The Progesterone Challenge Test as a Functional Biomarker of Endometrial Cancer Risk: Results from a Prospective Feasibility Study

Endometrial cancer (EC) incidence continues to rise globally, driven mainly by obesity. Current diagnostic pathways rely on symptom presentation; no validated approach exists to identify asymptomatic individuals who may benefit from targeted prevention. The Progesterone Challenge Test (PCT) is a physiologic assessment of endometrial hormonal responsiveness that could pragmatically guide EC prevention interventions. The RESToRE study (NCT05651282) prospectively assessed the feasibility of the PCT as a community-based risk-stratification tool for EC prevention in British Columbia, Canada, between 2023 and 2024. Asymptomatic postmenopausal participants, defined by the absence of vaginal bleeding, with body mass index ≥34.9 kg/m² and an intact uterus, completed a 10-day course of oral medroxyprogesterone acetate (MPA) 10 mg daily. Feasibility, tolerability, and acceptability were evaluated. Of 96 eligible individuals, 68 enrolled, 53 initiated, and 51 completed the PCT. Sixteen participants experienced withdrawal bleeding (+PCT) (30.2% of those with evaluable results). All +PCT individuals were referred to a gynecologist for standard-of-care evaluation, including an endometrial biopsy. Among the 15 who underwent biopsy, 2 had a proliferative endometrium, and 1 had simple hyperplasia. Participants and providers found the test acceptable, citing its simplicity and low administrative burden. Side effects were mild (median severity ≤ 3/10), resulting in 3.8% (2/53) of participants discontinuing the MPA. The PCT was feasible, well-tolerated, and acceptable among higher-risk postmenopausal individuals, supporting its use as a physiologic, functional biomarker of endometrial responsiveness. These findings provide early evidence for a scalable, low-cost strategy to identify individuals likely to benefit from targeted EC prevention.