Re-Evaluating the Progesterone Challenge Test as a Physiologic Marker of Endometrial Cancer Risk: A Systematic Review and Meta-Analysis

<b>Background/Objectives</b>: With the rising incidence of obesity-related endometrial cancer, there is renewed interest in physiologic, low-cost approaches to identify women with hormonally active endometrium who may benefit from early preventive interventions. The progesterone challenge test (PCT), an established clinical tool for evaluating amenorrhea, has been previously proposed as a method to detect endometrial pathology. This study systematically evaluated the diagnostic accuracy of the PCT for detecting endometrial hyperplasia, intraepithelial neoplasia, and carcinoma in asymptomatic postmenopausal women to determine its potential role as a physiologic marker of endometrial cancer risk. <b>Methods</b>: A systematic review and meta-analysis were conducted following PRISMA-DTA guidelines. MEDLINE, EMBASE, EBM Reviews, and CINAHL were searched from inception to 20 January 2025, along with ClinicalTrials.gov and grey literature. Eligible studies prospectively evaluated the PCT with endometrial biopsy as the reference standard. Data extraction and risk-of-bias assessment were performed in duplicate. Risk of bias was assessed using QUADAS-2. Pooled sensitivity, specificity, and predictive values were estimated using hierarchical summary receiver operating characteristic models. <b>Results</b>: Nineteen studies (n = 3902) met the inclusion criteria. The pooled sensitivity and specificity of the PCT for detecting endometrial pathology were 95% (95% CI 86-100%) and 87% (76-96%), respectively. The positive predictive value was 32% (95% CI, 16-50%) and the negative predictive value was 100% (100-100%). When endometrial proliferation was included in the target condition, sensitivity decreased to 82%, but positive predictive value increased to 70%. <b>Conclusions</b>: The PCT shows high diagnostic accuracy for identifying estrogen-driven endometrial pathology in asymptomatic postmenopausal women. Re-evaluating this simple, physiologic test as a functional risk-stratification tool could inform precision prevention strategies for endometrial cancer.