Growth hormone (GH) modulates the hypothalamic release of somatostatin and GH-releasing hormone;however, there has been no evidence of GH autoregulation on the pituitary somatotroph. To determine the effects of GH on ...
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Growth hormone (GH) modulates the hypothalamic release of somatostatin and GH-releasing hormone;however, there has been no evidence of GH autoregulation on the pituitary somatotroph. To determine the effects of GH on its own regulation, we examined the pituitaries of giant transgenic mice expressing a GH agonist (E117L), dwarf transgenic mice expressing a GH antagonist (G119K), and dwarf mice devoid of the GH receptor/binding protein (GHR/BP). In the E117L, transgenic mice, the number and distribution of pituitary GH-immunoreactive cells were unchanged from nontransgenic littermate controls;an ultrastructural examination revealed typical, densely granulated somatotrophs. In contrast, the pituitaries of the G119K mice contained both moderately granulated somatotrophs and a sparsely granulated (SG) population with well-developed synthetic organelles and a distinct juxtanuclear globular GH-staining pattern, GHR/BP-deficient mice exhibited a marked reduction in the intensity of cytoplasmic GH immunoreactivity;however, prominent GH staining in the juxtanuclear Golgi was seen. GH-immunoreactive cells were increased in number, and the reticulin network pattern was distorted;stains for proliferating cell nuclear antigen confirmed mild hyperplasia, Electron microscopy showed that the somatotrophs were hyperactive SG tells with prominent endoplasmic reticulum membranes, large Golgi complexes, and numerous mitochondria, These findings are consistent with synthetic and secretory hyperactivity in pituitary somatotrophs due to the reduced GH feedback regulation, The changes are most striking in animals that are devoid of GHR/BP and less marked in animals expressing a GH antagonist;both models had reduced insulin-like growth factor-I levels, but the more dramatic change in the GHR/BP animals can be explained by abrogated GH signaling, This represents the first evidence of direct GH feedback inhibition on pituitary somatotrophs, which may have implications for the use of GH analogs
Growth hormone (GH) is important for skeletal growth as well as for a normal bone metabolism in adults. The skeletal growth and adult bone metabolism was studied in mice with an inactivated growth hormone receptor (GH...
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Growth hormone (GH) is important for skeletal growth as well as for a normal bone metabolism in adults. The skeletal growth and adult bone metabolism was studied in mice with an inactivated growth hormone receptor (GHR) gene, The lengths of femur, tibia, and crown-rump were, as expected, decreased in GHR-/- mice. Unexpectedly, GHR-/- mice displayed disproportional skeletal growth reflected by decreased femur/crown-rump and femur/tibia ratios. GHR-/- mice demonstrated decreased width of the growth plates in the long bones and disturbed ossification of the proximal tibial epiphysis. Furthermore, the area bone mineral density (BMD) as well as the bone mineral content (BMC)/body weight were markedly decreased in GHR-/- mice. The decrease in BMC in GHR-/- mice was not due to decreased trabecular volumetric BMD but to a decreased cross-sectional cortical bone area In conclusion, GHR-/- mice demonstrate disproportional skeletal growth and markedly decreased bone mineral content, (C) 2000 academic Press.
The physiological effects of insulin-like growth factor I(IGF-I) on intermediate metabolism of substrates have been extensively studied in a variety of experimental situations in man, and its effects on linear growth ...
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The physiological effects of insulin-like growth factor I(IGF-I) on intermediate metabolism of substrates have been extensively studied in a variety of experimental situations in man, and its effects on linear growth of children with GH receptor mutations have proven beneficial. However, there is a paucity of data on the metabolic effects of IGF-I as replacement therapy in adults with GH receptor deficiency (Laron's syndrome). We designed these studies to investigate the in vivo effects of 8 weeks of therapy with recombinant human IGF-I (rhIGF-I) in a unique group of 10 adult subjects with profound IGF-I deficiency due to a mutation in the GH receptor gene (mean +/- SEM age, 29.2 +/- 2.0 yr;4 males and 6 females). At baseline, patients had infusions of stable tracers, including L-[C-13] leucine, [H-2(2)] glucose, and d(5)-glycerol, as well as indirect calorimetry, assessment of body composition (dual energy x-ray absortiometry), and measurements of growth factor concentrations. Patients were then discharged to receive twice daily rhIGF-I (60 mu g/kg, sc) for the next 8 week when the studies were repeated identically. Plasma IGF-I concentrations increased during rhIGF-I treatment from 9.3 +/- 1.5 mu g/L to 153 +/-. 23 (P = 0.0001). There was no change in weight during these studies, but a significant change in body composition was observed, with a decrease in percent fat mass (P = 0.003) and an increase in lean body mass (P = 0.001). These were accompanied by increased rates of protein turnover, decreased protein oxidation, and increased rates of whale body protein synthesis, as measured by leucine tracer methods (P < 0.01). These results are similar to those observed in GH-deficient subjects treated with GH. All measures of lipolytic activity and fat oxidation increased during treatment, with an 18% increase in the glycerol turnover rate (P = 0.04), an increase in free fatty acid and beta-hydroxybutyrate concentrations, and a significant increase in fat oxidation, a
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