Growth Hormone & Igf Research最新文献

Objective

Cachexia is a systemic metabolic syndrome characterized by loss of body weight and skeletal muscle mass during chronic wasting diseases, such as cancer. Skeletal muscle in cancer cachexia is less responsive to anabolic factors including mechanical loading; however, the precise molecular mechanism is largely unknown. In this study, we examined the underlying mechanism of anabolic resistance in skeletal muscle in a cancer cachexia model.

Methods

CD2F1 mice (male, 8 weeks old) were subcutaneously transplanted (1 × 10⁶ cells per mouse) with a mouse colon cancer-derived cell line (C26) as a model of cancer cachexia. Mechanical overload of the plantaris muscle by synergist tenotomy was performed during the 2nd week and the plantaris muscle was sampled at the 4th week following C26 transplantation.

Results

The hypertrophic response of skeletal muscle (increased skeletal muscle weight/protein synthesis efficiency and activation of mechanistic target of rapamycin complex 1 signaling) associated with mechanical overload was significantly suppressed during cancer cachexia. Screening of gene expression profile and pathway analysis using microarray revealed that blunted muscle protein synthesis was associated with cancer cachexia and was likely induced by downregulation of insulin-like growth factor-1 (IGF-1) and impaired activation of IGF-1-dependent signaling.

Conclusions

These observations indicate that cancer cachexia induces resistance to muscle protein synthesis, which may be a factor for inhibiting the anabolic adaptation of skeletal muscle to physical exercise in cancer patients.

Growth Hormone-Releasing Hormone (GHRH) is a hypothalamic peptide which regulates the release of Growth Hormone from the anterior pituitary gland, and has been involved in inflammatory processes. On the other hand, GHRH antagonists (GHRHAnt) were developed to counteract those effects. Herein we demonstrate for the first time that GHRHAnt can suppress hydrogen peroxide (H₂O₂) - induced paracellular hyperpermeability in bovine pulmonary artery endothelial cells. Increased production of reactive oxygen species (ROS) and barrier dysfunction have been associated with the development of potentially lethal disorders, including sepsis and acute respiratory distress syndrome (ARDS). Our study supports the protective actions of GHRHAnt in the impaired endothelium, and suggests that those compounds represent an exciting therapeutic possibility towards lung inflammatory disease.

Objective

We investigated the coexistence of newly diagnosed acromegaly with primary empty sella (ES), which is considered to be a rare association, and the impact of ES on the laboratory, radiological and prognostic status of acromegaly.

Design

Acromegaly patients diagnosed and followed-up between 2012 and 2021 were included. Empty sella was defined as the pituitary gland and adenoma filling <50% of the sella turcica on preoperative T1 magnetic resonance imaging (MRI).

Results

102 acromegalic patients (45 male, 57 female, 45.5 ± 12.8 (range: 20–70 years) were included and data of a median 3 years (range: 0.5–9 years) were presented. ES was detected in 19 (18.6%) patients and 4 had complete and 15 had partial ES. Although not significant, adenoma size and residual adenoma on MRI on postoperative 3rd month, and disease remission at last control were lower in acromegaly with ES than in acromegaly without ES, while the rate of female gender and remission on postoperative 3rd month were higher. While preoperative serum prolactin and nadir GH responses to OGTT were significantly lower in patients with ES, there was no difference in terms of other pituitary hormones among both groups.

Conclusion

The present study revealed the coexistence of newly diagnosed acromegaly with primary ES at a rate of nearly 20% which is more frequent than expected and this association is not rare. The presence of ES was not associated with any preoperative/postoperative pituitary hormone levels and remission status, except lower preoperative prolactin and nadir GH responses to OGTT.

Objective

Prediction models that calculate the growth response in children on recombinant growth hormone (GH) have shown to be helpful tools in deciding who should start treatment, as identifying GH deficiency can be a challenge. The aim of the study is to compare two prediction models; the KIGS (Pfizer International Growth Study) prediction models which are more accessible and the Gothenburg model which has previously been clinically validated.

Design

All prepubertal patients who commenced GH treatment at Queen Silvia Children's Hospital in Gothenburg during a 13-year-period were candidates for the study. Children were excluded if suspected syndrome, malignant disease, chronic disease, or poor adherence to treatment were found. The KIGS model and the Gothenburg model were used to make predictions. Data was obtained from medical charts for the period from birth to the end of the first year of treatment. The predicted height outcome was compared against observed.

Results

The study included 123 prepubertal children (76 males). The average age at treatment start and standard deviation (SD) was 5.7 (1.8) years. Correlation analyses were performed between predicted growth by both the Gothenburg and KIGS models versus the first year observed growth response showing strong correlations of r = 0.990 and r = 0.991 respectively with studentized residuals of 0.10 (0.81) for the Gothenburg model and 0.03 (0.96) for the KIGS model.

Conclusion

We found that both the Gothenburg model and the KIGS model are equivalent when applying to our clinical cohort. Both models are very precise, hence it is encouraged to use either based on accessibility for the clinic.

Objective

Extremely low gestational age neonates (ELGANs) experience frequent intermittent hypoxia (IH) episodes during therapeutic oxygen. ELGANs exhibit poor postnatal growth requiring lipid supplementation. Lipids are targets of reactive oxygen species resulting in lipid peroxidation and cell death, particularly in preterm infants with compromised antioxidant systems. We tested the hypothesis that early supplementation with lipids and/or antioxidants promotes growth and influences biomarkers of carbohydrate metabolism in neonatal rats exposed to IH.

Design

Newborn rats (n = 18/group) were exposed to brief hypoxia (12% O₂) during hyperoxia (50% O₂), or room air (RA), from birth (P0) to P14 during which they received daily oral supplementation with: 1) fish oil; 2) Coenzyme Q10 (CoQ10) in olive oil; 3) glutathione nanoparticles (nGSH); 4) fish oil+CoQ10; or 5) olive oil. At P21, plasma samples were assessed for glucose, insulin, glucokinase (GCK), glucagon, glucagon-like peptide (GLP)-1, growth hormone (GH), corticosterone, and ghrelin. Liver was assessed for histopathology, apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labeling, TUNEL stain), and GH, insulin-like growth factor (IGF)-I, GH binding protein (GHBP), and IGF binding protein (IGFBP)-3.

Results

Neonatal IH resulted in decreased liver weight and liver/body weight ratios, as well as hepatocyte swelling, steatosis, and apoptosis, which were attenuated with fish oil, nGSH, and combined fish oil+CoQ10. IH also decreased plasma glucose, insulin, GCK, and ghrelin, but increased GLP-1. All treatments improved plasma glucose in IH, but insulin was higher with CoQ10 and nGSH only. Glucagon was increased with CoQ10, fish oil, and CoQ10 + fish oil, while corticosterone was higher with nGSH and CoQ10 + fish oil. IGF-I and IGFBP-3 were significantly higher in the liver with CoQ10 in IH, while deficits in GH were noted with CoQ10 and fish oil in RA and IH. Treatment with nGSH and combined CoQ10 + fish oil reduced IGF-I in RA and IH but increased IGFBP-3.

Conclusions

Neonatal IH impairs liver growth with significant hepatocyte damage. Of all supplements in IH, nGSH and combined fish oil+CoQ10 were most effective for preserving liver growth and carbohydrate metabolism. Data suggest that these supplements may improve poor postnatal organ and body growth; and metabolic dysfunction associated with neonatal IH.

Background

Children with auxological parameters defining a ‘short stature’ is routinely subjected to various blood tests and, if necessary, to growth hormone stimulation test (GHST) for differentiating GH deficiency (GHD) and other causes of stunted growth.

Aim

This retrospective monocentric study aimed to evaluate any correlations between GH peaks during GHST in children assessed for short stature and their auxological/metabolic parameters, highlighting differences between GHD and idiopathic short stature.

Patients and methods

We reviewed the medical records of 74 children with short stature (height lower than the third percentile according to standardized growth curves for the Italian population) managed at the Pediatric Day Hospital of our Department of Life Sciences and Public Health in Università Cattolica Sacro Cuore, Rome, who performed at least two GHSTs, using arginine and clonidine as stimulants, for assessment of GH secretion. The results of a total number of 161 GHSTs, performed in 42 children diagnosed with GHD and in 32 children with other causes of short stature, were analyzed.

Results

We found significantly lower serum levels of insulin growth factor-1 (IGF-1) and increased levels of thyroid-stimulating hormone (TSH) in children with GHD, without other metabolic differences in comparison to children with other causes of short stature. There was also a correlation between triglycerides and GH peak during arginine test, while fT4 and LDL concentrations correlated with GH peak during the third test, if performed. Pre-test BMI (rho −0.274, p = 0.01) and weight (rho −0.251, p = 0.03) have influenced GH peak during clonidine stimulation test. Metabolic and auxological parameters could influence GH peak during clonidine and arginine stimulation tests and must be taken into account when interpreting GHST results.

Purpose

To determine whether biochemical responses to long-acting forms of first-generation somatostatin analogue (SSA) therapy in patients with acromegaly could be predicted from baseline and postoperative hormone concentrations, and tumor radiological and histopathological characteristics.

Methods

A total of 68 patients with acromegaly for whom postoperative SSA therapy was started were categorized according to their responses to treatment (SSA-responders vs. non-responders). The patients were compared based on their demographic characteristics, hormone levels, magnetic resonance imaging (MRI), and histopathological findings. Receiver-operating-characteristic (ROC) curves were constructed using the predictive factors that were significant in the univariate analysis to determinate the optimal cut-off values.

Results

The SSA-responders were significantly older (p = 0.041). Lower GH at diagnosis (p = 0.036), the postoperative 1st-week GH level (p = 0.027), baseline GH, insulin-like growth factor-1 (IGF-1) and IGF-1% upper limit of normal (ULN) (p = 0.001, p = 0.006, p = 0.023, respectively) were associated with biochemical response. T2-hypointensity and lower tumor volume were more common in the SSA-responders (p = 0.018, p = 0.03, respectively). Compared to sparsely granulated somatotroph tumors, densely granulated somatotroph tumors and other PitNETs causing GH excess including mammosomatotroph and mixed somatotroph and lactotroph tumors were more likely to respond to SSA therapy (p = 0.026, p = 0.03, respectively). The cut-off values generated by ROC curve analysis were GH at diagnosis of ≤8.8 ng/mL, GH at baseline of ≤2.69 ng/mL, IGF-1 at baseline ≤461.5 ng/mL, IGF-1% ULN at baseline ≤180.4%, and tumor volume of ≤1.11 cm³ (all p < 0.05). There were no differences between the groups in terms of tumor invasiveness, proliferative activity (mitotic count per 2 mm² and Ki-67 labeling index) and quantitative analyses of T2-weighted MRI.

Conclusion

This study underscores that advanced age, low baseline GH and IGF-1 at diagnosis, low tumor volume, densely granulated tumor subtype, and T2 hypointensity may help predict biochemical response to SSA therapy in cases of acromegaly. These variables should be assessed with utmost attention for all patients prior to SSA treatment. In cases of possible resistance to SSA therapy, therapeutic activity should be monitored more closely and other therapies should be administered immediately in the event of poor response.

Objective

Under clinical development for patients with growth hormone deficiency, JR-142 is a long-acting growth hormone with a half-life extended by fusion with modified serum albumin. We conducted a Phase 1 study to investigate the safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) profiles of once-weekly subcutaneous administrations of JR-142. The study consisted of two parts: an open-label single ascending dosing study (Part 1), and a randomized, placebo-controlled, assessor-blinded multiple ascending dosing study (Part 2).

Design

A total of 31 healthy Japanese male participants were enrolled. In Part 1, seven of them received a single subcutaneous injection of JR-142 each at dosages of 0.15 mg/kg (n = 1), 0.25 mg/kg (n = 2), 0.5 mg/kg (n = 2), or 1.0 mg/kg (n = 2). In Part 2, one weekly subcutaneous injection of JR-142 at 0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg or a placebo were given for four weeks to each of the other 24 participants (six in each group). Plasma JR-142 and serum insulin-like growth factor-1 (IGF-1) concentrations were measured for PK and PD assessments. Safety was evaluated on the basis of adverse events (AEs), laboratory tests, and other measures.

Results

JR-142 induced dose-dependent increases in the maximum plasma JR-142 concentration (C_max) and the area under the plasma concentration-time curve from time 0 to τ (AUC_0-τ). A similar dose-response relationship was observed in serum IGF-1 concentrations. All trough IGF-1 levels were well sustained one week after the final administrations of JR-142 at the three dosages, while the peak concentrations of IGF-1 remained mildly elevated. No serious AEs were observed, and laboratory tests, including assessment of anti-drug antibodies, uncovered no significant safety issues.

Conclusions

Once-weekly subcutaneous injections of JR-142 produced positive dose-dependent PK and PD profiles over the dosage range. Drug accumulation was observed after the four-week administration period but did not raise safety concerns, indicating that JR-142 is well-tolerated in healthy participants. The PD profiles observed in terms of IGF-1 concentrations were also positive, and we believe the encouraging results of this study warrant substantiation in further clinical trials in patients with GHD.

Ethics

This clinical study was conducted at one investigational site in Osaka, Japan, where the clinical study and the non-clinical data of JR-142 were reviewed and approved by its Institutional Review Board on 9th May 2019. The study was conducted in compliance with the approved study protocol, the Declaration of Helsinki, 1964, as revised in 2013, and Good Clinical Practice.

A number of reports show that high endogenous, or therapeutic administration of human growth hormone (hGH) cause an increase of serum lipoprotein a, Lp(a). Being thrombogenic Lp(a) is an independent risk factor of atherosclerotic cardiovascular disease (ASCVD). Hence, it is hypothesized that the recently reported association between childhood hGH treatment and cardiovascular morbidity is probably due to the GH effect on Lp(a) synthesis. It is therefore suggested to determine serum Lp(a) levels before and during hGH treatment in children and adults.