Multi-Steroid Profiling and Machine Learning Reveal Androgens as Candidate Biomarkers for Endometrial Cancer Diagnosis: A Case-Control Study

Objective: To evaluate the diagnostic and prognostic potential of preoperative serum steroid levels in endometrial cancer (EC) alone and in combination with clinical parameters and biomarkers CA-125 and HE4. Methods: This single-center observational study included 62 patients with EC and 70 controls with benign uterine conditions who underwent surgery between June 2012 and February 2020. Preoperative serum levels of classic androgens, 11-oxyandrogens, glucocorticoids and mineralocorticoids were measured using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Machine learning was used to assess their diagnostic and prognostic value alone and combined with clinical parameters and tumor biomarkers. Results: Patients with EC had significantly higher serum levels of classic androgens (androstenedione, testosterone), 11-oxyandrogens (11β-hydroxy-androstenedione, 11β-hydroxy-testosterone) and glucocorticoids (17α-hydroxy-progesterone, 11-deoxycortisol) compared to controls. While individual steroids had limited diagnostic value, a multivariate model including classic androgens, CA-125, HE4, BMI and parity achieved an AUC 0.87, 79.1% sensitivity and 74.7% specificity in distinguishing EC from benign uterine condition. This model outperformed our previously published model based on CA-125, HE4 and BMI (AUC: 0.81, p < 0.0001). Prognostically, HE4 was the strongest marker for lymphovascular space invasion (LVSI) (AUC: 0.79) and deep myometrial invasion (MI) (AUC: 0.71). Among steroids, androstenedione was the most predictive of LVSI (AUC: 0.67), while 11β-hydroxy-testosterone was the strongest predictor of deep MI (AUC: 0.64). Conclusions: Patients with EC exhibit distinct steroid hormone profiles. While steroids alone offer modest diagnostic and prognostic value, integrating them into multivariate models improves diagnostic accuracy.