scholarly journals Serum Insulin-Like Growth Factor I (IGF-I), IGF-Binding Proteins 2 and 3, and the Risk for Development of Malignancies in Adults with Growth Hormone (GH) Deficiency Treated with GH: Data from KIMS (Pfizer International Metabolic Database)

2010 ◽  
Vol 95 (9) ◽  
pp. 4449-4454 ◽  
Author(s):  
Vera Popovic ◽  
Anders F. Mattsson ◽  
Rolf C. Gaillard ◽  
Patrick Wilton ◽  
Maria Kołtowska-Häggström ◽  
...  
Keyword(s):  
De Novo ◽  
Gh Deficiency ◽  
Serum Insulin ◽  
Reference Ranges ◽  
Gh Therapy ◽  
Gh Replacement ◽  
Age Related ◽  
Igf I ◽  
Igf Binding ◽  
Igfbp 3

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

Growth hormone deficiency in 'little' mice results in aberrant body composition, reduced insulin-like growth factor-I and insulin-like growth factor-binding protein-3 (IGFBP-3), but does not affect IGFBP-2, -1 or -4

1993 ◽  
Vol 136 (1) ◽  
pp. 91-104 ◽  
Author(s):  
L. R. Donahue ◽  
W. G. Beamer
Keyword(s):  
Body Composition ◽  
Growth Factor ◽  
Gh Deficiency ◽  
Body Water ◽  
Insulin Like Growth Factor ◽  
Gh Therapy ◽  
Factor I ◽  
Igf I ◽  
Body Compartments ◽  
Igfbp 3

ABSTRACT Although GH is known to regulate somatic growth during development, its role in regulating adult body composition is less well defined. The effects of GH on individual body compartments – water, fat, protein and mineral – are achieved both by the action of GH and by a GH-induced hormone, insulin-like growth factor-I (IGF-I). We used a genetic model of GH deficiency, the 'little' (gene symbol lit) mouse, to determine the GH regulation of IGF-I and its insulin-like growth factor-binding proteins (IGFBPs) and to define the interaction between these hormones and each body compartment in adults. Our results showed that GH-deficient lit/lit mice had reduced levels of serum IGF-I (range 38–130 μg/l) compared with normal lit/+ littermates (range 432–567 μg/l) between 2 and 52 weeks of age. The lit/lit mice did not experience the fivefold increase in IGF-I between 2 and 4 weeks of age that was seen in lit/+ mice. In lit/lit serum, overall binding of 125I-labelled IGF-I to the four IGFBPs was reduced, solely in response to a reduced amount of IGFBP-3. No overall differences were found between lit/lit and lit/+ mice in the binding of 125I-labelled IGF-I to IGFBP-2, -1 or -4. Age-related declines in IGF-I and IGFBPs were seen in lit/lit mice. However, adult levels of IGF-I were maintained in lit/+ mice to at least 52 weeks of age, as were levels of IGFBP-1 and -4, while IGFBP-3 and -2 declined with age. With respect to body composition, comparison of lit/lit with lit/+ mice showed that the lit/lit mice were characterized by abnormally large adipose tissue stores and reduced body water, protein and mineral from 2 weeks onward. These changes occurred despite normal energy intake in lit/lit mice up to 52 weeks of age, indicating that neither undernutrition nor hyperphagia is characteristic of this GH-induced model of obesity. Furthermore, lit/lit males accrued more body fat beginning at an earlier age than lit/lit females. With advancing age, the per cent body fat increased in both lit/lit and lit/+ mice, while the per cent body water and mineral declined. In lit/lit but not lit/+ mice, per cent protein also declined with age. The changes in body water and fat are attributable to lack of adequate GH in the genetically GH-deficient lit/lit mouse. On the other hand, the changes in body protein are more likely to be effects of IGF-I. Changes in mineral observed in lit/lit mice could be the result of action by GH, IGF-I or both hormones. Therefore, when GH is chronically manipulated by GH deficiency as in lit/lit mice, by GH excess as in acromegaly, or by GH therapy, all four body compartments are affected, suggesting that GH therapy is most valuable when the treatment goal is to alter overall body composition. Journal of Endocrinology (1993) 136, 91–104

scholarly journals Effect of GH and/or testosterone deficiency on the prostate: an ultrasonographic and endocrine study in GH-deficient adult patients

2000 ◽  
pp. 61-69 ◽  
Author(s):  
A Colao ◽  
S Spiezia ◽  
C Di Somma ◽  
P Marzullo ◽  
G Cerbone ◽  
...  
Keyword(s):  
Gh Deficiency ◽  
Specific Antigen ◽  
Transitional Zone ◽  
Study Entry ◽  
Testosterone Deficiency ◽  
Prostate Hyperplasia ◽  
Free Psa ◽  
Igf I ◽  
Igf Binding ◽  
Igfbp 3

BACKGROUND: The role of IGF-I in prostate development is currently under thorough investigation since it has been claimed that IGF-I is a positive predictor of prostate cancer. OBJECTIVE: To investigate the effect of chronic GH and IGF-I deficiency alone or associated with testosterone deficiency on prostate pathophysiology in a series of patients with hypopituitarism. DESIGN: Pituitary, androgen and prostate hormonal assessments and transrectal prostate ultrasonography (TRUS) were performed in 30 men with adulthood onset GH deficiency (GHD) and 30 age-matched healthy controls, free from previous or concomitant prostate disorders. RESULTS: Plasma IGF-I levels were significantly lower in GHD patients than in controls (Pearson's coefficient P<0.0001). At study entry, 6 of the 13 hypogonadal patients and 7 of the 17 eugonadal patients had plasma IGF-I below the age-adjusted normal range. At study entry, testosterone levels were low in 13 patients (mean +/-s.e.m., 3.8+/-1.0 nmol/l) while they were normal in the remaining 17 (19.4+/-1.4 nmol/l). No difference in prostate-specific antigen (PSA), and PSA density was found between GHD patients (either hypo- or eugonadal) and controls, while free PSA levels were significantly higher in eugonadal GHD than in controls (0.4+/-0.04 vs 0.2+/-0.03 microg/l; P<0.01). No difference in antero-posterior prostate diameter and transitional zone volume (TZV) was observed among groups, while both transverse and cranio-caudal diameters were significantly lower in hypogonadal (P<0.01) and eugonadal GHD patients (P<0.05) than in controls. Prostate volume (PV) was significantly lower in hypogonadal GHD patients (18.2+/-3.0 ml) and eugonadal GHD patients (22.3+/-1.6 ml), than in controls (25.7+/-1.4, P<0.05). The prevalence of prostate hyperplasia (PV>30 ml) was significantly lower in hypogonadal and eugonadal GHD patients, without any difference between them (15.3% and 5.8%), than in controls (43.3%) (chi(2)=6.90, P=0.005). No difference was found in PV between patients with normal or deficient IGF-I levels both in the hypogonadal group (19. 9+/-4.7 vs 17.3+/-4.0 ml) and in the eugonadal group (22.6+/-2.3 vs 21.8+/-2.5 ml). When controls and patients were divided according to age (<60 years and >60 years), PV was significantly lower in hypogonadal GHD patients aged below 60 years than in age-matched controls (P<0.01) or eugonadal GHD patients (P<0.01), without any difference between controls and eugonadal GHD patients. Controls aged above 60 years had significantly higher PV than both hypogonadal and eugonadal GHD patients (P<0.01). Calcifications, cysts or nodules were found in 56.7% of patients and in 50% of controls (chi(2)=0.067, P=0.79). In controls, but not in GHD patients, PV and TZV were correlated with age (r=0.82, r=0.46, P<0. 0001 and P<0.01 respectively). PV was also correlated with GH (r=-0. 52, P=0.0026), IGF-I (r=-0.62, P=0.0002) and IGF-binding protein 3 (IGFBP-3) levels (r=-0.39, P=0.032) but neither with testosterone or dihydrotestosterone (DHT) levels. In GHD patients TZV but not PV was correlated with age (r=0.58, P=0.0007) and neither TZV nor PV were correlated with GH, IGF-I or IGFBP-3 levels. CONCLUSIONS: Chronic GH deficiency in adulthood causes a decrease in prostate size, mostly in patients with concomitant androgen deficiency and age below 60 years, without significant changes in the prevalence of structural prostate abnormalities.

scholarly journals Optimizing GH Therapy in Adults and Children

2001 ◽  
Vol 22 (4) ◽  
pp. 425-450 ◽  
Author(s):  
W. M. Drake ◽  
S. J. Howell ◽  
J. P. Monson ◽  
S. M. Shalet
Keyword(s):  
Clinical Practice ◽  
Linear Growth ◽  
Gh Deficiency ◽  
Physiological Role ◽  
Health Concern ◽  
Cumulative Exposure ◽  
Gh Therapy ◽  
Gh Replacement ◽  
Pituitary Disease ◽  
Igf I

Abstract Until the advent of modern neuroradiological imaging techniques in 1989, a diagnosis of GH deficiency in adults carried little significance other than as a marker of hypothalamo-pituitary disease. The relatively recent recognition of a characteristic clinical syndrome associated with failure of spontaneous GH secretion and the potential reversal of many of its features with recombinant human GH has prompted a closer examination of the physiological role of GH after linear growth is complete. The safe clinical practice of GH replacement demands a method of judging overall GH status, but there is no biological marker in adults that is the equivalent of linear growth in a child by which to judge the efficacy of GH replacement. Assessment of optimal GH replacement is made difficult by the apparent diverse actions of GH in health, concern about the avoidance of iatrogenic acromegaly, and the growing realization that an individual’s risk of developing certain cancers may, at least in part, be influenced by cumulative exposure to the chief mediator of GH action, IGF-I. As in all areas of clinical practice, strategies and protocols vary between centers, but most physicians experienced in the management of pituitary disease agree that GH is most appropriately begun at low doses, building up slowly to the final maintenance dose. This, in turn, is best determined by a combination of clinical response and measurement of serum IGF-I, avoiding supraphysiological levels of this GH-dependent peptide. Numerous studies have helped define the optimum management of GH replacement during childhood. The recent requirement to measure and monitor GH status in adult life has called into question the appropriateness of simplistic weight- and surface area-based dosing regimens for the management of GH deficiency in childhood, with reliance on linear growth as the sole marker of GH action. It is clear that the monitoring of parameters other than linear growth to help refine GH therapy should now be incorporated into childhood GH treatment protocols. Further research will be required to define the optimal management of the transition from pediatric to adult GH replacement; this transition will only be possible once the benefits of GH in mature adults are defined and accepted by pediatric and adult endocrinologists alike.

scholarly journals GH response to provocation and circulating IGF-I and IGF-binding protein-3 concentrations, the IGF-I generation test and clinical response to GH therapy in children with beta-thalassaemia

1998 ◽  
pp. 394-400 ◽  
Author(s):  
AT Soliman ◽  
N El Banna ◽  
BM Ansari
Keyword(s):  
Standard Deviation ◽  
Standard Deviation Score ◽  
Thalassaemia Major ◽  
Height Standard Deviation Score ◽  
Gh Therapy ◽  
Igf I ◽  
Igf Binding ◽  
Igf Binding Protein ◽  
Generation Test ◽  
Igfbp 3

The causes of growth retardation of children with thalassaemia major are multifactorial. We studied the GH response to provocation by clonidine and glucagon, measured the circulating concentrations of insulin, IGF-I, IGF-binding protein-3 (IGFBP-3) and ferritin, and evaluated IGF-I generation after a single dose of GH (0.1 mg/kg per dose) in 15 prepubertal patients with thalassaemia, 15 age-matched children with constitutional short stature (CSS) (height standard deviation score less than -2, with normal GH response to provocation) and 11 children with isolated GH deficiency (GHD). Children with thalassaemia had significantly lower peak GH response to provocation by clonidine and glucagon (6.2 +/- 2.3 and 6.8 +/- 2.1 microg/l respectively) than the CSS group (18.6 +/- 2.7 and 16.7 +/- 3.7 microg/l respectively). They had significantly decreased circulating concentrations of IGF-I and IGFBP-3 (47.5 +/- 19 ng/ml and 1.2 +/- 0.27 mg/l respectively) compared with those with CSS (153 +/- 42 ng/ml and 2.06 +/- 0.37 mg/l respectively), but the IGF-I and IGFBP-3 concentrations were not different from those with GHD (56 +/- 25 ng/ml and 1.1 +/- 0.32 mg/l respectively). These data demonstrate that the GH-IGF-I-IGFBP-3 axis in thalassaemic children is defective. Serum ferritin concentration correlated significantly with GH peak response to provocation (r = -0.36, P < 0.05) and circulating IGF-I (r = -0.47, P < 0.01) and IGFBP-3 (r = -0.42, P < 0.01) concentrations. In the IGF-I generation test, after GH injection, the thalassaemic children had significantly lower IGF-I and IGFBP-3 levels 86.7 +/- 11.2 ng/ml and 2.05 +/- 0.51 mg/l respectively) than those in the CSS group (226 +/- 45.4 ng/ml and 2.8 +/- 0.43 mg/l respectively). The IGF-I response was significantly higher in children with GHD (158 +/- 50 ng/ml) than in thalassaemic children. Six short (height standard deviation score less than -2) thalassaemic children who had defective GH response to provocation (< 10 microg/l), all the children with GHD and eight short normal children (CSS) were treated for 1 year with human GH (18 units/m2 per week divided into daily s.c. doses). After 1 year of GH therapy there was a marked acceleration of growth velocity in both thalassaemic children (from 3.8 +/- 0.6 cm/year to 7.2 +/- 0.8 cm/year) and controls. However, the linear acceleration of growth velocity on GH therapy was significantly slower in thalassaemic children (3.3 +/- 0.3 cm/year increment) compared with those with CSS (5.3 +/- 0.4 cm/year increment) and GHD (6.9 +/- 1.2 cm/year increment) (P < 0.05). Their circulating IGF-I concentration (105 +/- 36 ng/ml) was significantly lower than those for CSS (246 +/- 58 ng/ml) and GHD (189 +/- 52 ng/ml) after 1 year of GH therapy. These data prove that some children with beta-thalassaemia major have a defective GH-IGF-I-IGFBP-3 axis and suggest the presence of partial resistance to GH.

IGFBP mRNA expression in small intestine of rat during postnatal development

2001 ◽  
Vol 281 (6) ◽  
pp. G1378-G1384 ◽  
Author(s):  
C. A. Shoubridge ◽  
C.-B. Steeb ◽  
L. C. Read
Keyword(s):  
Mrna Expression ◽  
Postnatal Development ◽  
Age Groups ◽  
Rat Intestine ◽  
Age Related ◽  
Igf I ◽  
Igf Binding ◽  
Old Rats ◽  
Igf Binding Protein ◽  
Igfbp 3

In contrast to the adult gut, the immature intestine is refractory to subcutaneously infused insulin-like growth factor I (IGF-I). IGF binding protein (IGFBP) mRNA expression was characterized in intestinal tissues from 6-, 19-, and 90-day-old rats to determine if changes in local expression could account for this age-related change in IGF-I potency. For all age groups, IGFBP-3 to -6, but not IGFBP-1 or -2, were detected by Northern blot analysis. IGFBP-3, -4, and -5 were more intensely expressed in the 6-day-old rat intestine compared with weanling or adult tissue. In contrast, IGFBP-6 expression peaked at the time of weaning. In situ hybridization showed IGFBP-3 to -6 expression was confined to cells of the lamina propria and submucosa and also in the muscularis layer for IGFBP-5. Furthermore, the pattern of IGFBP-5 localization in the intestine changed with development. The findings indicate that the expression of IGFBP-3 to -6 is higher in the immature intestine compared with the adult intestine, suggesting locally produced IGFBPs may inhibit systemically derived IGF-I action in the intestine. Therefore, changes to local IGFBP expression may contribute to the varying response of the rat intestine to IGF-I peptides during postnatal development.

Investigation into the potential physiological sources of rat milk IGF-I and IGF-binding proteins

1995 ◽  
Vol 145 (3) ◽  
pp. 569-578 ◽  
Author(s):  
S M Donovan ◽  
R L Hintz ◽  
R G Rosenfeld
Keyword(s):  
Binding Proteins ◽  
De Novo ◽  
Northern Analysis ◽  
Mammary Tissue ◽  
Maternal Circulation ◽  
Igf Binding Proteins ◽  
Variable Expression ◽  
Igf I ◽  
Igf Binding ◽  
Igfbp 3

Abstract We have previously reported the presence of IGF-I and IGF-binding proteins (IGFBP-2, -3 and -4) in rat milk. Herein, the potential sources of rat milk IGF-I and IGFBPs were investigated. Lactating dams (day 14 postpartum) were separated from their pups and injected intraperitoneally with 0·45 μCi 125I-IGF-I or 125I-IGFBP-3. After 3 h, serum and milk of rats receiving 125I-IGF-I contained 7642 ± 3121 and 14 455 ± 7837 c.p.m./ml respectively. Serum and milk of rats given 125I-IGFBP-3 contained 7232 ± 1366 and 10 371 ± 4091 c.p.m./ml respectively. Sephacryl S-200 gel filtration chromatography demonstrated that the 125I-IGF-I in both serum and milk was primarily in the 150 kDa IGF-binding complex, whereas the distribution of 125I-IGFBP-3 differed between serum and milk. In serum, most of the 125I-IGFBP-3 was in the 150 kDa fraction, while most 125I-IGFBP-3 in milk was in the 40 kDa fraction. Northern analysis of liver showed IGFBP-1 and -3 mRNA expression, with variable expression of IGFBP-2 and -4 mRNA. In contrast, mammary tissue expressed only IGFBP-2 and -4 mRNA, suggesting that these IGFBPs in milk may arise from de novo synthesis within the mammary gland. The lack of detectable IGFBP-3 mRNA in mammary tissue and the translocation of 125I-IGFBP-3 from the serum suggest that milk IGFBP-3 arises from the maternal circulation. Journal of Endocrinology (1995) 145, 569–578

scholarly journals Metabolic parameters and adipokine profile during GH replacement therapy in children with GH deficiency

2007 ◽  
Vol 156 (3) ◽  
pp. 353-360 ◽  
Author(s):  
A Ciresi ◽  
M C Amato ◽  
A Criscimanna ◽  
A Mattina ◽  
C Vetro ◽  
...  
Keyword(s):  
Replacement Therapy ◽  
Linear Growth ◽  
Gh Deficiency ◽  
Final Height ◽  
Inverse Correlation ◽  
Hdl Cholesterol ◽  
Metabolic Parameters ◽  
Gh Therapy ◽  
Gh Replacement ◽  
Igf I

Objective: GH replacement therapy in children with GH deficiency (GHD) mainly promotes linear growth. Not only have very few studies fully analyzed the metabolic consequences of GH therapy, but also the question as to whether GH may affect adipokine secretion has been insufficiently investigated. Our aim was to study the effects of GH replacement therapy on auxological data, lipid and glycemic profiles, insulin homeostasis (HOMA-IR) and serum adipokines in children. Methods: This was a 1-year prospective study. Thirty-four GHD children (11.6 ± 2.6 years) and thirty healthy matched controls were enrolled. Children affected by GHD were studied both before beginning continuous GH replacement therapy and again at 12 months. Results: At the beginning of the study, total and LDL cholesterol were higher in GHD children than in controls (P<0.001), whereas HDL cholesterol, triglycerides, insulin, HOMA-IR, leptin, and adiponectin were similar. At 12 months of continuous GH replacement therapy in the GHD group, there was a significant increase in both auxological data and IGF-I (P<0.001); total cholesterol (P<0.001), LDL (P<0.001), triglycerides (P<0.005), and leptin (P<0.001) decreased significantly; HDL (P<0.003), insulin (P<0.001), HOMA-IR (P<0.001) increased while adiponectin was unmodified. Furthermore, IGF-IΔ showed an inverse correlation with leptin Δ (ρ = −0.398, P = 0.02). Conclusions: In GHD children, the evaluation of metabolic parameters proves to be a useful tool for the evaluation of auxological parameters during GH replacement therapy. In our study, GH replacement therapy in GHD children improved final height, restored IGF-I levels, reduced leptin levels, and improved the lipid profile, without producing any unfavorable effects on glucose metabolism.

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