It has been suggested that menstrual irregularities in hyperprolactinemia are secondary to an increase in hypothalamic dopaminergic activity via a short loop positive feedback of prolactin (PRL). We have studied this question in a relatively new syndrome characterized by hyperprolactinemia without derangements of the hypothalamic-pituitary-ovarian function due to macroprolactinemia (abnormal high amounts of big-big PRL). Central dopaminergic activity was investigated by the administration of the dopamine antagonist domperidone to normal women (n = 7) and women with anovulatory (n = 6) and ovulatory hyperprolactinemia (n = 2). The effects of domperidone were evaluated in all subjects by the measurements of radioimmunoassayable circulating serum PRL and TSH levels. All subjects had a significant increase in serum PRL levels after 90 min of domperidone administration. Anovulatory hyperprolactinemic subjects showed the highest response to domperidone in terms of TSH, whereas normal women and women with ovulatory hyperprolactinemia had similar increments in TSH serum levels after the administration of the dopamine antagonist. These results support the observation that an increase of hypothalamic dopaminergic activity in hyperprolactinemia may account in part for the presence of menstrual irregularities. The presence of a similar pituitary responsiveness in terms of TSH to domperidone in normal and ovulatory hyperprolactinemic women suggests a similar hypothalamic dopaminergic activity in both group of subjects. These findings might offer an explanation for the coexistence of normal ovulatory cycles in spite of hyperprolactinemia.