The growth hormone and insulin-like growth factor 1 axis in heart failure

Experimental data suggests that growth hormone and IGF-1 have beneficial effects on myocardial function in animal models of heart failure. Preliminary evidence suggests an abnormality in the growth hormone-IGF-1 axis in heart failure with relative growth hormone resistance. Beneficial effects of growth hormone and IGF-1 include vasodilatation, stimulation of cardiac hypertrophy, increase in calcium sensitivity of cardiac myofilaments and prevention of apoptosis. Recently, cardiac cachexia has been shown to be a powerful negative predictive factor in heart failure. Cachectic patients have higher angiotensin II levels. In the rat there is an important interaction between the renin-angiotensin system and IGF-1. Thus, angiotensin II infusion causes weight loss in part through a catabolic effect. This effect results from increased protein degradation. Angiotensin II reduces circulating and skeletal muscle IGF-1 but increases IGF-1 and the IGF-IR expression in cardiac muscle. Preliminary data suggest a potential beneficial effect of growth hormone in heart failure. Further trials are necessary to test the potential beneficial effect of growth hormone and/or IGF-1 in heart failure.     

Growth hormone/insulin-like growth factor I axis in neurodegenerative diseases

Neurodegenerative diseases (ND) are a group of heterogeneous disorders characterized by unknown etiology, subtle onset, and progressive involvement of neuronal systems leading to degeneration and dysfunction. They represent a challenge for basic science and clinical medicine because of increasing prevalence, social cost, complex biochemistry and pathology, and lack of mechanism-based treatments. Endocrine modifications may accompany the progression of ND, due to the intimate connections between central nervous and endocrine systems. Reported data on endocrine changes in different ND have often been non-conclusive or conflicting. GH/IGF-I axis is involved in the regulation of brain growth, development, and metabolism. Dysfunctions in GH/IGF-I axis in most of ND are therefore reviewed. Whether GH deficiency, when present, may act as a contributory factor in the pathogenesis of these diseases, or might represent a consequence of it is presently unknown. A thorough effort in investigating every possible involvement of GH/IGF-I axis is warranted, in the light of future possible therapeutic strategies.     

The intrahepatic biliary epithelium is a target of the growth hormone/insulin-like growth factor 1 axis

BACKGROUND/AIMS: We evaluated the role and mechanisms by which the GH/IGF1 axis modulates cholangiocyte proliferation. METHODS: GH-receptors (GH-R), IGF1, IGFBP3 (binding protein 3), IGF1-R and receptor substrates (IRS) were evaluated in cholangiocytes of normal or bile duct-ligated (BDL) rat livers. The effects of GH and IGF1 on proliferation of normal quiescent cholangiocytes and the transduction pathways involved were investigated. RESULTS: IGF1, GH-R, IGF1-R, IRS-1/2 were expressed in normal cholangiocytes and overexpressed in cholangiocytes proliferating after BDL which also secrete IGF1 in a higher amount than normal cells. IGFBP3, which may counter-regulate IGF1 effects, was decreased in BDL cholangiocytes. IGF1 promoted cholangiocyte proliferation in association with overexpression of p-IGF1R, IRS1, IRS-2, p-ERK1/2 and p-AKT. GH induced IGF1 expression and release in isolated cholangiocytes, and reproduced the effects of IGF1 but GH effects were abolished by IGF1-R blocking antibody, suggesting IGF1 as a mediator of GH. Finally, IGF1 and 17beta-estradiol reciprocally potentiated their proliferative effects on cholangiocytes, and by interacting at both receptor and post-receptor levels. CONCLUSIONS: Cholangiocytes respond to GH with production and release of IGF1 that modulates cell proliferation by transduction pathways involving IGF1-R, IRS1/2 and both ERK and PI3-kinase pathways. The biliary epithelium is a target of GH/IGF1 liver axis.     

Growth hormone/insulin-like growth factor axis in patients with subclinical thyroid dysfunction

ObjectiveOur aim was to evaluate serum concentrations of GH, IGF-I, and insulin-like growth factor-binding protein-3 (IGFBP-3) in patients with subclinical thyroid dysfunction before and after normalization of thyroid function.Design and methodsThe study included 51 patients (mean age 42.2 ± 1.8 years) with subclinical hypothyroidism and 30 patients (mean age 44.3 ± 2.4 years) with subclinical hyperthyroidism. A group of 37 euthyroid healthy subjects were studied as controls. Serum concentrations of TSH, FT4, FT3, GH, insulin, IGF-I, and IGFBP-3 were measured in all patients before starting therapy and after normalization of thyroid function. The dosage of levothyroxine (LT4) and antithyroid drugs was adjusted in attempt to keep the serum-free thyroxine (FT4) and thyrotropin (TSH) concentrations within the normal range.Main outcomeBaseline growth hormone levels were similar with hypothyroid group and hyperthyroid group in relation to euthyroid control subjects. Fasting serum IGF-I levels were significantly lower in the subclinical hypothyroid group compared with the control group. On the other hand, IGF-I levels of subclinical hyperthyroid patients and control group were similar. After normalization of thyroid function tests, IGF-I concentrations were increased in subclinical hypothyroid subjects, but unchanged in subclinical hyperthyroid subjects. Patients with subclinical hyperthyroidism showed slightly lower mean serum IGFBP-3 concentrations than those found in control group, but the difference was not statistically significant. Serum GH and IGFBP-3 levels were unaltered by treatment.ConclusionsIn this study, it was shown that GH–IGF axis was not affected in patients with subclinical hyperthyroidism, while it was affected in patients with subclinical hypothyroidism. That is, investigation of the axis in subclinical hyperthyroidism would not bring any extra advantages, but LT4 replacement therapy could prevent abnormalities related to GH–IGF axis in patients with subclinical hypothyroidism.     

Growth cartilage expression of growth hormone/insulin-like growth factor I axis in spontaneous and growth hormone induced catch-up growth

IntroductionCatch-up growth following the cessation of a growth inhibiting cause occurs in humans and animals. Although its underlying regulatory mechanisms are not well understood, current hypothesis confer an increasing importance to local factors intrinsic to the long bones' growth plate (GP).AimThe present study was designed to analyze the growth-hormone (GH)-insulin-like growth factor I (IGF-I) axis in the epiphyseal cartilage of young rats exhibiting catch-up growth as well as to evaluate the effect of GH treatment on this process.Material and methodsFemale Sprague–Dawley rats were randomly grouped: controls (group C), 50% diet restriction for 3 days + refeeding (group CR); 50% diet restriction for 3 days + refeeding &; GH treatment (group CRGH). Analysis of GH receptor (GHR), IGF-I, IGF-I receptor (IGF-IR) and IGF binding protein 5 (IGFBP5) expressions by real-time PCR was performed in tibial growth plates extracted at the time of catch-up growth, identified by osseous front advance greater than that of C animals.ResultsIn the absence of GH treatment, catch-up growth was associated with increased IGF-I and IGFBP5 mRNA levels, without changes in GHR or IGF-IR. GH treatment maintained the overexpression of IGF-I mRNA and induced an important increase in IGF-IR expression.ConclusionsCatch-up growth that happens after diet restriction might be related with a dual stimulating local effect of IGF-I in growth plate resulting from overexpression and increased bioavailability of IGF-I. GH treatment further enhanced expression of IGF-IR which likely resulted in a potentiation of local IGF-I actions. These findings point out to an important role of growth cartilage GH/IGF-I axis regulation in a rat model of catch-up growth.     

Growth hormone and insulin-like growth factor I in German shepherd dwarf dogs

The roles of growth hormone (GH) and insulin-like growth factor I (IGF I) were studied in 9 German Shepherd dwarf dogs. GH deficiency was evidenced in all dogs by an absence of increase in GH levels in response to clonidine administration. While the mean IGF I concentration in normal adult German Shepherds was 280 +/- 23 ng/ml and 345 +/- 50 ng/ml in immature animals, the mean IGF I concentration in the dwarf dogs was 11 +/- 2 ng/ml (mean +/- SEM, P less than 0.001). In the affected animals, plasma thyroxine (T4) levels were only slightly subnormal and there was an increase in these levels in response to thyroid stimulating hormone (TSH) administration. The findings indicate 1) that dwarfism in German Shepherds is caused by primary GH-deficiency resulting in low circulating levels of IGF I and 2) that IGF I levels in the dog as in man are subject to control by GH.     

Role of the growth hormone/insulin-like growth factor-1 paracrine axis in rheumatic diseases

OBJECTIVES: Hypothalamic-pituitary axis abnormalities have been associated with systemic disturbances in several rheumatic diseases. Longitudinal analysis of erythrocyte, serum, urinary and synovial fluid growth hormone (GH), insulin-like growth factor-1 (IGF-1), and somatostatin levels could provide important surrogate measures of disease activity in rheumatic diseases. METHODS: The authors reviewed the population and longitudinal studies literature on GH, IGF-1, and somatostatin levels in rheumatic disorders using the PubMed and Medlines databases from the National Library of Medicine. In addition to the literature search, primary data were analyzed for basal somatostatin levels in patients with hand, knee, and spine osteoarthritis (OA) as well as primary and secondary hip OA. RESULTS: A review of the literature supports the view that hypothalamic-pituitary axis dysfunction accompanies clinical symptoms in many rheumatic diseases. In studies from our laboratory, serum GH levels were elevated in patients with OA, rheumatoid arthritis (RA), fibromyalgia, and diffuse idiopathic skeletal hyperostosis but not in patients with gout, pseudogout, or systemic lupus erythematosus. In OA and RA, synovial fluid GH levels exceeded serum GH levels. However, the literature remains controversial regarding the significance of changes in IGF-1 levels in rheumatic disorders. Many studies support an inverse relationship between age and IGF-1. Elevated serum GH levels in various rheumatic diseases were not coupled to changes in serum IGF-1 in diffuse idiopathic skeletal hyperostosis, RA, and fibromyalgia. In particular, serum IGF-1 levels in OA were shown to be lower or no different compared with age-matched normal subjects. Further, in OA, impaired articular chondrocyte response to IGF-1 was attributed, in part, to low synovial fluid IGF-1 that further compromised IGF-1 chondrocyte responses as a result of increased levels of synovial fluid IGF-1 binding proteins. Of note, serum somatostatin levels and "specific" somatostatin receptor levels were often lower in RA and systemic lupus erythematosus, but basal serum somatostatin levels were generally not altered in OA. CONCLUSIONS: The results of these analyses support the view that some rheumatic diseases such as OA and diffuse idiopathic skeletal hyperostosis, heretofore considered to be purely focal and degenerative, could be reclassified as systemic metabolic disturbances. We propose that serum GH, IGF-1, and somatostatin levels be monitored on a longitudinal basis during the course of medical therapy of rheumatic diseases to determine the extent to which changes in clinical symptoms (exemplified by reduced pain and inflammation and improved range of joint motion) are accompanied by changes in the basal concentration of these hypothalamic/pituitary-related hormones.     

Sexual dimorphism in the growth hormone and insulin-like growth factor axis at birth

In rodents and humans there is a sexually dimorphic pattern of GH secretion that influences the serum concentration of IGF-I. Pattern differences can be identified in children, but it is not known how early this difference is established. We studied the plasma concentrations of IGF-I, IGF-II, IGF-binding protein-3 (BP-3), and GH in cord blood taken from the offspring of 1650 singleton Caucasian pregnancies born at term and related these values to birth weight, length, and head circumference. Pregnancies complicated by preterm delivery, antepartum hemorrhage, pregnancy-induced hypertension, preeclampsia, or gestational diabetes and where cigarette smoking continued were excluded, resulting in a cohort of 987. Cord plasma concentrations of IGF-I, IGF-II, and IGFBP-3 were influenced by factors influencing birth size: gestational age at delivery, mode of delivery, maternal height, and parity of the mother. Plasma GH concentrations were inversely related to the plasma concentrations of IGF-I and IGFBP-3; 10.2% of the variability in cord plasma IGF-I concentration and 2.7% for IGFBP-3 was explained by sex of the offspring and parity. None of the factors, apart from maternal height, influenced cord serum IGF-II concentrations (adjusted r(2) = 1%). Sex of the baby, mode of delivery, and parity influenced cord serum GH concentrations (adjusted r(2) = 2.6%). Birth weight, length, and head circumference measurements were greater in males than females (P < 0.001). Mean cord plasma concentrations of IGF-I (males, 66.4 +/- 1.2 micro g/liter; females, 74.5 +/- 1.3 micro g/liter; P < 0.001) and IGFBP-3 (males, 910 +/- 13 micro g/liter; females 978 +/- 13 micro g/liter; P < 0.001) were significantly lower in males than females. Cord plasma GH concentrations were higher in males than females (males, 30.0 +/- 1.2 mU/liter; females, 26.9 +/- 1.1 mU/liter; P = 0.05), but no difference was noted between the sexes for IGF-II (males, 508 +/- 6 micro g/liter; females, 519 +/- 6 micro g/liter; P = NS). After adjustment for gestational age, parity, and maternal height, cord plasma concentrations of IGF-I and IGFBP-3 along with sex explained 38.0% of the variability in birth weight, 25.0% in birth length, and 22.7% in head circumference. These data demonstrate that in a group of singleton Caucasian babies born at term, cord plasma IGF-I, IGFBP-3, and GH concentrations relate to birth size, with evidence for sexual dimorphism in the GH-IGF axis.     

Memory performance and the growth hormone/insulin-like growth factor axis in elderly: a positron emission tomography study

The relationship between the growth hormone/insulin-like growth factor (GH-IGF)-I status and memory performance is studied in 24 elderly males and females, aged 75-85 years. Positron emission tomography (PET) was used to measure differences in regional cerebral blood flow during the performance of a delayed-non-match-to-sample (DNMTS) working memory task. Quality and speed of performance on the DNMTS task were measured separately for the easy items (3, 4 and 5 letters) and difficult items (6, 7 and 8 letters). Results were analyzed in two different groups based on the IGF-I level of the subjects (low or high IGF-I). Error rates on the working memory task were not different, but the high IGF-I group had shorter reaction times on the easy items. The high IGF-I group showed a significantly greater increase in cerebral blood flow in the left premotor cortex (easy items) and left dorsolateral prefrontal cortex (difficult items) compared to the low IGF-I group. It is concluded that elderly with high IGF-I levels are capable of faster working memory performance and increased recruitment of task-associated prefrontal regions.     

The growth hormone/insulin-like growth factor-I axis in exercise and sport

The syndrome of adult GH deficiency and the effects of GH replacement therapy provide a useful model with which to study the effects of the GH/IGF-I axis on exercise physiology. Measures of exercise performance including maximal oxygen uptake and ventilatory threshold are impaired in adult GH deficiency and improved by GH replacement, probably through some combination of increased oxygen delivery to exercising muscle, increased fatty acid availability with glycogen sparing, increased muscle strength, improved body composition, and improved thermoregulation. In normal subjects, in addition to the long-term effects of GH/IGF-I status, there is evidence that the acute GH response to exercise is important in regulating substrate metabolism after exercise. Administration of supraphysiological doses of GH to athletes increases fatty acid availability and reduces oxidative protein loss, particularly during exercise, and increases lean body mass. Despite a lack of evidence that these metabolic effects translate to improved performance, GH abuse by athletes is widespread. Tests to detect GH abuse have been developed based on measurement in serum of 1) indirect markers of GH action, and 2) the relative proportions of the two major naturally occurring isoforms (20 and 22kDa) of GH. There is evidence that exercise performance and strength are improved by administration of GH and testosterone in combination to elderly subjects. The potential benefits of GH in these situations must be weighed against potential adverse effects.     

Tissue-specific regulation of the growth hormone/insulin-like growth factor axis during fasting and re-feeding: Importance of muscle expression of IGF-I and IGF-II mRNA in the tilapia

The effects of prolonged nutrient restriction (fasting) and subsequent restoration (re-feeding) on the growth hormone (GH)/insulin-like growth factor (IGF) axis were investigated in the tilapia (Oreochromis mossambicus). Mean weight and specific growth rate declined within 1 week in fasted fish, and remained lower than controls throughout 4 weeks of fasting. Plasma levels of IGF-I were lower than fed controls during 4 weeks of fasting, suggesting a significant catabolic state. Following re-feeding, fasted fish gained weight continuously, but did not attain the weight of fed controls at 8 weeks after re-feeding. Specific growth rate increased above the continuously-fed controls during the first 6 weeks of re-feeding, clearly indicating a compensatory response. Plasma IGF-I levels increased after 1 week of re-feeding and levels were not otherwise different from fed controls. Plasma GH levels were unaffected by either fasting or re-feeding. No consistent effect of fasting or re-feeding was observed on liver expression of GH receptor (GH-R), somatolactin (SL) receptor (SL-R), IGF-I or IGF-II. In contrast, muscle expression of GH-R increased markedly during 4 weeks of fasting, and then declined below control levels upon re-feeding for weeks 1 and 2. Similarly, muscle expression of SL-R increased after 4 weeks of fasting, and reduced below control levels after 1 and 2 weeks of re-feeding. On the other hand, muscle expression of IGF-I was strongly reduced throughout the fasting period, and levels recovered 2 weeks after re-feeding. Muscle expression of IGF-II was not affected by fasting, but was reduced after 1 and 2 weeks of re-feeding. These results indicate that GH/IGF axis, particularly muscle expression of GH-R, SL-R and IGF-I and -II, is sensitive to nutritional status in the tilapia.     

Changes within the growth hormone/insulin-like growth factor I/IGF binding protein axis during critical illness.

Interest in the somatotropic axis,with its complex network of interactions, during critical illness arose only a few decades ago. Te distinguishing neuroendocrine features of prolonged critical illness were not differentiated from those during the acute phase until the early 1990s. This incomplete understanding of the somatotropic axis contributed to some disastrous results, such as the multicenter growth hormone trial. The goal of stimulating the somatotropic axis without a proper preceding neuroendocrine diagnosis should be held obsolete. Moreover, the fascinating link between regulators of carbohydrate metabolism, such as insulin and insulin-like growth factor I, and the somatotropic axis may lead to future therapeutic possibilities.     

Growth hormone/insulin-like growth factor 1 axis alterations contribute to disturbed protein metabolism in cirrhosis patients after hepatectomy.

BACKGROUND/AIM: Liver cirrhosis is accompanied by a fall in whole-body protein turnover and alterations of the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis. However, the influence of liver cirrhosis on the GH/IGF-1 axis in the perioperative period, and the contribution of the GH/IGF-1 axis alteration in cirrhosis to postoperative nitrogen metabolism are not known. METHODS: Plasma GH, IGF-1 and IGF binding protein 3 (IGF-BP3) levels were measured sequentially in patients undergoing hepatectomy with or without cirrhosis. Postoperative nitrogen excretion and whole-body protein turnover rate were also determined. RESULTS: Preoperative plasma IGF-1 level showed a negative correlation with indocyanine green retention rate. Cirrhosis patients undergoing hepatectomy had low IGF-1 and IGF-BP3 levels, despite extremely high GH levels in the perioperative period. Perioperative IGF-1 levels were lower in patients with postoperative complications than in those without complications. Postoperative nitrogen excretion was higher and whole-body protein turnover rate was lower in patients with cirrhosis than in those without cirrhosis. The post-operative IGF-1 level showed a positive correlation with whole-body protein turnover rate. CONCLUSIONS: Postoperative hepatic IGF-1 production may be severely disturbed in patients with cirrhosis, and the impaired IGF-1 production contributes to the suppressed postoperative protein metabolism in cirrhosis. It may be appropriate to increase plasma IGF-1 level in patients with cirrhosis to enhance postoperative protein metabolism and improve the postoperative outcome.     

A paradoxical gender dissociation within the growth hormone/insulin-like growth factor I axis during protracted critical illness

Female gender appears to protect against adverse outcome from prolonged critical illness, a condition characterized by blunted and disorderly GH secretion and impaired anabolism. As a sexual dimorphism in the GH secretory pattern of healthy humans and rodents determines gender differences in metabolism, we here compared GH secretion and responsiveness to GH secretagogues in male and female protracted critically ill patients. GH secretion was quantified by deconvolution analysis and approximate entropy estimates of 9-h nocturnal time series in 9 male and 9 female patients matched for age (mean +/- SD, 67+/-11 and 67+/-15 yr), body mass index, severity and duration of illness, feeding, and medication. Serum concentrations of PRL, TSH, cortisol, and sex steroids were measured concomitantly. Serum levels of GH-binding protein, insulin-like growth factor I (IGF-I), IGF-binding proteins (IGFBPs), and PRL were compared with those of 50 male and 50 female community-living control subjects matched for age and body mass index. In a second study, GH responses to GHRH (1 microg/kg), GH-releasing peptide-2 (GHRP-2; 1 microg/ kg) and GHRH plus GHRP-2 (1 and 1 microg/kg) were examined in comparable, carefully matched male (n = 15) and female (n = 15) patients. Despite identical mean serum GH concentrations, total GH output, GH half-life, and number of GH pulses, critically ill men paradoxically presented with less pulsatile (mean +/- SD pulsatile GH fraction, 39+/-14% vs. 67+/-20%; P = 0.002) and more disorderly (approximate entropy, 0.946+/-0.113 vs. 0.805+/-0.147; P = 0.02) GH secretion than women. Serum IGF-I, IGFBP-3, and acid-labile subunit (ALS) levels were low in patients compared with controls, with male patients revealing lower IGF-I (P = 0.01) and ALS (P = 0.005) concentrations than female patients. Correspondingly, circulating IGF-I and ALS levels correlated positively with pulsatile (but not with nonpulsatile) GH secretion. Circulating levels of GH-binding protein and IGFBP-1, -2, and -6 were higher in patients than controls, without a detectable gender difference. In female patients, PRL levels were 3-fold higher, and TSH and cortisol tended to be higher than levels in males. In both genders, estrogen levels were more than 3-fold higher than normal, and testosterone (2.25+/-1.94 vs. 0.97+/-0.39 nmol/L; P = 0.03) and dehydroepiandrosterone sulfate concentrations were low. In male patients, low testosterone levels were related to reduced GH pulse amplitude (r = 0.91; P = 0.0008). GH responses to GHRH were relatively low and equal in critically ill men and women (7.3+/-9.4 vs. 7.8+/-4.1 microg/L; P = 0.99). GH responses to GHRP-2 in women (93+/-38 microg/L) were supranormal and higher (P<0.0001) than those in men (28+/-16 microg/L). Combining GHRH with GHRP-2 nullified this gender difference (77+/-58 in men vs. 120+/-69 microg/L in women; P = 0.4). In conclusion, a paradoxical gender dissociation within the GH/ IGF-I axis is evident in protracted critical illness, with men showing greater loss of pulsatility and regularity within the GH secretory pattern than women (despite indistinguishable total GH output) and concomitantly lower IGF-I and ALS levels. Less endogenous GHRH action in severely ill men compared with women, possibly due to profound hypoandrogenism, accompanying loss of the putative endogenous GHRP-like ligand action with prolonged stress in both genders may explain these novel findings.     

Tissues of the Laron dwarf are sensitive to insulin-like growth factor I but not to growth hormone

Tissues from patients with Laron dwarfism are resistant to the actions of endogenous or exogenous GH. As a result, insulin-like growth factor I (IGF-I) levels are low, possibly contributing to the severe growth deficiency that occurs in patients with this syndrome. In this study, we found that erythroid progenitor cells and permanently transformed T-cell lines from two patients with Laron dwarfism responded in vitro to added IGF-I in concentrations ranging between 1-10 ng/mL despite no stimulatory response to added GH in concentrations of up to 500 ng/mL. Normal or near-normal responsiveness to insulin was also demonstrated. The persistence of GH resistance in the cultured T-cell lines confirms the primary genetic nature of the defect in Laron dwarfism. The preservation of in vitro growth responsiveness to IGF-I in hematopoietic tissue from the Laron dwarfs suggests that affected individuals are sensitive to this factor and may respond to it in vivo.     

Alterations in the growth hormone/insulin-like growth factor I pathways in feline GM1 gangliosidosis

Cats affected with feline GM1 gangliosidosis, an autosomal, recessively inherited, lysosomal enzymopathy, have progressive neurological dysfunction, premature thymic involution, stunted growth, and premature death. Although increased membrane GM1 gangliosides can result in increased apoptosis of thymocytes, there is not a direct correlation between thymocyte surface GM1 and thymic apoptosis in vivo, suggesting that other factors may be important to the pathogenesis of thymic involution in affected cats. Because GH and insulin-like growth factor I (IGF-I) are important hormonal peptides supporting thymic function and affecting growth throughout the body, particularly in the prepubescent period, several components of the GH/IGF-I pathway were compared in GM1 mutant and normal age-matched cats. GM1 mutant cat serum IGF-I concentrations were reduced significantly compared with those in normal cats by 150 days of age, and GM1 mutant cats had no peripubertal increase in serum IGF-I. Additionally, IGF-binding protein-3 was reduced, and IGF-binding protein-2 was elevated significantly in GM1 mutant cats more than 200 days of age. Liver IGF-I messenger RNA and pituitary GH messenger RNA both were reduced significantly in GM1 mutant cats. After stimulation by exogenous recombinant canine GH, serum IGF-I levels increased significantly in GM1 mutant cats, indicating that GH/IGF-I signaling pathways within the liver remain intact and suggesting that alterations are external to the liver.     

Growth hormone and insulin-like growth factor I treatment increase testicular luteinizing hormone receptors and steroidogenic responsiveness of growth hormone deficient dwarf mice

To test the hypothesis that insulin-like growth factor (IGF-I) is required for the in vivo development of testicular Leydig cell function, either recombinant human GH [(hGH) (1.5 micrograms/g BW) or recombinant IGF-I (1 microgram/g BW) was injected three times daily into immature Snell dwarf mice (dw/dw) and into phenotypically normal control (Dw/-) for 7 days. In dw/dw mice hGH enhanced significantly body, liver, kidney, and testicular weight. In addition, hGH increased testicular LH receptors and the acute steroidogenic response to human CG, but there was no significant effect on basal plasma testosterone or plasma LH levels. The effects of IGF-I in body and kidney weight were less pronounced than those produced by hGH, but its effects on testicular weight and LH receptors, as well as on the acute steroidogenic response to human CG, were similar to that observed after hGH treatment. In Dw/- mice hGH had no effect on either body or organ weight or on testicular function, despite the fact that it induced a significant increase in plasma IGF-I levels. These results indicated that IGF-I is able to induce the maturation of Leydig cell function and that the effects of hGH on the testis are probably mediated by IGF-I. They also suggest that the delayed puberty associated with GH deficiency or resistance is most likely related to an IGF-I deficiency.     

Interactive regulation of postmenopausal growth hormone insulin-like growth factor axis by estrogen and growth hormone-releasing peptide-2

Estrogen is the proximate sex steroid sustaining GH secretion throughout the human life span in both sexes. However, very little is known about the specific neuroendocrine mechanisms by which estrogen activates and maintains GH secretion in the young or aging human. The identification of somatostatin in 1973 as a key negative peptidyl regulator of the GH axis and the discovery of GH-releasing hormone (GHRH) in 1982 as a dominant feedforward agonist of GH secretion provided an initial basic science foundation for exploring sex-steroid control of the GH-IGF-1 axis. Although GH-releasing peptides (GHRPs) were first recognized in 1977-1981, subsequent cloning of hypothalamopituitary receptors transducing potent secretagogue actions of GHRPs in 1996 and of an endogenous ligand for this effector pathway in 1999 now extend the framework for examining the mechanisms of estrogen-driven GH secretion in aging. Herein, we review several novel and multifaceted interactions in postmenopausal women between estrogen and GHRP-2. We combine these observations into a simplified construct of GH-axis neuroregulation comprising the somatostatin, GHRH, and GHRP effector pathways, as well as GH and IGF-1 autofeedback. We suggest the thesis that estrogen controls the interfaces among these pivotal regulatory peptides in hyposomatotropic postmenopausal individuals.     

Evidence for integrity of the growth hormone/insulin-like growth factor-1 axis in patients with severe head trauma during rehabilitation

Severe traumatic head injury has been recognized to be associated with hypothalamo-hypophyseal impairment and subsequent abnormalities in hormone secretion, which can contribute to a prolonged clinical course and to hampered recovery in many head-injured patients. Most of the data on the growth hormone/insulin-like growth factor -1 (GH/IGF-1) axis function have been obtained early after head injury, whereas GH secretory pattern has not been fully elucidated after patients had left the intensive care unit. We examined the activity of the GH/IGF-1 axis in 16 severely closed head-injured (CHI) patients (14 males; age range, 17 to 47 years; body mass index [BMI], 21.4 +/- 0.8 kg/m(2)) during the rehabilitation period at least 1 month after leaving the intensive care unit and in 12 sex-, age-, and weight-matched healthy controls. The severity of trauma was assessed by the Glasgow Coma Scale (GCS) score (8 or less), posttraumatic amnesia (PTA, more than 24 hours), and initial computed tomography (CT) scan. The clinical picture at time of the study was evaluated by the Rancho Los Amigos Scale of Cognitive Functioning (CFS) and the Functional Independence Measure (FIM). In all subjects, we evaluated basal levels of anterior pituitary hormones, IGF-1, insulin-like growth factor-binding protein (IGFBP)-3, and IGFBP-1, as well as the GH responses to intravenous (IV) infusion of growth hormone-releasing hormone (GHRH) alone, GHRH plus arginine (ARG), and the GH release evoked by somatostatin (SRIH) infusion withdrawal, which is related to endogenous GHRH tone. In all subjects, nutritional parameters and nitrogen balance were normal. Basal plasma concentrations of GH, IGF-1, IGFBP-3, and IGFBP-1 did not significantly differ between CHI patients and controls. The GH responses to GHRH and GHRH plus ARG did not significantly differ between CHI patients (GH peak, 10.7 +/- 3.0 microg/L; area under the curve [AUC], 5.9 +/- 1.5 microg/L. min; and GH peak, 34.7 +/- 6.1 microg/L; AUC, 20.25 +/- 3.3 microg/L. min, respectively) and normal subjects (GH peak at 30 minutes, 7.23 +/- 1.35 microg/L; AUC, 4.7 +/- 0.8 microg/L. min; and GH peak at 60 minutes, 41.0 +/- 5.1 microg/L; AUC, 24.3 +/- 1.7 microg/L. min, respectively). SRIH withdrawal resulted in an unequivocal increase in plasma GH concentrations both in CHI patients and in controls, without any significant difference between the 2 groups. A negative correlation was found between the GH response (deltaGH peak) to SRIH withdrawal and CFS (r = -.615, P <.005). In conclusion, our study indicates that patients receiving rehabilitation after leaving the intensive care unit for severe traumatic head injury have no significant changes of GH secretion with normal central regulation of the GH-IGF-1 axis.     

Mechanisms of disease: metabolic effects of growth hormone and insulin-like growth factor 1

Insulin-like growth factor (IGF) 1 is a member of a family that is involved in growth, development, cell differentiation, and metabolism. IGF1, IGF2 and insulin act primarily through tyrosine-kinase-linked receptors--the IGF1 receptor (IGF1R) and insulin receptor (IR). The IGF1R binds IGF1 and IGF2 with high affinity and the IR binds insulin with high affinity; however, since both receptors share a high degree of structural and functional homology, the IGF1R can bind insulin and the IR can bind the IGFs with reduced affinity. These two receptors can, moreover, form heterodimers, which bind both ligands. Upon binding to the receptors, cascades of tyrosine and serine kinases are stimulated to facilitate growth or metabolism. The IGF2 receptor is a scavenger receptor, and is, therefore, not involved in mediation of growth or metabolic effects of the IGF family and will not be discussed in the current article. IGF1 is a major gene target of growth hormone and its product mediates many of the actions of growth hormone on growth and development; however, IGF1 has actions distinct from those of growth hormone in carbohydrate, lipid, and protein metabolism. For example, excess growth hormone causes insulin resistance and hyperglycemia, whereas IGF1 has insulin-like effects that reduce blood glucose levels and has been used experimentally to treat both type 1 and type 2 diabetes.