Effects of pharmacological inhibition of hyaluronic acid synthesis on experimental endometriosis.

BACKGROUND: Dysregulated hyaluronic acid (HA) metabolism has been shown to be implicated in several pathologies including endometriosis. 4-Methylumbelliferone (4MU) is an HA synthesis inhibitor with proven antitumour activity. In this study, we aim to evaluate the effect of 4MU on endometriosis development both in vivo and in vitro. METHODS: Endometriosis was surgically induced by uterine tissue auto-transplantation in 32 two-month-old BALB/c mice. Animals were designated into the early or late starting treatment group, which initiated on day 2 or day 15 after surgery, respectively. Within each group, 4MU 200 mg/kg/day or vehicle (Control) were administered by oesophageal gavage for 28 days. After sacrifice, the percentage of developed lesions, lesion size, cell proliferation, vascularization and HA deposition within the endometriotic-like lesions were evaluated. Cell viability was assessed in endometrial epithelial cells (ECC-1) and in endometrial stromal cells (t-HESC); and migration was evaluated in t-HESC. RESULTS: There was a significant reduction in the percentage of developed lesions in mice that started the 4MU treatment on day 2 compared with its respective control group, and compared with those that started treatment on day 15. However, no significant changes were found when analysing endometriotic-like lesion's cell proliferation, vascularization and HA deposition. In vitro, both cell viability and migration were inhibited by 4MU treatment. CONCLUSIONS: The inhibition of HA synthesis could be a beneficial and alternative option to treat endometriosis at the early stage of the disease. Further research is necessary to elucidate 4MU's mechanism of action and better strategies for delivering this promising drug.

Effect of urolithins A and B on ectopic endometrial growth in a murine model of endometriosis.

Endometriosis is an often painful disease in reproductive-aged women, in which endometrial-like tissue grows outside the uterine cavity. Since the limited current therapeutic alternatives fail in alleviating the symptoms and based on our previous research in in vitro models using the same compounds as the ones used in the present study, we aimed to evaluate the effects of urolithins A (UA) and B (UB) on the growth and survival of endometriotic-like lesions in a murine model of endometriosis. Female BALB/C mice were surgically induced with endometriosis and treated with 2.5 mg kg-1 day-1 intraperitoneal UA or UB. The mice were monitored daily and weighed and the estrous stage was determined. After 28 days of treatment, lesions were counted, measured, excised, and fixed. Both urolithins proved not to affect the estrous cycle or body weight of the mice. UA completely prevented endometriotic-like lesions, while UB diminished the implant volume (p < 0.05). Treatment also reduced epithelial and stromal cell proliferation within the implants (p < 0.001 and p < 0.01, respectively) and apoptosis was enhanced (p < 0.05 and p < 0.01, respectively). These results are promising and reveal that urolithins A and B, separately, have a beneficial effect on the overall endometriotic growth without affecting the body weight or estrous cycle.

PI3K/AKT pathway is altered in the endometriosis patient's endometrium and presents differences according to severity stage.

Based on the inflammatory nature and hormone-dependency of endometriosis, PI3K/AKT signaling appears to influence its progression. Could the endometriosis stages be linked to differential changes in PI3K/AKT pathway regulation? The objective is to evaluate the expression of PI3K, PTEN, AKT and p-AKT in endometrial human biopsies, according to the presence or absence of the disease, and to assess the underlying differences regarding the endometriosis stages. Biopsy specimens of the ectopic and eutopic endometrium were obtained from twenty women with untreated peritoneal endometriosis as well as endometrium biopsies from nine controls. Our study revealed an increased expression of PI3K in eutopic and ectopic endometrium from patients with endometriosis, and a reduced expression of PTEN and increased levels of AKT phosphorylation, compared to control endometrium. Both eutopic and ectopic endometrium from patients with minimal-mild endometriosis expressed a significant reduced PTEN level compared to the respective endometrium from patients with moderate-severe endometriosis. The ratio p-AKT/total AKT showed higher levels of AKT phosphorylation in endometriotic tissue from patients with minimal-mild endometriosis. This study has firmly confirmed the alteration in PI3K/AKT pathway regulation and demonstrated clear differences between the stages of endometriosis, emphasizing the importance of this pathway in the first stage of the disease.

Exposure to environmental concentrations of hexachlorobenzene induces alterations associated with endometriosis progression in a rat model.

Hexachlorobenzene (HCB) is a dioxin-like compound widely distributed and is a weak ligand of the aryl hydrocarbon receptor (AhR). Endometriosis is a disease characterized by growth of endometrial tissue in ectopic sites. Our aim was to investigate the impact of HCB on the endocrine, invasion and inflammatory parameters in a rat endometriosis model surgically induced. Female rats were exposed to HCB (1, 10 and 100 mg/kg b.w.) during 30 days. Results showed that HCB increases endometriotic like-lesions (L) volume in a dose-dependent manner. In L, HCB10 increases microvessel density (immunohistochemistry) and the vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2) and AhR levels (Western Blot), while HCB1 enhances aromatase expression (Western Blot). In addition, in eutopic endometrium (EU), HCB10/HCB100 augments microvessel density, VEGF and MMP-9 expression, while HCB1/HCB10 increases tumor necrosis factor-α (TNF-α) content in peritoneal fluid (ELISA). Interestingly, both L and EU from HCB-treated rats exhibited higher estrogen receptor α (ERα) (immunohistochemistry) and metalloproteases (MMP)-2 and -9 levels (Western Blot), as well as lower progesterone receptor (PR) expression (immunohistochemistry) than in control rats. Environmentally relevant concentrations of HCB could contribute to abnormal changes associated with endometriosis progression and development.

Active compounds present inRosmarinus officinalis leaves andScutellaria baicalensis root evaluated as new therapeutic agents for endometriosis.

RESEARCH QUESTION: Can carnosic acid, (CA) rosmarinic acid (RA) and wogonin (WG) inhibit the growth of cultured human endometrial stromal cells and endometriotic-like lesions induced in a BALB/c model of endometriosis? DESIGN: Primary stromal cell cultures were established from endometrial biopsies from women with endometriosis and controls. The human endometrial stromal cell line T-HESC was also used for in-vitro experiments. Endometriosis was surgically induced in BALB/c mice, which were randomly assigned to CA 2 mg/kg/day (n = 11); CA 20 mg/kg/day (n = 10); RA 1 mg/kg/day (n = 11); RA 3 mg/kg/day (n = 10); WG 20 mg/kg/day (n = 12); intraperitoneal vehicle control (n = 8) or oral vehicle control (n = 11). After surgery, CA and RA were administered intraperitoneally on days 14-28. WG was administered orally by intragastric gavage on days 14-26. RESULTS: CA, RA and WG significantly inhibited in-vitro cell proliferation in primary and T-HESC cell cultures (P < 0.05). CA and WG induced cell cycle arrest of T-HESC at the G2/M phase (P < 0.01). RA reduced intracellular ROS accumulation (P < 0.001), whereas WG increased it (P < 0.05). WG significantly inhibited oestrogen receptor alpha expression in T-HESC (P < 0.01). In-vivo, CA, RA and WG significantly reduced lesions size (P < 0.05). All compounds significantly decreased the percentage of cells in proliferation (P < 0.05) whereas RA and WG further increased the percentage of apoptotic cells (P < 0.05) in endometriotic-like lesions. CONCLUSIONS: The results are promising; further investigation of these compounds as new therapeutics is needed.

Interplay between Endometriosis and Pregnancy in a Mouse Model.

OBJECTIVES: To evaluate the effect of endometriosis on fertility and the levels of the IL-2 and IFN-γ in the peritoneal fluid in a mouse model; to evaluate the effect of pregnancy on endometriotic lesion growth, apoptosis and cell proliferation. STUDY DESIGN: Two month old C57BL/6 female mice underwent either a surgical procedure to induce endometriosis or a sham surgery. Four weeks after surgery mice were mated and sacrificed at day 18 of pregnancy. Number of implantation sites, fetuses and fetal weight were recorded. Endometriotic lesions were counted, measured, excised and fixed. Apoptosis and cell proliferation were evaluated in lesions by TUNEL and immunohistochemistry for PCNA respectively. Levels of IL-2 and IFN-γ were assessed by ELISA in the peritoneal fluid. RESULTS: Pregnancy rate (i.e. pregnant mice/N) decreased in mice with endometriosis. However there were no significant differences in resorption rate, litter size and pup weight between groups. IFN-γ augmented in endometriosis mice independently of pregnancy outcome. Additionally IFN-γ increased in pregnant endometriosis mice compared to pregnant sham animals. While IFN-γ increased in non pregnant versus pregnant mice in the sham group, IL-2 was increased in non pregnant mice in the endometriosis group. The size of endometriotic lesions increased in pregnant mice while apoptosis increased in the stroma and cell proliferation decreased in the epithelium of these lesions. Additionally, leukocyte infiltration, necrosis and decidualization were increased in the same lesions. CONCLUSIONS: Pregnancy rate is reduced in this mouse model of endometriosis. Levels of IL-2 are increased in the peritoneal fluid of mice with endometriosis suggesting a role of this cytokine in infertility related to this disease. The size of endometriotic lesions is increased in pregnant mice; however pregnancy has a beneficial effect on lesions by decreasing cell proliferation and by increasing apoptosis, decidualization and necrosis.

Targeting galectin-1-induced angiogenesis mitigates the severity of endometriosis.

Endometriosis is characterized by the presence of endometrial tissue outside the uterus that causes severe pelvic pain and infertility in women of reproductive age. Although not completely understood, the pathophysiology of the disease involves chronic dysregulation of inflammatory and vascular signalling. In the quest for novel therapeutic targets, we investigated the involvement of galectin-1 (Gal-1), an endogenous glycan-binding protein endowed with both immunosuppressive and pro-angiogenic activities, in the pathophysiology of endometriotic lesions. Here we show that Gal-1 is selectively expressed in stromal and endothelial cells of human endometriotic lesions. Using an experimental endometriosis model induced in wild-type and Gal-1-deficient (Lgals1(-/-) ) mice, we showed that this lectin orchestrates the formation of vascular networks in endometriotic lesions in vivo, facilitating their ectopic growth independently of vascular endothelial growth factor (VEGF) and the keratinocyte-derived CXC-motif (CXC-KC) chemokine. Targeting Gal-1 using a specific neutralizing mAb reduced the size and vascularized area of endometriotic lesions within the peritoneal compartment. These results underline the essential role of Gal-1 during endometriosis and validate this lectin as a possible target for the treatment of disease.

Anastrozole and celecoxib for endometriosis treatment, good to keep them apart?

Endometriosis is a benign gynecological disease. Cyclooxygenase-2 (COX-2) and aromatase proteins have been shown to be overexpressed in eutopic endometrium from women suffering from this disease compared to disease-free women. Furthermore, inhibition of these molecules individually was demonstrated to have antiproliferative and proapoptotic effects both in vitro and in vivo in several models. In this study, the effect of combining celecoxib, a selective COX-2 inhibitor, and anastrozole, an aromatase inhibitor, on the implantation and growth of endometriotic like lesions in a murine model of endometriosis was evaluated. Endometriosis was surgically induced in female BALB/c mice. After 28 days of treatment with celecoxib, anastrozole, or their combination, animals were killed and lesions were counted, measured, excised, and fixed. Immunohistochemistry for proliferating cell nuclear antigen and CD34 was performed for assessment of cell proliferation and vascularization. TUNEL technique was performed for apoptosis evaluation. Celecoxib was the only treatment to significantly reduce the number of lesions established per mouse, their size and vascularized area. In addition, cell proliferation was significantly diminished and apoptosis was significantly enhanced by both individual treatments. When the therapies were combined, they reversed their effects. These results confirm that celecoxib and anastrozole separately decrease endometriotic growth, but when combined they might have antagonizing effects.

The inhibitory effect of celecoxib and rosiglitazone on experimental endometriosis.

OBJECTIVE: To evaluate the effects of celecoxib and rosiglitazone on the implantation and growth of endometriotic-like lesions in a murine model of endometriosis. DESIGN: Prospective experimental study. SETTING: Animal research and laboratory facility. ANIMAL(S): Two-month-old female BALB/c mice. INTERVENTION(S): Surgically induced endometriosis in female BALB/C mice; 28 days of treatment with celecoxib, rosiglitazone, or their combination; counting, measuring, excising, and fixing lesions. MAIN OUTCOME MEASURE(S): Immunohistochemical examination for proliferating cell nuclear antigen (PCNA), CD31, and CD34 to assess cell proliferation and vascularization, with the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) technique for apoptosis evaluation. RESULT(S): Celecoxib and the combined treatment (celecoxib and rosiglitazone) statistically significantly reduced the mean number of lesions established per mouse, and all treatments diminished the implant volume. In addition, cell proliferation within the implants was statistically significantly reduced, and apoptosis was statistically significantly enhanced by all treatments. Also, we found that all treatments diminished the vascularized area in the lesion. CONCLUSION(S): These results are promising and reveal that celecoxib and rosiglitazone, combined or separately, have a beneficial effect on overall endometriotic growth.

Effect of vascular endothelial growth factor inhibition on endometrial implant development in a murine model of endometriosis.

The main factor involved in neovascularization of ectopic endometrial tissue in endometriosis is the vascular endothelial growth factor (VEGF), which is produced both by the endometrial implant and by peritoneal macrophages. On the other hand, bevacizumab is an antiangiogenic agent used in the treatment of different tumors, like colorectal, pulmonary, and recently mammary. We evaluated the effect of the inhibition of VEGF activity with bevacizumab (Avastin) on ectopic endometrial growth in a murine model of endometriosis. Two months old female BALB/c mice had surgery performed to induce endometriotic-like lesions. Treatment with bevacizumab started on post-surgery day 15 and continued during 2 weeks. Then, animals were sacrificed, peritoneal fluid was collected, and endometriotic-like lesions were counted, measured, and removed. Cell proliferation, vascular density, and apoptosis were assessed by immunohistochemistry for proliferating cell nuclear antigen (PCNA), immunohistochemistry for CD34, and Terminal Deoxynucleotidil Transferase-Mediated dUTP Nick End Labeling (TUNEL), respectively. Vascular endothelial growth factor levels were evaluated in the peritoneal fluid by enzyme-linked immunoassay (ELISA). Treatment with bevacizumab significantly inhibited endometriotic lesion development (P < .05). Consistently, bevacizumab significantly inhibited cell proliferation in lesions (P < .01), reduced vascular density (P < .001), as well as increased the apoptotic cell percentage (P < .001). In addition, bevacizumab reduced VEGF levels in peritoneal fluid of endometriosis-induced animals (P < .05). In conclusion, this study suggests a direct effect of bevacizumab on the reduction of endometrial implant growth and supports further research on VEGF inhibition as a novel therapeutic modality in endometriosis.

Effect of vascular endothelial growth factor and interleukin-1beta on apoptosis in endometrial cell cultures from patients with endometriosis and controls.

The aim of this study was to evaluate the effect of vascular endothelial growth factor (VEGF) and interleukin-1beta (IL-1beta) on apoptosis induced by leuprolide acetate (LA) in endometrial epithelial cell cultures from patients with endometriosis. Primary endometrial epithelial cell cultures were obtained from uterine endometrial biopsies of patients with endometriosis and control women. Endometrial epithelial cells were incubated with LA; a combination of LA and VEGF; a combination of LA and IL-1beta; or in basal conditions. LA was added 3h prior to addition of VEGF and IL-1beta. After stimulation, the percentage of apoptotic cells was evaluated by the acridine orange-ethidium bromide technique and Bax expression was assessed by western blot. Treatment with LA enhanced the percentage of apoptotic cells in endometrial epithelial cells from subjects with endometriosis and control subjects. Addition of either VEGF or IL-1beta after exposure to LA restored the percentage of apoptotic cells to basal levels. Moreover, treatment with LA increased Bax expression in endometrial epithelial cells from patients with endometriosis. This effect was reverted by the addition of either VEGF or IL-1beta. Our results show that VEGF and IL-1beta reduce apoptosis and decrease Bax expression in endometrial epithelial cells from patients with endometriosis. This study suggests that VEGF and IL-1beta may protect endometriotic cells from undergoing apoptosis in addition to exerting their pro-angiogenic role.

Effect of aromatase inhibitors on ectopic endometrial growth and peritoneal environment in a mouse model of endometriosis.

OBJECTIVE: To evaluate the effect of aromatase inhibitors on ectopic endometrial growth and on the release of proangiogenic and proinflammatory factors in peritoneal fluid (PF). DESIGN: Prospective experimental study. SETTING: Animal research and laboratory facility. ANIMAL(S): Female Balb/c mice 2 months of age. INTERVENTION(S): Mice had surgery performed to induce endometriosis-like lesions. Treatment with anastrozole or letrozole was started on either postoperative day 1 or 28 and continued for 4 weeks. MAIN OUTCOME MEASURE(S): Endometriotic lesions were counted and measured and aromatase expression, cell proliferation, and apoptosis were assessed. Vascular endothelial growth factor (VEGF) and prostaglandin E (PGE) levels were evaluated in the PF. RESULT(S): Endometriosis-like lesions express aromatase P-450. Treatment with either anastrozole or letrozole did not prevent lesion establishment; however, it significantly decreased the size of the endometriotic lesion. When treatment was initiated on postoperative day 1, letrozole and anastrozole decreased cell proliferation and increased apoptosis. When treatment was started on postoperative day 28, both aromatase inhibitors decreased cell proliferation, but only anastrozole augmented apoptosis levels. In addition, letrozole reduced VEGF and PGE levels in PF. Anastrozole diminished VEGF content but did not cause any significant change in PGE levels. CONCLUSION(S): These findings support the further investigation of aromatase inhibition as a treatment option for endometriosis.

The role of GnRH analogues in endometriosis-associated apoptosis and angiogenesis.

It has been postulated that gonadotropin-releasing hormone (GnRH) analogues may act directly on endometrial cells and inhibit their growth and proliferation by regulation of apoptotic and angiogenic mechanisms. Eutopic endometrial cells from patients with endometriosis show an increased proliferation rate and are less susceptible to cell death by apoptosis than those from subjects without the disease. Notably, the GnRH analogue, leuprorelin, inhibits cell proliferation and increases the apoptotic rate in eutopic endometrial cell cultures, an effect that appears to be mediated by an increase in the expression of the pro-apoptotic proteins Bax and FasL and a decrease in the expression of the anti-apoptotic protein Bcl-2. Angiogenesis is an important process in the development of endometrial tissue, and it is regulated by vascular endothelial growth factors (VEGFs) and angiopoietins. VEGF levels are elevated in peritoneal fluid and endometriotic tissue from patients with endometriosis. In addition, it has been demonstrated that the expression of VEGF is potentiated by a variety of cytokines, including IL-1beta. Recent studies show that leuprorelin reduces the production of VEGF-A and IL-1beta in eutopic endometrial cell cultures, suggesting a mechanism by which it could inhibit the development of endometriosis. Thus, GnRH analogues appear to be effective in reducing the growth of endometrial cells, not only due to their classical pituitary endocrine effects, but also via a direct effect on the endometrial cells themselves.

Effects of aromatase inhibitors on proliferation and apoptosis in eutopic endometrial cell cultures from patients with endometriosis.

OBJECTIVE: To study the effect of letrozole (Let) and anastrozole (Anas) on apoptosis and cell proliferation in epithelial endometrial cells (EEC) from patients with endometriosis (EDT). DESIGN: Prospective study. SETTING: Research institute and clinical fertility center. PATIENT(S): Eighteen women with untreated EDT. INTERVENTION(S): Biopsy specimens of eutopic endometrium were obtained from all subjects. Apoptosis and cell proliferation were examined in EEC after incubation with Let or Anas. MAIN OUTCOME MEASURE(S): Percentage of apoptotic cells (ApC) was evaluated by the acridine orange-ethidium bromide technique; cell proliferation was assessed by 3H-thymidine incorporation. RESULT(S): Treatment with Let 10 nM and Let 100 nM enhanced values of ApC in cultures from EDT patients. Epithelial endometrial cells treated with Anas 100 nM or Anas 500 nM showed a statistically significant induction on apoptosis levels. Cultures treated with Let 1 nM or Anas 50 nM did not show any significant differences in ApC levels compared with basal conditions. 3H-Thymidine uptake was down regulated by Let 10 nM and Let 100 nM. Similarly, Anas 100 nM and Anas 500 nM showed a significantly lower degree of cell proliferation in EEC. Lower concentrations of Let and Anas did not induce any significant change in cell proliferation rates. CONCLUSION(S): Our results show that Let and Anas produced a significant and positive effect on apoptosis and cell proliferation on EEC from EDT patients. These findings support the further investigation of aromatase inhibitors as a treatment option in EDT.

Gonadotropin-releasing hormone agonist induces apoptosis and reduces cell proliferation in eutopic endometrial cultures from women with endometriosis.

OBJECTIVE: There is growing evidence that suggests a direct action of gonadotropin-releasing hormone agonist (GnRH-a) on endometrial growth. Consequently, our purpose was to evaluate the effect of GnRH-a on in vitro eutopic endometrial cell growth and apoptosis. DESIGN: Prospective study. SETTING: Research institute and clinical fertility center. PATIENT(S): Sixteen women with untreated endometriosis and 14 controls. INTERVENTION(S): Biopsy specimens of eutopic endometrium were obtained from all subjects. Apoptosis and cell proliferation were examined in epithelial endometrial cell cultures after incubation with leuprolide acetate (LA), antide, and a combination of both. MAIN OUTCOME MEASURE(S): The percentage of apoptotic cells was evaluated by the acridine orange-ethidium bromide technique; cell proliferation was assessed by (3)H-thymidine incorporation. RESULT(S): Leuprolide acetate (LA) (100 ng/mL) enhanced apoptosis in endometrial cultures from patients with endometriosis and controls, and this effect was reversed by antide 10(-7)M. Cell proliferation was down-regulated by LA at 1, 10, and 100 ng/mL in cultures from women without and with endometriosis. The addition of antide 10(-7)M reversed this inhibition. CONCLUSION(S): GnRH-a appears to have a direct effect by enhancing the apoptotic index and decreasing the cell proliferation in endometrial cells.

Effect of GnRH analogues on apoptosis and release of interleukin-1beta and vascular endothelial growth factor in endometrial cell cultures from patients with endometriosis.

BACKGROUND: The aim of the present study was to evaluate the effect of GnRH analogues on the in-vitro eutopic endometrial cell apoptosis and release of interleukin-1beta (IL-1beta) and vascular endothelial growth factor (VEGF). METHODS: Biopsy specimens of eutopic endometrium obtained from 16 women with untreated endometriosis and 14 controls were studied. Apoptosis, IL-1beta and VEGF release were evaluated in epithelial endometrial cell cultures after incubation with leuprolide acetate (LA) as GnRH agonist, antide as GnRH antagonist, and a combination of both. The percentage of apoptotic cells was evaluated by the acridine orange-ethidium bromide technique, and IL-1beta and VEGF concentrations were assessed by using commercial enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: We found that LA (100 ng/ml) enhanced apoptosis in endometrial cell cultures from endometriosis patients and controls and this effect was reversed by antide at 10(-7) mol/l. IL-1beta and VEGF release was downregulated by LA in cultures from controls and endometriosis patients. The addition of antide 10(-7) mol/l reversed this inhibition. Endometrial cultures treated with antide at 10(-7) mol/l did not show any significant effects compared with basal conditions. CONCLUSIONS: GnRH agonists appear to have a direct effect in endometrial cells cultures, by enhancing the percentage of apoptotic cells and decreasing the release of pro-mitogenic cytokines such as IL-1beta and VEGF.

Endometriosis pelviana: estudio de las variables que afectan la etiopatogenia y la infertilidad asociada a la endometriosis / Pelvic endometriosis: study of the variables that affect etiopathogenia and the infertility associated to the endometriosis

Desde hace más de un siglo la endometriosis (EDT) se ha definido por la presencia de focos de endometrio ectópico fuera de la cavidad uterina, sin embargo en la actualidad, muchos conceptos clásicos referentes a su etiolgía, fisiopatología y tratamiento están siendo cuestionados. En el presente trabajo se presentan los resultados de una serie de estudios realizados en nuestro laboratorio durante los últimos años los cuales tuvieron como objetivo explicar o clarificar muchos de estos aspectos enigmáticos. Para ello hemos analizado: 1) la correlación de las lesiones endometriósicas pelvianas clasificadas por laparoscopia, histología e inmunohistoquímica, 2) el papel del endometrio eutópico en la etiopatogenia y 3) el ambiente peritoneal y sus componentes, su efecto sobre la etiopatogenia y la infertilidad. Como resultado de nuestras investigaciones hemos hallado que la etiopatogenia de la EDT está relacionada con múltiples factores. El endometrio eutópico de estas pacientes, que por menstruación retrógrada llega a cavidad peritoneal, posee características particulares en relación a una disminución significativa de la apoptosis y un incremento en la proliferación celular que favorecerían su mayor sobrevida e implantación en sitios extópicos. Además hemos observado que los anticonceptivos orales administrados por corto tiempo fueron capaces de revertir estas anormalidades celulares. Paralelamente hemos hallado que los componentes celulares y solubles del líquido peritoneal pueden tener un efecto sinergístico con lo mencionado, favoreciendo la implantación a través de un aumento de la angiogénesis y alterando la capacidad de respuesta del sistema inmunológico como mecanismo de defensa de limpieza o barrido. es evidente además, que los diferentes tipos de lesiones representan un arco evolutivo donde las lesiones rojas representarían las lesiones iniciales mientras que las negras y blancas con menor grado de vascularización y mayor grado de fibrosis, representarían estadios más crónicos de la enfermedad. La importancia de estos hallazgos radica, en la posibilidad de individualizar la terapéutica, dado que la indicación de propuestas farmacológicas actuales basadas en el bloqueo de la agniogénesis o contrarrestar las proteasas que erosionan el matriz extracelular, estarían indicadas sólo en circunstancias específicas... (TRUNCADO)

Endometriosis pelviana: estudio de las variables que afectan la etiopatogenia y la infertilidad asociada a la endometriosis / Pelvic endometriosis: study of the variables that affect etiopathogenia and the infertility associated to the endometriosis

Desde hace más de un siglo la endometriosis (EDT) se ha definido por la presencia de focos de endometrio ectópico fuera de la cavidad uterina, sin embargo en la actualidad, muchos conceptos clásicos referentes a su etiolgía, fisiopatología y tratamiento están siendo cuestionados. En el presente trabajo se presentan los resultados de una serie de estudios realizados en nuestro laboratorio durante los últimos años los cuales tuvieron como objetivo explicar o clarificar muchos de estos aspectos enigmáticos. Para ello hemos analizado: 1) la correlación de las lesiones endometriósicas pelvianas clasificadas por laparoscopia, histología e inmunohistoquímica, 2) el papel del endometrio eutópico en la etiopatogenia y 3) el ambiente peritoneal y sus componentes, su efecto sobre la etiopatogenia y la infertilidad. Como resultado de nuestras investigaciones hemos hallado que la etiopatogenia de la EDT está relacionada con múltiples factores. El endometrio eutópico de estas pacientes, que por menstruación retrógrada llega a cavidad peritoneal, posee características particulares en relación a una disminución significativa de la apoptosis y un incremento en la proliferación celular que favorecerían su mayor sobrevida e implantación en sitios extópicos. Además hemos observado que los anticonceptivos orales administrados por corto tiempo fueron capaces de revertir estas anormalidades celulares. Paralelamente hemos hallado que los componentes celulares y solubles del líquido peritoneal pueden tener un efecto sinergístico con lo mencionado, favoreciendo la implantación a través de un aumento de la angiogénesis y alterando la capacidad de respuesta del sistema inmunológico como mecanismo de defensa de limpieza o barrido. es evidente además, que los diferentes tipos de lesiones representan un arco evolutivo donde las lesiones rojas representarían las lesiones iniciales mientras que las negras y blancas con menor grado de vascularización y mayor grado de fibrosis, representarían estadios más crónicos de la enfermedad. La importancia de estos hallazgos radica, en la posibilidad de individualizar la terapéutica, dado que la indicación de propuestas farmacológicas actuales basadas en el bloqueo de la agniogénesis o contrarrestar las proteasas que erosionan el matriz extracelular, estarían indicadas sólo en circunstancias específicas... (TRUNCADO) (AU)