The insulin-like growth factors I and II (IGF-I and IGF-II), which function as both endocrine and paracrine hormones, are of importance for growth throughout life. Growth hormone (GH) starts to stimulate IGF-I expression and growth after birth. In addition, GH more directly mobilises endogenous substrate. The beneficial effects on growth by GH replacement therapy in GH deficient children and pharmacological GH therapy in girls with Turner syndrome and uraemic children are well established. During the last decade beneficial effects of GH therapy on body composition and physical performance in GH deficient adults have been demonstrated in several placebo controlled clinical studies. GH increases lean body mass, body water and bone density concomitantly with a decrease in fat mass. GH therapy has also been discussed as therapy in catabolic conditions of other causes than GH deficiency (GHD). In the future IGF-I but not GH would be the hormone of preference for therapy in patients with genetic or functional defects in the GH receptors.

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The clinical spectrum of autoimmune pituitary disease is still being defined. In the pediatric age group, autoimmune mechanisms have been postulated for some cases of growth hormone (GH) deficiency and the empty sella syndrome. The classical presentation in adulthood is of peripartum hypopituitarism associated with a pituitary mass and visual failure. Biopsy reveals lymphocytic infiltration of the pituitary, mainly with CD4+ T helper cells, and is termed lymphocytic hypophysitis. Secondary adrenal insufficiency is a prominent feature of the hypopituitarism and isolated adrenocorticotropin (ACTH) deficiency and the empty sella syndrome are thought to be endstages of the disease spectrum. There has been no specific pre-operative serological test for this condition.
We have developed a new assay based on immunoblotting, for evaluating autoantibodies in pituitary disease. The assay uses autopsy pituitaries which are homogenized and ultracentrifuged to give membrance and cytosolic fractions. Proteins are immunoblotted and reactivity of patient sera to autoantigens is detected using an alkaline-phosphatase conjugated second antibody.
A pituitary specific 45 kDa membrane protein was identified by serum from a child with isolated GH dificiency and an empty sella. The target autoantigen in some cases of isolated ACTH deficiency appears to be a 49 kDa cytosolic protein.

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Growth hormone (GH) and insulin-like growth factor I (IGF-I) have immunostimulatory effects in addition to their anabolic action. In this review the immunoenhancing effects of exogenous anabolic hormones will be described according to our findings in a bacterial peritonitis model. Pretreatment with GH (0.48 or 4.8 mg/kg/day) or IGF-I (24 mg/kg/day) increased the survival time in a murine model of Escherichia coli (E. coli) peritonitis. In addition, the numbers of peritoneal exudative cells in the GH-and IGF-I-treated mice were greater than those of the controls after bacterial challenge. Moreover, pretreatment with GH or IGF-I improved clearance of E. coli from the peritoneal cavity. GH and IGF-I increased CD11b and CD32/16 expression on peritoneal exudative neutrophils. These hormones directly enhanced the E. coli killing activity of murine peritoneal exudative cells in vitro. In this E. coli peritonitis model, GH and IGF-I both primed exudative phagocytes for enhanced production of cytokines, tumor nectosis factor (TNF), interleukin-1 (IL-1) and IL-6. Pretreatment with either GH or IGF-I also enhanced the capacity of plasma to support the in vitro bactericidal activity of peritoneal exudative cells. This suggests that GH and IGF-I improve host defense against infection.

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Growth hormone (GH) and insulin-like growth factor I (IGF-I) may be able to modulate some functions of the immune system. In this study, we examined the expression of the receptors for GH and IGF-I on human peripheral blood cells in physiological and pathological conditions.
By using two-colour analysis on flow cytometry with a biotinavidin system, there was a specific GH binding site on human peripheral lymphocytes. GH-binding was more prominent on CD20+ (=B cells) than on CD2+ (=T cells), although GH receptor messenger ribonucleic acid (mRNA) could be detected in the T cells as well as in the B cells. There was no age-dependency of GH-binding on the CD20 cells, and there was no relationship between GH-binding and serum GHbinding protein activities, which reflect the tissue levels of GH receptors.
We detected αIR3, anti IGF-I receptor antibody, bindings and IGF-I receptor mRNA expression in peripheral blood cells. Based on two-colour analysis, there were relatively higher bindings of αIR3 on CD4+ and CD16+ cells, intermediate bindings on CD8+ cells and weak bindings on CD20+ cells. In cord blood cells, αIR3 bindings and IGF-I receptor mRNA were higher than in adult cells. In GH-deficient patients, αIR3 bindings were higher than in control subjects, and reverted to normal after GH therapy.
These results suggest that 1) GH and IGF-I may have hormonal effects on the immune system, 2) GH receptors on lymphocytes dose not correlate with the tissue levels of GH receptors, and 3) the cellular levels of IGF-I receptors may be inversely related to the ambient IGF-I concentrations.

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The development of techniques for large scale production of human growth hormone (GH) and insulin like growth factor-I (IGF-I) by recombinant deoxyribonucleic acid (DNA) technology has led to a resurgence in interest in their metabolic actions and clinical applications. The metabolic actions of GH can be divided into direct effects on carbohydrate, fat and protein, and indirect actions mediated primarily through IGF-I and insulin. IGF-I and insulin increase in response to GH treatment and the metabolic effects on carbohydrate, fat and protein of each are similar but not identical. Although the primary regulator of IGF-I is GH, nutritional effects on IGF-I may predominate during conditions of extreme undernutrition or overnutrition. Obesity is associated with impaired GH secretion, and total IGF-I concentrations in blood are reduced, assuming energy balance is maintained. GH treatment is associated with reduced percent body fat and increased lean body mass, although treatment of obesity with GH has been relatively ineffective, if combined with nutrient restriction.
The direct effects of GH on glucose and fat metabolism are intimately related. GH-stimulated lipolysis leads to release of free fatty acids and inhibition of insulin-stimulated glucose uptake by skeletal muscle. This effect, combined with stimulation of glycogenolysis and gluconeogenesis, leads to hyperglycemia. The principal protein metabolic action of GH is a rapid reduction in amino acid oxidation. Within hours of exposure to GH, whole body protein synthesis (WBPS) increases, followed by an increase in the rate of skeletal muscle protein synthesis. This effect is associated with an increase in blood flow to muscle tissue, likely mediated by IGF-I and/or insulin. In summary, the effects of GH on body composition reflect a complex interaction between GH and its metabolic fuels in the short term, and the metabolic actions of IGF-I and insulin on carbohydrate, fat, and protein subsequently.

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Growth hormone (GH) is important in the regulation of fat, carbohydrate, and protein metabolism. These metabolic effects subsequently affect health risk factors, such as body composition, atherogenic risk factors, and glucose intolerance. GH deficiency is associated with obesity which reportedly responds to GH treatment. Children and adults with GH deficiency often have hypercholesterolemia and thus might be at increased risk of having atherosclerotic diseases in later life. In fact, adults with GH deficiency have been reported to have an increased mortality rate as a result of cardiovascular disease. On the other hand, the results of GH treatment in relation to carbohydrate metabolism are inconsistent in GH-deficient children. We evaluated the changes in health risk factors during GH replacement therapy in 40 children, 31 boys and 9 girls, with GH deficiency and compared our results with those in adult patients. In conclusion, GH replacement therapy in children and adults with GH deficiency can reduce health risk factors without altering glucose metabolism. These beneficial effects are reportedly reversed after the discontinuation of GH therapy. It therefore seems prudent to continue life-long GH replacement therapy in these patients.

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To clarify the mechanism by which visceral adipose tissue developed in growth hormone (GH) deficient patients, and was reduced by GH supplementation, the effects of GH on the triglyceride metabolism in the visceral and subcutaneous adipose tissues of the rats were compared.
Visceral and subcutaneous adipose tissues were obtained from omentum and abdominal wall. [¹⁴C] deoxyglucose uptake and the triglyceride synthetic activity from [¹⁴C] oleic acid, and heparin-releasable lipoprotein lipase activity were not changed by the addition of GH (10ng/mL) in both visceral and subcutaneous adipose tissues, but the lipolysis by GH (10ng/mL) was much more remarkable in the visceral adipose tissue than in subcutaneous adipose tissue, whereas adrenaline-induced lipolysis occurred almost equally in both tissues.
These results suggest that the preponderance of visceral adipose tissue in GH deficiency might partly be due to the lack of GH-preferential lipolysis in visceral adipose tissue.

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The present study was performed to investigate age-dependent changes in bone mineral density (BMD) and body composition, and the role of growth hormone (GH), insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) in these changes in healthy middleaged and elderly Japanese women. BMD and body composition [bone mineral content (BMC), lean body mass (LBM) and fat] were measured by dual energy X-ray absorptiometry. BMD, BMC and LBM declined with aging, while fat mass did not. Plasma IGF- I and IGFBP-3 levels also declined with aging. Urinary GH, plasma IGF-I and IGFBP-3 levels were positively correlated with BMD and BMC, even when BMD was adjusted for age and body size. The plasma IGF-I level was positively correlated with LBM. GH and IGFBP-3 levels also showed the tendency to be correlated with LBM. The urinary GH level was negatively correlated with fat mass, whereas plasma IGF-I and IGFBP-3 levels were positively correlated with fat mass. The GH-IGF-I-IGFBP-3 axis positively regulates bone and muscle mass, while GH and IGF-I-IGFBP-3 negatively and positively regulate fat mass, respectively.

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In this review we discuss our progress in investigating the pro tease which is responsible for generating des (1-3) insulin-like growth factor-I (IGF-I), a more potent form of IGF-I devoid of the first 3 N-terminal amino acid residues. Characterization of the protease activity indicated that it was most likely to be a member of the serine protease family. Although some activity was detected at neutral pH, the activity was optimal at pH 5.5. The enzyme was purified from rat liver utilizing ion-exchange, chromatofocusing, phenylsepharose chromatography followed by high performance liquid chematography (HPLC). A single band of - 31 kD was observed on silver stained sodium dodecyl sulphate-polyachylamide gel electrophoresis (SDS-PAGE) gels. We developed a rapid assay to quantify this protease activity in serum and tissue extracts. The activity was detected in mouse, rat, human serum and rat tissue extracts. The level of protease activity in the tissue extracts demonstrated the following order: liver>testes>heart>skeletal muscle>lung>thymus>kidney>brain>spleen. Protease activity was significantly higher in sera from hypophysectomized rats than in intact rats and growth hormone (GH) replacement reduced enzyme activity. In addition, serum protease activity was significantly elevated in diabetic rats and correlated with serum glucose concentrations. These data demonstrate that the proteolytic conversion of IGF-I to a more active form is enhanced under conditions associated with low IGF-I, insulin and GH levels and suggest that this conversion may be an additional site of regulation of IGF-I action.

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Insulin-like growth factor-II (IGF-II) has an insulin-like effect in vitro and in vivo. Recently, mutants of IGF-II have been synthesized by the site-directed mutagenesis technique, and the structure determinants for the function of IGF-II have been studied. With the availability of the biosynthetic IGF-II and IGF-II mutants, we have investigated the hypoglycemic effect of IGF-II in normal rats and insulin resistant mice.
When the IGF-II mutants with markedly decreased affinities for both insulin and IGF-I receptors were injected in normal rats, the blood glucose levels slightly decreased. However, when IGF-II mutant with slightly decreased affinities for both insulin and IGF-I receptors was injected, the blood glucose decreased to the same extent as with IGF-II.
In insulin resistant mice, insulin did not decrease the blood glucose levels, but, the blood glucose levels decreased after IGF-I and IGF-II injection. The hypoglycemic effect of IGF-II was greater than that of IGF-I. The IGF-II mutant without affinity for IGF-II receptor but with affinities for both IGF-I and insulin receptors the same as IGF-II, caused hypoglycemia the same as IGF-I. However, the IGF-II mutant with markedly decreased affinities for both insulin and IGF-I receptors did not decrease blood glucose levels, and the IGF-II mutant with slightly decreased affinities for both insulin and IGF-II receptors slightly decreased blood glucose levels.
These data indicate that the hypoglycemic effect of IGF-II is mediated mainly through insulin and/or IGF-I receptor but not IGF-II receptor. Furthermore, the data suggest that IGF-II might also be useful for the treatment of the insulin resistant status.

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Biosynthetic Insulin-like growth factor I (IGF-I) was administered subcutaneously twice a day for 3 years to a patient with isolated growth hormone deficiency (IGHD) type IA with high titers of GH antibody. He showed a good growth response to IGF-I therapy without any side effect. IGF-I is potentially useful in the treatment of growth hormone (GH) insensitivity syndromes such as Laron syndrome and IGHD type IA with poor response to GH therapy.

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