Oxandrolone Treatment Results in an Increased Risk of Gonadarche in Prepubertal Boys With Klinefelter Syndrome

Abstract

Context: Klinefelter syndrome (KS) is a common genetic condition in which males have an extra X chromosome. KS is associated with testosterone deficiency, neurodevelopmental delays, and cardiometabolic disorders. There has been recent interest in prepubertal androgen treatment; however, the effects on puberty and gonadal function are unknown.

Objective: To compare onset of puberty and testicular function in prepubertal boys treated with 2 years of oxandrolone (Ox) vs placebo (Pl).

Design: Double-blind, randomized, controlled trial.

Setting: Single tertiary care referral center.

Participants: Eighty prepubertal boys with KS; mean age: 8.0 ± 2.2 years (range: 4 to 12).

Interventions: Ox 0.05 mg/kg vs identical-appearing Pl capsule given for 2 years.

Outcome measures: Onset of gonadarche (testicular volume ≥4 mL) and onset of pubarche (Tanner 2 pubic hair); change in testicular hormone concentrations.

Results: Ox-treated group had 20.5 times higher odds of reaching gonadarche (OR 95% CI: 6.5, 77.8) and 28.1 times higher odds of reaching pubarche (OR 95% CI: 8.8, 110.4) during the 2-year study period after adjusting for baseline age. Gonadarche and pubarche both occurred at a younger age in the Ox group (gonadarche: 9.8 ± 1.5 vs 12.1 ± 1.0 years, P < 0.001; pubarche: 10.2 ± 1.1 vs 11.6 ± 1.3 years, P = 0.02). Serum concentrations of testicular hormones and gonadotropins were not different between groups.

Conclusions: Two years of Ox treatment in prepubertal boys with KS results in an increased risk of early gonadarche, on average 2 years earlier than in Pl-treated boys. Ox did not affect serum concentrations of testicular hormones.

Trial registration: ClinicalTrials.gov NCT00348946.

Figures

Figure 1.

Testicular hormone concentrations over the study period for all subjects. LH, FSH, and TT significantly increased during the 2-y study period in both Ox (solid) and Pl (dashed) (P < 0.001 for all), but Ox treatment did not significantly alter this (P > 0.05). INHB and AMH concentrations were stable during the study and also did not significantly differ between treatment groups (P > 0.05). Points and error bars represent mean and 95% CI, respectively.

Figure 2.

Change scores between baseline and final visit for testicular volume and stretched penile length z scores were compared between treatment groups. Mean testicular volume increased to 3.6 ± 2.2 mL in the Ox group compared with 2.2 ± 1.8 mL in the Pl group (P = 0.016). Stretched penile length increased to 6.2 ± 1.5 cm in the Ox group and 5.4 ± 1.4 cm in the Pl group, with corresponding z scores to adjust for the age differences depicted in the figure on the right (P = 0.003).

Figure 3.

Means and 95% CIs for testicular volume and hormone concentrations in relation to gonadarche (time 0) between Ox (black solid line) and Pl (gray dashed line). The number of subjects (n) for each time interval are indicated in the table. There were no statistical differences between groups using t tests at each time point (+18 mos excluded due to too few of subjects).