{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T06:02:07Z","timestamp":1789970527941,"version":"4.0.1"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>Polycystic ovary syndrome(PCOS) is increasingly recognized for its substantial depressive burden, however, the underlying mechanism remains unclear. In this study, the neuro-metabolic pathway was explored to unravel the mechanism in PCOS-related depression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Participants recruited from the UK Biobank comprised a cross-sectional population, the outcome as female depression, with 2,826 individuals among whom 471 diagnosed with PCOS. Progressive regression, interaction and mediation analyses, linearity and threshold examinations, relative weight analysis and principal component analysis(PCA), as well as stratified analyses were conducted in this study.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The two brain magnetic resonance imaging(MRI) metrics as volume of grey matter in frontal orbital cortex(FOC GMVol) and mean thickness of caudalanteriorcingulate(CaudalAntCing Thk) showed prominent links with PCOS-related depression, with CaudalAntCing Thk serving as the final common executor to depression. FOC GMVol and CaudalAntCing Thk interacted with PCOS in a metabolic-dependent and a metabolic-independent way respectively. A PCOS\u00d7free androgen index(FAI)\u00d7FOC GMVol three-way interaction was observer only in normal body mass index(BMI) individuals with high FAI. The FOC GMVol-CaudalAntCing Thk association, correlated with concurrent increases in BMI and FAI, existed exclusively in non-PCOS. Metabolic factors exhibited mediating effects (BMI and FAI) and formed a network among which BMI served as a hub linking the antagonistic FAI and the auxiliary triglyceride-glucose index(TyG), while systemic immune-inflammation index(SII) acted as an independent risk factor irrelevant to PCOS. A two-tiered brain protective hypothesis was proposed against depression: neural compensation reflected the protective FOC GMVol-CaudalAntCing Thk coupling in non-PCOS, and protective threshold patterns of both FOC GMVol and CaudalAntCing Thk in PCOS, with FAI playing pivotal and distinct roles at both peripheral and central levels across the entire pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Given the intricate neuro-metabolic correlates underlying PCOS-related depression, further studies were warranted and a synergistic therapeutic strategy of androgen suppression plus weight management might be considered.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1925127","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T05:34:46Z","timestamp":1789968886000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["From metabolic network to brain loop: unraveling the neuro-metabolic correlates in PCOS-related depression"],"prefix":"10.3389","volume":"17","author":[{"given":"Yi","family":"Cao","sequence":"first","affiliation":[{"name":"Women and Children\u2019s Hospital, Qingdao University","place":["Qingdao, Shandong, China"]},{"name":"Biomedical Center of Qingdao University","place":["Qingdao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoying","family":"Li","sequence":"additional","affiliation":[{"name":"Women and Children\u2019s Hospital, Qingdao University","place":["Qingdao, Shandong, China"]},{"name":"Biomedical Center of Qingdao University","place":["Qingdao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Women and Children\u2019s Hospital, Qingdao University","place":["Qingdao, Shandong, China"]},{"name":"Biomedical Center of Qingdao University","place":["Qingdao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Wen","sequence":"additional","affiliation":[{"name":"Biomedical Center of Qingdao University","place":["Qingdao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Shi","sequence":"additional","affiliation":[{"name":"Biomedical Center of Qingdao University","place":["Qingdao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Xie","sequence":"additional","affiliation":[{"name":"Women and Children\u2019s Hospital, Qingdao University","place":["Qingdao, Shandong, China"]},{"name":"Biomedical Center of Qingdao University","place":["Qingdao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongfeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Health Statistics, Public Health College, Qingdao University","place":["Qingdao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.2139\/ssrn.4689131","article-title":"Recommendations from the 2023 international evidence-based guideline for the assessment and management of polycystic ovary syndrome","volume":"120","author":"Teede","year":"2023","journal-title":"Fertil Steril"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1080\/09513590.2022.2118708","article-title":"Depression, anxiety, body image scores, and sexual dysfunction in patients with polycystic ovary syndrome according to phenotypes","volume":"38","author":"Altuntas","year":"2022","journal-title":"Gynecol Endocrinol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2018.01.038","article-title":"Androgen excess- polycystic ovary syndrome society: position statement on depression, anxiety, quality of life, and eating disorders in polycystic ovary syndrome","volume":"109","author":"Dokras","year":"2018","journal-title":"Fertil Steril"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dex044","article-title":"High prevalence of moderate and severe depressive and anxiety symptoms in polycystic ovary syndrome: a systematic review and meta-analysis","volume":"32","author":"Cooney","year":"2017","journal-title":"Hum Reprod"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s11920-017-0834-2","article-title":"Depression and anxiety in polycystic ovary syndrome: etiology and treatment","volume":"19","author":"Cooney","year":"2017","journal-title":"Curr Psychiatry Rep"},{"key":"B6","doi-asserted-by":"publisher","first-page":"6446","DOI":"10.3390\/jcm12206446","article-title":"Depression in polycystic ovary syndrome: a systematic review and meta-analysis","volume":"12","author":"Dybciak","year":"2023","journal-title":"J Clin Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1111\/cen.70124","article-title":"The relationship between polycystic ovary syndrome (PCOS) and depression","volume":"105","author":"Karampela","year":"2026","journal-title":"Clin Endocrinol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2021.709674","article-title":"The prevalence and factors associated with anxiety-like and depression-like behaviors in women with polycystic ovary syndrome","volume":"12","author":"Lin","year":"2021","journal-title":"Front Psychiatry"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-024-01057-w","article-title":"Polycystic ovary syndrome as a metabolic disease","volume":"21","author":"Helvaci","year":"2025","journal-title":"Nat Rev Endocrinol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"994","DOI":"10.1111\/cns.12835","article-title":"Brain structure alterations in depression: psychoradiological evidence","volume":"24","author":"Zhang","year":"2018","journal-title":"CNS Neurosci Ther"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/s41386-021-01101-7","article-title":"Prefrontal cortex and depression","volume":"47","author":"Pizzagalli","year":"2022","journal-title":"Neuropsychopharmacology"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2025.150101","article-title":"Hyperandrogenism associated deregulation of hippocampal adipokines may contribute to impaired memory function in mice","volume":"1872","author":"Dutta","year":"2026","journal-title":"Brain Res"},{"key":"B13","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1038\/s41380-018-0017-5","article-title":"Depression and obesity: evidence of shared biological mechanisms","volume":"24","author":"Milaneschi","year":"2019","journal-title":"Mol Psychiatry"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1111\/dom.15630","article-title":"Depression and type 2 diabetes: a causal relationship and mechanistic pathway","volume":"26","author":"Khawagi","year":"2024","journal-title":"Diabetes Obes Metab"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2020.01.001","article-title":"Metabolic dysfunction in polycystic ovary syndrome: pathogenic role of androgen excess and potential therapeutic strategies","volume":"35","author":"Sanchez-Garrido","year":"2020","journal-title":"Mol Metab"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.yhbeh.2025.105844","article-title":"Polycystic ovary syndrome: unveiling the multifaceted contributors, mechanisms, and psychological impacts","volume":"176","author":"Bhati","year":"2025","journal-title":"Horm Behav"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.13489","article-title":"Why are women with polycystic ovary syndrome at increased risk of depression? Exploring the etiological maze","volume":"13","author":"Gnawali","year":"2021","journal-title":"Cureus"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa843","article-title":"Polycystic ovary syndrome and brain: an update on structural and functional studies","volume":"106","author":"Saydam","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"key":"B19","doi-asserted-by":"publisher","first-page":"695","DOI":"10.32598\/bcn.2022.2985.1","article-title":"Structural changes in the medial prefrontal cortex and anterior cingulate cortex of dehydroepiandrosterone-induced Wistar rat model of polycystic ovarian syndrome","volume":"13","author":"Igbo","year":"2022","journal-title":"Basic Clin Neurosci"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s40618-024-02329-y","article-title":"Psychological symptoms and brain activity alterations in women with PCOS and their relation to the reduced quality of life: a narrative review","volume":"47","author":"Pinto","year":"2024","journal-title":"J Endocrinol Invest"},{"key":"B21","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1038\/s41380-024-02667-6","article-title":"Integration of valence and conflict processing through cellular-field interactions in human subgenual cingulate during emotional face processing in treatment-resistant depression","volume":"30","author":"Zalasky","year":"2025","journal-title":"Mol Psychiatry"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2024.105583","article-title":"Distinctive intrinsic functional connectivity alterations of anterior cingulate cortex subdivisions in major depressive disorder: a systematic review and meta-analysis","volume":"159","author":"Zhou","year":"2024","journal-title":"Neurosci Biobehav Rev"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2023.1159175","article-title":"Preliminary findings on the effect of childhood trauma on the functional connectivity of the anterior cingulate cortex subregions in major depressive disorder","volume":"14","author":"Rong","year":"2023","journal-title":"Front Psychiatry"},{"key":"B24","doi-asserted-by":"crossref","DOI":"10.1016\/j.biopsych.2023.02.634","article-title":"Anterior cingulate cortex metabolism in adolescent depression","volume":"93","author":"Basg\u00f6ze","year":"2023","journal-title":"Biol Psychiatry"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.jad.2022.01.035","article-title":"Associations between anterior cingulate thickness, cingulum bundle microstructure, melancholia and depression severity in unipolar depression","volume":"301","author":"Mertse","year":"2022","journal-title":"J Affect Disord"},{"key":"B26","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/j.fertnstert.2013.02.054","article-title":"Functional neuroimaging of emotional processing in women with polycystic ovary syndrome: a case-control pilot study","volume":"100","author":"Marsh","year":"2013","journal-title":"Fertil Steril"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-023-02380-w","article-title":"Roles of the medial and lateral orbitofrontal cortex in major depression and its treatment","volume":"29","author":"Zhang","year":"2024","journal-title":"Mol Psychiatry"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcaa196","article-title":"The orbitofrontal cortex: reward, emotion and depression","volume":"2","author":"Rolls","year":"2020","journal-title":"Brain Commun"},{"key":"B29","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1093\/scan\/nsaa014","article-title":"Functional connectivity of the right inferior frontal gyrus and orbitofrontal cortex in depression","volume":"15","author":"Rolls","year":"2020","journal-title":"Soc Cogn Affect Neurosci"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2019-00065","article-title":"Regional cerebral activation accompanies sympathoexcitation in women with polycystic ovary syndrome","volume":"104","author":"Lansdown","year":"2019","journal-title":"J Clin Endocrinol Metab"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2018.00279","article-title":"Androgen regulation of the mesocorticolimbic system and executive function","volume":"9","author":"Tobiansky","year":"2018","journal-title":"Front Endocrinol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2020.117087","article-title":"The influence of microsatellite polymorphisms in sex steroid receptor genes ESR1, ESR2 and AR on sex differences in brain structure","volume":"221","author":"Tan","year":"2020","journal-title":"Neuroimage"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.2139\/ssrn.3506198","article-title":"Common and distinct patterns of intrinsic brain activity alterations in major depression and bipolar disorder: voxel-based meta-analysis","volume":"10","author":"Gong","year":"2020","journal-title":"Transl Psychiatry"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaa106","article-title":"Blunted medial prefrontal cortico-limbic reward-related effective connectivity and depression","volume":"143","author":"Rupprechter","year":"2020","journal-title":"Brain"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2022.102216","article-title":"The neural substrate and underlying mechanisms of executive control fluctuations in primates","volume":"209","author":"Mansouri","year":"2022","journal-title":"Prog Neurobiol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2017.10.042","article-title":"Interaction of the left dorsolateral prefrontal cortex (l-DLPFC) and right orbitofrontal cortex (OFC) in hot and cold executive functions: evidence from transcranial direct current stimulation (tDCS)","volume":"369","author":"Nejati","year":"2018","journal-title":"Neuroscience"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.yfrne.2025.101203","article-title":"The overlooked mental health burden of polycystic ovary syndrome: neurobiological insights into PCOS-related depression","volume":"78","author":"Dub\u00e9-Zinatelli","year":"2025","journal-title":"Front Neuroendocrinol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1002\/ijgo.14988","article-title":"New insights into the interaction between polycystic ovary syndrome and psychiatric disorders: a narrative review","volume":"164","author":"Hu","year":"2024","journal-title":"Int J Gynecol Obstet"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1007\/s10787-026-02117-5","article-title":"Polycystic ovary syndrome (PCOS): current insights, emerging therapeutics, and future treatment strategies","volume":"34","author":"Panchpuri","year":"2026","journal-title":"Inflammopharmacology"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1007\/s43032-021-00765-2","article-title":"PCOS and depression: common links and potential targets","volume":"29","author":"Kolhe","year":"2022","journal-title":"Reprod Sci"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2022.1001484","article-title":"Depression in polycystic ovary syndrome: focusing on pathogenesis and treatment","volume":"13","author":"Xing","year":"2022","journal-title":"Front Psychiatry"},{"key":"B42","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1016\/j.jpsychires.2023.05.034","article-title":"Obesity as a causal risk factor for depression: systematic review and meta-analysis of Mendelian randomization studies and implications for population mental health","volume":"163","author":"Jokela","year":"2023","journal-title":"J Psychiatr Res"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1007\/s13679-024-00603-x","article-title":"Depression and obesity","volume":"14","author":"Gerardo","year":"2025","journal-title":"Curr Obes Rep"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2018.07.200","article-title":"Clinical course of depression symptoms and predictors of enduring depression risk in women with polycystic ovary syndrome: results of a longitudinal study","volume":"111","author":"Greenwood","year":"2019","journal-title":"Fertil Steril"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1007\/s43032-019-00061-0","article-title":"Disparate relationship of sexual satisfaction, self-esteem, anxiety, and depression with endocrine profiles of women with or without PCOS","volume":"27","author":"Glowinska","year":"2020","journal-title":"Reprod Sci"},{"key":"B46","article-title":"Differences in the psychological and hormonal presentation of lean and obese patients with polycystic ovary syndrome","volume":"34","author":"Komarowska","year":"2013","journal-title":"Neuroendocrinol Lett"},{"key":"B47","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.psyneuen.2017.12.013","article-title":"Longitudinal change instead of baseline testosterone predicts depressive symptoms","volume":"89","author":"Kische","year":"2018","journal-title":"Psychoneuroendocrinology"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.jad.2018.11.052","article-title":"Prospective associations of androgens and sex hormone-binding globulin with 12-month, lifetime and incident anxiety and depressive disorders in men and women from the general population","volume":"245","author":"Asselmann","year":"2019","journal-title":"J Affect Disord"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-021-01249-2","article-title":"Plasma androgens and the presence and course of depression in a large cohort of women","volume":"11","author":"de Wit","year":"2021","journal-title":"Transl Psychiatry"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.652559","article-title":"The effect of free androgen index on the quality of life of women with polycystic ovary syndrome: a cross-sectional study","volume":"12","author":"Abdalla","year":"2021","journal-title":"Front Physiol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2016-1896","article-title":"Weight loss and lowering androgens predict improvements in health-related quality of life in women with PCOS","volume":"101","author":"Dokras","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-63166-w","article-title":"Effects of weight loss intervention on anxiety, depression and quality of life in women with severe obesity and polycystic ovary syndrome","volume":"14","author":"Kataoka","year":"2024","journal-title":"Sci Rep"},{"key":"B53","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1055\/s-0043-1777720","article-title":"Considerations in the treatment of depression and anxiety in women with PCOS","volume":"41","author":"Alur-Gupta","year":"2023","journal-title":"Semin Reprod Med"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1925127\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T05:34:49Z","timestamp":1789968889000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1925127\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,21]]},"references-count":53,"alternative-id":["10.3389\/fendo.2026.1925127"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1925127","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,21]]},"article-number":"1925127"}}