Aim of this study was to verify whether arginine (ARG), which likely inhibits hypothalamic somatostatin release, has an enhancing effect on the GHRH-induced GH rise, even when administered orally at low dose. To this goal we studied the effects of 4 g orally administered ARG, either hydrochloride (ARG-H) or aspartate (ARG-A), on both basal and GHRH (1 mug/Kg iv) -stimulated GH secretion in 31 children with familial short stature (11 males and 20 females, aged 5.5-13.8 yr, pubertal stage I-III, and compared the results with those of iv infusion of 0.5 g/kg ARG-H. Oral ARG-H (Group A, n=11) induced a significant increase of basal GH levels (4.2+/-1.3 vs 1.0+/-0.4 mug/L, p<0.02) and enhanced the GH response to GHRH (41.1+/-8.6 vs 25.3+/-6.7 mug/L, p<0.02). Oral ARG-A (Group B, n=10) induced a slight, but not statistically significant increase in serum GH levels (3.4+/-1.5 vs 1.0+/-0.3 mug/L) and enhanced the GHRH-induced GH rise (49.7+/-9.8 vs 26.1+/-8.4 mug/L, p<0.05). Intravenous ARG-H (Group C, n=10) stimulated basal GH levels (6.2+/-1.2 vs 1.2+/-0.3 mug/L, p<0.005) and increased the GHRH-induced GH rise (46.7+/-5.0 vs 17.1+/-2.3 mug/L, p<0.005). This response was similar to those after oral ARG-H or ARG-A plus GHRH. No variation was observed in PRL levels after oral ARG (either ARG-H or ARG-A) and/or GHRH. These results show that a low dose of orally administered ARG is able to enhance the GHRH-induced GH rise with the same extent of a high dose iv administered ARG in normal short children. The potential usefulness of oral ARG combined with GHRH to restore GH secretion in hypothalamic GH deficiency might be envisaged.