Please wait a minute...
浙江大学学报（医学版）
J Zhejiang Univ (Med Sci)  2020, Vol. 49 Issue (3): 275-282    DOI: 10.3785/j.issn.1008-9292.2020.04.01
    
Reconsideration of the third-generation non-steroidal aromatase inhibitors in pediatrics
WANG Chunlin(),LIANG Li*()
Department of Pediatrics, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
Download: HTML( 51 )   PDF(1066KB)
Export: BibTeX | EndNote (RIS)      

Abstract  

Aromatase is the rate-limiting enzyme in estrogen biosynthesis. The third generation aromatase inhibitors (AIs), represented by letrozoleand and anastrozole, can combine with aromatase, effectively reducing the estrogen level in the body. Because of its high efficiency, selectivity and reversibility, it has been used in the treatment of McCune-Albright syndrome, familial male-limited precocious puberty, gynecomastia, and adolescent boy with short stature. The good efficacy and safety of AIs have been observed. However, so far the drug instructions of AIs usually do not show indications for children; there are risks of adverse reactions involving liver and kidney function, lipid metabolism, hyperandrogenemia and bone metabolism; especially the long-term effects on reproductive system and bone metabolism are still not clear. Therefore, it is necessary to prescribe it carefully and follow up closely. It was not recommended that AIs be routinely used to improve adult height of adolescent boy with short stature. And more clinical evidences are needed for the safety and effectiveness of AIs prescribed in pediatrics.

Key words： Aromatase inhibitors/therapeutic use      Child      Treatment outcome      Safety     
Received: 29 November 2019      Published: 29 May 2020
CLC:  R588  
  R725.8  
Corresponding Authors: LIANG Li     E-mail: hzwangcl@zju.edu.cn;zdliangli@zju.edu.cn
Service
E-mail this article
Add to my bookshelf
Add to citation manager
E-mail Alert
RSS
Articles by authors
WANG Chunlin
LIANG Li
Cite this article:

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

URL:

http://www.zjujournals.com/med/10.3785/j.issn.1008-9292.2020.04.01     OR     http://www.zjujournals.com/med/Y2020/V49/I3/275


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

芳香化酶是雌激素生物合成的限速酶，以来曲唑和阿那曲唑为代表的第三代非甾体类芳香化酶抑制剂（AI）与芳香化酶结合，可有效降低雌激素水平，因其具有高效性、选择性及可逆性结合等特点，近20年来在国内外被应用于儿童内分泌疾病如纤维性骨营养不良综合征、家族性男性限制性性早熟、青春期男性乳房发育治疗和改善青春期矮小男童成年终身高等，观察到较好的疗效和安全性。然而，AI药品说明书并无儿童用药适应证，较大样本量的临床研究发现AI存在肝肾功能损害、脂代谢紊乱、高雄激素血症及骨代谢紊乱等药物不良反应的风险，尤其是对男性生殖系统损害和骨代谢的远期影响尚不清楚。因此，儿童使用AI时须权衡利弊、谨慎使用，通过收集AI安全性和有效性的临床证据积累经验，为规范AI在儿科的临床应用奠定基础。


关键词： 芳香酶抑制剂/治疗应用,  儿童,  治疗结果,  安全性 
种类 第一代 第二代 第三代
药物名称 适应证 药物名称 适应证 药物名称 适应证
甾体类 睾内酯 乳腺癌姑息性治疗 福美司坦 用于自然或人工绝经的乳腺癌患者 依西美坦 适用于以他莫昔芬治疗后病情进展的绝经后晚期乳腺癌患者
非甾体类 氨鲁米特 主要适用于绝经后晚期乳腺癌、乳腺癌骨转移、皮质醇增多症的治疗 法曲唑 绝经期后乳腺癌 来曲唑 用于治疗抗雌激素治疗无效的晚期乳腺癌绝经后患者
阿那曲唑 用于绝经后妇女的晚期乳腺癌的治疗
Tab 1 Classification and indications of aromatase inhibitors
[1]   SHOZU M , SEBASTIAN S , TAKAYAMA K et al. Estrogen excess associated with novel gain-of-function mutations affecting the aromatase gene[J]. N Engl J Med, 2003, 348 (19): 1855- 1865
doi: 10.1056/NEJMoa021559
[2]   SCHIFF J D , PALERMO G D , VEECK L L et al. Success of testicular sperm extraction[corrected] and intracytoplasmic sperm injection in men with Klinefelter syndrome[J]. J Clin Endocrinol Metab, 2005, 90 (11): 6263- 6267
doi: 10.1210/jc.2004-2322
[3]   于冰青, 聂敏, 伍学焱 et al. 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): 283- 287
YU Bingqing , NIE Min , WU Xueyan et al. Efficacy and safety of letrozole in treatment of male children with disorders of sex development[J]. Journal of Zhejiang University (Medical Sciences), 2020, 49 (3): 283- 287
doi: 10.3785/j.issn.1008-9292.2020.04.02.YU
[4]   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
[5]   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
[6]   孔元梅, 陈虹, 梁黎 et al. 芳香化酶抑制剂联合生长激素治疗青春期矮身材男性患儿的临床研究[J]. 浙江大学学报(医学版), 2020, 49 (3): 307- 314
KONG Yuanmei , CHEN Hong , LIANG Li et al. Aromatase inhibitors combined with growth hormone in treatment of adolescent boys with short stature[J]. Journal of Zhejiang University (Medical Sciences), 2020, 49 (3): 307- 314
doi: 10.3785/j.issn.1008-9292.2020.04.06.KONG
[7]   CHO E K , KIM J , YANG A et al. Clinical and endocrine characteristics and genetic analysis of Korean children with McCune-Albright syndrome:a retrospective cohort study[J]. Orphanet J Rare Dis, 2016, 11 (1): 113
doi: 10.1186/s13023-016-0496-x
[8]   徐德, 陆文丽, 王雪晴 et al. 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): 288- 293
D e , LU Wenli , WANG Xueqing et al. Efficacy and safety of letrozole in treatment of McCune-Albright Syndrome girls with peripheral precocious puberty[J]. Journal of Zhejiang University (Medical Sciences), 2020, 49 (3): 288- 293
doi: 10.3785/j.issn.1008-9292.2020.04.03.XU
[9]   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
[10]   慎琳, 袁珂, 赵方圆 et al. 儿童青少年男性乳腺增生的影响因素分析[J]. 中国循证儿科杂志, 2019, 14 (1): 40- 43
L in , YUAN Ke , ZHAO Fangyuan et al. Analysis of the risk factors of gynecomastia in children and adolescents[J]. Chinese Journal of Evidence Based Pediatrics, 2019, 14 (1): 40- 43
doi: 10.3969/j.issn.1673-5501.2019.01.008.SHEN
[11]   MAURAS N , BISHOP K , MERINBAUM D et al. Pharmacokinetics and pharmacodynamics of anastrozole in pubertal boys with recent-onset gynecomastia[J]. J Clin Endocrinol Metab, 2009, 94 (8): 2975- 2978
doi: 10.1210/jc.2008-2527
[12]   王敏, 李敏, 刘悦笙 et al. LHCGR基因突变(Asp578His)致家族性男性性早熟1例临床特点及基因分析[J]. 中国当代儿科杂志, 2017, 19 (11): 1159- 1164
WANG Min , LI Min , LIU Yuesheng et al. Familial male-limited precocious puberty due to Asp578His mutations in the LHCGR gene:clinical characteristics and gene analysis in an infant[J]. Chinese Journal of Contemporary Pediatrics, 2017, 19 (11): 1159- 1164
doi: 10.7499/j.issn.1008-8830.2017.11.007
[13]   LESCHEK E W , FLOR A C , BRYANT J C et al. Effect of antiandrogen, aromatase inhibitor, and gonadotropin-releasing hormone analog on adult height in familial male precocious puberty[J]. J Pediatr, 2017, 190 229- 235
doi: 10.1016/j.jpeds.2017.07.047
[14]   林娟, 马华梅, 苏喆 et al. 先天性肾上腺皮质增生症21-羟化酶缺乏患儿身高单中心25年随访研究[J]. 中国实用儿科杂志, 2016, 31 (6): 438- 443
Ju an , MA Huamei , SU Zhe et al. Near-final height of 82 Chinese patients with congenital adrenal hyperplasia due to classic 21-hydroxylase deficiency:A single-center study of 25 years' follow-up[J]. Chinese Journal of Practical Pediatrics, 2016, 31 (6): 438- 443
doi: 10.7504/ek2016060610.LIN
[15]   王倩, 张书乐, 马雪 et al. 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): 294- 299
Qi an , ZHANG Shule , MA Xue et al. Efficacy of letrozole in treatment of children with congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency[J]. Journal of Zhejiang University (Medical Sciences), 2020, 49 (3): 294- 299
doi: 10.3785/j.issn.1008-9292.2020.04.04.WANG
[16]   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
[17]   MCGRATH N , O'GRADY M J . Aromatase inhibitors for short stature in male children and adolescents[J]. Cochrane Database Syst Rev, 2015, (10): CD010888
doi: 10.1002/14651858.CD010888.pub2
[18]   PEDROSA L F , DE OLIVEIRA J M , THOMé P R V 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
[19]   COHEN P , ROGOL A D , DEAL C L et al. Consensus statement on the diagnosis and treatment of children with idiopathic short stature:a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop[J]. J Clin Endocrinol Metab, 2008, 93 (11): 4210- 4217
doi: 10.1210/jc.2008-0509
[20]   李燕虹, 杜敏联, 马华梅 et al. 来曲唑改善青春期特发性矮小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): 300- 306
LI Yanhong , DU Minlian , MA Huamei et al. Efficacy of aromatase inhibitor in treatment of male adolescents with idiopathic short stature[J]. Journal of Zhejiang University (Medical Sciences), 2020, 49 (3): 300- 306
doi: 10.3785/j.issn.1008-9292.2020.04.05.LI
[21]   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
[22]   SHARMA S, GHOSH S, SINGH S, et al. Congenital malformations among babies born following letrozole or clomiphene for infertility treatment[J/OL]. PLoS One, 2014, 9(10): e108219. DOI: 10.1371/journal.pone.0108219.
[23]   WANG R , KIM B V , VAN WELY M et al. Treatment strategies for women with WHO group II anovulation:systematic review and network meta-analysis[J]. BMJ, 2017, 356 j138
doi: 10.1136/bmj.j138
[24]   CHARMANDARI E , KINO T . Chrousos syndrome:a seminal report, a phylogenetic enigma and the clinical implications of glucocorticoid signaling changes[J]. Eur J Clin Invest, 2010, 40 (10): 932- 942
doi: 10.1111/j.1365-2362.2010.02336.x
[25]   WIT J M , OOSTDIJK W . Novel approaches to short stature therapy[J]. Best Pract Res Clin Endocrinol Metab, 2015, 29 (3): 353- 366
doi: 10.1016/j.beem.2015.01.003
[26]   PILUTIN A , MISIAKIEWICZ-HAS K , KOLASA A et al. The immunoexpression of androgen receptor, estrogen receptors alpha and beta, vanilloid type 1 receptor and cytochrome p450 aromatase in rats testis chronically treated with letrozole, an aromatase inhibitor[J]. Folia Histochem Cytobiol, 2014, 52 (3): 206- 217
doi: 10.5603/FHC.2014.0024
[27]   CAPPON G D , CHAPIN R E , HURTT M E et al. Impaired reproduction in adult male, but not female, rats following juvenile treatment with the aromatase inhibitor, exemestane[J]. Birth Defects Res B Dev Reprod Toxicol, 2011, 92 (4): 304- 313
doi: 10.1002/bdrb.20307
[28]   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
Ju an , 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
[29]   HAYES F J , SEMINARA S B , DECRUZ S et al. Aromatase inhibition in the human male reveals a hypothalamic site of estrogen feedback[J]. J Clin Endocrinol Metab, 2000, 85 (9): 3027- 3035
doi: 10.1210/jcem.85.9.6795
[30]   REZK M , SHAHEEN A E , SAIF EL-NASR I . Clomiphene citrate combined with metformin versus letrozole for induction of ovulation in clomiphene-resistant polycystic ovary syndrome:a randomized clinical trial[J]. Gynecol Endocrinol, 2018, 34 (4): 298- 300
doi: 10.1080/09513590.2017.1395838
[31]   ROSENFELD C S , SHAY D A , VIEIRA-POTTER V J . Cognitive effects of aromatase and possible role in memory disorders[J]. Front Endocrinol (Lausanne), 2018, 9 610
doi: 10.3389/fendo.2018.00610
[32]   GERVAIS N J , REMAGE-HEALEY L , STARRETT J R et al. Adverse effects of aromatase inhibition on the brain and behavior in a nonhuman primate[J]. J Neurosci, 2019, 39 (5): 918- 928
doi: 10.1523/JNEUROSCI.0353-18.2018
[33]   CHERRIER M M , MATSUMOTO A M , AMORY J K et al. The role of aromatization in testosterone supplementation:effects on cognition in older men[J]. Neurology, 2005, 64 (2): 290- 296
doi: 10.1212/01.WNL.0000149639.25136.CA
[34]   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
[35]   SANTA-MARIA C A , BLACKFORD A , NGUYEN A T et al. Association of variants in candidate genes with lipid profiles in women with early breast cancer on adjuvant aromatase inhibitor therapy[J]. Clin Cancer Res, 2016, 22 (6): 1395- 1402
doi: 10.1158/1078-0432.CCR-15-1213
[36]   MANDAL A K , MOUNT D B . The molecular physiology of uric acid homeostasis[J]. Annu Rev Physiol, 2015, 77 323- 345
doi: 10.1146/annurev-physiol-021113-170343
[37]   ROCHIRA V , ZIRILLI L , MADEO B et al. Skeletal effects of long-term estrogen and testosterone replacement treatment in a man with congenital aromatase deficiency:evidences of a priming effect of estrogen for sex steroids action on bone[J]. Bone, 2007, 40 (6): 1662- 1668
doi: 10.1016/j.bone.2007.01.022
[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] 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), 2020, 49(3): 283-290.
[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] CHEN Zhimin,FU Junfen,SHU Qiang,WANG Wei,CHEN Yinghu,HUA Chunzhen,LI Fubang,LIN Ru,TANG Lanfang,WANG Tianlin,WANG Yingshuo,XU Weize,YANG Zihao,YE Sheng,YUAN Tianming,ZHANG Chenmei,ZHANG Yuanyuan. Diagnosis and treatment recommendation for pediatric COVID-19 (the second edition)[J]. J Zhejiang Univ (Med Sci), 2020, 49(2): 139-146.
[8] 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.
[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] 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.
[11] 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.
[12] LIN Jing,CHEN Zhimin. Research progress on early identification of severe adenovirus pneumonia in children[J]. J Zhejiang Univ (Med Sci), 2019, 48(5): 567-572.
[13] 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.
[14] 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.
[15] NIU Yubai,ZHANG Lingyan,HAO Zesheng,JI Yuzhu. Relationship between temperament, parenting style and resilience of children aged 3-5 years[J]. J Zhejiang Univ (Med Sci), 2019, 48(1): 75-82.