Skip to main content
SpringerLink
Log in

Apoptosis in Endometriosis

  • Chapter
  • First Online:
Endometriosis

  • 2350 Accesses

Abstract

Endometriosis is an inflammatory, estrogen-dependent disease characterized by the growth of endometrial tissues outside the uterus. The eutopic endometrium from women with endometriosis has some fundamental differences compared with the normal endometrium of women without endometriosis. The differences could contribute to the survival of regurgitating endometrial cells into the peritoneal cavity and the development of endometriosis. One mechanism that gained a lot of interests is the finding that apoptosis appeared in eutopic and ectopic endometrium of patients with endometriosis. A common characteristic of endometriotic cells is their ability to evade the apoptotic machinery. Endometriosis could result from increased cellular proliferation or decreased apoptosis in response to appropriate stimuli. This chapter focused on the physiological role of apoptosis in normal endometrium and the alterations in regulation of apoptosis in eutopic and ectopic endometrium from women with endometriosis. Finally, the role of apoptosis in the treatment of endometriosis is reviewed to link the basic research findings into clinical applications.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Halme J, Hammond MG, Hulka JF, Raj S, Talbert LM. Retrograde menstruation in healthy women and in patients with endometriosis. Obstet Gynecol. 1984;64:151–4.

    CAS  PubMed  Google Scholar 

  2. Arumugam K, Lim JM. Menstrual characteristics associated with endometriosis. Br J Obstet Gynecol. 1997;104:948–50.

    Article  CAS  Google Scholar 

  3. Kruitwagen RFPM, Poels LG, Willemsen WNP, de Ronde IJ, Jap PH, Rolland R. Endometrial epithelial cells in peritoneal fluid during the early follicular phase. Fertil Steril. 1991;55:297–303.

    CAS  PubMed  Google Scholar 

  4. Sharpe Timms KL. Endometrial anomalies in women with endometriosis. Ann N Y Acad Sci. 2001;943:131–47.

    Article  CAS  PubMed  Google Scholar 

  5. Leyendecker G, Kunz G, Noe M, Herbertz M, Mall G. Endometriosis: a dysfunction and disease of the archimetra. Hum Reprod Update. 1998;4:752–62.

    Article  CAS  PubMed  Google Scholar 

  6. Meresman GF, Vighi S, Buquet RA, Contreras-Ortiz O, Tesone M, Rumi LS. Apoptosis and expression of Bcl-2, Bax in eutopic endometrium from women with endometriosis. Fertil Steril. 2000;74:760–6.

    Article  CAS  PubMed  Google Scholar 

  7. Aplin AE, Howe A, Alahari SK, Juliano RL. Signal transduction and signal modulation by cell adhesion receptors: the role of integrins, cadherins, immunoglobulin-cell adhesion molecules, and selectins. Pharmacol Rev. 1998;50:197–263.

    CAS  PubMed  Google Scholar 

  8. Ballester M, Gonin J, Rodenas A, Bernaudin JF, Rouzier R, Coutant C, Darai E. Eutopic endometrium and peritoneal, ovarian and colorectal endometriotic tissues express a different profile of nectin-1, -3, -4 and nectin-like molecule 2. Hum Reprod. 2012;27:3179–86.

    Article  CAS  PubMed  Google Scholar 

  9. Bilotas M, Meresman G, Buquet R, Sueldo C, Baranao RI. Effect of vascular growth factor and interleukin-1β on apoptosis in endometrial cell cultures from patients with endometriosis and controls. J Reprod Immunol. 2010;84:193–8.

    Article  CAS  PubMed  Google Scholar 

  10. Cinar O, Seval Y, Uz YH, Cakmak H, Ulukus M, Kayisli UA, Arici A. Differential regulation of Akt phosphorylation in endometriosis. Reprod Biomed Online. 2009;19:864–71.

    Article  CAS  PubMed  Google Scholar 

  11. Aghajanova L, Horcajadas JA, Weeks JL, Esteban FJ, Nezhat CN, Conti M, Giudice LC. The protein kinase A pathway-regulated transcriptome of endometrial stromal fibroblasts reveals compromised differentiation and persistent proliferative potential in endometriosis. Endocrinology. 2010;151:1341–55.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Kaponis A, Iwabe T, Taniguchi F, Ito M, Deura I, Decavalas G, Terakawa N, Harada T. The role of NF-kappaB in endometriosis. Front Biosci. 2012;4:1213–34.

    Article  Google Scholar 

  13. Gonzalez-Ramos R, Van Langendonckt A, Defrere S, Lousse JC, Mettelen M, Guillet A, Donnez J. Agents blocking the nuclear factor-kappaB (NF-κB) pathway are effective inhibitors of endometriosis in an in vivo experimental model. Gynecol Obstet Invest. 2008;65:174–86.

    Article  CAS  PubMed  Google Scholar 

  14. Arimoto T, Katagiri T, Oda K, Tsunoda T, Yasugi T, Osuga Y, Yoshikawa H, Nishii O, Yano T, Taketani Y, Nakamura Y. Genome-wide cDNA microarray analysis of gene-expression profiles involved in ovarian endometriosis. Int J Oncol. 2003;22:551–60.

    CAS  PubMed  Google Scholar 

  15. Ueda M, Yamashita Y, Takehara M, Terai Y, Kumagai K, Ueki K, Kanda K, Yamaguchi H, Akise D, Hung YC, Ueki M. Survivin gene expression in endometriosis. J Clin Endocrinol Metab. 2002;87:3452–9.

    Article  CAS  PubMed  Google Scholar 

  16. Watanabe A, Taniguchi F, Izawa M, Suou K, Uegaki T, Takai E, Terakawa N, Harada T. The role of surviving in the resistance of endometriotic stromal cells to drug-induced apoptosis. Hum Reprod. 2009;24:3172–9.

    Article  CAS  PubMed  Google Scholar 

  17. Abe W, Nasu K, Nakada C, Kawano Y, Moriyama M, Narahara H. miR-196b targets c-myc and Bcl-2 expression, inhibits proliferation and induces apoptosis in endometriotic stromal cells. Hum Reprod. 2013;28:750–61.

    Article  CAS  PubMed  Google Scholar 

  18. Reis FM, Petraglia F, Taylor RN. Endometriosis: hormone regulation and clinical consequences of chemotaxis and apoptosis. Hum Reprod Update. 2013;19:406–18.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Kokawa K, Shikone T, Nakano R. Apoptosis in the human uterine endometrium during the menstrual cycle. J Clin Endocrinol Metabol. 1996;81:4144–7.

    CAS  Google Scholar 

  20. Vaskivuo TE, Stenback F, Karhumaa P, Risteli J, Dunkel L, Tapanainen JS. Apoptosis and apoptosis-related proteins in human endometrium. Mol Cell Endocrinol. 2000;165:75–83.

    Article  CAS  PubMed  Google Scholar 

  21. Watanabe H, Kanzaki H, Narukawa S, Inoue T, Katsuragawa H, Kaneko Y, Mori T. Bcl-2 and Fas expression in eutopic and ectopic human endometrium during the menstrual cycle in relation to endometrial cell apoptosis. Am J Obstet Gynecol. 1997;176:360–8.

    Article  CAS  PubMed  Google Scholar 

  22. Rogers PA, Lederman F, Plunkett D, Affandi B. Bcl-2, Fas, and caspase-3 expression in endometrium from levonorgestrel implant users with and without breakthrough bleeding. Hum Reprod. 2000;15:152–61.

    Article  CAS  PubMed  Google Scholar 

  23. Chittenden T, Harrington EA, O’Connor R, Flemington C, Lutz RJ, Evan GI, Guild BC. Induction of apoptosis by the Bcl-2 homologue Bak. Nature. 1995;374:731–3.

    Article  Google Scholar 

  24. Narkar M, Kholkute S, Chitlange S, Nandedkar T. Expression of steroid hormone receptors, proliferation and apoptotic markers in primate endometrium. Mol Cell Endocrinol. 2006;246:107–13.

    Article  CAS  PubMed  Google Scholar 

  25. Tao XJ, Sayegh RA, Tilly JT, Isaacson KB. Elevated expression of the proapoptotic BCL-2 family member, BAK, in the human endometrium coincident with apoptosis during the secretory phase of the cycle. Fertil Steril. 1998;70:338–43.

    Article  CAS  PubMed  Google Scholar 

  26. Bilotas M, Baranao RI, Buquet R, Sueldo C, Tesone M, Meresman G. Effects of GnRH analogues on apoptosis and expression of Bcl-2, Bax, Fas, and FasL proteins in endometrial epithelial cell cultures from patients with endometriosis and controls. Hum Reprod. 2007;22:644–53.

    Article  CAS  PubMed  Google Scholar 

  27. Peng X, Maruo T, Matsuo H, Takekida S, Deguchi J. Serum deprivation-induced apoptosis in cultures porcine granulosa cells is characterized by increased expression of p53 protein, Fas antigen and Fas ligand and by decreased expression of PCNA. Endocr J. 1998;45:247–53.

    Article  CAS  PubMed  Google Scholar 

  28. Abe H, Shibata MA, Otsuki Y. Caspase of Fas-mediated apoptosis in human normal endometrium and endometrial carcinoma cells. Mol Hum Reprod. 2006;12:535–41.

    Article  CAS  PubMed  Google Scholar 

  29. Gebel HM, Braun DP, Tambur A, Frame D, Rana N, Dmowski DP. Spontaneous apoptosis of endometrial tissue is impaired in women with endometriosis. Fertil Steril. 1998;9:1042–7.

    Article  Google Scholar 

  30. Jones RK, Searle RF, Bulmer JN. Apoptosis and bcl-2 expression in normal human endometrium, endometriosis and adenomyosis. Hum Reprod. 1998;13:3496–502.

    Article  CAS  PubMed  Google Scholar 

  31. Fujishita A, Chavez RO, Nakane PK, Yamabe T, Koji T, Ishimau T, Masuzaki H. Expression of estrogen and progesterone receptors in endometrium and peritoneal endometriosis: an immunohistochemical and in situ hybridization study. Fertil Steril. 1997;67:856–64.

    Article  CAS  PubMed  Google Scholar 

  32. McLaren J, Prentice A, Charnock-Jones DS, Sharkey AM, Smith SA. Immunocolonization of the apoptosis regulating proteins Bcl-2 and Bax in human endometrium and isolated peritoneal fluid macrophages in endometriosis. Hum Reprod. 1997;12:146–52.

    Article  CAS  PubMed  Google Scholar 

  33. Braun DP, Ding J, Shaheen F, Willey JC, Rana N, Dmowski WP. Quantitative expression of apoptosis-regulating genes in endometrium from women with and without endometriosis. Fertil Steril. 2006;87:263–8.

    Article  PubMed  Google Scholar 

  34. Banu SK, Lee JH, Speights VO, Starzinski-Powitz A, Arosh JA. Selective Inhibition of Prostaglandin E2 Receptors EP2 and EP4 Induces Apoptosis of Human Endometriotic Cells through suppression of ERK1/2, Akt, NF_B, and β-Catenin Pathways and activation of intrinsic apoptotic mechanisms. Mol Endocrinol. 2009;23:1291–305.

    Article  CAS  PubMed  Google Scholar 

  35. Harada M, Suganuma N, Furuhashi M, Nagasaka T, Nakashima N, Kikkawa F, Tomoda Y, Furui K. Detection of apoptosis in human endometriotic tissues. Mol Hum Reprod. 1996;2:307–15.

    Article  CAS  PubMed  Google Scholar 

  36. Eidukaite A, Siaurys A, Tamosiunas V. Aberrant expression of CD95 and CD69 molecules among CD56+ cells in women with endometriosis. Am J Reprod Immunol. 2006;55:276–81.

    Article  CAS  PubMed  Google Scholar 

  37. Garcia Velasco JA, Mulayim N, Kayisli UA, Arici A. Elevated soluble Fas ligand levels may suggest a role for apoptosis in women with endometriosis. Fertil Steril. 2002;78:855–9.

    Article  PubMed  Google Scholar 

  38. Garcia Velasco J, Arici A, Zreick T, Naftolin F, Mor G. Macrophage-derived growth factors regulate FasL expression in endometrial stromal cells: a role in endometriosis. Mol Hum Reprod. 1999;5:642–50.

    Article  CAS  PubMed  Google Scholar 

  39. Selam B, Kayisli UA, Garcia Velasco JA, Arici A. Extracellular matrix-dependent regulation of Fas ligand expression in human endometrial stromal cells. Biol Reprod. 2002;66:1–5.

    Article  CAS  PubMed  Google Scholar 

  40. Kayagaki N, Kawasaki A, Ebata T, Ohmoto H, Ikeda S, Inoue S, Yoshino K, Okumura K, Yagita H. Metalloproteinase-mediated release of human Fas ligand. J Exp Med. 1995;182:1777–83.

    Article  CAS  PubMed  Google Scholar 

  41. Harada T, Iwabe T, Terakawa N. Role of cytokines in endometriosis. Fertil Steril. 2001;76:1–10.

    Article  CAS  PubMed  Google Scholar 

  42. Iwabe T, Harada T, Tsudo T, Nagano Y, Yoshida S, Tanikawa M, Terakawa N. Tumor necrosis factor-alpha promotes proliferation of endometriotic stromal cells by inducing interleukin-8 gene and protein expression. J Clin Endocrinol Metab. 2000;85:824–9.

    CAS  PubMed  Google Scholar 

  43. Selam B, Kayisli UA, Garcia Velasco JA, Akbas GE, Arici A. Regulation of Fas ligand expression by IL-8 in human endometrium. J Clin Endocrinol Metabol. 2002;8:3921–7.

    Article  Google Scholar 

  44. Li MQ, Luo XZ, Meng YH, Mei J, Zhu XY, Jin LP, Li DJ. CXCL8 enhances proliferation and growth and reduces apoptosis in endometrial stromal cells in an autocrine manner via a CXCR-triggered PTEN/AKT signal pathway. Hum Reprod. 2012;27:2107–16.

    Article  CAS  PubMed  Google Scholar 

  45. Li MQ, Li HP, Meng YH, Wang XQ, Zhu XY, Mei J, Li DJ. Chemokine CCL2 enhances survival and invasiveness of endometrial stromal cells in an autocrine manner by activating Akt and MAPK/Erk1/2 signal pathway. Fertil Steril. 2012;97:919–29.

    Article  CAS  PubMed  Google Scholar 

  46. Meresman GF, Bilotas MA, Buquet RA, Baranao R, Sueldo C, Tesone M. Gonadotropin-releasing hormone agonist induces apoptosis and reduces cell proliferation in eutopic endometrial cultures from women with endometriosis. Fertil Steril. 2003;80:702–7.

    Article  PubMed  Google Scholar 

  47. Khan ΚΝ, Kitajima Μ, Hiraki Κ, Fujishita Α, Sekine Ι, Ishimaru Τ, Masuzaki Η. Changes in tissue inflammation, angiogenesis and apoptosis in endometriosis, adenomyosis and uterine myoma after GnRH agonist therapy. Hum Reprod. 2010;25:642–53.

    Article  CAS  PubMed  Google Scholar 

  48. Tesone M, Bilotas M, Barañao RI, Meresman G. The role of GnRH analogues in endometriosis-associated apoptosis and angiogenesis. Gynecol Obstet Invest. 2008;66 Suppl 1:10–8.

    Article  CAS  PubMed  Google Scholar 

  49. Sakamoto Y, Harada T, Horie S, Iba Y, Taniguchi F, Yoshida S, Iwabe T, Terakawa N. Tumor necrosis factor-a-induced interleukin-8 (IL-8) expression in endometriotic stromal cells, probably through nuclear factor-kappaB activation: gonadotropin-releasing hormone agonist treatment reduced IL-8 expression. J Clin Endocrinol Metabol. 2003;88:730–5.

    Article  CAS  Google Scholar 

  50. Nasu K, Nishida M, Ueda T, Yuge A, Takai N, Narahara H. Application of the nuclear factor-kappaB inhibitor, BAY 11-7085, for the treatment of endometriosis: an in vitro study. Am J Physiol Endocrinol Metab. 2007;293:E16–23.

    Article  CAS  PubMed  Google Scholar 

  51. Suou K, Taniguchi F, Tagashira Y, Kiyama T, Terakawa N, Harada T. Apigenin inhibits tumor necrosis factor α-induced cell proliferation and prostaglandin E2 synthesis by inactivating NFκB in endometriotic stromal cells. Fertil Steril. 2011;95:1518–21.

    Article  CAS  PubMed  Google Scholar 

  52. Zhang JJ, Xu ZM, Zhang CM, Dai HY, Ji XQ, Wang XF, Li C. Pyrrolidine dithiocarbamate inhibits nuclear factor-κB pathway activation, and regulates adhesion, migration, invasion and apoptosis of endometriotic stromal cells. Mol Hum Reprod. 2011;17:175–81.

    Article  CAS  PubMed  Google Scholar 

  53. Othman EE, Salama S, Ismail N, Al-Hendy A. Toward gene therapy of endometriosis:adenovirus-mediated delivery of dominant negative estrogen receptor genes inhibits cell proliferation, reduces cytokine production, and induces apoptosis of endometriotic cells. Fertil Steril. 2007;88:462–71.

    Article  CAS  PubMed  Google Scholar 

  54. Meresman GF, Bilotas M, Abello V, Buquet R, Tesone M, Sueldo C. Effects of aromatase inhibitors on proliferation and apoptosis in eutopic endometrial cell cultures from patients with endometriosis. Fertil Steril. 2005;84:459–63.

    Article  CAS  PubMed  Google Scholar 

  55. Harada T, Momoeda M, Taketani Y, Hoshiai H, Terakawa N. Low-dose oral contraceptive pill for dysmenorrhea associated with endometriosis: a placebo-controlled, double-blind, randomized trial. Fertil Steril. 2008;90:1583–8.

    Article  PubMed  Google Scholar 

  56. Meresman GF, Auge L, Baranao RI, Lombardi E, Tesone M, Sueldo C. Oral contraceptives suppress cell proliferation and enhance apoptosis of eutopic endometrial tissue from patients with endometriosis. Fertil Steril. 2002;77:1141–7.

    Article  PubMed  Google Scholar 

  57. Yuan P, Huang Y, Wu H, Teng Z, Zhang J, Xin X. Induction of a local pseudo-pregnancy via levonorgestrel-loaded microspheres for the treatment of endometriosis in a rabbit model. Hum Reprod. 2010;25:462–9.

    Article  CAS  PubMed  Google Scholar 

  58. Nasu K, Nishida M, Ueda T, Takai N, Bing S, Narahara H, Miyakawa I. Bufalin induces apoptosis and G0/G1 cell cycle arrest of endometriotic stromal cells a promising agent for treatment of endometriosis. Mol Hum Reprod. 2005;11:817–23.

    Article  CAS  PubMed  Google Scholar 

  59. Nishida M, Nasu K, Ueda T, Yuge A, Takai N, Narahara H. Beta-hydroxyisovalerylshikonin induces apoptosis and G0/G1 cell cycle arrest of endometriotic stromal cells preliminary in vitro study. Hum Reprod. 2006;21:2850–6.

    Article  CAS  PubMed  Google Scholar 

  60. Altintas D, Kokcu A, Kandemir B, Tosun M, Cetinkaya MB. Comparison of the effects of raloxifene and anastrozole on experimental endometriosis. Eur J Obstet Gynecol Reprod Biol. 2010;150:84–7.

    Article  CAS  PubMed  Google Scholar 

  61. Tsuno A, Nasu K, Kawano Y, Yuge A, Li H, Abe W, Narahara H. Fasudil inhibits the proliferation and contractility and induces cell cycle arrest and apoptosis of human endometriotic stromal cells: a promising agent for the treatment of endometriosis. J Clin Endocrinol Metab. 2011;96:E1944–52.

    Article  CAS  PubMed  Google Scholar 

  62. Kawano Y, Nasu K, Li H, Tsuno A, Abe W, Takai N, Narahara H. Application of the histone deacetylase inhibitors for the treatment of endometriosis: histone modifications as pathogenesis and novel therapeutic target. Hum Reprod. 2011;26:2486–98.

    Article  CAS  PubMed  Google Scholar 

  63. Banu SK, Lee J, Speights Jr VO, Starzinski-Powitz A, Arosh JA. Cyclooxygenase-2 regulates survival, migration and invasion of human endometriotic cells through multiple mechanisms. Endocrinology. 2008;149:1180–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Patra University School of Medicine, Rio, 26441, Peloponnisos, Patra, Greece

    Apostolos Kaponis M.D., Ph.D., Georgia Kollia & George Decavalas

  2. Department of Obstetrics and Gynecology, Tottori University Faculty of Medicine, Yonago, Japan

    Fuminori Taniguchi & Tasuku Harada

Authors
  1. Apostolos Kaponis M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Georgia Kollia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fuminori Taniguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tasuku Harada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. George Decavalas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Apostolos Kaponis M.D., Ph.D. .

Editor information

Editors and Affiliations

  1. Department of Obstetrics and Gynecology, Tottori University Faculty of Medicine, Yonago, Tottori, Japan

    Tasuku Harada

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Japan

About this chapter

Cite this chapter

Kaponis, A., Kollia, G., Taniguchi, F., Harada, T., Decavalas, G. (2014). Apoptosis in Endometriosis. In: Harada, T. (eds) Endometriosis. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54421-0_12

Download citation

  • DOI: https://doi.org/10.1007/978-4-431-54421-0_12

  • Published:

  • Publisher Name: Springer, Tokyo

  • Print ISBN: 978-4-431-54420-3

  • Online ISBN: 978-4-431-54421-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation