The overall goal of this revised R01 application is to define the relative contributions of sex steroids, GH, and IGF-1 to anabolic protein and calcium balance during puberty and in adults. To accomplish these goals, two specific aims are proposed. The first specific aim will study the tissue interactions among GH, IGF-1, and sex steroids in two models, GH- deficient youngsters and in GnRH agonist treated (hypogonadal adults). In the first series of experiments, GH deficient, prepubertal youngsters will be selectively primed with appropriate sex steroids and later treated with either hGH or rhIGF-1 for 1 month. Clinical endpoints will be obtained before sex steroid replacement, after steroid treatment and after hGH or rhIGF-1 replacement. These endpoints will include assessment of changes in whole body protein degradation, oxidation, and synthesis as well as calcium absorption, retention, and bone accretion and resorption. A second series of experiments will be carried out in a similar fashion in GnRH agonist treated adults. In these subjects, GH secretory dynamics will also be determined as well. In the third series of experiments, the effects of dihydrotestosterone (DHT), a nonaromatizable androgen, on GH pulsatility will be determined in prepubertal boys to determine if anabolic effects of androgens are direct or mediated indirectly by aromatization to estrogens.
The second aim will determine the longterm effects of rhIGF-1 on measures of whole body protein, calcium kinetics, and carbohydrate metabolism in adults with GH deficiency. These studies should help define therapeutic roles for GH, IGF-1, and sex steroids in treatment of growth disorders and in diseases with increased protein-catabolic states.
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