Abstract: SAT 035
Low-Dose Androgen Treatment in Pre-Pubertal Boys with Klinefelter Syndrome Leads to Earlier Puberty
Background: Klinefelter syndrome (KS) affects 1/600 males resulting in nearly universal testicular failure and associated sequelae of chronic hypogonadism. The treatment effects of exogenous androgen on testicular function in pre-pubertal boys with KS are unknown.view more
Background: Klinefelter syndrome (KS) affects 1/600 males resulting in nearly universal testicular failure and associated sequelae of chronic hypogonadism. The treatment effects of exogenous androgen on testicular function in pre-pubertal boys with KS are unknown.
Methods: 93 boys with KS age 4-12 years were randomized 1:1 in a double-blind design to receive oral oxandrolone (Ox) 0.06 mg/kg/day or placebo (Pl) for two years (NCT00348946). Physical examination with pubertal staging and fasting morning hormone concentrations were obtained every 6 months. Outcomes included gonadarche (4mL testes or greater), pubarche (pubic hair development), and serum hormone concentrations including luteinizing hormone (LH), follicle stimulating hormone (FSH), total testosterone (TT), inhibin B (INHB), and anti-mullerian hormone (AMH). A mixed effect logistical regression model was used to compare these outcomes between groups while adjusting for age, and descriptive statistics were used to compare subgroups.
Results: 80 of the 93 participants were pre-pubertal (no gonadarche or pubarche) at baseline (43 Ox, 37 Pl). The pre-pubertal Ox group was more likely to reach pubarche (odds ratio 28.1 95% CI 8.8, 110.4) and gonadarche (odds ratio 20.5, 95% CI 6.5, 77.8) during the two-year study period after controlling for age. Of all subjects that reached gonadarche (16 Ox, 8 Pl), the Ox group was significantly younger at the time of gonadarche (9.8±1.5 years versus 12.1±1.0, p<0.001). Five subjects in the Ox group reached gonadarche prior to age 9 years and none in the placebo group. The Ox group tended to have lower LH concentrations at the time of gonadarche (0.50[range 0.17-1.2] v 1.1[0.67-2.2], p=0.06), but TT, INHB, and AMH did not differ between the groups. Of the 16 subjects in the Ox group who reached gonadarche, 12 had more than two years bone age advancement and all were pubarchal with pubertal LH concentrations by the end the two year study. Within the Ox group, baseline characteristics associated with reaching gonadarche within the two-year study period include older age, greater testicular volume z-score, and higher LH, TT, and INHB.
Conclusion: Ox treatment in pre-pubertal boys with KS leads to earlier gonadarche and pubarche. Ox is a weak agonst of the androgen receptor therefore explaining pubarche. Gonadarche associated with Ox appears to be centrally mediated based on pubertal LH levels, but the mechanism of early testicular enlargement requires further study.