Elevated Insulin-like Growth factor-I Research Articles

Combined Growth Hormone (GH) and Insulin-Like Growth Factor-I (IGF-I) Treatment is More Effective than GH or IGF-I Alone at Enhancing Recovery from Neonatal Malnutrition in Rats

The effect of hormonal therapy on enhancing recovery from neonatal malnutrition was assessed in rats. Malnutrition was induced by maternal food restriction (60% control intake) during lactation. On d 16 postpartum, restricted pups were refed by cross-fostering to control dams and were subcutaneously administered growth hormone (GH), insulin-like growth factor-I (IGF-I), GH + IGF-I or saline. At d 21, pups were weaned and continued hormonal treatments until d 39 postpartum. By d 39, body weight of GH (96% control) and GH + IGF-I- (98%) treated animals were normal, whereas IGF-I (88%) and saline- (85%) treated animals were still stunted. Hormone effectiveness was age dependent, with growth rates of GH + IGF-I-, IGF-I- and GH-treated pups being greatest between d 16 and 30, d 16 and 21 and after d 30, respectively. Protein accretion by d 39 was higher (P < 0.01) in GH and GH + IGF-I groups than saline- or IGF-I-treated groups. On d 39, serum IGF-I concentrations were as follows: GH + IGF-I > IGF-I > GH = saline (placebo), indicating that an elevated serum IGF-I was not required for GH-stimulated growth. Of the three hormonal treatments, GH + IGF-I therapy was most efficacious at promoting rapid and complete body weight recovery and supporting lean body mass accretion.

SNPs of miR-23b, miR-107 and HMGA2 and their Relations with the Response to Medical Treatment in Acromegaly Patients.

Acromegaly is a chronic disease of increased growth hormone (GH) secretion and elevated insulin-like growth factor-I (IGF-I) levels induced by a pituitary adenoma. HMGA2 (high mobility group A2) and AIP (aryl hydrocarbon receptor-interacting protein) expression levels are related to GH-secreting adenomas, and also a response to Somatostatin Analogs (SSAs). We studied SNPs in miR-107 and miR-23b that related with AIP and HMGA2 genes respectively and control their expression, and also SNP in the 3'UTR of HMGA2 gene. Our aim was to investigate genotype distributions of the studied SNPs, as well as the possible relationship between disease and/or response to SSAs treatment in patients with acromegaly. Genotypes were determined by qRT-PCR method from DNA materials obtained blood samples of acromegaly patients (141) and healthy individuals (99). The genotype distributions of patients and healthy groups, as well as the relationship between the clinical data of the disease and genotypes were statistically compared. In acromegaly patients with T-allele, p53 expression (p=0.049) was significantly higher. In patients with CT+TT genotype and T-allele who were responder to SSA-treatment Ki-67 index (respectively p=0.019, p=0.020 respectively) was higher. We did not observe the genotypes for miR-23b and miR-107 polymorphisms in the patients and control group of Turkish population. The genetic variations of the miRNAs genes related with HMGA2 and AIP genes were not seen in our study. Although there is no relationship between HMGA2-rs1351394 polymorphism and acromegaly disease, T allele was associated with some clinical features related to adenoma in patients with acromegaly.

Mechanisms of putative IGF-I receptor resistance in active acromegaly

Acromegaly is a disease characterized by overproduction of growth hormone (GH). As a consequence of excessive GH secretion, circulating insulin-like growth factor-I (IGF-I) is elevated in active (untreated) acromegaly. IGF-I is often used as a marker of disease activity and growth hormone status in acromegaly. Although IGF-I can directly improve insulin sensitivity and glucose uptake in muscles, the excessive GH secretion in active acromegaly frequently leads to insulin resistance, glucose intolerance and even diabetes. In this review evidence will be discussed that in active acromegaly chronically elevated IGF-I, insulin and soluble Klotho (S-Klotho) levels play a pathophysiological role in the development of IGF-I receptor (IGF-IR) resistance. It is postulated that as soon as circulating IGF-I, insulin and S-Klotho rise above a certain level the IGF-IR becomes relatively resistant to actions of IGF-I. The development of a degree of IGF-IR resistance for metabolic actions may help to explain why in active acromegaly diabetogenic effects of GH predominate and are not completely counteracted and neutralized by elevated circulating levels of IGF-I. Further studies are necessary in order to support this hypothesis.

THE IGF -I IN DIABETIC PATIENTS WITH RESISTANT HYPERTENSION DECREASES INSULIN RESISTANCE BUT IS ASSOCIATED WITH CARDIOVASCULAR TARGET ORGAN DAMAGE

Objective: The insulin-like growth factor-I (IGF-I) is involved in glucose metabolism and may contribute to the accelerated cardiovascular disease. The aim of the study was to assess IGF-I level in diabetic patients with resistant hypertension (RHTN) and to evaluate its association with glucose metabolism and cardiac, renal and brain tissues. Design and method: The study included 19 diabetic patients with RHTN (mean age 58.9 ± 7.6 years, five men, mean office BP (systolic/diastolic) 174.8 ± 20.7/94.6 ± 15mmHg, mean HbA1c 7 ± 0.8%) and 21 age- and sex-matched patients with RHTN without diabetes mellitus (DM). Office BP, echocardiography, kidney and brain MRI, lab tests (IGF-1, plasma glucose and insulin levels, HOMA-index, HbA1c, serum creatinine, serum cystatin, eGFR (MDRD formula) and 24 h microalbuminuria) were performed in all patients. On average, patients were taking 4.2 ± 0.8 antihypertensive drugs. Results: IGF-I level was in the normal range in 18 (95%) patients with DM+RHTN and in 100% of patients with RHTN without DM, one diabetic patient with RHTN had elevated IGF-I levels. The mean IGF-I values in hypertensive patients with DM and those without DM were the same. In diabetic patients with RHTN the IGF-I level was inversely correlated to HOMA-IR index (R = -0.87, P = 0.002), but had a direct correlation with basal glucose level (R = 0.48, P = 0.04). In addition, increase in IGF-I level was associated with both of left ventricular mass (R = 0.49, P = 0.03), and the end-diastolic interventricular septum thickness (R = 0.59, P = 0.008), with decreased renal function (R = 0.64, P = 0.003 for serum creatinine; R = 0.76, p = 0.01 for serum cystatin; R = -0.50, P = 0.03 for eGFR), microalbuminuria level (R = 0.61, P = 0.03), as well as with structural kidney damage (R = -0.67, P = 0.04 for the medulla volume according to kidney MRI) and brain damage (R = 0.89, P = 0.015 for Evans’ index as a MRI- sign of brain atrophy) Conclusions: Most diabetic patients with RHTN have a normal IGF-I level, which does not differ from that in patients with RHT without DM. Although an increase in IGF-I level is associated with a decrease in insulin resistance, our data suggest the possible participation of IGF-I in the development of myocardial hypertrophy, the progression both of chronic kidney disease and brain atrophy.

Chronic adult-onset of growth hormone/IGF-I hypersecretion improves cognitive functions and LTP and promotes neuronal differentiation in adult rats.

Besides their metabolic and endocrine functions, the growth hormone (GH) and its mediated factor, the insulin-like growth factor I (IGF-I), have been implicated in different brain functions, including neurogenesis. Long-lasting elevated GH and IGF-I levels result in non-reversible somatic, endocrine and metabolic morbidities. However, the subcutaneous implantation of the GH-secreting (GH-S) GC cell line in rats leads to the controllable over-secretion of GH and elevated IGF-I levels, allowing the experimental study of their short-term effects on brain functions. Adult rats were implanted with GC cells and checked 10weeks later, when a GH/IGF-I-secreting tumour was already formed. Tumour-bearing rats acquired different operant conditioning tasks faster and better than controls and tumour-resected groups. They also presented better retentions of long-term memories in the passive avoidance test. Experimentally evoked long-term potentiation (LTP) in the hippocampus was also larger and longer lasting in the tumour bearing than in the other groups. Chronic adult-onset of GH/IGF-I hypersecretion caused an acceleration of early progenitors, facilitating a faster neural differentiation, maturation and integration in the dentate gyrus, and increased the complexity of dendritic arbours and spine density of granule neurons. Thus, adult-onset hypersecretion of GH/IGF-I improves neurocognitive functions, long-term memories, experimental LTP and neural differentiation, migration and maturation.

The Impact of Initial Energy Reserves on Growth Hormone Resistance and Plasma Growth Hormone-Binding Protein Levels in Rainbow Trout Under Feeding and Fasting Conditions.

The growth hormone (GH)–insulin-like growth factor I (IGF-I) system regulates important physiological functions in salmonid fish, including hydromineral balance, growth, and metabolism. While major research efforts have been directed toward this complex endocrine system, understanding of some key aspects is lacking. The aim was to provide new insights into GH resistance and growth hormone-binding proteins (GHBPs). Fish frequently respond to catabolic conditions with elevated GH and depressed IGF-I plasma levels, a condition of acquired GH resistance. The underlying mechanisms or the functional significance of GH resistance are, however, not well understood. Although data suggest that a significant proportion of plasma GH is bound to specific GHBPs, the regulation of plasma GHBP levels as well as their role in modulating the GH–IGF-I system in fish is virtually unknown. Two in vivo studies were conducted on rainbow trout. In experiment I, fish were fasted for 4 weeks and then refed and sampled over 72 h. In experiment II, two lines of fish with different muscle adiposity were sampled after 1, 2, and 4 weeks of fasting. In both studies, plasma GH, IGF-I, and GHBP levels were assessed as well as the hepatic gene expression of the growth hormone receptor 2a (ghr2a) isoform. While most rainbow trout acquired GH resistance within 4 weeks of fasting, fish selected for high muscle adiposity did not. This suggests that GH resistance does not set in while fat reserves as still available for energy metabolism, and that GH resistance is permissive for protein catabolism. Plasma GHBP levels varied between 5 and 25 ng ml−1, with large fluctuations during both long-term (4 weeks) fasting and short-term (72 h) refeeding, indicating differentiated responses depending on prior energy status of the fish. The two opposing functions of GHBPs of prolonging the biological half-life of GH while decreasing GH availability to target tissues makes the data interpretation difficult, but nutritional regulatory mechanisms are suggested. The lack of correlation between hepatic ghr2a expression and plasma GHBP levels indicate that ghr2a assessment cannot be used as a proxy measure for GHBP levels, even if circulating GHBPs are derived from the GH receptor molecule.

The ongoing challenge of discrepant growth hormone and insulin-like growth factor I results in the evaluation of treated acromegalic patients: a systematic review and meta-analysis.

Growth hormone (GH) and insulin-like growth factor I (IGF-I) are the principal biomarkers used to assess disease activity in acromegaly, and any discrepancy between them renders interpretation of results inconclusive. Purpose of this study was to assess the frequency of this discrepancy and identify parameters that might affect its occurrence. A systematic review of MEDLINE and Scopus was performed (1987-2013) followed by a meta-analysis to address the frequency of discrepant results between GH and IGF-I levels. Meta-regression and subgroup analyses were performed assessing the effects of the year of publication, the different types of GH testing and GH assays used, as well as the impact of treatment with somatostatin analogues (SSAs) on the occurrence of this discrepancy. The analysis retrieved 39 eligible studies totalling 7071 patients. The pooled discordance rate between GH and IGF-I was 25·7% (95% CI: 22·3-29·4), and the predominant format was that of elevated IGF-I with normal GH levels (15·3%, 95% CI: 12·5-18·7). No significant correlation between the discordance rate and the year of publication was shown; whereas, the use of ultrasensitive GH assays resulted in higher discordance rates (30·7%, 95% CI: 25·9-35·9 vs 19·8%, 95% CI: 14·1-27·2, P = 0·04) as did treatment with SSAs (32·5%, 95% CI: 27·8-37·4) vs (21·6%, 95% CI: 17·8-25·6, P = 0·001). Discrepancy between GH and IGF-I results is encountered in a quarter of treated patients with acromegaly, especially when using ultrasensitive GH assays or in patients receiving SSAs, a fact that the clinician should take into consideration when making clinical decisions.

IGF-I in major depression and antidepressant treatment response

We analyzed insulin-like growth factor I (IGF-I) in serum of 78 inpatients with depression and 92 healthy controls. Patients were selected according to remission status after 6 weeks of antidepressant treatment with remission defined by Hamilton depression rating scale (HAM-D) 21-item score <10 (39 remitters and 39 non-remitters).IGF-I was analyzed in patients at admission and after 6 weeks of psychopharmacological treatment. IGF-I levels were compared between patients and controls and between remitters and non-remitters with general linear model using age, gender, and body mass index as covariates.In patients, IGF-I levels were significantly higher at admission (p=3.29E−04) and in week 6 (p=0.002) compared to controls. Furthermore, non-remitters showed significantly higher IGF-I levels at admission (p=0.046) and a trend for higher IGF-I levels in week 6 (p=0.11) compared to remitters. In remitters change in IGF-I levels during treatment was significantly correlated with change in cortisol levels (p=0.019).A genetic association analysis of polymorphisms in 10 genes contributing to the IGF-I system (IGF1, IGF1R, IGFBP1 to IGFBP7, and IGFBPL1) in the currently largest genetic databases for major depression (Psychiatric Genomics Consortium) revealed nominal associations with susceptibility for depression and treatment response, although results did not remain significant after multiple testing correction.In our study, elevated IGF-I levels were significantly associated with depression and impaired treatment response. Based on these findings IGF-I signaling could play a role in the pathophysiology of depression and could possibly influence the response to antidepressant treatment.

Endoscopic endonasal transsphenoidal treatment for acromegaly: 2010 consensus criteria for remission and predictors of outcomes.

Acromegaly is a chronic disorder characterized by enhanced growth hormone (GH) secretion and elevated insulin-like growth factor-I (IGF-I) levels, usually caused by pituitary adenomas. In this retrospective study, we reviewed our experience with endoscopic endonasal transsphenoidal surgery (EETS) with in remission rates using the 2010 consensus criteria, predictors of remission and associated complications. The authors retrospectively analyzed data from 56 acromegalic patients who underwent pure EETS. Tumors were classified according to size and suprasellar/parasellar extension. The criteria of remission were GH levels < 1 ng/mL randomly, < 0.4 ng/mL after oral glucose tolerance test and normal IGF-I levels for age and sex within the first 3 and 6 months after surgery. Biochemical remission was achieved in 4 of 5 microadenomas (80%) and in 33 of 51 macroadenomas (64.7%). The total remission rate was 66.1% (37 of 56 adenomas). Age, gender and suprasellar extension did not affect the remission rate. However, cavernous sinus invasion, sphenoid sinus invasion and history of prior surgery were associated with lower rates of disease control. EETS represents an effective and safe option for the treatment of patients with acromegaly. High disease control rates and a small number of complications are some of the most important points related to the technique.

Abstract P1-13-08: Arthralgia and changes in serum levels of IGF-I, its binding protein and estrogen in breast cancer patients on endocrine agents

Abstract Objective Aromatase inhibitors (AIs) frequently induce or enhance musculoskeletal problems, also known as the AI-induced musculoskeletal syndrome (AIMSS). Underlying mechanisms are unknown, likely multiple and induced by low estrogen levels. We hypothesized a role for the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis (Lintermans et al, Ann of Oncol 2011). Recently, Gallicchio et al. (J Cancer Res Clin Oncol 2013) confirmed our hypothesis. Here we report the effect of tamoxifen and AIs on AIMSS, IGF-I, its binding protein and estrogen levels from a prospective study. Material &amp; Methods In this prospective cohort study postmenopausal women with an early breast cancer scheduled to start adjuvant endocrine therapy with any of the third generation AIs or tamoxifen were included. After providing informed consent, a rheumatologic questionnaire was completed and serum was collected. AI-induced musculoskeletal pain was defined as an increase in joint or muscle pain relative to baseline; AIMSS presence was defined as the presence of ≥ 3 out of five features (arthralgia, myalgia, joint stiffness, tingling, carpal tunnel syndrome). IGF-I levels were determined in batch with an inhouse radio-immunoassay; levels of IGF binding protein 3 (IGFBP-3) with a commercial EASIA from DiaSource. A sensitive liquid chromatography dual mass spectrometry was used for assessment of estradiol (E2) and estrone (E1) values, with a limit of quantification of 1.3 and 1.2 ng/l, respectively. SHBG levels were determined with the Roche Modular E170 analyzer. Re-evaluation was done after 3, 6 and 12 months of therapy. Results 84 patients started on tamoxifen (n = 42) or an AI (n = 42; anastrozole n = 6, letrozole n = 36). In the AI group, 4 patients discontinued due to AIMSS. In the tamoxifen group, 1 patient developed a deep vein thrombolic event and discontinued tamoxifen therapy. In all BMI categories, AI and not tamoxifen decreased E1 and E2 levels below limit of quantification from month 3 onwards. SHBG values dropped on AI while they increased on tamoxifen. AI therapy resulted in elevated IGF-I and IGF-I/IGFBP-3 ratio levels, whereas tamoxifen users had a decrease. AI-induced musculoskeletal symptoms were characterized by a higher increase from baseline in IGF-I levels and IGF-I/IGFBP-3 ratio than AI users without any complaints. Patients experiencing AIMSS showed a significant decrease in IGFBP-3 levels (p = 0.0007) and an increase in IGF-I/IGFBP-3 ratio (p = 0.07) compared to patients without AIMSS. This divergence was most pronounced at 3 months following AI start. Conclusion These findings provide preliminary evidence that AI-induced musculoskeletal symptoms are associated with changes in the GH/IGF-I axis. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-08.

The influence of growth hormone/insulin-like growth factor deficiency on prostatic dysplasia in pbARR2-Cre, PTEN knockout mice

Elevated insulin-like growth factor-I (IGF-I) serum levels and phosphatase and tensin homolog (PTEN) loss are prostate cancer (PCa) risk factors that enhance androgen-responsive and castration-resistant PCa xenografts growth. The impact of suppressed growth hormone (GH)/IGF-I levels on neoplastic initiation of PTEN-deficient prostate epithelia was assessed histologically and by epithelial-to-mesenchymal marker expression in Ghrhr D60G homozygous (lit/lit) and heterozygous (lit/+) pbARR2-Cre, PTEN(fl/fl) (PTEN-/-) mice. How suppressed GH/IGF-I levels impacted growth of PTEN-/- mouse-derived prostate cells (MPPK) was examined by growth and survival signaling of cells cultured in lit/+ or lit/lit serum. Body weight, prostate weight and serum GH and IGF-I levels were reduced in lit/lit relative to lit/+ PTEN-/- littermates. While the anterior lobes of lit/+ PTEN-/- prostates consistently presented swollen, indicative of ductal blockage, the degree of prostatic dysplasia in 15- and 20-week-old lit/lit and lit/+ PTEN-/- mice was indistinguishable as measured by normalized prostatic weight, tissue histology, or probasin, PSP94, E-cadherin, N-cadherin and vimentin expression. However, growth and AKT activation of MPPK cells was decreased when cultured in lit/lit serum as compared with lit/+ serum and restored in lit/lit serum supplemented with IGF-I and, to a lesser extent, GH. These results suggest that initiation of prostate carcinogenesis by loss of PTEN is not influenced by germline variation of genes encoding signaling molecules in the GH/IGF-I axis, but suggests that these factors may affect the progression of dysplastic phenotype and supports previous studies, indicating that the GH/IGF milieu does impact the growth of PTEN-deficient dysplastic prostatic cells once transformed.

Efficacy, safety, and pharmacokinetics of sustained-release lanreotide (lanreotide Autogel) in Japanese patients with acromegaly or pituitary gigantism

The somatostatin analog lanreotide Autogel has proven to be efficacious for treating acromegaly in international studies and in clinical practices around the world. However, its efficacy in Japanese patients has not been extensively evaluated. We examined the dose-response relationship and long-term efficacy and safety in Japanese patients with acromegaly or pituitary gigantism. In an open-label, parallel-group, dose-response study, 32 patients (29 with acromegaly, 3 with pituitary gigantism) received 5 injections of 60, 90, or 120 mg of lanreotide Autogel over 24 weeks. Four weeks after the first injection, 41% of patients achieved serum GH level of <2.5 ng/mL and insulin-like growth factor-I (IGF-I) level was normalized in 31%. Values at Week 24 were 53% for GH and 44% for IGF-I. Dose-dependent decreases in serum GH and IGF-I levels were observed with dose-related changes in pharmacokinetic parameters. In an open-label, long-term study, 32 patients (30 with acromegaly, 2 with pituitary gigantism) received lanreotide Autogel once every 4 weeks for a total of 13 injections. Dosing was initiated with 90 mg and adjusted according to clinical responses at Weeks 16 and/or 32. At Week 52, 47% of patients had serum GH levels of <2.5 ng/mL and 53% had normalized IGF-I level. In both studies, acromegaly symptoms improved and treatment was generally well tolerated although gastrointestinal symptoms and injection site induration were reported. In conclusion, lanreotide Autogel provided early and sustained control of elevated GH and IGF-I levels, improved acromegaly symptoms, and was well tolerated in Japanese patients with acromegaly or pituitary gigantism.

Tracking growth hormone abuse in sport: Performance of marker proteins in a controlled setting

Human growth hormone (hGH) abuse in sport is a challenge at present. The current strategy used, known as direct method, is based on the quantification of hGH variants in serum. An alternative strategy, known as indirect method, focuses on serum markers such as insulin-like growth factor I (IGF-I) and procollagen type III N-terminal propeptide (P-III-NP). The indirect method allows a longer window of detection (WOO) of hGH abuse. To evaluate the performance of the indirect method, in parallel to the direct method, a clinical trial with recombinant hGH (rhGH) was conducted on healthy male subjects during 7 days (0.026mg−1kg−1person−1day−1). The data were fit to the discriminant formula proposed in the previously published GH-2000 project. The low sensitivity of the scores, judged from the high number of false negative outcomes, imposed a new discriminant analysis, standarised using local population subjects demographically similar to the ones of the study. The sensitivity of the method significantly increased, highlighting the importance of the standardisation. The indirect method allowed extended window of opportunity (WOO), although two false positive evaluations were observed derived from elevated basal IGF-I and P-III-NP concentrations stressing the need for an independent confirmation method. When direct and indirect methods were combined the best selectivity and sensitivity were achieved.

Reverse Remodeling With Left Ventricular Assist Devices

Over the last 2 decades, numerous advancements in medical therapies have improved patient outcomes in heart failure (HF). However, a significant number of patients still progress to end-stage HF, in which treatment options are largely limited to cardiac transplantation. As patient demands for transplant continue to exceed the supply of available organs, mechanical assist devices—specifically, the left ventricular assist device (LVAD)—were initially introduced as a bridge to cardiac transplantation. LVADs have 2 important beneficial effects. First, LVADs are placed in parallel to the native left ventricle (LV), causing pressure and volume unloading of the LV. Second, LVADs restore cardiac output and subsequent perfusion to the organs. As a result of these 2 effects, it became evident that some patients had actual improvement in LV function after LVAD placement. The term reverse remodeling was used to describe the improvement in myocardial function that was observed in patients with a seemingly end-stage disease. With reverse remodeling, a new hope for the treatment of HF was born—using LVADs as a bridge to recovery; however, to date, this promise has largely been unrealized. This probably is reflective of the fact that the sequela of mechanical ventricular unloading are quite complex and appear to involve the engagement of competing biological pathways including regression of cardiomyocyte hypertrophy as well as progressive cell atrophy. Although the promise of ventricular recovery still persists, its actualization will await a more comprehensive dissection of these competing biological processes. This review will discuss the beneficial clinical effects of LVAD support as well as review what is known about the cellular and molecular response to mechanical unloading and mechanisms of reverse remodeling. Key research findings have been summarized in the Table. View this table: Table. Summary of Research of LVAD Support on Clinical Effects and the Cellular and Molecular Changes That May Contribute to Reverse …

Pharmacological management of acromegaly: a current perspective

Acromegaly is a chronic disorder of enhanced growth hormone (GH) secretion and elevated insulin-like growth factor–I (IGF-I) levels, the most frequent cause of which is a pituitary adenoma. Persistently elevated GH and IGF-I levels lead to substantial morbidity and mortality. Treatment goals include complete removal of the tumor causing the disease, symptomatic relief, reduction of multisystem complications, and control of local mass effect. While transsphenoidal tumor resection is considered first-line treatment of patients in whom a surgical cure can be expected, pharmacological therapy is playing an increased role in the armamentarium against acromegaly in patients unsuitable for or refusing surgery, after failure of surgical treatment (inadequate resection, cavernous sinus invasion, or transcapsular intraarachnoid invasion), or in select cases as primary treatment. Three broad drug classes are available for the treatment of acromegaly: somatostatin analogs, dopamine agonists, and GH receptor antagonists. Somatostatin analogs are considered as the first-line pharmacological treatment of acromegaly, although efficacy varies among the different formulations. Octreotide long-acting release (LAR) appears to be more efficacious than lanreotide sustained release (SR). Lanreotide Autogel (ATG) has been shown to result in similar biological control as octreotide LAR, and there may be a benefit in switching from one to the other in some cases of treatment failure. The novel multireceptor somatostatin analog pasireotide, currently in Phase II clinical trials, also shows promise in the treatment of acromegaly. Dopamine agonists have been the earliest and most widely used agents in the treatment of acromegaly but have been found to be less effective than somatostatin analogs. In this class of drugs, cabergoline has shown greater efficacy and tolerability than bromocriptine. Dopamine agonists have the advantage of oral administration, resulting in increased use in select patient groups. Selective GH receptor antagonists, such as pegvisomant, act by blocking the effects of GH, resulting in decreased IGF-I production despite persistent elevation of GH serum levels. Thus far, tumor growth has not been a concern during pegvisomant therapy. However, combination treatment with somatostatin analogs may counteract these effects. The authors discuss the latest guidelines for biochemical cure and highlight the efficacy of combination therapy. In addition, the effects of pharmacological presurgical treatment on surgical outcome are explored.

Elevated Insulin-Like Growth Factor-I Values in Children with Prader-Willi Syndrome Compared with Growth Hormone (GH) Deficiency Children over Two Years of GH Treatment

Children with Prader-Willi syndrome (PWS) are routinely treated with GH and have a response comparable with that observed in children with GH deficiency (GHD). The objective of the study was to compare changes in serum IGF-I, IGF binding protein 3 (IGFBP-3), IGF-I to IGFBP-3 molar ratio, and growth velocity during the first 2 yr of GH therapy in PWS and GHD children. Thirty-three children with PWS (14 boys, 4.9 ± 3.8 yr) and 591 with GHD (351 boys, 9.6 ± 3.6 yr), all naive to GH treatment, were included in this study. Serum IGF-I and IGFBP-3 were measured at 0, 6, 12, and 24 months of GH therapy. The mean initial dose of GH was 0.9 and 1 mg/m(2) · d in the PWS and GHD groups, respectively. Mean ± SD IGF-I sdscore (SDS) and IGFBP-3 SDS were significantly higher in PWS compared with GHD. The IGF-I to IGFBP-3 molar ratio was significantly lower at baseline and subsequently not different. Despite significantly lower GH doses in PWS children at 6, 12, and 24 months (P = 0.021, P = 0.021, P = 0.001), IGF-I reached 2.8 ± 1.2 SDS at 24 months (72% of values > 2 SDS), and remained at 0.7 ± 1.6 SDS in GHD children (17% of values > 2 SDS). IGFBP-3 did not exceed 2 SDS in either group. There was no significant change in the IGF-I to IGFBP-3 molar ratio. IGF-I SDS increases to a greater extent in PWS than GHD. Bioavailable IGF-I is apparently not different, suggesting that any possible safety issues related to elevated IGF-I are similar in both groups.

Appraising the mitogenicity of insulin analogues relative to human insulin—response to: Weinstein D, Simon M, Yehezkel E, Laron Z, Werner H. Insulin analogues display IGF‐I‐like mitogenic and anti‐apoptotic activity in cultured cancer cells. Diabetes Metab Res Rev 2009; 25(1): 41–9

Interest in mitogenic and potentially carcinogenic effects of insulin and insulin analogues has been renewed by several recent publications that have examined the relationship between cancer and insulin analogues. Actions mediated through the insulin-like growth factor-I receptor in a hyperinsulinaemic state have been implicated mechanistically. Both type 2 diabetes and endogenously elevated insulin-like growth factor-I have been epidemiologically linked to malignancies. Therefore, in vitro mitogenic effects and binding affinities of the various analogues have been analysed. A recent publication by Weinstein et al. studied the in vitro mitogenic and anti-apoptotic activities of insulin analogues, and their conclusion asserts that insulins glargine, detemir, and lispro displayed proliferative and anti-apoptotic effects in a number of malignant cell lines. However, their conclusions are not supported by the data which are not complete and lack clear statistical significance. This data should be interpreted cautiously in light of all other presently available scientific evidence. Prospective, randomized clinical trials will best address any direct relationship between insulin analogues and cancer. Until those studies are designed and completed, clinicians should consider the demonstrated strong benefit of glycaemic control in balance with any alleged risk.

Insulin-Like Growth Factor I as a Biomarker of Health, Fitness, and Training Status

Whereas there are many varied roles of insulin-like growth factor I (IGF-I), and it exists in different biocompartments, there is abundant scientific evidence demonstrating that IGF-I is an important metabolic biomarker associated with a variety of health- and exercise-related outcomes. In most cases (muscle, bone, tendon, body composition, and cognitive function), elevated IGF-I concentrations are considered beneficial; however, cancer remains a notable exception. Although the fact that both increased and decreased IGF-I concentrations can be considered as reflective of favorable and beneficial health outcomes and may seem as a paradox and even contradictory, it is important to emphasize that, in both cases, measured IGF-I concentrations do offer important insight into physiological processes. The precise and relative role of systemic versus locally produced IGF-I in mediating the outcomes of physical activity is still not clearly delineated, but it does seem as though local IGF-I is consistently upregulated with both acute and chronic exercises; whereas in certain situations, circulating IGF-I may actually decrease. Although perhaps counterintuitive to the known anabolic role that IGF-I exerts, positive neuromuscular training adaptations can occur in the presence of decreases or no changes in circulating IGF-I. These observations, however, should not be interpreted to conclude that the role of circulating IGF-I lacks importance or relevance in contributing to enhanced musculoskeletal health as evidenced by the liver IGF-I-deficient mouse model. Because of the ubiquitous nature of IGF-I, prospective experimental approaches involving physical activity that can sample and measure IGF-I in the body's various biocompartments (i.e., blood, interstitial fluid, muscle) with the most biologically relevant assays are encouraged. We believe that such endeavors will provide greater understanding in the complex role that IGF-I possesses in mediating exercise-induced adaptations.

Relationships between critical period of estrogen exposure and circulating levels of insulin‐like growth factor‐I (IGF‐I) in breast cancer: evidence from a case‐control study

Epidemiological observations suggest that insulin-like growth factor-I (IGF-I), a potent mitogenic and anti-apoptotic peptide, plays a role in the etiology of breast cancer. Estrogen, which is crucial in breast carcinogenesis, both regulates and is influenced by IGF-I family. A case-control study was conducted to assess the role of IGF-I as a biomarker for breast cancer and to evaluate the potential joint effect of circulating IGF-I and critical period of estrogen exposure, as estimated by the interval between age at menarche and age at first full-term pregnancy on the risk of breast cancer. Questionnaire information and blood samples were taken before treatment from 297 incident cases with breast cancer and 593 controls admitted for health examination at the Tri-Service General Hospital, Taipei between 2004 and 2006. Plasma levels of IGF-I and IGFBP-3 were measured by immunoradiometric assay. Conditional logistic regression was used to calculate odds ratios (ORs) and their 95% confidence intervals (CIs). Our case-control data indicate that breast cancer risk related to IGF-I differs according to menopausal status. High circulating levels of IGF-I increased risk of pre- but not postmenopausal breast cancer (top vs. bottom tertile, adjusted OR, 1.86; 95% CI, 1.01-3.44). Furthermore, elevated IGF-I concentrations in conjunction with prolonged interval of critical period of estrogen exposure were associated with significantly increased risk of breast cancer, particularly among estrogen-positive cases (adjusted OR, 2.42, 95% CI, 1.33-4.38). These results suggest that the joint effect of IGF-I and estrogens may provide novel methods of breast cancer risk reduction among women.

Increased Intraocular Insulin-like Growth Factor-I Triggers Blood-Retinal Barrier Breakdown

Blood-retinal barrier (BRB) breakdown is a key event in diabetic retinopathy and other ocular disorders that leads to increased retinal vascular permeability. This causes edema and tissue damage resulting in visual impairment. Insulin-like growth factor-I (IGF-I) is involved in these processes, although the relative contribution of increased systemic versus intraocular IGF-I remains controversial. Here, to elucidate the role of this factor in BRB breakdown, transgenic mice with either local or systemic elevations of IGF-I have been examined. High intraocular IGF-I, resulting from overexpression of IGF-I in the retina, increased IGF-I receptor content and signaling and led to accumulation of vascular endothelial growth factor. This was parallel to up-regulation of vascular Intercellular adhesion molecule I and retinal infiltration by bone marrow-derived microglial cells. These alterations resulted in increased vessel paracellular permeability to both low and high molecular weight compounds in IGF-I-overexpressing retinas and agreed with the loss of vascular tight junction integrity observed by electron microscopy and the altered junctional protein content. In contrast, mice with chronically elevated serum IGF-I did not show alterations in the retinal vasculature structure and permeability, indicating that circulating IGF-I cannot initiate BRB breakdown. Consistent with a key role of IGF-I signaling in retinal diseases, a strong up-regulation of the IGF-I receptor in human retinas with marked gliosis was also observed. Thus, this study demonstrates that intraocular IGF-I, but not systemic IGF-I, is sufficient to trigger processes leading to BRB breakdown and increased retinal vascular permeability. Therefore, therapeutic interventions designed to counteract local IGF-I effects may prove successful to prevent BRB disruption.