Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians-Universität, Ziemssenstraße 5, München 80336, Germany.
Department for Neurosurgery, University Hospital Tübingen, Hoppe-Seyler-Straße 3, Tübingen 72076, Germany.
EBioMedicine. 2024 Jan;99:104907. doi: 10.1016/j.ebiom.2023.104907. Epub 2023 Dec 20.
Diagnosing Cushing's syndrome (CS) is highly complex. As the diagnostic potential of urinary steroid metabolome analysis by gas chromatography-mass spectrometry (GC-MS) in combination with systems biology has not yet been fully exploited, we studied a large cohort of patients with CS.
We quantified daily urinary excretion rates of 36 steroid hormone metabolites. Applying cluster analysis, we investigated a control group and 168 patients: 44 with Cushing's disease (CD) (70% female), 18 with unilateral cortisol-producing adrenal adenoma (83% female), 13 with primary bilateral macronodular adrenal hyperplasia (PBMAH) (77% female), and 93 ruled-out CS (73% female).
Cluster-Analysis delineated five urinary steroid metabotypes in CS. Metabotypes 1, 2 and 3 revealing average levels of cortisol and adrenal androgen metabolites included patients with exclusion of CS or and healthy controls. Metabotype 4 reflecting moderately elevated cortisol metabolites but decreased DHEA metabolites characterized the patients with unilateral adrenal CS and PBMAH. Metabotype 5 showing strong increases both in cortisol and DHEA metabolites, as well as overloaded enzymes of cortisol inactivation, was characteristic of CD patients. 11-oxygenated androgens were elevated in all patients with CS. The biomarkers THS, F, THF/THE, and (An + Et)/(11β-OH-An + 11β-OH-Et) correctly classified 97% of patients with CS and 95% of those without CS. An inverse relationship between 11-deoxygenated and 11-oxygenated androgens was typical for the ACTH independent (adrenal) forms of CS with an accuracy of 95%.
GC-MS based urinary steroid metabotyping allows excellent identification of patients with endogenous CS and differentiation of its subtypes.
The study was funded by the Else Kröner-Fresenius-Stiftung and the Eva-Luise-und-Horst-Köhler-Stiftung.
库欣综合征（CS）的诊断非常复杂。由于气相色谱-质谱联用（GC-MS）检测尿甾体代谢组分析在结合系统生物学方面的诊断潜力尚未得到充分开发，因此我们对大量 CS 患者进行了研究。
我们定量分析了 36 种类固醇激素代谢物的日常尿排泄率。通过聚类分析，我们对对照组和 168 例患者进行了研究：库欣病（CD）44 例（70%为女性），单侧皮质醇产生肾上腺腺瘤 18 例（83%为女性），原发性双侧大结节性肾上腺增生（PBMAH）13 例（77%为女性），93 例排除 CS（73%为女性）。
聚类分析描绘了 CS 中五种尿甾体代谢型。代谢型 1、2 和 3 显示皮质醇和肾上腺雄激素代谢物的平均水平，包括排除 CS 或健康对照者。代谢型 4 反映中等程度升高的皮质醇代谢物，但降低的 DHEA 代谢物特征是单侧肾上腺 CS 和 PBMAH 患者。代谢型 5 表现为皮质醇和 DHEA 代谢物均显著增加，以及皮质醇失活酶的过载，是 CD 患者的特征。所有 CS 患者的 11-氧化雄激素均升高。生物标志物 THS、F、THF/THE 和（An + Et）/（11β-OH-An + 11β-OH-Et）正确分类了 97%的 CS 患者和 95%的非 CS 患者。11-去氧雄激素与 11-氧化雄激素之间的反比关系是 CS 中 ACTH 非依赖性（肾上腺）形式的典型特征，其准确性为 95%。
基于 GC-MS 的尿甾体代谢分型可极好地识别内源性 CS 患者，并对其亚型进行区分。
本研究由 Else Kröner-Fresenius-Stiftung 和 Eva-Luise-und-Horst-Köhler-Stiftung 资助。
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