We investigated the pattern of GH secretion in response to repetitive GH-releasing hormone (GHRH) administration in patients with active acromegaly and in normal subjects. Twelve acromegalic patients (nine women and 3 men; aged 21-76 yr) were studied. Eight had never been treated, whereas four had undergone neurosurgery but still had active disease. All patients and eight normal subjects received three doses of 50 micrograms GHRH, iv, at 2-h intervals. Seven patients were retested 6-8 weeks after transsphenoidal removal of a pituitary adenoma. There was a marked serum GH rise in acromegalic patients and normal subjects after the first GHRH dose [area under the curve, 2070 +/- 532 (+/- SE) vs. 1558 +/- 612 ng/min X ml, respectively; P = NS]. Successive GHRH doses stimulated GH release only in acromegalic patients (second dose, 1123 +/- 421 ng/min X ml; third dose, 2293 +/- 1049 ng/min X ml). In normal subjects, the GH response to the second and third GHRH doses was blunted (second dose, 86 +/- 32 ng/min X ml; third dose, 210 +/- 63 ng/min X ml; P less than 0.01). PRL secretion did not change in normal subjects, whereas 6 of 12 acromegalic patients had PRL release after each GHRH dose (PRL responders to GHRH). Transsphenoidal surgery led to normalization (less than 5 ng/ml) of the preoperatively elevated GH levels in all but 2 patients, who, however, had reduction of somatomedin-C levels. The amount of GH released in the postoperative test was significantly lower than that released preoperatively (first dose, 722 +/- 209 vs. 2945 +/- 743 ng/min X ml; second dose, 358 +/- 117 vs. 1737 +/- 633 ng/min X ml; third dose, 320 +/- 144 vs. 1776 +/- 676 ng/min X ml, respectively; P less than 0.05 in all instances). Thus, patients with active acromegaly, but not normal subjects, respond to repetitive GHRH administration at 2-h intervals with an increase in GH levels. This increase may be due to a larger releasable GH pool and/or faster GH turnover in the adenomatous cell.