The Physiology Of Hypercortisolism

库欣综合征（CS）与高凝状态相关，导致静脉血栓栓塞（VTE）风险增加。与一般人群相比，未经治疗的活动性CS静脉血栓栓塞发生率高达18倍，而垂体和肾上腺手术后静脉血栓栓塞风险在2.6 - 5.6%之间。有趣的是，手术后静脉血栓栓塞的风险不仅在第一周增加，而且在术后几个月也增加。CS的高凝状态被认为至少部分是由促凝途径和抗凝途径之间的不平衡引起的。然而，并不是在每个CS患者中都观察到活化的部分凝血活酶时间和血浆促凝因子和抗凝因子浓度的变化。只有回顾性研究表明血栓预防可降低CS的静脉血栓栓塞风险。未来的前瞻性研究应评估CS患者血栓预防的最佳时机、持续时间和类型，以改善静脉血栓栓塞相关的发病率和死亡率。

Cushing's syndrome (CS) is associated with a hypercoagulable state resulting in an increased risk on venous thromboembolism (VTE). In patients with untreated active CS VTE incidence is up to 18-fold higher compared to the general population, whereas after pituitary and adrenal surgery a postoperative VTE risk between 2.6 and 5.6% has been reported. Interestingly, after surgery the VTE risk is not only increased in the first week but also during several months postoperatively. The hypercoagulable state in CS is thought to be caused, at least in part, by an imbalance between activity of pro- and anticoagulant pathways. However, changes in activated partial thromboplastin time and plasma concentrations of pro-and anticoagulant factors are not observed in every CS patient. Only retrospective studies have shown that thromboprophylaxis lowers VTE risk in CS. Future prospective studies should asses the optimal timing, duration and type of thromboprophylaxis in CS to improve VTE-related morbidity and mortality. Using single-cell RNA sequencing (RNA-seq) analysis of 27594 cells, we identified CD adenoma transcriptomic signatures compared with adjacent normal cells, with validation by bulk RNA-seq, DNA methylation, qRT-PCR, and immunohistochemistry in 25 corticotrope adenomas. CD adenoma cells include a subpopulation of proliferating, terminally differentiated corticotrophs. We found recurrent promoter hypomethylation and transcriptional upregulation of PMAIP1 (encoding pro-apoptotic BH3-only bcl-2 protein noxa) but paradoxical noxa downregulation. Using primary CD adenoma cell cultures and a corticotroph-enriched mouse cell line, we find that selective proteasomal inhibition with bortezomib stabilizes noxa and induces apoptosis, indicating its utility as an anti-tumor agent.