Thyroid function has been evaluated in 6 prepubertal male and 9 female thalassemic patients. Four of the latter were sexually immature (Group I), with very low estradiol levels and the remainder had more advanced sexual development (Group II). Subjects were challenged with TRH and the response compared to adult controls and a group of 15 males aged 13-18 years with constitutional delayed adolescence. All patient groups and controls had normal levels of T4, T3 and T3 resin uptake. When compared to adult controls or males with constitutional delayed adolescence, the male thalassemic patients had increased basal TSH levels with an exaggerated response to TRH. Long term testosterone enanthate led to a decrease in integrated TSH secretion, showing that androgens may decrease the TSH response to TRH. The more sexually mature females of Group II also had increased basal and stimulated TSH levels; however, the sexually immature females of Group I had basal TSH and TSH responses to TRH equivalent to female controls. In Group I patients there were, moreover, no changes in TSH response during administration of estradiol valearate for 3 months and conjugated estrogens for 8 months. The high basal and stimulated TSH levels in the males and Group II females are most likely due to subclinical primary hypothyroidism. This has been previously described in thalassemia. On the other hand, failure of estrogens to increase the TSH response to TRH in Group I females is evidence of pituitary involvement, which is also well documented in this clinical condition.(ABSTRACT TRUNCATED AT 250 WORDS)