Cyproterone acetate (CA), an antiandrogenic synthetic steroid with inhibitory effects on gonadotropin secretion, has been used in the treatment of precocious puberty (PP) in Europe for the last decade. CA has been proven to be effective in reducing the clinical manifestations of sexual maturation without serious side effects. However, the effect of CA on adult height in patients with PP is still controversial, and the mechanism of action of this drug in PP remains to be investigated. We recently collected reports of 74 cases (17 males and 57 females) of PP treated with CA through a questionnaire sent to 14 hospitals all over the country. They comprised 50 cases of idiopathic PP, 14 cases of PP secondary to organic brain lesions, 7 cases of PP secondary to congenital adrenal hyperplasia and 3 cases of McCune Albright syndrome. In this report, the effect of CA on clinical manifestations, linear growth and pituitary-gonadal and adrenocortical functions as well as side effects were studied by summing up these questionnaires.
The CA therapy was started between one and thirteen years of age and was continued for three to 54 months. CA was administered orally in a dose ranging from 44 to 147mg/ m2 /day in all but four patients. CA was markedly effective in 15, moderately effective in 38, slightly effective in 17 and ineffective in only four patients on a clinical basis. Minor clinical side effects such as excessive weight gain (one case), gynecomastia (two cases), headache (two cases), depression (one case) and easy fatigability (one case) were observed in 6 out of 74 patients, however, CA was not discontinued or tapered off because of these side effects in any of the patients.
Plasma cortisol concentrations were depressed occasionally during the CA therapy, but there were no definite clinical signs of depressed adrenocortical function. The mean basal level of LH and the mean response after LH-RH stimulation were significantly reduced by CA, while FSH secretion and its responsiveness to LH-RH were not significantly affected. Plasma testosterone levels were abruptly suppressed by CA in two out of three boys, but they rose again after prolonged therapy. The mean serum estradiol level in girls was suppressed to a similar degree with LH though this was statistically insignificant because of a smaller amount of data. These findings suggest that the suppression of LH secretion from the pituitary is the most important mechanism of action of CA on PP.
In order to evaluate the effect of CA on linear growth, the ratio of height age (HA) and bone age (BA), the predicted adult height estimated by the method of Bayley and Pinneau and the ratio of the increase of height age (ΔHA) to the increase of bone age (ΔBA), were studied in 34 patients in whom change of BA could be followed up for more than one year. HA/BA ratios were increased after the treatment with CA in 25 out of 34 cases. Predicted adult heights were also increased in 24 out of 28 cases evaluated, and AHA/ABA ratios during the CA therapy were more than 1.0 in 26 out of 34 cases. The increase of predicted height and the ΔHA/ΔBA ratio of more than 1.0 were statistically significant, while the increase of HA/BA ratio was statistically significant only in a group of 14 cases in whom the change of BA could be followed up for more than two years. These data suggest that treatment with CA exerts a beneficial effect on linear growth in PP and that this effect may be further increased by a longer period of the therapy.