11 KETOCONAZOLE THERAPY IN LHRH ANALOG RESISTANT PRECOCIOUS PUBERTY

Three boys with familial gonadotropin-independent precocious puberty(Rosenthal et al,JCEM 57:571,1983) were treated with LHRH analog for periods of 1-4 mos,without clinical or biochemical response.The effects of the antifungal drug ketoconazole were studied in these boys prompted by the observation that this agent may interfere with testosterone biosynthesis.With 200 mg/12 h P.O. there was an immediate significant fall in serum testosterone(T) from a pre-Rx level of 7.0±1.6 nM/L (mean±SEM) to 1. 3±1.1(P < 0.05),with a reciprocal rise in 17-OHP from 2.3±1.5 to 7.2±1.1 nM/L.DHAS and androstenedione levels were unchanged.The T response to hCG remained intact. Major improvement in behavior, linear growth & skeletal maturation were sustained for the duration of treatment.The cortisol response to ACTH1−24 was significantly blunted after 5 days of Rx,but returned to normal after 1 mo with normal diurnal rhythm.Hepatic abnormalities were not observed in up to 13 mos of treatment.We conclude that ketoconazole may provide effective long-term control of precocious puberty in males through C 17-20 lyase inhibition,and speculate that this drug may play an important therapeutic role in other conditions of androgen excess.