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Hormones are both growth stimulatory and growth inhibitory in utero. They regulate tissue growth and development by controlling the rates of cell proliferation, apoptosis and differentiation in many fetal tissues. They also signal the level of resources available for intrauterine growth to the fe- tal tissues and relay back to the placenta the degree of mismatch between the actual fetal nutrient supply and the fetal nutrient demands for growth. They affect intrauterine growth by anabolic and catabolic actions on fetal metabolism and by altering the nutrient transfer capacity and endocrine function of the placenta. By modifying the fetal growth trajectory, hormones have a central role in programming development in utero and in determining the phenotypic outcome of changes in feto-placental growth during adverse intrauterine conditions. This review examines the role of hormones in feto-placental growth with particular emphasis on insulin, the insulin-like growth factors and glucocorticoids. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The majority of insulin-like growth factor (IGF)-I and IGF-II circulate in the serum as a complex with the insulin-like growth factor binding protein (IGFBP)-3 or IGFBP-5, and an acid-labile subunit (ALS). The function of ALS is to prolong the half-life of the IGF-I-IGFBP-3/IGFBP-5 binary complexes. Fourteen different mutations of the human IGFALS gene have been identified in 17 patients, suggesting that ALS deficiency may be prevalent in a subset of patients with extraordinarily low serum levels of IGF-I and IGFBP-3 that remain abnormally low upon growth hormone stimulation. Postnatal growth was clearly affected. Commonly, the height standard deviation score before puberty was between –2 and –3, and approximately 1.4 SD shorter than the midparental height SDS. Pubertal delay was found in 50% of the patients. Circulating IGF-II, IGFBP-1, -2 and -3 levels were reduced, with the greatest reduction observed for IGFBP-3. Insulin insensitivity was a common finding, and some patients presented low bone mineral density. Human ALS deficiency represents a unique condition in which the lack of ALS proteins results in the disruption of the entire IGF circulating system. Despite a profound circulating IGF-I deficiency, there is only a mild impact on postnatal growth. The preserved expression of locally produced IGF-I might be responsible for the preservation of linear growth near normal limits. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aim: We investigated whether the insulin-like growth factor (IGF)-I response to growth hormone (GH) is regulated by body mass index (BMI) in short children with normal weight. Methods: We studied 37 prepubertal children with idiopathic short stature (ISS), comparing children with high-normal BMI (standard deviation scores, SDS 1.23 ± 0.11, n = 20) and low-normal BMI (SDS –0.93 ± 0.12, n = 17). The IGF-I response to GH was determined with an abbreviated IGF-I generation test, by measuring serum IGF-I concentrations at baseline and 24 h after the administration of GH (0.033 mg/kg). Results: Children with high- and low-normal BMI had similar age (8.5 ± 0.7 vs. 8.7 ± 0.7 years) and height (–2.0 ± 0.1 vs. –2.2 ± 0.2 SDS). However, children with high-normal BMI exhibited higher mean basal IGF-I (191 ± 15 vs. 139 ± 11 ng/ml, p < 0.05), higher mean IGF-I levels 24 h after GH administration (261 ± 22 vs. 164 ± 14 ng/ml, p < 0.05) and a higher IGF-I percent increase after GH administration (37 ± 5 vs. 17 ± 4%, p < 0.05) compared with children with normal-low BMI. Conclusion: BMI modulates the IGF-I response to GH, suggesting that GH sensitivity may be influenced by the nutritional status in children with ISS and normal body weight. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aims: There are many controversies regarding side effects on craniofacial and extremity growth due to growth hormone (GH) treatment. Our aim was to estimate GH action on craniofacial development and extremity growth in GH-deficient patients. Methods: Twenty patients with GH deficiency with a chronological age ranging from 4.6 to 24.3 years (bone age from 1.5 to 13 years) were divided in 2 groups: group 1 (n = 6), naive to GH treatment, and group 2 (n = 14), ongoing GH treatment for 2–11 years. GH doses (0.1–0.15 U/kg/day) were adjusted to maintain insulin-like growth factor 1 and insulin-like growth factor binding protein 3 levels within the normal range. Anthropometric measurements, cephalometric analyses and facial photographs to verify profile and harmony were performed annually for at least 3 years. Results: Two patients with a disharmonious profile due to mandibular growth attained harmony, and none of them developed facial disharmony. Increased hand or foot size (>P97) was observed in 2 female patients and in 4 patients (1 female), respectively, both not correlated with GH treatment duration and increased levels of insulin-like growth factor 1. Conclusions: GH treatment with standard doses in GH-deficient patients can improve the facial profile in retrognathic patients and does not lead to facial disharmony although extremity growth, mainly involving the feet, can occur. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Immunoassays that measure circulating concentrations of insulin-like growth factor I (IGF-I) are increasingly used to diagnose and monitor growth hormone (GH)-related diseases. Specifically, IGF-I measured by immunoassay is used to diagnose GH deficiency and acromegaly, and to monitor treatment efficacy in patients with acromegaly, particularly those treated with the GH receptor antagonist pegvisomant, as measurement of circulating GH is no longer suitable for monitoring disease activity. While techniques for measuring IGF-I have evolved over the decades, immunoassays are still the primary tool used in routine laboratories. Immunoassays depend on the interaction between antibodies and the analyte, and all factors that modify the accessibility of the epitopes recognized by the antibodies can influence results. With IGF-I assays, interference from binding proteins is an important variable affecting assay results. Conclusions: It is generally accepted that assay- and age-specific reference ranges are mandatory for meaningful interpretation of IGF-I concentrations. High-quality, method-specific reference ranges and a high degree of methodological consistency in the assay are essential for reliable comparison of results across studies and for long-term monitoring of individual patients. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background and Methods: We assessed the value of in- sulin-like growth factor I (IGF-I) monitoring during growth hormone (GH) treatment by retrospectively examining the relationships between (1) GH dose and IGF-I response, (2) baseline serum IGF-I concentration and growth response and (3) serum IGF-I response and growth response after 1 year of GH treatment among patients in the Pfizer International Growth Study database (KIGS). KIGS patients were eligible for the study if they were classified as having idiopathic GH deficiency, acquired GH deficiency, Turner syndrome or were born small for gestational age. Results: Correlations between GH dose and IGF-I response and between pretreatment IGF-I values and first-year growth response were weak across all groups. Correlations between the IGF-I response and growth response after 1 year of treatment were greater than those between baseline serum IGF-I values and first-year growth response. Pre- and posttreatment clinical characteristics were consistently different across all groups, but the numerous technical factors affecting these relationships are remediable. Conclusions: IGF-I monitoring during GH therapy is a valuable tool to monitor compliance and ensure that IGF-I levels do not exceed the normal range for extended periods. IGF-I monitoring may help clinicians increase GH doses as needed during puberty to achieve normal serum IGF-I values and normal or enhanced growth. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: The process of aging is associated with progressive remodeling. The age-dependent remodeling process mainly affects anthropometrics and endocrine function, which subsequently impact metabolic factors. In some individuals, e.g., the very select group of healthy centenarians, the remodeling process is successful. The reasons why centenarians are able to reach the extreme limits of human life span are still largely unknown; however, several studies in humans have shown that longevity is associated with a significant improvement in glucose handling – mainly, a rise in insulin sensitivity and a decline in plasma insulin-like growth factor I levels. Conclusions: Caloric restriction seems to be the best positive modulator of metabolism to achieve longevity. Other specific metabolic adaptations, even those genetically induced, might also play a role in the health of centenarians. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The article presents abstracts on medical topics, including abnormal growth hormone (GH) signaling in GH transduction defect (GHTD), the behavior of human osteoclasts in the presence of recombinant human GH and insulin-like growth factor-I (IGF-I), and the age-dependent effects of GH on the osteoclasts of individuals with GH deficiency.

Background: Insulin-like growth factor-I (IGF-I) and insulin are structurally related proteins with similar receptors and signal transduction systems. Aim: We postulate that some low birth weight (LBW) children may have decreased sensitivity to both insulin and IGF-I. Methods: We studied 48 prepubertal LBW children aged 7.6 ± 2.4 years. Insulin sensitivity was determined using an oral glucose tolerance test, and IGF-I sensitivity was assessed by determining nocturnal GH concentrations at baseline and after administration of recombinant human IGF-I/IGFBP-3 complex. Results: Children were classified into quartiles of insulin sensitivity based on their glucose AUC/insulin AUC index. Children in the lowest quartile of insulin sensitivity exhibited a lower IGF-I sensitivity after administration of the rhIGF-I/rhIGFBP-3 complex compared to children in the highest quartile of insulin sensitivity (percent change in GH AUC: –44.2 ± 5.7 vs. –21.6 ± 6.8, p < 0.05). Conclusion: LBW children in the lowest quartile of insulin sensitivity exhibited a lower pituitary GH response to the administration of rhIGF-I/rhIGFBP-3. Our findings suggest that reduced sensitivity to insulin and IGF-I may coexist in some prepubertal LBW children. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aim: To evaluate the postpartum time course of changes in insulin-like growth factors (IGFs) and their binding proteins (IGFBPs). Methods: Breast milk IGF-I and IGF-II and IGFBP-1, IGFBP-2, and IGFBP-3 levels were determined in 23 women with babies born at term, from day 4 until up to 9 months after birth. Results: The IGFBP-3 levels were highest from day 4 to day 6 and then decreased by days 10–12. In contrast, IGF-I and IGF-II and IGFBP-1 and IGFBP-2 showed little change over the first 2 weeks after birth. Subsequently, all the IGF components showed a moderate decline over approximately the first 1–3 months and then stable levels up to 9 months after birth. Conclusion: Although the possibility cannot be excluded that these changes in levels of IGFs and their binding proteins in human milk represent passive loss from the mammary gland, we speculate that higher early levels of the human milk IGF system contribute to maturation of the infant gut. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: To make a diagnosis of growth hormone deficiency (GHD), individuals with normal GH levels must be distinguished from those who are deficient. This requires an understanding of how GH secretion and other related factors differs between these two groups. The presence of a normal insulin-like growth factor I (IGF-I) level does not necessarily preclude a diagnosis of GHD, whereas a low IGF-I level in a subject with three or four other hormone deficiencies and no conditions that would otherwise lower IGF-I might be sufficient to make the diagnosis. Provocative testing is a clinically relevant method of testing, but not all tests in use have comparable specificity and sensitivity. Conclusions: Insulin-induced hypoglycemia is the recommended test to diagnose GHD, but the arginine-GH-releasing hormone test achieves comparable separation between normal and hypopituitary subjects in most groups. Future studies using large surveillance databases may further expand our understanding of concepts underlying GHD and its diagnosis. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background:Concomitant evaluation of the metabolic and growth-promoting effects of growth hormone (GH) therapy in Turner syndrome (TS) may be used in the prediction of the growth response to GH therapy. Aim: To evaluate the metabolic effects of GH therapy in TS and correlation with the short-term growth response. Patients: 24 prepubertal children with TS, aged 9.4 ± 2.6 years were followed for auxology and IGF-I, IGFBP-3, leptin, ghrelin, adiponectin, lipids and OGTT results in a prospective multicenter study. Intervention: GH (Genotropin®) in a dose of 50 μg/kg/day for 1 year. Results: Height standard deviation score (SDS) increased from –3.9 ± 1.5 to –3.5 ± 1.4 (p = 0.000) on therapy. BMI did not change. IGF-I SDS increased from –2.3 ± 0.4 to –1.6 ± 1.1 at 3 and 6 months (p = 0.001) and decreased thereafter. Serum leptin decreased significantly from 2.3 ± 3.9 to 1.7 ± 5.3 ng/ml (p = 0.022) at 3 months and increased afterwards. Serum ghrelin decreased from 1.2 ± 0.8 to 0.9 ± 0.4 ng/ml (p = 0.005) with no change in adiponectin. Basal and stimulated insulin levels also increased significantly. Δ height SDS over 1 year showed a significant correlation with Δ IGF-I0–3 months (r = 0.450, p = 0.027). Conclusion: IGF-I may be considered as a marker of growth response in TS at short term. Leptin shows a decrease at short term but does not have a correlation with growth response. The decrease in ghrelin in face of unchanged weight seems to be associated with increase in IGF-I and insulin levels. The unchanged adiponectin levels in spite of an increase in insulin levels indicates that adiponectin is mainly affected by weight, not insulin. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/ Aims: Leptin is linked to hormonal disturbances occurring in anorexia and positively linked with bone mineral density. The aim of this study was to determine whether hypoleptinemia occurring in rhythmic gymnasts may affect bone health. Method: Leptin, insulin, cortisol, IGF1 levels and bone markers were determined in 36 rhythmic gymnasts (EG) and 20 controls (C). Body composition, BMD at the whole body (WBBMD), lumbar spine (LSBMD) and bone ultrasound properties (SOS, BUA) were measured. Results: The rhythmic gymnasts had lower fat mass and leptin level than the controls. There was no difference for IGF1, cortisol and insulin levels. Bone turnover rate was higher in elite gymnasts. The uncoupling index showed that remodeling favored the bone formation. LSBMD, WBBMD, SOS and BUA were higher in elite gymnasts after adjustment for fat mass. Leptin correlated positively with fat mass and negatively with physical activity. Conclusion: High impact training is able to counterbalance bone effects usually encountered in hormonally disturbed subjects. Our results suggest that hypoleptinaemia might be related to direct osteogenic effects and indirect hormonal mechanisms including preservation of IGF and cortisol levels. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aims: Our aim was to investigate glucose homeostasis, insulin sensitivity and insulin-like growth factor (IGF) system status in children born small for gestational age (SGA). Methods: A case-control study was carried out at birth, infancy and childhood, comparing SGA with children appropriate for gestational age strictly matched for age, gender, pubertal status and body mass index. Ninety newborns, 52 infants, and 68 children were studied. Fasting insulin (IF), fasting glucose (GF) to IF ratio (GF/IF), the homeostasis model assessment of insulin sensitivity, the quantitative insulin sensitivity check index, insulinogenic index and the triglyceride/high-density lipoprotein-cholesterol ratio were measured. IGF-I, IGF-binding protein-3 and the IGF-I/IGF-binding protein-3 molar ratio were assessed. Results: Glucose concentrations were lower in SGA newborns (p < 0.0001), infants (p = 0.01), and children (p = 0.001). Birth weight correlated with glucose levels at birth (r = 0.59, p < 0.0001), 12 months (r = 0.29, p = 0.04) and childhood (r = 0.44, p < 0.0001). Conclusion: Our results provide evidence for a developmental adaptation of glucose metabolism in SGA children leading to reduced glucose concentrations. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Noonan syndrome (NS) is a relatively common, clinically heterogeneous disorder, with an estimated incidence of 1:1,000 to 1:2,500 live births. It is characterized by proportionate postnatal short stature, dysmorphic facial features, chest deformities and congenital heart disease. This report describes a child with NS who harbors the N308D mutation in protein tyrosine phosphatase, nonreceptor type 11 (NM_002834; PTPN11) gene. Because of his short stature, poor growth rate and low levels of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein 3 (IGFBP-3), recombinant human growth hormone (rhGH) therapy was initiated at 11.5 years. During the first year of therapy, the child remained prepubertal and had a significant increase in growth velocity (from 3.0 to 7.8 cm/year). Treatment was maintained throughout puberty, and after approximately 5 years of therapy, the subject still has a good growth velocity (7.6 cm/year) and his height is 0.5 standard deviation score (SDS) above pretreatment height. When the subject’s growth evolution is analyzed using an NS-specific growth chart, it is evident that his height increased almost 2 SD. During treatment, IGF-I and IGFBP-3 levels increased progressively and reached normal ranges for sex and age. Data strongly suggest that PTPN11 mutations identified in NS patients cause partial GH insensitivity. Long-term treatment with rhGH doses in this NS child with a PTPN11 mutation, in whom a partial postreceptor GH insensitivity was expected, normalized IGF-I and IGFBP-3 levels, improved growth velocity and increased his final height prediction. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: A major objective when using recombinant human growth hormone (rhGH) in childhood is to attain the maximum sustained growth response that can be achieved in an individual child while avoiding adverse events and ensuring that biomarkers of response, such as insulin-like growth factor I (IGF-I), remain within acceptable limits. Conclusion: In practice, this is currently achieved by titrating GH dose against growth rate and serum IGF-I concentration. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: The autosomal-dominant Noonan syndrome (MIM 163950) is characterized by short stature, heart defects, characteristic facial dysmorphic features and other major and minor anomalies. Its incidence has been estimated to be 1 in 1,000 to 2,500 live births. Familial cases are frequent. Methods and Results: Recently, molecular data have suggested that deregulation of signaling through the Ras-mitogen-activated protein kinase (Ras-MAPK) pathway was the main molecular basis of Noonan syndrome. The frequently detected upstream defects of this pathway are gain-of-function mutations of PTPN11, which are associated with a mild form of growth hormone (GH) resistance and insulin-like growth factor I (IGF-I) deficiency, presumably due to interference with the Janus kinase 2 and signal transducer and activator of transcription 5b (JAK2-STAT) signaling of the GH receptor. Present data suggest reduced GH responsiveness in these cases. Conclusions: Downstream defects of the Ras-MAPK pathway (like K-ras mutations) do not affect the JAK2-STAT pathway, and therefore response to GH therapy is likely to be better in these cases. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: The increased risk for development of type 2 diabetes mellitus (T2DM) in adults with growth hormone deficiency (GHD) has been attributed to insulin resistance arising from increased visceral fat accumulation and the putative effects of low insulin-like growth factor I (IGF-I) levels on pancreatic β-cell mass and insulin secretion. Failure of GH replacement to reverse these abnormalities may reflect nonphysiological GH replacement or inability of the β-cell to recover. Methods and Results: We have demonstrated in normal subjects and in those with GHD that very low doses of GH can improve postabsorptive insulin sensitivity in direct relation to increased free IGF-I, reduce fasting glucose levels and potentially improve β-cell secretory capacity. Conclusions: These low doses of GH should prevent the development of T2DM in adult subjects, but this needs to be confirmed by long-term studies. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6, that are released in response to injury are thought to inhibit growth and cause muscle wasting, at least in part by inhibiting anabolic hormones such as insulin-like growth factor I (IGF-I). Because critical illness in humans is accompanied by high circulating concentrations of growth hormone (GH), which is the main stimulus for IGF-I production by the liver, resistance to GH is thought to contribute to the IGF-I decline observed in catabolic diseases. While TNF-α seems to cause GH resistance mainly through downregulation of liver GH receptor expression, IL-6 may inhibit the GH-stimulated Janus kinase and signal transducer and activator of transcription pathways by induction of suppressors of cytokine signaling proteins. Elevations in circulating IGF binding protein-1 levels, as observed in many catabolic situations, may play a role in the decline in muscle mass by decreasing the rate of protein synthesis in skeletal muscle. Furthermore, the increase in local muscle cytokines produced during inflammation makes the muscle GH-resistant and reduces its own IGF-I production. Finally, not only decreased IGF-I production by muscle, but also decreased muscle sensitivity to the anabolic effects of IGF-I, may contribute to muscle wasting observed in response to severe stress. Conclusions: Taken together, proinflammatory cytokines may contribute to the growth retardation and muscle wasting that occur after injury by impairing the GH/IGF-I axis at several levels. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The provision of dietary nutrients is a powerful method by which to alter plasma substrate and hormone concentrations, and to impact cell signalling and protein balance positively in skeletal muscle. Growth hormone, insulin-like growth factor I, testosterone, cortisol and insulin are each uniquely affected by dietary nutrients and exercise. This article summarizes some of the work that has been conducted to assess how diet affects these hormones, in particular the exercise-induced hormone response, with an emphasis on skeletal muscle as a target tissue. Clearly, certain combinations of nutrients, such as carbohydrate combined with protein, can be used to alter nutrient and hormone availability to augment skeletal muscle protein balance. There is a need to link acute diet-induced hormonal responses with chronic muscle adaptations to training, and to determine how chronic manipulations in diet affect training adaptations specific to skeletal muscle. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The precise effects of growth hormone (GH) and insulin-like growth factor I (IGF-I) on muscle development and physiology are relatively unknown. Furthermore, there have been conflicting reports on the effects of GH/IGF-I on muscle. Distinguishing the direct effects of GH versus those of IGF-I is problematic, but animal models with altered GH/IGF-I action could help to alleviate some of the conflicting results and help to determine the independent actions of GH and IGF-I. The phenotypes of several mouse models, namely the GH receptor-gene-disrupted (GHR –/–) mouse and a variety of IGF-I –/– mice, are summarized, which ultimately will aid our understanding of this complex area. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Growth hormone (GH) deficiency in adulthood, irrespective of aetiology, is associated with decreases in lean body mass (LBM) and muscle strength. Early studies indicated that GH replacement in adults with GH deficiency (GHD) normalized LBM and muscle strength, but these findings were complicated because the GH dose used in these early studies was calculated based on weight (as in children) and was subsequently found to be too high for adults, resulting in insulin-like growth factor I levels as high as those seen in individuals with acromegaly. More recent studies have, however, confirmed that GH replacement has a long-term beneficial effect on muscle mass and function in patients with GHD of all ages, although there appears to be a greater effect in normalizing muscle mass and function in young males and in adults with adult-onset GHD compared with those with childhood-onset GHD. Results also suggest that concomitant exercise training might further improve the outcome of GH replacement therapy. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The article presents abstracts on insulin-like growth factors or insulin-like growth factor binding protein including "Differential expression of IGF-I and IGFBPs in proliferating vs. differentiating growth plate chrondrocytes," "Comparative catch-up growth of height, foot and brain in children with Laron syndrome (LS) treated by IGF-1 to that of children with IGHD treated by HGH," and "Study of the IGF system in children with diabetes mellitus type-1 (DM-1)."

The article presents abstracts of research about thyroiditis. These include "Acute suppurative thyroiditis: prevalence and natural history in an Italian pediatric population," "Interaction of anthropometric indices, thyroid hormones, and IGF system in school children with goiter detected by palpation," and "Thyroid function in children treated with antiepileptic drugs."

Fetal growth is a complex process depending on the genetics of the fetus, the availability of nutrients and oxygen to the fetus, maternal nutrition and various growth factors and hormones of maternal, fetal and placental origin. Hormones play a central role in regulating fetal growth and development. They act as maturational and nutritional signals in utero and control tissue development and differentiation according to the prevailing environmental conditions in the fetus. The insulin-like growth factor (IGF) system, and IGF-I and IGF-II in particular, plays a critical role in fetal and placental growth throughout gestation. Disruption of the IGF1, IGF2 or IGF1R gene retards fetal growth, whereas disruption of IGF2R or overexpression of IGF2 enhances fetal growth. IGF-I stimulates fetal growth when nutrients are available, thereby ensuring that fetal growth is appropriate for the nutrient supply. The production of IGF-I is particularly sensitive to undernutrition. IGF-II plays a key role in placental growth and nutrient transfer. Several key hormone genes involved in embryonic and fetal growth are imprinted. Disruption of this imprinting causes disorders involving growth defects, such as Beckwith-Wiedemann syndrome, which is associated with fetal overgrowth, or Silver-Russell syndrome, which is associated with intrauterine growth retardation. Optimal fetal growth is essential for perinatal survival and has long-term consequences extending into adulthood. Given the high incidence of intrauterine growth retardation and the high risk of metabolic and cardiovascular complications in later life, further clinical and basic research is needed to develop accurate early diagnosis of aberrant fetal growth and novel therapeutic strategies. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Children born small for gestational age (SGA) are at high risk of permanent short stature, with approximately 10% continuing to have stature below the third centile throughout childhood and adolescence and into adulthood. The mechanisms involved in catch-up growth, and those that prevent catch-up growth, are still unknown. To date, no reliable anthropometric or endocrine parameter predictive of postnatal catch-up growth has been identified. However, subtle abnormalities in the growth hormone-insulin-like growth factor axis, the hypothalamic-pituitary-adrenal axis and thyroid function have been described, and a mechanism involving intrauterine programming of hypothalamic-pituitary function has been proposed. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

There is still a lack of data from randomized, controlled, long-term studies of growth hormone (GH) treatment in children born small for gestational age (SGA), but the available evidence indicates consistently that GH therapy is a valid growth-promoting treatment in these children, particularly if started early. Whilst side effects appear uncommon, ongoing surveillance is required and treated children should be monitored for changes in glucose homeostasis, lipid profiles and blood pressure, especially during puberty. We provide an update on the safety and efficacy of GH treatment in short children born SGA. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The article focuses on the insulin-like growth factor-I (IGF-I) system, which is described as the major mediator of both intra-uterine and postnatal growth. The IGF-I receptor appears to mediate the growth-promoting effects of both IGF-I and IGF-II. The role of IGF binding proteins in mediating the growth-promoting actions of the IGF is complex and remains incompletely understood.

The article discusses the effects of insulin-like growth factor-I (IGF-I) therapy on bone growth, metabolism and multiple body systems. Treatment of children with terrible primary IGF-I deficiency due to growth hormone insensitivity syndrome with IGF-I effectively promotes statural growth. As the cellular targets of IGF-I and specific biological effects attributed to the IGF are manifold, therapeutic uses of IGF-I apart from increases in stature should be explored.

Aims/Methods: We established age- and sex-related reference ranges for serum insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) levels in 807 healthy Turkish children (428 boys, 379 girls), and constructed a model for calculation of standard deviation scores of IGF-I and IGFBP-3 according to age, sex and pubertal stage. Results: Serum IGF-I and IGFBP-3 concentrations tended to be higher in girls compared to boys of the same ages, but the differences were statistically significant only in pubertal ages (9–14 years) for IGF-I and only in prepubertal ages for IGFBP-3 (6–8 years) (p < 0.05). Peak IGF-I concentrations were observed earlier in girls than boys (14 vs. 15 years, Tanner stage IV vs. V) starting to decline thereafter. IGFBP-3 levels peaked at age 13 and at Tanner stage IV in both sexes with a subsequent fall. Serum levels of IGF-I and IGFBP-3 increased steadily with age in the prepubertal stage followed by a rapid increase in IGF-I in the early pubertal stages. A relatively steeper increase in IGF-I but not in IGFBP-3 levels was observed at age 10–11 years in girls and at 12–13 years in boys which preceded the reported age of pubertal growth spurt. At late pubertal stages, both IGF-I and IGFBP-3 either did not change or decreased by increasing age. Interrelationships between growth factors and anthropometric measurements have been described, and the physiologic consequences of these have been discussed in detail. Conclusions: Differences in the pattern of IGF-I and IGFBP-3 in the present paper and those reported in other studies emphasize the importance of locally established reference ranges. Establishment of this reference data and a standard deviation score prediction model based on age, sex and puberty will enhance the diagnostic power and utility of IGF-I and IGFBP-3 in evaluating growth disorders in our population. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aims: Decreased GH and IGF-I levels and increased GH responsiveness are frequently reported in obesity. As GH-deficient adults are commonly obese, the role of obesity in affecting hepatic responsiveness of IGF-I generation to GH stimulation is unclear in severe GH-deficient states. To address this question, we challenged a cohort of severely GH-deficient non-obese and obese adults with a fixed low GH dose (0.2 mg/day), and examined the relationship of body mass index (BMI) with IGF-I response. Methods: 12 non-obese (6 males, median BMI 24.7 kg/m2) and 14 obese (7 males, median BMI 45.2 kg/m2) adults with severe GH deficiency were studied for 8 weeks. Blood samples were collected at baseline, and weeks 4 and 8. Results: There was a larger increment and reduced variability of IGF-I levels in obese compared to non-obese GH-deficient adults at week 8, but not at week 4. A similar but smaller increment and less variability was observed with IGFBP-3. Increment IGF-I positively correlated with baseline BMI at weeks 4 (r = 0.49, p < 0.02) and 8 (r = 0.47, p < 0.02). No gender differences were observed with the IGF-I and IGFBP-3 response. Conclusions: This study demonstrates that there is a larger increment and deceased individual variability of IGF-I to the low GH replacement dose in obese compared to non-obese adults with severe GH deficiency, regardless of gender. The positive association of IGF-I increment with BMI implies a greater impact of obesity rather than GH deficiency in enhancing hepatic sensitivity to GH. These findings, thus, question the reliability of interpreting single serum IGF-I levels in non-obese adults with severe GH deficiency treated with low GH replacement doses. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Growth hormone (GH) and insulin-like growth factor I (IGF-I) are expressed in specific regions of the central nervous system during early human development. They may consequently influence aspects of cognition, or emotional and behavioural adjustment from childhood to adulthood, in conditions associated with abnormalities of the somatotropic axis. GH receptors are relatively common within hippocampal and perihippocampal regions that are primarily involved in declarative memory for facts and events. They are also located in structures (e.g. the putamen) that are involved in the processing of social perceptions. IGF-I receptors have been discovered in the amygdala and prefrontal cortex, which contribute to the neural circuits known as the ‘social brain’. The evaluation of emotional, social and behavioural adjustment among children who have deficiencies in GH or IGF-I functional integrity requires the objective assessment of their social-cognitive competence. We describe a computerized test battery, the Schedules for the Assessment of Social Intelligence (SASI), which has been shown to possess excellent psychometric properties in terms of reliability and validity. The SASI, which can be used by both children and adults, may provide new evidence for deficits and treatment effects of GH/IGF-I on emotional, behavioural and cognitive functions. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The clinical condition of growth hormone deficiency (GHD) as a consequence of pituitary or hypothalamic disease has been associated with reduced cognitive performance. In several studies, neuropsychological assessment has been performed in adults with GHD both before and after growth hormone (GH) replacement therapy. Interpretation of the available data is complicated by the variation in patient selection as well as the neuropsychological tests used in such studies. Most of the available studies indicate that GHD can lead to small, but clinically relevant changes in memory, processing speed and attention. Some of these changes may be reversed by GH replacement, although the number of reliable intervention studies is limited. In addition to the possible clinical relevance of neuropsychological improvement following GH replacement in patients with GHD, the observed findings may be of interest for studies in neurocognitive performance in other conditions associated with changes in the activity of the somatotrophic axis, and in the understanding of underlying pathophysiological mechanisms. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

In healthy adults insulin-like growth factor (IGF)-I levels do not differ between males and females, whereas spontaneous growth hormone (GH) secretion is approximately twofold higher in females. Untreated GH-deficient (GHD) women exhibit lower IGF-I levels compared with men and the increase in serum IGF-l during GH replacement is also significantly less. These data suggest a resistance to GH in women, which in healthy subjects is compensated for by increased GH secretion. Administration of oral oestrogen in healthy postmenopausal women suppresses hepatic IGF-I production and increases pituitary GH release, and oral oestrogen replacement in women with GHD lowers IGF-I concentrations and increases the amount of GH necessary to achieve IGF-I target levels during treatment. These data clearly suggest that hepatic suppression of IGF-I production by oestrogen subserves the gender difference in GH sensitivity, but it is also likely that sex steroids may interact with the GH/IGF axis at other levels. There is also circumstantial evidence to indicate that testosterone stimulates IGF-l production and it is speculated that a certain threshold level of androgens is essential to ensure hepatic IGF-l production. Whether these data should translate into earlier discontinuation of oestrogen replacement therapy in women with hypopituitarism merits consideration. [ABSTRACT FROM AUTHOR]

Biochemical assessment of growth hormone (GH) status is required in both suspected GH deficiency and GH excess. GH secretion can either be measured through investigation of the pituitary or by monitoring markers that change as a consequence of GH action on its target tissues. The two most widely used and, to date, best validated biochemical parameters are immunoassay measurement of either human GH (hGH) or insulin-like growth factor (IGF)-l. The fundamental difference between measurement of hGH and IGF-l is that the first reflects GH secretion while the second reflects GH action. However, because GH secretion is pulsatile in nature, random blood sampling for determination of hGH levels is only minimally informative. Analytical methods for measuring GH and IGF-l show considerable between- method variability. Since these parameters are used in establishing diagnoses and in monitoring GH-related diseases, the endocrinologist should be aware of the specifications and limitations of the analytical methods available. [ABSTRACT FROM AUTHOR]

Aims: The aim of our in vitro studies was to understand the role of leptin and the insulin-like growth factor I/insulin-like growth factor protein (IGF/IGFBP) system in controlling human ovarian function. Methods: We studied the action of leptin (0, 1, 10, or 100 ng/ml) and immunoneutralization of IGF-I using specific antiserum (0.1%) on the release of progesterone (P), estradiol (E), oxytocin (OT), IGF-I, IGFBP-3, and prostaglandins F (PGF) by these cells using radioimmunoassay/immunoradiometric assay. Results: It was found that leptin stimulated the secretion of OT, IGFBP-3, and PGF. It suppressed the secretion of E and IGF-I, but not P, into the medium. The addition of antiserum against IGF-I decreased IGF-I output, increased P, OT, IGFBP-3, and PGF secretion, and had no effect on E release. Immunoneutralization of IGF-I also prevented or reversed the effects of leptin on P, E, IGF-I, IGFBP-3, PGF, but not on OT. Conclusions: These observations (1) demonstrate that leptin directly controls the secretory activity of human ovarian cells, (2) confirm the involvement of IGF-I in the regulation of ovarian cells, and (3) suggest an inter-relationship between leptin and the IGF/IGFBP system in the control of these functions and the involvement of IGF/IGFBP system in mediating leptin action on the ovary. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aim: To report effects of weight-based recombinant human insulin-like growth factor-I (rhIGF-I) on IGF axis parameters in children with hyperinsulinism. Methods: Open label trial with subcutaneous rhIGF-I (40 μg/kg/dose). Patients studied were children (1 month to 11 years) with diffuse hyperinsulinism (n = 7). Serial serum IGF and insulin-like growth factor binding protein (IGFBP) concentrations were measured by RIA and analyzed by linear Pearson regression. Results: Following the initial rhIGF-I dose, total insulin-like growth factor-I (IGF-I) rose by 56% at 30 min (p < 0.01) and 85% at 120 min (p < 0.02). Serum IGF-II, IGFBP-2, and IGFBP-3 levels did not change. Peak serum IGF-I levels within 12 h of the initial rhIGF-I dose were 167–700 mg/ml. The variable peak IGF-I response is attributable in part to IGFBP-3 differences across this pediatric age range. Models of rhIGF-I dosing based upon body surface area (BSA) or initial IGFBP-3 resulted in predictable peak serum IGF-I levels (r = 0.78; p < 0.03). Recalculating rhIGF-I dosing based upon the BSA · IGFBP-3 product correlated closely with peak IGF-I level (r = 0.85; p < 0.007). Conclusions: Weight-based IGF-I dosing in this cohort resulted in variable IGF-I levels. Considering BSA and serum IGFBP-3 concentration in children is appropriate for subcutaneous IGF-I administration. A combination of these values may yield predictable individualization of rhIGF-I dosing. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aims: Numerous clinical and experimental studies suggest that growth factors may contribute to the development of diabetic microvascular complications. The aim of the study was to test the hypothesis that in adolescents with type-1 diabetes mellitus and microalbuminuria (MA) there are specific disorders of serum insulin-like growth factor-1 (IGF-1) and concentrations of its binding proteins, IGFBP-1 and IGFBP-3, that could be of importance in the pathogenesis of microvascular diabetic complications. Methods: 25 adolescents with MA, 24 adolescents with diabetes without complications, and 17 controls were examined. There were no differences with regard to age, puberty stage, HbA1c and body mass index between the groups examined. Two of the patients in the first group also had diabetic retinopathy. Serum fasting concentrations of IGF-1 and overnight urine albumin concentrations were measured by radioimmunoassay, IGFBP-1 and IGFBP-3 concentrations by immunoradiometric assay and HbA1c by high-performance liquid chromatography methods. Diabetic patients were examined by an experienced ophthalmologist and neurologist. The data were analyzed using Kruskal-Wallis ANOVA and multiple regression analysis. Results: Significantly lower IGF-1 concentrations were found in adolescents with diabetes and MA compared to diabetic patients without complications and healthy contemporaries. IGFBP-1 concentrations were significantly higher and IGFBP-3 concentrations were statistically lower in diabetic patients with MA than in patients without complications. Conclusions: The IGF-IGFBP system is deranged in adolescents with type-1 diabetes mellitus and MA. Our results suggest the participation of circulating IGFBP-1 in the origin of diabetic complications. It could be also possible that IGFBP-3 takes part in the protection from them. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Recent animal studies have demonstrated evidence of the involvement of insulin and insulin-like growth factor (IGF)-I signalling in the control of ageing and longevity. Disruption of insulin/IGF-I signalling pathways significantly extends lifespan in several animal models. Similarities among these signalling pathways in animals and humans raise the possibility that modifications in the IGF-I signalling system could also extend lifespan in humans. However, in contrast to the findings in animal studies, reduced IGF-I activity in humans is not associated with longevity. In humans, low IGF-I activity is even associated with an increased risk of developing cardiovascular disease and diabetes. High IGF-I activity in humans is associated with an increased risk of developing cancer. In addition, genetic predisposition and lifestyle play a major role in determining age-associated disease. For each individual there is probably a specific optimal ‘setpoint’ for the insulin/growth hormone/IGF-I axis which co-determines survival. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aims: To study the relationships between serum IGF-1, IGFBP-3 and IGFBP-2 and interleukin (IL)-1β and IL-6 in inflammatory bowel disease (IBD). Methods: Thirty-seven patients (18 males, 19 females, aged 8.8–26.1 years) with IBD (Crohn’s disease, CD, n = 17, and ulcerative colitis, UC, n = 20) were studied. Patients were in relapse or remission according to established criteria. Serum IGF-1, IGFBP-3, IGFBP-2, IL-1β and IL-6 levels were determined in patients and 15 healthy controls (aged 8.2–19.0 years). Results: IGF-1 levels were lower in patients with CD in relapse compared with controls (p < 0.05). IGFBP-2 levels were higher in CD in relapse compared with other groups (all p < 0.05). In CD and UC patients (n = 37), IGF-1 levels were inversely correlated with the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). IGFBP-2 levels correlated positively with ESR and IL-1β. IL-6 levels correlated positively with ESR and CRP. IL-1β levels were elevated in CD in relapse compared to controls (p < 0.05) and were higher in UC in relapse than in other groups (all p < 0.05). In combined CD/UC patients in relapse (n = 20), IL-1β levels were higher (p < 0.05) in patients with recto-sigmoiditis (n = 5) than in other patients. Conclusions: IGF-1, IGFBP-2 levels were related to IL levels, disease activity and anatomical distribution, consistent with active inflammation modifying the IGF-IGFBP system, possibly relevant to disturbance of growth. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Recombinant human growth hormone (GH) has been shown to be efficacious and safe in the treatment of various growth disorders and GH deficiency. We here report a 61-year-old man with idiopathic hypopituitarism in whom clinically active acromegaly developed. Complete GH deficiency had been diagnosed earlier by arginine stimulation testing, and therapy with recombinant human GH (maintenance dose 2 IU/day) was implemented at the age of 54 years. At presentation, the patient’s insulin-like growth factor 1 (IGF-1; 439 ng/ml) and insulin-like growth factor binding protein 3 (4.3 mg/l) levels were highly elevated. Endogenous GH production and pituitary adenoma were excluded. Retrospectively, IGF-1 levels up to 621 ng/ml had been documented (but not appreciated) in the preceding 7 years. Upon GH dose reduction, the IGF-1 serum levels returned to normal, and the patient’s clinical status stabilized. No GH receptor polymorphisms were identified in the patient’s genomic DNA. This observation demonstrates that the indiscriminate use of recombinant GH bears the risk of active acromegaly, emphasizing the need for long-term patient monitoring programs as integral part of GH therapy. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Growth hormone (GH) deficiency in children covers a spectrum of disorders involving an impairment in GH secretion and a clinical syndrome characterized by permanent stunting of growth. Ascertaining impairments in GH secretion directly is complex, especially if GH deficiency (GHD) is isolated and not caused by congenital or acquired pituitary defects or genetic abnormalities. It has been established that the concentrations of GH-dependent peptides, such as insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3), are low in patients with GHD. Their levels are, however, also influenced by a multitude of factors, such as age, gender, height, liver function, nutritional status and other hormones. In addition, the type of complex formed, e.g. either binary or ternary, may influence the measurements of IGFs and their binding proteins. Therefore, levels of IGF-I and IGFBP-3 are generally lower in short children compared with age-matched norms. The reported diagnostic value of sub-normal basal levels of IGF-I and IGFBP-3 is, in terms of sensitivity and specificity, approximately 70%. Thus, definite proof of GHD can only be achieved by means of GH measurements. As the diagnosis of GHD is somewhat unlikely if IGF testing shows normal values, it is clearly advantageous to schedule these tests as part of the initial diagnostic work-up in short children, as their implementation is not only practical but also inexpensive. The Pfizer International Growth Database (KIGS) analysis of IGF-I (n = 2,750) and IGFBP-3 (n = 1,300) levels in children with idiopathic GHD shows that these two parameters are now firmly embedded in diagnostic strategies around the world. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Measurement of insulin-like growth factor I (IGF-I) levels is used during the assessment of a child for the presence of growth hormone (GH) deficiency and to monitor the efficacy of GH replacement therapy. In either case, robust normative data are required to allow IGF-I values to be expressed as standard deviation scores, enabling comparison between individuals and assessment of change over time. However, IGF-I levels in healthy children are affected by a number of parameters, including age, gender, pubertal status, height, nutrient intake, body composition, intercurrent illness and ethnicity, and the generation of such data requires the collection of samples from significant numbers of healthy children. As external quality assurance schemes for IGF-I and an international standard based on authentic recombinant IGF-I are not widely used, it is imperative for the clinician to understand the performance characteristics and limitations of the IGF-I assay used and to be aware of the source and quality of control data. It must also be recognized that IGF-I measurement is only one component of the diagnostic process and has its limitations, as tissue sensitivity to circulating serum IGF-I levels will differ between individuals. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Insulin-like growth factor I (IGF-I) has significant structural homology with insulin. IGF-I has been shown to bind to insulin receptors to stimulate glucose transport in fat and muscle, to inhibit hepatic glucose output and to lower blood glucose while simultaneously suppressing insulin secretion. However, the precise role of IGF-I in maintaining normal glucose homeostasis and insulin sensitivity is not well defined. Studies in patients with diabetes have shown that in insulin-deficient states, serum IGF-I concentrations are low and increase with insulin therapy. Similarly, administration of insulin via the portal vein results in optimization of plasma IGF-I concentrations. A patient with an IGF1 gene deletion was shown to have severe insulin resistance that improved with IGF-I therapy. Studies conducted in experimental animals have shown that if IGF-I synthesis by the liver is deleted, the animals become insulin-resistant, and this is improved when IGF-I is administered. Likewise, deletion of the IGF-I receptor in muscle in mice induces severe insulin resistance. Administration of IGF-I to patients with type 2 diabetes mellitus has been shown to result in an improvement in insulin sensitivity and a reduction in the requirement for exogenously administered insulin to maintain glucose homeostasis. A polymorphism in the IGF1 gene that has been shown to reduce serum IGF-I results in an increased prevalence of type 2 diabetes. Taken together, these findings support the conclusion that IGF-I is necessary for normal insulin sensitivity, and impairment of IGF-I synthesis results in a worsening state of insulin resistance. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Insulin-like growth factor I (IGF-I) levels mainly reflect secretion of growth hormone (GH) in the body. The aims of this study were to compare different IGF-I assay methods in healthy individuals, test the reliability of the methods and discuss the utility of IGF-I measurement in adults. The Nichols Institute Diagnostics radioimmunoassay was used to evaluate IGF-I in two random population samples of men and women (aged 25–64 years, n = 392) taken 10 years apart, in 1985 and 1995. This method for IGF-I testing was also compared with an immunoradiometric assay (IRMA) method in 387 men and women participating in the World Health Organization MONICA (MONItoring of trends and determinants for CArdiovascular diseases) Project, Göteborg, Sweden, in 1995. Serum IGF-I decreased with increasing age in both men and women. IGF-I was higher in young women compared with young men in both cohorts, while the opposite was found in the highest age group. Age-adjusted significant correlations were found between IGF-I and smoking, fibrinogen, coffee consumption, lipoprotein (a), osteocalcin and IGF-binding protein 3. The two cohorts showed similar mean IGF-I concentrations irrespective of method. The correlation between the Nichols and the IRMA methods was high: r = 0.93 (p < 0.0001). Based on this and previous studies, population-based IGF-I measurements are robust irrespective of which commercially available method of assay is used. IGF-I levels can be used in diagnosing acromegaly as well as providing target values. IGF-I assay can be used as a complement to stimulation testing in the diagnosis of GH deficiency, and as a tool for GH dose titration. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Growth hormone (GH) therapy has evolved rapidly over the past decade, and continuing research has established a clear role for therapeutic GH in a wide spectrum of disorders, including idiopathic GH deficiency (childhood- and adult-onset), Turner syndrome, Prader-Willi syndrome, small-for-gestational age children with failure of catch-up growth, AIDS-related catabolism, children with chronic renal failure, and idiopathic short stature. Although GH is used therapeutically in a wide variety of conditions, actual guidelines regarding the logistics of GH dosing continue to evolve, with data emerging regarding efficacy and safety. This review proposes a role for insulin-like growth factor I measurement in optimizing GH dosing. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The current guidelines state that, within the appropriate clinical context, the diagnosis of adult growth hormone (GH) deficiency must be made biochemically using provocative tests. Measurement of insulin-like growth factor I (IGF-I) and binding protein 3 (IGFBP-3) levels cannot always distinguish between healthy and GH-deficient individuals. In particular, IGFBP-3 as a marker of GH status is clearly less sensitive than IGF-I and there is general agreement that its measurement does not provide useful diagnostic information. However, the diagnostic value of measuring IGF-I levels has been revisited recently. It has been confirmed that normal IGF-I levels do not rule out severe GH deficiency (GHD) in adults, in whom the diagnosis has therefore to be based on the demonstration of severe impairment of the peak GH response to provocative tests. It has also been emphasized that very low IGF-I levels in patients with high suspicion of GHD could be considered to be definite evidence for severe GHD. This assumption particularly applies to patients with childhood-onset, severe GHD or with multiple hypopituitary deficiencies acquired in adulthood. In addition, the use of IGF-I levels to monitor the efficacy and adequacy of recombinant human GH replacement remains widely accepted. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Inactivation of insulin-like growth factor I (IGF-I) signalling pathways have been shown to extend lifespans in various lower species, including the nematode Caenorhabditis elegans. In order to investigate this relationship in a mammalian species, a series of experiments were carried out with a mouse model heterozygous for a mutation in the IGF-I receptor gene. These heterozygous mice only had slight post-natal growth retardation, but had a lifespan 26% longer than normal. Their fertility and dietary intake were unaffected. The mechanism for increased lifespan in these mutant mice appears to be enhanced resistance to oxidative stress: heterozygous mice had a greater survival rate subsequent to severe oxidative stress generated in vivo than wild-type mice, and cells from heterozygous animals had a better resistance to hydrogen peroxide in vitro than cells from wild-type animals. Resistance to oxidative stress in these mutant animals could be caused by decreased phosphorylation of molecules downstream of the IGF-I receptor in the IGF-I signalling pathway, one of which is thought to be p66shc. Whether this link between reduced IGF-I signalling and longevity is conserved in other mammalian species, including humans, is presently not known. If it was, it could have implications for growth hormone therapy, which increases serum IGF-I levels. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The insulin-like growth factor I (IGF-I) generation test has the potential to assess the ability of an individual to respond to an acute bolus of growth hormone (GH), in terms of IGF-I, IGF-binding protein 3 and acid-labile subunit responses. This article will discuss something of the history of the IGF-I generation test, and review some of the major studies to date. The IGF-I generation test was first used in adults by Lieberman et al., who studied the effects of ageing and oestrogen administration, and suggested that decreased responsiveness to GH occurs with increasing age and oral oestrogen administration. Our results, however, show that, while activity of the GH/IGF-I axis declines with age, peripheral responsiveness to GH is not affected. As in the Lieberman study, we found that oral oestrogen replacement reduces responses of GH-dependent peptides to GH stimulation in healthy post-menopausal women. Transdermal oestrogen administration also reduced responsiveness to GH, although to a lesser degree than orally administered oestrogen. In addition, utilizing a non-weight-based dose of GH we have demonstrated that obese individuals produce greater increases in IGF-I following an acute bolus of GH. In GH deficiency (GHD), data suggesting enhanced peripheral responsiveness should be interpreted with caution, and with awareness of differences between these groups in terms of age and obesity. The IGF-I generation test may allow a fresh approach to unanswered questions in the field of GHD, but as the IGF-I response to GH is not strictly associated with protein anabolism or clinical benefit, the question remains whether this test will predict the effect of longer-term GH administration. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Determinations of serum concentrations of total insulin-like growth factor I (tIGF-I) are important in the diagnosis, monitoring of treatment and safety evaluation of patients with growth disorders and/or metabolic disease. It is well established that tIGF-I status varies over time. Changes in tIGF-I levels in relation to an acute bout of exercise or repeated bouts, known as training, are likely to contribute to this variation. Serum tIGF-I has also been found to be of predictive value in growth prediction models employed before the start of growth hormone (GH) treatment. Furthermore, IGF-I generation tests have been suggested to be of value in the assessment of the growth response to GH administration in patients suspected of GH deficiency with or without some degree of GH insensitivity. This is discussed elsewhere in this issue. Recent progress in our understanding of growth hormone-dependent and -independent expression of the IGF1 gene in skeletal muscle and the role of sufficient energy intake during training for muscle and liver generation of IGF-I raises important questions regarding their relative contribution to the circulating pool of IGF-I. The present review is focused on circulating levels of tIGF-I in relation to a single bout of exercise or to a period of training. In addition, the expression of IGF-I locally in muscle in response to these stimuli will be discussed. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]