Study of local estrogen metabolism in endometriosis

Endometriosis is defined as the presence of endometrial glands and stroma outside the uterine cavity. Dysmenorrhea, pelvic pain, infertility and decreased quality of life are the main problems caused by this condition. Endometriotic lesions can present as three different forms, i.e. peritoneal, ovarian and rectovaginal, each with its own pathogenesis. Present treatments (medical and/or surgical) are relatively ineffective, as proved by disease recurrence after cessation of therapy in many cases, and severe and intolerable side effects. Novel medical approaches are therefore needed.\nEndometriosis is known to be an estrogen-dependent disease. Local estrogen biosynthesis has been evidenced in several reports, showing dysregulated steroid enzyme and receptor expression or activity in endometriotic samples. The aim of this research project was to better characterize this local estrogen production in the three types of endometriosis and its involvement in endometriosis development, to allow more specific targeting of future treatment modalities. \nSurprisingly, the aromatase enzyme, involved in the conversion of androgens to estrogens, was not detected in the endometriotic samples analyzed. Non-specific staining was evidenced, however, and contamination by surrounding tissues (follicular, adipose or peritoneal cells) was hypothesized to be the cause of aromatase detection in the literature. After critical review of case reports and clinical trials on endometriosis treatment with aromatase inhibitors, no clear evidence of a beneficial effect was found. \nOn the other hand, steroid sulfatase (STS), the enzyme catalyzing the conversion of sulfated estrogens (inactive form) to their unconjugated (active) form, was readily detected in endometriotic biopsies. All lesion types exhibited high levels of STS mRNA expression, with nodules showing the highest concentrations. E2MATE, an STS inhibitor, proved to be effective on endometrial tissue in vitro, and to suppress endometriosis development in vivo.\nThe STS pathway appears to play a key role in endometriosis, and therefore offers a promising approach to its management, by preventing local formation of active estrogens around endometriotic lesions.