Studies on the hormonal regulation of bone metabolism in men have indicated covariation between insulin-like growth factor-I (IGF-I) and sex hormones with bone mineral density (BMD). In this study the relationships between BMD in total body, lumbar spine, femoral neck, distal and ultradistal (UD) radius and circulating levels of IGFs, IGF binding proteins (IGFBPs), and sex steroids were investigated in 55 Swedish men between 22 and 85 (52 +/- 18, mean +/- SD) years of age. BMD in total body, distal and UD radius, and femoral neck was positively correlated with serum IGF-I (r = 0.31 to 0.49), IGF-II (r = 0.32 to 0.48), IGFBP-3 (r = 0.37 to 0.53), and free androgen index (FAI) (r = 0.32 to 0.40), and negatively with IGFBP-1 (r = -0.37 to -0.41) and IGFBP-2 (r = -0.29 to -0.41) levels. A positive correlation was observed between BMD in femoral neck and estradiol/SHBG ratio (r = 0.34, P = 0.01). Age correlated negatively with serum IGF-I, IGF-II, IGFBP-3, FAI, estradiol/SHBG ratio, and BMD in total body, distal and UD radius, and femoral neck, and positively with IGFBP-1, IGFBP-2, and SHBG levels. According to stepwise multiple regression analyses, a combination of weight, IGFBP-3, and testosterone accounted for 43% of the variation in BMD in femoral neck, 34% in ultradistal radius and 48% in total body (P
Insulin-like growth factor (IGF)-I, a mitogenic and anti-apoptotic peptide, has been implicated in the development of several cancers. We hypothesized that high circulating IGF-I concentrations may be associated with an increased risk of ovarian cancer. A case-control study was nested within 3 prospective cohorts in New York (USA), Ume? (Sweden) and Milan (Italy). One hundred thirty-two women with primary invasive epithelial ovarian cancer diagnosed at least 1 year after blood donation were case subjects. For each case, 2 control subjects were selected, matching the case subject on cohort, menopausal status, age and date of recruitment (n = 263). Only women who did not use exogenous hormones at blood donation were included in the study. There was no association between IGF-I concentrations and ovarian cancer risk in the study group as a whole. In analyses restricted to subjects who had developed ovarian cancer at a young age (
OBJECTIVE: The study was to determine the incidence of GH deficiency (GHD) following cranial radiotherapy (RT) for a childhood brain tumour in a large population based study and analyse the biological effective dose (BED) to the hypothalamus/pituitary (HP) region as a risk factor. DESIGN: BED was assessed by use of the linear-quadratic (LQ) model, which gives a means of expressing the biological effect of various treatment schedules in a uniform way. In patients aged >/= 18 years (n = 53) GH status was assessed by an insulin-tolerance test (ITT) (n = 34), however, in patients with seizure disorders (n = 19), and in 20 children aged /= 18 and
Effect of severe growth hormone (GH) deficiency due to a mutation in the GH-releasing hormone receptor on insulin-like growth factors (IGFs), IGF-binding proteins, and ternary complex formation throughout life.
Measurement of the insulin-like growth factors (IGFs) and their binding proteins has become commonplace in the indirect assessment of the integrity of the GH axis. However, the relative effect of GH deficiency (GHD) on each component of the IGF axis and the merit of any one parameter as a diagnostic test have not been defined in a homogeneous population across all ages. We therefore measured IGF-I, IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-2, IGFBP-3, and acid labile subunit (ALS) in 27 GHD subjects (aged 5-82 yr) from an extended kindred in Northeast Brazil with an identical GHRH receptor mutation and in 55 indigenous controls (aged 5-80 yr). The effect of GHD on the theoretical distribution of IGFs between the IGFBPs and the ternary complex was also examined. All components of the IGF axis, measured and theoretical, showed complete separation between GHD and control subjects, except IGFBP-1 and IGFBP-2 concentrations, which did not differ. The most profound effects of GHD were on total IGF-I, IGF-I in the ternary complex, and ALS. The proportion of IGF-I associated with IGFBP-3 remained constant throughout life, but was significantly lower in GHD due to an increase in IGF-I/IGFBP-2 complexes. IGF-I in the ternary complex was determined principally by concentrations of ALS in GHD and IGFBP-3 in controls, implying that ALS has greater GH dependency. In the controls, IGF-II was associated primarily with IGFBP-3 and to a lesser extent with IGFBP-2, whereas in GHD the reverse was found. There was also a dramatic decline in the proportion of free ALS in GHD adults that was not evident in controls. As diagnostic tests, IGF-I in the ternary complex and total IGF-I provided the greatest separation between GHD and controls in childhood. Similarly, in older adults the best separation was achieved with IGF-I in the ternary complex, with free ALS being optimal in younger adults. Severe GHD not only reduces the amounts of IGFs, IGFBP-3, and ALS, but also modifies the distribution of the IGFs bound to each IGFBP. Diagnostic tests used in the investigation of GHD should be tailored to the age of the individual. In particular, measurement of IGF-I in the ternary complex may prove useful in the diagnosis of GHD in children and older adults, whereas free ALS may be more relevant to younger adults.
Effect of sex hormone replacement on the insulin-like growth factor system and bone mineral: a cross-sectional and longitudinal study in 595 perimenopausal women participating in the Danish Osteoporosis Prevention Study.
This study used a cross-sectional design to investigate relationships among serum insulin-like growth factor (IGF) parameters (total serum IGF-I, IGF-II, and IGF-binding protein-3), serum estradiol, and bone mineral density (BMD) stratified for potential confounders, and a longitudinal design to investigate the effects of hormonal replacement therapy (HRT) on IGFs and BMD. Five hundred and ninety-five perimenopausal women (median age, 50.0 yr; range, 45-56 yr) participating in the Danish Osteoporosis Prevention Study were investigated in a cross-sectional study, and a randomly selected subgroup of 110 was followed after 5 yr in a longitudinal study for changes in serum IGFs and BMD of lumbar spine, femoral neck, and ultradistal forearm during (n = 46) or without HRT (n = 64). In the cross-sectional study, serum IGF-I correlated positively to distal forearm BMD and spine BMD, but not to femoral neck BMD, after stratification for age, body mass index, and other variables. In the follow-up study, HRT decreased IGF-I and IGF-II, but did not influence the age-related decline in IGF-binding protein-3 significantly. Serum alkaline phosphatase and urinary hydroxyproline/creatinine ratio both decreased during HRT, whereas BMD increased compared to control values. After adjustment for age, body mass index, treatment, and other factors, IGF-I correlated positively to changes in forearm and femoral neck BMD, but not to changes in spine BMD. We conclude that serum IGF-I was positively associated to bone mineral density. Oral HRT decreases IGF-I and IGF-II.
OBJECTIVE: Antiepileptic drugs (AEDs) have endocrine effects that may interfere with growth and sexual maturation in children. The aim of this study was to evaluate the effects of AEDs on growth and pubertal development in girls with epilepsy. STUDY DESIGN: Forty girls taking valproate (VPA), 19 girls taking carbamazepine (CBZ), and 18 girls taking oxcarbazepine (OXC) for epilepsy and 49 healthy control girls participated in the study, which included a cross-sectional clinical examination when the girls were 8 to 18 years old and a longitudinal growth analysis from the age of 1 year. RESULTS: VPA, CBZ, or OXC did not affect linear growth or pubertal development in girls with epilepsy. However, the patients taking VPA gained weight, and an increase in relative weight was seen in girls who started their medication before as well as during puberty. The body mass index of the VPA-treated girls (19.8 +/- 4.8 kg/m2) was higher than that of the control girls (18.0 +/- 2.5 kg/m2) at clinical examination. The weight of the girls taking CBZ or OXC for epilepsy was similar to that of the control girls. Plasma insulin-like growth factor-I (IGF-I) levels were higher in girls treated with CBZ and OXC than in the control girls, but AEDs did not affect fasting serum insulin, IGF-binding protein-1, or IGF-binding protein-3 concentrations in girls on VPA, CBZ, or OXC medication during the period of exposure (average 2.8, 4.1, and 1.9 years, respectively) in this study. CONCLUSIONS: AEDs do not seem to have any adverse effects on linear growth or sexual maturation in girls with epilepsy. VPA-related weight gain can be seen already in prepuberty and it is not associated with hyperinsulinemia in these young patients. The clinical significance of high circulating concentrations of IGF-I in patients taking CBZ or OXC remains to be defined.
Patients with beta-thalassemia major still suffer growth retardation. After excluding patients with cortisol deficiency, hypothyroidism, hypogonadism, delayed puberty, malnutrition, severe congestive heart failure, and severely impaired liver function, 29 patients were enrolled in this study. Fifteen (52%) patients exhibited growth retardation and underwent two growth hormone (GH) provocation tests. Eight (53%) of the 15 patients had GH deficiency and were subsequently treated with subcutaneous recombinant human GH (Genotropin, Pharmacia Corporation, Sweden). Growth velocity increased from the pretreatment rate of 3.1+/-0.4 cm/year to 7.1+/-1.6 cm/yr (p
PURPOSE: Insulin-like growth factor-I (IGF-I) stimulates proliferation and inhibits apoptosis in prostate cancer cells, and IGF-I has been associated with increased prostate cancer risk in some, but not all, epidemiologic studies. SUBJECTS AND METHODS: We extended our previous case-control study nested in the Northern Sweden Health and Disease Cohort, a population-based cohort from a region where little prostate specific antigen (PSA) screening is done. Levels of IGF-I and IGF binding protein-3 (IGFBP-3) were measured in prediagnostic blood samples from a total of 281 men who were subsequently diagnosed with prostate cancer after recruitment (median, 5 years after blood collection) and from 560 matched controls. RESULTS: Logistic regression analyses showed increases in prostate cancer risk with increasing plasma peptide levels, up to an odds ratio (OR) for top versus bottom quartile of IGF-I of 1.67 (95% CI, 1.02 to 2.71; Ptrend = .05), which was attenuated after adjustment for IGFBP-3 to an OR of 1.47 (95% CI, 0.81 to 2.64; P (trend) =.32). For men younger than 59 years at recruitment, OR for top versus bottom quartile of IGF-I was 4.12 (95% CI, 1.01 to 16.70; Ptrend = .002), which was significantly stronger than for men older than 59 years (P (interaction) = .006). For men with advanced cancer, OR for top versus bottom quartile of IGF-I was 2.87 (95% CI, 1.01 to 8.12; Ptrend = .10). CONCLUSION: Our data add further support for IGF-I as an etiologic factor in prostate cancer and indicate that circulating IGF-I levels measured at a comparatively young age may be most strongly associated with prostate cancer risk.
Prospective cohort studies on breast cancer risk among premenopausal women and insulin-like growth factor I (IGF-I) concentrations have so far included only few cases, and have shown inconsistent relative risk estimates. We pooled 220 cases of breast cancer diagnosed before age 50, and 434 control subjects, from three prospective studies in New York (USA), Umeå (Northern Sweden) and Milan (Italy), and we measured IGF-I and insulin-like growth factor binding protein 3 (IGFBP-3) with common enzyme-linked immunosorbent assays. Overall, IGF-I and IGFBP-3 measurements obtained by the common method showed a positive but not significant relationship with breast cancer risk (odds ratios (ORs) 0.90 [95% confidence intervals (95% CI) 0.50-1.62], 1.63 [0.89-2.97], 1.46 [0.78-2.73] and 1.41 [0.75-2.63] for quintiles of IGF-I, and ORs 0.98 [0.54-1.75], 1.06 [0.59-1.91], 1.04 [0.58-1.87] and 1.77 [0.97-3.24] for quintiles of IGFBP-3). Our results give only moderate support for an association of blood IGF-I with breast cancer risk in young women.