Endometrial breakdown with sustained progesterone release involves NF-κB-mediated functional progesterone withdrawal...

Area of Science:

• Reproductive Biology
• Endocrinology
• Molecular Medicine

Background:

• Irregular uterine bleeding is a primary side effect of progestogen-only contraceptives, leading to discontinuation.
• Understanding the mechanisms of endometrial breakdown is crucial for improving contraceptive options.

Purpose of the Study:

• To investigate the mechanism of irregular uterine bleeding in a mouse model of endometrial breakdown induced by progestogen.
• To test the hypothesis that functional progesterone withdrawal, mediated by nuclear factor kappa-b (NF-κB), contributes to endometrial breakdown.

Main Methods:

• Established a mouse model using subcutaneous progesterone implants to induce endometrial breakdown.
• Utilized co-immunoprecipitation assays to examine interactions between NF-κB p65 and progesterone receptor (PGR).
• Assessed PGR transcriptional activity and PGR-B to PGR-A ratios in primary mouse and human decidual stromal cells and in the mouse model.

Main Results:

• Progestogens sustained decidualization, yet endometrial breakdown occurred in the progesterone implant model.
• Constitutive activation of NF-κB p65 and its interaction with PGR were observed.
• NF-κB activity repressed PGR transcriptional activity in decidual cells.
• NF-κB inhibition prevented endometrial breakdown, indicating NF-κB-mediated functional progesterone withdrawal is involved.

Conclusions:

• Functional progesterone withdrawal, driven by NF-κB-mediated repression of PGR activity, contributes to endometrial breakdown during sustained progestogen exposure.
• This mechanism offers a potential explanation for irregular uterine bleeding associated with progestogen-only contraceptives.
• Further research is warranted to explore the relevance of this mechanism in the human endometrium.