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

National Human Genome Research Institute (P.F.), Clinical Center (K.C., S.H., T.S.), National Institute of Dental and Craniofacial Research (P.G.R., M.T.C.), National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Penelope Feuillan, National Institutes of Health, Building 49, Room 4a28, MSC 4472, Bethesda, Maryland 20892. E-mail: feuillap{at}mail.nih.gov.

Context: Girls with McCune-Albright syndrome (MAS) and related disorders have gonadotropin-independent precocious puberty due to estrogen secretion from ovarian cysts. Their puberty does not respond to GnRH agonist therapy, and short-acting aromatase inhibitors have had limited effectiveness.

Objective: Our objective was to assess the effectiveness of the potent, third-generation aromatase inhibitor letrozole in decreasing pubertal progression in girls with MAS and to assess the response of indices of bone turnover associated with the patients’ polyostotic fibrous dysplasia.

Design: Subjects were evaluated at baseline and every 6 months for 12–36 months while on treatment with letrozole 1.5–2.0 mg/m²·d.

Setting: This was an open-label therapeutic trial at a single clinical center.

Patients: Patients included nine girls aged 3–8 yr with MAS and/or gonadotropin-independent puberty.

Main Outcome Measures: Measures included rates of linear growth, bone age advance, mean ovarian volume, estradiol, episodes of vaginal bleeding, and levels of the indices of bone metabolism: serum osteocalcin, alkaline phosphatase, urinary hydroxyproline, pyridinoline, deoxypyridinoline, and N-telopeptides.

Results: Girls had decreased rates of growth (P 0.01) and bone age advance (P 0.004) and cessation or slowing in their rates of bleeding over 12–36 months of therapy. Mean ovarian volume, estradiol, and indices of bone metabolism fell after 6 months (P 0.05) but tended to rise by 24–36 months. Uterine volumes did not change. One girl had a ruptured ovarian cyst after 2 yr of treatment.

Conclusions: This preliminary study suggests that letrozole may be effective therapy in some girls with MAS and/or gonadotropin-independent precocious puberty. Possible adverse effects include ovarian enlargement and cyst formation.

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