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.
Guzeloglu-Kayisli O., Basar M., Arici A.Basic aspects of implantation . Reprod Biomed Online. 2007;15(6):728-739.
2.
Edwards RGHuman implantation: the last barrier in assisted reproduction technologies ? Reprod Biomed Online. 2006;13(6): 887-904.
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.
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.
5.
Wang JX, Davies M., Norman RJBody mass and probability of pregnancy during assisted reproduction treatment: retrospective study. BMJ. 2000;321(7272):1320-1321.
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.
7.
Druckmann R. , Rohr UDIGF-1 in gynaecology and obstetrics: update 2002. Maturitas. 2002;41(suppl 1):S65-S83.
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.
9.
Cunningham MJ , Clifton DK, Steiner RALeptin’s actions on the reproductive axis: perspectives and mechanisms. Biol Reprod. 1999;60(2):216-222.
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.
11.
Mantzoros CS , Flier JSEditorial: leptin as a therapeutic agent- trials and tribulations. J Clin Endocrinol Metab. 2000;85(11): 4000-4002.
12.
Moschos S., Chan JL, Mantzoros CSLeptin and reproduction: a review. Fertil Steril. 2002;77(3):433-444.
13.
Gonzalez RR , Rueda BR, Ramos MP, Littell RD, Glasser S., Leavis PCLeptin-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.
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.
15.
Gualillo O. , Caminos J., Blanco M., et al. Ghrelin, a novel placental-derived hormone. Endocrinology. 2001;142(2):788-794.
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.
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.
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.
19.
Li A., Cheng G., Zhu GH, Tarnawski ASGhrelin stimulates angiogenesis in human microvascular endothelial cells: Implications beyond GH release. Biochem Biophys Res Commun . 2007;353(2):238-243.
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.
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.
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.
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.
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.
25.
Kojima M., Hosoda H., Date Y., Nakazato M., Matsuo H., Kangawa K.Ghrelin is a growth-hormone-releasing acylated peptide from stomach . Nature. 1999;402(6762):656-660.
26.
Petersenn S. , Rasch AC, Penshorn M., Beil FU, Schulte HMGenomic structure and transcriptional regulation of the human growth hormone secretagogue receptor . Endocrinology . 2001;142(6): 2649-2659.
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.
28.
Cruz CR, Smith RGThe growth hormone secretagogue receptor. Vitam Horm . 2008;77:47-88.
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.
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.
31.
Noyes RW, Hertig AT, Rock J.Dating the endometrial biopsy. Am J Obstet Gynecol . 1975;122(2):262-263.
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.
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.
34.
Tulac S., Overgaard MT, Hamilton AE, Jumbe NL, Suchanek E., Giudice LCDickkopf-1, an inhibitor of Wnt signaling, is regulated by progesterone in human endometrial stromal cells. J Clin Endocrinol Metab . 2006;91(4):1453-1461.
35.
Aghajanova L., Hamilton A., Kwintkiewicz J., Vo KC, Giudice LCSteroidogenic enzyme and key decidualization marker dysregulation in endometrial stromal cells from women with versus without endometriosis. Biol Reprod.2009;80(1):105-114.
36.
Higuchi R., Fockler C., Dollinger G., Watson R.Kinetic PCRanalysis: real-time monitoring of DNA amplification reactions. Biotechnology (N Y). 1993 ;11(9):1026-1030.
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.
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.
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.
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.
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.
