{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T15:52:50Z","timestamp":1792165970452,"version":"4.4.0"},"reference-count":261,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T00:00:00Z","timestamp":1760227200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Polycystic ovary syndrome (PCOS) is a systemic metabolic and endocrine disorder that significantly disrupts reproductive physiology and endometrial function. In this narrative review, we examine the molecular impact of metabolic and hormonal imbalances on the endometrium of women with PCOS. We investigate the specific mechanisms that delineate how hyperinsulinemia and insulin resistance, chronic low-grade inflammation, and estrogen\/progesterone\/androgen imbalance contribute to altered epigenetic, transcriptomic, metabolomic, and signaling profiles in a wide array of different cell types within endometrial tissues. The synergistic interplay between upregulated inflammatory cytokines (e.g., IL-1,2,6,8,17,18, and TNF-\u03b1), along with key changes in critical molecular pathways associated with hyperinsulinemia and insulin resistance (e.g., PI3K\/AKT\/MAPK, and Wnt\/\u03b2-catenin), in addition to aberrant sex steroid hormone signaling (e.g., CYP19A1, COX-2, PGE2, HOXA10, 11\u03b2HSD2), promotes deleterious changes within the endometrial microenvironment. These anomalies underpin a spectrum of clinical manifestations observed in women with PCOS at each stage of the life course, including abnormal uterine bleeding in reproductive-age women, impaired decidualization in pregnancy, and altered postmenopausal endometrial physiology. Clinically, these alterations are associated with abnormal uterine bleeding, subfertility, implantation failure, miscarriage, pregnancy complications, and postmenopausal endometrial hyperplasia and cancer. Overall, our review provides novel insights into the molecular mechanisms linking systemic metabolic and endocrine dysfunction with endometrial pathology in PCOS and has broader implications that apply to all women.<\/jats:p>","DOI":"10.3390\/ijms26209926","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T16:13:03Z","timestamp":1760717583000},"page":"9926","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Molecular Impact of Metabolic and Endocrine Disturbance on Endometrial Function in Polycystic Ovary Syndrome"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5018-5555","authenticated-orcid":false,"given":"Jim","family":"Parker","sequence":"first","affiliation":[{"name":"School of Medicine, University of Wollongong, Wollongong 2522, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"Faculty of Science and Technology, University of Canberra, Canberra 2617, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5255-0522","authenticated-orcid":false,"given":"Talat","family":"Uppal","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Sciences, Macquarie University, Macquarie Park, NSW 2109, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelton","family":"Tremellen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology and Reproductive Medicine, Flinders University, Bedford Park, SA 5042, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Parker, J., O\u2019Brien, C., Hawrelak, J., and Gersh, F.L. 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