Aromatase and Endometriosis

Serdar E. Bulun; Zongjuan Fang; Gonca Imir; Bilgin Gurates; Mitsutoshi Tamura; Bertan Yilmaz; David Langoi; Sanober Amin; Sijun Yang; Santanu Deb

doi:10.1055/s-2004-823026

Seminars in Reproductive Medicine, Table of Contents

Semin Reprod Med 2004; 22(1): 45-50
DOI: 10.1055/s-2004-823026

Aromatase and Endometriosis

Serdar E. Bulun¹ , Zongjuan Fang¹ , Gonca Imir¹ , Bilgin Gurates¹ , Mitsutoshi Tamura² , Bertan Yilmaz¹ , David Langoi² , Sanober Amin¹ , Sijun Yang² , Santanu Deb¹

¹Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois
²Department of Obstetrics and Gynecology, University of Illinois at Chicago, Illinois

Abstract

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.

KEYWORDS

Aromatase - aromatase inhibitor - endometriosis - endometrium - estrogen biosynthesis - pelvic pain

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References

REFERENCES

1 Vessey M P, Villard-Mackintosh L, Painter R. Epidemiology of endometriosis in women attending family planning clinics. BMJ. 1993; 306 182-184
2 Kjerulff K H, Erickson B A, Langenberg P W. Chronic gynecological conditions reported by US women: findings from the National Health Information Survey, 1984 to 1992. Am J Public Health. 1996; 86 195-199
3 Olive D L, Schwartz L B. Endometriosis. N Engl J Med. 1993; 328 1759-1769
4 Sampson J A. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. 1927; 14 422-425
5 Halme J, White C, Kauma S, Estes J, Haskill S. Peritoneal macrophages from patients with endometriosis release growth factor activity in vitro. J Clin Endocrinol Metab. 1988; 66 1044-1049
6 Noble L S, Simpson E R, Johns A, Bulun S E. Aromatase expression in endometriosis. J Clin Endocrinol Metab. 1996; 81 174-179
7 Zeitoun K, Takayama K, Michael M D, Bulun S E. Stimulation of aromatase P450 promoter (II) activity in endometriosis and its inhibition in endometrium are regulated by competitive binding of SF-1 and COUP-TF to the same cis-acting element. Mol Endocrinol. 1999; 13 239-253
8 Khorram O, Taylor R N, Ryan I P, Schall T J, Landers D V. Peritoneal fluid concentrations of the cytokine RANTES correlate with the severity of endometriosis. Am J Obstet Gynecol. 1993; 169 1545-1549
9 Sharpe-Timms K L, Penney L L, Zimmer R L, Wright J A, Zhang Y, Surewicz K. Partial purification and amino acid sequence analysis of endometriosis protein-II (ENDO-II) reveals homology with tissue inhibitor of metalloproteinases-1 (TIMP-1). J Clin Endocrinol Metab. 1995; 80 3784-3787
10 Bruner K L, Matrisian L M, Rodgers W H, Gorstein F, Osteen K G. Suppression of matrix metalloproteinases inhibits establishment of ectopic lesions by human endometrium in nude mice. J Clin Invest. 1997; 99 2851-2857
11 Osteen K G, Bruner K L, Sharpe-Timms K L. Steroid and growth factor regulation of matrix metalloproteinase expression and endometriosis. Semin Reprod Endocrinol. 1996; 14 247-255
12 Zeitoun K, Takayama K, Sasano H et al.. Deficient 17β-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize estradiol-17β. J Clin Endocrinol Metab. 1998; 83 4474-4480
13 Michael M D, Michael L F, Simpson E R. A CRE-like sequence that binds CREB and contributes to cAMP-dependent regulation of the proximal promoter of the human aromatase P450 (CYP19) gene. Mol Cell Endocrinol. 1997; 134 147-156
14 Michael M D, Kilgore M W, Morohashi K I, Simpson E R. Ad4BP/SF-1 regulates cyclic AMP-induced transcription from the proximal promoter (PII) of the human aromatase P450 (CYP19) gene in the ovary. J Biol Chem. 1995; 270 13561-13566
15 Simpson E R, Mahendroo M S, Means G D et al.. Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr Rev. 1994; 15 342-355
16 Ackerman G E, Smith M E, Mendelson C R, MacDonald P C, Simpson E R. Aromatization of androstenedione by human adipose tissue stromal cells in monolayer culture. J Clin Endocrinol Metab. 1981; 53 412-417
17 MacDonald P C, Rombaut R P, Siiteri P K. Plasma precursors of estrogen, I: Extent of conversion of plasma Δ⁴-androstenedione to estrone in normal males and non-pregnant normal, castrate and adrenalectomized females. J Clin Endocrinol Metab. 1967; 27 1103-1111
18 MacDonald P C, Edman C D, Hemsell D L, Porter J C, Siiteri P K. Effect of obesity on conversion of plasma androstenedione to estrone in postmenopausal women with and without endometrial cancer. Am J Obstet Gynecol. 1978; 130 448-455
19 Bulun S E, Price T M, Mahendroo M S, Aitken J, Simpson E R. A link between breast cancer and local estrogen biosynthesis suggested by quantification of breast adipose tissue aromatase cytochrome P450 transcripts using competitive polymerase chain reaction after reverse transcription. J Clin Endocrinol Metab. 1993; 77 1622-1628
20 Yue W, Wang J P, Hamilton C J, Demers L M, Santen R J. In situ aromatization enhances breast tumor estradiol levels and cellular proliferation. Cancer Res. 1998; 58 927-932
21 Bulun S E, Simpson E R, Word R A. Expression of the CYP19 gene and its product aromatase cytochrome P450 in human leiomyoma tissues and cells in culture. J Clin Endocrinol Metab. 1994; 78 736-743
22 Noble L S, Takayama K, Zeitoun K M et al.. Prostaglandin E₂ stimulates aromatase expression in endometriosis-derived stromal cells. J Clin Endocrinol Metab. 1997; 82 600-606
23 Bulun S E, Mahendroo M S, Simpson E R. Polymerase chain reaction amplification fails to detect aromatase cytochrome P450 transcripts in normal human endometrium or decidua. J Clin Endocrinol Metab. 1993; 76 1458-1463
24 Tamura M, Deb S, Sebastian S, Okamura K, Bulun S E. Estrogen up-regulates cyclooxygenase-2 via estrogen receptor in human uterine microvascular endothelial cells. Fertil Steril. 2004; , In press
25 Hill J A. Immunology and endometriosis. Fertil Steril. 1992; 58 262-264
26 Takayama K, Zeitoun K, Gunby R T, Sasano H, Carr B R, Bulun S E. Treatment of severe postmenopausal endometriosis with an aromatase inhibitor. Fertil Steril. 1998; 69 709-713
27 Ailawadi R K, Jobanputra S, Kataria M, Gurates B, Bulun S E. Treatment of endometriosis and chronic pelvic pain with petrozole and norethindrone acetate: a pilot study. Fertil Steril. 2004; , In press
28 Henzl M R, Corson S L, Moghissi K, Buttram V C, Berqvist C, Jacobson J. Administration of nasal nafarelin as compared with oral danazol for endometriosis. N Engl J Med. 1988; 318 485-489
29 Waller K G, Shaw R W. Gonadotropin-releasing hormone analogues for the treatment of endometriosis: long-term follow-up. Fertil Steril. 1993; 59 511-515
30 Metzger D A, Lessey B A, Soper J T, McCarty Jr K S, Haney A F. Hormone-resistant endometriosis following total abdominal hysterectomy and bilateral salpingo-oophorectomy: correlation with histology and steroid receptor content. Obstet Gynecol. 1991; 78 946-950

Serdar E BulunM.D.

Department of Obstetrics and Gynecology, Northwestern University

333 E. Superior Street, Suite 484, Chicago, IL 60611