促性腺激素释放激素类似物治疗特发性中枢性性早熟女童的疗效分析

doi:10.3760/cma.j.issn.1007-1245.2024.10.025

摘要/Abstract

摘要：

目的　探讨促性腺激素释放激素类似物（GnRHa）治疗特发性中枢性性早熟女童的疗效及对体质量指数、性腺轴激素水平的影响。方法　选取2021年3月至2023年5月在开平市中心医院生长发育专科诊断和治疗的42例特发性中枢性性早熟女童作为研究对象，年龄（7.5±2.3）岁，病程（10.98±2.75）个月，均予以GnRHa治疗，以注射用醋酸曲普瑞林为主要治疗药物，肌肉注射，每28～32 d注射1次。第1、2、3针剂量均为3.75 mg（最大剂量不超过180 µg/kg），个别体质量较高患儿可间隔21 d加强1针；于第3针治疗后第14天行GnRH简易激发试验，根据黄体生成素（LH）峰值结果调整剂量至80～100 µg/kg（最大剂量不超过3.75 mg）。测量治疗前、治疗半年后患儿的身高、体质量、骨龄、预测成年终身高（FAH）等生长发育相关指标，比较治疗前后体质量指数的变化以及卵泡刺激素（FSH）、LH、雌二醇（E2）等激素水平的改变，观察治疗前后子宫容积、卵巢容积、卵泡直径的变化，记录不良反应发生情况。采用Wilcoxon符号秩和检验。结果　治疗半年后，患儿第二性征明显抑制，其中8例患儿月经撤退，34例患儿乳房分期退缩；患儿的身高、体质量、骨龄、FAH均高于治疗前［131.1（8.7）cm比127.8（8.2）cm、29.5（6.9）kg比27.0（5.5）kg、9.4（1.7）岁比9.0（1.6）岁、157.4（3.7）cm比154.9（2.8）cm］（Z=-5.648、-5.600、-5.713、-5.125，均P<0.001）；体质量指数标准差分值（BMISDS）无明显变化［16.7（1.6）kg/m²比16.5（1.4）kg/m²］（Z=-0.356，P=0.682）；子宫容积、卵巢容积、卵泡直径均较治疗前缩小［2.1（1.6）ml比3.1（2.1）ml、1.2（0.9）ml比2.0（2.8）ml、3.0（1.3）mm比8.0（2.3）mm］，差异均有统计学意义（Z=-5.646、-5.579、-5.622，均P<0.001）。第3针治疗后，E2水平、FSH激发峰值、LH激发峰值均较治疗前下降［36.5（10.0）pmol/L比80.0（44.8）pmol/L、2.6（3.6）U/L比13.3（9.3）U/L、0.7（0.3）U/L比12.9（11.6）U/L］（均P<0.001）。治疗过程中1例患儿出现臀部脂肪纹，其余患儿在治疗过程中并未诉不适，血常规、肝肾功能等相关指标未见异常。结论　GnRHa治疗特发性中枢性性早熟女童能改善FAH，对体质量指数无明显影响，能抑制性腺轴激素水平，具有较好的临床疗效和较高的安全性。

关键词:

促性腺激素释放激素类似物, 特发性中枢性性早熟, 下丘脑-垂体-性腺轴, 成年终身高, 体质量指数, 女童

Abstract:

Objective　To investigate the effect of gonadotropin-releasing hormone analogue (GnRHa) in the treatment of idiopathic central precocious puberty (ICPP) in girls and its effects on body mass index and gonadal axis hormone levels. Methods　A total of 42 girls with ICPP diagnosed and treated in the growth and development department of Kaiping Central Hospital from March 2021 to May 2023, were selected as the study subjects. The age was (7.5±2.3) years old, and the duration of disease was (10.98±2.75) months. All children were treated with GnRHa, with triptorelin acetate for injection as the main therapeutic drug, intramuscular injection, every 28 to 32 days. The first, second, and third doses were 3.75 mg (the maximum dose was not more than 180 µg/kg), and children with higher body mass could be strengthened with 1 injection at an interval of 21 days. The GnRH simple stimulation test was performed on the 14th day after the third injection, and the dose was adjusted to 80 to 100 µg/kg according to the results of luteinizing hormone (LH) peak (the maximum dose was not more than 3.75 mg). Their growth and development-related indicators such as height, body mass, bone age, and final adult height (FAH) were measured before treatment and 6 months after treatment. The changes in body mass index (BMI) and hormone levels such as follicle stimulating hormone (FSH), LH, and estradiol (E2) before and after treatment were compared. The changes in uterine volume, ovarian volume, and follicle diameter before and after treatment were observed, and the occurrence of adverse reactions was recorded. Wilcoxon signed rank sum test was used. Results　After 6 months of treatment, the secondary sexual characteristics of the children were significantly suppressed, including 8 children with menstrual withdrawal and 34 children with staged breast withdrawal. After 6 months of treatment, the height, body mass, bone age, and FAH of the children were all higher than those before treatment [131.1 (8.7) cm vs. 127.8 (8.2) cm, 29.5 (6.9) kg vs. 27.0 (5.5) kg, 9.4 (1.7) years vs. 9.0 (1.6) years, 157.4 (3.7) cm vs. 154.9 (2.8) cm] (Z=-5.648, -5.600, -5.713, and -5.125, all P<0.001); the standard deviation score of body mass index (BMISDS) had no significant change [16.7 (1.6) kg/m² vs. 16.5 (1.4) kg/m²] (Z=-0.356, P=0.682). After 6 months of treatment, both uterine volume and ovarian volume decreased [2.1 (1.6) ml vs. 3.1 (2.1) ml, 1.2 (0.9) ml vs. 2.0 (2.8) ml], and the follicle diameter decreased [3.0 (1.3) mm vs. 8.0 (2.3) mm] compared with those before treatment, with statistically significant differences (Z=-5.646, -5.579, and -5.622, all P<0.001). After three injections, the levels of E2, the peak of FSH activation, and the peak of LH activation were all lower than those before treatment [36.5 (10.0) pmol/L vs. 80.0 (44.8) pmol/L, 2.6 (3.6) U/L vs. 13.3 (9.3) U/L, 0.7 (0.3) U/L vs. 12.9 (11.6) U/L] (all P<0.001). One child developed fat streaks on the buttocks, and the other children did not complain of discomfort during the treatment; there were no abnormalities in blood routine, liver and kidney function, or other related indicators. Conclusion　The treatment of GnRHa in girls with ICPP can improve the FAH, has no significant effect on body mass index, and can inhibit the levels of gonadal axis hormones, which has good clinical efficacy and high safety.

Key words:

Gonadotropin-releasing hormone analogue, Idiopathic central precocious puberty, Hypothalamic-pituitary-gonadal axis, Final adult height, Body mass index, Girls

余艳媚余淑娟陈清凤陈雪冰.

促性腺激素释放激素类似物治疗特发性中枢性性早熟女童的疗效分析 [J]. 国际医药卫生导报, 2024, 30(10): 1707-1711.

Yu Yanmei, Yu Shujuan, Chen Qingfeng, Chen Xuebing.

Effect analysis of gonadotropin-releasing hormone analogue in the treatment of idiopathic central precocious puberty in girls [J]. International Medicine and Health Guidance News, 2024, 30(10): 1707-1711.

参考文献

[1] 中华医学会儿科学分会内分泌遗传代谢学组,中华儿科杂志编辑委员会. 中枢性性早熟诊断与治疗专家共识(2022)[J]. 中华儿科杂志,2023,61(1):16-22. DOI:10.3760/cma.j.cn112140-20220802-00693.
[2] 杨芳,周静茹,张艳,等. 特发性中枢性性早熟女童心理社会适应与自我意识、性别角色的相关分析[J]. 数理医药学杂志,2023,36(2):110-117. DOI:10.12173/j.issn.1004-4337.202301056.
[3] 杨婷,梁希,郭婷婷,等. 醋酸曲普瑞林联合膳食干预对特发性中枢性性早熟女童代谢及卵巢功能的影响[J]. 中国现代医学杂志,2023,33(11):81-86. DOI:10.3969/j.issn.1005- 8982.2023.11.014.
[4] 中华医学会儿科学分会.儿科内分泌与代谢性疾病诊疗规范[M].北京:人民卫生出版社,2016: 77-83.
[5] 黄卫保,林剑军,黄华驰,等. 3种儿童骨龄评估方法一致性比较研究[J]. 实用放射学杂志,2023,39(4):631-634. DOI:10.3969/j.issn.1002-1671.2023.04.028.
[6] 马华梅,杜敏联. 促性腺激素释放激素类似物治疗改善真性性早熟女孩成年身高[J]. 中华内分泌代谢杂志,2005,21(3):240-243. DOI:10.3760/j.issn:1000-6699.2005.03.015.
[7] 卢一丽,金佳蕙,单小鸥. 建立新的可预测成年终身高及青春期进程的模型及其在特发性中枢性性早熟女童中的应用[J]. 中国现代医生,2018,56(4):98-100,104.
[8] 孙曼青,陆文丽,王伟,等. 女童快速进展型中枢性性早熟早期预警及随访标志物的多中心研究[J]. 中华内分泌代谢杂志,2017,33(4):312-316. DOI:10.3760/cma.j.issn.1000- 6699.2017.04.008.
[9] Eckert-Lind C, Busch AS, Petersen JH, et al. Worldwide secular trends in age at pubertal onset assessed by breast development among girls: a systematic review and meta-analysis[J]. JAMA Pediatr, 2020, 174(4): e195881. DOI: 10.1001/jamapediatrics.2019.5881.
[10] 罗小平.身材矮小症儿童诊疗规范[M].北京: 人民卫生出版社,2019: 63-67.
[11] 周静茹,杨芳,刘彦君,等. 中枢性性早熟儿童心理社会状态的范围综述[J]. 中国性科学,2023,32(4):143-147. DOI:10.3969/j.issn.1672-1993.2023.04.034.
[12] 董关萍,傅君芬. 促性腺激素释放激素类似物在儿童中枢性性早熟中的应用[J]. 中华实用儿科临床杂志,2021,36(4):241-243. DOI:10.3760/cma.j.cn101070-20200603- 00931.
[13] 梁雁,罗小平. 进一步规范中枢性性早熟的诊疗[J]. 中华儿科杂志,2015,53(6):405-408. DOI:10.3760/cma.j.issn.0578-1310.2015.06.002.
[14] 周志红,刘丽,赵小媛,等. 中枢性性早熟女童GnRHa治疗前后骨代谢生化指标及骨密度变化的研究[J]. 国际医药卫生导报,2014,20(18):2790-2792. DOI:10.3760/cma.j.issn.1007-1245.2014.18.007.
[15] 张莉,刘俊莉,杨柳,等. 促性腺激素释放激素类似物联合生长激素治疗中枢性性早熟女童疗效观察[J]. 中国性科学,2017,26(8):54-57. DOI:10.3969/j.issn.1672-1993.2017. 08.017.
[16] 徐丽琴,洪庆荣,方圆. 曲普瑞林对特发性中枢性性早熟女童的临床疗效和对骨龄的影响[J]. 国际医药卫生导报,2022,28(6):829-832. DOI:10.3760/cma.j.issn.1007-1245. 2022.06.024.
[17] 王琦. 醋酸曲普瑞林联合维生素D3治疗特发性中枢性性早熟女童的效果[J]. 中国民康医学,2023,35(10):76-78,82. DOI:10.3969/j.issn.1672-0369.2023.10.023.
[18] 储昭乐,江辉,吴倩. 促性腺激素释放激素类似物治疗对中枢性性早熟和快速进展型青春期患儿成年终身高改善的Meta分析[J]. 中国当代儿科杂志,2021,23(11):1161-1168. DOI:10.7499/j.issn.1008-8830.2108078.
[19] 张晓菲,罗静思,唐晴,等. 促性腺激素释放激素类似物治疗中枢性性早熟女性患儿的远期效果及不良反应[J]. 广西医学,2022,44(7):730-734. DOI:10.11675/j.issn.0253-4304. 2022.07.09.
[20] 陈秋莉,马华梅,李燕虹,等. 促性腺激素释放激素类似物改善中枢性性早熟和快速进展型早发育女孩成年身高:单中心15年102例病例追踪研究[J]. 中华内分泌代谢杂志,2013,29(3):236-240. DOI:10.3760/cma.j.issn.1000-6699. 2013.03.011.
[21] 黎琳琳,胡韶华,尹小琴,等. 特发性中枢性性早熟女童血清不饱和游离脂肪酸谱的变化及其与体质量指数、性激素水平的相关性分析[J]. 上海交通大学学报(医学版),2021,41(11):1405-1411. DOI:10.3969/j.issn.1674-8115.2021. 11.001.
[22] 傅君芬,周雪莲. 肥胖对儿童青春期性发育的影响及作用机制[J]. 中华实用儿科临床杂志,2014,29(8):574-577. DOI:10.3760/cma.j.issn.2095-428X.2014.08.005.
[23] 陈秋莉,苏喆,李燕虹,等. GnRHa治疗对中枢性性早熟和快速进展型早发育女孩体重指数的影响[J]. 中华内分泌代谢杂志,2015(8):690-695. DOI:10.3760/cma.j.issn.1000- 6699.2015.08.008.
[24] Sinthuprasith P, Dejkhamron P, Wejaphikul K, et al. Near final adult height, and body mass index in overweight/obese and normal-weight children with idiopathic central precocious puberty and treated with gonadotropin-releasing hormone analogs[J]. J Pediatr Endocrinol Metab, 2019, 32(12): 1369-1375. DOI: 10.1515/jpem-2019-0136.
[25] Lazar L, Lebenthal Y, Yackobovitch-Gavan M, et al. Treated and untreated women with idiopathic precocious puberty: BMI evolution, metabolic outcome, and general health between third and fifth decades[J]. J Clin Endocrinol Metab, 2015, 100(4):1445-1451. DOI: 10.1210/jc.2014-3748.