IGF-I Measurements Research Articles

IGF-I assay methods and biologic variability: evaluation of acromegaly treatment response.

Serum insulin-like growth factor (IGF-I) is the primary biochemical measure of disease activity in patients with acromegaly, and the 2014 Endocrine Society guidelines recommended normal age-adjusted serum IGF-I as the biochemical target of treatment. However, quantification and interpretation of IGF-I levels are subject to limitations that may affect therapeutic decisions. Techniques for measuring IGF-I have evolved greatly over the past 40 years and continue to do so. Results can vary substantially for different assays, procedures, and laboratories. For any assay, the interpretation of IGF-I values requires robust reference ranges. Using currently available large normative databases, the upper limit of normal (ULN) for IGF-I in middle-aged and elderly individuals is lower than historical reference ranges. Thus, the goal of achieving IGF-I < 1× ULN is more demanding than in the past, and some patients with acromegaly who were classified as "normal" (IGF-I < 1× ULN) in previous studies would be reclassified as above the ULN based on newer normative data. In addition, substantial intra-individual, week-to-week variation in serum IGF-I levels (unrelated to assay performance) has been observed. With changes over time in the measurement of IGF-I and the advent of updated reference ranges derived from large normative databases, it is difficult to justify rigid adherence to the goal of maintaining IGF-I below the ULN for all patients with acromegaly. Instead, symptoms, comorbidities, and quality of life should be considered, along with growth hormone and IGF-I levels, when evaluating the need for further treatment.

Consensus on criteria for acromegaly diagnosis and remission

PurposeThe 14th Acromegaly Consensus Conference was convened to consider biochemical criteria for acromegaly diagnosis and evaluation of therapeutic efficacy.MethodsFifty-six acromegaly experts from 16 countries reviewed and discussed current evidence focused on biochemical assays; criteria for diagnosis and the role of imaging, pathology, and clinical assessments; consequences of diagnostic delay; criteria for remission and recommendations for follow up; and the value of assessment and monitoring in defining disease progression, selecting appropriate treatments, and maximizing patient outcomes.ResultsIn a patient with typical acromegaly features, insulin-like growth factor (IGF)-I > 1.3 times the upper limit of normal for age confirms the diagnosis. Random growth hormone (GH) measured after overnight fasting may be useful for informing prognosis, but is not required for diagnosis. For patients with equivocal results, IGF-I measurements using the same validated assay can be repeated, and oral glucose tolerance testing might also be useful. Although biochemical remission is the primary assessment of treatment outcome, biochemical findings should be interpreted within the clinical context of acromegaly. Follow up assessments should consider biochemical evaluation of treatment effectiveness, imaging studies evaluating residual/recurrent adenoma mass, and clinical signs and symptoms of acromegaly, its complications, and comorbidities. Referral to a multidisciplinary pituitary center should be considered for patients with equivocal biochemical, pathology, or imaging findings at diagnosis, and for patients insufficiently responsive to standard treatment approaches.ConclusionConsensus recommendations highlight new understandings of disordered GH and IGF-I in patients with acromegaly and the importance of expert management for this rare disease.

Interpreting growth hormone and IGF-I results using modern assays and reference ranges for the monitoring of treatment effectiveness in acromegaly.

Standard treatment for acromegaly focuses on the achievement of target absolute levels of growth hormone (GH) and insulin-like growth factor (IGF-I). The appropriateness of these targets when measured using modern assay methods is not well defined. This paper reviews biochemical status assessed using methods available at the time and associated clinical outcomes. GH measurements were shown to provide an indication of changes in tumor size, and failure of GH suppression after glucose stimulation is associated with tumor recurrence. IGF-I levels were more closely associated with changes in symptoms and signs. Reduced GH and IGF-I concentrations were shown to be associated with increased longevity, although the degree of increase has only been analyzed for GH. Lowering of GH and IGF-I has consistently been associated with improved outcomes; however, absolute levels reported in previous studies were based on results from methods and reference ranges that are now obsolete. Applying previously described absolute thresholds as targets (e.g. "normal" IGF-I level) when using current methods is best applied to those with active acromegaly symptoms who could benefit from further lowering of biochemical markers. In asymptomatic individuals with mild IGF-I or GH elevations, targeting biochemical "normalization" would result in the need for combination pharmacotherapy in many patients without proven benefit. Measurement of both GH and IGF-I remains an essential component of diagnosis and monitoring the effectiveness of treatment in acromegaly; however, treatment goals based only on previously identified absolute thresholds are not appropriate without taking into account the assay and reference ranges being employed. Treatment goals should be individualized considering biochemical improvement from an untreated baseline, symptoms of disease, risks, burdens and costs of complex treatment regimens, comorbidities, and quality of life.

THU171 Reference Intervals For Bioavailable IGF-I Values In Dutch Healthy Children, Adolescents And Young Adults

Abstract Disclosure: K. Pellikaan: None. M. Elizabeth: None. A.C. Hokken-Koelega: None. S.A. van den Berg: None. L. de Graaff-Herder: None. Background: Immunoreactive ‘total’ IGF-I is the main biochemical marker for titration of growth hormone (GH) treatment. However, in several endocrine disorders like Prader-Willi syndrome (PWS) and Silver-Russell syndrome, total IGF-I levels are often higher than expected based on GH dose and clinical effects. When patients reach total IGF-I concentrations above +2SDS, fear of negative long-term effects makes clinicians reduce GH dose. This dose reduction often leads to a deterioration in body composition, growth (in children) and quality of life, which suggests that bioavailability of IGF-I is reduced in patients with these disorders. Measurement of bioavailable IGF-I could improve GH dose titration. However, use of bioavailable IGF-I assays has been hindered by the lack of proper reference intervals. We report reference intervals of bioavailable IGF-I in a large group of healthy children, adolescents and adults. Methods: Serum was collected of 260 Dutch healthy controls aged 1-21 years. Total IGF-I and unbound, bioavailable IGF-I were measured manually using Ansh Labs total and free IGF-I assays. We calculated male and female age-related reference intervals for total and bioavailable IGF-I. Results: We present male and female age-related reference intervals. Both total and bioavailable IGF-I increased with age and were significantly higher in females than in males (p &amp;lt; 0.001). Conclusions: the reported reference intervals for bioavailable IGF-I concentrations will facilitate the use of bioavailable IGF-I levels as an alternative marker for GH dose titration in patients with disorders in which total IGF-I levels are unreliable. Presentation: Thursday, June 15, 2023

RF13 | PMON59 Tracking and Cumulative Lifetime Exposure to Circulating IGF-I in 6,459 Healthy Individuals and in SGA Children Treated with GH

Abstract Background: /objective Insulin-like-growth-factor-I (IGF-I) levels in the lower or upper normal range have been proposed as a biomarker of risk for later disease in healthy adults, specifically cardiovascular disease and cancer. In addition, concern has been raised about the frequently observed supraphysiological IGF-I levels in non-growth-hormone-deficient children treated with growth hormone (GH). However, whether a single IGF-I measurement is a valid indicator of cumulative lifetime exposure to IGF-I and thus disease risk is not established. We aimed to evaluate intra-individual longitudinal tracking of IGF-I and IGF-binding-protein-3 (IGFBP-3) levels and to estimate cumulative lifetime exposure to IGF-I in healthy and GH-treated individuals. We hypothesized that individuals follow a certain IGF-I trajectory throughout life and that GH therapy in childhood does not increase lifetime IGF-I exposure substantially. Methods We performed a combined cross-sectional (n=5,326) and longitudinal (n=1,133) study of 6,459 healthy participants (49% male) aged 0­­­–76 years recruited as part of six Danish population-based studies, resulting in a total of 9,963 serum samples. In addition, we included 238 samples from nine short children born small-for-gestational-age (SGA) before, during and after GH treatment. Serum samples were analyzed for IGF-I and IGFBP-3 with the IDS-iSYS immunoassay and anthropometric measures were obtained. Intra-individual tracking was determined by intraclass correlation coefficients (ICC) derived from a linear mixed model with IGF-I (SDS) or IGFBP-3 (SDS) as dependent variable and subject as random effect, unadjusted and adjusted for BMI-changes. Cumulative lifetime exposure to IGF-I was estimated by calculating area under the curve of the predicted SD trajectory from 0-76 years. Results Sex- and age-specific reference curves for IGF-I and IGFBP-3 were established. For IGF-I, ICCs were 0.50 (95% CI: 0.47–0.53) and 0.53 (0.50–0.56) for male and female participants, respectively. ICCs for IGFBP-3 were 0.52 (0.49–0.55) for male participants and 0.59 (0.56–0.62) for female. Cumulative lifetime IGF-I exposure was significantly higher in female (mean ± SD, 12,723 ± 3,691) than in male participants (12,563 ± 3,393); p=0.02. The SGA patients had a mean (range) GH-treatment duration of 9.2 years (5.2–11.9). Treatment caused an increase in estimated cumulative lifetime IGF-I exposure of 1,759 ± 556 shifting them from a mean estimated lifetime exposure without treatment of 9,512 ± 1,889 to 11,271 ± 1,689 with treatment. This corresponded to a rise in IGF-I trajectory (SDS) of 0.55 SD ± 0.18, from -0.89 SD ± 0.57 to -0.35 SD ± 0.49. Conclusion Our results suggest that IGF-I and IGFBP-3 levels are tracking throughout life and that a single measurement reliably reflects lifetime exposure. We, for the first time, estimated lifetime exposure to IGF-I in healthy individuals and show that pediatric GH therapy only slightly increases lifetime exposure and not beyond levels commonly found in the reference population. Presentation: Sunday, June 12, 2022 12:42 p.m. - 12:47 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

IGF-I Variability Over Repeated Measures in Patients With Acromegaly Under Long-Acting Somatostatin Receptor Ligands.

In patients with acromegaly on long-term treatment with long-acting somatostatin receptor ligands (SRLs), the time of blood collection for IGF-I measurement after injection is not well defined. We aimed to assess serum IGF-I dynamics and variability in SRL-treated patients compared with surgically cured patients and healthy controls. Thirty patients under SRLs considered controlled based on a normal previous IGF-I level, 10 patients cured by pituitary surgery, and 7 healthy subjects underwent 4 weekly IGF-I determinations. In SRL-treated patients, the IGF-I SDS (mean ± SD) was higher just before injection (0.34 ± 0.66) than at Day 7 (-0.33 ± 0.61; P = 0.0041) and Day 14 (-0.23 ± 0.60; P = 0.047) after injection, but it did not significantly vary in cured patients and healthy controls. The IGF-I CV was higher in SRL-treated patients than in cured patients or healthy controls (14.4 ± 7.6% vs 7.9 ± 4.4% and 8.3 ± 3.2%, respectively; P < 0.05 for both). Among SRL-treated patients, IGF-I CV was higher in "nonoptimally controlled patients"-i.e., patients with at least one elevated IGF-I value out of 4 (n = 9) compared with "optimally controlled" patients for whom all 4 IGF-I SDS values were < 2.0 (21.3 ± 9.3 vs 11.6 ± 6.0%; P = 0.0019). The latter did not differ from surgically cured patients and healthy controls. The measurement at the farthest distance from the SRL injection was the most predictive of patients with nonoptimally controlled disease. In patients treated with long-acting SRLs, IGF-I sampling at the farthest distance from SRL injection is the most informative and best predictor of optimal disease control.

Time course and reaction types of serum IGF-1 and its relationship to BMI and leptin regarding inpatients with anorexia nervosa

ObjectiveAnorexia nervosa (AN) is a severe mental disorder that is characterized by restriction of energy intake, low weight, and endocrine abnormalities. One of the known endocrine changes in relation to underweight is in the GH/IGF-I axis. The aim of the study was (a) to investigate longitudinal characteristics of the IGF-I-change during therapy and weight gain in adult AN, (b) to determine relationships between IGF-I and leptin, (c) to characterize patients with weak and pronounced hormonal reactions to underweight. DesignData was assessed from 19 AN patients. Over the first two months, serum IGF-I concentrations were assessed on a weekly basis; thereafter on a monthly basis. The trend of IGF-I values over time was analyzed using individual growth models. ResultsIn total, n = 177 IGF-I measurements were analyzed. IGF-I increased significantly dependent on BMI (slope = 20.81, p < 0.001), not modulated by duration of disease. The increase in IGF-I was significantly related to the increase in leptin concentrations over time (slope = 15.57, p < 0.001). Patients with a weaker hormonal reaction to underweight were significantly older compared to patients with a pronounced hormonal reaction (t(17) = 3.07, p = 0.007). ConclusionsDuring treatment, IGF-I change is clearly related to BMI as well as to leptin. Age appears to be associated with the IGF-I response to underweight.

Diagnostic Value of Serum Acid-Labile Subunit Alone and in combination with IGF-I and IGFBP-3 in the Diagnosis of Growth Hormone Deficiency

Background: The acid-labile subunit (ALS) is a crucial factor in the tertiary complex. IGF-I and IGFBP-3 are routinely measured during the diagnostic work-up for growth hormone deficiency (GHD). The aim of the study is to evaluate the relevance of serum ALS as an additional biomarker in the diagnosis of GHD. Methods: Ninety-one children undergoing standard diagnostic work-up for GHD were included in this retrospective study. Inclusion criteria were evidence-based auxological cutoffs, IGF-I and IGFBP-3 <−2 SDS at first presentation, at least 1 growth hormone (GH) stimulation test, and IGF-I, IGFBP-3, and ALS measurements on the same day. Statistical analysis was performed by ROC as well as by odds ratio calculations. Results: Forty-seven of 90 participants presented with peak GH values under the cutoff of 7 ng/mL. AUC from a model containing only IGF-I was 0.76 and 0.68 when using only ALS. A model containing IGF-I, IGFBP-3, and ALS (AUC = 0.77) did not improve the result compared to the combination of IGF-I/IGFBP-3 (0.77) or IGF-I/ALS (0.76). Furthermore, the variation in the outcome (GH peak </≥7) explained by IGF-I only amounts to 20.4%, while that explained by IGFBP-3 and ALS is only 10.6 and 7.8%, respectively. The sensitivity to diagnose GHD at respective concentrations of −2.0 SDS was 48% for IGF-I, 38% for IGFBP-3, and only 8% for ALS. Conclusion: Determination of serum ALS alone or in combination with IGF-I and IGFBP-3 did not improve definition of biochemical GHD in a cohort of short children and adolescents with suspected growth disorder. However, performance of IGFBP-3 in this context was not statistically superior to ALS.

Optimization, validation, and comparison of a rapid method for the quantification of insulin-like growth factor 1 in serum using liquid chromatography-high-resolution mass spectrometry.

Human insulin-like growth factor 1 (IGF-I) is the primary mediator of the effects of the growth hormone (GH). Therefore, it has been used as a biomarker to detect the abuse of GH in sports. The measurement of IGF-I relies on mass-based and immunological approaches to analysis. Among the mass-based analysis methods, liquid chromatography-mass spectrometry (LC-MS) has a number of functional advantages. LC-MS measurements based on the quantification of IGF-I, according to trypsin digestion, are used in the most common method of analyzing doping. However, this method is time-consuming and subject to experimental variability. In this study, we optimized a rapid method for detecting IGF-I without the trypsin digestion step. This method of analysis uses an ultra-centrifugal filter and an LC-HRMS through narrow-range mass scan method. To verify the validity of this method, eight categories of validation testing were applied with the following results: linearity, R2 > 0.99; limit of detection, 15 ng/ml; limit of quantification, 20 ng/ml; accuracy, >99%; recovery rate, >95%; carryover, <0.03; and inter- and intra-day precision values, %CV < 2% and %CV < 6%, respectively. Furthermore, we discussed the correlation of the quantified concentration from two other methods, immunoradiometric assay (IRMA) and parallel reaction monitoring method, using 209 serum samples. In conclusion, although both mass spectrometry-based methods worked equally well in terms of analytical performance and correlation with IRMA results, narrow-range mass scan method had several advantages, such as time and cost savings and reliable reproducibility, over the existing methods.

A high-throughput assay for the quantification of intact Insulin-like Growth Factor I in human serum using online SPE-LC-HRMS

Quantification of IGF-I is relevant in both doping control as a biomarker of growth hormone (GH) misuse in sports, and in the clinical field for longitudinal follow-up of patients with disorders related to the GH axis. Currently, better standardization of IGF-I measurements using mass spectrometry is in our best interest as it would enable long-term monitoring of an athletes’ IGF-I levels by its addition to the Athlete Biological Passport (ABP).Here, a simplified and rapid top-down LC-HRMS method for quantification of IGF-I in human serum is presented. A ten-minute precipitation-based offline sample preparation is combined with online sample clean-up and separation on a conventional LC, resulting in a total runtime of nine minutes in between injections. The method was validated in the relevant range of 50–1000 ng/mL for the following parameters: linearity, precision, bias, Limit Of Quantification (LOQ), carry-over, selectivity, recovery and ion suppression. As proof of concept, the presented LC-HRMS assay was compared with results from a previous inter-laboratory study on intact IGF-I quantification using four human GH administration samples. It was additionally compared with the IDS-iSYS immunoassay using 47 athlete serum samples, showing good overall agreement with a slight positive bias of 24.2 ng/mL for the LC-HRMS assay at a mean sample concentration of 234 ng/mL. Also, a discrepancy between commercially available IGF-I reference material for the calibration of quantitative assays is discussed. This is of importance if LC-MS assays for IGF-I are to be harmonized.

The prevalence of silent acromegaly in prolactinomas is very low.

The aim of this study was to evaluate the somatotroph axis in a large series of patients with prolactinoma to verify the prevalence of silent acromegaly in this population. A hundred and forty-four patients were enrolled in a multicenter study: 90 were already on cabergoline (CAB) and enrolled in a cross-sectional arm (group A) with random PRL, GH and IGF-I determination on treatment (≥3months), whereas 54 untreated patients were enrolled at diagnosis in a prospective arm (group B) with PRL, GH and IGF-I measurement before and after 6 and 12months of treatment. In the presence of high IGF-I, CAB was withdrawn for 3months and GH, IGF-I, PRL and GH during an oral Glucose Tolerance Test (OGTT) were obtained. High IGF-I levels (ULN 1.01-1.56) were observed in 9 patients (6.25%, 5F). After CAB withdrawal, IGF-I levels normalized in 5/9 patients, GH was<0.4ng/ml after OGTT in 7/9 cases or at random GH determination in one case. After CAB re-introduction, IGF-I levels re-increased in a single case. Overall, a single young female patient harboring a macroadenoma in group A was diagnosed with silent acromegaly and underwent successful transsphenoidal removal of a GH/PRL-secreting adenoma. The prevalence of silent acromegaly in prolactinomas (0.7%) is lower than previously reported and OGTT is helpful to recognize silent acromegaly. We suggest that the somatotroph axis should be evaluated at diagnosis in all cases and not systematically during follow-up.

Use of Capillary Dried Blood for Quantification of Intact IGF-I by LC–HRMS for Antidoping Analysis

Background:IGF-I is used as a biomarker to detect Growth Hormone doping in athletes' blood samples. Objective: Our aim was to develop and validate a fast, high-throughput and accurate quantification of intact IGF-I from volumetric absorptive microsampling (VAMS) dried blood using LC coupled to high resolution mass spectrometry (LC-HRMS). Methodology & results: IGF-I was extracted from the VAMS, released from its binding proteins, concentrated using microelution SPE and analyzed by LC-HRMS. The method was successfully validated in accordance with the World Anti-Doping Agency's requirements. Subsequently, IGF-I measurements from capillary dried blood and serum were compared. Conclusion: The combination of VAMS, microelution SPE and LC-HRMS is a promising strategy applicable to IGF-I quantification in athletes' samples.

SUN-LB46 Differences in IGF-I Concentrations Between European and US Populations - Consequences for Reference Intervals

Background: IGF-I is the most widely used biomarker for management of GH related diseases. Reproducible assays and method-specific reference intervals (RIs) are crucial determinants of its clinical utility. Assay validation and RIs based on >15,000 subjects were published for the IDS iSYS IGF-I assay (J Clin Endocrinol Metab 2014). We now analyzed distribution of IGF-I results obtained in routine samples analyzed by accredited laboratories in the US and Europe, all using the IDS iSYS assay. Methods: All results from routine IGF-I measurements during the past 5 years in 4 laboratories were included (US lab n=778,173 males/710,752 females; European labs (Germany/Belgium, n=23,220 males/40,183 females). Assay performance across laboratories was confirmed through proficiency testing schemes and exchange of patient samples. We constructed RIs adjusted for age/sex from European and US cohorts separately using a modified Hoffmann approach (Am J Clin Pathol 2015), and compared to the originally published RIs (n=6697 males/8317 females, adults from Europe). A subset of US samples was used to compare IGF-I between regions with lower (Colorado) and higher (Alabama) mean body mass index (BMI). Results: Lower limits (LLs) of RIs calculated from routine results are superimposable to LLs from the original publication for all ages and sexes, regardless whether IGF-I results were from Europe or the US. For groups with sufficient n, upper limits (ULs) of RIs calculated from European routine data were also not statistically different from the originally published central 95%. However, a striking difference exists in calculated ULs from data of European and US origin: For ages 10-18 years, calculated UL on average was 149.3 ng/mL (34.6%) higher in boys and 94.9 ng/mL (19.8%) in girls from the US. In adults (19-95 years), calculated UL on average was 45 ng/mL (20.3%) higher in males and 29.7 ng/mL (13.8%) in females from the US. Within the US, mean IGF-I was significantly higher in samples from Colorado (lower mean BMI) than in Alabama (p<0.0001) across age- and sex groups, although the difference between the two states was smaller than between each of them and Europe. Conclusion: This study provides evidence that in sufficiently large datasets, both, direct sampling (as in the original publication) and the indirect Hoffmann algorithms provide statistically comparable RI limits and may be considered as accurate representation of results distribution in the disease-free populations. More importantly, we demonstrate that even with tight cross-correlation and continuous monitoring of IGF-I assay performance RIs generated in different populations can be different. Notably, in our extremely large study, the difference between Europe and the US was clinically relevant only at the UL. Although our study cannot reveal the cause of the difference, we suggest using adapted RIs for the US.

Random Gh and Igf-I levels after transsphenoidal surgery for acromegaly: relation with long-term remission

To evaluate the role of IGF-I and random GH measurements 3 months after transsphenoidal surgery (TSS) in predicting long-term remission in acromegaly patients. Retrospective analysis of 54 acromegaly patients who underwent TSS with the same neurosurgery team. Random GH and IGF-I values evaluated 3 months after TSS were related to long-term outcomes. The initiation of adjuvant therapy at any time defined surgical failure. At 3 months, 14 (25.9%) patients had controlled disease (CD; normal IGF-I and GH < 1.0 µg/L), 25 (46.3%) had uncontrolled disease (UD; high IGF-I and GH), and 15 (27.8%) had biochemical discrepancies (BD): 12 BDI (normal IGF-I + GH ≥ 1.0 μg/L) and 3 BDII (high IGF-I + GH < 1.0 μg/L). All patients of the CD group, 2 of the UD, 11 of the BDI, and 2 of the BDII, progressed with long-term remission and had IGF-I ≤ 1.25-fold the Upper Limit of Normal (ULN), in contrast with all cases of surgical failure where IGF-I was ≥1.3-fold ULN. Only one patient with normal IGF-I had recurrence, resulting in 100% sensitivity and 96% specificity of post-surgical IGF-I ≤ 1.25-fold ULN to predict long-term remission, observed in 54% of our cohort. Post-surgical random GH ≥ 1.7 µg/L was the best cutoff to identify surgical failure, but its accuracy to predict long-term outcomes was limited. IGF-I levels ≤ 1.25-fold ULN 3 months after TSS was the best guide for long-term remission in acromegaly patients with both initial surgical failure and discrepant biochemical results.

The IGF system and longitudinal growth in preterm infants in relation to gestational age, birth weight and gender

ObjectiveGrowth factors in the blood of very preterm infants may reflect growth and contribute to the understanding of early development. We investigated postnatal levels of insulin-like growth factors (IGFs) in infants born very preterm and related them to early growth development. DesignBlood samples were analyzed weekly for IGF-I, IGF-II, IGF binding protein (BP)-1, IGFBP-3, and acid-label subunit (ALS). Methods73 children born very preterm (gestational age (GA) <32 weeks) were divided according to their gender-specific birth weight standard deviation score (SDS) into either appropriate for GA (AGA) or small for GA (SGA). Fifty-two (71%) and forty-three (59%) infants completed follow-up with anthropometry at approximately 3 years and at 5 years of age respectively. Thirty-six subjects (49%) had blood sampling for IGF-I and IGFBP-3 measurements up to 3 years of age. ResultsIGF-I, IGFBP-3, and ALS levels increased in all groups from week 31 to week 36, with generally lower levels in the SGAs, with a concomitant lower growth velocity. Postnatal ALS was strongly associated with IGF-I and IGFBP-3 in boys, girls and AGA infants. IGF-II was higher in earlier born preterms (GA < 27 weeks) at postmenstrual ages 27.5–29.9 weeks compared with SGAs and late GA (GA ≥ 27 weeks) preterms (p < .0001). IGF-II, in contrast to IGF-I, did not differ between SGAs and AGAs at weeks 31–36. Mean IGFBP-1 was highest in the SGAs compared to AGAs at mean week 28,5 and 31 (p = .001) and IGFBP-1 levels were elevated in relation to IGF-I in the SGAs at that period. At follow-up, the increase in IGF-I between week 31 and 33.5 was a significant positive determinant of height SDS at 3 and 5 years of age in forward multiple regression analysis, independent of target height. ConclusionThis is the first study to investigate postnatal ALS levels in preterm infants. In very preterm infants, IGF-II is less affected by size at birth during early postnatal weeks compared with IGF-I. Early elevated IGFBP-1 might protect the SGA infants from an intense metabolic rate. Our results indicate that anabolic and metabolic processes during weeks 31–36 predicts later height.

SUN-256 Limited Usefulness of Single IGF-I Measurement as a Screening Test for Growth Hormone Deficiency in Children and Adolescents

Introduction: IGF-I measurement has been proposed as a screening tool for the diagnosis of Growth Hormone Deficiency (GHD). However, few studies evaluated the accuracy of IGF-I measurement as a screening test and the results have been controversial. Objective: To evaluate the value of a single IGF-I measurement as screening test in the diagnosis of GHD in short children and adolescents. Patients and Methods: 439 short children (median-IQR age 10.5 (7.1-12.8) y, 273 boys), were included in this retrospective analysis. The patient group consisted of 102 subjects (54 boys) with GHD (peak GH <7.0 μg/L after two provocative tests with Arginine, Insuline Tolerance Test, and Clonidine), 60 of whom had GHD of organic or genetic origin (OGHD) and 42 were idiopathic (IGHD). The 337 subjects with a GH peak ≥7 μg/L and no other recognizable cause for their shortness were considered as controls. All provocative tests were performed between 8.00 and 9.00 am after fasting overnight, without steroid priming. GH and IGF-I were measured by the same chemiluminescence assay in all samples (Immulite, Siemens). Receiver operating characteristic (ROC) analysis was used to evaluate the optimal IGF-I cut-offs and the diagnostic accuracy of IGF-I. The analysis was repeated including only 67 patients with severe GHD (SGHD, peak GH <5.0 μg/L after two provocative tests): 54 organic/genetic (SOGHD) and 18 idiopathic (SIGHD). Results: IGF-I SDS was significantly lower in patients than in controls (-2 (-2.9 - -1.7), -1 (-1.8 - -0.1), respectively, p<0.0001). IGF-I SDS ≥ -2 was found in 42% and 69% of OGHD and IGHD patients, respectively. The Area Under the Curve (AUC, measure of discriminative ability of the test) of IGF-I SDS was 0.73. The IGF-I SDS cut-off of -2 had 50% sensitivity (Se), 80% specificity (Sp), 2.4 likelihood ratio for positive test results (LR+), and 74% diagnostic efficiency (Ef). The best pair of values for Se and Sp was found at IGF-I SDS cut-off of -1.8 (B cut-off, Se 60%, Sp 75%, LR+ 2.3, Ef 71%). For OGHD, AUC was 0.82. For cut-off -2 SDS: Se 60%, Sp 80%, LR+ 3, Ef 80%. B cut-off was -1.9 SDS (Se 68%, Sp 78%, LR+ 3.1, EF 77%). For IGHD, AUC was 0.61. For cut-off -2 SDS: Se 36%, Sp 79%, LR+ 1.7, Ef 77%. B cut-off was -1.4 SDS (Se 52%, Sp 65%, LR+ 1.5, Ef 64%). The results were similar when only patients with SGHD were analysed. Among them, 42% had IGF-I SDS ≥ -2. IGF-I SDS ≥ -2 was found in 41% of SOGHD and in 67% of SIGHD. Conclusions: In our large cohort of short children, IGF-I measurement has shown suboptimal accuracy in discriminating GHD from non-GHD patients. The accuracy is better for patients with organic or genetic GHD. IGF-I values should be interpreted in combination with other clinical and biochemical parameters, and cannot be used alone as a screening tool.

OR32-2 Alpha Klotho as a Marker of Disease Activity in Acromegaly

Introduction: Measurements of GH and IGF-I are considered gold standard for biochemical acromegaly diagnosis and follow-up, but have limitations. Novel laboratory tools would be of interest, especially when results for GH and IGF-I are discrepant. Soluble alpha-klotho (αKL) might have endocrine functions and few studies have investigated αKLs role in acromegaly. Methods: We measured αKL in treatment-naïve patients before surgery (A; n=29), after surgery (controlled, B; n=32; not controlled, C; n=15) in postoperative patients on SSA (controlled, D; n=22; not controlled, E; n=11), in patients with non-functioning pituitary adenomas (NFPA, F; n=20) and in healthy controls (HC, G; n=31). Control was defined by IGF-I≤1.3XULN. Random GH was also measured. Agreement between categorizations based on IGF-I ≤1.3XULN, GH <1.0ng/mL and normal αKL was investigated. ROC analysis was used to define cut-offs above which αKL indicates lack of control of acromegaly. Results: As expected, GH and IGF-I significantly dropped after surgery and with pharmacological control. αKL was markedly elevated in treatment-naïve patients before surgery, decreased after surgery and normalized with biochemical control (A vs. B, D; p<0.0001). It remained higher in uncontrolled patients after surgery as compared to controlled patients, NPFA and HC (C, E vs. B, D, F, G; p<0.05) and did not differ between controlled patients, NFPA and HC (B, D vs. F, G; p>0.05). αKL was correlated with IGF-I (r=0.8) and - to a lesser degree - with random GH (r=0.6; p<0.0001 for both). High GH concentrations (>10ng/mL) still correlated significantly with αKL (r=0.50; p=0.03), but no longer with IGF-I. Concentrations of αKL were not correlated to prolactin and markers of calcium metabolism. In contrast to IGF-I, αKL did not change with sex and age in acromegaly, NFPA and HC. In patients which were controlled based on normalized IGF-I, but not on GH, αKL was also normalized in >95% of the cases. Concentrations of αKL>1617pg/mL indicate lack of control (ROC; 98.1% sensitivity, 76.3% specificity). Conclusion: Similar to GH and IGF-I, circulating αKL reflects disease activity in acromegaly. It might be useful as a surrogate parameter at diagnosis and during follow up, particularly if GH and IGF-I are discrepant. αKL has potential advantages over IGF-I as it seems to be unaffected by age and sex, and remains correlated to GH hypersecretion at very high GH concentrations.

SUN-LB080 ACROSTUDY - Safety and Efficacy of a Cohort of 110 Naïve Patients with Acromegaly Treated with Pegvisomant

Background: ACROSTUDY is an open-label, non-interventional post-authorization safety study that began in 2004 to evaluate safety in at least 1000 acromegaly patients treated with the GH receptor antagonist pegvisomant (PEGV). This commitment was fulfilled in Jan 2013. ACROSTUDY was later amended to enroll an additional 110 patients that were naïve/semi-naive to PEGV treatment. Semi-naïve patients are defined as not having received PEGV therapy for at least 6 months prior to enrollment. Objectives: The primary objectives were to: 1) assess the long-term safety of PEGV in real world practice; 2) assess the effect of IGF-I normalization on treatment outcomes, including safety, glucose control and patient-reported outcomes (PROs). Patients & Methods: 110 patients with Acromegaly 53.6% male, 81.8% Caucasian, median age 42.4 years at diagnosis; median age 48.9 years at PEGV start. Patients were considered ‘IGF-I Controlled’ if the most temporally-related IGF-I measurement was normal for that laboratory. Safety data including adverse events and liver tests were collected. IGF-I and HbA1C were measured; PROs were evaluated using the Acromegaly Quality of Life Questionnaire (AcroQoL) and PatientAssessed Acromegaly Symptom Questionnaire (PASQ), stratified by IGF-I control. Results: No new safety signals were identified in this sub-study. IGF-I SDS >2 decreased from 87% of patients at baseline to 31% at year 2 at a mean dose(±SD) of 10.4(±7.45) mg/day; patients with IGF-I SDS <2 had a mean dose of 14.8(±6.7). Among IGF-I controlled patients, median (range) HbA1C levels were 5.8% (5.4-6.1) at baseline and 5.6% (4.5-7.2) at year 2; in IGF-I uncontrolled patients, HbA1C was 6.1% (4.9-6.6) at baseline and 6.3% (2.9-10.6) at year 2. Among IGF-I controlled patients, median (range) global AcroQoL scores were 54.6 (24-73) at baseline and 61.4 (13-86) at year 2; while in IGF-I uncontrolled patients, median global AcroQoL score was 59.7 (8-92) at baseline and 63.6 (25-76) at year 2. Among IGF-I controlled patients, median (range) total PASQ score was 20 (3-38) at baseline and 17.5 (1-40) at year 2; in IGF-I uncontrolled patients, median total PASQ score was 17 (0-44) at baseline and 14 (3-39) at year 2. A greater number of the six individual symptoms of the PASQ score showed a positive trend for improvement from baseline to year 2 in the IGF-I controlled patients than in the uncontrolled patients. Summary: In this real-life world international study, overall biochemical control (i.e. normal IGF-I) was achieved with pegvisomant in 64.3% patients by year 2. Improved IGF-I control was associated with improved HbA1C, QoL and symptoms of acromegaly. One limitation of the study was that the PEGV dose may not have been adequately titrated to achieve IGF-I normalization. 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.

SUN-LB079 Acrostudy - Safety And Treatment Outcomes In 2221 Patients With Acromegaly Treated With Pegvisomant: Real World Experience

ACROSTUDY is an open-label, non-interventional post-authorization safety study (PASS) that began in 2004 to evaluate safety in at least 1000 acromegaly patients treated for 5 years with the GH receptor antagonist pegvisomant (PEGV). This commitment was fulfilled in 2013 but ACROSTUDY was extended as a voluntary PASS, ultimately collecting data on 2221 patients who were followed through Dec 2017. Objectives: To monitor the long-term safety of PEGV including the pituitary tumor volume, as prescribed in clinical practice. Patients & Methods: 50.8% were male, 92.4% Caucasian with median age 41.1 years (1.7-83.7) at diagnosis and median age 49.7 years (3.9-85.6) at start of PEGV. Mean duration of PEGV treatment was 9.3 years (0.0-20.8); 80.8% of patients started PEGV on a daily schedule and patients came from fifteen countries. Safety data included adverse events, change in tumor volume and liver tests. Efficacy was measured by IGF-I control (Patients were considered ‘IGF-I Controlled’ if the most temporally-related IGF-I measurement was normal for the local reference laboratory). Patient-reported outcomes (PROs) were evaluated using the PatientAssessed Acromegaly Symptom Questionnaire (PASQ). Results: No new safety signals were identified in the study. IGF-I SDS >2 decreased progressively from 88.4% of patients at baseline to 34.8% at year 5 at a mean dose(±SD) of 19.2(±12.9) mg/day; 63.3% of patients with a documented normal IGF-I SDS had a mean dose of 16.2(±9.03), while 1.9% had IGF-I SDS < -2 at a mean dose of 16.5(±5.81). 1795 Patients had at least 1 local pituitary imaging result reported: 71.1% of patients reported no change, 17.3% reported a decrease and 7.1% reported an increase in tumor size while 4.5% reported both an increase and a decrease. Scans reported as showing a meaningful change in tumor volume (n=264) were re-evaluated centrally by an independent expert: 54 were corroborated enlarged, 84 were decreased, 12 were read as both increased and decreased, 23 were read as no change and 40 inconclusive; thus the overall incidence of (corroborated) tumor increases was 3.0% and decreases 4.7%. In the overall cohort, AST and/or ALT were >3 × ULN at any time during PEGV treatment in 3.2% of patients. PASQ score was 15 (0-46) at baseline and 10 (0-41) at year 8. Summary: In this real world international study, overall biochemical control (i.e. normal IGF-I) progressively improved with pegvisomant, and was achieved in 63.3% patients by year 5. Improved IGF-I control was associated with improved symptoms of acromegaly. Importantly, in this large cohort of patients the incidence of pituitary tumor increase and liver test elevations were low, and similar to previously reported rates. One limitation of this observational study was that the PEGV dose may not have been adequately titrated to achieve IGF-I normalization. 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.

The relationship between IGF-I and -II concentrations and body composition at birth and over the first 2 months.

Background:Insulin-like growth factors (IGF)-I and -II play an important role in prenatal growth. During the first two months from birth, body fat doubles, and rapid weight gain during this time increases future risk of cardiometabolic disease.Objective:To determine if IGF measurements at birth associate with body composition and the trajectory of its changes in the first two months.Methods:Umbilical cord IGF-I and -II concentrations were measured in term infants. Air displacement plethysmography was performed at birth and two months. Fat mass (FM) and fat free mass (FFM) were corrected for infant length (L) to FM/L3 and FFM/L2 respectively.Results:In 601 (317 male) infants, IGF-I concentrations at birth were associated with FM/L3 and FFM/L2 Z-scores at birth (R2=0.05 and 0.04 respectively, P<0.001), and IGF-II concentrations were associated with FFM/L2 Z-scores at birth (R2=0.01, P=0.02). Lower IGF-I concentrations were weakly associated with increases in FM/L3 Z-scores over the first two months (R2= 0.01, P=0.003).Conclusion:IGF-I concentrations at birth are associated with adiposity and lean mass at birth and inversely with the trajectory of FM accumulation over the first two months. IGF-I measurements only account for a small amount of the variance in these measures.