Altered Follicular Fluid Metabolic Pattern Correlates with Female Infertility and Outcome Measures of In Vitro Fertilization Original paper

What was studied?

This original research investigated the metabolic profile of follicular fluid (FF) in women undergoing in vitro fertilization (IVF) to determine whether specific biochemical alterations correlate with female infertility and IVF outcomes. Using a targeted metabolomics approach, the study quantified 55 low molecular weight compounds, encompassing energy metabolites, purines, pyrimidines, antioxidants, oxidative/nitrosative stress markers, and amino acids, in FF samples. The research aimed to identify distinct metabolic signatures in infertile women compared to controls (fertile women whose partner’s infertility was the only impediment to conception), and to evaluate the relationship between these metabolic patterns and clinical IVF outcome measures, including oocyte development, embryo quality, and pregnancy rates. A cumulative Biomarker Score, based on deviations in 27 key FF metabolites, was developed to distinguish between fertile and infertile women and to predict IVF success.

Who was studied?

The study cohort consisted of 180 women attending a fertility clinic in Rome, Italy, from 2018 to 2020. The control group (n=35) was composed of women whose infertility was exclusively due to a male factor, ensuring their reproductive competence. The infertile group (n=145) included women diagnosed with endometriosis (n=19), polycystic ovary syndrome (PCOS; n=14), age-related reduced ovarian reserve (AR-ROR; n=58), reduced ovarian reserve (ROR; n=29), unexplained infertility (UI; n=14), and genetic infertility (GI; n=11). All participants underwent standardized ovarian stimulation and IVF/ICSI protocols, with FF collected during oocyte retrieval. The study excluded women with mechanical reproductive barriers, cancer history, or premature ovarian failure, and controlled for confounding lifestyle and nutritional factors.

Most important findings

The metabolomic analysis revealed that 27 of 55 measured metabolites significantly differed between infertile and control groups. Infertile women generally exhibited lower FF glucose, higher lactate, elevated purine and pyrimidine catabolites (hypoxanthine, xanthine, uracil, pseudouridine), decreased antioxidants (ascorbic acid, glutathione, vitamin A, vitamin E, coenzyme Q10, carotenoids), increased oxidative/nitrosative stress markers (malondialdehyde, 8-hydroxy-2′-deoxyguanosine, nitrite, nitrate), and reduced levels of several amino acids (notably serine, threonine, arginine, valine, methionine, tryptophan, isoleucine, leucine). These metabolic anomalies were largely consistent across different infertility diagnoses, though some subgroup-specific patterns emerged (e.g., PCOS and GI showed normal FF glucose). The composite Biomarker Score robustly discriminated between control and infertile groups, with scores correlating inversely with key IVF outcomes—number and quality of oocytes/blastocysts, clinical pregnancy, and healthy live birth rates. The Biomarker Score showed high specificity and sensitivity in predicting fertility status and IVF success.

Key implications

This study underscores the central role of FF metabolic composition in female fertility and IVF outcomes. The identification of a 27-metabolite signature and its integration into a Biomarker Score offers a powerful, noninvasive tool for distinguishing fertile from infertile patients and predicting assisted reproduction success. The findings suggest that metabolic profiling of FF could inform personalized interventions to optimize the follicular environment, enhance oocyte quality, and improve IVF success rates. Furthermore, these metabolomic biomarkers could be incorporated into microbiome-multimetabolite databases, facilitating personalized reproductive medicine and potentially guiding future research into the interplay between follicular metabolites, the ovarian microenvironment, and the local microbiome.