Refereed journal article or data article (A1)
Letrozole versus testosterone for promotion of endogenous puberty in boys with constitutional delay of growth and puberty: a randomised controlled phase 3 trial
List of Authors: Tero Varimo, Hanna Huopio, Laura Kariola, Sirpa Tenhola, Raimo Voutilainen, Jorma Toppari, Sanna Toiviainen-Salo, Esa Hämäläinen, Mari-Anne Pulkkinen, Mitja Lääperi, Annika Tarkkanen, Kirsi Vaaralahti, Päivi J Miettinen, Matti Hero, Taneli Raivio
Publisher: ELSEVIER SCI LTD
Publication year: 2019
Journal: The Lancet Child & Adolescent Health
Journal name in source: LANCET CHILD & ADOLESCENT HEALTH
Journal acronym: LANCET CHILD ADOLESC
Volume number: 3
Issue number: 2
Start page: 109
End page: 120
Number of pages: 12
ISSN: 2352-4642
DOI: http://dx.doi.org/10.1016/S2352-4642(18)30377-8
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.
Method
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.