Introduction/Background Endometrial cancer (EC) is a gynaecological pathology affecting the inner uterine epithelium, for which a global rise in incidence is observed due to demographic changes. The involvement of 11-oxyandrogens - androgen metabolites with an oxygen atom at carbon 11 in EC is unexplored yet might hold diagnostic and prognostic relevance.

Methodology Multi-steroid profiling was conducted by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in a cohort of 70 tumour-free women and 62 EC patients. In vitro metabolism studies were performed to characterize metabolic profiles following incubation with classic androgen and 11-oxyandrogen precursors. Public transcriptomic datasets of primary EC were analysed to assess androgen responsiveness across molecular types and stages.

Results We observed distinct hormonal profiles in EC patients, wherein low-grade cases exhibited an elevated bioactive androgen pool, while high-grade cases had increased levels of 11-oxyandrogen precursors and cortisol compared to tumour-free women. 11β-hydroxylated androgens emerged as EC risk factors, whereas serum testosterone and 11β-hydroxylated testosterone demonstrated good diagnostic potential in a multivariate logistic regression model. Using in vitro models, we showed that endometrial tumours cannot synthesize 11-oxyandrogens from classic androgen precursors, however, can effectively exploit 11-oxyandrogen precursors to create a microenvironment enriched with androgen receptor (AR)-activating 11-oxymetabolites, especially prominent in low-grade tumours and clinically favourable molecular subtypes. Transcriptomic analysis of primary EC unveiled a diminishing tumour responsiveness to (11-oxy)-androgens with increasing tumour grade and stage.

Conclusion We demonstrated distinct hormonal alterations in the androgen metabolome in EC patients. We identified tumours of non-specific molecular profile as EC subset where hormonal therapy might be particularly beneficial. Our findings provide novel insights on the intricate hormonal landscape of EC and propose the further exploration of 11-oxyandrogens and AR as prognostic biomarkers.

Disclosures None.