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

Reproductive Biology and Endocrinology

Horacio B Croxatto²  David J Munroe⁵  Juan Carlos Marín¹  Julio Brito³  Paula Figueroa³  Alejandro Tapia-Pizarro⁴ 

[1] Facultad de Ciencias, Universidad del Bio-Bío, Chillán, Chile;Center for Integrative Medicine and Innovative Sciences, Universidad Andrés Bello, Santiago, Chile;Facultad de Medicina, Universidad Mayor, Santiago, Chile;Instituto de Investigaciones Materno Infantil, Facultad de Medicina, Universidad de Chile, Santiago, Chile;Advanced Technology Program, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD 21701, USA

关键词: Implantation failure;    PROGINS;    Gene expression;    Endometrium;   

Others  :  1139767
DOI  :  10.1186/1477-7827-12-92

 received in 2014-05-30, accepted in 2014-09-17,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Tapia-Pizarro et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]O’Malley BW, Tsai MJ: Molecular pathways of steroid receptor action. Biol Reprod 1992, 46:163-167.
• [2]Gellersen B, Brosens IA, Brosens JJ: Decidualization of the human endometrium: mechanisms, functions, and clinical perspectives. Semin Reprod Med 2007, 25:445-453.
• [3]Beato M: Gene regulation by steroid hormones. Cell 1989, 56:335-344.
• [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.
• [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.
• [6]Danielsson KG, Marions L, Bygdeman M: Effects of mifepristone on endometrial receptivity. Steroids 2003, 68:1069-1075.
• [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.
• [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.
• [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.
• [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. BioMed Central Full Text
• [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.
• [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.
• [14]Noyes RW, Hertig AT, Rock J: Dating the endometrial biopsy. Am J Obstet Gynecol 1975, 122:262-263.
• [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.
• [17]Dennis G Jr, 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. BioMed Central Full Text
• [18]Chang JT, Nevins JR: GATHER: a systems approach to interpreting genomic signatures. Bioinformatics 2006, 22:2926-2933.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [30]Ace CI, Okulicz WC: Microarray profiling of progesterone-regulated endometrial genes during the rhesus monkey secretory phase. Reprod Biol Endocrinol 2004, 2:54. BioMed Central Full Text
• [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.
• [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. 60 e51-15
• [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.
• [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.
• [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.
• [36]Seppala M, Bohn H, Tatarinov Y: Glycodelins. Tumour Biol 1998, 19:213-220.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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. discussion 847–849
• [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.
• [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.
• [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.
• [46]Aghajanova L, Velarde MC, Giudice LC: Altered gene expression profiling in endometrium: evidence for progesterone resistance. Semin Reprod Med 2010, 28:51-58.
• [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.
• [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.
• [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.
• [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. BioMed Central Full Text
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [57]Cunha GR, Cooke PS, Kurita T: Role of stromal-epithelial interactions in hormonal responses. Arch Histol Cytol 2004, 67:417-434.
• [58]Gellersen B, Fernandes MS, Brosens JJ: Non-genomic progesterone actions in female reproduction. Hum Reprod Update 2009, 15:119-138.