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Reproductive Biology and Endocrinology
Published in: Reproductive Biology and Endocrinology 1/2014

Open Access 01-12-2014 | Research

Endometrial gene expression reveals compromised progesterone signaling in women refractory to embryo implantation

Authors: Alejandro Tapia-Pizarro, Paula Figueroa, Julio Brito, Juan Carlos Marín, David J Munroe, Horacio B Croxatto

Published in: Reproductive Biology and Endocrinology | Issue 1/2014

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Abstract

Background

Endometrial function is essential for embryo implantation. The aim of this study was to analyze gene expression profiles from individual endometrial samples obtained from women with repeated implantation failure after IVF in oocyte donation programs.

Methods

Seventeen volunteers were recruited: women who had previously participated as recipients in oocyte donation cycles and repeatedly exhibited implantation failure (Group A, study group, n = 5) or had at least one successful cycle (Group B, control group, n = 6) and spontaneously fertile women (Group C, normal fertility group, n = 6). An endometrial cycle was induced with exogenous estradiol (E2) and progesterone (P) and an endometrial sample was collected on the seventh day of P treatment.

Results

Transcriptome analysis showed 82 genes with consistent differential gene expression when comparing A vs. B and A vs. C. One hundred transcripts differentially expressed in group A vs. B have been shown to be regulated by P, suggesting compromised P signaling in the endometrium. The P receptor (PR) mutation PROGINS was not detected in women from group A. Semi-quantitation of immunoreactive PRA/B, PRB and Sp1 (a transcription factor related to P signaling) in paraffin-embedded endometrial sections, did not show statistically significant differences amongst groups. However immunostaining glycodelin was significantly decreased in endometrial samples from group A

Conclusions

We conclude that some cases of repeated implantation failure could be associated with an aberrant gene expression profile. Compromised P signaling might be the underlying mechanism for such endometrial gene expression deregulation in women with repeated implantation failure.
Appendix
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Literature
1.
O’Malley BW, Tsai MJ: Molecular pathways of steroid receptor action. Biol Reprod. 1992, 46: 163-167. 10.1095/biolreprod46.2.163.CrossRefPubMed
2.
Gellersen B, Brosens IA, Brosens JJ: Decidualization of the human endometrium: mechanisms, functions, and clinical perspectives. Semin Reprod Med. 2007, 25: 445-453. 10.1055/s-2007-991042.CrossRefPubMed
3.
Beato M: Gene regulation by steroid hormones. Cell. 1989, 56: 335-344. 10.1016/0092-8674(89)90237-7.CrossRefPubMed
4.
Burney RO, Talbi S, Hamilton AE, Vo KC, Nyegaard M, Nezhat CR, Lessey BA, Giudice LC: Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology. 2007, 148: 3814-3826. 10.1210/en.2006-1692.CrossRefPubMed
5.
Hapangama DK, Critchley HO, Henderson TA, Baird DT: Mifepristone-induced vaginal bleeding is associated with increased immunostaining for cyclooxygenase-2 and decrease in prostaglandin dehydrogenase in luteal phase endometrium. J Clin Endocrinol Metab. 2002, 87: 5229-5234. 10.1210/jc.2002-020429.CrossRefPubMed
6.
Danielsson KG, Marions L, Bygdeman M: Effects of mifepristone on endometrial receptivity. Steroids. 2003, 68: 1069-1075. 10.1016/S0039-128X(03)00131-4.CrossRefPubMed
7.
Catalano RD, Critchley HO, Heikinheimo O, Baird DT, Hapangama D, Sherwin JR, Charnock-Jones DS, Smith SK, Sharkey AM: Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007, 13: 641-654. 10.1093/molehr/gam021.CrossRefPubMed
8.
Horcajadas JA, Pellicer A, Simon C: Wide genomic analysis of human endometrial receptivity: new times, new opportunities. Hum Reprod Update. 2007, 13: 77-86.CrossRefPubMed
9.
Ruiz-Alonso M, Blesa D, Simon C: The genomics of the human endometrium. Biochim Biophys Acta. 1822, 2012: 1931-1942.
10.
Haouzi D, Dechaud H, Assou S, De Vos J, Hamamah S: Insights into human endometrial receptivity from transcriptomic and proteomic data. Reprod Biomed Online. 2012, 24: 23-34. 10.1016/j.rbmo.2011.09.009.CrossRefPubMed
11.
Tapia A, Vilos C, Marin JC, Croxatto HB, Devoto L: Bioinformatic detection of E47, E2F1 and SREBP1 transcription factors as potential regulators of genes associated to acquisition of endometrial receptivity. Reprod Biol Endocrinol. 2011, 9: 14-10.1186/1477-7827-9-14.PubMedCentralCrossRefPubMed
12.
Tapia A, Gangi LM, Zegers-Hochschild F, Balmaceda J, Pommer R, Trejo L, Pacheco IM, Salvatierra AM, Henriquez S, Quezada M, Vargas M, Ríos M, Munroe DJ, Croxatto HB, Velasquez L: Differences in the endometrial transcript profile during the receptive period between women who were refractory to implantation and those who achieved pregnancy. Hum Reprod. 2008, 23: 340-351.CrossRefPubMed
13.
Damario MA, Lesnick TG, Lessey BA, Kowalik A, Mandelin E, Seppala M, Rosenwaks Z: Endometrial markers of uterine receptivity utilizing the donor oocyte model. Hum Reprod. 2001, 16: 1893-1899. 10.1093/humrep/16.9.1893.CrossRefPubMed
14.
Noyes RW, Hertig AT, Rock J: Dating the endometrial biopsy. Am J Obstet Gynecol. 1975, 122: 262-263.PubMed
15.
Benjamini Y, Hochberg Y: Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. J Roy Statist Soc Ser B (Method). 1995, 57: 289-300.
16.
Joliffe IT, Morgan BJ: Principal component analysis and exploratory factor analysis. Stat Methods Med Res. 1992, 1: 69-95. 10.1177/096228029200100105.CrossRefPubMed
17.
Dennis G, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC, Lempicki RA: DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol. 2003, 4: P3-10.1186/gb-2003-4-5-p3.CrossRefPubMed
18.
Chang JT, Nevins JR: GATHER: a systems approach to interpreting genomic signatures. Bioinformatics. 2006, 22: 2926-2933. 10.1093/bioinformatics/btl483.CrossRefPubMed
19.
Kanehisa M, Goto S, Hattori M, Aoki-Kinoshita KF, Itoh M, Kawashima S, Katayama T, Araki M, Hirakawa M: From genomics to chemical genomics: new developments in KEGG. Nucleic Acids Res. 2006, 34: D354-357. 10.1093/nar/gkj102.PubMedCentralCrossRefPubMed
20.
Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G: Gene ontology: tool for the unification of biology. Gene Ontology Consortium Nat Genet. 2000, 25: 25-29.PubMed
21.
Gonzalez-Ramos R, Rocco J, Rojas C, Sovino H, Poch A, Kohen P, Alvarado-Diaz C, Devoto L: Physiologic activation of nuclear factor kappa-B in the endometrium during the menstrual cycle is altered in endometriosis patients. Fertil Steril. 2012, 97: 645-651. 10.1016/j.fertnstert.2011.12.006.CrossRefPubMed
22.
Koistinen H, Koistinen R, Dell A, Morris HR, Easton RL, Patankar MS, Oehninger S, Clark GF, Seppala M: Glycodelin from seminal plasma is a differentially glycosylated form of contraceptive glycodelin-A. Mol Hum Reprod. 1996, 2: 759-765. 10.1093/molehr/2.10.759.CrossRefPubMed
23.
Pisarska MD, Carson SA, Casson PR, Tong X, Buster JE, Kieback DG: A mutated progesterone receptor allele is more prevalent in unexplained infertility. Fertil Steril. 2003, 80: 651-653. 10.1016/S0015-0282(03)00755-6.CrossRefPubMed
24.
Kao LC, Tulac S, Lobo S, Imani B, Yang JP, Germeyer A, Osteen K, Taylor RN, Lessey BA, Giudice LC: Global gene profiling in human endometrium during the window of implantation. Endocrinology. 2002, 143: 2119-2138. 10.1210/endo.143.6.8885.CrossRefPubMed
25.
Borthwick JM, Charnock-Jones DS, Tom BD, Hull ML, Teirney R, Phillips SC, Smith SK: Determination of the transcript profile of human endometrium. Mol Hum Reprod. 2003, 9: 19-33. 10.1093/molehr/gag004.CrossRefPubMed
26.
Carson DD, Lagow E, Thathiah A, Al-Shami R, Farach-Carson MC, Vernon M, Yuan L, Fritz MA, Lessey B: Changes in gene expression during the early to mid-luteal (receptive phase) transition in human endometrium detected by high-density microarray screening. Mol Hum Reprod. 2002, 8: 871-879. 10.1093/molehr/8.9.871.CrossRefPubMed
27.
Riesewijk A, Martin J, van Os R, Horcajadas JA, Polman J, Pellicer A, Mosselman S, Simon C: Gene expression profiling of human endometrial receptivity on days LH + 2 versus LH + 7 by microarray technology. Mol Hum Reprod. 2003, 9: 253-264. 10.1093/molehr/gag037.CrossRefPubMed
28.
Mirkin S, Arslan M, Churikov D, Corica A, Diaz JI, Williams S, Bocca S, Oehninger S: In search of candidate genes critically expressed in the human endometrium during the window of implantation. Hum Reprod. 2005, 20: 2104-2117. 10.1093/humrep/dei051.CrossRefPubMed
29.
Talbi S, Hamilton AE, Vo KC, Tulac S, Overgaard MT, Dosiou C, Le Shay N, Nezhat CN, Kempson R, Lessey BA, Nayak NR, Giudice LC: Molecular phenotyping of human endometrium distinguishes menstrual cycle phases and underlying biological processes in normo-ovulatory women. Endocrinology. 2006, 147: 1097-1121. 10.1210/en.2005-1076.CrossRefPubMed
30.
Ace CI, Okulicz WC: Microarray profiling of progesterone-regulated endometrial genes during the rhesus monkey secretory phase. Reprod Biol Endocrinol. 2004, 2: 54-10.1186/1477-7827-2-54.PubMedCentralCrossRefPubMed
31.
Haouzi D, Mahmoud K, Fourar M, Bendhaou K, Dechaud H, De Vos J, Reme T, Dewailly D, Hamamah S: Identification of new biomarkers of human endometrial receptivity in the natural cycle. Hum Reprod. 2009, 24: 198-205.CrossRefPubMed
32.
Diaz-Gimeno P, Horcajadas JA, Martinez-Conejero JA, Esteban FJ, Alama P, Pellicer A, Simon C: A genomic diagnostic tool for human endometrial receptivity based on the transcriptomic signature. Fertil Steril. 2011, 95: 50-60. 10.1016/j.fertnstert.2010.04.063. 60 e51-15CrossRefPubMed
33.
Bulun SE, Cheng YH, Yin P, Imir G, Utsunomiya H, Attar E, Innes J, Julie Kim J: Progesterone resistance in endometriosis: link to failure to metabolize estradiol. Mol Cell Endocrinol. 2006, 248: 94-103. 10.1016/j.mce.2005.11.041.CrossRefPubMed
34.
Attia GR, Zeitoun K, Edwards D, Johns A, Carr BR, Bulun SE: Progesterone receptor isoform A but not B is expressed in endometriosis. J Clin Endocrinol Metab. 2000, 85: 2897-2902.PubMed
35.
Coulam CB, Jeyendran RS, Roussev R: Association of progesterone receptor polymorphisms with recurrent implantation failure after in vitro fertilization and embryo transfer. J Assist Reprod Genet. 2008, 25: 119-122. 10.1007/s10815-008-9210-9.PubMedCentralCrossRefPubMed
36.
37.
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: 401-430. 10.1210/er.2001-0026.CrossRefPubMed
38.
Bell SC, Hales MW, Patel S, Kirwan PH, Drife JO: Protein synthesis and secretion by the human endometrium and decidua during early pregnancy. Br J Obstet Gynaecol. 1985, 92: 793-803. 10.1111/j.1471-0528.1985.tb03048.x.CrossRefPubMed
39.
Kao LC, Germeyer A, Tulac S, Lobo S, Yang JP, Taylor RN, Osteen K, Lessey BA, Giudice LC: Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility. Endocrinology. 2003, 144: 2870-2881. 10.1210/en.2003-0043.CrossRefPubMed
40.
Mackenna A, Li TC, Dalton C, Bolton A, Cooke I: Placental protein 14 levels in uterine flushing and plasma of women with unexplained infertility. Fertil Steril. 1993, 59: 577-582.PubMed
41.
Seppala M, Koistinen H, Koistinen R, Chiu PC, Yeung WS: Glycosylation related actions of glycodelin: gamete, cumulus cell, immune cell and clinical associations. Hum Reprod Update. 2007, 13: 275-287. 10.1093/humupd/dmm004.CrossRefPubMed
42.
Taylor RN, Vigne JL, Zhang P, Hoang P, Lebovic DI, Mueller MD: Effects of progestins and relaxin on glycodelin gene expression in human endometrial cells. Am J Obstet Gynecol. 2000, 182: 841-847. 10.1016/S0002-9378(00)70333-4. discussion 847–849CrossRefPubMed
43.
Taylor RN, Savouret JF, Vaisse C, Vigne JL, Ryan I, Hornung D, Seppala M, Milgrom E: Promegestone (R5020) and mifepristone (RU486) both function as progestational agonists of human glycodelin gene expression in isolated human epithelial cells. J Clin Endocrinol Metab. 1998, 83: 4006-4012.PubMed
44.
Vaisse C, Atger M, Potier B, Milgrom E: Human placental protein 14 gene: sequence and characterization of a short duplication. DNA Cell Biol. 1990, 9: 401-413. 10.1089/dna.1990.9.401.CrossRefPubMed
45.
Gao J, Mazella J, Seppala M, Tseng L: Ligand activated hPR modulates the glycodelin promoter activity through the Sp1 sites in human endometrial adenocarcinoma cells. Mol Cell Endocrinol. 2001, 176: 97-102. 10.1016/S0303-7207(01)00450-6.CrossRefPubMed
46.
Aghajanova L, Velarde MC, Giudice LC: Altered gene expression profiling in endometrium: evidence for progesterone resistance. Semin Reprod Med. 2010, 28: 51-58. 10.1055/s-0029-1242994.CrossRefPubMed
47.
Taylor HS, Bagot C, Kardana A, Olive D, Arici A: HOX gene expression is altered in the endometrium of women with endometriosis. Hum Reprod. 1999, 14: 1328-1331. 10.1093/humrep/14.5.1328.CrossRefPubMed
48.
Hirota Y, Tranguch S, Daikoku T, Hasegawa A, Osuga Y, Taketani Y, Dey SK: Deficiency of immunophilin FKBP52 promotes endometriosis. Am J Pathol. 2008, 173: 1747-1757. 10.2353/ajpath.2008.080527.PubMedCentralCrossRefPubMed
49.
Aghajanova L, Velarde MC, Giudice LC: The progesterone receptor coactivator Hic-5 is involved in the pathophysiology of endometriosis. Endocrinology. 2009, 150: 3863-3870. 10.1210/en.2009-0008.PubMedCentralCrossRefPubMed
50.
Caballero V, Ruiz R, Sainz JA, Cruz M, Lopez-Nevot MA, Galan JJ, Real LM, de Castro F, Lopez-Villaverde V, Ruiz A: Preliminary molecular genetic analysis of the Receptor Interacting Protein 140 (RIP140) in women affected by endometriosis. J Exp Clin Assist Reprod. 2005, 2: 11-10.1186/1743-1050-2-11.PubMedCentralCrossRefPubMed
51.
Suzuki A, Horiuchi A, Oka K, Miyamoto T, Kashima H, Shiozawa T: Immunohistochemical detection of steroid receptor cofactors in ovarian endometriosis: involvement of down-regulated SRC-1 expression in the limited growth activity of the endometriotic epithelium. Virchows Arch. 2010, 456: 433-441. 10.1007/s00428-010-0884-x.CrossRefPubMed
52.
Kim JJ, Taylor HS, Lu Z, Ladhani O, Hastings JM, Jackson KS, Wu Y, Guo SW, Fazleabas AT: Altered expression of HOXA10 in endometriosis: potential role in decidualization. Mol Hum Reprod. 2007, 13: 323-332. 10.1093/molehr/gam005.CrossRefPubMed
53.
Lee B, Du H, Taylor HS: Experimental murine endometriosis induces DNA methylation and altered gene expression in eutopic endometrium. Biol Reprod. 2009, 80: 79-85. 10.1095/biolreprod.108.070391.PubMedCentralCrossRefPubMed
54.
Shazand K, Baban S, Prive C, Malette B, Croteau P, Lagace M, Racine JB, Hugo P: FOXO1 and c-jun transcription factors mRNA are modulated in endometriosis. Mol Hum Reprod. 2004, 10: 871-877. 10.1093/molehr/gah119.CrossRefPubMed
55.
Wu Y, Halverson G, Basir Z, Strawn E, Yan P, Guo SW: Aberrant methylation at HOXA10 may be responsible for its aberrant expression in the endometrium of patients with endometriosis. Am J Obstet Gynecol. 2005, 193: 371-380. 10.1016/j.ajog.2005.01.034.CrossRefPubMed
56.
Yang S, Fang Z, Suzuki T, Sasano H, Zhou J, Gurates B, Tamura M, Ferrer K, Bulun S: Regulation of aromatase P450 expression in endometriotic and endometrial stromal cells by CCAAT/enhancer binding proteins (C/EBPs): decreased C/EBPbeta in endometriosis is associated with overexpression of aromatase. J Clin Endocrinol Metab. 2002, 87: 2336-2345.PubMed
57.
Cunha GR, Cooke PS, Kurita T: Role of stromal-epithelial interactions in hormonal responses. Arch Histol Cytol. 2004, 67: 417-434. 10.1679/aohc.67.417.CrossRefPubMed
58.
Gellersen B, Fernandes MS, Brosens JJ: Non-genomic progesterone actions in female reproduction. Hum Reprod Update. 2009, 15: 119-138.CrossRefPubMed
Metadata
Title
Endometrial gene expression reveals compromised progesterone signaling in women refractory to embryo implantation
Authors
Alejandro Tapia-Pizarro
Paula Figueroa
Julio Brito
Juan Carlos Marín
David J Munroe
Horacio B Croxatto
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Reproductive Biology and Endocrinology / Issue 1/2014
Electronic ISSN: 1477-7827
DOI
https://doi.org/10.1186/1477-7827-12-92

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