Medication Summary
The underlying pathophysiology of gonadotropin-independent precocious puberty is autonomous function of the gonadal axis; thus, the use of gonadotropin-releasing hormone (GnRH) analogs does not appear to be effective in the management of these disorders. No medications are routinely used in young children with an FDA-approved indication for the treatment of gonadotropin-independent precocious puberty. Therefore, a physician with expertise in the area should closely monitor the use of medications.
Steroid synthesis inhibitors
Class Summary
Ketoconazole blocks enzymes in the steroid biosynthetic pathway. It primarily inhibits C-17,29-desmolase, the enzyme responsible for androstenedione biosynthesis.
Ketoconazole (Nizoral)
More commonly used in treating fungal infections, but may be used in treating precocious pseudopuberty. It inhibits steroid synthesis at the level of 17 α -hydroxylase/17,20-lyase, a key enzyme in sex steroid production. It also inhibits testosterone binding to its binding globulin. In some cases, especially in those children with markedly advanced bone age, a rapid decrease in sex hormone levels may trigger true central puberty. In this event, add GnRH analogs to the treatment regimen.
Antiandrogens
Class Summary
These drugs block the effect of testosterone and dihydrotestosterone at the androgen receptor.
Spironolactone (Aldactone)
Mainly used as an antimineralocorticoid diuretic. It is also a weak competitive androgen antagonist. Other properties include inhibition of 17 α -hydroyxlase/17,20-lyase and interference with testosterone binding to sex hormone binding globulin. It is typically used to treat precocious pseudopuberty in conjunction with another drug (eg, an aromatase inhibitor). Specific nonsteroidal androgen antagonists (eg, flutamide) are more effective; however, they also carry greater toxicity. Therefore, the latter class of drug is used only in children in the context of clinical trials in the United States. As noted above, adjunctive use of GnRH analogs may be required if true central puberty occurs as a complication of treatment.
Aromatase inhibitors
Class Summary
This category of drugs is usually used in conjunction with an antiandrogen. Aromatase inhibitors prevent the conversion of androstenedione to estrone and testosterone to estrogen. Because estrogens play a major role in epiphyseal maturation (besides their obvious role in generating female secondary sexual effects), inhibiting estrogen production has salutary effects on slowing the progress of precocious pseudopuberty.
Testolactone (Teslac)
First-generation aromatase inhibitor used to prevent conversion of androstenedione to estrone and testosterone to estrogen in children. Newer preparations are now available, but no new agents have had published clinical trials. As noted above, adjunctive use of GnRH analogs may be required if true central puberty occurs as a complication of treatment.
Antiestrogens
Class Summary
Estrogen receptor blockade (eg, with tamoxifen) may be an alternative to aromatase inhibitors and progestins in the treatment of MAS in girls. The predominant problem in childhood is precocious pseudopuberty associated with excess estrogen secretion from ovarian cysts.
Tamoxifen (Nolvadex)
Competitively binds to estrogen receptor, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects. This drug is currently being tested in clinical trials. A single case report suggested a dose of 10-30 mg PO daily is effective in controlling estrogenic affects in MAS.
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Graph represents the prevalence of breast development at Tanner stage 2 or greater by age and race.
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Graph represents the prevalence of pubic hair at Tanner stage 2 or greater by age and race.
