Growth responses to patterned GH delivery

Abstract

We have investigated the effects of different patterns of administration of recombinant human growth hormone (rhGH) on weight gain, organ growth, serum GH binding protein (GHBP) and insulin-like growth factor-l (IGF-1) levels in a series of studies using hypophysectomized (Hx) or GH-deficient dwarf (dw/dw) rats. Animals were given rhGH either by subcutaneous (s.c.) injections (1 or 2 per day) or s.c. infusions and rhlGF-1 (2 mg/kg/day) by s.c. infusion. In Hx rats, all rhGH regimes increased body weight, tibial epiphyseal plate width, and organ weights in a dose-related manner. Dwarf rats showed a smaller growth response to rhGH than Hx rats, whereas rhGH induced greater elevations in serum GHBP in drarf rats. Growth responses depended on the pattern of rhGH administration (twice daily injections > continuous infusions > daily injections). The shape of the body growth curves also differed; rhGH injections increased weight gain linearly, whereas infusions gave an initial rapid weight gain which slowed with time (a curvilinear response). For both regimens, tibial epiphyseal plate width increased linearly with rhGH dose but infusions were 5-fold more potent than daily injections. Spleen and thymus weights were markedly increased by rhGH and were also affected by the pattern of GH exposure. At 5 mg rhGH/kg/day, thymus weights were 390±35 mg for injectionsvs. 613 ± 34 mg for infusions (P<0.001) compared with 248 ± 16 mg in vehicle-treated Hx controls. Infusions of rhlGF-1 also stimulated specific organ growth but caused less weight gain. RhlGF-1 additively increased the weight gain caused by rhGH injections but not by rhGH infusions. Circulating IGF-1 and GHBP levels were increased in a dose-dependent manner by rhGH infusion, whereas daily injections were ineffective. Thus, differential organ growth could be related to the higher serum IGF-1 concentrations induced by continuous rhGH administration. These studies show that whole body growth is best maintained by intermittent rhGH exposure, whereas, paradoxically, differential organ growth is most pronounced with continuous rhGH administration.