Medizinische Klinik and Poliklinik IV, Klinikum der Universität München, LMU München, Munich, Germany.
Division of Pediatric Endocrinology & Diabetology, Laboratory for Translational Hormone Analysis in Pediatric Endocrinology, Steroid Research & Mass Spectrometry Unit, Center of Child and Adolescent Medicine, Justus-Liebig-University, Giessen, Germany.
Eur J Endocrinol. 2022 Sep 29;187(5):663-673. doi: 10.1530/EJE-22-0320. Print 2022 Nov 1.
Symptoms of hyperandrogenism are common in patients with Cushing's disease (CD), yet they are not sufficiently explained by androgen concentrations. In this study, we analyzed the contribution of 11-oxygenated C19 steroids (11oxC19) to hyperandrogenemia in female patients with CD.
We assessed saliva day profiles in females with CD pre (n = 23) and post (n = 13) successful transsphenoidal surgery, 26 female controls, 5 females with CD treated with metyrapone and 5 treated with osilodrostat for cortisol, cortisone, androstenedione (A4), 11-hydroxyandrostenedione (11OHA4), testosterone (TS), 11-ketotestosterone (11KT), as well as metabolites of classic and 11-oxygenated androgens in 24-h urine. In addition, morning baseline levels of gonadotropins and estradiol, sex hormone-binding globulin, cortisol and dehydroepiandrosterone sulfate (DHEAS) in serum and adrenocorticotrophic hormone in plasma in patients and controls were investigated.
Treatment-naïve females with CD showed a significantly elevated area under the curve of 11OHA4 and 11KT in saliva 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, TS and DHEAS were comparable to controls. Gonadotropin concentrations were normal in all patients with CD. After transsphenoidal surgery, 11oxC19 and their metabolites dropped significantly in saliva (11OHA4 P < 0.0001; 11KT P = 0.0010) and urine (11-oxo-androsterone P = 0.0011; 11-hydroxy-androsterone P < 0.0001), treatment with osilodrostat and metyrapone efficaciously blocked 11oxC19 synthesis.
Hyperandrogenemia in CD is predominantly caused by excess of 11oxC19 steroids.
库欣病（CD）患者常有高雄激素血症的症状，但这些症状不能仅用雄激素浓度来解释。在这项研究中，我们分析了 11-氧代 C19 甾体（11oxC19）对 CD 女性患者高雄激素血症的贡献。
我们评估了术前（n=23）和术后（n=13）成功经蝶窦手术的 CD 女性患者、26 名女性对照者、5 名接受美替拉酮治疗和 5 名接受奥曲肽治疗的 CD 女性患者的唾液日内谱，以及 24 小时尿液中经典和 11-氧代雄激素的代谢物。此外，还检测了患者和对照者的血清中促性腺激素和雌二醇、性激素结合球蛋白、皮质醇和硫酸脱氢表雄酮（DHEAS）以及血浆中促肾上腺皮质激素的清晨基线水平。
未经治疗的 CD 女性患者的唾液日内 11OHA4 和 11KT 曲线下面积明显高于对照组（11OHA4 平均秩差（mrd）18.13，P=0.0002；11KT mrd 17.42；P=0.0005），而 A4、TS 和 DHEAS 与对照组相似。所有 CD 患者的促性腺激素浓度均正常。经蝶窦手术后，11oxC19 及其代谢物在唾液（11OHA4 P <0.0001；11KT P=0.0010）和尿液（11-氧代雄甾酮 P=0.0011；11-羟基雄甾酮 P<0.0001）中显著下降，奥曲肽和米托坦的治疗有效地阻断了 11oxC19 的合成。
CD 中的高雄激素血症主要是由 11oxC19 类固醇过多引起的。
