Glucocorticoids, their uses, sexual dimorphisms, and diseases: new concepts, mechanisms, and discoveries.
Glucocorticoids, their uses, sexual dimorphisms, and diseases: new concepts, mechanisms, and discoveries.
复制标题
糖皮质激素、其用途、性别二态性和疾病：新概念、机制和发现。
DOI：
10.1152/physrev.00021.2023
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发表时间：
2024
影响因子：
33.6
通讯作者：
HindsJr,TerryD
中科院分区：
文献类型：
--
作者：
Martinez,GeneseeJ;Appleton,Malik;Kipp,ZacharyA;Loria,AnaliaS;Min,Booki;HindsJr,TerryD
人类的正常应激反应是由下丘脑-垂体-肾上腺 (HPA) 轴通过应激期间的强化机制控制的，从而提高血液中糖皮质激素皮质醇的水平。糖皮质激素是平衡哺乳动物体内众多系统正常功能的典型化合物。它们也是合成产生的，是治疗炎症性疾病的卓越疗法。它们通过与核受体转录因子糖皮质激素受体 (GR) 结合发挥作用，该受体有两种主要亚型（GRα 和 GRβ）。我们对糖皮质激素信号传导的经典理解来自 GRα 亚型，它与激素结合，而 GRβ 没有已知的配体。由于糖皮质激素参与许多生理和细胞过程，即使是通过 HPA 轴释放的微小干扰，或 GR 亚型表达的变化，也会对健康产生可怕的影响。长期慢性糖皮质激素治疗可能导致糖皮质激素抵抗状态，我们探讨这如何影响疾病治疗。长期糖皮质激素治疗可能会导致明显的副作用，例如体重增加、肥胖、糖尿病以及我们详细讨论的其他副作用。对糖皮质激素的反应存在性别二态性，女性的 HPA 轴往往比男性更敏感。这篇综述总结了我们对糖皮质激素的理解，并批判性地分析了 GR 亚型及其有益和有害的机制，以及导致反应二分法的性别差异。我们还讨论了糖皮质激素治疗的未来，并提出了双重 GR 同工型激动剂的新概念，并假设为什么激活两种同工型可以预防糖皮质激素抵抗。
The normal stress response in humans is governed by the hypothalamic-pituitary-adrenal (HPA) axis through heightened mechanisms during stress, raising blood levels of the glucocorticoid hormone cortisol. Glucocorticoids are quintessential compounds that balance the proper functioning of numerous systems in the mammalian body. They are also generated synthetically and are the preeminent therapy for inflammatory diseases. They act by binding to the nuclear receptor transcription factor glucocorticoid receptor (GR), which has two main isoforms (GRα and GRβ). Our classical understanding of glucocorticoid signaling is from the GRα isoform, which binds the hormone, whereas GRβ has no known ligands. With glucocorticoids being involved in many physiological and cellular processes, even small disruptions in their release via the HPA axis, or changes in GR isoform expression, can have dire ramifications on health. Long-term chronic glucocorticoid therapy can lead to a glucocorticoid-resistant state, and we deliberate how this impacts disease treatment. Chronic glucocorticoid treatment can lead to noticeable side effects such as weight gain, adiposity, diabetes, and others that we discuss in detail. There are sexually dimorphic responses to glucocorticoids, and women tend to have a more hyperresponsive HPA axis than men. This review summarizes our understanding of glucocorticoids and critically analyzes the GR isoforms and their beneficial and deleterious mechanisms and the sexual differences that cause a dichotomy in responses. We also discuss the future of glucocorticoid therapy and propose a new concept of dual GR isoform agonist and postulate why activating both isoforms may prevent glucocorticoid resistance.