性腺功能对生长激素缺乏症患儿终身高的影响

Influence of Sexual Glandular Function on Final Adult Height of Growth Hormone Deficiency Children

目的观察生长激素缺乏症(growth hormone deficiency,GHD)患儿经基因重组人生长激素(recombinant human growth hormone,rhGH)治疗后,性腺功能对其成年终身高(final adult height,FAH)的影响。方法将1993年10月至2004年8月在中山大学附属第一医院儿童生长中心确诊为生长激素缺乏症患儿15例,排除慢性器质性疾病、骨骼异常、营养不良和精神心理方面异常所致的生长迟缓,按照有或无自发青春发育,将其分为自发青春发育组(n=9,男性为5例,女性为4例);无自发青春发育组(n=6,男性为3例,女性为3例)(本研究遵循的程序符合中山大学附属第一医院人体试验委员会制定的伦理学标准,得到该委员会批准,分组征得受试对象监护人的知情同意,并与其签署临床研究知情同意书)。无自发青春发育组6例患儿均有性腺功能低下,其中5例伴中枢性甲状腺功能减退症。对中枢性甲状腺功能减退症患儿,首先采用甲状腺片或左旋甲状腺素钠替代治疗,直至血T3,T4水平稳定在正常水平后,再开始基因重组人生长激素治疗。对15例患儿的基因重组人生长激素治疗方法为:于每晚睡前皮下注射,剂量为每周0.7I U/kg(0.23mg/kg),疗程为1.1～7.7年。治疗结束后定期复诊,当年生长速率(growthvelocity,GV)<2cm,或将女性患儿骨龄(bone age,BA)≥14岁,男性患儿骨龄≥16岁时的身高,视为近似终身高或成年终身高。采用相关统计学方法分析两组患儿成年终身高,影响成年终身高的因素和青春期的生长因素。结果生长激素缺乏症标准差分值(standard deviation score,SDS)在自发青春发育组患儿为(-1.13±0.54),无自发青春发育组患儿为(-1.00±0.47)。以遗传靶身高(target height,THt)校正的成年终身高标准差分值(FAH-SDS)在自发青春发育组患儿为(-0.33±0.58),无自发青春发育组患儿为(0.04±0.62)。77.8%(7/9)自发青春发育组患儿的成年终身高达到或超过遗传靶身高范围,所有无自发青春发育组患儿的成年终身高达到或超过遗传靶身高范围,两组患儿成年终身高标准差分值与遗传靶身高标准差分值(THt-SDS)比较,差异无显著意义(P>0.05),两组之间的成年终身高标准差分值和以遗传靶身高校正的成年终身高标准差分值比较,差异亦无显著意义(P>0.05)。自发青春发育组患儿的成年终身高标准差分值与第1年的生长速率、治疗开始按年龄判断的身高标准差分值(HtSDSCA)、青春发育开始时的身高标准差分值和遗传靶身高标准差分值呈正相关。而无自发青春发育组患儿的成年终身高标准差分值,与上述因素均不相关。自发青春发育组男、女患儿青春发育开始年龄分别为(12.98±0.59)岁和(10.75±0.84)岁,无自发青春发育组男、女性患儿性激素诱导发育年龄分别为(21.92±5.81)岁和(19.44±0.68)岁,两者比较,差异有显著意义(P<0.05)。自发青春发育组男、女性患儿青春期身高获得分别为(24.38±1.86)cm和(22.47±2.65)cm,占终身高的(14.91±1.15)%和(15.21±1.43)%。无自发青春发育组患儿青春期的身高获得男、女性分别为(3.07±2.64)cm和(3.63±2.18)cm,占终身高的(1.86±1.61)%和(2.35±1.40)%,两组男、女性患儿间比较显示,差异有显著意义(P<0.05)。结论生长激素缺乏症患儿经基因重组人生长激素治疗,能改善性腺功能,性腺功能可影响生长激素缺乏症患儿的终身高。对于治疗开始晚,治疗开始身高明显落后的无自发青春发育患儿,可通过延缓诱导其青春发育年龄的方法 ,改善终身高。

Objective To evaluate the influence of sexual gonadal function on the final adult height （FAH） in growth hormone （GH）-treated growth hormone deficiency （GHD） children.Methods From October 1993 to August 2004,15 children with growth hormone deficiency who reached final adult height（FAH）after receiving recombinant human growth hormone （rhGH） treatment were included in this study.They were divided into two groups,spontaneous puberty development group （n=9,5 boys and 4 girls） and induced puberty group （n=6,3 boys and 3 girls）.Informed consent was obtained from all participates.All cases of induced puberty group had low sex gland function,among them,5 were central hypothyroidism.All these 5 cases were treated with thyroid tablet or levothyroxine sodium replacement therapy until serum T3,T4 levels back to the normal,then they began recombinant human growth hormone treatment.The approach of recombinant human growth hormone treatment were the following steps,subcutaneous injections of recombinant human growth hormone 0.7 IU/（kg·w）[0.23 mg/（kg·w）] before sleep for 1.1 to 7.7 years.Regular follow-up observation was taken after treatment.Final adult height was defined as a bone age（BA） ≥16 years for boys and ≥14 years for girls or the growth rate（GV） 〈2 cm/year.Final adult height,factors determining final adult height and pubertal growth factors were evaluated.Results Standard deviation score （SDS） of final adult height were （-1.13±0.54） in spontaneous puberty development group and（-1.00±0.47） in induced puberty group.Corrected for genetic target height （THt） of standard deviation score of final adult height were （-0.33±0.58） and （0.04±0.62） for spontaneous puberty development group and induced puberty group,respectively.A total of 77.8% （7/9） of spontaneous puberty development group and all induced puberty group achieved final adult height which was comparable to or above their target height.There had no statistic significance difference of standard deviation score of final adult height and genetic target height of standard deviation score （THt-SDS） between two groups （P〉0.05）.Standard deviation score of final adult height in spontaneous puberty development group was positively correlated with the growth velocity at the first year of therapy,height standard deviation score at initiation of the treatment determined by age,height standard deviation score at the beginning of puberty,genetic target height of standard deviation score,however,negative correlation was found among the above variables in induced puberty group.Age at puberty of spontaneous puberty development group were （12.98±0.59） years old for boys and （10.75±0.84） years old for girls,and the development age induced by growth hormone in induced puberty group were （21.92±5.81） years old and （19.44±0.68） years old.There had a significant difference between two groups （P〈0.05）.Adolescent height gain of spontaneous puberty development group were （24.38±1.86）cm for boys and （22.47±2.65） cm for girls,which accounted for （14.91±1.15）% and （15.21±1.43）% of final adult height,respectively.Adolescent height gain of induced puberty group were （3.07±2.64） cm for boys and （3.63±2.18） cm for girls,which accounted for （1.86±1.61）% and （2.35±1.40）%,respectively.Conclusion Growth hormone deficiency children who were treated by recombinant human growth hormone could improve gonadal function which can influence the final adult height of growth hormone deficiency children.Induced puberty children who start recombinant human growth hormone treatment late and height significantly behind normal children at the beginning of the therapy can receive delayed induction of puberty age method to improve final adult height.