-
Endocrine-related Cancer Jun 2023Meta-analyses from 2018-2022 have shown that obesity increases the risk of various cancers such as acute myeloid lymphoma, chronic myeloid lymphoma, diffuse beta cell...
Meta-analyses from 2018-2022 have shown that obesity increases the risk of various cancers such as acute myeloid lymphoma, chronic myeloid lymphoma, diffuse beta cell lymphoma, Hodgkin's lymphoma, leukemia, multiple myeloma, non-Hodgkin's lymphoma, bladder, breast, cholangiocarcinoma, colorectal, ovarian, esophageal, kidney, liver, prostate, thyroid, and uterus. Contextually, obesity, and its comorbidities, is the largest, most lethal pandemics in the history of mankind; hence, identification of underlying mechanisms is needed to adequately address this global health threat. Herein, we present the metabolic and hormonal mechanisms linked to obesity that might etiologically contribute to neoplasia, including hyperinsulinemia and putative places in the insulin-signaling pathway. Excess insulin, acting as a growth factor, might contribute to tumorigenesis, while abundant ATP and GDP supply the additional energy needed for proliferation of rapidly dividing cells. Our observations in the Ecuadorian cohort of subjects with Laron syndrome (ELS) prove that obesity does not always associate with increased cancer risk. Indeed, despite excess body fat from birth to death, these individuals display a diminished incidence of cancer when compared to their age- and sex-matched relatives. Furthermore, in cell cultures exposed to potent oxidizing agents, addition of ELS serum induces less DNA damage as well as increased apoptosis. ELS individuals have absent growth hormone (GH) counter-regulatory effects in carbohydrate metabolism due to a defective GH receptor. The corresponding biochemical phenotype includes extremely low basal serum concentrations of insulin and insulin-like growth factor-I, lower basal glucose and triglyceride (TG) levels, and diminished glucose, TG, and insulin responses to orally administered glucose or to a mixed meal.
Topics: Male; Female; Humans; Laron Syndrome; Ecuador; Insulin-Like Growth Factor I; Insulin; Neoplasms; Obesity; Glucose
PubMed: 36971780
DOI: 10.1530/ERC-22-0389 -
Growth Hormone & IGF Research :... Jun 2022Chagas disease (CD) is caused by the protozoan parasite, Trypanosoma cruzi. It affects 7 to 8 million people worldwide and leads to approximately 50,000 deaths per year....
OBJECTIVE
Chagas disease (CD) is caused by the protozoan parasite, Trypanosoma cruzi. It affects 7 to 8 million people worldwide and leads to approximately 50,000 deaths per year. In vitro and in vivo studies had demonstrated that Trypanosoma cruziinfection causes an imbalance in the hypothalamic-pituitary-adrenal (HPA) axis that is accompanied by a progressive decrease in growth hormone (GH) and prolactin (PRL) production. In humans, inactivating mutations in the GH receptor gene cause Laron Syndrome (LS), an autosomal recessive disorder. Affected subjects are short, have increased adiposity, decreased insulin-like growth factor-I (IGFI), increased serum GH levels, are highly resistant to diabetes and cancer, and display slow cognitive decline. In addition, CD incidence in these individuals is diminished despite living in highly endemic areas. Consequently, we decided to investigate the in vitro effect of GH/IGF-I on T. cruzi infection.
DESIGN
We first treated the parasite and/or host cells with different peptide hormones including GH, IGFI, and PRL. Then, we treated cells using different combinations of GH/IGF-I attempting to mimic the GH/IGF-I serum levels observed in LS subjects.
RESULTS
We found that exogenous GH confers protection against T. cruzi infection. Moreover, this effect is mediated by GH and not IGFI. The combination of relatively high GH (50 ng/ml) and low IGF-I (20 ng/ml), mimicking the hormonal pattern seen in LS individuals, consistently decreased T. cruzi infection in vitro.
CONCLUSIONS
The combination of relatively high GH and low IGF-I serum levels in LS individuals may be an underlying condition providing partial protection against T. cruzi infection.
Topics: Chagas Disease; Growth Hormone; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Laron Syndrome; Prolactin
PubMed: 35490602
DOI: 10.1016/j.ghir.2022.101460 -
Journal of the ASEAN Federation of... 2023Primary growth hormone (GH) resistance or growth hormone insensitivity syndrome, also called Laron syndrome, is a hereditary disease caused by mutations in the GH...
Primary growth hormone (GH) resistance or growth hormone insensitivity syndrome, also called Laron syndrome, is a hereditary disease caused by mutations in the GH receptor or in the post-receptor signaling pathway. This disorder is characterized by postnatal growth failure resembling GH deficiency. Differentiating the two conditions is necessary. We present the cases of two siblings, a 16-year-old female and a 9-year-old male, born from a consanguineous union. Both had normal birth weights with subsequent severe short stature and delayed teeth eruption, with no features suggestive of any systemic illness. Serum insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) were both low. Suspecting GH deficiency, provocative testing with clonidine was done revealing peak growth hormone >40 ng/mL in both patients. In view of low IGF1 and IGFBP3 and high GH on stimulation, IGF1 generation test was done for both siblings, with values supporting the diagnosis of GH insensitivity or Laron syndrome.
Topics: Male; Female; Humans; Adolescent; Child; Laron Syndrome; Siblings; Growth Hormone; Human Growth Hormone; Receptors, Somatotropin
PubMed: 38045665
DOI: 10.15605/jafes.038.02.22 -
European Journal of Endocrinology Jul 2021The aim of the study is to find possible explanations for vanishing juvenile hypoglycemia in growth hormone receptor deficiency (GHRD) in human patients and animal... (Review)
Review
The aim of the study is to find possible explanations for vanishing juvenile hypoglycemia in growth hormone receptor deficiency (GHRD) in human patients and animal models. We reviewed parameters of glucose metabolism in distinct age groups into two human cohorts (Israeli and Ecuadorian) of Laron syndrome (LS) patients, a mouse model (Ghr-KO mouse) and provided additional data for a porcine model (GHR-KO pig). Juvenile hypoglycemia is a common symptom of GHRD and vanishes in adulthood. In the Israeli cohort, developing metabolic syndrome is associated with decreasing insulin sensitivity, insulinopenia and glucose intolerance, and increasing glucose levels with age. In the Ecuadorian patients and both animal models, insulin sensitivity is preserved or even enhanced. Alterations in food intake and energy consumption do not explain the differences in glucose levels; neither is the accumulation of body fat associated with negative effects in the Ecuadorian cohort nor in the animal models. A reduced beta-cell mass and resulting insulin secretory capacity is common and leads to glucose intolerance in Ghr-KO mice, while glucose tolerance is preserved in Ecuadorian patients and the GHR-KO pig. In human patients and the GHR-KO pig, a simultaneous occurrence of normoglycemia with the onset of puberty is reported. Reduced gluconeogenesis in GHRD is discussed to cause juvenile hypoglycemia and a counter-regulatory stimulation of gluconeogenesis can be hypothesized. A coherent study assessing endogenous glucose production and beta-cell capacity in the hypoglycemic and normoglycemic age group is needed. This can be performed in GHR-KO pigs, including castrated animals.
Topics: Age Factors; Animals; Animals, Genetically Modified; Cohort Studies; Disease Models, Animal; Ecuador; Humans; Hypoglycemia; Israel; Laron Syndrome; Mice; Mice, Knockout; Receptors, Somatotropin; Signal Transduction; Swine
PubMed: 34048365
DOI: 10.1530/EJE-21-0013 -
Diabetes Research and Clinical Practice Feb 2023We examined the effect of growth hormone (GH) counter-regulation on carbohydrate metabolism in individuals with life-long diminished insulin secretion (DIS).
AIMS
We examined the effect of growth hormone (GH) counter-regulation on carbohydrate metabolism in individuals with life-long diminished insulin secretion (DIS).
METHODS
Adults homozygous for the E180 splice site mutation of GHR [Laron syndrome (LS)], adults with a gain-of-function mutation in CDKN1c [Guevara-Rosenbloom syndrome (GRS)], and controls were evaluated for body composition, leptin, total and high molecular weight (HMW) adiponectin, insulin-like growth factor (IGF) axis molecules, and a 5-hour oral glucose tolerance test (OGTT), with measurements of glucose, insulin, glucagon, ghrelin, pancreatic polypeptide, gastric inhibitory peptide, glucagon-like peptide-1, peptide YY, and islet amyloid polypeptide (IAPP).
RESULTS
Both syndromic cohorts displayed DIS during OGTT. LS subjects had higher serum concentrations of total and HMW adiponectin, and lower levels of IGF-I, IGF-II, and IGF-Binding Protein-3 than individuals in other study groups. Furthermore, they displayed normal glycemic responses during OGTT with the lowest IAPP secretion. In contrast, individuals with GRS had higher levels of protein glycation, deficient glucose control during OGTT, and increased secretion of IAPP.
CONCLUSIONS
A distinct metabolic phenotype depending on GH counter-regulatory status, associates with diabetes development and excess glucose-induced IAPP secretion.
Topics: Humans; Insulin Secretion; Adiponectin; Syndrome; Insulin; Human Growth Hormone; Glucose; Islet Amyloid Polypeptide; Phenotype; Insulin-Like Growth Factor I
PubMed: 36549505
DOI: 10.1016/j.diabres.2022.110228 -
Cureus Dec 2022Laron syndrome is a rare, genetic, growth hormone insensitivity disorder caused by mutations in the growth hormone receptor gene. Affected patients have severe postnatal...
Laron syndrome is a rare, genetic, growth hormone insensitivity disorder caused by mutations in the growth hormone receptor gene. Affected patients have severe postnatal growth failure, characteristic facial features, and metabolic abnormalities, including severe obesity and metabolic syndrome. Women with Laron syndrome are usually subfertile, mainly due to obesity and metabolic dysregulation, and require treatment for their chronic reproductive dysfunction. To date, infertility in Laron syndrome patients is a rarely addressed problem and, as a result, adequate data regarding its treatment are lacking. Here we present, for the first time in the literature, a rare case of successful treatment of a young woman with Laron syndrome who suffered from infertility due to hyperprolactinemia.
PubMed: 36721555
DOI: 10.7759/cureus.33090 -
Pituitary Dec 2023Growth hormone receptor knockout (GHR-KO) pigs have recently been developed, which serve as a large animal model of Laron syndrome (LS). GHR-KO pigs, like individuals...
PURPOSE
Growth hormone receptor knockout (GHR-KO) pigs have recently been developed, which serve as a large animal model of Laron syndrome (LS). GHR-KO pigs, like individuals with LS, are obese but lack some comorbidities of obesity. The purpose of this study was to examine the histological and transcriptomic phenotype of adipose tissue (AT) in GHR-KO pigs and humans with LS.
METHODS
Intraabdominal (IA) and subcutaneous (SubQ) AT was collected from GHR-KO pigs and examined histologically for adipocyte size and collagen content. RNA was isolated and cDNA sequenced, and the results were analyzed to determine differentially expressed genes that were used for enrichment and pathway analysis in pig samples. For comparison, we also performed limited analyses on human AT collected from a single individual with and without LS.
RESULTS
GHR-KO pigs have increased adipocyte size, while the LS AT had a trend towards an increase. Transcriptome analysis revealed 55 differentially expressed genes present in both depots of pig GHR-KO AT. Many significant terms in the enrichment analysis of the SubQ depot were associated with metabolism, while in the IA depot, IGF and longevity pathways were negatively enriched. In pathway analysis, multiple expected and novel pathways were significantly affected by genotype, i.e. KO vs. controls. When GH related gene expression was analyzed, SOCS3 and CISH showed species-specific changes.
CONCLUSION
AT of GHR-KO pigs has several similarities to that of humans with LS in terms of adipocyte size and gene expression profile that help describe the depot-specific adipose phenotype of both groups.
Topics: Humans; Animals; Swine; Obesity; Receptors, Somatotropin; Adipose Tissue; Growth Hormone; Gene Expression Profiling; Insulin-Like Growth Factor I
PubMed: 37747600
DOI: 10.1007/s11102-023-01355-y -
The Journal of Clinical Endocrinology... Oct 2021Growth hormone insensitivity (GHI) in children is characterized by short stature, functional insulin-like growth factor (IGF)-I deficiency, and normal or elevated serum...
CONTEXT
Growth hormone insensitivity (GHI) in children is characterized by short stature, functional insulin-like growth factor (IGF)-I deficiency, and normal or elevated serum growth hormone (GH) concentrations. The clinical and genetic etiology of GHI is expanding.
OBJECTIVE
We undertook genetic characterization of short stature patients referred with suspected GHI and features which overlapped with known GH-IGF-I axis defects.
METHODS
Between 2008 and 2020, our center received 149 GHI referrals for genetic testing. Genetic analysis utilized a combination of candidate gene sequencing, whole exome sequencing, array comparative genomic hybridization, and a targeted whole genome short stature gene panel.
RESULTS
Genetic diagnoses were identified in 80/149 subjects (54%) with 45/80 (56%) having known GH-IGF-I axis defects (GHR n = 40, IGFALS n = 4, IGFIR n = 1). The remaining 35/80 (44%) had diagnoses of 3M syndrome (n = 10) (OBSL1 n = 7, CUL7 n = 2, and CCDC8 n = 1), Noonan syndrome (n = 4) (PTPN11 n = 2, SOS1 n = 1, and SOS2 n = 1), Silver-Russell syndrome (n = 2) (loss of methylation on chromosome 11p15 and uniparental disomy for chromosome 7), Class 3-5 copy number variations (n = 10), and disorders not previously associated with GHI (n = 9) (Barth syndrome, autoimmune lymphoproliferative syndrome, microcephalic osteodysplastic primordial dwarfism type II, achondroplasia, glycogen storage disease type IXb, lysinuric protein intolerance, multiminicore disease, macrocephaly, alopecia, cutis laxa, and scoliosis syndrome, and Bloom syndrome).
CONCLUSION
We report the wide range of diagnoses in 149 patients referred with suspected GHI, which emphasizes the need to recognize GHI as a spectrum of clinical entities in undiagnosed short stature patients. Detailed clinical and genetic assessment may identify a diagnosis and inform clinical management.
Topics: Adolescent; Adult; Biomarkers; Body Height; Child; Child, Preschool; Comparative Genomic Hybridization; DNA Copy Number Variations; Female; Follow-Up Studies; Genetic Testing; Growth Disorders; Human Growth Hormone; Humans; Infant; Insulin-Like Growth Factor I; Laron Syndrome; Male; Prognosis; Young Adult
PubMed: 34136918
DOI: 10.1210/clinem/dgab437 -
Biomolecules Mar 2023Laron syndrome (LS) is a rare genetic disorder characterized by low levels of insulin-like growth factor 1 (IGF1) and high levels of growth hormone (GH) due to mutations...
Laron syndrome (LS) is a rare genetic disorder characterized by low levels of insulin-like growth factor 1 (IGF1) and high levels of growth hormone (GH) due to mutations in the growth hormone receptor gene (). A -knockout (-KO) pig was developed as a model for LS, which displays many of the same features as humans with LS-like transient juvenile hypoglycemia. This study aimed to investigate the effects of impaired GHR signaling on immune functions and immunometabolism in -KO pigs. GHR are located on various cell types of the immune system. Therefore, we investigated lymphocyte subsets, proliferative and respiratory capacity of peripheral blood mononuclear cells (PBMCs), proteome profiles of CD4 and CD4 lymphocytes and IFN-α serum levels between wild-type (WT) controls and -KO pigs, which revealed significant differences in the relative proportion of the CD4CD8α subpopulation and in IFN-α levels. We detected no significant difference in the respiratory capacity and the capacity for polyclonal stimulation in PBMCs between the two groups. But proteome analysis of CD4 and CD4 lymphocyte populations revealed multiple significant protein abundance differences between -KO and WT pigs, involving pathways related to amino acid metabolism, beta-oxidation of fatty acids, insulin secretion signaling, and oxidative phosphorylation. This study highlights the potential use of -KO pigs as a model for studying the effects of impaired GHR signaling on immune functions.
Topics: Humans; Animals; Swine; Receptors, Somatotropin; Laron Syndrome; Leukocytes, Mononuclear; Proteome; Growth Hormone
PubMed: 37189345
DOI: 10.3390/biom13040597 -
European Journal of Endocrinology Feb 2021The European Increlex® Growth Forum Database Registry monitors the effectiveness and safety of recombinant human insulin-like growth factor-1 (rhIGF1; mecasermin,... (Observational Study)
Observational Study
OBJECTIVE
The European Increlex® Growth Forum Database Registry monitors the effectiveness and safety of recombinant human insulin-like growth factor-1 (rhIGF1; mecasermin, Increlex®) therapy in patients with severe primary IGF1 deficiency (SPIGFD). We present data from patients with and without a reported genetic diagnosis of Laron syndrome (LS).
DESIGN
Ongoing, open-label, observational registry (NCT00903110).
METHODS
Children and adolescents receiving rhIGF1 therapy from 10 European countries were enrolled in 2008-2017 (n = 242). The treatment-naïve/prepubertal (NPP) cohort (n = 138) was divided into subgroups based on reported genetic diagnosis of LS (n = 21) or non-LS (n = 117). Multivariate analysis of the NPP-non-LS subgroup was conducted to identify factors predictive of growth response (first-year-height standard deviation score (SDS) gain ≥ 0.3). Assessments included change in height and weight over 5 years and adverse events (AEs).
RESULTS
Height SDS gain from baseline was greater in the NPP-LS than the NPP-non-LS subgroup after 1 years' treatment (P < 0.05). In the NPP-non-LS subgroup, 56% were responders; young age at baseline was a positive independent predictive factor (P < 0.001). NPP-non-LS-responders and the NPP-LS subgroup had a similar mean age (6.07 years vs 7.00 years) at baseline and height SDS gain in year 1 (0.64 vs 0.70), although NPP-non-LS-responders were taller (P < 0.001) at baseline. BMI SDS changes did not differ across subgroups. Treatment-emergent AEs were experienced by 65.3% of patients; hypoglycaemia was most common.
CONCLUSIONS
In most NPP children with SPIGFD, with or without LS, rhIGF1 therapy promotes linear growth. The safety profile was consistent with previous studies.
Topics: Adolescent; Body Height; Body Weight; Child; Female; Growth; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypoglycemia; Insulin-Like Growth Factor I; Laron Syndrome; Longitudinal Studies; Male; Patient Safety; Puberty; Recombinant Proteins; Treatment Outcome; Young Adult
PubMed: 33434161
DOI: 10.1530/EJE-20-0325