Assessment of compatibility of rhIGF-1/rhIGFBP-3 with neonatal intravenous medications.

BACKGROUND: Recombinant human (rh)IGF-1/IGFBP-3 protein complex, administered as a continuous intravenous infusion in preterm infants, is being studied for the prevention of complications of prematurity. METHODS: We conducted in vitro studies to evaluate the physical and chemical compatibility of rhIGF-1/IGFBP-3 with medications routinely administered to preterm neonates. In vitro mixing of rhIGF-1/IGFBP-3 drug product with small-molecule test medications plus corresponding controls was performed. Physical compatibility was defined as no color change, precipitation, turbidity, gas evolution, no clinically relevant change in pH/osmolality or loss in medication content. Chemical compatibility of small molecules was assessed using liquid chromatography (e.g., reverse-phase HPLC and ion chromatography), with incompatibility defined as loss of concentration of ≥ 10%. A risk evaluation was conducted for each medication based on in vitro compatibility data and potential for chemical modification. RESULTS: In vitro physical compatibility was established for 11/19 medications: caffeine citrate, fentanyl, fluconazole, gentamicin, insulin, intravenous fat emulsion, midazolam, morphine sulfate, custom-mixed parenteral nutrition solution (with/without electrolytes), parenteral nutrition solution + intravenous fat emulsion, and vancomycin (dosed from a 5 mg/mL solution), but not for 8/19 medications: amikacin, ampicillin, dopamine, dobutamine, furosemide, meropenem, norepinephrine, and penicillin G, largely owing to changes in pH after mixing. Small-molecule compatibility was unaffected post-mixing, with no loss of small-molecule content. For physically compatible medications, risk analyses confirmed low probability and severity of a risk event. CONCLUSION: Co-administration of rhIGF-1/rhIGFBP-3 drug product with various medications was assessed by in vitro studies using case-by-case risk analyses to determine the suitability of the products for co-administration.

[Research advances on common detection biomarkers and methodology of children's growth and development assessment].

With the rapid dissemination of information in modern society, Chinese residents pay more attention to the scientific concept of childcare, which makes the child prevention and health care industry develop rapidly. The law of children's growth and development is extremely complex, so it is necessary to detect different biomarkers according to different growth and development evaluation angles. Human growth hormone(hGH), insulin-like growth factor-1(IGF-1), insulin-like growth factor binding protein-3(IGFBP-3), thyroid hormone, sex hormone, anti-müllerian hormone(AMH) and 25-hydroxy vitamin D(25-OH VD) are common biomarkers to monitor children's growth and development. This article aims to explain the concept and characteristics of common biomarkers of growth and development, summarize the detection methods of common biomarkers of growth and development evaluation developed in recent years, and provide a reference for children's prevention and health care to select appropriate detection biomarkers.

p.R209H GH1 variant challenges short stature assessment.

OBJECTIVE: to describe the marked variability in clinical and biochemical patterns that are associated with a p.R209H GH1 missense variant in a large Argentinean pedigree, which makes the diagnosis of GHD elusive. DESIGN: We describe a non-consanguineous pedigree composed by several individuals with short stature, including 2 pediatric patients with typical diagnosis of isolated growth hormone deficiency (IGHD) and 4 other siblings with severe short stature, low serum IGF-1 and IGFBP-3, but normal stimulated GH levels, suggesting growth hormone insensitivity (GHI) in the latter group. RESULTS: Patients with classical IGHD phenotype carried a heterozygous variant in GH1: c.626G>A (p.R209H). Data from the extended pedigree suggested GH1 as the initial candidate gene, which showed the same pathogenic heterozygous GH1 variant in the four siblings with short stature and a biochemical pattern of GHI. CONCLUSIONS: We suggest considering GH1 sequencing in children with short stature associated to low IGF-1 and IGFBP-3 serum levels, even in the context of normal response to growth hormone provocative testing (GHPT).

Etiology of short stature in Indian children and an assessment of the growth hormone-insulin-like growth factor axis in children with idiopathic short stature.

Background Our objectives were to evaluate the etiology of short stature, assess the prevalence of idiopathic short stature (ISS) and assess the growth hormone (GH)-insulin-like growth factor (IGF) axis in children with ISS. Methods A stepwise diagnostic evaluation was done in 394 children aged 4-16 years with short stature. Children with no definitive etiology were labeled as ISS. In these children, baseline IGF-1, IGF binding protein-3 (IGFBP-3) and stimulated IGF-1 after administration of GH for 4 days were measured. Results Hypothyroidism (in 18.1%) and ISS (in 15.5%) were the commonest causes of short stature. In children with ISS (n=61), the mean baseline and stimulated IGF-1 standard deviation scores (SDSs) were -1.2±1.0 and -0.3±1.4, respectively, with levels below -2 SDS in 13 (21%) and six (10%) children, respectively. In 33 (54%) of the ISS patients, response to GH was suboptimal (increment in the IGF-1 level <40%). There was no difference in the mean peak GH, IGFBP-3 and baseline and stimulated IGF-1 levels between children with familial and non-familial ISS. A significant positive correlation of height SDS with baseline IGF-1 SDS (r=0.28, p=0.026), stimulated IGF-1 SDS (r=0.32, p=0.010) and ΔIGF-1 SDS (r=0.26, p=0.036) was observed in children with ISS. Conclusions Hypothyroidism and ISS were the commonest etiologies for short stature. The baseline IGF-1 was below -2 SDS in 21% and the increment after GH stimulation was suboptimal in 54% of children, indicating that a substantial proportion of children with ISS had an impaired GH-IGF axis.

Assessment of insulin like growth factor-1 and IGF binding protein-3 in healthy Indian girls from Delhi and their correlation with age, pubertal status, obesity and thyroid hormonal status.

BACKGROUND: Population specific data and influence of sub-clinical hypothyroidism on insulin like growth factor-1 (IGF-1) and its binding protein-3 (IGFBP-3) in Indian children is lacking. This study was undertaken to evaluate serum IGF-1 and IGFBP-3 and their correlation with age, gender, pubertal status and thyroid functions. METHODS: A total of 840 apparently healthy school girls aged 6-18 years, were recruited for the study and underwent assessment of height, weight, body mass index, pubertal status and serum T3, T4, TSH, IGF-1, IGFBP-3 and IGF-1/IGFBP-3 molar ratio. RESULTS: The mean serum levels of IGF-1, IGFBP-3 levels and IGF-1/IGFBP-3 molar ratio were 381.8±240.5 ng/mL, 4.19±2.08 µg/mL and 40.5±37.2%, respectively. The serum IGF-1 and IGF-1/IGFBP-3 molar ratio increased significantly (p<0.0001) at 11 years followed by a steady yet non-significant rise till 16 years of age. A similar pattern was observed for IGFBP-3 showing a steep rise at 12 years and peaking at 16 years. Likewise, serum levels of IGF-1 and molar ratio of IGF-1/IGFBP-3 increased significantly with pubertal maturation from stage 1 to 3 and were higher in overweight girls compared to normal weight and obese girls. The growth factors were no different in girls with or without subclinical hypothyroidism. CONCLUSIONS: There was no significant impact of age on IGF-1 and IGFBP-3 in pre-pubertal girls. A sudden marked increase at 11 years followed by a gradual rise in growth factors till 16 years is indicative of pubertal initiation and maturation. Subclinical hypothyroidism did not influence growth factors in girls.

Nonandrogenic Anabolic Hormones Predict Risk of Frailty: European Male Ageing Study Prospective Data.

Context: Low levels of nonandrogenic anabolic hormones have been linked with frailty, but evidence is conflicting and prospective data are largely lacking. Objective: To determine associations between nonandrogenic anabolic hormones and prospective changes in frailty status. Design/Setting: A 4.3-year prospective observational study of community-dwelling men participating in the European Male Ageing Study. Participants: Men (n = 3369) aged 40 to 79 years from eight European centers. Main Outcome Measures: Frailty status was determined using frailty phenotype (FP; n = 2114) and frailty index (FI; n = 2444). Analysis: Regression models assessed relationships between baseline levels of insulinlike growth factor 1 (IGF-1), its binding protein 3 (IGFBP-3), dehydroepiandrosterone sulfate (DHEA-S), 25-hydroxyvitamin D (25OHD), and parathyroid hormone (PTH), with changes in frailty status (worsening or improving frailty). Results: The risk of worsening FP and FI decreased with 1 standard deviation higher IGF-1, IGFBP-3, and 25OHD in models adjusted for age, body mass index, center, and baseline frailty [IGF-1: odds ratio (OR) for worsening FP, 0.82 (0.73, 0.93), percentage change in FI, -3.7% (-6.0, -1.5); IGFBP-3: 0.84 (0.75, 0.95), -4.2% (-6.4, -2.0); 25OHD: 0.84 (0.75, 0.95); -4.4%, (-6.7, -2.0)]. Relationships between IGF-1 and FI were attenuated after adjusting for IGFBP-3. Higher DHEA-S was associated with a lower risk of worsening FP only in men >70 years old [OR, 0.57 (0.35, 0.92)]. PTH was unrelated to change in frailty status. Conclusions: These longitudinal data confirm the associations between nonandrogenic anabolic hormones and the changes in frailty status. Interventional studies are needed to establish causality and determine therapeutic implications.

Assessment of the Pharmacokinetics, Pharmacodynamics, and Safety of Single Doses of TV-1106, a Long-Acting Growth Hormone, in Healthy Japanese and Caucasian Subjects.

TV-1106 is a human serum albumin genetically fused to recombinant human growth hormone, designed to provide a long-acting alternative to daily growth hormone (GH) injections in patients with GH deficiency. This study investigated the pharmacokinetics, pharmacodynamics, and safety of single subcutaneous doses of TV-1106 (7.5, 15, 50, and 100 mg) in Japanese (n = 44) and caucasian (n = 44) healthy subjects. TV-1106 pharmacokinetics and pharmacodynamics were comparable in Japanese and caucasian populations. TV-1106 demonstrated relatively slow absorption (median tmax , 10-30 hours) and a mean elimination half-life of 26-36 hours. Apparent clearance and volume of distribution decreased with increasing TV-1106 doses in both populations and appeared to increase more than dose proportionality across the tested doses. Insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) increased in a dose-related manner, with maximum responses observed at 33-96 and 42-109 hours, respectively. IGF-1 and IGFBP-3 returned to baseline values at 168 hours following 7.5 and 15 mg of TV-1106, and 336 hours following 50 and 100 mg of TV-1106. TV-1106 appeared safe in both populations. There was no evidence of differences in pharmacokinetics, pharmacodynamics, or safety of TV-1106 between Japanese and caucasian populations. The data also demonstrate long-acting growth hormone properties of TV-1106 and support its potential for once-weekly dosing.

[Factors modulating food intake and energy expenditure prior to liver transplantation]. / Moduladores de la ingesta y el gasto calorico en un grupo de pacientes pre-transplante hepático.

BACKGROUND: There is a high prevalence of nutritional disorders in patients with liver cirrhosis (LC). This study was designed to assess the relationships between liver function, IFG-I/IGFBP-3, nutritional status, leptin, ghrelin and glucagon in 21 patients waiting for liver transplantation (LT). METHODS: We studied 21 men aged 56±2.1 years who were on the LT list. They were classified according to Child-Pugh(CP) score from low to high liver dysfunction in CPA (n=4),CPB (n=11) and CPC (n=6). Body mass index (BMI) was calculated and body fat (%) was measured by air-displacement plethysmography. Resting energy expenditure (REE) and its variation over Harris-Benedict values (GER%) were assessed by indirect calorimetry. Fasting serum samples were taken to measure albumin, glucose, insulin, HbA1c, leptin, total ghrelin,glucagon, IGF-I and IGFBP3. RESULTS: There were no differences in fat % and leptin values in the three groups according to CP classification. The CPC group showed higher ghrelin values than CPA and CPB(p<0.05). All groups displayed high glucagon levels and GER%values superior to 100%. Positive correlations were found between glucagon and GER% (r=0.56; p<0.01) and between glucagon and ghrelin values (r=0.66; p<0.01). IGF-I and IGFBP3 were low in all groups and showed a positive correlation with plasma albumin (r=0.52; p<0.05 and r=0.45; p<0.05 respectively). CONCLUSIONS: These results show an increase in ghrelin plasma values in patients with severe liver dysfunction. Hyperglucagonemia was correlated with GER%, supporting a role of glucagon in the hypermetabolic state associated to LC,raising the possibility of becoming a therapeutic target. The measurement of IGF-I/IGFBP3 represents a good marker of liver function in patients with LC.

Capacity to consent to biomedical research's evaluation among older cognitively impaired patients. A study to validate the University of California Brief Assessment of Capacity to Consent questionnaire in French among older cognitively impaired patients.

CONTEXT: Some studies have highlighted the difficulty for physicians to evaluate patient's ability to consent to bio-medical research in the elderly population. The University of California Brief Assessment of Capacity to Consent (UBACC) is a rapid questionnaire to assess the ability to consent, previously validated among schizophrenic patients. OBJECTIVE: To evaluate the accuracy of the UBACC scale, French version, to determine the capacity to consent to biomedical studies of older people with normal cognition, mild cognitive impairment (MCI) or Alzheimer Disease (AD). DESIGN: A prospective validation study between September 2008 to November 2011. SETTING: A Memory clinic. PATIENTS: We included 61 subjects in a memory clinic who had already consented to participate to a biomedical research and had signed a consent form. Those subjects, who had memory impairment, had a comprehensive neuro-psychological (including Mini Mental State Examination (MMSE)/30), clinical, biological assessment and brain imagery during day-care hospital. They were classified as MCI or AD patients. Control group included patients' caregivers without memory complaints and a normal comprehensive neuro-psychological assessment. INTERVENTION AND MEASUREMENTS: The consent form was once again explained to the subjects by a physician who subjectively evaluated if subjects had understood the study. Then, the 10 questions of the French version of the UBACC scale (max score 20) were asked to the participants. This scale evaluates the understanding of the study's aim, risks and benefits. A comparison was made between subjective assessment and the UBACC score. RESULTS: The physician considered that 18/61 patients (2 MCI and 16 AD) had not understood. These ones had a lower UBACC score (Score/20 (SD) [range]: 7.56 (3.03) [0-12] versus 17.72 (2.68) [13-28], p<0.001), a lower MMSE (Score/ 30 (SD): 21.1 (5.9) versus 27.3 (2.9); p<0.001) and were older (age (years old) 80.8 versus 76.6. p<0.0001) compared to those who had understood. Moreover, all the patients who had not understood had an UBACC score ≤ 12. The administration time was accurate in this population (<10 minutes). CONCLUSION: The UBACC scale, in its French version, was accurate to assess capacity to consent in an older, cognitively impaired population.

Functional and total IGFBP3 for the assessment of disorders of the GH/IGF1 axis in children with chronic kidney disease, GH deficiency, or short stature after SGA status at birth.

OBJECTIVE: IGFBP3 immunoreactivity may appear elevated in patients with chronic kidney disease (CKD), in part due to accumulation of low molecular fragments. The importance of these IGFBP3 variants for binding and inactivation of IGF1 and their relevance for the impaired growth of uremic children are unclear. Nevertheless, IGFBP3, measured as total (t-)IGFBP3, is frequently used as a diagnostic parameter in pediatric CKD patients. A new assay for functional (f-)IGFBP3 exclusively detects IGFBP3 capable of IGF binding. The aim of the study was to evaluate the significance of f-IGFBP3 measurements for the assessment of uremic abnormalities of the GH/IGF1 axis. DESIGN: Prospective cross-sectional study. METHODS: t-IGFBP3, f-IGFBP3, and IGF1 were measured in pediatric CKD patients, including patients with CKD stage 3-4 not on dialysis (CKD, n=33), on dialysis treatment (DT, n=26), patients after renal transplantation (RTx, n=89), healthy children (n=29), children with GH deficiency (GHD, n=42), and small for gestational age (SGA) children (SGA, n=34). RESULTS: Mean t-IGFBP3 SDS was elevated in CKD, DT, and RTx children compared with controls and GHD patients (P≤0.0004). Highest values were reached in DT (P<0.0001 vs all groups). In contrast, mean f-IGFBP3 was similar in all groups (P=0.30). CONCLUSIONS: Pediatric CKD patients displayed elevated serum concentrations of t-IGFBP3 but not f-IGFBP3, supporting the hypothesis that IGFBP3 fragments not binding IGF1 accumulate during uremia. f-IGFBP3 is an indicator of IGFBP3 fragmentation and seems to reflect IGF1 binding in CKD better than t-IGFBP3. However, the role of f-IGFBP3 for the diagnosis of disturbances of the GH/IGF hormonal axis appears to be limited.

Serum IGF-1, IGF-2 and IGFBP-3 as parameters in the assessment of liver dysfunction in patients with hepatic cirrhosis and in the diagnosis of hepatocellular carcinoma.

BACKGROUND/AIMS: Insulin like growth factor system becomes impaired in liver cirrhosis. Hepatocellular carcinoma (HCC) is associated with altered synthesis and secretion of several growth factors. METHODOLOGY: Studying the relation between serum levels of IGF-I, IGF-II and IGFBP-3 and clinical grades of liver disease according to Child-Pugh (C-P) score. Also, evaluation of their role in the diagnosis of HCC. IGF-I, IGF-II and IGFBP-3 were measured in 20 healthy subjects, 60 liver cirrhosis patients and 20 HCC patients included in the study. RESULTS: IGF-I, IGF-II and IGFBP-3 levels were significantly lower in cirrhotic patients compared to the healthy subjects and were correlated with the degree of liver dysfunction. IGF-I and IGFBP-3 levels in patients with HCC were significantly lower than in both healthy subjects and in patients with liver cirrhosis. Both IGF-II and AFP levels in HCC were significantly higher than in healthy subjects and in patients with liver cirrhosis. CONCLUSIONS: Estimation of serum IGF-I, IGF-II and IGFBP-3 together with C-P score is more effective in predicting hepatic dysfunction and its severity than C-P score alone. Serum IGF-II level can be used as a serological marker to discriminate HCC from cirrhosis.

Association of IGF-I and IGFBP-3 with health care costs and hospitalization: results from a prospective observational study.

OBJECTIVE: Previous cohort studies found robust associations of serum insulin-like growth factor I (IGF-I) and its main binding protein IGFBP-3 with increased morbidity or mortality. This study investigates the relationships between IGF-I and IGFBP-3 with health care costs and hospitalization in a general population and whether adding IGF-I or IGFBP-3 to a model of established health care predictors improves prediction. METHODS: Data from a population-based cohort study of 3139 men and women in Germany, aged 20 to 80 years at baseline were used (median follow-up time: 5.0 years). Self-reported physician visits, length of hospital stay were used to estimate annual costs. IGF-I and IGFBP-3 were categorized at the 10th and 90th percentile, to indicate 'low', 'intermediate', and 'high' concentrations, respectively. RESULTS: Total annual health care costs, with the major component of inpatient costs, and risk of hospitalization at baseline and follow-up were higher in subjects with low compared to intermediate IGF-I or IGFBP-3, after multivariable-adjustment. Subjects with low in contrast to intermediate IGF-I exhibited 30.6% higher annual total costs 5 years after baseline examination, corresponding to a difference in adjusted costs of EUR436.61. CONCLUSIONS: Low IGF-I and IGFBP-3 independently predict future health care costs and hospitalization. IGF-I or IGFBP-3 might be useful to identify subjects with excess health care use. The predictive performance of cross-sectional and longitudinal models of total and inpatient costs were slightly improved by adding IGF-I or IGFBP-3 but the cost-effectiveness of inclusion into prediction models needs to be examined.

Serum insulin-like growth factor I (IGF-I), IGF-binding proteins 2 and 3, and the risk for development of malignancies in adults with growth hormone (GH) deficiency treated with GH: data from KIMS (Pfizer International Metabolic Database).

CONTEXT: The association between IGFs and cancer in adults with GH deficiency (GHD) receiving GH replacement requires investigation. OBJECTIVE: The objective was to examine the association between IGF-I, IGF-binding protein 2 (IGFBP-2), and IGFBP-3 SD scores (SDSs) in GH-deficient adults receiving GH therapy and the occurrence of de novo malignancies. DESIGN: Serum IGF-I, IGFBP-2, and IGFBP-3 levels in GH-deficient patients who developed a malignancy since receiving GH were compared with patients with idiopathic GHD but without malignancy. Measurements were related to age-, sex-, and body mass index-specific SDS reference regions. SETTING: The setting included the KIMS (the Pfizer International Metabolic Database). PATIENTS: One hundred patients with de novo malignancy during GH therapy were compared with 325 patients with idiopathic GHD without malignancy. INTERVENTION(S): Serum samples were obtained as close as possible to the diagnosis of malignancy, or after approximately 2 yr of GH replacement in KIMS. MAIN OUTCOME MEASURES: Associations between relative risk (RR) of malignancy and IGF-I, IGFBP-2, and IGFBP-3 SDSs were assessed in multiple log-linear Poisson working regression models, controlling for age, sex, onset of GHD, and GH naivety at KIMS entry. RESULTS: No association between IGF-I SDSs and RR was observed (P = 0.48). Increasing IGFBP-2 and IGFBP-3 SDSs were associated with increasing RRs [18% per unit IGFBP-2 SDSs (95% confidence interval, 7-30%; P = 0.0006), 13% per unit IGFBP-3 SDS (2-26%; P = 0.01)]. CONCLUSIONS: IGF-I levels targeted to within normal age-related reference ranges during GH replacement were not associated with the occurrence of malignancies. Higher IGFBP-2 and/or IGFBP-3 SDSs may be associated with increased cancer risk.

Usefulness of serum insulin-like growth factor I assessment in the diagnosis of childhood-onset growth hormone deficiency.

The diagnosis of childhood-onset growth hormone (GH) deficiency (GHD) is not straightforward, requiring a comprehensive clinical, anthropometric, biochemical, endocrine, and neuroradiological assessment. Although pharmacological GH stimulation tests are still considered the gold standard for GHD diagnosis, they are burdened by both poor specificity and side effects. The measurement of insulin-like growth factor I (IGF-I), due to its close GH dependency, was proposed for diagnosing GHD. However, a number of factors may affect the measurements. Herein, we propose an algorithm based on both IGF-I determination and anthropometry, aimed at simplifying the diagnosis of GHD in prepubertal children.

Predictors of variation in serum IGF1 and IGFBP3 levels in healthy African American and white men.

BACKGROUND: Individual variation in circulating insulinlike growth factor-1 (IGF1) and its major binding protein, insulinlike growth factor binding protein-3 (IGFBP3), have been etiologically linked to several chronic diseases, including some cancers. Factors associated with variation in circulating levels of these peptide hormones remain unclear. METHODS: Multiple linear regression models were used to determine the extent to which sociodemographic characteristics, lifestyle factors, personal and family history of chronic disease, and common genetic variants, the (CA)n repeat polymorphism in the IGF1 promoter and the IGFBP3-202 A/C polymorphism (rs2854744) predict variation in IGF1 or IGFBP3 serum levels in 33 otherwise healthy African American and 37 white males recruited from Durham Veterans Administration Medical Center. RESULTS: Predictors of serum IGF1, IGFBP3, and the IGF1:IGFBP3 molar ratio varied by race. In African Americans, 17% and 28% of the variation in serum IGF1 and the IGF1:IGFBP3 molar ratio, were explained by cigarette smoking and carrying the IGF1 (CA)19 repeat allele, respectively. Not carrying at least 1 IGF1 (CA)19 repeat allele and a high body mass index explained 8% and 14%, respectively, of the variation IGFBP3 levels. These factors did not predict variation of these peptides in whites. CONCLUSION: If successfully replicated in larger studies, these findings would add to recent evidence, suggesting known genetic and lifestyle chronic disease risk factors influence IGF1 and IGFBP3 circulating levels differently in African Americans and whites.

Mortality and serum insulin-like growth factor (IGF)-I and IGF binding protein 3 concentrations.

BACKGROUND: Previous studies provided conflicting results regarding the association of serum IGF-I or IGF-binding protein-3 (IGFBP-3) and mortality. The aim of this study was to assess the relation of IGF-I and IGFBP-3 levels with mortality from all causes, cardiovascular disease (CVD), and cancer in a prospective population-based study. METHODS: From the Study of Health in Pomerania (SHIP) 1988 men and 2069 women aged 20-79 yr were followed up on average 8.5 yr. Causes of deaths were coded according to the International Classification of Diseases, 10th revision. Serum IGF-I and IGFBP-3 levels were determined by chemiluminescence immunoassays and categorized into three groups (low, normal, high) according to the sex- and age-specific 10th and 90th percentiles. RESULTS: Adjusted analyses revealed that men with low but not high IGF-I levels had an almost 2-fold higher risk of all-cause mortality [hazard ratio (HR) 1.92 (95% confidence interval [CI] 1.35; 2.73)], CVD mortality [HR 1.92 (95% CI 1.00; 3.71)], and cancer mortality [HR 1.85 (95% CI 1.00; 3.45)] compared with men with normal IGF-I levels. In women, no association between IGF-I and mortality was found. Moreover, low IGFBP-3 levels were associated with higher all-cause mortality in men [HR 1.87 (95% CI 1.31; 2.64)] and women [HR 1.63 (95% CI 0.96; 2.76)]. CONCLUSIONS: The present study found inverse associations between IGF-I or IGFBP-3 levels and mortality from all causes, CVD, or cancer in men and between IGFBP-3 and all-cause mortality in women.

Deoxybenzoins are novel potent selective estrogen receptor modulators.

Deoxybenzoins are plant compounds with similar structure to isoflavones. In this study, we evaluated the ability of two synthesized deoxybenzoins (compound 1 and compound 2) (a) to influence the activity of the estrogen receptor subtypes ERalpha and ERbeta in HeLa cells co-transfected with an estrogen response element-driven luciferase reporter gene and ERalpha- or ERbeta-expression vectors, (b) to modulate the IGFBP-3 and pS2 protein in MCF-7 breast cancer cells, (c) to induce mineralization of KS483 osteoblasts and (d) to affect the cell viability of endometrial (Ishikawa) and breast (MCF-7, MDA-MB-231) cancer cells. Docking and binding energy calculations were performed using the mixed Monte Carlo/Low Mode search method (Macromodel 6.5). Compound 1 displayed significant estrogenic activity via ERbeta but no activity via ERalpha. Compound 2 was an estrogen-agonist via ERalpha and antagonist via ERbeta. Both compounds increased, like the pure antiestrogen ICI182780, the IGFBP-3 levels. Compound 2 induced, like 17beta-estradiol, significant mineralization in osteoblasts. The cell viability of Ishikawa cells was unchanged in the presence of either compound. Compound 1 increased MCF-7 cell viability consistently with an increase in pS2 levels, whereas compound 2 inhibited the cell viability. Molecular modeling confirmed the agonistic or antagonistic behaviour of compound 2 via ER subtypes. Compound 2, being an agonist in osteoblasts, an antagonist in breast cancer cells, with no estrogenic effects in endometrial cancer cells, makes it a potential selective estrogen receptor modulator and a choice for hormone replacement therapy.

The effect of economic status on height, insulin-like growth factor (IGF)-I and IGF binding protein-3 concentrations in healthy Turkish children.

OBJECTIVES: The effect of economic status (ES) on growth, insulin-like growth factor (IGF)-I and IGF-binding protein (IGFBP)-3 in healthy children is not well characterized. We aimed to study the interrelationship between height, weight, IGF-I, IGFBP-3, mid-parental height (MPH) and ES. DESIGN/SUBJECTS: Eight hundred and fourteen healthy children (428 boys, 386 girls; age 3-18 years) were classified according to income of the families as low, middle and high. Standard deviation scores (SDSs) of height, weight, MPH, IGF-I and IGFBP-3 were compared between the groups. The combined effect of these parameters and ES on height SDS was investigated with complex statistical models. RESULTS: There was a significant trend for height and weight SDSs to increase with higher income levels in boys, but not in girls. Body mass index (BMI) SDSs were similar in three groups. There was a general trend for MPH SDS to increase with income levels in both sexes. In boys, IGF-I SDS was significantly higher in high ES group than low ES. In girls, IGFBP-3 SDSs were significantly higher in high ES group than in middle ES group. For both genders, height SDS was highly correlated with weight SDS and moderately correlated with BMI SDS, MPH SDS and IGF-1 SDS. All correlations were significant and positive. Complex models showed that MPH (19%), IGF-I (13%) and ES (3%) in boys, and MPH (16%) and IGF-I (7%) in girls have significant contribution to height SDSs. CONCLUSIONS: ES per se, independent of overt malnutrition, affects height, weight, IGF-I and IGFBP-3 with some gender differences in healthy children. Influence of income on height and weight show sexual dimorphism, a slight but significant effect is observed only in boys. MPH is the most prominent variable effecting height in healthy children. Higher height and MPH SDSs observed in higher income groups suggest that secular trend in growth still exists, at least in boys, in a country of favorable economic development.

Timing of puberty determines serum insulin-like growth factor-I in late adulthood.

CONTEXT: IGFs may play an important role in disease etiology, especially cancer. Changes in diet can alter acute levels, but little is known about life course influences on IGF levels. OBJECTIVE: The objective of the study was to examine the association between timing of puberty and adulthood serum IGFs (IGF-I and IGF binding protein-3). DESIGN: This was a retrospective cohort study. SETTING: Male pupils who attended a single school in Southern England were part of the study. PARTICIPANTS: Participants in the study were a cohort of 1028 men born between 1927 and 1956 with anthropometric measures between 9 and 18 yr and adulthood serum IGF levels. MAIN OUTCOME MEASURE: The study measured serum IGF-I and IGF binding protein-3 at mean age 63 yr. RESULTS: Age at peak height velocity (APHV) was inversely associated with adult IGF-I levels. IGF-I decreased by 3.7 ng/ml (95% confidence interval 1.0-6.4, P = 0.007) for each sd increase in APHV. Prepubertal childhood height and body mass index were both inversely associated with APHV (P trend < 0.001). APHV was positively associated with adult height and inversely associated with adult body mass index. Adjustment for childhood, adult anthropometry, and other lifestyle factors did not substantially alter the association between APHV and adult IGF-I. CONCLUSIONS: This is the first study to document an association between timing of puberty and adult IGF-I levels. A better understanding of life course determinants of the IGF system may provide new insights into disease etiology and primary prevention.

Ghrelin test for the assessment of GH status in successfully treated patients with acromegaly.

OBJECTIVE: Posttreatment assessment of disease activity and definition of cure of acromegaly, using measurement of GH secretion, remains problematic. Furthermore, with our efforts to achieve tight biochemical control of the disease it is foreseeable that a proportion of patients may be rendered GH deficient, thus requiring testing for GH deficiency. The aim of our study was to evaluate residual GH secretion in cured patients with acromegaly. DESIGN AND METHODS: At baseline, circulating GH, IGF-I, IGFBP-3, leptin and lipid (cholesterol and tri-glycerides) levels were measured in 33 acromegalic patients nine years after treatment with surgery of whom 6 were additionally irradiated. Two tests were performed: the GH suppression test--oral glucose tolerance test (OGTT) and the GH provocation test--ghrelin test (1 microg/kg i.v. bolus) and the results were compared with 11 age- and sex-matched control subjects. RESULTS: According to the consensus criteria (normal IGF-I levels and post-OGTT GH nadir <1 microg/l), 21 treated acromegalic patients were cured, 6 had discordant IGF-I and GH nadir values during OGTT, while 6 had persistent acromegaly. After the GH provocative test with ghrelin (cut-off for severe GH deficiency is GH <3 microg/l), we detected 9 severely GH deficient patients (GHD) among 21 cured acromegalic patients. Mean GH peak (+/-s.e.m.) response to the ghrelin test in GHD acromegalics was significantly lower compared with acromegalics with sufficient GH secretory capacity and control subjects (1.2 +/- 0.2 microg/l vs 20.1 +/- 2.4 microg/l vs 31.1 +/- 2.5 microg/l respectively, P<0.0001). Mean IGF-I and IGFBP-3 levels were not different between GHD and GH-sufficient cured acromegalics. Leptin levels and body mass index (BMI) were significantly higher in GHD male acromegalics compared with GH-sufficient male acromegalics. GHD female acromegalics tended to have higher BMIs while leptin levels were not different. CONCLUSIONS: The assessment of residual GH secretory capacity by the GH provocation test is necessary in the long-term follow-up of successfully treated acromegalics since a large proportion of these patients are rendered GH deficient.