Diagnosis-dependent metabolic reprogramming of follicular fluid

Kurdi C, Csilla Kurdi, Dávid Hesszenberger, Hesszenberger D, Csabai D, Dávid Csabai, Lajtai A, Anikó Lajtai, Ágnes Lakatos, Lakatos Á, Gödöny K, Krisztina Gödöny, Péter Mauchart, Mauchart P, Várnagy Á, Ákos Várnagy, Kovács GL, Gábor L Kovács, Kőszegi T, Tamás Kőszegi
Reproductive biology and endocrinology : RB&E · 2026 · vol. 24(1) · doi:10.1186/s12958-026-01579-0 · PMID:42321783 · PMC13528167
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This study quantified amino acid profiles in follicular fluid from patients with insulin resistance, endometriosis, or thyroid dysfunction, revealing disease-specific alterations independent of BMI.

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This study analyzed 171 follicular fluid samples from patients undergoing IVF to compare amino acid profiles across insulin resistance, endometriosis, and thyroid dysfunction, using targeted UHPLC quantification of 20 proteogenic amino acids and univariate/multivariate statistics with BMI-adjusted generalized linear models plus pathway enrichment. Global amino acid composition was largely conserved, but disease status showed a statistically significant, moderate effect on overall amino acid profiles; after BMI adjustment, insulin resistance corresponded to decreased glycine and arginine, while thyroid dysfunction was associated with lower histidine, tryptophan, and lysine, and endometriosis showed a selective increase in histidine. Pathway analysis indicated branched-chain amino acid metabolism alterations in insulin resistance and broader central amino acid metabolism disruptions in thyroid dysfunction, while ROC and multivariate analyses found limited discrimination by individual amino acids (AUC ≤ 0.71), implying subtle, distributed changes. This paper is centrally about endometriosis — it reports a disease-specific follicular fluid amino acid signature in patients with endometriosis, characterized specifically by increased histidine.

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Abstract

BACKGROUND: The 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. OBJECTIVE: This 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. METHODS: We 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. RESULTS: PCA 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. CONCLUSIONS: FF 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.
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Abstract

Background The 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.

Objective

This 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.

Methods

We 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.

Results

PCA 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.

Conclusions

FF 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. Similar content being viewed by others Abbreviations - AUC: - Area under curve - ART: - Assisted reproductive technology - BMI: - Body mass index - BCAA: - Branched-chain amino acids - EM: - Endometriosis - FDR: - False discovery rate - FF: - Follicular fluid - GZLM: - Generalized linear models - HOMA-IR: - Homeostatic model assessment of insulin resistance - IR: - Insulin resistance - IVF: - In vitro fertilization - KEGG: - Kyoto Encyclopedia of Genes and Genomes - PLS-DA: - Partial least squares-discriminant analysis - PERMANOVA: - Permutational multivariate analysis of variance - PCA: - Principal component analysis - RF: - Random Forest - ROC: - Receiver operating characteristics - TD: - Thyroid dysfunction - UHPLC: - Ultra-high-performance chromatography - VIP: - Variable importance in projection

Acknowledgements

Not applicable. Funding Open 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. Author information Authors and Affiliations Corresponding author Ethics declarations Ethics approval and consent to participate The 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. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Additional information Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Open 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/. About this article Cite this article Kurdi, 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 Received: Accepted: Published: DOI: https://doi.org/10.1186/s12958-026-01579-0

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MeSH descriptors

Amino Acids Amino Acids Amino Acids Amino Acids Amino Acids Amino Acids Amino Acids Amino Acids Amino Acids Amino Acids Amino Acids Amino Acids Amino Acids Amino Acids Amino Acids Amino Acids Amino Acids Amino Acids Amino Acids Amino Acids

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chemicals 15
amino acid palmitoyl amino acid amino acid amino acid glycine arginine histidine tryptophan lysine histidine amino acid amino acid palmitoyl amino acid amino acid palmitoyl amino acid

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