Immunoinflammatory and Metabolic Drivers of Endometrial Hyperplasia: From Unopposed Estrogen to Precision Medicine

Endometrial hyperplasia (EH) is a precursor to carcinoma, with the risk amplified by obesity, polycystic ovary syndrome, insulin resistance, and delayed childbearing through estrogen excess and anovulatory “unopposed estrogen” states. This review synthesizes endocrine, metabolic, molecular, diagnostic, and therapeutic evidence in EH, distinguishing findings from unvalidated mechanisms to inform biomarker development without displacing histopathology. The literature was searched in PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar (January 2000–March 2026; 2020 onward) using terms spanning EH/Endometrial intraepithelial neoplasia, cytokines, oxidative stress, PI3K/AKT/mTOR, obesity, microbiome, and biomarkers; English-language studies, reviews, meta-analyses, and guidelines were weighted toward human EH data, guided by the Scale, without a formal risk-of-bias tool. Evidence supports endocrine driving: estrogen receptor signaling promotes proliferation via cyclins and PI3K/AKT and MAPK pathways, whereas progesterone loss facilitates persistence. EH shows elevated interleukin-6 (IL-6), TNF-α, IL-1β, and IL-8, engaging NF-κB/STAT3 circuits, although limited. Oxidative stress may affect progression through reactive oxygen species-driven peroxidation and DNA (Deoxyribonucleic Acid) damage. Recurrent alterations (PTEN loss; PIK3CA, KRAS, and β-catenin changes) inform the stratification and therapy resistance in atypical EH/Endometrial intraepithelial neoplasia. Histopathology remains central, with immunohistochemistry. Clinically, levonorgestrel-releasing intrauterine system shows superior regression compared to progestins, and metformin is adjunctive. The rate of occult carcinoma at hysterectomy was 45.3%. Fertility-sparing levonorgestrel-releasing intrauterine system is effective but carries a risk of disease progression/recurrence. Overall, EH is hormone-driven and involves metabolic, inflammatory, oxidative, and molecular modifiers. Precision care requires the prospective validation of biomarker panels beyond histology and clinical risk.