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 d imerization and subsequent activation of the growth hormone receptor. Pegvi somant and fasting both lead to GH resistance. Design and Patients: We performed a double-blind placebo-controlled cross-o ver study comparing the effects of pegvisomant and fasting on the GH-releas ing hormone (GHRH)- and GH-releasing peptide-6 (GHRP-6)-stimulated GH-relea se 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 th e second test either pegvisomant (80 mg as a single subcutaneous injection) or placebo was administered. On day 4, GHRP-6 and GHRH tests were performe d in the same order as on day 1. During the cross-over study, subjects fast ed from 2400 h on day 1 until the end of the study. Measurements: During the GH stimulation tests, blood samples were drawn eve ry 15 min from 15 to 120 min. GH was determined in all samples. Total insul in-like growth factor (IGF)-I and free IGF-I were determined from the sampl es at 0 min only. Results: Three days of fasting alone and pegvisomant alone as well as in co mbination increased GH concentrations, whereas a decrease in serum-free, bu t not total, IGF-I concentrations was observed. On day 4, fasting and pegvi somant, either alone or in combination, significantly increased GH concentr ations after GHRH compared to baseline. Pegvisomant alone did not increase GH concentrations after GHRP-6 administration. Fasting alone increased GH l evels after GHRP-6 administration. The combination of fasting and pegvisoma nt 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 rol e 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.