GnRH analogues may increase endometrial Hoxa10 promoter methylation and affect endometrial receptivity

Li,Fei; Zhang,Ming; Zhang,Yuanzhen; Liu,Teng; Qu,Xinlan

doi:10.3892/mmr.2014.2680

GnRH analogues may increase endometrial Hoxa10 promoter methylation and affect endometrial receptivity

Authors:
- Fei Li
- Ming Zhang
- Yuanzhen Zhang
- Teng Liu
- Xinlan Qu
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, Reproductive Medicine Center, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
Published online on: October 16, 2014 https://doi.org/10.3892/mmr.2014.2680
Pages: 509-514

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The present study aimed to investigate whether gonadotropin‑releasing hormone analogues (GnRH‑as), including GnRH agonists and antagonists, affect endometrial homeobox (Hox) a10 DNA methylation during the implantation window in mice. GnRH analogue mouse models were used and were treated with either human menopausal gonadotropin (HMG) and a GnRH agonist or HMG and a GnRH antagonist. Uterus samples were collected 48 h after GnRH analogue treatment or ovulation. Bisulfite sequencing polymerase chain reaction (PCR), quantitative-PCR and western blot analysis were performed to assess Hoxa10 and integrin β3 expression. Scanning electron microscope analyses were conducted to analyze pinopode development. Compared with the natural cycle control mice, mice in the GnRH analogue groups were found to exhibit increased levels of methylation at the Hoxa10 promoter, decreased Hoxa10 mRNA and protein expression and disrupted pinopode development. These findings suggest that GnRH‑as may be associated with altered Hoxa10 DNA methylation, thus GnRH‑as may affect uterine Hoxa10 expression and endometrial receptivity.

View Figures

View References

1	Rackow BW, Kliman HJ and Taylor HS: GnRH antagonists may affect endometrial receptivity. Fertil Steril. 89:1234–1239. 2008. View Article : Google Scholar : PubMed/NCBI
2	Al-Inany HG, Abou-Setta AM and Aboulghar M: Gonadotrophin-releasing hormone antagonists for assisted conception: a Cochrane review. Reprod Biomed Online. 14:640–649. 2007. View Article : Google Scholar : PubMed/NCBI
3	Bourgain C and Devroey P: The endometrium in stimulated cycles for IVF. Hum Reprod Update. 9:515–522. 2003. View Article : Google Scholar : PubMed/NCBI
4	Devroey P, Bourgain C, Macklon NS and Fauser BC: Reproductive biology and IVF: ovarian stimulation and endometrial receptivity. Trends Endocrinol Metab. 15:84–90. 2004. View Article : Google Scholar : PubMed/NCBI
5	Kolibianakis E, Bourgain C, Albano C, et al: Effect of ovarian stimulation with recombinant follicle-stimulating hormone, gonadotropin releasing hormone antagonists, and human chorionic gonadotropin on endometrial maturation on the day of oocyte pick-up. Fertil Steril. 78:1025–1029. 2002. View Article : Google Scholar
6	Taylor HS: The role of HOX genes in human implantation. Hum Reprod Update. 6:75–79. 2000. View Article : Google Scholar : PubMed/NCBI
7	Taylor HS, Vanden Heuvel GB and Igarashi P: A conserved HOX axis in the mouse and human female reproductive system: late establishment and persistent adult expression of the HOXA cluster genes. Biol Reprod. 57:1338–1345. 1997. View Article : Google Scholar : PubMed/NCBI
8	Satokata I, Benson G and Maas R: Sexually dimorphic sterility phenotypes in HOXA10-deficient mice. Nature. 374:460–463. 1995. View Article : Google Scholar : PubMed/NCBI
9	Wu Y, Halverson G, Basir Z, et al: Aberrant methylation at HOXA10 may be responsible for its aberrant expression in the endometrium of patients with endometriosis. Am J Obstet Gynecol. 193:371–380. 2005. View Article : Google Scholar : PubMed/NCBI
10	Daftary GS, Troy PJ, Bagot CN, et al: Direct regulation of beta3-integrin subunit gene expression by HOXA10 in endometrial cells. Mol Endocrinol. 16:571–579. 2002.PubMed/NCBI
11	Taylor HS, Daftary GS and Selam B: Endometrial HOXA10 expression after controlled ovarian hyperstimulation with recombinant follicle-stimulating hormone. Fertil Steril. 80(Suppl 2): 839–843. 2003. View Article : Google Scholar : PubMed/NCBI
12	Kim JJ, Taylor HS, Lu Z, et al: Altered expression of HOXA10 in endometriosis: potential role in decidualization. Mol Hum Reprod. 13:323–332. 2007. View Article : Google Scholar : PubMed/NCBI
13	Nasu K, Kawano Y, Tsukamoto Y, et al: Aberrant DNA methylation status of endometriosis: epigenetics as the pathogenesis, biomarker and therapeutic target. J Obstet Gynaecol Res. 37:683–695. 2011. View Article : Google Scholar : PubMed/NCBI
14	Rackow BW, Jorgensen E and Taylor HS: Endometrial polyps affect uterine receptivity. Fertil Steril. 95:2690–2692. 2011. View Article : Google Scholar : PubMed/NCBI
15	Widschwendter M, Apostolidou S, Jones AA, et al: HOXA methylation in normal endometrium from premenopausal women is associated with the presence of ovarian cancer: a proof of principle study. Int J Cancer. 125:2214–2218. 2009. View Article : Google Scholar : PubMed/NCBI
16	Bromer JG, Wu J, Zhou Y and Taylor HS: Hypermethylation of homeobox A10 by in utero diethylstilbestrol exposure: an epigenetic mechanism for altered developmental programming. Endocrinology. 150:3376–3382. 2009. View Article : Google Scholar : PubMed/NCBI
17	Varayoud J, Ramos JG, Bosquiazzo VL, Muñoz-de-Toro M and Luque EH: Developmental exposure to Bisphenol a impairs the uterine response to ovarian steroids in the adult. Endocrinology. 149:5848–5860. 2008. View Article : Google Scholar : PubMed/NCBI
18	Hiyama M, Choi EK, Wakitani S, et al: Bisphenol-A (BPA) affects reproductive formation across generations in mice. J Vet Med Sci. 73:1211–1215. 2011. View Article : Google Scholar : PubMed/NCBI
19	Ruan HC, Zhu XM, Luo Q, et al: Ovarian stimulation with GnRH agonist, but not GnRH antagonist, partially restores the expression of endometrial integrin beta3 and leukaemia-inhibitory factor and improves uterine receptivity in mice. Hum Reprod. 21:2521–2529. 2006. View Article : Google Scholar
20	Shapiro BS, Daneshmand ST, Garner FC, et al: Evidence of impaired endometrial receptivity after ovarian stimulation for in vitro fertilization: a prospective randomized trial comparing fresh and frozen-thawed embryo transfer. Fertil Steril. 96:344–348. 2011. View Article : Google Scholar
21	Yamagata Y, Asada H, Tamura I, et al: DNA methyltransferase expression in the human endometrium: down-regulation by progesterone and estrogen. Hum Reprod. 24:1126–1132. 2009. View Article : Google Scholar : PubMed/NCBI
22	Munro SK, Farquhar CM, Mitchell MD and Ponnampalam AP: Epigenetic regulation of endometrium during the menstrual cycle. Mol Hum Reprod. 16:297–310. 2010. View Article : Google Scholar : PubMed/NCBI
23	Vincent ZL, Farquhar CM, Mitchell MD and Ponnampalam AP: Expression and regulation of DNA methyltransferases in human endometrium. Fertil Steril. 95:1522–1525. 2011. View Article : Google Scholar : PubMed/NCBI
24	Logan PC, Ponnampalam AP, Rahnama F, et al: The effect of DNA methylation inhibitor 5-Aza-2′-deoxycytidine on human endometrial stromal cells. Hum Reprod. 25:2859–2869. 2010.
25	van Montfoort AP, Hanssen LL, de Sutter P, et al: Assisted reproduction treatment and epigenetic inheritance. Hum Reprod Update. 18:171–197. 2012.
26	Horsthemke B and Ludwig M: Assisted reproduction: the epigenetic perspective. Hum Reprod Update. 11:473–482. 2005. View Article : Google Scholar : PubMed/NCBI
27	Tarlatzis BC and Bili HN: Gonadotropin-releasing hormone antagonists: im-pact of IVF practice and potential nonassisted reproductive technologyapplications. Curr Opin Obstet Gynecol. 15:259–264. 2003. View Article : Google Scholar : PubMed/NCBI
28	Ludwig M, Katalinic A and Diedrich K: Use of GnRH antagonists in ovarian stimulation for assisted reproductive technologies compared to the long protocol. Meta-analysis. Arch Gynecol Obstet. 265:175–182. 2001. View Article : Google Scholar : PubMed/NCBI
29	Olivennes F, Cunha-Filho JS, Fanchin R, et al: The use of GnRH antagonists in ovarian stimulation. Hum Reprod Update. 8:279–290. 2002. View Article : Google Scholar : PubMed/NCBI
30	Grimaldi G, Christian M, Quenby S and Brosens JJ: Expression of epigenetic effectors in decidualizing human endometrial stromal cells. Mol Hum Reprod. 18:451–458. 2012. View Article : Google Scholar : PubMed/NCBI
31	Quinn CE and Casper RF: Pinopodes: a questionable role in endometrial receptivity. Hum Reprod Update. 15:229–236. 2009. View Article : Google Scholar : PubMed/NCBI
32	Creus M, Ordi J, Fábregues F, et al: αvβ3 integrin expression and pinopod formation in normal and out-of-phase endometria of fertile and infertile women. Hum Reprod. 17:2279–2286. 2002.
33	Creus M, Ordi J, Fábregues F, et al: The effect of different hormone therapies on integrin expression and pinopode formation in the human endometrium: a controlled study. Hum Reprod. 18:683–693. 2003. View Article : Google Scholar : PubMed/NCBI