Aromatase inhibitors combined with growth hormone in treatment of adolescent boys with short stature

doi:10.3785/j.issn.1008-9292.2020.04.06

J Zhejiang Univ (Med Sci)

2020, Vol. 49

Issue (3): 283-290 DOI: 10.3785/j.issn.1008-9292.2020.04.06

Aromatase inhibitors combined with growth hormone in treatment of adolescent boys with short stature

KONG Yuanmei(

),CHEN Hong,LIANG Li,ZHENG Maoni,FANG Yanlan,WANG Chunlin*(

)

Department of Pediatrics, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China

Download:

HTML( 28 )

PDF(1058KB)
Export: BibTeX | EndNote (RIS)

Abstract

Objective: To assess the efficacy and safety of aromatase inhibitors (AIs) combined growth hormone in treatment of adolescent boys with short stature. Methods: One hundred and fifty-one short stature pubertal boys with age of 10-14 years and bone age of 13-15 years, who were admitted to the Department of Pediatrics, the First Affiliated Hospital, Zhejiang University School of Medicine, were included in this trial. According to their own or parents' intention, the children were divided into recombinant human growth hormone (rhGH)+AI group (n=108) and rhGH group (n=43). All children were injected subcutaneously with rhGH 0.15-0.2 IU·kg^-1·d^-1, and those in rhGH+AI group were additionally given 2.5 mg/d letrozole or 1 mg/d anastrozole, orally for 12 months or longer. The children were followed-up every 3 months. During the follow-up visit, the predicted adult height (PAH), sex hormone level, glucose and lipid metabolism, and other indicators were measured, and adverse reactions were monitored. Results: After intervention, there were significant differences in ΔBA(bone age)/ΔCA(chronological age), ΔHtSDS_BA(height standard deviation score based on bone age)and ΔPAH between rhGH+AI group and the rhGH group(P < 0.05 or P < 0.01). During follow-up, 63.9%of the children in the rhGH+AI group had elevated uric acid and 51.9%had decreased high-density lipoprotein (HDL); 25.9%showed severe acne, excitement, hyperactivity and irritability, 11.1%had knee pain; 4.6%had fracture; 2.8%had mild renal dysfunction; 1.9%had inactivity, drowsiness, memory loss and performance decline; 1.9%showed mild abnormal liver function; 0.9%showed impaired fasting glucose; 0.9%showed granulocytopenia. In the rhGH group, 11.6%of the children presented with knee pain and 2.3%with impaired fasting glucose. Conclusions: AI combined with rhGH can delay the growth of BA and effectively improve the PAH of adolescent boys with larger bone age. However, the occurrence of adverse reactions of AI should be closely monitored during treatment.

Key words： Short stature Aromatase inhibitors Recombinant human growth hormone Puberty Boys Treatment outcome Safety Short stature Aromatase inhibitors Recombinant human growth hormone Puberty Boys Treatment outcome Safety

Received: 09 January 2020 Published: 29 May 2020

CLC:	R588
	R725.8
	R588
	R725.8

Corresponding Authors: WANG Chunlin E-mail: 6512039@zju.edu.cn;hzwangcl@zju.edu.cn

	Service
	E-mail this article
	Add to my bookshelf
	Add to citation manager
	E-mail Alert
	RSS
	Articles by authors
	KONG Yuanmei
	CHEN Hong
	LIANG Li
	ZHENG Maoni
	FANG Yanlan
	WANG Chunlin

Cite this article:

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 Zhejiang Univ (Med Sci), 2020, 49(3): 283-290.

URL:

http://www.zjujournals.com/med/10.3785/j.issn.1008-9292.2020.04.06 OR http://www.zjujournals.com/med/Y2020/V49/I3/283

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

目的: 研究第三代非甾体类芳香化酶抑制剂（AI）改善大骨龄（≥13岁）男性身材矮小症青少年成年身高的有效性，同时监测药物的安全性。方法: 2015年12月—2018年11月在浙江大学医学院附属第一医院就诊的预测成年身高受损的骨龄为13~15岁的青春期男性患儿151例，经充分告知AI的潜在风险后，由患儿及其家长选择入组：重组人生长激素（rhGH）联用AI组108例（联用AI组），单用rhGH组43例（rhGH单用组）。治疗时间12月以上，每3个月复查一次，监测药物不良反应。结果: 与rhGH单用组比较，联用AI组骨龄差值与时序年龄差值的比值（ΔBA/ΔCA）、骨龄别身高标准差分值的差值（ΔHtSDS_BA）以及预测成年身高的差值（ΔPAH）改善更加明显（P < 0.05或P < 0.01）。随访期间，联用AI组尿酸升高69例（63.9%），高密度脂蛋白（HDL）降低56例（51.9%），严重痤疮、兴奋多动、性格暴躁28例（25.9%），膝关节疼痛12例（11.1%），骨折5例（4.6%），轻度肾功能异常3例（2.8%），精神不振、嗜睡、记忆力减退和成绩下降2例（1.9%），轻度肝功能异常2例（1.9%），空腹血糖受损1例（0.9%），粒细胞减少1例（0.9%），停药后监测指标逐渐恢复正常。rhGH单用组出现膝关节疼痛5例（11.6%），空腹血糖受损1例（2.3%）。结论: 长疗程的AI联合rhGH治疗可以延缓骨龄增长，有效改善青春期大骨龄矮小男性患儿的成年终身高，但治疗期间需要密切监测AI的不良反应。

关键词： 身材矮小症, 芳香酶抑制剂, 重组人生长激素, 青春期, 男童, 治疗效果, 安全性, 身材矮小症, 芳香酶抑制剂, 重组人生长激素, 青春期, 男童, 治疗效果, 安全性

Tab 1 Baseline characteristics of rhGH+AI group and rhGH group (${\bar x}$±s)

Tab 2 Efficacy of rhGH+AI and rhGH therapy for adolescent boys with short stature (${\bar x}$±s)

Tab 3 Adverse events of rhGH+AI and rhGH therapy for adolescent boys with short stature [n(%)]


[1]	NAVARRO R , DUNN J D , LEE P A et al. Translating clinical guidelines into practice:the effective and appropriate use of human growth hormone[J]. Am J Manag Care, 2013, 19 (15 Suppl): s281- s289

[2]	WIT J M , RANKE M B , ALBERTSSON-WIKLAND K et al. Personalized approach to growth hormone treatment:clinical use of growth prediction models[J]. Horm Res Paediatr, 2013, 79 (5): 257- 270 doi: 10.1159/000351025

[3]	HERO M , TOIVIAINEN-SALO S , WICKMAN S et al. Vertebral morphology in aromatase inhibitor-treated males with idiopathic short stature or constitutional delay of puberty[J]. J Bone Miner Res, 2010, 25 (7): 1536- 1543 doi: 10.1002/jbmr.56

[4]	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

[5]	PEDROSA L F , DE OLIVEIRA J M , THOMé P et al. Height increment and laboratory profile of boys treated with aromatase inhibitors with or without growth hormone[J]. Horm Metab Res, 2017, 49 (10): 778- 785 doi: 10.1055/s-0043-116944

[6]	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

[7]	中华医学会儿科学分会内分泌遗传代谢学组 . 矮身材儿童诊治指南[J]. 中华儿科杂志, 2008, 46 (6): 428- 430 Endocrine Genetic Metabolism Group, Chinese Pediatric Society, Chinese Medical Association . Guidelines for diagnosis and treatment of children with short stature[J]. Chinese Journal of Pediatrics, 2008, 46 (6): 428- 430

[8]	王卫平, 孙锟, 常立文 . 儿科学[M]. 9版北京: 人民卫生出版社, 2018: 66 WANG Weiping , SUN Kun , CHANG Liwen . Pediatrics[M]. 9th Ed Beijing: People's Medical Publishing House, 2018: 66

[9]	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

[10]	ROTHENBUHLER A , LINGLART A , BOUGNèRES P . A randomized pilot trial of growth hormone with anastrozole versus growth hormone alone, starting at the very end of puberty in adolescents with idiopathic short stature[J]. Int J Pediatr Endocrinol, 2015, 2015 (1): 4 doi: 10.1186/1687-9856-2015-4

[11]	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 H ui , 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.LI

[12]	WICKMAN S , SAUKKONEN T , DUNKEL L . The role of sex steroids in the regulation of insulin sensitivity and serum lipid concentrations during male puberty:a prospective study with a P450-aromatase inhibitor[J]. Eur J Endocrinol, 2002, 146 (3): 339- 346 doi: 10.1530/eje.0.1460339

[13]	HERO M , ANKARBERG-LINDGREN C , TASKINEN M R et al. Blockade of oestrogen biosynthesis in peripubertal boys:effects on lipid metabolism, insulin sensitivity, and body composition[J]. Eur J Endocrinol, 2006, 155 (3): 453- 460 doi: 10.1530/eje.1.02226

[14]	HERO M , WICKMAN S , HANHIJ?RVI R et al. Pubertal upregulation of erythropoiesis in boys is determined primarily by androgen[J]. J Pediatr, 2005, 146 (2): 245- 252 doi: 10.1016/j.jpeds.2004.09.002

[15]	HERO M , MAURY S , LUOTONIEMI E et al. Cognitive effects of aromatase inhibitor therapy in peripubertal boys[J]. Eur J Endocrinol, 2010, 163 (1): 149- 155 doi: 10.1530/EJE-10-0040

[16]	WIT J M , HERO M , NUNEZ S B . Aromatase inhibitors in pediatrics[J]. Nat Rev Endocrinol, 2011, 8 (3): 135- 147 doi: 10.1038/nrendo.2011.161

[17]	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.

[18]	T'SJOEN G G , GIAGULLI V A , DELVA H et al. Comparative assessment in young and elderly men of the gonadotropin response to aromatase inhibition[J]. J Clin Endocrinol Metab, 2005, 90 (10): 5717- 5722 doi: 10.1210/jc.2005-0982

[19]	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

[20]	GOUDRIAAN A E , LAPAUW B , RUIGE J et al. The influence of high-normal testosterone levels on risk-taking in healthy males in a 1-week letrozole administration study[J]. Psychoneuro-endocrinology, 2010, 35 (9): 1416- 1421 doi: 10.1016/j.psyneuen.2010.04.005

[21]	KIL K E , BIEGON A , DING Y S et al. Synthesis and PET studies of[(11)C-cyano]letrozole (Femara), an aromatase inhibitor drug[J]. Nucl Med Biol, 2009, 36 (2): 215- 223 doi: 10.1016/j.nucmedbio.2008.11.010

[22]	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

[23]	MORRISON J A , SPRECHER D L , BIRO F M et al. Serum testosterone associates with lower high-density lipoprotein cholesterol in black and white males, 10 to 15 years of age, through lowered apolipoprotein AI and AII concentrations[J]. Metabolism, 2002, 51 (4): 432- 437 doi: 10.1053/meta.2002.31321

[24]	TAKIUE Y , HOSOYAMADA M , KIMURA M et al. The effect of female hormones upon urate transport systems in the mouse kidney[J]. Nucleos Nucleot Nucl, 2011, 30 (2): 113- 119 doi: 10.1080/15257770.2010.551645

[25]	ZENG M , CHEN B , QING Y et al. Estrogen receptor beta signaling induces autophagy and downregulates Glut9 expression[J]. Nucleos Nucleot Nucl, 2014, 33 455- 465 doi: 10.1080/15257770.2014.885045

[26]	BUDHIRAJA R , KAYYALI U S , KARAMSETTY M et al. Estrogen modulates xanthine dehydrogenase/xanthine oxidase activity by a receptor-independent mechanism[J]. Antioxid Redox Signal, 2003, 5 (6): 705- 711 doi: 10.1089/152308603770380007

[27]	BRYZGALOVA G , GAO H , AHREN B et al. Evidence that oestrogen receptor-alpha plays an important role in the regulation of glucose homeostasis in mice:insulin sensitivity in the liver[J]. Diabetologia, 2006, 49 (3): 588- 597 doi: 10.1007/s00125-005-0105-3

[28]	KANBAY M , SEGAL M , AFSAR B et al. The role of uric acid in the pathogenesis of human cardiovascular disease[J]. Heart, 2013, 99 (11): 759- 766 doi: 10.1136/heartjnl-2012-302535

[1]	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]. J Zhejiang Univ (Med Sci), 2020, 49(3): 308-314.

[2]	WANG Chunlin,LIANG Li. Reconsideration of the third-generation non-steroidal aromatase inhibitors in pediatrics[J]. J Zhejiang Univ (Med Sci), 2020, 49(3): 275-282.

[3]	YU Bingqing,NIE Min,WU Xueyan,MAO Jiangfeng,WANG Xi,MA Wanlu,JI Wen,HUANG Qibin,ZHANG Rui. Efficacy and safety of letrozole in treatment of male children with disorders of sex development[J]. J Zhejiang Univ (Med Sci), 2020, 49(3): 297-301.

[4]	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), 2020, 49(3): 291-296.

[5]	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), 2020, 49(3): 302-307.

[6]	SUN Jinhong,QIU Chenyang,WU Ziheng,ZHANG Hongkun. Preliminary result of stents implantation for spontaneous isolated dissection of the superior mesenteric artery: a prospective single-arm study[J]. J Zhejiang Univ (Med Sci), 2020, 49(3): 383-388.

[7]	JIANG Saiping,LI Lu,RU Renping,ZHANG Chunhong,RAO Yuefeng,LIN Bin,WANG Rongrong,CHEN Na,WANG Xiaojuan,CAI Hongliu,SHENG Jifang,ZHOU Jianying,LU Xiaoyang,QIU Yunqing. Pharmaceutical care for severe and critically ill patients with COVID-19[J]. J Zhejiang Univ (Med Sci), 2020, 49(2): 158-169.

[8]	ZHANG Xiaoyan, SUN Wei, SHANG Shiqiang, MAO Jianhua, FU Junfen, SHU Qiang, JIANG Kewen. Principles and suggestions on biosafety protection of biological specimen preservation during prevalence of COVID-19[J]. J Zhejiang Univ (Med Sci), 2020, 49(2): 170-177.

[9]	CHEN Jun,LIU Danping,LIU Li,LIU Ping,XU Qingnian,XIA Lu,LING Yun,HUANG Dan,SONG Shuli,ZHANG Dandan,QIAN Zhiping,LI Tao,SHEN Yinzhong,LU Hongzhou. A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19[J]. J Zhejiang Univ (Med Sci), 2020, 49(2): 215-219.

[10]	GAO Mingxuan,NIE Dejun,CHANG Yanfeng,XIE Weiqiang,WANG Yue,PU Xingyu,ZHANG Wei,LUO Wenyuan. Internal fixation of lateral and medial borders for displaced scapular body fractures via minimally invasive approach: results of 23 cases[J]. J Zhejiang Univ (Med Sci), 2019, 48(6): 651-656.

[11]	LOU Junyao,HUANG Xiufeng,ZHANG Lifeng,XU Ping,ZHANG Xinmei,CHEN Zhengyun. The second generation endometrial ablation (NovaSure) improves efficacy of levonorgestrel-releasing intrauterine system in management of adenomyosis[J]. J Zhejiang Univ (Med Sci), 2019, 48(2): 136-141.

[12]	ZHANG Lifeng,YANG Hui,ZHANG Xinmei,CHEN Zhengyun. Efficacy and adverse effects of levonorgestrel-releasing intrauterine system in treatment of adenomyosis[J]. J Zhejiang Univ (Med Sci), 2019, 48(2): 130-135.

[13]	YU Zuanbiao,LIN Zuodong,LANG Dehai. Long-term efficacy of percutaneous mechanical thrombectomy combined with stent implantation in treatment of acute iliofemoral venous thrombosis[J]. J Zhejiang Univ (Med Sci), 2018, 47(6): 623-627.

[14]	SHEN Hong,JI Feng. Efficacy and safety of digestive tract stent placement under direct visual endoscopy without X-ray monitoring in treatment of digestive tract stricture[J]. J Zhejiang Univ (Med Sci), 2018, 47(6): 643-650.

[15]	YIN Xiaoliang,LANG Dehai,WANG Di. Comparison of mechanical thrombectomy with transcatheter thrombolysis for acute iliac femoral venous thrombosis[J]. J Zhejiang Univ (Med Sci), 2018, 47(6): 588-594.

Viewed

Full text

Abstract

Cited

Shared

Discussed