Growth Hormone & Igf Research最新文献

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.

Background

The nadir growth hormone (nGH) during the oral glucose tolerance test (OGTT) is the gold standard method for diagnosing acromegaly. A paradoxical growth hormone (GH) response to oral glucose (OG) in acromegaly can be observed. The role of the paradoxical GH response on how the patients with acromegaly respond to the treatment has been addressed in few studies. The aim of this study was to investigate the association between glucose-dependent growth hormone results and and the responses of acromegalic patients to surgical and/or medical therapy following surgery.

Material and methods

This retrospective cohort study included patients with acromegaly who underwent surgery (n = 189) or received primary medical treatment (n = 9). The mean age was 50.44 ± 12.81 years (M/F: 84/114). The patients were grouped into paradoxical (GH-P) and non-paradoxical (GH-nP) according to GH response to OG and were compared in terms of clinical and pathological features, pituitary tumor size, invasiveness, biochemical profiles, and how they responded to the treatment.

Results

The mean age, gender distribution, and basal tumor diameter were all similar in both groups (p > 0.05). The GH-P group had a higher remission rate in response to medical therapy followed by surgery (83% vs. 55%; p = 0.026). Although a higher surgical remission rate in favor of GH-P was observed, it did not reach statistical significance (63% vs. 48%; p = 0.059). Overall treatment response rates were also higher in the GH-P group compared to the GH-nP group (89% vs. 71%; p = 0.005).

Conclusion

A paradoxical GH response to OG load may help to predict the response to medical treatment in patients with acromegaly.

Objective

Insulin-like growth factors (IGFs) are involved in regulating growth and metabolism and increase insulin sensitivity, improve glucose metabolism, and are potentially related to gestational diabetes mellitus (GDM) and its complications for mothers and fetuses.

Design

This study aimed to assess serum levels and cord blood levels of IGF system components in pregnant women with (39 participants) and without GDM (22 participants). Blood samples were obtained at 28–32 and 36–38 weeks of gestation and 6–12 months after delivery. Cord blood samples were obtained during delivery. Results between both groups as well as between single visits were statistically compared.

Results

Both IGF1 and IGF2 maternal serum levels did not differ between the GDM and non-GDM groups. However, levels of IGF-binding proteins (IGFBPs) were different. IGFBP4 levels were decreased during pregnancy and after delivery in women with GDM, while IGFBP7 levels were increased during pregnancy in women with GDM. Cord blood IGFBP3 and IGFBP7 levels were increased (p < 0.001 for IGFBP3, p = 0.003 for IGFBP7), while IGFBP4 levels were decreased (p < 0.001) in the GDM group compared with the non-GDM group.

Conclusions

Although IGF levels did not differ, changes in their function level could still persist possibly because of the effects of the binding proteins, especially their promoting or inhibitory effects on IGFs. These results should be considered in interpretation of IGF levels.

Objective

Little is known of the effects of a fixed very low dose of growth hormone (GH) replacement on cardiovascular risk factors, bone mass, muscle strength and quality of life (QoL) in hypopituitary patients.

Design/patients/methods

This was an open-label randomized study performed at a single center. Consecutive hypopituitary patients with adult onset GH deficiency (GHD) and BMI ≥ 27 kg/m² were randomized to receive a very low fixed dose of GH (LG, n = 9) or a standard dose of GH (SG, n = 9). Body composition, glucose and lipid metabolism, bone mineral content (BMC) and density (BMD), muscle strength, and QoL were measured at baseline and after 6, 12 and 18 months.

Results

The fixed GH dose in LG was 0.1 mg/day. In SG, the mean baseline GH dose of 0.13 mg/day was gradually increased to 0.31 mg/day at study end. Lean body mass (LBM) as measured using DEXA as well as total body water (TBW) and extracellular water (ECW) were increased only in SG (P < 0.01, P < 0.05, and P < 0.01 vs. LG, respectively). There were no between-groups differences in BMD, BMC, insulin sensitivity, lipids, or muscle strength. Finally, although not significant compared with SG, a sustained improvement in QoL was seen in LG according to the QoL-AGHDA questionnaire.

Conclusion

In this pilot study, a fixed very low GH dose improved QoL in GHD adults without any induction of fluid retention. Other effects were comparable to those produced by the standard GH dose. Replacement with a very low GH dose could therefore be a treatment option in hypopituitary patients, especially in patients who do not tolerate higher GH dosage.

Trial registration

This study is registered at ClinicalTrials.gov, EU-nr 2009–016783-37.