Age-Dependent Metabolomic Profile of the Follicular Fluids From Women Undergoing Assisted Reproductive Technology Treatment

Abstract

Female fertility declines with age, and this natural variation culminates in reproductive senescence. Human follicular fluids are rich in low-molecular weight metabolites which are responsible for the maturation of oocytes. The metabolomic approaches are powerful tools to study biochemical markers of oocyte quality in the follicular fluids. It is necessary to identify and quantify the reliable metabolites in follicular fluids reflecting oocyte developmental potential. The goal of this study is to conduct a metabolomic analysis of the follicular fluids in women of different ages and study the metabolomic profile of the follicular fluids in relationship with oocyte quality in assisted reproductive technology (ART) treatment. A total of 30 women seeking for ART treatment at the Women’s Hospital, Zhejiang University School of Medicine from October 2014 to April 2015 were recruited for the present study. Fifteen women aged from 39 to 47 were grouped as advanced maternal age, and the other 15 women aged from 27 to 34, as young controls. Ovarian stimulation and oocyte retrieval were conducted using a regular protocol involving mid-luteal pituitary down-regulation and controlled ovarian stimulation. Follicular fluids from mature follicles were collected and centrifuged for analyses. Liquid Chromatography-Mass Spectrometry (LC-MS) and Gas Chromatography-Mass Spectroscopy (GC-MS) were used to perform the quantitative metabolomic analysis. The follicular fluid levels of 311 metabolites and the metabolic significance were assessed. 70 metabolites showed significant differences between women with young and advanced ages. Follicular fluids from women with advanced age showed significantly higher levels of creatine, histidine, methionine, trans-4-hydroxyproline, choline, mevalonate, N2,N2-dimethylguanosine and gamma-glutamylvaline, as compared to those from the young age group. 8 metabolites were found significantly correlated with maternal age positively. Moreover, 3 metabolites were correlated with the number of oocytes retrieved, and 5 metabolites were correlated with cleaved embryo numbers, both negatively. The follicular fluids from women undergoing ART treatment exhibited age-dependent metabolomic profile. Metabolites associated with oocyte quality were identified, suggesting them as potential biomarkers for oocyte maturation and ART outcomes.

Transcriptomics and metabolomics of blood, urine and ovarian follicular fluid of yak at induced estrus stage

“…Similarly, metabolites in follicular fluid, such as advanced glycosylation end products, have been found to improve the developmental potential of oocytes. Steroid metabolism in follicles appears to be closely related to ovarian function and oocyte quality [ 58 , 59 ]. In addition, studies have shown that vitamin b6 supplementation can significantly increase luteinizing hormone (LH) production in sows during estrus [ 60 , 61 ].…”

Metabolomics and its applications in assisted reproductive technology

“…Yun et al. [18] studied the oocyte metabolites of 30 women who received ART treatment. The women were divided into an advanced maternal age group and a young control group.…”

“… Schematic representation of the metabolic pathways that are putatively altered in follicular fluids as age advances [18]. …”

“…Although no evidence has shown that metabolomics can improve ART outcomes (such as clinical pregnancy and live birth rates), many studies have used metabolomics to analyse the fluid components in the female reproductive tract, which could lead to new technologies and methods to treat infertility. [17] Metabolites associated with oocyte quality could serve as biomarkers for oocyte maturation and ART outcomes [18]. These small molecules can be used to evaluate the quality of gametes and embryos to improve pregnancy rates and reduce the risk of multiple pregnancies.…”

Sperm DNA integrity does play a crucial role for embryo development after ICSI, notably when good-quality oocytes from young donors are used

“…This is especially pertinent in studies including infertile couples, where impaired oocyte quality can either be competent to repair sperm DNA [26,27], or bring additional alterations in embryo development [28]. Indeed, because oocytes are arrested at meiotic prophase I since fetal stages, they are more likely to accumulate alterations and exhibit reduced fertilizing ability in women with advanced age [29][30][31][32]. Second, alterations in sperm count, motility and morphology may result from unknown physiological or molecular alterations that ultimately affect embryo development [33][34][35][36].…”