We propose to study a population of patients with a specific defect in the ability to synthesize IGF-I due to growth hormone receptor deficiency (GHRD) as a unique human model for the discrete effects of pure IGF-I deficiency on body composition. The hypotheses to be explored are: 1) IGF-I deficiency due to GH resistance results in increased body fat content with decreased muscle and bone mass in adults, despite adequate sex hormone status and; 2) replacement therapy with IGF-I will increase muscle and bone mass and reduce total percent fat in adults with IGF-I deficiency due to GHRD. These hypotheses will be tested in 16 adult Ecuadorian patients with GHRD, and 30 of their unaffected siblings (including 15 heterozygotes for GHRD and 15 homozygous normals) serving as controls. Patients will be treated with recombinant human IGF-I for 24 months following 6 months of nutritional monitoring and baseline studies, and they will be followed for a year after stopping treatment. Measures will include height, weight, body mass index, upper to lower segment ratio, span, skinfold thickness, radiographic skeletal survey, muscular strength, dietary recall, biochemical measures (IGF-I and -II, GH, IGFBP-1, -2, and -3, GH binding protein, osteocalcin, bone alkaline phosphatase, PTH, vitamin D metabolites, urine calcium, creatinine and hydroxyproline, lipid profile, renal and hepatic profiles, sex steroids, FSH and LH in serum and urine, and thyroid function studies). Body composition will be determined by dual energy x-ray absorptiometry with calculation of total percent body fat, lean to fat ratios for various regions, total and regional BMC and BMD, and BMAD as a correction for bone volume, every 3 months in patients and annually in controls. Bone biopsy will be obtained for dynamic histomorphometric studies before and during IGF-I treatment. This study takes advantage of the support of Kabi Pharmacia for provision of IGF-I for trials of replacement therapy, and the infrastructural development stemming from a study of body composition in children with GHRD receiving IGF-I treatment in this population. This group of patients with extreme deficiency of IGF-I and body composition changes early in adulthood that are similar to normal aging, will serve as a guide to trials of replacement therapy with IGF-I in GH deficient and normal adults.
NIH ExPorter
NIH ExPorter