GROWTH-RESPONSES TO PATTERNED GH DELIVERY

We have investigated the effects of different patterns of administrati on of recombinant human growth hormone (rhGH) on weight gain, organ gr owth, serum GH binding protein (GHBP) and insulin-like growth factor-1 (IGF-1) levels in a series of studies using hypophysectomized (Hx) or GH-deficient dwarf (dw/dw) rats. Animals were given rhGH either by su bcutaneous (s.c.) injections (1 or 2 per day) or s.c. infusions and rh lCF-1 (2 mg/kg/day) by s.c. infusion. In Hx rats, all rhGH regimes inc reased body weight, tibial epiphyseal plate width, and organ weights i n a dose-related manner. Dwarf rats showed a smaller growth response t o rhGH than Hx rats, whereas rhGH induced greater elevations in serum GHBP in drarf rats. Growth responses depended on the pattern of rhGH a dministration (twice daily injections > continuous infusions > daily i njections). The shape of the body growth curves also differed; rhGH in jections increased weight gain linearly, whereas infusions gave an ini tial 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 inject ions. Spleen and thymus weights were markedly increased by rhGH and we re also affected by the pattern of GH exposure. At 5 mg rhGH/kg/day, t hymus weights were 390 +/- 35 mg for injections vs. 613 +/- 34 mg for infusions (P < 0.001) compared with 248 +/- 16 mg in vehicle-treated H x controls. Infusions of rhlGF-1 also stimulated specific organ growth bud 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 rhG H infusion, whereas daily injections were ineffective. Thus, different ial organ growth could be related to the higher serum IGF-1 concentrat ions induced by continuous rhGH administration. These studies show tha t whole body growth is best maintained by intermittent rhGH exposure, whereas, paradoxically, differential organ growth is most pronounced w ith continuous rhGH administration.