Low-dose Aspirin Can Increase The Expression Of LIF And Downregulate Progesterone Resistance In Endometriosis Rat During The Implantation Window

BackgroundEndometriosis(Endometriosis,EMs)is a kind of benign hormone dependent and chronic inflammatory diseases in female reproductive system.Epidemiological data shows that about 30-50%of patients with endometriosis sustains infertility or subfertility.Although the relationship between endometriosis and infertility has been sufficiently recognized,the underlying pathogenesis is yet still unclear.Currently the diagnosis and treatment of endometriosis-related infertility have become attractive and difficult problems of modern gynecology.Leukemia inhibitory factor(LIF),a pluripotent factor,is indispensable during embryo implantation.The knockout of Lif results in embryo implantation failure and decidualization defect.While LIF was supplied exogenously,the embryos floating in the uterine cavity could be successfully implanted.Studies have shown that the expression of LIF decreases in the eutopic endometrium of endometriosis and adenomyosis during the window period.The expression of LIF is regulated by estrogen and progesterone,while antiprogestin therapy can decrease its expression.Low level of progesterone receptor,abnormal expression of progesterone signaling pathway regulators,aberrant epigenetic changes and the inflammatory reaction all make progesterone responsiveness decreased,which cause the changes in systemic hormonal response characterized with the estrogen dominance and progesterone resistance.Aspirin,as one of the commonly used non-steroidal anti-inflammatory drugs in clinical PR-Actice,can inhibit the production of COX enzyme,thereby reducing the synthesis of prostaglandins and inhibiting the inflammatory response.Many researches have shown that aspirin can improve the pregnancy rate of assisted reproductive technology and improve the endometrial receptivity of patients with idiopathic recurrent miscarriage.Meanwhile,animal studies have indicated that low-dose aspirin can increase the expression of LIF and β3 integrin in the endometrium of mice during implantation.However,whether aspirin can improve the receptivity of the eutopic endometrium in endometriosis has not been reported.This study aims to explore the effect of low-dose aspirin on the eutopic endometrial receptivity of endometriosis and to provide an another perspective for the research and treatment of endometriosis-related infertility.Material and methodThis study established rats model of endometriosis including the control group(n=12),endometriosis group(EMs)(n=15)and endometriosis rats treated with low-dose aspirin(Aspirin)(n=17).Western blot,qRT-PCR and ELISA were used to detect the expression of LIF in the eutopic endometrium and plasma.Semi-quantitative analysis and localization of PR and LIFR were confirmed by immunohistochemistry and western blot and qRT-PCR were applied to detect the PR isoforms and LIFR protein and nucleic acid levels.Results1.The expression of LIF was increased after low-dose aspirin treatment in the eutopic endometrium and serum of endometriosis.Western blot,ELISA,and qRT-PCR results showed that the expression of LIF in the EMs group was lower than that in the Control group.While low-dose aspirin intervention can increase the expression of LIF.There was no significant difference in the expression of LIF between the Aspirin group and the Control group.2.The expression of LIFR was not affected after aspirin treatment.The results of immunohistochemistry,Western blot and qRT-PCR showed that the expression of LIFR was not significantly different between EMs group and Control group,which couldn’t be altered by low-dose aspirin.3.The expression of PR-A and PR-B were increased and PR-A/PR-Bwas decreased after aspirin treatment in endometriosis rat model.Immunohistochemistry was used to localize PR in the eutopic endometrium and to analyze its semi-quantitative expression.The results showed that the expression of PR in the Aspirin group was higher than in the EMs group.Secondly,Western blot and qRT-PCR were used to detect the PR isoforms PR-A and PR-B.The data showed that both PR-A and PR-B expression were increased but PR-A/PR-B was decreased after low-dose aspirin treatment.Conclusions1.The expression of LIF was decreased in endometriosis,but low-dose aspirin could increase its level.2.The endometriosis couldn’t cause the change of expression of LIFR and the intervention of low-dose aspirin could not affect its expression.3.The expression of PR-A and PR-B were decreased and the ratio of PR-A/PR-B was increased in endometriosis.The low-dose aspirin could reverse this situation.It is speculated that low-dose aspirin can downregulate the progesterone resistance of the eutopic endometrium in endometriosis during the implantation window,thereby increasing the expression of the receptivity-related molecules such as LIF.