Association between estrogen receptor alpha 36 expression and the risk of deep infiltrating endometriosis

Background Deep infiltrating endometriosis (DIE) is a severe subtype of endometriosis, often associated with dysmenorrhea and significant diagnostic challenges. Conventional biomarkers, such as cancer antigen 125 (CA125), lack sufficient specificity for accurate DIE diagnosis. Estrogen receptor α36 (ERα36) is a novel isoform of the estrogen receptor, distinct from the classic estrogen receptor α66 (ERα66), and has been implicated in the pathogenesis of several gynecologic disorders, including breast and endometrial cancer. However, the expression pattern of ERα36 in DIE tissues and its potential role as a diagnostic biomarker for DIE have not yet been investigated. This study aimed to examine the expression of ERα36 in DIE tissues, explore its association with disease presence, and evaluate its potential as a diagnostic biomarker and a candidate for future therapeutic targeting. Methods A case-control study was conducted between 2014 and 2016, enrolling 80 DIE patients as the case group and 132 healthy women as the control group. The expression of ERα36 was evaluated at both the mRNA and protein levels: reverse transcription-polymerase chain reaction was used for mRNA expression and immunohistochemistry was performed for protein detection. Statistical analyses were performed using SPSS version 26.0, and receiver operating characteristic curve analysis was employed to assess the diagnostic performance of ERα36 for DIE. Results No significant differences were observed between control and endometriosis groups in demographic or reproductive characteristics (all P >0.05). ERα36 mRNA was detected in 71.2% of endometriosis tissues, compared with 36.4% of controls ( P < 0.01). Among 80 patients with endometriosis, ERα36 expression was observed in 57 cases and absent in 23. ERα36-positive patients exhibited younger age, higher rFAS (revised American Fertility Society) stage, more severe and longer-lasting dysmenorrhea, increased absenteeism during menstruation, greater adnexal adhesions, and a higher prevalence of DIE (all P < 0.05). Protein gene product 9.5 (PGP9.5) was present in eutopic endometrium, with significantly higher density in DIE lesions compared with ovarian and superficial peritoneal endometriosis ( P < 0.01). Notably, ERα36-positive patients showed a higher proportion of strong PGP9.5 expression than ERα36-negative patients ( P < 0.05). These findings indicate that ERα36 expression is associated with more severe disease phenotypes and increased neural marker expression in endometriosis, particularly in DIE. Conclusion ERα36 is highly expressed in DIE tissues and exhibits good diagnostic performance with high sensitivity and specificity. These findings suggest that ERα36 may serve as a novel tissue-level biomarker for DIE, representing a potential target for future therapeutic strategies.