Effect Of Bazedoxifene On ER??ER?? AP-1 And VEGF Levels In Rat Endometriosis Models

Background and ObjectiveEndometriosis(EMs)is a chronic gynecological disease that is harmful to women's health.It reveals the benign change in histopathology,but mimics malignant neoplasms in the biological and clinical behaviour of tumours,such as implantation metastasis ? invasive metastasis and distant metastasis.Studies have shown that its molecular biological behavior may be derived from estrogen exposure and then exclusively start the corresponding signal path by estrogenreceptors.The results of multiple signaling pathways facilitate that the countercurrent endometrial cells can grow outside the uterine cavity.The current clinical laparoscopic surgery as the treatment of endometriosis gold standard has achieved very good results,but sometimes still need to assist in drug treatment.The drugs used for the treatment of endometriosis clinically are more to reduce the endogenous estrogen production currently.However,long-term medication can easily lead to low estrogen and a series of perimenopausal symptoms,limiting the clinical application of these drugs.Bazedoxifene as the third generation of selective estrogen receptor modulators(SERMs)can significantly inhibit the proliferation of endometrium in rats,narrow the volume of ectopic lesions,and decrease the protein expression levels of ER in the endometriosis lesions and eutopic endometrium.Bazedoxifene as the new drug for the treatment of endometriosis gradually comes into the people's vision and because of the treatment in rats,it shows a high clinical prospect of its application.To investigate the expression of ER??ER??AP-1?VEGF on endometriosis model in rats and analyze the possible mechanism of bazedoxifene treating endometriosis model in rats,we established rat EMs models in this study and the expression levels of ER??ER??AP-1?VEGF in the eutopic endometrium and endometriosis lesions were observed by immunohistochemistry in each experimental group.Materials and methodsMaterialsHealthy and clean non-pregnant female SD rats 100,aged 60 d ~ 90 d,weighing 220~250g,were purchased from the Experimental Animal Center of Henan Province.There was no significant difference in age and quality between the rats in the study group(control group,model group,bazedoxifene group).MethodsAfter observing the normal estrus cycle,the rats were chosen which had at least two continuous estrous cycles to establish the rat endometriosis models.The day before establishing the models,we gived the right amount of estrogen to rats,that resulting in rats all being in estrus.The endometrial tissue form donor rats after stripping were cut into 5x5 mm size fragments,and then were planted between abdominal and subcutaneous fascia of the receptor rats.Intramuscular injection of 0.1ml of gentamicin sulfate for preventing infection to the third day after surgery,and routine feeding was performed for 3 weeks?Three weeks after the model induced,56 rats with successful ectopic implants were randomly divided into two groups: bazedoxifene group(3mg/kg·d,gavage,n=28)and model group(equal volume of saline,gavage,n=28).The same batch of 10 normal female rats were randomly selected as the control group(The feeding conditions were the same as those in the postoperative group).Take the eutopic endometrium and ectopic lesion tissue of the rats under sterile conditions,then fixed in 10% paraformaldehyde,embedded in paraffin,sliced.Part of the specimens were routinely HE stained to observe the changes of lesions glands?stroma and epithelial.The expression levels of ER??ER??AP-1?VEGF in the eutopic endometrium and endometriosis lesions were observed by immunohistochemistry in each experimental group.Results1.The model group compared with the control group:(1)The histological changes of endometriosis lesions and the eutopic endometrium of the model group: it had more glands and blood vessels in the stroma.(2)there was no statistically significant difference in ER? expression level between the endometriosis lesions of EMs model and the control group(P=0.107),but the expression levels in the eutopic endometrium was obviously increased compared with the control group,(P<0.01).The expression levels of ER??AP-1 and VEGF in the endometriosis lesions and eutopic endometrium of the rat modes were obviously increased compared with the control group(P<0.01),but there was no statistically significant difference between the endometriosis lesions and eutopic endometrium of the EMs model.2.The bazedoxifene group compared with the model group:there was no statistically significant difference in ER? expression level among the two groups,but the expression levels of ER??AP-1 and VEGF in the endometriosis lesions and eutopic endometrium were obviously decreased in the bazedoxifene group(P<0.01).Conclusion1.According to the expression characteristics f ER??ER??AP-1 and VEGF in the rat model of endometriosis,"eutopic endometrial determinism" was supported.2.ER??ER? were obviously increased in the eutopic endometrium of EMs model in rats,but in the endometriosis lesions,ER? was significantly increased only.Moreover,up-regulat the expression of AP-1 and VEGF in the EMs model.ER? may play a more important role than ER? in the occurrence of endometriosis.3.bazedoxifene showing the significantly antagonistic effect on the expression of ER?,down-regulating the expression of AP-1 and VEGF,could be an important mechanism of treating the EMs in rats.