Please wait a minute...
J Zhejiang Univ (Med Sci)
    
Efficacy of aromatase inhibitor 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
Download: HTML (   PDF(412KB)
Export: BibTeX | EndNote (RIS)      

Abstract  To evaluate the efficacy and safety of aromatase inhibitors (AIS) 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 First Affiliated Hospital, Sun Yat-Sen University. Among 75 patients, 28 in AI group received letrozole and spironolactone; 30 in GnRHa group received GnRHa injection and 17 had no intervention. Height velocity (HV), increment of bone age/chronological age (ΔBA/△CA),the final adult height (FAH) were compared among three groups and the safety of AIS was evaluated. Results: HV maintained faster during AI therapy 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 AI group (P<0.05). The maturation of BA slowed down in both AI and GnRHa groups. But the △BA/△CA in AI group during the first and the second year of treatment were significantly higher (0.67±0.09, 0.50±0.1, respectively) when compared with GnRHa group (0.59±0.16, 0.44±0.13, respectively) (t=2.78, P<0.05, t=2.20,P<0.05). FAH in AI group and GnRHa group were (170±4)cm and (170±6)cm, there was no significant differences between the 2 groups (P>0.05), and both were higher than that in no intervention group (162±4cm, P<0.01). After 6 months of AI treatment, testicular volumes and serum testerone levels increased significantly; 39.2% (11/28) had clinical manifestations of hyperandrogenemia. During AI therapy, 82.1% (23/28) had serum high-density lipoprotein cholesterol (HDL-C) levels decreased slightly, however, serum levels of HDL-C and testerone returned normal and the hyperandrogenemia disappeared after the cessation of AI therapy. No significant changes of serum triglyceride, serum low-density lipoprotein cholesterol (LDL-C), fating serum levels of insulin and glucose, HOMA-IR were found. No one had abnormal liver function, myalgia, scoliosis or aggravations of scoliosis. Conclusion: Long term AI (letrozole) therapy during puberty in male with idiopathic short stature can delay bone maturation without significant decrease of linear growth, and thus can improve the final adult height. No severe adverse reactions were found in our study.

Key wordsShort stature      Aromatase inhibitors      Letrozole      Boys      Adult height      Puberty     
Received: 11 December 2019      Published: 29 May 2020
CLC:  R588  
  R745.8  
Cite this article:

LI Yanhong, DU Minlian, MA Huamei, CHEN Qiuli, CHEN Hongshan, ZHANG Jun.. Efficacy of aromatase inhibitor in treatment of male adolescents with idiopathic short stature. J Zhejiang Univ (Med Sci), 0, 0(0): 5-0.

URL:

http://www.zjujournals.com/med/10.3785/j.issn.1008-9292.2020.04.05     OR     http://www.zjujournals.com/med/Y0/V0/I0/5


芳香化酶抑制剂改善青春期特发性矮小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治疗已进入青春期的特发性矮小身材(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AI组、促性腺激素释放激素类似物(GnRHa)组和无干预组。其中,AI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60~100μg/kg每28 d注射1次;无干预组17例,无任何干预措施。比较各组身高生长速度(HV)、骨龄/年龄增长比值(ΔBA/△CA)及成年身高,同时观察AI治疗的不良反应。结果 AI组在治疗过程中HV维持在相对较高水平,而GnRHa组治疗的头半年HV稍低于AI组,半年后HV回落明显,显著低于AI组(P<0.05)。在骨龄控制方面,AI组第一年和次年的△BA/△CA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AI组且差异有统计学意义(t=2.78和2.20,均P<0.05)。AI及GnRHa治疗后成年身高分别为(170±4)cm,(170±6)cm,差异无统计学意义(P>0.05),均高于无干预组的成年身高(162±4)cm(均P <0.01)。AI治疗6个月后,患儿睾丸容积及血睾酮增加。39.2%(11/28)出现高雄激素表现,82.1%(23/28)治疗过程中出现血高密度脂蛋白(HDL)降低,但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)、空腹胰岛素及血糖以及胰岛素抵抗指数在治疗过程无显著变化(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,长疗程的芳香化酶抑制剂(来曲唑)可有效延缓骨龄增长,同时不会使身高生长速度减速,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,  芳香化酶抑制剂,  来曲唑,  男童,  成年身高,  青春期 
[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. (in Chinese)
[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. (in Chinese)
[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, SIPILÄ 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 adolescent males 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,等. 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.DOI:10.3760/cma.j.issn.0578-1310.2013.11.002. 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. (in Chinese)
[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,等. 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.(in Chinese)
[1] ZHU Mingqiang,FU Junfen,LIANG Li,GONG Cunxiu,XIONG Feng,LIU Geli,LUO Fei. Epidemiologic study on current pubertal development in Chinese school-aged children
 
[J]. J Zhejiang Univ (Med Sci), 2013, 42(4): 396-.
[2] WANG Anru,YANG Fangling YU Baosheng,SHAN Ye,GAO Lanying,ZHANG Xiaoxiao,PENG Ya. Hand and wrist bone maturation in children with central precocious puberty and idiopathic short stature[J]. J Zhejiang Univ (Med Sci), 2013, 42(4): 411-.
[3] 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]. J Zhejiang Univ (Med Sci), 0, 0(0): 6-0.
[4] WANG Chunlin, LIANG Li. Reconsideration of the third-generation non-steroidal aromatase inhibitors in clinical pediatrics[J]. J Zhejiang Univ (Med Sci), 0, 0(0): 1-0.
[5] YU Bingqing, NIE Min, WU Xueyan, MAO Jiangfeng, WANG Xi, MA Wanlu, JI Wen, HUANG Qibin, ZHANG Rui. Efficacy and safety of aromatase inhibitor letrozole in treatment of male children with disorders of sex development[J]. J Zhejiang Univ (Med Sci), 0, 0(0): 2-0.
[6] 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]. J Zhejiang Univ (Med Sci), 0, 0(0): 3-0.
[7] 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]. J Zhejiang Univ (Med Sci), 0, 0(0): 4-0.