Letrozole versus testosterone for promotion of endogenous puberty in boys with constitutional delay of growth and puberty: a randomised controlled phase 3 trial.
Adolescent
Androgens
/ administration & dosage
Aromatase Inhibitors
/ adverse effects
Biomarkers
/ blood
Drug Administration Schedule
Hormones
/ blood
Humans
Hypothalamo-Hypophyseal System
/ drug effects
Injections, Intramuscular
Letrozole
/ therapeutic use
Male
Puberty, Delayed
/ blood
Testis
/ drug effects
Testosterone
/ administration & dosage
Treatment Outcome
Journal
The Lancet. Child & adolescent health
ISSN: 2352-4650
Titre abrégé: Lancet Child Adolesc Health
Pays: England
ID NLM: 101712925
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
28
09
2018
revised:
15
11
2018
accepted:
17
11
2018
pubmed:
8
1
2019
medline:
13
5
2020
entrez:
8
1
2019
Statut:
ppublish
Résumé
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.
Sections du résumé
BACKGROUND
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.
METHODS
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.
FINDINGS
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.
INTERPRETATION
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.
FUNDING
Helsinki University Hospital, Academy of Finland, and Finnish Foundation for Pediatric Research.
Identifiants
pubmed: 30612946
pii: S2352-4642(18)30377-8
doi: 10.1016/S2352-4642(18)30377-8
pii:
doi:
Substances chimiques
Androgens
0
Aromatase Inhibitors
0
Biomarkers
0
Hormones
0
Testosterone
3XMK78S47O
Letrozole
7LKK855W8I
Banques de données
ClinicalTrials.gov
['NCT01797718']
Types de publication
Clinical Trial, Phase III
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
109-120Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.