Please wait a minute...
J Zhejiang Univ (Med Sci)
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 (   PDF(493KB)
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 year 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 patients were divided into AIs+rhGH group (n=108) and rhGH group (n=43). All patients were injected subcutaneously with recombinant human growth hormone (rhGH) 0.15~0.2 IU/kg·d, those in AIs +rhGH group were additionally given 1 mg anastrozole or 2.5 mg letrozole q.d. orally for 12 months or longer. Patients 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 △BA(bone age)/△CA(chronological age), △HtSDS-BA(height standard deviation-based on bone age)and △PAH between AIs+ rhGH group and the rhGH group(P=0.003, 0.024 and 0.015, respectively). During follow-up, 63.89% of the boys in the AIs+ rhGH group had elevated uric acid and 51.85% had decreased high-density lipoprotein (HDL); 25.93% showed severe acne, excitement, hyperactivity and irritability, 11.11% had knee pain, 4.63% had fracture, 2.78% had mild renal dysfunction, 1.85% had inactivity, drowsiness, memory loss and performance decline. In addition, 1.85% of the boys showed mild abnormal liver function, 0.93% showed impaired fasting glucose, and 0.93% showed granulocytopenia. In the rhGH group, 11.63% of patients presented with knee pain and 2.33% with impaired fasting glucose. Conclusion: AIs 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 AIs should be closely monitored during treatment. The effects of letrozole and anastrozole on adolescent boys with larger bone age and short stature need to be further studied.

Key wordsShort stature      Aromatase inhibitors      Recombinant human growth hormone      Puberty      Boys     
Received: 09 January 2020      Published: 29 May 2020
CLC:  R588  
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), 0, 0(0): 6-0.

URL:     OR


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)男性矮身材青少年的成年身高的有效性,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13岁≤骨龄≤ 15岁的青春期男孩151例,经充分告知AI的药物潜在风险后,由患儿及其家长选择入组:AIs+重组人生长激素(rhGH)联用组108例,单用rhGH组43例。治疗时间12月以上,每3个月复查一次,监测不良反应。结果:与rhGH单用组比较,AI+rhGH联用组骨龄差值/生理年龄差值(△BA/△CA)、按骨龄的身高标准差分值的差值(△HtSDS-BA)以及预测成年身高的差值(△PAH)改善更加明显(P<0.05或P<0.01)。随访期间,AI+rhGH联用组尿酸升高69例(63.89%),高密度脂蛋白(HDL)降低56例(51.85%),出现严重痤疮、兴奋多动、性格暴躁28例(25.93%),出现膝关节疼痛12例(11.11%),发生骨折5例(4.63%),出现轻度肾功能异常3例(2.78%),出现精神不振、嗜睡、记忆力减退和成绩下降2例(1.85%),出现轻度肝功能异常2例(1.85%),空腹血糖受损1例(0.93%),粒细胞减少1例(0.93%),停药后监测指标逐渐正常。rhGH单用组出现膝关节疼痛5例(11.63%),空腹血糖受损1例(2.33%)。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孩的成年终身高,但治疗期间需要密切监测AI的不良反应;来曲唑与阿那曲唑在改善大骨龄矮身材男孩治疗上的差异有待进一步研究。

关键词: 身材矮小症,  芳香化酶抑制剂,  重组人生长激素,  青春期,  男童 
[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. (in Chinese)
[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. (in Chinese)
[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,等. 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. DOI: 10.3760/cma.j.issn.0578-1310.2009.07.003. 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. (in Chinese)
[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, HANHIJÄRVI 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]. 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]. Psychoneuroendocrinology, 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]. Nucleosides Nucleotides Nucleic Acids, 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]. Nucleosides Nucleotides Nucleic Acids, 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.
[29] DIÉRAS V, HARBECK N, JOY A A, et al. Palbociclib with letrozole in postmenopausal women with er+/her2-advanced breast cancer:hematologic safety analysis of the randomized PALOMA-2 trial[J]. Oncologist, 2019,24(12):1514-1525.DOI:10.1634/theoncologist.2019-0019.
[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] 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]. J Zhejiang Univ (Med Sci), 0, 0(0): 5-0.
[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.