Letrozole Treatment of Precocious Puberty in Girls With the McCune-Albright Syndrome: A Pilot Study

Young girls with McCune-Albright syndrome (MAS), a rare disorder characterized by precocious puberty, cafe-au-lait pigment, and polyostotic fibrous dysplasia (PFD), frequently present with precocious puberty and vaginal bleeding. In this setting, precocious puberty is independent of gonadotropins and is a result of estrogen secretion by large ovarian cysts. It does not respond to treatment with a gonadotropin-releasing hormone agonist, and short-acting aromatase inhibitors have limited efficacy. Adult stature often is markedly reduced in MAS patients with precocious puberty. This study evaluated a potent third-generation aromatase inhibitor, letrozole, for slowing pubertal development in 9 girls 3 to 8 years of age with gonadotropin-independent precocious puberty. They had presented at ages 1.3 to 6 years with breast development, vaginal bleeding or discharge, and suppressed gonadotropin levels. All the girls had advanced bone age, and all but one had significantly increased growth rate scores. In an open-label therapeutic trial, participants were followed for 1 to 3 years during and after a 6-month period during which they received letrozole orally in a daily dose of 1.5 to 2.0 mg/m 2 . Rates of growth slowed during treatment with letrozole, and the change in bone age versus change in chronological age declined. Estradiol levels fell in the only patient with detectable estradiol at the outset. Bleeding slowed or ceased during treatment. Breast stage and pubic hair stage decreased in some patients. After 6 months, mean ovarian volume and indices of bone metabolism both decreased, but tended to increase at 24 to 36 months. There was no change in uterine volume. Mean levels of serum markers of bone formation as well as a urinary marker of bone resorption decreased. Treatment resumed in 4 girls who had recurrent symptoms and signs of puberty after 6 months of letrozole therapy. The remaining patients were treated without interruption for as long as 3 years. One child had a ruptured ovarian cyst after 2 years of treatment and underwent laparoscopic surgery. PFD progressed during treatment in 2 patients with relatively advanced disease. These preliminary findings indicate that letrozole can be an effective initial treatment for girls with gonadotropin-independent precocious puberty. It also may prove useful for treating girls who fail to respond to estrogen blockers such as tamoxifen.