Expression of Aromatase and Estrogen Sulfotransferase in Eutopic and Ectopic Endometrium: Evidence for Unbalanced Estradiol Production in Endometriosis

Abstract

Endometriosis is an estrogen-dependent gynecological disease causing pelvic pain and infertility. Impaired estrogen metabolism is thought to play a pivotal role in the pathogenesis of the disease. While there is some information on factors involved in the synthesis of E2, information on E2-deactivating enzymes is still very limited. To elucidate the intracrinology of endometriotic tissues, the authors analyze the expression of aromatase and E2-inactivating estrogen sulfotransferase (EST) in paired biopsies obtained simultaneously from the endometrium and from endometrial lesions of each of 35 patients with peritoneal or ovarian endometriosis and in cycling endometria from 33 women without endmetriosis. Protein localization was demonstrated by immunohistochemistry. Aromatase expression was found in endometriotic glands in 32 of 35 cases and was elevated in comparison to corresponding uterine endometria (25 of 35 cases, P = .021, χ ² test). The difference was even more pronounced when uterine endometria from endometriosis patients were compared with that of healthy controls (8 of 33 cases, P < .001, χ ² test). The EST levels were essentially unchanged. The elevated expression of aromatase in eutopic and ectopic endometrium from patients with endometriosis in the presence of comparable EST provides further evidence for unopposed local biosynthesis of estrogens in endometriosis.

Keywords

Endometriosis aromatase estrogen sulfotransferase autonomous E2 production.

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References

Melis GB , Ajossa S. , Guerriero S. , et al. Epidemiology and diagnosis of endometriosis. Ann N Y Acad Sci. 1994;734:352-357.

Kjerulff KH , Erickson BA , Langenberg PW Chronic gynecological conditions reported by US women: findings from the National Health Interview Survey, 1984 to 1992. Am J Public Health. 1996;86(2):195-199.

Vignali M. , Infantino M. , Matrone R. , et al. Endometriosis: novel etiopathogenetic concepts and clinical perspectives. Fertil Steril. 2002;78(4):665-678.

Valle RF Endometriosis: current concepts and therapy. Int J Gynaecol Obstet. 2002;78(2):107-119.

Waller KG , Shaw RW Gonadotropin-releasing hormone analogues for the treatment of endometriosis: long-term follow-up. Fertil Steril. 1993;59(3):511-515.

Bulun SE , Zeitoun KM , Takayama K. , Sasano H. Estrogen biosynthesis in endometriosis: molecular basis and clinical relevance . J Mol Endocrinol. 2000;25(1):35-42.

Kitawaki J. , Noguchi T. , Amatsu T. , et al. Expression of aromatase cytochrome P450 protein and messenger ribonucleic acid in human endometriotic and adenomyotic tissues but not in normal endometrium. Biol Reprod. 1997;57(3):514-519.

Matsuzaki S. , Canis M. , Pouly JL , Dechelotte PJ , Mage G. Analysis of aromatase and 17beta-hydroxysteroid dehydrogenase type 2 messenger ribonucleic acid expression in deep endometriosis and eutopic endometrium using laser capture microdissection. Fertil Steril. 2006;85(2):308-313.

Attar E. , Bulun SE Aromatase and other steroidogenic genes in endometriosis: translational aspects . Hum Reprod Update. 2006;12(1):49-56.

10.

Bulun SE , Gurates B. , Fang Z. , et al. Mechanisms of excessive estrogen formation in endometriosis . J Reprod Immunol. 2002;55(1-2):21-33.

11.

Abul-Hajj YJ , Iverson R. , Kiang DT Aromatization of androgens by human breast cancer. Steroids. 1979;33(2):205-222.

12.

Lipton A. , Santner SJ , Santen RJ , et al. Aromatase activity in primary and metastatic human breast cancer . Cancer. 1987;59(4): 779-782.

13.

Suzuki T. , Miki Y. , Nakamura Y. , et al. Sex steroid-producing enzymes in human breast cancer. Endocr Relat Cancer. 2005;12(4):701-720.

14.

Zhang H. , Varlamova O. , Vargas FM , Falany CN , Leyh TS Sulfuryl transfer: the catalytic mechanism of human estrogen sulfotransferase . J Biol Chem. 1998;273(18):10888-10892.

15.

Geisler J. Breast cancer tissue estrogens and their manipulation with aromatase inhibitors and inactivators. J Steroid Biochem Mol Biol. 2003;86(3-5):245-253.

16.

Geisler J. , Lonning PE Aromatase inhibition: translation into a successful therapeutic approach. Clin Cancer Res. 2005;11(8): 2809-2821.

17.

Bulun SE , Zeitoun K. , Takayama K. , et al. Estrogen production in endometriosis and use of aromatase inhibitors to treat endometriosis. Endocr Relat Cancer. 1999;6(2):293-301.

18.

Zeitoun KM , Bulun SE Aromatase: a key molecule in the pathophysiology of endometriosis and a therapeutic target. Fertil Steril. 1999;72(6):961-969.

19.

Rock JA The revised American Fertility Society classification of endometriosis: reproducibility of scoring. ZOLADEX Endometriosis Study Group. Fertil Steril. 1995;63(5):1108-1110.

20.

Sasano H. , Frost AR , Saitoh R. , et al. Aromatase and 17 beta-hydroxysteroid dehydrogenase type 1 in human breast carcinoma. J Clin Endocrinol Metab. 1996;81(11):4042-4046.

21.

Sasano H. , Nagura H. , Harada N. , Goukon Y. , Kimura M. Immunolocalization of aromatase and other steroidogenic

22.

enzymes in human breast disorders. Hum Pathol. 1994;25(5): 530-535.

23.

Singer CF , Fink-Retter A. , Gschwantler-Kaulich D. , et al. Selective spatial up-regulation of intratumoral stromal aromatase in breast cancer patients: evidence for imbalance of local estrogen metabolism. Endocr Relat Cancer. 2006;13(4): 1101-1107.

24.

Remmele W. , Stegner HE Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue [in German]. Pathologe. 1987;8(3):138-140.

25.

Bulun SE , Lin Z. , Imir G. , et al. Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment. Pharmacol Rev. 2005;57(3):359-383.

26.

Bulun SE , Fang Z. , Imir G. , et al. Aromatase and endometriosis. Semin Reprod Med. 2004;22(1):45-50.

27.

Maia H. , Pimentel K. , Casoy J. , et al. Aromatase expression in the eutopic endometrium of myomatous uteri: the influence of the menstrual cycle and oral contraceptive use. Gynecol Endocrinol. 2007;23(6):320-324.

28.

Watanabe K. , Sasano H. , Harada N. , et al. Aromatase in human endometrial carcinoma and hyperplasia: immunohistochemical, in situ hybridization, and biochemical studies. Am J Pathol. 1995;146(2):491-500.

29.

Heilier JF , Donnez O. , Van Kerckhove V. , Lison D. , Donnez J. Expression of aromatase (P450 aromatase/CYP19) in peritoneal and ovarian endometriotic tissues and deep endometriotic (adenomyotic) nodules of the rectovaginal septum . Fertil Steril. 2006;85(5):1516-1518.

30.

Falany JL , Falany CN Regulation of estrogen sulfotransferase in human endometrial adenocarcinoma cells by progesterone. Endocrinology. 1996 ;137(4):1395-1401.

31.

Hata H. , Holinka CF , Pahuja SL , Hochberg RB , Kuramoto H. , Gurpide E. Estradiol metabolism in Ishikawa endometrial cancer cells. J Steroid Biochem. 1987;26(6):699-704.

32.

Zeitoun K. , Takayama K. , Sasano H. , et al. Deficient 17beta-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17beta-estradiol. J Clin Endocrinol Metab. 1998;83(12):4474-4480.