Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: Alterations in cortisol pharmacokinetics at puberty
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: Alterations in cortisol pharmacokinetics at puberty
复制标题
DOI：
10.1210/jc.86.6.2701
复制
发表时间：
2001-06-01
影响因子：
5.8
通讯作者：
Brook, CGD
中科院分区：
文献类型：
--
作者：
Charmandari, E;Hindmarsh, PC;Brook, CGD
在先天性肾上腺皮质增生（CAH）由于21-羟化酶缺乏症，糖皮质激素和盐皮质激素替代治疗并不总是令人满意的。在青春期患者中经常观察到次优控制，尽管有足够的替代剂量和治疗依从性。我们研究了青春期过程是否与皮质醇药代动力学的改变有关，皮质醇药代动力学的改变导致下丘脑-垂体-肾上腺轴失控。对14名青春期前（中位年龄，9.4岁;范围，6.1-10.8岁）、20名青春期（中位年龄，13.5岁;范围，10.6-16.8岁）和6名青春期后（中位年龄，18.2岁;范围，17.2-20.3岁）的盐耗性CAH患者给予15 mg/m2体表面积的剂量。所有患者均接受氢化可的松和9 α-氟氢可的松的标准替代治疗。用固相放射免疫分析法测定静脉推注氢化可的松后6小时内每隔10分钟测定一次血清总皮质醇浓度，血清总皮质醇清除率曲线呈单指数曲线。青春期组的平均清除率（平均值，427.0 mL/min; SD，133.4）显著高于青春期前组（平均值，248.7 mL/min; SD，100.6）和青春期后组（平均值，292.4 mL/min; SD，106.3）（单因素方差分析，F = 9.8，P < 0.001）。这种效应在调整体重指数后仍然存在。青春期患者的平均分布容积（平均值，49.5 L; sq，12.2）也显著高于青春期前患者（平均值，27.1 L; SD，8.4），但青春期后患者的平均分布容积（平均值，40.8 L; sn，16）无显著差异（ANOVA，F = 15.2，P < 0.001）。经体重指数校正后仍有显著性差异。青春期前（平均值，80.2分钟;标准差，19.4），青春期（平均值，84.4分钟;标准差，24.9），青春期后（平均值，96.7分钟;标准差，9.9）患者的总皮质醇的平均半衰期无显著差异。当检查游离皮质醇的药代动力学参数时，观察到组间相似的差异。此外，女性游离皮质醇的半衰期显著短于男性（P = 0.04）。这些数据表明，青春期与皮质醇药代动力学的改变，导致清除率和分布容积增加，而半衰期无变化。这些变化可能反映了青春期内分泌环境的变化，并可能对CAH和其他需要皮质醇替代的青少年疾病的治疗产生影响。
In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, treatment with glucocorticoid and mineralocorticoid substitution is not always satisfactory. Suboptimal control is often observed in pubertal patients, despite adequate replacement doses and adherence to treatment. We investigated whether the pubertal process is associated with alterations in cortisol pharmacokinetics resulting in a loss of control of the hypothalamic-pituitary-adrenal axis.We determined the pharmacokinetics of hydrocortisone administered iv as a bolus. A dose of 15 mg/m(2) body surface area was given to 14 prepubertal (median age, 9.4 yr; range, 6.1-10.8 yr), 20 pubertal (median, 13.5 yr; range, 10.6-16.8 yr), and 6 postpubertal (median, 18.2 yr; range, 17.2-20.3 yr) patients with salt-wasting CAH. All patients were on standard replacement therapy with hydrocortisone and 9 alpha -fludrocortisone. Serum total cortisol concentrations were measured at 10-min intervals for 6 h following iv hydrocortisone bolus and analyzed using a solid-phase RIA.The serum total cortisol clearance curve was monoexponential. Mean clearance was significantly higher in the pubertal group (mean, 427.0 mL/min; SD, 133.4) compared with the prepubertal (mean, 248.7 mL/min; SD, 100.6) and postpubertal (mean, 292.4 mL/min; SD, 106.3) tone-way ANOVA, F = 9.8, P < 0.001) groups. This effect persisted after adjustment for body mass index. The mean volume of distribution was also significantly higher in the pubertal (mean, 49.5 L; so, 12.2) than the prepubertal (mean, 27.1 L; SD, 8.4) patients but not in the postpubertal(mean, 40.8 L; sn, 16) (ANOVA, F = 15.2, P < 0.001) patients. The significance remained after correction for body mass index. There was no significant difference in mean half-life of total cortisol in prepubertal (mean, 80.2 min; SD, 19.4), pubertal (mean, 84.4 min; SD, 24.9), and postpubertal (mean, 96.7 min; SD, 9.9) patients. Similar differences between groups were observed when the pharmacokinetic parameters of free cortisol were examined. In addition, the half-life of free cortisol was significantly shorter in females compared with males (P = 0.04).These data suggest that puberty is associated with alterations in cortisol pharmacokinetics resulting in increased clearance and volume of distribution with no change in half-life. These alterations probably reflect changes in the endocrine milieu at puberty and may have implications for therapy of CAH and other conditions requiring cortisol substitution in the adolescent years.