Aromatase and Endometriosis

Serdar E. Bulun, M.D.; Zongjuan Fang, M.D.; Gonca Imir, M.D.; Bilgin Gurates, M.D.; Mitsutoshi Tamura, M.D.; Bertan Yilmaz, M.S.; David Langoi, D.V.M.; Sanober Amin, B.S.; Sijun Yang, M.D.; Santanu Deb, Ph.D.

Disclosures

Semin Reprod Med. 2004;22(1) 

In This Article

Aromatase in Endometriosis

Endometrium and myometrium contain extremely high levels of estrogen receptors and, thus, are prime targets of estrogen. Until recently, estrogen action has been classically viewed to occur only via an "endocrine" mechanism: in other words, it was thought that only circulating estradiol, whether secreted by the ovary or formed in the adipose tissue, could exert an estrogenic effect after delivery to target tissues via the bloodstream. Studies on aromatase expression in breast cancer demonstrated that paracrine mechanisms play an important role in estrogen action in this tissue.[19] Estrogen produced by aromatase activity in breast adipose tissue fibroblasts was demonstrated to promote the growth of adjacent malignant breast epithelial cells.[20] Finally, we demonstrated an "intracrine" effect of estrogen in uterine leiomyomas and endometriosis: Estrogen produced by aromatase activity in the cytoplasm of leiomyoma smooth muscle cells or endometriotic stromal cells can exert its effects by readily binding to its nuclear receptor within the same cell.[6,21,22] Disease-free endometrium and myometrium, on the other hand, lack aromatase expression.[21,22]

Among estrogen-responsive pelvic disorders, aromatase expression was studied in greatest detail in endometriosis.[6,7,22,23] First, extremely high levels of aromatase mRNA were found in extraovarian endometriotic implants and endometriomas. Second, endometriosis-derived stromal cells in culture incubated with a cAMP analog displayed extraordinarily high levels of aromatase activity comparable to that in placental syncytiotrophoblast.[22] These exciting findings led us to test a battery of growth factors, cytokines, and other substances that might induce aromatase activity via a cAMP-dependent pathway in endometriosis. Prostaglandin E2 (PGE2) was found to be the most potent known inducer of aromatase activity in endometriotic stromal cells.[22] In fact, this PGE2 effect was found to be mediated via the cAMP-inducing EP2 receptor subtype (our unpublished observations). Moreover, estrogen was reported to increase PGE2 formation by stimulating cyclooxygenase type 2 (COX-2) enzyme in endometrial stromal cells in culture.[24] Thus, a positive feedback loop for continuous local production of estrogen and prostaglandins (PGs) is established, favoring the proliferative and inflammatory characteristics of endometriosis (Fig. 2). Additionally, aromatase mRNA was also detected in the eutopic endometrial samples of women with moderate to severe endometriosis (but not in those of disease-free women) albeit in much smaller quantities compared with endometriotic implants.[6] This may be suggestive of a genetic defect in women with endometriosis, which is manifested by this subtle finding in the eutopic endometrium. We propose that, when defective endometrium with low levels of aberrant aromatase expression reaches the pelvic peritoneum by retrograde menstruation, it causes an inflammatory reaction that exponentially increases local aromatase activity (i.e., estrogen formation) induced directly or indirectly by PGs and cytokines.[22] It would be rather naive to propose that aberrant aromatase expression is the only important molecular mechanism in the development and growth of pelvic endometriosis. There may be many other molecular mechanisms that favor the development of endometriosis: abnormal expression of proteinase type enzymes that remodel tissues or their inhibitors (matrix metalloproteinases, tissue inhibitor of metalloproteinase-1), certain cytokines (IL-6, RANTES [regulated on activation, normal T cell expressed and secreted]), and growth factors (epidermal growth factor) represent some of the mechanisms.[8,9,10,11] Alternatively, a defective immune system that fails to clear peritoneal surfaces of the retrograde menstrual efflux has been proposed in the development of endometriosis.[5,25] The development of endometriosis in an individual woman probably requires the coexistence of a threshold number of these aberrations. Nonetheless, the clinical importance of aromatase expression pertains because we could treat endometriosis using aromatase inhibitors.[26,27]

A positive feedback cycle for estrogen and prostaglandin formation. Estradiol (E2) in an endometriotic lesion arises from several body sites. In an ovulatory woman, estradiol is secreted directly from the ovary in a cyclic fashion. In the early follicular phase and after menopause, peripheral tissues (adipose and skin) are the most important sources to account for the circulating estradiol. Estradiol is also produced locally in the endometriotic implant itself in both ovulatory and postmenopausal women. The most important precursor, androstenedione (A) of adrenal origin, becomes converted to estrone (E1), which is in turn reduced to estradiol in the peripheral tissues and endometriotic implants. We demonstrated significant levels of 17β-hydroxysteroid dehydrogenase type 1 (reductase) expression in endometriosis, which catalyzes the conversion of estrone to estradiol.[12] Estradiol both directly and indirectly (through cytokines) induces cyclo-oxygenase-2 (COX-2), which gives rise to elevated concentrations of prostaglandin E2 (PGE2) in endometriosis.[24] PGE2 in turn, is the most potent known stimulator of aromatase in endometriotic stromal cells.[22] This establishes a positive feedback loop in favor of continuous estrogen formation in endometriosis.

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