Advertisement

Subtle Endometriosis and Unexplained Infertility

  • Paula Andrea de Albuquerque de Salles Navarro
  • Anderson Sanches de Melo
  • Rui Alberto Ferriani
Chapter

Abstract

Unexplained infertility (UI) is a diagnosis of exclusion for infertile couples; within an otherwise asymptomatic patient with a normal clinical examination and ultrasound evaluation revealing no pelvic pathology, UI may be associated with undiagnosed pelvic diseases. We may speculate whether UI is really unexplained or if there are undocumented subtle pathological pelvic conditions that might interfere with the processes involved in natural fertilization. Subtle endometriosis may be related to various mechanisms involved in the different stages of fertilization, embryo development, and implantation, and there is speculation about its role in cases of UI. There is no consensus about whether milder stages of endometriosis are a cause of infertility or merely an incidental finding in some patients with UI. Studies by our group and others have shown that even cases of milder disease may inhibit mechanisms involved in conception, such as follicular steroidogenesis and oocyte competence. There appears to be an increase in oxidative stress (OS) markers in both the follicular and peritoneal compartments of patients with endometriosis as well as a possible increase in enzyme expression in cumulus granulosa cells (CC) which may alter oocyte development.

Cases of UI, especially those experiencing a long duration of infertility, may be due to subtle endometriosis with possible alterations in the mechanisms of oocyte maturation and response, fertilization, as well as later embryonic implantation. Assisted reproduction is an effective treatment option that can overcome as of yet unidentified intrinsic disturbances in patients with subtle endometriosis and UI.

Keywords

Endometriosis Mild endometriosis Oxidative stress Unexplained infertility Gene expression Oocyte quality Ovarian steroidogenesis 

References

  1. 1.
    National Institute of Clinical Excellence. Clinical guideline. Fertility: assessment and treatment for people with fertility problems (update); May 2012. http://www.nice.org.uk/nicemedia/live/12157/59278/59278.pdf. Accessed 21 June 2014.
  2. 2.
    Aboulghar MA, Mansour RT, Serour GI, Al-Inany HG. Diagnosis and management of unexplained infertility: an update. Arch Gynecol Obstet. 2003;267(4):177–88.PubMedGoogle Scholar
  3. 3.
    Isaksson R, Tiitinen A. Present concept of unexplained infertility. Gynecol Endocrinol. 2004;18(5):278–90.PubMedCrossRefGoogle Scholar
  4. 4.
    Polyzos NP, Tzioras S, Mauri D, Tsappi M, Cortinovis I, Tsali L, Casazza G. Treatment of unexplained infertility with aromatase inhibitors or clomiphene citrate: a systematic review and meta-analysis. Obstet Gynecol Surv. 2008;63(7):472–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Brandes M, Hamilton CJ, van der Steen JO, de Bruin JP, Bots RS, Nelen WL, Kremer JA. Unexplained infertility: overall ongoing pregnancy rate and mode of conception. Hum Reprod. 2011;26(2):360–8.PubMedCrossRefGoogle Scholar
  6. 6.
    American Society for Reproductive Medicine (ASRM). Endometriosis and infertility: a committee opinion. Fertil Steril. 2012;98(3):591–5.CrossRefGoogle Scholar
  7. 7.
    Bonneau C, Chanelles O, Sifer C, Poncelet C. Use of laparoscopy in unexplained infertility. Eur J Obstet Gynecol Reprod Biol. 2012;163(1):57–61.PubMedCrossRefGoogle Scholar
  8. 8.
    Cook AS, Rock JÁ. The role of laparoscopy in the treatment of endometriosis. Fertil Steril. 1995;55:663–80.Google Scholar
  9. 9.
    Johnson NP, Hummelshoj L, World Endometriosis Society Montpellier Consortium. Consensus on current management of endometriosis. Hum Reprod. 2013;28(6):1552–68.PubMedCrossRefGoogle Scholar
  10. 10.
    Guidice LC, Kao LC. Endometriosis. Lancet. 2004;364:1789–1799.CrossRefGoogle Scholar
  11. 11.
    Cramer DW, Missmer SA. The epidemiology of endometriosis. Ann N Y Acad Sci. 2002;955:11–22. (discussion 34–6, 396–406).PubMedCrossRefGoogle Scholar
  12. 12.
    Augoulea A, Alexandrou A, Creatsa M, Vrachnis N, Lambrinoudaki I. Pathogenesis of endometriosis: the role of genetics, inflammation and oxidative stress. Arch Gynecol Obstet. 2012;286(1):99–103.PubMedCrossRefGoogle Scholar
  13. 13.
    Holoch KJ, Lessey BA. Endometriosis and infertility. Clin Obstet Gynecol. 2010;53(2):429–38.PubMedCrossRefGoogle Scholar
  14. 14.
    Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;98(3):511–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Crain DA, Janssen SJ, Edwards TM, Heindel J, Ho SM, Hunt P, Iguchi T, Juul A, McLachlan JA, Schwartz J, Skakkebaek N, Soto AM, Swan S, Walker C, Woodruff TK, Woodruff TJ, Giudice LC, Guillette LJ Jr. Female reproductive disorders: the roles of endocrine-disrupting compounds and developmental timing. Fertil Steril. 2008;90(4):911–40.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268–79.PubMedCrossRefGoogle Scholar
  17. 17.
    Iwanoff N. Dusiges cystenhaltiges uterusfibromyom compliciert durch sarcom und carcinom. (Adenofibromyoma cysticum sarcomatodes carcinomatosum). Monatsch Geburtshilfe Gynakol. 1898;7:295–300.Google Scholar
  18. 18.
    Sampson A. Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. 1927;14:442–69.Google Scholar
  19. 19.
    Garcia-Velasco JA, Arici A. Is the endometrium or oocyte/embryo affected in endometriosis? Hum Reprod. 1999;14(Suppl 2):77–89.PubMedCrossRefGoogle Scholar
  20. 20.
    Garrido N, Navarro J, Remohí J, Simón C, Pellicer A. Follicular hormonal environment and embryo quality in women with endometriosis. Hum Reprod Update. 2000;6(1):67–74.PubMedCrossRefGoogle Scholar
  21. 21.
    Barnhart K, Dungsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertil Steril. 2002;77(6):148–55.CrossRefGoogle Scholar
  22. 22.
    Brizek CL, Schlaff S, Pellegrini VA, Frank JB, Worrilow KC. Increased incidence of aberrant morphological phenotypes in human embryogenesis-an association with endometriosis. J Assist Reprod Genet. 1995;12(2):106–12.PubMedCrossRefGoogle Scholar
  23. 23.
    Pellicer A, Oliveira N, Ruiz A, Remohí J, Simón C. Exploring the mechanism(s) of endometriosis-related infertility: an analysis of embryo development and implantation in assisted reproduction. Hum Reprod. 1995;10(Suppl 2):91–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Pellicer A, Navarro J, Bosch E, Garrido N, Garcia-Velasco JA, Remohí J, Simón C. Endometrial quality in infertile women with endometriosis. Ann N Y Acad Sci. 2001;943:122–30.PubMedCrossRefGoogle Scholar
  25. 25.
    Barbosa MAP, Teixeira DM, Navarro PAAS, Ferriani RA, Nastri CO, Martins WP. The impact of endometriosis and its staging on assisted reproduction outcomes: a systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2014;44(3):261–78.PubMedCrossRefGoogle Scholar
  26. 26.
    Albertini DF. Cytoplasmic microtubular dynamics and chromatin organization during mammalian oogenesis and oocyte maturation. Mutat Res. 1992;296(1/2):57–68.PubMedCrossRefGoogle Scholar
  27. 27.
    Ferreira EM, Vireque AA, Adona PR, Meirelles FV, Ferriani RA, Navarro PA. Cytoplasmic maturation of bovine oocytes: structural and biochemical modifications and acquisition of developmental competence. Theriogenology. 2009;71(5):836–48.PubMedCrossRefGoogle Scholar
  28. 28.
    Wang WH, Keefe DL. Prediction of chromosome misalignment among in vitro matured human oocytes by spindle imaging with the Polscope. Fertil Steril. 2002;78(5):1077–81.PubMedCrossRefGoogle Scholar
  29. 29.
    Navarro PA, Liu L, Keefe DL. In vivo effects of arsenite on meiosis, preimplantation development and apoptosis in the mouse. Biol Reprod. 2004;70(4):980–5.PubMedCrossRefGoogle Scholar
  30. 30.
    Navarro PA, Liu L, Ferriani, RA, Keefe DL. Arsenite induces aberrations in meiosis that can be rescued by co-administration of N-acetylcysteine in mice. Fertil Steril. 2006;85(Suppl 1):1187–94.PubMedCrossRefGoogle Scholar
  31. 31.
    Liu L, Trimarchi JR, Navarro P, Blasco MA, Keefe DL. Oxidative stress contributes to arsenic-induced telomere attrition, chromosome instability, and apoptosis. J Biol Chem. 2003;278(34):31998–2004.PubMedCrossRefGoogle Scholar
  32. 32.
    Dib LA, Araújo MCPM, Giorgenon RC, Romão GS, Ferriani RA, Navarro PAAS. Noninvasive imaging of the meiotic spindle of in vivo matured oocytes from infertile women with endometriosis. Reprod Sci. 2013;20(4):456–62.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Agarwal A, Aponte-Mellado A, Premkumar BJ, Shaman A, Gupta S. The effects of oxidative stress on female reproduction: a review. Reprod Biol Endocrinol. 2012;10(1):49.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Gupta S, Goldberg JM, Aziz N, Goldberg E, Krajcir N, Agarwal A. Pathogenic mechanisms in endometriosis-associated infertility. Fertil Steril. 2008;90(2): 247–57.PubMedCrossRefGoogle Scholar
  35. 35.
    Ngô C, Chéreau C, Nicco C, Weill B, Chapron C, Batteux F. Reactive oxygen species controls endometriosis progression. Am J Pathol. 2009;175(1):225–34.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Alpay Z, Saed GM, Diamond MP. Female infertility and free radicals: potential role in adhesions and endometriosis. J Soc Gynecol Investig. 2006;13(6):390–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Oner-Iyidoğan Y, Koçak H, Gürdöl F, Korkmaz D, Buyru F. Indices of oxidative stress in eutopic and ectopic endometria of women with endometriosis. Gynecol Obstet Invest. 2004;57(4):214–7.PubMedCrossRefGoogle Scholar
  38. 38.
    Andrade AZ, Rodrigues JK, Dib LA, Romão GS, Ferriani RA, Jordão Junior AA, Navarro PA. Serum markers of oxidative stress in infertile women with endometriosis. Rev Bras Ginecol Obstet. 2010;32(6):279–85.PubMedCrossRefGoogle Scholar
  39. 39.
    Mansour G, Abdelrazik H, Sharma RK, Radwan E, Falcone T, Agarwal A. L-carnitine supplementation reduces oocyte cytoskeleton damage and embryo apoptosis induced by incubation in peritoneal fluid from patients with endometriosis. Fertil Steril. 2009;91:2079–86.PubMedCrossRefGoogle Scholar
  40. 40.
    Barcelos ID, Vieira RC, Ferreira EM, Martins WP, Ferriani RA, Navarro PA. 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. 2009;92(5):1749–52.PubMedCrossRefGoogle Scholar
  41. 41.
    Ma CH, Yan LY, Qiao J, Sha W, Li L, Chen Y, Sun QY. Effects of tumor necrosis factor-alpha on porcine oocyte meiosis progression, spindle organization, and chromosome alignment. Fertil Steril. 2010;93:920–6.PubMedCrossRefGoogle Scholar
  42. 42.
    Jackson LW, Schisterman EF, Dey-Rao R, Browne R, Armstrong D. Oxidative stress and endometriosis. Hum Reprod. 2005;20:2014–20.PubMedCrossRefGoogle Scholar
  43. 43.
    Campos Petean C Ferriani RA Reis RM de Moura MD Jordao AA Jr Navarro PA. 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. 2008;90:2080–5.PubMedCrossRefGoogle Scholar
  44. 44.
    Da Broi MG Andrade AZ Rodrigues JK Paz CCP. Total antioxidant capacity (TAC) levels in follicular fluid of infertile patients undergoing ICSI: a possible predictor of clinical pregnancy. Fertil Steril. 2013;100(3):S425.CrossRefGoogle Scholar
  45. 45.
    Matorras R, Corcostegui B, Esteban J, Ramon O, Prieto B, Exposito A, Pijoan JI. Fertility in women with minimal endometriosis compared with normal women was assessed by means of a donor insemination program in unstimulated cycles. Am J Obstet Gynecol. 2010;203:341–5.CrossRefGoogle Scholar
  46. 46.
    Da Broi MG Malvezzi H Paz CC Ferriani RA Navarro PA. Follicular fluid from infertile women with mild endometriosis may compromise the meiotic spindles of bovine metaphase II oocytes. Hum Reprod. 2014;29(2):315–23.PubMedCrossRefGoogle Scholar
  47. 47.
    Prieto L, Quesada JF, Cambero O, Pacheco A, Pellicer A, Codoceo R, Garcia-Velasco JA. Analysis of follicular fluid and serum markers of oxidative stress in women with infertility related to endometriosis. Fertil Steril. 2012;98:126–30.PubMedCrossRefGoogle Scholar
  48. 48.
    Harlow CR, Cahill DJ, Maile LA, Talbot WM, Mears J, Wardle PG, Hull MG. Reduced preovulatory granulosa cell steroidogenesis in women with endometriosis. J Clin Endocrinol Metab. 1996;81(1):426–9.PubMedGoogle Scholar
  49. 49.
    Gomes FM, Navarro PA, de Abreu LG, Ferriani RA, dos Reis RM, de Moura MD. Effect of peritoneal fluid from patients with minimal/mild endometriosis on progesterone release by human granulosa-lutein cells obtained from infertile patients without endometriosis: a pilot study. Eur J Obstet Gynecol Reprod Biol. 2008;138(1):60–5.PubMedCrossRefGoogle Scholar
  50. 50.
    Wardle PG, Mitchell JD, McLaughlin EA, Ray BD, McDermott A, Hull MG. Endometriosis and ovulatory disorder: reduced fertilisation in vitro compared with tubal and unexplained infertility. Lancet. 1985;2(8449):236–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Eppig JJ, Wigglesworth K, Pendola FL. The mammalian oocyte orchestrates the rate of ovarian follicular development. Proc Natl Acad Sci U S A. 2002;99(5):2890–4.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Tanghe S, Van Soom A, Nauwynck H, Coryn M, de Kruif A. Minireview: functions of the cumulus oophorus during oocyte maturation, ovulation, and fertilization. Mol Reprod Dev. 2002;61(3):414–24.PubMedCrossRefGoogle Scholar
  53. 53.
    Hamel M, Dufort I, Robert C, Gravel C, Leveille MC, Leader A, et al. Identification of differentially expressed markers in human follicular cells associated with competent oocytes. Hum Reprod. 2008;23(5):1118–27.PubMedCrossRefGoogle Scholar
  54. 54.
    Haouzi D, Hamamah S. Pertinence of apoptosis markers for the improvement of in vitro fertilization (IVF). Curr Med Chem. 2009;16(15):1905–16.PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Tesfaye D, Ghanem N, Carter F, Fair T, Sirard MA, Hoelker M, et al. Gene expression profile of cumulus cells derived from cumulus-oocyte complexes matured either in vivo or in vitro. Reprod Fertil Dev. 2009;21(3):451–61.PubMedCrossRefGoogle Scholar
  56. 56.
    Barcelos ID, Donabella FC, Ribas CP, Meola J, Ferriani RA, Navarro PAAS. Gene expression of aromatase (CYP19A1) and 3β-hydroxysteroid dehydrogenase in cumulus oophorus cells of endometriosis and control infertile patients submitted to ICSI. Fertil Steril. 2011;96(3):S75.CrossRefGoogle Scholar
  57. 57.
    Lachapelle MH, Hemmings R, Roy DC, Falcone T, Miron P. Flow cytometric evaluation of leukocyte subpopulations in the follicular fluids of infertile patients. Fertil Steril. 1996;65:1135–40.PubMedGoogle Scholar
  58. 58.
    Oosterlynck DJ, Meuleman C, Waer M, Koninckx PR, Vandeputte M. Immunosuppressive activity of peritoneal fluid in women with endometriosis. Obstet Gynecol. 1993;82:206–12.PubMedGoogle Scholar
  59. 59.
    Weed JC, Arquembourg PC. Endometriosis: can it produce an autoimmune response resulting in infertility? Clin Obstet Gynecol. 1980;23:885–93.PubMedCrossRefGoogle Scholar
  60. 60.
    Lebovic DI, Mueller MD, Taylor RN. Immunobiology of endometriosis. Fertil Steril. 2001;75:1–10.PubMedCrossRefGoogle Scholar
  61. 61.
    Lessey BA, Castelbaum AJ, Buck CA, Lei Y, Yowell CW, Sun J. Further characterization of endometrial integrins during the menstrual cycle and in pregnancy. Fertil Steril. 1994;62:497–506.PubMedGoogle Scholar
  62. 62.
    Lessey BA, Castelbaum AJ, Sawin SW, Buck CA, Schinnar R, Bilker W, et al. Aberrant integrin expression in the endometrium of women with endometriosis. J Clin Endocrinol Metab. 1994;79:643–9.PubMedGoogle Scholar
  63. 63.
    Kao LC, Germeyer A, Tulac S, Lobo S, Yang JP, Taylor RN, et al. Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility. Endocrinology. 2003;144:2870–81.PubMedCrossRefGoogle Scholar
  64. 64.
    Hughes EG. The effectiveness of ovulation induction and intrauterine insemination in the treatment of persistent infertility: a meta-analysis. Hum Reprod. 1997;12:1865–72.PubMedCrossRefGoogle Scholar
  65. 65.
    Lessey BA. Medical management of endometriosis and infertility. Fertil Steril. 2000;73:1089–96.PubMedCrossRefGoogle Scholar
  66. 66.
    Olive DL, Stohs GF, Metzger DA, et al. Expectant management and hydrotubations in the treatment of endometriosis associated infertility. Fertil Steril. 1985;44:35–41.PubMedGoogle Scholar
  67. 67.
    Marcoux S, Maheux R, Berube S. Laparoscopic surgery in infertile women with minimal or mild endometriosis. Canadian collaborative group on endometriosis. N Engl J Med. 1997;337:217–22.PubMedCrossRefGoogle Scholar
  68. 68.
    Soares SR, Martinez-Varea A, Hidalgo-Mora JJ, Pellicer A. Pharmacologic therapies in endometriosis: a systematic review. Fertil Steril. 2012;98:529–55.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2015

Authors and Affiliations

  • Paula Andrea de Albuquerque de Salles Navarro
    • 1
  • Anderson Sanches de Melo
    • 1
  • Rui Alberto Ferriani
    • 1
  1. 1.Department of Obstetrics and GynecologyUniversity of São PauloRibeirão PretoBrazil

Personalised recommendations