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Frontiers in Pediatrics 2023In 1957, Maurice Raben at Yale was able to isolate and purify growth hormone from cadaveric pituitary glands. Pituitary growth hormone was the only way to treat children... (Review)
Review
In 1957, Maurice Raben at Yale was able to isolate and purify growth hormone from cadaveric pituitary glands. Pituitary growth hormone was the only way to treat children with growth hormone (GH) deficiency, until 1985 when recombinant GH became available for daily subcutaneous injection. For many years, the pediatric endocrine community longed for a long-acting recombinant GH formulation that would decrease the inconvenience of daily injections. Several mechanisms were employed to develop a GH that is rapidly absorbed into the blood stream after subcutaneous injection, but provides slow removal from the circulatory system to potentially optimize patient adherence to GH therapy. Four long-acting growth hormones are currently available in the world, or are close to regulatory approval. They are: (1) Pegylated formulations, (2) Prodrug formulations which are converted into active drug, (3) Nonvalent transient albumin binding GH compounds and (4) GH fusion proteins where a protein si fused with GH. All four formulations have undergone detailed phase 3 studies and were found to show non-inferiority in these clinical studies. All four demonstrate a safety and tolerability profile that is comparable to that of daily somatropin with an excellent adherence profile.
PubMed: 37842029
DOI: 10.3389/fped.2023.1254231 -
Molecular Genetics & Genomic Medicine Nov 2023To analyze the clinical data and genetic characteristics of Noonan syndrome, both the effect and side effects of recombinant human growth hormone (rhGH) treatment.
OBJECTIVE
To analyze the clinical data and genetic characteristics of Noonan syndrome, both the effect and side effects of recombinant human growth hormone (rhGH) treatment.
METHODS
We collected clinical data from 8 children with Noonan syndrome diagnosed from November 2017 to June 2021. The diagnosis was clarified by exome second-generation sequencing and parental PCR-NGS validation and interpretation of the preceding evidence, and growth hormone therapy was administered. Of the cases, four males and four females were seen for slow height growth and the median age at diagnosis was 8 years 7 months (1 year 7 months to 12 years 6 months).
RESULTS
Here, 7 children were treated with rhGH. Compared to the pre-treatment period, the growth rate increased after rhGH treatment [3.7 ± 0.5 cm/year before treatment and 8.0 ± 1.0 cm/year after treatment, p < 0.01], with the maximum growth rate between 3 and 6 months of treatment and decreasing with the duration of treatment thereafter. The growth hormone treatment was discontinued and the orthopedic consultation was ordered with regular follow-up, which was considered to be related to the PTPN11 mutation.
CONCLUSION
Noonan syndrome is characterized by slow growth, short stature, mental retardation, peculiar facial features, structural heart abnormalities and abnormal bone metabolism. and osteochondroma was found after case 2 rhGH treatment. Genetic examination is mostly caused by PTPN11 mutation. It is recommended to pay attention to bone metabolism abnormalities before growth hormone treatment, especially in children with PTPN11 mutations.
Topics: Child; Male; Female; Humans; Noonan Syndrome; Human Growth Hormone; Genetic Testing; Recombinant Proteins; Mutation; Protein Tyrosine Phosphatase, Non-Receptor Type 11
PubMed: 37525886
DOI: 10.1002/mgg3.2266 -
Protein Science : a Publication of the... Sep 2023Recombinant human growth hormone (rhGH) and GH receptor antagonists (GHAs) are used clinically to treat a range of disorders associated with GH deficiency or... (Review)
Review
Recombinant human growth hormone (rhGH) and GH receptor antagonists (GHAs) are used clinically to treat a range of disorders associated with GH deficiency or hypersecretion, respectively. However, these biotherapeutics can be difficult and expensive to manufacture with multiple challenges from recombinant protein generation through to the development of long-acting formulations required to improve the circulating half-life of the drug. In this review, we summarize methodologies and approaches used for making and purifying recombinant GH and GHA proteins, and strategies to improve pharmacokinetic and pharmacodynamic properties, including PEGylation and fusion proteins. Therapeutics that are in clinical use or are currently under development are also discussed.
Topics: Humans; Human Growth Hormone; Recombinant Proteins; Receptors, Somatotropin
PubMed: 37428391
DOI: 10.1002/pro.4727 -
IScience Oct 2023Diabetes mellitus and alterations in thyroid hormone (TH) signaling are closely linked. Though the role of TH signaling in cell differentiation and growth is well known,...
Diabetes mellitus and alterations in thyroid hormone (TH) signaling are closely linked. Though the role of TH signaling in cell differentiation and growth is well known, it remains unclear whether its alterations contribute to the pathobiology of diabetic cells. Here, we aim to investigate whether the administration of exogenous T3 can counteract the cellular remodeling that occurs in diabetic cardiomyocytes, podocytes, and pancreatic beta cells. Treating diabetic rats with T3 prevents dedifferentiation, pathological growth, and ultrastructural alterations in podocytes and cardiomyocytes. , T3 reverses glucose-induced growth in human podocytes and cardiomyocytes, restores cardiomyocyte cytoarchitecture, and reverses pathological alterations in kidney and cardiac organoids. Finally, T3 treatment counteracts glucose-induced transdifferentiation, cell growth, and loss in pancreatic beta cells through TH receptor alpha1 activation. Our studies indicate that TH signaling activation substantially counteracts diabetes-induced pathological remodeling, and provide a potential therapeutic approach for the treatment of diabetes and its complications.
PubMed: 37752946
DOI: 10.1016/j.isci.2023.107826 -
Frontiers in Endocrinology 2023Isolated childhood growth hormone deficiency (GHD) can persist into adulthood, and re-testing at the transition period is needed to determine whether continued growth...
OBJECTIVE
Isolated childhood growth hormone deficiency (GHD) can persist into adulthood, and re-testing at the transition period is needed to determine whether continued growth hormone therapy is indicated. Here, our objective was to identify predictors of permanent GHD.
DESIGN
Retrospective single-centre study of patients with childhood-onset GHD who were re-tested after adult height attainment.
METHODS
Auxological, clinical, laboratory, and MRI data throughout follow-up were collected.
RESULTS
We included 101 patients. At GH treatment initiation, age was 8.1 ± 0.4 years, height -2.25 ± 0.8, and BMI -0.27 ± 0.1 SDS. The 29 (28.7%) patients with persistent GHD had lower height SDS (-2.57 ± 0.1 vs. -2.11 ± 0.1, <0.001) and mean GH peaks (8.4 ± 1.0 vs.13.2 ± 0.5 mIU/L, <0.001) at GHD diagnosis; at adult height, they had lower IGF1 (232 ± 19.9 vs. 331 ± 9.1 ng/mL, <0.001) and higher BMI SDS (-0.15 ± 0.27 vs. -0.73 ± 0.13, <0.005). By multivariate analysis, the best predictive model included height and BMI SDS, both GH peaks, and MRI findings at diagnosis. Patients with height at diagnosis <-3 SDS had a 7.7 (95% IC 1.4-43.1, p=0.02) fold higher risk of persistent GHD after adjustment on BMI SDS. An abnormal pituitary region by MRI was the strongest single predictor (7.2 times, 95% CI 2.7-19.8) and after multivariate analysis adjustment for GH peaks and height SDS at diagnosis, the risk increased to 10.6 (1.8 - 61.3) times.
CONCLUSIONS
Height <-3 SDS at GHD diagnosis and pituitary MRI abnormalities should lead to a high index of suspicion for persistent GHD.
Topics: Adult; Child; Humans; Dwarfism, Pituitary; Human Growth Hormone; Hypopituitarism; Retrospective Studies
PubMed: 37881494
DOI: 10.3389/fendo.2023.1270845 -
Metabolism: Clinical and Experimental Jul 2023Evidence is accumulating that growth hormone (GH) protects against the development of steatosis and progression of non-alcoholic fatty liver disease (NAFLD). GH may...
BACKGROUND
Evidence is accumulating that growth hormone (GH) protects against the development of steatosis and progression of non-alcoholic fatty liver disease (NAFLD). GH may control steatosis indirectly by altering systemic insulin sensitivity and substrate delivery to the liver and/or by the direct actions of GH on hepatocyte function.
APPROACH
To better define the hepatocyte-specific role of GH receptor (GHR) signaling on regulating steatosis, we used a mouse model with adult-onset, hepatocyte-specific GHR knockdown (aHepGHRkd). To prevent the reduction in circulating insulin-like growth factor 1 (IGF1) and the subsequent increase in GH observed after aHepGHRkd, subsets of aHepGHRkd mice were treated with adeno-associated viral vectors (AAV) driving hepatocyte-specific expression of IGF1 or a constitutively active form of STAT5b (STAT5b). The impact of hepatocyte-specific modulation of GHR, IGF1 and STAT5b on carbohydrate and lipid metabolism was studied across multiple nutritional states and in the context of hyperinsulinemic:euglycemic clamps.
RESULTS
Chow-fed male aHepGHRkd mice developed steatosis associated with an increase in hepatic glucokinase (GCK) and ketohexokinase (KHK) expression and de novo lipogenesis (DNL) rate, in the post-absorptive state and in response to refeeding after an overnight fast. The aHepGHRkd-associated increase in hepatic KHK, but not GCK and steatosis, was dependent on hepatocyte expression of carbohydrate response element binding protein (ChREBP), in re-fed mice. Interestingly, under clamp conditions, aHepGHRkd also increased the rate of DNL and expression of GCK and KHK, but impaired insulin-mediated suppression of hepatic glucose production, without altering plasma NEFA levels. These effects were normalized with AAV-mediated hepatocyte expression of IGF1 or STAT5b. Comparison of the impact of AAV-mediated hepatocyte IGF1 versus STAT5b in aHepGHRkd mice across multiple nutritional states, indicated the restorative actions of IGF1 are indirect, by improving systemic insulin sensitivity, independent of changes in the liver transcriptome. In contrast, the actions of STAT5b are due to the combined effects of raising IGF1 and direct alterations in the hepatocyte gene program that may involve suppression of BCL6 and FOXO1 activity. However, the direct and IGF1-dependent actions of STAT5b cannot fully account for enhanced GCK activity and lipogenic gene expression observed after aHepGHRkd, suggesting other GHR-mediated signals are involved.
CONCLUSION
These studies demonstrate hepatocyte GHR-signaling controls hepatic glycolysis, DNL, steatosis and hepatic insulin sensitivity indirectly (via IGF1) and directly (via STAT5b). The relative contribution of these indirect and direct actions of GH on hepatocytes is modified by insulin and nutrient availability. These results improve our understanding of the physiologic actions of GH on regulating adult metabolism to protect against NAFLD progression.
Topics: Male; Mice; Animals; Lipogenesis; Non-alcoholic Fatty Liver Disease; Receptors, Somatotropin; Insulin Resistance; Liver; Growth Hormone; Insulin; Glycolysis; Glucose; Human Growth Hormone
PubMed: 37182789
DOI: 10.1016/j.metabol.2023.155589 -
Frontiers in Oncology 2023Idiosyncratic drug-induced liver injury (DILI) is a rare, unpredictable hepatic adverse event and the most common cause of acute liver failure in Europe and the US....
BACKGROUND
Idiosyncratic drug-induced liver injury (DILI) is a rare, unpredictable hepatic adverse event and the most common cause of acute liver failure in Europe and the US. Ribociclib is a potent Cyclin-dependent kinase 4 and 6 (CDK4/6)-inhibitor administered for advanced hormone-receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Previous reports have shown hepatotoxicity without liver necrosis related to ribociclib.
CASE PRESENTATION
A 41-year-old female patient with primary metastatic HR-positive, HER2-negative breast cancer developed liver enzyme elevation under treatment with ribociclib. Ribociclib was withdrawn 8 weeks after initiation due to liver enzyme elevation. A liver biopsy, performed due to further enzyme increase (peak ALT 2836 U/l), onset of jaundice (peak bilirubin 353 µmol/l) and coagulopathy (INR 1.8) two weeks later, revealed acute hepatitis with 30% parenchymal necrosis. Roussel Uclaf Causality Assessment Method (RUCAM) score was 7 points (probable). Under treatment with prednisone (60mg), initiated 2 weeks after drug withdrawal, and subsequently N-acetylcysteine (Prescott regimen) liver enzymes normalized within 8 weeks along with prednisone tapering.
CONCLUSION
This case illustrates the development of a severe idiosyncratic hepatocellular pattern DILI grade 3 (International DILI Expert Working Group) induced by ribociclib. Routine liver enzyme testing during therapy, immediate hepatologic work-up and treatment interruption in case of liver enzyme elevation are highly recommended. Corticosteroid treatment should be considered in cases of severe necroinflammation.
PubMed: 38107071
DOI: 10.3389/fonc.2023.1256783 -
Frontiers in Oncology 2023Prostate cancer is the only human malignancy that generates predominantly osteoblastic bone metastases, and osteoblastic bone metastases account for more than 90% of... (Review)
Review
Prostate cancer is the only human malignancy that generates predominantly osteoblastic bone metastases, and osteoblastic bone metastases account for more than 90% of osseous metastases of prostate cancer. Prostate-specific antigen (PSA) plays an important role in the osteoblastic bone metastasis of prostate cancer, which can promote osteomimicry of prostate cancer cells, suppress osteoclast differentiation, and facilitate osteoblast proliferation and activation at metastatic sites. In the meantime, it can activate osteogenic factors, including insulin-like growth factor, transforming growth factor β2 and urokinase-type plasminogen activator, and meanwhile suppress osteolytic factors such as parathyroid hormone-related protein. To recapitulate, PSA plays a significant role in the osteoblastic predominance of prostate cancer bone metastasis and bone remodeling by regulating multiple cells and factors involved in osseous metastasis.
PubMed: 37746292
DOI: 10.3389/fonc.2023.1127637 -
International Journal of Molecular... Sep 2023This study investigated the interplay between transforming growth factor beta (TGF-β1/T1 and TGF-β3/T3), and sex hormone receptors using our 3D in vitro cornea stroma...
This study investigated the interplay between transforming growth factor beta (TGF-β1/T1 and TGF-β3/T3), and sex hormone receptors using our 3D in vitro cornea stroma model. Primary human corneal fibroblasts (HCFs) from healthy donors were plated in transwells at 10 cells/well and cultured for four weeks. HCFs were supplemented with stable vitamin C (VitC) and stimulated with T1 or T3. 3D construct proteins were analyzed for the androgen receptor (AR), progesterone receptor (PR), estrogen receptor alpha (ERα) and beta (ERβ), luteinizing hormone receptor (LHR), follicle-stimulating hormone receptor (FSHR), gonadotropin-releasing hormone receptor (GnRHR), KiSS1-derived peptide receptor (KiSS1R/GPR54), and follicle-stimulating hormone subunit beta (FSH-B). In female constructs, T1 significantly upregulated AR, PR, ERα, FSHR, GnRHR, and KiSS1R. In male constructs, T1 significantly downregulated FSHR and FSH-B and significantly upregulated ERα, ERβ, and GnRHR. T3 caused significant upregulation in expressions PR, ERα, ERβ, LHR, FSHR, and GNRHR in female constructs, and significant downregulation of AR, ERα, and FSHR in male constructs. Semi-quantitative Western blot findings present the interplay between sex hormone receptors and TGF-β isoforms in the corneal stroma, which is influenced by sex as a biological variable (SABV). Additional studies are warranted to fully delineate their interactions and signaling mechanisms.
Topics: Humans; Female; Male; Corneal Stroma; Transforming Growth Factor beta3; Estrogen Receptor alpha; Receptors, Kisspeptin-1; Estrogen Receptor beta; Transforming Growth Factor beta1; Transforming Growth Factor beta; Follicle Stimulating Hormone
PubMed: 37686439
DOI: 10.3390/ijms241713635 -
Drug Design, Development and Therapy 2024Growth hormone (GH) replacement therapy for growth hormone deficiency (GHD) in children and adults has for over 25 years, until recently, been administered as daily... (Review)
Review
Growth hormone (GH) replacement therapy for growth hormone deficiency (GHD) in children and adults has for over 25 years, until recently, been administered as daily injections. This daily treatment regimen often incurs a burden to patients and caregivers, leading to high rates of non-adherence and, consequently, decreased treatment efficacy outcomes. To address this shortcoming, long-acting growth hormones (LAGHs) have been developed with the aim of reducing the burden of daily injections, thereby potentially improving treatment adherence and outcomes. Somapacitan (Sogroya) (Novo Nordisk, Bagsværd, Denmark) is a LAGH currently approved for the treatment of adult and childhood GHD (AGHD and CGHD, respectively) in several countries. Other LAGHs, such as somatrogon (Ngenla) (Pfizer, New York, United States) and lonapegsomatropin/TransCon GH (Skytrofa) (Ascendis Pharma, Copenhagen, Denmark), are also currently approved and available for the treatment of CGHD in several countries. In this review, we will consider the method of protraction, pharmacokinetics (PK) and pharmacodynamics (PD), efficacy, and safety results of somapacitan in adult and pediatric trials and how these characteristics differ from those of the other aforementioned LAGHs. Additionally, the administration of somapacitan and timing of measurement of serum insulin-like growth factor-I (IGF-I) levels are summarized. Information on administration, advice on missed doses, and clinical guidelines are discussed, as well as identifying which patients are suitable for somapacitan therapy, and how to monitor and adjust dosing whilst on therapy.
Topics: Adult; Humans; Child; United States; Human Growth Hormone; Dwarfism, Pituitary; Growth Hormone; Treatment Outcome; Insulin-Like Growth Factor I; Histidine; Mannitol; Phenol
PubMed: 38333899
DOI: 10.2147/DDDT.S315172