Low Insulin-like Growth factor-I Levels Research Articles

The effects of exercise on spatial learning and anxiety-like behavior are mediated by an IGF-I-dependent mechanism related to hippocampal neurogenesis

Knowledge about the effects of physical exercise on brain is accumulating although the mechanisms through which exercise exerts these actions remain largely unknown. A possible involvement of adult hippocampal neurogenesis (AHN) in the effects of exercise is debated while the physiological and pathological significance of AHN is under intense scrutiny. Recently, both neurogenesis-dependent and independent mechanisms have been shown to mediate the effects of physical exercise on spatial learning and anxiety-like behaviors. Taking advantage that the stimulating effects of exercise on AHN depend among others, on serum insulin-like growth factor I (IGF-I), we now examined whether the behavioral effects of running exercise are related to variations in hippocampal neurogenesis, by either increasing or decreasing it according to serum IGF-I levels. Mutant mice with low levels of serum IGF-I (LID mice) had reduced AHN together with impaired spatial learning. These deficits were not improved by running. However, administration of exogenous IGF-I ameliorated the cognitive deficit and restored AHN in LID mice. We also examined the effect of exercise in LID mice in the novelty-suppressed feeding test, a measure of anxiety-like behavior in laboratory animals. Normal mice, but not LID mice, showed reduced anxiety after exercise in this test. However, after exercise, LID mice did show improvement in the forced swim test, a measure of behavioral despair. Thus, many, but not all of the beneficial effects of exercise on brain function depend on circulating levels of IGF-I and are associated to increased hippocampal neurogenesis, including improved cognition and reduced anxiety.

Serum insulin-like growth factor I and ischemic brain injury

Serum insulin-like growth factor I (IGF-I), which is mostly produced by the liver, has recently been shown to have the unexpected ability to modulate normal brain function as well as brain response to injury. Moreover, serum IGF-I levels are modified in many brain diseases, including stroke. However, whether these modifications are related to the disease process remains uncertain. We now examined a potential relationship between serum IGF-I and ischemic brain injury after middle cerebral artery occlusion (MCAo) and reperfusion in mice with either high or low serum IGF-I levels prior to insult. Surprisingly, we found that chronic high serum IGF-I correlates with increased brain infarct size following MCAo, while low levels correlate with reduced lesion size. Immunocytochemistry and immunoblot analyses revealed that levels of phosphorylated (i.e., activated) MAPK, known to be associated with the severity of ischemic brain injury, were increased in IGF-I treated mice. No overall effect of IGF-I treatment on IGF family mRNA expression in the brain was observed. Altogether, these results indicate that serum IGF-I levels negatively correlate with stroke outcome. Therefore, lowering serum IGF-I levels in aging mammals, including humans, may be beneficial against the increased risk of stroke associated to old age.

Session 7: Early nutrition and later health early developmental pathways of obesity and diabetes risk.

Size at birth and patterns of postnatal weight gain have been associated with adult risk for the development of type 2 diabetes in many populations, but the putative pathophysiological link remains unknown. Studies of contemporary populations indicate that rapid infancy weight gain, which may follow fetal growth restriction, is an important risk factor for the development of childhood obesity and insulin resistance. Data from the Avon Longitudinal Study of Pregnancy and Childhood shows that rapid catch-up weight gain can lead to the development of insulin resistance, as early as 1 year of age, in association with increasing accumulation of central abdominal fat mass. In contrast, the disposition index, which reflects the beta-cells ability to maintain insulin secretion in the face of increasing insulin resistance, is much more closely related to ponderal index at birth than postnatal catch-up weight gain. Infants with the lowest ponderal index at birth show a reduced disposition index at aged 8 years associated with increases in fasting NEFA levels. The disposition index is also closely related to childhood height gain and insulin-like growth factor-I (IGF-I) levels; reduced insulin secretory capacity being associated with reduced statural growth, and relatively short stature with reduced IGF-I levels at age 8 years. IGF-I may have an important role in the maintenance of beta-cell mass, as demonstrated by recent studies of pancreatic beta-cell IGF-I receptor knock-out and adult observational studies indicating that low IGF-I levels are predictive of subsequent risk for the development of type 2 diabetes. However, as insulin secretion is an important determinant of IGF-I levels, cause and effect may be difficult to establish. In conclusion, although rapid infancy weight gain and increasing rates of childhood obesity will increase the risk for the development of insulin resistance, prenatal and postnatal determinants of beta-cell mass may ultimately be the most important determinants of an individual's ability to maintain insulin secretion in the face of increasing insulin resistance, and thus risk for the development of type 2 diabetes.

IGF-I measurements in the diagnosis of adult growth hormone deficiency

Although serum insulin-like growth factor I (IGF-I) concentrations have utility as a screening test for growth hormone (GH) deficiency in children and young adults, they are less accurate for screening in adults over 40 years of age. There are two main limitations in the clinical use of IGF-I levels as a marker of GH secretion. First, IGF-I synthesis is not only regulated by GH but also by nutrient supply and by other hormones; second, low IGF-I levels in the presence of normal or increased GH secretion may reflect a peripheral resistance to GH action. Although serum IGF-I cannot be used as a stand-alone test for the diagnosis of adult GH deficiency, very low IGF-I levels in the context of documented hypothalamic or pituitary disease may be helpful in identifying patients with a high probability of GH deficiency. In the presence of two or more additional pituitary hormone deficiencies, an IGF-I level <84 microg/l (assayed by Esoterix Endocrinology, Inc. Calabasas Hills, CA, USA) indicates a 99% probability of GH deficiency. As this cut-off value has not been validated for other IGF-I assays, an IGF-I standard deviation score (SDS) of <-3 may be considered in adults over age 28; an even lower IGF-I SDS is needed for diagnosis in younger adults. In clinical practice, other causes of low serum IGF-I such as malnutrition, diabetes, hypothyroidism, liver disease, etc., should be excluded before applying these diagnostic criteria.

The Relationship in Japanese Infants between a Genetic Polymorphism in the Promoter Region of the Insulin-Like Growth Factor I Gene and the Plasma Level

Background: Evidence is accumulating that the promoter region of the insulin-like growth factor I (IGF-I) gene polymorphism and low levels of IGF-I are associated with type 2 diabetes, cardiovascular disease and birth weight; however, the number of wild-type alleles is different in each country. Objectives: This study aimed to examine the 737/738 marker, a cytosine–adenine repeat in the promoter region of the IGF-I gene polymorphism, and plasma IGF-I levels in Japanese infants and analyze the genetic background. Methods: Data were collected for 15 months in Kyoto Prefectural University of Medicine. The body composition parameters of all infants were determined at birth. At 5 days after birth, we took blood samples to measure the product size of the promoter region of the IGF-I gene polymorphism and plasma IGF-I. Results: In a population-based sample of 160 subjects, 6 different alleles and 16 genotypes were identified in the promoter region of the IGF-I gene polymorphism. The existence of a 196-bp allele has proved to result in a low plasma IGF-I level, a small head and chest circumference (p < 0.05) and no significant for premature birth, short-birth height and low-birth weight. Conclusions: This is the first study showing the role of the promoter region of the IGF-I gene polymorphism and the level of plasma IGF-I and body composition parameters in Japanese infants. Our results suggest genetical influence on prenatal growth and serum IGF-I levels.

Effects of feeding two levels of propionibacteria to dairy cows on plasma hormones and metabolites

To determine the effect of feeding propionibacteria on metabolic indicators during lactation, multiparous and primiparous Holstein cows were fed one of three dietary treatments in a 2 x 3 factorial design from 2 weeks prepartum to 30 weeks post partum: (1) Control (primiparous n=5, multiparous n=8) fed a total mixed ration (TMR); (2) high-dose group (primiparous n=6, multiparous n=5) fed TMR plus 6 x 10 (11) cfu/head daily (high-dose P169) of propionibacterium strain P169; or (3) low-dose group (primiparous n=8, multiparous n=6) fed TMR plus 6 x 10(10) cfu/head daily (low-dose P169) of P169. Blood samples were collected weekly and analysed for plasma concentrations of glucose, insulin, insulin-like growth factor-I (IGF-I), leptin, nonesterified fatty acids (NEFA) and cholesterol. Between weeks 25 and 30, all groups received bovine somatotropin (bST) every 2 weeks. Low-dose P169 multiparous cows had lower (P<0.05) plasma insulin and glucose concentrations than high-dose P169 multiparous cows, whereas high-dose P169 primiparous cows had lower glucose but greater insulin concentartions than low-dose P169 primiparous cows (P<0.05). Plasma insulinratioglucose molar ratios were 13-18% lower (P<0.05) in low-dose P169 cows than in control or high-dose P169 cows. Plasma IGF-I, NEFA and leptin levels did not differ among diet groups between weeks 1 and 25. Low-dose P169 multiparous cows had 25% greater plasma cholesterol levels than high-dose P169 and control multiparous cows, but cholesterol levels in primiparous cows did not differ. During bST treatment, high-dose P169 multiparous cows and low-dose P169 primiparous cows had lower IGF-I levels than their respective controls and, regardless of parity, high-dose P169 cows had greater NEFA than control cows. Although supplemental feeding of P169 altered plasma hormones and metabolites, the particular effects were dependent on dose of P169 and parity of cows.

RELATIONSHIP OF SERUM AND VITREOUS VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF), INSULIN-LIKE GROWTH FACTOR I, AND SOLUBLE VEGFR-1 IN A RAT MODEL FOR RETINOPATHY OF PREMATURITY.

Insulin-like growth factor I (IGF-I) is necessary for vascular growth in the neonatal retina by acting as a permissive factor for vascular endothelial growth factor (VEGF) angiogenic activity. Low IGF-I levels in serum from extremely premature newborn infants were found to be predictive for retinopathy of prematurity (ROP). Soluble VEGFR-1 (sVEGFR-1) blocks VEGF activity by binding VEGF and preventing activation of its receptors. We examined the relationship of serum and vitreous VEGF, sVEGFR-1, and IGF-I in rats exposed to repeated cycles of hyperoxia with brief episodes of hypoxia (simulating oxygen fluctuations seen in preterm infants). At birth (P0), newborn rats were exposed to alternating cycles of 50% oxygen followed by brief episodes of 12% oxygen for 7 and 14 days. Rats were sacrificed immediately following 7-day (7DO2) or 14-day (14DO2) hyperoxia or allowed to recover in room air until P21 (7DO2/14DRA and 14DO2/7DRA). Room air littermates were sacrificed at P7 (7DRA), P14 (14DRA), and P21 (21DRA). Retinal vasculature; and serum and vitreous levels of VEGF, sVEGFR-1, and IGF-I were examined. All hyperoxia-exposed retinas displayed evidence of neovascularization with “plus disease.” In the serum, VEGF levels (pg/mL) were elevated with 7DO2/14DRA (15.4 ± 1.3, p

Serum Insulin-Like Growth Factor-I Levels Among Women in Hawaii and Japan With Different Levels of Tofu Intake

: Insulin-like growth factor-I (IGF-I) has been proposed as the link between diet and breast cancer risk. Due to their estrogen-like structure, soy isoflavones may affect IGF-I levels in a similar way as exogenous estrogens. In a cross-sectional design, we compared IGF-I levels between women with high and low soy intake. The analysis included 611 pre- and postmenopausal women: Japanese in Japan and Japanese and Caucasians in Hawaii. The subjects had participated in a previous study, were never diagnosed with breast cancer, provided a screening mammogram and a blood sample, and completed validated food-frequency questionnaires. The same laboratory analyzed all serum samples for IGF-I and IGF binding protein (IGFBP)-3 by enzyme-linked immunosorbent assay. We estimated covariate-adjusted mean IGF-I and IGFBP-3 levels by tofu intake. The respective mean IGF-I levels were 213, 257, and 255 ng/ml for Japanese in Japan, Japanese in Hawaii, and Caucasians in Hawaii. Tofu intake was higher in Japan than among Japanese and Caucasians in Hawaii (11.0 vs. 9.4 and 4.9 g/1,000 kcal). Mean IGF-I levels were 11% lower among women in the highest tofu intake category compared with the lowest, but the difference in IGF-I levels between the highest and lowest tofu category was only significant among women in Japan. Inclusion of total energy, total protein, meat, and dairy intake did not materially alter the association between tofu consumption and IGF-I levels. These findings suggest that a diet rich in soy foods and low in meats may be related to lower IGF-I levels, but it is unclear whether soy or other characteristics of diet and lifestyle are responsible for this association.

Three-locus and four-locus QTL interactions influence mouse insulin-like growth factor-I.

A previous analysis of serum insulin-like growth factor I (IGF-I) levels in a mouse population (n = 961) derived from a cross of (BALB/cJ x C57BL/6J) F1 females and (C3H/HeJ x DBA/2J) F1 males documented quantitative trait loci (QTL) on chromosomes 1, 10, and 17. We employed a newly developed, random walk-based method to search for three- and four-way allelic combinations that might influence IGF-I levels through nonadditive (conditional or epistatic) interactions among 185 genotyped biallelic loci and with significance defined by experiment-wide permutation (P < 0.05). We documented a three-locus combination in which an epistatic interaction between QTL on paternal-derived chromosomes 5 and 18 had an opposite effect on the phenotype based on the allele inherited at a third locus on maternal-derived chromosome 17. The search also revealed three four-locus combinations that influence IGF-I levels through nonadditive genetic interactions. In two cases, the four-allele combinations were associated with animals having high levels of IGF-I, and, in the third case, a four-allele combination was associated with animals having low IGF-I levels. The multiple-locus genome scan algorithm revealed new IGF-I QTL on chromosomes 2, 4, 5, 7, 8, and 12 that had not been detected in the single-locus genome search and showed that levels of this hormone can be regulated by complex, nonadditive interactions among multiple loci. The analysis method can detect multilocus interactions in a genome scan experiment and may provide new ways to explore the genetic architecture of complex physiological phenotypes.

Effects of arginine treatment on nutrition, growth and urea cycle function in seven Japanese boys with late-onset ornithine transcarbamylase deficiency

The aim of this study was to investigate the effects of arginine on nutrition, growth and urea cycle function in boys with late-onset ornithine transcarbamylase deficiency (OTCD). Seven Japanese boys with late-onset OTCD enrolled in this study resumed arginine treatment after the cessation of this therapy for a few years. Clinical presentations such as vomiting and unconsciousness, plasma amino acids and urinary orotate excretion were followed chronologically to evaluate urea cycle function and protein synthesis with and without this therapy. In addition to height and body weight, blood levels of proteins, lipids, growth hormone (GH), insulin-like growth factor-I (IGF-I) and IGF-binding protein -3 (IGFBP-3) were monitored. The frequency of hyperammonemic attacks and urinary orotate excretion decreased significantly following the resumption of arginine treatment. Despite showing no marked change in body weight, height increased gradually. Extremely low plasma arginine increased to normal levels, while plasma glutamine and alanine levels decreased considerably. Except for a slight increase in high-density lipoprotein cholesterol level, blood levels of markers for nutrition did not change. In contrast, low serum IGF-I and IGFBP-3 levels increased to age-matched control levels, and normal urinary GH secretion became greater than the level observed in the controls. Arginine treatment is able to reduces attacks of hyperammonemia in boys with late-onset OTCD and to increase their growth.

Body mass index, free insulin-like growth factor I, and physical function among older adults: results from the ilSIRENTE study

The aim of the present study was to evaluate the mediating role played by obesity on the relationship of free insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) with muscle strength and physical performance. Data were from baseline evaluation of the ilSIRENTE Study. Muscle strength was measured by hand grip strength. Physical performance was assessed using the walking speed and the 0-3 Short Physical Performance Battery (SPPB) score. Based on its median value, free IGF-I was categorized in the following two groups: low IGF-I (IGF-I <0.65 ng/ml; n = 174) and high IGF-I (IGF-I > or =0.65 ng/ml; n = 175). Similarly, IGFBP-3 was categorized in the following two groups: low IGFBP-3 (IGFBP-3 <4,319.9 ng/ml; n = 174) and high IGFBP-3 (IGFBP-3 > or =4,319.9 ng/ml; n = 175). Body mass index (BMI) was categorized as follows: <25 kg/m(2) (n = 160), 25-29.9 kg/m(2) (n = 133), > or =30 kg/m(2) (n = 56). Mean age of the 349 participants was 85.8 yr, and 234 (67%) were women. After adjusting for potential confounders, no significant association of IGF-I and IGFBP-3 with study outcomes was observed. After the study sample was stratified by BMI groups, compared with participants with low IGF-I level, those with high IGF-I level had a significantly better grip strength [35.2 +/- 1.6 vs. 29.2 +/- 2.0 (SE) kg, P = 0.03], walking speed (0.55 +/- 0.04 vs. 0.40 +/- 0.04 m/s, P = 0.01), and SPPB score (1.9 +/- 0.1 vs. 1.5 +/- 0.1 m/s, P = 0.01) but only in the group with BMI > or =30 kg/m(2) and not in other BMI groups. A statistically significant interaction between BMI and IGF-I level was observed on all study outcomes. By contrast, no association was observed between IGFBP-3 and study outcomes, independently of BMI. In conclusion, high IGF-I level is associated with better physical function in older persons with obesity, but not in nonobese subjects.

Soy Intake and Insulin‐like Growth Factor‐I Levels among Women in Hawaii and Japan

Insulin-like growth factor-I (IGF-I) has been proposed as the link between diet and breast cancer risk. Due to their estrogen-like structure, soy isoflavones may affect IGF-I levels in a similar way as exogenous estrogens. In a cross-sectional design, we compared IGF-I levels between women with high and low soy intake. The analysis included 611 pre- and postmenopausal women: Japanese in Japan (JJ), and Japanese (JH) and Caucasians (CH) in Hawaii. The subjects had participated in a previous study, were never diagnosed with breast cancer, and provided a screening mammogram and blood sample. The same lab analyzed all serum samples for IGF-I and IGF binding protein (IGFBP)-3 by double-antibody ELISA. Soy intake was assessed by validated food frequency questionnaires. We estimated mean IGF-I and IGFBP-3 levels by tofu intake after adjustment for covariates. The respective mean IGF-I levels were 213, 257, and 255 ng/ml for JJ, JH, and CH. Tofu intake was higher among JJ than among JH and CH (11.0 vs. 9.4 and 4.9 g/1000kcal). Mean IGF-I levels were 11% lower (p = 0.01) and mean IGFBP-3 levels were 5% higher (p = 0.22) among women in the highest tofu intake category as compared to the lowest, but the relation was strongest among JJ women. These findings suggest that a diet rich in soy foods may be related to lower IGF-I levels. This project was funded by NCI grants R03 CA105948 and R01 CA80843 and by AICR grant 02A021.

A Prospective Study of Serum Insulin-Like Growth Factor I (IGF-I) and IGF-Binding Protein-3 in 942 Healthy Infants: Associations with Birth Weight, Gender, Growth Velocity, and Breastfeeding

Many aspects of hormonal regulation and mechanisms of normal infancy growth are poorly understood. The objective of this study was to establish the determinants of serum growth factor levels in infancy and their association with growth. A prospective, longitudinal, population-based birth cohort between 1997-2001 was studied. Study participants were 942 healthy appropriate weight for gestational age (AGA) infants (538 boys and 404 girls) and 49 small for gestational age (SGA) children (29 boys and 20 girls). INTERVENTIONS were anthropometrical measurements (0, 3, 18, and 36 months) and serum samples (3 months). Height, weight, and serum IGF-I and IGF-binding protein-3 (IGFBP-3) were the main outcome measures. IGF-I levels showed no gender difference [boys, 92 ng/ml (confidence interval, 49, 162); girls, 91 ng/ml (47, 149); P = 0.50]. IGFBP-3 levels were significantly higher in females [2174 ng/ml (1295, 3330)] than in males [2103 ng/ml (1266, 3143); P = 0.04]. Infants receiving breast milk had lower IGF-I levels [90 ng/ml (48, 154)] than infants receiving formula [n = 62; 97 ng/ml (58, 165)] or both [n = 123; 94 ng/ml (48, 169); P < 0.001]. IGF-I and IGFBP-3 levels were positively associated with weight gain and height gain from birth to 3 months of age in AGA, but not in SGA, children. SGA children had significantly lower IGF-I [88.0 ng/ml (28, 145); P = 0.05] and IGFBP-3 [1835 ng/ml (1180, 2793); P < 0.001] levels than AGA children. We found a significant, but weak, association between IGF-I and IGFBP-3 levels at 3 months and postnatal growth in AGA, but not SGA, children. Factors other than IGF-I must contribute to the regulation of normal postnatal growth, and these may differ between AGA and SGA children. IGFBP-3, but not IGF-I, showed a gender difference, which may reflect an influence of the postnatal activation of the pituitary-gonadal axis on binding protein levels.

Insulin-like growth factor I promoter polymorphism, risk of stroke, and survival after stroke: the Rotterdam study

Background and purpose: Low levels of insulin-like growth factor I (IGF-I) predispose to atherosclerosis and may therefore increase the risk of stroke. Low levels have also been found to influence...

Lack of association between insulin-like growth factor I receptor G+3174A polymorphism and retinopathy of prematurity

Retinopathy of prematurity (ROP) is a potentially blinding eye disorder that affects premature infants. Insulin-like growth factor I (IGF-I) has been established as being necessary for vascular growth in the neonatal retina. Low IGF-I levels during the early postnatal days have been found to be predictive for ROP. The effects of IGF-I are mediated through IGF-I receptors (IGF-IR), which, in turn, suppress IGF-I production. The G(+3174)A polymorphism of the IGF-IR gene has been shown to be associated with low IGF-I levels. We tested the association of this IGF-IR polymorphism with ROP. We enrolled in the ROP group those infants (n=108) who had been treated with laser or cryo therapy due to ROP stage 2+ or 3 (n=91) or had a ROP stage 4 or 5 (n=17) (ROP group). The median gestational age of these infants was 28 weeks (range 24-35 weeks) and birth weight was 970 g (range 630 to 2,000 g). The distribution of IGFR-1 G(+3174)A genotype in the ROP group was compared to that in 120 gestational age-matched infants with ROP stage 1 or 2 not requiring intervention [gestational age 30 (range 24-37) weeks, birth weight 1,235 (640-1,960) g] (LBW group) and 164 term newborns [gestational age 39 (range 35-42) weeks, birth weight 3,450 (2,500-4,350) g] (term group). Genotyping was done using PCR-RFLP methods. The prevalence of IGF-IR G(+3174)A polymorphism was the same in the ROP group, the LBW group and the term group, showing no association between this single-nucleotide polymorphism (SNP) and ROP. Our results do not support the hypothesis that the carrier state of IGF-IR G(+3174)A polymorphism has an impact on the risk of ROP in infants. A possible cause for the lack of association is that the rapid nutritional and metabolic changes during postnatal life have a greater effect on IGF-I levels than this SNP does.

Relationship of Obesity and Physical Activity with C-Peptide, Leptin, and Insulin-Like Growth Factors in Breast Cancer Survivors

Obese and physically inactive breast cancer patients may have poorer survival compared with lighter weight and more active women. Several obesity-related and physical activity-related hormones and peptides may explain this association, including insulin, leptin, insulin-like growth factor-I (IGF-I), and IGF-binding protein-3. Few studies have examined the associations between obesity, physical activity, and these hormones/peptides among breast cancer survivors. To determine whether obesity and physical activity are associated with insulin, IGFs, and leptin levels in a population-based sample of 710 women diagnosed with in situ to stage IIIA breast cancer and enrolled in the Health, Eating, Activity, and Lifestyle Study. We collected a blood sample and information on physical activity among women diagnosed 2 to 3 years earlier using an interview-administered questionnaire. Trained staff measured weight. C-peptide, leptin, and IGFs were assayed by RIA. Mean hormone levels within body mass index and physical activity categories were adjusted for confounders using analysis of covariance methods. We observed higher C-peptide (P for trend = 0.0001) and leptin (P for trend = 0.0001) levels and lower IGF-I levels (P for trend = 0.0001) with higher levels of body mass index. We observed lower C-peptide (P for trend = 0.001) and leptin (P for trend = 0.001) levels and higher IGF-I (P for trend = 0.0037) and IGF-binding protein-3 (P for trend = 0.055) levels with higher levels of physical activity. Increasing physical activity and decreasing body fat may be a reasonable intervention approach toward changing insulin and leptin, thereby potentially influencing breast cancer prognosis.

Association of Insulin-like Growth Factor I and Insulin-like Growth Factor–Binding Protein-3 With Intelligence Quotient Among 8- to 9-Year-Old Children in the Avon Longitudinal Study of Parents and Children

Insulin-like growth factor I (IGF-I) is a hormone that mediates the effects of growth hormone and plays a critical role in somatic growth regulation and organ development. It is hypothesized that it also plays a key role in human brain development. Previous studies have investigated the association of low IGF-I levels attributable to growth hormone receptor deficiency with intelligence but produced mixed results. We are aware of no studies that investigated the association of IGF-I levels with IQ in population samples of normal children. To investigate the association of circulating levels of IGF-I and its principle binding protein, IGF-binding protein-3 (IGFBP-3), in childhood with subsequent measures of IQ. The cohort study was based on data for 547 white singleton boys and girls, members of the Avon Longitudinal Study of Parents and Children, with IGF-I and IGFBP-3 measurements (obtained at a mean age of 8.0 years) and IQ measured with the Wechsler Intelligence Scale for Children (at a mean age of 8.7 years). We also investigated associations with measures of speech and language based on the Wechsler Objective Reading Dimensions test (measured at an age of 7.5 years) and the Wechsler Objective Language Dimensions test (listening comprehension subtest only, measured at an age of 8.7 years). For some children (n = 407), IGF-I (but not IGFBP-3) levels had been measured at approximately 5 years of age in a previous study. Linear regression models were used to investigate associations of the IGF-I system with the measures of cognitive function. Three hundred one boys and 246 girls were included in the sample. IGF-I levels (mean +/- SD) were 142.6 +/- 53.9 ng/mL for boys and 154.4 +/- 51.6 ng/mL for girls. IQ scores (mean +/- SD) were 106.05 +/- 16.6 and 105.27 +/- 15.6 for boys and girls, respectively. IGF-I levels were associated positively with intelligence. For every 100 ng/mL increase in IGF-I, IQ increased by 3.18 points (95% confidence interval [CI]: 0.52 to 5.84 points). These positive associations were seen in relation to the verbal component (coefficient: 4.27; 95% CI: 1.62 to 6.92), rather than the performance component (coefficient: 1.06; 95% CI: -1.67 to 3.78), of IQ. There was no evidence that associations with overall IQ differed between boys and girls. In a data set with complete information on confounders (n = 484), controlling for birth weight (adjusted for gestation), breastfeeding, and BMI slightly strengthened the associations of IGF-I levels with IQ. Additionally controlling for maternal education and IGFBP-3 levels attenuated the associations (change in IQ for every 100 ng/mL increase in IGF-I levels: 2.51 points; 95% CI: -0.42 to 5.44 points). The weakening of associations in models controlling for markers of parental socioeconomic position and education could reflect shared influences of parental IGF levels on parents' own educational attainment and their offspring's IGF-I levels. In unadjusted models examining associations of Wechsler Objective Reading Dimensions and Wechsler Objective Language Dimensions test scores with IGF-I levels, there was no strong evidence that performance on either of these tests was associated with circulating IGF-I levels, although positive associations were seen with both measures. Associations between IGF-I levels measured at age 5 and Wechsler Intelligence Scale for Children scores (n = 407) were similar to those for IGF-I levels measured at age 7 to 8. For every 100 ng/mL increase in IGF-I levels at 5 years of age, IQ increased by 2.3 points (95% CI: -0.21 to 4.89 points). This study provides some preliminary evidence that IGF-I is associated with brain development in childhood. Additional longitudinal research is required to clarify the role of IGF-I in neurodevelopment. Because IGF-I levels are modifiable through diet and other environmental exposures, this may be one pathway through which the childhood environment may influence neurodevelopment.

Insulin-like growth factor I (IGF-I) measurements in growth hormone (GH) therapy of idiopathic short stature (ISS)

Growth hormone (GH) therapy has evolved rapidly over the past decade. Ongoing research has demonstrated a clear role for therapeutic GH in a wide spectrum of pediatric disorders involving both poor growth and abnormal body composition. Although guidelines for GH dosing are not fully established, a series of key studies has delineated the range of dosages that are useful in the treatment of children with growth disorders. The recent approval of idiopathic short stature (ISS) as an indication for GH therapy presents further challenges in optimizing the care of GH-treated patients. ISS is now recognized as a diverse collection of environmental and molecular abnormalities, some of which involve the GH–IGF axis. Emerging data indicate that serum IGF-I measurements are not only useful in the diagnosis of growth abnormalities but, in conjunction with auxological measurements, are also a powerful tool for assessing GH efficacy. While it is clear that many ISS patients respond to GH, some individuals will not show a satisfactory response. Monitoring IGF-I levels and change in height SDS during treatment can assist the physician in distinguishing those patients in whom GH successfully and safely induces statural growth from those with partial or complete GH insensitivity who might benefit from modified GH treatment protocols or alternate therapies. In addition, serum IGF-I measurements are increasingly used as part of a rational monitoring strategy to ensure safety of GH dosing in light of cumulative data associating high IGF-I levels with potential malignancy risk, and low IGF-I levels with cardiovascular disease risk.

Treatment of the adult growth hormone deficiency syndrome: Directions for future research

The adult growth hormone deficiency syndrome (AGHD) is a well-defined clinical entity characterized by decreased lean body mass and bone mineral density, increased visceral adiposity, abnormal lipid profile, decreased muscle strength and exercise endurance, and diminished quality of life. Recent studies have emphasized the increased morbidity and mortality of hypopituitary patients, and there are now data implicating growth hormone (GH) deficiency as a cause of this increase. GH replacement therapy has been shown to reverse many of these abnormalities and to be well tolerated. Meta-analyses have demonstrated that GH treatment positively affects cardiovascular risk factors, and controlled trials have shown that visceral adiposity decreases in treated patients. Improvements in bone mineral density and decreases in fracture rates have also been reported, and new studies using disease-specific questionnaires provide convincing evidence that GH greatly enhances quality of life. Epidemiologic studies indicate that higher insulin-like growth factor I (IGF-I) levels may predict risk for certain cancers, but other studies suggest that lower IGF-I levels increase risk for ischemic heart disease. However, much of the community of endocrine caregivers remains skeptical of GH treatment and, therefore, a large fraction of patients with AGHD are not treated. The accumulation of long-term treatment data will be required to provide reassurance that GH treatment is a safe and necessary form of hormone replacement therapy for patients with AGHD.

Serum Insulin-Like Growth Factor I Levels in Growth Hormone-Deficient Adults: Influence of Sex Steroids

Measurement of serum insulin-like growth factor I (IGF-I) concentrations remains the single most important tool in the evaluation of growth hormone (GH) replacement in GH-deficient adults, and the therapeutic goal is to maintain the level within the age-adjusted normal range. In healthy adults, IGF-I levels do not differ between males and females, whereas spontaneous GH secretion is approximately twofold higher in females. Untreated GH-deficient women exhibit lower IGF-I levels compared with men, and the increase in serum IGF-I during GH replacement is also significantly less. Put together, these data suggest resistance to GH in women, which in healthy individuals is compensated for by increased GH secretion. Administration of oral oestrogen in healthy post-menopausal women suppresses hepatic IGF-I production and increases pituitary GH release, and oral oestrogen replacement in women with GH deficiency lowers IGF-I concentrations and increases the amount of GH necessary to obtain 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 further levels. There is also circumstantial evidence to indicate that testosterone stimulates IGF-I production, and it is speculated that a certain threshold level of androgens is essential to ensure hepatic IGF-I production. Whether these data should translate into earlier discontinuation of oestrogen replacement therapy in adult women with hypopituitarism merits consideration.