Progesterone resistance in atypical endometrial hyperplasia: Expression and mechanisms of hormone-responsive molecules

This study aimed to delineate the molecular profile underlying progesterone resistance in atypical endometrial hyperplasia (AEH), a precancerous condition associated with a high risk of malignant transformation. Using a retrospective cohort of 20 AEH patients who completed a 6-month progestin therapy, we compared protein expression between 10 progesterone-resistant and 10 progesterone-sensitive tissues using immunohistochemistry and Western blot analysis. The results revealed a distinct molecular signature in resistant tissues, characterized by significant upregulation of estrogen signaling components (ERa, pS2, and MUC1) and proliferation markers (SOX7 and Ki-67). Concurrently, the key progesterone receptor signaling elements (PR, FKBP4, FKBP5, and FOSL2) were markedly downregulated. These findings indicate that progesterone resistance is associated with sustained activation of estrogen-driven proliferative pathways coupled with impaired progesterone signaling, leading to unabated cellular growth. The coordinated dysregulation of these hormone-responsive and proliferation-related molecules highlights a fundamental hormonal imbalance and proliferative disruption in progesterone-resistant AEH. This study provides a molecular framework for understanding progesterone resistance and suggests potential targets, such as SOX7, for future therapeutic strategies aimed at restoring hormonal sensitivity and controlling disease progression in conservative fertility-sparing management.