Endometrial Hyperplasia

BackgroundEndometrial hyperplasia (EH) is a uterine pathology representing a spectrum of morphological endometrial alterations. It is predominantly characterized by an increase in the endometrial gland-to-stroma ratio when compared to normal proliferative endometrium. The clinical significance of EH lies in the associated risk of progression to endometrioid endometrial cancer (EC) and 'atypical' forms of EH are regarded as premalignant lesions. Traditional histopathological classification systems for EH exhibit wide and varying degrees of diagnostic reproducibility and, as a consequence, standardized patient management can be challenging.Objective and rationaleEC is the most common gynaecological malignancy in developed countries. The incidence of EC is rising, with alarming increases described in the 40-44-year-old age group. This review appraises the current EH classification systems used to stratify women at risk of malignant progression to EC. In addition, we summarize the evidence base regarding the use of immunohistochemical biomarkers for EH and discuss an emerging role for genomic analysis.Search methodsPubMed, Medline and the Cochrane Database were searched for original peer-reviewed primary and review articles, from January 2000 to January 2016. The following search terms were used: 'endometrial hyperplasia', 'endometrial intraepithelial neoplasia', 'atypical hyperplasia', 'complex atypical hyperplasia', 'biomarker', 'immunohistochemistry', 'progression', 'genomic', 'classification' and 'stratification'.OutcomesRecent changes to EH classification reflect our current understanding of the genesis of endometrioid ECs. The concept of endometrial intraepithelial neoplasia (EIN) as a mutationally activated, monoclonal pre-malignancy represents a fundamental shift from the previously held notion that unopposed oestrogenic stimulation causes ever-increasing hyperplastic proliferation, with accumulating cytological atypia that imperceptibly leads to the development of endometrioid EC. Our review highlights several key biomarker candidates that have been described as both diagnostic tools for EH and markers of progression to EC. We propose that, moving forwards, a 'panel' approach of combinations of the immunohistochemical biomarkers described in this review may be more informative since no single candidate can currently fill the entire role.Wider implicationsEC has historically been considered a predominantly postmenopausal disease. Owing in part to the current unprecedented rates of obesity, we are starting to see signs of a shift towards a rising incidence of EC amongst pre- and peri-menopausal woman. This creates unique challenges both diagnostically and therapeutically. Furthering our understanding of the premalignant stages of EC development will allow us to pursue earlier diagnosis and facilitate appropriate stratification of women at risk of developing EC, permitting timely and appropriate therapeutic interventions.

Endometrial cancers are complex ecosystems composed of cells with distinct phenotypes, genotypes, and epigenetic states. Current models do not adequately reflect oncogenic origin and pathological progression in patients. Here we use single-cell RNA sequencing to profile cells from normal endometrium, atypical endometrial hyperplasia, and endometrioid endometrial cancer (EEC), which altogether represent the step-by-step development of endometrial cancer. We find that EEC originates from endometrial epithelial cells but not stromal cells, and unciliated glandular epithelium is the source of EEC. We also identify LCN2 + /SAA1/2 + cells as a featured subpopulation of endometrial tumorigenesis. Finally, the stromal niche and immune environment changes during EEC progression are described. This study elucidates the evolution of cell populations in EEC development at single-cell resolution, which would provide a direction to facilitate EEC research and diagnosis.

Endometrial hyperplasia (EH) is the precursor lesion for endometrioid adenocarcinoma of the endometrium (EC), which represents the most common malignancy of the female reproductive tract in industrialized countries. The most important risk factor for the development of EH is chronic exposure to unopposed estrogen. Histopathologically, EH can be classified into EH without atypia (benign EH) and atypical EH/endometrial intraepithelial neoplasia (EIN). Clinical management ranges from surveillance or progestin therapy through to hysterectomy, depending on the risk of progression to or concomitant EC and the patient´s desire to preserve fertility. Multiple studies support the efficacy of progestins in treating both benign and atypical EH. This review summarizes the evidence base regarding risk factors and management of EH. Additionally, we performed a systematic literature search of the databases PubMed and Cochrane Controlled Trials register for studies analyzing the efficacy of progestin treatment in women with EH.

ImportanceAs endometrial cancer (EC) incidence rises, particularly among individuals with obesity and metabolic disorders, effective strategies targeting hormonal and metabolic risks are needed.ObjectiveTo evaluate EC risk in patients with endometrial hyperplasia (EH) or benign uterine pathology treated with progestins vs combined progestins and glucagon-like peptide-1 receptor agonists (GLP-1RAs).Design, setting, and participantsThis cohort study used TriNetX to analyze EC and hysterectomy among adult women with EH or benign uterine pathology who received progestins between May 1, 2005 (GLP-1RA approval date), and December 31, 2022. Analyses were based on deidentified electronic health records identified via International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes, and data were obtained on February 23, 2025. Four treatment comparisons were analyzed: GLP-1RA plus progestins vs progestins only; GLP-1RA plus progestins vs metformin progestins; triple therapy (GLP-1RA, metformin, and progestins) vs metformin plus progestins; triple therapy vs progestins only. Subgroup analyses GLP-1RA plus progestins vs progestins only stratified patients by progestin route, risk level, body mass index (BMI), and age.ExposuresGLP-1RAs, progestins, and/or metformin.Main outcomes and measuresThe primary outcome was the incidence of EC. The secondary outcome was the incidence of subsequent hysterectomy.ResultsA total of 18 414 and 426 406 adult female patients received GLP-1RA combined with progestin and progestin alone, respectively (mean [SD] age, 43.1 [10.2] years vs 35.2 [10.9] years). GLP-1RA with progestins was associated with a significantly lower risk of EC compared with progestins only (HR, 0.34 [95% CI, 0.27-0.44]). This protective association remained consistent across subgroups, stratified by progestin route, baseline risk, BMI, and age. GLP-1RA plus progestins also showed a lower EC risk than metformin plus progestins (HR, 0.30 [95% CI, 0.15-0.59]). Triple therapy was more effective in reducing EC risk than dual (metformin plus progestins) (HR, 0.37 [95% CI, 0.25-0.53]) or progestin monotherapy (HR, 0.44 [95% CI, 0.29-0.66]). Hysterectomy rates were lower in the GLP-1RA plus progestins group at 2-year (HR, 0.47 [95% CI, 0.42-0.53]) and 5-year (HR, 0.59 [95% CI, 0.54-0.64]) follow-up.Conclusions and relevanceIn this cohort study of women with benign uterine pathology or endometrial hyperplasia, combined GLP-1RA and progestin was associated with reduced EC risk. Further investigation is warranted to assess its applicability and underlying mechanisms.