title: Endometrial breakdown with sustained progesterone release involves NF-κB-mediated functional progesterone withdrawal in a mouse implant model.
abstract: Irregular uterine bleeding is a major side effect of long-acting progestogen-only contraceptives in women, and is the primary reason women discontinue their use. In this study, a mouse model of endometrial breakdown was established using a subcutaneous progesterone implant to understand how irregular bleeding begins. Although progestogens sustained decidualization, endometrial breakdown was still observed in this model. We, therefore, hypothesized that endometrial breakdown might involve functional progesterone withdrawal. Using co-immunoprecipitation assays, we observed the constitutive activation of nuclear factor kappa-b (NF-κB) p65 and its interaction with the progesterone receptor (PGR); moreover, transcriptional activity of the PGR was also repressed by NF-κB activity in primary mouse and human decidual stromal cells that mimic progesterone maintenance. Yet the ratio of PGR-B to PGR-A was not increased in the mouse model. In vivo comparison of endometrial breakdown induced by progesterone withdrawal to that seen during sustained progesterone exposure, in the presence of NF-κB inhibitors, revealed that NF-κB-mediated functional progesterone withdrawal is involved in endometrial breakdown in this implant model. These data prompt further studies to determine the homology of this functional progesterone withdrawal mechanism in human endometrium. Mol. Reprod. Dev. 83: 780-791, 2016 © 2016 Wiley Periodicals, Inc.
authors: Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Hebei University of Chinese Medicine, Shijiazhuang, P. R. China. fengzong117@aliyun.com.
authors: Guo-Hong
authors: GH
authors: Zhang
authors: Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Hebei University of Chinese Medicine, Shijiazhuang, P. R. China.
authors: Li-Jing
authors: LJ
authors: Cui
authors: Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Hebei University of Chinese Medicine, Shijiazhuang, P. R. China.
authors: Ai-Ying
authors: AY
authors: Li
authors: Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Hebei University of Chinese Medicine, Shijiazhuang, P. R. China.
authors: Jian-Ping
authors: JP
authors: Zhang
authors: Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Hebei University of Chinese Medicine, Shijiazhuang, P. R. China.
authors: Yu
authors: Y
authors: Liu
authors: Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Hebei University of Chinese Medicine, Shijiazhuang, P. R. China.
authors: Jing-Shan
authors: JS
authors: Zhao
authors: National Research Institute for Family Planning, Beijing, P. R. China.
authors: Xiang-Bo
authors: XB
authors: Xu
authors: National Research Institute for Family Planning, Beijing, P. R. China.
authors: Bin
authors: B
authors: He
authors: National Research Institute for Family Planning, Beijing, P. R. China.
authors: Jie-Dong
authors: JD
authors: Wang
authors: Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Hebei University of Chinese Medicine, Shijiazhuang, P. R. China.
authors: Li
authors: L
authors: Chu
authors: Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Hebei University of Chinese Medicine, Shijiazhuang, P. R. China.
authors: Yun-Feng
authors: YF
authors: Li
mesh_terms: D000818:Animals; D003278:Contraceptives, Oral, Hormonal / Q000009:adverse effects* / Q000494:pharmacology; D004195:Disease Models, Animal; D004717:Endometrium / Q000378:metabolism / Q000473:pathology; D005260:Female; D051379:Mice; D011374:Progesterone / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism*; D014591:Uterine Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D014592:Uterine Hemorrhage / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology
chemical_list: D003278:Contraceptives, Oral, Hormonal; D011980:Receptors, Progesterone; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D011374:Progesterone