Oxidative Cell Injury as a Predictor of Endometriosis Progression

Background There is increasing evidence that oxidative stress is one of the key factors for progression of endometriosis. In this prospective controlled trial, we measured 6 different biomarkers of oxidative stress targeting protein, lipid, and DNA to quantify the severity and progression of endometriosis and establish a diagnostic marker for the disease.

A total of 62 consecutive patients were identified and enrolled in this study. After exclusion criteria, 44 patients were allocated to 3 groups: stage I/II (n = 14), stage III/IV (n = 16), and a control group (n = 14). The levels of 8-hydroxy-2-deoxyguanosine (8-OHdG), 8-oxoguanine DNA glycosylase (OGG1), protein carbonyl (PC), lipid peroxidation (LPO), reactive oxygen species (ROS), and total antioxidant capacity (TAC) were accessed in peritoneal fluid and tissue.

Significantly higher levels of 8-OHdG and PC were seen in patients with endometriosis, in addition OGG1 expression was found to be significantly lower in patients with endometriosis (P < .001, P = .001, P = .033, respectively); ROS, TAC, and LPO were similar in stages I/II, stages III/IV, and control group. A predictive model was built using multivariable analyses and receiver–operating characteristics curves. The ability to predict and distinguish between patients without endometriosis, stage I/II endometriosis, and stage III/IV was very high. This model was highly discriminatory and had a concordance index of 0.87.

In this cohort, higher DNA damage and lower DNA repair activity was related to endometriosis progression. Our results indicate that oxidative stress as a biomarker of cell injury can be used as a reliable quantitative test of endometriosis severity. Similar content being viewed by others

Carvalho L, Podgaec S, Bellodi-Privato M, Falcone T, Abrao MS. Role of eutopic endometrium in pelvic endometriosis. J Minim Invasive Gynecol. 2011;18(4):419–427. Falcone T, Lebovic DI. Clinical management of endometriosis. Obstet Gynecol. 2011;118(3):691–705. Bassi MA, Podgaec S, Dias Junior JA, Sobrado CW, D Amico Filho N. Bowel endometriosis: a benign disease? [in Portuguese]. Rev Assoc Med Bras. 2009;55(5):611–616. Giudice LC. Clinical practice. Endometriosis. N Engl J Med 2010;362 25: 2389–2398. The National Women’s Health Information Council. Understanding endometriosis: Past, present and future. 2005. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67(5):817–821. Bedaiwy MA, Hussein MR, Biscotti C, Falcone T. Pelvic endometriosis is rarely associated with ovarian borderline tumours, cytologic and architectural atypia: a clinicopathologic study. Pathol Oncol Res. 2009;15(1):81–88. Ngo C, Chereau C, Nicco C, Weill B, Chapron C, Batteux F. Reactive oxygen species controls endometriosis progression. Am J Pathol. 2009;175(1):225–234. Kao SH, Huang HC, Hsieh RH, Chen SC, Tsai MC, Tzeng CR. Oxidative damage and mitochondrial DNA mutations with endometriosis. Ann N Y Acad Sci. 2005;1042:186–194. Szczepanska M, Kozlik J, Skrzypczak J, Mikolajczyk M. Oxidative stress may be a piece in the endometriosis puzzle. Fertil Steril. 2003;79(6):1288–1293. Gupta S, Agarwal A, Krajcir N, Alvarez JG. Role of oxidative stress in endometriosis. Reprod Biomed Online. 2006;13(1):126–134. Watt J, Ewart MA, Greig FH, Oldroyd KG, Wadsworth RM, Kennedy S. The effect of reactive oxygen species on whole blood aggregation and the endothelial cell-platelet interaction in patients with coronary heart disease. Thromb Res. 2012;130(2):210–215. Galea E, Launay N, Portero-Otin M, et al. Oxidative stress underlying axonal degeneration in adrenoleukodystrophy: a paradigm for multifactorial neurodegenerative diseases? Biochim Biophys Acta. 2012;1822(9):1475–1488. Wu LL, Chiou CC, Chang PY, Wu JT. Urinary 8-OHdG: a marker of oxidative stress to DNA and a risk factor for cancer, atherosclerosis and diabetics. Clin Chim Acta. 2004;339(1–2):1–9. Carvalho LFP, Samadder AN, Agarwal A, Fernandes LFC, Abrão MS. Oxidative stress biomarkers in patients with endometriosis: systematic review. Arch Gynecol Obstet. 2012;286(4):1033–1040. Hendin BN, Kolettis PN, Sharma RK, Thomas AJ, Jr. Agarwal A. Varicocele is associated with elevated spermatozoal reactive oxygen species production and diminished seminal plasma antioxidant capacity. J Urol. 1999;161(6):1831–1834. Sharma RK, Pasqualotto FF, Nelson DR, Thomas AJ, Jr. Agarwal A. The reactive oxygen species - total antioxidant capacity score is a new measure of oxidative stress to predict male infertility. Hum Reprod. 1999;14(11):2801–2807. Shekarriz M, Thomas AJ, Jr. Agarwal A. Effects of time and sperm concentration on reactive oxygen species formation in human semen. Arch Androl. 1995;34(2):69–75. Ma H, Wang J, Abdel-Rahman SZ, Boor PJ, Khan MF. Oxidative DNA damage and its repair in rat spleen following subchronic exposure to aniline. Toxicol Appl Pharmacol. 2008;233(2):247–253. Valavanidis A, Vlachogianni T, Fiotakis C. 8-hydroxy-2′ -deoxyguanosine(8-OHdG): a critical biomarker of oxidative stress and carcinogenesis J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2009;27(2):120–139. Matsuzaki S, Schubert B. Oxidative stress status in normal ovarian cortex surrounding ovarian endometriosis. Fertil Steril. 2010;93(7):2431–2432. Fujii H, Kono K, Nakai K, et al. Oxidative and nitrosative stress and progression of diabetic nephropathy in type 2 diabetes. Am J Nephrol. 2010;31(4):342–352. Isobe C, Abe T, Terayama Y. Levels of reduced and oxidized coenzyme Q-10 and 8-hydroxy-2′-deoxyguanosine in the cerebrospinal fluid of patients with living parkinson’s disease demonstrate that mitochondrial oxidative damage and/or oxidative DNA damage contributes to the neurodegenerative process. Neurosci Lett. 2010;469(1):159–163. Mahfouz R, Sharma R, Sharma D, Sabanegh E, Agarwal A. Diagnostic value of the total antioxidant capacity(TAC) in human seminal plasma. Fertil Steril. 2009;91(3):805–811. Van Langendonckt A, Casanas-Roux F, Donnez J. Oxidative stress and peritoneal endometriosis. Fertil Steril. 2002;77(5):861–870. Oner-Iyidogan Y, Kocak H, Gurdol F, Korkmaz D, Buyru F. Indices of oxidative stress in eutopic and ectopic endometria of women with endometriosis. Gynecol Obstet Invest. 2004;57(4):214–217. Janero DR. Malondialdehyde and thiobarbituric acid-reactivity as diagnostic indices of lipid peroxidation and peroxidative tissue injury. Free Radic Biol Med. 1990;9(6):515–540. Bedaiwy MA, Goldberg JM, Falcone T, et al. Relationship between oxidative stress and embryotoxicity of hydrosalpingeal fluid. Hum Reprod. 2002;17(3):601–604. Jackson LW, Schisterman EF, Dey-Rao R, Browne R, Armstrong D. Oxidative stress and endometriosis. Hum Reprod. 2005;20(7):2014–2020. Verit FF, Erel O, Celik N. Serum paraoxonase-1 activity in women with endometriosis and its relationship with the stage of the disease. Hum Reprod. 2008;23(1):100–104. Shanti A, Santanam N, Morales AJ, Parthasarathy S, Murphy AA. Autoantibodies to markers of oxidative stress are elevated in women with endometriosis. Fertil Steril. 1999;71(6):1115–1118. Foyouzi N, Berkkanoglu M, Arici A, Kwintkiewicz J, Izquierdo D, Duleba AJ. Effects of oxidants and antioxidants on proliferation of endometrial stromal cells. Fertil Steril. 2004;82(suppl 3):1019–1022. Leconte M, Nicco C, Ngo C, et al. The mTOR/AKT inhibitor temsirolimus prevents deep infiltrating endometriosis in mice. Am J Pathol. 2011;179(2):880–889. Yamaguchi K, Mandai M, Toyokuni S, et al. Contents of endometriotic cysts, especially the high concentration of free iron, are a possible cause of carcinogenesis in the cysts through the iron-induced persistent oxidative stress. Clin Cancer Res. 2008;14(1):32–40. Poljsak B, Milisav I, Lampe T, Ostan I. Reproductive benefit of oxidative damage: An oxidative stress “malevolence”? Oxid Med Cell Longev. 2011;2011:760978. Dalle-Donne I, Rossi R, Giustarini D, Milzani A, Colombo R. Protein carbonyl groups as biomarkers of oxidative stress. Clin Chim Acta. 2003;329(1–2):23–38. Podgaec S, Abrao MS, Dias JA Jr, Rizzo LV, de Oliveira RM, Baracat EC. Endometriosis: an inflammatory disease with a Th2 immune response component. Hum Reprod. 2007;22(5):1373–1379. Parazzini F, Chiaffarino F, Surace M, et al. Selected food intake and risk of endometriosis Hum Reprod. 2004;19(8):1755–1759. Mier-Cabrera J, Aburto-Soto T, Burrola-Mendez S, et al. Women with endometriosis improved their peripheral antioxidant markers after the application of a high antioxidant diet. Reprod Biol Endocrinol. 2009;7:54. Defrere S, Lousse JC, Gonzalez-Ramos R, Colette S, Donnez J, Van Langendonckt A. Potential involvement of iron in the pathogenesis of peritoneal endometriosis. Mol Hum Reprod. 2008;14(7):377–385. Agarwal A, Gupta S, Sharma RK. Role of oxidative stress in female reproduction. Reprod Biol Endocrinol. 2005;3:28. Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article Carvalho, L.F.P., Abrão, M.S., Biscotti, C. et al. Oxidative Cell Injury as a Predictor of Endometriosis Progression. Reprod. Sci. 20, 688–698 (2013). https://doi.org/10.1177/1933719112466301 Published: Issue date: DOI: https://doi.org/10.1177/1933719112466301