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Markers of Local and Systemic Estrogen Metabolism in Endometriosis

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Abstract

Estrogen metabolites (EMs) can work independently from their parent hormones. We hypothesize that in endometriosis, estrogen is metabolized preferentially along hormonally active pathways. We recruited 62 women with endometriosis (proven laparoscopically and histologically) and 52 control women (normal findings with laparoscopy) among patients undergoing surgery for pelvic pain and/or infertility during the proliferative phase of the menstrual cycle. Urinary samples were collected preoperatively. Biopsies from eutopic endometrium of control women and women with endometriosis were collected during surgery. EMs in urine and endometrial tissues were extracted and determined using Liquid Chromatography-Electrospray Ionization Tandem Mass Spectrometry (LC-ESI-MS/MS). These included: 2-hydroxyestrone (2OHE1), 16-α hydroxyestrone (16α-OHE1), 2OHE1/16α-OHE1 ratio, 4-hydroxyestrone (4OHE1), 2-hydroxyestradiol (2OHE2), and 4-hydroxyestradiol (4OHE2). Eutopic endometrium of endometriosis patients, as compared to control endometrium, contained significantly higher level of 4OHE1 (0.03 (IQR: 0.03–0.265) versus 0.03 (IQR: 0.03–0.03) μg/g, respectively, P = 0.005), 2-OHE2 (0.241 (IQR: 0.1–0.960) versus 0.1 (IQR: 0.1–0.1) μg/g, respectively, P < 0.001), and 4-OHE2 (0.225 (IQR: 0.22–1.29) versus 0.0.2 (IQR: 0.2–0.2) μg/g, respectively, P < 0.001). Only 2OHE1 showed higher concentration in urine of women with endometriosis than controls (9.9 (IQR: 3.64–14.88) versus 4.5 (IQR: 1.37–17.00) μg/mg creatinine, respectively, P = 0.042). Eutopic endometrium of women with endometriosis metabolizes estrogen preferentially to the biologically active 2OHE2, and potentially genotoxic 4OHE1 and 4OHE2 metabolites. This contributes to further understanding of endometriosis etiology, its link to ovarian cancer, and could help identifying an endometrial biomarker of the disease.

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References

  1. Hickey M, Ballard K, Farquhar C. Endometriosis. BMJ. 2014;348:g1752.

    PubMed  Google Scholar 

  2. Adamson GD, Kennedy S, Hummelshoj L. Creating solutions in endometriosis: global collaboration through the World Endometriosis Research Foundation. J Endometr Pelvic Pain Disord. 2010;2:3–6.

    Google Scholar 

  3. Bedaiwy MA, Allaire C, Yong P, Alfaraj S. Medical management of endometriosis in patients with chronic pelvic pain. Semin Reprod Med. 2017;35(1):38–53.

    PubMed  Google Scholar 

  4. Tomassetti C, D’Hooghe T. Endometriosis and infertility: Insights into the causal link and management strategies. Best Pract Res Clin Obstet Gynaecol. 2018;51:25–33.

    PubMed  Google Scholar 

  5. Agarwal SK, Chapron C, Giudice LC, Laufer MR, Leyland N, Missmer SA, et al. Clinical diagnosis of endometriosis-a call to action. Am J Obstet Gynecol. 2019;220(4):354.e1–354.e12.

    Google Scholar 

  6. Zondervan KT, Becker CM, Koga K, Missmer SA, Taylor RN, Viganò P. Endometriosis. Nat Rev Dis Primers. 2018;4(1):9.

    PubMed  Google Scholar 

  7. Seo JW, Lee DY, Yoon BK, Choi D. The age-related recurrence of endometrioma after conservative surgery. Eur J Obstet Gynecol Reprod Biol. 2017;208:81–5.

    PubMed  Google Scholar 

  8. Giudice LC. Clinical practice: endometriosis. N Engl J Med. 2010;362(25):2389–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Zondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med. 2020;382(13):1244–56.

    CAS  PubMed  Google Scholar 

  10. Gurates B, Bulun SE. Endometriosis: the ultimate hormonal disease. Semin Reprod Med. 2003;21(2):125–34.

    CAS  PubMed  Google Scholar 

  11. Yilmaz BD, Bulun SE. Endometriosis, and nuclear receptors. Hum Reprod Update. 2019;25(4):473–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Missmer SA, Hankinson SE, Spiegelman D, Barbieri RL, Malspeis S, Willett WC, et al. Reproductive history and endometriosis among premenopausal women. Obstet Gynecol. 2004;104:965–74.

    PubMed  Google Scholar 

  13. Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268–79.

    CAS  PubMed  Google Scholar 

  14. Bulun SE, Yilmaz BD, Sison C, Miyazaki K, Bernardi L, Liu S, et al. Endometriosis. Endocr Rev. 2019;40(4):1048–79.

    PubMed  PubMed Central  Google Scholar 

  15. Vercellini P, Vigano P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol. 2013;10:261–75.

    PubMed  Google Scholar 

  16. Bulun SE, Lin Z, Imir G, Amin S, Demura M, Yilmaz B, et al. Regulation of aromatase expression in estrogen responsive breast and uterine disease: from bench to treatment. Pharmacol Rev. 2005;57:359–83.

    CAS  PubMed  Google Scholar 

  17. Attar E, Bulun SE. Aromatase and other steroidogenic enzymes in endometriosis-a translational aspect. Hum Reprod Update. 2006;12(1):49–56.

    CAS  PubMed  Google Scholar 

  18. Rizner TL. Estrogen metabolism and action in endometriosis. Mol Cell Endocrinol. 2009;307(1–2):8–18.

    CAS  PubMed  Google Scholar 

  19. Zhu BT, Conney AH. Functional role of estrogen metabolism in target cells: review and perspectives. Carcinogenesis. 1998;19:1–27.

    PubMed  Google Scholar 

  20. Sepkovic DW, Bradlow HL. Estrogen hydroxylation- the good and the bad. Ann N Y Acad Sci. 2009;1155:57–67.

    CAS  PubMed  Google Scholar 

  21. Van Aswegen CH, Purdy RH, Wittliff JL. Binding of 2-hydroxyestradiol and 4-hydroxyestrdiol to estrogen receptor human breast cancers. J Steroid Biochem. 1989;32:485–92.

    PubMed  Google Scholar 

  22. Chun YJ, Kim S. Discovery of cytochrome P450 1B1 inhibitors as new promising anti-cancer agents. Med Res Rev. 2003;23:657–68.

    CAS  PubMed  Google Scholar 

  23. Samavat H, Kurzer MS. Estrogen metabolism and breast cancer. Cancer Lett. 2015;356(2 Pt A):231–43.

    CAS  PubMed  Google Scholar 

  24. Cavalieri EL, Stack DE, Devanesan PD, Todorovic R, Dwivedy I, Higginbotham S, et al. Molecular origin of cancer: catechol estrogen-3,4-quinones as endogenous tumor initiators. Proc Natl Acad Sci U S A. 1997;94:10937–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Salama SA, Kamel M, Awad M, Nasser AH, Al-Hendy A, Botting S, et al. Catechol estrogens induce oxidative stress and malignant transformation in human endometrial glandular cells: protective effect of catechol-O-methyltransferase. Int J Cancer. 2008;123:1246–54.

    CAS  PubMed  Google Scholar 

  26. Cavalieri EL, Rogan EG. Depurinating estrogen-DNA adducts generators of cancer initiation: their minimization leads to cancer prevention. Clin Transl Med. 2016;5(1):12.

    PubMed  PubMed Central  Google Scholar 

  27. Maeda N, Tanaka E, Suzuki T, Okumura K, Nomura S, Miyasho T, et al. Accurate determination of tissue steroid hormones, precursors and conjugates in adult male rat. J Biochem. 2013;153(1):63–71.

    CAS  PubMed  Google Scholar 

  28. Xu X, Veenstra TD, Fox SD, Roman JM, Issaq HJ, Falk R, et al. Measuring fifteen endogenous estrogens simultaneously in human urine by high-performance liquid chromatography-mass spectrometry. Anal Chem. 2005;77(20):6646–54.

    CAS  PubMed  Google Scholar 

  29. Xu X, Keefer LK, Ziegler RG, Veenstra TD. A liquid chromatography-mass spectrometry method for the quantitative analysis of urinary endogenous estrogen metabolites. Nat Protoc. 2007;2(6):1350–5.

    CAS  PubMed  Google Scholar 

  30. Fotsis T, Järvenpää P, Adlercreutz H. Purification of urine for quantification of the complete estrogen profile. J Steroid Biochem. 1980;12:503–8. https://doi.org/10.1016/0022-4731(80)90314-3.

    Article  CAS  PubMed  Google Scholar 

  31. Hart A. Mann-Whitney test is not just a test of medians: differences in spread can be important. BMJ. 2001;323(7309):391–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Ziegler RG, Fuhrman BJ, Moore SC, Matthews CE. Epidemiologic studies of estrogen metabolism and breast cancer. Steroids. 2015;99(Pt A):67–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Fouda S, Kelany M, Moustafa N, et al. Tobacco smoking in Egypt: a scoping literature review of its epidemiology and control measures. East Mediterr Health J. 2018;24(2):198–215 Published 2018 May 3.

    PubMed  Google Scholar 

  34. Kabat GC, Chang CJ, Sparano JA, Sepkovie DW, Hu XP, Khalil A, et al. Urinary estrogen metabolites and breast cancer: a case-control study. Cancer Epidemiol Biomark Prev. 1997;6(7):505–9.

    CAS  Google Scholar 

  35. Kabat GC, O’Leary ES, Gammon MD, Sepkovie DW, Teitelbaum SL, Britton JA, et al. Estrogen metabolism and breast cancer. Epidemiology. 2006;17(1):80–8.

    PubMed  Google Scholar 

  36. Ho GH, Luo XW, Ji CY, Foo SC, Ng EH. Urinary 2/16 alpha-hydroxyestrone ratio: correlation with serum insulin-like growth factor binding protein-3 and a potential biomarker of breast cancer risk. Ann Acad Med Singap. 1998;27(2):294–9.

    CAS  PubMed  Google Scholar 

  37. Meilahn EN, De Stavola B, Allen DS, Fentiman I, Bradlow HL, Sepkovic DW, et al. Do urinary oestrogen metabolites predict breast cancer? Guernsey III cohort follow-up. Br J Cancer. 1998;78(9):1250–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Muti P, Bradlow HL, Micheli A, Krogh V, Freudenheim JL, Schunemann HJ, et al. Estrogen metabolism and risk of breast cancer: a prospective study of the 2:16alpha-hydroxyestrone ratio in premenopausal and postmenopausal women. Epidemiology. 2000;11(6):635–40.

    CAS  PubMed  Google Scholar 

  39. Arslan AA, Shore RE, Afanasyeva Y, Koenig KL, Toniolo P, Zeleniuch-Jacquotte A. Circulating estrogen metabolites and risk for breast cancer in premenopausal women. Cancer Epidemiol Biomark Prev. 2009;18(8):2273–9.

    CAS  Google Scholar 

  40. Eliassen AH, Spiegelman D, Xu X, Keefer LK, Veenstra TD, Barbieri RL, et al. Urinary estrogens and estrogen metabolites and subsequent risk of breast cancer among premenopausal women. Cancer Res. 2012;72(3):696–706.

    CAS  PubMed  Google Scholar 

  41. Obi N, Vrieling A, Heinz J, Chang-Claude J. Estrogen metabolite ratio: is the 2-hydroxyestrone to 16α-hydroxyestrone ratio predictive for breast cancer? Int J Women's Health. 2011;3:37–51.

    Google Scholar 

  42. Dallal CM, Stone RA, Cauley JA, Ness RB, Vogel VG, Fentiman IS, et al. Urinary estrogen metabolites and breast cancer: a combined analysis of individual level data. Int J Biol Markers. 2013;28(1):3–16.

    CAS  PubMed  Google Scholar 

  43. Samartzis EP, Imesch P, Twiehaus A, Dubey RK, Leeners B. The estrogen metabolites 2-methoxyestradiol and 2-hydroxyestradiol inhibit endometriotic cell proliferation in estrogen-receptor-independent manner. Gynecol Endocrinol. 2016;32(7):529–33.

    CAS  PubMed  Google Scholar 

  44. Devoto L, Henríquez S, Kohen P, Strauss JF 3rd. The significance of estradiol metabolites in human corpus luteum physiology. Steroids. 2017;123:50–4.

    CAS  PubMed  Google Scholar 

  45. Lippert C, Seeger H, Mueck AO, Lippert TH. The effects of A-ring and D-ring metabolites of estradiol on the proliferation of vascular endothelial cells. Life Sci. 2000;67(13):1653–8.

    CAS  PubMed  Google Scholar 

  46. Paquette B, Bisson M, Therriault H, Lemay R, Pare M, Banville P, et al. Activation of matrix metalloproteinase-2 and -9 by 2- and 4-hydroxyestradiol. J Steroid Biochem Mol Biol. 2003;87(1):65–73.

    CAS  PubMed  Google Scholar 

  47. Roy D, Weisz J, Liehr JG. The O-methylation of 4-hydroxyestradiol is inhibited by 2-hydroxyestradiol: implications for estrogen-induced carcinogenesis. Carcinogenesis. 1990;11(3):459–62.

    CAS  PubMed  Google Scholar 

  48. Westerlind KC, Gibson KJ, Evans GL, Turner RT. The catechol estrogen, 4-hydroxyestrone, has tissue-specific estrogen actions. J Endocrinol. 2000;167:281–7.

    CAS  PubMed  Google Scholar 

  49. Bolton JL, Thatcher GR. Potential mechanisms of estrogen quinone carcinogenesis. Chem Res Toxicol. 2008;21(1):93–101.

    PubMed  Google Scholar 

  50. Cavalieri EL, Rogan EG. Depurinating estrogen-DNA adducts in the etiology and prevention of breast and other human cancers. Future Oncol. 2010;6(1):75–91.

    CAS  PubMed  Google Scholar 

  51. Yager JD, Davidson NE. Estrogen carcinogenesis in breast cancer. N Engl J Med. 2006;354(3):270–82.

    CAS  PubMed  Google Scholar 

  52. Zhao H, Jiang Y, Liu Y, Yun C, Li L. Endogenous estrogen metabolites as biomarkers for endometrial cancer via a novel method of liquid chromatography-mass spectrometry with hollow fiber liquid-phase microextraction. Horm Metab Res. 2015;47(2):158–64.

    CAS  PubMed  Google Scholar 

  53. Fussell KC, Udasin RG, Smith PJ, Gallo MA, Laskin JD. Catechol metabolites of endogenous estrogens induce redox cycling and generate reactive oxygen species in breast epithelial cells. Carcinogenesis. 2011;32(8):1285–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact. 2006;160(1):1–40.

    CAS  PubMed  Google Scholar 

  55. Poole EM, Lin WT, Kvaskoff M, De Vivo I, Terry KL, Missmer SA. Endometriosis and risk of ovarian and endometrial cancers in a large prospective cohort of U.S. nurses. Cancer Causes Control. 2017;28(5):437–45.

    PubMed  PubMed Central  Google Scholar 

  56. Li J, Liu R, Tang S, Feng F, Liu C, Wang L, et al. Impact of endometriosis on risk of ovarian, endometrial and cervical cancers: a meta-analysis. Arch Gynecol Obstet. 2019;299(1):35–46.

    CAS  PubMed  Google Scholar 

  57. Anglesio MS, Yong PJ. Endometriosis-associated ovarian cancers. Clin Obstet Gynecol. 2017;60(4):711–27.

    PubMed  Google Scholar 

  58. Jiang X, Morland SJ, Hitchcock A, Thomas EJ, Campbell IG. Allelotyping of endometriosis with adjacent ovarian carcinoma reveals evidence of a common lineage. Cancer Res. 1998;58:1707–12.

    CAS  PubMed  Google Scholar 

  59. Prowse AH, Manek S, Varma R, Liu J, Godwin AK, Maher ER, et al. Molecular genetic evidence that endometriosis is a precursor of ovarian cancer. Int J Cancer. 2006;119:556–62.

    CAS  PubMed  Google Scholar 

  60. Borrelli GM, Abrao MS, Taube ET, Darb-Esfahani S, Kohler C, Chiantera V, et al. (Partial) Loss of BAF250a (ARID1A) in rectovaginal deep-infiltrating endometriosis, endometriomas and involved pelvic sentinel lymph nodes. Mol Hum Reprod. 2016;22:329–37.

    CAS  PubMed  Google Scholar 

  61. Fuhrman BJ, Pfeiffer RM, Wu AH, Xu X, Keefer LK, Veenstra TD, et al. Green tea intake is associated with urinary estrogen profiles in Japanese American women. Nutr J. 2013;12:25.

    PubMed  PubMed Central  Google Scholar 

  62. Fuhrman BJ, Pfeiffer RM, Xu X, Wu AH, Korde L, Gail MH, et al. Soy intake is associated with increased 2-hydroxylation and decreased 16alpha-hydroxylation of estrogens in Asian-American women. Cancer Epidemiol Biomark Prev. 2009;18(10):2751–60.

    CAS  Google Scholar 

  63. Lord RS, Bongiovanni B, Bralley JA. Estrogen metabolism and the diet-cancer connection: rationale for assessing the ratio of urinary hydroxylated estrogen metabolites. Altern Med Rev. 2002;7(2):112–29.

    PubMed  Google Scholar 

  64. Bradlow HL, Sepkovic DW, Telang NT, Osborne MP. Multifunctional aspects of the action of indole-3-carbinol as an antitumor agent. Ann N Y Acad Sci. 1999;889:204–13.

    CAS  PubMed  Google Scholar 

  65. Smith AJ, Phipps WR, Thomas W, Schmitz KH, Kurzer MS. The effects of aerobic exercise on estrogen metabolism in healthy premenopausal women. Cancer Epidemiol Biomark Prev. 2013;22(5):756–64.

    CAS  Google Scholar 

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Acknowledgments

The authors would like to thank Dr. Ayman Al-Hendy, and Dr. Abdeljabar El Andaloussi; University of Illinois at Chicago for generously providing the glucuronidase enzyme. Gratefulness is to be extended also to physicians and nurses in laparoscopy unit, Assiut University Women’s Hospital for their valuable support during the laparoscopic surgeries.

Funding

The study was supported by a grant (ID# 5525) from Science and Technology Development Fund (STDF), Egyptian Ministry of Higher Education to ERO.

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Authors and Affiliations

  1. OB-GYN Department, Assiut University, Asyut, Egypt

    Essam R. Othman, Ibrahim I. Abdelaal & Ahmed N. Fetih

  2. Department of Reproductive Medicine, Academic Endometriosis Center, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

    Essam R. Othman, Lisette E. Van der Houwen, Cornelis B. Lambalk & Velja Mijatovic

  3. Reproductive Sciences Research Center, Assiut University, Asyut, Egypt

    Essam R. Othman & Maha Y. Khashbah

  4. Chemistry Department, Faculty of Science, Assiut University, Asyut, Egypt

    Ahmad Abo Markeb

  5. Clinical Pathology Department, Assiut University, Asyut, Egypt

    Tarek T. ElMelegy

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  1. Essam R. Othman
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Correspondence to Essam R. Othman.

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The study was approved by the ethical review board, Assiut Faculty of Medicine, Assiut University, Egypt. The research was conducted in full compliance with ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments.

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Othman, E.R., Markeb, A.A., Khashbah, M.Y. et al. Markers of Local and Systemic Estrogen Metabolism in Endometriosis. Reprod. Sci. 28, 1001–1011 (2021). https://doi.org/10.1007/s43032-020-00383-4

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