Showing papers in "Growth Hormone & Igf Research in 2000"
189 citations
TL;DR: On-going cancer surveillance and routine monitoring of serum IGF-I and IGFBP-3 levels in GH-recipients should be the standard of care and do not warrant a change in the current management of approved indications for GH therapy.
Abstract: Recent case-controlled studies have found increases in the serum levels of insulin-like growth factor-I (IGF-I) in subjects who had, or who eventually developed, prostate or premenopausal breast cancers. Since growth hormone (GH) increases IGF-I levels, concern has been raised regarding its potential role as a cancer initiation factor. The epidemiological studies, which indicate an association between serum IGF-I levels and cancer risk, have not established causality. In fact, several alternative explanations for the elevated serum IGF-I levels in cancer patients may be proposed based on human and animal models. First, an effect of IGF-I causing symptomatic benign tissue hyperplasia may result in an ascertainment bias leading to an initiation of procedures resulting in the diagnosis of asymptomatic cancers. Second, elevated serum IGF-I in cancer patients may originate within the tumor (as suggested by some animal studies). Thirdly, serum IGF-I may actually be a surrogate marker of tissue IGF-I levels or of nutritional factors, which are not under GH control and may be involved in cancer initiation. The role of GH in cancer initiation is further negated by the fact that in acromegaly, the incidence of cancer, other than possibly colonic neoplasia does not appear to be significantly increased. Furthermore, GH transgenic mice, with high IGF-I levels, do not develop breast, prostate, or colonic malignancies. It is known that IGFBP-3 can inhibit IGF action on cancer cells in vitro and also can induce apoptosis via an IGF-independent mechanism. Importantly, in addition to increasing IGF-I levels, GH also increases the serum levels of IGFBP-3 and serum IGFBP-3 levels have been shown to be negatively correlated with the risk of cancer in the above mentioned epidemiological studies and in a similar study on colon cancer. These studies suggest that cancer risk is increased in individuals in whom both high IGF-I levels and low IGFBP-3 levels are present. In subjects treated with GH, IGF-I and IGFBP-3 levels both rise together and are not within the elevated cancer-risk range, based on published studies. Long-term studies are needed to assess the potential risks, including the long-term cancer risk associated with GH therapy. These should take into account several factors, including the duration of exposure, the risk magnitude associated with the degree of serum IGF-I elevation, and the adjusted risk based on a concomitant increase in IGFBP-3 levels. Since GH treated patients often have sub-normal IGF-I serum levels, which normalize on therapy, one might predict that their cancer risk on GH therapy should not increase above the normal population. Until further research in the area dictates otherwise, on-going cancer surveillance and routine monitoring of serum IGF-I and IGFBP-3 levels in GH-recipients should be the standard of care. At present, the data that are available do not warrant a change in our current management of approved indications for GH therapy.
168 citations
TL;DR: Studies evaluating the correlation between the cognitive deficits associated with ageing and age-related decreases in GH or IGF-I secretion and the deterioration of cognitive functions observed in the elderly are reviewed.
Abstract: This review focuses on the possible contribution of the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis to cognitive function. Binding sites for GH and IGF-I are found in various areas of the brain. Their distribution suggests that GH and IGF-I contribute to the function of the hippocampus, a brain structure important for the maintenance of cognitive functions such as learning and memory. Evidence for cognitive deficits in GH-deficient individuals has been found in various studies, some of which have shown that these deficits can be reversed by GH substitution therapy. In addition to examining conditions of GH deficiency, this article reviews studies evaluating the correlation between the cognitive deficits associated with ageing and age-related decreases in GH or IGF-I secretion. Based on the available data, one might hypothesize that relative GH or IGF-I deficiency could contribute to the deterioration of cognitive functions observed in the elderly.
142 citations
TL;DR: GH therapy in large multicentre international databases has demonstrated a low frequency of adverse events, and tumour recurrence or new malignancy are not increased, but a recent report of increased incidence of Type 2 diabetes mellitus in children undergoing GH therapy requires prospective surveillance.
Abstract: The action of growth hormone (GH) via its receptor involves many organ systems and metabolic pathways. These diverse actions are reviewed in this paper in the context that they may represent unwanted side-effects of GH therapy for growth promotion. The monitoring of GH therapy in large multicentre international databases has demonstrated a low frequency of adverse events. Tumour recurrence or new malignancy are not increased. Headaches, especially in the first few months of therapy, require close evaluation as benign intracranial hypertension is found infrequently, especially in children with GH deficiency and chronic renal failure (CRF). Children at risk for slipped capital femoral epiphysis and scoliosis require close monitoring during therapy. Decreased insulin sensitivity that is dose-dependent is observed during GH therapy. Glucose homeostasis, however, is not affected, but a recent report of increased incidence of Type 2 diabetes mellitus in children undergoing GH therapy requires prospective surveillance.
83 citations
TL;DR: Evidence indicates the existence of a consistent relationship between slow-wave (SW) sleep and increased GH secretion, and compounds that increase SW sleep may therefore represent a novel class of GH secretagogues.
Abstract: In healthy young adults, the 24-hour profile of plasma growth hormone (GH) levels consists of stable low levels abruptly interrupted by bursts of secretion. In normal women, daytime GH secretory pulses are frequent. However, in normal men, a sleep-onset-associated pulse is generally the major or even the only daily episode of active secretion. Extensive evidence indicates the existence of a consistent relationship between slow-wave (SW) sleep and increased GH secretion. There is a linear relationship between the amount of SW sleep (measured by either visual scoring or spectral analysis of the EEG) and the amount of concomitant GH secretion. During ageing, SW sleep and GH secretion decrease exponentially and with the same chronology. Pharmacological stimulation of SW sleep results in increased GH release, and compounds that increase SW sleep may therefore represent a novel class of GH secretagogues.
81 citations
60 citations
TL;DR: Differential utilization of the same signal transduction molecules indicates that GH and IGF-I possess distinct overlapping roles in CNS function.
Abstract: The growth hormone (GH) receptor and binding protein are synthesized in the CNS and are regulated differentially to their hepatic counterparts. GH is also synthesized in the CNS and is regulated differentially to its hypophyseal counterpart. Insulin-like growth factor I (IGF-I) is synthesized in the CNS and in the early postnatal period is regulated by peripherally secreted GH. Both GH and IGF-I alter the size and morphology of the CNS during development and affect differentiated cell function in the CNS, with consequent modulation of cognitive function. Differential utilization of the same signal transduction molecules indicates that GH and IGF-I possess distinct overlapping roles in CNS function.
55 citations
TL;DR: GHD is seen, not only in children with Prader-Willi syndrome, but also in adults with the syndrome, and levels of insulin-like growth factor I were decreased in 87%.
Abstract: Summary Prader-Willi syndrome is characterized by a typical clinical phenotype and by a complex genetic basis that includes large deletions, uniparental disomy and imprinting mutations of chromosome region 15q11-q13. This report delineates the clinical characteristics, morbidity and growth hormone secretory status of 19 adults with Prader-Willi syndrome. The patients were 18–34 years of age. Morbidity included marked obesity with body mass index in excess of 30 kg/m 2 (grade 1–3 according to WHO), metabolic diseases, sleep apnoea and lipolymphoedema. Severe growth hormone deficiency (GHD) was seen in 38% of the patients, and levels of insulin-like growth factor I were decreased in 87%. Thus, GHD is seen, not only in children with Prader-Willi syndrome, but also in adults with the syndrome.
52 citations
50 citations
TL;DR: The present data suggest that IGF1's augmentation of granulosal and oocyte GLUT1 expression may be essential for oocyte maturation and successful ovulation.
Abstract: Granulosa cells provide nutritional and trophic support for growing oocytes in ovarian follicles. The granulosa cells closest to the oocyte produce abundant insulin-like growth factor 1 (IGF1) and the IGF1 receptor is highly expressed by oocytes, suggesting that granulosa-derived IGF1 may have trophic effects on oocyte growth and development. To investigate this possibility, in the present study we used in situ hybridization and immunohistochemistry to examine glucose transporter (GLUTs 1, 3 & 4) expression in follicles from pre-pubertal Igf1-/- and littermate wildtype (wt) mice. Pre-pubertal mice were used for this study because the Igf1 null mice do not mature sexually. GLUT1 mRNA and immunoreactivity were most abundant in oocytes and in granulosa cells immediately surrounding the oocyte. Expression of this transporter was significantly reduced in Igf1 null oocytes and granulosa cells and was restored by exogenous IGF1 treatment to wt levels. These effects on GLUT expression were significant at both the mRNA and immunoreactive protein levels. Oestrogen treatment significantly increased GLUT1 levels in oocytes and granulosa from both wt and Igf1-/-, although the latter were still significantly lower than wt. Oocyte glycogen stores, determined by PAS staining, did not appear different in Igf1-/- and wt mice.GLUT3 was expressed in thecal cells surrounding growing follicles and was not appreciably different in Igf1 null compared with wt ovaries. GLUT4 expression was not detected in the prepubertal mouse ovary. Together with observations from previous studies showing that ovulation is blocked in Igf1 null mice, the present data suggest that IGF1's augmentation of granulosal and oocyte GLUT1 expression may be essential for oocyte maturation and successful ovulation.
48 citations
TL;DR: Insulin-like growth factor I stimulates osteoblastic cells in culture to proliferate and to synthesize bone matrix proteins, but local IGF-I action is modulated by a family of IGFFBPs that, in turn, are modified by specific IGFBP proteases.
Abstract: Insulin-like growth factor I (IGF-I) stimulates osteoblastic cells in culture to proliferate and to synthesize bone matrix proteins However, local IGF-I action is modulated by a family of IGF-binding proteins (IGFBPs) that, in turn, are modified by specific IGFBP proteases All these components of the IGF-I regulatory system are present and operative in bone cells in vitro
TL;DR: In males, termination of the intracellular signalling stimulated by a plasma GH pulse is proposed to be additionally facilitated by GH-STAT5b-inducible SOCS-CIS proteins, which block the further activation of STAT5b by binding to and inhibiting the action of the GHR-JAK2 complex via multiple mechanisms.
Abstract: The intracellular signalling molecule and transcriptional activator STAT5b is a key mediator of the effects of intermittent plasma growth hormone (GH) pulses on the male-specific pattern of liver gene expression and pubertal body growth rates in rodents. Experiments with Stat5b gene-knockout mice have revealed that these GH-regulated, male-specific phenotypes are a direct consequence of GH pulse-dependent STAT5b activation and that loss of function of STAT5b cannot be compensated for by the closely related signalling molecule STAT5a. Physiological plasma GH pulses are required to obtain the high levels of activated STAT5b seen in the livers of males, and down-regulation of the GH receptor (GHR)-JAK-STAT5b pathway in hepatocytes exposed to GH in a near-continuous fashion underlies the low level of liver STAT5b activity that is characteristic of adult female rats. Termination of nuclear STAT5b signalling occurs at the conclusion of a plasma GH pulse, with STAT5b deactivation catalysed by a tyrosine phosphatase. In males, termination of the intracellular signalling stimulated by a plasma GH pulse is proposed to be additionally facilitated by GH-STAT5b-inducible SOCS-CIS proteins, which block the further activation of STAT5b by binding to and inhibiting the action of the GHR-JAK2 complex via multiple mechanisms. In this manner, the liver cell is rendered temporarily unresponsive to further GH-signalling events. SOCS-CIS proteins synthesized in liver cells stimulated continuously with GH may also contribute to the apparent down-regulation of STAT5b signalling that is observed in the female rat liver.
TL;DR: Observations indicate that hepatic over-expression of IGFBP-1 may have endocrine effects on brain development, and that insertional mutagenesis may have been involved in mice with disruption of the igf-I gene.
Abstract: Insulin-like growth factors (IGFs) produced in the brain are known to participate in brain development via activation of the type 1 IGF receptor. IGF binding proteins (IGFBPs) modulate the cellular action of IGFs and some are expressed in the fetal brain. Under normal conditions IGFBP-1 is not one of these, but IGFBP-1 expression obtained via transgenesis using ubiquitous promoters affects brain development. In earlier work, we established a model of transgenic mouse in which liver-specific IGFBP-1 expression begins during fetal life. The repercussions of this IGFBP-1 over-expression include reproductive defects, ante- and perinatal mortality and post-natal growth retardation, the extent of which is related to the degree of transgene expression. Unexpectedly, during the first 2 months of postnatal life, there were some cases of head enlargement revealing hydrocephalus among homozygotes, frequently associated with motor disorders. Brain sections showed dilatation of the lateral ventricles in 10 out of 15 homozygotes examined. Histologically, dilatation was evident in four out of nine heterozygotes. Brain weight in transgenics was relatively less reduced than the weights of other organs. Hence, brain weight/body weight ratios were normal in heterozygotes and on average higher than normal in homozygotes. The width of the cerebral cortex was reduced in homozygotes, with disorganized neuronal layers. The corpus callosum was underdeveloped, particularly in homozygotes. The area of the hippocampus was reduced in homozygotes and one-third of the heterozygotes, with a short and thick dentate gyrus in the former. Similar anomalies have been reported in mice with disruption of the igf-I gene and in a model of transgenic mice over-expressing IGFBP-1 in all tissues, including the brain. Hydrocephalus was not mentioned in these reports, raising the possibility that insertional mutagenesis may have been involved in our mice. Nevertheless, our observations indicate that hepatic over-expression of IGFBP-1 may have endocrine effects on brain development.
TL;DR: The effects of GH on burn wound repair and gut healing are reviewed and it is suggested that insulin-like growth factor I (IGF-I), stimulated through the GH axis, plays an important role in the reconstitution of intestinal epithelial integrity following mucosal injury.
Abstract: Severe illness or trauma alters the body's metabolic rate. After injury, host-defence protein synthesis and increased energy requirements are satisfied from available protein, usually active muscle tissue. A prolonged hypercatabolic state persists and may lead to increased morbidity and mortality in severely burned patients. Growth hormone (GH) is an anabolic agent shown to decrease some of the deleterious effects of hypermetabolism. This article will review the effects of GH on burn wound repair and gut healing. Studies on GH have shown a significant reduction in wound-healing times in burned patients given GH at a dose of 0.6 IU/kg/day (0.2 mg/kg/day). At this dose, other studies have shown no increase in mortality, and a number of beneficial effects in critically burned children have been demonstrated. Animal studies have suggested that insulin-like growth factor I (IGF-I), stimulated through the GH axis, plays an important role in the reconstitution of intestinal epithelial integrity following mucosal injury. Many encouraging papers report positive results regarding both the efficacy and safety of GH and IGF-I, therefore warranting continued investigation.
TL;DR: In this article, the effects of environmental contaminants on the reproductive and endocrine systems of alligators have been examined and it was shown that any environmental pollutant that disrupts the normal steroid milieu of the developing embryo will have significant lifelong consequences on sex determination and on the organization and function of the reproductive system.
Abstract: Summary Environmental contaminants have posed a threat to the health of wildlife since the onset of the industrial age. Over the last four decades, much concern has focused on the lethal, carcinogenic and/or extreme teratogenic manifestations of environmental pollution. During the last decade, evidence suggests that the disruption of normal endocrine signalling by environmental contaminants is a mechanism that must also be examined. Man-made chemicals, known as xenochemicals, released into the environment can act as hormone agonists or antagonists and thereby disrupt hormone synthesis, action and metabolism, that is, act as endocrine-disrupting contaminants. Our recent studies show that reptiles living in contaminated environments exhibit: (1) population declines due to the lethal and reproductive effects of the contaminants on embryos, juveniles or adults; (2) developmental abnormalities of embryos, including subtle effects in the reproductive system of alligators; and (3) abnormalities of the endocrine system. Numerous studies now demonstrate that any environmental pollutant that disrupts the normal steroid milieu of the developing embryo will have significant lifelong consequences on sex determination and on the organization and function of the reproductive and endocrine systems. @ 2000 Harcourt Publishers Ltd
TL;DR: The actions and interactions of the IGF system as it relates to Alzheimer's disease will be investigated.
Abstract: Insulin-like growth factors (IGF) are pleiotrophic polypeptides affecting all aspects of growth and development The IGF system, including ligands, receptors, binding proteins and proteases is also involved in pathophysiological conditions, such as cancer and degenerative conditions In this review, the actions and interactions of the IGF system as it relates to Alzheimer's disease will be investigated
TL;DR: The effects ofGH replacement on muscle and bone in GH-deficient individuals are significant and beneficial, although the longer-term effects of GH replacement in terms of reducing the number of fractures and prevention of frailty in old age are not yet established.
Abstract: The decade since the initial availability of recombinant growth hormone (GH) has seen an increase in our understanding of the effects of GH on muscle and bone. Adult GH deficiency (GHD) is associated with osteopenia, the severity of which is related to three factors: the timing, age of onset and severity of GHD. Epidemiological data suggest that this osteopenia is associated with an increased risk of fracture. The impact of GH replacement therapy on bone mineral density (BMD) appears to be related to a large number of interrelated factors, including the dose and duration of therapy, timing of onset of GHD, skeletal site, degree of osteopenia at baseline, and age and gender of the patient. Overall, the effect of GH replacement on BMD in the majority of patients is beneficial. As yet, however, no data are available that demonstrate a reduction in fracture rate following GH therapy. In comparison with normal individuals, GH-deficient individuals have reduced lean body mass and muscle strength, both of which increase within 12 months of GH therapy. Therefore, the effects of GH replacement on muscle and bone in GH-deficient individuals are significant and beneficial, although the longer-term effects of GH replacement in terms of reducing the number of fractures and prevention of frailty in old age are not yet established. The effects of GH on bone and muscle in GH-replete individuals have been studied less fully. While GH therapy modulates markers of bone resorption and formation, its effects in patients with idiopathic osteoporosis are disappointing, with oestrogen therapy or bisphosphonates proving to be more effective in post-menopausal women. To date, however, there have been no GH treatment trials of adequate duration (longer than 18 months), and it remains possible that longer-term trials may demonstrate more profound effects. The effects of GH therapy on muscle have been examined in normal elderly individuals. Generally, the doses used have been supraphysiological and associated with an unacceptable incidence of side-effects. GH therapy has resulted in an increase in lean body mass, but functional ability and strength have not improved in the majority of studies. Thus, clear-cut beneficial effects of GH on muscle and bone in GH-replete individuals have not been demonstrated. It seems unlikely that normal elderly individuals will benefit significantly from GH therapy, but frail individuals or those with musculoskeletal or neuromuscular pathology are potential candidates for study.
TL;DR: In this article, the authors compared the immunoreactive (IR) vs immunofunctional (IF) GH concentrations before and after acute resistance exercise (i.e., six sets of 10 repetition maximum squats separated by 2 min rest periods) in 8 men and 6 women.
Abstract: Immunoassays for growth hormone (GH) may yield variable concentrations for the same sample due to the molecular heterogeneity of growth hormone and epitope specificity of their antibodies. Strasburger et al. developed an "immunofunctional" assay that only detects those GH molecules possessing intact sites 1 and 2, which are necessary for inducing receptor dimerization and subsequent signal transduction. This study compared the immunoreactive (IR) vs immunofunctional (IF) GH concentrations before and after acute resistance exercise (i.e. six sets of 10 repetition maximum squats separated by 2 min rest periods) in 8 men and 6 women. IF concentrations were determined by an ELISA(DSL)and IR GH by a monoclonal IRMA(Nichols). Both men (M) and women (W) demonstrated similar increases for IR (M: 1.47 vs 25.0 ng/ml; W: 4.0 vs 25.4 ng/ml) and IF (M: 0.55 vs 11.66 ng/ml; W: 1.94 vs 10.41 ng/ml) GH following exercise. Post-exercise IF GH was significantly less than IR GH for both M and W. The ratio of IR/IF after exercise was approximately 2 and similar for both M and W. In summary, dynamic exercise elicited a similar rise in M and W for immunofunctionally active GH molecules, but the magnitude is lower than when detected with another conventional assay.
TL;DR: The cytokine receptor-associated Janus kinases convert the latent monomeric form of the STAT molecules to the activated dimeric form through tyrosine phosphorylation, which acts as a strong suppressor of wild-type action in the short form of STAT5.
Abstract: Extracellular hormones, growth factors and cytokines relay their effects on the transcription of genes through the recognition of specific receptors and intracellular signalling molecules. Signal transducers and activators of transcription (STATs) have been recognized as crucial intracellular signalling molecules. The cytokine receptor-associated Janus kinases (JAKs) convert the latent monomeric form of the STAT molecules to the activated dimeric form through tyrosine phosphorylation. The dimers bind to specific DNA response elements and are able to induce transcription. This induction requires the full-length form of the STAT molecules. Negative regulatory potential is exerted by the short form of the molecule, which lacks the trans-activation domain. This short form is activated and dimerized, but dephosphorylation is impaired. The short form of STAT occupies the DNA-binding sites in a stable fashion and acts as a strong suppressor of wild-type action. Positive enhancement of STAT5 trans-activation potential is provided by the glucocorticoid receptor. Ligand activation of this receptor causes the formation of a complex with STAT5 and deviation to the STAT5 DNA-binding site. An additional regulatory loop is provided by the reactivation of the short form of STAT5 through glucocorticoid receptor association. Conversely, classical glucocorticoid-responsive genes are negatively affected by STAT5 activation.
TL;DR: There is no study, however, measuring free IGF-I levels in patients with diabetic retinopathy which mediate the biological effects of IGF-i and are modulated by a complex system of six specific IGF binding proteins (IGFBPs) and several IGFBP proteases.
Abstract: In patients with diabetic retinopathy, elevated serum levels of total circulating insulin-like growth factor-I (IGF-I) have been implicated as an important mediator of the disease. There is no study, however, measuring free IGF-I levels in patients with diabetic retinopathy which mediate the biological effects of IGF-I and are modulated by a complex system of six specific IGF binding proteins (IGFBPs) and several IGFBP proteases.
TL;DR: It is demonstrated that any environmental pollutant that disrupts the normal steroid milieu of the developing embryo will have significant lifelong consequences on sex determination and on the organization and function of the reproductive and endocrine systems.
Abstract: Summary Environmental contaminants have posed a threat to the health of wildlife since the onset of the industrial age. Over the last four decades, much concern has focused on the lethal, carcinogenic and/or extreme teratogenic manifestations of environmental pollution. During the last decade, evidence suggests that the disruption of normal endocrine signalling by environmental contaminants is a mechanism that must also be examined. Man-made chemicals, known as xenochemicals, released into the environment can act as hormone agonists or antagonists and thereby disrupt hormone synthesis, action and metabolism, that is, act as endocrine-disrupting contaminants. Our recent studies show that reptiles living in contaminated environments exhibit: (1) population declines due to the lethal and reproductive effects of the contaminants on embryos, juveniles or adults; (2) developmental abnormalities of embryos, including subtle effects in the reproductive system of alligators; and (3) abnormalities of the endocrine system. Numerous studies now demonstrate that any environmental pollutant that disrupts the normal steroid milieu of the developing embryo will have significant lifelong consequences on sex determination and on the organization and function of the reproductive and endocrine systems.
TL;DR: The purification, characterization and actions of a peptide derived from proteolysis of IGFBP-3 by an enzyme secreted by MCF-7 breast cancer cells suggest that the IGF BP-3 protease in MCf-7 cell medium can generate an inhibitor of IGF-dependent and independent breast cancer cell growth.
Abstract: This study describes the purification, characterization and actions of a peptide derived from proteolysis of IGFBP-3 by an enzyme secreted by MCF-7 breast cancer cells. One millilitre of cell-conditioned medium at pH 5.5 fully proteolysed 10 microg plasma-derived IGFBP-3, yielding an immunoreactive fragment of apparent molecular mass 21 kDa by SDS-PAGE. After purification to homogeneity by IGF-I affinity chromatography and reverse-phase HPLC, sequence analysis revealed the amino-terminus of IGFBP-3, and mass spectrometry indicated a molecular mass of 12 295 Da. Analysis of the corresponding fragment generated by proteolysis of a non-glycosylated IGFBP-3 mutant indicated a molecular mass of 9855 Da, consistent with cleavage after Arg97. This suggests that the fragment derived from glycosylated IGFBP-3 contains approximately 2.5 kDa carbohydrate on Asn89. IGFBP-3[1-97] formed binary complexes with IGFs, but with reduced efficiency compared with intact IGFBP-3. IGFBP-3[1-97] at 11 nM inhibited IGF-I-stimulated DNA synthesis by 50-60% in MCF-7 breast cancer cells, similar to the inhibition observed with the intact protein. In the absence of IGF-I, DNA synthesis was inhibited by IGFBP-3[1-97], but not intact IGFBP-3. This suggests that the IGFBP-3 protease in MCF-7 cell medium can generate an inhibitor of IGF-dependent and independent breast cancer cell growth.
TL;DR: The results suggest that adrenal steroids are necessary for normal GHS-receptor expression and GHRP-6-induced weight gain, but long-term stimulation of the HPA axis by continuous GHS exposure may be detrimental to the growth response.
Abstract: Synthetic GH-releasing peptides such as GHRP-6 are potent GH secretagogues (GHSs) in several species, but attempts to stimulate growth by continuous GHS exposure have had limited success. GHSs also release ACTH and adrenal steroids. Since glucocorticoid excess is associated with poor linear growth, stimulation of the hypothalamo-pituitary-adrenal (HPA) axis by continuous GHS administration may compromise their growth-promoting effects. We have now examined the effects of continuous GHRP-6 infusion (100 mg/day, s.c. for 14 days) in normal 150-day-old female rats, and in adrenalectomized (Adx) rats with or without dexamethasone (Dex) replacement. Infusion of GHRP-6 did not significantly affect body weight gain compared with excipient-treated controls in either intact rats (controls, 9.0 +/- 1.6 vs GHRP-6, 11.8 +/- 0.9 g) or Adx rats (4.4 +/- 1.5 vs 7.9 +/- 2.7 g). However, GHRP-6 significantly increased weight gain in Adx rats treated with Dex (controls, 3.5 +/- 1.4 vs GHRP-6, 15.4 +/- 1.6 g;P<0.01). Adrenalectomy decreased plasma triglycerides (P<0.01), and Dex treatment increased plasma cholesterol (P<0.001), GHRP-6 treatment did not affect these plasma lipids. Dex treatment also reduced plasma GH-binding protein levels and hepatic GH binding (P<0.05). Pituitary GH content was decreased in Adx rats (P<0.05) but not in Dex-treated Adx rats. Adrenalectomy markedly decreased GHS-receptor mRNA expression in the arcuate (P<0. 001) and ventromedial nuclei (P<0.01), whilst Dex treatment normalized GHS-receptor expression. These results suggest that adrenal steroids are necessary for normal GHS-receptor expression and GHRP-6-induced weight gain, but long-term stimulation of the HPA axis by continuous GHS exposure may be detrimental to the growth response.
TL;DR: It is confirmed that age and cardiac condition affect IGFs and IGFBP-3 levels, and older patients with a cardiac condition are less able to maintain their blood IGF-I levels during the recovery period compared to younger patients.
Abstract: Aging retards the repair process by decreasing hormone secretion from the somatotrophic axis, which plays a major role in tissue reconstruction after injury. The aim of this study was to determine the effect of aging on serum insulin-like growth factor-I (IGF-I), IGF-II and IGF-binding protein-3 (IGFBP-3) levels following myocardial infarction (MI). For four consecutive days, we monitored the variation of serum IGF-I, IGF-II and IGFBP-3 concentrations in 26 patients aged 19-71 years who were diagnosed with MI. Serum IGF-I, IGF-II and IGFBP-3 were measured daily by double antibody radioimmunoassay. Daily serum IGF-I concentrations showed a significant negative correlation with age (r = -0.528, P< 0.001). Total serum IGF-I was significantly (P = 0.002) higher in the younger age group (patients under 50 years) compared to the older group (50 years and over); 206 +/- 16 ng/ml vs 136 +/- 12 ng/ml. During this investigation, younger patients (under 50 years) showed no significant daily variations in IGF-I levels compared to older patients (50 years and over) who presented a significant decline (P = 0.012). Total serum IGF-II in both groups decreased significantly with time. Total serum IGFBP-3 in the younger age group was significantly higher (P = 0.046) than in the older age group (3.42 +/- 0.18 microgram/ml vs 2.95 +/- 0.13 microgram/ml). MI patients in both groups showed significantly lower IGF-I and IGF-II (IGFs) with higher IGFBP-3 compared to age- and sex-adjusted levels of normal adults (controls). The present results confirm that age and cardiac condition affect IGFs and IGFBP-3 levels. We are inclined to believe that older patients with a cardiac condition are less able to maintain their blood IGF-I levels during the recovery period compared to younger patients. Given the biological impact of IGF-I on regeneration, this could explain why older patients take longer to recover and heal poorly in comparison to younger patients.