Increasing doses of biosynthetic human GH (R-hGH) were given sc to seven GH-deficient patients for three consecutive 14-day periods (2, 4, and 6 IU/day at 2000 h), followed by 14 days of no GH therapy. At the end of each period each patient was hospitalized for frequent blood sampling from 2000 to 1100 h the following day. A dose-dependent increase in serum GH and serum insulin-like growth factor I (IGF-I) levels occurred. However, the time course of the serum IGF-I concentrations was different on the four occasions; there was a significant fall in the evening when no therapy was given (P less than 0.01), a significant increase after injections of 2 IU R-hGH, and constant levels during treatment with 4 and 6 IU R-hGH. Plasma glucose levels were within the normal range, with a significantly lower fasting level (at 0400 h) when no GH was given. Breakfast induced a plasma glucose rise when GH was administered, but no rise without GH, and a postprandial serum insulin response that was GH dose dependent. GH therapy increased serum FFA (P less than 0.05) and blood 3-hydroxybutyrate levels, but had no effect on blood alanine or lactate or serum triglyceride and cholesterol levels. We conclude that the serum IGF-I response to GH is dose dependent, and that a GH replacement dose of 2 IU/day (equalling 1.5 IU/m2.day) is insufficient to maintain normal diurnal serum IGF-I levels. Furthermore, a GH-independent diurnal variation in serum IGF-I in these patients is suggested. This GH preparation also has diabetogenic and lipolytic actions.