Cited by 566Endometriosis Research and TreatmentEstrogen and related hormone effectsEndometrial and Cervical Cancer Treatments

The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.

Aromatase expression in endometriosis.

Noble, L S, Simpson, E R, Johns, A, Bulun, S E·1996·The Journal of Clinical Endocrinology & Metabolism

DOI 10.1210/jcem.81.1.8550748

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Abstract

The conversion of C19 steroids to estrogens occurs in a number of tissues, such as the ovary and placenta, and is catalyzed by aromatase P450 (P450arom; the product of the CYP19 gene). P450arom expression has also been detected in a number of uterine tumors, such as leiomyomas and endometrial cancer. On the other hand, P450arom expression was undetectable in normal endometrial and myometrial tissues. The present study was conducted to determine the presence or absence of aromatase expression in peritoneal endometriotic implants and in the eutopic endometrium of women with endometriosis. Endometriotic implants in pelvic peritoneum (n = 17; e.g. posterior culdesac, bladder, and anterior culdesac) and eutopic endometrial curettings (n = 11) of 14 patients with histologically documented pelvic endometriosis were obtained at the time of laparoscopy or laparotomy. Pelvic peritoneal biopsies distal to endometriotic implants as well as normal endometrial tissues (n = 7) from disease-free women were used as negative controls. We used competitive RT-PCR technology employing an internal standard to amplify P450arom transcripts in total ribonucleic acid (RNA) isolated from these tissues. P450arom transcripts were detected in all endometriotic implants and in all eutopic endometrial tissues from patients with endometriosis. P450arom messenger RNA species were not detectable in endometrial tissues from disease-free women or in endometriosis-free peritoneal tissues. The highest levels of transcripts were detected in an endometriotic implant that involved the full thickness of the anterior abdominal wall. The P450arom transcript level within the core of this endometriotic mass was 4-fold higher than that in the surrounding adipose tissue. It has been shown recently that aromatase expression in various human tissues is regulated by the use of tissue-specific promoters via alternative splicing. To analyze promoter usage, we amplified by RT-PCR the most likely promoter-specific untranslated 5'-termini of P450arom transcripts in 2 endometriotic implants. It appears that these endometriotic implants use both the adipose-type promoter I.4 and gonadal-type promoter II for aromatase expression. The use of promoter I.4 for aromatase expression in adipose tissue has been recently observed to be regulated by members of the interleukin-6 (IL-6) cytokine family. Based on these findings, we examined by RT-PCR, IL-6 and IL-11 messenger RNA expression in 5 endometriotic tissues and 1 eutopic endometrial sample from a patient with endometriosis. We detected IL-6 and IL-11 transcripts in all endometriotic tissues and in the eutopic endometrial tissue sample studied. Our findings indicate that both eutopic endometrial tissues and endometriotic implants from patients with endometriosis are biochemically different from normal endometrial tissues of disease-free women. The presence of aromatase expression in eutopic endometrial tissues from patients with endometriosis may be related to the capability of implantation of these tissues on peritoneal surfaces. Furthermore, the possibility of estrogen production in these implants may serve to promote their growth. Increased IL-6 and IL-11 expression in these tissues suggests that P450arom expression in endometriosis may be regulated in part by these cytokines.

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Background
Environmental Dioxins and Endometriosis
Rier, S. (2002) · Toxicological Sciences · doi:10.1093/toxsci/70.2.161 · Cited by 119
CXCL8 enhances proliferation and growth and reduces apoptosis in endometrial stromal cells in an autocrine manner via a CXCR1-triggered PTEN/AKT signal pathway
Li, M., Luo, X., Meng, Y.-H., Mei, J., Zhu, X., Jin, L.-P., & Li, D.-J. (2012) · Human Reproduction · doi:10.1093/humrep/des132 · Cited by 81
Steroidogenic factor-1 and endometriosis
Bulun, S. E., Utsunomiya, H., Lin, Z., Yin, P., Cheng, Y.-H., Pavone, M. E., Tokunaga, H., Trukhacheva, E., Attar, E., Gurates, B., et al. (2009) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2008.12.012 · Cited by 80
Self-citation
Epigenetic regulation of the pathological process in endometriosis
Hsiao, K., Wu, M., & Tsai, S. (2017) · Reproductive Medicine and Biology · doi:10.1002/rmb2.12047 · Cited by 79
PPAR-gamma receptor ligand induces regression of endometrial explants in baboons: A prospective, randomized, placebo- and drug-controlled study
Lebovic, D. I., Mwenda, J. M., Chai, D. C., Mueller, M. D., Santi, A., Fisseha, S., & D’Hooghe, T. M. (2007) · Fertility and Sterility · doi:10.1016/j.fertnstert.2006.12.072 · Cited by 79
“The discovery that these lesions possess the functional aromatase enzyme whereas normal endometrium from control subjects does not (33), allows for a reconciliation of separate pathophysiologies—namely, the inflammatory component and the estrogen dependency of the disease.”
Background
Multiple Splicing Events Involved in Regulation of Human Aromatase Expression by a Novel Promoter, I.6
Shozu, M., Zhao, Y., Bulun, S. E., & Simpson, E. R. (1998) · Endocrinology · doi:10.1210/endo.139.4.5878 · Cited by 79
Self-citation
Weighted Gene Co-expression Network Analysis of Endometriosis and Identification of Functional Modules Associated With Its Main Hallmarks
Bakhtiarizadeh, M. R., Hosseinpour, B., Shahhoseini, M., Korte, A., & Gifani, P. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00453 · Cited by 78
Regulation of Aromatase P450 Expression in Endometriotic and Endometrial Stromal Cells by CCAAT/Enhancer Binding Proteins (C/EBPs): Decreased C/EBPβ in Endometriosis Is Associated with Overexpression of Aromatase
Yang, S., Fang, Z., Suzuki, T., Sasano, H., Zhou, J., Gurates, B., Tamura, M., Ferrer, K., & Bulun, S. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.87.5.8486 · Cited by 77
Self-citation
Increased leptin expression in endometriosis cells is associated with endometrial stromal cell proliferation and leptin gene up-regulation
Wu, M.-H. (2002) · Molecular Human Reproduction · doi:10.1093/molehr/8.5.456 · Cited by 77
“One of the examples is the acquisition of estrogen-producing ability in ectopic endometriotic implants (Noble et al., 1996; Bulun et al., 1999, 2000).”
Background
Apoptosis and endometriosis
Harada, T. (2007) · Frontiers in bioscience · doi:10.2741/2302 · Cited by 77
MAP kinases and the inflammatory signaling cascade as targets for the treatment of endometriosis?
Santulli, P., Marcellin, L., Tosti, C., Chouzenoux, S., Cerles, O., Borghese, B., Batteux, F., & Chapron, C. (2015) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2015.1090974 · Cited by 75
“2 Inflammation and stimulation of steroidogenesis It has been shown that endometriotic stromal cells exhibit an abnormal level of estrogen production [34,51,52].”
Background
Estradiol Amplifies Interleukin-1-Induced Monocyte Chemotactic Protein-1 Expression by Ectopic Endometrial Cells of Women with Endometriosis
Akoum, A., Jolicoeur, C., & Boucher, A. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.2.6348 · Cited by 85
“dometrial tissue may have the inherent capability to produce E2 locally, as they were found to express P450 aromatase, which catalyses C19 steroid conversion to estrogens (48).”
Demethylation of a nonpromoter cytosine-phosphate-guanine island in the aromatase gene may cause the aberrant up-regulation in endometriotic tissues
Izawa, M., Taniguchi, F., Uegaki, T., Takai, E., Iwabe, T., Terakawa, N., & Harada, T. (2011) · Fertility and Sterility · doi:10.1016/j.fertnstert.2010.06.024 · Cited by 73
Treatment strategies for endometriosis
Rodgers, A. K., & Falcone, T. (2008) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.9.2.243 · Cited by 72
“Transcription of the aromatase gene is tightly controlled within endometriosis implants and can be upregulated by prostaglandin E2 [63-65] .”
Background
Aromatase inhibitors and cyclooxygenase-2 (COX-2) inhibitors in endometriosis: New questions—old answers?
Ebert, A. D., Bartley, J., & David, M. (2005) · European Journal of Obstetrics & Gynecology and Reproductive Biology · doi:10.1016/j.ejogrb.2005.04.017 · Cited by 73
“Recently the overexpression of aromatase [54,55] and a deficiency of 17b-hydroxysteroid dehydrogenase type 2 (17b-HSD-Typ2) were also detected in endometriosis tissue [71,72].”
Background
Upstream stimulatory factor-2 regulates steroidogenic factor-1 expression in endometriosis
Utsunomiya, H., Cheng, Y.-H., Lin, Z., Reierstad, S., Yin, P., Attar, E., Xue, Q., Imir, G., Thung, S., Trukhacheva, E., et al. (2008) · Molecular Endocrinology · doi:10.1210/me.2006-0302 · Cited by 72
Self-citation
Collagen gel contractility is enhanced in human endometriotic stromal cells: a possible mechanism underlying the pathogenesis of endometriosis-associated fibrosis
Yuge, A., Nasu, K., Matsumoto, H., Nishida, M., & Narahara, H. (2007) · Human Reproduction · doi:10.1093/humrep/del485 · Cited by 72
“…receptor type I (Nishida et al., 2004), decreased expression of HOXA10 (Browne and Taylor, 2006), aberrant expression of aromatase P450 (Noble et al., 1996) and enhanced expression of interleukin-6 (Tseng et al., 1996), B-cell lymphoma/ leukemia-2 (Bcl-2) (Nishida et al., 2005),…”
Background
WT1 and DAX-1 inhibit aromatase P450 expression in human endometrial and endometriotic stromal cells.
Gurates, B., Sebastian, S., Yang, S., Zhou, J., Tamura, M., Fang, Z., Suzuki, T., Sasano, H., & Bulun, S. E. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2002-020522 · Cited by 70
“activity was either undetectable or barely detectable (6, 7).”
BackgroundSelf-citation
Novel therapeutic targets to improve IVF outcomes in endometriosis patients: a review and future prospects
Corachán, A., Pellicer, N., Pellicer, A., & Ferrero, H. (2021) · Human Reproduction Update · doi:10.1093/humupd/dmab014 · Cited by 70
Treatment of severe recurrent endometriosis with an aromatase inhibitor in a young ovariectomised woman
Razzi, S., Fava, A., Sartini, A., Simone, S. D., Cobellis, L., & Petraglia, F. (2004) · BJOG An International Journal of Obstetrics & Gynaecology · doi:10.1046/j.1471-0528.2003.00038.x · Cited by 69
Is the endometrium or oocyte/embryo affected in endometriosis?
Garcia-Velasco, J. A., & Arici, A. (1999) · Human Reproduction · doi:10.1093/humrep/14.suppl_2.77 · Cited by 68
The influence of maternal diet on breast cancer risk among female offspring
Hilakivi-Clarke, L. A., Clarke, R. C., & Lippman, M. E. (1999) · Nutrition · doi:10.1016/s0899-9007(99)00029-5 · Cited by 66
Diagnostic and therapeutic options in recurrent implantation failure
Moustafa, S. M., & Young, S. L. (2020) · F1000Research · doi:10.12688/f1000research.22403.1 · Cited by 67
“Occult endometriosis is considered a possible etiology for RIF and is associated with decreased integrin expression and increased aromatase expression 78,79 .”
Background
Effect of aromatase inhibitors on ectopic endometrial growth and peritoneal environment in a mouse model of endometriosis
Bilotas, M. A., Meresman, G. F., Stella, I., Sueldo, C. E., & Barañao, R. I. (2009) · Fertility and Sterility · doi:10.1016/j.fertnstert.2009.08.058 · Cited by 67
“One of the most recent significant findings has been the discovery that ectopic endometrium expresses high levels of the aromatase P-450 (2, 3).”
Background
Eutopic endometrium and peritoneal, ovarian and bowel endometriotic tissues express a different profile of matrix metalloproteinases-2, -3 and -11, and of tissue inhibitor metalloproteinases-1 and -2
Uzan, C., Cortez, A., Dufournet, C., Fauvet, R., Siffroi, J., & Daraï, É. (2004) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s00428-004-1117-y · Cited by 65
“dometriosis and peritoneal endometriotic tissue supports the concept that endometrial changes play a major pathophysiological role in endometriosis [3, 15, 21 , 35].”
Background
Successful treatment of an aggressive recurrent post-menopausal endometriosis with an aromatase inhibitor
Fatemi, H. M., Al-Turki, H., Papanikolaou, E. G., Kosmas, L., Sutter, P. D., & Devroey, P. (2005) · Reproductive BioMedicine Online · doi:10.1016/s1472-6483(10)61140-6 · Cited by 66
“New medical treatments, which are now being studied, include progesterone receptor modulators, GnRH antagonists, aromatase inhibitors, angiogenesis inhibitors and oestrogen receptor beta agonists (Olive et al., 2004). Recently Dogan (2004) showed complete regression of endometriosis in experimental animals by using Co…”
Background
Tissue‐Specific Estrogen Biosynthesis and Metabolism
SIMPSON, E. R., Clyne, C. D., Speed, C. J., RUBIN, G., & Bulun, S. E. (2001) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2001.tb04002.x · Cited by 65
Self-citation
Expression and Mitogenic Effect of Fibroblast Growth Factor-9 in Human Endometriotic Implant Is Regulated by Aberrant Production of Estrogen
Wing, L. C., Chuang, P.-C., Wu, M., Chen, H., & Tsai, S. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030597 · Cited by 65
Macrophage Migration Inhibitory Factor Is Markedly Expressed in Active and Early-Stage Endometriotic Lesions
Kats, R., Metz, C. N., & Akoum, A. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.87.2.8260 · Cited by 64
Gonadotropin-releasing hormone agonist and add-back therapy: what do the data show?
Surrey, E. S. (2010) · Current Opinion in Obstetrics & Gynecology · doi:10.1097/gco.0b013e32833b35a7 · Cited by 64
Coordination of AUF1 and miR-148a destabilizes DNA methyltransferase 1 mRNA under hypoxia in endometriosis
Hsiao, K.-Y., Wu, M.-H., Chang, N., Yang, S.-H., Wu, C.-W., Sun, H. S., & Tsai, S.-J. (2015) · Molecular Human Reproduction · doi:10.1093/molehr/gav054 · Cited by 64
“For example, the growth of both endometrial and endometriotic cells is estradioldependent, but ectopic endometriotic stromal cells acquire the steroidogenic capacity and develop a self-supporting microenvironment (Noble et al., 1996; Tsai et al., 2001; Wu et al., 2010).”
Background
Intracrine Regulation of Estrogen and Other Sex Steroid Levels in Endometrium and Non-gynecological Tissues; Pathology, Physiology, and Drug Discovery
Konings, G. F. J., Brentjens, L. S., Delvoux, B., Linnanen, T., Cornel, K. M. C., Koskimies, P., Bongers, M. Y., Kruitwagen, R. F. P. M., Xanthoulea, S., & Romano, A. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00940 · Cited by 66
The link between environmental toxicant exposure and endometriosis
Dana, L. A. (2007) · Frontiers in bioscience · doi:10.2741/2782 · Cited by 64
“Increased expression of aromatase, the rate limiting enzyme responsible for the conversion of androgens to estrogen, has also been documented (26;27) and evidence suggests that endometriotic implants acquire the capacity for local estrogen production in order to support their growth.”
Background
Endometriosis: New Genetic Approaches and Therapy
Barlow, D. H., & Kennedy, S. (2005) · Annual Review of Medicine · doi:10.1146/annurev.med.55.091902.103805 · Cited by 64
“The application builds on the evidence that aromatase is aberrantly expressed in endometriotic tissue (50).”
Background
Pharmacological Treatment of Endometriosis
Ferrero, S., Venturini, P. L., Ragni, N., Camerini, G. B., & Remorgida, V. (2009) · Drugs · doi:10.2165/00003495-200969080-00001 · Cited by 64
Do estrogens always increase breast cancer risk?
Hilakivi-Clarke, L. A., Cabanes, A., Olivo, S. E., Kerr, L., Bouker, K. B., & Clarke, R. C. (2002) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/s0960-0760(01)00184-4 · Cited by 64
“Some metabolites of fat have also been shown to activate the P450 aromatase enzyme that converts testosterone to estrogens [120,121].”
Background
Dysregulated Expression ofebaf, a Novel Molecular Defect in the Endometria of Patients with Infertility1
TABIBZADEH, S. S., Mason, J. M., Shea, W., Cai, Y., Murray, M. J., & Lessey, B. A. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.7.6674 · Cited by 63
Aromatase expression in low-grade endometrial stromal sarcomas: an immunohistochemical study
Reich, O., & Regauer, S. (2003) · Modern Pathology · doi:10.1038/modpathol.3800031 · Cited by 62
Aromatase and cyclooxygenase-2 expression in endometrial polyps during the menstrual cycle
Maia, H., Pimentel, K., Silva, T. M. C., de Freitas, L. A. R., Zausner, B., Athayde, C., & Coutinho, E. M. (2006) · Gynecological Endocrinology · doi:10.1080/09513590600585955 · Cited by 62
“Molecular studies have shown that an altered response of the promoter gene for aromatase due to an aberrant production of SF-1 transcription factor is probably the underlying mechanism for the activation of aromatase in response to PGE2 in endometriosis [13,14].”
Background
Analysis of aromatase and 17β-hydroxysteroid dehydrogenase type 2 messenger ribonucleic acid expression in deep endometriosis and eutopic endometrium using laser capture microdissection
Matsuzaki, S., Canis, M. J., Pouly, J. L., Déchelotte, P. J., & Mage, G. (2006) · Fertility and Sterility · doi:10.1016/j.fertnstert.2005.08.017 · Cited by 61

Authors: Noble, L. S., Simpson, E. R., Johns, A., & Bulun, S. E.
Affiliations: The University of Texas Southwestern Medical Center (US)
ORCID: Bulun, S E
Venue: The Journal of Clinical Endocrinology & Metabolism
Publisher: The Endocrine Society
Published: 1996-01
Volume: 81
Issue: 1
Pages: 174-179
ISSN: 0021-972X (ISSN-L)
1945-7197
DOI: 10.1210/jcem.81.1.8550748
OpenAlex: W2023838867
Cited by: 566
References: 10
Citations by year: 2025: 9 · 2024: 6 · 2023: 10 · 2022: 7 · 2021: 14 · 2020: 17 · 2019: 14 · 2018: 9 · 2017: 10 · 2016: 20 · 2015: 28 · 2014: 22 · 2013: 18 · 2012: 22
FWCI: 17.42
Type: journal article
Language: en
Open access: closed
Locations: The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute on Aging (R-37AG08174, R37AG008174)
Topics: Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
Health Sciences › Medicine › Obstetrics and Gynecology › Endometrial and Cervical Cancer Treatments
Keywords: endometriosis, aromatase, P450arom, endometriotic implants, eutopic endometrium, estrogen synthesis, promoter usage, alternative splicing, tissue-specific gene expression, peritoneal endometriosis, aromatase mRNA expression
MeSH terms: Adult, Aromatase, Base Sequence, Endometriosis, Endometrium, Female, Humans, Molecular Sequence Data, Promoter Regions, Genetic, RNA, Messenger, Interleukin-6, Gene Expression Regulation, Enzymologic, Interleukin-11

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Aromatase expression in endometriosis.

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