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.

Decidualization of Human Endometrial Stromal Fibroblasts is a Multiphasic Process Involving Distinct Transcriptional Programs

“…67 A recent study suggested that repression of PGR by NF-κB p65 may mediate functional progesterone withdrawal in a mouse model. 68 Strikingly, in human DSCs a co-immunoprecipitation time series revealed that NF-κB p65 and PGR interaction is strongest during late decidulization. 68 Thus, in the early phase, PGR-induced NFκBIα and GILZ may act as a sink and exhaust a considerable proportion of free NF-κB p65.…”

“…68 Strikingly, in human DSCs a co-immunoprecipitation time series revealed that NF-κB p65 and PGR interaction is strongest during late decidulization. 68 Thus, in the early phase, PGR-induced NFκBIα and GILZ may act as a sink and exhaust a considerable proportion of free NF-κB p65. As the levels of NFκBIα and GILZ decrease in progressed DSCs, this repression is subsequently relieved, and free NF-κB p65 may repress PGR and prime functional progesterone withdrawal.…”

Network Pharmacology‐Based Prediction of Active Ingredients and Potential Targets of ShengDiHuang Decoction for Treatment of Dysfunctional Uterine Bleeding

“…After treatment with SDHD, the content of progesterone was significantly higher than that of the model group. It was indicated that SDHD can increase the progesterone and then acts through the PGR to regulate changes in endometrial tissue [36]. In the screening of network pharmacology pathways, we found that PGR is mostly involved in molecular function in GO analysis, such as steroid binding, sequence-specific DNA binding, steroid hormone receptor activity, transcription factor activity, transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding, and Zinc ion binding.…”

“…PGR, progesterone receptor, is an intracellular protein that is activated by the steroid hormone progesterone. Progesterone, acting through the PGR, is one of the most critical regulators of endometrial differentiation and helps regulate the cyclic changes in endometrial tissue [36,37]. Related studies have found the gene network that operates downstream of each PGR isoform, which contains PGR-A and PGR-B, to mediate critical functions of regulation of the cell cycle and angiogenesis [37].…”

An Update on the Multifaceted Role of NF-kappaB in Endometriosis

“…The p65 subunit of NF-κB and progesterone receptor (PR) can repress each other through direct contact. The mutual repression of p65 and PR in the endometrium is involved in endometrial biologic alterations during the menstrual cycle and pathophysiologic processes, such as irregular uterine bleeding [38][39][40]. In a study of 109 patients with endometriosis, increased p65 expression and decreased PRB (a PR isoform) expression jointly served as biomarkers for the recurrence of ovarian endometrioma [41].…”