{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T22:14:33Z","timestamp":1790460873476,"version":"4.1.0"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"7","license":[{"start":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T00:00:00Z","timestamp":1750291200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T00:00:00Z","timestamp":1750291200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100008347","name":"Bezmialem Vakif University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100008347","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Reprod. Sci."],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Infertility affects approximately 15% of reproductive-age couples, with polycystic ovary syndrome and poor ovarian reserve being major contributing factors. Metabolomic profiling of follicular fluid offers insights into the underlying metabolic disturbances associated with these infertility phenotypes. This study aims to identify metabolic biomarkers distinguishing PCOS, POR, and male factor infertility, which may facilitate improved diagnostic and therapeutic strategies.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>A total of 119 participants were categorized into three groups: PCOS (<jats:italic>n<\/jats:italic> = 39), POR (<jats:italic>n<\/jats:italic> = 40), and NOR (<jats:italic>n<\/jats:italic> = 40). Liquid chromatography\u2013high-resolution mass spectrometry was used for untargeted metabolomic profiling. Metabolites were identified using HMDB, MassBank, and MoNA, while pathway analysis was performed using KEGG. Statistical analyses were conducted using R and Python, including one-way ANOVA, t-tests, and Mann-Whitney U tests, with False Discovery Rate correction applied.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Distinct metabolic alterations were observed among the groups. Trehalose-6-phosphate, taurocholate, and N,N-dimethylglycine emerged as the most significantly altered metabolites, showing strong discriminatory potential between PCOS and POR. PCOS patients exhibited reduced levels of taurocholate, mycalemide, and trehalose-6-phosphate, whereas NOR patients showed elevated levels of N,N-dimethylglycine and argininosuccinate. The POR group demonstrated increased levels of 1-methyl-2-pyrrolidone and haplopine, along with a broader metabolite distribution.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>This study reveals phenotype-specific metabolic signatures in PCOS and POR, identifying taurocholate, mycalemide, and N,N-dimethylglycine as potential follicular biomarkers. These findings contribute to a deeper understanding of the metabolic basis of infertility and highlight the potential of follicular fluid metabolomics for precision medicine in reproductive health.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s43032-025-01908-5","type":"journal-article","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T13:07:08Z","timestamp":1750338428000},"page":"2270-2282","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Mass Spectrometry-Based Untargeted Metabolomics Identifies Distinct Metabolic Signatures in Infertility: A Comparative Analysis of PCOS, POR, and NOR"],"prefix":"10.1007","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4810-6771","authenticated-orcid":false,"given":"Metin","family":"Demirel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0818-7714","authenticated-orcid":false,"given":"Mehtap","family":"Alim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3201-5923","authenticated-orcid":false,"given":"Fatmanur","family":"Koktasoglu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3874-8797","authenticated-orcid":false,"given":"Nil","family":"Atakul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ebru","family":"Guner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayse Nur I\u015f\u0131k","family":"Ayd\u0131n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanem Naz","family":"Kafali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0934-4278","authenticated-orcid":false,"given":"Yild\u0131z","family":"Atamer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1235-3957","authenticated-orcid":false,"given":"Sahabettin","family":"Selek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,19]]},"reference":[{"key":"1908_CR1","volume-title":"Infertility prevalence estimates, 1990\u20132021","author":"World Health Organization","year":"2023","unstructured":"World Health Organization. Infertility prevalence estimates, 1990\u20132021. World Health Organization; 2023."},{"key":"1908_CR2","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1210\/er.2015-1018","volume":"36","author":"DA Dumesic","year":"2015","unstructured":"Dumesic DA, Oberfield SE, Stener-Victorin E, Marshall JC, Laven JS, Legro RS. Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome. Endocr Rev. 2015;36:487\u2013525. https:\/\/doi.org\/10.1210\/er.2015-1018.","journal-title":"Endocr Rev"},{"key":"1908_CR3","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1093\/humrep\/deh098","volume":"19","author":"The Rotterdam ESHRE\/ASRM-sponsored PCOS Consensus Workshop Group","year":"2004","unstructured":"The Rotterdam ESHRE\/ASRM-sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19:41\u20137. https:\/\/doi.org\/10.1093\/humrep\/deh098.","journal-title":"Hum Reprod"},{"key":"1908_CR4","doi-asserted-by":"publisher","first-page":"1616","DOI":"10.1093\/humrep\/der092","volume":"26","author":"AP Ferraretti","year":"2011","unstructured":"Ferraretti AP, La Marca A, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L, et al. ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod. 2011;26:1616\u201324. https:\/\/doi.org\/10.1093\/humrep\/der092.","journal-title":"Hum Reprod"},{"key":"1908_CR5","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1210\/er.2009-0006","volume":"30","author":"FJ Broekmans","year":"2009","unstructured":"Broekmans FJ, Soules MR, Fauser BC. Ovarian aging: mechanisms and clinical consequences. Endocr Rev. 2009;30:465\u201393. https:\/\/doi.org\/10.1210\/er.2009-0006.","journal-title":"Endocr Rev"},{"key":"1908_CR6","doi-asserted-by":"publisher","first-page":"109453","DOI":"10.1016\/j.abb.2022.109453","volume":"732","author":"H Shen","year":"2022","unstructured":"Shen H, Wang L, Gao M, Wei L, Liu A, Wang B, et al. The follicular fluid metabolome in infertile individuals between polycystic ovary syndrome and diminished ovarian reserve. Arch Biochem Biophys. 2022;732:109453. https:\/\/doi.org\/10.1016\/j.abb.2022.109453.","journal-title":"Arch Biochem Biophys"},{"key":"1908_CR7","doi-asserted-by":"publisher","first-page":"1810","DOI":"10.3390\/biomedicines12081810","volume":"12","author":"J Yu","year":"2024","unstructured":"Yu J, Wei Y, Zhang Z, Chen J, Fu R, Ye P, et al. Metabolomic analysis of follicular fluid in normal-weight patients with polycystic ovary syndrome. Biomedicines. 2024;12:1810. https:\/\/doi.org\/10.3390\/biomedicines12081810.","journal-title":"Biomedicines"},{"key":"1908_CR8","doi-asserted-by":"publisher","first-page":"2534","DOI":"10.1093\/bioinformatics\/btn323","volume":"24","author":"D Kessner","year":"2008","unstructured":"Kessner D, Chambers M, Burke R, Agus D, Mallick P. ProteoWizard: open source software for rapid proteomics tools development. Bioinformatics. 2008;24:2534\u20136. https:\/\/doi.org\/10.1093\/bioinformatics\/btn323.","journal-title":"Bioinformatics"},{"key":"1908_CR9","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1038\/nmeth.3393","volume":"12","author":"H Tsugawa","year":"2015","unstructured":"Tsugawa H, Cajka T, Kind T, Ma Y, Higgins B, Ikeda K, et al. MS-DIAL: data-independent MS\/MS deconvolution for comprehensive metabolome analysis. Nat Methods. 2015;12:523\u20136. https:\/\/doi.org\/10.1038\/nmeth.3393.","journal-title":"Nat Methods"},{"key":"1908_CR10","doi-asserted-by":"publisher","first-page":"4365","DOI":"10.1038\/s41467-022-32155-w","volume":"13","author":"X Shen","year":"2022","unstructured":"Shen X, Yan H, Wang C, Gao P, Johnson CH, Snyder MP. TidyMass an object-oriented reproducible analysis framework for LC-MS data. Nat Commun. 2022;13:4365. https:\/\/doi.org\/10.1038\/s41467-022-32155-w.","journal-title":"Nat Commun"},{"key":"1908_CR11","doi-asserted-by":"publisher","first-page":"W398","DOI":"10.1093\/nar\/gkae253","volume":"52","author":"Z Pang","year":"2024","unstructured":"Pang Z, Lu Y, Zhou G, Hui F, Xu L, Viau C, et al. MetaboAnalyst 6.0: towards a unified platform for metabolomics data processing, analysis and interpretation. Nucleic Acids Res. 2024;52:W398\u2013406. https:\/\/doi.org\/10.1093\/nar\/gkae253.","journal-title":"Nucleic Acids Res"},{"key":"1908_CR12","doi-asserted-by":"publisher","first-page":"e4993","DOI":"10.1002\/bmc.4993","volume":"35","author":"E Hou","year":"2021","unstructured":"Hou E, Zhao Y, Hang J, Qiao J. Metabolomics and correlation network analysis of follicular fluid reveals associations between l-tryptophan, l-tyrosine and polycystic ovary syndrome. Biomed Chromatogr. 2021;35:e4993. https:\/\/doi.org\/10.1002\/bmc.4993.","journal-title":"Biomed Chromatogr"},{"key":"1908_CR13","doi-asserted-by":"publisher","first-page":"6877541","DOI":"10.1155\/2022\/6877541","volume":"2022","author":"R Liu","year":"2022","unstructured":"Liu R, Bai S, Zheng S, Zhu X, Zhang Y, Xu B, et al. Identification of the metabolomics signature of human follicular fluid from PCOS women with insulin resistance. Dis Markers. 2022;2022:6877541. https:\/\/doi.org\/10.1155\/2022\/6877541.","journal-title":"Dis Markers"},{"key":"1908_CR14","doi-asserted-by":"publisher","first-page":"1254","DOI":"10.3390\/biomedicines10061254","volume":"10","author":"AT Brinca","year":"2022","unstructured":"Brinca AT, Ramalhinho AC, Sousa A, Oliani AH, Breitenfeld L, Passarinha LA, et al. Follicular fluid: a powerful tool for the understanding and diagnosis of polycystic ovary syndrome. Biomedicines. 2022;10:1254. https:\/\/doi.org\/10.3390\/biomedicines10061254.","journal-title":"Biomedicines"},{"key":"1908_CR15","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1007\/s11306-019-1481-x","volume":"15","author":"MA Castiglione Morelli","year":"2019","unstructured":"Castiglione Morelli MA, Iuliano A, Schettini SCA, Petruzzi D, Ferri A, Colucci P, et al. NMR metabolic profiling of follicular fluid for investigating the different causes of female infertility: a pilot study. Metabolomics. 2019;15:19. https:\/\/doi.org\/10.1007\/s11306-019-1481-x.","journal-title":"Metabolomics."},{"key":"1908_CR16","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/j.freeradbiomed.2015.05.013","volume":"86","author":"H Zhao","year":"2015","unstructured":"Zhao H, Zhao Y, Li T, Li M, Li J, Li R, et al. Metabolism alteration in follicular niche: The nexus among intermediary metabolism, mitochondrial function, and classic polycystic ovary syndrome. Free Radic Biol Med. 2015;86:295\u2013307. https:\/\/doi.org\/10.1016\/j.freeradbiomed.2015.05.013.","journal-title":"Free Radic Biol Med"},{"key":"1908_CR17","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1186\/s12958-019-0490-y","volume":"17","author":"Z Sun","year":"2019","unstructured":"Sun Z, Chang HM, Wang A, Song J, Zhang X, Guo J, et al. Identification of potential metabolic biomarkers of polycystic ovary syndrome in follicular fluid by SWATH mass spectrometry. Reprod Biol Endocrinol. 2019;17:45. https:\/\/doi.org\/10.1186\/s12958-019-0490-y.","journal-title":"Reprod Biol Endocrinol"},{"key":"1908_CR18","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1016\/j.cca.2019.11.016","volume":"502","author":"X Chen","year":"2020","unstructured":"Chen X, Lu T, Wang X, Sun X, Zhang J, Zhou K, et al. Metabolic alterations associated with polycystic ovary syndrome: A UPLC Q-Exactive based metabolomic study. Clin Chim Acta. 2020;502:280\u20136. https:\/\/doi.org\/10.1016\/j.cca.2019.11.016.","journal-title":"Clin Chim Acta"},{"key":"1908_CR19","doi-asserted-by":"publisher","first-page":"818888","DOI":"10.3389\/fendo.2022.818888","volume":"13","author":"Y Huang","year":"2022","unstructured":"Huang Y, Tu M, Qian Y, Ma J, Chen L, Liu Y, et al. Age-dependent metabolomic profile of the follicular fluids from women undergoing assisted reproductive technology treatment. Front Endocrinol. 2022;13:818888. https:\/\/doi.org\/10.3389\/fendo.2022.818888.","journal-title":"Front Endocrinol"},{"key":"1908_CR20","doi-asserted-by":"publisher","first-page":"1132621","DOI":"10.3389\/fendo.2023.1132621","volume":"14","author":"J Li","year":"2023","unstructured":"Li J, Zhang Z, Wei Y, Zhu P, Yin T, Wan Q. Metabonomic analysis of follicular fluid in patients with diminished ovarian reserve. Front Endocrinol. 2023;14:1132621. https:\/\/doi.org\/10.3389\/fendo.2023.1132621.","journal-title":"Front Endocrinol"},{"key":"1908_CR21","doi-asserted-by":"publisher","first-page":"103762","DOI":"10.1016\/j.rbmo.2023.103762","volume":"48","author":"J Fiscus","year":"2024","unstructured":"Fiscus J, Fraison E, Renault L, Salle B, Panthu B, Labrune E. Metabolic signature of follicular fluid in infertility-related diseases: a narrative review. Reprod Biomed Online. 2024;48:103762. https:\/\/doi.org\/10.1016\/j.rbmo.2023.103762.","journal-title":"Reprod Biomed Online"},{"key":"1908_CR22","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/j.jsbmb.2018.08.008","volume":"185","author":"L Liu","year":"2019","unstructured":"Liu L, Yin TL, Chen Y, Li Y, Yin L, Ding J, et al. Follicular dynamics of glycerophospholipid and sphingolipid metabolisms in polycystic ovary syndrome patients. J Steroid Biochem Mol Biol. 2019;185:142\u20139. https:\/\/doi.org\/10.1016\/j.jsbmb.2018.08.008.","journal-title":"J Steroid Biochem Mol Biol"},{"key":"1908_CR23","doi-asserted-by":"publisher","first-page":"845","DOI":"10.3390\/metabo11120845","volume":"11","author":"X Yang","year":"2021","unstructured":"Yang X, Wu R, Qi D, Fu L, Song T, Wang Y, et al. Profile of bile acid metabolomics in the follicular fluid of PCOS patients. Metabolites. 2021;11:845. https:\/\/doi.org\/10.3390\/metabo11120845.","journal-title":"Metabolites"},{"key":"1908_CR24","doi-asserted-by":"publisher","first-page":"117860","DOI":"10.1016\/j.cca.2024.117860","volume":"557","author":"X Liu","year":"2024","unstructured":"Liu X, Zhang C, Huang J, Liu H, Li B, Zhang F, et al. Biomarkers identification in follicular fluid in relation to live birth in in vitro fertilization of women with polycystic ovary syndrome in different subtypes by using UPLC-MS method. Clin Chim Acta. 2024;557:117860. https:\/\/doi.org\/10.1016\/j.cca.2024.117860.","journal-title":"Clin Chim Acta"},{"key":"1908_CR25","doi-asserted-by":"publisher","first-page":"214","DOI":"10.3390\/biomedicines13010214","volume":"13","author":"A Potiris","year":"2025","unstructured":"Potiris A, Stavros S, Alyfanti E, Machairiotis N, Drakaki E, Zikopoulos A, et al. Metabolomics-driven insights into biomarkers for poor ovarian response: a narrative review. Biomedicines. 2025;13:214. https:\/\/doi.org\/10.3390\/biomedicines13010214.","journal-title":"Biomedicines"},{"key":"1908_CR26","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1186\/s12958-021-00825-x","volume":"19","author":"C Liang","year":"2021","unstructured":"Liang C, Zhang X, Qi C, Hu H, Zhang Q, Zhu X, et al. UHPLC-MS-MS analysis of oxylipins metabolomics components of follicular fluid in infertile individuals with diminished ovarian reserve. Reprod Biol Endocrinol. 2021;19:143. https:\/\/doi.org\/10.1186\/s12958-021-00825-x.","journal-title":"Reprod Biol Endocrinol"},{"key":"1908_CR27","doi-asserted-by":"publisher","first-page":"774667","DOI":"10.3389\/fendo.2021.774667","volume":"12","author":"H Song","year":"2021","unstructured":"Song H, Qin Q, Yuan C, Li H, Zhang F, Fan L. Metabolomic profiling of poor ovarian response identifies potential predictive biomarkers. Front Endocrinol. 2021;12:774667. https:\/\/doi.org\/10.3389\/fendo.2021.774667.","journal-title":"Front Endocrinol"},{"key":"1908_CR28","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1186\/s13048-023-01166-6","volume":"16","author":"V Viardot-Foucault","year":"2023","unstructured":"Viardot-Foucault V, Zhou J, Bi D, Takinami Y, Chan JKY, Lee YH. Dehydroepiandrosterone supplementation and the impact of follicular fluid metabolome and cytokinome profiles in poor ovarian responders. J Ovarian Res. 2023;16:107. https:\/\/doi.org\/10.1186\/s13048-023-01166-6.","journal-title":"J Ovarian Res"},{"key":"1908_CR29","doi-asserted-by":"publisher","first-page":"328","DOI":"10.3390\/jcm13020328","volume":"13","author":"A Potiris","year":"2024","unstructured":"Potiris A, Perros P, Drakaki E, Mavrogianni D, Machairiotis N, Sfakianakis A, et al. Investigating the association of assisted reproduction techniques and adverse perinatal outcomes. J Clin Med. 2024;13:328. https:\/\/doi.org\/10.3390\/jcm13020328.","journal-title":"J Clin Med"}],"container-title":["Reproductive Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s43032-025-01908-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s43032-025-01908-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s43032-025-01908-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T18:24:28Z","timestamp":1752776668000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s43032-025-01908-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,19]]},"references-count":29,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2025,7]]}},"alternative-id":["1908"],"URL":"https:\/\/doi.org\/10.1007\/s43032-025-01908-5","relation":{},"ISSN":["1933-7191","1933-7205"],"issn-type":[{"value":"1933-7191","type":"print"},{"value":"1933-7205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,19]]},"assertion":[{"value":"21 February 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 June 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 June 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no conflicts of interest related to this study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of Interest"}},{"value":"This study was approved by the Research Ethics Committee of Bezmialem Vak\u0131f University (Approval Number: 173773)","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"All participants provided written informed consent prior to their inclusion in the study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate"}},{"value":"All authors have reviewed and approved the manuscript for publication.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}}]}}