Journal of Assisted Reproduction and Genetics

, Volume 35, Issue 8, pp 1385–1393 | Cite as

Ovarian environment aging: follicular fluid lipidomic and related metabolic pathways

  • Fernanda Bertuccez Cordeiro
  • Daniela Antunes MontaniEmail author
  • Eduardo Jorge Pilau
  • Fábio Cesar Gozzo
  • Renato Fraietta
  • Edson Guimaraes Lo Turco
Reproductive Physiology and Disease



The decline in female fecundity with age may be caused by decreased oocyte quality, a factor that may be associated with the altered composition of follicular fluid (FF).


In an effort to better understand follicular aging and the role of lipids in a given biological system, we present a prospective study that compares lipid profiles of FF from women older than 35 years (aging group, n = 12) to women equal or younger than 35 years old (control group, n = 17). FF lipids were extracted, and mass spectra were generated using a Waters Synapt G1 Q-TOF in MS mode. MS data was evaluated for both multi- and univariate statistics. The lipids identified as potential biomarkers of follicle aging were attributed by the online databases Lipid Maps, followed by pathway network analysis using Cytoscape software.


The in vitro fertilization (IVF) parameters showed significant differences in aging, number of follicles, total number of oocytes and oocytes in MII, and number of injected oocytes. Additionally, FF from the aging group revealed 11 lipids with higher abundance, while FF from the control group included 4 lipids with higher abundance.


We suspect that aging may influence lipid metabolism in a downstream cascade leading, ultimately, to decreased oocyte quality. The discovery of target lipids may assist oocyte selection for IVF in the future. Furthermore, systems biology approach based on post-genomic medicine may help unravel a number of altered mechanisms not previously understood.


Aging Oocyte quality In vitro fertilization Lipidomics Mass spectrometry MALDI-TOF 


Compliance with ethical standards

The authors comply with Springer’s Ethical Policies. The study received approval by the Ethics in Research Committee of São Paulo Federal University. Informed consent was obtained from all individual participants included in the study. All experiments were performed in accordance with relevant guidelines and regulations.

Supplementary material

10815_2018_1259_MOESM1_ESM.pdf (534 kb)
ESM 1 (PDF 534 kb)


  1. 1.
    Luk J, Greenfeld DA, Seli E. Third party reproduction and the aging couple. Maturitas. 2010;66:389–96.CrossRefPubMedGoogle Scholar
  2. 2.
    Sauer MV. Reproduction at an advanced maternal age and maternal health. Fertil Steril. 2015;103:1136–43.CrossRefPubMedGoogle Scholar
  3. 3.
    Wang T, Gao YY, Chen L, Nie ZW, Cheng W, Liu X, et al. Melatonin prevents postovulatory oocyte aging and promotes subsequent embryonic development in the pig. Aging. 2017;9:1552–64.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Schmidt T, Sobotka JG, Bentzen A, Nyboe A. On behalf of the ESHRE reproduction and society task force. Demographic and medical consequences of the postponement of parenthood. Hum Reprod Update. 2012;1:29–43.CrossRefGoogle Scholar
  5. 5.
    Kedem A, Yung Y, Yerushalmi GM, Haas J, Maman E, Hanochi M, et al. Anti Müllerian hormone (AMH) level and expression in mural and cumulus cells in relation to age. J Ovarian Res. 2014;11:113.CrossRefGoogle Scholar
  6. 6.
    Klein NA, Houmard BS, Hansen KR, Woodruff TK, Sluss PM, Bremner WJ, et al. Age-related analysis of inhibin A, inhibin B, and activin a relative to the intercycle monotropic follicle-stimulating hormone rise in normal ovulatory women. J Clin Endocrinol Metab. 2004;89:2977–81.CrossRefPubMedGoogle Scholar
  7. 7.
    Bracewell-Milnes T, Saso S, Abdalla H, Nikolau D, Norman-Taylor J, Johnson M, et al. Metabolomics as a tool to identify biomarkers to predict and improve outcomes in reproductive medicine: a systematic review. Hum Reprod Update. 2017;23:723–36.CrossRefPubMedGoogle Scholar
  8. 8.
    O'Gorman A, Wallace M, Cottell E, Gibney MJ, McAuliffe FM, Wingfield M, et al. Metabolic profiling of human follicular fluid identifies potential biomarkers of oocyte developmental competence. Reproduction. 2013;146:389–95.CrossRefPubMedGoogle Scholar
  9. 9.
    Schiller J, Arnhold J, Benard S, Müller M, Reichl S, Arnold K. Lipid analysis by matrix-assisted laser desorption and ionization mass spectrometry: a methodological approach. Anal Biochem. 1999;267:46–56.CrossRefPubMedGoogle Scholar
  10. 10.
    Montani DA, Cordeiro FB, Regiani T, Victorino AB, Pilau EJ, Gozzo FC, et al. The follicular microenvironment as a predictor of pregnancy: MALDI-TOF MS lipid profile in cumulus cells. J Assist Reprod Genet. 2012;29:1289–97.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Bligh EG, Dyer WJ. A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 1959;37:911–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Cordeiro FB, Cataldi TR, Perkel KJ, do Vale Teixeira da Costa L, Rochetti RC, Stevanato J, et al. Lipidomics analysis of follicular fluid by ESI-MS reveals potential biomarkers for ovarian endometriosis. J Assist Reprod Genet. 2015;32:1817–25.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Takahashi T, Igarashi H, Amita M, Hara S, Kurachi H. Cellular and molecular mechanisms of various types of oocyte aging. Reprod Med Biol. 2011;10:239–49.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Dumesic DA, Meldrum DR, Katz-Jaffe MG, Krisher RL, Schoolcraft WB. Oocyte environment: follicular fluid and cumulus cells are critical for oocyte health. Fertil Steril. 2015;103:303–16.CrossRefPubMedGoogle Scholar
  15. 15.
    Lin PY, Huang FJ, Kung FT, Chiang HJ, Lin YJ, Lin YC, et al. Evaluation of serum anti-Mullerian hormone as a biomarker of early ovarian aging in young women undergoing IVF/ICSI cycle. Int J Clin Exp Pathol. 2014 Aug 15;7(9):6245–53.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Ng EH, Ho PC. Ageing and ART: a waste of time and money? Best Pract Res Clin Obstet Gynaecol. 2007;21:5–20.CrossRefPubMedGoogle Scholar
  17. 17.
    Zhang D, Keilty D, Zhang ZF, Chian RC. Mitochondria in oocyte aging: current understanding. Facts Views Vis Obgyn. 2017;9:29–38.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Cordeiro FB, Cataldi TR, do Vale Teixeira da Costa L, de Lima CB, Stevanato J, Zylbersztejn DS, et al. Follicular fluid lipid fingerprinting from women with PCOS and hyper response during IVF treatment. J Assist Reprod Genet. 2015;32:45–54.CrossRefPubMedGoogle Scholar
  19. 19.
    Andrieu-Abadie N, Levade T. Sphingomyelin hydrolysis during apoptosis. Biochim Biophys Acta. 2002;1585:126–34.CrossRefPubMedGoogle Scholar
  20. 20.
    Lucki NC, Sewer MB. The interplay between bioactive sphingolipids and steroid hormones. Steroids. 2010;75:390–9.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Hannun YA. The sphingomyelin cycle and the second messenger function of ceramide. J Biol Chem. 1994;4:3125–8.Google Scholar
  22. 22.
    Yang X, Wu LL, Chura LR, Liang X, Lane M, Norman RJ, et al. Exposure to lipid-rich follicular fluid is associated with endoplasmic reticulum stress and impaired oocyte maturation in cumulus-oocyte complexes. Fertil Steril. 2012;97:1438–43.CrossRefPubMedGoogle Scholar
  23. 23.
    Ruebel ML, Cotter M, Sims CR, Moutos DM, Badger TM, Cleves MA, et al. Obesity modulates inflammation and lipid metabolism oocyte gene expression: a single-cell transcriptome perspective. J Clin Endocrinol Metab. 2017;102:2029–38.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Cataldi T, Cordeiro FB, Costa Ldo V, Pilau EJ, Ferreira CR, Gozzo FC, et al. Lipid profiling of follicular fluid from women undergoing IVF: young poor ovarian responders versus normal responders. Hum Fertil. 2013;16:269–77.CrossRefGoogle Scholar
  25. 25.
    Onalan G, Selam B, Baran Y, Cincik M, Onalan R, Gündüz U, et al. Serum and follicular fluid levels of soluble Fas, soluble Fas ligand and apoptosis of luteinized granulosa cells in PCOS patients undergoing IVF. Hum Reprod. 2005;20:2391–5.CrossRefPubMedGoogle Scholar
  26. 26.
    Wonnacott KE, Kwong WY, Hughes J, Salter AM, Lea RG, Garnsworthy PC, et al. Dietary omega-3 and -6 polyunsaturated fatty acids affect the composition and development of sheep granulosa cells, oocytes and embryos. Reproduction. 2010;139:57–69.CrossRefPubMedGoogle Scholar
  27. 27.
    Ciepiela P, Bączkowski T, Drozd A, Kazienko A, Stachowska E, Kurzawa R. Arachidonic and linoleic acid derivatives impact oocyte ICSI fertilization—a prospective analysis of follicular fluid and a matched oocyte in a ‘one follicle—one retrieved oocyte—one resulting embryo’ investigational setting. PLoS One. 2015;10(3):e0119087.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Gougeon A. Human ovarian follicular development: from activation of resting follicles to preovulatory maturation. Ann Endocrinol (Paris). 2010;71:132–43.CrossRefGoogle Scholar
  29. 29.
    Franciosi F, Manandhar S, Conti M. FSH regulates mRNA translation in mouse oocytes and promotes developmental competence. Endocrinology. 2016;157:872–82.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Surgery, Division of Urology, Human Reproduction SectionSao Paulo Federal UniversitySao PauloBrazil
  2. 2.Laboratorio Para Investigaciones BiomédicasEscuela Superior Politécnica del Litoral, ESPOLGuayaquilEcuador
  3. 3.Institute of ChemistryUniversity of CampinasCampinasBrazil

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