancy after IVF and combined CLDN4/LIF expression patterns were evaluated. Results: Four patterns of immunolabeling were observed in the endometrial samples: 16% showed weak CLDN4 and strong LIF (CLDN4(-)/LIF(+)); 20% showed strong CLDN4 and strong LIF (LIF(+)/CLDN4(+)); 28% showed strong CLDN4 and weak LIF (CLDN4(+)/LIF(-)); and 36% showed weak CLDN4 and weak LIF (CLDN4(-)/LIF(-)). Successful implantation after IVF was associated with CLDN4(-)/LIF(+)(p = 0.003). Patients showing this endometrial CLDN4(-)/LIF(+) immunolabeling were also 6 times more likely to achieve pregnancy than patients with endometrial CLDN4(+)/LIF(-) immunolabeling (p = 0.007). Conclusion: The combined immunolabeling expression of CLDN4(-)/LIF(+) in endometrial tissue is a potential biomarker for predicting successful pregnancy in IVF candidates.

Association between intratumoral lymphatic microvessel density (LMVD) and clinicopathologic features in endometrial cancer: a retrospective cohort study

Background: Lymph node metastasis in endometrial cancer significantly decreases survival rate. Few data on the influence of intratumoral lymphatic microvessel density (LMVD) on survival in endometrial cancer are available. Our aim was to assess the intratumoral LMVD of endometrial carcinomas and to investigate its association with classical pathological factors, lymph node metastasis and survival. Methods: Fifty-seven patients with endometrial carcinoma diagnosed between 2000 and 2008 underwent complete surgical staging and evaluation of intratumoral LMVD and other histologic variables. Lymphatic microvessels were identified by immunohistochemical staining using monoclonal antibody against human podoplanin (clone D2-40) and evaluated by counting the number of immunostained lymphatic vessels in 10 hot spot areas at 400x magnification. The LMVD was expressed by the mean number of vessels in these 10 hot spot microscopic fields. We next investigated the association of LMVD with the clinicopathologic findings and prognosis. Results: The mean number of lymphatic vessels counted in all cases ranged between 0 and 4.7. The median value of mean LMVD was 0.5, and defined the cut-off for low and high LMVD. We identified low intratumoral LMVD in 27 (47.4%) patients and high LMVD in 30 (52.6%) patients. High intratumoral LMVD was associated with lesser miometrial and adnaexal infiltration, lesser cervical and peritoneal involvement, and fewer fatal cases. Although there was lower lymph node involvement among cases with high LMVD, the difference did not reach significance. No association was seen between LMVD and FIGO staging, histological type, or vascular invasion. On the other hand, low intratumoral LMVD was associated with poor outcome. Seventy-five percent of deaths occurred in patients with low intratumoral LMVD. Conclusion: Our results show association of high intratumoral LMVD with features related to more localized disease and better outcome. We discuss the role of lymphangiogenesis as an early event in the endometrial carcinogenesis.

Development of an animal model for endometrial ablation using trichloroacetic acid

Objective: To develop an animal model of endometrial ablation, and to evaluate the histologic effects of trichloroacetic acid (TCA) in the uterine cavity. Design: Experimental prospective. Setting: Department of gynecology. Patient(s): Thirty female adult rats. Intervention(s): Animals were submitted to injection of TCA in one uterine horn and saline solution in the other. Group 1 was sacrificed the day after the procedure. Group 2 was sacrificed in phase of diestrus. Superficial epithelia of the endometrium, stromal thickness, endometrial glands, and myometrium thickness were compared among the uterine horns of the same rats of group 1. The same evaluation was performed in group 2. Endometrial regeneration was evaluated. Main Outcome Measure(s): Histologic effects. Result(s): In group 1, histologic parameters showed endometrial destruction on TCA injected uterine horn. In group 2, four rats died after the procedure, and six rats had no viable material. In the rest of the group, TCA-injected uterine horns showed endometrial destruction. Superficial epithelia of the endometrium and stromal thickness were similar between TCA uterine horn from groups. However, the number of endometrial glands was higher in group 1. Conclusion(s): The study developed an experimental model for endometrial ablation. TCA acid is a potent agent for endometrial ablation in rat model. No endometrial regeneration was observed after recovery of cycle. (Fertil Steril (R) 2011; 95: 2418-21. (C) 2011 by American Society for Reproductive Medicine.)

Endometrial leukemia inhibitory factor as a predictor of pregnancy after in vitro fertilization

Objective: To determine whether there is an association between endometrial expression of leukemia inhibitory factor (LIF) in the luteal phase of the menstrual cycle preceding in vitro fertilization (IVF) and treatment outcome. Methods: Biopsy specimens from the endometria of 52 women in the luteal. phase were immunostained against LIF Embryo culture and transfer were done according to standard procedures. Results: Clinical pregnancy occurred in 39% of the women following IVF, and strong endometrial immunohistochemical staining for LIF was associated with pregnancy (P=0.01). The women with a strong LIF expression had a 6.4-fold higher chance of becoming pregnant than those with weaker intensities (P=0.005). Conclusion: Endometrial expression of LIF during the luteal phase can be used as a predictor of IVF success. (C) 2008 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

Effects of melatonin on the endometrial morphology and embryo implantation in rats

Objective: To determine the effects of melatonin on rat endometrium morphology and embryo implantation. Design: Experimental study. Setting: Federal University of Sao Paulo, Brazil. Animal(s): Forty female rats. Intervention(s): GI: control, GII: sham-operated, GIII: pinealectomized, and GIV: pinealectomized rats that received melatonin during 3 months. The GI, GII, and Gin groups received the vehicle of melatonin (NaCl + ethanol). At the end of the treatment, the animals were killed during the estrous phase; the uterus was removed for morphometric analysis. Urine was collected for 6-sulfatoxymelatonin. Blood was collected for estrogen (E) and progesterone (P) level determinations. In a second experiment, female rats were used to evaluate the endometrial embryo implantation. Main Outcome Measure(s): Endometrial morphology and embryo implantation. Result(s): Gin presented the highest values for endometrial area and thickness index, number of endometrial glands, and eosinophils. The number of vessels of groups I, II, and IV was fewer than that of Gin. The highest number of eosinophils was detected in Gin in comparison to other groups. The implantation rate in Gin was the lowest of all groups. This implantation rate was significantly increased and restored toward normal in GIV. Conclusion(s): Our data suggested that, in nonphotoperiodic animals such as rats, melatonin may positively affect the endometrial morphology and improve embryo implantation.

A standardized measurement technique may improve the reliability of measurements of endometrial thickness and volume

Objective To investigate whether standardization of the multiplanar view (SMV) when evaluating the uterus using three-dimensional ultrasonography (3D-US) improves intra-and interobserver reliability and agreement with regard to endometrial measurement. Methods Two-dimensional (2D) and 3D-US was used to measure endometrial thickness by two observers in 30 women undergoing assisted reproduction treatment. Endometrial volume was measured with Virtual Organ Computer-aided AnaLysis (VOCAL (TM)) in the longitudinal (A) and coronal (C) planes using an unmodified multiplanar view (UMV) and a standardized multiplanar view (SMV). Measurement reliability was evaluated by intraclass correlation coefficient (ICC) and agreement was examined using Bland-Altman plots with limits of agreement (LoA). The ease of outlining the endometrial-myometrial interface was compared between the A-and C-planes using subjective assessment. Results Endometrial volume measurements using the SMV and A-plane were more reliable (intra-and interobserver ICCs, 0.979 and 0.975, respectively) than were measurements of endometrial thickness using 2D-US (intra-and interobserver ICCs, 0.742 and 0.702, respectively) or 3D-US (intra-and interobserver ICCs, 0.890 and 0.784, respectively). The LoAs were narrower for SMV than for UMV. Reliability and agreement were not much different between the A- and C-planes. However the observers agreed that delineating the endometrial-myometrial interface using the A-plane was easier (first and second observer, 50.0 and 46.7%, respectively) or `comparable` (50 and 53.3%, respectively), but never more difficult than using the C-plane. Conclusions Endometrial volume measurements are more reliable than endometrial thickness measurements and are best performed using SMV and the A-plane. Copyright (C) 2011 ISUOG. Published by John Wiley & Sons, Ltd.

Calpain5 expression is decreased in endometriosis and regulated by HOXA10 in human endometrial cells

Calpains have been implicated in the regulation of apoptosis. Here, we identified Calpain5 as a target of HOXA10 transcriptional regulation in endometrial cells as well as its aberrant regulation in endometriosis. Histologically confirmed biopsies of endometriosis were obtained from 20 women. Eutopic endometrium was collected by endometrial biopsy from 30 controls and from the 20 subjects with endometriosis. First trimester decidual samples were obtained from five subjects at the time of pregnancy termination. Immunohistochemistry was used to identify Calpain5 expression. Calpain5 was expressed in endometrial stromal and glandular cells throughout the menstrual cycle and in decidua. Calpain5 protein expression was decreased in both stromal and glandular cells from women with endometriosis compared with that of fertile controls. Human endometrial stromal and epithelial cell lines were transfected with pcDNA/HOXA10, HOXA10 siRNA or respective controls. Quantitative real-time RT-PCR was performed to determine expression of HOXA10 and Calpain5 in each group. Transfection of HESC cells with an HOXA10 expression construct led to increased Calpain5 expression, whereas transfection with siRNA resulted in decreased expression. In conclusion, Calpain5 expression is regulated by HOXA10. Calpain5 expression was decreased in endometriosis likely as a result of decreased HOXA10 expression. Decreased apoptosis in endometrial cells may promote the development of endometriosis through a pathway involving HOXA10, Calpain5 and caspase.