Tero Varimo1, Hanna Huopio2, Laura Kariola1, Sirpa Tenhola3, Raimo Voutilainen2, Jorma Toppari4, Sanna Toiviainen-Salo5, Esa Hämäläinen6, Mari-Anne Pulkkinen1, Mitja Lääperi1, Annika Tarkkanen7, Kirsi Vaaralahti8, Päivi J Miettinen1, Matti Hero1, Taneli Raivio9. 1. Pediatric Research Center, Children's Hospital, Helsinki University Hospital, Helsinki, Finland. 2. Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland. 3. Kymenlaakso Central Hospital, Kotka, Finland. 4. Department of Pediatrics, Turku University Hospital, and Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland. 5. Medical Imaging Center, Department of Pediatric Radiology, Helsinki University Hospital, Helsinki, Finland. 6. Pediatric Research Center, Children's Hospital, Helsinki University Hospital, Helsinki, Finland; Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland. 7. Pediatric Research Center, Children's Hospital, Helsinki University Hospital, Helsinki, Finland; Department of Physiology, Medicum Unit, and Translational Stem Cell Biology and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland. 8. Department of Physiology, Medicum Unit, and Translational Stem Cell Biology and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland. 9. Pediatric Research Center, Children's Hospital, Helsinki University Hospital, Helsinki, Finland; Department of Physiology, Medicum Unit, and Translational Stem Cell Biology and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Electronic address: taneli.raivio@helsinki.fi.
Abstract
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.
RCT Entities:
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.
Authors: Andrea Salonia; Giulia Rastrelli; Geoffrey Hackett; Stephanie B Seminara; Ilpo T Huhtaniemi; Rodolfo A Rey; Wayne J G Hellstrom; Mark R Palmert; Giovanni Corona; Gert R Dohle; Mohit Khera; Yee-Ming Chan; Mario Maggi Journal: Nat Rev Dis Primers Date: 2019-05-30 Impact factor: 52.329
Authors: E Kohva; T Varimo; H Huopio; S Tenhola; R Voutilainen; J Toppari; P J Miettinen; K Vaaralahti; J Viinamäki; J T Backman; M Hero; T Raivio Journal: Hum Reprod Date: 2020-02-29 Impact factor: 6.918