Efficacy and safety of the third-generation non-steroidal aromatase inhibitors for children with short stature: a systematic review_Chinese Journal of Evidence-Based Medicine

Authors：

LIU Zheng ^1,2,3,4,5 , YANG Chunsong ^1,2,3,4 , ZENG Linan ^1,2,3,4 , JIA Zhijun ^1,2,3,4,6 , CHENG Guo ^4,7,8 , YU Qin ^4,9 ,  WU Jin ^4,7 ,  ZHANG Lingli ^1,2,3,4,10

1. Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu 610041, P. R. China;
2. Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu 610041, P. R. China;
3. NMPA Key Laboratory for Technical Research on Drug Products In Vitro and In Vivo Correlation, Chengdu 610041, P. R. China;
4. Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu 610041, P. R. China;
5. West China School of Medicine, Sichuan University, Chengdu 610041, P. R. China;
6. West China School of Pharmacy, Sichuan University, Chengdu 610041, P. R. China;
7. Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, P. R. China;
8. Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Sichuan University, Chengdu 610041, P. R. China;
9. National Drug Clinical Trial Institute, West China Second University Hospital, Sichuan University, Chengdu 610041, P. R. China;
10. Chinese Evidence-based Medicine Center, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;

Corresponding?author：

WU Jin, Email: wangdo620@163.com

Keywords：

Aromatase inhibitors; Letrozole; Anastrozole; Recombinant human growth hormone; Short stature; Systematic review

DOI：

10.7507/1672-2531.202307118

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Objective The growth potential of children with short stature in middle and late adolescence may be limited by the effect of estrogen on epiphyseal closure. In recent years, the third generation of non-steroidal aromatase inhibitors (AIs) have been used in the treatment of short stature but with off-label. This study aimed to systematically review the efficacy and safety of the third-generation non-steroidal AIs in the treatment of children with short stature, and to provide evidences for rational drug use in clinical practice. Methods We searched PubMed, Embase, Cochrane Library, CNKI, WanFang Data, VIP and CBM from inception to December 28, 2022. Relevant studies on the treatment for children with short stature using the recombinant human growth hormone (rhGH) combined with or without the third-generation non-steroidal AIs were collected. Two reviewers independently screened the literature, extracted data, and evaluated the risk of bias of the included studies. Meta-analysis was performed using RevMan 5.3 software. Results A total of 18 articles were finally included, involving 9 randomized controlled trials and 9 cohort studies, with a total of 1 053 patients. The Meta-analysis showed that: (1) in terms of efficacy, the final adult height (MD=2.48, 95%CI 2.02 to 2.94, P<0.01), predicted adult height (MD=4.27, 95%CI 2.71 to 5.83, P<0.01), predicted adult height difference (MD=4.26, 95%CI 3.23 to 5.28, P<0.01), bone age (MD=?0.62, 95%CI ?0.89 to ?0.36, P<0.01), bone age difference/actual age difference (MD=?0.47, 95%CI ?0.56 to ?0.37, P<0.01), and growth velocity (MD=1.34, 95%CI 0.89 to 1.78, P<0.01) at the end of treatment in the experimental group were better than those in the control group, but there was no statistical difference in the height at the end of treatment between the two groups (MD=4.03, 95%CI ?0.01 to 8.06, P=0.05). (2) in terms of safety, the total incidence of adverse events in the experimental group (RR=2.10, 95%CI 1.48 to 2.99, P<0.01) was higher than that in the control group, among which the incidence of adverse events in the endocrine system and skin and subcutaneous tissue system was statistically different between the two groups (P<0.05), and the incidence of adverse events in the hepatobiliary system, kidney and urinary system, metabolism and nutrition, gastrointestinal system, musculoskeletal system, blood and lymph system, vascular and lymphatic system, and neuropsychiatric system was not statistically different between the two groups (P>0.05). Conclusion Current evidence shows that the third-generation non-steroidal AIs combined with rhGH can effectively improve the final height of children with short stature, but it may increase the incidence of adverse drug events. Limited by the quality and the follow-up period of the included studies, high-quality studies are still needed to demonstrate the above conclusions and further evaluate the long-term safety of AIs in children with short stature.

Citation： LIU Zheng, YANG Chunsong, ZENG Linan, JIA Zhijun, CHENG Guo, YU Qin, WU Jin, ZHANG Lingli. Efficacy and safety of the third-generation non-steroidal aromatase inhibitors for children with short stature: a systematic review. Chinese Journal of Evidence-Based Medicine, 2024, 24(4): 429-438. doi: 10.7507/1672-2531.202307118 Copy

1.	Ma J, Pei T, Dong F, et al. Spatial and demographic disparities in short stature among school children aged 7-18 years: a nation-wide survey in China, 2014. BMJ Open, 2019, 9(7): e026634.
2.	潘丹丹, 劉建華, 魯承熙, 等. 重組人生長激素治療青春晚期大骨齡特發性矮小女童必要性研究. 中國兒童保健雜志, 2016, 24(10): 1077-1080.
3.	Peng X, Cao R, Wang Y, et al. Body image dissatisfaction and aggressive behavior among chinese children at different pubdertal stages: a path analysis. Psychol Res Behav Manag, 2022, 15: 2573-2586.
4.	Murray PG, Clayton PE, Chernausek SD. A genetic approach to evaluation of short stature of undetermined cause. Lancet Diabetes Endocrinol, 2018, 6(7): 564-574.
5.	中華醫學會兒科學分會內分泌遺傳代謝學組, 《中華兒科雜志》編輯委員會, 梁雁. 基因重組人生長激素兒科臨床規范應用的建議. 中華兒科雜志, 2013, 51(6): 426-432.
6.	Frank GR. The role of estrogen in pubertal skeletal physiology: epiphyseal maturation and mineralization of the skeleton. Acta Paediatr, 1995, 84(6): 627-630.
7.	歐陽力雪, 楊凡. 芳香化酶抑制劑在矮身材青少年男童中的應用研究進展. 中華實用兒科臨床雜志, 2020, 35(9): 712-715.
8.	McGrath N, O'Grady MJ. Aromatase inhibitors for short stature in male children and adolescents. Cochrane Database Syst Rev, 2015(10): CD010888.
9.	Brown EG, Wood L, Wood S. The medical dictionary for regulatory activities (MedDRA). Drug Saf, 1999, 20(2): 109-117.
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. Int J Pediatr Endocrinol, 2015, 2015(1): 4.
11.	Mauras N, Ross JL, Gagliardi P, et al. Randomized Trial of Aromatase Inhibitors, Growth Hormone, or Combination in Pubertal Boys with Idiopathic, Short Stature. J Clin Endocrinol Metab, 2016, 101(12): 4984-4993.
12.	王偉, 王燕, 肖雅, 等. 分析來曲唑聯合重組人生長激素對快進展型青春期大骨齡特發性矮小男童的療效. 中文科技期刊數據庫(引文版)醫藥衛生, 2022(3): 278-281.
13.	喬玉. 青春期大骨齡矮身材兒童治療方案的真實世界研究. 濟南: 山東大學, 2021.
14.	王曉寧. 芳香化酶抑制劑聯合rhGH治療男性特發性矮小癥患兒的療效觀察. 國際內分泌代謝雜志, 2019, 39(5): 298-301.
15.	王強, 牛忠鵬. 來曲唑輔助治療生長激素缺乏型矮小癥男童的臨床價值. 兒科藥學雜志, 2022, 28(3): 41-44.
16.	劉洪清. 芳香化酶抑制劑聯合重組人生長激素治療青春期大骨齡療效觀察. 自我保健, 2022, 26(21): 60-61.
17.	孔元梅, 陳虹, 梁黎, 等. 芳香化酶抑制劑聯合生長激素治療青春期身材矮小癥男性患兒的臨床研究. 浙江大學學報(醫學版), 2020, 49(3): 283-290.
18.	Mauras N, Gonzalez de Pijem L, Hsiang HY, 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 Clin Endocrinol Metab, 2008, 93(3): 823-831.
19.	宋靖榮, 董焱. AI聯合rhGH對男性特發性矮小癥患兒生長速率、骨密度及骨代謝的影響. 醫學綜述, 2020, 26(24): 4952-4956.
20.	張薔, 劉麗君, 李金英, 等. 來曲唑改善青春期特發性矮小癥男童身高的療效觀察. 實用醫學雜志, 2021, 37(3): 369-373.
21.	張先來. 基因重組人生長激素聯合來曲唑治療大骨齡矮小兒童的療效研究. 中國婦幼健康研究, 2017, (S4): 495-496.
22.	王慧, 莊昭明. 重組人生長激素聯合芳香化酶抑制劑治療特發性矮小癥的效果及安全性. 中外醫學研究, 2020, 18(8): 32-34.
23.	連群, 蔣清斌, 李伶俐, 等. 來曲唑聯合生長激素治療青春期生長激素缺乏癥男孩對成年身高的影響. 中國衛生標準管理, 2016, 7(13): 105-108.
24.	張薔, 劉麗君, 李金英, 等. 重組人生長激素聯合來曲唑治療青春期特發性矮小癥男性患兒的療效觀察. 中國兒童保健雜志, 2021, 29(7): 802-805.
25.	王俊輝. 芳香化酶抑制劑聯合生長激素治療男性青春期矮小的療效評價. 杭州: 杭州師范大學, 2019.
26.	張瑩, 陳瑞敏, 楊曉紅, 等. 重組人生長激素聯合來曲唑治療男性青春期矮小臨床分析. 中國實用兒科雜志, 2019, 34(9): 775-779.
27.	Mauras N, Welch S, Rini A, et al. An open label 12-month pilot trial on the effects of the aromatase inhibitor anastrozole in growth hormone (GH)-treated GH deficient adolescent boys. J Pediatr Endocrinol Metab, 2004, 17(12): 1597-1606.
28.	詹舒敏, 彭偉, 董關萍, 等. 生長板成熟與分化調控機制概述. 中華實用兒科臨床雜志, 2022, 37(20): 1596-1600.
29.	王春林, 梁黎. 第三代非甾體類芳香化酶抑制劑在兒科內分泌臨床應用的再認識. 浙江大學學報(醫學版), 2020, 49(3): 275-282.
30.	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. Folia Histochem Cytobiol, 2014, 52(3): 206-217.
31.	Pilutin A, Misiakiewicz-Has K, Rzeszotek S, et al. Morphological and morphometric changes and epithelial apoptosis are induced in the rat epididymis by long-term letrozole treatment. Eur J Histochem, 2021, 65(3): 3259.
32.	林娟, 馬華梅, 李燕虹, 等. 來曲唑對青春早中期男童生殖功能與線性生長的近期影響. 中山大學學報(醫學科學版), 2018, 39(3): 386-392.

1. Ma J, Pei T, Dong F, et al. Spatial and demographic disparities in short stature among school children aged 7-18 years: a nation-wide survey in China, 2014. BMJ Open, 2019, 9(7): e026634.
2. 潘丹丹, 劉建華, 魯承熙, 等. 重組人生長激素治療青春晚期大骨齡特發性矮小女童必要性研究. 中國兒童保健雜志, 2016, 24(10): 1077-1080.
3. Peng X, Cao R, Wang Y, et al. Body image dissatisfaction and aggressive behavior among chinese children at different pubdertal stages: a path analysis. Psychol Res Behav Manag, 2022, 15: 2573-2586.
4. Murray PG, Clayton PE, Chernausek SD. A genetic approach to evaluation of short stature of undetermined cause. Lancet Diabetes Endocrinol, 2018, 6(7): 564-574.
5. 中華醫學會兒科學分會內分泌遺傳代謝學組, 《中華兒科雜志》編輯委員會, 梁雁. 基因重組人生長激素兒科臨床規范應用的建議. 中華兒科雜志, 2013, 51(6): 426-432.
6. Frank GR. The role of estrogen in pubertal skeletal physiology: epiphyseal maturation and mineralization of the skeleton. Acta Paediatr, 1995, 84(6): 627-630.
7. 歐陽力雪, 楊凡. 芳香化酶抑制劑在矮身材青少年男童中的應用研究進展. 中華實用兒科臨床雜志, 2020, 35(9): 712-715.
8. McGrath N, O'Grady MJ. Aromatase inhibitors for short stature in male children and adolescents. Cochrane Database Syst Rev, 2015(10): CD010888.
9. Brown EG, Wood L, Wood S. The medical dictionary for regulatory activities (MedDRA). Drug Saf, 1999, 20(2): 109-117.
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. Int J Pediatr Endocrinol, 2015, 2015(1): 4.
11. Mauras N, Ross JL, Gagliardi P, et al. Randomized Trial of Aromatase Inhibitors, Growth Hormone, or Combination in Pubertal Boys with Idiopathic, Short Stature. J Clin Endocrinol Metab, 2016, 101(12): 4984-4993.
12. 王偉, 王燕, 肖雅, 等. 分析來曲唑聯合重組人生長激素對快進展型青春期大骨齡特發性矮小男童的療效. 中文科技期刊數據庫(引文版)醫藥衛生, 2022(3): 278-281.
13. 喬玉. 青春期大骨齡矮身材兒童治療方案的真實世界研究. 濟南: 山東大學, 2021.
14. 王曉寧. 芳香化酶抑制劑聯合rhGH治療男性特發性矮小癥患兒的療效觀察. 國際內分泌代謝雜志, 2019, 39(5): 298-301.
15. 王強, 牛忠鵬. 來曲唑輔助治療生長激素缺乏型矮小癥男童的臨床價值. 兒科藥學雜志, 2022, 28(3): 41-44.
16. 劉洪清. 芳香化酶抑制劑聯合重組人生長激素治療青春期大骨齡療效觀察. 自我保健, 2022, 26(21): 60-61.
17. 孔元梅, 陳虹, 梁黎, 等. 芳香化酶抑制劑聯合生長激素治療青春期身材矮小癥男性患兒的臨床研究. 浙江大學學報(醫學版), 2020, 49(3): 283-290.
18. Mauras N, Gonzalez de Pijem L, Hsiang HY, 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 Clin Endocrinol Metab, 2008, 93(3): 823-831.
19. 宋靖榮, 董焱. AI聯合rhGH對男性特發性矮小癥患兒生長速率、骨密度及骨代謝的影響. 醫學綜述, 2020, 26(24): 4952-4956.
20. 張薔, 劉麗君, 李金英, 等. 來曲唑改善青春期特發性矮小癥男童身高的療效觀察. 實用醫學雜志, 2021, 37(3): 369-373.
21. 張先來. 基因重組人生長激素聯合來曲唑治療大骨齡矮小兒童的療效研究. 中國婦幼健康研究, 2017, (S4): 495-496.
22. 王慧, 莊昭明. 重組人生長激素聯合芳香化酶抑制劑治療特發性矮小癥的效果及安全性. 中外醫學研究, 2020, 18(8): 32-34.
23. 連群, 蔣清斌, 李伶俐, 等. 來曲唑聯合生長激素治療青春期生長激素缺乏癥男孩對成年身高的影響. 中國衛生標準管理, 2016, 7(13): 105-108.
24. 張薔, 劉麗君, 李金英, 等. 重組人生長激素聯合來曲唑治療青春期特發性矮小癥男性患兒的療效觀察. 中國兒童保健雜志, 2021, 29(7): 802-805.
25. 王俊輝. 芳香化酶抑制劑聯合生長激素治療男性青春期矮小的療效評價. 杭州: 杭州師范大學, 2019.
26. 張瑩, 陳瑞敏, 楊曉紅, 等. 重組人生長激素聯合來曲唑治療男性青春期矮小臨床分析. 中國實用兒科雜志, 2019, 34(9): 775-779.
27. Mauras N, Welch S, Rini A, et al. An open label 12-month pilot trial on the effects of the aromatase inhibitor anastrozole in growth hormone (GH)-treated GH deficient adolescent boys. J Pediatr Endocrinol Metab, 2004, 17(12): 1597-1606.
28. 詹舒敏, 彭偉, 董關萍, 等. 生長板成熟與分化調控機制概述. 中華實用兒科臨床雜志, 2022, 37(20): 1596-1600.
29. 王春林, 梁黎. 第三代非甾體類芳香化酶抑制劑在兒科內分泌臨床應用的再認識. 浙江大學學報(醫學版), 2020, 49(3): 275-282.
30. 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. Folia Histochem Cytobiol, 2014, 52(3): 206-217.
31. Pilutin A, Misiakiewicz-Has K, Rzeszotek S, et al. Morphological and morphometric changes and epithelial apoptosis are induced in the rat epididymis by long-term letrozole treatment. Eur J Histochem, 2021, 65(3): 3259.
32. 林娟, 馬華梅, 李燕虹, 等. 來曲唑對青春早中期男童生殖功能與線性生長的近期影響. 中山大學學報(醫學科學版), 2018, 39(3): 386-392.

Chinese Journal of Evidence-Based Medicine

Efficacy and safety of the third-generation non-steroidal aromatase inhibitors for children with short stature: a systematic review

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