Top

Journal of Assisted Reproduction and Genetics

Published in:

01-01-2020 | Polymerase Chain Reaction | Reproductive Physiology and Disease

Effects of high progesterone in in-vitro fertilization cycle on DNA methylation and gene expression of adhesion molecules on endometrium during implantation window

Authors: Yujing Xiong, Linli Hu, Tao Zhang, Mengying Wang, Hui Xu, Tin Chiu Li, Yingpu Sun, Chi Chiu Wang

Published in: Journal of Assisted Reproduction and Genetics | Issue 1/2020

Abstract

Purpose

High progesterone is associated with low implantation rate. Our previous study demonstrated that DNA methylation in endometrium was increased in women with high progesterone in IVF cycles. However, the DNA methylation status is still not yet confirmed, and how it affects endometrial receptivity in high progesterone is still unknown. Current study investigated the effects of high progesterone on DNA methylation and gene expression of adhesion molecules on endometrium during implantation window.

Methods

A cohort study included 20 women with high progesterone (HP) and 20 with normal progesterone (NP) on the day of human chorionic gonadotropin (hCG) administration after controlled ovarian hyperstimulation in IVF cycle. Endometrial tissues were collected on the 7th day after hCG administration. Immunohistochemical staining of DNA methyltransferases (DNMT1 and DNMT3B) and adhesion molecules (MUC1, CDH1 and CTNNB1) were performed. Methylation of MUC1, CDH1, and CTNNB1 promoter regions was detected by Sequenom MassARRAY or bisulfite sequencing PCR. RT-qPCR was used to quantify mRNA expression levels, and correlation of methylation and gene expression level of the adhesion molecules were determined.

Results

DNMT3B, but not DNMT1, in nucleus of luminal and glandular epithelial cells in HP group was significantly higher than that in NP group. Promoter regions of CDH1 and CTNNB1, but not MUC1, in endometrium of HP group were hypermethylated. Protein and mRNA expression of MUC1, CDH1, and CTNNB1 in endometrium of HP group was significantly lower than that in NP group. Level of DNA methylation was negatively correlated with the gene expression of CDH1 and CTNNB1, but not MUC1.

Conclusions

DNA hypermethylation and low expression of adhesion molecules on endometrium were associated with high progesterone during implantation window, which may contribute to the underlying epigenetic mechanism in the failure of IVF treatment.

Available only for authorised users

Schoolcraft W, Sinton E, Schlenker T, Huynh D, Hamilton F, Meldrum DR. Lower pregnancy rate with premature luteinization during pituitary suppression with leuprolide acetate. Fertil Steril. 1991;55(3):563–6.CrossRef

Venetis CA, Kolibianakis EM, Papanikolaou E, Bontis J, Devroey P, Tarlatzis BC. Is progesterone elevation on the day of human chorionic gonadotropin administration associated with the probability of pregnancy in in vitro fertilization? A systematic review and meta-analysis. Hum Reprod Update. 2007;13(4):343–55. https://doi.org/10.1093/humupd/dmm007.CrossRefPubMed

Bosch E, Labarta E, Crespo J, Simon C, Remohi J, Jenkins J, et al. Circulating progesterone levels and ongoing pregnancy rates in controlled ovarian stimulation cycles for in vitro fertilization: analysis of over 4000 cycles. Hum Reprod. 2010;25(8):2092–100. https://doi.org/10.1093/humrep/deq125.CrossRefPubMed

Venetis CA, Kolibianakis EM, Bosdou JK, Tarlatzis BC. Progesterone elevation and probability of pregnancy after IVF: a systematic review and meta-analysis of over 60 000 cycles. Hum Reprod Update. 2013;19(5):433–57. https://doi.org/10.1093/humupd/dmt014.CrossRefPubMed

Kolibianakis EM, Venetis CA, Bontis J, Tarlatzis BC. Significantly lower pregnancy rates in the presence of progesterone elevation in patients treated with GnRH antagonists and gonadotropins: a systematic review and meta-analysis. Curr Pharm Biotechnol. 2012;13(3):464–70.CrossRef

Huang CC, Lien YR, Chen HF, Chen MJ, Shieh CJ, Yao YL, et al. The duration of pre-ovulatory serum progesterone elevation before hCG administration affects the outcome of IVF/ICSI cycles. Hum Reprod. 2012;27(7):2036–45. https://doi.org/10.1093/humrep/des141.CrossRefPubMed

Kilicdag EB, Haydardedeoglu B, Cok T, Hacivelioglu SO, Bagis T. Premature progesterone elevation impairs implantation and live birth rates in GnRH-agonist IVF/ICSI cycles. Arch Gynecol Obstet. 2010;281(4):747–52. https://doi.org/10.1007/s00404-009-1248-0.CrossRefPubMed

Legro RS, Ary BA, Paulson RJ, Stanczyk FZ, Sauer MV. Premature luteinization as detected by elevated serum progesterone is associated with a higher pregnancy rate in donor oocyte in-vitro fertilization. Hum Reprod. 1993;8(9):1506–11.CrossRef

Labarta E, Martinez-Conejero JA, Alama P, Horcajadas JA, Pellicer A, Simon C, et al. Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011;26(7):1813–25. https://doi.org/10.1093/humrep/der126.CrossRefPubMed

10.

Van Vaerenbergh I, Fatemi HM, Blockeel C, Van Lommel L, In't Veld P, Schuit F, et al. Progesterone rise on HCG day in GnRH antagonist/rFSH stimulated cycles affects endometrial gene expression. Reprod BioMed Online. 2011;22(3):263–71. https://doi.org/10.1016/j.rbmo.2010.11.002.CrossRefPubMed

11.

Haouzi D, Bissonnette L, Gala A, Assou S, Entezami F, Perrochia H, et al. Endometrial receptivity profile in patients with premature progesterone elevation on the day of HCG administration. Biomed Res Int. 2014;2014:951937. https://doi.org/10.1155/2014/951937.CrossRefPubMedPubMedCentral

12.

Li R, Qiao J, Wang L, Li L, Zhen X, Liu P, et al. MicroRNA array and microarray evaluation of endometrial receptivity in patients with high serum progesterone levels on the day of hCG administration. Reprod Biol Endocrinol. 2011;9:29. https://doi.org/10.1186/1477-7827-9-29.CrossRefPubMedPubMedCentral

13.

Seppala M, Taylor RN, Koistinen H, Koistinen R, Milgrom E. Glycodelin: a major lipocalin protein of the reproductive axis with diverse actions in cell recognition and differentiation. Endocr Rev. 2002;23(4):401–30. https://doi.org/10.1210/er.2001-0026.CrossRefPubMed

14.

Lessey BA. Assessment of endometrial receptivity. Fertil Steril. 2011;96(3):522–9. https://doi.org/10.1016/j.fertnstert.2011.07.1095.CrossRefPubMed

15.

Brayman M, Thathiah A, Carson DD. MUC1: a multifunctional cell surface component of reproductive tissue epithelia. Reprod Biol Endocrinol. 2004;2:4. https://doi.org/10.1186/1477-7827-2-4.CrossRefPubMedPubMedCentral

16.

Achache H, Revel A. Endometrial receptivity markers, the journey to successful embryo implantation. Hum Reprod Update. 2006;12(6):731–46. https://doi.org/10.1093/humupd/dml004.CrossRefPubMed

17.

Xiong Y, Wang J, Liu L, Chen X, Xu H, Li TC, et al. Effects of high progesterone level on the day of human chorionic gonadotropin administration in in vitro fertilization cycles on epigenetic modification of endometrium in the peri-implantation period. Fertil Steril. 2017;108(2):269–76.e1. https://doi.org/10.1016/j.fertnstert.2017.06.004.CrossRefPubMed

18.

Ziller MJ, Muller F, Liao J, Zhang Y, Gu H, Bock C, et al. Genomic distribution and inter-sample variation of non-CpG methylation across human cell types. PLoS Genet. 2011;7(12):e1002389. https://doi.org/10.1371/journal.pgen.1002389.CrossRefPubMedPubMedCentral

19.

Smith ZD, Meissner A. DNA methylation: roles in mammalian development. Nat Rev Genet. 2013;14(3):204–20. https://doi.org/10.1038/nrg3354.CrossRefPubMed

20.

Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999;99(3):247–57.CrossRef

21.

Li E, Bestor TH, Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell. 1992;69(6):915–26.CrossRef

22.

Liu L, Zhao L, Li TC, Zhu H, Lin X, Jin X, et al. Comparison of progesterone measurement on day of, and day after, HCG administration in IVF-embryo transfer cycles. Reprod BioMed Online. 2015;30(2):157–65. https://doi.org/10.1016/j.rbmo.2014.10.017.CrossRefPubMed

23.

Feng S, Jacobsen SE, Reik W. Epigenetic reprogramming in plant and animal development. Science. 2010;330(6004):622–7. https://doi.org/10.1126/science.1190614.CrossRefPubMedPubMedCentral

24.

Jeltsch A, Jurkowska RZ. New concepts in DNA methylation. Trends Biochem Sci. 2014;39(7):310–8. https://doi.org/10.1016/j.tibs.2014.05.002.CrossRefPubMed

25.

Grady WM, Willis J, Guilford PJ, Dunbier AK, Toro TT, Lynch H, et al. Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer. Nat Genet. 2000;26(1):16–7. https://doi.org/10.1038/79120.CrossRefPubMed

26.

Li Y, Ran R, Guan Y, Zhu X, Kang S. Aberrant methylation of the E-cadherin gene promoter region in the endometrium of women with uterine fibroids. Reprod Sci. 2016;23(8):1096–102. https://doi.org/10.1177/1933719116630415.CrossRefPubMed

27.

Yamada N, Nishida Y, Tsutsumida H, Hamada T, Goto M, Higashi M, et al. MUC1 expression is regulated by DNA methylation and histone H3 lysine 9 modification in cancer cells. Cancer Res. 2008;68(8):2708–16. https://doi.org/10.1158/0008-5472.can-07-6844.CrossRefPubMed

28.

Hey NA, Graham RA, Seif MW, Aplin JD. The polymorphic epithelial mucin MUC1 in human endometrium is regulated with maximal expression in the implantation phase. J Clin Endocrinol Metab. 1994;78(2):337–42. https://doi.org/10.1210/jcem.78.2.8106621.CrossRefPubMed

29.

Thathiah A, Carson DD. MT1-MMP mediates MUC1 shedding independent of TACE/ADAM17. Biochem J. 2004;382(Pt 1):363–73. https://doi.org/10.1042/bj20040513.CrossRefPubMedPubMedCentral

30.

Meseguer M, Aplin JD, Caballero-Campo P, O'Connor JE, Martin JC, Remohi J, et al. Human endometrial mucin MUC1 is up-regulated by progesterone and down-regulated in vitro by the human blastocyst. Biol Reprod. 2001;64(2):590–601. https://doi.org/10.1095/biolreprod64.2.590.CrossRefPubMed

31.

Hoffman LH, Olson GE, Carson DD, Chilton BS. Progesterone and implanting blastocysts regulate Muc1 expression in rabbit uterine epithelium. Endocrinology. 1998;139(1):266–71. https://doi.org/10.1210/endo.139.1.5750.CrossRefPubMed

32.

Simon C, Martin JC, Pellicer A. Paracrine regulators of implantation. Baillieres Best Pract Res Clin Obstet Gynaecol. 2000;14(5):815–26. https://doi.org/10.1053/beog.2000.0121.CrossRefPubMed

Title: Effects of high progesterone in in-vitro fertilization cycle on DNA methylation and gene expression of adhesion molecules on endometrium during implantation window
Authors: Yujing Xiong
Linli Hu
Tao Zhang
Mengying Wang
Hui Xu
Tin Chiu Li
Yingpu Sun
Chi Chiu Wang
Publication date: 01-01-2020
Publisher: Springer US
Keywords: Polymerase Chain Reaction
Progesterone
Published in: Journal of Assisted Reproduction and Genetics / Issue 1/2020
Print ISSN: 1058-0468
Electronic ISSN: 1573-7330
DOI: https://doi.org/10.1007/s10815-019-01623-6

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Effects of high progesterone in in-vitro fertilization cycle on DNA methylation and gene expression of adhesion molecules on endometrium during implantation window

Abstract

Purpose

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2020

Sperm DNA fragmentation on the day of fertilization is not associated with embryologic or clinical outcomes after IVF/ICSI

Pregnancy loss: more a matter of chromosomes or maternal discretion?

Universal strategy for preimplantation genetic testing for cystic fibrosis based on next generation sequencing

The impact of culture conditions on blastocyst formation and aneuploidy rates: a comparison between single-step and sequential media in a large academic practice

What is the true place of a double stimulation and double oocyte retrieval in the same cycle for patients diagnosed with poor ovarian reserve? A systematic review including a meta-analytical approach

A novel “embryo-endometrial” adhesion model can potentially predict “receptive” or “non-receptive” endometrium