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DOI: 10.1055/s-2003-41319
Endometriosis: The Ultimate Hormonal Disease
Publication History
Publication Date:
14 August 2003 (online)
ABSTRACT
Estrogen is an extremely potent mitogen for endometrium and endometriosis. Progesterone, on the other hand, inhibits the mitogenic action of estrogen on endometrium and enhances differentiation. These antiproliferative and differentiative effects of progesterone are less pronounced on endometriosis tissue compared with endometrium. Thus, endometriosis is, at least in part, resistant to progesterone action. The product of a single gene named aromatase synthesizes estrogen. The potent estrogen estradiol is metabolized and thus inactivated by an enzyme termed 17β-hydroxysteroid dehydrogenase (HSD) type 2 that is normally induced by progesterone in endometrium. Progesterone action is mediated by its receptor subtypes progesterone receptor (PR)-A and PR-B. We found a number of abnormalities in the expression of aromatase, 17β-HSD type 2, and the PR-B/PR-A ratio in endometriosis tissue. These abnormalities and their functional consequences are discussed in this review article.
KEYWORDS
Endometriosis - aromatase - aromatase inhibitor - endometrium - estrogen - estrogen biosynthesis - estrogen metabolism - 17β-hydroxysteroid dehydrogenase type 2 - steroidogenesis - progesterone - estrone - estradiol - progesterone receptor
REFERENCES
- 1 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
- 2 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
- 3 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
- 4 Sharpe-Timms K L, Penney L L, Zimmer R L. et al . 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
- 5 Noble L S, Simpson E R, Johns A, Bulun S E. Aromatase expression in endometriosis. J Clin Endocrinol Metab . 1996; 81 174-179
- 6 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 steroidogenic factor-1 and chicken ovalbumin upstream promoter transcription factor to the same cis-acting element. Mol Endocrinol . 1999; 13 239-253
- 7 Zeitoun K, Takayama K, Sasano H. et al . Deficient 17β-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17β-estradiol. J Clin Endocrinol Metab . 1998; 83 4474-4480
- 8 Attia G R, Zeitoun K, Edwards D. et al . Progesterone receptor isoform A but not B is expressed in endometriosis. J Clin Endocrinol Metab . 2000; 85 2897-2902
- 9 Dizerega G S, Barber D L, Hodgen G D. Endometriosis: role of ovarian steroids in initiation, maintenance, and suppression. Fertil Steril . 1980; 33 649-653
- 10 Scott R B, Wharton Jr R L. The effect of estrone and progesterone on the growth of experimental endometriosis in rhesus monkeys. Am J Obstet Gynecol . 1957; 74 852-858
- 11 Takayama K, Zeitoun K, Gunby R T. et al . Treatment of severe postmenopausal endometriosis with an aromatase inhibitor. Fertil Steril . 1998; 69 709-713
- 12 Yang S, Fang Z, Gurates B. et al . Stromal PRs mediate induction of 17β-hydroxysteroid dehydrogenase type 2 expression in human endometrial epithelium: a paracrine mechanism for inactivation of E2 . Mol Endocrinol . 2001; 15 2093-2105
- 13 Casey M L, MacDonald P C, Andersson S. 17β-Hydroxysteroid dehydrogenase type 2: chromosomal assignment and progestin regulation of gene expression in human endometrium. J Clin Invest . 1994; 94 2135-2141
- 14 Simpson E R, Zhao Y, Agarwal V R. et al . Aromatase expression in health and disease. Recent Prog Horm Res . 1997; 52 185-213
- 15 Bruch H R, Wolf L, Budde R, Romalo G, Schweikert H U. Androstenedione metabolism in cultured human osteoblast-like cells. J Clin Endocrinol Metab . 1992; 75 101-105
- 16 Bayard F, Clamens S, Delsol G. et al . Oestrogen biosynthesis, oestrogen metabolism and functional oestrogen receptors in bovine aortic endothelial cells. Ciba Found Symp . 1995; 191 122-132
-
17 Murakami H, Sasano H, Satoh A. et al .Aromatase in human aortic tissue. Presented at the 79th Annual Meeting of the Endocrine Society, Minneapolis, 1998; p. 212 (Abstract)
- 18 Naftolin F, Ryan K J, Davies I J. et al . The formation of estrogens by central neuroendocrine tissues. Recent Prog Horm Res . 1975; 31 295-319
- 19 Ryan K J, Petro Z. Steroid biosynthesis by human ovarian granulosa and thecal cells. J Clin Endocrinol Metab . 1966; 26 46-52
- 20 Ryan K J, Petro Z, Kaiser J. Steroid formation by isolated and recombined ovarian granulosa and thecal cells. J Clin Endocrinol Metab . 1968; 28 355-358
- 21 Sasano H, Okamoto M, Mason J I. et al . Immunolocalization of aromatase, 17α-hydroxylase and side-chain-cleavage P-450 in the human ovary. J Reprod Fertil . 1989; 85 163-169
- 22 Carr B R. Disorders of the Ovary and Female Reproductive Tract. Philadelphia: WB Saunders 1992: 733-798
- 23 Adashi E Y, Resnick C E, Brodie A M, Svoboda M E, VanWyck J J. Somatomedin-C-mediated potentiation of follicle-stimulating hormone induced aromatase activity of cultured rat granulosa cells. Endocrinology . 1985; 117 2313-2320
- 24 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
- 25 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
- 26 Labrie F, Belanger A, Cusan L, Gomez J L, Candas B. Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging. J Clin Endocrinol Metab . 1997; 82 2396-2402
- 27 Pasqualini J R, Chetrite G, Blacker C. et al . Concentrations of estrone, estradiol, and estrone sulfate and evaluation of sulfatase and aromatase activities in pre- and postmenopausal breast cancer patients. J Clin Endocrinol Metab . 1996; 81 1460-1464
- 28 Castagnetta L A, Lo Casto M, Granata O M. et al . Estrogen content and metabolism in human breast tumour tissue and cells. Ann N Y Acad Sci . 1996; 784 314-324
- 29 Bulun S E, Zeitoun K M, Takayama K Simpson E R, Sasano H. Aromatase as a therapeutic target in endometriosis. Trends Endocrinol Metab . 2000; 11 22-27
- 30 Castagnetta L A, Lo Casto M, Granata O M. et al . Estrogen content and metabolism in human breast tumor tissue and cells. Ann N Y Acad Sci . 1996; 784 314-324
- 31 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; 57 514-519
- 32 Zeitoun K, Bulun S E. Aromatase: a key molecule in the pathophysiology of endometriosis and a therapeutic target. Fertil Steril . 1999; 72 961-969
- 33 Huang J-C, Liu D-Y, Yadollahi S, Wu K K, Dawood M Y. Interleukin-1b induces cyclooxygenase-2 gene expression in cultured endometrial stromal cells. J Clin Endocrinol Metab . 1998; 83 538-541
- 34 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
- 35 Sharpe K L, Vernon M W. Polypeptides synthesized and released by rat ectopic uterine implants differ from those of the uterus in culture. Biol Reprod . 1993; 48 1334-1340
- 36 Sharpe K L, Zimmer R L, Griffin W T, Penney L L. Polypeptides synthesized and released by human endometriosis differ from those of the uterine endometrium in cell and tissue explant culture. Fertil Steril . 1993; 60 839-851
- 37 Lebovic D I, Mueller M D, Taylor R N. Vascular endothelial growth factor in reproductive biology. Curr Opin Obstet Gynecol . 1999; 11 255-260
- 38 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
- 39 Dmowski W P, Steele R W, Baker G F. Deficient cellular immunity in endometriosis. Am J Obstet Gynecol . 1981; 141 377-383
- 40 Hill J A. Immunology and endometriosis. Fertil Steril . 1992; 58 262-264
- 41 Hill J, Anderson D. Lymphocyte activity in the presence of peritoneal fluid from fertile women and infertile women with and without endometriosis. Am J Obstet Gynecol . 1989; 161 861-864
- 42 Steele W R, Dmowski W P, Marmer D J. Immunologic aspects of human endometriosis. Am J Obstet Gynecol . 1984; 6 33-36
- 43 Halme J, Hammond M G, Hulka J F, Raj S G, Talbert L M. Retrograde menstruation in healthy women and in patients with endometriosis. Obstet Gynecol . 1984; 64 151-154
- 44 Mathur S, Peress M R, Williamson H O. Autoimmunity to endometrium and ovary in endometriosis. Clin Exp Immunol . 1982; 50 259-266
- 45 Gurates B, Sebastian S, Yang S. et al . WT1 and DAX-1 inhibit aromatase P450 expression in human endometrial and endometriotic stromal cells. J Clin Endocrinol Metab . 2002; 87 4369-4377
- 46 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
- 47 Henzl M R, Corson S L, Moghissi K. et al . Administration of nasal nafarelin as compared with oral danazol for endometriosis. N Engl J Med . 1988; 318 485-489
- 48 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
- 49 Metzger D A, Lessey B A, Soper J T, McCarty Jr S K, 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
- 50 Labrie F, Luu-The V, Labrie C. et al . Characterization of two mRNA species encoding human estradiol 17β dehydrogenase and assignment of the gene to chromosome 17. J Steroid Biochem . 1989; 34 189-197
- 51 Labrie Y, Durocher F, Lachance Y. et al . The human type II 17β-hydroxysteroid dehydrogenase gene encodes two alternatively spliced mRNA species. DNA Cell Biol . 1995; 14 849-861
- 52 Wu L, Einstein M, Geissler W M. et al . Expression cloning and characterization of human 17β-hydroxysteroid dehydrogenase type 2, a microsomal enzyme possessing 20α-hydroxysteroid dehydrogenase activity. J Biol Chem . 1993; 268 12964-12969
- 53 Andersson S, Moghrabi N. Physiology and molecular genetics of 17β-hydroxysteroid dehydrogenases. Steroids . 1997; 62 143-147
- 54 Satyaswaroop P G, Wartell D J, Mortel R. Distribution of progesterone receptor, estradiol dehydrogenase, and 20α-dihydroprogesterone dehydrogenase activities in human endometrial glands and stroma: progestin induction of steroid dehydrogenase activities in vitro is restricted to the glandular epithelium. Endocrinology . 1982; 111 743-749
- 55 Tseng L, Gurpide E. Estradiol and 20α-dihydroprogesterone dehydrogenase activities in human endometrium during the menstrual cycle. Endocrinology . 1974; 94 419-423
- 56 Bruner K L, Rodgers W H, Gold L I. et al . Transforming growth factor beta mediates the progesterone suppression of an epithelial metalloproteinase by adjacent stroma in the human endometrium. Proc Natl Acad Sci U S A . 1995; 92 7362-7366
- 57 Chwalisz K, Brenner R M, Fuhrmann U U, Hess-Stumpp H, Elger W. Antiproliferative effects of progesterone antagonist and progesterone receptor modulators on the endometrium. Steroids . 2000; 65 741-751
-
58 Huang J C, Dawood M Y, Wu K K. Regulation of cyclooxygenase-2 gene in cultured endometrial stromal cells by sex steroids [abstract]. Proceedings of the American Society for Reproductive Medicine Meeting, Boston, October 1996
- 59 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; 146 491-500
- 60 Tamura M, Sebastian S, Yang S. et al . Up-regulation of cyclooxygenase-2 expression and prostaglandin synthesis in endometrial stromal cells by malignant endometrial epithelial cells. J Biol Chem . 2002; 277 26208-26216
- 61 Tamura M, Sebastian S, Gurates B. et al . Vascular endothelial growth factor up-regulates cyclooxygenase-2 expression in human endothelial cells. J Clin Endocrinol Metab . 2002; 87 3504-3507
- 62 Tamura M, Sebastian S, Yang S, Gurates B, Bulun S E. Interleukin-1β regulates the level and stability of cyclooxygenase-2 mRNA through activation of nuclear factor-κB and extracellularly regulated kinase in human endometrial stromal cells. J Clin Endocrinol Metab . 2002; 87 3263-3273