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浙江大学学报(医学版)  2020, Vol. 49 Issue (3): 283-290    DOI: 10.3785/j.issn.1008-9292.2020.04.06
专题报道:芳香化酶抑制剂的临床应用     
芳香化酶抑制剂联合生长激素治疗青春期身材矮小症男性患儿的临床研究
孔元梅(),陈虹,梁黎,郑卯昵,方燕兰,王春林*()
浙江大学医学院附属第一医院儿科, 浙江 杭州 310003
Aromatase inhibitors combined with growth hormone in treatment of adolescent boys with short stature
KONG Yuanmei(),CHEN Hong,LIANG Li,ZHENG Maoni,FANG Yanlan,WANG Chunlin*()
Department of Pediatrics, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
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摘要:

目的: 研究第三代非甾体类芳香化酶抑制剂(AI)改善大骨龄(≥13岁)男性身材矮小症青少年成年身高的有效性,同时监测药物的安全性。方法: 2015年12月—2018年11月在浙江大学医学院附属第一医院就诊的预测成年身高受损的骨龄为13~15岁的青春期男性患儿151例,经充分告知AI的潜在风险后,由患儿及其家长选择入组:重组人生长激素(rhGH)联用AI组108例(联用AI组),单用rhGH组43例(rhGH单用组)。治疗时间12月以上,每3个月复查一次,监测药物不良反应。结果: 与rhGH单用组比较,联用AI组骨龄差值与时序年龄差值的比值(ΔBA/ΔCA)、骨龄别身高标准差分值的差值(ΔHtSDSBA)以及预测成年身高的差值(ΔPAH)改善更加明显(P < 0.05或P < 0.01)。随访期间,联用AI组尿酸升高69例(63.9%),高密度脂蛋白(HDL)降低56例(51.9%),严重痤疮、兴奋多动、性格暴躁28例(25.9%),膝关节疼痛12例(11.1%),骨折5例(4.6%),轻度肾功能异常3例(2.8%),精神不振、嗜睡、记忆力减退和成绩下降2例(1.9%),轻度肝功能异常2例(1.9%),空腹血糖受损1例(0.9%),粒细胞减少1例(0.9%),停药后监测指标逐渐恢复正常。rhGH单用组出现膝关节疼痛5例(11.6%),空腹血糖受损1例(2.3%)。结论: 长疗程的AI联合rhGH治疗可以延缓骨龄增长,有效改善青春期大骨龄矮小男性患儿的成年终身高,但治疗期间需要密切监测AI的不良反应。

关键词: 身材矮小症芳香酶抑制剂重组人生长激素青春期男童治疗效果安全性身材矮小症芳香酶抑制剂重组人生长激素青春期男童治疗效果安全性    
Abstract:

Objective: To assess the efficacy and safety of aromatase inhibitors (AIs) combined growth hormone in treatment of adolescent boys with short stature. Methods: One hundred and fifty-one short stature pubertal boys with age of 10-14 years and bone age of 13-15 years, who were admitted to the Department of Pediatrics, the First Affiliated Hospital, Zhejiang University School of Medicine, were included in this trial. According to their own or parents' intention, the children were divided into recombinant human growth hormone (rhGH)+AI group (n=108) and rhGH group (n=43). All children were injected subcutaneously with rhGH 0.15-0.2 IU·kg-1·d-1, and those in rhGH+AI group were additionally given 2.5 mg/d letrozole or 1 mg/d anastrozole, orally for 12 months or longer. The children were followed-up every 3 months. During the follow-up visit, the predicted adult height (PAH), sex hormone level, glucose and lipid metabolism, and other indicators were measured, and adverse reactions were monitored. Results: After intervention, there were significant differences in ΔBA(bone age)/ΔCA(chronological age), ΔHtSDSBA(height standard deviation score based on bone age)and ΔPAH between rhGH+AI group and the rhGH group(P < 0.05 or P < 0.01). During follow-up, 63.9%of the children in the rhGH+AI group had elevated uric acid and 51.9%had decreased high-density lipoprotein (HDL); 25.9%showed severe acne, excitement, hyperactivity and irritability, 11.1%had knee pain; 4.6%had fracture; 2.8%had mild renal dysfunction; 1.9%had inactivity, drowsiness, memory loss and performance decline; 1.9%showed mild abnormal liver function; 0.9%showed impaired fasting glucose; 0.9%showed granulocytopenia. In the rhGH group, 11.6%of the children presented with knee pain and 2.3%with impaired fasting glucose. Conclusions: AI combined with rhGH can delay the growth of BA and effectively improve the PAH of adolescent boys with larger bone age. However, the occurrence of adverse reactions of AI should be closely monitored during treatment.

Key words: Short stature    Aromatase inhibitors    Recombinant human growth hormone    Puberty    Boys    Treatment outcome    Safety    Short stature    Aromatase inhibitors    Recombinant human growth hormone    Puberty    Boys    Treatment outcome    Safety
收稿日期: 2020-01-09 出版日期: 2020-05-29
CLC:  R588  
基金资助: 浙江省科技计划(2020C03121);浙江省教育厅科研项目(Y201840363);浙江省科技计划(2020C03121);浙江省教育厅科研项目(Y201840363)
通讯作者: 王春林     E-mail: 6512039@zju.edu.cn;hzwangcl@zju.edu.cn
作者简介: 孔元梅(1987-), 女, 硕士, 主治医师, 主要从事生长性疾病研究; E-mail:6512039@zju.edu.cn; https://orcid.org/0000-0002-3250-1892|孔元梅(1987-), 女, 硕士, 主治医师, 主要从事生长性疾病研究; E-mail:6512039@zju.edu.cn; https://orcid.org/0000-0002-3250-1892
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引用本文:

孔元梅,陈虹,梁黎,郑卯昵,方燕兰,王春林. 芳香化酶抑制剂联合生长激素治疗青春期身材矮小症男性患儿的临床研究[J]. 浙江大学学报(医学版), 2020, 49(3): 283-290.

KONG Yuanmei,CHEN Hong,LIANG Li,ZHENG Maoni,FANG Yanlan,WANG Chunlin. Aromatase inhibitors combined with growth hormone in treatment of adolescent boys with short stature. J Zhejiang Univ (Med Sci), 2020, 49(3): 283-290.

链接本文:

http://www.zjujournals.com/med/CN/10.3785/j.issn.1008-9292.2020.04.06        http://www.zjujournals.com/med/CN/Y2020/V49/I3/283

组别 n 年龄(岁) 骨龄(岁) 体质量(kg) HtSDS-CA HtSDS-BA HOMA-IR 骨密度(g/cm2) 睾酮(nmol/L)
“—”:无相关数据.rhGH:重组人生长激素;AI:芳香化酶抑制剂;HtSDSCA:时序年龄别身高标准差分值;HtSDSBA:骨龄别身高标准差分值;HOMA-IR:胰岛素抵抗指数.
联用AI组 108 12.5±0.9 13.9±0.9 46±4 -2.0±1.0 -2.2±0.9 3.1±0.7 1.05±0.54 12.4±1.8
rhGH单用组 43 12.3±1.2 14.0±0.7 47±5 -1.9±1.2 -2.1±0.8 3.0±0.8 0.98±0.22 13.3±1.7
t 0.743 0.951 0.734 1.156 0.726 0.473 0.374 2.134
P >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05
表 1  联用AI组与rhGH单用组基线资料比较
组别 n 身高(cm) 骨龄(岁) 骨密度(g/cm2) ΔBA/ΔCA ΔHtSDSCA ΔHtSDSBA ΔPAH(cm)
“—”:无相关数据.rhGH:重组人生长激素;AI:芳香化酶抑制剂;ΔBA/ΔCA:骨龄差值与时序年龄差值的比值;ΔHtSDSCA:时序年龄别身高标准差分值的差值;ΔHtSDSBA:骨龄别身高标准差分值的差值;ΔPAH:预测成年身高的差值.
联用AI组 108 168.9±5.8 15.0±1.0 1.02±0.43 0.57±0.24 0.73±0.38 1.19±0.47 7.8±3.6
rhGH单用组 43 165.1±5.0 15.7±1.2 1.07±0.36 1.21±0.82 0.40±0.29 0.83±0.41 3.8±2.9
t 1.245 0.754 0.653 2.982 0.654 0.837 2.320
P < 0.05 < 0.05 0.094 <0.01 <0.05 <0.05 <0.05
表 2  是否联用AI治疗青春期身材矮小症男性患儿疗效比较
组别 n 严重痤疮、兴奋、易怒 嗜睡、记忆力减退 骨折 关节痛 ALT升高 肌酐升高 高尿酸血症 低高密度脂蛋白血症 空腹血糖受损 粒细胞减少
“—”:无相关数据.rhGH:重组人生长激素;AI:芳香化酶抑制剂;ALT:丙氨酸转氨酶.
联用AI组 108 28(25.9) 2(1.9) 5(4.6) 12(11.1) 2(1.9) 3(2.8) 69(63.9) 56(51.9) 1(0.9) 1(0.9)
rhGH单用组 43 0(0.0) 0(0.0) 0(0.0) 5(11.6) 0(0.0) 0(0.0) 0(0.0) 0(0.0) 1(2.3) 0(0.0)
χ2 13.686 0.807 2.059 0.008 0.807 1.219 50.589 35.439 0.461 0.401
P < 0.01 >0.05 >0.05 >0.05 >0.05 >0.05 < 0.01 < 0.01 >0.05 >0.05
表 3  是否联用AI治疗青春期身材矮小症男性患儿不良反应比较
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