Aromatase expression in endometriotic tissues and cell cultures of patients with endometriosis

Abstract

Cytochrome P-450 aromatase is responsible for catalysing the conversion of androstendione into estrone, so its expression in endometriotic tissue could contribute to the development of endometriosis. The aims of this study were, on the one hand, to determine the presence of aromatase in eutopic and ectopic endometrium, healthy peritoneum, myometrium and leiomyomas from patients with (n = 61) and without endometriosis (n = 12) and, on the other hand, to determine the effect of peritoneal fluid (PF), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNFalpha) on aromatase activity from endometriotic stromal cells and subcutaneous adipocytes. After immunohistochemical analysis, aromatase expression was detected in the endometriotic tissue of 61% of patients, whereas the rest of the tissues, as well as those from disease-free women, were negative. Cell cultures were made to determine aromatase activity in endometriotic stromal cells and adipocytes. The addition of PF, TNFalpha and especially IL-6 (P < 0.05) stimulated the basal enzymatic activity observed in both cell types. Our findings confirm the presence of aromatase in endometriosis and probably the existence of a local estrogen production that may be stimulated by some factors such as cytokines present in the PF of these patients. Therefore, the use of aromatase inhibitors combined with immunomodulator agents could be a novel approach to be investigated in future clinical trials.

How can macroscopically normal peritoneum contribute to the pathogenesis of endometriosis?

“…The reduced ferritin mRNA expression in macroscopically normal peritoneum from women with endometriosis suggests that iron overload may be limited to endometriotic lesions and not extend to normal peritoneum. Because peritoneal mRNA expression of aromatase was not affected by the presence or absence of endometriosis, it is also possible that the main activity of aromatase is restricted to endometriosis lesions (10), confirming previous research (11), showing undetectable aromatase in healthy peritoneum of women with (proximal to endometriotic lesions) and without endometriosis. Eutopic endometrial expression of aromatase was increased in women with endometriosis compared with that of controls, according to some (5,(12)(13)(14)(15) but not all investigators (11,(16)(17)(18).…”

“…Because peritoneal mRNA expression of aromatase was not affected by the presence or absence of endometriosis, it is also possible that the main activity of aromatase is restricted to endometriosis lesions (10), confirming previous research (11), showing undetectable aromatase in healthy peritoneum of women with (proximal to endometriotic lesions) and without endometriosis. Eutopic endometrial expression of aromatase was increased in women with endometriosis compared with that of controls, according to some (5,(12)(13)(14)(15) but not all investigators (11,(16)(17)(18). Increased peritoneal mRNA expression of TGF-b and IL-1b in women with endometriosis compared with controls, observed in our previous study (5,6), was not confirmed in this study, possibly because of a different sample set or more robust methods for analysis, like normalization on 4 housekeeping genes in the current study compared with 1 housekeeping gene in our previous study (5,6).…”

Aromatase expression in endometriotic tissues and its relationship to clinical and analytical findings

“…This is probably caused by the local biosynthesis of E and the stimulation of PGE 2 , which are associated with proliferation, migration, angiogenesis, apoptosis resistance, and even invasiveness in several human cell lines. We reported (14) that the addition of peritoneal fluid, TNF␣, and especially IL-6 stimulated the basal enzymatic activity observed in endometriotic stromal cells, which suggests that the local production of E in endometriosis may be stimulated by factors such as cytokines or prostanoids present in the peritoneal fluid of patients with endometriosis. Thus, the presence of aromatase and the consequent synthesis of E may promote the growth of endometriotic implants, and probably favor the formation of leiomyomas, which are more frequent in women with endometriosis (22,23).…”

“…Immunohistochemistry for P450 aromatase was described by Velasco et al (14). Briefly, tissue samples were fixed with 10% paraformaldehyde solution, paraffin-embedded, and cut into 8-m serial sections.…”

“…Recently, we reported on the expression of aromatase in endometriotic tissues and aromatase activity in cell cultures of endometriotic fibroblasts and adipocytes (14). The addition of peritoneal fluid, tumor necrosis factor (TNF)-␣, and especially interleukin (IL)-6 stimulated the basal enzymatic activity observed in both types of cells, which suggests that there is local production of E in endometriosis that may be stimulated by some factors, such as cytokines, present in the peritoneal fluid of patients with endometriosis.…”