{"paper_id":"328a24f6-28ad-43a6-9850-f79b7ad82656","body_text":"Abstract\nBackground\nThe follicular fluid (FF) microenvironment plays a critical role in oocyte maturation and embryo development, reflecting local ovarian activity and systemic metabolic status. While metabolic alterations in FF have been described in different diseases, comparative analyses across different infertility-related disorders remain limited.\nObjective\nThis study aimed to characterize and compare amino acid profiles in FF from patients undergoing in vitro fertilization (IVF) with insulin resistance (IR), endometriosis (EM), thyroid dysfunction (TD) and to identify disease-specific metabolic signatures.\nMethods\nWe analyzed 171 FF samples using targeted ultra-high-performance liquid chromatography. The twenty proteogenic amino acids were quantified and analyzed using univariate and multivariate statistical analyses, including Kruskal-Wallis testing with post-hoc correction, generalized linear modeling adjusted for BMI, principal component analysis (PCA) and pathway enrichment analysis.\nResults\nPCA revealed that the global amino acid composition of FF was largely conserved across all groups. However, disease status had a statistically significant but moderate effect on the overall amino acid profile (PERMANOVA, R²=0.081, p = 0.001). After adjusting for BMI, IR was associated with decreased glycine and arginine levels and TD was associated with lower histidine, tryptophan and lysine concentrations. In contrast, EM was characterized by a selective increase in the histidine content. Pathway analysis revealed alterations in branched-chain amino acid (BCAA) metabolism in IR group and broader disruptions in central amino acid metabolism in TD group. Multivariate and ROC analyses indicated limited discriminative performance of individual amino acids (AUC ≤ 0.71), suggesting that metabolic alterations are subtle and distributed across multiple pathways.\nConclusions\nFF amino acid composition is tightly regulated but distinct disease-specific metabolic alterations can be detected in IR, EM and TD. These changes are independent of BMI and reflect coordinated alterations in the metabolism of different amino acids rather than strong individual biomarkers. These results show the sensitivity of the follicular environment to overall metabolic health and support the idea of using multivariable metabolic patterns to better understand reproductive dysfunction.\nSimilar content being viewed by others\nAbbreviations\n- AUC:\n-\nArea under curve\n- ART:\n-\nAssisted reproductive technology\n- BMI:\n-\nBody mass index\n- BCAA:\n-\nBranched-chain amino acids\n- EM:\n-\nEndometriosis\n- FDR:\n-\nFalse discovery rate\n- FF:\n-\nFollicular fluid\n- GZLM:\n-\nGeneralized linear models\n- HOMA-IR:\n-\nHomeostatic model assessment of insulin resistance\n- IR:\n-\nInsulin resistance\n- IVF:\n-\nIn vitro fertilization\n- KEGG:\n-\nKyoto Encyclopedia of Genes and Genomes\n- PLS-DA:\n-\nPartial least squares-discriminant analysis\n- PERMANOVA:\n-\nPermutational multivariate analysis of variance\n- PCA:\n-\nPrincipal component analysis\n- RF:\n-\nRandom Forest\n- ROC:\n-\nReceiver operating characteristics\n- TD:\n-\nThyroid dysfunction\n- UHPLC:\n-\nUltra-high-performance chromatography\n- VIP:\n-\nVariable importance in projection\nAcknowledgements\nNot applicable.\nFunding\nOpen access funding provided by University of Pécs. National Laboratory on Human Reproduction, University of Pécs; Project no. RRF-2.3.1- 21-2022-00012, titled National Laboratory on Human Reproduction, has been implemented with the support provided by the Recovery and Resilience Facility of the European Union within the framework of Program Széchenyi Plan Plus.\nAuthor information\nAuthors and Affiliations\nCorresponding author\nEthics declarations\nEthics approval and consent to participate\nThe study protocol was approved by the Regional Research Ethics Committee of the University of Pécs (No. 4327.316–2900/KK15/2011, approved on 26 April 2012). Detailed information was given to all patients or their next-of-kin regarding our study protocol, while written consent was obtained from all.\nConsent for publication\nNot applicable.\nCompeting interests\nThe authors declare no competing interests.\nAdditional information\nPublisher’s note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\nRights and permissions\nOpen Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.\nAbout this article\nCite this article\nKurdi, C., Hesszenberger, D., Csabai, D. et al. Diagnosis-dependent metabolic reprogramming of follicular fluid. Reprod Biol Endocrinol (2026). https://doi.org/10.1186/s12958-026-01579-0\nReceived:\nAccepted:\nPublished:\nDOI: https://doi.org/10.1186/s12958-026-01579-0","source_license":"CC-BY-4.0","license_restricted":false}