Skip to main content

Advertisement

Log in

The lipidome of endometrial fluid differs between implantative and non-implantative IVF cycles

Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Objective

To characterize the most relevant changes in the lipidome of endometrial fluid aspirate (EFA) in non-implantative cycles.

Design

Lipidomics in a prospective cohort study.

Settings

Reproductive unit of a university hospital.

Patients

Twenty-nine women undergoing an IVF cycle. Fifteen achieved pregnancy and 14 did not.

Intervention

Endometrial fluid aspiration immediately before performing embryo transfer.

Main outcome measures

Clinical pregnancy rate and lipidomic profiles obtained on an ultra-high performance liquid chromatography coupled to time-of-flight mass spectrometry (UHPLC-ToF-MS)-based analytical platform.

Results

The comparative analysis of the lipidomic patterns of endometrial fluid in implantative and non-implantative IVF cycles revealed eight altered metabolites: seven glycerophospholipids and an omega-6 polyunsaturated fatty acid. Then, women with a non-implantative cycle were accurately classified with a support vector machine algorithm including these eight lipid metabolites. The diagnostic performances of the algorithm showed an area under the receiver operating characteristic curve, sensitivity, specificity, and accuracy of 0.893 ± 0.07, 85.7%, 80.0%, and 82.8%, respectively.

Conclusion

A predictive lipidomic signature linked to the implantative status of the endometrial fluid has been found.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Matorras R, Urquijo E, Mendoza R, Corcóstegui B, Expósito A, Rodríguez-Escudero FJ. Ultrasound-guided embryo transfer improves pregnancy rates and increases the frequency of easy transfers. Hum Reprod. 2002;17:1762–6.

    CAS  PubMed  Google Scholar 

  2. Matorras R, Quevedo S, Corral B, Prieto B, Exposito A, Mendoza R, et al. Proteomic pattern of implantative human endometrial fluid in in vitro fertilization cycles. Arch Gynecol Obstet. 2018;297:1577–86.

    CAS  PubMed  Google Scholar 

  3. Vilella F, Ramirez LB, Simón C. Lipidomics as an emerging tool to predict endometrial receptivity. Fertil Steril. 2013;99:1100–6.

    CAS  PubMed  Google Scholar 

  4. Dominguez F, Galan A, Martin JJL, Remohi J, Pellicer A, Simon C. Hormonal and embryonic regulation of chemokine receptors CXCR1, CXCR4, CCR5 and CCR2B in the human endometrium and the human blastocyst. Mol Hum Reprod. 2003;9:189–98.

    CAS  PubMed  Google Scholar 

  5. Edgell TA, Rombauts LJF, Salamonsen LA. Assessing receptivity in the endometrium: the need for a rapid, non-invasive test. Reprod BioMed Online. 2013;27:486–96.

    PubMed  Google Scholar 

  6. 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.

    CAS  PubMed  Google Scholar 

  7. Kolibianakis E, Bourgain C, Albano C, Osmanagaoglu K, Smitz J, Van Steirteghem A, 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. 2002;78:1025–9.

    PubMed  Google Scholar 

  8. Zapantis G, Szmyga MJ, Rybak EA, Meier UT. Premature formation of nucleolar channel systems indicates advanced endometrial maturation following controlled ovarian hyperstimulation. Hum Reprod. 2013;28:3292–300.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. van der Gaast MH, Beier-Hellwig K, Fauser B, Beier HM, Macklon NS. Endometrial secretion aspiration prior to embryo transfer does not reduce implantation rates. Reprod BioMed Online. 2003;7:105–9.

    PubMed  Google Scholar 

  10. Azkargorta M, Escobes I, Iloro I, Elortza F, Osinalde N, Exposito A, et al. Differential proteomic analysis of endometrial fluid suggests increased inflammation and impaired glucose metabolism in non-implantative IVF cycles and pinpoints PYGB as a putative implantation marker. Hum Reprod. 2018;33:1898–906.

    CAS  PubMed  Google Scholar 

  11. Botros L, Sakkas D, Seli E. Metabolomics and its application for non-invasive embryo assessment in IVF. MHR Basic Sci Reprod Med. 2008;14:679–90.

    CAS  Google Scholar 

  12. Domínguez F, Ferrando M, Díaz-Gimeno P, Quintana F, Fernández G, Castells I, et al. Lipidomic profiling of endometrial fluid in women with ovarian endometriosis. Biol Reprod. 2017;96:772–9.

    PubMed  Google Scholar 

  13. Li J, Guan L, Zhang H, Gao Y, Sun J, Gong X, et al. Endometrium metabolomic profiling reveals potential biomarkers for diagnosis of endometriosis at minimal-mild stages. Reprod Biol Endocrinol. 2018;16:42.

    PubMed  PubMed Central  Google Scholar 

  14. Lee YH, Tan CW, Venkatratnam A, Tannenbaum SR, Cui L, Griffith L, et al. Dysregulated sphingolipid metabolism in endometriosis. J Clin Endocrinol Metab. 2014;99:E1913–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Trousil S, Lee P, Pinato DJ, Ellis JK, Dina R, Aboagye EO, et al. Alterations of choline phospholipid metabolism in endometrial cancer are caused by choline kinase alpha overexpression and a hyperactivated deacylation pathway. Cancer Res. 2014;74:6867–77.

    CAS  PubMed  Google Scholar 

  16. Wallace M, Cottell E, Gibney MJ, McAuliffe FM, Wingfield M, Brennan L. An investigation into the relationship between the metabolic profile of follicular fluid, oocyte developmental potential, and implantation outcome. Fertil Steril. 2012;97:1078–84.

    CAS  PubMed  Google Scholar 

  17. Vilella F, Ramirez L, Berlanga O, Martínez S, Alamá P, Meseguer M, et al. PGE2 and PGF2alpha concentrations in human endometrial fluid as biomarkers for embryonic implantation. J Clin Endocrinol Metab. 2013;98:4123–32.

    CAS  PubMed  Google Scholar 

  18. Braga DPAF, Borges E Jr, Godoy AT, Montani DA, Setti AS, Zanetti BF, et al. Lipidomic profile as a noninvasive tool to predict endometrial receptivity. Mol Reprod Dev. 2019;86:145–55.

    CAS  PubMed  Google Scholar 

  19. ASEBIR Special Interest Group of Embryology. Cuadernos de Embriología línica. Criterios ASEBIR de valoración morfológica de oocitos, embriones tempranos y blastocistos humanos, 2nd ed. Madrid: ASEBIR; 2008.

    Google Scholar 

  20. Manni MM, Valero JG, Pérez-Cormenzana M, Cano A, Alonso C, Goñi FM. Lipidomic profile of GM95 cell death induced by Clostridium perfringens alpha-toxin. Chem Phys Lipids. 2017;203:54–70.

    CAS  PubMed  Google Scholar 

  21. Barr J, Caballería J, Martínez-Arranz I, Domínguez-Díez A, Alonso C, Muntané J, et al. Obesity-dependent metabolic signatures associated with nonalcoholic fatty liver disease progression. J Proteome Res. 2012;11:2521–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Hrydziuszko O, Viant M. Missing values in mass spectrometry based metabolomics: an undervalued step in the data processing pipeline. Metabolomics. 2012;8:161–74.

    CAS  Google Scholar 

  23. Hair JF. Multivariate data analysis. New Jersey: Prentice Hall; 2009.

    Google Scholar 

  24. Baraldi AN, Enders CK. An introduction to modern missing data analyses. J Sch Psychol. 2010;48:5–37.

    PubMed  Google Scholar 

  25. Box GEP, Cox DR. An analysis of transformations. J R Stat Soc Ser B. 1964;26:211–52.

    Google Scholar 

  26. van den Berg RA, Hoefsloot HCJ, Westerhuis JA, Smilde AK, van der Werf MJ. Centering, scaling, and transformations: improving the biological information content of metabolomics data. BMC Genomics. 2006;7:142.

    PubMed  PubMed Central  Google Scholar 

  27. Yang J, Zhao X, Lu X, Lin X, Xu G. A data preprocessing strategy for metabolomics to reduce the mask effect in data analysis. Front Mol Biosci. 2015;2:4.

    PubMed  PubMed Central  Google Scholar 

  28. Kuhn M, Johnson K. Applied predictive modeling. Berlin: Springer Science & Business Media; 2013.

    Google Scholar 

  29. Gray CA, Bazer FW, Taylor KM, Ramsey WS, Spencer TE, Hill JR, et al. Endometrial glands are required for preimplantation conceptus elongation and survival. Biol Reprod. 2001;64:1608–13.

    CAS  PubMed  Google Scholar 

  30. Dunlap KA, Filant J, Hayashi K, Rucker EB 3rd, Song G, Deng JM, et al. Postnatal deletion of wnt7a inhibits uterine gland morphogenesis and compromises adult fertility in mice. Biol Reprod. 2011;85:386–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Salamonsen LA, Evans J, Nguyen HP, Edgell TA. The microenvironment of human implantation: determinant of reproductive success. Am J Reprod Immunol. 2016;75:218–25.

    PubMed  Google Scholar 

  32. Stubbs CD, Smith AD. The modification of mammalian membrane polyunsaturated fatty acid composition in relation to membrane fluidity and function. Biochim Biophys Acta. 1984;779:89–137.

    CAS  PubMed  Google Scholar 

  33. Matorras R, Ruiz JI, Mendoza R, Ruiz N, Sanjurjo P, Rodriguez-Escudero FJ. Fatty acid composition of fertilization-failed human oocytes. Hum Reprod. 1998;13:2227–30.

    CAS  PubMed  Google Scholar 

  34. Jamro EL, Bloom MS, Browne RW, Kim K, Greenwood EA, Fujimoto VY. Preconception serum lipids and lipophilic micronutrient levels are associated with live birth rates after IVF. Reprod BioMed Online. 2019;39:665–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Li J, Gao Y, Guan L, Zhang H, Chen P, Gong X, et al. Lipid profiling of peri-implantation endometrium in patients with premature progesterone rise in the late follicular phase. J Clin Endocrinol Metab. 2019;104:5555–65.

    PubMed  Google Scholar 

  36. Dunning KR, Cashman K, Russell DL, Thompson JG, Norman RJ, Robker RL. Beta-oxidation is essential for mouse oocyte developmental competence and early embryo development. Biol Reprod. 2010;83:909–18.

    CAS  PubMed  Google Scholar 

  37. Tsai JH, Chi MM, Schulte MB, Moley KH. The fatty acid beta-oxidation pathway is important for decidualization of endometrial stromal cells in both humans and mice. Biol Reprod. 2014;90:34.

    PubMed  PubMed Central  Google Scholar 

  38. Casado-Vela J, Rodriguez-Suarez E, Iloro I, Ametzazurra A, Alkorta N, García-Velasco JA, et al. Comprehensive proteomic analysis of human endometrial fluid aspirate. J Proteome Res. 2009;8:4622–32.

    CAS  PubMed  Google Scholar 

  39. Azkargorta M, Bregón-Villahoz M, Escobes I, Iloro I, Iglesias M, Diez Zapirain M, et al. In-depth proteomics and natural peptidomics analyses reveal the presence of antibacterial peptides in human endometrial fluid. (under editorial revision).

  40. Fuchs B, Muller K, Paasch U, Schiller J. Lysophospholipids: potential markers of diseases and infertility? Mini Rev Med Chem. 2012;12:74–86.

    CAS  PubMed  Google Scholar 

  41. Nagamatsu T, Iwasawa-Kawai Y, Ichikawa M, Kawana K, Yamashita T, Osuga Y, et al. Emerging roles for lysophospholipid mediators in pregnancy. Am J Reprod Immunol. 2014;72:182–91.

    CAS  PubMed  Google Scholar 

  42. Tokumura A, Kanaya Y, Miyake M, Yamano S, Irahara M, Fukuzawa K. Increased production of bioactive lysophosphatidic acid by serum lysophospholipase D in human pregnancy. Biol Reprod. 2002;67:1386–92.

    CAS  PubMed  Google Scholar 

  43. Sordelli MS, Beltrame JS, Cella M, Gervasi MG, Perez Martinez S, Burdet J, et al. Interaction between lysophosphatidic acid, prostaglandins and the endocannabinoid system during the window of implantation in the rat uterus. PLoS One. 2012;7:e46059.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Boruszewska D, Kowalczyk-Zieba I, Sinderewicz E, Grycmacher K, Staszkiewicz J, Woclawek-Potocka I. The effect of lysophosphatidic acid together with interferon tau on the global transcriptomic profile in bovine endometrial cells. Theriogenology. 2017;92:111–20.

    CAS  PubMed  Google Scholar 

  45. Sher G, Maassarani G, Fisch JD, Chong P, Ching W, Matzner W. Antibodies to phosphatidylethanolamine and phosphatidylserine are associated with increased natural killer cell activity in non-male factor infertility patients. Hum Reprod. 2000;15:1932–6.

    CAS  PubMed  Google Scholar 

  46. Akerele OA, Cheema SK. A balance of omega-3 and omega-6 polyunsaturated fatty acids is important in pregnancy. J Nutr Intermed Metab. 2016;5:23–33.

    Google Scholar 

  47. Jungheim ES, Frolova AI, Jiang H, Riley JK. Relationship between serum polyunsaturated fatty acids and pregnancy in women undergoing in vitro fertilization. J Clin Endocrinol Metab. 2013;98:E1364–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Jungheim ES, Macones GA, Odem RR, Patterson BW, Moley KH. Elevated serum alpha-linolenic acid levels are associated with decreased chance of pregnancy after in vitro fertilization. Fertil Steril. 2011;96:880–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Koletzko B, Lattka E, Zeilinger S, Illig T, Steer C. Genetic variants of the fatty acid desaturase gene cluster predict amounts of red blood cell docosahexaenoic and other polyunsaturated fatty acids in pregnant women: findings from the Avon Longitudinal Study of Parents and Children. Am J Clin Nutr. 2010;93:211–9.

    PubMed  Google Scholar 

  50. Matorras R, Exposito A, Ferrando M, Mendoza R, Larreategui Z, Lainz L, et al. Oocytes of obese and overweight women have lower levels of n-3 polyunsaturated fatty acids compared to oocytes of normal weight women. Fertil Steril. (in press).

Download references

Funding

This study was partially funded by a Grant for Fertility Innovation (GFI, 2011) from Merck (Darmstadt, Germany).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Roberto Matorras.

Ethics declarations

Conflict of interest

IM-A, EA, MI-L, and CA are OWL Metabolomics’ employees.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(XLSX 20 kb)

ESM 2

(DOCX 16 kb)

ESM 3

(PDF 62 kb)

ESM 4

(DOCX 38.9 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Matorras, R., Martinez-Arranz, I., Arretxe, E. et al. The lipidome of endometrial fluid differs between implantative and non-implantative IVF cycles. J Assist Reprod Genet 37, 385–394 (2020). https://doi.org/10.1007/s10815-019-01670-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-019-01670-z

Keywords

Navigation