Browsing by Subject "Endometriosis"

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    A GFP endometriosis model reveals important morphological characteristics of the angiogenic process that govern benign and malignant diseases
    (F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Machado, Daniel Escorsim; Júnior, Antônio Palumbo; Santos, João Marcos; Mattos, Rômulo Medina; dos Santos, Thiago Alves; Seabra, Sergio Henrique; Boldrini, Leonardo da Cunha; Machado, Jamila Alessandra Perini; Nasciutti, Luiz Eurico
    Endometriosis involves the growth of endometriotic tissue outside the uterine cavity, and is frequently associated with different malignancies. A well-reported alteration in the disease microenvironment is the proliferation of new blood vessels around the lesions, as part of a necessary repertory to contribute to the invasiveness and development of infiltrating endometriosis. Therefore, the establishment of a reliable experimental model is essential to elucidate the contribution of angiogenesis and to develop new therapeutic approaches to endometriosis treatment. For this purpose we transplanted endometrial fragments from green fluorescent protein (GFP)-mice (n=20) into the peritoneal cavity of wild-type mice (n=20), and then analyzed the morphological changes and the process of angiogenesis. The lesions were cystic and vascularized, and showed morphological hallmarks such as endometrial glands and stroma. An increase in endometriotic lesion vascular density was revealed by immunostaining and RNAm expression for Vegf and its receptor Flk-1, and the lesions were confirmed as a tissue-donor source by GFP fluorescent cells. The same pattern was observed through staining of activated macrophages and an increase of about 25% in the number of macrophage-positive cells was also demonstrated in endometriotic lesions by flow cytometry, which concords with previous data that correlate endometriosis, angiogenesis and inflammation. According to our understanding, this is the first demonstration that the pattern of the angiogenic process in the GFP endometriosis model is very similar to that of cancer. These observations will be useful for investigation of the process of angiogenesis involved in the attachment and invasion of endometrial cells, as well as an in vivo platform model to study the effects of antiangiogenic drugs.
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    Aberrant levels of Wnt/β-catenin pathway components in a rat model of endometriosis
    (Universidad de Murcia. Departamento de Biología Celular e Histología, 2016) Medina de Mattos, Rômulo; Rodrigues Pereira, Paula; Gouvêa de Oliveira Barros, Eliane; Henriques da Silva, Julianna; Yelimar Palmero, Celia; Meireles da Costa, Nathália; Ribeiro Pinto, Luis Felipe; Rodrigues Pereira Gimba, Etel; Hecht, Fábio; Bueno Ferreira, Luciana; Escorsim Machado, Daniel; Leite de Oliveira, Felipe; Eurico Nasciutti, Luiz
    Endometriosis is a benign gynecological disease affecting approximately 10-15% of women of reproductive age and 25-50% of all infertile women. It is characterized by the presence of glands and/or endometrial stroma outside the uterine cavity. Angiogenesis is a crucial process for the development and maintenance of endometriotic lesions. The Wnt/βcatenin pathway is a major promoter of angiogenesis in both physiological and pathological conditions. In the present study, we evaluated the expression of molecules related to the Wnt/β-catenin pathway in a rat model of peritoneal endometriosis. mRNA analyses showed significantly increased expression of Wnt4 and Wnt7b and decreased expression of Gsk3beta and E-cadherin in endometriotic lesions. However, there were no differences in β-catenin and Fzd2 mRNA expression. In addition, we observed a significant increase of nuclear β-catenin in endometriotic lesions, a hallmark of Wnt/ β -catenin pathway activation. Stromal β-catenin staining was found in 45.4% of endometrial tissues and 77.8% of endometriotic lesions. β-catenin nuclear localization was found in 18.2% of the endometrial tissues and 33.3% of endometriotic lesions. Finally, the expression of galectin-3, a regulator of this pathway, was increased in endometriosis. In summary, this pattern of Wnt/βcatenin components expression suggests an increased activity of this pathway in endometriosis.
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    Accuracy of anogenital distance and anti-Müllerian hormone in the diagnosis of endometriosis without surgery
    (Wiley, 2019) Sánchez-Ferrer María L.; Jiménez-Velázquez, Raquel; Mendiola, Jaime; Prieto-Sánchez, María T.; Cánovas-López, Laura; Carmona-Barnosi, Ana; Corbalán-Biyang, Shiana; Hernández-Peñalver, Ana I.; Adoamnei, Evdochia; Nieto, Aníbal; Torres-Cantero, Alberto M.; Cirugía, Pediatría y Obstetricia y Ginecología; ciencias sociosanitarias
    Objective: To assess the predictive ability of a combination of anogenital distance (AGD) and anti-Müllerian hormone (AMH) to diagnosis the presence of endometriosis without surgery. Methods: The present study included women diagnosed with endometriosis and a control group who attended the "Virgen de la Arrixaca" University Hospital, Murcia, Spain, between September 1, 2014, and May 31, 2015. Serum concentrations of AMH were measured, and two AGD measurements were obtained: from the anterior clitoral surface to the upper verge of the anus (AGDAC ), and from the posterior fourchette to the upper verge of the anus (AGDAF ). Data were assessed by receiver operator characteristic (ROC) curves. Results: Women in the endometriosis group (n=57) had significantly shorter AGDAF (22.8 ± 4.6 vs 27.2 ± 5.7 mm; P<0.001) and lower AMH (2.2 ± 2.5 vs 3.3 ± 1.9 ng/mL; P<0.003) compared with the control group (n=93). Women with serum AMH below the clinical cut-off (1 ng/mL) were 17.40-times more likely to have endometriosis (95% confidence interval [CI] 5.64-53.82). The area under the ROC curve of combined AMH and AGDAF was 0.77 (95% CI 0.70-0.85). Conclusion: The model for predicting endometriosis on the basis of AMH and AGD could be useful for clinicians and epidemiologists to improve diagnosis and prognosis of this condition.
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    Brassica bioactives could ameliorate the chronic inflammatory condition of Endometriosis
    (MDPI, ) García Ibánez, Paula; Yepes Molina, Lucía; Ruiz Alcaraz, Antonio José; Martínez Esparza, M.; Moreno, Diego A.; Carvajal, Micaela; García Peñarrubia, Pilar; Bioquímica y Biología Molecular B e Inmunología
    Endometriosis is a chronic, inflammatory, hormone-dependent disease characterized by histological lesions produced by the presence of endometrial tissue outside the uterine cavity. Despite the fact that an estimated 176 million women are a ected worldwide by this gynecological disorder, risk factors that cause endometriosis have not been properly defined and current treatments are not e cient. Although the interaction between diet and human health has been the focus of many studies, little information about the correlation of foods and their bioactive derivates with endometriosis is available. In this framework, Brassica crops have emerged as potential candidates for ameliorating the chronic inflammatory condition of endometriosis, due to their abundant content of health-promoting compounds such as glucosinolates and their hydrolysis products, isothiocyanates. Several inflammation-related signaling pathways have been included among the known targets of isothiocyanates, but those involving aquaporin water channels have an important role in endometriosis. Therefore, the aim of this review is to highlight the promising e ects of the phytochemicals present in Brassica spp. as major candidates for inclusion in a dietary approach aiming to improve the inflammatory condition of women a ected with endometriosis. This review points out the potential roles of glucosinolates and isothiocyanates from Brassicas as anti-inflammatory compounds, which might contribute to a reduction in endometriosis symptoms. In view of these promising results, further investigation of the e ect of glucosinolates on chronic inflammatory diseases, either as diet coadjuvants or as therapeutic molecules, should be performed. In addition, we highlight the involvement of aquaporins in the maintenance of immune homeostasis. In brief, glucosinolates and the modulation of cellular water by aquaporins could shed light on new approaches to improve the quality of life for women with endometriosis.
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    Distancia anogenital : un nuevo biomarcador de endometriosis
    (2016-02-08) Canóvas López, Laura; Sánchez Ferrer, María Luisa; Torres Cantero, Alberto Manuel; Departamento de Ciencias Sociosanitarias
    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.
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    Distancia anogenital como marcador antropométrico de origen prenatal de endometriosis
    (Universidad de Murcia, 2019-05-03) Jiménez Velázquez, Raquel; Sánchez Ferrer, María Luisa; Mendiola Olivares, Jaime; Escuela Internacional de Doctorado
    Introducción: La endometriosis es una enfermedad estrógeno dependiente definida como la presencia de tejido endometrial funcionalmente activo fuera de la cavidad uterina. Puede afectar a diferentes órganos pero fundamentalmente afecta a los ovarios. Existe diferentes formas de endometriosis que incluyen endometriosis ovárica (endometriomas), endometriosis profunda (DIE) y endometriosis con implantes superficiales. La endometriosis tiene una prevalencia aproximada del 10%, afectando a entre el 4 y 30% de mujeres en edad reproductiva. Está asociada a infertilidad, puesto que entre el 30 y el 50% de las mujeres con endometriosis presentan problemas reproductivos. La distancia anogenital (DAG) es la distancia comprendida entre el ano y los genitales externos. Se trata de un dimorfismo sexual característico de los mamíferos placentarios y es considerado un marcador de desarrollo genital que refleja la exposición hormonal a la que el feto ha estado expuesto durante su desarrollo intrauterino, concretamente en el periodo conocido como ventana crítica de crecimiento genital, y se correlaciona con la DAG en la vida adulta. La hormona antimülleriana (AMH) parece ser, en la actualidad, el mejor marcador bioquímico de la función ovárica, debido a su capacidad para reflejar el número de folículos antrales y preantrales presentes en los ovarios. Se utiliza para evaluar la respuesta a la estimulación ovárica en técnicas de reproducción asistida, el daño iatrogénico en la cirugía ovárica y estimar la llegada de la menopausia. También se ha utilizado como biomarcador de seguimiento para mujeres con endometriosis grave confirmada histológicamente (estadios III-IV). El objetivo general de esta tesis es estudiar la DAG como marcador antropométrico de origen prenatal de la endometriosis. Material y Método: Se realizó un estudio observacional de casos y controles en el Servicio de Ginecología del Hospital Clínico Universitario Virgen de la Arrixaca en Murcia (España), entre el 1 de septiembre de 2014 y 31 de mayo del 2015. El grupo de los casos estaba formado por mujeres diagnosticadas de endometriosis mediante historia clínica y ecografía transvaginal en la Unidad de Endometriosis del Servicio, y el grupo control estaba formado por mujeres sin endometriosis seleccionadas de la consulta de ginecología de dicho hospital. En ambos grupos se realizaron análisis de AMH en suero sanguíneo y mediciones de la DAG: desde el capuchón clitoiroideo hasta el margen superior anal (DAGAC), y desde el introito, concretamente en la horquilla vulvar hasta el margen superior del ano (DAGAF). Se realizaron análisis estadísticos para estimar la asociación entre la DAG y la presencia de endometriomas y/o DIE, así como su utilidad clínica como prueba diagnóstica, además de la asociación entre la DAG y niveles de AMH con la presencia de endometriosis en pacientes no operadas de endometriosis. Resultados: En el primer trabajo la DAGAF se relacionó con la presencia de endometriosis y/o DIE. Las mujeres en el tercil inferior de la distribución total de DAGAF mostraron más riesgo de sufrir endometriosis en comparación con las del tercil superior: OR=7.6 (IC95%: 2.8-21.0; p de tendencia = 0.001). Con respecto a la DIE, las mujeres con AGDAF por debajo de la mediana mostraron un riesgo mayor de padecer endometriosis en comparación con las que tenían AGDAF por encima de la mediana con una OR=41.6 (IC95%: 3.9-438; valor de p = 0.002). En el segundo trabajo la DAGAF, pero no la DAGAC, se asoció con la presencia de endometriomas, DIE o ambas (valores de p entre <0.001–0.02). El área bajo la curva más alta (0.91; IC95%: 0.84-0.97) se obtuvo para el subgrupo de DIE con la medición DAGAF, con una sensibilidad y especificidad del 84.4% y 91.4%, respectivamente. En el tercer trabajo las pacientes en el grupo de endometriosis no operadas (n=57) tuvieron una DAGAF significativamente más corta (22.8 ± 4.6 vs 27.2 ± 5.7 mm; valor de p <0.001) y una AMH menor (2.2 ± 2.5 vs 3.3 ± 1.9 ng/mL; valor de p <0.003) en comparación con el grupo control (n=93). Las mujeres con una AMH sérica por debajo del límite clínico (1 ng/ml) presentaron 17.4 veces más riesgo de tener endometriosis (IC95%: 5.64-53.82). El área bajo la curva ROC de AMH y AGDAF combinadas fue de 0.77 (IC95%: 0.70-0.85) para el diagnóstico de endometriosis. Conclusiones: Nuestros resultados proporcionan la primera evidencia publicada de una asociación significativa entre un marcador de un ambiente prenatal hormonal (DAG) en mujeres y la presencia de endometriomas y DIE. Esto sugiere que el medio hormonal intrauterino podría desempeñar un papel importante en el desarrollo de la endometriosis, pudiendo tener ésta un origen prenatal. La DAGAF podría discriminar eficientemente la presencia de DIE y ser una herramienta clínica útil en su prevención, diagnóstico y práctica clínica. Además, el estudio de la DAGAF junto con los niveles séricos de AMH podría predecir la presencia de endometriosis con un mayor rendimiento que ambos parámetros por separado y complementar a las técnicas de imagen (ecografía, RMN) para evitar recurrir a un diagnóstico invasivo. SUMMARY Introduction: Endometriosis is a estrogen-dependent disease defined as the presence of endometrial glands and stroma outside the uterus. It can damage many organs, but the most frequently affected one is the ovary. There are different types of endometriosis including endometriotic cyst (endometriomas), deep infiltrating endometriosis (DIE), and superficial implants. Endometriosis has a prevalence of approximately 10%, affecting 4-30% of women of reproductive age, and is usually associated with infertility. Between 30% and 50% of women with endometriosis have reproductive problems; this percentage rises to 70%-80% if pelvic pain is present. The anogenital distance (AGD) is the distance between the anus and the external genitalia. It is a sexual dimorphism feature in placental mammals, and is considered a biomarker of genital development that reflects hormonal exposure during prenatal life, specifically in the period known as critical window of genital growth, and predicts AGD in adulthood. The antimülleriana hormone (AMH) seems to be the best biochemical marker of ovarian function, owing to its ability to reflect the number of antral and pre-antral follicles present in the ovaries. It has been applied to various clinical situations, such as monitoring the response to ovarian stimulation in assisted reproductive techniques, timing of menopause, and iatrogenic damage of the ovarian follicle reserve. It has also been used to assess ovarian reserve depletion after surgery for endometriomas, and as follow-up biomarker for women with histologically confirmed severe endometriosis (stages III-IV). The general aim of this thesis is to evaluate AGD as an anthropometric biomarker of prenatal origin of endometriosis. Material & Methods: An observational case-control study was conducted between September 2014 and May 2015 at the Department of Obstetrics and Gynecology of the ‘Virgen de la Arrixaca’ University Clinical Hospital in Murcia (Spain). Cases were women diagnosed with endometriosis by clinical history and transvaginal ultrasound at the Endometriosis Unit of the Hospital. The Control group included women without endometriosis attending the gynecological outpatient clinic for routine examinations. In both groups, blood serum AMH levels and DAG measurements were obtained: AGDAC, from clitoral surface to the upper verge of the anus; and AGDAF, from the posterior fourchette to the upper verge of the anus. Statistical analyses were performed to estimate associations between AGD and the presence of endometriomas and/or DIE, as well as a diagnostic tool in endometriosis, in addition to assess the combined ability of AGD and AMH to detect endometriosis in non-operated patients. Results: In the first article, AGDAF was associated with the presence of endometriosis and/or DIE. Women in the lower tertile of the AGDAF total distribution showed higher risk of endometriosis compared with the upper tertile: OR=7.6 (95% CI: 2.8-21.0, p-trend=0.001). With regard to the DIE, women with AGDAF below the median showed a higher risk of endometriosis compared with AGDAF above the median with an OR=41.6 (95% CI: 3.9-438; p-value=0.002). In the second article, AGDAF, but not AGDAC, was associated with the presence of endometriomas, DIE, or both (p-values <0.001-0.02). The highest area under curve (0.91, 95% CI: 0.84-0.97) was obtained for the DIE subgroup with the AGDAF measurement, with a sensitivity and specificity of 84.4% and 91.4%, respectively. In the third article, women in the non-operated endometriosis group (n=57) had a significantly shorter AGDAF (22.8 ± 4.6 vs 27.2 ± 5.7 mm, p value <0.001) and a lower AMH (2.2 ± 2.5 vs 3.3 ± 1.9 ng/mL; p value <0.003) compared with the control group (n=93). Women with serum AMH levels below the clinical cut-off (1 ng/ml) were 17.4 times more likely to have endometriosis (95%CI: 5.64-53.82). The area under the ROC curve of combined AMH and AGDAF was 0.77 (95%CI: 0.70-0.85) for the diagnosis of endometriosis. Conclusions: Our results provide the first evidence of a strong association between a biomarker of hormonal prenatal environment (AGD) in women and the presence of endometriomas and DIE. This suggests that the intrauterine hormonal milieu might play an important role in the development of endometriosis, which may have a prenatal origin. The AGDAF could efficiently discriminate the presence of DIE and be an useful clinical tool in its prevention, diagnosis and clinical practice. In addition, our study has shown than AGDAF and serum AMH levels can be combined in a model to predict endometriosis with a higher performance than both parameters separately and enhance imaging techniques (ultrasound, MRI) to avoid invasive diagnosis.
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    Hypothetical roadmap towards endometriosis: prenatal endocrine- disrupting chemical pollutants exposure, anogenital distance, gut-genital microbiota and subclinical infections.
    (Oxford University Press, 2020-02) Martínez-Esparza, M.; Ruiz-Alcaraz, Antonio J.; Marín, Pilar; Machado-Linde, Francisco; Bioquímica y Biología Molecular B e Inmunología
    Background: Endometriosis is a gynaecological hormone-dependent disorder that is defined by histological lesions generated by the growth of endometrial-like tissue out of the uterus cavity, most commonly engrafted within the peritoneal cavity, although these lesions can also be located in distant organs. Endometriosis affects ~10% of women of reproductive age, frequently producing severe and, sometimes, incapacitating symptoms, including chronic pelvic pain, dysmenorrhea and dyspareunia, among others. Furthermore, endometriosis causes infertility in ~30% of affected women. Despite intense research on the mechanisms involved in the initial development and later progression of endometriosis, many questions remain unanswered and its aetiology remains unknown. Recent studies have demonstrated the critical role played by the relationship between the microbiome and mucosal immunology in preventing sexually transmitted diseases (HIV), infertility and several gynaecologic diseases. Objective and rationale: In this review, we sought to respond to the main research question related to the aetiology of endometriosis. We provide a model pointing out several risk factors that could explain the development of endometriosis. The hypothesis arises from bringing together current findings from large distinct areas, linking high prenatal exposure to environmental endocrine-disrupting chemicals with a short anogenital distance, female genital tract contamination with the faecal microbiota and the active role of genital subclinical microbial infections in the development and clinical progression of endometriosis. Search methods: We performed a search of the scientific literature published until 2019 in the PubMed database. The search strategy included the following keywords in various combinations: endometriosis, anogenital distance, chemical pollutants, endocrine-disrupting chemicals, prenatal exposure to endocrine-disrupting chemicals, the microbiome of the female reproductive tract, microbiota and genital tract, bacterial vaginosis, endometritis, oestrogens and microbiota and microbiota-immune system interactions. Outcomes: On searching the corresponding bibliography, we found frequent associations between environmental endocrine-disrupting chemicals and endometriosis risk. Likewise, recent evidence and hypotheses have suggested the active role of genital subclinical microbial infections in the development and clinical progression of endometriosis. Hence, we can envisage a direct relationship between higher prenatal exposure to oestrogens or estrogenic endocrine-disrupting compounds (phthalates, bisphenols, organochlorine pesticides and others) and a shorter anogenital distance, which could favour frequent postnatal episodes of faecal microbiota contamination of the vulva and vagina, producing cervicovaginal microbiota dysbiosis. This relationship would disrupt local antimicrobial defences, subverting the homeostasis state and inducing a subclinical inflammatory response that could evolve into a sustained immune dysregulation, closing the vicious cycle responsible for the development of endometriosis. Wider implications: Determining the aetiology of endometriosis is a challenging issue. Posing a new hypothesis on this subject provides the initial tool necessary to design future experimental, clinical and epidemiological research that could allow for a better understanding of the origin of this disease. Furthermore, advances in the understanding of its aetiology would allow the identification of new therapeutics and preventive actions.
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    Insights into iron and nuclear factor-kappa B (NF-κB) involvement in chronic inflammatory processes in peritoneal endometriosis
    (Murcia: F. Hernández y J.F. Madrid, Universidad de Murcia, Departamento de Biología Celular e Histología, 2011) Defrère, Sylvie; González-Ramos, Reinaldo; Lousse, Jean-Christophe; Colette, Sébastien; Donnez, Olivier; Donnez, Jacques; Van Langendonckt, Anne
    Endometriosis is a chronic pelvic inflammatory process. Local inflammation is known to play a role in pain and infertility associated with the disease, and may be extensively involved in molecular and cellular processes leading to endometriosis development. In this review, we focus on two inflammatory mediators clearly implicated in the pathogenesis of endometriosis, iron and NF-κB, and their potential association. Iron is essential for all living organisms, but excess iron results in toxicity and is linked to pathological disorders. In endometriosis patients, iron overload has been demonstrated in the different compartments of the peritoneal cavity (peritoneal fluid, endometriotic lesions, peritoneum and macrophages). This iron overload affects numerous mechanisms involved in endometriosis development. Moreover, iron can generate free radical species able to react with a wide range of cellular constituents, inducing cellular damage. Overproduction of reactive oxygen species also impairs cellular function by altering gene expression via regulation of redox-sensitive transcription factors such as NF-κB, which is clearly implicated in endometriosis. Indeed, NF-κB is activated in endometriotic lesions and peritoneal macrophages of endometriosis patients, which stimulates synthesis of proinflammatory cytokines, generating a positive feedback loop in the NF-κB pathway. NF-κB-mediated gene transcription promotes a variety of processes, including endometriotic lesion establishment, maintenance and development. In conclusion, iron and NF-κB appear to be linked and both are clearly involved in endometriosis development, making these pathways an attractive target for future treatment and prevention of this disease.
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    Involvement of resistance to apoptosis in the pathogenesis of endometriosis
    (Murcia : F. Hernández, 2009) Nasu, K.; Yuge, A.; Tsuno, A.; Nishida, M.; Narahara, H.
    Endometriosis, a disease affecting 3-10% of women of reproductive age, is characterized by the ectopic growth of endometrial tissue. Increasingly, endometriosis is also becoming recognized as a condition in which ectopic endometrial cells exhibit abnormal proliferative and apoptotic regulation in response to appropriate stimuli. Apoptosis plays a critical role in maintaining tissue homeostasis and represents a normal function to eliminate excess or dysfunctional cells. Accumulated evidence suggests that, in healthy women, endometrial cells expelled during menstruation do not survive in ectopic locations because of programmed cell death, while decreased apoptosis may lead to the ectopic survival and implantation of these cells, resulting in the development of endometriosis. Both the inability of endometrial cells to transmit a ‘death’ signal and the ability of endometrial cells to avoid cell death have been associated with increased expression of anti-apoptotic factors and decreased expression of pre-apoptotic factors. This paper is a review of the recent literature focused on the differential expression of apoptosisassociated molecules in the normal endometria of women without endometriosis, and in the eutopic and ectopic endometria of women with endometriosis. The role of apoptosis in the pathogenesis of endometriosis and the basic and clinical research on the current medical treatment for endometriosis from the view of apoptosis will be discussed.
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    New potential pharmacological options for endometriosis associated pain
    (MDPI, 2024-06-27) Martínez-Esparza, M.; García-Izquierdo, Laura; Marín-Sánchez, Pilar; García-Peñarrubia, Pilar; Bioquímica y Biología Molecular B e Inmunología
    Endometriosis is a chronic inflammatory disorder characterized by the abnormal growth of endometrial-like tissue outside the uterine cavity, affecting 10–15% of women of reproductive age. Pain is the most common symptom. Treatment options include surgery, which has limited ef fectiveness and high recurrence rates, and pharmacotherapy. Hormonal therapies, commonly used for symptom management, can have side effects and contraceptive outcomes, contributing to the infertility associated with endometriosis, with pain and lesions often reappearing after treatment cessation. Among its etiological factors, immunological and inflammatory dysregulation plays a significant role, representing an interesting target for developing new therapeutic strategies. This review critically analyzes recent studies to provide an updated synthesis of ongoing research into potential new pharmacotherapies focusing on lesion progression, pain relief, and improving quality of life. Immunotherapy, natural anti-inflammatory and antioxidant compounds and drug repurpos ing show promise in addressing the limitations of current treatments by targeting immunological factors, potentially offering non-invasive solutions for managing pain and infertility in endometri osis. Promising results have been obtained from in vitro and animal model studies, but clinical trials are still limited. More effort is needed to translate these findings into clinical practice to effectively reduce disease progression, alleviate pain symptoms and preserve the reproductive capacity, im proving patients’ overall wellbeing.
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    Optimization of peritoneal fluid and leukocyte collection in patients with endometriosis
    (ELSEVIER, 2023-10-04) Martínez-Esparza, M.; Ramirez-Pavez, Tamara N.; Machado-Linde, Francisco; García-Peñarrubia, Pilar; Nieto-Meca, Lucía; Marín-Sánchez, Pilar; Bioquímica y Biología Molecular B e Inmunología
    Objective: To propose a standardized protocol for peritoneal free fluid and leukocyte sample collection in women with endometriosis suitable for biomedical research on the basis of the surgical procedure, the clinical and technical conditions, and the quality of the samples obtained. Design: Video showing the step-by-step collection procedure and the suitability of samples obtained for biomedical research. Subjects: This study included 103 women with confirmed endometriosis by pathology analysis, who signed informed consent and were recruited from the Hospital ‘‘Virgen de la Arrixaca’’, Murcia, Spain. The study was approved by the Ethics Committee of University of Murcia (CEI 3156/2020). Main Outcome Measures: We analyzed the presence of free fluid in the peritoneal cavity and its relationship with hormonal treatment intake. In addition, the presence of blood contamination, the number of viable leukocytes and macrophages in free peritoneal fluid and lavages as well as their relationship with the lavage volume used, the body mass index, and the age of patients were analyzed. Results: The presence of free peritoneal fluid, in which cells and molecules could be quantified, was scarce in the patients (21%), and it was not significantly related to hormonal treatment intake. The cell viability was higher than 98% in all collected samples; although 54% showed good quality and enough cellularity to be used in biomedical research, 40% were contaminated with blood and 6% had low cellularity. The number of leukocytes and macrophages recovered from the peritoneal lavages correlated positively with the lavage volume used and negatively with the body mass index and was independent of the age of the patients. Conclusion: We describe a standardized step-by-step procedure for peritoneal fluid and leukocyte collection in women with endometriosis, suitable for biomedical research, taking into account that not all women present free fluid in the peritoneal cavity. We propose to increase the lavage volume recommended by the World Endometriosis Research Foundation from 10 mL to at least 40 mL of sterile saline solution and its mobilization for at least 30 seconds within the peritoneal cavity, especially in patients with higher body mass index, to improve the efficiency of the procedure.
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    The biological role of Treg cells in ectopic endometrium homeostasis
    (F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2014) Basta, Pawel; Koper, Krzysztof; Kazmierczak, Wojciech; Wisniewski, Michal; Makarewicz, Adrianna; Dutsch-Wicherek, Magdalena; Kojs, Zbigniew; Popiela, Tadeusz J.; Slusarz, Robert; Dubiel, Mariusz; Wicherek, Lukasz
    Although retrograde menstruation is observed in up to 90% of women, endometriosis actually develops in only15% of women. There is considerable evidence in the literature that ectopic endometrial cells are able to evade immune surveillance and that the immune response in the microenvironment of ectopic lesions is limited. Endometriosis develops when a deficiency in the local immune response has been generated, and progression of the disease is related to the intensity of this process. Over the last couple of decades it has been well known that T regulatory lymphocytes (Tregs) play a crucial role in controlling a variety of physiological and pathological immune responses. In this review we have focused on the physiological alteration of Treg cell infiltration into the endometrium during the reproductive processes of women. We discuss how a disturbance in Treg cell expansion is involved in generating such pathological processes as miscarriage and ectopic pregnancy development. We hypothesize about the role Treg cells might play in the survival of endometriosis foci in ectopic localization and in the evasion of such lesions from host immune surveillance.
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    The ENDO-Study: A qualitative study to assess the impactof a short film on medical students’ understanding andperception of endometriosis.
    (Universidad de Murcia. Servicio de publicaciones, 2025) Piñel Pérez, Carlos Santiago; Alfonso González, Rosendo; Alvarez García, Eva; Durán Somacarrera, Alfonso; Irazola Laguna, Alejandra; Gómez-Roso Jareño, María José; Departamentos
    This study investigates the effectiveness of a short film, END-O, as an educational tool forenhancing medical students' understanding of endometriosis and its impact on patients' quality of life.Endometriosis, a prevalent yet often underdiagnosed condition affecting women, presents significantphysical and emotional challenges. A qualitative approach was employed, involving 23 sixth-year medicalstudents randomly assigned to either a study group (n=11) that viewed the film or a control group (n=12) thatdid not. Following a lecture on endometriosis, both groups completed questionnaires assessing theirunderstanding and perceptions of the disease. The study group demonstrated significantly greaterrecognition of symptoms (p = 0.005) and expressed more detailed insights regarding the disease's impact onlife, including emotional and social dimensions. The findings suggest that the film effectively promotesempathy and a deeper understanding of endometriosis among future healthcare providers, highlighting theimportance of integrating humanistic approaches in medical education. This intervention may contribute toaddressing the critical underdiagnosis and undertreatment of endometriosis
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    The role of peritoneal macrophages in Endometriosis.
    (MDPI, 2021-10-06) Ramírez Pavez, Tamara N.; Martínez Esparza, M.; Ruiz Alcaraz, Antonio J.; Marín Sánchez, Pilar; Machado Linde, Francisco; García Peñarrubia, Pilar; Bioquímica y Biología Molecular B e Inmunología
    Endometriosis is an estrogen-dependent gynecological disorder, defined as the growth of endometrial stromal cells and glands at extrauterine sites. Endometriotic lesions are more frequently located into the abdominal cavity, although they can also be implanted in distant places. Among its etiological factors, the presence of immune dysregulation occupies a prominent place, pointing out the beneficial and harmful outcomes of macrophages in the pathogenesis of this disease. Macrophages are tissue-resident cells that connect innate and adaptive immunity, playing a key role in maintaining local homeostasis in healthy conditions and being critical in the development and sustainment of many inflammatory diseases. Macrophages accumulate in the peritoneal cavity of women with endometriosis, but their ability to clear migrated endometrial fragments seems to be inefficient. Hence, the characteristics of the peritoneal immune system in endometriosis must be further studied to facilitate the search for new diagnostic and therapeutic tools. In this review, we summarize recent relevant advances obtained in both mouse, as the main animal model used to study endometriosis, and human, focusing on peritoneal macrophages obtained from endometriotic patients and healthy donors, under the perspective of its future clinical translation to the role that these cells play on this pathology.
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    Up-regulation of CMKLR1 in endometriosis and its relationship with inflammatory responses
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2023) Zhang, Zhe; Ding, Yumei; Li, Junjie; Su, Shan
    Inflammation plays a critical role in the pathogenesis of endometriosis. We aimed to study the proinflammatory effect of Chemerin chemokine-like receptor 1 (CMKLR1) in patients with endometriosis. Sixty patients with endometriosis and 50 healthy controls were recruited in this study for the collection of endometrial samples and peritoneal fluid. The expression levels of CMKLR1, IL-6, MCP-1, and TNFα in peritoneal fluid and endometrial tissues were detected by ELISA, qRT-PCR, and immunohistochemical staining. Human endometrial stromal cells (HESCs) were used to measure the Chemerin-induced CMKLR1 activation and inflammatory responses. CMKLR1 level was significantly up-regulated in peritoneal fluid and endometrial tissues in patients with endometriosis. Interestingly, CMKLR1 overexpression positively correlated with pro-inflammatory cytokines and chemokine in both peritoneal fluid and ectopic endometrium. Chemerin treatment increased the expression of CMKLR1, and aggravated inflammatory responses in HESCs. CMKLR1 is up-regulated in peritoneal fluid and endometrial tissues, and promotes the inflammatory responses in of endometriosis.