Please wait a minute...
浙江大学学报(医学版)  2020, Vol. 49 Issue (3): 291-296    DOI: 10.3785/j.issn.1008-9292.2020.04.03
专题报道:芳香化酶抑制剂的临床应用     
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
徐德(),陆文丽*(),王雪晴,王俊祺,谢轶雯,董治亚,王伟
上海交通大学医学院附属瑞金医院儿内科, 上海 200025
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
 全文: PDF(1026 KB)   HTML( 11 )
摘要:

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    
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
收稿日期: 2019-12-05 出版日期: 2020-05-29
CLC:  R588  
基金资助: 上海市科委医学引导项目(14411958600);上海市科委医学引导项目(14411958600)
通讯作者: 陆文丽     E-mail: xd01975@rjh.com.cn;lwl11146@rjh.com.cn
作者简介: 徐德(1993-), 男, 硕士研究生, 住院医师, 主要从事儿童外周性性早熟的临床研究; E-mail:xd01975@rjh.com.cn; https://orcid.org/0000-0003-2560-2588|徐德(1993-), 男, 硕士研究生, 住院医师, 主要从事儿童外周性性早熟的临床研究; E-mail:xd01975@rjh.com.cn; https://orcid.org/0000-0003-2560-2588
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  
徐德
陆文丽
王雪晴
王俊祺
谢轶雯
董治亚
王伟

引用本文:

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.

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.

链接本文:

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

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
表 1  21例纤维性骨营养不良综合征女性患儿初诊及来曲唑治疗前各参数一览
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
表 2  21例纤维性骨营养不良综合征女性患儿临床表现及基因型分布
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)
表 3  21例纤维性骨营养不良综合征女性患儿来曲唑治疗前后骨龄和预测成年身高变化
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
表 4  21例纤维性骨营养不良综合征患儿来曲唑治疗前后激素水平、子宫附件容积及乳房分期变化比较
1 DUMITRESCU C E , COLLINS M T . McCune-Albright syndrome[J]. Orphanet J Rare Dis, 2008, 3 (1):
doi: 10.1186/1750-1172-3-12
2 HOLBROOK L, BRADY R. McCune-Albright syndrome[M]//StatPearls. Treasure Island (FL): StatPearls Publishing, 2020.
3 LIETMAN S A , SCHWINDINGER W F , LEVINE M A . Genetic and molecular aspects of McCune-Albright syndrome[J]. Pediatr Endocrinol Rev, 2007, 4 (Suppl 4): 380- 385
4 DE G BUFF PASSONE C , KUPERMAN H , CABRAL DE MENEZES-FILHO H et al. Tamoxifen improves final height prediction in girls with mccune-albright syndrome:a long follow-up[J]. Horm Res Paediatr, 2015, 84 (3): 184- 189
doi: 10.1159/000435881
5 EUGSTER E A , RUBIN S D , REITER E O et al. Tamoxifen treatment for precocious puberty in McCune-Albright syndrome:a multicenter trial[J]. J Pediatr, 2003, 143 (1): 60- 66
doi: 10.1016/S0022-3476(03)00128-8
6 CHEN M , EUGSTER E A . Central precocious puberty:update on diagnosis and treatment[J]. Paediatr Drugs, 2015, 17 (4): 273- 281
doi: 10.1007/s40272-015-0130-8
7 FEUILLAN P , CALIS K , HILL S et al. Letrozole treatment of precocious puberty in girls with the McCune-Albright syndrome:a pilot study[J]. J Clin Endocrinol Metab, 2007, 92 (6): 2100- 2106
doi: 10.1210/jc.2006-2350
8 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
9 ZHU G , YE X , DONG Z et al. Highly sensitive droplet digital PCR method for detection of EGFR-activating mutations in plasma cell-free DNA from patients with advanced non-small cell lung cancer[J]. J Mol Diagn, 2015, 17 (3): 265- 272
doi: 10.1016/j.jmoldx.2015.01.004
10 NARUMI S, MATSUO K, ISHII T, et al. Quantitative and sensitive detection of GNAS mutations causing mccune-albright syndrome with next generation sequencing[J/OL]. PLoS One, 2013, 8(3): e60525. DOI: 10.1371/journal.pone.0060525.
11 秦雪艳, 陆文丽, 王俊祺 et al. 41例McCune-Albright综合征女童临床及基因分析[J]. 中华内分泌代谢杂志, 2016, 32 (12): 995- 998
QIN Xueyan , LU Wenli , WANG Junqi et al. Analysis of clinical features and related genes variation in 41 girls with McCune-Albright syndrome[J]. Chinese Journal of Endocrinology and Metabolism, 2016, 32 (12): 995- 998
doi: 10.3760/cma.j.issn.1000-6699.2016.12.004
12 梁雁, 罗小平 . 进一步规范中枢性性早熟的诊疗[J]. 中华儿科杂志, 2015, 53 (6): 405- 408
LIANG Yan , LUO Xiaoping . Further standardize the diagnosis and treatment of central precocious puberty[J]. Chinese Journal of Pediatrics, 2015, 53 (6): 405- 408
doi: 10.3760/cma.j.issn.0578-1310.2015.06.002
13 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- 492
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- 492
doi: 10.3760/cma.j.issn.0578-1310.2009.07.003
14 FEUILLAN P P , JONES J , CUTLER G B JR . Long-term testolactone therapy for precocious puberty in girls with the McCune-Albright syndrome[J]. J Clin Endocrinol Metab, 1993, 77 (3): 647- 651
doi: 10.1210/jcem.77.3.8370686
15 FEUILLAN P P , FOSTER C M , PESCOVITZ O H et al. Treatment of precocious puberty in the McCune-Albright syndrome with the aromatase inhibitor testolactone[J]. N Engl J Med, 1986, 315 (18): 1115- 1119
doi: 10.1056/NEJM198610303151802
[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] 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.
[6] 孙缙红,邱宸阳,吴子衡,张鸿坤. 孤立性自发性肠系膜上动脉夹层腔内治疗的前瞻性单臂临床研究初步结果[J]. 浙江大学学报(医学版), 2020, 49(3): 383-388.
[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] 高明暄,聂德军,常彦峰,谢伟强,王悦,普星宇,张伟,骆文远. 内、外侧联合双柱内固定治疗23例肩胛骨体部移位骨折患者疗效分析[J]. 浙江大学学报(医学版), 2019, 48(6): 651-656.
[9] 张丽凤,杨慧,张信美,陈正云. 左炔诺孕酮宫内节育系统治疗子宫腺肌病患者的疗效和不良反应观察[J]. 浙江大学学报(医学版), 2019, 48(2): 130-135.
[10] 楼俊瑶,黄秀峰,张丽凤,徐萍,张信美,陈正云. 第二代子宫内膜消融术可提高左炔诺孕酮宫内节育系统对子宫腺肌病患者的疗效[J]. 浙江大学学报(医学版), 2019, 48(2): 136-141.
[11] 余钻标,林作栋,郎德海. 经皮机械血栓清除联合支架植入治疗急性髂股静脉血栓形成患者中远期疗效评估[J]. 浙江大学学报(医学版), 2018, 47(6): 623-627.
[12] 沈宏,季峰. 无X射线监视内镜下消化道支架置入治疗消化道狭窄的疗效和安全性[J]. 浙江大学学报(医学版), 2018, 47(6): 643-650.
[13] 尹孝亮,郎德海,王迪. 经皮机械血栓清除治疗急性髂股静脉血栓形成患者疗效观察[J]. 浙江大学学报(医学版), 2018, 47(6): 588-594.
[14] 王晓辉,何杨燕,吴子衡,张鸿坤. 一体化微创手术治疗髂静脉压迫综合征伴下肢静脉曲张患者疗效观察[J]. 浙江大学学报(医学版), 2018, 47(6): 577-582.
[15] 林作栋,郎德海. 经皮机械血栓清除联合球囊血管成形治疗髂股静脉血栓形成患者疗效分析[J]. 浙江大学学报(医学版), 2018, 47(6): 595-600.