Effects of fasting and pegvisomant on the GH-releasing hormone and GH-releasing peptide-6 stimulated growth hormone secretion

Objective: Pegvisomant is a mutated GH molecule which prevents functional dimerization and subsequent activation of the growth hormone receptor. Pegvisomant and fasting both lead to GH resistance. Design and Patients: We performed a double-blind placebo-controlled cross-over study comparing the effects of pegvisomant and fasting on the GH-releasing hormone (GHRH)- and GH-releasing peptide-6 (GHRP-6)-stimulated GH-release before and after 3 days of fasting in 10 healthy lean male subjects. We also performed a single-arm open label study under nonfasting conditions in five of these subjects. On day 1, in random order, at 0800 h, a GHRP-6 or GHRH test was performed. At 1600 h, a GHRH (if the first test was a GHRP-6 test) or GHRP-6-test (if the first test was a GHRH test) was done. After the second test either pegvisomant (80 mg as a single subcutaneous injection) or placebo was administered. On day 4, GHRP-6 and GHRH tests were performed in the same order as on day 1. During the cross-over study, subjects fasted from 2400 h on day 1 until the end of the study. Measurements: During the GH stimulation tests, blood samples were drawn every 15 min from 15 to 120 min. GH was determined in all samples. Total insulin-like growth factor (IGF)-I and free IGF-I were determined from the samples at 0 min only. Results: Three days of fasting alone and pegvisomant alone as well as in combination increased GH concentrations, whereas a decrease in serum-free, but not total, IGF-I concentrations was observed. On day 4, fasting and pegvisomant, either alone or in combination, significantly increased GH concentrations after GHRH compared to baseline. Pegvisomant alone did not increase GH concentrations after GHRP-6 administration. Fasting alone increased GH levels after GHRP-6 administration. The combination of fasting and pegvisomant had a synergistic effect on GH release after GHRP-6. Conclusion: These human in vivo data suggest that: (1) circulating free IGF-I, and not total IGF-I, is the major component in the negative feedback on GH secretion; (2) increased pituitary GHRH receptor expression plays a role in the mechanism whereby fasting leads to increased GH concentrations; (3) in vivo, GHRP-6 sensitivity seems to be regulated primarily by metabolic factors and not by changes in GH-IGF-I axis.