Fulvestrant treatment of precocious puberty in girls with McCune-Albright syndrome

BACKGROUND: McCune-Albright Syndrome (MAS) is usually characterized by the triad of precocious puberty (PP), fibrous dysplasia, and café au lait spots. Previous treatments investigated for PP have included aromatase inhibitors and the estrogen receptor modulator, tamoxifen. Although some agents have been partially effective, the optimal pharmacologic treatment of PP in girls with MAS has not been identified. The objective of this study was to evaluate the safety and efficacy of fulvestrant (Faslodex(TM)), a pure estrogen receptor antagonist, in girls with progressive precocious puberty (PP) associated with McCune-Albright Syndrome (MAS). METHODS: In this prospective international multicenter trial, thirty girls ≤ 10 years old with MAS and progressive PP received fulvestrant 4 mg/kg via monthly intramuscular injections for 12 months. Changes in vaginal bleeding, rates of bone age advancement, growth velocity, Tanner staging, predicted adult heights, and uterine and ovarian volumes were measured. RESULTS: Median vaginal bleeding days decreased from 12.0 days per year to 1.0 day per year, with a median change in frequency of -3.6 days, (95% confidence interval (CI) -10.10, 0.00; p = 0.0146). Of patients with baseline bleeding, 74% experienced a ≥50% reduction in bleeding, and 35% experienced complete cessation during the study period (95% CI 51.6%, 89.8%; 16.4%, 57.3%, respectively). Average rates of bone age advancement (ΔBA/ΔCA) decreased from 1.99 pre-treatment to 1.06 on treatment (mean change -0.93, 95% CI -1.43, -0.43; p = 0.0007). No significant changes in uterine volumes or other endpoints or serious adverse events occurred. CONCLUSIONS: Fulvestrant was well tolerated and moderately effective in decreasing vaginal bleeding and rates of skeletal maturation in girls with MAS. Longer-term studies aimed at further defining potential benefits and risks of this novel therapeutic approach in girls with MAS are needed. TRIAL REGISTRATION: NCT00278915