Low IGF-1 Levels Research Articles

Short stature related to Growth Hormone Insensitivity (GHI) in childhood.

Linear growth during childhood is the result of the synergic contribution of different factors. The best growth determinant system during each period of life is represented by the growth hormone-insulin-like growth factor axis (GH-IGF), even if several other factors are involved in normal growth. Within the broad spectrum of growth disorders, an increased importance has been placed on growth hormone insensitivity (GHI). GHI was reported for the first time by Laron as a syndrome characterized by short stature due to GH receptor (GHR) mutation. To date, it is recognized that GHI represents a wide diagnostic category, including a broad spectrum of defects. The peculiar characteristic of GHI is the low IGF-1 levels associated with normal or elevated GH levels and the lack of IGF-1 response after GH administration. Recombinant IGF-1 preparations may be used in the treatment of these patients.

The STC2-PAPP-A-IGFBP4-IGF1 axis and its associations to mortality and CVD in T2D.

Physiologically, pregnancy-associated plasma protein-A (PAPP-A) serves to liberate bound IGF1 by enzymatic cleavage of IGF-binding proteins (IGFBPs), IGFBP4 in particular. Clinically, PAPP-A has been linked to cardiovascular disease (CVD). Stanniocalcin-2 (STC2) is a natural inhibitor of PAPP-A enzymatic activity, but its association with CVD is unsettled. Therefore, we examined associations between the STC2-PAPP-A-IGFBP4-IGF1 axis and all-cause mortality and CVD in patients with type 2 diabetes (T2D). We followed 1284 participants with T2D from the ADDITION trial for 5 years. Circulating concentrations of STC2, PAPP-A, total and intact IGFBP4 and IGF1 and -2 were measured at inclusion. End-points were all-cause mortality and a composite CVD event: death from CVD, myocardial infarction, stroke, revascularisation or amputation. Survival analysis was performed by Cox proportional hazards model. During follow-up, 179 subjects presented with an event. After multivariable adjustment, higher levels of STC2, PAPP-A, as well as intact and total IGFBP4, were associated with all-cause mortality; STC2: hazard ratio (HR) = 1.84 (1.09-3.12) (95% CI); P = 0.023, PAPP-A: HR = 2.81 (1.98-3.98); P < 0.001, intact IGFBP4: HR = 1.43 (1.11-1.85); P = 0.006 and total IGFBP4: HR = 3.06 (1.91-4.91); P < 0.001. Higher PAPP-A levels were also associated with CVD events: HR = 1.74 (1.16-2.62); P = 0.008, whereas lower IGF1 levels were associated with all-cause mortality: HR = 0.51 (0.34-0.76); P = 0.001. This study supports that PAPP-A promotes CVD and increases mortality. However, STC2 is also associated with mortality. Given that STC2 inhibits the enzymatic effects of PAPP-A, we speculate that STC2 either serves to counteract harmful PAPP-A actions or possesses effects independently of the PAPP-A-IGF1 axis. PAPP-A has pro-atherosclerotic effects and exerts these most likely through IGF1. IGF1 is regulated by the STC2-PAPP-A-IGFBP4-IGF1 axis, where STC2, an irreversible inhibitor of PAPP-A, has been shown to reduce the development of atherosclerotic lesions in mice. We examined the association of this axis to mortality and CVD in T2D. We demonstrated an association between PAPP-A and CVD. All components of the STC2-PAPP-A-IGFBP4-IGF1 axis were associated with mortality and it is novel that STC2 was associated with mortality in T2D. Our study supports that inhibition of PAPP-A may be a new approach to reducing mortality and CVD. Whether modification of STC2 could serve as potential intervention warrants further investigation.

Early detection methods of chronic diabetic nephropathy in diabetes mellitus patients in primary health services

Introduction: The prevalence of diabetic kidney disease increases along with the increase in the number of patients with diabetes mellitus. Early detection of diabetic nephropathy in DM patients is an essential step in preventing the incidence of diabetic kidney disease. The study aimed to obtain a method of early detection of diabetic kidney disease in DM patients in primary health care via identifying factors associated with decreased glomerular filtration rate (GFR). Methods: We conducted a case-controlled study at the public health center in Bantul. The research subjects were patients at Kasihan 1 public health center aged 18-75 years. In-depth interviews will be conducted to obtain clinical and social risk factors for GFR decreasing as an early detection tool for diabetic nephropathy (DN) incidence. The IGF-1 levels were checked using ELISA. The Pearson correlation test observed a significant association between patient risk factors and GFR. Results: This study is expected to obtain a model of the method of early detection of chronic diabetic kidney disease in diabetes mellitus patients in primary health services. The results showed that the GFR was related to systolic blood pressure, diastolic blood pressure, hyperglycemia, nicotine levels, and IGF-1 levels (P&lt;0.00). Increased nicotine levels, increased blood pressure, hyperglycemia, and decreased levels of IGF-1 are associated with decreased GFR. Identifying factors related to the glomerular filtration rate can be used to predict impaired renal function. Conclusion: Reduced glomerular filtration rates are linked to higher nicotine levels, higher blood pressure, hyperglycemia, and lower IGF-1 levels.

Diagnostic Value of IGF-1 in Growth Hormone-Deficient Children: Is a Second Growth Hormone Stimulation Test Necessary?

we assessed the diagnostic accuracy of insulin-like growth factor (IGF) 1 measurements with 1 growth hormone stimulation test (GHST) vs performing 2 GHSTs as the standard test to confirm the diagnosis of growth hormone deficiency (GHD) in children. We retrospectively analyzed the baseline characteristics, anthropometric measurements, and laboratory data of 703 children with short stature, aged 4-14 years (mean age, 8.46 ± 2.7 years), who had undergone 2 GHSTs. We compared the diagnostic values of IGF-1 levels by using a cut-off value of ≤0 SD score, along with results of a single clonidine stimulation test (CST). We evaluated the false-positive rate, specificity, likelihood ratio, and area under the curve (AUC) of the 2 diagnostic methods. GHD was diagnosed if the peak growth hormone level was <7 ng/mL on 2 GHSTs. Of the 724 children, 577 (79.7%) had a low IGF-1 level (mean 104.9 ± 61.4 ng/mL), and 147 (20.3%) had a normal IGF-1 level (mean 145.9 ± 86.9 ng/mL). GHD was diagnosed in 187 patients (25.8%), of whom 146 (25.3%) had a low IGF-1 level. An IGF-1 level reflecting ≤0 SDs in combination with results of a single CST had a specificity of 92.6%, a false-positive rate of 5.5%, and an AUC of 0.6088. Using an IFG-1 cut-off level of ≤-2 SDs did not alter the diagnostic accuracy. Low IGF-1 values of ≤0 SDs or ≤-2 SDs in combination with results of a single CST had poor diagnostic accuracy for GHD.

PMON35 An Unusual Case of Sporadic Congenital Hypopituitarism Presenting With Micropenis and Infantile Adrenal Crisis

Abstract Introduction Congenital hypopituitarism is a rare and potentially devastating disorder occurring in 1 in 4000 to 1 in 10,000 live births. Congenital hypopituitarism can occur due to mutations in transcription factors and signaling molecules involved in the embryologic development of the pituitary. In a small number of cases there is a family history of the disorder. In these cases, multiple genes have been implicated including HESX1, PROP1, POU1F1, LHX3, LHX4, SOX2, SOX3, OTX2, PAX6, FGFR1, GLI2, and FGF8 with different forms of inheritance. However, the majority (80-90%) of these cases are sporadic, and patients do not have an identifiable genetic mutation. We present a case of sporadic congenital hypopituitarism to bring awareness to this unusual disorder. Case At birth, the patient's pediatrician noted that he had a micropenis on physical exam. Six weeks later he became hypotonic in his mother's arms and was rushed to a local hospital where he was found to a blood glucose of 18 mg/dL. As part of this evaluation, a head CT was performed which revealed an empty sella. Endocrinology was consulted and found that he was adrenally insufficient and hypothyroid. He was started on hormone replacement, improved and was discharged. At 18 months old, he had a grand mal seizure in the setting of an infection during which he required stress dosing of steroids. Since that time, he has remained seizure-free and without any episodes of adrenal crisis. At age 12, he was started on testosterone injections for the initiation of puberty and remained on this therapy for 2 years. He was also briefly on growth hormone supplementation during this time. He had mood swings with this formulation and so was converted topical testosterone though has had intermittent adherence to this. He had some excess urination in the past and was trialed on DDAVP, but this was eventually discontinued as laboratory evaluation was not consistent with diabetes insipidus. On presentation to adult endocrinology, his hormone replacement was adequate aside from low testosterone levels related to intermittent adherence and a low IGF-1 level. Conclusion Congenital hypopituitarism is a rare, potentially life-threatening disorder that can be difficult to diagnose. Patients that present at birth with hypoglycemia and micropenis should be evaluated for this condition early in their course. These patients require a complete pituitary evaluation and prompt treatment for pituitary hormone abnormalities. Ophthalmic evaluation is also indicated as many patients have abnormal development of optic nerves. We present this case to bring awareness to this unusual disorder.

ODP187 Doedge-Potter syndrome and papillary thyroid carcinoma: An unusual association

Abstract Hypoglycemia can occur in non-diabetic individuals. Doege-Potter is a rare paraneoplastic syndrome presented as a hypoinsulinemic hypoglycemia caused by ectopic secretion of insulin-like growth factor-2 (IGF-2) from a solitary fibrous tumor. There is recent evidence of the involvement of the IGF system in different malignancies as papillary thyroid carcinoma, being exceptional. A 69-year-old female was brought to Emergency after a routine analysis uncovered severe hypoglycemia. She mentioned a history of morning sickness, dizziness, and confusion for the last week that reverted after breakfast, and dry cough for three months. She had a 25-pack-year history of smoking, no history of alcohol use, no other antecedent of interest, no history ofdiabetes mellitus or weight loss surgery, nor chronic treatments. Physical examinations revealed diminished breath sounds in the left middle lung. A thorax radiography showed a submassive left pleural effusion and toracocentesis revealed a hemorrhagic exudate. Laboratory data showed normal GH, and cortisol levels. Despite marked hypoglycemia, insulin level was 0.4 μIU/mL (2,6-24,9), C-peptide 0.11ng/ml (1,1-4,4) and hydroxy butyrate &amp;lt;0.1 mg/dl. The serum IGF-2 level was 428μg/dL (350-1000), and the IGF-1 level was 55.4 μg/L(161-384). Anti-insulin antibodies and sulfonylureas concentration were negative. CT showed a solid mass concerning parietal pleura with areas of necrosis and calcifications, measuring 14.6×15.4×20cm. Low blood glucose with suppressed insulin, C-peptide and IGF-1 levels, elevated IGF-2/IGF-1 ratio (7,7, normal&amp;lt;3) and CT findings suggested the possibility of non-islet cell tumor hypoglycemia (NICTH). Corticoid treatment was initiated to manage the hypoglycemia. Biopsy of the mass showed a malignant solitary fibrous tumor, positive for CD34 and BCL2. After surgery, glucose and IGF-2 levels returned to normal, the patient didn't experience further episodes of hypoglycemia, and corticoid treatment was gradually suspended. A FDG-PET scan, part of extension study, found a PET-positive thyroid nodule. A thyroid ultrasound confirmed a solid, taller than wide thyroid nodule, measuring 6.7×6.4×9,5mm and fine-needle aspiration biopsy was suggestive of papillary thyroid carcinoma. Hemithyroidectomy was performed. The patient is with no evidence of disease. Doege-Potter syndrome is a rare cause of hypoglycemia, resulting from a tumor producing elevated levels of IGF-2. Diagnosis is suggested by low insulin, C-peptide and IGF-1 levels, normal or elevated IGF-2, and elevated IGF2/IGF1 ratio. High levels of ''big-IGF-2'' are associated with high risk papillary thyroid carcinoma, suggesting the relation between the IGF-system and tumor growth, nevertheless there are few cases reported describing this association. Surgical resection of the tumor is the treatment of choice. Presentation: No date and time listed

Loss of NECTIN1 triggers melanoma dissemination upon local IGF1 depletion

Cancer genetics has uncovered many tumor-suppressor and oncogenic pathways, but few alterations have revealed mechanisms involved in tumor spreading. Here, we examined the role of the third most significant chromosomal deletion in human melanoma that inactivates the adherens junction gene NECTIN1 in 55% of cases. We found that NECTIN1 loss stimulates melanoma cell migration in vitro and spreading in vivo in both zebrafish and human tumors specifically in response to decreased IGF1 signaling. In human melanoma biopsy specimens, adherens junctions were seen exclusively in areas with low IGF1 levels, but not in NECTIN1-deficient tumors. Our study establishes NECTIN1 as a major determinant of melanoma dissemination and uncovers a genetic control of the response to microenvironmental signals.

Pre- and postdiagnosis growth failure, adult short stature, and untreated growth hormone deficiency in radiotherapy-treated long-term survivors of childhood brain tumor.

PurposeGrowth failure is common in radiotherapy-treated long-term survivors of pediatric brain tumors, but studies on longitudinal growth in this patient group are lacking. Here, the aim was to assess the changes in growth patterns before and after brain tumor diagnosis, the adult height, and the risk factors for compromised growth. The incidence and treatment practices of growth hormone deficiency were analyzed.MethodsA cohort of 73 survivors of childhood brain tumor (median age 27.2 years, range 16.2 to 43.8 years) was studied after a median follow-up period of 20.4 years from diagnosis (IQR 14.9 to 22.9 years). Patients were treated in five university hospitals in Finland between 1970 and 2008. Growth curves, final height, and patient- and disease-related risk factors for compromised growth during different growth periods were analyzed. Laboratory analyses for IGF-1 and IGFBP-3 were performed at the follow-up.ResultsGrowth failure was evident at diagnosis, with a mean height decline of -0.6 SDS (standard deviation score) from birth (95% CI -1.15 to -0.05). Mean height SDS decline after the diagnosis was -1.09 SDS (95%CI -1.51 to -0.66). At follow-up, 37% of the study subjects (27/73) had true short stature (height < -2 SDS). The mean height deficit corrected for target height was -1.9 SDS (95% CI -1.45 to -2.40). Growth failure was associated with the age at diagnosis, corticosteroid dose, radiotherapy modality and mean dose of irradiation in the thalamic area. Low IGF-1 level (below -2.0 SDS) was found in 32% (23/72), and untreated growth hormone deficiency in 40% (29/72) of the subjects.ConclusionLongitudinal growth impairment was common in radiotherapy-treated survivors of childhood brain tumor, resulting in compromised adult height. Loss of growth potential was evident already at diagnosis and further accelerated by the treatments. At young adulthood, unrecognized growth hormone deficiency was common.

Growth factors in anorexia nervosa: a systematic review and meta-analysis of cross-sectional and longitudinal data

Objectives Growth factors are signalling molecules that play roles in the survival, proliferation, migration, and differentiation of cells. Studies have found alterations in specific growth factors in anorexia nervosa (AN). Methods This systematic review and meta-analysis examined articles from three databases, measuring growth factors in AN cross-sectionally and longitudinally, and in recovered AN (rec-AN) cross-sectionally. Random-effects meta-analyses were conducted for brain-derived neurotrophic factor (BDNF) and insulin growth factor-I (IGF-1) for cross-sectional and longitudinal studies. Results A total of 82 studies were included: 56 cross-sectional (BDNF: n = 15; IGF-1: n = 41) and 24 longitudinal (BDNF: n = 5; IGF-1: n = 19) were meta-analysed and 20 studies were narratively synthesised. In cross-sectional analyses, BDNF and IGF-1 were lower in AN compared to controls, and BDNF was marginally greater in rec-AN compared to controls. In longitudinal meta-analyses, BDNF and IGF-1 increased from baseline to follow-up. Cross-sectional subgroup analyses revealed no differences in BDNF between controls and AN binge-eating/purging subtypes. Conclusions It is likely that the low BDNF and IGF-1 levels found in AN are consequences of starvation, which are reversible with weight restoration. The increase in BDNF and IGF-1 during therapeutic weight restoration might improve neuroplasticity, which is the basis of learning, and thus psychotherapeutic success.

The prevalence of hypothyroidism in infertile women and its correlation with the pituitary gland hormones

Infertility is defined as a condition in which a woman cannot conceive after 12 months of a normal sexual relationship without the use of contraception. The study aimed to evaluate hypothyroidism prevalence, thyroid and pituitary gland hormones assessment in infertile women's serum, and their correlation in Basra, Iraq. The research was conducted at Ibn-Gzouan Hospital for Obstetrics and Gynecology in Basra, southern Iraq, between October 2021 and March 2022. In our research, 28 infertile women with hypothyroidism, 30 infertile women without hypothyroidism, and 30 fertile women aged 18 to 45 were studied. Our research found that infertile hypothyroid women had greater TSH and PRL levels than fertile women, but lower T3 and T4 levels. Without hypothyroidism, infertile women exhibited greater PRL, cortisol, and LH levels than fertile women, but lower IGF-1 levels. T4 and T3 levels (r=0.640), LH, and LH/FSH ratio(r=0.536) correlated positively in hypothyroid infertile women. TSH and T4 levels (r = -0.514) and FSH and LH/FSH ratio (r =-0.481) correlated negatively. T4 and T3 levels, LH, and LH/FSH were positively correlated (r = 0.666) in infertile women without hypothyroidism. TSH was negatively correlated with T4 (r = -0.547) and T3 (r = -0.580).

Zfp580 Regulates Paracrine and Endocrine Igf1 and Igfbp3 Differently in the Brain and Blood After a Murine Stroke.

Insulin-like growth factor 1 (Igf1) and insulin-like growth factor binding protein 3 (Igfbp3) are endocrine and paracrine factors that influence stroke occurrence, severity, and recovery. Low levels of endocrine Igf1 and Igfbp3 were associated with larger infarct volumes and unfavorable outcomes. Paracrine Igf1 is brain cytoprotective and improves functional recovery after stroke. In this study, we evaluated the effects of zinc finger protein 580 (Zfp580) on endocrine and paracrine Igf1 and Igfbp3 after stroke. Zfp580 suppressed the expression of Igf1 and Igfbp3 in cerebral microvascular endothelial cells (bEnd.3) as determined by real-time RT-PCR. Zfp580 was suppressed by combined oxygen and glucose deprivation (OGD) and mediated the effect of OGD on Igf1 and Igfbp3. In vivo, we evaluated paracrine regulation by real-time RT-PCR of brain lysates and endocrine regulation by ELISA of blood samples. Genomic ablation of Zfp580 did not alter basal paracrine or endocrine Igf1 and Igfbp3 levels. After transient middle cerebral artery occlusion (MCAo), Zfp580 was globally elevated in the brain for up to 3 days. Paracrine Igf1 and Igfbp3 were selectively induced in the ischemic hemisphere from day 2 to day 3 or day 1 to day 7, respectively. In Zfp580 knockout mice, the paracrine regulations of Igf1 and Igfbp3 were attenuated while endocrine Igf1 and the molar Igf1/Igfbp3 ratio were increased. In conclusion, Zfp580 differentially controls paracrine and endocrine Igf1 and Igfbp3 after stroke. Inhibition of Zfp580 might be a new treatment target leading to increased activity of Igf1 to improve stroke outcome.

Macrophage-derived IGF-1 protects the neonatal intestine against necrotizing enterocolitis by promoting microvascular development

Necrotizing enterocolitis (NEC) is a deadly bowel necrotic disease of premature infants. Low levels of plasma IGF-1 predispose premature infants to NEC. While increasing evidence suggests that defective perinatal intestinal microvascular development plays a role in NEC, the involved mechanism remains incompletely understood. We report here that serum and intestinal IGF-1 are developmentally regulated during the perinatal period in mice and decrease during experimental NEC. Neonatal intestinal macrophages produce IGF-1 and promote endothelial cell sprouting in vitro via IGF-1 signaling. In vivo, in the neonatal intestine, macrophage-derived IGF-1 promotes VEGF expression and endothelial cell proliferation and protects against experimental NEC. Exogenous IGF-1 preserves intestinal microvascular density and protects against experimental NEC. In human NEC tissues, villous endothelial cell proliferation and IGF-1- producing macrophages are decreased compared to controls. Together, our results suggest that defective IGF-1-production by neonatal macrophages impairs neonatal intestinal microvascular development and predisposes the intestine to necrotizing enterocolitis.

Correlation between Salivary Levels of IGF-1, IGFBP-3, IGF-1/IGFBP3 Ratio with Skeletal Maturity Using Hand-Wrist Radiographs.

Objective: The relevance of growth determination in orthodontics is driving the search for the most precise and least invasive way of tracking the pubertal growth spurt. Our aim was to explore whether minimally invasive salivary estimation of biomarkers Insulin-like growth factor (IGF-1) and Insulin-like growth factor binding protein-3 (IGFBP-3) could be used to estimate skeletal maturity for clinical convenience, especially in children and adolescent age groups. Materials and Method: The cross-sectional study was conducted on 90 participants (56 girls and 34 males) with ages ranging from 6 to 25 years. Each subject’s hand-wrist radiograph was categorized based on skeletal maturity, and saliva samples were estimated for IGF-1 and IGFBP-3 using the respective ELISA kits. Kruskal–Wallis nonparametric ANOVA was applied to compare different skeletal stages. Results: The study demonstrated low salivary IGF-1 levels at the prepubertal stage, with increase during pubertal onset and peak pubertal stage followed by a decline during pubertal deceleration to growth completion. Spearman’s correlation coefficient demonstrated a strong positive association (r = 0.98 p < 0.01) between salivary IGF/IGFBP-3 ratio and different stages of skeletal maturity. Conclusion: Salivary IGF-1, IGFBP-3, and IGF/IGFBP-3 ratio could serve as a potential biochemical marker for predicting the completion of skeletal maturity.

GH/IGF-1 axis in a large cohort of ß-thalassemia major adult patients: a cross-sectional study

PurposeGH deficit (GHD) could represent an endocrine issue in ß-Thalassemia Major (ßTM) patients. GH/IGF-1 axis has not been extensively explored in ßTM adults, so far. We aim to assess GHD and IGF-1 deficiency prevalence in ßTM adult population, focusing on the relationship with liver disease.MethodsCross-sectional multi-centre study conducted on 81 adult ßTM patients (44 males, mean age 41 ± 8 years) on transfusion and chelation therapy. GHD was investigated by GHRH + arginine test. IGF-1 levels, routine biochemical exams, Fibroscan, Hepatic Magnetic Resonance Imaging (MRI) and pituitary MRI were collected.ResultsEighteen patients were affected by GHD and 63 were not (nGHD) according to GHRH + arginine test, while basal GH levels did not differ. GHD was associated with a higher BMI and a worse lipid profile (p < 0.05). No significant differences were observed regarding liver function between the two groups. Pituitary MRI scan was normal except for one case of empty sella. The 94.4% and 93.6% of GHD and nGHD, respectively, presented lower IGF-1 levels than the reference range, and mean IGF-1 SDS was significantly lower in GHD patients.ConclusionGHD is frequent in adult ßTM patients and is associated with higher BMI and worse lipid profile. nGHD patients present lower IGF-1 levels as well. There was no relationship between IGF-1 levels and liver disease. Further, multicentric studies with larger cohorts and standardized diagnostic protocols are needed.

Factors affecting sarcopenia in older patients with chronic diseases.

Sarcopenia is an age-related disease characterized by a progressive loss of systemic muscle mass and/or decreased muscle strength and physical function. The occurrence of sarcopenia in patients with chronic diseases will not only cause further deterioration of diseases and adverse clinical outcomes, but also lead to high medical cost, suggesting a necessity and a great significance to explore the associated factors of sarcopenia in chronic patients in order to improve their quality of life. This study aimed to investigate factors affecting sarcopenia among older hospitalized patients with chronic diseases. A total of 121 older patients with chronic diseases admitted to the Department of Geriatrics of Affiliated Kunshan Hospital of Jiangsu University from May 2019 to April 2021 were enrolled. According to the diagnostic criteria of sarcopenia formulated by the Asian Working Group for Sarcopenia (AWGS), the subjects were divided into a sarcopenia group (n=57) and a non-sarcopenia group (n=64). We analyzed the associated factors including bone mineral density, nutritional biomarkers, hormone levels and inflammatory cytokines. Compared to the non-sarcopenia group, the sarcopenia group was of older average age (P<0.001), exhibited a lower body mass index (BMI) (P<0.001), a lower bone mineral density (BMD) of the femoral neck (P<0.01), and a higher incidence of osteoporosis. In terms of hematology, the sarcopenia group exhibited significantly lower serum iron and zinc levels (both P<0.05), a higher growth hormone (GH) level (P<0.05), a significantly lower IGF-1 level (P<0.01), and a lower level of iron (P<0.01). Poor nutritional status (assessed via measurement of albumin and prealbumin levels) positively correlated with sarcopenia (P<0.01). Sarcopenia is closely associated with aging, and has a close relationship with osteoporosis. Anemia, malnutrition, vitamin and trace element deficiencies, changes in hormone levels, and chronic inflammation are correlated with sarcopenia. Patients with these features above call for the screenig of sarcopenia. Additionally, these characteristics may help providing clues for further research on the pathogenesis and risk factors of sarcopenia, along with disease prevention and intervention.

Oral Intake of L-Ornithine-L-Aspartate Is Associated with Distinct Microbiome and Metabolome Changes in Cirrhosis.

L-ornithine L-aspartate (LOLA) is administered as a therapeutic and/or preventive strategy against hepatic encephalopathy either intravenously or orally in patients with liver cirrhosis. Here, we analyzed how LOLA influences the microbiome and metabolome of patients with liver cirrhosis. We retrospectively analyzed the stool microbiome, stool, urine and serum metabolome as well as markers for gut permeability, inflammation and muscle metabolism of 15 cirrhosis patients treated orally with LOLA for at least one month and 15 propensity-score-matched cirrhosis patients without LOLA. Results were validated by comparing the LOLA-treated patients to a second set of controls. Patients with and without LOLA were comparable in age, sex, etiology and severity of cirrhosis as well as PPI and laxative use. In the microbiome, Flavonifractor and Oscillospira were more abundant in patients treated with LOLA compared to the control group, while alpha and beta diversity were comparable between groups. Differences in stool and serum metabolomes reflected the pathophysiology of hepatic encephalopathy and confirmed LOLA intake. In the urine metabolome, ethanol to acetic acid ratio was lower in patients treated with LOLA compared to controls. LOLA-treated patients also showed lower serum levels of insulin-like growth factor (IGF) 1 than patients without LOLA. No differences in gut permeability or inflammation markers were found. A higher abundance of Flavonifractor and Oscillospira in LOLA-treated patients could indicate LOLA as a potential microbiome modulating strategy in patients with liver disease. The lower levels of IGF1 in patients treated with LOLA suggest a possible link between the pathophysiology of hepatic encephalopathy and muscle health.

Efficacy and Safety of Ketone Supplementation or Ketogenic Diets for Alzheimer's Disease: A Mini Review.

Alzheimer's disease (AD) is the most frequent age-related neurodegenerative disorder, with no curative treatment available so far. Alongside the brain deposition of β-amyloid peptide and hyperphosphorylated tau, neuroinflammation triggered by the innate immune response in the central nervous system, plays a central role in the pathogenesis of AD. Glucose usually represents the main fuel for the brain. Glucose metabolism has been related to neuroinflammation, but also with AD lesions. Hyperglycemia promotes oxidative stress and neurodegeneration. Insulinoresistance (e.g., in type 2 diabetes) or low IGF-1 levels are associated with increased β-amyloid production. However, in the absence of glucose, the brain may use another fuel: ketone bodies (KB) produced by oxidation of fatty acids. Over the last decade, ketogenic interventions i.e., ketogenic diets (KD) with very low carbohydrate intake or ketogenic supplementation (KS) based on medium-chain triglycerides (MCT) consumption, have been studied in AD animal models, as well as in AD patients. These interventional studies reported interesting clinical improvements in animals and decrease in neuroinflammation, β-amyloid and tau accumulation. In clinical studies, KS and KD were associated with better cognition, but also improved brain metabolism and AD biomarkers. This review summarizes the available evidence regarding KS/KD as therapeutic options for individuals with AD. We also discuss the current issues and potential adverse effects associated with these nutritional interventions. Finally, we propose an overview of ongoing and future registered trials in this promising field.

Management of growth failure and other endocrine aspects in patients with Noonan syndrome across Europe: A sub-analysis of a European clinical practice survey

To date, there is a lack of international guidelines regarding the management of the endocrine features of individuals with Noonan syndrome (NS). The aim was to develop a clinical practice survey to gather information on current treatment and management of these patients across Europe. A group of 10 experts from three clinical specialities involved in the management of NS patients (clinical geneticists, paediatric endocrinologists, and paediatric cardiologists) developed a 60-question clinical practice survey. The questionnaire was implemented in Survey Monkey and sent to physicians from these three specialities via European/national societies. Contingency tables and the Chi-Squared test for independence were used to examine differences between specialities and countries. In total, responses of 364 specialists (paediatric endocrinologists, 40%; geneticists, 30%; paediatric cardiologists, 30%) from 20 European countries were analysed. While endocrinologists mostly referred to national growth charts for the general population, geneticists mostly referred to NS-specific growth charts. Approximately half of the endocrinologists perform growth hormone (GH) stimulation tests in short patients with low IGF1 levels. Two thirds of endocrinologists begin GH treatment for short patients in early childhood (4-6.9 years), and over half of them selected a threshold of -2 standard deviation score (SDS) according to national growth charts. The main concerns about GH treatment appear to be presence of hypertrophic cardiomyopathy (HCM) (59%), increased risk of malignancy (46%), and limited efficacy (31%). When asked if they consider HCM as a contraindication for GH treatment, one third of respondents skipped this question, and among those who replied, two thirds selected 'cannot answer', suggesting a high level of uncertainty. A total of 21 adverse cardiac responses to GH treatment were reported. Although most respondents had not encountered any malignancy during GH treatment, six malignancies were reported. Finally, about half of the endocrinologists expected a typical final height gain of 1-1.5 SDS with GH treatment. This survey describes for the first time the current clinical practice of endocrine aspects of NS across Europe and helps us to identify gaps in the management but also in the knowledge of this genetic disorder.

Outcomes Based on Plasma Biomarkers for the Phase 3 CELESTIAL Trial of Cabozantinib versus Placebo in Advanced Hepatocellular Carcinoma

Introduction: Cabozantinib, an inhibitor of MET, AXL, and VEGF receptors, significantly improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with previously treated advanced hepatocellular carcinoma (HCC). In this exploratory analysis, outcomes were evaluated according to plasma biomarker levels. Methods: Baseline plasma levels were evaluated for MET, AXL, VEGFR2, HGF, GAS6, VEGF-A, PlGF, IL-8, EPO, ANG2, IGF-1, VEGF-C, and c-KIT for 674/707 randomized patients; and Week 4 levels were evaluated for MET, AXL, VEGFR2, HGF, GAS6, VEGF-A, PlGF, IL-8, and EPO for 614 patients. OS and PFS were analyzed by baseline levels as dichotomized or continuous variables and by on-treatment changes at Week 4 as continuous variables; biomarkers were considered potentially prognostic if p < 0.05 and predictive if p < 0.05 for the interaction between treatment and the biomarker. Multivariable analyses adjusting for clinical covariates were also performed. Results: In the placebo group, high levels of MET, HGF, GAS6, IL-8, and ANG2 and low levels of IGF-1 were associated with shorter OS in univariate and multivariable analyses; these associations were also observed for MET, IL-8, and ANG2 in the cabozantinib group. Hazard ratios for OS and PFS favored cabozantinib over the placebo at low and high baseline levels for all biomarkers. No baseline biomarkers were predictive of a treatment benefit. Cabozantinib promoted pharmacodynamic changes in several biomarkers, including increases in VEGF-A, PlGF, AXL, and GAS6 levels and decreases in VEGFR2 and HGF levels; these changes were not associated with OS or PFS. Conclusion: Cabozantinib improved OS and PFS versus placebo at high and low baseline concentrations for all biomarkers analyzed. Low baseline levels of MET, HGF, GAS6, IL-8, and ANG2 and high levels of IGF-1 were identified as potential favorable prognostic biomarkers for survival in previously treated advanced HCC. Although cabozantinib promoted pharmacodynamic changes in several biomarkers, these changes were not associated with survival.

Applying growth hormone as an adjuvant to correct poor prognosis outcomes in IVF: Study 2 compares dehydroepiandrosterone

This retrospective study examines the influence of recombinant growth hormone (rGH) and dehydroepiandrosterone (DHEA) adjuvants on oocyte numbers, embryo utilization and live births arising from 3637 autologous IVF±ICSI treatment cycles undertaken on 2376 women across ten years (2011-2020) within a pioneer Australian facility. Despite using an FSH-dosing algorithm enabling maximal doses up to 450 IU for women with reduced ovarian reserve, younger women had significantly higher mean numbers of oocytes recovered than older women ranging from 11.1 for women &lt;35 years to 9.4 for women aged 35-39 years reducing to 6.5 for women aged 40-44 years and 4.1 for those aged ≥45 years (p&lt;0.0001). Overall, the embryo utilization rate was 48.5% and live birth productivity rate was 35.4 % across all ages and neither rGH nor DHEA showed any benefit on these rates, in fact, those women with nil adjuvants showed the highest live birth rate per initiated cycle (44.94% overall: p&lt;0.0001, and 55.2% for the youngest group: p&lt;0.001). Embryo utilization was increased by rGH in those women aged 40-44 years who had low ovarian reserve (p&lt;0.0001), but this benefit did not translate into any improvement in the live birth rate, in fact those women who did not use adjuvants had the highest overall birth rate (p&lt;0.0001). Similarly, other factors known to cause a poor prognosis, including low IGF-1 profile, recurrent implantation failure, and low oocyte numbers at OPU, showed no improvement in embryo utilization nor in live births from the adjuvants. The relevance of embryo quality was examined on 1135 women whose residual embryos after a single fresh-embryo transfer failed to develop to a suitable grade for cryopreservation. From 1727 cycles such women often displayed an improved embryo utilization rate with both rGH, and with DHEA or combined rGH+DHEA. Even so, live birth rates were not improved by either of the adjuvants excepting young women &lt;35 years using rGH without DHEA (p&lt;0.05). Examining poor prognosis sub-groups, indicated both rGH and DHEA or combined rGH+DHEA consistently improved embryo utilization in those women with low ovarian reserve (p&lt;0.0001), or those with low IGF-1 levels (p&lt;0.0001) or with recurrent implantation failure (p&lt;0.02). All the poor-prognosis sub-groups showed low live birth rates and, notwithstanding the improvements in embryo utilization, the live birth rates were not significantly improved by the adjuvants, albeit the rates were closer to the nil adjuvant groups (not significantly different).