Assessing short-statured children for growth hormone deficiency

AIM: To optimize the workup of short-statured children by defining the most appropriate tools for diagnosing growth hormone (GH) deficiency. METHODS: Patients were assigned to prepubertal (n = 113) or pubertal (n = 112, including 25 boys primed with testosterone) age groups. Mean plasma GH concentration during sleep, GH peak after provocative test, and insulin-like growth factor I (IGF-I) were measured in a single evaluation. RESULTS: The mean GH concentration during sleep was more often normal (n = 155) than the GH peak after provocative tests (n = 105) or the IGF-I concentration (n = 88). Prepubertal patients with a normal body mass index (BMI) had mean GH concentrations during sleep that correlated positively with height, growth rate, GH peak after provocative tests, and IGF-I (p < 0.0005 for all) and negatively with the difference between target and patient heights (p = 0.01) and BMI (p < 0.05). Pubertal patients with a normal BMI had a mean GH concentration during sleep that correlated positively with GH after provocative tests (p < 0.0001) and IGF-I (p < 0.005). Mean GH concentration during sleep and IGF-I concentration for boys primed with testosterone were more often normal (n = 23) than the GH peak after provocative tests (n = 14). All 9 patients with pituitary stalk interruption had low IGF-I concentrations; 1 patient had a normal GH peak after provocative test, and 2 patients had normal mean GH concentrations during sleep. CONCLUSIONS: Measuring the GH concentration during sleep and priming boys with pubertal delay can help to exclude idiopathic GH deficiency. Magnetic resonance imaging is needed to exclude anatomic abnormalities when GH and/or IGF-I concentrations are low.     

Normal growth spurt and final height despite low levels of all forms of circulating insulin-like growth factor-I in a patient with acid-labile subunit deficiency

BACKGROUND: In a recently described patient with acid-labile subunit (ALS) deficiency, the inability to form ternary complexes resulted in a marked reduction in circulating total insulin-like growth factor (IGF)-I, whereas skeletal growth was only marginally affected. To further study the role of circulating versus locally produced IGF-I in skeletal growth in this patient, we now describe in detail growth changes and their relationship with several components of the circulating IGF system. DESIGN AND METHODS: We followed growth and development up to the final height in a patient with complete ALS deficiency and determined both spontaneous and growth hormone (GH)-stimulated changes in the IGF system, including measurements of total, free and bioactive IGF-I, total IGF-II and insulin-like growth factor binding protein (IGFBP)-1, IGFBP-2 and IGFBP-3. RESULTS: The patient had a delayed growth and pubertal onset. Six months of GH treatment had no effect on growth. At the age of 19.3 years, he spontaneously completed puberty and had a normal growth spurt for a late adolescent (peak height velocity of 8.4 cm/year). A normal final height was attained at 21.3 years (167.5 cm; -0.78 SDS). During as well as after puberty, basal levels of total, free and bioactive IGF-I were low, as were total IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3. GH treatment for 6 months normalized free IGF-I and increased bioactive IGF-I, but had no effect on growth velocity. CONCLUSIONS: This case story shows that in the presence of complete ALS deficiency, a height within normal limits can be obtained despite low levels of all forms of circulating IGF-I. Furthermore, the patient presented a delayed but normal growth spurt without any marked increment of circulating IGF-I.     

Reproducibility in patterns of IGF generation with special reference to idiopathic short stature

BACKGROUND/AIM: Insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein 3 (IGFBP-3) generation tests are both sensitive and specific measures of growth hormone (GH) sensitivity. Recently, the question of reproducibility of IGF generation tests has been raised. We report our analysis of the correlation of low- and high-dose GH IGF-I and IGFBP-3 generation tests among patients with GH deficiency, GH insensitivity, and idiopathic short stature. METHODS: A total of 198 subjects were randomized to either high- or low-dose GH for 7 days; the alternate dose was received after a 2-week washout period. Samples were collected at baseline and on days 5 and 8 of GH administration. RESULTS: The serum concentrations of IGF-I and IGFBP-3 correlated significantly from one test to the other, regardless of the diagnosis. In normal subjects and patients with GH insensitivity and GH deficiency, the delta over baseline in IGF-I and IGFBP-3 in the low-dose test was highly predictive of the delta values in the high-dose test. The delta correlation was greatly diminished, however, in the patient population having idiopathic short stature. CONCLUSIONS: These observations support partial GH insensitivity effecting IGF-I generation specifically, as a possible etiology for idiopathic short stature, and thus such patients may warrant appropriate biochemical and/or molecular evaluation for partial GH insensitivity.     

Insulin-like growth factor I levels in healthy adults

Insulin-like growth factor I (IGF-I) levels mainly reflect secretion of growth hormone (GH) in the body. The aims of this study were to compare different IGF-I assay methods in healthy individuals, test the reliability of the methods and discuss the utility of IGF-I measurement in adults. The Nichols Institute Diagnostics radioimmunoassay was used to evaluate IGF-I in two random population samples of men and women (aged 25-64 years, n = 392) taken 10 years apart, in 1985 and 1995. This method for IGF-I testing was also compared with an immunoradiometric assay (IRMA) method in 387 men and women participating in the World Health Organization MONICA (MONItoring of trends and determinants for CArdiovascular diseases) Project, Goteborg, Sweden, in 1995. Serum IGF-I decreased with increasing age in both men and women. IGF-I was higher in young women compared with young men in both cohorts, while the opposite was found in the highest age group. Age-adjusted significant correlations were found between IGF-I and smoking, fibrinogen, coffee consumption, lipoprotein (a), osteocalcin and IGF-binding protein 3. The two cohorts showed similar mean IGF-I concentrations irrespective of method. The correlation between the Nichols and the IRMA methods was high: r = 0.93 (p < 0.0001). Based on this and previous studies, population-based IGF-I measurements are robust irrespective of which commercially available method of assay is used. IGF-I levels can be used in diagnosing acromegaly as well as providing target values. IGF-I assay can be used as a complement to stimulation testing in the diagnosis of GH deficiency, and as a tool for GH dose titration.     

Relevance of IGF-I, IGFBP-3, and IGFBP-2 measurements during GH treatment of GH-deficient and non-GH-deficient children and adolescents

BACKGROUND: Little information is available on the relevance of parameters representing the insulin-like growth factor (IGF) system with regard to growth hormone (GH) treatment during childhood. In adults, high IGF-I levels were found to be associated with side effects and long-term risks. AIM/METHOD: Our aim was to monitor the serum levels of IGF-I, IGF-binding protein (IGFBP) 3, and IGFBP-2 during long-term GH treatment of 156 patients with GH deficiency (GHD) and of 153 non-GHD patients. We determined the extent to which the IGF parameters exceed the normal ranges and identified those parameters which are predictive of 1st-year growth. RESULTS: In prepubertal GHD children, the levels of IGF-I, IGFBP-3, and IGF-I/IGFBP-3 exceeded the 95th centile of the reference values for this age group in 2.3, 0.3, and 7.9% of the cases, respectively, whereas in prepubertal non-GHD children, the same parameters exceeded the 95th reference centile in 20.1, 3.5, and 32.2%, respectively. In pubertal GHD children IGF-I, IGFBP-3, and IGF-I/IGFBP-3 levels exceeded the 95th reference centile in 11.1, 1.5, and 15.4%, respectively. In pubertal non-GHD children, these levels also exceeded the 95th centile in 26.7, 7.0, and 41.4%, respectively. In both GHD and non-GHD groups, however, some patients had IGF parameters which were below the reference values. Our analysis showed that, in both groups, in addition to maximum GH, all IGF parameters (IGF-I, IGFBP-3, IGF-I/IGFBP-3 ratio, IGFBP-2 or derivatives) significantly extend the scope of a calculated model for predicting 1st-year height velocity. CONCLUSION: For reasons of safety and optimization of GH therapy, it is essential to follow up IGF-I, IGFBP-3, and IGFBP-2 levels regularly during childhood.     

Cell-specific localization of insulin-like growth factor binding protein mRNAs in rat liver

The liver is a major source of circulating insulin-like growth factor I (IGF-I), and it also synthesizes several classes of IGF binding proteins (IGFBPs). Synthesis of IGF-I and IGFBPs is regulated by hormones, growth factors, and cytokines. They are nutritionally regulated and expressed in developmentally specific patterns. To gain insight into cellular regulatory mechanisms that determine hepatic synthesis of IGF-I and IGFBPs and to identify potential target cells for IGF-I within the liver, we studied the cellular sites of synthesis of IGF-I, IGF receptor, growth hormone (GH) receptor, and IGFBPs in freshly isolated rat hepatocytes, endothelial cells, and Kupffer cells. We also localized cellular sites of IGFBP synthesis by in situ hybridization histochemistry. Western ligand and immunoblot analyses were used to determine IGFBP secretion by isolated cells. Two IGF-I mRNA subtypes with different 5' ends (class 1 and class 2) were detected in all isolated liver cell preparations. Type 1 IGF receptor mRNA was detected in endothelial cells, indicating that these cells are a local target for IGF actions in liver. GH receptor was expressed in all cell preparations, consistent with GH regulation of IGF-I and IGFBP synthesis in multiple liver cell types. The IGFBPs expressed striking cell-specific expression. IGFBP-1 was synthesized only in hepatocytes, and IGFBP-3 was expressed in Kupffer and endothelial cells. IGFBP-4 was expressed at high levels in hepatocytes and at low levels in Kupffer and endothelial cells. Cell-specific expression of distinct IGFBPs in the liver provides the potential for cell-specific regulation of hepatic and endocrine actions of IGF-I.     

Insulin-like growth factor (IGF) parameters and tools for efficacy: the IGF-I generation test in children

Serum levels of growth hormone (GH)-dependent peptides could provide important and valuable measures of GH sensitivity and, potentially, responsiveness. In normal individuals, serum insulin-like growth factor I (IGF-I) concentrations are dependent on the dose of GH given, with IGF-I responsiveness not decreasing with age. Individuals heterozygous for the E180 GH receptor (GHR) splice mutation have normal IGF-I generation, but those homozygous for the E180 splice mutation have very low basal and stimulated IGF-I concentrations. Similar results are observed for the serum IGF-binding protein 3 (IGFBP-3) response to GH, with a correlation between changes in serum concentrations of IGF-I and changes in IGFBP-3 in normal, heterozygotic, GH-insensitive and GH-deficient participants. In individuals with the E180 splice mutation, IGF-I and IGFBP-3 tests show sensitivity and specificity for detecting GH insensitivity (GHI). In children with idiopathic short stature, it appears that some individuals have selective resistance to GH, with their ability to generate IGF-I more impaired than their ability to generate other GH-dependent peptides. This heterogeneous group may require individualization of GH dosage. IGF generation tests remain the best short-term, in vivo test for classic GHI, although diagnostic tests will undoubtedly require further modification to identify milder pathophysiologic abnormalities.     

Association of IGF-I and the IGF-I/IGFBP-3 ratio with plasma aldosterone levels in the general population

Several studies in patients with acromegaly or growth hormone (GH) deficiency suggest a stimulatory effect of the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis on the renin-angiotensin-aldosterone system (RAAS). We analyzed the association of serum IGF-I with plasma aldosterone and the aldosterone-to-renin ratio in a large sample from the general population. In addition to serum IGF-I levels, we also considered the IGF-I-to-IGF binding protein (IGFBP)-3 ratio. A total of 1 504 men and 1 566 women aged 25-88 were selected from the first follow-up of the population-based Study of Health in Pomerania. Plasma aldosterone and renin concentrations, as well as serum IGF-I and IGFBP-3 levels were determined with immunoassays. Analyses of variance and linear regression analyses were performed. We found positive associations between serum IGF-I or the IGF-I/IGFBP-3 ratio with plasma aldosterone in women but not in men. Plasma aldosterone levels increased by 2.91 ng/l per IGF-I standard deviation (SD) and by 2.17 ng/l per IGF-I/IGFBP-3 SD. The associations remained significant after exclusion of subjects taking RAAS-altering medication and of subjects with serum IGF-I levels and aldosterone-to-renin ratios outside the reference range. We conclude that, serum IGF-I and the IGF-I/IGFBP-3 ratio are associated with plasma aldosterone levels in women but not in men from the general population.     

Long-term monitoring of insulin-like growth factor I in adult growth hormone deficiency: a critical appraisal

Serum insulin-like growth factor I (IGF-I) levels predominantly reflect the hepatic effect of growth hormone (GH). Compared with serum GH levels, which reflect pulsatile GH secretion, serum IGF-I levels exhibit no major diurnal variation and thus provide a better estimate of integrated GH secretion in an individual patient. Measurement of serum IGF-I levels allows reliable identification of states of GH excess. In contrast, in a large proportion of adults with severe GH deficiency, serum IGF-I levels are within the normal range. Serum IGF-I levels increase markedly in response to GH administration and are often used as a surrogate variable for overall responsiveness to such treatment. Current data, however, suggest a poor relationship between changes in or levels of IGF-I and efficacy variables such as body composition, muscle function and well-being. The use of serum IGF-I as a guide during dose titration in the initial phase of treatment and during long-term monitoring of GH replacement therapy in adults, and its use as a safety marker or predictor of future morbidity and mortality are discussed here.     

Differential regulation of insulin-like growth factor-(IGF) I and IGF-binding protein (IGFBP) secretion by human peripheral blood mononuclear cells

BACKGROUND: Recent studies have shown that immunocompetent cells synthesize and express growth hormone (GH), growth hormone receptors (GH-R), insulin-like growth factor I (IGF-I), IGF-I receptors (IGF-I-R) and different insulin-like growth factor binding proteins (IGFBPs). The aim of the current study was to evaluate the regulation of IGFBP and IGF-I secretion from immunocompetent cells by different mitogens. METHODS/RESULTS: We studied the in vitro secretion pattern of IGFBPs and IGF-I from human peripheral blood mononuclear cells (PBMC), derived from 10 normal adults and 8 GH-deficient patients with adult onset. In serum-free conditioned medium of unstimulated PBMC, derived from normal adults, Western ligand blotting (1D-WLB) revealed a 24-kD, a 34-kD and a 39/43-kD doublet band to be most prominent. According to their molecular weight and two-dimensional Western ligand blot analysis (2D-WLB), these bands are deglycosylated IGFBP-4, IGFBP-2 and IGFBP-3, respectively. When the cells were treated with the T-cell mitogen phytohemagglutinin (PHA) (10 microg/ml), a differential stimulation of IGFBPs was found with a 2.57 +/- 0.48-fold increase of IGFBP-4 (p < 0.01), a 1.55 +/- 0.13-fold increase of IGFBP-2 (p < 0.01), and a 1.35 +/- 0.19-fold increase of IGFBP-3 (n.s.). In contrast, treatment with the B-cell mitogen pokeweed mitogen (PWM) (10 microg/ml) caused only a modest 1.40 +/- 0.07-fold increase of IGFBP-4 (p < 0.01). Treatment with rhGH (100 ng/ml) or rhIGF-I (200 ng/ml) caused no significant induction of any specific band, respectively. In contrast to the secretion pattern of IGFBPs, IGF-I secretion of the PBMC was not stimulated by either PHA or PWM, but showed a significant increase after GH incubation (p < 0.01). A similar differentiated secretion pattern of IGFBPs and IGF-I was also observed in the conditioned medium of PBMC, derived from GH-deficient patients. CONCLUSION: In summary, at least three different IGFBPs are secreted by human PBMC. Secretion of IGFBPs by PBMC is differentially regulated by different lymphocyte mitogens. Secretion of IGFBPs by PBMC is independent of GH or IGF-I, whereas the secretion of IGF-I is stimulated by GH. PBMC derived from normal adults and GH-deficient patients show similar patterns of IGF-I and IGFBPs secretion, thus indicating that the paracrine/autocrine IGF-I-IGFBPs interactions of the PBMC are not altered by pituitary GH deficiency.     

Serum leptin, insulin-like growth factor-I components and sex-hormone binding globulin. Relationship with sex, age and body composition in healthy population

Leptin plays an important role in the regulation of food intake and thermogenesis, regulates long term energy balance and reproductive function and its concentrations are closely linked to body mass index. Leptin secretion is influenced by many factors and the age-related changes in different hormones might modify circulating leptin concentrations. Sex dimorphism in leptin concentrations has been clearly shown in previous studies and its concentrations were lower in men than in women in all decades of life. Insulin growth factor-I (IGF-I) is a peptide growth factor that is present in all types of physiologic fluids and is also produced by connective tissue cell types and its autocrine/paracrine secretion is nearly always present within tissues. There is a physiological decline of the growth hormone (GH)/IGF-I axis with ageing and in addition, insulin, thyroid hormones and the supply of dietary energy may directly regulate the circulating levels of the IGFs and growth hormone binding protein (GHBP). Furthermore, there is no doubt that GH participates in the regulation of body composition, and with advanced age there is a decrease in muscle and an increase in adiposity associated with a decline in GH and total IGF-I. The biological activities of the IGF ligands are modulated by the family of high affinity GHBP. Sex hormone binding globulin (SHBG) concentrations are thought to be regulated primarily through opposing actions of sex steroids on hepatic SHBG production, with oestrogen stimulating and androgen inhibiting SHBG production, and thyroid hormones are also a potent stimulator of SHBG production concentrations. Some studies support an independent IGFBP3 contribution to SHBG variability and these findings are compatible with the hypothesis that some of the anabolic effects ascribed to the GH/IGF axis may be caused by SHBG-mediated changes in testosterone activity or SHBG/total testosterone index.     

Tissue regulation of somitic colloid-like1 gene expression

The progression to nonalcoholic steatohepatitis (NASH) from simple steatosis is associated with the mitochondrial dysfunction, enhanced oxidative stress, and inflammation. Recently, it has been reported that the prevalence of NAFLD (nonalcoholic fatty liver disease)/NASH is increased in patients with adult growth hormone deficiency (AGHD), suggesting that the deficiencies in GH and insulin-like growth factor (IGF-I) are involved in the development of NAFLD/NASH; however, the precise underlying mechanism remains to be elucidated. To clarify the mechanisms and the specific contribution of GH and IGF-I in these conditions, we examined the liver of a GH-deficient rat model, spontaneous dwarf rat (SDR) and the effect of GH and IGF-I administration. SDR showed steatosis and fibrosis in the liver in line with the phenotype observed in AGHD. Serum AST and ALT levels and triglyceride content in the liver were significantly increased in the SDR compared with the control. Intriguingly, the mitochondrial morphology in the SDR hepatocyte was impaired and the area was significantly decreased. Furthermore, oxidative stress in the SDR liver was enhanced. These changes were improved not only by GH but also by IGF-I administration, suggesting that GH-independent IGF-I action plays an essential role in the liver. In conclusion, we demonstrated that GH-deficient rat exhibits NASH and IGF-I plays an essential role to prevent the development of NASH. The improved mitochondrial function and reduced oxidative stress may contribute the effect of IGF-I in the liver.     

Effect of pulsatile growth hormone administration to the growth-restricted fetal sheep on somatotrophic axis gene expression in fetal and placental tissues

We have previously reported (Bauer MK, Breier BH, Bloomfield FH, Jensen EC, Gluckman PD, and Harding JE. J Endocrinol 177: 83-92, 2003) that a chronic pulsatile infusion of growth hormone (GH) to intrauterine growth-restricted (IUGR) ovine fetuses increased fetal circulating IGF-I levels without increasing fetal growth. We hypothesized a cortisol-induced upregulation of fetal hepatic GH receptor (GH-R) mRNA levels, secondary increases in IGF-I mRNA levels, and circulating IGF-I levels, but a downregulation of the type I IGF receptor (IGF-IR) as an explanation. We, therefore, measured mRNA levels of genes of the somatotrophic axis by real-time RT-PCR in fetal and placental tissues of fetuses with IUGR (induced by uteroplacental embolization from 110- to 116-days gestation) that received either a pulsatile infusion of GH (total dose 3.5 mg/day) or vehicle from 117-126 days and in control fetuses (n = 5 per group). Tissues were collected at 127 days (term, 145 days). Fetal cortisol concentrations were significantly increased in IUGR fetuses. However, in liver, GH-R, but not IGF-I or IGF-IR, mRNA levels were decreased in both IUGR groups. In contrast, in placenta, GH-R, IGF-I, and IGF-IR expression were increased in IUGR vehicle-infused fetuses. GH infusion further increased placental GH-R and IGF-IR, but abolished the increase in IGF-I mRNA levels. GH infusion reduced IGF-I expression in muscle and increased GH-R but decreased IGF-IR expression in kidney. IUGR increased hepatic IGF-binding protein (IGFBP)-1 and placental IGFBP-2 and -3 mRNA levels with no further effect of GH infusion. In conclusion, the modest increases in circulating cortisol concentrations in IUGR fetuses did not increase hepatic GH-R mRNA expression and, therefore, do not explain the increased circulating IGF-I levels that we found with GH infusion, which are likely due to reduced clearance rather than increased production. We demonstrate tissue-specific regulation of the somatotrophic axis in IUGR fetuses and a discontinuity between GH-R and IGF-I gene expression in GH-infused fetuses that is not explained by alterations in phosphorylated STAT5b.     

Insulin-like growth factor-binding protein-2 levels in pediatric patients with growth hormone deficiency, eating disorders and acute lymphoblastic leukemia

Insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2) is altered in different diseases and might be used as an indication of its severity. The aims of our study were to investigate: (1) the developmental pattern of the serum IGFBP-2 concentration at birth and during childhood and adolescence; (2) whether the serum IGFBP-2 level could be a marker for the diagnosis and evolution of diseases where the growth hormone (GH)-IGF axis is altered, and (3) whether this binding protein shows a relationship with IGF-I, its free fraction, IGFBP-1 and -3. We report reference values for 55 normal full-term newborns and 221 normal children who were divided into 5 groups according to their Tanner stage. Serum levels were higher in newborns when compared with Tanner stages I-V (p < 0.001, ANOVA), with no further changes throughout development. Furthermore, we studied IGFBP-2 levels in 24 children with congenital GH deficiency (GHD), 26 with acute lymphoblastic leukemia (ALL), 75 obese children, and 60 girls with anorexia nervosa (AN) at diagnosis and during a follow-up period. IGFBP-2 at diagnosis was increased in GHD, ALL and AN, and decreased in obesity (p < 0.05, ANOVA). During the follow-up, IGFBP-2 concentrations tended to normalize. IGFBP-2 correlated positively with IGFBP-1 and negatively with IGF-I and IGFBP-3 in normal subjects and at diagnosis of the pathologies studied. Although IGFBP-2 functions are not well understood, these results suggest a possible role for this protein in diseases where the GH-IGF axis is altered.     

The challenges of reliance on insulin-like growth factor I in monitoring disease activity in patients with acromegaly

Serum insulin-like growth factor I (IGF-I) is an important marker of disease activity in patients with acromegaly, and epidemiological data indicate control of circulating IGF-I in patients with acromegaly restores life expectancy to normal. Improvements in the quality of, and access to, IGF-I assays has encouraged monitoring of acromegaly with IGF-I, although circulating growth hormone (GH) and IGF-I values provide different information, so ideally both should be monitored. However, the introduction of the GH receptor antagonist pegvisomant poses new challenges. Pegvisomant binds with high affinity to GH receptors, thereby blocking the action of GH at the tissue level and rendering the hormone biologically inactive. This leaves IGF-I as the principal marker of disease activity. It is conceptually possible to induce a state of functional GH deficiency (GHD) with pegvisomant with IGF-I values within the normal range. With the goal of minimizing the risk of over-treatment and GHD, we have provided preliminary guidance on the target range for IGF-I in patients receiving pegvisomant based on the gender- and decade-based percentile ranges for IGF-I of adult patients with untreated GHD enrolled in the Pfizer International Metabolic Database (KIMS).     

GH administration and renal IGF-I system in arthritic rats

Experimental arthritis in rats results in a growth failure and a decrease in circulating and hepatic concentrations of insulin-like growth factor I (IGF-I). Renal damage has also been reported in arthritic rats. The aim of this study was 1) to analyse if alterations in the IGF-I system in the kidney occurs in adjuvant-induced arthritis and 2) to analyse if recombinant human GH (rhGH) administration is able to reverse these effects. Male Wistar rats were injected with complete Freund's adjuvant or vehicle and 22 days later they were killed. Arthritis increased serum creatinine levels, relative kidney weight and IGF-I concentrations in this organ. In a second experiment, arthritic and control rats received rhGH (3 UI/Kg sc) or 250 microl saline from day 14, after adjuvant or vehicle injection, until day 22. IGF-I concentrations were higher in both the renal cortex and medulla of arthritic rats. In contrast, kidney IGF-I mRNA was lower in both areas of arthritic animals. GH treatment significantly decreased serum creatinine levels and IGF-I concentrations in the kidney cortex and medulla of arthritic rats. However, the administration of rhGH to arthritic animals significantly increased the IGF-I gene expression in both the renal cortex and medulla. Serum and kidney concentrations of IGF-I binding proteins (IGFBPs) were increased in arthritic animals and they were reduced by GH administration. CONCLUSION: These data suggest that experimental arthritis causes renal dysfunction and GH treatment can ameliorate this effect.     

IGFs and human cancer: implications regarding the risk of growth hormone therapy

Perturbations of the insulin-like growth factor (IGF) axis, including the autocrine production of IGFs, IGF binding proteins (IGFBPs) and IGFBP proteases such as prostate specific antigen (PSA), and cathepsin D have been identified in prostate, lung and breast cancer cells and tissues. Serum IGFBP-3 levels have been found to be negatively correlated to the risk of cancer. Interestingly, IGFBP-3 is a potent inhibitor of IGF action and also mediates apoptosis via an IGF-independent mechanism. Recent case-control studies have found an approximately 10% increase in the serum levels of IGF-I in patients with prostate, breast and lung cancers, which are among the most frequently diagnosed cancers. While the studies indicate an association between serum IGF-I levels and cancer risk, causality has not been established. Thus, serum IGF-I level may actually be a confounding variable, serving as a marker for autocrine tissue IGF-I production. Growth hormone (GH) therapy raises both IGF-I and IGFBP-3 levels in serum. However, the role of GH in controlling prostate, breast and lung growth and carcinogenesis remains unclear from animal studies. Increased GH levels as seen in acromegaly have been associated with benign prostatic hyperplasia but not with prostate, breast or lung cancers, although colon cancer mortality may be increased. Should serum IGF-I levels be proven to play a causal role in the pathogenesis of cancer, interpreting the risk associated with therapies such as GH replacement must take into account both the duration of exposure and the risk magnitude associated with the degree of serum IGF-I elevation. Since GH-deficient patients often have a subnormal IGF-I serum level, which normalizes on therapy, their cancer risk on GH therapy probably does not increase substantially above that of the normal population. Until further research in the area dictates otherwise, ongoing surveillance and routine monitoring of IGF-I levels in GH recipients should become standard of care.     

Age-dependent onset of liver-specific IGF-I gene deficiency and its persistence in old age: implications for postnatal growth and insulin resistance in LID mice

To explore the limitations of the liver-specific IGF-I gene-deficient (LID) model and to further evaluate the role of endocrine IGF-I in early postnatal life and old age, we have studied these mice during the prepubertal period (from birth to 3 wk of age) and when they are 2 yr old. During the first 2 wk of life, IGF-I gene deficiency and the resulting reduction in serum IGF-I levels in LID mice did not reach sufficiently low levels when mice experience the most rapid and growth hormone (GH)-independent growth. It suggests that the role of liver-derived IGF-I in prepubertal, GH-independent postnatal growth cannot be established. From our previous studies, liver IGF-I mRNA level was abolished in adult LID mice, which causes elevated GH level, insulin resistance, pancreatic islet enlargement, and hyperinsulinemia. Interestingly in 2-yr-old LID mice, although liver IGF-I mRNA and serum IGF-I levels were still suppressed, serum insulin and GH levels had returned to normal. Compared with same-sex control littermates, aged male LID mice had significantly reduced body weight and fat mass and exhibited normal insulin sensitivity. On the other hand, aged female LID mice exhibited normal weight and marginal resistance to insulin actions. The pancreatic islet percentage (reflecting islet cell mass) was also restored to normal levels in aged LID mice. Thus, although the IGF-I gene deficiency is well maintained into old age, the insulin sensitivity, islet enlargement, and hyperinsulinemia that occurred in young adult mice have been mostly restored to normal levels, further supporting the age-dependent and sexual dimorphic features of the LID mice.     

Acromegaly and serum insulin-like growth factor I

Random levels of growth hormone (GH) are usually not helpful in diagnosing either GH deficiency or GH hypersecretion because GH is secreted in a pulsatile fashion. Insulin-like growth factor I (IGF-I), however, is a good indicator of GH secretion and action, particularly at the level of the liver. There is a good correlation between IGF-I and several clinical indices of acromegaly. Measurements of both IGF-I and GH are cornerstones of biochemical diagnosis and follow-up of acromegaly, although in patients treated with pegvisomant, IGF-I levels should be followed rather than GH levels. IGF-I immunoassays differ in assay design, label, intra- and inter-assay precision, and calibrator or standard used, so IGF-I assays may be difficult to compare with one another. Hence, it is essential that the assays used in the laboratory are well validated and adequate normal ranges are available for the levels to be interpreted in a robust manner.