In acromegaly, GH hypersecretion occurs despite elevated insulin-like growth factor-I (IGF-I) levels, implying defective IGF-I feedback. To study the possible mechanisms of defective IGF-I negative feedback in acromegaly, we assessed parameters of pulsatile GH secretion during fasting-induced decrease in plasma IGF-I. Seven patients with active acromegaly and six normal controls were fasted for 6 days and GH secretory profiles were obtained by frequent (every 10 min) blood sampling for 24 h and analyzed by Cluster. Fasting resulted in similar decreases in IGF-I, body weight, and blood glucose levels, and increases in free fatty acid and beta-hydroxybutyrate in all subjects. Normal subjects showed increases in 24-h total and pulsatile GH production, GH pulse frequency, maximal pulse amplitude, interpulse and nadir levels, implying suppression of hypothalamic somatostatin secretion and increase in GH-releasing hormone (GHRH) pulse frequency. In acromegalic patients, GH (and, by inference, GHRH) pulse frequency was unchanged. Three patients had increases in GH production, interpulse, and nadir levels similar to the normals while the other four had no change or paradoxical decreases in these parameters. Percentage change in GH production was highly correlated with percentage change in interpulse and nadir levels in both normals and patients. Mean GH response to GHRH (0.33 micrograms/kg iv) did not change significantly in any group as a result of fasting. Our data suggest that in healthy humans IGF-I negative feedback on GH secretion involves suppression of GHRH pulse frequency. GH (and, by inference, GHRH) pulse frequency is resistant to decrease in IGF-I in acromegaly, suggesting that lowered sensitivity of GHRH neurons to IGF-I may be the mechanism of high GH pulse frequency in this disease.