Preconception folic acid use influences the follicle fluid proteome

Eur J Clin Invest. 2015 Aug;45(8):833-41. doi: 10.1111/eci.12478. Epub 2015 Jul 3.


Background: The investigation of the human follicle fluid proteome has gained much interest in the search of new markers as predictors for in vitro fertilization and intracytoplasmic sperm injection (IVF/ICSI) treatment outcome. Follicular fluid folate, as substrate of one carbon (1-C) metabolism, affects follicular metabolism and oocyte and embryo quality. From this background, we aim to identify a folate-related follicle fluid proteome that associates with IVF/ICSI treatment outcome.

Methods: In a nested case-control study embedded in a periconception cohort, we performed qualitative and quantitative proteomic analyses using nanoflow LC-MS/MS and TMT labelling in 30 monofollicular fluid samples from women undergoing IVF/ICSI treatment of which 15 used and 15 did not use a folic acid supplement. The protein data are analysed using scaffold proteome Software and differential abundances are expressed as Log2-fold change. Blood samples were obtained before and after treatment for determination of biomarkers of 1-C metabolism and estradiol.

Results: We identified 227 uniquely expressed proteins in follicular fluid. In folic acid supplement users compared to nonusers, we established a lower abundance of C-reactive protein (-2.03; P = < 0.01) and higher abundances of apolipoproteins from high-density lipoprotein (HDL), most notably A-I (+1.28; P = < 0.01) and C-I (+1.11; P = 0.016).

Conclusion: Preconception folic acid supplement use is associated with suppression of the inflammatory pathway and upregulation of the HDL pathway in human follicular fluid, being a preferential source of cholesterol for steroid hormone synthesis. Studies are needed on the tissue specificity and on the beneficial effects of embryo quality and IVF/ICSI treatment outcome of the proteome of these pathways.

Keywords: Folic acid; follicle fluid; in vitro fertilization and intracytoplasmic sperm injection; proteomics.

Publication types

  • Observational Study

MeSH terms

  • Adult
  • Apolipoproteins / metabolism
  • C-Reactive Protein / metabolism
  • Case-Control Studies
  • Complement C4b-Binding Protein / metabolism
  • Down-Regulation
  • Female
  • Fertilization in Vitro*
  • Folic Acid / therapeutic use*
  • Follicular Fluid / metabolism*
  • Gene Expression Regulation
  • Geranyltranstransferase / metabolism
  • Humans
  • Interleukin-1 Receptor Accessory Protein / metabolism
  • Kallikreins / metabolism
  • Ovarian Follicle
  • Preconception Care / methods*
  • Prospective Studies
  • Proteins / metabolism
  • Proteome / metabolism*
  • Receptors, IgG / metabolism
  • Sperm Injections, Intracytoplasmic*
  • Up-Regulation
  • Vitamin B Complex / therapeutic use*


  • Apolipoproteins
  • Complement C4b-Binding Protein
  • IL1RAP protein, human
  • Interleukin-1 Receptor Accessory Protein
  • Proteins
  • Proteome
  • Receptors, IgG
  • histidine-rich proteins
  • Vitamin B Complex
  • C-Reactive Protein
  • Folic Acid
  • Geranyltranstransferase
  • Kallikreins