Comprehensive transcript and protein profiling reveals ERα rather than ERβ as the predominant estrogen receptor in human endometriotic lesions.

Endometriosis (EMS) is a chronic estrogen-dependent inflammatory disease. Although several studies have suggested a key role for estrogen receptor ERβ in EMS lesion development, its detection has been challenged by the lack of specificity of many ERβ antibodies. To clarify the status of sex steroid receptors in the endometrium and matched EMS lesions, we perform RNAScope and immunohistochemistry on a tissue microarray cohort, mapping the expression of estrogen receptors ERα and ERβ, as well as progesterone and androgen receptors (PR and AR).We find that ERα is the predominant estrogen receptor in epithelial and stromal compartments across lesion types, including ovarian endometriomas. By contrast, ERβ expression remains low and is mainly restricted to endothelial cells. ERα expression is reduced in stromal cells across lesion types relative to matched endometrium and in the epithelium of superficial peritoneal lesions. In deep endometriosis lesions, reduced stromal ERα expression is associated with a significant increase in epithelial PR and AR expression, suggesting compartment-specific perturbations of ERα/PR signaling and broader remodeling of steroid hormone responses. Together, these findings identify ERα as the dominant but dysregulated estrogen receptor in EMS lesions and support steroid receptor profiling as a framework for lesion stratification and improved endometriosis diagnosis.