Please wait a minute...
浙江大学学报(医学版)  2020, Vol. 49 Issue (3): 302-307    DOI: 10.3785/j.issn.1008-9292.2020.04.04
专题报道:芳香化酶抑制剂的临床应用     
来曲唑对21-羟化酶缺乏型先天性肾上腺皮质增生症患儿生长发育的影响
王倩1(),张书乐2,马雪2,李桂梅1,*(),王增敏1,王凤雪1
1. 山东第一医科大学附属省立医院小儿内分泌综合科, 山东 济南 250014
2. 山东大学附属省立医院小儿内分泌综合科, 山东 济南 250014
Efficacy of letrozole in treatment of children with congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency
WANG Qian1(),ZHANG Shule2,MA Xue2,LI Guimei1,*(),WANG Zengmin1,WANG Fengxue1
1. Department of Pediatric Endocrine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250014, China
2. Department of Pediatric Endocrine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250014, China
 全文: PDF(1030 KB)   HTML( 7 )
摘要:

目的: 探讨来曲唑联合常规方法治疗21-羟化酶缺乏型先天性肾上腺皮质增生症(CAH)患儿的可行性。方法: 选取2010年12月至2016年1月确诊的4~10岁21-羟化酶缺乏型CAH患儿共28例,其中男性19例,女性9例。入组患儿前6个月为常规治疗(氢化可的松、氟氢可的松),第6个月末开始加用来曲唑联合治疗。通过自身前后对照的方法,对联合治疗前后患儿的骨龄进展速度、预期成年身高、性征发育程度及性激素水平、可能的不良反应等指标进行统计。结果: 加用来曲唑联合治疗后,患儿身高增长速度在短期(6个月内)有所下降,但很快恢复正常;联合治疗12个月后患儿骨龄别身高标准差分值(HtSDSBA)较入组时及常规治疗均显著改善(P < 0.05或P < 0.01);骨龄与时序年龄差值在联合治疗18个月后较常规治疗显著改善(P < 0.05);女性患儿预期成年身高在联合治疗12个月后较常规治疗显著改善(P < 0.05),男性患儿在联合治疗18个月后预期成年身高亦显著改善(P < 0.05);患儿卵泡刺激素、促黄体生成素升高,但未达到中枢性性早熟标准;患儿雌二醇水平降低(P < 0.01);患儿睾酮水平无显著改变。来曲唑联合治疗24个月,患儿未见多毛、严重痤疮、头疼、骨痛、肥胖、高血压、皮疹等不良反应。结论: 来曲唑联合常规治疗的方案可用于21-羟化酶缺乏型CAH患儿长期治疗,特别是骨龄明显超期、预期成年身高受损的患儿,可实现抑制骨龄进展、改善预期成年身高的治疗目的。

关键词: 肾上腺增生, 先天性21-羟化酶缺乏症儿童芳香酶抑制剂来曲唑治疗效果安全性肾上腺增生, 先天性21-羟化酶缺乏症儿童芳香酶抑制剂来曲唑治疗效果安全性    
Abstract:

Objective: To assess the efficacy of letrozole in treatment of children with congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency (21-OHD). Methods: Twenty eight children, including 19 boys and 9 girls aged 4-10y, with CAH due to 21-OHD were enrolled in the study. At the first six months of study, all children received conventional treatment with hydrocortisone or fludrocortisone, then letrozole was added to original regimen. The height velocity (HV), difference between bone age and chronological age (BA-CA), height standard diviation score based on bone age (HtSDSBA), predicted adult height (PAH), Tanner phase, sex hormone, and possible adverse reaction were evaluated and compared between those before and after letrozole treatment. Results: After 6 months of letrozole treatment, there was significant deceleration of HV, but it would recover soon. There was significant increase of HtSDSBA after 12 months of letrozole treatment (P < 0.05 or P < 0.01), and significant changes in BA-CA after 18 months of letrozole treatment (P < 0.05). PAH of female children was significantly increased during letrozole treatment (P < 0.05), whereas PAH of male children was significantly increased 18 months after letrozole treatment (P < 0.05). Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were significantly increased, but did not meet the diagnostic criteria of central precocious puberty. Estradiol was significantly decreased (P < 0.01), but no changes in testosterone level was observed. During 24 months letrozole treatment, no hirsutism, severe acne, headache, bone pain, obesity, hypertension, rash and other adverse reactions were observed. Conclusions: Letrozole can delay bone maturation and improve PAH, which can be used with conventional treatment for children with CAH due to 21-OHD, especially for those with high BA and low PAH.

Key words: Adrenal hyperplasia, congenital    21-hydroxylase deficiency    Child    Aromatase inhibitors    Letrozole    Treatment outcome    Safety    Adrenal hyperplasia, congenital    21-hydroxylase deficiency    Child    Aromatase inhibitors    Letrozole    Treatment outcome    Safety
收稿日期: 2019-12-04 出版日期: 2020-05-29
CLC:  R588  
通讯作者: 李桂梅     E-mail: wangqian8482752@163.com;liguimei2013@126.com
作者简介: 王倩(1984-), 女, 博士, 主治医师, 主要从事儿科内分泌疾病研究; E-mail:wangqian8482752@163.com; https://orcid.org/0000-0002-2166-8611|王倩(1984-), 女, 博士, 主治医师, 主要从事儿科内分泌疾病研究; E-mail:wangqian8482752@163.com; https://orcid.org/0000-0002-2166-8611
服务  
把本文推荐给朋友
加入引用管理器
E-mail Alert
RSS
作者相关文章  
王倩
张书乐
马雪
李桂梅
王增敏
王凤雪

引用本文:

王倩,张书乐,马雪,李桂梅,王增敏,王凤雪. 来曲唑对21-羟化酶缺乏型先天性肾上腺皮质增生症患儿生长发育的影响[J]. 浙江大学学报(医学版), 2020, 49(3): 302-307.

WANG Qian,ZHANG Shule,MA Xue,LI Guimei,WANG Zengmin,WANG Fengxue. Efficacy of letrozole in treatment of children with congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency. J Zhejiang Univ (Med Sci), 2020, 49(3): 302-307.

链接本文:

http://www.zjujournals.com/med/CN/10.3785/j.issn.1008-9292.2020.04.04        http://www.zjujournals.com/med/CN/Y2020/V49/I3/302

治疗时间 n 身高增长速度(cm/年) 骨龄与时序年龄差值(岁) HtSDSBA 预期成年身高(cm)
男性 女性
*与常规治疗期末比较, P<0.05;HtSDSBA:骨龄别身高标准差分值.
常规治疗期末 28 9.79±2.95 4.9±1.9 -3.62±1.23 146.2±9.1 131.4±10.1
联合治疗6个月 28 8.29±2.35* 4.9±1.8 -3.21±1.31 150.0±9.4 133.5±10.3
12个月 28 9.17±2.42 4.5±1.5 -2.75±1.03* 151.6±8.1 140.7±7.1*
18个月 26 8.55±2.42 4.1±1.8* -2.33±1.25* 155.6±10.3* 141.3±6.2*
24个月 26 9.32±1.60 4.2±1.6* -2.15±1.30* 157.2±10.4* 144.2±10.1*
表 1  不同治疗时间点患儿身高增长速度、骨龄及预期成年身高的变化
治疗期别 n 卵泡刺激素(U/L) 促黄体生成素(U/L) 雌二醇(pmol/L) 睾酮(nmol/L)
“—”:无相关数据.*3例患儿因Tanner分期进展退出联合治疗.
常规治疗期 19 0.57±0.27 0.15±0.09 68.60±44.59 0.56±0.10
联合治疗期* 16 2.16±1.34 0.33±0.11 28.45±14.09 0.52±0.15
t -3.37 -1.61 3.43 0.20
P <0.05 <0.05 <0.01 >0.05
表 2  联合治疗后男性患儿垂体-性腺轴激素变化
1 EL-MAOUCHE D , ARLT W , MERKE D P . Congenital adrenal hyperplasia[J]. Lancet, 2017, 390 (10108): 2194- 2210
doi: 10.1016/S0140-6736(17)31431-9
2 MERKE D P , KEIL M F , JONES J V et al. Flutamide, testolactone, and reduced hydrocortisone dose maintain normal growth velocity and bone maturation despite elevated androgen levels in children with congenital adrenal hyperplasia[J]. J Clin Endocrinol Metab, 2000, 85 (3): 1114- 1120
doi: 10.1210/jcem.85.3.6462
3 PIGNATELLI D , PEREIRA S S , PASQUALI R . Androgens in congenital adrenal hyperplasia[J]. Front Horm Res, 2019, 53 65- 76
doi: 10.1159/000494903
4 MUTHUSAMY K , ELAMIN M B , SMUSHKIN G et al. Clinical review:Adult height in patients with congenital adrenal hyperplasia:a systematic review and metaanalysis[J]. J Clin Endocrinol Metab, 2010, 95 (9): 4161- 4172
doi: 10.1210/jc.2009-2616
5 JUAN L , HUAMEI M , ZHE S et al. Near-final height in 82 Chinese patients with congenital adrenal hyperplasia due to classic 21-hydroxylase deficiency:a single-center study from China[J]. J Pediatr Endocrinol Metab, 2016, 29 (7): 841- 848
doi: 10.1515/jpem-2015-0406
6 MAHESHWARI A , KHADILKAR V , GANGODKAR P et al. Long-term growth in congenital adrenal hyperplasia[J]. Indian J Pediatr, 2019, 86 (2): 154- 158
doi: 10.1007/s12098-018-2753-6
7 GVVEN A , NURCAN CEBECI A , HANCILI S . Gonadotropin releasing hormone analog treatment in children with congenital adrenal hyperplasia complicated by central precocious puberty[J]. Hormones (Athens), 2015, 14 (2): 265- 271
doi: 10.14310/horm.2002.1555
8 中华医学会儿科学分会内分泌遗传代谢病学组 . 先天性肾上腺皮质增生症21-羟化酶缺陷诊治共识[J]. 中华儿科杂志, 2016, 56 (8): 569- 575
Group of Pediatric Endocrine and Genetic Metabolic, Chinese Pediatric Society, Chinese Medical Association . Diagnosis and treatment of congenital adrenal hyperplasia with 21-hydroxylase deficiency[J]. Chinese Journal of Pediatrics, 2016, 56 (8): 569- 575
doi: 10.3760/cma.j.issn.0578-1310.2016.08.003
9 李辉, 季成叶, 宗心南 et al. 中国0~18岁儿童、青少年身高、体重的标准化生长曲线[J]. 中华儿科杂志, 2009, 47 (7): 487- 490
LI Hui , JI Chengye , ZONG Xinnan et al. Height and weight standardized growth charts for Chinese children and adolescents aged 0 to 18 years[J]. Chinese Journal of Pediatrics, 2009, 47 (7): 487- 490
doi: 10.3760/cma.j.issn.0578-1310.2009.07.003
10 THODBERG H H, JUUL A, LOMHOLT J, et al. Adult height prediction models[M]//RODRIGUES D, WOLFORD L. Handbook of Growth and Growth Monitoring in Health and Disease. Springer Science + Business Media, 2012: 27-57.
11 潘嘉严, 张先来, 徐东 . TW3成年身高预测改良法在中国儿童中的应用研究[J]. 现代医学, 2018, 46 (7): 773- 780
PAN Jiayan , ZHANG Xianlai , XU Dong . Application of improved TW3 method in predicting adult height in Chinese children[J]. Modern Medical Journal, 2018, 46 (7): 773- 780
doi: 10.3969/j.issn.1671-7562.2018.07.011
12 SHULMAN D I, FRANCIS G L, PALMERT M R, et al. Use of aromatase inhibitors in children and adolescents with disorders of growth and adolescent development[J/OL]. Pediatrics, 2008, 121(4): e975-e983. DOI: 10.1542/peds.2007-2081.
13 MAURAS N , ROSS J L , GAGLIARDI P et al. Randomized trial of aromatase inhibitors, growth hormone, or combination in pubertal boys with idiopathic, short stature[J]. J Clin Endocrinol Metab, 2016, 101 (12): 4984- 4993
doi: 10.1210/jc.2016-2891
14 ESTRADA A , BOYCE A M , BRILLANTE B A et al. Long-term outcomes of letrozole treatment for precocious puberty in girls with McCune-Albright syndrome[J]. Eur J Endocrinol, 2016, 175 (5): 477- 483
doi: 10.1530/EJE-16-0526
15 LANE L C , FLOWERS J , JOHNSTONE H et al. Adult height in patients with familial male-limited precocious puberty and the role of an aromatase inhibitor in patient management[J]. J Pediatr Endocrinol Metab, 2018, 31 (5): 551- 560
doi: 10.1515/jpem-2017-0363
16 HERO M , NORJAVAARA E , DUNKEL L . Inhibition of estrogen biosynthesis with a potent aromatase inhibitor increases predicted adult height in boys with idiopathic short stature:a randomized controlled trial[J]. J Clin Endocrinol Metab, 2005, 90 (12): 6396- 6402
doi: 10.1210/jc.2005-1392
[1] 李燕虹,杜敏联,马华梅,陈秋莉,陈红珊,张军. 来曲唑改善青春期特发性身材矮小症男性患儿成年身高的疗效评价[J]. 浙江大学学报(医学版), 2020, 49(3): 308-314.
[2] 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.
[3] 王春林,梁黎. 第三代非甾体类芳香化酶抑制剂在儿科内分泌临床应用的再认识[J]. 浙江大学学报(医学版), 2020, 49(3): 275-282.
[4] 于冰青,聂敏,伍学焱,茅江峰,王曦,马婉璐,季文,黄奇彬,张睿. 来曲唑有效提高性发育异常男性患儿的睾酮水平[J]. 浙江大学学报(医学版), 2020, 49(3): 297-301.
[5] 徐德,陆文丽,王雪晴,王俊祺,谢轶雯,董治亚,王伟. 来曲唑治疗纤维性骨营养不良综合征女性患儿外周性性早熟疗效观察[J]. 浙江大学学报(医学版), 2020, 49(3): 291-296.
[6] 陈志敏,傅君芬,舒强,汪伟,陈英虎,华春珍,李甫棒,林茹,唐兰芳,汪天林,王颖硕,徐玮泽,杨子浩,叶盛,袁天明,张晨美,张园园. 儿童2019冠状病毒病(COVID-19)诊疗指南(第二版)[J]. 浙江大学学报(医学版), 2020, 49(2): 139-146.
[7] 陈军,刘丹萍,刘莉,刘萍,徐庆年,夏露,凌云,黄丹,宋树丽,张丹丹,钱志平,李涛,沈银忠,卢洪洲. 硫酸羟氯喹治疗2019冠状病毒病(COVID-19)普通型患者的初步研究[J]. 浙江大学学报(医学版), 2020, 49(2): 215-219.
[8] 林静,陈志敏. 儿童重症腺病毒肺炎早期识别的研究进展[J]. 浙江大学学报(医学版), 2019, 48(5): 567-572.
[9] 牛玉柏,张凌燕,郝泽生,季雨竹. 气质、父母教养方式与幼儿心理韧性的关系[J]. 浙江大学学报(医学版), 2019, 48(1): 75-82.
[10] 徐玮泽,叶菁菁,李建华,张泽伟,俞建根,石卓,俞劲,舒强. 单纯食管超声心动图引导经皮房间隔缺损封堵术治疗房间隔缺损患儿的疗效[J]. 浙江大学学报(医学版), 2018, 47(3): 244-249.
[11] 宋春泽,蒋国平,叶菁菁,何瑾,俞劲. 超声心动图显像诊断儿童肺动脉吊带的价值[J]. 浙江大学学报(医学版), 2018, 47(3): 250-254.
[12] 黄婷,张晓乐,梁靓,谭征,高跃,李建华,舒强. 腔镜手术治疗肺隔离症患儿47例[J]. 浙江大学学报(医学版), 2018, 47(3): 272-277.
[13] 彭丹丹,周旭东. 宁波市儿童家长抗菌药物知识、使用行为及其影响因素分析[J]. 浙江大学学报(医学版), 2018, 47(2): 156-162.
[14] 郑琪,卢美萍. 儿童风湿免疫性疾病研究热点[J]. 浙江大学学报(医学版), 2018, 47(2): 213-217.
[15] 冯梦宇,张太平,赵玉沛. 加速康复外科在胰腺外科中的应用[J]. 浙江大学学报(医学版), 2017, 46(6): 666-674.