de Boer H, Blok G J, Popp-Snijders C, Stuurman L, Baxter R C, van der Veen E
Department of Endocrinology, Free University Hospital, Amsterdam, The Netherlands.
J Clin Endocrinol Metab. 1996 Apr;81(4):1371-7. doi: 10.1210/jcem.81.4.8636336.
The optimal dose for GH replacement therapy in GH-deficient (GHD) adults is not known, nor is there a consensus as to which method is the most appropriate for the monitoring of treatment. To establish a general guideline for GH replacement therapy in adults, we evaluated the relationship between the administered GH dose and the achieved serum levels of three GH-dependent serum markers. Serum levels of insulin-like growth factor I (IGF-I), IGF-binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS) were measured in 46 GHD men participating in a 1-yr, double blind, and placebo-controlled dose-response study. The doses of recombinant human GH ranged from 0.33-3.0 IU/m(2)-day. During GH treatment, dose reduction was necessary because of side-effects in 18 of 46 patients, i.e. in 18% of the patients receiving a maintenance dose of 1 IU/M(2)-day, in 35% of the patients receiving a dose of 2 IU/m(2)-day, and in 67% of the patients receiving a dose of 3 IU/M(2)-day. In the untreated state, serum levels of all three markers were below the normal range in 90% of the patients. The rise in serum marker concentrations during the first month of treatment was dose dependent. Significant increases in IGF-I, IGFBP-3, and ALS levels were observed with a dose as low as 0.33 IU/M(2)-day. The minimal GH dose required for normalization of the serum IGF-I concentration was 0.66 IU/M(2)-day, and it was 1.0 IU/M(2)-day for ALS and IGFBP-3. In patients receiving 2.0 IU/M(2)-day, the mean serum IGF-I concentration rose to an abnormally high level, whereas at this dose, the mean IGFBP-3 and ALS levels were not different from normal. The lower sensitivity of IGFBP-3 and ALS to GH doses in the high range was also apparent during long term treatment. The number of patients who developed IGFBP-3 or ALS levels that exceeded the upper normal limit was substantially smaller than the number of patients with elevated IGF-I concentrations (2, 8, and 19 of 46 patients, respectively). In conclusion, serum IGF-I appears to be the preferred biochemical marker for the detection of GH excess in adults receiving GH replacement therapy, because it is more sensitive than IGFBP-3 and ALS to GH doses in the high range. If normalization of the serum IGF-I concentration is taken as the criterion for optimal GH replacement therapy, the predicted optimal GH dose for GHD men 20 - 40 yr old is 1.4 IU/M(2)-day, and the 95% confidence interval is 1.2-1.6 IU/M(2)-day.
生长激素缺乏（GHD）成人患者生长激素替代治疗的最佳剂量尚不清楚，对于哪种监测治疗的方法最为合适也未达成共识。为了制定成人生长激素替代治疗的一般指南，我们评估了给予的生长激素剂量与三种生长激素依赖性血清标志物所达到的血清水平之间的关系。在参与一项为期1年的双盲、安慰剂对照剂量反应研究的46名GHD男性中，测量了胰岛素样生长因子I（IGF-I）、IGF结合蛋白-3（IGFBP-3）和酸不稳定亚基（ALS）的血清水平。重组人生长激素的剂量范围为0.33 - 3.0 IU/m²·天。在生长激素治疗期间，46名患者中有18名因副作用需要减少剂量，即接受1 IU/m²·天维持剂量的患者中有18%、接受2 IU/m²·天剂量的患者中有35%以及接受3 IU/m²·天剂量的患者中有67%。在未治疗状态下，90%的患者所有三种标志物的血清水平均低于正常范围。治疗第一个月期间血清标志物浓度的升高呈剂量依赖性。在低至0.33 IU/m²·天的剂量下，观察到IGF-I、IGFBP-3和ALS水平有显著升高。使血清IGF-I浓度恢复正常所需的最小生长激素剂量为0.66 IU/m²·天，对于ALS和IGFBP-3则为1.0 IU/m²·天。接受2.0 IU/m²·天治疗的患者中，平均血清IGF-I浓度升至异常高水平，而在此剂量下，平均IGFBP-3和ALS水平与正常无异。在长期治疗期间，IGFBP-3和ALS对高剂量生长激素的较低敏感性也很明显。IGFBP-3或ALS水平超过正常上限的患者数量明显少于IGF-I浓度升高的患者数量（46名患者中分别为2名、8名和19名）。总之，血清IGF-I似乎是接受生长激素替代治疗的成人中检测生长激素过量的首选生化标志物，因为在高剂量范围内它比IGFBP-3和ALS对生长激素剂量更敏感。如果将血清IGF-I浓度恢复正常作为最佳生长激素替代治疗的标准，20 - 40岁GHD男性的预测最佳生长激素剂量为1.4 IU/m²·天，95%置信区间为1.2 - 1.6 IU/m²·天。
