Thomas Natalie, Ubhayasekera S J Kumari A, Armstrong Christopher W, Huang Katherine, Bergquist Jonas
Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC, 3010, Australia.
Analytical Chemistry and Neurochemistry, Department of Chemistry - BMC, Uppsala University, Box 599, Uppsala, 75124, Sweden.
J Transl Med. 2025 Jul 25;23(1):829. doi: 10.1186/s12967-025-06841-4.
Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a multisystem disorder characterised by unrelenting fatigue, post-exertional malaise, and dysfunction across immune, nervous, metabolism, and endocrine systems. Given the broad role of steroid hormones in regulating these systems, this study investigated differences in the steroid metabolome and network dynamics between ME/CFS patients and matched controls.
Blood plasma steroid levels were quantified using Ultra-Performance Supercritical Fluid Chromatography- Tandem Mass Spectrometry (UPSFC-MS/MS) in ME/CFS patients (n = 24) and age and gender matched controls (n = 24). Group comparisons of absolute steroid concentrations were performed using Mann-Whitney U tests. Partial Spearman correlation networks were evaluated to examine direct associations between steroids within each group, and centrality metrics were used to evaluate structural differences. Steroid-steroid ratios were analysed to reflect biochemical relationships. Multivariate analysis with Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA) was also conducted.
No significant group differences in absolute steroid concentrations were observed following FDR correction. However, network analysis revealed a marked reduction in direct steroid-steroid relationships in ME/CFS, with controls exhibiting 52 significant partial correlations, while the ME/CFS group retained only one (cortisol - corticosterone). Centrality analysis further revealed a shift in network structure, with cortisone emerging as highly central in ME/CFS (degree = 7, betweenness = 16.7), despite being peripheral in controls, and progesterone showing reduced integration in ME/CFS (degree = 3 vs. 12, eigenvector = 0.40 vs. 0.93). Steroid-steroid ratio analysis revealed a higher cortisol-to-pregnanolone ratio and a lower pregnanolone-to-progesterone ratio in ME/CFS, although these findings did not remain significant after FDR correction. OPLS-DA indicated a modest relationship between steroid levels and group classification (R²Y = 22.8%), but negative Q² values suggested poor predictive power.
Despite no significant differences in absolute steroid levels, network analysis revealed profound disruptions in steroid-steroid relationships in ME/CFS compared to controls, suggesting disrupted steroid homeostasis. Collectively the results suggest dysregulation of HPA axis function and progestogen pathways, as demonstrated by altered partial correlations, centrality profiles, and steroid ratios. These findings illustrate the importance of hormone network dynamics in ME/CFS pathophysiology and underscores the need for more research into steroid metabolism.
肌痛性脑脊髓炎/慢性疲劳综合征（ME/CFS）是一种多系统疾病，其特征为持续疲劳、运动后不适，以及免疫、神经、代谢和内分泌系统功能障碍。鉴于类固醇激素在调节这些系统中发挥广泛作用，本研究调查了ME/CFS患者与匹配对照组之间类固醇代谢组和网络动力学的差异。
使用超高效超临界流体色谱-串联质谱法（UPSFC-MS/MS）对24例ME/CFS患者及年龄和性别匹配的24例对照组的血浆类固醇水平进行定量。使用曼-惠特尼U检验对类固醇绝对浓度进行组间比较。评估偏斯皮尔曼相关网络以检查每组内类固醇之间的直接关联，并使用中心性指标评估结构差异。分析类固醇-类固醇比率以反映生化关系。还进行了正交偏最小二乘判别分析（OPLS-DA）的多变量分析。
经FDR校正后，未观察到类固醇绝对浓度存在显著组间差异。然而，网络分析显示ME/CFS中类固醇-类固醇直接关系显著减少，对照组有52个显著的偏相关性，而ME/CFS组仅保留一个（皮质醇-皮质酮）。中心性分析进一步揭示了网络结构的转变：可的松在ME/CFS中成为高度中心节点（度=7，中介中心性=16.7），而在对照组中处于边缘位置；孕酮在ME/CFS中的整合度降低（度=3对12，特征向量中心性=0.40对0.93）。类固醇-类固醇比率分析显示ME/CFS中皮质醇与孕烷醇酮的比率较高，孕烷醇酮与孕酮的比率较低，尽管这些发现经FDR校正后不再显著。OPLS-DA表明类固醇水平与组分类之间存在适度关系（R²Y=22.8%），但负Q²值表明预测能力较差。
尽管类固醇绝对水平无显著差异，但网络分析显示与对照组相比，ME/CFS中类固醇-类固醇关系存在严重破坏，提示类固醇稳态受到干扰。总体结果表明HPA轴功能和孕激素途径失调，这通过改变的偏相关性、中心性分布和类固醇比率得以证明。这些发现说明了激素网络动力学在ME/CFS病理生理学中的重要性，并强调了对类固醇代谢进行更多研究的必要性。
