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浙江大学学报（医学版）
浙江大学学报（医学版）  2020, Vol. 49 Issue (3): 297-301    DOI: 10.3785/j.issn.1008-9292.2020.04.02
专题报道：芳香化酶抑制剂的临床应用     
来曲唑有效提高性发育异常男性患儿的睾酮水平
于冰青(),聂敏,伍学焱*(),茅江峰,王曦,马婉璐,季文,黄奇彬,张睿
中国医学科学院北京协和医学院北京协和医院内分泌科 卫健委内分泌重点实验室, 北京 100730
Efficacy and safety of letrozole in treatment of male children with disorders of sex development
YU Bingqing(),NIE Min,WU Xueyan*(),MAO Jiangfeng,WANG Xi,MA Wanlu,JI Wen,HUANG Qibin,ZHANG Rui
Department of Endocrinology, National Health Commission Key laboratory of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
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摘要：

目的: 评价第三代非甾体类芳香化酶抑制剂来曲唑治疗男性性发育异常（DSD）患儿的疗效和安全性。方法: 收集2014年1月至2016年1月就诊于北京协和医院内分泌科门诊的男性DSD患儿12例，来曲唑治疗（1.25~2.5 mg，1次/d）不少于3个月，随访半年至2.5年。采集其临床资料及实验室检查结果，比较治疗前后激素水平及生化指标的差异，并观察治疗中的不良反应。结果: 本组患儿来曲唑治疗的平均年龄为（14.6±2.5）岁。来曲唑治疗半年后患者血促性腺激素黄体生成素（LH）、卵泡刺激素（FSH）及睾酮水平较基线升高（均P < 0.05），雌二醇水平较基线下降（P < 0.05）；治疗1年后患者睾酮水平较基线高（P < 0.05），LH及FSH水平较基线高，雌二醇水平较基线下降，但差异无统计学意义（均P>0.05）。8例患儿进行精液常规检测，其中3例尿道下裂患儿精液中可检测到精子。所有患儿治疗前后生化检查无明显变化，用药后无明显不良反应。结论: 来曲唑可有效提高DSD患儿的睾酮水平，促进精子生成，且短期应用未见明显不良反应。
关键词： 性发育障碍/药物疗法;  芳香酶抑制剂/治疗应用;  来曲唑;  睾酮;  儿童;  性发育障碍/药物疗法;  芳香酶抑制剂/治疗应用;  来曲唑;  睾酮;  儿童    
Abstract:

Objective: To investigate the efficacy and safety of aromatase inhibitor letrozole in treatment of male children with disorders of sex development (DSD). Methods: Clinical data of 12 male DSD children with a mean age of 14.6±2.5 years admitted to Peking Union Medical College Hospital from January 2014 to January 2016 were retrospectively analyzed. The patients were treated with letrozole (1.25-2.5 mg, once a day) for 3 months or longer, and followed up for 0.5-2.5 years. Clinical manifestation and laboratory test findings were documented, and the efficacy and safety were evaluated. Results: After half-year treatment, the blood luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone levels of patients increased (all P < 0.05), and estrogen levels decreased from baseline (P < 0.05). After 1 year of treatment, the blood testosterone level was significantly higher (P < 0.05); the LH and FSH levels tended to increase and the estrogen level tended to decrease, but there was no significant statistical difference (P>0.05). Semen was routinely detected in 8 patients, and sperms were detected in semen of 3 patients with hypospadias. There were no significant changes in biochemical results after treatment, and no significant adverse event was observed during the treatment. Conclusion: Letrozole can effectively increase testosterone levels in patients with disorders of sex development and promote spermatogenesis, it has no significant adverse effects in short-term administration.
Key words: Disorders of sex development/drug therapy    Aromatase inhibitors/therapeutic use    Letrozole    Testosterone    Child    Disorders of sex development/drug therapy    Aromatase inhibitors/therapeutic use    Letrozole    Testosterone    Child
收稿日期: 2019-12-15 出版日期: 2020-05-29
CLC:  R588  
基金资助: 国家重点研发计划(2016YFC0905102);中国医学科学院医学与健康科技创新工程经费资助(2016-I2M-1-002);国家重点研发计划(2016YFC0905102);中国医学科学院医学与健康科技创新工程经费资助(2016-I2M-1-002)
通讯作者: 伍学焱     E-mail: 113ybq@sina.com;wsheyan@vip.sina.com
作者简介: 于冰青(1994-), 女, 博士研究生, 主要从事下丘脑-垂体-性腺疾病研究; E-mail:113ybq@sina.com; https://orcid.org/0000-0002-0459-1923|于冰青(1994-), 女, 博士研究生, 主要从事下丘脑-垂体-性腺疾病研究; E-mail:113ybq@sina.com; https://orcid.org/0000-0002-0459-1923
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于冰青
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季文
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张睿

引用本文:

于冰青,聂敏,伍学焱,茅江峰,王曦,马婉璐,季文,黄奇彬,张睿. 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): 297-301.

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 Zhejiang Univ (Med Sci), 2020, 49(3): 297-301.

链接本文:

http://www.zjujournals.com/med/CN/10.3785/j.issn.1008-9292.2020.04.02    或    http://www.zjujournals.com/med/CN/Y2020/V49/I3/297

检测时间 n 黄体生成素(U/L) 卵泡刺激素(U/L) 睾酮(nmol/L) 雌二醇(pmol/L)
正常值范围：黄体生成素为1.24~8.62 U/L, 卵泡刺激素为1.27~19.26 U/L, 睾酮为6.1~27.1 nmol/L, 雌二醇为0~168.8 pmol/L.与治疗前比较, *P＜0.05.
治疗前 12 5.2(3.7, 16.5) 14.1(5.3, 24.7) 5.2(3.8, 10.0) 120.7±51.0
治疗后半年 12 16.2(10.1, 23.2)* 37.7(17.9, 49.6)* 20.1(5.9, 28.1)* 64.9±55.1*
治疗后一年 12 13.0(4.0, 21.3) 39.8(6.2, 40.5) 19.7(7.9, 27.4)* 71.2±50.6
表 1  性发育异常患儿来曲唑治疗前后激素水平比较
检测时间 n ALT(U/L) AST(U/L) GGT(U/L) 总胆红素(μmol/L) 直接胆红素(μmol/L) 肌酐(μmol/L) 尿素(μmol/L)
“—”：无相关数据.ALT:丙氨酸转氨酶；AST:天冬氨酸转氨酶；GGT:谷氨酰转移酶.
治疗前 12 24±15 23±6 30±16 12±3 4.5±1.5 61.4±15.9 4.3±0.9
治疗后 12 25±6 22±4 35±18 12±6 4.3±2.4 73.0±11.7 4.5±1.2
t值 — -0.155 0.177 -0.500 -0.038 0.253 -1.611 -0.440
P值 — ＞0.05 ＞0.05 ＞0.05 ＞0.05 ＞0.05 ＞0.05 ＞0.05
表 2  性发育异常患儿来曲唑治疗前后生化指标比较
1 RAMAN J D , SCHLEGEL P N . Aromatase inhibitors for male infertility[J]. J Urol, 2002, 167 (2 Pt 1): 624- 629
doi: 10.1097/00005392-200202000-00038
2 DEL GIUDICE F , BUSETTO G M , DE BERARDINIS E et al. A systematic review and meta-analysis of clinical trials implementing aromatase inhibitors to treat male infertility[J]. Asian J Androl, 2019,
doi: 10.4103/aja.aja_101_19
3 TAN R B , GUAY A T , HELLSTROM W J . Clinical use of aromatase inhibitors in adult males[J]. Sex Med Rev, 2014, 2 (2): 79- 90
doi: 10.1002/smrj.23
4 刘兆祥, 茅江峰, 伍学焱 et al. 芳香化酶抑制剂(来曲唑)可有效治疗男性部分性特发性低促性腺激素性性腺功能减退症[J]. 中华内分泌代谢杂志, 2016, 32 (2): 125- 127
LIU Zhaoxiang , MAO Jiangfeng , WU Xueyan et al. Aromatase inhibitor (letrozole) in effective in activating the function of hypothalamus-pituitary-gonad axis in male patients with partial idiopathic hypogonadotropic hypogonadism[J]. Chinese Journal of Endocrinology and Metabolism, 2016, 32 (2): 125- 127
doi: 10.3760/cma.j.issn.1000-6699.2016.02.009
5 LOVES S , DE JONG J , VAN SORGE A et al. Somatic and psychological effects of low-dose aromatase inhibition in men with obesity-related hypogonadotropic hypotestosteronemia[J]. Eur J Endocrinol, 2013, 169 (5): 705- 714
doi: 10.1530/EJE-13-0190
6 MITWALLY M F , CASPER R F . Aromatase inhibitors for the treatment of infertility[J]. Expert Opin Investig Drugs, 2003, 12 (3): 353- 371
doi: 10.1517/13543784.12.3.353
7 WISNIEWSKI A B , BATISTA R L , COSTA E et al. Management of 46, xy differences/disorders of sex development (dsd) throughout life[J]. Endocr Rev, 2019, 40 (6): 1547- 1572
doi: 10.1210/er.2019-00049
8 MEHTA A , CLEARMAN T , PADUCH D A . Safety and efficacy of testosterone replacement therapy in adolescents with Klinefelter syndrome[J]. J Urol, 2014, 191 (5 Suppl): 1527- 1531
doi: 10.1016/j.juro.2013.09.015
9 MEHTA A , BOLYAKOV A , ROOSMA J et al. Successful testicular sperm retrieval in adolescents with Klinefelter syndrome treated with at least 1 year of topical testosterone and aromatase inhibitor[J]. Fertil Steril, 2013, 100 (4): 970- 974
doi: 10.1016/j.fertnstert.2013.06.010
10 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
11 MOON J E , KO C W , YANG J D et al. Combined surgical and medical treatment in an adolescent with severe gynecomastia due to excessive estradiol secretion:a case report[J]. BMC Pediatr, 2019, 19 (1): 515
doi: 10.1186/s12887-019-1887-7
12 MA N S , GEFFNER M E . Gynecomastia in prepubertal and pubertal men[J]. Curr Opin Pediatr, 2008, 20 (4): 465- 470
doi: 10.1097/MOP.0b013e328305e415
13 SALTZSTEIN D , SIEBER P , MORRIS T et al. Prevention and management of bicalutamide-induced gynecomastia and breast pain:randomized endocrinologic and clinical studies with tamoxifen and anastrozole[J]. Prostate Cancer Prostatic Dis, 2005, 8 (1): 75- 83
doi: 10.1038/sj.pcan.4500782
14 PARADA-BUSTAMANTE A , RíOS R , EBENSPERGER M et al. 46, XX/SRY-negative true hermaphrodite[J]. Fertil Steril, 2010, 94 (6): 2330
doi: 10.1016/j.fertnstert.2010.03.066
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