We have demonstrated the time course of the suppressive effect induced by exogenous 20K-hGH on endogenous 22K-hGH secretion in humans. The reduction of serum 22K-hGH level after 20K-hGH administration required a period of ca. 4 h, and the level tended to recover by 24 h. However, the delay in suppression of endogenous 22K-hGH by exogenous 20K-hGH is difficult to define precisely because of the intermittent nature of hGH secretion. Additional studies are required to clarify the time lag between 20K-hGH exposure and suppression of endogenous 22K-hGH. In previous studies (31, 32), single intramuscularly or sc administration of hGH (with monitoring of the resulting plasma profiles) showed a delayed and prolonged suppressive effect on rat GH secretion. The time course of endogenous GH suppression in rats was similar to but faster than that in humans reported here. The fast time course in rats was probably due to the rapid absorption of hGH in this species (14, 33). Willoughby et al. (31) suggested that suppression is achieved through metabolic or other intermediary processes, rather than acutely by a direct membrane effect of the hGH molecule.
The marked suppression of endogenous 22K-hGH secretion occurred in parallel with the FFA elevation; serum FFA levels increased with maximum levels at 4–8 h and recovered by 24 h after 20K-hGH administration. In contrast, serum IGF-I levels increased after 8 h and were prolonged up to 24 h or more, and no increase in circulating glucose levels was observed for 24 h. Our data are consistent with those of Rosenthal et al. (34), who found that 6-h methionyl 22K-hGH infusion raised plasma FFA levels but not IGF-I or glucose levels and blunted GHRH-induced GH secretion in normal men. Of the main hGH-dependent substances, elevation of FFA rather than IGF-I levels may play a leading role at least in the marked 22K-hGH suppression at AUC6–12 h after a single sc administration of 20K-hGH. Administration of FFA markedly reduced the basal GH secretion and blocked GH secretion induced by pharmacological and physiological stimuli in humans (23, 35). Recently, Briard et al. (36) reported that FFA acts both at the hypothalamic level, through increased somatostatin secretion, and at the pituitary level in sheep.
The suppression of 22K-hGH secretion was observed even at the lowest dose of 20K-hGH administered (0.01 mg/kg), with a Cmax of 8.1 ± 4.1 ng/mL. Rosenthal et al. (34) reported that the GHRH-induced GH response in humans was significantly inhibited during 6-h methionyl 22K-hGH infusion, whereas the plasma GH level remained constant (9–13 ng/mL). Therefore, the effect of 20K-hGH on negative feedback may be as potent as that of 22K-hGH.