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Previous studies have shown that growth hormone (GH)-deficient children are more responsive to exogenous human growth hormone (HGH) than non-GH-deficient children. In six GH-deficient children, velocity of linear growth was less than 2.5 cm/yr. By the metabolic balance study technique, anabolic responses (increments in elemental balances) were measured to a 7 day course of 0.0532 U HGH/kg body weight (BW)3/4 per day (dose B) and to 0.168 U/kg BW3/4 per day (dose C). They were then treated for 1 yr with HGH at a dose intermediate between B and C. Velocity of linear growth accelerated to 15-25 cm/yr for the first 4-7 mo, then declined to 0-8 cm/yr. At 12 mo, responsiveness to doses B and C was measured again; the responses were only 20-60% as great as before treatment. After 3 mo without HGH treatment, responsiveness to the anabolic effects of doses B and C returned to the magnitudes observed before treatment. A low titer of plasma antibodies to HGH was detected in two of the six children at the end of the year's treatment; these titers showed little change after 3 mo without HGH. Thus the hyperresponsiveness of GH-deficient subjects to exogenous HGH, compared to non-GH-deficient individuals, declines during long-term HGH treatment and is restored by 3 mo interruption of treatment. These changes in peripheral responsiveness may be related to the decline in velocity of linear growth which occurs after 4-7 mo of continuous treatment. When HGH was withdrawn after 12 mo, all six patients exhibited negative balances of N, P, Na, and K and loss of BW. Ratios of elemental balances showed about half the weight loss to represent protoplasm, and about half extracellular fluid. These observations indicate a role of GH in the continuing regulation of nitrogen and mineral metabolism in addition to its function as a growth-promoting hormone.