The present clinical study implements a novel interventional strategy of short-term profound and selective blockade of GH receptors to reduce plasma insulin-like growth factor I ( @entity442 ) concentrations reversibly in healthy eumetabolic adults. Thereby, we examine the feedback role of systemic @entity442 on GH secretion without introducing the complex metabolic disarray that can otherwise accompany secondary @entity442 deprivation. To this end, we sampled blood at 10-min intervals for 10 h overnight in 8 @entity1 (aged 19-46 yr) and 4 @entity1 (aged 19-39 yr) to quantitate endogenous GH secretion and half-life 72 h after the prospective, randomly ordered, double blind, and within-subject cross-over administration of pegvisomant (1 mg/kg) or saline (0.5 mL) sc. Pegvisomant is an oligopegylated recombinant @entity1 GH peptide mutated to antagonize @entity9045 -dependent signaling. Statistical analyses of paired plasma @entity442 concentrations and deconvolution-based quantitation of pulsatile GH secretion revealed that @entity9045 blockade 1) suppressed fasting total @entity442 concentrations by 31%, viz. from (mean +/- SEM) 276 +/- 42 (placebo) to 190 +/- 20 microg/L (pegvisomant; P = 0.006) 84 h after drug injection; 2) increased the 10-h mean serum GH concentration by 71% from 1.4 +/- 0.33 (placebo) to 2.4 +/- 0.58 (pegvisomant; P = 0.024); 3) augmented the amplitude of underlying GH secretory bursts by 2.1-fold (i.e. from 0.13 +/- 0.032 to 0.27 +/- 0.076 microg/L.min; P = 0.0088); and 4) elevated the basal/nonpulsatile rate of GH secretion by 2.5-fold (from 2.3 +/- 0.77 to 5.07 +/- 1.8 microg/L.10 h; P = 0.022). The rise in the amplitude of GH secretory bursts correlated with the fall in plasma @entity442 concentrations (r = 0.603; P = 0.038). In contrast, @entity442 depletion did not alter GH secretory pulse frequency, half-duration, interpulse interval, percentage of pulsatile GH release, or half-life of endogenous GH. In summary, selective short-term reduction of systemic @entity442 concentrations in healthy eumetabolic adults drives GH secretion via the specific bipartite neuroregulatory mechanism of amplified GH secretory burst amplitude and elevated basal/nonpulsatile GH release. Endogenous GH half-life and frequency-related features of pulsatile GH secretion are not measurably affected, thus identifying a highly distinctive mode of @entity442 feedback-dependent control of GH output. As the increment in GH secretory burst amplitude correlated with the decrement in plasma @entity442 concentrations, we infer that variations in circulating @entity442 availability within the adult midphysiological range can influence pulsatile and basal GH production by way of negative feedback. Based on data in experimental animals, we speculate that the negative feedback actions of systemic @entity442 on GH secretion are mediated via increased hypothalamic @entity1943 release, decreased @entity7704 (or GH-releasing peptide) secretion, and/or suppressed pituitary GH biosynthesis.

Lowering total plasma insulin-like growth factor I concentrations by way of a novel, potent, and selective @entity9045 antagonist, pegvisomant (B2036-peg), augments the amplitude of GH secretory bursts and elevates basal/nonpulsatile GH release in healthy XXXX and @entity1 .

@entity1 :: ('9606', 'Species') :: ['women', 'human', 'men'] @entity7704 :: ('2691', 'Gene') :: ['GHRH'] @entity442 :: ('3479', 'Gene') :: ['IGF-I'] @entity1943 :: ('MESH:D013004', 'Chemical') :: ['somatostatin'] @entity9045 :: ('2690', 'Gene') :: ['GH receptor']
@entity1 :: (9606,Species) :: ['women']
