Irregular uterine bleeding,a major side effect of long-acting progestogen(p)-only contraceptives in women,is the main reason for discontinuation of their use.In this study,a mouse model of endometrial breakdown established with a subcutaneous progesterone implant was adapted to better understand the mechanism underlying irregular bleeding.Although progestogen is responsible for maintaining decidualization,endometrial breakdown was still observed in the model.Therefore,we hypothesized that the mechanism of endometrium breakdown involves functional progesterone withdrawal(F-PW),but the specific molecular mechanisms are unclear.By co-immunoprecipitation assays,we observed the constitutive activity and interaction of NF-κB p65 with the 60 kD(mouse)or 116kD(human)progesterone receptor(PR),which may lead to F-WP.The expression of the 60 kD PR was also higher at 72 h(mouse)or 10 d(human)compared with those from all other stages of tissue shedding process in the model,suggesting that transcriptional ctivity of the 60 kD PR was mainly repressed by NF-κB activity.In decidual stromal cells from mice and humans mimicking progesterone maintenance,transcription activity of the PR was also repressed by NF-κB activity.Meanwhile,the mRNA ratio of PR-A to PR-B was not shown to be increased in the model.In addition,we compared differences between endometrial breakdown induced by progesterone withdrawal and that during sustained progesterone exposure.These results suggest that NF-κB-mediated F-PW is involved in endometrial breakdown in the progesterone implant model,prompts further studies to confirm the presence of this mechanism of F-PW in the human endometrium.