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Endocrine-related Cancer May 2023Interest in investigating the role of the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis in the initiation and progression of experimentally induced... (Review)
Review
Interest in investigating the role of the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis in the initiation and progression of experimentally induced carcinomas has arisen due to several observations in the human population. First, subjects with Laron syndrome who lack GH signaling have significantly lower rates of cancer than people who have normal GH signaling. Second, epidemiologic studies have found strong associations between elevated circulating IGF-1 and the incidence of several common cancers. Third, women who bear children early in life have a dramatically reduced risk of developing breast cancer, which may be due to differences in hormone levels including GH. These observations have motivated multiple studies that have experimentally altered activity of the GH/IGF-1 axis in the context of experimental carcinoma models in mice and rats. Most of these studies have utilized carcinoma models for four organ systems that are also frequent sites of carcinomas in humans: the mammary gland, prostate gland, liver, and colon. This review focuses on these studies and describes some of the most common genetic models used to alter the activity of the GH/IGF-1 axis in experimentally induced carcinomas. A recurring theme that emerges from these studies is that manipulations that reduce the activity of GH or mediators of GH action also inhibit carcinogenesis in multiple model systems.
Topics: Male; Female; Rats; Mice; Humans; Animals; Growth Hormone; Insulin-Like Growth Factor I; Neoplasm Recurrence, Local; Human Growth Hormone; Carcinoma
PubMed: 36826838
DOI: 10.1530/ERC-22-0403 -
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 -
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 -
Hormone Research in Paediatrics 2022The growth hormone (GH)-insulin-like growth factor (IGF) cascade is central to the regulation of growth and metabolism. This article focuses on the history of the... (Review)
Review
The growth hormone (GH)-insulin-like growth factor (IGF) cascade is central to the regulation of growth and metabolism. This article focuses on the history of the components of the IGF system, with an emphasis on the peptide hormones, IGF-I and -II, their cell surface receptors, and the IGF binding proteins (IGFBPs) and IGFBP proteases that regulate the availability of the peptide hormones for interaction with their receptors in relevant target tissues. We describe landmark events in the evolution of the somatomedin hypothesis, including evidence that has become available from experiments at the molecular and cellular levels, whole animal and tissue-specific gene knockouts, studies of cancer epidemiology, identification of prismatic human cases, and short- and long-term clinical trials of IGF-I therapy in humans. In addition, this new evidence has expanded our clinical definition of GH insensitivity (GHI) beyond growth hormone receptor mutations (classic Laron syndrome) to include conditions that cause primary IGF deficiency by impacting post-receptor signal transduction, IGF production, IGF availability to interact with the IGF-I receptor (IGF-1R), and defects in the IGF-1R, itself. We also discuss the clinical aspects of IGFs, from their description as insulin-like activity, to the use of IGF-I in the diagnosis and treatment of GH deficiency, and to the use of recombinant human IGF-I for therapy of children with GHI.
Topics: Animals; Humans; Insulin-Like Growth Factor I; Laron Syndrome; Peptide Hormones; Protein Processing, Post-Translational; Signal Transduction; Somatomedins; Insulin-Like Growth Factor II
PubMed: 36446332
DOI: 10.1159/000527123 -
Cells Oct 2022The growth hormone (GH)-insulin-like growth factor-1 (IGF1) signaling pathway plays a major role in orchestrating cellular interactions, metabolism, growth and aging....
The growth hormone (GH)-insulin-like growth factor-1 (IGF1) signaling pathway plays a major role in orchestrating cellular interactions, metabolism, growth and aging. Studies from worms to mice showed that downregulated activity of the GH/IGF1 pathway could be beneficial for the extension of lifespan. Laron syndrome (LS) is an inherited autosomal recessive disorder caused by molecular defects of the GH receptor (GHR) gene, leading to congenital IGF1 deficiency. Life-long exposure to minute endogenous IGF1 levels in LS is associated with low stature as well as other endocrine and metabolic deficits. Epidemiological surveys reported that patients with LS have a reduced risk of developing cancer. Studies conducted on LS-derived lymphoblastoid cells led to the identification of a novel link between IGF1 and thioredoxin-interacting protein (TXNIP), a multifunctional mitochondrial protein. TXNIP is highly expressed in LS patients and plays a critical role in cellular redox regulation by thioredoxin. Given that IGF1 affects the levels of TXNIP under various stress conditions, including high glucose and oxidative stress, we hypothesized that the IGF1-TXNIP axis plays an essential role in helping maintain a physiological balance in cellular homeostasis. In this study, we show that TXNIP is vital for the cell fate choice when cells are challenged by various stress signals. Furthermore, prolonged IGF1 treatment leads to the establishment of a premature senescence phenotype characterized by a unique senescence network signature. Combined IGF1/TXNIP-induced premature senescence can be associated with a typical secretory inflammatory phenotype that is mediated by STAT3/IL-1A signaling. Finally, these mechanistic insights might help with the understanding of basic aspects of IGF1-related pathologies in the clinical setting.
Topics: Animals; Mice; Carrier Proteins; Cellular Senescence; Glucose; Growth Hormone; Insulin-Like Growth Factor I; Laron Syndrome; Mitochondrial Proteins; Thioredoxins; Humans; Fibroblasts; 3T3-L1 Cells
PubMed: 36291127
DOI: 10.3390/cells11203260 -
Stem Cell Reviews and Reports Feb 2023Pathway involving insulin-like growth factor 1 (IGF-1) plays significant role in growth and development. Crucial role of IGF-1 was discovered inter alia through studies...
Pathway involving insulin-like growth factor 1 (IGF-1) plays significant role in growth and development. Crucial role of IGF-1 was discovered inter alia through studies involving deficient patients with short stature, including Laron syndrome individuals. Noteworthy, despite disturbances in proper growth, elevated values for selected stem cell populations were found in IGF-1 deficient patients. Therefore, here we focused on investigating role of these cells-very small embryonic-like (VSEL) and hematopoietic stem cells (HSC), in the pathology. For the first time we performed long-term observation of these populations in response to rhIGF-1 (mecasermin) therapy. Enrolled pediatric subjects with IGF-1 deficiency syndrome were monitored for 4-5 years of rhIGF-1 treatment. Selected stem cells were analyzed in peripheral blood flow cytometrically, together with chemoattractant SDF-1 using immunoenzymatic method. Patients' data were collected for correlation of experimental results with clinical outcome. IGF-1 deficient patients were found to demonstrate initially higher levels of VSEL and HSC compared to healthy controls, with their gradual decrease in response to therapy. These changes were significantly associated with SDF-1 plasma levels. Correlations of VSEL and HSC were also reported in reference to growth-related parameters, and IGF-1 and IGFBP3 values. Noteworthy, rhIGF-1 was shown to efficiently induce development of Laron patients achieving at least proper rate of growth (compared to healthy group) in 80% of subjects. In conclusion, here we provided novel insight into stem cells participation in IGF-1 deficiency in patients. Thus, we demonstrated basis for future studies in context of stem cells and IGF-1 role in growth disturbances.
Topics: Humans; Child; Insulin-Like Growth Factor I; Laron Syndrome; Stem Cells
PubMed: 36269524
DOI: 10.1007/s12015-022-10457-2 -
Frontiers in Physiology 2022Growth hormone (GH) is a peptide hormone that can signal directly through its receptor or indirectly through insulin-like growth factor 1 (IGF-1) stimulation. GH draws... (Review)
Review
Growth hormone (GH) is a peptide hormone that can signal directly through its receptor or indirectly through insulin-like growth factor 1 (IGF-1) stimulation. GH draws its name from its anabolic effects on muscle and bone but also has distinct metabolic effects in multiple tissues. In addition to its metabolic and musculoskeletal effects, GH is closely associated with aging, with levels declining as individuals age but GH action negatively correlating with lifespan. GH's effects have been studied in human conditions of GH alteration, such as acromegaly and Laron syndrome, and GH therapies have been suggested to combat aging-related musculoskeletal diseases, in part, because of the decline in GH levels with advanced age. While clinical data are inconclusive, animal models have been indispensable in understanding the underlying molecular mechanisms of GH action. This review will provide a brief overview of the musculoskeletal effects of GH, focusing on clinical and animal models.
PubMed: 35665221
DOI: 10.3389/fphys.2022.867921 -
Cells May 2022Normal growth and development in mammals are tightly controlled by numerous genetic factors and metabolic conditions. The growth hormone (GH)-insulin-like growth...
Normal growth and development in mammals are tightly controlled by numerous genetic factors and metabolic conditions. The growth hormone (GH)-insulin-like growth factor-1 (IGF1) hormonal axis is a key player in the regulation of these processes. Dysregulation of the GH-IGF1 endocrine system is linked to a number of pathologies, ranging from growth deficits to cancer. Laron syndrome (LS) is a type of dwarfism that results from mutation of the GH receptor () gene, leading to GH resistance and short stature as well as a number of metabolic abnormalities. Of major clinical relevance, epidemiological studies have shown that LS patients do not develop cancer. While the mechanisms associated with cancer protection in LS have not yet been elucidated, genomic analyses have identified a series of metabolic genes that are over-represented in LS patients. We hypothesized that these genes might constitute novel targets for IGF1 action. With a fold-change of 11.09, UDP-glucuronosyltransferase 2B15 () was the top up-regulated gene in LS. The gene codes for an enzyme that converts xenobiotic substances into lipophilic compounds and thereby facilitates their clearance from the body. We investigated the regulation of gene expression by IGF1 and insulin. Both hormones inhibited UGT2B15 mRNA levels in endometrial and breast cancer cell lines. Regulation of UGT2B15 protein levels by IGF1/insulin, however, was more complex and not always correlated with mRNA levels. Furthermore, expression was dependent on p53 status. Thus, UGT2B15 mRNA levels were higher in cell lines expressing a wild-type p53 compared to cells containing a mutated p53. Animal studies confirmed an inverse correlation between UGT2B15 and p53 levels. In summary, increased UGT2B15 levels in LS might confer upon patient's protection from genotoxic damage.
Topics: Animals; Glucuronosyltransferase; Glycosyltransferases; Growth Hormone; Humans; Insulin; Insulin-Like Growth Factor I; Laron Syndrome; Mammals; Neoplasms; RNA, Messenger; Tumor Suppressor Protein p53; Uridine Diphosphate
PubMed: 35626664
DOI: 10.3390/cells11101627 -
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 -
Hormone Research in Paediatrics 2022The aim of the study was to describe focal epilepsy in patients with Laron syndrome (LS).
OBJECTIVE
The aim of the study was to describe focal epilepsy in patients with Laron syndrome (LS).
METHODS
Data were retrieved from medical records of a single-center cohort of 75 patients with LS.
RESULTS
We describe for the first time 4 patients with concomitant focal epilepsy and LS. Two of them experienced episodes of status epilepticus. Electroencephalogram examination in all 4 patients showed interictal epileptiform discharges in the temporal regions. Three achieved long-term seizure freedom on antiseizure medications.
CONCLUSION
Patients with LS may be at risk of developing focal epilepsy, which seems to be unrelated to hypoglycemic episodes in childhood.
Topics: Electroencephalography; Epilepsies, Partial; Humans; Laron Syndrome; Retrospective Studies; Seizures
PubMed: 35358968
DOI: 10.1159/000524350