Cell and Tissue Research

, Volume 364, Issue 1, pp 1–7 | Cite as

Oxidative stress and oocyte quality: ethiopathogenic mechanisms of minimal/mild endometriosis-related infertility



Endometriosis, a highly prevalent gynecological disease, is often associated with infertility, even in its milder forms (minimal and mild endometriosis). However, no consensus has been established with regard to this relationship and the possible mechanisms involved have not been completely elucidated. The oocyte is believed to have an important role in the infertility presented by these patients. Hence, oxidative stress events associated with alterations in the peritoneal, serum and/or follicular microenvironments might result in poor oocyte quality and compromise the reproductive potential of these women. Here, we review possible mechanisms involved in oocyte quality impairment that might lead to infertility in patients with early endometriosis.


Early endometriosis Infertility Oocyte quality Oxidative stress Follicular microenvironment 


  1. Agarwal A, Saleh RA, Bedaiwy MA (2003) Role of reactive oxygen species in the pathophysiology of human reproduction. Fertil Steril 79:829–843CrossRefPubMedGoogle Scholar
  2. Agarwal A, Gupta S, Sharma RK (2005) Role of oxidative stress in female reproduction. Reprod Biol Endocrinol 3:28CrossRefPubMedPubMedCentralGoogle Scholar
  3. Akande VA, Hunt LP, Cahill DJ, Jenkins JM (2004) Differences in time to natural conception between women with unexplained infertility and infertile women with minor endometriosis. Hum Reprod 19:96–103CrossRefPubMedGoogle Scholar
  4. Albertini DF (1992) Cytoplasmic microtubular dynamics and chromatin organization during mammalian oogenesis and oocyte maturation. Mutat Res 296:57–68CrossRefPubMedGoogle Scholar
  5. Al-Fadhli R, Kelly SM, Tulandi T, Tanr SL (2006) Effects of different stages of endometriosis on the outcome of in vitro fertilization. J Obstet Gynaecol Can 28:888–891CrossRefPubMedGoogle Scholar
  6. Alpay Z, Saed GM, Diamond MP (2006) Female infertility and free radicals: potential role in adhesions and endometriosis. J Soc Gynecol Investig 13:390–398CrossRefPubMedGoogle Scholar
  7. Appasamy M, Jauniaux E, Serhal P, Al-Qahtani A, Groome NP, Muttukrishna S (2008) Evaluation of the relationship between follicular fluid oxidative stress, ovarian hormones, and response to gonadotropin stimulation. Fertil Steril 89:912–921CrossRefPubMedGoogle Scholar
  8. Attaran M, Pasqualotto E, Falcone T, Goldberg JM, Miller KF, Agarwal A, Sharma RK (2000) The effect of follicular fluid reactive oxygen species on the outcome of in vitro fertilization. Int J Fertil Womens Med 45:314–320PubMedGoogle Scholar
  9. Augoulea A, Alexandrou A, Creatsa M, Vrachnis N, Lambrinoudaki I (2012) Pathogenesis of endometriosis: the role of genetics, inflammation and oxidative stress. Arch Gynecol Obstet 286:99–103CrossRefPubMedGoogle Scholar
  10. Barcelos ID, Vieira RC, Ferreira EM, Martins WP, Ferriani RA, Navarro PA (2009) Comparative analysis of the spindle and chromosome configurations of in vitro-matured oocytes from patients with endometriosis and from control subjects: a pilot study. Fertil Steril 92:1749–1752CrossRefPubMedGoogle Scholar
  11. Barcelos ID, Donabella FC, Ribas CP, Meola J, Ferriani RA, Paz CC de, Navarro PA (2015) Down-regulation of the CYP19A1 gene in cumulus cells of infertile women with endometriosis. Reprod Biomed Online 30:532–541Google Scholar
  12. Bellelis P, Dias JA Jr, Podgaec S, Gonzales M, Baracat EC, Abrao MS (2010) Epidemiological and clinical aspects of pelvic endometriosis—a case series. Rev Assoc Med Bras 56:467–471CrossRefPubMedGoogle Scholar
  13. Bergqvist A, D’Hooghe T (2002) Mini symposium on pathogenesis of endometriosis and treatment of endometriosis-associated subfertility. Introduction: the endometriosis enigma. Hum Reprod Update 8:79–83CrossRefPubMedGoogle Scholar
  14. Brizek CL, Schlaff S, Pellegrini VA, Frank JB, Worrilow KC (1995) Increased incidence of aberrant morphological phenotypes in human embryogenesis—an association with endometriosis. J Assist Reprod Genet 12:106–112CrossRefPubMedGoogle Scholar
  15. Campos Petean C, Ferriani RA, Reis RM dos, Moura MD de, Jordao AA Jr, Navarro PA (2008) Lipid peroxidation and vitamin E in serum and follicular fluid of infertile women with peritoneal endometriosis submitted to controlled ovarian hyperstimulation: a pilot study. Fertil Steril 90:2080–2085Google Scholar
  16. Carvalho LF, Samadder AN, Agarwal A, Fernandes LF, Abrao MS (2012) Oxidative stress biomarkers in patients with endometriosis: systematic review. Arch Gynecol Obstet 286:1033–1040CrossRefPubMedGoogle Scholar
  17. Da Broi MG, Andrade AZ, Rodrigues JK, Paz CCP, Jordão AA, Navarro PA (2013) Total antioxidant capacity (TAC) levels in follicular fluid of infertile patients undergoing ICSI: a possible predictor of clinical pregnancy. IFFS/ASRM Conjoint Meeting. Fertil Steril 100:S425CrossRefGoogle Scholar
  18. Da Broi MG, Albuquerque FO, Andrade AZ de, Cardoso RL, Jordão AA Jr, Navarro PA (2014a) Systemic and follicular oxidative stress in infertile women with endometriosis undergoing controlled ovarian stimulation for ICSI: is there a role in the ethiopathogenesis of infertility? Fertil Steril 102:e79Google Scholar
  19. Da Broi MG, Malvezzi H, Paz CC, Ferriani RA, Navarro PA (2014b) Follicular fluid from infertile women with mild endometriosis may compromise the meiotic spindles of bovine metaphase II oocytes. Hum Reprod 29:315–323CrossRefPubMedGoogle Scholar
  20. Da Broi MG, Rodrigues JK, Andrade AZ, Giorgi VSI, Jordão AA, Navarro P (2014c) Systemic and follicular oxidative stress in infertile women with minimal/mild endometriosis undergoing controlled ovarian stimulation for ICSI: is there a role in the etiopathogenesis of infertility? JBRA Assist Reprod 18:117Google Scholar
  21. De Santis L, Cino I, Rabellotti E, Calzi F, Persico P, Borini A, Coticchio G (2005) Polar body morphology and spindle imaging as predictors of oocyte quality. Reprod Biomed Online 11:36–42CrossRefPubMedGoogle Scholar
  22. Donabela F, Barcelos I, Pavdovan C, Meola J, Ferriani RA, Navarro P (2011) PTGS2 gene expression (COX2) in cummulus oophorus cells of endometriosis and control infertile patients submitted to ICSI. ASRM 67th Annual Meeting. Fertil Steril 96: S236–S237CrossRefGoogle Scholar
  23. Eichenlaub-Ritter U, Shen Y, Tinneberg HR (2002) Manipulation of the oocyte: possible damage to the spindle apparatus. Reprod Biomed Online 5:117–124CrossRefPubMedGoogle Scholar
  24. Eppig JJ, Wigglesworth K, Pendola FL (2002) The mammalian oocyte orchestrates the rate of ovarian follicular development. Proc Natl Acad Sci U S A 99:2890–2894CrossRefPubMedPubMedCentralGoogle Scholar
  25. Ferreira EM, Vireque AA, Adona PR, Meirelles FV, Ferriani RA, Navarro PA (2009) Cytoplasmic maturation of bovine oocytes: structural and biochemical modifications and acquisition of developmental competence. Theriogenology 71:836–848CrossRefPubMedGoogle Scholar
  26. Ferriani RA, Barcelos I, Donabela F, Ribas C, Meola J, Navarro PA (2013) Lower expression of the gene CYP19A1 in cumulus oophorus cells from infertile women with minimal and mild endometriosis may be involved in the infertility related to this disease. 5th International IVI Congress, Seville, Spain. http://comtecmed.com/ivi/2013/Uploads/Editor/abstract_41.pdf
  27. Garcia-Velasco JA, Arici A (1999) Is the endometrium or oocyte/embryo affected in endometriosis? Hum Reprod 14(Suppl 2):77–89CrossRefPubMedGoogle Scholar
  28. Garrido N, Navarro J, Remohi J, Simon C, Pellicer A (2000) Follicular hormonal environment and embryo quality in women with endometriosis. Hum Reprod Update 6:67–74CrossRefPubMedGoogle Scholar
  29. Giorgi VS, Da Broi MG, Paz CC, Ferriani RA, Navarro PA (2015) N-acetyl-cysteine and L-carnitine prevent meiotic oocyte damage induced by follicular fluid from infertile women with mild endometriosis. Reprod Sci (in press)Google Scholar
  30. Giudice LC, Kao LC (2004) Endometriosis. Lancet 364:1789–1799CrossRefPubMedGoogle Scholar
  31. Gnoth C, Godehardt D, Godehardt E, Frank-Herrmann P, Freundl G (2003) Time to pregnancy: results of the German prospective study and impact on the management of infertility. Hum Reprod 18:1959–1966CrossRefPubMedGoogle Scholar
  32. Gupta S, Agarwal A, Krajcir N, Alvarez JG (2006) Role of oxidative stress in endometriosis. Reprod Biomed Online 13:126–134CrossRefPubMedGoogle Scholar
  33. Gupta S, Goldberg JM, Aziz N, Goldberg E, Krajcir N, Agarwal A (2008) Pathogenic mechanisms in endometriosis-associated infertility. Fertil Steril 90:247–257CrossRefPubMedGoogle Scholar
  34. Halliwell B (1994) Free radicals, antioxidants, and human disease: curiosity, cause, or consequence? Lancet 344:721–724CrossRefPubMedGoogle Scholar
  35. Hamel M, Dufort I, Robert C, Gravel C, Leveille MC, Leader A, Sirard MA (2008) Identification of differentially expressed markers in human follicular cells associated with competent oocytes. Hum Reprod 23:1118–1127CrossRefPubMedGoogle Scholar
  36. Haouzi D, Hamamah S (2009) Pertinence of apoptosis markers for the improvement of in vitro fertilization (IVF). Curr Med Chem 16:1905–1916CrossRefPubMedPubMedCentralGoogle Scholar
  37. Hu Y, Betzendahl I, Cortvrindt R, Smitz J, Eichenlaub-Ritter U (2001) Effects of low O2 and ageing on spindles and chromosomes in mouse oocytes from pre-antral follicle culture. Hum Reprod 16:737–748CrossRefPubMedGoogle Scholar
  38. Hughes EG, Fedorkow DM, Collins JA (1993) A quantitative overview of controlled trials in endometriosis-associated infertility. Fertil Steril 59:963–970CrossRefPubMedGoogle Scholar
  39. Jackson LW, Schisterman EF, Dey-Rao R, Browne R, Armstrong D (2005) Oxidative stress and endometriosis. Hum Reprod 20:2014–2020CrossRefPubMedGoogle Scholar
  40. Jianini BTGM, Giorgi VSI, Malvezzi H, Da Broi MG, Paz CCP da, Navarro PAAS (2014) Peritoneal fluid from infertile women with minimal/mild endometriosis may compromise the spindle of metaphase II bovine oocytes. 8th Annual Congress of the SBRA. JBRA Assist Reprod 18:117–118Google Scholar
  41. Kim NH, Chung HM, Cha KY, Chung KS (1998) Microtubule and microfilament organization in maturing human oocytes. Hum Reprod 13:2217–2222CrossRefPubMedGoogle Scholar
  42. Kumbak B, Kahraman S, Karlikaya G, Lacin S, Guney A (2008) In vitro fertilization in normoresponder patients with endometriomas: comparison with basal simple ovarian cysts. Gynecol Obstet Invest 65:212–216CrossRefPubMedGoogle Scholar
  43. Liu L, Trimarchi JR, Navarro P, Blasco MA, Keefe DL (2003) Oxidative stress contributes to arsenic-induced telomere attrition, chromosome instability, and apoptosis. J Biol Chem 278:31998–32004CrossRefPubMedGoogle Scholar
  44. Ma CH, Yan LY, Qiao J, Sha W, Li L, Chen Y, Sun QY (2010) Effects of tumor necrosis factor-alpha on porcine oocyte meiosis progression, spindle organization, and chromosome alignment. Fertil Steril 93:920–926CrossRefPubMedGoogle Scholar
  45. Mandelbaum J, Anastasiou O, Levy R, Guerin JF, Larouziere V de, Antoine JM (2004) Effects of cryopreservation on the meiotic spindle of human oocytes. Eur J Obstet Gynecol Reprod Biol 113 (Suppl 1):S17–S23Google Scholar
  46. Mansour G, Abdelrazik H, Sharma RK, Radwan E, Falcone T, Agarwal A (2009) L-carnitine supplementation reduces oocyte cytoskeleton damage and embryo apoptosis induced by incubation in peritoneal fluid from patients with endometriosis. Fertil Steril 91:2079–2086CrossRefPubMedGoogle Scholar
  47. Marcoux S, Maheux R, Berube S (1997) Laparoscopic surgery in infertile women with minimal or mild endometriosis. Canadian Collaborative Group on Endometriosis. N Engl J Med 337:217–222CrossRefPubMedGoogle Scholar
  48. Mullen SF, Agca Y, Broermann DC, Jenkins CL, Johnson CA, Critser JK (2004) The effect of osmotic stress on the metaphase II spindle of human oocytes, and the relevance to cryopreservation. Hum Reprod 19:1148–1154CrossRefPubMedGoogle Scholar
  49. Murphy AA, Santanam N, Morales AJ, Parthasarathy S (1998) Lysophosphatidyl choline, a chemotactic factor for monocytes/T-lymphocytes is elevated in endometriosis. J Clin Endocrinol Metab 83:2110–2113CrossRefPubMedGoogle Scholar
  50. Navarro PA, Liu L, Keefe DL (2004) In vivo effects of arsenite on meiosis, preimplantation development, and apoptosis in the mouse. Biol Reprod 70:980–985CrossRefPubMedGoogle Scholar
  51. Navarro PA, Liu L, Ferriani RA, Keefe DL (2006) Arsenite induces aberrations in meiosis that can be prevented by coadministration of N-acetylcysteine in mice. Fertil Steril 85 (Suppl 1):1187–1194CrossRefPubMedGoogle Scholar
  52. Navarro PA, Malvezzi H, Da Broi MG, Rosa e Silva JC, Vireque AA, Meola J (2013) The peritoneal fluid of infertile women with and without minimal/mild endometriosis reduces the expression of genes GSR and CAT in bovine oocytes. 5th International IVI Congress, Seville, Spain. http://comtecmed.com/ivi/2013/Uploads/Editor/abstract_88.pdf
  53. Ngo C, Chereau C, Nicco C, Weill B, Chapron C, Batteux F (2009) Reactive oxygen species controls endometriosis progression. Am J Pathol 175:225–234CrossRefPubMedPubMedCentralGoogle Scholar
  54. Parazzini F (1999) Ablation of lesions or no treatment in minimal-mild endometriosis in infertile women: a randomized trial. Gruppo Italiano per lo Studio dell’Endometriosi. Hum Reprod 14:1332–1334CrossRefPubMedGoogle Scholar
  55. Pasqualotto EB, Agarwal A, Sharma RK, Izzo VM, Pinotti JA, Joshi NJ, Rose BI (2004) Effect of oxidative stress in follicular fluid on the outcome of assisted reproductive procedures. Fertil Steril 81:973–976CrossRefPubMedGoogle Scholar
  56. Pellicer A, Oliveira N, Ruiz A, Remohi J, Simon C (1995) Exploring the mechanism(s) of endometriosis-related infertility: an analysis of embryo development and implantation in assisted reproduction. Hum Reprod 10 (Suppl 2):91–97CrossRefPubMedGoogle Scholar
  57. Practice Committee of the ASRM (2012) Endometriosis and infertility: a committee opinion. Fertil Steril 98:591–598CrossRefGoogle Scholar
  58. Shkolnik K, Tadmor A, Ben-Dor S, Nevo N, Galiani D, Dekel N (2011) Reactive oxygen species are indispensable in ovulation. Proc Natl Acad Sci U S A 108:1462–1467CrossRefPubMedPubMedCentralGoogle Scholar
  59. Signorile PG, Baldi A (2010) Endometriosis: new concepts in the pathogenesis. Int J Biochem Cell Biol 42:778–780CrossRefPubMedGoogle Scholar
  60. Simon C, Gutierrez A, Vidal A, de los Santos MJ, Tarin JJ, Remohi J, Pellicer A (1994) Outcome of patients with endometriosis in assisted reproduction: results from in-vitro fertilization and oocyte donation. Hum Reprod 9:725–729PubMedGoogle Scholar
  61. Singh N, Lata K, Naha M, Malhotra N, Tiwari A, Vanamail P (2014) Effect of endometriosis on implantation rates when compared to tubal factor in fresh non donor in vitro fertilization cycles. J Hum Reprod Sci 7:143–147CrossRefPubMedPubMedCentralGoogle Scholar
  62. Sung L, Mukherjee T, Takeshige T, Bustillo M, Copperman AB (1997) Endometriosis is not detrimental to embryo implantation in oocyte recipients. J Assist Reprod Genet 14:152–156CrossRefPubMedPubMedCentralGoogle Scholar
  63. Szczepanska M, Kozlik J, Skrzypczak J, Mikolajczyk M (2003) Oxidative stress may be a piece in the endometriosis puzzle. Fertil Steril 79:1288–1293CrossRefPubMedGoogle Scholar
  64. Tanghe S, Van Soom A, Nauwynck H, Coryn M, Kruif A de (2002) Minireview: functions of the cumulus oophorus during oocyte maturation, ovulation, and fertilization. Mol Reprod Dev 61:414–424Google Scholar
  65. Tesfaye D, Ghanem N, Carter F, Fair T, Sirard MA, Hoelker M, Schellander K, Lonergan P (2009) Gene expression profile of cumulus cells derived from cumulus-oocyte complexes matured either in vivo or in vitro. Reprod Fertil Dev 21:451–461CrossRefPubMedGoogle Scholar
  66. Van Blerkom J, Davis P (2001) Differential effects of repeated ovarian stimulation on cytoplasmic and spindle organization in metaphase II mouse oocytes matured in vivo and in vitro. Hum Reprod 16:757–764CrossRefPubMedGoogle Scholar
  67. Van Langendonckt A, Casanas-Roux F, Donnez J (2002) Oxidative stress and peritoneal endometriosis. Fertil Steril 77:861–870CrossRefPubMedGoogle Scholar
  68. Volarcik K, Sheean L, Goldfarb J, Woods L, Abdul-Karim FW, Hunt P (1998) The meiotic competence of in-vitro matured human oocytes is influenced by donor age: evidence that folliculogenesis is compromised in the reproductively aged ovary. Hum Reprod 13:154–160CrossRefPubMedGoogle Scholar
  69. Wang WH, Keefe DL (2002) Prediction of chromosome misalignment among in vitro matured human oocytes by spindle imaging with the PolScope. Fertil Steril 78:1077–1081CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Human Reproduction Division, Department of Obstetrics and Gynecology, Ribeirão Preto School of MedicineUniversity of São PauloRibeirão PretoBrazil

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