Higher IGF-I Levels Research Articles

The impact of IGF-I, puberty and obesity on early retinopathy in children: a cross-sectional study

BackgroundChildhood obesity has been correlated with coronary heart disease, but the correlation with microvascular disease remains unclear. The retinal microcirculation is affected early in the process of atherosclerosis and it offers the opportunity to indirectly study the effects of obesity on small brain vessels. Insulin-like growth factor 1 (IGF-I) is involved in angiogenesis and it has a crucial role in retinal vascularization.MethodsA single-centre cross-sectional study was performed in 268 children and adolescents (116 males; mean age 13.03 ± 1.9 years,) with overweight/obesity, in order to identify risk factors for early retinopathy.ResultsNine patients (3.3%) showed signs of retinopathy, defined as arteriovenous crossings and/or papilledema. Body mass index and fat mass, analysed by Dual X-ray Absorptiometry, were not different in patients with or without retinopathy. Patients with retinopathy were pubertal and showed higher waist circumference (107.78 ± 15.83 versus 99.46 ± 10.85 cm; p: 0.027), waist circumference/height ratio (0.66 ± 0.07 versus 0.62 ± 0.05; p: 0.04) and IGF-I SDS (0.03 ± 1.3 versus − 0.66 ± 0.9; p: 0.04). Multivariate analysis (after correction for sex, age, family history of type 2 diabetes mellitus, obesity, cardiovascular disease, hypertension and dyslipidaemia) showed that waist circumference/height ratio and IGF-I SDS were the only variables independently correlated with the presence of retinopathy.ConclusionsRetinal vascular changes may become evident as an early complication of overweight and obesity, even during childhood and adolescence. Relatively high levels of IGF-I during this phase may act as an additional risk factor for microvascular damage. The screening for retinopathy should be proposed to all children and adolescents with overweight/obesity.

SAT-LB078 Acromegaly Disease Activity According to ACRODAT® in Spain: ACROVAL Study

Introduction: ACRODAT® (Acromegaly Disease Activity Tool) is a new disease-specific tool intended to assist endocrinologists in evaluating disease activity in patients with acromegaly. ACRODAT® uses five disease-specific parameters (IGF-1, tumor status, comorbidities, symptoms and quality of life) to classify disease activity as stable (S), mild (M-DA), or significant (S-DA). Due to the recent development of the tool, its clinical application has not been studied yet. Aim: This study was aimed to evaluate disease activity status using ACRODAT® in a cohort of Spanish patients with acromegaly. Other secondary objectives were to assess the relationship between patient demographic characteristics and ACRODAT® disease categories; to analyze the correlation between classification of disease activity by ACRODAT® and by physician criteria and to study the potential discrepancies between symptoms perception between physicians and patients. Methodology: Multicenter, observational, descriptive, cross-sectional study in adult patients with acromegaly under pharmacological treatment during at least 6 months. Quality of life (QoL) was determined by the AcroQoL questionnaire. Severity of symptoms was quantified using PASQ questionnaire, fulfilled by patients (paPASQ) and by physicians (phPASQ). ACRODAT® tool was used to assess disease activity entering the data collected in the study. Results: 111 patients were included in the analysis with a mean age of 59.7 years (51.4% women). According to ACRODAT®, 48.2%, 31.8% and 20.0% of patients were classified as S, M-DA and S-DA respectively. Patients with S-DA were younger, had higher IGF-1 levels, worst QoL and less stable treatment than S patients. M-DA patients had higher IGF-1 levels (but lower than S-DA patients), more severe symptoms and worst QoL than S-patients. ACRODAT® classification of disease activity significantly correlated with physicians opinion, with a moderate inter-rater agreement and a specificity of 92.45% (PPV=86.21%). phPASQ significantly correlated with paPASQ with a substantial inter-rater agreement. No correlation was found between IGF-1 levels and PASQ or AcroQoL. Decision taken by physician was significantly more frequent in S-DA patients than S patients, but no action was taken in 5 (22.7%) S-DA patients. Conclusions: ACROVAL® detected disease activity in 51.8% of patients. Interestingly, although S-DA patients were likely to be in the process of being controlled, action was not always taken in these patients. This study demonstrated that ACRODAT® is a validated and highly specific tool that may be useful to identify patients with non-obvious disease activity by incorporating “patient-centered” parameters like PASQ and AcroQoL. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

SAT-LB081 Growth Hormone and Prolactin Secreting Plurihormonal Pituitary Adenomas, Experience of a National Health Institute in Mexico

Introduction Pituitary adenomas represent approximately 15% of all intracranial neoplasms. Those with the ability to produce more than one hormone are called plurihormonal pituitary adenomas. They are divided into monomorphic, single cell type may produces two or more hormones, and plurimorphic, different cell types may produce multiple hormones. Materials and methods We performed a retrospective review of all patients diagnosed with hyperprolactinemia and acromegaly secondary to pituitary adenoma during the period 2004-2018. Then, we identified 10 patients with high serum levels of PRL and IGF-1. Six of these patients were excluded due to hyperprolactinemia secondary to pituitary stalk compression. We collected clinical, biochemical and medical imaging information. We compared the clinical and biochemical characteristics before and after treatment. Results We identified 4 female patients with GH/PRL-secreting plurihormonal pituitary adenoma. The average age at diagnosis was 25 years-old (20-32). We documented high serum levels of IGF-1 with average of 818 ng/mL (474-1340 ng/ml) and PRL with average of 185.62 ng/mL (120.95 to 280.13 ng/ml). On admission, a pituitary Magnetic Resonance Imaging (MRI) revealed macroadenoma, with mean diameter 23.5 mm (18-32 mm). All patients were prescribed cabergoline in average dose of 0.75 mg (0.5-1 mg) per week. Half of the patients had their IGF-1 ng/mL plasma level normalized. PRL ng/ml plasma levels were decreased in all patients. In their last pituitary MRI, the size of the macroadenoma decreased in all patients (8.1mm), with a mean diameter of 15.4 mm. Conclusion We consider that the primary management of the plurihormonal pituitary adenomas is the use of dopamine receptor agonists; in case there is not a clinical or biochemical control of the disease, we suggest to evaluate using additional therapy. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

SAT-431 Parameters of Glucose Metabolism Independently Predict Post Glucose Load Growth Hormone Concentrations in Patients with Acromegaly

Background: In healthy subjects, growth hormone (GH) concentrations following an oral glucose suppression test (OGTT) are known to be under the impact of gender, age, BMI an estrogen use. To date, very few data exist on factors influencing nadir GH in patients with acromegaly. Methods: In the present study, we evaluated factors related to nadir GH concentrations during a 2h-75g-OGTT analysing data from 410 OGTTs performed in 134 patients with acromegaly in a tertiary care center. All patients were not receiving any acromegaly-specific medical therapy, 119 OGTTs were performed at the initial disease diagnosis, 281 were performed after at least one pituitary surgery. The relationship between GH supression and IGF-1, morphological data and parameters of lipid and glucose metabolism was tested using uni- and multivariate regression analysis. Results: In the whole cohort (43% males), nadir GH concentrations were neither related to gender, nor to BMI, but positively correlated to fasting GH (P=0.000), IGF-1 (P=0.000), tumour size (P<0.001), plasma glucose (P=0.000), insulin (P=0.000), C-peptide (P=0.000), fasting and OGTT-based indices of insulin secretion and sensitivity, and also to the gonadotropic activity with gonadotropic insufficiency observed in male and female patients with higher disease activity (P=0.000). In addition, nadir GH negatively correlated to age (P=0.001) and HDL-cholesterol concentrations (P=0.003). Only parameters of glucose metabolism (prehepatic beta-cell function, HOMA-insulin resistance index, OGIS-insulin sensitivity index) independently predicted nadir GH concentrations in the whole cohort, as well as in the group of patients with high IGF-1 levels (pre- and postoperative), and also when OGTTs performed in men and women were separately analysed. In OGTTs performed after normalisation of IGF-1 postoperatively, nadir GH remained in a positive relationship to fasting GH and IGF-1, but negatively correlated to all parameters of glucose metabolism, and positively correlated to HDL-cholesterol. Conclusion: In a large single center series, we find that parameters of glucose metabolism are the main direct predictors of nadir GH concentrations in patients with active acromegaly. The relationship between nadir GH and glucose metabolism reflects the diabetogenic effects of GH, and might also impact the cutt off value of nadir GH during OGTT used for the biochemical definition of acromegaly.

SAT-473 Acromegaly and Drug-Induced Parkinsonism Were Controlled by Lanreotide

BACKGROUND Serum IGF-1 is reported as possible marker for risk and early diagnosis of Parkinson's disease in Neurology. Acromegaly is a disease that causes organ symptoms as a result of the high level of IGF-1. Despite the elevation of IGF-1 in acromegaly patients, there is little report on Parkinson's syndrome of acromegaly. A clinical course of acromegaly with co-morbidity of diabetes mellitus and depression suggested a possible relationship between IGF-1 transition and drug-induced Parkinsonism. CASE A 55-year-old woman with co-morbidity of diabetes mellitus and depression was diagnosed as acromegaly. Her HbA1C was 14.4% because of untreated diabetes. Her GH was elevated to 777 ng/mL and MRI indicated macroadenoma of pituitary gland. Contrary to GH elevation, her IGF-1 was in the normal range of 103 ng/mL (normal range: 75-210 ng/mL), that was a false negative result due to untreated diabetes. The continuation of insulin therapy produced a gradual rise in IGF-1 as a result of glycemic control. Antidepressants were continued by psychiatrists. Three months after starting insulin treatment, her IGF-1 increased to 305 ng/mL . From then on, her coarse tremor was observed and she was not capable to write letters at all. 111In-pentetreotide scintigraphy (Octreoscan) showed radiotracer accumulation in her pituitary gland, excluding the existence of ectopic GHRH-producing tumors. For the treatment of pituitary tumor and Parkinsonism, bromocriptine was tried but stopped because of liver dysfunction. After checking the safety and response of octreotide, monthly injection of lanreotide was started. Fourteen months after starting lanreotide, her IGF-1 was decreased to 71 ng/mL and her coarse tremor disappeared. She also became capable of writing and self-monitoring of blood glucose for diabetes. Disappearance of her tremor improved her activity of daily life. A woman with acromegaly with comorbidity of depression and diabetes was treated. An elevation of IGF-1 produced coarse tremor and lowering of IGF-1 improved the symptom. Lanreotide controlled drug-induced Parkinsonism by lowering IGF-1 level. CLINICAL LESSONS This clinical course and transition of IGF-1 suggested the involvement of IGF-1 in parkinsonism. There has been no report of drug-induced Parkinsonism with comorbidity of acromegaly of which IGF-1 and symptoms were observed chronologically. This case suggested a possibility that an elevation of IGF-1 lowers the threshold of drug-induced Parkinsonism.

MON-311 GH Action Upregulates ABC Transporters And EMT Markers In A Syngeneic Melanoma Mouse Model

Compared to many other forms of malignancies, melanoma expresses growth hormone receptors (GHRs) to a uniquely higher degree than other human cancers. Attenuating these receptors in cultured human melanoma cells resulted in decreased proliferation, and suppressed expression of ATP-binding cassette (ABC) transporters and epithelial-mesenchymal transition (EMT) markers. We hypothesize that GH promotes both the growth of mouse melanoma in vivo and the expression of ABC transporters and EMT markers. Thus, we propose that the use of a GH antagonist (GHA) could be effective at reversing these changes. To test these hypotheses, a syngeneic mouse B16-F10 melanoma model, cell proliferation assays, Western blotting, ELISAs, and real-time RT-qPCR were used. First, the high expression levels of GHR in B16-F10 cells were verified. Then, by knocking down GHR expression via small interfering RNA, the increased cell growth stimulated by GH administration was effectively reversed, independent of (insulin-like growth factor-1) IGF-1. To distinguish the effects of GH and IGF-1 on melanoma in vivo, bovine GH overexpressing transgenic mice (bGH) and GHR-knock out mice (GHR-/-) were used. Both mouse lines have significantly elevated GH, while bGH mice also exhibit high levels of IGF-1 whereas extremely low levels found in GHR-/- mice. Mouse melanoma cells were subcutaneously injected into bGH mice, GHR-/- mice, and their corresponding wild type (WT) littermate controls. Our data revealed that the ABC transporters and EMT markers in both bGH and GHR-/- mouse melanomas were significantly higher compared to their WT controls, implying that some of these effects were attributable directly to GH as opposed to IGF-1. Data analyzed from the Cancer Genome Atlas repository also suggests that human melanomas with higher GHR levels have significantly elevated expression levels of EMT markers, validating this syngeneic mouse melanoma model. On the other hand, transgenic mice that express a GHA and that have decreased GH action as well as circulating IGF-1 showed significantly decreased melanoma sizes, suggesting that targeting GHR, resulting in a compromised GH/IGF-1 axis, could delay the progression of melanoma. In summary, these results reveal the role of GH action in the upregulation of ABC transporters and EMT markers in vivo, both relevant with regards to tumor progression and poor clinical prognoses. Importantly, GH antagonism may inhibit the progression of melanoma in vivo. Studies are ongoing to determine whether GHA treatment is beneficial in the treatment of mouse melanoma in mice, and if so, blocking GH action may be considered as an anti-melanoma therapy in humans.

PNNS-Conjugated Chitosan Mediated IGF-1 and miR-140 Overexpression in Articular Chondrocytes Improves Cartilage Repair

The aim of the present study was to investigate the effects of phosphorylatable nucleus localization signal linked nucleic kinase substrate short peptide (pNNS)-conjugated chitosan (pNNS-CS) mediated miR-140 and IGF-1 in both rabbit chondrocytes and cartilage defects model. pNNS-CS was combined with pBudCE4.1-IGF-1, pBudCE4.1-miR-140, and negative control pBudCE4.1 to form pDNA/pNNS-CS complexes. Then these complexes were transfected into chondrocytes or injected intra-articularly into the knee joints. High levels of IGF-1 and miR-140 expression were detected both in vitro and in vivo. Compared with pBudCE4.1 group, in vitro, the transgenic groups significantly promoted chondrocyte proliferation, increased glycosaminoglycan (GAG) synthesis, and ACAN, COL2A1, and TIMP-1 levels, and reduced the levels of nitric oxide (NO), MMP-13, and ADAMTS-5. In vivo, the exogenous genes enhanced COL2A1, ACAN, and TIMP-1 expression in cartilage and reduced cartilage Mankin score and the contents of NO, IL-1β, TNF-α, and GAG contents in synovial fluid of rabbits, MMP-13, ADAMTS-5, COL1A2, and COL10A1 levels in cartilage. Double gene combination showed better results than single gene. This study indicate that pNNS-CS is a better gene delivery vehicle in gene therapy for cartilage defects and that miR-140 combination IGF-1 transfection has better biologic effects on cartilage defects.

Why Do Normal Children Have Acromegalic Levels of IGF-I During Puberty?

The rapid pubertal height growth is unique to humans, but why do we have it? Although the spurt contributes 13% to 15% to the final adult height, we hypothesized that the biological significance of the high acromegalic levels of GH and IGF-I, which are behind the pubertal growth spurt, might primarily occur to stimulate the reproductive organs. Animal data have demonstrated that adult Igf1 and Igf2 gene knockout mice that survive show a dramatic reduction in the size of the reproductive organs and are infertile. In humans, case reports of mutations in the genes affecting the GH-IGF axis and growth (GH, GHRH, GH-R, STAT5b, IGF-I, IGF-II, IGF-1R, PAPPA2) are also characterized by delayed pubertal onset and micropenis. Furthermore, GH treatment will tend to normalize the penile size in patients with GH deficiency. Thus, the endocrine effects of high IGF-I levels might be needed for the transition of the sexual organs, including the secondary sex characteristics, from the "dormant" stages of childhood into fully functioning reproductive systems. The peak IGF-I levels, on average, occur 2 years after the peak height growth velocity, suggesting reasons other than longitudinal growth for the high IGF-I levels, and remain high in the years after the height spurt, when the reproductive systems become fully functional. We suggest that the serum levels of IGF-I should be monitored in children with poor development of sexual organs, although it remains to be investigated whether GH should be added to sex steroids in the management of hypogonadism for some pubertal children (e.g., boys with micropenis).

Abstract WP196: MicroRNA and IGF-1 as Predictive Biomarkers for Stroke Outcomes

Background: Although several studies focus on biomarkers for stroke diagnosis, few studies have identified biomarkers that predict stroke recovery. In our preclinical studies, we identified that the peptide hormone insulin-like growth factor (IGF-1) and specific small non-coding RNA (miRNA) are inversely corelated with stroke severity as measured by infarct volume. The objective of this study is to assess the potential of miRNA and IGF-1 to serve as predictors of stroke outcomes in patients as assessed by NIHSS at 90 days after stroke. Methods: Male and female patients ages (19-91) years were enrolled at the emergency department of a local hospital. NIHSS scores were obtained at presentation, discharge from the hospital, and 90-day follow-up. Scores were binned into mild (1-4), moderate (5-20) and severe (≥ 21). Prospective blood specimens were collected from the participant within 24 hours of presentation to the emergency department and at 90 + 7 days after initial presentation. Plasma IGF-1 levels were estimated using the Quantikine ELISA for human IGF-1 and and miR-363 expression was determined by qRT-PCR using hsa-miR-363-3p primers. IGF-1 and mir363-3p levels from blood samples collected within 24h of presentation were correlated with binned NIHSS-90 days, separately for males and females. Results: In males, there was no correlation between the degree of stroke severity at 90 days with either IGF-1 levels or mir363-3p. In females, there was significant inverse correlation between IGF-1 levels and NIHSS-90d scores (r=-0.467; p&lt;0.05), indicating that higher IGF-1 levels were predictive of better stroke recovery. However, miR-363 levels did not correlate with the 90d NIHSS. Conclusion: These pilot data suggest that IGF-1 is a strong predictor of stroke severity in females and has the potential to serve as a surrogate measure for stroke recovery. Supported by TAMUOVPR and TBSI seed grant to FS

Self-Reported Physical Activity and Relations to Growth and Neurotrophic Factors in Diabetes Mellitus: The Framingham Offspring Study.

Aims Circulating insulin-like growth factor- (IGF-) 1, vascular endothelial growth factor (VEGF), and brain-derived neurotrophic factor (BDNF) levels are often lower in individuals with diabetes mellitus (DM) and are important for repairing vascular and neuronal dysfunction. The purpose of this investigation was to determine the cross-sectional relations of physical activity to circulating concentrations of IGF-1, VEGF, and BDNF in individuals with and without DM. Methods In 1730 participants from the Framingham Offspring Study examination cycle 7, including those with DM (n = 179, mean age 64 years, 39% women) and without DM (n = 1551, mean age 60 years, 46% women), we related self-reported physical activity variables to circulating concentrations of IGF-1, VEGF, and BDNF using linear multivariable regression models. We also tested for interactions by age. Participants with prevalent cardiovascular disease, stroke, and dementia or taking hormone replacement therapy were excluded. Results In participants with DM, more ambulatory physical activity was associated with higher IGF-1 levels (β ± standard error (SE) = 0.22 ± 0.08, p = 0.009), and more total physical activity was related to higher BDNF levels (β ± SE = 0.18 ± 0.08, p = 0.035), but physical activity was not significantly related to circulating VEGF. In participants without DM, no associations were observed. Moreover, in the examination of interactions by age, the association of ambulatory physical activity with IGF-1 levels was only observed in older adults with DM (age ≥ 60 years, β ± SE = 0.23 ± 0.11, p = 0.042) but not in middle-aged adults with DM (age < 60 years, β ± SE = 0.06 ± 0.13, p = 0.645). Conclusion Our results suggest that more physical activity is associated with higher circulating IGF-1 and BDNF in participants with DM. These results, dissecting interactions by both age and DM status, may also help to explain some of the inconsistent results in studies relating physical activity to growth and neurotrophic factors.

The insulin-like growth factor family and breast cancer prognosis: A prospective cohort study among postmenopausal women in Denmark

ObjectiveCirculating levels of insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) have been associated with breast cancer (BC) risk. The evidence in relation to BC prognosis is limited. We aimed to evaluate the association between pre-diagnostic serum levels of IGF-I, IGF-II, IGFBP-2, IGFBP-3 and BC prognosis (i.e. recurrence, BC specific mortality and all-cause mortality) among women diagnosed with BC. We hypothesized that higher serum levels of IGFs and IGFBPs were associated with poor BC prognosis and that the associations were modified by estrogen receptor (ER) status. DesignFrom the Danish Diet, Cancer and Health cohort, 412 postmenopausal women diagnosed with incident BC within 5 years of cohort baseline (1993–1997) were identified. Baseline serum samples were analyzed for IGF-I, IGF-II, IGFBP-2 and IGFBP-3. Follow-up was carried out through 2014 by linkage to national Danish registries. Exposures were related to BC prognosis by Cox Proportional Hazard models; effect modification by ER status was investigated and sensitivity analyses by follow-up time were made. ResultsDuring a median of 15 years, 106 women experienced recurrence and 172 died (118 due to BC). Overall, no associations were observed between IGF-I, IGF-II, IGFBP-2, IGFBP-3 and BC prognosis and no effect modification by ER status was observed. However, higher levels of IGF-II were associated with higher BC specific mortality [Hazard Ratio (HR) (95% Confidence Intervals (CI)): 1.43 (1.01–2.04)] within 10 years of follow-up. Likewise, higher levels of IGFBP-2 were associated with higher BC specific mortality [HR (95% CI): 1.87 (1.19–2.94)] within 5 years of follow-up. In contrast, higher levels of IGFBP-3 were associated with lower risk of recurrence [HR (95% CI): 0.76 (0.60–0.97)] at 5 years of follow-up and BC specific mortality [HR (95% CI): 0.80 (0.65–0.98)] within 10 years of follow-up. ConclusionsThe present study did not support an association between higher serum levels of IGFs, IGFBPs and adverse BC prognosis. However, it is possible that the role of the IGF family in the etiology of the 5–10 year BC prognosis is different from that of longer-term BC prognosis.

Growth Hormone's Links to Cancer.

Several components of the GH axis are involved in tumor progression, and GH-induced intracellular signaling has been strongly associated with breast cancer susceptibility in genome-wide association studies. In the general population, high IGF-I levels and low IGF-binding protein-3 levels within the normal range are associated with the development of common malignancies, and components of the GH-IGF signaling system exhibit correlations with clinical, histopathological, and therapeutic parameters in cancer patients. Despite promising findings in preclinical studies, anticancer therapies targeting the GH-IGF signaling system have led to disappointing results in clinical trials. There is substantial evidence for some degree of protection against tumor development in several animal models and in patients with genetic defects associated with GH deficiency or resistance. In contrast, the link between GH excess and cancer risk in acromegaly patients is much less clear, and cancer screening in acromegaly has been a highly controversial issue. Recent studies have shown that increased life expectancy in acromegaly patients who attain normal GH and IGF-I levels is associated with more deaths due to age-related cancers. Replacement GH therapy in GH deficiency hypopituitary adults and short children has been shown to be safe when no other risk factors for malignancy are present. Nevertheless, the use of GH in cancer survivors and in short children with RASopathies, chromosomal breakage syndromes, or DNA-repair disorders should be carefully evaluated owing to an increased risk of recurrence, primary cancer, or second neoplasia in these individuals.

Statin administration is associated with higher IGF-1 levels in patients without diabetes mellitus

Background: Research makes it clear that the IGF-1 level correlates with cardiovascular disease, chronic heart failure, and mortality. Yet, little is known about the effect of statins on IGF-1.&#x0D; Aims: to evaluate the effect of statin treatment on IGF-1 and its association with a cardiovascular risk.&#x0D; Material and methods: The study included 115 patients (mean age, 55.8±6.1 years) who either were overweight or had mild obesity (body mass index 28.6±3.8 kg/m2) without diabetes. Group 1 consisted of 70 patients with verified coronary artery disease receiving statin therapy; group 2 included 45 healthy subjects. Coronary angiography and treadmill test were used to diagnose coronary artery disease. Impaired glucose tolerance and total cholesterol, triglycerides, LPHD, LPLD, fibrinogen, and IGF-1 levels were evaluated in all the subjects. Heart chamber geometry was assessed by echocardiography.&#x0D; Results: The IGF-1 level was significantly higher in group 1 compared to the control group (196 and 167 ng/ml, respectively; р=0.014). Serum levels of IGF-1 were associated with duration of statin therapy (R=0.311; p=0.000), stage of hypertension (R=0.187; p=0.04), fibrinogen (R=0.274; p=0.033), TG (R=0.316; p=0.006), total cholesterol (R=–0.213; p=0.016), LPLD (R=–0.184; p=0.038), smoking (R=0.3; p=0.009), ejection fraction (R=0.298; p=0.041), end-diastolic volume (R=0.422; p=0.036), end-systolic volume (R=0.407; p=0.042), end-diastolic dimension (R=0.27; p=0.014), interventricular septal thickness (R=0.247; p=0.02), and left ventricular posterior wall thickness (R=0.258; p=0.019). Rosuvastatin dose positively correlated with the IGF-1 level (R=0.521; p=0.028).&#x0D; Conclusions: Statin administration is associated with higher IGF-1 levels in patients without diabetes. High IGF-1 level correlates with the risk factors of coronary artery disease: hypertension, lipid profile, and fibrinogen level and has an adverse effect on chronic heart failure by altering the cardiac remodeling.

LBA29 - CARRIE: A randomized, double-blind, placebo-controlled phase II study of istiratumab (MM-141) plus nab-paclitaxel and gemcitabine versus nab-paclitaxel and gemcitabine in front-line metastatic pancreatic cancer

Background: High serum IGF-1 levels have been associated with more aggressive pancreatic cancer (PDAC). Pre-clinical data suggest that dual blockade of the IGF-1 and HER3 pathways has superior activity to IGF-1 blockade alone in PDCA. We tested whether istiratumab, an IGF-1R and ErbB3 bi-specific antibody, can enhance the efficacy of standard of care (SOC) chemotherapy in patients with high serum IGF-1 levels. Methods: CARRIE was a randomized, double-blind, placebo-controlled, international Phase 2 study of nab-paclitaxel/gemcitabine alone or in combination with istiratumab in front-line metastatic PDAC. In Part 1, 10 patients were evaluated for PK and safety. In Part 2, patients with high free serum IGF-1 levels were randomized 1:1 to receive either istiratumab (2.8 g. IV Q2W) or placebo plus nab-paclitaxel/gemcitabine at the approved dose schedule. Heregulin (HRG) was tested in pre-treatment tumor samples. The co-primary endpoints were Progression Free Survival (PFS) in patients with high IGF-1 levels and in patients with both high IGF-1 levels and HRG+ tumors. Key secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR) by RECIST v1.1, and adverse events (AEs) rate. Results: A total of 317 patients were screened to enroll 88 patients (experimental arm n = 43; control n = 45) in Part 2. In the high IGF-1 cohort, median PFS was 3.6 and 7.3 months in the experimental vs. control arms, respectively (HR = 1.88, p = 0.027). In the combined high IGF-1/HRG+ subgroup (n = 44), median PFS was 4.1 and 7.3 months, respectively (HR = 1.39, p = 0.42). Median OS and ORR for the overall population were similar between two arms (8.9 and 11.7 months, HR = 1.36, p = 0.22 and 39.5 vs. 51.2%, p = 0.33, respectively). No significant difference in serious or Grade > 3 AEs was observed, although low-grade AEs leading to early discontinuation were higher in the experimental (39.5%) vs. control arm (24.4%). Conclusions: Istiratumab failed to improve the efficacy of SOC chemotherapy in the front-line treatment of patients with metastatic PDAC and high IGF-1. High serum IGF-1 levels did not appear to be an adverse prognostic factor in this setting. Clinical trial identification: NCT02399137. Legal entity responsible for the study: Merrimack Pharmaceuticals, Inc. Funding: Merrimack Pharmaceuticals, Inc. Disclosure: A.H. Ko: Clinical research support for conduct of this study to institution: Merrimack; Clinical research support for conduct of a separate study paid to institution: Celgene; Advisory board (self): Celgene. M. Kundranda: Consulting: Bayer; Speaker bureau: Bayer, Amgen. F. Rivera Herrero: Consulting: Celgene; Research fundings: Amgen, Merck-Serono, Roche, Sanofi, Bayer, Lilly, Celgene; Honoraria: Amgen, Merck-Serono, Roche, Sanofi, Bayer, Lilly, Celgene, Tecnofarma. D. Watkins: Funding to support educational conference attendance: Amgen. W. Downing, B. Wang, G. Kuesters, J.M. Pipas, V. Askoxylakis: Employee and stock share holder: Merrimack. S.L. Santillana: Employee and stock share holder: Merrimack Pharmaceuticals. All other authors have declared no conflicts of interest.

Prevalence and Course of Endocrinopathy in POEMS Syndrome.

POEMS syndrome is a rare multisystem disorder characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma-proliferative disorder, and skin changes, among other features. To describe the prevalence and course of endocrine dysfunction in POEMS. Cohort study with systematic review of the endocrinopathy in POEMS. Seventy-five patients with POEMS were evaluated by the multidisciplinary team at our tertiary specialist center. Endocrine data were available for 59 patients who attended the clinic from June 1999 to May 2018. All patients had regular endocrine screening, including testing for diabetes, pituitary and thyroid dysfunction and assessment of bone metabolism. Prevalence and survival time to develop endocrinopathy in POEMS. Thirty-four (63%) patients presented with an endocrinopathy at POEMS diagnosis and 54 (92%) had at least one endocrine abnormality at follow-up. The median follow-up was 4.4 (interquartile range, 1.5, 7.9) years. The most common endocrine abnormality was hypogonadism in 68%, followed by hyperprolactinemia (56%), hypothyroidism (54%), abnormal glucose metabolism (24%), adrenal insufficiency (17%), and high IGF-1 levels (15%). Spontaneous resolution of endocrine abnormalities at the end of follow-up was observed: 14% of patients with hypogonadism; 42%, hyperprolactinemia; 34%, hypothyroidism; and 38%, high IGF-1 levels. Endocrinopathy was found in 63% of patients at diagnosis and in 92% of patients during follow-up in our cohort. Therefore, patients with POEMS should be systematically assessed for endocrinopathy. The most common deficiencies were hypogonadism and hypothyroidism; however, but endocrinopathy can normalize, so ongoing treatment should remain under review.

Adenoma size and postoperative IGF-1 levels predict surgical outcomes in acromegaly patients: results of the Swiss Pituitary Registry (SwissPit).

Acromegaly due to a growth hormone-secreting pituitary adenoma is a rare disease with high morbidity if not treated adequately. Using data of the Swiss Pituitary Registry (SwissPit), we studied initial presentation and predictors for adverse clinical outcomes in acromegalic patients treated during the last 10 years in our institution. We evaluated 21 patients from the SwissPit registry with a final diagnosis of acromegaly confirmed by laboratory results (insulin-like growth factor-1 [IGF-1] and growth hormone suppression tests) and magnetic resonance imaging. Our main endpoint was clinical cure defined as complete remission, remission with need for medical treatment and uncontrolled disease defined by non-normalisation of IGF-1 and growth hormone levels. The most prevalent clinical symptoms at presentation were acral enlargement (81%), headache (29%), macroglossia (29%) and visual field defects (19%). Arterial hypertension was present in 67%, carpal tunnel syndrome in 38% and diabetes in 24%. A total of 19 of the 21 patients underwent initial surgical treatment. Eight patients had complete remission and 13 patients had active disease, with 7 having remission with need for medical treatment and 6 uncontrolled disease. Larger initial adenoma size (odds ratio [OR] 12.0, 95% confidence interval [CI] 1.02-141.3; p = 0.048) and high post-operative IGF-1 levels (OR 4.5, 95% CI 1.1-19.2; p = 0.040) were predictors for non-full remission and uncontrolled disease, respectively. This small, observational registry study showed a relevant success rate of initial pituitary surgery in patients with confirmed acromegaly. Initial tumour size and postoperative IGF-1 levels help to risk stratify patients regarding expected outcomes. In the case of disease persistence, a multimodal approach using drug and radiotherapy is mandatory.

Prevalence and risk factors for low bone mineral density in antiretroviral therapy-naive HIV-infected young men

ObjectiveWe aimed to investigate the prevalence of low bone mineral density (BMD) and associated factors in antiretroviral therapy (ART)-naive HIV-infected young men. MethodsIn this cross-sectional study, dual-energy X-ray absorptiometry (DXA) was used to measure BMD. BMD at the lumbar spine, total hip and femoral neck sites was expressed as a Z-score (number of standard deviations away from the mean in an age, race and sex-matched reference population). Low BMD was defined as Z-scores≤−2 at any of the three sites. The prevalence of low BMD was evaluated at the lumbar spine, total hip and femoral neck sites, as were risk factors associated with Z-scores. ResultsThe study cohort comprised 49 men, of whom 87.8% were white. Mean age was 31.6 (±7.7) years and mean BMI was 22.7 (±4.0)kg/m2. Half of patients (51.0%) were current smokers. The prevalence of low BMD was 24.5% [95% CI, 13.3–38.9]. Low estradiol levels and low BMI were associated with low Z-scores at each skeletal site, whereas current smoking and high IGF1 levels were associated with low Z-scores at the lumbar spine site. Among the HIV-related factors, low CD4+ cell count was associated with low Z-scores at the lumbar spine site. ConclusionsWe observed a high prevalence of low BMD in our ART-naive cohort of young men. Risk factors associated with low Z-scores were those usually observed in HIV-infected individuals (low BMI, current smoking and CD4+ cell count) or linked to endocrine hormone levels (estradiol, IGF-1).

High serum IGF-1 levels are associated with pregnancy loss following frozen-thawed euploid embryo transfer cycles

An elevated level of insulin growth factor (IGF-1) in rat uterine fluid has been shown to exert detrimental effects of embryo development possibly leading to an increase in pregnancy loss. Interestingly, the administration of somatostatin to rats undergoing superovulation reduced IGF-1 levels in uterine luminal fluid and thus reversed its deleterious effects on embryo development and increased the number of normal embryos. Therefore, we investigated whether serum levels of IGF-1 correlate with the incidence of pregnancy loss following IVF. To account for aneuploidy and the effect of hormonal supplementation on serum IGF levels, we only included natural frozen-thawed euploid embryo transfer (N-FET) cycles. Sera collected in the follicular phase (cycle day 10) were tested for levels of IGF-1, IGF-2, and IGF-binding protein 1 (IGFBP-1) using quantitative ELISA. A total of 156 N-FET cycles were included: 120 resulted in a live birth whereas 36 led to a first trimester pregnancy loss. Women with a pregnancy loss had significantly higher serum IGF-1 levels compared to those who achieved a live birth (18.0 ± 1.1 vs. 14.6 ± 0.7 ng/mL, respectively). The two groups had comparable serum IGF-2 and IGFBP-1 levels. There was no significant difference in maternal age, body mass index, gravidity, parity, number of prior miscarriages, peak endometrial thickness, or infertility diagnosis between the two groups. In conclusion, women undergoing euploid blastocyst transfer with elevated serum IGF-1 concentrations may be at increased risk of pregnancy loss. This may constitute a novel molecular explanation of pregnancy loss of euploid conceptus.

IGF-1 Levels Among Adolescent Girls Living In Jakarta and It's relation to Nutritional Status

Background and Objective:Insulin-like growth factor (IGF)-1 is one of the hormones that plays a role in the growth of adolescent girls. Its level will rise at puberty and begin to decline at the end of puberty. High IGF-1 levels in adult is associated with the incidence of breast cancer. This study aims to know the level of IGF-1 and investigates its relationship with dietary intake, nutritional status, and physical activity of adolescent girls aged 13-15 in Jakarta.Methods and Study Design:This cross-sectional study used secondary data from a previous study (titled "Determinant Factor Levels of Estradiol, IGF-1, and Early Menarche in Adolescent Girls Aged 13-15 in Jakarta: Nutritional Epidemiology Study Related to Breast Cancer Risk Factors") and primary data from stored blood serum to measure IGF-1 levels by colorimetric method. The secondary data such as dietary intake, anthropometric data, and physical activities were obtained from 178 subjects with a total population sampling method.Results and Conclusions:There was a positive correlation between IGF-1 levels and carbohydrate intake (p=0.041, r=0.153) and a negative correlation between IGF-1 levels and fat intake (p=0.042, r=-0.152). No correlation between IGF-1 and body mass index was found, but there was a tendency that IGF-1 values would increase in overweight and decrease in obesity. IGF-1 levels have nonlinear pattern by carbohydrates intake, fat intake and nutritional status. In conclusion, the adolescent girls should maintain their nutritional status by maintaining diet, choosing the right and balanced foods, as well as increasing physical activities.

Affinity to host population stimulates physical growth in adult offspring of Turkish migrants in Germany.

Because of political conflicts and climate change, migration will be increased worldwide and integration in host societies is a challenge also for migrants. We hypothesize that migrants, who take up the challenge in a new social environment are taller than migrants who do not pose this challenge. We analyze by a questionnaire possible social, nutritional and ethnic influencing factors to body height (BH) of adult offspring of Turkish migrants (n = 82, 39 males) aged from 18 to 34 years (mean age 24.6 years). The results of multiple regression (downward selection) show that the more a male adult offspring of Turkish migrants feels like belonging to the Turkish culture, the smaller he is (95% CI, -3.79, -0.323). Further, the more a male adult offspring of Turkish migrants feels like belonging to the German culture, the taller he is (95% CI, -0.152, 1.738). We discussed it comparable to primates taking up their challenge in dominance, where as a result their body size increase is associated with higher IGF-1 level. IGF-1 is associated with emotional belonging and has a fundamental role in the regulation of metabolism and growth of the human body. With all pilot characteristics of our study results show that the successful challenge of integration in a new society is strongly associated with the emotional integration and identification in the sense of a personal sense of belonging to society. We discuss taller BH as a signal of social growth adjustment. In this sense, a secular trend of BH adaptation of migrants to hosts is a sign of integration.