Skip to main content

Advertisement

SpringerLink
Log in

Diminished Endometrial Expression of Ghrelin and Ghrelin Receptor Contributes to Infertility

  • Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

The objectives were to investigate the presence, distribution and sex steroid hormone regulation of ghrelin and its receptor, growth hormone secretagogue receptor (GHSR), in human endometrium in relation to endometrial receptivity and fertility. Endometrial biopsies were obtained from women with unexplained infertility and healthy fertile volunteers. Ishikawa cells were used to mimic the action of ghrelin in endometrium. Immunostaining of GHSR was strong in luminal epithelium and stroma during mid-secretory phase. Ghrelin and GHSR expression is less intense in mid-secretory endometrium of infertile women compared to fertile controls. Treatment with estrogen and/or progesterone or their antagonists did not significantly change the relative expression of GHSR in Ishikawa and stromal cells. Ghrelin was present in and secreted from human blastocysts, which suggest that the communication between human blastocyst and endometrium might involve ghrelin. Low levels of GHSR in endometrium from women with unexplained infertility may in part explain the infertility.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Guzeloglu-Kayisli O, Basar M, Arici A. Basic aspects of implantation. Reprod Biomed Online. 2007;15(6):728–739.

    Article  CAS  PubMed  Google Scholar 

  2. Edwards RG. Human implantation: the last barrier in assisted reproduction technologies? Reprod Biomed Online. 2006;13(6): 887–904.

    Article  PubMed  Google Scholar 

  3. Aghajanova L, Altmae S, Bjuresten K, Hovatta O, Landgren BM, Stavreus-Evers A. Disturbances in the LIF pathway in the endometrium among women with unexplained infertility. Fertil Steril. 2009;91(6):2602–2610.

    Article  CAS  PubMed  Google Scholar 

  4. Aghajanova L, Bjuresten K, Altmae S, Landgren BM, Stavreus-Evers A. HB-EGF but not amphiregulin or their receptors HER1 and HER4 is altered in endometrium of women with unexplained infertility. Reprod Sci. 2008;15(5):484–492.

    Article  CAS  PubMed  Google Scholar 

  5. Wang JX, Davies M, Norman RJ. Body mass and probability of pregnancy during assisted reproduction treatment: retrospective study. BMJ. 2000;321(7272):1320–1321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bellver J, Rossal LP, Bosch E, et al. Obesity and the risk of spontaneous abortion after oocyte donation. Fertil Steril. 2003;79(5): 1136–1140.

    Article  PubMed  Google Scholar 

  7. Druckmann R, Rohr UD. IGF-1 in gynaecology and obstetrics: update 2002. Maturitas. 2002;41(suppl 1):S65–S83.

    Article  CAS  PubMed  Google Scholar 

  8. Pasquali R, Pelusi C, Genghini S, Cacciari M, Gambineri A. Obesity and reproductive disorders in women. Hum Reprod Update. 2003;9(4):359–372.

    Article  PubMed  Google Scholar 

  9. Cunningham MJ, Clifton DK, Steiner RA. Leptin’s actions on the reproductive axis: perspectives and mechanisms. Biol Reprod. 1999;60(2):216–222.

    Article  CAS  PubMed  Google Scholar 

  10. Budak E, Fernandez-Sanchez M, Bellver J, Cervero A, Simon C, Pellicer A. Interactions of the hormones leptin, ghrelin, adiponectin, resistin, and PYY3–36 with the reproductive system. Fertil Steril. 2006;85(6):1563–1581.

    Article  CAS  PubMed  Google Scholar 

  11. Mantzoros CS, Flier JS. Editorial: leptin as a therapeutic agent— trials and tribulations. J Clin Endocrinol Metab. 2000;85(11): 4000–4002.

    CAS  PubMed  Google Scholar 

  12. Moschos S, Chan JL, Mantzoros CS. Leptin and reproduction: a review. Fertil Steril. 2002;77(3):433–444.

    Article  PubMed  Google Scholar 

  13. Gonzalez RR, Rueda BR, Ramos MP, Littell RD, Glasser S, Leavis PC. Leptin-induced increase in leukemia inhibitory factor and its receptor by human endometrium is partially mediated by interleukin 1 receptor signaling. Endocrinology. 2004;145(8): 3850–3857.

    Article  CAS  PubMed  Google Scholar 

  14. Fernandez-Fernandez R, Navarro VM, Barreiro ML, et al. Effects of chronic hyperghrelinemia on puberty onset and pregnancy outcome in the rat. Endocrinology. 2005;146(7):3018–3025.

    Article  CAS  PubMed  Google Scholar 

  15. Gualillo O, Caminos J, Blanco M, et al. Ghrelin, a novel placental-derived hormone. Endocrinology. 2001;142(2):788–794.

    Article  CAS  PubMed  Google Scholar 

  16. Gaytan F, Morales C, Barreiro ML, et al. Expression of growth hormone secretagogue receptor type 1a, the functional ghrelin receptor, in human ovarian surface epithelium, mullerian duct derivatives, and ovarian tumors. J Clin Endocrinol Metab. 2005;90(3): 1798–1804.

    Article  CAS  PubMed  Google Scholar 

  17. Tawadros N, Salamonsen LA, Dimitriadis E, Chen C. Facilitation of decidualization by locally produced ghrelin in the human endometrium. Mol Hum Reprod. 2007;13(7):483–489.

    Article  CAS  PubMed  Google Scholar 

  18. Gaytan F, Barreiro ML, Chopin LK, et al. Immunolocalization of ghrelin and its functional receptor, the type 1a growth hormone secretagogue receptor, in the cyclic human ovary. J Clin Endocrinol Metab. 2003;88(2):879–887.

    Article  CAS  PubMed  Google Scholar 

  19. Li A, Cheng G, Zhu GH, Tarnawski AS. Ghrelin stimulates angiogenesis in human microvascular endothelial cells: Implications beyond GH release. Biochem Biophys Res Commun. 2007;353(2):238–243.

    Article  CAS  PubMed  Google Scholar 

  20. Conconi MT, Nico B, Guidolin D, et al. Ghrelin inhibits FGF-2-mediated angiogenesis in vitro and in vivo. Peptides. 2004;25(12):2179–2185.

    Article  CAS  PubMed  Google Scholar 

  21. Baiguera S, Conconi MT, Guidolin D, et al. Ghrelin inhibits in vitro angiogenic activity of rat brain microvascular endothelial cells. Int J Mol Med. 2004;14(5):849–854.

    CAS  PubMed  Google Scholar 

  22. Gambineri A, Pagotto U, Tschop M, et al. Anti-androgen treatment increases circulating ghrelin levels in obese women with polycystic ovary syndrome. J Endocrinol Invest. 2003;26(7):629–634.

    Article  CAS  PubMed  Google Scholar 

  23. Pagotto U, Gambineri A, Vicennati V, Heiman ML, Tschop M, Pasquali R. Plasma ghrelin, obesity, and the polycystic ovary syndrome: correlation with insulin resistance and androgen levels. J Clin Endocrinol Metab. 2002;87(12):5625–5629.

    Article  CAS  PubMed  Google Scholar 

  24. Tanaka K, Minoura H, Isobe T, et al. Ghrelin is involved in the decidualization of human endometrial stromal cells. J Clin Endocrinol Metab. 2003;88(5):2335–2340.

    Article  CAS  PubMed  Google Scholar 

  25. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptid from stomach. Nature. 1999;402(6762):656–660.

    Article  CAS  PubMed  Google Scholar 

  26. Petersenn S, Rasch AC, Penshorn M, Beil FU, Schulte HM. Genomic structure and transcriptional regulation of the human growth hormone secretagogue receptor. Endocrinology. 2001;142(6): 2649–2659.

    Article  CAS  PubMed  Google Scholar 

  27. Howard AD, Feighner SD, Cully DF, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996;273(5277):974–977.

    Article  CAS  PubMed  Google Scholar 

  28. Cruz CR, Smith RG. The growth hormone secretagogue receptor. Vitam Horm. 2008;77:47–88.

    Article  CAS  PubMed  Google Scholar 

  29. Muccioli G, Tschop M, Papotti M, Deghenghi R, Heiman M, Ghigo E. Neuroendocrine and peripheral activities of ghrelin: implications in metabolism and obesity. Eur J Pharmacol. 2002;440(2–3):235–254.

    Article  CAS  PubMed  Google Scholar 

  30. Kawamura K, Sato N, Fukuda J, et al. Ghrelin inhibits the development of mouse preimplantation embryos in vitro. Endocrinology. 2003;144(6):2623–2633.

    Article  CAS  PubMed  Google Scholar 

  31. Noyes RW, Hertig AT, Rock J. Dating the endometrial biopsy. Am J Obstet Gynecol. 1975;122(2):262–263.

    Article  CAS  PubMed  Google Scholar 

  32. Lalitkumar PG, Lalitkumar S, Meng CX, et al. Mifepristone, but not levonorgestrel, inhibits human blastocyst attachment to an in vitro endometrial three-dimensional cell culture model. Hum Reprod. 2007;22(11):3031–3037.

    Article  CAS  PubMed  Google Scholar 

  33. Wanggren K, Stavreus-Evers A, Olsson C, Andersson E, Gemzell-Danielsson K. Regulation of muscular contractions in the human Fallopian tube through prostaglandins and progestagens. Hum Reprod. 2008;23(10):2359–2368.

    Article  CAS  PubMed  Google Scholar 

  34. Tulac S, Overgaard MT, Hamilton AE, Jumbe NL, Suchanek E, Giudice LC. Dickkopf-1, an inhibitor of Wnt signaling, is regulated by progesterone in human endometrial stromal cells. J Clin Endocrinol Metab. 2006;91(4):1453–1461.

    Article  CAS  PubMed  Google Scholar 

  35. Aghajanova L, Hamilton A, Kwintkiewicz J, Vo KC, Giudice LC. Steroidogenic enzyme and key decidualization marker dysregulation in endometrial stromal cells from women with versus without endometriosis. Biol Reprod. 2009;80(1):105–114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Higuchi R, Fockler C, Dollinger G, Watson R. Kinetic PCR analysis: real-time monitoring of DNA amplification reactions. Biotechnology (N Y). 1993;11(9):1026–1030.

    CAS  Google Scholar 

  37. Altmae S, Martinez-Conejero JA, Salumets A, Simon C, Horcajadas JA, Stavreus-Evers A. Endometrial gene expression analysis at the time of embryo implantation in women with unexplained infertility. Mol Hum Reprod. 2010;16(3):178–187.

    Article  CAS  PubMed  Google Scholar 

  38. Tanaka T, Utsunomiya T, Bai T, Nakajima S, Umesaki N. Leptin inhibits decidualization and enhances cell viability of normal human endometrial stromal cells. Int J Mol Med. 2003;12(1): 95–98.

    CAS  PubMed  Google Scholar 

  39. Wanggren K, Lalitkumar PG, Hambiliki F, Stabi B, Gemzell-Danielsson K, Stavreus-Evers A. Leukaemia inhibitory factor receptor and gp130 in the human Fallopian tube and endometrium before and after mifepristone treatment and in the human preimplantation embryo. Mol Hum Reprod. 2007;13(6):391–397.

    Article  CAS  PubMed  Google Scholar 

  40. Aydin S, Guzel SP, Kumru S, et al. Serum leptin and ghrelin concentrations of maternal serum, arterial and venous cord blood in healthy and preeclamptic pregnant women. J Physiol Biochem. 2008;64(1):51–59.

    Article  CAS  PubMed  Google Scholar 

  41. Vidal C, Roa J, Pinilla L, Pellicer A, Tena-Sempere M. Maternal serum ghrelin levels in early IVF pregnancies: lack of prognostic value for viable pregnancy and altered post-prandial responses. Hum Reprod. 2008;23(4):958–963.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California San Francisco, San Francisco, CA, USA

    Lusine Aghajanova MD, PhD

  2. Department of Clinical Science, Intervention and Technology, Division of Obstetrics and Gynecology, Karolinska Institutet, Stockholm, Sweden

    Lusine Aghajanova MD, PhD & Signe Altmäe PhD

  3. Department of Women’s and Children’s Health, Uppsala University, SE-751 85, Uppsala, Sweden

    Amani Rumman BS, Kjell Wånggren MD, PhD & Anneli Stavreus-Evers PhD

Authors
  1. Lusine Aghajanova MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amani Rumman BS
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Signe Altmäe PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kjell Wånggren MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anneli Stavreus-Evers PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anneli Stavreus-Evers PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Aghajanova, L., Rumman, A., Altmäe, S. et al. Diminished Endometrial Expression of Ghrelin and Ghrelin Receptor Contributes to Infertility. Reprod. Sci. 17, 823–832 (2010). https://doi.org/10.1177/1933719110371683

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719110371683

Keywords

Search

Navigation