Trial Information

Effects of the Aromatase Inhibitor Letrozole on Pubertal Progression and Indices of Bone Turnover in Girls With Precocious Puberty and McCune-Albright Syndrome (MAS)

Girls ages 1 - 8 years with the McCune-Albright syndrome (MAS) and girls with other
conditions characterized by precocious puberty due to estrogen hypersecretion from ovarian
cysts will be eligible for this pilot study. Patients who have previously enrolled in
Protocol 98-D-0145 (Screening and natural history of patients with polyostotic fibrous
dysplasia and the McCune-Albright Syndrome) will also be eligible. Patients will be treated
with letrozole, a potent, nonsteroidal aromatase inhibitor, to suppress their elevated serum
estrogen levels. We will confirm the safety and efficacy of letrozole, and study its
effectiveness in controlling the elevated sex steroid levels, and the advanced rates of
linear growth, bone maturation, and pubertal progression in these patients. We will also
study the effect of decreased estrogen levels on the status of their polyostotic fibrous
dysplasia by measuring serum and urine values for bone biomarkers, including calcium,
phosphate, organic amino acids, and vitamin D metabolites, which are known to be abnormal in
many patients with MAS. Patients will act as their own controls. We will compare serum and
urine parameters of pubertal progression and bone biomarkers before, during, and after
discontinuation of letrozole. This trial will be carried out in parallel with in-vitro and
in-vivo laboratory studies using an animal model of fibrous dysplasia. In this model,
osteogenic precursor cells from patient bone biopsies will be cultured in a
hydroxyapatite/tricalcium phosphate matrix and transplanted into immunocompromised mice. We
anticipate that our laboratory findings will complement the care of our patients, resulting
in more effective treatment for the precocious puberty and the bone disease in children with
MAS. Because our initial studies have indicated that letrozole is effective in treating
precocious puberty in MAS patients, this protocol also enrolls girls who have a related
condition, gonadotropin-independent precocious puberty without the bone disease polyostotic
fibrous dysplasia. We also believe that this study complements the recent FDA and NIH
mandates that children be included in the evaluation of pharmaceutical products and in
federally funded clinical research studies.