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

Abstract and Introduction

Aromatase P450 (P450arom) is the key enzyme for biosynthesis of estrogen, which is an essential hormone for the establishment and growth of endometriosis. There is no detectable aromatase enzyme activity in normal endometrium; therefore, estrogen is not locally produced in endometrium. Endometriosis tissue, however, contains very high levels of aromatase enzyme, which leads to production of significant quantities of estrogen. Moreover, one of the best-known mediators of inflammation and pain, prostaglandin E2, strikingly induces aromatase enzyme activity and formation of local estrogen in this tissue. Additionally, estrogen itself stimulates cyclo-oxygenase-2 and therefore increases the formation of prostaglandin E2 in endometriosis. We were able to target this positive feedback cycle in endometriosis using aromatase inhibitors. In fact, pilot trials showed that aromatase inhibitors could decrease pelvic pain associated with endometriosis.

Endometriosis is one of the most prominent public health problems in the United States.[1,2] It is characterized by the presence of endometrial glands and stroma within the pelvic peritoneum and other extrauterine sites and is linked to pelvic pain and infertility. It is estimated to affect 5% of women in the reproductive age group.[1,2] Endometriosis is a polygenically inherited disease of complex multifactorial etiology.[3] Sampson's theory of transplantation of endometrial tissue on the pelvic peritoneum via retrograde menstruation is the most widely accepted explanation for the development of pelvic endometriosis because of convincing circumstantial and experimental evidence.[4] Given that retrograde menstruation is observed in almost all cycling women, endometriosis is postulated to develop as a result of the coexistence of a defect in clearance of the menstrual efflux from pelvic peritoneal surfaces, possibly involving the immune system.[5] Alternatively, intrinsic molecular aberrations in pelvic endometriotic implants were proposed to significantly contribute to development of endometriosis. Aberrant expression of aromatase, certain cytokines and tissue metalloproteinases, deficiency of 17β-hydroxysteroid dehydrogenase (17β-HSD) type 2 and resistance to the protective action of progesterone are some of these molecular abnormalities.[6,7,8,9,10,11,12] Because endometriosis is an estrogen-dependent disorder, aromatase expression and 17β-HSD type 2 deficiency are of paramount importance in the pathophysiology of endometriosis. Aromatase causes accumulation of the biologically active estrogen estradiol (E2) in this tissue. 17β-HSD type 2 that metabolizes E2 to estrone (E1) is deficient in endometriosis. The combination of these two abnormalities serves to maintain high levels of E2 in endometriosis tissue.

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