Gonadotropin-Independent Precocious Puberty (“Testotoxicosis”): Influence of Maturational Status on Response to Ketoconazole

Three boys, 5.0-7.4 yr of age, with clinical and biochemical features consistent with familial gonadotropin-independent precocious puberty ("testotoxicosis") were treated with the antifungal drug ketoconazole in a dose of 200 mg every 8 h. Serum testosterone levels fell significantly within 24 h in all three patients, with reciprocal changes in serum 17-hydroxyprogesterone, consistent with inhibition of C17-20 lyase activity. However, after 1-3 months of continuing treatment, an "escape" phenomenon occurred, characterized by progressive increases in serum LH, FSH, and testosterone concentrations. Furthermore, for the first time, a marked pubertal-type LH response was found after GnRH administration in contrast to the absent response consistently found in all patients before ketoconazole therapy. Combination treatment with ketoconazole and the GnRH analog buserelin resulted in restoration of pituitary and gonadal hormone concentrations to the upper range of normal for prepubertal children. We hypothesize that the advanced state of maturation of the boys in this study [mean bone age, 13.2 +/- 0.8 (+/- SE) yr] was the major contributing factor to this escape, with the set-point of the GnRH pulse generator (gonadostat) functioning at the adult level of sensitivity. Such escape may limit the successful use of ketoconazole alone. These data together with evidence of normal testosterone responses to hCG during ketoconazole therapy indicate that in testotoxicosis, pituitary and gonadal receptors are functionally intact, with appropriate negative feedback relationships.