Inhibition of Type 1 17β-Hydroxysteroid Dehydrogenase Impairs the Synthesis of 17β-Estradiol in Endometriosis Lesions

Context: Endometriosis affects 10% of the women before menopause and has important personal, professional, and societal economic burdens. Because current medical treatments are aimed at reducing the symptoms only, novel therapeutic targets should be identified. Endometriosis is estrogen dependent and in some patients the endometriosis tissue is able to produce estrogens in an autocrine/paracrine manner. In a number of patients, this is the consequence of the high local activity of the 17 beta-hydroxysteroid-dehydrogenases (17 beta-HSDs), enzymes able to generate active estrogens from precursors with low activity. Objective: The objective of the study was to identify the 17 beta-HSD(s) responsible for the high local generation of estrogens in endometriosis and test the possibility to inhibit these enzymes for therapeutic purposes. Design: The expression of different 17 beta-HSDs involved in the estrogen metabolism was assessed by real-time PCR in eutopic and ectopic tissue from endometriosis patients (n = 14). These biopsies had previously confirmed unbalanced local 17 beta-HSD activity, which caused high estrogen generation. The possibility to block the synthesis of estrogens by one inhibitor specific for type 1 17 beta-HSD was assessed by HPLC in tissue lysates from endometriosis tissues (n = 27). Results: In all but one of the patients, a high type 1 17 beta-HSD level is associated with the unbalanced metabolism of estrogens, leading to higher estrogen synthesis in endometriosis than in the endometrium inside the uterus. Inhibition of type 1 17 beta-HSD restores to various extents, depending on the patient, the correct metabolism. In 19 of 27 patients analyzed (70%), the 17 beta-HSD type 1 inhibitor decreased the generation of 17 beta-estradiol by greater than 85%. Conclusions: Inhibition of 17 beta-HSD type 1 can be a potential future treatment option aimed at restoring the correct metabolic balance of estrogens in endometriosis patients with increased local 17 beta-HSD type 1 enzyme activity.