Higher IGF-I Research Articles

Randomized, open label, phase III trial of figitumumab in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin in patients with non-small cell lung cancer (NSCLC).

7500 Background: The Insulin-like growth factor type I receptor (IGF-IR) plays an important role in normal cellular growth and development and is implicated in the regulation of tumor growth. A phase III study was conducted to test the efficacy of the combination of paclitaxel, carboplatin, and figitumumab (CP-751871), a monoclonal antibody targeting the IGF-IR, as first-line treatment of advanced NSCLC. Methods: Eight hundred twenty pts were to be randomized 1:1 to receive paclitaxel (200 mg/m2), carboplatin (AUC = 6), and figitumumab (20 mg/Kg) (PCF) or paclitaxel and carboplatin alone (PC) q3weeks for up to 6 cycles. The primary study endpoint was overall survival (90% power, one sided 0.025 alpha, hazard ratio [HR] 0.77). Results: Accrual has been permanently suspended at 681 pts (median age 62 years, 77% male, 86% squamous cell carcinoma, 88% stage IV, 42% current smokers) enrolled based on a planned interim analysis at 225 events with a HR that crossed the prespecified futility boundary of 1.1 favoring PC. Serious adverse events in the PCF arm included dehydration, hyperglycemia, and hemoptysis. The potential relationship with early death (within 42 days of randomization) of a series of clinical and laboratory parameters was investigated. Low pre-treatment body mass index (p = 0.003) and creatinine clearance (p = 0.1) were predictive of early death for patients receiving figitumumab. Furthermore, PFC/PC survival HR estimates favored PC in pts with low baseline IGF-1 (minimum p = 0.006 for IGF1 < 120 ng/mL; HR 1.6) and PCF in those with high baseline IGF-1 (minimum p = 0.13 for IGF1 > 145 ng/mL; HR = 0.62). Conclusions: Potential subsets of pts with differential safety and efficacy profiles on figitumumab treatment were identified. Additional analyses will be submitted as a late breaking abstract. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Pfizer

Expression and Protein Content of IGF-I and IGF-I Receptor in Placentas from Small, Adequate and Large for Gestational Age Newborns

In humans, a direct relationship between IGF-I cord blood levels and birth weight has been demonstrated. To determine the placental IGF-I, IGF-II and IGF-IR mRNA and protein contents in full-term pregnancies from appropriate for gestational age (AGA), small for gestational age (SGA) and large for gestational age (LGA) newborns, we studied the placentas from 35 AGA, 30 SGA and 28 LGA pregnancies. The IGF-I, IGF-II and IGF-I receptor (IGF-IR) placental mRNA and protein contents were determined in the basal and chorionic plates of the placenta. IGF1 and IGF1R mRNA was higher in SGA compared to AGA and LGA placentas and lower in LGA compared with AGA placentas. In addition, a higher protein content of IGF-I and IGF-IR was observed in SGA compared with AGA and LGA placentas and lower contents in LGA compared with AGA placentas. These results suggest that the higher IGF-I and IGF-IR contents observed in SGA placentas and the lower contents observed in LGA placentas compared with AGA placentas may be influencing human fetal growth.

A Heterozygous Mutation of the Insulin-Like Growth Factor-I Receptor Causes Retention of the Nascent Protein in the Endoplasmic Reticulum and Results in Intrauterine and Postnatal Growth Retardation

Abstract Background: Mutations in the IGF-I receptor (IGF1R) gene can be responsible for intrauterine and postnatal growth disorders. Objective: Here we report on a novel mutation in the IGF1R gene in a female patient. The aim of our study was to analyze the functional impact of this mutation. Patient: At birth, the girl’s length was 47 cm [−1.82 sd score (SDS)], and her weight was 2250 g (−2.26 SDS). Clinical examination revealed microcephaly and retarded cognitive development. She showed no postnatal catch-up growth but had relatively high IGF-I levels (+1.83 to +2.17 SDS). Results: Denaturing HPLC screening and direct DNA sequencing disclosed a heterozygous missense mutation resulting in an amino acid exchange from valine to glutamic acid at position 599 (V599E-IGF1R). Using various cell systems, we found that the V599E-IGF1R mutant was not tyrosine phosphorylated and had an impaired downstream signaling in the presence of IGF-I. Flow cytometry and live cell confocal laser scanning microscopy revealed a lack of cell surface expression due to an extensive retention of V599E-IGF1R proteins within the endoplasmic reticulum. Conclusion: The V599E-IGF1R mutation interferes with the receptor’s trafficking path, thereby abrogating proreceptor processing and plasma membrane localization. Diminished cell surface receptor density solely expressed from the patient’s wild-type allele is supposed to lead to insufficient IGF-I signaling. We hypothesize that this mechanism results in intrauterine and postnatal growth retardation of the affected patient. The reported retention of the nascent IGF1R in the endoplasmic reticulum presents a novel mechanism of IGF-I resistance.

A Heterozygous Mutation of the Insulin-Like Growth Factor-I Receptor Causes Retention of the Nascent Protein in the Endoplasmic Reticulum and Results in Intrauterine and Postnatal Growth Retardation

Mutations in the IGF-I receptor (IGF1R) gene can be responsible for intrauterine and postnatal growth disorders. Here we report on a novel mutation in the IGF1R gene in a female patient. The aim of our study was to analyze the functional impact of this mutation. At birth, the girl's length was 47 cm [-1.82 sd score (SDS)], and her weight was 2250 g (-2.26 SDS). Clinical examination revealed microcephaly and retarded cognitive development. She showed no postnatal catch-up growth but had relatively high IGF-I levels (+1.83 to +2.17 SDS). Denaturing HPLC screening and direct DNA sequencing disclosed a heterozygous missense mutation resulting in an amino acid exchange from valine to glutamic acid at position 599 (V599E-IGF1R). Using various cell systems, we found that the V599E-IGF1R mutant was not tyrosine phosphorylated and had an impaired downstream signaling in the presence of IGF-I. Flow cytometry and live cell confocal laser scanning microscopy revealed a lack of cell surface expression due to an extensive retention of V599E-IGF1R proteins within the endoplasmic reticulum. The V599E-IGF1R mutation interferes with the receptor's trafficking path, thereby abrogating proreceptor processing and plasma membrane localization. Diminished cell surface receptor density solely expressed from the patient's wild-type allele is supposed to lead to insufficient IGF-I signaling. We hypothesize that this mechanism results in intrauterine and postnatal growth retardation of the affected patient. The reported retention of the nascent IGF1R in the endoplasmic reticulum presents a novel mechanism of IGF-I resistance.

Comparison between Culture Conditions Improving Growth and Differentiation of Blood and Bone Marrow Cells Committed to the Endothelial Cell Lineage

The aim of this study was to compare different cell sources and culture conditions to obtain endothelial progenitor cells (EPCs) with predictable antigen pattern, proliferation potential and in vitro vasculogenesis. Pig mononuclear cells were isolated from blood (PBMCs) and bone marrow (BMMCs). Mesenchymal stem cells (MSCs) were also derived from pig bone marrow. Cells were cultured on fibronectin in the presence of a high concentration of VEGF and low IGF-1 and FGF-2 levels, or on gelatin with a lower amount of VEGF and higher IGF-1 and FGF-2 concentrations. Endothelial commitment was relieved in almost all PBMCs and BMMCs irrespective of the protocol used, whilst MSCs did not express a reliable pattern of EPC markers under these conditions. BMMCs were more prone to expand on gelatin and showed a better viability than PBMCs. Moreover, about 90% of the BMMCs pre-cultured on gelatin could adhere to a hyaluronan-based scaffold and proliferate on it up to 3 days. Pre-treatment of BMMCs on fibronectin generated well-shaped tubular structures on Matrigel, whilst BMMCs exposed to the gelatin culture condition were less prone to form vessel-like structures. MSCs formed rough tubule-like structures, irrespective of the differentiating condition used. In a relative short time, pig BMMCs could be expanded on gelatin better than PBMCs, in the presence of a low amount of VEGF. BMMCs could better specialize for capillary formation in the presence of fibronectin and an elevated concentration of VEGF, whilst pig MSCs anyway showed a limited capability to differentiate into the endothelial cell lineage.

Maternal hormones during early pregnancy: a cross-sectional study

Little is known about correlates of first-trimester pregnancy hormones as in most studies maternal hormones have been measured later in gestation. We examined the associations of maternal characteristics and child sex with first-trimester maternal concentrations of four hormones implicated in breast cancer: human chorionic gonadotropin (hCG), alpha-fetoprotein (AFP), insulin-like growth factor (IGF)-I, and IGF-II. About 338 serum samples donated to the Northern Sweden Maternity Cohort (NSMC), 1975-2001, during the first trimester of uncomplicated pregnancies, were analyzed for the hormones of interest as a part of a case-control study. The associations of maternal characteristics and child sex with hormone concentrations were investigated by correlation, general linear regression, and multivariate regression models. In the first trimester, greater maternal age was inversely correlated with IGF-I and IGF-II. In comparison with women carrying their first child, already parous women had higher IGF-I but lower hCG. Greater maternal weight and smoking were inversely correlated with hCG. No differences in hormone levels by child sex were observed. Our analyses indicated that potentially modifiable maternal characteristics (maternal weight and smoking) influence first-trimester pregnancy maternal hormone concentrations.

IGF1 and its binding proteins 3 and 1 are differentially associated with metabolic syndrome in older men

Circulating IGF1 declines with age, and reduced circulating IGF1 is associated with increased cardiovascular mortality in some but not all studies. The relationship between IGF-binding proteins 3 and 1 (IGFBP3 and IGFBP1) with risk of cardiovascular disease remains unclear. We sought to examine associations between IGF1, IGFBP3 and IGFBP1 with metabolic syndrome in older men. Cross-sectional analysis of 3980 community-dwelling men aged >or=70 years. Methods Morning plasma levels of IGF1, IGFBP3 and IGFBP1 were assayed. Metabolic syndrome was defined according to National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) criteria. For IGF1 and IGFBP3, there was a U-shaped relationship, with middle quintiles possessing the lowest odds ratios (OR) for metabolic syndrome (reference Q1, Q3 IGF1: OR 0.74, 95% confidence intervals 0.57-0.96, Q3 IGFBP3: OR 0.67, 0.51-0.87). Increasing IGFBP1 was associated with reduced risk of metabolic syndrome with a dose-response gradient (reference Q1, OR for Q2 to Q5 IGFBP1: 0.56, 0.33, 0.22 and 0.12 respectively, P<0.001). IGF1 was associated with two, IGFBP1 with four and IGFBP3 with all five components of the metabolic syndrome. The ratio of IGF1/IGFBP3 was not associated with metabolic syndrome. In older men, both lower and higher IGF1 and IGFBP3 levels may be metabolically unfavourable. IGFBP1, as a marker of insulin sensitivity, is relevant in the assessment of metabolic syndrome, while the IGF1/IGFBP3 ratio is less informative. Longitudinal follow-up of this cohort would be needed to determine whether these distributions of IGF1, IGFBP3 and IGFBP1 predict incidence of cardiovascular events during male ageing.

Serum insulin-like growth factor-I and body composition in community dwelling older people

The decline in the growth hormone/insulin-like growth factor-I (GH/IGF-I) axis during normal aging might be involved in the changes in body composition associated with increasing age. We conducted a study to investigate serum IGF-I levels across different age categories and a possible association between serum IGF-I and measurements of body composition in older people. A cross-sectional analysis of community dwelling older people, which participated in a large longitudinal cohort study (Longitudinal Aging Study Amsterdam). 1319 subjects, 644 men, mean age 75.6 +/- 6.6 years and 675 women, mean age 75.4 +/- 6.6 years. IGF-I, body mass index (BMI), waist, waist-hip ratio (WHR), fat mass, lean body mass and total bone mineral density. IGF-I levels were significantly lower in the highest age categories. BMI and biceps skinfold measurements were lower in the lowest IGF-I quartile in men aged > or =75.5 years. In men with a low total physical activity score (<131 min/day), BMI, WHR and skinfolds were significantly lower in the lowest IGF-I quartile. In women with a high total physical activity score (>174 min/day), WHR was lower in the lowest IGF-I quartiles. In this large cohort of community dwelling older people, we observed lower serum IGF-I levels in the higher age categories. A low serum IGF-I was associated with significantly lower measurements of body composition, such as BMI, skinfolds and WHR. These results do not support previous findings that high IGF-I levels are favourable for a healthy body composition in community dwelling older people.

Effects of two levels of feed allocation on IGF‐I concentrations and metabolic parameters in GnRH‐immunized boars

Immunocastration of boars leads to a maintenance of growth harmone (GH) and a loss of anabolic hormones [androgens, oestrogens, insulin-like growth factor (IGF-I)] but an increase of voluntary feed intake. The aim of the experiment was to clarify whether IGF-I is increased by increasing feed supply in immunocastrated boars leading to improved anabolism. Two groups of six boars were given 2 or 3 kg of feed (13.5 MJ ME/kg) daily from 18–28 weeks of age. Because in boars feed intake is limited by gonadal hormones, a group with further increased feed supply could not be included. Until week 22 (second vaccination) gonadal steroids in blood were normal but dropped rapidly thereafter. Growth harmone levels did not change following vaccination. Pigs allocated 3 kg feed had 28% higher circulating IGF-I after the second immunization compared with pigs fed 2 kg feed daily. Higher IGF-I was associated with increased weight gain (682.4 g/day vs. 466.7 g/day; p < 0.01) and protein synthesis ((13)C-leucine infusion; 405 g/day vs. 247 g/day, p < 0.01). Protein breakdown (urea) was not different. Body fat (D(2)O) decreased in the low feed group from 15.2% (week 19) to 6.1% (week 25). In the high feed group it remained at the level found before second vaccination (13.7% vs. 15.0%). It is concluded that in the phase of reduced testicular steroids which inhibit appetite it is possible to increase feed intake which in turn increases IGF-I and protein deposition without accumulating excessive fat.

Acromegaly pathogenesis and treatment

Dysregulated growth hormone (GH) hypersecretion is usually caused by a GH-secreting pituitary adenoma and leads to acromegaly - a disorder of disproportionate skeletal, tissue, and organ growth. High GH and IGF1 levels lead to comorbidities including arthritis, facial changes, prognathism, and glucose intolerance. If the condition is untreated, enhanced mortality due to cardiovascular, cerebrovascular, and pulmonary dysfunction is associated with a 30% decrease in life span. This Review discusses acromegaly pathogenesis and management options. The latter include surgery, radiation, and use of novel medications. Somatostatin receptor (SSTR) ligands inhibit GH release, control tumor growth, and attenuate peripheral GH action, while GH receptor antagonists block GH action and effectively lower IGF1 levels. Novel peptides, including SSTR ligands, exhibiting polyreceptor subtype affinities and chimeric dopaminergic-somatostatinergic properties are currently in clinical trials. Effective control of GH and IGF1 hypersecretion and ablation or stabilization of the pituitary tumor mass lead to improved comorbidities and lowering of mortality rates for this hormonal disorder.

Safety, Pharmacokinetics, and Pharmacodynamics of the Insulin-Like Growth Factor Type 1 Receptor Inhibitor Figitumumab (CP-751,871) in Combination with Paclitaxel and Carboplatin

This phase 1 study was conducted to determine the recommended phase 2 dose of the selective insulin-like growth factor type 1 receptor (IGF-IR) inhibitor figitumumab (F, CP-751,871) given in combination with paclitaxel and carboplatin in patients with advanced solid tumors. Patients received paclitaxel 200 mg/m2, carboplatin (area under the curve of 6), and F (0.05-20 mg/kg) q3 weeks for up to six cycles. Patients with objective response or stable disease were eligible to receive additional cycles of single agent F until disease progression. Safety, efficacy, pharmacokinetic, and pharmacodynamic endpoints were investigated. Forty-two patients, including 35 with stages IIIB and IV non-small cell lung cancer (NSCLC), were enrolled in eight dose escalation cohorts. A maximum tolerated dose was not identified. Severe adverse events possibly related to F included fatigue, diarrhea, hyperglycemia, gamma glutamyl transpeptidase elevation, and thrombocytopenia (one case each). F plasma exposure parameters increased with dose. Fifteen objective responses (RECIST) were reported, including two complete responses in NSCLC and ovarian carcinoma. Notably, levels of bioactive IGF-1 seemed to influence response to treatment with objective responses in patients with a high baseline-free IGF-1 to IGF binding protein-3 ratio seen only in the 10 and 20 mg/kg dosing cohorts. F was well tolerated in combination with paclitaxel and carboplatin. Based on its favorable safety, pharmacokinetic, and pharmacodynamic properties, the maximal feasible dose of 20 mg/kg has been selected for further investigation.

Two Short Children Born Small for Gestational Age with Insulin-Like Growth Factor 1 Receptor Haploinsufficiency Illustrate the Heterogeneity of Its Phenotype

Small for gestational age (SGA)-born children comprise a heterogeneous group in which only few genetic causes have been identified. To determine copy number variations in 18 growth-related genes in 100 SGA children with persistent short stature. Copy number variations in 18 growth-related genes (SHOX, GH1, GHR, IGF1, IGF1R, IGF2, IGFBP1-6, NSD1, GRB10, STAT5B, ALS, SOCS2, and SOCS3) were determined by an "in house" multiplex ligation-dependent probe amplification kit. The deletions were further characterized by single-nucleotide polymorphism array analysis. Two heterozygous de novo insulin-like growth factor 1 receptor (IGF1R) deletions were found: a deletion of the complete IGF1R gene (15q26.3, exons 1-21), including distally flanking sequences, and a deletion comprising exons 3-21, extending further into the telomeric region. In one case, serum IGF-I was low (-2.78 sd score), probably because of a coexisting growth hormone (GH) deficiency. Both children increased their height during GH treatment (1 mg/m(2) per day). Functional studies in skin fibroblast cultures demonstrated similar levels of IGF1R autophosphorylation and a reduced activation of protein kinase B/Akt upon a challenge with IGF-I in comparison with controls. IGF1R haploinsufficiency was present in 2 of 100 short SGA children. GH therapy resulted in moderate catch-up growth in our patients. A review of the literature shows that small birth size, short stature, small head size, relatively high IGF-I levels, developmental delay, and micrognathia are the main predictors for an IGF1R deletion.

Rams genetically superior for IGF-I do not exhibit improved male reproductive traits

Insulin-like growth factors (IGFs) play an important role in regulating normal physiology, and may be involved in the control of reproduction. The aim of this study was to define the relationship between IGF-I concentrations and reproductive performance over the breeding and non-breeding seasons in lines of New Zealand Romney rams that had been selected for low and high blood serum IGF-I concentration. Yearling rams from two selection lines (13 from the high line and 19 from the low line) were examined in July (winter), September (autumn) and November (summer) 2006 and March (spring) 2007. Scrotal circumference including the inguinal skin was recorded. Semen was collected by electroejaculation on 4 occasions over a 12-month period. Semen was evaluated according to standard procedures (volume, motility, density and morphology). Samples were collected from four animals from each group for measurements of mRNA for IGF-I and the IGF type 1 receptor (IGF 1R) in the testis, and IGF-I, IGF 1R and the insulin receptor (IR) in the liver. Blood samples were collected via jugular venipuncture for the measurement of IGF-I, insulin and testosterone. The incidences of morphologically abnormal sperm cells, the scrotal circumference and sperm motility were higher in the breeding than in non-breeding season. Seasonal changes were found in the percentage of abnormal sperm, scrotal circumference, sperm motility and sperm density, but there were no differences between lines in any reproductive parameters. IGF-I mRNA levels were higher in the high than the low line in the liver but not in the testis, whereas the opposite was found for levels of IGF 1R mRNA. mRNA levels for the insulin receptor in the liver were higher in the high line. Plasma testosterone concentrations did not differ between lines, whereas the concentrations of IGF-I and insulin were higher in the high line. The results suggest that IGF-I may be locally produced in the liver and the testis, and that selection for high IGF-I may not be associated with improved reproductive performance in rams.

The value of IGF1 estimation in adults with GH deficiency

The GH/IGF1 system, like other endocrine systems, is dynamic and its activity changes with age and sexual maturation, and is influenced by body composition and other factors. A normal level of IGF1 does not exclude a diagnosis of GH deficiency (GHD) in adults, and the usefulness of IGF1 in the diagnosis of adult GHD has historically been confusing and contentious. The regulation of IGF1 secretion in adults is complex, and is not solely dependent on GH status with factors recognized to influence IGF1 status in patients with GHD including age, gender, exogenous estrogen therapy, prolactin status, and severity of GHD. The usefulness of IGF1 for monitoring treatment of GH disorders in adulthood is now widely accepted, especially as GH-dosing regimens for GHD have evolved from weight-based dosing (associated with overtreatment and side effects) to individualized dose-titration strategies, which maintain IGF1 within target limits. Sub-optimal replacement therapy may be associated with morbidity and mortality risk from a continuing state of functional GHD. Conversely, avoiding iatrogenic biochemical acromegaly is clearly important and other potential safety issues may be associated with a persistently high IGF1. Analysis and interpretation of IGF1 status therefore represent a useful diagnostic tool especially in the younger adult patients with severe GHD and an essential measurement for monitoring GH replacement in all adults with GHD. High-quality, method-specific reference ranges for IGF1 and a high degree of methodological consistency in the assay are essential for reliable comparison of results.

Associations of Anthropometric Parameters with Serum TSH, Prolactin, IGF-I, and Testosterone Levels: Results of the Study of Health in Pomerania (SHIP)

Obesity is a major risk factor for chronic diseases including cardiovascular disorders. Divergent associations between obesity and hormonal changes have been reported. The objective of the present study was to analyse the associations between anthropometric measurements and hormone levels including serum thyroid stimulating hormone (TSH), prolactin, insulin-like growth factor (IGF) I, and testosterone. Form the cross-sectional Study of Health in Pomerania 1 women and 1 864 men aged 20-79 years were included in the analyses. Serum TSH, prolactin, IGF-I, and testosterone levels were determined by immunochemiluminescent procedures. Body height, weight as well as waist and hip circumferences were measured. Body mass index (BMI), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) were calculated. Our analyses revealed inverse linear associations of waist and hip circumferences, BMI and WHtR with serum TSH levels and linear associations between waist circumference as well as WHtR and serum prolactin levels in women. In men, inverse linear and quadratic associations between anthropometric parameters and serum IGF-I as well as serum testosterone levels were found. Additionally, men with high waist circumference had more often low serum IGF-I or testosterone levels and less often high serum IGF-I or testosterone levels compared to men with low waist circumference. These sex-specific differences should be noted in studies regarding hormones and obesity.

Optimizing Medical Therapy of Acromegaly: Beneficial Effects of Cabergoline in Patients Uncontrolled with Long-Acting Release Octreotide

Background: Previous data indicate a beneficial effect of cabergoline (CAB) association to somatostatin analogs (SA) in acromegalics resistant to SA monotherapy. Objective: To assess the efficacy of CAB association on acromegalics with high IGF-I on stable long-acting release octreotide (OCT-LAR) (30 mg/28 days). Design, Subjects and Methods: 34 patients (17 male, 25–85 years, 33 macroadenomas) were enrolled in this prospective study. OCT-LAR was administered as primary (n = 4) and as secondary (n = 30) treatment: after surgery (n = 16), after surgery + radiotherapy (RT) (n = 11), and after RT only (n = 3). Duration of OCT-LAR therapy prior to CAB was 24 ± 12 months. The immunohistochemical features of the tumors disclosed GH/PRL co-secretion in 11/21 patients. 13 patients had high PRL levels prior to CAB. The initial CAB dose was 1.5 mg/week. No IGF-I normalization led to a dose increase to 3.5 mg/week. The OCT-LAR dose was kept stable during treatment. IGF-I, GH and PRL levels were compared before and after CAB association. OCT-LAR was withdrawn in patients who achieved IGF-I normalization, in order to assess the influence of CAB. Results: Comparing OCT-LAR to OCT-LAR/CAB treatment, there was a significant decrease in mean GH, IGF-I, %ULNR-IGF-I and PRL levels. During OCT-LAR/CAB treatment, IGF-I normalized in 19 patients (56%). IGF-I normalization was correlated to lowest IGF-I levels on OCT-LAR monotherapy, but not to baseline PRL levels or GH/PRL co-expression. OCT-LAR withdrawn in all who had achieved IGF-I normalization on combined therapy resulted in IGF-I elevation to abnormal levels in all patients. Gastrointestinal symptoms were reported by 12 patients. Conclusion: OCT-LAR and CAB association has been shown to be an effective alternative therapy for those acromegalics who still have active acromegaly despite monotherapy with SA, mainly for those with lower pretreatment IGF-I concentrations. According to previous studies, the beneficial effects of CAB occur even when pretreatment PRL is normal and/or there is no tumor GH/PRL co-expression.

Further Insights into the Insulin‐like Growth Factor‐I System of Bony Fish Pituitary with Special Emphasis on Reproductive Phases and Social Status

Insulin-like growth factor (IGF)-I, which is crucially involved in fish growth, differentiation, and reproduction, occurs in tilapia pituitary. IGF-I peptide, which is probably produced in hypothalamic perikarya, is present in axons of the neurohypophysis, and IGF-I mRNA and peptide are present in the adenohypophysis in adrenocorticotrophic hormone cells, melanocyte-stimulating hormone cells, with interindividual differences in growth hormone cells, and, starting with puberty, in gonadotrophic hormone (GTH) cells. Subordinate males showed a high IGF-I but a lower beta-luteinizing hormone expression, while in dominant males the opposite was found. IGF-I from the GTH cells may act as auto/paracrine regulators of GTH cell proliferation and enhance GTH synthesis and release during puberty and reproduction, depending on the social status.

Influence of Growth Hormone Receptor d3 and Full-Length Isoforms on Biochemical Treatment Outcomes in Acromegaly

In acromegaly, a discrepancy between what are defined as "normal" levels of GH and IGF-I for every given patient is observed in up to 35% of subjects at diagnosis and during the follow-up. The aim of the study was to evaluate the impact of GH receptor (GHR) polymorphism on the biochemical assessment of the treatment of acromegaly and on prevalence of discordant levels of GH and IGF-I. The study was performed in an institutional referral center at a tertiary care hospital. We studied prospectively and retrospectively 84 consecutive acromegalic patients with active disease after neurosurgery and treated them with somatostatin analogs. The GHR genotype (flfl, fld3, or d3d3) was determined from peripheral blood. Lack of exon 3 of GH receptor (d3-GHR) was found in 40 of 84 patients (47.6%). After neurosurgery, 67 subjects (79.8%) of the study population, concordant active acromegalic patients, had high IGF-I and mean GH levels above 2 ng/ml, whereas the remaining 17 patients (20.2%, discordant active acromegalic patients) showed discordance between these two parameters (high IGF-I and GH levels < or = 2 ng/ml). Overall, 70.6% of discordant patients were carriers of the d3-GHR. After somatostatin analogs, discordant active acromegalic patients increased to 30.9%, 69.2% of whom were carriers of the d3-GHR. Logistic regression analysis demonstrated that d3-GHR carriers maintained the significant correlation with discordant GH and IGF-I values either after neurosurgery or after somatostatin analog treatment, independently of the effects of age, sex, duration of acromegaly, serum GH, and IGF- I values either at diagnosis of acromegaly or after neurosurgery. The GHR polymorphism seems to have a relevant impact on the posttreatment biochemical assessment of acromegaly. Moreover, the d3-GHR isoform could be an independent predictor of GH and IGF-I discrepancy during the follow-up in acromegaly.

Mortality and Serum Insulin-Like Growth Factor (IGF)-I and IGF Binding Protein 3 Concentrations

Previous studies provided conflicting results regarding the association of serum IGF-I or IGF-binding protein-3 (IGFBP-3) and mortality. The aim of this study was to assess the relation of IGF-I and IGFBP-3 levels with mortality from all causes, cardiovascular disease (CVD), and cancer in a prospective population-based study. From the Study of Health in Pomerania (SHIP) 1988 men and 2069 women aged 20-79 yr were followed up on average 8.5 yr. Causes of deaths were coded according to the International Classification of Diseases, 10th revision. Serum IGF-I and IGFBP-3 levels were determined by chemiluminescence immunoassays and categorized into three groups (low, normal, high) according to the sex- and age-specific 10th and 90th percentiles. Adjusted analyses revealed that men with low but not high IGF-I levels had an almost 2-fold higher risk of all-cause mortality [hazard ratio (HR) 1.92 (95% confidence interval [CI] 1.35; 2.73)], CVD mortality [HR 1.92 (95% CI 1.00; 3.71)], and cancer mortality [HR 1.85 (95% CI 1.00; 3.45)] compared with men with normal IGF-I levels. In women, no association between IGF-I and mortality was found. Moreover, low IGFBP-3 levels were associated with higher all-cause mortality in men [HR 1.87 (95% CI 1.31; 2.64)] and women [HR 1.63 (95% CI 0.96; 2.76)]. The present study found inverse associations between IGF-I or IGFBP-3 levels and mortality from all causes, CVD, or cancer in men and between IGFBP-3 and all-cause mortality in women.

Invasive Giant Prolactinoma with Loss of Therapeutic Response to Cabergoline: Expression of Angiogenic Markers

The present study reports the case of a 70-year-old Caucasian man who was referred to the Military Hospital of Buenos Aires for evaluation of a giant sellar-extrasellar mass with extension in the right temporal lobe and compression of the third ventricle. Patient was initially responsive to cabergoline with reduction of prolactin levels and shrinkage of tumor burden for at least 36 months. Thereafter, prolactin levels and tumor size increased even though cabergoline dosage was increased. Transcraneal surgery was performed at 56 months of treatment. Prolactin levels and tumor proliferation did not subside and the patient died 14 months later. High GH and IGF-I levels were observed in the late stages of tumor development, with no evidence of acromegalic features. Immunohistochemistry of the excised tumor revealed strong immunoreactivity for VEGF and FGF-2, two potent angiogenic factors, and CD31 (an endothelial marker) indicating high vascularization of the adenoma.