Evidence that sensitivity to growth hormone (GH) is growth period and tissue type dependent: studies in GH-deficient lit/lit mice

Abstract

We previously found that the magnitude of skeletal deficits caused by GH deficiency varied during different growth periods. To test the hypothesis that the sensitivity to GH is growth period dependent, we treated GH-deficient lit/lit mice with GH (4 mg/kg body weight.d) or vehicle during the prepubertal and pubertal (d 7-34), pubertal (d 23-34), postpubertal (d 42-55), and adult (d 204-217) periods and evaluated GH effects on the musculoskeletal system by dual energy x-ray absorptiometry (DEXA) and peripheral quantitative computed tomography. GH treatment during different periods significantly increased total body bone mineral content, bone mineral density (BMD), bone area, and lean body mass and decreased percentage of fat compared with vehicle; however, the magnitude of change varied markedly depending on the treatment period. For example, the increase in total body BMD was significantly (P < 0.01) greater when GH was administered between d 42-55 (15%) compared with pubertal (8%) or adult (7.7%) periods, whereas the net loss in percentage of body fat was greatest (-56%) when GH was administered between d 204 and 216 and least (-27%) when GH was administered between d 7 and 35. To determine whether GH-induced anabolic effects on the musculoskeletal system are maintained after GH withdrawal, we performed DEXA measurements 3-7 wk after stopping GH treatment. The increases in total body bone mineral content, BMD, and lean body mass, but not the decrease in body fat, were sustained after GH withdrawal. Our findings demonstrate that the sensitivity to GH in target tissues is growth period and tissue type dependent and that continuous GH treatment is necessary to maintain body fat loss but not BMD gain during a 3-7 wk follow-up.

FIG 1

Effects of PBS (circle) or GH (square) treatment on the body weight in GH-deficient lit/lit mice during: A, pre-pubertal and pubertal period, groups 1 and 2; B, pubertal period, groups 3 and 4; C, postpubertal period, groups 5 and 6; D, adult period, groups 7 and 8. The body weights were measured weekly during experiment. The values are expressed as mean ± sem (n = 5–8). A, P < 0.05 compared with the corresponding control mice treated with vehicle by t test or post hoc test.

FIG 2

Effects of GH treatment at different times on the femoral bone length in GH-deficient lit/lit mice. The femur length was measured at the end of experiment (on d 84 for groups 1–6 and on d 239 for groups 7 and 8). The values are expressed as mean ± sem (n = 5–8). A, P < 0.05 compared with the corresponding control mice treated with vehicle by t test or post hoc test. B, P < 0.05 compared with groups 2, 6, and 8. C, P < 0.05 compared with groups 2 and 4. D, P < 0.05 compared with groups 1, 3, and 5.

FIG 3

Effects of GH treatment on net changes in total-body parameters measured by DEXA during four different treatment periods at the end of treatment. A, The net gains in total-body BMD. B, The net gains in total-body BMC. C, The net gains in lean body mass. D, The net loss of % body-fat. The values are expressed as mean ± sem (n = 5–8). A, P < 0.05 compared with group 2 by post hoc test. B, P < 0.05 compared with group 4 by post hoc test. C, P < 0.05 compared with group 8 by post hoc test.

FIG 4

Effects of GH treatment on net changes of femur parameters measured by pQCT during four different treatment periods. The net changes were calculated from the results at the mid-diaphysis. A, The net gains in vBMD. B, The net gains periosteal circumference. C, The net gains in endosteal circumference. The values are expressed as mean ± sem (n = 5–8). A, P < 0.05 compared with group 2 by post hoc test. B, P < 0.05 compared with group 4 by post hoc test. C, P < 0.05 compared with group 8 by post hoc test.

FIG 5

Effects of GH treatment during pubertal and postpubertal growth periods on serum IGF-I levels in lit/lit mice. Serum IGF-I measurements were performed in serum samples collected 12 h after final GH or PBS injection. The values are expressed as mean ± sem (n = 7–8). A, P < 0.01 compared with PBS-treated group by t test. B, P < 0.05 compared with GH-treated pubertal group 4 by t test.