What is the role of pharmacologic therapy in the treatment of precocious puberty in McCune-Albright syndrome (MAS)?

Updated: Jan 05, 2021
  • Author: Gabriel I Uwaifo, MD; Chief Editor: George T Griffing, MD  more...
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Therapy for precocious puberty is available and should be tried; however, it is still largely experimental. Precocious puberty in MAS is gonadotropin-independent and therefore does not respond to the gonadotropin-releasing hormone (GnRH) agonist therapy that is so successful with gonadotropin-dependent central precocious puberty, [11] though one study did find GnRH analogue therapy for children to have some success in girls with MAS. [46]

For female patients, the central aim is to block estrogen effects. To this end, the aromatase inhibitors have been the mainstay of therapy in girls with persistent estradiol elevation.

Patients who respond to treatment should continue therapy until the age of normal puberty or until a bone age of 15-16 years.

A GnRH analogue may be added to aromatase inhibitors as an adjunct in the treatment of precocious puberty to suppress pituitary gonadotropin production. Depot leuprolide acetate at a dosage of 7.5 mg (300-500 µg/kg) every 28 days is a typical regimen; the dosage can be adjusted upward or downward on the basis of clinical and laboratory findings.

Preliminary trials of other aromatase inhibitors have been initiated with the aim of achieving better management of precocious puberty. [47] In 1 clinical trial, fadrozole, a more potent aromatase inhibitor, was ineffective in preventing progression of precocious puberty [48] ; however, anastrozole, a highly selective aromatase inhibitor, significantly slowed precocious puberty in 1 case and offered the added benefit of once-daily dosing. [49] The third-generation aromatase inhibitor letrozole has had some success. [50]

Ketoconazole was used in 1 study as an alternative therapy in 2 girls, who also showed significant improvement in signs of precocious puberty. [51] Unfortunately, ketoconazole’s dosing frequency is 3 times daily, which is a drawback in comparison with the once-daily dosing of anastrozole or tamoxifen.

Estrogen receptor antagonists, such as tamoxifen, may have a therapeutic role but have not yet been systematically investigated. Tamoxifen has shown some evidence of efficacy for treating precocious puberty in girls with MAS. In a multicenter study that used a regimen of 20 mg of tamoxifen once daily, the investigators reported significant improvement in growth velocity and rate of skeletal maturation. [52]

Other pilot clinical trials have been performed, in which the antiandrogen cyproterone acetate was used to block pubertal development in young female patients, while ketoconazole was used in males.

Adequate response to these therapies can be assessed by administering serial GnRH stimulation tests after 3-6 months of therapy.

Additional treatment options include medroxyprogesterone acetate, which is particularly useful for controlling menstrual bleeding. The preferred agent is Depo-Provera in intramuscular (IM) doses of 4-15 mg/kg monthly. No definitive clinical trials have determined the efficacy of this medication in the setting of MAS.

In males, adequate medical therapy for precocious puberty consists of the use of antiandrogen and antiestrogen preparations, typically a combination of spironolactone and aromatase inhibitors. Alternative antiandrogens (eg, ketoconazole) may also be used, in a dosage range of 600-800 mg/day. In one report, combined treatment with ketoconazole and cyproterone acetate was used in a boy with MAS and peripheral precocious puberty, with some positive effect. [53]

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