Growth Hormone, Insulin-Like Growth Factor-I and the Cortisol-Cortisone Shuttle
Growth Hormone, Insulin-Like Growth Factor-I and the Cortisol-Cortisone Shuttle
复制标题
生长激素、胰岛素样生长因子-I 和皮质醇-可的松穿梭
DOI：
10.1159/000048126
复制
发表时间：
2001
影响因子：
3.2
通讯作者：
J. Tomlinson
中科院分区：
文献类型：
--
作者：
P. Stewart;A. Toogood;J. Tomlinson
在外周组织中，皮质类固醇激素的作用部分是通过11β-羟基类固醇脱氢酶（11β-HSD）的活性来确定的，11 β-HSD是两种同工酶，它们相互转化具有生理活性的皮质醇（F）和无活性的可的松（E）。11β-HSD 2型（11β-HSD 2）在肾脏中使F失活为E，而11β-HSD 1型（11β-HSD 1）主要在肝脏和脂肪组织中进行从E活化F的逆反应。外周组织中这些11β-HSD 2同工酶表达的改变改变皮质类固醇的作用：肾脏中11β-HSD 2活性的丧失导致皮质醇诱导的盐皮质激素过量，肝脏11β-HSD 1活性的丧失通过皮质醇诱导的胰岛素生成和肝脏葡萄糖输出的减少来改善胰岛素敏感性。相反，11β-HSD 1在网膜脂肪组织中的过表达可刺激糖皮质激素诱导的脂肪细胞分化，这可能导致向心性肥胖。垂体功能减退症患者与库欣综合征患者有许多共同的临床特征-特别是内脏肥胖、胰岛素抵抗、骨质疏松和血管性死亡率增加。我们的假设是，这些特征中的许多可以通过生长激素（GH）对11β-HSD同工酶的影响来解释。通过尿游离皮质醇/尿游离可的松比值评估并通过体外研究证实，GH和胰岛素样生长因子（IGF）-I均不影响11β-HSD 2活性。肢端肥大症患者表现出皮质醇/可的松的肝源性代谢产物减少-当GH浓度正常化时，水平恢复正常。相反，在垂体功能减退症的情况下，GH缺乏的患者表现出皮质醇/皮质醇代谢物比率增加，并且在接受氢化可的松替代治疗的患者中循环皮质醇浓度降低。低剂量GH替代治疗可逆转这些异常。这些临床数据表明，GH（和/或IGF-I）抑制11β-HSD 1（即E至F转化）（平行体外研究表明，IGF-I而非GH抑制11β-HSD 1）。这些发现具有重要的临床意义。首先，GH介导的皮质醇代谢增加（通过减少E至F转化介导）可能会促使开始GH治疗的部分促肾上腺皮质激素缺乏症患者出现肾上腺功能不全。其次，垂体功能减退症的许多表型特征可以通过11β-HSD 1活性的改变来解释：GH缺乏有效地增加了关键靶组织（包括肝脏和脂肪组织）中皮质醇的产生，促进了胰岛素抵抗和内脏肥胖。第三，GH对垂体功能减退症患者心血管危险因素的有益作用可能是通过改变皮质醇代谢产生的间接作用。最后，GH/IGF-I调节皮质醇代谢可能是常见疾病如中心性肥胖和特发性骨质疏松症的发病机制的基础。中心性肥胖但无垂体功能减退证据的患者存在相对的GH缺乏，令人兴奋的是，推测低剂量GH治疗通过抑制网膜脂肪内皮质醇的产生，可能提供一种新的治疗方法。
In peripheral tissues, corticosteroid hormone action is determined, in part, through the activity of 11β-hydroxysteroid dehydrogenases (11β-HSD), two isozymes of which interconvert hormonally active cortisol (F) and inactive cortisone (E). 11β-HSD type 2 (11β-HSD2) inactivates F to E in the kidney, whilst 11β-HSD type 1 (11β-HSD1) principally performs the reverse reaction activating F from E in the liver and adipose tissue. Alteration in expression of these 11β-HSD isozymes in peripheral tissues modifies corticosteroid action: loss of 11β-HSD2 activity in the kidney results in cortisol-induced mineralocorticoid excess, and loss of hepatic 11β-HSD1 activity improves insulin sensitivity through a reduction in cortisol-induced gluconeogenesis and hepatic glucose output. Conversely, overexpression of 11β-HSD1 in omental adipose tissue can stimulate glucocorticoid-induced adipocyte differentiation which may lead to central obesity. Patients with hypopituitarism have many clinical features in common with patients with Cushing’s syndrome – notably visceral obesity, insulin resistance, osteoporosis and increased vascular mortality. Our hypothesis was that many of these features may be explained by an effect of growth hormone (GH) on the 11β-HSD isozymes. As assessed by urinary free cortisol/urinary free cortisone ratios and endorsed through in vitro studies, neither GH nor insulin-like growth factor (IGF)-I affect 11β-HSD2 activity. Patients with acromegaly show a reduction in hepatic-derived metabolites of cortisol/cortisone – levels return to normal when GH concentrations are normalized. Conversely, patients with GH deficiency in the setting of hypopituitarism demonstrate an increased cortisol/cortisone metabolite ratio and reduction in circulating cortisol concentrations in patients on hydrocortisone replacement. Treatment with low-dose GH replacement reverses these abnormalities. These clinical data suggest that GH (and/or IGF-I) inhibits 11β-HSD1 (i.e. E to F conversion) (parallel in vitro studies suggest that IGF-I and not GH inhibits 11β-HSD1). These findings have important clinical ramifications. Firstly, the GH-mediated increase in cortisol metabolism (mediated via reduced E to F conversion) may precipitate adrenal insufficiency in hypopituitary patients with partial adrenocorticotropic hormone deficiency commencing GH therapy. Secondly, many of the phenotypic features of hypopituitarism can be explained by an alteration in 11β-HSD1 activity: GH deficiency effectively increases cortisol production in key target tissues including liver and adipose tissue, promoting insulin resistance and visceral adiposity. Thirdly, the reported beneficial effects of GH on cardiovascular risk factors in patients with hypopituitarism may be an indirect effect via alterations in cortisol metabolism. Finally, the GH/IGF-I modulation of cortisol metabolism may underpin the pathogenesis of common diseases such as central obesity and idiopathic osteoporosis. Patients with central obesity but with no evidence of hypopituitarism have relative GH deficiency and it is exciting to speculate that low-dose GH treatment in this group, by inhibiting cortisol generation within omental fat, may offer a novel therapeutic approach.
DOI：
10.1152/ajpendo.1997.272.6.e1108
发表时间：
1997-06-01
影响因子：
5.1
作者：
Vahl, N;Jorgensen, JOL;Christiansen, JS
通讯作者：
Christiansen, JS
人类生长激素、胰岛素样生长因子 I 以及饮食和运动对肥胖绝经后妇女身体成分的影响。
DOI：
10.1210/jcem.83.5.4826
发表时间：
1998
期刊：
The Journal of clinical endocrinology and metabolism.
影响因子：
--
作者：
Thompson,JL;Butterfield,GE;Gylfadottir,UK;Yesavage,J;Marcus,R;Hintz,RL;Pearman,A;Hoffman,AR
通讯作者：
Hoffman,AR