Physiological Importance of Growth Hormone Pulsatility

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DESCRIPTION (provided by applicant): The role of GH pulse pattern has been carefully studied in animals. Extensive data from rodents demonstrate that pulsatile and continuous GH profiles have very different endocrine and metabolic effects. In contrast, the present clinical use of GH in humans is empiric and does not reproduce the normal pulsatile pattern of GH release. Suboptimal responses to GH replacement in children and adults might relate to non-physiological GH profiles obtained by daily subcutaneous GH injections. We have previously shown that GH secretion in humans is gender-specific, with woman having more continuous exposure to GH throughout the day. Moreover, we have demonstrated that woman have higher hepatic CYP3A4 activity than do men and that CYP3A4 activity can be increased or decreased by female (continuous) or male (pulsatile) GH administration. We hypothesize that pulsatile and continuous GH patterns have differential effects on the liver and other peripheral tissues in humans. We predict that continuous GH will increase the activity of CYP3A4 and the expression of hepatic IGF-I whereas the pulsatile GH will more effectively increase muscle IGF-I, muscle protein synthesis, fatty acid oxidation and bone turnover. We will test this hypothesis by administering GH intravenously (iv.) in two different patterns to 15 men and 15 women with GH deficiency. Subjects will be admitted to the GCRC three times for 7 days of control or GH treatment. During the first (control) admission, they will receive an iv. infusion of D5W (control). The order of the second and third admissions will be randomized to receive either iv. GH as a continuous infusion or as 6 boluses given over 20 min every 6 h. Whole body fatty acid and amino acid disposition will be measured using iv infusions of [13C]-palmitate and [2H3]-Ieucine. Percutaneous needle muscle biopsies will be performed and ]GF-I mRNA and protein and [2H3]-Ieucine incorporation measured. The effect of each treatment on the liver will determined using measurements of serum IGF-I, erythromycin breath test (CYP3A4) and lipoproteins. The effects on bone will be assessed using markers of bone formation and resorption. A role for STAT as a mediator of pulse-dependent effects of GH will be investigated by quantifying muscle phosphorylated STAT5. Insulin sensitivity will be assessed. The results of this study will add to our understanding of the physiology and pathophysiology of GH action and will help in designing more effective means of GH replacement therapy.