PGRMC1 suppression enhances progesterone responsiveness in stromal cells of ovarian endometrioma

In brief: Progesterone resistance in endometriosis reduces the efficacy of progestin therapy. This study demonstrates that progesterone receptor membrane component 1 (PGRMC1) inhibition enhances progesterone responsiveness in endometriotic cells and may improve the efficacy of progestin-based therapies for endometriosis. Abstract: Progesterone resistance in endometriosis reduces the efficacy of progestin. The nonclassical progesterone receptor, progesterone receptor membrane component 1 (PGRMC1), may regulate progesterone signaling in the normal endometrium, but its expression and role in endometriosis remain unknown. We aimed to investigate PGRMC1 expression in endometriosis and its role in progesterone resistance. PGRMC1 expression in normal endometrium (NE), eutopic endometrium in patients with endometriosis (EE), and ovarian endometrioma (OE) was examined using immunohistochemistry. Cultured OE stromal cells (SCs) were subjected to PGRMC1 knockdown using small interfering RNA (siRNA) and treated with AG205 (a PGRMC1 inhibitor) and RU486 (a progesterone receptor [PR] inhibitor) under progesterone stimulation. Progesterone responsiveness was assessed by measuring insulin-like growth factor binding protein 1 (IGFBP1) and prolactin (PRL) expression through real-time PCR and enzyme-linked immunosorbent assay. PGRMC1 expression in NESCs and EESCs was significantly lower in the secretory phase than in the proliferative phase (p < 0.01), with no similar changes observed in OE. Following siRNA-mediated PGRMC1 knockdown in OESCs, IGFBP1 and PRL expression was significantly upregulated (p < 0.05). Notably, treatment with siRNA and progestin induced significantly higher IGFBP1 and PRL expression than treatment with progestin alone (p < 0.05). AG205 induced similar effects on IGFBP1and PRL expression (p < 0.05), suggesting that suppression of PGRMC1 expression enhances progestin responsiveness in OESCs. However, AG205-induced IGFBP1 expression was abolished following treatment with RU486, suggesting that PGRMC1 acts through PR. In conclusion, suppressing PGRMC1, which is consistently expressed throughout the menstrual cycle in endometriotic lesions, may restore progesterone sensitivity and improve the efficacy of progestin-based therapies for endometriosis.