OR27-1 11-Oxygenated C19 Steroids Are the Predominant Androgens Responsible for Hyperandrogenemia in Cushing's Disease

BACKGROUND: Symptoms of hyperandrogenism are common in patients with Cushing's disease (CD), but they cannot be sufficiently explained by measured concentrations of circulating androgens. In this study we analyzed the contribution of 11-oxygenated (11oxC19) androgens to hyperandrogenemia in female patients with CD as well as the influence of treatment with steroidogenesis inhibitors osilodrostat and metyrapone on 11oxC19 and classic androgens. METHODS: In this single-center study, we assessed saliva day profiles of 23 females with treatment naïve CD, 26 female controls, 5 females with CD treated with metyrapone and 5 treated with osilodrostat for cortisol, cortisone, androstenedione (A4), 11-hydroxyandrostenedione (11OHA4), testosterone (T), 11-ketotestosterone (11KT) by by liquid chromatography tandem mass spectrometry as well as morning baseline levels of gonadotropins and estradiol, sex hormone-binding globulin, cortisol anddehydroepiandrosterone sulfate (DHEAS) in serum and adrenocorticotropic hormone in plasma. RESULTS: Treatment naïve females with CD showed significantly elevated area under the curve (AUC) of 11OHA4 and 11KT throughout the day compared to controls (11OHA4 mean rank difference (mrd) 18.13, p = 0.0002; 11KT mrd 17.42; p = 0.0005) whereas A4, T and DHEAS were comparable to controls. Patients with more symptoms of hyperandrogenism displayed higher concentrations of 11oxC19 androgens and had significantly lower SHBG concentrations. Gonadotropin levels were normal in all patients with CD (LH 7.18 U/l (SD 14.28 U/l); FSH 7.68 U/l (SD 12.0 U/l)) and did not correlate with any other parameters. Treatment with osilodrostat and metyrapone efficaciously blocked 11oxC19 synthesis. In metyrapone but not in osilodrostat treatment a trend towards increased concentrations of T and significantly increased A4-concentrations were observed (A4 mrd 23.07, p = 0.0119). CONCLUSION: Hyperandrogenemia in CD is predominantly caused by excess of 11oxC19 androgens. Due to lower compensatory increase of A4 and T, osilodrostat seems to be more suitable for treatment of females with CD and hyperandrogenism than metyrapone. Presentation: Tuesday, June 14, 2022 9:45 a.m. - 10:00 a.m.