Pediatric Research Center, Children's Hospital, Helsinki University Hospital, Helsinki, Finland.
Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland.
Lancet Child Adolesc Health. 2019 Feb;3(2):109-120. doi: 10.1016/S2352-4642(18)30377-8. Epub 2019 Jan 4.
The treatment of constitutional delay of growth and puberty (CDGP) is an underinvestigated area in adolescent medicine. We tested the hypothesis that peroral aromatase inhibition with letrozole is more efficacious than intramuscular injection of low-dose testosterone in inducing puberty in boys with CDGP.
We did a randomised, controlled, open-label trial at four paediatric centres in Finland. Boys aged at least 14 years with CDGP who wanted medical intervention and exhibited the first signs of puberty were randomly assigned in blocks of ten to receive either six intramuscular injections of low-dose testosterone (about 1 mg/kg bodyweight) every 4 weeks for 6 months or peroral letrozole 2·5 mg once daily for 6 months. All boys were followed up for 6 months after the end of treatment. The primary outcomes were changes in testicular volume and hormonal markers of puberty at 6 months after treatment initiation, which were assessed in all participants who received the assigned treatment. All patients were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01797718.
Between Aug 1, 2013, and Jan 30, 2017, 30 boys were randomly assigned to receive testosterone (n=15) or letrozole (n=15). One boy in the testosterone group was excluded from the primary analyses because of a protocol deviation. During treatment, boys in the letrozole group had higher serum concentrations of luteinising hormone, follicle-stimulating hormone, testosterone, and inhibin B than did boys in the testosterone group. Testicular growth from baseline to 6 months was greater in the letrozole group than in the testosterone group (7·2 mL [95% CI 5·2-9·3] vs 2·2 mL [1·4-2·9]; between-group difference per month 0·9 mL [95% CI 0·6-1·2], p<0·0001). Most adverse events were mild. One boy in the testosterone group had aggressive behaviour for 1 week after each injection, and one boy in the letrozole group had increased irritability at 6 months.
Letrozole might be a feasible alternative treatment to low-dose testosterone for boys with CDGP who opt for medical intervention. However, the risks and benefits of manipulating the reproductive axis during early puberty should be weighed carefully.
Helsinki University Hospital, Academy of Finland, and Finnish Foundation for Pediatric Research.
生长和青春期发育迟缓（CDGP）的治疗是青少年医学中研究不足的领域。我们检验了这样一个假设，即口服芳香酶抑制剂来曲唑比肌内注射低剂量睾酮更能有效诱导 CDGP 男孩的青春期。
我们在芬兰的四个儿科中心进行了一项随机、对照、开放标签试验。年龄至少 14 岁、希望接受医学干预且出现青春期第一体征的 CDGP 男孩，以 10 人为一组进行分组，随机接受 6 个月的肌内注射低剂量睾酮（约 1mg/kg 体重），每 4 周一次，或口服来曲唑 2.5mg，每天一次，持续 6 个月。所有男孩在治疗结束后 6 个月内接受随访。主要结局是治疗开始后 6 个月时睾丸体积和青春期激素标志物的变化，所有接受指定治疗的参与者均进行了评估。所有患者均纳入安全性分析。本研究在 ClinicalTrials.gov 注册，编号为 NCT01797718。
2013 年 8 月 1 日至 2017 年 1 月 30 日期间，共有 30 名男孩被随机分配接受睾酮（n=15）或来曲唑（n=15）治疗。由于违反方案，睾酮组的 1 名男孩被排除在主要分析之外。在治疗期间，来曲唑组的血清黄体生成素、卵泡刺激素、睾酮和抑制素 B 浓度均高于睾酮组。从基线到 6 个月时，来曲唑组的睾丸生长大于睾酮组（7.2ml[95%CI5.2-9.3]vs2.2ml[1.4-2.9]；每月差异 0.9ml[95%CI0.6-1.2]，p<0.0001）。大多数不良事件为轻度。睾酮组有 1 名男孩在每次注射后 1 周内出现攻击性行为，来曲唑组有 1 名男孩在 6 个月时出现易怒。
对于选择医学干预的 CDGP 男孩，来曲唑可能是低剂量睾酮的可行替代治疗方法。然而，在青春期早期操纵生殖轴的风险和益处需要仔细权衡。
赫尔辛基大学医院、芬兰科学院和芬兰儿科研究基金会。
