Fukuoka Hidenori, Shichi Hiroki, Yamamoto Masaaki, Takahashi Yutaka
Division of Diabetes and Endocrinology, Kobe University Hospital, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Int J Mol Sci. 2020 Nov 30;21(23):9132. doi: 10.3390/ijms21239132.
Cushing's disease caused due to adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (ACTHomas) leads to hypercortisolemia, resulting in increased morbidity and mortality. Autonomous ACTH secretion is attributed to the impaired glucocorticoid negative feedback (glucocorticoid resistance) response. Interestingly, other conditions, such as ectopic ACTH syndrome (EAS) and non-neoplastic hypercortisolemia (NNH, also known as pseudo-Cushing's syndrome) also exhibit glucocorticoid resistance. Therefore, to differentiate between these conditions, several dynamic tests, including those with desmopressin (DDAVP), corticotrophin-releasing hormone (CRH), and Dex/CRH have been developed. In normal pituitary corticotrophs, ACTH synthesis and secretion are regulated mainly by CRH and glucocorticoids, which are the ACTH secretion-stimulating and -suppressing factors, respectively. These factors regulate ACTH synthesis and secretion through genomic and non-genomic mechanisms. Conversely, glucocorticoid negative feedback is impaired in ACTHomas, which could be due to the overexpression of 11β-HSD2, HSP90, or TR4, or loss of expression of CABLES1 or nuclear BRG1 proteins. Genetic analysis has indicated the involvement of several genes in the etiology of ACTHomas, including , , , and . However, the association between glucocorticoid resistance and these genes remains unclear. Here, we review the clinical aspects and molecular mechanisms of ACTHomas and compare them to those of other related conditions.
由分泌促肾上腺皮质激素（ACTH）的垂体腺瘤（ACTH瘤）引起的库欣病会导致皮质醇增多症，从而增加发病率和死亡率。ACTH的自主分泌归因于糖皮质激素负反馈（糖皮质激素抵抗）反应受损。有趣的是，其他情况，如异位ACTH综合征（EAS）和非肿瘤性皮质醇增多症（NNH，也称为假性库欣综合征）也表现出糖皮质激素抵抗。因此，为了区分这些情况，已经开发了几种动态试验，包括使用去氨加压素（DDAVP）、促肾上腺皮质激素释放激素（CRH）和地塞米松/CRH的试验。在正常垂体促肾上腺皮质细胞中，ACTH的合成和分泌主要受CRH和糖皮质激素调节，它们分别是刺激和抑制ACTH分泌的因素。这些因素通过基因组和非基因组机制调节ACTH的合成和分泌。相反，ACTH瘤中糖皮质激素负反馈受损，这可能是由于11β-HSD2、HSP90或TR4的过度表达，或CABLES1或核BRG1蛋白表达缺失所致。基因分析表明，包括 、 、 和 在内的几个基因参与了ACTH瘤的病因。然而，糖皮质激素抵抗与这些基因之间的关联仍不清楚。在这里，我们综述了ACTH瘤的临床方面和分子机制，并将它们与其他相关情况进行比较。
