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Reproductive Endocrinology |
The Cecil H. and Ida Green Center for Reproductive Biology Sciences and the Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas 75235
Address all correspondence and requests for reprints to: Serdar E. Bulun, M.D., The Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235-9051. E-mail: bulun{at}grnctr.swmed.edu
C19 steroids are converted to estrogens by aromatase P450
(P450arom). Aromatase expression in humans is regulated by use of
tissue-specific promoters in the placenta (promoter I.1), adipose
tissue (promoters I.4, I.3, and II), and gonads (promoter II). The use
of each promoter gives rise to a population of P450arom messenger
ribonucleic acid (mRNA) species with a unique untranslated 5'-terminus.
Aromatase is not expressed in the endometrium of disease-free women. We
demonstrated, however, the presence of P450arom mRNA in pelvic
endometriotic implants and eutopic endometrial curettings of women with
endometriosis. In the current report, aromatase activity and P450arom
gene expression were investigated in cultured stromal cells derived
from eutopic endometrium and ovarian endometriomas of women with pelvic
endometriosis. We also investigated the hormonal regulation of
aromatase expression and alternative promoter use in these cells. The
effects of interleukin-1ß (IL-1ß), IL-2, IL-6, IL-11, oncostatin M,
IL-15, tumor necrosis factor-
, PGE2, estradiol, R5020,
dexamethasone, and dibutyryl cAMP (Bt2cAMP) on aromatase
activity in endometriosis-derived stromal cells were assessed. We chose
treatments with PGs and ILs because of the inflammatory nature of
endometriosis. PGE2 stimulated aromatase activity in
endometriosis-derived stromal cells by 19- to 44-fold (37–221 pmol/mg
protein·4 h), whereas Bt2cAMP induction was 26- to
60-fold the baseline level. No stimulation was observed by estradiol or
R5020 or by IL-1ß, IL-2, IL-6, IL-11, IL-15, or TNF in the
presence or absence of glucocorticoids. A modest induction of aromatase
activity (2-fold) was observed in dexamethasone- plus oncostatin
M-treated cells. These changes in aromatase activity were accompanied
by comparable changes in the levels of P450arom mRNA levels, determined
by a quantitative reverse transcription-PCR method. Promoter-specific
5'-ends of P450arom transcripts in total RNA from endometriosis-derived
stromal cells treated with PGE2 and Bt2cAMP
were amplified employing a novel modified rapid
amplification of cDNA 5'-ends/Southern hybridization method using
exon-specific oligonucleotide probes. The majority of P450arom
transcripts in these cells contained the gonadal-type promoter
II-specific sequences, whereas very few transcripts contained
adipose-type promoter I.3- and I.4-specific sequences.
PGE2 appears to be the most potent known stimulator of aromatase in endometriosis. Aromatase expression in PGE2-stimulated stromal cells of endometriosis is regulated primarily by the classically located promoter II, which, in turn, is regulated by cAMP. As PGE2 is known to increase intracellular cAMP levels, estrogen biosynthesis in endometriosis may be primarily regulated by PGE2 that is locally produced. Consequent local estrogen production may promote the growth of endometriotic implants.
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B. Gurates, S. Sebastian, S. Yang, J. Zhou, M. Tamura, Z. Fang, T. Suzuki, H. Sasano, and S. E. Bulun WT1 and DAX-1 Inhibit Aromatase P450 Expression in Human Endometrial and Endometriotic Stromal Cells J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4369 - 4377. [Abstract] [Full Text] [PDF]
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Z. Fang, S. Yang, B. Gurates, M. Tamura, E. Simpson, D. Evans, and S. E. Bulun Genetic or Enzymatic Disruption of Aromatase Inhibits the Growth of Ectopic Uterine Tissue J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3460 - 3466. [Abstract] [Full Text] [PDF]
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M. Shozu, H. Sumitani, T. Segawa, H.-J. Yang, K. Murakami, T. Kasai, and M. Inoue Overexpression of Aromatase P450 in Leiomyoma Tissue Is Driven Primarily through Promoter I.4 of the Aromatase P450 Gene (CYP19) J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2540 - 2548. [Abstract] [Full Text] [PDF]
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S. Yang, Z. Fang, T. Suzuki, H. Sasano, J. Zhou, B. Gurates, M. Tamura, K. Ferrer, and S. Bulun Regulation of Aromatase P450 Expression in Endometriotic and Endometrial Stromal Cells by CCAAT/Enhancer Binding Proteins (C/EBPs): Decreased C/EBP{beta} in Endometriosis Is Associated with Overexpression of Aromatase J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2336 - 2345. [Abstract] [Full Text] [PDF]
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S.-J. Tsai, M.-H. Wu, C.-C. Lin, H. S. Sun, and H.-M. Chen Regulation of Steroidogenic Acute Regulatory Protein Expression and Progesterone Production in Endometriotic Stromal Cells J. Clin. Endocrinol. Metab., December 1, 2001; 86(12): 5765 - 5773. [Abstract] [Full Text] [PDF]
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S. Ramachandran, M. Song, A. A. Murphy, and S. Parthasarathy Expression of Scavenger Receptor Class B1 in Endometrium and Endometriosis J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3924 - 3928. [Abstract] [Full Text] [PDF]
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I.A. Brosens and J.J. Brosens Redefining endometriosis: Is deep endometriosis a progressive disease? Hum. Reprod., January 1, 2000; 15(1): 1 - 3. [Full Text] [PDF]
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G. Leyendecker Redefining endometriosis: Endometriosis is an entity with extreme pleiomorphism Hum. Reprod., January 1, 2000; 15(1): 4 - 7. [Full Text] [PDF]
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G. Kunz, D. Beil, P. Huppert, and G. Leyendecker Structural abnormalities of the uterine wall in women with endometriosis and infertility visualized by vaginal sonography and magnetic resonance imaging Hum. Reprod., January 1, 2000; 15(1): 76 - 82. [Abstract] [Full Text] [PDF]
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K. Zeitoun, K. Takayama, M. D. Michael, and S. E. Bulun 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., February 1, 1999; 13(2): 239 - 253. [Abstract] [Full Text]
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K. Zeitoun, K. Takayama, H. Sasano, T. Suzuki, N. Moghrabi, S. Andersson, A. Johns, L. Meng, M. Putman, B. Carr, et al. Deficient 17{beta}-Hydroxysteroid Dehydrogenase Type 2 Expression in Endometriosis: Failure to Metabolize 17{beta}-Estradiol J. Clin. Endocrinol. Metab., December 1, 1998; 83(12): 4474 - 4480. [Abstract] [Full Text]
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 L. Hilakivi-Clarke, R. Clarke, I. Onojafe, M. Raygada, E. Cho, and M. Lippman A maternal diet high in n - 6 polyunsaturated fats alters mammary gland development, puberty onset, and breast cancer risk among female rat offspring PNAS, August 19, 1997; 94(17): 9372 - 9377. [Abstract] [Full Text] [PDF]
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