The ratio between serum levels of insulin-like growth factor (IGF)-I and the IGF binding proteins (IGFBP-1, 2 and 3) decreases with age in healthy adults and is increased in acromegalic patients

OBJECTIVE Several in-vitro studies have suggested that the biological actions of IGF-I can be modified by the presence of specific IGF binding proteins. In man, the 24-hour serum levels of IGF-I and IGFBP-3 remain constant, but short-term changes in the IGF-l/IGFBP-3 ratio have been described following GH administration. Serum levels of IGF-I and IGFBP-3 decrease with age in normal adults and are elevated In active acromegaly due to excessive GH secretion. However, the Individual ratios between serum levels of IGF-I and IGFBP-3 in acromegalic and healthy adults have not been described previously. METHODS AND MATERIALS We studied this ratio In 198 healthy adults and In 56 acromegalic patients, grouped according to their serum GH levels (group I GH < 2mLU/l II GH 2–10mLU/l; III GH > 10mLU/l). In all subjects a single blood sample was drawn for IGF-I, IGF-II, IGFBP-1, IGFBP-2, IGFBP-3 and GH measurements by specific RIAs. In 38 of the patients a 24-hour urinary collection was performed for GH determination. RESULTS In healthy adults serum levels of IGF-I and IGFBP-3 decreased with Increasing age (r =?0.52 and r=?0.34, respectively, P< 0.0001). In addition, the molar IGF-l/IGFBP-3 ratio declined with increasing age (r =?0.44, P – 0.0001). In patients with acromegaly and high serum GH levels (group III), circulating IGF-I was increased 7–97 standard deviations (SDS) and IGFBP-3 was increased 4.20 SOS (P < 0.0001). Serum levels of IGF-II were normal in all three groups (588 ± 240μ/l) whereas IGFBP-1 and IGFBP-2 levels were low and IGFBP-2 levels decreased significantly with increasing serum GH levels (P < 0.0001). The molar IGF-l/IGFBP-3 ratio in the acromegalic patients was significantly higher than in the controls (P < 0.0001) and correlated significantly with urinary GH excretion (r = 0.67, P < 0.0001) as well as with serum GH levels (r = 0.73, P < 0.0001). CONCLUSION We demonstrated a decreasing molar IGF-l/IGFBP-3 ratio with increasing age in healthy adults and an increased ratio between serum IGF-I and IGFBP-3 levels in acromegalic patients. As IGF-II is normal and IGFBP-1 and IGFBP-2 are inversely correlated to the serum GH levels In the acromegalic patients, we speculate that the molar ratio between IGF-I and IGFBP-3 reflects free (biologically active) IGF-I and Is dependent on GH levels.     

Paradoxical elevations in serum IGF-II and IGF binding protein-2 in acromegaly: insights into the regulation of these peptides

OBJECTIVE: Circulating insulin-like growth factor (IGF)-II and IGF binding protein-2 (IGFBP-2) are frequently altered, often in parallel, in numerous pathologies including neoplastic disease but little is known about their normal regulation. This study compared serum IGF-II and IGFBP-2 distributions between acromegalics and a large normal adult population to explore possible determinants. PATIENTS: Sixty acromegalic patients undergoing screening colonoscopy (age range 25-81 years); normative data from 306 healthy adults (age range 20-89 years). MEASUREMENTS: Serum IGF-I, IGF-II, IGFBP-2 and IGFBP-3 were measured in healthy adults and acromegalics. Mean growth hormone (GH) levels were obtained for acromegalic patients. Differences were compared using t-tests (unadjusted) and multiple regression models (adjusted for age and gender). Correlations were expressed as Pearson's coefficient (r). RESULTS: For acromegalic patients, GH was significantly correlated with IGF-I (r = 0.50; P < 0.001) and IGFBP-3 (r = 0.29; P = 0.03) but not IGF-II or IGFBP-2. Contrary to expectations, mean IGF-II and IGFBP-2 levels were significantly raised in the acromegalics compared with normals [adjusted mean difference (95% CI) = 226 (181, 271) microg/l and 305 (200, 410) microg/l, respectively]. Ten acromegalic patients had colorectal neoplasia but their presence did not contribute to the elevations in serum IGF-II and IGFBP-2. The (IGF-I + IGF-II)/IGFBP-3 molar ratios were remarkably constant in both healthy adults and acromegalics, but the relationships of the ligands individually with IGFBP-3 were not linear: as IGFBP-3 increased, IGF-I also increased whereas IGF-II initially increased but then decreased. IGFBP-2 did not correlate with IGF-II, but molar concentration significantly correlated with the IGF-II/IGFBP-3 molar ratio (r = 0.40; P = 0.001). CONCLUSIONS: Serum IGF-II and IGFBP-2 levels were paradoxically elevated in acromegalics, independent of the presence of colorectal neoplasia. The (IGF-I + IGF-II)/IGFBP-3 molar ratio appears to be pivotal in determining IGF-II values, which, in turn, expressed as a ratio of IGFBP-3, is related to IGFBP-2. These observations offer new insights into the regulation of these peptides.     

Short-term changes in serum insulin-like growth factors (IGF) and IGF binding protein 3 after different modes of intravenous growth hormone (GH) exposure in GH-deficient patients.

Virtually all circulating insulin-like growth factors I and II (IGF-I and IGF-II) are bound to specific binding proteins (IGFBP), of which IGFBP-3 is the quantitatively most important. The mechanisms regulating the close coordination between serum levels of IGFs and IGFBP-3 is poorly understood. We therefore evaluated the temporal association of serum IGF-I, IGF-II, and IGFBP-3 measured by RIAs after well defined short-term GH exposure in GH-deficient patients. Six patients (mean +/- SE age: 20.5 +/- 1.1 yr) each underwent three GH study protocols in random order. Each study was preceded by 4 weeks without GH therapy. Two units of GH were administered iv as either: 1) two boluses, 2) eight boluses, or 3) a constant infusion. The duration of each study was 44 h including at least 16 h after termination of GH administration. Increments in serum IGF-I occurred 4-6 h after initiated GH exposure in all studies. In the two-bolus study the IGF-I increase was modest with mean +/- SE peak values of 12.4 +/- 2.1 nmol x L-1 after GH administration. In the eight bolus and constant infusion studies significantly higher IGF-I levels were generated: 17.0 +/- 2.2 nmol x L-1 (8 bolus) and 18.8 +/- 1.1 h nmol x L-1 (infusion). In contrast the time course change in serum IGF-II did not differ in the three studies, and it was characterised by a sluggish increase of approximately 30% evidenced after 16-20 h. The changes in IGFBP-3 were almost identical in the three studies. After a lag phase of approximately 18-20 h a gradual increase of approximately 40%, which had not ceased at the end of the study period, was observed. The molar ratio of serum IGF-I plus IGF-II:serum IGFBP-3 remained constant with values between 0.8-0.9 except in the constant infusion experiment, in which the ratio increased significantly with time reaching a mean peak value, which exceeded 1.0, after 24 h. Our data suggest that a pulsatile GH pattern is not superior to constant GH levels as regards generation of IGFs and IGFBP. The earlier increase in serum IGF-I compared to IGF-II and IGFBP-3 suggests that IGF-I may be the main regulator of IGFBP-3 production. Accordingly, the slow increase in serum IGF-II, which paralleled that of IGFBP-3, could indicate that serum IGF-II levels mainly depend on the concentration or binding site availability of IGFBP-3.     

Influence of a single course of antenatal betamethasone on the maternal-fetal insulin-IGF-GH axis in singleton pregnancies.

OBJECTIVE: We examined the hypothesis that a single course of antenatal betamethasone influences the maternal-fetal insulin-IGF-GH axis. DESIGN: A prospective, observational, pilot study consisting of four groups of pregnant women: (I) received betamethasone and delivered <2 weeks post treatment; (II) received betamethasone and delivered >2 weeks post treatment; (III) untreated women who delivered <37 weeks (preterm controls); (IV) untreated women who delivered >37 weeks (term controls). Maternal and mixed umbilical cord blood was collected at delivery and analyzed for insulin, glucose, IGF-I, IGF-II, IGFBP-1, IGFBP-3, GH, and GHBP. RESULTS: Betamethasone increased maternal insulin, glucose and IGF-I levels without affecting IGFBPs. In the fetal compartment, betamethasone treatment was associated with a delayed suppressive effect on GH and a sustained suppressive effect on IGF-II levels. There were no differences in infant size or neonatal morbidities between patients who delivered <2 weeks or >2 weeks post betamethasone treatment. In Group IV, birth weight correlated positively with cord IGF-I levels (r2=0.41, p=0.0098) and negatively with cord IGFBP-1 levels (r2=0.51, p=0.0039), and ponderal index correlated negatively with cord IGFBP-1 levels (r2=0.27, p<0.05). CONCLUSIONS: A single course of antenatal betamethasone influences the maternal-fetal insulin-IGF-GH axis, particularly fetal IGF-II levels, without measurable anthropometric changes at birth. Whether these effects have implications beyond the neonatal period remains to be determined.     

Effects of growth hormone treatment on serum levels of insulin-like growth factors (IGFs) and IGF binding proteins 1-4 in postmenopausal women

BACKGROUND AND OBJECTIVE: Insulin-like growth factor binding proteins (IGFBPs) modulate the actions and bioavailability of insulin-like growth factors (IGFs), however, their regulation in vivo is incompletely understood. In this study we investigated the effects of different doses of growth hormone (GH) on circulating levels of IGFs and IGFBPs. DESIGN: The study was double-blind and placebo-controlled. Patients were treated with either GH in doses of 0.05, 0.10, or 0.20 lU/kg/day of placebo for one week. PATIENTS: Forty post-menopausal women aged 52-73 years with low bone mass. MEASUREMENTS: Serum IGF-I and IGF-II were measured by RIA while IGFBP-1-3 were measured by Western ligand blot (WLB) and compared with determinations by specific immunoassays. IGFBP-4 was measured by WLB alone. RESULTS: Both IGF-I (P < 0.001) and IGF-II (P < 0.01) increased significantly during GH treatment. Additionally, IGFBP-1 (P < 0.001) and IGFBP-2 (P < 0.001) decreased significantly while IGFBP-3 (P < 0.001) and IGFBP-4 (P < 0.05) increased all in a dose-dependent manner. Stepwise (backwards) multiple regression analyses showed that the changes in IGF-I and IGF-II, and age correlated with the change in serum IGFBP-1. Both GH-dosage, the increase in IGF-II, and body mass index correlated with the decrease in IGFBP-2. Furthermore, the increase in serum IGF-I, IGF-II, and triiodothyronine correlated with the increase in IGFBP-3. Moreover, GH-dosage correlated with the increase in serum IGFBP-4. CONCLUSION: GH significantly increased serum IGF-I, IGF-II, IGFBP-3, and IGFBP-4 and decreased serum IGFBP-1 and IGFBP-2 in post-menopausal women.     

Circadian variation in serum free and total insulin-like growth factor (IGF)-I and IGF-II in untreated and treated acromegaly and growth hormone deficiency

OBJECTIVE: It is generally accepted that there is no clinically significant circadian variation in total insulin-like growth factor (IGF)-I or total IGF-II in healthy subjects. In contrast there is a significant nocturnal decrease in free IGF-I in healthy subjects, corresponding to the nocturnal increase in IGF binding protein-1. In this study we have investigated the circadian variation in circulating free IGF-I and IGF-II in patients with acromegaly and patients with adult onset growth hormone deficiency. PATIENTS: Seven acromegalic patients were studied with and without treatment with a slow-release formulation of octreotide. Seven GH-deficient patients were studied without GH replacement. In addition 5 of the GH-deficient patients were studied during GH replacement. DESIGN: Serum samples were obtained every hour for 24 h. Free IGF-I and IGF-II were measured every 2nd hour. Total IGF-I and IGF-II were measured every 2nd hour (acromegalic patients) or every 4th hour (GH deficient patients). IGF binding protein (IGFBP)-1 was measured every 2nd hour (acromegalic patients) or every hour (GH deficient patients). RESULTS: In the untreated acromegalic patients there was a significant nocturnal decrease in free IGF-I, but not free IGF-II, before treatment. During treatment there was a significant nocturnal decrease in both free IGF-I and free IGF-II. Peak values of free IGF-I were 112% and 75% above trough (treatment and withdrawal, respectively). In the GH-deficient patients there were no significant circadian variations in free IGF-I or free IGF-II in either of the two occasions. In contrast, there was a significant circadian variation of total IGF-I after adjustment for changes in plasma volume in both treated and untreated acromegaly and GH deficiency in all cases with a peak between 0300 h and 0400 h. The nocturnal increase in total IGF-I ranged from 20% to 35%. CONCLUSIONS: A significant circadian variation in free IGF-I and IGF-II was demonstrated in acromegalic patients. In contrast no significant circadian variation in free IGF-I and IGF-II was found in GH-deficient patients. Part of the variations may be due to poorly understood variations in IGF-I release. It is not clear whether and to what extent the observed circadian changes in free and total IGF-I are involved in circadian changes in IGF-I bioactivity.     

Increased levels of circulating free insulin-like growth factors in patients with non-islet cell tumour hypoglycaemia

Summary Non-islet cell tumour hypoglycaemia (NICTH) is characterised by severe and recurrent fasting hypoglycaemia, and is usually caused by secretion of insulin-like growth factor-II (IGF-II) by the tumour. This induces secondary changes in the circulating levels of insulin, growth hormone (GH), and the IGF-binding proteins (IGFBPs), resulting in an increased insulin-like hypoglycaemic activity of IGF-II. A participating role of IGF-I is not established. We measured serum levels of free IGF-I and free IGF-II, total IGF-I, total IGF-II, big IGF-II and IGFBP-1, IGFBP-2 and IGFBP-3 in patients with NICTH before (n = 14) and after surgical removal of the tumour (n = 3). A control group (n = 20) was included for comparison. In NICTH patients, free IGF-II was 20-fold increased (26.8 ± 8.1 [mean ± SEM] vs. 1.3 ± 0.1 μg/l), and free IGF-I was four fold increased (2.8 ± 0.4 vs. 0.7 ± 0.1 μg/l), as compared to control subjects (p < 0.0001). In accordance with earlier observations levels of total IGF-I, total IGF-II, and IGFBP-3 were decreased, whereas IGFBP-1 and IGFBP-2 were increased in NICTH (all p-values < 0.05). The highly elevated levels of free IGF-I and free IGF-II most likely imply a considerable hypoglycaemic insulin-like activity, and may, by negative feedback explain the marked suppression of the GH/IGF-I axis observed in NICTH. Finally, free IGF-II seems to be a powerful biochemical marker in the diagnosis of NICTH. [Diabetologia (1998) 41: 589–594] Received: 21 October 1997 and in final revised form: 15 December 1997     

Size at birth and cord blood levels of insulin, insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-3, and the soluble IGF-II/mannose-6-phosphate receptor in term human infants. The ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood

Experimental rodent studies demonstrate that insulin-like growth factor II (IGF-II) promotes fetal growth, whereas the nonsignaling IGF-II receptor (IGF2R) is inhibitory; in humans their influence is as yet unclear. A soluble, circulating form of IGF2R inhibits IGF-II mediated DNA synthesis and may therefore restrain fetal growth. We measured cord blood levels of IGF-II, soluble IGF2R, insulin, IGF-I, IGF-binding protein-1 (IGFBP-1), and IGFBP-3 and examined their relationships to weight, length, head circumference, ponderal index, and placental weight at birth in 199 normal term singletons. IGF-II levels correlated with levels of IGF-I (r = 0.29; P < 0.0005), IGFBP-3 (r = 0.45; P < 0.0005), and soluble IGF2R (r = 0.20; P < 0.005). Insulin and IGF-I were positively related to all parameters of size at birth. IGF-II was weakly related to ponderal index (r = 0.18; P < 0.05) and placental weight (r = 0.18; P < 0.05), and the molar ratio of IGF-II to IGF2R was also related to birth weight (r = 0.15; P < 0.05). Correlations between the IGFs and size at birth were stronger in nonprimiparous pregnancies; in these, IGF-I (r = 0.52; P < 0.0005), IGFBP-3 (r = 0.41; P < 0.0005), and the IGF-II to IGF2R ratio (r = 0.40; P < 0.0005) were most closely related to placental weight, together accounting for 39% of its variance. We demonstrate for the first time relationships between circulating IGF-II and soluble IGF2R levels and size at birth, supporting their putative opposing roles in human fetal growth.     

Coordinated regulation of the GH/IGF system genes during refeeding in rainbow trout (Oncorhynchus mykiss)

The GH/IGF system is a complex regulation network strongly dependent on nutrient availability. While the effect of starvation on the GH/IGF system has been extensively studied, the time course of events leading to the restoration of GH/IGF system activity after starvation is largely unknown. We, therefore, measured the plasma levels of GH, IGF-I and IGF-II and the expression of the GH/IGF system in liver and muscle. Starvation increased the plasma GH level and 1 day of refeeding completely restored it (1.10 +/- 0.27 vs 1.12 +/- 0.28 ng/ml). Thereafter, plasma GH continued to decrease until day 7 and returned to control values from day 15. Starvation decreased plasma IGF-I and IGF-II and refeeding raised plasma IGF-I only from day 4. In contrast, the plasma IGF-II level doubled after 1 day's refeeding (26.5 +/- 1.9 vs 44.0 +/- 3.4 ng/ml; P < 0.01). Starved fish exhibited higher GH receptor (GHR)1 mRNA abundance in liver and muscle than in controls, whereas GHR2 mRNA abundance was increased only in muscle. In liver, 1 day of refeeding, decreased GHR1 (twofold), but increased GHR2 mRNA abundance (twofold). Thereafter, a progressive return to normal values was observed. Liver IGFBP-4 mRNA abundance was lowered in starved fish followed by a progressive restoration during refeeding. Starvation had no effect on liver IGFBP-2 and IGFBP-6 mRNA abundance, whereas refeeding provoked a peak of IGFBP-2 and IGFBP-6 expression at day 7. In muscle, starvation led to a decrease of the IGFBP-2 mRNA level, which was restored only from day 7. IGFBP-4 mRNA abundance in starved fish was lower than in the controls and refeeding led to a transient upregulation (sevenfold) of IGFBP-4 gene at day 1. IGF-I, IGFBP-5, and IGFBP-related protein 1 (rP1) expression profiles were similar, showing a decrease of expression after starvation, a first peak of expression at day 2, a second peak at day 7, and a return to normal value from day 15. Moreover, IGF-I, IGFBP-5, and IGFBP-rP1 mRNA abundance were positively correlated (r = 0.6-0.8; P < 0.0001). In conclusion, plasma IGF-I was restored later than plasma GH level, which suggests that plasma IGF-I levels cannot account for plasma GH changes. The coordinated regulation of IGF-I, IGFBP-5, and IGFBP-rP1 expression would be a signature for the resumption of myogenic activity.     

Relationships between cortisol, dehydroepiandrosterone sulphate and insulin-like growth factor-I system in dementia

Changes in the hypothalamus-pituitary-adrenal axis (HPAA) function, entailing elevated cortisol circulating titres, occur in aging and in some neurological conditions, such as Alzheimer's disease (AD). Excess cortisol has neurotoxic effects which affect hippocampal neurones. Dehydroepiandrosterone sulphate (DHEAS) has an antiglucocorticoid activity and neuroprotective effects, but its levels decrease with aging. Glucocorticoids influence the production of insulin-like growth factor-I (IGF-I) and modify its systemic and neurotrophic biological activity by inducing changes in IGF-binding proteins (IGFBPs). We looked for relationships between cortisol, DHEAS levels, and IGF-I - IGFBPs system in AD. Cortisol, DHEAS and GH levels at 02:00, 08:00, 14:00, 20:00 h, basal IGF-I, IGFBP-1 and IGFBP-3 levels were determined by RIAs or IRMA in 25 AD patients, aged 58-89 yr, and in 12 age-matched healthy controls. AD subjects had higher cortisol, lower DHEAS levels and increased cortisol/DHEAS ratio (C/Dr) than controls. In AD cases, total IGF-I, IGFBP-3, and IGF-I/IGFBP ratios were significantly lowered, while IGFBP-1 levels were significantly higher than in controls. We found a significant inverse correlation between IGF-I and IGFBP-3 levels vs C/Dr, and between both IGF-I/IGFBPs ratios vs mean cortisol levels. IGFBP-3 correlated directly with DHEAS. Cortisol was directly and IGF-I inversely correlated with cognitive impairment. In AD patients we found that alterations in HPAA function and elevated C/Dr are related to lowered total and free IGF-I levels. These findings and their relationship to cognitive impairment suggest that changes in hormonal set-up might influence the clinical presentation of the disease.     

Insulin-like growth factors, insulin-like growth factor-binding proteins, insulin-like growth factor-binding protein-3 protease, and growth hormone-binding protein in lipodystrophic human immunodeficiency virus-infected patients

Human immunodeficiency virus (HIV)-lipodystrophy is associated with impaired growth hormone (GH) secretion. It remains to be elucidated whether insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs), IGFBP-3 protease, and GH-binding protein (GHBP) are abnormal in HIV-lipodystrophy. These parameters were measured in overnight fasting serum samples from 16 Caucasian males with HIV-lipodystrophy (LIPO) and 15 Caucasian HIV-infected males without lipodystrophy (NONLIPO) matched for age, weight, duration of HIV infection, and antiretroviral therapy. In LIPO, abdominal fat mass and insulin concentration were increased (>90%, P < .01) and insulin sensitivity (Log10ISI(composite)) was decreased (-50%, P < .001). Total and free IGF-I, IGF-II, IGFBP-3, and IGFBP-3 protease were similar between groups (all P > .5), whereas, in LIPO, IGFBP-1 and IGFBP-2 were reduced (-36%, P < .05 and -50%, P < .01). In pooled groups, total IGF-I, free IGF-I, total IGF-II, and IGFBP-3, respectively, correlated inversely with age (all P < .01). In pooled groups, IGFBP-1 and IGFBP-2 correlated positively with insulin sensitivity (age-adjusted all P < .05). IGFBP-3 protease correlated with free IGF-I in pooled groups (r(p) = 0.47, P < .02), and in LIPO (r(p) = 0.71, P < .007) controlling for age, total IGF-I, and IGFBP-3. GHBP was increased, whereas GH was decreased in LIPO (all P < .05). GH correlated inversely with GHBP in pooled groups (P < .05). Taken together the similar IGFs and IGFBP-3 concentrations between study groups, including suppressed GH, and increased GHBP in LIPO, argue against GH resistance of GH-sensitive tissues in LIPO compared with NONLIPO; however, this notion awaits examination in dose-response studies. Furthermore, our data suggest that IGFBP-3 protease is a significant regulator of bioactive IGF-I in HIV-lipodystrophy.     

Growth hormone, IGF-I and its binding proteins (IGFBP-1 and -3) in adult uraemic patients undergoing peritoneal dialysis and haemodialysis

OBJECTIVE: The GH/IGF axis is altered in chronic renal failure (CRF). CRF patients usually show normal or high serum concentrations of GH and IGF-I, whereas all IGF binding proteins (IGFBP-1 to -6), except IGFBP-5, considerably increase with declining renal function. The aims of the present study were to quantify serum concentrations of GH, IGF-I, IGFBP-1 and IGFBP-3 in a group of patients with CRF, and determine whether there were differences according to the type of dialysis, that is, peritoneal dialysis (PD) and haemodialysis (HD). DESIGN: A cross-sectional study in the setting of a dialysis unit of a general hospital. PATIENTS AND MEASUREMENTS: We studied 108 dialysis patients treated by PD (n = 54, 32 males and 22 females, mean age 61.0 +/- 1.4 years) or HD (n = 54, 31 males and 23 females, age 62.6 +/- 1.5 years). A group of 42 healthy subjects of similar age, sex and body mass index (BMI) served as the control group. Baseline serum concentrations of GH, insulin, IGF-I, IGFBP-1 and IGFBP-3 were measured in all patients and control subjects. RESULTS: Fasting serum concentrations of IGF-I and its binding proteins (IGFBP-1 and IGFBP-3) were significantly higher in dialysis patients than in subjects with normal renal function. IGF-I (248.9 +/- 23.4 vs. 205.5 +/- 15.5 micro g/l, NS), IGFBP-3 (5.6 +/- 0.4 vs. 5.5 +/- 0.2 mg/l, NS) and IGFBP-1 (36.1 +/- 5.9 vs. 44.1 +/- 6.5 micro g/l, NS) concentrations were similar in both groups of dialysis (PD vs. HD) patients. However, GH (2.3 +/- 0.3 vs. 1.1 +/- 0.1 micro g/l, P < 0.001) and insulin (40.4 +/- 4.5 vs. 30.1 +/- 3.1 micro U/ml, P < 0.05) levels were significantly higher in the PD group than in the HD group. Both groups of dialysis patients showed significantly higher levels of insulin than healthy subjects (14.7 +/- 1.9 micro U/ml, P < 0.0001 and P < 0.01 for PD and HD, respectively). In both groups of dialysis patients, IGF-I correlated inversely with IGFBP-1 (PD group r = -0.46, P = 0.0006; HD group r = -0.57, P = 0.0001) and directly with IGFBP-3 (PD group r = 0.44, P = 0.001; HD group r = 0.73, P = 0.001). No correlation between insulin and IGFBP-1 was found in any of the groups studied. CONCLUSIONS: These findings demonstrate that adult dialysis patients have elevated IGF-I, IGFBP-1 and IGFBP-3 serum concentrations compared with subjects with normal renal function. Only GH and insulin show statistically significant differences in relation to type of dialysis. Finally, the negative correlation between IGF-I and IGFBP-1 and the positive correlation between IGF-I and IGFBP-3 are maintained in both groups of adult dialysis patients.     

The effect of anorexia nervosa and refeeding on growth hormone-binding protein, the insulin-like growth factors (IGFs), and the IGF-binding proteins.

We studied the relationship of serum insulin-like growth factor-I (IGF-I), IGF-II, the IGF-binding proteins IGFBP-1, IGFBP-2, and IGFBP-3, and GH-binding protein (GHBP; which is postulated to be derived from the extracellular portion of the GH receptor) in normal volunteers and patients with anorexia nervosa before and after a refeeding program. Serum GHBP, IGF-I, and IGFBP-3 were all significantly decreased in low weight patients with anorexia nervosa and returned to nearly normal levels with refeeding. Fasting serum GH and serum IGFBP-1 and IGFBP-2 were significantly increased in low weight patients with anorexia nervosa and also returned to nearly normal levels with refeeding. Serum IGF-II was 27% lower in the low weight group than in normal subjects, but this difference was not statistically significant. Both serum IGF-I and IGF-II were positively correlated with serum IGFBP-3 and negatively correlated with serum IGFBP-1 and IGFBP-2. These data are consistent with the hypothesis that nutritional deprivation alters the GH-IGF axis by down-regulation of the GH receptor or its postreceptor mechanisms, and that this effect is reversible with refeeding.     

Sexual dimorphism in the growth hormone and insulin-like growth factor axis at birth

In rodents and humans there is a sexually dimorphic pattern of GH secretion that influences the serum concentration of IGF-I. Pattern differences can be identified in children, but it is not known how early this difference is established. We studied the plasma concentrations of IGF-I, IGF-II, IGF-binding protein-3 (BP-3), and GH in cord blood taken from the offspring of 1650 singleton Caucasian pregnancies born at term and related these values to birth weight, length, and head circumference. Pregnancies complicated by preterm delivery, antepartum hemorrhage, pregnancy-induced hypertension, preeclampsia, or gestational diabetes and where cigarette smoking continued were excluded, resulting in a cohort of 987. Cord plasma concentrations of IGF-I, IGF-II, and IGFBP-3 were influenced by factors influencing birth size: gestational age at delivery, mode of delivery, maternal height, and parity of the mother. Plasma GH concentrations were inversely related to the plasma concentrations of IGF-I and IGFBP-3; 10.2% of the variability in cord plasma IGF-I concentration and 2.7% for IGFBP-3 was explained by sex of the offspring and parity. None of the factors, apart from maternal height, influenced cord serum IGF-II concentrations (adjusted r(2) = 1%). Sex of the baby, mode of delivery, and parity influenced cord serum GH concentrations (adjusted r(2) = 2.6%). Birth weight, length, and head circumference measurements were greater in males than females (P < 0.001). Mean cord plasma concentrations of IGF-I (males, 66.4 +/- 1.2 micro g/liter; females, 74.5 +/- 1.3 micro g/liter; P < 0.001) and IGFBP-3 (males, 910 +/- 13 micro g/liter; females 978 +/- 13 micro g/liter; P < 0.001) were significantly lower in males than females. Cord plasma GH concentrations were higher in males than females (males, 30.0 +/- 1.2 mU/liter; females, 26.9 +/- 1.1 mU/liter; P = 0.05), but no difference was noted between the sexes for IGF-II (males, 508 +/- 6 micro g/liter; females, 519 +/- 6 micro g/liter; P = NS). After adjustment for gestational age, parity, and maternal height, cord plasma concentrations of IGF-I and IGFBP-3 along with sex explained 38.0% of the variability in birth weight, 25.0% in birth length, and 22.7% in head circumference. These data demonstrate that in a group of singleton Caucasian babies born at term, cord plasma IGF-I, IGFBP-3, and GH concentrations relate to birth size, with evidence for sexual dimorphism in the GH-IGF axis.     

The role of IGF binding protein-3 as a parameter of activity in acromegalic patients.

OBJECTIVE: The production of insulin-like growth factor binding protein-3 (IGFBP-3), the main IGF-I binding protein, is regulated by GH, and its serum levels are increased in acromegaly. We investigated its potential value as a parameter of acromegaly activity or remission in comparison with IGF-I, taking GH suppression below 2 microg/l after glucose load as the normal standard. METHODS: Data from 40 acromegalic patients (12 males and 28 females, aged 28 to 79 years) were obtained retrospectively from stored samples. From these, 145 pairs of IGF-I/IGFBP-3 values were collected; in 67 of them, simultaneous measurement of GH after glucose loading allowed their classification as active or inactive acromegaly. Relationships between IGF-I, IGFBP-3 and GH after glucose load were assessed, as well as differences between IGF-I and IGFBP-3 levels in active and inactive acromegaly. RESULTS: Significant positive correlation between IGF-I and IGFBP-3 in 145 samples was observed (r=0.49, P<0. 0001). As for the 67 samples in which activity or remission could be defined in terms of GH after glucose load, 50 were active and 17 inactive. Both IGF-I and IGFBP-3 significantly correlated with minimum GH (r=0.53, P<0.0001 and r=0.41, P<0.001 respectively). For both parameters, significant differences of means between active and inactive cases were observed (623+/-296 vs 300+/-108 ng/ml, P<0.0001 for IGF-I, and 4.1+/-1.3 vs 3.2+/-0.9 microg/ml, P<0.006 for IGFBP-3). Yet, when comparing in individual cases their classification as active or inactive with the finding of normal or increased IGF-I and IGFBP-3, among active cases 16% appeared as normal according to IGF-I, and 50% appeared as normal in terms of IGFBP-3. Among inactive cases, 23.5% appeared as active according to IGF-I, while 17.5% appeared as active in terms of IGFBP-3. CONCLUSION: Even though IGFBP-3 reflects GH secretion, it offers no advantage over IGF-I in the assessment of acromegaly, and it may underestimate disease activity in acromegalic patients.     

Usefulness of different biochemical markers of the insulin-like growth factor (IGF) family in diagnosing growth hormone excess and deficiency in adults.

The diagnostic approach to acromegaly and GH deficiency frequently includes measurement of several components of the insulin-like growth factor (IGF) system. IGF-I levels are reported to be good predictors of active and cured acromegaly, but are commonly found within the normal age-adjusted range in adult GH-deficient (GHD) patients. Circulating concentrations of IGF-binding protein-3 (IGFBP-3), acid-labile subunit (ALS), and free IGF-I reflect the GH secretory status, but their diagnostic accuracy is still debated. In this study serum levels of total and free IGF-I, IGFBP-3, ALS, and IGFBP-3-IGF-I and IGFBP-3-ALS complexes were determined in patients previously diagnosed with active (n = 67) or inactive (n = 16) acromegaly and adult GHD (n = 34) and compared with results obtained in 58 healthy controls. In healthy subjects, IGF-I, IGFBP-3, ALS, and both IGFBP-3 complexes declined with age; a correlation was found between IGF-I and IGFBP-3 (r = 0.59; P < 0.001), ALS (r = 0.67; P < 0.001), and free IGF-I (r = 0.40; P < 0.05). Active acromegalic patients showed a significant increase in all parameters tested. IGF-I concentrations were above +2 SD in 100% of patients, whereas slightly lower sensitivities were shown for IGFBP-3 (85%), ALS (88%), and free IGF-I (94%). In this group, IGF-I exhibited a slightly higher correlation with IGFBP-3 (r = 0.83; P < 0.001) than with ALS levels (r = 0.78; P < 0.001). In cured acromegalic patients, we observed the normalization of all parameters but free IGF-I levels. Adult GHD patients showed a significant reduction of all hormones. Unlike active acromegalic patients, all parameters had only a modest sensitivity in GHD; suppression below -2 SD was observed in 41% of GHD patients for IGF-I, 47% for IGFBP-3, 32% for ALS, and 35% for free IGF-I measurements. Previous radiotherapy and GH peak response below 3 microg/L were associated with significantly lower IGF-I, IGFBP-3, and ALS levels. IGF-I levels were significantly correlated to ALS (r = 0.68; P < 0.001) and IGFBP-3 (r = 0.64; P < 0.001) as well as with free IGF-I (r = 0.67; P < 0.001) levels. By multiple regression analysis, the number of anterior pituitary hormones impaired was the most predictive indicator of IGF-I, IGFBP-3, and free IGF-I levels in GHD patients; conversely, the GH peak response better anticipated ALS concentrations. The pattern of IGFBP-3 complexes paralleled previous hormonal findings. In active acromegalic patients, IGFBP-3-IGF-I levels were 5.4-fold higher than in controls and were above +2 SD in 95% of patients, whereas IGFBP-3-ALS levels were elevated in 15% of cases. On the other hand, both IGFBP-3 complexes were able to predict GHD in only a minority of cases. Taken together, these data support the diagnostic role of IGF-I in acromegaly and suggest that free IGF-I and the IGFBP-3-IGF-I complex can assist diagnostic strategies in this condition. All markers are of limited predictive value in adult GHD, as hormonal values are commonly found within the normal limits. In these patients, low IGFBP-3 and IGF-I concentrations can add further clinical information on the residual GH activity.     

Inter-relations between growth hormone, insulin, insulin-like growth factor-l (IGF-I), IGF-binding protein-1 (IGFBP-1) and sex hormone-binding globulin in acromegaly

Acromegaly is characterized by a hypersecretion of GH, which in turn results in an excess of IGF-I, an important mediator of its actions. IGF-I itself is intimately related to insulin both in structure and function. IGF-I circulates associated with specific binding proteins which appear to have important effects on its activity. We have examined the inter-relations between GH, prolactin, insulin, IGF-I and one of the binding proteins, IGFBP-1, in 62 patients with acromegaly of varying activity. Serum IGF-I levels were closely related to the logarithm of mean GH levels (r = 0.76; n = 62; P less than 0.001) but multiple regression analysis suggested that, after accounting for the variation due to GH, insulin accounted for some of the additional variation of IGF-I. IGF-I concentrations were independent of prolactin. Fasting insulin levels were high and unrelated to mean GH levels but correlated with those of IGF-I (r = 0.542; n = 57; P less than 0.001). This correlation coefficient was further improved by also accounting for variations in IGFBP-1 (r = 0.684; n = 57; P less than 0.001). Even in subjects whose acromegaly was well controlled or cured, as indicated by GH levels of less than 1 mU/l or IGF-I levels of less than 2 U/ml, fasting insulin levels remained significantly elevated in some individuals. The reason for this persistent abnormality is not clear. Fasting IGFBP-1 levels were low and unrelated to mean GH but were inversely related to fasting insulin levels (r = -0.593; n = 57; P less than 0.001). We propose that a cascade of events occurs in acromegaly.(ABSTRACT TRUNCATED AT 250 WORDS)     

The growth hormone-insulin-like growth factor axis in adult patients with Prader Willi syndrome.

OBJECTIVE: Prader Willi syndrome (PWS) is a genetic disorder characterised by short stature, extreme obesity, body composition abnormalities and behavioural problems. Hypothalamic dysfunction with low growth hormone (GH) secretion and low levels of GH-related growth factors is common. However, the interpretation is difficult because of the concomitant obesity, which in itself has important effects on the GH-IGF-I-system. We therefore analysed free and total IGF-I, total IGF-II and their binding proteins in obese PWS adults before and during 12 months GH treatment. Seventeen adults, 9 men and 8 women, 17-32 years of age with a mean BMI of 35+/-2.3 kg/m(2) participated. All had clinical PWS. They were randomized to treatment with placebo or GH (Genotropin, Pharmacia) 0.8 IU (0.26 mg) for one month, and then 1.6 IU (0.53 mg) for 5 months. Subsequently GH doses were individually titrated to normal levels for age. Overnight fasting levels of free and total IGF-I, total IGF-II, GH-binding protein (GHBP) and IGF-binding proteins (IGFBP)-1, -2 and -3 were measured by RIA at baseline and after 6 and 12 months GH treatment. Mean levels+/-SEM of free IGF-I were 1.02+/-0.12 microg/L as compared to a reference value of 0.95+/-0.15 microg/L, while mean total IGF-I was 128+/-15 microg/L (212+/-14 microg/L) and total IGF-II was 704+/-45 microg/L (825+/-34 microg/L). Mean IGFBP-2 158+/-24 microg/L (764+/-72 microg/L) and GHBP 2.65 nmol/L (1.71+/-0.3 1nmol/L). IGFBP-1 and IGFBP-3 levels were normal. Both free and total IGF-I increased significantly during GH treatment, while IGF- and GH-binding proteins as well as total IGF-II remained unchanged. CONCLUSION: Low total IGF-I and, in relation to the obesity, low free IGF-I, low total IGF-II and non-suppressed IGFBP-1 are consistent with the concept that PWS patients have a partial GH deficiency, which can be corrected by GH replacement.     

Serum leptin response to the acute and chronic administration of growth hormone (GH) to elderly subjects with GH deficiency

In human studies, the principal determinant of serum leptin concentrations is fat mass (FM), but lean mass (LM) also has a significant negative influence. GH treatment in GH deficiency (GHD) alters body composition, increasing LM and decreasing FM, and thus would be expected to alter leptin concentrations. We have therefore examined the acute and chronic effects of GH on serum leptin in 12 elderly GHD subjects (ages 62-85 yr; 3 women and 9 men). FM (kilograms) and LM (kilograms) were determined by dual energy x-ray absortiometry. Leptin, insulin, insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-2, and IGFBP-3 were measured by specific immunoassays. Leptin, insulin, and IGFBP-1 concentrations were log10 transformed, and data were expressed as the geometric mean (-1, +1 tolerance factor). All other data are presented as the mean +/- SD. In the acute study, patients received a single bolus dose of GH (0.1 mg/kg BW) at time zero, with blood samples drawn at 0, 12, 24, 48, and 72 h and 1 and 2 weeks. There was a significant rise in leptin, insulin, and IGF-I at a median time of 24 h, followed by a significant fall, and nadir concentrations were reached at a median time of 1.5 weeks (leptin) or 2 weeks (insulin and IGF-I). IGFBP-3 concentrations were also significantly increased, but peak concentrations were not achieved until 48 h. IGF-II, IGFBP-1, and IGFBP-2 exhibited transient decreases before returning to baseline levels. There was no relationship between increased leptin concentrations and either insulin or IGF-I concentrations. In the chronic study, patients received daily GH treatment at doses of 0.17, 0.33, and 0.5 mg/day, each for 3 months (total time on GH, 9 months), and were then followed off GH for a further 3 months. Dual energy x-ray absortiometry was undertaken at 0, 3, 6, 9, and 12 months, and blood samples were drawn at these time points. Over 9 months on GH there was a significant fall in FM and a significant rise in LM, but no change in leptin. There were also significant increments in insulin, IGF-I, and IGFBP-3, whereas IGF-II, IGFBP-1, and IGFBP-2 did not change over 9 months of GH treatment. After 3 months off GH, there was a significant rise in FM and leptin. High dose single bolus GH led to an increase in serum leptin within 24 h apparently independent of changes in insulin or IGF-I. Despite the changes in body composition during chronic GH treatment, there was no change in leptin. However, discontinuation of GH led to a rapid reversal of the favorable body composition and a rise in serum leptin.     

Effects of a 7-day continuous infusion of octreotide on circulating levels of growth factors and binding proteins in growth hormone (GH)-treated GH-deficient patients

In patients with acromegaly, clinical improvement has been reported after octreotide (OCT) treatment, even in cases of only a moderate suppression of growth hormone (GH) levels. In rats, OCT suppresses IGF-I mRNA expression and generation of serum and tissue IGF-I levels. A direct effect of OCT on the IGF system could have therapeutical implications in diabetes mellitus, cardiovascular disease, and certain malignancies in which IGF-I might be involved. The aim of this study was to examine possible GH-independent effects of OCT on IGF components in humans. Six GH-deficient (GHD) patients were studied for 24 h after each of the following treatment regimens (each of 1 weeks duration): (a) daily s.c. GH injection (2 IU/m(2)); (b) as (a) + continuous s.c. infusion of OCT (200 microg/24 h) by means of a portable pump (Nordic Infuser); (c) no treatment. Serum GH binding protein (GHBP) levels tended to be lower after GH and OCT than after GH alone (P =0.10). OCT reduced the GH induced increase in serum IGF-I levels (P<0.05, ANOVA). Mean integrated levels (microg/l) were 359.1+/-49.6 (GH), and 301.6+/-58.9 (GH+OCT). OCT did not significantly reduce serum IGFBP-3 levels (microg/l) [3460+/-270 (GH), and 3112+/-435 (GH+/-OCT);P =0.14]. Serum levels of free IGF-I (P =0.39), IGF-II (P =0.54), and of the acid-labile subunit (ALS) of the ternary complex (P =0.50) were similar during GH+/-OCT as compared with GH alone. After 1 week off GH treatment, significantly lower levels of IGF-I, IGF-II, IGFBP-3, and ALS were recorded (P<0.001). Serum IGFBP-1 levels were significantly higher after GH+OCT than after GH alone (P<0.0001), and levels were even higher without GH. Serum insulin levels (pmol/l) were significantly higher after GH alone as compared with no GH (P<0.05, ANOVA), whereas OCT partly suppressed the insulinotropic effect of GH (P<0. 05) [mean: 114.5+/-33.0 (GH), 91.3+/-29.6 (GH+OCT), 65.9+/-22.5 (no GH)]. This was also reflected in higher blood glucose levels during GH+OCT. Finally, GH+OCT reduced glucagon levels significantly as compared with GH alone (P =0.02). In conclusion, 7 days' administration of OCT to GH-treated GHD patients slightly attenuated serum IGF-I generation, and tended to decrease levels of the other components of the 150 kDa ternary complex. Whether these effects are mediated directly by OCT or indirectly via the accompanying changes in insulin levels remains to be investigated.