The effect of domperidone, a specific blocker of dopamine receptors, on serum TSH and PRL levels was evaluated in 16 euthyroid men affected by insulin-dependent diabetes mellitus (IDDM) of different duration and in 7 age-matched normal controls. Diabetics were divided into 2 groups of 8 men according to the duration of their disease (group I: 1-9 years; group II: 11-18 years). Both groups had normal basal levels of TSH and PRL. Responses of these hormones to domperidone were similar in normal controls and in group I diabetics, whereas they were significantly reduced in patients of group II. When all 16 diabetics were studied together, a significant negative correlation was found between mean maximal peaks of TSH and PRL responses to domperidone and duration of diabetes. In order to evaluate whether the reduced effect of domperidone in diabetics was due to alterations of the dopaminergic control of TSH and PRL secretion, the domperidone test was repeated in 6 normal controls and in 6 diabetics of group II after infusion of dopamine (4 µg/kg/min for 2 h). Dopamine infusion induced parallel decreases in TSH and PRL concentrations, without modifying hormonal secretory patterns in response to domperidone. These data suggested that the reduced TSH and PRL responses to domperidone in diabetics were not due to alterations of the dopaminergic control of pituitary function but to a defect at the pituitary level. To test this hypothesis, TSH and PRL responses to TRH were evaluated in group I and group II diabetics and in normal controls. Results showed reduced TSH and PRL responses in diabetics of group II, but not in those of group I; when all 16 diabetics were studied together, a significant negative correlation was found between maximal peaks of TSH and PRL responses to TRH and duration of diabetes. These data indicate that the acute releasing pools of both TSH and PRL are reduced with time after the onset of IDDM.