Novel treatment of short stature with aromatase inhibitors.
Estrogens have an essential role in the regulation of bone maturation and importantly in the closure of growth plates in both sexes. This prospective, randomized, placebo-controlled study was undertaken to evaluate whether suppression of estrogen synthesis in pubertal boys delays bone maturation and ultimately results in increased adult height. A total of 23 boys with constitutional delay of puberty (CDP) received a conventional, low-dose testosterone treatment for inducing progression of puberty. Eleven of these 23 boys were randomized to receive a specific and potent P450-aromatase inhibitor, letrozole, for suppression of estrogen action, and 12 boys were randomized to receive placebo. Estradiol concentrations in the letrozole-treated boys remained at the pretreatment level during the administration of letrozole, whereas the concentrations increased during the treatment with testosterone alone and during spontaneous progression of puberty. Testosterone concentrations increased in all groups, but during the letrozole treatment, the increase was more than fivefold higher than in the group treated with testosterone alone. The inhibition of estrogen synthesis delayed bone maturation. The slower bone maturation in the boys treated with testosterone and letrozole, despite higher androgen concentrations, than in the boys treated with testosterone indicate that estrogens are more important than androgens in regulation of bone maturation in pubertal boys. During the 18 months follow-up, an increase of 5.1 cm in predicted adult height was observed in the boys who received testosterone and letrozole, but no change was seen in the boys who received testosterone alone or in the untreated boys. This finding indicates that an increase in adult height can be attained in growing adolescent boys by inhibiting of estrogen action.
Dunkel
Leo
L
Hospital for Children and Adolescents, University of Helsinki, PO Box 281, Helsinki 00029 HUS, Finland. leo.dunkel@hus.fi
Wickman
Sanna
S
D000293:Adolescent; D047072:Aromatase Inhibitors; D001827:Body Height / Q000187:drug effects*; D015519:Bone Density / Q000187:drug effects; D001846:Bone Development / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004958:Estradiol / Q000097:blood; D005640:Follicle Stimulating Hormone / Q000097:blood; D006801:Humans; D007265:Inhibins / Q000097:blood; D007328:Insulin / Q000097:blood; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D000077289:Letrozole; D008055:Lipids / Q000097:blood; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D009570:Nitriles / Q000627:therapeutic use; D011446:Prospective Studies; D011628:Puberty, Delayed / Q000188:drug therapy; D013737:Testis / Q000033:anatomy & histology / Q000187:drug effects; D013739:Testosterone / Q000097:blood / Q000627:therapeutic use; D014230:Triazoles / Q000627:therapeutic use
D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D007328:Insulin; D018972:Insulin-Like Growth Factor Binding Protein 3; D008055:Lipids; D009570:Nitriles; D014230:Triazoles; C422364:inhibin B; D013739:Testosterone; D004958:Estradiol; D007265:Inhibins; D007334:Insulin-Like Growth Factor I; D000077289:Letrozole; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone