Ketoconazole in the Management of Precocious Puberty Not Responsive to LHRH-Analogue Therapy

Abstract

Three boys 3.3 to 3.9 years old, who had precocious puberty that was unresponsive to an analogue of gonadotropin-releasing hormone, were treated with the antifungal agent ketoconazole for up to 12 months. Within 48 hours the serum testosterone concentration fell to normal in two boys and was significantly reduced in the third, paralleling major improvements in behavior. Reciprocal changes in serum levels of 17-hydroxyprogesterone suggested that C17-20 lyase was the principal site of drug action. Although there was evidence of a blunted cortisol reserve during the first week of treatment, the cortisol response to ACTH1-24 had returned to normal by one month of continuous treatment, and normal diurnal cortisol rhythm was preserved. No adverse clinical or biochemical side effects were noted during 9 to 12 months of continuing treatment. During that time, growth velocity was significantly reduced in all three boys, from a mean rate of 1.5 +/- 2.0 cm per year before treatment to 5.9 +/- 0.6 cm per year after ketoconazole therapy. There was a simultaneous retardation of the rate of skeletal maturation. The striking improvements in behavior were sustained for the duration of treatment. These preliminary data suggest that administration of ketoconazole may be a satisfactory treatment for precocious puberty in boys and possibly for other conditions characterized by androgen excess.

Long-Term Outcome of Male-Limited Gonadotropin-Independent Precocious Puberty

“…Female car riers do not show cither early sexual development or other endocrine abnormalities [1,2], There are occasional nonfamilial cases, as our patient 4. The disease is due to autonomous testicular testosterone secretion [2][3][4]10], sustained by constitutive activation of the LH receptor for a missense mutation in the LH receptor gene [10. 11], This pathogenetic mechanism has been confirmed in two of our boys (patients 1 and 5), in whom the mutation (Met398Thr) was identified [10; Shenkcr, pers.…”

“…Current thera pies are based on diminishing androgen production [3] or on inhibition of their peripheral effects [4], We treated patient 1 and 3 with cyproterone acetate for its inhibiting effect on testosterone and dihydrotestosterone at receptorial level. Such a treatment did not decrease pubertal and bone age progression.…”

“…Male-limited precocious puberty (MPP), also called familial male precocious puberty or testotoxicosis, is a rare form of gonadotropin-independent sexual precocity [1,2], Endocrine findings are pubertal testosterone levels associated with prepubertal or suppressed gonadotropin values [1][2][3]. Therapy has been conducted with drugs which block either testicular steroidogenesis [2,3] or peripheral androgen action [4], Longitudinal follow-up of patients has been reported rarely.…”

“…Therapy has been conducted with drugs which block either testicular steroidogenesis [2,3] or peripheral androgen action [4], Longitudinal follow-up of patients has been reported rarely.…”

Effects of ciprofloxacin on testosterone and cortisol concentrations in healthy males

“…Ketoconazole and omeprazole have been shown to cause a blunted response to adrenocorticotropin hormone administration (3,10,16,18), and there have been several reports of patients who have experienced adrenal insufficiency while receiving ketoconazole (2,14). These effects on steroidogenesis have resulted in the clinical use of ketoconazole in diseases such as prostatic cancer, precocious puberty, hirsutism, and Cushing's disease (9,11,13,21,22). Metyrapone is a potent inhibitor of cortisol production, and as a result, its primary indication is to assess hypothalamic-pituitary function.…”