Low Insulin-like Growth Factor-1 Research Articles

Long-Term Treatment for Laron Syndrome with IGF-1 Injection over 22 Years in Saudi Arabia: A Cohort Study

Introduction: Laron syndrome (LS) is a rare autosomal recessive disorder caused by mutations in the growth hormone (GH) receptor gene, resulting in GH resistance and reduced levels of insulin-like growth factor 1 (IGF-1). Patients with LS exhibit severe growth retardation, low IGF-1 levels, elevated basal GH, and poor response to GH stimulation. Recombinant IGF-1 is the only approved treatment and has been shown to improve linear growth. This study evaluates the long-term efficacy and safety of IGF-1 therapy in a large cohort of LS patients treated at King Faisal Specialist Hospital and Research Center (KFSH & RC), Riyadh, Saudi Arabia over 22 years. Methods: We conducted a retrospective review of medical records for 28 patients with growth hormone insensitivity syndrome, including 12 males and 16 females, treated with IGF-1 from 1998 to 2020. Patients were selected based on criteria including age over 2 years, height standard deviation score (SDS) ≤−2.8, normal or elevated GH secretion (>2.5 ng/mL), IGF-1 levels <50 ng/mL, and insensitivity to exogenous GH. IGF-1 was administered initially at 40 μg/kg/dose subcutaneously twice daily, escalating to a maximum of 120 μg/kg/dose as tolerated. Dosage was adjusted to minimize hypoglycemia risk, with blood glucose monitored frequently during hospitalization. In addition, molecular genetic results were reviewed for each patient in the cohort. Results: IGF-1 treatment significantly increased height velocity (HV) from a baseline of 3.4 cm/year to 6.5 cm/year in the first year (mean difference of 3.1 cm/year, p < 0.0001). In the second year, HV remained elevated at 5 cm/year (mean difference of 1.6 cm/year, p = 0.0015). Long-term follow-up over 10 years demonstrated sustained improvements in HV compared to baseline, with the most substantial gains occurring within the initial 5 years. Weight SDSs also showed significant improvement. Age at the start of therapy did not notably affect growth outcomes, though longer treatment durations were associated with greater growth. Ten disease-causing variants in the GHR gene were identified in 24 of the 28 LS patients. Conclusion: IGF-1 therapy significantly enhanced linear growth in children with Laron syndrome and was generally well tolerated. Although many patients did not reach normal adult height, the growth achieved with IGF-1 treatment was markedly better than expected without therapy. This study underscores the effectiveness of IGF-1 in improving growth outcomes and highlights the need for continued longitudinal studies to optimize treatment strategies and manage potential complications.

PPARγ alleviates damage to chorionic trophoblast cells induced by high glucose and high lipids through regulation of IGF-1.

Overweight and obesity are the most common high-risk conditions that increase the risk of adverse outcomes during pregnancy, childbirth, and the postpartum period. Dysfunctions in trophoblastic peroxisome proliferator-activated receptor gamma (PPARγ) contribute to a variety of related pregnancy disorders. This study investigated whether PPARγ influences chorionic trophoblast cell damage induced by high glucose (HG) and high lipid (HL) by regulating insulin-like growth factor-1 (IGF-1). Human trophoblast HTR-8/SVneo cells were exposed to HG and HL conditions to simulate damaged trophoblasts during pregnancy in vitro. Cell Counting Kit-8 (CCK-8) was used to assess cell proliferation. The Scratch test was used to test cell migration. Cell invasion ability was assessed by Transwell assay. ELISA was used to assess the inflammatory factor levels. Glucose, lactic acid, and adenosine triphosphate (ATP) levels were measured using biochemical kits. High glucose/HL inhibited the proliferation, migration, and invasion of HTR-8/SVneo cells. High glucose and HL increased tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and IL-6 expression while decreasing IL-10 expression. High glucose and HL decreased glucose uptake and ATP levels. High glucose and HL reduced the expressiofns of PPARγ, IGF-1, insulin receptor substrate (IRS) 1, IRS2, GLUT1, and GLUT4. High PPARγ expression promoted cell proliferation, migration, and invasion induced by HG and HL, increased glucose uptake and ATP levels and inhibited inflammation. Low IGF-1 expression inhibited cell proliferation, migration, and invasion under HG and HL conditions, reduced glucose uptake and ATP levels, and increased inflammation. Low IGF-1 expression reversed the effects of PPARγ on HTR-8/SVneo cells under HG and HL conditions. Peroxisome proliferator-activated receptor gamma alleviated HTR-8/SVneo cell damage induced by HG and HL by regulating IGF-1, suggesting a potentially effective approach for treating gestational obesity.

The impact of insulin resistance and glycaemic control on insulin-like growth factor-1 in patients with type 2 diabetes: a cross-sectional study

BackgroundType 2 diabetes mellitus (T2DM) is a multifaceted metabolic disorder. Over the past decade, the potential role of Growth Hormone (GH) and Insulin-like Growth Factor-1 (IGF-1) in the pathogenesis and progression of T2DM has garnered scientific interest. These hormones, while interrelated, exert differential effects on glucose homeostasis; GH elevates blood glucose levels, whereas IGF-1 sustains insulin secretion and augments insulin sensitivity.ObjectiveThe study aimed to investigate the impact of insulin resistance and glycaemic control on IGF-1 levels and to assess other risk factors influencing IGF-1 in T2DM.MethodsA cross-sectional study was conducted at the National Diabetes Centre, Baghdad, Iraq, from May 2020 to May 2021. Sixty patients with T2DM were evaluated for fasting plasma glucose (FPG), GH, IGF-1, HbA1c, HOMA-IR, HOMA-B, and anthropometric measures following a comprehensive history and physical examination, focusing on any variables that could influence their metabolic profile. Patients with Type 1 diabetes mellitus, thyroid disease, pituitary disease, chronic kidney disease, hepatic disease, and pregnancy were excluded from the study.ResultsPatients with poorly controlled diabetes (HbA1c > 8) exhibited significantly elevated IGF-1 levels compared to those with HbA1c < 8 (166 vs. 134, P = 0.016). The mean IGF-1 was significantly lower in patients with insulin resistance (IR) compared to those without IR (143 vs. 192, P = 0.001), with a significant negative correlation with Body Mass Index (BMI) and a significant positive correlation with HbA1c and Quantitative Insulin Sensitivity Index (QUICKI). Elevated IGF-1 levels were observed with increasing age, duration of T2DM, higher HbA1c, higher QUICKI, and lower BMI. No significant difference was found in IGF-1 values with regards to HOMA-B, fasting insulin, and waist-hip ratio.ConclusionPatients with poorly controlled T2DM exhibit higher IGF-1 levels, while those with obesity and high insulin resistance demonstrate lower IGF-1 levels. Further prospective studies are warranted to evaluate the potential of using IGF-1 to reduce insulin resistance and improve metabolic and glycaemic measures in individuals with T2DM and obesity or insulin resistance.

IGF-1 levels in the general population, heart failure patients, and individuals with acromegaly: differences and projections from meta-analyses-a dual perspective.

The complex relationship between insulin-like growth factor 1 (IGF-1) levels and heart failure (HF) is not fully understood, particularly across different populations and conditions. This meta-analysis aims to elucidate the dual perspectives of IGF-1 levels in the general population, HF patients, and individuals with treatment-naïve acromegaly, highlighting IGF-1 as a biomarker and potential therapeutic target in HF management. Studies were searched across multiple electronic databases up to January 2024 and independently identified by reviewers. The outcomes were analyzed using RevMan 5.4 and STATA 15. A total of 25 articles were ultimately included in the analysis. Six studies compared IGF-1 levels between HF patients and non-HF controls, revealing significantly lower IGF-1 levels in HF patients (mean difference -20.93; 95% CI -37.88 to -3.97; p = 0.02). This reduction was consistent across various HF subtypes and severities. In addition, individuals with intermediate IGF-1 levels had a lower risk of developing HF [risk ratio (RR) 0.78; 95% CI 0.74-0.83; p < 0.01] and HF-related mortality (RR 0.98; 95% CI 0.97, 0.99; p < 0.01) compared to those with low IGF-1 levels, suggesting a protective role for maintaining adequate IGF-1 levels. Conversely, treatment-naïve acromegaly patients, characterized by excessively high IGF-1 levels, showed a significantly higher incidence of both diastolic HF [odds ratio (OR) 9.08; 95% CI 6.20-13.29; p < 0.01] and systolic HF (OR 13.1; 95% CI 6.64-25.84; p < 0.01), implicating supraphysiological IGF-1 levels in adverse cardiac outcomes. Our meta-analysis highlights the complex interplay between IGF-1 levels and HF. We found that reduced IGF-1 levels are commonly observed in HF patients and are associated with an increased risk of HF and higher HF-related mortality. Conversely, excessively high levels, as observed in acromegaly, are linked to a higher incidence of HF. Based on these results, it is recommended that cardiac function be closely monitored in patients with reduced IGF-1 levels and in those with acromegaly. These findings suggest that IGF-1 could hold potential prognostic value for risk stratification in HF.

Evaluation of insulin-like growth factor-1 in apparently healthy infants and prepubertal Egyptian children with different nutritional statuses

Objectivesto estimate insulin-like growth factor-1 (IGF-1) levels in apparently healthy infants and prepubertal children and compare results among different nutritional statuses.MethodsOur cross-sectional work is a sub-study of a screening project for anemia and nutritional status. We included 252 apparently healthy infants and children with a mean age of 3.7 ± 1.3 years (1.1–6.6), with equal gender distribution. Data retrieved included breastfeeding and anthropometric measures. We tested the stored blood samples for IGF-1 levels. The sample size was reached when all kits were consumed.Resultsabnormal anthropometric measures were detected in 32.9%, either a single or multiple, and 86.5% were breastfed. Girls had significantly higher serum IGF-1 levels than boys (P: <0.001), which was noticeable in girls with abnormal nutritional status detected with anthropometry. Breastfeeding showed no significant association with IGF-1 levels. No significant difference was observed between IGF-1 levels between children with normal versus those with abnormal growth measures. Children with overweight or obesity had significantly lower IGF-1 than children with other body mass index (BMI) categories. Serum IGF-1 levels correlated positively with arm muscle area Z scores in infants and toddlers and weight and BMI Z scores in children between three and four. Also, IGF-1 correlated positively with the triceps skinfold Z score and arm muscle area Z score between four and five.ConclusionsAmong studied infants and prepubertal children, serum IGF-1 was significantly higher in girls than boys and was considerably lower in children with overweight or obesity. Breastfeeding showed no association with IGF-1 levels.

6996 Optimal Growth Hormone Response Despite Low Insulin-Like Growth Factor-1: Clinical Picture of an A67T IGF-1 Variant

Abstract Disclosure: E.M. Bomberg: Research Investigator; Self; Novo Nordisk. Z. Wu: Employee; Self; Quest Diagnostics. I. Motorykin: Employee; Self; Quest Diagnostics. J. Torkelson: None. N. Schmitz: None. A. Drilling: None. M.J. McPhaul: Employee; Self; Quest Diagnostics. B.S. Miller: Advisory Board Member; Self; Abbvie, Ascendis Pharma, Biomarin, Bristol-Myers Squibb, Eton Pharmaceuticals, EMD Serono, Endo Pharmaceuticals, GenSci, Novo Nordisk, Pfizer, Inc., Provention Bio, Sanofi, Tolmar. Consulting Fee; Self; Abbvie, Ascendis Pharma, Biomarin, Bristol-Myers Squibb, Eton Pharmaceuticals, EMD Serono, Endo Pharmaceuticals, GenSci, Provention Bio, Sanofi, Tolmar. Grant Recipient; Self; Alexion Pharmaceuticals, Inc., Abbvie, Aeterna Zentaris, Amicus, Foresee Pharmaceuticals, Lumos Pharma, Lysogene, Novo Nordisk, OPKO Health, Pfizer, Inc., Prevail Therapeutics, Sangamo Therapeutics. Research Investigator; Self; Alexion Pharmaceuticals, Inc., Abbvie, Aeterna Zentaris, Amicus, Foresee Pharmaceuticals, Lumos Pharma, Lysogene, Novo Nordisk, OPKO Health, Pfizer, Inc., Prevail Therapeutics, Sangamo Therapeutics. Speaker; Self; Biomarin, Novo Nordisk, Pfizer, Inc., Tolmar. Introduction: Insulin-like growth factor-1 (IGF-1) measurements are used for growth hormone (GH) deficiency screening and helpful in monitoring GH treatment effectiveness. However, IGF-1 variants have been reported with mass spectrometry (MS)-based assays, potentially limiting interpretation of reported results. Clinical Case: A 14-year-old male presented for short stature. Evaluation was non-revealing aside from low serum IGF-1 measured via liquid chromatography (LC)-MS assay (58 ng/mL; -3.8 standard deviation score [SDS]), and IGF-Binding Protein 3 (3.7 ug/mL; -1.7 SDS). Height was 148.2 cm (1st percentile, -2.08 SDS; mid-parental height 172.7 cm [31st percentile, -0.48 SDS]), pubertal exam Tanner stage 2, and bone age 2.5 years delayed. A GH stimulation test showed a peak GH of 8.1 ug/L; brain MRI was normal. GH was started at 0.29 mg/kg/wk. One month later, IGF-1 remained low (89 ng/mL; -3.2 SDS) and GH was increased to 0.36 mg/kg/wk, and over time to 0.52 mg/kg/wk due to persistently low IGF-1 (-2.9 to -2.3 SDS), despite reports of good compliance and significant catch-up growth (height increased to 19th percentile, -0.84 SDS). He reported no significant side effects during GH treatment. At 17.5 years old, he returned to clinic reporting self-discontinuing GH 1 month prior. Height was at the 27th percentile (171.5 cm, -0.59 SDS), he was fully pubertal, IGF-1 128 ng/mL (-3.1 SDS), and bone age 1.5 years delayed. Further review of IGF-1 linked reports accompanying lab values directly entered into the electronic health record (EHR; starting 2021) described the presence of a rare heterozygous IGF-1 functional variant with unknown clinical significance based on MS data. Concentration of the variant was expected to be identical to that reported for the wild type IGF-1 protein, potentially explaining the lower than expected values. Analysis of the raw LC-MS data (variant peak at m/z 1098.09, isotopic peak index [IP6], relative retention time [rRT]=0.00 min) was consistent with either an A67T or A70T IGF-1 variant. To resolve this ambiguity, the specimen was reanalyzed with an LC-tandem MS/MS fragmentation method, which identified distinguishing peaks at m/z 503.28 (y5 ion) and 305.18 (y3 ion) characteristic of A67T, a known benign variant. Conclusions: Benign IGF-1 variants should be considered in cases of unexplained low IGF-1 levels, including when these remain low despite increasing GH doses, good adherence, and optimal growth velocity. Presence of IGF-1 variants should not affect GH stimulation results (e.g., GH levels), however, may lower reported IGF-1 levels used to determine need for diagnostic testing and followed when monitoring GH response. Careful review of IGF-1 lab reports and full abstraction of these into the EHR should be performed. Knowing a variant is benign could help providers set lower wild-type IGF-1 targets when monitoring GH response to avoid unnecessarily high GH doses. Presentation: 6/3/2024

12566 Adult Growth Hormone Deficiency, Replacement Therapy Use, and IGF1 Levels in Association with Physical, Psychosocial, and Neurocognitive Outcomes Among Childhood Cancer Survivors

Abstract Disclosure: T. Yoshida: None. J.L. Baedke: None. H. Wang: None. C.H. Yu: None. C.L. Wilson: None. D.A. Mulrooney: None. S.B. Dixon: None. I. Huang: None. T.M. Brinkman: None. K.R. Krull: None. S. Mostoufi-Moab: None. J. Miguel Martínez: None. K.K. Ness: None. M.M. Hudson: None. Y. Yasui: None. A. Delaney: None. Background: Adult growth hormone deficiency (aGHD) is a common and often untreated late effect among childhood cancer survivors. Untreated aGHD likely adds to the burden of health outcomes in survivors already experiencing cancer treatment related late toxicities. As comprehensive data on the consequences of untreated aGHD in survivors are scarce, we assessed the clinical impact of untreated aGHD among survivors, together with socioeconomic factors as potential contributing factors, utilizing a large, clinically characterized cohort of childhood cancer survivors. Methods: 3902 five-year survivors ≥ 18 years old [median (25th-75th percentile) age, 31.7y (25.2-40.0); age at cancer diagnosis 8.1y (3.5-13.6); 47.5% female] were examined. We assessed the: 1) proportion of survivors with aGHD on GH therapy (GHT); 2) association between GHT and socioeconomic factors (e.g., household income, area deprivation index) by multivariable logistic regression; and 3) associations between age- and sex-adjusted insulin-like growth factor 1 (IGF1) z-score and prevalence of clinically-assessed (i.e., body composition, metabolic/cardiovascular factors, neurocognitive function) and self-reported [i.e., quality of life (QoL), emotional symptom] outcomes by multivariable logistic regression with trend test, adjusting for potential confounders (e.g., radiation to the hypothalamic-pituitary region). Results: aGHD was observed in 9.1% (354/3902) of survivors; among them, 9.0% (32/354) were on GHT. Survivors on GHT were more likely to have higher household income, hold health insurance, and reside in less socioeconomically disadvantaged neighborhoods, compared to survivors with untreated aGHD. Socioeconomic factors had significant independent associations with GHT use in multivariable analysis [e.g., annual household income &amp;lt;$40,000 vs. ≥$80,000, adjusted odds ratio (aOR) of GHT use, 0.28; 95% confidence interval (CI), 0.08-0.86]. Lower IGF1 z-score (IGF1 z-score ≤ -2, vs. IGF1 z-score &amp;gt;0) was associated with a higher prevalence of various outcomes (aOR, 95% CI), such as abdominal obesity (2.56, 1.98-5.26), weak handgrip strength (2.49, 1.65-3.73), hypertension (1.47, 1.06-2.04), abnormal glucose metabolism (2.07, 1.49-2.86), impaired health-related QoL (e.g., physical functioning, 1.97, 1.35-2.86), depression (1.58, 1.06-2.33), and impairment in multiple neurocognitive functions (e.g., verbal reasoning, a global measure of intelligence, 2.22, 1.49-3.30) with a dose-response relationship. Conclusions: Our data support a negative impact of untreated aGHD on physical, psychosocial, and neurocognitive outcomes among survivors and suggest the potential of GHT to improve QoL of survivors with aGHD. As lower socioeconomic status may affect survivors’ access to GHT, this disparity should be considered in interventions evaluating GHT for survivors with aGHD. Presentation: 6/3/2024

6743 Decline in IGF-1 after surgery of the nonfunctioning pituitary neuroendocrine tumor

Abstract Disclosure: J. Sugata: None. S. Fujio: None. R. Makino: None. T. Hanada: None. R. Hanaya: None. Background: Patients undergoing surgical treatment for nonfunctioning pituitary neuroendocrine tumors (PitNET) may experience impaired secretion of growth hormone (GH). The optimal timing for assessing GH secretory function postoperatively remains unclear. In our department, we typically conduct hormone-loading tests three months after surgery. However, even in some cases without a diagnosis of growth hormone deficiency (GHD) at that point, there might be a gradual decline in Insulin-like growth factor-1 (IGF-1). Methods: We studied patients who exhibited peak GH levels &amp;gt; 1.8ng/ml in an insulin tolerance test (ITT) three months after undergoing surgery for nonfunctioning PitNET. We evaluated the levels of IGF-1 during the last observation, excluding cases where reoperation or radiosurgery was performed. Results: We identified 67 cases (29 males, 38 females) meeting the study criteria, with a median age of 54 years. The median follow-up time spanned 6 years (range 1-13 years). The median standard deviation (SD) scores of IGF-1 three months after surgery were -0.96, with 14 cases (21%) below -2.0 SD. At the end of the follow-up period, the median SD scores of IGF-1 were -1.31. This was significantly lower than the three-month time point (p&amp;lt;0.01), and 21 cases (31%) recorded were below -2.0 SD. In 6 cases suspected of severe GHD due to subjective symptoms or decreased IGF-1, ITT, or GH-releasing peptide-2 were retested. Among these, 2 cases were diagnosed with severe GHD, while the remaining demonstrated normal secretion of GH despite the low concentration of IGF-1. The IGF-1 SD scores at the end of follow-up and the three-month time-point exhibited a significant correlation (R2=0.74, p&amp;lt;0.01). However, no correlation was found between IGF-1 scores and peak GH concentration, age, tumor size, pituitary apoplexy, or preoperative IGF-1 SD scores. Conclusions: IGF-1 exhibited a progressive decrease in the majority of cases without severe GHD, with some cases showing reductions greater than -2.0 SD. Our findings emphasize the importance of cases with long-term clinical follow-up low IGF-1 after PitNET surgery, even when GH secretion appears normal. Presentation: 6/1/2024

8193 Mauriac Syndrome Uncovered, The Insulin Access Impact in Type 1 Diabetes Mellitus

Abstract Disclosure: D.H. Sacoto: None. R. Belokovskaya: None. K. Gebran: None. K. Madani: None. A. De Rosairo: None. D. Patel: None. A.A. Franco-Akel: None. Introduction: Mauriac syndrome is a rare complication of poorly controlled type 1 diabetes mellitus (T1DM). It is reversible with appropriate glycemic control; however, factors affecting healthcare access to insulin are leading to its re-emergence. We present a case of Mauriac syndrome as a complication of uncontrolled T1DM due to insulin access. Case: A 22-year-old Hispanic female with a history of T1DM presented to the emergency department with a two-day history of abdominal pain. She was diagnosed with diabetic ketoacidosis (DKA) (blood glucose: 802 mg/dL; pH 7.14; bicarbonate: 7 mmol/L; anion gap: 34; positive serum ketones). Incidental transaminitis was noted. R factor showed a cholestatic pattern of 0.6 (AST: 136 U/L, ALT: 49 U/L, alkaline phosphatase:286 U/L). US liver revealed an enlarged liver (craniocaudal: 16.5 cm) without biliary obstruction. Her phenotype consisted of short stature (4.8 feet) with a moon face and a protuberant abdomen. Her records revealed a normal karyotype 46 XX, with a bone age of 4 years, pubertal delay, low insulin-like growth factor-1 levels (58 ng/mL), and long-standing hyperlipidemia. Over the years, she experienced multiple DKA episodes in the context of uncontrolled T1DM (hemoglobin A1c:11-13 %). The main problem identified included difficulty with insulin access, specifically related to insurance coverage as well as managing her disease. Glycemic control has significantly improved with continuous glucose monitoring and updated insurance status. Discussion: Mauriac syndrome is characterized by hepatomegaly, transaminitis, delayed pubertal maturation, growth failure, and cushingoid features. Hyperglycemia leads to intrahepatic glycogen deposition and the lack of insulin to lipolysis and ketosis, leading to high cortisol levels and growth delay. Factors leading to uncontrolled T1DM include lack of insulin access. The high cost is considered a major barrier, with an average price per millimeter of insulin tripled from 231 to 736 US dollars. Even patients with insurance tend to have high co-pays and deductibles, with a 61% chance of delay or denial due to pre-approval requirements. Lower socioeconomic status, lack of access to devices such as insulin pumps, migratory status, social support, and ethnic background are other factors related to glycemic control. Our patient belongs to a family of immigrants with low socioeconomic status, which might have contributed to the development of Mauriac syndrome. Since clinical and laboratory abnormalities are reversible with appropriate glycemic control, advocating for policies that facilitate better insulin access is paramount. Presentation: 6/2/2024

Insulin-like growth factor-1 in cirrhosis is linked to hepatic dysfunction and fibrogenesis and predicts liver-related mortality.

We aimed to characterise insulin-like growth factor-1 (IGF-1) signalling in patients with advanced chronic liver disease (ACLD). Consecutive patients undergoing hepatic venous pressure gradient [HVPG] measurement were prospectively included. Clinical stages were defined as follows: probable ACLD (pACLD): liver stiffness ≥10 kPa and HVPG ≤5 mmHg, S0: mild PH (HVPG 6-9 mmHg), S1: clinically significant PH (CSPH), S2: CSPH with varices, S3: past variceal bleeding, S4: past/current non-bleeding hepatic decompensation and S5: further decompensation. In total, 269 patients were included; 105 were compensated (pACLD: n = 18; S0: n = 30; S1: n = 20; S2: n = 37), and 164 were decompensated (S3: n = 11; S4: n = 89; S5: n = 64). Median levels of IGF-1 decreased with progressive cirrhosis (from pACLD: 88.5 ng/mL to S5: 51.0 ng/mL; p < 0.001). Patients with CSPH had significantly lower IGF-1 levels (63.5 ng/mL vs. 81.0 ng/mL; p = 0.001). IGF-1 showed an independent negative association with body mass index (BMI; aB: -1.56; p < 0.001), enhanced liver fibrosis (ELF) test (aB: -8.43; p < 0.001), MELD (aB: -1.13; p = 0.042) and age (per 10 years; aB: -6.87; p < 0.001). IGF-1 exhibited an excellent AUROC (0.856) for the prediction of liver-related death at 6 months of follow-up. Lower IGF-1 (per 10 ng/mL) was linked to higher risk of (further) decompensation (0.90; 95% CI: 0.83-0.98; p = 0.016), acute-on-chronic liver failure (ACLF; asHR: 0.80; 95% CI: 0.68-0.93; p = 0.004) and liver-related death (asHR: 0.76; 95% CI: 0.63-0.91; p = 0.004). Decreased levels of IGF-1 reflect impaired hepatic function and fibrogenesis in patients with cirrhosis, which seems particularly relevant in obesity since low IGF-1 was independently linked to high BMI. Lower IGF-1 in cirrhosis predicts decompensation, ACLF and liver-related death.

Slow growth and short stature in children with attention deficit hyperactivity disorder (ADHD): aretrospective study of 493 children who underwent growth hormone provocation testing at one tertiary paediatric endocrine centre.

We hypothesised that growth hormone (GH) deficiency (GHD) in children with attention deficit hyperactivity disorder (ADHD) is rare. This study aimed to determine any distinct clinical or biochemical parameters, including GH provocation testing, in children with ADHD on psychostimulants or idiopathic short stature (ISS). Retrospective cross-sectional study of children who had GH provocative testing between 1998 and 2013 at one tertiary paediatric endocrine centre. Clinical data included age, sex, anthropometry, pubertal staging, bone age, diagnostic code as per the European Society Paediatric Endocrinology (ESPE), GH provocation test results, thyroid function tests, serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein-3 (IGFBP-3) levels. Four hundred ninety-three subjects underwent GH provocation testing for investigation of short stature to exclude GHD during the study period. Fifty-one children hada diagnosis of ADHD. In the remaining children, the diagnosis was Idiopathic short stature (n=240), GHD +/- hypopituitarism (n=60), and 142 subjects had other causes of short stature. Children with ADHD were older, had higher height and weight SDS and were GH-sufficient. All 51 children with ADHD had a normal serum IGFBP-3, while 20 out of these 51 subjects had a low serum IGF-1. GHD in children with ADHD on psychostimulant medication is rare. GH testing in children with ADHD may not be necessary, particularly if serum IGFBP-3 is in thenormal range. We suggest IGFBP-3 could be used as a surrogate marker of GH sufficiency in children with ADHD. However, this needs to be confirmed with a larger study group.

Anterior pituitary hormone dysfunction among individuals with complete heart block requiring pacemaker.

Background & objectives Neuronal hypoxia associated with conditions like traumatic brain injury and cardiac tachyarrhythmia has been implicated in causing hypopituitarism. Individuals with complete heart block (CHB) may be predisposed to develop anterior pituitary hormone dysfunction in the long term. The objective of this study was to investigate anterior pituitary hormone functions in individuals after CHB. Methods This prospective cohort study included 30 individuals (21 men and 9 women) with CHB requiring pacemaker implantation, who were evaluated at admission and then at a mean follow up of 12.4 ± 2.2 months to look for development of any degree of hypopituitarism. In addition to the measurement of hormones like follicle-stimulating hormone (FSH), luteinising hormone (LH), thyroid stimulating hormone (TSH), total tetra iodothyronines (TT4), free tetraiodothyronines (FT4), cortisol, insulin-like growth factor-1 (IGF-1), testosterone and estradiol, a fixed-dose glucagon stimulation test (GST) was performed to assess growth hormone (GH) and adrenocorticotrophic hormone (ACTH) axis. Results The mean age of the participants was 64.9 ± 11.3 yr. At follow up evaluation, 17 (56.7%) had low serum IGF-1, and among them, seven (23%) had growth hormone deficiency (GHD) (peak GH <1.0 ng/ml after GST). Six participants (20%) had ACTH deficiency (peak cortisol <9 ug/dl after GST) and one had TSH deficiency. None had prolactin (PRL) or gonadotropin deficiency. Overall, hormone deficiencies were observed in nine patients (30%). Interpretation & conclusions This pilot study detected loss of anterior pituitary hormones in a significant number of individuals of CHB at 12 months follow up. Unrecognised hypopituitarism may have resulted in significant morbidity and mortality in these individuals.

Can the reduced GH, IGF-1, and ovarian steroids concentrations be considered as suspected biomarkers of age-associated functional deficit in mares?

In humans' and experimental animals’ components of the somatotropic axis, such as growth hormone (GH) and insulin-like growth factor 1 (IGF-1) concentrations, decrease with advancing age. Although there is evidence regarding IGF-1, the effect of age on GH in mares, as well as the relationships between both parameters, have not yet been elucidated. On the other hand, although GH and IGF-1 are related to follicular development, it is unknown if they could be correlated with the circulating concentrations of ovarian steroids in mares, as occurs in other species. The hypothesis of this study was that both GH and IGF-1 could experience physiological changes with advancing age also in mares, and that both GH/IGF-1 could be correlated with oestradiol-17β (E2) and progesterone (P4), as recorded for other species. Hence, the objective of this study was to evaluate the concentrations of GH, IGF-1, E2, and P4 in mares, according to the different ages. Blood samples were drawn from 56 healthy cyclic Spanish Purebred mares belonging to four different age groups: 6–9 years, 10–13 years, 14–16 years and >16 years. Mares aged 6–9 years and 10–13 years showed higher GH concentrations (P < 0.05) than mares of 14–16 and >16 years; and mares aged 14–16 showed higher GH concentrations (P < 0.05) than >16 years (P < 0.05). Mares aged >16 years showed lower IGF-1 concentrations (P < 0.05) than mares of 6–9, 10–13 and 14–16 years (P < 0.05). The concentrations of E2 and P4 showed no significant differences among different age groups. Both GH and IGF-1 were not correlated with each other or with E2 and P4. The concentrations of E2 and P4 did not change with age. Advancing age leads to a decrease in the activity of the somatotropic axis in physiological cyclic mares, represented by a significant GH reduction, which, however, was ascribed for IGF-1 exclusively to mares over 16 years of age, without alterations in steroid hormone patterns.

Assessment of Anthropometric and Pubertal Growth of Children and Adolescents with Type 1 Diabetes Mellitus

Abstract Background Type 1 diabetes mellitus (T1DM) is a wasting disease which is characterized by a severe deficiency or absence of insulin. It can interfere with growth and pubertal development, especially in uncontrolled patients with diabetes. Aim of the Work Our primary aim was to assess the anthropometric measures and pubertal growth of children and adolescents with T1DM regularly attending Pediatric and Adolescents Diabetes Unit (PADU), Ain Shams University. Our secondary aim was to detect risk determinants affecting these measures and their link to glycemic control. Patients and Methods This cross-sectional observational study was carried out on 200 children and adolescents with T1DM attending the PADU clinic. Patients were assessed using anthropometric measurements, lipid profile (Fasting serum triglycerides, total cholesterol, HDL and LDL) and HbA1c%. Those with short stature were further evaluated using insulin like growth factor1 (IGF1), bone age, lipid profile and thyroid profile. while those with delayed puberty were evaluated using sex hormones. Results we found that 12.5% of our patients were short (SD&amp;lt;-2), Cut off point of IGF-1 SDS (≤ -1.2) and GF1( 2ng/ml) was low in72% of them. Diabetic patients with short stature have significantly earlier age of onset of diabetes, earlier age at diagnosis and longer duration of diabetes compared to those with normal stature (P &amp;lt; 0.05). Additionally, patients with short stature and those with delayed puberty have higher HbA1c. Patients with short stature also have higher lipid profile and lower IGF1 compared to those with normal stature (p &amp;lt; 0.05). Conclusion Children with uncontrolled T1DM are at risk of being short and had delayed puberty. IGF-1 level can be used as a screening test for short stature in diabetic children.

Serum insulin-like growth factor-1 and leptin concentrations in Black Bengal goats at different ages and gestation periods and their relationship to kid growth performance.

The impact of maternal hormone concentration on kid growth performance in relation to insulin-like growth factor 1 (IGF-1) and leptin is minimal. This study examined IGF-1 and leptin levels at varying ages and gestation periods for their correlation with Black Bengal goat kids' growth during the preweaning phase. Blood samples were collected from 43 dams with different reproductive cycles and 28 prepubertal goats to measure serum concentrations of IGF-1 and leptin. Among dams, both hormones were investigated in different age ranges (<2, 2-3, 3-4, and >4 years old) and reproductive cycles (non-pregnancy, early gestation (1-50 days), mid-gestation (51-100 days), late gestation (101-135 days), and the last 15 days before delivery). After delivery, 65 kids from 34 dams were weighted weekly for 8 weeks to calculate average daily weight gain (ADG) at 0-4 weeks (ADG0-4 W) and 4-8 weeks (ADG4-8 W) and growth performance, including weight (W), height (H), length (L), chest girth (C) measured at birth (W0, H0, L0, and C0) and at 10 weeks of age (W10, H10, L10, and C10) were related to hormone serum concentrations in their dams at different gestation periods including the last 15 days before delivery. Dams had higher mean serum IGF-1 (p < 0.001) and leptin (p < 0.05) than prepubertal goats. Dams at late gestation had higher IGF-1 concentrations than those at early and mid-gestation and during the last 15 days before delivery. However, it was consistent with non-pregnant goats. The kid's growth performance correlated positively with IGF-1 concentration, which was collected in the last 15 days before delivery. Multivariate analysis showed that ADG0-4 W was higher in kids born from dams with high IGF-1 than those with low IGF-1 measured during the last 15 days of delivery, whereas leptin tended to have a similar effect. Serum IGF-1 and leptin concentrations of dams measured during the last 15 days before delivery were associated with kid's growth during the preweaning period.

The positive impact of smoking on poor sleep quality is moderated by IGF1 levels in cerebrospinal fluid: a case-control study among Chinese adults.

Previous research indicates associations between cigarette smoking, insulin-like growth factor-1 (IGF1), and sleep disturbances. This study aimed to examine the association between smoking and sleep quality and investigate the moderating role of IGF1. This case-control study involved 146 Chinese adult males (53 active smokers and 93 non-smokers) from September 2014 to January 2016. Sleep quality and disturbances were evaluated using the Pittsburgh Sleep Quality Index (PSQI), which includes seven scales. Pearson correlation analysis and logistic regression analysis were utilized to examine the link between IGF1 levels in cerebrospinal fluid (CSF) and PSQI scores. The effect of IGF1 was assessed using the moderation effect and simple slope analysis, with adjustments made for potential confounders. Active smokers exhibited significantly higher global PSQI scores and lower IGF1 levels in CSF compared to non-smokers. A significant negative correlation was observed between IGF1 and PSQI scores (â = -0.28, P < 0.001), with a stronger association in non-smokers (Pearson r = -0.30) compared to smokers (Pearson r = -0.01). Smoking was associated with higher global PSQI scores (â = 0.282, P < 0.001), and this association was moderated by IGF1 levels in CSF (â = 0.145, P < 0.05), with a stronger effect at high IGF1 levels (Bsimple = 0.402, p < 0.001) compared to low IGF1 levels (Bsimple = 0.112, p = 0.268). Four subgroup analysis revealed similar results for sleep disturbances (Bsimple = 0.628, P < 0.001), with a marginal moderation effect observed on subjective sleep quality (Bsimple = 0.150, P = 0.070). However, independent associations rather than moderating effects were observed between IGF1 and sleep efficiency and daytime disturbance. We provided evidence to demonstrate the moderation effect of IGF1 on the relationship between smoking and sleep in CSF among Chinese adult males.

Sex-based differences in growth-related IGF1 signaling in response to PAPP-A2 deficiency: comparative effects of rhGH, rhIGF1 and rhPAPP-A2 treatments

BackgroundChildren with pregnancy-associated plasma protein-A2 (PAPP-A2) mutations resulting in low levels of bioactive insulin-like growth factor-1 (IGF1) and progressive postnatal growth retardation have improved growth velocity and height following recombinant human (rh)IGF1 treatment. The present study aimed to evaluate whether Pappa2 deficiency and pharmacological manipulation of GH/IGF1 system are associated with sex-specific differences in growth-related signaling pathways.MethodsPlasma, hypothalamus, pituitary gland and liver of Pappa2ko/ko mice of both sexes, showing reduced skeletal growth, and liver of these mice treated with rhGH, rhIGF1 and rhPAPP-A2 from postnatal day (PND) 5 to PND35 were analyzed.ResultsReduced body and femur length of Pappa2ko/ko mice was associated with increases in: (1) components of IGF1 ternary complexes (IGF1, IGFBP5/Igfbp5, Igfbp3, Igfals) in plasma, hypothalamus and/or liver; and (2) key signaling regulators (phosphorylated PI3K, AKT, mTOR, GSK3β, ERK1/2 and AMPKα) in hypothalamus, pituitary gland and/or liver, with Pappa2ko/ko females having a more prominent effect. Compared to rhGH and rhIGF1, rhPAPP-A2 specifically induced: (1) increased body and femur length, and reduced plasma total IGF1 and IGFBP5 concentrations in Pappa2ko/ko females; and (2) increased Igf1 and Igf1r levels and decreased Ghr, Igfbp3 and Igfals levels in the liver of Pappa2ko/ko females. These changes were accompanied by lower phospho-STAT5, phospho-AKT and phospho-ERK2 levels and higher phospho-AMPK levels in the liver of Pappa2ko/ko females.ConclusionsSex-specific differences in IGF1 system and signaling pathways are associated with Pappa2 deficiency, pointing to rhPAPP-A2 as a promising drug to alleviate postnatal growth retardation underlying low IGF1 bioavailability in a female-specific manner.

Very low serum IGF-1 levels are associated with vertebral fractures in adult males with beta-thalassemia major.

Patients with beta-thalassemia major (BTM) often develop several endocrine disorders due to chronic iron overload. They are also prone to osteoporosis and vertebral fractures. Plasmatic insulin-like growth factor-1 (IGF-1) levels are often low in subjects with BTM, which origin is multifactorial. The aim of this study was to evaluate a possible relationship between serum IGF-1 levels and the presence of osteoporosis and/or vertebral fractures. We retrospectively evaluated the occurrence of vertebral fractures in 30 adult male patients affected by BTM (mean age 43.3 ± 7.9years) with low serum IGF-1 (median value 52.4ng/ml, 38.5-83.4). Only 6 of them (20.0%) were diagnosed with GH deficiency (GHD) after GHRH/arginine stimulation test, while 23 (76.7%) had osteoporosis and 12 (40.0%) had known vertebral fractures. All patients except one also showed at least one endocrine disorder. Serum IGF-1 was significantly lower in BTM patients with vertebral fractures compared to patients without vertebral fractures (U = 41.0, p = 0.005) while it was not significantly different between patients with low bone mass compared to patients without low bone mass. The diagnosis of GHD was significantly associated with lower serum IGF-1 (p = 0.001) and vertebral fractures (p = 0.002) but not with low bone mass. After ROC analysis, we found that very low IGF-1 (≤ 50.0ng/dl) was associated with vertebral fractures (sensitivity 83.3%, specificity 75.0%) and was also predictive of GHD (sensitivity 75.0%, specificity 100.0%). Our study shows that, in male patients with BTM, serum IGF-1 ≤ 50.0ng/dl is a marker of vertebral fractures and it is predictive of a diagnosis of GHD.

Early IGF-1 receptor inhibition in mice mimics preterm human brain disorders and reveals a therapeutic target.

Besides recent advances in neonatal care, preterm newborns still develop sex-biased behavioral alterations. Preterms fail to receive placental insulin-like growth factor-1 (IGF-1), a major fetal growth hormone in utero, and low IGF-1 serum levels correlate with preterm poor neurodevelopmental outcomes. Here, we mimicked IGF-1 deficiency of preterm newborns in mice by perinatal administration of an IGF-1 receptor antagonist. This resulted in sex-biased brain microstructural, functional, and behavioral alterations, resembling those of ex-preterm children, which we characterized performing parallel mouse/human behavioral tests. Pharmacological enhancement of GABAergic tonic inhibition by the U.S. Food and Drug Administration-approved drug ganaxolone rescued functional/behavioral alterations in mice. Establishing an unprecedented mouse model of prematurity, our work dissects the mechanisms at the core of abnormal behaviors and identifies a readily translatable therapeutic strategy for preterm brain disorders.

Association between Expression of Insulin-like Growth Factor-1 (IGF-1), IGF-1 Receptor (IGF-1R), and Hypertension-Mediated Organ Damage (HMOD) Parameters in Leukocytes and Plasma of Children/Adolescents with Primary Hypertension.

A decrease in IGF-1 is often linked to inflammation. Low systemic and local IGF-1 production and downregulation of IGF-1R expression may precede and predict PH development in children/adolescents. Leukocyte mRNA expression of IGF-1 and its receptor (IGF-1R) and plasma IGF-1 were measured in a group of 39 PH children/adolescents (29 boys and 10 girls) and 35 age-matched normotensive children (19 boys and 16 girls) using the RT-PCR and ELISA tests. The expression of the IGF-1R protein was assessed by flow cytometry. Plasma IGF-1 concentration was evaluated with ELISA. The expression of IGF-1 and IGF-1R and plasma concentrations of IGF-1 did not differ between groups. However, the PH children had a decreased percentage in IGF-1R-bearing lymphocytes (p = 0.02) and monocytes (p = 0.0003), as well as a low density of IGF-R in monocytes (p = 0.02). The IGF-1 expression was negatively correlated with pulse-wave velocity (PWV) (r = -0.49), systolic blood pressure (SBP) (-0.44), and carotid intima-media thickness (cIMT) (-0.43). The IGF-1R expression was negatively correlated with PWV (r = -0.42) and SBP (r = -0.41). Our results suggest that early subclinical hypertensive arterial injury is associated with lower activity of IGF-1-IGF-1R expression and loss of protective actions.