Immunoreactivity of Kisspeptin and Kisspeptin Receptor in Eutopic and Ectopic Endometrial Tissue of Women With and Without Endometriosis

Abstract

Endometriosis is characterized by the presence of ectopic endometrial tissues. Mechanisms of tissue dissemination in endometriosis may be similar to those involved in tumor metastasis. We hypothesize that dysregulation of kisspeptin (KISS1), a metastasis suppressor in endometrial carcinoma, may contribute to the pathogenesis of endometriosis. In this study, we characterized the immunoreactivity of kisspeptin and its receptor, KISS1R, in eutopic and ectopic endometrial tissue of women with and without endometriosis, in proliferative and secretory menstrual cycle phases. Immunohistochemistry was performed using KISS1 and KISS1R antibodies on samples from women with (n = 35) and without (n = 14) endometriosis. Samples from women with endometriosis included eutopic endometrium (n = 20) samples, superficial endometriotic implants (SUP, n = 10) deep infiltrating endometriotic implants (DIE, n = 15), and ovarian endometriomas (OMA, n = 15). Immunoreactivity was quantified using histoscores. KISS1 and KISS1R immunoreactivity was significantly lower in eutopic endometrial stroma of women with versus without endometriosis, regardless of the menstrual cycle phase (P = 0.001 and P = 0.015 respectively). In endometriotic implants, KISS1 levels were significantly lower in both glandular and stromal components of DIE (P < 0.01) and OMA (P < 0.01) compared to SUP. KISS1R immunoreactivity was lower in the glandular component of OMA (P = 0.035) compared to SUP. KISS1 and KISS1R levels are lower in eutopic endometrial stroma from women with versus without endometriosis, consistent with a role for decreased KISS1 expression in the pathogenesis of endometriosis. As deeply invasive lesions showed lower KISS1 levels than superficial lesions, downregulation of KISS1 levels may contribute to implant invasiveness.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. 1.

    Vigano P, Parazzini F, Somigliana E, Vercellini P. Endometriosis: epidemiology and aetiological factors. Best practice & research. Clin Obstet Gynaecol. 2004;18:177–200.

    Google Scholar 

  2. 2.

    Sinaii N, Plumb K, Cotton L, Lambert A, Kennedy S, Zondervan K, et al. Differences in characteristics among 1,000 women with endometriosis based on extent of disease. Fertil Steril. 2008;89:538–45.

    PubMed  Google Scholar 

  3. 3.

    Sampson JA. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. 14:422–69.

  4. 4.

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

    CAS  PubMed  Google Scholar 

  5. 5.

    Filigheddu N, Gregnanin I, Porporato PE, et al. Differential expression of microRNAs between eutopic and ectopic endometrium in ovarian endometriosis. J Biomed Biotechnol. 2010;2010:369549.

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Bulun SE, Monsivais D, Kakinuma T, Furukawa Y, Bernardi L, Pavone ME, et al. Molecular biology of endometriosis: from aromatase to genomic abnormalities. Semin Reprod Med. 2015;33:220–4.

    CAS  PubMed  Google Scholar 

  7. 7.

    Mizumoto H, Saito T, Ashihara K, Nishimura M, Takehara M, Tanaka R, et al. Expression of matrix metalloproteinases in ovarian endometriomas: immunohistochemical study and enzyme immunoassay. Life Sci. 2002;71:259–73.

    CAS  PubMed  Google Scholar 

  8. 8.

    Szamatowicz J, Laudański P, Tomaszewska I. Matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1: a possible role in the pathogenesis of endometriosis. Hum Reprod. 2002;17:284–8.

    CAS  PubMed  Google Scholar 

  9. 9.

    Wolber E-M, Kressin P, Meyhöfer-Malik A, Diedrich K, Malik E. Differential induction of matrix metalloproteinase 1 and 2 in ectopic endometrium. Reprod BioMed Online. 6:238–43.

  10. 10.

    Chung HW, Lee JY, Moon HS, Hur SE, Park MH, Wen Y, et al. Matrix metalloproteinase-2, membranous type 1 matrix metalloproteinase, and tissue inhibitor of metalloproteinase-2 expression in ectopic and eutopic endometrium. Fertil Steril. 2002;78:787–95.

    PubMed  Google Scholar 

  11. 11.

    Uzan C, Cortez A, Dufournet C, Fauvet R, Siffroi JP, Darai E. Eutopic endometrium and peritoneal, ovarian and bowel endometriotic tissues express a different profile of matrix metalloproteinases-2, −3 and −11, and of tissue inhibitor metalloproteinases-1 and -2. Virchows Archiv : an international journal of pathology. 2004;445:603–9.

    CAS  Google Scholar 

  12. 12.

    Pitsos M, Kanakas N. The role of matrix metalloproteinases in the pathogenesis of endometriosis. Reprod Sci (Thousand Oaks, Calif). 2009;16:717–26.

    CAS  Google Scholar 

  13. 13.

    Visse R, Nagase H, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res. 2006;69:562–73.

    PubMed  Google Scholar 

  14. 14.

    Nomura H, Sato H, Seiki M, Mai M, Okada Y. Expression of membrane-type matrix metalloproteinase in human gastric carcinomas. Cancer Res. 1995;55:3263–6.

    CAS  PubMed  Google Scholar 

  15. 15.

    West A, Vojta PJ, Welch DR, Weissman BE. Chromosome localization and genomic structure of the KiSS-1 metastasis suppressor gene (KISS1). Genomics. 1998;54:145–8.

    CAS  PubMed  Google Scholar 

  16. 16.

    Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, le Poul E, et al. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem. 2001;276:34631–6.

    CAS  PubMed  Google Scholar 

  17. 17.

    Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K, et al. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature. 2001;411:613–7.

    CAS  PubMed  Google Scholar 

  18. 18.

    Muir AI, Chamberlain L, Elshourbagy NA, Michalovich D, Moore DJ, Calamari A, et al. AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1. J Biol Chem. 2001;276:28969–75.

    CAS  PubMed  Google Scholar 

  19. 19.

    Lee DK, Nguyen T, O'Neill GP, Cheng R, Liu Y, Howard AD, et al. Discovery of a receptor related to the galanin receptors. FEBS Lett. 1999;446:103–7.

    CAS  PubMed  Google Scholar 

  20. 20.

    Navarro VM, Fernandez-Fernandez R, Castellano JM, et al. Advanced vaginal opening and precocious activation of the reproductive axis by KiSS-1 peptide, the endogenous ligand of GPR54. J Physiol. 2004;561:379–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Navarro VM, Castellano JM, Fernandez-Fernandez R, et al. Developmental and hormonally regulated messenger ribonucleic acid expression of KiSS-1 and its putative receptor, GPR54, in rat hypothalamus and potent luteinizing hormone-releasing activity of KiSS-1 peptide. Endocrinology. 2004;145:4565–74.

    CAS  PubMed  Google Scholar 

  22. 22.

    Han SK, Gottsch ML, Lee KJ, Popa SM, Smith JT, Jakawich SK, et al. Activation of gonadotropin-releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of puberty. J Neurosci. 2005;25:11349–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Shahab M, Mastronardi C, Seminara SB, Crowley WF, Ojeda SR, Plant TM. Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates. Proc Natl Acad Sci U S A. 2005;102:2129–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Lee JH, Miele ME, Hicks DJ, Phillips KK, Trent JM, Weissman BE, et al. KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. J Natl Cancer Inst. 1996;88:1731–7.

    CAS  PubMed  Google Scholar 

  25. 25.

    Dhar DK, Naora H, Kubota H, Maruyama R, Yoshimura H, Tonomoto Y, et al. Downregulation of KiSS-1 expression is responsible for tumor invasion and worse prognosis in gastric carcinoma. Int J Cancer. 2004;111:868–72.

    CAS  PubMed  Google Scholar 

  26. 26.

    Yao HL, Yang ZL, Li YG, Liu GW. [In situ hybridization study on the expression of Kiss-1 and KAI-1 metastasis suppressor genes in gastric cancer]. Zhonghua wei chang wai ke za zhi =. Chinese Journal of Gastrointestinal Surgery. 2007;10:274–7.

    PubMed  Google Scholar 

  27. 27.

    Guan-Zhen Y, Ying C, Can-Rong N, Guo-Dong W, Jian-Xin Q, Jie-Jun W. Reduced protein expression of metastasis-related genes (nm23, KISS1, KAI1 and p53) in lymph node and liver metastases of gastric cancer. Int J Exp Pathol. 2007;88:175–83.

    PubMed  PubMed Central  Google Scholar 

  28. 28.

    Hata K, Dhar DK, Watanabe Y, Nakai H, Hoshiai H. Expression of metastin and a G-protein-coupled receptor (AXOR12) in epithelial ovarian cancer. Eur J Cancer. 2007;43:1452–9.

    CAS  PubMed  Google Scholar 

  29. 29.

    Jiang Y, Berk M, Singh LS, Tan H, Yin L, Powell CT, et al. KiSS1 suppresses metastasis in human ovarian cancer via inhibition of protein kinase C alpha. Clin Exp Metastasis. 2005;22:369–76.

    CAS  PubMed  Google Scholar 

  30. 30.

    Jiang T, Zhang SL, Lin B, Meng LR, Gao H. Expression and clinical significance of KISS-1 and GPR54 mRNA in endometrial carcinoma. Zhonghua Zhong Liu Za Zhi. 2005;27:229–31.

    CAS  PubMed  Google Scholar 

  31. 31.

    Sanchez-Carbayo M, Capodieci P, Cordon-Cardo C. Tumor suppressor role of KiSS-1 in bladder cancer: loss of KiSS-1 expression is associated with bladder cancer progression and clinical outcome. Am J Pathol. 2003;162:609–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Yan C, Wang H, Boyd DD. KiSS-1 represses 92-kDa type IV collagenase expression by down-regulating NF-kappa B binding to the promoter as a consequence of Ikappa Balpha -induced block of p65/p50 nuclear translocation. J Biol Chem. 2001;276:1164–72.

    CAS  PubMed  Google Scholar 

  33. 33.

    Bilban M, Ghaffari-Tabrizi N, Hintermann E, Bauer S, Molzer S, Zoratti C, et al. Kisspeptin-10, a KiSS-1/metastin-derived decapeptide, is a physiological invasion inhibitor of primary human trophoblasts. J Cell Sci. 2004;117:1319–28.

    CAS  PubMed  Google Scholar 

  34. 34.

    Takino T, Koshikawa N, Miyamori H, Tanaka M, Sasaki T, Okada Y, et al. Cleavage of metastasis suppressor gene product KiSS-1 protein/metastin by matrix metalloproteinases. Oncogene. 2003;22:4617–26.

    CAS  PubMed  Google Scholar 

  35. 35.

    Mead EJ, Maguire JJ, Kuc RE, Davenport AP. Kisspeptins: a multifunctional peptide system with a role in reproduction, cancer and the cardiovascular system. Br J Pharmacol. 2007;151:1143–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Timologou A, Zafrakas M, Grimbizis G, et al. Immunohistochemical expression pattern of metastasis suppressors KAI1 and KISS1 in endometriosis and normal endometrium. Eur J Obstet Gynecol Reprod Biol. 2016;199:110–5.

    CAS  PubMed  Google Scholar 

  37. 37.

    Makri A, Msaouel P, Petraki C, et al. KISS1/KISS1R expression in eutopic and ectopic endometrium of women suffering from endometriosis. In vivo (Athens, Greece). 2012;26:119–27.

    CAS  Google Scholar 

  38. 38.

    Noyes RW, Hertig AT, Rock J. Dating the endometrial biopsy. Am J Obstet Gynecol. 1975;122:262–3.

    CAS  PubMed  Google Scholar 

  39. 39.

    Koninckx PR, Martin D. Treatment of deeply infiltrating endometriosis. Curr Opin Obstet Gynecol. 1994;6:231–41.

    CAS  PubMed  Google Scholar 

  40. 40.

    Peng B, Zhu H, Leung PC. Gonadotropin-releasing hormone regulates human trophoblastic cell invasion via TWIST-induced N-cadherin expression. J Clin Endocrinol Metab. 2015;100:E19–29.

    CAS  PubMed  Google Scholar 

  41. 41.

    Browne H, Taylor H. HOXA10 expression in ectopic endometrial tissue. Fertil Steril. 2006;85:1386–90.

    CAS  PubMed  Google Scholar 

  42. 42.

    Sharpe-Timms KL, Ricke EA, Piva M, Horowitz GM. Differential expression and localization of de-novo synthesized endometriotic haptoglobin in endometrium and endometriotic lesions. Hum Reprod (Oxford, England). 2000;15:2180–5.

    CAS  Google Scholar 

  43. 43.

    Hauge-Evans AC, Richardson CC, Milne HM, Christie MR, Persaud SJ, Jones PM. A role for kisspeptin in islet function. Diabetologia. 2006;49:2131–5.

    CAS  PubMed  Google Scholar 

  44. 44.

    Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertility and sterility. 1997;67:817–821.

  45. 45.

    Baba T, Kang HS, Hosoe Y, Kharma B, Abiko K, Matsumura N, et al. Menstrual cyclic change of metastin/GPR54 in endometrium. Med Mol Morphol. 2015;48:76–84.

    CAS  PubMed  Google Scholar 

  46. 46.

    Gao GL, Liu LD, Zou XS, Chen WX. Expression of KiSS-1, matrix metalloproteinase-9, nuclear factor-kappaBp65 in ovarian tumour. Zhonghua fu chan ke za zhi. 2007;42:34–8.

    CAS  PubMed  Google Scholar 

  47. 47.

    Balkowiec M, Maksym RB, Wlodarski PK. The bimodal role of matrix metalloproteinases and their inhibitors in etiology and pathogenesis of endometriosis (review). Mol Med Rep. 2018;18:3123–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Sotnikova NY, Antsiferova YS, Posiseeva LV, Shishkov DN, Posiseev DV, Filippova ES. Mechanisms regulating invasiveness and growth of endometriosis lesions in rat experimental model and in humans. Fertil Steril. 2010;93:2701–5.

    PubMed  Google Scholar 

  49. 49.

    Collette T, Bellehumeur C, Kats R, et al. Evidence for an increased release of proteolytic activity by the eutopic endometrial tissue in women with endometriosis and for involvement of matrix metalloproteinase-9. Hum Reprod (Oxford, England). 2004;19:1257–64.

    CAS  Google Scholar 

  50. 50.

    Collette T, Maheux R, Mailloux J, Akoum A. Increased expression of matrix metalloproteinase-9 in the eutopic endometrial tissue of women with endometriosis. Hum Reprod (Oxford, England). 2006;21:3059–67.

    CAS  Google Scholar 

  51. 51.

    Di Carlo C, Bonifacio M, Tommaselli GA, Bifulco G, Guerra G, Nappi C. Metalloproteinases, vascular endothelial growth factor, and angiopoietin 1 and 2 in eutopic and ectopic endometrium. Fertil Steril. 2009;91:2315–23.

    PubMed  Google Scholar 

  52. 52.

    Banerjee SK, Ballard KD, Wright JT. Endometriomas as a marker of disease severity. J Minim Invasive Gynecol. 2008;15:538–40.

    PubMed  Google Scholar 

  53. 53.

    Gargett CE, Schwab KE, Brosens JJ, Puttemans P, Benagiano G, Brosens I. Potential role of endometrial stem/progenitor cells in the pathogenesis of early-onset endometriosis. Mol Hum Reprod. 2014;20:591–8.

    CAS  PubMed  Google Scholar 

  54. 54.

    Kang HS, Baba T, Mandai M, Matsumura N, Hamanishi J, Kharma B, et al. GPR54 is a target for suppression of metastasis in endometrial cancer. Mol Cancer Ther. 2011;10:580–90.

    CAS  PubMed  Google Scholar 

  55. 55.

    Klemmt PAB, Starzinski-Powitz A. Molecular and cellular pathogenesis of endometriosis. Current women's health reviews. 2018;14:106–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Patel BG, Rudnicki M. Progesterone resistance in endometriosis: origins, consequences and interventions 2017;96:623–632.

  57. 57.

    Makri A, Pissimissis N, Lembessis P, Polychronakos C, Koutsilieris M. The kisspeptin (KiSS-1)/GPR54 system in cancer biology. Cancer Treat Rev. 2008;34:682–92.

    CAS  PubMed  Google Scholar 

  58. 58.

    Panidis D, Rousso D, Koliakos G, Kourtis A, Katsikis I, Farmakiotis D, et al. Plasma metastin levels are negatively correlated with insulin resistance and free androgens in women with polycystic ovary syndrome. Fertil Steril. 2006;85:1778–83.

    CAS  PubMed  Google Scholar 

  59. 59.

    Park DW, Lee SK, Hong SR, Han AR, Kwak-Kim J, Yang KM. Expression of Kisspeptin and its receptor GPR54 in the first trimester trophoblast of women with recurrent pregnancy loss. Am J Reprod Immunol (New York, NY : 1989). 2012;67:132–9.

    CAS  Google Scholar 

  60. 60.

    Logie JJ, Denison FC, Riley SC, Ramaesh T, Forbes S, Norman JE, et al. Evaluation of kisspeptin levels in obese pregnancy as a biomarker for pre-eclampsia. Clin Endocrinol. 2012;76:887–93.

    CAS  Google Scholar 

  61. 61.

    Gaytan M, Castellano JM, Roa J, Sanchez-Criado JE, Tena-Sempere M, Gaytan F. Expression of KiSS-1 in rat oviduct: possible involvement in prevention of ectopic implantation? Cell Tissue Res. 2007;329:571–9.

    CAS  PubMed  Google Scholar 

  62. 62.

    Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, et al. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003;349:1614–27.

    CAS  PubMed  Google Scholar 

  63. 63.

    de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A. 2003;100:10972–6.

    PubMed  PubMed Central  Google Scholar 

  64. 64.

    Castellano JM, Navarro VM, Fernandez-Fernandez R, et al. Expression of hypothalamic KiSS-1 system and rescue of defective gonadotropic responses by kisspeptin in streptozotocin-induced diabetic male rats. Diabetes. 2006;55:2602–10.

    CAS  PubMed  Google Scholar 

  65. 65.

    Roseweir AK, Kauffman AS, Smith JT, Guerriero KA, Morgan K, Pielecka-Fortuna J, et al. Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation. J Neurosci. 2009;29:3920–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Dhillo WS, Chaudhri OB, Patterson M, Thompson EL, Murphy KG, Badman MK, et al. Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab. 2005;90:6609–15.

    CAS  PubMed  Google Scholar 

  67. 67.

    Blumenfeld Z. Investigational and experimental GnRH analogs and associated neurotransmitters. Expert Opin Investig Drugs. 2017;26:661–7.

    CAS  PubMed  Google Scholar 

  68. 68.

    Kuohung W, Burnett M, Mukhtyar D, Schuman E, Ni J, Crowley WF, et al. A high-throughput small-molecule ligand screen targeted to agonists and antagonists of the G-protein-coupled receptor GPR54. J Biomol Screen. 2010;15:508–17.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors thank Professor Eman M. S. Muhammad from the pathology department at Sohag University in Egypt and Dr. Julia Naso from the pathology department at The University of British Columbia in Canada for their help with the study.

Funding

This project was internally funded by the Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada, and by the joint supervision scholarships program, Egyptian Ministry of higher education, Cairo, Egypt.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Mohamed A. Bedaiwy.

Ethics declarations

Conflict of Interests

The authors declare that they have is no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This work was completed at the British Columbia Women’s Hospital, Vancouver, Canada and the BC Children’s Hospital Research Institute, Vancouver, Canada.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Abdelkareem, A.O., Alotaibi, F.T., AlKusayer, G.M. et al. Immunoreactivity of Kisspeptin and Kisspeptin Receptor in Eutopic and Ectopic Endometrial Tissue of Women With and Without Endometriosis. Reprod. Sci. 27, 1731–1741 (2020). https://doi.org/10.1007/s43032-020-00167-w

Download citation

Keywords

  • Kisspeptin
  • KISS1
  • Endometriosis
  • Metastin
  • Immunohistochemistry