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J Zhejiang Univ (Med Sci)  2020, Vol. 49 Issue (3): 308-314    DOI: 10.3785/j.issn.1008-9292.2020.04.05
    
Efficacy of letrozole in treatment of male adolescents with idiopathic short stature
LI Yanhong*(),DU Minlian,MA Huamei,CHEN Qiuli,CHEN Hongshan,ZHANG Jun
Department of Pediatrics, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China
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Abstract  

Objective: To evaluate the efficacy and safety of aromatase inhibitor letrozole in treatment of male adolescents with idiopathic short stature (ISS). Method: Seventy five boys with height less than 2 standard deviation (SD) below the mean who had entered puberty were enrolled in our study from 2004 to 2017, in the Pediatric Department of the First Affiliated Hospital, Sun Yat-Sen University. Among 75 patients, 28 in letrozole group received letrozole and spironolactone, 30 in gonadotrophin releasing hormone analogue (GnRHa) group received GnRHa injection and 17 had no intervention. Height velocity (HV), increment of bone age/chronological age (ΔBA/ΔCA), the final adult height (FAH) were compared among groups and the safety of letrozole treatment was evaluated. Results: HV maintained faster during letrozole treatment when compared with other groups. HV during GnRHa treatment showed slightly decline in the first 6 months, but decreased remarkably after 6 months, and was significantly lower than that in letrozole group (P < 0.05). The maturation of BA slowed down in both letrozole and GnRHa groups. But the ΔBA/ΔCA in letrozole group during the first and the second year of treatment were significantly higher (0.67±0.09, 0.50±0.15, respectively) when compared with GnRHa group (0.59±0.16, 0.44±0.13, respectively) (t=2.78 and 2.20, all P < 0.05). FAH in letrozole group and GnRHa group were (170±4) cm and (170±6)cm, there was no significant differences between the two groups (P>0.05), and both were higher than that in no intervention group (162±4 cm, P < 0.01). After 6 months of letrozole treatment, testicular volumes and serum testerone levels increased; 39.2% (11/28) boys had clinical manifestations of hyperandrogenemia, and 82.1% (23/28) boys had decreased serum high-density lipoprotein (HDL) levels. Serum levels of HDL and testerone returned normal and the hyperandrogenemia disappeared after the cessation of letrozole treatment. No significant changes in serum triglyceride, serum low-density lipoprotein (LDL), fating serum levels of insulin and glucose, HOMA-IR were observed. No abnormal liver function, myalgia, scoliosis or aggravations of scoliosis was found. Conclusions: Long term letrozole therapy during puberty in boys with ISS can delay bone maturation without significant decrease of linear growth, and thus can improve the final adult height. No severe adverse reactions were found.



Key wordsShort stature      Aromatase inhibitors      Letrozole      Boys      Puberty      Treatment outcome      Safety      Short stature      Aromatase inhibitors      Letrozole      Boys      Puberty      Treatment outcome      Safety     
Received: 11 December 2019      Published: 29 May 2020
CLC:  R588  
  R745.8  
  R588  
  R745.8  
Corresponding Authors: LI Yanhong     E-mail: lyhsysu@163.com
Cite this article:

LI Yanhong,DU Minlian,MA Huamei,CHEN Qiuli,CHEN Hongshan,ZHANG Jun. Efficacy of letrozole in treatment of male adolescents with idiopathic short stature. J Zhejiang Univ (Med Sci), 2020, 49(3): 308-314.

URL:

http://www.zjujournals.com/med/10.3785/j.issn.1008-9292.2020.04.05     OR     http://www.zjujournals.com/med/Y2020/V49/I3/308


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

目的: 观察和评估芳香化酶抑制剂来曲唑治疗已进入青春期的特发性身材矮小症(ISS)男性患儿的疗效和安全性。方法: 收集2004—2017年在中山大学附属第一医院儿科内分泌专科门诊就诊,身高低于同年龄、同性别平均水平2个标准差以下并已经进入青春期的ISS男性患儿75例,按所选择的治疗方案分为来曲唑组、促性腺激素释放激素类似物(GnRHa)组和无干预组。其中,来曲唑组28例,应用来曲唑治疗,剂量为1.5~2.0 mg·m-2·d-1(最大剂量不超过2.5 mg/d),1次/d顿服,同时给予螺内酯1~2 mg·kg-1·d-1,分次口服;GnRHa组30例,采用GnRHa治疗,首剂3.75 mg,以后按60~100 μg/kg每28 d注射1次;无干预组17例,无任何干预措施。比较各组身高增长速度(HV)、骨龄差值/时序年龄差值比值(ΔBA/ΔCA)及成年身高,同时观察来曲唑治疗的不良反应。结果: 来曲唑组在治疗过程中HV维持在相对较高水平,而GnRHa组治疗的前半年HV稍低于来曲唑组,半年后HV回落明显,显著低于来曲唑组(P < 0.05)。在骨龄控制方面,来曲唑组第一年和次年的ΔBA/ΔCA逐渐下降,分别为0.67±0.09和0.50±0.15;而GnRHa组则分别为0.59±0.16和0.44±0.13,均低于来曲唑组且差异有统计学意义(t=2.78和2.20,均P < 0.05)。来曲唑及GnRHa治疗后患儿成年身高分别为(170±4)cm和(170±6)cm,差异无统计学意义(P>0.05),均高于无干预组患儿成年身高(162±4)cm(均P < 0.01)。来曲唑治疗6个月后,患儿睾丸容积及血睾酮增加。39.2%(11/28)的患儿出现高雄激素临床表现,82.1%(23/28)的患儿治疗过程中出现血高密度脂蛋白(HDL)降低,终止治疗后高雄激素表现消失,血睾酮及血HDL恢复正常。血三酰甘油、血低密度脂蛋白(LDL)、空腹胰岛素、血糖及胰岛素抵抗指数在治疗过程中无显著变化(均P>0.05),未见肝功能异常、关节或肌肉疼痛、脊柱侧弯发生或加重者。结论: 对于青春期ISS男性患儿,长疗程来曲唑可有效延缓骨龄增长,同时不会使HV减速,从而达到有效改善成年身高的远期效果,且未见明显不良反应。


关键词: 身材矮小症,  芳香酶抑制剂,  来曲唑,  男童,  青春期,  治疗效果,  安全性,  身材矮小症,  芳香酶抑制剂,  来曲唑,  男童,  青春期,  治疗效果,  安全性 
组别 n 年龄(岁) 骨龄(岁) 年龄别身高标准差分值 骨龄别身高标准差分值 睾丸容积
(mL)
预测成年身高
(cm)
遗传靶身高
(cm)
“—”:无相关数据.GnRHa:促性腺激素释放激素类似物.
来曲唑组 28 13.2±0.7 12.9±0.5 -2.3±0.8 -1.65±0.51 10.5±4.6 160.9±3.3 168.1±2.7
GnRHa组 30 12.4±1.1 13.0±0.4 -2.2±0.7 -1.58±0.75 11.1±4.4 160.2±3.0 168.5±3.2
无干预组 17 13.7±1.4 12.6±0.9 -2.4±0.9 -1.61±0.85 10.6±5.2 160.3±3.3 170.0±3.7
F 1.47 2.35 0.73 2.12 0.13 0.11 1.31
P 0.05 0.05 0.05 0.05 0.05 0.05 0.05
Tab 1 Baseline characteristics of the participants (${\bar x}$±s)
组别 n 疗程(年) 第一个半年HV(cm/年) 第二个半年HV(cm/年) 次年HV(cm/年) ΔBA/ΔCA ΔHtSDSBA 成年身高(cm) FHSDSTHt
“—”:无相关数据.与来曲唑组比较, *P<0.05, **P<0.01.GnRHa:促性腺激素释放激素类似物;HV:身高增长速度;ΔBA/ΔCA:骨龄差值/时序年龄差值;ΔHtSDSBA:骨龄别身高标准差分值;FAHSDSTHt:按遗传靶身高校正的成年身高标准差分值.
来曲唑组 28 2.1±0.7 8.4±1.7 7.4±1.9 6.2±2.1 0.60±0.16 0.96±0.48 170±4 0.3±0.9
GnRHa组 30 2.3±0.6 7.2±1.8* 4.8±1.4* 4.4±1.0* 0.53±0.33* 0.87±0.41 170±6 0.2±0.7
无干预组 17 8.6±1.3 7.4±1.9 4.2±1.7* 1.12±0.35 0.11±0.26* 162±4** -1.6±0.8*
F 4.49 11.52 7.08 39.55 20.51 17.60 29.63
P <0.05 0.01 0.01 0.01 0.01 0.01 0.01
Tab 2 The height velocity, bone age and final adult height in three groups (${\bar x}$±s)
[1]   杜敏联 . 青春期内分泌学[M]. 北京: 人民卫生出版社, 2006: 320- 323
DU Minlian . Adolescent endocrinology[M]. Beijing: People's Medical Publishing House, 2006: 320- 323
[2]   罗小平 . 身材矮小症儿童诊疗规范[M]. 北京: 人民卫生出版社, 2019: 24- 29
LUO Xiaoping . Diagnosis and management of short stature in children[M]. Beijing: People's Medical Publishing House, 2019: 24- 29
[3]   MAGIAKOU M A , MANOUSAKI D , PAPADAKI M et al. The efficacy and safety of gonadotropin-releasing hormone analog treatment in childhood and adolescence:a single center, long-term follow-up study[J]. J Clin Endocrinol Metab, 2010, 95 (1): 109- 117
doi: 10.1210/jc.2009-0793
[4]   HERO M . Aromatase inhibitors in the treatment of short stature[J]. Endocr Dev, 2016, 30 130- 140
doi: 10.1159/000439338
[5]   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
[6]   WICKMAN S , SIPIL? I , ANKARBERG-LINDGREN C et al. A specific aromatase inhibitor and potential increase in adult height in boys with delayed puberty:a randomised controlled trial[J]. Lancet, 2001, 357 (9270): 1743- 1748
doi: 10.1016/S0140-6736(00)04895-9
[7]   SALEHPOUR S , ALIPOUR P , RAZZAGHY-AZAR M et al. A double-blind, placebo-controlled comparison of letrozole to oxandrolone effects upon growth and puberty of children with constitutional delay of puberty and idiopathic short stature[J]. Horm Res Paediatr, 2010, 74 (6): 428- 435
doi: 10.1159/000315482
[8]   NEELY E K , KUMAR R B , PAYNE S L et al. Letrozole vs anastrozole for height augmentation in short pubertal males:first year data[J]. J Clin Endocrinol Metab, 2014, 99 (11): 4086- 4093
doi: 10.1210/jc.2014-2432
[9]   SHAMS K , CAMEO T , FENNOY I et al. Outcome analysis of aromatase inhibitor therapy to increase adult height in males with predicted short adult stature and/or rapid pubertal progress:a retrospective chart review[J]. J Pediatr Endocrinol Metab, 2014, 27 (7-8): 725- 730
doi: 10.1515/jpem-2013-0470
[10]   MAURAS N , GONZALEZ DE PIJEM L , HSIANG H Y et al. Anastrozole increases predicted adult height of short adolescentmales treated with growth hormone:a randomized, placebo-controlled, multicenter trial for one to three years[J]. J Clin Endocrinol Metab, 2008, 93 (3): 823- 831
doi: 10.1210/jc.2007-1559
[11]   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
[12]   GEFFNER M E . Aromatase inhibitors to augment height:continued caution and study required[J]. J Clin Res Pediatr Endocrinol, 2009, 1 (6): 256- 261
doi: 10.4274/jcrpe.v1i6.256
[13]   CAREL J C , LéGER J . Clinical practice. Precocious puberty[J]. N Engl J Med, 2008, 358 (22): 2366- 2377
doi: 10.1056/NEJMcp0800459
[14]   李燕虹, 朱顺叶, 马华梅 et al. 促性腺激素释放激素类似物联合司坦唑醇治疗改善大骨龄特发性中枢性性早熟女孩成年身高的疗效评价[J]. 中华儿科杂志, 2013, 51 (11): 807- 812
LI Yanhong , ZHU Shunye , MA Huamei et al. Effect of gonadotropin-releasing hormone analog combined with stanazolol on final height in girls with idiopathic central precocious puberty and apparent decrease of linear growth[J]. Chinese Journal of Pediatrics, 2013, 51 (11): 807- 812
doi: 10.3760/cma.j.issn.0578-1310.2013.11.002
[15]   LAZAR L , LEVY S , ORON T et al. The beneficial effect of combined gh/gnrha therapy in increasing adult height outcome in children with ISS[J]. J Clin Endocrinol Metab, 2019, 104 (8): 3287- 3295
doi: 10.1210/jc.2019-00233
[16]   KHAWAJA N , OWAINEH H , BATIEHA A et al. The effect of gonadotropin-releasing hormone analogue on final adult height in children with idiopathic short stature[J]. Med Princ Pract, 2019, 28 (6): 509- 516
doi: 10.1159/000499929
[17]   BULUN S E , TAKAYAMA K , SUZUKI T et al. Organization of the human aromatase p450(CYP19) gene[J]. Semin Reprod Med, 2004, 22 (1): 5- 9
doi: 10.1055/s-2004-823022
[18]   CARANI C , QIN K , SIMONI M et al. Effect of testosterone and estradiol in a man with aromatase deficiency[J]. N Engl J Med, 1997, 337 (2): 91- 95
doi: 10.1056/NEJM199707103370204
[19]   SMITH E P , BOYD J , FRANK G R et al. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man[J]. N Engl J Med, 1994, 331 (16): 1056- 1061
doi: 10.1056/NEJM199410203311604
[20]   VARIMO T , TOIVIAINEN-SALO S , RAIVIO T et al. Letrozole monotherapy in pre-and early-pubertal boys does not increase adult height[J]. Front Endocrinol (Lausanne), 2019, 10 201
doi: 10.3389/fendo.2019.00201
[21]   HERO M , WICKMAN S , DUNKEL L . Treatment with the aromatase inhibitor letrozole during adolescence increases near-final height in boys with constitutional delay of puberty[J]. Clin Endocrinol (Oxf), 2006, 64 (5): 510- 513
doi: 10.1111/j.1365-2265.2006.02499.x
[22]   林娟, 马华梅, 李燕虹 et al. 来曲唑对青春早中期男童生殖功能与线性生长的近期影响[J]. 中山大学学报(医学版), 2018, 39 (3): 386- 392
LIN Juan , MA Huamei , LI Yanhong et al. Effect of letrozole on the reproductive function and linear growth in the early and mid puberty boys[J]. Journal of Sun Yat-sen University (Medical Sciences), 2018, 39 (3): 386- 392
doi: 10.13471/j.cnki.j.sun.yat-sen.univ(med.sci).2018.0059
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