Impairment of thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) has been documented in patients with uncontrolled diabetes mellitus (DM). In acromegalic patients, however, there have been no data regarding TSH secretion studied taking the existence of DM into consideration. Therefore, we investigated the TSH response to TRH [expressed as TSH increment (delta TSH)] in 14 untreated acromegalic patients, who did not show the suprasellar extension of adenoma, divided into two groups on the basis of either presence or absence of uncontrolled DM, and in 28 normal subjects. The mean max delta TSH was significantly reduced (p less than 0.02) in acromegalic patients despite similar mean serum T4 and free T4 index (FT4l) levels. Furthermore, the mean basal and max delta TSH in 7 patients with DM (FBS, 120-300 mg/dl; HbA1, 8.8-15.2%) were significantly lower than those in 7 patients without DM (p less than 0.05 and p less than 0.02, respectively) despite similar the mean serum T3, T4, FT4l, growth hormone (GH) and prolactin (PRL) levels and sellar volume. In 4 patients with DM the TSH response to TRH 6-8 weeks after insulin therapy, when their HbA1 levels were normal, increased compared to that before insulin therapy. The mean max delta TSH after selective adenomectomy in 8 patients (3 in DM group and 5 in non-DM group), whose fasting basal GH fell to less than 5 ng/ml, was almost identical to that in normal subjects. In conclusion, the present study suggests that the abnormality in TSH secretion in acromegalic patients may be increased by the existence of uncontrolled DM.