Serum Insulin-like Growth factor-I Levels Research Articles

Serum Insulin-like Growth Factor-I (IGF-I), IGF-Binding Protein-3, and Growth Hormone Levels in Collodion Babies: A Case-Control Study

Because growth failure occurs in many collodion babies, we investigated serum growth hormone (GH), insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) levels in collodion babies admitted to Gevher Nesibe Hospital, Kayseri, Turkey between 1999 and 2006. The newborns diagnosed clinically as 'collodion baby' were included in the study group (group 1). Because collodion babies are usually born small for gestational age (SGA) and/or premature, a control group (group 2) was formed by selecting the first infant admitted immediately after each study infant who matched for gestational age (+/- 7 days) and birth weight (+/- 100 g). All infants' blood samples were collected within the first 2 h of life for measurements of serum GH, IGFBP-3 and IGF-I levels. Group 1 consisted of 23 collodion babies (13 males and 10 females) with gestational ages ranging from 32 to 42 weeks, and birth weights ranging from 1,300 to 3,600 g. Ten were born premature and 16 were SGA. Serum IGF-I and IGFBP-3 levels were lower but serum GH levels were higher in collodion babies than in controls. Birth weight was positively correlated with serum IGF-I (r = 0.310, p = 0.046) and IGFBP-3 (r = 0.389, p = 0.011) levels. Serum GH level was negatively correlated with birth weight (r = -0.376, p = 0.014), serum IGF-I (r = -0.567, p <0.001) and IGFBP-3 (r = -0.444, p = 0.003). Collodion babies had lower serum IGF-I and IGFBP-3 levels but higher serum GH levels than controls in the present case-control study. The underlying mechanism needs to be explored.

Nutrition-induced Catch-up Growth at the Growth Plate

The effect of 40% food restriction (FR) and replenishment on the growth hormone (GH) and insulin-like growth factor-I (IGF-I) axis in the epiphyseal growth plate (EGP) was examined in a mouse model. Changes in RNA and protein levels were evaluated with real time PCR and immunohistochemistry, respectively, and serum levels of IGF-I and leptin were measured with radioimmunoassay. Dramatic changes in weight, tibial length and EGP height were observed following 10 days of 40% FR. The protein levels of IGF-I receptor (IGF-IR) and GH receptor (GHR), which were reduced during FR, increased during catch-up growth without an apparent change in the level of their RNA. The levels of type II and X collagens were unchanged. Serum IGF-I and leptin levels were reduced during FR and increased during catch-up growth. Following 40% FR, there was a significant decrease in the level of GHR and IGF-IR in the EGP which may explain the reduced effect of GH treatment in malnourished animals and children.

A Study of Anthropomorphic and Biochemical Characteristics in Girls with Central Precocious Puberty and Thelarche Variant

Premature thelarche in later childhood may progress to central precocious puberty (CPP), which does not spontaneously resolve. Thelarche variant (TV) is a slowly progressive variant of precocious puberty. To determine and compare levels of insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3) and anthropomorphic measures in girls with TV and CPP. Prepubertal controls and girls with TV and CPP. Chronological and bone age, weight, height, BMI, height velocity (HV), and serum IGF-I, IGFBP-3, leptin, follicle-stimulating hormone (FSH) and lutenizing hormone (LH) levels were assessed. Serum IGF-I levels, HV and IGF-I/ IGFBP-3 ratio were significantly higher in girls with CPP compared to both controls and girls with TV. IGFBP-3 values for bone age (IGFBP-3BA) were significantly higher in the TV group compared to both controls and girls with CPP. FSH and LH concentrations were significantly higher in the CPP group compared to TV. HV, IGF-I, LH and FSH levels and IGF-I/IGFBP-3 ratio are elevated in girls with CPP compared to those with TV.

Insulin-like growth factor-I and complications of prematurity: a focus on bronchopulmonary dysplasia

At least four premature newborn complications have been reported to be associated with low serum insulin-like growth factor-I (IGF-I) levels: bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis and brain damage. Local IGF-I concentrations have only been reported for bronchopulmonary dysplasia and these findings show that lung IGF-I levels are clearly increased (epithelial lining fluid levels), emphasizing the fact that IGF-I is differently regulated in the general circulation or at local level. The present review discusses the meaning of the association between serum IGF-I amounts and development of complications in premature newborns. Finally, some methodological indications are reported regarding the IGF-I assay procedures. It is important to establish what are the possible relationships between blood levels and those of different compartments involved in the diseases.

Common genetic variation in the IGF-1 gene, serum IGF-I levels and breast density

High breast density is one of the strongest known risk factors for developing breast cancer. Insulin-like growth factor I (IGF-I) is a strong mitogen and has been suggested to increase breast cancer risk by increasing the amount of dense tissue in the female breast. We wanted to investigate the effect of common variation in the IGF-1 gene on serum IGF-I levels and on breast density. Mammograms and blood samples of 1,928 premenopausal participants of the Dutch Prospect-EPIC cohort were collected at baseline. Using a haplotype tagging approach, 16 single nucleotide polymorphisms (SNP) from three blocks covering the IGF-1 gene were genotyped in all study participants. Breast density was assessed using a quantitative computer-assisted method. For a subgroup of women, who went through menopause within 5 years after recruitment (n=656), premenopausal IGF-I levels and additionally postmenopausal breast density were determined. False positive report probabilities (FPRP) for statistically significant relations were calculated using the Wacholder method. The minor alleles of five SNPs in block 3 were significantly associated with elevated levels of IGF-I (rs9989002, rs2033178, rs7136446, rs978458, rs6220; P-values: 0.01-0.04). The same SNPs were related with modestly higher percent breast density before menopause and-in the subgroup of women that became postmenopausal during follow-up-with a modestly higher percent breast density after menopause. The most significant result, i.e. the relation between rs6220 and IGF-I levels, had an FPRP<0.5 assuming prior probabilities of 0.01 and higher. Common genetic variation in the IGF-1 gene is related to circulating levels of IGF-I, but the relationship with breast density is indecisive.

Excess Mortality in Acromegaly

Background: Increased production of growth hormone (GH) and insulin-like growth factor-I (IGF-I) in patients with acromegaly is associated with a twofold increase in mortality compared with the general population. The range of standardised mortality rates in various studies ranges from 1.2 to 3.6. Predictors of Mortality: Multivariate analysis has indicated that post-treatment serum GH levels and, in a number of studies, serum IGF-I levels are the most powerful predictors of outcome. Normal IGF-I concentrations and random GH levels <2.5 µg/l measured by polyclonal radioimmunoassay result in optimal outcome. Other factors adversely influencing mortality include hypertension and a long interval between onset of the disorder and diagnosis. Conclusions: Analysis of recent reports suggests that adoption of treatment guidelines with appropriate post-treatment target ranges for GH and IGF-I, together with the availability of newer methods to control GH oversecretion, has significantly improved patient outcomes.

Persistent Osteopenia in Adult Cystic Fibrosis Transmembrane Conductance Regulator–deficient Mice

A loss of function mutation in the cystic fibrosis transmembrane conductance regulator gene is believed to be an independent risk factor for bone disease in patients with cystic fibrosis. The objective of this work was to use congenic mice as a preclinical model to examine the bone phenotype of Cftr(-/-) mice and control littermates at 8, 12, and 28 weeks of age. The bone phenotype of control and Cftr(-/-) mice was evaluated by quantitative imaging, histologic and histomorphometric analyses, and serum levels of bone biomarkers. At 12 weeks of age, Cftr(-/-) mice were smaller, had lower bone mineral density, cortical bone thinning, and altered trabecular architecture compared with Cftr(+/+) or Cftr(+/-) control mice. In skeletally mature 28-week-old mice, there were persistent deficits in cortical and trabecular bone structure in Cftr(-/-) mice despite significant, quantifiable improvements. Cftr(-/-) mice also had lower serum insulin-like growth factor-I levels at 12 weeks of age than did control mice, whereas parathyroid hormone and 25-hydroxyvitamin D levels were not significantly different. Persistent osteopenia and structural abnormalities in adult Cftr(-/-) mice, in the absence of overt respiratory and gastrointestinal disease, suggest that loss of Cftr function has a direct impact on bone metabolism in Cftr(-/-) mice that is not sex specific or subject to haplotype insufficiency.

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 and Biliary Insulin-like Growth Factor I and Vascular Endothelial Growth Factor in Determining the Cause of Obstructive Cholestasis

Cholangiocarcinoma cells express and secrete insulin-like growth factor I (IGF-I) and vascular endothelial growth factor (VEGF). To measure IGF-I and VEGF in bile and serum of patients with extrahepatic cholangiocarcinoma and to evaluate their performance as diagnostic markers. Cross-sectional study. Inpatients at the Division of Gastroenterology, University Hospital, Ancona, Italy. 73 patients who consecutively had endoscopic retrograde cholangiopancreatography (ERCP), including patients with extrahepatic cholangiocarcinoma (n = 29), pancreatic cancer (n = 19), and benign biliary abnormalities (n = 25; bile duct stones, primary sclerosing cholangitis, and cholangitis). Diagnosis was based on conventional radiology, ERCP, and follow-up. Insulin-like growth factor I and VEGF were measured by using enzyme-linked immunosorbent assay. The biliary IGF-I concentration was 15- to 20-fold higher (P < 0.001) in extrahepatic cholangiocarcinoma (mean, 84.6 nmol/L [95% CI, 74.0 to 95.2 nmol/L]) than in pancreatic cancer (5.8 nmol/L [CI, 4.0 to 7.5 nmol/L]) or benign biliary abnormalities (4.1 nmol/L [CI, 3.1 to 5.2 nmol/L]). The area under the receiver-operating characteristic curve was 1 when biliary IGF-I values in the extrahepatic cholangiocarcinoma were compared with benign biliary abnormalities or pancreatic cancer. In contrast, biliary VEGF concentration was similar in the 3 groups. Serum IGF-I levels were similar among the groups, whereas serum VEGF levels were higher in the cholangiocarcinoma (0.97 ng/mL [CI, 0.59 to 1.35 ng/mL]; P = 0.0016) and pancreatic cancer groups (0.66 ng/mL [CI, 0.43 to 0.88 ng/mL]; P < 0.001) compared with patients with benign biliary abnormalities (0.28 ng/mL [CI, 0.17 to 0.37 ng/mL]). Data were obtained in a small sample, the study was performed in a single center, and few patients had a tissue diagnosis. Biliary IGF-I levels in patients undergoing ERCP for biliary obstruction may differentiate extrahepatic cholangiocarcinoma from either pancreatic cancer or benign biliary abnormalities.

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.

Intradialytic parenteral nutrition abolishes the increase of insulin-like growth factor binding protein-1 (IGFBP-1) during hemodialysis and elevates the IGF-I/IGFBP-1 ratio, an anticatabolic effect?

Summary Background Malnutrition is a severe clinical problem in hemodialysis (HD) patients. We have earlier shown that insulin-like growth factor binding protein-1 (IGFBP-1) increases during HD and may thus limit the bioavailability of free insulin-like growth factor-I (IGF-I). The present study was performed with the aim to test if intradialytic parenteral nutrition (IDPN) would influence the IGF system in HD patients with the hypothesis that IDPN would attenuate the increase of IGFBP-1 and thus alter the IGF system to give a more anticatabolic effect. Methods Nine HD patients aged 69±3 years were studied during one HD session with IDPN and one without IDPN. The nutritional product used contained 1000 kcal (1000 ml, 53 g amino acids, 75 g glucose and 50 g long chain triglycerides—soybean oil). Blood samples were collected pre- and post-dialysis. Serum concentrations of IGF-I, insulin and IGFBP-1 were determined by RIA. Results During HD without IDPN serum levels of IGFBP-1 increased from 84±21 to 139±26 μg/l ( p =0.01). In contrast IGFBP-1 tended to decrease from 126±37 to 85±18 μg/l ( p =0.087) during HD with IDPN. The difference between post- and pre-HD IGFBP-1 was significantly larger without IDPN than with IDPN (+55±17 vs. −41±21 μg/l, p =0.0056). The ratio IGF-I/IGFBP-1, indicative of free IGF-I, decreased significantly during HD without IDPN (4.5±1.6 vs. 2.8±1.1 p =0.02). In contrast, during IDPN this ratio tended to increase from 2.6±1.0 to 4.3±1.7 ( p =0.059). The difference between post- and pre-HD was −1.7±0.5 without IDPN vs. 1.6±0.7 μg/l with IDPN ( p =0.022). Without IDPN the change in IGF-I was non-significant during HD but on IDPN IGF-I serum levels increased significantly from 156±35 to 193±44 μg/l ( p =0.004). The serum levels of insulin differed significantly during HD with a decrease without IDPN and an increase with IDPN (−17±7 vs. +19±8 μg/l p =0.009). Glucose levels decreased without IDPN but remained unchanged with IDPN (5.9±0.9 to 4.1±0.4 mmol/l p =0.021 vs. 5.8±0.8 to 6.1±0.9 mmol/l NS). Conclusions IDPN blunts the increase of IGFBP-1 and the IGF-I/IGFBP-1 ratio increases. The increased IGF-I bioavailability suggests an anticatabolic effect.

Central actions of liver-derived insulin-like growth factor I underlying its pro-cognitive effects

Increasing evidence indicates that circulating insulin-like growth factor I (IGF-I) acts as a peripheral neuroactive signal participating not only in protection against injury but also in normal brain function. Epidemiological studies in humans as well as recent evidence in experimental animals suggest that blood-borne IGF-I may be involved in cognitive performance. In agreement with observations in humans, we found that mice with low-serum IGF-I levels due to liver-specific targeted disruption of the IGF-I gene presented cognitive deficits, as evidenced by impaired performance in a hippocampal-dependent spatial-recognition task. Mice with serum IGF-I deficiency also have disrupted long-term potentiation (LTP) in the hippocampus, but not in cortex. Impaired hippocampal LTP was associated with a reduction in the density of glutamatergic boutons that led to an imbalance in the glutamatergic/GABAergic synapse ratio in this brain area. Behavioral and synaptic deficits were ameliorated in serum IGF-I-deficient mice by prolonged systemic administration of IGF-I that normalized the density of glutamatergic boutons in the hippocampus. Altogether these results indicate that liver-derived circulating IGF-I affects crucial aspects of mature brain function; that is, learning and synaptic plasticity, through its trophic effects on central glutamatergic synapses. Declining levels of serum IGF-I during aging may therefore contribute to age-associated cognitive loss.

Alterations in IGF-I affect elderly: role of physical activity

AbstractThe growth hormone–insulin-like growth factor I (IGF-I) axis is an important physiological regulator muscle for development. Although there is evidence that aging muscle retains the ability to synthesize IGF-I, there is also evidence that aging may be associated with attenuation of the ability of exercise to induce an isoform of IGF-I that promotes satellite cell proliferation. However, it is clear that overexpression of IGF-I in the muscle can protect against age-related sarcopenia. Strength training appears to be the intervention of choice for the prevention and treatment of sarcopenia. IGF-I has been implicated in the loss of the muscle with age, and IGF-I expression levels change as a consequence of strength training in older adults. However, it seems that advancing age, rather than declining serum levels of IGF-I, appears to be a major determinant of life-time changes in body composition in women and men. We concluded that resistive exercise is a significant determinant of muscle mass and function. Elevated levels of IGF-I have been found in physically active compared to sedentary individuals. Recent work suggests that IGF-I as a mediator plays an important role in muscle hypertrophy and angiogenesis, both of which characterize the anabolic adaptation of muscles to exercise.

Use of serum insulin-like growth factor-I levels to predict psychiatric non-response to donepezil in patients with Alzheimer’s disease

Objective Insulin-like growth factor-I (IGF-I) deficiency may be involved in cognitive deficits seen with aging and in neurodegenerative diseases such as Alzheimer’s disease (AD). This study was aimed at investigating whether non-responder to donepezil could be predicted using decreased serum levels of IGF-I in AD patients. Design This study involved 106 elderly subjects: 50 patients with AD and 56 age-matched controls without dementia. In patients with AD, donepezil was given orally 3 mg/day for 4 weeks and 5 mg/day for another 12 weeks. AD patients were divided into responders and non-responders based on the changes in mini-mental state examination (MMSE) scores before and 16 weeks after treatment with donepezil. Serum levels of IGF-I and atherogenic biomarkers were determined. Results Before treatment with donepezil, there was a significant positive correlation between serum IGF-I levels and the MMSE scores in all subjects. Serum IGF-I levels and the MMSE scores were significantly lower in AD patients than in non-demented controls and were the lowest in non-responders to donepezil. Atherogenic biomarkers (LDL cholesterol, triglycerides, lipoprotein(a), lipid peroxide, apolipoprotein E, and glucose levels) did not differ significantly among these groups. On multiple logistic regression, non-responders to donepezil showed decreased serum IGF-I levels <110 ng/ml and MMSE scores <15 points before treatment. Conclusions These findings suggest that decreased levels of serum IGF-I combined with MMSE scores before treatment could predict non-responders to donepezil among AD patients, which may be a simple and practical method for selecting patients expected to show a response to treatment.

Relationships between insulin-like growth factor-I (IGF-I) and OPG, RANKL, bone mineral density in healthy Chinese women

Serum IGF-I level was negatively correlated with OPG and OPG/RANKL ratio, but positively correlated with RANKL. Serum OPG level in the highest quintile of IGF-I was significantly lower than that in the lowest. We conclude that the effect of IGF-I on bone remodeling may be mediated by the OPG/RANKL system. Insulin-like growth factor I (IGF-I) is an important factor in coupling bone remodeling, activating both formation and resorption. Compared with the many studies on the role of IGF-I in bone formation, the information regarding its effects on bone resorption is limited and conflicting. The balance of the two peptides produced by osteoblasts, osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand (RANKL), is critical for the bone resorption process. Our study was designed to analyze the relationships of serum concentrations of IGF-I with OPG, RANKL, OPG/RANKL ratio as well as BMDs in healthy Chinese women. BMDs at lumbar spine and proximal femur in 504 pre- and postmenopausal women were measured by DXA. Serum levels of IGF-I, OPG and RANKL were also measured. Pearson's correlation and partial correlation analysis, ANOVA, covariance analysis and stepwise multiple regression analysis were used as appropriate. Age was negatively correlated with serum levels of IGF-I (r = -0.702, p < 0.001). IGF-I was negatively correlated with OPG and OPG/RANKL ratio, but positively correlated with RANKL. The relationship between IGF-I and BMDs disappeared after adjustment for age. In postmenopausal women, IGF-I was lower in women with osteoporosis than in those with normal BMD (p = 0.056), but no differences were found among OPG, RANKL and OPG/RANKL ratio. Serum levels of OPG in the highest quintile of IGF-I were significantly lower than those in the lowest quintile of IGF-I, while no difference was found in RANKL. In the multiple regression analysis model, serum levels of IGF-I were the main determinants of the bone mass in Chinese women. In conclusion, the relationship between decreasing IGF-I and BMDs in healthy Chinese women influenced by age, whereas the effect of IGF-I on bone remodeling (bone resorption) may be mediated by the OPG/RANKL system.

Subnormal Serum Insulin-Like Growth Factor-I Levels in Young Adults with Childhood-Onset Nonacquired Growth Hormone (GH) Deficiency Who Recover Normal GH Secretion May Indicate Less Severe but Persistent Pituitary Failure

The unexpected observation of a normal GH peak in 22% of young adults with childhood-onset GH deficiency (GHD) and ectopic neurohypophysis has raised questions about the criteria defining GHD in young adults and whether patients with subsequent increases in GH secretion nonetheless have a subtle form of GHD. Our objective was to determine the characteristics of patients with childhood-onset nonacquired GHD who recover normal peak GH secretion when adult height has been achieved. We conducted a university hospital-based observational follow-up study. Sixty-two patients with ectopic neurohypophysis (n = 24), isolated hypoplastic anterior pituitary (n = 14), or normal hypothalamic pituitary area (n = 24) on magnetic resonance imaging (MRI) at the time of GHD diagnosis underwent reevaluation of the GH-IGF-I axis at a mean age of 16.8 +/- 1.6 yr. Outcome measures included clinical and MRI findings and serum IGF-I and peak GH levels. On retesting, peak GH exceeded 10 microg/liter in 31 patients (50%): six (20%) patients with ectopic neurohypophysis, 10 (32%) patients with initially isolated hypoplastic anterior pituitary, and 15 (48%) patients with normal MRI findings. Among these patients, serum IGF-I levels were significantly lower in patients with ectopic neurohypophysis than in those without structural abnormalities of the hypothalamic pituitary axis (n = 25), but patients without structural abnormalities also had significantly lower serum IGF-I levels than control subjects, after controlling for age, sex, and body mass index (mean serum IGF-I levels of 374 +/- 83 vs. 446 +/- 108 microg/liter; beta-coefficient = -72; P = 0.003). The severity of the disease seems to have decreased over time in these patients, who may nonetheless present persistent pituitary failure. The natural history and clinical implications of these findings remain to be clarified. The possibility of a deterioration in the secretion of GH and other pituitary hormones later in life in a subset of these patients warrants the careful long-term follow-up of this population.

Association between Serum Insulin-Like Growth Factor-I Levels and Thyroid Disorders in a Population-Based Study

There is current debate on whether serum IGF-I levels are associated with thyroid disorders. The aims of the present study were: 1) to investigate possible associations between serum IGF-I levels and thyroid disorders and 2) to analyze the role of serum IGF binding protein (IGFBP)-3 and TSH levels for these associations. This was a cross-sectional Study of Health in Pomerania. The study was conducted in the general population of northeast Germany. The study population comprised 3662 subjects (1746 women) without history of thyroid disorders. No interventions have been performed. Goiter and thyroid nodules were determined by ultrasound. Serum TSH levels less than 0.25 mIU/liter were considered decreased. Adjusted for major confounders and risk factors for thyroid disorders, subjects with serum IGF-I levels above the upper tertile had higher odds for goiter relative to subjects with serum IGF-I levels below the lower tertile [odds ratio (OR) 1.67; 95% confidence interval (CI) 1.24-2.26 in women; OR 2.04; 95% CI 1.55-2.68 in men]. A similar association was present for thyroid nodules in men (OR 1.64; 95% CI 1.17-2.32) and for decreased serum TSH levels in women (OR 1.65; 95% CI 1.00-2.69). Serum IGFBP-3 levels were not associated with thyroid disorders and did not represent effect modifiers for the association between serum IGF-I levels and the endpoints. We conclude that high serum IGF-I levels are associated with goiter. Whereas high serum IGF-I levels are also related to thyroid nodules in men, they are related to decreased serum TSH levels in women. Serum IGFBP-3 and TSH levels did not modulate these associations.

Serum insulin-like growth factor-I level is associated with the presence of vertebral fractures in postmenopausal women with type 2 diabetes mellitus

Multivariate logistic regression analysis showed that serum IGF-I level was significantly lower in postmenopausal diabetic women with vertebral fractures than in those without fractures. Serum IGF-I level could be clinically useful for assessing the risk of vertebral fractures independent of BMD in postmenopausal women with type 2 diabetes. We investigated the relationships among serum IGF-I and C-peptide levels, BMD, and vertebral fractures in postmenopausal women with type 2 diabetes. A total of 131 postmenopausal women with type 2 diabetes were consecutively recruited, and radiographic and biochemical characteristics were collected. Either IGF-I or C-peptide was not correlated with BMD at any site or bone metabolic markers, such as osteocalcin (OC) and urinary N-terminal cross-linked telopeptide of type-I collagen (uNTX). However, serum IGF-I level was significantly lower in subjects with vertebral fractures than in those without fractures (mean +/- SD: 106.9 +/- 50.0 vs. 142.8 +/- 50.8 ng/ml, p = 0.0006). When multivariate logistic regression analysis was performed with the presence of vertebral fractures as a dependent variable and serum IGF-I adjusted for the parameters described above as independent variables, IGF-I was selected as an index affecting the presence of vertebral fractures [odds ratio = 0.436, 95% confidential interval 0.234-0.814 per SD increase, p = 0.0092]. This significance was almost the same after additional adjustment for lumbar BMD or C-peptide. Serum IGF-I level could be clinically useful for assessing the risk of vertebral fractures independent of BMD in postmenopausal women with type 2 diabetes.

Age‐related changes in bile acid synthesis and hepatic nuclear receptor expression

Recent data highlighted the role of nuclear receptors in the transcriptional regulation of the limiting enzyme of bile acid synthesis, cholesterol 7alpha-hydroxylase, in cellular and animal models. This study was designed to analyze the effects of age on cholesterol 7alpha-hydroxylase and related nuclear receptor expression in human livers. Surgical liver biopsies were obtained in 23 patients requiring operation on the gastrointestinal tract. mRNA levels of cholesterol 7alpha-hydroxylase and related nuclear receptors and co-activators were assayed by quantitative real-time RT-PCR. Serum levels of 7alpha-hydroxy-4-cholesten-3-one, a marker of bile acid synthesis, were assayed by gas-liquid chromatography:mass spectrometry. Ageing was inversely correlated with serum 7alpha-hydroxy-4-cholesten-3-one and with cholesterol 7alpha-hydroxylase mRNA levels (r = -0.44 and r = -0.45 on a semi-log scale, respectively, P < 0.05). Among different nuclear factors, cholesterol 7alpha-hydroxylase mRNA best correlated with hepatocyte nuclear factor-4 (r = 0.55 on a log scale, P < 0.05); hepatocyte nuclear factor-4 levels were also inversely correlated with age (r = -0.64 on a semi-log scale, P < 0.05). Age was inversely correlated with serum insulin-like growth factor-I levels, which were directly correlated with hepatocyte nuclear factor-4 and cholesterol 7alpha-hydroxylase expression. No suppressive effect of short heterodimer partner expression on cholesterol 7alpha-hydroxylase was observed. Ageing associates with reduced bile acid synthesis, possibly related to decreased hepatic expression of hepatocyte nuclear factor-4 and consequently of cholesterol 7alpha-hydroxylase. Age-related modifications of the growth hormone/insulin-like growth factor axis might play a role. These findings may help to elucidate the pathophysiology of age-related modifications of cholesterol metabolism.

Normal levels of serum IGF-I: determinants and validity of current reference ranges

Insulin like growth factor I (IGF-I) represents the key marker for the evaluation of Growth hormone (GH) status. As a large number of determinants including age, gender, genetic factors, nutrition, and disease states influence IGF-I serum levels, accurate normative data are essential to translate patient data into diagnostic meaning or even use IGF-I levels for adequate monitoring of patients with an over- or under-active GH axis. Even though reference ranges have been developed in large cohorts of healthy subjects, the dependency of these data on a given assay technology argues for assay specific normative data for IGF-I.