How to combat tuberculosis in the year 2000?

Serum IGF-I and IGFBP-3 levels are growth hormone (GH) dependent and reflect the endogenous GH secretion. Two hundred and forty-four healthy children were evaluated for serum IGF-I and IGFBP-3 levels and then the age-defined normal values for Thai children were constructed. The results showed that the serum IGF-I and IGFBP-3 levels were age dependent, gradually increased from birth and reached the peak values around the age of 14-16 years. In addition, we studied the IGF-I and IGFBP-3 values in 28 GH deficient children and 26 normal variant short stature (NVSS) by using our normal constructed values as the reference. To minimize the influence of age, both IGF-I and IGFBP-3 values were transformed to standard deviation score (SDS). In clinical practice, we recommend using the IGF-I SDS and IGFBP-3 SDS of -1 and -1.3 respectively as a cut-off point to discriminate between GH deficiency and NVSS to avoid risky GH provocative tests and unnecessary GH replacement with the sensitivity of 71 per cent and the specificity of 92 per cent.     

Algorithm on the clinical evaluation of epilepsy

The aetiology of growth retardation in children with X-linked hypophosphatemic rickets (HPR) has not been totally defined. We evaluated growth hormone (GH)/insulin-like growth factor-I (IGF-I) changes in relation to linear growth and biochemical parameters in seven children with X-linked hypophosphatemic rickets before and after treatment with 1,25-dihydroxyvitaminD3 and phosphate therapy for a year or more. Moreover, we compared patients' growth data and GH/IGF-I changes with those for 20 age-matched children with normal variant short stature (NVSS)[with normal GH secretion and height standard deviation score (HtSDS) before -2]. Before treatment, all children with HPR secreted normal GH in response to clonidine provocation (> 10 microgram/l) and their IGF-I concentration was significantly lower than those with NVSS. The HtSDS and growth velocity (GV) of children with HPR improved significantly after (-3.05, 8.9 cm/year, respectively) v. before (-3.9 and 4.1 cm/year, respectively) therapy. Their serum IGF-I concentration increased significantly from 76.7 ng/ml before to 99.6 ng/ml after treatment. In summary children with HPR had no abnormality of GH secretion but improvement of their linear growth was associated with significant increase of circulating IGF-I concentration after treatment.     

Serum growth hormone (GH) binding protein, IGF-I and IGFBP-3 in patients with beta-thalassaemia major and the effect of GH treatment

OBJECTIVE: Levels of IGFI have been shown to be low in transfusion-dependent thalassaemia and there is preliminary evidence to suggest that this may be reversed by GH treatment. In this further study we have evaluated serum growth hormone (GH) binding protein (GHBP), IGF-I and IGFBP-3 in patients with beta-thalassaemia major and the effects of GH treatment on these various parameters. PATIENTS: Fifty-six transfusion dependent patients with beta-thalassaemia major without GH deficiency between 2 and 20 years of age were studied. Thirteen non-GH deficient patients with heights of -1.5 SD or more were treated with GH at a dose of 0.14 IU/kg/day subcutaneously for 1 year. MEASUREMENTS: Serum GHBP, IGF-I and IGFBP-3 were measured in all the patients. In the 13 patients treated with GH, these serum parameters were measured before and after 3, 6 and 12 months of treatment. RESULTS: The mean serum GHBP concentrations were normal in both prepubertal and pubertal children but the serum IGF-I and IGFBP-3 concentrations were low throughout childhood and adolescence. There was a significant correlation between serum IGF-I and IGFBP-3 concentrations (r = 0.79; P = 0.0001) but there was no correlation between the height SDS of the patients with serum GHBP, IGF-I or IGFBP-3 levels. GH treatment in the 13 patients resulted in significant growth acceleration associated with a significant rise in the serum IGF-I and IGFBP-3 and a significant fall in serum GHBP concentrations. CONCLUSIONS: The low serum concentrations of IGF-I and IGFBP-3 in the presence of normal GH reserve and serum GHBP concentrations in patients with beta-thalassaemia suggest a state of partial GH insensitivity at the post-receptor level. This partial GH insensitivity state can be overcome by supraphysiological doses of exogenous GH. The lack of correlation of IGF-I, IGFBP-3 and GHBP with height SDS of the patients imply that the growth failure commonly observed in patients with beta-thalassaemia major may not be specifically related to dysregulation of the GH-IGF-I axis. GH therapy resulted in significant increase in serum IGF-I and IGFBP-3 but a significant fall in GHBP.     

Feeding colostrum increases circulating insulin-like growth factor I in newborn pigs independent of endogenous growth hormone secretion

Our objective was to examine the influence of feeding and endogenous GH secretion on circulating IGF-I in colostrum-deprived newborn pigs fed colostrum (n = 4), formula (control, n = 4), or water (n = 4). In another four formula-fed pigs, GH was ablated (GRF-A) with two intravenous injections of a GH releasing-factor antagonist (N-Ac-Tyr1,D-Arg2)-GRF(1-29)-NH2. Blood was serially sampled in all pigs to measure plasma IGF-I and GH profiles. Feeding increased plasma IGF-I concentration two- to fourfold and decreased GH secretion. Despite a more than 80% decrease in the plasma GH in GRF-A pigs, the circulating IGF-I concentration was similar to that in control pigs. In colostrum-fed pigs, plasma IGF-I was higher than that in control pigs, despite equal nutrient intake and lower circulating GH. There were no differences in plasma IGF binding protein (IGFBP)-3 levels among the treatment groups. However, the relative abundance of plasma IGFBP-4 was lower, and that of IGFBP-1 higher, in unfed pigs than in any of the three fed groups. The plasma insulin concentration was not different among fed pigs, but it was lower in unfed pigs. Our results indicate that the circulating IGF-I concentration is more dependent on nutrient intake than on GH in newborn pigs, despite relatively high GH concentrations. However, because the nutrient content in the formula was designed to match that of colostrum, a factor other than nutrient intake and GH was responsible for the maximal increase in circulating IGF-I concentration observed in colostrum-fed pigs.     

Growth hormone bioactivity, insulin-like growth factors (IGFs), and IGF binding proteins in obese children

In obese children, both spontaneous and stimulated growth hormone (GH) secretion are impaired but a normal or increased height velocity is usually observed. This study was undertaken to explain the discrepancy between impaired GH secretion and normal height velocity. We evaluated the GH bioactivity (GH-BIO), GH serum level by immunofluorimetric assay (GH-IFMA), insulin-like growth factor-I (IGF-I), IGF-II, and IGF binding protein-1 (IGFBP-1), IGFBP-2, and IGFBP-3 in 21 prepubertal obese children (13 boys and eight girls) aged 5.7 to 9.4 years affected by simple obesity and in 32 (22 boys and 10 girls) age- and sex-matched normal-weight controls. The results were as follows (obese versus [v] controls): GH-IFMA, 4.84 +/- 3.54 v 23.7 +/- 2.04 microg/L (P < .001); GH-BIO, 0.60 +/- 0.45 v 1.84 +/- 0.15 U/mL (P < .001); IGF-I, 173.8 +/- 57.2 v 188.6 +/- 132.6 ng/mL (nonsignificant); IGF-II, 596.1 +/- 139.7 v 439.3 +/- 127.4 ng/mL (P < .001); IGFBP-1, 23.25 +/- 14.25 v 107 +/- 165.7 ng/mL (P < .05); IGFBP-2, 44.37 +/- 62.18 v 385.93 +/- 227.81 ng/mL (P < .001); IGFBP-3, 3.31 +/- 0.82 v 2.6 +/- 0.94 microg/mL (P < .05); and IGFs/IGFBPs, 1.32 +/- 0.32 v 1.07 +/- 0.34 (P < .05). In conclusion, in prepubertal obese children, not only immunoreactive but also bioactive GH concentrations were low. In these subjects, therefore, nutritional factors and insulin may contribute to sustain normal growth also by modulating several components of the IGF-IGFBP system.     

Short stature associated with high circulating insulin-like growth factor (IGF)-binding protein-1 and low circulating IGF-II: effect of growth hormone therapy

We report a case of short stature associated with high circulating levels of insulin-like growth factor (IGF)-binding protein-1 (IGFBP-10 and low levels of IGF-II responsive to pharmacological treatment with GH. Our patient suffered severe growth failure from birth (2.06 SD below the mean for normal full-term boys, and 5.2 and 7.3 SD below the mean at 5 and 10 months). Studies carried out before referral to our pediatric unit included normal 46,XY karyotype and normal encephalic imaging. Other endocrine and metabolic alterations and other systemic diseases were excluded. At 1.7 yr of age (length, 6.1 SD; weight, 4.6 SD; head circumference, 1.4 SD below the mean, respectively) the patient was referred to our pediatric unit. The baseline GH concentration was 31 microg/L, and the peak after an arginine load was 59.6 microg/L. In the same samples GH bioactivity was nearly superimposable (RIA/Nb2 bioactivity ratio = 0.9). Fasting insulin and glucose concentrations were 7.4 microU/mL and 65 mg/dL, respectively, both normally responsive to an oral glucose load. GH insensitivity was excluded by a basal IGF-I concentration (64 ng/mL) in the normal range for 0- to 5-yr-old boys and its increase after 2 IU/day hGH administration for 4 days. IGFBP-3 (0.5 microg/mL) was slightly reduced, whereas IGFBP-1 (2218 and 1515 ng/mL in two different basal samples) was well above the normal values for age and was suppressible by GH (maximum suppression, -77% at 84 h) and glucose load (maximum suppression, -46% at 150 min). The basal IGF-II concentration was below the normal range (86 ng/mL), whereas IGFBP-2 was normal (258 ng/mL). Analysis of the promoter region of IGFBP-1 and IGF-II failed to find major alterations. Neutral gel filtration of serum showed that almost all IGF-I activity was in the 35- to 45-kDa complex, coincident with IGFBP-1 peak, while the 150-kDa complex was absent, although the acid-labile subunit was normally represented. At 2.86 yr (height, 65.8 cm; height SD score, -7.3; height velocity SD score, -5) the patient underwent treatment with 7 IU/week human GH; after 4 months, the patient's height was 68.5 cm (height SD score, -6.9) corresponding to a growth velocity of 8.3 cm/yr (0.3 height velocity SD score). IGFBP-1 was reduced (216 ng/mL), although still in the high range, whereas IGF-I (71 ng/mL), IGFBP-3 (0.62 microg/mL), and IGF-II (111 ng/mL) were only slightly increased. The IGF-I profile showed activity in the 150-kDa region. In conclusion, we speculate that the increased IGFBP-1 values found in this patient produce 1) inhibition of IGF-I biological activity and, therefore, a resistance to IGF-I not due to a receptor defect for this hormone; 2) inhibition of formation of the circulating 150-kDa ternary complex and, therefore, an accelerated clearance rate of IGF peptides; 3) inhibition of the feedback action on GH, leading to increased GH levels, which could suggest the diagnosis of GH insensitivity syndrome; and 4) inhibition of body growth.     

Long-term effects of insulin-like growth factor (IGF)-I on serum IGF-I, IGF-binding protein-3 and acid labile subunit in Laron syndrome patients with normal growth hormone binding protein

A minority of patients with Laron syndrome have normal serum GH binding protein (GHBP), indicating that the defect is elsewhere than in the extracellular domain of the GH receptor. We have evaluated the effect of long-term IGF-I treatment on serum IGF-binding protein (IGFBP)-3 and the acid-labile subunit (ALS) in three sibling with Laron syndrome caused by a GH post-receptor defect and with normal GHBP. The children (a boy aged 3 years, a girl aged 4 years and a boy aged 10 years) were treated by daily s.c. injection of IGF-I in a dose of 150 micrograms/kg. IGFBP-3 was measured by RIA and Western ligand blotting, ALS by RIA. Based values of IGFBP-3 and ALS were low. During IGF-I treatment, the IGFBP-3 concentrations in the girl gradually increased, whereas in the boys there was a 60% decrease during the first week, followed by gradual increase towards baseline. The ALS concentrations followed a similar pattern. We conclude that IGF-I treatment induces and initial suppression and then an increase in the IGFBP-3 and ALS concentrations, confirming data from animal experiments that IGFBP-3 synthesis is not solely under GH control. The differences in responsiveness between the female and male siblings may reflect genetic differences, or lower circulating concentrations of IGF-I in the boys compared with the girl.     

Effects of growth hormone and pregnancy on expression of growth hormone receptor, insulin-like growth factor-I, and insulin-like growth factor binding protein-2 and -3 genes in bovine uterus, ovary, and oviduct

The effects of growth hormone (GH) and pregnancy on insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-2, and IGFBP-3 mRNA in reproductive tissues were studied in cattle. Lactating dairy cows were inseminated at estrus and treated with 25 mg/day GH (n = 8) or saline (n = 8) for 16 days. Corpus luteum (CL), ovary (CL removed), oviduct, endometrium, and myometrium were collected at the end of treatment. Messenger RNA for GH receptor, IGF-I, IGFBP-2, IGFBP-3, and actin were measured by nuclease protection assays. The CL contained more GH receptor mRNA than the other reproductive tissues examined. Expression of IGF-I mRNA was highest in myometrium, with lower amounts found in endometrium; the CL expressed the least amount of IGF-I mRNA. The IGFBP-2 mRNA was most abundant in endometrium and least abundant in CL. Expression of IGFBP-3 mRNA was detected in all reproductive tissues examined. However, endometrium, a tissue that expressed the most IGFBP-2 mRNA, had the lowest amount of IGFBP-3 mRNA. The GH receptor mRNA was decreased in cows treated with GH whereas the mRNA for IGF-I, IGFBP-2, or IGFBP-3 was not changed. In the reproductive tissues evaluated, cows that contained a conceptus at tissue collection (pregnant) had higher amounts of IGF-I mRNA than did nonpregnant cows. In summary, the level of mRNA encoding GH receptor, IGF-I, IGFBP-2, and IGFBP-3 varied within the tissues examined, suggesting that these genes may play a variety of roles in the bovine female reproductive tract. Supplemental GH failed to change the expression of IGF-I, IGFBP-2, and IGFBP-3 mRNA, possibly because of low GH receptor mRNA levels in tissues other than CL. A direct action of GH on IGF-I, IGFBP-2, or IGFBP-3 gene expression within cow reproductive tissues was not supported because the amount of IGF-I, IGFBP-2, or IGFBP-3 mRNA was not altered by GH.     

Reconstruction of lateral skull base oncological defects: the role of free tissue transfer

The present study was performed to investigate the age-dependent changes in body composition and the possible role of growth hormone (GH), insulin-like growth factor (IGF)-I and IGF-binding protein-3 (IGFBP-3) in these changes in postmenopausal Japanese women. A total of 161 Japanese women aged 45-88 years (mean 62) were enrolled in the cross-sectional study. Body composition (bone mineral content (BMC), lean body mass (LBM) and fat) was measured by dual-energy X-ray absorptiometry, and the percentage of BMC, LBM and fat was calculated by dividing each absolute value of body composition by total body mass. Urinary GH concentration divided by creatinine in nocturnal urine samples collected just after waking was used as an index of endogenous GH secretion. Serum levels of IGF-I and IGFBP-3 were measured by RIA. Urinary GH levels as well as serum levels of IGF-I and IGFBP-3 declined with age. BMC, %BMC and LBM also declined with age, while fat mass and %fat did not obviously change with age. Urinary GH levels as well as serum levels of IGF-I and IGFBP-3 correlated positively with BMC, even if age was taken into account. On the other hand, urinary GH correlated negatively with fat and %fat. In contrast, serum levels of IGF-I and IGFBP-3 correlated positively with fat and %fat. LBM did not correlate with either urinary GH or serum IGFBP-3 levels but exhibited a weakly positive correlation with serum IGF-I level. The present study suggests that the GH-IGF-I-IGFBP-3 axis positively regulates bone mass, and that GH and IGF-I-IGFBP-3 inversely regulate fat mass, i.e. GH negatively and IGF-I-IGFBP-3 positively regulates it.     

Serum concentrations of free and total insulin-like growth factor-I, IGF binding proteins -1 and -3 and IGFBP-3 protease activity in boys with normal or precocious puberty

OBJECTIVE: Circulating IGF-I and IGF binding protein-3 (IGFBP-3) levels both increase in puberty where growth velocity is high. The amount of free IGF-I is dependent on the IGF-I level and on the concentrations of the specific IGFBPs. Furthermore, IGFBP-3 proteolysis regulates the bioavailability of IGF-I. However, the concentration of free IGF-I and possible IGFBP-3 proteolytic activity in puberty has not previously been studied. SUBJECTS AND MEASUREMENTS: We investigated serum levels of easily dissociable IGF-I concentrations and ultrafiltrated free IGF-I levels by specific assays in 60 healthy boys and in 5 boys with precocious puberty before and during GnRH agonist treatment. In addition, total serum IGF-I, IGFBP-1 and IGFBP-3 levels as well as IGFBP-3 protease activity were determined. RESULTS: Free (dissociable and ultrafiltrated) IGF-I concentrations were significantly higher in pubertal boys than in prepubertal children and correlated significantly with the molar ratio between IGF-I and IGFBP-3 (r = 0.69, P < 0.0001 and r = 0.54, P = 0.0008, respectively) and inversely with IGFBP-1 (r = -0.47, P < 0.0001 and r = -0.43, P = 0.0003, respectively). Multiple regression analysis suggested that IGFBP-3 level, and not IGFBP-1, was the major determinant of the free IGF-I serum level in normal boys. Free IGF-I levels were elevated in boys with precocious puberty and decreased during GnRH treatment. IGFBP-3 proteolysis was constant throughout puberty (mean 20%). CONCLUSIONS: We conclude that easily dissociable and ultrafiltrated free IGF-I serum levels are increased in boys with normal and precocious puberty and suggest that the increased free IGF-I serum concentration in puberty primarily reflects changes in total concentrations of IGF-I and IGFBPs secondary to increased GH secretion, but that it is not influenced by changes in IGFBP-3 proteolysis.     

Short stature and failure of pubertal development in thalassaemia major: evidence for hypothalamic neurosecretory dysfunction of growth hormone secretion and defective pituitary gonadotropin secretion

In patients with beta-thalassaemia major, frequent blood transfusions combined with desferrioxamine chelation therapy lead to an improved rate of survival. Endocrine disorders related to secondary haemosiderosis such as short stature, delayed puberty and hypogonadism are major problems in both adolescent and adult patients. A total of 32 patients with beta-thalassaemia major undergoing treatment at the Children's Hospital, University of G?ttingen were examined. Fourteen of these were short in stature. Growth hormone (GH) secretion was investigated in 13 patients exhibiting either a short stature or reduced growth rate. The stimulated GH secretion of 10 patients in this subgroup lay within the normal range. Studies of their spontaneous GH secretion during the night revealed that these patients had a markedly reduced mean GH and reduced amplitudes in their GH peaks. Low insulin-like growth factor (IGF)-I levels were seen in the growth-retarded thalassaemic patients. Eight were subjected to an IGF generation test and showed a strong increase in both IGF-I and insulin-like growth factor binding protein (IGFBP)-3 levels indicating intact IGF-I generation by the liver. Hypogonadotropic hypogonadism was found to be present in both the male and female patients with impaired sexual development. After priming with LH-releasing hormone (GnRH) per pump in 2 female and 5 male patients, no change in either their serum oestradiol or testosterone levels or in LH/FSH response to GnRH was observed suggesting that they were suffering from a severe pituitary gonadotropin insufficiency. Three male patients at the age of puberty but exhibiting short stature. low GH, low IGF-I and hypogonadism received low dose long-acting testosterone. After 3 12 months of therapy there was a marked growth spurt, higher nocturnal GH levels and an increase in both IGF-I and IGFBP-3. CONCLUSION: Reduced GH secretion and low IGF-I in thalassaemic patients are related to a neurosecretory dysfunction due to iron overload rather than to liver damage. Hypogonadotropic hypogonadism is caused by the selective loss of pituitary gonadotropin function. In patients with both GH deficiency and hypogonadism, low dose sexual steroid treatment should be considered either as an alternative or an additional treatment before starting GH therapy.     

Regulation of the growth hormone-insulin-like growth factor I axis in developing and adult monkeys is affected by estradiol replacement and supplementation with insulin-like growth factor I

Developmental changes in the GH-insulin-like growth factor I (IGF-I) axis were evaluated in female rhesus monkeys to test the hypothesis that estradiol differentially regulates IGF-I secretion and molar ratios of IGF-I to IGF-binding protein-3 (IGFBP-3) from adolescence into adulthood and that estradiol can reestablish GH secretion in the face of enhanced IGF-I negative feedback inhibition of GH. Adult ovariectomized females were compared to ovariectomized adolescent females studied from 18-36 months of age, a period encompassing the juvenile phase through the expected age at first ovulation. A subgroup of adult (n = 5) and adolescent females (n = 5) was treated continuously with human IGF-I (110 micrograms/kg.day, s.c.) throughout the study period and were compared to age-matched, untreated adults (n = 5) and adolescent animals (n = 6). To further understand how IGF-I affects the GH-IGF-I axis, the acute response to IGF-I (100 micrograms/kg, s.c.) was assessed in adults and at two ages in developing females. Furthermore, all females were treated periodically with estradiol (4 micrograms/kg.day) to assess the effects on the parameters of the GH-IGF-I axis from adolescence into adulthood. Finally, the response to GHRH (1.0 microgram/kg, i.v.) was assessed in adult females and in adolescent females at 18 and 24 months during no estradiol and estradiol replacement. Serum IGF-I and IGFBP-3, in the absence of estradiol replacement, increased significantly throughout puberty before declining from late adolescence into adulthood. Supplementation with IGF-I resulted in a significant increase in both serum IGF-I and IGFBP-3 concentrations at all ages, although the effect was less in juvenile females. Nevertheless, the age-dependent increase and decline in IGF-I and IGFBP-3 were maintained in these supplemented animals. Estradiol replacement significantly increased both serum IGF-I and IGFBP-3 through adolescence, even in IGF-I-supplemented animals. However, with the transition from adolescence, estradiol suppressed serum IGF-I secretion, yet continued to increase IGFBP-3 in young adult and fully adult females. This change in proportionately less IGF-I compared with IGFBP-3 resulted in a significant age-dependent decrease in the molar ratio of IGF-I to IGFBP-3. Indeed, the molar ratio was highest during midadolescence, when both IGF-I and IGFBP-3 were at their zeniths. Serum IGFBP-1 was significantly higher in adolescent compared with adult females. However, estradiol replacement significantly elevated serum IGFBP-1 in adult, but not adolescent, females, abolishing the age differences observed under no estradiol conditions. Serum GH was significantly higher in adolescent compared with adult females; levels in juvenile animals were intermediate. Replacement with estradiol significantly elevated serum GH in adolescent and adult females, particularly in females supplemented with IGF-I. In contrast, estradiol had no effect on serum GH during the juvenile phase. Supplementation with IGF-I significantly dampened the response to GHRH in young and fully adult females, but not in juvenile animals. However, estradiol replacement restored the response to GHRH in these adult, IGF-I-supplemented females. These data indicate that in the absence of any ovarian influence, the decline in serum IGF-I and IGFBP-3 begins in postpubertal, young adult females and is not necessarily a consequence of old age. Furthermore, there is an age-dependent uncoupling of estradiol regulation of the GH-IGF-I axis, as estradiol stimulates GH and IGFBP-3 at all ages but increases serum IGF-I only during adolescent and decreases IGF-I in postpubertal, young adult females. Furthermore, IGF-I has a greater suppressive effect on GH secretion with advancing age, an effect reversed by estradiol replacement. These data suggest that the deficits in the GH-IGF-I axis observed in aged individuals may reflect a continuation of the regulatory changes that begin in young adult females.     

Stimulation of intestinal growth is associated with increased insulin-like growth factor-binding protein 5 mRNA in the jejunal mucosa of insulin-like growth factor-I-treated parenterally fed rats

Surgically stressed rats maintained with total parenteral nutrition (TPN) exhibit jejunal atrophy, which can be attenuated by insulin-like growth factor-I (IGF-I) but not by growth hormone (GH) treatment. In order to understand the basis for the selective action of IGF-I, the levels of mRNAs encoding IGF-I, IGF-binding proteins (IGFBPs), IGF-I receptor, and GH receptor/binding protein (GHR/GHBP) were determined in rats given TPN and treated with GH, IGF-I, or GH + IGF-I. GH treatment significantly stimulated hepatic IGF-I mRNA. IGF-I treatment did not alter liver IGF-I mRNA, nor was there any evidence for interaction between GH and IGF-I. Jejunal mucosa IGF-I mRNA was extremely low and was not altered by TPN or by any of the hormonal treatments. The inability of GH to stimulate jejunal growth was not associated with a deficiency in GHR/GHBP mRNA. In jejunal mucosa, IGF-I and GH treatment independently and synergistically stimulated IGFBP-3 mRNA. IGF-I stimulated jejunal IGFBP-5 mRNA, but GH had no effect on IGFBP-5 mRNA. The levels of IGF-I receptor and IGFBP-1, 2, 4, and 6 mRNAs were extremely low and/or were not altered by any of the treatments. These results suggest that the ability of exogenous IGF-I, but not GH, to induce IGFBP-5 mRNA in jejunal mucosa may lead to the selective growth-promoting effect of IGF-I. Jejunal mucosa IGFBP-3 mRNA levels were not correlated with altered growth. We postulate that IGFBP-5 positively modulates the anabolic effects induced by exogenous IGF-I in the jejunum.     

Free and total insulin-like growth factors and insulin-like growth factor binding proteins during 14 days of growth hormone administration in healthy adults

The objective was to investigate the effect of growth hormone (GH) administration on circulating levels of free insulin-like growth factors (IGFs) in healthy adults. Eight healthy male subjects were given placebo and two doses of GH (3 and 6 IU/m2 per day) for 14 days in a double-blind crossover study. Fasting blood samples were obtained every second day. Free IGF-I and IGF-II were determined by ultrafiltration of serum. Total IGF-I and IGF-II were measured after acid-ethanol extraction. In addition, GH, insulin, IGF binding protein 1 (IGFBP-1) and IGFBP-3 were measured. Serum-free and total IGF-I increased in a dose-dependent manner during the 14 days of GH administration. After 14 days, serum-free IGF-I values were 610 +/- 100 ng/l (mean +/- SEM) (placebo), 2760 +/- 190 ng/l (3 IU/ m2) and 3720 +/- 240 ng/l (6 IU/m2) (p = 0.0001 for 3 and 6 IU/m2 vs placebo; p = 0.004 for 3 IU/m2 vs 6 IU/m2). Total IGF-I values were 190 +/- 10 micrograms/l (placebo), 525 +/- 10 (3 IU/m2), and 655 +/- 40 micrograms/l (6 IU/m2) (p < 0.0001 for 3 and 6 IU/m2 vs placebo; p = 0.04 for 3 IU/m2). There were no differences in the levels of free or total IGF-II during the three study periods. Insulin-like growth factor binding protein 1 was decreased during GH administration (p = 0.04 for placebo vs 3 IU/m2; p = 0.006 for placebo vs 6 IU/m2). In conclusion, fasting serum free IGF-I increased dose dependently during GH administration and free IGF-I increased relatively more than total IGF-I. This may partly be due to the decrease in IGFBP-1.     

Use of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 in the diagnosis of acromegaly and growth hormone deficiency in adults

The goal of our study was to compare the clinical usefulness of plasma insulin-like growth factor-I (IGF-I) (with and without binding protein extraction) and IGF binding protein-3 (IGFBP-3) measurements in the diagnosis of growth hormone (GH) disorders in adults. IGF-I and IGFBP-3 concentrations were measured in 25 acromegalic and 25 GH-deficient adult (GHDA) subjects (20-76 years) by comparison to a control population (n = 81) after age and sex stratification. In untreated acromegaly, IGF-I and IGFBP-3 were clearly increased (10 times the mean of controls for unextracted IGF-I, 4 times for extracted IGF-I and 2 times for IGFBP-3). Using the mean + 2SD of the control population as the cut-off point, the sensitivity of IGF-I for the diagnosis of acromegaly was higher than that of IGFBP-3 (unextracted IGF-I: 96% and extracted IGF-I: 100% vs IGFBP-3: 76%). In GHDAs, IGF-I and IGFBP-3 were decreased (34% of the mean of controls for unextracted IGF-I, 37% for extracted IGF-I and 70% for IGFBP-3). Using the mean - 2SD of the control population as the cut-off point, the sensitivity of IGF-I measurement for the diagnosis of GHDA was relatively low, but better for unextracted (68%) than for extracted IGF-I (52%). The sensitivity of IGFBP-3 was much lower (36%), thus invalidating this parameter for the diagnosis of GHDA. Our observations demonstrate that IGF-I measurement is a more powerful tool than IGFBP-3 measurement for the diagnosis of GH disorders in adults. Both IGF-I and IGFBP-3 are very useful for the diagnosis of acromegaly, but they are less reliable for diagnosing GHDA, as normal IGF-I or IGFBP-3 values do not rule out GH deficiency.     

Alcohol withdrawal-induced change in lipoprotein(a): association with the growth hormone/insulin-like growth factor-I (IGF-I)/IGF-binding protein-1 (IGFBP-1) axis

Lipoprotein(a) [Lp(a)] is an important risk factor for cardiovascular disease. Alcohol is one of the few nongenetic factors that lower Lp(a) levels, but the metabolic mechanisms of this action are unknown. Alcohol inhibits the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. Alcohol might also affect IGF-binding protein-1 (IGFBP-1), which is an acute inhibitor of IGF-I. We studied how alcohol withdrawal affects Lp(a) levels and the GH/IGF-I/IGFBP-1 axis. Male alcohol abusers (n=27; 20 to 64 years old) were monitored immediately after alcohol withdrawal for 4 days. Twenty-six healthy men, mainly moderate drinkers, served as control subjects. Fasting blood samples were drawn to determine Lp(a), IGF-I, and IGFBP-1 (by ELISA, RIA, and immunoenzymometric assay, respectively). Nocturnal (12 hours) urine collection was performed in 9 alcoholics and 11 control subjects for GH analyses (RIA). The groups were similar in age and body mass index. Lp(a), GH, and IGF-I tended to be lower and IGFBP-1 higher in the alcoholics immediately after alcohol withdrawal than in the control subjects. During the 4-day observation in alcoholics, Lp(a) levels increased by 64% and IGF-I levels by 41%, whereas IGFBP-1 levels decreased by 59% (P<.001 after ANOVA for all comparisons). Urinary GH levels tended to decline. The increase in Lp(a) correlated inversely with the changes in IGFBP-1 (r= -.63, P<.001, n=27) and GH (r=-.70, P<.05, n=9), but not with IGF-I. In multiple regression analysis, the main predictors for the increase in Lp(a) were IGFBP-1 and urinary GH. In conclusion, alcohol withdrawal induces interrelated and potentially atherogenic changes in Lp(a) and IGFBP-1 levels.     

Long [R3] insulin-like growth factor-I reduces growth, plasma growth hormone, IGF binding protein-3 and endogenous IGF-I concentrations in pigs

Growth hormone (GH) improves growth performance in the pig. Analogues of insulin-like growth factor-I (IGF-I) that bind poorly to IGF binding proteins (IGFBP) stimulate growth in the rat but, in contrast, inhibit growth in the pig. This study was designed to determine the effect of IGF peptides alone or in combination with porcine GH (pGH) on growth characteristics and plasma hormone concentrations in finisher pigs. A four-day infusion of Long [R3] IGF-I (LR3IGF-I; 180 micrograms/kg/day) decreased the average daily gain, food intake, and plasma IGFBP-3, IGF-I and insulin concentrations. The mean plasma GH concentration was decreased by 23% and the area under the GH peaks was reduced by 60%. Co-administration of pGH (30 micrograms/kg/day) with LR3IGF-I had no interactive effect on growth performance, and plasma insulin, IGFBP-3 and IGF-I concentrations remained suppressed. The area under the GH peaks was not restored with this combination treatment although mean plasma GH concentrations were elevated in all animals receiving pGH. Infusion of IGF-I (180 micrograms/kg/day) decreased plasma insulin and mean GH concentrations but had no significant effect on IGFBP-3 concentrations. Average daily gain and feed intake were not changed by IGF-I treatment. A combination of IGF-I and pGH injection (30 micrograms/kg/day) increased plasma IGFBP-3 concentrations but plasma insulin levels remained suppressed. Plasma glucose levels were unaffected by any treatment. The study demonstrates that both IGF-I and LR3IGF-I suppress plasma GH concentrations in finisher pigs. This, in turn, may be responsible for the reduction in the plasma concentration of IGF-I, IGFBP-3 and insulin seen in LR3IGF-I-treated animals. The decrease in these parameters may contribute to the inhibitory effect of LR3IGF-I on growth performance in the pig.     

Effects of alcohol and liver cirrhosis on the GH-IGF-I axis

Decreased serum insulin-like growth factor (IGF-I) levels have been shown in malnutrition and liver diseases. To analyse which of them is the main cause of GH-IGF-I axis alterations, serum levels of growth hormone (GH), growth-hormone releasing factor (GHRH), IGF-I and its binding protein IGFBP-3 were measured in 85 hospitalized alcoholics (51 without cirrhosis, 15 with compensated cirrhosis and 19 with cirrhosis with ascites) and in 25 healthy controls. Liver function tests and objective nutritional assessment were also performed. Serum IGF-I and IGFBP-3 levels were lower in alcoholics, particularly in those with liver cirrhosis. Serum GH was raised in cirrhotics with ascites but GHRH levels were not significantly altered. Although these patients were frequently malnourished there was no relationship between data derived from GH-IGF-I axis and nutritional parameters. However, there was a significant positive correlation between serum GH concentrations and impaired liver function and a significant negative correlation between serum IGF-I and IGFBP-3 and impaired liver function. This suggests that, in this population, serum IGF-I and IGFBP-3 levels reflect liver dysfunction rather than malnutrition.     

Progress in diagnosis of gastric cancer and improvement of treatment results]

It is known that growth hormone (GH) contributes to glomerulosclerosis and that this probably occurs via insulin-like growth factor-I (IGF-I). However, the manner by which GH and nephrectomy (Nx) alter IGF-binding protein (IGFBP) mRNA in the kidney has not been fully explained. The effects of GH on renal IGF-I and IGFBP-1, 2, 3, 4, and 5 following Nx were examined in spontaneous dwarf rats (SDRs) which have a complete and specific lack of GH among pituitary hormones. In normal Sprague-Dawley rats (SDs), Nx resulted in significant decreases in levels of IGFBP-1 mRNA and IGFBP-5 mRNA to 62.7 +/- 4.9 and 56.5 +/- 5.0% those of sham-operated kidneys, respectively. Nx did not alter the IGF-I mRNA level in SDs. The levels of IGFBP-2, IGFBP-3, and IGFBP-4 mRNAs were likewise unchanged following nephrectomy. In SDRs, Nx significantly decreased the levels of IGFBP-1, IGFBP-4, and IGFBP-5 mRNA, to 57 +/- 2.6, 46 +/- 12, and 64 +/- 8.1% of sham-operated animals. However, Nx did not alter the levels of IGF-I, IGFBP-2, and IGFBP-3 mRNA. GH injections of nephrectomized SDRs fully normalized the decreased IGFBP-4 mRNA levels, whereas levels of IGFBP-1 and IGFBP-5 mRNA were not reversed. The altered expression of IGFBP-4 mRNA following Nx of SDRs compared to that of SDs appears highly significant since it is known that, unlike SDs, glomerulosclerosis does not fully develop in SDRs following renal ablation. The change in the IGFBP-4 mRNA level might be related to the development of glomerulosclerosis in SDs.