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Reproductive Biology and Endocrinology
Published in: Reproductive Biology and Endocrinology 1/2018

Open Access 01-12-2018 | Research

Endometrium metabolomic profiling reveals potential biomarkers for diagnosis of endometriosis at minimal-mild stages

Authors: Jingjie Li, Lihuan Guan, Huizhen Zhang, Yue Gao, Jiahong Sun, Xiao Gong, Dongshun Li, Pan Chen, Xiaoyan Liang, Min Huang, Huichang Bi

Published in: Reproductive Biology and Endocrinology | Issue 1/2018

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Abstract

Background

The sensitivity and specificity of non-invasive diagnostic methods for endometriosis, especially at early stages, are not optimal. The clinical diagnostic indicator cancer antigen 125 (CA125) performs poorly in the diagnosis of minimal endometriosis, with a sensitivity of 24%. Therefore, it is urgent to explore novel diagnostic biomarkers. We evaluated the metabolomic profile variation of the eutopic endometrium between minimal-mild endometriosis patients and healthy women by ultra-high-performance liquid chromatography coupled with electrospray ionization high-resolution mass spectrometry (UHPLC-ESI-HRMS).

Methods

Our study comprised 29 patients with laparoscopically confirmed endometriosis at stages I-II and 37 infertile women who underwent diagnostic laparoscopy combined with hysteroscopy from January 2014 to January 2015. Eutopic endometrium samples were collected by pipelle endometrial biopsy. The metabolites were quantified by UHPLC-ESI-HRMS. The best combination of biomarkers was then selected by performing step-wise logistic regression analysis with backward elimination.

Results

Twelve metabolites were identified as endometriosis-associated biomarkers. The eutopic endometrium metabolomic profile of the endometriosis patients was characterized by a significant increase in the concentration of hypoxanthine, L-arginine, L-tyrosine, leucine, lysine, inosine, omega-3 arachidonic acid, guanosine, xanthosine, lysophosphatidylethanolamine and asparagine. In contrast, the concentration of uric acid was decreased. Metabolites were filtered by step-wise logistic regression with backward elimination, and a model containing uric acid, hypoxanthine, and lysophosphatidylethanolamine was constructed. Receiver-operating characteristic (ROC) analysis confirmed the prognostic value of these parameters for the diagnosis of minimal/mild endometriosis with a sensitivity of 66.7% and a specificity of 90.0%.

Conclusions

Metabolomics analysis of the eutopic endometrium in endometriosis was effectively characterized by UHPLC-ESI-HRMS-based metabolomics. Our study supports the importance of purine and amino acid metabolites in the pathophysiology of endometriosis and provides potential biomarkers for semi-invasive diagnosis of early-stage endometriosis.
Literature
1.
Olive DL, Pritts EA. Treatment of endometriosis. N Engl J Med. 2001;345:266–75.PubMed
2.
Counseller VS, Crenshaw JL Jr. A clinical and surgical review of endometriosis. Am J Obstet Gynecol. 1951;62:930–42.PubMed
3.
Simoens S, Dunselman G, Dirksen C, Hummelshoj L, Bokor A, Brandes I, Brodszky V, Canis M, Colombo GL, DeLeire T, et al. The burden of endometriosis: costs and quality of life of women with endometriosis and treated in referral centres. Hum Reprod. 2012;27:1292–9.PubMed
4.
Revised American Society for Reproductive Medicine classification of endometriosis. Fertil Steril. 1996;1997(67):817–21.
5.
Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertil Steril. 2002;77:1148–55.PubMed
6.
Bergendal A, Naffah S, Nagy C, Bergqvist A, Sjoblom P, Hillensjo T. Outcome of IVF in patients with endometriosis in comparison with tubal-factor infertility. J Assist Reprod Genet. 1998;15:530–4.PubMed
7.
Hadfield R, Mardon H, Barlow D, Kennedy S. Delay in the diagnosis of endometriosis: a survey of women from the USA and the UK. Hum Reprod. 1996;11:878–80.PubMed
8.
Hirsch M, Duffy J, Davis CJ, Nieves Plana M, Khan KS. International collaboration to harmonise O, measures for E: diagnostic accuracy of cancer antigen 125 for endometriosis: a systematic review and meta-analysis. BJOG. 2016;123:1761–8.PubMed
9.
Ahn SH, Singh V, Tayade C. Biomarkers in endometriosis: challenges and opportunities. Fertil Steril. 2017;107:523–32.PubMed
10.
Marianna S, Alessia P, Susan C, Francesca C, Angela S, Francesca C, Antonella N, Patrizia I, Nicola C, Emilio C. Metabolomic profiling and biochemical evaluation of the follicular fluid of endometriosis patients. Mol BioSyst. 2017;13:1213–22.PubMed
11.
Cheema AK, Pathak R, Zandkarimi F, Kaur P, Alkhalil L, Singh R, Zhong X, Ghosh S, Aykin-Burns N, Hauer-Jensen M. Liver metabolomics reveals increased oxidative stress and fibrogenic potential in gfrp transgenic mice in response to ionizing radiation. J Proteome Res. 2014;13:3065–74.PubMed
12.
Bi H, Krausz KW, Manna SK, Li F, Johnson CH, Gonzalez FJ. Optimization of harvesting, extraction, and analytical protocols for UPLC-ESI-MS-based metabolomic analysis of adherent mammalian cancer cells. Anal Bioanal Chem. 2013;405:5279–89.PubMed
13.
Want EJ, Masson P, Michopoulos F, Wilson ID, Theodoridis G, Plumb RS, Shockcor J, Loftus N, Holmes E, Nicholson JK. Global metabolic profiling of animal and human tissues via UPLC-MS. Nat Protoc. 2013;8:17–32.PubMed
14.
Yu T, Wang Y, Zhang H, Johnson CH, Jiang Y, Li X, Wu Z, Liu T, Krausz KW, Yu A, et al. Metabolomics reveals mycoplasma contamination interferes with the metabolism of PANC-1 cells. Anal Bioanal Chem. 2016;408:4267–73.PubMed
15.
Zhang H, Jiang Y, Wu J, Zheng C, Ran X, Li D, Huang M, Bi H. Metabolic mapping of Schisandra sphenanthera extract and its active lignans using a metabolomic approach based on ultra high performance liquid chromatography with high-resolution mass spectrometry. J Sep Sci. 2017;40:574–86.PubMed
16.
Dunselman GA, Vermeulen N, Becker C, Calhaz-Jorge C, D'Hooghe T, De Bie B, Heikinheimo O, Horne AW, Kiesel L, Nap A, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014;29:400–12.PubMed
17.
Slack A, Child T, Lindsey I, Kennedy S, Cunningham C, Mortensen N, Koninckx P, McVeigh E. Urological and colorectal complications following surgery for rectovaginal endometriosis. BJOG. 2007;114:1278–82.PubMed
18.
Check JH. CA-125 as a biomarker for malignant transformation of endometriosis. Fertil Steril. 2009;91:e35. author reply e36PubMed
19.
Mol BW, Bayram N, Lijmer JG, Wiegerinck MA, Bongers MY, van der Veen F, Bossuyt PM. The performance of CA-125 measurement in the detection of endometriosis: a meta-analysis. Fertil Steril. 1998;70:1101–8.PubMed
20.
May KE, Conduit-Hulbert SA, Villar J, Kirtley S, Kennedy SH, Becker CM. Peripheral biomarkers of endometriosis: a systematic review. Hum Reprod Update. 2010;16:651–74.PubMed
21.
Zhang A, Sun H, Wang X. Serum metabolomics as a novel diagnostic approach for disease: a systematic review. Anal Bioanal Chem. 2012;404:1239–45.PubMed
22.
Patel NR, McPhail MJ, Shariff MI, Keun HC, Taylor-Robinson SD. Biofluid metabonomics using (1)H NMR spectroscopy: the road to biomarker discovery in gastroenterology and hepatology. Expert Rev Gastroenterol Hepatol. 2012;6:239–51.PubMed
23.
Weiss RH, Kim K. Metabolomics in the study of kidney diseases. Nat Rev Nephrol. 2011;8:22–33.PubMed
24.
Rhee EP, Gerszten RE. Metabolomics and cardiovascular biomarker discovery. Clin Chem. 2012;58:139–47.PubMed
25.
Vicente-Munoz S, Morcillo I, Puchades-Carrasco L, Paya V, Pellicer A, Pineda-Lucena A. Pathophysiologic processes have an impact on the plasma metabolomic signature of endometriosis patients. Fertil Steril. 2016;106:1733–41. e1731PubMed
26.
Vicente-Munoz S, Morcillo I, Puchades-Carrasco L, Paya V, Pellicer A, Pineda-Lucena A. Nuclear magnetic resonance metabolomic profiling of urine provides a noninvasive alternative to the identification of biomarkers associated with endometriosis. Fertil Steril. 2015;104:1202–9.PubMed
27.
Cordeiro FB, Cataldi TR, Perkel KJ, Do Vale Teixeira da Costa L, Rochetti RC, Stevanato J, Eberlin MN, Zylbersztejn DS, Cedenho AP, Turco EG. Lipidomics analysis of follicular fluid by ESI-MS reveals potential biomarkers for ovarian endometriosis. J Assist Reprod Genet. 2015;32:1817–25.PubMed
28.
Rizner TL. Diagnostic potential of peritoneal fluid biomarkers of endometriosis. Expert Rev Mol Diagn. 2015;15:557–80.PubMed
29.
Joshi NR, Su RW, Chandramouli GV, Khoo SK, Jeong JW, Young SL, Lessey BA, Fazleabas AT. Altered expression of microRNA-451 in eutopic endometrium of baboons (Papio anubis) with endometriosis. Hum Reprod. 2015;30:2881–91.PubMed
30.
Laudanski P, Charkiewicz R, Tolwinska A, Szamatowicz J, Charkiewicz A, Niklinski J. Profiling of selected MicroRNAs in proliferative Eutopic endometrium of women with ovarian endometriosis. Biomed Res Int. 2015;2015:760698.PubMed
31.
Goteri G, Altobelli E, Tossetta G, Zizzi A, Avellini C, Licini C, Lorenzi T, Castellucci M, Ciavattini A, Marzioni D. High temperature requirement A1, transforming growth factor beta1, phosphoSmad2 and Ki67 in eutopic and ectopic endometrium of women with endometriosis. Eur J Histochem. 2015;59:2570.PubMed
32.
Chelariu-Raicu A, Wilke C, Brand M, Starzinski-Powitz A, Kiesel L, Schuring AN, Gotte M. Syndecan-4 expression is upregulated in endometriosis and contributes to an invasive phenotype. Fertil Steril. 2016;106:378–85.PubMed
33.
Li Y, An D, Guan YX, Kang S. Aberrant methylation of the E-cadherin gene promoter region in endometrium and ovarian Endometriotic cysts of patients with ovarian endometriosis. Gynecol Obstet Investig. 2017;82:78–85.
34.
Witte DP, Wiginton DA, Hutton JJ, Aronow BJ. Coordinate developmental regulation of purine catabolic enzyme expression in gastrointestinal and postimplantation reproductive tracts. J Cell Biol. 1991;115:179–90.PubMed
35.
Hong L, Mulholland J, Chinsky JM, Knudsen TB, Kellems RE, Glasser SR. Developmental expression of adenosine deaminase during decidualization in the rat uterus. Biol Reprod. 1991;44:83–93.PubMed
36.
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;144:2870–81.PubMed
37.
Karanjgaokar VC, Murphy DJ, Samra JS, Mann CH. Malignant transformation of residual endometriosis after hysterectomy: a case series. Fertil Steril. 2009;2037(92):e2019–21.
38.
Lin J, Zhang X, Chen Y. Mutagen sensitivity as a susceptibility marker for endometriosis. Hum Reprod. 2003;18:2052–7.PubMed
39.
Munksgaard PS, Blaakaer J. The association between endometriosis and gynecological cancers and breast cancer: a review of epidemiological data. Gynecol Oncol. 2011;123:157–63.PubMed
40.
Denkert C, Budczies J, Weichert W, Wohlgemuth G, Scholz M, Kind T, Niesporek S, Noske A, Buckendahl A, Dietel M, Fiehn O. Metabolite profiling of human colon carcinoma--deregulation of TCA cycle and amino acid turnover. Mol Cancer. 2008;7:72.PubMed
41.
Chen JQ, Russo J. Dysregulation of glucose transport, glycolysis, TCA cycle and glutaminolysis by oncogenes and tumor suppressors in cancer cells. Biochim Biophys Acta. 2012;1826:370–84.PubMed
42.
Dutta M, Joshi M, Srivastava S, Lodh I, Chakravarty B, Chaudhury K. A metabonomics approach as a means for identification of potential biomarkers for early diagnosis of endometriosis. Mol BioSyst. 2012;8:3281–7.PubMed
43.
Zhang J, Liu L, Wei S, Nagana Gowda GA, Hammoud Z, Kesler KA, Raftery D. Metabolomics study of esophageal adenocarcinoma. J Thorac Cardiovasc Surg. 2011;141:469–75. 475 e461–464PubMed
44.
Zhang J, Bowers J, Liu L, Wei S, Gowda GA, Hammoud Z, Raftery D. Esophageal cancer metabolite biomarkers detected by LC-MS and NMR methods. PLoS One. 2012;7:e30181.PubMed
Metadata
Title
Endometrium metabolomic profiling reveals potential biomarkers for diagnosis of endometriosis at minimal-mild stages
Authors
Jingjie Li
Lihuan Guan
Huizhen Zhang
Yue Gao
Jiahong Sun
Xiao Gong
Dongshun Li
Pan Chen
Xiaoyan Liang
Min Huang
Huichang Bi
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Reproductive Biology and Endocrinology / Issue 1/2018
Electronic ISSN: 1477-7827
DOI
https://doi.org/10.1186/s12958-018-0360-z

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