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浙江大学学报（医学版）
J Zhejiang Univ (Med Sci)  2020, Vol. 49 Issue (3): 291-296    DOI: 10.3785/j.issn.1008-9292.2020.04.03
    
Efficacy and safety of letrozole in treatment of McCune-Albright syndrome girls with peripheral precocious puberty
XU De(),LU Wenli*(),WANG Xueqing,WANG Junqi,XIE Yiwen,DONG Zhiya,WANG Wei
Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Abstract  

Objective: To evaluate the efficacy and safety of the third-generation aromatase inhibitor letrozole in the treatment of McCune-Albright syndrome (MAS) girls with peripheral precocious puberty. Methods: Twenty-one MAS girls with peripheral precocious puberty treated in Pediatrics Department of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine from March 2012 to June 2017 were enrolled in the study. Patients presented with repeated vaginal bleeding, premature breast enlargement, café-au-lait spots or dysplasia of bone fibers, and low levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH); and the congenital adrenal hyperplasia, estrogen-producing tumors, and exogenous estrogen intake were excluded. Letrozole were administrated at a dose of 0.5-2 mg·m-2·d-1 for 6 to 12 months. The patients were observed for changes in breast staging, vaginal bleeding, sex hormone levels, liver function and bone age changes, and changes in uterine and ovarian volume. Results: After treatment, bone age/chronological age (BA/CA)was decreased from 1.23±0.30 to 1.11±0.18 (P < 0.01); the predicted adult height (PAH) increased from (156.2±5.9)cm to (158.4±2.1)cm after treatment (P < 0.05); the vaginal bleeding was reduced and the estradiol level decreased, while the teststosterone level and the uterus showed no significant increase, and no adverse reactions such as ovarian torsion and abnormal liver function were observed. Conclusion: Precocious puberty is one of the most common endocrine manifestations in MAS. Our findings suggest that letrozole may be an effective and safe therapy to precocious puberty in girls with McCune-Albright Syndrome.

Key words： Puberty, precocious      McCune-Albright syndrome      Aromatase inhibitors/therapeutic use      Letrozole      Girls      Treatment outcome      Safety      Puberty, precocious      McCune-Albright syndrome      Aromatase inhibitors/therapeutic use      Letrozole      Girls      Treatment outcome      Safety     
Received: 05 December 2019      Published: 29 May 2020
CLC:  R588  
  R725.8  
  R588  
  R725.8  
Corresponding Authors: LU Wenli     E-mail: xd01975@rjh.com.cn;lwl11146@rjh.com.cn
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XU De
LU Wenli
WANG Xueqing
WANG Junqi
XIE Yiwen
DONG Zhiya
WANG Wei
Cite this article:

XU De,LU Wenli,WANG Xueqing,WANG Junqi,XIE Yiwen,DONG Zhiya,WANG Wei. Efficacy and safety of letrozole in treatment of McCune-Albright syndrome girls with peripheral precocious puberty. J Zhejiang Univ (Med Sci), 2020, 49(3): 291-296.

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http://www.zjujournals.com/med/10.3785/j.issn.1008-9292.2020.04.03     OR     http://www.zjujournals.com/med/Y2020/V49/I3/291


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

目的: 探讨应用第三代芳香化酶抑制剂来曲唑治疗纤维性骨营养不良综合征（MAS）女性患儿外周性性早熟的疗效及安全性。方法: 选取2012年3月至2017年6月在上海交通大学医学院附属瑞金医院儿科就诊的MAS女性患儿21例。患儿反复阴道出血、乳房增大同时伴或不伴咖啡牛奶色斑或骨纤维发育不良，黄体生成素（LH）和卵泡刺激素（FSH）水平低下，排除先天性肾上腺皮质增生症、分泌雌激素的肿瘤及外源性雌激素摄入所致等情况。给予来曲唑0.5~2 mg·m-2·d-1治疗，疗程6~12个月，观察患儿乳房分期变化、阴道出血次数、性激素水平、肝功能、骨龄变化、子宫卵巢容积变化及有无不良事件发生。结果: 经过来曲唑治疗后，患儿骨龄与时序年龄比值减小（1.23±0.30降至1.11±0.18，P < 0.01）；预测成年身高从（156.2±5.9）cm增加至（158.4±2.1）cm（P < 0.05）；阴道出血次数减少，雌二醇水平下降，睾酮未见明显升高；子宫未见明显增大，也未发生卵巢扭转及肝酶升高等不良反应。结论: 来曲唑治疗MAS相关的外周性性早熟可延缓骨龄进展，减少阴道出血的频率，未观察到肝功能受损等不良反应。


关键词： 青春期, 早熟,  纤维性骨营养不良综合征,  芳香酶抑制剂/治疗应用,  来曲唑,  女童,  治疗结果,  安全性,  青春期, 早熟,  纤维性骨营养不良综合征,  芳香酶抑制剂/治疗应用,  来曲唑,  女童,  治疗结果,  安全性 
时间点 年龄(岁) 骨龄(岁) BA/CA HtSDSCA PAHSDS 子宫容积
(mL)		 卵巢容积
(mL)		 雌二醇
(pmol/L)		 睾酮
(nmol/L)
**与初诊时比较, P＜0.01.BA/CA：骨龄与时序年龄比值；HtSDSCA：时序年龄别身高标准差分值；PAHSDS：预测成年身高标准差分值.
初诊时 4.9±1.6 5.8±2.8 1.14±0.28 0.86(-0.33, 1.64) -0.54(-1.01, 0.13) 4.0±2.7 1.5±1.0 114±95 1.15±0.87
治疗前 6.8±2.0 8.2±2.0** 1.23±0.30 0.83(-0.41, 1.52) -1.04(-1.27, 0.07) 4.5±3.9 1.0±0.8 268±250** 0.35±0.31
Tab 1 Baseline characteristics of 21 girls with McCune-Albright syndrome [${\bar x}$±s或M(Q1, Q3), n=21]
诊断 n 外周性性早熟 纤维性骨结构不良 咖啡牛奶色斑 基因型
R201H R201C R201S
确诊 6 6 6 6 3 3 0
疑似 15 15 3 4 3 10 2
Tab 2 Clinical characteristics and genotype of 21 McCune-Albright syndrome girls (n)
时间 BA/CA PAH HtSDSCA HtSDSBA HtSDSBA-HtSDSCA PAHSDS
与治疗前比较, *P < 0.05, **P < 0.01.BA/CA：骨龄与时序年龄比值；PAH：预测成年身高；HtSDSBA:骨龄别身高标准差分值；HtSDSCA:时序年龄别身高标准差分值；PAHSDS：预测成年身高标准差分值.
治疗前 1.23±0.30 156.2±5.9 0.830(-0.41~1.52) -0.91(-1.33~0.31) -1.29(-2.80~0.25) -1.04(-1.27~0.07)
治疗6个月 1.14±0.25* 158.0±6.7* 0.710(-0.57~1.62) -0.48(-0.97~0.82) -0.84(-2.18~0.23) -0.67(-0.85~0.44)
治疗12个月 1.11±0.18** 158.4±2.1* 0.785(-0.67~1.48) -0.51(-1.18~0.01) -0.34(-2.22~0.20) -0.58(-0.85~0.20)
Tab 3 Changes in bone age and predicted adult height in 21 McCune-Albright syndrome girls before and after letrozole treatment [${\bar x}$±s或M(Q1, Q3), n=21]
时间 乳房Tanner分期 子宫容积(mL) 卵巢容积(mL) 雌二醇(pmol/L) 睾酮(nmol/L)
与治疗前比较, **P < 0.01.
治疗前 B2~B3 4.5±3.9 1.02±0.83 268±250 0.35±0.31
治疗3个月 B1~B3 4.0±3.2 0.99±0.76 59±11** 0.56±0.38
治疗6个月 B1~B2 4.1±3.6 1.88±0.98 37±7** 0.59±0.31
治疗9个月 B1~B2 4.8±3.1 1.79±0.86 62±11** 低于最低检测浓度
治疗12个月 B1~B2 4.7±3.2 1.76±0.89 低于最低检测浓度 低于最低检测浓度
Tab 4 Hormone levels, uterine accessory volume and breast staging before and after letrozole treatment in girls with McCune-Albright syndrome ($\bar x \pm s$, n=21)
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