Azcona C, Preece M A, Rose S J, Fraser N, Rappaport R, Ranke M B, Savage M O
Paediatric Endocrinology Section, St Bartholomew's Hospital, London, UK.
Clin Endocrinol (Oxf). 1999 Dec;51(6):787-92. doi: 10.1046/j.1365-2265.1999.00887.x.
rhIGF-I has been used effectively to promote growth in growth hormone insensitivity syndrome (GHIS) in doses ranging from 40 microg/kg twice daily to 150-200 microg/kg once daily. It appears that the dose of 80 microg/kg twice daily s.c. may induce an equivalent response to higher doses with less side-effects.
To study the efficacy and safety of rhIGF-I, 80 microg/kg twice daily s.c., in children with GHIS and to analyse the relationship of growth response to severity of phenotype.
Eleven prepubertal children (3 females, 8 males) with GHIS; basal GH > 2.5 microg/l, IGF-I < 50 microg/l, IGFBP-3 < - 2SD; were treated with IGF-I 80 microg/kg twice daily in a multi-centre study. The baseline characteristics of these patients were as follows (mean +/- SD): age, 7.5 +/- 2.5 years (range, 2.5-11.7 years), bone age (Tanner-Whitehouse - 2 RUS), 5.2 +/- 2.4 years (range, 2.3-9.1 years), mean height SDS, - 5.6 +/- 1.6 (range, - 3.1 to - 8.1), height velocity (HV), 3.1 +/- 1.1 cm/year (range, 1.9-4.9 cm/year). Height, HV, weight, skinfold thickness, puberty stage and bone age were measured at baseline and 6 monthly for 2 years.
During the first 12 months of IGF-I therapy, the mean +/- SD HV was 7.7 +/- 1.6 cm/year (range, 6.1-11.2 cm/year), the mean +/- SD increase in HV was 4.7 +/- 2.1 cm/year (range, 1.7-8.8 cm/year) and the mean +/- SD progression of bone age was 1.9 +/- 1.0 years (range, 0.8-3.8 years). Pre-treatment height SDS at the start of IGF-I therapy correlated positively with pretreatment serum IGFBP-3 SDS levels (r = 0.85; P < 0.01). There was a significant inverse correlation between gain in height SDS and pre-treatment height SDS (r = - 0.76; P < 0.01). During the 2nd 12 months of therapy, mean HV was 7.0 +/- 3.4 cm/year (range 3.8-12.4) change in height SDS from 12 to 24 months was not significantly correlated with pre-treatment height SDS. Subscapular skinfold SDS decreased significantly (P < 0.05) during the study period, whereas there was no significant change in body mass index and triceps skinfold thickness SDS. Adverse events reported in the patient group included headache (2 patients), hypoglycaemia (2 patients), papilloedema (transient, 1 patient), lipohypertrophy (5 patients) and tonsillectomy/adenoidectomy (2 patients).
This study reveals that IGF-I treatment at a dose of 80 microg/kg twice daily is effective in patients with growth hormone insensitivity syndrome. During the first 12 months of therapy, there was a significant inverse relationship between growth response to IGF-I therapy and the severity of the phenotype of growth hormone insensitivity syndrome, as measured by height SDS, at the start of therapy. Patients with a more severe clinical phenotype of growth hormone insensitivity syndrome, who also had most severe IGFBP-3 deficiency, responded better than those who were more mildly affected. An analogous situation has been shown to be the case in GH-deficient patients treated with hGH.
重组人胰岛素样生长因子 -I（rhIGF-I）已被有效用于促进生长激素不敏感综合征（GHIS）患者的生长，剂量范围为每日两次，每次40μg/kg至每日一次，150 - 200μg/kg。每日两次皮下注射80μg/kg的剂量似乎可以产生与更高剂量相当的反应，且副作用更少。
研究每日两次皮下注射80μg/kg rhIGF-I对GHIS患儿的疗效和安全性，并分析生长反应与表型严重程度之间的关系。
11例青春期前GHIS患儿（3例女性，8例男性）；基础生长激素（GH）>2.5μg/L，胰岛素样生长因子-I（IGF-I）<50μg/L，胰岛素样生长因子结合蛋白-3（IGFBP-3）<-2标准差；在一项多中心研究中接受每日两次80μg/kg的IGF-I治疗。这些患者的基线特征如下（均值±标准差）：年龄，7.5±2.5岁（范围2.5 - 11.7岁），骨龄（坦纳 - 怀特豪斯 - 2 桡尺骨远端），5.2±2.4岁（范围2.3 - 9.1岁），平均身高标准差分值（SDS），-5.6±l.6（范围 - 3.1至 - 8.1），身高增长速度（HV），3.1±1.1cm/年（范围1.9 - 4.9cm/年）。在基线时以及之后的2年中每6个月测量身高、HV、体重、皮褶厚度、青春期阶段和骨龄。
在IGF-I治疗的前12个月，均值±标准差的HV为7.7±1.6cm/年（范围6.1 - 11.2cm/年），HV的均值±标准差增加为4.7±2.1cm/年（范围1.7 - 8.8cm/年），骨龄的均值±标准差进展为1.9±1.0岁（范围0.8 - 3.8岁）。IGF-I治疗开始时的治疗前身高SDS与治疗前血清IGFBP-3 SDS水平呈正相关（r = 0.85；P < 0.01）。身高SDS的增加与治疗前身高SDS之间存在显著负相关（r = - 0.76；P < 0.01）。在治疗的第2个12个月期间，平均HV为7.0±3.4cm/年（范围3.8 - 12.4），12至24个月身高SDS的变化与治疗前身高SDS无显著相关性。在研究期间，肩胛下皮褶SDS显著降低（P < 0.05），而体重指数和肱三头肌皮褶厚度SDS无显著变化。患者组报告的不良事件包括头痛（2例患者）、低血糖（2例患者）、视乳头水肿（短暂性，1例患者）、脂肪增生（5例患者）以及扁桃体切除术/腺样体切除术（2例患者）。
本研究表明，每日两次80μg/kg的IGF-I治疗对生长激素不敏感综合征患者有效。在治疗的前12个月，根据治疗开始时身高SDS测量，IGF-I治疗的生长反应与生长激素不敏感综合征表型的严重程度之间存在显著负相关。生长激素不敏感综合征临床表型更严重且IGFBP-3缺乏最严重的患者，比病情较轻的患者反应更好。在接受重组人生长激素（hGH）治疗的生长激素缺乏患者中也显示出类似情况。
