GROWTH HORMONE HAS ANABOLIC EFFECTS IN GLUCOCORTICOSTEROID-DEPENDENT CHILDREN WITH INFLAMMATORY BOWEL DISEASE: A PILOT STUDY

Authors: MAURAS, NELLY - NEMOURS CHILDRENS CLINIC; GEORGE, DONALD - NEMOURS CHILDRENS CLINIC; EVANS, JONATHAN - NEMOURS CHILDRENS CLINIC; MILOV, DAVID - NEMOURS CHILDRENS CLINIC; Abrams, Steven; RINI, ANNIE - NEMOURS CHILDRENS CLINIC; WELCH, SUSAN - NEMOURS CHILDRENS CLINIC; Haymond, Morey

Submitted to: Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/19/2001
Publication Date: 1/1/2002
Citation: Mauras,N., George,D., Evans,J., Milov,D., Abrams,S., Rini,A., Welch,S., Haymond,M.W. 2002. Growth hormone has anabolic effects in glucocorticosteroid-dependent children with inflammatory bowel disease: a pilot study. Metabolism. 51(1):127-135.

Interpretive Summary: Treating a group of children with inflammatory bowel Disease (IBD) on chronic glucocorticosteroid therapy with rhGH resulted in positive changes in body composition, linear growth, and bone anabolism without detrimental effects in carbohydrate metabolism or the intermediate metabolism of substrates. After 4 months of treatment, rhGH was associated with a measurable increase in fat free mass and a parallel decrease in percent fat mass without any change in body mass index. Longer term studies are needed to assess increasing ultimate adult height and rhGH in this setting. There were no measurable changes in rates of whole body protein synthesis or turnover during the concomitant administration of glucocorticosteroids and rhGH in these experiments contrary to the protein-anabolic effects observed after rhGH therapy in healthy volunteers and in GH-deficient patients. Actually, 1 of the 10 subjects studied here had leucine turnover studies performed 1 month after treatment and a substantial increase in rates of whole body protein synthesis was observed. There were subtle, yet positive changes in bone metabolism as well, with an increase in Vo+, a kinetic measure of the rate of calcium deposition into bone and in bone-specific alkaline phosphorous concentrations. Longer term studies with growth-promoting agents such as GH and/or bisphosphonates will be needed to asses the best way to prevent further bone loss in this condition. It is unlikely that the positive effects observed after rhGH treatment would have been observed spontaneously during continuous steroid administration. Collectively, these data suggest that the effects observed in our present studies are the result of rhGH treatment. RhGH was well tolerated by all children in these studies. Even though the rhGH treatment did not worsen the underlying disease in our present studies, these data also underscore the fact that GH should not be considered a treatment for the disease itself but rather for some of its chronic complications, mostly related to steroid use. RhGH treatment of glucocorticosteroid-treated children with IBD was associated with increased lean body mass, decreased adiposity and increased linear growth. We conclude that the administration of rhGH to glucocorticosteroid-treated growing children has beneficial effects on whole body metabolism and linear growth while the child remains on steroids. Larger randomized trials will be needed to determine the long-term safety and benefit of this intervention.

Technical Abstract: The present studies were designed to determine whether recombinant human growth hormone (rhGH) can counteract some of the catabolic effects of glucocorticosteroid therapy in children chronically treated with glucocorticosteroids. Whether rhGH can safely improve short-term linear growth was also investigated. The effect of rhGH on disease activity was also assessed. Ten children (6 boys, 4 girls) with inflammatory bowel disease (IBD) on oral prednisone for at least 4 months prior to these studies were recruited (mean +/- SE, 11.9 +/- 0.9 years). Leucine and glucose isotope studies, body composition, substrate oxidation and energy expenditure rates, and growth factors were measured at baseline (D1) and at 4 months after treatment with rhGH (0.05 mg/kg.d subcutaneously [SC]) while continuing oral prednisone. Dual-emission x-ray absorptiometry (DEXA) and calcium kinetic analysis ((42)Ca/(46)Ca) were performed also. rhGH was continued for 6 months to assess linear growth in all 10 subjects, 7 of whom continued rhGH for 12 months. Body composition changed favorably with increased fat free mass (+3 kg, P =.001) and decreased percent fat mass (-3.5%, P =.001) after 4 months of treatment. Rates of whole body protein turnover, oxidation, and synthesis remained invariant, with no changes in substrate oxidation or resting energy expenditure rates. Linear growth velocity increased from 3.5 +/- 0.4 cm/yr when the patients were treated with prednisone only, to 7.7 +/- 0.9 after 6 months of combined prednisone/rhGH (P =.001). The growth velocity was sustained in the 7 patients treated with rhGH for 12 months. Plasma insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) concentrations also increased significantly while on rhGH treatment. No changes in calcium absorption were observed but there was a significant increase in kinetic rates of bone calcium accretion (P =.045) as well as in bone-specific alkaline phosphatase concentrations, a measure of bone formation (P =.03). Fasting and 2-hour postprandial glucose concentrations, fasting insulin levels, and HbA(1C) were invariant during combined rhGH/prednisone treatment. The Crohn's disease activity score was unchanged with rhGH therapy. In summary, rhGH treatment of corticosteroid-dependent patients with IBD was associated with positive changes in body composition, bone metabolism, and linear growth, without deterioration of carbohydrate tolerance or intermediate metabolism of substrates. We conclude that treatment with rhGH has beneficial effects in prednisone-dependent growing children. Larger studies will be needed to assess the long-term safety and efficacy of this approach.