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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK045830-01
Application #
3247357
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Project Start
1993-02-05
Project End
1997-01-31
Budget Start
1993-02-05
Budget End
1994-01-31
Support Year
1
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Florida
Department
Type
Schools of Medicine
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Rosenbloom, A L (2000) Physiology and disorders of the growth hormone receptor (GHR) and GH-GHR signal transduction. Endocrine 12:107-19
Rosenbloom, A L (1999) Growth hormone insensitivity: physiologic and genetic basis, phenotype, and treatment. J Pediatr 135:280-9
Rosenbloom, A L; Guevara-Aguirre, J; Rosenfeld, R G et al. (1999) Growth hormone receptor deficiency in Ecuador. J Clin Endocrinol Metab 84:4436-43
Rosenbloom, A L (1999) IGF-I deficiency due to GH receptor deficiency. Horm Metab Res 31:161-71
Rosenbloom, A L; Almonte, A S; Brown, M R et al. (1999) Clinical and biochemical phenotype of familial anterior hypopituitarism from mutation of the PROP1 gene. J Clin Endocrinol Metab 84:50-7
Bachrach, L K; Marcus, R; Ott, S M et al. (1998) Bone mineral, histomorphometry, and body composition in adults with growth hormone receptor deficiency. J Bone Miner Res 13:415-21
Rosenbloom, A L; Guevara-Aguirre, J; Berg, M A et al. (1998) Stature in Ecuadorians heterozygous for growth hormone receptor gene E180 splice mutation does not differ from that of homozygous normal relatives. J Clin Endocrinol Metab 83:2373-5
Rosenbloom, A L; Rosenfeld, R G; Guevara-Aguirre, J (1997) Growth hormone insensitivity. Pediatr Clin North Am 44:423-42
Guevara-Aguirre, J; Rosenbloom, A L; Vasconez, O et al. (1997) Two-year treatment of growth hormone (GH) receptor deficiency with recombinant insulin-like growth factor I in 22 children: comparison of two dosage levels and to GH-treated GH deficiency. J Clin Endocrinol Metab 82:629-33
Rosenfeld, R G; Rosenbloom, A L; Guevara-Aguirre, J (1994) Growth hormone (GH) insensitivity due to primary GH receptor deficiency. Endocr Rev 15:369-90

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